EP1087938A1 - 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 Neuraminidases

Technical Field

The present invention relates to novel compounds, compositions and methods for inhibiting neuraminidase, especially influenza neuraminidase. The invention also contemplates a composition and methods for preventing and treating an influenza infection and processes for making such compounds and synthetic intermediates employed in these processes.

Background of the Invention

Many disease-causing microorganisms possess a neuraminidase neuraminidase (also known as sialidase) which is involved in the replication process of the microorganism. In particular, viruses of the orthomyxovirus and paramyxovirus groups possess a neuraminidase. Diseases associated with paramyxoviruses include RSV (respiratory syncytial virus-related diseases), pneumonia and bronchiolitis (associated with paramyxovirus type 3) and laryngotracheobronchitis (associated with paramyxovirus type 1). Some of the more important disease-causing microorganisms in man and/or animals which possess a neuraminidase include Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae, Arthrobacter sialophilus, influenza virus, parainfluenza virus, mumps virus, Newcastle disease virus, fowl plague virus, equine influenza virus and Sendai virus.

Mortality due to influenza is a serious problem throughout the world. The disease is devastating to man, lower mammals and some birds. Although vaccines containing attenuated influenza virus are available, those vaccines only provide immunological protection toward a few influenza strains and are less effective in otherwise immunologically compromised populations such as the elderly, young children, and in those who suffer from chronic respiratory illness. The productivity loss from absence due to sickness from influenza virus infection has been estimated to be more than $1 billion per year.

There are two major strains of influenza virus (designated A and B). Currently, there are only a few pharmaceutical products approved for treating influenza. These include amantadine and rimantadine, which are active only against the A strain of influenza viruses, and ribavirin, which suffers from dose-limiting toxicity. Mutant virus which is resistant to amantadine and rimantadine emerges quickly during treatment with these agents.

Neuraminidase is one of two major viral proteins which protrude from the envelope of influenza virus. During the release of progeny virus from infected cells, neuraminidase cleaves terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides on the cell surface. Inhibition of neuraminidase enzymatic activity leads to aggregation of progeny virus at the surface. Such virus is incapable of infecting new cells, and viral replication is therefore retarded or blocked. X-ray crystallographic studies and sequence alignments have shown that the residues which directly contact the sialic acid portion of the substrate are strictly conserved in the neuraminidase from all A and B influenza strains. Thus, a compound which binds to the sialic acid binding region of the neuraminidase active site will block the replication of both the A and B strains of influenza virus. Compounds which are influenza neuraminidase inhibitors will be useful for the

-2- 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 which are useful as neuraminidase inhibitors and treatments for influenza.

The following references disclose neuraminic acid derivatives with the disclosed 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. EP823428, published February 11 , 1998 (sialidase inhibitor; influenza treatment);

T. Honda, et al., International Patent Application No. WO98/06712, published February 19, 1998 (sialidase inhibitor; influenza remedy);

L. Von Itzstein, et al., International Patent Application No. WO95/20583, published August 3, 1995 (viral neuraminidase inhibitor; influenza treatment);

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., U.S. Patent No. 5,648,379, issued July 15, 1997 (influenza treatment);

P. Reece, et al., International Patent Application No. W097/32214, published September 4, 1997 (bind to influenza virus neuraminidase active site); and

P. Reece, et al., International Patent Application No. W098/21243, published May 23, 1998 (anti-influenza agent). The following references disclose sialic acid derivatives with the disclosed 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., Helvetica Chimica Acta 74 343-369 (1991) (Vibrio cholerae neuraminidase inhibitor).

The following references disclose benzene derivatives, cyclohexane derivatives or cyclohexene derivatives with the disclosed utility listed after each reference:

Y. Babu, et al., U.S. Patent No. 5,602,277, issued February 11 , 1997 (neuraminidase inhibitors);

M. Luo, et al., U.S. Patent No. 5,453,533, issued September 26, 1995 (influenza neuraminidase inhibitor; influenza treatment);

Y. 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); and

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. W098/17647, published April 30, 1998 discloses piperidine derivatives which are useful as neuraminidase inhibitors. N. Bischofberger, et al., International Patent Application No. W096/269^'33, published September 6, 1996 discloses various substituted 6-membered ring compounds which are useful as neuraminidase inhibitors.

The following references disclose dihydropyran derivatives which are useful as viral neuraminidase inhibitors:

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., U.S. Patent No. 5,512,596, issued April 30, 1996 discloses 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 discloses substituted pyridazines which are useful for treatment of influenza.

B. Horenstein, et al., International Patent Application No. WO99/06369, published February 11 , 1999 discloses piperazine derivatives which are useful as neuraminidase inhibitors.

L. Czollner, et al., Helvetica Chimica Acta 73 1338-1358 (1990) discloses pyrrolidine analogs of neuraminic acid which are useful as Vibrio cholerae sialidase inhibitors.

The following references disclose siastatin B analogs which are useful as neuraminidase inhibitors: Y. Nishimura, et al., Natural Product Letters 1 39-44 (1992); and

Y. Nishimura, et al., Natural Product Letters 1 33-38 (1992). C. Penn, UK Patent Application No. GB2292081 , published February 14, 1996 discloses the use of a neuraminidase inhibitor in combination with an influenza vaccine.

An object of the invention is to provide compounds which inhibit neuraminidase of disease-causing microorganisms; especially, viral neuraminidase; and, most especially, influenza neuraminidase.

An object of the invention is also to provide compounds which inhibit neuraminidase from both A and B strains of influenza.

Another object of the invention is to provide prohylaxis of influenza infection in humans and other mammals.

Another object of the invention is to provide treatment of influenza infection in humans and other mammals.

Another object of the invention is to provide compounds which exhibit activity against influenza A virus and and influenza B virus by virtue of inhibiting influenza neuraminidase when such compounds are administered orally.

Another object of the invention is to provide a compound which can be effectively transported from the plasma into the lung bronchoaveolar fluid of humans and other mammals in order to block the replication of influenza virus in that tissue.

Disclosure of the Invention

The present invention discloses compounds having Formula I, II or III

I

III

harmaceutically acceptable salt, ester or prodrug thereof, wherein R¹ is selected from the group consisting of (a) -CO₂H, (b) -CH₂CO₂H, (c) -SO₃H, (d) -CH₂SO₃H, (e) -S0₂H, (f) -CH2SO2H, (g) -PO3H2, (h) -CH2PO3H2, (i) -PO₂H, (j) -CH₂PO₂H, (k) tetrazolyl, (I) -CH₂-tetrazolyl, (m) -C(=O)-NH-S(O)₂-R >¹11 (n) -CH₂C(=O)-NH-S(0)₂-R¹¹, (o) -SO₂N(T-R¹¹)R¹² and (p) -CH₂SO₂N(T-R ¹)R¹² wherein T is selected from the group consisting of

-7- (i) a bond, (ii) -C(=O)-, (iii) -C(=O)O-, (iv) -C(=O)S-, (v) -C(=O)NR³⁶-

(vi) -C(=S)O-, (vii) -C(=S)S-, and (viii) -C(=S)NR³⁶-,

R¹¹ is selected from the group consisting of

(i) C-₁-C12 alkyl, (ii) C₂-C-|₂ alkenyl, (iii) cycloalkyl, (iv) (cyclo- alkyl)alkyl,

(v) (cycloalkyl)alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl)alkyl,

(viii) (cycloalkenyl)alkenyl, (ix) aryl, (x) (aryl)alkyl, (xi) (aryl)alkenyl,

(xii) heterocyclic, (xiii) (heterocyciic)alkyl and

(xiii) (xiv) (heterocyclic)alkenyl; and

R ² and R³⁶ are independently selected from the group consisting of

(i) hydrogen, (ii) C₁-C₁₂ alkyl, (iii) C -Cι₂ alkenyl, (iv) cycloalkyl,

(v) (cycloalkyl)alkyl, (vi) (cycloalkyl)alkenyl, (vii) cycloalkenyl,

(viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl,

(xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic,

(xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkenyl;

X is selected from the group consisting of

(a) -C(=O)-N(R^*)-, (b) -N(R^*)-C(=0)-, (c) -C(=S)-N(R*)-, (d) -N(R^*)-C(=S)-,

(e) -N(R^*)-SO₂-, and (f) -SO₂-N(R^*)- wherein R* is hydrogen, C C₃ loweralkyi or cyclopropyl;

R² is selected from the group consisting of

(a) hydrogen, (b) Cι-C₆ alkyl, (c) C₂-C₆ alkenyl, (d) C₃-C₆ cycloalkyl,

(e) C₅-C₆ cycloalkenyl, (f) halo Cι-C₆ alkyl and (g) halo C₂-C₆ alkenyl; or R²-X- is

-8- Ύ² < wherein Y¹ is -CH₂-, -O-, -S- or -NH- and Y² is -C(=O)- or -C(R^aa)(R ^b)- wherein R^aa and R^bb are indepedently selected from the group consisting of hydrogen,

C1-C₃ loweralkyi, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;

Z' is -O-, -S-, or C(R^D)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-R¹⁴ wherein Z is

(i) -C(R^37a)(R^37b)-, (ii) -C(R⁴⁷)=C(R⁴⁸)-, (iii) -C≡C-, (iv) -C(=O)-,

(v) -C(=S)-, (vi) -C(=NR¹⁵)-, (vii) -C(R^37a)(OR^37c)-, (viii) - C(R^37a)(SR^37c)-,

(ix) -C(R^37a)(N(R^37b)(R^37c))-, (x) -C(R^37a)(R^37b)-0-,

(xi) -C(R^37a)(R^37b)-N(R^37c)-, (xii) -C(R^37a)(R^37b)-N(O)(R^37c)-,

(xiii) -C(R^37a)(R^37b)-N(OH)-, (xiv) -C(R^37a)(R^37b)-S-,

(xv) -C(R^37a)(R^37b)-S(O)-, (xvi) -C(R^37a)(R^37b)-S(O)₂-, (xvii) -C(R^37a)(R^37b)-C(=O)-, (xviii) -C(R^37a)(R^37b)-C(=S)-,

(xix) -C(R^37a)(R^37b)-C(=NR¹⁵)-, (xx) -C(R^37a)(OR^37c)-C(=O)-,

(xxi) -C(R^37a)(SR^37c)-C(=O)-, (xxii) -C(R^37a)(OR^37c)-C(=S)-,

(xxiii) -C(R^37a)(SR^37c)-C(=S)-, (xxiv) -C(=O)-C(R^37a)(OR^37c)-,

(xxv) -C(=O)-C(R^37a)(SR^37c)-, (xxvi) -C(=S)-C(R^37a)(OR^37c)-,

(xxvii) -C(=S)-C(R^37a)(SR^37c)-, (xxviii) -C(R^37a)(OR^37c)-C(R^37a)(OR^37c)-,

(xxix) -C(R^37a)(SR^37c)-C(R^37a)(OR^37c)-,

(xxx) -C(R^37a)(OR^37c)-C(R^37a)(SR^37c)-,

(xxxi) -C(R^37a)(SR^37c)-C(R^37a)(SR^37c)-, (xxxii) -C(=O)-C(=O)-,

(xxxiii) -C(=S)-C(=S)-, (xxxiv) -C(=O)-O-, (xxxv) -C(=O)-S-,

(xxxvi) -C(=S)-O-, (xxxvii) -C(=S)-S-, (xxxviii) -C(=O)-N(R^37a)-,

(xxxix) -C(=S)-N(R^37a)-, (xl) -C(R^37a)(R^37b)-C(=O)-N(R^37a)-,

(xii) -C(R^37a)(R^37b)-C(=S)-N(R^37a)-, (xiii) -C(R^37a)(R^37b)-C(=O)-O-,

(xliii) -C(R^37a)(R^37b)-C(=O)-S-, (xliv) -C(R^37a)(R^37b)-C(=S)-O-,

(xiv) -C(R^37a)(R^37b)-C(=S)-S-, (xlvi) -C(R^37a)(R^37b)-N(R^37b)-C(=O)-,

(xlvii) -C(R^37a)(R^37b)-N(R^37b)-C(=S)-, (xlviii) -C(R^37a)(R^37b)-O-C(=O)-,

(xlix) -C(R^37a)(R³⁷ )-S~C(=0)-, (I) -C(R^37a)(R^37b)-O-C(=S)-,

(Ii) -C(R^37a)(R^37b)-S-C(=S)-, (Iii) -C(R^37a)(R^37b)-N(R^37b)-C(=O)-N(R^37a)-,

(liii) -C(R^37a)(R^37b)-N(R³⁷ )-C(=S)-N(R^37a)-,

(liv) -C(R^37a)(R^37b)-N(R^37b)-C(=O)-O-,

-10- (Iv) -C(R^37a)(R^37b)-N(R^37b)-C(=O)-S-,

(lvi) -C(R^37a)(R^37b)-N(R³⁷ )-C(=S)-O-,

(lvii) -C(R^37a)(R^37b)-N(R^37b)-C(=S)-S-,

(lviii) -C(R^37a)(R³⁷ )-O-C(=O)-N(R^37a)-,

(lix) -C(R^37a)(R^37b)-S-C(=O)-N(R^37a)-,

(lx) -C(R^37a)(R^37b)-O-C(=S)-N(R^37a)-,

(Ixi) -C(R^37a)(R^37b)-S-C(=S)-N(R^37a)-, (Ixii) -C(R^37a)(R^37b)-O-C(=O)-O-,

(Ixiii) -C(R^37a)(R^37b)-S-C(=O)-O-, (Ixiv) -C(R^37a)(R^37b)-0-C(=O)-S-,

(Ixv) -C(R^37a)(R^37b)-S-C(=O)-S-, (Ixvi) -C(R^37a)(R³⁷ )-O-C(=S)-O-,

(Ixvii) -C(R^37a)(R^37b)-S-C(=S)-O-, (Ixviii) -C(R^37a)(R^37b)-O-C(=S)-S-,

(Ixix) -C(R^37a)(R^37b)-S-C(=S)-S- or (Ixx) -C(R^37a)(R³⁷ )-C(R^37a)(OR^37c)-;

is

(i) hydrogen, (ii) C Cι₂ alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,

(v) thiol-substituted alkyl, (vi) R^37cO-substituted alkyl,

(vii) R^37cS-substituted alkyl, (viii) aminoalkyl,

(ix) (R^37c)NH-substituted alkyl, (x) (R^37a)(R^37c)N-susbstituted alkyl,

(xi) R^37aO-(O=)C-substituted alkyl, (xii) R^37aS-(O=)C-substituted alkyl, (xiii) R^37aO-(S=)C-substituted alkyl,

(xiv) R^37aS-(S=)C-substituted alkyl,

(xv) (R^37aO)₂-P(=O)-substituted alkyl, (xvi) cyanoalkyl,

(xvi) C₂-C₁₂ alkenyl, (xviii) haloalkenyl, (xix) C₂-Cι₂ alkynyl,

-11- (xx) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl,

(xxiii) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl,

(xxv) (cycloalkenyl)alkyl,

(xxvi) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)alkynyl, (xxviii) aryl,

(xxix) (aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl,

(xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl,

(xxxiv) (heterocyclic)alkenyl or (xxxv) (heterocyclic)alkynyl,

with the proviso that R¹⁴ is other than hydrogen when Z is

-C(R^37a)(R^37b)-N(R^37b)-C(=O)-O-, -C(R^37a)(R^37b)-N(R^37b)-C(=S)-O-,

-C(R^37a)(R^37b)-N(R^37b)-C(=O)-S-, -C(R^37a)(R^37b)-N(R^37b)-C(=S)-S-,

-C(R^37a)(R³⁷ )-O-C(=O)-O-, -C(R^37a)(R^37b)-O-C(=S)-O-,

-C(R^37a)(R^37b)-S-C(=O)-O-, -C(R^37a)(R^37b)-S-C(=S)-O-,

-C(R^37a)(R^37b)-O-C(=O)-S-, -C(R^37a)(R^37b)-O-C(=S)-S-,

-C(R^37a)(R^37b)-S-C(=O)-S- or -C(R^37a)(R^37b)-S-C(=S)-S-;

_R3^7a _R3^7b _R ⁷ _{and R} ⁴8 _{gt each occurrence are} independently selected from the group consisting of

(i) hydrogen, (ii) C₁-C-₁₂ alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) alkoxyalkyl, (vi) C₂-C₁₂ alkenyl, (vii) haloalkenyl, (viii) C2-C12 alkynyl, (ix) cycloalkyl,

(x) (cycloalkyl)alkyl, (xi) (cycioalkyl)alkenyl, (xii) (cycloalkyl)alkynyl,

-12- (xiii) cycloalkenyl, (xiv) (cycloalkenyl)alkyl, (xv) (cycloalkenyl)- alkenyl,

(xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl,

(xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic,

(xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and

(xxiv) (heterocyclic)alkynyl;

R^37c at each occurrence is independently selected from the group consisting of

(i) hydrogen, (ii) C₁-C-₁₂ alkyl, (iii) haloalkyl, (iv) C₂-C1₂ alkenyl,

(v) haloalkenyl, (vi) C2-C₁₂ alkynyl, (vii) cycloalkyl,

(viii) (cycloalkyl)alkyl, (ix) (cycloalkyl)alkenyl, (x) (cycloalkyl)alkynyl,

(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) (heterocyclic)alkyl, (xxi) (heterocyclic)alkenyl,

(xxii) (heterocyclic)alkynyl, (xxiii) -C(=O)-R¹⁴, (xxiv) -C(=S)-R¹⁴,

(xxv) -S(O)₂-R¹⁴ and (xxvi) hydroxyalkyl;

or when Z is -C(R^37a)(R^37b)-N(R^37c)-, then N(R^37c) and R¹⁴ when taken together are an azido group;

-13- or when Z is -C(R^37a)(R^37b)-N(O)(R^37c)-, then N(O)(R^37c) and R¹⁴ when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;

or when Z is -C(R^37a)(OR^37c)-, -C(R^37a)(SR^37c)- or

-C(R^37a)(N(R^37b)(R^37c))-, then R^37a, R¹⁴ and the carbon atom to which they are bonded when taken together form a cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl ring;

R ⁵ is selected from the group consisting of

(i) hydrogen, (ii) hydroxy, (iii) amino, (iv) Cι-C₁₂ alkyl, (v) haloalkyl,

(vi) C₂-C₁₂ alkenyl, (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, (xvii) heterocyclic,

(xviii) (heterocyclic)alkyl and (xix) (heterocyclic)alkenyl;

or R³ and R⁴ taken together, with the atom to which they are attached, form a carbocyciic or heterocyclic ring having from 3 to 8 ring atoms;

R⁵ at each occurrence is independently selected from the group consisting of

(a) hydrogen, (b) -CH(R³⁸)₂, (c) -(CH₂)_rO-R⁴⁰, (d) C₂-C₄ alkynyl, (e) cyclopropyl,

(f) cyclobutyl, (g) -C(=Q¹)-R¹⁷, and (h) -(CH₂)_r-N(R¹⁹)₂

-14- wherein r is 0, 1 or 2; with the proviso that when one R⁵ is -O-R⁴⁰ or -N(R¹⁹)₂, ^' then the other R⁵ is other than -O-R⁴⁰ or -N(R¹⁹)₂; wherein Q¹ is O, S, or N(R¹⁸);

R¹⁷ and R¹⁸ are independently selected, at 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, (ii) C-1-C₁₂ alkyl, (iii) haloalkyl, (iv) C₂-C12 alkenyl,

(v) haloalkenyl, (vi) cycloalkyl, (vii) (cycloalkyl)alkyl,

(viii) (cycloalkyl)alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl)alkyl,

(xi) (cycloalkenyl)alkenyl, (xii) aryl, (xiii) (aryl)alkyl, (xiv) (aryl)alkenyl,

(xv) heterocyclic, (xvi) (heterocyclic)alkyl and

(xvii) (heterocyclic)alkenyl;

or one R₁₉ is an N-protecting group;

or the two R⁵ groups taken together with the carbon atom to which they are bonded, form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms;

Y is selected from the group consisting of

(a) C1-C5 alkyl, (b) d-C₅ haloalkyl, (c) C₂-C₅ alkenyl, (d) C₂-C₅ haloalkenyl, (e) C₂-C₅ alkynyl, (f) C₃-C₅ cycloalkyl, (g) C₃-C₅ cycloalkyl-Cι-to-C₃-alkyl, (h) C₅ cycloalkenyl, (i) C₅ cycloalkenyl-Crto-C₃-alkyl, (j) C₅ cycloalkenyl-C₂-to-C3- alkenyl, (k) -(CHR³⁹)_nOR²⁰, (I) -CH(OR²⁰)-CH₂(OR²⁰), (m) -(CHR³⁹)_nSR²¹ , (n) phenyl, (0) halo-substituted phenyl, (p) -(CHR³⁹)_nC(=Q²)R²², (q)

-15- -(CHR³⁹)_nN(=Q³), (r) -N(0)=CHCH₃, (s) -(CHR³ )_nN(CH₃)R²⁴ 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 at each occurrence is independently

(i) methyl, (ii) ethyl, (iii) n-propyl, (iv) isopropyl,

(v) C₁-C₃ haloalkyl, (vi) vinyl, (vii) propenyl, (viii) isopropenyl,

(ix) allyl, (x) C₂-C₃ haloalkenyl, (xi) amino, (xii) -NHCH₃, (xiii) -N(CH₃)₂,

(xiv) -NHCH2CH3, (xv) -N(CH₃)(CH₂CH₃), (xvi) -N(CH₂CH₃)₂ or

(xvii) -N(=CH₂);

R²¹ is

(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,

(vi) C₁-C₃ haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) allyl or (xi) C₂-C₃ haloalkenyl;

R²² is

(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,

(vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy,

(xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio,

(xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii) vinyl, (xix) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii) -N(R^28a)(R^28b), (xxiii) -CH₂R²⁹, (xxiv) aminomethyl, (xxv) hydroxymethyl, (xxvi) thiolmethyl, (xxvii) -NHNH₂, (xxviii) -N(CH₃)NH₂ or (xxix) -NHNH(CH₃);

R²³ and R³⁹ are independently hydrogen or methyl;

-16- R⁴ and R⁴² are independently hydrogen, methyl, or ethyl;

R²⁴ is selected from the group consisting of

(i) hydrogen, (ii) C C₄ alkyl, (iii) C₂-C₄ alkenyl, (iv) C₂-C₄ alkynyl,

(v) cyclopropyl, (vi) -C(=Q )-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 group is hydrogen, methyl or ethyl ;

R^28a hydrogen, hydroxy, methyl, ethyl, amino, -NHCH₃, -N(CH₃)₂, methoxy, ethoxy, or -CN;

R^28b is hydrogen, methyl or ethyl;

or R^28a, R^28b and the nitrogen to which they are bonded taken together represent azetidinyl;

R²⁹ group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;

R³⁰ group is hydrogen, methyl, ethyl, -OR³⁴, -SR³⁴, -N(R³⁵)₂, -NHOH, -NHNH₂, -N(CH₃)NH₂, or -N(CH₂CH₃)NH₂;

R³¹ and R³² substituents, at each occurrence, are independently hydrogen, methyl or ethyl;

R³³ group is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -N0₂;

R³⁴ group is methyl or ethyl;

R³⁵ group is independently hydrogen, methyl or ethyl;

-17- with the proviso that when Q² is CHR²⁶ then R²² is selected from the group consisting of hydrogen, -CH₃, -C₂H₅, -C₃H₇, -OCH₃, -SCH₃, -0-C₂H₅, and -S-C₂H₅;

R⁶ and R⁷ are independently selected from the group consisting of

(a) hydrogen, (b) C-1-C12 alkyl, (c) C₂-C-ι₂ alkenyl, (d) cycloalkyl,

(e) (cycloalkyl)alkyl, (f) (cycloalkyl)alkenyl, (g) cycloalkenyl, (h) (cycloalkenyl)alkyl,

(i) (cycloalkenyl)alkenyl, (j) aryl, (k) (aryl)alkyl, (I) (aryl)alkenyl, (m) heterocyclic, (n) (heterocyclic)alkyl, (0) (heterocyclic)alkenyl, (p) -OR^37a and (q) -N(R^37a)₂; and

R >8 , _D R9 , and R ,10 are independently selected from the group consisting of

(a) hydrogen, (b) C C₆ alkyl, (c) C₂-C₆ alkenyl, (d) C₃-C₆ cycloalkyl,

(e) C₃-C₆ cycloalkenyl, and (f) fluorine, with the proviso that the total number of atoms, other than hydrogen, in each of R⁸, R⁹, and R¹⁰, is 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 depicted by Formula IV, V, VI, VII, VIII or IX:

IV

-18-

VI VII

R⁹

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 Formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R¹ is defined as above;

-X-R² is R²-C(=0)-NH-, R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is C1-C₃ loweralkyi, halo C-₁-C₃ loweralkyi, C₂-C₃ alkenyl or halo C₂-C₃ alkenyl or -X-R² is

-19- Y² wherein Y¹ is -CH₂-, -0-, -S- or -NH- and Y² is -C(=0)- or -C(R^aa)( R^bb)- wherein R^aa and R^bb are independently selected from the group consisting of hydrogen,

C₁-C₃ loweralkyi, 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 defined as above and wherein one of R³ and R⁴ is other than hydrogen;

Z¹ is -0-, -S- or -CH(R⁵)- wherein R⁵ is hydrogen, loweralkyi or - (CH₂)rN(R ⁹)₂ wherein r and R₁₉ are defined as above; or R⁵ is hydrogen, loweralkyi or -(CH₂)_rN(R¹⁹)₂ wherein r and R₁₉ are defined as above;

R⁶ and R⁷ are independently hydrogen or loweralkyi;

R⁸ and R⁹ are independently hydrogen, fluoro or loweralkyi;

R¹⁰ is hydrogen, fluoro or loweralkyi; and

Y is C₂-C5 alkenyl, C_2-C₅ haloalkenyl, -C(=Q²)R²², -N(=Q³), -N(0)=CHCH₃, -NR²³R²⁴ or a heterocyclic ring having from 3 to 6 ring atoms, wherein R²², R²³, R²⁴, Q² and Q³ are defined as above.

More preferred compounds of the invention are compounds having Formula I, II, III. IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R¹ is defined as above;

-20- -X-R² is R²-C(=0)-NH-, R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is C₁-C₃ loweralkyi, halo C C₃ loweralkyi, C₂-C₃ alkenyl or halo C₂-C₃ alkenyl or -X-R² is

Ύ² > wherein Y¹ is -CH₂- and Y² is -C(=0)- or -C(R^aa)( R^bb)- wherein R^aa and R^bb are independently selected from the group consisting of hydrogen,

C₁-C₃ loweralkyi, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;

R³ and R⁴ are independently selected from hydrogen, heterocyclic and

-Z-R¹⁴ wherein Z and R ⁴ are defined as above and wherein one of R³ and R⁴ is other than hydrogen;

Z¹ is -0-, -S- or -CH(R⁵)- wherein R⁵ is hydrogen, loweralkyi or - (CH₂)rN(R¹⁹)₂ wherein r and R¹⁹ are defined as above; or R⁵ is hydrogen, loweralkyi or -(CH₂)_rN(R¹⁹)₂ wherein r and R¹⁹ are defined as above;

R⁶ and R⁷ are independently hydrogen or loweralkyi;

R⁸ and R⁹ are independently hydrogen or loweralkyi;

R¹⁰ is hydrogen or loweralkyi; and

Y is C₂-C₅ alkenyl, C_2-C₅ haloalkenyl, -C(=Q²)R²², -N(=Q³), -N(0)=CHCH₃ or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R²², Q² and Q³ are defined as above.

-21- Even more preferred compounds of the invention are compounds having Formula Formula I, II, III, IV, V, VI, VII, VIII or IX or a salt, ester or prodrug thereof wherein R¹ is defined as above;

-X-R² is R²-C(=0)-NH-, R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is C₁-C₃ loweralkyi, halo C₁-C₃ loweralkyi, C₂-C₃ alkenyl or halo C1-C3 alkenyl or -X-R² is

Y² wherein Y¹ is -CH₂- and Y² is -C(=0)- or -C(R^aa)( R^bb)- wherein R^aa and R ^b are independently selected from the group consisting of hydrogen,

C1-C₃ loweralkyi, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;

R³ and R⁴ are independently selected from hydrogen, heterocyclic and

-Z-R¹⁴ wherein Z and R¹⁴ are defined as above and wherein one of R³ and R⁴ is other than hydrogen;

Z¹ is -0-, -S- or -CH(R⁵)- wherein R⁵ is hydrogen, loweralkyi or - (CH₂)_rN(R¹⁹)₂ wherein r and R ₉ are defined as above; or R⁵ is hydrogen, loweralkyi or -(CH₂)_rN(R¹⁹)₂ wherein r and R-ι₉ are defined as above;

R⁶ and R⁷ are independently hydrogen or loweralkyi;

R⁸ and R⁹ are independently hydrogen or loweralkyi;

R¹⁰ is hydrogen or loweralkyi; and

Y is C₂-C₅ alkenyl, C₂-C₅ haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

-22- More highly preferred compounds of the invention are compounds having 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- wherein R² is C_TC_S loweralkyi or halo- C-₁-C₃ loweralkyi;

R³ and R⁴ are independently selected from hydrogen, heterocyclic and

-Z-R¹⁴ wherein Z and R¹⁴ are defined as above and wherein one of R³ and R⁴ is other than hydrogen;

Z¹ is -0-, -S- or -CH₂-; or R⁵ is hydrogen;

R⁶ and R⁷ are independently hydrogen or loweralkyi;

R⁸ and R⁹ are hydrogen independently hydrogen or loweralkyi;

R¹⁰ is hydrogen or loweralkyi; and

Y is C₂-C_δ alkenyl, C_2-C haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

Even more highly preferred compounds of the invention are compounds having 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- wherein R² is C1-C₃ loweralkyi or halo- C₁-C₃ loweralkyi;

R⁴ is hydrogen or ioweralkyl and R³ is heterocyclic or -Z-R¹⁴ wherein Z and R¹⁴ are defined as above;

Z¹ is -0-, -S- or -CH₂-; or R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

-23- R⁸ and R⁹ are hydrogen;

R¹⁰ is hydrogen; and

Y is C₂-C₅ alkenyl, C₂.C₅ haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

Other even more highly preferred compounds of the invention are compounds having 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- wherein R² is C1-C₃ loweralkyi or halo C-₁-C₃ loweralkyi;

R⁴ is hydrogen or loweralkyi and R³ is (a) heterocyclic, (b) alkyl,

(c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) -C(=0)-R¹⁴,

(h) -C(R^37a)(OR^37c)-R¹⁴ or (i) -C(R^37a)(R^37b)-N(0)(R^37c)R¹⁴ wherein R¹⁴ is

(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,

(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,

(x) (heterocyciic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R^37aO)-(0=)C-substituted alkyl or (xv) (R^37aO)₂-P(=0)-substituted alkyl;

R^37a and R^37b are independently selected from the group consisting of

(i) hydrogen, (ii) loweralkyi and (iii) loweralkenyl; and

R^37c is

hydrogen, (ii) loweralkyi or (iii) loweralkenyl;

Z¹ is -0-, -S- or -CH₂-; or R⁵ is hydrogen;

-24- R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen;

R¹⁰ is hydrogen; and

Y is C₂-C₅ alkenyl, C_2-C₅ haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

Most highly preferred compounds of the invention are compounds having 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-, R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is C-₁-C₃ loweralkyi or halo C₁-C₃ loweralkyi;

R⁴ is hydrogen and R³ is (a) heterocyclic, (b) alkyl or (c) -C(R^37a)(0R^37c)- R¹⁴ wherein R¹⁴ is

(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,

(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,

(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R^37aO)-(0=)C-substituted alkyl or (xv) (R^37aO)₂-P(=0)-substituted alkyl;

R^37a and R^37b are independently selected from the group consisting of

(i) hydrogen, (ii) loweralkyi and (iii) loweralkenyl; and

R^37c is

hydrogen, (ii) C-_t-C₃ loweralkyi or (iii) allyl;

Z¹ is -0-, -S- or -CH₂-; or R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

-25- R⁸ and R⁹ are hydrogen ;

R¹⁰ is hydrogen; and

Y is C₂-C₅ alkenyl, C_2-C₅ haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

Other most highly preferred compounds of the invention are compounds having 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- or R²-S0₂-NH- wherein R² is C C₃ loweralkyi or halo C C₃ loweralkyi;

R⁴ is hydrogen and R³ is (a) heterocyclic, (b) alkyl or (c) -C(R^37a)(OR^37c)- R¹⁴ wherein R¹⁴ is

(i) loweralkyi, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyi or

(iv) alkoxy-substituted loweralkyi;

R^37a is

(i) hydrogen, (ii) loweralkyi or (iii) loweralkenyl; and

R^37c is

(i) hydrogen, (ii) C₁-C₃ loweralkyi or (iii) allyl;

Z is -0-, -S- or -CH₂-; or R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen;

R¹⁰ is hydrogen; and

-26- Y is C₂-C₅ alkenyl, C_2-C₅ haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

Other most highly preferred compounds of the invention are compounds having 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- or R²-S0₂-NH- wherein R² is d-Cs loweralkyi or halo C C₃ loweralkyi;

R⁴ is hydrogen and R³ is -C(R^37a)(OR^37c)-R¹⁴ wherein R¹⁴ is

loweralkyi or loweralkenyl;

R^37a is

loweralkyi or loweralkenyl; and

R^37c is

hydrogen, C₁-C₃ loweralkyi or allyl;

Z¹ is -0-, -S- or -CH₂-; or R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen;

R¹⁰ is hydrogen; and

Y is C₂-C₅ alkenyl, C₂-C₅ haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

Preferred substituents R¹ include -C0₂H or esters or prodrugs thereof. Preferred esters include C₂-C₆ loweralkyi esters or substituted or unsubstituted

-27- benzyl esters. Preferred substituents R¹ also include -S(0)₂NHC(=0)R¹¹ wherein R¹¹ is defined as above.

Most highly preferred substituents R¹ include -C0₂H or esters or prodrugs thereof. Most highly preferred esters include C₂-Cβ loweralkyi esters or substituted or unsubstituted benzyl esters.

Preferred substituents -X-R² include R²-C(=0)-NH-, R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is C C₃ loweralkyi, halo C C₃ loweralkyi, C₂-C₃ alkenyl or halo C₂-C₃ alkenyl or -X-R² is

_γ2 * wherein Y¹ is -CH₂-, -0-, -S- or -NH- and Y² is -C(=0)- or -C(R^aa)( R^bb)- wherein R^aa and R^bb are independently selected from the group consisting of hydrogen,

C₁-C₃ loweralkyi, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl.

More preferred substituents -X-R² include R²-C(=0)-NH-, R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is C C₃ loweralkyi, halo d-d loweralkyi, C₂-C₃ alkenyl or halo d-d alkenyl or -X-R² is

^■ _γ2 * wherein Y¹ is -CH₂- and Y² is -C(=0)- or -C(R^aa)( R^b )- wherein R™ and R^bb are independently selected from the group consisting of hydrogen,

-28- d-d loweralkyi, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl.

Even more preferred substituents -X-R² include R²-C(=0)-NH-, R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is C C₃ loweralkyi, halo C₁-C₃ loweralkyi, C₂-C₃ alkenyl or halo C₂-d alkenyl.

More highly preferred substituents -X-R² include R²-C(=0)-NH-, R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is d-C₃ loweralkyi or halo- d-d loweralkyi.

Even more highly preferred substituents -X-R² include R²-C(=0)-NH-, R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is d-C₂ loweralkyi or halo d-d loweralkyi, and especially, CH₃-C(=0)-NH-, CF₃-C(=0)-NH-, CH₃-S0₂-NH- or CF₃-S0₂-NH-.

Preferred substituents Z¹ include -0-, -S- or -CH(R⁵)- wherein R⁵ is hydrogen, loweralkyi or -(CH₂)_rN(R¹⁹)₂ wherein r and R-ig are defined as above; or R⁵ is hydrogen, loweralkyi or -(CH₂)_rN(R¹⁹)₂ wherein r and Rig are defined as above;

More preferred substituents Z¹ are -0-, -S- or -CH(R⁵)- wherein R⁵ is hydrogen or loweralkyi.

More highly preferred substituents Z¹ are -O-, -S- or -CH2-.

Even more highly preferred substituents Z¹ are -O- or -CH -.

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 most broadly defined previously herein and wherein one of R³ and R⁴ is other than hydrogen.

-29- More highly preferred, substituent R⁴ is hydrogen or loweralkyi and R³ includes heterocyclic or -Z-R¹⁴ wherein Z and R¹⁴ are defined as most broadly defined previously herein.

Even more highly preferred, substituent R⁴ is hydrogen or loweralkyi and R³ includes

(a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) -C(=0)-R¹⁴, (h) -C(R^37a)(OR^37c)-R¹⁴ or (i) -C(R^37a)(R^37b)-N(0)(R^37o)R¹⁴ wherein R¹⁴ is

(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,

(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,

(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R^37aO)-(0=)C-substituted alkyl or (xv) (R^37aO)₂-P(=0)-substituted alkyl;

R^37a and R^37b are independently selected from the group consisting of

(i) hydrogen, (ii) loweralkyi and (iii) loweralkenyl; and

R^37c is (i) hydrogen, (ii) loweralkyi or (iii) loweralkenyl.

Most highly preferred, substituent R⁴ is hydrogen and R³ includes

(a) heterocyclic, (b) alkyl or (c) -C(R^37a)(OR^37c)-R¹⁴ wherein R¹⁴ is

(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,

(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,

(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R^37aO)-(0=)C-substituted alkyl or (xv) (R^37aO)₂-P(=0)-substituted alkyl;

-30- R^37a and R^37b are independently selected from the group consisting of

(i) hydrogen, (ii) loweralkyi and (iii) loweralkenyl; and

R^37c is (i) hydrogen, (ii) d-d loweralkyi or (iii) allyl.

Also most highly preferred, substituent R⁴ is hydrogen and R³ includes

(a) heterocyclic, (b) alkyl or (c) -C(R^37a)(OR^37o)-R¹⁴ wherein R¹⁴ is

(i) loweralkyi, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyi or

(iv) alkoxy-substituted loweralkyi;

R^37a is (i) hydrogen, (ii) loweralkyi or (iii) loweralkenyl; and

R^37c is (i) hydrogen, (ii) d-d loweralkyi or (iii) allyl.

Also most highly preferred, substituent R⁴ is hydrogen and R³ includes

-C(R^37a)(OR^37c)-R¹⁴ wherein R¹⁴ is loweralkyi or loweralkenyl;

R^37a is loweralkyi or loweralkenyl; and

R^37c is hydrogen, d-C₃ loweralkyi or allyl, and especially, wherein R^37c is hydrogen or methyl.

Preferred substituents R⁵ include those independently selected from hydrogen, loweralkyi and -(CH₂)_rN(R ⁹)₂ wherein r and R¹⁹ are defined as above.

More preferred substituents R⁵ are independently selected from hydrogen, loweralkyi and -(CH₂)_rN(R¹⁹)₂ wherein r is 0 or 1 and one R¹⁹ is hydrogen or loweralkyi and the other R¹⁹ is hydrogen, loweralkyi or an N-protecting group.

Even more preferred substituents R⁵ are independently selected from hydrogen and loweralkyi.

Most highly preferred, R⁵ is hydrogen.

-31- Preferred substituents R⁶ and R⁷ include independently hydrogen and loweralkyi. Most highly preferred, R⁶ and R⁷ are hydrogen.

Preferred substituents R⁸, R⁹ and R¹⁰ include independently hydrogen, fluoro and loweralkyi. Most highly preferred, R⁸, R⁹ and R ⁰ are hydrogen.

Preferred substituent Y includes C₂-C₅ alkenyl, C_2-C₅ haloalkenyl,

-C(=Q²)R²², -N(=Q³), -N(0)=CHCH₃, -NR²³R²⁴ or a heterocyclic ring having from 3 to 6 ring atoms, wherein R²², R²³, R²⁴, Q² and Q³ are defined as above.

More preferred substituent Y includes C₂-C₅ alkenyl,

C_2-C₅ haloalkenyl, -C(=Q²)R²², -N(=Q³), -N(0)=CHCH₃ or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R²², Q² and Q³ are defined as above.

Even more preferred substituent Y includes C₂-C₅ alkenyl, C_2-C₅ haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. Representative alkenyl and haloalkenyl substituents Y include:

-CH=CH₂, -CH=CHF, -CH=CH-CH₃, -CH=CH-CF₃, -CH=CHCI, -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=CCl₂,

-CF=CCIBr, -C(CH₃)=CH₂. -C(CH₃)=CHF, -C(CH₃)=CH-CH₃, -C(CH₃)=CH-CF₃,

-32- -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)=CHCI,

-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)=CC1₂, -C(CF₃)=CCIBr,

-CCI=CH₂, -CCI=CHF, -CCI=CH-CH₃, -CCI=CH-CF₃, -CC CHCI, -CCNCHBr,

-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, -CC CCIBr,

-CH=CH-CH₂CH₃, -CH=CF-CH₂CH₃, -CF=CH-CH₂CH₃, -CF=CF-CH₂CH₃,

-CH=C(CH₃)(CH₂CH₃), -CF=C(CH₃)(CH₂CH₃), -CH=CCI(CH₂CH₃),

-CF=CCI(CH₂CH₃), -C(CH₃)=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)=CFC1.

-33- Representative Y substituents which are heterocyclic rings having 5 ring atoms and also containing one or two double bonds include:

furanyl, dihydrofuranyl, didehydrodioxolanyl, dithiolyl, imidazolyl, imidazolinyl, isothiazolyl, isothiazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, oxadiazolinyl, oxathiolyl, oxazolyl, oxazolinyl, pyrazolyl, pyrazolinyl, pyrrolyl, dihydropyrrolyl, tetrazolyl, tetrazolinyl, thiadiazolyl, thiadiazolinyl, thiazolyl, thiazolinyl, thienyl, dihydrothienyl, triazolyl, triazolinyl.

More highly preferred substituents Y include cis-propenyl, trans-propenyl, isobutenyl, cis-2-chlorovinyl, vinyl, 2,2-difluorovinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.

Most highly preferred substituents Y include cis-propenyl, cis-2-chlorovinyl, vinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.

The term "acid protecting group" as used herein refers to groups used to protect acid groups (for example, -C0₂H, -S0₃H, -S0₂H, -PO₃H₂, -P0₂H groups and the like) against undesirable reactions during synthetic procedures. Commonly used acid protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991). Most frequently, such acid protecting groups are esters.

Such esters include:

alkyl esters, especially loweralkyi esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;

arylalkyl esters including, but not limited to, benzyl, phenethyl, 3- phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;

-34- silylesters, especially, (tri-loweralkyl)silyl esters, (di-loweralkyl)(aryl)silyl esters and (loweralkyl)(di-aryl)silyl esters, including, but not limited to, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropylsilyl esters and the like; and the like.

Preferred acid protecting groups are loweralkyi 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, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, anhydrides derived from reaction of the carboxylic acid with N,N'-carbonyldiimidazole and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3-dicarboximide derived esters, 2,4,5- trichiorophenol derived esters, p-nitrophenol derived esters, phenol derived esters, pentachlorophenol derived esters, 8-hydroxyquinoiine derived esters 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 as R⁹⁵ are loweralkyi groups. Representative examples of acyl groups include groups such as, for example, formyl, acetyl, propionyl, and the like.

The term "acylamino" as used herein, refers to groups having the formula -NHR⁸⁹ wherein R⁸⁹ is an acyl group. Representative examples of acylamino include acetylamino, propionylamino, and the like.

-35- The term "alkenyl" 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 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 groups such as, for example, vinyl, 2-propenyl, 2-methyl-1 -propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like.

The term "alkenylene" 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 double bond. The term "lower alkenylene" refers to a divalent group derived from a straight or branched chain alkene 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 where 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 loweralkyi groups. Representative examples of alkoxy groups include groups such as, for example, methoxy, ethoxy, e/f-butoxy, and the like.

The term "alkoxyalkoxy" as used herein, refers to groups having the formula -0-R⁹⁶-0-R⁹⁷ wherein R⁹⁷ is loweralkyi, as defined herein, and R⁹⁶ is a lower alkylene group. Representative examples of alkoxyalkoxy groups include groups such as, for example, methoxymethoxy, ethoxymethoxy, f-butoxymethoxy and the like.

-36- The term "alkoxyalkyl" as used herein refers to an alkyl radical to which is appended an alkoxy group, for example, methoxymethyl, methoxylpropyl and the like.

The term "alkoxycarbonyl" as used herein, refers to groups having the formula, -C(=0)- R⁸⁰, where R⁸⁰ is an alkoxy group.

The term "alkoxycarbonylalkyl" as used herein, refers to groups having the formula, -C(=0)- R⁷⁹, appended to the parent molecular moiety through an alkylene linkage, where R⁷⁹ is an 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 "loweralkyi" 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, so-propyl, n-butyl, /so-butyl, sec-butyl, -butyl n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethyl- propyl, n-hexyl, and the like. The hydrocarbon chains in alkyl groups or the alkyl portion of an alkyl-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, -N(R²⁷)- and sulfur wherein R²⁷ at each occurrence is independently hydrogen, loweralkyi, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.

The term "alkylamino" as used herein, refers to groups having the formula -NHR⁹¹ wherein R⁹¹ is an alkyl group. Preferred R⁹¹ groups are loweralkyi 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 from 1 to 15

-37- carbon. 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 groups such as, 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. The hydrocarbon chains in alkylene groups or the alkylene portion of an alkylene-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, -N(R²⁷)- and sulfur wherein R²⁷ at each occurrence is independently hydrogen, loweralkyi, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.

The term "alkylsulfonyl" as used herein refers to the group having the formula, -S0₂-R⁷⁸, where R⁷⁸ is an alkyl group. Preferred groups R⁷⁸ are loweralkyi groups.

The term "alkylsulfonyiamino" as used herein refers to the group having the formula, -S0₂-R⁷⁷, appended to the parent molecular moiety through an amino linkage (-NH-), where R⁷⁷ is an alkyl group. Preferred groups R⁷⁷ are loweralkyi 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- propynyl, 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

-38- 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 from 2 to 6 carbon atoms. Representative examples of alkynylene groups include groups such as, for example, -C≡C-, -CH₂-C≡C-, -CsC-CH₂-, -CH(CH₃)-C≡C-, and the like.

The term "aminoalkyl" as used herein refers to an alkyl radical to which is appended an amino (-NH₂) group.

The term "aryl" as used herein refers to a carbocyclic ring system having 6-10 ring atoms and one or two aromatic rings. Representative examples of aryl groups include groups such as, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.

The aryl groups can be unsubstituted or substituted with one, two or three substituents, each independently selected from loweralkyi, halo, 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, NH₂C(=0)-, cycloalkyl, carboxyalkyl, alkylsulfonyiamino, unsubstituted heterocyclic, unsubstituted (heterocyclic)alkyl, unsubstituted (heterocyciic)alkoxy, unsubstituted (heterocyclic)oxy and -SO3H. Preferred aryl substituents are each independently selected from the group consisting of loweralkyi, halo, 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.

-39- The term "(aryl)alkenyl" refers to a lower alkenyl group having appended thereto an aryl group. Representative examples of (aryl)alkenyl groups include groups such as, for example phenylethylenyl, phenylpropenyl, and the like.

The term "(aryl)alkyl" refers to a loweralkyi group having appended thereto an aryl group. 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 where R⁷⁶ is an arylalkyl group.

The term "(aryl)alkynyl" refers to an alkynylene group having appended thereto an aryl group. Representative examples of (aryl)alkynyl groups 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, where R⁷² is an aryl group.

The term "carbamoyl" as used herein refers to the group having the formula, -C(=0)-NH₂.

The term "carboxyalkyl" as used herein, refers to the group having the formula, -R^-COOH, where R⁶⁴ is a lower alkylene group.

The term "cyanoalkyl" as used herein refers to an alkyl radical to which is appended a cyano group (-CN).

The term "cycloalkenyl" as used herein refers to an aliphatic ring system having 5 to 10 carbon atoms and 1 or 2 rings containing at least one double bond in the ring structure. Representative examples of cycloalkenyl groups include groups such as, for example, cyclohexene, cyclopentene, norbomene and the like.

-40- Cycloalkenyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyi. Preferred substitutents are independently selected from loweralkyi, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.

The term "(cycloalkenyl)alkenyl" as used herein refers to a cycloalkenyl group appended to a lower alkenyl radical. Representative examples of (cycloalkenyl)alkenyl groups include groups such as, for example, cyclohexenylethylene, cyclopentenylethylene, and the like.

The term "(cycloalkenyl)alkyl" as used herein refers to a cycloalkenyl group appended to a lower alkyl radical. Representative examples of (cycloalkenyl)alkyl groups include groups such as, for example, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, and the like.

The term "(cycloalkenyl)alkynyl" as used herein refers to a cycloalkenyl group appended to a lower alkynyl radical. Representative examples of (cycloalkenyl)alkynyl groups include groups such as, for example, cyclohexenylacetylenyl, cyclopentenylpropynyl, and the like.

The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 or 2 rings. Representative cylcoalkyl groups include, for example, cyclopropyl, cyclobutyi, cyclopentyl, cyclohexyl, cycloheptyl, norbomane, bicyclo[2.2.2]octane and the like.

Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyi. Preferred substitutents are independently selected from loweralkyi, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.

-41- The term "(cycloalkyl)alkyl" as used herein refers to a cycloalkyl group appended to a loweralkyi 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 appended to a lower alkenyl radical. Representative examples of (cycloalkyl)- alkenyl groups include groups such as, for example, cyclohexylethylene, cyclopentylethylene, and the like.

The term "(cycloalkyl)alkynyl" as used herein refers to a cycloalkyl group appended to a lower alkynyl radical. Representative examples of (cycloalkyl)- alkynyl groups 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 R⁹⁰ is independently a lower alkyl group. Representative examples of dialkylamino include dimethylamino, diethylamino, N- methyl-N-isopropylamino and the like.

The term "halo" as used herein refers to F, Cl, Br or I.

The term "haloalkenyl" as used herein refers to a loweralkenyl 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 ,1-trifluoro-2-propylene and the like.

The term "haloalkoxy" as used herein refers to the group having the formula, -OR⁶⁹, where R⁶⁹ is a haloalkyl group as defined herein. Examples of haloalkoxy include chloromethoxy, fluoromethoxy, dichloromethoxy, trifluoromethoxy and the like.

-42- The term "haloalkyl" as used herein, refers to a loweralkyi 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-dichloroethyl, pentafluoroethyl and the like.

The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein, refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two, three, or four nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen atom and one sulfur atom; two nitrogen atoms and one sulfur atom; one nitrogen atom and one oxygen atom; two nitrogen atoms and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen atom and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized. The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring, such as, for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like.

Heterocyclic groups include, but are not limited to groups such as, for example, aziridinyl, azetidinyl, epoxide, oxetanyl, thietanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, dihydrofuranyl, tetrahydrofuranyl,

-43- dihydropyranyl, tetrahydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, triazolyl, triazolinyl, tetrazolyl, tetrazolinyl, isoxazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4- oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, oxadiazolinyl, , 1 ,2,3- thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiadiazolinyM ,3-dithioiinyl, 1,2-dithiolyl, 1,3-dithiolyl, 1 ,3-dioxolinyl, didehydrodioxolanyl, 1 ,3-oxathiolinyl, oxathiolyl, pyrimidyl, benzothienyl and the like. Heterocyclic groups also include compounds of the formula

where X^* is -CH₂ or -O- and Y^* is -C(O)- or [-C(R⁹²)₂-]v where R⁹² is hydrogen or C C₄ alkyl where v is 1, 2, or 3 such as 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl and the like. Heterocyclic groups also include bicyclic rings such as quinuclidinyl and the like.

Heterocyclic groups can be unsubstituted or substituted with from one to three substituents, each independently selected from loweralkyi, hydroxy, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino and halogen. In addition, nitrogen containing heterocyclic rings can be N-protected.

The term "(heterocyclic)alkenyl" as used herein refers to a heterocyclic group appended to a lower alkenyl radical including, but not limited to, pyrrolidinylethenyl, morpholinylethenyl and the like.

The term "(heterocyclic)alkoxy" as used herein refers to the group having the formula, -OR⁶⁸, where R⁶⁸ is a (heterocyclic)alkyl group.

The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group appended to a loweralkyi radical including, but not limited to, pyrrolidinylmethyl, morpholinylmethyl and the like.

-44- The term "(heterocyclic)alkynyl" as used herein refers to a heterocyclic group appended to a lower alkynyl radical including, but not limited to, pyrrolidinylacetylenyl, morpholinylpropynyl and the like.

The term "(heterocyclic)oxy" as used herein refers to a heterocyclic group appended to the parent molecular moiety through an oxygen atom (-0-).

The term "hydroxy protecting group", "hydroxyl protecting group" or "-OH protecting group" as used herein refers to refers to groups used to hydroxy groups against undesirable reactions during synthetic procedures. Commonly used hydroxy protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991). Such hydroxy protecting groups include:

methyl ether;

substituted methyl ethers, including, but not limited to, methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, t- butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl ether and the like;

substituted ethyl ethers, including, but not limited to, 1-ethoxyethyl, 1- methyl-1 -methoxyethyl, 1-methyl-1-benzyloxyethyl, 2,2,2-trichloroethyl, trimethylsilylethyl, t-butyl ether and the like;

benzyl ether;

substituted benzyl ethers, including, but not limited to, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitorbenzyl, p-halobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl ether and the like;

-45- silyl ethers, including, but not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl ether and the like;

esters, including, but not limited to, formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, pivaloate, benzoate ester and the like; 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, where R⁶⁵ is an alkylene group

The term "leaving group" as used herein refers to a group which is easily displaced from the compound by a nucleophile. Examples of leaving groups include a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like) and the like.

The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991). N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-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-meth- oxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,

-46- p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxy- benzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycar- bonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycar- bonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, , -dimethyl-3,5-dimethoxy- benzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropyl- methoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyl- oxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitro-phen- oxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyl- oxycarbonyl, 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 loweralkyi groups.

The term "thio-substituted alkyl" as used herein refers to an alkyl radical to which is appended a thiol group (-SH).

As used herein, the terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.

The compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers. By "substantially free" is meant greater than about 80% free of other enantiomers or diastereomers of the compound,

-47- more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound.

In addition, compounds comprising the possible geometric isomers of carbon-carbon double bonds and carbon-nitrogen double are also meant to be included in this invention.

Individual stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill 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 or inversion of stereochemistry at the chiral centers.

Diastereomeric mixtures of compounds resulting from a synthetic reaction can often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art.

Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded

-48- onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC.

Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries. The resulting diastereomers can then be separated by column chromatography. This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that 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 by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again.

Enzymes, such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers 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 hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester.

In addition, solvates and hydrates of the compounds of Formula I, II, III, IV, V, VI, VII, VIII or IX are meant to be included in this invention.

When any variable (for example R , R², R³, m, n, etc.) occurs more than one time in any substituent or in the compound of Formula I, II, III, IV, V, VI, VII, VIII or IX or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents are permissible only if such combinations result in stable

-49- compounds. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.

This invention is intended to encompass compounds having Formula I, II, III, IV, V, VI, VII, VIII or IX when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body {in vivo) or processes occurring in vitro.

Compounds of the invention can be prepared according to the methods 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 R¹ substituents can (a) be obtained either from the carboxylic acid or carboxylic acid ester group, (b) can be introduced by similar methods to those used to introduce the carboxylic acid or carboxylic acid ester group or (c) can be introduced by other methods generally known in the art.

In adddition, throughout the schemes, methods will be illustrated wherein R⁴, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are hydrogen. It will be understood by those skilled in the art that compounds wherein one or more of these substituents is other than hydrogen can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.

In addition, throughout the schemes, methods will be illustrated for obtaining compounds of the invention having the preferred relative stereochemistry. It will be understood by those skilled in the art that compounds of the invention having other relative stereochemistry can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.

-50- In addition, throughout the schemes, methods will be illustrated wherein X ^' is -C(=0)-NH-. It will be understood by those skilled in the art that other X groups can be prepared by methods analogous to those disclosed 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. N-protected amino acid 1 (P¹ is an N-protecting group, for example, t-butoxycarbonyl or the like) can be prepared by N-protection of amino acid ((±)-(2R,3S)-2-Amino-bicyclo[2.2.1]hept-5-ene-3-carboxylic acid; Stajer, G. et al. Tetrahedron, 40, 2385 (1984)). Formation of an anhydride derivative of the acid (for example, by reaction with ethyl chloroformate or the like), followed by reduction (for example, with sodium borohydride or the like) provides alcohol 2. The alcohol group is oxidized (for example, by Swern oxidation or the like) to provide aldehyde 3. Reductive amination of the aldehyde (for example with benzyl amine and Na(AcO)sBH or the like) provides N- protected amine 4 (P² is an N-protecting group, such as benzyl and the like). A second N-protecting group can be introduced to give 5 (P³ is an N-protecting group, for example, benzyloxycarbonyl or the like). Optionally, the mono- protected amino group can be alkylated (for example, by 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 diester 6 (P⁴ is a carboxylic acid protecting group, for example, loweralkyi, such as methyl, ethyl or the like). The N-protecting groups P² and P³ are selectively removed (for example, by hydrogenation or the like) to provide amine 7. Amine 7 can be further functionalized to complete the introduction of the R²- X- substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like) to give 8. Removal of the acid protecting groups P⁴ (for example, by base hydrolysis) provides diacid 9. Diacid 9 can be monoprotected (for example, by treatment with acetic anhydride, followed by methanol and triethylamine) and chromatographic separation to give 10 (P⁵ is a

-51- carboxylic acid protecting group, for example, loweralkyi 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 11, followed by N-deprotection, to give compounds of the invention 12.

As shown in Scheme 2, substituents R³ can be introduced via reaction of aldehyde 3 with a Grignard reagent (for example, R³MgBr or the like) to give alcohol 13. Oxidation of alcohol 13 (for example, Swern oxidation or the like) provides ketone 14. Reductive amination of ketone 14 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 15. Amine 15 can be further functionaiized to complete introduction of the R²-X- substituent (for example, by reaction of the amine with an acyiating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 16a. The other diastereomer (16b) can also be isolated and further transformed according to the scheme.

Oxidation of 16a and esterifi cation gives 17 (in a manner analogous to that disclosed in Scheme 1). Also similar to Scheme 1 , the diacid resulting from hydrolysis of diester 17 can be selectively protected to give give 18, which can then be transformed to compounds of the invention 19.

As shown in Scheme 3, diol 20 is selectively diprotected (Culbertson, et al., Journal of the American Chemical Society 82, 2541-2547 (1960)) by reaction with one equivalent of a hydroxy protecting agent, followed by reaction with a second hydroxy protecting agent, to give 2 _. (P⁶ is a hydroxy protecting group, for example, acetyl or the like and P⁷ is a hydroxy protecting group, for example, benzyl or the like). Oxidation and esterification provide 22. Removal of protecting group P⁷, followed by transformation of the hydroxy group to an amine, which is then N-protected, provides 24. Transformation of 24 in a manner

-52- analogous to the transformation of 2 to H or 12 in Scheme 1 provides compounds of the invention 27 or 28.

As shown in Scheme 4, alcohol 31 can be transformed to compounds of the invention 38 in a manner analogous to the transformation of 13 to 19 in Scheme 2.

As shown in Scheme 5, aldehyde 39 can be reacted with a Grignard reagent to introduce substituent R³ to give 40. Oxidation (for example, by Swern oxidation or the like) provides 41a, which can be epimerized (for example, with sodium methoxide or the like) and 41b can be obtained by chromatography. Ketone 41b can be transformed to compounds of the invention 47 in a manner analogous to the transformation of 14 to 19 in Scheme 2.

As shown in Scheme 6, olefin 48 (P⁸ is a hydroxy protecting group) is converted to alcohol 48a (for example, by reaction with borane dimethylsulfide complex and hydrogen peroxide or the like). Oxidation of the alcohol to a carboxylic acid, followed by esterification with a carboxylic acid protecting group P⁹ and deprotection of the diol, provides 49. Selective protection of the primary alcohol with a hydroxy protecting group P¹⁰ gives 50. Oxidation of 50 (for example, Swern oxidation or the like) provides ketone 5 Reductive amination of ketone 51 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 52. Amine 52 can be further functionalized to complete the introduction of the R²-X- substituent ( for example, by reaction with an acylating agent such as acetic anhydride or the like or by 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 scheme.

Selective removal of the P⁸ hydroxy protecting group in 53a provides alcohol 54. Oxidation of the alcohol to an aldehyde (for example, Swern

-53- oxidation or the like) provides 55. The aldehyde can serve as a precursor for various substituents Y in the compounds of the invention. For example, olefination of 55 (for example, with Ph₃PCH₂, or triphenylphosine/methylene chloride/n-BuLi, or rPh₃P⁺CH₂CH₃/KOtBu, or the like) provides 56 wherein Y is an olefinic substituent. Removal of the P¹⁰ hydroxy protecting group gives alcohol 57.

The alcohol can serve as a precursor for a variety of R³ substituents in the compounds of the invention. For example, the alcohol of 57 can be oxidized to an aldehyde (for example, by Dess-Martin oxidation or the like) to give 58. Aldehyde 58 can be reacted with Grignard reagents (R¹⁴MgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R ⁴Li or the like) to provide 59 as a mixture of alcohol diastereomers which can be separated chromatographically to provide the major isomer 59a and the other isomer 59b. Isomer 59a or the mixture of isomers 59 can be oxidized (for example, by Dess-Martin oxidation or the like) to give ketone 62. Reduction of ketone 62 (for example, with sodium borohydride in ethanol or the like) provides alcohol 59b as the major isomer, which can be isolated by chromatography. Ester hydrolysis provides compounds of the invention 63a or 63b, respectively, wherein Y is an olefinic substituent.

Alkylation of alcohol 59a or 59b provides ethers 60a or 60b, respectively. Ester hydrolysis provides compounds of the invention 61a or 61b, respectively, wherein Y is an olefinic substituent.

As shown in Scheme 7, reaction of ketone 62 with with Grignard reagents (R^37aMgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R^37aLi or the like) provides 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.

-54- Alkylation of alcohol 64a or 64b provides ethers 66a or 66b, respectively. Ester hydrolysis provides compounds of the invention 67a or 67b, respectively, wherein Y is an olefinic substituent.

Scheme 8 shows the preparation of precursor 74 for compounds of the invention which are substituted tetrahydrofurans. Alcohol 68 is oxidized to a ketone (for example, by Swern oxidation or the like), followed by oxidation of the olefin to a diol (for example, by treatment with Os0 and N-methylmorpholine N- oxide or the like) to give 69. Diol 69 is protected as the acetonide 70. Oxidation of 70 (for example, with MCPBA or the like) provides lactone 71. lodination via the enolate of 71 provides 72- Reaction of 72 with potassium carbonate and methanol provides ester 73. Reduction of the ester provides aldehyde 74. The aldehyde provides a functional group via which substituents R³ and R²-X- can be introduced. Deprotection of the diol and oxidation of the diol provides functional groups via which substituents Y and R¹ can be introduced.

Esters or prodrugs of the compounds of the invention can be prepared by methods known in the art.

-55- SCHEME 1

H

O NHP'

P"N

NHP'

O o

P⁴0_^// p o-^

.OP"

\ "2™-^, ""if y ^'"if II o 0

NP¹ NP¹

I H H

o o

P⁴0_^/ HO--/'

OH

R²C(0)HN OP⁴ R²C(0)HN y ( o 1 O

NP NP

H H

8

-56- SCHEME 1 (cont'd.)

.0

HO-^

OP⁵

R²C(O)HN π h.. /^0H R²C(O)HN^^Λ.

"i IfI ₁ ^""if ϊ O

NP¹

NP¹, T O

H

H 10 11

R²C(O)H ^^ /^0H

NH₂ ° 12

-57- SCHEME 2

H,N

14

R²C(O)HN_/, ^> R²C(O)HN R³ NHP¹

16a

O O

P⁴0^ HO-/

R ₃2^OJHN,, OP⁴ R C(O)HN/,_ OP^α

R° O R^J O

NP' f

NP'

H

18

17

-58- SCHEME 2 (cont'd.)

o~y/

F C(0)HN OP^s R²C(O)HN,,^ ^~ .. , /^0H

R^w O R³ ' O

NP^{1 R} NH₂

H

18 19

-59- SCHEME 3

23 24

P O HO ,

O^' O

OP R C(O)HN OH

X O O

24

25 26

-60- SCHEME 3 (cont'd.)

HO „

26 R²C(O)HN OP°

O

NHP'

27

Y/, ,_</^0H

O

NH,

28

-61- SCHEME 4

P⁶O P⁶O

R³ CH NHP¹ '

21 30 31

₀ T.Θ I _Λ _y^ R³ *H₂NHP ,¹

31 R³ (»;H₂NHP¹

33

32 /

R²C(O)HN/ R³ CH₂NHP¹

34b

O

HO~J/

.OH

R²C(O)HN,,

CH₂NH °P¹

36

35

.0

Ho-y/ X,

R²C(O)HN/_/, .OP" R²C(O)HN . -^0H

O R° ^'"I Of CH₂NHP¹ CH₂NHP¹

37 38

-62- SCHEME 5

H HO 0.

Y Ύ

O R:° 1 R°

39 40 41a

H N

41b 42

R²C(O)HN

R²C(O)HN, R^c

R°

43b

43a

.0 .0

P O-// Y\ ~J/

D4 ₀2 .OH

R²C(O)HN, OP R C(O)HN,, y

R° o R° O

45

44

-63-

SCHEME 5 (cont'd.)

.0

HO-^ X

R²C(O)HN/ OP^α R²C(O)HN/ .OH

R° O R° O

46 47

-64- SCHEME 6

P⁸O- ^—<-, P⁸O-

^ ,OH

Λr Ό 48 ^■y 48a

P⁸O— 4 p°o— *

HO

,OP^s OP^" Y ''1

48a

O O

49 50 p^Bo- P⁸O— _<.

OP^s op-

50 ''', ''1 _pιo₀ O _pιo₀ O

51 52

P°O— « p⁸o—

R (O)HN. ^/'.. OP^s R C(O)HN ^...^ „_/ ^0P

52 _pιo₀ O

^"P¹⁰O^ O

53a 53b

-65- SCHEME 6 (cont'd.)

O

HO- H _^

OP^b R²C(0)HN,, PP^b

53a ^"f _pιo₀ O P"θf O

54 55

X X.

Op⁹ R²C(O)HN_7/ OP"

'Α

55 O HO y

56 Y is an alkene 57 or haloalkene

Y.

R^C(O)HN_// 0P^S

57 ^"if °

58

-66- SCHEME 6 (cont'd.)

X X

R²C(O)HN,, / \ _np9 R²C(0)HN,, OP^a

O O

^R OH R¹⁴

59a 59b

Y.

R²C(O)HN_/, J^~Λ _OP9

R ,1'4 O

^'θR^37a

60a

X. X

R C(O)HN_/ .OH R (O)HN_/; O. OH

R 14 ^* -Λ^'r O O

^R Λ _QR 3377aa

OR 37a 61a 61b

-67- SCHEME 6 (cont'd.)

X. X. _op9 R²C(O)HN OP" a O

R 14 O

O R OH

62 59b

X

OH Y X

R 14 O R (0)HN,, ,OH

OH ''« 63a _□ 14 - > O

R OH

63b

-68- SCHEME 7

62

X Y,

-69- SCHEME 7 (cont'd.)

X X

R²C(0)HN^ OP^a

R 14 o

,37a OH

64a 64b

X oP^M

R ,1'4 Y O R 66b

X

R²C(O)HN _, OH .OH

R o O 3 "7aA⁷ O ORR 3³°7⁷

R 67a

-70- SCHEME 8

OH

68 70

71 72

CO₂Me

-CHO

73 74

-71- The other compounds of the invention can be readily prepared from the compounds available through commercial sources, in the chemical lliterature or as described herein using techniques well known in the chemical literature. The procedures required are well known and can be readily practiced by those having ordinary skill in the art.

All patents, patent applications, and literature references cited in the specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, 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, Wl, 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 which are not commercially available can be prepared by employing known methods from the chemical literature.

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

-72- W wOυ 9 v9v/^/5₅429y0υ PCT/US99/07949

Example 1

(±)-(1S.2S,3R.4R)-2-(N-Methyl-N-f-butyloxycarbonylamino)-3-acetamidomethyl-4- methoxycarbonyl-cyclopentane-1 -carboxylic Acid

1A. (±H2R.3S)-2-Aminobicvclof2.2.1]hept-5-ene-3-carboxylic acid.

The title compound was synthesized from norbornadiene by a cycloaddition reaction with chlorosulfonyl isocyanate followed by a reduction and acidic hydrolysis as reported by Stajer, G. et al. Tetrahedron._. 40, 2385 (1984).

1 B. (±)-(2R,3S)-2-(f-Butyloxycarbonylamino)bicvclor2.2.nhept-5-ene-3- carboxylic acid.

A solution of (±)-(2R,3S)-2-aminobicyclo[2.2.1]hept-5-ene-3-carboxylic acid (6.3 g, 0.04 mole) , NaOH (3.3 g, 0.082 mole), and di-tert-butyl dicarbonate (0.082 mmole) in water (200 mL) was stirred at room temperature for 48 hours. The reaction mixture was acidified using 1M aqueous HCI, 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 MgS0 , filtered and concentrated to provide the title compound as a white solid (yield: 5.6 g, 55%).

¹H NMR (CDCI₃) 51.44 (s, 9H), 1.64 (d, 1H), 2.08 (d, 1 H), 2.58 (m, 1H), 2.72 (s, 1 H), 2.97 (s,1 H), 6.18 (m, 2H), 6.96 (d, 1 H).

-73-

NHBoc

1C. (±)-(2R,3S)-2-(f-Butyloxycarbonylamino)-3-hvdroxymethylbicvclor2.2.nhept- 5-ene.

Ethyl chloroformate (2.3 mL, 23.7 mmole) was added slowly to a solution of (±)-(2R,3S)-2-(f-butyloxycarbonylamino)bicyclo[2.2.1]hept-5-ene-3-carboxylic acid (6 g, 23.7 mmole) and N-methylmorpholine (2.6 mL, 23.7 mmole) in THF (110 mL) at -20 °C . The reaction mixture was warmed to 0 °C, and the slurry-like reaction became nearly homogeneous. The reaction mixture was cooled to -20 °C, and treated with sodium borohydride ( 3.7g, 66 mmole). Methanol (10 mL) was added dropwise, over 20 minutes. The reaction mixture was neutralized with 1 N HCI and the reaction mixture was concentrated by removal of volatile materials, in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with 1 N HCI, water, and brine, dried over MgS0 , filtered and concentrated in vacuo. Purification by silica gel column chromatography using 15% ethyl acetate/hexanes provided the title compound (yield: 4.27 g, 75 %).

¹H NMR (CDCI₃) δ 1.45 (s, 9H), 1.52 (m, 2H), 1.85 (q, 1 H), 2.09 (bs, 1 H), 2.68 (m, 2H), 3.66 (m, 3H), 4.83 (bs, 1H), 6.11 (m, 1H), 6.27 (m, 1H).

-74-

1 D. (±)-(2R₁3S)-2-(f-Butyloxycarbonylamino)-3-formylbicvclo[2.2.11hept-5-ene.

DMSO (3.4 mL) in dichloromethane (5 mL) was added slowly to oxalyl chloride (2 mL, 22 mmole) in dichloromethane (50 mL) at -78 ^°C. After 5 minutes, (±)-(2R,3S)-2-( -butyloxycarbonylamino)-3-hydroxymethyl-bicyclo[2.2.1]hept-5- ene (4.27g, 17.8 mmole) in 15 mL of dichloromethane and 10 mL of DMSO was added. Stirring was continued for 20 minutes at -78 ^°C. The solution was treated with triethylamine (14 mL). After 5 minutes, the cooling bath was removed and the reaction stirred for an additional 30 minutes. The reaction mixture was partitioned with water (100 mL). The aqueous layer was extracted with dichloromethane (3 x 50 mL). The organic layers were combined, washed with brine, dried over MgS0 , filtered and concentrated. The crude product was chromatographed on silica gel with 0-10% ethyl acetate/dichloromethane, to provide the title compound, (yield: 3.8 g, 90%)

¹H NMR (CDCI₃) 51.43 (s, 9H), 1.63 (m, 2H), 2.74 (m, 2H), 3.11 (s, 1 H), 3.99 (t, 1 H). 4.85 (d, 1 H), 6.22 (m, 2H), 9.81 (s, 1H).

NHBoc

1 E. (±)-(2R,3R)-2-(f-Butyloxycarbonylamino)-3-N-benzylaminomethylbicyclo- r2.2.1lhept-5-ene.

A solution of (±)-(2R,3S)-2-(f-butyloxycarbonylamino)-3-formyl- bicyclo[2.2.1]hept-5-ene (3.8g, 16.0 mmole), benzylamine (1.9 mL, 17.6 mmole) and acetic acid (1 mL) in dichloromethane (80 mL) was stirred at 0 °C for 10

-75- minutes followed by addition of Na(AcO) BH (5.09g, 24 mmole). The reaction mixture was stirred at 0 °C for 2 hours then allowed to warm slowly to room temperature for 2 hours. After completion, the reaction mixture was washed with aqueous sodium bicarbonate, dried over MgS0 _l filtered and concentrated. The crude product was purified by silica gel chromatography using 0-2.5% methanol/chloroform to provide the title compound (yield: 4.0 g, 77%).

¹H NMR (CDCI₃) 51.47 (s, 9H), 1.51 (m, 2H), 1.78 (t, 1H), 2.72 (m, 4H), 3.57 (t, 1 H), 3.78 (s, 1 H), 6.10 (m, 1 H), 6.21 (m, 1 H), 7.30 (m, 5H).

MS: (M+H)⁺ = 329.

NHBoc

1 F. (±)-(2R.3R)-2-(f-Butyloxycarbonylamino)-3-(N-benzyl-N-(benzyloxycarbonyl- amino)methyl)bicyclo[2.2.11hept-5-ene.

A solution of (±)-(2R,3R)-2-(f-butyloxycarbonylamino)-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 NaHC0₃ and brine, dried over MgS0₄ and concentrated in vacuo. The product was purified by silica gel chromatography using hexanes/ethyl acetate (3:1) to provide the title compound (yield: 3.37 g, 85%).

¹H NMR (CDCI₃) 51.32 (m,2H), 1.36 (s, 9H), 1.56 (m, 1 H), 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, 11 H).

-76-

CbzN I NBoc

Bn CH₃

1G. (±H2R.3R)-2-(N-Methyl-N-f-butyloxycarbonylamino)-3-(N-benzyl-N-benzyl- oxycarbonylamino)methyl-bicvclo[2.2.1lhept-5-ene.

Sodium hydride (300 mg , 60% in oil) was added to a solution of (±)- (2R,3R)-2-(f-butyloxycarbonylamino)-3-(N-benzyl-N-benzyloxycarbonylamino)- methylbicyclo[2.2.1]hept-5-ene (3.37 g, 7.27 mmole) and iodomethane (0.9 mL) in anhydrous DMF (60 mL) at 0 °C. After 4 hours, the reaction mixture was concentrated in vacuo and purified by silica gel chromatography using hexanes/ethyl acetate (4:1) to provide the title compound (yield: 3.3 g, 95%).

¹H NMR (CDCI₃) 51.40 (s, 9H), 1.82 (m, 2H), 2.26 (m, 1H), 2.78 (m, 1H), 2.85 (m, 1H), 2,90 (s, 3H), 2.94 (m, 2H), 3.63 (m, 1H), 4.22 (m, 2H), 5.34 (s, 2H), 5.60 (m, 2H), 7.15 (m, 10H).

MS: (M+H)⁺ = 477.

-77- CH₃O J r9, ,OCH,

^{C z}N NBoc O, ^Bπ CH,

1H. (±)-(1S,2S,3R,4R)-2-(N-Methyl-N-f-butyloxycarbonylamino)-3-(N-benzyl-N- benzyloxycarbonylamino)methylcvclopentane-1 ,4-dicarboxylic Acid Dimethyl Ester.

A mixture of NalO₄ (10 g, 47 mmole) and Ru0₂ (45 mg, 0.3 mmol) in 25 mL of carbon tetrachloride 50 mL of acetonitrile, and 75 mL of water was rapidly stirred for 30 minutes. A solution of (±)-(2R,3R)-2-(N-methyl-N-f- butyloxycarbonylamino)-3-(N-benzyl-N-benzyloxycarbonylamino)methyl- bicyclo[2.2.1]hept-5-ene (3.3 g, 6.9 mmole) in 25 mL of carbon tetrachloride was added to the bright yellow mixture. The resultant 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 MgS0₄, 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 purified by silica gel chromatography using ethyl acetate/hexanes (1 :1) to provide the title compound as a white solid (yield: 1.91 g, 50%).

¹H NMR (CDCI₃) 51.41 (s, 9H), 2.21 (m, 2H), 2.33 (m, 1 H), 2.90 (s, 3H), 2.92 (m, 2H), 2.96 (m, 1H), 3.38 (t, 1H), 3.67 (s, 6H), 4.23 (m, 3H), 5.38 (s, 2H), 7.12 (m, 10H).

MS: (M+H)⁺ = 569.

-78- O CH₃0-^

^N r^HV2 NBo^"c O ^CH3 CH₃

11. (±)-(1S.2S,3R,4R)-2-(N-Methyl-N-f-Butyloxycarbonylamino)-3-aminomethyl- cyclopentane-1 ,4-dicarboxylic Acid Dimethyl Ester.

A mixture of (±)-(1S,2S,3S,4R)-2-(N-methyl-N-^-butyloxycarbonylamino)-3- (N-benzyl-N-benzyloxycarbonylamino)methyl-cyclopentane-1 ,5-dicarboxylic acid dimethyl ester (1.91 g, 3.36 mmole) and Pd(OH)₂ (380 mg, 20% on carbon) in 50 mL of isopropanol was stirred at room temperature under an hydrogen atmosphere, for 16 hours. The catalyst was removed by vacuum filtration through a bed of Celite®, and the filtrate concentrated in vacuo to provide the title compound (yield: 1.2 g 100 %).

¹H NMR (CDC ) 51.48 (s, 9H), 2.00 (m, 2H), 2.42 (m, 1H), 2.64 (m, 2H), 2.90 ( bs, 3H), 3.00 (m, 2H), 3.71 (s, 3H), 3.73 (s, 3H), 4.4 (bs, 1H), 5.4 (bs, 2H).

MS: (M+H)⁺ = 345.

-79- O

CH3O-"?

,OCH,

^AcHN NBoc O CH₃

U. (±)-(1S,2S,3R,4R)-2-(N-Methyl-N-f-butyloxycarbonylamino)-3-acetamido- methyl-cvclopentane-1 ,4-dicarboxylic Acid Dimethyl Ester.

A solution of (±)-(1S,2S,3R,4R)-2-(N-methyl-f- butyloxycarbonylamino)-3-aminomethylcyclopentane-1 ,5-dicarboxylic acid dimethyl ester (1.2 g, 3.5 mmole), acetic anhydride (0.5 mL) and triethylamine (1 mL) in 25 mL of dichloromethane was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed successively with 1 N HCI, water and brine, dried over MgSO₄, and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate/hexanes (1:1) to provide the title compound (yield: 790 mg, 58 %).

¹H NMR (CDCI₃) 51.45 (s, 9H), 1.92 (s, 3H), 2.05 (m, 1 H), 2.40 (m, 1 H), 2.62 (m, 1 H), 2.85 (s, 3H), 3.1 (m, 1 H), 3.3 (m, 1 H), 3.42 (m, 1 H), 3.71 (s, 6H), 4.62 (bs, 1 H), 6.38 (bs, 1 H).

MS: (M+H)⁺= 387.

-80- O

HO

,OH

. j "if

AcHN _NBoc O

CH

1K. (±)-(1S.2S,3R.4R)-2-(N-Methyl-N-f-butyloxycarbonylamino)-3-acetamido- methyl-cyclopentane-1 ,4-dicarboxylic Acid.

A solution of (±)-(1 S,2S,3S,4R)-2-(N-methyl-N- - butyloxycarbonylamino)-3-acetamidomethylcyclopentane-1 ,5-dicarboxylic acid dimethyl ester (720 mg, 1.86 mmole) and 5 equivalents of lithium hydroxide in methanol (40 mL) and H₂0 (10 mL) was stirred at room temperature for two hours. The solution was concentrated in vacuo. The residue was partitioned between 1 N HCI and ethyl acetate. The aqueous layer was back extracted with ethyl acetate (3 x 50 mL). The organic layers were combined and washed with brine, dried over Na₂S0 , filtered, and concentrated in vacuo to provide the title compound (yield: 500 mg, 75 %).

¹H NMR (CDCI₃) 51.45 (s, 9H), 1.92 (s, 3H), 2.05 (m, 1 H), 2.40 (m, 1H), 2.62 (m, 1 H), 2.85 (s, 3H), 3.1 (m, 1 H), 3.3 (m, 1H), 3.42 (m, 1 H), 3.71 (s, 6H), 4.62 (bs, 1 H), 6.38 (bs, 1 H).

-81- O

CH₃O-

.OH

AcHN ^"O1 CH₃

1L. (±)-(1S.2S,3R.4R)-2-(N-Methyl-N- -butyloxycarbonylamino)-3-acetamido- methyl-4-methoxycarbonylcvclopentane-1 -carboxylic Acid

A solution of (±)-(1S,2S,3R,4R)-2-(N-methyl-N-f- butyloxycarbonylamino)-3-acetamidomethylcyclopentane-1 ,5-dicarboxylic acid (500 mg, 11.4 mmole), in 5 mL of dichloromethane and 5 mL of acetic anhydride, was stirred at room temperature for two 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 HCI and brine. The solution was dried over MgS0₄, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using chloroform/methanol/acetic acid (97:2:1) to provide the title compound (yield: 155 mg, 30 %).

¹H NMR (CDCI₃) 51.47 (s, 9H), 1.95 (s, 3H), 2.10 (m, 2H), 2.43 (m, 1H), 2.64 (m, 1 H), 2.88 ( m, 4H), 3.20 (m, 1 H), 3.30 (m, 1 H), 3.44 (m, 1 H), 3.72 (s, 3H), 4.66 (t, 1H), 6.48 (bs, 1H).

MS (M+H)⁺= 373.

-82- Example 2

O CH₃O--(

.OH

AcHN O CH₃ HCI

(±)-(1S.2S.3R.4R)-2-N-Methyl-3-acetamidomethyl-4-methoxycarbonyl- cyclopentanecarboxylic Acid Hvdrochloride.

A solution of (±)-(1 S,2S,3R,4R)-2-(N-methyl-N-f-butyloxycarbonylamino)-3- acetamidomethyl-4-methoxycarbonylcyclopentanecarboxylic acid (130 mg, 0.35 mmole) in 4.5 mL of dichloromethane was reacted with trifluoroacetic acid (1.5 mL) for 1 hr, at room temperature. The solution was concentrated in vacuo, at 25 °C. The residue was treated with 1 N HCI and concentrated in vacuo to provide the title compound as a white solid (yield: 100 mg, 92 %).

¹H NMR (D₂0) 52.02 (s, 3H), 2.08 (m, 1H), 2.54 (m, 2H), 2.76 (s, 3H), 2.85 (m, 2H), 3.36 (m, 2H), 3.76 (s, 3H), 3.81 (t, 1H).

Example 3 o

CH₃O-^/(

OH

AcHN _NCbz O CH₃

(±)-(1S.2S,3R,4R)-2-(N-Methyl-N-benzyloxycarbonylamino)-3-acetamidomethyl- 4-methoxycarbonyl-cvclopentanecarboxylic Acid.

A solution of (±)-(1S,2S,3R,4R)-2-N-methyl-3-acetamidomethyl-4- methoxycarbonyl-cyclopentanecarboxylic acid hydrochloride (100 mg), N-

-83- (benyloxycarbonyloxy)succinimide (183 mg) and triethylamine (0.160 mL) in dichloromethane (10 mL) was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate and washed successively with 1 N HCI, and brine, dried over MgS0 , and concentrated in vacuo. The residue was purified by silica gel chromatography using chloroform/methanol/acetic acid (97:2:1) to provide the title compound as a white solid.

¹H NMR (CDCI₃) 51.88 (s, 3H), 2.08 (m, 2H), 2.46 (m, 1 H), 2.66 (m, 1 H), 2.92 (m, 1 H), 2.96 (s, 3H), 3.18 (m, 1H), 3.35 (m, 1H), 3.70 (s, 3H), 4.64 (bs, 1 H), 5.14 (s, 2H), 6.29 (bs, 1 H), 7.34 (m, 5H).

MS: (M+H)⁺ = 407.

Example 4

(±)-(1S.2S,3R,4R)-2-( -Butyloxycarbonylamino)-3-(acetamidomethvn-4-(methoxy- carbonyl)-cyclopentane-1 -carboxylic Acid.

NHBoc

4A. (±)-(2R.3S)-2- -Butyloxycarbonylamino-3-acetoxymethylbicvclo[2.2.1lhept-5- ene.

A solution of (±)-(2R,3S)-2-(f-butyloxycarbonylamino)-3- hydroxymethylbicyclo[2.2.1]hept-5-ene (1.0 g, 4.18 mmole), acetic anhydride (0.55 mL), triethylamine (2 mL) and N,N-dimethylaminopyridine (catalytic) in 50 mL of dichloromethane was reacted for 2 hours, at room temperature. The reaction mixture was diluted with 200 mL of ethyl acetate, washed with 0.5 N HCI, water, saturated sodium bicarbonate, and brine. The organic layer was dried over MgS0₄, filtered and concentrated. The crude product was purified by silica

-84- gel chromatography using 10% ethyl acetate/hexanes to provide the title compound, (yield: .92 g, 78 %)

MS: (M+H)⁺ = 282.

HO- //

BocHN O

4B. (±)-(1S,2S,3S,4R)-2-(r-Butyloxycarbonylamino)-3-(acetoxymethyl)-cvclo- pentane-1 ,4-dicarboxylic Acid

Ruthenium dioxide hydrate (43mg, 0.32 mmole) was added to a vigorously stirred mixture of Nal0₄ (7.12 g, 33 mmole) 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 homogeneous yellow color was attained. A solution of (±)-(2R,3S)-2-(f-butyloxycarbonylamino)-3-acetoxymethyl- bicyclo[2.2.1]hept-5-ene (2.28 g, 8.11 mmole) 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 partitioned between ethyl acetate and 0.5 N HCI. The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated to provide the diacid compound which was used in the following reaction without additional purification.

-85- P HO-

^H0^ >γ⁰

BocHN O

4C. (±)-(1S,2S,3S.4R)-2-( -Butyloxycarbonylamino)-3-(hvdroxymethyl)-cvclo- pentane-1 ,4-dicarboxylic Acid.

The crude diacid, (±)-(1S,2S,3S,4R)-2-(f-butyloxycarbonylamino)-3- (acetoxymethyl)-cyclopentane-1 ,4-dicarboxylic acid, prepared in example 4B, and sodium hydroxide (1.2 g) in 45 mL of water was reacted for 6 hours, at room temperature. The reaction mixture was acidified to pH 1 with and extracted with ethyl acetate (3 x 40 mL). The organic layer was washed with brine and dried over Na₂S0 , filtered and concentrated. The crude diacid-alcohol was used in the following reaction without additional purification.

.o

CH₃O-^ HO^ > _γOCH₃

BocHN O

4D. (±)-(1 S.2S.3S,4R)-2-(f-Butyloxycarbonylamino)-3-(hvdroxymethyl)-cyclo- pentane-1 ,4-dicarboxylic Acid Dimethyl Ester.

The diacid-alcohol, (±)-(1 S,2S,3S,4R)-2-(f-butyloxycarbonylamino)-3- (hydroxymethyl)-cyclopentane-1 ,5-dicarboxyiic acid, prepared in Example 4C, was dissolved in 40 mL of tetrahydrofuran (THF) and reacted with diazomethane in ethyl ether until complete conversion to the dimethyl ester. The reaction mixture was monitored by TLC, using 10% methanol in chloroform with 1% acetic acid. The reaction was concentrated in vacuo to provide the title compound as a colorless oil (yield: 1.3 g, 85 %).

-86- MS: (M+H)⁺ = 331.

O CH₃O^

N₃ ^) ._γOCH₃ BocHN O

4E. (±)-(1S,2S.3R,4R)-2-(f-Butyloxycarbonylamino)-3-(azidomethyl)-cvclo- pentane-1 ,4-dicarboxylic Acid Dimethyl Ester.

Methanesulfonyl chloride (1.3 mL, 17.0 mmole) was added slowly to a solution of (±)-(1 S,2S,3S,4R)-2-(f-butyloxycarbonylamino)-3-(hydroxymethyl)- cyclopentane-1 ,4-dicarboxylic acid dimethyl ester (2.76g, 8.34 mmole) and triethylamine (2.4 mL, 17.0 mmole) 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 HCI and brine, dried over MgS0₄, filtered and concentrated in vacuo to provide the crude mesylate. The mesylate and lithium azide (4 g) were reacted in 35 mL of N.N-dimethylformamide for 1 hour, at 90 °C. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgS0 , filtered and concentrated. The crude product was purified by silica gel chromatography using 20% ethyl acetate in hexanes to provide the title compound, (yield: 1.8 g, 48%)

MS: (M+H)⁺ = 373.

-87- O CH₃O-^

AcHN^ ) .^OCH₃ BocHN O

4F. (±H1S,2S.3R.4R)-2-(f-Butyloxycarbonylamino)-3-(acetamidomethyl)- cyclopentane-1 ,5-dicarboxylicAcid Dimethyl Ester.

(±)-(1S,2S,3R,4R)-2-(f-Butyloxycarbonylamino)-3-(azidomethyl)- cyclopentane-1 ,4-dicarboxylic acid dimethyl ester (506 mg, 1.42 mmole) and thiolacetic acid (0.4 mL) were reacted at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel chromatography using 3% methanol in chloroform to provide the title compound (yield: 255 mg, 48%).

MS: (M+H)⁺ = 373.

.0

HO - l

^AcHN^O- ^0H N IHBo όc

4G. (±)-(1S.2S.3R,4R)-2-(f-Butyloxycarbonylamino)-3-(acetamidomethyl)- cyclopentane-1 ,4-dicarboxylic Acid

(±)-(1S,2S,3R,4R)-2-(f-Butyloxycarbonylamino)-3-(acetamidomethyl)- cyclopentane-1 ,4-dicarboxylic acid dimethyl ester (255 mg, 0.68 mmole) and lithium hydroxide (2.2 equivalents) in 15 mL of 4:1 methanol.waterwere reacted at room temperature for 2 hours. The reaction was acidified with dilute HCI and extracted with ethyl acetate (3 X 60 mL). The organic layers were combined, dried over Na₂S0₄, filtered and concentrated to provide the title compound.

-88- O CH₃O-^

AcHN ^ J \ OH

BocHN O 4H. (±)-(1 S,2S,3R,4R -2-(f-Butyloxycarbonylamino)-3-(acetamidomethyl)-4-

(methoxycarbonvD-cyclopentane-l -carboxylic Acid

The crude diacid, (±)-(1S,2S,3R,4R)-2-(f-butyloxycarbonylamino)-3- (acetamidomethyl)-cyclopentane-1 ,4-dicarboxylic acid, prepared in Example 4G was reacted with acetic anhydride (20 mL) for approximately 1 hour at 60 °C to provide the bicyclic anhydride. The reaction mixture was concentrated in vacuo and the crude anhydride was treated with methanol (50 mL) and triethylamine (2- 3 equivalents) at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with 0.5N HCI and brine. The organic solution was dried over Na₂SO₄, filtered and concentrated. Chromatographic separation of the diastereomers was accomplished by silica gel chromatography using 25% ethyl acetate in hexanes and 0.5% acetic acid to provide the title compound (yield: 146 mg, 60 %).

¹H NMR (methanol-d4) 5 1.44 (s, 9H), 1.90 (s, 3H), 2.04 (m, 1H), 2.32 (m,1 H), 2.54 (m,1H), 2.72 (m,2H), 3.11 (m, 1 H), 3.36 (m,1 H), 4.38 (m,1 H), 6.92 (broad d, 1H), 7.8 (broad s, 1H).

MS: (M+H)⁺ = 359.

-89- Example 5 o

CH₃O- M

AcHN_^ ) OH

NH₂ O

HCI

(±)-(1S.2S,3R.4R)-2-Amino-3-(acetamidomethvn-4-(methoxycarbonyl)- cyclopentane-1 -carboxylic Acid Hydrochloride

A solution of (±)-(1S,2S,3R,4R)-2-(f-butyloxycarbonylamino)-3-(acetamido- methyl)-4-(methoxycarbonyl)-cyclopentane-1 -carboxylic acid (66 mg, 0.18 mmole) in 3 mL of dichloromethane was reacted with trifluoroacetic acid (1.0 mL) for 1 hr, at room temperature. The solution was concentrated in vacuo at 25 °C. The crude product was treated with 1 N HCI and concentrated in vacuo to provide the title compound as a white solid.

¹H NMR (D₂0) 52.01 (s, 3H), 2.19 (m, 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, 1 H).

MS = (M+H)⁺ = 259.

-90- Example 6

(±)-(1S,2S.3R.4R)-3-Acetamidomethyl-2-(N- -butoxycarbonylamino)methyl-4- methoxycarbonyl-cyclopentane-1 -carboxylic Acid

OBn

6A. (±)-exo-exo-3-Acetoxymethyl-2-benzyloxymethyl-bicvclo[2.2.1lhept-5-ene.

(±)-exo-exo-2,3-Dihydroxymethylbicyclo[2.2.1]hept-5-ene (620 mg, 4.0 mmole), 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 (300mg, 60% oil dispersion) in 10 mL of N,N-dimethyl- formamide (DMF) for 15 min, at 0 °C. This was followed by treatment of the dianion with benzyl bromide (0.5 mL) for an additional 2 hours. The reaction mixture was diluted with ethyl acetate washed with water, and brine, dried over MgS0 , filtered and concentrated in vacuo.

The crude benzylated product was reacted with acetic anhydride (0.7 mL), triethylamine (3 mL) and N,N-dimethylaminopyridine (catalytic) in dichloromethane (20 mL) at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography using 10% ethyl acetate in hexanes to provide the title compound (yield: .845 g, 74%).

¹H NMR (CDCI₃) 51.41 (m, 2H), 1.85 (m, 2H), 2.05 (s, 3H), 2.73 (brs, 1 H), 2.78(brs, 1H), 3.38 (m, 1H), 3.57 (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.

-91- O CH₃O^

AcO^ OCH₃

OBn

6B. (±)-(1S,2S,3R.4R)-3-Acetoxymethyl-2-benzyloxymethyl-cvclopentane-1.4- dicarboxylic Acid Dimethyl Ester.

A rapidly stirred mixture of Nal0 (10 g) and Ru0₂ (45 mg) in 25 mL of carbon tetrachloride, 50 mL of acetonitrile, 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 mmole) in 25 mL of carbon tetrachloride was added to the bright yellow mixture. The resultant black mixture was stirred for 1.5 hours, at room temperature. Water (250 mL) 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 MgS0 , 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 purified by silica gel chromatography using ethyl acetate: hexanes (1 :1) to provide the title compound as a white solid (yield: 1.91 g, 44%).

¹H NMR (CDCI₃) 52.00 (s, 3H), 2.14 (m, 1H), 2.34 (m, 1H), 2.77 (m, 3H), 2.89 (m, 1 H), 3.51 (m, 2H), 3.67 (s, 3H), 3.70 (s, 3H), 4.18 (m, 2H), 4.47 (s, 2H), 7.32 (m, 5H).

MS: (M+H)⁺ = 379.

-92- .0

CH3O--

ACO ^y _^ 1 y PCH

''/,

OH,

6C. (±)-(1 S.2S.3R.4R) -3-Acetoxymethyl-2-hvdroxymethyl-cvclopentane-1.4- dicarboxylic Acid Dimethyl Ester.

A mixture of (±)-(1S,2S,3R,4R)-3-acetoxymethyl-2- benzyloxymethylcyclopentane-1 ,4-dicarboxylic acid dimethyl ester (3.3 g, 8.72 mmole) and palladium (600 mg, 10% on carbon) in ethanol (100 mL) was stirred vigorously at room temperature under an hydrogen atmosphere. Upon completion, as determined by TLC, the reaction mixture was filtered and concentrated in vacuo to provide the title compound (yield: 2.56 g, 100%).

¹H NMR (CDCI₃) 51.84 (t, 1H), 2.05 (s, 3H), 2.16 (m, 1 H), 2.36 (m, 1H), 2.75 (m, 4H), 3.70 (s, 3H), 3.71 (s, 3H), 3.73 (m, 1H), 4.19 (m, 2H).

MS = (M+H)⁺ = 289.

CH₃O _//

AcO

6D. (±H1S,2S,3R,4R -3-Acetoxymethyl-2-azidomethylcvclopentane-1.4-di- carboxylic Acid Dimethyl Ester.

Methanesulfonyl chloride (2.1 mL, 26.6 mmole) was added slowly to a solution of (±)-(1S,2S,3R,4R)-3-acetoxymethyl-2-hydroxymethylcyclopentane- 1 ,4-dicarboxylic acid dimethyl ester (2.56g, 8.72 mmole) and triethylamine (3.7

-93- mL, 26.6 mmole) in 100 mL of dichloromethane at -30 °C. The reaction mixture ^' was stirred at -30 °C for 0.5 hour then allowed to warm to 0 °C over 1 hour. The reaction mixture was diluted with ethyl acetate washed with 0.1 N HCI and brine, dried over MgS0 , filtered and concentrated in vacuo to provide 4.32 g of crude mesylate.

The crude mesylate, prepared above, and lithium azide (4.2 g, 87.2 mmole) 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 MgS0₄, filtered and concentrated. The crude product was purified by silica gel chromatography using 25 % ethyl acetate in hexanes to provide the title compound (yield: 2.0 g, 72%).

H NMR (CDCI₃) 52.07 (s, 3H), 2.17 (m, 1 H), 2.37 (m, 1H), 2.76 (m, 4H), 3.47 (m, 2H), 3.71 (s, 3H), 3.73 (s, 3H), 4.16 (m, 2H).

O

CH₃O -ii AcO CH 3 O

6E. (±)-(1S.2S.3R.4R -3-Acetoxymethyl-2-(N-f-butoxycarbonylamino)methyl- cyclopentane-1,4-dicarboxylic Acid Dimethyl Ester.

A mixture of (±)-(1 S,2S,3R,4R)-3-acetoxymethyl-2-azidomethylcyclo- pentane-1 ,4-dicarboxylic acid dimethyl ester (2.0 g, 6.6 mmole), di-f-butyl- dicarbonate (3.79 g), and palladium (900mg, 10% on carbon) in 100 mL of ethyl acetate was stirred vigorously at room temperature under an hydrogen atmosphere. Upon completion, as determined by TLC, the reaction mixture was

-94- filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate in hexanes to provide the title compound (yield: 2.3 g, 94%).

¹H NMR (CDCI₃) 51.43 (s, 9H), 2.06 (s, 3H), 2.17 (m, 1H), 2.35 (m, 1H), 2.72 (m, 4H), 3.21 (m, 2H), 3.70 (s, 3H), 3.72 (s, 3H), 4.12 (m, 2H), 4.74 (t, 1 H).

MS = (M+H)⁺ = 388.

O

CH₃O- //

OCH

"/, O

6F. (±)-(1S.2S.3R,4R)-2-(N-f-Butoxycarbonylamino)methyl-3-hvdroxymethyl- cvclopentane-1 ,4-dicarboxylic Acid Dimethyl Ester.

(±)-(1 S,2S,3R,4R)-3-Acetoxymethyl-2-(N-^butoxycarbonylamino)- methylcyclopentane-1 ,4-dicarboxylic acid dimethyl ester (600 mg,11.55 mmole) was treated with potassium carbonate (catalytic) in 10 mL of methanol, at room temperature for 6h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and brine. The organic layer was dried over MgS0₄, filtered and concentrated to provide the title compound, (yield: 510 mg, 95%)

¹H NMR (CDCI₃) 51.44 (s, 9H), 2.24 (m, 2H), 2.59 (m, 2H), 2.77 (m, 2H), 3.28 (m, 2H), 3.73 (m, 8H), 5.04 (t, 1H).

-95- O CH₃O-^

N,. OCH₃ Y O

6G. (±)-(1 S.2S.3R,4R)-3-Azidomethyl-2-(N-f-butoxycarbonylamino)methylcvc- lopentane-1.4-dicarboxylic Acid Dimethyl Ester.

Methanesulfonyl chloride (0.35 mL, 4.5 mmole) was added slowly to a solution of (±)-(1 S,2S,3R,4R)-2-(N-f-butoxycarbonylamino)methyl-3- hydroxymethyl-cyclopentane-1 ,4-dicarboxylic acid dimethyl ester (560 mg, 1.48 mmole) and triethylamine (0.6 mL) in dichloromethane (10 mL) at -30 °C. The reaction mixture was stirred at -30 °C for 2 hours then allowed to warm to 0 °C over 1 hour. The reaction mixture was then diluted with ethyl acetate washed with 0.1 N HCI and brine, dried over MgS0₄, filtered and concentrated in vacuo to provide the crude mesylate.

The crude mesylate, prepared above, and lithium azide (0.7 g, 14.3 mmole) 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 MgS0₄, filtered and concentrated. The crude product was purified by silica gel chromatography using 25% ethyl acetate in hexanes to provide the title compound (yield: 386 mg, 70%).

¹H NMR (CDCI₃) 51.43 (s, 1 H), 2.26 (m, 2H), 2.69 (m, 4H), 3.23 (m, 2H), 3.46 (m, 2H), 3.70 (s, 3H), 3.71 (s, 3H), 4.74 (bs, 1 H).

-96- O

CH ^₃O^ .OCH

''</ O

6H. (±)-(1S,2S,3R.4R)-3-Acetamidomethyl-2-(N- -butoxycarbonylamino)methyl- cyclopentane-1 ,4-dicarboxylic Acid Dimethyl Ester.

A mixture of (±)-(1 S,2S,3R,4R)-3-azidomethyl-2-(N-f-butoxycarbonyl- amino)methylcyclopentane-1 ,4-dicarboxylic acid dimethyl ester (386 mg, 1.04 mmole) , acetic anhydride (0.25 mL) and palladium (25 mg, 10% on carbon) in 10 mL of ethyl acetate was stirred vigorously at room temperature under an hydrogen atmosphere. Upon completion, as determined by TLC, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 75% ethyl acetate in hexanes to provide the title compound, (yield: 232 mg, 58%).

¹H NMR (CDCI₃) 51.44 (s, 9H), 1.97 (s, 3H), 2.27 (m, 2H), 2.64 (m, 2H), 3.18 (m, 2H), 3.32 (t, 1H), 3.71 (s, 3H), 3.73 (s, 3H), 7.78 (bs, 1H), 6.19 (bs, 1 H).

MS = (M+H)⁺ = 387.

-97- .0

CH₃O-^ .OH O

61. (±)-(1S,2S,3R,4R)-3-Acetamidomethyl-2-(N-f-butoxycarbonylamino)methyl-4- methoxycarbonylcyclopentane-1 -carboxylic Acid.

(±)-(1S,2S,3R,4R)-3-Acetamidomethyl-2-(N-f- butoxycarbonylamino)methylcyclopentane-1 ,4-dicarboxylic acid dimethyl ester (232 mg, 0.60 mmole) was reacted with 5 equivalents of lithium hydroxide in 5 mL of (4:1) methanol.water for 2 hours, at room temperature. The reaction mixture was neutralized with 0.1 N HCI and partitioned between ethyl acetate and brine. The organic layer was concentrated to provide 194 mg of crude diacid.

The crude diacid (190 mg), prepared above, was reacted with acetic anhydride (10 mL) for 3 hours, at room temperature. The reaction mixture was concentrated in vacuo. The crude product was treated with methanol (10 mL) and triethylamine (.250 mL) for 16 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and 0.1 N HCI. 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%) methanol in chloroform and acetic acid (0.5%) to provide the title compound, (yield: 72 mg, 32%)

H NMR (CD₃OD) 51.44 (s, 9H), 1.93 (s, 3H), 2.24 (m, 2H), 2.64 (m, 4H), 3.12 (m, 3H), 3.67 (s, 3H).

MS = (M+H)⁺ = 373.

-98- Example 7 O

CH₃O-^ AcHN, / \_, .OH

HCI ^NH₂

(±)-(1S.2S,3R,4R)-2-Aminomethyl-3-acetamidomethyl-4-methoxycarbonyl-cyclo- pentane-1 -carboxylic Acid Hydrochloride.

A solution of (±)-(1S,2S,3R,4R)-3-Acetamidomethyl-2-(N-f-butoxycarbonyl- amino)methyl-4-methoxycarbonylcyclopentane-1 -carboxylic acid (62 mg, 0.16 mmol) in of dichloromethane (4 mL) was reacted with trifluoroacetic acid (1.0 mL) for 1 hour, at room temperature. The solution was concentrated in vacuo, at 25 °C. The residue was treated with 1 N HCI and concentrated in vacuo to provide the title compound as a white solid (yield: 39 mg, 75 %).

¹H NMR (D₂0) 51.95 (s, 3H), 2.22 (m, 1H), 2.46 (m, 1H), 2.71 (m, 2H), 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.

-99- Example 8

(±)-(1S.2S,3R,4R)-2-N-^-Butoxycarbonylamino-3-(acetamidomethyl)-4-carbamoyl- cvclopentane-1 -carboxylic Acid.

o

H₉N-

AcHN O. X )-. OCH₃

O NHBoc

8A. (±)-(1S,2S,3R.4R -2-N-f-Butoxycarbonylamino-3-(acetamidomethyl)-4- carbamoyl-cyclopentane-1 -carboxylic Acid Methyl Ester.

The title compound was prepared in two steps starting by reacting (±)- (1 S,2S,3R,4R)-2-(N-Nbutyloxycarbonylamino)-3-(acetamidomethyl)- cyclopentane-1 ,4-dicarboxylic acid in place of (±)-(1S,2S,3R,4R)-2-(f- butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1 ,4-dicarboxyiic acid, according to the method described in Example 4H, and substituting anhydrous liquid ammonia for methanol and triethylamine.

In the second step the crude product (54 mg, 0.16 mmole), prepared above, in 4 ml of THF was cooled to 0 °C and treated with an ethereal solution of CH₂N₂ until the yellow reaction color persisted. The reaction mixture was warmed slowly to room temperature and concentrated in vacuo to provide a colorless oil. Purification using flash chromatography eluting with 5% methanol/chloroform provided the title compound as a white solid (yield: 16 mg, 28%).

¹H NMR (CDCy 51.43 (s, 9H), 1.90 (s, 3H), 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.

-100- O H₂N-^

^AcHNvOγ^0H

NHBoc

8B. (±)-(1S,2S.3R.4R)-2-N-f-Butoxycarbonylamino-3-(acetamidomethyl)-4- carbamoyl-cyclopentane-1 -carboxylic Acid.

A solution of (±)-(1S,2S,3R,4R)-2-N-f-butoxycarbonyiamino-3-(acetamido- methyl)-4- carbamoyl-cyclopentane-1 -carboxylic acid methyl ester (16 mg, 0.045 mmole) in 0.2 ml methanol/H₂0 (3:1) was treated with (1 mg, 0.045 mmole) of LiOH. After stirring at room temperature overnight, the reaction mixture was quenched with 5% HCI and extracted 3 times with ethyl acetate. The combined extracts were dried over Na₂S0 , filtered and concentrated in vacuo to provide the title compound as a white solid (yield: 11 mg, 73%).

¹H NMR (methanol-d4) 51.44 (s, 9H), 1.91 (s, 3H), 2.02 (m, 1H), 2.24 (m, 1 H), 2.60 (m, 5H), 4.32 (m, 1H), 6.90 (br d, 1H).

MS (M-H)- = 342.

-101- Example 9

(±)-(1S.2S,3R,4R)-2.3-Acetamidomethyl-4-methoxycarbonylcvclopentane-1- carboxylic Acid.

^{^}OAc

9A. (±)-exo-exo-2,3-diacetoxymethyl-bicvclof2.2.11hept-5-ene.

(±)-exo-exo-2,3-dihydroxymethyl-bicyclo[2.2.1]hept-5-ene was treated with acetic anhydride and triethylamine in dichloromethane. Standard workup provided the title compound.

MS: (M+H)⁺ = 329.

.0

CH₃O -ii

ACO. OCH O

9B. (±)-(1 S.2S.3R.4R)-2.3-Diacetoxymethylcvclopentane-1 ,4-dicarboxylic Acid Dimethyl Ester.

The title compound was prepared according to the method described in Example 6B, substituting (±)-exo-exo-2,3-diacetoxymethylbicyclo[2.2.1]hept-5- ene (1 g, 4.2 mmol) in place of (±)-(2R,3S)-2-acetoxymethyl-3-benzyloxymethyl- bicyclo[2.2.1]hept-5-ene. Purification, using flash chromatography eluting with 50% ethyl acetate/hexanes, provided the title compound as a colorless oil. (yield: 0.8 g, 58%).

¹H NMR (CDCI₃) 52.05 (s, 6H), 2.29 (m, 2H), 2.79 (m, 4H), 3.72 (s, 6H), 4.14 (m, 4H).

-102- MS: (M+H)⁺ = 331.

.0

CH₃o -ii

HO ^y. xs y OCH₃

OH

9C. (±)-(1 S.2S.3R,4R)-2.3-Dihvdroxymethylcvclopentane-1 ,4-dicarboxylic Acid Dimethyl Ester.

A solution of (±)-(1 S,2S,3R,4R)-2,3-diacetoxymethylcyclopentane-1 ,4- dicarboxylic acid dimethyl ester (5.0 g, 0.015 mole) in 60 ml of methanol was treated with a catalytic amount of K₂C0₃. The reaction mixture was stirred, under a nirogen amosphere, at room temperature, for 16 hours. The reaction mixture was diluted with ethyl acetate and quenched with 5% HCI. The organic layer was separated, dried over Na₂S0₄, filtered, and concentrated in vacuo, at 30 °C to provide the title compound as a colorless oil. (yield: 3.3 g, 89%)

¹H NMR (CDCI₃) 52.06 (m, 1H), 2.29 (m, 2H), 2.54 (m, 3H), 2.80 (m, 2H), 3.67 (m, 8H).

MS: (M+H)⁺ = 247.

-103- .0

CH₃O-^

MsO. 1 \ OCH

OMs

9D. (±H1S.2S.3R,4R)-2,3-Dimethansulfonyloxymethylcvclopentane-1.4-di- carboxylic Acid Dimethyl Ester.

A solution of (±)-(1S,2S,3R,4R)-2,3-dihydroxymethylcyclopentane-1 ,4- dicarboxylic acid dimethyl ester (200 mg, 0.81 mmole) 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 mmole) followed by dropwise addition of triethylamine (0.34 mL, 2.4 mmole). After 30 minutes of stirring under a nirogen amosphere, at -30 °C, the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na₂S0 , filtered and concentrated in vacuo to provide the title compound as a colorless oil (yield: 302 mg, 93%).

¹H NMR (CDCI₃) 5 52.16 (m, 1H), 2.45 (m, 1H), 2.87 (m, 4H), 3.06 (s, 6H), 3.72 (s, 6H), 4.38 (m, 4H).

MS: (M+H)⁺ = 403.

-104- .0

CH₃O

N^ ,OC^Hπ₃

1 O

9E. (±)-(1 S.2S,3R,4R)-2,3-Diazidomethyl-cvclopentane-1 ,4-dicarboxyiic Acid Dimethyl Ester.

A solution of (±)-(1 S,2S,3R,4R)-2,3-dimethansulfonyloxymethyl- cyclopentane-1 ,4-dicarboxylic acid dimethyl ester (300 mg, 0.75 mmole) in 3 mL of DMF was treated with LiN₃ (400 mg, 8.2 mmole) and heated to 100 °C under a nitrogen amosphere. After heating for 1 hour, the reaction mixture was diluted with ethyl acetate and washed twice with water, brine, dried over Na₂S0₄, filtered and concentrated in vacuo to provide the title compound as a copper colored oil (yield: 204 mg, 92%).

¹H NMR (CDCI₃) δ 52.12 (m, 1H), 2.37 (m, 1 H), 2.71 (m, 4H), 3.50 (m, 4H), 3.72 (m, 6H).

MS: (M+H)⁺ = 297.

.0

CH₃O _//

AcHN. OCH

- ³ O

9F. (±)-(1 S.2S.3R,4R)-2,3-Acetamidomethyl-cvclopentane-1 ,4-dicarboxylic Acid Dimethyl Ester.

A solution of (±)-(1S,2S,3R,4R)-2,3-diazidomethyl-cyclopentane- 1 ,4-dicarboxylic acid dimethyl ester (145 mg, 0.49 mmole) in 2 ml of isopropyl

-105- alcohol was treated with Pd/C. The reaction mixture stirred vigorously overnight under a hydrogen atmosphere, 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 excess 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%).

H NMR (CDCI₃) 51.98 (s, 6H), 2.30 (m, 1H), 2.36 (m, 1 H), 2.56 (m, 2H), 2.68 (m, 2H), 3.30 (m, 4H), 3.71 (s, 6H), 6.16 (br s, 2H).

MS: (M+H)⁺ = 329.

.0 CH₃0-^

AcHN

9F. (±)-(1 S.2S.3R.4R)-2.3-Acetamidomethyl-4-methoxycarbonylcvclopentane-1- carboxylic Acid.

A solution of (±)-(1S,2S,3R,4R)-2,3-acetamidomethyl-cyclopentane- 1 ,4-dicarboxylic acid dimethyl ester (100 mg, 0.33 mmole) in 1 ml of a mixture of methanol/H₂0 (3:1) was treated with LiOH (16 mg, 0.66 mmole). After stirring for 1 hour, at room temperature, the reaction mixture was acidified with 5% HCI and extracted three times with ethyl acetate. The organic extracts were dried over Na₂S0₄, filtered and concentrated in vacuo to provide the diacid intermediate as a white solid (69 mg, 70%). The diacid was taken up in acetic anhydride (2 ml)

-106- and heated for 1 hour at 60°C. The reaction mixture was then concentrated in vacuo, taken up in 1 mL of methanol and treated with triethyl amine. 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% HCI. The organic layer was dried over Na₂S0 , 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 solid, (yield: 6 mg, 6%)

¹H NMR (methanol-d₄) 51.92 (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.

-107- Example 10

(±)-(1S.2S,3R.4R)-2-N- -Butoxycarbonylamino-3-(acetamidomethyl)-4-N- methylcarboxamido-cyclopentane-1 -carboxylic Acid and (±H1 R,2R.3S,4S)-3-N-f- butoxycarbonylamino-2-(acetamidomethyl)-4-N-methylcarboxamido-cyclopent- ane-1 -carboxylic Acid.

O O

H₃CHN^f HO^f

AcHN, I \ OH AcHN, I \ NHCH₃

N iHBloc N iHBosc

10A. (±)-(1S.2S.3R.4R)-2-N-f-butoxycarbonylamino-3-(acetamidomethvn-4-N- methylcarboxamido-cyclopentane-1 -carboxylic Acid Methyl Ester and (±)-(1 R,- 2R,3S.4S)-3-N- -butoxycarbonylamino-2-(acetamidomethyl)-4-N-methylcarbox- amido-cyclopentane-1 -carboxylic Acid Methyl Ester.

A solution of (±)-(1S,2S,3R,4R)-2-N-f-butoxycarbonylamino-3-(acetamido- methyl)-4-N-methylcarboxamido-cyclopentane-1 -carboxylic acid methyl ester and (±)-(1 R,2R,3S,4S)-3-N- -butoxycarbonylamino-2-(acetamidomethyl)-4-N-methyl- carboxamido-cyclopentane-1 -carboxylic acid methyl ester (1 :1) (260 mg, 0.72 mmole) in 3 ml of dichloromethane was treated with hydroxybenzotriazole (1 equiv.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.5 equivalents), and methylamine (5 equivalents). After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and washed 3 times with 5% HCI. The organic layer was dried over Na₂SO , filtered and concentrated in vacuo to provide the title ester-amide compounds as a white solid, (yield: 111 mg, 42%)

MS: (M+H)⁺ = 372.

-108- .0 O

CH₃N^ HO-^

^Ac0\ ^ ^~} - /^{0H Ac0}\ ^ - NHCH₃ NHBoc NHBoc

10B. (±)-(1S.2S.3R,4R)-2-N-f-Butoxycarbonylamino-3-(acetamidomethyl)-4-N- methylcarboxamido-cyclopentane-1 -carboxylic Acid and (±)-(1 R,2SR,3S,4S)-3-N- ^-butoxycarbonylamino-2-(acetamidomethyl)-4-N-methylcarboxamido-cvclopent- ane-1 -carboxylic Acid.

A solution of the ester-amide mixture (125 mg, 0.34 mmole) prepared in Example 10A, in 1 ml of methanol/H₂0 (3:1) was treated with LiOH (8 mg, 0.34 mmole). After stirring for 1 hour at room temperature, the reaction mixture was quenched with 5% HCI and extracted 3 times with ethyl acetate. The combined organic extracts were dried over Na₂S0₄ , filtered and concentrated in vacuo to provide the title compound as a white solid, (yield: 85 mg, 70%)

1 H NMR (methanol-d₄) 51.44 (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).

MS: (M+H)⁺ = 358.

-109- Example 11

(±)-(1S,2S.3R.4R)-3-Acetamidomethyl-2,4-diamino-cvclopentane-1 -carboxylic Acid Hvdrochloride.

.0 p

<Z ^,^■y0~i HO-%

N₃/ ., /⁰ _/OCH

BocHN Y O BocHN O

11 A. (±)-(1 S.2S,3R,4R)-2-(f-Butyloxycarbonylamino)-3-(azidomethyl)-4-meth- oxycarbonyl-cvclopentane-1 -carboxylic Acid and (±)-(1S,2S,3R,4R)-2-(f-butyl- oxycarbonylamino)-3-(azidomethyl)-1-methoxycarbonyl-cvclopentane-4-carbox- ylic Acid.

The title compound was prepared, in two steps, first following the procedure described in Example 4G and 4H substituting (±)-(1S,2S,3R,4R)-2-(f- butyloxycarbonylamino)-3-(azidomethyl)-cyclopentane-1 ,4-dicarboxylic acid dimethyl ester ( 98 mg, 0.28 mmole) in place of (±)-(1 S,2S,3R,4R)-2-( - butyloxycarbonylamino)-3-(acetamidomethyl)-cyclopentane-1 ,4-dicarboxylic acid dimethyl ester (yield: 76 mg, 79 %).

MS: (M+H)⁺ = 343

.0

CbzHN. H₃CO-

^N. _/OCH₃ N₃^

"If 'NHCbz BocHN 0 BocHN

11 B. (±)-(1S.2S.3S,4R -2-(f-Butyloxycarbonylamino)-3-(azidomethvn-4-benzyl- oxycarbonylamino-cvclopentane-1 -carboxylic Acid Methyl Ester and (±)-(1 R,2R,-

-110- 3S,4S)-3-( -Butyloxycarbonylamino)-2-(azidomethyl)-4-benzyloxycarbonylamino- cyclopentane-1 -carboxylic Acid Methyl Ester.

A solution of (250 mg,0.73 mmole) of the above mixture of regioisomers of methyl ester azide cyciopentanes, prepared in Example 11A, was treated with diphenylphosphorylazide, in 8 ml of toluene, Et₃N, ( 0.2 mL) and 0.75 mL of benzyl alcohol, under a nitrogen atmosphere, and heated to 80 °C for 3 hours. The reaction mixture was diluted with ethyl acetate and washed 3 times with 5% HCI. The organic layer was dried over Na₂S0 , filtered and concentrating 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 white solid (yield: 278 mg, 85%)

MS: (M+H)⁺ = 448.

CbzHN^ AcHN,,^T ,OCH₃

BocHN °

11C. (±)-(1S,2S,3S.4R)-2-(f-Butyloxycarbonylamino)-3-(acetamido)methyl-4- benzyloxycarbonylamino-cyclopentane-1 -carboxylic Acid Methyl Ester.

A solution of the methyl ester diastereomers (278 mg, 0.62 mmole), 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.

-111- CbzHN, AcHN/, JT ., _/ ^{0H '}^Y "if

BocHN °

11 D. (±)-(1 S.2S,3S,4R)-2-(f-Butyloxycarbonylamino)-3-(acetamido)methyl-4- benzyloxycarbonylamino-cyclopentane-1 -carboxylic Acid.

A solution of (±)-(1S,2S,3S,4R)-2-(f-butyloxycarbonylamino)-3- (acetamido)methyl-4-benzyloxycarbonylamino-cyclopentane-1 -carboxylic acid methyl ester (70 mg, 0.15 mmole) in 1 mL of methanol/H₂0 (3:1) was treated with (4 mg, 0.15 mmole) of LiOH. After stirring at room temperature for 2 hours the reaction mixture was quenched with 5% HCI and extracted 3 times with ethyl acetate. Standard workup, as described above, provided the title compound as a white solid (yield: 51 mg, 76%).

MS: (M+H)⁺ = 450.

H₂N, AcHN 1 \ OH

NH₂ O ^{2 HCI}

11E. (±)-(1S.2S,3S.4R)-3-Acetamidomethyl-2.4-diamino-cvclopentane-1-car- boxylic Acid Dihvdrochloride

A solution of (±)-(1S,2S,3S,4R)-2-(f-butyloxycarbonylamino)-3- (acetamido)methyl-4-benzyloxycarbonylaminocyclopentane-1 -carboxylic acid (51 mg, 0.11 mmole) in 0.2 ml of isopropyl alcohol and Pd/C was reacted under 1 atmosphere of hydrogen 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%)

-112- MS: (M+H)⁺ = 216.

Example 12

(±)-(1 R.2R.4R.1 'S)-4-(1 '-Acetamido-3'-ethyl)pentyl-3-methoxycarbonyl- cvclopentane-1 -carboxylic Acid.

12A. (±Hexo. RS) and (endo.1'RSV2-(3-ethyl-1- hvdroxy)pentylbicvclo[2.2.1]hept-5-ene.

1-bromo-2-ethylbutane (12.5 mL) and a catalytic amount of 1 ,2- dibromoethane were added to a suspension of 2.1 g Mg turnings in 200 mL of tetrahydrofuran. This mixture was heated to 50 °C for 2 hours, and cooled to -78 °C. A solution of 5.4 mL (±)-enoO-2-formylbicyclo[2.2.1]hept-5-ene, in 75 mL tetrahydrofuran, was added dropwise to the Grignard solution. The mixture was warmed to 0 °C and stirred for 1 hour. The reaction was quenched by addition of 20 mL saturated ammonium chloride and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and the solvent is evaporated. The crude material was purified by flash chromatography using 10% ethyl acetate: hexanes (1:9) to provide the title compounds, (yield: 4.9 g, 53%)

¹H NMR (CDCI₃) 5 0.78-0.91 (m, 6H), 1.15-1.50 (m, 11 H ), 1.70-2.10 (m, 1H), 2.60-2.95 (m, 2H), 2.95-3.55 (m, 1H),6.0-6.2(m,2H),

MS: (M+H)⁺ = 208.

-113-

12B. (±)-exo and endo-2-(1'-oxo-3'-ethyl)pentyl-bicvclor2.2.nhept-5-ene.

A solution of of oxalyl chloride, (2.3 mL) in 100 mL dichloromethane, maintained at -78 °C, was treated dropwise with dimethyl suifoxide, (4.0 mL). The mixture was stirred under nitrogen for 20 minutes and a solution of (±)- (2S,1'R) and (2S,1'S)-2-(r-hydroxy-3'ethyl)pentyl-bicyclo[2.2.1]hept-5-ene (4.9 g) in 50 mL of dichloromethane was added. The mixture was stirred at -78 °C for 0.5 hours warmed to 0 °C for 15 minutes, treated with 16.4 mL triethylamine at 0 °C and stirred for 10 minutes. Water (100 mL), at 25 °C, was added over 10 minutes. The organic layer was separated, washed with brine, dried over MgSO , filtered and the solvent 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, 14.9 mmole) was dissolved in 50 mL of methanol and combined with 22 mL of 1 M sodium methoxide. This mixture is heated to 70 °C for 18 hours. The solvent was evaporated and the residue dissolved in 300 mL ethyl acetate. The organic layer was washed with 100 mL of 0.5M HCI, brine, dried over magnesium sulfate, filtered, and the solvent is evaporated. The ketones were separated by flash chromatography using chloroform: hexanes (1:3) to provide title compound (±) (2R)-2-(3-ethyl-1- oxo)pentyl-bicyclo[2.2.1]hept-5-ene (yield: 0.99 g, exo ketone) (higher Rf) and (±) (2S)-2-(3-ethyl-1-oxo)pentyl-bicyclo[2.2.1]hept-5-ene (yield: 1.7 g, endo ketone, 87%).

-114- ¹H NMR (CDCI3) 5 0.85 (2t, 6H), 1.19-1.42 (m, 7H ), 1.70-1.92 (m, 2H), 2.32-2.39 (m, 1 H), 2.39-2.47 (2d, 2H), 2.88-2.98 (d,2H), 6.10-6.17 (m, 2H).

12C. (±)-(2R)-2-(1-Hvdroxyimino-3-ethyl)pentyl-bicvclor2.2.nhept-5-ene.

A solution of (±) (2R)-2-(1 '-oxo-3'ethyl)pentyl-bicyclo[2.2.1]hept-5-ene (1.1 g, 5.4 mmole) in 45 mL methanol was reacted with hydroxylamine hydrochloride (1.5 g, 21.6 mmole) and 1 N NaOH (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 MgS0 , filtered, and the solvent evaporated to provide the title compound (yield: 1.16 g, 97%).

¹ H NMR (CDCI3) 5 0.87 (2t, 6H), 1.24-1.40 (m, 8H ), 1.50 (d, 1 H), 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

-115-

12D. (±H2R.1'S)-2-(1-Amino-3-ethyl)pentyl-bicvclor2.2.nhept-5-ene.

The crude (±)-(2R)-2-(1-hydroxyimino-3-ethyl)pentylbicyclo[2.2.1]hept-5- ene (0.49 g, 2.13 mmole), prepared in Example 12C, in 10 mL toluene, was treated with 1 M lithium aluminum hydride bis(tetrahydrofuran) (4.3 mL). The mixture was heated to 100 °C for 2 hours, under a nitrogen atmosphere. The mixture was cooled to 0 °C, and consecutively combined with water (0.16 mL), 15% NaOH (0.16 mL), and water (0.49 mL). The solids were filtered, and the solution diluted with 150 mL ethyl acetate. The organic layer was washed with water, and brine, dried over MgS0 , filtered and the solvent evaporated. The crude amines were separated by 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 (±)-(2R,1'R)- isomer (77 mg) and 77 mg of a mixture of the amines overall yield 52%.

12E. (±)-(2R.1'S)-2-(1-Acetamido-3-ethyl-)pentyl-bicvclor2.2.nhept-5-ene.

(±)-(2R,1'S)-2-(r-amino-3'-ethyl-)pentyl-bicyclo[2.2.1]hept-5-ene (78 mg, 0.38 mmole) was dissolved in 3 mL dichloromethane . Triethylamine (0.16 mL)

-116- and acetic anhydride (0.07 mL) were added to the mixture. After 1 hour at 25 °C the solvent was evaporated and the residue purified by flash chromatography using ethyl acetate: hexanes (1 :4) to provide the title compound (yield: 78 mg, 83%).

¹ H NMR (CDCI₃, 300 MHz) δ 0.77-0.88 (m, 6H), 1.10-1.57 (m, 11 H ), 2.02 (s, 3H), 2.65 (s, 1 H), 2.84 (s, 1 H), 3.80-3.95 (m,1 H), 5.0-5.15(m, 1 H), 6.05 (s,2H).

MS: (M+H)⁺= 250.

12F. (±)-(1R,3R.4R,1'S)-4-(1-Acetamido-3-ethyl)pentylcvclopentane-1 ,3- Dicarboxylic Acid.

A solution of ruthenium tetroxide was prepared from 5.5 mg of ruthenium dioxide, suspended in carbon tetrachloride:acetonitrile (2:1), and 219 mg sodium periodate in 3 mL of water. The mixture was stirred 15 minutes at 0 °C. A solution of (±)-(2R,1'S)-2-(1'-acetamido-3'-ethyl)pentylbicyclo[2.2.1]hept-5-ene (64 mg, 0.256 mmol) in 1 mL of carbon tetrachloride was added to the ruthenium mxture. The reaction mixture was allowed to warm to 25 °C and stirred for 3 hours. 1 M Sodium bicarbonate (2 mL) was added and the aqueous layer was separated and acidified with 5 mL 1 M HCI 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

-117- methanol:dichloromethane :acetic acid (3:20:0.5) to provide the title compound ^' (yield: 50 mg, 62%).

¹H NMR (CD3OD) 5 0.78-0.92 (2t, 6H), 1.14-1.47 (m, 7H ), 1.62-1.75 (m, 1H), 1.92 (s, 3H), 1.95-2.03 (m, 1H), 2.08-2.20 (m,1H), 2.22-2.33 (m, 1H), 2.35- 2.49 (m,1H), 2.58-2.68 (m, 1 H), 2.82-2.94 (m, 1 H), 3.83-3.95 (m,1H),.

MS: (M+H)⁺= 314

12G. (±)-(1R,3R.4R.1'S)-4-(1'-Acetamido-3'-ethvnpentyl-3-methoxycarbonyl- cyclopentane-1 -carboxylic Acid.

(±)-(1R,3R,4R,1'S)-2-(1-Acetamido-3-ethyl)pentylcyclopentane-1 ,3- dicarboxylic acid was reacted with acetic anhydride (0.1 mL), 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 methanol and 0.1 mL of triethylamine, and heated for 1 hour, at 70 °C. The solvents were evaporated and the crude acid/ester purified by flash chromatography using ethyl acetate:methanol:acetic acid (97:2:1) to provide of the mixture of acid/esters (yield: 30 mg, 57%). The two isomers were separated by preparative thin layer chromatography using ethyl acetate:methanol:acetic acid (97:2:1) to provide the title compound (yield: 6.9mg, 13%).

-118- ¹H NMR (CD3OD, 300 MHz) δ 0.83 (2t, 6H), 1.14-1.48 (m, 8H ), 1.67 (m, 1 H), 1.91 (s, 3H), 1.98 (m, 1 H), 2.11 (m,1 H), 2.25 (m, 1 H), 2.42 (m,1 H), 2.62 (m, 1 H), 2.92 (m, 1H), 3.68 (s,3H), 3.89 (m, 1 H ).

MS: (M+H)⁺= 328

Example 13

(1 R.3R,4R,1'S)-3-Hvdroxymethyl-4-(1 '-acetamido-3'-ethyl pentyl-cvclopentane-1- carboxylic Acid.

.0

CH

13A. (±)-1 R.2R.4'S) and (±)-(1 S.2S.4'S)-2-(2.2-dimethyl-1.3-dioxolan-4-vn-4- methylenecyclopentane-1 -carboxylic Acid Methyl Ester.

A solution of 2-[(trimethylsilyl)methyl]-2-propen-1-yl-acetate (5 g, 26.9 mmole), methyl (S)-(+)-3-(2,2-dimethyl-1 ,3-dioxolan-4-yl)-frans-2-propenoate (5 g, 26.9 mmole), Pd(OAc)₂ (0.42 g, 1.8 mmole) and (/^'-PrO)₃P (2 mL, 8.1 mmole) 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%).

¹H NMR (CDCI₃) 54.88 (m, 2H), 4.18-3.95 (m, 2H), 3.70 (s), 3.69 (s) [3H overall], 3.68-3.55 (m, 1 H), 2.78-2.29 (m, 6H), 1.40 (s), 1.38 (s) [3H, overall], 1.34 (s), 1.32 (s) [3H, overall].

-119- MS: (M+H)⁺=241.

OH

13B. (1 R,2R,4'S)-2-Hvdroxymethyl-1 -(2,2-dimethyl-1 ,3-dioxolan-4-yl)-4- methylene-cyclopentane

Lithium aluminum hydride (0.63g, 16.6 mmole) 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-cyclopentane-1-carboxylate (2.0g, 8.33 mmole) in 40 mL of THF maintained at -78 °C. The reaction was allowed to warm to 0 °C and stirred for 1 hour. The reaction was quenched (at 0 °C) by adding sequentially H₂0 (1.9 mL), 10% NaOH (2.8 mL), and H₂O (2.8 mL). The reaction was allowed to warm to room temperature then dried over MgS0₄. The reaction was filtered and the solids were washed with ethyl acetate (200 mL). The filtrate was concentrated in vacuo to provide 1.83 g of the crude product mixture. Preparative HPLC on silica gel with (0-75%) ethyl acetate in hexanes provided the title compound (yield; 1.15 g, 65%).

¹H NMR (CDCI₃) 54.84 (m, 2H), 4.21 (m, 1 H), 4.03 (dd, J=6, 8 Hz, 1H), 3.64 (t, J=8 Hz, 1 H), 3.56 (m, 2H), 2.60-2.05 (m, 6H), 1.44 (s, 3H), 1.36 (s, 3H).

MS: (M+H)⁺=213.

-120- OTBDPS

/

13C. (1 R.2R.4'S)-2-(t-Butyldiphenylsilyloxymethyl)-1 -(2,2-dimethvi-1 ,3-dioxolan- 4-yl)-4-methylenecyclopentane

A solution of (1R,2R,4'S)-2-hydroxymethyl-1-(2,2-dimethyl-1 ,3-dioxolan-4- yl)-4-methylenecyclopentane (1.15g, 5.4 mmole), t-butyldiphenyisilyl chloride (1.6 mL, 6.8 mmole) and imidazole (1.11g, 16.3 mmole) in 30 mL of dichloromethane was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with methanol (.2 mL) 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 NaHCO₃, dried over MgSO₄, filtered and concentrated to provide the title compound.

¹H NMR (CDCI₃) 57.65 (m, 4H), 7.39 (m, 6H), 4.82 (m, 2H), 4.00 (m, 1H), 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.

-121- OTBDPS

/

13D. (1 R.2R.1 'S)-2-(t-Butyldiphenylsilyloxymethyl)-1 -d .2-dihvdroxy)ethyl-4- methylene-cyclopentane

(1R,2R,4'S)-2-(t-Butyldiphenylsilyloxymethyl)-1-(2,2-dimethyl-1 ,3-dioxolan- 4-yl)-4-methylene-cyclopentane and pyridinium p-toluenesulfonate (0.68g, 2.7 mmole) in 110 mL of methanol were heated to 45 °C for 16 hours. The reaction was cooled, concentrated in vacuo and partitioned between dichloromethane and water. The organic layer was washed with brine, dried over MgS0₄, filtered and concentrated. The crude product was chromatographed on silica gel with 15% ethyl acetate in hexanes to provide the title compound and recovered starting material (yield: 1.2 g, 54%).

¹H NMR (CDCI₃) 57.65 (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.

OTBDPS

/

O

H

-122- 13E. (1 R.2R)-2-(t-Butyldiphenylsilyloxymethyl)-1-formyl-4-methylene- cyclopentane

A solution of (1 R,2R, 1 'S)-2-(t-butyldiphenylsilyloxymethyl)-1 -(1 ,2- dihydroxy)ethyl-4-methylene-cyclopentane (1.2 g, 2.92 mmole), Nal0₄ (2.5 g, 11.6 mmole) in ethanol (4 mL) and water (4 mL) was stirred at 0 °C for 4 hours. The reaction was diluted with ethyl ether (90 mL) and filtered through a celite pad. The filtrate was concentrated in vacuo. The crude product was dissolved in toluene and concentrated in vacuo to azeotropically remove water. The reaction was redissolved in ethyl ether and filtered again followed by concentration to provide the title compound as a crude oil.

¹H NMR (CDCI₃) 59.68 (d, J=3 Hz, 1 H), 7.65 (m, 4H), 7.39 (m, 6H), 4.87 (m, 2H), 3.68 (dd, J=5, 10 Hz, 1 H), 3.56 (dd, J=7, 10 Hz, 1 H), 2.83-2.09 (m, 6H), 1.04 (s, 9H).

MS: (M+H)⁺= 379.

OTBDPS

/

13F. (1 R.2R.1'R)-2-(t-Butyldiphenylsilyloxymethyl)-1-(3-ethyl-1-hvdroxy)pentyl-4- methylene-cyclopentane

A 0.9 M solution of 2-ethylbutyl magnesium bromide (15.3 mL), prepared from 1-bromo-2-ethylbutane (3.8 mL, 27.1 mmole), magnesium (1 g, 41.6 mmole)

-123- and iodine (170 mg) in ethyl ether (30 mL) and stirred overnight at room temperature, was added to a solution of (1 R,2R)-2-(t-butyldiphenylsilyloxy- methyl)-1-formyl-4-methylene-cyclopentane (2.92 mmole) in ethyl ether (15 mL) at 0 °C for 20 minutes. The reaction was quenched with saturated ammonium chloride and stirred for 30 minutes. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgS0₄, filtrered and concentrated. The crude product was purified by preparative HPLC on silica gel with (5-50%) ethyl acetate in hexanes to provide the title compound (yield: 0.7 g, 51%).

¹H NMR (CDCI₃) 57.65 (m, 4H), 7.39 (m, 6H), 4.80 (m, 2H), 3.79 (m, 1 H), 3.64 (dd, =5, 10 Hz, 1 H), 3.56 (dd, J=7, 10 Hz, 1 H), 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.

OTBDPS

/

13G. (1 R,2R,1'S)-1-(t-Butyldiρhenylsilyloxymethyl)-2-(3-ethyl-1-azido)pentyl-4- methylene-cyclopentane

A solution of (1 R,2R,1'R)-2-(t-butyldiphenylsilyloxymethyl)-1-(3-ethyl-1- hydroxy)pentyl-4-methylene-cyclopentane (0.7g, 1.51 mmole), methanesulfonyl chloride (.25 mL, 3.23 mmole) and triethylamine (1 mL) in dichloromethane (15 mL) was stirred for 0.5 hours, at 0 °C. The reaction was quenched with saturated NaHC0₃ solution (3 mL) and then partitioned between ethyl acetate and 10%

-124- citric acid. The organic layer was washed with saturated NaHC0₃ and brine, dried over MgS0 , filtered and concentrated in vacuo to provide the intermediate mesylate. A solution of the crude mesylate and sodium azide (1g, 15.3 mmole) in dimethyiformamide (15 mL) 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 MgS0 , filtered and concentrated to provide the title compound.

¹H NMR (CDCIs) 57.66 (m, 4H), 7.39 (m, 6H), 4.81 ( , 2H), 3.64 (dd, J=6, 10 Hz, 1 H), 3.52 (dd, J=7, 10 Hz, 1 H), 3.22 (m, 1 H), 2.58-2.0 (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) .

OTBDPS

/

13H. (1 R.2R.1'S)-1-(t-Butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'- ethvπpentyl-4-methylene-cvclopentane

A solution of the crude (1R,2R,1'S)-1-(t-butyldiphenylsilyloxymethyl)-2-(3- ethyl-1-azido)pentyl-4-methylene-cyclopentane (-1.5 mmole), prepared in Example 13G, and triphenylphosphine (1.39g, 5.3 mmole) in 20% H₂0 in THF (25 mL) was stirred at 75 °C for 16 hours. The reaction was cooled and concentrated in vacuo to provide the crude amine. The amine, acetic anhydride (.25 mL) and pyridine (.55 mL) in dichloromethane (13 mL) were stirred at room temperature for 2 hours. The reaction was quenched with methanol (2 mL) 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

-125- MgS0₄, filtered and concentrated. Chromatography on silica gel with 2.5 -10%- ethyl acetate in dichloromethane provided the title compound (yield: 0.404 g, 60%).

¹H NMR (CDCI₃) 57.65 (m, 4H), 7.39 (m, 6H), 4.93 (d, J=10 Hz, 1 H), 4.77 (m, 2H), 3.92 (m, 1 H), 3.60 (dd, J=6, 10 Hz, 1 H), 3.52 (dd, J=6, 10 Hz, 1 H), 2.54- 1.83 (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. (1 R.2R.4R.1'S)-1-(t-Butyldiphenylsilyloxymethyl)-2-(1 '-acetamido-3'-ethyl) pentyl-4-hvdroxymethyl-cvclopentane

A solution of (1 R,2R,1'S)-1-(t-butyldiphenylsilyloxymethyl)-2-(1 '-acetamido- 3'-ethyl)pentyl-4-methylene-cyclopentane (50 mg, 0.1 mmole) and 2M borane dimethylsulfide complex, in THF ( 75 uL, 0.15 mmole) in THF (1 mL) was stirred at 0 °C for 7 hours. Water (0.1 mL) and 1 N NaOH (0.2 mL) were added and the reaction allowed to warm to room temperature. After 15 minutes, 30% hydrogen peroxide (2 mL) was added and the reaction was stirred for an additional 0.5 hour. The reaction was diluted with ethyl acetate washed with water (2X) and with brine. The organic layer was dried over MgS0₄, filtered and concentrated in vacuo. The crude product was purified by chromatography using preparative

-126- HPLC in silica gel using 0-15% ethyl acetate in dichloromethane to provide the title compound (yield: 22 mg, 42%).

¹H NMR (CDCI₃) 57.65 (m, 4H), 7.43 (m, 6H), (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.

OTBDPS

/

13J. (1 R.3R.4R,1'S) 3-(t-Butyldiphenylsilyloxymethyl)-4-(r-acetamido-3'- ethyl)pentyl-cvclopentane-1 -carboxylic Acid

A solution of (1 R,2R,4R,1'S) 1-(t-butyldiphenylsilyloxymethyl)-2-(1'- acetamido-3'-ethyl) pentyl-4-hydroxymethyl-cyclopentane (22 mg, 0.042 mmole) and pyridinium dichromate (100mg, 0.26 mmole) in N,N-dimethylformamide (0.75 mL) was stirred at room temperature for 48 hours. The reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgS0₄, filtered and concentrated to provide the title compound, which was used without further purification.

-127- OH

13K. (1R.3R.4R,1'S) 3-Hvdroxymethyl-4-(1'-acetamido-3'-ethyl) pentyl- cvclopentane-1 -carboxylic Acid

A solution of (1 R,3R,4R,1'S) 3-(t-butyl-diphenylsilyloxymethyl)-4-(1 '- acetamido-3'-ethyl) pentyl-cyclopentane-1 -carboxylic acid from 1 L and 1 M tetrabutylammonium fluoride in THF (0.8 mL) in THF (2 mL) 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 MgS0₄, filtered and concentrated in vacuo. The crude product was chromatographed using a C-18 reverse phase column with 10-25% acetonitrile in water to provide the title compound (yield: 6.6 mg, 52 %).

¹H NMR (CD₃OD) 67.81 (d, J=10 Hz, 1 H), 3.88 (m, 1H), 3.61 (dd, J=5, 11 Hz, 1 H), 3.38 (dd, J=8, 11 Hz, 1 H), 2.75 (m, 1 H), 2.19-1.00 (m, 13H), 1.95 (s, 3H), 0.87 (t, J=7 Hz, 3H), 0.83 (t, J=7 Hz, 3H).

MS: (M+H)⁺= 300.

-128-

(1R,3R,4R,1'S) 3-Formyl-4-(1 '-acetamido-3'-ethvnpentyl-cvclopentane-1- carboxylic Acid.

A solution of (1R,3R,4R,1'S)-3-hydroxymethyl-2-(1 '-acetamido-3'-ethyl)- pentyl-cyclopentane-1 -carboxylic acid (34 mg, 0.11 mmole) and pyridinium dichromate (40 mg, 0.1 mmole) in dichloromethane (1.5 mL) 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.

-129- Example 15

(1 R,3R,4R,1'S)-3-(lmidazol-2-yl)-4-(1-acetamido-3-ethyl)pentyl-cvclopentane-1- carboxylic Acid

OTBDPS

/

15A. (1 R,2R.4R.1 'S)-1-(t-Butyldiphenylsilyloxymethvn-2-(1 '-acetamido-3'- ethyl)pentyl-4-thphenylmethyloxymethyl-cyclopentane

A solution of (1 R,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 dichloromethane (2 mL) was reacted with trityl chloride (0.248 g, 0.89 mmol) and DMAP (16.3 mg, 0.13 mmol) at room temperature for 16 hours. The reaction was partitioned between ethyl acetate and 10% citric acid. The organic layer was separated and washed with brine, dried over MgS0 , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 2% methanol/dichloromethane to provide the title compound (yield: 0.5 g, 95%).

¹H NMR (CDCI₃) δ 7.62 (m, 4H), 7.4 (m, 12H), 7.23 (m, 9H), 3.57 (s, 2H), 2.96 (s, 2H), 2.26 (m. 1 H), 1.97 (m, 2H), 1.62 (m, 3H), 1.52 (s, 3H), 1.25-1.5 (m, 7H), 1.06 (s, 9H), 0.83 (br s, 6H).

MS: (M+Na)⁺ = 788

-130- OH

15B. (1R.2R.4R.1'S)-1-Hvdroxymethyl-2-(1'-acetamido-3'-ethvπpentyl-4- (triphenylmethyloxy)methylcvclopentane

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 (1 R,3R,4R,1 'S) 3-(t-butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3'-ethyl) pentyl- cyclopentane-1 -carboxylic acid (yield: 0.33 g, 98%).

¹H NMR (CDCI₃) δ 7.42 (m, 6H), 7.26 (m, 9H), 5.59 (d, 1 H), 3.86 (m, 1 H), 3.6 (2d, 1 H), 3.42 (2d, 1 H), 3.95 (2d, 2H), 2.25 (m, 1 H), 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

-131-

15C. (1 R.2R.4R, 1 'S)-1 -Formyl-5-(1 '-acetamido-3'-ethvDpentyl-3- (triphenylmethyloxy)methyl-cyclopentane

The title compound was prepared according to the method described in Example 13L substituting (1R,2R,4R,1'S)-1-hydroxymethyl-2-(1'-acetamido-3'- ethyl)pentyl-4-(triphenylmethyloxy)methyl-cyclopentane for (1R,3R,4R,1'S)-3- hydroxymethyl-4-(1 '-acetamido-3'-ethyl) pentyl-cyclopentane-1 -carboxylic acid (yield: 0.3 g, 91%).

¹H NMR (CDCI₃) δ 9.56 (d, 1 H), 7.42 (m, 6H), 7.27 (m, 9H), 5.13 (d, 1 H), 3.86 (m, 1 H), 2.94 (m, 2H), 2.72 (m, 1 H), 2.42 (m, 1 H), 2.16 (m, 2H), 1.90 (s, 3H), 1.1-1.7 (m, 10H), 0.83 (2t, 6H)

MS: (M-H)- = 524

15D. (1 R.3R.4R,1'S)-3-(lmidazol-2-yl)-4-(1-acetamido-3-ethvnpentyl-1- (triphenylmethyloxy)methyl-cvclopentane

(1 R,3R,4R, 1 'S)-1 -Formyl-2-(1 '-acetamido-3'-ethyl)pentyl-4- (triphenylmethyloxy)methyl-cyclopentane (80 mg, 0.15 mmol) was reacted with ammonia and 40% glyoxal (0.264mL, 7.5 mmol) in methanol (7 mL) according the

-132- procedure of Rothenberg, A. and coworkers in Angew. Chem. Int. Ed. 1983, 22, p. 560 to provide the title compound (yield: 60 mg, 70%).

¹H NMR (CDCI₃) δ 7.7 (d, 1 H), 7.42 (m, 7H), 7.27 (m, 9H), 5.72 (d, 1 H), 3.86 (m, 1 H), 3.2 (m, 2H), 3.08 (m, 2H), 2.54 (m, 1 H), 2.42 (m, 2H), 1.77 (s, 3H), 1.1-1.7 (m, 10H), 0.78 (2t, 6H).

MS: (M-H)- = 562, (M+35)" = 598; (M+H)⁺ = 564, (M+Na)⁺ = 586

15E. (1 R,3R,4R,1'S)-3-(lmidazol-2-yl)-4-(1 '-acetamido-3'-ethvnpentyl-1- hydroxymethyl-cyclopentane

(1 R,3R,4R, 1 'S)-3-(lmidazol-2-yl)-4-(1 '-acetamido-3-ethyl)pentyl-1 - (triphenylmethyloxy)methyl-cyclopentane (60 mg, 0.106 mmol) was reacted with p-toluenesulfonic acid monohydrate (61 mg, 0.32 mmol) in MeOH (1 mL) for 1 hour. The reaction was quenched with water (10 mL) and diluted with ethyl acetate (25 mL). The organic layer was washed with water, and brine, dried over MgS0 , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% methanol/dichloromethane to provide the title compound (yield: 30 mg, 88%).

¹H NMR (CDCI₃) δ 7.83 (d, 1 H), 7.2 (d, 1 H), 6.47 (d, 1 H), 3.86 (m, 1 H), 3.6 (m, 2H), 3.2 (m, 1H), 2.61 (m, 1 H), 2.32 (m, 2H), 1.82 (m, 1 H), 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

-133-

15F. (1 R.3R.4R.1 'S)-3-(lmidazol-2-yl)-4-(1-acetamido-3-ethyl)pentyl- cyclopentane-1 -carboxylic Acid

The title compound was prepared according to the procedure described ing Example 13J substituting (1 R,3R,4R,1'S)-3-(imidazol-2-yl)-4-(1-acetamido-3- ethyl)pentyl-1-hydroxymethylcyclopentane for (1 R,2R,4R,1 'S) 1-(t- butyldiphenylsilyloxymethyl)-2-(1 '-acetamido-3'-ethyl) pentyl-4-hydroxymethyl- cyclopentane (yield: 5.2 mg, 17%).

¹H NMR (d₆-MeOH) 67.12 (br s, 2H), 3.92 (m, 1 H), 2.95 (m, 1H), 2.42 (m,

1 H), 2.22 (m, 1 H), 1.96 (m, 1 H), 1.82 (m, 1 H), 1.72 (s, 3H), 1.15-1.45 (m, 7H), 0.82 (2t, 6H)

MS: (M-H)^" = 334, (M+35)" = 370; (M+H)⁺ = 336, (M+Na)⁺ = 358

Example 16

(1 R.3R.4R.1 'S)-3-(oxazol-5-yl)-4-(1 '-acetamido-3'-ethyl)pentyl-cvclopentane-1 ^■ carboxylic acid

-134- N^-O

16A. (1 R.3R.4R, 1 'S)-Diphenylmethyl 3-(oxazol-5-yl)-4-(1 '-acetamido-3'-ethyl) pentylcvclopentane-1-carboxylate

(1R,3R,4R,1'S)- Diphenylmethyl 3-formyl-4-(1'-acetamido-3'-ethyl) pentyl- cyclopentane-1-carboxylate is reacted with p-toluensulfonylmethylisocyanide following the procedure of van Leusen and coworkers in Tetrahedron Letters, 2369 (1977) to provide the title compound.

N^O

\=

16B. (1 R,3R.4R.1'SV3-(oxazol-5-vn-4-(1'-acetamido-3'-ethyl) pentyl- cyclopentane-1 -carboxylic acid

(1 R,3R,4R,1'S)-diphenylmethyl 3-(oxazol-5-yl)-4-(1'-acetamido-3'- ethyl)pentyl-cyclopentane-1-carboxylate is reacted with anhydrous trifluoroacetic acid in dichloromethane concentration in vacuo provides the title compound.

-135- Example 17

(1 R,3R.4R.1'S)-3-(N,N-dimethylcarbamovπ-4-(1 '-acetamido-3'-ethvnpentyl- cvclopentane-1 -carboxylic Acid

17A. (1 R.3R,4R,1 'S)-Diphenylmethyl 3-carboxy-4-f1 '-acetamido-3'-ethyl)pentyl- cyclopentane-1 -carboxylate

The title compound is prepared according to the procedure described in Example 14J substituting (1 R,3R,4R,1'S)-diphenylmethyl-3-hydroxymethyl-4-(1'- acetamido-3'-ethyl) pentyl-cyclopentane-1 -carboxylate for (1 R,2R,4R,1'S) 1-(t- butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl) pentyl-4-hydroxymethyl- cyclopentane

-136- 17B. (1 R.3R.4R.1'SVDiphenylmethyl 3-(N.N-dimethylcarbamoyl)-4-(1 '- acetamido-3'-ethyl)pentyl-cvclopentane-1 -carboxylate

(1 R,3R,4R, 1 'S)- Diphenylmethyl 3-carboxy-4-(1 '-acetamido-3'-ethyl) pentyl-cyclopentane-1 -carboxylate is reacted with isobutyl chloroformate in the presence of N-methylmorpholine at 0°C. The intermediate activated ester is reacted with N,N-dimethylamine to provide the title compound.

17B. (1R.3R,4R.1'S)-3-(N,N-dimethylcarbamoyl)-4-(1'-acetamido-3'- ethyl)pentyl-cyclopentane-1 -carboxylic Acid

The title compound is prepared according to the procedure described in Example 16B substituting (1R,3R,4R,1'S)- diphenylmethyl-3-(N,N- dimethylcarbamoyl)-4-(1 '-acetamido-3'-ethyl) pentyl-cyclopentane-1 -carboxylate for (1R,3R,4R,1'S)-diphenylmethyl-3-(imidazol-2-yl)-4-(1'-acetamido-3'-ethyl) pentyl-cyclopentane-1 -carboxylate.

Example 18

(1R.3R.4R.1'S)-3-propionyl-4-(1'-acetamido-3'-ethyl)pentyl-cvclopentane-1- carboxylic Acid

-137-

18A (1 R.3R.4R 1'S,1"SV and (1 R,3R.4R.1 'S.1"R)-Dιphenylmethyl 3-(1- hydroxypropyl)-4-(1 '-acetamιdo-3'-ethyl) pentyl-cyclopentane-1 -carboxylate

(1 R.3R.4R 1 'S)- Diphenylmethyl 3-formyl-4-(1 '-acetamιdo-3'-ethyl) pentyl- cyclopentane-1 -carboxylate is reacted with ethyl magnesium bromide in THF at 0°C The reaction is quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water The organic layer is dried over MgS0₄, filtered, and concentrated in vacuo to provide the title compound

p

18B (1 R.3R.4R,1'S)-Dιphenylmethyl 3-propιonyl-4-(1 '-acetamιdo-3'-ethyl) pentyl-cvclopentane-1 -carboxylate

The title compound is prepared according to the procedure of Example 12B substituting (1R,3R 4R,1'S,1"S)- and (1 R,3R,4R,1'S,1"R)-dιphenylmethyl3- (1-hydroxypropyl)-4-(1 -acetamιdo-3'-ethyl) pentyl-cyclopentane-1 -carboxylate for (±)-(2S,1'R) and (2S,rS)-2-(3'ethyl-1'-hydroxy)pentyl-bιcyclo[2 2 1]hept-5-ene

-138- .0

//

18C. (1R.3R,4R.1'S)-3-propionyl-4-(1'-acetamido-3'-ethvnpentyl-cvclopentane- 1 -carboxylic Acid

The title compound is prepared according to the procedure described in Example 16B substituting (1 R,3R,4R,1'S)-diphenylmethyl 3-propionyl-4-(1 '- acetamido-3'-ethyl) pentyl-cyclopentane-1 -carboxylate for (1R,3R,4R,1'S)- diphenylmethyl 3-(imidazol-2-yl)-4-(1 '-acetamido-3'-ethyl) pentyl-cyclopentane-1 - carboxylate.

Example 19

(±)-(2R.3R.5R, 1 'S)-2-(1 '-acetamido-3'-methyl)butyl-3-methoxycarbonyl- tetrahydrofuran-5-carboxylic acid

19A (±)-Bicvclo[2.2.1lhept-5-en-2-one

In a three-necked flask equipped with a mechanical stirrer, a N₂ inlet and an additional funnel, a solution of oxalyl chloride (2.0 M in dichloromethane, 136 mL, 0.272 mole) in dichloromethane (250 mL) was cooled to -78 °C and a solution of DMSO (40 mL) in 40 mL of dichloromethane was added dropwise over 30 min. After stirring for 5 additional minutes, a solution of 5-norbornen-2-ol (24 g, 0.218 mole) in 40 mL of dichloromethane was added dropwise. The solution was stirred for another 10 minutes and triethylamine (150 mL) was added over 40 minutes. The mixture was then stirred for 10 minutes at -78 °C and allowed to

-139- warm up to 0 °C over 1 hour. Water (250 mL) was added. Following the separation of two layers, the organic layer was washed with 0.2 N HCI (4 x 200 mL) and brine (2 x 200 mL). After drying (MgS0₄), the solution was concentrated to about 80 mL. The residue was distilled with a 12" Vigreux column at reduced pressure to give the title compound b. p. 100-105 °C /15 mmHg, (yield: 20.1 g, 86%).

¹H NMR (CDCI₃): 1.85 (dd, 1 H), 1.90-2.00 (m, 2H), 3.00 (brs, 1 H), 3.20 (b.s, 1H), 6.01 (t, 1H), 6.58 (t, 1H).

19B (±)-exo,exo-5,6-Dihvdroxybicyclo[2..2.1]heptan-2-one

A solution of (±)-bicyclo[2.2.1]hept-5-en-2-one (10.8 g, 0.1 mole) and N- methyl morpholine oxide (12.7 g, 0.12 mole) in 300 mL of 90% THF-water was reacted with a solution of osmium tetroxide (2.5% wt in t-BuOH, 8.0 mL) for 5 hours at ambient 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 (MgS0 ) and filtered. The filtrate was passed through a short silica gel plug, eluting with ethyl acetate. 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-Dihvdroxyacetonide-bicvclor2.2.1lheptan-2-one

A solution of (±)-exo,exo-5,6-dihydroxybicyclo[2.2.1]heptan-2-one (14.5 g, crude) in 250 mL of 2,2-dimethoxypropane was cooled to 0 °C and p- toluensulfonic acid (125 mg) was added. The solution was stirred for 30 minutes when TLC indicated complete reaction. The solution was loaded on an aluminum

-140- oxide (neutral) column and eluted with 15-30% ethyl acetate in hexane, to give^' the title compound as a white solid (yield: 11.9 g, 65% for two steps).

MS (DCI-NH3): m/z 200 for (M+NH₄), base peak.

1 H NMR (CDCI₃): δ 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, 1 H), 4.34 (d, 1 H). ¹³C NMR (CDCI3): 6 21.1 , 25.3, 31.2, 39.4, 39.5, 55.3, 76.8, 81.2, 111.2, 214.0. Analysis: C₁₀H₁₄O₃, calc. 65.92% C, 7.75% H;: found, 66.01% C, 7.79% H.

-o

19D (±)-exo.exo-6.7-dihvdroxyacetonide-2-oxabicvclor3.2.11octan-3-one

To a solution of (±)-exo,exo-5,6-dihydroxyacetonide-bicyclo[2.2.1]heptan- 2-one (14.76 g, 0.081 mole) in 500 mL of dichloromethane was added NaHC0₃ (13.6 g, 0.16 mole). The mixture was cooled with a water bath and MCPBA (30.3 g, -60%) was added portionwise over 30 minutes. The solution was then stirred for 2 hours at ambient temperature and washed with 10% aqueous Na₂S₂O₅ (500 mL), saturated NaHC0₃ solution (3 x 200 mL) and brine (3 x 200 mL). The organic solution was then dried (MgS0₄), filtered and concentrated. The residue was loaded on an aluminum oxide (neutral) column for 30 minutes, 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.

¹H NMR (CDCI₃): δ 1.30 (s, 3H), 1.45 (s, 3H), 1.84 (d, 1H), 2.10-2.20 (m, 1 H), 2.48-2.56 (m, 2H), 2.80 (dd, 1 H), 4.56 (d, 1 H), 4.60 (s, 1 H), 4.70 (d, 1 H). ¹³C NMR (CDCI₃): 23.79, 25.58, 29.17, 35.97, 36.51 , 80.70, 82.49, 82.55, 83.24,

-141- 110.83, 167.95. Analysis: C₁₀H₁₄O₄, cal. 60.59% C, 7.12% H; found, 60.52% C, 6.97% H.

19E (±)-exo,exo-6,7-dihvdroxyacetonide-4-exo-iodo-2-oxabicvclo[3.2.11octan-3- one

To a mixture of lithium bis(thmethylsilyl)amide (1.0 M in THF, 32.6 mL) and distilled THF (60 mL), 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 over 30 minutes. After stirring for another 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 over 30 minutes. The resulting solution was stirred for another 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 10% aqueous Na₂S₂θ3 solution (2 x 100 mL) and brine (2 x 200 mL), and dried (MgS0₄). After filtration, the solution was evaporated and the residue chromatograhed on a silica gel column 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.

¹H NMR (CDCI₃): δ 1.30 (s, 3H), 1.45 (s, 3H), 1.55 (s, 1 H), 2.12-2.20 (m, 1 H), 2.42 (d, 1 H), 2.80 (m, 1H), 4.56 (d, 1 H), 4.54 (d, 1H), 4.70 (m, 2H).

Analysis: Cι₀H₁₃IO₄, cal. 37.06% C, 4.04% H, 39.15% I; found, 37.08% C, 3.98% H, 39.55% I.

-142- CO₂Me

19F (±)-Methyl-exo.exo-5,6-dihvdroxyacetonide-2-oxabicyclor2.2.nheptane-3- exo-carboxylate.

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 4 A sieves) was added K₂C0₃ (3.54 g, 25.6 mmol). The mixture was stirred vigorously for 30 min. The undissoived potassium carbonate was removed by filtration and the filtrate was concentrated to dryness. The residue was triturated with ethyl acetate several times until complete extraction of the product (TLC). The ethyl acetate solution was then concentrated and directly chromatographed on a silica gel column eluting with 10-25% ethyl acetate in hexane, giving 4.86 g of the title compound as a white solid. Yield: 92.0%.

MS (DCI-NH3): m/z 246 for (M+NH₄), base peak.

¹H NMR (CDCI₃): δ 1.30 (s, 3H), 1.45 (s, 3H), 1.62 (d, 1 H), 1.85 (d, 1H), 2.82 (s, 1 H), 3.78 (s, 3H), 3.80 (s, 1 H), 4.20 (d, 1H), 4.30 (d, 1 H), 4.40 (s, 1H).

Analysis:CnH₁₆0₅, calc: 57.88% C, 7.07% H; found: 57.98% C, 7.10% H.

19G (±)-exo-3-Formyl-exo,exo-5,6-dihydroxyacetonide-2- oxabicyclof2.2.1]heptane

To a well-stirred solution of (±)-methyl-exo,exo-5,6-dihydroxyacetonide-2- oxabicyclo[2.2.1]heptane-exo-3-carboxylate (0.82 g, 3.62 mmol) in 30 mL of anhydrous dichloromethane at -78 °C was added a solution of diisobutylaluminum hydride in toluene (1.0 M, 5.77 mL) dropwise. The mixture was then stirred at -78

-143- °C for 1 hour and quenched with 2 mL of methanol and 15 mL of saturated aqueous sodium potassium tartrate solution. The mixture was then stirred vigorously and allowed to warm to ambient temperature over 1 hour. The phases were separated and the aqueous phase was extracted with Et₂0 (5 x 50 mL). After drying, solvent removal gave the title compound as an oil (0.8 g) which was used directly for the next step.

19H (±)-(1'RS)-exo-3-(1 '-hvdroxy-3'-methyl)butyl-exo.exo-5.6- dihvdroxyacetonide-2-oxabicyclo[2.2.11heptane.

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 at -78 °C was added a solution of isobutylmagnesium chloride (2.0 M in ether, 30 mL) dropwise over 30 minutes. The mixture was then allowed to warm up to ambient temperature over 2 hours and quenched with 100 mL of saturated aqueous NH CI solution. The solution was then extracted with Et₂0 (3x100 mL). The combined organic layers were washed with brine (3x100 mL) and dried. After filtration, evaporation of solvent gave title compound as an oil (1.28 g) which was used directly for the next step.

-144-

191 (±)-exo-3-(1 '-oxo-3'-methyl)butyl-exo,exo-5,6-dihydroxyacetonide-2- oxabicyclo 2.2.11heptane

A solution of oxalyl chloride (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. A solution of DMSO (1.06 mL) in 10 mL of anhydrous dichloromethane was then 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[2.2.1]heptane (~1.28 g, 5.0 mmol) in anhydrous dichloromethane (10 mL) was added dropwise and the solution was stirred for another 10 minutes. Triethylamine (4.3 mL) in 10 mL of dichloromethane was then added. The mixture was then stirred at -78 °C for 2 hours and allowed to warm up to ambient temperature. The solution was washed with water (100 mL), 5% aqueous citric acid (100 mL), saturated NaHC0₃ (100 mL) and brine. After drying and concentration, the crude material was purified by flash chromatography on a silica gel column using 5%-20% ethyl acetate-hexane to give the title compound as a white solid, 0.65 g, 51% for three steps.

MS (DCI-NH₃): m/z 272 for (M+NH₄)⁺ base peak.

¹H NMR (CDCI₃): δ 0.84 (dd, 6H), 1.30 (s, 3H), 1.34, 1.38 (bd, 1 H), 1.43 (s, 3H), 1.77, 1.82 (dd, 1 H), 2.10-2.10 (m, 1 H), 2.30-2.50 (dq, 2H), 2.86 (s, 1 H), 3.62 (s, 1 H), 4.16-4.20 (m, 1 H), 4.28-4.32 (bd, 1 H), 4.37 (s, 1 H).

Analysis: d₄H₂₂0₄, cal. 66.12% C, 8.72% H; found, 65.99% C, 8.58% H.

-145-

19J (±)-exo-3-(1 '-oxo-3'-methyl)butyl-exo,exo-5,6-dihvdroxy-2- oxabicyclo[2.2.11heptane.

(±)-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 HCI. The solution was stirred at 60 °C for 2.5 hours. After cooling to ambient temperature, the solution was partially concentrated and then extracted with ethyl acetate (4x50 mL). The combined ethyl acetate solution was washed with saturated aqueous NaHC0₃ solution (2x50 mL) and brine (2x50 mL), and dried. After filtration, removal of solvent gave the title compound as an off-white crystalline solid, (yield: 0.53 g, 98.0%).

MS (DCI-NH3): m/z 232 for (M+NH₄)⁺, base peak.

¹H NMR (CDCI₃): δ 0.92 (dd, 6H), 1.34, 1.44 (bd, 1H), 1.77, 1.82 (dd, 1H), 2.10-2.20 (m, 1 H), 2.30-2.45 (dq, 2H), 2.65 (d, 1H), 2.74-2.80 (m, 2H), 3.72 (s, 1 H), 3.94-4.00 (m, 1 H), 4.00-4.05 (bd, 1H), 4.24 (s, 1H).

"CO₂Me

19K (±)-(2R.3R.5R)-Dimethyl 2-(1'-oxo-3'-methvnbutyltetrahvdrofuran-3.5- dicarboxylate

(±)-exo-3-(1'-Oxo-3'-methyl)butyl-exo,exo-5,6-dihydroxy-2- oxabicyclo[2.2.1]heptane.(0.50 g, 2.3 mmol) was dissolved in a mixture of

-146- acetonitrile (6.5 mL), carbon tetrachloride (6.5 mL) and water (10 mL). To this ^' solution was added sodium periodate (2.1 g, 10 mmol) and RuCI₃.H₂0 (10 mg). The solution was stirred at ambient temperature for 3 hours and filtered to remove the solid. The filtrate was loaded on a short silica gel column, eluted with 5% methanol in ethyl acetate containing 5% acetic acid. The resulting crude diacid (yellow oil, 0.53 g) was dissolved in ethyl acetate (25 mL). 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 silica gel column eluting with 10-40% ethyl acetate in hexane, giving the title compound as a colorless liquid (0.40g, 68.0% for two steps).

MS (DCI-NH₃): m/z 290 for (M+NH₄)⁺, base peak.

¹H NMR (CDCI₃): δ 0.92 (d, 3H, CH₃), 0.93 (d, 3H, CH₃), 2.19 (m, 1 H, H₇), 2.40-2.60 (m, 4H, H_6a, H_6b, H_3a, H_3b), 3.30 (m, 1 H, H₃), 3.75 (s, 3H, OCH₃), 3.78 (s, 3H, OCH₃), 4.65 (dd, 1 H, H₅), 4.85 (d, 1 H, H₂).

MeO₂C

'CO₂Me

19L (±)-(2R.3R.5R)-Dimethyl-2-(1 '-N-hvdroxyimino-3'-methvnbutyl- tetrahydrofuran-3,5-dicarboxylate

A solution of (±)-(2R,3R,5R)-dimethyl-2-(1 '-oxo-3'-methyl)butyl- tetrahydrofuran-3,5-dicarboxylate(0.3 g, 1.09 mole), hydroxylamine hydrochloride (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.

-147- The solution was concentrated and purified directed on a 10-g silica gel cartridge, eluting with 30% ethyl acetate in hexane, giving the title compound as a mixture of cis and trans oximes.

MS (DCI-NH3): m/z 287 (M+H), 305 (M+NH₄)⁺.

¹H NMR (CDCI3): δ 0.95-1.0 (m, 6H), 2.19 (m, 1 H), 2.40-2.60 (m, 4H,), 3.45 (m, 1 H), 3.65-3.80 (4 s, 6H), 4.50-4.60 (bs, 1 H), 4.70 (m, 1 H), 5.0 (bs, 1H)

MeO₂C

Boc ^'"cO₂ e

19M (±)-(2R.3R. 5R.1 'S) and (±H2R,3R, 5R, 1 'R) Dimethyl 2-(1 '-f- butoxycarbonylamino-3'-methv0butyl-tetrahydrofuran-3,5-dicarboxylate.

A solution of (±)-(2R,3R,5R)-dimethyl-2-(1'-N-hydroxyimino-3'- methyl)butyl-tetrahydrofuran-3,5-dicarboxylate (0.27 g, 0.94 mmol) and Boc₂0 (2.11 mL, 10x) in 70 mL of isopropanol was hydrogenated with Raney Nickel at 4 atm of hydrogen for 15 hours. After concentration of the solution, separation on a silica gel column with 10% ethyl acetate in hexane gave (±)-(2R,3R, 5R,1'S) isomer (137 mg) and (±)-(2R,3R, 5R,1'R) isomer (176 mg).

(±)-(2R,3R, 5R,1'S) MS (DCI-NH₃): m/z 374, 391 , 317, 335.

¹H NMR (CDCI₃): 0.9-0.95 (2d, 6H), 1.22-1.31 (m, 1H), 1.49 (s, 9H), 1.50- 1.55 (m, 1 H), 1.62-1.75 (m, 1 H), 2.40-2.60 (m, 2H), 2.95-3.10 (m, 1 H), 3.70 (s, 3H), 3.75 (s, 3H), 4.20 (t, 1 H), 4.37 (bd, 1H), 4.60 (dd, 1H).

-148- ''/,CO₂Me

19N (±H2R,3R.5R,1S)-Dimethyl 2-(1'-acetamido-3'-methyl)butyl- tetrahydrofuran-3,5-dicarboxylate.

A solution of (±)-(2R,3R, 5R,1 'S) dimethyl 2-(1 '-f-butoxycarbonylamino-3'- methyl)butyl-tetrahydrofuran-3,5-dicarboxylate (40 mg, 0.11 mmol) in 2 mL of 50% trifluoroacetic acid/dichloromethane was stirred at ambient temperature for 1 hours. 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 diisopropylethylamine (192 mL, 10.0 eq.) were added. After stirring for 2 hours, the mixture was directly loaded on a 5-g silica gel cartridge and eluted with 60% ethyl acetate in hexane, giving the title compound as a solid (34 mg ,100%).

MS (DCI-NH₃): m/z 316 (M+H) ⁺, 333 (M+NH₄)⁺.

H NMR (CDCI₃): δ 0.9-0.95 (2d, 6H), 1.25-1.35 (m, 1 H), 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), 4.60 (dd, 1H), 5.30 (bd, 1H).

MeO₂C^ γ^R'rO-"^<co₂H

0

190 (±H2R, 3R, 5R,1^,S)-2-(1 '-acetamido-3'-methvnbutyl-3-methoxycarbonyl- tetrahydrofuran-5-carboxylic acid

To a solution of (±)-(2R,3R,5R,1 'S)-dimethyl 2-(1'-acetamido-3'- methyl)butyl-tetrahydrofuran-3,5-dicarboxylate (32 mg, 0.1 mmol) in 1.0 mL of

-149- THF cooled to 0 °C was added a solution of LiOH (0.1 M, 1.0 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 (3x1 mL), the organic solution was dried (MgS0 ) and purified on a 5-g silica gel cartridge, eluting with 0-20% methanol/ethyl acetate containing 5% acetic acid. The product obtained was further purified by recrystallization from ethyl acetate and isopropanol. (yield: 22 mg, 71%).

HRMS: C₁₄H₂₄0₆N, calculated: 302.1604, found: 302.1592.

¹H NMR (CDCI₃): δ 0.9-0.95 (2d, 6H), 1.25-1.35 (m, 1H), 1.50-1.70 (m, 2H), 1.99 (s, 3H), 2.40-2.50 (m, 1 H), 2.60-2.70 (m, 1 H), 2.95-3.10 (m, 1 H), 3.70 (s, 3H), 4.10-4.40 (m, 2H), 4.60 (dd, 1H), 5.30 (bd, 1 H). The relative stereochemistry was confirmed by the X-ray structure of a single crystal.

Example 20

20A (±H2R.3R,5R.1 'S)-2-(1'-Acetamido-3'-methyl)butyl-3-methoxycarbonyl- tetrahydrofuran-5-carboxylic Acid t-Butyl Ester.

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 ferf-butyl 2,2,2-trichloroacetimidate (54 mg, 0.24 mmol) in 0.3 mL of cyclohexane. After cooling to 0 °C, 3 drops of boron trifluoride etherate was added. The mixture was stirred for another 40 minutes and quenched with 2 mL of 5% NaHC0₃ solution. After diluting with 10 mL of dichloromethane, the mixture was filtered to remove insoluble by-product

-150- and the organic phase was further washed with 5% NaHC0₃ solution, dried, and concentrated. The residue was purified on a 5-g silica gel cartridge to give the title compound as an oil (26 mg) which was used directly for the next step.

20B (±H2R.3R.5R,1'S)-2-(1'-acetamido-3'-methvnbutyl-3-carboxyl- tetrahvdrofuran 5-carboxylic acid t-Butyl Ester

A solution of (±)-(2R,3R,5R,1'S)-2-(1'-acetamido-3'-methyl)butyl-3- methoxycarbonyl-tetrahydrofuran-5-carboxylic acid t-butyl ester (26 mg, 0.073 mmol) in 1.5 mL of THF was cooled to 0 °C and a solution of 0.1 N LiOH (0.73 mL) was added. The mixture was allowed to warm up to ambient temperature over 90 minutes, then acidified to pH 2-3 with 1 N HCI and extracted with ethyl acetate. The combined ethyl acetate solution was dried and concentrated. 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)⁺.

¹H NMR (methanol-d₄): δ 0.87, 0.89 (d, 3H), 0.92, 0.94 (d, 3H), 1.35-1.45 (m, 1 H), 1.47 (s, 9H), 1.50-1.70 (m, 2H), 1.92 (s, 3H), 2.30-2.37 (m, 1 H), 2.45- 2.55 (m, 1 H), 2.90-2.97 (m, 1H), 4.00-4.07 (m, 1 H), 4.20 (t, 1H), 4.45 (dd, 1H).

-151-

20C (±H2R,3R,5R,1'S)-2-(1'-acetamido-3'-methvnbutyl-3-(1"-oxo-2"- bromo)ethyl-tetrahvdrofuran-5-carboxylic Acid t-Butyl Ester

To a solution of (±)-methyl (2R,3R,5R,1'S)-2-(1'-acetamido-3'-methyl)butyl- 3-carboxyl-tetrahydrofuran-5-carboxylic acid t-butyl ester (10 mg, 0.029 mmol) in 1.0 mL of THF, cooled to 0 °C, was added N-methyl morpholine (0.13 mL) and /so-butyl chloroformate (0.15 mL, 0.12 mmol). The mixture was stirred at 0 °C for 1 h. A solution of diazomethane generated from Diazald (0.21 g, 1.0 mmol) and KOH (0.8 g) in 2 mL of Et₂0 was then added via a syringe until the yellow color persisted. The solution was then stirred for 3 hours, washed with brine (2 x 2.0 mL) and dried (MgS0₄). Evaporation of solvent gave a yellow solid which was redissolved in 1.5 mL of dioxane. To this solution was added 48% HBr (aq.) solution (0.125 mL) and the mixture was stirred for 10 minutes. Saturated NaHC0₃ solution (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 (MgS0₄), filtered and concentrated. Chromatography on a 5-g silica gel cartridge eluting with 60% ethyl acetate-hexane give the title compound (7.3 mg) as a solid which was used directly for the next step.

-152-

20D (±)-(2R.3S,5R,1'S)-2-(1'-acetamido-3'-methvnbutyl-3-(imidazol-4-yl)- tetrahydrofuran-5-carboxylic Acid t-Butyl Ester

To a vial containing (±)-(2R,3R,5R,1 'S)-2-(r-acetamido-3'-methyl)butyl-3- (1"-oxo-2"-bromo)ethyl-tetrahydrofuran-5-carboxyIic acid t-butyl ester (7 mg, 0.014 mmol) and formamidine acetate (30 mg, excess) was added liquid ammonia (-2.0 mL). The vial was sealed and stirred at 45 °C overnight. The ammonia was allowed to evaporate slowly. The residue was taken up in 5% Na₂C0₃ (aq. 1.0 mL) and extracted with ethyl acetate (4x1.0 mL). The combined ethyl acetate solution 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 (1.0 mg).

MS (APCI+): m/z 366 (M+H)⁺, 310 (M-C₄H₉)⁺, base peak.

¹H NMR (methanol-d₄): δ 0.87, 0.89 (d, 3H), 0.95, 0.97 (d, 3H), 1.27-1.37 (m, 1 H), 1.47 (s, 9H), 1.42-1.67 (m, 2H), 1.84 (s, 3H), 2.10-2.17 (dt, 1 H), 2.77- 2.87 (dt, 1 H), 3.50 (q, 1 H), 4.02-4.06 (m, 1 H), 4.16 (t, 1 H), 4.55 (t, 1 H), 7.34 (s, 1 H), 8.64 (s, 1 H).

-153-

20E (±)-(2R,3S.5R,1'S)-2-(1 '-Acetamido-3'-methyl)butyl-3-(imidazol-4-yl)- tetrahydrofuran 5-carboxylic Acid

A solution of (±)-(2R,3S,5R,1'S)-2-(1 '-acetamido-3'-methyl)butyl-3- (imidazol-4-yl)-tetrahydrofuran-5-carboxylic acid t-butyl ester (1.0 mg) in 1.0 mL of 6N aqueous HCI was stirred for 1 h. The solution was then concentrated to give the title compound as a white solid (0.8 mg).

¹H NMR (D₂0): 5 0.81 , 0.83 (d, 3H), 0.87, 0.89 (d, 3H), 1.30-1.58 (m, 4H), 1.84 (s, 3H), 2.10-2.22 (m, 1H), 2.85-2.95 (m, 1H), 3.58 (q, 1 H), 3.90-3.94 (m, 1 H), 4.00-4.04 (m, 1 H), 4.20 (t, 1 H), 7.32 (s, 1 H), 8.64 (s, 1 H).

-154- Example 21

(1 S.3R.4S.1 'S)-3-(1 '-Acetamido-3'-ethyl)pentyl-4-vinyl-cvclopentane-1 -carboxylic Acid

21 A. (1 S,3R,4S,1'S)-3-(1'-acetamido-3'-ethyl-)pentyl-1- (triphenylmethyloxy)methyl-4-vinyl-cyclopentane

A solution of (1 R.2R,4R,1'S)-1 -formyl-2-(1'-acetamido-3'-ethyl)pentyl-4- (triphenylmethyloxy)methyl-cyclopentane (60 mg, 0.11 mmol) prepared according to the method of Example 15C in THF (1 mL) was added to a mixture prepared from the reaction of methyltriphenylphosphonium iodide (69 mg, 0.17 mmol) and 2.5M n-Buϋ/hexane (64 mg, 0.16 mmol) in THF (1 mL) 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 MgS0₄, 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%).

¹H NMR (CDCI₃) 5 7.52 (m, 6H), 7.24 (m, 9H), 5.64 (m, 1 H), 4.84-5.04 (m, 3H), 3.98 (m, 1 H), 2.95 (m, 2H), 2.7 (m, 2H), 2.0 (m, 1 H), 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.

-155-

21 B. (1S,3R,4S,1'S) 3-vinyl-4-(1-acetamido-3-ethyl)pentyl-1-hvdroxymethyl- 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)pentyl-1- (thphenylmethyloxy)methyl-4-vinyl-cyclopentane for (1 R,3R,4R,1'S)-3-(imidazol- 2-yl)-4-(1 '-acetamido-3'-ethyl)pentyl-1-(triphenylmethyloxy)methyl-cyclopentane (yield: 7 mg, 87%).

¹H NMR (CDCI₃) 5 5.68 (m, 1H), 4.84-5.05 (m, 3H), 3.98 (m, 1H), 3.54 (2d, 2H), 2.4 (m, 1H), 2.18 (m, 1 H), 1.92 (s, 3H), 1.1-1.5 (m, 10H), 0.83 (2t, 6H).

MS: (M+H)⁺ = 282, (M+18)⁺ = 299

21C. (1 S.3R.4S, 1 'S)-3-(1 -acetamido-S-ethyl-toentvM-vinyl-cvclopentane-l - 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-vinyl-cyclopentane for (1R,2R,4R,1'S)-1-(f- butyldiphenylsilyloxymethyl)-2-(1'-acetamido-3'-ethyl)pentyl-4-hydroxymethyl- cyclopentane (yield: 4.2 mg, 33%).

-156- ¹H NMR (CDCI₃) δ 5.65-5.78 (m, 1 H), 5.05 (d, 1 H), 5.02 (2d, 1 H), 4.92 ^" (2d, 1H), 3.99 (q, 1H), 2.88 (m, 1H), 2.43 (m, 1H), 2.15 (m, 2H), 1.91 (s, 3H), 1.87 (m, 1 H), 1.71 (m, 1 H), 1.1-1.5 (m, 8H), 0.83 (2t, 6H)

MS: (M-H)- = 294; (M+H)⁺ = 296, (M+Na)⁺ = 318

Example 22

(±)-(1 R.3R,4R.1'S)-3-N-methylcarbamoyl-4-(1 '-acetamido-3'-ethyl)pentyl- cvclopentane-1 -carboxylic Acid

o

MeHN-^

The title compound was prepared according to the procedure described ing Example 12G substituting methylamine for methanol (yield: .029 g, 30%).

¹H NMR (CD₃OD) δ 7.52 (d, 1 H), 3.78-3.90 (m, 1 H), 2.80-2.95 (m, 1 H), 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, 6H).

MS: (M+H)⁺= 327, (M+NH4)⁺=344

-157- Example 23

(1 R,3R,4R.1'S)-3-(imidazol-4-vn-4-(1'-acetamido-3'-methvπbutyl-cvclopentane-1- carboxylic Acid

OTBDPS

/

23A. (1R.3R.4R,1'S) 3-(t-Butyldiphenylsilyloxymethvn-4-(1'-acetamido-3'- methyl)butyl-cyclopentane-1 -carboxylic Acid.

The title compound was prepared by the methods described in Examples 13F-13J substituting isobutylmagnesium bromide for 3-pentylmagnesium bromide in Example 13F and substituting the resulting products in the subsequent steps.

H NMR (d -methanol) δ 7.68 (m, 4H), 7.42 (m, 6H), 3.88 (m, 1H), 3.74

(2d, 1 H), 3.48 (2d, 1 H), 2.77 (m, 1 H), 2.15-2.27 (m, 2H), 1.68-2.05 (m, 3H), 1.80 (s, 3H), 1.5 (m, 1 H), 1.1-1.32 (m, 2H), 1.03 (s, 9H), 0.84 (2d, J=6.44 Hz, 6H).

MS: (M-H)^" = 508; (M+H)⁺ = 510, (M+Na)⁺ = 532

OTBDPS

/

23B. (1 R.3R.4R.1 'S)-3-(t-Butyldiphenylsilyloxymethyl)-4-(1 '-acetamido-3'- methvObutyl-cvclopentane-1 -carboxylic Acid t-Butyl Ester.

(1 R,3R,4R, 1 'S)-3-(t-Butyldiphenylsilyloxymethyl)-4-(1 '-acetamido-3'- methyl)butyl-cyclopentane-1 -carboxylic acid (0.65 g, 1.27 mmol) was reacted

-158- with t-butyl trichloroacetimidate (1.36 mL, 7.56 mmol) in toluene at 100°C for 16 hours. The reaction was quenched with water (20 mL) and diluted with ethyl acetate (50 mL). The organic layer was washed with water, and brine, dried over MgS0 , 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%).

¹H NMR (d₄-methanol) δ 7.65 (m, 4H), 7.4 (m, 6H), 3.88 (m, 1 H), 3.72

(2d, 1 H), 3.46 (2d, 1 H), 2.68 (m, 1 H), 2.12 (m, 1 H), 1.76-2.0 (m, 2H), 1.79 (s, 3H), 1.68 (m, 1 H), 1.48 (m, 1 H), 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

OH

/

23C. (1R.3R.4R.1'SV3-Hvdroxymethyl-4-(1'-acetamido-3'-methyl)butyl- cyclopentane-1 -carboxylic Acid t-Butyl Ester

The title compound was prepared according to the method described in Example 13K substituting (1 R,3R,4R,1'S) 3-(t-butyldiphenylsilyloxymethyl)-4-(1'- acetamido-3'-methyl)butyl-cyclopentane-1 -carboxylic acid t-butyl ester for (1 R,3R,4R,1'S)-3-(t-butyldiphenylsilyloxymethyl)-4-(1'-acetamido-3^,-ethyl)pentyl- cyclopentane-1 -carboxylic acid (yield: 0.35 g, 93%).

¹H NMR (d₄-methanol) δ 3.88 (m, 1 H), 3.58 (2d, 1 H), 3.35 (2d, 1 H), 2.7

(m, 1 H), 2.08 (m, 1H), 1.95 (s, 3H), 1.94 (m, 1 H), 1.78 (m, 1 H), 1.5-1.7 (m, 3H), 1.43 (s, 9H), 1.2-1.4 (m, 2H), 0.9 (2d, J=6.44 Hz, 6H)

-159- MS: (M-H)- = 326, (M+35)" = 362; (M+H)⁺ = 328, (M+Na)⁺= 350

23D. (1 R.3R,4R,1'S)-3-Formyl-4-(1'-acetamido-3'-methyl)butyl-cvclopentane-1- carboxylic Acid t-Butyl Ester

The title compound was prepared according to the method described in Example 1D substituting (1R,3R,4R,1'S)-3-hydroxymethyl-4-(1'-acetamido-3'- methyl)butyl-cyclopentane-1-carboxylic acid t-butyl ester for (±)-(2R,3S)-2-(f- butyloxycarbonylamino)-3-hydroxymethylbicyclo[2.2.1]hept-5-ene (yield: 0.32 g, 92%).

¹H NMR (d₄-methanol) 5 9.5 (d, 1 H), 7.85 (d, 1 H), 3.88 (m, 1 H), 2.85 (m,

1 H), 2.62 (m, 1 H), 2.47 (m, 1 H), 2.05 (m, 2H), 1.91 (m, 1 H), 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: (M-H)" = 324; (M+H)⁺ = 326, (M+Na)⁺ = 348.

23E. (1 R,3R.4R.1'S)-3-Carboxyl-4-(1'-acetamido-3'-methyl)butyl-cvclopentane- 1 -carboxylic Acid t-Butyl Ester

A solution of (1R,3R,4R,1'S)-3-formyl-4-(1 '-acetamido-3'-methyl)butyl- cyclopentane-1 -carboxylic acid t-butyl ester (0.3 g, 0.93 mmol) and 2-methyl-2-

-160- 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 NaCI0₂ (0.3 g, 3.31 mmol) and NaH₂P0₄.H₂0 (0.3 g, 2.17 mmol) in water (6 mL) 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 (MgS0₄) 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%).

¹H NMR (d -methanol) 5 3.86 (m, 1H), 2.8 (m, 1 H), 2.7 (m, 1H), 2.4 (m,

1H), 2.22 (m, 1H), 2.08 (m, 1H), 1.97 (m, 1 H), 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. (1 R,3R,4R,1'S) 3-(2-Bromo-1-oxo)ethyl-4-(1-acetamido-3-methyl)butyl- cvclopentane-1 -carboxylic Acid t-Butyl Ester

(1R,3R,4R,rS)-3-Carboxyl-4-(1'-acetamido-3'-methyl)butyl-cyclopentane- 1 -carboxylic acid t-butyl ester (286 mg, 0.84 mmol) and N-methylmorpholine (111 μL, 1.01 mmol) in ether (15 mL) was reacted with isobutyl chloroformate (120 μL, 0.93 mmol) at 0°C for 45 minutes. To the reaction flask was cannuiated a distilled diazomethane solution in ether prepared from the reaction of Diazald (2.4 g) in ether (60 mL) with a solution of potassium hydroxide (2.4 g) in ethanol (15 mL) and water (15 mL). The reaction was stirred for 8 hours at room temperature

-161- then diluted with ether. The organic layer was washed with brine, dried (Na₂S0 ) and concentrated to give the intermediate diazo ketone. The diazoketone was reacted with 48% HBr (90 μL) in dioxane (10 mL) at 23°C for 45 minutes. The reaction was quenched with water (50 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water, and brine, dried over MgS0 , 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%).

¹H NMR (d -methanol) 64.18 (2d, J=14.07 Hz, 2H), 3.8 (m, 1 H), 3.08 (m,

1 H), 2.83 (m, 1 H), 2.48 (m, 1 H), 2.3 (m, 1 H), 2.07 (m, 1 H), 1.89 (s, 3H), 1.45 (m, 1 H), 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

HN

23G. (1 R.3R.4R.1'SV3-(lmidazol-4-yl)-4-(1'-acetamido-3'-methvnbutyl- cyclopentane-1 -carboxylic Acid t-Butyl Ester

(1R,3R,4R,1'S)-3-(2-Bromo-1-oxo)ethyl-4-(1'-acetamido-3'-methyl)butyl- cyclopentane-1 -carboxylic acid t-butyl ester (105 mg, 0.28 mmol) was reacted with formamidine acetate (0.52 g, 4.99 mmol) in liquid ammonia (5 mL) and heated at 45 °C in a sealed tube for 18 hours. The reaction was concentrated in vacuo. The residue was treated with aqueous NaHC0₃ and extracted with dichloromethane (5x20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue

-162- was purified by chromatography on silica gel using 10% methanol in dichloromethane to provide the title compound as an oil (40 mg, 39%).

¹H NMR(d₄-methanol) 67.57(brs, 1H), 6.81 (brs, 1H), 3.93 (m, 1H), 2.96

(m, 1H), 2.7 (m, 1H), 2.1-2.4 (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

HN N

23G. (IR.SR R.rS^-fimidazo -yl -d'-acetamido-S'-methvπbutyl- cyclopentane-1 -carboxylic Acid Hydrochloride

(1 R,3R,4R, 1 'S) 3-(imidazol-4-yl)-4-(1 '-acetamido-3'-methyl)butyl- cyclopentane-1 -carboxylic acid t-butyl ester (40 mg, 0.11 mmol) was reacted with 6N HCI (4 mL) for 1 hour. The reaction concentrated in vacuo to provide the title compound (yield: 37mg, 98%).

¹HNMR(d₄-methanol) 68.83 (d, J=1.01 Hz, 1H), 7.36 (d, J=1.01 Hz, 1H),

3.92 (m, 1H), 3.18 (m, 1H), 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

-163- Example 24

(3R.4R.1 'S)-4-(imidazol-2-yl)-3-(1 '-acetamido-3'-ethyl)pentyl-cvclopent-1 -ene-1 - carboxylic Acid

OTBDPS

/

24A. (3R,4R,rS)-3-(t-Butyldiphenylsilyloxymethyl)-4-(1'-azido-3'-ethyl)pentyl- cyclopentan-1-one

(3R.4R, 1 'S)-3-(f-Butyldiphenyisilyloxymethyl)-4-(1 '-azido-3'-ethyl)pentyl-1 - methylene-cyclopentane (0.455g, 0.93 mmol) was reacted with 4% osmium tetroxide in water (0.59 mL, 0.093 mmol) and sodium periodate (0.8 g, 3.73 mmol) in THF (15 mL) and water (3 mL) at room temperature for 3 hours. The mixture was filtered and the filtrate was diluted with ethyl acetate, washed with 10% Na₂S₂0₃ solution, water, dried over MgS0₄, filtered, and concentrated in vacuo. Chromatography on silica gel using 10% ethyl acetate/hexane afforded the title compound (yield: 240 mg, 52%).

H NMR (CDCI₃) δ 7.64 (m, 4H), 7.4 (m, 6H), 3.68 (m, 2H), 3.36 (m, 1 H), 2.3-2.6 (m, 4H), 2.23 (2d, 1H), 2.08 (m, 1H), 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

-164- OTBDPS OTBDPS

/ /

OTf OTf

24B. (3R.4R, 1 'S)-4-(t-Butyldiphenylsilyloxymethyl)-3-(1 '-azido-3'-ethyl)pentyl-1 - trifluoromethansulfonyloxy-cvclopent-1-ene and (3R.4R,1'S)-3-(t- Butyldiphenylsilyloxymethyl)-4-(1 '-azido-3'-ethyl)pentyl-1 - trifluoromethansulfonyloxy-cvclopent-2-ene

(3R.4R, 1 'S)-3-(t-Butyldiphenylsilyloxymethyl)-4-(1 -azido-3-ethyl)pentyl- cyclopentan-1-one (230 mg, 0.468 mmol) was reacted with 1M lithium hexamethyldisilazide (1.17 mL) in THF (1 mL) at -78°C for 45 minutes. The reaction mixture was treated with N-phenyltrifluoromethanesulfonimide (0.2 g, 0.56 mmol) and reacted at 0°C for 0.5 hour. The reaction was quenched with water (10 mL) and diluted with ethyl acetate (50 mL). The organic layer was washed with water, brine, dried over MgS0 , 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%).

¹H NMR (CDCI₃) δ 7.64 (m, 4H), 7.4 (m, 6H), 5.58-5.5 (m, 1 H), 3.55-3.72 (m, 2H), 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), 0.78-0.9 (m, 6H)

-165- OTBDPS

/

OCH.

24C. (3R,4R.1'S)-4-(t-Butyldiphenylsilyloxymethyl)-3-(1'-azido-3'-ethyl)pentyl- cvclopent-1-ene-1 -carboxylic Acid Methyl Ester and (3R,4R,1'S)-3-(t- Butyldiphenylsilyloxymethyl)-4-(1 '-azido-3'-ethyl)pentyl-1-cvclopent-1-ene1- carboxylic Acid Methyl Ester

Carbon monoxide was bubbled into a mixture consisting of (3R,4R,1 'S)-4- (t-Butyldiphenylsilyloxymethyl)-3-(1 '-azido-3'-ethyl)pentyl-1 - trifluoromethansulfonyloxy-cyclopent-1-ene and (3R,4R,1'S)-3-(t- Butyldiphenylsilyloxymethyl)-4-(1 '-azido-3'-ethyl)pentyl-1 - trifluoromethansulfonyloxy-cyclopent-1-ene (280 mg, 0.45 mmol), triethylamine (0.125 mL, 0.9 mmol), bis(acetato)bis(triphenylphosphine)palladium(ll) (34 mg, 0.045 mmol) in DMF (4 mL) and methanol (2 mL) at 40°C for 2 hours. The reaction was quenched with water (10 mL) and diluted with ethyl acetate (50 mL). The organic layer was washed with water, brine, dried over MgS0₄, 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%).

¹H NMR (CDCI₃) δ 7.64 (m, 4H), 7.4 (m, 6H), 6.58-6.7 (2 br s, 1 H), 3.74 (br s, 3H), 3.25-3.62 (m, 3H), 2.7-2.95 (m, 2H), 2.22-2.49 (m, 2H), 1.16-1.5 (m, 6H), 1.05 (s, 9H), 0.78-0.9 (m, 6H)

MS: (M+18)⁺ = 551 , (M+Na)⁺ = 556

-166- OTBDPS OTBDPS

/ /

24D. (3R.4R,1'S)-4-(t-Butyldiphenylsilyloxymethvn-3-(1'-acetamido-3'- ethyl)pentyl-cvclopent-1-ene-1 -carboxylic Acid Methyl Ester and (3R,4R,1'S)-3-(t- Butyldiphenylsilyloxymethyl)-4-(1 '-acetamido-3'-ethyl)pentyl-cvclopent-1 -ene-1 - carboxylic Acid Methyl Ester

A solution of the mixture of (3R,4R,1'S)-4-(t-butyldiphenylsilyloxymethyl)-3- (1 '-azido-3'-ethyl)pentyl-1 -trifluoromethansulfonyloxy-cyclopent-1 -ene-1 - carboxylic acid methyl ester and (3R,4R,1'S)-3-(t-butyldiphenylsilyloxymethyl)-4- (1'-azido-3'-ethyl)pentyl-1-trifluoromethansulfonyloxy-cyclopent-1-ene-1- carboxylic acid methyl ester (0.18 g, 0.33 mmol) in THF (12 mL) and water (3 mL) was reacted with triphenylphosphine (0.265 mg, 1.01 mmol) at 65°C for 4 hours. The reaction mixture was concentrated in vacuo, redissolved in chloroform, dried over MgS0₄, 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 dichloromethane (1 mL) at room temperature for 2 hours. The reaction was quenched with 10% citric acid solution (10 mL) and diluted with ethyl acetate (50 mL). The organic layer was washed with water, and brine, dried over MgS0 , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 40% ethyl acetate/hexane to provide the title compounds (3R,4R,1'S)-4-(t-butyldiphenylsilyloxymethyl)-3-(1'-acetamido-3'-ethyl)pentyl- cyclopent-1-ene-1 -carboxylic acid methyl ester (yield: 109 mg, 60%) and (3R.4R, 1 'S)-3-(t-butyldiphenylsilyloxymethyl)-4-(1 '-acetamido-3'-ethyl)pentyl- cyclopent-1-ene-1 -carboxylic acid methyl ester (yield: 37mg, 20%).

-167- (3R,4R,1'S)-4-(t-butyldiphenylsilyloxymethyl) ¹H NMR (CDCI₃) δ 7.63 (m, 4H), 7.4 (m, 6H), 6.58 (s, 1 H), 4.95 (br s, 1 H), 4.0 (br s, 1 H), 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: (M-H)" = 548, (M+35)" = 584; (M+H)⁺ = 550, (M+Na)⁺ = 572

(3R,4R,1'S)-3-(t-butyldiphenylsilyloxymethyl) ¹H NMR (CDCI₃) δ 7.63 (m, 4H), 7.4 (m, 6H), 6.64 (d, 1H), 4.72 (d, 1 H), 3.95 (m, 1 H), 3.74 (s, 3H), 3.73 (2d, 1 H), 3.57 (2d, 1 H). 2.9 (m, 1 H), 2.75 (m, 1 H), 2.3 (m, 1 H), 2.14 (m, 1 H), 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: (M-H)- = 548, (M+35)" = 584; (M+H)⁺ = 550, (M+Na)⁺ = 574

OH

/

24E. (3R.4R, 1 'S)-4-hvdroxymethyl-3-(1 '-acetamido-3'-ethyl)pentyl-cvclopent-1 - enel -carboxylic acid methyl ester

The title compound was prepared according to the method described in Example 13K substituting (3R,4R,1'S)-4-(t-butyldiphenylsilyloxymethyl)-3-(1- acetamido-3-ethyl)pentyl-1 -trifluoromethansulfonyloxy-cyclopent-1 -ene-1 - carboxylic acid methyl ester for (1R,3R,4R,1'S)-3-(t-butyldiphenylsilyloxymethyl)- 4-(3-ethyl-1-acetamido)pentyl-cyclopentane-1 -carboxylic acid (yield: 53 mg, 85%).

¹H NMR (CDCI₃) δ 6.63 (m, 1H), 5.49 (d, 1 H), 3.98 (m, 1H), 3.74 (s, 3H), 3.5-3.7 (m, 2H), 2.87 (m, 1 H), 2.75 (m, 1 H), 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)

-168- MS: (M-H)" = 310, (M+35)^" = 346; (M+H)⁺ = 312, (M+Na)⁺ = 334

24F. (3R.4R.1 'S)-4-formyl-3-(1 -acetamido-3-ethyl)pentyl-cvclopent-1 -ene-1 - carboxylic acid methyl ester

The title compound was prepared according to the method described in Example 1D substituting (3R,4R,1'S)-4-hydroxymethyl-3-(1'-acetamido-3'- ethyl)pentyl-cyclopent-1-ene-1 -carboxylic acid methyl ester for (±)-(2R,3S)-2-(f- butyloxycarbonylamino)-3-hydroxymethyl-bicyclo[2.2.1]hept-5-ene (yield: 38 mg, 72%).

¹H NMR (CDCI₃) 6 9.71 (s, 1 H), 6.62 (m, 1 H), 5.2 (d, 1 H), 4.06 (m, 1H), 3.75 (s, 3H), 3.25 (m, 1 H), 3.1 (m, 1 H), 2.96 (m, 1 H), 2.83 (m, 1 H), 1.96 (s, 3H), 1.2-1.5 (m, 8H), 0.77-0.9 (2t, J=7.12 Hz, 6H)

MS: (M-H)^" = 308; (M+H)⁺ = 310

-169-

24G. (3R.4R, 1 'S)-4-(imidazol-2-yl)-3-(1 '-acetamido-3'-ethyl)pentyl-cyclopent-1 - enel -carboxylic acid methyl ester

The title compound was prepared according to the method described in Example 15D substituting (3R,4R,1 'S)-4-formyl-3-(1 '-acetamido-3'-ethyl)pentyl- cyclopent-1-ene1 -carboxylic acid methyl ester for (1 R,3R,4R,1'S)-1-formyl-2-(1'- acetamido-3'-ethyl)pentyl-4-(triphenylmethyloxy)methyl-cyclopentane (yield: 6 mg, 14%).

¹H NMR (CDCI₃) δ 7.06 (s, 2H), 6.69 (s, 1H), 3.95 (m, 1H), 3.74 (s, 3H), 3.5-3.7 (m, 2H), 3.23 (m, 1 H), 2.8 (m, 1 H), 1.90 (s, 3H), 1.1-1.5 (m, 8H), 0.73- 0.87 (2t, J=7.12 Hz, 6H)

MS: (M-H)" = 346, (M+35)- = 382; (M+H)⁺ = 348, (M+Na)⁺ = 370

24H. (3R,4R,1'S)-4-(lmidazol-2-yl)-3-(1 '-acetamido-3'-ethvnpentyl-cvclopent-1- ene-1 -carboxylic Acid

(3R,4R,1'S)-4-(lmidazol-2-yl)-3-(1'-acetamido-3'-ethyl)pentyl-cyclopent-1- ene-1 -carboxylic acid methyl ester (6 mg, 0.017 mmol) was reacted with lithium hydroxide (1 mg, 0.026 mmol) in THF (0.5 mL) and water (0.2 mL) at 0°C for 4

-170- 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 MgS0 , 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 into 25% isopropanol/dichloromethane to provide the title compound (yield: 4.3 mg, 74%).

¹ H NMR (d₄-methanol) 6 7.06 (br s, 2H), 6.48 (br s, 1 H), 4.08 (m, 1 H),

3.45-3.7 (m, 2H), 3.1 (m, 1H), 2.62 (m, 1H), 1.98 (br s, 2H), 1.82 (br s, 3H), 1.1- 1.42 (m, 8H), 0.73-0.87 (m, 6H)

MS: (M-H)^" = 332, (M+35)^" = 368; (M+H)⁺ = 334, (M+Na)⁺ = 356

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 one core from Table 1 (wherein Ac is acetyl), one Y substituent from Table 2, one R substituent from Table 3, one R³ substituent from Table 4a, 4b, 4c, 4d, 4e, 4f or 4g and one R⁵ substituent from Table 5.

Table 1

Y_N

\

ACHN. j ^Acmyy O R^{3 H} V O ^0R

-171- CH₃S0₂ΗN^ ^^0Rr C ^-"H 13gS^^OsΗ1 ιNιι^₄ ^ yy- ^OR

,3H i Of R 3H O

0

O Y Y

II

CF₃C-HN, OR CF₃C-HN OR ϊf

R O R i Of

Y Y

AcH N ~ X -_/OR AcHN^^ .OR

R^3H O R^3fil O

CH₃SO₂ΗN. ^\ OR CH₃SO₂ΗN^(^y .OR

9 10

O O

CF₃C-HN. _/OR .OR R^3H O R^3[i| O

11 12

Y Y

AcHN. 1 ^ ^OR AcHN^V^ ^^OR

_R3H _{0 R}3H ₀

13 14

-172- Y Y

CH₃so₂ΗN CH₃S0₂ΗN_< OR

,3H O

15 16

O Y O Y

II

CF3C-HN. OR CF3C-HN OR ϊf ϊf

R O R O

16 17

Y Y

AcHN. OR AcHN OR i

R _R5 f O

R 5 Of

19

Y Y

CH₃SOZHN 7^~Λ OR CH₃S0₂ΗN^ ^~ .OR

J R3^ύH ^πT _RC5 O _D R3^ύH ^π _R5 O

20 21

O Y o Y

^CF3"^HN- R^{3 H}γ _R5 O ^{R F3C_H}\ R³i ^Hγ _R 22 ^C V5 O 23 ^R

-173- Table 2

H,C H

HN

H,C H Cl

H₃C H,C O

O

^Nb-'/ H₃C

N

10 11 12

F C

HN ^N ^N

HN- y N=<?

Cl

13 14 15 16

H*C H₃C H F₃C

Cl F-,C H

17 18 19 20

H₃Q HN^N N P H₃C

21 22 23 24

F*C F*C -^

N

N=

F,C Cl

25 26 27 28

-174- H

NH

Et Et Et

29 30 31 32

F,C Cl Cl Et H₃C 0

F*C H

33 34 35 36

H CH₃ Cl

H K Cl ^H H 37 38 39 40

HO ,0 O

N N-N

41 42 43 44

'^N^s N ϊ

^HNvJ N N-N

45 46 47 48

,N_

-N HN ^{^}N HN ^"N HN N N ^N \^^^ ^

49 50 51 52

H

H Λ

N-N

53 54 55 56

N^

N=_s

57 58 59 60

-175- ,N ϋ 0^'

^ //

61 62 63 64

65 66 67 68

CH, H₃C CH,

F <~÷~ H₃C

69 70 71 72

H,C CH Cl Cl. Cl Cl. Cl

H,C H Cl

73 74 75 76

Cl Cl CF, F₃C CF₃

Cl Cl

77 78 79 80

F₃C Cl Cl. CH,

F,C F₃C H C Cl'

81 82 83 84

Cl CH, F,C CF, H₃C Cl

H,C Cl F,C H₃C

85 86 87 88

CH, HaC Cl H,C CH, Cl CH,

Cl H₃C

89 90 91 92

-176- CH, H,C Cl

H,C Cl s/s/w~

93 94 95 96

Cl. Cl CH, CH,

H₃C - H,C H,C \ 97 98 99 100

H,C CH, H,C F,

H,C

101 102 103 104

H₃C F,C H,C CF, H₃C CH₃ F₃C H₃C — H₃C F₃C

105 106 107 108

H,C CF, F,C CH, CF, F₃Q CH,

109 110 111 112

CH, H,C CF, F,C CF, Cl

F,C F,C H,C F

113 114 115 116

Cl Cl Cl. l

117 118 119 120

Cl. F Cl Cl

Cl Cl F C ^FlH^F

121 122 123 124

-177- Cl. Cl. Cl Cl. Cl. CF,

F,C F,C

125 126 127 128

F,C Cl F,C Cl F,C Cl F,C CF,

F,C Cl

129 130 131 132

CF, Cl Cl. CF, Cl CF,

Cl F,C Cl F,C

133 134 135 136

CF, F_\ CF_{3 x} CF₃

.H F,C H F,C

137 138 139 140

F,C F,C CF, F,C

F,C

141 142 143 144

F F,C CF, H₃C F H₃C Cl

F₃C ⁾y F

145 146 147 148

Cl. Cl F CH, Cl. CH,

H₃C — H^C Cl

149 150 151 152

H₃C CF₃ H₃C Cl ^CK ^F3 F₃C Cl i \ _{F r}^ l. \

H₃C H₃C

153 154 155 156

-178- F,C CH, Cl CH, H,C CF, H,C . F₃C F,C

157 158 159 160

CF, F₃C F F,C CH,

H, KC ^F3 H,C H₃C

161 162 163 164

CH, Cl CF, Cl CF,

F,C F,C Cl

165 166 167 168

Table 3

-H CH "CH₃ ->

CH,

.CH, -CH,

CH

CH₃ CH, CH₃

CH CH >

H,C CH₃ CH₃

-^x CH, λ CH₃

10 CH₃ CH_{3 j}2

1 1 H, CH, -CH,

-N -N

CH CH -CH

14 3 15

-179- Table 4a

CH

H,C OH OH

CH,

3

H,C H₃C OH OH

CHs CH,

H,C

H,C

10 11

H,C.

OH OH H₃C CH H₃C CH

13 14 15 16

H,C CH₃ OCH₃ HsC^^^oCH;

CH,

17 18 19 20

H₃C OCHs ^H3°

_CH H₃C

CHs H₃C

21 22 23 24

-180- Hrf ^cxΛ-H∞

25 26 27 28

H,(

OCH, OCH, H₃C CH H₃C CH

29 30 31 32

OH

H,C HsC OCH,

OCH H^CM,""* W

35 36

33 34

HsC

HsC

HsC

H,C X OH OH OH OH

37 38 39 40

OH OH

OH OH

HsC CHs

41 42 43 44

HsC

HsC

HsC

HsC X OCHs OCHs OCHs OCHs

45 46 47 48

OCH, OCH,

OCH₃ OCH,

H₃C CH₃

49 50 51 52

-181- Table 4b

^*OH "CH,

OH r *OCH

OH OH OH CHs

OH { ~OCH₃ "θ"CH₃ ~θ"

OH OH OH OH CH₃

5 6 7 8

HO^' y ΌH HO^' y "OCH₃ ^HO Y ^'° ^CHS HO" ^o

OH OH °^H OH CH₃

9 10 11 12

HO^' ^ ^OH HO^' y^ "OCH₃ ^0" Υ "° ^CHS HO" >f ^O

OH OH °^H OH CH₃

13 14 15 16

HO" " H HO"^"" ^{^}OCH₃ HO" ~0" "CH₃ HO^^ "O"

OH OH °H OH CH₃

17 18 19 20

HO-^' ^OH HO" ^OCH₃ H0^' γ ^{^}0^' -CH₃ HO^γ^O"

OH OH °^H OH CH₃

21 22 23 24

O' ^i ^ y HO" y -o" ^ HO" y "o

OH " OH " OH " OH

25 26 27 28

-182- OCH, O^' -" ~0 HO' y o *OCH₃ - OH OH OCH₃ OCH₃

29 30 31 32

CH₃0 Y ^OCH₃ CH₃0"^' " -" CH₃ CH₃0"' ^ -OCH₃ CH₃O" y ^"OCH; OCH₃ OCH₃ OCH₃ OCH₃ 33 34 35 36

H₃C H₃C H₃C H₃C

OH OCH, H₃C O CH, HsC O HsC HsC

OH OH OH CH₃

OH

38 39 40

37

H₃C^Λ₀H HsC^^oCHs H₃c ^°"^CH3 ^ ^O^ _u θH H₃C OH H₃C ^0H ₀ O_HH c CH₃

H3C ..

41 42 43 444

41 4

H₃C

HsC HsC HsC

3^^-^OH "³ ^OCH₃ ^ ^ CH₃ O

OH OH OH OH CH₃

46 47 48

45

HsC V" 'O

OH HsC^' *OCH₃ H₃C CH₃ HsC

OH

OH OH OH CHs

49 50 51 52

HsC

H₃C H₃ 3 ⁰C¹-\ ''

OH \^.- ^»r^r^ _J H₃C^ ^ --, , -._,,

OC-H₃. ~^γ~ (j v_>π₃ ^'O

OH OH OH OH CH₃

56

53 54 55

HsC^^^OH H₃C-^^₀CH₃ H₃C^^O^CH₃ ^H3C V^ O

OH OH °^{H 0H} ^

57 58 59 60

-183- H₃C HsC^ H₃C

~OH OCH₃ H₃C O CH₃ H₃C ° HsC

OH OH OH CH₃

61 62 63 64

πjww

OH OCHs HsC ^"0 CH₃ OH O H₃C OH CH₃

H₃C

65 66 67 68

H₃C OH H₃C r-OH HsC OCH₃ HsC OCH3 CH₃ CH₃ CH₃ -CH₃

OH OH OH OH

69 70 71 72

HsC OH H₃C OH H₃C OCHs HsC' ^■OCH₃ CH₃ -CH₃ CH₃ -CH₃

OH OH OH OH

73 74 75 76

H₃C OH H₃C^ -OH H₃C^ -OCH₃ H₃C_> -OCH₃ H₃C CH₃ H₃C^_H -CH₃ HsCl CH₃ ^C L , ""CHs

OH ^π3U OH""³ OH

77 78 79 80

CH_r CH HsC yy OCH3 H₃C OCH3

^H3C"r^ CH3 X '—CHs H₃c~~y _CH3 -CH₃ H₃C OH OH^" ° OH

C^ΓH?^H

81 82 83 84

Table 4c

HsC

^H3^C _0H NH₂ OH CH₃ CH₃

-184- CHs CH₃ H₃ CH₃ CH₃ CHs

CH ,C

H₃C -^-— . H 3^ CHs

"CH, ^"CH₃ ~CHs

CHs CH,

10 11 12

CH₃ -

~CH₃ H₃C ' CHs HsC ^"CH, A CH₃ CHs H₃C CHs

13 14 15 16

HsC H₃C

^"CH, ~CH, H₃C

CHs CH,

17

CHs CH ^"CHs ^'CH, ^"CH, ^"CH,

H₃C CH, CHs CH₃ H₃C CH₃

21 22 23 24

CH, HsC

HsC

^"CHs -CHs -CHs

OH OH

OH

25 26 27

CH CH, HsC

-CH, ^"CH, -CH, -CHs

OH OH OH OH

29 30 31

-185- OH -CH, ^"CHs -CH,

-CH,

OH OH H₃C CH,

34 33 36

CH HsC

HsC

HsC^CHs CH, CHs CH, 7 39 40

CH, CHs CH,

CHs CH₃

41 42 43 44

CH

HsC Hs CH₃ H,C CHs

CHs CH₃ CH,

45 46 47 48

CH

CH, HsC CH, HsC CHs CHs CHs H₃C CH₃ 49 50 51 52

HsC H₃C

CHs CHs CHs H₃C

CHs CH,

53 54 55 56

CH CHs CHs CHs

H y₃C CHs CHs CHs H₃C CH₃

57 ~. 58 59 60

-186- HsC

HsC

CHs

OH OH

OH OH 1 62 64

CHs CH, HsC

CH, X CHs CHs CHs

OH OH OH OH

65 66 67 68

OH CHs CHs CH₃

CHs

H₃C CH₃

OH OH

69 70 71 72

CH HsC H₃ H₃C ,CHs

H₃C ,CHs XH₃

73 74 75 76

,CHs ,CH, .CHs

_^CH

CHs

77 78 79 80

CH

XHs XHs

^ . XH₃ HsC ,CHs HsC CHs

CH,

81 82 84

CH y -^CH₃ H₃C XHs CH,

HsC ^■y .^CH₃

CH, CH₃

H₃C 85 86 87

-187- .CHs Hs CH,

H₃C H₃C XH,

^■y H₃C

CHs CH,

89 90 91 92

CH, CH

XH, CH, .CHs XHs

^■y

H₃C CH₃ CHs CHs H₃C CHs

93 94 95 96

H₃C

XHs .CHs

H-aC-- -y XH, XH,

OH OH OH OH

97 98 99 100

CH CH H₃C

XH, XHs CH₃

^■y XHs

OH OH OH OH

101 102 103 104

OH Hs XHs XH XHs X

OH OH _CH₃

105 106 107 108

CH HsC

CH, H₃C XH,

H₃C CHs XH₃ 109 110 111 112

113 114 115 116

-188- C4— T ^ CH,

H₃C

CH₃

CH3

117 118 119 120

CH,

CH, H₃C" XHs CHs

HsC CHs

CHs H₃C CH₃

H₃C J

121 122 123 124

HsC CHs H₃C XHs CHs H₃C

CHs CH,

125 126 127

CHs CH

CHs CHs CH, CHs

H₃C CHs CH, CH, H₃C CHs

129 130 131 132

CH₃ H₃C

HsC CHs I ,CH,

CHs CH,

OH OH OH OH

134 135 136

CH HsC

HsC CHs XH, CHs CHs

OH OH OH OH

137 138 139 140

OH CHs XHs CH, CHs

OH H₃C cH₃

141 142 143 144

-189- CH, CH, CHs HsC

CH, CH_{3 3}C

H₃C X H HsC 145 146 147 148

CH,

CHs CH, CHs

CH₃

149 150 150A 150B

CHs CHs CH₃ — CHs CH₃

H₃C CHs

CH,

151 152 153 154

CH CHs C VH^π.3s CHs CH₃

CHs

HsC HsC CHs CH₃

155 156 157 158

CHs CH, CHs CHs

H₃C H₃C H₃C

CHs CHs

159 160 161 162

CH, CHs CH, CH CHs CH,

H₃C CH, CHs CHs H₃C CH₃ 163 164 165 166

CH₃ CHs ^HsC CHs

HsC

OH OH OH

167 168 169

-190- CH CHs CHs CH, HsC

CHs CH,

OH OH OH OH

171 172 173 174

OH CH, CHs CHs

CH

OH OH CHs

175 176 177 178

CHs CH CHs H₃C

CHs

H₃C

H₃C 179 180 181 182

CHs

CH₃

184 185 186

CH CHs CH₃ CH CH₃ HsC CH₃

CHs

187 189 190

CH₃ CHs CHs CHs

HsC H,C CHs 191 192 193

HsC H₃C

CHs CHs

195 196

-191- CH, CH, CH CHs

H₃C CHs CH, CH, H₃C CHs 199 200 201 202

CH, CH, HsC

H₃C

OH OH OH OH

203 204 205 206

CHs T CH₃ CH₃ T PH₃ H₃C

OH OH OH OH

207 208 209 210

OH CH,

211 212 213 214

CH HsC ₃C

HsC XJ H HsC

13

215 216 217 218

x.j y CHs

219 220 221 222

CH

H₃C HsC

CHs CH,

77- 224 225 226

-192- CH

HsC H₃C CH, H₃C CH₃

227 228 229 230

HsC H₃C H₃C J

CHs CHs

231 232 2JJ 234

CH

H₃C CH₃ CH, CHs H₃C CH,

235 236 237 238

HsC

HsC

OH OH

OH OH

239 240 241 242

CH CH HsC

J λj

OH OH

OH OH

243 244 245 246

J H₃C

OH OH CHs

247 248 249 250

CH H₃C

HsC

H₃C

251 252 253 254

-193-

CHs

255 256 257 258

CH

H₃C HsC

CHs CHs

259 260 261 262

CH

HsC HsC

CH, 264 265

HsC H₃C H₃C

CH, CHs

267 268 270

CHs

H₃C CHs CH, H₃C CHs

271 272 274

HsC

HsC

OH OH OH OH

275 276 277 278

HsC

OH OH OH OH

279 280 281 282

-194- OH

OH OH CHs

283 284 285 286

H CH, H₃α

H₃C

287 288 289 290

H₃C.

H,C

CH,

291 292

Table 4d

HsC CHs HsC CHs HsC

H₃C

"0 O HsC O HsC H₃C

10 11 12

-195- H₃C HsC H₃C !

V. H₃C ^•o 14 15 16

^"O HsC HsC O H₃C

17 18 19 20

HsC

V

H₃C 22 23 24

H₃C H₃C O

32

H₃C H₃C

33 34

-196- Table 4e

CH HsC

XH HsC OH XH

HsC XH

XH XH XH XH

CHs

CHs

XH

XH XH

HsC XH

CHs CHs

10 11 12

CH

XH XH OH

HsC HsC ^■y XH CHs H₃C CH,

13 14 15 16

H,C XH HsC XH OH XH

^■y

HsC ι

CHs CHs

17 18 19 20

CH H OH

XH .O XH

^■y ^■y

H,C CHs CHs CHs H₃C CH₃

21 22 23 24

-197- HsC

H₃C XH OH

^•y XH XH

OH OH

OH OH

25 26 27 28

CHs CHs HsC

XH XH OH XH ^■y

OH OH OH OH

29 30 31 32

OH XH XH XH XH

OH OH CHs

33 34 35 36

CH H₃C

OH HsC OH

HsC OH OH

37 38 39 40

OH OH OH OH

CHs

41 42 43 44

CH ^°^H Hs OH

HsC

_^/

HsC

49 50

-198- H₃C OH OH H₃C

CH, CHs

53 54 55 56

CH

OH .OH OH

H₃C CH₃ CHs C <_Hπs₃ HsC CHs

57 58 59 60

HsC

OH

OH OH

OH OH

OH OH

61 62 63 64

CH HsC

HsC_^^^_/OH OH OH

OH OH OH OH

65 66 67 68

OH

OH OH XH

OH CH₃

69 70 71 72

OH r ^0H

HO OH H,C OCH3 69 70 71 72

-199- Table 4f

HsC

H₃c "CH₃

³ OH NH₂ OH CH₃ CH₃

CH CH₃ CH₃ CH, CH₃ CHs HsC CHs

CH

H₃C CH₃ CH₃

CH?^H= CHs CH

11 12

CH

XH₃ HsC -CH CH₃

HsC CHs

CHs CHs H₃C CH?^H=

13 14 15 16

HsC XH₃ H₃C -CH₃ CH₃

CHs CHs

17 IS 19

CH CH

CH₃ CH₃ CH₃ CH₃ Λ_; CH₃ CH₃ CH₃ CH₃

HTC CΓ CH, CHs H₃C CH₃

11 24

-200- CH, HsC

HsC ^■■X - -CCHH₃₃ XH₃ CH₃ CH₃ i CCHHs₃ CH₃

OH OH OH OH 5 26 27 28

CHs CH HsC

-CH₃ CH₃ CH₃ CH₃ CH₃ ³ CH₃

OH OH ³

OH OH 9 31

OH

CH₃ CH₃ CH₃ CH₃ CHs CH₃ ³ CH₃ ³

OH OH H₃C CH 3

34 3D 36

CH, CHs HsC

CHs CHs

H,C

HsC

CH, HsC CHs

37 39 40

CH₃ CH₃ CH₃ CH,

CHs °

41 43 44

CH

CH₃ CHs CHs

CHs y y HsC HsC

CHs CH,

CHs

45 46 47 48

CHs ^H3 I .CHs

HsC H_sC^Y^^ CH₃ CH CH₃ H₃C CH 50 51 52

-201- CHs CH, CHs sC Hs XH, 3 54 55 56

CH, CH₃

..y

CH, CH₃ -CH, CH,

H₃C CHs CHs CH, H₃C CH, 7 58 59 60

CH₃ CHs CH,

/

HsC -y CH₃ CHs

OH OH

61 62

CH CHs CHs

CHs

-y

CHs CHs

OH OH

65 66

OH OH

CH₃ CHs

-,~y -y CH₃ CHs

-CHs CHs

OH OH H₃C CH₃

69 70 71 72

HsC

HsC- H₃C^>1

H₃C

73 74 75 76

77 78 79 80

-202- HsC

H₃C- H₃C

H₃C 82 84

HsC

HsC

85 86 87

HsC

89 90 91

HsC

CHT H₃C CH₃ CHs

HsC CH₃

94 95 96

CHs CHs

97 100

H₃C

H₃C

HsC

101 102 104

105 107

-203- CHs

HO. HO

CH₃ HO CH₃ HC CH₃ CH₃

CH,

109 110 111 112

CHs

3 HO^'

CHs

113 114 115

,OH HsC

.OH

H_C- HsC

\

OH / HO OH OH

117 118 119 120

OH HsC OH

HsC

-OH

121 122 123 124

Table 4g

CH C CH ₃

Hs CH₃ Hs CH ₃ -CH₃ OH OH OH OH

1 2 3

-204- CHs CHs CH 3 τ~ CH₃ CHs

.. / HsC _y y

H,C ^"

OH OH OH OH

- Γ-CH₃ I — CH₃ ^H T^" r^~CH CHs ^{" H}3 A-^y -i

³ OH OH OH OH 9 10 11 12

CH

HsC

HsC A O--H' OH OH OH

13 14 15 16

CH

HsC -CH₃

Hs CH₃ CH₃ CH₃ OCHs OCH₃ OCH₃ OCH₃

17 18 19 20

CHs CHs CH — CH₃ CH₃ y J y

H_scΛ^"" H₃C

OCHs OCH₃ OCH₃

21 22 23 24

- CCHH₃s CCHH₃₃ ~ ^CH₃ -CHs

HsC

HsC Λ r CH₃

O-CH₃ OCH₃ OCHs OCHs 25 26 27 28

CH

H₃C

HsC^ _

OCHs OCH₃ OCH, OCHs

29 30 31 32

CH

HsC ^-OH

Hs OH -OH OH CH₃ CH₃ CH₃ CH₃

33 34 35 36

-205- -OH HsC

HsC XH₃ CH₃ CH₃ CH₃ 37 38 39 40

HsC

HsC

CH₃ CH₃

41 44

HsC

HsC

45 48

CH

HsC -OCH₃

Hs OCH₃ OCH₃ OCH₃ CH₃ CH₃ CH₃ CH₃

49 50 51 52

XCH₃ HsC

HsC Hs CH₃ CH₃ CH₃

53 54 55 56

-OCHs HsC

HsC

CH₃ CH₃ CH₃ CH₃ 57 58 59 60

HsC

HsC

-206- ^

CH₃ CH₃ -CHs CH₃ OH

65 66 67 68

CHs CH, CH, CH,

_y J y OH

69 70 71 72

-CH, -CHs -CH, -CH₃

73 74 75 76

OH OH

77 78 79 80

CH₃ CH₃ XH₃ CH₃ OCH₃

81 82 83 84

CHs CH₃ CH CH, CH₃ .J / ³ OCHs

85 86 87

r-CH₃ -CH, r CHs -CHs OCHs 89 90 91 92

OCHs

-207- 93 94 95 96

OH OH -OH OH CH₃ CH₃

97 98 99 100

CHs

OH CH₃ CH₃ CH₃ CH₃

101 102 103 104

CH,

CH₃ CHs

CHs CH₃ 105 106 107 108

CH,

109 110 111

CHs

-OCH₃ -OCHs OCH₃ OCH₃ CH₃ CH₃ CH₃

113 114 115 116

CH,

OCH₃ CH₃ CH₃ CH₃ CH₃

117 118 119 120

CH₃ OCH₃ 3 CH₃ CH, CHs

-208- 121 122 123 124

CH

H₃C -OH -OH

OH OH OH 129 130 131

CH

H₃C^A-OCH₃ -OCHs

\ OH OH OH OH

133 134 135 136

CH,

HsC-^Λ-OCHs -OCHs

OCH OCH₃ OCH₃ OCH

137 138 139 140

CHs

HsC xXH OH OH OH OH

141 142 143 144

CHs

HsC -OCH₃ OH ^— OH OH OH

145 146 147 148

CH₃

H,C OCH₃ OCH₃ OCH₃ OCH₃ OCH₃

-209- 149 150 151 152

OH OH OH OH

153 154 155

ΛxXHs OH OH y\ ^—OH

157 158 159

-OCHs OCH₃ S OCH₃ y\Λ ^^_—^Oo^Cc^H OCH₃ H 3

CH,

161 162 163

CH

OH OH OH OH

OH OH OH

OH

165 166 167 168

CH

OCHs OCHs OCHs OCHs

OH OH OH

OH 169 170 171 172

CH

OCH₃ OCHs OCH₃ OCHs

OCH OCH₃ OCH₃

OCH₃

173 174 175 176

CH,

^■OH OH OH OH -OH OH -OH -OH

-210- 177 178 179 180

CH

OCHs OCH₃ OCH₃ OCH₃ -OH -OH -OH -OH

181 182 183 184

CH

OCH₃ OCH₃ OCHs OCH₃ -OCH₃ -OCH₃ -OCH₃ -OCH₃

185 186 187 188

OH \ *-OH OH OH -OH A -OH -OH -OH

189 190 191 192

OCH₃ \ ^OCH₃ OCH₃ OCH₃ -OH \ '—OH -OH -OH

193 194 195 196

OCH₃ OCHs OCH₃ OCHs -OCHs -OCH₃ -OCHs

CHs -OCHs

197 198 199 200

-OH ^AXCH₃ -OH .- -OCHs

201 202 203 ; 204

OH OH OCH, OCH,

205 206 207 208

-211- OH CH,

209 α^0H OCHs O

210 211 212

> OH / — T-OCHs 0 :-<

-CH₃ -CH₃

213 214 215 216

v CH₃ ^--CH₃ O b CH₃

217 218 x° 219 220

,-CH₃ ^A-CH₃ O 0 CH₃

221 222 223 224

Table 5

NH₂ I NH₂ OH

1 2 3

-212- The ability of the compounds of the invention to inhibit neuraminidase in ^' vitro can be determined according to the method described below. Neuraminidase Inhibition Assay:

Influenza virus A/N1/PR/8/34 was grown in the allantoic cavity of fertilized eggs and purified by sucrose density gradient centrifugation (Laver, W. G. (1969) in "Fundamental Techniques in Virology" (K. Habel and N. P. Salzman, eds.) pp. 92-86, Academic Press, New York). Influenza virus A/N2/Tokyo/3/67 was obtained from the tissue culture supematents of virus grown on MDCK cells. Neuraminidase from B/Memphis/3/89 virus was prepared by digestion of the virus with TPCK-trypsin followed by centrifugation and then purification of the neuraminidase catalytic fragment using sucrose density gradient centrifugation and dialysis as described previously (Air, G. M., Laver, W. G., Luo, M., Stray, S. J., Legrone, G., and Webster, R. G. (1990) Virology 177. 578-587).

The neuraminidase inhibition assays used the neuraminidase enzymatic activity associated with the A/N1/PR/8/34 or A/N2/Tokyo/3/67 whole virus, or the B/Memphis/3/89 catalytic head fragment. The whole virus or catalytic fragment was diluted appropriately with 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer on the day of the experiment. Neuraminidase inhibition assays were conducted in 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer with 5% DMSO. Reaction mixtures included neuraminidase, inhibitor (test compound) and 20-30 μM 4-methylumbelliferyl sialic acid substrate in a total volume of 200 μL and were contained in white 96-well U-shaped plates. Typically, five to eight concentrations of inhibitor were used for each Ki value measurement. The reactions were initiated by the addition of enzyme and allowed to proceed for 30-60 minutes at room temperature. The fluorescence for each well of the plate was measured once each minute during the reaction period by a Fluoroskan II plate reader (ICN Biomedical) equipped with excitation and emission filters of 355 +/- 35 nm and 460 +/- 25 nm, respectively. The plate reader was under the control of DeltaSoft II software (Biometallics) and a Macintosh computer. If the

-213- compound exhibited linear reaction velocities during the reaction period, then the reaction velocities for the dose-response study were fit to equation 1 using a nonlinear regression program (Kaleidagraph) to determine the overall Ki value (Segel, I. H. (1975) in Enzyme Kinetics, pp. 105-106, Wiley-lnterscience, New York).

(1 - Vi/Vo) = [I]/ {[I] + Ki(1 + [S]/Km)} eqn 1

In equation 1 , Vi and Vo represent inhibited and uninhibited reaction velocities, respectively, and Km = 16 - 40 μM depending on the neuraminidase strain tested. For those compounds exhibiting slow-binding inhibition (Morrison, J. F. (1982) Trends Biochem. Sci. 7, 102-105), a second experiment was performed in a manner identical to the first except that neuraminidase and inhibitor were preincubated in the absence of substrate for 2 hours at room temperature prior to initiating the reactions with substrate. Data analysis for the resulting linear velocities was conducted as described above.

Equation 2 was used to measure Ki values in the sub-nanomolar range (Morrison, J. F. And Stone, S. R. (1985) Comments Mol. Cell Biophys. 2, 347- 368).

V = A{sqrt{(Ki' + It -Et)^Λ2 + 4KϊEt} - (Ki' + It - Et)] eqn. 2

In equation 2, V = velocity; A = αkcat[S]/2(Km + [S]); a is a factor to convert fluorescence units to molar concentrations; Ki' = Ki(1 + [S]/Km); It = total inhibitor concentration and Et = total active concentration of neuraminidase.

The compounds of the invention inhibit influenza A neuraminidase and influenza B neuraminidase with Kj values between about 24 micromolar and about 0.9 micromolar.

-214- The ability of the compounds of the invention to inhibit plaque formation in cell culture can be determined by the method described below.

Cell Culture Plaque Formation Inhibition Assay

Cell Cultures: MDCK cells obtained from the American Type Culture Collection were grown in Dulbecco's Modified Eagle Medium (DMEM) high glucose (GibcoBRL) supplemented with 10% fetal calf serum (JRH Biosciences), 40 mM HEPES buffer (GibcoBRL) and antibiotics (GibcoBRL). Cells were routinely cultured in flasks or roller bottles at 37°C and 5% C0₂. At confluence cells were reduced to a density of 500,000 cells in a ml using trypsin/EDTA (GibcoBRL) treatment of the monolayer followed by cell centrifugation, resuspension, and dilution into growth media. Cells were planted at a volume to surface area ratio of 1 mi over 1 cm² of growth surface.

Plaque Assay Protocol: On MDCK cell confluent 6 well plates growth media was removed and the cells were overlaid with 1.5 ml of assay media (DMEM with 1% fetal calf serum, 40 mM HEPES buffer and antibiotics) containing pre-mixed virus (influenza A/Tokyo/3/67 [H2N2]) (40 -100 plaque forming units) and 2x concentration test compound. The plates were placed on a rocker and incubated for 2 hours at room temperature. During the virus adsorption period agar overlay media was prepared. In a microwave oven 2X agarose (final concentration of 0.6% agarose) in overlay media (DMEM with 40 mM HEPES buffer) was melted and then placed in a 48°C water bath for temperature equilibration. After the virus adsorption period was completed 1.5 ml agar over media was added and mixed with the 1.5 ml virus and test compound containing media per well. Cultures were incubated at 35°C for the period required for plaque development, usually several days. Plaques were fixed with 3.7% formalin in PBS for 20 minutes followed by removal of the agar overlay and staining with 0.1% crystal violet in distilled water for 15 minutes. Plaques were counted and

-215- EC 50 concentration determined from multiple concentrations of the tested compound using regression analysis.

Viral Stocks: Stocks were prepared in MDCK confluent roller bottles incubated at 37°C in DMEM supplemented with 1 % FCS, 40mM HEPES buffer, and antibiotics. Bottles were inoculated with a multiplicity of infection of approximately 0.1 plaque forming unit for each cell. Roller bottles were harvested after the cytopathic effect of the virus was observed to be complete. Stocks were prepared from the supernatant resulting from the low speed centrifugation of the media and cell lysate. Stocks were titered and stored at -80°C.

The compounds of the invention can be tested for in vivo antiviral activity using the method described below.

In Vivo Antiviral Efficacy Method

Female BALB/c mice were placed under anesthesia (sevoflurane) and inoculated intranasally (IN) with 0.1 ml of influenza A VR-95 (Puerto Rico PR8- 34) at 10^"2 (diluted from frozen stock). This viral concentration consistently produced disease in mice within 5 days of inoculation. Animals were treated 4h. pre-infection and 4h. post-infection, and periodically thereafter, with one of the following therapies: no treatment; test compound (100, 25, 6.25, 1.39 mg/kg/day BID, PO); or vehicle (sterile water BID, PO). A group of ten animals (designated as control) was inoculated with 0.9% saline. Percent survival was determined. On day five, lungs were harvested, weighed and assigned scores of 0,1 , 2, 3 or 4 based on percentage consolidation (0; 10-20; 25-50; 50-75; 75-100%, respectively). In addition, each lung pair was image analyzed to determine objective lung consolidation percentages.

The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate,

-216- benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, 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, basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, lithium, calcium or magnesium or with ammonium or N(R^**)₄ ⁺ salts (where R^** is loweralkyi).

In addition, salts of the compounds of this invention with one of the naturally occurring amino acids are also contemplated.

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

The compounds of the Formula I, II, III, IV, V, VI, VII, VIII or IX of this invention can have a substituent which is an acid group (for example, -C0₂H,

-217- -SO₃H, -S0₂H, -PO₃H₂, -P0 H). Compounds of the Formula I, II, III, IV, V, VI, VII, VIII or IX of this invention having a substituent which is an ester of such an acidic group are also encompassed by this invention. Such esters may serve as prodrugs. The prodrugs of this invention are metabolized in vivo to provide the above-mentioned acidic substituent of the parental compound of Formula I, II, III, IV, V, VI, VII, VIII or IX. Prodrugs may also serve to increase the solubility of these substances and/or absorption from the gastrointestinal tract. These prodrugs may also serve to increase solubility for intravenous administration of the compounds. Prodrugs may also serve to increase the hydrophobicity of the compounds. Prodrugs may also serve to increase the oral bioavailability of the compounds by increasing absorption and/or decreasing first-pass metabolism. Prodrugs may also serve to increase tissue penetration of the compounds, thereby leading to increased activity in infected tissues and/or reduced rate of clearance.

Such esters contemplated by this invention include:

alkyl esters, especially loweralkyi esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;

alkoxyalkyl esters, especially, loweralkoxyloweralkyl esters, including, but not limited to, methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl, isopropoxymethyl, t-butoxymethyl esters and the like;

alkoxyalkoxyalkyl esters, especially, alkoxyalkoxy-substituted loweralkyi esters, including, but not limited to, 2-methoxyethoxymethyl esters and the like;

aryloxyalkyl esters, especially, aryloxy-substituted loweralkyi esters, including, but not limited to, phenoxymethyi esters and the like, wherein the aryl group is unsubstituted or substituted as previously defined herein;

-218- haloalkoxyalkyl esters, especially, haloalkoxy-substituted loweralkyi esters, including, but not limited to, 2,2,2-trichloroethoxymethyl esters and the like;

alkoxycarbonylalkyl esters, especially, loweralkoxycarbonyl-substituted loweralkyi esters, including, but not limited to, methoxycarbonylmethyl esters and the like;

cyanoalkyl esters, especially, cyano-substituted loweralkyi esters, including, but not limited to, cyanomethyl, 2-cyanoethyl esters and the like;

thioalkoxymethyl esters, especially, Iowerthioalkoxy-substituted methyl esters, including, but not limited to, methylthiomethyl, ethylthiomethyl esters and the like;

alkylsulfonylalkyl esters, especially, loweralkylsulfonyl-substituted loweralkyi esters, including, but not limited to, 2-methanesulfonylethyl esters and the like;

arylsulfonylalkyl esters, especially, arylsulfonyl-substituted loweralkyi esters, including, but not limited to, 2-benzenesulfonylethyl and 2- toluenesulfonylethyl esters and the like;

acyloxyalkyl esters, especially, loweralkylacyloxy-substituted loweralkyi esters, including, but not limited to, formyloxymethyl, acetoxymethyl, pivaloyloxy methyl, acetoxyethyl, pivaloyloxyethyl esters and the like;

cycloalkylcarbonyloxyalkyl esters including, but not limited to, cyclopentanecarbonyloxymethyl, cyclohexanecarbonyloxymethyl, cyclopentanecarbonyloxyethyl, cyclohexanecarbonyloxyethyl esters and the like;

arylcarbonyloxyalkyl esters including, but not limited to, benzoyloxymethyl esters and the like;

-219- (alkoxycarbonyloxy)alkyl esters, especially, (loweralkoxycarbonyloxy)- substituted loweralkyi esters, including, but not limited to, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 1- (methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)ethyl esters and the like;

(cycloalkyloxycarbonyloxy)alkyl esters, especially, (cycloalkyloxycarbonyloxy)-substituted loweralkyi esters, including, but not limited to, cyclohexyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxyethyl, cyclohexyloxycarbonyloxypropyl esters and the like;

oxodioxolenylmethyl esters including, but not limited to, (5-phenyl-2-oxo- 1 ,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl, [5- (4-methoxyphenyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1 ,3- dioxolen-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl, (2-oxo- 1 ,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1 ,3-dioxolen-4-yl)methyl, (5-ethyl-2- oxo-1 ,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1 ,3-dioxolen-4-yl)methyl, (5- isopropy l-2-oxo-1 ,3-dioxolen-4-yl)methyl, (5-butyl-2-oxo-1 ,3-dioxolen-4-yl)methyl esters and the like;

phthalidyl esters wherein the phenyl ring of the phthalidyl group is unsubstituted or substituted as defined previously herein, including, but not limited to, phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl esters and the like;

aryl esters including, but not limited to, phenyl, naphthyl, indanyl esters and the like;

arylalkyl esters, especially, aryl-substitued loweralkyi esters, including, but not limited to, benzyl, phenethyl, 3-phenyipropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;

-220- dialkylaminoalkyl esters, especially dialkylamino-substituted loweralkyi esters, including, but not limited to, 2-(N,N-dimethylamino)ethyl, 2-(N,N- diethylamino)ethyl ester and the like

(heterocyclic)alkyl esters, especially, heterocyclic-substituted loweralkyi esters wherein the heterocycle is a nitrogen-containing heterocycle, including, but not limited to, (heterocyclic)methyl esters and the like, wherein the heterocyclic part of the (heterocyclic)alkyl group is unsubstituted or substituted as previously defined herein; and

carboxyalkyl esters, especially, carboxy-substituted loweralkyi esters, including, but not limited to carboxymethyl esters and the like;

and the like.

Preferred prodrug esters of acid-containing compounds of the Formula I, II, III, IV, V, VI, VII, VIII or IX are loweralkyi esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and benzyl esters wherein the phenyl ring is unsubstituted or substituted as previously defined herein.

Methods for the preparation of prodrug esters of compounds of the Formula I, II, III, IV, V, VI, VII, VIII or IX are well-known in the art and include:

reacting the acid with the corresponding halide (for example, chloride or acyl chloride) and a base (for example, triethylamine, DBU, N,N- dimethylaminopyridine and the like) in an inert solvent (for example, DMF, acetonitrile, N-methylpyrrolidone and the like);

reacting an activated derivative of the acid (for example, an acid chloride, sulfonyl chloride, monochlorophosphonate and the like) with the corresponding alcohol or alkoxide salt; and the like.

-221- Other examples of prodrugs of the present invention include esters of hydroxyi-substituted compounds of Formula I, II, 111, IV, V, VI, VII, VIII or IX which have been acylated with a blocked or unblocked amino acid residue, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R¹⁰⁰C(O)- or R¹⁰⁰C(S)- wherein R¹⁰⁰ is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula Ra-C(R )(R^d)-C(0)- or Ra-C(Rb)(Rd)-C(S)- wherein R^b and R^d are independently selected from hydrogen or lower alkyl and R^a is -N(R^e)(R^f), -OR^e or -SR^e wherein R^e and R^f are independently selected from hydrogen, lower alkyl and haloalkyl, or an amino-acyl residue having the formula R¹⁰¹NH(CH₂)₂NHCH₂C(O)- or R¹⁰¹NH(CH₂)₂OCH₂C(O)- wherein R¹⁰¹ is hydrogen, lower alkyi, (aryl)alkyl, (cycloalkyl)alkyl, acyl, benzoyl or an α-amino acyl group. The amino acid esters of particular interest are of glycine and lysine; however, other amino acid residues can also be used, including any of the naturally occuring amino acids and also including those wherein the amino acyl group is -C(O)CH2NR¹⁰²R¹⁰³ wherein R¹⁰² and R¹⁰³ are independently selected from hydrogen and lower alkyl, or the group -NR¹⁰² R¹⁰³, where R¹⁰² and R¹⁰³, taken together, forms a nitrogen containing heterocyclic ring.

Other prodrugs include a hydroxyi-substituted compound of Formula I, II, 111, IV, V, VI, VII, VIII or IX wherein the hydroxyl group is functionalized with a substituent of the formula -CH(R¹⁰⁴)OC(O)R¹⁰⁵ or -CH(R¹⁰⁴)OC(S)R¹⁰⁵ wherein R¹⁰⁵ is lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R¹⁰⁴ is hydrogen, lower alkyi, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl. Such prodrugs can be prepared according to the procedure of Schreiber {Tetrahedron Lett. 1983, 24, 2363) by ozonolysis of the corresponding methallyl ether in methanol followed by treatment with acetic anhydride.

-222- The preparation of esters of hydroxyi-substituted compounds of formula Formula I, II, III, IV, V, VI, VII, VIII or IX is carried out by reacting a hydroxyi-substituted compound of formula Formula I, II, III, IV, V, VI, VII, VIII or IX, with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative.

Prodrugs of hydroxyl-substituted-compounds of the invention can also be prepared by alkylation of the hydroxyl substituted compound of formula Formula I, II, III, IV, V, VI, VII, VIII or IX, with (halo)alkyl esters, transacetalization with bis-(alkanoyl)acetals or condensation of the hydroxyl group with an activated aldehyde followed by acyiation of the intermediate hemiacetal.

In preparing prodrugs it often is necessary to protect other reactive functional groups, in order to prevent unwanted side reactions. After protection of the reactive groups the desired group can be functionalized. The resulting functionalized product is then deprotected, to remove the protecting groups that were added to prevent unwanted side reactions. This will provide the desired prodrug. Suitable reaction conditions for preparing protecting groups are well known in the art. One source for reaction conditions is found in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991).

This invention also encompasses compounds of the 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 can be an ester of a carboxylic acid and also an acid addition salt of an amine or nitrogen-containing substituent 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

-223- mammals and fowl) for treating or preventing diseases caused by microorganisms which comprise a neuraminidase

The compounds of the present invention are useful for inhibiting influenza A virus neuraminidase and influenza B virus neuraminidase, in vitro or in vivo (especially in mammals and, in particular, in 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 A viruses and influenza B viruses 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 in vivo, especially the human diseases caused by influenza A and influenza B viruses. The compounds of the present invention are also useful for the prophylaxis of infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo in humans and other mammals, especially the prophylaxis of influenza A and influenza B viral infections; and, in particular, the prophylaxis of influenza A and influenza B viral infections in human subjects who are at high risk of developing other respiratory diseases concurrent with or as a consequence of influenza virus infections, or who suffer from chronic respiratory illness, such as asthma, emphysema, or cystic fibrosis.

Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 10 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

-224- It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.

Administration of a compound of this invention will begin before or at the time of infection or after the appearance of established symptoms and/or the confirmation of infection.

The compounds of the present invention may be administered orally, parenterally, sublingually, intranasally, by intrapulmonary administration, by inhalation or insufflation as a solution, suspension or dry powder (for example, in a spray), or rectally, in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

-225- Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonir tating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore 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 may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally 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. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming 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 by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.

-226- Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more anti-infective agents and/or other agents used to treat other acute or chronic respiratory ailments. Other agents to 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 influenza neuraminidase inhibitor, such as, for example, zanamivir or GS 4104 and the like; agents used to treat respiratory bacterial infections and bronchitis, such as, for example, erythromycin, clarithromycin, azithromycin and the like; and agents used to treat asthma, such as, for example, zileuton, albuterol (salbutamol), salmeterol, formoterol, ipratropium bromide, inhaled steroids and the like, or anti-inflammatory agents for treating asthma such as, for example, beclomethasone dipropionate, fluticasone propionate, budesonide, t amcinolone acetonide, flunisolide, cromolyn, zafirlukast, montelukast 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 different times, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

-227-

Claims

What is claimed is:

1. A compound of the formula:

I

or

-228- III

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R is selected from the group consisting of

(b) -C0₂H, (b) -CH₂C0₂H, (c) -S0₃H, (d) -CH₂S0₃H, (e) -S0₂H,

(g) -CH₂S0₂H, (g) -P0₃H₂, (h) -CH₂P0₃H₂, (i) -P0₂H, G) -CH₂P0₂H,

(I) tetrazolyl, (I) -CH₂-tetrazolyl, (m) -C(=0)-NH-S(0)₂-R¹¹,

(o) -CH₂C(=0)-NH-S(0)₂-R¹¹, (o) -S0₂N(T-R¹¹)R¹² and

(p) -CH₂S0₂N(T-R ¹)R¹² wherein T is selected from the group consisting of

(i) a bond, (ii) -C(=0)-, (iii) -C(=0)0-, (iv) -C(=0)S-, (v) -C(=0)NR³⁶-,

(vi) -C(=S)0-, (vii) -C(=S)S-, and (viii) -C(=S)NR³⁶-,

R¹¹ is selected from the group consisting of

(i) C Cι₂ alkyl, (ii) C₂-C₁₂ alkenyl, (iii) cycloalkyl, (iv) (cyclo- alkyl)alkyl,

(w) (cycloalkyl)alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl)alkyl,

(ix) (cycloalkenyl)alkenyl, (ix) aryl, (x) (aryl)alkyl, (xi) (aryl)alkenyl,

(xviii) heterocyclic, (xiii) (heterocyclic)alkyl and

(xix) (xiv) (heterocyclic)alkenyi; and

R¹² and R³⁶ are independently selected from the group consisting of

(i) hydrogen, (ii) C Cι₂ alkyl, (iii) C₂-C₁₂ alkenyl, (iv) cycloalkyl,

(v) (cycloalkyl)alkyl, (vi) (cycloalkyl)alkenyl, (vii) cycloalkenyl,

(viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl,

(xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic,

(xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkenyl;

X is selected from the group consisting of

-229- (a) -C(=0)-N(R^*)-, (b) -N(R^*)-C(=0)-, (c) -C(=S)-N(R^*)-, (d) -N(R^*)-C(=S)-,

(e) -N(R^*)-S0₂-, and (f) -S0₂-N(R^*)- wherein R^* is hydrogen, d-C₃ loweralkyi or cyclopropyl;

R² is selected from the group consisting of

(a) hydrogen, (b) C C₅ alkyl, (c) C₂-C₆ alkenyl, (d) C₃-C₆ cycloalkyl,

(e) C₅-C₆ cycloalkenyl, (f) halo C C₆ alkyl and (g) halo C₂-C₆ alkenyl; or R²-X- is ^y

Y² < wherein Y is -CH₂-, -0-, -S- or -NH- and Y² is -C(=0)- or -C(R^aa)(R^bb)- wherein R^aa and R^bb are indepedently selected from the group consisting of hydrogen,

C₁-C₃ loweralkyi, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;

Z¹ is -0-, -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-R¹⁴ wherein Z is

(ii) -C(R ^a)(R^37b)-, (ii) -C(R ⁷)=C(R⁴⁸)-, (iii) -C≡C-, (iv) -C(=0)-

-230- (v) -C(=S)-, (vi) -C(=NR¹⁵)-, (vii) -C(R^37a)(OR^37c)-, (viii) - C(R^37a)(SR^37c)-,

(ix) -C(R^37a)(N(R^37b)(R^37c))-, (x) -C(R ^7a)(R^37b)-0-,

(xi) -C(R^37a)(R³⁷ )-N(R^37c)-, (xii) -C(R^37a)(R³⁷ )-N(0)(R^37c)-,

(xiii) -C(R^37a)(R^37b)-N(OH)-, (xiv) -C(R^37a)(R^37b)-S-,

(xv) -C(R^37a)(R^37b)-S(0)-, (xvi) -C(R^37a)(R^37b)-S(0)₂-,

(xviii) -C(R^37a)(R^37b)-C(=0)-, (xviii) -C(R^37a)(R^37b)-C(=S)-,

(xxi) -C(R^37a)(R^37b)-C(=NR¹⁵)-, (xx) -C(R^37a)(OR^37c)-C(=0)-,

(xxi) -C(R^37a)(SR^37c)-C(=0)-, (xxii) -C(R^37a)(OR^37c)-C(=S)-,

(xxiii) -C(R^37a)(SR^37c)-C(=S)-, (xxiv) -C(=0)-C(R^37a)(OR^37c)-,

(xxv) -C(=0)-C(R^37a)(SR^37c)-, (xxvi) -C(=S)-C(R^37a)(OR^37c)-,

(xxvii) -C(=S)-C(R^37a)(SR^37c)-, (xxviii) -C(R^37a)(OR^37c)-C(R^37a)(OR^37c)-

(xxix) -C(R^37a)(SR^37c)-C(R^37a)(OR^37c)-,

(xxx) -C(R^37a)(OR^37c)-C(R^37a)(SR^37c)-,

(xxxi) -C(R^37a)(SR^37c)-C(R^37a)(SR^37c)-, (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(R^37a)-,

(xxxix) -C(=S)-N(R^37a)-, (xl) -C(R^37a)(R³⁷ )-C(=0)-N(R^37a)-,

(xii) -C(R^37a)(R^37b)-C(=S)-N(R^37a)-, (xiii) -C(R^37a)(R^37b)-C(=0)-0-,

(xiiii) -C(R^37a)(R^37b)-C(=0)-S-, (xliv) -C(R^37a)(R^37b)-C(=S)-0-,

(xiv) -C(R^37a)(R^37b)-C(=S)-S-, (xlvi) -C(R^37a)(R^37b)-N(R^37b)-C(=0)-,

-231- xlvii) -C(R^37a)(R^37b)-N(R^37b)-C(=S)-, (xlviii) -C(R^37a)(R^37b)-0-C(=0)-,

xlix) -C(R^37a)(R³⁷ )-S-C(=0)-, (I) -C(R^37a)(R^37b)-0-C(=S)-,

Ii) -C(R^37a)(R^37b)-S-C(=S)-, (Iii) -C(R^37a)(R^37b)-N(R^37b)-C(=0)-N(R^37a)-,

liii) -C(R^37a)(R^37b)-N(R^37b)-C(=S)-N(R^37a)-,

liv) -C(R^37a)(R^37b)-N(R^37b)-C(=0)-0-,

lv) -C(R^37a)(R^37b)-N(R^37b)-C(=0)-S-,

lvi) -C(R^37a)(R³⁷ )-N(R^37b)-C(=S)-0-,

lvii) -C(R^37a)(R^37b)-N(R^37b)-C(=S)-S-,

lviii) -C(R^37a)(R^37b)-0-C(=0)-N(R^37a)-,

lix) -C(R^37a)(R^37b)-S-C(=0)-N(R^37a)-,

lx) -C(R^37a)(R^37b)-0-C(=S)-N(R^37a)-,

Ixi) -C(R^37a)(R³⁷ )-S-C(=S)-N(R^37a)-, (Ixii) -C(R^37a)(R^37b)-0-C(=0)-0-,

Ixiii) -C(R^37a)(R^37b)-S-C(=0)-0-, (Ixiv) -C(R^37a)(R^37b)-0-C(=0)-S-,

Ixv) -C(R^37a)(R^37b)-S-C(=0)-S-, (Ixvi) -C(R^37a)(R^37b)-0-C(=S)-0-,

Ixvii) -C(R^37a)(R^37b)-S-C(=S)-0-, (Ixviii) -C(R^37a)(R^37b)-0-C(=S)-S-,

Ixix) -C(R^37a)(R^37b)-S-C(=S)-S- or (Ixx) -C(R^37a)(R^37b)-C(R^37a)(OR^37c)-;

is

(i) hydrogen, (ii) C Cι₂ alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,

(v) thiol-substituted alkyl, (vi) R^37cO-substituted alkyl,

(vii) R^37cS-substituted alkyl, (viii) aminoalkyl,

(ix) (R^37c)NH-substituted alkyl, (x) (R^37a)(R^37c)N-susbstituted alkyl,

-232- (xi) R^37aO-(0=)C-substituted alkyl, (xii) R^37aS-(0=)C-substituted alkyl, (xiii) R^37aO-(S=)C-substituted alkyl,

(xx) R^37aS-(S=)C-substituted alkyl,

(xxi) (R^37aO)₂-P(=0)-substituted alkyl, (xvi) cyanoalkyl,

(xxii) C₂-C ₂ alkenyl, (xviii) haloalkenyl, (xix) C₂-Cι₂ alkynyl,

(xxii) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl,

(xxiv) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl,

(xxv) (cycloalkenyl)alkyl,

(xxvii) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)alkynyl, (xxviii) aryl,

(xxx) (aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl,

(xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl,

(xxxiv) (heterocyclic)alkenyl or (xxxv) (heterocyclic)alkynyl,

with the proviso that R¹⁴ is other than hydrogen when Z is

-C(R^37a)(R^37b)-N(R^37b)-C(=0)-0-, -C(R^37a)(R^37b)-N(R^37b)-C(=S)-0-,

-C(R^37a)(R^37b)-N(R^37b)-C(=0)-S-, -C(R^37a)(R^37b)-N(R^37b)-C(=S)-S-,

-C(R^37a)(R^37b)-0-C(=0)-0-, -C(R^37a)(R^37b)-0-C(=S)-0-,

-C(R^37a)(R^37b)-S-C(=0)-0-, -C(R^37a)(R^37b)-S-C(=S)-0-,

-C(R^37a)(R^37b)-0-C(=0)-S-, -C(R^37a)(R^37b)-0-C(=S)-S-,

-C(R^37a)(R^37b)-S-C(=0)-S- or -C(R^37a)(R^37b)-S-C(=S)-S-;

-233- R^37a, R^37b, R⁴⁷, and R⁴⁸ at each occurrence are independently selected from the group consisting of

(i) hydrogen, (ii) Cι-C₁₂ alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) alkoxyalkyl, (vi) C₂-Cι₂ alkenyl, (vii) haloalkenyl, (viii) C₂-C-ι₂ alkynyl, (ix) cycloalkyl,

(x) (cycloalkyl)alkyl, (xi) (cycloalkyl)alkenyl, (xii) (cycloalkyl)alkynyl,

(xiii) cycloalkenyl, (xiv) (cycloalkenyl)alkyl, (xv) (cycloalkenyl)- alkenyl,

(xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl,

(xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic,

(xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and

(xxiv) (heterocyclic)alkynyl;

R^37c at each occurrence is independently selected from the group consisting of

(i) hydrogen, (ii) Cι-Cι₂ alkyl, (iii) haloalkyl, (iv) C₂-Cι₂ alkenyl,

(v) haloalkenyl, (vi) C₂-C-ι₂ alkynyl, (vii) cycloalkyl,

(viii) (cydoalkyl)alkyl, (ix) (cycloalkyl)alkenyl, (x) (cycloalkyl)alkynyl,

(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) (heterocyclic)alkyl, (xxi) (heterocyclic)alkenyl,

-234- (xxiii) (heterocyclic)alkynyl, (xxiii) -C(=0)-R¹⁴, (xxiv) -C(=S)-R¹⁴,

(xxv) -S(0)₂-R¹⁴ and (xxvi) hydroxyalkyl;

or when Z is -C(R^37a)(R^37b)-N(R^37c)-, then N(R^37c) and R¹⁴ when taken together are an azido group;

or when Z is -C(R^37a)(R^37b)-N(0)(R^37c)-, then N(0)(R^37c) and R¹⁴ when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;

or when Z is -C(R^37a)(OR^37c)-, -C(R^37a)(SR^37c)- or

-C(R^37a)(N(R^37b)(R^37c))-, then R^37a, R¹⁴ and the carbon atom to which they are bonded 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) C Cι₂ alkyl, (v) haloalkyl,

(vi) C₂-C₁₂ alkenyl, (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, (xvii) heterocyclic,

(xviii) (heterocyclic)alkyl and (xix) (heterocyclic)alkenyl;

or R° and R taken together, with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 8 ring atoms;

-235- R⁵ at each occurrence is independently selected from the group consisting of

(a) hydrogen, (b) -CH(R³⁸)₂, (c) -(CH₂)_rO-R⁴⁰, (d) C₂-C₄ alkynyl, (e) cyclopropyl,

(f) cyclobutyi, (g) -C(=Q¹)-R¹⁷, and (h) -(CH₂)_rN(R¹⁹)₂

wherein r is 0, 1 or 2, with the proviso that when one R⁵ is -O-R⁴⁰ or -N(R ⁹)₂, then the other R⁵ is other than -O-R⁴⁰ or -N(R¹⁹)₂, wherein Q¹ is O S, or N(R¹⁸),

R¹⁷ and R¹⁸ are independently selected, at 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) C-₁-C₁₂ alkyl, (in) haloalkyl, (iv) C₂-Cι₂ alkenyl,

(v) haloalkenyl, (vi) cycloalkyl, (vii) (cycloalkyl)alkyl,

(VIII) (cycloalkyl)alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl)alkyl

(xi) (cycloalkenyl)alkenyl, (xn) aryl, (XIII) (aryl)alkyl, (xiv) (aryl)alkenyl,

(xv) heterocyclic, (xvi) (heterocyclιc)alkyl and

(XXIII) (heterocyclιc)alkenyl,

or one R₁ is an N-protecting group,

or the two R⁵ groups taken together with the carbon atom to which they are bonded form a carbocyclic or heterocyclic ring having from 3 to 6 ring atoms

Y is selected from the group consisting of

-236- (a) C₁-C₅ alkyl, (b) C C₅ haloalkyl, (c) C₂-C₅ alkenyl, (d) C₂-C₅ haloalkenyl, (e) C₂-C₅ alkynyl, (f) C₃-C₅ cycloalkyl, (g) C₃-C₅ cycloalkyl-d-to-C-3-alkyl, (h) C₅ cycloalkenyl, (i) C₅ cycloalkenyl-C to-C₃-alkyl, (j) C₅ cycloalkenyl-C₂-to-C₃- alkenyl, (k) -(CHR³⁹)_nOR²⁰, (I) -CH(OR²⁰)-CH₂(OR²⁰), (m) -(CHR³⁹)_nSR²¹, (n) phenyl, (o) halo-substituted phenyl, (p) -(CHR³⁹)_nC(=Q²)R²², (q)

-(CHR³⁹)_nN(=Q³), (r) -N(0)=CHCH₃, (s) -(CHR³⁹)_nN(CH₃)R²⁴ 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 at each occurrence is independently

(i) methyl, (ii) ethyl, (iii) n-propyl, (iv) isopropyl,

(v) C₁-C₃ haloalkyl, (vi) vinyl, (vii) propenyl, (viii) isopropenyl,

(ix) allyl, (x) C₂-C₃ haloalkenyl, (xi) amino, (xii) -NHCH₃, (xiii) -N(CH₃)₂,

(xiv) -NHCH₂CH₃, (xv) -N(CH3)(CH₂CH₃), (xvi) -N(CH₂CH₃)₂ or

(xvii) -N(=CH₂);

R²¹ is

(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,

(vi) C₁-C₃ haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) allyl or (xi) C₂-C₃ haloalkenyl;

R²² is

(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,

(vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy,

(xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio,

(xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii) vinyl, (xix) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii) -N(R^28a)(R^28b),

-237- (xxiii) -CH₂R²⁹, (xxiv) aminomethyl, (xxv) hydroxymethyl, (xxvi) thiolmethyl, (xxvii) -NHNH₂, (xxviii) -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, (ii) d-d alkyl, (iii) C₂-C₄ alkenyl, (iv) C₂-C₄ alkynyl,

(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 group is hydrogen, methyl or ethyl ;

R^28a hydrogen, hydroxy, methyl, ethyl, amino, -NHCH₃, -N(CH₃)₂, methoxy, ethoxy, or -CN;

R^28b is hydrogen, methyl or ethyl;

or R^28a, R^28b and the nitrogen to which they are bonded taken together represent azetidinyl;

R²⁹ group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;

R³⁰ group is hydrogen, methyl, ethyl, -OR³⁴, -SR³⁴, -N(R³⁵)₂, -NHOH, -NHNH₂, -N(CH₃)NH₂, or -N(CH₂CH₃)NH₂;

R³¹ and R³² substituents, at each occurrence, are independently hydrogen, methyl or ethyl;

R³³ group is hydrogen, hydroxy, methyl, ethyl, amino. -CN, or -N0₂;

-238- R³⁴ group is methyl or ethyl;

R³⁵ group is independently hydrogen, methyl or ethyl;

with the proviso that when Q² is CHR²⁶ then R²² is selected from the group consisting of hydrogen, -CH₃, -C₂H₅, -C₃H₇, -OCH₃, -SCH₃, -0-C₂H₅, and -S-C₂H₅;

R⁶ and R⁷ are independently selected from the group consisting of

(b) hydrogen, (b) C1-C12 alkyl, (c) C₂-C₁₂ alkenyl, (d) cycloalkyl,

(e) (cycloalkyl)alkyl, (f) (cycloalkyl)alkenyl, (g) cycloalkenyl, (h) (cycloalkenyl)alkyl,

G) (cycloalkenyl)alkenyl, G) aryl, (k) (aryl)alkyl, (I) (aryl)alkenyl, (m) heterocyclic, (n) (heterocyclic)alkyl, (0) (heterocyclic)alkenyl, (p) -OR^37a and (q) -N(R^37a)₂; and

R⁸, R⁹, and R¹⁰ are independently selected from the group consisting of

(a) hydrogen, (b) C C₆ alkyl, (c) C₂-C₆ alkenyl, (d) C₃-C₆ cycloalkyl,

(e) C₃-C₆ cycloalkenyl, and (f) fluorine, with the proviso that the total number of atoms, 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:

-239-

II

wherein R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein.

3. The compound according to Claim 2 having the relative stereochemistry depicted by the formula:

R^fc

IV v,

-240- R^h

IX

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein and wherein R³ and R⁴ are not both the same.

4. The compound according to Claim 1 wherein R¹ is defined as therein;

-X-R² is R²-C(=0)-NH-, R²-NH-C(=0)-, R²-NH-S0₂- or R -S0₂-NH- wherein R² is C-₁-C₃ loweralkyi, halo d-d loweralkyi, C₂-C₃ alkenyl or halo C₂-C₃ alkenyl or -X-R² is

Λ

Y

N-:

wherein Y¹ is -CH₂-, -0-, -S- or -NH- and Y" is -C(=0)- or -C(R^aa)( R b^Db^D\)- wherein

R^aa and R are independently selected from the group consisting of hydrogen,

C1-C₃ loweralkyi, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-amiπoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;

R³ and R⁴ are independently selected from hydrogen, heterocyclic and

-241- -Z-R¹⁴ wherein Z and R¹⁴ are defined as above and wherein one of R³ and R⁴ is other than hydrogen;

Z¹ is -0-, -S- or -CH(R⁵)- wherein R⁵ is hydrogen, loweralkyi or - (CH₂)_rN(R¹⁹)₂ wherein r and R ₉ are defined as above; or R⁵ is hydrogen, loweralkyi or -(CH₂)_rN(R¹⁹)₂ wherein r and R₁₉ are defined as above;

R⁶ and R⁷ are independently hydrogen or loweralkyi;

R⁸ and R⁹ are independently hydrogen, fluoro or loweralkyi;

R¹⁰ is hydrogen, fluoro or loweralkyi; and

Y is C2-C5 alkenyl, C_2-C₅ haloalkenyl, -C(=Q²)R²², -N(=Q³), -N(0)=CHCH₃, -NR²³R²⁴ or a heterocyclic ring having from 3 to 6 ring atoms, wherein R²², R²³, R²⁴, Q² and Q³ are defined as therein.

5. The compound according to Claim 4 having the formula:

-242- wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein.

6. The compound according to Claim 4 having the relative stereochemistry depicted by the formula:

R⁹

R

-243- R R^fc

IX

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein and wherein R³ and R⁴ are not both the same.

7. The compound according to Claim 1 wherein R¹ is defined as therein;

-X-R² is R²-C(=0)-NH-, R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is C₁-C₃ loweralkyi, halo d-d loweralkyi, C₂-C₃ alkenyl or halo C₂-C₃ alkenyl or -X-R² is

O

\

N-S-

wherein Y¹ is -CH₂- and Y² is -C(=0)- or -C(R^aa)( R^bb)- wherein R^aa and R >b^Db^D are independently selected from the group consisting of hydrogen,

C1-C₃ loweralkyi, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;

R³ and R⁴ are independently selected from hydrogen, heterocyclic and

-Z-R¹⁴ wherein Z and R¹⁴ are defined as above and wherein one of R³ and R⁴ is other than hydrogen;

-244- Z is -0-, -S- or -CH(R⁵)- wherein R⁵ is hydrogen, loweralkyi or - (CH₂)_rN(R¹⁹)₂ wherein r and R¹⁹ are defined as above; or R⁵ is hydrogen, loweralkyi or -(CH₂)_rN(R¹⁹)₂ wherein r and R¹⁹ are defined as above;

R⁶ and R⁷ are independently hydrogen or loweralkyi;

R⁸ and R⁹ are independently hydrogen or loweralkyi;

R ⁰ is hydrogen or loweralkyi; and

Y is C₂-C₅ alkenyl, C_2-C₅ haloalkenyl, -C(=Q²)R²², -N(=Q³), -N(0)=CHCH₃ or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R²², Q² and Q³ are defined as above.

8. The compound according to Claim 7 having the formula:

or

-245-

II

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein.

9. The compound according to Claim 7 having the relative stereochemistry depicted by the formula:

IV v,

-246-

IX

wherein R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein and wherein R³ and R⁴ are not both the same.

11. The compound according to Claim 1 wherein R¹ is defined as above;

-X-R² is R²-C(=0)-NH-, R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is d-d loweralkyi, halo d-d loweralkyi, C₂-C₃ alkenyl or halo C1-C3 alkenyl or -X-R² is o

Λ.

\

N- y

wherein Y¹ is -CH₂- and Y² is -C(=0)- or -C(R^aa)( R^bb)- wherein R^aa and R^bb are independently selected from the group consisting of hydrogen,

C₁-C₃ loweralkyi, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;

R³ and R⁴ are independently selected from hydrogen, heterocyclic and

-Z-R¹⁴ wherein Z and R¹⁴ are defined as above and wherein one of R³ and R⁴ is other than hydrogen:

-247- Z¹ is -0-, -S- or -CH(R⁵)- wherein R⁵ is hydrogen, loweralkyi or - (CH₂)_rN(R¹⁹)₂ wherein r and R₁₉ are defined as above; or R⁵ is hydrogen, loweralkyi or -(CH₂)_rN(R¹⁹)₂ wherein r and R-ι₉ are defined as above;

R⁶ and R⁷ are independently hydrogen or loweralkyi;

R⁸ and R⁹ are independently hydrogen or loweralkyi;

R¹⁰ is hydrogen or loweralkyi; and

Y is C₂-C₅ alkenyl, C_2-C₅ haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

12. The compound according to Claim 11 having the formula:

or

-248- R⁹

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein.

13. The compound according to Claim 11 having the relative stereochemistry depicted by the formula:

-249- R*

IX

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R ⁰, X , Y and Z¹ are as defined therein and wherein R³ and R⁴ are not both the same.

14. The compound according to Claim 1 wherein R¹ is -CO2H;

-X-R² is R²-C(=0)-NH-, R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is C1-C₃ loweralkyi or halo- d-d loweralkyi;

R³ and R⁴ are independently selected from hydrogen, heterocyclic and

-Z-R¹⁴ wherein Z and R¹⁴ are defined as above and wherein one of R³ and R⁴ is other than hydrogen;

Z¹ is -0-, -S- or -CH₂-; or R⁵ is hydrogen;

R⁶ and R⁷ are independently hydrogen or loweralkyi;

R⁸ and R⁹ are hydrogen independently hydrogen or loweralkyi;

R¹⁰ is hydrogen or loweralkyi; and

Y is C₂-C₅ alkenyl, C_2-C₅ haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

14. The compound according to Claim 14 having the formula:

-250-

or

wherein R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein.

15. The compound according to Claim 14 having the relative stereochemistry depicted by the formula:

-251-

IV

VIII or IX

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein and wherein R³ and R^Λ are not both the same.

16. The compound according to Claim 1 wherein R¹ is -C0₂H;

-X-R² is R²-C(=0)-NH-, R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is C1-C₃ loweralkyi or halo- d-C₃ loweralkyi;

,14

R is hydrogen or loweralkyi and R is heterocyclic or -Z-R wherein Z and R , 14 are defined as above;

Z¹ is -0-, -S- or -CH₂-; or R⁵ is hydrogen;

-252- R^δ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen;

R > 10 is hydrogen; and

Y is C₂-C₅ alkenyl, C_2-C₅ haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

17. The compound according to Claim 16 having the formula:

or

wherein R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein.

18. The compound according to Claim 16 having the relative stereochemistry depicted by the formula:

-253- ⁹

IV

VIII or IX

wherein R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein and wherein R³ and R⁴ are not both the same.

19. The compound according to Claim 1 wherein R¹ is -C0₂H;

-X-R² is R²-C(=0)-NH-. R²-NH-C(=0)-, R²-NH-S0₂- or R²-S0₂-NH- wherein R² is C₁-C₃ loweralkyi or halo d- loweralkyi;

R⁴ is hydrogen or loweralkyi and R³ is (a) heterocyclic, (b) alkyl,

(c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) -C(=0)-R¹⁴,

(h) -C(R^37a)(OR^37c)-R¹⁴ or (i) -C(R^37a)(R^37b)-N(0)(R^37c)R¹⁴ wherein R¹⁴ is

-254- G) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,

(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,

(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R^37aO)-(0=)C-substituted alkyl or (xv) (R^37aO)₂-P(=0)-substituted alkyl;

R^37a and R^37b are independently selected from the group consisting of

(i) hydrogen, (ii) loweralkyi and (iii) loweralkenyl; and

R^37c is

hydrogen, (ii) loweralkyi or (iii) loweralkenyl;

Z¹ is -0-, -S- or -CH₂-; or R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen;

R¹⁰ is hydrogen; and

Y is C₂-C₅ alkenyl. C_2-C₅ haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

19. The compound according to Claim 19 having the formula:

or

-255- R^b

II

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein.

2 , The compound according to Claim 19 having the relative stereochemistry depicted by the formula:

-256-

VIII or IX

wherein R¹, R², R³, R⁴, R⁵, R⁵, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein and wherein R³ and R⁴ are not both the same.

22. The compound according to Claim 1 wherein R¹ is -C0₂H;

-X-R is R^z-C(=0)-NH-, R -NH-C(=0)-, R -NH-S0₂- or R^-S0₂-NH- wherein R 2 ; i,s d-d loweralkyi or halo C₁-C₃ loweralkyi;

R⁴ is hydrogen and R³ is (a) heterocyclic, (b) alkyl or (c) -C(R^37a)(OR^37c)- R¹⁴ wherein R¹⁴ is

(ii) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,

(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,

(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R^37aO)-(0=)C-substituted alkyl or (xv) (R^37aO)₂-P(=0)-substituted alkyl;

R^37a and R^37b are independently selected from the group consisting of

hydrogen, (ii) loweralkyi and (iii) loweralkenyl; and

R 37c is

hydrogen, (ii) d-C₃ loweralkyi or (iii) allyl;

-257- Z¹ is -0-, -S- or -CH₂-; or R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen ;

R¹⁰ is hydrogen; and

Y is C₂-C₅ alkenyl, C_2-C₅ haloalkenyl 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:

or

II

wherein R , R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein.

-258-

24. The compound according to Claim 22 having the relative stereochemistry depicted by the formula:

R⁹

VIII or IX

wherein R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein and wherein R³ and R⁴ are not both the same.

25. The compound according to Claim 1 wherein R¹ is -C0₂H;

-X-R is R -C(=0)-NH- or R -S0₂-NH- wherein R² is C C₃ loweralkyi or halo Ci C₃ loweralkyi;

R⁴ is hydrogen and R^J is (a) heterocyclic, (b) alkyl or (c) -C(R 3^J7'a^a\)(O^_DR3^J7c^cs)

R¹⁴ wherein R¹⁴ is

-259- (i) loweralkyi, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyi or

(iv) alkoxy-substituted loweralkyi;

R^37a is

(i) hydrogen, (ii) loweralkyi or (iii) loweralkenyl; and

R^37c is

(i) hydrogen, (ii) C1-C₃ loweralkyi or (iii) allyl;

Z¹ is -0-, -S- or -CH₂-; or R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen;

R ⁰ is hydrogen; and

Y is C₂-C₅ alkenyl, C_2-C₅ haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

26. The compound according to Claim 25 having the formula:

or

-260- R⁹

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein.

27. The compound according to Claim 25 having the relative stereochemistry depicted by the formula:

-261-

IX

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein and wherein R³ and R⁴ are not both the same.

28. The compound according to Claim 1 wherein R is -C0₂H;

-X-R² is R²-C(=0)-NH- or R²-S0₂-NH- wherein R² is d-C₃ loweralkyi or halo d- C₃ loweralkyi;

R⁴ is hydrogen and R³ is -C(R^37a)(0R^37c)-R¹⁴ wherein R¹⁴ is

loweralkyi or loweralkenyl;

R^37a is

loweralkyi or loweralkenyl; and

R^37c is

hydrogen, d-d loweralkyi or allyl;

Z¹ is -0-, -S- or -CH₂-; or R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen;

-262- R¹⁰ is hydrogen; and Y is C -C₅ alkenyl, C_2-C₅ haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.

29. The compound according to Claim 28 having the formula:

or

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein.

30. The compound according to Claim 28 having the relative stereochemistry depicted by the formula:

-263- R^fc R^c

IV

VIII or IX

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X , Y and Z¹ are as defined therein and wherein R³ and R⁴ are not both the same.

31. A pharmaceutical composition for inhibiting influenza neuraminidase comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.

32. A pharmaceutical composition for treating an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.

-264-

33. A pharmaceutical composition for preventing an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.

34. A method for inhibiting neuraminidase from a disease-causing microorganism comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.

35. The method of Claim 34 wherein the disease-causing microorganism is a virus.

36. The method of Claim 35 wherein the virus is influenza virus.

37. A method for treating a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.

38. The method of Claim 37 wherein the disease-causing microorganism is a virus.

39. The method of Claim 38 wherein the virus is influenza virus.

40. A method for preventing a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.

41. The method of Claim 40 wherein the disease-causing microorganism is a virus.

42. The method of Claim 41 wherein the virus is influenza virus.

-265-