EP1581496A2

EP1581496A2 - 2-substituted-3-propenamide derivatives and methods of using the same

Info

Publication number: EP1581496A2
Application number: EP03812482A
Authority: EP
Inventors: Marcos Sznaidman; George R. Painter; Merrick R. Almond; Darryl G. Cleary; Amir Pesyan
Original assignee: Gilead Sciences Inc
Current assignee: Gilead Sciences Inc
Priority date: 2002-12-02
Filing date: 2003-12-02
Publication date: 2005-10-05
Also published as: AU2003297612A8; AU2003297612A1; WO2004050613A3; EP1581496A4; WO2004050613A2

Abstract

This invention provides 2-substituted-propenamide derivatives and their compositions for the treament of hepatitis B virus and/or hepatitis D virus.

Description

2-SUBSTITUTED-3-PROPENAMIDE DERIVATIVES AND METHODS OF USING THE

SAME

Cross Reference Section

This application claims priority to U.S. Provisional Application No. 60/430,556, filed on December 2, 2002.

Field of the Invention

This invention is in the area of 2-substituted-propenamide derivatives, compositions and methods useful for the treatment of hepatitis B virus (also referred to as "HBV") and/or hepatitis D virus (also referred to as "hepatitis delta virus" or "HDV").

Background of the Invention

Hepatitis B virus and hepatitis D virus have reached epidemic levels worldwide. The viruses have severe and often tragic effects on the infected patient. There remains a strong need to provide new effective pharmaceutical agents to treat humans infected with one or both of these viruses that have low toxicity to the host.

I. Hepatitis B Virus

HBV is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unknown, although it is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection. Hepatitis B virus has reached epidemic levels worldwide. After a two to six month incubation period in which the host is unaware of the infection, HBN infection can lead to acute hepatitis and liver damage that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. HBN can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed.

Patients typically recover from acute hepatitis. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite period causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBN are most common in developing countries. By mid- 1991, there were approximately 225 million chronic carriers of HBN in Asia alone, and worldwide, almost 300 million carriers. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer.

In western industrialized countries, high risk groups for HBN infection include those in contact with HBN carriers or their blood samples. The epidemiology of HBN is very similar to that of acquired immune deficiency syndrome (AIDS), which accounts for why HBN infection is common among patients with AIDS or AIDS related complex.

However, HBN is more contagious than HIN.

Human hepatitis B virus (HBN) is a member of the hepadnavirus family which is characterized by a circular partially double-stranded DΝA genome of approximately 3,000 base pairs in length, an enveloped capsid, and the ability to infect liver cells (Ganem, D., et al, Ann. Rev. of Biochem., vol. 56, pp. 651-693 (1987)). After the primary infection of the host, the virus may establish a chronic infection in the liver, which in turn can lead to cirrhosis and hepatocellular carcinoma (Beasley, R. P., et al in Viral Hepatitis and liver Disease, G. Ν. Nynas, et al, Eds., Grune and Stratton, New York, pp. 209-224 (1984); and Popper, H., et al, Hepatology, vol. 7, pp. 764-772 (1987)). It is estimated that of the approximately 300 million individuals worldwide who are chronic carriers of HBV, one million die annually from HBN induced disease [Lau, J. Y. Ν., et al, Lancet, vol. 342, pp. 1335-1340 (1993)].

Vaccines have been produced through genetic engineering and are currently used widely. Unfortunately, vaccines cannot help those already infected with HBV. Daily treatments with α-interferon, a genetically engineered protein, has also shown promise, but this therapy is only successful in about one third of treated patients. Furthermore, interferon cannot be given orally.

U.S. Patent No. 6,020,167 assigned to Medeva Holdings B.V. discloses a method for treating chronic hepatitis, and in particular, hepatitis B, that includes administering a composition containing HBsAg.

U.S. Patent No. 5,770,584 discloses a method for treating hepatitis virus infection by administering alkyl lipids or alkyl lipid derivatives.

United States statutory invention registration HI, 345 discloses a method for preventing or treating hepatitis virus by administering a protein-prenyl transferase inhibitor.

A number of synthetic nucleosides have been identified which exhibit activity against HBN. The (-)-enantiomer of BCH-189, known as 3TC, has been approved by the U.S. Food and Drug Administration for the treatment of hepatitis B. See EPA 0 494 119 filed by BioChem Pharma, Inc.

Cis-2-hydroxymethyl-5-(5-fluorocytosin-l-yl)-l,3-oxathiolane ("FTC") exhibits activity against HBN. See WO 92/15308; Furman et al., "The Anti-Hepatitis B Virus Activities, Cytotoxicities, and Anabolic Profiles of the (-) and (+) Enantiomers of cis-5- Fluoro-l-[2-(Hydroxymethyl)-l ,3-oxathiolane-5-yl]-Cytosine" Antimicrobial Agents and Chemotherapy, December 1992, page 2686-2692; and Cheng, et al., Journal of Biological Chemistry. Volume 267(20), 13938-13942 (1992).

Von Janta-Lipinski et al. disclose the use of the L-enantiomers of 3'-fluoro- modified β-2'-deoxyribonucleoside 5'-triphosphates for the inhibition of hepatitis B polymerases (J. Med. Chem., 1998, 41, 2040-2046). Specifically, the 5'-triphosphates of 3'-deoxy-3'-fluoro-β-L-thymidine (β-L-FTTP), 2',3'-dideoxy-3'-fluoro-β-L-cytidine (β-L- FdCTP), β-LdT and 2',3'-dideoxy-3'-fluoro-β-L-5-methylcytidine (β-L-FMethCTP) were disclosed as effective inhibitors of HBV DΝA polymerases in vitro.

β-L-2'-deoxythymidine (β-L-dT) is known in the art to inhibit herpes simplex virus type 1 (HSV-1) thymidine kinase (TK). Iotti et al., WO 92/08727, teaches that β-L-dT selectively inhibits the phosphorylation of D-thymidine by HSV-1 TK, but not by human TK. Spaldari et al. reported that L-thymidine is phosphorylated by herpes simplex virus type 1 thymidine kinase and inhibits viral growth, J. Med. Chem. (1992), 35(22), 4214-20. WO 96/13512 to Genencor International, Inc. and Lipitek, Inc. discloses that certain L-ribofuranosyl nucleosides can be useful for the treatment of cancer and viruses. Specifically disclosed is the use of this class of compounds for the treatment of cancer and HIV.

U.S. Patent Nos. 5,565,438, 5,567,688 and 5,587,362 (Chu, et al.) disclose the use of 2'-fluoro-5-methyl-β-L-arabinofuranyluridine (L-FMAU) for the treatment of hepatitis B and Epstein Barr virus.

Yale University and University of Georgia Research Foundation, Inc. disclose the use of L-FddC (β-L-5-fluoro-2',3'-dideoxycytidine) for the treatment of hepatitis B virus in WO 92/18517.

The synthetic nucleosides β-L-2'-deoxycytidine (β-L-2'-dC), β-L-2'- deoxythymidine (β-L-dT), β-L-2'-deoxyinosine (β-L-dl) and β-L-2'-deoxyadenosine (β-L- 2'-dA) have recently been disclosed in the art for the treatment of hepatitis B virus. Gilles Gosselin et al. disclosed the use of β-L-dT, β-L-dA, β-L-dC and β-L-dl, and pharmaceutically acceptable salts and prodrugs thereof for the treatment of hepatitis B virus.

PCT/US01/09987 filed by Georgetown University, Cornell University and the University of Georgia Research Foundation, Inc. describes that the administration of a nucleoside or nucleoside analog that substantially reduces the level of hepatitis B surface antigen (referred to therein as HBsAg) in a host is useful in the treatment of hepatitis delta viral infection in that host. In one embodiment PCT/USO 1/09987 describes that 2'-fluoro- 5-methyl-beta-L-arabinofuranosyluridine (L-FMAU) significantly reduces the level of hepatitis B surface antigen.

Hepsera^®, also known as Adefovir dipivoxil (Bis(pivaloyloxymethyl)-9-(2- phosphonylmethoxyethyl)adenine), has been approved by the FDA to treat hepatitis B infection and is sold by Gilead Sciences, Inc.

Hepsera®

In light of the fact that hepatitis B virus has reached epidemic levels worldwide, and has severe and often tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat humans infected with the virus that have low toxicity to the host.

11. Hepatitis D Virus

Type D hepatitis, the most severe form of viral hepatitis, is caused by infection with hepatitis D (delta) virus (HDV), a sub-viral satellite of hepatitis B virus (HBV)

(Smedile, A. et al. Prog Liver Pis 1994, 12, 157-75). Compared with other agents of viral hepatitis, acute HDV infection is more often associated with fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive amounts of the liver are destroyed. Chronic type D hepatitis is typically characterized by necroinflammatory lesions, similar to chronic HBV infection, but is more severe, and frequently progresses rapidly to cirrhosis and liver failure, accounting for the disproportionate association of chronic HDV infection with terminal liver disease (Smedile, A. et al. Prog Liver Pis 1994,

12, 157-75; Rizzetto, M. et al. Ann Intern Med 1983, 98, 437-41). Although HDV infection affects fewer individuals than HBV alone, the resulting acute or chronic liver failure is a common indication for liver transplantation in Europe as well as North

America (Smedile, A. and Rizzetto, M. Int J Clin Lab Res 1992, 22, 211-215; Wright, T. L. and Pereira, B. Liver Transplant Surgery 1995, 1, 30-42). Chronic disease affects 15 million persons worldwide, about 70,000 of whom are in the U.S. The Center for Disease Control estimates 1,000 deaths annually in the U.S. due to HDV infection (Alter, M. J. and Hadler, S. C. Prog Clin Biol Res 1993, 382, 243-50; Alter, M. J. and Mast, E. E. Gastroenterol Clin North Am 1994, 23, 437-55).

The HDV virion is composed of a ribonucleoprotein core and an envelope. The core contains HDV-RNA, and hepatitis delta antigen (HDAg), which is the only protein encoded by this virus (Wang, K. S. et al. Nature 1986, 323, 508-14). The envelope is formed by the surface antigen protein (hepatitis B surface antigen, or HBsAg) of the helper virus, hepatitis B (Bonino, F. Infect Immun 1984, 43, 1000-5; Bonino, F. et al. Hepatology 1981, 1, 127-31; Bonino, F. et al. J Virol 1986, 58, 945-50). The envelope is the sole helper function provided by HBV. HDV is able to replicate its RNA within cells in the absence of HBV (Kuo, M. Y. et al. J Virol 1989, 63, 1945-50), but requires HBsAg for packaging and release of HDV virions (Wu, J. C. et al. J Virol 1991, 65, 1099-104; Ryu, W. S. et al. J Virol 1992, 66, 2310-2315.), as well as for infectivity (Sureau, C, et al. J Virol. 1992, 66, 1241-5). As a result of the dependence of HDV on HBV, HDV infects individuals only in association with HBV.

There is currently no generally accepted effective therapy for type D hepatitis, and liver transplantation is the only option for the associated end-stage liver disease. Although interferon alpha has been moderately successful in treating some cases of type D hepatitis, the need for better treatment options is indicated by the very high doses required, variable responses, frequent relapse after cessation of treatment, and difficulties in drug administration (Thomas, H. C. et al. Prog Clin Biol Res 1987, 234, 277-90; Hoofnagle, J. et al. Prog Clin Biol Res 1987, 234, 291-8; Rosina, F. et al. Prog Clin Biol Res 1987, 234, 299-303; Rosina, F. et al. Hepatology 1991, 13, 1052-6; Farci, P. et al. N Engl J Med 1994, 330, 88-94; Hadziyannis, S. J. J Hepatol 1991, 73(Suppl 1), S21-6; Di Marco, V. et al. J Viral Hepat 1996, 3, 123-8; Porres, J. C. et al. J Hepatol 1989, 9, 338-44).

The dependence of HDV on its helper virus, HBV, could suggest that successful treatment of HDV infection would follow successful treatment of the supporting HBV infection, although, this does not appear to be the case, as illustrated by recent results obtained with the drug lamivudine (Glaxo-Wellcome, Inc.) (Honkoop, P. et al. Hepatology 1997, 2 (Suppl), 1219 (Abstract); Lau, D. T. et al. Hepatology 1999, 30, 546-9). Lamivudine (β-L-2',3'-dideoxy-3'-thiacytidine, 3TC) is a synthetic nucleoside shown to be effective in treating HIV and HBV infection (see U.S. Patent No. 5,539,116 to Liotta et al). Lamivudine is known to cause sustained suppression of HBV replication during treatment and was recently approved in the U.S. and several other countries for treatment of chronic HBV infection. Prolonged treatment of chronic HBV carriers with lamivudine leads to decreased levels of HBV in serum and improved liver histology (Lai, C. L. et al. N Engl J Med 1998, 339, 61-8; Tyrrell, D. et al. Hepatology 1993, 18, 112A; Nevens, F. et al. Gastroenterology 1997, 113, 1258-63; Dienstag, J. L. et al. N Engl J Med 1995, 333,

1657-61). Despite the dramatic effects on HBV, lamivudine treatment of patients chronically infected with both HBV and HDV has little effect on circulating levels of HDV or lower HDV-RNA levels; more importantly, there is no improvement in disease activity even though HBV levels are suppressed (Honkoop, P. et al. Hepatology 1997, 24(Suppl), 1219 (Abstract); Lau, P. T. et al. Hepatology 1999, 30, 546-9). The lack of an effect of lamivudine on disease in HBV-HPV infected patients underscores the direct role of HPV in disease severity in such patients. Although lamivudine inhibits HBV and WHV replication, it does not affect the production of viral surface antigen (Poong, S. L. et al. Proc Natl Acad Sci USA 1991, 88, 8495-9; Korba, B. E. et al. Hepatology 2000, 52(4 Pt n. 807-817: Korba. B. E. et al. Hepatology 2000. 31(5). 1165-1175).

The life cycle of HBV and other representatives of this family of viruses (for example, WHV) is unique in that the process of replicating genomic copies of the virus and the production of viral proteins (for example, HBV or WHV surface antigens) are differentially regulated (Ganem, P. Hepadnaviridae In "Fields Virology", Fields BN, Knipe PM, Howley P, ed. Lippincott-Raven 1996 Philadelphia, 2703-2737). Therefore, antiviral agents such as synthetic nucleosides (for example, lamivudine) which target viral polymerases, may significantly inhibit HBV replication (for example, as measured by a reduction in viremia), but not affect the level of viral mRNA or viral protein production (for example, as measured by the levels of HBV surface antigen in plasma or serum). Because formation of the viral envelope by the surface antigen protein is the only HBV and WHV function important for HPV, the failure to inhibit HBsAg production might play a role in the failure of lamivudine to affect HPV replication and disease.

Additional forms of treatment have been tried. For example, suramin in vitro blocks the entry of the virion into hepatocytes, but it is too toxic to be acceptable for long term use in humans (Smedile, A. et al. Prog Liver Pis 1994, 12, 157-75). Acyclovir enhances HDV replication in vitro (Smedile, A. et al. Prog Liver Pis 1994, 12, 157-75). Ribavirin did not significantly affect virological or biochemical parameters and had severe side-effects (Smedile, A. et al. Prog Liver Pis 1994, 12, 157-75). Synthetic analogs of thymosin have also been ineffective in the treatment of HPV infection (Smedile, A. et al. Prog Liver Pis 1994, 12, 157-75).

U.S. Patent No. 5,747,044 discloses recombinantly produced immunogenic HDV polypeptides useful as vaccines.

U.S. Patent No. 5,932,219 to Chiron discloses the entire genome of the hepatitis D virus, a family of cDNA replicas of the entire HDV genome, and teaches that portions of these cDNA sequences are useful as probes to diagnose the presence of virus in clinical samples. The patent also discloses proteins encoded by the cDNA that are useful in the production of vaccines. In particular, the '219' patent discloses a vaccine for hepatitis D which incorporates the p24 and p27 viral polypeptides. U.S. Patent No. 5,750,350 to

Chiron claims a kit useful in the analysis of hepatitis D virus which includes a peptide encoded by ORF 5 of the HDV genome. U.S. Patent No. 5,747,044 claims a recombinantly produced immunogenic particle which raises antibodies against HDV, wherein the particle includes an immunogenic polypeptide encoded within ORF 5 of the HDV nucleotide sequence or its complement.

U.S. Patent No. 4,619,896 discloses a process for unmasking delta antigen in the blood of an animal, that includes treating serum with a surfactant and optionally with an antibody-antigen dissociating agent. The blood derived delta antigen is used as a diagnostic agent in the detection and determination of different classes of antibodies to hepatitis D virus.

Sureau, et al. "Production of Infectious Hepatitis Delta Virus In Vitro and Neutralization with Antibodies Directed against Hepatitis B Virus Pre-S Antigens" Journal of Virology 1992, 1241-1245 discloses that HDV particles produced in vitro are infectious and that (i) infectious particles are coated with HBV envelope proteins that contain the pre-Sl and pre-S2 regions, (ii) epitopes of the pre-Sl and pre-S2 domains of HBV envelope proteins are exposed at the surface of HDV particles, and (iii) that antibodies directed against those epitopes have neutralizing activity against HDV.

Recently, it has been reported that L-FMAU is a potent inhibitor of HDV in chronically infected animals. (Casey, J. L. et al., Antiviral Therapy 2000, 5(Suppl. 1), 32, Abstract 057). Because of the large number of persons infected with hepatitis delta virus, the devastating effects of hepatitis delta virus infection on the individual, and the lack of effective treatments, there is a critical need for new and effective pharmaceutical agents for the treatment of hepatitis delta virus infection.

III. 2-Amino-3-Propenamide Derivatives.

WO 00/24392 to Kojima et al. discloses compounds of the formula:

for the treatment of Alzheimer's disease by inhibiting the formation of β-amyloid and senile plaques as well as the degeneration of nerve cells caused by pptn.

Japanese patent No. 03114031, to Kawakadomae et al. discloses a series of β- aminoacrylate derivatives including the following structure:

WO 98/33501 to Avid Therapeutics, Inc first disclosed that 2-benzoyl-amino-3- phenylpropenamides of the general structure:

are active anti-HBV agents that exhibit a novel mechanism of action. These compounds were found to have potent anti-HBV activity, with synergy with nucleoside analogues, and were active against HBV strains resistant to other known antivirals such as lamivudine and ganciclovir. In particular AT-61 of the formula:

AT-61 is a potent inhibitor of replication of both wild-type and 3TC resistant HBV in HepAD38, HepAD79, 2.2.15, and transiently transfected HepG2 cell lines, with very low toxicity in a number of cell lines. Moreover, when used in combination with 3TC, AT-61 acted synergistically to inhibit HBV replication in HepAD38 cells. Data published by King et al., Antimicrobial Agents and Chemotherapy 1998, 42, 3179, and Perni et al. Bioorg. Med. Chem. Lett. 200, 10, 2687, suggest that this compound may exert its antiviral effect by interfering with packaging of the genomic RNA into immature core particles. However, AT-61 does not inhibit the replication of duck HBV (DHBV), woodchuck HBV (WHBV), human immunodeficiency virus (HIV) type 1 (HIV-1), herpes simplex virus (HSV), type 1

(HSV-1), vesicular stomatitis virus (VSV) or Newcastle disease virus (NDV).

Therefore, it is one object of the present invention to provide compounds that are useful for treating viral infections and in particular hepatitis B virus or hepatitis Delta virus infections.

It is another object of the present invention to provide pharmaceutical compositions that are useful for treating viral infections and in particular hepatitis B virus or hepatitis Delta virus infections.

It is yet another object of the present invention to provide methods for treating viral infections, and in particular hepatitis B or hepatitis D virus infections. Summary of the Invention

Compounds, compositions and methods for the treatment of hepatitis B and/or D infection are described that include an effective hepatitis B and/or hepatitis D treatment with a known amount of a 2-substituted-3-propenamide derivative of the Formulas (I) or (X), or a pharmaceutically acceptable salt or prodrug thereof.

In one principle embodiment of the invention, the compound is of formula (I)

(I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

i) the wavy line indicates that the compound can be in the form of the E or Z isomer;

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

1 ") carbocycle, aryl, heterocycle or heteroaryl; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

iii) X is a halogen, -CN or an optionally substituted lower alkyl (such as CH₃ and

CF₃), or H;

iv) Z and Z are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic;

v) Y is -NR³C(O)-, -NR³C(O)O-, -NR³C(O)NR⁴-, -NR³C(S)-, -NR³C(S)O-, -NR³C(S)NR⁴-, -NR³S(O)_ra-, -NR³(CH₂)_n-, -C(O)NR³- or -C(S)NR³-; such that when Y is -NR C(O)-, then the compound is in the form of the Z isomer or at least one of Z and Z is not an optionally substituted phenyl;

vi) m is 1 or 2; and n is 1-4;

vii) R³ and R⁴ are independently H or lower alkyl; and viii) alternatively, R³ or R⁴ can independently form a bridged carbocycle, aryl,

1 9 1 9 heterocycle or heteroaryl with each other or with R , R , Z or Z .

In one particular embodiment, the compound is in the form of the E isomer. Alternatively, in another particular embodiment, the compound is in the form of the Z isomer.

In one embodiment of the invention is provided a pharmaceutical composition of the compound of the present invention together with a pharmaceutically acceptable carrier or diluent.

In another embodiment of the invention is provided a pharmaceutical composition of the compound of the present invention in combination with one or more other anti-viral agent, in particular with one or more anti-HBV and/or anti-HDV agent.

In one embodiment of the invention, a method is provided for the treatment or prophylaxis of a viral infection, and in particular an HBV and/or HDV infection, in a host in need of such treatment that includes administering an effective amount of the compound of the present invention.

In one embodiment of the invention, a method for the treatment or prophylaxis of a viral infection, and in particular an HBV and/or HDV infection, in a host in need of such treatment is provided that includes administering the compound of the present invention in combination or alternation with one or more other anti- viral agent.

In yet another embodiment of the invention is provded a use of the compound of the present invention for the treatment or prophylaxis of a viral infection, and in particular an HBV and/or HDV infection, in a host in need of such treatment.

Another embodiment of the invention provides a use of the compound of the present invention for the treatment or prophylaxis of a viral infection, and in particular an

HBV and/or HDV infection, in a host in need of such treatment in combination or alternation with one or more other anti- viral agent.

Still another embodiment of the invention provides a use of the compound of the present invention in the manufacture of a medicament for the treatment or prophylaxis of a .*^* viral infection, and in particular an HBV and/or HDV infection, in a host in need of such treatment.

Detailed Description of the Invention

A compound useful for the treatment of hepatitis B and/or hepatitis D infection in a host is disclosed. In addition, a method for the treatment of hepatitis B and/or hepatitis D infection in a host that includes administering an effective amount of a biologically active 2-substituted-3-propenamide derivative or a pharmaceutically acceptable salt or prodrug thereof, administered either alone or in combination, optionally in a pharmaceutically acceptable carrier. The disclosed 2-substituted-3-propenamide derivatives, or pharmaceutically acceptable prodrugs, salts or pharmaceutically acceptable formulations containing these compounds are useful in the prevention and treatment of hepatitis B and/or hepatitis D infections and other related conditions such as anti-HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV and/or HDV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue.

These compounds or formulations can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are infected with HBV and/or HDV, anti-HBV and/or anti-HDV antibody positive or HBV- and/or HDV-antigen positive as well as in individuals who have been exposed to HBV and/or HDV.

In summary, the present invention includes the following features:

(a) 2-substituted-3-propenamide derivatives as described herein, and pharmaceutically acceptable salts and prodrugs thereof;

(b) pharmaceutical formulations comprising the 2-substituted-3-propenamide derivatives or pharmaceutically acceptable salts or prodrugs thereof together with a pharmaceutically acceptable carrier or diluent;

(c) pharmaceutical formulations comprising the 2-substituted-3-propenamide derivatives or pharmaceutically acceptable salts or prodrugs thereof optionally in a pharmaceutically acceptable carrier or diluent together with one or more other antiviral agents; (d) methods for the treatment or prophylaxis of an HBV and/or HDV infection in a host, especially in individuals diagnosed as having an HBV and/or HDV infection or being at risk for becoming infected with HBV and/or HDV, comprising administering an effective amount of a 2-substituted-3-propenamide derivative as described herein, or a pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier or diluent;

(e) methods for the treatment or prophylaxis of an HBV and/or HDV infection in a host, especially in individuals diagnosed as having an HBV and/or HDV infection or being at risk for becoming infected with HBV and/or HDV, comprising administering an effective amount of a 2-substituted-3-propenamide derivative as described herein, or a pharmaceutically acceptable salt or prodrugs thereof, optionally in a pharmaceutically acceptable carrier or diluent, in combination or alternation with one or more other anti-viral agent;

(f) 2-substituted-3-propenamide derivatives as described herein, and pharmaceutically acceptable salts and prodrugs thereof, optionally in a pharmaceutically acceptable carrier or diluent, for use in the treatment or prophylaxis of an HBV and/or HDV infection in a host, especially in individuals diagnosed as having an HBV and/or HDV infection or being at risk for becoming infected with HBV and/or HDV;

(g) 2-substituted-3-propenamide derivatives as described herein, and pharmaceutically acceptable salts and prodrugs thereof, optionally in a pharmaceutically acceptable carrier or diluent, for use in the treatment or prophylaxis of an HBV and/or HDV infection in a host, especially in individuals diagnosed as having an HBV and/or HDV infection or being at risk for becoming infected with HBV and/or HDV, in combination or alternation with one or more other anti- viral agent;

(h) use of these 2-substituted-3-propenamide derivatives, and pharmaceutically acceptable salts and prodrugs thereof in the manufacture of a medicament for treatment of an HBV and/or HDV infection; and

(i) processes for the preparation of 2-substituted-3-propenamide derivatives, as described in more detail below. I. Active Compound

In one principle embodiment of the invention, the compound is of formula (I)

(i) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

1 9 carbocycle, aryl, heterocycle or heteroaryl; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

iii) X is a halogen, -CN or an optionally substituted lower alkyl (such as CH₃ and CF₃);

iv) Z¹ and Z² are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic;

v) Y is -NR³C(O)-, -NR³C(O)O-, -NR³C(O)NR⁴-, -NR³C(S)-, -NR³C(S)O-,

-NR³C(S)NR⁴-, -NR³S(O)_m-, -NR³(CH₂)_n-, -C(O)NR³- or -C(S)NR³-; such that when Y is -NR³C(O)-, then the compound is in the form of the Z isomer or at

1 9 least one of Z and Z is not an optionally substituted phenyl;

vi) m is 1 or 2; n is 1-4; and

vii) R³ and R⁴ are independently H or lower alkyl;

viii) alternatively, R³ or R⁴ can independently form a bridged carbocycle, aryl,

1 1 9 heterocycle or heteroaryl with each other or with R , R , Z or Z .

In a sub-embodiment, the compound of formula (I) is provided wherein:

i) the wavy line indicates that the compound can be in the form of the E or Z isomer; ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl, carbocycle; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

iii) X is a halogen;

v) Y is -NR³C(O)-, -NR³C(O)O-, -NR³C(O)NR⁴-, -NR³C(S)-, -NR³C(S)O-, -NR³C(S)NR⁴-, -NR³S(O)_m-, -NR³(CH₂)„-, -C(O)NR³- or -C(S)NR³-; such that when Y is -NR³C(O)-, then the compound is in the form of the Z isomer or at least one of Z¹ and Z² is not an optionally substituted phenyl;

vi) m is 1 or 2; n is 1-4; and

vii) R³ and R⁴ are independently H or lower alkyl;

alternatively, R³ or R⁴ can independently form a bridged carbocycle, aryl, heterocycle or

1 9 1 9 heteroaryl with each other or with R , R , Z or Z .

In a second embodiment, the compound is of the formula (II)

(II) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

i) the wavy line indicates that the compound can be in the form of the E or Z isomer; and

ii) R¹, R², R³, X, Z¹ and Z² are as previously defined. In a preferred embodiment, the compound of the formula (II) is of the formula

or a pharmaceutically acceptable salt or prodrug thereof.

In a third embodiment, the compound is of the formula (III)

(III) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

1 9 ^ 4 1 9 ii) R , R , R , R , X, Z and Z are as previously defined.

In a preferred embodiment, the compound of the formula (III) is of the formula

or a pharmaceutically acceptable salt or prodrug thereof.

In a fourth embodiment, the compound is of the formula (IV)

(IV)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

ii) R¹, R², R³, R⁴, X, Z¹ and Z² are as previously defined.

In a preferred embodiment, the compound of the formula (IV) is of the formula

or a pharmaceutically acceptable salt or prodrug thereof.

In a fifth embodiment, the compound is of the formula (V)

(N) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

ii) R¹, R², R³, X, Z¹ and Z² are as previously defined.

In a preferred embodiment, the compound of the formula (V) is of the formula

or a pharmaceutically acceptable salt or prodrug thereof.

In a sixth embodiment, the compound is of the formula (VI)

(VI)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

1 9 ^ 4. 1 9 ii) R , R , R , R , X, Z and Z are as previously defined. In a preferred embodiment, the compound of the formula (VI) is of the formula

or a pharmaceutically acceptable salt or prodrug thereof.

In a seventh embodiment, the compound is of the formula (VII)

(VII)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

ii) R¹, R², R³, R⁴, X, Z¹ and Z² are as previously defined. In a preferred embodiment, the compound of the formula (VII) is of the formula

or a pharmaceutically acceptable salt or prodrug thereof.

In another preferred embodiment, the compound of the formula (VII) is of the formula

or a pharmaceutically acceptable salt or prodrug thereof.

In an eighth embodiment, the compound is of the formula (VIII)

(VIII)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

ii) R¹, R², X, Z¹ and n are as previously defined.

In a preferred embodiment, the compound of the formula (VIII) is of the formula

or a pharmaceutically acceptable salt or prodrug thereof.

In a ninth embodiment of the invention, the compound is of formula (X)

(X)

or a pharmaceutically acceptable salt or prodrug thereof, wherein: i) the wavy line indicates that the compound can be in the form of the E or Z isomer;

ii) R , R , R and X are as previously defined;

iii) Z and Z is an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic; and

iv) when the compound is in the form of the E isomer, then at least one of Z¹ and Z² is not an optionally substituted phenyl.

In one sub-embodiment, the invention provides the Z isomer of the compound of formula (XI)

(XI) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R¹ is selected from the group consisting of but not limited to the moieties of the following Table 1. Table 1

In a second sub-embodiment, the invention provides the Z isomer of the compound of formula (XII)

(XII)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R¹ and R² come together to form a bridged compound selected from, but not limited to, the group consisting of the moieties of the following Table 2.

Table 2

In a third sub-embodiment, the invention provides the Z isomer of the compound of formula (XIII)

(XIII) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

Z¹ is selected from the group consisting of but not limited to the moieties of the following Table 3. Table 3

In a fourth sub-embodiment, the invention provides the Z isomer of the compound of formula (XIV)

(XIV) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

Z² is selected from the group consisting of, but not limited to, the moieties of the following Table 4. Table 4

In another preferred embodiment the invention provides the following compounds, particularly the active compounds are in the Z formation:

or their pharmaceutically acceptable salts or prodrugs thereof.

1 9

In a preferred embodiment, both R and R are not hydrogen.

In one particular embodiment of the invention, the compound is in the form of the E isomer. Alternatively, in another embodiment of the invention, the compound is in the form of the Z isomer.

In one embodiment the efficacy of the anti-HBV or anti-HDV compound is measured according to the concentration of compound necessary to reduce the plaque number of the virus in vitro, according to methods set forth more particularly herein, by 50% (i.e. the compound's EC₅₀). In preferred embodiments the compound exhibits an EC₅o of less than 15 or 10 micromolar.

II. Definitions:

The term alkyl, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon, preferably of the length Ci to C₁₀, and even more preferably Cι-C₄, including methyl, ethyl, propyl, isopropyl, cyclopropyl, methylcyclopropyl, butyl, isobutyl, t-butyl, sec-butyl, cyclobutyl, and (cyclopropyl)methyl. The alkyl group specifically includes fluorinated alkyls such as CF₃ and other halogenated alkyls such as CH CF₂, CF₂CF_3; the halo analogs.

The alkyl group can be optionally substituted with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclic, carbocycle, alkoxy, heterocycloxy, heterocylalkoxy, aryloxy; arylalkoxy; heteroaryloxy; heteroarylalkoxy, carbohydrate, amino acid, amino acid esters, amino acid amides, alditol, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, nitro, cyano, thiol, imide, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphate, phosphonate, phosphinate, sulfonamido, carboxamido, hydroxamic acid, sulfonylimide, substituted or unsubstituted urea connected through nitrogen including but not limited to NHCONH and NHCONHR; or any other desired functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.

The term carbocycle, as used herein, and unless otherwise specified, refers to carbon-based ring formed from primary, secondary or tertiary hydrocarbons, including but not limited to C₃ to C₈, and preferably C₅-C rings. Alternatively, one or more of the carbons can be -C(O)-, -C(S)- or C(NR)- and the like. The carbocycle can be optionally substituted with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclic, carbocycle, alkoxy, heterocycloxy, heterocylalkoxy, aryloxy; arylalkoxy; heteroaryloxy; heteroarylalkoxy, carbohydrate, amino acid, amino acid esters, amino acid amides, alditol, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, nitro, cyano, thiol, imide, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphate, phosphonate, phosphinate, sulfonamido, carboxamido, hydroxamic acid, sulfonylimide, substituted or unsubstituted urea connected through nitrogen including but not limited to NHCONH₂ and NHCONHR; or any other desired functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al. , Protective Groups in Organic Synthesis. John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.

The term aryl, as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphthyl, and preferably phenyl. The aryl group can be optionally substituted with one or more of the moieties selected from the group consisting of alkyl, heteroaryl, heterocyclic, carbocycle, alkoxy, aryloxy, aryloxy; arylalkoxy; heteroaryloxy; heteroarylalkoxy, carbohydrate, amino acid, amino acid esters, amino acid amides, alditol, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, nitro, cyano, thiol, imide, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, carboxylic ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphate, phosphonate, phosphinate, sulfonamido, carboxamido, hydroxamic acid, sulfonylimide or any other desired functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, "Protective Groups in Organic Synthesis," John Wiley and Sons, Second Edition, 1991. Alternatively, adjacent groups on the aryl ring may combine to form a 5 to 7 membered carbocyclic, aryl, heteroaryl or heterocyclic ring. In another embodiment, the aryl ring is substituted with an optionally substituted cycloalkyl (such as cyclopentyl or cyclohexyl), or an alkylene dioxy moiety (for example methylenedioxy).

The term heterocyclic refers to a nonaromatic cyclic group that may be partially (contains at least one double bond) or fully saturated and wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen, or phosphorus in the ring. The term heteroaryl or heteroaromatic, as used herein, refers to an aromatic that includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring. Nonlimiting examples of heterocycles and heteroaromatics are pyrrolidinyl, tetrahydrofuryl, piperazinyl, piperidinyl, morpholino, thiomorpholino, tetrahydropyranyl, imidazolyl, pyrolinyl, pyrazolinyl, indolinyl, dioxolanyl, 1,4-dioxanyl aziridinyl, furyl, furanyl, pyridyl, pyrimidinyl, benzoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, indazolyl, 1,3,5-triazinyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, thiazine, pyridazine, or pteridinyl wherein said heteroaryl or heterocyclic group can be optionally substituted with one or more substituent selected from the same substituents as set out above for aryl groups. Functional oxygen and nitrogen groups on the heteroaryl group can be protected as necessary or desired. Suitable protecting groups can include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl and t- butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenelsulfonyl.

The term aralkyl, as used herein, and unless otherwise specified, refers to an aryl group as defined above linked to the molecule through an alkyl group as defined above. The aryl and alkyl portions can be optionally substituted as described above.

The term heteroaralkyl, as used herein, and unless otherwise specified, refers to an heteroaryl group as defined above linked to the molecule through an alkyl group as defined above.

The term heterocyclealkyl, as used herein, refers to a heterocyclic group bound to the molecule through an alkyl group. The heterocyclic group and the alkyl group can be optionally substituted as described above.

The term aryloxy, as used herein, refers to an aryl group bound to the molecule through an oxygen atom. The aryl group can be optionally substituted as set out above for aryl groups.

The term heteroaryloxy, as used herein, refers to a heteroaryl group bound to the molecule through an oxygen atom. The heteroaryl group can be optionally substituted as set out above for aryl groups.

The term aralkoxy refers to an aryl group attached to an alkyl group that is attached to the molecule through an oxygen atom. The aryl and alkyl groups can be optionally substituted as described above.

The term heterocyclearalkoxy refers to a heterocyclic group attached to an aryl group attached to an alkyl-O- group. The heterocyclic, aryl and alkyl groups can be optionally substituted as described above. The term halo or halogen, as used herein, includes chloro, bromo, iodo and fluoro.

The term alkoxy, as used herein, and unless otherwise specified, refers to a moiety of the structure -O-alkyl, wherein alkyl is as defined above. The alkyl group can be optionally substituted as described above. Alkoxy groups can include OCF₃ , OCH₂CF , OCF₂CF₃ and the like.

The term alkylthio as used herein refers to an alkyl group attached to the molecule tlirough a sulfur atom. The alkyl group can be optionally substituted as described above.

The term acyl, as used herein, refers to a group of the formula C(O)R', wherein R' is an alkyl, aryl, alkaryl or aralkyl group, or substituted alkyl, aryl, aralkyl or alkaryl, wherein these groups are as defined above.

The term "alditol," as referred to herein, and unless otherwise specified, refers to a carbohydrate in which the aldehyde or ketone group has been reduced to an alcohol moiety. The alditols of the present invention can also be optionally substituted or deoxygenated at one or more positions. Exemplary substituents include hydrogen, halo, haloalkyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, amino acid, amino acid esters and amides, phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound. Particular exemplary substituents include amine and halo, particularly fluorine. The substituent or alditol can be either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, Protective Groups in Organic Synthesis. John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference. The alditol may have 3, 4, 5, 6 or 7 carbons. Examples of useful alditols are those derived from reduction of monosaccharides, including specifically those derived from the reduction of pyranose and furanose sugars.

The term "carbohydrate," as referred to herein, and unless otherwise specified, refers to a compound of carbon, hydrogen and oxygen that contains an aldehyde or ketone group in combination with at least two hydroxyl groups. The carbohydrates of the present invention can also be optionally substituted or deoxygenated at one or more positions.

Carbohydrates thus include substituted and unsubstituted monosaccharides, disaccharides, oligosaccharides and polysaccharides. The saccharide can be an aldose or ketose, and may comprise 3, 4, 5, 6 or 7 carbons. In one embodiment the carbohydrates are monosaccharides. In another embodiment the carbohydrates are pyranose and furanose sugars. Non limiting examples of pyranose and furanose sugars include threose, ribulose, ketose, gentiobiose, aldose, aldotetrose, aldopentose, aldohexose, ketohexose, ketotetrose, ketopentose, erythrose, threose, ribose, deoxyribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, glactose, talose, erythrulose, xylulose, psicose, fructose, sorbose, tagatose, dextrose, maltose, lactose, sucrose, cellulose, aldose, amylose, palatinose, trehalose, turanose, cellobiose, amylopectin, glucosamine, mannosamine, fucose, phamnose, glucuronate, gluconate, glucono-lactone, muramic acid, abequose, rhamnose, gluconic acid, glucuronic acid, and galactosamine. The carbohydrate can be optionally deoxygenated at any corresponding C-position, and/or substituted with one or more moieties such as hydrogen, halo, haloalkyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, amino acid, amino acid esters, amides, phosphonyl, phosphinyl, phosphoryl, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound. Particular exemplary substituents include amine and halo, particularly fluorine. The substituent or carbohydrate can be either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.

The term "protected" as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. The term aryl, as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphthyl, and preferably phenyl. The aryl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.

As used herein, the term hepatitis B and related conditions refers to hepatitis B and related conditions such as anti-HBV antibody positive and HBV-positive conditions, chronic liver inflammation caused by HBV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis and fatigue. The method of the present invention includes the use of 2-substituted-3-propenamide derivatives prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-HBV antibody or HBV-antigen positive or who have been exposed to HBV. Simiraly, the term hepatitis D and related conditions refers to hepatitis D and related conditions such as anti-HDV antibody positive and HDV-positive conditions, chronic liver inflammation caused by HDV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis and fatigue. The method of the present invention includes the use of 2-substituted-3-propenamide derivatives prophylactically to prevent or retard the progression of clinical illness in individuals who are anti-HDV antibody or HDV-antigen positive or who have been exposed to HDV.

The term biologically active compound, as used herein, refers to a compound that exhibits an EC₅0 of 15 micromolar or less when tested in 2.2.15 cells transfected with the hepatitis virion. The term host, as used herein, refers to a unicellular or rnulticellular organism in which the virus can replicate, including cell lines and animals, and preferably a human. Alternatively, the host can be carrying a part of the viral genome, whose replication or function can be altered by the compounds of the present invention. The term host specifically refers to infected cells, cells transfected with all or part of the viral genome and animals, in particular, mammals such as primates (including chimpanzees) and humans. In most animal applications of the present invention, the host is a human patient. Veterinary applications, in certain indications, however, are clearly anticipated by the present invention (such as chimpanzees). III. Salt or Prodrug Formulations

The term "pharmaceutically acceptable salt or prodrug" is used throughout the specification to describe any pharmaceutically acceptable form (including but not limited to a salt, ester, phosphate ester, salt of an ester or other group) of a compound which, upon administration to a patient, provides the compound. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, in the host to form the compound of the present invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound. The compounds of this invention possess antiviral activity against HBV and/or HDC, or are metabolized to a compound that exhibits such activity.

Pharmaceutically acceptable salts or complexes of the 2-substituted-3-propenamide derivatives retain the desired biological activity of the parent compound and exhibit minimal, if any, undesired toxicological effects. Nonlimiting examples of such salts are

(a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acids, naphthalenedisulfonic acids, and polygalacturonic acid; (b) base addition salts formed with cations such as sodium, potassium, zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with an organic cation formed from N,N-dibenzyl-ethylenediamine, ammonium, or ethylenediamine; or (c) combinations of

(a) and (b); e.g., a zinc tannate salt or the like.

In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate. Suitable inorganic salts may also be formed, including, sulfate, nitrate, bicarbonate and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

IV. Combination or Alternation Therapy

It has been recognized that drug-resistant variants of HBV and/or HDV can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in the viral life cycle, and most typically in the case of HBV, DNA polymerase. Recently, it has been demonstrated that the efficacy of a drug against HBV and/or HDV infection can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principle drug. Alternatively, the pharmacokinetics, biodistribution or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.

The anti-hepatitis B or hepatitis D viral activity of the 2-substituted-3-propenamide derivatives provided herein, or the prodrugs, phosphates, or salts of these compounds, can be enhanced by administering in combination or alternation with 3TC, FTC, L-FMAU,

DAPD, famciclovir, penciclovir, BMS-200475, bis pom PMEA (adefovir dipivoxil); lobucavir, ganciclovir, entecavir, or ribavarin.

In an alternative embodiments, an immunomodulator can be used in combination and/or alternation with the anti-HBV agents of the present invention. In one embodiment the compounds of the present invention can be used in combination and/or alternation with an immunomodulator, such as a TH1 cytokine, and in particular an interferon, preferably interferon gamma. In one embodiment of the invention, the immunomodulator is delivered in the form of a protein. In an alternate embodiment, the immunomodulator is delivered in the form of a gene or gene fragment that expresses the immunomodulator protein. In one particular embodiment of the present invention, the immunomodulator is delivered in the form of a gene or gene fragment thereof, and the delivery is mediated by an adenovirus. In one particular embodiment of the invention, the immunomodulator is interferon (such as interferon gamma), and its delivery is in the form of a gene or gene fragment that is mediated by an adenovirus.

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Interferons that can be administered include but are not limited to: interferon alpha-2a, interferon alpha-2b, ROFERON®-A (interferon alpha-2a, Roche), PEGASYS® (pegylated interferon alpha-2a, Roche), INTRON®A (Interferon alpha-2b, Schering

Corporation), PEG-INTRON® (pegylated Interferon alpha-2b, Schering Corporation), interferon alpha, interferon beta, interferon gamma, interferon tau, interferon omega, INFERGEN (interferon alphacon-1) by InterMune, OMNIFERON (natural interferon) by Viragen, ALBUFERON by Human Genome Sciences, REBIF (interferon beta- la) by Ares-Serono, Omega Interferon by BioMedicine, Oral Interferon Alpha by Amarillo

Biosciences, interferon gamma- lb by InterMune, SuperFeron (natural human multi- subtype IFN-alpha, Genetrol, Inc.), and HuFeron (human IFN-beta, Genetrol, Inc.)

The term "immunomodulatory" or "modulating an immune response" as used herein includes immunostimulatory as well as immunosuppressive effects. Immunomodulation is primarily a qualitative alteration in an overall immune response, although quantitative changes may also occur in conjunction with immunomodulation. Immunomodulation may involve an immune response that is shifted towards a "Thl-type" immune response, as opposed to a "Th2-type" immune response. Thl-type responses are typically considered cellular immune system (e.g., cytotoxic lymphocytes) responses, while Th2-type responses are generally "humoral", or antibody-based. Thl-type immune responses are normally characterized by "delayed-type hypersensitivity" reactions to an antigen, and can be detected at the biochemical level by increased levels of Thl -associated cytokines such as IFN-gamma, IL-2, IL-12, and TNF-beta, as well as IFN-alpha and IL-6, although IL-6 may also be associated with Th2-type responses as well. Thl-type immune responses are generally associated with the production of cytotoxic lymphocytes (CTLs) and low levels or transient production of antibody. Th2-type immune responses are generally associated with higher levels of antibody production, including IgE production, an absence of or minimal CTL production, as well as expression of Th2-associated cytokines such as IL-4. Accordingly, immunomodulation in one embodiment can be recognized by, for example, an increase in IFN-gamma and/or a decrease in IgE production in an individual treated in accordance with the methods of the invention as compared to the absence of treatment.

Immunomodulatory agents include, but are not limited to, a molecule such as a chemokine or cytokine that affects either directly or indirectly an immune response. Non- limiting examples of immunomodulators include TH1 cytokines, and in particular, interferon, interferon-α, purified interferon-α, interferon-α2a, interferon-α2b, interferon-β, interferon-γ, consensus interferon, pegylated interferon, pegylated interferon-α, granulocyte macrophage colony-stimulating factor, interleukin, interleukin-2, and interleukin- 12. In one embodiment, the immunomodulator is interferon, e.g., interferon-γ.

V. Pharmaceutical Compositions

A host, including humans, infected with HBV and/or HDV, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously or topically, in liquid or solid form.

A preferred dose of the compound for HBV and/or HDV infection will be in the range from about 1 to 50 mg/kg, preferably 1 to 20 mg/kg, of body weight per day, more generally 0.1 to about 100 mg per kilogram body weight of the recipient per day. The effective dosage range of the pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent compound to be delivered. If the salt or prodrug exhibits activity in itself, the effective dosage can be estimated as above using the weight of the salt or prodrug, or by other means known to those skilled in the art.

The compound is conveniently administered in unit any suitable dosage form, including but not limited to one containing 7 to 3000 mg, preferably 70 to 1400 mg of active ingredient per unit dosage form. An oral dosage of 50-1000 mg is usually convenient.

Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.2 to 70 μM, preferably about 1.0 to

10 μM. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or administered as a bolus of the active ingredient.

The concentration of active compound in the drug composition will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.

A preferred mode of administration of the active compound is oral. Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.

The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.

The compound can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The compound or a pharmaceutically acceptable prodrug or salt thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti-inflammatories or other antivirals, including nucleoside or non-nucleoside transcriptase inhibitors. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parental preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.

If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS). Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.

In a preferred embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.

Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation.

The controlled release formulation can be a degradable or nondegradable polymer, hydrogel or ganogel or other physical construct that modifies the bioabsorption, half life or biodegradation of the active compound. The controlled release formulation can be a material that is painted or otherwise applied onto the afflicted site, either internally or externally.

The field of biodegradable polymers has developed rapidly since the synthesis and biodegradability of polylactic acid was first reported in 1966 by Kulkarni et al. "Polylactic acid for surgical implants," Arch. Surg., 93, 839. Several other polymers are now known to biodegrade, such as polyanhydrides and polyorthoesters, which take advantage of labile backbone linkages (see: Domb et al. Macromolecules, 22, 3200, 1989; and Heller et al. Biodegradable Polymers as Drug Delivery Systems, Dekker, NY: 1990). Several polymers which degrade into naturally occurring materials have also been described, such as crosslinking gelatin, hyaluronic acid (della Valle et al. U.S. Patent No. 4,987,744 and U.S. Patent No. 4,957,744) and polyaminoacids (Miyake et al, 191 A), which spurred the usage of polyesters by Holland et al. Controlled Release, 4, 155, 1986 and alph-hydroxy acids (i.e. lactic acid and glycolic acid), which remain the most widely used biodegradable materials for applications ranging from closure devices (sutures and staples) to drug delivery systems (Smith et al. U.S. Patent No. 4,741,337; Spilizeqski et al. J. Control.

Rel., 2, 197, 1985).

These polymers can be tailored to degrade at a desired rate and with a desired kinetics by selecting the appropriate monomers, method of preparation and molecular weight. Differences in crystallinity of the monomer can alter the polymeric degradation rate. Due to the relatively hydrophobic nature of most polymers, actual mass loss can begin with the oligomeric fragments that are small enough to be water soluble; hence, even the initial molecular weight can influence the degradation rate.

Hydrogels can be used in controlled release formulations. Such polymers are formed from macromers with a polymerizable, non-degradable, region that is separated by at least one degradable region. For example, the water soluble non-degradable region can form the central core of the macromer and have at least two degradable regions which are attached to the core, such that upon degradation, the non-degradable regions (in particular a polymerized gel) are separated. Specifically, as disclosed in U.S. Patent No. 5,626,863 to Hubbell et al, the macromers are PEG-oligoglycolyl-acrylates, with the appropriate end caps to permit rapid polymerization and gelation. Acrylates can be polymerized readily by several initiating systems such as eosin dye, ultraviolet or visible light. The polyethyleneglycol (PEG) is highly hydrophilic and biocompatible. The oligoglycolic acid is a poly(a-hydroxy acid) which can be readily degraded by hydrolysis of the ester linkage into glycolic acid, a nontoxic metabolite. Other chain extensions include polylactic acid, polycaprolactone, polyorthoesters, polyanhydrides and polypeptides. This entire network can be gelled into a biodegradable network that can be used to entrap and homogeneously disperse water-soluble drugs for delivery at a controlled rate. Further, the gel can entrap particulate suspensions of water-insoluble drugs. (See also: U.S. Patent No. 4,591,496 to Cohen et al. (Process for Making Systems for the Controlled Release of Macromolecules); U.S. Patent No. 5,545,442 to Van Savage et al. (Method for Using a

Radiation Cured Drug Release Controlling Membrane); U.S. Patent No. 5,330,768 to Park et al. (Controlled Drug Delivery Using Polymer/Pluronic Blends); U.S. Patent No. 5,122,367 to Ron et al. (Polyanhydride Bioerodible Controlled Release Implants for Administration of Stabilized Growth Hormone); U.S. Patent No. 5,545,409 to Laurencin et al. (Delivery System for Controlled Release of Bioactive Factors); U.S. Patent No. 5,629,009 to Laurencin et al. (Delivery System for Controlled Release of Bioactive Factors).

Alternatively, delivery of biologically active substances, both in vitro and in vivo, via encapsulation has been well described in the prior art. U.S. Patent No. 4,352,883 to Lim et al. entitled "Encapsulation of Biological Material" discloses the encapsulation of proteins within a membrane by suspending the protein in an aqueous medium containing a water-soluble gum that can be reversibly gelled to form the suspension into droplets. These droplets can be gelled further into discrete, shape-retaining, water insoluble temporary capsules with the aid of a solution of multivalent cations. The temporary capsules then can be further wrapped by an ionically cross-linking surface layer to form a semipermeable membrane around the capsules that is permeable to small molecules but impermeable to larger molecules. Microencapsulations of glycoproteins have also been well described. U.S. Patent No. 4,324,683 to Lim et al. entitled "Encapsulation of Labile

Biological Material" encapsulates a glycoprotein by a two-step interfacial polymerization process to form capsules with well-controlled porosity. The microcapsules serve to protect the active substances from attack by microorganisms and from any immunological response. U.S. Patent No. 5,718,921 to Mathiowitz et al. (Microspheres Comprising Polymer and Drug Dispersed There Within) discloses a method to encapsulate relatively temperature-labile drugs into a microsphere.

Several methods have been developed to reversibly encapsulate biologically active substances. One that can be applied both to in vitro and in vivo studies has been described in U.S. Patent No. 4,900,556 by Wheatley et al. entitled "System for Delayed and Pulsed Release of Biologically-Active Substances." In this disclosed system, the biologically- active substance can be released either at a constant rate over a period of time or in discrete pulses. The biologically active materials are entrapped within liposomes encapsulated within semipermeable microcapsules or permeable polymeric matrix. Release of the desired materials is governed by the permeability of both the liposome and the surrounding matrix (the matrix integrity is directly proportional to the liposome integrity); the permeability of the liposome can be engineered by modifying the composition and the method for making the liposome to produce liposome that are sensitive to specific stimuli such as temperature, pH or light. For example, by including a phospholipase that degrades the liposome within some or all of the liposomes or the surrounding matrix, the liposome can be destabilized and broken down over a period of time. Other systems have been developed, e.g. U.S. Patent No. 4,933,185 by Wheatley et al, which utilize a core made up of a polymer (such as an ionically cross-linked polysaccharide with calcium alginate or chitin) around which there is an ionically bound skin (such as a polycationic skin of poly-L-lysine) whose integrity is dependent on the core polymer. With an impermeable skin, when the core polymer can be degraded by enzymes (such as alginase from the bacteria, chitinase or hydrolase), there is a sudden release of biologically active substance from the core. Alternatively, the skin can be partially permeable for a gradual release of drug upon degradation of the core.

Nanoparticles are especially useful in the delivery of drugs parenterally or intravenously such that the delivery device is small with a long circulating half-life. A number of injectable drug delivery systems have been investigated, including microcapsules, microparticles, liposomes and emulsions. The major obstacle for these delivery systems is the rapid clearance of the materials from the blood stream by the macrophages of the reticuloendothelial system (RES). For example, polystyrene particles as small as sixty nanometers in diameter are cleared from the blood within two to three minutes. Liposomal drug delivery systems have also been extensively studied for this application because they were expected to freely circulate in the blood. Coating of the liposomes with poly(ethylene glycol) (PEG) increased the half-life of the carriers due to

PEG's hydrophobic chains which reduced its protein absorption and thus its RES uptake. U.S. Patent No. 5,543,158 to Gref et al. (Biodegradable Injectable Nanoparticles) describes a carrier system specifically targeted towards carriers suitable for intravenous delivery with a controlled release mechanism with modified polyglycols.

U.S. Patent No. 5,626,862, U.S. Patent No. 5,651,986 and U.S. Patent No.

5,846,565 to Brem et al. (Controlled Local Delivery of Chemotherapeutic Agents for Treating Solid Tumors) discloses the use of these carriers for the specific delivery of chemotherapeutic agents to increase bioavailability. Therefore, the devices act as reservoirs that release drugs over an extended period of time while at the same time preserves the bioactivity and bioavailability of the agent. U.S. Patent No. 5,286,763 to

Gerhard et al. (Bioerodible Polymers for Drug Delivery in Bone) further discloses that bioerodible polymers can be used to deliver chemotherapeutic agents directly into the bone. Cohen et al. U.S. Patent No. 5,562,099 (Polymeric Microparticles Containing Agents for Imaging) discusses the usage of these carriers as contrast agents. The polymeric microparticle is filled with contrast agents for enhanced imaging.

Books describing methods of controlled delivery that are appropriate for the delivery of the active compounds of the present invention include: Robert S. Langer, Donald L. Wise, editors; Medical applications of controlled release (Volumes 1 and 2);

Boca Raton, FL: CRC Press, 1984; and William J. M. Hrushesky, Robert Langer and Felix Theeuwes, editors; Temporal control of drug delivery (series); New York: New York Academy of Sciences, 1991.

Nonlimiting examples of U.S. Patents that describe controlled release formulations are: U.S. Patent No. 5,356,630 to Laurencin et al. (Delivery System for Controlled Release of Bioactive Factors); ; U.S. Patent No. 5,797,898 to Santini, Jr. et al. (Microchip Drug Delivery Devices); U.S. Patent No. 5,874,064 to Edwards et al. (Aerodynamically Light Particles for Pulmonary Drug Delivery); U.S. Patent No. 5,548,035 to Kim et al. (Biodegradable Copolymer as Drug Delivery Matrix Comprising Polyethyleneoxide and Aliphatic Polyester Blocks); U.S. Patent No. 5,532,287 to Savage et al (Radiation Cured

Drug Release Controlling Membrane); U.S. Patent No. 5,284,831 to Kahl et al. (Drug Delivery Porphyrin Composition and Methods); U.S. Patent No. 5,741,329 to Agrawal et al. (Methods of Controlling the pH in the Vicinity of Biodegradable Implants); U.S. Patent No. 5,820,883 to Tice et al. (Methods for Delivering Bioactive Agents into and Through the Mucosally-Associated Lymphoid Tissues and Controlling Their Release);U.S. Patent

No. 5,955,068 to Gouin et al. (Biodegradable polyanhydrides Derived from Dimers of Bile Acids and Use Thereof as Controlled Drug Release Systems); U.S. Patent No. 6,001,395 to Coombes et al. (Polymeric Lamellar Substrate Particles for Drug Delivery); U.S. Patent No. 6,013,853 to Athanasiou et al. (Continuous Release Polymeric Implant Carriers); U.S. Patent No. 6,060,582 to Hubbell et al. (Photopolymerizable Biodegradable

Hydrogels as Tissue Contacting Materials and Controlled Release Carriers); U.S. Patent No. 6,113,943 to Okada et al. (Sustained-Release Preparation Capable of Releasing a Physiologically Active Substance); and PCT Publication No. WO 99/59548 to Oh et al. (Controlled Drug Delivery System Using the Conjugation of Drug to Biodegradable Polyester); U.S. Patent No. 6,123,861 (Fabrication of Microchip Drug Delivery Devices);

U.S. Patent No. 6,060,082 (Polymerized Liposomes Targeted to M cells and Useful for Oral or Mucosal Drug Delivery); U.S. Patent No. 6,041,253 (Effect of Electric Field and Ultrasound for Transdermal Drug Delivery); U.S. Patent No. 6,018,678 (Transdermal protein delivery or measurement using low-frequency sonophoresis); U.S. Patent No. 6,007,845 Nanoparticles And Microparticles Of Non-Linear Hydrophilic-Hydrophobic Multiblock Copolymers; U.S. Patent No. 6,004,534 Targeted Polymerized Liposomes For Improved Drug Delivery; U.S. Patent No. 6,002,961 Transdermal Protein Delivery Using Low-Frequency Sonophoresis; U.S. Patent No. 5,985,309 Preparation Of Particles For

Inhalation; U.S. Patent No. 5,947,921 Chemical And Physical Enhancers And Ultrasound For Transdermal Drug Delivery; U.S. Patent No. 5,912,017 Multiwall Polymeric Microspheres; U.S. Patent No. 5,911,223 Introduction Of Modifying Agents Into Skin By Electroporation; U.S. Patent No. 5,874,064 Aerodynamically Light Particles For Pulmonary Drug Delivery; U.S. Patent No. 5,855,913 Particles Incorporating Surfactants

For Pulmonary Drug Delivery; U.S. Patent No. 5,846,565 Controlled Local Delivery Of Chemotherapeutic Agents For Treating Solid Tumors; U.S. Patent No. 5,837,752 Semi- Interpenetrating Polymer Networks; U.S. Patent No. 5,814,599 Transdermal Delivery Of Encapsulated Drugs; U.S. Patent No. 5,804,178 Implantation Of Cell-Matrix Structure Adjacent Mesentery, Omentum Or Peritoneum Tissue; U.S. Patent No. 5,797,898

Microchip Drug Delivery Devices; U.S. Patent No. 5,770,417 Three-Dimensional Fibrous Scaffold Containing Attached Cells For Producing Vascularized Tissue In vivo; U.S. Patent No. 5,770,193 Preparation Of Three-Dimensional Fibrous Scaffold For Attaching Cells To Produce Vascularized Tissue In vivo; U.S. Patent No. 5,762,904 Oral Delivery Of Vaccines Using Polymerized Liposomes; U.S. Patent No. 5,759,830 Three-

Dimensional Fibrous Scaffold Containing Attached Cells For Producing Vascularized Tissue In vivo; U.S. Patent No. 5,749,847 Delivery Of Nucleotides Into Organisms By Electroporation; U.S. Patent No. 5,736,372 Biodegradable Synthetic Polymeric Fibrous Matrix Containing Chondrocyte For In vivo Production Of A Cartilaginous Structure; U.S. Patent No. 5,718,921 Microspheres Comprising Polymer And Drug Dispersed There

Within; U.S. Patent No. 5,696,175 Preparation Of Bonded Fiber Structures For Cell Implantation; U.S. Patent No. 5,667,491 Method For Rapid Temporal Control Of Molecular Transport Across Tissue; U.S. Patent No. 5,654,381 Functionalized Polyester Graft Copolymers; U.S. Patent No. 5,651,986 Controlled Local Delivery Of Chemotherapeutic Agents For Treating Solid Tumors; U.S. Patent No. 5,629,009

Delivery System For Controlled Release Of Bioactive Factors; U.S. Patent No. 5,626,862 Controlled Local Delivery Of Chemotherapeutic Agents For Treating Solid Tumors; U.S. Patent No. 5,593,974 Localized Oligonucleotide Therapy; U.S. Patent No. 5,578,325 Nanoparticles And Microparticles Of Non-Linear Hydrophilic-Hydrophobic Multiblock Copolymers; U.S. Patent No. 5,562,099 Polymeric Microparticles Containing Agents For Imaging; U.S. Patent No. 5,545,409 Delivery System For Controlled Release Of Bioactive Factors; U.S. Patent No. 5,543,158 Biodegradable Injectable Nanoparticles; U.S. Patent No. 5,514,378 Biocompatible Polymer Membranes And Methods Of Preparation Of Three Dimensional Membrane Structures; U.S. Patent No. 5,512,600

Preparation Of Bonded Fiber Structures For Cell Implantation; U.S. Patent No. 5,500,161 Method For Making Hydrophobic Polymeric Microparticles; U.S. Patent No. 5,487,390 Gas-filled polymeric microbubbles for ultrasound imaging; U.S. Patent No. 5,399,665 Biodegradable polymers for cell transplantation; U.S. Patent No. 5,356,630 Delivery system for controlled release of bioactive factors; U.S. Patent No. 5,330,768 Controlled drug delivery using polymer/pluronic blends; U.S. Patent No. 5,286,763 Bioerodible polymers for drug delivery in bone; U.S. Patent No. 5,149,543 Ionically cross-linked polymeric microcapsules; U.S. Patent No. 5,128,420 Method of making hydroxamic acid polymers from primary amide polymers; U.S. Patent No. 5,122,367 Polyanhydride bioerodible controlled release implants for administration of stabilized growth hormone;

U.S. Patent No. 5,100,668 Controlled release systems containing heparin and growth factors; U.S. Patent No. 5,019,379 Unsaturated polyanhydrides; U.S. Patent No. 5,010,167 Poly(amide-and imide-co-anhydride) for biological application; .S. Patent No. 4,948,587 Ultrasound enhancement of transbuccal drug delivery; U.S. Patent No. 4,946,929 Bioerodible articles useful as implants and prostheses having predictable degradation rates; U.S. Patent No. 4,933,431 One step preparation of poly(amide- anhydride); U.S. Patent No. 4,933,185 System for controlled release of biologically active compounds; U.S. Patent No. 4,921,757 System for delayed and pulsed release of biologically active substances; U.S. Patent No. 4,916,204 Pure polyanhydride from dicarboxylic acid and coupling agent; U.S. Patent No. 4,906,474 Bioerodible polyanhydrides for controlled drug delivery; U.S. Patent No. 4,900,556 System for delayed and pulsed release of biologically active substances; U.S. Patent No. 4,898,734 Polymer composite for controlled release or membrane formation; U.S. Patent No. 4,891,225 Bioerodible polyanhydrides for controlled drug delivery; U.S. Patent No. 4,888,176 Controlled drug delivery high molecular weight polyanhydrides; .S. Patent No.

4,886,870 Bioerodible articles useful as implants and prostheses having predictable degradation rates; U.S. Patent No. 4,863,735 Biodegradable polymeric drug delivery system with adjuvant activity; U.S. Patent No. 4,863,611 Extracorporeal reactors containing immobilized species; U.S. Patent No. 4,861,627 Preparation of multiwall polymeric microcapsules; U.S. Patent No. 4,857,311 Polyanhydrides with improved hydrolytic degradation properties; U.S. Patent No. 4,846,786 Bioreactor containing suspended, immobilized species; U.S. Patent No. 4,806,621 Biocompatible, bioerodible, hydrophobic, implantable polyimino carbonate article; U.S. Patent No. 4,789,724 Preparation of anhydride copolymers; U.S. Patent No. 4,780,212 Ultrasound enhancement of membrane permeability; U.S. Patent No. 4,779,806 Ultrasonically modulated polymeric devices for delivering compositions; U.S. Patent No. 4,767,402 Ultrasound enhancement of transdermal drug delivery; U.S. Patent No. 4,757,128 High molecular weight polyanhydride and preparation thereof; .S. Patent No. 4,657,543 Ultrasonically modulated polymeric devices for delivering compositions; U.S. Patent No. 4,638,045 Non-peptide polyamino acid bioerodible polymers; U.S. Patent No. 4,591,496 entitled "Process for making systems for the controlled release of macromolecules."

VI. Processes for the Preparation of Active Compounds

The 2-substituted-propenamide derivatives can be synthesized by any means known in the art. In particular, the 2-substituted-propenamide derivatives can be synthesized via the procedure disclosed in International Application No. PCT/US98/00968, published as WO 98/33501 to Perni et al.; Buck and Ide in Organic Synthesis, vol. 13, pp. 8-9 (1933) and Barnes and Shriner, J Am. Chem Soc, vol. 70, pp. 1769-1772 (1948), as depicted as follows.

If the 2-substituted-propenamide derivatives wherein X is halogen or CN are desired, the following procedure is depicted as follows.

R¹ \

N— R^

H

Alternatively, the 2-substituted-propenamide derivatives can be synthesized as follows.

Examples

Melting points were determined in open capillary tubes on a Gallenkamp MFB- 595-010 M apparatus and are uncorrected. The UV absorption spectra were recorded on an Uvikon 931 (KONTRON) spectrophotometer in ethanol. 1H-NMR spectra were run at room temperature in OMSO-dβ with a Bruker AC 250 or 400 spectrometer. Chemical shifts are given in ppm, DMSO--ij being set at 2.49 ppm as reference. Deuterium exchange, decoupling experiments or 2D-COSY were performed in order to confirm proton assignments. Signal multiplicities are represented by s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q (quadruplet), br (broad), m (multiplet). All J- values are in Hz. FAB mass spectra were recorded in the positive- (FAB>0) or negative- (FAB<0) ion mode on a JEOL DX 300 mass spectrometer The matrix was 3-nitrobenzyl alcohol

(NBA) or a mixture (50:50, v/v) of glycerol and thioglycerol (GT). Specific rotations were measured on a Perkin-Elmer 241 spectropolarimeter (path length 1 cm) and are given in units of 10^"1 deg cm² g^"1. Elemental analysis were carried out by the "Service de Microanalyses du CNRS, Division de Vernaison" (France). Analyses indicated by the symbols of the elements or functions were within ± 0.4% of theoretical values. Thin layer chromatography was performed on precoated aluminum sheets of Silica Gel 60 F₂₅₄ (Merck, Art. 5554), visualization of products being accomplished by UV absorbency followed by charring with 10% ethanolic sulfuric acid and heating. Column chromatography was carried out on Silica Gel 60 (Merck, Art. 9385) at atmospheric pressure.

Example 1

2-Phenyl-4-(Z)-phenylmethylene-5-oxo-oxazole.

Hippuric acid (28.8 g, 161 mmol), benzaldehyde (15.3 g, 144 mol), sodium acetate (12.0 g, 146 mmol) and acetic anhydride (42 mL) were combined in an Erlenmeyer flask and heated on a hot plate until the mixture just began to boil. The flask was transferred to a stream bath and heated for 1 hour with occasional manual stirring. Hot ethanol (60 mL) was added; the mixture was stirred until homogenous, and then cooled to room temperature. The resulting solid was collected by suction filtration and washed with a minimum quantity of cold ethanol, then with boiling water, and then dried in vacuo. Recrystallization from benzene yielded 16.5 g (46%) of fine yellow needles.

Example 2

1 -[(Z) -1 -oxo-2- (benzoylamino) -3-phenyl-3-bromopropenyl] piper idine.

To a solution of (1) (10.0 g, 40.1 mmol) in chloroform (200 mL) at 0° C was added dropwise a solution of piperidine (4.2 g, 49 mmol) in chloroform (60 mL). The yellow solution was stirred at 0° C for 1 hour. Solid calcium carbonate (6.0 g, 50 mmol) was added, followed by dropwise addition of bromine (6.4 g, 40 mmol) in chloroform (60 mL). The suspension was filtered to remove calcium salts, and the supernatant liquid was evaporated to dryness. The resulting orange oil was crystallized from ethanol, and further purified by recrystallization from ethanol/water. 8.18 g (49%) of pale green crystals were obtained, 158.2-158.5 °C.

Example 3 l-[(E)-l-oxo-2-(benzoylamino)-3-phenyl-3-chloropropenyl] piperidine

To a solution of (1) (10.0 g, 40.1 mmol) in chloroform (200 mL) at 0 °C was added dropwise a solution of piperidine (4.2 g, 49 mmol) in chloroform (60 mL). The yellow solution was stirred at 0 °C for lh. Chlorine was introduced through a Pasteur pipet at a rate of approximately 5 bubbles per second until TLC showed no further traces of starting material (approximately 2.5 min per mmol of starting material; an excessive amount of chlorine must be avoided, as it leads to the formation of undesirable side products). The solvent was removed in vacuo, yielding a yellow oil which was purified by chromatography (silicia gel, 2% CH₃OH/CH₃Cl.). The product was further purified by recrystallization from ethanol/water, yielding 7.67 g (52%) of white crystals, mp 175.8-

176.6 °C.

Example 4

N-[(4-tert-Butyl) benzoyl] glycine.

Glycine (0.78 g, 1.0 mmol) was dissolved in 1.0 N aqueous NaOH (10 mL) at room temperature. 4-tert-Butylbenzoyl chloride was added, and the biphasic mixture was heated to 60 °C and vigorously stirred overnight. A heavy white precipitate gradually formed; it was collected by suction filtration and washed with ether to remove 4-tert- butybenzoic acid. The product, a white powder, weighed 0.70 g (30%) and was used without further purification .

Example 5

N-[(4-Carbomethoxy) benzoyl] glycine.

1,1 '-Carbonyldiimidazole (1.94 g, 12.0 mmol) was added to a suspension of mono- methylterephthalate 2.16 g, 12.0 mmol) in CH.C1 (50 mL). A clear solution resulted after approximately 5 min. A solution of sodium hydroxide (0.60 g, 15.0 mmol) and glycine (1.13 g, 15.1 mmol) in water (5 mL) was added, and the mixture was stirred vigorously. A semisolid mass formed and gradually dissolved until a clear biphasic mixture was formed. The reaction mixture was acidified to pH 5 with concentrated HC1. CH.C1 was removed in vacuo, and the solid residue, shown by TLC (1:2:97 HOAc/CH.OH/CHCl.) to be starting material, was removed by filtration. The supernatant liquid was further acidified and cooled on ice to yield fine, colorless crystals. A second crop was collected after reduction of the volume of the mother liquor. The total yield was 0.54 g (19%) of colorless crystals, which were used without further purification.

Example 6

4-(2-methoxy-benzylidene)-2-(4-nitro-phenyl)-4H-oxazol-5-one.

A dry 500 ml 3 -necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with 4-nitrohippuric acid (25.34 g, 113.04 mmol) and acetic anhydride (200 ml, 2.12 mol). The reaction mixture was stirred at room temperature for thirty minutes and potassium bicarbonate (5.66 g, 56.52 mmol) added.

Stirring was continued at room temperature for an additional thirty minutes. The reaction mixture was stirred in an ice/brine bath for 45 minutes and o-anisaldehyde (17 ml, 130 mmol) was added dropwise. Once the addition was complete, stirring was continued at 0

°C for one hour and overnight at room temperature. The mixture was diluted with distilled water (500 ml) and the product was collected by filtration. The product was washed with hot distilled water (2 X 1000 ml), cold methanol (2 X 500 ml), hexanes (2 X 500 ml) and dried in vacuo. The product, a yellow solid, 23.4 g, 64% yield had a melting point of 256- 257.8 °C.

Example 7

N-[l-cyclobutylcarbamoyl-2-(2-methoxy-phenyl)-vinyl]-4-nitro-benzamide.

A dry 50 ml 3 -necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with 4-(2-methoxy-benzylidene)-2-(4- nitro-phenyl)-4H-oxazol-5-one (350 mg, 1.1 mmol) and anhydrous chloroform (10 ml).

The reaction was stirred at room temperature for fifteen minutes and cyclobutylamine (0.145 ml, 1.65 mmol) was added. Stirring was continued for an additional four hours at room temperature. The reaction was diluted with water (20 ml) and the aqueous and organic layers were separated. The organic layer was washed with 0.2N citric acid (20 ml), water (2 X 50 ml) and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The final product was triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a yellow solid 360- g, 83% yield, m.p. 218.1-219.4 °C.

Example 8

N-[2-bromo-l-cyclobutylcarbamoyl-2-(2-methoxy-phenyl)-vinyl]-4-nitro-benzamide.

A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[l-cyclobutylcarbamoyl-2-(2- methoxy-phenyl)-vinyl]-4-nitro-benzamide (250 mg, 0.63 mmol) and anhydrous chloroform (10 ml). The reaction was stirred at room temperature for thirty minutes and calcium carbonate (130 mg, 1.26 mmol) added. Stirring was continued for an additional thirty minutes. The reaction flask was transferred to an ice/brine bath and stirring in the bath continued for thirty minutes. Bromine (0.5M in chloroform, 1.9 ml) was added dropwise. After an additional 1.5 h, the reaction mixture was filtered and the solids washed with chloroform. The organic layer was washed with water (2 X 60 ml), saturated aqueous sodium hydrogen sulfite (25 ml), water (2 X 60 ml), saturated sodium bicarbonate

(30 ml), water (2 X 75 ml), and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified on a flash chromatography column, which was eluted with hexane: acetone (1:1, v:v). The product was obtained as a pale yellow solid, 95 mg, 32% yield, m.p. 213.4-214.6 °C. The product was isolated as the Z isomer.

Example 9

N-[2-(2-methoxy-phenyl)-l-(3-methyl-piperidine-l-carbonyl)-vinyl]-4-nitro-benzamide.

A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with the compound of formula:

(350 mg, 1.1 mmol) and anhydrous chloroform (10 ml). The reaction was stirred at room temperature for fifteen minutes and 3,5-dimethylpiperidine (0.21 ml, 1.6 mmol) was added. Stirring was continued for an additional four hours at room temperature. The reaction was filtered and the organic layer was washed with sat. NaHSO₃ (50 lm), water (2 X 75 ml), sat. NaHCO3 solution (75 ml), water (2 X 75 ml), and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was isolated as a pale yellow oil. The material was used directly in the next step.

Example 10

N-[2-bromo-l-(3,5-dimethyl-piperidine-l-carbonyl)-2-(2-methoxy-phenyl)-vinyl]-4-nitro- benzamide.

A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[2-(2-methoxy-phenyl)-l-(3- methyl-piperidine-1-carbonyl)- vinyl] -4-nitro-benzamide. (350 mg, 0.8 mmol) and anhydrous chloroform (10 ml). The reaction was stirred at room temperature for fifteen minutes and calcium carbonate (160 mg, 1.6 mmol) added. The reaction flask was transferred to an ice/brine bath and stirring in the bath continued for twenty minutes. Bromine (0.5M in chloroform, 2.4 ml) was added dropwise. After an additional twenty minutes, the reaction mixture was filtered and the solids washed with chloroform. The organic layer was washed with water (2 X 60 ml), saturated aqueous sodium hydrogen sulfϊte (25 ml), water (2 X 60 ml), saturated sodium bicarbonate (30 ml), water (2 X 75 ml), and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was triturated with diethyl ether, filtered and dried in vacuo. The product was obtained as a pale yellow solid, 246 mg, 60% yield. The product was isolated as a mixture of E and Z isomers.

Example 11

N-[2-(2-methoxy-phenyl)-l-(4-methyl-piperidine-l-carbonyl)-vinyl]-4-nitro-benzamide.

(380 mg, 1.17 mmol) and anhydrous chloroform (10 ml). The reaction was stirred at room temperature for fifteen minutes and 4-methylpiperidine (0.17 ml, 1.41 mmol) was added. Stirring was continued for an additional four hours at room temperature. The reaction was diluted with water (20 ml) and the aqueous and organic layers were separated. The organic layer was washed with 0.2N citric acid (20 ml), water (2 X 50 ml) and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The final product was triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a yellow solid 424-mg, 85.5% yield, m.p. 193.3-193.8 °C.

Example 12

N-[2-bromo-2-(2-methoxy-phenyl)-l-(4-methyl-piperidine-l-carbonyl)-vinyl]-4-nitro~ benzamide.

A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[2-(2-methoxy-phenyl)-l-(4- methyl-piperidine-l-carbonyl)-vinyl]-4-nitro-benzamide (250 mg, 0.59 mmol) and anhydrous chloroform (10 ml). The reaction was stirred at room temperature for thirty minutes and calcium carbonate (120 mg, 1.2 mmol) added. Stirring was continued for an additional fifteen minutes. The reaction flask was transferred to an ice/brine bath and stirring in the bath continued for thirty minutes. Bromine (0.5M in chloroform, 2 equiv.) was added dropwise. After an additional hour, the reaction mixture was filtered and the solids washed with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen sulfite (50 ml), water (2 X 75 ml), saturated sodium bicarbonate (75 ml), water (2 X 75 ml), and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was triturated with diethyl ether, filtered, and dried in vacuo. The product was obtained as an off-white solid, 150 mg, 51% yield, m.p. 191.5-192.8 °C.

Example 13 N-[l-(cyclopentyl-methyl-carbamoyl)-2-(2-methoxy-phenyl)-vinyl]-4-nitro-benzamide.

A dry 50 ml three-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with the compound of formula:

(350 mg, 1.1 mmol) and anhydrous chloroform (10 ml). The reaction was stirred at room temperature for fifteen minutes and N-methyl cyclobutylamine (0.18 ml, 1.6 mmol) was added dropwise. Stirring was continued for an additional sixteen hours at room temperature. The reaction was diluted with water (20 ml) and the aqueous and organic layers were separated. The organic layer was washed with 0.2N citric acid (20 ml), water (2 X 50 ml) and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The final product was triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a yellow solid 150-mg, 39% yield, m.p. 185.5-187.1 °C.

Example 14

N-[2-bromo-l-(cyclopentyl-methyl-carbamoyl)-2-(2-methoxy-phenyl)-vinyl]-4-nitro- benzamide.

A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[l-(cyclopentyl-methyl- carbamoyl)-2-(2-methoxy-phenyl)-vinyl]-4-nitro-benzamide (100 mg, 0.236 mmol) and anhydrous chloroform (10 ml). The reaction was stirred at room temperature for ten minutes and calcium carbonate (50 mg, 0.47 mmol) added. The reaction flask was transferred to an ice/brine bath and stirring in the bath continued for thirty minutes. Bromine (0.5M in chloroform, 0.71 ml) was added dropwise. After an additional twenty minutes, the reaction mixture was filtered and the solids washed with chloroform. The organic layer was washed with water (2 X 60 ml), saturated aqueous sodium hydrogen sulfite (25 ml), water (2 X 60 ml), saturated sodium bicarbonate (30 ml), water (2 X 75 ml), and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was obtained as a yellow solid, 60 mg,

51% yield, m.p. 185.7-186.9 °C.

Example 15 N-[l-(2,6-dimethyl-morpholine-4-carbonyl)-2-(2-methoxy-phenyl)-vinyl]-4-nitro- benzamide.

(350 mg, 1.1 mmol) and anhydrous chloroform (10 ml). The reaction was stirred at room temperature for fifteen minutes and 2,6-dimethylmoφholine (0.2 ml, 1.6 mmol) was added dropwise. Stirring was continued for an additional four hours at room temperature. The reaction was diluted with water (20 ml) and the aqueous and organic layers were separated. The organic layer was washed with 0.2N citric acid (20 ml), water (2 X 50 ml) and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The final product was triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a yellow solid 335-mg, 89% yield, m.p. 120.4-122.7 °C.

Example 16

N-[2-bromo-l-(2,6-dimethyl-morpholine-4-carbonyl)-2-(2-methoxy-phenyl)-vinyl]-4- nitro-benzamide.

A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[l-(2,6-dimethyl-morpholine-4- carbonyl)-2-(2-methoxy-phenyl)-vinyl]-4-nitro-benzamide (250 mg, 0.57 mmol) and anhydrous chloroform (10 ml). The reaction was stirred at room temperature for ten minutes and calcium carbonate (115 mg, 1.14 mmol) added. The mixture was stirred at ambient for thirty minutes and then transferred to an ice/brine bath and stirring in the bath was continued for an additional thirty minutes. Bromine (0.5M in chloroform, 1.72 ml) was added dropwise. After an additional twenty minutes, the reaction mixture was filtered and the solids washed with chloroform. The organic layer was washed with water (2 X 60 ml), saturated aqueous sodium hydrogen sulfite (25 ml), water (2 X 60 ml), saturated sodium bicarbonate (30 ml), water (2 X 75 ml), and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was obtained as a pale yellow solid, 170 mg, 58% yield. The product was isolated as a mixture of E and Z isomers.

Example 17

N-[l-(azepane-l-carbonyl)-2-(2-methoxy-phenyl)-vinyl]-4-nitro-benzamide.

(380 mg, 1.17 mmol) and anhydrous chloroform (10 ml). The reaction was stirred at room temperature for fifteen minutes and cycloheptylamine (0.16 ml, 1.41 mmol) was added dropwise. Stirring was continued for an additional four hours at room temperature. The reaction was diluted with water (20 ml) and the aqueous and organic layers were separated. The organic layer was washed with 0.2N citric acid (20 ml), water (2 X 50 ml) and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The final product was triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a yellow solid 417-mg, 84% yield, m.p.. 165.8-166.6 °C. The material was taken directly into the next step. Example 18

N-[l-(azepane-l-carbonyl)-2-bromo-2-(2-methoxy-phenyl)-vinyl]-4-nitro-benzamide.

A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[l-(azepane-l-carbonyl)-2-(2- methoxy-phenyl)-vinyl]-4-mtro-benzarnide (250 mg, 0.59 mmol) and anhydrous chloroform (10 ml). The reaction was stirred at room temperature for fifteen minutes and calcium carbonate (120 mg, 1.2 mmol) added. The reaction was stirred at room temperature for thirty minutes and transferred to an ice/brine bath and stirring in the bath was continued for an additional twenty minutes. Bromine (0.5M in chloroform, 1.8 ml) was added dropwise. After an additional hour, the reaction mixture was filtered and the solids washed with chloroform. The organic layer was washed with water (2 X 60 ml), saturated aqueous sodium hydrogen sulfite (25 ml), water (2 X 60 ml), saturated sodium bicarbonate (30 ml), water (2 X 75 ml), and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was obtained as a pale yellow solid, 180 mg, 61%) yield, m.p. 220.5-221.6 °C.

Example 19

N-[cyclopropylcarbamoyl-2-(2-methoxy-phenyl)-vinyl]-4-nitro-benzamide.

A dry 200 ml three-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with 4-(2-methoxy-benzylidene)-2-(4- nitro-phenyl)-4H-oxazol-5-one,

(2.74 g, 8.4 mmol) and anhydrous chloroform (50 ml). The reaction was stirred at room temperature for fifteen minutes and cyclopropylamine (0.87 ml, 12.7 mmol) was added dropwise. Stirring was continued for an additional three hours at room temperature. The organic layer was washed with sodium bisulfite (50 ml), water (2 X 75 ml), saturated sodium bicarbonate (75 ml), water (75 ml) and brine (2 X 75 ml). The organic layer was dried .over anhydrous sodium sulfate, filtered and concentrated in vacuo. The final product was triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a yellow solid 3.3 g, 100% yield, m.p. 202.2-203.5 °C.

Example 20

N-[2-bromo-l-cyclopropylcarbamoyl-2-(2-methoxy-phenyl)-vinyl]-4-nitro-benzamide.

A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[cyclopropylcarbamoyl-2-(2- methoxy-phenyl)-vinyl]-4-nitro-benzamide (500 mg, 1.3 mmol) and anhydrous chloroform (20 ml). The reaction was stirred at room temperature for thirty minutes and calcium carbonate (260 mg, 2.6 mmol) added. The reaction was stirred at room temperature for thirty minutes and transferred to an ice/brine bath and stirring in the bath was continued for an additional thirty minutes. Bromine (0.5M in chloroform, 4 ml) was added dropwise. After an additional 1.5 h, the reaction mixture was filtered and the solids washed with chloroform. The organic layer was washed with water (2 X 60 ml), saturated aqueous sodium hydrogen sulfite (25 ml), water (2 X 60 ml), saturated sodium bicarbonate (30 ml), water (2 X 75 ml), and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by column chromatography. The column was eluted with acetone :hexane (1 :1). The fractions containing product were combined and concentrated in vacuo. The product was obtained as an off-white solid, 175 mg, 30% yield, m.p. 201.9-204.1 °C.

Example 21

N-[cyclopentylcarbamoyl-2-(2-methoxy-phenyl)-vinyl]-4-nitro-benzamide.

A dry 100 ml three-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with the compound of formula:

(1.5 g, 4.63 mmol) and anhydrous chloroform (20 ml). The reaction was stirred at room temperature for twenty minutes, transferred to a brine ice bath and stirred an additional thirty minutes. Cyclopentylamine (0.69 ml, 6.94 mmol) was added dropwise. Stirring was continued for an additional 3.5 h at room temperature. The organic layer was washed with water (2 X70 ml), 0.2 N citric acid (40 ml), water (2 X 100 ml), saturated sodium bicarbonate (30 ml), water (2 X 100 ml) and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The final product was triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a yellow solid 1.82 g, 84% yield, m.p. 227.7-230 °C. The material was taken directly into the next step.

Example 22

N-[2-bromo-l-cyclopentylcarbamoyl-2-(2-methoxy-phenyl)-vinyl]-4-nitro-benzamide. A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[cyclopentylcarbamoyl-2-(2- methoxy-phenyl)-vinyl]-4-nitro-benzamide (700 mg, 1.71 mmol), anhydrous chloroform (10 ml), and calcium carbonate (342 mg, 3.42 mmol) added. The reaction was stirred at room temperature for thirty minutes and transferred to an ice/brine bath and stirring in the bath was continued for an additional twenty minutes. Bromine (0.5M in chloroform, 0.52 ml) was added dropwise. After an additional 2 h, the reaction mixture was filtered and the solids washed with chloroform. The organic layer was washed with water (2 X 100 ml), 0.2 N citric acid (30 ml), water (100 ml), saturated sodium bicarbonate (50 ml), water (2 X 100 ml), and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was triturated with diethyl ether, filtered and dried in vacuo. The product was obtained as an off-white solid, 380 mg, 46%) yield, m.p. 215.9-217.9 °C.

Example 23

N-[l-cyclohexylcarbamoyl-2-(2-methoxy-phenyl)-vinyl]-4-nitro-benzamide.

A dry 100 ml three-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with the compound of formula

(1.5 g, 4.63 mmol) and anhydrous chloroform (20 ml). The reaction was stirred at room temperature for twenty minutes, transferred to a brine ice bath and stirred an additional fifteen minutes. Cyclohexylamine (0.8 ml, 6.94 mmol) was added dropwise. Stirring was continued for an additional 3.5 h at room temperature. The organic layer was washed with water (2 X75 ml), 0.2 N citric acid (2 X 25 ml), water (2 X 75 ml), saturated sodium bicarbonate (2 X 30 ml), water (2 X 100 ml) and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The final product was triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a yellow solid 1.8 g, 92% yield, m.p. 238.1-240 °C. The material was taken directly into the next step.

Example 24

N-[2-bromo-l-cyclohexylcarbamoyl-2-(2-methoxy-phenyl)-vinyl]-4-nitro-benzamide.

A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[l-cyclohexylcarbamoyl-2-(2- methoxy-phenyl)-vinyl]-4-nitro-benzamide (700 mg, 1.65 mmol), anhydrous chloroform

(10 ml), and calcium carbonate (330 mg, 3.31 mmol) added. The reaction was stirred at room temperature for thirty minutes and transferred to an ice/brine bath and stirring in the bath was continued for an additional twenty minutes. Bromine (0.5M in chloroform, 5.0 ml) was added dropwise. The reaction was stirred at room temperature for 1.5 h. The reaction mixture was filtered and the solids washed with chloroform. The organic layer was washed with water (2 X 75 ml), 0.2 N citric acid (30 ml), water (2 X 50 ml), saturated sodium bicarbonate (50 ml), water (2 X 50 ml), and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was triturated with diethyl ether, filtered and dried in vacuo. The product was obtained as an off-yellow solid, 340 mg, 41% yield, m.p. 240-241 °C.

Example 25

N-[2-(2-methoxy-phenyl)-l-(thiomorpholine-4-carbonyl)-vinyl]-4-nitro-benzamide.

(1.5 g, 4.63 mmol) and anhydrous chloroform (20 ml). The reaction was stirred at room temperature for twenty minutes, transferred to a brine ice bath and stirred an additional fifteen minutes. Thiomorpholine (0.66 ml, 6.94 mmol) was added dropwise. Stirring was continued for an additional 16 h at room temperature. The reaction mixture was filtered and the yellow solid (product) was washed with water. The filtrate was washed with water (2 X 100 ml), 0.2 N citric acid (30 ml), water (2 X 100 ml), saturated sodium bicarbonate (50 ml), water (2 X 100 ml) and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The solids were combined, triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a yellow solid 1.8 g, 91% yield, m.p. 235.9-237.8 °C. The material was taken directly into the next step.

Example 26

N-[2-bromo-2-(2-methoxy-phenyl)-l-(thiomorpholine-4-carbonyl)-vinyl]-4-nitro- benzamide.

A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[2-(2-methoxy-phenyl)-l- (thiomorpholine-4-carbonyl)-vinyl]-4-nitro-benzamide (700 mg, 1.64 mmol), anhydrous chloroform (15 ml), anhydrous 1,2-dichloroethane (15 ml) and calcium carbonate (330 mg, 3.3 mmol). The reaction was stirred at room temperature for twenty minutes and transferred to an ice/brine bath and stirring in the bath was continued for an additional thirty minutes. Bromine (0.5M in chloroform, 5.0 ml) was added dropwise. The reaction was stirred at 0 °C for 1.5 h. The reaction mixture was filtered and the organic layer was washed with water (2 X 75 ml), saturated sodium bicarbonate (50 ml), water (2 X 75 ml), and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography. The column was eluted with ethyl acetate :hexane (1:1 v:v). The fractions containing the product were combined and concentrated in vacuo. The product was triturated with diethyl ether, filtered and dried in vacuo. The product was obtained as a yellow solid, 160 mg, 19% yield, m.p. 223.2-228.4 °C.

Example 27

N~[2~(2~methoxy-phenyl)-l-(morpholine-4-carbonyl)-vinyl]-4-nitro-benzamide.

(1.5 g, 4.63 mmol) and anhydrous chloroform (20 ml). The reaction was stirred at room temperature for twenty minutes, transferred to a brine ice bath and stirred an additional fifteen minutes. Morpholine (0.6 ml, 6.94 mmol) was added dropwise and stirring was continued in the bath for 1 h. Stirring was continued at room temperature while the reaction was monitored by TLC. Once complete, the reaction was washed with water (2 X 75 ml), 0.2 N citric acid (30 ml), water (2 X 70 ml), saturated sodium bicarbonate (2 X 25 ml), water (2 X 75 ml) and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The solids were combined, triturated with diethyl ether, filtered and dried in vacuo. The product was triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a yellow solid 1.8 g, 94% yield, m.p. 197.4-199.1 °C. The material was taken directly into the next step. Example 28

N-[2-bromo-2-(2-methoxy-phenyl)-l-(morpholine-4-carbonyl)-vinyl]-4-nitro-benzamide.

A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[2-(2-methoxy-phenyl)-l- (morpholine-4-carbonyl)-vinyl]-4-nitro-benzamide (700 mg, 1.70 mmol), anhydrous chloroform (15 ml), and calcium carbonate (340 mg, 3.4 mmol). The reaction was stirred at room temperature for twenty minutes and transferred to an ice/brine bath and stirring in the bath was continued for an additional thirty minutes. Bromine (0.5M in chloroform, 5.2 ml) was added dropwise. The reaction was stirred at 0 °C for 0.5 h and then at room temperature for 3.5 h. The reaction mixture was filtered and the solids were washed with chloroform. The organic layer was washed with water (2 X 75 ml), saturated sodium bicarbonate (2 X 30 ml), water (2 X 100 ml), and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was triturated with diethyl ether, filtered and dried in vacuo. The product was obtained as a pale yellow solid, 550 mg, 66% yield, m.p. 217.5-219.6 °C.

Example 29

N-[2- (2-methoxy-phenyl) -1- (pyrrolidine-1 -carbonyl) -vinyl] -4-nitro-benzamide.

(1.5 g, 4.63 mmol) and anhydrous chloroform (20 ml). The reaction was stirred for twenty minutes in a brine ice bath. Pyrrolidine (0.6 ml, 6.94 mmol) was added dropwise and stirring was continued in the bath for 1 h. Stirring was then continued at room temperature for 16 h. Once complete, the reaction was washed with water (2 X 75 ml), 0.2 N citric acid (50 ml), water (2 X 75 ml), saturated sodium bicarbonate (30 ml), water (2 X 75 ml) and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a yellow solid 1.7 g, 93% yield, m.p. 193- 193.5 °C. The material was taken directly into the next step.

Example 30

N-[2-bromo-2-(2-methoxy-phenyl)-l-(pyrrolidine-l-carbonyl)-vinyl]-4-nitro-benzamide.

A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[2-(2-methoxy-phenyl)-l- (pyrrolidine-1-carbonyl)- vinyl] -4-nitro-benzamide (700 mg, 1.77 mmol), anhydrous chloroform (20 ml), and calcium carbonate (354 mg, 3.54 mmol). The reaction was stirred at room temperature for thirty minutes and transferred to an ice/brine bath and stirring in the bath was continued for an additional twenty minutes. Bromine (0.5M in chloroform, 5.3 ml) was added dropwise. The reaction was stirred at room temperature for 3.5 h. The reaction mixture was filtered and the solids were washed with chloroform (2 X 150 ml). The organic layer was washed with water (2 X 100 ml), saturated sodium bicarbonate (50 ml), water (2 X 100 ml), and brine (2 X 100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified on a silica gel chromatography column, which was eluted with ethyl acetate :hexane (1:1, v:v). The fractions containing the product were combined and concentrated in vacuo. The product was triturated with diethyl ether, filtered and dried in vacuo. The product was obtained as a pale yellow solid, 600 mg, 71.5% yield.

Example 31

2-(4-nitro-phenyl)-4-pyridin-3-ylmethyl-4H-oxazol-5-one A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar and condenser was continuously purged with nitrogen and charged with 4-nitrohippuric acid (8.0 g, 35.69 mmol), sodium acetate (3.5 g, 42.83 mmol) and acetic anhydride (10 ml, 44.61 mmol). The reaction flask was placed in a 60 °C oil bath and 3- pyridinecarboxaldehyde (4.0 ml, 42.39 mmol) added. The oil bath temperature was increased to 110 °C and stirring was continued at this temperature for 1 h. A precipitate formed over this period of time. The reaction was cooled to room temperature and the solid was collected by filtration. The dark solid was washed with hot water (1.5 L) and cold methanol (1 L). The product was finally triturated with hexane (500 ml), filtered and dried in vacuo. The product, a yellow-green solid, 4.03 g, 38% yield was used directly in the next step.

Example 32

4-nitro-N-[l -(piperidine- l-carbonyl)-2-pyridin-3-yl-vinyl]-benzamide.

A dry 250 ml three-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with 2-(4-nitro-phenyl)-4-pyridin-3- ylmethyl-4h-oxazol-5-one (1.5 g, 4.63 mmol) and anhydrous dichloromethane (50 ml). The reaction was stirred at room temperature for fifteen minutes and then in a brine ice bath for thirty minutes. Piperidine (1.5 ml, 14.91 mmol) was added dropwise and stirring was continued in the bath for 2 h. Stirring was then continued at room temperature for 16 h. Once complete, the reaction was washed with water (100 ml, 2 X 150 ml)), 0.2 N citric acid (2 X 100 ml), water (2 X 100 ml), saturated sodium bicarbonate (100 ml), water (2 X 100 ml) and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified using a silica gel chromatography column that was eluted with chloroform:methanol (95:5, v:v). The products (2 isomers) were individually isolated.

Top spot by TLC product 2.0g, 38.8%. Bottom spot by TLC product 400 mg.

Example 33 N-[2-bromo-l-(piperidine-l-carbonyl)-2-pyridin-3-yl-vinyl]-4-nitro-benzamide. A dry 250 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with 4-nitro-N-[l-(piperidine-l-carbonyl)- 2-pyridin-3-yl- vinyl] -benzamide (1.63 g, 4.3 mmol), anhydrous dichloromethane (100 ml). The reaction was stirred at room temperature to produce a solution and the reaction flask was then placed in a brine/ice bath and stirred for fifteen minutes. DABCO (0.724 g, 6.5 mmol) was added and stirring was continued an additional thirty minutes. Bromine (0.3 ml in 30 ml of anhydrous dichloromethane) was added dropwise over a fifteen minute period. The reaction was stirred in the bath for 1.5 h and then overnight at room temperature. The reaction mixture was washed with water (2 X 200 ml), 0.2 N citric acid (50 ml), water (2 X 150 ml), and brine (2 X 200 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a solid (1.58 g, 80% yield).

Example 34 Amino- (dimethoxy-phosphoryl) -acetic acid methyl ester.

A 500 ml Parr flask was charged with N-(benzyloxycarbonyl)-alpha-phosphonoglycine, trimethyl ester (30 g, 90.6 mmol) and methanol (100 ml). Next was added a mixture containing 10% palladium on carbon (2.7 g) and methanol (50 ml). The flask was charged with hydrogen gas (50 psi) and shaken for 1.5 h. The mixture was filtered through a Celite plug and the Celite was washed with methanol. The reaction was concentrated in vacuo to pale yellow oil. The crude product (17.3 g, 96.9% yield) was diluted with benzene (4 X 200 ml) and concentrated in vacuo. The material was used directly in the next step.

Example 35

(Dimethoxy-phosphoryl)-(4-nitro-benzoylamino)-acetic acid methyl ester.

A dry 300 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with amino-(dimethoxy-phosphoryl)- acetic acid methyl ester (17.4 g, 88.3 mmol), anhydrous DMF (150 ml), and diisopropylethylamine (31 ml, 176.6 mmol). The reaction was stirred at room temperature for 20 minutes and 4-nitrobenzoic acid (16.23 g, 97.13) was added. The reaction flask was placed in a brine/ice bath and stirring was continued. A solution containing HATU (38.61 g, 101.51 mmol) and anhydrous DMF (100 ml) was added dropwise. Once the addition was complete, the bath was removed and the reaction was stirred at room temperature overnight. DMF was removed in vacuo and the crude product was diluted with ethyl acetate (200 ml). The organic layer was washed with 1.0M HC1 (50 ml), water (2 X 100 ml), a saturated solution of sodium bicarbonate (2 X 75 ml), water (2 X 100 ml), and brine (2 X 150 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with diethyl ether, filtered and dried. The product was obtained as a tan-brown solid 11.6 g, 38%, mp 134-136 °C.

Example 36

2-(4-nitro-benzoylamino)-3(-pyridin-3-y)l-acrylic acid methyl ester.

A dry 100 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with (dimethoxy-phosphoryl)-(4-nitro- benzoylamino)-acetic acid methyl ester (1.73 g, 5 mmol) and anhydrous chloroform (20 ml). TMG (633 mg, 5.5 mmol) was added dropwise. After twenty minutes at room temperature, 3-pyridylcarboxaldehyde (590 mg, 5.5 mmol) in anhydrous chloroform (10 ml) was added dropwise. The reaction was stirred at room temperature overnight. The reaction was diluted with chloroform (100 ml), washed with water (3 X 100 ml), dried, filtered, and concentrated in vacuo. The product was crystallized from acetone:hexane, filtered, and dried. The product was isolated as a light brown solid, 770 mg, 47%, m.p.

169-171 °C.

Example 37

2-(4-nitro-benzoylamino)-3-(pyridin-3-yl)-acrylic acid.

To a well-stirred solution of 2-(4-nitro-benzoylamino)-3-pyridin-3-yl-acrylic acid methyl ester (654.6 mg, 2 mmol) in THF (5 ml) was added a solution of 2N lithium hydroxide (1 ml, 2 mmol) and the reaction was monitored by HPLC. Once complete, the reaction was neutralized with IN HC1 and diluted with water. The product precipitated out of solution as a yellow solid. The product was collected and dried in vacuo. The yield was 230 mg, 36%. The product's melting point was 204-206 °C. Example 38

4-nitro-N-[l - (piperidine- 1 -carbonyl) -2 (-pyridin-3-yl) -vinyl] -benzamide

A dry 25 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with 2-(4-nitro-benzoylamino)-3-pyridin-

3-yl-acrylic acid methyl ester (156 mg, 0.55 mmol), anhydrous DMF (1 ml), piperidine (47 mg, 0.55 mmol), and N,N-diisopropylethylamine (129 mg, 1 mmol) and stirred at 0 °C. A mixture containing HATU (212 mg, 0.55 mmol) in anhydrous DMF (0.5 ml) was added and the reaction was monitored by HPLC. Once complete, the reaction was quenched by the addition of water. The reaction was diluted with dichloromethane and the two resulting layers were separated. The organic layer was washed with water (4 X 50 ml), dried, filtered, and concentrated in vacuo. To afford the crude product in a 100% yield.

Example 39

N-[2-bromo-l-(piperidine-l-carbonyl)-2(-pyridin-3-yl-vinyl)]-4-nitro-benzamide.

A dry 25 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with 4-nitro-N- [1 -(piperidine- 1 -carbonyl)- 2-pyridin-3-yl- vinyl] -benzamide (114 mg, 0.3 mmol), anhydrous chloroform (3 ml), and calcium carbonate (45 mg, 0.45 mmol). The reaction transferred to an ice/brine bath and stirring in the bath was continued for an additional twenty minutes. Bromine (0.5M in chloroform, 0.75 ml) was added dropwise. The reaction was stirred at room temperature for 5 min. The reaction mixture was diluted with dichloromethane (25 ml). The reaction was washed with saturated sodium bicarbonate solution (30 ml), saturated sodium metabisulfite (2 X 30 ml), water (2 X 30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified on a silica gel chromatography column, which was eluted with hexane: acetone (2:1, v:v). The fractions containing the product were combined and concentrated in vacuo. The product was triturated with diethyl ether, filtered and dried in vacuo. The product was obtained as a pale yellow solid, Z:E (1 :2.3) mixture 43%. The components were separated by HPLC to afford the pure E and Z isomers. Example 40

2-(4-nitro-benzoylamino)-3(-pyridin-4-y)l-acrylic acid methyl ester.

A dry 250 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with the compound of formula

(1.0 g, 2.9 mmol), anhydrous chloroform (50 ml), and 1,1,3,3,-tetramethylguanidine (633 mg, 5.5 mmol) was added dropwise. After twenty minutes at room temperature, 4- pyridylcarboxaldehyde (590 mg, 5.5 mmol) in anhydrous chloroform (0 ml) was added dropwise. The reaction was stirred at room temperature overnight. The reaction was diluted with chloroform (100 ml), washed with water (3 X 100 ml), dried, filtered, and concentrated in vacuo. The product was crystallized from acetone :hexane, filtered, and dried. The product was isolated as a light brown solid, 770 mg, 47%, m.p. 169-171 °C.

Example 50

2-(4-nitro-benzoylamino)-3(-pyridin-4-y)l-acrylic acid.

A 100 ml round-bottomed flask was charged with 2-(4-nitro-benzoylamino)-3-pyridin-4- yl-acrylic acid methyl ester (500 mg, 1.5 mmol), and dioxane (15 ml) and the reaction was stirred at room temperature for twenty minutes. A solution of 2M LiOH (2.5 ml) was added and the reaction was stirred at room temperature overnight. The pH was adjusted to 5.5-6.0 by addition of 1.0M HC1. The reaction was concentrated in vacuo and diluted with water (50 ml). The aqueous layer was extracted with n-butanol (6 X 100 ml). The organic fractions were combined and extracted with brine (2 X 100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was triturated with diethyl ether, filtered, and dried in vacuo at 50 °C overnight. The product was used directly in the next step. Example 51

4-Nitro-N-[l -piperidine- l-carbonyl)-2(-pyridin-4-yl-vinyl)] -benzamide

4-yl-acrylic acid (500 mg, 1.6 mmol), anhydrous DMF (5 ml), and N,N- diisopropylethylamine (414 mg, 3.2 mmol) and stirred at room temperature for twenty minutes. Piperidine (0.2 ml, 1.9 mmol) was added and the reaction was stirred an additional ten minutes at room temperature. The reaction flask was transferred to a brine- ice bath and stirred for fifteen minutes. A mixture containing HATU (685 mg, 1.8 mmol) in anhydrous DMF (5 ml) was added. The reaction was stirred in the bath for fifteen minutes and then at room temperature as it was monitored by HPLC. Once complete, the reaction was concentrated in vacuo. The crude product was diluted with ethyl acetate (50 ml) and water (50 ml). The layers were separated and the organic layer was washed with water (2 X 50 ml), saturated aqueous sodium bicarbonate (2 X 30 ml), water (2 X 50 ml), and brine (2 X 50ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The product was triturated with diethyl ether, filtered, and dried in vacuo. The product was obtained as a pale brown solid, 36 mg, 6 % yield, m.p. 236.9-239.3 °C. The product was used directly in the next step.

Example 52

N-[2-bromo-l-(piperidine-l-carbonyl)-2-(pyridin-4-yl-viny)l]-4-nitro-benzamide.

A dry 10 ml round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with 4-Nitro-N-[l-piperidine-l-carbonyl)-2-pyridin-4- yl-vinyl] -benzamide (38 mg, 0.1 mmol), and anhydrous chloroform (1 ml) at 0 °C. A solution containing DABCO (17 mg, 0.15 mmol) in anhydrous chloroform (0.5 ml) was added followed by a 0.5M solution of bromine in chloroform (0.2 ml, 0.1 mmol). Additional 0.5M bromine in chloroform was added (2 X 0.5 ml). After work-up, the product was purified on a flash chromatography column that was eluted with hexane:acetone (1:1, v:v). The fractions containing product were combined and concentrated. The product was obtained as a white solid 16 mg, 35% yield. The material was a mixture of isomers with a Z:E ratio of 10:1.

Example 53

3-Furan-2-yl-2-(4-nitro-benzoylamino)-acrylic acid methyl ester.

A dry 100 ml round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with (dimethoxy-phosphoryl)-(4-nitro- benzoylamino)-acetic acid methyl ester (1.7 g, 4.9 mmol), anhydrous chloroform (25 ml). The reaction was stirred at room temperature for fifteen minutes, transferred to a brine ice bath and stirred for an additional twenty minutes. 1,1,3,3,-Tetramethylguanidine (0.62 g, 5.4 mmol) was added dropwise and stirring was continued for fifteen minutes. 2-

Furaldehyde (0.45 ml, 5.4 mmol) was added and the reaction was stirred in the bath for fifteen minutes and then at room temperature for three hours. The reaction was washed with water (2 X 100 ml), 1M HC1 (20 ml), water (2 X 100 ml), ), saturated aqueous sodium bicarbonate (30 ml), water (2 X 100 ml), and brine (2 X 100 ml). The reaction was dried over sodium sulfate, filtered, and concentrated in vacuo. The product was isolated as a pale yellow solid, 770 mg, 90%, m.p. 169.9-170.3 °C,

Example 54

3-Furan-2-yl-2-(4-nitro-benzoylamino)-acrylic acid.

A 100 ml round-bottomed flask was charged with 3-Furan-2-yl-2-(4-nitro-benzoylamino)- acrylic acid methyl ester (750 mg, 2.37 mmol), and dioxane (20 ml) and the reaction was stirred at room temperature for thirty minutes. The flask was transferred to a brine ice bath and stirred for an additional thirty minutes. A solution of 2M LiOH (2.5 ml) was added dropwise and stirring was continued for thirty minutes. The reaction was stirred at room temperature for four hours and worked up in the usual manner. The product was triturated from diethyl ether, filtered and dried in vacuo. The product was isolated as a yellow solid, 0.65 g, 92% yield, and used immediately in the next step.

Example 55

N-[2-Furan-2-yl-l-(piperidine-l-carbonyl)-vinyl]-4-nitro-benzamide A dry 100 ml round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with 3-Furan-2-yl-2-(4-nitro- benzoylamino)-acrylic acid (650 mg, 2.2 mmol), anhydrous DMF (30 ml), and N,N- diisopropylethylamine (0.85 ml, 4.84 mmol) and stirred at room temperature for twenty minutes. Piperidine (0.3 ml, 2.64 mmol) was added and the reaction flask was transferred to a brine-ice bath and stirred for thirty minutes. A solution containing HATU (912 mg, 2.4 mmol) in anhydrous DMF (10 ml) was added. The reaction was stirred in the bath for thirty minutes and then at room temperature overnight. Once complete, the reaction was concentrated in vacuo. The crude product was diluted with ethyl acetate (50 ml) and water (50 ml). The layers were separated and the organic layer was washed with water (2 X 50 ml), saturated aqueous sodium bicarbonate (2 X 30 ml), water (2 X 50 ml), and brine (2 X 50ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The product was triturated with diethyl ether, filtered, and dried in vacuo. The product was obtained as a green-yellow solid, 600 mg, 74 % yield, m.p. 184.6-185.2 °C. The product was used directly in the next step.

Example 56

N-[-2- (5-bromo-furan-2-yl)-l- (piperidine- 1-carbonyl) -vinyl] -4-nitro-benzamide .

A 10 ml round-bottomed flask was charged with N-[2-Furan-2-yl-l -(piperidine- 1- carbonyl)-vinyl]-4-nitro-benzamide (74 mg, 0.2 mmol), anhydrous chloroform (2 ml), and calcium carbonate (30 mg, 0.3 mmol). The reaction was cooled in a brine ice bath and a 0.5M solution of bromine in chloroform (0.4 ml, 0.2 mmol) was added dropwise. After two minutes additional bromine solution was added (0.2 ml). After the usual work-up, the product was purified on a flash chromatography column that was eluted with ethyl acetate:hexane (1:1, v:v). The fractions containing product were combined and concentrated in vacuo.

Example 57

N-[2-Bromo-2-furan-2-yl-l-(piperidine-l-carbonyl)-vinyl]-4-nitro-benzamide. A dry 10 ml round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[2-Furan-2-yl-l-(piperidine-l-carbonyl)-vinyl]- 4-nitro-benzamide (74 mg, 0.2 mmol), anhydrous chloroform (2 ml), and calcium carbonate (30 mg, 0.3 mmol). The reaction was cooled to -15 °C and bromine (0.5M in chloroform, 0.4 ml, 0.2 mmol) was added dropwise. The reaction was stirred at room temperature for 5 min. The reaction mixture was diluted with dichloromethane (25 ml). The reaction was washed with saturated sodium bicarbonate solution (30 ml), saturated sodium metabisulfite (2 X 30 ml), water (2 X 30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified on a silica gel chromatography column, which was eluted with hexane:ethyl acetate (1 :1, v:v). The fractions containing the product were combined and concentrated in vacuo. The product was obtained as a yellow solid, 47 mg, 52% yield.

Example 58

3-Benzo[l,3]dioxol-4-yl-2-(4-nitro-benzoylamino)-acrylic acid methyl ester.

A dry 200 ml round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with the compound of formula

(1 g, 2.9 mmol), anhydrous chloroform (40 ml), and 1,1,3,3,-tetramethylguanidine (0.37 g, 3.2 mmol). Stirring was continued at room temperature for twenty minutes and 2,3- (methylenedioxy)-benzaldehyde (0.4 ml, 3.5 mmol) added. The reaction was stirred at room temperature overnight. The reaction was washed with water (3 X 100 ml), 0.2N citric acid (50 ml), water (2 X 150 ml), ), saturated aqueous sodium bicarbonate (50 ml), water (2 X 150 ml), and brine (2 X 150 ml). The reaction was dried over sodium sulfate, filtered, and concentrated in vacuo. The product was triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a pale yellow solid, 820 mg, 76%, m.p. 182.7-184.9 °C.

Example 59

3-Benzo[l, 3]dioxol-4-yl-2-(4-nitro-benzoylamino)-acrylic acid.

A 100 ml round-bottomed flask was charged with 3-Benzo[l,3]dioxol-4-yl-2-(4-nitro- benzoylamino)-acrylic acid methyl ester (500 mg, 1.35 mmol), and dioxane (10 ml) and the reaction was stirred at room temperature for twenty minutes. A solution of 2M LiOH (2.5 ml) was added dropwise and stirring was continued overnight at room temperature. The reaction was adjusted to pH = 5 by the addition of 1.0M HC1. The dioxane was removed in vacuo and wateπethyl acetate (50:50, 200 ml) added. The aqueous layer was extracted with ethyl acetate (2 X 100 ml) and the organic fractions were combined, and washed with brine (2 X 150 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The product was triturated from diethyl ether, filtered and dried in vacuo. The product was isolated as an off- white solid, 0.38 g, 79% yield, m.p.

239.6-244.2 °C, and used immediately in the next step.

Example 60

N-[2-Benzo[l,3]dioxol-4-yl-l-(piperidine-l-carbonyl)-vinyl]-4-nitro-benzamide.

A dry 25 ml round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with 3-Benzo[l,3]dioxol-4-yl-2-(4-nitro- benzoylamino)-acrylic acid (300 mg, 0.84 mmol), anhydrous DMF (5 ml), and N,N- diisopropylethylamine (0.3 ml, 1.7 mmol) and stirred at room temperature for twenty minutes. Piperidine (0.1 ml, 1.01 mmol) was added and the reaction flask was transferred to a brine-ice bath and stirred for twenty minutes. A solution containing HATU (350 mg, 0.93 mmol) in anhydrous DMF (3 ml) was added. The reaction was stirred in the bath for thirty minutes and then at room temperature overnight. Once complete, the reaction was concentrated in vacuo. The crude product was diluted with ethyl acetate (50 ml) and water (50 ml). The layers were separated and the organic layer was washed with water (2 X 60 ml), saturated aqueous sodium bicarbonate (35 ml), water (2 X 50 ml), and brine (100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The product was triturated with diethyl ether, filtered, and dried in vacuo. The product was obtained as a pale yellow solid, 290 mg, 82 % yield, m.p. 169.9-171.7 °C. The product was used directly in the next step.

Example 61

N-[2-Benzo[l,3]dioxol-4-yl-2-bromo-l-(piperidine-l-carbonyl)-vinyl]-4-nitro-benzamide.

A dry 10 ml round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[2-Benzo[l,3]dioxol-4-yl-l-(piperidine-l- carbonyl)-vinyl]-4-nitro-benzamide (66 mg, 0.156 mmol), anhydrous chloroform (1 ml), and calcium carbonate (22.5 mg, 0.225 mmol). The reaction was cooled to 0 °C and bromine (0.5M in chloroform, 0.3 ml) was added dropwise. The reaction was stirred for thirty minutes and bromine (0.5M in chloroform, 0.31ml) added. After an additional fifteen minutes additional bromine (0.5M in chloroform, 0.05 ml) was added. The reaction was filtered and diluted with dichloromethane. The solvent was removed in vacuo and dichloromethane (10 ml) added. The reaction was washed with saturated sodium bicarbonate solution (2 X 10 ml), saturated sodium metabisulfite (2 X 20 ml), water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was crystallized from dichloromethane:ethyl acetate :hexane. 30 mg, 38% yield. The product was isolated as a 5:1 mixture of Z:E isomers.

Example 62 A dry 50 ml 3-necked round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with the compound of formula:

(380 mg, 1.17 mmol) and anhydrous chloroform (10 ml). The reaction was stirred at room temperature for fifteen minutes and 4-methylpiperidine (0.14 g, 1.41 mmol) was added.

Stirring was continued for an additional four hours at room temperature. The reaction was diluted with water (20 ml) and the aqueous and organic layers were separated. The organic layer was washed with 0.2N citric acid (20 ml), water (2 X 50 ml) and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The final product was triturated with diethyl ether, filtered and dried in vacuo. The product was isolated as a pale yellow solid 150-mg, 47% yield, m.p. 167.2-169.4 °C.

Example 63

A dry 50 ml round-bottomed flask equipped with a magnetic stirring bar was continuously purged with nitrogen and charged with N-[2-(2-Methoxy-phenyl)-l-(4-methyl-piperidine- l-carbonyl)-vinyl]-4-nitro-benzamide (250 mg, 0.59 mmol), anhydrous chloroform (10 ml), and calcium carbonate (120 mg, 1.2 mmol). The reaction was cooled to 0 °C and bromine (0.5M in chloroform, 1.5 equivalents) added. The reaction was monitored by TLC. The reaction was filtered and diluted with chloroform. The reaction was washed with saturated sodium bisulfite (50 ml), water (2 X 75 ml), saturated sodium bicarbonate solution (2 X 75 ml), 20 ml), and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was triturated with diethyl ether, filtered, and dried in vacuo. The product was isolated as an off-white solid 150-mg, 51% yield, m.p. 191.5-192.8 °C.

Example 64 (Dimethoxy-phosphoryl)-phenylacetylamino-acetic acid methyl ester.

A dry 100 ml round-bottomed flask with an inert nitrogen atmosphere was charged with phenylacetic acid (1.47 g, 10.8 mmol), anhydrous tetrahydrofuran (10 ml), and 1,1'- carbonyldiimidazole (2.19 g, 16.2 mmol), and the solution was stirred at room temperature for one hour. Amino-(dimethoxy-phosphoryl)-acetic acid methyl ester (9.06 mmol) in anhydrous tetrahydrofuran (10 ml) was added and the reaction was stirred for an additional sixteen hours at room temperature. The reaction was diluted with ethyl acetate (100 ml), washed with IN HC1, a saturated solution of sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was obtained as a white solid, 1.6 g, 56% yield and had a melting point - 114- 115.5 °C.

Example 65

Benzoylamino-(dimethoxy-phosphoryl) -acetic acid methyl ester.

A dry 100 ml round-bottomed flask with an inert nitrogen atmosphere was charged with benzoyl chloride (1.26 ml, 10.87 mmol), anhydrous dichloromethane (10 ml), and triethylamine(2.17 ml, 16.3 mmol). The solution was cooled to 0 °C in a brine ice bath and a solution containing amino-(dimethoxy-phosphoryl)-acetic acid methyl ester (9.06 mmol) in anhydrous dichloromethane (10 ml) was added. The reaction was stirred for one hour at 0 °C, and then at room temperature for sixteen hours. The reaction was diluted with ethyl acetate (100 ml), washed with water, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified on a silica gel flash chromatography column which was eluted with a gradient of 97:3 to 95:5 dichloromethane methanol. The fractions containing the product were combined and concentrated. The product was obtained as a solid, 1.61 g, 59% yield, and had a melting point = 112-114 °C. Example 66

(Dimethoxy-phosphoryl)-[(furan-2-carbonyl)-amino] -acetic acid methyl ester.

The compound was synthesized accordin to the procedure for benzoylamino-(dimethoxy- phosphoryl)-acetic acid methyl ester, substituting 2-furoyl chloride for benzyl chloride. The product was obtained as a solid, 1.31 g, 49% yield, and had a melting point = 102- 103.5°C.

Example 67

(Dimethoxy-phosphoryl)-[(2, 4-dimethyl-thiazole-5-carbonyl)-amino] -acetic acid methyl ester.

A dry 100 ml round-bottomed flask with an inert nitrogen atmosphere was charged with amine (9.06 mmol), anhydrous DMF (20 ml), diisopropylethylamine (2.3 ml, 12.96 mmol), a thiazole (1.7 g, 10.8 mmol), and HATU (6.16 g, 16.2 mmol). The reaction was stirred at room temperature for sixteen hours and diluted with ethyl acetate (100 ml). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified on a silica gel flash chromatography column that was eluted with 97:3 dichloromethane :methanol. The fractions containing the product were combined and concentrated. The product was obtained as a solid, 2.27 g, 74.5% yield, and had a melting point = 118.5-120.5 °C.

Example 68

2-Benzoylamino-3-(2-methoxy-phenyl)-acrylic acid methyl ester.

A dry 250 ml round-bottomed flask with an inert nitrogen atmosphere was charged with, anhydrous chloroform (40 ml), benzoylamino-(dimethoxy-phosphoryl)-acetic acid methyl ester (1.47 g, 4.9 mmol), and 1,1,3,3-tetramethylguanidine (0.92 ml, 7.35 mmol). The solution was stirred at room temperature for twenty minutes and O-anisaldehyde (0.65 ml, 5.39 mmol) added. The reaction was stirred at room temperature for sixteen hours and then heated at reflux for an additional three hours. The reaction was cooled to room temperature and diluted with ethyl acetate (100 ml). The organic layer was washed with water (10 ml), brine (3 X 10 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified on a silica gel flash chromatography column that was eluted with a 20:80 to 30:70 ethyl acetate :hexane gradient. The fractions containing the product were combined and concentrated in vacuo. The product was obtained as a solid, 900 mg, 59.1%, and had a melting point = 159-160 °C.

Example 69

2-[(Furan-2-carbonyl)-amino]-3-(2-methoxy-phenyl)-acrylic acid methyl ester.

The procedure used to synthesize 2-benzoylamino-3-(2-methoxy-phenyl)-acrylic acid methyl ester was used. The starting material in this example is (dimethoxy-phosphoryl)- [(furan-2-carbonyl)-amino] -acetic acid methyl ester

Example 70

3-(2-Methoxy-phenyl)-2-phenylacetylamino-acrylic acid methyl ester

The procedure used to synthesize 2-benzoylamino-3-(2-methoxy-phenyl)-acrylic acid methyl ester was used. The actual starting material in this example is (dimethoxy- phosphoryl)-phenylacetylamino-acetic acid methyl ester. The product was isolated in a 98% yield and had a melting point = 113.5-114.5 °C.

Example 71

2-[(2,4-Dimethly-thia∑ole-5-carbonyl)-amino]-3-(2-methoxy-phenyl)-acrylic acid methyl ester

The procedure used to synthesize 2-benzoylamino-3-(2-methoxy-phenyl)-acrylic acid methyl ester was used. The actual starting material in this example is (dimethoxy- phosphoryl)-[(2,4-dimethyl-thiazole-5-carbonyl)-amino]-acetic acid methyl ester. The flash chromatography column gradient in this case was 35 to 70% ethyl acetate:hexane.

The product was isolated in a 55% yield and had a melting point = 98-100.5 °C.

Example 72 2-Benzoylamino-3-(2-methoxy-phenyl)-acrylic acid

To a well stirred solution of 2-benzoylamino-3-(2-methoxy-phenyl)-acrylic acid methyl ester (778 mg, 2.5 mmol) in THF (6.25 ml) was added a 2N LiOH solution (1.25 ml, 2.5 mmol). The reaction was monitored by thin layer chromatography. Once complete, the reaction was neutralized with IN HCl (2.5 ml) and the THF was removed in vacuo. The product precipitated from solution and was collected by filtration. The product was dried in a vacuum oven at 50 °C. The product was isolated as a yellow solid, 690 mg, 92% yield.

Example 73

2-[(Furan-2-carbonyl)-amino]-3-(2-methoxy-phenyl)-acrylic acid

To a well stirred solution of 2-[(furan-2-carbonyl)-amino]-3-(2-methoxy-phenyl)-acrylic acid methyl ester (904 mg, 3 mmol) in THF (7.55 ml) was added a 2N LiOH solution (1.5 ml, 3 mmol). The reaction was monitored by thin layer chromatography (hexane:acetone 1:1). Once complete, the reaction was diluted with IN NaOH (20 ml) and washed with dichloromethane (2 X 20 ml). It was neutralized with IN HCl and extracted with ethyl acetate (3 X 50 ml). The organic fractions were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The product was isolated as a yellow solid,

570 mg, 66% yield.

Example 74

3-(2-Methoxy-phenyl)-2-phenylacetylamino-acrylic acid

To a well stirred solution of 3-(2-methoxy-ρhenyl)-2-phenylacetylamino-acrylic acid methyl ester (1.3 g, 4 mmol) in THF (10 ml) was added a 2N LiOH solution (2 ml, 4 mmol). The reaction was monitored by thin layer chromatography (hexane:acetone, 1:1). Once complete, the reaction was neutralized with IN HCl (4 ml) and the THF was removed in vacuo. The product precipitated from solution and was collected by filtration. The product was dried in a vacuum oven at 50 °C overnight. The product was isolated as a yellow solid, 1.0 g, 80% yield.

Example 75

2-[ (2, 4-Dimethyl-thiazole-5-carbonyl)-amino]-3-(2-methoxy-phenyl)-acrylic acid

To a well stirred solution of 2-[(2,4-dimethly-thiazole-5-carbonyl)-amino]-3-(2-methoxy- phenyl)-acrylic acid methyl ester (1.04 g, 3 mmol) in THF (7.5 ml) was added a 2N LiOH solution (1.5 ml, 3 mmol). The reaction was monitored by thin layer chromatography (hexane:acetone 1:1). After 2 days, more 2N LiOH (0.5 ml) was added and stirring was continued for an additional six hours. The THF was removed in vacuo and the reaction was diluted with water ( -20 ml), and extracted with dichloromethane (2 X 20 ml). The aqueous layer was neutralized with IN HCl and extracted with dichloromethane (3 X 20 ml). The organic fractions were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The product was isolated as a white solid, 0.75 g, 75% yield.

Example 76

N-[2-(2-Methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-2-phenyl-acetamide

A dry 25 ml three-necked round-bottomed flask under a nitrogen atmosphere was charged with 3-(2-Methoxy-phenyl)-2-phenylacetylamino-acrylic acid (778 mg, 2.5 mmol), anhydrous DMF (5 ml), diisopropylethylamine(0.871 ml, 5 mmol) and piperidine (234 mg, 2.75 mmol).The reaction was transferred to a brine ice bath and cooled to 0 °C. A solution containing HATU (1.062 g, 2.75 ml) and anhydrous DMF (2.5 ml) was slowly added. The ice bath was removed and stirring was continued for four hours at room temperature. The reaction was diluted with ethyl acetate (60 ml), washed with water (6 X 60 ml), dried, filtered and concentrated in vacuo. The product was crystallized from acetone to afford a yellow solid 642 mg, 68% yield.

Example 77

N-[2-(2-Methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-benzamide A dry 25 ml three-necked round-bottomed flask under a nitrogen atmosphere was charged with 2-benzoylamino-3-(2-methoxy-phenyl)-acrylic acid (594.2 mg, 2. mmol), anhydrous DMF (4 ml), diisopropylethylamine(0.69 ml, 4 mmol) and piperidine (187 mg, 2.2 mmol).The reaction was transferred to a brine ice bath and cooled to 0 °C. A suspension containing HATU (0.85 g, 2.2 ml) and anhydrous DMF (2 ml) was slowly added. The ice bath was removed and stirring was continued for four hours at room temperature. The reaction was diluted with ethyl acetate (60 ml), washed with water (6 X 60 ml), dried, filtered and concentrated in vacuo. The product was crystallized from acetone:water to afford a yellow solid 578 mg, 78% yield, m.p. 164-166 °C.

Example 78

N-[2-(2-Methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-2,4-dimethyl-thiazole-5- carboxylic amide

A dry 25 ml three-necked round-bottomed flask under a nitrogen atmosphere was charged with 2-[(2,4-dimethyl-thiazole-5-carbonyl)-amino]-3-(2-methoxy-phenyl)-acrylic acid

(664 mg, 2 mmol), anhydrous DMF (4 ml), diisopropylethylamine(0.696 ml, 4 mmol) and piperidine (187 mg, 2.2 mmol). The reaction was transferred to a brine ice bath and cooled to 0 °C. A suspension containing HATU (850 mg, 2.2 ml) and anhydrous DMF(2 ml) was slowly added. The ice bath was removed and stirring was continued for four hours at room temperature. Additional piperidine (1.0 mmol) was added and stirring was continued overnight. The reaction was diluted with ethyl acetate, and washed with IN NaOH, water, dried, filtered and concentrated in vacuo. The product was crystallized from acetone:water to afford a solid 480 mg, 60% yield, m.p. 151-153 °C.

Example 79

Furan-2-carboxylic acid [2-(2-methoxy-phenyl)-l -(piperidine-1 -carbonyl)-vinylJ-amide

A dry 25 ml three-necked round-bottomed flask under a nitrogen atmosphere was charged with 2-[(Furan-2-carbonyl)-amino]-3-(2-methoxy-phenyl)-acrylic acid (778 mg, 2.5 mmol), anhydrous DMF (3 ml), diisopropylethylamine(387 mg, 3 mmol) and piperidine (140 mg, 1.65 mmol).The reaction was transferred to a brine ice bath and cooled to 0 °C. A solution containing HATU (637 mg, 1.65 mmol) and anhydrous DMF(1.5 ml) was slowly added. The ice bath was removed and stirring was continued for four hours at room temperature. The reaction was diluted with ethyl acetate (60 ml), washed with water (6 X 60 ml), dried, filtered and concentrated in vacuo. The product was purified on a flash chromatography column that was eluted with hexane:ethyl acetate (1:1, v.v). The product was isolated as a white foam, 300 mg, 56% yield.

Example 80

N-[2-Bromo-2- (2-methoxy-phenyl) -1 -(piperidine- 1 -carbonylfvinyl] -benzamide (A, B)

A dry 25 ml three-necked round-bottomed flask under a nitrogen atmosphere was charged with N-[2-(2-methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-benzamide (423 mg, 1.16 mmol), anhydrous chloroform, and calcium carbonate (150 mg, 1.5 mmol). The suspension was cooled to 0 °C and a solution of 0.5M bromine in chloroform (2.0 ml, 1.0 mmol) was added dropwise. Additional 0.5M bromine in chloroform (0.2 ml) was added dropwise. The suspension was stirred for five minutes and the reaction was diluted with water (50 ml) and dichloromethane (50 ml). The layers were separated and the organic layer was washed with saturated sodium bicarbonate (2 X 50 ml), aqueous sodium metabisulfite (2 X 50 ml), water (2 X 50 ml), dried, filtered, and concentrated in vacuo. The reaction was purified on a flash chromatography column that was eluted with hexane:ethyl acetate (3:2). The appropriate fractions were combined and concentrated in vacuo. Compound was crystallized from acetone: water to afford a white solid that was labeled (N-[2-bromo-2-(2-methoxy-phenyl)- 1 -(piperidine- 1 -carbonyl)-vinyl]-benzamide A). The product was isolated in a 66% yield, m.p. = 193-194 °C. This isomer is the Z isomer. A second compound was isolated and crystallized from acetone:water to afford (N-[2-bromo-2-(2-methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-benzamide B), 15 mg, 3%, m.p. = 170-174 °C. This is the E-isomer.

Example 81

N-[2-Bromo-2-(2-methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-2-phenyl-acetamide (A,B) A dry 25 ml three-necked round-bottomed flask under a nitrogen atmosphere was charged with N-[2-(2-methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-2-phenyl-acetamide (378 mg, 1 mmol), anhydrous chloroform (7.5 ml), and calcium carbonate (150 mg, 1.5 mmol). The suspension was cooled to 0 °C and a solution of 0.5M bromine in chloroform (2.0 ml, 1.0 mmol) was added dropwise. The suspension was stirred for five minutes and the reaction was diluted with water (50 ml) and dichloromethane (50 ml). The layers were separated and the organic layer was washed with saturated sodium bicarbonate (2 X 50 ml), aqueous sodium metabisulfite (2 X 50 ml), water (2 X 50 ml), dried, filtered, and concentrated in vacuo. The reaction was purified on a flash chromatography column that was eluted with hexane:ethyl acetate (1:1). The appropriate fractions were combined and concentrated in vacuo. Compound was isolated as a white solid. The product was crystallized from acetone:water to afford a white solid N-[2-bromo-2-(2-methoxy-phenyl)- 1 -(piperidine- l-carbonyl)-vinyl]-2-phenyl-acetamide A in a 43% yield, m.p. = 160-165 °C. This is the Z isomer. A second compound was isolated to afford N-[2-bromo-2-(2- methoxy-phenyl)- 1 -(piperidine- 1 -carbonyl)-vinyl] -2-phenyl-acetamide B that was crystallized from acetone:water 169-142-4, 37 mg, 8%, m.p. = 170-176 °C. This is the E isomer.

Example 82

N-[2-Bromo-2-(2-methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-2,4-dimethyl- thiazole-5-carboxamide (A,B)

A dry 25 ml three-necked round-bottomed flask under a nitrogen atmosphere was charged with N- [2-(2-methoxy-phenyl)- 1 -(piperidine- 1 -carbonyl)-vinyl] -2,4-dimethyl-thiazole-5- carboxylic amide (399 mg, 1 mmol), anhydrous chloroform (7.5 ml), and calcium carbonate (150 mg, 1.5 mmol). The suspension was cooled to 0 °C and a solution of 0.5M bromine in chloroform (2.0 ml, 1.0 mmol) was added dropwise. The suspension was stirred for five minutes and the reaction was diluted with water (50 ml) and dichloromethane (50 ml). The layers were separated and the organic layer was washed with saturated sodium bicarbonate (2 X 50 ml), aqueous sodium metabisulfite (2 X 50 ml), water (2 X 50 ml), dried, filtered, and concentrated in vacuo. The reaction was purified on a flash chromatography column that was eluted with hexane:ethyl acetate (2:1). The appropriate fractions were combined and concentrated in vacuo. Compound was isolated as a colorless oil. The product was crystallized twice from acetone:water to afford a white solid N-[2-bromo-2-(2-methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-2,4-dimethyl- thiazole-5-carboxamide A in a 14% yield, m.p. = 167-168 °C. This is the Z isomer. A second compound N-[2-bromo-2-(2-methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]- 2,4-dimethyl-thiazole-5-carboxamide B was isolated as a colorless oil. It was repurified on a flash chromatography column that was eluted with hexane: acetone (2:1) and crystallized from acetone:water to afford a white solid 169-143-6, 119 mg, 25%, m.p. = 162-164 °C. This is the E isomer.

Example 83

N-[2-Bromo-2-(2-methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-furan-2-carboxamide (Λ,B)

A dry 25 ml three-necked round-bottomed flask under a nitrogen atmosphere was charged with furan-2-carboxylic acid [2-(2-methoxy-phenyl)-l -(piperidine- 1 -carbonyl)-vinyl] - amide (177 mg, 0.5 mmol), anhydrous chloroform (3.75 ml), and calcium carbonate (75 mg, 0.75 mmol). The suspension was cooled to 0 °C and a solution of 0.5M bromine in chloroform (1.0 ml, 0.5 mmol) was added dropwise. The suspension was stirred for five minutes and the reaction was diluted with water (50 ml) and dichloromethane (50 ml). The layers were separated and the organic layer was washed with saturated sodium bicarbonate (2 X 50 ml), aqueous sodium metabisulfite (2 X 50 ml), water (2 X 50 ml), dried, filtered, and concentrated in vacuo. The reaction was purified on a flash chromatography column that was eluted with hexane:ethyl acetate (1:1). The appropriate fractions were combined and concentrated in vacuo. Compound N-[2-bromo-2-(2- methoxy-phenyl)-l -(piperidine- l-carbonyl)-vinyl]-furan-2-carboxamide A was isolated as a white foam in a 64% yield. This is the Z isomer.

A second compound N-[2-Bromo-2-(2-methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]- furan-2-carboxamide B was isolated as a white solid, 20 mg, 9.2%. This is the E isomer.

Example 84

(Cyclohexanecarbonyl-amino)-(dimethoxy-phosphoryl)-acetic acid methyl ester An oven dried 500 ml Parr flask was equipped with a magnetic stirring bar, continuously flushed with nitrogen gas, and charged with the triester (10.0 g, 30.2 mmol), methanol (100 ml), and 10% Pd/C (500 mg). The flask was fitted into a Parr hydrogenation apparatus and the mixture was treated with hydrogen gas at 50 psi for forty-five minutes.

The reaction was filtered through Celite and concentrated in vacuo. The crude oil was diluted with heptane (3 X 150 ml) and concentrated in vacuo. The crude product was diluted with anhydrous chloroform (100 ml) and transferred to an oven dried 300 ml round-bottomed flask equipped with a dropping funnel and magnetic stirring bar. The reaction was diluted with anhydrous triethylamine (10 ml) and DMAP (810 mg). Stirring was continued for fifteen minutes and the flask was transferred to a brine-ice bath and cooled to 0 °C. Cyclohexanecarbonyl chloride (4.87 g, 33.22 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo and diluted with ethyl acetate (250 ml), washed with 1.0M HCl, water (2 X 150 ml), a saturated solution on sodium bicarbonate (2 X 60 ml), water (2 X 200 ml), and brine

(2 X 200 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The product was isolated as a white solid, 2.14 g, 23%> yield, m.p. = 92.0-92.8 °C.

Example 85

(Cyclopentanecarbonyl-amino)-(dimethoxy-phosphoryl)-acetic acid methyl ester

An oven dried 500 ml Parr flask was equipped with a magnetic stirring bar, continuously flushed with nitrogen gas, and charged with the trimester (11.0 g, 33.2 mmol), anhydrous DMF (100 ml), and 10% Pd/C (500 mg). The flask was fitted into a Parr hydrogenation apparatus and the mixture was treated with hydrogen gas at 50 psi for sixty minutes. The reaction was filtered through Celite and transferred to a 250 ml round-bottomed flask. The reaction was diluted with anhydrous triethylamine (9.5 ml) and DMAP (810 mg). The flask was transferred to a brine-ice bath and cooled to 0 °C for fifteen minutes. Cyclopentanecarbonyl chloride (5.28 g, 39.84 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo and diluted with ethyl acetate (250 ml), washed with 1.0M HCl (20 ml), water (2 X 150 ml), a saturated solution on sodium bicarbonate (2 X 60 ml), water (2 X 200 ml), and brine (2 X 200 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The product was triturated with 1,2-dimethoxyethane, filtered and concentrated in vacuo. The product was isolated as a tan colored solid, 1.44 g, 15% yield, m.p. = 90.1-90.9 °C.

Example 86 (Dimethoxy-phosphoryl)-[(pyridine-2-carhonyl)-amino]-acetic acid methyl ester

An oven dried 500 ml Parr flask was equipped with a magnetic stirring bar, continuously flushed with nitrogen gas, and charged with the trimester (10.0 g, 30.2 mmol), methanol (60 ml), and 10% Pd/C (500 mg). The flask was fitted into a Parr hydrogenation apparatus and the mixture was treated with hydrogen gas at 50 psi for forty-five minutes. The reaction was filtered through Celite and concentrated in vacuo. The crude oil was diluted with heptane (3 X 150 ml) and concentrated in vacuo. The crude product was diluted with anhydrous chloroform (100 ml) and transferred to an oven dried 300 ml round-bottomed flask equipped with a dropping funnel and magnetic stirring bar. The reaction was diluted with anhydrous triethylamine (15 ml, 107.6 mmol) and DMAP (200 mg, 1.64 mmol). Stirring was continued for fifteen minutes and the flask was transferred to a brine-ice bath and cooled to 0 °C. Picolinoyl chloride hydrochloride (5.0 g, 28.1 mmol), was added dropwise and the reaction was stirred at room temperature overnight. Work-up as in on B278-005-1. The product was purified on a flash chromatography column that was eluted with ethyl acetate:hexane (20:80: v:v). The fractions containing product were combined and concentrated in vacuo. The product was obtained as a pale yellow oil, 2.13 g, 23% yield. The product was used directly.

Example 87

(Dimethoxy-phosphoryl)-[(pyridine-4-carbonyl)-amino]-acetic acid methyl ester

An oven dried 500 ml Parr flask was equipped with a magnetic stirring bar, continuously flushed with nitrogen gas, and charged with the trimester (10.0 g, 30.2 mmol), methanol

(100 ml), and 10% Pd/C (500 mg). The flask was fitted into a Parr hydrogenation apparatus and the mixture was treated with hydrogen gas at 50 psi for forty-five minutes. The reaction was filtered through Celite and concentrated in vacuo. The crude oil was diluted with heptane (3 X 150 ml) and concentrated in vacuo. The crude product was diluted with anhydrous chloroform (100 ml) and transferred to an oven dried 300 ml round-bottomed flask equipped with a dropping funnel and magnetic stirring bar. The reaction was diluted with anhydrous triethylamine (10 ml) and DMAP (810 mg). Stirring was continued for fifteen minutes and the flask was transferred to a brine-ice bath and cooled to 0 °C. Isonicotinoyl chloride hydrochloride (5.91 g, 33.22 mmol), was added dropwise and the reaction was stirred at room temperature overnight. Work-up on B278- 005-1. The product was obtained impure as a brownish-yellow oil, 4.9 g, 54 % yield.

Example 88

3-(2-methoxy-phenyl)-2-[(pyridine-4-carbonyl)-amino]-acrylic acid methyl ester

An oven dried 100 ml round-bottomed flask was equipped with a magnetic stirring bar and continuously purged with anhydrous nitrogen gas. The flask was charged with (dimethoxy-phosphoryl)-[(pyridine-4-carbonyl)-amino]-acetic acid methyl ester (4.71 g,

15.58 mmol), anhydrous chloroform (25 ml) and stirred at room temperature for fifteen minutes. The reaction was diluted with 1,1,3,3-tetramethylguanidine (2.15 g, 18.7 mmol) and stirred for an additional ten minutes at room temperature. O-Anisaldehyde (2.23 g, 16.36 mmol) was added dropwise and the reaction was stirred at room temperature overnight. Work-up. The product was obtained as a pale yellow hydroscopic solid, 650 mg, 12% yield.

Example 89

2-(Cyclopentanecarbonyl-amino)-3-(2-methoxy-phenyl)-acrylic acid methyl ester

An oven dried 50 ml round-bottomed flask was equipped with a magnetic stirring bar and continuously purged with anhydrous nitrogen gas. The flask was charged with

(cyclopentanecarbonyl-amino)-(dimethoxy-phosphoryl)-acetic acid methyl ester (0.8 g,

2.73 mmol), anhydrous chloroform (10 ml) and stirred at room temperature for fifteen minutes. The reaction was diluted with 1,1,3,3-tetramethylguanidine (0.378 g, 3.28 mmol) and stirred for an additional five minutes at room temperature. O-Anisaldehyde (0.45 g, 3.28 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The reaction was diluted with chloroform and washed with water (2 X 75 ml),

1.0M HCL (10 ml), water (2 X 50 ml), a saturated sodium bicarbonate solution (2 X 50 ml), water (2 X 75 ml), and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filter, and concentrated in vacuo. The product was purified on a flash chromatography column that was eluted with hexane:ethyl acetate (80:20, v:v).

The product was obtained as a white solid, 620 mg, 75% yield, m.p. 145.5-146.3 °C. Example 90

3-(2-Methoxy-phenyl)-2-[(pyridine-2-carbonyl)-amino]-acrylic acid methyl ester

An oven dried 100 ml round-bottomed flask was equipped with a magnetic stirring bar and continuously purged with anhydrous nitrogen gas. The flask was charged with

(dimethoxy-phosphoryl)-[(pyridine-4-carbonyl)-amino]-acetic acid methyl ester (1.54 g, 5.1 mmol), anhydrous chloroform (15 ml) and stirred at room temperature for fifteen minutes. The reaction was diluted with 1,1,3,3-tetramethylguanidine (0.705 g, 6.12 mmol) and stirred for an additional ten minutes at room temperature. O-Anisaldehyde (0.762 g, 5.6 mmol), was added dropwise and the reaction was stirred at room temperature overnight. The reaction was washed with water (2 X 75 ml), 1.0M HCL (10 ml), water (2 X 50 ml), a saturated sodium bicarbonate solution (2 X 50 ml), water (2 X 75 ml), and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filter, and concentrated in vacuo. The product was obtained as a pale yellow oil 1.5 g, overall yield was 94%.

Example 91

2-(Cyclohexanecarbonyl-amino)-3-(2-methoxy-phenyl)-acrylic acid methyl ester

An oven dried 50 ml round-bottomed flask was equipped with a magnetic stirring bar and continuously purged with anhydrous nitrogen gas. The flask was charged with (cyclopentanecarbonyl-amino)-(dimethoxy-phosphoryl)-acetic acid methyl ester (1.0 g,

3.25 mmol), anhydrous chloroform (10 ml) and stirred at room temperature for fifteen minutes. The reaction was diluted with 1,1,3,3-tetramethylguanidine (0.45 g, 3.91 mmol) and stirred for an additional fifteen minutes at room temperature. O-Anisaldehyde (0.532 g, 3.91 mmol), was added dropwise and the reaction was stirred at room temperature overnight. The reaction was washed with water (2 X 75 ml), 1.0M HCL (10 ml), water (2

X 50 ml), a saturated sodium bicarbonate solution (2 X 50 ml), water (2 X 75 ml), and brine (2 X 75 ml). The organic layer was dried over anhydrous sodium sulfate, filter, and concentrated in vacuo. The product was obtained as a white solid, 725 mg, 70 % yield, m.p. = 172.2-174.0 °C.

Example 92 3-(2-Methoxy-phenyl)-2-[(pyridine-4-carbonyl)-amino]-acrylic acid

A 50 ml round-bottomed flask equipped with a magnetic stirring bar was charged with 3- (2-methoxy-phenyl)-2-[(pyridine-4-carbonyl)-amino]-acrylic acid methyl ester (0.65 g, 2.1 mmol), dioxane (20 ml), and stirred at room temperature for fifteen minutes. A 2.0M LiOH solution (3.2 ml) was added dropwise. Stirring was continued at room temperature overnight. The reaction was worked up in the usual maimer and the product was obtained as a yellow solid (365 mg, 58 % yield).

Example 93

3-(2-Methoxy-phenyl)-2-[(pyridine-2-carbonyl)-amino] -acrylic acid

A 50 ml round-bottomed flask equipped with a magnetic stirring bar was charged with 3- (2-Methoxy-phenyl)-2-[(pyridine-2-carbonyl)-amino]-acrylic acid methyl ester (0.27 g, 0.86 mmol), dioxane (10 ml), and stirred at room temperature for fifteen minutes. A 2.0M LiOH solution (1.3 ml) was added dropwise. Stirring was continued at room temperature overnight. The reaction was worked up in the usual manner and the product was obtained as a pale yellow solid (135 mg, 53 %> yield).

Example 94

2-(Cyclopentanecarbonyl-amino)-3-(2-methoxy-phenyl)-acrylic acid

A 50 ml round-bottomed flask equipped with a magnetic stirring bar was charged with 2-

(cyclohexanecarbonyl-amino)-3-(2-methoxy-phenyl)-acrylic acid methyl ester (0.45 g, 1.5 mmol), dioxane (10 ml), and stirred at room temperature for fifteen minutes. A 2.0M LiOH solution (2.25 ml) was added dropwise. Stirring was continued at room temperature overnight. The reaction was worked up in the usual manner and the product was obtained as a white solid (250 mg, 58 %> yield).

Example 95

2-(Cyclohexanecarbonyl-amino)-3-(2-methoxy-phenyl)-acrylic acid A 50 ml round-bottomed flask equipped with a magnetic stirring bar was charged with 2- (cyclohexanecarbonyl-amino)-3-(2-methoxy-phenyl)-acrylic acid methyl ester (0.46 g, 1.45 mmol), dioxane (10 ml), and stirred at room temperature for fifteen minutes. A 2.0M LiOH solution (2.17 ml) was added dropwise. Stirring was continued at room temperature overnight. The reaction was worked up in the usual manner and the product was obtained as a white solid (310 mg, 70 % yield).

Example 96

N-[2-(2-Methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-cyclohexanecarboxamide

(cyclohexanecarbonyl-amino)-3-(2-methoxy-phenyl)-acrylic acid (0.25 g, 0.83 mmol), anhydrous DMF (5 ml) and diisopropylethylamine (0.3 ml, 1.66 mmol). The solution was stirred at room temperature for fifteen minutes and diluted with piperidine (0.1 ml, 1 mmol). Stirring was continued for ten minutes and a solution of HATU (346 mg, 0.91 mmol) added. Stirring was continued at room temperature overnight. The DMF was removed in vacuo and the reaction diluted with ethyl acetate (75 ml). The organic layer was washed with 1.0N HCl (25 ml), water (2 X 50 ml), a saturated solution of sodium bicarbonate (30 ml), water (2 X 25 ml) and brine (2 X 70 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The product was obtained as a white solid, 265 mg, 86.5% yield, m.p. = 184.4-185.8 °C.

Example 97

N-[2-(2-Methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-isonicotinamide

A 50 ml round-bottomed flask equipped with a magnetic stirring bar was charged with 3- (2-methoxy-phenyl)-2-[(pyridine-4-carbonyl)-amino] -acrylic acid (0.3 g, 1 mmol), anhydrous DMF (10 ml) and diisopropylethylamine (0.35 ml, 2 mmol). The solution was stirred at room temperature for fifteen minutes and diluted with piperidine (0.11 ml, 1.1 mmol). Stirring was continued for ten minutes and a solution of HATU (420 mg, 1.1 mmol) added. Stirring was continued at room temperature overnight. The DMF was removed in vacuo and the reaction diluted with ethyl acetate (75 ml). The organic layer was washed with 1.0N HCl (25 ml), water (2 X 50 ml), a saturated solution of sodium bicarbonate (30 ml), water (2 X 25 ml) and brine (2 X 70 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The product was obtained as a yellow solid, 140 mg, 38% yield.

Example 98

N-[2-(2-Methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-pyridine-2-carboxamide

A 50 ml round-bottomed flask equipped with a magnetic stirring bar was charged with

B278-029-1 (0.5 g, 1.68 mmol), anhydrous DMF (10 ml) and diisopropylethylamine (0.6 ml, 3.36 mmol). The solution was stirred at room temperature for twenty minutes and diluted with piperidine (0.157 mg, 1.84 mmol). Stirring was continued for ten minutes and a solution of HATU (700 mg, 1.84 mmol) added. Stirring was continued at room temperature overnight. The DMF was removed in vacuo and the reaction diluted with ethyl acetate (75 ml). The organic layer was washed with 1.0N HCl (25 ml), water (2 X 50 ml), a saturated solution of sodium bicarbonate (30 ml), water (2 X 25 ml) and brine (2 X 70 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The product was obtained as a orange-yellow oil, 740 mg, 100% yield.

Example 99

N-[2-(2-Methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-cyclopentanecarboxamide

A 50 ml round-bottomed flask equipped with a magnetic stirring bar was charged with 2- (cyclopentanecarbonyl-amino)-3-(2-methoxy-phenyl)-acrylic acid (0.2 g, 0.69 mmol), anhydrous DMF (5 ml) and diisopropylethylamine (0.24 ml). The solution was stirred at room temperature for twenty minutes and diluted with piperidine (0.06 g, 0.76 mmol).

Stirring was continued for ten minutes and a solution of HATU (270 mg, 0.76 mmol) added. Stirring was continued at room temperature overnight. The DMF was removed in vacuo and the reaction diluted with ethyl acetate (75 ml). The organic layer was washed with 1.0N HCl (25 ml), water (2 X 50 ml), a saturated solution of sodium bicarbonate (30 ml), water (2 X 25 ml) and brine (2 X 70 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The product was obtained as a white solid, 210 mg, 85% yield, m.p. 168.5-169.6 °C.

Example 100

N-[2-Bromo-2-(2-Methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-isonicotinamide A 25 ml round-bottomed flask equipped with a magnetic stirring bar was charged with N- [2-(2-Methoxy-phenyl)-l -(piperidine- l-carbonyl)-vinyl]-isonicotinamide (100 mg, 0.27 mmol), anhydrous chloroform (5 ml) and calcium carbonate (60 mg, 0.55 mmol). The reaction was placed in a brine ice bath and stirred for fifteen minutes. A 0.5M bromine in chloroform (0.81 ml) solution was added dropwise and the reaction was monitored by

TLC. After five minutes the reaction was complete. The reaction was diluted with chloroform and washed with water (2 X 50 ml), a saturated solution of sodium bisulfite, 1.0M HCl, a saturated solution of sodium bicarbonate (2 X 25 ml), water (2 X 100 ml), and brine (2 X 100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified on a flash chromatography column that was eluted with chloroform:methanol (90:10, v:v). The product was obtained as a light orange solid, 47 mg, 39% yield. The product was a 1 :1 mixture of E:Z isomers by NMR.

Example 101

N-[2-Bromo-2-(2-Methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-pyridine-2- carboxamide

A 25 ml round-bottomed flask equipped with a magnetic stirring bar was charged with N- [2-(2-methoxy-phenyl)- 1 -(piperidine- 1 -carbonyl)-vinyl] -pyridine-2-carboxamide (520 mg, 1.4 mmol), anhydrous chloroform (10 ml) and calcium carbonate (280 mg, 2.8 mmol). The reaction was placed in a brine ice bath and stirred for fifteen minutes. A 0.5M bromine in chloroform (4.2 ml) solution was added dropwise and the reaction was monitored by TLC. After five minutes the reaction was complete. The reaction was diluted with chloroform and washed with water (2 X 50 ml), a saturated solution of sodium bisulfite, 1.0M HCl, a saturated solution of sodium bicarbonate (2 X 25 ml), water (2 X 100 ml), and brine (2 X 100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified on a flash chromatography column that was eluted with chlorofornumethanol (95:5, v:v). The product was obtained as a white solid, 145 mg, 23% yield, m.p. 188.1-189.2 °C. The product was isolated as the Z isomer.

Example 102 N-[2-Bromo-2-(2-Methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]- cyclohexanecarboxamide

A 25 ml round-bottomed flask equipped with a magnetic stirring bar was charged with N- [2-(2-methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]-cyclohexanecarboxamide (200 mg, 0.54 mmol), anhydrous chloroform (10 ml) and calcium carbonate (110 mg, 1.1 mmol). The reaction was placed in a brine ice bath and stirred for fifteen minutes. A 0.5M bromine in chloroform (1.62 ml) solution was added dropwise and the reaction was monitored by TLC. After five minutes the reaction was complete. The reaction was diluted with chloroform and washed with water (2 X 50 ml), a saturated solution of sodium bisulfite, 1.0M HCl, a saturated solution of sodium bicarbonate (2 X 25 ml), water

(2 X 100 ml), and brine (2 X 100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified on a flash chromatography column that was eluted with chloroform:methanol (90:10, v:v). The product was obtained as a white solid, 210 mg, 87% yield, m.p. 194.5-195.3 °C. The product was isolated as a mixture of Z:E isomers in a 10: 1 ratio.

Example 103

N-[2-Bromo-2-(2-methoxy-phenyl)-l-(piperidine-l-carbonyl)-vinyl]- cyclopentanecarboxamide

A 50 ml round-bottomed flask equipped with a magnetic stirring bar was charged with N- [2-(2-methoxy-phenyl)-l -(piperidine- 1 -carbonyl)-vinyl]-cyclopentanecarboxamide (170 mg, 0.48 mmol), anhydrous chloroform (7 ml) and calcium carbonate (96 mg, 0.96 mmol). The reaction was placed in a brine ice bath and stirred for twenty minutes. A 0.5M bromine in chloroform (1.44 ml) solution was added dropwise and the reaction was monitored by TLC. After five minutes the reaction was complete. After the usual work- up and purification, the product was obtained as a white solid, 175 mg, 84% yield, m.p.

201.9-202.8 °C. The product was isolated as a mixture of Z:E isomers in a 5:1 ratio.

Example 104

Table 5 shows anti-hepatitis B virus activity of 2-substituted-propenamide derivatives.

Table 5

Example 105 Table 6 shows the anti-hepatitis B virus activity of 2-substituted-propenamide derivatives was tested in transfected Hep G-2 (2.2.15) cells.

Table 6

This invention has been described with reference to its preferred embodiments. Variations and modifications of the invention, will be obvious to those skilled in the art from the foregoing detailed description of the invention. It is intended that all of these variations and modifications be included within the scope of this invention.

Claims

We Claim:

1. A compound of Formula (I) :

(i) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

1 9 ii) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

vi) m is 1 or 2; and n is 1-4; and

vii) R³ and R⁴ are independently H or lower alkyl;

1 9 1 9 heteroaryl with each other or with R , R , Z or Z .

2. A compound of formula (II)

(II) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

ii) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

iv) R³ is H or lower alkyl; and

v) Z and Z are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic.

3. The compound of claim 2, wherein:

i) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

1 9 carbocycle, or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; and

ii) X is a halogen.

4. The compound of claim 3, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

5. A compound of formula (III)

(HI) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

iv) Z and Z are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic; and

v) R³ and R⁴ are independently H or lower alkyl;

alternatively, R or R can independently form a bridged carbocycle, aryl, heterocycle or heteroaryl with each other or with R¹, R², Z¹ or Z².

6. The compound of claim 5, wherein:

i) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; and

ii) X is a halogen.

The compound of claim 6, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

8. A compound of formula (IV) :

(IV)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

i) the wavy line indicates that the compound can be in the form of the E or Z isomer; ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

iv) Z¹ and Z² are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic; v) R³ and R⁴ are independently H or lower alkyl;

1 9 1 9 heteroaryl with each other or with R , R , Z or Z .

8. The compound of claim 7, wherein: i) R¹ and R² are independently hydrogen, an optionally substituted alkyl, carbocycle; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; ii) X is a halogen; and iii) R³ and R⁴ are H.

9. The compound of claim 8, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

I l l

10. A compound of formula (V)

(V) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

iv) Z¹ and Z² are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic; and

v) R³ is H or lower alkyl.

11. The compound of claim 10, wherein:

i) R¹ and R² are independently hydrogen, an optionally substituted alkyl, carbocycle; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

ii) X is a halogen; and

iii) R³ is H.

12. The compound of claim 11, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

13. A compound of formula (VI) :

(VI)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

v) R is H or lower alkyl.

14. The compound of claim 13 , wherein: i) R¹ and R² are independently hydrogen, an optionally substituted alkyl, carbocycle; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

ii) X is a halogen; and

iii) R³ is H.

15. The compound of claim 14, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof. 16. A compound of formula (VII)

(VII) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H; iv) Z¹ and Z² are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic;

v) R³ is H or lower alkyl; alternatively, R³ can independently form a bridged carbocycle, aryl, heterocycle or heteroaryl with R¹, R², Z¹ or Z².

17. The compound of claim 16, wherein: i) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl;

ii) X is a halogen; and

iii) R³ is H.

18. The compound of claim 17, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

19. The compound of claim 16, wherein the compound is of the formula: or a pharmaceutically acceptable salt or prodrug thereof.

20. A compound of formula (VIII)

(VIII)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

iv) Z is an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic; and

v) n is 1-4.

21. The compound of claim 20, wherein: i) R¹ and R² are independently hydrogen, an optionally substituted alkyl, carbocycle; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; and

ii) X is a halogen, and n is 5.

22. The compound of claim 21 , wherein the compound is of the formula

or a pharmaceutically acceptable salt or prodrug thereof. 23. A compound of formula (X)

(X) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

1 9 ii) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H; iv) Z¹ and Z² are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic;

v) R³ is independently H or lower alkyl; and

vi) when the compound is in the form of the E isomer, then at least one of Z¹ and Z² is not an optionally substituted phenyl.

24. A compound of a Z isomer of the formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R¹ is selected from the group consisting of

25. A compound of a Z isomer of formula (XII)

(XII)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R and R come together to form a bridged compound selected from the group consisting

and

26. A compoimd of a Z isomer of formula (XIII)

(XIII)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

Z¹ is selected from the group consisting of:

27. A compound of a Z isomer of formula (XIV)

(XIV) or a pharmaceutically acceptable salt or prodrug thereof, wherein: Z z2 is selected from the group consisting of

28. A compound of a Z formation selected from the group consisting of

or a pharmaceutically acceptable salt or prodrug thereof.

29. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of Formula (I):

(I) or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, wherein:

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

v) Y is -NR³C(O)-, -NR³C(O)O-, -NR³C(O)NR⁴-, -NR³C(S)-, -NR³C(S)O-, 5 -NR³C(S)NR⁴-, -NR³S(O)_m-, -NR³(CH₂)_n-, -C(O)NR³- or -C(S)NR³-; such that when Y is -NR C(O)-, then the compound is in the form of the Z isomer or at least one of Z¹ and Z² is not an optionally substituted phenyl;

vi) m is 1 or 2; and n is 1-4; and

vii) R³ and R⁴ are independently H or lower alkyl;

10 alternatively, R³ or R⁴ can independently form a bridged carbocycle, aryl, heterocycle or

1 9 1 9 heteroaryl with each other or with R , R , Z or Z .

30. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of formula (II)

(H) or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, wherein:

i) the wavy line indicates that the compound can be in the form of the E or Z 20 isomer;

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H; iv) Z¹ and Z² are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic;

v) R³ is H or lower alkyl;

alternatively, R³ can independently form a bridged carbocycle, aryl, heterocycle or heteroaryl with R¹, R², Z¹ or Z².

31. The compound of cliam 30, wherein:

i) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

1 9 carbocycle; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

ii) X is a halogen; and

iii) R³ is H.

32. The pharmaceutical composition of claim of claim 31, wherein the composition is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent.

33. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of formula (III)

(III)

or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, wherein:

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

v) R³ and R⁴ are independently H or lower alkyl;

alternatively, R³ or R⁴ can independently form a bridged carbocycle, aryl, heterocycle or 1 9 heteroaryl with each other or with R , R , Z or Z .

34. The composition of claim 33, wherein:

ii) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; iii) X is a halogen;

v) R³ and R⁴ are H;

alternatively, R³ or R can independently form a bridged carbocycle, aryl, heterocycle or heteroaryl with each other or with R¹, R², Z¹ or Z².

35. The composition of claim 34, wherein the composition is of the formula:

36. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of formula (TV):

(IV)

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

v) R³ and R⁴ are independently H or lower alkyl;

alternatively, R³ or R⁴ can independently form a bridged carbocycle, aryl, heterocycle or heteroaryl with each other or with R¹, R², Z¹ or Z².

37. The composition of claim 36, wherein:

ii) X is a halogen; and

iii) R³ and R⁴ are H.

38. The composition of claim 37, wherein, wherein the composition is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent,.

39. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of formula (V)

(V) or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, wherein:

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

1 9 iv) Z and Z are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic; v) R is H or lower alkyl;

alternatively, R can independently form a bridged carbocycle, aryl, heterocycle or heteroaryl with R¹, R², Z¹ or Z².

40. The composition of claim 39, wherein:

i) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

1 o carbocycle,; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

ii) X is a halogen; and

iii) R³ is H.

41. The composition of claim 40, wherein the composition is of the formula:

42. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of formula (VI):

(VI)

ii) R and R are independently hydrogen, an optionally substituted alkyl,

1 -_j carbocycle, aryl, heterocycle or heteroaryl; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

v) R³ is H or lower alkyl;

43. The composition of claim 42, wherein:

1 9 i) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

ii) X is a halogen; and

iii) R³ is H.

44. The composition of claim 43, wherein the composition is of the formula:

45. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of formula (VII)

(VII)

ii) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H; iv) Z¹ and Z² are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic; and

v) R³ is H or lower alkyl; alternatively, R³ can independently form a bridged carbocycle, aryl, heterocycle or 9 1 9 heteroaryl with each other or with R , R , Z or Z .

46. The composition of claim 45, wherein:

1 9 i) R and R are independently hydrogen, an optionally substituted alkyl,

1 9 carbocycle; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; ii) X is a halogen; and iii) R³ is H.

47. The composition of claim 45, wherein the compound is of the formula:

48. The composition of claim 45, wherein the composition is of the formula:

49. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of formula (VIII)

(VIII)

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H; iv) Z¹ is an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic; and

v) n is 1-4.

50. The composition of claim 49, wherein:

i) R and R are independently hydrogen, an optionally substituted alkyl,

1 9 carbocycle; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; and

ii) X is a halogen.

51. The composition of claim 50, wherein the composition is of the formula

52. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of formula (X)

(X)

or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, wherein: i) the wavy line indicates that the compound can be in the form of the E or Z isomer;

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

iv) Z¹ and Z² are an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic;

1 9 v) when the compound is in the form of the E isomer, then at least one of Z and Z is not an optionally substituted phenyl; and

vi) R³ is H or lower alkyl.

alternatively, R³ can independently form a bridged carbocycle, aryl, heterocycle or

1 1 9 heteroaryl with each other or with R , R , Z or Z .

53. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of a Z isomer of the formula:

or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, wherein: R¹ is selected from the group consisting of

54. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of a Z isomer of formula (XII)

(XII)

or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, wherein: R¹ and R² come together to form a bridged compound selected from the group consisting

55. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of a Z isomer of formula (XIII)

(XIII)

Z¹ is selected from the group consisting of:

56. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of a Z isomer of formula (XIV)

(XIV) or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent, wherein:

Z² is selected from the group consisting of

57. A pharmaceutical composition for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus in a host, comprising an effective amount of a compound of a Z formation selected from the group consisting of

or their pharmaceutically acceptable salts or prodrugs thereof, together with a pharmaceutically acceptable carrier or diluent.

58. The pharmaceutical composition of any one of claims 32-57, wherein the said compound is in the form of a dosage unit.

59. The pharmaceutical composition of claim 58, wherein the dosage unit contains 10 to 1000 mg of said compound.

60. The pharmaceutical composition of claim 58 or 59, wherein said dosage unit is a tablet or capsule.

61. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound Formula (I):

(I) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

v) Y is -NR³C(O)-, -NR³C(O)O-, -NR³C(O)NR⁴-, -NR³C(S)-, -NR³C(S)O-, -NR³C(S)NR⁴-, -NR³S(O)_m-, -NR³(CH₂)_n-, -C(O)NR³- or -C(S)NR³-; such that when Y is -NR³C(O)-, then the compound is in the form of the Z isomer or at least one of Z and Z is not an optionally substituted phenyl;

vi) m is 1 or 2; and n is 1-4; and

vii) R³ and R⁴ are independently H or lower alkyl;

62. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound of formula (II)

(ID or a pharmaceutically acceptable salt or prodrug thereof, wherein:

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H; iv) Z and Z are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic; and

v) R³ is H or lower alkyl;

alternatively, R³ can independently form a bridged carbocycle, aryl, heterocycle or heteroaryl with each other or with R¹, R², Z¹ or Z².

63. The method of claim 62, wherein:

1 9 i) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

ii) X is a halogen; and

iii) R³ is H.

64. The method of claim 63, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

65. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound of formula (III)

(III)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

ii) R and R are independently hydrogen, an optionally substituted alkyl,

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

v) R³ and R⁴ are independently H or lower alkyl;

66. The method of claim 65, wherein:

ii) X is a halogen; and

iii) R³ and R⁴ are independently H or lower alkyl.

67. The method of claim 66, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

68. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound of formula (IV):

(IV) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

1 9 carbocycle, aryl, heterocycle or heteroaryl; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H; iv) Z and Z are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic;

v) R³ and R are independently H or lower alkyl;

69. The method of claim 68, wherein:

i) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

ii) X is a halogen; and

iii) R³ and R⁴ are H.

70. The method of claim 69, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

71. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound of formula (V)

(V)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

1 9 iv) Z and Z are independently an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic; and

v) R is H or lower alkyl;

72. The method of claim 71 , wherein:

ii) X is a halogen; and

iii) R³ is H.

73. The method of claim 72, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

74. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound of formula (VI):

(VI)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

1 9 ii) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

v) R³ is H or lower alkyl; alternatively, R³ can independently form a bridged carbocycle, aryl, heterocycle or heteroaryl with with R¹, R², Z¹ or Z².

74. The method of claim 73, wherein:

ii) X is a halogen; and

iii) R³ is H.

75. The method of claim 74, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

76. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound of formula (VII)

(VII)

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R¹ and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

v) R³ is H or lower alkyl;

77. The method of claim 76, wherein:

1 i) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

ii) X is a halogen; and

iii) R³ is H.

78. The method of claim 76, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

79. The method of claim 76, wherein the compound is of the formula: or a pharmaceutically acceptable salt or prodrug thereof.

80. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound of formula (VIII)

(VIII) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H; iv) Z¹ is an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic; and v) n is 1-4.

81. The method of claim 80, wherein: i) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; and

ii) X is a halogen.

82. The method of claim 81 , wherein the compound is of the formula

or a pharmaceutically acceptable salt or prodrug thereof.

83. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound of formula (X)

(X) or a pharmaceutically acceptable salt or prodrug thereof, wherein:

1 9 carbocycle, aryl, heterocycle or heteroaryl; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H; iv) Z¹ and Z² are an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic;

v) R³ is H or lower alkyl; and

vi) when the compound is in the form of the E isomer, then at least one of Z¹ and Z² is not an optionally substituted phenyl;

84. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound of a Z isomer of the formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R¹ is selected from the group consisting of

85. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound of a Z isomer of formula (XII)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R¹ and R² come together to form a bridged compound selected from the group consisting

y ^Nχπ₃ .CH,

and

86. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound of a Z isomer of formula (XIII)

(XIII)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

Z¹ is selected from the group consisting of:

13

87. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound of a Z isomer of formula (XIV)

(XIV)

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

Z is selected from the group consisting of

88. A method for the treatment or prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, comprising administering an anti-virally effective amount of a compound of a Z formation selected from the group consisting of

aceutically acceptable salts or prodrugs thereof.

89. The method of any of claims 61-88, wherein the said compound is in the form of a dosage unit.

90. The method of claim 89, wherein the dosage unit contains 10 to 1000 mg of said compound.

91. The method of claim 89 or 90, wherein said dosage unit is a tablet or capsule.

92. Use of the compoimd of Formula (I), or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host:

(I) wherein:

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

v) Y is -NR³C(O)-, -NR³C(O)O-, -NR³C(O)NR⁴-, -NR³C(S)-, -NR³C(S)O-, -NR³C(S)NR⁴-, -NR³S(O)_m-, -NR³(CH₂)_n-, -C(O)NR³- or -C(S)NR³-; such that when Y is -NR³C(O)-, then the compound is in the form of the Z isomer or at least one of Z¹ and Z² is not an optionally substituted phenyl; vi) m is 1 or 2; and n is 1-4; and vii) R³ and R⁴ are independently H or lower alkyl;

alternatively, R³ or R⁴ can independently form a bridged carbocycle, aryl, heterocycle or 9 1 9 heteroaryl with each other or with R , R , Z or Z .

93. Use of the compoimd of Formula (II), or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host:

(II)

wherein: i) the wavy line indicates that the compound can be in the form of the E or Z isomer; ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

94. The use of claim 93, wherein:

i) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

ii) X is a halogen; and

iii) R³ is H.

95. The use of claim 94, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

96. Use of the compound of Formula (III), or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host:

(III)

wherein:

i) the wavy line indicates that the compound can be in the form of the E or Z isomer; 1 9 ii) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

v) R³ and R⁴ are independently H or lower alkyl;

97. The use of claim 96, wherein:

ii) X is a halogen; and

iii) R³ and R⁴ are H.

98. The use of claim 97, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

99. Use of the compound of Formula (IV), or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host:

(IN) wherein:

iii) X is a halogen, -CΝ, an optionally substituted lower alkyl, or H;

v) R³ and R⁴ are independently H or lower alkyl;

alternatively, R³ or R can independently form a bridged carbocycle, aryl, heterocycle or

1 9 1 9 heteroaryl with each other or with R , R , Z or Z .

100. The use of claim 99, wherein:

ii) X is a halogen; and

iii) R³ and R⁴ are H.

101. The use of claim 100, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

102. Use of the compound of Formula (V), or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host:

(V) wherein:

ii) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

103. The use of claim 102, wherein:

1 i) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

ii) X is a halogen; and

iii) R³ is H.

104. The use of claim 103, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

105. Use of the compound of Formula (VI), or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host:

(VI)

wherein:

1 • ii) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring;

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

v) R³ is H or lower alkyl;

106. The use of claim 105, wherein:

ii) X is a halogen; and

iii) R³ is H.

106. The use of claim 105, wherein the compound is of the formula: or a pharmaceutically acceptable salt or prodrug thereof.

107. Use of the compound of Formula (VII), or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host:

(VII)

wherein: i) the wavy line indicates that the compound can be in the form of the E or Z isomer; ii) R and R are independently hydrogen, an optionally substituted alkyl, carbocycle, aryl, heterocycle or heteroaryl; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

108. The use of claim 107, wherein:

ii) X is a halogen; and

iii) R³ is H or lower alkyl.

109. The use of claim 107, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

110. The use of claim 107, wherein the compound is of the formula:

or a pharmaceutically acceptable salt or prodrug thereof.

111. Use of the compound of Formula (VIII), or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host:

(VIII)

wherein:

iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

iv) Z¹ is an optionally substituted carbocycle, aryl, heterocycle or heteroaromatic; and

v) n is 1-4.

112. The use of claim 111, wherein:

i) R¹ and R² are independently hydrogen, an optionally substituted alkyl, carbocycle; or R¹ and R² can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; and

ii) X is a halogen.

113. The use of claim 112, wherein, wherein the compound is of the formula

or a pharmaceutically acceptable salt or prodrug thereof.

114. Use of the compound of Formula (X), or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host:

(X)

wherein:

ϋ) R¹ and R² are independently hydrogen, an optionally substituted alkyl,

1 9 carbocycle, aryl, heterocycle or heteroaryl; or R and R can come together to form a bridged 3-8 membered heterocyclic or heteroaromatic ring; iii) X is a halogen, -CN, an optionally substituted lower alkyl, or H;

v) R³ is H or lower alkyl; and

115. Use of the compound of formula:

or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host, wherein:

R¹ is selected from the group consisting of

116. Use of the compound of Formula (XII), or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host:

(XII)

wherein:

1 9

117. Use of the compound of Formula (XIII), or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host:

(XIII)

wherein

Z is selected from the group consisting of:

111

118. Use of the compound of Formula (XIV), or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host:

(XIV)

wherein:

Z is selected from the group consisting of

119. Use of the compound selected from the group comprising of:

or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment and prophylaxis of a hepatitis B and/or hepatitis D virus infection in a host.

120. The use of any one of claims 92- 119, wherein the host is a mammal.

121. The use of claim 120, wherein the host is a human.

122. The use of any one of claims 92-119, wherein said compound is in the form of a dosage unit.

123. The use of claim 122, wherein the dosage unit contains 10 to 1000 mg of said compound.

124. The use of claim 122 or 123, wherein said dosage unit is a tablet or capsule.

i

125. The method of any one of claims 61-88, wherein the host is a mammal.

126. The method of claim 125, wherein the host is a human.