WO1997027200A1

WO1997027200A1 - Thienoxazinone derivatives useful as antiviral agents

Info

Publication number: WO1997027200A1
Application number: PCT/EP1997/000367
Authority: WO
Inventors: Richard Lewis Jarvest; Leslie John Arthur Jennings; Ivan Leo Pinto
Original assignee: Smithkline Beecham Plc
Priority date: 1996-01-26
Filing date: 1997-01-22
Publication date: 1997-07-31
Also published as: AU1595997A

Abstract

Herpesvirus protease inhibitor 4H-thieno[2,3-d][1,3]oxazin-4-one derivatives which are: 2-substituted by XNH-CHR1- wherein X is R4CO wherein R4 is a moiety containing one or more functional groups selected from an aromatic or heteroaromatic group, an alkenyl group, an alkynyl group; and R1 is hydrogen or an amino acid side chain.

Description

THIENOXAZINONE DERIVATIVES USEFUL AS ANTIVIRAL AGENTS.

The present invention relates to compounds which are of potential use as antiviral agents.

WO 96/19482 (SmithKline Beecham pic) describes 2-substituted herpesvirus protease inhibitor 4H-thieno[2,3-d][1,3]oxazin-4-one derivatives.

It has now been discovered that certain novel thienoxazinone derivatives are potentially useful in the treatment of infection caused by herpesviruses, especially herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), cytomegalovirus, and varicella-zoster virus.

Accordingly, the present invention provides herpesvirus protease inhibitor 4H-thieno[2,3-d][1,3]oxazin-4-one derivatives which are:

2-substituted by XNH-CHR₁- wherein X is R₄CO wherein R₄ is a moiety containing one or more functional groups selected from an aromatic or heteroaromatic group, an alkenyl group, an alkynyl group; and

R₁ is hydrogen or an amino acid side chain;

the derivatives hereinafter referred to as compounds of formula (i).

The 4H-thieno[2,3-d][1,3]oxazin-4-one ring system is numbered thus:

There may be substituents in the 5 and 6 positions (designated R₃ and R₂ respectively) as well as the 2-substituent. These may be selected from halo,

C_{1 -6} alkyl or C_{1 -6} alkoxy, C_{1 -6} alkylthio, amino optionally substituted by one or two C_{1 -6} alkyl or optionally substituted benzyl groups, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, optionally substituted phenyl or R₅ZCONΗ wherein Z is a bond, O, NH or NCOCH₃, and R₅CO is an acyl group where values of R₅ include aryl, alkyl or aralkyl, or R₃ and R₂ may be joined to form C₃, C₄, C₅, C₆, C₇, or C₈ polymethylene.

Preferably the 5-substituent is methyl and the 6-substituent is CH₂R_a, OCH₂R_b, or NR_cR_d wherein R_a and R_b are selected from hydrogen or a substituent, R_c is alkyl and R_d is alkyl or substituted alkyl or R_c and R_d are joined to form a heterocyclic ring containing one or more heteroatoms.

The substituents R_a and R_b may be selected from one or more of halo, trifluoromethyl, cyano, alkyl, alkoxy, aryloxy, aryl(alkyl)oxy, alkylthio, amino optionally substituted by one or two alkyl or optionally substituted benzyl groups, hydroxy, alkylcarbonyl, alkoxycarbonyl, trifluoromethylcarbonyl, optionally substituted phenyl or R_eZCOY wherein Z is a bond, O, NH or NCOCH₃, and R_eCO is an acyl group where values of R_e include aryl, alkyl, aralkyl, or heteroaryl-alkyl; and Y is O or NR_f wherein R_f is hydrogen, alkyl, aryl, or aralkyl, or R_e and R_f may together form C_2-6 polymethylene; or R_a/R_b may be alkyl or alkenyl substituted by one or more of the values listed above for substituents R_a and R_b.

Values of R_d substituents are as defined for R_a and R_b above. Values for R_c and R_d when joined to form a heterocyclic ring include optionally substituted piperidine, pyrrolidine, azetidine morpholine, or piperazine. Suitable substituents are as listed above for R_a and R_b, or the heterocyclic ring may contain an exocyclic optionally protected carbonyl group.

Examples of alkyl or alkyl containing groups include C₁, C₂, C₃, C₄, C₅,

C₆, branched, straight chained and/or cyclic and/or primary, secondary or tertiary alkyl, as appropriate. C_{1 -4} alkyl groups include methyl, ethyl n- and iso-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. Alkenyl includes all suitable values including E and Z forms.

Aryl includes phenyl and naphthyl optionally substituted by one or more substituents. Such substituents may be selected from halo, C_{1 -6} alkyl, C_{1 -6} alkoxy,

C_{1 -6} alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, nitro, C_{1 -6} alkylcarbonyl,

C_{1 -6} alkylcarbonyloxy, amino optionally substituted by one or two C_{1 -6} alkyl groups, and acetylamino.

Heteroaryl includes 5 or 6 membered monocyclic heteroaryl or 9 or 10 membered fused bicyclic heteroaryl linked through carbon. Monocyclic heteroaryl include pyridyl, pyrimidyl, pyrazinyl, pyrryl, imidazolyl, thienyl, furanyl, oxazole or thiazole (all possible isomers). Bicyclic heteroaryl include benzofuranyl,

benzothiophenyl, indolyl and indazolyl, quinolyl and woquinolyl (all possible isomers).

Heteroaryl may be optionally substituted by one or more substituents. These may be selected from those described above for aryl substituents.

Halo includes fluoro, chloro, bromo and iodo.

Suitable R₄ moieties include (aryl or heteroaryl)-Q- wherein Q- is optionally present and is a spacing moiety selected from CH₂-, C≡C-, CHR₆CH₂-, CR₆=CH- wherein R₆ is hydrogen or a halo, alkyl or aryl substituent; or the spacing moiety may be any one of those described in the Examples described herein. Similary, R₄ may be any one of the values described in the Examples described herein. Preferred R₄ values are wherein there is 2 or 3 carbon atoms separating the aryl or heteroaryl moiety from the carbonyl group of X. Preferably R₄ is

(aryl or heteroaryl)-CR₆=CH-. The amino acid side chain may be of one or more amino acids. Suitable examples of amino acids are as described in the literature relating to synthetic peptides and includes natural and 'unnatural' amino acids. The amino acids may be in the D or L form, preferably the L form. Particular aminoacyl moieties

-NH-CHR₁-CO- , resulting in NH-CHR₁- in the compound of formula (I), include alanine (R₁ = CH₃), serine (R₁ = CH₂OH), and α-aminobutyric (R₁ = CH₂CH₃).

Examples of pharmaceutically acceptable salts of the compound of formula (I) are included in the invention, as appropriate.

The compounds of formula (I) including their pharmaceutically acceptable salts may form solvates such as hydrates and these are included wherever a compound of formula (I) or a salt thereof is herein referred to.

The compounds are prepared by activating an R₁ containing amino acid derivative by standard peptide procedures such as:

i) formation of an activated ester with a carbodiimide or other coupling reagent and a moiety such as 1-hydroxybenzotriazole, or

ii) formation of a mixed anhydride with a reagent such as iyobutyl chloroformate and reacting with a 2-aminothiophene 3-carboxylic acid or ester.

The intermediate amide may be isolated or the crude reaction product cyclised directly. Reagents suitable for the cyclisation of the thiophene acid derivatives include coupling agents or dehydrating agents such as carbodiimides, acetic anhydride or sulphonyl chlorides. Reagents suitable for the cyclisation of the thiophene ester derivatives include triphenylphosphine/carbon tetrachloride. If the amino acid has a functionalised side-chain with a protecting group, then a final stage is the removal of the protecting group, for example, the removal of an acid-labile group with trifluoroacetic acid. Following cyclisation the optionally present amino protecting group can be removed and the free amine or its salt can be acylated by an acid R₄COOH or derivative. Suitable coupling agents would include those described in i) and ii) above and derivatives would include the acid chloride and the anhydride. It will be appreciated that according to the nature of the 5- and 6- substituents in the required product, the cyclisation may occur prior to or after introduction/modification of the relevant substituent(s).

Pharmaceutically acceptable salts may be prepared in conventional manner, for example, in the case of acid addition salts, by reaction with the appropriate organic or inorganic acid.

The compounds of the invention are of potential use in the treatment of infections caused by herpesviruses such as herpes simplex types 1 and 2,

varicella-zoster virus, Epstein-Barr virus and cytomegalovirus. Other herpesviruses are also of potential interest, such as herpesvirus-6. Compounds of the invention may be formulated for use in a pharmaceutical composition. Accordingly, in a further aspect of the invention, there is provided a pharmaceutical composition which comprises a compound of formula (I) or pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or excipient.

A composition which may be administered by the oral route to humans may be compounded in the form of a syrup, tablet or capsule. When the composition is in the form of a tablet, any pharmaceutical carrier suitable for formulating such solid compositions may be used, for example magnesium stearate, starch, lactose, glucose, rice, flour and chalk. The composition may also be in the form of an ingestible capsule, for example of gelatin, to contain the compound, or in the form of a syrup, a solution or a suspension. Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerine, saline and water to which flavouring or colouring agents may be added to form syrups. The compounds may also be presented with a sterile liquid carrier for injection.

The composition may possibly also be formulated for topical application to the skin or eyes.

For topical application to the skin, the composition may be in the form of a cream, lotion or ointment. These formulations may be conventional formulations well known in the art, for example, as described in standard books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books and the British Pharmacopoeia.

The composition for application to the eyes may be a conventional eye-drop composition well known in the art, or an ointment composition.

Preferably, the composition of this invention is in unit dosage form or in some other form that may be administered in a single dose. A suitable dosage unit might contain from 50 mg to 1 g of active ingredient, for example 100 to 500 mg.

Such doses may be administered 1 to 4 times a day or more usually 2 or 3 times a day. The effective dose of compound will in general be in the range of from 1.0 to 20 mg/kg of body weight per day or more usually 2.0 to 10 mg/kg per day.

No unacceptable toxicological effects are indicated at the above described dosage levels.

The invention also provides a method of treating viral infections in a human or non-human animal, which comprises administering to the animal an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for the treatment of viral infections.

The following examples illustrate the invention.

Examples

The following examples were prepared:

wherein R has the following values:

The compounds wherein R is as follows are also prepared:

Compounds corresponding to any of the compounds described herein but wherein R₂ (the 6-substituent) is as follows are also prepared:

The chemical formula of each Compound was confirmed by appropriate analytical methods. The following methods and analytical data are for selected Compounds listed in the table above as indicated. The remaining Compounds listed in the table were prepared in a similar manner and/or by known methods.

Example 2, Step 1

(S)-2-[N-(t-Butoxycarbonyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]-oxazin-4-one

A solution of N-(t-butoxycarbonyl)alanine (495 mg, 2.6 mmol) in dry N,N-dimethylformamide (5 ml) at 0-5°C was treated with 1-hydroxybenzotriazole (390 mg, 2.87 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (550 mg, 2.87 mmol) and the reaction was stirred for 15 min at 0-5°C. 2-Amino-4-methylthiophene-3-carboxylic acid (410 mg, 2.6 mmol) was then added in one portion, the reaction was allowed to come to room temperature and stirred for 18 h. A further portion of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (550 mg, 2.87 mmol) was then added and the reaction was stirred at room

temperature for a further 18 h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and washed with water (2 × 50 ml) and saturated sodium bicarbonate (1 × 50 ml) and the organic layer was dried (MgSO₄) and filtered. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with ethyl acetate-hexane (15-85%) to give a yellow solid which was crystallised from acetone/hexane to give yellow crystals (410 mg, 50%), mp 109-111°C; ʋ_max (KBr) 3347, 3103, 2986, 1759, 1693, 1607, 1533, 1454, 1345, 1266, 1249, 1175 and 1054 cm^{- 1}; δ_H [(CD₃)₂SO] 1.38 (12H, m, (CH₃)₃C, + CH₃CH ), 2.42 (3H, s, CH₃ ), 4.46 (1H, m, CHCH₃ ), 7.30 (1H, s, 5-H), 7.54 (1H, d, J = 7.4 Hz. CHNH). (C₁₄H₁₈N₂O₄S requires: C, 54.18; H, 5.85; N, 9.03 %. Found: C, 53.81; H, 5.74; N, 8.90%. C₁₄H₁₈N₂O₄S requires C, 54.18; H, 5.85; N, 9.03%.) Example 2 Step 2

(S)-2-(1-Aminoethyl)-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one, trifluoroacetic acid salt

A solution of (S)-2-[N-(t-butoxycarbonyl)-1-aminoethyl]-5-methyl-4H- thieno[2,3-d][1,3]oxazin-4-one (200 mg, 0.61 mmol) in dry dichloromethane (10 ml) was treated with anisole (0.075 ml, 0.73 mmol) and trifluoroacetic acid (1.0 ml) and allowed to stand at RT for 1 h. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene (2 × 50 ml). The residue was purified by column chromatography on silica gel, eluting with 3% methanol/dichloromethane to give the product as a pale gum; δ_H (DMSO-d₆) 1.54 (3H, d, J = 6.9Hz, CH₃CH), 2.45 (3H, d, J = 1.4Hz, CH,), 4.52 (1H, m, CHCH₃),7.42 (1H, d, J = 1.1Hz, 6-H), and 8.60-8.80 (3H, v. broad, NH₃ ⁺); FABMS (+ve ion) 211 (MIT).

Example 2 Step 3

(S)-2-[N-(2-Thienylcarbonyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]-oxazin-4-one (E2)

A solution of 2-thiophenecarboxylic acid (48 mg, 0.37 mmol) in dry DMF (5 ml) was treated with 1-hydroxybenzotriazole (50 mg, 0.37 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (71 mg, 0.37 mmol) and stirred at RT for 15 min. A solution of (S)-2-(1-aminoethyl)-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one, trifluoroacetic acid salt (100 mg, 0.37 mmol) in dry DMF (5 ml) was treated with N-N-diisopropylethylamine (0.065 ml, 0.37 mmol) and then added to the reaction and stirred at RT for 2 h. The solvent was then evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water (25 ml) and saturated aqueous sodium bicarbonate (25 ml), dried (MgSO₄), filtered and

evaporated. The residue was purified by column chromatography on silica gel, eluting with 1 % methanol/dichloromethane, followed by crystallisation from diethyl ether, to give the product as colourless crystals, mp 131-3°C; δ_H (DMSO-d₆) 1.54 (3Η, d, J = 7.15Hz, CH₃CH), 2.42 (3H, d, J = 1.1Hz, CH₃), 4.92 (1H, m, CHCH₃), 7.18 (1H, dd, J = 3.5 and 5Hz, ArH), 7.32 (1H, d, J = 1.1Hz, ArH), 7.80 (1H, q, J = 1.1 and 5Hz, ArH), 7.88 (1H, q, J = 1.1 and 3.8Hz, ArH), and 9.05 (1H, d, J = 7.2Hz, NH) (Found: C, 52.19; H, 3.43; N, 8.42% C₁₄H₁₂N₂O₃S₂ requires C, 52.49; H, 3.78; N, 8.74%.) Example 10

(S)-2-[N-(2-Thienylacetyl)-1-aminoethyI]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E10)

Prepared in a similar way to Example 2 . Mp 178-80°C; δ_H (DMSO-d₆) 1.45

(3H, d, J = 6.9Hz, CH₃CH), 2.42 (3H, d, J = 1.1Hz, CH₃), 3.72 (2H, s, COCH₂), 4.71 (1H, quin, J = 7.1Hz, HNCHCH₃), 6.93 (2H, m, 2 × ArH), 7.34 (2H, m, 2 × ArH), and 8.80 (1H, d, J = 6.9Hz, NHCO) (Found: C, 53.69; H, 4.12; N, 8.09%.

C₁₅H₁₄N₂O₃S₂ requires C, 53.88; H, 4.22; N, 8.38%.)

Example 11

(S)-2-[N-(2-Thienylglyoxylyl)-1-aminoethyl]-5-methyl-4H- thieno[2,3-d][1,3]oxazin-4-one (E11)

Prepared in a similar way to Example 2 . Mp 130-2°C; δ_Η (DMSO-d₆) 1.53 (3Η, d, J = 7.1Hz, CH₃CH), 2.43 (3H, d, J = 1.1Hz, CH₃),

4.93 (1H, quin, J = 7.1Hz, HNCHCH₃), 7.32 (2H, m, 2 × ArH),

8.20 (2H, m, 2 × ArH), and 9.58 (1H, d, J = 7.4Hz, NHCO) (Found:

C, 51.61; H, 3.31; N, 7.99%. C.₅H₁₂N₂O₄S₂ requires C, 51.71; H, 3.47; N, 8.04%.) Example 18

(S)-2-[N-(3-(2-Chlorophenyl)propionyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E18)

δ_H [(CD₃)₂SO] 1.46 (3H, d, J = 7.15 Hz, CH₃CH), 2.42 (3H, d, J = 1.1 Hz, CH₃), 2.48 (2H, t, J = 7.15 Hz, CH₂CH₂), 2.92 (2H, t, J = 7.15 Hz, CH₂CH₂), 4.70 (1H, quint, J app. = 6.8 Hz, NHCHCH₃), 7.20 - 7.40 (5H, m, ArH and 6-H), and 8.57 (1H, d, J = 7.15 Hz, NH). Example 22

(S)-2-[N-(trans-Cinnamoyl)-1-aminoethyl]-5-methyl-4H- thieno[2,3-d][1,3]oxazin-4-one (E22)

δ_H [(CD₃)₂SO] 1.49 (3H, d, J = 7.15 Hz, CH₃CH), 2.42 (3H, d, J = 1.1 Hz, CH₃), 4.85 (1H, quint, J app. = 7.15 Hz, NHCHCH₃), 6.71 (1H, d, J = 15.9 Hz, =CH), 7.32 (1H, d, J = 1.3 Hz, 6-H), 7.41 (5H, m, ArH), 7.46 (1H, d, J = 15.6 Hz, =CH), and 8.79 (1H, d, J = 6.9 Hz, NH).

Example 27

(S)-2-[N-(trans-2,6-Dichlorocinnamoyl)-1-aminoethyI]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E27)

δ_H (CDCl₃) 1.6 (3H, d, J = 7 Hz, CH₃CH), 2.5 (3H, s, CH₃), 5.15 (1H, app. q, J = 7 Hz, NHCHCH₃), 6.5 (1H, br d, J = 7 Hz, NH), 6.7 (1H, d, J = 16 Hz, =CH), 6.8 (1H, s, 6-H), 7.2 (1H, app t, J = 7 Hz, ArH), 7.35 (2H, d, J = 7 Hz, ArH), and 7.8 (1H, d, J = 16 Hz, =CH).

Example 39

(S)-2-[N-(trans-4-Acetoxycinnamoyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E39)

δ_H [(CD₃)₂SO] 1.48 (3H, d, J = 7.15 Hz, CH₃CH), 2.28 (3H, s, COCH₃), 2.42

(3H, d, J = 1.1 Hz, CH₃), 4.85 (1H, quint, J app. = 7.15 Hz, NHCHCH₃), 6.68 (1H, d, J = 15.7 Hz, =CH), 7.18 (2H, d, J = 10.5 Hz, ArH), 7.32 (1H, d, J = 1.3 Hz, 6-H), 7.46 (1H, d, J = 15.6 Hz, =CH), 7.63 ( 2H, d, J = 8.8 Hz, ArH), and 8.79 (1H, d, J = 6.9 Hz, NH).

Example 43

(S)-2-[N-(trans-3-Furanylacryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E43)

A solution of rra/u-3-furanylacrylic acid (56 mg, 0.5 mmol) in

dichloromethane (1 ml) was treated with 1-hydroxybenzotriazole (75 mg, 0.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (105 mg, 0.55 mmol) in dichloromethane (2 ml) and stirred for 0.5 h. A solution of (S)-2-(1- aminoethyl)-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one, trifluoroacetic acid salt (134 mg, 0.5 mmol) in dichloromethane (1 ml) treated with N ,N-diisopropylethylamine (0.088 ml, 0.5 mmol.), was added to the reaction mixture, and the mixture was then stirred for 18 h. The solution was washed with water (1 × 10 ml), 1M hydrochloric acid (1 × 10 ml) and saturated sodium bicarbonate (1 × 10 ml), dried (MgSO₄), filtered and evaporated. The residue was crystallised from

acetone/hexane to give the product as a buff solid. (51 mg, 31%); δ_H [(CD₃)₂SO] 1.46 (3Η, d, J = 7.15 Hz. CH₃CH), 2.42 (3H, d, J = 1.1 Hz, CH₃), 4.82 (1H, quint, J app. = 7.0 Hz. NHCHCH₃), 6.41 (1H, d, J = 15.4 Hz, CH), 6.73 (1H, m, 6-H), 7.31 (1H, m, furan-H), 7.36 (1H, d, J = 15.6 Hz, CH), 7.74 (1H, m, furan-H), 8.02 (1H, m, furan-H), 8.69 (1H, d, J = 6.9 Hz, NH).

Example 46

(S)-2-[N-(trans-2-QuinoIinylacryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E46)

δ_H [(CD₃)₂SO] 1.52 (3H, d, J = 7.15 Hz, CH₃CH), 2.42 (3H, d, J = 1.1 Hz,

CH₃), 4.88 (1H, quint, J app. = 6.9 Hz, NHCHCH₃), 7.32 (2H, m, 6-H and =CH),

7.63 (2H, m, ArH and =CH), 7.77 ( 2H, m, ArH), 8.00 (2H, m, ArH), 8.43 (1H, d, J

= 8.5 Hz, ArH), and 9.06 (1H, d, J = 7.15 Hz, NH).

Example 51

(S)-2-[N-(1,2,3,4-Tetrahydro-(2RS)-naphthylcarbonyl)-(1S)-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E51)

δ_H (CDCl₃) 1.55 (3H, d, J = 7 Hz, CH₃CH), 1.9 (1H, m, CH₂.) 2.15 (1H, m, CH₂), 2.5 (3H, s, CH₃), 2.65 (1H, m, CH), 3.0 (4H, m, 2 × ArCH₂), 5.0 (1H, app. q, J

= 7 Hz, NHCHCH₃), 6.4 (1H, br m, NH), 6.8 (1H, s, 6-H), and 7.1 (4H, br s, ArH). Example 54

(S)-2-[N-(Phenylpropiolyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin- 4-one (E54)

δ_H [(CD₃)₂SO] δ_H 1.48 (3Η, d, J = 6.9 Hz, CH₃CH), 2.43 (3H, d, J = 1.1Hz, CH₃), 4.82 (1H, quint, J app. = 6.9 Hz, NHCHCH₃), 7.33 (1H, d, J = 1.3 Hz, 6-H), 7.47-7.64 (5H, m, ArH), and 9.48 (1H, d, J = 6.9 Hz, NH).

Example 58

(S)-2-[N-(trans-Benzoylacryloyl)-1-aminoethyl]-5-methyl-4H- thieno[2,3-d][1,3]oxazin-4-one (E58)

δ_H (CDCl₃) 1.6 (3H, d, J = 7 Hz, CH₃CH), 2.5 (3H, s, CH₃), 5.1 (1H, app. q, J = 7 Hz, NHCHCH₃), 6.8 (1H, s, 6-H), 7.1 (1H, d, J = 15 Hz, =CH), 7.2 (1H, d, J = 7 Hz, NH), 7.5 (3H, m, ArH), and 8.0 (3H, m, ArH). Example 80

(S)-2-[N-(trans-2-Chlorocinnamoyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E80)

δ_H (CDCI₃) δ 1.6 (3H, d, J = 7Hz), 2.5 (3H, s); 5.2 (1H, q, J = 7Hz), 6.5 (1H, d, J = 16Hz), 6.6 (1H, br d, J = 8 Hz), 6.8 (1H, s), 7.3 (4H, m), 8.0 (1H, d, J = 16 Hz).

Example 82 (S)-2-[N-(trans-2-BromocinnamoyI)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E81)

δ_H (CDCI₃) 1.6 (3H, d, J = 7 Hz), 2.5 (3H, s), 5.2 (1H, q, J = 7 Hz), 6.5 (1H, d, J = 16 Hz), 6.7 (1H, br d, J = 8 Hz), 6.9 (1H, s), 7.5 (4H, m), 8.0 (1H, d, J = 16 Hz). Example 85

(S)-2-[N-(trans-2-Ethoxycinnamoyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E85)

δ_H (CDCl₃) 1.44 (3H, t, J = 7 Hz, CH₃), 1.6 (3H, d, J = 7 Hz, CH₃CH), 2.5 (3H, s, CH₃), 4.05 (2H, q, J = 7 Hz, CH₂), 5.3 (1H, m, NHCH), 6.6 (1H, d, J = 16 Hz, =CH), 6.7 (1H, d, J = 7 Hz, NH), 6.8 (3H, m, 6-H and ArH), 7.25 (1H, app t, J = 6 Hz, ArH), 7.5 (1H, app d, J = 8 Hz, ArH), and 8.0 (1H, d, J = 16 Hz, =CH).

Example 93

(S)-2-[N-(trans-3-Indolylacryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E93)

δ_Η [(CD₃)₂SO] 1.49 (3Η, d, J = 7.15 Hz, CH₃CH), 2.42 (3H, d, J = 1.1 Hz, CH₃), 4.85 (1H, m, CH₃CH ), 6.71 (1H, d, J = 15.9 Hz, =CH), 7.19 (2H, m, 2 × ArH), 7.31 (1H, d, J = 1.1 Hz, 6-H), 7.46 (1H, m, ArH), 7.62 (1H, d, J = 15.7 Hz, =CH), 7.77 (1H, d, J = 2.7 Hz, ArH), 7.92 (1H, m, ArH), 8.53 (1H, d, J = 6.9 Hz, NH).

Example 98

(S)-2-[N-(trans-4-Quinolinylacryloyl)-1-aminoethyI]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E98)

δ_H [(CD₃)₂SO] 1. 53 (3H, d, J = 6.9 Hz, CH₃CH), 2.43 (3H, d, J = 1.1Hz, CH₃), 4.92 (1H, quint, 7.1 Hz, CH₃CH), 6.97 (1H, d, J = 15.9 Hz, =CH), 7.33 (1H, d, J = 1.1 Hz, 6-H), 7.69-7.75 (2H, m, ArH), 7.83 (1H, m, ArH), 8.08 (1H, d, J = 8.2 Hz, ArH), 8.24 (2H, m, ArH + =CH), 8.95 (1H, d, J = 5.6 Hz, ArH), 9.05 (1H, d, J = 6.9 Hz, NH). Example 100

(S)-2-[N-(2-thieno[3,2-b]thiophenylcarbonyl)-1-aminoethyl]-5-methyl-4H- thieno[2,3-d][1,3]oxazin-4-one (E100)

δ_H [(CD₃)₂SO] 1.57 (3Η, d, J = 7.15 Hz, CH₃CH), 2.42 (3H, d, J = 0.8 Hz, CH₃), 4.95 (1H, quint, J = 6.8 Hz, CH₃CH ), 7.33 (1H, d, J = 0.9 Hz, 6-H), 7.50 (1H, d, J = 5.2 Hz, ArH), 7.87 (1H, d, J = 5.0 Hz, ArH), 8.23 (1H, s, ArH), 9.17 (1H, d, J = 6.9 Hz, NH).

Example 186

(S)-2-[N-(trans-3-Quinolinylacryioyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E186)

δ_Η [(CD₃)₂SO] 1.52 (3H, d, J = 7.1 Hz, CH₃), 2.43 (3H, d, J = 1.1 Hz, CH₃), 4.89 (1H, m, CH), 6.99 (1H, d, J = 16 Hz, =CH), 7.33 (1H, d, J = 1.1 Hz, ArH), 7.65 (2H, m, 2 × ArH), 7.80 (1H, m, ArH), 8.02 (2H, m, 2 × ArH), 8.55 (1H, s, ArH), 8.91 (1H, d, J = 7.1Hz, NH), 9.14 (1H, d, J = 2.0 Hz, ArH).

Example 188

(S)-2-[N-(6-Bromothieno[3,2-b]thiophen-2-ylcarbonyl)-1-aminoethyl]-5-methyl- 4H-thieno[2,3-d][1,3]oxazin-4-one (E188)

δ_H [(CD₃)₂SO] 1.57 (3H, d, J = 6.9 Hz, CH₃ ), 2.42 (3H, d, J = 1.1 Hz, CH₃

), 4.96 (1H, m, CH), 7.33 (1H, d, J = 1.1 Hz, ArH), 8.03 (1H, s, ArH), 8.32 (1H, s, ArH), 9.30 (1H, d, J = 6.9 Hz, NH).

Example 191 (S)-2-[N-(1H-1,3-Dimethylthieno[2,3-c]pyrazole-5-carbonyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E191)

δ_Η [(CD₃)₂SO] 1.54 (3H, d, J = 7 Hz, CH₃), 2.36 (3H, s, CH₃), 2.42, (3H, d, J = 1 Hz, CH₃), 3.85 (3H, s, CH₃), 4.91 (1H, m, CH), 7.32 (1H, d, J = 1 Hz, ArH), 7.92 (1H, s, ArH), 9.03 (1H, d, J = 7 Hz, NH). Example 204

(S)-2-[N-(trans-{2,5-Dimethoxybenzoyl}acryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E204)

δ_H (CDCl₃), δ 7.87 (1H,dJ=15 ),7.24(1H,d, J=4 ),7.08(1H,dd,J=4,10 ), 6.94(1H,d,J=10), 6.90(1H,d,J=15 ), 6.88(1H,s), 6.66(!h,d,J=7.5), 5.12(1H,dt,J= 6.5,7.5 ), 3.88(3H,s), 3.80(3H,s), 2.53(3H,s),1.64(3H,dJ=6.5).

Example 205

(S)-2-[N-(trans-{2-NitrobenzoyI}acryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E205)

δ_H (CDCI₃), δ 8.20(1H,dd,J= 8, 2), 7.79(1H,dt,J= 8, 2 ), 7.69(1H,dt,J= 8, 2 ), 7.50(1H,dd,J= 8,2 ), 7.31(1H,d, J=16.5), 6.99(1H,s), 6.62(1H,brdJ=7),

6.62(1H,d,J=16.5 ), 5.09(1H,dt,J= 7,7 ), 2.51(3H,s), 1.61(3H,d,J= 7 ). Example 206

(S)-2-[N-(trans-{3-Nitrobenzoyl}acryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E206)

δ_H (CDCI₃), δ 8.86(1H,t,J=1.5), 8.48(1H,ddJ=1.5,7.5), 8.36(1H,dd,J=1.5, 7.5), 8.00(1H,d,J=14), 7.74(1H,t,J=7.5), 7.14(1H,d,J=14), 6.90(1H,s),

6.83(1H,d,J=7), 5.15(1H,dt,J=7, 7), 2.52(3H,s), 1.67(3H,d J=7).

Example 207

(S)-2-[N-(trans-{3-Methoxybenzoyl}acryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E207)

δ_H (CDCI₃), δ 7.97(1H,d,J=15 ), 7.61(1H,d,J=7.5 ), 7.54(1H,m),

7.42(1H,t,6.5 ), 7.18(1H,m), 7.05(1H,d,J=15), 6.90(1H,s), 6.75(1H,d,J=7.5 ), 5.12(1H,dt,J=7,7 ), 3.87(3H,s), 2.52(3H,s), 1.66(3H,d,J=7 ). Example 208

(S)-2-[N-(trans-{3-Cyanobenzoyl}acryloyl)-1-aminoethyI]-5-methyl-4H- thieno[2,3-d][1,3]oxazin-4-one (E208)

6H (CDCl₃),

8.31(1H,t,J=1.5), 8.23(1H,dd,J=1.5,7), 7.94(1H,d,J=15), 7.89(1H,dd,J=1.5,7), 7.67(1H,t,J=7), 7.09(1H,d,J=15), 6.90(1H,s), 6.79(1H,d,J=7), 5.14(1H,dt,J=7, 7), 2.52(3H,s), 1.67(3H,d,J=7). Example A-10

(S)-2-[N-(trans-Cinnamoyl)-1-aminoethyI]-5,6-dimethyl-4H-thieno[2,3-d][1,3]oxazin-4-one (EA-10)

δ_H [(CD₃)₂SO] 1.48 (3H, d, J = 6.6 Hz. CH₃CH), 2.33 (3H, s, CH₃), 2.39 (3H, s, CH₃), 4.85 (1H, m, CH₃CH), 6.71 (1H, d, J = 15.7 Hz, =CH), 7.35 - 7.60 (6H, m, 5 × ArH + =CH), 8.77 (1H, d, J = 7.1 Hz, NH).

Example B-10

(S)-2-[N-(trans-2-ChlorocinnamoyI)-1-aminoethyl]-5-methyl-6-[2-(2-propyIcarbamoyloxy)ethyl]-4H-thieno[2,3-d][1,3]oxazin-4-one (EB-10)

δ_Η [(CD₃)₂SO] 1.02 (6H, d, J = 7 Hz), 1.49 (3H, d, J = 7 Hz), 2.37 (3H, s),

3.09 (2H, t, J = 6 Hz), 3.55 (1H, sept, J = 7 Hz), 4.11 (2H, t, J = 6 Hz), 4.84 (1H, quin, J = 7 Hz), 6.77 (1H, d, J = 16 Hz), 7.03 (1H, d, J = 8 Hz), 7.39-7.78 (5H, m), and 8.90 (1H, d, J = 7 Hz).

Peptidolytic Assay for Proteases

Compounds are assayed in the following way:

A solution of inhibitor is added to a solution of enzyme (0.5 - 1 uM) diluted in buffer (50 mM sodium phosphate, 150 mM sodium chloride, 0.001 mM EDTA, 0.01% PEG 3400; pH 8.0) to give a final inhibitor concentration of 0.01 to 300 uM in a total volume of 25 microliters. Following a 15 minute preincubation, 15 microliters of a solution of the 14-mer peptide substrate, Ac-HTYLQASEKFKMWG, is added to give a final substrate concentration of 250 uM. The sample is incubated at 27°C for 1 hour and reaction is by the addition of 40 microliters of 5% trifluoroacetic acid in water. The sample is analyzed by HPLC to quantitate the amounts of the substrate peptide and of the N-terminal and C-terminal cleavage fragments. The percentage cleavage is calculated and expressed as a fraction of the value obtained for an uninhibited control sample.

The enzyme used in the assay for HSV-2 consists of the proteolytically active domain of the HSV-2 UL26 homologue protein (amino acid residues 1 to 247).

WO 95/06055 (SmithKline Beecham Corp.) describes the HSV-2 protease sequence.

The enzyme used in the assay for CMV consists of the proteolytically active domain of the CMV UL80 protein (amino acid residues 1 to 256) with the addition of an amino terminal MGHHHHHHHHSSGHIDDDDK. The polypeptide has cleaved beween A 143 and A 144 (natural UL 80 numbering) to give an active heterodimer.

The enzyme used in the assay for VZV consists of the proteolytically active domain of the VZV gene 33 protein (amino acid residues 1 to 237).

The compounds of the Examples 1 to 69 showed activity in one or more of the above tests at a concentration of 10uM or luM. The Compounds E22 to E39 showed good activity and Compounds E22, E39, E46, E54 showed preferred activity for HSV-2, Compounds E22, E43, E44, E45, E54, E58 showed preferred activity for CMV and Compounds E22, E27, E46, E51, E54, E58 showed preferred activity for VZV. Quenched fluorescence assay for protease inhibition

A quenched fluoresecence based assay is currently used to generate IC₅₀ data for compounds screened against HSV-2, VZV and CMV proteases. The cleavage of a quenched fluorescent (QF) peptide substrate by the protease yields an increase in measured fluorescence over the time of incubation. The assay currently uses a final volume of 200ul of assay mixture in each well. However, volume additions and dilution steps can be altered to cope with any changes in starting and/or final concentrations for each assay component. The steps described below have been configured to run using a Beckman Biomek 2000 robot. Compounds for screening are made up as stock solutions in 100% DMSO. Four compounds in duplicate are arranged per plate for screening against all three proteases. The compound stock solution, in the first well, is serially diluted 1/1 (v/v) with DMSO to produce a 1000 fold decrease in stock concentration across the plate in 11 points. Eight wells are included containing 100% DMSO only for addition to four control and four blank wells on the reaction plate.

The reaction plate is an opaque 96 well plate designed for use with a fluorometric plate reader. Compound/DMSO from the dilution plate are transfered to the reaction plate which already contains assay buffer. The type of assay buffer used depends on which of the proteases is being assesed in the screen. For HSV-2 and VZV proteases this is 50mM hepes/150mM NaCl/lmM EDTA/0.01%PEG

3.400/0.8M sodium citrate* in 30% sucrose, pH 7.5

*For CMV protease the 0.8M sodium citrate is omitted from the assay buffer.

Each protease is stored at -20°C, thawed and stored on ice for ~1hr. The protease stock is then diluted using the correct buffer to 50X the final concentration needed. The diluted protease stock is added to all but the four wells designed to be used as blanks. Buffer only is used in these wells. The final concentrations are

500nm, 20nm and 20nm for HSV-2, VZV and CMV respectively.

The assay mixture is incubated at 27°C for 15 minutes.

Solid QF peptide substrate is resuspended in 10% DMSO/water at 400mM. This is further diluted 1/10 with assay buffer and added to each well of the reaction plate to give the final concentration of 10uM. FQ-7 peptide is used as the substrate for HSV-2 and VZV proteases. FQ-8 peptide is used as the substrate for CMV protease. FQ7: Dabs-DNAVEASSKAPLK-Dans

FQ8: Dabs-RGWNASSALAKK-Dans

The plate is read every 30 seconds with a Fluostar SLT fluorometric plate reader using Annelisa software, for 15tnin at 27°C. Ex 355/Em 495nm.

Data is transferred to Graphit software where rates of fluorescence are plotted against inhibitor concentrations. IC₅₀ values are calculated for each of the four compounds against all three proteases.

The results were as follows:

The Compounds of the Examples 70 onwards showed activity in one or more of the above tests with an IC₅₀ value of 15uM or less. Compounds E90, E125, E127, E128, E130, EA-10 showed preferred activity for HSV-2, Compounds E90, E116, E117, E118, E188, E191, E204, E205, E206, E207, E208, EB-10, showed preferred activity for CMV and Compounds E85, E89, E125, E126, E128, E186, showed preferred activity for VZV.

Claims

1. Herpesvirus protease inhibitor 4H-thieno[2,3-d][1,3]oxazin-4-one derivatives which are:

R₁ is hydrogen or an amino acid side chain. 2. A compound according to claim 1 wherein the 4H-thieno[2,3-d][1,3]oxazin-4- one ring system, numbered thus:

is optionally substituted in the 5 and 6 positions (designated R₃ and R₂ respectively) as well as by the 2-substituent.

3. A compound according to claim 2 wherein R₃ and R₂ when present are selected from halo, C_{1 -6} alkyl or C_{1 -6} alkoxy, C_{1 -6} alkylthio, amino optionally substituted by one or two C_{1 -6} alkyl or optionally substituted benzyl groups, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, optionally substituted phenyl or R₅ZCONH wherein Z is a bond, O, NH or NCOCH₃, and R₅CO is an acyl group where values of R5 include aryl, alkyl or aralkyl, or R₃ and R₂ may be joined to form C₃, C₄, C₅, C₆, C₇, or C₈ polymethylene.

4. A compound according to claim 3 wherein the 5-substituent is methyl and the 6-substituent is CH₂R_a, OCH₂R_b, or NR_cR_d wherein R_a and R_b are selected from hydrogen or a substituent, R_c is alkyl and R_d is alkyl or substituted alkyl or R_c and R_d are joined to form a heterocyclic ring containing one or more heteroatoms.

5. A compound according to any one of claims 1 to 4, wherein R₄ is

(aryl or heteroaryl)-Q- wherein Q- is optionally present and is a spacing moiety selected from CH₂-, C≡C-, CHR₆CH₂-, CR₆=CH- wherein R₆ is hydrogen or a halo, alkyl or aryl substituent.

6. A compound selected from me compounds of the Examples, as described herein.

7. A compound selected from:

(S)-2-[N-(2-Thienylcarbonyl)-1-aminoethyl]-5-methyI-4H-thieno[2,3-d][1,3]oxazin- 4-one (E2),

(S)-2-[N-(2-Thienylacetyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4- one (E10),

(S)-2-[N-(2-Thienylglyoxylyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin- 4-one (E11),

(S)-2-[N-(3-(2-Chlorophenyl)propionyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E18),

(S)-2-[N-(trans-Cinnamoyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E22),

(S)-2-[N-(trans-2,6-Dichlorocinnamoyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E27),

(S)-2-[N-(trans-4-Acetoxycinnamoyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E39),

(S)-2-[N-(trans-3-Furanylacryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E43),

(S)-2-[N-(trans-2-Quinolinylacryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E46),

(S)-2-[N-(1,2,3,4-Tetrahydro-(2RS)-naphthylcarbonyl)-(1S)-aminoethyl]-5-methyl- 4H-thieno[2,3-d][1,3]oxazin-4-one (E51),

(S)-2-[N-(Phenylpropiolyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E54),

(S)-2-[N-(trans-Benzoylacryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E58),

(S)-2-[N-(trans-2-Chlorocinnamoyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E80), (S)-2-[N-(trans-2-Bromocinnamoyl)-1-aminoethyl]-5-methyl-4H- thieno[2,3-d][1,3]oxazin-4-one (E81),

(S)-2-[N-(trans-2-Ethoxycinnamoyl)-1-aminoethyl]-5-methyl-4H- thieno[2,3-d][1,3]oxazin-4-one (E85),

(S)-2-[N-(trans-3-Indolylacτyloyl)-1-aminoethyl]-5-methyl-4H- thieno[2,3-d][1,3]oxazin-4-one (E93),

(S)-2-[N-(trans-4-QuinolinylacryloyI)-1-aminoethyl]-5-methyl-4H- thieno[2,3-d][1,3]oxazin-4-one (E98),

(S)-2-[N-(2-thieno[3,2-b]thiophenylcarbonyl)-1-aminoethyl]-5-methyl-4H- thieno[2,3-d][1,3]oxazin-4-one (E 100),

(S)-2-[N-(trans-3-Quinolinylacryloyl)-1-aminoethyl]-5-methyl-4H- thieno[2,3-d][1,3]oxazin-4-one (E 186),

(S)-2-[N-(6-Bromothieno[3,2-b]thiophen-2-ylcarbonyl)-1-aminoethyl]-5-methyl-4H- thieno[2,3-d][1,3]oxazin-4-one (E 188),

(S)-2-[N-(1H-1,3-Dimethylthieno[2,3-c]pyrazole-5-carbonyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E 191 ),

(S)-2-[N-(trans-{2,5-Dimethoxybenzoyl}acryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E204),

(S)-2-[N-(trans-{2-Nitrobenzoyl}acryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E205),

(S)-2-[N-(trans-{3-Nitrobenzoyl}acryloyl)-1-aminoethyI]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E206),

(S)-2-[N-(trans-{3-Methoxybenzoyl}acryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E207),

(S)-2-[N-(trans-[ 3-Cyanobenzoyl}acryloyl)-1-aminoethyl]-5-methyl-4H-thieno[2,3-d][1,3]oxazin-4-one (E208),

(S)-2-[N-(trans-Cinnamoyl)-1-aminoethyl]-5,6-dimethyl-4H-thieno[2,3-d][1,3]oxazin-4-one (EA-10),

(S)-2-[N-(trans-2-ChlorocinnamoyI)-1-aminoethyl]-5-methyl-6-[2-(2-propylcarbamoyloxy)ethyl]-4H-thieno[2,3-d][1,3]oxazin-4-one (EB-10); or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier.

9. A compound according to any one of claims 1 to 7 for use as an active therapeutic substance.

10. A compound according to any one of claims 1 to 7 for use in treating viral diseases.

11. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for use in the treatment of viral diseases caused by herpesviruses.

12. A method of treatment of viral diseases caused by herpesviruses in mammals, which comprises the administration to mammal in need of such treatment, an effective amount of a compound according to any one of claims 1 to 7.