WO2001029050A2

WO2001029050A2 - Condensed pyrrole derivatives as neuraminidase inhibitors

Info

Publication number: WO2001029050A2
Application number: PCT/US2000/026071
Authority: WO
Inventors: Clarence J. Maring; David A. Degoey; William J. Flosi; Vincent L. Giranda; Dale J. Kempf; April Kennedy; Larry L. Klein; Allan C. Krueger; Keith F. Mcdaniel; Vincent S. Stoll; Minghua Sun; Chen Zhao
Original assignee: Abbott Laboratories
Priority date: 1999-10-19
Filing date: 2000-09-22
Publication date: 2001-04-26
Also published as: AU7831200A; WO2001029050A3

Abstract

The instant invention provides compounds of formula (I) or a pharmaceutically acceptable salt, prodrug, or ester thereof, useful in the inhibition of neuraminidase enzymes from disease-causing microorganisms, especially influenza neuraminidase, pharmaceutical formulations containing same, processes and intermediates for preparing said compounds, as well as methods of using said compounds, including preventing and treating diseases caused by microorganisms having said neuraminidase enzyme.

Description

NEURAMINIDASE INHIBITORS

Technical Field The present invention relates to novel compounds, compositions, and methods for inhibiting neuraminidase, especially influenza neuraminidase. The invention also contemplates compositions 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 (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.

Very recently the first influenza neuraminidase inhibitor, zanamivir, was approved. However, it can only be administered by inhalation. Therefore, there is a continuing need for improved agents for treatment and/or prevention of influenza infection. 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 prevention of influenza infection and will be useful for the treatment of influenza infection.

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. O98/06712, published February 19, 1998 (sialidase inhibitor; influenza remedy) ;

L. Von Itzstein, et al . , International Patent Application No. O95/20583, 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) ;

. 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. 097/32214, published September 4, 1997 (bind to influenza virus neuraminidase active site) ; and

P. Reece, et al . , International Patent Application No. 098/21243, 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. O98/11083, 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. O96/30329, 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) ;

C. Kim, et al., International Patent Application No. WO99/31047, published June 24, 1999 (neuraminidase inhibitor; influenza treatment) ;

V. Atigadda, et al . , J. Med. Chem. 42 2332-2343 (1999) (influenza 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. 098/17647, published April 30, 1998 discloses piperidine derivatives that are useful as neuraminidase inhibitors. N. Bischofberger, et al . , International Patent Application No. 096/26933, published September 6, 1996 and N. Bischofberger, et al . , International Patent Application No. 099/14185, published March 25, 1999 disclose various substituted 6-membered ring compounds that are useful as neuraminidase inhibitors.

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

D. Andrews, et al . , International Patent Application No. O97/06157, published February 20, 1997 and U.S. Patent No. 5,919,819, issued July 6, 1999; and

P. Cherry, et al . , International Patent Application No. 096/36628, 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 that are useful as neuraminidase inhibitors .

G. Diana, et al . , International Patent Application No. O98/03487, published January 29, 1998 discloses substituted pyridazines that are useful for treatment of influenza.

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

The following references disclose substituted cyclopentanes that are useful as neuraminidase inhibitors and treatments for influenza:

Y. Babu, et al., International Patent Application No. 097/47194, published December 18, 1997; and

Y. Babu, et al . , International Patent Application No. 099/33781, published July 8, 1999.

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

W. Brouillette, et al . , International Patent Application No. 099/14191, published March 25, 1999, discloses substituted pyrrolidin-2-one compounds that are useful as neuraminidase inhibitors and treatments for influenza.

The following references disclose siastatin B analogs that 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.

Thus, it would be an important contribution to the art to provide compounds which are neuraminidase inhibitors.

Summary of the Invention

The present invention provides compounds of formula I

or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein

W is selected from the group consisting of

-OC(O)-, -O(CHR')-, -(CH₂)_n-, -(CH₂)_nC(0) -, - (CH₂) _nC (S) - ,

-C(O)-, -C(S)-, -CHR'C(O)-, -CHR'C(S)-, -OC(S)-, -NHC(O)-,

-NHC(S)-, -NR'C(O)-, -NR'C(S)-, -0(CH₂)_n-,

-0(CR'R")-, -CHR' (CH₂)_n-, -CR'R" (CH₂) _n- , -CHCH-, -S(CH₂)_n-,

-S(CHR')-, and -S(CR'R")-, wherein n is 1-3; and R' and R" are independently selected from the group consisting of

(i) hydrogen, (ii) Cι-C₁₂ 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-substituted alkyl,

(xi) R^37aO- (0=)C-substituted alkyl,

(xii) R^37aS- (0=)C-substituted alkyl,

(xiii) R^{3 a}O- (S=)C-substituted alkyl,

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

(xv) (R^37aO)₂-P(=0) -substituted alkyl,

(xvi) cyanoalkyl,

(xvii) C₂-Ci₂ alkenyl,

(xviii) haloalkenyl, (xix) C₂-Cι₂ alkynyl,

(xx) cycloalkyl, (xxi) (cycloalkyl) alkyl,

(xxii) (cycloalkyl) alkenyl,

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

(xxv) (cycloalkenyl) alkyl, (xxvi) (cycloalkenyl) alkenyl,

(xxvii) (cycloalkenyl) alkynyl,

(xxviii) aryl, (xxxix) (aryl) alkyl, (xxx) (aryl) alkenyl,

and

(xxxi) (aryl) alkynyl;

selected from the group consisting of

(a) -C0₂H, (b) -CH₂C0₂H, (c) -S0₃H, (d) -CH₂S0₃H, (e) -S0₂H, (f) -CH₂S0₂H, (g) -P0₃H₂, (h) -CH₂P0₃H₂, (i) -P0₂H,

(j)^' -CH₂P0₂H, (k) tetrazolyl, (1) -CH₂-tetrazolyl, (m) -C (=0) -NH-S (O) ₂-R¹¹,

(n) -CH₂C(=0) -NH-S (0) ₂-R¹¹, (o) -S0₂N(T-R¹¹)R¹² and (p) -CH₂S0₂N(T-R¹¹)R¹²;

wherein

T is selected from the group consisting of

(i) a bond, (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 ) C₁-C₁₂ alkyl , ( ii ) C₂ - Cι₂ alkenyl ,

(iii) cycloalkyl, (iv) (cycloalkyl) alkyl,

(v) (cycloalkyl) alkenyl, (vi) ^'cycloalkenyl,

(vii) (cycloalkenyl) alkyl ,

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

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

(xiv) (heterocyclic) alkenyl ; and

R¹² and R³⁶ are independently selected from the group consisting of

(i) hydrogen, (ii) C1-C12 alkyl,

(ii) C₂-Cχ alkenyl, (iv) cycloalkyl,

(v) (cycloalkyl) alkyl,

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

(ix) (cycloalkenyl) alkenyl,

(ix) 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(=0) -N(R*) -, (b) -N(R*) -C(=0) -,

(b) -C(=S)-N(R*)-, (d) -N(R*)-C(=S)-,

(e) -N(R*)-S0₂-, and (f) -S0₂-N(R*)-, wherein R* is hydrogen, Cι-C₃ loweralkyl or cyclopropyl;

R² is selected from the group consisting of

(a) hydrogen, (b) Cx-Cg alkyl, (c) C₂-C₆ alkenyl, (d) C₃-C₆ cycloalkyl, (e) C₅-C₆ cycloalkenyl,

(f) halo Ci-Ce alkyl and (g) halo C₂-C₆ alkenyl;

or R -X- is

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, Cι-C₃ loweralkyl,

hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl,

1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl , 2-thiolethyl, methoxymethyl, N-methylaminomethyl and

methylthiomethyl ;

R_2a is selected from the group consisting of

(a) hydrogen, (b) C_ι-C₆ alkyl, (c) C₂-C₆ alkenyl, (d) halo Cι-C₆ alkyl, and (e) halo C₂-C₆ alkenyl;

Ri₄ and R_ι5 are independently selected from the group consisting of

(ii) hydrogen, (ii) Cι-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-substituted alkyl,

(xi) R^37aO- (0=)C-substituted alkyl,

(xii) R^37aS- (0=)C-substituted alkyl,

(xiii) R^37a0- (S=)C-substituted alkyl,

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

(xv) (R^37a0)₂-P(=0) -substituted alkyl,

(xvi) cyanoalkyl, (xvii) C₂-C₁₂ alkenyl,

(xviii) haloalkenyl, (xix) C₂-Cι₂ alkynyl,

(xx) cycloalkyl, (xxi) (cycloalkyl) alkyl,

(xxii) (cycloalkyl) alkenyl,

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

(xxv) (cycloalkenyl) alkyl,

(xxvi) (cycloalkenyl) alkenyl, (xxvii) (cycloalkenyl) - alkynyl,

(xxviii) aryl, (xxxix) (aryl) alkyl, (xxx) (aryl) alkenyl,

(xxxi) (aryl) alkynyl,

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

(xxxiv) (heterocyclic) alkenyl,

(xxxv) (heterocyclic) alkynyl , (xxxvi) -0-alkyl,

(xxxvii) -NHalkyl, (xxxviii) -NH₂, (xxxix) -N(alkyl)₂,

(xxxx) -OH, (xxxxi) -NHacyl, (xxxxii) -Nalkylacyl,

(xxxxiii) -NHcarbamoyl, (xxxxiv) -Nalkylcarbamoyl,

(xxxxv) -NHcarbamidyl, and (xxxxvi) -Nalkylcarbamidyl;

R is selected from the group consisting of

(i) hydrogen, (ii) Cι-Cι₂ alkyl, (iii) haloalkyl, (iii) hydroxyalkyl, (v) alkoxyalkyl,

(vi) C2-C12 alkenyl,

(vii) haloalkenyl, (viii) C₂-Cι₂ alkynyl,

(x) 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) C₁-C₁₂ alkyl, (iii) haloalkyl,

(iv) C₂-C₁₂ alkenyl, (v) haloalkenyl,

(vi) C₂-C12 alkynyl, (vii) cycloalkyl, (viii) (cycloalkyl) alkyl, (ix) (cycloalkyl) - alkenyl,

(x) (cycloalkyl) alkynyl,

(xii) cycloalkenyl, (xii) (cyclo- alkenyl) 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(=0)-R ,

(xxiii) -C(=S)-R¹⁴, (xxv) -S(0)₂-R¹⁴ and

(xxvi) hydroxyalkyl ;

Y is selected from the group consisting of (a) hydrogen, (b) Cι-C₅ alkyl, (c) Cχ-C₅ haloalkyl,

(c) C₂-C₅ alkenyl, (e) C₂-C₅ haloalkenyl,

(f) C₂-C₅ alkynyl,

(f) C₃-C₅ cycloalkyl, (h) C₃-C₅ cycloalkyl-C_ι-to-C₃- alkyl, (i) C₅ cycloalkenyl, (j) C₅ cycloalkenyl-Ci-to-C alkyl,

(k) C₅ cycloalkenyl-C₂-to-C₃-alkenyl, (1) - (CHR³⁹) _nOR²⁰,

(m) -CH(OR²⁰)-CH₂(OR²⁰) , (n) - (CHR³⁹) _nSR²¹,

(o) -(CHR³⁹)_nCN, (p) -(CHR³⁹)_nN₃, (q), phenyl,

(r) halo- substituted phenyl, (s) - (CHR³⁹) _nC (=Q²) R²²,

(t) - (CHR³⁹)_nN(=Q³) , (u) -N(0)=CHCH₃, (v) - (CHR³⁹) _nNR²³R²⁴,

(w) halo, and (x) a heterocyclic rijπg having from

3 to 6 ring atoms ;

wherein n is 0, 1, or 2; Q is 0, S, NR , or CHR ;

and Q³ is NR⁴¹, or CHR⁴² ;

⁰ at each occurrence is independently

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

(v) isopropyl, (vi) Cχ-C₃ haloalkyl, (vii) vinyl,

(viii) propenyl, (ix) isopropenyl, (x) allyl,

(xi) C₂-C₃ haloalkenyl, (xii) amino, (xiii) -NHCH₃,

(xiv) -N(CH₃)₂, (xv) -NHCH₂CH₃,

(xvi) -N(CH₃) (CH₂CH₃) ,

(xvii) -N(CH₂CH₃)₂ or (xviii ) -N ( =CH₂ ) ;

R²¹ is

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

(xv) n-propylthio, (xvi) isopropylthio,

(xvii) cyclopropylthio, (xviii) vinyl,

(xix) propenyl, (xx) isopropenyl, (xxi) allyl,

(xxii) -N(R^28a) (R²⁸ ) , (xxiii) -CH₂R²⁹,

(xxiv) aminomethyl, (xxv) hydroxymethyl,

(xxvi) thiolmethyl, (xxvii) -NHNH₂, (xxviii) -N(CH₃)NH₂, or

(xxix) -NHNH(CH₃) ; R 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) Cι-C₄ alkyl, (iii) C₂-C₄ alkenyl,

(iv) C₂-C₄ alkynyl, (v) cyclopropyl, (vi) -C(=Q⁴)-R³⁰,

(v) (v) -OR³¹, and (vi) -N(R³²)₂,

wherein Q⁴ is O, S, or N(R³³);

R is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or

-N0₂

R²⁶ is hydrogen, methyl or ethyl

R^28a is 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 is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;

R³⁰ 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 is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or

-N0₂;

R³⁴ is methyl or ethyl;

R³⁵ 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-C₂H_5; R⁶ and R⁷ are independently selected from the group consisting of

(a) hydrogen, (b) Cι-Cι₂ alkyl, (c) C₂-C₁₂ alkenyl,

(d) cycloalkyl, (e) (cycloalkyl) alkyl,

(f) (cyclo alkyl) alkenyl, (g) cycloalkenyl,

(h) (cycloalkenyl) alkyl,

(i) (cycloalkenyl) alkenyl, (j) aryl, (k) (aryl) alkyl,

(1) (aryl) alkenyl, (m) heterocyclic,

(n) (heterocyclic) alkyl, and (o) (heterocyclic) alkenyl ;

and

R⁸ and R⁹ and are independently selected from the group consisting of

(a) hydrogen , (b) Cι-C₆ alkyl , (c ) C₂-C_e alkenyl ,

(d) C₃ -C₆ cycloalkyl , (e) C₃-C_ε cycloalkenyl ,

(f) fluorine, and (g) -NH₂,

with the proviso that the total number of atoms, other than hydrogen, in each of R⁸ and R⁹, is 6 atoms or less; and

R¹⁰ is selected from the group consisting of (a) hydrogen, (b) Cι-C₆ alkyl, (c) C₂-C₃ alkenyl,

(d) C₃-C₆ cycloalkyl, (e) C₃-C₆ cycloalkenyl,

(f) fluorine, (g) -NH₂, and (h) -OH

with the proviso that the total number of atoms, other than hydrogen in R¹⁰ is 6 atoms or less;

with the proviso that if Y is

- (CHR³⁹)_nOR²⁰,

- (CHR³⁹)_nSR²¹,

-CHR³⁹)_nN(=Q³) ,

-N(0)=CHCH₃,

(CHR^Ja)_nNR 2"ⁱ ₃ ^J _lR_->24

or halo,

where n is 0,

then R¹⁰ is not -OH, -NH₂, or -F.

Further provided are compounds of formula la and lb

Ia lb

or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein all substituents are as defined above.

Still further provided are intermediates and processes for preparing compounds of formula I, la, and lb.

Additionally provided are methods of using compounds of formula I for the inhibition of a neuraminidase enzyme of disease-causing microorganisms; particularly viral neuraminidase, and, especially influenza neuraminidase.

Also provided are compounds of formula I that inhibit neuraminidase from both A and B strains of influenza.

Still further provided are methods for the prophylaxis and/or treatment of influenza infection in humans and other mammals using compounds of formula I .

Additionally provided are compounds that exhibit activity against influenza A virus and and influenza B virus by virtue of inhibiting influenza neuraminidase when such compounds are administered orally.

Also provided are compounds that 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.

Detailed Description of the Invention

The term "acid protecting group" as used herein refers to groups used to protect acid groups (for example, -C0₂H, -S0₃H, -S0₂H, -P0₃H₂, -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) which is incorporated herein by reference. Most frequently, such acid protecting groups are esters.

Such esters include:

alkyl esters, especially loweralkyl 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; 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 loweralkyl 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- trichlorophenol derived esters, p-nitrophenol derived esters, phenol derived esters, pentachlorophenol derived esters, 8-hydroxyquinoline 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 loweralkyl groups. Representative examples of acyl groups include groups such as, for example, formyl , acetyl, propionyl, and the like.

The term "acylalkyl" as used herein refers to an acyl group appended to an alkyl radical. Representative examples of acylalkyl groups include acetylmethyl, acetylethyl, propionylmethyl, propionylethyl 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.

The term "acyloxyalkyl" as used herein refers to an acyloxy group (i.e., R⁹⁵-C(0)-0- wherein R⁹⁵ is hydrogen or an alkyl group) which is appended to an alkyl radical. Representative examples of acyloxyalkyl include acetyloxymethyl, acetyloxyethyl, propioyloxymethyl, propionyloxyethyl and the like.

The term "alkenyl" as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also 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 loweralkyl groups. Representative examples of alkoxy groups include groups such as, for example, methoxy, ethoxy, tert-butoxy, and the like.

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

The term "alkoxyalkyl" as used herein refers to an alkyl radical to which 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.

The term "alkoxycarbonyloxyalkyl" as used herein refers to an alkoxycarbonyloxy group (i.e., R⁸⁰-C(O)-O wherein R⁸⁰ is an alkoxy group) appended' to an alkyl radical. Representative examples of alkoxycarbonyloxyalkyl include methoxycarbonyloxymethyl , ethoxycarbonyloxymethyl, methoxycarbonyloxyethyl and the like.

As used herein, the term "alkyl" refers to straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms. The term "loweralkyl" 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, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl n-pentyl, 1-methylbutyl, 2 , 2-dimethylbutyl, 2-methylpentyl , 2 , 2-dimethylpropyl, 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, loweralkyl, 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 loweralkyl 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-'l to 15 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, loweralkyl, 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 loweralkyl groups.

The term "alkylsulfonylamino" 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 loweralkyl 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 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-, -C≡C-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 loweralkyl, 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, alkylsulfonylammo, unsubstituted heterocyclic, unsubstituted (heterocyclic) alkyl, unsubstituted (heterocyclic) alkoxy, unsubstituted (heterocyclic) oxy and -S0₃H. Preferred aryl substituents are each independently selected from the group consisting of loweralkyl, 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.

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 loweralkyl 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 "carbamidyl" as used herein refers to the group having the formula, -NH-C (=0) -NH₂.

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, -R⁶⁴-COOH, where R^G4 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, norbornene and the like.

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 loweralkyl. Preferred substitutents are independently selected from loweralkyl, 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, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornane, 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 loweralkyl. Preferred substitutents are independently selected from loweralkyl, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.

The term " (cycloalkyl) alkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl 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 "dialkylaminoalkyl" as used herein refers to a dialkylamino group appended to an alkyl radical.

Representative examples of dialkylaminoalkyl include dimethylaminomethyl, dimethylaminoethyl, N-methyl-N- ethylaminoethyl .and the like.

The term "dialkylaminocarbonylalkyl" as used herein refers to a

-C (O) -N(R⁹⁰) group (wherein each R⁹⁰ is independently a lower alkyl group) appended to an alkyl radical. Representative examples of dialkylaminocarbonylalkyl include dimethylaminocarbonylmethyl , diethylaminocarbonylmethyl, N-methyl-N- ethylaminocarbonylethyl and the like.

The term "dialkylaminocarbonyloxyalkyl" as used herein refers to a -0-C (O) -N (R⁹⁰) ₂ group (wherein each R⁹⁰ is independently a lower alkyl group) appended to an alkyl radical. Representative examples of dialkylaminocarbonyloxyalkyl include dimethylaminocarbonyloxymethyl , diethylaminocarbonyloxymethyl , N-methyl-N- ethylaminocarbonyloxyethyl and the like.

The term "enantiomerically enriched" as used herein refers to a compound which comprises unequal amounts of the enantiomers of an enantiomeric pair. In other words, an enantiomerically enriched compound comprises more than 50% of one enantiomer of an enantiomeric pair and less than 50% of the other enantiomer of the enantiomeric pair. Preferably, a compound that is enantiomerically enriched comprises predominantly one enantiomer of an enantiomeric pair. Preferably, an enantiomerically enriched compound comprises greater than 80% of one enantiomer of an enantiomeric pair and less than 20% of the other enantiomer of the enantiomeric pair. More preferably, an enantiomerically enriched compound comprises greater than

90% of one enantiomer of an enantiomeric pair and less than 10% of the other enantiomer of the enantiomeric pair. Even more preferably, an enantiomerically enriched compound comprises greater than 95% of one enantiomer of an enantiomeric pair and less than 5% of the other enantiomer of the enantiomeric pair. Even more highly preferably, an enantiomerically enriched compound comprises greater than 97% of one enantiomer of an enantiomeric pair and less than 3% of the other enantiomer of the enantiomeric pair. Yet even more highly preferably, an enantiomerically enriched compound comprises greater than 98% of one enantiomer of an enantiomeric pair and less than 2% of the other enantiomer of the enantiomeric pair. Most preferably, an enantiomerically enriched compound comprises greater than 99% of one enantiomer of an enantiomeric pair and less than 1% of the other enantiomer of the enantiomeric pair.

The term "halo" or "halide" 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.

The term "haloalkyl" as used herein, refers to a loweralkyl 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, 2 , 2 , 2-trichloroethyl, 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, orpholinyl, thiomorpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl , tetrahydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, triazolyl, triazolinyl, tetrazolyl, tetrazolinyl, isoxazolyl, 1, 2 , 3-oxadiazolyl, 1,2,4- 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, thiadiazolinyl, 1, 3- dithiolinyl, 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_3.-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 loweralkyl, 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 loweralkyl radical including, but not limited to, pyrrolidin-ylmethyl, morpholinylmethyl and the like.

The term " (heterocyclic) lkynyl" 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) carbonylalkyl" as used herein refers to a heterocyclic group appended to an alkyl radical via a carbonyl group. Representative examples of (heterocyclic) carbonylalkyl include pyridylcarbonylmethyl, morpholinocarbonylethyl , piperazinylcarbonylmethyl and the like.

The term " (heterocyclic) carbonyloxyalkyl" as used herein refers to a heterocyclic group appended to an alkyl radical via a carbonyloxy group (i.e., -C(O)-O-).

Representative examples of (heterocyclic) carbonylalkyl include pyridylcarbonylmethyl, morpholinocarbonylethyl, piperazinylcarbonylmethyl 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) which is incorporated by reference herein. 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-l- 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;

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, dichloroacet^'ate-; 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, alpha-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromo- benzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; sulfenyl groups such as phenylsulfenyl ^'"(phenyl-S-) , triphenylmethyl-sulfenyl (trityl-S-) and the like; sulfinyl groups such as p-methylphenylsulfinyl (p-methylphenyl-S (0) - ), t-butylsulfinyl (t-Bu-S(O)-) and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyl- oxycarbonyl, p-methoxybenzyloxycarbonyl , p-nitrobenzyloxy- carbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycar- bonyl , 3,4 -dimethoxybenzyloxycarbonyl , 3 , 5-dimethoxybenzyl- oxycarbonyl, 2 , 4 -dimethoxybenzyloxycarbonyl, 4 -methoxy- benzyloxycarbonyl, 2 -nitro-4 , 5-dimethoxybenzyloxycarbonyl, 3 , 4 , 5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -

1-methylethoxycarbonyl, alpha, alpha-dimethyl-3 , 5-

dimethoxybenzyl-oxycarbonyl , benzhydryloxycarbonyl , t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyl- oxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycar- bonyl , 2,2, 2 -trichloroethoxycarbonyl , phenoxycarbonyl , 4 -nitro-phenoxycarbonyl , fluorenyl- 9-methoxycarbonyl , cyclopentyloxycarbonyl, adamantyloxycarbonyl , cyclohexyl- oxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, benzyl- oxymethyl and the like; p-methoxyphenyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups include 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 loweralkyl 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, 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 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, la, or lb are meant to be included in this invention.

When any variable (for example R¹, R², R³ , m, n, etc.) occurs more than one time in any substituent or in the compound of Formula I, la, or lb 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 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, la, or lb 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 vi tro .

Compounds of the invention can be prepared according to the methods described in the Schemes as shown below. 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 . The term "hydroxy-protecting group, " as used herein, refers to selectively removable groups which protect hydroxyl groups against undesirable reactions during synthetic procedures. The use of hydroxy-protecting groups is well-known in the art and is discussed in T.H. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd edition, John Wiley & Sons, New York (1991), pp 10-86. Examples of hydroxy-protecting groups include methylthiomethyl, tertiary-butyldimethylsilyl, tertiary- butyldiphenylsilyl, acetyl, benzoyl, and the like.

Numerous asymmetric centers exist in the compounds of the invention. The invention contemplates the various stereoisomers and mixtures thereof. Individual stereoisomers of compounds of the present invention are made by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation as, for example, by conversion to a mixture of diastereomers followed by separation by recrystallization or chromatographic techniques, or by direct separation of the optical enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods detailed below and resolved by techniques well known in the art. Synthetic Methods

The compounds and processes of the invention will be better understood in connection with the following synthetic Schemes which illustrate methods by which the compounds of the invention can be prepared. The compounds of the invention can be prepared by a variety of procedures. Representative procedures are shown in Schemes 1-56.

It will be readily apparent that other compounds of the invention can by synthesized by the' substitution of appropriate starting materials and reagents in the syntheses shown below. It will also be apparent that protection and deprotection steps, as well as the order of the steps themselves, can be carried out in varying order, to successfully complete the syntheses of compounds of the invention. Commonly used protecting groups are disclosed in Greene, (op. Cit) .

The other compounds of the invention can be readily prepared from the compounds described herein using techniques known in the chemical literature. The methods required are known and can be readily practiced by those having ordinary skill in the art.

The reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, WI, USA); Sigma Chemical Co. (St. Louis, MO, USA); and Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, MA 01835-9953) ; Eastman Chemical Company (Rochester, New York 14652-3512) ; Lancaster Synthesis Inc.

(Windham, NH 03087-9977) ; Spectrum Chemical Manufacturing

Corp. (Janssen Chemical) (New Brunswick, NJ 08901) ; Pfaltz and Bauer (Waterbury, CT . 06708) . Compounds which are not commercially available can be prepared by employing known methods from the chemical literature.

Starting materials and reagents are available commercially or can be prepared synthetically by known methods such as those disclosed in Larock, "Comprehensive Organic Transformation. A Guide to Functional Group Preparations," VCH Publishers, New York' (1989) .

All of the reactions discussed in the Schemes are run in solvents in which the starting materials and products are not reactive, unless otherwise specified and those in which the starting materials are at least partially soluble. The appropriate solvent for each reaction will be apparent to one skilled in the art. For example, possible solvents, which can be used include THF, DCM, MeCN, DMF, EtOAc, hexanes, toluene, benzene, DMSO, MeOH, EtOH, i-PrOH, water, dioxane, anisole, pyridine, aniline, TEA, NMP, HMPA, glyme, diglyme, xylene, DME, acetone, cyclohexane, glycerol,

1, 2-dichloroethane, tertiary-butyl methyl ether, ethyl ether, methyl ether, PhOPh, chloroform, carbon tetrachloride, dioxane, morpholine, 1, 1, l-trichloroethane, trifluoroacetic acid, AcOH, hydrochloric acid, sulfuric acid, perchloric acid, nitric acid and mixtures thereof. Abbreviations

Abbreviations which have been used in the descriptions of the Schemes and the examples that follow are: THF for tetrahydrofuran; Ac for acetate; MeCN for acetonitrile; MeOH for methanol; TMSCl for trimethylsilyl chloride; TMSBr for trimethylsilyl bromide; TMSN₃ for trimethylsilyl azide;

BF₃»OEt₂ for boron trifluoride diethyl etherate; TEA for triethylamine; DBU for 1, 8-diazabicyclo [ .4.0] ndec-7-ene;

TMSOTf for trimethylsilyl .triflate; DMF for N,N-dimethyl formamide; Ph for phenyl; DCM for dichloromethane, dppf for 1,1' -bis (diphenylphosphino) ferrocene ; dba for dibenzylideneacetone; DME for dimethoxyethane; DMSO for dimethyl sulfoxide; Et for ethyl; i-Pr for isopropyl; TBME for tertiary-butyl methyl ether; PhOPh for diphenylether; HMPA for hexamethylphosphoramide; NMP for N- methylpyrrolidine; AIBN for 2, 2 ' -azobisisobutyronitrile; MCPBA for meta-chloroperbenzoic acid; NMO for N- methylmorpholine N-oxide; TBAF for tetrabutylammonium fluoride; DEAD for ethyl azodicarboxylate; TsOH for para- toluene sulfonic acid; TFA for trifluoroacetic acid; CBzCl for carbobenzyloxy chloride; Boc for t-butoxycarbonyl; TIPSC1 for triisopropylsilyl chloride; PCC for pyridinium chlorochromate ; DIBAL for diisobutylaluminum hydride; DCC for dicyclohexyldiimide; Dess-Martin periodinane for 1,1,1- triacetoxy-1, 1-dihydro-l, 2-benziodoxol-3-one; DIAD for diisopropyl azodicarboxylate. Scheme 1

As shown in Scheme 1, the preparation of (1A) can be accomplished by treating two equivalents of a dipolarophile (i) with a 1,3-dipole (ii) in the presence of an acid catalyst in a solvent. Specific examples of dipolarophiles include acrolein, methyl acrylate, styrene, acetylene, (+) - (S) -isopropylidene-3-buten-l , 2-diol, and DEAD. Examples of 1,3-dipoles include, non-isolable 1,3-dipoles generated in situ and carbethoxyformonitrile oxide. Specific examples of acids include triflie acid, TsOH, TFA and AcOH. Specific examples of solvents include toluene, benzene or xylene. The reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure. The reaction time is generally about 1 hour to 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, a non-isolable 1,3-dipole is generated in si tu by reacting t-butyl N-benzyl-glycinate with acrolein and AcOH in refluxing toluene for about one hour. The reaction mixture is then cooled to about 50 °C and acrolein is added. The reaction mixture is then refluxed for about an additional two hours.

Conversion of (1A) to (IB) can be accomplished by treating the former with a reducing agent in a solvent.

Specific examples of reducing agents include NaBH₄, NaBH₃CN, and BH₃»NH₂ (C (CH₃) ₃) . Specific examples of solvents include methanol, ethanol, and isopropanol . Although the reaction generally proceeds at 0 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1A) in 0 °C methanol is treated with NaBH₄, stirred for about 30 minutes, warmed to room temperature and stirred for about an additional hour.

Scheme 2

(IB) (IC) (ID)

As shown in Scheme 2, conversion of (IB) to (IC) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include, acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of organic bases include TEA, DMAP, pyrrolidine, diisopropylethylamine and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine or diethyl ether. Although the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (IB) in 0 °C pyridine is treated with acetic anhydride, and DMAP for about 16 hours.

Conversion of (IC) to (ID) can be accomplished by treating the former with an oxidant and bulk oxidant and a base in a solvent. Specific examples of oxidant and bulk oxidants are Os0₄ and NMO, or KMn0₄ and a base such as KOH, LiOH or NaOH. Specific examples of solvents include toluene, benzene, xylene, acetone, and water, or mixtures thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 36 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (IC) in room temperature 9:1 acetone : ater is treated with NMO and Os0₄ for about 24 hours.

Scheme 3

As shown in Scheme 3, conversion of (ID) to (IE) can be accomplished by treating the former with a hydrogen source and a catalyst in a solvent. Specific sources of hydrogen include ammonium formate and hydrogen gas . Specific examples of catalysts include Pd on carbon, Pt on carbon and Pd(PPh₃)₄. Specific examples of solvents include methanol, ethanol, EtOAc, or isopropyl acetate. The reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure. The reaction time is generally about 1 hour to about 8 hours and can be selected depending on the reaction temperature and amount of catalyst used. In a preferred embodiment, (ID) in ethanol is treated with ammonium formate and 10% Pd on carbon and refluxed for about 2 hours.

Conversion of (IE) to (IF) can be accomplished by treating the former with a protecting group precursor in a solvent. Specific examples of protecting group precursors include Boc anhydride, di-tertiary butyl dicarbonate, CBzCl, benzyl bromide, and acetic anhydride. Specific examples of solvents include DCM, chloroform, methanol, ethanol, water, and THF, or mixtures thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 3 days and can be selected depending on the reaction temperature. In a preferred embodiment, (IE) in a room temperature 5:1 methanol :water mixture is treated with di-tertiary butyl dicarbonate for about 2 days .

(IF) (1G) (1H) As shown in Scheme 4, conversion of (IF) to (1G) can be accomplished by treating the former with a protecting group precursor and a base in a suitable solvent. Specific examples of protecting group precursors include Boc anhydride, di-tertiary butyl dicarbonate, CBzCl, TIPSCl, and acetic anhydride. Specific examples of bases include TEA, imidazole, DMAP, diisopropylethylamine and pyridine. Specific examples of solvents include DCM, chloroform, diethyl ether, DMF and THF, or mixtures thereof. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 3 days and can be selected depending on the reaction temperature. In a preferred embodiment, (IF) in room^''temperature DMF is treated with imidazole and TIPSCl for about four hours. Conversion of (1G) to (1H) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of oxidizing agents include DMSO and oxalyl chloride, DMSO and DCC, Dess-Martin periodinane, and PCC. Specific examples of solvents include DCM, chloroform, diethyl ether, or THF. Although the reaction generally proceeds at about -78 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, example (1G) in DCM is slowly added to about a -78 °C solution of DMSO and oxalyl chloride in DCM. After about 1.5 hours, TEA is added and the reaction mixture is warmed to about 0 °C before quenching. Scheme 5

( 1J-2 )

As shown in Scheme 5, conversion of (1H) to (II) can be accomplished by treating the former with an a ine and a reducing agent in a solvent. Specific examples of amines include ammonia, benzylamine, N,N-diethylamine, methylamine, pyrrolidine, and ammonium salts. More preferred are the following ammonium salts: ammonium formate, ammonium acetate and ammonium chloride. Specific examples of reducing agents include, NaCNBH₃, LiAlH₄, NaBH₄ and DIBAL. Specific examples of solvents include methanol, ethanol, THF and DCM. Although the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure. The reaction time is generally about 1 hour to about 8 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, Example (1H) in room temperature methanol is treated with NaCNBH₃ and ammonium acetate for about two hours.

Conversion of (II) to (1J) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include, acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of organic bases include TEA, DMAP, pyrrolidine, diisopropylethylamine and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine or diethyl ether. Although the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about -24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (II) in room temperature DCM is treated with acetic anhydride, TEA and DMAP for about 18 hours.

Scheme 6

As shown in Scheme 6, conversion of (1J-1) to (IK) can be accomplished by treating the former with a base, an alcohol and a cosolvent . Specific examples of bases include K₂C0₃, NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include, methanol, ethanol, and isopropanol. Specific examples of cosolvents include water, DCM and THF. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, a room temperature solution of (1J-1) in methanol-water is treated with K₂C0₃ for about two hours.

Conversion of (IK) to (IL) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of oxidizing agents include DMSO and oxalyl chloride, DMSO and DCC, Dess-Martin periodinane, and PCC. Specific examples of solvents include DCM, chloroform, diethyl ether, or THF. Although the reaction generally proceeds at about -78 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, example (IK) in DCM is slowly added to about a -78 °C solution of DMSO and oxalyl chloride in DCM. After about 1.5 hours, TEA is added and the reaction mixture is warmed to about 0 °C before quenching.

Scheme 7

As shown in Scheme 7, conversion of (IL) to (1M) can be accomplished by treating the former with an olefination reagent and a base in ,a solvent. Specific olefination reagents include phosphorus ylides, phosphonium salts, phosphine oxides, phosphonates, silicon based reagents, sulfonyl stabilized anions, selenium reagents, and titanium reagents. More preferred are the following phosphorus ylides : benzylidenetriphenyl-phosphorane, (methyl) triphenylphosphonium bromide, and

(ethyl) triphenylphosphonium bromide. Specific examples of bases include KOt-Bu, NaNH₂, NaHMDS, or n-butyl lithium. Specific examples of solvents include toluene, benzene,

DCM, DMSO or THF. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, KOt-Bu is added to a room temperature solution of (ethyl) triphenylphosphonium bromide in toluene and stirred overnight. (1M) in toluene is then added and the reaction mixture is stirred for about 30 minutes. The conversion of (1M) to (IN) can be accomplished by treating the former with a deprotecting agent in a solvent. Specific examples of deprotecting agents include HF and TBAF. Specific examples of solvents include THF, TBME, DCM and diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1M) in room temperature THF is treated with TBAF for about 30 minutes. Scheme 8

( 1P-2 )

As shown in Scheme 8, conversion of (IN) to (10) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of solvents include DCM, chloroform, and THF. Specific examples of oxidizing agents include DMSO and oxalyl chloride, DMSO and DCC, Dess-Martin periodinane, and PCC. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (IN) in room temperature DCM is treated with Dess-Martin periodinane for about one hour. The conversion of (10) to (IP) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, l-buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2 -butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a room temperature solution of ethyl magnesium bromide in THF is treated with (10) in THF for about 40 minutes.

Scheme 9

( 1R- 2 )

As shown in Scheme 9, conversion of (1P-1) to (1Q) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of solvents include DCM, chloroform, and THF. Specific examples of oxidizing agents include DMSO and oxalyl chloride, DMSO and DCC,

Dess-Martin periodinane, and PCC. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1P-1) in room temperature DCM is treated with Dess-Martin periodinane for about 17 hours.

Conversion of (1Q) to (1R) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include, NaCNBH₃, LiAlH₄, NaBH₄ and DIBAL. Specific examples of solvents include THF, diethyl ether, TBME, methanol, and ethanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1Q) in room temperature methanol is treated with NaBH₄ for about 30 minutes.

Scheme 10

As shown in Scheme 10, conversion of (1R-2) to (IS) can be accomplished by treating the former with a chloride source in a solvent. Specific examples of chloride sources include thionyl chloride, sulfuryl chloride, and HCl. Specific examples of solvents include DCM, chloroform, CC1₄, and 1 , 2-dichloroethane . Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 4 hours to about 36 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (1R-2) in room temperature chloroform is treated with thionyl chloride for about 24 hours.

The conversion of (IS) to (IT) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include .TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although^"" the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (IS) in room temperature DCM is treated with TFA for about 3.5 hours .

Scheme 11

(2A-2) As shown in Scheme 11, conversion of (10) to (2A) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, l-buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2 -butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl' acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a room temperature solution of n-propyl magnesium bromide in THF is treated with (10) in THF for about 40 minutes.

Scheme 12

(2A-2) (2B) (2C)

As shown in Scheme 12, the conversion of (2A-2) to (2B) can be accomplished by treating the former with a chloride source in a solvent. Specific examples of chloride sources include thionyl chloride, sulfuryl chloride, and HCl. Specific examples of solvents include DCM, chloroform, CC1₄, and 1, 2-dichloroethane . Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 4 hours to about 36 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (2A-2) in room temperature chloroform is treated with thionyl chloride for about 24 hours . The conversion of (2B) to (2C) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (2B) in room temperature DCM is treated with TFA for about 3 hours.

Scheme 13

As shown in Scheme 13, the conversion of (10) to (3A) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n- propyl magnesium bromide, isopropyl magnesium bromide, 1- buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2-butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a room temperature solution of iso-propyl magnesium bromide in THF is treated with (10) in THF for about 40 minutes.

Scheme 14

As shown in Scheme 14, conversion of (3A-2) to (3B) can be accomplished by treating the former with a chloride source in a solvent. Specific examples'of chloride sources include thionyl chloride, sulfuryl chloride, and HCl. Specific examples of solvents include DCM, chloroform, CC1₄, and 1, 2-dichloro.ethane . Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 4 hours to about 36 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (3A-2) in room temperature chloroform is treated with thionyl chloride for about 24 hours.

The conversion of (3B) to (3C) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (3B) in room temperature DCM is treated with TFA for about 3 hours .

Scheme 15

As shown in Scheme 15, conversion of (3A-1) to (4A) can be accomplished by treating the former with a chloride source in a solvent. Specific examples'of chloride sources include thionyl chloride, sulfuryl chloride, and HCl. Specific examples of solvents include DCM, chloroform, CC1₄, and 1, 2-dichloroethane . Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 4 hours to about 36 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (3A-1) in room temperature chloroform is treated with thionyl chloride for about 24 hours.

The conversion of (4A) to (4B) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (4A) in room temperature DCM is treated with TFA for about 3 hours.

Scheme 16

(1N) (5A) (5B)

As shown in Scheme 16, conversipn of (IN) to (5A) ) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflie acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (IN) in room temperature DCM is treated with TFA for about 3.5 hours.

The conversion of (5A) to (5B) can be accomplished by treating the former with an aldehyde or ketone in a solvent. Specific examples of aldehydes include formaldehyde, acetaldehyde, benzaldehyde, furfural, 4-bromobenzaldehyde, and cyclohexanecarboxaldehyde . Specific examples of ketones include acetone, butanone, acetophenone, 3-pentanone, 2-pentanone and benzophenone . Specific examples of solvents include THF, diethyl ether, DCM, chloroform or TBME. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 2 days and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (5A) in room temperature THF is treated with formaldehyde for about 1 hour.

Scheme 17

( 1P-2 ) ( 6A) (6B ) As shown in Scheme 17, conversion of (1P-2) to (6A) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflie acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (IP-2) in room temperature DCM is treated with TFA for about 3.5 hours.

The conversion of (6A) to (6B) can be accomplished by treating the former with an aldehyde or ketone in a solvent. Specific examples of aldehydes include formaldehyde, acetaldehyde, benzaldehyde, furfural, 4-bromobenzaldehyde, and cyclohexanecarboxaldehyde .

Specific examples of ketones include acetone, butanone, acetophenone, 3-pentanone, 2-pentanpne and benzophenone . Specific examples of solvents include THF, diethyl ether, DCM, chloroform or TBME. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 2 days and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (6A) in room temperature THF is treated with formaldehyde for about 1 hour.

Scheme 18

(2A-1) " (7A) (7B)

As shown in Scheme 18, conversion of (2A-1) to (7A) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflie acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (2A-1) in room temperature DCM is treated with TFA for about 3.5 hours .

The conversion of (7A) to (7B) can be accomplished by treating the former with an aldehyde or ketone in a solvent. Specific examples of aldehydes include formaldehyde, acetaldehyde, benzaldehyde, furfural, 4-bromobenzaldehyde, and cyclohexanecarboxaldehyde . Specific examples of ketones include acetone, butanone, acetophenone, 3-pentanone, 2-pentanone and benzophenone . Specific examples of solvents include THF, diethyl ether, DCM, chloroform or TBME. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 2 days and can be selected depending on the reaction .temperature . In a particularly preferred embodiment, (7A) in room temperature THF is treated with formaldehyde for about 1 hour.

Scheme 19

(8A-2)

¹ As shown in Scheme 19, conversion of (10) to (8A) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin eriolateS' and nitriles. More preferred are the following- : nucleophiles: ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, l-buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2-butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at -78 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 5 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a -78 °C solution of the anion of acetonitrile in THF is treated with (10) in THF for about 15 minutes.

Scheme 20

(8A-2) (8B) (8C)

As shown in Scheme 20, conversion of (8A-2) to (8C) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflie acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the 'reaction generally proceeds at room temperature, it can be i run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (8A-2) in room temperature DCM is treated with TFA for about 3.5 hours.

The conversion of (8B) to (8C) can be accomplished by treating the former with an aldehyde or ketone in a solvent. Specific examples of aldehydes include formaldehyde, acetaldehyde, benzaldehyde, furfural, 4-bromobenzaldehyde, and cyclohexanecarboxaldehyde . Specific examples of ketones include acetone, butanone, acetophenone, 3-pentanone,. 2-pentanone and benzophenone . Specific examples of solvents include THF, diethyl ether, DCM, chloroform or TBME. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 2 days and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (8B) in room temperature THF is treated with formaldehyde for about 1 hour.

Scheme 21

(9A-2) As shown in Scheme 21, conversion of (10) to (9A) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, l-buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2-butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl' acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 5 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a room temperature solution of l-buten-4-yl magnesium bromide in THF is treated with (10) in THF for about one hour.

Scheme 22

As shown in Scheme 22, conversion of (9A-1) to (9B) pan be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflie acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (9A-1) in room temperature DCM is treated with TFA for about 3.5 hours.

The conversion of (9B) to (9C) can be accomplished by treating the former with an aldehyde or ketone in a solvent . Specific examples of aldehydes include formaldehyde, acetaldehyde, benzaldehyde, furfural, 4-bromobenzaldehyde, and cyclohexanecarboxaldehyde . Specific examples of ketones include acetone, butanone, acetophenone, 3-pentanone, 2-pentanone and benzophenone. Specific examples of solvents include THF, diethyl ether, DCM, chloroform or TBME. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 2 days and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (9B) in room temperature THF is treated with formaldehyde for about 1 hour.

Scheme 23

(10) (lOA-1) (10B)

As shown in Scheme 23, conversion of (10) to (lOA-1) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles . More preferred are the following nucleophiles: ethyl magnesium bromide, n- propyl magnesium bromide, isopropyl magnesium bromide, 1- buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2 -butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 5 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a room temperature solution of isobutyl magnesium bromide in THF is treated with (10) in THF for about one hour.

Conversion of (lOA-l) to (10B) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of solvents include DCM, chloroform, and THF. Specific examples of oxidizing agents include DMSO and oxalyl chloride, DMSO and DCC, Dess-Martin periodinane, and PCC. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (IN) in room temperature DCM is treated with Dess-Martin periodinane for about one hour .

Scheme 24

( 10B) ( IOC) ( 10D)

As shown in Scheme 24, conversion of (10B) to (10C) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include, NaCNBH₃, LiAlH₄, NaBH₄ and DIBAL. Specific examples of solvents include THF, diethyl ether, TBME, methanol, and ethanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (10B) in room temperature methanol is treated with NaBH₄ for about 30 minutes. Conversion of (IOC) to (10D) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (IOC) in room temperature DCM is treated with TFA for about 3.5 hours.

Scheme 25

(10D) (10E)

As shown in Scheme 25, conversion of (10D) to (10E) can be accomplished by treating the former with an aldehyde or ketone in a solvent. Specific examples of aldehydes include formaldehyde, acetaldehyde, benzaldehyde, furfural, 4-bromobenzaldehyde, and cyclohexanecarboxaldehyde . Specific examples of ketones include acetone, butanone, acetophenone, 3-pentanone, 2-pentanone and benzophenone. Specific examples of solvents include THF, diethyl ether, DCM, chloroform or TBME. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 2 days and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (10D) in room temperature THF is treated with formaldehyde for about 1 hour.

Scheme 26

As shown in Scheme 26, conversion of (10) to (11A) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, l-buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2 -butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 5 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a room temperature solution of 2 -butyl magnesium bromide in THF is treated with (10) in THF for about one hour.

Scheme 27

As shown in Scheme 27, conversion of (11A-1) to (11B) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of solvents include DCM, chloroform, and THF. Specific examples of oxidizing agents include DMSO and oxalyl chloride, DMSO and DCC, Dess-Martin periodinane, and PCC. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (11A-1) in room temperature DCM is treated with Dess-Martin periodinane for about one hour .

Conversion of (11B) to (11C) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include, NaCNBH₃, LiAlH₄, NaBH₄ and DIBAL. Specific examples of solvents include THF, diethyl ether, TBME, methanol, and ethanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (11B) in room temperature methanol is treated with NaBH₄ for about 30 minutes.

Scheme 28

As shown in Scheme 28, conversion of (11C-2) to (11D) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflie acid, TFA, and AcOH. _ι Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (11C-2) in room temperature DCM is treated with TFA for about 3.5 hours.

Conversion of (11D) to (HE) can be accomplished by treating the former with an aldehyde or ketone in a solvent. Specific examples of aldehydes include formaldehyde, acetaldehyde, benzaldehyde, furfural, 4-bromobenzaldehyde, and cyclohexanecarboxaldehyde . Specific examples of ketones include acetone, butanone, acetophenone, 3-pentanone, 2-pentanone and benzophenone. Specific examples of solvents include THF, diethyl ether, DCM, chloroform or TBME. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 2 days and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (11D) in room temperature THF is treated with formaldehyde for about 1 hour.

Scheme 29

As shown in Scheme 29, conversion of (1Q) to (12A) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, l-buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2-butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 5 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a room temperature solution of ethyl magnesium bromide in THF is treated with (1Q) in THF for about one hour.

Conversion of (12A) to (12B) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (12A) in room temperature DCM is treated with TFA for about 3.5 hours. Scheme 30

(12B) (12C)

As shown in Scheme 30, conversion of (12B) to (12C) can be accomplished by treating the former with an aldehyde or ketone in a solvent. Specific examples of aldehydes include formaldehyde, acetaldehyde, benzaldehyde, furfural, 4-bromobenzaldehyde, and cyclohexanecarboxaldehyde . Specific examples of ketones include acetone, butanone, acetophenone, 3-pentanone, 2-pentanone and benzophenone. Specific examples of solvents include THF, diethyl ether, DCM, chloroform or TBME. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 2 days and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (12B) in room temperature THF is treated with formaldehyde for about 1 hour.

Scheme 31

(13B-2)

As shown in Scheme 31, conversion of (2A-2) to (13A) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of solvents include DCM, chloroform, and THF. Specific examples of oxidizing agents include DMSO and oxalyl chloride, DMSO and DCC, Dess-Martin periodinane, and PCC. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected .depending on the reaction temperature. In a preferred embodiment, (2A-2) in room temperature DCM is treated with Dess-Martin periodinane for about one hour.

Conversion of (13A) to (13B) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, l-buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2 -butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature^*, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 5 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a room temperature solution of methyl magnesium bromide in THF is treated with (13A) in THF for about one hour.

Scheme 32

( 13B- 1 ) ( 13C) ( 13D)

As shown in Scheme 32, conversion of (13B-1) to (13C) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflie acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (13B-1) in room temperature DCM is treated with TFA for about 3.5 hours. Conversion of (13C) to (13D) can be accomplished by treating the former with an aldehyde or ketone in a solvent. Specific examples of aldehydes include formaldehyde, acetaldehyde, benzaldehyde, furfural, 4-bromobenzaldehyde, and cyclohexanecarboxaldehyde .

Specific examples of ketones include acetone, butanone, acetophenone, 3-pentanone, 2-pentanone and benzophenone. Specific examples of solvents include THF, diethyl ether, DCM, chloroform or TBME. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 2 days and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (13C) in room temperature THF is treated with formaldehyde for about 1 hour.

Scheme 33

As shown in Scheme 33, conversion of (10) to (14A) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, l-buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2-butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 5 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a -78 °C solution of the anion of ethyl acetate in THF is treated with (10) in THF for about 15 minutes.

Scheme 34

(14A-2) (14B) (14C)

As shown in Scheme 34, conversion of (14A-2) to (14B) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include, NaCNBH₃ , LiAlH₄, NaBH₄, LiBH₄, and DIBAL. Specific examples of solvents include THF, diethyl ether, TBME, methanol, and ethanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (11B) in room temperature methanol is treated with LiBH₄ for about 6 hours . Conversion of (14B) to (14C) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the nitrogen is selectively deprotected by treating a dilute solution of (14B) in DCM with TFA for about two hours .

Scheme 35

As shown in Scheme 35, conversion of (14C) to (14D) can be accomplished by treating the former with a hydroxyl activating group precursor, in a solvent. Specific examples of hydroxyl activating groups include trifluoroacetic anhydride, azo compounds with a phosphine, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para-toluenesulfonyl chloride. Specific examples of azo compounds include DEAD, and DIAD. Specific examples of phosphines include PPh₃, PEt₃, and PMe₃. Specific examples of solvents include DCM, chloroform, CC1₄, THF and 1, 1, l-trichloroethane . Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (14C) in room temperature DCM is treated with DEAD and PPh₃ for about 30 minutes.

Conversion of (14D) to (14E) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (14D) in room temperature DCM is treated with TFA for about 3.5 hours. Scheme 36

(14A-1) (15A) (15B)

As shown in Scheme 36, conversion of (14A-1) to (15A) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of solvents include DCM, chloroform, and THF. Specific examples of oxidizing agents include DMSO and oxalyl chloride, DMSO and DCC, Dess-Martin periodinane, and PCC. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (14A-1) in room temperature DCM is treated with Dess-Martin periodinane for about one hour.

Conversion of (15A) to (15B) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the nitrogen is selectively deprotected by treating a dilute solution of (15A) in DCM with TFA for about two hours .

Scheme 37

( 15D- 2 )

As shown in Scheme 37, conversion of (15B) to (15C) can be accomplished by treating the former with a base in a solvent. Specific examples of solvents include toluene, benzene, or xylene . Specific examples of bases include NaHC0₃, K₂C0₃, and K₃P0₄. In a preferred embodiment, (15B) in toluene is treated with NaHC0₃ and heated to about 105 °C for about 6 hours .

Conversion of (15C) to (15D) can be accomplished by treating, the former with a reducing agent in a solvent. Specific examples of reducing agents include, NaCNBH₃, LiAlH₄, NaBH₄, LiBH₄, and DIBAL. Specific examples of solvents include THF, diethyl ether, TBME, methanol, and ethanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (15C) in room temperature methanol is treated with NaBH₄ for about 30 minutes.

Scheme 38

(15D-1) (15E)

As shown in Scheme 38, conversion of (15D-1) to (15E) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (15D-1) in room temperature DCM is treated with TFA for about 6 hours.

Scheme 39

(15D-2) (16A)

As shown in Scheme 39, conversion of (15D-2) to (16A) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (15D-2) in room temperature DCM is treated with TFA for about 6 hours.

Scheme 40

(14A-1) ( 17A) (17B)

( 17D) ( 17C)

As shown in Scheme 40, conversion of (14A-1) to (17A) is accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include, NaCNBH₃, LiAlH₄, NaBH₄, LiBH₄, and DIBAL. Specific examples of solvents include THF, diethyl ether, TBME, methanol, and ethanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (15C) in room temperature methanol is treated with LiBH₄ for about 6 hours. Conversion of (17A) to (17B) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the nitrogen is selectively deprotected by treating a dilute solution of (17A) in DCM with TFA for about two hours.

Conversion of (17B) to (17C) can be accomplished by treating the former with a hydroxyl activating group precursor, in a solvent. Specific examples of hydroxyl activating groups include trifluoroacetic anhydride, azo compounds with a phosphine, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para- toluenesulfonyl chloride. Specific examples of azo compounds include DEAD, and DIAD. Specific examples of phosphines include PPh₃, PEt₃, and PMe₃. Specific examples of solvents include DCM, chloroform, CC1₄, THF and 1,1,1- trichloroethane . Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17B) in room temperature DCM is treated with DEAD and PPh₃ for about 30 minutes.

Conversion of (17C) to (17D) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17C) in room temperature DCM is treated with TFA for about 6 hours.

Scheme 41

( 1J-2 ) ( 17E ) ( 17F)

( 171 ) ( 17H) ( 17G)

As shown in Scheme 41, conversion of (1J-2) to (17E) can be accomplished by treating the former with a base, an alcohol and a cosolvent . Specific examples of bases include K₂C0₃ , NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include, methanol, ethanol, and isopropanol. Specific examples of cosolvents include water, DCM and THF. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, a room temperature solution of (1J-2) in methanol-water is treated with K₂C0₃ for about two hours. Conversion of (17E) to (17F) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of oxidizing agents include DMSO and oxalyl chloride, DMSO and DCC, Dess-Martin periodinane, and PCC. Specific examples of solvents include DCM, chloroform, diethyl ether, or THF. Although the reaction generally proceeds at about -78 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, example (17E) in DCM is slowly added to about a -78 °C solution of DMSO and oxalyl chloride in DCM. After about 1.5 hours, TEA is added and the reaction mixture is warmed to about 0 °C before quenching.

Conversion of (17F) to (17G) can be accomplished by treating the former with an olefination reagent and a base in a solvent. Specific olefination reagents include phosphorus ylides, phosphonium salts, phosphine oxides, phosphonates, silicon based reagents, sulfonyl stabilized anions, selenium reagents, and titanium reagents. More preferred are the following phosphorus ylides: benzylidenetriphenyl-phosphorane, (methyl) triphenylphosphonium bromide, and

(ethyl) triphenylphosphonium bromide. Specific examples of bases include KOt-Bu, NaNH₂, NaHMDS, or n-butyl lithium. Specific examples of solvents include toluene, benzene, DCM, DMSO or THF. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, KOt-Bu is added to a room temperature solution of (ethyl) triphenylphosphonium bromide in toluene and stirred overnight. (17F) in toluene is then added and the reaction mixture is stirred for about 30 minutes.

Conversion of (17G) to (17H) can be accomplished by treating the former with a deprotecting agent in a solvent. Specific examples of deprotecting agents include HF and TBAF. Specific examples of solvents include THF, TBME, DCM and diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17G) in room temperature THF is treated with TBAF for about 30 minutes.

Conversion of (17H) to (171) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of solvents include DCM, chloroform, and THF. Specific examples of oxidizing agents include DMSO and oxalyl chloride, DMSO and DCC, Dess-Martin periodinane, and PCC. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17H) in room temperature DCM is treated with Dess-Martin periodinane for about one hour.

Scheme 42

As shown in Scheme 42, conversion of (171) to (17Jis accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, l-buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2 -butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 5 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a -78 °C solution of the anion of ethyl acetate in THF is treated with (171) in THF for about 15 minutes.

Conversion of (17J) to (17K) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include, NaCNBH₃, LiAlH₄, NaBH₄, LiBH₄, and DIBAL. Specific examples of solvents include THF, diethyl ether, TBME, methanol, and ethanol . Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (11B) in room temperature methanol is treated with LiBH₄ for about 6 hours.

Conversion of (17K) to (17L) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment,' the nitrogen is selectively deprotected by treating a dilute solution of (17K) in DCM with TFA for about two hours. Conversion of (17L) to (17M) can be accomplished by treating the former with a hydroxyl activating group precursor, in a solvent. Specific examples of hydroxyl activating groups include trifluoroacetic anhydride, azo compounds with a phosphine, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para- toluenesulfonyl chloride. Specific examples of azo compounds include DEAD, and DIAD. Specific examples of phosphines include PPh₃, PEt₃, and PMe₃. Specific examples of solvents include DCM, chloroform, CC1₄, THF and 1,1,1- trichloroethane . Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17L) in room temperature DCM is treated with

DEAD and PPh₃ for about 30 minutes.

Conversion of (17M) to (17N) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of oxidizing agents include DMSO and oxalyl chloride, DMSO and DCC, Dess-Martin periodinane, and PCC. Specific examples of solvents include DCM, chloroform, diethyl ether, or THF. Although the reaction generally proceeds at about -78 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, example (17M) in DCM is slowly added to about a -78 °C solution of DMSO and oxalyl chloride in DCM. After about 1.5 hours, TEA is added and the reaction mixture is warmed to about 0 °C before quenching.

Scheme 43

(17N) (170) (17P)

As shown in Scheme 43, conversion of (17N) to (170) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include AcOH, TFA, monofluoroacetic acid, TsOH, HCl, H₃P0₄ and monochloroacetic acid. Specific examples of solvents include DCM, chloroform, THF, 1, 2-dichloroethane, and 1,1,1- trichloroethane . Although the equilibration reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17N) in room temperature DCM is treated with AcOH for about 6 hours .

Conversion of (170) to (17P) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include NaBH₄, NaBH₃CN, and BH₃*NH₂ (C (CH₃) ₃) . Specific examples of solvents include methanol, ethanol, and isopropanol . Although the reaction generally proceeds at 0 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (170) in 0 °C methanol is treated with NaBH₄, stirred for about 30 minutes, warmed to room temperature and stirred for about an additional hour.

Scheme 44

(17P) (17Q)

As shown in Scheme 44, conversion of (17P) to (17Q) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17C) in room temperature DCM is treated with TFA for about 6 hours. Scheme 45

( 17C) ( 18A) ( 18B)

As shown in Scheme 45, conversion of (17C) to (18A) can be accomplished by treating the former with a base, an electrophile and an additive in a solvent. Specific examples of bases include KOH, NaOH, LiOH, K₂C0₃, and K₃P0₄. Specific examples of electrophiles include methyl iodide, ethyl iodide, isopropyl iodide and benzyl bromide. Specific examples of additives include 18-Crown-6, 15- Crown-5, and 12-Crown-4. Specific examples of solvents include DMF, THF, DMSO and NMP. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (17C) , 18-Crown-6 and powdered KOH in room temperature DMF are treated with ethyl iodide for about 4.5 hours . Conversion of (18A) to (18B) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (18A) in room temperature DCM is treated with TFA for about 3.5 hours.

Scheme 46

As shown in Scheme 46, conversion of (13A) to (19A) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions,

Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n- propyl magnesium bromide, isopropyl magnesium bromide, 1- buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2 -butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 5 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a -78 °C solution of the anion of ethyl acetate in THF is treated with (13A) in THF for about 15 minutes.

Conversion of (19A) to (19B) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include, NaCNBH₃, LiAlH₄, NaBH , LiBH₄, and DIBAL. ^"Specific examples of solvents include THF, diethyl ether, TBME, methanol, and ethanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (19A) in room temperature methanol is treated with LiBH₄ for about 6 hours .

Conversion of (19B) to (19C) ^"can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the nitrogen is selectively deprotected by treating a dilute solution of (19B) in DCM with TFA for about two hours. Conversion of (19C) to (19D) can be accomplished by treating the former with a hydroxyl activating group precursor, in a solvent. Specific examples of hydroxyl activating groups include trifluoroacetic anhydride, azo compounds with a phosphine, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para- toluenesulfonyl chloride. Specific examples of azo compounds include DEAD, and DIAD. Specific examples of phosphines include PPh₃, PEt₃, and PMe₃. Specific examples of solvents include DCM, chloroform, CC1₄, THF and 1,1,1- trichloroethane . Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (19C) in room temperature DCM is treated with DEAD and PPh₃ for about 30 minutes.

Conversion of (19D) to (19E) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (19D) in room temperature DCM is treated with TFA for about 3.5 hours. Scheme 47

As shown in Scheme 47, conversion of (170) to (21A) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n- propyl magnesium bromide, isopropyl magnesium bromide, 1- buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2 -butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 5 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a -78 °C solution of the anion of ethyl acetate in THF is treated with (17A) in THF for about 15 minutes.

Conversion of (21A) to (21B) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include, NaCNBH₃ , LiAlH₄, NaBH₄, LiBH , and DIBAL. Specific examples of solvents include THF, diethyl ether, TBME, methanol, and ethanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (21A) in room temperature methanol is treated with LiBH₄ for about 6 hours . Conversion of (21B) to (21C) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (2IB) in room temperature DCM is treated with TFA for about 3.5 hours. Scheme 48

As shown in Scheme 48, conversion of (10) to (22A) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, l-buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2-butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 5 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a -78 °C solution of the anion of (ethoxyethyloxymethyl) tributylstannane in THF is treated with (17A) in THF for about 30 minutes.

Scheme 49

As shown in Scheme 49, conversion of (22A-1) to (22B) can be accomplished by treating the former with dilute aqueous acid in a solvent to afford an intermediate compound which is then treated with an acid in a solvent. Specific examples of aqueous acids include HCl, H₂S0₄, HC10₄ and HN0₃. Specific examples of solvents include THF, diethyl ether, DCM and TBME. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 8 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (22A-1) in THF is treated with 0.5N aqueous HCl for about one hour to afford an intermediate compound .

The conversion of the intermediate compound to (22B) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the nitrogen is selectively deprotected by treating a dilute solution of the intermediate compound in DCM with TFA for about two hours .

Conversion of (22B) to (22C) can be accomplished by treating the former with a hydroxyl activating group precursor, in a solvent. Specific examples of hydroxyl activating groups include trifluoroacetic anhydride, azo compounds with a phosphine, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para- toluenesulfonyl chloride. Specific examples of azo compounds include DEAD, and DIAD. Specific examples of phosphines include PPh₃, PEt₃, and PMe₃. Specific examples of solvents include DCM, chloroform, CC1₄, THF and 1,1,1- trichloroethane . Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (22B) in room temperature DCM is treated with DEAD and PPh₃ for about 30 minutes. Scheme 50

(22C) (22D)

As shown in Scheme 50, conversion of (22C) to (22D) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (22C) in room temperature DCM is treated with TFA for about 3.5 hours.

Scheme 5l

As shown in Scheme 51, conversion of (22A-2) to (23A) can be accomplished by treating the former with dilute aqueous acid in a solvent to afford an intermediate compound which is then treated with an acid in a solvent. Specific examples of aqueous acids include HCl, H₂S0₄, HC10₄ and HN0₃. Specific examples of solvents include THF, diethyl ether, DCM and TBME. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 8 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (22A-2) in THF is treated with 0.5N aqueous HCl for about one hour to afford an intermediate compound . The conversion of the intermediate compound to (23A) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the nitrogen is selectively deprotected by treating a dilute solution of the intermediate compound in DCM with TFA for about two hours.

Conversion of (23A) to (23B) can be accomplished by treating the former with a hydroxyl activating group precursor, in a solvent. Specific examples of hydroxyl activating groups include trifluoroacetic anhydride, azo compounds with a phosphine, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para- toluenesulfonyl chloride. Specific examples of azo compounds include DEAD, and DIAD. Specific examples of phosphines include PPh₃ , PEt₃, and PMe₃. Specific examples of solvents include DCM, chloroform, CC1₄, THF and 1,1,1- trichloroethane . Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (23A) in room temperature DCM is treated with DEAD and PPh₃ for about 30 minutes.

Scheme 52

(23B) (23C)

As shown in Scheme 52, conversion of (23B) to (23C) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (23B) in room temperature DCM is treated with TFA for about 3.5 hours. Scheme 53

(IF) (24A) (24B)

(24D) (24C)

As shown in Scheme 53, conversion of (IF) to (24A) can be accomplished by treating the former with a protecting group precursor and an additive in a solvent. Specific examples of protecting group precursors include 1,1- dimethoxypropane, TBDMSC1, and benzaldehyde. Specific examples of additives include acids, and bases. More preferred are the following acids: TsOH, triflic acid, TFA and HCl. Specific examples of solvents include acetone, DCM, chloroform and THF. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (IF) in room temperature acetone is treated with 1, 1-dimethoxypropane and a catalytic amount of TsOH for about 16 hours.

Conversion of (24A) to (24B) can be accomplished by treating the former with a base, an alcohol and a cosolvent. Specific examples of bases include K₂C0_3| NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include, methanol, ethanol, and isopropanol . Specific examples of cosolvents include water, DCM and THF. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, a room temperature solution of (24A) in methanol-water is treated with K₂C0₃ for about two hours. Conversion of (24B) to (24C) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of oxidizing agents include DMSO and oxalyl chloride, DMSO and DCC, Dess-Martin periodinane, and PCC. Specific examples of solvents include DCM, chloroform, diethyl ether, or THF. Although the reaction generally proceeds at about -78 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, example (24B) in DCM is slowly added to a -78 °C solution of DMSO and oxalyl chloride in DCM. After about 1.5 hours, TEA is added and the reaction mixture is warmed to about 0 °C before quenching. Conversion of (24C) to (24D) can be accomplished by treating the former with an olefination reagent and a base in a solvent. Specific olefination reagents include phosphorus ylides, phosphonium salts, phosphine oxides, phosphonates , silicon based reagents, sulfonyl stabilized anions, selenium reagents, and titanium reagents. More preferred are the following phosphorus ylides: benzylidenetriphenyl-phosphorane, (methyl) triphenylphosphonium bromide, and (ethyl) triphenylphosphonium bromide. Specific examples of bases include KOt-Bu, NaNH₂, NaHMDS, or n-butyl lithium. Specific examples of solvents include toluene, benzene, DCM, DMSO or THF. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 24 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, KOt-Bu is added to a room temperature solution of (ethyl) triphenylphosphonium bromide in toluene and stirred for about four hours. The reaction mixture is then cooled to about 0°C and treated with (24C) in toluene for about 15 minutes.

The conversion of (24D) to (24E) can be accomplished by treating the former with a deprotecting agent in a solvent. Specific examples of deprotecting agents include aqueous acid, TBAF and hydrogen with a catalyst. More preferred are the following aqueous acids, AcOH, TFA, and TsOH. Specific examples of solvents include THF, MeOH, EtOAc, TBME, DCM, AcOH, and diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (24D) in room temperature acetic acid:water is stirred for about 16 hours.

Scheme 54

(24E) (24F) (24G)

( 24J- 2 )

As shown in Scheme 54, conversion of (24E) to (24F) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of oxidizing agents include NaI0₄, HI0₄, and Pb(0Ac)₄.

Specific examples of solvents include methanol, ethanol, isopropanol, and water, or mixtures thereof. Although the reaction generally proceeds at 0 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (24E) in 30% aqueous EtOH is treated with NaI0₄ for about one hour.

Conversion of (24F) to (24G) can be accomplished by treating the former with a nucleophile in a solvent such as diethyl ether, THF or TBME. Specific examples of nucleophiles include anions, Grignard reagents, azides, organozincates, organophosphorus compounds, tin enolates and nitriles. More preferred are the following nucleophiles: ethyl magnesium bromide, n-propyl magnesium bromide, isopropyl magnesium bromide, l-buten-4-yl magnesium bromide, isobutyl magnesium bromide, 2 -butyl magnesium bromide, the anion of acetonitrile, the anion of ethyl ethoxyacetate, the anion of ethyl acetate, the anion of (ethoxyethyloxymethyl) tributylstannane and methyl magnesium bromide. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 5 minutes to about 4 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, a -78 °C solution of the anion of ethyl ethoxyacetate in THF is treated with (24F) in THF for about one hour.

Conversion of (24G) to (24H) can be accomplished by treating the former with a reducing agent in a solvent. Specific examples of reducing agents include, NaCNBH₃, LiAlH₄, NaBH₄, LiBH , and DIBAL. Specific examples of solvents include THF, diethyl ether, TBME, methanol, and ethanol. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (24G) in room temperature methanol is treated with LiBH₄ for about 30 minutes. Conversion of (24H) to (241) can be accomplished by treating the former with a protecting group precursor and a base in a solvent. Specific examples of protecting group precursors include TBDPSC1, TBDMSC1, TMSCl, TESCl , benzyl bromide and TMSCl. Specific examples of bases include imidazole, TEA, 2 , 6-lutidine, pyridine, and diisopropylethylamine . Specific examples of solvents include DCM, chloroform, THF, methanol, water, and mixtures thereof. Although the reaction generally proceeds at 0 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 8 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (24H) in 0 °C DCM is treated with TBDPSCl and imidazole for about 45 minutes. Conversion of (241) to (24J) can be accomplished by treating the former with an oxidizing agent in a solvent. Specific examples of solvents include DCM, chloroform, and THF. Specific examples of oxidizing agents include DMSO and oxalyl chloride, DMSO and DCC, Dess-Martin periodinane, and PCC. Although the reaction generally proceeds at room temperature, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (241) in room temperature DCM is treated with Dess-Martin periodinane for about one hour .

Scheme 55

As shown in Scheme 55, conversion of (24J-2) to (24K) is accomplished by treating the former with an amine and a reducing agent in a solvent to afford the first intermediate which is converted to a second intermediate which is converted to a third intermediate which is converted into (24K) . Specific examples of amines include ammonia, benzylamine, N, N-diethylamine, methylamine, pyrrolidine, and ammonium salts. More preferred are the following ammonium salts: ammonium formate, ammonium acetate and ammonium chloride. Specific examples of reducing agents include, NaCNBH₃, LiAlH₄, NaBH₄ and DIBAL. Specific examples of solvents include methanol, ethanol, THF and DCM. Although the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure. The reaction time is generally about 1 hour to about 8 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (24J- 2) in methanol is treated with NaCNBH₃ and ammonium acetate and heated to about 60 °C for about 36 hours to afford the first intermediate.

Conversion of the first intermediate to the second intermediate is accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include, acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of organic bases include TEA, DMAP, pyrrolidine, diisopropylethylamine and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine or diethyl ether. Although the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the first intermediate in room temperature DCM is treated with acetic anhydride, TEA and DMAP for about 12 hours.

Conversion of the second intermediate to the third intermediate is accomplished by treating the former with a deprotecting agent in a solvent. Specific examples of deprotecting agents include HF and TBAF. Specific examples of solvents include THF, TBME, DCM and diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the second intermediate in room temperature THF is treated with TBAF for about three hours. Conversion of the third intermediate to (24K) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include, acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of organic bases include TEA, DMAP, pyrrolidine, diisopropylethylamine and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine or diethyl ether. Although the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the third intermediate in room temperature DCM is treated with acetic anhydride, TEA and DMAP for about 12 hours. Conversion of (24K) to (24L) can be accomplished by treating the former with a base, an alcohol and a cosolvent . Specific examples of bases include K₂C0₃, NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include, methanol, ethanol, and isopropanol. Specific examples of cosolvents include water, DCM and THF. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, a room temperature solution of (24K) in methanol is treated with K₂C0₃ for about 5 hours.

Conversion of (24L) to (24M) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the nitrogen is selectively deprotected by treating a dilute solution of (24L) in DCM with TFA for about two hours . Conversion of (24M) to (24N) can be accomplished by treating the former with a hydroxyl activating group precursor, in a solvent. Specific examples of hydroxyl activating groups include trifluoroacetic anhydride, azo compounds with a phosphine, trifluoromethanesulfonic anhydride, methanesulfonyl chloride, and para- toluenesulfonyl chloride. Specific examples of azo compounds include DEAD, and DIAD. Specific examples of phosphines include PPh₃, PEt₃, and PMe₃. Specific examples of solvents include DCM, chloroform, CC1₄, THF and 1,1,1- trichloroethane . Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (24M) in room temperature DCM is treated with DEAD and PPh₃ for about 30 minutes.

Conversion of (24N) to (240) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (24N) in room temperature DCM is treated with TFA for about 3.5 hours.

Scheme 56

As shown in Scheme 56, conversion of (24J-1) to (25A) can be accomplished by treating the former with an amine and a reducing agent in a solvent to afford the first intermediate which is converted to a second intermediate which is converted to a third intermediate which is converted into (25A) . Specific examples of amines include ammonia, benzylamine, N,N-diethylamine, methylamine, pyrrolidine, and ammonium salts. More preferred are the following ammonium salts: ammonium formate, ammonium acetate and ammonium chloride. Specific examples of reducing agents include, NaCNBH₃, LiAlH_4/ NaBH₄ and DIBAL. Specific examples of solvents include methanol, ethanol, THF and DCM. Although the reaction generally proceeds at reflux, the temperature of which can be determined by using a solvent of known boiling point at atmospheric pressure. The reaction time is generally about 1 hour to about 8 hours and can be selected depending on the reaction temperature. In a particularly preferred embodiment, (24J- 1) in methanol is treated with NaCNBH₃ and ammonium acetate and heated to about 60 °C for about about 36 hours to afford the first intermediate.

Conversion of the second intermediate to the third intermediate is accomplished by treating the former with a deprotecting agent in a solvent. Specific examples of deprotecting agents include HF and TBAF. Specific examples of solvents include THF, TBME, DCM and diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 4 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the second intermediate in room temperature THF is treated with TBAF for about three hours.

Conversion of the third intermediate to (25A) can be accomplished by treating the former with an acylating agent and a base in a solvent. Specific examples of acylating agents include, acetyl chloride, benzoyl chloride, and acetic anhydride. Specific examples of organic bases include TEA, DMAP, pyrrolidine, diisopropylethylamine and pyridine. Specific examples of solvents include DCM, chloroform, THF, TBME, pyridine or diethyl ether. Although the reaction generally proceeds at about 0 °C, it can be run at elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 24 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the third intermediate in room temperature DCM is treated with acetic anhydride, TEA and DMAP for about 12 hours. Conversion of (25A) to ,(25B) can be accomplished by treating the former with a base, an alcohol and a cosolvent . Specific examples of bases include K₂C0₃, NaOMe, NaOEt, NaOH, and KOH. Specific examples of alcohols include, methanol, ethanol, and isopropanol. Specific examples of cosolvents include water, DCM and THF. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 30 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, a room temperature solution of (25A) in methanol is treated with K₂C0₃ for about 5 hours .

Conversion of (25B) to (25C) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, the nitrogen is selectively deprotected by treating a dilute solution of (25B) in DCM with TFA for about two hours.

Conversion of (25C) to (25D) can be accomplished by treating the former with a hydroxyl activating group precursor, in a solvent. Specific examples of hydroxyl activating groups include trifluoroacetic anhydride, azo compounds with a phosphine, trifluoromethanesulfonic anhydride, ethanesulfonyl chloride, and para- toluenesulfonyl chloride. Specific examples of azo compounds include DEAD, and DIAD. Specific examples of phosphines include PPh₃, PEt₃, and PMe₃. Specific examples of solvents include DCM, chloroform, CC1₄, THF and 1,1,1- trichloroethane . Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 15 minutes to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (25C) in room temperature DCM is treated with DEAD and PPh₃ for about 30 minutes.

Conversion of (25D) to (25E) can be accomplished by treating the former with an acid in a solvent. Specific examples of acids include TsOH, triflic acid, TFA, and AcOH. Specific examples of solvents include DCM, THF, chloroform, or diethyl ether. Although the reaction generally proceeds at room temperature, it can be run at lower or elevated temperatures, as needed. The reaction time is generally about 1 hour to about 12 hours and can be selected depending on the reaction temperature. In a preferred embodiment, (25D) in room temperature DCM is treated with TFA for about 3.5 hours .

Compounds of formula I include compounds of formula la and lb. Representative compounds of formula I include: (±) - (3S,4£,4ai?,5S,7i?) -4- (acetylamino) -3-ethyl-l-oxo-5- [ (IZ) - 1-propenyl] hexahydropyrrolo [1, 2-c] [1,3] oxazine-7-carboxylic acid;

(±) - (35,4i?,4ai?,5S, 7R) -4- (acetylamino) -l-oxo-5- [ (IZ) -1- propenyl] -3-propylhexahydropyrrolo [1, 2-c] [1, 3] oxazine-7- carboxylic acid;

(±) - (3S, 4i?,4ai?,5S, 7R) -4- (acetylamino) -3-isopropyl-l-oxo-5- [ (IZ) -1-propenyl] hexahydropyrrolo [1, 2-c] [1, 3] oxazine-7- carboxylic acid;

(±) - (3i?,4i?,4aJR, 55, 1R) -4- (acetylamino) -3-isopropyl-l-oxo-5- [ (IZ) -1-propenyl] hexahydropyrrolo [1, 2-c] [1,3] oxazine-7- carboxylic acid; (±) - (4i?,4ai?, 5S, 7R) -4- (acetylamino) -5- [ (IZ) -1- propenyl] hexahydropyrrolo [1, 2-c] [1, 3] oxazine-7-carboxylic acid;

(±) - (3S,4i?,4ai?,5S, 7R) -4- (acetylamino) -3-ethyl-5- [ (IZ) -1- propenyl] hexahydropyrrolo [1, 2-c] [1,3] oxazine-7-carboxylic acid;

(±) - (3S,4i?,4ai?,5S,7i?) -4- (acetylamino) -5- [ (IZ) -1-propenyl] -3- propylhexahydropyrrolo [1, 2-c] [1,3] oxazine-7-carboxylic acid;

(±) - (35,4i?,4aJ?,5S, 7R) -4- (acetylamino) -3- (cyanomethyl) -5- [ (IZ) -1-propenyl] hexahydropyrrolo [1, 2-c] [1, 3] oxazine-7- carboxylic acid; (±) - (3S,4i?,4ai?,5S, 722) -4- (acetylamino) -3- (3-butenyl) -5- [ (IZ) -

1-propenyl] hexahydropyrrolo [1, 2-c] [1,3] oxazine-7-carboxylic acid;

(±) - (3S,4i?,4aJR,5S, 7R) -4- (acetylamino) -3 -isobutyl-5- [ (IZ) -1- propenyl] hexahydropyrrolo [1, 2-c] [1, 3] oxazine-7-carboxylic acid;

(±) - (3S,4i?,4ai?, 5S, 7R) -4- (acetylamino) -3- [ ( 1R) -1- methylpropyl] -5- [ (IZ) -1-propenyl] hexahydropyrrolo [1,2- c] [1, 3] oxazine-7-carboxylic acid; (±) - (4i?,4ai?,5S,7i?) -4- (acetylamino) -3 , 3-diethyl-5- [ (IZ) -1- propenyl] hexahydropyrrolo [1, 2-c] [1,3] oxazine-7-carboxylic acid;

(±) - (3S,4I?,4a. ,5S, 7R) -4- (acetylamino) -3-methyl-5- [ (IZ) -1- propenyl] -3-propylhexahydropyrrolo [1, 2-c] [1, 3] oxazine-7- carboxylic acid;

(±) - (3S, 4i?,4ai?, 5S, 7R) -4- (acetylamino) -3-hydroxy-5- [ (IZ) -1- propenyl] hexahydropyrrolo [1, 2-c] [1,3] oxazine-7-carboxylic acid monotrifluoro acetic acid salt;

(+) - (IS, 3R, 7S, 8R, 8aR) -8- (acetylamino) -7-hydroxy-5-oxo-l- [ (IZ) -1-propenyl] octahydro-3-indolizinecarboxylic acid;

(±) - (IS, 3R, 7R, 8J , 8ai?) -8- (acetylamino) -7-hydroxy-5-oxo-l-

[ (IZ) -1-propenyl] octahydro-3-indolizinecarboxylic acid;

(±) - ( 1S, 3R, 7R, 8R, 8&R) -8- (acetylamino) -7-hydroxy-l- [ (IZ) -1- propenyl] octahydro-3-indolizinecarboxylic acid monotrifluoro acetic acid salt;

(±) - (IS, 3R, 7R, 8R, 8aR) -8- (acetylamino) -7-ethoxy-l- [ (IZ) -1- propenyl] octahydro-3-indolizinecarboxylic acid monotrifluoro acetic acid salt; (±) - { 1S, 3R, 7R, 8R, 8aR) -8- (acetylamino) -7-hydroxy-l- [ (IZ) -1- propenyl] -7-propyloctahydro-3-indolizinecarboxylic acid monotrifluoro acetic acid salt;

(±) - ( 1S, 3R, 7S, 8R, 8aR) -8- (acetylamino) -7-hydroxy-7- (2- hydroxyethyl) -1- [ (IZ) -1-propenyl] octahydro-3- indolizinecarboxylic acid monotrifluoro acetic acid salt; (±) - (IS, R, 6S, 7R, 7aR) - 7 - (acetylamino) -6-hydroxy-l- [ (IZ) -1- propenyl] hexahydro-li-pyrrolizine-3 -carboxylic acid; (±) - (IS, 3R, 6R, 7R, 7aR) - 7 - (acetylamino) -6-hydroxy-l- [ (IZ) -1- propenyl] hexahydro-lH-pyrrolizine-3 -carboxylic acid;

(±) - (lS,3i?, βR, 7R, 7aR) -7- (acetylamino) -6-ethoxy-l- [ (IZ) -1- propenyl] hexahydro-lH-pyrrolizine-3-carboxylic acid monotrifluoroacetic acid salt; and

(±) - (lS,3i?,6S, 7R, 7aR) -7- (acetylamino) -6-ethoxy-l- [ (IZ) -1- propenyl] hexahydro-lH-pyrrolizine-3-carboxylic acid monotrifluoroacetic acid salt.

Preferred for the practice of the present invention are compounds of formula I wherein is selected from the group consisting of -OC(O)-, -CH₂C(0)-, -OCH₂-, and -(CH₂)_n-, Rx is -C0₂H, X is -N (R*) -C (=0) - , R* is hydrogen,

-R₂ is Cι-C₆ alkyl, Y is C₂-C₅ alkenyl, and

R₁₄ is -O-alkyl.

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, trifluoroacetate, adipate, alginate, citrate, aspartate, benzoate, 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, thio.cyanate, 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 loweralkyl) .

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, la, or lb of this invention can have a substituent which is an acid group (for example, -C0₂H, -S0₃H, -S0₂H, -P0₃H₂, -P0₂H) . Compounds of the formula I, la, or lb 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, la, or lb. 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:

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 loweralkyl esters, including, but not limited to, 2-methoxyethoxymethyl esters and the like;

aryloxyalkyl esters, especially, aryloxy-substituted loweralkyl esters, including, but not limited to, phenoxymethyl esters and the like, wherein the aryl group is unsubstituted or substituted as^" previously defined herein;

haloalkoxyalkyl esters, especially, haloalkoxy- substituted loweralkyl esters, including, but not limited to, 2 , 2 , 2-trichloroethoxymethyl esters and the like;

alkoxycarbonylalkyl esters, especially, loweralkoxycarbonyl-substituted loweralkyl esters, including, but not limited to, methoxycarbonylmethyl esters and the like; cyanoalkyl esters, especially, cyano-substituted loweralkyl esters, including, but not limited to, cyanomethyl, 2-cyanoethyl esters and the like;

thioalkoxymethyl esters, especially, lowerthioalkoxy- substituted methyl esters, including, but not limited to, methylthiomethyl, ethylthiomethyl esters and the like;

alkylsulfonylalkyl esters, especially, loweralkylsulfonyl-substituted loweralkyl esters, including, but not limited to, 2 -methanesulfonylethyl esters and the like;

arylsulfonylalkyl esters, especially, arylsulfonyl- substituted loweralkyl esters, including, but not limited to, 2 -benzenesulfonylethyl and 2 -toluenesulfonylethyl esters and the like;

acyloxyalkyl esters, especially, loweralkylacyloxy- substituted loweralkyl esters, including, but not limited to, formyloxymethyl , acetoxymethyl, pivaloyloxymethyl, 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;

(alkoxycarbonyloxy) alkyl esters, especially,

(loweralkoxycarbonyloxy) -substituted loweralkyl esters, including, but not limited to, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, 2- (ethoxycarbonyloxy) ethyl esters and the like;

(cycloalkyloxycarbonyloxy) alkyl esters, especially, (cycloalkyloxycarbonyloxy) -substituted loweralkyl esters, including, but not limited to, cyclohexyloxycarbonyloxymethyl , cyclopentyloxycarbonyloxyethyl , cyclohexyloxycarbonyloxypropyl esters and the like;

oxodioxolenylmethyl esters including, but not limited to, (5-phenyl-2-oxo-l, 3-dioxolen-4-yl) methyl, [5- (4- methylphenyl) -2-oxo-l, 3-dioxolen-4-yl] methyl, [5- (4- methoxyphenyl) -2-oxo-l, 3-dioxolen-4-yl] methyl, [5- (4- fluorophenyl) -2-oxo-l, 3-dioxolen-4-yl] methyl, [5- (4- chlorophenyl) -2-oxo-l, 3-dioxolen-4-yl] methyl, (2-oxo-l, 3- dioxolen-4-yl) methyl, (5-methyl-2-oxo-l, 3-dioxolen-4- yl) methyl, (5-ethyl-2-oxo-l, 3-dioxolen-4-yl) methyl, (5- propyl-2-oxo-l, 3-dioxolen-4-yl) methyl, (5 -isopropyl-2 -oxo- 1, 3-dioxolen-4-yl)methyl, (5-butyl-2-oxo-l, 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 loweralkyl 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;

dialkylaminoalkyl esters, especially dialkylamino- substituted loweralkyl 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 loweralkyl 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 loweralkyl 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, la, or lb are loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters, 3- pentyl esters, cycloalkyl esters, cycloalkylalkyl 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, la, or lb 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.

Other examples of prodrugs of the present invention include amides derived from the substituent which is an acid group.

Such amides contemplated by this invention include:

simple amides, such as -C(0)NH₂ and the like;

alkylamino amides, especially, loweralkylamino amides, including, but not limited to, methylamino, ethylamino, n-propylamino, isopropylamino amides and the like;

cylcoalkylamino amides, including, but not limited to, cylopropylamino, cylcobutylamino, cyclopentylamino, cyclohexylamino amides and the like; acylamino amides, including, but not limited to acetylamino, propionylamino, butanoylamino amides and the like;

cylcoalkylcarbonylamino amides, including, but not limited to, cyclopropylcarbonylamino, cyclobutylcarbonylamino amides and the like;

alkoxycarbonylalkylamino amides, including, but not limited to, ethoxycarbonylmethylamino, t- butyloxycarbonylmethylamino and the like;

aminoacylamino amides, including, but not limited to, aminoacetylamino amides and the like;

dialkylaminoacylamino amides, including, but not limited to, dimethylaminoacetylamino,- diethylaminoacetylamino amides and the like;

(heterocyclic) acylamino amides, including, but not limited to, piperidin-1-ylacetylamino amides and the like;

amides derived from single naturally occuring L-amino acids (or from acid-protected L-amino acids, for example, esters of such amino acids and the like) or from dipeptides comprising two naturally occuring L-amino acids wherein each of the two amino acids is the same or is different (or from acid-protected dipeptides, for example, esters of such dipeptides and the like) ;

and the like.

Methods for preparation of prodrug amides of compounds of the invention are well-known in the art and include reacting the acid with the appropriate amine in the presence of an amide bond or peptide bond- forming coupling reagent or reacting an activated derivative of the acid with the appropriate amine and the like.

Other examples of prodrugs of the present invention include esters of hydroxyl-substituted compounds of formula I, la, and lb 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(0)- 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(_Rb) (_Rd)__C(₀)- or R^a-C(R ) (R^d)-C(S)- wherein R 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 alkyl, (aryl) alkyl, (cycloalkyl) alkyl, acyl, benzoyl or an -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 hydroxyl-substituted compound of formula I, la, and lb 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 alkyl, 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.

The preparation of esters of hydroxyl-substituted compounds of formula I, la, and lb is carried out by reacting a hydroxyl-substituted compound of formula formula I, la, or lb 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, la, or lb with (halo) alkyl esters, transacetalization with bis- (alkanoyl) acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation 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, la, or lb 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 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 vi tro 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.

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 .

Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating 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 Iiposomes. As is known in the art, Iiposomes 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.

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, triamcinolone 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 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/Nl/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 supernatents 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/Nl/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 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-Interscience, New York) .

(1 - Vi/Vo) = [I]/ {[I] + Ki(l + [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 + 4Ki'Et} - (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(l + [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 Ki values between about 0.1 nanomolar and about 500 micromolar. Preferred compounds of the invention invention inhibit influenza A neuraminidase and influenza B neuraminidase with Ki values between about 0.1 nanomolar and about 3.5 micromolar.

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 Plague 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 ml 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 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.

Compounds of the invention provided plaque formation inhibition for influenza virus A/N2/Tokyo in MDCK cells with EC50 values between about 100 micromolar and about 1 nanomolar. Preferred compounds of the invention provided plaque formation inhibition for influenza virus A/N2/Tokyo in MDCK cells with EC50 values between about 1 micromolar and about 1 nanomolar. 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 IO^"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, andperiodically 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 following Examples will serve to further illustrate the preparation of the compounds of the invention, without limitation.

Examples

Example 1

(±) - (3S,4K,4ai?,5S.7i?) -4- (acetylamino) -3-ethyl-l-oxo-5- \ (IZ) - 1-propenyl] hexahydropyrrolo [1.2-c] [1,31 oxazine- 7-carboxylic acid

Example 1A (+) -tert-butyl {2R. R, 5S) -l-benzyl-4-formyl-5-vinyl-2- pyrrolidinecarboxylate (Example 1A-1) and

(±) -tert-butyl (2i?,4S,5S) -1-benzyl-4-formyl-5-vinyl-2- pyrrolidinecarboxylate (Example 1A-2) Acrolein (8 mL, 120 mmol) was added to a solution of t-butyl N-benzyl-glycinate (4.34 g, 19.6 mmol) and acetic acid (5 drops) in toluene (100 mL) . The reaction was refluxed for 1 hour, cooled to approximately 50 °C and additional acrolein (3 mL) was added. The reaction was heated at reflux for an additional 2 hours and concentrated. The concentrate was chromatographed on silica gel using 5% ethyl acetate in hexanes to afford 2.78 g (45%) of an oil. The oil was equilibrated to an 8/1 ratio (as determined by ¹H NMR) at position 3 by stirring the chromatographed product with triethylamine (0.5 mL) in ethyl acetate at room temperature, followed by evaporation of the solvents.

Example 1A-1, ^XHNMR (CDC1₃) : δ 1.45 (s, 9H) , 2.26 (m, 1H) , 2.69 (m, 1H) , 3.49 (dd, J=7.8, 3.0 Hz, 1H) , 3.61 (d, J=13.5 Hz, 1H) , 3.93 (m, 1H) , 3.94 (d, J=13.5 Hz, 1H) , 5.22-5.33 (two dd, 2H) , 5.7 (ddd, J=17.7, 10.2, 7.8 Hz, 1H) , 7.21- 7.35 (m, 5H) , 9.71 (d, J=1.2 Hz, 1H) . MS: (M+H)⁺ = 316.

Example IB

(±) -tert-butyl ( 2R. 4R. 5S) -l-benzyl-4- (hydroxymethyl) -5- vinyl-2 -pyrrolidinecarboxylate Sodium borohydride (0.72 g, 19.0 mmol) was added to a 0 °C solution of Example 1A (6.0 g, 19.0 mmol) in methanol (100 mL) . The reaction mixture was stirred for 0.5 hours, warmed to room temperature, and stirred for an additional 1 hour. The reaction mixture was quenched with aqueous ammonium chloride, and concentrated. The concentrate was partitioned between ethyl acetate and water, the layers were separated and the ethyl acetate was dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using a gradient of 20- 30% ethyl acetate in hexanes to afford 4.0 g (66%) of the desired product as a colorless oil.

^XH NMR (CDC1₃) : δ 1.46 (s, 9H) , 1.80 (m, 1H) , 2.16 ( , 1H) , 2.39 (m, 1H) , 2.54 (m, 1H) , 3.48-3.53 (m, 2H) , 3.08 (d, 2H) , 3.91 (d, 2H) , 5.17-5.22 (m, 2H) , 5.70 (m, 1H) , 7.23- 7.34 (m, 5H) . MS: (M+H)⁺ = 318.

Example IC

(±) -tert-butyl (2K.4K.5S) -4- [ (acetyloxy) methyll -l-benzyl-5- vinyl-2-pyrrolidinecarboxylate Acetic anhydride (30 mL, 0.32 mol) was added to a 0 °C solution of Example IB (54.2 g, 0.17 mol) and 4- (dimethylamino) pyridine (0.5 g, 4.1 mmol), in anhydrous pyridine (400 mL) . The reaction mixture was stirred for 1 hour, allowed to warm to room temperature and stirred for an additional 16 hours. The reaction mixture was concentrated, and partitioned between ethyl acetate (100 mL) and water (400 mL) . The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and the combined ethyl acetate layers were washed with brine, dried (MgS0 ) , filtered, and concentrated. The concentrate was purified by column chromatography on silica gel using 10% ethyl acetate in hexanes to afford 49.6 g (81%) of the desired product as a colorless oil.

*H NMR (CDC1₃) : δ 7.28 (m, 4H) , 7.21 (m,lH), 5.68 (m,lH), 5.21 (m, 2H) , 4.16 (dd, J=6.3, 10.7 Hz, 1H) , 4.10 (dd, J=7.3, 10.7 Hz, 1H) , 3.92 (d, J=13.7 Hz, 1H) , 3.64 (d, J=13.7 Hz, 1H) , 3.52 (m, 1H) , 3.50 (m, 1H) , 2.33 (m, 1H) , 2.26 (m, 1H) , 2.02 (s, 3H) , 1.62 (m, 1H) , 1.45 (s, 9H) . MS: (M+H)⁺ = 360. Example ID (±) -tert-butyl ( 2R. R . 5R) -4- [ (acetyloxy) methyl] -1-benzyl -5- ( 1R) -1, 2-dihvdroxyethyl] -2 -pyrrolidinecarboxylate (Example 1D-1) and

(±) -tert-butyl (2R.4K.5i?) -4- f (acetyloxy) methyl! -l-benzyl-5- r (IS) -1, 2-dihydroxyethvπ -2-pyrrolidinecarboxylate (Example

1D-2) Osmium tetroxide (200 mg, 0.8 mmol) was added to a solution of Example IC (52.5 g, 0.15 mol) and 4- methylmorpholine N-oxide (54.7 g, 0.47 mol) in acetone (540 mL) and water (60 mL) . After 24 hours, the reaction mixture was quenched with 10% sodium thiosulfate (250 mL) and partially concentrated. The resulting aqueous layer was extracted with ethyl acetate (3 x 300 mL) and the combined ethyl acetate layers were washed with brine, dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using a gradient of ethyl acetate and dichloromethane to afford 41.2 g, (72%) of a mixture of the desired products as a viscous oil . H NMR (DMSO-d₆) : δ 7.32 (m, 3H) , 7.30 (m, 1H) , 7.22 (m, 1H) , 4.48 (t, J=5.4 Hz, 1H) , 4.42 (d, J=5.4 Hz, 1H) , 4.04 (m, 1H) , 4.01 (m, 1H) , 3.97 (m, 1H) , 3.80 (d, J=13.2 Hz, 1H) , 3.78 (m, 1H) , 3.43 (m, 1H) , 3.39 (m, 1H) , 3.32 (m, 1H) , 3.07 (t, J=4.9 Hz,lH), 2.48 (m, 1H) , 2.19 (m, 1H) , 1.99 (s, 3H) , 1.57 (dt, J=13.7, 2.0 Hz, 1H) , 1.38 (s, 9H) . MS: (M+H)⁺ = 394. Example IE (±) -tert-butyl (2i?.4i?.5i?)-4- \ (acetyloxy) methyll -5- \ (li?) -1.2- dihydroxyethyll -2 -pyrrolidinecarboxylate (Example 1E-1) and (±) -tert-butyl (2i?.4i?, 5i?) -4- (acetyloxy) methyll -5- [ (IS) -1.2- dihydroxyethyl] -2 -pyrrolidinecarboxylate (Example 1E-2) Example ID (24 g, 61 mmol), ammonium formate (38.5 g, 0.61 mol), and 10% Pd/C (2g) were combined in ethanol (300 mL) and refluxed for 2 hours. The reaction mixture was cooled and the catalyst removed by filtering through a plug of celite. The filtrate was concentrated to afford 16.7 g, (90%) of the desired products as a mixture. ^XH NMR (DMSO-ds) : δ 4.56 (m, 1H) , 4.30 (m, 1H) , 4.06 (dd, J=5.8, 10.9 Hz, 2H) , 3.79 (dd, J=8.8, 10.5 Hz, 2H ), 3.49 (m, 4H) , 3.00 (m, 1H) , 2.35 (m, 1H) , 2.16 (dt, J=12.6, 8.5 Hz, 1H) , 2.01 (s, 3H) , 1.52 (m, 1H) , 1.40 (s, 9H) . MS: (M+H)⁺ = 304.

Example IF (±) -di (tert-butyl) (2i?.4i?.5i?) -4- \ (acetyloxy) methyll -5- r (li?) - 1, 2-dihydroxyethyll -1.2-pyrrolidinedicarboxylate (Example 1F-1) and

(+) -di (tert-butyl) (2i?, 4i?.5i?) -4- T (acetyloxy) methyll -5- r (IS) -

1 , 2 -dihydroxyethyll -1 , 2-pyrrolidinedicarboxylate (Example

1F-2) di- -butyl dicarbonate (33.6 g, 0.15 mol) Was added to Example IE (33.4 g, 0.11 mol) in room temperature methanol (250 mL) and water (50 mL) . After stirring for 48 hours the reaction mixture was partially concentrated. The resulting aqueous layer was diluted with water (500 L) , and extracted with ethyl acetate (3 x 200 mL) . The combined ethyl acetate layers were washed with brine, dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using methanol in dichloromethane to afford 32.8 g (78%) of a mixture of the desired products as a white solid. U NMR (DMSO-de) : δ 4.80 (m, 1H) , 4.45 (m, 1H) , 4.08 (m, 1H) , 3.91 (m, 2H) , 3.82 (m, 1H) , 3.71 (m, 1H) , 3.28 (m, 2H) , 2.48 (m, 1H) , 2.07 (m, 2H) , 2.01 (m, 3H) , 1.39 ( , 18H) . MS: (M+H)⁺ = 404.

Example 1G (±) -di (tert-butyl) 12R. 4R . 5R) -4- r (acetyloxy) methyll -5-( (li?) l-hydroxy-2- [ (triisopropylsilyl) oxyl ethyl} -1,2- pyrrolidinedicarboxylate (Example 1G-1) and (±) -di (tert-butyl) (2R. 4R .5i?) -4- [ (acetyloxy) methyll -5-( (IS) - 1-hydroxy-2- [ (triisopropylsilyl) oxy] ethyl} -1,2- pyrrolidinedicarboxylate (Example 1G-2) Triisopropylsilyl chloride (19.0 g, 99 mmol) was added to a room temperature solution of Example 1F-1 (26.5 g, 66 mmol) and imidazole (8.9 g, 0.13 mol) in anhydrous dimethylformamide (200 mL) . After 4 hours, the reaction mixture was concentrated. The concentrate was partitioned between water (300 mL) and ethyl acetate (150 mL) . The aqueous layer was extracted with ethyl acetate (2 x 100 mL) , and the combined ethyl acetate layers were washed with brine, dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 10% ethyl acetate in hexanes to provide 28.9 g (79%) of a mixture of the desired products as a colorless oil .

^XH NMR (CDC1₃) : δ 4.22 (m, 1H) , 4.04 (m, 3H) , 3.87 (t, J=2.0 Hz, 1H) , 3.74 (dd, J=4.9, 9.8 Hz, ^"lH), 3.58 (dd, J=7.8, 10.2 Hz, 1H) , 3.39 (bs, 1H) , 2.61 (m, 2H) . 2.03 (s, 3H) , 1.75 (m, 1H) , 1.46 (m, 18H) , 1.07 (m , 18H) . MS: (M+H)⁺ = 560.

Example 1H

(±) -di (tert-butyl) (2i?, 4i?, 5i?) -4- r (acetyloxy) methyll -5-

{ [ (triisopropylsilyl) oxy] acetyl} -1,2- pyrrolidinedicarboxylate Dimethylsulfoxide (6 mL, 85 mmol) was slowly added to a -78 °C solution of oxalyl chloride (2 M, 19.3 mL, 38.6 mmol) in dichloromethane (70 mL) . After 10 minutes, a solution of Example IG (14.4 g, 26 mmol) in dichloromethane (75 mL) was slowly added to the reaction mixture so that the reaction temperature did not exceed -70 °C. After 1.5 hours, triethylamine (18 mL, 130 mmol) was added and the reaction was warmed to 0°C. The reaction was quenched with a solution of ammonium chloride, diluted with water, and extracted with dichloromethane (3 x 100 mL) . The combined dichloromethane layers were washed with brine, dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 10% ethyl acetate in hexanes to afford 11 g (77%) of the desired product as a colorless oil.

^XH NMR (CDC1₃) : δ 4.32 (m, 6H) , 2.43 (m, 2H) , 2.04 (s. 3H) , 1.78 (m, 1H) , 1.48 (s, 9H) , 1.41 (s, 9H) , 1.1 (m, 21H) . MS: (M+H)⁺ = 558.

Example II (±) -di (tert-butyl) ( 2i?. 4R. 5i?) -4 - (acetyloxy) methyll -5 - ( ( li?) l-amino- 2 - T (triisopropylsilyl) oxyl ethyl } - 1 , 2 - pyrrolidinedicarboxylate (Example 11 - 1 ) and (±) -di (tert-butyl) (2i?.4i?.5i?) -4- T (acetyloxy) methyll -5-( (IS) - l-amino-2- [ (triisopropylsilyl) oxyl ethyl} -1.2- pyrrolidinedicarboxylate (Example 11-2) Sodium cyanoborohydride (24.8 g, 390 mmol) was added to Example 1H (22 g, 39 mmol) and ammonium acetate (77 g, 1.0 mol) in methanol (1 L) . The reaction mixture was refluxed for 2 hours and then concentrated. The concentrate was partitioned between water (300 mL) and dichloromethane (300 mL) . The aqueous layer was extracted with dichloromethane (2 x 100 mL) and the combined dichloromethane layers were washed with brine, dried (MgS0₄) , filtered and concentrated to afford 22. Og (100%) of the crude, desired product.

Example 1J (±) -di (tert-butyl) (2i?.4i?.5i?) -5-{ (li?) -1- (acetylamino) -2- F (triisopropylsilyl) oxy] ethyl} -4- I (acetyloxy) methyl] -1,2- pyrrolidinedicarboxylate (Example 1J-1) and

(+) -di (tert-butyl) (2i?, 4i?, 5i?) -5-{ (IS) -1- (acetylamino) -2-

[ (triisopropylsilyl) oxy] ethyl} -4- I (acetyloxy) methyl] -1.2- pyrrolidinedicarboxylate (Example 1J-2) Acetic anhydride (18 mL, 190 mmol) , was added to a room temperature solution of Example II (approx. 39 mmol) , triethylamine (27.5 mL, 0.20 mol) and dimethylaminopyridine (50 mg, 0.39 mmol) in dichloromethane (500 mL) . After 18 hours, the reaction mixture was quenched with a solution of ammonium chloride. The aqueous layer was extracted with dichloromethane (3 x 100 mL) and the combined dichloromethane layers were washed with brine, dried (MgS0₄) , filtered, and concentrated. The concentrate was purified by column chromatography on silica gel using ethyl acetate in hexanes to afford 9.14 g (39%) of the desired product, Example 1J-1, as a white solid.

Example 1J-1, ^XH NMR (CDC1₃) : δ 7.38 (d, J=8.3 Hz, IH) , 4.34 (m, IH) , 4.20 (dd, J=2.4, 10.3 Hz, IH) , 4.09 (dd, J=8.8, 10.2 Hz. IH) , 4.02 (dd, J=7.3, 10.1 Hz, IH) , 3.88 (m, IH) , 3.71 (dd, J=4.4, 10.3 Hz, IH) , 3.65 (dd, J=7.9, 10,3 Hz, IH) , 2.74 (m, IH) , 2.60 (m, IH) , 2.04 (s, 3H) , 1.98 (s, 3H) , 1.69 (dt, J=14.1, 2.5 Hz, IH) , 1.46 (s, 9H) , 1.42 (s, 9H) , 1.07 (m, 21H) . MS: (M+H)⁺ = 601.

Example 1J-2, ^XH NMR (CDC1₃) : δ 6.82 (d, IH) , 4.10 (m, 4H) , 3.81 (m, 3H) , 2.55 (m, 2H) , 1.98 (m, 7H) , 1.46 (s, 9H) , 1.42 (s, 9H) , 1.07 (m, 21H) . MS: (M+H)⁺ = 601.

Example IK (±) -di (tert-butyl) (2i?.4i?, 5i?) -5-( (li?) -1- (acetylamino) -2- [ (triisopropylsilyl) oxy] ethyl} -4- (hydroxymethyl) -1.2- pyrrolidinedicarboxylate

Potassium carbonate (19 g, 136 mmol) was added to a room temperature solution of Example 1J-1 (8.2 g, 13.66 mmol) in methanol (200 mL) and water (50 mL) . After 2 hours, the reaction mixture was concentrated and the concentrate was partitioned between water (100 mL) and dichloromethane. The aqueous layer was extracted with dichloromethane (3 x 100 mL) and the combined dichloromethane layers were washed with brine, dried (MgS0₄) , filtered and concentrated to afford 6.56 g (86%) of the crude, desired product as a colorless oil. ^XH NMR (CDC1₃) : δ 7.31 (d, J=8.8 Hz, IH) , 4.35 (ddt, J=1.5, 7.4, 6.8 Hz, IH) , 4.18 (dd, J=3.4, 9.7 Hz, IH) , 3.83 (dd, J=1.2, 4.6 Hz, IH) , 3.64 (m, 4H) , 2.50 (m, 3H) , 1.99 (s, 3H) , 1.70 (dt, J=13.2, 3.9 Hz, IH) , 1.46 (s, 9H) , 1.43 (s, 9H) , 1.07 (m, 21H) . MS: (M+H)⁺ = 559.

Example IL

(±) -di (tert-butyl) (2i?.4i?.5i?) -5-{ (li?) -1- (acetylamino) -2- [ (triisopropylsilyl) oxy] ethyl} -4-formyl-l .2- pyrrolidinedicarboxylate Dimethylsulfoxide (6.5 mL, 92 mmol) was slowly added to a -78 °C solution of oxalyl chloride (2 M, 20 mL, 40 mmol) in dichloromethane (75 mL) . After 10 minutes, a solution of Example IK (6.56 g, 11.7 mmol) in dichloromethane (75 mL) was slowly added to the reaction mixture so that the reaction temperature did not exceed -70 °C. After 1.5 hours, triethylamine (22 mL, 158 mmol) was added and the reaction was warmed to 0°C. The reaction was quenched with a solution of ammonium chloride, diluted with water (200mL) , and extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 50% ethyl acetate in hexanes to afford 5.9 g (78%) of the desired product as a colorless solid.

^XH NMR (CDC1₃) : δ 1.04-1.07 (m, 21H) , 1.42 (s, 9H) , 1.43 (s, 9H) , 1.99 (s, 3H) , 2.42 (m, IH) , 2.62 (m, IH) , 3.04 (m, IH) , 3.69 (m, IH) , 3.82 (m, IH) , 4.08 (m, IH) , 4.38 (m, IH) , 4.57 (t, IH) , 7.33 (br d, IH) , 9.65 (s, IH) . MS: (M+H)⁺= 557.

Example 1M (±) -di (tert-butyl) (2i?.4S,5i?) -5-( (li?) -1- (acetylamino) -2- [ (triisopropylsilyl) oxyl ethyl} -4- f (IZ) -1-propenyl] -1,2- pyrrolidinedicarboxylate

Potassium tert-butoxide (1M in THF, 9.2 mL, 9.2 mmol) was added dropwise to a room temperature solution of (ethyl) triphenylphosphonium bromide (4.54 g, 12.22 mmol) in toluene (100 mL) . After stirring overnight, Example IL (3.4 g, 6.12 mmol) in toluene (100 mL) was added dropwise. After 30 minutes, water (100 mL) was added followed by extraction with dichloromethane (3 x 200 mL) . The combined dichloromethane layers were dried (MgS0₄) , filtered, and concentrated. The concentrate was purified by column chromatography using 33% ethyl acetate in hexanes to afford 2.75g (79%) of the desired product as a colorless solid. ^XH NMR (CDC1₃) : δ 1.03-1.10 (m, 21H) , 1.44 (s, 9H) , 1.47 (s, 9H) , 1.55 (m,lH), 1.64 (dd, 3H) , 1.96 (s, 3H) , 2.55 (m, IH) , 3.42 (m, IH) , 3.62-3.71 (m, 3H) , 4.20 (dd, IH) , 4.30 (m, IH) , 5.39 (m, IH) , 5.48 (m, IH) , 7.73 (br d, IH) . MS: (M+H)⁺ = 569.

Example IN (±) -di (tert-butyl) (2i?.4S.5i?) -5- \ (li?) -1- (acetylamino) -2- hvdroxyethyl] -4- [ (IZ) -1-propenyl] -1,2- pyrrolidinedicarboxylate Tetrabutyl ammonium fluoride (1M in THF, 12.8 mL, 12.8 mmol) was added to a room temperature solution of Example 1M (4.85 g, 8.54 mmol) in THF (100 mL) . After 30 minutes, water (100 mL) was added followed by extraction with dichloromethane (2 x 100 mL) . The combined dichloromethane layers were dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 66% ethyl acetate in hexanes to afford 3. Ig (89%) of the desired product as a colorless solid.

^XH NMR (CDC1₃) : δ 1.44 (s, 9H) , 1.47 (s, 9H) , 1.56 (dd, 3H) , 1.80 (m, IH) , 2.02 (s, 3H) , 2.67 (m, IH) , 3.11 (t, 3H) ,

3.44 (dd, IH) , 3.59 (dd, IH) , 3.74-3.84 (m, 2H) , 4.15 (dd, IH) 5.39 (m, IH) , 5.58 (m, IH) , 6.42 (br d, IH) . MS: (M+H)⁺ = 413.

Example 10

(±) -di (tert-butyl) (2i?.4S, 5i?) -5- \ (li?) -1- (acetylamino) -2- oxoethyl] -4- [ (IZ) -1-propenyl] -1 , 2-pyrrolidinedicarboxylate Dess-Martin Periodinane (928 mg, 2.18 mmol) was added to a room temperature solution of Example IN (600 mg, 1.46 mmol) in dichloromethane (50 mL) . After 1 hour, the reaction was quenched with 1M aqueous sodium thiosulfate (50 mL) , stirred for 20 minutes, and then extracted with dichloromethane (3 x 100 mL) . The combined dichloromethane layers were dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 66% ethyl acetate in hexanes to afford 547 mg (92%) of the desired product.

^XH NMR (CDC1₃) : δ 9.40 (d, J=l Hz, IH) , 7.88 (bd) , 5.69 (m, IH) , 5.27 (m, IH) , 4.78 (dd, J=9.5, 1. Hz, IH) , 4.21 (t, J=8. Hz, IH) , 3.45 (m, 2H) , 2.41 (m, IH) , 2.09 (s, 3H) , 1.69 (dd, J= 7.0, 1. Hz, 3H) , 1.55 (m, IH) , 1.46 (s, 9H) , 1.40 (s, 9H) .

MS: (M+H)⁺ = 411, (M-H) ^" = 409.

Example IP (±) -di (tert-butyl) (2i?.4S, 5i?) -5- I ( 1R. 2R) -1- (acetylamino) -2- hydroxybutyl] -4- [ (IZ) -1-propenyl] -1.2- pyrrolidinedicarboxylate (Example 1P-1) and (±) -di (tert-butyl) (2i?,4S.5i?) -5- [ (li?.2S) -1- (acetylamino) -2- hydroxybutyl] -4- [ (IZ) -1-propenyl] -1.2- pyrrolidinedicarboxylate (Example 1P-2) A solution of Example 10 (780 mg, 1.90 mmol) in THF (20 mL) was added dropwise to a room temperature solution of ethylmagnesium bromide (3M in ether, 3.17 mL, 9.51 mmol) in THF (15 mL) . After 40 minutes, the reaction was quenched with water (20 mL) and saturated aqueous ammonium chloride (20 mL) , and extracted with dichloromethane (3 x 50 mL) . The combined dichloromethane layers were dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 66% ethyl acetate in hexanes to afford 472 mg, (56%) of Example 1P-1, and 82 mg (10%) of Example 1P-2, both as colorless oils . Example 1P-1, ^XH NMR (CDC1₃) : 5.96 (d, J=9.8Hz, IH) , 5.61

(m, IH) , 5.36 (m, IH) , 4.63 (d, J=3.7Hz, IH) , 4.16 (dd,

J=10.2, 1.4Hz, IH) , 3.73 (m, 2H) , 3.39 (m, IH) , 3.10 (m,

IH) , 2.71 (m, IH) , 2.01 (s, 3H) , 1.82 (d, J=13.5Hz, IH) ,

1.55 (dd, J=6.8, 1.7Hz , 3H) , 1.47 (s, 9H) , 1.45 (s, 9H) , 1.34 (m, IH) , 0.93 (t, J=7.5Hz, 3H) .

MS: (M+H)⁺ = 441, (M+Na)⁺ = 463, (M-H) ^" = 439. Example 1P-2, ^XH NMR (CDC1₃) 7.39 (d, J=8.5Hz, IH) , 5.47 (m, 2H) , 4.17 (dd, J=9.8, 3.1Hz, IH) , 4.08 (m, IH) , 3.81 (m, IH) , 3.67 (m, IH) , 3.45 (m, IH) , 3.22 (m, IH) , 2.61 (m, IH) , 2.01 (s, 3H) , 1.71 (dt, J=13.4, 3.1Hz, IH) , 1.61 (d, J=5.4Hz, 3H) , 1.47 (s, 9H) , 1.44 (s, 9H) , 1.38 (m, IH) , 0.98 (t, J=7.3Hz, 3H) . MS: (M+H)⁺ = 441, (M+Na)⁺ = 463, (M-H)^" = 439.

Example 10 (±) -di (tert-butyl) (2i?.4S.5i?) -5- [ (li?) -1- (acetylamino) -2- oxobutyll -4- [ (IZ) -1-propenyl] -1 , 2-pγrrolidinedicarboxylate Dess-Martin Periodinane (666 mg, 1.57 mmol) was added to a room temperature solution of Example 1P-1 (460 mg, 1.05 mmol) in dichloromethane (30 mL) . After 17 hours, the reaction was quenched with 1M aqueous sodium thiosulfate (50 mL) , stirred for 20 minutes, and extracted with dichloromethane (3 x 100 mL) . The combined dichloromethane layers were dried (MgS0 ) , filtered, and concentrated. The concentrate was purified by column chromatography on silica gel using 66% ethyl acetate in hexanes to afford 440 mg (96%) of the desired product as a colorless semi-solid. ^XH NMR (CDC1₃) d 7.61 (d, J=8.5Hz, IH) , 5.54 ( , IH) , 5.33 (m, IH) , 4.95 (dd, J=8.8, 1.7Hz, IH) , 4.19 (dd, J=8.5,

6.1Hz, IH) , 3.69 (dd, J=6.3, 1.6Hz , IH) , 3.36 (m, IH) , 2.62 (m, IH) , 2.47 (m, IH) , 2.41 (m, IH) , 2.06 (s, 3H) , 1.61 (dd, J=6.8, 1.7 Hz, 3H) , 1.56 (m, IH) , 1.46 (s, 9H) , 1.42 (s, 9H) , -0.97 (t, J=7.1Hz, 3H) . MS: (M+H)⁺ = 439, (M+Na) ⁺ = 461, (M-H)^'" = 437.

Example 1R (±) -di (tert-butyl) (2i?.4S.5i?) -5- [ (li?.2S) -1- (acetylamino) -2- hydroxybutyl] -4- [ (IZ) -1-propenyl] -1, 2- pyrrolidinedicarboxylate (Example 1R-1) and (±) -di (tert-butyl) (2i?, 4S.5i?) -5- [ (li?.2i?) -1- (acetylamino) -2- hydroxybutyll -4- [(IZ) -1-propenyl] -1,2- pyrrolidinedicarboxylate (Example 1R-2)

Sodium borohydride (188 mg, 4.97 mmol) was added to a room temperature solution of Example IQ (435 mg, 0.99 mmol) in methanol (30 mL) . After 0.5 hours, the reaction mixture was concentrated and water (30 mL) was added. The aqueous layer was extracted with dichloromethane (3 x 50 mL) . The combined dichloromethane layers were dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 66% ethyl acetate in hexanes to afford 305 mg (70%) of Example 1R-1, and 17 mg (4%) of Example 1R-2.

Example IS (±) -tert-butyl (3S.4i?.4ai?, 5S.7i?) -4- (acetylamino) -3-ethyl-l- oxo-5- T (IZ) -1-propenyll hexahydropyrrolo , 2-c] [1,31 oxazine-

7-carboxylate Thionyl chloride (12.1 mg, 0.102 mmol) was added to a room temperature solution of Example 1R-2 (11.2 mg, 0.0254 mmol) in chloroform (0.5 mL) . After 24 hours, the reaction was concentrated. The concentrate was purified by column chromatography on silica gel using 66% ethyl acetate in hexanes to afford 3.0 mg (32%) of the desired product. MS: (M+H)⁺ = 311, (M+Na)⁺ = 333, (M-H)^" = 309.

Example IT (+) - (3S,4i?,4ai?,5S,7i?) -4- (acetylamino) -3-ethyl-l-oxo-5- r (IZ) - 1-propenyl1 hexahydropyrrolo [1, 2-c] [1,3] oxazine-7-carboxylic acid

Trifluoroacetic acid (0.8 mL) was added to a room temperature solution of Example IS (2.3 mg, 0.0063 mmol) in dichloromethane (0.2 mL) . After 3.5 hours, the reaction was concentrated to provide 2.2 mg (100 %) of the desired product as a colorless oil.

^XH NMR (DMSO-de) : δ 7.73 (d, J=9.2Hz, IH) , 5.46 (dq, J=11.0,

7.3Hz, IH) , 5.18 (bt, J=9.2 Hz, IH) , 4.25 (dd, J=8.9,

7.9Hz, IH) , 4.02 (m, IH) , 3.84 (q, J=9.8Hz, IH) , 3.32 (t,

J=9.8Hz, IH) , 2.95 (m, IH) , 2.33 (dt, J=12.2, 7.3Hz , IH) ,

1.75 (s, 3H) , 1.66 (m, IH) , 1.53 (dd, J=7.0,1.6Hz, 3H) ,

1.5-1.35 (m, 2H) , 0.90 (t, J=7.6Hz, 3H) .

MS: (M+H)⁺ = 311, (M+Na)⁺ = 333, (M-H)^" = 309.

Example 2

(±) - (3S.4i?.4ai?,5S.7i?) -4- (acetylamino) -l-oxo-5- r (IZ) -1- propenyl] -3-propylhexahvdropyrrolo [1, 2-cl Tl , 3] oxazine-7- carboxylic acid

Example 2A

(±) -di (tert-butyl) (2i?.4S.5i?) -5- (li?.2S) -1- (acetylamino) -2- hvdroxypentyll -4- [ (IZ) -1-propenyll -1,2- pyrrolidinedicarboxylate (Example 2A-1) and

(±) -di (tert-butyl) (2i?.4S.5i?) -5- [ (li?.2i?) -1- (acetylamino) -2- hydroxypenty1]-4-[(lZ)-l-propenyl1 -1,2- pyrrolidinedicarboxylate

The title compounds were prepared according to the method described in Example IP, substituting propyl magnesium bromide for ethyl magnesium bromide to afford 1 mg (1%) of Example 2A-1, and 32 mg (39%) Example 2A-2. Example 2A-1, ^XH NMR (CDC1₃) : δ 7.51 (d, J=8.2Hz, IH) , 5.46 (m, 2H) , 4.17 (dd, J=3.1, 6.8Hz, IH) „ 4.05 (m, IH) 3.81 (t, J=3.4Hz, IH) , 3.54 (m, IH) , 3.21 (m, IH) , 2.60 (m, IH) , 2.02 (s, 3H) , 1.70 (dt, J=3.0, 7.4Hz, IH) , 1.61 (d, J=5.4Hz, 3H) , 1.54 (m, IH) , 1.47 (s, 9H) , 1.44 (s, 9H) , 1.32 (m, 4H) , 0.90 (t, J=7.1Hz, 3H) . MS: (M+H)⁺ = 455, (M+Na) ⁺ = 477, (M-H)^' = 453. Example 2A-2, ^XH NMR (CDC1₃) : δ 5.98 (d, J=9.5Hz, IH) , 5.60 (t, J=9.8Hz, IH) , 5.36 (m, IH) , 4.16 (m, IH) , 3.75 (d, J=10.1Hz, IH) , 3.64 (m, IH) , 3.51 (m, IH) , 3.09 (br t, IH) , 2.68 (m, IH) , 2.02 (s, 3H) , 1.81 (d, J=13.9Hz, IH) , 1.57 (m, 4H) , 1.54 (dd, J=l .7 , 5.1Hz, 3H) , 1.46 (s, 9H) , 1.45 (s, 9H) , 0.88 (t, J=6.8Hz, 3H) . MS: (M-H)^" = 453; (M+H) ⁺ = 455.

Example 2B (±) -tert-butyl (3S, 4i?, 4ai?, 5S.7i?) -4- (acetylamino) -l-oxo-5- [(1Z) -1-propenyl] -3-propylhexahvdropyrrolo Tl , 2- cl ri, 31 oxazine-7-carboxylate Thionyl chloride (19.0 mg, 0.159 mmol) was added to a room temperature solution of Example 2A-1 (18.0 mg, 0.0396 mmol) in chloroform (2.0 mL) . After 24 hours, the reaction mixture was concentrated. The concentrate was purified by column chromatography on silica gel using 50% ethyl acetate in hexanes to afford 4.6 mg (30%) of the desired product. MS: (M+H)⁺ = 381, (M+Na)⁺ = 403, (M-H)^" = 379.

Example 2C (±) - (3S, 4i?.4ai?, 5S, 7i?) -4- (acetylamino) -l-oxo-5- r (IZ) -1- propenyl] -3-propylhexahvdropyrrolo [1 , 2-cl [1.3] oxazine-7- carboxylic acid Trifluoroacetic acid (0.8 mL) was added to a room temperature solution of Example 2B (3.9 mg, 0.010 mmol) in dichloromethane (0.2 mL) . After 3 hrs, the reaction was concentrated to provide 3.7 mg (100 %) of the desired product as a colorless oil.

^XH NMR (DMSO-dg) : δ 7.74 (d, J=9.8Hz, IH) , 5.46 (dq, J=10.7, 7.0Hz, IH) , 5.18 (bt, J=8.2 Hz, IH) , 4.25 (dd, J=9.8, 7.9Hz, IH) , 4.04 (m, IH) , 3.82 (q, J=9.8Hz, IH) , 3.31 (t, J=9.8Hz, IH) , 2.95 (m, IH) , 2.33 (dt, J=12.8 , 7.3Hz, IH) ,

1.75 (s, 3H) , 1.53 (dd, J=6.7,1.8Hz, 3H) , 1.6-1.2 (m, 5H) ,

0.87 (t, J=7.3Hz, 3H) .

MS: (M+H)⁺ = 325, (M+Na)⁺ = 347, (M-H)^" = 323, (2M-1)^" = 647. Example 3

( + ) - ( 3S. 4i?.4ai?, 5S, 7i?) -4 - (acetylamino) - 3 - isopropyl- l-oxo- 5- [ ( IZ) - 1 -propenyll hexahydropyrrolo [1 , 2 - c] [1 , 31 oxazine-7- carboxylic acid

Example 3A (±) -di (tert-butyl) (2i?.4S.5i?) -5- f (li?.2S) -1- (acetylamino) -2- hydroxy-3-methylbutyll -4- ϊ (IZ) -1-propenyll -1,2- pyrrolidinedicarboxylate (Example 3A-1) and (+) -di (tert-butyl) (2i?, 4S.5i?) -5- \ (li?.2i?) -1- (acetylamino) -2- hydroxγ-3-methylbutyl] -4- [ (IZ) -1-propenyl] -1.2- pyrrolidinedicarboxylate (Example 3A-2) The title compounds were prepared according to the method described in Example IP, substituting isopropyl magnesium bromide for ethyl magnesium bromide to afford 9.2 mg (10%) of Example 3A-1 and 38.5 mg (40%) of Example 3A-2. Example 3A-1, MS: (M+H) ⁺ = 455, (M+Na)⁺ = 477, (2M+Na)⁺ = 931, (M-H)^" = 453. Example 3A-2, MS: (M+H) ⁺ = 455, (M+Na)⁺ = 477, (2M+Na)⁺ = 931, (M-H) ^" = 453.

Example 3B

(±) -tert-butyl (3S.4i?.4ai?.5S, 7i?) -4- (acetylamino) -3- isopropyl-l-oxo-5- [ (IZ) -1-propenyll hexahydropyrrolo [1,2- cl ri, 31 oxazine-7-carboxylate The title compound was prepared according to the method described in Example IS, substituting Example 3A-2 for Example 1R-2 to afford 7.5 mg (45%) of the desired product .

Example 3C

(±) - (3S, 4i?, 4ai?, 5S, 7i?) -4- (acetylamino) -3 -isopropyl-1- oxo-5- [ (IZ) -1-propenyll hexahydropyrrolo Tl , 2-c] [1,31 oxazine-

7-carboxylic acid The title compound was prepared according to the method described in Example IT, substituting Example 3B for Example IS to afford 7.2 mg (100%) of the desired product. ^XH NMR (DMSO-de) : δ 7.73 (d, J=9.3Hz, IH) , 5.45 (m, IH) , 5.18 (m, IH) , 4.24 (m, IH) , 3.98 (m, IH) , 3.92 (m, IH) , 3.31 (m, IH) , 2.98 (m, IH) , 2.34 (m, IH) , 1.89 (m, IH) , 1.74 (s, 3H) , 1.54 (dd, J=6.8, 1.5 Hz, 3H) , 1.41 (m, IH) , 0.98 (d, J=6.8Hz, 3H) , 0.83 (d, J=6.4Hz, 3H) . MS: (M+H)⁺ = 325, (M+Na)⁺ = 347, (M-H)^" = 323. Example 4

(±) - (3i?, 4i?, 4aR, 5S, 7i?) -4- (acetylamino) -3-isopropyl-l-oxo-5- f (IZ) -1-propenyll hexahydropyrrolo [1 , 2-c] [1,31 oxazine-7- carboxylic acid

Example 4A (±) -tert-butyl (3i?.4i?, 4ai?, 5S.7i?) -4- (acetylamino) -3- isopropyl-l-oxo-5- [ (IZ) -1-propenyll hexahydropyrrolo [1,2- cl fl, 31 oxazine-7-carboxylate The title compound was prepared according to the method described in Example IS, substituting Example 3A-1 for Example 1R-2 to afford 8.5 mg, (35%) of the desired product .

Example 4B (±) - (3i?, 4i?.4ai?.5S, 7i?) -4- (acetylamino) -3-isopropyl-l-oxo-5- [ (IZ) -1-propenyll hexahydropyrrolo [1.2-cl [1.31 oxazine-7- carboxylic acid

The title compound was prepared according to the method described in Example IT, substituting Example 4A for Example IS to afford 9.6 mg, (100%) of the desired product. *H NMR (DMS0-d₆) : δ 8.26 (d, J=8.8Hz, IH) , 5.59 (m, IH) , 5.23 (m, IH) , 4.29 (m, 2H) , 3.85 (dd, J=8.5, 3.2Hz, IH) , 3.11 (dd, J=10.7, 3.4Hz, IH) , 2.92 (m, IH) , 2.42 (m, IH) , 1.86 (m, IH) , 1.84 (s, 3H) , 1.61 (m, 3H) , 1.46 (m, IH) , 0.99 (d, J=6.4Hz, 3H) , 0.84 (d, J=6.4Hz, 3H) . MS: (M+H)⁺ = 325, (M+Na) ⁺ = 347, (M-H)^" = 323.

Example 5

(±) - (4i?.4ai?.5S.7i?) -4- (acetylamino) -5- \ (IZ) -1- propenyll hexahydropyrrolo [1 , 2-cl Tl .31 oxazine-7-carboxylic acid Example 5A (±) - (2i?,4S, 5-) -5- [ (li?) -1- (acetylamino) -2-hvdroxyethyll -4- f (IZ) -1-propenyll -2-pyrrolidinecarboxylic acid Example 5A was prepared according to the method described in Example IT, substituting Example IN for Example IS to afford 18.0 mg (100%) of the desired product. ^XH NMR (DMSO-dg) : δ 1.66 (dd, 3H) , 1.71 (dt, IH) , 1.87 (s, 3H) , 2.41 (dt, IH) , 3.18 (m, IH) , 3.43 (dd, IH) , 3.61 (m, IH) , 4.13 (m, IH) , 4.35 (m, IH) , 5.25 (m, IH) , 5.51 (m, IH) , 8.05 (d, IH) , 9.16 (br s, 2H) . MS: (M+H)⁺ = 257.

Example 5B

(±) - (4i?,4ai?.5S.7i?) -4- (acetylamino) -5- r (IZ) -1- propenyl] hexahydropyrrolo Tl , 2-cl [1.31 oxazine-7-carboxylic acid Formaldehyde (37% by weight solution in water, 0.01 mL, 1.4 mmol) was added to a room temperature solution of Example 5A (10 mg, 0.02 mmol) in THF (0.5 mL) . After 1 hour, the reaction mixture was concentrated, and the concentrate was purified on silica gel eluting with 10% methanol in chloroform with 1% acetic acid to afford 6.7 mg (90%) of the desired product.

^XH NMR (DMSO-d₆) δ 7.70 (d, J=9.2Hz, IH) , 5.47 (t, J=9.8Hz, IH) , 5.32 (m, IH) , 4.80 (d, J=7.9Hz, 2H) , 4.57 (m, IH) , 4.23 (d, J=11.0Hz, IH) , 3.77 (m, IH) , 3.70 (m, IH) , 3.11 (t, J=11.0Hz, IH) , 2.82 (br t, IH) , 2.76 (d, J=10.3Hz, IH) , 2.44 (m, IH) , 1.80 (s, 3H) , 1.65 (m, IH) , 1.51 (dd, J=1.8,

4.9Hz, 3H) .

MS: (M-H)^" = 267, (M+H) ⁺ = 269, (M+Na)⁺ = 291.

Example 6

(±) - (3S,4i?.4ai?.5S.7i?) -4- (acetylamino) -3-ethyl-5- [ (IZ) - 1-propenyll hexahydropyrrolo [1 , 2-cl [1,3] oxazine-7-carboxylic acid

Example 6A

(±) - (2i?.4S.5i?) -5- r (li?.2S) -1- (acetylamino) -2 -hvdroxybutyll -4- T (IZ) -l-propenyll -2-pyrrolidinecarboxylic acid trifluoroacetic acid salt The title compound was prepared according to the method described in Example IT, substituting Example IP-2 for Example IS to afford 300 mg (100%) of the desired product .

^XH NMR (500 MHz, DMSO-d₆) : δ 7.89 (d, J=8.7 Hz, IH) , 5.48 (m, IH) , 5.29 (m, IH) , 4.30 (m, IH) , 4.02 (m, IH) , 3.73 (m, IH) , 3.43 (m, IH) , 3.15 (m, IH) , 2.41 (m, IH) , 1.82 (s,

3H) , 1.63 (m, IH) , 1.59 (dd, J=6.8, 1.9 Hz, 3H) , 1.55 (m, IH) , 1.27 (m, IH) , 0.85 (t, J=7.3 Hz, 3H) . MS : (M+H) ⁺ = 285 , (M+Na) ⁺ = 307 , (M-H) ^" = 283

Example 6B (±) - (3S,4i?,4ai?,5S,7i?) -4- (acetylamino) -3-ethyl-5- [ (IZ) -1- propenyll hexahydropyrrolo [1 , 2-cl [1,31 oxazine-7-carboxylic acid Formaldehyde (37% by weight solution in water, 0.01 mL, 1.4 mmol) was added to a room temperature mixture of Example 6A (5.7 mg, 0.0018 mmol) in THF (0.5 mL) . After 1 hour, the reaction mixture was concentrated, and the concentrate was purified on silica gel eluting with 10% methanol in chloroform with 1% acetic acid to afford 1.7 mg (33%) of the desired product. K NMR (DMSO-d₆) : δ 7.70 (m, IH) , 5.46 (m, IH) , 5.31 (m,

IH) , 4.52 (d, J=11.2Hz, IH) , 4.31 (d, J=10.8Hz, IH) , 3.81 (m, IH) , 3.45 (t, J=9.3Hz, IH) , 3.09 (m, IH) , 2.81 (m, IH) , 2.74 (d, J=9.8Hz, IH) , 2.45 (m, IH) , 1.81(s, 3H) , 1.63 (m, IH) , 1.50 (d, J=5.4Hz, 3H) , 1.35 (m, 2H) , 0.88 (m, 3H) . MS: (M+H)⁺ = 297, (M+Na)⁺ = 319, (M-H)^" = 295, (2M-1)^" = 591.

Example 7

(±) - (3S,4i?.4ai?.5S.7i?) -4- (acetylamino) -5- r (IZ) -l-prooenyll -3- propylhexahydropyrrolo fl , 2-c] [1 , 3] oxazine-7-carboxylic acid

Example 7A

(±) - (2i?,4S.5i?) -5- r (li?.2S) -1- (acetylamino) -2-hvdroxypentyll -

4- r (IZ) -1-propenyl! -2-pyrrolidinecarboxylic acid trifluoroacetic acid salt The title compound was prepared according to the method described in Example IT, substituting Example 2A-1 for Example IS to afford 30 mg (100%) of the desired product .

^XH NMR (DMSO-dg) : δ 7.83 (d, J=9.2Hz, IH) , 5.43 (m, IH) , 5.23 (m, IH) , 3.98 (m, IH) , 3.56 (br t, IH) , 3.46 (m, IH) , 3.08 (m, 2H) , 2.32 (m, IH) , 1.80 (s, 3H) , 1.57 (dd, J=1.4, 5.4Hz, 4H) , 1.43 (m, 2H) , 1.23 (m, 2H) , 0.85 (br t, 3H) . MS: (M+H)⁺ = 299, (M+Na) ⁺ = 321. Example 7B (±) - (3S,4i?.4ai?.5S.7i?) -4- (acetylamino) -5- [ (IZ) -1-propenyll -3- propylhexahvdropyrrolo [1 .2-cl [1.31 oxazine-7-carboxylic acid The title compound was prepared according to the method described in Example 5B, substituting Example 7A for Example 5A to afford 6.7 mg (90%) of the desired product. ^XH NMR (DMSO-d₆) δ 12.38 (br s, IH) , 7.71 (d, J=9.7Hz, IH) , 5.45 (t, J=7.8Hz, IH) , 5.31 (m, IH) , 4.50 (d, J=11.3Hz, IH) , 4.30 (d, J=11.2Hz, IH) , 3.81 (dd, J=2.9, 6.9Hz, IH) , 3.43 (m, IH) , 3.15 (br t, IH) , 2.80 (br t, IH) , 2.74 (d, J=10.3Hz, IH) , 2.45 (m, IH) , 1.82 (s, 3H) , 1.63 (m, IH) , 1.50 (dd, J=1.5, 5.3Hz, 3H) , 1.44 (m, IH) , 1.22-1.28 (m, 3H) , 0.84 (t, J=6.9Hz, 3H) . MS: (M-H)^" = 309, (M+H) ⁺ = 311, (M+Na)⁺ = 333.

Example 8

(±) - (3S,4i?,4ai?, 5S, 7i?) -4- (acetylamino) -3- (cyanomethyl) -5- [ (IZ) -1-propenyll hexahydropyrrolo [1.2-cl [1,31 oxazine- 7- carboxylic acid Example 8A

(±) -di (tert-butyl) (2i?.4S,5i?) -5- [ (li?.2i?) -1- (acetylamino) -3- cyano-2-hvdroxypropyl] -4- f (IZ) -1-propenyll -1,2- pyrrolidinedicarboxylate (Example 8A-1) and (±) -di (tert-butyl) (2i?,4S.5i?) -5- T (li?.2S) -1- (acetylamino) -3- cyano-2-hydroxypropyl1 -4- \ (IZ) -1-propenyll -1,2- pyrrolidinedicarboxylate (Example 8A-2)

Example 10 (150 mg, 0.37 mmol) in THF (10 mL) was added dropwise to a -78 °C solution of the lithium enolate of acetonitrile (1.83 mmol, 5 equivalents) in THF (15 mL) . After 15 minutes, the reaction was quenched with saturated aqueous ammonium chloride (10 mL) and water (lOmL) , followed by extraction with dichloromethane (2 X 50 mL) . The combined dichloromethane layers were dried (MgS0 ) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 66% ethyl acetate in hexanes to afford 95 mg (58%) of Example 8A-1 and 30 mg (18%) of Example 8A-2, both as colorless oils. Example 8A-1, MS: (M+H)⁺ = 452, (M-H)^" = 450. Example 8A-2, ^XH NMR (CDC1₃) δ 8.14 (d, J=8.9Hz, IH) , 5.51 (m, IH) , 5.38 (m, IH) , 4.25 (m, IH) , 4.19 (m, IH) , 3.94 (m, IH) , 3.74 (m, IH) , 3.22 (m, IH) , 2.54 (m, IH) , 2.47 (m, 2H) , 2.04 (s, 3H) , 1.69 (m, IH) , 1.65 (dd, J=6.5, 1.8Hz, 3H) , 1.47 (s, 9H) , 1.45 (s, 9H) . MS: (M+H)⁺ = 452, (M-H)^" = 450. Example 8B (±) - (2i?,4S,5i?) -5- r ( 1R . 2S) -1- (acetylamino) -3-cvano-2- hydroxypropyll -4- I (IZ) -1-propenyll -2 -pyrrolidinecarboxylic acid trifluoroacetic acid salt The title compound was prepared according to the method described in Example IT, substituting Example 8A-2 for Example IS to afford 4.5 mg (95%) of the desired product .

^XH NMR (DMSO-dg) : δ 7.98 (d, J=10.0 Hz, IH) , 5.49 ( , IH) , 5.27 ( m, IH) , 4.30 (m, IH) , 4.15 (m, IH) , 3.75(m, IH) , 3.18 (m, IH) , 2.72-2.58 (m, 2H) , 2.41 (m, IH) , 1.85 (s, 3H) , 1.65 (m, IH) , 1.61 (dd, J=6.70, 1.80 Hz, 3H) . MS: (M+H)⁺ = 296, (M-H)^" = 294.

Example 8C (±) - (3S,4i?,4ai?,5S, 7i?) -4- (acetylamino) -3- (cvanomethyl) -5- [ (IZ) -1-propenyl! hexahydropyrrolo [1, 2-cl [1,31 oxazine-7- carboxylic acid

The title compound was prepared according to the method described in Example 5B, substituting Example 8B for Example 5A to afford 10 mg (99%) of the desired product. IH NMR (DMSO-d_e) : δ 7.78 (m, IH) , 5.43 (m, IH) , 5.30 (m, IH) , 4.73 (m, IH) , 4.39 (m, IH) , 3.77 (m, IH) , 3.54 (m, IH) , 3.46 (m, IH) , 2.79 (m, 3H) , 2.58 (m, IH) , 2.39 (m, IH) , 1.82 (s, 3H) , 1.64 (m, IH) , 1.50 (m, 3H) . MS: (M+H)⁺ = 308, (M+Na)⁺ = 330, (M-H)^" = 306. Example 9

(±) - (3S,4i?,4ai?,5S,7i?) -4- (acetylamino) -3- (3-butenyl) -5- r (IZ) - 1-propenyll hexahydropyrrolo [1 , 2-cl [1,31 oxazine-7-carboxylic acid

Example 9A (±) -di (tert-butyl) (2i?,4S,5i?) -5- \ ( 1R . 2S) -1- (acetylamino) -2-hvdroxy-5-hexenyll -4- I (IZ) -1-propenyll -1.2- pyrrolidinedicarboxylate (Example 9A-1) and

(±) -di (tert-butyl) (2i?.4S.5i?) -5- rdi?,2i?) -1- (acetylamino) -2- hydroxy-5-hexenyll -4- [ (IZ) -1-propenyll -1,2- pyrrolidinedicarboxylate (Example 9A-2)

The title compounds were prepared according to the method described in Example IP, substituting l-buten-4-yl magnesium bromide for ethyl magnesium bromide to afford 3.0 mg (6%) of Example 9A-1 and 14.5 mg (28%) of Example 9A-2. Example 9A-1, MS: (M+H) ⁺ = 467, (M+Na)⁺ = 489, (2M+Na)⁺ = 955, (M-H)^" = 465. Example 9A-2, MS: (M+H) ⁺ = 467, (M+Na)⁺ = 489, (2M+Na)⁺ = 955, (M-H)^" = 465. Example 9B (±) - (2i?,4S.5i?) -5- r ( 1R. 2S) -1- (acetylamino) -2-hvdroxy-5- hexenyll -4- [ (IZ) -1-propenyll -2-pyrrolidinecarboxylic acid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described in Example IT, substituting Example 9A-1 for Example IS to afford 2.7 mg (100%) of the desired product . NMR (DMSO-de) : δ 8.93 (bs, IH) , 7.90 (d, J=9.2 Hz, IH) ,

5.80 ( , IH) , 5.48 (m, IH) , 5.28 (m, IH) , 5.00 (dd, J=17.1, 1.8Hz, IH) , 4.94 (dd, J=10.4 , 1.8Hz, IH) , 4.29 (bt, J=8.3Hz, IH) , 4.03 (m, IH) , 3.71 (m, IH) , 3.49 (m, IH) , 3.15 (quint., J=8.5Hz, IH) , 2.41 (dt, J=12.8 , 7.3Hz , IH) , 2.16 (M, IH) , 2.05 (m, IH) , 1.83 (s, 3H) , 1.79-1.75 (m, IH) , 1.64 (m, IH) , 1.58 (dd, J=6.7,1.8Hz, 3H) , 1.34 (m, 2H) . MS: (M+H)⁺ = 311, (M+Na)⁺ = 333, (M-H)^" = 309, (M+CF₃COO^") ^" = 423.

Example 9C

(±) - (3S,4i?.4ai?.5S, 7i?) -4- (acetylamino) -3- (3-butenyl) -5- [ (IZ) - 1-propenyll hexahydropyrrolo .2-cl [1, 3! oxazine-7-carboxylic acid The title compound was prepared according to the method described in Example 5B, substituting Example 9B for Example 5A to afford 3.0 mg (>100%) of the desired product ^XH NMR (DMS0-d₆) : δ 7.79 (d, J=9.3Hz, IH) , 5.83 (m, IH) , 5.42 (m, IH) , 5.37 (m, IH) , 5.03 (d, J=15.1Hz, IH) , 4.96 (d, J=7.9Hz, IH) , 4.50 (d, J=11.0Hz, IH) , 4.18 (d, J=10.7Hz, IH) , 3.95 (m, IH) , 3.85 (m, IH) , 3.77 (m, IH) , 2.99 (m, IH) , 2.84 (m, IH) , 2.44 (m, IH) , 2.09 (m, IH) , 1.97 (m, IH) , 1.89 (m, 1H),1.83 (s, 3H) , 1.60 (m, IH) , 1.55 (dd, J=1.4, 4.9Hz, 3H) , 1.42 (m, IH) . MS: (M-H)^" = 321, (M+H) ⁺ = 323.

Example 10

(±) - (3S.4i?.4ai?.5S.7i?) -4- (acetylamino). -3-isobutyl-5- (IZ) -1- propenyl] hexahydropyrrolo [1 , 2-cl [1,3] oxazine-7-carboxylic acid

Example 10A (±) -di (tert-butyl) (2i?.4S.5i?) -5- f (li?.2i?) -1- (acetylamino) -2- hydroxy-4-methylpentyll -4- [ (IZ) -1-propenγl] -1,2- pyrrolidinedicarboxylate (Example 1QA-1) and

(±) -di (tert-butyl) (2i?.4S.5i?) -5- (li?.2S) -1- (acetylamino) -2- hydroxy-4-methylpentyll -4- [ (IZ) -1-propenyll -1,2- pyrrolidinedicarboxylate (Example 10A-2) The title compounds were prepared according to the method described in Example IP, substituting isobutyl magnesium bromide for ethyl magnesium bromide to afford 31 mg (51%) of Example 10 A-l.

^XH NMR (CDC1₃) : δ 5.98 (d, J=9.5Hz, IH) , 5.61 (t, J=8.2Hz, IH) , 5.35 (m, IH) , 4.51 (dd, J=1.3, 3.1Hz, IH) , 4.15 (m, IH) , 3.74 (d, J=10.5Hz, IH) , 3.61 (m, 2H) , 3.09 (t, J=7.5Hz, IH) , 2.71 (m, IH) , 2.02 (s, 3H) , 1.81 (d, J=13.9Hz, IH) , 1.58 (br s, IH) , 1.54 (dd, J=1.7, 5.1Hz, 3H) , 1.47 (s, 9H) , 1.45 (s, 9H) , 1.42 (m, IH) , 0.87 (dd, J=2.4, 6.7Hz, 6H) MS: (M-H)^" = 467, (M+H) ⁺ = 469, (M+Na)⁺ = 491.

Example 10B (±) -di (tert-butyl) (2i?.4S,5i?) -5- r (li?) -1- (acetylamino) -4- methyl-2 -oxopentyll -4- [ (IZ) -1-propenyl] -1,2- pyrrolidinedicarboxylate The title compound was prepared according to the method described in Example IQ, substituting Example lOA-1 for Example 1P-1 to afford 4.8 mg^"(61%) of the desired product as a colorless semi-solid.

Example 10C (±) -di (tert-butyl) (2i?.4S.5i?) -5- f (li?,2S) -1- (acetylamino) -2- hydroxy-4-methylpentyll -4- [ (IZ) -1-propenγl] -1,2- pyrrolidinedicarboxylate The title compound was prepared according to the method described in Example 1R, substituting Example 10B for Example IQ to afford 2.4 mg (51%) of the desired product .

Example 10D

(±) - (2i?,4S.5i?) -5- f (1R.2S) -1- (acetylamino) -2-hvdroxy-4- methylpentyll -4- [ (IZ) -1-propenyll -2 -pyrrolidinecarboxylic acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example IT, substituting Example 10C-2 for Example IS to afford 4.4 mg (100%) of the desired product .

^XH NMR (D₂0) : δ 5.45 (m, IH) , 5.15 (t, J=11.0Hz, IH) , 3.88 ( , IH) , 3.62 (t, J=8.0Hz, IH) , 3.43 (br t, IH) , 2.98 (m, IH) , 2.36 (m, IH) , 1.81 (s, 3H) , 1.60 (m, IH) , 1.51 (m,

IH) , 1.45 (dd, J=1.3, 5.4Hz, 3H) , 1.17 (m, 3H) , 0.74 (dd,

J=6.7, 14Hz, 6H) .

MS: (M-H)^" = 311, (M+H) ⁺ = 313, (M+Na) ⁺ = 335.

Example 10E (±) - (3S.4i?.4ai?.5S.7i?) -4- (acetylamino) -3 -isobutyl-5- [(IZ) -1- propenyll hexahydropyrrolo [1.2-cl Tl .31 oxazine-7-carboxylic acid monotrifluoro acetic acid salt

The title compound was prepared according to the method described in Example 5B, substituting Example 10D for Example 5A to afford 5.8 mg (89%) of the desired product . ^λH NMR (DMSO-de): δ 7.70 (d, J=9.2Hz, IH) , 5.46 (t, J=9.8Hz, IH) , 5.30 (m, IH) , 4.53 (d, J=11.0Hz, IH) , 4.29 (d, J=11.0Hz, IH) , 3.79 (t, J=6.7Hz, IH) , 3.39 (m, IH) , 3.20 (m, IH) , 2.76 (m, 2H) , 2.43 (m, IH) , 1.81 (s, 3H) , 1.73 (m, IH) , 1.64 (m, IH) , 1.50 (dd, J=1.8, 4.9Hz , 3H) , 1.24 (m, 3H) , 0.84 (dd, J=5.5, 6.7Hz, 6H) . MS: (M-H)^" = 323, (M+H)⁺ = 325, (M+Na)⁺ = 347.

Example 11

( +) - (3S.4i?,4ai?.5S, 7i?) -4- (acetylamino) -3- [ (li?) -1- methylpropyll -5- f (IZ) -1-propenyll hexahydropyrrolo [1 , 2- c] [1, 31 oxazine-7-carboxylic acid

Example 11A

(+) -di( tert-butyl) (2i?.4S.5i?) -5- r (li?, 2i?.3i?) -1-

(acetylamino) -2-hydroxy-3 -methylpentyl] -4- [ (IZ) -1- propenyll -1.2-pyrrolidinedicarboxylate (Example 11A-1) and ( + ) -di(tert-butγl) ( 2R . A S. 5R) - 5 - \ ( 1R . 2R . 3S) - 1 -

(acetylamino) -2-hydroxy-3-methylpentyl] -4- [ (IZ) -1- propenyll -1, 2-pyrrolidinedicarboxylate (Example 11A-2) The title compounds were prepared according to the method described in Example IP, substituting 2 -butyl magnesium bromide for ethyl magnesium bromide to afford 19 mg (27%) of Example 11 A-l and 19 mg (27 %) of Example 11 A-2.

Example 11 A-l, Rf= 0.5 (1:1 ethyl acetate : hexanes) ^XH NMR (CDC1₃) δ 6.00 (d, J=10.2Hz, IH) , 5.61 (br t, IH) , 5.36 (m, IH) , 4.58 (d, J=4.7Hz , IH) , 4.14 (d, J=8.8Hz, IH) , 3.82 (m, 3H) , 3.13 (m, 2H) , 2.73 (m, IH) , 1.99 (s, 3H) ,

1.80 (d, J=13.9Hz, IH) , 1.54 (br s, 3H) , 1.46 (s, 9H) , 1.44 (s, 9H) , 1.43 (m, IH) , 0.97 (d, J=6.8Hz, 3H) , 0.81 (t,

J=7.2Hz, 3H) .

MS: (M-H)^" = 467; (M+H) ⁺ = 469.

Example 11 A-2, Rf= 0.65 (1:1 ethyl acetate : hexanes) ^XH NMR (CDC1₃) δ 5.98 (d, J=8.8Hz, IH) , 5.62 (t, J=10.5Hz,

IH) , 5.35 (m, IH) , 4.66 (d, J=4.4Hz, IH) , 4.16 (d, J=9.5Hz, IH) , 3.78 (m, 3H) , 3.12(m, 2H),^2.73 (m, IH) , 2.0 (s, 3H) ,

1.81 (d, J=13.2Hz, IH) , 1.54 (br s, 3H) , 1.47 (s, 9H) , 1.44 (s, 9H) , 1.25 (m, IH) , 0.81 (m, 6H) MS: (M-H)^" = 467; (M+H) ⁺ = 469.

Example 11B (+) -di (tert-butyl) (2i?.4S.5i?) -5- [ (li?) -1- (acetylamino) -3- methyl-2-oxopentyll -4- [ (IZ) -1-propenyll -1.2- pyrrolidinedicarboxylate The title compound was prepared according to the method described in Example IQ, substituting Example 11A-1 for Example 1P-1 to afford 12.0 mg (67%) of the desired product as a colorless semi-solid.

Example 11C

(+) -di( tert-butyl) (2i?.4S.5i?) -5- [ (li?.2S.3i?) -1-

(acetylamino) -2-hydroxy-3-methylpentyll -4- [ (IZ) -1- propenyll -1 , 2-pyrrolidinedicarboxylate Example llC-1) and ( + ) -di( tert-butyl) ( 2R . A S. 5R) - 5 - ( 1R . 2S. 3S) - 1 -

(acetylamino) -2-hvdroxy-3-methylpentyll -4- [ (IZ) -1- propenyll -1 , 2-pyrrolidinedicarboxylate (Example 11C-2) The title compounds were prepared according to the method described in Example 1R, substituting Example 11B for Example IQ to afford 2.5 mg (21%)^' of Example llC-1 and 6.0 mg (50%) of Example 11C-2.

Example llC-1, Rf= 0.11, 1:1, ethyl acetate: hexanes) Example 11C-2, Rf= 0.15, 1:1, ethyl acetate: hexanes)

Example IIP

( +) - (2i?.4S.5i?) -5- f (li?.2S.3S) -1- (acetylamino) -2-hvdroxy-3- methylpentyll -4- [ (IZ) -1-propenyll -2-pyrrolidinecarboxylic acid trifluoroacetic acid salt The title compound was prepared according to the method described in Example IT, substituting Example 11C-2 for Example IS to afford 6.0 mg (100%) of the desired product . E NMR (DMS0-d₆) δ 7.78 (d, J=9.2Hz, IH) , 5.42 (m, IH) , 5.29 (t, J=10.3Hz, IH) , 4.08 (m, IH) , 3.96 (br t, IH) , 3.51 (m, 2H) , 3.08 (m, IH) , 2.33 (m, IH) , 1.78 (s, 3H) , 1.56 (d, J=6.3Hz, 3H) , 1.52 (m, IH) , 1.40 (m, IH) , 1.29 (m, IH) , 1.21 (m, IH) , 0.84 (t, J=7.3Hz, 3H) , 0.73 (d, J=6.9Hz, 3H) MS: (M-H)^" = 311; (M+H) ⁺ = 313, (M+Na)⁺ = 335.

Example HE (3S,4i?,4ai?, 5S, 7i?) -4- (acetylamino) -3- [ (li?) -1-methylpropyll - 5- [ (IZ) -1-propenyll hexahydropyrrolo d.2-c] Tl, 31 oxazine-7- carboxylic acid

The title compound was prepared according to the method described in Example 5B, substituting Example 11D for Example 5A to afford 6.0 mg (100%) of the desired product . ^XH NMR (DMSO-dg) : δ 7.69 (d, J=9.8Hz, IH) , 5.46 (t, J=9.8Hz, IH) , 5.30 (m, IH) , 4.54 (d, J=HHz, IH) , 3.76 (t, J=7.4Hz, IH) , 3.65 (m, 2H) , 3.17 (d, J=8.6, IH) , 2.82 (br t, IH) , 2.74 (d, J=9.7Hz, IH) , 2.45 (m, IH) , 1.81 (s, 3H) , 1.61 (m, IH) , 1.50 (d, J=4.9Hz, 3H) , 1.45 (m, IH) , 1.33 (m, IH) , 1.24 (m, IH) , 0.85 (t, J=7.3Hz, 3H) , 0.80 (d, J=6.7Hz, 3H) . MS: (M-H)^" = 323, (M+H) ⁺ = 325, (M+Na) ⁺ = 347.

Example 12

(+) - (4i?,4ai?, 5S, 7i?) -4- (acetylamino) -3.3 -diethyl-5- r (IZ) -1- propenyll hexahydropyrrolo d , 2-cl [1,31 oxazine-7-carboxylic acid

Example 12A

(±) -di (tert-butyl) (2i?.4S.5i?) -5- \ (li?) -1- (acetylamino) -2- ethyl-2-hydroxybutyl! -4- [ (IZ) -1-propenyl] -1.2- pyrrolidinedicarboxylate The title compound was prepared according to the method described in Example IP, substituting Example IQ for Example 10 to afford 21 mg (51%) of the desired compound. MS: (M+H)⁺ = 469, (M+Na)⁺ = 491, (2M+Na)⁺ =959, (M-H)^" = 467.

Example 12B

(±) - (2i?.4S.5i?) -5- [ (li?) -1- (acetylamino) -2-ethyl-2- hydroxybutyll -4- [ (IZ) -1-propenyll -2-pyrrolidinecarboxylic acid trifluoroacetic acid salt The title compound was prepared according to the method described in Example IT, substituting Example 12A for Example IS to afford 3.9 mg (100%) of Example 12B. ^XH NMR (DMSO-dg) : δ 7.52 (d, J=10.3Hz, IH) , 5.45 (m, IH) , 5.28 (m, IH) , 4.32 (m, 2H) , 3.68 (t, J=8.8Hz, IH) , 3.16

(quint., J=8.5Hz, IH) , 2.41 (dt, J=13.2 , 8.3Hz , IH) , 1.81(s, 3H) , 1.59 (m, IH) , 1.53 (dd, J=6.8,1.5Hz, 3H) , 1.52-1.42

(m, 3H) , 1.30 (m, IH) , 0.86 (t, J=7.3Hz, 3H) , 0.83 (t, J=7.3Hz, 3H) . MS: (M+H)⁺ = 313, (M+Na) ⁺ = 335, (M-H)^" = 311, (2M-H) ^" = 623.

Example 12C

(±) - (4i?.4ai?.5S.7i?) -4- (acetylamino) -3 , 3-diethyl-5- [ (IZ) -1- propenyll hexahydropyrrolo [1.2-cl Tl .31 oxazine-7-carboxylic acid The title compound was prepared according to the method described in Example 5B, substituting Example 12B.for Example 5A to afford 3.7 mg, (84%) of the desired product .

^XH NMR (DMSO-dg) : δ 7.52 (d, J=10.2Hz, IH) , 5.47 (t, J=8.1Hz, IH) , 5.31 (m, IH) , 4.40 (d, J=11.2Hz, IH) , 4.24 (d, J=11.2Hz, IH) , 3.93 (m, 2H) , 3.00 (d, J=10.8Hz, IH) , 2.73 (br t, IH) , 2.43 (m, IH) , 2.00 (m, IH) , 1.82 (s, 3H) , 1.50 (dd, J=1.3, 5.1Hz, 3H) , 1.18 (m, 4H) , 0.85 (t, J=7.4Hz, 3H) , 0.76 (t, J=7.4Hz, 3H) . MS: (M-H)^" = 323, (M+H) ⁺ = 325. Example 13

(±) - (3S.4i?.4ai?.5S.7i?) -4- (acetylamino) -3-methyl-5- r (IZ) 1-propenyll -3-propylhexahydropyrrolo [1.2-cl [1.3] oxazine-7- carboxylic acid

Example 13A (±) -di (tert-butyl) (2i?.4S.5i?) -5- \ (li?) -1- (acetylamino) -2- oxopentyll -4- [(IZ) -1-propenyll -1 , 2 -pyrrolidinedicarboxylate The title compound was prepared according to the method described in Example IQ, substituting Example 2A-2 for Example 1P-1 to afford the desired product.

Example 13B (±) -di (tert-butyl) (2i?.4S, 5i?) -5- F (li?.2S) -1- (acetylamino) -2- hydroxy-2-methylpentyll -4- [ (IZ) -1-propenyll -1,2- pyrrolidinedicarboxylate (Example 13B-1) and (+) -di (tert-butyl) (2i?, 4S, 5i?) -5- \ (li?, 2i?) -1- (acetylamino) -2- hydroxy-2 -methylpentyll -4- \ (IZ) -1-propenyll -1,2- pyrrolidinedicarboxylate (Example 13B-2) The title compounds were prepared according to the method described in Example IP, substituting Example 13A for Example IQ and substituting methyl magnesium bromide for ethyl magnesium bromide to afford 28.5 mg (45%) of the desired product, Example 13B-1. MS: (M+H)⁺ = 469, (M+Na)⁺ = 491.

Example 13C (+) - (2i?,4S.5i?) -5- [ (li?.2S) -1- (acetylamino) -2-hvdroxy-2- methylpentyll -4- [ (IZ) -1-propenyll -2-pyrrolidinecarboxylic acid trifluoroacetic acid salt

Trifluoroacetic acid (0.8 mL) was added to a solution of Example 13B-1 (4.1 mg, 0.00876 mmol) in room temperature dichloromethane (0.2 mL) . After 3 hours, the reaction mixture was concentrated to afford 4.0 mg (100%) of the desired product as a colorless oil.

^XH NMR (DMSO-dg) : δ 7.54 (d, J=10.3 Hz, IH) , 5.45 (m, IH) , 5.29 (m, IH) , 4.37 (t, J=7.3Hz, IH) , 4.22 (t, J=9.3Hz, IH) , 3.62 (t, J=8.3Hz, IH) , 3.12 (quint., J=8.3Hz, IH) , 2.42 (dt, J=12.7,7.8Hz, IH) , 1.78(s, 3H) , 1.58 (m, IH) , 1.53 (dd, J=6.8,2.0Hz, 3H) , 1.4-1.25 (m, 4H) , 1.17 (s, 3H) , 0.81 (t, J=6.4Hz, 3H) . MS: (M+H)⁺ = 313, (M+Na)⁺ = 335, (M-H)^" = 311, (2M-1)^" = 623. Example 13D (+) - (3S.4i?.4ai?.5S.7i?) -4- (acetylamino) -3 -methyl-5- \ (IZ) 1-propenyll -3-propylhexahydropyrrolo [1 , 2-cl [1,3] oxazine-7- carboxylic acid

The title compound was prepared according to the method described in Example 5B, substituting Example 13C for Example 5A to afford 4.5 mg (85%) of the desired product . ^XH NMR (DMSO-de): δ 7.50 (d, J=9.8Hz, IH) , 5.47 (t, J=8.5Hz, IH) , 5.29 (m, IH) , 4.50 (d, J=11.2Hz, IH) , 4.31 (d, J=11.2Hz, IH) , 3.74 (m, 2H) , 2.92 (d, J=10.9Hz, IH) , 2.68 (m, IH) , 2.30 (m, IH) , 1.83 (s, 3H) , 1.49 (dd, J=1.7, 5.1Hz, 3H) , 1.26 (m, 5H) , 0.80 (br t, 3H) . MS: (M-H)^" = 323, (M+H) ⁺ = 325.

Example 14

(±) - (3S,4i?.4ai?.5S.7i?) -4- (acetylamino) -3-hγdroxy-5- [ (IZ) -1- p openyll hexahydropyrrolo [1, 2-c] [1,31 oxazine-7-carboxylic acid monotrifluoro acetic acid salt Example 14A (±) -di (tert-butyl) (2i?.4S.5i?) -5- f (li?.2i?) -1- (acetylamino) -4- ethoxy-2-hvdroxy-4-oxobutvn -4- [ (IZ) -1-propenyl] -1.2- pyrrolidinedicarboxylate (Example 14A-1) and

(±) -di (tert-butyl) (2i?.4S.5i?) -5- r (li?.2S) -1- (acetylamino) -4- ethoxy-2-hydroxy-4-oxobutyll -4- [ (IZ) -1-propenyll -1,2- pyrrolidinedicarboxylate (Example 14A-2) Example 10 (900 mg, 2.187 mmol) in THF (40 mL) was added dropwise to a -78 °C solution of the lithium enolate of ethyl acetate (8.748 mmol, 4 equivalents) in THF (40 mL) . After 15 minutes, the reaction was quenched with saturated aqueous ammonium chloride followed by extraction with dichloromethane (3 X) . The combined dichloromethane layers were dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 50% ethyl acetate in hexanes to afford 690 mg (63%) of Example 14A-1 and 246 mg (22.5%) of Example 14A-2. Example 14A-1, ^XH NMR (CDC1₃) : δ 5.99 (d, IH) , 5.60 (m, IH) , 5.36 (m, IH) , 4.81 (m, IH) , 4.15 (m, 4H) , 3.74 (m, IH) , 3.07 (m, IH) , 2.68 (m, IH) , 2.48 (m IH) , 2.33 (m, IH) , 2.03 (s, 3H) , 1.54 (dd, 3H) , 1.47 (s, 9H) , 1.46 (s, 9H) , 1.24 (t, J=7.5Hz, 3H) . MS: (M+H)⁺ = 499.

Example 14A-2, ^XH NMR (CDC1₃) : δ 7.93 (d, IH) , 5.44 (m, 2H) , 4.19 (m, 4H) , 4.03 (m, IH) , 3.72 (m, IH) , 3.37 (m, IH) , 2.63 (m. IH) , 2.48 (m, 2H) , 2.01 (s, 3H) , 1.65 (dd, 3H) , 1.48 (s, 9H) , 1.46 (s, 9H) , 1.26 (t, J=7.5Hz, 3H) . MS : (M+H) ⁺ = 499

Example 14B (±) -di (tert-butyl) (2i?.4S,5i?) -5- \ (li?.2S) -1- (acetylamino) - 2,4-dihydroxybutyll -4- [ (IZ) -1-propenyl] -1, 2- pyrrolidinedicarboxylate Lithium borohydride (23.2 mg, 1.06 mmol) was added to a room temperature solution of Example 14A-2 (100 mg, 0.21 mmol) in THF (5 mL) . After 6 hours, the reaction was quenched with saturated aqueous sodium bicarbonate (5 mL) , and extracted with dichloromethane (4 X 10 mL) . The combined dichloromethane layers were dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 5% methanol in dichloromethane to afford 62.4 mg (64.3%) of the desired product .

MS: (M+H)⁺ = 457.

Example 14C (±) -tert-butyl (2i?,4S.5i?) -5- r (li?,2S) -1- (acetylamino) -2,4- dihydroxybutyll -4- T (IZ) -1-propenyll -2- pyrrolidinecarboxylate Trifluoroacetic acid (0.4 mL) was added to a room temperature solution of Example 14B (60 mg, 0.13 mmol) in dichloromethane (2 mL) . After stirring for 2 hours, the reaction was quenched with saturated aqueous sodium bicarbonate (2 mL) , and extracted with dichloromethane (5 x 5 mL) . The combined dichloromethane layers were dried (MgS0₄) , filtered and concentrated to afford 33.8 mg (72.2%) of the crude desired product as an off white foam. MS: (M+H)⁺ = 357.

Example 14D

(+) -tert-butyl (IS, 3i?, 7S, 8i?, 8ai?) -8- (acetylamino) -7-hvdroxy-

1- f (IZ) -1-propenyll octahydro-3-indolizinecarboxylate Diethyl azodicarboxylate (26 μL, 0.17 mmol) was added to a room temperature solution of Example 14C (30 mg, 0.084 mmol) and triphenylphosphine (44.2 mg, 0.17 mmol) in dichloromethane (2 mL) . The reaction mixture was stirred for 0.5 hours, quenched with water ( 2 mL) , and extracted with dichloromethane (4 x 5 mL) . The combined dichloromethane layers were dried (MgS0₄) , filtered and concentrated. The residue was purified by column chromatography on silica gel using 10% methanol in dichloromethane to afford 16.8 mg (59.3%) of the desired compound as a white foam.

^XH NMR (CDC1₃) : δ 1.48 (s, IH) , 1.53-1.68 (m, 7H) , 1.82 (m, IH) , 1.92 (s, 3H) , 2.43 (m, IH) , 2.77 (m, IH) , 3.02 (m, 2H) , 3.72 (m, IH) , 3.87 (m, IH) , 4.06 (m, IH) , 5.44 (m, 2H) , 5.84 (br, IH) . MS: (M+H)⁺ = 339. Example 14E (±) - (3S,4i?,4ai?,5S,7i?) -4- (acetylamino) -3-hvdroxy-5- [ (IZ) -1- propenyll hexahydropyrrolo [1 , 2-cl [1 , 31 oxazine-7-carboxylic acid Monotrifluoro Acetic Acid Salt

Trifluoroacetic acid (0.8 mL) was added to a room temperature solution of Example 14D (10.0 mg, 0.03 mmol) in dichloromethane (0.2 mL) . After 6 hours, the reaction mixture was concentrated and the concentrate was triturated with dichloromethane (2 x 0.5 mL) to afford 12.1 mg of the desired product as an off white solid.

^XH NMR (DMSO-de): δ 1.45 (dd, 3H) , 1.63 (m, IH) , 1.72 (m, IH) , 1.79 (s, 3H) , 1.99 (m, IH) , 2.68 (dt, IH) , 3.10 (m, IH) , 3.23 (m, IH) , 3.39 (m, IH) , 3.73 (m. IH) , 4.01 (m, IH) , 4.54 (t, IH) , 5.32 (m, IH) , 5.41 (m, IH) , 7.85 (d, IH) . MS: (M+H)⁺ = 283.

Example 15

(+) - (lS,3i?,7S, 8i?, 8ai?) -8- (acetylamino) -7-hvdroxy-5-oxo-l- f (IZ) -1-propenyll octahvdro-3-indolizinecarboxylic acid Example 15A (+) -di (tert-butyl) (2i?,4S,5i?) -5- \ (li?) -1- (acetylamino) -4- ethoxy-2,4-dioxobutyll -4- [ (IZ) -1-propenyll -1.2- pyrrolidinedicarboxylate

Dess-Martin Periodinane (345 mg, 0.81 mmol) was added to a room temperature solution of Example 14A-1 (270 mg, 0.54 mmol) in dichloromethane (25 mL) . After 1 hour, the reaction mixture was quenched with 1M aqueous sodium thiosulfate (25 mL) and extracted with dichloromethane (3 x 50 mL) . The combined dichloromethane layers were dried (MgS0₄) , filtered, and concentrated. The concentrate was purified by column chromatography on silica gel using 2% methanol in dichloromethane to afford 260 mg (96.7%) of the desired product as a white foamy solid.

^XH NMR (CDC1₃) : δ 1.26 (t, J=7.2 Hz, 3H) , 1.41(s, 9H) , 1.46 (s, 9H) , 1.61(d, 3H) , 1.71 (m, IH) , 2.02 (s, 3H) , 2.50 (m, IH) , 3.08 (m, IH) , 3.63 (d, 2H) , 4.15 (m, 3H) , 4.30 (m, IH) , 4.72 (m, IH) , 5.48 (m, 2H) , 6.75 (d, IH) . MS: (M+H)⁺ = 497.

Example 15B (±) -tert-butyl (2i?,4S,5i?) -5- f (li?) -1- (acetylamino) -4- ethoxy-2,4-dioxobutyll -4- [ (IZ) -1-propenyll -2- pyrrolidinecarboxylate The title compound was prepared according to the method described in Example 14C, substituting Example 15A for Example 14B to afford 128 mg (80.2%) of the desired product .

MS: (M+H)⁺ = 397.

Example 15C (+) -tert-butyl (IS, 3i?, 8i?, 8ai?) -8- (acetylamino) -5, 7-dioxo-l- [ (IZ) -1-propenyll octahydro-3-indolizinecarboxylate Sodium bicarbonate (500 mg) was added to a solution of Example 15B (100 mg, 0.25 mmol) in toluene (25 mL) and heated at 105 °C for 6 hours. The reaction was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were dried (MgS0₄) , filtered, and concentrated. The concentrate was purified by column chromatography on silica gel using 5% methanol in dichloromethane to afford 40 mg, (45.2%) of the desired product as a white foamy solid.

^JH NMR (CDC1₃) : δ 1.47 (s, 9H) , 1.57 (m, IH) , 1.65 (dd, J=1.7, 7.1 Hz, 3H) , 1.97(s, 3H) , 2.50 (m, IH) , 3.30-3.50 (m, 4H) , 4.44 (t, J=9 Hz, IH) , 4.90 (m, IH) , 5.17 (m, IH) , 5.55 (m, IH) , 5.87 (d, J=7.8 Hz, IH) . MS: (M+H)⁺ = 351.

Example 15D (±) -tert-butyl (IS, 3i?, 7S, 8i?, 8ai?) -8- (acetylamino) -7-hvdroxy- 5-oxo-l- T (IZ) -1-propenyll octahydro-3-indolizinecarboxylate (Example 15D-1) and (±) -tert-butyl (IS, 3i?.7i?, 8i?, 8ai?) -8- (acetylamino) -7-hvdroxy- 5-oxo-l- [ (IZ) -1-propenyll octahγdro-3-indolizinecarboxylate

(Example 15D-2) Sodium borohydride (8 mg, 0.13 mmol) was added to a room temperature solution of Example 15C (47 mg, 0.13 mmol) in methanol (2 mL) . After stirring for 0.5 hours, the reaction was quenched with saturated aqueous ammonium chloride and extracted with dichloromethane. The combined dichloromethane layers were dried (MgS0₄) , filtered, and concentrated. The concentrate was purified by column chromatography on silica gel using 7% methanol and 0.35% ammonium hydroxide in dichloromethane to afford 5.7 mg (12.4%) of Example 15D-1 and 30 mg (65.6%) of Example 15D-2. Example 15D-1, ^XH NMR (CDC1₃) : δ 5.87 (d, IH) , 5.55 (m, IH) , 5.21 (m, IH) , 4.39 (t, J=8.7 Hz, IH) , 4.22-4.08 (m, 2H) , 3.65 (t, J=10.2 Hz, IH) , 3.12-3.00 (m, 2H) , 2.75-2.58 (m, 2H) , 2.44 (m IH) , 1.93 (s, 3H) , 1.64 (dd, J=1.7, 6.8 Hz, 3H) , 1.47 (s, 9H) . MS: (M+H)⁺ = 353.

Example 15D-2, ^XH NMR (CDC1₃) : δ 5.65 (m, IH) , 5.48 (d, IH) , 5.26 (m, IH) , 4.37 (t, J=8.4 Hz, IH) , 3.97 (m, 2H) , 3.32 (t, J=9.6 Hz, IH) , 3.22 (br, IH) , 3.08-2.95 (m, 2H) , 2.50- 2.39 (m 2H) , 1.97 (s, 3H) , 1.66 (dd, J=1.7, 6.8 Hz, 3H) , 1.47 (s, 9H) . MS: (M+H)⁺ = 353.

Example 15E (±) - (IS, 3i?, 75.8i?, 8ai?) -8- (acetylamino) -7-hydroxy-5-oxo-l- [(1Z) -1-propenyll octahydro-3-indolizinecarboxylic acid The title compound was prepared according to the method described in Example 14E, substituting Example 15D-1 for Example 14D to afford 5 mg (100%) of Example 15E. ^XH NMR (DMSO-d₆) : δ 7.64 (d, J=9.8 Hz, IH) , 5.40 (m, IH) , 5.26 (m, IH) , 4.23 (t, J=8.9 Hz, IH) , 3.96 (m, IH) , 3.81 (m, IH) , 3.57 (t, J=10.1 Hz, IH) , 2.88 (m, IH) , 2.54 (m, IH) , 2.33 (m, IH) , 2.27 (m, IH) , 1.74 (s, 3H) , 1.52 (dd, J=1.8, 6.7 Hz, 3H) , 1.35 (m, IH) . MS: (M+H)⁺ = 297.

Example 16

(±) - (IS, 3i?, 7i?, 8i?, 8ai?) -8- (acetylamino) -7-hydroxy-5-oxo-l- T (IZ) -l-propenyll octahvdro-3-indolizinecarboxylic acid Example 16A (±) - (1S.3J?.7i?.8i?, 8ai?) -8- (acetylamino) -7-hydroxy-5-oxo-l- [ (IZ) -1-propenyl! octahydro-3-indolizinecarboxylic acid The title compound was prepared according to the method described in Example 14E, substituting Example 15D-2 for Example 14D to afford 15 mg (100%) of the desired product .

^XH NMR (DMSO-d₆) : δ 7.61 (d, J=8.6 Hz, IH) , 5.42 (m, IH) , 5.18 (m, IH) , 4.24 (t, J=8.6 Hz, IH) , 3.73 (m, 2H) , 3.22 (t, J=9.2 Hz, IH) , 2.93 (m, IH) , 2.65 (m, IH) , 2.35 (m, IH) , 2.18 (m, IH) , 1.73 (s, 3H) , 1.55 (dd, J=1.8, 6.7 Hz, 3H) , 1.35 (m, IH) . MS: (M+H)⁺ = 297.

Example 17

(±) - (lS.3i?.7i?.8i?.8ai?) -8- (acetylamino) -7-hydroxy-l- [(IZ) -1- propenyll octahydro-3-indolizinecarboxylic acid monotrifluoro acetic acid salt Example 17A (±) -di (tert-butyl) (2i?.4S.5i?) -5- \ ( 1R . 2R) -1- (acetylamino) - 2,4-dihvdroxybutyll -4- [ (IZ) -1-propenyll -1.2- pyrrolidinedicarboxylate

The title compound was prepared according to the method described in Example 14B, substituting Example 14A-1 for Example 14A-2 to afford 561 mg (88.8%) of the desired product . ^XH NMR (CDC1₃) : δ 5.97 (d, IH) , 5.60 (m, IH) , 5.36 (m, IH) , 5.06 (m, IH) , 4.16 (m, IH) , 3.85-3.13 (m, 5H) , 3.08 (m, IH) , 2.67 (m, 2H) , 2.05 (s, 3H) , 1.85-1.70 (m, 2H) , 1.54 (dd, 3H) , 1.47 (s, 9H) , 1.44 (s, 9H) . MS: (M+H)⁺ = 457.

Example 17B (±) -tert-butyl (2i?.4S.5i?) -5- [ ( 1R . 2R) -1- (acetylamino) -2.4- dihvdroxybutyl! -4- I (IZ) -1-propenyll -2- pyrrolidinecarboxylate

The title compound was prepared according to the method described in Example 14C, substituting Example 17A for Example 14B to afford 159 mg (71.0%) of the desired product . MS: (M+H)⁺ = 357. Example 17C (±) -tert-butyl (15, 3i?, 7i?, 8i?.8ai?) -8- (acetylamino) -7-hydroxy- 1- [ (IZ) -1-propenyll octahydro-3-indolizinecarboxγlate The title compound was prepared according to the method described in Example 14D, substituting Example 17B for Example 14C to afford 82 mg (55.0%) of the desired product . MS: (M+H)⁺ = 339.

Example 17D (±) - (lS,3i?.7i?,8i?,8ai?) -8- (acetylamino) -7-hvdroxy-l- [ (IZ) -1- propenyll octahvdro-3-indolizinecarboxylic acid monotrifluoro acetic acid salt

The title compound was prepared according to the method described in Example 14E, substituting Example 17C for Example 14D to afford 9.9 mg (100%) of the desired product . ^XH NMR (CDC1₃) : δ 1.55 (dd, 3H) , 1.65 (m, IH) , 1.74 (m, 2H) , 1.79 (s, 3H) , 1.99 (m, IH) , 2.69 (m, IH) , 3.25 (m, IH) , 3.37 (m, 2H) , 3.52 (m, IH) , 3.78 (m, IH) , 4.48 (br, IH) , 5.30 (m, IH) , 5.50 (m, IH) , 7.85 (br, IH) . MS: (M+H)⁺ = 283.

An alternative synthesis of Example 17 is the following: Example 17E ( +) -di (tert-butyl) (2i?.4i?, 5i?) - 5 - 1 (IS) -1- (acetylamino) -2- [ (triisopropylsilyl) oxy! ethyl} -4- (hydroxymethyl) -1,2- pyrrolidinedicarboxylate

The title compound was prepared according to the method described in Example IK, substituting Example 1J-2 for Example 1J-1 to afford 9.2 g (81%) of the desired product . ^λU NMR (CDC1₃) : δ 6.97 (d, J=7.8 Hz, IH) , 4.26 (d, J=9.8 Hz, IH) , 4.11 (dd, J=1.5, 10.3 Hz, IH) , 3.83 (m, 3H) , 3.71 (dq, J=10.7, 3.9 Hz, IH) , 3.54 (m, IH) , 2.51 (m, IH) , 2.36 (q, J=7.8 Hz, IH) , 2.00 (m, 2H) , 1.91 (s, 3H) , 1.47 (s, 9H) , 1.42 (s, 9H) , 1.02-1.11 (m, 21H) .

Example 17F (+) -di (tert-butyl) (2i?.4i?, 5i?) -5-( (IS) -1- (acetylamino) -2- [ (triisopropylsilyl) oxyl ethyl} -4-formyl-1.2- pyrrolidinedicarboxylate

The title compound was prepared according to the method described in Example IL, substituting Example 17E for Example IK to afford 5.6 g (64%) of the desired product . ¹H NMR (CDC1₃) : δ 9.66 (d, J=0.6 Hz, IH) , 7.12 (d, J=7.5 Hz, IH) , 4.85 (d, J=9.6 Hz, IH) , 4.08 (dd, J=1.7, 8.4 Hz, IH) , 3.90 (m, IH) , 3.82 (d, J=4.8 Hz, 2H) , 2.96 (dt, J=7.4, 1.4 Hz, IH) , 2.51 (m, 2H) , 1.93 (s, 3H) , 1.44 (s, 9H) , 1.42 (s, 9H) , 1.02-1.11 (m, 21H) . Example 17G (+) -di( tert-butyl) (2i?,4S,5i?) -5-( (IS) -1- (acetylamino) -2- [ (triisopropylsilyl) oxy] ethyl} -4- [ (IZ) -1-propenyll -1,2- pyrrolidinedicarboxylate The title compound was prepared according to the method described in Example 1M, substituting Example 17F for Example IL to afford 5.3 g (92%) of the desired product.

^XH NMR (CDC1₃) : δ 6.96 (d, J=7.8 Hz, IH) , 5.60 (m, IH) , 5.36 (dq, J=1.0, 6.9 Hz, IH) , 4.20 (d, J=9.8 Hz, IH) , 4.11 (d, J=9.8 Hz, IH) , 3.81 (m, 3H) , 3.04 (t, J=8.1 Hz, IH) , 2.64 (m, IH) , 1.92 (s, 3H) , 1.82 (d, J=14.7 Hz, IH) , 1.58 (dd, J=1.5, 6.8 Hz, 3H) , 1.45 (s, 9H) , 1.42 (s, 9H) , 1.02-1.11 (m, 21H) .

Example 17H (+) -di( tert-butyl) (2i?.4S,5i?) -5- [ (IS) -1- (acetylamino) -2- hydroxyethyl] -4- [ (IZ) -1-propenyll -1, 2- pyrrolidinedicarboxylate The title compound was prepared according to the method described in Example IN, substituting Example 17G for Example 1M to afford 11.2 g (90%) of the desired product .

^:H NMR (CDC1₃) : δ 6.95 (d, J=1.3 Hz, IH) , 6.56 (m, IH) , 5.39 (dq, J=1.2, 6.8 Hz, IH) , 4.16 (dd, J=1.3, 10.2 Hz, IH) , 3.97 (m, 2H) , 3.64 (m, 2H) , 3.36 (t, J=6.4 Hz, IH) , 3.05 (t, J=8.4 Hz, IH) , 2.64 (m, IH) , 1.98 (s, 3H) , 1.82 (d, J=13.6 Hz, IH) , 1.61 (dd, J=1.7, 6.8 Hz, 3H) , 1.46 (s, 9H) , 1.44 (s, 9H) .

Example 171 (+) -di ( ert-butyl) (2i?, 4S.5i?) -5- \ (IS) -1- (acetylamino) -2- oxoethyll -4- [ (IZ) -1-propenyll -1.2-pyrrolidinedicarboxylate The title compound was prepared according to the method described in Example 10, substituting Example 17H for Example IN to afford 9.2 g (85%) of the desired product .

^XH NMR (CDC1₃) : δ 9.53 (s, IH) , 6.29 (d, J=8.1 Hz, IH) , 5.58 (ddq, J=l.l, 10.9, 6.8 Hz, IH) , 5.37 (m, IH) , 4.53 (dd, J=3.1, 8.5 Hz, IH) , 4.13 (m, 3H) , 3.14 (m, IH) , 2.43 (m, IH) , 2.08 (s, 3H) , 1.65 (dd, J=1.7, 6.8 Hz, 3H) , 1.46 (s, 9H) , 1.42 (s, 9H) .

Example 17J

( + ) -di ( tert-butyl) (2i?.4S.5i?) -5- [ (IS) -1- (acetylamino) -4- ethoxy-2-hvdroxy-4-oxobutyll -4- [(IZ) -1-propenyll -1,2- pyrrolidinedicarboxylate The title compound was prepared according to the method described in Example 14A, substituting Example 171 for Example 10 to afford 1.02 g (85%) of the desired product . ^λU NMR (CDC1₃) : δ 6.47 (d, J=9Hz, IH) , 5.6 (m, 1H),5.41 (m, IH) 3.85-4.20 (m, 7H) , 2.97 and 3.12 (t, J=9Hz, IH) , 2.53- 2.75 (m, IH) , 2.53-2.75 ( , IH) , 2.45-2.52 (m, 2H) , 1.98 (s, 3H) , 1.62 (m, 3H) , 1.45 (s, 9H) , 1.42 (s, 9H) , 1.27 (m, 3H) .

Example 17K

( +) -di( tert-butyl) (2i?.4S.5i?) -5- \ (IS) -1- (acetylamino) -2.4- dihydroxybutyll -4- \ ( IZ) -1-propenyll -1.2- pyrrolidinedicarboxylate The title compound was prepared according to the method described in Example 14B, substituting Example 17J for Example 14A to afford 0.8 g (90%) of the desired product .

^XH NMR (CDC1₃) : δ 6.72(d, .25H), 6.52 (d, .25H), 6.35(d,.5H), 5.56 (m, IH) , 5.40(m, IH) , 3.8-4.2 (m, 8H) , 2.82-3.12 (m, IH) , 2.53-2.73 (m, IH) , 2.01 (d, 3H) , 1.50-1.88 (m, 6H) , 1.44 (d, 18H) .

Example 17L

( +) -tert-butyl (2i?.4S.5i?) -5- [ (IS) -1- (acetylamino) -2.4- dihydroxybutyll -4- [ (IZ) -1-propenyll -2- pyrrolidinecarboxylate The title compound was prepared according to the method described in Example 14C, substituting Example 17K for Example 14B to afford 178 mg (84%) of the desired product .

Example 17M (+) -tert-butyl (15, 3i?, 85.8ai?) -8- (acetylamino) -7-hvdroxy-i- [ (IZ) -1-propenyll octahvdro-3-indolizinecarboxylate The title compound was prepared according to the method described in Example 14D, substituting Example 17L for Example 14C to afford 258 mg (22%) of the desired product .

^XH NMR (DMSO-d₆) : δ 7.44 (d, J=9Hz, IH) , 5.40(m, IH) , 5.28 (m, IH) , 4.74 (d, J=4Hz, IH) , 4.70 (d, J=3Hz, IH) , 3.77(m, IH) , 3.58(m, IH) , 3.55(m, IH) , 3.10(q, J=3 , 10Hz, IH) , 2.87(m, IH) , 2.70(m, IH) , 2.55(m, IH) , 2.22(m, IH) ,

1.86(s, 3H),1.73(m, IH) , 1.46(m, 3H) , 1.43(s, 9H) , 1.40(m, IH) .

Example 17N

( +) -tert-butyl (15, 3i?, 8ai?) -8- (acetylamino) -7-oxo-l- [ (IZ) -1- propenyl] octahydro-3-indolizinecarboxylate The title compound was prepared according to the method described in Example IL, substituting Example 17M for Example IK to afford 262 mg (94%) of the desired product .

Example 170 (+) -tert-butyl (IS, 3i?, 8i?, 8ai?) -8- (acetylamino) -7-oxo-l- [ (IZ) -1-propenyl] octahydro-3-indolizinecarboxylate Acetic acid (0.8 mL) was added to a room temperature solution of Example 17N (10.0 mg, 0.03 mmol) in dichloromethane (0.2 mL) . ^' After 6 hours, the reaction mixture was concentrated and the concentrate was chromatographed on silica gel to afford 65 mg (80%) of the desired product.

^XH NMR (CDC1₃) : δ 5.80 (d, J=9 Hz, IH) , 5.39 (m, 2H) , 4.69 (t, J=10 Hz, IH) , 3.78 (m, IH) , 3.29 (m, 2H) , 2.97 (m, IH) , 2.81 (m,lH), 2.64 (m,2H), 2.40 (m, IH) , 1.97 (s, 3H) , 1.66 (m, IH) , 1.59 (d, J=6Hz, 3H) , 1.46(s, 9H) . MS: (M+H)⁺ = 337.

Example 17P

(+) -tert-butyl (IS, 3i?, 7i?, 8i?, 8ai?) -8- (acetylamino) -7-hvdroxy- 1- r (IZ) -1-propenyll octahydro-3-indolizinecarboxylate The title compound was prepared according to the method described in Example IB, substituting Example 170 for Example 1A to afford 75mg (60%) of the desired product. ^XH NMR (DMSO-de) : δ 7.39 (d, J=10Hz, IH) , 5.37( m, IH) , 5.28 (m, IH) , 4.49 (d, J=5Hz, IH) , 3.53 (m, IH) , 3.40 (q, J=10Hz, IH) , 3.16 (m, IH) , 2.86 (m, IH) , 2.79 (m, IH) , 2.53 (M, IH) , 2.48 (m, IH) , 2.35 (m, IH) , 1.75 (m, IH) , 1.70 (s, 3H) , 1.49 (q, J=2.8 Hz, 3H) , 1.41 (s, 9H) , 1.41 (m, IH) , 1.34 (m, IH) . MS: (M+H)⁺ = 339.

Example 170

(+) - (lS,3i?.7i?,8i?,8ai?) -8- (acetylamino) -7-hvdroxy-l- r (IZ) -1- propenyll octahydro-3-indolizinecarboxylic acid trifluoroacetic acid salt The title compound was prepared according to the method described in Example 14E, substituting Example 17P for Example 14D to afford the desired product.

Example 18

(+) - (IS, 3i?, 7i?, 8i?, 8ai?) -8- (acetylamino) -7-ethoxy-1- r (IZ) -1- propenyll octahydro-3-indolizinecarboxylic acid monotrifluoro acetic acid salt

Example 18A

(±) -tert-butyl (15, 3i?, 7i?, 8i?, 8ai?) -8- (acetylamino) -7-ethoxy-l- T (IZ) -1-propenyll octahydro-3-indolizinecarboxylate Ethyliodide (0.095 mL, 1.2 mmol) was added to a room temperature mixture of Example 17C (40 mg, 0.12 mmol), 18- Crown-6 (3 mg) and potassium hydroxide powder (38 mg, 0.59 mmol) in DMF (2 mL) . After 4.5 hours, the reaction was quenched with acetic acid (10 drops) and concentrated. The concentrate was treated with brine and extracted with ether. The combined ether layers were dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 2-5% methanol in dichloromethane to afford 19.4 mg (44.7%) of the desired product .

^XH NMR ( CDC1₃) : δ 1.13 (t, 3H) , 1.47 (s, 9H) , 1.59 (dd, 3H) , 1.52 (m, IH) , 1.64 (m, IH) , 1.90 (s, 3H) , 1.94 (m, IH) , 2.46 (m, IH) , 2.68-2.71 (m, 2H) , 2.92-3.16 (m, 3H) ,

3.40 (m, IH) , 3.51 (m, 2H) , 3.80 (m, IH) , 5.06 (d, IH) ,

5.41 (d, 2H) . MS: (M+H)⁺ = 367.

Example 18B

(±) - (IS, 3i?.7i?, 8i?, 8ai?) -8- (acetylamino) -7-ethoxy-l- [ (IZ) -1- propenyl] octahydro-3-indolizinecarboxylic acid monotrifluoro acetic acid salt The title compound was prepared according to the method described in Example 14E, substituting Example 18A for Example 14D to afford 24.5 mg (100%) of Example 18B. ^XH NMR (DMSO-de): δ 1.09 (t, 3H) , 1.58 (dd, 3H) , 1.64 (m, IH) , 1.74 (m, IH) , 1.80 (s, 3H) , 2.07 (m, IH) , 2.62 (m, IH) , 3.19 (m, IH) , 3.23 (m, IH) , 3.27 (m, IH) , 3.30 (m, IH) , 3.37 (m, IH) , 3.43 (m, IH) , 3.55 (m, IH) , 3,84 (m, IH) , 4.27 (m, IH) , 5.32 (m, IH) , 5.49 (m, IH) , 7.72 (d, IH) .

MS: (M+H)⁺ = 311. Example 19

(±) - ( 15, 3i? , 7i?, 8i?, 8ai?) - 8 - (acetylamino) - 7 -hvdroxy- l - [ ( IZ) - 1 - propenyll -7-propyloctahvdro-3-indolizinecarboxylic acid monotrifluoro acetic acid salt

Example 19A (±) -di (tert-butyl) (2R.4S.5i?) -5- r (li?, 2i?) -1- (acetylamino) -2- (2-ethoxy-2-oxoethyl) -2-hydroxypentyll -4- [ (IZ) -1-propenyl] 1, 2-pyrrolidinedicarboxylate

The title compound was prepared according to the method described in Example 14A, substituting Example 13A for Example 10 to afford 139 mg (44.6%) of the desired product . ^Η NMR (CDC1₃) : δ 0.89 (t, 3H) , 1.26 (m, 5H) , 1.43 (s, 9H) , 1.44 (s, 9H) , 1.54 (m, IH) , 1.61 (dd, 3H) , 1.68 (m, IH) , 2.02 (s, 3H) , 2.45-2.55 (m, 2H) , 3.53 (m, IH) , 4.15-4.20 (m, 4H) , 4.33-4.58 (m, 2H) , 5.36 (m, IH) , 5.62 (m, IH) , 6.00 (m, IH) , 6.46 (d, IH) . S: (M+H)⁺ = 541. Example 19B (±) -di (tert-butyl) ( 2R .45.5i?) -5- f (li?.2i?) -1- (acetylamino) -2- hydroxy-2- (2 -hydroxyethyl) pentyl] -4- [ (IZ) -1-propenyl! -1,2- pyrrolidinedicarboxylate

The title compound was prepared according to the method described in Example 14B, substituting Example 19A for Example 14A-2 to afford 139 mg (44.6%) of the desired product . ²H NMR (CDC1₃) : δ 0.92 (m, 3H) , 1.27 (m, 3H) , 1.45 (s, 9H) , 1.46 (s, 9H) , 1.58-1.70 (m, 5H) , 2.01(m, IH) , 2.03 (s, 3H) , 2.30 (m, IH) , 2.50 (m, IH) , 3.40 (m, IH) , 3.60-4.20 (m, 4H) , 4.44 (m, IH) , 5.38 (m, IH) , 5.62 (m, IH) , 6.17 (br, IH) . MS: (M+H)⁺= 499.

Example 19C (±) -tert-butyl (2i?,4S,5i?) -5- I ( 1R. 2R) -1- (acetylamino) -2- hydroxy-2- (2-hvdroxyethyl) entyl] -4- [ (IZ) -1-propenyl] -2- pyrrolidinecarboxylate The title compound was prepared according to the method described in Example 14C, substituting Example 19B for Example 14B to afford 36 mg (59.3%) of the desired product. hi NMR (CDC1₃) : δ 0.89 (t, J=7.5 Hz, 3H) , 1.34 (m, IH) , 1.46 (s, 9H) , 1.58 (dd, 3H) , 1.78-1.90 (m, 2H) , 1.92 (s, 3H) , 2.44 (m, IH) , 3.80 (m, IH) , 3.45 (m, IH) , 3.75 (m, 2H) , 3.95 (m, IH) , 3.99 (m, IH) , 5.26 (m, IH) , 5.62 (m, IH) , 6.67 (d, IH) . MS: (M+H)⁺ = 399.

Example 19D

(+) -tert-butyl (15, 3i?, 7i?, 8i?, 8ai?) -8- (acetylamino) -7-hvdroxy-

1- [ (IZ) -1-propenyll -7-propyloctahydro-3- indolizinecarboxylate The title compound was prepared according to the method described in Example 14D, substituting Example 19C for Example 14C to afford 19 mg (76.9%) of the desired product .

^XH NMR (CDC1₃) : δ 0.93 (m, 3H) , 1.30 (m, 4H) , 1.48 (s, 9H) , 1.50 (m, 3H) , 1.64 (dd, J=l.l, 6.4 Hz, 3H) , 1.70(m, IH) , 1.96 (s, 3H) , 2.00 (m, IH) , 2,45 (m, IH) , 2.59 (m, IH) , 2.75-2.95 (m, IH) , 3.70 (m,2H), 4.55 (s, IH) , 5.45-5.60 (m, 3H) .

MS: (M+H)⁺ = 381.

Example 19E (±) - (IS, 3i?.1R. 8R.8ai?) -8- (acetylamino) -7-hvdroxy-l- r (IZ) -1- propenyl! -7-propyloctahvdro-3 -indolizinecarboxylic acid monotrifluoroacetic acid salt

The title compound was prepared according to the method described in Example 14E, substituting Example 19D for Example 14D to afford 20.9 mg (100%) of the desired product . ^XH NMR (DMSO-de): δ 0.83 (m, 3H) , 1.20-1.36 (m, 3H) , 1.43

(m, IH) , 1.63(m, 3H) , 1.85 (s, 3H) , 1.97 (m, IH) , 2.62 (m, IH) , 3.26 (m, IH) , 3.28-3.42 (m, 2H) , 3.73 (m, IH) , 3.87 (m, IH) , 4.40 (m, IH) , 5.22 (m, IH) , 5.59 (m, IH) , 7.82 (d, IH) . MS: (M+H)⁺ = 325.

Example 20

This example intentionally left blank.

Example 21

(±) - ( IS, 3i?, 75, 8i?, 8ai?) - 8 - (acetylamino) - 7-hydroxy-7 - ( 2 - hvdroxyethyl) -1- [ (IZ) -1-propenyll octahydro-3- indolizinecarboxylic acid monotrifluoro acetic acid salt

Example 21A (±) -tert-butyl (15, 3i?, 7i?, 82?, 8ai?) -8- (acetylamino) -7- (2- ethoxy-2-oxoethyl) -7-hydroxy-l- [ (IZ) -1-propenyll octahydro- 3-indolizinecarboxylate

The title compound was prepared according to the method described in Example 14A, substituting Example 170 for Example 10 to afford 18.9 mg (75.0%) of the desired product . ^XH NMR (CDC1₃) : δ 1.27 (t, 3H) , 1.47 (s, 9H) , 1.50 ( , IH) , 1.57 (d, 3H) , 1.66 (m, IH) , 1.81 (m, IH) , 1.90 (s, 3H) , 2.28 (d, IH) , 2.39 (m, IH) , 2.54 (d, IH) , 2.63 (m, IH) , 2.92-3.04 (m, 3H) , 3.65 (m, IH) , 3.72 (m, IH) , 3.83 (m, IH) , 4.16 (q, 2H) , 5.40 (m, 2H) , 5.58 (br d, IH) . MS: (M+H)⁺ = 425. Example 2IB (±) -tert-butyl (15.32?.72?, 82?, 8a2?) -8- (acetylamino) -7-hydroxy- 7- (2-hvdroxyethyl) -1- T(1Z) -1-propenyl] octahydro-3- indolizinecarboxylate The title compound was prepared according to the method described in Example 14B, substituting Example 21A for Example 14A-2 to afford 9.9 mg (62.6%) of the desired product.

²H NMR (CDC1₃) : δ 1.47 (s, 9H) , 1.53 (m, IH) , 1.58 (d, 3H) , 1.70 (m, IH) , 1.86 (m, IH) , 1.93 (s, 3H) , 1.98 (m, IH) , 2.14 (m, IH) , 2.41 (m, IH) , 2.80 (, m, IH) , 2.94 (m, 2H) , 3.03 (m, IH) , 3.64-3.76 (m, 2H) , 3.84-4.02 (m, 2H) , 5.41 (m, 2H) , 5.60 (br d, IH) . MS: (M+H)⁺ = 383.

Example 21C (±) - (15, 32?.72?, 82?.8ai?) -8- (acetylamino) -7-hvdroxy-7- (2- hydroxyethyl) -1- f (IZ) -1-propenyl! octahydro-3- indolizinecarboxylic acid Monotrifluoro Acetic Acid Salt The title compound was prepared according to the method described in Example 14E, substituting Example 21B for Example 14D to afford 10.3 mg (100%) of the desired product .

^XH NMR (pyridine-d₅) : 1.68 (dd, 3H) , 1.96 (m, IH) , 2.04 (m, IH) , 2.09 (m, 2H) , 2.10 (s, 3H) , 2.43 (m, IH) , 2.68 (m, IH) , 3.18 (m, IH) , 3.39 (m, IH) , 3.72 (m, IH) , 4.19 (m, 2H) , 4.31 (dd, IH) , 4.42 (t, IH) , 5.39 (m, IH) , 8.05 (d, IH) , 9.54 (br s, 3H) . MS: (M+H)⁺ = 327.

Example 22

(±) - (IS.32?, 65, 72?.7a2?) -7- (acetylamino) -6-hydroxy-l- [ (IZ) -1- propenyl] hexahydro-lH-pyrrolizine-3-carboxylic acid

Example 22A (±) -di (tert-butyl) (22?.45.52?) -5- \ (12?.22?) -1- (acetylamino) -3- (1-ethoxyethoxy) -2-hydroxypropyl]- -4- [ (IZ) -1-propenyll -1.2- pyrrolidinedicarboxylate (Example 22A-1) and

(+) -di (tert-butyl) (22?.45.52?) -5- [ (12?.25) -1- (acetylamino) -3- (1-ethoxyethoxy) -2-hvdroxypropyl] -4- [ (IZ) -1-propenyl! -1,2- pyrrolidinedicarboxylate (Example 22A-2) n-Butyllithium (1.6M, 0.6 ml, 0.96 mmol) was added dropwise to a -78 °C solution of

(ethoxyethyloxymethyl) tributylstannane (prepared according to the procedure of W. Clark Still, J^". Am. Chem. Soc , 100, 1481 (1978)) (575 mg, 1.46 mmol) in THF (4ml). After stirring for 15 minutes, Example 10 (70 mg, 0.17 mmol) in THF (2 ml) was added. The reaction mixture was stirred at -78 °C for 30 min, quenched with saturated aqueous ammonium chloride (3 ml) , and extracted with dichloromethane (5 x 10 ml) . The combined dichloromethane layers were dried (MgS0₄) , filtered, and concentrated. The concentrate was purified by column chromatography on silica gel using 5% methanol in dichloromethane to afford 25.1 mg (28.7%) of Example 22A-1 and 30.9 mg, (35.3%) of Example 22A-2, both as white foamy solids. Example 22A-1, ^λE NMR (CDC1₃) : δ 1.20 (dt, J=7.2, 2.4Hz,

3H) , 1.30 (dd, J=5.4, 3.9 Hz, 3H) , 1.44 (s, 9H) , 1.47 (s, 9H) , 1.61 (m, IH) , 1.65 (dd, J=6.6, 1.5 Hz, 3H) , 2.04 (s, 3H) , 2.62 (m, IH) , 3.38-3.70 (m, 8H) , 4.23 (dd, J=9.3, 5.1 Hz, IH) , 4.67 (qd, J=5.1, 2.4 Hz, IH) , 4.37-4.48 (m, 2H) , 7.77 (br t, J=9.9 Hz, IH) . MS: (M+H)⁺ = 515.

Example 22A-2, ^XH NMR (CDC1₃) : δ 1.19 (dt, J=7.2, 2.4Hz, 3H) , 1.29 (t, J=5.1 Hz, 3H) , 1.44 (s, 9H) , 1.46 (s, 9H) , 1.54 (dd, 3H) , 1.64 (m, IH) , 2.00 (s, 3H) , 2.66 (m, IH) , 3.13 (m, IH) , 3.41-3.49 (m, 2H) , 3.59-3.69 (m, 2H) , 3.75 (d, J=9.9 Hz, IH) , 3.89 (td, J=10.2, 3.0 Hz, IH) , 4.15 (ddd, J=10.2, 3.0, 1.2 Hz, IH) , 4.65 (dd, J=9.6, 5.1 Hz, IH) , 4.72 (dd, J=6.6, 4.8 Hz, IH) , 5.35 (m, IH) , 5.60 (br t, J=10.2 Hz, IH) , 5.99 (br d, J=10.2 Hz, IH) . MS: (M+H)⁺ = 515.

Example 22B (±) -tert-butyl (22?, 45, 52?) -5- r (12?, 22?) -1- (acetylamino) -2.3- dihvdroxypropyll -4- [ (IZ) -1-propenyll -2- pyrrolidinecarboxylate Hydrochloric acid (0.5N, 1 ml) was added to a room temperature solution of Example 22A-1 (12.8 mg, 0.025 mmol) in THF (1ml) . After stirring for 1 hour, the reaction mixture was concentrated. The concentrate was dissolved in room temperature dichloromethane (0.5 ml) and treated with trifluoroacetic acid (0.08 ml, 1.0 mmol). After stirring for 2 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (2 ml) , and extracted with dichloromethane (5 x 5 ml) . The combined dichloromethane layers were dried (Na₂S0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using 10% methanol in dichloromethane to afford 10.2 mg (83.6%) of the desired product .

^XH NMR (CDC1₃) : δ 1.46 (s, 9H) , 1.51 (dt, J=12.9, 8.4 Hz, IH) , 1.62 (dd, J=6.6, 1.8 Hz, 3H) ,^' 1.97 (s, 3H) , 2.41 (dt, J=12.9, 7.5 Hz, IH) , 3.03 (m, IH) , 3.18 (dd, J=9.0, 6.0 Hz, IH) , 3.62 (br d, J=3.0 Hz, 2H) , 3.68-3.76 (m, 2H) , 3.85 (dt, J=6.6, 9.0 Hz, IH) , 5.27 (m, IH) , 5.49 (m, IH) , 5.56 (br d, J=9.6 Hz, IH) . MS: (M+H)⁺ = 343.

Example 22C

(±) -tert-butyl (IS, 32?, 6S, 72?.7a2?) -7- (acetylamino) -6-hydroxy-

1- [ (IZ) -1-propenyl! hexahydro-lH-pyrrolizine-3 -carboxylate The title compound was prepared according to the method described in Example 14D, substituting Example 22B for Example 14C to afford the desired product.

Example 22D (±) - (IS.32?. SS.72?.7a2?) -7- (acetylamino) -6-hvdroxy-l- \ (IZ) -1- propenyll hexahydro-lH-pyrrolizine-3 -carboxylic acid The title compound was prepared according to the method described in Example 14E, substituting Example 22C for Example 14D to afford the desired product.

^:H NMR (DMSO-dg): δ 8.07(d, J=8.3Hz, IH) , 5.56-5.52(m, IH) , 5.25-5.21(m, IH) , 4.67-4.63 (dd, J=12.2, 5.86Hz, IH) , 4.59- 4.55(m, IH) , 4.29(m, IH) , 3.84-3.81(m, IH) , 3.61-3.52(m, 2H) , 3.36(m, IH) , 2.51-2.44 (m, IH) , 1.98-1.91(m, IH) , 1.83(s, 3H) , 1.55(d, J=6.84Hz, 3H) . MS: (M+H)⁺ = 269, (M+Na)⁺ = 291, (M-H)^" = 267, (M+Cl) ^" = 303

Example 23

(±) - (IS, 32?, 62?, 72?.7a2?) -7- (acetylamino) -6-hvdroxy-l- [ (IZ) -1-propenyll hexahydro-lH-pyrrolizine-3 -carboxylic acid Example 23A (±) -tert-butyl (22?,4S,52?) -5- ( 1R . 2S) -1- (acetylamino) -2,3- dihydroxypropyll -4- T (IZ) -1-propenyl! -2- pyrrolidinecarboxylate

The title compound was prepared according to the method described in Example 22B, substituting Example 22A-2 for Example 22A-1 to afford 4.9 mg (57.6%) of the desired product . ^JH NMR (CDC1₃) : δ 1.47 (s, 9H) , 1.55 (td, J=10.2, 2.1 Hz,

IH) , 1.67 (dd, J=6.6, 2.1 Hz, 3H) , 2.03 (s, 3H) , 2.37 (dt, J=12.6, 6.6 Hz, IH) , 3.08 (m, IH) , 3.34-3.40 (m, 2H) , 3.58 (dd, J=11.4, 6.6 Hz, IH) , 3.76 (dd, J=9.9, 6.9 Hz, IH) , 3.92 (ddd, J=9.0, 3.0, 1.2 Hz, IH) , 4.20 (t, J=7.2 Hz, IH) , 5.24 (m, IH) , 5.61 (m, IH) , 6.14 (br d, J=9.0 Hz, IH) . MS: (M+H)⁺= 343.

Example 23B (±) -tert-butyl (IS, 32?, 62?.72?.7a2?) -7- (acetylamino) -6- hydroxy-1- \ ( IZ) -1-propenyl! hexahydro-lif-pyrrolizine-3- carboxylate The title compound was prepared according to the method described in Example 14D, substituting Example 23B for Example 14C to afford the desired product.

Example 23C (±) - (IS.32?, 62?, 72?.7a2?) -7- (acetylamino) -6-hydroxy-l- f (IZ) -1-propenyl] hexahvdro- Iff- yrrolizine-3 -carboxylic acid The title compound was prepared according to the method described in Example 14E, substituting Example 23C for Example 14D to afford the desired product.

^XH NMR (DMSO-d₆) : δ 8.08(d, J=6.8Hz, IH) , 5.62-5.58(m, IH) , 5.27-5.23(m, IH) , 4.61-4.57 (dd, J=11.72, 5.86Hz, IH) , 4.25 ( , IH) , 4.13(m, IH) , 3.77-3.74(m, 2H) , 3.64-3.57(m, IH) , 3.50-3.47(m, IH) , 2.48-2.45(m, IH) , 1.92-1.85 (m, IH) , 1.82(8, 3H) , 1.65(d, J=6.83Hz, 3H) .

MS: (M+H)⁺ = 269, (M+Na) ⁺ = 291, (M-H)^" = 267, (M+Cl)^" = 303.

Example 24

(±) - (IS.32?.62?.72?.7a2?) -7- (acetylamino) -6 -ethoxy- 1- [ (IZ) -1- propenyl] hexahydro-lff-pyrrolizine-3 -carboxylic acid monotrifluoroacetic acid salt

Example 24A (±) -di (tert-butyl) (22?.42?.52?) -4- \ (acetyloxy) methyll -5- (2.2- dimethyl-1, 3-dioxolan-4-yl) -1.2-pyrrolidinedicarboxylate 1, 1-Dimethoxypropane (18.6 g, 0.18 mol) and a catalytic amount of p-toluenesulfonic acid were added to a room temperature solution of Example IF (2.0 g, 4.96 mmol) in acetone (22 mL) . After stirring for 16 hours, triethylamine (1 mL) was added and the reaction mixture was concentrated to afford 2.2 g (100%) of the crude desired product as a colorless oil.

¹H NMR (CDC1₃) δ 4.66 (m, IH) , 4.22 (dd, J=10.1, 1.4 Hz, IH) , 4.15-3.90 ( , 4H) , 3.68 (dd, J=8.5, 5.8 Hz, IH) , 2.7- 2.5 (m, 2H) , 2.09 (s, 3H) , 1.76 (dd, J = 13.3, 1.4 Hz, IH) , 1.47 (s, 9H) , 1.45 (s, 3H) , 1.43 (s, 9H) , 1.32 (s, 3H) . MS: (M+H)⁺ = 444, (M+Na) ⁺ = 466.

Example 24B

(±) -di( tert-butyl) (22?.42?.52?) -5- (2.2-dimethyl-l .3-dioxolan- 4-yl) -4- (hydroxymethyl) -1 , 2-pyrrolidinedicarboxylate Potassium carbonate (6.8 g, 0.050 mol) was added to a room temperature mixture of Example 24A (2.2 g, 4.96 mmol) in methanol (16 mL) and water (4 mL) . After 30 minutes, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 25 mL) . The combined ethyl acetate layers were dried (MgS0₄) , filtered, and concentrated to afford 1.7 g (85%) of the crude desired product. MS: (M+H)⁺ = 402, (M+Na) ⁺ = 424, (2M+Na)⁺ = 825.

Example 24C (+) -di (tert-butyl) (22?, 42?, 52?) -5- (2 , 2 -dimethyl-1 , 3-dioxolan- 4-yl) -4-formyl-l, 2-pyrrolidinedicarboxylate Dimethylsulfoxide (0.58 g, 7.47 mmol) was slowly added to a -78 °C solution of oxalyl chloride (0.48 g, 3.74 mmol) in dichloromethane (25 mL) . After 30 minutes, a solution of Example 24B (1.7 g, 2.49 mmol) in dichloromethane (5 mL) was slowly added to the reaction mixture so that the reaction temperature did not exceed -70 °C. After 1.5 hours at -78 °C, triethylamine (1.52 g, 14.9 mmol) was added and the mixture allowed to warm to room temperature. After 2 hours, the reaction was quenched with water (100 mL) and extracted with dichloromethane (3 x 100 mL) . The combined dichloromethane layers were dried (MgS0₄) , filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel using a gradient of 9-50% ethyl acetate in hexanes to afford 790 mg (46%) of the desired product and 410 mg (24%) of recovered starting material .

Example 24D (±) -di (tert-butyl) (22?, 45, 52?) -5- (2 , 2-dimethyl-1 , 3-dioxolan- 4-yl) -4- T (IZ) -1-propenyll -1 , 2-pyrrolidinedicarboxylate Potassium tert-butoxide (1.0 M solution in THF, 3.96 mL, 3.96 mmol) was added to a room temperature slurry of ethyl triphenylphosphonium bromide (1.8 g, 4.94 mmol) in toluene (20 mL) . After stirring for 4 hours, the reaction mixture was cooled to 0 °C and a solution of Example 24C (0.79 g, 1.98 mmol) in toluene (5 mL) was slowly added dropwise. The reaction mixture was stirred at 0 °C for 15 minutes, quenched with saturated aqueous ammonium chloride (20 mL) , and extracted with ethyl acetate (3 x 30 mL) . The combined ethyl acetate layers were dried (MgS0₄) , filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel using 5% ethyl acetate in dichloromethane to afford the desired product 540 mg (66%) as a colorless oil. ^XH NMR (CDC1₃) δ 5.59 (td, J=9.8,2.0 Hz, IH) , 5.35 (m, IH) , 4.64 (m, IH) , 4.23 (dd, J=10.2,1.4 Hz, IH) , 4.05 (dd,

J=8.5,7.4 Hz, IH) , 3.81 (m, IH) , 3.64 (dd, J=8.8,6.4 Hz, IH) , 3.22 (t, J=9.7 Hz, IH) , 2.65 (m, IH) , 1.73 (d, J=12.9 Hz, IH) , 1.62 (dd, J=6.8,1.7 Hz, 3H) , 1.48 (s, 3H) , 1.46 (s, 9H) , 1.45 (s, 3H) , 1.43 (s, 9H) . MS: (M+H)⁺ = 412, (M+Na) ⁺ = 434, (2M+Na)⁺ = 845.

Example 24E (±) -di (tert-butyl) (22?,4S,52?) -5- (1, 2-dihvdroxyethyl) -4- [ (IZ) -1-propenyll -1 , 2-pyrrolidinedicarboxylate

A solution of Example 24D (0.54 g, 1.3 mmol) in room temperature acetic acid (8 mL) and water (2 mL) was stirred for 16 hours. The reaction mixture was concentrated and the concentrate was purified by flash chromatography on silica gel using 50% ethyl acetate in hexanes to afford 400 mg (81%) of the desired product as a white solid. MS: (M+H)⁺ = 372, (M+Na)⁺ = 394, (2M+Na)⁺ = 765. Example 24F (±) -di (tert-butyl) (22?.45.52?) -5-formyl-4- \ (IZ) -1-propenyll -

1 , 2 -pyrrolidinedicarboxylate Sodium periodate (0.175 g, 0.82 mmol) was added to a 0 °C solution of Example 24E (0.10 g, 0.27 mmol) in 30% aqueous ethanol (1.5 ml) . After stirring for 1 hour, ethyl acetate (10 ml) was added and the solution was dried (MgS0₄) , filtered through a celite pad, and concentrated to afford 100 mg (99%) of the crude desired product as an oil. *H NMR (CDC1₃) (rotamers) δ 9.49 and 9.37 (2d, J=3.1 and 4.1 Hz, IH) , 5.65-5.53 (m, IH) , 5.43-5.32 (m, IH) , 4.33 and 4.28 (2dd, J=7.1, 7.8 and 8.8, 6.1 Hz , IH) , 4.04 and 3.88 (2 dd, J=3.4, 7.1 and 3.7, 7.8 Hz, IH) , 3.21-3.09 (m, IH) , 2.55-2.40 (m, IH) , 1.83-1.73 (m, IH) , 1.59 (m, 3H) , 1.48- 1.42 (m, 18H) . MS: (M+H)⁺ = 340, (M-H) ⁺ = 338.

Example 2 G (±) -di (tert-butyl) (22?,4S,52?) -5- (2.3-diethoxy-l-hvdroxy-3- oxopropyl) -4- [ (IZ) -1-propenyl] -1 , 2-pyrrolidinedicarboxylate Ethyl ethoxyacetate (0.18 ml, 1.47 mmol) in THF (0.60 ml) was added dropwise to a -78 °C solution of LDA (1.32 mmol) in THF (1.2 ml) . After 1.5 hours at -78 °C, Example 24F (0.20 g, 0.59 mmol) in THF (1.0 ml) was added at -78 °C, and the reaction was stirred for 1 hour. The reaction was quenched with saturated ammonium chloride and diluted with ethyl acetate. The ethyl acetate was washed with water, brine, dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using a gradient, hexanes to 30% ethyl acetate in hexanes, to afford 230 mg (81%) of the desired products as a mixture of isomers. MS: (M+H)⁺ = 472, (M+Na) ⁺ = 494.

Example 24H

(±) -di (tert-butyl) (22?, 45.52?) -5- (2-ethoxy-l , 3- dihydroxypropyl) -4- [ (IZ) -1-propenyl! -1,2- pyrrolidinedicarboxylate Lithium borohydride (51 mg, 2.34 mmol) was added to a room temperature solution of Example 24G (220 mg, 0.47 mmol) in THF (5.0 ml) . After 0.5 hours, the reaction was quenched with water and diluted with ethyl acetate. The ethyl acetate was washed with 10% aqueous citric acid, saturated sodium bicarbonate solution, and brine, dried (MgS0 ) , filtered and concentrated. The concentrate (0.20 g) was used in the next reaction without further purification. MS: (M+H)⁺ = 430, (M-H)^" = 428.

Example 241 (±) -di (tert-butyl) (22?, 45, 52?) -5- (3-( [tert- butyl (diphenyl) silyll oxy} -2-ethoxy-1-hvdroxypropyl) -4- [(IZ) -1-propenyl! -1.2-pyrrolidinedicarboxylate

Imidazole (65 mg, 0.94 mmol) and tert- butylchlorodiphenylsilane (0.12 ml, 0.51 mmol) were added to a 0 °C solution of Example 24H (0.20 g, 0.47 mmol) in dichloromethane (5.0 ml) . After 45 minutes, the reaction was quenched with methanol (50 μl) and diluted with ethyl acetate. The ethyl acetate was washed with 10% aqueous citric acid, saturated sodium bicarbonate solution, and brine, dried (MgS0₄) , filtered and concentrated. The concentrate (0.31 g) was used in the next reaction without further purification.

MS: (M+H)⁺ = 668, (M-H)^" = 666.

Example 24J (±) -di (tert-butyl) (22?, 4S.52?) -5- ( (25) -3-( [tert- butyl (diphenyl) silyll oxy} -2-ethoxypropanoyl) -4- [ (IZ) -1- propenyl! -1, 2-pyrrolidinedicarboxylate (Example 24J-1) and (±) -di (tert-butyl) (22?, 45.52?) -5- ( (22?) -3-{ Ttert- butyl (diphenyl) silyl! oxy} -2-ethoxypropanoyl) -4- I (IZ) -1- propenyl! -1, 2-pyrrolidinedicarboxylate (Example 24J-2) Dess Martin periodinane (0.30 g, 0.70 mmol) was added to a room temperature solution of Example 241 (0.31 g, 0.47 mmol) in dichloromethane (5.0 ml) . After one hour, the reaction was diluted with ether and filtered. The ether was washed with 1M sodium thiosulfate, water and brine, dried (MgS0₄) , filtered and concentrated. The concentrate was purified by chromatography on silica gel using a gradient, hexanes to 15% tert-butyl methyl ether in hexanes to afford 100 mg (33%) of Example 24D-1 and 140 mg (46%) of Example 24D-2.

Example 24J-1, ^XH NMR (CDC1₃) : (rotamers) δ 7.73-7.66 (m, 4H) , 7.43-7.34 (m, 6H) , 5.62-5.28 (m, 2H) , 4.52 (m, IH) , 4.41-4.26 (m, 2H) , 4.06-3.61 (m, 4H) , 3.18-3.04 (m, IH) , 2.57-2.33 (m, IH) , 1.79-1.68 (m, IH) , 1.53-1.04 (m, 33H) . MS: (M+H)⁺ = 666.

Example 24J-2, ^XH NMR (CDC1₃) : (rotamers) δ 7.72-7.68 (m, 4H) , 7.45-7.33 (m, 6H) , 5.66-5.58 (m, IH) , 5.48-5.36 (m, IH) , 4.79 and 4.66 (2d, J=1.7 and 2.0 Hz, IH) , 4.45 and

4.36 (2dd, J=10.2, 2.0 and 10.2, 2.0 Hz, IH) , 4.05-3.55 (m, 5H) , 3.30 (m, IH) , 2.45-2.26 (m, IH) , 1.73 (m, IH) , 1.53 (m, 3H) , 1.47-1.01 (m, 30H). MS: (M+H)⁺ = 666.

Example 24K (±) -di (tert-butyl) (22?, 45.52?) -5- [ (12?.25) -1- (acetylamino) -3- (acetyloxy) -2-ethoxypropyl1 -4- [ (IZ) -1-propenyl1 -1,2- pyrrolidinedicarboxylate

Sodium cyanoborohydride (0.280 g, 4.36 mmol) and ammonium acetate (0.690 g, 8.72 mmol) were added to a room temperature solution of Example 24J-2 (0.145 g, 0.22 mmol) in methanol (3.0 ml) . The reaction mixture was heated to 60 °C for 36 hours, quenched with water and diluted with ethyl acetate. The ethyl acetate was washed with water and brine, dried (MgS0₄) , filtered and concentrated.

Acetic anhydride (0.150 ml, 1.59 mmol) was added to a room temperature solution of the concentrate, triethylamine (0.400 ml, 2.86 mmol), and 4- (dimethylamino) pyridine (5 mg, 0.040 mmol) in dichloromethane (3.0 ml) . After 12 hours, the reaction was quenched with water and diluted with ethyl acetate. The ethyl acetate was washed with water, brine, dried (MgS0₄) , filtered and concentrated.

TBAF (1M in THF, 0.70 ml) was added to a room temperature solution of the concentrate in THF (2.0 ml) . After 3 hours, the reaction was quenched with water and diluted with ethyl acetate. The ethyl acetate was washed with water and brine, dried (MgS0₄) , filtered and concentrated .

Acetic anhydride (0.150 ml, 1.59 mmol) was added to a room temperature solution of the concentrate, triethylamine (0.400 ml, 2.86 mmol), and 4- (dimethylamino) pyridine (5 mg, 0.040 mmol) in dichloromethane (3.0 ml). After 12 hours, the reaction was quenched with water and diluted with ethyl acetate. The ethyl acetate was washed with water, brine, dried (MgS0₄) , filtered and concentrated.

The concentrate was purified by column chromatography on silica gel using a gradient, hexanes to ethyl acetate, to afford 25 mg (22%) of the desired product. MS: (M+H)⁺ = 513, (M-H)^" = 511. Example 24L (±) -di (tert-butyl) (22?,4S,52?) -5- [ (12?.25) -1- (acetylamino) -2- ethoxy-3-hydroxypropyl] -4- [ (IZ) -1-propenyll -1,2- pyrrolidinedicarboxylate

Potassium carbonate (0.050 g, 0.362 mmol) was added to a room temperature solution of Example 24K (0.025 g, 0.049 mmol) in methanol (1.5 ml) . After 5 hours, the reaction mixture was concentrated, quenched with water and diluted with ethyl acetate. The ethyl acetate was washed with water and brine, dried (MgS0₄) , filtered and concentrated. The concentrate was purified by column chromatography on silica gel using a gradient, hexanes to ethyl acetate, to afford 16 mg (70%) of the desired product. MS: (M+H)⁺ = 471, (M-H)^" = 469.

Example 24M (+) -tert-butyl (22?, 45, 52?) -5- r 11R . 2S) -1- (acetylamino) -2- ethoxy-3 -hydroxypropyl] -4- I (IZ) -1-propenyll -2- pyrrolidinecarboxylate

The title compound was prepared according to the method described in Example 14C, substituting Example 24L for Example 14B to afford the desired product.

Example 24N (±) -tert-butyl (IS, 32?, 62?, 72?, 7a2?) -7- (acetylamino) -6-ethoxy-l- T (IZ) -1-propenyll hexahydro- Iff-pyrrolizine-3 -carboxylate

The title compound was prepared according to the method described in Example 14D substituting Example 24M in place of Example 14C to afford 17 mg (52%) of the desired product.

^XH NMR (DMSO-de): δ 7.98 (d, J=7.8 Hz, IH) , 5.53-5.42 (m, IH) , 5.28-5.18 (m, IH) , 3.99 (m, IH) , 3.64 (m, IH) , 3.59- 3.38 (m, 3H) , 3.09 (dd, J=4.4, 12.2 Hz, IH) , 3.06 (m, IH) , 2.93 (dd, J=2.7, 8.8 Hz, IH) , 2.80 (dd, J=2.0, 12.2 Hz, IH) , 2.10-2.03 (m, IH) , 1.76 (s, 3H) , 1.69-1.58 (m, IH) ,

1.61 (dd, J=1.7, 6.8 Hz, 3H) , 1.40 (s, 9H) , 1.11 (t, J=6.8

Hz, 3H) .

MS: (M+H)⁺ = 353. Example 240 (±) - (15,32?.62?,72?,7a2?) -7- (acetylamino) -6-ethoxy-l- f (IZ) -1- propenyll hexahvdro- Iff-pyrrolizine-3 -carboxylic acid monotrifluoroacetic acid salt

The title compound was prepared according to the method described in Example 14E substituting Example 24N for Example 14D to afford the desired product. ^XH NMR (DMSO-de) δ 8.06 (d, J=7.5 Hz, IH) , 5.67-5.57 (m,

IH) , 5.29-5.22 (m, IH) , 4.47 (dd, J=6.4, 11.9 Hz, IH) , 4.21 (ra, IH) , 4.03 (m, IH) , 3.82 (dd, J=4.7, 13.2 Hz, IH) , 3.76 (dd, J=3.1, 9.8 Hz, IH) , 3.65 (dd, J=2.4 , 13.2 Hz, IH) , 3.56 (q, J=7.1 Hz, 2H) , 3.49 (m, IH) , 2.51-2.43 (m, IH) , 1.94-1.84 (m, IH) , 1.83 (s, 3H) , 1.64 (dd, J=1.7, 6.8 Hz, 3H) , 1.16 (t, J=7.1 Hz, 3H) . MS: (M+H)⁺ = 297.

Example 25

(±) - (15, 32?, 6S, 72?, 7a2?) -7- (acetylamino) -6-ethoxy-l- [ (IZ) -1- propenyl! hexahydro-lff-pyrrolizine-3 -carboxylic acid monotrifluoroacetic acid salt Example 25A (±) -di (tert-butyl) (22?,4S,52?) -5- [ (12?, 22?) -1- (acetylamino) -3- (acetyloxy) -2-ethoxypropyl] -4- [ (IZ) -1- propenyl! -1.2-pyrrolidinedicarboxylate

The title compound was prepared according to the method described in Example 24K, substituting Example 24J-1 for Example 24D-2 to afford 58 mg (18%) of the desired product.

MS: (M+H)⁺ = 513, (M-H)^" = 511.

Example 25B (±) -di (tert-butyl) (22?.45, 52?) -5- \ (1R . 2R) -1- (acetylamino) -2- ethoxy-3 -hvdroxypropy11 -4- \ ( IZ) -1-propenyll -1.2- pyrrolidinedicarboxylate

The title compound was prepared according to the method described in Example 24F substituting Example 25A for Example 24L to afford 40 mg (75%) of the desired product . MS: (M+H)⁺ =471, (M-H)^" =469.

Example 25C (±) -tert-butyl (22?.45.52?) -5- [ (12?.22?) -1- (acetylamino) -2- ethoxy-3-hydroxypropyll -4- \ (IZ) -1-propenyll -2- pyrrolidinecarboxylate

The title compound was prepared according to the method described in Example 14C substituting Example 25B for Example 14B to afford the desired product .

Example 25D tert-butyl (15, 32?, 6S, 72?, 7ai?) -7- (acetylamino) -6-ethoxy-l- [ (IZ) -1-propenyl] hexahydro-lff-pyrrolizine-3-carboxylate The title compound was prepared according to the method described in Example 14D substituting Example 25C for Example 14C to afford 7 mg (33%) of the desired product .

^XH NMR (DMSO-de) δ 7.67 (d, J=8.8 Hz, IH) , 5.47-5.36 (m, IH) , 5.30-5.22 (m, IH) , 4.09 (m, IH) , 3.94 (m, IH) , 3.47- 3.28 (m, 3H) , 3.03 (m, 2H) , 2.85 (m, IH) , 2.75 (dd, J=4.8 , 11.5 Hz, IH) , 2.15-2.08 (m, IH) , 1.79 (s, 3H) , 1.73-1.60 (m, IH) , 1.56 (dd, J=1.7, 6.8 Hz, 3H) , 1.39 (s, 9H) , 1.08 (t, J=6.8 Hz, 3H) . MS: (M+H)⁺ = 353. Example 25E

(+) - (IS, 32?, 6S, 72?, 7a2?) -7- (acetylamino) -6-ethoxy-l- \ (IZ) -1- propenyll hexahydro-Iff-pyrrolizine-3 -carboxylic acid monotrifluoro acetic acid salt The title compound was prepared according to the method described in Example 14E substituting Example 25D for Example 14D to afford the desired product . ^XH NMR (DMSO-de) δ 8.04 (d, J=8.5 Hz, IH) , 5.61-5.50 (m, IH) , 5.25-5.18 (m, IH) , 4.68-4.59 (m, 2H) , 4.14 (m, IH) , 3.77-3.30 (m, 6H) , 2.53-2.44 (m, IH) , 1.96-1.84 (m, IH) , 1.84 (s, 3H) , 1.57 (dd, J=1.7, 6.8 Hz, 3H) , 1.14 (t, J=7.1 Hz, 3H) . MS: (M+H)⁺ = 297.

Example 26 i±l (3S, 42?, 4a2?, 55, 72?) -4- (acetylamino) -3-methyl-l- thiono-5- [ (IZ) -1-propenyll -3-propylhexahvdropyrrolo [1,2-cl [1, 31 oxazine-7-carboxylic acid

Example 26A (±) - (tert-butyl) (2R.4S.5R) -5- r (1R.2S) -1- (acetylamino) - 2-hvdroxy-2-methylpentyl] -4- [ (IZ) -1-propenyll -2- pyrrolidinecarboxylate (Example 13B-1)

The title compound can be prepared according to the method described in Example 14C substituting the product of Example 13B-1 for Example 14B to afford the desired product .

Example 26B (±) - (tert-butyl) (35.42?.4ai?.5S.72?) -4- (acetylamino) -3- methyl-l-thiono-5- [ (IZ) -1-propenyll -3- propylhexahvdropyrrolo [1 , 2-cl [1,31 oxazine-7-carboxylate

The product of Example 26A can be reacted with thiocarbonyl diimidazole in tetrahydrofuran at ambient temperature in the presence of a catalytic amount of N,N- dimethylaminopyridine to afford the desired compound.

Example 26C (±) - (35.42?,4a2?,5S,72?) -4- (acetylamino) -3 -methyl-1- thiono-5- [(IZ) -1-propenyll -3-propylhexahydropyrrolo Tl , 2- cl [1.31 oxazine-7-carboxylic acid

The title compound can be prepared according to the method described in Example IT substituting the product of Example 26B for Example IS to afford the desired product.

Example 27 (±) - (12?,35,42?,4a2?, 55, 72?) -4- (acetylamino) -1, 3 -dimethyl- 5- [ (IZ) -1-propenyll -3-propylhexahydropyrrolo [1,2-cl [1, 3] oxazine-7-carboxylic acid

The product of Example 13C can be reacted according to the procedure of Example 5B substituting acetaldehyde for formaldehyde to provide the title compound.

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 R¹⁴/R¹⁵ substituent from Table 3 , one R* substituent from Table 4 and one R substituent from Table 5 .

Table 1 Substituents for Core Group

Table 2 Substituents for Y Group

13 14 15 16

21 22 23 24

25 26 27 28

29 30 31 32

37 38 39 40

HO O w O. N-N

41 42 43 44

45 46 47 48

wvw

49 50 51 52

53 54 55 56

61 62 63 64

117 118 119 120

129 130 131 132

H₃C H₃C ^FH~^α~ ^F|H «W°Λ^H>³

149 150 151 152

157 158 159 160

Table 3

Substituents for R"/R" Group

10 11 12

13 14 15 16

17 18 19 20

53 54 55 56

CH3 -" ^ H₃C ,C

H₃C X H, H CH₃ xX_^ H, .CH₃

73 74 75 76

77 78 79 80

81 82 83 84

89 90 91 92

OH

101 102 103 104

H₃C

CH, H₃C CH,

H₃C CH, CH₃ 09 110 111 112

133 134 135 136

137 138 139 140

155 156 157 158

167 168 169 170

CH, τ~ . r CH₃ ^H3^C

OH OH

171 172 173 174

175 176 177 178

179 180 181 182

183 184 185 186

195 196 197 198

203 204 205 206

207 208 209 210

211 212 213 214

¹3' XJ »XJ Xj. "^*χ_j 215 216 217 218

247 248 249 250

_H3C^ ^ J 'O ^ J

251 252 253 254

259 260

267 268 269 270

295 296

Table 4 Substituents for R* Group

H CH, ) H,C.

H₃C

OH

10

Table 5 Substituents for R Group

-OH -OCH₃ — O CH₃

2 3

13 14 15

19 20 21

25 26 27

38 39 40

-NH₂ -N' - ^ H H

47 48 49

H H H — N-Ala-OH — N-Ala-OCH₃ — N-Ala-OEt

65 66 67

H H H — N-Val-OH — N-Val-OCH₃ — N-Val-OEt

68 69 70

H H H — N-Leu-OH — N-Leu-OCH₃ — N-Leu-OEt

71 72 73

H H H — N-lle-OH — N— lle-OCH₃ — N-lle-OEt

74 75 76

H H H — N-Phe-OH — -Phe-OCH₃ — N-Phe-OEt

77 78 79

H H H — N-Tyr-OH — N-Tyr-OCH₃ — N-Tyr-OEt

80 81 82

H H H — N-Asn-OH — N-Asn-OCH₃ — N-Asn-OEt

83 84 85

H H H — N-GIU-OH — N-Glu-OCH₃ — N-Glu-OEt

86 87 88

H H H — N-Gln-OH — N-Gln-OCH₃ — N-Gln-OEt

89 90 91

H H H — N-Asp-OH — N-Asp-OCH₃ — N-Asp-OEt

92 93 94

H H H — -Lys-OH — -Lys-OCH₃ — -Lys-OEt

95 96 97

H H H — N-Ser-OH — N-Ser-OCH₃ — N-Ser-OEt

98 99 100

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 .

Claims

We Claim:

A compound of formula I

or a pharmaceutically acceptable salt, ester, or prodrug

thereof, wherein

W is selected from the group consisting of

-0C(0)-, -O(CHR')-, -(CH₂)„-, - (CH₂)_nC(0) -, - (CH₂) _nC (S) - ,

^■C(O)-, -C(S)-, -CHR'C(O)-, -CHR'C(S)-, -OC(S)-, -NHC(O)-, -NHC(S) -, -NR'C(O) -, -NR'C(S) -, -0(CH₂)_n-,

-0(CR'R") -, -CHR' (CH₂)_n-, -CR' R" (CH₂) _n- , -CHCH-, -S(CH₂)_n-,

-S(CHR' ) -, and -S(CR'R") -,

wherein n is 1-3; and R' and R" are independently selected from the group consisting of

(iii) hydrogen, (ii) Cι-C₁₂ alkyl, (iii) haloalkyl,

(iv) hydroxyalkyl, (v) thiol-substituted alkyl,

(vi) R^37c0-substituted alkyl,

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

(ix) (R^37c)NH-substituted alkyl,

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

(xi) R^37a0- (0=)C-substituted alkyl,

(xii) R^{3 a}S- (0=)C-substituted alkyl,

(xiii) R^37a0- (S=)C-substituted alkyl,

(xiv) R^37aS- (S=)C-substituted alkyl, (xv) (R^37aO)₂-P(=0) -substituted alkyl,

(xvi) cyanoalkyl,

(xvii) C₂-Ci2 alkenyl,

(xviii) haloalkenyl, (xix) C₂-Cι₂ alkynyl,

(xx) cycloalkyl, (xxi) (cycloalkyl) alkyl,

(xxii) (cycloalkyl) alkenyl,

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

(xxv) (cycloalkenyl) alkyl,

(xxvi) (cycloalkenyl) alkenyl,

(xxvii) (cycloalkenyl) alkynyl,

(xxviii) aryl, (xxxix) (aryl) alkyl, (xxx) (aryl) alkenyl,

and

(xxxi) (aryl) alkynyl;

selected from the group consisting of

(b) -C0₂H, (b) -CH₂C0₂H, (c) -SO₃H, (d) -CH₂S0₃H, (e) -S0₂H, (f) -CH₂S0₂H, (g) -P0₃H₂, (h) -CH₂P0₃H₂,

(i) -P0₂H,

(j) -CH₂P0₂H, (k) tetrazolyl, (1) -CH₂-tetrazolyl,

(m) -C(=0) -NH-S (O) 2-R¹¹,

(p) -CH₂C(=0) -NH-S (0) ₂-R¹¹, (o) -S0₂N (T-R¹¹) R¹² and

(p) -CH₂S0₂N(T-R¹¹)R¹²;

wherein

T is selected from the group consisting of

(ii) 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

(ii) ₁.-C12 alkyl, (ii) C₂-C₁₂ alkenyl,

(iii) cycloalkyl,

(iv) (cycloalkyl) alkyl,

(w) (cycloalkyl) alkenyl, (vi) cycloalkenyl,

(vii) (cycloalkenyl) alkyl,

(xiii) (cycloalkenyl) alkenyl, (ix) aryl,

(x) (aryl) alkyl, (xi) (aryl) alkenyl,

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

(xiv) (heterocyclic) alkenyl; and

R¹² and R³⁶ are independently selected from the group

consisting of

(vi) hydrogen, (ii) Cι-C₁₂ alkyl,

(vii) C₂-C₁₂ alkenyl, (iv) cycloalkyl,

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

(viii) (cycloalkenyl) alkyl,

(ix) (cycloalkenyl) alkenyl,

(xiv) aryl, (xi) (aryl) alkyl,

(xii) (aryl) alkenyl,

(xiii) heterocyclic,

(xiv) (heterocyclic) alkyl, and

(xv) (heterocyclic) alkenyl;

X is selected from the group consisting of

(d) -C(=0)-N(R*)-, (b) -N(R*)-C(=0)-,

(e) -C(=S)-N(R*)-, (d) -N(R*)-C(=S)-,

(e) -N(R*)-S0₂-, and (f) -S0₂-N(R*)-,

wherein R* is hydrogen, Cι.-C₃ loweralkyl or

cyclopropyl;

R is selected from the group consisting of (b) hydrogen, (b) Cι-C₆ alkyl, (c) C₂-C₆ alkenyl,

(d) C₃-C_e cycloalkyl, (e) C₅-C₆ cycloalkenyl,

(f) halo Cι-C₆ alkyl and (g) halo C₂-C₆ alkenyl;

or R -X- is

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, Cι-C₃ loweralkyl,

hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl,

1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and

methylthiomethyl ;

R_a is selected from the group consisting of

(b) hydrogen, (b) Cι-C₆ alkyl, (c) C₂-C₆ alkenyl,

(d) halo Cι-C₆ alkyl, and (e) halo C₂-C₆ alkenyl;

R_i4 and R₁₅ are independently selected from the group consisting

of

(iv) 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-substituted alkyl,

(xi) R^37aO- (0=)C-substituted alkyl, (xii) R^37aS- (0=)C-substituted alkyl,

(xiii) R^37aO- (S=)C-substituted alkyl,

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

(xv) (R^37aO)₂-P(=0) -substituted alkyl,

(xvi) cyanoalkyl,

(xvii) C₂-C12 alkenyl,

(xviii) haloalkenyl, (xix) C₂-C₁₂ alkynyl,

(xx) cycloalkyl, (xxi) (cycloalkyl) alkyl,

(xxii) (cycloalkyl) alkenyl,

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

(xxv) (cycloalkenyl) alkyl,

(xxvi) (cycloalkenyl) alkenyl, (xxvii) (cycloalkenyl) - alkynyl ,

(xxviii) aryl, (xxxix) (aryl) alkyl, (xxx) (aryl) alkenyl,

(xxxi) (aryl) alkynyl,

(xxxii) heterocyclic, (xxxiii) (heterocyclic) alkyl, (xxxiv) (heterocyclic) alkenyl,

(xxxv) (heterocyclic) alkynyl, (xxxvi) -0-alkyl,

(xxxvii) -NHalkyl, (xxxviii) -NH₂, (xxxix) -N (alkyl) ₂,

(xxxx) -OH, (xxxxi) -NHacyl, (xxxxii) -Nalkylacyl,

(xxxxiii) -NHcarbamoyl, (xxxxiv) -Nalkylcarbamoyl,

(xxxxv) -NHcarbamidyl, and (xxxxvi) -Nalkylcarbamidyl;

R^{3 a} is selected from the group consisting of

(ii) hydrogen, (ii) Cx-C^ alkyl, (iii) haloalkyl,

(viii) hydroxyalkyl, (v) alkoxyalkyl,

(vi ) C₂-Cι₂ alkenyl ,

(vii ) haloalkenyl , (viii ) C₂-Cι₂ alkynyl ,

(xv) cycloalkyl, (x) (cycloalkyl) alkyl,

(xvi) (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

(ii) hydrogen, (ii) C_x-Ci₂ alkyl, (iii) haloalkyl,

(iv) C₂-C₁₂ alkenyl, (v) haloalkenyl,

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

(viii) (cycloalkyl) alkyl, (ix) (cycloalkyl) - alkenyl,

(x) (cycloalkyl) alkynyl, (xvii) 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,

(xxiv) (heterocyclic) alkynyl, (xxiii) -C(=0)-R¹⁴,

(xxv) -C(=S)-R¹⁴, (xxv) -S(0)₂-R¹⁴ and

(xxvi) hydroxyalkyl ;

Y is selected from the group consisting of

(b) hydrogen, (b) Cι-C₅ alkyl , (c) Cι-C₅ haloalkyl ,

(d) C₂-C₅ alkenyl , (e) C₂ -C₅ haloalkenyl ,

( f ) C₂-C₅ alkynyl , (g) C₃-C₅ cycloalkyl, (h) C₃-C₅ cycloalkyl-Cι-to-C₃-

alkyl ,

(j) C₅ cycloalkenyl, (j) C₅ cycloalkenyl -Ci- to -C₃- alkyl,

(k) C₅ cycloalkenyl-C₂-to-C₃-alkenyl, (1) - (CHR³⁹)_nOR²⁰,

(o) -CH(OR²⁰) -CH₂(OR²⁰) , (n) - (CHR³⁹) _nSR²¹,

(q) -(CHR³⁹)_nCN, (p) -(CHR³⁹)_nN₃, (q) phenyl,

(r) halo- substituted phenyl, (s) - (CHR³⁹) _nC (=Q²) R²²,

(t) -(CHR³⁹)_nN(=Q³) , (u) -N(0)=CHCH₃, (v) - (CHR³⁹) _nNR²³R²⁴,

(w) halo, and (x) a heterocyclic ring having from

3 to 6 ring atoms;

wherein n is 0, 1, or 2; Q' is O, S, NR", or CHR ,26

⁰ at each occurrence is independently

(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) Cx-Cj haloalkyl, (vii) vinyl,

(viii) propenyl, (ix) isopropenyl, (x) allyl,

(xi) C₂-C₃ haloalkenyl, (xii) amino, (xiii) -NHCH₃,

(xiv) -N(CH₃)₂, (xv) -NHCH2CH3,

(xvi) -N(CH₃) (CH₂CH₃) ,

(xvii) -N(CH₂CH₃)₂ or

(xviii) -N(=CH₂);

R²¹ is

(j) 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) ethyl- thio,

(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;

R⁴¹ and R⁴² are independently hydrogen, methyl, or ethyl;

R²⁴ is selected from the group consisting of (i) hydrogen, (ii) C₁-C₄ alkyl, (iii) C₂-C₄ alkenyl,

(ix) C₂-C₄ alkynyl, (v) cyclopropyl, (vi) -C(=Q⁴)-R³⁰,

(x) (v) -OR³¹, and (vi) -N(R³²)₂,

wherein Q is O, S, or N(R ) ;

R is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or

R²⁶ is hydrogen, methyl or ethyl ;

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

R³⁰ is hydrogen, methyl, ethyl, -OR³⁴, -SR³⁴, -N(R³⁵)₂,

-NHOH, -NHNH₂, -N(CH₃)NH₂, or -N (CH₂CH₃) NH₂;

R is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or

R is methyl or ethyl; R³⁵ 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-C₂H_5;

R^e and R⁷ are independently selected from the group consisting

of

(b) hydrogen, (b) C -C₁₂ alkyl, (c) C₂-Cι₂ alkenyl,

(d) cycloalkyl, (e) (cycloalkyl) alkyl,

(f) (cyclo alkyl) alkenyl, (g) cycloalkenyl,

(j) (cycloalkenyl) alkyl,

(k) (cycloalkenyl) alkenyl, (j) aryl, (k) (aryl) alkyl,

(1) (aryl) alkenyl, (m) heterocyclic,

(p) (heterocyclic) alkyl, and (o) (heterocyclic) alkenyl;

and R⁸ and R⁹ and are independently selected from the group consisting of

(b) hydrogen , (b) Cι-C₆ alkyl , ( c ) C₂ - C_s alkenyl ,

(d) C₃ -C₆ cycloalkyl , (e ) C₃ -C₆ cycloalkenyl ,

(f) fluorine, and (g) -NH₂,

R¹⁰ is selected from the group consisting of

(b) hydrogen, (b) Cι-C₆ alkyl, (c) C₂-C₆ alkenyl,

(d) C₃-C₆ cycloalkyl, (e) C₃-C₆ cycloalkenyl,

(f) fluorine, (g) -NH₂, and (h) -OH

with the proviso that if Y is - ( CHR^{j y} ) _nOR--

- (CHR³⁹)_nN(=Q³) ,

-N(0)=CHCH₃,

- (CHR³⁹)_nNR²³R²⁴,

or halo,

where n is 0,

then R¹⁰ is not -OH, -NH₂, or -F.

2. The compound of Claim 1 wherein is selected from the group consisting of -0C(O)-, -O(CHR')-, -(CH₂)_n-,

-(CH₂)_nC(0) -, -0(CH₂)_n-, -O-C(S)-, -NHC(O)-, -NR'C(O), -CHR' (CH₂)_n-, -CR'R" (CH₂)_n-, and -CHCH- .

3. The compound of Claim 2 wherein is selected from the group consisting of -OC(O)-, -CH₂C(0)-,

-0CH₂-, and - (CH₂)_n-.

The compound of Claim 1 wherein R¹ is -C0₂H,

The compound of Claim 2 wherein R¹ is -C0₂H.

The compound of Claim 3 wherein R¹ is -C0₂H.

7. The compound of Claim 1 wherein X is -N(R*)- C(=0)-, R* is hydrogen, and -R₂ is Cι-C₆ alkyl

8. The compound of Claim 2 wherein X is -N(R*)- C(=0)-, R* is hydrogen, and -R₂ is Cι-C₆ alkyl

9. The compound of Claim 6 wherein X is -N(R*)- C(=0)-, R* is hydrogen, and -R₂ is Cι-C₆ alkyl,

10. The compound of Claim 1 wherein Y is selected from the group consisting of

(a) hydrogen, (b) Cι-C₃ alkyl, (c) Ci-Cs haloalkyl,

(d) C₂-C₅ alkenyl, (e) C₂-C₅ haloalkenyl,

(f) C₂-C₅ alkynyl,

(g) C₃-C₅ cycloalkyl,

(h) C₃-C₃ cycloalkyl-C_ι-to-C₃-alkyl,

(i) C₅ cycloalkenyl,

(j) C₅ cycloalkenyl-Cι-to-C₃-alkyl,

(k) C₅ cycloalkenyl-C₂-to-C₃-alkenyl, and

(1) a heterocyclic ring having from

3 to 6 ring atoms.

11. The compound of Claim 10 wherein Y is C₂-C₅ alkenyl .

12. The compound of Claim 1 wherein R_i4 is alkyl or

-O-alkyl.

13. The compound of Claim 9 wherein R₁₄ is alkyl or -O - alkyl .

14. The compound of Claim 1 wherein

W is selected from the group consisting of -OC(O)-, -CH₂C(0)-, -OCH2-, and -(CH₂)_n-,

Ri is -C0₂H,

X is -N(R*) -C(=0) -,

R* is hydrogen,

-R₂ is Cι-C₆ alkyl,

Y is C₂-C₅ alkenyl,

and

R₁₄ is alkyl or -O-alkyl .

15 . A compound of formula la

la

or a pharmaceutically acceptable salt, ester, or prodrug

thereof, wherein

W is selected from the group consisting of

-OC(O) -O(CHR')-, -(CH₂)_n-, -(CH₂)_nC(0)-, -(CH₂)_nC(S)

-C(O)-, -C(S)-, -CHR'C(O)-, -CHR'C(S)-, -OC(S) -NHC(O)

-NHC(S) -NR'C(O)-, -NR'C(S) -0⁽CH₂ ⁾ _n-

-0(CR'R")-, -CHR' (CH₂)_n-, -CR' R" (CH₂) _n- , -CHCH-, -S(CH₂)_n-,

(v) hydrogen, (ii) Ci-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-substituted alkyl,

(xi) R^37aO- (0=)C-substituted alkyl,

(xii) R^37aS- (0=)C-substituted alkyl,

(xiii) R^37aO- (S=)C-substituted alkyl,

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

(xv) (R^37aO)₂-P(=0) -substituted alkyl,

(xvi) cyanoalkyl,

(xvii) C₂-Ci₂ alkenyl , (xviii) haloalkenyl, (xix) C₂-C₁₂ alkynyl,

(xx) cycloalkyl, (xxi) (cycloalkyl) alkyl,

(xxii) (cycloalkyl) alkenyl,

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

(xxv) (cycloalkenyl) alkyl,

(xxvi) (cycloalkenyl) alkenyl,

(xxvii) (cycloalkenyl) alkynyl,

(xxviii) aryl, (xxxix) (aryl) alkyl, (xxx) (aryl) alkenyl,

and

(xxxi) (aryl) alkynyl;

selected from the group consisting of

(c) -C0₂H, (b) -CH₂C0₂H, (c) -S0₃H, (d) -CH₂S0₃H,

(e) -S0₂H, (f) -CH₂S0₂H, (g) -P0₃H₂ (h) -CH₂P0₃H₂,

(i) -P0₂H,

(j) -CH₂P0₂H, (k) tetrazolyl, (1) -CH₂-tetrazolyl, (m) -C(=0) -NH-S (O) ₂-R¹¹,

(r) -CH₂C(=0) -NH-S (0) ₂-R¹¹, (o) -S0₂N (T-R¹¹) R¹² and

(p) -CH₂S0₂N(T-R^1:L)R¹²;

wherein

T is selected from the group consisting of

(iii) a bond, (ii) -C(=0)-, (iii) -C(=0)0-,

(iv) -C(=0)S-, (v) -C(=p)NR³⁶-,

(vi) -C(=S)0-, (vii) -C(=S)S-, and

(viii) -C(=S)NR³⁶-;

R is selected from the group consisting of

(iii) Ci-Cι₂ alkyl, (ii) C₂-C₁₂ alkenyl,

(iii) cycloalkyl, (iv) (cycloalkyl) alkyl,

(x) (cycloalkyl) alkenyl, (vi) cycloalkenyl,

(vii) (cycloalkenyl) alkyl,

(xviii) (cycloalkenyl) alkenyl, (ix) aryl,

(x) (aryl) alkyl, (xi) (aryl) alkenyl,

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

(xiv) (heterocyclic) alkenyl; and

R¹² and R³⁶ are independently selected from the group

consisting of

(xi) hydrogen, (ii) Cι-Cι₂ alkyl,

(xii) C₂-C_ι2 alkenyl, (iv) cycloalkyl,

(v) (cycloalkyl) alkyl,

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

(viii) (cycloalkenyl) alkyl,

(ix) (cycloalkenyl) alkenyl, (xix) aryl, (xi) (aryl) alkyl,

(xii) (aryl) alkenyl,

(xiii) heterocyclic,

(xiv) (heterocyclic) alkyl, and

(xv) (heterocyclic) alkenyl;

X is selected from the group consisting of

(f) -C(=0) -N(R*)-, (b) -N(R*)-C(=0) -,

(g) -C(=S) -N(R*)-, (d) -N(R*)-C(=S) -,

(e) -N(R*)-S0₂-, and (f) -S0₂-N(R*)-,

wherein R* is hydrogen, Cι-C₃ loweralkyl or

cyclopropyl ;

R² is selected from the group consisting of

(c ) hydrogen, (b) Cι-C₆ alkyl , (c) C₂-C_e alkenyl ,

(d) C₃ -C₆ cycloalkyl , (e) C₅-C₆ cycloalkenyl ,

( f ) halo Ci-C₆ alkyl and (g) halo C₂-C₆ alkenyl ; or R -X- is

wherein Y¹ is -CH₂-, -O- , -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, Cι-C₃ loweralkyl,

hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl,

1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl,

2-thiolethyl, methoxymethyl, N-methylaminomethyl and

methylthiomethyl ;

R_2a is selected from the group consisting of

(c) hydrogen, (b) _L-C_S alkyl, (c) C₂-C_e alkenyl,

(d) halo Cι-C₆ alkyl, and (e) halo C₂-C₆ alkenyl; R₁₄ and R₁₅ are independently selected from the group consisting

of

(vi) hydrogen, (ii) Ci-C^ 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-substituted alkyl,

(xi) R^37aO- (0=)C-substituted alkyl,

(xii) R^37aS- (0=)C-substituted alkyl,

(xiii) R^37aO- (S=)C-substituted alkyl,

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

(xv) (R^37aO)₂-P(=0) -substituted alkyl,

(xvi) cyanoalkyl,

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

(xx) cycloalkyl, (xxi) (cycloalkyl) alkyl ,

(xxii) (cycloalkyl) alkenyl,

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

(xxv) (cycloalkenyl) alkyl,

(xxvi) (cycloalkenyl) alkenyl, (xxvii) (cycloalkenyl) - alkynyl ,

(xxviii) aryl, (xxxix) (aryl) alkyl, (xxx) (aryl) alkenyl,

(xxxi) (aryl) alkynyl,

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

(xxxiv) (heterocyclic) alkenyl,

(xxxv) (heterocyclic) alkynyl, (xxxvi) -O-alkyl,

(xxxvii) -NHalkyl, (xxxviii) -NH₂, (xxxix) -N (alkyl) ₂,

(xxxx) -OH, (xxxxi) -NHacyl, (xxxxii) -Nalkylacyl,

(xxxxiii) -NHcarbamoyl, (xxxxiv) -Nalkylcarbamoyl,

(xxxxv) -NHcarbamidyl, and (xxxxvi) -Nalkylcarbamidyl; selected from the group consisting of

(iii) hydrogen, (ii) Cι-C₁₂ alkyl, (iii) haloalkyl,

(xiii) hydroxyalkyl, (v) alkoxyalkyl,

(vi) C₂-C₁₂ alkenyl,

(vii) haloalkenyl, (viii) C₂-C_x2 alkynyl,

(xx) cycloalkyl, (x) (cycloalkyl) alkyl,

(xxi) (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

(iii) hydrogen, (ii) Cχ-C_X2 alkyl, (iii) haloalkyl ,

(iv) C₂-C_ι2 alkenyl, (v) haloalkenyl,

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

(viii) (cycloalkyl) alkyl, (ix) (cycloalkyl) - alkenyl,

(x) (cycloalkyl) alkynyl,"

(xxii) 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,

(xxvi) (heterocyclic) alkynyl, (xxiii) -C(=0)-R¹⁴,

(xxvii) -C(=S) -R¹⁴, (xxv) -S(0)₂-R¹⁴ and

( xxv i ) hydroxy a 1 ky 1 ;

Y is selected from the group consisting of

(a) hydrogen, (b) Cι-C₅ alkyl, (c) C₁-C₅ haloalkyl,

(d) ^' C₂-C₅ alkenyl, (e) C₂-C₅ haloalkenyl,

(f) C₂-C₅ alkynyl,

(h) C₃-C₅ cycloalkyl, (h) C₃-C₅ cycloalkyl-Cι-to-C₃- alkyl ,

(k) C₅ cycloalkenyl, (j) C₅ cycloalkenyl-Cι-to-C₃- alkyl,

(k) C₅ cycloalkenyl-C₂-to-C₃-alkenyl, (1) - (CHR³⁹)_n0R²⁰,

(q) -CH(OR²⁰) -CH₂(OR²⁰) , (n) - (CHR³⁹) _nSR²¹,

(s) -(CHR³⁹)_nCN, (p) -(CHR³⁹)_nN₃, (q) phenyl, (r) halo-substituted phenyl, (s) - (CHR³⁹) _nC (=Q²) R²²,

(t) - (CHR³⁹)_nN(=Q³) , (u) -N(0)=CHCH₃, (v) - (CHR³⁹) _nNR²³R²⁴ ,

(w) halo, and (x) a heterocyclic ring having from

3 to 6 ring atoms;

wherein n is 0, 1, or 2; Q is O, S, NR", or CHR ,26

and 0 is NR*¹, or CHR ,^'42

at each occurrence is independently

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

(v) isopropyl, (vi) Cι-C₃ haloalkyl, (vii) vinyl,

(viii) propenyl, (ix) isopropenyl, (x) allyl,

(xi) C₂-C₃ haloalkenyl, (xii) amino, (xiii) -NHCH₃,

(xiv) -N(CH₃)₂, (xv) -NHCH₂CH₃,

(xvi) -N(CH₃) (CH₂CH₃) ,

(xvii) -N(CH₂CH₃)₂ or

(xviii) -N(=CH₂); R²¹ is

(k) 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) ;

R and R 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) Cι-C₄ alkyl, (iii) C₂-C₄ alkenyl,

(xiv) C₂-C₄ alkynyl, (v) cyclopropyl, (vi) -C(=Q⁴)-R³⁰,

(xv) (v) -OR³¹, and (vi) -N(R³²)₂,

wherein Q* is O, S, or N(R^JJ) R^2S is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or

R²⁶ is hydrogen, methyl or ethyl ;

R is hydrogen, methyl or ethyl;

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

R³⁰ is hydrogen, methyl, ethyl, -OR³⁴, -SR³⁴, -N(R^3S)₂,

-NHOH, -NHNH₂, -N(CH₃)NH₂, or -N (CH₂CH₃) NH₂ ; R³¹ and R³² substituents, at each occurrence, are independently hydrogen, methyl or ethyl;

R is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or

R^J is methyl or ethyl;

R³⁵ is independently hydrogen, methyl or ethyl;

with the proviso that when Q² is CHR^2S then R²² is selected from the group consisting of hydrogen, -CH₃, -C₂H₅, -C₃H7, -OCH₃, -SCH₃, -0-C₂H₅, and -S-C₂H_5;

R⁶ and R⁷ are independently selected from the group consisting

of

(c) hydrogen, (b) Cι-C₁₂ alkyl , ( c ) C₂-Cι₂ alkenyl , (d) cycloalkyl, (e) (cycloalkyl) alkyl,

(f) (cyclo alkyl) alkenyl, (g) cycloalkenyl,

(1) (cycloalkenyl) alkyl,

(m) (cycloalkenyl) alkenyl, (j) aryl, (k) (aryl) alkyl,

(1) (aryl) alkenyl, (m) heterocyclic,

(r) (heterocyclic) alkyl, and (o) (heterocyclic) alkenyl;

and

R⁸ and R⁹ and are independently selected from the group consisting of

(c) hydrogen, (b) Cι-C₆ alkyl, (c) C₂-C₆ alkenyl,

(d) C₃-C₆ cycloalkyl, (e) C₃-C₆ cycloalkenyl,

(f) fluorine, and (g) -NH₂,

with the proviso that the total number of atoms, other

than hydrogen, in each of R⁸ and R⁹, is 6 atoms or less; and R¹⁰ is selected from the group consisting of

(a) hydrogen, (b) Ci-Cg alkyl, (c) C₂-C₆ alkenyl,

(d) C₃-C₆ cycloalkyl, (e) C₃-C₆ cycloalkenyl,

(f) fluorine, (g) -NH₂, and (h) -OH

with the proviso that if Y is

(CHR^Λ9)_n0Rⁱ

- (CHR^J3)_nSR ι21

-(CHR³⁹)_nN(=Q³) ,

-N(0)=CHCH₃,

-(CHR³⁹)_nNR²³R²⁴,

or halo, where n is 0,

then R ,10^u is not -OH, -NH 2 / or -F,

16. The compound of Claim 15 wherein W is selected from the group consisting of -OC(O)-, -O(CHR')-, -(CH₂)_n-,

- (CH₂)_nC(0) -, -0(CH₂)_n-, -O-C(S)-, -NHC(O)-, -NR'C(O),

-CHR' (CH₂)_n-, -CR'R" (CHa)n-. and -CHCH- .

17. The compound of Claim 16 wherein W is selected from the group consisting of -OC(O)-, -CH₂C(0)-,

-0CH₂-, and - ⁽CHa)n-.

18. The compound of Claim 15 wherein R¹ is -C0₂H.

19. The compound of Claim 16 wherein R¹ is -C0₂H.

20. The compound of Claim 17 wherein R¹ is -C0₂H.

21. The compound of Claim 15 wherein X is -N(R*)- C(=0)-, R* is hydrogen, and -R₂ is Cι-C₆ alkyl.

22. The compound of Claim 16 wherein X is -N(R*)- C(=0)-, R* is hydrogen, and -R₂ is Cι-C₆ alkyl.

23. The compound of Claim 17 wherein X is -N(R*)- C(=0)-, R* is hydrogen, and -R₂ is Cι-C_e alkyl.

24. The compound of Claim 15 wherein Y is selected from the group consisting of

(a) hydrogen,

(b) Ci-C₅ alkyl,

(c) C₁-C₅ haloalkyl,

(d) C₂-C₅ alkenyl,

(e) C₂-C₅ haloalkenyl,

(f) C₂-C₅ alkynyl,

(g) C₃-C₅ cycloalkyl,

(h) C₃-C₅ cycloalkyl-Cι-to-C₃-alkyl,

(i) C₅ cycloalkenyl,

(j) C₅ cycloalkenyl-Cι-to-C₃-alkyl,

(k) C₅ cycloalkenyl-C₂-to-C₃-alkenyl, and

(1) a heterocyclic ring having from 3 to 6 ring atoms .

25. The compound of Claim 24 wherein Y is C₂-C₅ alkenyl .

26. The compound of Claim 23 wherein R_i4 is alkyl or

-O-alkyl.

27. The compound of Claim 25 wherein R₁₄ is alkyl or

-O-alkyl.

28. The compound of Claim 15 wherein is selected from the group consisting of -OC(O)-, -CH₂C(0)-, -OCH2-, and -(CH₂)_n-,

R_x is -C0₂H,

X is -N(R*) -C(=0) -,

R* is hydrogen,

-R₂ is Cι-C₆ alkyl ,

Y is C₂-C₅ alkenyl ,

and R₁₄ is alkyl or -O-alkyl

29. A compound of formula lb

lb

or a pharmaceutically acceptable salt, ester, or prodrug thereof wherein

is selected from the group consisting of

-OC(O)-, -O(CHR')-, -(CH₂)_n-, - (CH₂)_nC(0) -, - (CH₂) _nC (S) - ,

-C(O)-, -C(S)-, -CHR'C(O)-, -CHR'C(S)-, -OC(S)-, -NHC(O)-,

-NHC(S)-, -NR'C(O)-, -NR'C(S)-, -0(CH₂)_n-,

-0(CR'R")-, -CHR' (CH₂)_n-, -CR' R" (CH₂) _n- , -CHCH-, -S(CH₂)_n-,

(vii) hydrogen, (ii) Cχ-C_ι2 alkyl, (iii) haloalkyl,

(iv) hydroxyalkyl, (v) thiol-substituted alkyl,

(vi) R^{3 c}O-substituted alkyl,

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

(ix) (R³⁷ )NH-substituted alkyl,

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

(xi) R^37aO- (0=)C-substituted alkyl,

(xii) R³⁷ S- (0=)C-substituted alkyl,

(xiii) R^37aO- (S=)C-substituted alkyl,

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

(xv) (R^37aO)₂-P(=0) -substituted alkyl,

(xvi) cyanoalkyl,

(xvii) C₂-C₁₂ alkenyl, (xviii) haloalkenyl, (xix) C₂-C₁₂ alkynyl,

(xx) cycloalkyl, (xxi) (cycloalkyl) alkyl ,

(xxii) (cycloalkyl) alkenyl,

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

(xxv) (cycloalkenyl) alkyl,

(xxvi) (cycloalkenyl) alkenyl,

(xxvii) (cycloalkenyl) alkynyl,

(xxviii) aryl, (xxxix) (aryl) lkyl, (xxx) (aryl) alkenyl,

and

(xxxi) (aryl) alkynyl;

selected from the group consisting of

(d) -C0₂H, (b) -CH₂C0₂H, (c) -S0₃H, (d) -CH₂S0₃H,

(e) -S0₂H, (f) -CH₂S0₂H, (g) -P0₃H₂, (h) -CH₂P0₃H₂,

(i) -P0₂H,

(j) -CH₂P0₂H, (k) tetrazolyl, (1) -CH₂-tetrazolyl, (m) -C(=0) -NH-S (O) ₂-R

(t) -CH₂C(=0) -NH-S (0) ₂-R¹¹, (o) -S0₂N (T-R¹) R¹ and

(p) -CH₂S0₂N(T-R^1J-)R-¹

wherein

T is selected from the group consisting of

(iv) 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-;

R is selected from the group consisting of

(iv) C_ι-C₁₂ alkyl, (ii) C₂-C₁₂ alkenyl,

(iii) cycloalkyl, (iv) (cycloalkyl) alkyl,

(y) (cycloalkyl) alkenyl, (vi) cycloalkenyl,

(vii) (cycloalkenyl) alkyl,

(xxiii) (cycloalkenyl) alkenyl, (ix) aryl,

(x) (aryl) alkyl, (xi) (aryl) alkenyl,

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

(xiv) (heterocyclic) alkenyl; and

R¹² and R³⁶ are independently selected from the group

consisting of

(xvi) hydrogen, (ii) C_x-Cι₂ alkyl,

(xvii) C₂-C₁₂ alkenyl, (iv) cycloalkyl,

(v) (cycloalkyl) alkyl,

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

(viii) (cycloalkenyl) alkyl,

(ix) (cycloalkenyl) alkenyl, (xxiv) aryl, (xi) (aryl) alkyl,

(xii) (aryl) alkenyl,

(xiii) heterocyclic,

(xiv) (heterocyclic) alkyl, and

(xv) (heterocyclic) alkenyl;

X is selected from the group consisting of

(h) -C(=0)-N(R*)-, (b) -N(R*)-C(=0)-,

(i) -C(=S) -N(R*) -, (d) -N(R*)-C(=S)-,

(e) -N(R*)-S0₂-, and (f) -S0₂-N(R*)-,

wherein R* is hydrogen, C₁-C₃ loweralkyl or

cyclopropyl;

R² is selected from the group consisting of

(d) hydrogen, (b) d-Cg alkyl, (c) C₂-C₆ alkenyl,

(d) C₃-C₆ cycloalkyl, (e) C₅-C₆ cycloalkenyl,

(f) halo Cx-Cg alkyl and (g) halo C₂-C₆ alkenyl; or R -X- is

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, Cι-C₃ loweralkyl,

hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl,

1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl,

2-thiolethyl, methoxymethyl, N-methylaminomethyl and

methylthiomethyl ;

R_2a is selected from the group consisting of

(b) hydrogen, (b) Cι-C₆ alkyl, (c) C₂-C₆ alkenyl, (d) halo Ci-Cg alkyl, and (e) halo C₂-C₆ alkenyl;

R₁₄ and R₁₅ are independently selected from the group consisting

of

(viii) hydrogen, (ii) d-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-substituted alkyl,

(xi) R^37aO- (0=)C-substituted alkyl,

(xii) R³⁷ S- (0=)C-substituted alkyl,

(xiii) R^37a0- (S=)C-substituted alkyl,

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

(xv) (R^37aO)₂-P(=0) -substituted alkyl,

(xvi) cyanoalkyl, (xvii) C₂-C₁₂ alkenyl,

(xviii) haloalkenyl, (xix) C₂-C₁₂ alkynyl,

(xx) cycloalkyl, (xxi) (cycloalkyl) alkyl,

(xxii) (cycloalkyl) alkenyl,

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

(xxv) (cycloalkenyl) alkyl,

(xxvi) (cycloalkenyl) alkenyl, (xxvii) (cycloalkenyl) - alkynyl,

(xxviii) aryl, (xxxix) (aryl) alkyl, (xxx) (aryl) alkenyl,

(xxxi) (aryl) alkynyl,

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

(xxxiv) (heterocyclic) alkenyl,

(xxxv) (heterocyclic) alkynyl, (xxxvi) -O-alkyl,

(xxxvii) -NHalkyl, (xxxviii) -NH₂, (xxxix) -N (alkyl) ,

(xxxx) -OH, (xxxxi) -NHacyl, (xxxxii) -Nalkylacyl,

(xxxxiii) -NHcarbamoyl, (xxxxiv) -Nalkylcarbamoyl, (xxxxv) -NHcarbamidyl, and (xxxxvi) -Nalkylcarbamidyl;

R is selected from the group consisting of

( iv) hydrogen, ( ii ) d-C_ι2 alkyl , ( iii ) haloalkyl ,

(xviii) hydroxyalkyl, (v) alkoxyalkyl,

(vi) C₂-Ci₂ alkenyl,

(vii) haloalkenyl, (viii) C₂-Cι₂ alkynyl,

(xxv) cycloalkyl, (x) (cycloalkyl) alkyl,

(xxvi) (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

(iv) hydrogen, (ii) C₁-C₁₂ alkyl, (iii) haloalkyl,

(iv) C₂-Cι₂ alkenyl, (v) haloalkenyl,

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

(viii) (cycloalkyl) alkyl, (ix) (cycloalkyl) - alkenyl,

(x) (cycloalkyl) alkynyl,

(xxvii) 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,

(xxviii) (heterocyclic) alkynyl, (xxiii) -C(=0)

R¹⁴,

(xxix) -C(=S)-R¹⁴, (xxv) -S(0)₂-R¹⁴ and

( xxvi ) hydroxyalkyl ;

selected from the group consisting of

(a) hydrogen, (b) Cι-C₅ alkyl, (c) Cι-C₅ haloalkyl,

(d) C₂-C₅ alkenyl, (e) C₂-C₅ haloalkenyl,

(f) C₂-C₅ alkynyl,

(i) C₃-C₅ cycloalkyl, (h) C₃-C₅ cycloalkyl -C -to- C₃- alkyl,

(1) C₅ cycloalkenyl, (j) C₅ cycloalkenyl-Cι-to-C₃- alkyl,

(k) C₅ cycloalkenyl-C₂-to-C₃-alkenyl, (1) - (CHR³⁹) _n0R²⁰,

(s) -CH(OR²⁰) -CH₂(OR²⁰) , (n) - (CHR³⁹) _nSR²¹, (u) -(CHR³⁹)_nCN, (p) -(CHR³⁹)_nN₃, (q) phenyl,

(r) halo-substituted phenyl, (s) - (CHR³⁹) _nC (=Q²) R²²,

(t) - (CHR³⁹)_nN(=Q³) , (u) -N(0)=CHCH₃, (v) - (CHR³⁹) _nNR²³R²⁴,

(w) halo, and (x) 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 Q^J is NR^*\ or CHR 42

at each occurrence is independently

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

(v) isopropyl, (vi) d-C₃ haloalkyl, (vii) vinyl,

(viii) propenyl, (ix) isopropenyl, (x) allyl,

(xi) C₂-C₃ haloalkenyl, (xii) amino, (xiii) -NHCH₃,

(xiv) -N(CH₃)₂, (xv) -NHCH₂CH₃,

(xvi) -N(CH₃) (CH₂CH₃) ,

(xvii) -N(CH₂CH₃)₂ or (xviii ) -N ( =CH₂ ) ;

R²¹ is

(1) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl,

(v) isopropyl, (vi) C_ι-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) ethyl- thio,

(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;

R⁴¹ and R⁴² are independently hydrogen, methyl, or ethyl;

R²⁴ is selected from the group consisting of

(i) hydrogen, (ii) Cι-C₄ alkyl, (iii) C₂-C₄ alkenyl ,

(xix) C₂-C₄ alkynyl, (v) cyclopropyl, (vi) -C(=Q⁴)-R³⁰,

(xx) (v) -OR³¹, and (vi) -N(R³²)₂,

wherein Q⁴ is O, S, or N(R³³); R²⁵ is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or

R is hydrogen, methyl or ethyl

R is hydrogen, methyl or ethyl;

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

R is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or

R^J is methyl or ethyl;

R 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 (a) hydrogen, (b) C₁-C₁₂ alkyl, (c) C₂-Cι₂ alkenyl,

(d) cycloalkyl, (e) (cycloalkyl) alkyl ,

(j) (cyclo alkyl) alkenyl, (g) cycloalkenyl,

(k) (cycloalkenyl) alkyl,

(i) (cycloalkenyl) alkenyl, (j) aryl, (k) (aryl) alkyl,

(1) (aryl) alkenyl, (m) heterocyclic,

(n) (heterocyclic) alkyl, and (o) (heterocyclic) alkenyl ;

and

R⁸ and R⁹ and are independently selected from the group consisting of

(a) hydrogen, (b) d-Cg alkyl, (c) C₂-C₆ alkenyl,

(d) C₃-C₆ cycloalkyl, (e) C₃-C₆ cycloalkenyl,

(f) fluorine, and (g) -NH₂, with the proviso that the total number of atoms, other than hydrogen, in each of R⁸ and R⁹, is 6 atoms or less; and

R¹⁰ is selected from the group consisting of

(c) hydrogen, (b) d-Cg alkyl, (c) C₂-C₆ alkenyl,

(d) C₃-C₃ cycloalkyl, (e) C₃-C₆ cycloalkenyl,

(f) fluorine, (g) -NH₂, and (h) -OH

with the proviso that if Y is

(-(CHR³⁹)_nSR²¹,

-(CHR³⁹)_nN(=Q³) ,

-N(0)=CHCH₃, ( CHR³⁹ ) _nNR ³R²⁴ ,

or halo,

where n is 0,

then R¹⁰ is not -OH , -NH₂ , or -F .

30. The compound of Claim 29 wherein is selected from the group consisting of -OC(O)-, -O(CHR')-, -(CH₂)_n-,

-(CH₂)_πC(0)-, -0(CH₂)_n-, -O-C(S)-, -NHC(O)-, -NR'C(O), -CHR' (CH₂)_n-, -CR'R" (CH₂)_n-, and -CHCH- .

31. The compound of Claim 30 wherein is selected from the group consisting of -OC (O) - , -CH₂C(0)-, -0CH₂-, and - (CH₂)_n-.

32. The compound of Claim 29 wherein R¹ is -C0₂H.

33. The compound of Claim 30 wherein R¹ is -C0₂H.

34. The compound of Claim 31 wherein R¹ is -C0₂H.

35. The compound of Claim 29 wherein X is -N(R*)- C(=0)-, R* is hydrogen, and -R₂ is d-C₆ alkyl.

36. The compound of Claim 30 wherein X is -N(R*)- C(=0)-, R* is hydrogen, and -R₂ is d-Cg alkyl.

37. The compound of Claim 31 wherein X is -N(R*)- C(=0)-, R* is hydrogen, and -R₂ is Ci-Cg alkyl.

38. The compound of Claim 29 wherein Y is selected

from the group consisting of

(a) hydrogen,

(b) d-C₅ alkyl,

(c) Cι-C₅ haloalkyl,

(d) C₂-C₅ alkenyl,

(e) C₂-C₅ haloalkenyl,

(f) C₂-C₅ alkynyl,

(g) C₃-C₅ cycloalkyl,

(h) C₃-C₅ cycloalkyl-Cι-to-C₃-alkyl,

(i) C₅ cycloalkenyl,

(j) C₅ cycloalkenyl-Cι-to-C₃-alkyl,

(k) C₅ cycloalkenyl-C₂-to-C₃-alkenyl, and

(1) a heterocyclic ring having from 3 to 6 ring atoms .

39. The compound of Claim 38 wherein Y is C₂-C₅ alkenyl .

40. The compound of Claim 37 wherein R₁₄ is -O-alkyl

41. The compound of Claim 39 wherein R_i4 is -O-alkyl.

42. The compound of Claim 29 wherein is selected from the group consisting of -OC(O)-, -CH₂C(0)-, -OCH₂-, and -(CH₂)_n-,

Ri is -C0₂H,

X is -N(R*) -C(=0) -,

R* is hydrogen,

-R₂ is Ci-C alkyl,

Y is C₂-C₅ alkenyl,

and

R_i4 is -O-alkyl .

43. The compound of Claim 1 selected from the group consisting of

(±) - ( 3S, 4R, 4aR, 5S, 7R) -4- (acetylamino) -3-ethyl-l-oxo-5- [ (IZ) -

1-propenyl] hexahydropyrrolo [1, 2-c] [1,3] oxazine-7-carboxylic acid;

(±) - (3S,4i?,4aR,5≤^*, 7R) -4- (acetylamino) -l-oxo-5- [ (IZ) -1- propenyl] -3-propylhexahydropyrrolo [1, 2-c] [1 , 3] oxazine-7- carboxylic acid;

(±) - (3S,4i?,4aJ?, 5S, 7R) -4- (acetylamino) -3-isopropyl-l-oxo-5- [ (IZ) -1-propenyl] hexahydropyrrolo [1, 2-c] [1 , 3] oxazine-7- carboxylic acid;

(±) - (3J?,4J?,4aR, 55, 7R) -4- (acetylamino) -3-isopropyl-l-oxo-5- [ (IZ) -1-propenyl] hexahydropyrrolo [1, 2-c] [1, 3] oxazine-7- carboxylic acid;

(±) - (4i?,4ai?,5S, 7R) -4- (acetylamino) -5- [ (IZ) -1- propenyl] hexahydropyrrolo [1, 2-c] [1,3] oxazine-7-carboxylic acid;

(±) - (3S, R,4_:aR_l5S_l7R) -4- (acetylamino) -3-ethyl-5- [(IZ) -1-

propenyl] hexahydropyrrolo [1, 2-c] [1,3] oxazine-7-carboxylic acid;

(±) - (3S,4R,4aR,5S,7R) -4- (acetylamino) -5- [ (IZ) -1-propenyl] -3-

propylhexahydropyrrolo [1,2-c] [1, 3] oxazine-7-carboxylic acid;

(±) - (3S, R,4aR,5S_l7R) -4- (acetylamino) -3- (cyanomethyl) -5-

[ (IZ) -1-propenyl] hexahydropyrrolo [1,2-c] [1,3] oxazine-7- carboxylic acid;

(±) - (3S,4R,4aR,5S, R) -4- (acetylamino) -3- (3-butenyl) -5- [(IZ) -

1-propenyl] hexahydropyrrolo [1,2-c] [1,3] oxazine-7-carboxylic acid;

(±) - (35,4i?,4ai?,5S,7i?) -4- (acetylamino) -3-isobutyl-5- [(IZ) -1-

propenyl] hexahydropyrrolo [1,2-c] [1-, 3] oxazine-7-carboxylic acid;

(±) - (3S,4i?,4ai?,5S, 7R) -4- (acetylamino) -3- [(li?) -1- methylpropyl] -5- [ (IZ) -1-propenyl] hexahydropyrrolo [1, 2- c] [1, 3] oxazine-7-carboxylic acid; (±) - (4i?,4afl, 55, 7R) -4- (acetylamino) -3 , 3-diethyl-5- [ (IZ) -1-

propenyl] hexahydropyrrolo [1,2-c] [1,3] oxazine-7-carboxylic acid;

(±) - (3S,4i?,4ai?,5S, 7R) -4- (acetylamino) -3-methyl-5- [ (IZ) -1- propenyl] -3-propylhexahydropyrrolo [1, 2-c] [1, 3] oxazine-7- carboxylic acid;

(+) - (35,4i?,4ai?,5S,7i?) -4- (acetylamino) -3-hydroxy-5- [(IZ) -1-

propenyl] hexahydropyrrolo [1, 2-c] [1, 3] oxazine-7-carboxylic acid monotrifluoro acetic acid salt;

(±) - (IS, 3R, 75, 8R, 8aR) -8- (acetylamino) -7-hydroxy-5-oxo-l-

[ (IZ) -1-propenyl] octahydro-3-indolizinecarboxylic acid;

(±) - (15, 3R, 7R, 8R, 8aR) -8- (acetylamino) -7-hydroxy-5-oxo-l-

[(1Z) -1-propenyl] octahydro-3-indolizinecarboxylic acid;

(±) - (15, 3R, 7R, 8R, 8aR) -8- (acetylamino) -7-hydroxy-l- [(IZ) -1- propenyl] octahydro-3-indolizinecarboxylic acid monotrifluoro acetic acid salt;

(±) - (15, 3R, 7R, 8R, 8aR) - 8 - (acetylamino) -7-ethoxy-l- [ (IZ) -1-

propenyl] octahydro-3 -indolizinecarboxylic acid monotrifluoro acetic acid salt; (±) - ( lS, 3R, 7R, 8R, 8aR) -8- (acetylamino) -7-hydroxy-l- [ (IZ) -1- propenyl] -7-propyloctahydro-3 -indolizinecarboxylic acid monotrifluoro acetic acid salt;

(±) - (15,3i?,75, 8i?,8ai?) -8- (acetylamino) -7-hydroxy-7- (2- hydroxyethyl) -1- [ (IZ) -1-propenyl] octahydro-3- indolizinecarboxylic acid monotrifluoro acetic acid salt;

(+) - (15, 3R, 65, 7R, 7aR) - 7 - (acetylamino) -6-hydroxy-l- [ (IZ) -1- propenyl] hexahydro-lH-pyrrolizine-3 -carboxylic acid;

(±) - (15, 3R, 6Ri 7R, 7aR) -7- (acetylamino) -6-hydroxy-l- [(IZ) -1- propenyl] hexahydro-lH-pyrrolizine-3 -carboxylic acid;

(±) - (15, 3R, 6R, 7R, 7aR) -7- (acetylamino) -6-ethoxy-l- [ (IZ) -1- propenyl] hexahydro-lH-pyrrolizine-3 -carboxylic acid monotrifluoroacetic acid salt;

(±) - (15, 3J , 65, 7R, 7aR) - 7 - (acetylamino) -6-ethoxy-l- [ (IZ) -1- propenyl] hexahydro-lH-pyrrolizine-3-carboxylic acid monotrifluoroacetic acid salt;

or a pharmaceutically acceptable salt, ester or prodrug thereof .

44. A pharmaceutical composition for inhibiting influenza neuraminidase comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.

45. A pharmaceutical composition for inhibiting influenza neuraminidase comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 15.

46. A pharmaceutical composition for inhibiting influenza neuraminidase comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 29.

47. A pharmaceutical composition for treating an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.

48. A pharmaceutical composition for preventing an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.

49. A pharmaceutical composition for inhibiting influenza neuraminidase comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 14.

50. A pharmaceutical composition for treating an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 14.

51. A pharmaceutical composition for preventing an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 14.

52. 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, 15, or 29.

53. A method for treating an influenza infection comprising administering to a human or other mammal in need thereof a therapeutically effective amount of a compound of Claim 1, 15, or 29.