Background of the Invention Herpesviruses inflict a wide range of diseases against humans and animals.

For instance, herpes simplex viruses, types 1 and 2 (HSV-1 and HSV-2), are responsible for cotd sores and genital lesions, respectively; varicella zoster virus (VZV) causes chicken pox and shingles; and the human cytomegalovirus (HCMV) is a leading cause of opportunistic infections in immunosuppressed individuals.

Herpesviruses are complex double-stranded DNA viruses that encode all the enzymes that directly mediate viral chromosomal replication. Seven DNA replication-associated polypeptides are required for human herpesvirus replication. Six of these seven polypeptides show a high degree of homology across all studied human herpesviruses. These six polypeptides, when expressed by the virus, constitute a heterodimeric DNA-dependent DNA polymerase, a monomeric single-stranded DNA binding protein, and a heterotrimeric helicase-primase complex. The seventh DNA replication- associated polypeptide does not display sequence or functional conservation and is involved in the initiation of lytic viral replication.

Without the function of each of the seven herpesvirus-specific DNA replication proteins, herpesvirus chromosomal replication will not initiate or propagate. This has been demonstrated in two ways for DNA replication in

HSV-1. First, temperature sensitive HSV-1 strains have been developed and the complementation groups within these strains mapped on a one-to- one correspondence to the seven HSV DNA replication genes. Additionally, transient replication assays that utilized recombinant DNA plasmids containing single DNA replication genes have found that the presence of each of the seven genes was required for the efficient replication of a tester plasmid containing an HSV-1 origin of DNA replication.

More recently, the DNA replication genes in other herpesviruses (i. e., Epstein-Barr virus, cytomegalovirus and varicella zoster virus) have been delineated. These gene sequences were identified as homologous to the HSV-1 DNA replication genes. Furthermore, transient replication assays containing either an Epstein-Barr virus or cytomegalovirus lytic origin of DNA replication confirmed their identity. In varicella zoster virus (the human herpesvirus most closely related to HSV-1) DNA replication genes were found to be highly homologous to HSV-1 (>50% at the amino acid level) and present at identical relative locations on the two viral chromosomes.

Although no follow-up analysis on varicella zoster virus DNA replication genes has been presented to date, it is highly unlikely that differences in the varicella zoster virus and HSV-1 DNA replication programs exist.

From the above, it is clear that human DNA replication proteins are unable to substitute for the HSV-1 encoded enzymes. Otherwise, temperature- sensitive viral polypeptides would have been complemented by human counterparts and the defective viruses would have continued to grow and replicate, even at elevated temperatures. Similarly, in transient replication assays, if human proteins were capable of complementing any of the seven herpesvirus-encoded polypeptides, an absolute dependence on the presence of each of these herpesvirus DNA replication-specific genes would not have been observed. Therefore, inhibiting the activity of those virally- encoded proteins represents an effective way of preventing herpesviral replication.

The helicase-primase enzyme occupies a key and critical place in the herpesvirus DNA replication program. The observation that the genes encoding the herpes helicase-primase are not only essential for replication, but are also highly conserved across the range of known herpesviruses underscores the importance of this enzyme in mediating viral chromosomal replication.

In the helicase-primase complex, two of the three polypeptides (e. g., the expression products of the UL5 and UL52 genes of HSV-1) promote catalysis of duplex DNA unwinding and RNA primer biosynthesis. The third polypeptide, encoded by the UL8 gene, appears to modulate primase activity. The assembled helicase-primase enzyme complex functions both in the initiation and propagation stages of herpesvirus DNA replication. It is responsible for the synthesis of RNA primers necessary for the initiation of all new DNA synthesis by the herpesvirus DNA polymerase. Additionally, for DNA replication to proceed, duplex viral chromosomal DNA must first be unwound to the single-stranded replicative intermediate because the herpesvirus DNA polymerase is inactive on fully duplex DNA. The helicase- primase is also responsible for this important DNA unwinding event.

Conventional anti-herpes therapies have not focused on inhibiting the activity of the herpes helicase-primase (see R. E. Boehme et al., Annual Reports in Medicinal Chemistry, The most widely used anti- herpes agents to date are purine and pyrimidine nucleoside analogs, such as acyclovir and ganciclovir. These nucleoside analogues inhibit replication of viral DNA by their incorporation into a growing DNA strand. The nucleoside analogue-based inhibitors of HSV-1 growth have found only limited success and are not generally useful in treating recurring infections in the majority of patients. In addition, the infection of humans by other herpesviruses, such as varicella zoster virus or cytomegalovirus, show little or no responsiveness to nucleoside-based therapies.

The lack of broad spectrum anti-herpesvirus activity by the nucleoside- based therapies is not surprising because these compounds act by indirect

biological mechanisms. Nucleoside analogues must first be activated to the nucleoside monophosphate by a virally-encoded thymidine kinase enzyme.

It should be pointed out that only HSV and varice ! ta zoster virus encode thymidine kinase enzymes. This may, in part, explain the inability to adapt nucleoside-based therapies to the treatment of other human herpesviruses.

After initial phosphorylation, the nucleoside analogue monophosphate must be further phosphorylated to the triphosphate by human-encoded enzymes prior to its action. Ultimately, the triphosphorylated nucleoside analogue is incorporated into a nascent DNA chain during viral genomic replication, thereby inhibiting the elongation of that DNA chain by the herpes DNA polymerase.

The final incorporation step of the nucleoside-based therapies has been characterized as"competitive"because the herpes DNA polymerase does not display a preference for the activated nucleoside drug versus normal deoxynucleoside triphosphates. However, because the action of the DNA polymerase is not considered rate-limiting for herpesvirus DNA replication, the utility of nucleoside-derived compounds in treating herpesvirus infections is necessarily limited. Accordingly, the need for effective, safe therapeutic agents for treating herpesvirus infections continues to exist.

Y. Kawamatsu et al., Eur. J. Med. Chem.-Chimica Therapeutica, 1981,16, 355; K. D. Hargrave et al., J. Med. Chem., 1983,26,1158; T. Nakao et al., Japanese patent application 63-060978, published September 1,1986; Chem. Abstr., 135228r; C. G. Caldwell et al., US patent 4,746,669, issued May 24,1988; J. A. Lowe, European patent application 279,598, published August 24, 1988; A. A. Nagel, European patent application 372,776 published June 13,1990; J. A. Lowe et al., J. Med. Chem., 1991,34,1860; A. Bernat et al., Canadian patent application 2,046,883, publisehd June 30, 1991; A. Wissner, US patent 5,077,409, issued December 31,1991;

Y. Katsura et al., European patent application 545,376, published June 9, 1993; J. E. Macor and J. T. Nowakowski, PCT patent application WO 93/18032, published September 16,1993; D. I. C. Scopes et al., UK patent application 2,276,164, published September 21,1994; A. Leonardi et al., PCT patent application WO 95/04049, published February 9,1995; G. D. Hartman et al., PCT patent application WO 95/32710, published December 7,1995; J. J. Crute et al., PCT patent application WO 97/24343, published July 10, 1997; C. N. Selway and N. K. Terret, Bioorganic & Medicinal Chemistry, 1996,4, 645; and F. C. Spector et al., J. Virol. 1998,72,6979.

The present non-nucleoside-based compounds can be distinguished from the prior art compounds by their different chemical structures and biological activities.

Summary of the Invention The invention described herein overcomes the above-mentioned limitations and satisfies the above-mentioned needs by providing non-nucleoside- based compounds, which are inhibitors of herpes viral replication, such as for example inhibitors that act directly in interfering with the likely rate- limiting process in herpesvirus DNA replication: the action of the helicase- primase enzyme. Furthermore, since the herpesvirus helicase-primase enzyme is conserved across the human herpesviruses, such compounds of this invention are effective against the full spectrum of herpesviruses, including HSV, varicella zoster virus and cytomegalovirus, and also against nucleoside-nonresponsive and nucleoside-resistant herpes infections.

The non-nucleoside-based compounds may be characterized by having a five-or six-membered heterocycle attached to a phenyl or pyridinyl ring. Compounds possessing such a moiety have been reported previously, for example: The non-nucleoside-based compounds are represented by formula 1 X-Aryl-Y-Z (1) wherein (i) X is selected from the group consisting of: H, H2NC (O) NHCHMe, NH2S (O) 2,

Aryl is selected from the group consisting of: wherein

R is H or lower alkyl, and R3 is H; lower alkyl; (lower cycloalkyl)- (lower alkyl) (e. g. CH2-(cyclohexyl); phenyl (lower alkyl); phenyl (lower alkyl) monosubstituted, disubstituted or trisubstituted on the aromatic portion thereof with a substituent or substituents selected independently from the group consisting of halo, hydroxy, lower alkoxy, lower alkoxy, lower alkyl, azido and trifluoromethyl; CH2-Het; or CH2- (bicyclic heterocyclic system); and Z is NR4R5 wherein R4 is H, phenyl (lower alkyl) (e. g. CH2Ph) or phenyl (lower alkyl) monosubstituted, disubstituted or trisubstituted on the aromatic portion thereof with a substituent or substituents selected independently from the group consisting of halo, hydroxy, lower alkoxy, lower alkyl, azido and trifluoromethyl, or R4 is selected from the group consisting of:

and Rs is selected from the group consisting of: C (O) (CH2) 5NH2; CH2C (O) N (Me) CH2Ph; CH2C (O) NHCH2Ph; C (O) CH20H; or R5 is when R4 is or a mono-, di-or trisubstituted phenyl (lower alkyl) wherein each substituent is on the aromatic portion and is selected independently from azido and trifluoromethyl; or R5 is when R4 is or a mono-, di-or trisubstituted phenyl (lower

alkyl) wherein each substituent is on the aromatic portion and is selected independently from azido and trifluoromethyl; or R5 is selected from the group consisting of: when R3 is CH2-(cyclohexyl);

or R5 is or C (O) OCMe3 when R3 is CH2CH2CH2NH2, or R5 is when X is or R5 is C (O) Ph, when X is NH2S (O) 2, H2NC (O) NHCHMe,

or R5 is phenyl (lower alkyl) or mono-, di-or trisubstituted phenyl (lower alkyl) wherein each substituent is on the aromatic portion and is selected independently from azido and trifluoromethyl, when X is or R5 is C (O) OCMe3, when X is

or (ii) X and Aryl are as defined above; wherein R is H or lower alkyl, and

Z is selected from the group consisting of: CH20CH2Ph, CH20Ph, OCH2CHMe2, CH2CH2Ph, CH2CH2CH2Ph, CH2SCH2Ph, CH=CHPh, CH2CH2CH2CH2C (O) NPh2, CH2CH2CH2CH2CH2NH2, CH2CH2NH2, CH (NH2) (CH2) 4NHC (O) OCH2Ph, (S)- CH (NHCH2Ph) (CH2) 4NHC (O) OCH2Ph, (S)-CH2C (O) NHCH (Me) Ph, (R)-CH (NH2) (CH2) 4NHC (O) OCH2Ph, CH2CH2NH2, CH2CH2NHC (O) CH2N (CH2Ph) 2, CH2CH2NHC (O) N (CH2Ph) 2, CH2CH2CH2C (O) N (CH2Ph) 2, CH2CH2C (O) N (CH2Ph) 2,

or (iii) X and Aryl are as defined above; Y is absent (i. e. a valence bond); and

Z is selected from the group consisting of: NHCH2C (O) N (Me) CH2Ph, NHCH2C (O) NHCH2Ph, OCH2C (O) N (Me) CMe3, OCH2C (S) NHCH2Ph, NHC (S) NHCH2Ph, C (O) OMe, CH2CH2NH-S (0) 2-CH2Ph, CH2CH2NHC (O) CH2CH2C (O) Ph, CH2CH2N (CH2Ph) C (O) CH2Ph, CH2CH2N (CH2Ph) S (0) 2CH2Ph, CH2CH2NHC (O) CH2CH2C (O) NHCH2Ph, CH2CH2NHC (O) CH2NHC (O) OCMe3, CH2CH2NHCH2C (O) N (CH2Ph) 2, CH2NHCH2C (O) N (CH2Ph) 2,

or (iv) X is selected from the group consisting of:

Y is absent; and Z is selected from the group consisting of: NHC (O) NH-CHPr2, NHC (S) NBu2, NHC (O) NBu2, NHC (O) CH2CH2N (CH2Ph) 2, or (v) X and Aryl together form X'which is defined as and Y and Z are as defined in paragraph (i).

A preferred group of compounds is represented by formula 1 wherein X is Aryl is wherein R2 is hydrogen and R3 is H,

Z is NR4R5 wherein R4 is H, CH2Ph, R5 is C (O) Ph or C (O) CMe3, A more preferred group is represented by formula 1 wherein X is as defined in the last instance, Aryl is

wherein R2 is H and R3 is H, Z is NR4R5 wherein R4 is H, CH2Ph,

, C (O) Ph or C (O) OCMe3.

A most preferred group is represented by formula 1 wherein X is

Aryl is wherein R2 is hydrogen and R3 is H, Z is NR4R5 wherein R4 is H, CH2Ph, R5 is Still another most preferred group is represented by formula 1 wherein X is as defined in the last instance, Aryl is Y is wherein R2 is H and R3 is H or and Z is NR4R5 wherein R4 is H or CH2Ph, and R5 is , C (O) Ph or C (O) OCMe3.

Another preferred group of compounds is represented by formula 1 wherein

X is Aryl is , Y is NH-C (O) and Z is

Another more preferred group is represented by formula 1 where X, Aryl and Y are as defined in the last instance and Z is Still another preferred group of compounds is represented by formula 1 wherein X is , Aryl is and Z is

Still another more preferred group of compounds is represented by formula 1 wherein X, Aryl and Y are defined in the last instance and Z is

Yet another preferred group of compounds is represented by formula wherein X is y Aryl and Y are as

defined herebefore, and Z is NHC (O) NBu2.

Again, another preferred group of compounds is represented by formula 1 wherein X and Aryl together form X1 which is defined as , Y is wherein R3 is H or PhCH2, Y is

as defined hereinbefore and Z is NR4R5 wherein R4 is H or CH2Ph and R5 is C (O) OCMe3.

A further aspect of this invention is to provide compounds useful in the methods of this invention and for pharmaceutical compositions comprising those compounds.

Another aspect of this invention is to provide processes for preparing the compounds of this invention.

Still a further aspect of this invention is to provide pharmaceutical compositions containing the compounds of this invention and methods for treating herpes infection in a mammal using those pharmaceutical compositions.

Detailed Description of the Invention As used herein, the following definitions apply unless otherwise noted: With reference to the instances where (R) or (S) is used to designate the configuration of a radical, e. g. R4 of the compound of formula 1, the designation is done in the context of the compound and not in the context of the radical alone.

The term"halo"as used herein means a halo radical selected from bromo, chloro, fluoro or iodo.

The term"herpes"as used herein refers to any virus in the herpes family of viruses and particularly, to those herpesviruses that encode a herpes helicase-primase homologous to the herpes helicase-primase of HSV-1.

The herpes family of viruses includes, but is not limited to, HSV-1, HSV-2, cytomegalovirus, varicella zoster virus and Epstein-Barr virus.

The term"lower alkanoyl"as used herein, either alone or in combination with another radical, means a straight chain 1-oxoalkyl containing from one to six carbon atoms or a branched chain 1-oxoalkyl containing from four to six carbon atoms; for example, acetyl, propionyl (1-oxopropyl), 2-methyl-1- oxopropyl, 2-methylpropionyl and 2-ethylbutyryl. Note that the term"lower alkanoyl"when used in combination with"lower cycloalkyl"would include " (lower cycloalkyl) carbonyl".

The term" (1-3C) alkyl" as used herein, either alone or in combination with another radical, means alkyl radicals containing from one to three carbon atoms and includes methyl, ethyl, propyl and 1-methylethyl.

The term"lower alkyl"as used herein, either alone or in combination with another radical, means straight chain alkyl radicals containing one to four carbon atoms and branched chain alkyl radicals containing three to four carbon atoms and includes methyl, ethyl, propyl, butyl, 1-methylethyl, 1- methylpropyl, 2-methylpropyl, 1,1-dimethylethyl and 2,2-dimethylpropyl.

The term" (1-8C) alkyl" as used herein means straight and branched chain alkyl radicals containing from one to eight carbon atoms and includes ethyl, butyl, 1-methylpropyl, 1-ethylpropyl, 2,2-dimethylpropyl, 1-ethylbutyl, 2-ethyl- 2-methylbutyl, 2-ethylbutyl, 1-propylbutyl, 2-propylpentyl and the like.

The term"lower alkenyl"as used herein means an aliphatic hydrocarbon containing two to four carbon atoms and one double bond and includes ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl.

The term"lower alkynyl"as used herein means an aliphatic hydrocarbon containing two to four carbon atoms and one triple bond and includes ethynyl, 1-propynyl, 2-propynyl and 1-butynyl.

The term" {1-(lower alkyl)-(lower cycloalkyl)}"as used herein means a lower cycloalkyl radical bearing a lower alkyl substituent at position 1; for example, 1-ethylcyclopropyl, 1-propylcyclopentyl and 1-propylcyclohexyl.

The term"lower cycloalkyl"as used herein, either alone or in combination with another radical, means saturated cyclic hydrocarbon radicals containing from three to seven carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term"lower alkoxy"as used herein means straight chain alkoxy radicals containing one to four carbon atoms and branched chain alkoxy radicals containing three to four carbon atoms and includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy. The latter radical is known commonly as tert-butoxy.

The term"amino"as used herein means an amino radical of formula-NH2.

The term"lower alkylamino"as used herein means alkylamino radicals containing one to six carbon atoms and includes methylamino, propylamino, (1-methylethyl) amino and (2-methylbutyl) amino. The term"di (lower alkyl) amino" means an amino radical having two lower alkyl substituents each of which contains one to six carbon atoms and includes dimethylamino, diethylamino, ethylmethylamino and the like.

The term"Het"as used herein means a monovalent radical derived by removal of a hydrogen from a five-or six-membered saturated or unsaturated heterocycle; said five-membered heterocycle containing from one to four nitrogen atoms (for example tetrazolyl), or said five-or six- membered heterocycle containing from one to three heteroatoms selected from nitrogen, oxygen and sulfur. Optionally, the heterocycle may bear one or two substituents; for example, N-oxido, lower alkyl, phenyl- (1-3C) alkyl, lower alkoxy, halo, amino or lower alkylamino. Examples of suitable heterocycles and optionally substituted heterocycles include pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, 1 H-imidazole, 1-methyl-1 H-imidazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole, 2-methylthiazole, 2- aminothiazole, 2- (methylamino)-thiazole, piperidine, 1-methylpiperidine, 1- methylpiperazine, 1,4-dioxane, morpholine, pyridine, pyridine N-oxide, pyrimidine, 2,4-dihydroxypyrimidine and 2,4-dimethylpyrimidine.

The term"bicyclic heterocyclic system"as used herein, either alone or in combination with another radical, means a heterocycle as defined above fused to one or more other cycle be it a heterocycle or a lower cycloalkyl.

Examples of suitable heterocyclic systems include: thiazolo [4,-b] pyridine, quinoline, or indole.

The term"pharmaceutically acceptable carrier"or"veterinarily acceptable carrier"as used herein means a non-toxic, generally inert vehicle for the active ingredient which does not adversely affect the ingredient.

The term"effective amount"means a predetermined antiviral amount of the antiviral agent, i. e. an amount of the agent sufficient to be effective against the virus in vivo.

The term"inhibit", when used in connection with enzymatic activity, refers generally to inhibiting the enzymatic activity by at least about 50% at a concentration of about 100 M (and preferably at a concentration of about 50 pM, more preferably, at a concentration of about 25; j. M, even more preferably, at a concentration of about 10 M and most preferably, at a concentration of about 5 M or less) in a conventional in vitro assay for enzymatic inhibition. In contrast, the term"inability to inhibit"refers generally to inhibiting enzymatic activity by no more than about 50% at concentration of about 100 lM. For example, a compound with an HSV-1 helicase-primase ICso value of 1.5 tM inhibits HSV-1 helicase-primase activity by 50% at a concentration of 1.5 HM. Therefore, this compound is an HSV-1 helicase-primase inhibitor, as the term is used herein. However, a compound having an Cgo value of 150 M inhibits enzymatic activity by 50% at a concentration of 150 lM and therefore, is not considered an inhibitor of that enzyme.

Processes for preparing the compounds The compounds of this invention can be prepared by a variety of processes.

Description of some such methods are found in standard textbooks such as

"Annual Reports In Organic Synthesis-1994", P. M. Weintraub et al., Eds., Academic Press, Inc., San Diego, CA, USA, 1994 (and the preceding annual reports),"Vogel's Textbook of Practical Organic Chemistry", B. S. Furniss et al., Eds., Longman Group Limited, Essex, UK, 1986, and"Comprehensive Organic Synthesis", B. M. Trost and 1. Fleming, Eds., Pergamon Press, Oxford, UK, 1991, Volumes 1 to 8.

One general process is represented by Scheme 1: Scheme 1

Ruz NC (O)-CH (R3)-N-R5 14AA Ri- i corresponding compound of formula 1 wherein R1, R2, R3 and R5 are as defined herein, Q is absent (i. e. a valance bond) or methylene, and R4AA is an amino protecting group or a radical as defined for R4 hereinbefore other than hydrogen.

According to Scheme 1, a thiazolylaniline derivative of formula 2 is coupled with an amino acid derivative of formula 3 to give a corresponding

aminoamide of formula 4. In the instance where R4AA has the same significance as R4 but excluding hydrogen, then the aminoamide of formula 4 so obtained is a compound of formula 1. In the instance where R4AA is an amino protecting group, the compound of formula 4 so obtained can be deprotected to give the corresponding compound of formula 1 in which R4 is hydrogen. The latter product, albeit a compound of formula 1, can also serve as an intermediate for further elaboration by standard methods to yield compounds of formula 1 in which R4 is other than hydrogen.

The coupling of the 4-thiazolylaniline derivative of formula 2 and the amino acid of formula 3 is effected by the classical dehydrative coupling of a free carboxyl of one reactant with the free amino group of the other reactant in the presence of coupling agent to form a linking amide bond. Description of such coupling agents are found in general textbooks on peptide chemistry; for example, M. Bodanszky,"Peptide Chemistry", 2nd rev ed, Springer- Verlag, Berlin, Germany, 1993. Examples of suitable coupling agents are N, N'-dicyclohexyl-carbodiimide, 1-hydroxybenzotriazole in the presence of N,N'-dicyclohexylcarbodiimide or N-ethyl-N' {(3- dimethylamino) propyl} carbodiimide. A very practical and useful coupling agent is the commercially available (benzotriazol-1-yloxy) tri- (dimethylamino) phosphonium hexafluorophosphate, either by itself or in the presence of 1-hydroxybenzotriazole. Still another very practical and useful coupling agent is commercially available 2- (1 H-benzotriazol-1-yl)-N, N, N', N'- tetramethyl-uronium tetrafluoroborate.

The coupling reaction is conducted in an inert solvent, e. g. dichloromethane, dimethylformamide, tetrahydrofuran or acetonitrile. An excess of a tertiary amine, e. g. diisopropylethylamine or N-methylmorpholine, is added to maintain the reaction mixture at a pH of about eight. The reaction temperature usually ranges between 0° and 50 °C and the reaction time usually ranges between 15 minutes and 24 hours.

A practical and convenient variation of the preceding process (Scheme 1) can be practiced by replacing the 4-thiazolylaniline derivative 2 with 4'- aminoacetophenone. This process is illustrated by Scheme 2: Scheme 2 /NH2 <(3) Me (O) C (5) NHC (O)-Q-CH (R3)-N-R= I R4an Me (O) C (6) /NC (O)-Q-CH (R3) N-R5 AA j4AA Me (O) C (8) NHC (0)-Q-CH (R3)-N-RS I I I/ NUA \ N t R4m/ " Corresponding compound of formula 1 (R2=H) formula 1 (R2=lower alkyl) of formula 1 R/=H)-" wherein R2AA is lower alkyl and R3, R4AA, R5 and Q are as defined hereinbefore.

In Scheme 2, the compound of formula 5, namely 4'-aminoacetophenone, is coupled with amino acid derivative of formula 3, noted hereinbefore, to give a corresponding terminal methyl ketone of formula 6.

The methyl ketone 6 can be used to prepare corresponding compounds of formula 1 wherein R2 is hydrogen as follows: The methyl ketone was reacted with thiourea and iodine according to the method of R. M. Dodson and L. C. King, J. Amer. Chem Soc. 1945,67,2242 to give the corresponding aminothiazole derivative of formula 7. In the instance where R4AA has the same significance as R4 but excluding hydrogen, then the aminothiazole derivative of formula 7 so obtained is a compound of formula 1. In the instance where R4AA is an amino protecting group then the derivative of formula 7 so obtained can be deprotected to give a corresponding compound of Group 1-formula 1 wherein R4 is hydrogen. If desired, the latter derivative can be converted by standard methods (e. g., N- alkylation, acylation, carbamate formation, etc.) with the appropriate agent to give corresponding compounds of formula 1 wherein R4 is as defined hereinbefore other than hydrogen.

Alternately, the methyl ketone of formula 6 can be used to prepare compounds of formula 1 wherein R2 is lower alkyl. Accordingly, the methyl ketone of formula 6 is subjected to N-alkylation with an appropriate lower alkyl bromide, chloride or iodide in the presence of a base to give the corresponding N-alkylated derivative of formula 8 wherein R2AA is lower alkyl and Q, R3, R4AA and R5 are as defined hereinbefore. The latter compound, when R4AA is a radical as defined for R4 of the compound of formula 1 other than hydrogen, can be transformed directly to the corresponding compound of formula 1, wherein R1 is amino, R2 is lower alkyl, R4 is a radical other than hydrogen and Q, R3 and R5 are as defined hereinbefore. The transformation is effected by employing the previously noted method of Dodson and King for aminothiazole formation. On the other hand, the N-alkylated derivative of formula 8 wherein R4AA is an amino protected group can be deprotected to give the corresponding

compounds of formula 1 wherein R1 is amino, R2 is lower alkyl, R4 is hydrogen, and Q, R3 and R5 are as defined hereinbefore.

Still another variation is illustrated by Scheme 3: Scheme 3 (R'is NH2, R2 and R3 each is H, Q is absent, R4 is as defined herein, and R5 is R55 which is as defined herein for R5 with the exception that it is not an acyl group) wherein PG is an amino protecting group, R1 is amino, R2 and R3 each is hydrogen, Q is absent and R4 and R55 are as defined hereinbefore.

According to Scheme 3, the protected aminothiazole derivative of formula 9 wherein PG represents an amino acid protecting group is reacted with bromoacetyl bromide to give the corresponding bromoacetamide 10.

Displacement of the bromine of the latter compound with the appropriate primary or secondary amine gives the corresponding intermediate of formula 11. Removal of the protecting group PG from the latter intermediate gives

the corresponding compound of formula 1 wherein R5 is R55 as defined hereinbefore.

Still another variation, which can be used for preparing compounds of formula 1 in which Q is methylene, is the process represented by Scheme 4: Scheme 4 NHC (O) CH=CH2 MeC (O) (12) 1-NHC (O) CH2CH2N-R5BB Riss MeC (O) (13) R4BB is other than hydroge Corresponding compound of formula 1 (R1 is NH2, R2 and R3 each is hydrogen, Q is CH2, R4 RBB is H is other than H and R5 is R4BB is H R5BB which has the same r significance as RS except that it is not an acyl NHC (0) CH2CH2N-RSBB group) I MeC (14) PG MeC (O) <) Corresponding compound of formula 1 (R1 is NH2, R2 and R3 each is hydrogen, Q is CH2, R4=H and R5 is R5BB as defined herein)

wherein R1 is NH2, R2 and R3 each is hydrogen, Q is methylene, R4BB has the same significance as R4 as described herein, R has the same significance as defined hereinbefore for R5 with the exception it is not an acyl group, and PG is as amino protection group.

According to Scheme 4, N- (4-acetylphenyl)-2-propenamide is reacted with the appropriate primary or secondary amine to give the Michael adduct of formula 13 wherein R4BB has the same significance as defined for R4 hereinbefore, and R5BB has the same significance as defined hereinbefore for R5 with the exception that it is not an acyl group. Thereafter, the Michael adduct of formula 13 wherein R4BB is other than hydrogen is transformed to corresponding compounds of formula 1 by the previously noted method of Dodson and King for aminothiazole formation. However, in the instance wherein R4BB of the Michael adduct is hydrogen, the transformation to corresponding compounds of formula 1 proceeds with protecting the inherent secondary amine with an amino protecting group and the resulting amino protected derivative of formula 14 then is subjected to the Dodson and King method of aminothiazole formation, whereby the amino protecting group is cleaved in situ and the corresponding compound of formula 1 wherein R4 is hydrogen is obtained. If desired, the compounds of formula 1 so obtained according to Scheme 4 can also serve as intermediates for elaboration to other compounds of formula 1 in which Q is methylene by conventional methods.

The amino acid derivative of formula 3, noted in Schemes 1 and 2, can be prepared readily by methods used in peptide chemistry. For example, the N-monosubstituted and N, N-disubstituted glycine derivatives of formula 3, wherein Q is absent, can be prepared by substituting the bromine of the appropriate ethyl bromoacetate with an appropriate primary or secondary amine in the presence of a tertiary amine for example, triethylamine or N- methylmorpholine, to obtain the corresponding a-aminoester having either a monosubstituted or disubstituted amino group. Subsequent hydrolysis with lithium hydroxide of the latter product (or an amino protected derivative thereof in the process involving the primary amine), gives the desired

protected N-monosubstituted, or the desired N, N disubstituted amino acid derivative of formula 3 wherein Q is absent. Likewise, N, N disubstituted a- amino acids of formula 3, wherein Q is methylene, can be prepared by a similar process wherein the ethyl bromoacetate derivative is replaced with the appropriate 3-bromopropionic ethyl ester derivative.

Examples of amino protective groups suitable for use in the above schemes include benzyloxycarbonyl, tert-butoxycarbonyl, 4- methoxybenzyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl.

Other starting materials for the preceding processes are known or they can readily be prepared by standard methods from known starting materials.

For example, 4'-aminoacetophenone (5) is available from the Aldrich Chemical Co., Milwaukee, WI, USA; and the requisite thiazolylaniline derivatives of formula 2 can be obtained by applying the classical thiazole preparation involving reacting the appropriate thioamide or thiourea of formula H2N-C (S)-R1 wherein R1 is hydrogen, amino, lower alkylamino or di (lower alkyl) amino with 2-bromo-4'-nitroacetophenone (Aldrich Chemical Co.) according to method described by R. H. Wiley et al., Organic Reactions 1951,6,369-373 followed by reducing the intermediate product (with a nitro group) with iron powder in the presence of hydrochloric acid to obtain the desired thiazolylaniline derivative of formula 2 wherein R1 is as defined in the last instance. Moreover, the preparation of N- (4-acetylphenyl)-2- propenamide (12) of Scheme 4 is described in example 3 herein; and the preparation of an example of the versatile starting material of formula 9 of Scheme 3 (wherein PG is tert-butoxycarbonyl) is given in example 2 herein.

Other useful starting materials are 3- (4-nitrophenyl) pyridine (M. Ishikura et al., Heterocycles 1984,22,265); 4- (4-aminophenyl) imidazole (I. E. Balaban and H. King, J. Chem. Soc., and 2- (4- aminophenyl) thiazole (B. S. Friedman et al., J. Amer. Chem. Soc., 1937,59, 2262). Similar starting materials which are aminophenyl substituted heterocycles are commercially available.

The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, the reaction can be successfully performed by conventional modification known to those skilled in the art, e. g. by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, or by modification illustrated in the examples herein.

Furthermore, if desired, the compound of formula 1 can be obtained in the form of a therapeutically acceptable acid addition salt. Such salts can be considered as biological equivalent of the compounds of formula 1.

Examples of such salts are those formed with hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid or citric acid.

Antiherpes Activity The antiviral activity of the compounds of formula 1 can be demonstrated by biochemical, microbiological and biological procedures showing the inhibitory effect of the compounds on the replication of herpes simplex viruses, types 1 and 2 (HSV-1 and HSV-2), cytomegalovirus, as well as acyclovir-resistant herpes simplex viruses and ganciclovir-resistant cytomegaloviruses.

A biochemical procedure for demonstrating antiherpes activity for compounds of formula 1 is described in the examples hereinafter. This particular assay is based on the evaluation of the ability of the test compound to inhibit HSV-1 helicase-primase, an essential enzyme for viral DNA replication.

Methods for demonstrating the inhibitory effect of the compounds of formula 1 on herpes viral replication involving in vitro and cell culture techniques are described in the examples.

The therapeutic effect of the compounds of formula 1 can be demonstrated in laboratory animais, for instance, the hairless mouse model for the topical treatment of cutaneous HSV-1 infections, P. H. Lee et al., International Journal of Pharmaceutics, 1993,93,139; the (HSV-2)-induced genitalis mouse model, R. W. Sidewell et al., Chemotherapy, 1990,36,58; and BALB/C mouse model infected with murine cytomegalovirus, D. L. Barnard et al., Antiviral Res., 1993,22,77, and J. Neyts et al., Journal of Medical Virology,1992,37,67.

When a compound of formula 1, or one of its therapeutically acceptable acid addition salts, is employed as an antiviral agent, it is administered orally, topically or systemically to warm-blooded animals, e. g. humans, pigs or horses, in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice. For oral administration, the compound or a therapeutically acceptable salt thereof can be formulated in unit dosage forms such as capsules or tablets each containing a predetermined amount of the active ingredient, ranging from about 25 to 500 mg, in a pharmaceutically acceptable carrier. For topical administration, the compound can be formulated in pharmaceutically accepted vehicles containing 0.1 to 5 percent, preferably 0.5 to 5 percent, of the active agent.

Such formulations can be in the form of a solution, cream or lotion.

For parenteral administration, the compound of formula 1 is administered by either intravenous, subcutaneous or intramuscular injection, in compositions with pharmaceutically acceptable vehicles or carriers. For administration by injection, it is preferred to use the compounds in solution in a sterile aqueous vehicle which may also contain other solutes such as buffers or

preservatives as well as sufficient quantities of pharmaceutically acceptable salts or of glucose to make the solution isotonic.

Suitable vehicles or carriers for the above noted formulations are described in standard pharmaceutical texts, e. g. in"Remington's The Science and Pratice of Pharmacy", 19th ed., Mack Publishing Company, Easton, Penn., 1995, or in"Pharmaceutical Dosage Forms And Drugs Delivery Systems", 6th ed., H. C. Ansel et al., Eds., Williams & Wilkins, Baltimore, Maryland, 1995.

The dosage of the compound will vary with the form of administration and the particular active agent chosen. Furthermore, it will vary with the particular host under treatment. Generally, treatment is initiated with small increments until the optimum effect under the circumstance is reached. In general, the compound of formula 1 is most desirably administered at a concentration level that will generally afford antivirally effective results without causing any harmful or deleterious side effects.

For oral administration, the compound or a therapeutically acceptable salt is administered in the range of 10 to 200 mg per kilogram of body weight per day, with a preferred range of 25 to 150 mg per kilogram.

With reference to topical application, the compound of formula 1 is administered topically in a suitable formulation to the infected area of the body e. g. the skin, the eye, the genitalia or part of the oral cavity, in an amount sufficient to cover the infected area. The treatment should be repeated, for example, every four to six hours until lesions heal.

For ocular administration, the compound of formula 1 is administered either topically or intraocularly (injection or implant) in a suitable preparation. For example, an implant containing the compound in a suitable formulation can be surgically placed in the posterior segment of the eye through a small incision.

With reference to systemic administration, the compound of formula 1 is administered at a dosage of 10 mg to 150 mg per kilogram of body weight per day, although the aforementioned variations will occur. However, a dosage level that is in the range of from about 10 mg to 100 mg per kilogram of body weight per day is most desirably employed in order to achieve effective results.

Although the formulations disclosed hereinabove are indicated to be effective and relatively safe medications for treating herpes viral infections, the possible concurrent administration of these formulations with other antiviral medications or agents to obtain beneficial results also included.

Such other antiviral medications or agents include the antiviral nucleosides, for example, acyclovir, penciclovir, famciclovir, valacyclovir and ganciclovir, and antiviral surface active agents or antiviral interferons such as those disclosed by S. S. Asculai and F. Rapp in U. S. patent 4,507,281, March 26, 1985.

The following examples further illustrate and teach this invention.

Temperatures are given in degrees Celsius. Solution percentages or ratios express a volume to volume relationship, unless stated otherwise. Nuclear magnetic resonance spectra were recorded on a Bruker 400 MHz spectrometer; the chemical shifts (8) are reported in parts per million. The concentrations for the optical rotations are expressed in grams of the compound per 100 mL of solution. Abbreviations or symbols used in the examples include ATP: adenosine triphosphate; Boc: tert-butoxycarbonyl or BOP: (benzotriazole-1-yloxy) tris- (dimethylamino) phosphonium hexafluorophosphate; Bu: butyl; DIPEA: diisopropylethylamine; DMAP: 4- (dimethylamino) pyridine; DMF: dimethyl- formamide; DMSO: dimethylsulphoxide; Et: ethyl; EtOAc: ethyl acetate; Et20: diethyl ether; Et3N: triethylamine; EtOH: ethanol; MS (FAB) or FAB/MS: fast atom bombardment mass spectrometry; Hex: hexane; mAb: monoclonal antibody; Me: methyl; MeOH: methanol; PFU: plaque forming units; Ph: phenyl; Pr: propyl; TBTU: 2-(1H-benzotriazol-1-yl)-N, N, N', N'

tetramethyluronium tetrafluoroborate; TFA: trifluoroacetic acid; THF: tetrahydrofuran.

EXAMPLES Example 1 N-{2-{{4-(2-amino-4-oxazolyl) phenyl} amino}-2-oXoethyl}-N- (benzyl) benzamide (a) 2-{(benzoyl) (benzyl) amino} acetic acid To a mixture of benzylamine (54.6 mL, 0.5 mol) and triethylamine (140 mL, 1 mol) in THF (1 L) at 0° was added ethyl bromoacetate (83.5 g, 0.5 mol) over a 15 min period. The resulting mixture was stirred at 0° for an additional 15 min then at room temperature for 45 min after which time, the reaction was complete as indicated by TLC. The mixture was then cooled to 0° and benzoyl chloride (58 mL, 0.5 mol) was added over a 30 min period.

Thereafter, the mixture was allowed to come to room temperature while being stirred for an additional 30 min. The reaction was complete (TLC).

The reaction mixture was then added to a solution of LiOH. H20 (83.92 g, 2 mol) in H20 (500 mL) followed the addition of MeOH (500 mL). After stirring at room temperature for 16h, 10 mL of aqueous 10N NaOH was added to the mixture, and the mixture was gently heated at reflux for 3h. Thereafter, THF and MeOH were removed under reduced pressure and the resulting

solution was diluted with H20 to 2L. This solution was washed with EtOAc, acidified to pH 3 with concentrated aqueous HCI, and then extracted with EtOAc. The organic solution was washed with brine, dried (MgS04) and concentrated under reduced pressure to afford 108.4 g of the desired acid as a white solid. MS (FAB) 270 (MH) +.'H NMR (400 MHz, DMSO) 10.37 (broad s, 1H), 7.22-7.44 (m, 10 H), 4.67,4.51 (2 s, 2 H, 1: 1 mixture of 2 rotamers), 3.98,3.82 (2 s, 2H, 2 rotamers). b) N-{2-{(4-acetylphenyl) amino}-2-oxoethyl}-N-(benzyl) benzamide To a solution of 4'-aminoacetophenone (5.27 g, 38.98 mmol) in DMF (100 mL) was added 2- {(benzyl)-(benzoyl) amino} acetic acid (10 g, 37.13 mmol), BOP reagent (17.24 g, 38.98 mmol) and DIPEA (19.4 mL, 111.4 mmol).

The resulting mixture was stirred for 16 h at room temperature. The resulting solution was diluted with EtOAc (1 L), washed with H20 (2 x 500 mL), aqueous 1 N HCI (2 x 250 mL), H20 (100 mL), saturated aqueous NaHC03 (2 x 220 mL) and brine (200 mL). The organic solution was dried (MgS04) and concentrated to afford 10.2 g of a light orange foam which was purified by trituration with EtOAc-hexane (1: 2) to afford 8.3 g of the desired acetamide intermediate as a white solid. MS (FAB) 287 (MH) +.'H NMR (400 MHz, DMSO) 10.18,10.36 (2 s, 1 H, 1: 1 mixture of 2 rotamers), 7.90- 7.94 (m, 2 H), 7.62,7.72 (2 d, J = 8.4 Hz, 1 H, 2 rotamers), 7.25-7.45 (m, 10 H), 70 (2 s, 2 H, 2 rotamers), 3.98,4.16 (2 s, 2 H, 2 rotamers). c) N-(benzyl)-N-{{{4-(2-bromoacetyl) phenyl} amino}-2- oxoethyl} benzamide

Phenyl trimethylammoniumtribromide (3.52 g, 4.37 mmol) was added portion wise to a stirred solution of N-{2-{(4-acetylphenyl) amino}-2-oxoethyl}-N- (benzyl) benzamide (2.5 g, 6.46 mmol) in THF (150 mL) at room temperature. The resulting mixture was then stirred for 2h. The reaction was stopped by the addition of EtOAc (300 mL). The resulting solution was washed with aqueous 1 N HCI, H2O, saturated aqueous NaHC03 and brine, dried (MgS04) and concentrated to afford 3.72 g of the desired bromoketone as a light yellow solid. MS (FAB) 467 (MH) +.'H NMR (400 MHz, DMSO) 46 (2 s, 1 H, 1: 1 mixture of 2 rotamers), 7.96 (t, J = 8.9 Hz, 2H), 7.65,7.75 (2d, J=8. 7Hz, 2H), 7.26-7.45 (m, 10H), 4.84,4.85 (2s, 2H, 2 rotamers), 4.57,4.71 (2 s, 2 H, 2 rotamers), 18 (2 s, 2 H, 2 rotamers). d) N-{2-{{4-(2-amino-4-oxazolyl) phenyl} amino}-2-oXoethyl}-N- (benzyl) benzamide To a solution of N-(benzyl)-N-{{{4-(2-bromoacetyi) phenyl} amino}-2- oxoethyl) benzamide (3.0 g, 6.46 mmol) in DMF (60 mL) was added urea (1.93 g, 32.9 mmol). The resulting mixture was stirred at room temperature for 14 h. The reaction mixture was diluted with EtOAc (250 mL). The resulting organic solution was washed with saturated aqueous NaHC03, H20 (3 x 100 mL), brine, dried (MgS04) and concentrated under reduced pressure. The resulting crude product was purified by two successive flash column chromatography operations using 2: 1 EtOAc-hexane, then 20: 1 CHC13-EtOH to afford 94 mg of the title compound. MS (FAB) 427 (MH) +.'H NMR (400 MHz, DMSO) 04 (2 s, 1 H, 1: 1 mixture of 2 rotamers), 7.77 (s, 1H), 7.31-7.57 (m, 14 H), 6.65 (s, 2 H), 4.56,4.65 (2 s, 2 H, 2 rotamers), 3.93,4.12 (2 s, 2H, 2 rotamers).

Example 2 tert-Butyl N- {4- (4-Aminophenyl)-2-thiazolyl}-carbamate (a versatile starting

material of Scheme 3) 2,2,2-Trichloroethyl N- {4-(2-amino-4-thiazolyl)-phenyl} carbamate: 2,2,2- Trichloroethyl chloroformate (72.3 mL, 0.52 mol) was added (5 min) to an ice cold suspension of 4'-aminoacetophenone (67.6 g, 0.50 mol) and pyridine (50.5 mL, 0.62 mol). The reaction mixture was stirred at 0° for 15 min and then at room temperature (20-22°) for 45 min. The solvent was removed under reduced pressure. Et20 (500 mL) and 1 N aqueous HCI (500 mL) were added to the residue. The resulting solid was collecte by filtration, washed with H20 (1 L) and Et20 (1 L), and dried over P205 in a desiccator under reduced pressure for 15 h to yield the expected carbamate (137.8 g, 89% yield). A mixture of the crude carbamate (137.8 g, 0.44 mol), thiourea (135.0 g, 1.77 mol) and 12 (202.6 g, 0.80 mol) in isopropanol (670 mL) was heated at reflux for 18 h. The reaction mixture was cooled to room temperature and EtOAc (1 L) was added. The solution was successively washed with H20 (2 x 600 mL), saturated aqueous NaHC03 (2 x 1 L) and then H20 (2 x 1 L). A mixture of the organic layer and saturated aqueous 4N HCI (750 mL) was stirred vigorously at room temperature for 1.5 h. Et20 (-800 mL) and H20 (-300 mL) were added to the mixture to facilitate stirring. The suspension was filtered and the solid was washed with a 1: 1 mixture of EtOAc and Et20 (2 L). The solid was suspended in 20% aqueous NaOH (1.2 L). The mixture was extracted with EtOAc. The EtOAc extract was washed with brine (700 mL), dried (MgSO4) and concentrated under reduced pressure to yield 2,2,2-trichloroethyl N- {4- (2-amino-4- thiazolyl) phenyl} carbamate (117.7 g, 75% yield) as a pale yellow solid: 1 H NMR (400 MHz, DMSO-d6) 6 10.18 (s, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8. 6 Hz, 2H), 7.01 (s, 2H) 6.88 (s, 1H), 4.95 (s, 2H); MS (FAB) m/z 366/368/370/372 (MH) +.

Example 3 N- (4-Acetylphenyl)-2-propenamide (a versatile starting material of Scheme 4)

A solution of acryloyl chloride (29.5 mL, 363 mmol) in CH2CI2 (50 mL) was added dropwise (30 min) to an ice-cold solution of 4'-aminoacetophenone (49.0 g, 363 mmol) and Et3N (50.6 mL, 363 mmol) in CH2CI2 (300 mL).

The reaction mixture was stirred at 0° for 15 min and then was concentrated under reduced pressure. The residue was dissolve with EtOAc. The solution was washed successively with 10% aqueous HCI, saturated aqueous NaHC03 and H20. The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford the desired N- (4- acetylphenyl)-2-propenamide (52 g, 76% yield) as a yellow solid: 1 H NMR (400 MHz, CDCI3) 6 8.17 (broad s, 1H), 7.93 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 8.9 Hz, 2H), 6.47 (dd, J = 1.0,16.9 Hz, 1 H), 6.33 (dd, J = 9 Hz, 1 H), 5.80 (dd, J = 2 Hz, 1 H), 2.58 (s, 3H); MS (FAB) mlz 190 (MH) +.

Example 4 The following four assays (A, B and Ci and Cii) were used to evaluate antiherpes activity, and a fifth assay (D) was used to measure the stabilization of the DNA-herpes helicase-primase interaction.

A) HSV-1 DNA-Dependent ATP Assay (an in vitro assay based on the inhibition of HSV-1 helicase-primase). a) Preparation of enzyme: HSV-1 helicase-primase holoenzyme was produced in triply infected Sf21 cells using recombinant baculoviruses expressing the UL5, UL8 and UL52 helicase-primase subunits, as described by S. Dracheva et al., J. Biol. Chem. 1995,270,14148. The crude enzyme was purified by ammonium sulfate precipitation, Source 15Q@ chromatography and SephacrylX S-300 HR gel filtration (both purification systems can be obtained from Pharmacia Biotech Inc., Montreal, Quebec, Canada), see S. Dracheva et al., supra.

b) Assav: The DNA-dependent ATPase assay, described by J. J. Crute et al., Nucleic Acids Res. was modified and used to evaluate the capability of the compounds of formula 1 to inhibit HSV-1 helicase-primase activity. The reaction mixtures (80; j. L each) contained 40 mM 4- (2- hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES, pH 7.5), 10% (vlv) glycerol, 5.5 mM MgCI2,1 mM DL-dithiothreitol (DTT), 50 g/mL acetylated bovine serum albumin, 3.3% (vlv) DMSO, 4 mM ATP, 25 M single-stranded M13 DNA hybridized to double-tailed 68-mer oligonucleotide and 3 g/mL HSV-1 helicase-primase. After incubation for 20 min at 34°, formation of inorganic phosphate from hydrolysis of ATP was monitored spectrophotometrically at 650 nm using acidic ammonium molybdate/malachite green reagent, P. A. Lanzetta et al., Anal. Biochem.

DNA-dependent ATPase activity was calculated from the net absorbance change in the presence and absence of inhibition.

B) Inhibition of Herpes Simplex Virus (HSV-1) Replication in Cell Culture Assav: BHK-21 cells clone 13 (ATCC CCL10) were incubated for two days in 850 cm2 roller bottles (2x107 cells/bottle) with a-MEM medium (Gibco Canada Inc., Burlington, Ontario, Canada) supplemented with 8% (vlv) fetal bovine serum (FBS, Gibco Canada, Inc.). The cells were trypsinized and then 3,000 cells in 100 pL of fresh medium were transferred into each well of a 96-well microtiter plate. The cells were incubated at 37° for a period of 3 days to reach a density of 50,000 cells per well. The cells were washed twice with 100 tL of a-MEM supplemented with 2% heat inactivated FBS and incubated for 1-2 hours in 100 pL of the same medium.

Thereafter, the cells were infected with HSV-1 strain F or KOS (multiplicity of infection = 0.05 PFU/cell) in 50 L of a-MEM supplemented with 2% heat inactivated FBS. Following one hour of virus absorption at 37°, the medium was removed and the cells were washed with a-MEM supplemented with 2% heat inactivated FBS (2 x 100 ut). The cells were incubated with or without 100 lu of the appropriate concentration of test reagent in a-MEM medium supplemented with 2% heat inactivated FBS. After 24 hours of incubation at

37°, the extent of viral replication was determined by an ELISA assay; for instance, the following assay that detects the late glycoprotein C of HSV-1.

Cells were fixed in the microtiter plate with 100 L of 0.063% glutaraldehyde in phosphate buffered saline for 30 min at room temperature. The microtiter plate was then washed once with casein blocking solution and blocked with 200 L of the same solution for one hour at room temperature. Thereafter, 100 L of mAb C11 recognizing the glycoprotein C of HSV-1 (see E. Trybala et al., Journal of General Virology, 1994,75,743) was added to each well for two hours at room temperature. The plate was washed three times with phosphate buffered saline containing 0.05% polyoxyethylene (20) sorbitan monooleate. The cells were incubated with 100 L of sheep anti-mouse IgG horseradish peroxidase for one hour at room temperature in the dark.

The plate was washed three times with 200 L of the above-noted phosphate buffer saline preparation, and then once with 0.1 M sodium citrate (pH 4.5). Thereafter, 100 L of orthophenylenediamine dihydrochloride (OPD, Gibco, Canada Inc.) was added to each well. The plate was agitated on a microplate shaker for 30 min in the dark. Color development was monitored at 450 nm using a microplate spectrophotometer.

SAS was used to calculate % inhibition of viral replication and to generate ECso values.

C) Inhibition of Human Cytomegalovirus (HCMV) replication The effect of compounds on the replication of HCMV has been measured by using an ELISA-based assay (ELISA) and a plaque reduction assay (PRA).

Ci) ELISA ASSAY: Hs-68 cells (ATCC # CRL 1635) were seeded in 96 well microtiter plates at 10,000 cells/well in 100 ptL of DMEM medium (Gibco Canada Inc.)

supplemented with 10% fetal bovine serum (FBS, Gibco Canada Inc.). The plates were incubated for 3 days at 37° to allow the cells to reach 80-90% confiuency prior to the assay.

The medium was removed from wells by aspiration. The cells then were infected at a multiplicity of infection (MOI) of 0.01 PFU/cell with 50 LL of HCMV (strain AD169, ATCC VR-538) in DMEM medium supplemented with 5% heat inactivated FBS (assay medium). The virus was allowed to adsorb to cetls for 2 h at 37°. Following viral adsorption, the medium was removed from the wells by aspiration. The cells were washed twice with 200 L of assay medium to remove unabsorbed virus. The cells were then incubated with or without 100 L of appropriate concentrations of test reagent in assay medium. After 8 days of incubation at 37°, the extent of viral replication was determined by an ELISA assay which detects the late structural protein p28 of HCMV.

Eight days after infection, the medium was aspirated from the wells. Non- specific binding sites were blocked by adding 200 FLL of phosphate buffered saline containing 1 % (wlv) bovine serum albumin (blocking buffer) to each well and incubating the plates for 30 min at room temperature. After removal of the blocking buffer by aspiration, the cells were fixed with 100 cl of cold ethanol-acetone solution (95: 5) per well. The plates were placed at- 20° for 30 min. The plates were washed 4 times with phosphate buffered saline containing 0.05% (vlv) polyoxyethylene sorbitan monolaurate (Tween 20@). Thereafter, 100 L of mAb UL99 (Advanced Biotechnologies Inc., # 13-130-100) recognizing HCMV protein p28 was added to each wells and plates were incubated for 2 h at room temperature. The plates were washed four times with 200 L of the above-noted phosphate buffered saline/Tween- 20@ solution. The cells were then incubated with 100 pL of sheep anti- mouse IgGy horseradish peroxidase conjugated for 2 h at room temperature. The plates were then washed four times with 200 pL of above- noted phosphate buffered saline/Tween-20@ solution. Thereafter, 100 IlL of ortho phenylenediamine dihydrochloride (OPD, Gibco Canada Inc.) solution was added to each well and the plates were agitated on a microplate shaker

for 30 min in the dark. Color development was monitored at 450 nm using a microplate spectrophotometer.

The SAS program was used to calculate the % inhibition of viral replication and to generate ECso values.

The EC50 values obtained according to this assay method for certain thiazolylphenyl derivatives of this invention are listed in the following tables under the heading ELISA CMV.

Cii) PRA ASSAY: Hs-68 cells (ATCC # CRL 1635) were seeded in 12-well plates at 83,000 cells/well in 1 mL of DMEM medium (Gibco Canada Inc.) supplemented with 10% fetal bovine serum (FBS, Gibco Canada Inc.). The plates were incubated for 3 days at 37° to allow the cells to reach 80-90% confluency prior to the assay.

The medium was removed from the cells by aspiration. The cells were then infected with approximately 50 PFU of HCMV (strain AD169, ATCC VR-538) in DMEM medium supplemented with 5% inactivated FBS (assay medium).

The virus was allowed to adsorb to cells for 2 h at 37°. Following viral adsorption, the medium was removed from the wells by aspiration. The cells were then incubated with or without 1 mL of appropriate concentrations of test reagent in assay medium. After 4 days of incubation at 37°, the medium was exchanged with fresh medium containing test compound and 4 days later the cells were fixed with 1 % aqueous formaldehyde and stained with a 2% crystal violet solution in 20% ethanol in water. Microscopic plaques were counted using a stereomicroscope. Drug effects were calculated as a percent reduction in the number of plaques in the presence of each drug concentration compared to the number observed in the absence of drug.

Ganciclovir was used as a positive control in all experiments.

The ECso values obtained according to this assay for certain thiazolyl derivatives of this invention are listed in the following tables under the heading PRA CMV.

Example 5 In conjunction with the appropriate starting materials and intermediates, the aforementioned procedures can be used to prepare other compounds of this invention. Examples of compounds thus prepared are listed in Tables 1 to 7, together with mass spectrum data for the individual compounds and the results obtained from three assays demonstrating antiherpes activity.

TABLE 1 Compound of formula 1 having the structure wherein R'is NH2, R2 is H, R3 is H, and R4 and R5 are designated as follows: Entry R4 R5 HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (m/z) HM tim ECso ECso (MH) + M) nM 101 H I w vCH2 102CHsPh/-\>5032>59450 103 \__i CH2< C (O) ^<tsNH CHZ-- () C (O)-- (. NH U U TABLE 1<BR> Compound of formula 1 having the structure wherein R¹ is NH2, R² is H, R3 is H, and R4 and Rs are designated as follows: tntry R R6 HSV-1 HSV-1 ELISA PRA FAB/MS No. ECso ECso CMV CMV (m/z) zM nM ECso ECso (MH) + M RM 104 CH2Ph >2 547 C 0.66 501 105 CH2<N C (O) 4 N3 0.66 501 CH---// OH 106 8. 9 548 TABLE 1 Compound of formula 1 having the structure wherein R'is NH2, R2 is H, R3 is H, and R4 and R5 are designated as follows: Entry R Rs HSV-1 HSV-1 ELISA PRA FAB/MS No. ECso ECso CMV CMV (m/z) , ut ECso ECso (MH + M M 107 CH2Ph Me 0.15 0.01 465 C (0)-N S-N 108 CH2Ph a N N 2. 1 0. 46 451 s 109 CH2Ph N 0. 12 0. 037g4 c (o) i TABLE 1<BR> Compound of formula 1 having the structure wherein R¹ is NH2, R2 is H, R3 is H, and R4 and R5 are designated as follows: Entry R'R'HSV-1 HSV-1 ELISA PRA FAB/MS No. lC50 ECso CMV CMV (m/z) gm RM ECso ECso (MH + p. MM 110 ci3 3.4 0.55 512 c on CH TriCF, -\069CU5512 111F3 0. 69 0. 15 512 CH CHZ 112 CH2Ph C (O) (CH2) sNH2 90 680 TABLE 1<BR> Compound of formula 1 having the structure wherein R¹ is NH2, R² is H, R3 is H, and R4 and RS are designated as follows: Entry R"R5 HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (m/z) MM ECso ECso (MH) + HM EM 113 CH N c (0) gm 114/ 0. 082 504 115Fx xFA 1. 0 15 576CH2eN3C (O) CH2<) F F l _ _ cocHz-- Chez F F TABLE 1<BR> Compound of formula 1 having the structure wherein R'is NH2, R2 is H, R3 is H, and R4 and R5 are designated as follows: Entry Rq R5 HSV-1 HSV-1 ELISA PRA FAB/MS No. tCso ECso CMV CMV (m/z) M JAM ECso ECso (MH) + MM 116 CH2Ph CH2C (O) N (Me) CH2Ph 1. 2 8. 5 500 117 CH2Ph CH2C (O) NHCH2Ph 1. 2 13 486 118 CH2Ph C (O) CH20H 11 397 119 CH20H 57 0. 24 474 I C (0)-C \N _oh TABLE2<BR> Compound of formula 1 having the structure wherein R'is NH2, R2 is H, and R3, R4 and R5 are designated as follows: Entry R° R"R'HSV-1 HSV-1 ELISA PRA FAB/MS No.! Cso ECso CMV CMV (m/z) pM pM ECso ECso (MH) + au M 201 H 0.71 0.091 450 CH2-- () C (0) N 202 H 1. 6 0. 25 450 CH r_o C (O) N H 0. 58 0. 81 449 CH2< C (O) <CH--o C (O)--o TABLE 2<BR> Compound of formula 1 having the structure wherein R'is NHz, R2 is H, and R3, R4 and R5 are designated as follows: Entry R3 R4 j HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (nez) M juM ECso ECso (MH M M 204 __o 3.4 1.2 464 CHz-- () C (O) CH2<, N CH2/N 205 H 0.48 0.30 464 c C (O) >N Me 206 =N H C (O) OCMe3 0. 13 0. 043 20 _ 440 CH TABLE 2<BR> Compound of formula 1 having the structure wherein R¹ is NH2, R2 is H, and R3, R4 and R5 are designated as follows: Entry R3 R4 R5 HSV-1 HSV-1 ELISA PRA FAB/MS No. {Cso ECso CMV CMV (m/z) gm uM ECso ECso (MH) + zip M 207 CH2 H C (O) OCMe3 0.095 18 478 1 ( N H 208 Entry 208 is the enantiomer at R3 of Entry 207 1.7 >16 478 209 (CH2) 4NH2 CH2P 2, 5 7.2 534 h \-/ TABLE 3<BR> Compound of formula 1 having the structure wherein R² and R³ each is hydrogen and X, R 4and R 5are designated as follows: Entry X R 4 R 5 HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (m/z) MM ECso ECso (MH) M M 301 N CH2Ph/\ 6.6 2.5 27 428 X c (o) Wco-<) 302 _ CH2Ph C (O} Pb >50 > 16 45 412 o 303 NH2S (0) 2 CH2Ph C (O) Ph 33 >51 16 424 304 N-N CH2Ph C (O) PH >50 >48 62 413 N-NH TABLE 3<BR> Compound of formula 1 having the structure wherein R2 and R3 each is hydrogen and X, R4 and R5 are designated as follows: Entry X R4 Rs HSV-1 HSV-1 ELISA PRA FAB/MS No.! Cso ECso CMV CMV (m/z) M M ECso ECso (MH + _, uM s1M _ 305 om CH2Ph C (O) Ph 0.38 0.054 41 427 N 306 H2NC (O) NHCHMe-CH2Ph C (O) Ph >50 >38 89 431 307 N H PhCH2 >50 11 36 422 HN I S HC=N-CMe3 308 N CH2Ph C (O) PH 0. 14 0. 42 25 457 sA s Me TABLE 3<BR> Compound of formula 1 having the structure wherein R and R³ each is hydrogen and X, R4 and R5 are designated as follows: Entry X R4 Rs HSV-1 HSV-1 ELISA PRA FAB/MS ICso ECso CMV CMV (m/z) IM M ECso ECso (MH + PU M 309 H CH2Ph >50 63 >70 318 310 C (0) OCMe3406. 867407 zon N H 311 </CH2Ph C (O) Ph >50 7. 9 25 411 N H 312 N CH2Ph C (O) Ph 45 >4 485 (H2N) 2C NXS) s TABLE 3<BR> Compound of formula 1 having the structure wherein R2 and R3 each is hydrogen and X, R4 and Rs are designated as follows: Entry X Rq R HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (m/z) M M ECso ECso (MH)' + s1M gm 313 rs CH2Ph C (O) Ph 0.63 22 428 N N 314 CHzPh C (O) OCMe3 0. 24 13 424 N N 315 N CH2Ph C (O) OCMe3 >50 3. 5 515 HAN s TABLE 4<BR> Compound of formula 1 having the structure is NH2, R2is H and Z is designated as follows:<BR> _, _ cniry z HSV-1 HSV-1 ELISA PRA FAB/MS No. ECso ECso CMV CMV (mut) M, M ECso ECso (MH) + _ _ FM pM 401 CH20CH2Ph 7.4 >15 1.5 430 402 CH2OPh _ >20 2. 8 326 403 Me 3. 2 4. 0 1. 6 23 354 cl 20-0 Me 404 0. 63 11 12 365 11 CH2N <405OCH2CHMe2281412292 TABLE 4<BR> Compound of formula 1 having the structure wherein R'is NH2, R2 is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (m/z) MM JIM ECso ECso (MH M RM 406 CH2CH2Ph 3.9 1.5 22 324 407 0. 44 18 20 346 CH20CH2 9) 408 4. 9 1. 3 4. 0 365 CH2 I I L ;"2 409CH2CH2CHzPh177>1. 0338 410 CH2SCH2Ph 2 >8 12 356 411 CH=CHPh 3. 8 0. 75 5. 6 222 TABLE 4<BR> Compound of formula 1 having the structure wherein R'is NH2, R2 is H and Z is designated as follows:<BR> tniry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (m/z) PIM PLM ECso ECso (MH + 4m M 412 0.41 2.0 7.0 344 CHZCH2CH2-- ( 413/\ 0. 14 11, 39 358 CH2CH2 CH 2CH20 U 414 r 4. 4 0. 91 1. 6 50 379 CH2N 0 oTABLE 4<BR> Compound of formula 1 having the structure wherein R'is NH2, R2 is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (m/z) M RM ECso ECso (MH)' + MU 1M 415 CH2Ph 2 0.73 0.85 >6 453 CH2/\NHC (O) OCMe3 416 CH CMe NzCH2Ph 0. 62 0. 86 4. 5 >8. 5 CHCMeN C (O) OCH2Ph 417 PhCH2. oEt 2. 6 1. 5 >12 453 I I CH2NgO CH, N 0 T 0 TABLE 4<BR> Compound of formula 1 having the structure wherein R'is NH2, R 2is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (/n/z) M M ECso ECso (MH) + M M 418 tN 9. 0 548 p N CH2 N, Cl (o c 419(Or499 419 __ 14 499 CHzCH2N\ C(O) OPh TABLE 4<BR> Compound of formula 1 having the structure wherein R'is NH2, R2 is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. tCso ECso CMV CMV (m/z) M M ECso ECso (MH) + RM 420, CH2Ph ° 13 42 478 CHZCHZN\ 2 2 2\ JCHZCHZCFf2 N 421, CH2Ph 13 459 CH2CH2N, OH OH 422, CH2Ph 1. 8 6. 8 457 CH2C (O) N, CH2ph 423 CH2CH2CH2CH2C (O) N (CH2Ph) 2 TABLE 4<BR> Compound of formula 1 having the structure wherein R'is NH2, R2 is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ECso ECso CMV CMV (m/z) MM ECso ECso (MH)' zip M 424 CH2CH2CH2CH2CH2NH2 30 305 425 CH2CH2NH2 35 263 426 HO 0.81 353 -b-N3 N 3 -JN, 337 Na TABLE 4<BR> Compound of formula 1 having the structure wherein R'is NH2, R2 is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (m/z) M I1M ECso ECso (MH) + M ut 428 19 >27 819 CH20H 429N30333 OCH- s 430 (S)-CH (NH2) (CH2) 4NHC (O) OCH2Ph 1. 4 454 431 (S)-CH (NHCH2Ph) (CH2) 4NHC (O) OCH2Ph 10 544 432 (S)-CH2C (O) NHCH (Me) Ph 1. 3 4. 5 381 433 (R)-CH (NH2) (CH2) 4NHC (O) OCH2Ph17454 TABLE 4<BR> Compound of formula 1 having the structure I wherein R'is NH2, R2 is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. tCso ECso CMV CMV (m/z) M IlM ECso ECso (MH + M gm 434 H 69 10 >55 289 435 (O) CH 2N< CH2Ph 20 7. 2 554 --- (, NC (O) CH2N< C (O) Ph 436 CH2Ph cH2Ph 7. 8 618 'CH2C (O) NCH2C (O) NHCH2Ph 437 CH2Ph CH Ph Me 2 17 632 CHZC (O) NCH2C (O) NCH2Ph TABLE 4<BR> Compound of formula 1 having the structure wherein R'is NH2, R2 is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. tCso ECso CMV CMV (m/z) M 1M ECso ECso (M H) + M M 438 CH2Ph 0.12 17 438 /\CH2C (O) OCMe3 439 CH CH N, CH2Ph CH Ph Me _ 18 680 CHZCHzN\ CH2Ph C(O) CH2N C (O) CH2SH % N Me 440 5. 4 36 540 ZON C (O) CH2N Ph C(O) Ph C (0) Ph TABLE 4<BR> Compound of formula 1 having the structure wherein R'is NH2, R2 is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ECso ECso CMV CMV (m/z) M M ECso ECso (MH + -LM M 441 2.1 0.91 14 512 N I C (O) N (CHzPh) 2 442 CH CH N CH2Ph CH Ph 0. 69 7. 6 600 7.6 600 C(O) CH2Ns C (O) OCMe3 443, CH2Ph 19 501 19 501 CHZCHZN C (O) CH20CH2Ph TABLE 4<BR> Compound of formula 1 having the structure | wherein R'is NH2, R2 is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (m/z) JIM M ECso ECso (MH) + 4m gm 444,, J. MM 23 524 CH., CH, N C C (O) CH2CH2NHC (O) OCMe3 445 N 22 7. 5 >38 297 446 0 26 >27 >81 379 446<26 >27 >81 379CH2N 0 . _ _ 447 CH2CH2NH2 _ 35 263 TABLE 4<BR> Compound of formula 1 having the structure wherein R'is NH2, R2 is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (m/z) s1M) 1M ECso ECso (MH) + Pu go 448CH. Ph 12 31 514 CH2CH2NHC (O) CH2N C (O) Ph 449 CH2CH2NHC (O) CH2N (CH2Ph) 2 2. 8 500 450 N-CH2Ph 40 341 OH 451 CH2CH2NHC (O) N (CH2Ph) 2 12 486 452 CH2Ph 18 485 CHCH2C (O) N (Me) CH2Ph TABLE 4<BR> Compound of formula 1 having the structure Iwherein R'is NH2, R2 is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (m/z) ZM RM ECso ECso (MH) + ZM JAM 453 CH, Ph 5.0 485 CH2CHC (O) N (Me) CH2Ph 454 0 0. 61 0. 58 483 S 1 1 1 1 1CH2Ph : TABLE 4<BR> Compound of formula 1 having the structure wherein R'is NH2, R2 is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ECso ECso CMV CMV (mut) 1M 1M ECso ECso (M H) + jus M 455 8. 0 1. 7 453 N 0 I CH2Ph 4. 1 0. 12 498 7Y PhCH-- ( N H H 0 TABLE 4<BR> Compound of formula 1 having the structure I wherein R'is NH2, R2 is H and Z is designated as follows: eniry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ECso ECso CMV CMV (m/z) M M ECso ECso (MH + tm M 457 ce 5.6 >14 455 O qu 458 CH2Ph 1. 3 >9. 2 465 CHZCHZN,/ 1 Ho HO TABLE 4<BR> Compound of formula 1 having the structure wherein R¹ is NH2, R² is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (m/z) MM ZM ECso ECso (MH) + M M 459 11.3 7. 5 395 7. 5 395 HzCHzC (o) NH Me 460 15 31 408 CH2CH2CH2C (O) NH Me 461 CH2CH2CH2C (O) N (CH2Ph) 2 3. 8 13 485 TABLE 4<BR> Compound of formula 1 having the structure wherein R'is NH2, R2 is H and Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (m/z) M M ECso ECso (MH) + M M 462 Bu 4.8 25 335 CH2CH20H 463 CH2CH2C (O) N (CH2Ph) 2220471 TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No.! Cso ECso CMV CMV (m/z) M PLM ECso ECso (MH) + zip M 501 NHCH2C (O) N (Me) CH2Ph >100 >37 33 353 502 NHCH2C (O) NHCH2Ph >100 >44 63 339 503 21 8. 2 56 365 -N NCH2Ph 0S 504 cH2NHc (O) cH NoCH2Ph 26 3. 9 19 457 C (O) Ph TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (m/z) M M ECso ECso (MH olim M 505 CH2Ph 15 5.0 30 >21 424 C (O) NH C (O) OCMe3 506 CH 2Ph >50 16 25 75 395 1 C (O) N (Me) C (O) NHMe 507 60 >86 494 C(O)-NHOCH<N C (O) NHCMe3 TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (m/z) lM I1M EC50 ECso (MH) + M M 508/--\ 22 >19 408 OCH2C (O)-N, r-CH2Ph 509 OCH2C (O) N (Me) CMe3 45 >76 319 510 OCH2C (S) NHCH2Ph 5. 5 18-3-56 511/CH2Ph 0. 42 12 455 NHC (S) CH. N ( C(O) OCMe3 512/CH2Ph >50 | 444 CH2CH2Ns C (O) OCH2Ph 513 NHC (S) NHCH2P h 33 341 TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows : znvy z HSV-1 HSV-1 ELISA PRA FAB/MS No. ECso ECso CMV CMV (m/z) gm M ECso ECso (MH) + go au 514 30 521 Me C (O) N CHaPh) CHzC (O) NH 515 CHZPh 40 542 C (O) N (CH2Ph) CH2C (O) N-N 0 516 C (O) OMe 43 235 517 CH2CH2NH-S (O) 2-CH2Ph 38 374 TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ECso ECso CMV CMV (m/z) M tm ECso ECM50 (MH + M M 518 CH. Ph 10 547 CH, N ( CH2C (O) NCH2Ph Ph''Me 519 CH2CH2NHC (O) CH2CH2C (O) Ph 49. 8. 1 380 520----9. 5 430 CH 2CH2 NHC (O) CH 2CH2 C (O) TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (m/z) M M ECso ECso (MH) + m M 521 26 4.3 471 CH2CH2NHC (O) CH2N\ C (O) Ph 522 XCH2Ph 7. 3 467 CH2CH2NHC (O) CH2N . C (O) OCMe3 523 NH >100 CH2CH2NHC (O) C (O) . U. _ TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. Cso ECso CMV CMV (m/z) MM nM ECso ECso (MH mM 524 16 391 CH2CH2NHC (O) CH2CHz I I / N H 525 CH2CH2N (CH2Ph) C (O) CH2Ph 7 428 526 CH2CH2N (CH2Ph) S (O) 2CH2Ph 9. 4 464 527 CH. Ph22472 CH2CHZNHC (O) CHZN "C (0)-- (/'N TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ECso ECso CMV CMV (m/z) M M ECso ECso (MH) + jus) M 528 N 30 458 CH2CH2NHC (O) X C (O) NHCH2Ph 529 CH2CH2NHC (O) CH2CH2C (O) NHCH2Ph 12 409 530 2. 4 18 457 CH2CH2NHC (O) C (O) NHCH2Ph TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (m/z) M MM ECso ECso (MH)' + M p1M pM 531/CH2 Ph 12 18 485 C (O) CH2CH2C (O) N) Me Ph 532/CH2Ph 32 18 470 CH2CH2N X CH2CH2C (O) Ph 533, CHzPh 1. 8 467 CH2CH2N X C (O) CH2NHC (O) OCMe3 534/CH2Ph >100 4. 2 470 CH2CH2N X C (O) NHC (O) Ph TABLE 5<BR> Compound of formula 1 having the structure I wherein Z is designated as follows: tntry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (m/z) s1M M ECso ECso (MH) + I1M I1M 535 CH2CH2NHC (O) CH2NHC (O) OCMe3 38 377 536, CH2Ph 0. 15 15 481 CHzCH2N/NH C (O) C (O) / 537 XCH2Ph 0. 60 19 457 C (O) NHCH2CH2N\ C(O) Ph 538 CHZPh 16 471 C (O) NHCH2CH2Ns C (O) CH2Ph TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (m/z) M IlM ECso ECso (MH) + M M 539 xCH2Ph 23 458 C (O) NHCHZCH2N C (O) =\ N 540 CH2Ph Me 19 533 C (O) NHCH CH N/NX C(O) CH2S-- ( v N Me 541 CH Ph C (O) NHCH2CH2Nu C (O) OCMe3 TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. Cso ECso CMV CMV (m/z) M jLtM ECso ECso (MH go 542/NH 27 376 CH2 CH2NHC (O) CH2 543.,-CH2Ph 18 420 C (O) CH-N -N I 'NN 544 XCH2Ph 14 507 C (O) NHCH2CH2Nx S (0) 2CH2Ph TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (m/z) luM s1M EC50 ECso (MH) + M M 545 CHZPh 5.2 493 C (O) NHCH2CH2Nu S (0) 2 Ph 546 CHZPh , 18 543 S (0),-- s (o>z 547 40 13 457 CHZCH2NHC (O) I C (O) NHCHZPh TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: tntry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. Cso ECso CMV CMV (m/z) uM IM ECso ECso (MH) + M ut 548 CH2Ph >100 2.2 442 CH. CH. N C (O) C (O) Ph 549 CH2CH2NHCH2C (O) N (CH2Ph) 2 15 457 CH2CH2Ph 22 481 1 CH2CH2NHC (O) CH-NHC (O) OCMe3 551 CH2Ph 13 484 CH2CH2N X C (O) CH2NHC (O) CH2Ph TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. icso ECso CMV CMV (m/z) gm ptm ECso ECso (MH) + M M 552 CH. Ph 23 464 CH2CH2N \ C (O) CH2NHC (O) OCMe3 553 ;/CH2Ph 30 611 CH2CH2N C (O) CH2CH2N/n S(0) 2< Me 554 zCH2Ph 14 15 467 C(O) NHCH2CH2N s CH2C (O) OCMe3 TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: Entry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. Cso ECso CMV CMV (m/z) , M ECso ECso (MH) + , uM, uM 555/CH2Ph 15 486 CH2CH2N X C (O) CH2NHC (O) NHPh CH Ph C (O) NHCH2CH2N \ CH2C (O) NHPh 557/CH2Ph 22 500 C (O) NHCH 2CH2N 500 CH2C (O) NHCH2Ph TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: tniry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (m/z) IlM IlM ECso ECso (MH + M RM 558/CH2Ph 16 466 CH2CH2N X C (O) CH2NHC (O) NHCMe3 559 CH CH N/CH2Ph _ 13 614 2 2 \ CH2Ph C (O) CH2NHC (O) CHzN C (O) OCMe3 560/CH2Ph 17 453 CH2N \ C (O) CH2NHC (O) OCMe3 TABLE 5<BR> Compound of formula 1 having the structure I wherein Z is designated as follows: cmry HSV-1 HSV-1 ELISA PRA FAB/MS No. tCso ECso CMV CMV (m/z) UM UM ECso ECso (MH M M 561 CH2CHMe2 40 358 C (O) NH- N, tz N HN-N 562/CH2Ph 4 2 557 C (O) CH2N \ C (O) OCMe3 563CHPh18467 . __ CH2CH2NHC (O)-CHNHC (O) OCMe3 564 CH2NHCH2C (O) N (CH2Ph) 2 10 443 TABLE 5<BR> Compound of formula 1 having the structure wherein Z is designated as follows: tntry Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (m/z) AM M ECso ECso (MH M M 565/CH2Ph 0.88 0.27 >4.0 435 NHCH2CH2N C (O) TABLE 6<BR> Compound of formula 1 having the structure wherein X and Z are designated as follows: Entry X Z HSV-1 HSV-1 ELISA PRA FAB/MS No. Cso ECso CMV CMV (m/z) M M ECso ECso (MH + PU Pu 601 H CH2Ph >50 >28 41 345 NHC (O) CH2N/ C (O) Ph 602 H/CH2Ph >50 >34 36 341 NHC(O) CH2N X C (O) OCMe3 603 N NHC (O) NH-CHPr2 1. 6 432 NH-C S C (O) OCMe3 TABLE 6<BR> Compound of formula 1 having the structure wherein X and Z are designated as follows: Entry X Z HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (m/z) pMM ECso ECso (MH LM FM ßM 604 N NHC (S) NBu2 17 463 NH-jr Ils C (O) OCMe3 605 N/'NHC (O) NBu2 35 443 NH-Y Ils C (O) CF3 TABLE 6<BR> Compound of formula 1 having the structure wherein X and Z are designated as follows: Entry X Z HSV-1 HSV-1 ELISA PRA FAB/MS No. lCso ECso CMV CMV (m/z) pM tm ECso ECso (MH)' + IM JIM 606 N N : : o 5. 3 464 NH</)/NHC (O) CH2CH2< 33 / | S HN C (O) OCMe3 _ X NHC (O) NBu2 2. 2 424 NH- y ON ILS TABLE 6<BR> Compound of formula 1 having the structure wherein X and Z are designated as follows: Entry X Z HSV-1 HSV-1 ELISA PRA FAB/MS No.! Cso ECso CMV CMV (m/z) M M ECso ECso (MH)' M) LiM 608 N NHC (O) NBu2 3. 8 424 NH-Y S i''N 609 N NHC (O) NBU2 >11 424 NH-- h . N TABLE 6<BR> Compound of formula 1 having the structure wherein X and Z are designated as follows: Entry X Z HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (m/z) MM ECso ECso (MH M M 610 N NHC (O) NBU2 46 415 CT N s 611 N/CH2Ph >100 22 526 H- NHC (O) CH2CH2N NCH Ph I s ( CH=N-CMe3 612 N/NHC (O) NBu2 27 462 S s- HNC (O) OCMe3 TABLE 6<BR> Compound of formula 1 having the structure wherein X and Z are designated as follows: Entry X Z HSV-1 HSV-1 ELISA PRA FAB/MS No. ECso ECso CMV CMV (m/z) MM ECso ECso (MH M M 613 H2N NHC (O) NBU2 69 19 362 t/ NoN+\ N 614 N NHC (O) NBu2 47 4. 7 362 H2NNH---/ s S 615 N CN2 NHC (O) CH2CHzN (CH2Ph) 2 >100 16 457 H2N--/ S S TABLE 7<BR> Compound of formula 1'having the structure wherein R2 is H, R3, R4 and R5 and X'are designated as follows: Entry X'R3 R4 R5 HSV-1 HSV-1 ELISA PRA FAB/MS No. ICso ECso CMV CMV (MH+) M gm ECso ECso M M 701 N H CH2Ph C (O) OCMe3 >50 >34 48 413 2 t< A S 702 CH2Ph H C (O) OCMe3 >50 16 40 407 zon H 703 N CH2Ph H C (O) OCMe3 >50 25 413 HzN/I S <S TABLE 7<BR> Compound of formula 1'having the structure wherein R2 is H, R3, R4 and R5 and X'are designated as follows: Entry X'R3 R4 R5 HSV-1 HSV-1 ELISA PRA FAB/MS No.! Cso ECso CMV CMV (MH+) 1lM RM ECso ECso _ uM uM 704 S CH2Ph H C (O) OCMe3 1.4 >8 424 N \=/_ N 705 H H CH2Ph >100 >42 18 339 N N/\/ H2N A/| eS TABLE 7<BR> Compound of formula 1'having the structure wherein R2 is H, R3, R4 and R5 and X'are designated as follows: Entry X'R3 R4 Rs HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (MH+) M) JLM ECso ECso P706 | | H | CHSPhjC (O) OCMe3 0 54 |ì| 31 +7HM 2 S706 N H CH2Ph C (O) OCMe3 0.54 31 440 N H2N S 707 N H CH2Ph C (O) OCMe3 2. 7 440 N H2N- I U s TABLE 7<BR> Compound of formula 1'having the structure wherein R is H, R3, R4 and R5 and X'are designated as follows: t X'R'R"R5 HSV-1 HSV-1 ELISA PRA FAB/MS No. IC50 ECso CMV CMV (MH+) IlM M ECso ECso gm uM uM 708 CHzPh 6. 6 7. 6 464 C (O) CHZ "2N"/I', H, N- JJ 709/H CH2Ph Me 19 519 N C (O) CHZS N N U Mu I L TABLE 7<BR> Compound of formula 1'having the structure wherein R² is H, R³, R4 and R5 and X' are designated as follows: : Entry X'R3 R4 Rs HSV-1 HSV-1 ELISA PRA FAB/MS i No. ICso ECso CMV CMV (MH') M M ECso ECso M M 710 N H CH2Ph e >100 16 520 . _. _ MM uM sD N Me Additional compounds are the following: HSV-1 Compound m . CHPh NHC(O) CH2N C (O) 25 'C (O) s mye N p CH2Ph NHC (O) CH2 10% inhibition at H (o) 100 IlM N ,-ira Ho mye N CH2Ph NHC (O) CH2N 100 C (O) N - J Ft O N

In an embodiment of this invention, a preferred group of compound of preceding TABLES 1 to 6 are those designated as entry numbers 107,109, 111 and 114 in TABLE 1; as entry numbers 201,203,205,206 and 207 in TABLE 2; as entry numbers 305,308,313 and 314 in TABLE 3; as entry numbers 407,412,413,427 and 438 in TABLE 4; and as entry numbers 511 and 536 in TABLE 5.