CZ195897A3 - Thienooxazine derivatives as antiviral agents, pharmaceutical preparation and use - Google Patents

Abstract

Herpesvirus protease inhibitor 4H-thieno (2,3-d)(1,3) oxazin-4-one derivatives of formula (I) which are 2-substituted by X(Y)NH-CHR1 - wherein X is hydrogen or a blocking group, Y is an optionally present amino acid, and R1 is hydrogen or an amino acid side chain.

Description

Technical field

The invention relates to thienoxazinone derivatives, to pharmaceutical compositions containing them and to the use of said compounds as antiviral agents.

BACKGROUND OF THE INVENTION

Certain thienoxazinone derivatives have been found to be effective in the treatment of infections caused by herpesviruses, in particular herpes simplex viruses of Groups 1 and 2 (HSV-1 and HSV-2), cytomegalovirus and varicella-zoster virus.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to herpesvirus protease inhibitors, 4H-thieno [2,3-d] [1,3] oxazin-4-one derivatives, which are substituted at the 2-position by X (Y) NH-CHR-? -, in which :

X represents a hydrogen atom or a blocking group, Y is an optionally present amino acid, and

R @ 1 represents a hydrogen atom or an amino acid side chain, which derivatives will hereinafter be referred to as the compounds of formula I.

This 4H-thieno [2,3-d] [1,3] oxazin-4-one ring system is numbered as follows:

<· · · 1 »» »<<<<<<<<<<<<<<<<<

9 9 9 9 9

9 99 99 99 99

Substituents at the 5 and 6 positions (referred to as R ₃ and R 2) may be present on this ring system, as well as a substituent at the 2-position. These substituents may be selected from halogen, alkyl of 1 to 6 atoms C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, amino optionally substituted by one or two C 1 -C 6 alkyl or optionally substituted benzyl, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, optionally substituted phenyl or R 4 ZCONH in which Z represents a bond, oxygen, NH or NCOCH 3, and R 4 CO represents an acyl group wherein the radical R 4 may be an aryl group, an alkyl group or an aralkyl group, or R ₃ and R 2 may be linked to each other and form a polymethylene group o containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms.

Examples of alkyl groups or groups containing alkyl groups are preferably straight or branched chain groups or cyclic alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of C 1-4 alkyl groups include methyl, ethyl, n-propyl or iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl. Cyclic alkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

9 · · 9 * * 9 9 9 9 9 9 9 9 9 9 9

9.9 9 9

9 99 9

99

9 9 «9.

Aryl groups include phenyl and naphthyl which are optionally substituted with one or more substituents selected from the group consisting of halogens, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy and alkoxycarbonyl groups in the alkoxy moiety 1 to 6 carbon atoms.

Halogens include fluorine, chlorine, bromine and iodine.

Suitable residues X include groups which are well known in the art of peptide chemistry. Particular examples of such groups include aryl, alkanoyl, (aryl) alkoxycarbonyl, (aryl) alkylaminocarbonyl, aroyl, or arylsulfonyl. Particular examples of X which are of particular interest to the present invention include benzyloxycarbonyl, t-butoxycarbonyl and optionally substituted phenyl.

Amino acid side chains may include one or more amino acids. Suitable examples of these amino acids are described in the prior art literature relating to synthetic peptides. These amino acids may be in the D-form or in the L-form, preferably the L-form. Particular examples of amino acids for Y include alanine, asparagine, valine and the like. Between · ···· · · · · · · · · · · · · · · · · · and · · · ·

Specific aminoacyl moieties -NH-CHR-4-CO- that are converted to NH-CHR-i in the compound of the formula I, alanine (i.e., R ^ = CH ^), asparagine, methionine, phenylalanine, serine (R ^ = = CH 2 OH), valine and α-aminobutyric group (R- = = Cb CHCH ^) may be included. ).

In a preferred embodiment, the present invention includes pharmaceutically acceptable salts of the compounds of formula (I) above.

The compounds of formula (I), including their pharmaceutically acceptable salts, may form solvates such as hydrates, and are also within the scope of the present invention, and when referring to the compounds of formula (I) or salts thereof, ormy.

The above compounds are prepared by activation of an amino acid or dipeptide containing R 6 by standard methods known in the art, such as:

(i) preparing an activated ester using a carbodiimide or other coupling reagent and a suitable moiety, such as 1-hydroxybenzotriazole, or (ii) preparing a mixed anhydride using such a reagent, such as isobutyl chloroformate, and reacting with 2-aminothiophene- 3-carboxylic acid or ester.

The intermediate amide compound thus obtained can be isolated or the crude reaction product can be cyclized directly. Among the appropriate reagents which may be used are: Are suitable for carrying out this cyclization of thiophenic acid derivatives, including addition agents or dehydrating agents such as carbodiimides, acetic anhydride or sulfonyl chlorides. Suitable reagents for carrying out the cyclization of thiophene ester derivatives include, for example, triphenylphosphine / carbon tetrachloride.

In cases where the amino acid has a functionalized side chain with a protecting group, the final step is to remove the protecting group, for example, removing an acid labile group using trifluoroacetic acid. Advantageously, according to the nature of the substituents at the 5 or 6 position in the desired end product, cyclization can be carried out before or after introduction / modification of the relevant substituent (s).

Pharmaceutically acceptable salts may be prepared by conventional methods known in the art, for example in the case of acid addition salts by reaction with a suitable organic or inorganic acid.

The compounds of the present invention are active when used in the treatment of infections caused by herpes viruses, such as herpes simplex virus types 1 and 2, varicellazoster virus, virus

Epstein-Barr and cytomegalovirus. Other herpes viruses, such as herpesvirus-6, are of potential interest in the present case.

The compounds of the present invention may be formulated for use in the form of pharmaceutical compositions. Accordingly, another aspect of the present invention is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

Compositions that can be administered orally in the treatment of humans may be formulated as a syrup, tablet or capsule. When formulated as a tablet, any pharmaceutically acceptable carrier suitable for formulating such solid formulations, such as magnesium stearate, starch, lactose, glucose, rice, flour, and chalk, may be used. These compositions may also be in the form of acceptable capsules, such as gelatin capsules containing the compound, or in the form of a syrup, solution or suspension. Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerin, saline and water to which flavorings or coloring agents may be added to give a syrup-like preparation. These compounds may also be combined with sterile liquid carriers for injection.

These compositions may also be formulated for topical application to the skin or eye.

Where the composition is for topical application to the skin, the composition may be in the form of a cream, ointment or lotion. These compositions may be commonly used and well known in the art, for example as described in standard pharmaceutical and cosmetic publications such as Harry's Cosmeticology, published by Leonard Hill Books and the British Pharmacopaeia.

Ί

The compositions to be administered to the eye may be conventional eye drops, as are known in the art, or may be formulated as an ointment.

Preferably, the compositions are in unit dosage form or other unit dose form. A suitable unit dosage form may contain 50 milligrams to 1 gram of the active ingredient, such as 100 to 500 milligrams of the active ingredient.

These doses may be administered one to four times a day or more, but are usually given two or three times a day. An effective dose of the compound is usually in the range of 1.0 milligrams / kilogram body weight per day to 20 milligrams / kilogram body weight per day or more usually in the range of 2.0 to 10 milligrams / kilogram body weight per day.

No undesirable and unacceptable toxicological effect was observed when using the above dosage amounts.

The present invention also provides a method of treating viral infections in humans and non-human animals comprising administering to said animals an effective, non-toxic amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as active

• therapeutic agents, especially in the treatment of viral infections.

DETAILED DESCRIPTION OF THE INVENTION

The thienoxazinone derivatives of the present invention, their preparation process and intermediates thereof, as well as the effects of the compounds and the pharmacological tests to determine these effects will be illustrated in more detail below with reference to specific examples, which are illustrative only and not limiting.

First, the following schemes illustrate processes for preparing the compounds of the present invention and intermediates thereof.

Scheme 1

Synthesis procedure according to Example 1

Individual stages:

(i) Et 2 N, methanol, (ii) NaOH / H ₂ O, (iii) N-methylmorpholine, isobutyl chloroformate, THF, DMF,

Cbz-L-alanine, (iv) DEC, DMF.

Scheme 1

and.

· 4 · 4 · 4 · 4 · 4 · 4 · 4

CO ₂ Me ^XxS ' ^{z / Xs} ' NH ₂ ii.

V _ C 0 ₂ Na s nh ₂ iii.

IN

iv.

CbzHN,

CH ₃

Β Β Β · · · · ·

Β · Β ·

Β Β Β

ΒΒ ΒΒΒΒ

Scheme 2

Synthesis procedure according to Examples 2, 3 and 4 and Example 2, Method 2.

CbzNH

S ·· ····

-1-1 li · ♦ li li li li li li li li li li li li li li li li *

Example (Grade 1)

Preparation of sodium 2-aminothiophene-3-carboxylate

A solution containing 2-aminothiophene-3-carboxylic acid methyl ester (see U.S. Pat

K. Gewald, Chem. Ber., 1965, 98, 3571-7; 2.5 g (0.016 mol) in dioxane (20 ml) was added and sodium hydroxide (0.64 g, 7.5 ml of a 2.13 M solution, 0.016 mol) was added. The reaction mixture was stirred at 60 ° C for 6 hours and heated at reflux for 1.5 hours. The solvent was then removed under reduced pressure, the residue was dissolved in water, and the unreacted starting material was extracted using dichloromethane (3 x 50 mL). Water was removed from the product and dried over phosphorus pentoxide at 60 ° C. Yield: 1.56 g, 59%.

δ _Η t (CD ₃ ) ₂ SO]:

5.95 (1H, d, J 5.5 Hz, thiophene proton),

6.75 (3H, m, thiophene proton and NH ₂ .

Example 1 (level 2)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 4H-thieno [2,3-d] [1,3] oxazin-4-one.

A solution containing N-benzyloxycarbonyl-L-alanine (1.68 g, 7.51 mmol) in tetrahydrofuran (50 mL) was added to which N- was added at -10 ° C. methylmorpholine (0.82 milliliters, 0.76 grams or 7.51 mmol) and isobutyl chloroformate (0.974 milliliters, 1.025 grams or 7.51 mmol), and the reaction mixture was stirred for 0 , 5 hours. A solution of sodium 2-aminothiophene-3-carboxylate (1.25 g, 7.51 mmol) in N, N-dimethylformamide (30 ml) was added dropwise, and the reaction mixture was stirred for an additional 18 hours. The excess solvent was then removed under reduced pressure and the residue was purified by column chromatography (eluting with 10% methanol in dichloromethane containing 0.5% acetic acid) to give the title compound as a white solid.

2 - [(N-benzyloxycarbonyl-L-alaninyl) amino] thiophene-3-carboxylic acid (1.77 g).

To a solution of this material in DMF (50 mL) at 0 ° C was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.979 g, 5.07 mmol) and the reaction mixture was stirred at room temperature. for 2.5 hours. Excess solvent was removed under reduced pressure and the residue was purified by column chromatography (eluting with 5% ethyl acetate in dichloromethane). The impure product was purified again, eluting with 10% isopropyl alcohol in hexane to afford (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] -4H-thieno [ 2,3-d] [1,3] oxazin-4-one,

Yield: 23 milligrams,

Melting point: 140-144 ° C;

^max (K ^ ^r) 3286, 1758, and 1686 cm @ ^-1;

^S H t (CD ₃ ) ₂ SO]:

«· · · · · · · · · · ·

1.44 (3H, d, J 7Hz, _CH3), 4.6 (1H, m, CH) 5,05 (2H, m, ch ₂ ), 7.3 (5H, m, C ₆ H _5); 7.45 (1H, d, J 5Hz, thiophene proton), 7.7 (1H, d, J 5Hz, thiophene proton), and 8.04 (1H, d, J 7Hz, NH).

Analysis calculated for:

^C 16 ^H 14 ^N 2 ^O 4 ^S 58.17% C 57.84% C

H 4.27% H 4.47%

8.48

8.57

N

N.

Examples 2 and 3 (general method for step 1)

Preparation of 2- [N- (benzyloxycarbonyl) -L-alaninyl] aminothiene-3-carboxetes

A solution containing N- (benzyloxycarbonyl) alanine (3 mmol) in dry tetrahydrofuran (25 mL) at -5 ° C was added followed by 4-methylmorpholine (3 mmol) followed by isobutyl chloroformate ( 3 mmoles). After 5 minutes, the appropriate aminothiophenester (3 mmol) was added and the reaction mixture was stirred at -5 ° C for 30 minutes and then at room temperature for 52 to 60 hours. The precipitate was filtered off, washed with dry tetrahydrofuran (2 x 10 mL), the combined filtrates and washings were evaporated to dryness and the residue was co-evaporated with toluene (2 x 50 mL). ). The product was purified by column chromatography on silica gel, eluting with ethyl acetate / hexane.

·· ··

Example 2 (level 1)

Preparation of 2- [N- (benzyloxycarbonyl) - L-alaninyl] amino-4-methylthiophene-3-carboxylic acid ethyl ester.

Yield: 73%;

ν _max (KBr) 3305, 1696, 1670, 1551, 1521, and 1452 cm ^-1 ;

N _H [(CD ₃ ) ₂ SO]:

1.17 (6H, m, 2 x CH _3), 2.32 (3H, d, J = 1.1Hz, _CH3);

4.29 (3H, m, CH and _CH2), 5.08 (2H, m, C ₂ Ph),

6.71 (1H, d, J = 1.1 Hz, 5-H), 7.36 (5H, m, aromatic protons), 8.15 (H, d, J = 6.32 Hz, D ₂₀ replaceable) , NH), and 11.58 (H, s, D ₂₀ replaceable, NH)

H, 5.68; N, 7.17. Found: 58.34; C, 5.67; H, 7.65.

Example 3 (level 1)

Preparation of 2 - [(N-benzyloxycarbonyl) -L-alaninyl] amino-4,5-dimethylthiophene-3-carboxylic acid ethyl ester.

Yield; 48%;

ν _max (KBr) 3276, 2985, 1687, 1565, 1529, and 1452 cm ^-1 ; S _H t (CD ₃ ) ₂ SO]:

1.32 (6H, m, 2.24 (3H, with, 5.08 (2H, m, 8.12 (1H, d, 11.5 (1H, with,

x CH ₃ ), 2.21 (3H, s, CH ₃ ),

CH ₃ ), 4.26 (3H, m, CH and CH ₂ ),

CH ₂ Ph), 7.36 (5H, m, aromatic protons), J = 6.6 Hz, D ₂ O exchangeable, NH), and D ₂ O exchangeable, NH).

Analysis for calculated:

^C 20 ^H 24 ^N 2 ° 5 ^N 59.39% C

H, 5.98

6.93% N

99 • 9 • 9 • 9

9 9 • 9

Found:% C, 59.40;% H, 5.93%;

Example 4 (level 1)

Preparation of 2- [N- (benzyloxycarbonyl) - L-alaninyl] amino-cyclopentane [b] thiophene-3-carboxylic acid ethyl ester.

A solution containing ethyl 2-aminocyclopentane [b] thiophene-3-carboxylic acid ethyl ester (1 gram, 4.8 mmol) in dry N, N-dimethylformamide (20 ml) was added to the solution. % of 1-hydroxy-7-azabenzotriazole (in amount of

5.7 mmol (0.77 g), N-benzyloxycarbonyl) alanine (5.7 mmol, 1.27 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (used 5 7 mmol (1.1 g). The resulting reaction mixture was stirred at room temperature for 52 hours. The solvent was removed and the residue was dissolved in dichloromethane (200 mL). The solution was washed with 10% aqueous citric acid (2 x 50 mL), saturated aqueous sodium bicarbonate (2 x 50 mL), and brine (1 x 50 mL) and dried. (magnesium sulfate). The solvent was then removed and the product was purified by silica gel column chromatography (eluting with 5-10% ethyl acetate in chloroform) to give 2- [N- (benzyloxycarbonyl) -Lalaninyl] amino ethyl ester. -cyclopentane [b] thiophene-3-carboxylic acid as a colorless solid.

Yield: 0.61 g (31%);

• · · · · ·

* · · ·

Λ · •. *......

^{max (^)} and 1453 cm ~ l; δ _Η t (CD ₃ ) ₂ SO]

1.33 (6H, m, 2.83 (4H, m, 5.09 (2H, m, 8.14 (1H, d,

II, 36 (1 H, br

3286, 2976, 2934, 1700, 1670, 1559, 1527, ₃ x CH), 2.32 (2H, m, CH ₂₎ x CH _2), 4.26 (3H, m, CH ₂ and CH)

CH ₂ Ph), 7.36 (5H, m, aromatic protons), J = 6.04 Hz, D ₂ O exchangeable, NH), as, D ₂ O exchangeable, NH).

Analysis calculated for:

^C 21 ^H 24 ^N 2 ^O 5 ^N 59.39% C 59.92% C

H ₂ °: 5.85% H 5.79% H

N 6.67% N 6.62%

2)

Examples 2, 3a (general method for step

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 4H-thieno [2,3-d] [1,3] oxazin-4-ones.

Triphenylphosphine (2 mmol) and carbon tetrachloride (3 mmol) were added to a solution containing a suitable amidothiophene ester (0.5 mmol) in dry dichloromethane (10 mL). The resulting mixture was refluxed at 70 ° C for 3.0 to 3.5 hours, diluted with dichloromethane (100 mL) and washed with a saturated aqueous sodium bicarbonate solution. (two portions of 20 ml each) and dried (magnesium sulfate). The solvent was removed and the product was purified by column chromatography on silica gel using ethyl acetate / hexane as eluent.

· * * * * * * * * * * * * *

Example 2 (level 2)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl-6-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one.

Yield: 41%;

Melting point: 145 - 150 ° C;

the _m ax ^(KBr) 3425, 3289, 1756, 1691, 1604, 1553, 1540, and 1453 cm ^- '·; ^HC (CD _{3) 2} SO]:

1.43 (3H, d, J = 7.15Hz, CH ₃ ), 2.42 (3H, d, J = 0.82Hz, CH ₃ ),

4.56 (IH, m, CH), 5.06 (2H, m, CH ₂ Ph),

7.32 (IH, d, J = 1.1Hz 6-H), 7.36 (5H, m, aromatic protons) and 8.02 (IH, d, J = 7.15 Hz, D ₂₀ replaceable, NH).

Analysis for ^C 17 ^H 16 ^N 2 ° 4 ^S: Calculated: 59.29% C 4.68% H 8.13% N Found: 59.20% C 4.69% H 8.19% N

Example 3 (level 2)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5,6-dimethyl-4H-thieno [2,3-d] [1,3] oxazin-4-one.

Yield: 90%; Melting point: 122

125 [deg.] C .;

ⁱⁿ max and 1455 cm ): -1. , 3302, 1757 1724 1685 , 1601, δ _Η [(cd ₄ ) ₂ SO] 1.42 (3H, d, J = 7.15Hz, CH ₃ ), 2.33 (3H, s, CH ₃ ), 2.40 (3 H, with, CH ₃ ), 4.56 (1 H, m, CH), 5.06 (2H, m, 7.36 (5H, m, aromatic protons), and 8.01 (IH, d, J = 7.43Hz, D ₂ 0 replaceable, NH). Analysis for ^C 18 ^H 18 ^N 2 ° 4 S:

calculated: 60.32% C 5.06% H 7.82% N found: 60.61% C 5.29% H 7.62% N.

Example 4 (level 2)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 6,7-dihydro-4H, 5H-cyclopenta [4,5] thieno [2,3-d] [1,3] oxazine-4- onu.

Yield: 28%;

^v max ^<KBr) '3414, 3295, 2986, 1775, 1687, 1600, 1537 and 1453 cm ^- ^; δ _Η [(CD ₃ ) ₂ SO]:

1.42 (3H, d, J = 6,87Hz, CH _3), 2.43 (2H, m, _CH2),

3.1 (4H, 2 * _CH2), 4.57 (1H, m, CH), 5.06 (2H, m, CH ₂ Ph),

7.36 (5H, m, aromatic protons), and

8.01 (1H, d, J = 7.43Hz, D ₂₀ replaceable, NH).

Example 2 (step 2, method 2)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one.

A solution containing 2- [N- (benzyloxycarbonyl) L-alaninyl] amino-4-methylthiophene-3-carboxylic acid ethyl ester (0.51 mmol, 0.2 grams) in dioxane (2 mL) was used. A 1 M aqueous sodium hydroxide solution (0.52 mL) was added to the solution. The resulting mixture was stirred at room temperature for 87 hours, and an additional 1 M aqueous sodium hydroxide solution (0.3 mL) was added and stirring continued. <

·· ·· for 12 hours. The solution was neutralized with dilute hydrochloric acid, the solvent was removed, and the residue was co-evaporated with toluene (2 x 20 mL). The residue was treated with dry N, N-dimethylformamide (10 mL) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1 mmol, 0.19 grams) was added to the resulting solution. and the resulting solution was stirred at room temperature for 60 hours. The solvent was removed, the residue was dissolved in dichloromethane (100 mL), washed with 10% aqueous citric acid solution (10 mL each), then saturated aqueous sodium bicarbonate solution (10 mL each) and brine (1 mL). 10 ml) and dried (magnesium sulfate). The product was purified by column chromatography on silica gel (eluting with 20-25% ethyl acetate in hexane) to give (S) -2- [N- (benzyloxycarbonyl) -1aminoethyl] as the eluent. 5-Methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one. Yield: 15 mg (8%);

in.

max 1453 cm (KBr) -1

3417, 3288, 1756, 1691, 1604, 1553, 1539 and δ _Η [(CD ₃ ) ₂ SO]:

1.43 (3H, d, J = 7,15Hz, CH _3), 4.56 (1H, m, CH)

2.42 (3H, d, J = 1.1Hz, CH _3), 5.05 (2H, m, CH ₂ Ph),

7.32 (1H, d, J = 1.1Hz, 6-H), 7.36 (5H, m, aromatic protons) and 8.02 (1H, d, J = 7.42 Hz, D ₂₀ replaceable) , NH).

Analysis for ^C 17 ^H 16 ^N 2 ^O 4 ^S Calculated: C 59.41 Found: C 59.29

H, 4.76; H, 4.68

N 8.08% N 8.13%

Example 5

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5,6,7,8-tetrahydro-4H- [1] benzothieno [2,3-d] [1,3] oxazin-4-one .

Melting point: 131-133 ° C.

Example 6

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-amino-ethyl] -ethoxycarbonyl-5-methylthieno [2,3-d] [1,3] oxazin-4-one. Melting point: 100 - 102 ° C.

Example 7 (level 1)

Preparation of 2- [N- (benzyloxycarbonyl) - L-alaninyl] amino-4-methyl-5-nitrothiophene-3-carboxylic acid ethyl ester.

A stirred solution containing the ethyl ester was used

2- [N- (benzyloxycarbonyl) -L-alaninyl] amino-4-methylthiophene-3-carboxylic acid (used 1 gram, 2.56 mmol) in copper nitrate (0.1 gram) in acetic anhydride (20 ml); To this solution was added copper nitrate (0.5 grams) over a period of 2 hours. The reaction mixture was cooled to room temperature, poured onto ice (500 g) and extracted with dichloromethane (three portions of 100 ml each). The solvent was evaporated and the residue was co-evaporated with toluene (2 x 50 ml), and the residue was purified on a silica gel column using ethyl acetate as the eluent. · And dichloromethane in a ratio of 2:98.

Yield: 0.61 g (55%).

_δ Η (DMSO-d₆):

1.35 (6H, m, 2 x CH ₃ ), 2.78 (3H, s, CH ₃ ), 4.37 (3H, m, CH and CH ₂ ) 5.08 (2H, m, CH ₂ Ph) ), 7.14 - 7.38 (5H, m, aromatic protons),

8.18 (1H, br.d, J = 6.6 Hz, D ₂₀ replaceable, NH), and

II, 86 (1H, br. S, D ₂₀ exchangeable, NH).

Analysis for C-j ^H ^N -OyS:

calculated: 52.41% C 4.86% H 9.65% N found: 52.29% C 4.80% H 9.65% N.

Example 7 (level 2)

Preparation of 2 - [(N-benzyloxycarbonyl-lalaninyl) amino] -4-methyl-5-aminothiophene-3-carboxylic acid ethyl ester.

A mixture containing the 5-nitrothiophene derivative (0.43 g, 1 mmol), iron (0.3 g) and 1 M ammonium chloride solution (5 ml) in dioxane / ethanol (20 ml) was used. individual components (1: 1), the mixture was sonicated at 40 ° C for 1 hour and 40 minutes. The iron was filtered off and washed with dioxane / ethanol (1: 1, two portions of 20 ml each). The filtrate and washings were combined and concentrated to a small volume. To this mixture was added water (50 mL) and the product was then extracted with dichloromethane (5 times with 15 mL). The combined extracts were then evaporated and the residue was co-evaporated with toluene (3 x 20 ml) to give the desired product which was used for the next step without further purification.

Yield: 0.40 g.

_H (DMSO-d _6):

1.36 (6H, m, 2 x CH-j), 2.07 (3H, s, _CH3);

4.22 (3H, m, CH and _CH2), 4.88 (2H, br s, NH _2),

5.08 (2H, m, _CH2 Ph), 7.14 - 7.39 (5H, m, aromatic protons), 8.08 (IH, d, J = 6.6 Hz, NH), 11.35 (1 H, s, NH).

Example 7 (level 3)

Preparation of 2 - [(N-benzyloxycarbonyl-L-alaninyl 1) amino] -4-methyl-5-aminothiophene-3-carboxylic acid ethyl ester and 2 - [(N-benzyloxycarbonyl-L-alaninyl 1) amino] -4-methyl ester -5-acetamidothiophene-3-carboxylic acid.

A mixture containing a 5-nitrothiophene derivative (0.53 mmol, 0.230 grams) and iron (100 milligrams) in acetic acid (15 ml) was used and the reaction mixture was sonicated at 30-40 ° C. ° C for 30 minutes. An additional portion of iron (100 milligrams) was then added and the ultrasonic treatment was continued at 30-40 ° C for an additional one hour. To the reaction mixture was added water (50 mL) and the mixture was allowed to stand at room temperature for 30 minutes. The products were extracted with dichloromethane (5 x 50 mL), the combined extracts were evaporated and the residue co-evaporated with toluene (3 x 50 mL). The products were separated on a silica gel column using ethyl acetate / hexane (2: 8) as the eluent.

5-aminothiophene derivative (50 milligrams, 23% yield) was obtained, and further elution with ethyl acetate / hexane (1: 1) gave the 5-acetamidothiophene derivative (40 milligrams, 17% yield).

¹ H NMR (DMSO-d ₆ ) δ:

I, 30 (6H, m, 2 x CH _3), 2.06 (3H, s, _CH3);

4.23 (3H, m, CH ₂ and CH), 4.88 (2H, br s, D ₂ 0 exchangeable, _NH2), 5.08 (2H, m, _CH2 Ph), 7.22 - 7.39 (5H, m, aromatic protons), 8.08 (1H, J = 6.32 Hz, D ₂₀ replaceable, NH),

II, 34 (1H, br.s, D ₂₀ exchangeable, NH).

HRMS calculated for C 19 H ₂₃ N ₃ O ₈ S: 405.1358, found: 405.1359.

¹ H NMR (DMSO-d 6) δ:

I, 32 (6H, m, 2 x CH ₃ ), 2.09 (3H, s, CH ₃ ), 2.24 (3H, s, CH ₃ CO),

4.26 (3H, m, CH ₂ and CH), 5.08 (2H, m, CH ₂ Ph),

7.34 - 7.39 (5H, m, aromatic protons),

8.12 (1H, J = 6.32 Hz, D ₂₀ replaceable, NH),

9.98 (1H, br.s, D ₂₀ replaceable, NH),

II, 49 (1H, br.s, D ₂₀ exchangeable, NH ₂ ).

HRMS calcd for C ₂₁ H ₂₇ N ₂ O ₃ S 8 S, 447.1463, found: 447.1464.

Example 7 (level 4)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6-acetamido-4H-thieno [2,3-d] [1,3] oxazin-4-one.

This compound was prepared in a similar manner to that described in Example 2, step 2.

Yield: 16%.

_δ Η (DMSO-d₆):

1.41 (3H, d, J = 7,15Hz, CH _3), 2.18 (3H, s, _CH3);

- 24 ·· ····

2.49 (3H, s, CH ₃ CO), 4.53 (1H, m, CH), 5.06 (2H, m, CH ₂ Ph),

7.31 - 7.36 (5H, m, aromatic protons),

8.00 (1H, J = 7.69 Hz, D ₂₀ replaceable, NH),

10.67 (1H, br. S, D ₂₀ replaceable, NH).

HRMS calcd for C ₁₉ H ₃ N _ig 0gS: 401.1046, found: 401.1048.

Example 8

Preparation of (S) -2- [N- (benzyl oxycarbonyl) -1-aminoethyl] -methyl-6- (N-isobutyrylamino) -4H-thieno [2,3-d] [1,3] oxazin-4-one.

This compound was prepared in a similar manner as in Example 9. δ _Η (DMSO-dg):

1.13 (6H, d, J = 6.87Hz, 2 x CH ₃ ), 1.42 (3H, d, J = 7.15Hz, CH ₃ )

2.43 (3H, s, CH ₃ ), 2.86 (1H, q, J = 6.87 Hz, CH),

4.56 (1H, m, CH), 5.06 (2H, m, CH ₂ Ph),

7.13 - 7.41 (5H, m, aromatic protons),

8.0 (1H, J = 7.43Hz, D ₂₀ replaceable, NH),

10.56 (1H, s, D ₂₀ exchangeable, NH).

HRMS calculated for C ₂₁ H ₂₃ ^N 3 ^O 5 S ^: 429.1359, found: 429.1359.

Example 9 (level 1)

Preparation of 2 - [(N-benzyloxycarbonyl-L-alaninyl) amino] -4-methyl-5- (N-hexanoylamino) thiophene-3-carboxylic acid ethyl ester.

A solution containing ethyl 2 - [(N-benzyloxycarbonyl-lalaninyl) amino] -4-methyl-5-aminothiene-3-carboxylic acid ethyl ester was used according to this procedure.

(0.4 grams, 1 mmol), hexanoyl chloride (0.17 mL, 1.2 mmol) and 4-methylmorpholine (0.13 mL, 1.2 mmol) in tetrahydrofuran (8 mL) The solution was stirred at 0-5 ° C for 1.5 hours. A precipitate precipitated in this manner, which was filtered off and washed with tetrahydrofuran (2 x 20 ml). The combined filtrates and filtrates and washings were evaporated to dryness, dissolved in dichloromethane (80 mL), washed with saturated aqueous sodium bicarbonate (2 x 20 mL) and dried (magnesium sulfate). The solvent was removed and the residue was co-evaporated with toluene (1 x 20 mL). The product was purified by column chromatography using ethyl acetate / dichloromethane (5/95) as eluent. The desired product was obtained.

Yield: 0.264 g (53%).

_δ Η (DMSO-d₆):

0.88 (3H, t, J = 6.6 Hz, CH ₃ ),

1.22 to 1.39 (10H, m, 2 x CH _3, 2x CH _2), 1.57 (2H, m, _CH2),

2.23 (3H, s, _CH3), 2.36 (2H, t, J = 7,15Hz, _CH2),

4.20 to 4.32 (3H, m, CH and _CH2), 5.08 (2H, m, CH ₂ Ph),

7.30 - 7.39 (5H, m, aromatic protons),

8.12 (1H, d, J = 6.33Hz, D ₂₀ replaceable, NH),

9.89 (1H, s, D ₂₀ replaceable, NH),

11.49 (1H, s, D ₂₀ replaceable, NH).

HRMS calcd for C ₃₃ N ₂ gH OGS _3: 503.209, found: 503.2104.

·· ··· »

·······················

Example 9 (level 2)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (N-hexanoylamino) -4H-thieno [2,3-d] [1,3] oxazin-4-one.

This compound was prepared in a similar manner to that described in Example 2, step 2.

Yield: 50%.

With _H (DMSO-d6):

0.88 (3H, 1, J = 6.6Hz, CH ₃₎ 1.41 (3H, d, J = 7,15Hz, CH ₃ 2.42 (3H, with, CH ₃ ), 2.45 (2H, 5,05 (2H, m, CH ₂ Ph), 7.13- 8.00 (1H, d, J = 7.7Hz, D ₂ 0 10.6 (1H, with, D ₂ 0 replaceable HRMS calcd for C ₂₃ H ₂₂ N ₃ 0

found: 457.1670.

m, CH ₂ ), 4.55 (1 H, m, CH),

7.43 (5H, m, aromatic protons)

457.1672,

Example 10 (level 1)

Preparation of 2- [N- (benzyloxycarbonyl) -L-alaninyl] amino-4-methyl-5- [N- (benzyloxycarbonyl) -β-alaninyl)] thiophene-3-carboxylic acid ethyl ester.

In this procedure, a solution containing N- (benzyloxycarbonyl) -β-alanine (0.27 g,

1.15 mmol) and 4-methylmorpholine (0.13 mL, 1.15 mmol) in tetrahydrofuran (10 mL) at 0 ° C was added isobutyl chloroformate (0.15 mL) is 1.15 mmol). After 15 minutes, the resulting reaction mixture was added dropwise over a period of 10 minutes to the reaction mixture.

• »

9 9

9 9

999

9 9

9

998 9 9 9

9 of a solution containing 2 - [(N-benzyloxycarbonyl) -L-alaninyl] -amino-4-methyl-5-amino-thiophene-3-carboxylic acid ethyl ester (1 mmol, crude material used) in tetrahydrofuran (10 mL) at 0 ° C and the reaction mixture was stirred at 0-5 ° C for 1 hour. An additional portion of mixed anhydride (1.15 mmol in 6 mL of tetrahydrofuran) prepared as described above was added to the reaction mixture. The reaction mixture was stirred for 1 hour, then the precipitate was filtered off and washed with tetrahydrofuran (20 ml). The combined washings and filtrates were combined and evaporated to dryness to give a 1: 1 mixture of ethyl acetate and dichloromethane as the eluent. The desired product was obtained.

Yield: 0.370 g (53% over two steps).

NMR (DMSO- -d ₆ ) S: 1.33 (6H, m, 2 x ch ₃ ), 2.23 (3H, s, _CH3); 2.58 (2H, t, J = 6.9Hz, ch ₂ ), 3.39 (2H, ΐ, J = 6.9Hz, after D ₂ 0 conversion, CH ₂ ) 4.27 (3H, m, ch ₂ and CH), 5.05 (4H, m, 2 x CH ₂ Ph),

7.17 - 7.39 (11H, m, aromatic protons and D ₂₀ replaceable, NH)

8.12 (1H, br. D, J = 5.78Hz, D2O replaceable, NH),

9.99 (1H, br. S, D ₂₀ replaceable, NH).

HRMS calcd for C 24 H 25 N 4 O 6 S: 611.2175, found: 611.2175.

Example 10 (level 2)

Preparation of 2- [N- (benzyloxycarbonyl) - (IS) -1- (aminoethyl)] - 5-methyl-6 - [(N-benzyloxycarbonyl-p-alaninyl) amino] -4H-thieno • 4 44 44 4444 «4 4 4 · 4444

4,444,444,444,444,444,444 [2,3-d] [1,3] oxazin-4-one.

The taxo compound was prepared in a similar manner to that described in Example 2, step 2.

Yield: 22%.

¹ H NMR (DMSO-d ₆ ) δ:

1.41 (3H, d, J = 6.9Hz, _CH3), 2.49 (3H, s, _CH3);

2.68 (2H, t, J = 6.9Hz, _CH2), 3.32 (2H, m, _CH2),

4.55 (1H, m, CH), 5.02 (2H, m, _CH2 Ph), 5.05 (2H, m, _CH2 Ph), 7.33 (10H, m, aromatic H);

7.43 (1H, D ₂₀ replaceable, NH),

8.01 (1H, br.d, D ₂₀ replaceable, NH),

10.7 (1H, s, D ₂₀ replaceable, NH).

HRMS calculated for C 24 H 25 N 4 O 2 S: 564.168, found: 564.1678.

Example 11

Preparation of 2- [N- (benzyloxycarbonyl) - (1S) -1- (aminoethyl)] 5-methyl-6 - [[6-N- (benzyloxycarbonyl) aminohexanoyl] amino] -4Hthieno [2,3-d] ] [1,3] oxazin-4-one.

This compound was prepared in a similar manner to that described in Example 10.

Yield: 5%.

¹ H NMR (DMSO-d 6) δ:

1.23 to 1.38 (2H, m, _CH2), 1.41 (3H, d, J = 6,88Hz, _CH3);

1.46 to 1.63 (2H, m, _CH2), 2.42 (3H, s, _CH3);

2.49 (2H, m, _CH2), 3.01 (2H, m, _CH2), 4.55 (1H, m, CH),

5.00 (2H, m, _CH2 Ph), 5.05 (2H, m, CH ₂ Ph),

7.25-7.42 (6H, m, D ₂₀ replaceable NH and aromatic protons), 8.01 (1H, d, J = 7.7Hz, D ₂₀ replaceable, NH),

10.6 (1H, s, D ₂₀ exchangeable, NH).

HRMS calcd for C ₃ H ₁₁ N ₃ O ₄ S: 607.2227, e ·

found: 607.2230.

Example 12 (level 1)

Preparation of 2- [N- (benzyloxycarbonyl) -L-alaninyl] amino-4-methyl-5- (N-benzyloxycarbonylamino) thiophene-3-carboxylic acid ethyl ester.

A stirred solution containing 2 - [(N-benzyloxycarbonyl) -L-alaninyl 1] amino-4-methyl-5-aminothiene-en-3-carboxylic acid ethyl ester (110 mg, 0.27) was used. mmole) and 4-methylmorpholine (0.038 mL, 0.35 mmol) in tetrahydrofuran (4 mL) at 0 ° C was added benzyl chloroformate (0.1 mL, as a 0.35 M solution). in tetrahydrofuran). The reaction mixture was stirred at 0-5 ° C for 1 hour, the precipitate was filtered off and washed with tetrahydrofuran (2 x 5 mL). The filtrate and washings were combined and the solvent was removed. The product was purified by column chromatography on silica gel using ethyl acetate / dichloromethane (1:89) as eluent to give the desired product.

Yield: 85 mg (57% over two steps).

% NMR (DMSO-d ₆ ) δ:

I, 32 (6H, m, 2 x CH ₃ ), 2.16 (3H, s, CH ₃ ),

4.26 (3H, m, CH and CH ₃ ), 5.08 (2H, s, CH ₂ Ph),

7.12 - 7.51 (10H, m, aromatic protons),

8.13 (1H, d, J = 6.32Hz, NH), 9.57 (1H, s, NH),

II, 55 (1 H, br.s, NH).

«9

·> ¢

♦ 9 t • • • • o o o o o>>>>>

Analysis for C 7 H _{2 2 3} gN 07S calculated: 60.10% C 5.42% H 7.79% N Found: 59.96% C 5.30% H 7.52% N

Example 12 (level 2)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (triphenylphosphoranylideneamino) -4H-thieno [2,3-d] [1,3] oxazin-4-one.

A solution containing thiophene-5-benzylcarbamate (70 mg, 0.13 mmol), triphenylphosphine (68 mg, 0.26 mmol) and carbon tetrachloride (0.05 mg) was used. ml of 0.5 mmol) in dichloromethane (5 ml) was refluxed at 60-70 ° C for 1 hour. A further portion of triphenylphosphine (30 mg, 0.11 mmol) was added and the reaction mixture was refluxed at 60-70 ° C for an additional hour. The solution was diluted with dichloromethane (50 mL), washed with aqueous saturated sodium bicarbonate (2 x 20 mL) and dried (magnesium sulfate). The product was purified by column chromatography on silica gel, eluting with ethyl acetate / dichloromethane (1: 9). The desired product was prepared in this way. Yield: 58.8 mg (73%).

¹ H NMR (DMSO-d 6) δ:

1.33 (3H, d, J = 6.88Hz, CH ₃ ), 2.33 (3H, d, J = 1.1Hz, CH ₃ ),

4.44 (1H, m, CH), 5.02 (2H, m, CH ₂ Ph),

7.08-7.31 (5H, m, aromatic protons), 4, 99, 4, 4, 4, and 4. 4 * 4 ο a ··· • 4 Ο 4

7.59 - 7.80 (15Η, m, aromatic protons),

7.86 (1H, d, J = 7.70Hz, NH).

N, 4.88; N, 6.78. Found: 67.12%, C, 4.71,%, H, 6.50,%.

Example 12 (level 3)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (N-benzoylamino) -4H-thieno [2,3-d] [1,3] oxazin-4-one.

A solution containing the iminophosphorane derivative (0.230 grams, 0.37 mmol), benzoyl chloride (0.05 milliliters, 0.45 mmol) and triethylamine (0.1 milliliters, 0.35 mmol) was used. 0.74 mmol) in dichloromethane (5 mL) was stirred at room temperature for 3 days. The reaction mixture was diluted with dichloromethane (80 mL), washed with a saturated aqueous sodium bicarbonate solution (2 x 10 mL portions) and finally dried (magnesium sulfate). The solvent was removed and the residue was purified by column chromatography on silica gel using ethyl acetate / dichloromethane (35:65) as eluent to give the desired product.

Yield: 45 mg (26%).

NMR (DMSO-d6) δ:

1.44 (3H, d, J = 6.87Hz, CH ₃ ), 2.51 (3H, s, CH ₃ ),

4.58 (1H, m, CH), 5.07 (2H, m, CH ₂ Ph),

7.30 - 7.42 (5H, m, aromatic protons),

7.54 - 7.69 (3H, m, aromatic protons), *

»Β '» · »

Β

Β ·

Β ·

Β »

7.98 - 8.04 (3Η, D ₂ 0 replaceable NH and aromatic protons),

10.93 (1Η, s, D ₂₀ replaceable, NH).

HRMS calcd for C 23 H 27 N 2 O 2 S: 463.1202, found: 463.1202.

Example 13

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (N-isopropoxycarbonyl) amino] -4H-thieno [2,3-d] [1,3] oxazine- 4-onu.

2- [N- (Benzyloxycarbonyl-L-alaninyl) amino-4-methyl-5- (N-isopropoxycarbonylamino) thiophene-3-carboxylic acid ethyl ester was prepared in a similar manner to that described in Example 12, Step 1, the product was then cyclized in a similar manner to that of Example 2, step 2.

Yield: 48%.

¹ H NMR (DMSO-d ₆ ) δ:

1,28 (6H, d, J = 6,05Hz, 2 x _CH3); 1.41 (3H, d, J = 7,15Hz, _CH3); 2.33 (3H, with, CH ₃ ) 4.54 (1 H, m, CH), 4.95 (1H, q, J = 6.05Hz, CH), 5.05 (2H, m , CH ₂ Ph), 7.14 - 7,63 (5H, aromatic protons), 8.00 (1H, d, 1 = 7.42Hz, D ₂ 0 replaceable, NH), 10.34 (1H, with , D ₂ 0 replaceable, NH).

HRMS calcd for C ₂₁ H ₂₃ N ₃ O ₅ S: 445.1308, found: 445.1310.

Example 14

Preparation of 2- [N- (benzyloxycarbonyl) -1-aminoethyl] -5-methyl-6 - [(N-isobutoxycarbonyl) amino] -4H-thieno [2,3-d] [1,3] oxazin-4-one.

This compound was prepared in a similar manner to that described in Example 13.

Yield: 48%.

_δ Η (DMSO-d₆):

0.94 (6H, d, J = 6.6 Hz, 2 x _CH3); 1.41 (3H, d, J = 6.88 Hz, CH ₃₎ 1.96 (1H, m, CH), 2.34 (3H, s, CH ₃ ), 3.94 (2H, d, J = 6.7Hz, CH _2), 4.55 (1H, m, CH), 5,05 (2H, m, CH ₂ Ph), 7.30 to 7.36 (5H, m, aromatic protons) 8.0 (1H, d, J = 7.69Hz, D ₂ 0 replaceable, NH),

10.32 (1H, br. S, D ₂₀ exchangeable, NH).

HRMS calcd for C ₂₂ H ₂ OGS Genesis _3: 459.1464, found: 459.1474.

General Method for Examples 15-22

A solution containing (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] -5-methyl-6- (triphenylphosphoranylideneamino) -4H-thieno [2,3-d] [1] was used in these procedures. 3] -oxazin-4-one (0.16 mmol used) and a suitable isocyanate (5.0-5.6 equivalents used) in dichloromethane (3 mL) or dichloromethane / acetonitrile (1: 1 ratio, used 5) The solution was stirred at ambient temperature for 3 to 64 hours.

(a) Alkyl ureas:

The solvent was removed and the residue was co-evaporated with toluene (2 x 5 mL) and treated with a mixture of dioxane and 10% aqueous citric acid (2: 1, 5 mL) at at room temperature for 6 hours. This mixture was then concentrated to a small volume.

• · ·· · · · · · · ·

volume and the product was extracted with dichloromethane (4 x 15 mL). The combined extracts were dried (magnesium sulfate) and then concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate / dichloromethane as the eluent. In some cases, the reaction mixture was concentrated, the residue was co-evaporated with toluene (2 x 5 mL), and the product was purified by silica gel column chromatography to obtain thiophene diamides and / or thiophenureas. The diimides were then treated with glacial acetic acid in dichloromethane (1: 9, 2 mL) at room temperature for 45 minutes to 130 minutes. The solvent was removed and the residue was co-evaporated with toluene (2 x 5 mL). The alkyl ureas were then purified by silica gel column chromatography using a mixture of ethyl acetate and hexane or a mixture of ethyl acetate and dichloromethane.

(b) Aryl ureas:

The solvent was removed and the residue was co-evaporated with toluene (2 x 5 mL) to give the desired crude product.

In some cases, the reaction mixture was diluted with dichloromethane (50 mL), washed with 10% aqueous citric acid (2 x 10 mL), aqueous sodium bicarbonate (1 x 10 mL), dried (magnesium sulfate), or the reaction mixture was concentrated, and the residue «·· · ·

And 99 were co-evaporated with toluene (2 x 5 mL) and dissolved in dichloromethane (50 mL) and worked up in the same manner as above. The solvent was removed and each residue was purified by silica gel column chromatography using a mixture of ethyl acetate and dichloromethane as eluent.

Example 15

(S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] -5-methyl-6- (3-isopropylureido) -4H-thieno [2,3-d] [1,3] oxazin-4-one .

Yield: 42%.

_δ Η [(CD ₃₎ SO]:

1.12 (6H, d, J = 6.6Hz, 2 x _CH3), 1.41 (3H, d, J = 7,15Hz, _CH3);

2.31 (3H, s, CH ₃ ), 3.77 (1H, m, CH), 4.54 (1H, m, CH),

5.05 (2H, m, _CH2 Ph), 6.49 (IH, d, J = 7,42Hz, D ₂ 0 exchangeable, _NH2)

7.30 - 7.39 (5H, m, aromatic protons),

7.98 (1H, d, J = 7.7Hz, D ₂₀ replaceable, NH), and 9.04 (IH, s, D ₂₀ replaceable, NH).

FABMS (positive ion): 445 (MH ⁺ ), 467 (MNa ⁺ ).

Example 16

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (3-butylureido) -4H-thieno [2,3-d] [1,3] oxazine-4- onu.

Yield: 44%;

^δ Η t (CD ₃ ) SO]:

0.9 (3H, t, J = 7.3 Hz, CH ₃ ), 1.27-1.36 (4H, m, 2 x CH ₂ ),

1.40 (3H, d, J = 6,88Hz, 3H), 2.31 (3H, s, _CH3);

3.13 (2H, m, CH ₂ ), 4.54 (1H, m, CH), 5.05 (2H, m, CH ₂ Ph), 9 ·· 9 9 9 9

99 9 9 9 9999 9 9 9 9 9 9 9 9

6.56 (IH, t, J = 5,4Hz, D ₂₀ replaceable, NH ₂ ),

7.30 - 7.40 (5H, m, aromatic protons),

7.98 (1H, d, J = 7.14Hz, D ₂₀ replaceable, NH), and

9.14 (IH, s, D ₂ 0 exchangeable, NH).

HRMS calculated for C ₂ H ₂ gN ₄ O ₃ S: 459.1702, found: 459.1722.

Example 17

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl-6-methyl-6- (3-butylureido) -4H-thieno [2,3-d] [1,3] oxazine-4- onu.

Yield: 19%;

With _H [(CD ₃ ) SO]:

1.52 (3H, d, J = 6,87Hz, CH _3), 2.20 (3H, br s, CH ₃₎

4.45 (2H, br s, CH ₂ Ph), 4.65 (IH, m, CH), 5.10 (2H, m, CH ₂ Ph),

5.51-5.56 (2H, m, 2 x NH), 6.92-7.19 (1H, v.br.s, NH), and 7.26-7.43 (10H, d, m , aromatic protons, NH).

HRMS calcd for C 25 H 24 N 4 O 5 S: 493.1546, found: 493.1544.

Example 18

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (3-phenylureido) -4H-thieno [2,3-d] [1,3] oxazine-4- onu.

Yield: 40%;

_δ Η [(CD ₃₎ SO]:

1.41 (3H, d, J = 6,87Hz, _CH3), 2.39 (3H, s, _CH3);

4.56 (IH, m, CH), 5.05 (2H, m, CH ₂ Ph),

7.03 (1H, t, J = 7.7Hz, aromatic protons),

7.29 - 7.36 (7H, m, aromatic protons),

7.47 (2H, d, J = 7.7Hz, aromatic protons),

8.01 (IH, d, J = 7.15Hz, D ₂₀ replaceable, NH); 9

9.02 (1H, s, D ₂ O replaceable, NH),

9.40 (1H, s, D ₂₀ replaceable, NH),

HRMS calcd for C 24 H 25 N 4 O 4 S: 478.1311, found: 478.1316.

Example 19

(S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- [3- (4-chlorophenyl) ureido] -4H-thieno [2,3-d] [1, 3] oxazin-4-one.

Yield: 30%;

_δ Η [(CD ₃₎ SO]:

1.42 (3H, d, J = 6.87Hz, CH ₃ ), 2.38 (3H, s, CH ₃ ),

4.56 (1H, m, CH), 5.06 (2H, m, CH ₂ Ph),

7.17 - 7.48 (7H, m, aromatic protons),

7.51 (2H, d, J = 8.80Hz, aromatic protons),

8.01 (1H, d, J = 7.15Hz, NH), 9.15 (1H, s, NH),

9.45 (1 H, s, NH),

HRMS calcd for C 24 H 25 N 4 O 3 SCl: 512.0922, found: 512.0928.

Example 20

(S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- [3- (4-methoxyphenyl) ureido] -4H-thieno [2,3-d] [1,3] Oxazin-4-one.

Yield: 18%;

_δ Η [(CD ₃₎ SO]:

1.42 (3H, d, J = 7,15Hz), 2.38 (3H, s, _CH3);

3.73 (3H, s, CH ₃ O), 4.55 (1H, m, CH), 5.06 (2H, m, _CH2 Ph), 6.91 (2H, d, J = 9,07Hz , aromatic protons),

7.17 - 7.41 (7H, m, aromatic protons),

8.00 (1H, d, J = 7.4Hz, D ₂₀ replaceable, NH), 9 · 99

9 9 9 9 ·· ··· ·

8.84 (1Η, s, D ₂ 0 replaceable, NH),

9.34 (1H, s, D ₂₀ exchangeable, NH).

HRMS calcd for C 25 H 24 F 4 O 4: 508.1417, found: 508.1416.

Example 21

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- [3- (2-methoxycarbonylphenyl) ureido] -4H-thieno [2,3-d] [1,3] Oxazin-4-one.

Yield: 14 S _R [(CD ₃ ) SO] 1.42 (3H, d, 3.90 (3H, s, 7.15 (1H, dt) 7.36 (5H, m, 7.61 (1H, dt) 7.96 (1H, dd, 8.01 (1H, d, 8.25 (1H, dd, 10.18 (1H, s), 10.53 (1H, s)

J = 7,15Hz, CH _3), 2.44 (3H, s, _CH3);

CH ₃ O), 4.55 (1H, m, CH), 5.06 (2H, m, CH ₂ Ph), aromatic protons), aromatic protons), aromatic proton), aromatic proton),

J = 7.7Hz, D ₂ 0 replaceable, NH), aromatic proton),

D ₂ 0 replaceable, NH),

D _{20 (} replaceable, NH).

+>

FABMS (positive ion): 537 (MH ⁺ ), 559 (MNa ⁺ ).

Example 22

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (3-acetyl, 3-benzylureido) -4H-thieno [2,3-d] [1,3] oxazin-4-one.

Yield: 42%;

_δ Η [(CD ₃₎ SO]:

1.41 (3H, d, J = 7.15Hz, CH ₃ ), 2.18 (3H, s, CH ₃ CO),

2.43 (3H, s, _CH3), 4.55 (1H, m, CH), 4.59 (2H, s, _CH2 Ph), • · · * 9

9 9

9 · * ·· ····

• ♦

«·

5.05 (2H, m, CH ₂ Ph), 7.28-7.43 (10H, m, aromatic H);

7.99 (1H, d, J = 5.91Hz, NH), 10.68 (1H, s, NH).

HRMS calcd for C 19 H 17 N 3 O 6 S: 535.1652, found: 535.1652.

Example 23

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6-amino-4H-thieno [2,3-d] [1,3] oxazin-4-one.

A solution containing 2- [N- (benzyloxycarbonyl) -L-alaninyl] amino-4-methyl-5- [N- (benzyloxycarbonyl) -3-aminobutyryl) thiophene-3-carboxylic acid ethyl ester (this was used) the compound was prepared in a similar manner to Example 10, step 1 (0.35 g, 0.56 mmol), triphenylphosphine (0.32 g, 1.23 mmol) and chloride carbon dioxide (0.3 mL, 3.1 mmol) in dichloromethane (10 mL) was heated at 60-70 ° C for 3 h.

An additional portion of triphenylphosphine (0.16 g, 0.6 mmol) and carbon tetrachloride (0.15 ml, 1.5 mmol) was added and the refluxing was continued for another 2 hours. The reaction mixture was allowed to stand at room temperature for 53 hours, diluted with dichloromethane (80 ml), washed with saturated aqueous sodium bicarbonate solution (2 x 15 ml) and water (15 ml) and dried. (potassium sulfate). The solvent was removed and the residue was purified by column chromatography eluting with 6-9% ethyl acetate / dichloromethane to give the desired product.

· · · · · · · · · · · · · · · · · · · · · ·

Yield: 0.10 g (50%).

_δ Η (DMSO-d₆):

1.38 (3H, d, J = 6.88Hz, CH ₃ ), 2.16 (3H, s.

4.51 (1H, m, CH), 5.06 (2H, m, CH ₂ Ph),

5.95 (2H, s, D ₂₀ replaceable, NH ₂ ),

7.31 - 7.41 (5H, m, aromatic protons),

7.93 (1H, J = 7.7Hz, D ₂₀ replaceable, NH). HRMS calculated for C 17 H 17 N 3 O 4 S: 359.094, found: 359.0941.

CH ₃ ),

Example 24 (level 1)

Preparation of 2- [N- (benzyloxycarbonyl) -L-alaninyl lamino-4-methyl-5- (N, N-dimethylamino) thiophene-3-carboxylic acid ethyl ester.

To a stirred solution containing 2- [N- (benzyloxycarbonyl) -L-alaninyl] amino-4-methyl-5-aminothiophene-3-carboxylic acid ethyl ester (0.2 grams = 0.5 grams) was added to the stirred solution. 37% aqueous formaldehyde solution (0.2 ml) in acetonitrile (5 ml), sodium cyanoborohydride (50 mg, 0.8 mmol) in acetonitrile (2 ml) was added at room temperature. The reaction mixture was stirred for 15 minutes and then neutralized by the addition of glacial acetic acid. The reaction mixture was stirred at room temperature for an additional 45 minutes. The reaction mixture was poured into diethyl ether (50 mL) and washed with aqueous 1 N potassium hydroxide solution (3 x 10 mL), brine (1 x 10 mL) and water (1 x 10 mL). The solvent was evaporated to give the desired product, which was then used in the next step without purification.

Yield: 0.2 g.

_δ Η (DMSO-d₆):

I, 31 (6H, m, 2 x CH ₃ ), 2.20 (3H, s, CH ₃ ), 2.61 (6H, s, (CH) ₃ N ₂ )

4.27 (3H, m, CH and _CH2), 5.07 (2H, m, CH ₂ Ph),

7.33 - 7.39 (5H, m, aromatic protons),

8.12 (1H, v.br.d, D ₂₀ replaceable, NH),

II, 58 (1H, br.s, D ₂₀ exchangeable, NH).

HRMS calculated for C 24 H 23 N 3 O 5 S: 434.1750, found: 434.1758.

Example 24 (level 2)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] -methyl-6- (Ν, Ν-dimethylamino) -4H-thieno [2,3-d] [1,3] oxazine-4 -onu.

This compound was prepared in a similar manner to that described in Example 2, step 2.

Yield: 36%.

_δ Η (DMSO-d₆):

1.39 (3H, d, J = 7,15Hz, CH _3), 2.28 (3H, s, _CH3);

2.69 (6H, s, (CH) ₃ N ₂ ), 4.50 (1H, m, CH), 5.07 (2H, m, CH ₂ Ph),

7.10 - 7.39 (5H, m, aromatic protons),

8.00 (1H, br. D, D ₂₀ exchangeable, NH).

HRMS calcd for C 18 H 18 N 3 O 2 S: 387.1253, found: 387.1253.

Example 25

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (Ν, N-dipropylamino) -4H-thieno [2,3-d] [1,3] oxazine- 4-onu.

• · φφφφ

This compound was prepared in a similar manner to that described in Example 24.

Yield: 50%.

_δ Η (DMSO-d _6):

0.86 (3H, t, J = 7.15Hz, 2 x CH ₃ ), 1.40 (7H, m, 2 x CH ₂ and CH ₃ )

2.30 (3H, s, CH ₃ ), 2.86 (3H, t, J = 7.15Hz, 2 x CH ₂ ),

4.52 (1H, m, CH), 5.07 (2H, m, CH ₂ Ph),

7.11 - 7.41 (5H, m, aromatic protons),

8.03 (1H, d, J = 7.42Hz, D ₂₀ replaceable, NH).

HRMS calcd for C ₂₃ H _{3 2} g N 04S: 443.1879, found: 443.1881.

Example 26

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (N-benzyl-N-methylamino) -4H-thieno [2,3-d] [1,3] oxazin-4-one.

This compound was prepared in a similar manner to that described in Example 24.

Yield: 40%.

¹ H NMR (DMSO-d 6) δ:

1.39 (3H, d, J = 6.87Hz, CH ₃ ), 2.31 (3H, s, CH ₃ ),

2.70 (3H, s, CH ₃ ), 4.09 (2H, s, CH ₂ Ph), 4.51 (1H, m, CH), 5.04 (2H, m, CH ₂ Ph), 7 26-7.40 (10H, m, aromatic protons), 7.98 (1H, d, J = 7.42Hz, D ₂₀ exchangeable, NH).

HRMS calculated for ^ 25 ^ 25 ^ ^{Ν 3θ4:} 464.1644, found: 464.1661.

Example 27 (level 1)

Preparation of 2 - [(N-benzyloxycarbonyl) - L-alaninyl] amino-4-methyl-5-bromothiophene-3-carboxylic acid ethyl ester.

A solution containing 2- [N- (benzyloxycarbonyl) L-alaninyl] amino-4-methylthiophene-3-carboxylic acid ethyl ester (0.61 g, 1.56 mmol) in dioxane was used and Water (5: 1, 18 mL) at 55 ° C was treated dropwise with a solution of bromine (0.25 g) in dioxane (30 mL) over a 2.5 hour period. . The solution was neutralized to pH 7.0 with Amberlite IR-45 (OH), the resin was filtered off and washed with dioxane (3 x 50 mL). The combined filtrates and washings were combined and evaporated to dryness to give the desired product.

Yield: 0.71 g (97%).

_δ Η (DMSO-d₆):

1.33 (6H, m, 2 x CH 3), 2.30 (3H, s, CH ₃ ), 4.31 (3H, m, CH, CH ₂ ) 5.09 (2H, m, CH ₂ Ph) 7.35-7.39 (5H, m, aromatic protons),

8.15 (1H, d, J = 6.32Hz, NH) 11.62 (1H, s, NH).

Analysis for ^C 19 ^H 21 ^N 2 ° 5 ^SBr: Calculated: 48.62% C 4.51% H 5.97% N found: 49.23% C 4.51% H 5.88% N

HRMS calcd for C-LpH1N4O5SBr: 468.0355, found: 468.0357.

Example 27 (level 2)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6-bromo-4H-thieno [2,3-d] [1,3] oxazin-4-one

This compound was prepared in a similar manner to that described in Example 2, step 2.

Yield: 47%.

*

• · ··· ·

• · • ·

_δ Η (DMSO-d₆):

1.42 (3Η, d, J = 7,15Hz, _CH3), 2.38 (3H, s, _CH3);

4.56 (1H, m, CH), 5.05 (2H, m, CH ₂ Ph),

7.14 - 7.41 (5H, m, aromatic protons),

8.04 (1H, d, J = 7.42Hz, D ₂ O exchangeable, NH). Analysis for ^C 17 ^H 15 ^N 2 ° 4 ^SBr: Calculated: C 48.24% C 3.57% H 6.62% Found: C 48.59% C 3.57% H 6.23% N.

Example 28 (level 1)

Preparation of 2- [N- (benzyloxycarbonyl) -L-alaninyl] amino-4-methyl-5-phenylthiophene-3-carboxylic acid ethyl ester.

A mixture containing ethyl 2- [N- (benzyloxycarbonyl) -L-alaninyl] amino-4-methyl-5-bromothiophene-3-carboxylic acid (0.150 grams, 0.320 grams), phenylboronic acid (used) was used. 70 mg (0.57 mmol) and bis (triphenylphosphine) palladium chloride (10 mg used) in tetrahydrofuran and 2 M sodium carbonate solution (2 ml-0.3 ml) were stirred for 2 hours and Fifteen minutes. The reaction mixture was diluted with dichloromethane (50 mL), washed with saturated aqueous sodium chloride solution (20 mL) and dried (magnesium sulfate). The solvent was removed and the product was purified by column chromatography on silica gel (ethyl acetate / dichloromethane 2: 98) to give the title compound.

Yield: 74.5 mg (50%).

_δ Η (DMSO-d₆)

• 4

4 4 4 ·· 4444

1.34 (6H, m, 2 x CH ₃ ), 2.34 (3H, s, CH ₃ ), 4.43 (3H, m, CH ₂ and CH)

5.10 (2H, m, CH ₂ Ph), 7.30-7.51 (10H, m, aromatic H);

8.17 (1H, d, J = 5.22Hz, D ₂ O replaceable, NH),

II, 63 (1H, s, D ₂₀ exchangeable, NH).

HRMS calcd for ^^ 25 ^ ^ ^ ^ ^ ^ 46θ 46 46: 466.1563.

Example 28 (level 2)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -L-aminoethyl] 5-methyl-6-phenyl-4H-thieno [2,3-d] [1,3] oxazin-4-one.

This compound was prepared in a similar manner to that described in Example 2, step 2.

Yield: 43%.

_δ Η (DMSO-d₆):

1.47 (3H, d, J = 7.06 Hz, CH _3), 2.49 (3H, s, _CH3);

4.58 (1H, m, CH), 5.07 (2H, m, CH ₂ Ph),

7.13 - 7.39 (5H, m, aromatic protons),

7.46 - 7.55 (5H, m, aromatic protons),

8.04 (1H, d, J = 6.61 Hz, D ₂₀ replaceable, NH).

HRMS calculated for C ₂₃ H ₂₁ N ₂ O ₄ S: 420.1144, found: 420.1148.

Example 29 (level 1)

Preparation of 2- [N- (benzyloxycarbonyl) -L-alaninyl] amino-4-methyl-5-iodo-thiophene-3-carboxylic acid ethyl ester.

In this embodiment, the ethyl ester was an acid ester

2- [N- (benzyloxycarbonyl) -L-alaninyl] amino-4-methylthiophene-3-carboxylic acid iodinated using a customized method, which is otherwise 9 9 9

9 99 ··· · ·

9 9

Commonly known in the art, see Y. Kobayashi, I. Kumadaki and T. Yoshida [J Chem Res (S), 1977, 215].

Melting point . : 104-105 ° C; _δ Η (CDC1 _3): 1.35 (3 H, t, J = 7Hz, CH ₂ CH ₃ ), 1.5 (3H, d, J = 7Hz, CH ₃ CH) 2.35 (3H, s, CH ₃ ), 4.3 (2H, q, J = 7Hz, ch ₂ ch ₃ ) 4.5 (1 H, m, CH ₃ CH ₃ , 5.15 (2H, s, CH ₂ Ph) , 5,5 (1 H, br, NH) 7.3 (5H, br, C ₆ H ₅ ), 11.8 (1 H, br, NH). Analysis for ^C 19 ^H 21 ^N 2 ° 5 ^SI calculated: 44.20% C 4.10% H 5.43 % N found: 44.35% C 3.87% H 5.21 % N. Example 1 a d 29

and (Grade 2)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6-iodo-4H-thieno [2,3-d] [1,3] oxazin-4-one.

2- [N- (Benzyloxycarbonyl) -L-alaninyl] amino-4-methyl-5-iodo-thiophene-3-carboxylic acid ethyl ester was cyclized in a similar manner to that described in Example 2, step 2.

Melting point: 142 - 144 ° C δ _Η (CDCl ₃ ):

1.55 (3H, d, J = 7Hz, CH 3 CH), 2.5 (3H, s, CH ₃ ),

4.75 (1H, m, CH ₃ CH), 5.1 (2H, s, CH ₂ Ph), 5.45 (1H, br, NH), and 7.35 (5H, br s, C 8 H 8).

(Found: M ⁺ 469.9797).

C17H15N2O4SI requires 469.9798.)

Example 30 (level 1)

Preparation of 2-amino-4-ethyl-5-methylthiophene-3-carboxylic acid methyl ester.

·· · * ··

- 47 according to the method. Bottcher [Chem.

·····················

2- [N- (benzyloxy) This compound was prepared by K. Gewald, E. Schinke and H Berichte, 1966, 99, 94-100].

Example 30 (level 2)

Preparation of carbonyl) -L-alaninyl] amino-4-ethyl-5-methylthiophene-3-carboxylic acid methyl ester.

A solution containing N- (benzyloxycarbonyl) -L-alanine (1.12 g, 5 mmol) in dry DMF (10 mL) at 0-5 ° C was used. N-methylmorpholine (0.5 ml, 5 mmol) was added, followed by dropwise addition of isobutyl chloroformate (0.65 ml, 5 mmol) with stirring. The reaction mixture was stirred for 15 minutes. 2-Amino-4-ethyl-methyl-thiophene-3-carboxylic acid methyl ester (1.0 g, 5 mmol) was added to the reaction mixture at a temperature between 0 and 5 ° C. The mixture was allowed to rise to room temperature and stirred for 18 hours. The solvent was evaporated under reduced pressure, the residue was partitioned between ethyl acetate (50 ml) and water (3 x 20 ml) and the organic layer was dried (magnesium sulfate), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 20% diethyl ether in hexane to give the title compound as a white solid, m.p.

B B «

· B ·

Β Β Β · Β Β #! Crystallization from acetone / hexane followed by the above procedure gave the desired product as a colorless solid.

Yield: 1.1 g (55%).

Example 30 (level 3)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-ethyl-6-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one.

2- [N- (Benzyloxycarbonyl) -L-alaninyl] amino-4-ethyl-5-methylthiophene-3-carboxylic acid methyl ester was cyclized in a similar manner to that described in Example 2, step 2.

Melting point: 90-92 ° C.

With _H (DMSO-d6):

1.08 (3H, t, J = 7.4Hz, CH ₃ CH _2), 1.42 (3H, d, J = 7.2Hz, CH ₃ CH)

2.42 (3H, s, CH ₃ ), 2.79 (2H, q, J = 7.4 Hz, CH ₃ CH ₂ ),

4.55 (1H, quin, J = 7.2Hz, CH ₃ C H NH), 5.06 (2H, m, CH ₂ Ph),

7.25-7.40 (5H, m, C 8 H 8), and 8.01 (1H, d, J = 7.4 Hz, NH).

Analysis for C- ^H ^^C ^S:

calculated: 61.27% C 5.41% H 7.52% N found: 61.53% C 5.52% H 7.45% N.

Example 31

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-isopropyl-4H-thieno [2,3-d] [1,3] oxazin-4-one.

This compound was prepared in a similar manner to that described in Example 30.

Melting point: 139-141 ° C.

With _H (DMSO-d6):

1.24 (6H, d, J = 6.9Hz, (CH _{3) 2} CH), 1.43 (3H, d, J = 7.2Hz, CH ₃ CH) «·

• *

·) ·

3.41 (1H, sept, J = 6.6Hz, (CH _{3) 2} CH),

4.57 (1H, quin, J = 7.2Hz, CH ₃ C H NH), 5.00 to 5.20 (2H, m, CH ₂ Ph),

7.25-7.50 (6H, m, C 8 H 8 and 6-H), and 8.03 (1H, d, J = 7.1 Hz, NH). N, 5.41. H, 7.52%. Found: 61.19%. C, 5.29%. H, 6.99%.

Example 32

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-isobutyl-4H-thieno [2,3-d] [1,3] oxazin-4-one

This compound was prepared in a similar manner to that described in Example 30.

M.p .: 137-139 ° C.

_δ Η (DMSO-d₆):

0.88 (6H, d, J = 6.6 Hz, (CH ₃ ) ₂ CH),

1.43 (3H, d, J = 7.2 Hz, CH ₃ CH),

1.90 (1H, sept, J = 6.6Hz, (CH _{3) 2} CH), 2.70 (2H, d, J = 6.2Hz, CH ₂ CH)

4.56 (1H, quin, J = 7.2Hz, CH ₃ C H NH), 5.00 to 5.15 (2H, m, CH ₂ Ph), 7.25-7.50 (6H, and 8.02 (1H, d, J = 7.15Hz, NH).

Analysis for ^C 20 ^H 22 ^N 2 ^O 4 ^S: m, ^C 8 ^H 8 and 6-H),

calculated: 62.16 % C 5.74 % H found: 62.08 % C 5.82 % H

N 7.25% N 7.35%

Example 33

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-cyclopropyl-4H-thieno [2,3-d] [1,3] oxazin-4-one.

This compound was prepared in a similar manner to that described in Example 30.

Melting point: 138-140 ° C.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 50 _δΗ (DMSO-dg):

0.70 (2Η, m, _CH2), 0.95 (2H, m, _CH2),

1.43 (3H, d, J = 7.1 Hz, CH ₃ CH), 2.41 (1H, m, CH),

4.56 (1H, quin, J = 6.0Hz, CH 2 CH 2 NH),

5.06 (2H, d, J = 2.5Hz, CH ₂ Ph), 7.12 (1H, s, 6-H)

7.35 (5H, m, 9 C 8 H 8) and 8.03 (1H, d, J = 7.2 Hz, NH). Analysis for ^C 19 ^H 18 ^N 2 ° 4 ^S: Calculated: 61.61% C 4.90% H 7.56% N Found: 61.46% C 4.90% H 7.50% N

Example 34 (level 1)

Preparation of 2-amino-4-methoxythiophene-3-carboxylic acid ethyl ester.

A solution containing 2-amino-4-hydroxythiophene-3-carboxylic acid ethyl ester (750 mg, 4.0 mmol) in dry dichloromethane was treated with trimethyloxonium tetrafluoroborate (882 mg, 6 mg). 1.0 mmol) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using 2% methanol in dichloromethane as the eluent, followed by crystallization of the product from acetone. to give the desired product as yellow crystals.

Melting point: 103 - 105 ° C. _δ Η (DMSO-d₆):

1.22 (3 H, t, J)

4.15 (2H, q, J = 7.1 Hz, CH ₃ CH ₂ ), 3.64 (3H, s, OCH ₃ ), = 6.8 Hz, CH ₂ CH ₃ , 5.29 (1H, s , 5-H), · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· 0 0 0 · »·· · 0 · *«. ύ 0 0 »· · 0 '' ♦ '0

7.34, (2H, s, NH ₂ ).

Analysis for C8H-L-jNO-jS:

calculated: 47.75% C 5.51% H 6.96% N found: 47.43% C 5.42% H 6.90% N.

Example 34 (level 2)

Preparation of 2- [N- (benzyloxycarbonyl) -L-alaninyl] amino-4-methoxythiophene-3-carboxylic acid ethyl ester.

2-Amino-4-hydroxythiophene-3-carboxylic acid ethyl ester was acylated in a similar manner to that described in Example 30, step 2.

Example 34 (step 3)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] 5-methoxy-4H-thieno [2,3-d] [1,3] oxazin-4-one.

In this example, the ethyl ester was an acid ester

2- [N- (benzyloxycarbonyl) - L-alaninyl] amino-4-methoxythiophene-3-carboxylic acid cyclized in a similar manner to that described in Example 2, Step 2.

Melting point: 173-175 ° C.

5 _h (DMSO-d6):

1.42 (3H, d, J = 7.2 Hz, CH ₃ CH), 3.85 (3H, s, OCH ₃ ), (1H, m, CH ₃ CHNH), 5.05 (2H, m, CH ₂ Ph), 6.72 (1 H, s, 6-H),

7.25 - 7.50 (5H, m, C 8 H 8), and 8.04 (1H, d, J = 7.4 Hz, NH)

Analysis for ^C 17 ^H 16 ^N 2 ^O 5 ^S Calculated: 56.66% C Found: 56.67% C

H, 4.48; H, 4.32

N 7.77% N 7.69%

··· · · ·

Example 35

Preparation of (S) -2- [N- (benzyloxycarbonyl) aminomethyl] 5-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one.

A solution containing N- (benzyloxycarbonyl) glycine (209 milligrams per mmol) in dry DMF (10 ml), at a temperature between 0 and -5 ° C, was used to treat the solution. -hydroxybenzotriazole (148 mg, 1.1 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (210 mg, 1.1 mmol) were stirred for 15 minutes . 2-Amino-4-methylthiophene-3-carboxylic acid (157 mg, 1 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 18 hours. Additional DEC (210 mg, 1.1 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (50 ml) and water (3 x 20 ml) to give an organic layer which was dried (magnesium sulfate), filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using 50% ethyl acetate / hexane as the eluent, followed by crystallization from acetone / hexane to give the desired product as colorless needles. Yield: 130 mg (39%).

Melting point: 120 - 122 ° C.

· Φ * · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ · · · · * ··· ··· ·· ·· · _φ δ Η (DMSO-d₆):

2.42 (3Η, d, J = 1.1Hz, CH _3), 4.22 (2H, d, J = 6.05 Hz, _CH2 NH), 5.08 (2H, s, _CH2 Ph) 7.25-7.50 (6H, m, C ₆ H ₅ and 6-H),

7.97 (1H, t, J = 6.1 Hz, NH).

Analysis for ^C 16 ^H 14 ^N 2 ° 4 ^S: Calculated: 58.17% C 4.27% H 8.48% N Found: 58.19% C 4.26% H 8.50% N

Example 36

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-aminopropyl-6-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one.

This compound was prepared in a similar manner to that described in Example 35.

Melting point

Mp 129-130 ° C.

δ _Η (DMSO-d 6) 0.94 (3H, t, 2.42 (3H, s, 7.25 - 7.50 8.00 (1H, d,

J = 7.4Hz, CH ₃ CH ₂₎ CH _3), 4.35 (IH, m, (5H, m, _{C6 H5),} 7.32 J = 7.7Hz, NH).

1.70-1.90 (2H, m, CH ₂ CH ₃ ), CHCH ₂ ), 5.04 (2H, m, CH ₂ Ph), (IH, s, 6-H),

Analysis calculated; found:

^C 18 ^H 18 ^N 2 ^O 4 ^S 60.32% C 60.15% C

5.06% H 5.13% H

N 7.82% N 7.68%

Example 37 (level 1)

In this example, (S) -2- [N- (benzyloxycarbonyl) -1-amino-2- (t-butoxy) ethyl] -4,5-dimethyl-4-thieno [2,3-d] [1,3] oxazin-4-one prepared in a manner similar to that described in Example 30, step 2.

* 9 *

• *

Example 37 (level 2)

Preparation of (S) -2- [N- (benzyloxycarbonyl) -1-amino-2-hydroxyethyl] -4,5-dimethyl-4H-thieno [2,3-d] [1,3] oxazin-4-one.

A solution containing (S) -2- [N- (benzyloxycarbonyl) -1-amino-2- (t-butoxy) ethyl] -4,5-dimethyl-4H-thieno [2,3- d] [1,3] oxazin-4-one (300 mg, 0.69 mmol) in dry dichloromethane (5 mL) was treated with trifluoroacetic acid (1 mL) and allowed to stand at room temperature. at room temperature for 18 hours. The solvent was then removed under reduced pressure and the resulting residue was azeotroped with toluene (2 x 50 mL). The residue was purified by silica gel chromatography eluting with 30% ethyl acetate in hexane to give the title compound as a pale gum.

_δ Η (DMSO-d₆):

2.33 (3H, s, CH ₃ ), 2.40 (3H, s, CH ₃ ), 3.75 (2H, m, CH ₂ ),

4.50 (1H, m, CH), 5.05 (3H, m, CH ₂ Ph OH)

7.25-7.50 (5H, m, C 8 H 8), and 7.85 (1H, d, J = 7.7 Hz, NH).

Example 38

Preparation of (S) -2- [N- (butoxycarbonyl) -1-aminoethyl] 5-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one.

This compound was prepared in a similar manner to that described in Example 35.

Melting point: 109 - 111 C.

• 4 • 4 • 4

4 ·· 4

_δ Η (DMSO-d _6):

1.38 (12Η, m, (CH ₃ ) ₃ C + CH ₃ CH), 2.42 (3H, s, CH ₃ ), 4.46 (1H, m, CHCH ₃ ), 7.30 (1H, s, 6-H), and 7.54 (1H, d, J = 7.4Hz, NH).

Analysis for C ₁₄ Hi ₈ N ₂ O ₄ S:

calculated: 54.18% C 5.85% H 9.03% N found: 53.81% C 5.74% H 8.90% N.

Example 39

Preparation of (S) -2- (1-aminoethyl) -5-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one salt with trifluoroacetic acid.

A solution containing (S) -2- [N- (t-butoxycarbonyl) -1-aminoethyl] -5-methyl-4H-thieno [2,3-d] [1,3] oxazine-4- was used in this example. he (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 The mixture was allowed to stand at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the residue was treated with azeotropic conditions with toluene (2 x 50 mL). The residue was purified by silica gel column chromatography using 3% methanol in dichloromethane as eluent to give the desired product as a pale gum.

_δ Η (DMSO-d₆):

1.54 (3H, d, J = 6.9Hz, CH ₃ CH), 2.45 (3H, d, J = 1.4 Hz, CH ₃₎

4.52 (1H, m, CHCH ₃ ), 7.42 (1H, d, J = 1.1Hz, 6-H), and 8.60-8.80 (3H, broad band, NH ₃ ⁺ ) ;

FABMS (positive ion) 211 (MH ⁺ ).

• 9 9 9 9 9

9 9 9 · 9 9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 99 99 9 9 9 9

Example 40

Preparation of (S) -2- [N- (4-methoxyphenoxycarbonyl) -1aminoethyl] -5-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one.

A solution containing (S) -2- (1-aminoethyl) -5-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one and trifluoroacetic acid salt (100 g) was used. milligrams (0.37 mmol) in dry dichloromethane treated with N, N-diisopropylethylamine (0.065 mL, 0.37 mmol) and 4-methoxyphenyl chloroformate (0.56 mL, 0.37 mmol) The solution was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane, followed by crystallization from acetone-hexane to give the desired product in silica gel. in the form of colorless crystals.

Melting point : 173-175 ° C; δ _Η (DMSO- ^d ó) 1.49 (3 H, d, J = 6.9Hz, CH ₃ CH), 2.43 (3H, d, J = 0.8Hz, _CH3); 3.37 (3 H, with, OCH ₃ ), 4.61 (1 H, m, CHCH ₃ ), 6.90 (2H, d, J = 9Hz, 2 x ArH), 7.02 (2H, d, J = 9.1Hz, 2 x ArH), 7.33 (1H, J = 1.1Hz, 6-H), and 8.42 (1 H, d, J = 7.2Hz, NH). Analysis for ^C 14 ^H 16 ^N 2 ° 5 ^N calculated • 56.66% C 4.48% H 7, 77% N found 56.75% C 4.25% H 7, 45% N.

The following compounds of the present invention were also prepared:

• · »

• · · · · ·

The compound wherein R 3 is a methyl group, the R ₂ substituent at the 6-position is Cbz-Ala-NH- and the substituent at the 2-position is CHMeNHCl 2.

Peptidolytic test for proteases.

The compounds of the present invention were tested as follows:

The inhibitor solution was added to the enzyme solution (0.5 to 1 μΜ) diluted in buffer (50 mM sodium phosphate solution, 150 mM sodium chloride solution, 0.001 mM EDTA solution).

0.01% PEG 3400; pH 8.0) to obtain a final inhibitor concentration of 0.01 to 300 μΜ in a total volume of 25 microliters. After a 15 minute preincubation interval, 15 microliters of a 14-mer peptide substrate solution, Ac-HTYLQASEKFKMVG, was added to a final substrate concentration of 250 µΜ. This sample was then incubated at 27 ° C for 1 hour, followed by addition of 40 microliters of 5% trifluoroacetic acid in water. This sample was then analyzed by high performance liquid chromatography (HPLC method) to quantify the amount of substrate peptide and N-terminal and C-terminal cleavage fragments. Next, the percentage cleavage was evaluated and this value was expressed as a fraction of the value obtained for the non-inhibited control sample.

The enzyme used for testing HSV-2 consisted of the proteolytically active region of HSV-2 UL26 homolog protein (amino acid residues 1-247) with the addition of an amino-terminal MGHHHHHHSSA. In International Patent Application WO 95/06055 (Applicant SmithKline Beecham

Corp.) describes this HSV-2 protease sequence.

The enzyme used in this CMV assay consisted of the proteolytically active region of the CMV UL80 protein (amino acid residues 1 to 256) with the addition of an amino-terminal MGHHHHHHHHSSGHIDDDDK. This polypeptide was cleaved in the region between A143 and A144 (natural UL 80 numbering) to yield the active heterodimer.

The enzyme used for VZV testing consisted of the proteolytically active region of VZV gene 33 protein (amino acid residues 1 to 237).

The results obtained were as follows:

The compounds of the examples showed efficacy in one or more of the above tests at a concentration of 10 μΜ or 1 μΜ. Examples 1-4,

7-10. 12-18, 21-22, 24-29 and 35 showed> 50% inhibition of one or more proteases at a concentration of 1 μ 1, with the compounds of Examples 10, 17, 18, 21, 27; 2, 3, 15, 21, 28; and 8, 15, 21, 28; preferably exhibited activity for HSV-2 and HSV-2, respectively. CMV and VZV.

Claims (54)

PATENT CLAIMS A herpesvirus protease inhibitor 4H-thieno [2,3-d] [1,3] oxazin-4-one derivative of the general formula I which is substituted in the 2-position by X (Y) NH-CHR 4 -, wherein: X represents a hydrogen atom or a blocking group, Y represents an optionally present amino acid and R @ 1 represents a hydrogen atom or an amino acid side chain. The compound of claim 1, wherein the 4H-thieno [2,3-d] [1,3] oxazin-4-one ring system is numbered as follows: whereupon substituents at the 5 and 6 positions, referred to as R ₃ and R ₂ , as well as a substituent at the 2-position, may optionally be present on this ring system. A compound according to claim 2, wherein R ₃ and R _2, if present, are selected from the group consisting of halogens, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, amino groups optionally substituted with one or two C 1 -C 6 alkyl groups or optionally substituted benzyl, hydroxyalkyl, alkylcarbonyl, alkoxycarbonyl, optionally substituted phenyl or R 4 ZCONH wherein Z is a bond, oxygen, NH or NCOCH ₃ , and R 4 CO represents an acyl group, wherein the radical R 4 may be an aryl group, an alkyl group or an aralkyl group, or R 3 and R ₂ may be joined together to form a polymethylene group containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms. A compound according to any one of claims 1 to 3, wherein X is selected from the group consisting of aryl, alkanoyl, (aryl) alkoxycarbonyl, (aryl) alkylaminocarbonyl, aroyl or arylsulfonyl. The compound of claim 4, wherein X is selected from the group consisting of benzyloxycarbonyl, t-butoxycarbonyl, and optionally substituted phenyl. A compound according to any one of claims 1 to 5, wherein Y if present is alanine, asparagine, valine or the like. A compound according to any one of claims 1 to 6, wherein the aminoacyl moieties -NH-CHR 1 -CO- resulting in NH-CHR 1 in the compound of formula I include alanine (R 1 = CH 3), asparagine, methionine, phenylalanine, serine (R 1 - CH ₂ OH), valine and α-aminobutyric group (R 1 = CH ₂ CH ₃ ). 8. (S) -2- [N-Benzyloxycarbonyl) -1-aminoethyl] -5-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one. 9. (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl) -5,6-dimethyl-4H-thieno [2,3-d] [1,3] oxazin-4-one 10. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] -7,7-dihydro-4H, 5H-cyclopenta [4,5] thieno [2,3-d] [1,3] oxazin-4-one. 11. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5,6,7,8-tetrahydro-4H [1] benzothieno [2,3-d] [1,3] oxazine-4- he 12. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 6-ethoxycarbonyl-5-methylthieno [2,3-d] [1,3] oxazin-4-one. 13. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6-acetamido-4H-thieno [2,3-d] [1,3] oxazin-4-one. 14. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (N-isobutyrylamino) -4H-thieno [2,3-d] [1,3] oxazine-4- he. 15. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (N-hexanoylamino) -4H-thieno [2,3-d] [1,3] oxazine-4- he. 16. 2- [N- (Benzyloxycarbonyl) - (1S) -1- (aminoethyl)] - 5-methyl-6 - [(N-benzyloxycarbonyl-β-alaninyl) amino] -4Hthieno [2,3-d] [1] 3] oxazin-4-one. 17. 2- [N- (benzyloxycarbonyl) - (1S) -1- (aminoethyl)] - 5-methyl-6 - [[6-N (benzyloxycarbonyl) aminohexanoyl] amino] 4H-thieno [2,3-d] [ 1,3] oxazin-4-one. 18. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 62 5-methyl-6- (triphenylphosphoranylideneamino) -4H-thieno [2,3-d] [1,3] oxazin-4-one. 19. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (N-benzoylamino) -4 H -thieno [2,3- d] [1,3] oxazine-4- he. 20. (S) -2- [N (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6 - [(N-isopropoxycarbonyl) amino] -4 H -thieno [2,3- d] [1,3] oxazine- 4-on. 21. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6 - [(N-isobutoxycarbonyl) amino] -4H-thieno [2,3-d] [1,3] oxazine -4-on. 22. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (3-isopropylureido) -4H-thieno [2,3-d] [1,3] oxazine-4 -he. 23. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (3-butylureido) -4H-thieno [2,3-d] [1,3] oxazine-4- he. 24. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (3-benzylureido) -4H-thieno [2,3-d] [1,3] oxazine-4- he. 25. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (3-phenylureido) -4H-thieno [2,3-d] [1,3] oxazin-4-one. 26. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- [3- (4-chlorophenyl) ureido] -4H-thieno [2,3-d] [1,3] ] Oxazin-4-one. 27. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- [3- (4-methoxyphenyl) ureido] -4H-thieno [2,3-d] [1,3] Oxazin-4-one. 28. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- [3- (2-methoxycarbonylphenyl) ureido] -4H-thieno [2,3-d] [1,3] Oxazin-4-one. 29. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (3-acetyl-3-benzylureido) -4 H -thieno [2,3- d] [1,3] oxazin-4-one. 30. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6-amino-4 H -thieno [2,3- d] [1,3] oxazin-4-one. 31. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (N, N-dimethylamino) -4H-thieno [2,3-d] [1,3] oxazine- 4-on. 32. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (Ν, Ν-dipropylamino) -4H-thieno [2,3-d] [1,3] oxazine -4-on. 33. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6- (N-benzyl-N-methylamino) -4 H -thieno [2,3- d] [1,3] oxazin-4-one. 34. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6-bromo-4 H -thieno [2,3- d] [1,3] oxazin-4-one. 35. (S) -2- [N- (benzyloxycarbonyl) -1-aminoethyl] ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · 5-methyl-6-phenyl-4H-thieno [2,3-d] [1,3] oxazin-4-one. 36. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] 5-methyl-6-iodo-4H-thieno [2,3-d] [1,3] oxazin-4-one. 37. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] -5-ethyl-6-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one. 38. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] -5-isopropyl-4H-thieno [2,3-d] [1,3] oxazin-4-one. 39. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] -5-isobutyl-4H-thieno [2,3-d] [1,3] oxazin-4-one. 40. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] -5-cyclopropyl-4H-thieno [2,3-d] [1,3] oxazin-4-one. 41. (S) -2- [N- (Benzyloxycarbonyl) -1-aminoethyl] -5-methoxy-4H-thieno [2,3-d] [1,3] oxazin-4-one. 42. (S) -2- [N- (Benzyloxycarbonyl) aminomethyl] 5-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one. 43. (S) -2- [N- (Benzyloxycarbonyl) -1-aminopropyl] -5-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one. 44. (S) -2- [N- (Benzyloxycarbonyl) -1-amino-2-hydroxyethyl] -4,5-dimethyl-4H-thieno [2,3-d] [1,3] oxazin-4-one. 45. (S) -2- [N- (t-butoxycarbonyl) -1-aminoethyl] 5-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· 46. (S) -2- (1-Aminoethyl) -5-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one. 47. (S) -2- [N- (4-methoxy-phenoxycarbonyl) -1-amino-ethyl] -5-methyl-4H-thieno [2,3-d] [1,3] oxazin-4-one. 48. any A pharmaceutically acceptable salt of the compound of claims 8 to 47. A compound according to claim 1, substantially described herein and with reference to examples. A pharmaceutical composition comprising a compound according to any one of claims 1 to 49 and a pharmaceutically acceptable carrier. A compound according to any one of claims 1 to 49 for use as an active therapeutic agent. A compound according to any one of claims 1 to 49 for use in the treatment of viral diseases. Use of a compound according to any one of claims 1 to 49 for the preparation of a medicament for use in the treatment of viral diseases caused by herpesviruses. 54. A method for treating viral diseases caused by herpesviruses in a mammal, comprising administering to said mammal in need thereof an effective amount of a compound of any one of claims 1 to 49.