WO2009022185A2 - 6, 6-fused heterocycles, their pharmaceutical compositions and methos of use - Google Patents

Abstract

The invention relates to chemical compounds, or pharmaceutically acceptable salts thereof of the formula (I): which have bacterial Murl inhibitory activity and are accordingly useful for their treatment and prophylaxis of bacterial infection, e.g., E.faecalis or S.aureus infection. Further, the invention relates to methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of the compounds, to pharmaceutical compositions containing them, and to their use in the manufacture of medicaments of use in the treatment and prevention of various bacterial diseases in a warm-blooded animal such as man.

Description

CHEMICAL COMPOUNDS -795 Field of the invention

[01] The present invention relates to novel 6,6 fused heterocycles, their pharmaceutical compositions and methods of use. In addition, the present invention relates to 5 therapeutic methods for the treatment and prevention of various diseases caused by bacteria, for example, Enterococcus faecalis or Staphylococcus aureus infection. Background of the invention

[02] Most bacteria, especially Gram positive bacteria, utilize a cell wall comprised of crosslinked peptidoglycan units to maintain shape and resist high osmotic pressure

10 potentials. Bacterial cell wall biosynthesis is a validated target for antimicrobial activity; cephalosphorins, penicillins and glycopeptides are antimicrobial agents, which block cell wall biosynthesis (Walsh, C, Molecular mechanisms that confer antibacterial resistance. Nature, 2000, 406: p. 775-781). Cell wall biosynthesis requires the enzyme Murl, a glutamate racemase, and therefore this enzyme is essential for bacterial viability (Doublet, P., et al., The

15 murl gene of Escherichia coli is an essential gene that encodes a glutamate racemase activity. Journal of Bacteriology, 1993, 175(10): p. 2970-9).

[03] As bacteria are constantly evolving to develop resistance to widely used antibiotics, there is a continuing need for new antibacterial compounds having different mechanisms of action to treat bacterial infections. Infections by multidrug resistant Gram

20 positive cocci, for example, such as staphylococcal, streptococcal or enterococcal infections, are a serious problem, especially in children, the elderly, and hospitalized patients.

[04] Pteridine derivatives have been studied. For example, U.S. Patent Publication No. 2005010047 describes the preparation of pteridinones as modulators of chemokine receptor activity. H. S. Forrest et al., J Chem. Soc, (1951):3-7, describes the synthesis of 8-

25 substituted pteridine derivatives. E.M. Gal, J.Amer. Chem. Soc, 72:3532-3534(1950), describes pteridine studies: mercaptopteridines. B.N. La Du et al., Proc. Soc. Exptl, Biol, 73_: 107- 109(1950) describes the toxicity of some synthetic pteridines in rats. W. Heinrich et al., Ann., 555:146-156(1944) describes pigments of butterflies: supplementary considerations on the properties of the pteridine. W. Pfieiderer et al., Chemische Berichte, 96(11):2964-

30 2976(1963) describes pteridines: synthesis and structure of 7-hydroxyisopteridines. U.S. Patent No. 7,148,236 describes the preparation of thio-bridges aryl substituted azabicyclic derivatives for use in pharmaceutical compositions as modulators of acetylcholine receptors. [05] Japanese Patent Publication No. JP 2003005355 describes chemically amplified negative working resist compositions for processing with electron beam or x-ray. Japanese Patent Publication No. JP 2002100363 describes Cathode active mass mixture for secondary lithium battery, the cathode, and the battery. Japanese Patent Publication No. JP 2000154139 describes insulin secretin promoters and antidiabetic agents containing condensed pyrazine derivatives. Japanese Patent Publication No. JP 2000038350 describes pyrimidine CRF antagonists as antidiabetics. Japanese Patent Publication No. JP 11223937 describes a positive-working photosensitive resin composition useful in production of semiconductor device. Japanese Patent Publication Nos. JP 10177243 and JP 3543249 describe a method for processing black-and-white silver halide photographic material of a low replenishment mode. Japanese Patent Publication No. JP 10036375 describes the preparation of cephalosporins as bactericides against methicillin resistant Staphylococcus aureus. Japanese Patent Publication No. JP 09188874 and JP 3650200 describe organic electroluminescent device using quinoxaline compound with high luminescent efficiency. Japanese Patent Publication No. JP 63057622 describes photoresists containing pteridine derivatives for improved adhesion to metals. European Patent No. 12444 describes a method of diagnosing, especially for the early recognition of malignant tumors and/or viral diseases, and means to carry it out.

[06] However, as described above, there is a need for novel 6,6 fused heterocycles, their pharmaceutical compositions and their use in therapeutic methods for the treatment and prevention of various diseases caused by bacteria, for example, E.faecalis or S.aureus infection. Summary of the Invention

[07] The present invention describes novel compounds, which inhibit bacterial Murl, e.g., E.faecalis or S.aureus Murl, compositions of such compounds and methods of use. The compounds disclosed herein represent a valuable contribution to the development of therapies directed to diseases resulting from bacterial infection, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections or, for example, E.faecalis or S.aureus infection. The compounds are of particular interest to treat infections that are resistant to conventional antibiotics, such as penicillin and cephalosporin.

[08] The invention relates to chemical compounds, or pharmaceutically acceptable salts thereof of the formula (I):

(I) which have bacterial, e.g., E.faecalis or S. aureus Murl inhibitory activity and are accordingly useful for their treatment and prophylaxis of various diseases caused by bacteria expressing Murl, for example E.faecalis or S.aureus infection, and thus in methods of treatment or prophylaxis for humans and animals. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the treatment and prophylaxis of various diseases caused by bacterial infection, e.g., E.faecalis or S.aureus infection, in a warm-blooded animal such as man. Detailed Description of the Invention

[09] Accordingly, the present invention provides a compound of formula (I):

R²? .R^2b N

R¹ R³

(I) in free or salt form, wherein:

A is C=O, or C-N(R^4a)(R^4b);

B is N, or N(R⁵);

X is S, -S(O)₂-, or O;

R¹ is C_1-6alkyl, Co-βalkyl-Cs-scyclalkyl-Co-_όalkyl — , Ci-ealkoxy-Co-βalkyl — , or aryl- Ci-_δalkyl — ; optionally substituted with 1-6 independent halo substituents;

R^2a is H or Ci-βalkyl;

R^2b is H, Ci_-6alkyl, hetcyclyl-Ci-galkyl— C_0-6alkyl-O-C(O)-C_0-6alkyl— , Ci_-6alkyl- SO₂ or — (Co-₆alkyl)-N(Co-₆alkyl)(Co-₆alkyl); optionally substituted with 1-6 independent halo or OH substituents; or R^2a and R^2b, together with the N to which they are attached, form a hetcyclyl; optionally substituted with 1-6 independent halo substituents; R³ is H, Ci-₆alkyl, Co-βalkyl-aryl-Ci-ealkyl — , Co-βalkyl-hetaryl-Ci-ealkyl — , or — (Co_-6alkyl)-N(Co-₆alkyl)(Co_-6alkyl); optionally substituted with 1-6 independent halo, CN, NO₂, Ci_-6alkyl, C_0-6alkyl-O-C(O)-C_0-6alkyl— , Ci_-6alkoxy, or Ci_-6alkyl-SO₂— , aryl substituents; R^4a is H or Ci_-6alkyl;

R^4b is H,

Co-₆alkyl-hetcyclyl-Co-₆alkyl — , Co-βalkyl-hetaryl-Co-_όalkyl — , Co-₆alkyl-C₃-₈cyclalkyl-Co-₆alkyl — , Ci.₆alkoxy-Co-₆alkyl — , or — Ci_₆alkyl- N(Co-₆alkyl)(Co-₆alkyl); optionally substituted with 1-6 independent halo, OH, or

substituents; or R^4a and R^4b, together with the N to which they are attached, form a hetcyclyl; optionally substituted with 1-6 independent halo, OH, or

substituents; and

R⁵ is H, Ci_-6alkyl, C_0-6alkyl-O-C(O)-C_0-6alkyl— , Co-ealkyl-aryl-Ci-ealkyl— , or Co-βalkyl-hetaryl-Co-_όalkyl — ; optionally substituted with 1-6 independent halo, NO₂, or Ci-δalkoxy substituents; provided that X-R¹ is not -S-Me, or optionally substituted -S-(CH₂)-phenyl.

[10] The term "alkyl" includes both straight and branched chain alkyl groups. References to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only. For example, "Ci-₆alkyl" includes

propyl, isopropyl and t-butyl. A similar convention applies to other radicals, for example "phenylCi-₆alkyl" includes phenylQ^alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. "Coalkyl" refers to a hydrogen terminus when the Coalkyl is terminal and refers to a direct bond when the "Coalkyl" is bridging (linking). The term "Co-βalkyl", for example, refers to adding "Coalkyl" to the scope of the "Ci-₆alkyl" definition. Thus, it is understood that substituents allowed for "Ci-6alkyl" would accordingly be allowed for the "Ci_-6alkyl" within the scope of "C_0-6alkyl".

[11] The term "halo" refers to fluoro, chloro, bromo and iodo. [12] Where optional substituents are chosen from, for example, "1-5 independent" substituents from a list of substituents, it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups in the list. Where a substituent is recited using the molecule (parent) name, it is understood that the substituent is the radical of such molecular parent. [13] An "aryl" is well understood by one in the art and includes phenyl and naphthyl.

[14] A "hetaryl" is a 4-12 membered fully unsaturated or partially unsaturated heterocyclic mono or bicyclic ring containing at least one nitrogen, sulphur or oxygen ring atom and in which, unless otherwise specified, a -CH₂- group can optionally be replaced by a -C(O)-. Examples of such hetaryl include indolyl, pyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, imidazo[l,2-a]pyridinyl, benzimidazolyl, quinolyl, pyrrolinyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, benzoxazolyl, benzoxazol-2-one, benzopyridazin-dione, pyridine-N-oxide, and quino line-N-oxide .

[15] A "hetcyclyl" is a saturated, mono or bicyclic ring containing 4-12 atoms containing at least one nitrogen, sulphur or oxygen ring atom. Examples of such "hetcyclyl" include pyrrolidinyl, imidazolidinyl, pyrazolininyl, tetrahydropyranyl, morpholino, piperidyl, and piperazinyl. [16] Examples of "Ci_6alkoxy" include methoxy, ethoxy and propoxy.

[17] Examples of " — (Co-₆alkyl)-N(Co-₆alkyl)(Co-₆alkyl)" include methylamino, ethylamino, di-7V-methylamino, di-(7V-ethyl)amino, and TV-ethyl-TV-methylamino.

[18] A suitable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[19] Some compounds of the formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess E.faecalis or S. aureus Murl inhibitory activity. The invention further relates to any and all tautomeric forms of the compounds of the formula (I) that possess E.faecalis or S. aureus Murl inhibitory activity.

[20] It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess E.faecalis or S. aureus Murl inhibitory activity.

[21] Thus, in an aspect, the present invention comprises a compound of Formula (I) above, described by Formula (II):

(H) in free or salt form, wherein X, R¹, R^2a, R^2b, R³, and R⁵ are as described above for Formula

(I)- [22] In an embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; and R¹, R^2a, R^2b, R³, and R⁵ are as described above for Formula (I).

[23] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; and R^2a, R^2b, R³, and R⁵ are as described above for Formula (I).

[24] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl, R^2a is H or Ci-6alkyl; and R^2b, R³, and R⁵ are as described above for Formula (I).

[25] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or Ci.₆alkyl optionally substituted with 1-6 independent halo or OH substituents; and R³ and R⁵ are as described above for Formula (I).

[26] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or R^2b is H or

optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or

and R³ is as described above for Formula (I).

[27] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or R^2b is H or

optionally substituted with 1-6 independent halo or OH substituents; R⁵ is Co-₆alkyl-0-C(0)-Co-₆alkyl — optionally substituted with 1-6 independent halo, NO₂, or Ci.6alkoxy substituents; and R³ is as described above for Formula (I).

[28] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or C^aUcyl optionally substituted with 1-6 independent halo or OH substituents; R⁵ is Co-βalkyl-aryl-Ci-ealkyl — optionally substituted with 1-6 independent halo, NO₂, or Ci-6alkoxy substituents; and R³ is as described above for Formula (I).

[29] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or Ci.₆alkyl optionally substituted with 1-6 independent halo or OH substituents; R⁵ is Co-βalkyl-hetaryl-Co-_όalkyl — optionally substituted with 1-6 independent halo, NO2, or Ci-δalkoxy substituents; and R³ is as described above for Formula (I).

[30] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or C_1-6alkyl; R^2b is hetcyclyl-Ci-_δalkyl — optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or C_1-6alkyl; and R³ is as described above for Formula (I).

[31] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or Ci_-6alkyl; R^2b is C_0-6alkyl-O-C(O)-C_0-6alkyl — optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or C_1-6alkyl; and R³ is as described above for Formula (I).

[32] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or Ci-6alkyl; R^2b is Ci-6alkyl-SO2 optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or C_1-6alkyl; and R³ is as described above for Formula (I). [33] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is C_2-6alkyl; R^2a is H or Ci_-6alkyl; R^2b is — (C_o-6alkyl)-N(Co_-6alkyl)(C_o-6alkyl) optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or C_1-6alkyl; and R³ is as described above for Formula (I). [34] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is Co-βalkyl- Cs-scyclalkyl-Co-ealkyl— ; and R^2a, R^2b, R³, and R⁵ are as described above for Formula (I).

[35] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is Co-βalkyl- Cs-scyclalkyl-Co-βalkyl — , R^2a is H or C^aUcyl; and R^2b, R³, and R⁵ are as described above for Formula (I).

[36] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is Co-βalkyl- C₃-₈cyclalkyl-Co-₆alkyl — ; R^2a is H or C_1-6alkyl; R^2b is H or

optionally substituted with 1-6 independent halo or OH substituents; and R³ and R⁵ are as described above for Formula (I).

[37] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is Co-βalkyl- C₃.₈Cyclalkyl-Co-₆alkyl — ; R^2a is H or C_1-6alkyl; R^2b is H or

optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or C_1-6alkyl; and R³ is as described above for Formula (I).

[38] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is Co-βalkyl- C₃-₈cyclalkyl-Co-₆alkyl — ; R^2a is H or C_1-6alkyl; R^2b is H or C_1-6alkyl optionally substituted with 1-6 independent halo or OH substituents; R⁵ is Co-₆alkyl-0-C(0)-Co-₆alkyl — ; and R³ is as described above for Formula (I).

[39] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is Ci_6alkoxy- Co-βalkyl — ; and R^2a, R^2b, R³, and R⁵ are as described above for Formula (I).

[40] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is Ci_6alkoxy- Co-βalkyl — , R^2a is H or C_1-6alkyl; and R^2b, R³, and R⁵ are as described above for Formula (I).

[41] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is Ci_6alkoxy- Co_-6alkyl — ; R^2a is H or C_1-6alkyl; R^2b is H or C_1-6alkyl optionally substituted with 1-6 independent halo or OH substituents; and R³ and R⁵ are as described above for Formula (I). [42] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is Ci_6alkoxy- Co_-6alkyl — ; R^2a is H or C_1-6alkyl; R^2b is H or C_1-6alkyl optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or C_1-6alkyl; and R³ is as described above for Formula (I).

[43] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is aryl-Ci.₆alkyl — optionally substituted with 1-6 independent halo substituents; and R^2a, R^2b, R³, and R⁵ are as described above for Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)- phenyl.

[44] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is aryl-Ci.₆alkyl — optionally substituted with 1-6 independent halo substituents; R^2a is H or C^aUcyl; and R^2b, R³, and R⁵ are as described above for Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)-phenyl.

[45] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is aryl-Ci.₆alkyl — optionally substituted with 1-6 independent halo substituents; R^2a is H or Ci.₆alkyl; R^2b is H or Ci-6alkyl optionally substituted with 1-6 independent halo or OH substituents; and R³ and R⁵ are as described above for Formula (I); provided that X-R¹ is not optionally substituted - S-(CH₂)-phenyl.

[46] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is aryl-Ci.₆alkyl — optionally substituted with 1-6 independent halo substituents; R^2a is H or Ci.₆alkyl; R^2b is H or Ci-₆alkyl optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or C_1-6alkyl; and R³ is as described above for Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)-phenyl.

[47] In still another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a and R^2b, together with the N to which they are attached, form a hetcyclyl optionally substituted with 1-6 independent halo substituents; and R³ and R⁵ are as described above for Formula (I).

[48] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a and R^2b, together with the N to which they are attached, form a hetcyclyl optionally substituted with 1-6 independent halo substituents; R⁵ is H; and R³ is as described above for Formula (I). [49] In yet still an embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is O; and R¹, R^2a, R^2b, R³, and R⁵ are as described above for Formula (I).

[50] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is O; R¹ is Ci.₆alkyl; and R^2a, R^2b, R³, and R⁵ are as described above for Formula (I).

[51] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is O; R¹ is Ci.₆alkyl, R^2a is H or Ci-6alkyl; and R^2b, R³, and R⁵ are as described above for Formula (I). [52] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is O; R¹ is C_1-6alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or C^aUcyl optionally substituted with 1-6 independent halo or OH substituents; and R³ and R⁵ are as described above for Formula (I).

[53] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is O; R¹ is Ci.₆alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or C^aUcyl optionally substituted with 1-6 independent halo or OH substituents; R⁵ is Co-βalkyl; and R³ is as described above for Formula (I).

[54] In yet still another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is O; R¹ is C_1-6alkyl; R^2a and R^2b, together with the N to which they are attached, form a hetcyclyl optionally substituted with 1-6 independent halo substituents; and R³ and R⁵ are as described above for Formula (I).

[55] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is O; R¹ is Ci.₆alkyl; R^2a and R^2b, together with the N to which they are attached, form a hetcyclyl optionally substituted with 1-6 independent halo substituents; R⁵ is H or Ci.6alkyl; and R³ is as described above for Formula (I).

[56] In an embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is -S(O)₂-; and R¹, R^2a, R^2b, R³, and R⁵ are as described above for Formula (I).

[57] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is -S(O)₂-; R¹ is C_1-6alkyl; and R^2a, R^2b, R³, and R⁵ are as described above for Formula (I). [58] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is -S(O)₂-; R¹ is C_1-6alkyl, R^2a is H or Ci-6alkyl; and R^2b, R³, and R⁵ are as described above for Formula (I).

[59] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is -S(O)₂-; R¹ is C_1-6alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or C^aUcyl optionally substituted with 1-6 independent halo or OH substituents; and R³ and R⁵ are as described above for Formula (I).

[60] In another embodiment of this aspect, the present invention comprises a compound of Formula (II) above, in free or salt form; wherein X is -S(O)₂-; R¹ is Ci.6alkyl; R^2a is H or C^aUcyl; R^2b is H or C^aUcyl optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or C_1-6alkyl; and R³ is as described above for Formula (I).

[61] A second aspect of the present invention comprises a compound of Formula (I) above, described by Formula (III):

(III) in free or salt form, wherein X, R¹, R^2a, R^2b, R³, R^4a, and R^4b are as described above for Formula (I).

[62] In an embodiment of this aspect, the present invention comprises a compound of Formula (III) above, in free or salt form; wherein X is S; and R¹, R^2a, R^2b, R³, R^4a, and R^4b are as described above for Formula (I).

[63] In another embodiment of this aspect, the present invention comprises a compound of Formula (III) above, in free or salt form; wherein X is S; R¹ is C_2-6alkyl; and R^2a, R^2b, R³, R^4a, and R^4b are as described above for Formula (I).

[64] In another embodiment of this aspect, the present invention comprises a compound of Formula (III) above, in free or salt form; wherein X is S; R¹ is C_2-6alkyl, R^2a is H or Ci-βalkyl; and R^2b, R³, R^4a, and R^4b are as described above for Formula (I).

[65] In another embodiment of this aspect, the present invention comprises a compound of Formula (III) above, in free or salt form; wherein X is S; R¹ is C_2-6alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or Ci.₆alkyl optionally substituted with 1-6 independent halo or OH substituents; and R³, R^4a, and R^4b are as described above for Formula (I). [66] In another embodiment of this aspect, the present invention comprises a compound of Formula (III) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or C^aUcyl optionally substituted with 1-6 independent halo or OH substituents; R^4a is H or C^aUcyl; R³ is H or C_1-6alkyl; and R^4b is as described above for Formula (I).

[67] In another embodiment of this aspect, the present invention comprises a compound of Formula (III) above, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or C^aUcyl optionally substituted with 1-6 independent halo or OH substituents; R^4a is H or Ci.6alkyl; R³ is Co-βalkyl-aryl-Ci-ealkyl — optionally substituted with 1-6 independent halo, CN, NO₂, Ci_-6alkyl, C_0-6alkyl-O-C(O)-C_0-6alkyl— , Ci_-6alkoxy, or Ci_6alkyl-Sθ2 — , aryl substituents;; and R^4b is as described above for Formula (I).

[68] In another embodiment of this aspect, the present invention comprises a compound of Formula (III) above, in free or salt form; wherein X is S; R¹ is aryl-Ci-₆alkyl — optionally substituted with 1-6 independent halo substituents; and R^2a, R^2b, R³, R^4a, and R^4b are as described above for Formula (I); provided that X-R¹ is not optionally substituted -S- (CH₂)-phenyl.

[69] In another embodiment of this aspect, the present invention comprises a compound of Formula (III) above, in free or salt form; wherein X is S; R¹ is aryl-Ci-₆alkyl — optionally substituted with 1-6 independent halo substituents; R^2a is H or Ci-6alkyl; and R^2b, R³, R^4a, and R^4b are as described above for Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)-phenyl.

[70] In another embodiment of this aspect, the present invention comprises a compound of Formula (III) above, in free or salt form; wherein X is S; R¹ is aryl-Ci-₆alkyl — optionally substituted with 1-6 independent halo substituents; R^2a is H or Ci-₆alkyl; R^2b is H or optionally substituted with 1-6 independent halo or OH substituents; and R³, R^4a, and R^4b are as described above for Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)-phenyl.

[71] In another embodiment of this aspect, the present invention comprises a compound of Formula (III) above, in free or salt form; wherein X is S; R¹ is

optionally substituted with 1-6 independent halo substituents; R^2a is H or Ci-₆alkyl; R^2b is H or optionally substituted with 1-6 independent halo or OH substituents; R^4a is H or R³ is H or

and R^4b is as described above for Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)-phenyl. [72] In another embodiment of this aspect, the present invention comprises a compound of Formula (III) above, in free or salt form; wherein X is S; R¹ is aryl-Ci.₆alkyl — optionally substituted with 1-6 independent halo substituents; R^2a is H or C^aUcyl; R^2b is H or Ci-₆alkyl optionally substituted with 1-6 independent halo or OH substituents; R^4a is H or C_1-6alkyl; R³ is Co-₆alkyl-aryl-Ci-₆alkyl — optionally substituted with 1-6 independent halo, CN, NO₂, Ci-βalkyl, C_0-6alkyl-O-C(O)-C_0-6alkyl— , Ci_-6alkoxy, or Ci_-6alkyl-SO₂— , aryl substituents; and R^4b is as described above for Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)-phenyl.

[73] In another embodiment of this aspect, the present invention comprises a compound of Formula (III) above, in free or salt form; wherein X is S; R¹ is C_2-6alkyl; R^2a is H or C_1-6alkyl; R^2b is H or

optionally substituted with 1-6 independent halo or OH substituents; R^4a and R^4b, together with the N to which they are attached, form a hetcyclyl; optionally substituted with 1-6 independent halo, OH, or

substituents; and R³ is as described above for Formula (I). [74] Particular values of variable groups are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.

[75] A is C=O.

[76] A is C-N(R^4a)(R^4b); and -N(R^4a)(R^4b) is (2-morpholin-4-ylethyl)amino. [77] A is C-N(R^4a)(R^4b); and -N(R^4a)(R^4b) is morpholin-4-yl.

[78] A is C-N(R^4a)(R^4b); and -N(R^4a)(R^4b) is (2-hydroxyethyl)amino.

[79] A is C-N(R^4a)(R^4b); and -N(R^4a)(R^4b) is [2-(diethylamino)ethyl] amino.

[80] A is C-N(R^4a)(R^4b); and -N(R^4a)(R^4b) is dimethylamino.

[81] B is N. [82] B is N(R⁵).

[83] X is S.

[84] X is -S(O)₂-.

[85] X is O.

[86] R¹ is butyl. [87] R¹ is 2-phenylethyl.

[88] R¹ is benzyl.

[89] R¹ is cyclopentyl.

[90] R¹ is methyl. [91] R^2a is H.

[92] R^2a is methyl.

[93] R^2b is H.

[94] R^2b is methyl. [95] R^2b is 2-moφholin-4-ylethyl.

[96] R^2b is2-(diethylamino)ethyl.

[97] R^2b is HO-C(O)-CH₂-.

[98] R^2b is CH₂(OH)-CH(OH)-CH(OH)-CH(OH)-CH(OH)-CH₂-.

[99] R^2b is methanesulfonyl. [100] R^2b is 4-methylpiperazin-l-yl.

[101] R^2b is 4-benzoic acid-1-yl.

[102] R^2a and R^2b together is 3-hydroxyazetiin- 1 -yl.

[103] R^2a and R^2b together is moφholin-4-yl.

[104] R³ is 3-chlorobenzyl. [105] R³ is biphenyl-2-ylmethyl.

[106] R³ is 4-(methylsulfonyl)benzyl.

[107] R³ is 3,4-dichlorobenzyl.

[108] R³ is 2,6-dichlorobenzyl.

[109] R³ is 3-(trifruoromethyl)benzyl. [110] R³ is 3,5-dimethoxybenzyl.

[Ill] R³ is 4-fluoro-3-nitrobenzyl.

[112] R³ is 4-methylbenzyl.

[113] R³ is 4-fluorobenzyl.

[114] R³ is 3-chloro-2,6-difluorobenzyl. [115] R³ is pyridin-3-ylmethyl.

[116] R³ is pyridin-4-ylmethyl.

[117] R³ is (5-methylisoxazol-3-yl)methyl.

[118] R³ is (2,6-dichloropyridin-4-yl)methyl.

[119] R³ is benzyl. [120] R³ is 2,6-difluorobenzyl.

[121] R³ is 2,6-difluoro-3-methylbenzyl.

[122] R³ is 4-cyano benzyl.

[123] R^4a is hydrogen and R^4b is 2-morpholino-ethyl. [124] R^4a and R^4b together with the nitrogen atom to which they are attached form morpholino.

[125] R^4a is hydrogen and R^4b is 2-hydroxyethyl.

[126] R^4a is hydrogen and R^4b is 2-(N,N-diethylamino)-ethyl. [127] R^4a and R^4b are both methyl.

[128] R^4a is hydrogen and R^4b is 3-morpholino-prop-l-yl.

[129] R^4a is hydrogen and R^4b is 2-hydroxy- 1 -methyl- ethyl.

[130] R^4a and R^4b together with the nitrogen atom to which they are attached form 3 ,5 -dimethylpiperazino . [131] R^4a is hydrogen and R^4b is 3-hydroxyprop- 1 -yl.

[132] R^4a is hydrogen and R^4b is 2-(furan-2-yl)-ethyl.

[133] R^4a is hydrogen and R^4b is 2-hydroxyprop- 1 -yl.

[134] R^4a and R^4b together with the nitrogen atom to which they are attached form 3- hydroxy-3-methyl-azetidin- IyI. [135] R^4a is hydrogen and R^4b is (5-methyl furan-2-yl)methyl;

[136] R^4a is hydrogen and R^4b is 4-hydroxycyclohexyl.

[137] R^4a is hydrogen and R^4b is 2-methoxyethyl.

[138] R^4a is hydrogen and R^4b is (pyridine-3-yl)methyl.

[139] R^4a and R^4b together with the nitrogen atom to which they are attached form 3- hydroxypyrolidino.

[140] R^4a is hydrogen and R^4b is 5-hydroxycyclopenten-3-yl.

[141] R⁵ is H.

[142] R⁵ is ethylacetyl.

[143] R⁵ is ethylbenzoacetyl. [144] R⁵ is 3-chloro-2,6-difluorobenzyl.

[145] R⁵ is 4-fluorobenzyl.

[146] R⁵ is (5-methylisoxazol-3-yl)methyl.

[147] R⁵ is (2,6-dichloropyridin-4-yl)methyl.

[148] In another aspect of the invention, compounds of the invention are any one of the Examples in free or salt form.

[149] In another aspect, the compounds of the invention are any one of:

[150] 4-amino-2-(butylthio)-8-(3-chlorobenzyl)-5,8-dihydropteridine-6,7-dione;

[151] 4-amino-8-(biphenyl-2-ylmethyl)-2-(butylthio)-5,8-dihydropteridine-6,7- dione;

[152] 4-amino-2-(butylthio)-8-[4-(methylsulfonyl)benzyl]-5,8-dihydropteridine-6,7- dione;

[153] 4-amino-2-(butylthio)-8-(3,4-dichlorobenzyl)-5,8-dihydropteridine-6,7-dione; [154] 4-amino-2-(butylthio)-8-(2,6-dichlorobenzyl)-5,8-dihydropteridine-6,7-dione;

[155] 4-amino-2-(butylthio)-8-[3-(trifluoromethyl)benzyl]-5,8-dihydropteridine-6,7- dione;

[156] 4-amino-2-(butylthio)-8-(3,5-dimethoxybenzyl)-5,8-dihydropteridine-6,7- dione; [157] 4-amino-2-(butylthio)-8-(4-fluoro-3-nitrobenzyl)-5 ,8-dihydropteridine-6,7- dione;

[158] 4-amino-2-(butylthio)-8-(4-methylbenzyl)-5,8-dihydropteridine-6,7-dione;

[159] 4-amino-2-(butylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione;

[160] 4-amino-2-(butylthio)-5,8-bis(3-chloro-2,6-difluorobenzyl)-5,8- dihydropteridine-6,7-dione;

[161] 4-amino-2-(butylthio)-5,8-bis(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione;

[162] 4-amino-8-butyl-2-(butylthio)-5,8-dihydropteridine-6,7-dione;

[163] 8-(3,4-dichlorobenzyl)-4-(dimethylamino)-2-(methylthio)-5,8- dihydropteridine-6,7-dione; [164] ethyl 4-{[4-amino-2-(butylthio)-6,7-dioxo-6,7-dihydropteridin-8(5H)- yl]methyl}benzoate;

[165] 2-butoxy-8-(3,4-dichlorobenzyl)-4-methyl-5,8-dihydropteridine-6,7-dione;

[166] 2-(butylthio)-8-(3,4-dichlorobenzyl)-4-(dimethylamino)-5,8-dihydropteridine- 6,7-dione; [167] 2-(butylthio)-4-(dimethylamino)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7- dione;

[168] 2-(butylthio)-4-(dimethylamino)-8-(pyridin-3-ylmethyl)-5,8-dihydropteridine- 6,7-dione;

[169] 2-(butylthio)-4-(dimethylamino)-8-(pyridin-4-ylmethyl)-5,8-dihydropteridine- 6,7-dione;

[170] 2-(butylthio)-4-(dimethylamino)-8-[(5-methylisoxazol-3-yl)methyl]-5,8- dihydropteridine-6,7-dione;

[171] (4-{[2-(butylthio)-4-(dimethylamino)-6,7-dioxo-6,7-dihydropteridin-8(5H)- yl]methyl}phenyl)acetic acid;

[172] 2-(butylthio)-8-[(2,6-dichloropyridin-4-yl)methyl]-4-(dimethylamino)-5,8- dihydropteridine-6,7-dione;

[173] 2-(butylthio)-4-(dimethylamino)-5,8-bis[(5-methylisoxazol-3-yl)methyl]-5,8- dihydropteridine-6,7-dione;

[174] ethyl [4-amino-2-(butylthio)-8-(4-fluorobenzyl)-6,7-dioxo-7,8-dihydropteridin- 5 (6H)-yl] acetate;

[175] ethyl [4-amino-2-(cyclopentylthio)-8-(4-fluorobenzyl)-6,7-dioxo-7,8- dihydropteridin-5 (6H)-yl] acetate; [176] 2-(butylthio)-5,8-bis[(2,6-dichloropyridin-4-yl)methyl]-4-(dimethylamino)-

5,8-dihydropteridine-6,7-dione;

[177] [4-amino-2-(butylthio)-8-(4-fluorobenzyl)-6,7-dioxo-7,8-dihydropteridin- 5 (6H)-yl] acetic acid;

[178] 2-(butylthio)-8-(4-fluorobenzyl)-4-[(2-moφholin-4-ylethyl)amino]-5,8- dihydropteridine-6,7-dione;

[179] 2-(butylthio)-4-{[2-(diethylamino)ethyl]amino}-8-(4-fluorobenzyl)-5,8- dihydropteridine-6,7-dione;

[180] 2-(butylthio)-8-(4-fluorobenzyl)-4-(3-hydroxyazetidin-l-yl)-5,8- dihydropteridine-6,7-dione; [181] N-[2-(butylthio)-8-(4-fluorobenzyl)-6,7-dioxo-5,6,7,8-tetrahydropteridin-4-yl]-

7V-methylglycine;

[182] l-[[2-(butylthio)-8-(4-fluorobenzyl)-6,7-dioxo-5,6,7,8-tetrahydropteridin-4- yl](methyl)amino]- 1 -deoxy-L-glucitol;

[183] 2-(butylthio)-8-(4-fluorobenzyl)-4-(methylamino)-5,8-dihydropteridine-6,7- dione;

[184] 2-(butylthio)-8-(4-fluorobenzyl)-4-(4-methylpiperazin-l-yl)-5,8- dihydropteridine-6,7-dione;

[185] 4-amino-2-(butylsulfonyl)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione;

[186] N-[2-(butylthio)-8-(4-fluorobenzyl)-6,7-dioxo-5,6,7,8-tetrahydropteridin-4- yljmethanesulfonamide;

[187] N-[2-(butylthio)-8-(4-fluorobenzyl)-6,7-dioxo-5,6,7,8-tetrahydropteridin-4-yl]- 7V-methylmethanesulfonamide;

[188] 4-bromo-2-(butylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione; [189] 4-{[4-amino-2-(butylthio)-6,7-dioxo-6,7-dihydropteridin-8(5H)- yl]methyl}benzoic acid;

[190] 4-amino-8-benzyl-2-(butylthio)-5,8-dihydropteridine-6,7-dione;

[191] 4-amino-2-(butylthio)-8-(2,6-difluorobenzyl)-5,8-dihydropteridine-6,7-dione; [192] 4-amino-2-(butylthio)-8-(2,6-difluoro-3-methylbenzyl)-5,8-dihydropteridine-

6,7-dione;

[193] 4-{[4-amino-2-(butylthio)-6,7-dioxo-6,7-dihydropteridin-8(5H)- yl]methyl}benzonitrile;

[194] 4-amino-2-(butylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione; [195] 2-{[4-amino-2-(butylthio)-6,7-dioxo-6,7-dihydropteridin-8(5H)- yl]methyl}benzonitrile;

[196] 3-{[4-amino-2-(butylthio)-6,7-dioxo-6,7-dihydropteridin-8(5H)- yl]methyl}benzonitrile;

[197] 4-amino-2-(butylthio)-8-(3-chloro-2,6-difluorobenzyl)-5,8-dihydropteridine- 6,7-dione;

[198] 4-amino-8-(4-fluorobenzyl)-2-[(2-phenylethyl)thio]-5,8-dihydropteridine-6,7- dione;

[199] 4-amino-8-benzyl-2-[(2-phenylethyl)thio]-5,8-dihydropteridine-6,7-dione;

[200] 4-amino-2-(benzylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione; [201] 4-amino-8-benzyl-2-(benzylthio)-5,8-dihydropteridine-6,7-dione;

[202] 4-amino-2-(cyclopentylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7- dione;

[203] 4-amino-8-benzyl-2-(cyclopentylthio)-5,8-dihydropteridine-6,7-dione;

[204] 2-butoxy-8-(3,4-dichlorobenzyl)-4-moφholin-4-yl-5,8-dihydropteridine-6,7- dione;

[205] 2-butoxy-8-(4-fluorobenzyl)-4-moφholin-4-yl-5,8-dihydropteridine-6,7-dione;

[206] 8-benzyl-2-(benzylamino)-5,8-dihydropteridine-6,7-dione;

[207]

[208] 4-amino-8-benzyl-2-(butylthio)-6-moφholin-4-ylpteridin-7(8H)-one; [209] 4-amino-8-benzyl-2-(butylthio)-6- {[2-(diethylamino)ethyl] amino }pteridin-

7(8H)-one; or

[210] 4-amino-8-benzyl-2-(butylthio)-6-(dimethylamino)pteridin-7(8H)-one

[211] in free or salt form. [212] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in association with a pharmaceutically-acceptable diluent or carrier. [213] The composition may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.

[214] In general the above compositions may be prepared in a conventional manner using conventional excipients.

[215] The compound of formula (I) will normally be administered to a warm-blooded animal at a unit dose within the range 1-1000 mg/kg, and this normally provides a therapeutically-effective dose. Preferably a daily dose in the range of 10-100 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.

[216] According to a further aspect of the present invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.

[217] We have found that the compounds defined in the present invention, or a pharmaceutically acceptable salt thereof, are effective anti-bacterial agents which property is believed to arise from their Murl inhibitory properties. Accordingly the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions resulting in whole or in part from infection by bacteria expressing Murl, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections or, for example, E.faecalis or S. aureus infection.

[218] Accordingly, one aspect of the invention provides a method of treatment or prophylaxis of bacterial infection, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections for example, E.faecalis or S. aureus infection, e.g treatment or prophylaxis of antibiotic resistant infection, or in treatment of pneumonia, septicemia, puerperal sepsis, endocarditis, toxic shock, osteomyelitis, enterocolitis, bacterial meningitis, or post-operative infection, in a patient in need of such treatment or prophylaxis, comprising administering to the patient an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[219] Thus according to this aspect of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use as a medicament.

[220] According to a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of a compound having a bacterial Murl inhibitory effect, e.g., a E.faecalis or S.aureus Murl inhibitory effect in a warm-blooded animal such as man.

[221] According to this aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment or prophylaxis of bacterial infection, e.g., infection by Murl expressing bacteria, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections, for example, E.faecalis or S.aureus infection; for example in the treatment of pneumonia, septicemia, puerperal sepsis, endocarditis, toxic shock, osteomyelitis, enterocolitis, bacterial meningitis, or post-operative infection; for example in the treatment or prophylaxis of antibiotic resistant infection; in a warm-blooded animal, e.g., man.

[222] According to a further feature of the invention, there is provided the use of a compound of the formula (I), in free or salt form, as defined herein before in the manufacture of a medicament for use in the treatment or prophylaxis of bacterial infection, e.g., infection by Murl expressing bacteria, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections, for example, E.faecalis or S.aureus infection; for example in the treatment of pneumonia, septicemia, puerperal sepsis, endocarditis, toxic shock, osteomyelitis, enterocolitis, bacterial meningitis, or post-operative infection; for example in the treatment or prophylaxis of antibiotic resistant infection; in a warm-blooded animal, e.g., man. [223] According to a further feature of this aspect of the invention there is provided a method for producing a bacterial Murl inhibitory effect, e.g., a E.faecalis or S.aureus inhibitory effect, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.

[224] According to a further feature of this aspect of the invention there is provided a method for producing an antibacterial effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above. [225] According to a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the production of a bacterial Murl inhibitory effect in a warm-blooded animal such as man. [226] According to another aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the production of an antibacterial effect in a warm-blooded animal such as man.

[227] According to a further feature of the invention, there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before for use in the treatment or prophylaxis of bacterial infection, e.g., infection by Murl expressing bacteria, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections, for example, E.faecalis or S.aureus infection; for example in the treatment of pneumonia, septicemia, puerperal sepsis, endocarditis, toxic shock, osteomyelitis, enterocolitis, bacterial meningitis, or post-operative infection; for example in the treatment or prophylaxis of antibiotic resistant infection; in a warm-blooded animal, e.g., man.

[228] In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a Murl inhibitory effect, e.g., a E.faecalis or S.aureus Murl inhibitory effect in a warm-blooded animal such as man.

[229] In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of an antibacterial effect in a warm-blooded animal such as man. [230] In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment or prophylaxis of bacterial infection, e.g., infection by Murl expressing bacteria, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections, for example, E.faecalis or S. aureus infection; for example in the treatment of pneumonia, septicemia, puerperal sepsis, endocarditis, toxic shock, osteomyelitis, enterocolitis, bacterial meningitis, or post-operative infection; for example in the treatment or prophylaxis of antibiotic resistant infection; in a warm-blooded animal, e.g., man.

[231] The treatment methods include administering the compounds of the present invention, in free or salt form, together with other antibacterial or therapeutic compounds. Such conjoint treatment may be advantageous because, for example, the bacterial attack may involve organisms better treated by such conjoint treatment. Other advantageous conjoint treatment may arise from a need to treat, for example, bacterial attack together with a need to treat a parallel infection or disease such as diabetes.

[232] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[233] In addition to their use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of Murl in bacteria, e.g., E.faecalis or S. aureus Murl, in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

[234] In the above other pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and preferred embodiments of the compounds of the invention described herein also apply. Examples

[235] The invention will now be illustrated by the following non limiting examples in which, unless stated otherwise: (i) temperatures are given in degrees Celsius (⁰C); operations are carried out at room or ambient temperature ("rt") are at a temperature in the range of 18-25°C; (ii) organic solutions are dried over anhydrous sodium sulphate; evaporation of solvent is carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperature of up to 60 ⁰C;

(iii) in general, the course of reactions is followed by TLC and reaction times are given for illustration only;

(iv) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral data; (v) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations are repeated if more material is required; (vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 400 MHz using perdeuterio dimethyl sulphoxide (DMSOd₆) as solvent unless otherwise indicated;

(vii) chemical symbols have their usual meanings; SI units and symbols are used; (viii) solvent ratios are given in volume:volume (v/v) terms; and (ix) mass spectra are run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization is effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported; and unless otherwise stated, the mass ion quoted is (MH)⁺;

(x) where a synthesis is described as being analogous to that described in a previous example the amounts used are the millimolar ratio equivalents to those used in the previous example; (xi) the following abbreviations have been used:

HATU O-(7-Azabenzotriazol- 1 -yl)-7V,7V,N',N'-tetramethyluronium hexafluorophosphate; THF tetrahydrofuran;

DMF Λ^N-dimethylformamide; EtOAc ethyl acetate;

DIEA N, N-diisopropylethylamine;

DCM dichloromethane;

DMSO dimethylsulphoxide; MeCN acetonitrile;

NBS 7V-bromosuccinimide; and

MeOH methanol; rt room temperature (xii) "ISCO" refers to normal phase flash column chromatography using 12 g and 40 g prepacked silica gel cartridges used according to the manufacturers instruction obtained from ISCO, Inc, 4700 superior street Lincoln, NE, USA.; and

(xiii) "Gilson HPLC" refers to a YMC-AQC 18 reverse phase HPLC Column with dimension 20 mm/ 100 and 50 mm/250 in water/MeCN with 0.1% TFA as mobile phase, obtained (xiv) Parr Hydrogenator or Parr shaker type hydrogenators are systems for treating chemicals with hydrogen in the presence of a catalyst at pressures up to 5 atmospheres (60 psig) and temperatures to 80 ⁰C.

Preparation of Starting Materials Core l

Intermediate 001: 4.6-diaminopyrimidine-2-thiol

[236] Commercially available.

5 Intermediate 002: 2-(butylthio)pyrimidine-4.,6-diamine

[237] To a suspension of commercially available 4,6-diaminopyrimidine-2-thiol (5g, 35mmol) in methanol (7OmL) is added IN sodium hydroxide (35mL). The resulting solution is stirred for Ih at rt then evaporated to give a tan solid. The tan solid and 1-bromobutane (4.ImL, 38.5mmol) are combined in DMF (5OmL) and stirred at rt overnight. The DMF is 10 evaporated to yield a brown oil, 6.9g. MS (ESP): 199 (MH⁺) for C₈Hi₄N₄S

[238] Prepared in an analogous manner using the appropriate alkylating agent are the intermediates shown in the table below

Intermediate 006: 2-(butylthio)-5-nitrosopyrimidine-4.,6-diamine

15 [239] A solution of 2-(butylthio)pyrimidine-4,6-diamine (Intermediate 002, 6.9g,

35mmol) in acetic acid (138mL) and water (3OmL) is cooled to 0°C and treated dropwise, over 20min, with sodium nitrite (4.4g, 63mmol) in water (3OmL). The reaction mixture turned dark brown and a bright pink solid formed. After 30min the pink solid is collected by filtration and washed with cold water (40OmL) to yield a bright blue solid, 6.8g. MS (ESP):

20 228 (MH⁺) for C₈Hi₃N₅OS

[240] Prepared in an analogous fashion are the intermediates in the table below:

Intermediate Oil: 2-(butylthio)pyrimidine-4.,5.,6-triamine

[241] A suspension of 2-(butylthio)-5-nitrosopyrimidine-4,6-diamine (Intermediate 006, 6.8g, 30mmol) in ethanol (10OmL) is flushed with N₂ and platinum(IV) oxide (0.34g, 1.5mmol) is added. The reaction is stirred under a H₂ balloon at rt overnight. The reaction mixture is filtered through celite and evaporated to yield a green solid, 6.5g. MS (ESP): 214

[242] Intermediates in the table below are prepared by an analogous manner:

Intermediate 016: 4-amino-2-(butylthio)-5.,8-dihvdropteridine-6.,7-dione

[243] To a solution of 2-(butylthio)pyrimidine-4,5,6-triamine (Intermediate 011,

11.3g, 53mmol) in NMP at 0°C is added dropwise ethyl oxalyl chloride (6.5mL, 58mmol). The reaction mixture is stirred at rt and monitored by LC/MS for formation of the acylated intermediate. Once the intermediate formed the reaction is heated at 120°C overnight. The reaction mixture is cooled to rt and poured into water (-300 mL). The light tan precipitate is collected by filtration and washed with water four times to yield 9.9g. MS (ESP): 268 (MH⁺)

[244] Intermediates in the table below are prepared by an analogous manner

Core 2

12

Intermediate 022 (6 in rxn above): 6-amino-2-mercaptopyrimidin-4-ol [245] Commercially available.

Intermediate 023 (7): 6-amino-2-(butylthio)pyrimidin-4-ol

[246] Commercially available 6-amino-2-mercaptopyrimidin-4-ol (1Og, 70mmol), 1- bromobutane (6.7mL, 63mmol) and potassium hydroxide (4g, 72mmol) are combined in DMF (10OmL) and water (3OmL) and stirred for Ih at rt. The reaction mixture is poured into water (30OmL) resulting in a white precipitate, 9.9g. MS (ESP): 200 (MH⁺) for C₈Hi₃N₃OS Intermediate 024 (8): 6-amino-2-(butylthio)pyrimidin-4-yl trifluoromethanesulfonate

[247] 6-amino-2-(butylthio)pyrimidin-4-ol (Intermediate 023, 2g, lOmmol) is dissolved in pyridine (15mL) and cooled to 0°C. Trifluoromethanesulfonic anhydride is added rapidly and the solution turned bright pink. After lOmin the reaction mixture is poured into water and extracted with dichloromethane. The organic extracts are dried over magnesium sulfate and evaporated to afford an orange oil, 3.3g crude. MS (ESP): 332 (MH⁺)

Intermediate 025 (9): 2-(butylthio)-A^fJV-dimethylpyrimidine-4.,6-diamine [248] To 2M dimethylamine in methanol (2OmL) is added 6-amino-2-

(butylthio)pyrimidin-4-yl trifluoromethanesulfonate (Intermediate 024, 3.3g, lOmmol). The reaction mixture is heated at 60°C for 90min. The excess solvent is evaporated. Silica gel chromatography (dichloromethane/methanol) afforded desired product, 2g. MS (ESP): 227

Intermediate 026 QO): 2-(butylthio)-A^fJV-dimethyl-5-nitrosopyrimidine-4.,6-diamine

[249] A solution of 2-(butylthio)-N,7V-dimethylpyrimidine-4,6-diamine (Intermediate 025, 3.9g, 17mmol) in acetic acid (8OmL) and water (2OmL) is cooled to 0°C and treated dropwise with sodium nitrite (2. Ig, 3 lmmol) in water (2OmL). The reaction mixture turned black and a blue solid formed. After 30min the blue solid is collected by filtration and washed with cold water to yield a blue solid, 2. Ig. MS (ESP): 256 (MH⁺) for

Intermediate 027 (11): 2-(butylthio)-A^JV⁴-dimethylpyrimidine-4.5.6-triamine [250] To a suspension of 2-(butylthio)-N,7V-dimethyl-5-nitrosopyrimidine-4, 6- diamine (Intermediate 026, 6.6g, 26mmol) in ethanol (10OmL) is added acetic acid (2OmL) and zinc dust (3.4g, 52mmol). The reaction mixture is heated at 70°C for 30min, cooled to rt, filtered through celite and concentrated. The resulting oil is dissolved in dichloromethane and washed twice with water. Silica gel chromatography afforded a yellow solid, 3.3g. MS (ESP): 242 (MH⁺) for Ci₀Hi₉N₅S

Intermediate 028 (12): 2-(butylthio)-4-(dimethylamino)-5.,8-dihvdropteridine-6.,7-dione

[251] To a solution of 2-(butylthio)-Λ^/4,Λ^/4-dimethylpyrimidine-4,5,6-triamine (Intermediate 027, 3.3g, 13.6mmol) in NMP at 0°C is added dropwise ethyl oxalyl chloride (1.6mL, 15 mmol). The reaction mixture is stirred at rt and monitored by LC/MS for formation of the acylated intermediate. Once the intermediate formed the reaction is heated at 120°C for 48h. The reaction mixture is cooled to rt and poured into water. The light brown precipitate is collected by filtration and washed with water to yield 2.6g. MS (ESP): 296

Intermediate 029: 4-(2,6-dichloropyrimidin-4-yl)morpholine

[252] A solution of 2,4,6- trichloro pyrimidine (3.66g, 20mmol) in dichloromethane (75mL) is cooled to -78⁰C. A mixture morpholine (1.7mL, 20mmol) and di- isopropylethylamine (0.6mL, 22mmol) is added dropwise. The reaction is allowed to warm to rt and stir overnight. The reaction mixture is partitioned between dichloromethane and water. The organic phase is dried over MgSO₄ and evaporated to obtain a white solid. (3.25g, 70%) MS (ESP): 234 (MH⁺) for C₈H₉Cl₂N₃O

Intermediate 030: 4-(2-butoxy-6-chloropyrimidin-4-yl)morpholine

_[253_] To a suspension of NaH (60% in oil, 0.834g, 20.8 mmol) in DMF (2OmL) at O⁰C is added n-butanol (1.33mL, 14.6mmol). A solution of 4-(2,6-dichloropyrimidin-4- yl)morpholine [Intermediate 029] (3.25g, 13.9mmol) in DMF (2OmL) is added dropwise. The reaction is allowed to stir at O⁰C for 3h. The reaction is allowed to warm to rt. The reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is washed with water (IX 50 mL). The organic layers are combined, washed with water (4 X 40 mL), dried over MgSO₄ and evaporated to obtain a white solid. Chromatography on silica gel using (4 - 10% ethyl acetate/hexane) gave the product as a white solid.(2.0g, 53 %) MS (ESP): 272

Intermediate 031: 2-butoxy-Λ^L(3.4-dichlorobenzylV6-morpholin-4-ylpyrimidin-4-amine

_[254_] A mixture of 4-(2-butoxy-6-chloropyrimidin-4-yl)morpholine (2.Og, 7.35mmol) [Intermediate 030] and 3,4- dichlorobenzylamine (1.96mL, 14.7mmol) is heated at 17O⁰C for 2h using microwave irradiation. The resultant product is dissolved in ethyl acetate and washed with IN hydrochloric acid. The organic extract is dried over MgSO₄ and evaporated to obtain a yellow solid. (2.14g, 70%) MS (ESP): 411 (MH⁺) for Ci₉H₂₄Cl₂N₄O₂

Intermediate 032: 2-butoxy-A^L(4-fluorobenzyl)-6-morpholin-4-ylpyrimidin-4-amine

[255] Prepared in an analogous manner to Intermediate 031 starting with 4-(2- butoxy-6-chloropyrimidin-4-yl)morpholine (Intermediate 030) and reacting with 4- fluorobenzylamine. MS (ESP): 411 (MH⁺) for Ci₉H₂₅FN₄O₂

Intermediate 033: 2-butoxy-7V-(3.,4-dichlorobenzyr)-6-morpholin-4-yl-5- nitrosopyrimidin-4-amine [_256] To a solution of 2-butoxy-7V-(3, 4-dichlorobenzyl)-6-moφholin-4-ylpyrimidin-

4-amine [Intermediate 031] (2.14g, 5.19mmol) in acetic acid (2OmL) and water (2mL) at O⁰C is added dropwise a solution OfNaNO₂ (0.65g, 9.34mmol). The reaction turns a dark red color. The reaction is allowed to stir in ice for Ih, dileted with water and filtered. The blue solid is dried under vacuum at 45⁰C overnight. (1.76g, 75%) MS (ESP): 440 (MH⁺) for

Intermediate 034: 2-butoxy-Λ^Lf4-fluorobenzyl)-6-morpholin-4-yl-5-nitrosopyrimidin-4- amine

[257] Prepared in an analogous manner to Intermediate 033 starting with 2-butoxy- 7V-(4-fluorobenzyl)-6-moφholin-4-ylpyrimidin-4-amine (Intermediate 032). MS (ESP): 391

Intermediate 035: 2-butoxy-A^-(3,4-dichlorobenzyl)-6-morpholin-4-ylpyrimidine-4.,5- diamine [258] A suspension of 2-butoxy-7V-(3,4-dichlorobenzyl)-6-moφholin-4-yl-5- nitrosopyrimidin-4-amine [Intermediate 033] (1.76g, 4.01mmol) in ethanol (35mL) and acetic acid (ImL) is heated to reflux. Zinc dust (1.6g, 24.6mmol) is added portionwise at a rate to maintain reflux. Once the addition is complete the reaction is heated at reflux for Ih. The reaction is allowed to cool slightly, then is filtered through a pad of Celite. The filtrate is evaporated. The crude product is carried on to the subsequent step. MS (ESP): 426 (MH⁺)

Intermediate 036: 2-butoxy-A^f4-(4-fluorobenzyl)-6-morpholin-4-ylpyrimidine-4.,5- diamine [259] Prepared in an analogous manner to Intermediate 035 starting with 2-butoxy-

7V-(4-fluorobenzyl)-6-moφholin-4-yl-5-nitrosopyrimidin-4-amine (Intermediate 034). MS

(ESP): 376 (MH+) for C19H26FN5O2 Intermediate 037: 7V2JV4-dibenzylpyrimidine-2.4.5-triamine

[260] To a suspension ofN,Λ^-dibenzyl-5-nitropyrimidine-2,4-diamine (5.37g, 16.04mmol) [Intermediate 038] in ethanol (75mL) is added glacial acetic acid (5mL). The mixture is heated to 75oC. Zinc dust (6.6g, lOlmmol) is added in portions. The reaction is heated to reflux for 2h. The reaction is cooled, filtered through Celite and evaporated. The crude material is carried on without further purification. MS (ESP): 306 (MH+) for C18H19N5

Intermediate 038: 7VJV'-dibenzyl-5-nitropyrimidine-2.,4-diamine [261] To an suspension of 2,4-dichloro-5-nitropyrimidine (5.Og, 25.77mmol) in diethyl ether (3OmL) is added dropwise a solution of benzyl amine (5.65g, 52.83mmol) in diethyl ether (33mL). A violent reaction occurs with the addition of the first drop. The reaction is cooled in ice bath and the addition is continued keeping the temperature below 2O⁰C. The reaction is allowed to warm to rt and stir for 4h. The precipitate is filtered and washed well with diethyl ether and ethyl acetate to give the product as a white solid. (5.4g, 79%). MS (ESP): 336 (MH⁺) for Ci₈Hi₇N₅O₂

Intermediate 039: Λ^fJV-dimethyl-2-fmethylthio)pyrimidine-4.,6-diamine

[262] 6-chloro-2-(methylthio)pyrimidin-4-amine (3.98g, 22.7mmol) is added to a solution of dimethylamine (2.0M in methanol, 2OmL). The mixture is heated to 8O⁰C for 18h. The reaction is allowed to cool, the precipitate is collected, washed with ethanol, (3.1g, 73%)

Intermediate 040: 4-amino-8-benzyl-6-bromo-2-(butylthio)pteridin-7(8H)-one

[263] To a suspension of 4-amino-8-benzyl-2-(butylthio)pteridin-7(8H)-one (0.5g, 1.46mmol) Intermediate 041 in acetonitrile (2OmL) is added bromine (1.2mL, 3.74g,

46.8mmol). The reaction is allowed to stir for Ih at rt. Evaporation of the solvent at reduced pressure gave an orange solid. Drying under vacuum gave the product (0.5g, 81%). MS (ESP): 420 (MH⁺) for Ci₇Hi₈BrN₅OS

Intermediate 041 : 4-amino-8-benzyl-2-(butylthio)pteridin-7(8H)-one

[264] A solution of 4-amino-2-(butylthio)pteridin-7(8H)-one (0.514 g, 2.03 mmol) [Intermediate 042] in DMF (3mL) is treated with triethyl amine (1.ImL, 8mmol) and benzyl bromide (0.376g, 2.2mmol). The reaction is allowed to stir at rt overnight. A further portion of benzyl bromide (O.lg, 0.58mmol) and triethyl amine (0.3mL, 2.2mmol) is added. The reaction is allowed to stir for 5h. Dilution with water (2OmL) afforded a precipitate. Filtration gave a solid that is recrystallized from ethanol to give the title compound. (0.54g, 51%). MS (ESP): 342 (MH⁺) for Ci₇Hi₉N₅OS

Intermediate 042; 4-amino-2-(butylthio)pteridin-7(8H)-one

[265] To a solution of ethyl (diethoxyphosphoryl)acetate (13.12g, 58.6mmol) in TΗF (6OmL) at O⁰C is added n-butyl lithium (1.6M in hexanes, 36.6mL, 58.6mmol). The mixture is allowed to stir for 30min at O⁰C. A solution of 2-(butylthio)-5-nitrosopyrimidine-4,6- diamine (5.76g, 25.3mmol) [Intermediate 006] in DMF (6OmL) is added. The reaction is allowed to warm to rt and stir for Ih. The reaction is then heated to reflux for 4h. Upon cooling to rt, acetic acid is added (6 mL). The solvents are evaporated at reduced pressure. Ethyl acetate is added to the greenish residue. The product is collected by filtration. MS (ESP): 252 (MH⁺) for Ci₀Hi₃N₅OS

Intermediate 043 : 2-butoxy-4-methyl-5.,8-dihvdropteridine-6.,7-dione

[266] To a suspension of sodium hydride (60% in oil, 0.4g, 5.0mmol) in butanol (5mL) is added 2-chloro-4-methyl-5,8-dihydropteridine-6,7-dione (0.398g, 1.88mmol). The reaction mixture is heated to 100⁰C in a sealed tube. After 24 h, sodium hydroxide is added (4 pellets) and the reaction is heated at 100⁰C for a further 14d. The reaction mixture is evaporated at reduced pressure to obtain a crude product. MS (ESP): 252 (MH⁺) for

EXAMPLES Table 1 Experimental EXAMPLE 1

[267] 4-amino-2-(butylthio)-5,8-dihydropteridine-6,7-dione (Intermediate 016,

0.2g, 0.75mmol), 3-chlorobenzyl bromide (0.1 L, 0.75mmol) and 7V,7V-diisopropylethylamine (0.13mL, 0.75mmol) are combined in DMF (2mL) and stirred at rt overnight. Water is added to the reaction mixture and the resulting precipitate collected by filtration. The solid is recrystallized from DMSO and triturated with water to afford the desired compound.

[268] The remaining compounds in Table 1 below are prepared according to the above procedure using the appropriate benzyl bromide.

SM = Synthetic Mode (as utilized in cited EXAMPLE).

1. Purified by suspending in methanol, filtering, drying.

2. Purified by recrystallization from acetone/methanol. EXAMPLE 17

2-(butylthio)-4-(dimethylamino)-5,8-dihydropteridine-6,7-dione (Intermediate 028, 0.17g, 0.57mmol), 3,4-dichlorobenzyl bromide (0.09mL, 0.57mmol) and 7V,7V-diisopropylethylamine (O.lmL, 0.57 mmol) are combined in DMF (2 mL) and stirred at rt overnight. Water is added to the reaction mixture and the resulting precipitate is collected by filtration. The solid is purified by silica gel chromatography to afford desired compound.

[269] The remaining compounds in Table 2 below are prepared according to the above procedure using the appropriate benzyl bromide.

1. Desired product separated from dialkylated compound by silica gel chromatography

EXAMPLE 19

[270] 2-(butylthio)-4-(dimethylamino)-5,8-dihydropteridine-6,7-dione (Intermediate 028, O.lg, 0.34mmol), 3-(bromomethyl)pyridine (0.09g, 0.34mmol) and N,N- diisopropylethylamine (0.12mL, 0.68mmol) are combined in DMF (2mL) and stirred at rt for 2h. The reaction mixture is diluted with dichloromethane and washed with water. Silica gel chromatography afforded the desired compound.

[271] The remaining compounds in Table 3 below are prepared according to the above procedure using the appropriate bromomethyl heterocycle.

1. Desired product separated from dialkylated compound by silica gel chromatography, no trituration with methanol. EXAMPLE 24 : 2-(butylthio)-4-(dimethylamino)-5,8-bis [(5-methylisoxazol-3-yDmethyll - 5,8-dihydropteridine-6.,7-dione

[272] 2-(butylthio)-4-(dimethylamino)-5,8-dihydropteridine-6,7-dione (Intermediate 028, O.lg, 0.34mmol), 3-(bromomethyl)-5-methylisoxazole (0.06g, 0.34mmol) and 7V,7V-diisopropylethylamine (0.12mL, 0.68mmol) are combined in DMF (2mL) and stirred at rt overnight. The reaction mixture is diluted with dichloromethane and washed with water. Silica gel chromatography and recrystallization from methanol afforded the dialkylated product. MS (ESP): 486 (MH⁺) for C₂₂H₂₇N₇O₄S ¹H-NMR (CDCl_rd) δ: 0.90 (t, 3H); 1.42 (m, 2H); 1.66 (m, 2H); 2.34 (s, 3H); 2.40 (s, 3H); 3.06 (t, 2H); 3.42 (s, 6H); 5.40 (s, 2H); 5.58 (s, 2H); 5.93 (s, IH); 6.14 (s, IH). EXAMPLE 25: ethyl [4-amino-2-fbutylthioV8-f4-fluorobenzylV6.7-dioxo-7.8- dihvdropteridin-5f 6HVvIl acetate

[273] 4-amino-2-(butylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione

[EXAMPLE 10] (0.2g, 0.53mmol), ethyl bromoacetate (0.23mL, 2.1mmol) and cesium carbonate (0.34g, l.lmmol) are combined in DMF (5mL) and heated at 50°C overnight. The reaction mixture is cooled and poured into water. The resulting precipitate is triturated with hot methanol then purified by silica gel chromatography. MS (ESP): 462 (MH⁺) for C₂IH₂₄FN₅O₄S ¹H-NMR (DMSO-d6) δ: 0.78 (t, 3H); 1.19 (t, 3H); 1.27 (m, 2H); 1.51 (m, 2H); 2.97 (t, 2H); 4.15 (m, 2H); 5.16 (s, 2H); 5.37 (s, 2H); 7.12 (m, 2H); 7.31 (m, 3H); 7.63 (bs, IH).

EXAMPLE 26: ethyl [4-amino-2-fcvclopentylthioV8-f4-fluorobenzylV6.7-dioxo-7.8- dihvdropteridin-5f 6HVvIl acetate

[274] 4-amino-2-(cyclopentylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7- dione [EXAMPLE 52] (O.lg, 0.26 mmol), ethyl bromoacetate (0.057mL, 0.52mmol) and cesium carbonate (0.17g, 0.52mmol) are combined in DMF (3mL) and heated at 50°C for 2h. The reaction mixture is cooled and poured into water. The resulting precipitate is triturated with hot methanol then heated in dichloromethane and collected by filtration to afford the desired product. MS (ESP): 474 (MH⁺) for C₂₂H₂₄FN₅O₄S ¹H-NMR (DMSO-d6) δ: 1.19 (t, 3H); 1.52 (m, 6H); 2.00 (m, 2H); 3.78 (m, IH); 4.15 (m, 2H); 5.15 (s, 2H); 5.36 (s, 2H); 7.12 (m, 2H); 7.30 (m, 3H); 7.62 (bs, IH). EXAMPLE 27: 2-(butylthioV5.8-bis[(2.6-dichloropyridin-4-vnmethyll-4- fdimethylamino)-5.,8-dihvdropteridine-6.,7-dione

[275] 2-(butylthio)-4-(dimethylamino)-5,8-dihydropteridine-6,7-dione

(Intermediate 28, 0.3g, lmmol), 2,6-dichloro-4-(chloromethyl)pyridine (0.2g, lmmol) and 7V,7V-diisopropylethylamine (0.35mL, 2mmol) are combined in DMF (5mL) and heated at 50°C overnight. The solvent is evaporated and the resulting oil is diluted with dichloromethane and washed with water. Silica gel chromatography afforded a monoalkylated product and the title compound. MS (ESP): 614 (MH⁺) for C₂₄H₂₃Cl₄N₇O₂S ¹H-NMR (CDCl_rd) δ: 0.91 (t, 3H); 1.42 (m, 2H); 1.67 (m, 2H); 3.04 (t, 2H); 3.39 (s, 6H); 5.34 (s, 2H); 5.50 (s, 2H); 7.31 (m, 4H).

EXAMPLE 28 : [4-amino-2-(butylthioy 8-(4-fluorobenzyl)-6 J-dioxo-7,8- dihydropteridin-5(6H)-vH acetic acid

[276] Ethyl [4-amino-2-(butylthio)-8-(4-fluorobenzyl)-6,7-dioxo-7,8- dihydropteridin-5(6H)-yl]acetate (EXAMPLE 25, 0.02g, 0.043mmol) is suspended in THF (2mL) and 2M lithium hydroxide (5mL) and stirred at rt for Ih. The THF is evaporated and IN hydrochloric acid is added. The resulting precipitate is collected by filtration. MS (ESP): 434 (MH⁺) for Ci₉H₂₀FN₅O₄S ¹H-NMR (DMSO-d6) δ: 0.78 (t, 3H); 1.26 (m, 2H); 1.51 (m, 2H); 2.97 (t, 2H); 4.52 (s, 2H); 5.37 (s, 2H); 6.84 (bs, IH); 7.11 (m, 2H); 7.31 (m, 2H); 7.55 (bs, IH). EXAMPLE 29 : 2-( butylthio V 8-( 4-fluorobenzylV4- [(2-morpholin-4-ylethvnaminol -5.8- dihvdropteridine-6.7-dione

[277] In a microwave vial is charged with Intermediate 044: 4-bromo-2- (butylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione (54mg, 0.123mmol) and 4-(2- aminoethyl)morpholine (48mg, 0.36mmol) in methanol (3mL). The reaction is heated in microwave at HO⁰C for Ih. The reaction mixture is cooled and evaporated. The desired product is obtained by preparative TLC chromatography (methanol/dichloromethane). Solid, 13mg, 22% yield. MS (ESP): 489(MH⁺) for C₂₃H₂₉ FN₆O₃S ¹H NMR (DMSO-Dn) δ: 0.75(t, 3H); 1.35(m, 2H); 1.60(m, 2H); 2.40(m, 6H), 3.00 (m, 2H); 3.50 (m, 8H); 5.10 (s, 2H); 6.70(m, 3H); 7.10(m, 2H)

[278] The compounds in Table 4 below are prepared in an analogous fashion starting from Intermediate 044: 4-bromo-2-(butylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7- dione using the appropriate amine.

1 Purified by reverse phase chromatography

EXAMPLE 35: 4-amino-2-(butylsulfonyl)-8-(4-fluorobenzyl)-5,8-dihvdropteridine-6J- dione

[279] In a capped pressure tube is charged with 4-amino-2- (butylthio)-8-(4- fluorobenzyl)-5,8-dihydropteridine-6,7-dione (50mg, 0.13mmol) and m-CPBA (0.78mmol) in DMF(ImL). The reaction is heated to 5O⁰C for 12h. The desired product is obtained after aqueous work-up (ethyl acetate/brine) and recrystallization from methanol. White solid, 20mg, 36% yield. MS (ESP): 408(MH⁺) for Ci₇Hi₈ FN₅O₄S ¹H NMR (DMSO-Dn) δ: 0.81(t, 3H); 1.29(m, 2H); 1.48(m, 2H); 3.35(m, 6H), 5.35(s, 2H); 7.16 (t, 2H); 7.48 (dd, 2H); 7.80(s, br, 2H); 11.77(s, IH)

EXAMPLE 36: AM2-(butylthio)-8-(4-fluorobenzyl)-6J-dioxo-5,6J,8- 5 tetrahvdropteridin-4-yllmethanesulfonamide

[280] To a solution of 4-amino-2-(butylthio)-8-(4-fluorobenzyl)-5,8- dihydropteridine-6,7-dione (lOOmg, 0.26mmo I)[EXAMPLE 10] and pyridine (3mL) at rt is added methane sulfonyl chloride (177mg, 1.56mmol) in one portion, the reaction is stirred for 10 2h at rt and then removed the volatiles with high vacuum. The residue is extracted with dichloromethane from water. After concentration, the product is recrystallized from methanol. Yellow solid, 38mg, 32% yield. MS (ESP): 454(MH⁺) for Ci₈H₂₀ FN₅O₄S₂ ¹H NMR (DMSO₁Dg) δ: 0.85(t, 3H); 1.35(m, 2H); 1.58(m, 2H); 3.07(m, 2H), 3.83(s, 3H); 5.45 (s, 2H); 7.20(t, 2H); 7.77(s, br, 2H); 8.05(s, br, IH)

15

EXAMPLE 37: AM2-(butylthio)-8-(4-fluorobenzyl)-6J-dioxo-5,6J,8- tetrahydropteridin-4-yll-Λ^Lmethylmethanesulfonamide

[281] The titled compound is prepared and in an analogous manner as EXAMPLE 20 31 except using corresponding Intermediate 045: 2-(butylthio)-8-(4-fluorobenzyl)-4- (methylamino)-5,8-dihydropteridine-6,7-dione. The desired product is purified by Gilson HPLC. MS (ESP): 468(MH⁺) for Ci₉H₂₂FN₅O₄S₂ ¹H NMR (DMSO-Dn) δ: 0.81(t, 3H); 1.32(m, 2H); 1.54(m, 2H); 2.94(d, 3H); 3.03(t, 2H), 3.77 (s, 3H); 5.39(s, 2H); 7.14(t, 2H); 7.35(m, 2H); 8.05(q, IH) EXAMPLE 38: (Intermediate 044): 4-bromo-2-(butylthio)-8-(4-fluorobenzyl)-5.8- dihydropteridine-6.,7-dione

[282] To a solution of 4-amino-2- (butylthio)-8-(4-fluorobenzyl)-5,8- dihydropteridine-6,7-dione [EXAMPLE 10] (200mg, 0.533mmol) in a mixture of DMSO (1OmL) and bromoform (1OmL) at 125⁰C is added slowly isoamylnitrite (2mL, 14.8mmol). The resulting brown solution is stirred for 5min and is gradually cooled down to rt and continued stirred for 12h at rt, then evaporated with heating to give a yellow solid. Recrystalization from dichloromethane afforded desired product. Yellow solid, 65mg, 28% yield. MS (ESP): 439(MH⁺) for Ci₇Hi₆ Br FN₄O₂S

EXAMPLE 39: 4-{[4-amino-2-(butylthio)-6J-dioxo-6J-dihvdropteridin-8(5H)- vUmethyllbenzoic acid [283] By hydrolysis of EXAMPLE 15: A solution of ethyl 4-{[4-amino-2-

(butylthio)-6,7-dioxo-6,7-dihydropteridin-8(5H)-yl]methyl}benzoate (0.215g, 0.5mmol) in methanol (3mL) is treated with sodium hydroxide (O.lg, 2.5mmol). The reaction is allowed to stir at rt overnight. The solvent is evaporated at reduced pressure, the residue is diluted with water (ImL) and acidified with HC 1 (2N). The mixture is extracted with ethyl acetate (3 X 5 mL). The organic extracts are dried over MgSO₄ and evaporated to obtain the title compound as an off-white solid. MS (ESP): 402 (MH⁺) for Ci₈Hi₉N₅O₄S

EXAMPLE 40 : 4-amino-8-benzyl-2-(butylthio)-5.,8-dihvdropteridine-6J-dione

[284] To a solution of 4-amino-2-(butylthio)-5,8-dihydropteridine-6,7-dione (0.247g, 0.924mmol) (Intermediate 016) in N-methyl pyrrolidone is added di-isopropyl ethylamine (0.63mL, 3.7mmol) and benzyl bromide (0.158g, 0.924mmol). The reaction is allowed to stir at rt overnight. The reaction mixture is poured into water (2OmL) and filtered. The aqueous filtrate is acidified with HCl (cone.) and filtered to obtain the crude product as an orange-red solid. This solid is suspended in methanol, cooled and filtered to obtain the title compound a pink solid. (0.068g. 21%). MS (ESP): 358 (MH⁺) for Ci₇Hi₉N₅O₂S IH NMR (300 MHz, DMSO-D6) δ ppm 0.75 (t, J=7.3 Hz, 3 H) 1.14 - 1.29 (m, 2 H) 1.45 (t, J=7.2 Hz, 2 H) 2.88 (t, J=7.3 Hz, 2 H) 5.32 (s, 2 H) 7.15 - 7.29 (m, 7 H) 11.45 (s, 1 H)

[285] The compounds in Table 5 below are prepared in an analogous fashion starting from Intermediate 016: 4-amino-2-(butylthio)-5,8-dihydropteridine-6,7-dione using the appropriate amine.

Purified by reverse phase chromatography Suspended in hot methanol a second time. EXAMPLE 54: 2-butoxv-8-G.4-dichlorobenzvn-4-morDholin-4-vl-5.8-dihvdroDteridine-6.7- dioneTo a suspension of 2-butoxy-Λ^/4-(3,4-dichlorobenzyl)-6-moφholin-4-ylpyrimidine-4,5- diamine [Intermediate 035] (approx. 1.7g, 4.0mmol) in n-methyl pyrrolidone (6mL) at O⁰C is added ethyl oxalyl chloride (0.5mL, 4.4mmol). The reaction is allowed to warm to rt for 20min and then heated at 12O⁰C overnight. The reaction is diluted with water and extracted with ethyl acetate. The organic extract is washed with water (4 times), dried over MgSO₄ and evaporated. Purification by reverse phase chromatography [50-80% acetonitrile/water/0.1% TFA] gave the product as a solid (0.037g). IH NMR (300 MHz, DMSO-D6) δ ppm 0.85 (t, J=6.9 Hz, 3 H) 1.22 - 1.37 (m, 2 H) 1.48 - 1.63 (m, 2 H) 3.69 - 3.75 (m, 3 H) 3.84 - 4.00 (m, 7 H) 4.11 - 4.18 (m, 2 H) 5.29 (s, 2 H) 7.24 - 7.39 (m, 1 H) 7.55 (d, J=7.9 Hz, 1 H) 7.64 (s, 1 H) MS (ESP): 480 (MH⁺) for C₂IH₂₃Cl₂N₅O₄

EXAMPLE 55 : 2-butoxy-8-(4-fluorobenzyl)-4-morpholin-4-yl-5,8-dihvdropteridine-6.,7- dione [286] Prepared in an analogous manner to EXAMPLE 54 using starting material

Intermediate 036. Product isolated by trituration. IH NMR (300 MHz, DMSO-D6) δ ppm 0.87 (t, J=7.3 Hz, 3 H) 1.26 - 1.40 (m, 2 H) 1.53 - 1.66 (m, 2 H) 3.71 (s, 5 H) 4.18 (t, J=6.7 Hz, 2 H) 5.30 (s, 2 H) 7.11 (t, J=8.9 Hz, 2 H) 7.38 (dd, J=8.2, 5.7 Hz, 2 H). MS (ESP): 430

EXAMPLE 56: 8-benzyl-2-(benzylamino)-5.,8-dihvdropteridine-6.,7-dione

[287] Prepared in a manner analogous to EXAMPLE 54 using starting material Intermediate 037. The product is isolated by dilution the reaction mixture with water and filtration of the precipitate. Heating in methanol followed by cooling and filtration glveS material with improved purity. Purification by reverse phase chromatography [30-50% acetonitrile/water/0.1 % TF A} gave the title compound as a yellow solid (TFA salt). MS (ESP): 360 (MH⁺) for C₂₀Hi₇N₅O₂ IH NMR (300 MHz, DMSO-D6) δ ppm 4.42 (s, 2 H) 5.24 (s, 2 H) 7.22 (s, 10 H) 7.78 (s, 1 H) 8.04 (s, 1 H) 11.86 (s, 1 H)

[288] EXAMPLE 57: 4-amino-8-benzyl-2-(butylthioV6-morpholin-4-ylpteridin-7(8HVone

[289] To a solution of 4-amino-8-benzyl-6-bromo-2-(butylthio)pteridin-7(8H)-one (O.lg, 0.238mmol) [intermediate 040] in n-methyl pyrrolidone (2mL) is added di-isopropyl ethylamine (0.34mL, 1.95mmol) and morpholine (0.2 mL, 0.2 g, 2.3 mmol). The reaction is heated to 100⁰C for 2h. The reaction mixture is evaporated at reduced pressure. The residue is taken up in ethyl acetate and treated with hexane. The precipitate is filtered off, recrystallized from ethanol to give the title compound. MS (ESP): 427 (MH⁺) for C₂IH₂₆N₆O₂S. IH NMR (300 MHz, DMSO-D6) δ ppm 0.77 (s, 3 H) 1.27 (s, 2 H) 1.50 (s, 2 H) 2.95 (s, 2 H) 3.68 (s, 4 H) 3.80 (s, 4 H) 5.38 (s, 2 H) 7.24 (s, 7 H)

EXAMPLE 58 : 4-amino-8-benzyl-2-(butylthio)-6- [(2-hvdr oxyethvDaminol pteridin-

7(8H)-one

[290] Prepared in a similar fashion to EXAMPLE 57 using Intermediate 040 as starting material and ethanolamine. MS (ESP): 401 (MH⁺) for Ci₉H₂₄N₆O₂S. IH NMR (300 MHz, DMSO-D6) δ ppm 0.77 (t, J=7.3 Hz, 3 H) 1.20 - 1.33 (m, 2 H) 1.44 - 1.56 (m, 2 H) 2.95 (t, J=7.3 Hz, 2 H) 3.53 (ddd, J=14.6, 5.5, 5.2 Hz, 4 H) 4.65 - 4.73 (m, 1 H) 5.41 (s, 2 H) 7.20 - 7.32 (m, 6 H) 7.35 - 7.40 (m, 1 H)

EXAMPLE 59: 4-amino-8-benzyl-2-(butylthio)-6-{[2- (diethylamino)ethyllamino}pteridin-7(8H)-one

[291] Prepared in a similar fashion to EXAMPLE 57 using Intermediate 040 as starting material and N,7V-diethylethane-l,2-diamine. MS (ESP): 456 (MH⁺) for C₂₃H₃₃N₇OS. IH NMR (300 MHz, DMSO-D6) δ ppm 0.77 (t, J=7.3 Hz, 3 H) 0.94 (t, J=7.0 Hz, 6 H) 1.19 - 1.33 (m, 2 H) 1.42 - 1.56 (m, 2 H) 2.60 (m, 2 H) 2.94 (t, J=7.3 Hz, 2 H) 3.38 - 3.53 (m, 2 H) 5.41 (s, 2 H) 7.18 - 7.32 (m, 7 H)

EXAMPLE 60: 4-amino-8-benzyl-2-(butylthio)-6-(dimethylamino)pteridin-7(8H)-one

[292] Prepared in a similar fashion to EXAMPLE 57 using Intermediate 040 as starting material and dimethyl amine. MS (ESP): 385 (MH⁺) for Ci₉H₂₄N₆OS. IH NMR (300 MHz, DMSO-D6) δ ppm 0.76 (t, J=7.3 Hz, 3 H) 1.17 - 1.32 (m, 2 H) 1.42 - 1.56 (m, 2 H) 2.94 (t, J=7.3 Hz, 2 H) 3.23 (s, 6 H) 5.38 (s, 2 H) 7.18 - 7.32 (m, 7 H).

EXAMPLE 61: HPLC Assay

[293] Compounds were tested for inhibition of glutamate racemase using an HPLC detection assay. Assays were performed in 96-well polypropylene V-bottom plates (Matrix 4919) in 102μL reactions containing 2μL compound dissolved in dimethylsulfoxide, 75μL Enzyme working solution (final concentrations were 10OmM Tris pH 8.0, 0.03 % PEG 8000, 5mM dithiothreitol, and either lμM E.faecalis Murl or lOμM S. aureus Murl) and 25μL 4X D-glutamate in water to initiate the reaction (final D-glutamate concentrations were IM for E. faecal is and 1OmM for S. aureus).

[294] The proteins of interest were prepared as follows: E. faecalis Murl and S. aureus Murl were cloned into pET28b expression vector to allow expression of N-terminal histidine tagged protein. Each vector was co-transformed with a groESL expression vector (to facilitate proper folding) into E. coli strain BL21(DE3). Cultures were grown in LB medium containing lOμg/mL tetracycline and 50μg/mL kanamycin to mid- log phase. Induction was carried out overnight at room temperature in the presence of 500μM IPTG and ImM D/L Glutamate.

[295] S. aureus murl cloned in pET28b (Thrombin cleavable his tag)

ATGGGCAGCAGCCATCATCATCATCATCACAGCAGCGGCCTGGTGCCGCGCGGCAGCCATAT GAATAAACCAATAGGTGTAATAGACTCTGGTGTCGGAGGTTTGACAGTAGCTAAAGAAATTA TGCGTCAGTTGCCAAATGAGACGATTTATTACTTAGGTGATATTGGGCGATGTCCATATGGG CCAAGACCAGGAGAACAAGTAAAACAATATACAGTTGAAATCGCTCGTAAATTAATGGAATT TGATATAAAAATGCTCGTGATTGCTTGTAATACTGCAACTGCTGTAGCTTTAGAATATTTAC AAAAGACCTTATCAATCTCAGTGATTGGCGTAATTGAACCAGGTGCTAGAACAGCAATAATG ACGACTAGAAATCAAAATGTATTAGTACTAGGAACGGAAGGCACAATTAAATCTGAAGCATA TCGAACACATATTAAACGTATAAATCCACATGTAGAGGTACATGGCGTTGCCTGTCCAGGTT TTGTGCCACTTGTAGAACAAATGAGATATAGTGATCCAACAATTACAAGCATTGTTATTCAT CAAACACTGAAACGTTGGCGTAATAGTGAGTCTGATACTGTCATTTTAGGATGTACCCACTA TCCATTGCTCTATAAACCTATCTATGATTATTTTGGTGGTAAAAAGACAGTGATTTCGTCTG GATTAGAAACGGCTCGTGAAGTTAGTGCATTGCTAACATTTAGTAATGAACATGCAAGTTAT ACTGAACATCCAGATCATCGATTTTTTGCAACAGGTGATACCACACATATTACTAACATTAT CAAAGAATGGCTAAATTTATCTGTCAATGTGGAACGTATATCAGTGAATGACTAG ( SEQ ID NO:1)

MGSSHHHHHHSSGLVPRGSHMNKPIGVIDSGVGGLTVAKEIMRQLPNETIYYLGDIGRCP YGPRPGEQVKQYTVEIARKLMEFDIKMLVIACNTATAVALEYLQKTLSISVIGVIEPGAR TAIMTTRNQNVLVLGTEGTIKSEAYRTHIKRINPHVEVHGVACPGFVPLVEQMRYSDPTI TSIVIHQTLKRWRNSESDTVILGCTHYPLLYKPIYDYFGGKKTVISSGLETAREVSALLT FSNEHASYTEHPDHRFFATGDTTHITNIIKEWLNLSVNVERISVND (SEQ ID NO: 2)

E. faecalis murl cloned in pET28b (Thrombin cleavable his tag)

ATGGGCAGCAGCCATCATCATCATCATCACAGCAGCGGCCTGGTGCCGCGCGGCAGCCATAT GAGCAATCAAGAAGCCATTGGATTAATTGATTCTGGCGTTGGTGGATTAACTGTTTTAAAGG AAGCGCTAAAGCAATTACCAAATGAACGATTAATTTATTTAGGAGATACAGCCCGTTGCCCA TATGGTCCACGACCAGCCGAACAAGTCGTTCAGTTTACTTGGGAAATGGCCGATTTTTTATT GAAAAAACGAATAAAAATGCTAGTAATCGCATGTAATACCGCGACGGCTGTCGCATTAGAAG AAATTAAAGCTGCCTTGCCAATTCCAGTTGTTGGTGTTATTTTACCTGGCGCACGAGCAGCC GTTAAAGTCACAAAAAATAACAAAATTGGTGTCATAGGTACCTTAGGGACAATCAAAAGTGC TTCCTATGAAATCGCCATTAAAAGTAAGGCACCAGCAATTGAGGTGACTAGTTTAGCTTGCC CTAAATTTGTCCCCATTGTTGAAAGTAATCAATATCGTTCTTCCGTAGCAAAAAAAATTGTG GCAGAAACACTTCAAGCACTACAATTAAAAGGACTTGATACGTTGATTTTAGGTTGTACCCA TTACCCGTTGTTACGTCCGGTGATTCAAAATGTGATGGGGAGTCATGTGACATTAATTGACT CAGGAGCCGAAACAGTTGGCGAAGTCAGCATGCTTCTCGATTATTTTGACATTGCCCACACG CCTGAAGCGCCTACACAGCCCCATGAATTTTATACAACTGGTTCTGCAAAAATGTTTGAAGA GATTGCAAGCAGTTGGCTTGGTATAGAGAACTTAAAAGCACAACAGATTCACTTAGGAGGAA ACGAAAATGATTAG (SEQ ID NO:3)

MGSSHHHHHHSSGLVPRGSHMSNQEAIGLIDSGVGGLTVLKEALKQLPNERLIYLGDTAR CPYGPRPAEQVVQFTWEMADFLLKKRIKMLVIACNTATAVALEEIKAALPIPVVGVILPG ARAAVKVTKNNKIGVIGTLGTIKSASYEIAIKSKAPAIEVTSLACPKFVPIVESNQYRSS VAKKIVAETLQALQLKGLDTLILGCTHYPLLRPVIQNVMGSHVTLIDSGAETVGEVSMLL DYFDIAHTPEAPTQPHEFYTTGSAKMFEEIASSWLGIENLKAQQIHLGGNEND (SEQ ID

NO : 4 )

[296] Purification of E. faecalis Murl and S. aureus Murl was carried out as follows.

The frozen cell paste was resuspended in 5OmL of Lysis Buffer [2OmM Tris/HCl, pH 7.5, 5mM DL-Glutamate, 1 EDTA-free protease inhibitor cocktail tablet (Roche Molecular Biochemical)]. Cells were disrupted by French press at 18,000psi twice at 4⁰C, and the crude extract was centrifuged at 20,000rpm (45Ti rotor, Bechman) for 30min at 4⁰C. The supernatant was loaded at a flow rate of 2.0mL/min onto a 5mL HiTrap Ni²⁺ chelating column (GE Healthcare Lifebioscinces) pre-equalibrated with Buffer A (2OmM Tris/HCl, pH 7.5, 5mM DL-GIu). The column was then washed with Buffer A, and the protein was eluted by a linear gradient from 0 to 0.5M Imidazole in Buffer A. Fractions containing Murl were pooled, and solid (NH₄)₂Sθ4 (0.4g/mL) was added to precipitate all the proteins and mixed on ice for Ih. The sample was centrifuged at 25,000rpm for 30min at 4⁰C (45Ti rotor, Beckman); the pellet was then dissolved in 9mL of Buffer A. The 5mL sample was applied at a flow rate of l.OmL/min to a 32OmL Sephacryl S-200 (HR 26/60) (GE Healthcare Lifebioscinces) pre-equalibrated with Buffer A. The fractions containing Murl were pooled and dialyzed against IL Storage buffer (1OmM Tris/HCl, pH 7.5, 0.ImM EGTA, 15OmM NaCl, ImM TCEP, 5mM DL-GIu, 50% Glycerol). The protein was characterized by SDS- PAGE analysis and analytical LC-MS and judged to be at 95% purity. The protein was stored at -2O⁰C.

[297] E.faecalis reactions were incubated at room temperature for 60min and S. aureus reactions were incubated at rt for 120min before reactions were quenched by addition of 50μL 1.5% acetic acid (final concentration was 0.5%). Quenched plates were centrifuged at rt for 30min at 3000rpm and supernatants transferred to clear flat-bottom polystyrene 96 well plates (Costar 9017) for HPLC. Chiral separation of D and L-glutamate was performed using a Phenomenex Chirex (D)-Penicillamine column (50 x 4.6mM) with 95% 2mM CuSO₄, 5% methanol as the eluent and a flow rate of 1.5mL/min at 5O⁰C. Data were reported as the increase in peak area for L-glutamate. Compound potency was based on IC50 measurements determined from reactions performed in the presence often different compound concentrations. Assay artifacts due to insoluble compounds under assay conditions were assessed using nephelometry to measure turbidity. The limit of compound solubility was defined as the maximum concentration before a detectable increase in turbidity was observed by nephelometry.

[298] All compounds except 4-amino-8-benzyl-5-methyl-2-(propylsulfonyl)-5,8- dihydropteridine-6,7-dione showed IC50 activity against at least either E.faecalis or S. aureus. Compounds showed an IC50 for E.faecalis in the range from 0.48μM to 300μM and for S. aureus in the range from 1.1 to 300μM. For example, 4-amino-8-benzyl-2-(butylthio)- 5,8-dihydropteridine-6,7-dione has an IC50 using the HPLC assay for E.faecalis of 2.38μM and an IC50 using the HPLC assay for S. aureus of 6.42μM. In another example, 4-amino-2- (butylthio)-8-(2,6-dichlorobenzyl)-5,8-dihydropteridine-6,7-dione has an IC50 using the HPLC assay for E.faecalis of 10.2μM and an IC50 using the HPLC assay for S. aureus of 12.2μM. In yet another example, 2-(butylthio)-4-(dimethylamino)-8-[(5-methylisoxazol-3-yl)methyl]- 5,8-dihydropteridine-6,7-dione has an IC50 using the HPLC assay for E.faecalis of 1.38μM and an IC50 using the HPLC assay for S. aureus of 18.5μM.

Claims

What is claimed is:

1. A compound of formula (I):

(I) in free or salt form, wherein:

A is C=O, or C-N(R^4a)(R^4b); B is N, or N(R⁵); X is S, -S(O)₂-, or O;

R¹ is C_1-6alkyl, Co-βalkyl-Cs-scyclalkyl-Co-_όalkyl — , Ci-ealkoxy-Co-βalkyl — , or aryl- C_1-6alkyl — ; optionally substituted with 1-6 independent halo substituents; R^2a is H or Ci-βalkyl;

R^2b is H, Ci_-6alkyl, hetcyclyl-d-galkyl— C_0-6alkyl-O-C(O)-C_0-6alkyl— , Ci_-6alkyl- SO₂ or — (Co-₆alkyl)-N(Co-₆alkyl)(Co-₆alkyl); optionally substituted with 1-6 independent halo or OH substituents; or R^2a and R^2b, together with the N to which they are attached, form a hetcyclyl; optionally substituted with 1-6 independent halo substituents;

R³ is H, C_1-6alkyl, Co-₆alkyl-aryl-Ci.₆alkyl — , Co-βalkyl-hetaryl-Ci-ealkyl — , or — (Co-₆alkyl)-N(Co-₆alkyl)(Co-₆alkyl); optionally substituted with 1-6 independent halo, CN, NO₂, Ci_-6alkyl, C_0-6alkyl-O-C(O)-C_0-6alkyl— , Ci_-6alkoxy, or Ci_-6alkyl-SO₂— , aryl substituents;

R^4a is H or Ci-ealkyl;

R^4b is H, Ci-ealkyl, Co-ealkyl-hetcyclyl-Co-ealkyl— , Co-ealkyl-hetaryl-Co-ealkyl— , Co-₆alkyl-C₃-₈cyclalkyl-Co-₆alkyl — , Ci.6alkoxy-Co-6alkyl — , or — Ci_6alkyl- N(Co-₆alkyl)(Co-₆alkyl); optionally substituted with 1-6 independent halo, OH, or

substituents; or R^4a and R^4b, together with the N to which they are attached, form a hetcyclyl; optionally substituted with 1-6 independent halo, OH, or

substituents; and

R⁵ is H, Ci_-6alkyl, C_0-6alkyl-O-C(O)-C_0-6alkyl— , Co-ealkyl-aryl-Ci-ealkyl— , or Co-βalkyl-hetaryl-Co-_όalkyl — ; optionally substituted with 1-6 independent halo, NO₂, or Ci-δalkoxy substituents; provided that X-R¹ is not -S-Me, or optionally substituted -S-(CH₂)-phenyl.

2. The compound according to claim 1, comprising a compound described by Formula (II):

(II) in free or salt form, wherein X, R¹, R^2a, R^2b, R³, and R⁵ are as described for Formula (I).

3. The compound according to claim 2, in free or salt form; wherein X is S; and R¹, R^2a, R^2b, R³, and R⁵ are as described above for Formula (I).

4. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; and R^2a, R^2b, R³, and R⁵ are as described for Formula (I).

5. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl, R^2a is Co_-6alkyl; and R^2b, R³, and R⁵ are as described for Formula (I).

6. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or R^2b is H or

optionally substituted with 1-6 independent halo ( OH substituents; and R³ and R⁵ are as described for Formula (I).

7. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or R^2b is H or

optionally substituted with 1-6 independent halo or OH substituents; R⁵ is Co-βalkyl; and R³ is as described for Formula (I).

8. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or

optionally substituted with 1-6 independent halo or OH substituents; R⁵ is Co-₆alkyl-0-C(0)-Co-₆alkyl — optionally substituted with 1-6 independent halo, NO2, or Ci-6alkoxy substituents; and R³ is as described for Formula (I).

9. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or C^aUcyl optionally substituted with 1-6 independent halo or OH substituents; R⁵ is Co-βalkyl-aryl-Ci-ealkyl — optionally substituted with 1-6 independent halo, NO₂, or Ci-δalkoxy substituents; and R³ is as described for Formula (I).

10. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or C_1-6alkyl; R^2b is H or

optionally substituted with 1-6 independent halo or OH substituents; R⁵ is Co-βalkyl-hetaryl-Co-_όalkyl — optionally substituted with 1-6 independent halo, NO₂, or Ci-6alkoxy substituents; and R³ is as described for Formula (I).

10

11. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or C_1-6alkyl; R^2b is hetcyclyl-Ci-_δalkyl — optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or C_1-6alkyl; and R³ is as described for Formula (I).

15 12. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or Ci-βalkyl; R^2b is C_0-6alkyl-O-C(O)-C_0-6alkyl— optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or C_1-6alkyl; and R³ is as described for Formula (I)-

20 13. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is C_2-6alkyl; R^2a is H or C_1-6alkyl; R^2b is Ci_6alkyl-SO2 optionally substituted with 1-6 independent halo o OH substituents; R⁵ is H or C_1-6alkyl; and R³ is as described above for Formula (I).

14. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is C_2-6alkyl; 25 R^2a is H or Ci_-6alkyl; R^2b is — (Co^alkyl)-N(Co-6alkyl)(C_O-6alkyl) optionally substituted with

1-6 independent halo or OH substituents; R⁵ is H or C_1-6alkyl; and R³ is as described for Formula (I).

15. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is Co-βalkyl- 30 Cs-scyclalkyl-Co-ealkyl— ; and R^2a, R^2b, R³, and R⁵ are as described for Formula (I).

16. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is Co-βalkyl- Cs-scyclalkyl-Co-ealkyl— , R^2a is H or Ci_-6alkyl; and R^2b, R³, and R⁵ are as described for Formula (I).

5 17. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is Co-βalkyl- C₃-₈cyclalkyl-Co-₆alkyl — ; R^2a is H or C_1-6alkyl; R^2b is H or

optionally substituted with 1-6 independent halo or OH substituents; and R³ and R⁵ are as described for Formula (I)-

10 18. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is Co-βalkyl- C₃.₈Cyclalkyl-Co-₆alkyl — ; R^2a is H or C_1-6alkyl; R^2b is H or

optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or C_1-6alkyl; and R³ is as described for Formula (I).

15 19. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is Co-βalkyl- C₃-₈cyclalkyl-Co-₆alkyl — ; R^2a is H or C_1-6alkyl; R^2b is Co-_όalkyi optionally substituted with 1- 6 independent halo or OH substituents; R⁵ is Co-₆alkyl-0-C(0)-Co-₆alkyl — ; and R³ is as described above for Formula (I).

20 20. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is Ci.₆alkoxy-Co-₆alkyl — ; and R^2a, R^2b, R³, and R⁵ are as described for Formula (I).

21. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is Ci.6alkoxy-Co-6alkyl — , R^2a is H or C_1-6alkyl; and R^2b, R³, and R⁵ are as described for 25 Formula (I).

22. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is Ci.₆alkoxy-Co-₆alkyl — ; R^2a is H or C_1-6alkyl; R^2b is Co-βalkyl optionally substituted wi independent halo or OH substituents; and R³ and R⁵ are as described for Formula (I).

30

23. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is Ci.₆alkoxy-Co-₆alkyl — ; R^2a is H or C_1-6alkyl; R^2b is H or C_1-6alkyl optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or C^aUcyl; and R³ is as described for Formula (I).

24. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is aryl-

5 Ci-δalkyl — optionally substituted with 1-6 independent halo substituents; and R^2a, R^2b, R³, and R⁵ are as described for Formula (I); provided that X-R¹ is not optionally substituted -S- (CH₂)-phenyl.

25. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is aryl- 10

optionally substituted with 1-6 independent halo substituents; R^2a is H or

Ci-δalkyl; and R^2b, R³, and R⁵ are as described for Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)-phenyl.

26. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is aryl- 15 Ci-δalkyl — optionally substituted with 1-6 independent halo substituents; R^2a is H or

Ci-_δalkyl; R^2b is H or

optionally substituted with 1-6 independent halo or OH substituents; and R³ and R⁵ are as described for Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)-phenyl.

20 27. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is aryl-

Ci-_δalkyl — optionally substituted with 1-6 independent halo substituents; R 2a is H or R^2b is Co-βalkyl optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or

and R³ is as described for Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)-phenyl. 25

28. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a and R^2b, together with the N to which they are attached, form a hetcyclyl optionally substituted with 1-6 independent halo substituents; and R³ and R⁵ are as described for Formula (I).

30

29. The compound according to claim 2, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a and R^2b, together with the N to which they are attached, form a hetcyclyl optionally substituted with 1-6 independent halo substituents; R⁵ is H; and R³ is as described for Formula (I).

30. The compound according to claim 2, in free or salt form; wherein X is O; and R¹, R^2a, 5 R^2b, R³, and R⁵ are as described for Formula (I).

31. The compound according to claim 2, in free or salt form; wherein X is O; R¹ is

and R^2a, R^2b, R³, and R⁵ are as described for Formula (I).

10 32. The compound according to claim 2, in free or salt form; wherein X is O; R¹ is

R^2a is H or Ci_-6alkyl; and R^2b, R³, and R⁵ are as described for Formula (I).

33. The compound according to claim 2, in free or salt form; wherein X is O; R¹ is

R^2a is H or Ci-₆alkyl; R^2b is H or C^aUcyl optionally substituted with 1-6 independent halo or 15 OH substituents; and R³ and R⁵ are as described for Formula (I).

34. The compound according to claim 2, in free or salt form; wherein X is O; R¹ is

R^2a is H or Ci-₆alkyl; R^2b is H or C^aUcyl optionally substituted with 1-6 independent halo or OH substituents; R⁵ is Co-βalkyl; and R³ is as described for Formula (I). 0

35. The compound according to claim 2, in free or salt form; wherein X is O; R¹ is

R^2a and R^2b, together with the N to which they are attached, form a hetcyclyl optionally substituted with 1-6 independent halo substituents; and R³ and R⁵ are as described for Formula (I). 5

36. The compound according to claim 2, in free or salt form; wherein X is O; R¹ is

R^2a and R^2b, together with the N to which they are attached, form a hetcyclyl optionally substituted with 1-6 independent halo substituents; R⁵ is H or C^aUcyl; and R³ is as described for Formula (I).

30

37. The compound according to claim 2, in free or salt form; wherein X is -S(O)₂-; and R¹, R^2a, R^2b, R³, and R⁵ are as described for Formula (I).

38. The compound according to claim 2, in free or salt form; wherein X is -S(O)₂-; R¹ is Ci-βalkyl; and R^2a, R^2b, R³, and R⁵ are as described for Formula (I).

39. The compound according to claim 2, in free or salt form; wherein X is -S(O)₂-; R¹ is d-ealkyl, R^2a is H or Ci_-6alkyl; and R^2b, R³, and R⁵ are as described for Formula (I).

40. The compound according to claim 2, in free or salt form; wherein X is -S(O)₂-; R¹ is Ci_-6alkyl; R^2a is H or Ci_-6alkyl; R^2b is H or Ci_-6alkyl optionally substituted with 1-6 independent halo or OH substituents; and R³ and R⁵ are as described for Formula (I).

41. The compound according to claim 2, in free or salt form; wherein X is -S(O)₂-; R¹ is Ci_-6alkyl; R^2a is H or Ci_-6alkyl; R^2b is H or Ci_-6alkyl optionally substituted with 1-6 independent halo or OH substituents; R⁵ is H or

and R³ is as described for Formula

(I)-

42. The compound according to claim 1, comprising a compound described by Formula (III):

(III) in free or salt form, wherein X, R¹, R^2a, R^2b, R³, R^4a, and R^4b are as described for Formula

(I)-

43. The compound according to claim 42, in free or salt form; wherein X is S; and R¹, R^2a, R^2b, R³, R^4a, and R^4b are as described above for Formula (I).

44. The compound according to claim 42, in free or salt form; wherein X is S; R¹ is C_2-6alkyl; and R^2a, R^2b, R³, R^4a, and R^4b are as described above for Formula (I).

45. The compound according to claim 42, in free or salt form; wherein X is S; R¹ is C_2-6alkyl, R^2a H or Ci_-6alkyl; and R^2b, R³, R^4a, and R^4b are as described above for Formula (I).

46. The compound according to claim 42, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or C^aUcyl optionally substituted with 1-6 independent halo or OH substituents; and R³, R^4a, and R^4b are as described above for Formula (I).

47. The compound according to claim 42, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or C^aUcyl optionally substituted with 1-6 independent halo or OH substituents; R^4a is H or Ci_6alkyl; R³ is Co-βalkyl; and R^4b is as described above for Formula (I).

48. The compound according to claim 42, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or Ci-₆alkyl; R^2b is H or

optionally substituted with 1-6 independent halo or OH substituents; R^4a is H or C_1-6alkyl; R³ is Co-6alkyl-aryl-Ci.6alkyl — optionally substituted with 1-6 independent halo, CN, NO₂, C_1-6alkyl, Co-6alkyl-0-C(0)-Co-6alkyl — ,

or Ci_6alkyl-Sθ2 — , aryl substituents;; and R^4b is as described above for Formula (I).

49. The compound according to claim 42, in free or salt form; wherein X is S; R¹ is aryl- Ci-δalkyl — optionally substituted with 1-6 independent halo substituents; and R^2a, R^2b, R³, R^4a, and R^4b are as described above for Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)-phenyl.

50. The compound according to claim 42, in free or salt form; wherein X is S; R¹ is aryl- Ci-_δalkyl — optionally substituted with 1-6 independent halo substituents; R^2a is H or Ci-βalkyl; and R^2b, R³, R^4a, and R^4b are as described above for Formula (I); provided that X- R¹ is not optionally substituted -S-(CH₂)-phenyl.

51. The compound according to claim 42, in free or salt form; wherein X is S; R¹ is aryl-

C_1-6alkyl — optionally substituted with 1-6 independent halo substituents; R 2a is H or

C_1-6alkyl; R ,2b is H or C_1-6alkyl optionally substituted with 1-6 independent halo or OH substituents; and R³, R^4a, and R^4b are as described above for Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)-phenyl.

52. The compound according to claim 42, in free or salt form; wherein X is S; R¹ is aryl-

Ci-_δalkyl — optionally substituted with 1-6 independent halo substituents; R 2a is H or

C_1-6alkyl; R ,2b is H or C^aUcyl optionally substituted with 1-6 independent halo or OH substituents; R^4a is H or C^aUcyl; R³ is H or C_1-6alkyl; and R^4b is as described above f 5 Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)-phenyl.

53. The compound according to claim 42, in free or salt form; wherein X is S; R¹ is aryl- Ci-_δalkyl — optionally substituted with 1-6 independent halo substituents; R^2a is H or C_1-6alkyl; R^2b is H or

optionally substituted with 1-6 independent halo or OH 10 substituents; R^4a is H or C_1-6alkyl; R³ is Co-6alkyl-aryl-Ci.6alkyl — optionally substituted with 1-6 independent halo, CN, NO₂, Ci_-6alkyl, C_0-6alkyl-O-C(O)-C_0-6alkyl— , Ci_-6alkoxy, or Ci_6alkyl-Sθ2 — , aryl substituents;; and R^4b is as described above for Formula (I); provided that X-R¹ is not optionally substituted -S-(CH₂)-phenyl.

15 54. The compound according to claim 42, in free or salt form; wherein X is S; R¹ is C₂-₆alkyl; R^2a is H or C_1-6alkyl; R^2b is H or

optionally substituted with 1-6 independent halo or OH substituents; R^4a and R^4b, together with the N to which they are attached, form a hetcyclyl; optionally substituted with 1-6 independent halo, OH, or

substituents; and R³ is as described above for Formula (I). 0

55. The compound according to claim 1 selected from:

4-amino-2-(butylthio)-8-(3-chlorobenzyl)-5,8-dihydropteridine-6,7-dione; 4-amino-8-(biphenyl-2-ylmethyl)-2-(butylthio)-5,8-dihydropteridine-6,7-dione; 4- amino-2-(butylthio)-8-[4-(methylsulfonyl)benzyl]-5,8-dihydropteridine-6,7-dione; 4- 5 amino-2-(butylthio)-8-(3,4-dichlorobenzyl)-5,8-dihydropteridine-6,7-dione; 4-amino-

2-(butylthio)-8-(2,6-dichlorobenzyl)-5,8-dihydropteridine-6,7-dione; 4-amino-2-(butylthio)-8-[3-(trifluoromethyl)benzyl]-5,8-dihydropteridine-6,7-dione; 4-amino-2-(butylthio)-8-(3,5-dimethoxybenzyl)-5,8-dihydropteridine-6,7-dione; 4-amino-2-(butylthio)-8-(4-fluoro-3-nitrobenzyl)-5,8-dihydropteridine-6,7-dione; 30 4-amino-2-(butylthio)-8-(4-methylbenzyl)-5,8-dihydropteridine-6,7-dione;

4-amino-2-(butylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione; 4-amino-2-(butylthio)-5,8-bis(3-chloro-2,6-difluorobenzyl)-5,8-dihydropteridine-6,7- dione; 4-amino-2-(butylthio)-5,8-bis(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione;

4-amino-8-butyl-2-(butylthio)-5,8-dihydropteridine-6,7-dione;

8-(3,4-dichlorobenzyl)-4-(dimethylamino)-2-(methylthio)-5,8-dihydropteridine-6,7- dione; ethyl 4- {[4-amino-2-(butylthio)-6,7-dioxo-6,7-dihydropteridin-8(5H)- yl]methyl}benzoate;

2-butoxy-8-(3,4-dichlorobenzyl)-4-methyl-5,8-dihydropteridine-6,7-dione;

2-(butylthio)-8-(3,4-dichlorobenzyl)-4-(dimethylamino)-5,8-dihydropteridine-6,7- dione;

2-(butylthio)-4-(dimethylamino)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione; 2-(butylthio)-4-(dimethylamino)-8-(pyridin-3-ylmethyl)-5,8-dihydropteridine-6,7- dione;

2-(butylthio)-4-(dimethylamino)-8-(pyridin-4-ylmethyl)-5,8-dihydropteridine-6,7- dione;

2-(butylthio)-4-(dimethylamino)-8-[(5-methylisoxazol-3-yl)methyl]-5,8- dihydropteridine-6,7-dione;

(4-{[2-(butylthio)-4-(dimethylamino)-6,7-dioxo-6,7-dihydropteridin-8(5H)- yl]methyl}phenyl)acetic acid;

2-(butylthio)-8-[(2,6-dichloropyridin-4-yl)methyl]-4-(dimethylamino)-5,8- dihydropteridine-6,7-dione; 2-(butylthio)-4-(dimethylamino)-5,8-bis[(5-methylisoxazol-3-yl)methyl]-5,8- dihydropteridine-6,7-dione; ethyl [4-amino-2-(butylthio)-8-(4-fluorobenzyl)-6,7-dioxo-7,8-dihydropteridin-5(6H)- yl] acetate; ethyl [4-amino-2-(cyclopentylthio)-8-(4-fluorobenzyl)-6,7-dioxo-7,8-dihydropteridin- 5 (6H)-yl] acetate;

2-(butylthio)-5,8-bis[(2,6-dichloropyridin-4-yl)methyl]-4-(dimethylamino)-5,8- dihydropteridine-6,7-dione;

[4-amino-2-(butylthio)-8-(4-fluorobenzyl)-6,7-dioxo-7,8-dihydropteridin-5(6H)- yl]acetic acid; 2-(butylthio)-8-(4-fluorobenzyl)-4-[(2-moφholin-4-ylethyl)amino]-5,8- dihydropteridine-6,7-dione;

2-(butylthio)-4-{[2-(diethylamino)ethyl]amino}-8-(4-fluorobenzyl)-5,8- dihydropteridine-6,7-dione; 2-(butylthio)-8-(4-fluorobenzyl)-4-(3-hydroxyazetidin-l-yl)-5,8-dihydropteridine-6,7- dione;

7V-[2-(butylthio)-8-(4-fluorobenzyl)-6,7-dioxo-5,6,7,8-tetrahydropteridin-4-yl]-7V- methylglycine; l-[[2-(butylthio)-8-(4-fluorobenzyl)-6,7-dioxo-5,6,7,8-tetrahydropteridin-4- yl](methyl)amino]- 1 -deoxy-L-glucitol;

2-(butylthio)-8-(4-fluorobenzyl)-4-(methylamino)-5,8-dihydropteridine-6,7-dione;

2-(butylthio)-8-(4-fluorobenzyl)-4-(4-methylpiperazin-l-yl)-5,8-dihydropteridine-6,7- dione; 4-amino-2-(butylsulfonyl)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione;

N-[2-(butylthio)-8-(4-fluorobenzyl)-6,7-dioxo-5,6,7,8-tetrahydropteridin-4- yljmethanesulfonamide;

N-[2-(butylthio)-8-(4-fluorobenzyl)-6,7-dioxo-5,6,7,8-tetrahydropteridin-4-yl]-N- methylmethanesulfonamide; 4-bromo-2-(butylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione;

4-{[4-amino-2-(butylthio)-6,7-dioxo-6,7-dihydropteridin-8(5H)-yl]methyl}benzoic acid;

4-amino-8-benzyl-2-(butylthio)-5,8-dihydropteridine-6,7-dione;

4-amino-2-(butylthio)-8-(2,6-difluorobenzyl)-5,8-dihydropteridine-6,7-dione; 4-amino-2-(butylthio)-8-(2,6-difluoro-3-methylbenzyl)-5,8-dihydropteridine-6,7- dione;

4-{[4-amino-2-(butylthio)-6,7-dioxo-6,7-dihydropteridin-8(5H)- yl]methyl}benzonitrile;

4-amino-2-(butylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione; 2-{[4-amino-2-(butylthio)-6,7-dioxo-6,7-dihydropteridin-8(5H)- yl]methyl}benzonitrile;

3-{[4-amino-2-(butylthio)-6,7-dioxo-6,7-dihydropteridin-8(5H)- yl]methyl}benzonitrile;

4-amino-2-(butylthio)-8-(3-chloro-2,6-difluorobenzyl)-5,8-dihydropteridine-6,7-dione; 4-amino-8-(4-fluorobenzyl)-2-[(2-phenylethyl)thio]-5,8-dihydropteridine-6,7-dione;

4-amino-8-benzyl-2-[(2-phenylethyl)thio]-5,8-dihydropteridine-6,7-dione;

4-amino-2-(benzylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione;

4-amino-8-benzyl-2-(benzylthio)-5,8-dihydropteridine-6,7-dione; 4-amino-2-(cyclopentylthio)-8-(4-fluorobenzyl)-5,8-dihydropteridine-6,7-dione; 4-amino-8-benzyl-2-(cyclopentylthio)-5,8-dihydropteridine-6,7-dione; 2-butoxy-8-(3,4-dichlorobenzyl)-4-moφholin-4-yl-5,8-dihydropteridine-6,7-dione; 2-butoxy-8-(4-fluorobenzyl)-4-moφholin-4-yl-5,8-dihydropteridine-6,7-dione; 5 8-benzyl-2-(benzylamino)-5,8-dihydropteridine-6,7-dione;

4-amino-8-benzyl-2-(butylthio)-6-moφholin-4-ylpteridin-7(8H)-one;

4-amino-8-benzyl-2-(butylthio)-6-{[2-(diethylamino)ethyl]amino}pteridin-7(8H)-one; or

10 4-amino-8-benzyl-2-(butylthio)-6-(dimethylamino)pteridin-7(8H)-one in free or salt form.

56. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-55, in association with a

15 pharmaceutically-acceptable diluent or carrier.

57. A compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-55 for use as a medicament.

20 58. The use of a compound, in free or salt form, as claimed in any one of claims 1-55 in the manufacture of a medicament for use in the production of bacterial Murl inhibitory effect in a warm-blooded animal such as man.

59. The use of a compound, in free or salt form, as claimed in any one of claims 1-55, in the 25 manufacture of a medicament for use in the production of an anti-bacterial effect in a warm-blooded animal such as man.

60. The use of a compound, in free or salt form, as claimed in any one of claims 1-55, in the manufacture of a medicament for use in the treatment or prophylaxis of bacterial infection,

30 e.g., infection by Murl expressing bacteria, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections, for example, E.faecalis or S. aureus infection; for example in the treatment of pneumonia, septicemia, pueφeral sepsis, endocarditis, toxic shock, osteomyelitis, enterocolitis, bacterial meningitis, or post-operative infection; for example in the treatment or prophylaxis of antibiotic resistant infection; in a warm-blooded animal, e.g., man.

61. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-55, in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a bacterial Murl inhibitory effect in a warm-blooded animal such as man.

62. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-55, in association with a pharmaceutically-acceptable diluent or carrier for use in the production of an anti-bacterial effect in a warm-blooded animal such as man.

63. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-55, in association with a pharmaceutically-acceptable diluent or carrier for use for use in the treatment or prophylaxis of bacterial infection, e.g., infection by Murl expressing bacteria, e.g., Gram positive bacterial infection, e.g., infection caused by Gram positive cocci such as staphylococcal, streptococcal or enterococcal infections, for example, E.faecalis or S. aureus infection; for example in the treatment of pneumonia, septicemia, puerperal sepsis, endocarditis, toxic shock, osteomyelitis, enterocolitis, bacterial meningitis, or post-operative infection; for example in the treatment or prophylaxis of antibiotic resistant infection; in a warm-blooded animal, e.g., man.

64. A method of treatment or prophylaxis of bacterial infection in a patient in need of such treatment or prophylaxis, comprising administering to the patient an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-

55.

65. The method of claim 64 wherein the infection is caused by Gram positive cocci.

66. The method of claim 64 or 65 wherein the infection is E.faecalis or S. aureus infection.

67. The method of any of claims 64-66 wherein the infection is resistant to penicillin or cephalosporin.

68. The method of any of claims 64-67 wherein the infection is selected from pneumonia, septicemia, puerperal sepsis, endocarditis, toxic shock, osteomyelitis, enterocolitis, bacterial meningitis, and post-operative infection.

69. A method of treatment or prophylaxis of bacterial infection in a patient in need of such treatment or prophylaxis, comprising administering to the patient an effective amount of a compound of formula (I):

R²? ^R^2b N

R¹ R³

(I) in free or salt form, wherein:

A is C=O, or C-N(R^4a)(R^4b); B is N, or N(R⁵);

X is S, -S(O)₂-, or O;

R¹ is C_1-6alkyl, Co-βalkyl-Cs-scyclalkyl-Co-_όalkyl — , Ci-ealkoxy-Co-βalkyl — , or aryl-

substituted with 1-6 independent halo substituents;

R^2a is H or Ci-βalkyl; R^2b is H, Ci_-6alkyl, hetcyclyl-Ci-galkyl— C_0-6alkyl-O-C(O)-C_0-6alkyl— , Ci_-6alkyl-

SO₂ or — (Co-₆alkyl)-N(Co-₆alkyl)(Co-₆alkyl); optionally substituted with 1-6 independent halo or OH substituents; or R^2a and R^2b, together with the N to which they are attached, form a hetcyclyl; optionally substituted with 1-6 independent halo substituents; R³ is H, Ci_-6alkyl, C_0-6alkyl-aryl-Ci_-6alkyl — , Co-ealkyl-hetaryl-Ci-ealkyl — , or —

(Co-₆alkyl)-N(Co-₆alkyl)(Co-₆alkyl); optionally substituted with 1-6 independent halo, CN, NO₂, Ci_-6alkyl, C_0-6alkyl-O-C(O)-C_0-6alkyl— , Ci_-6alkoxy, or Ci_-6alkyl-SO₂— , aryl substituents;

R^4a is H or Ci-βalkyl; R^4b is H, Ci-βalkyl, Co-ealkyl-hetcyclyl-Co-ealkyl— , Co-ealkyl-hetaryl-Co-ealkyl— , Co-₆alkyl-C₃-₈cyclalkyl-Co-₆alkyl — , Ci.6alkoxy-Co-6alkyl — , or — Ci_6alkyl- N(Co-₆alkyl)(Co-₆alkyl); optionally substituted with 1-6 independent halo, OH, or

substituents; or R^4a and R^4b, together with the N to which they are attached, form a hetcyclyl; optionally substituted with 1-6 independent halo, OH, or

substituents; and

R⁵ is H, Ci_-6alkyl, C_0-6alkyl-O-C(O)-C_0-6alkyl— , Co-ealkyl-aryl-Ci-ealkyl— , or Co-βalkyl-hetaryl-Co-_όalkyl — ; optionally substituted with 1-6 independent halo, NO₂, or Ci-δalkoxy substituents.