WO2009034386A1

WO2009034386A1 - Derivatives of adenine and 8-aza-adenine and uses thereof-796

Info

Publication number: WO2009034386A1
Application number: PCT/GB2008/050812
Authority: WO
Inventors: Gloria Breault; Charles Joseph Eyermann; Bolin Geng
Original assignee: AstraZeneca UK Ltd; AstraZeneca AB
Current assignee: AstraZeneca UK Ltd; AstraZeneca AB
Priority date: 2007-09-13
Filing date: 2008-09-10
Publication date: 2009-03-19
Anticipated expiration: 2010-03-13

Abstract

The invention relates to chemical compounds, or pharmaceutically acceptable salts thereof of the formula (I): which have bacterial MurI inhibitory activity and are accordingly useful for their treatment and prophylaxis of bacterial infection, e.g., E.faecalis or E. faeciuminfection. 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 animalsuch as man.

Description

DERIVATIVES OF ADENINE AND 8-AZA-ADENINE AND USES THEREOF-796

Field of the Invention

The present invention relates to novel derivatives of adenine and 8-aza-adeninine, their pharmaceutical compositions and methods of use. In addition, the present invention relates to the use of derivatives of adenine and 8-aza-adeninine for treatment and prevention of various diseases caused by bacteria, for example, Enterococcus faecalis or Enterococcus faecium infection.

Background of the Invention

Most bacteria, especially Gram positive bacteria, utilize a cell wall comprised of crosslinked peptidoglycan units to maintain shape and resist high osmotic pressure 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 murl gene of Escherichia coli is an essential gene that encodes a glutamate racemase activity. Journal of Bacteriology, 1993, 175(10): p. 2970-9). 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 positive cocci, for example, such as staphylococcal, streptococcal or enterococcal infections, are a serious problem, especially in children, the elderly, and hospitalized patients.

Summary of the Invention

The present invention describes novel derivatives of adenine and 8-aza-adeninine, which inhibit bacterial Murl, e.g., E.faecalis Murl or E. faecium Murl, and 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 E.faecium infection. The compounds are of particular interest to treat infections that are resistant to conventional antibiotics, such as penicillin and cephalosporin.

In one embodiment, the invention relates to compounds represented by formula (I):

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

Xi is a divalent Ci.₆alkyl, a divalent Ci-₆alkenyl or a divalent Ci-₆alkynyl, wherein the divalent alkyl, alkenyl or alkynyl may be optionally substituted with one or more substituent selected from the group consisting of halo, cyano, nitro, hydroxy, =0, =S,

Ci- 4alkylsulfanyl, amino,

and

X₂ is -O-, -S-, or -NR^a-, wherein R^a is hydrogen or a

Ri is a C₃_i₄carbocycle, morpholinyl, quinolinyl, benzodioxinyl, benzodioxolyl, 1-H- pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 2-oxo-2,3-dihydro-l,3-benzoxazolyl, tetrahydro-lH-pyran, 1-benzothiophenyl, furanyl, thiazolyl, isoxazolyl, or oxetanyl, wherein the carbocycle, morpholinyl, quinolinyl, benzodioxinyl, benzodioxolyl, 1-H-pyrazolyl, 1,3,4- oxadiazolyl, 1,2,4-oxadiazolyl, 2-oxo-2,3-dihydro-l,3-benzoxazolyl, tetrahydro-lH-pyran, 1- benzothiophenyl, furanyl, thiazolyl, isoxazolyl, and oxetanyl are optionally substituted on one or more carbon atom with one or more R₅; and wherein each =N- of the quinolinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, thiazolyl, and isoxazolyl, may be each independently optionally substituted with an oxo; and wherein the -NH- of morpholinyl, 1-H- pyrazolyl, and 2-oxo-2,3-dihydro-l,3-benzoxazolyl may be optionally substituted with Rn;

R₂ is a C_1-6alkyl, Ci_6alkenyl, C_1-6alkynyl, C_3-i4carbocycle, heterocycle, C_3- i₄carbocycleCi-₆alkyl, or heterocycleCi-_όalkyl, wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl may be optionally substituted on one or more carbon atoms with one or more R₆, and wherein if R₂ is a heterocycle or a heterocyclealkyl comprising one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₂ is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Rs;

R₃ and R₄ are each, independently, hydrogen, Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, C_3- πcarbocycle, heterocycle,

or heterocycloCi-_όalkyl, wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocycloalkyl may be optionally substituted on one or more carbon atoms with one or more R₇, and wherein if R₃ or R₄ is a heterocycle or a heterocyclealkyl comprising one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₃ or R₄ is a heterocycle or a heterocyclealkyl that contains one or more -NH-, each -NH- may be independently optionally substituted with R₉; or R₃ and R₄ taken together with the nitrogen atom to which they are attached form a heterocycle which may be optionally substituted on one or more carbon atoms with one or more R₇, wherein if the heterocycle comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if the heterocycle comprises one or more -NH-, each -NH- may be independently optionally substituted with R₉;

R₅, R5 and R₇, for each occurrence, are independently selected from the group consisting of a halo, nitro, cyano, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-i4carbocycle, heterocycle, C_3-14carbocycleC_1-6alkyl, heterocycleC_1-6alkyl, C_1-6haloalkyl, -ORn, -SRn, - NR₁₂R₁₃, -C(O)R₁₁, -C(O)OR₁₁, -C(O)NR₁₂R₁₃, -NR₁₁C(O)R₁₁, -OC(O)R₁₁, -NR₁₁C(O)OR₁₁, -OC(O)NR₁₂R₁₃, -NR₁₁C(O)NR₁₂R₁₃, -NR₁₁C(NR₁₄)NR₁₂R₁₃, -S(O)_pR_π, -NR_nS(0)_pRn, and -S(O)_pNR₁₂Ri₃, wherein if R₅, R₆ or R₇ is alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be optionally further substituted on one or more carbon atoms with one or more R₁₅; and wherein if R5, R₆ or R₇ is a heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₅, R₆ or R₇ is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with R₁₆;

R₈, R₉, or R₁₇, for each occurrence, are independently selected from the group consisting of C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-14carbocycle, heterocycle, C_3- ₁₄carbocycleC_1-6alkyl, heterocycleC_1-6alkyl, C_1-6haloalkyl, -C(O)R₁₁, -C(O)OR₁₁, - C(O)NRi₂Rn, -S(O)pRn,and -S(O)_pNRi₂Ri3, wherein if R₈, R₉ or R_n is alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be optionally substituted on one or more carbon atoms with one or more Ri₅; and wherein if R₈, R₉ or Rn is a heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₈, R₉ or Rn is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆;

Rio is hydrogen, a Ci_-6alkyl, a heterocycleCi_-6alkyl, -NRi₂Rn, -C(O)Rn, -C(O)ORn, -C(O)NRi₂R_n, -NRnC(O)Rn, -OC(O)Rn, -NRnC(O)ORn, -OC(O)NRi₂Ri₃, - NRnC(NRi₄)NRi₂Ri₃, -S(O)_pRn, -NRnS(0)_pRn, and -S(O)_pNRi₂Ri₃;

Rn, for each occurrence, is independently selected from the group consisting of hydrogen, C_2-6alkenyl, C_2-6alkynyl, C_3-i4carbocycle, heterocycle, C_3-i4carbocycleCi_ _δalkyl, heterocycleCi-_δalkyl, wherein if Rn is an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be independently optionally substituted on one or more carbon atom with one or more Ri 5, and wherein if Rn is heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if Rn is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆;

Ri₂ and Ri₃, for each occurrence, are independently selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-i4carbocycle, heterocycle, C_3- i₄carbocycleCi_₆alkyl, heterocycleCi_₆alkyl, wherein if Ri₂ or Ri₃ is an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be independently optionally substituted on one or more carbon atom with one or more Ri ₅, and wherein if Ri₂ or Ri₃ is heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if Ri₂ or Ri₃ is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆; or Ri₂ and Ri₃ taken together with the nitrogen atom to which they are attached for a heterocycle, wherein the heterocycle may be optionally substituted on one or more carbon atoms with one or more Ri 5, and wherein if the heterocycle comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if the heterocycle comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆; Ri5, for each occurrence, is independently selected from the group consisting of halo, nitro, cyano, Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, C_3-i4carbocycle, heterocycle, C_3- i4carbocycleCi_6alkyl, heterocycleCi-δalkyl, Ci-όhaloalkyl, -ORis, -SRis, -NR1₉R20, -C(O)RiS, -C(O)ORi₈, -C(O)NRi₉R₂₀, -NRi₈C(O)Ri₈, -OC(O)Ri₈, -NRi₈C(O)ORi₈, -OC(O)NRi₉R₂₀, - NRi₈C(O)NRi₉R₂₀, -NRi₈C(NR₂i)NRi₉R₂₀, -S(O)_pRi₈, -NRi₈S(O)_pRi₈, and -S(O)_pNRi₉R₂₀; Ri 4 and R₂1, for each occurrence, are independently selected from the group consisting of hydrogen, a Ci-6alkyl, nitro, cyano, amino, alkylamino, dialkylamino, or hydroxy;

R₁₆, for each occurrence, is independently selected from the group consisting of Ci- ₆alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-14carbocycle, heterocycle, C_3-14carbocycleC_1-6alkyl, heterocycleCi-ealkyl, Ci_-6haloalkyl, -C(O)Ri₈, -C(O)ORi₈, -C(O)NRi₉R₂₀, -S(O)_pRi₈, and -

Ri₈, for each occurrence, is independently selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-14carbocycle, heterocycle, C_3-i4carbocycleCi. ₆alkyl, heterocycleC_1-6alkyl;

Ri₉ and R₂₀, for each occurrence, are independently selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-14carbocycle, heterocycle, C_3-

₁₄carbocycleC_1-6alkyl, heterocycleC_1-6alkyl; or Ri₉ and R₂₀ taken together with the nitrogen atom to which they are attached for a heterocycle; and p is 1 or 2.

In some embodiments of the compounds of formula (I), one or more of the following provisos apply:

Ri is not an unsubstituted phenyl, unsubstituted biphenyl, an unsubstituted cyclopropyl, or 3-cyclopentyloxy-4-methoxyphenyl; when Ri is 4-chlorophenyl, 4-fiuorophenyl, cyclohexyl, or furanyl, R₂ is not unsubstituted naphthyl or unsubstituted cyclopentyl; when Ri is morpholinyl, one of R₃ and R₄ are not 4-aminobenzyl or phenylethyl; when X₂ is -NR^a-, R₂ is a C_1-6alkyl which is optionally substituted with on one or more carbon atom with one or more R₆, and Ri is not 4-aminophenyl, 2-chlorophenyl, 4- methylphenyl, 3-(methoxycarbonylmethyl)-phenyl, 2-fluorophenyl, or 2,6-difiuorophenyl. when -X₂-R₂ is methylsulfanyl, Ri is not 4-methylphenyl, 2-methoxyphenyl, or 2- fluorophenyl; when -X2-R2 is an unsubstituted n-butyloxy , Ri is not 3-(2-methoxy-2-oxoethyl)- phenyl, 3-cyanomethyl-phenyl, 3-chloromethyl-phenyl, 3-hydroxymethyl-phenyl, 4- benzyloxyphenyl, 3-cyanomethyl-4-fluoro-phenyl, 3-chloromethyl-4-fluoro-phenyl, 3- hydroxymethyl-4-fluoro-phenyl, 3-methoxycarbonyl-4-fluoro-phenyl, 2-methoxy-5- cyanomethyl-phenyl, 2-methoxy-5 -chloromethyl-phenyl, 2-methoxy-5 -hydroxymethyl- phenyl, 2-methoxy-5-methoxycarbonyl-phenyl, 3,4-di-(methoxycarbonyl)-phenyl, 4- hydroxyphenyl, or 3-(l,l,2-trimethoxy-2-oxoethyl)-phenyl; and when -X-R₂ is an unsubstituted n-butyloxy and -NR3R4 is -NH₂, Ri is not 3- methoxycarbonyl-phenyl or 4-acetoxyphenyl.

In another embodiment, the invention relates to compounds represented by formula (II):

(H) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein X₃, R₂, R3, and R4 are defined as above, and wherein: X₄ is -O- or -S-; R22 is a C3-6alkyl which is optionally substituted on one or more carbon atom with one or more substituents selected from the group consisting of halo, nitro, cyano, -ORn, -SRn, - NRi₂R_n, -C(O)Rn, -C(O)ORn, -C(O)NRi₂R_n, -NRnC(O)Rn, -OC(O)Rn, -NRnC(O)ORn, -OC(O)NRi₂Ri₃, -NRnC(O)NRi₂Ri3, -NRnC(NRi₄)NRi₂Ri₃, -S(O)_pRn, -NRnS(0)_pRn, and -S(O)_pNRi₂Ri₃; wherein Rn, Ri₂, Rn, RH, and p are defined as above. In some embodiments of the compounds of formula (II), one or both of the following provisos apply: when both R₃ and R₄ are hydrogen, R₂ and R₂₂ are not both n-hexyl or both n-propyl, or R₂₂ is not n-propyl and R₂ is not methyl; and when R₂ is methyl, R₃ and R₄ taken together with the nitrogen atom to which they are attached are not a substituted or unsubstituted piperazino.

Compounds represented by formula (I) or (II) have bacterial, e.g., E.faecalis Murl, or E.faecium 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 E.faecium infection, and thus in methods of treatment or prophylaxis for humans and animals. The invention also relates to processes for the manufacture of compounds represented by formula (I) or (II), to pharmaceutical compositions containing compounds represented by formula (I) or (II), and to their use in the manufacture of medicaments for use in the treatment and prophylaxis of various diseases caused by bacterial infection, e.g., E.faecalis ox E.faecium infection, in a warm-blooded animal such as man.

Detailed Description of the Invention

A. Definitions

Unless otherwise specified, the below terms used herein are defined as follows: As used herein, the term "carbocycle" refers to a monocyclic or polycyclic, saturated, partially saturated or unsaturated ring system having 3 to 14 ring atoms, wherein all the ring atoms are carbon atoms. Carbocyclic ring systems can be unsubstituted or substituted with one or more independently selected substituents. Carbocyclic ring systems include aryl, cycloalkenyl, and cycloalkyl ring systems. The term "C3_i4carbocycle" refers to a carbocycle having from 3 to 14 ring carbon atoms.

As used herein, the term "aryl" means a monocyclic or poly cyclic-aromatic ring system. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthacenyl, fiuorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted or substituted with one or more independently selected substituents. The term "Cό-πaryl" refers to an aryl group having from 6 to 14 ring carbon atoms. In certain embodiments, the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms. As used herein, the term "cycloalkyl" means a saturated, mono- or polycyclic alkyl radical typically having from 3 to 14 carbon atoms. Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantly, decahydronaphthyl, octahydropentalene, bicycle[l.l.l]pentanyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one or more independently selected substituents. The term "C₃-i₄cycloalkyl" refers to a cycloalkyl group having from 3 to 14 ring carbon atoms.

As used herein, the term "cycloalkenyl" means a cyclic non-aromatic alkenyl radical having at least one carbon-carbon double bond in the cyclic system and typically having from 5 to 14 carbon atoms. Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl and the like. Cycloalkenyl groups can be unsubstituted or substituted with one or more independently selected substituents. The term "C₃-i₄Cycloalkenyl" refers to a cycloalkenyl group having from 3 to 14 ring carbon atoms. As used herein, the term "alkyl" means a saturated straight chain or branched non- cyclic hydrocarbon typically having from 1 to 10 carbon atoms, preferably 1-6 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3- dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2- ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2- methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. Alkyl groups included in compounds of this invention may be optionally substituted with one or more independently selected substituents. The term "Ci-6alkyl" refers to an alkyl group having from 1 to 6 carbon atoms.

As used herein, the term "alkenyl" means a straight chain or branched, hydrocarbon radical typically having from 2 to 10 carbon atoms, preferably 2-6 carbon atom, and having at least one carbon-carbon double bond. Representative straight chain and branched alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1- butenyl, l-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1- heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3- nonenyl, 1-decenyl, 2-decenyl, 3-decenyl and the like. Alkenyl groups can be unsubstituted or substituted with one or more independently selected substituents on the saturated or unsaturated portion of the akenyl group. The term "C₂-₆alkenyl" refers to an alkenyl group having from 2 to 6 carbon atoms.

As used herein, the term "alkynyl" means a straight chain or branched, hydrocarbonon radical typically having from 2 to 10 carbon atoms, preferably 2-6 carbon atoms, and having at lease one carbon-carbon triple bond. Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3 -methyl- 1- butynyl, 4-pentynyl-l-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1- octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9- decynyl and the like. Alkynyl groups can be unsubstituted or substituted with one or more independently selected substituents. The term "C₂-₆alkynyl" refers to an alkynyl group having from 2 to 6 carbon atoms.

The term "alkylene," as used herein, refers to an alkyl group that has two points of attachment to two moieties (e.g., -CH₂-, -CH₂CH₂-, etc.). Alkylene groups may be unsubstituted or substituted with one or more independently selected substituents. The term

"Ci_6alkylene" refers to an alkylene group having from 1 to 6 carbon atoms. An alkylene group is also referred to herein as a divalent alkyl group.

The term "divalent alkenyl," as used herein refers to an alkenyl group that has two points of attachment to two or more moieties (e.g., -CH=CH-, -CH₂CH=CHCH₂-, - CH=CHCH₂-, and the like). Divalent alkenyl groups may be unsubstituted or substituted with one or more independently selected substituents. The term "divalent Ci-₆alkenyl" refers to a divalent alkenyl group having from 1 to 6 carbon atoms.

The term "divalent alkynyl," as used herein refers to an alkynyl group that has two points of attachment to two or more moieties (e.g., -C≡C-, -CH₂C=CCH₂-, -C=CCH₂-, and the like). Divalent alkynyl groups may be unsubstituted or substituted with one or more independently selected substituents. The term "divalent Ci-₆alkynyl" refers to a divalent alkynyl group having from 1 to 6 carbon atoms.

The term "carbocyclealkyl," as used herein, refers to a carbocycle group that is attached to another moiety via an alkylene linker. The term "Cs-πcarbocycleCi-ealkyl" refers to a C3_i4carbocycle group that is attached to another moiety via a

linker.

Carbocyclealkyl groups can be unsubstituted or substituted on the alkyl or carbocycle portion with one or more independently selected substituents. Representative carbocyclealkyl groups include benzyl, cyclopropylmethyl, phenylethyl, 2-(naphth-l-yl)-propyl, 2-(fluoren-9-yl)- ethyl, 3-cyclohexyl-propyl, and the like.

The term "arylalkyl," as used herein, refers to an aryl group that is attached to another moiety via an alkylene linker. The term "Ce-πarylCi-ealkyl" refers to a Cό-πaryl group that is attached to another moiety via a Ci-6alkylene linker. Arylalkyl groups can be unsubstituted or substituted with one or more independently selected substituents. Representative arylalkyl groups include benzyl, phenylethyl, 2-(naphth-l-yl)-propyl, 2-(fluoren-9-yl)-ethyl, and the like.

As used herein, the term "heterocycle," refers to a monocyclic or polycyclic heterocyclic ring having 3- to 14- ring members which is either a saturated ring, an unsaturated non-aromatic ring, or an aromatic ring. A 3-membered heterocycle can contain up to 3 heteroatoms, and a 4- to 14-membered heterocycle can contain from 1 to about 8 heteroatoms. Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The heterocycle may be attached to another moiety via a nitrogen or carbon atom. Any heteroatom in a heterocycle may be substituted with a protecting group known to those of ordinary skill in the art, for example, the hydrogen on a nitrogen may be substituted with an amine protecting group, such as a tert-butoxycarbonyl group. Furthermore, the heterocycle may be optionally substituted with one or more independently selected substituents on any carbon atom or nitrogen atom. Only stable isomers of such substituted heterocyclic groups are contemplated in this definition. The term "heterocycle" encompasses heteroaryl rings, heterocycloalkenyl rings, and heterocycloalkyl rings.

As used herein, the term "heteroaryl" means a monocyclic or polycyclic aromatic ring system having carbon atom ring members and one or more heteroatom ring members selected from oxygen, sulfur or nitrogen. Typically, a heteroaryl ring has from 5 to about 14 ring members in which at least 1 ring member is a heteroatom selected from oxygen, sulfur and nitrogen. In another embodiment, the heteroaryl ring is a 5 or 6 membered ring and may contain from 1 to about 4 heteroatoms. In another embodiment, the heteroaryl ring has a 7 to 14 ring members and may contain from 1 to about 7 heteroatoms. Representative heteroaryls include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl, thiadiazolyl, pyrazinyl, quinolyl, isoquniolyl, indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl, tetrazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, qunizaolinyl, purinyl, pyrrolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl or benzo(b)thienyl and the like. Heteroaryl groups may be optionally substituted on carbon or nitrogen ring atoms with one or more independently selected substituents.

The term "heterocycloalkyl" refers to a saturated, monocyclic or polycyclic ring system having carbon atom ring members and one or more heteroatom ring members selected from oxygen, sulfur or nitrogen. Heterocycloalkyl groups may be optionally substituted on a carbon or a nitrogen ring atom with one or more independently selected substituents. A heterocycloalkyl has from 3 to 14 ring members. Representative heterocycloalkyl groups include morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

The term "heterocycloalkenyl" refers to a partially unsaturated, non-aromatic, monocyclic or polycyclic ring system having carbon atom ring members and one or more heteroatom ring members selected from oxygen, sulfur or nitrogen. Heterocycloalkenyl groups may be optionally substituted on a carbon or a nitrogen ring atom with one or more independently selected substituents. A heterocycloalkenyl has from 3 to 14 ring members. Representative heterocycloalkenyl groups include 4H-pyranyl, tetrahydropyridinyl, dihydropyridinyl, and the like.

A heterocyclealkyl group refers to a heterocycle that is attached to another moiety via an alkylene linker. The term "heterocycleCi-₆alkyl" refers to a heterocycle group that is attached to another moiety via an alkylene having from 1 to 6 carbon atoms. Heterocyclealkyl groups can be unsubstituted or substituted on the heterocycle or alkyl portion with one or more independently selected substituents.

The term "alkoxy," as used herein, refers to an alkyl group which is linked to another moiety though an oxygen atom. The term "Ci-6alkoxy" refers to an alkoxy group that has from 1 to 6 carbon atoms. Alkoxy groups can be substituted or unsubstituted with one or more independently selected substituents. The term "alkylsulfanyl," as used herein, refers to an alkyl group which is linked to another moiety though a divalent sulfur atom. The term "Ci-₆alkylsulfanyl" refers to an alkylsulfanyl group that has from 1 to 6 carbon atoms. Alkylsulfanyl groups can be substituted or unsubstituted with one or more independently selected substituents. The term "arylsulfanyl," as used herein, refers to an aryl group which is linked to another moiety though a divalent sulfur atom. The term "Ce-πarylsulfanyl" refers to an arylsulfanyl group that has from 6-14 ring carbon atoms. Arylsulfanyl groups can be substituted or unsubstituted with one or more independently selected substituents. The term "amino" refers to -NH₂. The term "alkylamino," as used herein, refers to an amino group in which one hydrogen atom attached to the nitrogen has been replaced by an alkyl group. The term "Ci.6alkylamino," refers to an alkylamino group in which the alkyl portion has from 1 to 6 carbon atoms. The term "dialkylamino," as used herein, refers to an amino group in which two hydrogen atoms attached to the nitrogen have been replaced by alkyl groups, in which the alkyl groups can be the same or different. The term "C_1-

6dialkylamino," refers to a dialkylamino group in which each alkyl group, independently, has from 1 to 6 carbon atoms. Alkylamino groups and dialkylamino groups can be substituted or unsubstituted with one or more independently selected substituents.

As used herein, the term "halogen" or "halo" means fluoro, chloro, bromo, or iodo. As used herein, the term "haloalkyl" means an alkyl group in which one or more -H is replaced with a halo group. The term "Ci_-6IIaIo alkyl," refers to a haloalkyl that has 1-6 carbon atoms. Representative haloalkyl groups include -CF₃, -CHF₂, -CCl₃, -CH₂CH₂Br, - CH₂CH(CH₂CH₂Br)CH₃, -CHICH₃, and the like.

As used herein, the term "hydroxyalkyl" means an alkyl group in which one or more - H is replaced with an -OH group. The term "Ci-₆hydroxyalkyl," refers to a hydroxyalkyl that has 1-6 carbon atoms. Representative hydroxyalkyl groups include -CH₂OH, -CH(OH)₂, - CH₂CH₂OH, -CH₂CH(CH₂CH₂OH)CH₃, -CH(OH)CH₃, and the like.

As used herein, the term "lower" refers to a group having up to four carbon atoms. For example, a "lower alkyl" refers to an alkyl radical having from 1 to 4 carbon atoms, and a "lower alkenyl" or "lower alkynyl" refers to an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, respectively. A lower alkoxy or a lower alkylsulfanyl refers to an alkoxy or an alkylsulfanyl having from 1 to 4 carbon atoms. Lower substituents are typically preferred.

As used herein, the term "compound(s) of this invention" and similar terms refers to a compound of formula (I) or (II), or any exemplified compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

The term "displaceable group," refers to a group which can be displaced by a nucleophile under the reaction condition specified. Skilled artisan can select displaceable groups which can be displaced by a particular nucleophile under particular reaction conditions. Preferred displaceable groups are halo groups.

As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may only become active upon such reaction under biological conditions, but they may have activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of formulas (I) or (II), or any of the exemplified compounds disclosed herein that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of compounds of formulas (I) or (II), or any of the exemplified compounds disclosed herein that comprise -NO, -NO₂, -ONO, or -ONO₂ moieties. Prodrugs can typically be prepared using well-known methods, such as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949- 982 (Manfred E. Wolff ed., 5.sup.th ed), the entire teachings of which are incorporated herein by reference.

As used herein and unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide" and "biohydrolyzable phosphate analogue" mean an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, CC- amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocycle amines, and polyether amines.

In one embodiment, a biohydrolyzable ester of a compound of the invention containing carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include d-ealkoxymethyl esters for example methoxymethyl, d-ealkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C₃-₈cycloalkoxycarbonyloxyCi.₆alkyl esters for example l-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci-₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.

In another embodiment, a biohydrolyzable ester of a compound of the invention containing a hydroxy group includes inorganic esters such as phosphate esters and CC -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydro lyzable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and Λ/-(dialkylaminoethyl)-7V-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4- position of the benzoyl ring.

As used herein, the term "pharmaceutically acceptable salt," is a salt formed from an acid and a basic group of a compound of the invention. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis- (2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of the invention having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)-amine, 2-hydroxy-tert-butylamine, or tris-

(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)-amine, or tri-(2-hydroxyethyl)amine; N-methyl-D- glucamine; and amino acids such as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of the invention having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid. Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

As used herein, the term "pharmaceutically acceptable solvate," is a solvate formed from the association of one or more solvent molecules to one or more molecules of a compound of a compound of the invention. The term solvate includes hydrates (e.g., hemi- hydrate, mono-hydrate, dihydrate, trihydrate, tetrahydrate, and the like).

Some compounds of the invention may have chiral centres and/or geometric isomeric centres (e.g., 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 Murl or E. faecium Murl inhibitory activity.

The invention relates to any and all tautomeric forms of the compounds of the invention that possess E.faecalis Murl or E. faecium Murl inhibitory activity.

A "subject," as used herein, refers to a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

As noted above, one embodiment of the present invention is directed to treating or preventing diseases caused by bacterial infections, wherein the bacteria comprise a Murl enzyme for cell wall biosynthesis, such as E.faecalis and E. faecium infections. "Treating a subject with a disease caused by a bacterial infection" includes achieving, partially or substantially, one or more of the following: the reducing or amelioration of the progression, severity and/or duration of the infection, arresting the spread of an infection, ameliorating or improving a clinical symptom or indicator associated with a the infection (such as tissue or serum components), and preventing the reoccurrence of the infection.

As used herein, the terms "preventing a bacterial infection" refer to the reduction in the risk of acquiring the infection, or the reduction or inhibition of the recurrence of the infection. In a preferred embodiment, a compound of the invention is administered as a preventative measure to a patient, preferably a human, before a surgical procedure is preformed on the patient to prevent infection.

As used herein, the term "effective amount" refers to an amount of a compound of this invention for treating or preventing a bacterial infection is an amount which is sufficient to prevent the onset of an infection, reduce or ameliorate the severity, duration, or progression, of an infection, prevent the advancement of an infection, cause the regression of an infection, prevent the recurrence, development, onset or progression of a symptom associated with an infection, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.

B. Compounds of the Invention

In one embodiment, the present invention provides a compound of formula (I):

(I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Xi is a divalent C^aUcyl, a divalent Ci-₆alkenyl or a divalent Ci-₆alkynyl, wherein the divalent alkyl, alkenyl or alkynyl may be optionally substituted with one or more substituent selected from the group consisting of halo, cyano, nitro, hydroxy, =0, =S,

Ci- 4alkylsulfanyl, amino,

and

X₂ is -O-, -S-, or -NR^a-, wherein R^a is hydrogen or a

Ri is a C₃_i₄carbocycle, morpholinyl, quinolinyl, benzodioxinyl, benzodioxolyl, 1-H- pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 2-oxo-2,3-dihydro-l,3-benzoxazolyl, tetrahydro-lH-pyran, 1-benzothiophenyl, furanyl, thiazolyl, isoxazolyl, or oxetanyl, wherein the carbocycle, morpholinyl, quinolinyl, benzodioxinyl, benzodioxolyl, 1-H-pyrazolyl, 1,3,4- oxadiazolyl, 1,2,4-oxadiazolyl, 2-oxo-2,3-dihydro-l,3-benzoxazolyl, tetrahydro-lH-pyran, 1- benzothiophenyl, furanyl, thiazolyl, isoxazolyl, or oxetanyl is optionally substituted on one or more carbon atom with one or more R₅; and wherein each =N- of the quinolinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, thiazolyl, and isoxazolyl, may be each independently optionally substituted with an oxo; and wherein the -NH- of morpholinyl, 1-H-pyrazolyl, and 2-0X0-2, 3-dihydro-l,3-benzoxazo IyI may be optionally substituted with Rn;

R₂ is a C_1-6alkyl, Ci.6alkenyl, Ci.6alkynyl, C_3-i4carbocycle, heterocycle, C_3- i₄carbocycleCi-₆alkyl, or heterocycleCi-_όalkyl, wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl may be optionally substituted on one or more carbon atoms with one or more R₆, and wherein if R₂ is a heterocycle or a heterocyclealkyl comprising one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₂ is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Rs;

R₃ and R₄ are each, independently, hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3- Hcarbocycle, heterocycle, C_3-14carbocycleC_1-6alkyl, or heterocycloC_1-6alkyl, wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocycloalkyl may be optionally substituted on one or more carbon atoms with one or more R₇, and wherein if R₃ or R₄ is a heterocycle or a heterocyclealkyl comprising one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₃ or R₄ is a heterocycle or a heterocyclealkyl that contains one or more -NH-, each -NH- may be independently optionally substituted with R₉; or R₃ and R₄ taken together with the nitrogen atom to which they are attached form a heterocycle which may be optionally substituted on one or more carbon atoms with one or more R₇, wherein if the heterocycle comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if the heterocycle comprises one or more -NH-, each -NH- may be independently optionally substituted with R₉;

R₅, R5 and R₇, for each occurrence, are independently selected from the group consisting of a halo, nitro, cyano, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-i4carbocycle, heterocycle, C_3-14carbocycleC_1-6alkyl, heterocycleC_1-6alkyl, C_1-6haloalkyl, -ORn, -SRn, - NR₁₂R₁₃, -C(O)R₁₁, -C(O)OR₁₁, -C(O)NR₁₂R₁₃, -NR₁₁C(O)R₁₁, -OC(O)R₁₁, -NR₁₁C(O)OR₁₁, -OC(O)NR₁₂R₁₃, -NR₁₁C(O)NR₁₂R₁₃, -NR₁₁C(NR₁₄)NR₁₂R₁₃, -S(0)_pR_π, -NR₁₁S(O)_PR₁₁, and -S(O)_PNR₁₂R₁₃, wherein if R₅, R₆ or R₇ is alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be optionally further substituted on one or more carbon atoms with one or more R₁₅; and wherein if R₅, R₆ or R₇ is a heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₅, R₆ or R₇ is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with R₁₆;

Rs, R₉, or R₁₇, for each occurrence, are independently selected from the group consisting of C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-14carbocycle, heterocycle, C_3- ₁₄carbocycleC_1-6alkyl, heterocycleC_1-6alkyl, C_1-6haloalkyl, -C(O)R₁₁, -C(O)OR₁₁, - C(O)NR₁₂R₁₃, -S(O)pR_π,and -S(O)_PNR₁₂R₁₃, wherein if R₈, R₉ or R₁₇ is alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be optionally substituted on one or more carbon atoms with one or more R₁₅; and wherein if R₈, R₉ or R₁₇ is a heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₈, R₉ or R₁₇ is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with R₁₆;

R₁₀ is hydrogen, a C_1-6alkyl, a heterocycleC_1-6alkyl, -NR₁₂R₁₃, -C(O)R₁₁, -C(O)OR₁₁, -C(O)NR₁₂R₁₃, -NR₁₁C(O)R₁₁, -OC(O)R₁₁, -NR₁₁C(O)OR₁₁, -OC(O)NR₁₂R₁₃, - NR₁₁C(NR₁₄)NR₁₂R₁₃, -S(O)_pR_π, -NR₁₁S(O)_PR₁₁, and -S(O)_PNR₁₂R₁₃; R₁₁, for each occurrence, is independently selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-14carbocycle, heterocycle, C_3-14Ca^OCyCIeC_1- _δalkyl, heterocycleC^ealkyl, wherein if R₁₁ is an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be independently optionally substituted on one or more carbon atom with one or more R₁₅, and wherein if R₁₁ is heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₁₁ is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆;

Ri 2 and Rn, for each occurrence, are independently selected from the group consisting of hydrogen, Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, C_3-i₄carbocycle, heterocycle, C_3- i₄carbocycleCi_₆alkyl, heterocycleCi-_όalkyl, wherein if R₁₂ or Rn is an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be independently optionally substituted on one or more carbon atom with one or more Ri 5, and wherein if Ri 2 or Rn is heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R12 or Rn is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆; or R12 and Rn taken together with the nitrogen atom to which they are attached for a heterocycle, wherein the heterocycle may be optionally substituted on one or more carbon atoms with one or more Ri 5, and wherein if the heterocycle comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if the heterocycle comprises one or more -NH-, each -NH- may be independently optionally substituted with R₁₆;

Ri5, for each occurrence, is independently selected from the group consisting of halo, nitro, cyano, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C3_i4carbocycle, heterocycle, C_3-

₁₄carbocycleC_1-6alkyl, heterocycleC_1-6alkyl, C_1-6haloalkyl, -OR₁₈, -SR₁₈, -NR19R20, -C(O)RiS, -C(O)ORi₈, -C(O)NRi₉R₂₀, -NRi₈C(O)Ri₈, -OC(O)Ri₈, -NRi₈C(O)ORi₈, -OC(O)NRi₉R₂₀, - NRi₈C(O)NRi₉R₂₀, -NRi₈C(NR₂i)NRi₉R₂₀, -S(O)_pRi₈, -NRi₈S(O)_pRi₈, and -S(O)_pNRi₉R₂₀;

Ri 4 and R₂1, for each occurrence, are independently selected from the group consisting of hydrogen, a C_1-6alkyl, nitro, cyano, amino, alkylamino, dialkylamino, or hydroxy;

R₁₆, for each occurrence, is independently selected from the group consisting of Ci- ₆alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-i4carbocycle, heterocycle, C_3-14carbocycleC_1-6alkyl, heterocycleCi_-6alkyl, Ci_-6haloalkyl, -C(O)Ri₈, -C(O)ORi₈, -C(O)NRi₉R₂₀, -S(O)_pRi₈, and -

Ri₈, for each occurrence, is independently selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-i4carbocycle, heterocycle, C_3-i4carbocycleCi_ ₆alkyl, heterocycleC_1-6alkyl; R₁₉ and R20, for each occurrence, are independently selected from the group consisting of hydrogen, Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, C_3-i₄carbocycle, heterocycle, C_3- i₄carbocycleCi_₆alkyl, heterocycleCi-_όalkyl; or R₁₉ and R₂₀ taken together with the nitrogen atom to which they are attached for a heterocycle; and p is 1 or 2.

In some embodiments of the compounds of formula (I), one or more (including all) of the following provisos apply:

Ri is not an unsubstituted phenyl, unsubstituted biphenyl, an unsubstituted cyclopropyl, or 3-cyclopentyloxy-4-methoxyphenyl; when Ri is 4-chlorophenyl, 4-fiuorophenyl, cyclohexyl, or furanyl, R₂ is not unsubstituted naphthyl or unsubstituted cyclopentyl; when Ri is morpholinyl, one of R₃ and R₄ are not 4-aminobenzyl or phenylethyl; when X2 is -NR^a-, R2 is a

which is optionally substituted with on one or more carbon atom with one or more R₆, and Ri is not 4-aminophenyl, 2-chlorophenyl, 4- methylphenyl, 3-(methoxycarbonylmethyl)-phenyl, 2-fluorophenyl, or 2,6-difiuorophenyl. when -X₂-R₂ is methylsulfanyl, Ri is not 4-methylphenyl, 2-methoxyphenyl, or 2- fluorophenyl; when -X2-R2 is an unsubstituted n-butyloxy , Ri is not 3-(2-methoxy-2-oxoethyl)- phenyl, 3-cyanomethyl-phenyl, 3-chloromethyl-phenyl, 3-hydroxymethyl-phenyl, 4- benzyloxyphenyl, 3-cyanomethyl-4-fluoro-phenyl, 3-chloromethyl-4-fluoro-phenyl, 3- hydroxymethyl-4-fluoro-phenyl, 3-methoxycarbonyl-4-fluoro-phenyl, 2-methoxy-5- cyanomethyl-phenyl, 2-methoxy-5 -chloromethyl-phenyl, 2-methoxy-5 -hydroxymethyl- phenyl, 2-methoxy-5-methoxycarbonyl-phenyl, 3,4-di-(methoxycarbonyl)-phenyl, 4- hydroxyphenyl, or 3-(l,l,2-trimethoxy-2-oxoethyl)-phenyl; and when -X-R2 is an unsubstituted n-butyloxy and -NR₃R₄ is -NH₂, Ri is not 3- methoxycarbonyl-phenyl or 4-acetoxyphenyl.

(H) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein X₃, R₂, R₃, and R4 are defined as above, and wherein: X₄ is -O- or -S-;

R22 is a C_3-6alkyl which is optionally substituted on one or more carbon atom with one or more substituents selected from the group consisting of halo, nitro, cyano, -ORn, -SRn, - NR₁₂R₁₃, -C(O)R₁₁, -C(O)OR₁₁, -C(O)NR₁₂R₁₃, -NR₁₁C(O)R₁₁, -OC(O)R₁₁, -NR₁₁C(O)OR₁₁, -OC(O)NR₁₂R₁₃, -NR₁₁C(O)NR₁₂R₁₃, -NR₁₁C(NR₁₄)NR₁₂R₁₃, -S(O)_pR_π, -NR_nS(0)_pRn, and -S(O)_PNR₁₂R₁₃; wherein R₁₁, Ri₂, Ri₃, RH, and p are defined as above.

In some embodiments of the compounds of formula (II), one or both of the following provisos apply: when both R₃ and R₄ are hydrogen, R₂ and R₂₂ are not both n-hexyl or both n-propyl, or R₂₂ is not n-propyl and R₂ is not methyl; and when R₂ is methyl, R₃ and R₄ taken together with the nitrogen atom to which they are attached are not a substituted or unsubstituted piperazino.

In one embodiment of the compounds of formula (I), Ri is a C_3-i4carbocycle which is optionally substituted on one or more carbon atoms with one or more independently selected R₅. In one aspect of this embodiment, Ri is phenyl which is optionally substituted with one or more independently selected R₅. In another aspect of this embodiment, R₅, for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole-5-yl, 2-(N- methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2- methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fiuorophenyloxy, 4-fluorophenyloxy, and 1 -methyl-ethyl. In another aspect of this embodiment, Ri has one R₅ substituent. In another aspect of this embodiment, Ri has two independently selected R₅ substituents. In another aspect of this embodiment, Ri has three independently selected R₅ substituents.

In another embodiment of the compounds represented by formula (I), Ri is morpholinyl which is optionally substituted on one or more carbon atom with one or more independently selected R⁵, and wherein if the morpholinyl comprises -NH-, it may be optionally substituted on the nitrogen atom with Rn. In another aspect of this embodiment, R₅, for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fiuoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole-5-yl, 2- (N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2- methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fiuorophenyloxy, 4-fiuorophenyloxy, and 1 -methyl-ethyl. In another aspect of this embodiment, Ri has one R₅ substituent. In another aspect of this embodiment, Ri has two independently selected R₅ substituents. In another aspect of this embodiment, Ri has three independently selected R₅ substituents. In another aspect of this embodiment, Rn is selected from the group consisting of C_1-4alkyl, benzyl, acetyl, _Ci-₄alkoxycarbonyl, carbamoyl,

In another embodiment of the compounds represented by formula (I), Ri is benzodioxinyl or benzodioxolyl, which can be optionally substituted on one or more carbon atom with one or more independently selected R₅. In another aspect of this embodiment, R₅, for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fiuoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole-5-yl, 2- (N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2- methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fiuorophenyloxy, 4-fiuorophenyloxy, and 1 -methyl-ethyl. In another aspect of this embodiment, Ri has one R₅ substituent. In another aspect of this embodiment, Ri has two independently selected R₅ substituents. In another aspect of this embodiment, Ri has three independently selected R₅ substituents.

In another embodiment of the compounds represented by formula (I), Ri is quinolinyl which is optionally substituted with one or more independently selected R⁵ and which is optionally substituted on the nitrogen atom with an oxo. In another aspect of this embodiment, R₅, for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l- yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole- 5-yl, 2-(N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, amino sulfonyl, 4- chlorophenyl, 2-methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fluorophenyloxy, 4-fluorophenyloxy, and 1 -methyl-ethyl. In another aspect of this embodiment, Ri has one R₅ substituent. In another aspect of this embodiment, Ri has two independently selected R₅ substituents. In another aspect of this embodiment, Ri has three independently selected R₅ substituents.

In another embodiment of the compounds represented by formula (I), Xi is -CH₂-.

In another embodiment of the compounds represented by formula (I), Xi is - C(O)CH₂-, -CH₂C(O)-, -C(O)-, -CH(OH)CH₂-, or -CH₂CH₂-. In another embodiment of the compounds represented by formula (I), X₂ is -0-.

In another embodiment of the compounds represented by formula (I), X₂ is -S-.

In another embodiment of the compounds represented by formula (I), X₂ is -NR^a-. In one aspect of this embodiment, R^a is H. In another aspect of this embodiment, R^a is a Ci- ₆alkyl. In another aspect of this embodiment, R^a is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

In one embodiment of the compounds represented by formula (II), R₂₂ is an unsubstituted C3.6alkyl group.

In another embodiment of the compounds represented by formula (II), R₂₂ is propyl, butyl, 2,3-dihydroxy-propyl, 3-cycanopropyl, 2-methyl-propyl, 3-phenoxy-2-hydroxy-propyl, 2-hydroxy-2-methyl-propyl, 2-hydroxy-3-methoxy-propyl, 4,4,4-trifluoro-butyl, 2- hydroxybutyl, 2-ethyl-butyl, 4-cyanobutyl, or isopentyl.

In another embodiment of the compounds represented by formula (II), X4 is -0-.

In another embodiment of the compounds represented by formula (II), X4 is -S-.

In another embodiment of the compounds represented by formula (I) or (II), R₂ is Ci- 6alkyl which is optionally substituted on one or more carbon atoms with one or more R₆. In one aspect of this embodiment, R₂ is a Ci_₆alkyl selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopentyl, and 2-methylbutyl, wherein the Ci- 6alkyl may be optionally substituted on one or more carbon atom with one or more R₆. In one aspect of this embodiment, R₆, for each occurrence, is independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, N,N- dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.

In another embodiment of the compounds represented by formula (I) or (II), R₂ is a C₃_₆Cycloalkyl which may be optionally substituted on one or more carbon atom with one or more R₆. In one aspect of this embodiment, R₂ is cyclopentyl or cyclohexyl which may be optionally substituted on one or more carbon atom with one or more R₆. In one aspect of this embodiment, R₆, for each occurrence, is independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, Λ/,Λ/-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.

In another embodiment of the compounds represented by formula (I) or (II), R₂ is decahydronaphthalenyl, phenyl, but-2-en-l-yl, pent-2-yn-l-yl, but-2-yn-l-yl, or phenyl, each of which may be optionally substituted on one or more carbon atom with one or more R₆. In one aspect of this embodiment, R₆, for each occurrence, is independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, N, N- dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.

In another embodiment of the compounds represented by formula (I) or (II), R₂ is piperidinyl which may be optionally substituted on one or more carbon atom with one or more R₆, and wherein if the piperidinyl group comprises -NH-, it may be substituted with Rs. In one aspect of this embodiment, R₆, for each occurrence, is independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, N, N- dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl. In one aspect of this embodiment, Rs is methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, tert-butyl, acetyl, or methylsulfonyl. In another embodiment of the compounds represented by formula (I) or (II), R₃ and

R₄ are both hydrogen.

In another embodiment of the compounds represented by formula (I) or (II), one of R₃ or R₄ is hydrogen and the other is methyl, n-butyl, morpholinoethyl, (furan-3-yl)-methyl, (5- methyl-furan-2-yl)-methyl, benzyl, 2,6-difluourobenzyl, cyclopropyl, 2-phenyl-cyclopropyl, or benzoimidazol-2-yl.

In another embodiment of the compounds represented by formula (I) or (II), R₃ or R₄ are both methyl. In another embodiment of the compounds represented by formula (I) or (II), R₃ and R₄ together with the nitrogen atom to which they are attached form morpholino.

In another embodiment of the compounds represented by formula (I) or (II), X₃ is CRio. In one aspect of this embodiment, Rio is H. In another aspect of this embodiment, Rio is selected from the group consisting of 2-piperizino-ethylamino, 2-(4-methyl-piperazino)- ethylamino, 2-morpholino-ethylamino, 2-hydroxyethylamino, 2-(diethylamino)-ethylamino, morpholino, piperazine, methyl, carboxy, and ethoxycarbonyl.

In another embodiment of the compounds represented by formula (I) or (II), X₃ is N. In another embodiment of the compounds represented by formula (I), Ri is phenyl which is optionally substituted with from one to three independently selected R₅; R₂ is a Ci- 6alkyl which is optionally substituted with from one to three independently selected R₆; and Xi is -CH₂-. In one aspect of this embodiment, R5, for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fiuoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent- 2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole-5-yl, 2-(N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2-methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fiuorophenyloxy, 4-fiuorophenyloxy, and 1- methyl-ethyl. In another aspect of this embodiment, Ri has one R₅ substituent. In another aspect of this embodiment, Ri has two independently selected R₅ substituents. In another aspect of this embodiment, Ri has three independently selected R₅ substituents. In another aspect of this embodiment, R₂ is unsubstituted. In another aspect of this embodiment, R₂ is substituted with from one to three R₆ which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, N,N- dime thy lamino, acetamido, fiuoro, hydroxy, phenyl, and methylsulfonyl.

In another embodiment of the compounds represented by formula (I), Ri is phenyl which is optionally substituted with from one to three independently selected R₅; R₂ is a C_1-6 alkyl which is optionally substituted with from one to three independently selected R₆; Xi is - CH₂-; and R₃ and R₄ are both hydrogen. In one aspect of this embodiment, R₅, for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fiuoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole-5-yl, 2-(N- methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2- methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fluorophenyloxy, 4-fluorophenyloxy, and 1 -methyl-ethyl. In another aspect of this embodiment, Ri has one R₅ substituent. In another aspect of this embodiment, Ri has two independently selected R₅ substituents. In another aspect of this embodiment, Ri has three independently selected R₅ substituents. In another aspect of this embodiment, R₂ is unsubstituted. In another aspect of this embodiment, R₂ is substituted with from one to three R₆ which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, 7V,7V-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.

In another embodiment of the compounds represented by formula (I), Ri is phenyl which is optionally substituted with from one to three independently selected R₅; R₂ is a Ci_-6 alkyl which is optionally substituted with from one to three independently selected R₆; Xi is - CH₂-; and one of R₃ or R₄ is hydrogen and the other is 2-morpholinoethyl. In one aspect of this embodiment, R₅, for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l- yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole- 5-yl, 2-(N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4- chlorophenyl, 2-methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fluorophenyloxy, 4-fluorophenyloxy, and 1 -methyl-ethyl. In another aspect of this embodiment, Ri has one R₅ substituent. In another aspect of this embodiment, Ri has two independently selected R₅ substituents. In another aspect of this embodiment, Ri has three independently selected R₅ substituents. In another aspect of this embodiment, R₂ is unsubstituted. In another aspect of this embodiment, R₂ is substituted with from one to three R₆ which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, 7V,7V-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.

In another embodiment of the compounds represented by formula (I), Ri is phenyl which is optionally substituted with from one to three independently selected R₅; R₂ is a Ci_-6 alkyl which is optionally substituted with from one to three independently selected R₆; Xi is - CH₂-; R₃ and R₄ are both hydrogen; and X₃ is CH. In one aspect of this embodiment, R₅, for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole-5-yl, 2- (N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2- methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fluorophenyloxy, 4-fluorophenyloxy, and 1 -methyl-ethyl. In another aspect of this embodiment, Ri has one R₅ substituent. In another aspect of this embodiment, Ri has two independently selected R₅ substituents. In another aspect of this embodiment, Ri has three independently selected R₅ substituents. In another aspect of this embodiment, R₂ is unsubstituted. In another aspect of this embodiment, R₂ is substituted with from one to three R₆ which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, 7V,7V-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.

In another embodiment of the compounds represented by formula (I), Ri is phenyl which is optionally substituted with from one to three independently selected R₅; R₂ is a Ci_-6 alkyl which is optionally substituted with from one to three independently selected R₆; Xi is - CH₂-; R₃ and R₄ are both hydrogen; and X₃ is CR₁₀, wherein Rio is -NRi₂Ri₃. In one aspect of this embodiment, R₅, for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2- carboxyphenyl, tetrazole-5-yl, 2-(N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2-methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fluorophenyloxy, 4-fluorophenyloxy, and 1- methyl-ethyl. In another aspect of this embodiment, Ri has one R₅ substituent. In another aspect of this embodiment, Ri has two independently selected R₅ substituents. In another aspect of this embodiment, Ri has three independently selected R₅ substituents. In another aspect of this embodiment, R₂ is unsubstituted. In another aspect of this embodiment, R₂ is substituted with from one to three R₆ which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, N, N- dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl. In another aspect of this embodiment, -NRi₂Ri₃ is selected from the group consisting of 2-piperizino-ethylamino, 2-(4-methyl-piperazino)-ethylamino, 2-morpholino-ethylamino, 2-hydroxyethylamino, 2- (diethylamino)-ethylamino, morpholino, and piperazine.

In another embodiment of the compounds represented by formula (I), Ri is phenyl which is optionally substituted with from one to three independently selected R₅; R₂ is a C_3- πcycloalkyl which is optionally substituted with from one to three independently selected R₆; and Xi is -CH₂-. In one aspect of this embodiment, R₂ is a cyclopentyl or cyclohexyl which is optionally substituted with one or more independently selected R₆. In one aspect of this embodiment, R₅, for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l- yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole- 5-yl, 2-(N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, amino sulfonyl, 4- chlorophenyl, 2-methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fluorophenyloxy, 4-fiuorophenyloxy, and 1 -methyl-ethyl. In another aspect of this embodiment, Ri has one R₅ substituent. In another aspect of this embodiment, Ri has two independently selected R₅ substituents. In another aspect of this embodiment, Ri has three independently selected R₅ substituents. In another aspect of this embodiment, R₂ is unsubstituted. In another aspect of this embodiment, R₂ is substituted with from one to three R₆ which are independently selected from the group consisting of cyclopropyl, cyclo butyl, cyclopentyl, cyclohexyl, methoxy, methyl, 7V,7V-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.

In another embodiment of the compounds represented by formula (II), R₂ is a Ci- 6alkyl which is optionally substituted with from one to three independently selected R₆; X₃ is CH; and R₃ and R₄ are both hydrogen. In one aspect of this embodiment, R₂ is unsubstituted. In another aspect of this embodiment, R₂ is substituted with from one to three R₆ which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, 7V,7V-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.

In another embodiment of the compounds represented by formula (II), R₂ is a Ci- 6alkyl which is optionally substituted with from one to three independently selected R₆; X₃ is CH; and one of R₃ or R₄ is hydrogen and the other is 2-morpholinoethyl. In one aspect of this embodiment, R₂ is unsubstituted. In another aspect of this embodiment, R₂ is substituted with from one to three R₆ which are independently selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methyl, Λ/,Λ/-dimethylamino, acetamido, fluoro, hydroxy, phenyl, and methylsulfonyl.

In another embodiment, the invention provides compounds selected from the group consisting of:

2-(butylthio)-9-(3-nitrobenzyl)-9H-purin-6-amine;

2-(butylthio)-9- [3 -(trifiuoromethyl)benzyl] -9H-purin-6-amine;

2-(butylthio)-9-(3-chlorobenzyl)-9H-purin-6-amine;

3-{[6-amino-2-(butylthio)-9H-purin-9-yl]methyl}benzonitrile;

2-(butylthio)-9-(3-methylbenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(3,4-dichlorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(2-methoxy-5-nitrobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(2-chloro-4-fluorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(2,6-dichlorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(2-chloro-5-nitrobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(2,6-difluorobenzyl)-9H-purin-6-amine; methyl 3-{[6-amino-2-(butylthio)-9H-purin-9-yl]methyl}benzoate;

2-(butylthio)-9-(4-chloro-2-fluorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-[2-fluoro-6-(trifluoromethyl)benzyl]-9H-purin-6-amine;

2-(butylthio)-9-(3-methoxybenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(2-fluoro-3-methylbenzyl)-9H-purin-6-amine;

2-(butylthio)-9- [4-(methylsulfonyl)benzyl] -9H-purin-6-amine;

2-(butylthio)-9-(4-methoxy-3-nitrobenzyl)-9H-purin-6-amine;

2-(butylthio)-9- { [4-chloro-2-(trifluoromethyl)quinolin-6-yl]methyl} -9H-purin-6- amine;

2-(butylthio)-9-(2-chloro-5-fluorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(3-fluorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(2,4-difluorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(4,5-dimethoxy-2-nitrobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(5-chloro-2-fluorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(3-chloro-2,6-difiuorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(3,5-dimethoxybenzyl)-9H-purin-6-amine;

2-(butylthio)-9-{2-[(phenylsulfonyl)methyl]benzyl}-9H-purin-6-amine; 2-(butylthio)-9-(4-fluoro-3-nitrobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(4-nitrobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(3,4-difluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(3,5-difluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2,5-difluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2-fluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(4-fluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2-chlorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2-methylbenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(3-chloro-4-fluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2-nitrobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(3-chloro-4-fluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(3,5-dimethylbenzyl)-9H-purin-6-amine; 2-{[6-amino-2-(butylthio)-9H-purin-9-yl]methyl}benzonitrile; 4-{[6-amino-2-(butylthio)-9H-purin-9-yl]methyl}benzonitrile; 9-(4-bromo-2-fluorobenzyl)-2-(butylthio)-9H-purin-6-amine; 2-(butylthio)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2,5-dichlorobenzyl)-9H-purin-6-amine; methyl 4-{[6-amino-2-(butylthio)-9H-purin-9-yl]methyl}-3-methoxybenzoate; 2-(butylthio)-9-(3-fluoro-4-methylbenzyl)-9H-purin-6-amine; 9-(2,6-difluorobenzyl)-2-(isobutylthio)-9H-purin-6-amine; 9-(2,6-difluorobenzyl)-2-[(3-methylbutyl)thio]-9H-purin-6-amine; 9-(2,6-difluorobenzyl)-2-[(2-methylbutyl)thio]-9H-purin-6-amine; 2-(cyclopentylthio)-9-(2,6-difluorobenzyl)-9H-purin-6-amine; 2-(cyclohexylthio)-9-(2,6-difluorobenzyl)-9H-purin-6-amine; 9-(2,6-difluorobenzyl)-2-(2-methoxyethoxy)-9H-purin-6-amine; 2-(butylthio)-9-(cyclobutylmethyl)-9H-purin-6-amine; 2-(butylthio)-9-(cyclohexylmethyl)-9H-purin-6-amine; 2-(butylthio)-9-(tetrahydro-2H-pyran-2-ylmethyl)-9H-purin-6-amine; 9-(3-chloro-2,6-difluorobenzyl)-N-(2-morpholin-4-ylethyl)-2-(4,4,4- trifluorobutoxy)-9H-purin-6-amine;

2-(butylthio)-9-(2,3-dichlorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-[(5-chloro-l-benzothien-3-yl)methyl]-9H-purin-6-amine; 2-(butyl{9-(3-chloro-2,6-difluorobenzyl)-6-[(2-morpholin-4-ylethyl)amino]-9H- purin-2-yl} amino)ethanol;

2-butoxy-9-(2,3-dichlorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9- [4-(methylsulfonyl)benzyl] -7V-(2-morpho lin-4-ylethyl)-9H-purin-6- amine;

2-butoxy-9-(2-methoxy-5-nitrobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine;

3-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9-yl}methyl)benzonitrile;

9-(5-amino-2-methoxybenzyl)-2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine;

9-(2,6-difluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-2-phenoxy-9H-purin-6-amine;

5-(butylthio)-3-(3-chloro-2,6-difluorobenzyl)-3H-[l,2,3]triazolo[4,5-(i]pyrimidin-7- amine;

5-(butylthio)-3-(2,6-difluoro-3-methylbenzyl)-3H-[l,2,3]triazolo[4,5-(/Jpyrimidin-7- amine;

5-(butylthio)-3-(2,6-difluorobenzyl)-3H-[l,2,3]triazolo[4,5-(i]pyrimidin-7-amine;

2-butoxy-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(3-chloro-2,6-difluorobenzyl)-9H-purin-6-amine;

2-butoxy-9-(3-chloro-2,6-difluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine;

2-butoxy-9-(2,6-difluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(3-chloro-2,6-difluorobenzyl)-Λ/-(pyridin-3-ylmethyl)-9H-purin-6- amine;

2-butoxy-9-(3-chloro-2,6-difluorobenzyl)-Λ/-(3-furylmethyl)-9H-purin-6-amine;

4-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9-yl}methyl)benzonitrile;

2-(butylthio)-N,9-bis(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

2-(cyclopropylmethoxy)-9-[3-(trifluoromethyl)benzyl]-9H-purin-6-amine;

2-(cyclopentylmethoxy)-9- [3 -(trifluoromethyl)benzyl] -9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-(pentyloxy)-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-[(3-methylcyclopentyl)oxy]-9H-purin-6-amine;

2-(benzyloxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

2-(cyclobutylmethoxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

2-(cyclopentyloxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine; 2-(l-cyclopropylethoxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-[(l-methylcyclopropyl)methoxy]-9H-purin-6- amine;

2-(cyclopropylmethoxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine

9-(2,6-difluoro-3-methylbenzyl)-2-methoxy-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-propoxy-9H-purin-6-amine;

2-(cyclohexyloxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-isobutoxy-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-N²,N²-dimethyl-9H-purine-2,6-diamine;

9-(2,6-difluoro-3-methylbenzyl)-2-[2-(dimethylamino)ethoxy]-9H-purin-6-amine;

N-(2-{[6-amino-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-2- yl]oxy } ethyl)acetamide;

9-(2,6-difluoro-3-methylbenzyl)-2-[(4,4,5,5,5-pentafluoropentyl)oxy]-9H-purin-6- amine;

2-[[6-amino-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-2-yl](methyl)amino]ethanol;

9-(2,6-difluoro-3-methylbenzyl)-2-(4,4,4-trifluorobutoxy)-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-(piperidin-4-yloxy)-9H-purin-6-amine;

2-(decahydro-naphthalen-2-yloxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6- amine / 2-(decahydronaphthalen- 1 -yloxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6- amine;

Λ/²-butyl-9-(2,6-difluoro-3-methylbenzyl)-Λ/⁶-(2-morpholin-4-ylethyl)-Λ/²-propyl-9H- purine-2,6-diamine;

Λ/²-butyl-9-(2,6-difluoro-3-methylbenzyl)-Λ/²-methyl-Λ/⁶-(2-morpholin-4-ylethyl)- 9H-purine-2,6-diamine;

2-butoxy-9- [3 -(trifluoromethyl)benzyl] -9H-purin-6-amine;

3-[(6-amino-2-butoxy-9H-purin-9-yl)methyl]benzoic acid ;

2-butoxy-9-(2,6-difluorobenzyl)-9H-purin-6-amine;

2-butoxy-9-(2,6-difluorobenzyl)-N,Λ/-dimethyl-9H-purin-6-amine;

Λ/²-butyl-9-(2,6-difluorobenzyl)-9H-purine-2,6-diamine;

2-butoxy-9-(2,6-difluorobenzyl)-Λ/-methyl-9H-purin-6-amine;

2-butoxy-9-(2-butoxy-6-fluorobenzyl)-Λ/-methyl-9H-purin-6-amine;

2-(cyclopropylmethoxy)-9-[2-(cyclopropylmethoxy)-6-fluorobenzyl]-Λ/-methyl-9H- purin-6-amine;

9-(2,6-difluorobenzyl)-Λ/-methyl-2-[2-(methylsulfonyl)ethoxy]-9H-purin-6-amine;

9-(2,6-difluorobenzyl)-Λ/-methyl-2-(2-methylbutoxy)-9H-purin-6-amine;

2-(cyclobutylmethoxy)-9-(2,6-difluorobenzyl)-Λ/-methyl-9H-purin-6-amine;

9-(2,6-difluorobenzyl)-Λ/-methyl-2-(pentyloxy)-9H-purin-6-amine;

2-(cyclopentyloxy)-9-(2,6-difluorobenzyl)-Λ/-methyl-9H-purin-6-amine;

2-butoxy-9-(2,6-difluoro-3-methylbenzyl)-Λ/-ethyl-9H-purin-6-amine;

Λ/-benzyl-2-butoxy-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

Λ/-benzyl-9-(2,6-difluoro-3-methylbenzyl)-2-(pentyloxy)-9H-purin-6-amine;

2-butoxy-Λ/-cyclopropyl-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

2-(butylthio)-9-[(2,6-difluorophenyl)acetyl]-9H-purin-6-amine;

2-(butylthio)-9-(2,6-difluorobenzoyl)-9H-purin-6-amine;

2-butoxy-9-(3-chloro-2,6-difluorobenzoyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine;

2-butoxy-9-(2,6-difluoro-3-methylbenzoyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine; l-[6-amino-2-(butylthio)-9H-purin-9-yl]-2-(2,6-difluorophenyl)ethanol;

3-( {2-butoxy-6-[(2-morpholin-4-ylethyl)amino]- 1 -oxido-9H-purin-9- yl}methyl)benzamide;

3-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9-yl}methyl)benzamide;

2-{[6-amino-2-(butylthio)-9H-purin-9-yl]methyl}-4-nitrophenol;

4-( {2-butoxy-6-[(2-morpholin-4-ylethyl)amino]- 1 -oxido-9H-purin-9- yl}methyl)benzamide;

4-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9-yl}methyl)benzamide; l-[4-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9- y 1 } methyl)pheny 1] ethanone;

2-butoxy-9-(2,6-difluorobenzyl)-8-methyl-9H-purin-6-amine;

2-butoxy-9-(2,6-difluorobenzyl)-Λ/^s-(2-morpholin-4-ylethyl)-9H-purine-6,8-diamine;

2-butoxy-9-(2,6-difluorobenzyl)-8-(4-methylpiperazin-l-yl)-9H-purin-6-amine;

2-butoxy-Λ/^s-[2-(diethylamino)ethyl]-9-(2,6-difluorobenzyl)-9H-purine-6,8-diamine;

2-{[6-amino-2-butoxy-9-(2,6-difluorobenzyl)-9H-purin-8-yl]amino}ethanol;

2-butoxy-9-(2,6-difluorobenzyl)-8-morpholin-4-yl-9H-purin-6-amine;

2-butoxy-9-(2,6-difluorobenzyl)-Λ/^s-[2-(4-methylpiperazin-l-yl)ethyl]-9H-purine- 6,8-diamine;

2-butoxy-9-(2-fluoro-6-{[2-(4-methylpiperazin-l-yl)ethyl]amino}benzyl)-Λ/^s-[2-(4- methylpiperazin- 1 -yl)ethyl]-9H-purine-6,8-diamine;

2-butoxy-9-(2,6-difluorobenzyl)-Λ/^s-(2-piperazin-l-ylethyl)-9H-purine-6,8-diamine;

2-butoxy-Λ/-(2,6-difluorobenzyl)-9-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-N- [(5 -methyl-2-furyl)methyl] -9-(2-morpho lin-4-ylethyl)-9H-purin-6- amine;

2-butoxy-9-(2,3-difluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9-(2,3,5,6-tetrafluorobenzyl)-9H-purin-6- amine;

9-[3,5-bis(trifluoromethyl)benzyl]-2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine;

2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9-(2,3,4,5-tetrafluorobenzyl)-9H-purin-6- amine;

2-butoxy-9-(3,4-difluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2,5-dichlorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-Λ/-(2-morpho lin-4-ylethyl)-9- [4-(trifluoromethyl)benzyl] -9H-purin-6- amine;

2-butoxy-9-(2,6-dichlorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2,4-difluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2-chlorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-[2-chloro-5-(trifluoromethyl)benzyl]-N-(2-morpholin-4-ylethyl)-9H- purin-6-amine;

9-(4-bromo-2-fluorobenzyl)-2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-[2-fluoro-4-(trifluoromethyl)benzyl]-N-(2-morpholin-4-ylethyl)-9H- purin-6-amine;

2-butoxy-9-(3-chloro-2-fluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(4-ethylbenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2-fluoro-6-methylbenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine;

2-butoxy-9-(4-fluoro-3-methylbenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine;

2-butoxy-9-[3-(2-fluorophenoxy)benzyl]-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine;

9-(l,3-benzodioxol-5-ylmethyl)-2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine;

2-butoxy-9-[3-chloro-2-fluoro-5-(trifluoromethyl)benzyl]-Λ/-(2-morpholin-4- ylethyl)-9H-purin-6-amine;

2-butoxy-9- [3 -(4-fluorophenoxy)benzyl] -7V-(2-morpho lin-4-ylethyl)-9H-purin-6- amine;

2-butoxy-9-[3-fluoro-2-(trifluoromethyl)benzyl]-N-(2-morpholin-4-ylethyl)-9H- purin-6-amine;

2-butoxy-9-(2,3-dichlorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine; methyl 4-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9-yl}methyl)-3- methoxybenzoate; methyl 3-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9- yl}methyl)benzoate;

4-( { [2-butoxy-9-(2-morpholin-4-ylethyl)-9H-purin-6- yl]amino}methyl)benzenesulfonamide;

4-({2-butoxy-6-2-morpholin-4-ylethyl)amino]-9H-purin-9-yl}methyl)-3- methoxybenzoic acid;

2-butoxy-7V-(2-morpho lin-4-ylethyl)-9- [2-(trifluoromethyl)benzyl] -9H-purin-6- amine;

[4-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9- y 1 } methyl)pheny ljmethano 1;

2-butoxy-N-(2-morpholin-4-ylethyl)-9-(2,3,5,6-tetrafluoro-4-methylbenzyl)-9H- purin-6-amine;

2-butoxy-9-(4-chloro-2-nitrobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2-methyl-3-nitrobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

9-[(l-bromo-2-naphthyl)methyl]-2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine;

2-butoxy-9-[(6-fluoro-4H-l,3-benzodioxin-8-yl)methyl]-Λ/-(2-morpholin-4-ylethyl)- 9H-purin-6-amine;

Λ/-[4-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9- y 1 } methy l)pheny 1] acetamide; 9-(4-bromobenzyl)-2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(3-chlorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-N-(2-morpholin-4-ylethyl)-9-(2,3,5,6-tetramethylbenzyl)-9H-purin-6- amine;

2-butoxy-9-(2-fluoro-6-nitrobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(5-methyl-2-nitrobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

9-(2-bromo-5-methoxybenzyl)-2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine;

2-butoxy-9-(2,5-dimethoxybenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2,4-dichlorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(3-methoxybenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

4-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9-yl}methyl)phenyl acetate;

2-butoxy-9-(3-fluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9-(2-nitrobenzyl)-9H-purin-6-amine;

2-butoxy-9-(2-chloro-4-fluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(3-methylbenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-7V-(2-morpholin-4-ylethyl)-9-{4-[(E)-2-phenylvinyl]benzyl}-9H-purin-6- amine;

2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9-(2,4,6-triisopropylbenzyl)-9H-purin-6-amine; ethyl 3-( {2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9- yl}methyl)benzoate;

2-butoxy-9-(mesitylmethyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-[5-chloro-2-(trifluoromethyl)benzyl]-N-(2-morpholin-4-ylethyl)-9H- purin-6-amine;

2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9-(2,3,5-trifluorobenzyl)-9H-purin-6-amine;

2-butoxy-9-(2,3-dimethoxybenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2-chloro-6-fluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

9-[2-fluoro-6-(pent-2-yn-l-yloxy)benzyl]-Λ/-(2-morpholin-4-ylethyl)-2-(pent-2-yn- 1 -yloxy)-9H-purin-6-amine;

2-[(2E)-but-2-en- 1 -yloxy]-9- {2-[(2£)-but-2-en- 1 -yloxy]-6-fluorobenzyl} -N-(2- morpholin-4-ylethyl)-9H-purin-6-amine; 9-(2,6-difluoro-3-methylbenzyl)-2-(hex-2-yn-l-yloxy)-Λ/-(2-morpholin-4-ylethyl)- 9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-Λ/-(2-morpholin-4-ylethyl)-2-(pent-2-yn-l-yloxy)- 9H-purin-6-amine;

2-(allyloxy)-9-(2,6-difluoro-3-methylbenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin- 6-amine;

2-[(2E)-but-2-en-l-yloxy]-9-(2,6-difluoro-3-methylbenzyl)-Λ/-(2-morpholin-4- ylethyl)-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-[(3-methylbut-2-en-l-yl)oxy]-N-(2-morpholin-4- ylethyl)-9H-purin-6-amine;

2-(but-2-yn-l-yloxy)-9-(2,6-difluoro-3-methylbenzyl)-N-(2-morpholin-4-ylethyl)- 9H-purin-6-amine; ethyl 2-butoxy-9-(3,4-dichlorobenzyl)-6-morpholin-4-yl-9H-purine-8-carboxylate;

2-butoxy-9-(3,4-dichlorobenzyl)-6-morpholin-4-yl-9H-purine-8-carboxylic acid;

Λ/-(lH-benzimidazol-2-ylmethyl)-2-butoxy-9-(2-morpholin-4-ylethyl)-9H-purin-6- amine;

9-[4-(aminomethyl)benzyl]-2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine; and pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment the invention provides compounds selected from the group consisting of:

2-(butylthio)-9-(4,4,4-trifluorobutyl)-9H-purin-6-amine;

2-(butylthio)-9-(2-ethylbutyl)-9H-purin-6-amine;

2-(butylthio)-9-propyl-9H-purin-6-amine;

2-(butylthio)-9-(3 -methylbutyl)-9H-purin-6-amine ;

2-(butylthio)-9-isobutyl-9H-purin-6-amine;

4-[6-amino-2-(butylthio)-9H-purin-9-yl]butanenitrile;

5-[6-amino-2-(butylthio)-9H-purin-9-yl]pentanenitrile;

2-(benzyloxy)-9-butyl-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

9-butyl-Λ/-(2-morpholin-4-ylethyl)-2-phenoxy-9H-purin-6-amine;

9-butyl-Λ/-(2-morpholin-4-ylethyl)-2-(pyridin-2-yloxy)-9H-purin-6-amine;

9-butyl-2-[(4-methylpyridin-2-yl)oxy]-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine; and pharmaceutically acceptable salt, solvate, or prodrug thereof.

Where a particular substituent, such as an alkyl substituent, occurs multiple times in a given structure or moiety, the identity of the substitutent is independent in each case and may be the same as or different from other occurrences of that substituent in the structure or moiety. Furthermore, individual substituents in the specific embodiments and exemplary compounds of this invention are preferred in combination with other such substituents in the compounds of this invention, even if such individual substituents are not expressly noted as being preferred or not expressly shown in combination with other substituents.

C. METHODS OF PREPARING COMPOUNDS OF THE INVENTION In another embodiment, the present invention provides a process for preparing a compound of formula (I) or (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. An adenine derivative, represented by formula (I) or (II) in which X₂ or X₄, respectively, is -S- can be prepared by reacting a 4,6-diaminopyrimidine-2-thiol with an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl that has a displaceable group, such as a halo, in the presence of a base, such as NaOH, KOH or LiOH and a polar solvent, such as an alcohol, to form intermediate (i). Intermediate (i) is then converted to a nitroso compound by reacting it with sodium nitrite in the presence of acetic acid and water to form intermediate (ii). Intermediate (ii) is hydrogenated using platinum(IV)oxide and H₂ gas to convert the nitroso group to an amine group, forming intermediate (iii). Typically, this reaction is carried out in an alcoholic solvent such as ethanol. Intermediate (iii) is converted to a purine by refiuxing it in formamide to form intermediate (iv). Intermediate (iv) can be reacted in the presence of a carbonate, such as cesium carbonate or MP carbonate™, with an alkyl, a carbocyclealkyl, or a heterocyclealkyl that comprises a displaceable group to form a compound of formula (I) or (II) (see Scheme A).

Scheme A

X, for each occurrence, is an independently selected displaceable group such as a halo.

In another embodiment, compounds of the invention represented by formula (I) or (II) can be prepared by heating 2,6-dichloro-9H-purine with aqueous ammonia or with a primary or secondary amine to form intermediate (vi). The chloro substituent of intermediate (vi) can then be displaced by a thiol substituent of an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl in the presence of cesium carbonate and heat to form a compound of intermediate (vii). Alternatively, the chloro group of intermediate (vi) can be displaced by a hydroxy substituent or an amine substituent of an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl in the presence of a strong base, such as NaOH, and heat to form intermediate (viii) (see Scheme B). Intermediate (vii) or (viii) can be reacted in the presence of a carbonate, such as cesium carbonate or MP carbonate™, with an alkyl, a carbocyclealkyl, or a heterocyclealkyl that comprises a displaceable group to form a compound of formula (I) or (II), as shown in Scheme A.

Scheme B

Compounds of the invention in which X₃ is nitrogen can be prepared by reacting a 2- substituted-4,5,6-triaminopyrimidine with sodium nitrite in acetic acid and water to form intermediate (ix). The reaction is generally carried out at about -20 ⁰C to about 10 ⁰C (see Scheme C). Similarly to the reaction shown in Scheme A, intermediate (ix) can be reacted in the presence of a carbonate, such as cesium carbonate or MP carbonate™, with an alkyl, a carbocyclealkyl, or a heterocyclealkyl that comprises a displaceable group to form a compound of formula (I) or (II) wherein X₃ is nitrogen. Scheme C

It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogen group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.

It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric, sulphuric or phosphoric acid or trifiuoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifiuoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. Other suitable protecting groups for an alcohol include alkyl silyl group such as trimethylsilyl or t-butyl-dimethylsilyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon. Alkylsilyl groups may be removed by treatment with a fluoride such as tetra-n- butylammonium fluoride or by treatment with an acid such as aqueous HCl.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.

D. METHODS OF USE

As stated hereinbefore the compounds defined in the present invention have Murl inhibitory activity and are useful for treating or preventing bacterial infection. These properties may be assessed, for example, using the procedure described in Example 221. LGDH Coupled Enzyme Assay

Compounds of the invention were tested for inhibition of glutamate racemase using a coupled enzyme assay as previously described (Lundqvist et al, "Exploitation of structural and regulatory diversity in glutamate racemases" Nature, 2007, in press). Assays were performed in 96-well polystyrene flat-bottom black plates (FLUOTRAC 200) in 102μL reactions containing 2μL compound dissolved in dimethylsulfoxide, 85μL Enzyme Working Solution (final concentrations were 10OmM Tris pH 8.0, 0.03% PEG 8000, 0.03mg/mL bovine serum albumin, 15U/mL L-glutamate dehydrogenase (LGDH), 5mM dithiothreitol, 5 1OmM NAD⁺ and either 8OnM E.faecalis Murl or 10OnM E.faecium Murl or lμM S. aureus Murl) and 15μL 6.67mM D-glutamate to initiate the reaction (final concentration was ImM).

Purification of E. faecalis Murl, E. faecium Murl and S. aureus Murl was carried out as follows.

10 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

15 (GE Healthcare Lifebiosciences) 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 (NHL)₂SO₄ (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,

20 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-

25 PAGE analysis and analytical LC-MS and judged to be at 95% purity. The protein was stored at -2O⁰C.

E.faecalis reactions were incubated at rt 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

30 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 compounds of the invention described herein have a measured IC50 in this assay against at least one isozyme of Murl (e.g., E.faecalis Murl, E.faecium Murl or S. aureus Murl) of <400 μM or the compounds inhibit the glutamate racemase reaction by >20% at the limit of their solubility in the assay medium. Solubility is determined under assay conditions using a nephelometer to detect a change in turbidity as the concentration of compound increases. The limit of solubility is defined as the maximum concentration before a detectable increase in turbidity is measured.

According to a further aspect of the present invention there is provided a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.

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 for treating or preventing diseases or medical conditions resulting in whole or in part from an infection caused by bacteria expressing Murl.

In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Bacteroides spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Burkholderia spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Campylobacter spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydia spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydophila spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Clostridium spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterobacter spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterococcus spp.. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Escherichia spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Gardnerella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Haemophilus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Helicobacter spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Klebsiella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Legionella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Moraxella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Morganella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Mycoplasma spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Neisseria spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Proteus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Pseudomonas spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Serratia spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by

Staphylococcus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Strep toccocus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Stenotrophomonas spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Ureaplasma spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by aerobes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by obligate anaerobes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by facultative anaerobes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by gram-positive bacteria. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by gram-negative bacteria. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by gram- variable bacteria. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by atypical respiratory pathogens.

In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter baumanii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter haemolyticus . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter junii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter johnsonii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter Iwoffi. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by B 'acteroides bivius. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by B acteroides fragilis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Burkholderia cepacia. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Campylobacter jejuni. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydia pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydia urealyticus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydophila pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Clostridium difficili. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterobacter aerogenes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterobacter cloacae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterococcus faecalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by

Enterococcus faecium. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Escherichia coli. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Gardnerella vaginalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Haemophilus par ainfluenzae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Haemophilus influenzae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Helicobacter pylori. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Klebsiella pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Legionella pneumophila. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Methicillin-resistant Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Methicillin-susceptible Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Moraxella catarrhalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Morganella morganii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Mycoplasma pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Neisseria gonorrhoeae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Penicillin- resistant Streptococcus pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Penicillin-susceptible Streptococcus pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus magnus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus micros. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus anaerobius. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus asaccharolyticus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus prevotii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus tetradius. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus vaginalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Proteus mirabilis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Pseudomonas aeruginosa. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Quino lone-Resistant Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Quino lone-Resistant Staphylococcus epidermis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella typhi. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella paratyphi. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella enteritidis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella typhimurium. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Serratia marcescens. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus epidermidis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus saprophyticus . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptoccocus agalactiae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptococcus pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptococcus pyogenes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Stenotrophomonas maltophilia. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Ureaplasma urealyticum. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycin-Resistant Enter ococcus faecium. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycin-Resistant Enterococcus faecalis . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycin-Resistant Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycin-Resistant Staphylococcus epidermis.

In one aspect of the invention "infection" or "bacterial infection" refers to a gynecological infection. In one aspect of the invention "infection" or "bacterial infection" refers to a respiratory tract infection (RTI). In one aspect of the invention "infection" or "bacterial infection" refers to a sexually transmitted disease. In one aspect of the invention "infection" or "bacterial infection" refers to a urinary tract infection. In one aspect of the invention "infection" or "bacterial infection" refers to acute exacerbation of chronic bronchitis (ACEB). In one aspect of the invention "infection" or "bacterial infection" refers to acute otitis media. In one aspect of the invention "infection" or "bacterial infection" refers to acute sinusitis. In one aspect of the invention "infection" or "bacterial infection" refers to an infection caused by drug resistant bacteria. In one aspect of the invention "infection" or "bacterial infection" refers to catheter-related sepsis. In one aspect of the invention "infection" or "bacterial infection" refers to chancroid. In one aspect of the invention "infection" or "bacterial infection" refers to chlamydia. In one aspect of the invention "infection" or "bacterial infection" refers to community-acquired pneumonia (CAP). In one aspect of the invention "infection" or "bacterial infection" refers to complicated skin and skin structure infection. In one aspect of the invention "infection" or "bacterial infection" refers to uncomplicated skin and skin structure infection. In one aspect of the invention "infection" or "bacterial infection" refers to endocarditis. In one aspect of the invention "infection" or "bacterial infection" refers to febrile neutropenia. In one aspect of the invention "infection" or "bacterial infection" refers to gonococcal cervicitis. In one aspect of the invention "infection" or "bacterial infection" refers to gonococcal urethritis. In one aspect of the invention "infection" or "bacterial infection" refers to hospital-acquired pneumonia (HAP). In one aspect of the invention "infection" or "bacterial infection" refers to osteomyelitis. In one aspect of the invention "infection" or "bacterial infection" refers to sepsis. In one aspect of the invention "infection" or "bacterial infection" refers to syphilis. In a particular aspect, 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 E.faecium 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), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined hereinbefore. Thus according to this aspect of the invention there is provided a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined hereinbefore for use as a medicament.

According to a further aspect of the invention there is provided the use of a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug 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 E.faecium Murl inhibitory effect in a warm-blooded animal such as man. According to this aspect of the invention there is provided the use of a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug 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 E.faecium 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.

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 E.faecium 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), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined above.

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), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined above.

According to a further aspect of the invention there is provided the use of a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined hereinbefore for production of a bacterial Murl inhibitory effect in a warm-blooded animal such as man.

According to another aspect of the invention there is provided the use of a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined hereinbefore for production of an antibacterial effect in a warm-blooded animal such as man. According to a further feature of the invention, there is provided the use of a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined hereinbefore 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 E. faecium 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.

The compounds of the invention described herein may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination. Suitable classes and substances may be selected from one or more of the following: i) other antibacterial agents for example macrolides e.g. erythromycin, azithromycin or clarithromycin; quinolones e.g. ciprofloxacin or levofioxacin; β-lactams e.g. penicillins e.g. amoxicillin or piperacillin; cephalosporins e.g. ceftriaxone or ceftazidime; carbapenems, e.g. meropenem or imipenem etc; aminoglycosides e.g. gentamicin or tobramycin; or oxazolidinones; and/or ii) anti-infective agents for example, an antifungal triazole e.g. or amphotericin; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) efflux pump inhibitors.

Therefore, in a further aspect of the invention there is provided a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof and a chemotherapeutic agent selected from: i) one or more additional antibacterial agents; and/or ii) one or more anti-infective agents; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) one or more efflux pump inhibitors. 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.

E. PHARMACEUTICAL COMPOSITIONS

According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvates, or prodrugs thereof, as defined hereinbefore, in association with a pharmaceutically-acceptable diluent or carrier. In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug 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 E.faecium Murl inhibitory effect in a warm-blooded animal such as man.

In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug 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.

In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), (II), or any of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug 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 E.faecium 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. The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl /?-hydroxybenzoate; and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethyl or propyl p-hydroxybenzoate; anti-oxidants such as ascorbic acid); colouring agents; flavouring agents; and/or sweetening agents such as sucrose, saccharine or aspartame. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent. The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.

For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

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.

F. RESEARCH TOOLS

In addition to their use in therapeutic medicine, the compounds of formula (I) or (II) and pharmaceutically acceptable salts, solvates or prodrugs thereof are also useful as pharmacological tools in the development and standardization 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 E. faecium Murl, in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

Examples

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 that were carried out at room or ambient temperature ("rt") were at a temperature in the range of 18-25°C; (ii) organic solutions were dried over anhydrous sodium sulphate; evaporation of solvent was 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 was followed by thin layer chromatography (TLC) and reaction times are given for illustration only; (iv) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral (MS) data;

(v) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was 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 were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was 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)-ΛWN ',N '-tetramethyluronium hexafluorophosphate; THF tetrahydrofuran; DMF 7V,7V-dimethylformamide;

EtOAc ethyl acetate;

DIEA N, 7V-diisopropylethylamine;

DCM dichloromethane;

DMSO dimethylsulphoxide; MeCN acetonitrile;

NBS Λ/-bromosuccinimide; and

MeOH methanol;

(xii) "ISCO" refers to normal phase flash column chromatography using 12 g and 40 g pre-packed 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

Scheme I: Intermediates 1-5

5

Intermediate 1: 4,6-diaminopyrimidine-2-thiol Commercially available

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

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

Intermediate 3: 2-(butylthio)-5-nitrosopyrimidine-4.,6-diamine A solution of 2-(butylthio)pyrimidine-4,6-diamine (Intermediate 2, 6.9g, 35 mmol) in acetic acid (138 mL) and water (30 mL) was cooled to 0°C and treated dropwise, over 20 min, with sodium nitrite (4.4g, 63 mmol) in water (3OmL). The reaction mixture turned dark brown and a bright pink solid formed. After 30 min the pink solid was collected by filtration and washed with cold water (400 mL) to yield a bright blue solid, 6.8g. MS (ESP): 228 (MH⁺) for C₈Hi₃N₅OS Intermediate 4: 2-(butylthio)pyrimidine-4.,5.,6-triamine

A suspension of 2-(butylthio)-5-nitrosopyrimidine-4,6-diamine (Intermediate 3, 6.8g, 30 mmol) in ethanol (10OmL) was flushed with N₂ and platinum(IV) oxide (0.34g, 1.5mmol) was added. The reaction was stirred under a H₂ balloon at rt overnight. The reaction mixture was filtered through celite and evaporated to yield a green solid, 6.5g. MS (ESP): 214 (MH⁺)

Intermediate 5: 2-(butylthio)-9H-purin-6-amine

2-(butylthio)pyrimidine-4,5,6-triamine (Intermediate 4, 5.8g, 27mmol) was dissolved in formamide (13OmL) and refluxed for 5h. The reaction mixture was cooled to rt and water (150 mL) was added. The orange precipitate was collected by filtration, 4.9g. MS (ESP): 224 (MH⁺) for C₉H_nN₅S

Intermediate 6: 2,6-dichloro-9H-purine

Commercially available.

Intermediate 7: 2-chloro-9H-purin-6-amine Commercially available 2,6-dichloro-9H-purine (Ig, 5.2mmol) was dissolved in 7N ammonia/methanol (1OmL) and heated in microwave reactor for 50 min at 120°C. The reaction was filtered to collect a yellow solid, 0.75g. MS (ESP): 170 (MH⁺) for C₅H₄ClN₅

Intermediate 8 : 2-chloro-9- [3-(trifluoromethyl)benzyll -9H-purin-6-amine 2-chloro-9H-purin-6-amine (Intermediate 7, 0.56g, 3.3mmol), cesium carbonate (1.3g,

4mmol) and 3-(trifiuoromethyl)benzyl bromide (0.56mL, 3.6mmol) were combined in DMF (25mL) and stirred at rt overnight. The reaction mixture was poured into water and the off- white precipitate was collected by filtration, 0.95g. MS (ESP): 328 (MH⁺)

Intermediates 24 and 25 were prepared using an analogous method to that used to prepare Intermediate 8: Intermediate 24: 2-chloro-9-[3-cvanobenzyll-9H-purin-6-amine

The Intermediate 24 was prepared by alkylation of 2-chloro-9Η-purin-6-amine (Intermediate 7) with 3-cyanobenzyl bromide. MS (ES): 285(MH⁺) for Ci₃H₉N₆Cl

Intermediate 25 : 2-chloro-9- [2,6-difluorobenzyll -9H-purin-6-amine

2-chloro-9-[2,6-difluorobenzyl]-9H-purin-6-amine was prepared by alkylation of 2- chloro-9Η-purin-6-amine (Intermediate 7) with 2,6-difiuorobenzyl bromide. MS (ES):

Scheme III: Intermediates 9-14:

Intermediate 9: 2-(isobutylthio)-9H-purin-6-amine

In a pressure tube, 2-chloro-9H-purin-6-amine (Intermediate 7, O.lg, O.όmmol), 2- methyl-1-propanethiol (0.32mL, 3mmol) and cesium carbonate (0.38g, 1.2mmol) were combined in DMF (2mL) and heated at 150°C overnight. The reaction mixture was cooled to rt and poured into water. The resulting off-white precipitate was collected by filtration, O.lg. MS (ESP): 224 (MH⁺) for C₉H_nN₅S Intermediate 10: 2-[(3-methylbutyl)thiol-9H-purin-6-amine

In a pressure tube, 2-chloro-9H-purin-6-amine (Intermediate 7, O.lg, O.όmmol), 3- methyl-1-butanethiol (0.36mL, 3mmol) and cesium carbonate (0.38g, 1.2mmol) were combined in DMF (2mL) and heated at 150°C overnight. The reaction mixture was cooled to rt and poured into water. The resulting white precipitate was collected by filtration, 0.07 g. MS (ESP): 238 (MH⁺) for Ci₀Hi₅N₅S

Intermediate 11: 2-[(2-methylbutyl)thiol-9H-purin-6-amine In a pressure tube, 2-chloro-9H-purin-6-amine (Intermediate 7, 0.2g, 1.2mmol), 2- methyl-1-butanethiol (0.72mL, 6mmol) and cesium carbonate (0.77g, 2.4mmol) were combined in DMF (4mL) and heated at 150°C overnight. The reaction was not complete. More cesium carbonate (leq) and 2-methyl-l-butanethiol (5eq) were added and the reaction mixture was heated at 150°C overnight. The reaction mixture was cooled to rt and poured into water. The resulting white precipitate was collected by filtration, 0.2g. MS (ESP): 238

Intermediate 12: 2-(cvclopentylthio)-9H-purin-6-amine

In a pressure tube, 2-chloro-9H-purin-6-amine (Intermediate 7, 0.2g, 1.2mmol), cyclopentanethiol (0.63mL, 6mmol) and cesium carbonate (0.77g, 2.4mmol) were combined in DMF (4mL) and heated at 150°C overnight. The reaction was not complete. More cesium carbonate (leq) and cyclopentanethiol (5eq) were added and the reaction mixture was heated at 150°C overnight. The reaction mixture was cooled to rt and poured into water. The resulting white precipitate was collected by filtration, 0.188 g. MS (ESP): 236 (MH⁺) for

Intermediate 13: 2-(cvclohexylthio)-9H-purin-6-amine

In a pressure tube, 2-chloro-9H-purin-6-amine (Intermediate 7, 0.2g, 1.2mmol), cyclohexanethiol (0.72mL, 6mmol) and cesium carbonate (0.77g, 2.4 mmol) were combined in DMF (4mL) and heated at 150°C overnight. The reaction was not complete. More cesium carbonate (leq) and cyclohexanethiol (5eq) were added and the reaction mixture was heated at 150°C overnight. The reaction mixture was cooled to rt and poured into water. The resulting white precipitate was collected by filtration, 0.114g. MS (ESP): 250 (MH⁺) for CnHi₅N₅S Intermediate 14: 2-(2-methoxyethoxy)-9H-purin-6-amine

2-chloro-9H-purin-6-amine (Intermediate 7, O.lg, O.όmmol), 2-methoxyethanol (3mL) and sodium hydroxide (~O.lg) were heated in a pressure tube at 150°C overnight. The excess 2-methoxyethanol was evaporated to give a brown oil, 0.1 Ig crude. MS (ESP): 210 (MH⁺) for C₈HnN₅O₂

Scheme IV: Intermediate 15

Intermediate 15 : 2-chloro-9-(2.,6-difluoro-3-methylbenzyl)-9H-purin-6-amine

2-chloro-9H-purin-6-amine (Intermediate 7, Ig, 6.4mmol), 2,6-difiuoro-3- methylbenzyl bromine (1.7g, 7.6mmol) and cesium carbonate (2.5g, 7.6mmol) were combined in DMF (1OmL) and stirred at rt overnight. The reaction mixture was poured into water and the off-white precipitate was collected by filtration, 2g. MS (ESP): 310 (MH⁺) for C₁₃H₁₀ClF₂N₅

Scheme V: Intermediates 16 and 17

Intermediate 16 : 2-chloro-A^/-f2-morpholin-4-ylethyl)-9H-purin-6-amine

Commercially available 2,6-dichloro-9H-purine (0.7g, 3.7mmol) and 4-(2- aminoethyl)morpholine (0.63mL, 4.8mmol) were combined in TΗF (4mL) and heated in microwave reactor for 30min at 120°C. The resulting tan solid was collected by filtration, 0.85g. MS (ESP): 283 (MH⁺) for C_HH_{I 5}CIN₆O Intermediate 17: 2-butoxy-A^/-(2-morpholin-4-ylethyl)-9H-purin-6-amine

2-chloro-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 16, 0.2g, 0.7mmol), 1-butanol (3mL) and sodium hydroxide (~0.1g) were heated in a pressure tube at 150°C overnight. The excess 1-butanol was evaporated to give a tan oil, 0.22g crude. MS (ESP): 321 (MH⁺) for Ci₅H₂₄N₆O₂

Scheme VI: Intermediate 18

Intermediate 18: 9-butyl-2-chloro-A^/-f2-morpholin-4-ylethyl)-9H-purin-6-amine

2-chloro-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 16, 1.2g, 4.4mmol), 1-bromobutane (0.52mL, 4.8mmol) and cesium carbonate (1.6g, 4.8mmol) were combined in DMF (1OmL) and heated at 60°C overnight. The DMF was evaporated and the resulting oil was dissolved in water and extracted twice with chloroform. The organic layers were dried over magnesium sulfate and evaporated to give an orange oil. Silica gel chromatography (dichloromethane/methanol) afforded desired product, 0.95g. MS (ESP): 339 (MH⁺) for Ci₅H₂₃ClN₆O

Scheme VII: Intermediate 19

Intermediate 19 : Λ^L(2-morpholin-4-ylethyl)-2-(4.,4.,4-trifluor obutoxy)-9H-purin-6-amine

2-chloro-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 16, 0.2g, 0.7mmol), 4,4,4-trifiuoro-l-butanol (2mL) and sodium hydroxide (~0.2g) were heated in a pressure tube at 150°C overnight. The excess alcohol was evaporated to yield a brown oil, 0.26 g crude. MS (ESP): 375 (MH⁺) for Ci₅H₂IF₃N₆O₂

Scheme VIII: Intermediate 20

Intermediate 20 : 2-chloro-9-(2.,6-difluoro-3-methylbenzyl)-A^/-(2-morpholin-4-ylethyl)- 9H-purin-6-amine

2-chloro-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 16, 0.2g, 0.7mmol), 2,6-difluoro-3-methylbenzyl bromine (0.18g, 0.84mmol) and cesium carbonate (0.27g, 0.84 mmol) were combined in DMF (2mL) and stirred at 60°C overnight. The reaction mixture was filtered and evaporated to yield an orange oil, 0.29g crude. MS (ESP): 423 (MH⁺) for Ci₉H₂IClF₂N₆O

Intermediates 26, 27, 28, 29, and 30 were prepared using an analogous method to that used to prepare Intermediate 20:

Intermediate 26: 2-chloro-9-(^,6-difluorobenzyl)-NJV-dimethyl-9H-purin-6-amine

The titled intermediate was prepared by alkylation of 2-chloro-7V,7V-dimethyl-9H- purin-6-amine [JACS (1958) 80 404-408] with 2,6-difiuorobenzyl bromide. MS (ES): 324(MH⁺) for Ci₄Hi₂ F₂N₅

Intermediate 27: 2-chloro-9-(^,6-difluorobenzyl)-iV-methyl-9H-purin-6-amine

The titled intermediate was obtained by alkylation of 2-chloro-7V-methyl-9H-purin-6- amine (prepared as described in JACS (1958) 80 404-408) with 2,6-difiuorobenzyl bromide. MS (ES): 309(MH⁺) for C_I3H_I0CI F₂N₅ 1H NMR (DMSO-Dfi) δ: 2.95( d, 3H), 5.48 (s, 2H); 7.25 (t, 2H); 7.50 (quintet, IH); 8.22 (s, IH); 8.30 (s, br, IH)

Intermediate 28: 2-chloro-9-(^,6-difluoro-3-methylbenzyl)-Λ^/-ethyl-9H-purin-6-amine

The titled intermediate was obtained by alkylation of 2-chloro-7V-ethyl-9H-purin-6- amine (prepared as described in WO 2001/009134) with 2,6-difluoro-3-methyl-benzyl bromide MS (ES): 338(MH⁺) for Ci₅Hi₄ F₂N₅Cl

Intermediate 29: A^/-benzyl-2-chloro-9-(2.,6-difluoro-3-methylbenzyl)-9H-purin-6-amine

The titled intermediate was prepared by alkylation of 7V-benzyl-2-chloro-9H-purin-6- amine (prepared as described in Tet. Letters (1998) 39 (13) 1827-1830) with 2,6-difluoro-3- methyl-benzyl bromide. MS (ES): 400(MH⁺) for C₂₀Hi₆ Cl F₂N₅

Intermediate 30: 2-chloro-A^/-cvclopropyl-9-(2.,6-difluoro-3-methylbenzyl)-9H-purin-6- amine

The titled intermediate was prepared by alkylation of 2-chloro-7V-cyclopropyl-9H- purin-6-amine (prepared as described in J. Med. Chem. (1997) 40(20) 3207-3216) with 2,6- difluoro-3-methyl-benzyl bromide. MS (ES): 350(MH⁺) for Ci₆Hi₄Cl F₂N₅

Scheme IX: Intermediate 21

Intermediate 21 : 2-(butyl{6- [(2-morpholin-4-ylethyl)aminol -9H-purin-2- vU amino)ethanol

2-Chloro-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 16, 0.2g, 0.7mmol), N,N-butylethanolamine (2mL) and sodium hydroxide (~0.1g) were heated in a pressure tube at 150°C overnight. The excess alcohol was evaporated and the resulting oil was dissolved in 0.25M sodium hydroxide and extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate and evaporated to yield a green oil, 0.12g. MS (ESP): 364 (MH⁺) for Ci₇H₂₉N₇O₂

Scheme X: Intermediate 22

Intermediate 22 : A^/-f2-morpholin-4-ylethyl)-2-phenoxy-9H-purin-6-amine

2-Chloro-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 16, 0.22g, 0.78mmol), phenol (~lg) and sodium hydroxide (~0.1g) were combined in a pressure tube and heated at 150°C for 4h. The cooled reaction mixture was diluted with chloroform and washed with water. Silica gel chromatography (dichloromethane/methanol) afforded desired product, 0.17g. MS (ESP): 341 (MH⁺) for Ci₇H₂₀N₆O₂

Scheme XI: Intermediate 23

Intermediate 23 : 5-(butylthio)-3H- [ 1 ,2,31 triazolo [4,5-</| pyrimidin-7-amine

2-(butylthio)pyrimidine-4,5,6-triamine (Intermediate 4, Ig, 4.7mmol) was dissolved in water (3OmL) and acetic acid (1OmL) at 0°C. A solution of sodium nitrite (0.4g, 5.6mmol) in water (15mL) was added dropwise. After 30 min a green solid was collected by filtration and washed with water, Ig. MS (ESP): 225 (MH⁺) for C₈Hi₂N₆S

Scheme XII: Intermediates 31-35

anilinium chloride Ethanol

Intermediate 32 Intermediate 35

Intermediate 31 Intermediate 34 Intermediate 31 : 6-amino-8-bromo-9-(2.,6-difluorobenzyl)-9H-purin-2-ol

A mixture of 5-amino-2-bromo-l-(2,6-difluorobenzyl)-lH-imidazole-4-carbonitrile (1.58g, 5.05mmol) [Intermediate 32]and urea (3.Og, 65.2mmol) were heated at 16O⁰C for 16h. Water (15mL) was added to the hot reaction. After cooling to rt, the precipitate was filtered, washed with acetone and dried under vacuum to obtain a solid (2.76g). MS (ESP) M/z= 356 (MΗ+) for Ci₂H₈BrF₂N₅O

Intermediate 32: 5-amino-2-bromo-l-(^,6-difluorobenzyl)-lH-imidazole-4-carbonitrile To a solution of 5-amino l-(2,6-difluorobenzyl)-lH-imidazole-4-carbonitrile (2.5g,

10.7mmol) (Intermediate 33) in TΗF (5OmL) was added dropwise a solution of N-bromo succinimide (2.47g, 13.9mmol) in TΗF (4OmL). The reaction was allowed to stir for 10 min. The reaction mixture was partitioned between ethylacetate and sodium bicarbonate (saturated solution). The organic phase was washed with brine, dried over MgSO₄ and evaporated to obtain a solid (1.58g, 47%). MS (ESP) M/z= 313 (MΗ+) for CnH₇BrF₂N₄

Intermediate 33: 5-amino l-(2,6-difluorobenzyl)-lH-imidazole-4-carbonitrile

A mixture of ethyl [(Z)-2-amino-l,2-dicyanovinyl]imido formate (prepared as described in Syn Commun 31(4) 549-554) (6.5g, 39.63mmol) and anilinium chloride (0.08, 0.62mmol) in ethanol (13OmL) was cooled to O⁰C. 2,6- difiuorobenzylamine (4.45g,

31.3mmol) was added dropwise keeping the temperature between 10-15⁰C. The reaction was allowed to stir at rt overnight. To the reaction mixture was added a solution of NaOH (IN, 75mL). The reaction was allowed to stir for 2h and then concentrated at reduced pressure. The residue was diluted with water (5OmL) and filtered. The solid was dried overnight under vacuum. (3.8g, 52%)

MS (ESP) M/z= 235 (MΗ+) for CnH₈F₂N₄

Intermediate 34 : 6-amino-8-chloro-9-(2.,6-difluorobenzyl)-9H-purin-2-ol

A mixture of 5-amino-2-chloro-l-(2,6-difluorobenzyl)-lH-imidazole-4-carbonitrile (0.93g, 3.47mmol) (Intermediate 35) and urea (3.0g, 43.5mmol) was heated at 16O⁰C for 16h. Water (1OmL) was added to the hot reaction. After cooling to rt, the precipitate was filtered, washed with acetone and dried under vacuum to obtain a solid (1.76 g). MS (ESP) M/z= 312 (MΗ+) for Ci₂H₈ClF₂N₅O Intermediate 35: 5-amino-2-chloro -l-(^,6-difluorobenzyl)-lH-imidazole-4-carbonitrile

To a solution of 5-amino l-(2,6-difluorobenzyl)-lH-imidazole-4-carbonitrile (1.Og, 4.3mmol) (Intermediate 33) in TΗF (5OmL) was added dropwise a solution of N-chloro succinimide (0.67g, 5.01mmol) in TΗF (4OmL). The reaction was allowed to stir overnight. The reaction mixture was partitioned between ethyl acetate and sodium bicarbonate (saturated solution). The organic phase was washed with brine, dried over MgSO₄ and evaporated to obtain a solid (0.93g, 80%) MS (ESP) M/z= 269 (MΗ+) for CnH₇ClF₂N₄

Scheme XIII: Intermediates 36 and 37

Intermediate 36: A^/-QH-benzimidazol-2-ylmethyl)-2-chloro-9H-purin-6-amine:

A solution of 2,6-dichloropurine (1.Og, 5.3mmol) in TΗF (2.5mL) was treated with 2- aminomethyl benzimidazole (1.3g, 5.91mmol). The reaction was heated to reflux for 3 days. The reaction was concentrated at reduced pressure. The residue was triturated with water, filtered, washed with hexane to yield a solid product with purity adequate for synthesis.

Intermediate 37: A^/-QH-benzimidazol-2-ylmethyl)-2-chloro-9-(2-morpholin-4-ylethyl)- 9H-purin-6-amine:

A solution ofΛ/-(lH-benzimidazol-2-ylmethyl)-2-chloro-9H-purin-6-amine (Intermediate 36) (1.7g, 5.3mmol)above was dissolved in DMF (15mL) and treated with Cs₂CO₃ (4.9g, 15.04 mmol) and 4-(2-chloroethyl)-morpholine (1.4g, 7.53 mmol). The reaction was allowed to stir at rt overnight. The reaction mixture was diluted with dichloromethane, washed with water twice, dried over MgSO₄ and evaporated to obtain the title compound as a solid (2.Og, 91%)

Scheme XIV: Intermediates 38 and 39

lntermediate 38

Intermediate 38: 2-chloro-N-[(5-methyl-2-furyr)methyll-9H-purin-6-amine :

A solution of 2,6-dichloropurine (1.Og, 5.3mmol) in TΗF (2.5mL) was treated with [(5-methyl-2-furyl)methyl]amine (0.6g, 5.38mmol). The reaction was heated to reflux for 3 days. The reaction was concentrated at reduced pressure. The residue was triturated with water, filtered, washed with hexane to yield a solid product (0.86g, 61 %). Carried on without further purification. MS (ESP) M/z= 264 (MΗ+) for CnHi₀ClN₅O

Intermediate 39: 2-chloro-N-[f5-methyl-2-furyl)methyll-9-(2-morpholin-4-ylethyl)-9H- purin-6-amine: A solution of 2-chloro-Λ/-[(5-methyl-2-furyl)methyl]-9H-purin-6-amine

(Intermediate 38) (0.75g, 2.84mmol) was dissolved in DMF (1OmL) and treated with Cs₂CO₃ (2.78g, 8.55mmol) and 4-(2-chloroethyl)-morpholine (0.795g, 4.27mmol). The reaction was allowed to stir at rt overnight. The reaction mixture was diluted with dichloromethane, washed with water twice, dried over MgSO₄ and evaporated. The residue was purified by reverse phase chromatography [15-75% CΗ3CΝ/Η2O, 0.1% TFA] to obtain the product as a TFA salt (1.Og, 72%).

Scheme XV: Intermediates 40 and 41

Intermediate 40: 2-chloro-A^L(2.,6-difluorobenzyl)-9H-purin-6-amine:

A solution of 2,6-dichloropurine (1.Og, 5.3mmol) in TΗF (2.5mL) was treated with 2,6-difluorobenzylamine (1.135g, 7.93mmol). The reaction was heated at 12O⁰C for 30min using microwave irradiation. The reaction was concentrated at reduced pressure. The residue was triturated with water, filtered, washed with hexane to yield a solid product (1.4g, 89%) MS (ESP) M/z= 296 (MΗ+) for Ci₂H₈ClF₂N₅

Intermediate 41: 2-chloro-A^/-(2.,6-difluorobenzyl)-9-(2-morpholin-4-ylethyl)-9H-purin-6- amine:

A solution of 2-chloro-Λ/-(2,6-difluorobenzyl)-9H-purin-6-amine (Intermediate 40)

(1.4g, 4.73mmol) was dissolved in TΗF (7.5mL) and treated with Cs₂CO₃ (2.75g, 8.46mmol) and 4-(2-chloroethyl)-morpholine (1.4g, 7.53mmol). The reaction was allowed to stir at rt overnight. The reaction mixture was diluted with dichloromethane, washed with water twice, dried over MgSO₄ and evaporated to obtain the title compound as a solid (1.26 g, 65 %) MS (ESP) M/z= 409 (MH+) for Ci₈Hi₉ClF₂N₆O

Scheme XVI: Intermediates 42 and 43

Intermediate 42: 4-{[f2-chloro-9H-purin-6-yl)aminolmethyl}benzenesulfonamide :

A solution of 2,6-dichloropurine (1.Og, 5.3mmol) in TΗF (2.5mL) was treated with 4- (aminomethyl)benzenesulfonamide (1.3g, 5.84mmol). The reaction was heated at 75⁰C for 2h. The reaction was concentrated at reduced pressure. The residue was triturated with water, filtered, washed with hexane to yield a solid product. (1.83g, quant.) MS (ESP) M/z= 338 (MΗ+) for Ci₂Hi ₁ClN₆O₂S

Intermediate 43: 4-(U2-chloro-9-(2-morpholin-4-ylethyl)-9H-purin-6- yllaminojmethvDbenzenesulfonamide:

A solution of 4-{[(2-chloro-9H-purin-6-yl)amino]methyl}benzenesulfonamide (Intermediate 42) (1.5g, 4.73mmol) above was dissolved in DMF (1OmL) and treated with Cs₂CO₃ (4.3g, 13.23mmol) and 4-(2-chloroethyl)-morpholine (1.25g, 6.72mmol). The reaction was allowed to stir at rt overnight. The reaction mixture was diluted with dichloromethane, washed with water twice, dried over MgSO₄ and evaporated to obtain the title compound as a solid (0.73g, 34 %) MS (ESP) M/z= 452 (MH+) for Ci₈H₂₂ClN₇O₃S

Scheme XVII: Intermediate 44

Intermediate 44

Intermediate 44 : 2-chloro-9-(2.,6-difluorolbenzyl)-A^/-(2-morpholin-4-ylethyl)-9H-purin- 6-amine

2-chloro-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 16, 1.415g, 5.0mmol), 2,6-difluorobenzyl bromine (1.24g, ό.Ommol) and cesium carbonate (1.69g, ό.Ommol) were combined in DMF (6mL) and stirred at 60°C overnight. The reaction mixture was diluted with ethyl acetate and water. Aqueous layer was extracted twice with ethyl acetate (25mL). Combined organic extracts were washed with water (3X 25mL), dried over MgS04 and evaporated to yield a pale yellow oil, 0.35g crude. MS (ESP): 409 (MH⁺) for Ci₈H₁₉ClF₂N₆O

Scheme XVIII: Intermediates 45-49

Intermediate 45

Intermediate 46

Intermediate 45: 4-(2,6-dichloropyrimidin-4-yl)morpholine

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

Intermediate 46: 4-f2-butoxy-6-chloropyrimidin-4-yl)morpholine To a suspension of NaH (60% in oil, 0.834g, 20.8 mmol) in DMF (2OmL) at O⁰C was added n-butanol (1.33mL, 14.6mmol). A solution of 4-(2,6-dichloropyrimidin-4- yl)morpholine (Intermediate 45) (3.25g, 13.9mmol) in DMF (2OmL) was added dropwise. The reaction was allowed to stir at O⁰C for 3h. The reaction was allowed to warm to rt. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was washed with water (IX 5OmL). The organic layers were combined, washed with water (4 X 4OmL), 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 (MH⁺) for Ci₂Hi₈ClN₃O₂

Intermediate 47: 2-butoxy-N-(3,4-dichlorobenzyl)-6-morpholin-4-ylpyrimidin-4-amine

A mixture of 4-(2-butoxy-6-chloropyrimidin-4-yl)morpholine (2.Og, 7.35mmol) (Intermediate 46) and 3,4- dichlorobenzylamine (1.96mL, 14.7mmol) was heated at 17O⁰C for 2h using microwave irradiation. The resultant product was dissolved in ethyl acetate and washed with IN hydrochloric acid. The organic extract was dried over MgSO₄ and evaporated to obtain a yellow solid. (2.14g, 70%) MS (ESP): 411 (MH⁺) for Ci₉H₂₄Cl₂N₄O₂

Intermediate 48: 2-butoxy-N-(3,4-dichlorobenzyl)-6-morpholin-4-yl-5-nitrosopyrimidin- 4-amine

To a solution of 2-butoxy-Λ/-(3,4-dichlorobenzyl)-6-morpholin-4-ylpyrimidin-4-amine (Intermediate 47) (2.14g, 5.19mmol) in acetic acid (2OmL) and water (2mL) at O⁰C was added dropwise a solution OfNaNO₂ (0.65g, 9.34mmol). The reaction turned a dark red color. The reaction was allowed to stir in ice for one hour, dileted with water and filtered. The blue solid was dried under vacuum at 45⁰C overnight. (1.76g, 75%) MS (ESP): 440 (MH⁺) for Ci₉H₂₃Cl₂N₅O₃ Intermediate 49: 2-butoxy-Λ^-(3,4-dichlorobenzyl)-6-morpholin-4-ylpyrimidine-4.,5- diamine

A suspension of 2-butoxy-7V-(3,4-dichlorobenzyl)-6-morpholin-4-yl-5- nitrosopyrimidin-4-amine (Intermediate 48) (1.76g, 4.01mmol) in ethanol (35mL) and acetic acid (ImL) was heated to reflux. Zinc dust (1.6g, 24.6mmol) was added portionwise at a rate to maintain reflux. Once the addition was complete the reaction was heated at reflux for Ih. The reaction was allowed to cool slightly, then was filtered through a pad of Celite. The filtrate was evaporated. The crude product was carried on to the subsequent step. MS (ESP): 426 (MH⁺) for Ci₉H₂₅Cl₂N₅O₂

Scheme XIX: Intermediate 50

n-butanol/NaOH

Intermediate 50: 2-butoxy-9H-purin-6-amine

In a sealed pressure tube was charged with 6-amino-2-chloro-purine (300mg, 1.77mmol), n-butanol (12ml) and sodium hydroxide (400mg, lOmmol). The tube was heated at 12O⁰C for 12h. The reaction mixture was then cooled to rt and excess of n-butanol was removed under reduced pressure. The residue was extracted with ethyl acetate and water. The solid in aqueous phase was filtered and dried to afford 150mg desired product (41% yield) as white solid. MS (ES): 208(MH⁺) for C₉H_nN₅O

Scheme XX: Intermediate 51 n-butanol/NaOH

Intermediate 51 : 2-butoxy-A^/-(pyridin-3-ylmethyl)-9H-purin-6-amine

In a sealed pressure tube was charged with 2-chloro-Λ/-(pyridin-3-ylmethyl)-9H-purin- 6-amine (800mg, 3.08mmol) (prepared as described in GB patent 2392155) , n-butanol (7mL) and sodium hydroxide (800mg, 20mmol). The tube was heated at 15O⁰C for 24h. The reaction mixture was then cooled to rt and excess of n-butanol was evaporated at reduced pressure. The residue was purified by silica-gel chromatography (methanol/dichloromethane) to afford 140mg desired product (15% yield) as white solid. MS (ES): 299(MH⁺) for C₁₅H₁₈N₆O

Intermediate 52: 2-butoxy-A^/-(3-furylmethyl)-9H-purin-6-amine

The titled intermediate was prepared in an analogous manner to Intermediate 51 using 2-chloro-Λ/-(3-furylmethyl)-9H-purin-6-amine (prepared as described in JACS (1959) 81, 3789-3792).

MS (ES): 288(MH⁺) for Ci₄Hi₇Cl N₅O₂

Intermediate 53 : 8-bromo-2-butoxy-9-(2.,6-difluorobenzyl)-9H-purin-6-amine Scheme XXI

The title compound was prepared by treating a solution of 6-amino-8-bromo-9-(2,6- difluorobenzyl)-9H-purin-2-ol (2.5g, 7.02 mmol) [Intermediate 31] in DMF (5OmL) with 1- bromobutane (2.25mL, 20.95mmol) and K2CO3 (5.8g, 42mmol). The reaction mixture was heated at 45⁰C overnight. The reaction was concentrated at reduced pressure, diluted with water (25mL) neutralized with NaHSO₄ (10% solution) and extracted with EtOAc. Organic extracts were dried over MgSO₄ and evaporated. Purification by reverse phase chromatography [35-50% Acetonitrile/FtO/ 0.1 % TFA] gave the title compound as solid. IH NMR (300 MHz, DMSO-D₆) δ ppm 0.89 (t, J=7.3 Hz, 3 H) 1.27 - 1.41 (m, 2 H) 1.51 - 1.64 (m, 2 H) 4.13 (t, J=6.6 Hz, 2 H) 5.32 (s, 2 H) 7.10 (t, J=8.10 Hz, 2 H) 7.39 - 7.55 (m, 3 H) MS (ESP) M/z= 412 (MH+) for Ci₆Hi₆BrF₂N₅O

Scheme XXII: Intermediates 54 and 55

Intermediate 54: Λ^L(lH-benzimidazol-2-ylmethyl)-2-chloro-9H-purin-6-amine

A solution of 2,6-dichloropurine (1.0 g, 5.3 mmol) in TΗF (2.5 mL) was treated with 2-aminomethyl benzimidazole (1.3 g, 5.91 mmol). The reaction was heated to reflux for 3 days. The reaction was concentrated at reduced pressure. The residue was triturated with water, filtered, washed with hexane to yield a solid product (1.76 g, >100%) [Purity was adequate to proceed with the synthesis.

Intermediate 55: Λ^L(lH-benzimidazol-2-ylmethyl)-2-chloro-9-(2-morpholin-4-ylethyl)- 9H-purin-6-amine: A solution ofΛ/-(lH-benzimidazol-2-ylmethyl)-2-chloro-9H-purin-6-amine (Intermediate 54) (1.7g, 5.3 mmol)above was dissolved in DMF (15mL) and treated with Cs₂CO₃ (4.9g, 15.04 mmol) and 4-(2-chloroethyl)-morpholine (1.4g, 7.53 mmol). The reaction was allowed to stir at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with water twice, dried over MgSO₄ and evaporated to obtain the title compound as a solid (2.0 g, 91%)

EXAMPLES Table 1 Experimental Example 1: 2-fbutylthio)-9-(3-nitrobenzyl)-9H-purin-6-amine

Scheme XXIII

2-(Butylthio)-9H-purin-6-amine (Intermediate 5, 0.22g, lmmol), 3- nitrobenzylbromide (0.22g, lmmol) and cesium carbonate (0.33g, lmmol) were combined in DMF (5mL) and stirred at rt overnight. The reaction mixture was filtered and concentrated under reduced pressure. The resulting oil was triturated with cold methanol to afforded the desired compound as a solid. MS (ES): 359 (MH⁺) for Ci₆Hi₈N₆O₂S. ¹R NMR Data DMSO-d6 0.83 (t, 3H); 1.33 (m, 2H); 1.56 (m, 2H); 3.03 (t, 2H); 5.46 (s, 2H); 7.35 (bs, 2H); 7.65 (m, IH); 7.77 (m, IH); 8.16 (m, IH); 8.20 (s, IH); 8.20 (m, IH). The examples in Table 1 below were prepared by analogous methods. The starting material is Intermediate 5 unless otherwise noted.

Table 1 Footnotes

1. purification by trituration with cold methanol

2. purification by reverse phase chromatography 3. purification by silica gel chromatography

4. NMR ran in methanol-d⁴ 5. starting material Intermediate 9

6. starting material Intermediate 10

7. starting material Intermediate 11

8. starting material Intermediate 12

9. starting material Intermediate 13

10. starting material Intermediate 14

11. starting material Intermediate 19

12. starting material Intermediate 21

13. starting material Intermediate 17

14. starting material Intermediate 22

15. purification by trituration with DCM

16. starting material Intermediate 23

17. starting material intermediate 51

18. starting material intermediate 52

19. starting material intermediate 50

Example 85 : 2-fcvclopropylmethoxy)-9- [3-(trifluoromethyl)benzyll -9H-purin-6-amine

Scheme XXIV

Intermediate 8 2-Chloro-9-[3-(trifluoromethyl)benzyl]-9H-purin-6-amine (Intermediate 8, 0.1 g,

0.32 mmol) and excess sodium hydroxide were suspended in cyclopropylmethanol in a sealed tube and heated at 70°C for 72 hours. The excess cyclopropylmethanol was evaporated and the resulting oil was triturated with water to afford the desired compound as a solid.

MS (ESP) M/z: 364 (MH⁺) for Ci₇Hi₆F₃N₅O

¹U NMR Data DMSO-d6 0.25 (m, 2H); 0.49 (m, 2H); 1.18 (m, IH); 4.01 (d, 2H); 5.35 (s, 2H); 7.24 (bs, 2H); 7.59 (m, 2H); 7.66 (m, IH); 7.77 (s, IH); 8.09 (s, IH).

The compounds in Table 2 were prepared by methods analogous to the method used to prepare Example 85. Table 2: Starting material is Intermediate 15 unless otherwise noted

Table 2 Footnotes

1. purification by trituration with water

2. purification by trituration with cold methanol 3. purification by silica gel chromatography

4. product crashed out of reaction mixture upon addition of methanol

5. purification by reverse phase chromatography

6. 2/1 mixture of isomers 7. starting material intermediate 8

8. starting material intermediate 20

9. starting material intermediate 18

10. NMR ran in methanol-d⁴

11. starting material intermediate 24 12. starting material intermediate 25

13. starting material intermediate 26

14. starting material intermediate 27

15. starting material intermediate 28

16. starting material intermediate 29 17. starting material intermediate 30

Example 130: 2-Q)utylthio)-9-[(2,6-difluorophenyl)acetyll-9H-purin-6-amine

Scheme XXV

2-(Butylthio)-9H-purin-6-amine (Intermediate 5, 0.2 g, 0.9 mmol), (2,6- difluorophenyl)acetyl bromide (0.42 g, 1.8 mmol) and triethylamine (0.25 mL, 1.8 mmol) were combined in DMF (4 mL) and heated at 60°C overnight. The solvent was evaporated and the resulting oil was triturated with cold methanol to afford the desired compound as a solid.

MS (ESP) M/z: 378 (MH⁺) for Ci₇Hi₇F₂N₅OS

¹U NMR Data DMSO-d6 0.79 (t, 3H); 1.29 (m, 2H); 1.56 (m, 2H); 2.98 (t, 2H); 5.55 (s, 2H);

7.31 (m, 2H); 7.34 (bs, 2H); 7.72 (m, IH); 8.00 (s, IH).

Compounds in Table 3 were prepared by methods analogous to those used to prepare Example 130. Table 3: compounds made by acylation

Table 3 Footnotes

1. purification by trituration with cold methanol

2. purification by reverse phase chromatography 3. NMR ran in methanol-d4

Table 4: Additional compounds of the invention

Table 4 Experimentals

Example 134: l-[6-amino-2-fbutylthio)-9H-purin-9-yll-2-(2.,6-difluorophenyl)ethanol

Scheme XXVI

To a solution of 2-(butylthio)-9-[(2,6-difluorophenyl)acetyl]-9H-purin-6-amine

(Example 130, 0.05g, O.Dmmol) in TΗF (2mL) at 0°C was added IM lithium aluminum hydride (0.26mL, 0.26mmol). The reaction mixture was stirred overnight at rt, then at 60°C for 48h. The reaction was quenched with methanol and saturated ammonium chloride, then filtered to remove solid. The filtrate was evaporated and triturated with cold methanol to yield a yellow solid, which was purified by reverse phase chromatography (acetonitrile/water/ammonium acetate) to give desired product.

Example 135: 3-f{2-butoxy-6-[f2-morpholin-4-ylethyl)aminol-l-oxido-9H-purin-9- yljmethvDbenzamide Scheme XXVII

To a solution of 3-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9- yl}methyl)benzonitrile (Example 71, 0.16g, 0.37mmol) in ethanol (2mL) at 0°C was added IN sodium hydroxide (ImL) and 30% hydrogen peroxide (ImL). The reaction mixture was stirred for Ih then warmed to rt and evaporated. The resulting oil was triturated with methanol and filtered to remove solid. The filtrate was evaporated to give white solid, which was purified by reverse phase chromatography (acetonitrile/water/ammonium acetate) to give the N-oxide of the desired compound.

Example 136: 3-f{2-butoxy-6-[f2-morpholin-4-ylethyl)aminol-9H-purin-9- yljmethvDbenzamide

Scheme XXVIII

To a solution of 3-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9- yl}methyl)benzonitrile (Example 71, 0.16g, 0.37mmol) in ethanol (2mL) at 0°C was added IN sodium hydroxide (ImL) and 30% hydrogen peroxide (ImL). The reaction mixture was stirred for Ih then quenched with sodium bisulfite. Solution stirred for 30min, then solvent was evaporated to give an oil. The sticky oil was triturated with methanol and evaporated to yield a white foam.

Example 137: 2-{[6-amino-2-fbutylthio)-9H-purin-9-yllmethyl}-4-nitrophenol Scheme XXIX

Example 137

The titled compound was obtained by demethylation of 2-(butylthio)-9-(2-methoxy-5- 5 nitrobenzyl)-9H-purin-6-amine (Example 7) (30.5mg, 0.0786mmol) with boron tribromide solution in dichloromethane (IM, 3mL, 3mmol) in dichloromethane (6mL) at 50°C for 24h as monitored by LC-MS. The reaction was quenched with water at room temperature and extracted with dichloromethane. After drying (MgSO₄) and removal of solvent, the desired product was purified by reverse phase HPLC (acetonitrile/Water/TFA). Yield, 5%. MS (ES): 10 375(MH⁺) for Ci₆Hi₈ N₆O₃S ¹H NMR (DMSO-Dn) δ: 0.90 (t, 3H); 1.50(m, 2H); 1.70(m, 2H); 3.25(t, 2H); 2.92 (t, 2H); 5.25 (s, 2H); 6.48(d, IH); 7.90(dd, IH); 8.15(m, 3H)

Examples 138 and 139: 4-f{2-butoxy-6-[f2-morpholin-4-ylethyl)aminol-l-oxido-9H- purin-9-vU methvDbenzamide and 4-({2-butoxy-6- [(2-morpholin-4-ylethyl)aminol -9H- 15 purin-9-yl}methyl)benzamide

Scheme XXX

The titled compound was prepared by oxidizing 4-({2-butoxy-6-[(2-morpholin-4- ylethyl)amino]-9H-purin-9-yl}methyl)benzonitrile (Example 83) (2.Og, 4.60mmol) with hydrogen peroxide (1OmL, 30% solution) in presence of IM NaOH (1OmL) in ethanol (5mL) at 0°C for Ih. The reaction was quenched with Na₂S₂O₃. After removing water and ethanol from the aqueous phase, the mixture was purified by reverse phase HPLC (NH40 Ac/Water). Two products were isolated. The first peak of 17mg was assigned as 4-({2-butoxy-6-[(2- morpholin-4-ylethyl)amino]-l-oxido-9H-purin-9-yl}methyl)benzamide (Example 138) and The second peak of 1.3 mg as 4-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9- yl}methyl)benzamide (Example 139) Example 138: MS (ES): 470(MH⁺) for C₂₃H₃IN₇O₄ ¹H NMR (CDSOD-D₁) δ: 0.75 (t, 3H); 1.42(m, 2H); 1.64(m, 2H); 3.10(m, 2H); 3.50(m, 6H); 4.2(m, 3H); 4.25 (t, 2H); 5.25(s, 2H); 7.25(d, 2H); 7.76(d, 2H); 7.82(s, IH)

Example 139: MS (ES): 454(MH⁺) for C₂₃H₃ iN₇O₄ ¹H NMR (CD30D-D_£) δ: 0.85 (t, 3H); 1.38(m, 2H); 1.65(m, 2H); 2.45(s, br, 4H); 2.55(t, 2H); 3.60(m, 6H); 4.25 (t, 2H); 5.29(s, 2H); 7.30(d, 2H); 7.76(d, 2H); 7.85 (s, IH)

Example 140: l-[4-f{2-butoxy-6-[f2-morpholin-4-ylethyl)aminol-9H-purin-9- vUmethvDphenyllethanone Scheme XXXI

The titled compound was prepared by reacting 4-({2-butoxy-6-[(2-morpholin-4- ylethyl)amino]-9H-purin-9-yl}methyl)benzonitrile (Example 83) (280mg, 0.64mmol) with methyl magnesium bromide (3M solution in diethyl ether, 0.56mL, 1.68mmol) in diethyl ether (1OmL) at -78⁰C. The reaction was allowed to warm to rt. The reaction was quenched with ammonium chloride and extracted with ethyl acetate. After drying (MgSO₄) and removal of solvent, the product (60mg) was isolated by silica-gel chromatography (methanol/ dichloromethane) as an oil (21% yield). MS (ES): 453(MH⁺) for C₂₄H₃₂N₆O₃ ¹H NMR (CDC13) δ: 0.95 (t, 3H); 1.41(m, 2H); 1.80(m, 2H); 2.52(s, 3H); 2.65(t, 2H); 3.75(m, 8H); 4.25 (t, 2H); 5.29(s, 2H); 6.30(s, br, IH); 7.35(d, 2H); 7.68 (m, 3H)

Example 141 : 2-butoxy-9-d,6-difluorobenzyl)-8-methyl-9H-purin-6-amine

Scheme XXXII

The title compound was prepared from Intermediate 53 as follows: A solution of 8- bromo-2-butoxy-9-(2,6-difluorobenzyl)-9H-purin-6-amine (lOOmg, 0.242mmol) in THF (5mL) was treated with triphenyl phosphine (7.0mg, 0.027mmol) and palladium dichloride (2.4mg, 0.013mmol). The reaction was allowed to stir under argon for 5min. Trimethyl aluminum (2N in hexanes, 0.27mL) was added dropwise. The reaction was heated at 15O⁰C for 1800 sec using microwave irradiation. The reaction mixture was evaporated at reduced pressure, diluted with chloroform, filtered through Celilte, washed with brine. The organic phase was dried over MgSO₄ and evaporated. Purification by reverse phase chromatography [25-60% acetonitrile/H₂0/0.1% TFA] gave the title compound as a solid. IH NMR (300 MHz, DMSO-D6) δ ppm 0.89 (t, J=7.3 Hz, 3 H) 1.29 - 1.42 (m, 2 H) 1.54 - 1.65 (m, 2 H) 4.17 (t, J=6.6 Hz, 2 H) 5.32 (s, 2 H) 7.02 - 7.17 (m, 2 H) 7.36 - 7.51 (m, 1 H) MS (ESP) M/z= 348 (MH+) for Ci₇Hi₉F₂N₅O

Example 142: 2-butoxy-9-(2.,6-difluorobenzyl)-A^/8-(2-morpholin-4-ylethyl)-9H-purine-

6,8-diamine

Scheme XXXIII

The title compound was prepared from Intermediate 53 as follows: 8-bromo-2- butoxy-9-(2,6-difluorobenzyl)-9H-purin-6-amine (lOOmg, 0.24mmol) was added to 4-(2- aminoethyl)morpholine (ImL, 7.63mmol). The reaction was heated to 17O⁰C for 1800s using microwave irradiation. The reaction mixture was concentrated at reduced pressure. The product was purified by reverse phase chromatography [5-95 % CH3CN/H2θ/O.l% TFA] to give the title compound as a TFA salt. IH NMR (300 MHz, DMSO-D6) δ ppm 0.87 (t, J=7.3 Hz, 3 H) 1.22 - 1.38 (m, 2 H) 1.46 - 1.60 (m, 2 H) 3.29 - 3.44 (m, J=13.9 Hz, 5 H) 3.67 - 3.77 (m, 4H) 3.78 - 3.89 (m, 6H) 4.06 (t, J=6.6 Hz, 2 H) 5.18 (s, 2 H) 7.09 (t, J=8.1 Hz, 2 H) 7.39 - 7.49 (m, 1 H) MS(ESP) M/z= 462 (MH+) for C₂₂H₂₉F₂N₇O₂

Table 5: The Examples in Table 5 were prepared as described for Example 142 using the appropriate amines

Example 150: 2-butoxy-A^/-f2,6-difluorobenzyl)-9-f2-morpholin-4-ylethyl)-9H-purin-6- amine

Scheme XXXIV

The title compound was prepared from 2-chloro-7V-(2,6-difiuorobenzyl)-9-(2- morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 41) as follows: A solution of 2- chloro-Λ/-(2,6-difluorobenzyl)-9-(2-morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 4I)(1.26g, 3.09mmol) in n-butanol (7.5mL) was treated with sodium hydroxide pellets (l.Og, 25mmol). The reaction was heated at 12O⁰C for 1800s using microwave irradiation. The reaction was concentrated at reduced pressure, partitioned between dichloromethane and - Ill - water. The aqueous phase was extracted with CH₂Cl₂ (2 X 25 mL). The organic phases were dried over MgSO₄ and evaporated to obtain the crude product. Purification by reverse phase chromatography [5-95 % CH₃CN/H₂0/0.1% TFA] gave the final compound as a TFA salt. MS (ESP) m/z = 447 [MH+] for C₂₂H₂₈F₂N₆O₂

Example 151: 2-butoxy-N-[(5-methyl-2-furyl)methyll-9-q-morpholin-4-ylethyl)-9H- purin-6-amine

Scheme XXXV

A solution of 2-chloro-N-[(5-methyl-2-furyl)methyl]-9-(2-morpholin-4-ylethyl)-9H- purin-6-amine (Intermediate 39) (1.Og, 2.65mmol) in n-butanol (1OmL) was treated with sodium hydroxide pellets (2.Og, 50mmol). The reaction was heated in a sealed tube at 8O⁰C over night. The reaction was concentrated at reduced pressure to afford a light yellow solid. The solid was dissolved in ethyl acetate, washed with water, dried over MgSO₄ and evaporated to obtain the product as a solid. 1Η NMR (300 MHz, DMSO-D6) δ ppm 0.80 - 0.94 (m, 3 H) 1.39 (dq, J=14.8, 7.4 Hz, 2 H) 1.57 - 1.71 (m, 2 H) 2.19 (s, 3 H) 2.33 - 2.45 (m, 4 H) 2.65 (t, J=6.1 Hz, 2 H) 3.43 - 3.56 (m, 4 H) 4.14 (t, J=6.1 Hz, 2 H) 4.21 (t, J=6.5 Hz, 2 H) 4.53 (s, 2 H) 5.94 (d, J=2.7 Hz, 1 H) 6.07 (d, J=2.7 Hz, 1 H) 7.93 (s, 1 H) MS (ESP) m/z= 415 [MH⁺] for C₂IH₃₀N₆O₃ Example 152: 2-butoxy-9-(2.,3-difluorobenzyl)-A^/-(2-morpholin-4-ylethyl)-9H-purin-6- amine

Scheme XXXVI

Intermediate 17

To a solution of 2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 17) (200mg, 0.625mmole) in TΗF (3mL) was added Cs₂CO₃ (300mg 0.923mmol and 2,3-difluorobenzyl bromide (0.2mL, 1.57mmol). The reaction was heated at 6O⁰C for 2h, diluted with water (2mL). The mixture was extracted with ethyl acetate (2 X 5mL). The organic extracts were dried over MgSO₄ and evaporated. The residue was purified by reverse phase chromatography [5-95% acetonitrile, water, 0.1 % TFA] to obtain the product as a TFA salt. 1Η NMR (300 MHz, DMSO-D6) δ ppm 0.89 (t, J=7.3 Hz, 3 H) 1.30 - 1.44 (m, 2 H) 1.57 - 1.70 (m, 2 H) 3.38 - 3.54 (m, 3 H) 3.61 - 3.72 (m, 3 H) 3.96 - 4.02 (m, 5 H) 4.23 (t, J=6.6 Hz, 2 H) 5.40 (s, 2 H) 7.14 - 7.28 (m, 1 H) 7.30 - 7.44 (m, 1 H) 7.59 - 7.73 (m, J=9.6 Hz, 1 H) 8.11 (s, 1 H) MS (ESP) m/z= 445 [M-H^"] for C₂₂H₂₈F₂N₆O₂

Table 6: The Examples in Table 6 were prepared as described for Example 152 using the appropriate alkylating agent and Intermediate 17 as starting material.

Table 6 Footnotes

¹ Reaction carried out at ambient temperature. Purified by silica gel chromatography using 0-5% methanol in dichloro methane

Example 177: 4-α[2-butoxy-9-α-morpholin-4-ylethyl)-9H-purin-6- yll ami noj meth v Dbenzenesu lfonam ide

Scheme XXXVII

A solution of 4-({[2-chloro-9-(2-morpholin-4-ylethyl)-9H-purin-6- yl]amino}methyl)benzenesulfonamide (Intermediate 43) (0.73Og, 1.62mmol) in n-butanol (10 mL) was treated with sodium hydroxide pellets (1.Og, 25mmol). The reaction was heated in a sealed tube at 8O⁰C overnight. The reaction was concentrated at reduced pressure to afford a light yellow solid. The solid was dissolved in ethyl acetate, washed with water, dried over MgSO₄ and evaporated to obtain the product as a solid. Purification by reverse phase chromatography [5-95% acetonitrile/water/0.1% TFA] gave the product as a TFA salt (0.175g). IH NMR (300MHz, DMSO-D6) δ ppm 0.9 (t, J=7 Hz, 3 H) 1.3 - 1.44 (m, 2 H) 1.57 - 1.70 (m, 2 H) 3.1 - 4.0 (m, 11 H) 4.15 - 4.25 (m, 2 H) 4.7 (s, 2 H) 7.3 (s, 2 H) 7.5 (d, J= 8.2 Hz, 2 H) 7.8 (d, J= 8.2 Hz, 2 H) 8.65 (bs, 1 H) MS (ESP) m/z= 490 [MH+] for C₂₂H₃IN₇O₄S

Example 178: 4-f{2-butoxy-6-2-morpholin-4-ylethyl)aminol-9H-purin-9-yl}methyl)-3- methoxybenzoic acid

Scheme XXXVIII

To a solution of methyl 4-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9- yl}methyl)-3-methoxybenzoate [Example 175] (97mg, 0.197mmol) in methanol (4mL) and water (ImL) was added sodium hydroxide (1 pellet). The reaction was allowed to stir at rt overnight. The mixture was evaporated at reduced pressure, partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2 X 5mL). The organic extracts were dried over MgSO4 and evaporated to obtain the title compound as a solid. IH NMR (300MHz, DMSO-D6) δ ppm 0.84 -0.96 (m, 3 H) 1.3 - 1.44 (m, 2 H) 1.57 - 1.70 (m, 2 H) 3.0 - 3.1 (m, 2 H) 3.25 - 3.37 (m, 2 H) 3.43 - 3.7 (m, 5 H) 3.74 - 3.95 (m, 6 H) 4.16 - 4.24 (m, 2 H) 5.29 (s, 2 H) 7.04 (d, J= 7.7 Hz , 1 H) 7.44 -7.55 (m, 2 H) 8.09-8.21 (m, 2 H) 10.6 (bs, 1 H) MS (ESP) m/z= 485 [MH+] for C₂₄H₃₂N₆O₅

Example 179: 2-butoxy-N-f2-morpholin-4-ylethyl)-9-[2-(trifluoromethyl)benzyll-9H- purin-6-amine

Scheme XXXIX

Intermediate 17

To a solution of 2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine (Intermediate 17) (96mg, 0.3mmol) in DMF (ImL) was added 2-trifluoromethylbenzyl bromide (87mg, 0.33mmol) and MP carbonate TM (500mg) the reaction was allowed to stir for 24h. The reaction was treated with thiophenol resin (-lmmol thiophenol) and filtered. Purification by reverse phase chromatography (5-95% acetonitrile/water 0.1% TFA) gave the title compound as a TFA salt. 1Η NMR (300 MHz, DMSO-D6) δ ppm 0.85 (t, J=7.3 Hz, 3 H) 1.24 - 1.37 (m, 2 H) 1.49 - 1.63 (m, 2 H) 2.41 (s, 5 H) 3.47 - 3.59 (m, 7 H) 4.13 (t, J=6.6 Hz, 2 H) 5.47 (s, 2 H) 6.88 (d, J=7.5 Hz, 1 H) 7.47 - 7.62 (m, 2 H) 7.70 (s, 1 H) 7.79 (d, J=7.5 Hz, 1 H) 7.99 (s, 1 H) MS (ESP) m/z= 479 [MH+] for C₂₃H₂₉F₃N₆O₂

Table 7: The Examples in Table 7 were prepared as described for Example 179 using the appropriate alkylating agent and Intermediate 17 as starting material.

Example 209: 9-[2-fluoro-6-fpent-2-vn-l-yloxy)benzyll-A^/-(2-morpholin-4-ylethyl)-2- (pent-2-vn-l-yloxy)-9H-purin-6-amine

Scheme XL

Intermediate 44

A solution of 2-chloro-9-(2,6-difluorolbenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine (Intermediate 44) (0.115g, 0.282mmol) in dioxane (0.7mL) was treated with 2- pentyn-1-ol (0.2mL, 0.198g, 2.35mmol) and sodium hydroxide(one pellet). The reaction was heated at 8O⁰C for 6Oh. The reaction mixture was filtered and evaporated. The residue was purified by reverse phase chromatography [35-95% CΗ₃CN/Η₂O/0.1% TFA] to obtain the product as a solid TFA salt. (28mg) IH NMR (300 MHz, DMSO-D6) δ ppm 1.05 (m, 6 H) 2.15 - 2.28 (m, 4 H) 3.03 - 3.18 (m, 2 H) 3.26 - 3.40 (m, 2 H) 3.55 - 3.63 (m, 2 H) 3.65 - 3.74 (m, 4 H) 3.92 - 4.07 (m, 2 H) 4.84 (s, 2 H) 4.92 (s, 2 H) 5.24 (s, 2 H) 6.83 - 6.96 (m, 2 H) 7.26 - 7.41 (m, 1 H) 7.96 (s, 1 H) 8.11 (s, 1 H) MS ESP M/z: 521 [M+H] for C₂₈H₃₃FN₆O₃

Table 8: Compounds in Table 8 were prepared as for Example 209 using the appropriate alcohol and the starting material as shown.

Scheme XLI: Examples 217 and 218

Example 217: ethyl 2-butoxy-9-(3,4-dichlorobenzyl)-6-morpholin-4-yl-9H-purine-8- carboxylate

To a suspension of 2-butoxy-Λ/⁴-(3,4-dichlorobenzyl)-6-morpholin-4-ylpyrimidine- 4,5-diamine (Intermediate 49) (approx. 1.7g, 4.0mmol) in N-methyl pyrrolidone (NMP) (6mL) at O⁰C was added ethyl oxalyl chloride (0.5mL, 4.4mmol). The reaction was allowed to warm to rt for 20min and then heated at 12O⁰C overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic extract was 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 TFA salt (0.135g) IH NMR (300 MHz, DMSO-D6) δ ppm 0.89 (t, J=I Hz, 3 H) 1.24 (t, J=I Hz, 3 H) 1.30 - 1.44 (m, 2 H) 1.57 - 1.71 (m, 2 H) 3.73 (s, 4 H) 4.18 - 4.27 (m, 3 H) 4.32 (q, J=7 Hz, 2 H) 4.5 (m, 2H) 5.60 (s, 2 H) 7.12 (d, J=8 Hz, 1 H) 7.49 - 7.62 (m, 2 H) MS ESP M/z: 508 [M+H] for C₂₃H₂₇Cl₂N₅O₄

Example 218: 2-butoxy-9-(3,4-dichlorobenzyl)-6-morpholin-4-yl-9H-purine-8- carboxylic acid

To a solution of ethyl 2-butoxy-9-(3,4-dichlorobenzyl)-6-morpholin-4-yl-9H-purine-8- carboxylate [Example 226] (0.12g, 0.24mmol) in TΗF (20 mL) was added sodium hydroxide (IN, 2mL). The reaction was heated to 6O⁰C overnight. The reaction mixture was neutralized with IN HCl, partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2X) and dichloromethane (2X). The organic extracts were combined dried over MgSO₄ and evaporated. The solid was triturated with methanol to obtain the title compound. 1Η NMR (300 MHz, DMSO-D6) δ ppm 0.89 (t, J=7.3 Hz, 3 H) 1.31 - 1.44 (m, 2 H) 1.59 - 1.70 (m, 2 H) 3.66 - 3.79 (m, 5 H) 4.17 - 4.31 (m, Hz, 3 H) 5.61 (s, 2 H) 7.12 (dd, J=8.4, 2.0 Hz, 1 H) 7.52 - 7.59 (m, 2 H) MS ESP M/z: 480 [M+H] for C₂IH₂₃Cl₂N₅O₄

Example 219: N-αH-benzimidazol-2-ylmethyl)-2-butoxy-9-q-morpholin-4-ylethyl)-9H- purin-6-amine

Scheme XLII

n-butanol, NaOH

I

A solution ofΛ/-(lH-benzimidazol-2-ylmethyl)-2-chloro-9-(2-morpholin-4-ylethyl)-9H-purin- 6-amine (Intermediate 55) (1.5 g, 3.63 mmol) in n-butanol was treated with sodium hydroxide pellets (2.0 g, excess). The reaction was heated in a sealed tube at 8O⁰C over night. The reaction was concentrated at reduced pressure to afford a light yellow solid. The solid was dissolved in ethylacetate, washed with water, dried over MgSO₄ and evaporated to obtain the product as a yellow foam. 1U NMR (300 MHz, DMSO-D6) δ ppm 0.77 - 0.91 (m, 3 H) 1.24 - 1.38 (m, 2 H) 1.50 - 1.61 (m, 2 H) 2.30 - 2.40 (m, 4 H) 2.56 - 2.71 (m, 2 H) 3.24 - 3.36 (m, 3 H) 3.43 - 3.57 (m, 4 H) 4.16 (t, J=6.1 Hz, 2 H) 7.07 - 7.23 (m, 2 H) 7.52 (dd, J=7.3, 5.0 Hz, 2 H) 7.96 (s, 1 H) MS (ESP) m/z= 451 [MH⁺] for C₂₃H₃₀N₈O₂

Example 220: 9-[4-(aminomethyl)benzyl]-2-butoxy-Λ^L(2-morpholin-4-ylethyl)-9H- purin-6-amine

Scheme XLIII

Example 220 To a solution of 4-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9- yl}methyl)benzonitrile (Example 83) (95mg, 0.218mmol) in THF (4 ml) was added a solution of lithium aluminum hydride(0.436 ml, 0.436mmol) at room temperature. The reaction was completed in 2 hrs. The reaction was quenched by slow addition of methanol. After removing THF and methanol, the residue was extracted with ethyl acetate and washed with water. The aqueous phase was evaporated to obtain the crude product. The product was purified by reverse phase HPLC (Acetonitrile/Water /TFA). The product (80mg, 84% yield) was obtained as and oil. MS (ES): 440(MH⁺) for C₂₃H₃₃N₇O₂

¹H NMR (CDOD-D₁) δ: 1.0 (t, 3H); 1.45(m, 2H); 1.82(m, 2H); 3.20(m, 6H); 4.00 (m, 4H); 4.40(t, 2H); 5.00(m, 6H); 5.45 (s, 2H); 7.46(m, 4H); 8.20(m, br, 2H)

Example 221: LGDH Coupled Enzyme Assay Compounds were tested for inhibition of glutamate racemase using a coupled enzyme assay as previously described (Lundqvist et al, "Exploitation of structural and regulatory diversity in glutamate racemases" Nature, 2007, in press). Assays were performed in 96-well polystyrene flat-bottom black plates (FLUOTRAC 200) in 102 μl reactions containing 2 μl compound dissolved in dimethylsulfoxide, 85 μl Enzyme Working Solution (final concentrations were 100 mM Tris pH 8.0, 0.03 % PEG 8000, 0.03 mg/mL bovine serum albumin, 15 LVmL L-glutamate dehydrogenase (LGDH), 5 mM dithiothreitol, 10 mM NAD⁺ and either 80 nM E.faecalis Murl or 100 nM E.faecium Murl or 1 uM S. aureus Murl) and 15 μl 6.67 mM D-glutamate to initiate the reaction (final concentration was 1 mM).

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 lOug/ml tetracycline and 50ug/ml kanamycin to mid- log phase. Induction was carried out overnight at room temperature in the presence of 50OuM IPTG and ImM D/L Glutamate.

E. faecium Murl was cloned into a modified pET28b expression vector. This protein is contains an N-terminal histidine tag and was expressed in E. coli strain BL21(DE3) as follows: the culture was grown to mid-log phase in LB medium containing 25ug/ml kanamycin, then induced with 40OuM IPTG for 2 hours at 37C.

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

ATGGGCAGCAGCCATCATCATCATCATCACAGCAGCGGCCTGGTGCCGCGCGGCAGCCATAT GAATAAACCAATAGGTGTAATAGACTCTGGTGTCGGAGGTTTGACAGTAGCTAAAGAAATTA TGCGTCAGTTGCCAAATGAGACGATTTATTACTTAGGTGATATTGGGCGATGTCCATATGGG CCAAGACCAGGAGAACAAGTAAAACAATATACAGTTGAAATCGCTCGTAAATTAATGGAATT TGATATAAAAATGCTCGTGATTGCTTGTAATACTGCAACTGCTGTAGCTTTAGAATATTTAC AAAAGACCTTATCAATCTCAGTGATTGGCGTAATTGAACCAGGTGCTAGAACAGCAATAATG ACGACTAGAAATCAAAATGTATTAGTACTAGGAACGGAAGGCACAATTAAATCTGAAGCATA TCGAACACATATTAAACGTATAAATCCACATGTAGAGGTACATGGCGTTGCCTGTCCAGGTT TTGTGCCACTTGTAGAACAAATGAGATATAGTGATCCAACAATTACAAGCATTGTTATTCAT CAAACACTGAAACGTTGGCGTAATAGTGAGTCTGATACTGTCATTTTAGGATGTACCCACTA TCCATTGCTCTATAAACCTATCTATGATTATTTTGGTGGTAAAAAGACAGTGATTTCGTCTG GATTAGAAACGGCTCGTGAAGTTAGTGCATTGCTAACATTTAGTAATGAACATGCAAGTTAT ACTGAACATCCAGATCATCGATTTTTTGCAACAGGTGATACCACACATATTACTAACATTAT CAAAGAATGGCTAAATTTATCTGTCAATGTGGAACGTATATCAGTGAATGACTAG

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

MGSSHHHHHHSSGLVPRGSHMNKPIGVIDSGVGGLTVAKEIMRQLPNETIYYLGDIGRCP YGPRPGEQVKQYTVEIARKLMEFDIKMLVIACNTATAVALEYLQKTLS I SVIGVIEPGAR TAIMTTRNQNVLVLGTEGTIKSEAYRTHIKRINPHVEVHGVACPGFVPLVEQMRYSDPTI TSIVIHQTLKRWRNSESDTVILGCTHYPLLYKPIYDYFGGKKTVISSGLETAREVSALLT FSNEHASYTEHPDHRFFATGDTTHITNIIKEWLNLSVNVERISVND

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 MGSSHHHHHHSSGLVPRGSHMSNQEAIGLIDSGVGGLTVLKEALKQLPNERLIYLGDTAR CPYGPRPAEQWQFTWEMADFLLKKRIKMLVIACNTATAVALEEIKAALPIPWGVILPG ARAAVKVTKNNKIGVIGTLGTIKSASYEIAIKSKAPAIEVTSLACPKFVPIVESNQYRSS VAKKIVAETLQALQLKGLDTLILGCTHYPLLRPVIQNVMGSHVTLIDSGAETVGEVSMLL DYFDIAHTPEAPTQPHEFYTTGSAKMFEEIASSWLGIENLKAQQIHLGGNEND

E. faecium murl cloned in modified pET28b vector (Factor Xa cleavable his tag)

ATGGGCAGCAGCCATCATCATCATCATCACAGCAGCGGTACCATCGAGGGAAGGATGATACG ATTGACAGATAATCGCCCTATCGGATTTATTGATTCAGGTGTCGGCGGCTTGACTGTAGTAA AAGAAGCCCTGAAACAATTACCGAATGAAAATATTTTATTTGTAGGAGACACAGCACGCTGC CCATATGGCCCTAGACCCGCGGAACAGGTAATACAGTATACTTGGGAAATGACGGATTATCT GGTGGAGCAAGGAATCAAGATGCTGGTGATCGCCTGCAATACCGCAACTGCGGTGGCTTTAG AAGAAATCAAAGCTGCTCTTTCTATTCCAGTCATCGGTGTGATCCTTCCCGGTACTAGAGCG GCAGTAAAAAAAACACAAAATAAACAAGTTGGCATTATCGGTACGATTGGTACGGTAAAAAG TCAAGCTTATGAAAAAGCACTGAAAGAGAAAGTACCAGAATTGACTGTGACAAGTCTTGCTT GTCCAAAATTTGTTTCAGTTGTCGAAAGTAATGAATACCATTCATCGGTGGCGAAAAAAATT GTGGCAGAAACATTAGCTCCTTTAACCACTAAAAAAATCGATACATTGATTTTGGGATGCAC CCATTATCCATTATTACGCCCCATCATTCAAAATGTAATGGGAGAAAATGTTCAACTGATCG ATTCTGGAGCAGAAACAGTAGGTGAAGTATCTATGCTGTTAGATTATTTCAATCTGAGCAAT TCACCGCAAAATGGTCGGACATTATGCCAGTTTTATACAACTGGCTCTGCCAAACTTTTCGA GGAAATAGCTGAAGACTGGCTTGGAATCGGACACTTAAATGTAGAACATATCGAATTGGGAG GAAAATAA

MGSSHHHHHHSSGTIEGRMIRLTDNRPIGFIDSGVGGLTWKEALKQLPNENILFVGDTA RCPYGPRPAEQVIQYTWEMTDYLVEQGIKMLVIACNTATAVALEEIKAALS IPVIGVILP GTRAAVKKTQNKQVGIIGTIGTVKSQAYEKALKEKVPELTVTSLACPKFVSWESNEYHS SVAKKIVAETLAPLTTKKIDTLILGCTHYPLLRPI IQNVMGENVQLIDSGAETVGEVSML LDYFNLSNSPQNGRTLCQFYTTGSAKLFEEIAEDWLGIGHLNVEHIELGGK Purification of E. faecalis Murl and E. faecium Murl and S. aureus Murl was carried out as follows. The frozen cell paste was resuspended in 50 ml of Lysis Buffer [20 mM Tris/HCl, pH 7.5, 5 mM DL-Glutamate, 1 EDTA-free protease inhibitor cocktail tablet (Roche Molecular Biochemical)]. Cells were disrupted by French press at 18,000 psi twice at 4⁰C, and the crude extract was centrifuged at 20,000 rpm (45Ti rotor, Bechman) for 30 minutes at 4⁰C. The supernatant was loaded at a flow rate of 2.0 ml/min onto a 5 ml HiTrap Ni²⁺ chelating column (GE Healthcare Lifebioscinces) pre-equalibrated with Buffer A (20 mM Tris/HCl, pH 7.5, 5 mM DL-GIu). The column was then washed with Buffer A, and the protein was eluted by a linear gradient from 0 to 0.5 M Imidazole in Buffer A. Fractions containing Murl were pooled, and solid

(0.4 g/ml) was added to precipitate all the proteins and mixed on ice for 1 hour. The sample was centrifuged at 25,000 rpm for 30 min at 4⁰C (45Ti rotor, Beckman); the pellet was then dissolved in 9 ml of Buffer A. The 5 ml sample was applied at a flow rate of 1.0 ml/min to a 320 ml Sephacryl S-200 (HR 26/60) (GE Healthcare Lifebioscinces) pre-equalibrated with Buffer A. The fractions containing Murl were pooled and dialyzed against 1 L Storage buffer (10 mM Tris/HCl, pH 7.5, 0.1 mM EGTA, 150 mM NaCl, 1 mM TCEP, 5 mM 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.

The assay reactions were incubated at room temperature for 60 minutes. Plates were read using a Tecan Ultra plate reader (excitation wavelength 340 nm, emission wavelength 465 nm). Data were reported as the difference between the fluorescence reads at 60 and 0 minutes. 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.

The compounds of the invention described herein have a measured IC50 in this assay against at least one isozyme of Murl (e.g., E. faecalis Murl, E. faecium Murl or S. aureus Murl) of <400 μM or the compounds inhibit the glutamate racemase reaction by >20% at the limit of their solubility in the assay medium.

Representative IC50 values for E. faecalis Murl, E. faecium Murl or S. aureus Murl inhibition by the compounds of the instant invention is indicated in Table 9 below. Table 9

All publications, patent applications, patents, and other documents cited herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting in any way.

Claims

What we claim:

1. A compound represented by formula (I):

R₃^_N/R₄

amino,

and

X₂ is -O-, -S-, or -NR^a-, wherein R^a is hydrogen or a C_1-6alkyl;

Ri is a C₃_i₄carbocycle, morpholinyl, quinolinyl, benzodioxinyl, benzodioxolyl, 1-H-pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 2-oxo-2,3- dihydro-l,3-benzoxazolyl, tetrahydro-lH-pyran, 1-benzothiophenyl, furanyl, thiazolyl, isoxazolyl, or oxetanyl, wherein the carbocycle, morpholinyl, quinolinyl, benzodioxinyl, benzodioxolyl, 1-H-pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 2- oxo-2,3-dihydro-l,3-benzoxazolyl, tetrahydro-lH-pyran, 1-benzothiophenyl, furanyl, thiazolyl, isoxazolyl, and oxetanyl are optionally substituted on one or more carbon atom with one or more R₅; and wherein each =N- of the quinolinyl, pyrazolyl, 1,3,4- oxadiazolyl, 1,2,4-oxadiazolyl, thiazolyl, and isoxazolyl, may be each independently optionally substituted with an oxo; and wherein the -NH- of morpholinyl, 1-H- pyrazolyl, and 2-oxo-2,3-dihydro-l,3-benzoxazolyl may be optionally substituted with

Rn;

R₂ is a C_1-6alkyl, C_1-6alkenyl, C_1-6alkynyl, C3-i4carbocycle, heterocycle, C_3- ₁₄carbocycleC_1-6alkyl, or heterocycleC_1-6alkyl, wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl may be optionally substituted on one or more carbon atoms with one or more R₆, and wherein if R₂ is a heterocycle or a heterocyclealkyl comprising one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₂ is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with R₈;

R₃ and R₄ are each, independently, hydrogen, Ci.₆alkyl, C₂-₆alkenyl, C_2- 6alkynyl, C_3-14carbocycle, heterocycle,

or heterocycloCi.

₆alkyl, wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocycloalkyl may be optionally substituted on one or more carbon atoms with one or more R₇, and wherein if R₃ or R₄ is a heterocycle or a heterocyclealkyl comprising one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R3 or R₄ is a heterocycle or a heterocyclealkyl that contains one or more -NH-, each -NH- may be independently optionally substituted with R₉; or R₃ and R₄ taken together with the nitrogen atom to which they are attached form a heterocycle which may be optionally substituted on one or more carbon atoms with one or more R₇, wherein if the heterocycle comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if the heterocycle comprises one or more -NH-, each -NH- may be independently optionally substituted with R₉; R₅, R5 and R₇, for each occurrence, are independently selected from the group consisting of a halo, nitro, cyano, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C3_i4carbocycle, heterocycle, C_3-14carbocycleC_1-6alkyl, heterocycleC_1-6alkyl, C_1-6haloalkyl, -ORn, - SR₁₁, -NR₁₂R₁₃, -C(O)R₁₁, -C(O)OR₁₁, -C(O)NR₁₂R₁₃, -NR₁₁C(O)R₁₁, -OC(O)R₁₁, - NR₁₁C(O)OR₁₁, -OC(O)NR₁₂R₁₃, -NR₁₁C(O)NR₁₂R₁₃, -NR₁₁C(NR₁₄)NR₁₂R₁₃, - S(O)pRi 1 , -NR₁1 S(O)pRi 1 , and -S(O)_pNR₁₂Ri₃, wherein if R₅, R₆ or R₇ is alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be optionally further substituted on one or more carbon atoms with one or more R₁₅; and wherein if R5, R₆ or R₇ is a heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₅, R₆ or R₇ is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with R₁₆; Rs, R₉, or RiV, for each occurrence, are independently selected from the group consisting of Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, C_3-i₄carbocycle, heterocycle, C_3- i₄carbocycleCi-₆alkyl, heterocycleCi-_δalkyl, Ci-_όhaloalkyl, -C(O)Rn, -C(O)ORn, - C(O)NRi₂Rn, -S(O)pRn,and -S(O)_pNRi₂Ri₃, wherein if R₈, R₉ or R_n is alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be optionally substituted on one or more carbon atoms with one or more Ri₅; and wherein if R₈, R₉ or Rn is a heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₈, R₉ or Rn is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆;

Rio is hydrogen, a C_1-6alkyl, a heterocycleCi-δalkyl, -NRi₂Ri₃, -C(O)Rn, - C(O)ORn, -C(O)NRi₂R_n, -NRnC(0)Rn, -OC(O)Rn, -NRnC(O)ORn, - OC(O)NRi₂Ri₃, -NRnC(NRi₄)NRi₂Ri₃, -S(O)_pRn, -NRnS(0)_pRn, and -

Rn, for each occurrence, is independently selected from the group consisting of hydrogen,

C_2-6alkenyl, C_2-6alkynyl, C_3-i₄carbocycle, heterocycle, C_3- i₄carbocycleCi-₆alkyl, heterocycleCi-_δalkyl, wherein if Rn is an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be independently optionally substituted on one or more carbon atom with one or more Ri 5, and wherein if Rn is heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if Rn is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆;

Ri 2 and Ri₃, for each occurrence, are independently selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-i₄carbocycle, heterocycle, C_3-i₄carbocycleCi-₆alkyl, heterocycleCi-_δalkyl, wherein if Ri₂ or Ri₃ is an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be independently optionally substituted on one or more carbon atom with one or more Ri 5, and wherein if Ri₂ or Ri₃ is heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R12 or Rn is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆; or R12 and Rn taken together with the nitrogen atom to which they are attached for a heterocycle, wherein the heterocycle may be optionally substituted on one or more carbon atoms with one or more Ri 5, and wherein if the heterocycle comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if the heterocycle comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆;

Ri 5, for each occurrence, is independently selected from the group consisting of halo, nitro, cyano, Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, C_3-i4carbocycle, heterocycle, Cs-ncarbocycleCi-oalkyl, heterocycleCi-όalkyl, Ci-όhaloalkyl, -ORis, -SRis, -NR1₉R20, -C(O)Ri₈, -C(O)ORi₈, -C(O)NRi₉R₂₀, -NRi₈C(O)Ri₈, -OC(O)Ri₈, -NRi₈C(O)ORi₈, - OC(O)NRi₉R₂₀, -NRi₈C(O)NRi₉R₂₀, -NRi₈C(NR₂i)NRi₉R₂₀, -S(O)_pRi₈, -

NRi₈S(O)_pRi₈, and -S(O)_pNRi₉R₂₀;

Ri 4 and R₂1, for each occurrence, are independently selected from the group consisting of hydrogen, a C_1-6alkyl, nitro, cyano, amino, alkylamino, dialkylamino, or hydroxy; R₁₆, for each occurrence, is independently selected from the group consisting of C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C3_i4carbocycle, heterocycle, C_3-14CaIt)OCyCIeC_1- ₆alkyl, heterocycleCi-ealkyl, Ci_-6haloalkyl, -C(O)Ri₈, -C(O)ORi₈, -C(O)NRi₉R₂₀, - S(O)pRi₈, and -S(O)_pNRi₉R₂₀;

Ri₈, for each occurrence, is independently selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C3-i4carbocycle, heterocycle, C_3-

₁₄carbocycleC_1-6alkyl, heterocycleC_1-6alkyl;

Ri₉ and R₂₀, for each occurrence, are independently selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-i4carbocycle, heterocycle, C_3-14carbocycleC_1-6alkyl, heterocycleC_1-6alkyl; or Ri₉ and R₂₀ taken together with the nitrogen atom to which they are attached for a heterocycle; and p is 1 or 2, provided that Ri is not an unsubstituted phenyl, unsubstituted biphenyl, an unsubstituted cyclopropyl, or 3-cyclopentyloxy-4-methoxyphenyl; provided that when Ri is 4-chlorophenyl, 4-fluorophenyl, cyclohexyl, or furanyl, R₂ is not unsubstituted naphthyl or unsubstituted cyclopentyl; provided that when Ri is morpholinyl, one of R₃ and R₄ are not 4-aminobenzyl or phenylethyl; provided that when X₂ is -NR^a-, R₂ is a C^aUcyl which is optionally substituted with on one or more carbon atom with one or more R₆, and Ri is not 4- aminophenyl, 2-chlorophenyl, 4-methylphenyl, 3-(methoxycarbonylmethyl)-phenyl, 2-fluorophenyl, or 2,6-difiuorophenyl; provided that when -X₂-R₂ is methylsulfanyl, Ri is not 4-methylphenyl, 2- methoxyphenyl, or 2-fluorophenyl; provided that when -X₂-R₂ is an unsubstituted n-butyloxy , Ri is not 3-(2- methoxy-2-oxoethyl)-phenyl, 3-cyanomethyl-phenyl, 3-chloromethyl-phenyl, 3- hydroxymethyl-phenyl, 4-benzyloxyphenyl, 3-cyanomethyl-4-fluoro-phenyl, 3- chloromethyl-4-fluoro-phenyl, 3-hydroxymethyl-4-fluoro-phenyl, 3-methoxycarbonyl- 4-fluoro-phenyl, 2-methoxy-5-cyanomethyl-phenyl, 2-methoxy-5-chloromethyl- phenyl, 2-methoxy-5 -hydroxymethyl-phenyl, 2-methoxy-5 -methoxycarbonyl-phenyl, 3,4-di-(methoxycarbonyl)-phenyl, 4-hydroxyphenyl, or 3-(l,l,

2-trimethoxy-2- oxoethyl)-phenyl; and provided that when -X-R₂ is an unsubstituted n-butyloxy and -NR₃R₄ is -NH₂, Ri is not 3-methoxycarbonyl-phenyl or 4-acetoxyphenyl.

A compound represented by formula (II):

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

X₄ is -O- or -S-;

R₂ is a

Ci_6alkenyl, Ci_6alkynyl, C_3-i4carbocycle, heterocycle, C_3- i₄carbocycleCi_₆alkyl, or heterocycleCi-_όalkyl, wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl may be optionally substituted on one or more carbon atoms with one or more R₆, and wherein if R₂ is a heterocycle or a heterocyclealkyl comprising one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₂ is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Rs;

R₃ and R₄ are each, independently, hydrogen, Ci_₆alkyl, C₂-₆alkenyl, C_2- ₆alkynyl, C_3-14carbocycle, heterocycle, C3-i4carbocycleCi.6alkyl, or heterocycloCi. βalkyl, wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocycloalkyl may be optionally substituted on one or more carbon atoms with one or more R₇, and wherein if R₃ or R₄ is a heterocycle or a heterocyclealkyl comprising one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R3 or R₄ is a heterocycle or a heterocyclealkyl that contains one or more -NH-, each -NH- may be independently optionally substituted with R₉; or R₃ and R₄ taken together with the nitrogen atom to which they are attached form a heterocycle which may be optionally substituted on one or more carbon atoms with one or more R₇, wherein if the heterocycle comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if the heterocycle comprises one or more -NH-, each -NH- may be independently optionally substituted with R₉;

R22 is a C3_6alkyl which is optionally substituted on one or more carbon atom with one or more substituents selected from the group consisting of halo, nitro, cyano,

-OR₁₁, -SR₁₁, -NR₁₂R₁₃, -C(O)R₁₁, -C(O)OR₁₁, -C(O)NR₁₂R₁₃, -NR₁₁C(O)R₁₁, - OC(O)R₁₁, -NR₁₁C(O)OR₁₁, -OC(O)NR₁₂R₁₃, -NR₁₁C(O)NR₁₂R₁₃, - NR₁₁C(NR₁₄)NR₁₂R₁₃, -S(O)_pR_π, -NR₁₁S(O)_PR₁₁, and -S(O)_PNR₁₂R₁₃;

R5 and R₇, for each occurrence, are independently selected from the group consisting of a halo, nitro, cyano, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-14carbocycle, heterocycle, C_3-14carbocycleC_1-6alkyl, heterocycleC_1-6alkyl, C_1-6haloalkyl, -OR₁₁, - SR₁₁, -NR₁₂R₁₃, -C(O)R₁₁, -C(O)OR₁₁, -C(O)NR₁₂R₁₃, -NR₁₁C(O)R₁₁, -OC(O)R₁₁, - NR₁₁C(O)OR₁₁, -OC(O)NR₁₂R₁₃, -NR₁₁C(O)NR₁₂R₁₃, -NR₁₁C(NR₁₄)NR₁₂R₁₃, - S(O)pRn, -NRiiS(O)pRn, and -S(O)_pNRi₂Ri3, wherein if R₆ or R₇ is alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be optionally further substituted on one or more carbon atoms with one or more Ri₅; and wherein if R₆ or R₇ is a heterocycle or a heterocyclealkyl that comprises one or more - S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₆ or R₇ is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆; Rs or R₉, for each occurrence, are independently selected from the group consisting of C_1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-i4carbocycle, heterocycle, C_3- i₄carbocycleCi-₆alkyl, heterocycleCi-₆alkyl, Ci-_δhaloalkyl, -C(O)Rn, -C(O)ORn, - C(O)NRi₂Rn, -S(O)pRn,and -S(O)_pNRi₂Ri3, wherein if R₈ or R₉ is alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be optionally substituted on one or more carbon atoms with one or more Ri₅; and wherein if R₈ or R₉ is a heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R₈ or R₉ is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆; Rio is hydrogen, a C_1-6alkyl, a heterocycleC_1-6alkyl, -NRi₂Rn, -C(O)Rn, -

C(O)ORn, -C(O)NRi₂R_n, -NRnC(0)Rn, -OC(O)Rn, -NRnC(O)ORn, - OC(O)NRi₂Ri₃, -NRnC(NRi₄)NRi₂Ri₃, -S(O)_pRn, -NRnS(0)_pRn, and -

Rn, for each occurrence, is independently selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-i4carbocycle, heterocycle, C_3- i₄carbocycleCi-₆alkyl, heterocycleCi-₆alkyl, wherein if Rn is an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be independently optionally substituted on one or more carbon atom with one or more Ri 5, and wherein if Rn is heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if Rn is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆; Ri 2 and Rn, for each occurrence, are independently selected from the group consisting of hydrogen, Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, C_3-i₄carbocycle, heterocycle, C₃-i₄carbocycleCi.₆alkyl, heterocycleCi-_όalkyl, wherein if Ri₂ or Ri₃ is an alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, it may be independently optionally substituted on one or more carbon atom with one or more Ri 5, and wherein if Ri 2 or Rn is heterocycle or a heterocyclealkyl that comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if R12 or Rn is a heterocycle or a heterocyclealkyl that comprises one or more -NH-, each -NH- may be independently optionally substituted with Ri₆; or R12 and Rn taken together with the nitrogen atom to which they are attached for a heterocycle, wherein the heterocycle may be optionally substituted on one or more carbon atoms with one or more Ri 5, and wherein if the heterocycle comprises one or more -S-, =N- or both, each -S- may be independently optionally substituted with one or two oxo groups and each =N- may be independently optionally substituted with one oxo group; and wherein if the heterocycle comprises one or more -NH-, each -NH- may be independently optionally substituted with R₁₆; Ri 5, for each occurrence, is independently selected from the group consisting of halo, nitro, cyano, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C3-i4carbocycle, heterocycle, C_3-14CaTbOCyCIeC₁ -βalkyl, heterocycleC_1-6alkyl, C_1-6haloalkyl, -OR₁₈, -SR₁₈, -NR19R20,

-C(O)Ri₈, -C(O)ORi₈, -C(O)NRi₉R₂₀, -NRi₈C(O)Ri₈, -OC(O)Ri₈, -NRi₈C(O)ORi₈, - OC(O)NRi₉R₂₀, -NRi₈C(O)NRi₉R₂₀, -NRi₈C(NR₂i)NRi₉R₂₀, -S(O)_pRi₈, - NRi₈S(O)_pRi₈, and -S(O)_pNRi₉R₂₀;

R₁₆, for each occurrence, is independently selected from the group consisting of C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-i4carbocycle, heterocycle, C_3-i4carbocycleCi. ₆alkyl, heterocycleCi-ealkyl, Ci_-6haloalkyl, -C(O)Ri₈, -C(O)ORi₈, -C(O)NRi₉R₂₀, - S(O)pRi₈, and -S(O)_pNRi₉R₂₀;

Ri₈, for each occurrence, is independently selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-i4carbocycle, heterocycle, C_3- ₁₄carbocycleC_1-6alkyl, heterocycleC_1-6alkyl; R₁₉ and R20, for each occurrence, are independently selected from the group consisting of hydrogen, Ci_₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, Cβ-_Hcarbocycle, heterocycle, C₃-i₄carbocycleCi.₆alkyl, heterocycleCi-_όalkyl; or Ri₉ and R₂₀ taken together with the nitrogen atom to which they are attached for a heterocycle; and p is 1 or 2, provided that when both R3 and R₄ are hydrogen, R2 and R22 are not both n- hexyl or both n-propyl, or R22 is not n-propyl and R2 is not methyl; and provided that when R₂ is methyl, R₃ and R₄ taken together with the nitrogen atom to which they are attached are not a substituted or unsubstituted piperazino.

3. The compound of Claim 1, wherein Ri is a C₃_i₄carbocycle which is optionally substituted on one or more carbon atoms with one or more independently selected R₅.

4. The compound of Claim 1 or 3, wherein Ri is phenyl which is optionally substituted with one or more independently selected R₅.

5. The compound of Claim 1 or 3, wherein Ri is morpholinyl which is optionally substituted on one or more carbon atom with one or more independently selected R⁵ and which is optionally substituted on the nitrogen atom with Rn.

6. The compound of Claim 1 or 3, wherein Ri is benzodioxinyl or benzodioxolyl, which can be optionally substituted on one or more carbon atom with one or more independently selected R₅.

7. The compound of Claim 1 or 3, wherein Ri is quinolinyl which is optionally substituted with one or more independently selected R⁵ and which is optionally substituted on the nitrogen atom with an oxo.

8. The compound of any one of Claims 1 and 3 through 7, wherein R5, for each occurrence, is independently selected from the group consisting of nitro, methoxy, methyl, fiuoro, chloro, bromo, cyano, trifluoromethyl, acetyl, but-2-en-l-yloxy, methoxycarbonyl, methylsulfonyl, carbamoyl, pent-2-yn-l-yloxy, ethoxycarbonyl, carboxy, ethyl, carboxymethoxy, hydroxymethyl, acetoxy, amino, 2-carboxyphenyl, tetrazole-5-yl, 2-(N-methyl-piperazino)-ethyl-amino, acetamido, hydroxy, aminosulfonyl, 4-chlorophenyl, 2-methoxyphenyl, phenylsulfonylmethyl, butyloxy, cyclopropylmethoxy, phenyl, aminomethyl, 2-fluorophenyloxy, 4-fluorophenyloxy, and 1 -methyl-ethyl. 5

9. The compound of Claim 1 or 5, wherein Rn, for each occurrence, is independently selected from the group consisting of C_1-4alkyl, benzyl, acetyl, ci-₄alkoxycarbonyl, carbamoyl,

10 10. The compound of Claim 2, wherein R22 is an unsubstituted Cs^alkyl group.

11. The compound of Claim 2, wherein R22 is propyl, butyl, 2,3-dihydroxy-propyl, 3- cycanopropyl, 2-methyl-propyl, 3-phenoxy-2-hydroxy-propyl, 2-hydroxy-2-methyl- propyl, 2-hydroxy-3-methoxy-propyl, 4,4,4-trifluoro-butyl, 2-hydroxybutyl, 2-ethyl-

15 butyl, 4-cyanobutyl, or isopentyl.

12. The compound of any one of Claims 1 and 3 through 9, wherein Xi is -CH₂-.

13. The compound of any one of Claims 1 and 3 through 11, wherein Xi is -C(O)CH₂-, ■ 20 CH₂C(O)-, -C(O)-, -CH(OH)CH₂-, or -CH₂CH₂-.

14. The compound of any one of Claims 1, 3 through 9, 12 and 13, wherein X₂ is -O-.

15. The compound of any one of Claims 1, 3 through 9, 12 and 13, wherein X₂ is -S-. 25

16. The compound of any one of Claims 1, 3 through 9, 12 and 13, wherein X₂ is -NR^a-.

17. The compound of Claim 2, 10 or 11, wherein X₄ is -O-.

30 18. The compound of Claim 2, 10, or 11, wherein X4 is -S-.

19. The compound of any one of Claims 1 through 18, wherein R₂ is

which is optionally substituted on one or more carbon atoms with one or more R₆.

20. The compound of Claim 19, wherein R₂ is a C_1-6alkyl selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopentyl, and 2- methylbutyl, wherein the Cl-6alkyl may be optionally substituted on one or more carbon atom with one or more R₆.

21. The compound of any one of Claims 1 through 15, 17 and 18, wherein R₂ is cyclopentyl, cyclohexyl, piperidinyl, decahydronaphthalenyl, phenyl, but-2-en-l-yl, pent-2-yn-l-yl, but-2-yn-l-yl, or phenyl.

22. The compound of Claim 19, 20, or 21 wherein R₆, for each occurrence, is independently selected from the group consisting of cyclopropyl, cyclo butyl, cyclopentyl, cyclohexyl, methoxy, methyl, 7V,7V-dimethylamino, acetamido, fiuoro, hydroxy, phenyl, and methylsulfonyl.

23. The compound of any one of Claims 1 through 22, wherein R₃ and R₄ are hydrogen.

24. The compound of any one of Claims 1 through 22, wherein one of R₃ or R₄ is hydrogen and the other is methyl, n-butyl, morpholinoethyl, (furan-3-yl)-methyl, (5- methyl-furan-2-yl)-methyl, benzyl, 2,6-difluourobenzyl, cyclopropyl, 2-phenyl- cyclopropyl, or benzoimidazol-2-yl.

25. The compound of any one of Claims 1 through 22, wherein R₃ or R₄ are both methyl or R₃ and R₄ together with the nitrogen atom to which they are attached form morpholino.

26. The compound any one of Claims 1 through 25, wherein X₃ is CR₁₀.

27. The compound of Claim 26, wherein Rio is H.

28. The compound of Claim 26, wherein Rio is selected from the group consisting of 2- piperizino-ethylamino, 2-(4-methyl-piperazino)-ethylamino, 2-morpholino- ethylamino, 2-hydroxyethylamino, 2-(diethylamino)-ethylamino, morpholino, piperazine, methyl, carboxy, and ethoxycarbonyl.

29. The compound of any one of Claims 1 through 25, wherein X₃ is N.

30. The compound of Claim 1, wherein the compound is selected from the group consisting of: 2-(butylthio)-9-(3-nitrobenzyl)-9H-purin-6-amine;

2-(butylthio)-9- [3 -(trifiuoromethyl)benzyl] -9H-purin-6-amine; 2-(butylthio)-9-(3-chlorobenzyl)-9H-purin-6-amine; 3-{[6-amino-2-(butylthio)-9H-purin-9-yl]methyl}benzonitrile; 2-(butylthio)-9-(3-methylbenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(3,4-dichlorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2-methoxy-5-nitrobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2-chloro-4-fluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2,6-dichlorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2-chloro-5-nitrobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2,6-difluorobenzyl)-9H-purin-6-amine; methyl 3-{[6-amino-2-(butylthio)-9H-purin-9-yl]methyl}benzoate; 2-(butylthio)-9-(4-chloro-2-fluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-[2-fluoro-6-(trifluoromethyl)benzyl]-9H-purin-6-amine; 2-(butylthio)-9-(3-methoxybenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2-fluoro-3-methylbenzyl)-9H-purin-6-amine; 2-(butylthio)-9-[4-(methylsulfonyl)benzyl]-9H-purin-6-amine; 2-(butylthio)-9-(4-methoxy-3-nitrobenzyl)-9H-purin-6-amine; 2-(butylthio)-9- { [4-chloro-2-(trifluoromethyl)quinolin-6-yl]methyl} -9H-purin-6- amine;

2-(butylthio)-9-(2-chloro-5-fluorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(3-fluorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(2,4-difluorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(4,5-dimethoxy-2-nitrobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(5-chloro-2-fluorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(3-chloro-2,6-difiuorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(3,5-dimethoxybenzyl)-9H-purin-6-amine; 2-(butylthio)-9-{2-[(phenylsulfonyl)methyl]benzyl}-9H-purin-6-amine; 2-(butylthio)-9-(4-fluoro-3-nitrobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(4-nitrobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(3,4-difluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(3,5-difluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2,5-difluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2-fluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(4-fluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2-chlorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2-methylbenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(3-chloro-4-fluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2-nitrobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(3-chloro-4-fluorobenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(3,5-dimethylbenzyl)-9H-purin-6-amine; 2-{[6-amino-2-(butylthio)-9H-purin-9-yl]methyl}benzonitrile; 4-{[6-amino-2-(butylthio)-9H-purin-9-yl]methyl}benzonitrile; 9-(4-bromo-2-fluorobenzyl)-2-(butylthio)-9H-purin-6-amine; 2-(butylthio)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine; 2-(butylthio)-9-(2,5-dichlorobenzyl)-9H-purin-6-amine; methyl 4-{[6-amino-2-(butylthio)-9H-purin-9-yl]methyl}-3-methoxybenzoate; 2-(butylthio)-9-(3-fluoro-4-methylbenzyl)-9H-purin-6-amine; 9-(2,6-difluorobenzyl)-2-(isobutylthio)-9H-purin-6-amine; 9-(2,6-difluorobenzyl)-2-[(3-methylbutyl)thio]-9H-purin-6-amine; 9-(2,6-difluorobenzyl)-2-[(2-methylbutyl)thio]-9H-purin-6-amine; 2-(cyclopentylthio)-9-(2,6-difluorobenzyl)-9H-purin-6-amine; 2-(cyclohexylthio)-9-(2,6-difluorobenzyl)-9H-purin-6-amine; 9-(2,6-difluorobenzyl)-2-(2-methoxyethoxy)-9H-purin-6-amine; 2-(butylthio)-9-(cyclobutylmethyl)-9H-purin-6-amine; 2-(butylthio)-9-(cyclohexylmethyl)-9H-purin-6-amine; 2-(butylthio)-9-(tetrahydro-2H-pyran-2-ylmethyl)-9H-purin-6-amine; 9-(3-chloro-2,6-difluorobenzyl)-N-(2-morpholin-4-ylethyl)-2-(4,4,4- trifluorobutoxy)-9H-purin-6-amine; 2-(butylthio)-9-(2,3-dichlorobenzyl)-9H-purin-6-amine;

2-(butylthio)-9-[(5-chloro-l-benzothien-3-yl)methyl]-9H-purin-6-amine;

2-(butyl{9-(3-chloro-2,6-difluorobenzyl)-6-[(2-morpholin-4-ylethyl)amino]-9H- purin-2-yl} amino)ethanol;

2-butoxy-9-(2,3-dichlorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

9-(2,6-difluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-2-phenoxy-9H-purin-6-amine;

5-(butylthio)-3-(2,6-difluoro-3-methylbenzyl)-3H-[l,2,3]triazolo[4,5-^]pyrimidin-7- amine;

2-butoxy-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

2-(butylthio)-9-(3-chloro-2,6-difluorobenzyl)-9H-purin-6-amine;

2-butoxy-9-(2,6-difluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(3-chloro-2,6-difluorobenzyl)-Λ/-(3-furylmethyl)-9H-purin-6-amine;

2-(butylthio)-N,9-bis(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

2-(cyclopropylmethoxy)-9-[3-(trifluoromethyl)benzyl]-9H-purin-6-amine;

2-(cyclopentylmethoxy)-9- [3 -(trifluoromethyl)benzyl] -9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-(pentyloxy)-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-[(3-methylcyclopentyl)oxy]-9H-purin-6-amine;

2-(benzyloxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine; 2-(cyclobutylmethoxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

2-(cyclopentyloxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

2-(l-cyclopropylethoxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

2-(cyclopropylmethoxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-methoxy-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-propoxy-9H-purin-6-amine;

2-(cyclohexyloxy)-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-isobutoxy-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-N²,N²-dimethyl-9H-purine-2,6-diamine;

9-(2,6-difluoro-3-methylbenzyl)-2-[2-(dimethylamino)ethoxy]-9H-purin-6-amine;

Λ/-(2-{[6-amino-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-2- yl]oxy } ethyl)acetamide;

9-(2,6-difluoro-3-methylbenzyl)-2-(4,4,4-trifluorobutoxy)-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-(piperidin-4-yloxy)-9H-purin-6-amine;

2-butoxy-9- [3 -(trifluoromethyl)benzyl] -9H-purin-6-amine;

3-[(6-amino-2-butoxy-9H-purin-9-yl)methyl]benzoic acid;

2-butoxy-9-(2,6-difluorobenzyl)-9H-purin-6-amine;

2-butoxy-9-(2,6-difluorobenzyl)-N,Λ/-dimethyl-9H-purin-6-amine;

Λ/²-butyl-9-(2,6-difluorobenzyl)-9H-purine-2,6-diamine;

2-butoxy-9-(2,6-difluorobenzyl)-Λ/-methyl-9H-purin-6-amine;

2-butoxy-9-(2-butoxy-6-fluorobenzyl)-Λ/-methyl-9H-purin-6-amine; 2-(cyclopropylmethoxy)-9-[2-(cyclopropylmethoxy)-6-fluorobenzyl]-Λ/-methyl-9H- purin-6-amine;

9-(2,6-difluorobenzyl)-Λ/-methyl-2-(2-methylbutoxy)-9H-purin-6-amine;

2-(cyclobutylmethoxy)-9-(2,6-difluorobenzyl)-Λ/-methyl-9H-purin-6-amine;

9-(2,6-difluorobenzyl)-Λ/-methyl-2-(pentyloxy)-9H-purin-6-amine;

2-(cyclopentyloxy)-9-(2,6-difluorobenzyl)-Λ/-methyl-9H-purin-6-amine;

2-butoxy-9-(2,6-difluoro-3-methylbenzyl)-Λ/-ethyl-9H-purin-6-amine;

Λ/-benzyl-2-butoxy-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

Λ/-benzyl-9-(2,6-difluoro-3-methylbenzyl)-2-(pentyloxy)-9H-purin-6-amine;

2-butoxy-Λ/-cyclopropyl-9-(2,6-difluoro-3-methylbenzyl)-9H-purin-6-amine;

2-(butylthio)-9-[(2,6-difluorophenyl)acetyl]-9H-purin-6-amine;

2-(butylthio)-9-(2,6-difluorobenzoyl)-9H-purin-6-amine;

3-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9-yl}methyl)benzamide;

2-{[6-amino-2-(butylthio)-9H-purin-9-yl]methyl}-4-nitrophenol;

4-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9-yl}methyl)benzamide; l-[4-({2-butoxy-6-[(2-morpholin-4-ylethyl)amino]-9H-purin-9- y 1 } methy l)pheny 1] ethanone;

2-butoxy-9-(2,6-difluorobenzyl)-8-methyl-9H-purin-6-amine;

2-butoxy-9-(2,6-difluorobenzyl)-8-(4-methylpiperazin-l-yl)-9H-purin-6-amine;

2-{[6-amino-2-butoxy-9-(2,6-difluorobenzyl)-9H-purin-8-yl]amino}ethanol;

2-butoxy-9-(2,6-difluorobenzyl)-8-morpholin-4-yl-9H-purin-6-amine; 2-butoxy-9-(2,6-difluorobenzyl)-Λ/^s-[2-(4-methylpiperazin-l-yl)ethyl]-9H-purine- 6,8-diamine;

2-butoxy-Λ/-(2,6-difluorobenzyl)-9-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2,3-difluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(3,4-difluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2,5-dichlorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-7V-(2-morpho lin-4-ylethyl)-9- [4-(trifluoromethyl)benzyl] -9H-purin-6- amine;

2-butoxy-9-(2,6-dichlorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2,4-difluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2-chlorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(4-ethylbenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(4-fluoro-3-methylbenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine; 2-butoxy-9- [3 -(2-fluorophenoxy)benzyl] -7V-(2-morpho lin-4-ylethyl)-9H-purin-6- amine;

2-butoxy-9-[3-(4-fluorophenoxy)benzyl]-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6- amine;

2-butoxy-9-(3-chlorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2,5-dimethoxybenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2,4-dichlorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(3-methoxybenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(3-fluorobenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-Λ/-(2-morpholin-4-ylethyl)-9-(2-nitrobenzyl)-9H-purin-6-amine;

2-butoxy-9-(3-methylbenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(mesitylmethyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-butoxy-9-(2,3-dimethoxybenzyl)-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

2-[(2E)-but-2-en- 1 -yloxy]-9- {2-[(2£)-but-2-en- 1 -yloxy]-6-fluorobenzyl} -N-(2- morpholin-4-ylethyl)-9H-purin-6-amine;

9-(2,6-difluoro-3-methylbenzyl)-2-(hex-2-yn-l-yloxy)-Λ/-(2-morpholin-4-ylethyl)- 9H-purin-6-amine;

2-butoxy-9-(3,4-dichlorobenzyl)-6-morpholin-4-yl-9H-purine-8-carboxylic acid;

31. The compound of Claim 2, wherein the compound is selected from the group consisting of:

2-(butylthio)-9-(4,4,4-trifluorobutyl)-9H-purin-6-amine;

2-(butylthio)-9-(2-ethylbutyl)-9H-purin-6-amine;

2-(butylthio)-9-propyl-9H-purin-6-amine;

2-(butylthio)-9-(3 -methylbutyl)-9H-purin-6-amine ;

2-(butylthio)-9-isobutyl-9H-purin-6-amine;

4-[6-amino-2-(butylthio)-9H-purin-9-yl]butanenitrile;

5-[6-amino-2-(butylthio)-9H-purin-9-yl]pentanenitrile;

2-(benzyloxy)-9-butyl-Λ/-(2-morpholin-4-ylethyl)-9H-purin-6-amine;

9-butyl-Λ/-(2-morpholin-4-ylethyl)-2-phenoxy-9H-purin-6-amine;

9-butyl-Λ/-(2-morpholin-4-ylethyl)-2-(pyridin-2-yloxy)-9H-purin-6-amine;

32. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in any one of Claims 1 through 31 , in association with a pharmaceutically-acceptable diluent or carrier.

33. A compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in any one of Claims 1 through 31 for use as a medicament.

34. The use of a compound, in free or salt form, as claimed in any one of Claims 1 through 31 in the manufacture of a medicament for use in the production of bacterial

Murl inhibitory effect in a warm-blooded animal such as man.

35. The use of a compound, in free or salt form, as claimed in any one of Claims 1 through 31 , in the manufacture of a medicament for use in the production of an anti-bacterial effect in a warm-blooded animal such as man.

36. The use of a compound, in free or salt form, as claimed in any one of Claims 1 through 31 , 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 E.faecium 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.

37. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in any one of Claims 1 through 31 , 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.

38. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in any one of Claims 1 through 31 , 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.

5

39. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in any one of Claims 1 through 31 , 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

10 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 E.faecium 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

15 treatment or prophylaxis of antibiotic resistant infection; in a warm-blooded animal, e.g., man.

40. 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

20 of a compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as claimed in any one of Claims 1 through 31.

41. The method of Claim 40, wherein the infection is caused by Gram positive cocci.

25 42. The method of Claim 40 or 41, wherein the infection is E.faecalis ox E.faecium infection.

43. The method of any of Claims 40 through 42, wherein the infection is resistant to penicillin or cephalosporin.

30

44. The method of any of Claims 40 through 43, wherein the infection is selected from pneumonia, septicemia, puerperal sepsis, endocarditis, toxic shock, osteomyelitis, enterocolitis, bacterial meningitis, and post-operative infection.