MXPA00010373A - Inhibitors of neuraminidases - Google Patents

Abstract

Disclosed are compounds of formula (I), (II) or (III), which are useful for inhibiting neuraminidases from disease-causing microorganisms, especially, influenza neuraminidase. Also disclosed are compositions and methods for preventing and treating diseases caused by microorganisms having a neuraminidase, processes for preparing the compounds and synthetic intermediates used in these processes.

Description

INHIBITORS OF NEURAM INIDASAS TECHNICAL CAM PO The present invention relates to novel compounds, compositions and methods for inhibiting neuraminidase, especially influenza neuraminidase. The invention contemplates a composition and methods for preventing and treating an influenza infection and processes for making said synthetic intermediates and compounds used in these processes.

BACKGROUND OF THE INVENTION Many microorganisms that cause diseases have a neuraminidase (also known as sialidase), which is involved in the process of replication of the microorganism, in particular, the viruses of the orthomyxovirus and paramyxovirus groups possess a neurominidase. Diseases associated with paramyxoviruses include RSV (respiratory diseases related to the syncytial virus), pneumonia and bronchiolitis associated with paramyxovirus type 3) and laryngotracheobronchitis (associated with paramyxovirus type 1). Some of the microorganisms that cause major diseases in man and / or animals that possess a neuraminidase include Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae, Arthrobacter sialophilus, influenza virus, parainfluenza virus, mumps virus, Newcastle disease virus, poultry poultry virus, equine influenza virus and Sendal virus. Mortality due to influenza is a serious problem throughout the world. The disease is devastating for man, lower animals and some birds. Although vaccines containing attenuated influenza viruses are available, those vaccines only provide immunological protection against some strains of influenza and are less effective in otherwise immunologically compromised populations such as the elderly, young children, and those suffering from chronic respiratory diseases. The loss of productivity of the absence due to the disease of influenza virus infection has been estimated at more than $ 1 billion per year. There are two main strains of influenza virus (designated A and B). Currently, there are only few pharmaceutical products approved for the treatment of influenza. These include amantadine and rimantadine, which are only active against strain A of influenza viruses, and ribavirin which has dose-limiting toxicity. The mutant virus, which is resistant to amantadine and rimantadine, emerges rapidly during treatment with these agents. Neuraminidase is one of the two major viral proteins that leave the influenza virus envelope. During the release of the progeny virus from infected cells, the Neuraminidase cleaves terminal sialic acid residues of glycoproteins, glycolipids and oligosaccharides on the cell surface. The inhibition of the enzymatic activity of neuraminidase leads to the aggregation of the progeny virus on the surfaces. Said virus is incapable of infecting new cells, and, therefore, viral replication is delayed or blocked. X-ray crystallographic studies and sequence alignments have shown that the residues that make direct contact with the sialic acid portion of the substrate are strictly conserved in the neuraminidase of all strains of influenza A and B. In this way, a compound which binds to the sialic acid binding region of the active site of neuraminidase will block the replication of both strains A and B of the influenza virus. The compounds, which are influenza neuraminidase inhibitors, will be useful for the prevention of influenza infection and will be useful for the treatment of influenza infection. Y. Babu et al., International Patent Application No. W097 / 47194, published December 18, 1997, discloses substituted cyclopentanes that are useful as neuraminidase inhibitors and treatments for influenza. The following references describe neuraminic acid derivatives with the described utility listed after each reference: L. Von Itzstein et al., European Patent Application No. EP539204, published April 28, 1993 (antiviral agent); T. Honda et al., European Patent Application No. EP823 28, published February 1, 1998 (sialidase inhibitor, treatment for influenza); T. Honda et al., International Patent Application No. WO98 / 06712, published February 1, 1998 (sialidase inhibitor, remedy for influenza); L. Von Itzstein et al., International Patent Application No. WO95 / 20583, published August 3, 1995 (viral neu raminidase inhibitor, treatment for infection); P. Smith, International Patent Application No. WO95 / 18800, published July 13, 1995 (viral neuraminidase inhibitor); P. Colman et al., International Patent Application No. WO92 / 06691, published April 30, 1992 (viral neuraminidase inhibitor); L. Von Itzstein et al., Patent of E. U. A. 5.6 8, 379, issued on July 15, 1997 (treatment for influenza); P. Reece et al., International Patent Application No. W097 / 32214, published September 4, 1997 (binding to the active site of influenza virus neuraminidase); and P. Reece et al., International Patent Application No.

W098 / 21243 published May 23, 1,998 (anti-influenza agent). The following references describe sialic acid derivatives with the described utility listed after each reference: Y. Ohira et al., International Patent Application No.

WO98 / 11083, published March 19, 1998 (antiviral agent); Y. Ohira, European Patent Application No. EP882721, published December 9, 1998 (antiviral agent); and B. Glanzer et al., Helvética Chimica Acta 74.343-369 (1991) (Neuraminidase inhibitor of Vibrio cholerae). The following references describe benzene derivatives, cyclohexane derivatives or cyclohexene derivatives with the described utility listed after each reference: Y. Babu et al., Patent No. 5,602,277, filed February 11, 1997 (neuraminidase inhibitors); M. Luo et al., U. S. Patent of U. U. No. 5,453,533, filed September 26, 1995 (influenza neuraminidase inhibitor, treatment for influenza); And Babu et al., International Patent Application No. WO96 / 30329, published October 3, 1996 (neuraminidase inhibitor; viral infection treatment); N. Bischofberger et al., U.S. Patent No. 5,763,483, issued June 9, 1998 (neuraminidase inhibitor); Y K. Kent et al., International Patent Application No. 98/07685, published February 26, 1998 (intermediates for the preparation of neuraminidase inhibitors). C. Kim et al., International Patent Application No. No. W098 / 17647, published April 30, 1998, describes piperidine derivatives that are useful as neuraminidase inhibitors. N. Bischofberger et al., International Patent Application No.

W096 / 26933, published September 6, 1996, discloses several substituted six-membered ring compounds, which are useful as inhibitors of neu raminidase. The following references describe dihydropyran derivatives, which are useful as inhibitors of viral neuraminidase: D. Andrews et al., International Patent Application No. WO97 / 06157, published February 20, 1997; and P. Cherry et al., International Patent Application No. W096 / 36628, published November 21, 1996. C. Kim et al., Patent of E. U. A. No. 5, 512, 596, issued April 30, 1996, describing 6-membered aromatic ring derivatives, which are useful as neuraminidase inhibitors. G. Diana et al., International Patent Application No. WO98 / 03487, published January 29, 1998, which discloses substituted pyridazines which are useful for the treatment of influenza. B. Horenstein, et al., International Patent Application No. WO99 / 06369, published February 1, 1999, which discloses piperazine derivatives that are useful as neuraminidase inhibitors. L. Czolner et al., Helvética Chimica Acta 73. 1338-1358 (1990) describes pyrrolidine analogs of neuraminic acid which are useful as inhibitors of Vibrio cholerae sialidase. The following references describe analogues of siastatin B which are useful as inhibitors of neuraminidase Y. N ishim ura and others, Natu ral Prod uct Letters 1 39- 4 (1 992), and Y. N ishimura et al., Natural Product Letters 1 33-38 (1992).

C. Penn, U.S. Patent Application No. GB2292081, published February 14, 1996, which describes the use of a neuraminidase inhibitor in combination with an influenza vaccine. An object of the invention is to provide compounds that inhibit neuraminidase of microorganisms that cause diseases; especially, viral neuraminidase; and very especially, influenza neuraminidase. It is also an object of the invention to provide compounds that inhibit neuraminidase from both influenza A and B strains.

Another object of the invention is to provide prophylaxis of influenza infection in humans and other animals. Another object of the invention is to provide a treatment for the infection of influenza in humans and other animals. Another object of the invention is to provide compounds that exhibit activity against influenza A viruses and influenza B virus by virtue of inhibiting influenza neuraminidase when said compounds are administered orally. Yet another object of the invention is to provide a compound that can be effectively transported from the plasma into the alveolar bronchus fluid of humans and other animals in order to block the replication of the influenza virus. in that tissue DESCRIPTION OF THE INVENTION The present invention describes compounds that have the Formula I II or l l l or a pharmaceutically acceptable salt, ester or prodrug of the j i? ß m¿ ^ - ^ m m isms, wherein R1 is selected from the group consisting of (a) -C02H, (b) -CH2CO2H, (c) -SO3H, (d) -C H2S03H, (e) -S02H, (f) -CH2S02H, (g) -PO3H2, (h) -CH2PO3H2, (i) -PO2H, (j) -CH2PO2H, (k) tetrazolyl, (I) -CH2-tetrazolyl, (m) -C (= 0) -N H- S (?) 2- R11, (n) -CH2C (= 0) -N HS ( 0) 2-R11, (o) -S02N (T-R1,) R12 and (p) -CH2S02N (TR '1) R'2 wherein T is selected from the group consisting of: (i) a bond, (1) -C (= 0) -, (iii) -C (= 0 ) 0-, (iv) -C (= 0) S-, (v) - C (= 0) N R36-, (vi) -C (= S) 0-, (vii) -C (= S) S-, and (viii) -C (= S) N R36-, R11 is selected from the group consisting of: (i) alkyl of 1 to 12 carbon atoms, (i) alkenyl of 2 to 12 carbon atoms, (iii) cycloalkyl, (iv) (cycloalkyl) alkyl, (v) (cycloalkyl) alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl) alkyl, (viii) (c-chloralkenyl) alkenyl, (ix) aryl, (x) (aryl) alkylene, (xi) (aryl) alkenyl, (xii) heterocyclic,. { xi i) alkyl (heterocyclic) and (xiv) alkenyl (heterocyclic); Y R12 and R36 are independently selected from the group consisting of: (i) hydrogen, (ii) alkyl of 1 to 12 carbon atoms, (iii) alkenyl of 2 to 12 carbon atoms, (iv) cycloalkyl, (v) ( cycloalkyl) alkyl, (vi) (cycloalkyl) alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl) alkyl, (ix) (cycloalkenyl) alkenyl, (x) aryl, (xi) (aryl) alkyl, (xii) (ar?) alkenyl, (xni) heterocyclic, (xiv) alkyl (heterocyclic) and (xv) alkenyl (heterocyclic); X is selected from the group consisting of (a) -C (=?) - N (R *) -, (b) -N (R *) - C (=?) -, (c) -C (= S) -N (R *) -, (d) -N (R *) - C (= S) -, (e) -N (R *) - S02-, and (f) -S02-N (R *) -, wherein R * is hydrogen, lower alkyl of 1 to 3 carbon atoms or cyclopropyl, R 2 is selected from the group consisting of: (a) hydrogen, (b) alkyl of 1 to 6 carbon atoms, (c) alkenyl of 2 to 6 carbon atoms, (d) cycloalkyl of 3 to 6 carbon atoms, (e) cycloalkenyl of 5 to 6 carbon atoms, (f) haloalkyl of 1 to 6 carbon atoms and ( g) haloalkenyl of 2 to 6 carbon atoms; or R2-X- is: wherein Y1 is -CH2-, -O-, -S- or -NH, and Y2 is -C (=?) - or -C (R ") (Rbb) -, where Raa and Rbb are independently selected from the a group consisting of hydrogen, lower alkyl of 1 to 3 carbon atoms, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-t-oletyl, 2-t-olethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl or; Z1 is -O-, -S-, or C (R5) 2; R3 and R4 are independently selected from the group consisting of (a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl, (d) heterocyclic, (e) aryl and (f) -Z-R1 4; wherein Z is: (i) -C (R37a) (R37") -, (ii) -C (R47) = C (R48), (iii) -C = C-, (iv) -C (= 0 ), (v) -C (= S) -, (vi) -C (= NR15) -, (vii) -C (R37a) (OR37c) -, (viii) -C (R37a) (SR37 ,: ) -, (ix) -C (R37a) (N (R37b) (R37c)) -, (x) -C (R37a) (R37b) -0-, (xi) -C (R37a) (R37b) -N (R37c) -, (xii) -C (R37a) (R37b) -N (0) (R37c) -, (xiii) -C (R37a) (R37b) -N (OH) -, (XiV) -C ( R37a) (R37b) -S-, (xv) -C (R37a) (R37b) -S (0) -, (xvi) -C (R37a) (R37b) -S (0) 2-, (xvii) -C (R37a) (R37b) -C (= 0) -, (xviii) -C (R37a) (R37b) -C (= S) -, (xix) -C (R37a) (R37b) -C (= NR15) -, (xx) -C (R37a) (OR37o) -C (= 0) -, (xxi) -C (R37a) (SR3To) -C (= 0) -, (xxii) -C (R37a) (OR37o) -C (= S) -, (xxiii) -C (R37a) (SR37c) -C (= S) -, (xxiv) -C (= 0) -C (R37a) (OR370) -, (xxvii) -C (= S) -C (R37a) (SR37c) -, (xxviii) -C (R37a) (OR37c) -C (R37a) (OR37, :), (xxix) -C (R37a) ( SR37c) -C (R37a) (OR37c) -, (xxx) -C (R37a) (OR37c) -C (R37a) (SR37,!) -, (xxxi) -C (R3 a) (SR37c) -C ( R37a) (SR37c) -, (xxxii) -C (= 0) -C (= 0) -, (xxxiii) -C (= S) -C (= S) -, (xxxiv) -C (= 0) -0-, (xxxv) -C (= 0) -S-, (xxxvi) -C (= S) -0-, (xxxvii) -C (= S) -S-, (xxxviii) -C (= 0) -N (R37a) -, (xxxix) -C (= S) -N (R37a) -, (xl) -C (R37a) (R37b) -C (= 0) -N (R37a) -, ( xli) -C (R37a) (R37b) -C (-S) -N (R37a) -, (xlii) -C (R37a) (R37b) -C (= 0) -0-, (xliii) -C ( R37a) (R37b) -C (= 0) -S-, (xliv) -C (R37a) (R37b) -C (= S) -0-, xlvii) -C (R37a) (R37) -N (R37b) -C (= S) -, (xlviii) -C (R37a) (R37) -0-C (= 0) -xlix) -C (R37a) (R37b) -SC (= 0) -, (I) -C (R37a) (R37b) -0-C (= S) -, li) -C (R37a) (R37b) -SC (= S) -, (l? i) -C (R37a) (R37b) -N (R37) -C (= 0) -N (R37a) I iii) -C (R37a) (R37b) -N (R37b) -C (= S ) -N (R37a) -, I iv) -C (R37a) (R37b) -N (R37b) -C (= 0) -0-, I) -C (R37a) (R37b) -N (R37b) - C (-0) -S-, I vi) -C (R37a) (R7b) -N (R37b) -C (= S) -0-, I vii) -C (R37a) (R37) -N ( R37b) -C (= S) -S-, Iviii) -C (R37a) (R37b) -0-C (= 0) -N (R37a) -, Ix) -C (R37a) (R37b) -0-C (= S) -N (R37a) -, Ixi) -C (R37a) (R37b) -SC (= S) -N (R37a) -, (Ixii ) -C (R37a) (R37b) -0-C (= 0) -0-, Ixiii) -C (R37a) (R37b) -SC (= 0) -0-, (Ixiv) -C (R37a) ( R3 b) -0-C (= 0) -S-, Ixv) -C (R37a) (R37b) -SC (= 0) -S-, (Ixvi) -C (R37a) (R37b) -0-C (= S) -0-, Ixvii) -C (R37a) (R37b) -SC (= S) -0-, (Ixviii) -C (R37a) (R37) -0-C (= S) -S- , Ixix) -C (R37a) (R37b) -SC (= S) -S- or (Ixx) -C (R37a) (R37b) -C (R37a) (OR370) -; R'4 is: (i) hydrogen, (ii) alkyl of 1 to 12 carbon atoms, (iii) haloalkyl, (iv) hydroxyalkyl, (v) alkyl substituted with thiol, (vi) alkyl substituted with R37cO, (vii) ) alkyl substituted with R37oS, (vlii) aminoalkyl, (xi) alkyl substituted with (R37f) N H-, (x) alkyl substituted with (R37a) (R37c) N-, (xi) alkyl substituted with R37aO- (0 = ) C, (xii) alkyl substituted with R37aS- (0 =) C-, (xin) alkyl substituted with R37aO- (S =) C, (xiv) alkyl (R37aO) 2-P (= 0), (xvi) cyanoalkyl, (xvii) alkenyl of 2 to 1 2 carbon atoms, (xviii) haloalkenyl, (xix) alkynyl of 2 to 1 2 carbon atoms, (xx) ) cycloalkyl, (xxi) (cycloalkyl) alkyl, (xxii) (cycloalkyl) alkenyl, (xxiii) (cycloalkyl) alkynyl, (xxiv) cycloalkenyl, (xxv) (cycloalkenyl) alkyl, (xxvi) (c-chloralkenyl) alkenyl, (xxvii) (cycloalkenyl) alkynyl, (xxviii) aryl, (xxix) (aryl) aryl, (xxx) (aryl) alkenyl, (xxxi) ) (aryl) alkynyl, (xxxii) heterocyclic, (xxxiii) alkyl (heterocyclic), (xxxiv) alkenyl (heterocyclic) or (xxxv) alkynyl (heterocyclic), provided that R14 is other than hydrogen when Z is: -C (R37a) (R37b) -N (R37b) -C (= 0) -0-, -C (R37a) ( R37 b) -N (R37 b) -C (= S) -O-, -C (R37a) (R37b) -N (R37b) -C (= 0) -S-, -C (R37a) (R37b) -N (R37b) -C (= S) -S- , -C (R37a) (R37b) -0-C (= 0) -0-, -C (R37a) (R37b) -0-C (= S) -O-, -C (R37a) (R37b) - SC (= 0) -0-, -C (R37a) (R37b) -SC (= S) -0-, -C (R37a) (R37) -0-C (= 0) -S-, -C (R37a) (R37b) -0-C (= S) -S-, -C (R37a) (R37b) -S-C (= 0) -S- or -C (R37a) (R37b) -S-C (= S) -S-; R37a, R37, R47, and R48 in each occurrence are independently selected from the group consisting of: (i) hydrogen, (ii) alkyl of 1 to 12 carbon atoms, (ii) haloalkyl, (iv) hydroalkyl, (v) ) alkoxyalkyl, (vi) alkenyl of 2 to 12 carbon atoms, (vii) haloalkenyl, (viii) alkynyl of 2 to 12 carbon atoms, (ix) cycloalkyl, (x) (cycloalkyl) alkyl, (xi) (cycloalkyl) alkenyl, (xii) (cycloalkyl) alkynyl, (xiu) cycloalkeni lo, (xiv) (cycloalkenyl) alkyl, (xv) (c? alkalq uenyl) alken? what, (xvi) (cycloalkenyl) alkyne? lo, (xvii) aryl, (xviii) (aryl) alkyl, (xix) (aryl) alkenyl, (xx) (ar? l) alkynyl, (xxi) heterocyclic, (xxi i) alkyl (heterocycle) , (xxiii) alken? lo (heterocyclic) and (xxiv) alkynyl (heterocyclic); R37c in each occurrence is independently selected from the group consisting of: (i) hydrogen, (ii) alkyl of 1 to 12 carbon atoms, (iii) haloalkyl, (iv) alkenyl of 2 to 12 carbon atoms, (v) ) haloalkenyl, (vi) alkynyl of 2 to 12 carbon atoms, (vii) cycloalkyl, (viii) (cycloalkyl) alkyl, (ix) (cycloalkyl) alkenyl, (x) (cycloalkyl) alkylo, (xi) cycloalkenyl , (xii) (cycloalkenyl) alkyl, (xiii) (cycloalkenyl) alkenyl, (xiv) (cycloalkenyl) alkynyl, (xv) aryl, (xvi) (aryl) alkyl, (xvii) (aryl) alkenyl, (xviii) (aryl) alkynyl, (xix) heterocyclic, (xx) alkyl (heterocyclic), (xxi) alkenyl (heterocyclic, (xxii) alkynyl (heterocyclic), (xxiii) -C (= 0) -R14, (xxiv) -C (= S) -R14, (xxv) -S (0) 2 -R14 and (xxvi) hydroxyalkyl, or when Z is -C (R37a) (R37b) -N (R37c) - , then N (R37 °) and R14 when taken together are an azido group, or when Z is -C (R37a) (R37b) -N (0) (R37c) -, then N (0) (R37c) and R 4 when taken together are a N-oxidized 3-7 membered heterocyclic ring having at least one nitrogen atom of the N-oxidized ring; when Z is -C (R37a) (OR37c) -, -C (R37a) (SR37c) - or -C (R3 (N (R3'b) (R3 c)) -, then R3 and the carbon atom to which they are attached when taken together form a cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl ring; R15 is selected from the group consisting of: (i) hydrogen, (ii) hydroxy, (iii) amino, (iv) alkyl of 1 to 12 carbon atoms, (v) haloalkyl, (vi) alkenyl of 2 to 12 carbon atoms, (vii) haloalkenyl, (viii) cycloalkyl, (ix) (cycloalkyl) alkyl, (x) (cycloalkyl) alkenyl, (xi) cycloalkenyl, (xii) (cycloalkenyl) alkyl, (xiii) (cycloalkenyl) alkenyl, (xiv) aryl, (xv) (aryl) alkyl, (xvi) (aryl) alkenyl, (xviii) heterocyclic, (xviii) alkyl (heterocyclic) and (xix) alkenyl (heterocyclic); or R3 and R4 taken together, with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 8 atoms in the ring; R5 in each occurrence is independently selected from the group consisting of - (a) hydrogen, (b) -CH (R38) 2, (c) - (CH2) -0-R40, (d) alkynyl of 2 to 4 atoms carbon, (e) cyclopropyl, (f) cyclobutyl, (g) -C (= Q) -R17, and (h) - (CH2) -N (R19) 2, when r is 0, 1 or 2; provided when one of R5 is -O-R40 or N (R '9) 2, then the other R5 is different from -O-R40 or -N (R9) 2; wherein Q1 is O, S, or N (R18); R 17 and R 18 are independently selected, from each occurrence, from the group consisting of hydrogen, methyl and ethyl; occurrence, of g ru po consisting of (i) hydrogen, (ii) alkyl of 1 to 12 carbon atoms, (ni) haloalkyl, (iv) alkenyl of 2 to 12 carbon atoms, (v) haloalkenyl, (vi) ) cycloalkyl, (vii) (cycloalkyl) alkyl, (vn i) (cycloalkyl) alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl) alkyl, (xi) (c-chloralkenyl) alkenyl, (xii) aryl, (xiii) (aryl) alkyl, (xiv) (aryl) alkenyl, (xv) heterocyclic, (xvi) alkyl (heterocyclic) and ( xvii) alkenyl (heterocyclic); or one of R19 is an N-protecting group, or the two R5 groups taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms; Y is selected from the group consisting of (a) alkyl of 1 to 5 carbon atoms, (b) haloalkyl of 1 to 5 carbon atoms, (c) alkenyl of 2 to 5 carbon atoms, (d) haloalkenyl of 2 to 5 carbon atoms, (e) alkynyl of 2 to 5 carbon atoms, (f) cycloalkyl of 3 to 5 carbon atoms, (g) cycloalkyl of 3 to 5 carbon atoms-alkyl of 1 to 3 carbon atoms (h) cycloalkenyl of 5 carbon atoms, (i) cycloalkenyl of 5 carbon atoms-alkyl of 1 to 3 carbon atoms, (j) cycloalkenyl of 5 carbon atoms-alkenyl of 2 to 3 carbon atoms, ( k) - (CHR39) nOR20, (I) -CH (OR20) -CH2 (OR20), (m) - (CH R39) "SR21, (n) phenyl, (o) halo-substituted phenyl, (p) -CH R39) nC (= Q) R22, (q) - (CH R39)" N (= Q3), (r) -N (0) = CHCH3, (s) - (CHR39) "N (CH3) R34 and (t) a heterocyclic ring having from 3 to 6 ring atoms; wherein n is 0, 1 or 2; Q2 is O, S, NR25, or CHR26; and Q3 is NR41, or CHR42; R20 in each occurrence is independently: (i) methyl, (ii) ethyl, (iii), n-propyl, (iv) isopropyl, (v) haloalkyl dβ 1 to 3 carbon atoms, (vi) vinyl, (vii) propenyl, (viii) isopropenyl, (ix) allyl, (x) haloalkenyl of 2 to 3 carbon atoms, (xi) amino, (xii) -NHCH3, (xiii) -N (CH3) 2, (xiv) -NHCH2CH3 , (xv) -N (CH3) (CH2CH3), (xvi) -N (CH2CH3) 2 or (xvii) -N (= CH2); R2 'is (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) aspropyl, (vi) haloalkyl of 1 to 3 carbon atoms, (vii) vinyl, (viii) ) propenyl, (ix) isopropenyl, (x) allyl or (xi) haloalkenyl of 2 to 3 carbon atoms; R22 is (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) hydroxy, (vii) thiol, (viii) ethoxy, (ix) ethoxy, (vi) x) n-propoxy, (xi) isopropoxy, (xii) cyclopropoxy, (xiii) methylthio, (xiv) ethylthio, (xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii) vinyl, (xii) ) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii) -N (R28a) (R28b), (xxiii) -CH2R29, (xxiv) aminomethyl, (xxv) hydroxymethyl, (xxvi) thiolmethyl, (xvii) - NHNH2, (xviii) -N (CH3) NH2 or (xxii) -NHNH (CH3); R23 and R39 are independently hydrogen or methyl; R41 and R42 are independently hydrogen, methyl or ethyl; R24 is selected from the group consisting of: (i) hydrogen, (ii) alkyl of 1 to 4 carbon atoms, (iii) alkenyl of 2 to 4 carbon atoms, (iv) alkynyl of 2 to 4 carbon atoms, (v) cyclopropyl, (vi) -C = (Q4) -R30, (v) -OR31, and (vi) -N (R32) 2, wherein Q4 is O, S, or N (R33); R25 is hydroxy, methyl, ethyl, amino, -CN, or -N02; R26 is a group that is hydrogen, methyl or ethyl; R28a is hydrogen, hydroxy, methyl, ethyl, amino, -NHCH3, -N (CH3) 2, methoxy, ethoxy, or -CN; R28b is hydrogen, methyl or ethyl; or R2Sa, R28b and the nitrogen to which they are attached taken together represent azetidinyl; the group R29 is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino; the group R30 is hydrogen, methyl, ethyl, -OR34, -SR34, -N (R35) 2, -NHOH, -NHNH2, -N (CH3) NH2, or -N (CH2CH3) NH2; the substituents R31 and R32, in each occurrence, are independently hydrogen, methyl or ethyl; the group R33 is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -N02; the group R34 is methyl or ethyl; the group R35 is independently hydrogen, methyl or ethyl; provided that when Q2 is CHR26, then R22 is selected from a group consisting of hydrogen, -CH3, -C2H5, -C3H7, -OCH3, -SC H3, R6 and R7 are independently selected from the group consisting of: (a) hydrogen, (b) alkyl of 1 to 12 carbon atoms, (c) alkenyl of 2 to 12 carbon atoms, (d) cycloalkyl, ( and) (cycloalkyl) alkyl, (f) (cycloalkyl) alkenyl, (g) cycloalkenyl, (h) (cycloalkenyl) alkyl, (i) (cycloalkenyl) alken? lo, (i) arilo, (k) (aryl) alkyl, (I) (ar? l) alkenyl, (m) heterocyclic, (n) alkyl (heterocyclic), (o) alkenyl (heterocyclic), (p) -OR37a and (q) -N (R37a) 2; and R8, R9 and R10 independently are selected from the group consisting of: (a) hydrogen, (b) alkyl of 1 to 6 carbon atoms, (c) alkenyl of 2 to 6 carbon atoms, (d) cycloalkyl of 3 to 6 carbon atoms, (e) cycloalkenyl of 3 to 6 carbon atoms, and (f) fluorine, provided that the total number, other than hydrogen, in each of R8, R9 and R10, is of 6 atoms or less. Preferred compounds of the invention include compounds wherein R3 and R4 are not the same, and which have the relative stereochemistry represented by formula IV, V, VI, Vi l, VI I I or IX: *** - * "-» VIII IX or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined above. Other preferred compounds of the invention are compounds having the formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ether . ta-. or prodrug thereof, wherein R 'is as defined above; -X-R2 is R2 -C (= 0) -NH-, R2 -NH-C (= 0) -, R2 -NH-SOj- or R2-SO2-NH-, wherein R2 is lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms, or haloalkenyl of 2 to 3 carbon atoms, or -X-R2 is: wherein Y1 is -CH2 -O-, S- or -NH- and Y2 is -C (= 0) - or -C (Raa) (Rbb), wherein Raa and Rbb are independently selected from the group consisting of hydrogen lower alkyl of 1 to 3 carbon atoms, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl; R3 and R4 are independently selected from hydrogen, heterocyclic and: -Z-R14, wherein Z and R14 are as defined above, and wherein one of R3 and R4 is other than hydrogen; Z1 is -O-, -S- or -CH (R5) -, wherein R5 is hydrogen, lower alkyl or (CH2) rN (R19) 2, wherein r and R9 are as defined above; or R5 is hydrogen, lower alkyl or - (CH2) rN (R, 9) 2 in where R and R19 are as defined above, R6 and R7 are independently hydrogen or lower alkyl; R8 and R9 are independently hydrogen, fluoro or lower alkyl; R10 is hydrogen, fluoro or lower alkyl; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, -C (= Q2) R22, -N (= Q3), -N (0) = CHCH3, -NR23R24 or a heterocyclic ring having from 3 to 6 atoms in the ring, wherein R22, R23, R24, Q2 and Q3 are as defined above. The highly preferred compounds of the invention are compounds having the formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof, wherein R 'is as defined above; -X-R2 is R2 -C (= 0) -NH-, R2-NH-C (= 0) -, R2-NH-S02- or R2-S02-NH-, wherein R2 is lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms, or haloalkenyl of 2 to 3 carbon atoms, or -X-R2 is: wherein Y1 is -CH2- and Y2 is -C (= 0) - or -C (R ") (Rbb), wherein Raa and Rbt > are independently selected from the group consisting of ^^ j ^^ jíg ^ hydrogen, lower alkyl of 1 to 3 carbon atoms, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl; R3 and R4 are independently selected from hydrogen, heterocyclic and: -Z-R'4, wherein Z and R14 are as defined above, and wherein one of R3 and R4 is other than hydrogen; Z1 is -O-, -S- or -CH (R5) -, wherein R5 is hydrogen, lower alkyl or (CH2), N (R19) 2, wherein r and R19 are as defined above; or R5 is hydrogen, lower alkyl or - (CH2), N (R19) 2 wherein r and Ri9 are as defined above; R6 and R7 are independently hydrogen or lower alkyl; R8 and R9 are independently hydrogen, or lower alkyl; R10 is hydrogen, or lower alkyl; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, -C (= Q2) R22, -N (= Q3), -N (0) = CHCH3, or a heterocyclic ring having 5 to 5 carbon atoms. atoms in the ring and also containing one or two double bonds, wherein R22, Q2 and Q3 are as defined above. Still very preferred compounds of the invention are compounds having the formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof, wherein R1 is as defined above; -X-R2 is R2 -C (= Q) -NH-, R2 -NH-C (= 0) - -NH-SO2- or R2 SO2-NH-, wherein R is lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms, or haloalkenyl of 1 to 3 carbon atoms, or -X-R2 is: wherein Y1 is -CH2-, and Y2 is -C (= 0) - or -C (Raa) (Rbb), wherein Ra and Rb are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 3 carbon atoms, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl; R3 and R4 are independently selected from hydrogen, halocyclic and: -Z-R1 4, wherein Z and R1 4 are as defined above, and wherein one of R3 and R4 is other than hydrogen; Z1 is -O-, -S- or -C H (R5) -, wherein R5 is hydrogen, lower alkyl or (CH2) rN (R19) 2, wherein r and R19 are as defined above; or R5 is hydrogen, lower alkyl or - (CH2), N (R19) 2 wherein r and R19 are as defined above; R6 and R7 are independently hydrogen or lower alkyl; R8 and R9 are independently hydrogen, or lower alkyl; R10 is hydrogen, or lower alkyl; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

The most highly preferred compounds of the invention are compounds having the formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof, wherein R -C02H; -X-R2 is R2 -C (=?) - NH-, R2 -NH-C (= 0) -, R2 -NH-S02- or R2-S02-NH-, where R2 is lower alkyl of 1 to 3 carbon atoms, or lower haloalkyl of 1 to 3 carbon atoms; R3 and R4 are independently selected from hydrogen, heterocyclic and: -Z-R14, wherein Z and R14 are as defined above, and wherein one of R3 and R4 is other than hydrogen; Z1 is -O-, -S- or -CH; or R5 is hydrogen; R6 and R7 are independently hydrogen or lower alkyl; R8 and R9 are independently hydrogen, or lower alkyl; R10 is hydrogen, or lower alkyl; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. Still very highly preferred compounds of the invention are compounds having the formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof, wherein R1 is -C02H; -X-R2 is R2-C (= 0) -NH-, R2-NH-C (= 0) -, R2-NH-S02- or R2-S02-NH-, where R2 is lower alkyl of 1 to 3 carbon atoms or lower haloalkyl of 1 to 3 carbon atoms, R 4 is hydrogen or lower alkyl or R 3 is heterocyclic or -Z-R'4, wherein Z and R 14 are as defined above; Z1 is -O-, -S- or -CH ,; or R5 is hydrogen; R6 and R7 are hydrogen; R8 and R9 are hydrogen; R10 is hydrogen; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. Still other more highly preferred compounds of the invention are compounds having the formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof, wherein R is -C02H; -X-R2 is R2-C (= 0) -NH-, R2-NH-C (= 0) -, R2-NH-S02- or R2-S02-NH-, wherein R2 is lower alkyl of 1 to 3 carbon atoms or lower haloalkyl of 1 to 3 carbon atoms; R 4 is hydrogen or lower alkyl and R 3 is (a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) -C (= 0) -R '4, (h) -C (R37a) (OR37c) -R14 or (i) -C (R37a) (R370) -N (0) (R37o) R14, wherein R14 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (viii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) alkyl (heterocyclic), (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) alkyl substituted with (R37aO) - (0 =) C-, or (xv) alkyl substituted with (R37aO) 2-P (= 0); consists of (i) hydrogen, (ii) lower alkyl and (ii) lower alkenyl; Y a ** »'< ? R37c is (i) hydrogen, (ii) lower alkyl or (ii) lower alkenyl; Z1 is -O-, -S- or -CH2; or R5 is hydrogen; R6 and R7 are hydrogen; R8 and R9 are hydrogen; R10 is hydrogen; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. The very highly preferred compounds of the invention are compounds having the formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof, wherein R 'is -C02H; -X-R2 is R2-C (= 0) -NH-, R2-NH-C (= 0) -, or R2-S02-NH-, wherein R2 is lower alkyl of 1 to 3 carbon atoms or haloalkyl lower of 1 to 3 carbon atoms; R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C (R37a) (OR37c) -R14, wherein R4 is (i) alkyl, (i) cycloalkyl, (iii) cycloalkylalkyl , (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) alkyl (heterocyclic), (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) ) alkyl substituted with (R37aO) - (0 =) C-, or (xv) alkyl substituted with (R37O) 2-P (= 0); R37a and R37 independently are selected from the group consisting of (i) hydrogen, (ii) lower alkyl and (iii) lower alkenyl; Y R37c is (i) hydrogen, (ii) lower alkyl of 1 to 3 carbon atoms or (iii) allyl; Z1 is -O-, -S- or -CH; or R5 is hydrogen; R6 and R7 are hydrogen; R8 and R9 are hydrogen; R10 is hydrogen; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. Other very highly preferred compounds of the invention are compounds having the formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof, wherein R1 is -CO2H; -X-R2 is R2-C (= 0) -NH-, or R2-S02-NH-, wherein R2 is lower alkyl of 1 to 3 carbon atoms or lower haloalkyl of 1 to 3 carbon atoms; R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) (i) lower alkyl, (i) lower alkenyl, (iii) lower alkyl substituted with hydroxy or (iv) lower alkyl substituted with alkoxy; (R37a) is (i) hydrogen, (ii) lower alkyl or (iii) lower alkynyl; Y R37c is (i) hydrogen, (ii) lower alkyl of 1 to 3 carbon atoms or • Éütttai * .. (ni) aillo; Z1 is -O-, -S- or -CH2, or R5 is hydrogen, R6 and R7 are hydrogen; R8 and R9 are hydrogen; R10 is hydrogen; and Y is alkenyl of 2 to 5 carbon atoms, haloalkyl of 2 to 5 carbon atoms, or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. Other very highly preferred compounds of the invention are compounds having the formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof, wherein R1 is -C02H; -X-R2 as R2-C (= 0) -NH-, or R -S02-NH-, wherein R2 is lower alkyl of 1 to 3 carbon atoms or lower haloalkyl of 1 to 3 carbon atoms; R4 is hydrogen and R3 is -C (R37a) (OR37c) -R14, wherein R'4 is lower alkyl or lower alkenyl; R37a is lower alkyl or lower alkenyl; and R37c is hydrogen, lower alkyl of 1 to 3 carbon atoms or allyl; Z1 is -O-, S- or -CH2; or R5 is hydrogen, R6 and R7 are hydrogen; R8 and R9 are hydrogen; R10 is hydrogen; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. Preferred substituents of R1 include -C02H or esters or prodrugs thereof. Preferred esters include lower alkyl esters of 2 to 6 carbon atoms or substituted or unsubstituted benzyl esters. Preferred substituents R1 also include -S (0) 2NHC (= 0) R1 1, wherein R1 is as previously defined. Very highly preferred substituents, R1, include -C02H or esters or prodrugs thereof. Very highly preferred esters include lower alkyl esters of 2 to 6 carbon atoms or substituted or unsubstituted benzyl esters. Preferred substituents -X-R2 include R2-C (= 0) -N H-, R2-NH-C (= 0), R2-N H-S02- or R2-S02N H-, where R2 is lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms or haloalkenyl of 2 to 3 carbon atoms, or -X-R2 is where Y1 is -CH2-, -O-. -S- or -N H- and Y2 is -C (=?) - or -C (Raa) (Rbb) -, where Raa and Rbb are independently selected of the group consisting of hydrogen, - lower alkyl of 1 to 3 carbon atoms, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2- thiolethyl, methoxymethyl, N-methylaminomethyl and methyltiomethyl. Highly preferred substituents -X-R2 include R2-C (= 0) -NH-, R2-NH-C (= 0), R2-NH-S02- or R2-S02NH-, where R2 is lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms or haloalkenyl of 2 to 3 carbon atoms, or -X-R2 is: wherein Y1 is -CH2- and Y2 is -C (= 0) - or -C (Raa) (Rbb) -, wherein Raa and Rbb are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 3 atoms of carbon, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl. Still very preferred substituents, -X-R2 include R2-C (= 0) -NH-, R2-NH-C (= 0), R -NH-S02- or R2-S02NH-, where R2 is lower alkyl from 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms or haloalkenyl of 2 to 3 carbon atoms. The most highly preferred substituents -X-R2 include R2-C (= 0) -NH-, R2-NH-C (= 0), R2-NH-S02- or R2-S02NH-, where R2 - W? - - -df "- it is lower alkyl of 1 to 3 carbon atoms or lower haloalkyl of 1 to 3 carbon atoms. Even more highly preferred substituents-X-R2 include R2-C (= 0) -NH-, R2-NH-C (= 0), R -NH-S02- or R2-S02NH-, wherein R2 is lower alkyl of 1 to 2 carbon atoms or lower haloalkyl of 1 to 2 carbon atoms, and especially CH3-C (= 0) -NH-, CF3-C (= 0) -NH-, CH3-S02-NH- or CF3-S02-NH-. Preferred substituents Z1 include -O-, -S- or -CH (R5) -, wherein R5 is hydrogen, lower alkyl or - (CH2) rN (R1) 2, wherein r and R19 are as defined above; or R5 is hydrogen, lower alkyl or - (CH2) rN (R19) 2 wherein r and R19 are as defined above. The highly preferred substituents Z1 are -O-, -S- or -CH (R5) -where R5 is hydrogen or lower alkyl. The most highly preferred substituents Z1 are -O-, -S- or -CH--. The most highly preferred substituents Z1 are -O- or -CH2-. Preferred substituents R3 and R4 are independently selected from the group consisting of hydrogen, heterocyclic and -Z-R14, wherein Z and R14 are defined as more broadly defined above herein, and wherein one of R3 and R4 is other than hydrogen . The most highly preferred substituent, R4, is hydrogen or lower alkyl and R3 includes heterocyclic or -Z-R14, wherein Z and R14 they are as previously more broadly defined The even more highly preferred substituent, R4, is hydrogen or lower alkyl and R3 includes: (a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl , (f) alkynyl, (g) -C (= 0) -R 1 4, (h) -C (R37a) (OR37c) -R1 4 or (i) -C (R37a) (R37 b) -N ( 0) (R37c) R14, wherein R 4 is: (¡) alkyl, (ii) cycloalkyl, (ii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) alkyl (heterocyclic), (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) alkyl substituted with (R37aO) - (0 =) C, or (xv) alkyl substituted with (R37aO) 2-P (= 0); R 37a and R 37t > s e e c c e n n n independently of the group consisting of: (i) hydrogen, (ii) lower alkyl and (ii) lower alkenyl; Y R37c is (i) hydrogen, (ii) lower alkyl and (iu) lower alkenyl). The most highly preferred substituent, R4, is hydrogen and R3 includes: (a) heterocyclic, (b) alkyl or (c) -C (R37a) (OR37c) -R 14, wherein R14 is (i) alkyl, (ii) ) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) alkyl (heterocyclic), (xi) hydroxyalkyl , (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) alkyl substituted with (R37aO) - (0 =) C or (xv) alkyl substituted with (R37aO) 2-P (=?); R37a and R3Tb are independently selected from the group consisting of (i) hydrogen, (ii) lower alkyl or (ni) lower alkenyl, and R3To is (i) hydrogen, (li) lower alkyl of 1 to 3 carbon atoms or (iii) allyl. Also, the most highly preferred substituent R4 is hydrogen and R3 includes: (a) heterocyclic, (b) alkyl or (c) -C (R37a) (OR37c) -R14, wherein R14 is: (i) lower alkyl, ( ii) lower alkenyl, (iii) lower alkyl substituted with hydroxy or (iv) lower alkyl substituted with alkoxy; R37a is (i) hydrogen, (i) lower alkyl or (iii) lower alkenyl; and R37c is (i) hydronogen, (ii) lower alkyl of 1 to 3 carbon atoms or (iii) allyl. The most highly preferred substituent R4 is also lower or lower alkenyl; R37a is lower alkyl or lower alkenyl; and R37c is hydrogen, lower alkyl of 1 to 3 carbon atoms or allyl, and especially, wherein R37c is hydrogen or methyl. Preferred substituents R5 include those independently selected from hydrogen, lower alkyl and - (CH2) rN (R9) 2, wherein r and R19 are as defined above.

Most preferred substituents R are independently selected from hydrogen, lower alkyl and - (C H2) rN (R 1) 2, wherein r is 0 or 1 and not R 19 is hydrogen or lower alkyl and the other of R 19 is hydrogen, lower alkyl or an N-protecting group. The still highly preferred substituents R5 are independently selected from hydrogen and lower alkyl. Very highly preferred, R5, is hydrogen. Preferred substituents R6 and R7 independently include hydrogen and lower alkyl. Very highly preferred, R6 and R7 are hydrogen. Preferred substituents R i independently include hydrogen, fluoro or lower alkyl. Very highly preferred, R8, R9 and R10 are hydrogen. The preferred substituent Y includes alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, -C (= Q2) R22, N (= Q3), -N (0) = C HCH3, NR23R24, or a heterocyclic ring having from 3 to 6 atoms in the ring, wherein R22, R23, R24, Q2 and Q3 are as defined above. The most preferred substituent Y include alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, -C (= Q2) R22, N (= Q3), -N (0) = CHCH3, or a heterocyclic ring having 5 atoms in the ring and also containing one or two double bonds, wherein R22, Q2 and Q3 are as defined above. The most preferred substituent Y includes alkenyl from 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds Representative alkenyl and haloalkenyl Y substituents include -CH = CH2, -CH = CHF, -CH = CH-CH3, -CH = CH-CF3, -CH = CHCl, -CH = CHBr, -CH = CF2, -CH = CF (CH3), -CH = CF (CF3), -CH = CFCI, -CH = CFBr, -CH = C (CH3) 2, -CH = C (CH3) (CF3), -CH = CCI (CH3), -CH = CBr (CH3), -CH = C (CF3) 2, -CH = CCI (CF3), -CH = CBr (CF3), -CH = CCI2, -CH = CCIBr, -CF = CH2, -CF = CHF, -CF = CH-CH3, -CF = CH-CF3, -CF = CHCI, -CF = CHBr, -CF = CF2, -CF = CF (CH3), -CF = CF (CF3), -CF = CFCI, -CF = CFBr, -CF = C (CH3) 2, -CF = C (CH3) (CF3), -CF = CCI (CH3), -CF = CBr (CH3), -CF = C (CF3) 2, -CF = CCI (CF3), -CF = CBr (CF3), -CF = CCI2, -CF = CCIBr, -C (CH3) = CH2, -C (CH3) = CHF, -C (CH3) = CH-CH3, -C (CH3) = CH-CF3, -C (CH3) = CHCI , -C (CH3) = CHBr, -C (CH3) = CF2, -C (CH3) = CF (CH3), -C (CH3) = CF (CF3), -C (CH3) = CFCI, -C (CH3) = CFBr, -C (CH3) = C (CH3) 2, -C (CH3) = C (CH3) ( CF3), -C (CH3) = CCI (CH3), -C (CH3) = CBr (CH3), -C (CH3) = C (CF3) 2, -C (CH3) = CCI (CF3), -C (CH3) = CBr (CF3), -C (CH3) = CCI2, -C (CH3) = CCIBr -C (CF3) = CH2, -C (CF3) = CHF, -C (CF3) = CH-CH3, -C (CF3) ) = CH-CF3, -C (CF3) = CHCl, -C (CF3) = CHBr, -C (CF3) = CF2, -C (CF3) = CF (CH3), -C (CF3) = CF (CF3), -C (CF3) = CFCI, -C (CF3) = CFBr, -C (CF3) = C (CH3) 2, -C (CF3) = C (CH3) (CF3), -C (CF3) = CCI (CH3), -C (CF3) = CBr (CH3), -C (CF3) = C (CF3) 2, -C (CF3) = CCI ( CF3), -C (CF3) = CBr (CF3), -C (CF3) = CCI2, -C (CF3) = CCIBr, -CCI = CH2, -CCI = CHF, -CCI = CH-CH3, -CCI = CH-CF3, -CCI = CHCl, -CCI = CHBr, -CCI CF2, -CCI = CF (CH3), -CCI = CF (CF3), -CCI = CFCI, -CCI = CFBr, -CCI = C (CH3) 2, -CCI = C (CH3) (CF3), -CCI = CCI (CH3), -CCI = CBr (CH3), -CCI = C (CF3) 2, -CCI = CCI (CF3), -CCI = CBr (CF3), -CCI = CCI2, -CCI = CCIBr, -CH = CH-CH2CH3, -CH = CF-CH2CH3, -CF = CH-CH2CH3, -CF = CF- CH 2 C H 3, -CH = C (CH 3) (CH 2 CH 3), -CF = C (CH 3) (CH 2 CH 3), -CH = CCI (CH 2 CH 3), -CF = CCI (CH 2 CH 3), -C (CH 3) = CH-CH2CH3, -C (CH3) = CF-CH2CH3, -CCI = CH-CH2CH3, -CCI = CF-CH2CH3, -C (CH2CH3) = CH2, -C (CH2CH3) = CHF, -C (CH2CH3) = CF2, -C (CH2CH3) = CH-CH3, -C (CH2CH3) = CF-CH3, -C (CH2CH3) = CH-CI, -C (CH2CH3) = CFCI The representative Y substituents, which are rings heterocyclics having 5 atoms in the ring and also containing 1 or 2 double bonds include. Ranilo fu, dih idrofuranilo, didehidrodioxolanilo, dithiolyl, imidazolyl, imidazolinyl, isothiazolyl, isothiazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, oxadiazolin yl, oxathiolyl, oxazolyl, oxazolinyl, pyrazolyl, pyrazolinyl, pyrrolyl, dihydropyrrolyl, tetrazolyl, tetrazolinilo, thiadiazolyl, thiadiazolinyl, thiazolyl , thiazole and none, thienyl, dihydrothienyl, triazolyl, triazolinyl. The most highly preferred Y substituents include cis-propenyl, trans-propenyl, isobutenyl, cis-2-chlorovinyl, vinyl, 2,2-difluorovinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl. Very highly preferred Y substituents include cis-propenyl, cis-2-chlorovinyl, vinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl. The term "acid protection group" as used herein, refers to groups used to protect acid groups (for example, groups -C02H, -S03H, -S02H, -S02H, -P03H2, -P02H, and the like against undesirable reactions during synthetic procedures.The commonly used acid protecting groups are described by T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Svnthesis. 2o. edition, John Wiley & Sons, New York (1991).

With frequency, said acid protecting groups are esters. These esters include: Alkyl esters, especially lower alkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl ester, and the like; Arylalkyl esters include, but are not limited to, benzyl, phenethyl, 3-phenylpropyl, nhylmethyl esters, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as defined above; silyl esters especially esters (lower trialkyl) silyl esters (di-lower alkyl) (a ril) si l l? cos and esters (lower alkyl) (di-aryl) silyl, including, but not limited to, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropylsilyl esters Ilic, and the like; and similar. Preferred acid protecting groups are lower alkyl esters. The term "activated carboxylic acid group" as used herein, refers to acid halides such as acid chlorides and also refers to activated ester derivatives, including, but not limited to, anhydrous formic acid derivatives and acetic, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonyl chloride and the like similar anhydrides of the reaction of the carboxylic acid with N, N'-carbonidimidazole and the like, esters derived from N-hydroxysuccinimide, esters derived from N-hydroxyphthalimide, esters N-hydroxybenzotriazole derivatives, esters derived from N-hydrox? -5-norbornen-2, 3-dicarboxyimides, esters derived from 2,4,5-trichlorophenol, esters derived from p-nitrophenol, esters derived from phenol, esters pentachlorophenol derivatives, esters derived from 8-hydroquinoline, and the like. The term "acyl" as used herein, refers to groups having the formula -C (= 0) -R95, wherein R95 is hydrogen or an alkyl group. Preferred alkyl groups such as R95 are lower alkyl groups. Representative examples of acyl groups include such groups, for example, formyl, acetyl, propionyl, and the like. The term "acylamino" as used herein, refers to groups having the formula -NH R89, wherein R89 is an acyl group. Representative examples of acylamino include acetylamino, propionylamino, and the like. The term "alkenyl" as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also contains at least one carbon-carbon double bond. The term "lower alkenyl" refers to straight or branched chain alkenyl radicals containing from 2 to 6 carbon atoms. Representative examples of alkenyl groups include such groups, for example, vinyl, 2-propenyl, 2-methyl-1-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, and the like. The term "alkenylene" as used herein, is refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term "lower alkenylene" refers to a divalent group derived from a straight or branched chain alkyl group having from 2 to 6 carbon atoms. Representative examples of alkenylene groups include groups such as, for example, -CH = CH, -CH2CH = CH-, C (CH3) = CH-, CH2CH = CHCH2-, and the like.

The term "alkenyloxy" as used herein, refers to groups having the formula -OR81, wherein R81 is an alkenyl group. The term "alkoxy" as used herein, refers to groups having the formula -OR99, wherein R99 is an alkyl group. Preferred R99 groups are lower alkyl groups. Representative examples of alkoxy groups include groups such as, for example, methoxy, ethoxy, tert-butoxy, and the like. The term "alkoxyalkoxy" as used herein, refers to groups having the formula -O-R96 -O-R97, wherein R97 is lower alkyl, as defined above, and R96 is a lower alkylene group. Representative examples of alkoxyalkoxy groups include groups such as, for example, methoxymethoxy, ethoxymethoxy, t-butoxymethoxy, and the like. The term "alkoxyalkyl" as used herein, refers to an alkyl radical to which an alkoxy group is attached, for example, methoxymethyl, methoxypropyl, and the like.

The term "alkoxycarbonyl" as used herein, refers to groups having the formula, -C (= O) S0, wherein R80 is an alkoxy group. The term "alkoxycarbonylalkyl" as used herein, refers to groups having the formula -C (= 0) 79, attached to the parent molecular moiety through an alkylene linkage, wherein R79 is a alkoxy group. As used herein, the term "alkyl" refers to straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms. The term "lower alkyl" refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms Representative examples of alkyl groups include groups such as, for example, methyl, ethyl, n-propyl, isopropyl, n butyl, butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like. hydrocarbon in alkyl groups or the alkyl portion of an alkyl-containing substituent may be optionally interrupted by one or two heterogeneous atoms or heterogeneous groups, independently selected from the group consisting of oxygen, - (R27), and sulfur, wherein R27 in each The occurrence is independently hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl or arylalkyl and wherein 2 of these heterogeneous atoms or heterogeneous groups are separated by at least one carbon atom. used in the present, it refers to groups having the formula -N H R91 wherein R91 is an alkyl group. Preferred R91 groups are alkyl groups. Representative examples of alkylamino include methylamino, ethylamino, and the like. The term "alkylene" as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having 1 to 15 carbon atoms. The term "lower alkylene" refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms. Representative examples of alkylene groups include such groups, for example, methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,1-ethylene (-CH (CH3) -), 1,3-propylene ( -CH2CH2CH2), 2, 2-dimethylpropylene (-CH2C (CH3) 2CH2-), and the like. Hydrocarbon chains in alkylene groups The alkylene portion of an alkylene-containing substituent may be optionally interrupted by one or two heterogeneous atoms or heterogeneous groups independently selected from the group consisting of oxygen, -N (R27) - and sulfur, wherein R27 in each occurrence is independently hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl or arylalkyl, wherein two of these heterogeneous atoms or heterogeneous groups are separated by at least one carbon atom. The term "alkylsulfonyl" as used herein, refers to the group having the formula -S02-R78, wherein R78 is an alkyl group. Preferred R78 groups are lower alkyl groups The term "alkylsulfonylamino" as used herein, refers to the group having the formula -S02R77, attached to the parent molecular moiety through an amino- (NH-) bond, wherein R77 is an alkyl group. Preferred R77 groups are lower alkyl groups. The term "alkynyl" as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term "lower alkynyl" refers to straight or branched chain alkynyl radicals containing from 2 to 6 carbon atoms. Representative examples of alkynyl groups include groups such as, for example, acetylenyl, 1-propynyl, 2-prop? nyl, 3-butynyl, 2-pentynyl, 1-butynyl, and the like. The term "alkynylene" as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term "lower alkynylene" refers to a divalent group derived from a straight or branched chain alkynylene group of 2 to 6 carbon atoms. Representative examples of alkynylene groups include groups such as, for example, -CSC-, -C H2-C = C-, -CsC-CH2-, -CH (CH3) -CsC-, and the like. The term "aminoalkyl" as used herein, refers to an alkali radical to which an amino group (-N H2) is attached. . , tJ.-.- & The term "aryl" as used herein, refers to a carbocyclic ring system having 6-10 ring atoms and 1 or 2 aromatic rings. Representative examples of aryl groups They include groups such as, for example, phenyl, naphthyl, tetrah idronaphthyl, indanyl, indenyl, and the like. Aryl groups can be unsubstituted or substituted with 1, 2 or 3 substituents, each independently selected from lower alkyl, halogen, haloalkyl, haloalkoxy, hydroxy, oxo (= 0), hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl , thioalkoxy, amino, alkylamino, alkylsulfonyl, dialkylamino, acylamino, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted arylalkoxy, unsubstituted aryloxy, mercapto, cyano, nitro, carboxy, carboxaldehyde, N H2C (=) -, cycloalkyl, carboxylalkyl , alkylsulfonylamino, unsubstituted heterocyclic, unsubstituted (heterocyclic) alkyl, alkoxy (heterocyclic) unsubstituted, unsubstituted oxy (heterocyclic), and -S03H. Preferred aryl substituents are each independently selected from the group consisting of lower alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkenyloxy, alkoxy, alkoxyalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, alkylsulfonyl, acylamino, cyano and nitro. Examples of substituted aryl include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-methylsulfonylphenyl, and the like. The term "(aryl) alkenyl" refers to an alkenyl group lower one that has an aryl group attached to it. Representative examples of (aryl) alkenyl groups include groups such as, for example, phenylethylene, phenylpropenyl, and the like. The term "(aryl) alkyl" refers to a lower alkyl group having an aryl group attached thereto. Representative examples of (aryl) alkyl groups include groups such as, for example, benzyl and phenylethyl. The term "arylalkoxy" as used herein, refers to the group having the formula, -O-R76, wherein R76 is an arylalkyl group. The term "(aryl) alkynyl" refers to an alkynylene group having an aryl group attached thereto. Representative examples (aryl) alkyne include groups such as, for example, phenylacetylenyl, phenylpropynyl, and the like. The term "aryloxy" as used herein, refers to the group having the formula -O-R72, wherein R72 is an aryl group.

The term "carbamoyl" as used herein, refers to the group having the formula, -C (= 0) -N H2. The term "carboxyalkyl" as used herein, refers to the group having the formula -R64-COOH, wherein R64 is a lower alkylene group. The term "cyanoalkyl" as used herein, refers to an alkyl radical to which a cyano group (-CN) is attached.

The term "cycloalkenyl" as used herein refers to an aliphatic ring system having from 5 to 10 carbon atoms. carbon and 1 or 2 rings containing a double bond in the structure of the ring. Representative examples of the cycloalkenyl group include groups such as, for example, cyclohexene, cyclopentene, norbornene and the like. The cycloalkenyl groups can be unsubstituted or substituted with 1, 2 or 3 substituents independently selected from hydroxy, halogen, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, lower alkenyl and inner alkyl. Preferred substituents are independently selected from lower alkyl, lower alkenyl, haloalkyl, halogen, hydroxy, and alkoxy. The term "(cycloalkenyl) alkenyl" as used herein, refers to a cycloalkenyl group attached to a lower alkenyl radical. Representative examples of (cycloalkenyl) alkenyl groups include groups such as, for example, cyclohexenylethylene, cyclopentenethylene, and the like. The term "(cycloalkenyl) alkyl" as used herein, refers to a cycloalkenyl group attached to a lower alkyl radical. Representative examples of (cycloalkenyl) alkyl groups include groups such as, for example, cycloalkenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, and the like. The term "(cycloalkenyl) alkynyl" as used herein, refers to a cycloalkenyl group attached to a lower alkyl radical. Representative examples of groups ^ ^ * "" - J "3 - ^ -" - '" (c? alkoalkenyl) alkynyl include groups such as, for example, cyclohexenylacetylenyl, cyclopentephylpropynyl, and the like. The term "cycloalkyl" as used herein, refers to an aliphatic ring system having from 3 to 10 carbon atoms and one or two rings Representative cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornane, bicyclo [2.2.2] octane, and the like. Cycloalkyl groups may be unsubstituted or substituted by 1, 2 or 3 substituents independently selected from hydroxy, halogen, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, lower alkenyl and lower alkyl. Preferred substituents are independently selected of lower alkyl, lower alkenyl, haloalkyl, halogen, hydroxy and alkoxy. The term "(cycloalkyl) alkyl" as used herein, refers to a cycloalkyl group attached to a lower alkyl radical. Representative examples of "cycloalkyl" alkyl groups include groups such as, for example, cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl, and the like. The term "(cycloalkyl) alkenyl" as used herein, refers to a cycloalkyl group still attached. lower alkenyl radical. Representative examples of (cycloalkyl) alkenyl groups include groups such as, for example, cyclohexyletheylene, cyclopentylethylene, and if desired. -f ^ "" --- ».» i -,? a? a? The term "(cycloalkyl) alkynyl" as used herein, refers to a cycloalkyl group or a lower alkynyl radical. Representative examples of groups (cycloalkyl) alkynyl include groups such as, for example, cyclohexylacetylenyl, cyclopentylpropynyl, and the like. The term "dialkylamino" as used herein, refers to groups having the formula -N (R90) 2, wherein each R 90 is independently a lower alkyl group. Representative examples of dialkylamino include dimethylamino, diethylamino, N-methyl-N-isopropylamino, and the like. The term "halogen" as used herein refers to F, Cl, Br or I. The term "haloalkenyl" as used herein refers to a lower alkenyl group in which one or more hydrogen atoms is replaced with a halogen. Examples of haloalkenyl groups include 2-fluoroethylene, 1-chloroethylene, 1,2-difluoroethylene, trifluoroethylene, 1,1-trifluoroethylene, and the like.

The term "haloalkoxy" as used herein, refers to the group having the formula -OR69, wherein R69 is a haloalkyl group as defined above. Examples of haloalkoxy include chloromethoxy, fluoromethoxy, dichloromethoxy, trifluoromethoxy, and the like. The term "haloalkyl" as used herein, refers to a lower alkyl group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroetol, pentafluoroethyl, and the like. The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein, refers to any three to four member ring containing a heterogeneous atom selected from oxygen, nitrogen and sulfur; a ring of 5, 6 or 7 members containing 1, 2, 3 or 4 nitrogen atoms; an oxygen atom; a sulfur atom; a nitrogen atom and a sulfur atom; two nitrogen atoms and one sulfur atom; a nitrogen atom and an oxygen atom; two nitrogen atoms and one oxygen atom; two oxygen atoms in non-adjacent positions; an oxygen atom and a sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5-membered ring has 0-2 double bonds and 6-membered and 7-membered rings have 0-3 double bonds. The heterogeneous nitrogen atoms may optionally be quaternized. The term "heterocyclic" also includes bicyclic groups wherein any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or other heterocyclic ring, such as, for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl. , Decahydroquinolyl, Decahydro Isoquinolyl, Benzofuryl, Dihydrobenzofuryl or Benzothienyl, and the like. Heterocyclic groups include, but are not limited to, groups such as, for example, aziridinyl, azetidinyl, epoxide, oxetanyl, - * - ~ - - »- t! thietan yl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazinyl, pi perazinilo, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidine, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, triazolyl, triazolinyl, tetrazolyl, tetrazolinyl, isoxazolyl , 1,2,3-oxadiazolyl, 1,4-oxadiazolyl, 1,4-oxadiazolyl, 1,2,5-oxadiazolyl, oxadiazolinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl , 1,4-thiadiazolyl, 1, 2, 5-thiadiazolyl, thiadiazolinyl, 1,3-dithiolinyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,3-dioxolinyl, didehydrod ioxolanyl, 1,3-oxathiolinyl, oxathiolyl, pyrimidyl, benzothienyl, and the like. Heterocyclic groups also include compounds of the formula: wherein X * is -CH2 or -O- and Y * is -C (O) - or [-C (R9) 2-] v wherein R92 is hydrogen or alkyl of 1 to 4 carbon atoms, wherein is 1, 2 or 3 such as 1, 3-benzodioxoli lo, 1,4-benzodioxanil, and the like.

Heterocyclic groups also include bicyclic alcohols such as quinuclidinyl, and the like. Heterocyclic groups can be unsubstituted or substituted with one to three substituents, each independently selected from lower alkyl, hydroxy, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino. and halogen. In addition, the heterocyclic rings containing nitrogen can be N-protected.

The term "(heterocyclic) alkenyl" as used herein, refers to a heterocyclic group linked to a lower alkenyl radical including, but not limited to pyrrolidinyletenyl, morpholinyl ethenyl, and the like. The term "alkoxy" (heterocyclic) "as used herein, refers to the group having the formula, -OR68, wherein R68 is a (heterocyclic) alkyl group The term" (heterocyclic) alkyl "as used herein, it refers to a heterocyclic group attached to a lower alkyl radical including, but not limited to, pyrrolidinylmethyl, morpholinylmethyl, and the like. The term "alkynyl" (heterocyclic) as used herein, refers to a heterocyclic group linked to a lower alkynyl radical including, but not limited to, pyrrolidinylacetylenyl, morpholinylpropynyl, and the like The term "oxy (heterocyclic)" as used herein, it refers to a heterocyclic group attached to the molecular portion of origin through an oxygen atom (-O-).

The term "protective hydroxy group", "protective hydroxyl group" or "protective -OH group" as used herein, refers to groups used for hydroxy groups against undesirable reactions during synthetic procedures. The commonly used hydroxy protecting groups are described by THG Reene and PGM Wuts, Protective Groups in Organic Svnthesis. 2nd edition, John Wiley & These are s, New York (1991) Said hydroxy protecting groups include methyl ether, substituted methyl ethers, including, but not limited to, methoxymethyl ether, methylthiomethyl, t-butylthiomethyl, (fen? Ld? Met? Ls? L? L) methox Methanol, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methox? pheno?) methyl, t-butoxtmethyl, 2-methoxyethoxymethyl, 2, 2, 2-tr? chloroethoxy? met? 1, 2- (tr? met? l? l?) ethoxy? methyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, and the like, substituted ethyl ethers, including, but not limited to, ether 1-ethoxy? ethyl, 1-methyl-1-methoxy-ethyl, 1-methyl-1-benzyl, et? l, 2,2,2-tr? chloroethyl, methyl, t-butyl and the like, benzyl ether, substituted benzyl ethers, including, but not limited to, p-methoxybenzyl ether, 3,4-d? benzyl, trobenzyl, p-halobenzyl, p-cyanobenzyl, diphenyl methyl, t-phenyl methyl, and the like, silical ethers, including, but not limited to, dimethylsilyl ether, t-phenylsilyl ether. trnsopropylsilyl, dimethylisopropylsilyl, diethyl isopropylsilyl, di-ethylsilyl, p-butyldimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribephenylsilyl, trifluoride, diphenylmethylsilyl, and the like; esters, including, but not limited to, formate ester, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, pivaloate, benzoate, and the like. Preferred hydroxy protecting groups include substituted methyl ethers, benzyl ether, substituted benzyl ethers, silyl ethers and esters. The term "hydroxyalkyl" as used herein, refers to the group having the formula -R65-OH, wherein R65 is an alkylene group. The term "leaving group" as used herein, refers to a group that is easily displaced from the compound through a nucleophile. Examples of leaving groups include a halide (e.g., Cl, Br or I) or a sulfonate (e.g., mesylate, tosylate, triflate, and the like) and the like. The term "N-protecting group" or "N-protected" as used herein, refers to those groups that are intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. . The N-protecting groups commonly used are described by T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Svnthesis, 2nd edition, John Wiley & Sons, New York (1991).

The N-protecting groups comprise acyl groups such as acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2, 4 -dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-tpmethoxybenzylcarbonyl, 1- (p-biphenyl) -1-methylethoxycarbonyl, a, a-dimet? l-3, 5-dimethoxy-benzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, fluorenyl-9- methoxycarbonyl, cid or pentyloxycarbonyl or, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl, and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term "thioalkoxy" as used herein, refers to groups having the formula -SR98, wherein R98 is an alkyl group. Preferred groups R98 are lower alkyl groups. The term "thio-substituted alkyl" as used herein, refers to an alkyl radical which is attached to a thiol group (-SH). As used herein, the terms "S" and "R" configuration are as defined by the recommendations of the 1974 PAC for section E, Fundamental Stereochemistry, Puré Appl. Chem. (1976) 45, 13-30. The compounds of the invention may comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are intended to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, individual enantiomers and diastereomers of the compounds of the invention substantially free of its enantiomers or other diastereomers. By "substantially free" is meant greater than about 80% free of other enantiomers or diastereomers of the compound, most preferably greater than about 90% free of other enantiomers or diastereomers of the compound, yet most preferably greater than about 95% free of other enantiomers or diastereomers of the compounds, and still highly and preferably greater than about 98% free of other enantiomers or diastereomers of the compound, and most preferably greater than about 99% of other enantiomers or diastereomers of the compound. In addition, the compounds comprising the possible geometric isomers of carbon-carbon double bonds and carbon-nitrogen double bonds are also intended to be included in this invention. The individual stereoisomers of this invention can be prepared through any number of methods that are within the knowledge of one skilled in the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers and then chromatographically separating the diastereomers and regeneration of the individual enantiomers, enzymatic resolution, and the like. Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions, which do not cause racemization reversal of stereochemistry at chiral centers. Diastereomeric mixtures of compounds resulting from a synthetic reaction can generally be separated through chromatographic techniques that are well known to those skilled in the art. Chromatographic resolution of enantiomers can be achieved in chiral chromatography resins Chromatography columns Those containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral fixed phase. The enantiomers are then separated through H PLC. The resolution of enantiomers can also be achieved by converting the enantiomers into the mixture of diastereomers through reaction with chiral auxiliaries. The resulting diastereomers can then be separated through column chromatography. This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group which will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries. Once the diastereomers have been separated through chromatography the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again. Enzymes such as esterases, phosphatases and lipases may be useful for the resolution of enantiomer derivatives in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be prepared. Certain enzymes will selectively hydrolyse only one of the enantiomers in the mixture. Then, the resulting enantiomerically pure acid can be prepared from the non-hydrolyzed ester.

In addition, the solvates and hydrates of the compounds of formula I, II, III, IV, V, VI, VII, VIII or X are intended to be included in this invention. When any variable, (for example, R1, R2, R3, m, n, etc.) occurs more than once in any substituent or in the compound of formula I, II, III, IV, V, VI, VII, VIII or X, or any other formula of the present, its definition in each occurrence depends on its definition in each other occurrence. In addition, combinations of substituents are permitted only if such combinations result in stable compounds. Stable compounds are compounds that can be isolated in a useful degree of purity from a reaction mixture. This invention is intended to encompass compounds having the formula I, II, III, IV, V, VI, VII, VIII or X when prepared through synthetic processes or through metabolic processes. The preparation of the compounds of the invention through metabolic processes includes those that exist in the human body or of some animal (in vivo) or processes that occur in vitro. The compounds of the invention can be prepared according to the compounds described in Schemes 1-8 as shown below. Throughout the schemes, methods will be illustrated wherein R1 is a carboxylic acid or carboxylic acid ester substituent.

It will be understood by those skilled in the art that other R substituents can be (a) obtained either by the acid carboxylic acid or a carboxylic acid ester group, (b) introduced by methods similar to those used to introduce carboxylic acid or the carboxylic acid ester group or (c) introduced through other methods generally known in the art. In addition, methods will be illustrated through the schemes wherein R4, R6, R7, R8, R9 and R10 are hydrogens. It will be understood by those skilled in the art that compounds can be prepared wherein one or more of these substituents are not hydrogen, by analogous methods those described in the schemes or by other methods generally known in the art.

In addition, methods for obtaining compounds of the invention having the preferred relative stereochemistry will be illustrated through the schemes. It will be understood by those skilled in the art that compounds of the invention can be prepared by having other relative stereochemistry through methods analogous to those described in the formulas or by other methods generally known in the art. In addition, through the schemes, methods will be illustrated where X is -C (= 0) -N H-. It will be understood by those skilled in the art that other X groups may be prepared by methods analogous to those described in the schemes or by other methods generally known in the art. Compounds of the invention can be prepared according to the procedure described in Scheme 1. It can be prepared N-protected amino acid 1_ (P is an N-protecting group, eg, t-butoxycarbonyl, or the like) through the N-amino acid protection (acid (±) - (2 R, 3S) -2-Amino - B? C? Cio [2.2.1.] Hept-5-en-3-carboxylic, Stajer, G. and others Tetrahedron, 40, 2385 (1984)). The formation of an acid anhydride derivative (e.g., through reaction with ethyl chloroformate or the like), followed by reduction (e.g., with sodium borohydride or the like) provides alcohol 2. The alcohol group is oxidized (for example, through Swern oxidation, or the like) to provide the aldehyde 3. Reductive amination of the aldehyde (for example, with benzylamine and Na (AcO) 3BH or the like) provides the N-protected amine 4 (P2 is an N-protecting group, such as benzyl and the like). A second N-protecting moiety can be introduced to give 5 (P3 is an N-protecting group, eg, benzyloxycarbonyl and the like). Optionally, the mono-protected amino group can be alkylated (e.g., through the reaction with a non-nucleophilic base and an alkyl halide) The bicyclic ring is oxidatively cleaved (for example, with Ru02 and Nal0, or the like) to give a diacid, which is esterified to give the diester. (P4 is a carboxylic acid protective group, for example, lower alkyl, such as ethyl, methyl, or the like). The N-protecting groups P2 and P3 are selectively removed (e.g., through hydrogenation or the like) to provide the amine 7_. The amine 7 can also be functionalized to complete the introduction of the substituent R2-X- (for example, through the reaction of the amine with an acylating agent such as acetic anhydride or the like) to give 8. Removal of the P4 acid protecting groups (e.g., through base hydrolysis) provides the diacid 9 .. The diacid 9 can be monoprotected (for example, by treatment with acetic anhydride, followed by methanol and triethylamine) and the chromatographic separation to give 10 (P5 is a carboxylic acid protective group, for example, lower alkyl or the like). The acid group of 10. can also be transformed to a variety of substituents Y of the compounds of the invention using methods known to those skilled in the art to give U_, followed by N-deprotection, to give compounds of the invention 1_2 As shown in Scheme 2, substituents R3 can be introduced through the reaction of aldehyde 3. with a Grignard reagent (eg, R3MgBr or the like) to give the alcohol 13 .. The oxidation of the alcohol 13. (for example, Swern oxidation or the like) provides the ketone 14. The reductive amination of the ketone 14 (for example, through the reaction with ammonium acetate and sodium cyanoborohydride in methanol, or the like) gives the amine 1_5 . The amine 1_5 can also be functionalized to complete the introduction of the substituent R2-X- (for example, through the reaction of the amine with an acylating agent such as acetic anhydride or the like, or through other acylation methods), followed by chromatographic separation of the diastereomers to give 16a. The other diastereomer (16b) also - - - » it can be isolated and further processed according to the scheme Oxidation of 16a and esterification gives 17. (in a manner analogous to that described in Scheme 1). Also similar to scheme 1, the diacid resulting from hydrolysis of the diester 17 can be selectively protected to give 18., which can then be transformed to the compounds of the invention 19 .. As shown in Scheme 3, the diol 20 is selectively protected (Culbertson, et al., Journal of the American Chemical Society 82, 2541, 2547 (1960)) through the reaction with an equivalent of a hydroxy protecting agent, followed by the reaction with a second agent of Hydroxy protection, to give 21 (P6 is a hydroxy protecting group, eg, acetyl or the like, and P7 is a hydroxy protecting group, eg, benzyl or the like). Oxidation and esterification provide 22 ..

The removal of the protecting group P7, followed by the transformation of the hydroxy group to an amine, which is then N-protected, provides 24. The transformation of 24. in a manner analogous to the transformation from 2 to 12 in the scheme 1 provides the compounds of the invention 27. or 28 .. As shown in Scheme 4, the alcohol 3J_ can be transformed to the compounds of the invention 38. in a manner analogous to the transformation from 13 to 19 in Scheme 2 As shown in Scheme 5, the aldehyde 39 can react with a Grignard reagent to introduce the substituent R3 to give 40. Oxidation (for example, through similar Swern oxidation) provides 41 a, which can be epimerized (for example, with similar sodium methoxide) and 41 b can be obtained through chromatography. Ketone 41 b can be transformed to the compounds of the invention 47 in a manner analogous to the transformation of 14 to 19 in Scheme 2. As shown in Scheme 6, the olefin 48 (P8 is a hydroxy protecting group) is converted to the alcohol 48a (for example, through reaction with a complex of borane-dimethyl sulfide and hydroxide peroxide, or the like) the oxidation of the alcohol to a carboxylic acid, followed by esterification with a carboxylic acid protecting group P6 and the deprotection of the diol, provides 49 .. The selective protection of the primary alcohol with a group of hydroxy P10 gives 50 .. The oxidation of 50. (for example, Swern oxidation or the like) provides the ketone 51. Reductive amination of the ketone 51 (for example, through reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) yields the amine 52 ^ Amine 52. it may be further functionalized to complete the introduction of the substituent R2-X- (for example, through reaction with an acetylating agent such as acetic anhydride or the like, or through other acylation methods), followed by chromatographic separation of the diastereomers to give 53a. The other diastereomeric amide (53b) can also be isolated and further functionalized according to this ski Selective removal of the hydroxy P8 protective group at 53a provides the alcohol 54. The oxidation of the still-aldehyde alcohol (eg, Swern oxidation, or the like) provides 55 .. The aldehyde can serve as a precursor for several Y substituents in the compounds of the invention. For example, olefination of 55 (for example, with Ph3PCH2, or triphenylphosphine / methylene chloride / n-BuLi, or I Ph3P + CH2CH3 / KOtBu, or the like) provides 56, wherein Y is an olefinic substituent. Removal of the hydroxy protecting group P10 gives the alcohol 57 .. The alcohol can serve as a precursor for a variety of R3 substituents in the compounds of the invention. For example, the 57. alcohol can be oxidized to an aldehyde (for example, through Dess-Martin oxidation, or the like) to give 58. The aldehyde 58 can be reacted with Grignard reagents (R14Mg Br or the like) or other organometallic reagents (e.g., organolithium reagents such as R14Li or the like) to provide 59. as a mixture of diastereomers of alcohol, which can be separated chromatographically to provide the major isomer 59a and the other isomer 59b. isomer 59a or mixture of isomer 59. can be oxidized (for example, through Dess-Martin oxidation or the like) to give the ketone 62 .. The reduction of ketone 62. (for example, with sodium borohydride in ethanol or the like) provides alcohol 59b as a major isomer, which can be isolated through chromatography. Hydrolysis with ester provides compounds of the invention 63a or 63b, respectively, wherein Y is an olefinic substituent. The alkylation of alcohol 59a or 59b provides ethers 60a or 60b. respectively. Ester hydrolysis provides compounds of the invention 61 a or 61 b, respectively, wherein Y is an olefinic substituent. As shown in Scheme 7, the reaction of the ketone 62. with Grignard reagents (R37aMg Br or the like) or other organometallic reagents (e.g., organolithium reagents such as R37a or the like) provides the alcohols 64a and 64b as a mixture of alcohol diastereomers, which can be separated chromatographically. Ester hydrolysis provides compounds of the invention 65a or 65b, respectively, wherein Y is an olefinic substituent. The alkylation of the alcohol 64a or 64b provides the ethers 66a or 66b, respectively. Ester hydrolysis provides the compounds of the invention 67a or 67b. respectively, wherein Y is an olefinic substituent. Scheme 8 shows the preparation of the precursor 74. for the compounds of the invention, which are substituted tetrahydrofurans. Alcohol 6_8. is oxidized to a ketone (for example, through Swern oxidation or the like), followed by the oxidation of the olefin to a diol (for example, through treatment with OsO, and N-methylmorpholine N-oxide, or similar) to give 6_9. The diol 6_9 is protected as the acetonide 70.- The oxidation of 70. (by example, with MCPBA or the like) provides the lactone 71 Iodization through the enolate of J? _ provides 7_2 The reaction of 72 with potassium carbonate and methanol provides the ester 73. The reduction of the ester provides the aldehyde 74. The aldehyde provides a functional group through which substituents R3 and R2-X can be introduced. Deprotection of the diol and oxidation of the diol provide functional groups through which the substituents Y and R1 can be introduced. The esters or prodrugs of the compounds of The invention can be prepared by methods known in the art.

SCHEME 1 2 SCHEME 1 (Cont 1 12 J? Tí. -A-ai- SCHEME 2 fifteen SCHEME 2 (Cont.) SCHEME 3 SCHEME 3 (Cont) SCHEME 4 SCHEME 5 41b 42 Four. Five 44 «sai '..

SCHEME 5 (Cont.) 46 47 SCHEME 6 53a 53b SCHEME 6 (Cont.) " 56 And it's an alkene 57 or haloalkene 58 jg¡¡ ^ j? t &^ ^ SCHEME 6 (Cont.) 59a 59b "- ^ fif * -j ' SCHEME 6 (Cont.) 63b SCHEME 7 ate SCHEME 7 (Cont.) SCHEME 8 73 74 The other compounds of the invention can be readily prepared from the compounds available through commercial sources, in the chemical literature or as described herein using techniques well known in the chemical literature. The required procedures are well known and can easily be performed by those skilled in the art.

All patents, patent applications and literature references cited in the specification are incorporated here by ^ ^ ^^^^ reference in its entirety. In the case of inconsistencies, the present description, including definitions, will prevail. The reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, WI, USA); Sigma Chemical Co. (St. Louis, MO, USA); and Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, MA 01835-9953); Eastman Chemical Company (Rochester, New York 14652-3512); Lancaster Synthesis Inc. (Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901); Pfaltz and Bauer (Waterbury, CT 06708). Compounds that are not commercially available can be prepared using methods known from the chemical literature.

The following Examples will serve to further illustrate the preparation of the compounds of the invention, without limitation.

Example 1 Acid (±) - (1S.2S.3 R.4R) -2- (N -Methyl-N -f -buty I oxycarbonyl amine) -3-acetamidomethyl-4-methoxycarbonyl-cyclopentane-1-carboxylic acid 1A. Acid (±) - (2R.3S) -2-Aminobiciclof2.2.1lhept-5-en-3-carboxylic acid.

The title compound was synthesized from norbornadiene through a cycloaddition reaction with isocyanate of chlorosulfonyl followed by reduction and acid hydrolysis as reported by Stajer, G and others Tetrahedron 40, 2385 (1984).

And < ? NHBoc 1 B. Acid (±) - (2R.3S) -2- (f-Butyloxycarbonylamino) bicyclo [2.2.11hept-5-en-3-carboxylic acid. A solution of Acid (±) - (2R, 3S) -2-Aminobicyclo [2.2.1] hept-5-en-3-carboxylic acid (6.3 g, 0.04 mol), NaOH (3.3 g, 0.082 mol), and di-tert-butyl dicarbonate (0.082 mmol) in 200 ml of water was stirred at room temperature for 48 hours. The reaction mixture was acidified using 1 M aqueous HCl, while cooling the solution in an ice / water bath. The reaction mixture was extracted with dichloromethane (3 X 250 ml). The organic layer was dried over MgSO4, filtered and concentrated to provide the title compound as a white solid (yield: 5.6 g, 55%). 1 H NMR (CDCl 3) d 1.44 (s, 9 H), 1.64 (d, 1 H), 2.08 (d, 1 H), 2.58 (m, 1 H), 2 72 (s; 1 H), 2.97 (s) , 1 H), 6.18 (m, 2H), 6.96 (d, 1 H). 1 C. (+) - (2 .3S) -2- (f-Butyloxycarbonyllamino) -3-hydroxylmethylbicyclo-f2.2.1lhept-5-ßno. Ethyl chloroformate (2.3 ml, 23.7 mmol) was slowly added to a solution of (+) - (2R, 3S) -2- (f-Butyloxycarbonyl) laminojb [2. 3-carboxylic acid (6 g, 23.7 mmol) and N-methylmorpholine (2.6 ml, 23.7 mmol) in 110 Ml of THF at -20 ° C. The reaction mixture was heated to 0 ° C., and the slurry reaction was The homogeneous reaction was carried out and the reaction mixture was cooled to -20 ° C. and treated with sodium borohydride (3.7 g, 66 mmol), 10 ml of methanol were added dropwise over 20 minutes. with 1N HCl and the reaction mixture was concentrated through the removal of volatile materials in vacuo The residue was partitioned between ethyl acetate and water.The organic layer was washed with 1 N HCl, water and brine, dried over MgSO 4, it was filtered and concentrated in vacuo, purification through silica gel column chromatography using 15% ethyl acetate / hexanes provided the title compound ( Nation: 4.27 g, 75%). 1 H NMR (CDCl 3) d 1.45 (s, 9 H), 1.52 (m, 2 H), 1.85 (q, 1 H), 2.09 (bs, 1 H), 2.68 (m, 2 H), 3.66 (m, 3H), 4.83 (bs, 1H), 6.11 (m, 1H), 6 27 (m, 1H). c 1D. (± - (2, 3S) -2- (f-Butyloxycarbonylamino) -3-formylbicyclof2.2.phept-5-ene 3.4 ml of DMSO of 5 ml of dichloromethane were added slowly to oxalyl chloride (2 ml, mmoles) in 50 ml dichloromethane -78 ° C. After 5 minutes, (+) - (2R, 3S) -2 - (/ - butyloxycarbonyl) -3-hydroxymethyl-bicyclo [2.2.1] was added. ] hept-5-ene (4.27 g, 17.8 mmol) in 15 ml of dichloromethane and 10 ml of DMSO The stirring was continued for 20 minutes at -78 [deg.] C. The solution was treated with 14 ml of tpetila ina. After 5 minutes, the cooling bath was stirred and the reaction was stirred for a further 30 minutes The reaction mixture was partitioned with 100 ml of water The aqueous layer was extracted with dichloromethane (3 x 50 ml) .The organic layers were combined , washed with brine, dried over MgSO4, filtered and concentrated The crude product was chromatographed on silica gel with 0-10% ethyl acetate / dichloromethane to give the title compound (yield: 3.8 g, 90 %). 1 H NMR (CDCl 3) d 1.43 (s, 9 H), 1.63 (m, 2 H), 2.74 (m, 2 H), 3.11 (s, 1 H), 3.99 (t, 1 H). 4.85 (d, 1H), 6.22 (m, 2H), 9.81 (s, 1H). 1 E. (+) - (2R.3R) -2- (f-Butyloxycarbonylamino) -3-N-benzyl laminomethyl-bicyclo [2.2 Hhept-5-ene. A solution of (±) - (2R, 3S) -2- (f-but? Lox? Carbonylamino) -3-formylbicyclo [2.2.1] hept-5-ene (3.8 g, 16.0 mmol), benzylamine ( 1.9 ml, 17.6 mmol) and 1 ml of acetic acid in 80 ml of dichloromethane was stirred at 0 ° C for 10 minutes followed by the addition of Na (AcO) 3BH (5.09 g, 24 mmol). The reaction mixture was stirred at 0 ° C for 2 hours, then allowed to warm slowly to room temperature for 2 hours. After the end of the reaction mixture was washed with aqueous sodium bicarbonate, dried over MgSO 2, filtered and concentrated. The crude product was purified through silica gel chromatography using 0-2.5% methanol / chloroform to give the title compound (yield: 4.0 g, 77%). 1 H NMR (CDCl 3) d 1.47 (s, 9 H), 1.51 (m, 2 H), 1.78 (t, 1 H), 2.72 (m, 4 H), 3.57 (t, 1 H), 3.78 (s, 1 H), 6.10 ( m, 1H), 6.21 (m, 1H), 7.30 (m, 5H). MS: (M + H = 329. 1 F. (+) - (2R, 3R) -2- (f-Butyloxycarbonylamino) -3- (N-benzyl-N- (b-methyloxycarbonylamino) met? Nbiciclof2.2.11hept-5-ene. of (±) - (2R, 3R) -2- (1-Butyloxycarbon-lamino) -3-N-benzylaminomethylbicyclo- [2.2.1] hept-5-ene (2.8 g, 8.5 mmole) and N- (benzyloxycarbonyloxy) succinimide (2.3 g) in 50 ml of dichloromethane was reacted at room temperature for 6 hours.The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. The product was purified through silica gel chromatography using hexane / ethyl acetate (3: 1) to provide the title compound (yield: 337 g, 85%). H NMR (CDCl 3) d 1.32 (m, 2H ), 1.36 (s, 9H), 1.56 (, 1H), 1 88 (m, 1H), 2.63 (m, 2H), 3.06 (m, 1H), 4.34 (m, 1H), 4.63 (m, 1H) , 5.18 (m, 2H), 6.05 (bs, 2H), 7.28 (m, 11H). 1 G (±) - (2R.3R) -2- (N-Methyl-Nf-butyloxycarbonyllane) -3- (N-benzylN-benzyloxycarbonylamino) methyl-b? C? Clof22 1) hept-5-ene .

Sodium hydride (300 mg, 60% in oil) was added to a solution (+) - (2 R, 3 R) -2- (f- bu tyl oxycarboni lami) -3- (N-benzyl I- - benzyloxycarbonylamino) -methylbicyclo [22.1] hept-5-ene (3.37 g, 7.27 mmol) and 0.9 ml of iodomethane in 60 ml of anhydrous MF at 0 ° C. After 4 hours, the mixture was concentrated in vacuo and purified through silica gel chromatography using hexane / ethyl acetate (4: 1) to provide the title compound (yield: 3.3 g, 95%). 1 H NMR (CDCl 3) d 1.40 (s, 9 H), 1.82 (m, 2 H), 2.26 (m, 1 H), 2.78 (m, 1 H), 285 (m, 1 H), 2.90 (s, 3 H), 2.94 (m, 2H), 3.63 (m, 1H), 4.22 (m, 2H), 534 (s, 2H), 5.60 (m, 2H), 7.15 (m, 10H) MS: (M + H) * = 477 1 HOUR. Dimethyl acid ester (±) - (1S.2S.3R.4R) -2- (N-Methyl-N-f-butyloxycarbonylamino) -3- (N-benzyl-N-benzyloxycarbonylamino) methyl-cyclopentan-1,4-dicarboxylic acid. A mixture of Nal04 (10 g, 47 mmol) and Ru02 (45 mg, 03 mmol) in 25 ml of carbon tetrachloride, 50 ml of acetonitrile and 75 ml of water was stirred rapidly for 30 minutes. A solution of (±) - (2R, 3R) -2- (N-) was added to the bright yellow mixture. methyl-N-f-butyloxycarbonylamino) -3- (N-benzyl-N-benzylox? carbonynylamino) methyl-b? cyclo [2.2.1] hept-5-ene (3.3 g, 6.9 mmoles) in 25 ml of carbon tetrachloride The resulting black mixture was stirred at room temperature for 1.5 hours and diluted with 250 ml of water. The aqueous layer was extracted with ethyl acetate (5 x 200 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate and treated with a solution of diazomethane in ethyl ether. The reaction mixture was concentrated in vacuo, and the crude product was purified through silica gel chromatography using ethyl acetate / hexanes (1: 1) to provide the title compound as a white solid (yield: 1.91 g, 50%) 1 H NMR (CDCl 3) d 1.41 (s, 9 H), 2.21 (m, 2 H), 2.33 (m, 1 H), 2.90 (s, 3 H), 2.92 (m, 2 H), 2.96 (, 1 H) , 3.38 (t, 1H), 3.67 (s, 6H), 4.23 (m, 3H), 5.38 (s, 2H), 7.12 (m, 10H). MS: (M + H) + = 569. 11. Dimethyl acid ester (+) - (1S, 2S, 3R, 4R) -2- (N-Methyl-N-f-Butyloxycarbonylamino) -3-aminomethyl-cyclopentan-1, -dicarboxyl-co.

A mixture of (±) - (1S, 2S, 3R, 4R) -2- (N-Methyl-N-β-Butyloxycarbonylamino) -3- (N-benzyl-N-benzyloxycarbonyl-amino) methyl dimethyl ester Cyclopentane-1,5-dicarboxylic acid (1.91 g 3.36 mmol) and Pd (OH) 2 (380 mg, 20% on carbon) in 50 ml of isopropanol were stirred at room temperature under a nitrogen atmosphere for 16 hours. The catalyst was removed by vacuum filtration through a pad of Celite®, and the filtrate was concentrated in vacuo to provide the title compound (yield: 1.2 g 100%). 1 H NMR (CDCl 3) d 1.48 (s, 9 H), 2.00 (m, 2 H), 2.42 (m, 1 H), 2.64 (m, 2 H), 2.90 (bs, 3 H), 3.00 (m, 2 H), 3.71 ( s, 3H), 3.73 (s, 3H), 4.4 (bs, 1H), 5.4 (bs, 2H). MS: (M + H) + = 345.

U. Dimethyl acid ester (±) - (1S.2S.3R.4R) -2- (N-Methyl-N-r-butyloxycarbonylamino) -3-acetamido-methyl-cyclopentan-1,4-dicarboxylic acid. A solution of dimethyl acid ester (±) - (1S, 2S, 3R, 4R) -2- (N-Methyl-Nf-butyloxycarbonylamino) -3-aminomethylcyclopentan-1,5-dicarboxylic acid (1.2 g, 3.5 mmol), 0.5 ml of acetic anhydride and 1 ml of triethylamine in 25 ml of dichloromethane was stirred at room temperature environment for 2 hours. The reaction mixture was diluted with ethyl acetate and washed successively with 1 N HCl, water and brine, dried over MgSO 4, and concentrated in vacuo. The residue was purified through silica gel chromatography using ethyl acetate. hexanes (1: 1) to provide the title compound (yield: 790 mg, 58%). 1 H NMR (CDCl 3) d 1.45 (s, 9 H), 1.92 (s, 3 H), 2.05 (m, 1 H), 2.40 (m, 1 H), 2.62 (m, 1 H), 2.85 (s, 3 H), 3.1 ( m, 1H), 3.3 (m, 1H), 3.42 (m, 1H), 3.71 (s, 6H), 4.62 (bs, 1H), 6.38 (bs, 1H). MS: (M + H) * = 387 1K Acid (± - (1S.2S.3R, 4R) -2- (N-Methyl-N-butyloxycarbon-lamino) -3-acetates my do-methyl-cyclopen tan-1,4-di carboxylic acid. Dimethyl acid ester (±) - (1S, 2S, 3R, 4R) -2- (N-Methyl-Nf-butyloxycarbonylamino) -3-acetam-domethylcyclopentane-1,5-dicarboxylic acid (720 mg, 1.86 mmoles) and 5 equivalents of lithium hydroxide in 40 ml of methanol and 10 ml of H20 was stirred at room temperature for 2 hours.The solution was concentrated in vacuo.The residue was partitioned between 1N HCl and ethyl acetate. aqueous extract was extracted with ethyl acetate (3 x 50 ml) .The organic layers were Combine and wash with brine, dry over Na 2 SO 4, filter and concentrate in vacuo to provide the title compound (yield: 500 mg, 75%). 1 H NMR (CDCl 3) d 1.45 (s, 9 H), 1.92 (s, 3 H), 2.05 (m, 1 H), 2.40 (m, 1 H), 2.62 (m, 1 H), 2.85 (s, 3 H), 3.1 ( m, 1H), 3.3 (, 1H), 3.42 (m, 1H), 3.71 (s, 6H), 4.62 (bs, 1H), 6.38 (bs, 1H). 1L. Acid (±) - (1S, 2S, 3R, 4R) -2- (N-Methyl-N-butyloxycarbonyl-amino) -3-acetamide-methyl-4-methoxycarbonylcyclopentane-1-carboxylic acid. An acid solution (±) - (1S, 2S, 3R, 4R) -2- (N-Methyl-N-f-butyloxycarbonylamino) -3-acetamidole lcyclopentan-1, 5-carboxylic acid (500 mg, 11.4 mmol), in 5 ml of dichloromethane and 5 ml of acetic anhydride was stirred at room temperature for 2 hours. The solution was concentrated in vacuo at 20 ° C. The residue was dissolved in 10 ml of methanol and 0.2 ml of triethylamine and reacted for 16 hours at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with 100 ml of chloroform and washed successively with 0.1 N HCl and brine. The solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified through silica gel chromatography using chloroform / methanol / acetic acid (97: 2: 1) to provide the title compound (yield: 155 mg, 30%). 1 H NMR (CDCl 3) d 1.47 (s, 9 H), 1.95 (s, 3 H), 2.10 (m, 2 H), 2.43 (m, 1 H), 2.64 (m, 1 H), 2.88 (m, 4 H), 3.20 (m m, 1H), 3.30 (m, 1H), 3.4 (m, 1H), 3.72 (s, 3H), 4.66 (t, 1H), 6.48 (bs, 1H). MS (M + H) + = 373.

Example 2 Acid hydrochloride (±) - (1S.2S, 3R, 4R) -2-N-Methyl-3-acetamidomethyl-4-me toxic rbonylcyclopentanecarboxylic acid. A solution of (±) - (1S, 2S, 3R, 4R) -2- (N-Methyl-N-butyloxycarbonylamino) -3-acetamidomethyl-4-methoxycarbonylcyclopentanecarboxylic acid (130 mg, 0.35 mmol) in 4.5 ml of dichloromethane was reacted with 1.5 ml of trifluoroacetic acid for 1 hour at room temperature. The solution was concentrated in vacuo at 25 ° C. The residue was then treated with 1 N HCl and concentrated in vacuo to provide the title compound as a white solid (yield: 100 mg, 92%). 1 H NMR (D 20) d 202 (s, 3 H), 208 (m, 1 H), 2.54 (m, 2 H), 276 (s, 3 H), 285 (m, '2 H), 3.36 (m, 2 H), 3.76 (s, 3H), 381 (t, 1H) Example 3 Acid (±) - (1S.2S, 3R, 4) -2- (N-Methyl-N-benzyloxycarbon? Lam? -3-acetamidomethyl-4-methoxycarbon? Lcyclopentane-carboxylic acid solution of hydrochloride (±) - (1S, 2S, 3R, 4R) -2-N-methyl-3-acetamidomethyl-4-methoxycarbon-1-cyclopentanecarboxyl? Co (100 mg), N- (benzyloxycarbonyloxy) succinimide (183 mg), and triethylamine (0.160) ml) in 10 ml of dichloromethane was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate and washed successively with 1 N HCl and brine, dried over MgSO 4, and concentrated in vacuo. of silica gel chromatography using chloroform / methanol / acetic acid (9721) to provide the title compound as a white solid.1H NMR (CDCl3) 81.88 (s, 3H), 2.08 (m, 2H), 2.46 ( m, 1H), 2.66 (m, 1H), 2.92 (, 1H), 296 (s, 3H), 3.18 (m, 1H), 3.35 (m, 1H), 3.70 (s, 3H), 464 (bs, 1H), 514 (s, 2H), 629 (bs, 1H), 7.34 (m, 5H).

MS: (M + H) * = 407 Example 4 Acid (±) - (1 S, 2S, 3R.4R) -2- (f-Butyloxycarbonylamino) -3- (acetamido-5-methyl) -4- (methoxycarbonyl) -cyclopentan-1-carboxyl-co.

AcOa ^? X NHBoc 4A. (±) - (2R, 3S) -2-f-But? Loxycarbonylamino? -3-acetoxymethylb? Cycloof2.2.1 l- 10 hept-5-ene. A solution of (±) - (2R, 3S) -2- (f-butyloxycarbonylamino) -3-hydroxymethylbicyclo [2.2.1] hept-5-ene (1.0 g, 4.18 mmol), 0.55 ml of acetic anhydride, 2 ml of triethylamine and N. N-dimethylaminopyridine (catalytic) in 50 ml of dichloromethane was reacted for 2 hours. hours at room temperature. The reaction mixture was diluted with 200 ml of ethyl acetate, washed with 0.5 N HCl, water, saturated sodium bicarbonate and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified through silica gel chromatography using ethyl acetate 10% / hexanes to provide the title compound (yield: .92 g, 78%) MS: (M + H) * = 282 Or HO and? AcO X. BocHNV O 4B. Acid (±) - (1S, 2S, 3S, 4R) -2 - (.- Butyloxycarbonylamino) -3- (acetoxymethyl-p-cyclopentan-1,4-dicarboxylic acid) Ruthenium dioxide hydrate (43 mg, 0.32 mmol) was added to a vigorously stirred mixture of Nal04 (7.12 g, 33 mmol) in 33 ml of acetonitrile, 33 ml of carbon tetrachloride and 58 ml of water The mixture was stirred at room temperature for 5 minutes or until a yellow color was obtained homogeneous A solution of (±) - (2R, 3S) -2- (f-butyloxycarbonylamino) -3-acetoxymethyl-bicyclo [22.1] -hept-5-ene (2.28 g, 8.11 mmoles) in 10 ml of (1: 1) acetonitrile: carbon tetrachloride was added rapidly to the reaction mixture.The mixture was stirred vigorously for 1 hour at room temperature.The reaction mixture was divided between ethyl acetate and 0.5 N HCl The organic layer was washed with brine, dried over Na 2 SO 4, filtered and concentrated to provide the diacid compound, which was used in the next reaction without further purification. ^^ • ¿i - 4C. Acid (±) - (1S, 2S.3S.4R) -2-ff-Butyloxycarbonylamino) -3- (hydroxymethyl) -cyclopentan-1.4-d? carboxylic The crude diacid, (±) - (1S, 2S, 3S, 4R) -2- (f-butyloxycarbonylamino) -3- (acetoxymethyl) -c? Clopentane-1,4-dicarboxylic acid, prepared in Example 4B, and 1.2 g of sodium hydroxide in 45 ml of water was reacted for 6 hours at room temperature. The reaction mixture was acidified to a pH of 1 and extracted with ethyl acetate (3 x 40 ml). The organic layer was washed with brine and dried over Na 2 SO 4, filtered and concentrated. The crude diacid-alcohol was used in the next reaction without further purification. 4D. Dimethyl acid (±) - (1S, 2S, 3S.4R) -2 - (.- Butyloxycarbonylamino) -3- (hydroxymethyl) -cyclopentan-1,4-dicarboxylic ester.

The diacid-alcohol, (+) - (1S, 2S, 3S, 4R) -2- (f-butyloxycarbonylamino) -3- (hydroxymethyl) -cyclopentane-1,5-dicarboxylic acid, prepared in Example 4C, was dissolved in 40 ml of tetrahydrofuran (THF) and reacted with diazomethane in ethyl ether until complete conversion to dimethyl ester. The reaction mixture was checked through TLC, using 10% methanol in chloroform with 1% acetic acid. The reaction was concentrated in vacuo to provide the title compound as a colorless compound (yield: 1.3 g, 85%). MS: (M + H) * = 331.

CH30 -H N3 ^),, OCH3 BocHN 'Y 4E. Dimethyl acid (±) - (1S, 2S, 3S, 4R) -2- (f- Butyloxycarbonylamino) -3- (azidomethyl) -cyclopentan-1,4-dicarboxylic ester.

Methanesulfonyl chloride (1.3 ml, 17.0 mmol) was added slowly to a solution of dimethyl ester of (±) - (1S, 2S, 3S, 4R) -2- (f-bu ti loxycarbonyl) -3- (hydroxymethyl id) -cyclopentane-1,4-dicarboxylic acid (2.76 g, 8.34 mmol) and triethylamine (2.4 ml, 17.0 mmol) in 80 ml of 1: 1 dichloromethane: tetrahydrofuran, maintained at -30 ° C. The reaction mixture was stirred for 2.5 hours at -30 ° C, then diluted with ethyl acetate, washed with 0.1 N HCl and brine, dried over MgSO4, filtered and concentrated in vacuo to provide the crude mesylate. The mesylate and the lithium azide (4 g) were reacted in 30 ml of N, N-dimethylformamide for 1 hour at 90 ° C. The mixture of The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO, filtered and concentrated. The crude product was purified through silica gel chromatography using 20% ethyl acetate in hexanes to provide the title compound, (yield: 1.8 g, 48%). MS- (M + H) * = 373. 4F. Dimethyl acid ester (+) - (1 S.2S .3S. 4 R) -2 - (.- Butyloxycarbonylamino) -3- (acetamidomethyl) -cyclopentan-1,5-dicarboxylic acid. (+) - (1 S, 2S, 3S, 4R) -2- (r-Butyloxycarbonylamino) -3- (azidomethyl) -cyclopentane-1,4-di-carboxylic acid dimethyl ester was reacted for 6 hours. ) (506 mg, 1.42 mmol) and 0.4 ml of thiol acetic acid. The reaction mixture was concentrated in vacuo and the crude product was purified through silica gel chromatography using 3% methanol in chloroform to provide the title compound (yield: 255 mg, 48%). MS- (M + H) * = 373. 4G Acid (±) - (S, 2S, 3S.4 R) -2- (f-Butylox? Carboni lami no) -3- (acetamidomethyl) -cyclopentan-l, 4-dicarboxylic acid. Reaction was carried out at room temperature for 2 hours, dimethyl ester of (+) - (1S, 2S, 3S, 4R) -2- (f- Butyloxycarbonylamino) -3- (acetamidomethyl) -cyclopentan-1,4-dicarboxylic acid ester ( 255 mg, 0.68 mmol) and 2.2 equivalents of lithium in 15 ml of 4: 1 methanohagua. The reaction was acidified with dilute HCl and extracted with ethyl acetate (3 x 60 mL). The organic layers were combined, dried over Na 2 SO 4, filtered and concentrated to provide the title compound. 4H. Acid (±) - (1S.2S, 3S.4R) -2 - (.- Butyloxycarbonylamino) -3- (acetamidomethyl) -4- (methoxycarbonyl) -cyclopentan-1 -carboxylic acid.

The crude diacid acid (±) - (1S, 2S, 3S, 4R) -2- (r-butyloxycarbonyllamino) -3- (acetamidomethyl) -cyclopentan-1,4-dicarboxylic acid, prepared in Example 4G, was made react with 20 ml of acetic anhydride for about 1 hour at 60 ° C to provide the bicyclic anhydride. The reaction mixture was concentrated in vacuo and the crude anhydride was treated with 50 ml of methanol and 2-3 equivalents of triethylamine at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with 0.5 N HCl and brine. The organic solution was dried over Na 2 SO 4, filtered and concentrated. Chromatographic separation of the diastereomers was achieved through silica gel chromatography using 25% ethyl acetate in hexanes and 0.5% acetic acid to provide the title compound (yield: 146 mg, 60%). 1 H NMR (methanol-d 4) d 1.44 (s, 9 H), 1.90 (s, 3 H), 2.04 (m, 1 H), 2.32 (m, 1 H), 2.54 (m, 1 H), 2.72 (m, 2 H), 3.11 (m, 1H), 3.36 (m, 1H), 4.38 (m, 1H), 6.92 (broad d, 1H), 7.8 (broad s, 1H). MS: (M + H) * = 359.

Example 5 (+) - (1S.2S, 3R, 4R -2-Amino-3- (acetamidomethyl) -4- (I) rbonyl-cyclopentane-1-carboxylic acid hydrochloride.

A solution of (±) - (1 S, 2S, 3S, 4R) -2- (f-butyloxycarbonylamino) -3- (acetamidomethyl) -4- (methoxycarbonyl) -cyclopentan-1-carboxylic acid (66 mg, 0.18 mmol) ) in 3 ml of dichloromethane was reacted with 1.0 ml of trifluoroacetic acid for 1 hour at room temperature. The solution was concentrated in vacuo at 25 ° C. The crude product was treated with 1 N HCl and concentrated in vacuo to provide the title compound as a white solid. 1 H NMR (D 20) d 2.01 (s, 3 H), 2.19 (, 1 H), 2.58 (m, 1 H), 2.81 (t, 1 H), 2.95 (m, 1 H), 3.15 (m, 1 H), 3.38 (m , 3H), 3.75 (s, 3H), 4.08 (t, 1H). MS = (M + H) * = 259.

Example 6 Acid (±) - (1S, 2S, 3R, 4R) -3-Acetamidomethyl-2- (N -.-butoxycarbonyl-a) no methyl-4-methoxycarbonyl-cyclopentane-1-carboxylic acid. 6A. (±) -exo-exo-3-Acetoxymethyl-2-benzyloxymethyl-bicyclo [2.2.nhept-5-ene. (±) -exo-exo-2,3-Dihixodroxymethylbicyclo [2.2.1] hept-5-ene (620 mg, 4.0 mmol), prepared according to the procedure described by Culberson, C, et al., Journal of the American Chemical Society 82,2541-2547, (1960), was reacted with sodium hydride (300 mg, 60% oil dispersion) in 10 ml of N, N-dimet? L-formamide (DMF) for 15 minutes at 0 ° C. this was followed by the treatment of the dianion with 0.5 ml of benzyl bromide for 2 more hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude benzylated product was reacted with 0.7 ml of acetic anhydride, 3 ml of triethylamine and N.N-dimethylaminopyridine (catalytic) in 20 ml of dichloromethane at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified through silica gel chromatography using 10% ethyl acetate in hexanes to provide the title compound (yield: 845 g, 74%). 1 H NMR (CDCl 3) d 1.41 (m, 2 H), 1.85 (m, 2 H), 2.05 (s, 3 H), 2.73 (b, 1 H), 2.78 (brs, 1 H), 3.38 (m, 1 H), 357 ( m, 1H), 3.95 (m, 1H), 4.31 (m, 1H), 4.51 (m, 2H), 6.18 (m, 2H), 7.33 (m, 5H). MS: (M + H) * = 287. 6B. Dimethyl acid (±) - (1S, 2S, 3R, 4R) -3-Acetoxymethyl-2-benzyloxymethyl-cyclopentan-1,4-dicarboxylic acid ester A rapidly stirred mixture of Nal04 (10 g) and Ru02 (45 mg) and 25 ml of carbon tetrachloride, 50 ml of acetonitoplo, and 75 ml of water was reacted for 30 minutes. A solution of (+) - (2R, 3S) -2-acetoxymethyl-3-benzyloxymethyl-bicyclo [2.2.1] hept-5-ene (3.3 g, 11.5 mmol) in 25 ml of carbon tetrachloride was added to the bright yellow mixture. The resulting black mixture was stirred for 1.5 hours at room temperature. 250 ml of water was added to the reaction mixture and the aqueous layer was extracted with ethyl acetate (5 x 200 ml). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in ethyl acetate and treated with a solution of diazomethane in ethyl ether. The reaction mixture was concentrated in vacuo and the crude product was purified through silica gel chromatography using ethyl acetate: hexanes (1: 1) to provide the title compound as a white solid (yield: 1.91 g , 44%). 1 H NMR (CDCl 3) d 2.00 (s, 3 H), 2.14 (m, 1 H), 2.34 (m, 1 H), 2.77 (m, 3 H), 2.89 (, 1 H), 3.51 (m, 2 H), 3.67 (s) , 3H), 3.70 (s, 3H), 4.18 (m, 2H), 4.47 (s, 2H), 7.32 (m, 5H). MS: (M + H) * = 379.

~ ASSay ..., 6C. Dimethyl acid (±) - (1S, 2S, 3R, 4R) -3-Acetoxymethyl-2-hydroxy-1-cyclopentan-1,4-di-carboxylic acid ester. A mixture of dimethyl ether of (+) - (1S, 2S, 3R, 4R) -3-α ce toxymethyl-2-benzyl oxim eti Ici cl open tan-1,4-dicarboxílico (3.3 g, 8.72 mmoles) and Palladium (600 mg, 10% carbon) in 100 ml of ethanol was stirred vigorously at room temperature under a hydrogen atmosphere. After completion, as determined through TLC, the reaction mixture was filtered and concentrated in vacuo to provide the title compound (yield: 2.56 g, 100%). 1 H NMR (CDCl 3) d 1.84 (t, 1 H), 2.05 (s, 3 H), 2.16 (m, 1 H), 2.36 (m, 1 H), 2.75 (m, 4 H), 3.70 (s, 3 H), 3.71 ( s, 3H), 3.73 (m, 1H), 4.19 (m, 2H). MS = (M + H) * = 289. 6D. Dimethyl acid ester (±) - (1 S.2 S.3 R.4 R) -3- Acetoxy methyl-2-azidomethylc? Clopentan-1,4-dicarboxyl? Methanesulfonyl chloride (2.1 ml, 26.6 mmol) was added slowly to a solution of dimethyl ester of (±) - (1 S, 2S, 3 R, 4 R) -3-acetoxymethyl-2-hydroxylmethylc-clopentan-1. , 4-dicarboxyl? Co (2.56 g, 8.72 mmol) and triethylamine (3.7 ml, 26.6 mmol) in 100 ml of dichloromethane at -30 ° C. The reaction mixture was stirred for 0.5 hour, then allowed to warm to 0 ° C for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N HCl and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 4.32 g of the crude mesylate. The crude mesylate, prepared above, and lithium azide (4.2 g, 87.2 mmol) were reacted at 90 ° C in 50 ml of N, N-dimethylformamide for 1 hour. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified through silica gel chromatography using silica acetate using 25% ethyl acetate in hexanes to provide the title compound (yield: 2.0 g, 72%). 1 H NMR (CDCl 3) d 2.07 (s, 3 H), 2.17 (m, 1 H), 2.37 (, 1 H), 2.76 (m, 4 H), 3.47 (m, 2 H), 3.71 (s, 3 H), 3.73 (s, 3H), 4.16 (m, 2H). 6E. Dimethyl acid (±) - (1S.2S.3R.4R) -3-Acetoxymethyl-2- (N-f-butoxycarbonylamino) methyl-cyclopentan-1,4-dicarboxylic ester. A mixture of dimethyl ester of (±) - (1S, 2S, 3R, 4R) -3-acetoxymethyl-2-azidomethylcyclopentan-1,4-dicarboxylic acid ester (2.0 g, 6.6 mmole), di-f-butyl dicarbonate ( 3.79 g) and palladium (900 mg, 10% carbon) in 100 ml of ethyl acetate was stirred vigorously at room temperature under a hydrogen atmosphere. After completion, as determined by TLC, the reaction mixture was filtered and concentrated in vacuo. The residue was purified through silica gel chromatography using 50% ethyl acetate in hexanes to give the title compound (yield: 2.3 g, 94%). 1 H NMR (CDCl 3) d 1.43 (s, 9 H), 2.06 (s, 3 H), 2.17 (m, 1 H), 2.35 (m, 1 H), 2.72 (m, 4 H), 3.21 (m, 2 H), 3.70 ( s, 3H), 3.72 (s, 3H), 4.12 (m, 2H), 4.74 (t, 1H). MS = (M + H) * = 388. ,? ái c. \ 6F. Dimethyl acid ester (±) - (1S, 2S.3R, 4R) -2- (N-f-Butoxycarbonylamino) methyl-3-hydroxymethyl-cyclopentan-1,4-dicarboxylic acid. The dimethyl ester of (+) - (1S, 2S, 3R, 4R) -3-Acetoxippethyl-2- (N-butoxycarbonylamino) methylcyclopentan-1,4-dicarboxylic acid (600 mg, 11.55 mmol) was treated with potassium carbonate (catalytic) in 10 ml of methanol at room temperature for 6 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The organic layer was dried over MgSO4, filtered and concentrated to provide the title compound (yield: 510 mg, 95%). 1 H NMR (CDCl 3) d 1.44 (s, 9 H), 2.24 (m, 2 H), 2.59 (, 2 H), 2.77 (m, 2 H), 3.28 (m, 2 H), 3.73 (m, 8 H), 5.04 (t , 1 HOUR). 6G. Dimethyl acid ester (±) - (1 S, 2S, 3R, 4R) -3-Azidomethyl-2- (N-f-butoxycarbonyl) methylcyclopentan-1,4-dicarboxylic acid Methanesulfonyl chloride (0.35 ml) was added slowly, 4.5 mmol) to a solution of dimethyl ester of (±) - (1S.2S, 3 R, 4 R) -2- (N-α-bu toxic rbonylamino) methyl-3-h id roxymethyl-cyclopentan- 1,4-dicarboxylic acid (560 mg, 1.48 mmol) and 0.6 ml of triethylamine in 10 ml of dichloromethane at -30 ° C. The reaction mixture was stirred at -30 ° C for 2 hours, then heated at 0 ° C for 1 hour. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N HCl and brine, dried over MgSO4, filtered and concentrated in vacuo to provide the crude mesylate. The crude mesylate, prepared above, and lithium azide (0.7 g, 14.3 mmol) were reacted at 85 ° C in 10 ml of N, N-dimethylformamide for 1 hour. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO, filtered and concentrated. The crude product was purified through silica gel chromatography using 25% ethyl acetate in hexanes to provide the title compound (yield: 386 mg, 70%). 1 H NMR (CDCl 3) d 1.43 (s, 1 H), 2.26 (m, 2 H), 2.69 (m, 4 H), 3.23 (m, 2 H), 3.46 (m, 2 H), 3.70 (s, 3 H), 3.71 ( s, 3H), 4.74 (bs, 1H). 6H. Dimethyl acid ester (±) - (1S.2S.3R.4R) -3-Acetam-domethyl-2- (N- f- bu toxic rbonylamino) me ti I cyclopentan-1,4-di carboxylic acid. A mixture of (±) - (1S, 2S, 3R, 4R) -3-azidomethyl-2- (N-α-butoxycarbonylamino) methylcyclopentan-1,4-dicarboxylic acid dimethyl ester (386 mg, 1.04 mmol) 0.25 ml of acetic anhydride and palladium (25 mg, 10% on carbon) in 10 ml of ethyl acetate was stirred vigorously at room temperature under a hydrogen atmosphere. After completion, as determined by TLC, the reaction mixture was filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel using 75% ethyl acetate in hexanes to provide the title compound (yield: 238 mg, 58%). 1 H NMR (CDCl 3) d 1.44 (s, 9 H), 1.97 (s, 3 H), 2.27 (m, 2 H), 2.64 (, 2 H), 3.18 (m, 2 H), 3.32 (t, 1 H), 3.71 (s) , 3H), 3.73 (s, 3H), 7.78 (bs, 1H), 6.19 (bs, 1H). MS = (M + H) * = 387. 61. Acid (±) - (1S.2S.3R.4R) -3-Acetam? Domethyl-2- (N-f-butoxycarbonylamino) methyl-4-methoxycarbonylcyclopentane-1-carboxylic acid. Dimethyl ester of (±) - (1S, 2S, 3R, 4R) -3-A ketone midome ti l-2- (N-butoxycarbonylamino) methylcyclopentane-1,4-dicarboxylic acid (232 mg, 0.60 mmoles) with 5 equivalents of lithium hydroxide in 5 ml of methanol: water (4: 1) for 2 hours at room temperature. The reaction mixture was neutralized with 0.1N HCl and partitioned between ethyl acetate and brine. The organic layer was concentrated to provide 194 mg of the crude diacid. The crude diacid (190 mg) prepared above was reacted with 10 ml of acetic anhydride for 3 hours at room temperature. The reaction mixture was concentrated in vacuo, the crude product was treated with 10 ml of methanol and 250 ml of triethylamine for 16 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and 0.1 N HCl. The organic layer was dried over Na2SO4, filtered and concentrated. The diastereomeric mixture of methyl esters (174 mg) was chromatographed on silica gel using (5-10%) of methanol in chloroform and acetic acid (0.5%) to provide the title compound, (yield: 72 mg, 32%) . 1H NMR (CD3OD) d 1.44 (s, 9H), 1.93 (s, 3H), 2.24 (m, 2H), 2.64 (m, 4H), 3.12 (m, 3H), 367 (s, 3H) MS = (M + H) * = 373.

Example 7 Acid hydrochloride (±) - (1S, 2S.3R, 4R) -2-Aminomethyl-3-a ce rhamyl-cyclopentan-1-carboxylic acidic tamidomethyl-4-mene. A solution of (±) - (1S, 2S, 3R, 4R) -3-Acetamidomethyl-2- (N-butoxycarbonylamino) -methyl-4-methoxycarbonylcyclopentane-1-carboxylic acid (62 mg, 0.16 mmol) in 4 ml of dichloromethane was reacted with 1.0 ml of trifluoroacetic acid for 1 hour at room temperature. The solution was concentrated in vacuo at 25 ° C. the residue was treated with 1 N HCl and concentrated in vacuo to provide the title compound as a white solid (yield: 39 mg, 75%). 1 H NMR (D 20) d 1.95 (s, 3 H), 2.22 (m, 1 H), 2.46 (m, 1 H), 2.71 (m, 2 H), i 2.83 (m, 1 H), 2.96 (q, 1 H), 3.10 (m, 2H), 2.31 (m, 2H), 3.72 (s, 3H). MS: (M + H) * = 273.

Example 8 Acid (+) - (1 S.2S, 3, 4R) -2-N-f-Butoxylcarbonylamino-3- (acetamido-methyl) -4-carbamoylcyclopentan-1 -carboxylic acid. 8A. Acid methyl ester (±) - (1 S.2S.3R.4R) -2-N-f- Toxic Bu rbonylamino-3- (acetamidomethyl) -4-carbamoylcyclopentan-1-carboxylic acid. The title compound was prepared in two steps starting by reacting (+) - (1S, 2S, 3R, 4R) -2- (Nf-bu toxic rb onylamino) -3- (acetamidomethyl) -cicl open tan-1 acid. , 4-dicarboxylic acid instead of (+) - (1 S, 2S, 3R, 4R) -2- (1-butoxycarbonylamino) -3- (acetamidomethyl) -cyclopentan-1,4-dicarboxylic acid, according to the described Example in Example 4H, and replacing anhydrous liquid ammonia with methanol and triethylamine.

In the second step, the crude product (54 mg, 0.16 mmol) prepared above, in 4 ml of THF was cooled to 0 ° C and treated with an ethereal solution of CH2N2 until a yellow color persisted in the reaction. The reaction mixture was slowly warmed to room temperature and concentrated in vacuo to provide a colorless oil. Purification using flash chromatography eluting with 5% ethanol / chloroform provided the title compound as a white solid (yield- 16 mg, 28%). 1 H NMR (CDCl 3) d 1.43 (s, 9 H), 1.90 (s, 3 H), 2.03 (m, 1 H), 2.24 (m, 1H), 2.65 (m, 4H), 3.68 (s, 3H), 4.30 (m, 2H) MS: (M + H) * = 358. 8B. Acid (+) - (1S, 2S.3 R.4R) -2- N-f- Butoxy carboni lam i non-3- (acetamidomethyl) -4-carbamoylcyclopentane-1-carboxylic acid. A solution of (+) - (1S, 2S, 3R, 4R) -2-Nf-butoxycarbonylamino-3- (acetamidomethyl) -4-carbamoylcyclopentane-1-carboxylic acid methyl ester (16 mg, 0.045 mmol) in 0.02 ml of methanol / H20 (3: 1) was treated with (1 mg, 0.045 mmol) of LiOH. After stirring at room temperature overnight, the reaction mixture was quenched with 5% HCl and extracted 3 times with ethyl acetate.

The combined extracts were dried over Na2SO, filtered and concentrated in vacuo to provide the title compound as a white solid (yield: 11 mg, 73%). 1 H NMR (methanol-d 4) d 1.44 (s, 9 H), 1.91 (s, 3 H), 2.02 (m, 1 H), 2.24 (m, 1H), 2.60 (m, 5H), 4.32 (m, 1H), 6.90 (br d, 1H). MS (M-H) '= 342.

EXAMPLE 9 Acid (±) - (1S.2S, 3R, 4R) -2, 3- Acetamide omet i-l-4-methoxy bon i cyclope n tan-1 -carboxylic acid. 9A. (±) -exo-exo-2,3-diacetoxymethyl-bicyclo [2.2.1lhept-5-ene. (±) -Exo-Exo-2,3-diacetoxymethyl-bicyclo [2.2.1] hept-5-ene was treated with acetic anhydride and triethylamine in dichloromethane. The standard process provided the title compound. MS: (M + H) * = 329. 9B. Dimethyl acid ester (±) - (1S.2S, 3R.4R) -2.3- Diacetoxymethylcyclopentan-1,4-di carboxylic acid. The title compound was prepared according to the method described in Example 6B, substituting (+) - exo-exo-2,3-diacetoxymethyl-bicyclo [2.2.1] he? T-5-ene instead of (+ ) - (2R, 3S) -2-acetoxy? Methyl-3-benzyloxymethyl-bicyclo [22.1] hept-5-ene. Purification, using flash chromatography eluting with 5% ethyl acetate / hexanes Provided the title compound as a colorless oil (yield: 0.8 g, 58%) 1 H NMR (CDCl 3) d 2.05 (s, 6H), 2.29 (m, 2H), 2.79 ( m, 4H), 3.72 (s, 6H), 414 (m, 4H). MS: (M + H) * = 331. 9C. Dimethyl acid (±) - (1S.2S, 3R, 4R) -2.3-Dihydroxymethylcyclopentan-1,4-dicarboxylic ester. A solution of (±) - (1S, 2S, 3R, 4R) -2,3-diacetoxymethylcyclopentan-1,4-dicarboxylic acid dimethyl ester (5.0 g, 0.015 mmol) in 30 ml of methanol was treated with a catalytic amount of K2C03.

The reaction mixture was stirred under a nitrogen atmosphere, at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and quenched with 5% HCl. The organic layer was separated, dried over Na 2 SO, filtered and concentrated in vacuo at 30 ° C to provide the title compound as a colorless oil (yield: 3.3 g, 89%). 1 H NMR (CDCl 3) d 2.06 (, 1 H), 2.29 (m, 2 H), 2.54 (m, 3 H), 2.80 (m, 2H), 3.67 (, 8H). MS: (M + H) * = 247. 9D. Dimethyl acid ester (±) - (1S.2S.3R.4R) -2.3- Dimethylsulfonyloxymethylcyclopentap-1,4-dicarboxylic acid. A solution of (+) - (1S, 2S, 3R, 4R) -2,3-dihydroxymethylcyclopentane-1,4-dicarboxylic acid (200 mg, 0.81 mmol) in 4 ml of THF and 4 ml of dichloromethane was cooled to -30. ° C and treated with methanesulfonyl chloride (0.19 ml, 2.4 mmol) followed by the dropwise addition of triethylamine (034 ml, 2.4 mmol). After 30 minutes of stirring under a nitrogen atmosphere, at -30 ° C, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo to provide the title compound as a colorless oil (yield: 302 mg, 93%). 1 H NMR (CDCl 3) d 82.16 (, 1 H), 2.45 (m, 1 H), 2.87 (m, 4 H), 3.06 (s, 6 H), 3.72 (s, 6 H), 4.38 (m, 4 H) MS: (M + H) * = 403. - "*" '-'-- 3a -'- il- 9E. Dimethyl acid (±) - (1S.2S, 3R, 4R) -2.3-Diazidomethyl-cyclopentan-1,4-dicarboxylic ester. A solution of dimethyl ester of (±) - (1S, 2S, 3R, 4R) -2,3-dimethanesulfonyloxymethyl chloride tan-1,4-dicarboxylic acid (300 mg, 0.75 mmole) in 3 ml of DMF was treated with LiN3 (400 mg, 8.2 mmol) and heated to 100 ° C under a nitrogen atmosphere. After heating for 1 hour, the reaction mixture was diluted with ethyl acetate and washed twice with water, brine, dried over Na 2 SO, filtered and concentrated in vacuo to provide the title compound as a color oil. copper (yield: 204 mg, 92%). 1 H NMR (CDCl 3) d 32.12 (m, 1 H), 2.37 (m, 1 H), 2.71 (m, 4 H), 3.50 (m, 4 H), 3.72 (m, 6 H). MS: (M + H) * = 297. 9F. Dimethyl acid ester (±) - (1S, 2S.3R, 4R) -2,3-Acetam? Domethyl-cyclopentan-1,4-dicarboxyl? 12.1 A solution of dimethyl ester of (±) - (1S, 2S, 3R, 4R) -2,3-d? Az? Dometyl-c? Clopentan-1,4-d? Carboxyl? Co (145 mg , 049 mmoles) in 2 ml of isopropyl alcohol was treated with Pd / C. The reaction mixture was stirred vigorously overnight under an atmosphere of hydrogen at room temperature. The reaction mixture was filtered over Celite® and concentrated in vacuo to provide a pale yellow oil. The crude product was then taken up in dichloromethane and treated with an excess of acetic anhydride and N, N-dimethylaminopyridine. The reaction mixture was stirred at room temperature for 1 hour before concentrating in vacuo to provide a pale yellow oil. Purification, by flash chromatography eluting with 10% methanol / chloroform provided the title compound as a colorless oil (yield: 40 mg, 25%). 1 H NMR (CDCl 3) d 1.98 (s, 6 H), 2.30 (m, 1 H), 2.36 (m, 1 H), 2.56 (m, 2 H), 2.68 (m, 2 H), 3.30 (m, 4 H), 3.71. (s, 6H), 6.16 (br s, 2H). MS: (M + H) * = 329.

Acid (±) - (1S.2S.3R.4R) -2.3-Acetam? Domethyl-4-methox? Carbonylc? Clopentan-1-carboxyl? Co g.üaf,: -., ...

A solution of dimethyl ester of (±) - (1 S, 2S, 3R, 4R) -2,3-acetamidomethyl-cyclopentan-1,4-dicarboxylic acid ester (100 mg, 0.33 mmol) in 1 ml of a methanol mixture H20 (3.1) was treated with LiOH (16 mg, 0.66 mmol). After stirring for 1 hour at room temperature, the reaction mixture was acidified with 5% HCl and extracted three times with ethyl acetate. The organic extracts were dried with Na 2 SO 4, filtered and concentrated in vacuo to provide the acid as a white solid (69 mg, 70%). The diacid was taken up in 2 ml of acetic anhydride and heated for 1 hour at 60 ° C. the reaction mixture was then concentrated in vacuo, taken up in 1 ml of methanol and triethylamine was treated. The mixture was stirred at room temperature for 3 hours, under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and washed 3 times with 5% HCl. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification, using flash chromatography, eluting with 20% ethyl acetate / hexanes with 1% acetic acid, provided the title compound as a white compound (yield: 6 mg, 6%). 1 H NMR (methanol-d 4) 81.92 (d, J = 3 Hz, 6H), 2.15 (m, 2H), 2.35 (m, 2H), 2.67 (m, 4H), 3.15 (m, 2H), 3.67 ( s, 3H). MS: (M + H) * = 315.

EXAMPLE 10 Acid (±) - (1S, 2S.3R, 4R) -2-N-f-Butoxycarbonylamino-3- (acetamidomethyl) -4-N-methylcarboxamido-cyclopentane-1-carboxylic acid and (+) - (1R.2. 3S.4S) -3-N-f-Butoxycarbonylamino-2- (acetamidomethyl) -4-N-methylcarboxamido-cyclopentane-1-carboxylic acid. 10A. Methyl ester of acid (±) - (1S.2S.3R.4R) -2-N-f-bu toxic rbonylamino-3- (acetamidomethyl) -4-N-m eti Ica rboxamido-cyclopentan-1-carboxylic acid. and (+) - (1R, 2R, 3S, 4S) -3-N-f-butoxycarbonylamino-2- (acetamidomethyl) -4-N-methylcarboxamido-cyclopent tan-1-carboxylic acid methyl ester. A solution of methyl ester of acid (±) - (1S, 2S, 3R, 4R) -2-Nf-butoxycarbonylamino-3- (acetamidomethyl) -4-N-methylcarboxamido-cyclopentane-1-carboxylic acid, and methyl ester of (±) - (1R, 2R, 3S, 4S) -3-N-butoxycarbonylamino-2- (acetamidomethyl) -4-N-methylcarboxamido-cyclopentane-1-carboxylic acid (1: 1) (260 mg, 0.72 mmol) in 3 ml of dichloromethane was treated with one equivalent of hydroxybenzotriazole, 1.5 equivalents of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 5 equivalents of methylamine. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and washed three times with 5% HCl. The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo to provide the title ester-amide compounds as a white solid (yield: 111 mg, 42%). MS: (M + H) * = 372. 10B. Acid (±) - (1S, 2S, 3R.4R) -2-Nf-Butoxycarbonylamino-3- (acetamidomethyl) -4-N-methylcarboxamido-cyclopentan-1-carboxylic acid, and (±) - (1R, 2R, 3S, 4S) -3-N-butoxycarbonyllamino-2- (acetamidomethyl) -4-N-methylcarboxamido-cyclopentane-1-carboxylic acid.

A solution of the ester-amide mixture (125 mg, 0.34 mmol) prepared in Example 10A, in 1 mL of methanol / H20 (3: 1) was treated with LiOH (8 mg, 0.34 mmol). After stirring for 1 hour at room temperature, the reaction mixture was quenched with 5% HCl and extracted 3 times with ethyl acetate. The combined organic extracts were dried over Na 2 SO 4, filtered and concentrated in vacuo to provide the compound of the title as a white solid (yield: 85 mg, 70%). (H NMR (methanol-d4) 81.44 (br d, 18H), 1.91 (d, J = 5 Hz, 6H), 2.00 (m, 2H), 2.20 (m, 2H), 2.60 (m, 6H), 2 72 (br s, 6H), 3.08 (m, 4H), 4 35 (m, 2H). ^ u ^^ íim MS: (M + H) * = 358 Example 11 (±) - (1S.2S, 3R.4R) -3-Acetamidomethyl-2,4-diamino-cyclopentan-1-carboxylic acid hydrochloride 11 A. Acid (±) - (1S, 2S, 3R, 4R) -2-Nr-Butoxycarbonylamino-3- (azidomethyl) -4-methoxycarbonyl-c-clopentane-1-carboxylic acid, v (±) - (1R) acid , 2, 3S, 4S) -2- (r-butyloxycarbonyllamino) -3- (azidomethyl) -1-methoxycarbonyl-cyclopentan-4-carboxyl? Co. The title compound was prepared, in two steps, first by following the procedure described in Example 4G and 4H substituting dimethyl ester of (±) - (1S, 2S, 3R, 4R) -2- (f-butyl oxycarbonylamino) -3- (azidomethyl) -cicl open tan-1, -di carboxylic (98 mg, 0.28 mmol) in place of dimethyl ester of (±) - (1, 2R, 3S, 4S) -2- (f-butyloxycarbonylamino) -3- (azidomethyl) -cyclopentan-1,4-dicarboxylic acid ( yield: 76 mg.79%). MS (M + H) * = 343. 1 1 B Acid methyl ester (±) - (1 S.2S.3S.4R) -2- (t-But? Loxycarbon? Lamino) -3- (azidomethyl) -4-benzyloxycarbonylamino-cyclopentan-1 -carboxylic acid. and methyl ester of acid (±) - (1 R .2 R.3S.4S1-3- (f-buti loxycarboni lami) -2- (azi domethyl) -4-benzyloxycarbonylamino-cyclopentan-1-carboxylic acid. solution (250 mg, 0.73 mmol) of the above mixture of cyclopentane regioisomers of methyl ester azide, prepared in Example 1 1 a, was treated with diphenylphosphoryl azide, in 8 ml of toluene, 0.2 ml of Et3N, and 0.75 ml of benzyl alcohol, under a nitrogen atmosphere and heated at 80 ° C for 3 hours.The reaction mixture was diluted with ethyl acetate and washed 3 times with 5% HCl.The organic layer was dried over Na 2 SO, it was filtered and concentrated in vacuo to provide a pale yellow oil Purification using flash chromatography on silica gel eluting with 20% ethyl acetate / hexanes provided the title compounds (mixture of regioisomers) as a solid white (yield: 278 mg, 85%) MS: (M + H) * = 448. 11 C. Methyl ester of (+) - (1S.2S.3S, 4R) -2- (f-Butyloxycarbonylamino) -3- (acetamido) methyl-4-benzylcarbonylamino-pentyl or pen-1-carboxylic acid ester. A solution of the diastereomers of methyl ester (278 mg, 0.62 mmol), prepared in Example 11B, in 0.2 ml of thiolacetic acid was stirred under a nitrogen atmosphere at room temperature for 6 hours. The reaction mixture was concentrated in vacuo to provide a yellow oil. The crude oil was purified using flash chromatography, eluting with 50% ethyl acetate / hexanes to provide the title compound as a white solid (yield: 70 mg, 24%). MS: (M + H) * = 464. 11D. Acid (±) (1S.2S.3S, 4R) -2- (f-Butyloxycarbonylamino) -3- (acetamido) methyl-4-benzyloxycarbonylamino-cyclopentane-1-carboxylic acid. A solution of methyl ester of acid (±) (1S, 2S, 3S, 4R) -2- (f-Butyloxycarbonylamino) -3- (acetamido) methylene-4-benzylcarbonylamino- Ía.g.fe. ~ .ga..a. c-Clopentane-1-carboxylic acid (70 mg, 0 15 mmol) in 1 mL of methanol / H20 (3 1) was treated with (4 mg, O 15 mmol) of LiOH. After stirring at room temperature for 2 hours, the reaction mixture was quenched with 5% HCl and extracted 3 times with ethyl acetate. The standard process as described above, gave the title compound as a white solid (yield: 51 mg, 76%). MS: (M + H) * = 450. 11E. Acid dihydrochloride (±) -1S, 2S, 3S.4R) -3-Acetamidomethyl-2,4-diamino-cyclopentane-1-carboxylic acid. A solution of acid (±) (1S, 2S, 3S, 4R) -2- (f-butyloxycarbonyl) -3- (to be tested) methyl-4-benzylcarbon and lamino- Cyclopentane-1-carboxylic acid (51 mg, 0.11 mmol) in 0.2 ml of isopropyl alcohol and Pd / C was reacted under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo to provide the title compound as a tan foam (yield: 30 mg, 86%). MS: (M + H) * = 216.

Example 12 Acid (±) - (1R.2R.4R.1'S) -4- (1'-Acetamido-3'et? L) pent? L-3-methoxycarbonyl-c? Clopentane-1-carboxylic acid. 12 A. (±) - (exo.l'RS) v (endo, 1'RS) -2- (3-etl-1-hydroxy) pentivicyclo-f2.2.1lhept-5-ene . 1-Bromo-2-ethyl-butane (12.5 ml) and a catalytic amount of 1,2-dibromoethane were added to a suspension of 2.1 g of Mg rotations in 200 ml of tetrahydrofuran. This mixture was heated at 50 ° C for 2 hours and cooled to -78 ° C. a solution of 5.4 ml of (±) -endo-2-formylbicyclo [2.2.1] hept-5-ene in 75 ml of tetrahydrofuran was added dropwise the Grignard solution. The mixture was heated to 0 ° C and stirred for 1 hour. The reaction was quenched through the addition of 20 ml of saturated ammonium chloride and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and the solvent was evaporated. The crude material was purified by flash chromatography using 10% ethanol: hexanes (1: 9) to provide the title compounds (yield: 4.9 g, 53%). 1 H NMR (CDCl 3) d 0.78-0.91 (, 6H), 1.15-1.50 (m, 11H), 1.70-2.10 (m, 1H), 2.60-295 (m, 2H), 2.95-3.55 (m, 1H), 60-6.2 (m, 2H), MS (M + H) * = 208 12B. (+) - exo and end o-2- (1 '-oxo-3'-ethyl) pentyl-biciclof2.2.11hept-5-ene.

A solution of oxalyl chloride, (2.3 ml) in 100 ml of dichloromethane, maintained at -78 ° C, was treated dropwise with 4.0 ml of dimethyl sulfoxide. The mixture was stirred under nitrogen for 20 minutes and a solution of (±) - (2S, 1'R) and (2S, 1'S) -2- (1'-hydroxy-3'-ethyl) pentyl-bicyclo [2.2] was added. .1] hept-5-ene (4.9 g) in 50 ml of dichloromethane. The mixture was stirred at -78 ° C for 0.5 hours. It was heated at 0 ° C for 15 minutes, treated with 164 ml of triethylamine at 0 ° C and stirred for 10 minutes. 100 ml of water at 25 ° C were added for 10 minutes. The organic layer was separated, washed with brine, dried over MgSO 4, filtered and the solvent was evaporated. The crude ketone mixture was purified by flash chromatography using chloroform: hexanes (1: 3) to provide the products (yield: 3.72 g, 77%). The ketone mixture prepared above (3 1 g, 149 mmol) was dissolved in 50 ml of methanol and combined with 22 ml of 1M sodium methoxide. This mixture was heated at 70 ° C for 18 hours. The solvent was evaporated and the residue was dissolved in 300 ml of ethyl acetate. The organic layer was washed with 100 ml of 05M HCl, brine, dried over magnesium sulfate, filtered and the solvent was evaporated. The ketones were separated through flash chromatography using chloroform: hexanes (1: 3) to provide the title compound (+) (2R) -2- (3-ethyl-1-oxo) pentyl-bicyclo [2.2 .1] hept-5-ene (yield: 0.99 g, exo-ketone) (highest Rf) and (±) (2S) -2- (3-et? L-1-oxo) pentyl-bicyclo [2.2. 1] hept-5-ene (yield: 1.7 g, endo-ketone, 87%). 1 H NMR (CDCl 3) d 0.85 (2t, 6H), 1.19-1.42 (m, 7H), 1.70-1.92 (m, 10 2H), 2.32-2.39 (m, 1H), 2.39-2.47 (2d, 2H), 2.88-2.98 (d, 2H), 6-10-6.17 (m, 2H). 12C. (±) - (2) -2- (1-hydroxyimino-3-ethyl) pentyl-b.cyclo.2.2.1lhept-5-ene A solution of (+) (2R) -2- (1'-oxo-3'ethyl) phenyl-bicyclo [2.2.1] hept-5-ene (1.1 g, 5.4 mmol) in 45 ml of methanol was reacted with hydroxylamine chloride (1.5 g, 21.6 mmol) and 1N Na OH (16.3 ml). This mixture was heated at 40 ° C for 2 days.

The solvent was evaporated and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over MgSO4, filtered and the solvent was evaporated to provide the title compound (yield: 1.26 g, 97%) 1 H NMR (CDCl 3) d 0.87 (2t, 6H), 1.24-1.40 (m, 8H), 1.50 (d, 1H), 1.65 (m, 1H), 1.78 (m, 1H), 2.15 (m, 1H), 2.35 (m, 2H), 2.90 (m, 2H), 6.13 (m, 2H), 2.87 (m, 1H), 3.68 (s, 3H), 3.85 (m, 1H). MS: (M + H) * = 222 12D. (+) - / 2R.1'S) -2- (1-amino-3-ethyl) pentyl-bicyclo (2.2.1) hept-5-ene. (±) - (2R) -2- (1-hydroxyimino-3-ethyl) pentylbicyclo [2.2.1] hept-5-ene (0.49 g, 2.13 mmol), prepared in Example 12C, in 10 ml of toluene , it was treated with 1M lithium aluminum hydride, 4.3 ml of bis (tetrahydrofuran). The mixture was heated at 100 ° C for 2 hours under a nitrogen atmosphere. The mixture was cooled to 0 ° C and consecutively combined with 0.16 ml of water, 15% NaOH (0.16 ml) and 0.49 ml of water. The solids were filtered, and the solution was diluted with 150 ml of ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, filtered and the solvent was evaporated. The crude amines were separated through flash chromatography using ether: methanol: ammonium hydroxide (98: 2: 0.2) to provide the title compound, (±) - (2R, 1'S) -2- (1-amino -3-ethyl) pentylbicyclo [2.2.1] hept-5-ene (yield: 79 mg), and the isomer (±) - (2R, 1 'R) - (77 mg) and 77 mg of a mixture of the amines, total yield 52%. 12E. (±) - (2R. 1'S) -2- (1-Acetamido-3-ethyl-) pentyl-bicichlor.2.2.1lhept-5-ene. (±) - (2R, 1'S-2- (1'-amino-3'-ethyl-) pentyl-bicyclo [2.2.1] hept-5-ene (78 mg, 038 mmol) was dissolved in 3 ml of dichloromethane . to the mixture 0.16 ml of tpetilamina and 0.07 ml of acetic anhydride were added After 1 hour at 25 ° C, the solvent was evaporated and the residue was purified by flash chromatography using ethyl acetate. hexanes (1 : 4) to provide the title compound (yield: 78 mg, 83%) .1H NMR (CDCI3, 300 MHz) d 0.77-0.88 (m, 6H), 1.10-1.57 (m, 11H), 2 02 (s) , 3H), 2.65 (s, 1H), 2.84 (s, 1H), 3.80-3.95 (m, 1H), 5.0-5.15 (m, 1H), 6.05 (s, 2H) MS: (M + H) * * 250 12F. Acid (±) - (1R.3R.4R, 1'S) -4- (1-acetamido-3-ethyl) - pent? lc? clopentan-1.2-d? carbox? l? co A solution of ruthenium tetroxide was prepared from 55 mg of ruthenium dioxide suspended tetrachloride acetonitplo carbon (2 1) and 219 mg of pepodato sodium 3 ml of water The mixture was stirred for 15 minutes at 0 ° C. A solution of (±) - (2R, 1'S) -2- (1'-acetamido-3'-et? L) pent? Lb? C ? clo [222] hept-5-ene (64 mg, 0256 mmoles) in 1 ml of carbon tetrachloride was added to the ruthenium mixture. The reaction mixture was allowed to warm to 25 ° C and was stirred for 3 hours. 2 ml of 1 M sodium bicarbonate and the aqueous layer was separated and acidified with 5 ml of 1 M HCl and extracted with ethyl acetate. The organic layer was filtered through Celite® and the solvents were evaporated in vacuo. The crude mixture was purified by flash chromatography using methane dichloromethane acetic acid (32005) to provide the title compound (yield 50 mg, 62%) 1 H NMR (CD 3 OD) d 078-092 (2 t 6 H), 1 14-1 47 (m 7 H), 1 62-1 75 (m, 1 H), 1 92 (s, 3 H), 1 95-203 (m, 1H), 208-220 (m, 1H), 222-233 (m, 1H) 235249 (m, 1H), 258-268 (m, 1H), 282-294 (m, 1H), 383-395 (m 1H) MS (M + H) * = 314 12G Acid (+) - (1R, 3R.4R.1'S) -4- (1'-acetamido-3'-ethyl) pentyl-3-methoxycarbonyl-cyclopentane-1-carboxylic acid (±) - (1 R) was reacted , 3R, 4R, 1'S) -2- (1-acetamido-3-ethyl) pentilciclopentan-1, 3-dicarboxylic acid with 0.1 ml of acetic anhydride was suspended in 3 ml of chloroform, in a sealed tube and heated to 70 ° C for 3 hours. The solvents were evaporated and the residue was added to 1 ml of metal and 0.1 ml of triethylamine, and heated for 1 hour at 70 ° C. The solvents were evaporated and the crude acid / ester was purified by flash chromatography using ethyl acetate: methanol: acetic acid (97: 2: 1) to provide the acid / ester mixture (yield: 30 mg, 58%). The two isomers were separated through thin layer chromatography of preparation using ethyl acetate: methanol: acetic acid (97: 2: 1) to provide the title compound (yield: 6.9 mg, 13%). 1H NMR (CD3OD, 300 MHz) d 0.83 (2t, 6H), 1.14-1.48 (m, 8H), 1.67 (m, 1H), 1.91 (s ,: 3H), 1.98 (, 1H), 2.11 (m, 1H), 2.25 (m, 1H), 2.42 (m, 1H), 2.62 (m, 1H), 2.92 (m, 1H), 3.68 (s, 3H), 3.89 (m, 1H). MS: (M + H) * = 328 Example 13 Acid (1R, 3R.4R, 1'S) -3-hydroxyethyl-4- (1'-acetamido-3'-et? L) pent? cyclopentane-1-carboxylic 13A Acid methyl ester (±) -1 R.2R.4?) And (+) - (1S.2S.4'S) -2- (2.2-dime ti 1-1.3-dioxolan-4- il) -4- methylenecyclopentane-1-carboxylic acid A solution of methyl 2 - [(trimethylsilyl) methyl] -2-propene-1-yl (5 g, 26.9 mmol), (S) - (+) - 3- ( 2,2-dimet? L-1,3-dioxan-4-yl) -trans-2-propenoate (5 g, 26.9 mmol), Pd (OAc) 2 (0.42 g, 1.8 mmol) and (-PrO) 3P (2 ml, 8 1 mmol) in 27 ml of toluene was heated under an argon atmosphere for 24 hours. The reaction was cooled and concentrated in vacuo. The crude product was chromatographed on silica gel with 5-15% ethyl acetate in hexanes to provide the title compound (yield: 4.68 g, 73%). 1 H NMR (CDCl 3) d 488 (m, 2 H), 4.18-3.95 (m; 2 H), 3.70 (s), 3.69 (s) [3 H, total], 3.68-3.55 (m, 1 H), 2.78-2.29 (m. , 6H), 1.40 (s), 1.38 (s) [3H, total], 1.34 (s), 1.32 (s) [3H, total]. MS: (M + H) * = 241. 13B (1R, 2R.4'S) -2-hydroxymethyl-1- (2,2-dimethyl-1,3-d? Oxolan-4-yl) -4-methylenecyclopentane Lithium aluminum hydride (0.63 g, 16.6 mmol) was added to a solution of (1R, 2R, 4'S) and (1R, 2S, 4'S) -methyl 2- (2,2-dimethyl-1,3-dioxolan-4-yl) -4-methylene-cyclopentan-1-carboxylate (2.0 g, 8.33 mmol) in 40 ml of THF kept at -78 ° C. The reaction mixture was allowed to warm to 0 ° C and was stirred for 1 hour. The reaction was quenched (0 ° C) by sequentially adding H20 (1.9 ml), 10% NaOH (2.8 ml), and H20 (2.8 ml). The reaction was allowed to warm to room temperature, then dried over MgSO4. The reaction was filtered and the solids were washed with 200 ml of ethyl acetate. The filtrate was concentrated in vacuo to provide 1.83 g of the crude product mixture. HPLC preparation on silica gel with ethyl acetate (0-75%) in hexanes provided the title compound (yield: 1.15 g, 65%) 1 H NMR (CDCl 3) d 4.84 (, 2 H), 4.21 (m, 1H), 4.03 (dd, J = 6, 8 Hz, 1H), 3.64 (t, J = 8 Hz, 1H), 3.56 (m, 2H), 2.60-2.05 (m, 6H), 1.44 (s, 3H) ), 1.36 (s, 3H). MS: (M + H) * = 213. 13C (1, 2R, 4'S) -2- (t-butyldiphenylsilyloxymethyl) -1 - (2,2-dimethyl-1,3-dioxolan -yl) -methylenecyclopentane A solution of (1 R, 2R, 4'S ) -2-hydroxymethyl-1- (2,2-dimethyl-1,3-dioxan-4-yl) -4-methylenecyclopentane (1.15 g, 5.4 mmol), t-butyldiphenylsilyl chloride (1.6 ml, 6.8 mmol) and imidazole (1.11 g, 16.3 mmol) in 30 ml of dichloromethane was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with .2 ml of methanol and stirred for 1 hour. The mixture was partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with water and saturated NaHCO 3, dried over MgSO 4, filtered and concentrated to provide the title compound. 1 H NMR (CDCl 3) d 7.65 (m, 4 H), 7.39 (m, 6 H), 4.82 (m, 2 H), 4.00 (m, 1 H), 3.89 (dd, J = 6, 8 Hz, 1 H), 3.62- 3.48 (m, 3H), 2.51-1.98 (m, 6H), 1.37 (s, 3H), 1.31 (s, 3H), 1.05 (s, 9H). MS: (M + H) * = 451. 13D. (1R, 2R.1'S) -2- (t-butyldiphenylsilyloxymethyl) -2- (1,2-dihydroxy) ethyl-4- methylene cyclopentane were heated at 45 ° C for 16 hours (1 R, 2R, 4'S) -2- (t-butyldiphenylsilyloxymethyl) -1- (2,2-d? methyl-1,3-dioxolan-4-yl) - 4-methylene-cyclopentane and pyridinium p-toluenesulfonate (0.68 g, 2.7 mmol) in 110 ml of methanol. The reaction was cooled, concentrated in vacuo and partitioned between dichloromethane and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was chromatographed over that of silica with 15% ethyl acetate in hexanes to provide the title compound and the starting material was recovered (yield 1.2 g, 54%). H NMR (CDCl 3) d 7.65 (m, 4H), 7 39 (m, 6H), 4.81 (m, 2H), 3.75-3.46 (m, 5H), 2.54-1.89 (m, 6H), 1.06 (s, 9H). MS: (M + H) * = 411 13E (1R.2R) -2- (t-butyldiphenylsilyloxymethyl) -1-formyl-4-methylenecyclopentane A solution of (1R, 2R, 1'S) -2- (t-butyldiphenyllysilyloxymethyl) -1- (1, 2-dihydroxy) ethyl-4-methylene cyclopentane (1.2 g, 2.92 mmol), Nal04 (2.5 g, 11.6 mmol) in 4 ml of ethanol and 4 ml of water was stirred at 0 ° C for 4 hours. The reaction was diluted with 90 ml of ethyl ether and filtered through a pad of celite. The filtrate was concentrated to vacuum The crude product was dissolved in toluene and concentrated in vacuo to azeotropically remove the water. The reaction was redissolved in ethyl ether and filtered through followed by concentration to provide the title compound as a crude oil. 1 H NMR (CDCl 3) d 9.68 (d, J = 3 Hz, 1 H), 7.65 (m, 4 H), 7.39 (m, 6 H), 4.87 (, 2 H), 3.68 (dd; J = 5, 10 Hz, 1 H ), 3.56 (dd, J = 7, 10 Hz, 1H), 2.83-2.09 (, 6H), 1.04 (s, 9H). MS: (M + H) * = 379. 13F (1R.2R.1'R) -2- (t-butyldiphenylsilyloxymethyl) -1 - (3-ethyl-1-hydroxy) pentyl-4-ethylene-c-clopentane A solution of 0.9 M bromide of 2 methyl ethylutilus (15.3 ml), prepared from 1-bromo-2-ethylbutane (3.8 ml, 27.1 mmol), magnesium (1 g, 41.6 mmol) and iodine (170 mg) in 30 ml of ethyl ether and stirred for overnight at room temperature, was added to a solution of (1 R, 2R) -2- (t-butyldiphenylsilyloxy-methyl) -1-formyl-4-methylene-cyclopentane (2.92 mmol) in 15 ml of ethyl ether at 0 ° C for 20 minutes The reaction was quenched with saturated ammonium chloride and stirred for 30 minutes. The reaction divided between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, dried and concentrated. The crude product was purified by HPLC on silica gel with ethyl acetate (5-50%) in hexanes to provide the title compound ( yield: 0.7 g, 51%). 1 H NMR (CDCl 3) d 7.65 (m, 4 H), 7.39 (m, 6 H), 4.80 (m, 2 H), 3.79 (m, 1 H), 3.64 (dd, J = 5, 10 Hz, 1 H), 3.56 ( dd, J = 7, 10 Hz, 1H), 2.46-1.9 (m, 6H), 1.5-1.21 (m, 7H), 1.05 (s, 9H), 0.84 (t, J = 8 Hz, 3H), 0.83 (t, J = 8 Hz, 3H). MS: (M + H) * = 465. 13G (, 2R, VS) -1- (t-butyldiphenylsilyloxymethyl) -2- (3-ethyl-1-azido) pentyl-4-methylenecyclopentane A solution of (1R, 2R, 1'R) - 2- (t-butyldiphenylsilyloxymethyl) -1- (3-ethyl-1-hydroxy) pentyl-4-methylene-cyclopentane (0.7 g, 1.51 mmol), mentansulfonyl chloride (.25 ml, 3.23 mmol) and 1 ml of triethylamine in 15 ml of dichloromethane was stirred for 0.5 hours at 0 ° C. The reaction was quenched with 3 mL of a saturated NaHCO 3 solution and then partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with NaHCO 3 and brine, dried on MgSO4, filtered and concentrated in vacuo to provide the mesylate intermediate. A solution of the crude mesylate and sodium azide (1 g, 15.3 mmol) in 15 ml of dimethylformamide was reacted at 65 ° C for 16 hours. The reaction was cooled and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO, filtered and concentrated to provide the title compound. 1 H NMR (CDCl 3) d 7.66 (, 4 H), 7.39 (, 6 H), 4.81 (m, 2 H), 3.64 (dd, J = 6, 10 Hz, 1 H), 3.52 (dd, J = 7, 10 Hz, 1H), 3.22 (m, 1H), 2.58-2.0 10 (m, 6H), 1.48-1.11 (m, 7H), 1.05 (s, 9H), 0.86 (t, J = 7 Hz, 3H), 0 80 (t, J = 7 Hz, 3H). 13H (1R.2R.1'S) -1- (t-butyldiphenylsilyloxymethyl) -2- (1'acetamido-3'-ethyl) pentyl-4-methylenecyclopentane A solution of (1R, 1R, 1'S) -1- (t-butyl? phenylsilyloxymethyl) -2- (3-ethyl-1-azido) pentyl-4-methylene cycloopen crude (about 1.5 mmol), prepared in Example 13G, and triphenylphosphine (1.39 g, .3 mmol) in 20% H20 and in 25 ml of THF was stirred at 75 ° C for 16 hours. The reaction was cooled and concentrated in vacuo to provide the crude amine Amine, .25 ml acetic anhydride and .55 ml of pipdin in 13 ml of dichloromethane were stirred at room temperature for 2 hours. The reaction was quenched with 2 ml of methanol and stirred for an additional 1 hour. The reaction was diluted with ethyl acetate and washed sequentially with 10% citric acid, Saturated NaHC03 and brine, dried over MgSO4, filtered and concentrated. Chromatography on silica gel with 2.5-10% ethyl acetate in dichloromethane provided the title compound (yield: 0.404 g, 60%). 1 H NMR (CDCl 3) d 7.65 (, 4 H), 7.39 (m, 6 H), 4.93 (d, J = 10 Hz, 1 H), 4.77 (m, 2 H), 3.92 (m, 1 H), 3.60 (dd, J = 6, 10 Hz, 1H), 3.52 (dd, J = 6, 10 Hz, 1H), 2,541.83 (m, 6H), 1.71 (s, 3H), 1.40-1.10 (m, 7H), 1.07 ( s, 9H), 0.83 (t, J = 7 Hz, 3H), 0.77 (t, J = 7 Hz, 3H) MS: (M + H) * = 506. 131 (1R.2R.4R.1'S) -1- (t-butyldiphenylsilyloxymethyl) -2- (1'acetamido-3'-ethyl) pentyl-4-hydroxymethyl-cyclopentane A solution of (1R, 2R, 1'S) -1- (t-butyldiphenylsilyloxymethyl) -2- (1'-acetamido-3'ethyl) pentyl-4-methylene-cyclopentane (50 mg, 0.1 mmol) and a 2 M complex of borane-dimethyl sulfide in THF ( 75 uL, 015 mmoles), in 1 ml of THF was stirred at 0o for 7 hours. HE ^ jjjjj ^^^^^^ g ^^ they added 0.1 ml of water and 0.2 ml of 1N NaOH and the reaction was allowed to warm to room temperature. After 15 minutes, 2 ml of 30% hydrogen peroxide was added and the reaction was stirred for 0.5 hour more. The reaction was diluted with ethyl acetate, washed with water (2X) and with brine. The organic layer was dried over MgSO 4, filtered and concentrated in vacuo. The crude product was purified through chromatography using HPLC silica gel preparation using 0-15% ethyl acetate in dichloromethane to provide the title compound (yield: 22 mg, 42%). 1 H NMR (CDCl 3) d 7.65 (m, 4 H), 7.43 (m, 6 H), (m, H), 5.00 (d, J = 10 Hz, 1 H), 3.84 (m, 1 H), 3.66-3.54 (m , 2H), 3.52 (d, J = 7 Hz, 2H), 2.20-1.04 (m, 14H), 1.66 (s, 3H), 1.08 (s, 9H), 0.83 (t, J = 7 Hz, 3H) , 0.78 (t, J = 7 Hz, 3H). MS: (M + H) * = 524. 13J Acid (1R, 3R, 4R, 1'S) -4- (t-butyldiphenylsilyloxymethyl) -4- (1'-acetamido-3'-ethyl) pentyl-cyclopentan-1-carboxylic acid A solution of (1R, 2R, 4R, 1'S) 1- (t-butyldiphenylsilyloxymethyl) -2- (1'-acetamido-3'-ethyl) pentyl-4-hydroxymethyl-cyclopentane (22 mg, 0.042 mmoles) and pipdinium dichromate (100 mg, 0 26 mmol) in 0.75 ml of N, N-dimethylformamide was stirred at room temperature for 48 hours. The mixture was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound, which was used without further purification. 13K Acid (1R, 3R, 4R, 1'S) 3-hydrox? Met? L-4- (1'-acetamido-3'ethyl) pentyl-cyclo? Entan-1-carboxylic acid solution (1R, 3R, 4R, 1'S) 3- (t-butyl-diphenylsilyloxymethyl) -4- (1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylic acid from 1L 1 M of tetrabutylammonium fluoride in 0.8 ml of THF, in 2 ml of THF was stirred for 16 hours at room temperature. The reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The product is chromatographed using a C-18 reverse phase column with 10-25% acetonitrile of water to provide the title compound (yield: 6.6 mg, 52%). 1H NMR (CD3OD) d 7 81 (d, J = 10 Hz, 1H), 3.88 (m, 1H), 3.61 (dd, J = 5, 11Hz, 1H), 338 (dd, J = 8, 11Hz, 1H), 275 (m, 1H), 2.19-1 00 (m, 13H), 1.95 (s, 3H), 087 (t, J = 7 Hz, 3H), 083 (t, J = 7 Hz, 3H) MS: (M + H) * = 300.

Example 14 Acid (1R.3R.4R.1'S) 3-formyl-4- (1'-acetamido-39-ethyl) pentyl-cyclopentane-1-carboxylic acid solution (1R, 3R, 4R, 1'S) - 3-hydroxymethyl-2- (1'-acetamido-3'-ethyl) -pentyl-cyclopentane-1-carboxylic acid (34 mg, 0.11 mmol) and pyridinium dichromate (40 mg, 0.1 mmol) in 1.5 ml of dichloromethane was stirred at room temperature for 0.5 hours. The reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated. The crude product was chromatographed on a C18 column with 10-50% acetonitrile in water to provide the title compound.

Example 15 Acid (1R, 3R, 4R, 1'S) -3 - (? Midazole-2? N-4- (1-acetamido-3-ethyl) penti c? Clopentan-1-carboxyl? Co 15A (1R, 2R.4R.1'S) -1- (t-butyldiphenyl) -lyloxymethyl) -2- (1'-acetamido-3'-ethyl) pentyl-4-triphenylmethyloxymethyl-cyclopentane A solution of (1R, 2R, 4R , 1'S) 1- (t-butyldiphenylsilyloxymethyl) -2- (1-acetamido-3-ethyl) pentyl-4-hydroxymethylcyclopentane (0.357 g, 0.682 mmol) in pyridine (0.165 mL, 2.05 mmol) and 2 mL of dichloromethane was made react with trityl chloride (0.248 g0.89 mmole) and DMAP (16.3 mg, 0 13 mmole) at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgSO, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using metal / 2% dichloromethane to provide the title compound (yield: 0.5 g, 95%). 1 H NMR (CDCl 3) d 7.62 (m, 4H), 7.4 (m, 12H), 7.23 (m, 9H), 3.57 (s, 2H), 2.96 (s, 2H), 2.26 (.1H), 1 97 ( m, 2H), 1.62 (m, 3H), 1.52 (s, 3H), 1 25-1 5 (m, 7H), 1.06 (s, 9H), 083 (br s, 6H) MS (M + Na) * = 788 15B (1R.2R.4R, 1'S) -1-hydroxymethyl-2- (1'-acetamido-3'-ethyl) pentyl-4- (triphenylmethyloxy) methylcyclopentane The title compound was prepared according to the method described in Example 13K substituting (1R, 2R, 4R, 1'S) -1- (t-butyldiphenylsilyloxymethyl) -2- (1'-acetamido-3'-ethyl) pentyl-4- (triphenylmethyloxy) methyl-cyclopentane for acid ( 1R, 3R, 4R, 1'S) -3- (t-butyldif in ylsilyloxymethyl) -4- (1'-acetamido-3'-ethyl) pen ti I-cyclope n tan-1-carboxylic (yield 0.33 g, 98 %). 1 H NMR (CDCl 3) d 7.42 (m, 6 H), 7.26 (m, 9 H), 5.59 (d, 1 H), 3.86 (m, 1H), 3.6 (2d, 1H), 3.42 (2d, 1H), 3.95 (2d, 2H), 2.25 (m, 1H), 1.95 (s, 3H), 1.7-2.02 (m, 2H), 1.5-1.7 (m, 4H), 1.1-1.5 (m, 9H), 0.83 (2t, 6H) MS: (M-H) "= 526, (M + 35)" = 562; (M + Na) * = 550.

OTritilo 15C (1R, 2R, 4R, 1'S) -1-formyl-5- (1'-acetamido-3'-ethyl) pentyl-3- (triphenylmethyloxy) methyl-c-clopentane The title compound was prepared in accordance with the method described in Example 13L substituting (1R, 2R, 4R, 1'S) -1- hydroxymethyl-2- (1'-acetamido-3'-ethyl) pen ti I-4- (trif enyl methyloxy) me useful - cyclopentane by acid (1R, 3R, 4R, 1'S) -3-hydrox? methyl-4- (1'-acetamido-3'-ethyl) pentyl-cyclopentan-1-carboxylic (Yield 0.3 g, 91%). 1 H NMR (CDCl 3) d 9.56 (d, 1 H), 7.42 (m, 6 H), 7.27 (m, 9 H), 5. 13 (d, 1 H), 3.86 (m, 1 H), 2.94 (m, 2 H) , 2.72 (m, 1H), 2.42 (m, 1H), 2.16 (m, 2H), 1.90 (s, 3H), 1.1-1.7 (m, 10H), 0.83 (2t, 6H) MS: (MH) - = 524. 15 15D (1R, 3R, 4R.1'S) -3- (imidazol-2-in-4- (1-acetamido-3-ethyl) pent? L-1- (tnfen? Lmethylox?) Met? L-cyclopentane Reacted (1 R, 3R, 4R, 1'S) -1-form? L-2- (1'-acetamido-3'-et? L) pentyl-4- (tr? Phenylmethyloxy?) Methyl-cyclopentane (80 mg, 0.15 mmole) with ammonia and 40% glyoxal (0.264 ml, 7.5 mmol) in 7 ml of methanol according to the procedure of Rothenberg, A. and others in Angew. Chem. Int Ed. 1983, 22, p. 560 to provide the title compound (yield: 60 mg, 70%). 1 H NMR (CDCl 3) d 7.7 (d, 1 H), 7.42 (m, 7 H), 7.27 (m, 9 H), 5.72 (d, 1 H), 386 (m, 1 H), 3.2 (m, 2 H), 3.08 ( m, 2H), 2.54 (m, 1H), 2.42 (m, 2H), 1 77 (s, 3H), 1.1-1.7 (m, 10H), 0.78 (2t, 6H) MS: (MH) - = 562 , (M + 35) "= 598; (M + H) * = 564, (M + Na) * = 586 15E (1R.3R., 1'S -3- (imidazol-2-yl) -4- (1'-acetamido-3'-ethyl) pentyl-1-hydroxymethyl-cyclopentane Reacted (1 R, 3R, 4R, 1'S) -3- (imidazol-2-yl) -4- (1'-acetamido-3-ethyl) pentyl-1- (triphenylmethyloxy?) Methyl-c? Clopentane (60 mg, 0.106 mmol) with p-acid monohydrate toluene sulfonic acid (61 mg, 0.32 mmol) in MeOH (1 ml) for 1 hour The reaction was quenched with 10 ml of water and diluted with 25 ml of ethyl acetate.The organic layer was washed with water and brine, dried over MgSO4, dried and concentrated in vacuo. through chromatography on silica gel using methanol to the % / dichloromethane to provide the title compound (yield mg, 88%). 1 H NMR (CDCl 3) d 7.83 (d, 1 H), 7.2 (d, 1 H), 6.47 (d, 1 H), 3.86 (, 1H), 3.6 (m, 2H), 3.2 (m, 1H), 2.61 (m, 1H), 2.32 (m, 2H), 1.82 (m, 1H), 1.72 (s, 3H), 1.62 (m, 2H), 1.1-1.4 (m, 7H), 0.78 (2t, 6H) MS: (M-H) '= 320, (M + 35)' = 356; (M + H) * = 322, (M + Na) * = 344. 15F Acid (1R.3R.4R.1 'S) -3- (imidazol-2-yl) -4- (1-acetamido-3-ethyl) pentyl-cyclopentan-1-carboxylic acid The title compound was prepared in accordance with the procedure described in Example 13J substituting (1R, 3R, 4R, 1'S) -3- (imidazol-2-yl) -4- (1-acetamido-3-ethyl) pentyl-1-hydroxymethylcyclopentane for (1R, 2R , 4R, 1'S) -1- (t-butyldiphenylsilyloxymethyl) -2- (1'-acetamido-3'-ethyl) pentyl-4-hydroxymethyl-cyclopentane (yield 5.2 mg, 17%). 1 H NMR (de-MeOH) d 7.12 (br s, 2 H), 3.92 (m, 1 H), 2.95 (m, 1 H), 2.42 (m, 1 H), 2.22 (m, 1 H), 1.96 (m, 1 H) , 1.82 (m, 1H), 1.72 (s, 3H), 1.15- 1.45 (m, 7H), 0.82 (2t, 6H) MS: (MH) '= 334, (M + 35) "= 370; + H) * = 336, (M + Na) * = 358.

Example 16 Acid (1 .3R.4R.1'S) -3- (oxazol-5-yl) -4- (1'-acetamido-3'-et? L) pentyl c? Clopentan-1-carboxylic acid 16A 3- (Oxazol-5-yl) -4- (1'-acetamido-3'-ethyl) pent? Lcclopentan-1-carboxylate of (1R.3R, 4R.1'S) -diphenylmethyl was reacted -formyl-4- (1'-acetamido-3'-ethyl) pentyl-c-clopenta-1-carboxylate of (1R, 3R, 4R, 1'S) -diphenylmethyl with p-toluenesulfonylmethylcyanide following the van procedure Leusen et al. In Tetrahedron Letters, 2369 (1977) to provide the title compound. 16B Acid (1R.3R.4R.1'S) -3- (oxazol-5-yl) -4- (1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylic acid Reacted 3- (oxazol-5? L) -4- (1'-acetamido-3'-et? L) pentyl-cyclopentan-1-carboxylate of (1R, 3R, 4R, 1'S ) - Dissolve it with anhydrous trifluoroacetic acid in a dichloromethane concentration under vacuum to provide the title compound.

Example 17 Acid (1R, 3R, 4R, 1'S) -3- (N, N-dimethylcarbamoyl) -4- (1'-acetamido-3'-ethyl) pentyl-cyclopentan-1-carboxylic acid 17A 3-carboxy-4- (1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate of (1R, 3R, 4R, 1'S) -diphenylmethyl The title compound was prepared according to the procedure described in Example 14J, substituting (1R, 3R, 4R, 1'S) -difenyl methyl-3-hydroxymethyl- - (1'-acetamido-3'-ethyl) pentyl-cyclopentan-1-carboxylate for (1 R, 2R, 4R, 1'S) -1- (t-butyldiphenylsilyloxymethyl) -2- (1'-acetamido-3'-acetamido-3'-ethyl) pentyl-4-hydroxymethyl-cyclopentane. 17B 3- (N, N-dimethylcarbamoyl) -4- (1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate of (1 R.2R.4R.1'S) -diphenylmethyl was reacted -carboxy-4- (1'-acetamido-3'-ethyl) pentyl-cyclopentan-1-carboxylate of (1 R, 3R, 4R, 1'S) -diphenylmethyl with isobutyl chloroformate in the presence of N-methylmorpholine at 0 ° C. The activated ester intermediate was reacted with N, N-dimethylamine to provide the title compound. 17B Acid (1R, 3R, 4R, 1'S) -3- (NN-dimethylcarbamoyl) -4- (1'-acetamido-3'-ethyl) pentyl-cyclopentan-1-carboxylic acid The title compound was prepared according to the procedure described in Example 16B substituting 3- (N, N-dimethylcarbamoyl) -4- (1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate of (1R, 3R, 4R, 1'S) -diphenylmethyl by -3- (imidazol-2-yl) -4- (1'-acetamido-39-ethyl) pentyl-cyclopentan-1-carboxylate of (1R, 3R, 4R, 1'S) -diphenylmethyl EXAMPLE 18 Acid (1R, 3R, 4R, 1'S) -3-propionyl-4- (1'-acetamido-3'-ethyl) pentyl-cyclopentan-1-carboxylic acid 18A 3- (1-hydroxypropyl) -4- (1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate of (1 R.3R.4R.1'S.1'S) - y (1 R.3R, 4R, 1'S, 1"R) -diphenylmethyl 3-Formyl-4- (1'-acetamido-3'-ethyl) phenyl-cyclopentane-1-carboxylate of (1R, 3R, 4R, 1'S) -diphenylmethyl was reacted with ethyl bromide-magnesium at 0 ° C. The reaction was quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic layer was dried over MgSO, filtered and concentrated in vacuo to provide the title compound. 18B 3-propyl-4- (1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylate of (1R.3R.4R, 1'S) -diphenylmethyl The title compound was prepared according to the procedure of Example 12B substituting 3- (1-hydroxypropyl) -4- (1'-a-tamido-3'-ethyl) pentyl-cyclopentan-1-caboxboxylate (1R, 3R, 4R, 1'S, 1"S) - and (1R, 3R, 4R, 1'S, 1" R) diphenylmethanol by (+) - (2S, 1'R) and (2S, 1'S) -2- (3'-ethyl-1'-hydroxy) pentyl-bicyclo [2.2.1] hept-5-ene. 18C Acid (1R.3R.4R.1'S) -3-propionyl-4- (1'-acetamido-3'-ethyl) phenyl-cyclopentane-1-carboxylic acid The title compound was prepared according to the procedure described in Example 16B, substituting 3-propionyl) -4- (1'-ace-tamido-3'-ethyl) pentyl-cyclopentan-1-caboxylate of (1R, 3R, 4R, 1'S) diphenylmethyl 3- (? m? dazol-2-yl) -4- (1'-acetamido-3'- «Fc ^ A ^. ethyl) pen ti l-cyclopentan-1-carboxylate of (1 R, 3R, 4R, 1 's) di-n-methylmethyl EXAMPLE 19 Acid (±) - (2R, 3R. 5R, 1 'S) -2- (1'-Acetamido-3'-metin-butyl-3-methoxycarbonyl-tetrahydrofuran-5-carboxylate) = 0 19A (±) - Bicyclo.2.2. Hhept-5-en-2-one In a three-necked flask equipped with a mechanical stirrer, an N2 inlet and an additional funnel, a solution of oxalyl chloride (2.0 M in dichloromethane, 136 ml, 0.272 mol) in 250 ml of dichloromethane was cooled to -78 ° C and a solution of 40 ml of DMSO in 40 ml of dichloromethane was added dropwise over 30 minutes. After stirring for a further 5 minutes, a solution of 5-norbornen-2-ol (24 g) was added dropwise., 0.218 moles) in 40 ml of dichloromethane. The solution was stirred for a further 10 minutes and 150 ml of triethylamine was added for 40 minutes. The mixture was then stirred for 10 minutes at -78 ° C and allowed to warm to 0 ° C for 1 hour. 250 ml of water was added. After separation of the two layers, the organic layer was washed with 0.2 N HCl (4 x 200 ml) and brine (2 x 200 ml). After drying (MgSO4) the solution was concentrated to approximately 80 ml. The residue was distilled with a 30.48 cm Vigreux column under reduced pressure to give the title compound, bp 100-105 ° C / 15 mmHg (yield 20.1 g, 86%) 1 H NMR (CDCl 3): 1 85 (dd, 1H), 1 90-2.00 (m, 2H), 3.00 ( brs, 1H), 3 20 (bs, 1H), 6.01 (t, 1H), 6.58 (t, 1H).

HO HO ^. fc ^ C 19B (±) -exo, exo-5,6-dihydroxy-cyclo [2.2.11heptan-2-one A solution of (±) -bicyclo [2.2.1] hept-5-en-2-one (10.8 g, 0.1 mmol ) and N-methylmorpholine oxide (12.7 g, 0.12 mol) in 300 ml of 90% THF-water was reacted with an osmium tetroxide solution (2.5 wt.% in t-BuOH, 8.0 ml) for 5 hours at room temperature. The solvents were evaporated and the resulting residue was dried in vacuo. The residue was then taken up in 100 ml of ethyl acetate, dried (MgSO 4) and filtered. The filtrate was passed through a plug of short silica gel, eluting with ethyl acetate. The concentration gave the title compound as a thick oil (14.5 g), which was used directly for the next step. 19C (±) -exo, exo-5,6-dihydrox? Aceton? Da-b? Cycloi2.2.1lheptan-2-one A solution of (±) -exo, exo-56-d? H? Drob? Cycle [2 2 1] heptan-2- ona (14.5 g, crude) in 250 ml of 2,2-dimethoxypropane was cooled to 0 ° C and 125 mg of p-toluenesulfonic acid was added. The solution was stirred for 30 minutes when TLC indicated that the reaction was complete. The solution was loaded onto a column of aluminum oxide (neutral) and eluted with 15-30% ethyl acetate hexane to give the title compound as a white solid (yield: 11.9 g, 65% for two pasps). MS (DCl-NH3): m / z 200 for (M + NH4), base peak. H NMR (CDCl 3): d 1.34 (s, 3H), 1.50 (s, 3H), 1.63-1.74 (m, 2H), 2.12-2.20 (m, 2H), 2.70-2.76 (m, 2H), 4.28 ( d, 1H), 4.34 (d, 1H). 13C NMR (CDCI3): d 21.1, 25.3, 31.2, 39.4, 39.5, 55.3, 76.8, 81.2, 111.2, 214.0. Analysis: C, 0H, O3, cale. 65.92% C, 7.75% H;: was found, 66.01% C, 7.79% H. 19D (±) -exo, exo-6,7-dihydroxyacetonide-2-oxabicyclo.3.2.11octan-3-one To a solution of (+) - exo, exo-5,6-dihydroxyacetonide-bicyclo [2.2.1] heptan-2-one (14.76 g, 0.081 mol) in 500 ml of dichloromethane was added NaHCO3 (13.6 g, 0.16 mol). The mixture was cooled with a water bath and added MCPBA (30.3 g, approximately 60%) for 30 minutes. The solution was then stirred for 2 hours at room temperature and washed with % aqueous Na2S205 (500 ml), a saturated NaHCO3 solution (3 x 200 ml) and brine (3 x 200 ml). The organic solution was then dried (MgSO), filtered and concentrated. The residue was loaded onto a column of aluminum oxide (neutral) for 30 minutes. It was then eluted with 10-25% ethyl acetate in hexane to give the title compound as a white solid (yield: 7.7 g, 50%). MS (DCI-NH3): m / z 216 for (M + NH4) *, base peak. 1 H NMR (CDCl 3): d 1.30 (s, 3H), 1.45 (s, 3H), 1.84 (d, 1H), 2.10-2.20 (m, 1H), 2.48-2.56 (m, 2H), 2.80 (dd, 1H), 4.56 (d, 1H), 4.60 (s, 1H), 4.70 (d, 1H). 13C NMR (CDCI3): 23.79, 25.58, 29.17, 35.97, 36.51, 80.70, 82.49, 82.55, 83.24, 110.83, 167.95. Analysis: C, 0H, 40, cal. 60.59% C, 7.12% H; was found, 60.52% C; 6.97% H. 19E (+) - exo, exo-6,7-dihydrocyacetonide-4-exo-iodo-2-oxabicyclo [3.2.11octan-3-one To a mixture of lithium bis (trimethylsilyl) amide (1.0 M in THF, 32.6 ml) and 60 ml of distilled THF, cooled to -78 ° C, was added a solution of (±) -exo, exo-6,7-dihydroxyacetonide-2-oxabicyclo [3.2.1) octan-3-one ( 5.87 g, 29.6 mmol) in 60 ml of THF for 30 minutes. After stirring for a further 30 minutes, the solution was then cannulated into a flask containing a solution of ^^^^^ iodine (8.3 g, 32.6 mmol) in 60 ml of THF cooled to -78 ° C for 30 minutes. The resulting solution was stirred for a further 10 minutes and quenched with 300 ml of 5% aqueous citric acid. The mixture was then extracted with ethyl acetate (3 x 100 ml). The combined ethyl acetate solution was washed with a 10% aqueous Na2S203 solution (2 x 100 ml) and brine (2 x 100 ml), and dried (MgSO4). After the filtration, the solution was evaporated and the residue was chromatographed on a column of silica gel eluting with 15-25% ethyl acetate in hexane, to give a white crystalline solid (yield: 7.55 g, 79%). MS (DCI-NH3): m / z = 342 for (M + NH4) +, base peak. 'H NMR (CDCl 3): d 1.30 (s, 3H), 1.45 (s, 3H), 1.55 (s, 1H), 2.12-2.20 (m, 1H), 2.42 (d, 1H), 2.80 (m, 1H ), 4.56 (d, 1H), 4.54 (d, 1H), 4.70 (m, 2H). Analysis: C? 0H13IO4, cal. 37.06% C, 4.04% H, 39.15% I; was found, 37.08% C, 3.98% H, 39.55% I.

P CO-, Me 19F 3-exo-carboxylate of (±) -methyl-exo-exo-5,6-dihydroxyacetonide-2-oxa bicyclo f2.2.11hep to a solution of (+) - exo-exo-6,7-dihydroxyacetonide- 4-exo-iodo-2-oxabicyclo [3.2.1] octan-3-one (7.55 g, 23.3 mmol) in 300 ml of methanol (pre-dried with 4Á sieves) was added K2C03 (3.54 g, . 6 mmoles). The mixture was stirred vigorously for 30 minutes. The undissolved potassium carbonate was removed by filtration and the filtrate was concentrated to dryness. The residue was titrated with ethyl acetate several times to complete the extraction of the product (TLC). The ethyl acetate solution was then concentrated and directly chromatographed on a column of silica gel eluting with 10-25% ethyl acetate in hexane, giving 4.96 g of the title compound as a white solid. Yield: 92.0% MS (DCI-NH3): m / z 246 for (M + NH4), base peak. 1 H NMR (CDCl 3): d 1.30 (s, 3 H), 1 45 (s, 3 H), 1.62 (d, 1 H), 1.85 (d, 1 H), 2.82 (s, 1 H), 3.78 (s, 3 H), 3.80 (s, 1H), 4.20 (d, 1H), 4.30 (d, 1H), 4.40 (s, 1H). Analysis: C.iH.ßOs, cale: 57.88% C, 7.07% H; was found: 57.98% C, 7.10% H.

X .0 CHO 19G (±) -exo-3-formyl-exo-exo-5,6-dihydroxyacetonide-2-oxabicycloi2.2.11 hepta no To a well-stirred solution of (±) -methyl-exo exo-3-carboxylate, exo-5, 6-dihydroxyacetonide-2-oxabicyclo [2.2.1] heptan (0.82 g, 362 mmol) in 30 ml of anhydrous dichloromethane at -78 ° C, was added a solution of dibutylaluminum hydride in toluene (1.0 M, 77 ml) dropwise The mixture was then stirred at -78 ° C for 1 hour and quenched with 2 ml of methanol and 15 ml of a saturated aqueous sodium potassium tartrate solution. The mixture was then vigorously stirred and allowed to warm to room temperature for 1 hour. The phases were separated and the aqueous phase was extracted with Et20 (5 x 50 ml). After drying, removal of the compound gave the title compound as an oil (0.8 g) which was used directly for the next step. 1H (±) - (1 'RS) -exo-3- (1'-hydroxy-3'-methyl) butyl-exo, exo-5,6-dihydroxyacetonide-2-oxabicyclof2.2. 1-Heptane To a solution of (±) -exo-3-formyl-exo, exo-5,6-dihydroxyacetonide-2-oxabicyclo [2.2.1] heptane (0.99 g, 5.0 mmol) in 50 ml of anhydrous THF a - At 78 ° C, a solution of isobutylmagnesium chloride (2.0 M in ether, 30 ml) was added dropwise over 30 minutes. The mixture was then allowed to warm to room temperature for 2 hours and quenched with 1 00 ml of a saturated aqueous solution of NH 4 Cl. The solution was then extracted with Et20 (3 x 100 ml). The combined organic layers were washed with brine (3 x 100 ml) and dried. After filtration, evaporation of the solvent gave the title compound as an oil (1 29 g) which was used directly for the next step . 191 (±) -exo-3- (1'-oxo-3'-methyl) buh? To-exo, exo-5,6-dihydroxyacetonide-2-oxabicyclolol.2.2.1 lheptane OR oxalyl chloride solution (2.0 M in dichloromethane, 3.76 ml, 7.3 mmol) was mixed with 10 ml of anhydrous dichloromethane and the solution was cooled to -78 ° C. Then, a solution of 1.06 ml of DMSO in 10 ml of anhydrous dichloromethane was added dropwise. After stirring for 10 minutes, a solution of (±) - (1 'RS) -exo-3- (1'-hydroxy) -3'-methyl) butyl-exo, exo-5,6-dihydroxyacetonide-2-oxabicyclo (2.2) heptane (approximately 1.28 g, 5.0 mmol) in 10 ml of anhydrous dichloromethane was added dropwise, and the solution The mixture was stirred for a further 10 minutes, then 4.3 ml of triethylamine in 10 ml of dichloromethane were added, the mixture was then stirred at -78 ° C for 2 hours and allowed to warm to room temperature, the solution was washed with 100 ml of water. 100 ml of 5% aqueous citric acid, 100 ml of saturated NaHCO 3 and brine, After drying and concentration, the crude material was purified by flash chromatography on a column of silica gel using ethyl acetate-hexane. at 5-20% to give the title compound as a white solid, 0 65 g, 51% for the three steps. (DCI-NH3): m / z 272 for (M + N H4) "base peak.

H NMR (CDCl 3) d 0.84 (dd, 6H), 1:30 (s, 3H), 1.34, 1.38 (bd, 1H), 1 43 (s, 3H), 1.77, 1.82 (dd, 1H), 210- 2.10 (m, 1H), 2.30-2.50 (dq, 2H), 2.86 (s, 1H), 3.62 (s, 1H), 416-4.20 (m, 1H), 4.28-4.32 (bd, 1H), 4.37 ( s, 1H). Analysis: C14H2204, cale. 66.12% C, 8.72% H;, was found, 65.99% C, 8.58% H. 19J ± -exo-3- (1'-exo-3'-methyl) butyl-exo, exo-5,6-dihydroxy-2-oxabicyclo, 2.2.nheptan? (±) -Exo-3- (1'-oxo-3'-methyl) butyl-exo, exo-5,6-dihydroxyacetonide-2-oxabicyclo [2.2.1] heptane (0.64 g, 0.25 mmol) was dissolved in 12.5 ml of methanol and 12.5 ml of 2M HCl. The solution was stirred to 60 ° C for 2.5 hours. After cooling to room temperature, the solution was partially concentrated and then extracted with ethyl acetate (4 x 50 ml). The combined ethyl acetate solution was washed with a saturated NaHCO 3 solution (2 x 50 ml) and brine (2 x 50 ml) and dried. After filtration, the Removal of the solvent gave the title compound as an off-white crystalline solid (yield: 0.53 g, 98.9%). MS (DCI-NH3): m / z 232 for (M + NH4) +, base peak. 1 H NMR (CDCl 3): d 0.92 (dd, 6H), 1.34, 1.44 (bd, 1H), 1 77, 1.82 (dd, 1H), 2.10-2.20 (m, 1H), 2.30-245 (dq, 2H) , 2.65 (d, 1H), 2.74-2.80 f ^ ^^ Z ^. (m, 2H), 3.72 (s, 1 H), 3 94-400 (m, 1 H), 4 00-4 05 (bd, 1 H), 4.24 (s, 1 H). 19K 2- (1'-oxo-3'-methyl) butyltetrahydrofuran-3,5-dicarboxylate of (+) - (2 R. 3R. 5R) -dimethyl. (±) -Exo-3- (1'-oxo-) was dissolved. 3'-methyl) butyl-exo, exo-5,6-dihydroxy-2-oxabicyclo [2.2.1] heptane (0.50 g, 2.3 mmol) in a mixture of 6.5 ml of acetonitrile, 6.5 ml of carbon tetrachloride and ml of water. To this solution was added sodium periodate (2.1 g, 10 mmol) and RuCI3. H20 (10 mg). The solution was stirred at room temperature for 3 hours and filtered to remove the solid. The filtrate was loaded onto a column of silica gel coat, eluted with 5% methanol in ethyl acetate containing 5% acetic acid. The resulting crude diacid (yellow oil, 0.53 g) was dissolved in 25 ml of ethyl acetate. N, N-diisopropylethylamine (1.73 ml, 12 mmol) and methyl iodide (2.98 ml, 46 mmol) were added and the mixture was stirred at 50 ° C for 2 hours. The mixture was filtered to remove the solid and the filtrate was concentrated. The residue was purified by flash chromatography on a column of silica gel eluting with 10-40% ethyl acetate in hexane, giving the title compound as a colorless liquid (0.40).

«« ToS ^ aéaaaa g, 68 0% for two steps) MS (DCI-NH3): m / z 290 for (M + NH4) *, base peak. 1 H NMR (CDCl 3). d 0 92 (d, 3 H, CH 3), 0.93 (d, 3 H, CH 3), 2.19 (m, 1 H, H7), 2.40-2.60 (m, 4H, Hßa, H6b, H3a, H3ll), 330 (m, 1H, H3), 3.75 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 4.65 (dd, 1H, H5), 4 85 (d, 1H, H2). 19L 2- (1'-N-hydroxy-3'-methylbutyl-tetrahydrofuran-3,5-dicarboxylate of (±) -2 (2R, 3R, 5R) -dimethyl A solution of 2- (1'-oxo-3'- methyl) butyl-tetrahydrofuran-3,5-dicarboxylate of (±) - (2R, 3R, 5R) -dimethyl (0.3 g, 1.09 mol), hydroxylamine chloride (0.23 g, 3.3 mmol), diisopropylethylamine (0.57 ml, 3. 3 mmol) and tetrabutylammonium iodide in 10 ml of methanol was stirred at 40 ° C for 2 hours. The solution was concentrated and purified on a 10 g silica gel cartridge, eluting with 30% ethyl acetate in hexane to give the title compound as a mixture of cis and trans oximes. MS (DCI-NH3): m / z 287 (M + H), 305 (M + NH4) *. 1 H NMR (CDCl 3): d 0.95-1.0 (m, 6H), 2.19 (m, 1H), 2.40-2.60 (m, 4H,), 3.45 (m, 1H), 3.65-3.80 (4 s, 6H), 4.50-4.60 (bs, 1H), 4.70 (m, 1H), 5.0 (bs, 1H). 19M 2- (1'-t-Butoxycarbonylamino-3'-methyl) butyl-tetrahydrofuran-3,5-dicarboxylate of + - (2R.3R, 5R, 1'S) and ± - (2R.3R.5R, 1 'R) - dimethyl A solution of 2- (1'-N-hydroxymethyl-3'-methyl) butyl-tetrahydrofuran-3,5-dicarboxylate of (±) - (2R, 3R, 5R) -dimethyl (0.27 g, 0. 94 mmoles) and Boc20 (2.11 ml, 10x) in 70 ml of isopropanol are hydrogenated with Raney nickel at 4 atm of hydrogen for 15 hours.

After concentration of the solution, separation on a column of silica gel with 10% ethyl acetate in hexane gave the isomer (±) - (2R, 3R, 5R, 1'S) (137 mg) and the isomer ( ±) (2R, 3R, 5R, 1R) (176 mg). (±) - (2R, 3R, 5R, 1'S) MS (DCI-NH3): m / z 374, 391, 317, 335. H NMR (CDCI3): 0.9-0.95 (2d, 6H), 1.22-1.31 ( m, 1H), 1.49 (s, 9H), 1.501.55 (, 1H), 1.62-1.75 (m, 1H), 2.40-2.60 (m, 2H), 2.95-3.10 (m, 1H), 3.70 (s, 3H), 3.75 (s, 3H), 4.20 (t, 1H), 4.37 (bd, 1H), 4.60 (dd, 1H). 19N 2- (V-acetamido-3'-met? L) but? L-tetrahydrofuran-3,5-d? Carboxylate of (±) - (2R.3R.5R.1S) -d? methyl A solution of 2- (1'-t-butox? carbonylamino-3'-methyl) but? l-tetrahydrofuran-3,5-dicarboxylate of (±) - (2R, 3R, 5R, 1'S) -dimethyl (40 mg, 0.11 mmol) in 2 ml of 50% trifluoroacetic acid / dichloromethane was stirred at room temperature for 1 hour. The solution was then evaporated to dryness. The residue was dissolved in 0.5 ml of dichloromethane. Acetic anhydride (104 ml, 10.0 eq.) And diisopropylamine (192 ml, 10.0 eq.) Were added. After stirring for 2 hours, the mixture was loaded directly onto a 5 g silica gel cartridge and eluted with 5% ethyl acetate in hexane to give the title compound as a solid (34 mg, 100%). MS (DCI-NH 3): m / z 316 (M + H) +, 333 (M + NH 4) *. 1 H NMR (CDCl 3): d 0.9-0.95 (2d, 6H), 1.25-1.35 (, 1H), 1.50-1.70 (m, 2H), 1.99 (s, 3H), 2.40-2.60 (m, 2H), 2.95 -3.10 (m, 1H), 3.70 (s, 3H), 3.75 (s, 3H), 4.20-4.40 (m, 2H), 460 (dd, 1H), 5.30 (bd, 1H). 190 Acid (+) - (2R.3R.5R.1'S) -2- (1'-Acetamido-3'-methyl) butyl-3-metoxinic rboni l-tet rah id rof uran-5-carboxy I ico A a solution of 2- (1'-acetamido-3'-methyl) butyl-tetrahydrofuran-3,5-dicarboxylate of (±) - (2R, 3R, 5R, 1 'S) -dimethyl (32 mg, 0.1 mmol) 1.0 ml of THF cooled to 0 ° C was added with a solution of LiOH (0 1 M, 10 ml), slowly, dropwise The solution was then stirred for 15 minutes and quenched with 1.0 ml of acetic acid. After extracting with ethyl acetate (3 x 1 ml), the organic solution was dried (MgSO4) and purified on a 5 g silica gel cartridge, eluting with 0-20% methanol / ethyl acetate containing acid. acetic acid at 5%. The product obtained was further purified by recrystallization from ethyl acetate and isopropanol (yield: 22 mg, 71%). HRMS: C? 4H2406N, cale: 302.1604, was found: 302.1592. 1 H NMR (CDCl 3): d 0.9-0.95 (2d, 6H), 1.25-1.35 (, 1H), 1.50-1 70 (m, 2H), 1.99 (s, 3H), 2.40-2.50 (m, 1H), 2.60-2.70 (m, 1H), 2.95-3.10 (m, 1H), 3.70 (s, 3H), 4.10-4.40 (m, 2H), 4.60 (dd, 1H), 5.30 (bd, 1H). The relative stereochemistry was confirmed through the X-ray structure of an individual crystal.

Example 20 20A t-Butyl acid ester (±) - (2R, 3R, 5R, 1'S) -2- (1'-acetamido-3'-me ti I) bu ti I -3- methoxy carbon and I- tetrah id roturan -5- carboxylic acid To a solution of (+) - (2R, 3R, 5R, 1'S) -2- (1'-acetamido-3-methyl) butyl-3-methoxycarbonyltetrahydrofuran-5-carboxylic acid (25 mg, 0.08 mmol) in 1.0 ml of dichloromethane was added a solution of 2.2.2- t-butyl tert-chloroacetimidate (54 mg, 0.24 mmole) in 0 3 ml of cyclohexane. After cooling to 0 ° C, 3 drops of boron trifluoride etherate were added. The mixture was stirred for a further 40 minutes and quenched with 2 ml of a 5% NaHCO 3 solution. After diluting with 10 ml of dichloromethane, the mixture was filtered to remove the insoluble by-product and the organic phase was further washed with a 5% NaHC 3 solution, dried and concentrated. The residue was purified on a cartridge over 5 g silica gel to give the title compound as an oil (26 mg) which was used directly for the next step. 20B (±) - (2R .3R .5R .1 'S) -2- (1'-Acetamido-3'-methyl) butyl-3-carboxy-trahydrofuran-5-carboxylic acid ester (±) - (2R, 3R, 5R, 1 'S) -2- (1'-Acetamido-3'-methyl) bu tyl-3-methoxycarbonyl-tetrah id-5 carboxylic acid (26 mg, 0.073 mmol) in 1.5 ml of TH F was cooled to 0 ° C and a solution of 0.1 N LiOH (0.73 ml) was added. The mixture was allowed to warm to room temperature for 90 minutes, then acidified to a pH of 2-3 with 1 N HCl and extracted with ethyl acetate. The combined ethyl acetate solution was dried and concentrated. He The residue was purified on a 5 g silica gel cartridge to give the title compound (10 mg) as a solid. MS (DCI-NH3): m / z 344 (M + H) *, 361 (M + NH4) *. ? NMR (methanol-d4): d 0.87, 0.89 (d, 3H), 092, 0.94 (d, 3H), 1.35-1.45 (m, 1H), 1.47 (s, 9H), 1.50-1.70 (m, 2H) , 1.92 (s, 3H), 2.30-2.37 (m, 1H), 2.45255 (m, 1H), 2.90-2.97 (m, 1H), 4.00-4.07 (m, 1H), 4.20 (t, 1H), 4.45 (dd, 1H). 20C (±) - (2R, 3R, 5R, 1'S) -2- (1'-Acetamido-3'-methyl) butyl-3- (1'-oxo-s "-bromo) ethyl ester -tetrah? drofuran-5-carboxylic acid To a solution of (±) -methyl (2R, 3R, 5R, 1'S) -2- (1'-acetamido-3'-methyl) butyl-3-t-butyl ester. carboxyl-tetrahydrofuran-5-carboxylic acid (10 mg, 0.29 mmol) in 1.0 ml of THF cooled to 0 ° C, 0.13 ml of N-methyl morpholine and so-butyl chloroformate (0.15 ml, 0.12 mmol) were added. The mixture was stirred at 0 ° C for 1 hour, then a solution of diazomethane generated from Diazald (0.21 g, 1.0 mmol) and KOH (0.8 g) in 2 ml of Et2Of was added through a syringe until it persisted A yellow color The solution was then stirred for 3 hours, washed with brine (2 x 2.0 ml) and dried (MgSO 4). Evaporation of the solvent gave a yellow solid, which turned Dissolve in 5 ml of dioxane. To this solution was added a solution of 48% H Br (aqueous) (0.125 ml) and the mixture was stirred for 10 minutes. A solution of saturated NaHC03 (0.5 ml) was then added slowly and the mixture was extracted with ethyl acetate (5 x 1.0 ml). The combined ethyl acetate solution was dried (MgSO 4), filtered and concentrated. Chromatography on a 5 g silica gel cartridge, eluting with 60% ethyl acetate-hexane, gave the title compound (7.3 mg) as a solid which was used directly for the next pasp. 20D Acid t-butyl ester, ±) - (2 R, 3S.5R .1 S) -2- (1'-acetamido-3'-methyDbu ti l -3- (imidazol-4-yl) -te trahydrofuran-5-carboxylic acid To a flask containing t-butyl ether of (±) - (2 R, 3R, 5R, 1 'S) -2- (1'-acetamido-3'-methyl) butyl-3- ( 1 '-oxo-2"-bromo) ethyl-tetrahydrofuran-5-carboxylic acid (7 mg, 0.014 mmol) and formamidine acetate (30 mg, excess) were added with approximately 2.0 ml of liquid ammonia. The mixture was stirred at 45 ° C overnight, the ammonia was allowed to evaporate slowly, the residue was taken up in 5% Na 2 CO 3 (aqueous, 10 ml) and extracted with ethyl acetate (4 x 1.0 ml).

The combined ethyl acetate was dried and concentrated. The residue was chromatographed on a 2 g silica gel cartridge eluting with ethyl acetate to give the title compound as a solid (10 mg). MS (APCI +): m / z 366 (M + H) *, 310 (M-C4H9) +, base peak. H NMR (methanol-d4): d 0.87, 0.89 (d, 3H), 0.95, 0.97 (d, 3H), 1.27-1.37 (m, 1H), 1.47 (s, 9H), 1.42-1.87 (m, 2H ), 1.84 (s, 3H), 2.10-2.17 (dt, 1H), 2.772.87 (dt, 1H), 3.50 (q, 1H), 402-4.06 (m, 1H), 4.16 (t, 1H), 4.55 (t, 1H), 7.34 (s, 1H), 8.64 (s, 1H). 20E Acid (+) - (2R, 3S.5R, 1'S) -2- (1'-Acetamido-3'-methyl) butyl-3- (imidazol-4-yl) -tetrahydrofuran-5-carboxylic ester solution acid t-butyl (±) - (2R, 3S, 5R, 1'S) -2- (1'-Acetamido-3'-methyl) butyl-3- (i idazol-4-yl) -tetrahydrofuran-5-carboxylic acid (1.0 mg) in 1.0 ml of 6N aqueous HCl was stirred for 1 hour. The solution was then concentrated to give the title compound as a white solid (0.8 mg). 1H NMR (D20): d 0.81, 083 (d, 3H), 087, 0.89 (d, 3H), 1.30-1.58 (m, 4H), 1 84 (s, 3H), 2 10-222 (, 1H) , 285-295 (m, 1H), 3.58 (q, 1H), ifcj =., .rlfe. 3. 90 = 3 94 (m, 1H), 400-4 04 (m, 1H), 4.20 (t, 1H), 7 32 (s, 1H), 8.64 (s, 1H) EXAMPLE 21 Acid (1S, 3R, 4S, 1'S) -3- (1'-acetamido-3'-ethyl) phenyl) -4-vinyl-cyclopentane-1-carboxylic acid 21A (1S.3R.4S.1'S) -3- (1'-acetamido-3'-ethyl) -pent? L-1- (triphenylmethyloxy) methyl-4-vinyl-cyclopentane A solution of (1 R, 2R, 4R, 1'S) -1-formyl-2- (1'-acetamido-3'-et? L) phenyl-4- (triphenylmethyloxy) methyl-cyclopentane (60 mg, 0.11 mmole) prepared according to the method of Example 15C in 1 ml of THF was added to a mixture prepared from the reaction of methyltriphenylphosphonium iodide (69 mg, 0.17 mmol) and 2.5 M n-BuLi / hexane (64 mg). mg, 0.16 mmol) in 1 ml of THF for 2 hours at room temperature. After 1.5 hours, the reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 3% methanol / dichloromethane to provide the title compound (yield 29 mg, 49%).

TO - 1 H NMR (CDCl 3) d 7.52 (m, 6 H), 7.24 (m, 9 H), 564 (m, 1 H), 4.84- 5 04 (m, 3 H), 3.98 (m, 1 H), 2.95 (m, 2 H) , 2 7 (m, 2H), 2.0 (m, 1H), 1 88 (m, 2H), 1.66 (m, 1H), 1.56 (s, 3H), 1.1-1.5 (m, 9H), 0.83 (m, 6H). MS: (M-H) - = 522, (M + 35) - = 558; (M + Na) * = 546. 21 B (1S.3R.4S.1'S) -3-vinyl-4- (1-acetamido-3-ethyl) phenyl-1-hydroxyethyl-cyclopentane The title compound was prepared according to the method described in Example 15E substituting (1S, 3R, 4S, 1'S) -3- (1-acetamido-3-ethyl) phenyl-1- (triphenylmethyloxy) methyl-4-vinyl-cyclopentane for (1R, 3R, 4R, 1'S) - 3- (im-idazol-2-yl) -4- (1'-acetamido) -4- (1'-acetamido-3'-ethyl) pentyl-1- (triphenylmethyloxy) methyl-cyclopentane (yield: 7 mg , 87%). H NMR (CDCl 3) d 5.68 (m, 1H), 4.84-5.05 (m, 3H), 3 98 (m, 1H), 3.54 (2d, 2H), 2.4 (m, 1H), 2.18 (, 1H), 1.92 (s, 3H), 1.1-1.5 (m, 10H), 0.83 (2t, 6H). MS: (M + H) * = 282, (M + 18) * = 299 21C Acide (1S, 3R.4S, 1'S) -3- (1-Acetamido-3-ethyl) -pentyl-4-vinyl-cyclopentane-1-carboxylic acid The title compound was prepared according to the procedure described in Example 13J substituting (1S, 3R, 4S, 1'S) -3- (1-acetamido-3-ethyl) pentyl-1-hydroxymethyl-4-vi or I-penty for (1R, 2R, 4R, 1'S) -1- (t-butyldiphenylsilyloxyethyl) -2- (1'-acetamido-3'-ethyl) phenyl-4-hydroxyethyl-butyldiphenylsilyloxymethyl) -2- (1'-acetamido-3) '-ethyl) phenyl-4-hydroxymethyl-cyclopentane (yield: 4.2 mg, 33%). 1 H NMR (CDCl 3) d 5.65-5.78 (m, 1 H), 5.05 (d, 1 H), 5.02 (2 d, 1 H), 4.92 (2 d, 1 H), 3.99 (q, 1 H), 2.88 (m, 1 H), 2.43 (m, 1H), 2.15 (m, 2H), 1.91 (s, 3H), 1.87 (m, 1H), 1.71 (m, 1H), 1.1-1.5 (m, 8H), 0.83 (2t, 6H) MS- (MH) - = 294; (M + H) * = 296, (M + Na) * = 318 EXAMPLE 22 Acid (±) - (1R, 3R, 4R.1'S) -3-N-methylcarbamoyl-4- (1'-acetamido-3'-ethylaceyl-c-clopentan-1-carboxylate) The title compound was prepared according to the procedure described in Example 12G by substituting methylamine for methanol (yield: 0.29 g, 30%). 1H NMR (CD3OD) d 7.52 (d, 1H), 3.78-3.90 (m, 1H), 2.80-2.95 (m, 1H), 2.71 (s, 3H), 2.46-2.50 (m, 2H), 2.09-2.24 (m, 2H), 1.87 (s, 3H), 1.59-1.72 (m, 1H), 1.10-1.49 (m, 7H), 0.82, 0.87 (2t, 8H) MS: (M + H) * = 327, (M + NH4) * = 344 Example 23 Acid (1R, 3R.4R, 1'S-3- (imidazol-4-yl) -4- (1'-acetamido-3'-methyl) butyl-cyclopentan-1-carboxylic acid 23A Acid (1R.3R.4R, 1'S-3- (t-butyldiphen? Silylox? Methyl) -4- (1'-acetamido-3'met? L) but? Lc? Clopentan-1-carboxyl? Co The title compound was prepared according to the methods described in Examples 13F-13J by substituting isobutylmagnesium bromide for 3-pentylmagnesium bromide in Example 13F and substituting the resulting products of the subsequent pasps. 'H NMR (methanol-d4) b 7.68 (m, 4H), 7.42 (m, 6H), 3.88 (m, 1H), 3.74 (2d, 1H), 3.48 (2d, 1H), 2.77 (m, 1H), 2.15-2.27 (m, 2H ), 1.68-2.05 (m, 3H), 1.80 (s, 3H), 1.5 (, 1H), 1.1-1.32 (m, 2H), 1.03 (s, 9H), 0.84 (2d, J = 6.44 Hz, 6H) ) .MS. (MH) '= 508; (M + H) * = 510, (M + Na) * = 532 23B t-Butyl acid ester (1R, 3R, 4R.1'S) -3- (t-butyldiphenylsilyloxymethyl) -4- (1'-acetamido-3'-methyl) butyl-cyclopentane-1-carboxylic acid reacting acid (1 R, 3R, 4R, 1 'S) -3- (t-bu ti Id if in ilsilyloxy methyl) -4- (1'-acetamido-3'-methyl) bu til-ciclo pen tan- 1- carboxylic acid (0.65 g, 1.27 mmol) with t-butyl trichloroacetimidate (1.36 ml, 7.56 mmol) in toluene at 100 ° C for 16 hours. The reaction was quenched with 20 ml of water and diluted with 50 ml of ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 7% methanol / dichloromethane to provide the title compound (yield: 0.65 g, 90%). 1 H NMR (methanol-d 4) d 7.65 (m, 4 H), 7.4 (m, 6 H), 3.88 (m, 1 H), 3.72 (2 d, 1 H), 3.46 (2 d, 1 H), 2.68 (m, 1 H), 2.12 (m, 1H), 1.76-2.0 (m, 2H), 1.79 (s, 3H), 1.68 (m, 1H), 1.48 (m, 1H), 1.42 (s, 9H), 1.1-1.32 (m, 2H), 0.84 (2d, J = 6.44 Hz, 6H). MS: (M-H) '= 564, (M + 35)' = 600; (M + H) * = 566, (M + Na) * = 588 23C (1R.3R.4R.1'S) -3-Hydroxymethyl-4- (1'-acetamido-3'-methyl) butyl-cyclopentan-1-carbopylic acid t-butyl ester (1R.3R.4R.1'S) The title compound was prepared in accordance with the method described in Example 13K substituting t-butyl acid ester (1R, 3R, 4R, 1'S) -3- (t-butyldiphenylsilyloxymethyl) -4- (1'-acetamido-3'-methyl) butyl-cyclopentan-1 -carboxylic acid (1 R, 3R, 4R, 1'S) -3- (t-butyldiphenylsilyloxymethyl) -4- (1'-acetamido-3'-ethyl) pentyl-cyclopentane-1-carboxylic acid (yield 0.35 g, 93% ) 1 H NMR (methanol-d 4) d 3.88 (m, 1 H), 358 (2 d, 1 H), 335 (2 d, 1 H), 2.7 (m, 1H), 2 08 (m, 1H), 1.95 (s, 3H), 1.94 (m, 1H), 1.78 (m, 1H), 1 5-1.7 (m, 3H), 1.43 (s, 9H), 1 2-1.4 (m 2H), 0.9 (2d, J = 6.44 Hz, 6H) MS. (M-H) '= 326, (M + 35)' = 362; (M + H) * = 328, (M + Na) * = 350 23D T-Butyl acid ester (1R, 3R, 4R.1'S -3-formyl-4- (1'-acetamido-3'-metipbutyl-cyclopentan-1-carboxyl) The title compound was prepared according to the method described in Example 1D substituting (1, 3R, 4R, 1'S) -3-hydroxymethyl-4- (1'-acetamido-3'methyl) butyl-cyclopentan-1-carboxylic acid t-butyl ester for (±) - (2R, 3S) -2- (t-buti loxycarboni lami no) -3-hydrox? Methylbicyclo [2.2.1) hept-5-ene (yield: 0.32 g, 92%). 1H NMR (methanol-d4) d 9.5 (d, 1H), 7.85 (d, 1H), 3.88 (m, 1H), 2.85 (m, 1H), 2.62 (m, 1H), 2.47 (m, 1H), 2.05 (m, 2H), 1.91 (m, 1H), 1.87 (s, 3H), 1.5-1.72 (m, 2H), 1.44 (s, 9H), 1.23-1 4 (m, 2H), 0.9 (2d, J = 6.44 Hz, 6H) MS: (MH) '= 324; (M + H) * = 326, (M + Na) * = 348. 23E (1R, 3R, 4R.1'S) -3-carboxyl-4- (1'-acetamido-3'-methyl) butyl-cyclopentan-1-carboxylic acid t-butyl ester A solution of t-butyl acid ester (1 R, 3R, 4R, 1'S) -3-formyl-4- (1'-α-cephamido-3'-methyl) but i-cyclopentan-1-carboxylic acid (0.3 g, 0.93 mmoles) and 2-methyl -2-butene (1.5 ml, 14.15 mmol) dissolved in t-BuOH (7.5 ml) and acetonitrile (7.5 ml) was reacted with a solution of NaCl02 (0.3 g, 3.31 mmol) and NaH2P04.H 0 (0.3 f, 2.17 mmoles) in 6 ml of water at 0 ° C for 1 hour. The reaction was quenched with 10% aqueous Na2S203 and extracted with dichloromethane. The organic layer was washed with water and brine, dried (MgSO) and concentrated in vacuo. The residue was purified by chromatography on silica gel using 9% methanol / dichloromethane to provide the title compound (yield: 0.286 g, 90.8%). 1 H NMR (methanol-d 4) d 3.86 (m, 1 H), 2.8 (m, 1 H), 2.7 (, 1 H), 2.4 (, 1 H), 2.22 (m, 1 H), 2.08 (m, 1 H), 1.97 ( m, 1H), 1.90 (s, 3H), 1.5-1.68 (m, 2H), 1.44 (s, 9H), 1.23-1.4 (m, 2H), 0.9 (2d, J = 6.44 Hz, 6H). MS: (M-H) '= 340, (M + 35)' = 376; (M + H) * = 342, (M + Na) * = 364. 23F acid t-butyl ester (1 R .3R, 4R .1 S) -3- (2-bromo-1 -oxo) ethyl-4- (1 -acetamido-3-methyl) butyl-cyclopentan- 1 -carboxyl ico The t-butyl acid ester (1 R, 3R, 4R, 1 'S) -3-carboxyl-4- (1'-acetamido-3'-methyl) butyl-cyclopentan-1 -carboxylic acid (286 mg , 0.84 mmol) and N-methylmorpholine (11.1 μL, 1.01 mmol) in 15 ml of ether was reacted with isobutyl chloroformate (120 μL, 0.93 mmol) at 0 ° C for 45 minutes. The reaction flask was granulated with a solution of diazomethane distilled in ether prepared from the reaction of Diazald (2.4 g) in 60 ml of ether with a solution of 2.5 g of potassium hydroxide in 15 ml of ethanol and 15 ml. of water. The reaction was stirred for 8 hours at room temperature, then diluted with ether. The organic layer was washed with brine, dried (Na 2 SO 4) and concentrated to give the diazoketone intermediate. The diazoketone was reacted with 48% H Br (90 μl) in 10 ml of dioxane at 23 ° C for 45 minutes. The reaction was quenched with 50 ml of water and diluted with 200 ml of ethyl acetate. The prilled layer was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 20% ethyl acetate / hexane to provide the title compound (yield: 105 mg, 33%) 1 H NMR (methanol-d 4) 6 4 18 (2 d, J = 14.07 Hz, 2 H), 3.8 (m, 1 H), 308 (m, 1H), 2.83 (m, 1H), 2.48 (m, 1H), 2.3 (m, 1H), 2.07 (m, 1H), 1.89 (s, 3H), 1.45 (m, 1H), 1.5-1.7 (m, 2H), 1.15-1.46 (m, 2H), 1.43 (s, 9H), 1 2-1.4 (m, 3H), 0.88 (2d, J = 6.44 Hz, 6H). MS: (M-H) '= 372; (M + H) * = 374 23G t-Butyl acid ester (1R, 3R, 4R, 1'S) -3-.imidazol-4-yl) -4- (1'-acetamido-3'-methyl) butyl-cyclopentane-1-carboxylic acid react t-butyl acid ester (1R, 3R, 4R, 1'S) -3- (2-bromo-1-oxo) ethyl-4- (1'-acetamido-3'-methyl) butyl-cyclopentan-1-carboxylic acid (105 mg, 0.28 mmol with formamidine acetate (0.52 g, 4.99 mmol) in 5 ml of liquid ammonia and heated at 45 ° C in a sealed tube for 18 hours.The reaction was concentrated in vacuo. Aqueous NaHC03 and extracted with dichloromethane (5 x 20 ml) The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo, the residue was purified by chromatography on silica gel using 10% methanol in dichloromethane to provide the title compound as an oil (40 mg, 39%) 1 H NMR (methanol-d 4) d 7.57 (br s, 1 H), 6.81 (br s, 1 H), 3.93 (m, 1 H), 2. 96 (m, 1H), 2.7 (m, 1H), 21-2.4 (m, 3H), 1.85 (m, 1H), 1.72 (s, 3H), 1.48 (m, 1H), 1 43 (s, 9H), 1 15-1.46 (m, 2H), 0.85 (2d, J = 6.44 Hz, 6H). MS: (M-H) '= 362, (M + 35)' = 398; (M + H) * = 364, (M + Na) * = 386 23G Acid chlorhydrate (1 R.3R.4R.1'S) -3- (midazol-4-yl) -4- (1'-acetamido-3'-methyl) butyl-cyclopentan-1-carboxylic ester was reacted t-butylic acid (1R, 3R, 4R, 1 'S) -3- (imidazol-4-yl) -4- (1'-acetamido-3'-methyl) buyl-ciclo pen tan- 1 carboxylic acid (40 mg, 0.11 mmol) with 6N HCl (4 ml) for 1 hour. The reaction was concentrated in vacuo to provide the title compound (yield: 37 mg, 98%). 1 H NMR (methanol-d 4) 8 8.83 (d, J = 1.01 Hz, 1 H), 7.36 (d, J = 1.01 Hz, 1 H), 3.92 (m, 1 H), 3.18 (m, 1 H), 2.98 (m, 1H), 2.49 (m, 2H), 2.22 (m, 1H), 1.90 (m, 2H), 1.77 (s, 3H), 1.53 (m, 1H), 1.41 (m, 1H), 1.25 (m, 1H) ), 0.86 (2d, J = 6.45 Hz, 6H). MS: (M-H) '= 306, (M + 35)' = 342; (M + H) * = 308, (M + Na) * = 330 Example 24 Acid (3R, 4R, 1'S) -4- (imidazol-2-yl) -3- (1'-acetamido-3'-ethyl) pent? L-c? Clopent-1-en-1-carboxylic acid 24A (3R.4R.1'S) -3- (t-butyldiphenylsilobylmethyl) -4- (1'-azido-3'-e ti I) pen ti I-cyclope n tan-1-en a Was reacted ( 3R, 4R, 1'S) -3- (t-butyldiphenylsilyloxymethyl) -4- (1'-azido-3'-ethyl) pentyl-1-methylene-cyclopentane (0.455 g, 0.93 mmol) with 4% osmium tetraoxide in water (0.59 ml, 0.093 mmol) and sodium periodate (0.8 g, 3.73 mmol) in 15 ml of THF and 3 ml of water at room temperature for 3 hours. The mixture was filtered and the filtrate was diluted with ethyl acetate, washed with a 10% Na2S203 solution, water, dried over MgSO4, filtered and concentrated in vacuo. Chromatography on silica gel using 0% ethyl / hexane provided the title compound (yield: 240 mg, 52%). 1 H NMR (CDCl 3) d 7.64 (m, 4 H), 7.4 (m, 6 H), 3.68 (m, 2 H), 3.36 (m, 1 H), 2.3-2.6 (m, 4 H), 2.23 (2 d, 1 H), 2.08 (m, 1 H), 1.16-1.52 (m, 6H), 1.05 (s, 9H), 0.78-0.88 (2t, J = 7.12 Hz, 6H) MS. (M + 18) * = 509, (M + Na) * = 514 24B (3R.4R.1'S) -4- (t-butyldiphenylsilyloxymethyl) -3- (1'-azido-3'-ethyl) pentyl-1-trifluoro-ethanesulfonyloxy-cyclopent-1-ene and (3R, 4R.1'S) -3- (t-Butyldiphenylsilyloxymethyl) -4- (1'-azido-3'-ethyl) pentyl-1-tp fluoro-methansul-fonyloxy-cyclopent-2-ene Reacted (3R, 4R, 1'S) -3- ( t-butyldiphenylsilyloxymethyl) -4- (1-azido-3-ethyl) pentyl-c-clopent-1-one (230 mg, 0.468 mmol) in 1 M lithium hexamethyldisilazide (1.17 ml) in 1 ml of THF at -78 ° C for 45 minutes. The reaction mixture was treated with N-phenyltrifluoromethanesulfonimide (0.2 g, 0.56 mmole) and reacted at 0 ° C for 0.5 hour. The reaction was quenched with 10 mL of water and diluted with 50 mL of ethyl acetate. The organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% ethyl acetate / hexane to provide a mixture of the title compounds in a ratio of 3: 2 (yield: 280 mg, 96%). 1 H NMR (CDCl 3) d 7.64 (m, 4 H), 7.4 (m, 6 H), 5.58-5.5 (m, 1 H), 3.55-3.72 (m, 2 H), 3.36 (m, 1 H), 2 7-2.83 ( m, 2H), 2.3-2.47 (m, 2H), 1.16-1.5 (m, 6H), 1 05 (s, 9H), 0 78-09 (m, 6H). 24C (3R, 4R.1'S) -4- (t-butyldiphenylsilyloxymethyl) -3- (1'-azido-3'-ethyl) pentyl-cyclopentyl-1-en-1-carboxylic acid methyl ester methyl ester of acid (3R.4R, 1'S) -3- (t-butyldiphenylsilyloxymethyl) -4- (1'-azido-4'-ethyl) pentyl-1-cyclopent-1-en-1-ca-box Carbon monoxide was bubbled into a mixture consisting of (3R, 4R, 1'S) -4- (t-butyldiphenylsilyloxymethyl) -3- (1'-azido-3'-ethyl) pentyl-1-trifluoromethanesulfonyloxy-cyclopent-1- eno and (3R, 4R, 1'S) -3- (t-butyldiphenylsilyloxymethyl) -4- (1'-azido-3'-ethyl) pentyl-1-trifluoromethanesulfonyloxy-cyclopent-1-en? (280 mg, 0.45 mmol), triethylamine (0.125 ml, 0.9 mmol), palladium (II) of bis (acetate) bis (triphenylphosphine) (34 mg, 0.45 mmol) in 4 ml of DMF and 2 ml of 40% methanol. C for 2 hours. The reaction was quenched with 10 mL of water and diluted with 50 mL of ethyl acetate. The organic layer was washed with water, brine, dried MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% ethyl acetate / hexane to provide the title compounds in a ratio of 3: 2 as a mixture (yield: 181 mg, 75%). 1 H NMR (CDCl 3) d 7.64 (m, 4 H), 7.4 (m, 6 H), 658-6.7 (2 br s, 1 H), 374 (br s, 3 H), 3.25-362 (m, 3 H), 27- 295 (m, 2H), 222-2.49 (m, 2H), 1 16-1 5 (m, 6H), 1.05 (s, 9H), 0.78-09 (m, 6H) MS: (M + 18) * = 551, (M + Na) * = 556 24D Acid methyl ester (3R, 4R.1'S) -4- (t-butyldiphenylsilyloxymethyl) -3- (1'-acetamido-3'-ethyl) pentyl-cyclopent-1-en-1-carboxylic acid methyl ester (3R, 4R, 1'S) -3- (t-butyldiphenylsilyloxymethyl) -4- (1'-acetamido-3'-eti I) pentyl-cicle pent-1-en-1 -carboxylic A solution of the mixture acid methyl ester (3R, 4, 1'S) -4- (t-butyldiphenylsilyloxymethyl) -3- (1'-azido-3'-ethyl) pentyl-1-trifluoromethanesulfonyloxy-cyclopent-1-en-1-carboxylic acid methyl ester ( 3R, 4R, 1'S) -3- (t-butyldiphenylsilyloxymethyl) -4- (1'-azido-3'-ethyl) phenyl-1-trifluoromethanesulfonyloxy-cyclopent-1-en-1-carboxylic acid (0.18 g, 0.33 mmol) in 12 ml of THF and 3 ml of water was reacted with tpphenylphosphine (0.265 mg, 1.01 mmol) at 65 ° C for 4 hours. The reaction mixture was concentrated in vacuo, redissolved in chloroform, dried over MgSO, it was filtered and concentrated in vacuo. The crude amine was reacted with acetic anhydride (64 μL, 0.67 mmol) in pyridine (0.135 mL, 1.67 mmol) and 1 mL of dichloromethane at room temperature for 2 hours. The reaction was quenched with a 10% citric acid solution (10%). ÍÜ ^ ml) and diluted with 50 ml of ethyl acetate. The organic layer was washed with water and brine, dried MgSO 4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 40% ethyl acetate / hexane to provide the title compounds, methyl ester of (3R, 4R, 1'S) -4- (t-bu ti Id if in ilsilyloxy m eti l) -3- (1'-acetam id o-3'-ethyl) pentyl-cyclopent-1-en-1-carboxylic acid (yield: 109 mg, 60%), and methyl ester of acid (3R , 4R, 1 'S) -3- (t-butyl-phenyl Isi I-yloxymethyl) -4- (1'-acetamido-3-ethylf eni I-cyclopent-1-en-1-carboxylic acid (yield: 37 mg 20%). (3R, 4R, 1'S) -4- (t-butyldiphenylsilyloxymethyl) 1 H NMR (CDCl 3) d 7.63 (m, 4H), 7.4 (m, 6H), 6.58 (s, 1H), 4.95 (br s, 1H), 4.0 (br s, 1H), 3.73 (s, 3H), 3.57 (d, 2H), 2.72 (m, 2H), 1.78 (s, 3H), 1.47 (m, 3H), 1.18 (m, 3H), 1.06 (s, 9H), 0.74-0.88 (2t, J = 7.12 Hz, 6H) MS: (MH) '= 548, (M + 35)' = 584; (M + H) * = 550, (M + Na) * = 572 (3R, 4R, 1'S) -3- (t-butyldiphen? Silyloxymethyl) 1 H NMR (CDCl 3) d 7.63 (m, 4H), 7.4 (m, 6H), 6.64 (d, 1H), 4.72 (d, 1H), 3.95 (m, 1H), 3.74 (s, 3H), 3.73 (2d, 1H), 3.57 (2d, 1H), 2.9 (m, 1H), 2.75 (m, 1H), 2.3 (m, 1H) ), 2.14 (m, 1H), 1.71 (s, 3H), 1.45 (m, 3H), 1 18 (m, 3H), 1.05 (s, 9H), 0.72-0.86 (2t, J = 7 12 Hz, 6H) MS: (MH) '= 548, (M + 35)' = 584; (M + H) * = 550, (M + Na) * = 574 24E (3R, 4R. 1'S) -4-Hydroxymethyl-3- (1'-acetamido-3'-ethyl) pentyl-c-clopent-1-en-carboxylic acid methyl ester The title compound was prepared in accordance with the method described in Example 13K substituting methyl ester of acid (3R, 4R, 1'S) -4- (t-butyldiphenylsilyloxymethyl) -3- (1-acetamido-3-eti I) pen ti 1-1 -trif luoromethanesulfonyloxy-cyclopent-1-ene-1-carboxylic acid (1R, 3R , 4R, 1'S) -3- (t-butyldiphenylsilyloxymethyl) -4- (3-ethyl-1-acetamido) phenyl-cyclopentane-1-carboxylic acid (yield: 53 mg, 85%). 1 H NMR (CDCl 3) d 6.63 (m, 1 H), 5.49 (d, 1 H), 3.98 (m, 1 H), 3.74 (s, 3 H), 3.5-3.7 (m, 2 H), 2.87 (m, 1 H), 2.75 (m, 1H), 2.2-2.4 (m, 2H), 1.99 (s, 3H), 1.17-1.48 (m, 8H), 0.78-0.87 (2t, J = 7.12 Hz, 6H). MS: (M-H) "= 310, (M + 35) '= 346; (M + H) * = 312, (M + Na) * = 334 24 F Acid methyl ester (3R.4R.1'S) -4-formyl-3- (1-acetamido-3-et? L)? Ent? L-c? Clopent-1-en-1-carboxylic acid The title compound was prepared according to the method described in Example 1D by substituting methyl (3R.4R, 1'S) -4-hydroxymethyl-3- (1'-acetamido-3'-ethyl) pentyl-cyclopentyl methyl ester. 1-en-1-carboxylic acid by (±) - (2R, 3S) -2- (t-butyloxycarbonylamino) -3-hydroxyethyl-bicyclo [2.2.1] hept-5-ene (yield: 38 mg, 72%) . 1 H NMR (CDCl 3) d 9.71 (s, 1 H), 6.62 (m, 1 H), 5.2 (d, 1 H), 4.06 (m, 1 H), 3.75 (s, 3 H), 3.25 (m, 1 H), 3.1 ( m, 1H), 2.96 (m, 1H), 2.83 (m, 1H), 1.96 (s, 3H), 1.2-1.5 (m, 8H), 0.77-0.9 (2t, J = 7.12 Hz, 6H) MS: (MH) '= 308; (M + H) * = 310 24G. Methyl ester of acid (3R.4R.1'S) -4- (imidazol-2-yl) -3- (1'-acetamido-3'-ethyl) phenyl-cyclopent-1-en-1-carboxylic acid The title compound was prepared according to the method described in Example 15D by substituting methyl (3R, 4R, 1'S) -4-formyl-3- (1'-acetamido-3'-ethyl) pentyl-cyclopent-1-en-1 methyl ester. -carboxylic by (1 R, 3R, 4R, 1'S) -1-formyl-2- (1'-acetamido-3'-ethyl) pentyl-4- (triphenylmethyloxy) methyl-cyclopentane (yield: 6 mg, 14%) . 1 H NMR (CDCl 3) d 7.06 (s, 2 H), 6.69 (s, 1 H), 3.95 (m, 1 H), 3.74 (s, 3 H), 3.5-3.7 (m, 2 H), 3.23 (m, 1 H), 2.8 (m, 1H), 1.90 (s, 3H), 1.1-1.5 (m, 8H), 0.730.87 (2t, J = 7 12 Hz, 6H) MS- (M-H) '= 346, (M + 35)' = 382; (M + H) * = 348, (M + Na) * = 370 24H Acid (3R, 4R, 1'S) -4- (im-dazol-2-yl) -3- (1'-acetamido-3'-ethyl) pentyl-cyclopent-1-en-1-carboxylic ester was reacted methyl (3R, 4R, 1'S) -4- (imidazol-2-yl) -3- (1'-acetamido-3'-ethyl) pentyl-cyclopent-1-en-1-carboxylic acid (6 mg, 0.017) mmoles) with lithium hydroxide (1 mg, 0.026 mmol) in 0.5 ml of THF and 0.2 ml of water at 0 ° C for 4 hours. The reaction was quenched with 10% citric acid (1 ml) and diluted with 25% isopropanol / dichloromethane (10 ml). The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo, the residue was purified by chromatography on silica gel using 1: 3: 1: 1 water / ethyl acetate. n-butanol / acetic acid followed by extraction in 25% isopropanol / dichloromethane to provide the title compound (yield: 4.3 mg, 74%). 1 H NMR (CDCl 3) d 7.06 (s, 2 H), 6.69 (s, 1 H), 3.95 (m, 1 H), 3.74 (s, 3 H), 35-37 (m, 2 H), 3.23 (m, 1 H), 2.8 (m, 1H), 1.90 (s, 3H), 1.1-1.5 (m, 8H), 0.730.87 (2t, J = 7.12 Hz, 6H) MS: (MH) "= 346, (M + 35) '= 382; (M + H) * = 348, (M + Na) * = 370 Using the methods described above and the general knowledge of one skilled in the art, compounds of the invention can be prepared, which are represented by taking a core from Table 1 (where Ac is acetyl), a Y substituent of Table 2, a substituent R of the Quad ro 3, or a substituent R 3 of Table 4a, 4b, 4c, 4d, 4e, 4f or 4g and a substituent R5 of Table 5.

Table 1 Y. AcHN j. > R ACHN. > ^ 0R R3 H O R O And Y, CH3S02 + IN RX h .OORR C CHH3'SSOX2-HNX > XÍ > R 3. 4 or? ^ o \ CF3C-H ._ X -, X.0RK FP33C ° -H "'VXXy-'X .OR 5 6 Square 2 H3C H, Q F3C) = \ Cl > = \ F3C _ 17 19 20 NH N = Et -X Et - Et ~ 30 HO ^ 0 N = * o. O N-N 43 HtQ «-N < i_N N-N 47 48 Q 62 63 64 H3C; C CHH Cl Cl Cl Cl Cl H, C H - ^ Cl 74 75 76 Cl Cl PF3 F3? ._ / CF3 Cl '^ - Cl X 78 Cl CH3 F3C CF3 H3C Cl F = H3C ^ ^ 8"5" "- 87 88 H3C \ =, CH3 H3C F H, C 101 103 104 H3C F3C H3C CF3 Hs PH3 F3C. ^ H3C. H3C 106 107 H3C CF3 F3C CH3, CF3 F3C CH3 H, C FX 109 110 111 112 H3C CF3 H3C > Cl a CF, FC CI < / - X F3C X ~ \ ^ ~ H *: X ~ Hj X- 153 154 155 156 Table 3 -H 1 X CH3 2 X XH, 3 ^ _CH3 \ - 1 4 X_XCH3 6 CH3 5 Table 4a H, C 'OH OH CH3 I OH 3 Table 4b J3-L} ..a - a ^ -1 CHJO-? UHJ CHJOU-OCHJ CHJOU-OCH3 CHJO -8"3 OCHj OCHj ^ 33 34 8 twenty ifífc 81 tí '82 X & 83 ° "'84 Table 4c i? - CCHH33 \ CH3 UGCCH3 ^ CCHH33 C CHH3, CH3 CHj - HJC. H3C ^ .CH3 X - CH, H, C X .CH, .CH, 7: 74 75 76 113 11 115 - *** - • - "* > - T ~ CH, cH, '- r CH, H, C? H,? - CH, H3 ^ ~. ^ > ^ X T T ^ OH OH OH OH 167 168 169 170 and CH, OH CH3 OxxXX OH X r ^ OH. "> ? CH3 175 176 177 -178 219 220 221 251 252 253 254 ** 'A "3" CH3 H H33C H3C J C 287 288 289 290 Table 4d H3C? 9 ° 10 H ^ ° 11 H3C ^? ° & 33 & amp; 34 & amp; 35 CH, T CH OH H, C. OH OH H, C- ^ OH CH, CH, 45 46 47 - »**« - ~ - - 72 224 225 226 108 227 Table 4o H3C: CHj HlC- L.-CH, XC-CH3 C \ - CH, OH OR OH OH OH OH 2 228 -CH3 CHs CH3 -CH3 H3C H, C X UC OH CH3 OH OH OH OH H X-OH H, C ^^ r-OH? XH3t-OH 1 ^? 1; -OH H'C CH, CH, CH, "< CHj ,, 34 35 229 230 GCH,, ^ -CH, C .H ", 3 ~, -CCHH ,,, G -CH, OH 73 X O7H "'X OH OH 75 76 CH, -f CH, CH, T CH, ^ T CH3 I OCH3"OCH, \ O OCCrH3 OCH, 85 86 87 88 231 93 232 124 122 233 152 2. 3. 4 H3C Cr OCH3 ^ 3 iL-OCH, U-OCH3 l-OCH, -OH -OH "" "H '-OH 182 183 ocH, CGOCH, XA "OCHj XX-OCH, -OH A > -OH A ^ OH ~ a_0H 193 19 195 196 H-C.a i-OCH3 • r0CH3 XX-OCH, XJUoCH, T '-OCH, A ^ "OCH, A ^ -OCH,' -OCH, 3 197 198 199 200 205 206 cC 207 & 208 235 OH ^ OCH, ^ 0 ^ ^ -0 CH3 -CH3 215 216 221 222 Picture l NH2 L NH2 L OH 1 2 3 236 The ability of the compounds of the invention to inhibit neuraminidase in vitro can be determined according to the method described below Testing of Neuraminidase Inhibition Influenza A / N1 / PR8 / 34 virus was developed in an allantoic cavity of fertilized eggs and purified by sucrose density gradient centrifugation (Laver, WG (1969) em "Fundamental Techmques in Virology "(K Habel and NP Salzman, eds) p 92-86, Academic Press, New York) Influenza virus A / N2 / Tokyo / 3/67 was obtained from the supernatants of tissue culture of virus developed on cells MDCK B / Memph? S / 3/89 virus neuraminidase was prepared by virus digestion with TPCK-tppsin followed by centrifugation and then purification of the neuraminidase catalytic fragment using sucrose density gradient centrifugation and dialysis as previously described (Air, GM, Laver, WG, Luo,, Stray, SJ, Legrone, G, and Webster, RG (1990) Viroloqy 177. 578-587) Neuraminidase inhibition assays used I enzymatic neuraminidase activity associated with the whole virus of A / N 1 / PR / 8/34 or A / N2 / Tokyo / 3/67 or the catalytic head fragment B / Memph? S / 3/89 All the virus or catalytic fragment was properly diluted with 20 mM N-ethylmorpholine, 10 mM calcium chloride, pH regulator, at a pH of 7 5, on the day of the experiment. neuraminidase 237 in 20 mN N-ethylmorpholine, 10 mM calcium chloride, pH regulator, pH 7.5 with 5% DMSO. The reaction mixtures included neuraminidase, inhibitor (test compound) and 20-30 μM of 4-methylumbelliferyl sialic acid substrate in a total volume of 200 μl and were contained in 96-well white U-shaped plates. Typically, from 5 to 8 concentrations of the inhibitor were used for each measurement of the Ki value the reactions were initiated through the addition of enzyme and allowed to proceed for 30-60 minutes at room temperature. The fluorescence for each plate cavity was measured once every minute during the reaction period through a Fluoroskan II plate reactor (ICN Biomedical) equipped with excitation and emission filter of 355 +/- 35 nm and 460 +/- 25 nm, respectively. The plate reader was under the control of the DeltaSoft II software (Biometallics) and a Macintosh computer. If the compound exhibited linear reaction rates during the reaction period, then the reaction rates of dose-response studies were fixed to equation 1 using a non-linear regression program (Kaleidagraph) to determine the total value of Ki (Segel, I. H (1975) in Enzume Kinetics, p. 105-106, Wiley-lnterscience, New York). (1 -Vi / Vo) = [l] /. { [l] + Ki (1 + [S] / Km)} ec 1 In equation 1, Vi and Vo represent inhibited and non-inhibited reaction rates, respectively, and Km = 16-40 μM 238 depending on the neuraminidase strain tested. For those compounds exhibiting a slow binding inhibition (Morpson, J. F (1982) Trends Biochem.Sci. 7. 102-105), a second experiment was performed in a form identical to the first, except that the neuraminidase and the inhibitor they were pre-incubated in the absence of the substrate for 2 hours at room temperature before starting the reactions with the substrate. The data analysis for the resulting linear velocities was conducted as described above. Equation 2 was used to measure the Ki values and the sub-nanomolar scale (Morrison, J. F. and Atone, S. T. (1985) Comments Mol.Cell Biophvs., 2. 347-368).

V = A { root2. { (K¡ '+ It - Et)? 2 + 4Ki Et} - (Ki '+ It -Et)] ec. 2 In equation 2, V = velocity; A = akcat [S] / 2 (Km + [S]; a is a factor to convert fluorescence units to molar concentrations; Ki '= Ki (1 + [S] / Km); It = concentration of total inhibitor and Et = total active concentration of neuraminidase The compounds of the invention inhibit influenza A neuraminidase and influenza B neuraminidase with Ki values between approximately 24 micromolar and approximately 0.9 micromolar The ability of the compounds of the invention to inhibit plaque formation in a cell culture can be determined to 239 through the method described below.

Inhibition of Plate Formation Inhibition in Cell Cultures Cell Cultures: MDCK cells obtained from the American Type Culture Collection were grown in Dulbecco's modified Eagle medium (DMEM) with a high sucrose content (GibcoBRL) supplemented with bovine serum fetal at 10% (J RH Biosciences), 40 mM pH regulator of H EPES (GibcoBRL) and antibiotics. The cells were routinely cultured in flasks or roller bottles at 35 ° C and 5% C02. At confluence, the cells were reduced to a density of 500,000 cells in one ml using trypsin / EDTA (GibcoBRL), as treatment of the monolayer followed by cell centrifugation, additional suspension and dilution in growth media. Cells were planted at a ratio of volume to surface area of 1 ml on 1 cm2 of growth surface.

Plaque Assay Protocol: In the confluent of M DCK cells, the growth medium was removed from 6-well plates and the cells were covered with 1.5 ml of the assay medium (DMEM with 1% fetal bovine serum, 40 mM of pH regulator HEPES and antibiotic) containing pre-mixed virus (influenza A / Tokyo / 3/67 [H2N2]) (40-100 plaque forming units) and 2x of the concentration test compound. The plates were placed on an oscillator and incubated for 2 hours at room temperature. During the 240 period of virus adsorption, cover medium was prepared. In a microwave oven, 2x of agarose (final concentration of 0.6% agarose) was fused in the cover medium) DMEM with 40 M of the pH regulator HEPES) and then placed in a water bath at 48 ° C. for the balance of temperature. After the virus adsorption period was complete, 1.5 mg of agar was added to the medium and mixed with 1.5 ml of the virus and the test compound containing the medium per cavity. The cultures were incubated at 35 ° C during the period required for plaque development, usually several days. The plates were fixed with 3.7% formalin in PBS for 20 minutes followed by removal of the agar cover and staining with 0.1% crystal violet in distilled water for 15 minutes. The plates were counted and the EC 50 concentration was determined from multiple concentrations of the compound tested using regression analysis.

Viral Supply Materials: Supply materials were prepared in confluent roller bottles of MDCK incubated at 37 ° C in DMEM supplemented with 1% FCS, 40 M pH regulator HEPES and antibiotics. The bottles were inoculated with a multitude of infection of approximately 0.1 plaque forming units for each cell. The roller bottles were harvested after the cytopathic effect of the virus was observed as complete. The supply materials were prepared from a ^^^ 241 of the supernatant that resulted from low-speed centrifugation of the medium and cell lysate. The supply materials were titled and stored at -80 ° C. The compounds of the invention can be tested for antiviral activity in vivo using the method described below.

Antiviral Efficacy Method in Vivo Female BALB / c mice were placed under anesthesia (sevoflurane) and inoculated intranasally (IN) with 0.1 ml of AVR-95 (Puerto Rico PR8-34) infection at 10"2 (diluted from the material frozen supply) This viral concentration consistently produced disease in mice in 5 days of inoculation.The animals were treated 4 hours of preinfection and 4 hours post-infection, and periodically thereafter, with one of the following therapies, without treatment; test (100, 25, 6 25, 1 .39 mg / kg / day BID, PO), or vehicle (sterile water BID, PO) A group of 10 animals (designated as the control) was inoculated with 0.9% saline. The percentage of survival was determined, on day 5, the lungs were harvested, weighed and assigned classifications of 0, 1, 2, 3 or 4 based on the percentage of consolidation (0; 10-20; 25- 50; 50-75; 75-100%, respectively). In addition, each pair of lungs was formed n images and analyzed to determine the percentages of consolidation of the target lung. 242 The compounds of the present invention can be used in the form of salts derived from inorganic and organic acids. These salts include, but are not limited to the following, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, cyclopentanpropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, bromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate , tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, groups containing basic nitrogen can be quaternized with said agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkylsulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, benzyl and phenethyl bromides, and others. In this way, soluble or dispersible products can be obtained in water or oil.

Examples of acids which can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. . Other salts 243 include alkali metal or alkaline earth metal salts, such as sodium, potassium, lithium, calcium or magnesium salts, or with ammonium or N (R **) (wherein R ** is lower alkyl). In addition, salts of the compounds of this invention are also contemplated with one of the naturally occurring amino acids.

Preferred salts of the compounds of the invention include hydrochloride, methanesulfonate, sulfonate, phosphate and isethionate.

The compounds of formula I, 11, III, IV, V, VI, VII, VIII, or IX of this invention may have a substituent, which is an acidic group (eg, -C02H, -S03H, -S02H, -P03H2- P02H). The compounds of formula I, I I, I, I, IV, V, VI, VII, VII, or IX of this invention having a substituent, which is an ester of said acid group, are also encompassed by this invention. These esters can serve as prodrugs. The prodrugs of this invention are metabolized in vivo to provide the aforementioned acid substituent of the parenteral compound of the formula I, II, III, IV, V, VI, VII, VIII, or IX. The prodrugs may also serve to increase the solubility of this substance and / or absorption from the gastrointestinal tract. These prodrugs may also serve to increase the solubility for intravenous administration of the compounds. The prodrugs can also serve to increase the hydrophobic character of the compounds. The prodrugs can also serve to increase the oral bioavailability of the compounds by increasing the absorption and / or reducing the metabolism of the first 244 step. Prodrugs may also serve to increase tissue penetration of the compounds, thus leading to increased activity in affected tissues and / or reduced clearance regimen. Said esters contemplated by this invention include: Alkyl esters, especially lower alkyl esters, including, but not limited to ethyl esters, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, and the like; alkoxyalkyl esters, especially lower alkoxy-lower alkyl esters, including, but not limited to, methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl, idopropoxymethyl, t-butoxy methyl esters, and the like; alkoxyalkoxyalkyl esters, especially lower alkylsters substituted with alkoxyalkoxy, including, but not limited to, 2-methoxyethoxymethyl esters, and the like; aryloxyalkyl esters, especially lower alkyl esters substituted with aryloxy, including, but not limited to, phenoxymethyl esters and the like, wherein the aryl group is unsubstituted or substituted as defined herein; haloalkoxyalkyl esters, especially lower alkyl esters substituted with haloalkoxy, including, but not limited to, 2, 2,2-trichloroethoxymethyl esters, and the like; alkoxycarbonylalkyl esters, especially lower alkyl esters substituted with lower alkoxycarbonyl, 245 including, but not limited to, methoxycarbonylmethyl esters and the like, cyanoalkyl esters, especially, lower alkyl esters substituted with cyano, including, but not limited to, cyanomethyl, 2-cyanoethyl esters, and the like; thioalkoxymethyl esters, especially methyl esters substituted with lower thioalkoxy including, but not limited to, methylthiomethyl, ethylthiomethyl esters, and the like; alkylsulphonylalkyl esters, especially lower alkyl esters substituted with lower alkylsulfonyl, including, but not limited to, 2-methylsulfonylethyl esters and the like; arylsulfonylalkyl esters, especially, lower alkyl esters substituted with arylsulfonyl, including, but not limited to, esters 2-benzenesulfonyl ethyl and 2-toluenesulfonylethyl, and the like; acyloxyalkyl esters, especially lower alkyl esters substituted with lower alkylacyloxy, including, but not limited to, esters of alkyloxymethyl, acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, pivaloyloxyethyl, and the like; alkyl cycloalkylcarbonyloxy esters including, but not limited to, cyclopentanecarbonyloxy methyl, cyclohexanecarbonylxoxyl, cyclopentanecarbonyloxyethyl, cycloexancarbonyloxyethyl esters, and the like; esters arylcarbonyloxyalkyl, including, but not 246 limited to benzoyloxymethyl esters, and the like, alkylaryl (alkoxycarbonyloxy) esters, especially lower alkylaryl esters substituted with (lower alkoxycarbonyloxy), including, but not limited to, methoxycarbonyloxymethyl esters, ethoxycarbonyloxymethyl esters, 1- (methoxycarbon? Lox) ?) ethanol, 2- (ethoxycarbonyloxy) ethyl, and the like, esters (cycloalkyloxycarbonyloxy) alkyl, especially, lower alkyl esters substituted with (cycloalkyloxycarbonyloxy), including, but not limited to, esters cyclohexyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxyethyl, cyclohexyloxycarbonyloxypropyl esters, and the like, oxy-oxyloxymethyl esters including, but not limited to, esters 5-phenol-2-oxo-1,3-d-oxolen-4 -? l) methylated, [5- (4-met? lfen? l) -2-oxo-1,3-d? oxolen-4-? l] methyl, [5- (4-methox? phen (l) -2-oxo-1, 3-d? oxolen-5? l] methylene, [5- (4-fluorophen? l) -2-oxo-1, 3-d? oxolen- 4-? L] met? l? co, [5- (4-chlorophen? l) -2-oxo-1, 3-d? oxolen-4-? l] met? l? co, (2-oxo- 1, 3-d? oxolen -4- 11) met 11 ico, (5-met? L-2-oxo- 1, 3-d? Oxolen-4-? L) met? L? Co, (5-et? L-2-oxo- 1, 3-d? Oxolen-4-? L) methylene, [-prop? L-2-oxo-1,3-d? Oxolen-4-? I) methyl, (5-? Propyl-2-oxo-1,3-d? Oxolen-4-?) Methanol, (5-butyl-2-oxo-1,3-d? Oxolen- 4-?) Metal, and the like, phthalidyl esters wherein the phenyl ring of the f-idyl group is unsubstituted or substituted as previously defined herein, including, but not limited to, phthalidyl esters , dimethylptadilic, dimethoxy phthalidyl, and the like, aprotic esters, including, but not limited to, esters 247 phenolic, naphthyl, indanic, and the like; arylalkyl esters, especially lower alkyl esters substituted with aryl, including, but not limited to, benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl, and the like esters, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined , dialkylaminoalkyl esters, especially lower alkyl esters substituted with dialkylaminos, including, but not limited to, 2- (N, N-dimethylamino) ethyl ester, 2- (N, N-diethylamino) ethyl, and the like; alkyl (heterocyclic) esters, especially, lower alkyl esters substituted with heterocyclic, wherein the heterocycle is a nitrogen containing heterocycle, including, but not limited to, methyl esters (heterocyclic) and the like, wherein the heterocyclic part of the alkyl group ( heterocyclic) is unsubstituted or substituted as previously defined herein; and carboxyalkyl esters, especially, lower alkyl esters substituted with carboxy, including, but not limited to, carboxymethyl esters, and the like. Preferred prodrug esters of acid-containing compounds of formula I, II, III, IV, V, VI, VI, VI II or IX are lower alkyl esters including, but not limited to, ethyl esters, n-propyl esters, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl and benzylic esters, where the The ring is unsubstituted or substituted as previously defined herein. Methods for the preparation of prodrug esters of the compounds of formula I, II, III, IV, V, VI, VII, VIII or IX are well known in the art. They include: reacting the acid with the corresponding halide (eg, chloride or acyl chloride) and a base (eg, triethylamine, DBU, N, N-dimet? lamnopyridine, and the like) in a solvent inert (e.g., DMF, acetonitrile, N-methylpyrrolidone, and the like); reacting an activated derivative of the acid (eg, an acid chloride, a sulfonyl chloride, a monochlorophosphonate, and the like) with the corresponding alcohol or alkoxide salt; and similar. Other examples of prodrugs of the present invention include esters of hydroxyl-substituted compounds of the formula I, II, III, IV, V, VI, VI, VI II or IX, which have been acylated with a blocked amino acid residue or not blocked, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R100C (O) - or R 100C (S), wherein R100 is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy , or an acyl residue of the formula R "-C (Rb) (Rd) -C (0) - or Ra-C (Rt,) (Rd) -C (S) - where R" and Rd are selected independently of hydrogen or lower alkyl and Ra is -N (Re) (Rf), -ORß or -SRe, wherein R "and R 'are independently selected from hydrogen, 249 lower alkyl and haloalkyl, or an amino acyl residue having the formula R101 NH (CH2) 2NHCH2C (O) - or R1O NH (CH2) 2OCH2C (O) -, wherein R101 is hydrogen, lower alkyl, ( aryl) alkyl, (cycloalkyl) alkyl, acyl, benzoyl or an a-amino aciio group. The amino acid esters of particular interest are glycine and licina; however, other amino acid residues can also be used, including any of the naturally occurring amino acids and also including those wherein the aminoacyl group is -C (O) CH2N R10 R103, wherein R102 and R103 are independently selected from hydrogen and lower alkyl, or the group -NR102R103, wherein R102 and R103, taken together, form a heterocyclic ring containing nitrogen. Other prodrugs include a hydroxyl substituted compound of the formula I, II, II, IV, V, VI, VII, VI or IX, wherein the hydroxyl group is functionalized with a substituent of the formula -CH (R104) OC (O) R105 or -CHt ^^ OCYSÍR105, wherein R105 is lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy, and R104 is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or alkylaminocarbonyl. Said prodrugs can be prepared according to the Schreiber process (Tetrahedron Left, 1983, 24, 2363) through ozonolysis of the corresponding metal ether in methanol followed by treatment with acetic anhydride. The preparation of esters of hydroxyl substituted compounds of the Formula I, II, III, IV, V, VI, VI, VI, IX or IX is carried out 250 by reacting a hydroxyl substituted compound of the formula I, II, III, IV, V, VI, VII, HIV or IX, with an activated derivative of aminoacyl, phosphoryl, hemixuccinyl or acyl. Prodrugs of the hydroxyl-substituted compounds of the invention may also be prepared through alkylation of the substituted hydroxyl compound of formula I, II, III, IV, V, VI, VII, VIII or IX, with alkyl (halo) esters , transacetalization with bis- (alkanoyl) acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the hemiacetal as an intermediate. In order to prepare the prodrugs it is generally necessary to protect other reactive functional groups in order to avoid unwanted side reactions. After protection of the reactive groups, the desired group can be functionalized. The resulting functionalized product is then unprotected, to remove the protective groups that were added to avoid unwanted side reactions. This will provide the desired prodrug. Suitable reaction conditions for preparing protecting groups are well known in the art. A source for reaction conditions is found in T. H. Greene and P. G. Wuts, Protective Groups in Orqanic Svnthesis, 2nd. edition, John Wiley & Sons, New York (1991). This invention also encompasses compounds of formula I, II, III, IV, V, VI, VII, VIII or IX, which are esters or prodrugs and which are also salts. For example, a compound of The invention may be an ester of a carboxylic acid and also an acid addition salt of a substituent containing onyne amine in the same compound. The compounds of the present invention are useful for inhibiting neuraminidase from disease causing microorganisms, which comprise a neuraminidase The compounds of the invention are useful (in humans, other mammals and birds) for the treatment or prevention of diseases caused by microorganisms comprising a neuraminidase. The compounds of the present invention are useful for inhibiting neuraminidase from influenza A viruses and Influenza B neuraminidase, in vitro or in vivo (especially in mammals and, in particular, humans) the compounds of the present invention are also useful for the inhibition of influenza viruses, orthomyxoviruses and paramyxoviruses in vivo, especially the inhibition of influenza viruses. influenza A and influenza B virus in humans and Other Mammals The compounds of the present invention are also useful for the treatment of infections caused by influenza viruses, orthomyxoviruses and paramyxoviruses m vivo, especially diseases in humans caused by influenza A and influenza B viruses. The compounds of the present invention also are useful for the prophylaxis of infections caused by influenza viruses, orthomyxoviruses and paramyxoviruses in vivo in humans and other mammals, especially the prophylaxis of viral infections of influenza A and influenza B, and in particular, the prophylaxis of 252 viral infections of influenza A and influenza B in humans who are at risk of developing other concurrent respiratory diseases with or as a consequence of influenza virus infections or who suffer from chronic respiratory disease such as asthma, emphysema, or cystic fibrosis The daily dose administered to a human or other host mammal is individual or divided doses may be in amounts of for example 0,001 to 300 mg / kg body weight daily, and more usually from 0 1 to 10 mg / kg body weight of the body, daily The unit dose compositions may contain such amounts of their submultiples to develop the daily dose The amount of the active ingredient may be combined with the carrier materials to produce a varied individual dosage form depending on the host treated and the mode of administration particular however, it should be understood that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, drug combination excretion rate, and the severity of the particular disease the therapy is presenting Administration of a compound of this invention will begin before or at the time of infection or after the onset of 253 established symptoms and / or confirmation of infection. The compounds of the present invention can be administered orally, parenterally, sublingually, intranasally, through intrapulmonary administration, or through inhalation or insufflation as a solution, suspension or dry powder (eg, in a suspension), or rectally, in unit dose formulations containing conventional, non-toxic pharmaceutically acceptable carriers, auxiliaries, and carriers, as desired. The term "parenteral" as used herein, includes subcutaneous, intravenous, intramuscular injections, intrasternal injection, or infusion techniques. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing agents or humectants and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-propanedio. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and an isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any soft fixed oil can be employed, including mono or synthetic diglycerides. In addition, fatty acids such as oleic acid find use in the 254 preparation of injectable products. Suppositories for rectal administration of the drug can be prepared by displaying the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols, which are solid at ordinary temperatures but liquid at rectal temperature and, therefore, are They will melt in the rectum and release the drug. Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Said dosage forms may also comprise, as is normal in practice, additional substances other than inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules tablets and pills, the dosage forms may also comprise p H regulatory agents. Tablets and pills can also be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Said compositions may also comprise auxiliaries such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfume-providing agents.

The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed through liquid crystals and treated mono or multilamellar which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions herein in the form of liposomes may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are phospholipids and phosphatidylcholines (lecithin) both natural and synthetic. Methods for forming liposomes are well known in the art. See, for example, Prescott, Ed., Methods in Cell Bioloqy. Volume XIV, Academic Press, New York, N. Y. (1976), p. 33 et seq. The compounds of the present invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more agents against infection and / or other agents used to treat other acute or chronic respiratory conditions. Other agents that will be administered in combination with a compound of the present invention include: an influenza vaccine; other influenza inhibitors such as, for example, amantadine, rimantadine, ribavirin, and the like; another neuraminidase inhibitor a;: .. ts. 256 of influenza such as, for example, zanamivir or GS 4104, and the like; agents used to treat bacterial respiratory infections and brochitis such as, for example, erythromycin, clarithromycin, azithromycin, and the like; and agents used to treat asthma, such as, for example, sileuton, albuteroi (salbutamol), salmeterol, formoter, ipratropium bromide, inhaled steroids, the like, or anti-inflammatory agents for treating asthma, such as, for example, beclomethasone dipropionate, fluticasone propionate, budesonide, tracinolone acetonide, flunisolide, cromolyn, zarfilukast, montelukst, used in combination with a compound of the present invention. When administered as a combination, the therapeutic agents can be formulated as separate compositions, which are given at the same time or at different times, or the therapeutic agents can be given as an individual composition. The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes that are obvious to those skilled in the art are intended to be within the scope and nature of the invention, which are defined in the appended claims.

Claims (1)

1. 257 CLAIMS 1 - . 1 - A compound of the formula: or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R is selected from the group consisting of: (a) -C02H, (b) -CH2C02H, (c) -S03H, (d) -CH2S03H, (e ) - 258 S02H, (f) -CH2S02H, (g) -P03H2 (h) -CH2P03H2, (i) -P02H, (j) -CH2P02H (k) tetrazolyl (I) -CH2-tetrazole, () -C ( = 0) -N H- S (0) 2 -R11, (n) -CH2C (= 0) -N HS (0) 2 -R11, (o) -S02N (T-R11) R12 and (p) - CH2S02N (T-R11) R12 wherein T is selected from the group consisting of (i) a bond, (n) -C (= OJ- (MI) -C (= 0) 0-, (iv) -C ( = 0) S-, (v) - C (= 0) NR36-, (vi) -C (= S) 0-, (vil) -C (= S) S-, and (vin) -C (= S) N R3S-, R1 1 is selected from the group consisting of (i) alkyl of 1 to 12 carbon atoms, (n) alkenyl of 2 to 12 carbon atoms, (ni) cycloalkyl, (iv) (c? cloalqu? l) alkyl, (v) (c? cloalqu? l) alken? lo, (vi) cycloalkenyl, (vn) (c? cloalquen? l) alkyl, (vpi) (c? chloralquen? l) alken? lo, (ix) aplo, (x) (ar? l) alkalo, (xi) (apl) alken? lo, (xn) heterocyclic, (XIII) alkyl (heterocyclic) and (xiv) alkenyl (heterocyclic), and R 12 and R36 are independently selected from the group consisting of (i) hydrogen, (n) alkyl of 1 to 12 carbon atoms, (ni) alkenyl of 2 to 12 carbon atoms, (iv) cycloalkyl, (v) (c? cloalkyl) alkyl, (vi) (c? cloalkyl) alken? lo, (vn) cycloalkenyl, (vni) (c? chloralken? l) alkyl, (ix) (c? chloralken? l) alken? lo, (x) aplo, (xi) (ar? l) alkyl, (xn) (ar? l) alken? lo, (xm) heterocyclic, (xiv) alk? the (heterocyclic) and (xv) alkenyl (heterocyclic), X is selected from the group consisting of (a) -C (=?) - N (R *) -, (b ) -N (R *) - C (=?) - (c) -C (= S) -N (R *) - (d) -N (R *) - 259 C (= S) -, (e) -N (R *) - S02-, and (f) -S02-N (R *) -, wherein R * is hydrogen, lower alkyl of 1 to 3 carbon atoms carbon or cyclopropyl, R2 is selected from the group consisting of: (a) hydrogen, (b) alkyl of 1 to 6 carbon atoms, (c) alkenyl of 2 to 6 carbon atoms, (d) cycloalkyl of 3 to 6 carbon atoms, (e) cycloalkenyl of 5 to 6 carbon atoms, (f) haloalkyl of 1 to 6 carbon atoms and (g) haloalkenyl of 2 to 6 carbon atoms; or R'-X- is: wherein Y1 is -CH2-, -O-, -S- or -NH, and Y2 is -C (= 0) - or -C (Raa) (Rb) -, wherein Ra ° and Rbb independently are selected from a group consisting of hydrogen, lower alkyl of 1 to 3 carbon atoms, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-t-olethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl; Z1 is -O-, -S-, or C (R5) 2; R3 and R4 are independently selected from the group consisting of: (a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl, (d) heterocyclic, 260 (e) aryl and (f) -Z-R'4; wherein Z is- (i) -C (R37a) (R37b) -, (il) -C (R47) = C (R48), (iii) -C = C-, (iv) -C (= 0) , (v) -C (= S) -, (vi) -C (= NR15) -, (vii) -C (R37a) (OR37c) -, (viii) -C (R37a) (SR37c) -, (ix) -C (R37a) (N (R37b) (R370)) -, (x) -C (R37a) (R37b) -0-, (xi) -C (R37a) (R37b) -N (R37c) -, (xii) -C (R37a) (R37b) -N (0) (R37c) -, (xiii) -C (R37a) (R37b) -N (OH) -, (XiV) -C (R37a) ( R37b) -S-, (xv) -C (R37a) (R37b) -S (0) -, (xvi) -C (R37a) (R37b) -S (0) 2-, (xvii) -C (R37a ) (R37b) -C (= 0) -, (xviii) -C (R37a) (R37b) -C (= S) -, (xix) -C (R37a) (R37b) -C (= NR15) - , (xx) -C (R37a) (OR37c) -C (= 0) -, (xxi) -C (R37a) (SR37o) -C (= 0) -, (xxii) -C (R37a) (OR37c) -C (= S) -, (xxiii) -C (R37a) (SR37c) -C (= S) -, (xxiv) -C (= 0) -C (R37a) (OR37c) -, (xxv) - C (= 0) -C (R37a) (SR370) -, (xxvi) -C (= S) -C (R37") (OR37c) -, (xxvi i) -C (= S) -C (R37a) (SR37c) -, (xxviii) -C (R37a) (OR3 c) -C (R37a) (OR37c), (xxix) -C (R37a) (SR37o) -C (R37a) (OR37c) -, (xxx) -C (R37a) (OR37c) -C (R37a) (SR37c) -, (xxxi) -C (R7a) (SR37c) -C (R37a) (SR37c) -, (xxxii) -C (= 0) - C (= 0) -, (xxxiii) -C (= S) -C (= S) -, (xxxiv) -C (= 0) -0-, (xxxv) -C (= 0) -S-, (x xxvi) -C (= S) -0-, (xxxvií) -C (= S) -S-, (xxxviii) -C (= 0) -N (R37a) -, (xxxix) -C (= S) -N (R37a) -, (xl) -C (R37a) (R37b) -C (= 0) -N (R37a) -, (xl i) -C (R37a) (R37b) -C (-S) - N (R37a) -, (xlii) -C (R37a) (R37b) -C (= 0) -0-, (xliii) -C (R37a) (R37b) -C (= 0) -S-, (xliv) ) -C (R37a) (R37b) -C (= S) -0-, (xlv) -C (R37a) (R37b) -C (= S) -S-, (lvi) -C (R37a) (R37 ) -N (R37b) -C (= 0) -, (xlvii) -C (R37a) (R37b) -N (R37b) -C (= S) -, (xlviii) -C (R37a) (R37b) - 0-C (= 0) -, (xlix) -C (R37a) (R37b) -SC (= 0) -, (I) -C (R37a) (R37b) -0-C (= S) -, 261 (li) -C (R37a) (R37) -SC (= S) -, (l ii) -C (R37a) (R37b) -N (R37b) -C (= 0) -N (R- "a ) -, (liii) -C (R37a) (R37b) -N (R37b) -C (= S) -N (R37a) -, (l iv) -C (R37a) (R37b) -N (R37b) -C (= 0) -0-, (Iv) -C (R3ra) (R37b) -N (R37b) -C (-0) -S-, (Ivi) -C (R37a) (R37b) -N (R37b) -C (= S) -0-, (Ivii) -C (R37a) (R37b) -N (R37b) -C (= S) -S-, (Ivii) -C (R37a) (R37b) -0-C ( = 0) -N (R37a) -, (lix) -C (R37a) (R37b) -SC (-0) -N (R37a) -, (Ix) -C (R37a) (R37b) -0-C ( = S) -N (R37a) -, (Ixi) -C (R37a) (R3b) -SC (= S) -N (R37a) -, (Ixii) -C (R37a) (R37b) -0-C (= 0) -0-, (Ixiii) -C (R37a) (R37b) -S-C (= 0) -0-, (Ixiv) -C (R37a) (R37b) -0-C (= 0) -S-, (Ixv) -C (R37a) (R37b) -S-C (= 0) -S-, (Ixvi) -C (R37a) (R37b) -0-C (= S) -0-, (Ixvii) -C (R37a) (R37b) -S-C (= S) -0-, (Ixviii) -C (R37a) (R37b) -0-C (= S) -S-, (Ixix) -C (R37a) (R37b) -S-C (= S) -S- or (IXX) -C (R37a) (R37) -C (R37a) (OR370) -; R14 is: (i) hydrogen, (ii) alkyl of 1 to 12 carbon atoms, (iii) haloalkyl, (iv) hydroxyalkyl, (v) alkyl substituted with thiol, (vi) alkyl substituted with R37cO, (vii) alkyl substituted with R37cS, (viii) aminoalkyl, (xi) alkyl substituted with (R37c) N H-, (x) alkyl substituted with (R37a) (R37c) N-, (xi) alkyl substituted with R37aO- (0 =) C , (xii) alkyl substituted with R37aS- (0 =) C-, (xiii) alkyl substituted with R37aO- (S =) C, (xiv) alkyl substituted with R37aS- (S =) C, (xv) alkyl substituted with (R37aO) 2-P (= 0), (xvi) cyanoalkyl, (xvii) alkenyl of 2 to 12 carbon atoms, (xviii) haloalkenyl, (xix) alkynyl of 2 to 262 1 2 carbon atoms, (xx) cycloalkyl, (xxi) (c? cloalqu? l) alkyl, (xxn) (c? cloalqu? l) alken? lo, (xxm) (c? cloalqu? l) alkyl, (xxiv) cycloalkenyl, (xxv) (c? cloalquen? l) alkyl, (xxvi) (c? cloalquen? l) alken? lo, (xxvn) (c? cloalquen? l) alk? lo, (xxvm) ap lo, (xxix) (ar? l) ar? lo, (xxx) (ar? l) alken? lo, (xxxi) (ar? l) alkalo, (xxxn) heterocyclic, (xxxni) alkyl (heterocyclic), (xxxiv) alken? lo (heterocyclic) ) or (xxxv) alkyne (heterocyclic), provided that R14 is other than hydrogen when Z is -C (R37a) (R37b) -N (R37b) -C (= 0) -0- , -C (R37a) (R37b) -N (R37b) -C (= S) -O-, -C (R37a) (R37b) -N (R37b) -C (= 0) -S-, -C (R37a) (R37b) -N (R37") -C (= S) -S- , -C (R37a) (R37) -0-C (= 0) -0-, -C (R37a) (R37b) -0-C (= S) -O-, -C (R37a) (R37b) - SC (= 0) -0-, -C (R37a) (R37b) -SC (= S) -0-, -C (R37a) (R3b) -0-C (= 0) -S-, -C (R37a) (R37b) -0-C (= S) -S-, -C (R37a) (R37b) - SC (= 0) -S- or -C (R37a) (R37b) -SC (= S) -S-, R37a R37b Ri7 and R4β in each occurrence are independently selected from the group consisting of (i) hydrogen, (n ) alkyl of 1 to 12 carbon atoms, (ni) haloalkyl, (iv) hydroalkyl, (v) alkoxyalkyl, (vi) alkenyl of 2 to 12 carbon atoms, (vi i) haloalkenyl, (VIII) alkynyl of 2 to 12 carbon atoms, (ix) cycloalkyl, (x) (c? Cloalqu? L) alkyl, (xi) (c? Chloralqu? Lo) alken? Lo, (xn) (c? Cloalqu? L) alkyne, (xm) cycloalkenyl, (xiv) (c? cloalquen? l) alkalo, (xv) (c? cloalquen? l) alken? lo, (xvi) (c? cloalquen? l) al? n? lo, (xvn) aplo, (XVI II) (ar? l) rent, 263 (xix) (ar? L) alken? Lo, (xx) (ar? L) alkyl), (xxi) heterocyclic, (xxn) alkyl (heterocycle), (xxiu) alken? (heterocyclic) and (xxiv) alkylene (heterocyclic), R37c in each occurrence is independently selected from the group consisting of (i) hydrogen, (11) alkyl from 1 to 12 carbon atoms, (ni) haloalkyl, (iv) alkenyl of 2 to 12 carbon atoms, (v) haloalkenyl, (vi) alkynyl of 2 to 12 carbon atoms, (vn) cycloalkyl, (vm) (c? l) alkyl, (ix) (c? chloralqu? l) alken? lo, (x) (c? cloalqu? l) alkylene, (xi) cycloalkenyl, (xn) (c? cloalquen? l) alkyl, (xm) (c? cloalquen? l) alken? lo, (xiv) (c? cloalquen? l) alkalo, (xv) aplo, (xvi) ( ar? l) alkyl, (xvu) (ar? l) alken? lo, (xvm) (ar? l) alternating it, (xix) heterocyclic, (xx) alkyl (heterocyclic? co), (xxi) alken? lo (heterocyclic, (xxn) alkylene (heterocyclic), (xx ???) - C (= 0) -R14, (xxiv) -C (= S) -R14, (xxv) -S (0) 2-R14 and (xxvi) hydroxyalkyl, or when Z is -C (R37a) (R37b) -N (R37c) -, then N (R37 °) and R14 when taken together are a azido group, or when Z is -C (R37a) (R37b) -N (0) (R37c) -, then N (0) (R37c) and R14 when taken together are a 3-7 membered heterocyclic ring N- oxidized having at least one nitrogen atom of the N-oxidized ring, or when Z is -C (R37a) (0 R37c) -, -C (R37a) (SR37c) - or -C (R37a) (N (R37b) (R37c)) -, then R37a, R14 and the carbon atom to which they are attached when taken together form a 264 cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl ring, R15 is selected from the group consisting of (i) hydrogen, (n) hydroxy, (ni) amino, (iv) alkyl of 1 to 12 carbon atoms, (v) haloalkyl, (vi) alkenyl of 2 to 12 carbon atoms, (vn) haloalkenyl, (v ni) cycloalkyl, (ix) (c? cloalkyl) alkyl, (x) (c? cloalkyl) alkenyl, (xi) cycloalkenyl, (xi i) (c? cloalquen? l) alkyl, (xm) (c? cloalquen? l) alken? lo, (xiv) aplo, (xv) (ar? l) alkalo, (xvt) ( ar? l) alken? lo, (xvni) heterocyclic, (xvni) alkyl (heterocyclic) and (xix) alkenyl (heterocyclic), or R3 and R4 taken together, with the atom to which they are attached, form a carbocyclic or heterocyclic ring having 3 to 8 atoms in the ring, R5 in each occurrence is independently selected from the group consisting of (a) hydrogen, (b) -CH (R38) 2, (c) - (CH2) -0-R40, (d) alkylamide from 2 to 4 carbon atoms, (e) cyclopropyl, (f) cyclobutyl, (g) -C (= Q,) - R17, and (h) - (CH2) -N (R, 9) 2, when r is 0, 1 or 2, provided that one of R5 is -O-R40 or N (R 9) 2, then the other R5 is different from -O-R40 or -N (R19) 2, where Q1 is O, S, or N (R18), R17 and R8 are independently selected, from each occurrence, from the group consisting of hydrogen, methyl and ethyl, R19, R38, and R40 are independently selected, at each occurrence, from the group consisting of (i) hydrogen, (n) alkyl of 1 to 12 carbon atoms, (ni) 265 haloalkyl, (iv) alkenyl of 2 to 12 carbon atoms, (v) haloalkenyl, (vi) cycloalkyl, (vii) (cycloalkyl) alkylene, (viii) (cycloalkyl) alkenyl, (ix) cycloalkenyl , (x) (cycloalkenyl) alkyl, (xi) (cycloalkenyl) alkenyl, (xii) aryl, (xiii) (aryl) alkyl, (xiv) (aryl) alkenyl, (xv) heterocyclic, (xvi) alkyl (heterocyclic) and (xvii) alkenyl (heterocyclic); or one of R19 is an N-protecting group; or the two R5 groups taken together with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms; Y is selected from the group consisting of: (a) alkyl of 1 to 5 carbon atoms, (b) haloalkyl of 1 to 5 carbon atoms, (c) alkenyl of 2 to 5 carbon atoms, (d) haloalkenyl of 2 to 5 carbon atoms, (e) alkenyl of 2 to 5 carbon atoms, (f) cycloalkyl of 3 to 5 carbon atoms, (g) cycloalkyl of 3 to 5 carbon atoms-alkyl of 1 to 3 carbon atoms carbon, (h) cycloalkenyl of 5 carbon atoms, (i) cycloalkenyl of 5 carbon atoms-alkyl of 1 to 3 carbon atoms, (j) cycloalkenyl of 5 carbon atoms-alkenyl of 2 to 3 carbon atoms, (k) - (CHR39) "OR20, (I) -CH (OR20) -CH2 (OR20), (m) - (CH R39) "SR21, (n) phenyl, (o) halo-substituted phenyl, (p) -CH R39) "C (= Q2) R22, (q) - (CH R39)" N (= Q3), (r) -N (0) = CHCH3, (s) - (CHR39) "N (CH3) R34 and (t) a heterocyclic ring having from 3 to 6 ring atoms; wherein n is 0, 1 or 2; Q2 is O, S, N R25, or CH R26; and Q3 is N R41, or 266 CHR42, R20 in each occurrence is independently (I) methyl, (u) ethyl, (ni), n-propyl, (? V) isopropyl, (v) haloalkyl of 1 to 3 carbon atoms, (vi) vinyl, (vn) propenyl, (vn i) isopropenyl, (ix) halo, (x) haloalkenyl of 2 to 3 carbon atoms, (xi) amino, (xn) -NHCH3, (xm) -N (CH3) 2, (xiv) -NHCH2CH3, (xv) -N (CH3) (CH2CH3), (xvi) -N (CH2CH3) 2 or (xvn) -N (= CH2), R21 is (i) hydrogen (n) methyl, (ni) ethyl, (iv ) n-propyl, (v) isopropyl, (vi) haloalkyl of 1 to 3 carbon atoms, (vn) vinyl, (vui) propenyl, (ix) isopropenyl, (x) aillo or (xi) haloalkenyl of 2 to 3 carbon atoms, R22 is (i) hydrogen, (II) methyl, (MI) ethyl, (iv) n-propyl, (v) isopropyl, (vi) hydroxy, (vn) thiol , (vm) methoxy, (ix) ethoxy, (x) n-propoxy, (xi) isopropoxy, (xn) cyclopropoxy, (xpi) methylthio, (xiv) ethylthio, (xv) n-propylthio, (xvi) isopropylthio, (xvn) cyclopropylthio, (xvm) vmilo, (xix) propenyl, (xx) isopropenyl, (xxi) ayl, (xxn) -N (R28a) (Rb), (xxm) -CH2R29, (xxiv) to inomethyl, (xxv) hydroxymethyl, (xxvi) thiol ethyl, (xvu) -NHNH2 (XVIII) -N (CH3) NH2 or (xxix) -NHNH (CH3), R23 and R39 are independently hydrogen or methyl, R41 and R42 are independently hydrogen, methyl or ethyl, R24 is selected from the group consisting of (i) hydrogen, (n) alkyl of 1 to 4 carbon atoms (neither) 267 alkenyl of 2 to 4 carbon atoms, (iv) alkynyl of 2 to 4 carbon atoms, (v) cyclopropyl, (vi) -C = (Q4) -R30, (v) -OR3 ', and ( vi) -N (R32) 2, wherein Q4 is O, S, or N ('R33); R25 is hydroxy, methyl, ethyl, amino, -GN, or -N02; R26 is a group that is hydrogen, methyl or ethyl; R28a is hydrogen, hydroxy, methyl, ethyl, amino, -N HCH3 -N (CH3) 2, methoxy, ethoxy, or -CN, R28b is hydrogen, methyl or ethyl; or R28a, R28b and the nitrogen to which they are attached taken together represent azetidinyl, the group R29 is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino; the group R30 is hydrogen, methyl, ethyl, -OR34, -SR34, -N (R3a) 2, -NHOH, -NHNH2, -N (CH3) NH2, or -N (CH2CH3) NH2; the substituents R31 and R32, in each occurrence, are independently hydrogen, methyl or ethyl; the group R is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -N02 the group R is methyl or ethyl; the group R35 is independently hydrogen, methyl or ethyl; provided that when Q2 is CH R26, then R22 is selected from the group consisting of hydrogen, -CH3, C2H5, -C3H. , -OCH3, -SCH3, -0-C2H5, and -SC2H5; R6 and R7 are independently selected from the group 268 consists of: (a) hydrogen, (b) alkyl of 1 to 12 carbon atoms, (c) alkenyl of 2 to 12 carbon atoms, (d) cycloalkyl, (e) (cycloalkyl) alkyl, (f) (cycloalkyl) alkenyl, (g) cycloalkenyl, (h) (cycloalkenyl) alkyl, (i) (cycloalkenyl) alkenyl, (i) aryl, (k) (aryl) alkyl, (I) (aryl) alkenyl, ) heterocyclic, (n) alkyl (heterocyclic), (o) alkenyl (hetericcyclic), (p) -OR37a and (q) -N (R37a) 2; and R8, R9 and R10 independently are selected from the group consisting of: (a) hydrogen, (b) alkyl of 1 to 6 carbon atoms, (c) alkenyl of 2 to 6 carbon atoms, (d) cycloalkyl of 3 to 6 carbon atoms, (e) cycloalkenyl of 3 to 6 carbon atoms, and (f) fluorine, provided that the total number, other than hydrogen, in each of R8, R9 and R10, is 6 atoms or less . 2 - The compound according to claim 1, having the formula: 269 II wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined herein. 3 - The compound according to claim 2, having the relative stereochemistry illustrated by the formula: VIII IX wherein R \ Rz, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z are as defined herein and wherein R3 and R4 are both not hydrogen. 270 4 - The compound according to claim 1, wherein R is as defined herein; -X-R2 is R2 -C (= 0) -N H-, R2 -N HC (= 0) -, R2 -N H-S02- or R2-S02-N H-, where R2 is lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms, or haloalkenyl of 2 to 3 carbon atoms, or -X-R2 is: wherein Y1 is -CH2-, -O-, S- or -NH- and Y2 is -C (= 0) - or -C (Raa) (Rbb), wherein Raa and Rbb are independently selected from the group consisting of of hydrogen, lower alkyl of 1 to 3 carbon atoms, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl; R3 and R4 are independently selected from hydrogen, heterocyclic and: -Z-R14, wherein Z and R14 are as defined above, and wherein one of R3 and R4 is other than hydrogen; Z1 is -O-, -S- or -CH (RS) -, wherein R5 is hydrogen, lower alkyl or (CH2) rN (R19) 2, wherein r and R19 are as defined above; or R5 is hydrogen, lower alkyl or - (C H2), N (R, 9) 2 in 271 where r and R19 are as defined above; R6 and R7 are independently hydrogen or lower alkyl; R8 and R9 are independently hydrogen, fluoro or lower alkyl; R10 is hydrogen, fluoro or lower alkyl; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, -C (= Q2) R22, -N (= Q3), -N (0) = CHCH3, -N R23R24 or an anilo heterocyclic having from 3 to 6 atoms in the ring, wherein R22, R23, R24, Q2 and Q3 are as defined above. 5. - The compound according to claim 4, which has the formula: ll where R \ R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are like 272 were defined here 6 - The compound according to claim 2, which has the relative stereochemistry illustrated by the formula. VIII IX where R \ R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined here and where R3 and R4 are not equal 7. - The compound according to claim 1, wherein R1 is as defined herein; -X-R2 is R2 -C (= 0) -N H-, R2-N HC (= 0) -, R2-N H-S02- or R2-S02- N H-, where R2 is lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms, or haloalkenyl of 2 to 3 carbon atoms, or -X-R2 is 273 wherein Y1 is -CH2- and Y2 is -C (= 0) - or -C (Raa) (Rbb), wherein Raa and Rbb are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 3 carbon atoms carbon, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl; R3 and R4 are independently selected from hydrogen, heterocyclic and: -Z-R14, wherein Z and R4 are as defined above, and wherein one of R3 and R4 is other than hydrogen; Z1 is -O-, -S- or -CH (R5) -, wherein R5 is hydrogen, lower alkyl or (CH2) rN (R19) 2, wherein r and R19 are as defined above; or R5 is hydrogen, lower alkyl or - (CH) rN (R19) 2 wherein r and Ri9 are as defined above; R6 and R7 are independently hydrogen or lower alkyl; R8 and R9 are independently hydrogen, or lower alkyl; R10 is hydrogen, or lower alkyl; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, -C (= Q) R22, -N (= Q3), -N (0) = CHCH3, or a heterocyclic ring having 5 atoms in the ring and also containing one or two double bonds, wherein R22, Q2 and Q3 are as defined above. 274 8 - The compound according to claim 7, which has the formula: II wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined herein. 9. The compound according to claim 7, which has the relative stereochemistry illustrated by the formula: IV 275 VIII IX wherein R1, R2, R3, R4, R5, R6, R7, R8 X, Y and Z1 are as defined herein and wherein R3 and R4 are both non-equal. 1 - The compound according to claim 1, wherein R1 is as defined herein; -X-R2 is R2 -C (= 0) -NH-, R2 -NH-C (= 0) -, R2 -NH-S02- or R2-S02-N H-, where R2 is lower alkyl of 1 to 3 carbon atoms, lower haloalkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms, or haloalkenyl of 1 to 3 carbon atoms, or -X-R2 is: wherein Y1 is -CH2-, and Y2 is -C (= 0) - or -C (Raa) (Rbb), wherein Raa and Rbb are independently selected from the group consisting of hydrogen, lower alkyl of 1 to 3 atoms carbon, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl; 276 R3 and R4 are independently selected from hydrogen, heterocyclic and: -Z-R14, wherein Z and R14 are as defined above, and wherein one of R3 and R4 is other than hydrogen; Z is -O-, -S- or -CH (R5) -, wherein R5 is hydrogen, lower alkyl or (CH2), N (R19) 2, wherein r and R19 are as defined above; or R5 is hydrogen, lower alkyl or - (CH2), N (R19) 2 wherein r and R19 are as defined above; R6 and R7 are independently hydrogen or lower alkyl; R8 and R9 are independently hydrogen, or lower alkyl; R 10 is hydrogen, or lower alkyl; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. 12 - The compound according to claim 7, which has the formula: 277 VIII IX wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined herein and wherein R3 and R4 are both not the same. 14 - The compound according to claim 1, wherein R1 is -C02H; -X-R2 is R2 -C (= 0) -N H-, R2 -NH-C (= 0) -, R2 -N H-S02- or R2-S02-NH-, where R2 is lower alkyl of 1 to 3 carbon atoms, or lower haloalkyl of 1 to 3 carbon atoms; R3 and R4 are independently selected from hydrogen, heterocyclic and: -Z-R14, wherein Z and R1 4 are as defined above, and wherein one of R3 and R4 is other than hydrogen; Z is -O-, -S- or -CH; or R5 is hydrogen; R6 and R7 are independently hydrogen or lower alkyl; R8 and R9 are independently hydrogen, or lower alkyl; R10 is hydrogen, or lower alkyl; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. 14. The compound according to claim 1, which 278 has the formula II wherein R, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z are as defined herein. The compound according to claim 14, having the relative stereochemistry illustrated by the formula 279 VIII IX wherein R, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined herein and wherein R3 and R4 are both not the same. 16. The compound according to claim 1, wherein R1 is -C02H; -X-R2 is R2-C (= 0) -N H-, R2-NH-C (= 0) -, R2-NH-S02- or R2-S02-N H-, where R2 is lower alkyl of 1 to 3 carbon atoms or lower haloalkyl of 1 to 3 carbon atoms; R 4 is hydrogen or lower alkyl or R 3 is heterocyclic or -Z-R 14, wherein Z and R 14 are as defined above; Z1 is -O-, -S- or -CH2; or R5 is hydrogen; R6 and R7 are hydrogen; Rs and R9 are hydrogen; R 10 is hydrogen; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. 17. The compound according to claim 16, which has the formula: 280 II wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined herein. 18. The compound according to claim 16, which has the relative stereochemistry illustrated by the formula: IV 281 VIII IX wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined herein and wherein R3 and R4 are both non-equal. 19. The compound according to claim 1, wherein R1 is -C02H; -X-R2 is R2-C (= 0) -N H-, R2-N HC (= 0) -, R2-N H-S02- or R2-S02-N H-, where R2 is lower alkyl of 1 to 3 carbon atoms or lower haloalkyl of 1 to 3 carbon atoms; R 4 is hydrogen or lower alkyl and R 3 is (a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) N (0) (R37o) R14, wherein R14 is (i) alkyl, (i) cycloalkyl, (? I) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (viii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) alkyl (heterocyclic), (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) alkyl substituted with (R37aO) - (0 =) C-, or (xv) alkyl substituted with (R37aO) 2-P (= 0); R37a and R37b are independently selected from the group consisting of (i) hydrogen, (ii) lower alkyl and (iii) lower alkenyl; Y 282 R37c is (i) hydrogen, (ii) lower alkyl or (ii) lower alkenyl, Z1 is -O-, -S- or -CH2; or R5 is hydrogen; R5 and R7 are hydrogen; R8 and R9 are hydrogen; R10 is hydrogen; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. 19. The compound according to claim 19, which has the formula: ll where R 1, R2, R3, R4, R5, R6, R7, Ra, R9, R10, X, Y and Z1 are like 283 were defined here. 21 - The compound according to claim 16, which has the relative stereochemistry illustrated by the formula: IV VIII IX wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined herein and wherein R3 and R4 are both non-equal. 22. The compound according to claim 1, wherein R 1 is -C02H; -X-R2 is R2-C (= 0) -N H-, R2-NH-C (= 0) -, or R2-S02-N H-, where R2 is lower alkyl of 1 to 3 carbon atoms or lower haloalkyl of 1 to 3 carbon atoms; R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) 284 -C (R37a) (O R37o) -R14, wherein R14 is (i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) alkyl (heterocyclic), (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) alkyl substituted with (R37aO) - (0 =) C-, or (xv) alkyl substituted with (R37aO) 2-P (= 0); R37a and R37b independently are selected from the group consisting of (i) hydrogen, (ii) lower alkyl and (iii) lower alkenyl; and R37c is (i) hydrogen, (ii) lower alkyl of 1 to 3 carbon atoms or (iii) allyl; Z1 is -O-, -S- or -CH2; or R5 is hydrogen; R6 and R7 are hydrogen; R8 and R9 are hydrogen; R10 is hydrogen; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. 23 - The compound according to claim 22, having the formula: 285 II wherein R1, R2, R3, R4, Rs, R6, R7, R8, R9, R0, X, Y and Z1 are as defined herein. 24 - The compound according to claim 16, having the relative stereochemistry illustrated by the formula IV VIII IX 286 wherein R, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z are as defined herein and wherein R3 and R4 are both not the same. 25 - The compound according to claim 1, wherein R1 is -C02H; -X-R2 is R2-C (= 0) -NH-, or R2-S02-NH-, wherein R2 is lower alkyl of 1 to 3 carbon atoms or lower haloalkyl of 1 to 3 carbon atoms; R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C (R37a) (OR37c) -R14, wherein R14 is (i) lower alkyl, (i) lower alkenyl, (iii) lower alkyl substituted with hydroxy or (v) lower alkyl substituted with alkoxy; (R37a) is (i) hydrogen, (ii) lower alkyl or (ni) lower alkenyl; and R37c is (i) hydrogen, (ii) lower alkyl of 1 to 3 carbon atoms or (iii) allyl; Z1 is -O-, -S- or -CH2; or R5 is hydrogen; R6 and R7 are hydrogen; R8 and R9 are hydrogen; R 0 is hydrogen; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms, or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. 26 - The compound according to claim 25, which 287 has the formula: II wherein R1, R2, R3, R4, R5, R6, R7, Rd, R9, R0, X, Y and Z1 are as defined herein. 27. The compound according to claim 25, which has the relative stereochemistry illustrated by the formula: IV 288 VIII IX wherein R, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined herein and wherein R3 and R4 are both not the same. 28 - The compound according to claim 1, wherein R 1 is -C02H; -X-R2 is R2-C (= 0) -NH-, or R2-S02-N H-, wherein R2 is lower alkyl of 1 to 3 carbon atoms or lower haloalkyl of 1 to 3 carbon atoms; R4 is hydrogen and R3 is -C (R37a) (OR37c) -R14, wherein R14 is lower alkyl or lower alkenyl; lower alkyl or lower alkenyl; and R37c is hydrogen, lower alkyl of 1 to 3 carbon atoms or allyl, Z is -O-, S- or -CH2; or R5 is hydrogen, R6 and R7 are hydrogen; R8 and R9 are hydrogen; R 10 is hydrogen; and Y is alkenyl of 2 to 5 carbon atoms, haloalkenyl of 2 to 5 carbon atoms or a heterocyclic ring having 5 carbon atoms. 289 in the ring and also containing one or two double bonds. 29 - The compound according to claim 28, which has the formula: I II where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as 290 VIII IX wherein R, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y and Z1 are as defined herein and wherein R3 and R4 are both not the same. 31.- A pharmaceutical composition for inhi bir influenza neuraminidase, comprising a pharmaceutical carrier or a therapeutically effective amount of a compound of claim 1. 32. A pharmaceutical composition for treating influenza infection, comprising a pharmaceutical carrier or a therapeutically effective amount of a compound of claim 1. 33. - A pharmaceutical composition for preventing influenza infection, comprising a pharmaceutical carrier or a therapeutically effective amount of a compound of claim 1. 34.- A method for inhibiting neuraminidase of a disease-causing microorganism, comprising administering to a human being or other mammal, with the need thereof, a therapeutically effective amount of a compound of claim 1. 35 - The method according to claim 34, wherein 291 the disease-causing organism is a virus. 36.- The method according to claim 35, wherein the virus is influenza virus 37.- A method for treating a disease caused by a microorganism having a neuraminidase, which comprises administering to a human or other mammal with the need thereof, a therapeutically effective amount of a compound of claim 1. 38, - The method according to claim 37, wherein the disease-causing microorganism is a virus. 39. The method according to claim 38, wherein the virus is influenza virus. A method for preventing a disease caused by a microorganism having a neuraminidase, which comprises administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of claim 1. 41. The method according to claim 40, wherein the disease-causing microorganism is a virus. 42.- The method according to claim 41, wherein the virus is influenza virus ^ Sg,