SEMI-SYNTHETIC GLYCOPEPTIDES WITH ANTIBACTERIAL ACTIVITY

RELATED APPLICATIONS

[0001] The present application claims the benefit of U.S. Provisional Patent Application No 60/916,701 filed May 8, 2007, the entire contents of which are herein incorporated by reference

FIELD OF THE INVENTION

[0002] Described herein are semi-synthetic glycopeptides having antibacterial activity, to pharmaceutical compositions comprising these compounds, and to a medical method of treatment.

BACKGROUND OF THE INVENTION

[0003] The emergence of drug resistant bacterial strains has highlighted the need for synthesizing and identifying antibiotics with improved activity Naturally occurring and semi-synthetic glycopeptide antibiotics used to combat bacteria infections include compounds such as vancomycin, desmethylvancomycin, eremomycm, teicoplanin (complex of five compounds), dalbavancin, oπtavancin, telavancm, and A82846B (LY264826) having structures A, B, C, D, E, F, G and H

R = B-2-Acetylamido-glucopyranosyl- D

[0004] These compounds are used to treat and prevent bacterial infection, but as with other antibacterial agents, bacterial strains having resistance or insufficient susceptibility to these compounds have been identified, and these compounds have been found to have limited effect against certain bacterial infections e g , against pulmonary

S aureus infections caused by Compound A intermediate-resistant S aureus or infections due to Compound A resistant-enterococci.

SUMMARY OF THE INVENTION

[0005] Descπbed herein are semi-synthetic glycopeptides that have antibacterial activity. Also provided are methods for synthesis of the compounds, pharmaceutical compositions containing the compounds, and methods of use of the compounds for the treatment and/or prophylaxis of diseases, especially bacterial infections.

[0006] In one aspect described herein are compounds formed by modification of Compound A,

Compound B, Compound H or Compound C scaffolds to provide novel semi-synthetic glycopeptides that have antibacterial activity, as well as their pharmaceutical acceptable salts, esters, solvates, alkylated quaternary ammonium salts, stereoisomers, tautomers or prodrugs thereof, and which can be used as antibacterial agents for treatment of bacterial infections with superior microbiology and pharmacokinetic properties than currently available glycopeptide antibacterial agents.

[0007] In one aspect described herein are compounds having a structure selected from the group consisting of Formulas (1-IV)-

wherem,

R _A is selected from the group consisting of a) hydrogen, b) methyl, c) C ₂ -C ₁₂ -alkyl;

R ₁ and R ₂ are each independently selected from the group consisting of a) hydrogen, b) d-C.-alkyl, c) Ci-C ₁₂ -alkyl substituted with one or more substituents selected from the group consisting of

(a) halogen,

(b) hydroxy,

(c) C _r C ₃ -alkoxy,

(d) C _r C ₃ -alkoxy- C _r C ₃ -alkoxy,

(e) amino,

(f) Ci-Cπ-alkylamino,

(g) Ci-Cπ-dialkylamino,

(h) alkenyl,

(i) alkynyl, d) C _r Ci ₂ -alkyl substituted with aryl, e) C _r C ₁₂ -alkyl substituted with substituted aryl, f> C _r Ci ₂ -alkyl substituted with heteroaryl, g) Ci-C[ ₂ -alkyl substituted with substituted heteroaryl, h) cycloalkyl, i) cycloalkenyl,

j) heterocycloalkyl, or

R ₁ and R ₂ taken together with the atom to which they are attached form a 3-10 membered heterocycle ring which optionally contains one to three heteroatom or hetero functionalities selected from the group consisting of -O- , -NH, -N(C _r C ₆ -alkyl)-, -N(aryl)-, -N(aryl- C,-C ₆ -alkyl-

)-, -N(substituted-aryl- Ci-C ₅ -alkyl-)-, -N(heteroaryl)-, -N(heteroaryl- C]-C ₆ -alkyl-)-, - N(substituted-heteroaryl- Q-Cg-alkyl-)-, and -S- or S(O) _n - wherein n is 1 or 2 and the 3-10 membered heterocycle ring optionally substituted with one or more substituents independently selected from the group consisting of (a) halogen,

(b) hydroxyl,

(c) Q-Q-alkoxy,

(d) CrQ-alkoxy-CrQ-alkoxy,

(e) oxo, (f) C _r C ₃ -alkyl,

(g) halo-C _r C ₃ -alkyl,

(h) C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl, and k) C(=O) R ₇ , 1) C(=O) CHRNR ₁ R ₂ ,

R ₇ is selected from the group consisting of a) hydrogen, b) Crdralkyl, c) C _! -C ₁₂ -alkyl substituted with one or more substituents selected from the group consisting of (a) halogen,

(b) hydroxy,

(c) C _r C ₃ -alkoxy,

(d) CrQ-alkoxy-Ci-Cj-alkoxy,

(e) amino, (f) Ci-Cn-alkylammo,

(h) alkenyl,

(i) alkynyl, d) Ci-Cn-alkyl substituted with aryl, e) C _r Ci ₂ -alkyl substituted with substituted aryl, f) Q-C^-alkyl substituted with heteroaryl, g) C _r C ₎₂ -alkyl substituted with substituted heteroaryl, h) cycloalkyl, i) cycloalkenyl, j) heterocycloalkyl,

X is selected from the group consisting of

(1) hydrogen,

(2) chlorine,

R is selected from the group consisting of

(1) hydrogen, (2) cycloalkyl,

(3) cycloalkenyl,

(4) C _r C ₁₂ -aIkyl,

(5) C _r C ₁₂ -alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy,

(c) d-Cj-alkoxy,

(d) Ci-Cs-alkoxy- C,-C ₃ -alkoxy,

(e) -COOR ₅ wherein R ₅ is hydrogen or loweralkyl,

(f) -C(O)NR ₅ R ₆ wherein R ₅ is as previously defined and R ₆ is hydrogen or loweralkyl, (g) amino,

(h) -NR ₅ R ₆ wherein R ₅ and R ₆ are as previously defined, or

R ₅ and Re are taken together with the atom to which they are attached from a 3- 10 membered heterocycloalkyl ring which is optionally substituted with one or more substituents independently selected from the group consisting of

W halogen

(π) hydroxy,

(ill) C _r C ₃ -alkoxy,

(IV) C _r C ₃ -alkoxy-Ci-C ₃ -alkoxy,

(V) OXO ₇

(Vl) Ci-Ci ₂ -alkyl,

(VIl) halo-C _r C ₁₂ -alkyl, and

(vui) C _r C ₃ -alkoxy-Ci-C ₁₂ -alkyl,

(i) aryl.

0) substituted aryl,

(k) heteroaryl

(1) substituted heteroaryl,

(m) mercapto,

(n) C ₁ -C ₃ -UIiOaIkOXy;

R ₃ is selected from the group consisting of

(1) OH,

(2) 1 -adamantanamino ,

(3) 2-adamantanamino,

(4) 3 -amino- 1 -adamantanamino,

(5) l-amino-3-adamantanamino,

(6) 3-loweralkylanuno-l-adamantanaπuno,

(7) l-loweralkylamino-3-adamantanamino,

(8) amino

(9) NR ₈ R ₉ wherein R ₈ and R ₉ are independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl or

Rg and R ₉ together with the atom to which they are attached from a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of

(a) halogen.

(b) hydroxy, (c) C,-C ₃ -alkoxy,

(d) C-Cs-alkoxy-Ci-Ca-alkoxy,

(e) oxo,

(f) C,-C ₁₂ -alkyl,

(g) substituted loweralkyl, (h) halo-C _r C, ₂ -alkyl, and

(i) C ₁ -C ₃ -alkoxy-C ₁ -C ₁₂ -alkyl;

R ₄ is selected from the group consisting of

(D H, (2) CH ₂ NHCH ₂ PO ₃ H ₂ ,

(3) aminoloweralkyl wherein the amino portion of the ammoloweralkyl group is further substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy; or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof

[0008] In a further embodiment, the compound has the structure of Formula I

or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, wherein R, etc. have the meanings defined in claim 1. [0009] In a further embodiment, the compound has the structure of Formula II

or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, wherein R, etc have the meanings defined in claim 1. [0010] In a further embodiment, the compound has the structure of Formula III

or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, wherein R, etc have the meanings defined m claim 1.

[0011] In a further embodiment, the compound has the structure of Formula IV

₃

or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, wherein R, etc have the meanmgs defined in claim 1.

[0012] In a further embodiment of any of the above structures, R _A is methyl and R ₄ is hydrogen In an alternative embodiment, R _A is hydrogen and R ₄ is hydrogen In an alternative embodiment, X is hydrogen and R ₄ is hydrogen. In an alternative embodiment, X is chlorine and R ₄ is hydrogen. In an alternative embodiment, R _A is methyl and R ₄ is CH ₂ NHCH ₂ PO ₃ H ₂ . In an alternative embodiment, R _A is hydrogen and R ₄ is CH ₂ NHCH ₂ PO ₃ H ₂ .

[0013] In a further or alternative embodiment of any of the aforementioned embodiments, R ₃ is selected from the group consisting of

(1) OH,

(2) 1-adamantanamino,

(3) 2-adamantanammo,

(4) 3-amino-l-ad.amantanaπnno,

(5) l-amino-3-adamantanamino,

(6) 3-loweralkylairuiio- 1 -adamantanarmno,

(7) 1 -Io weralkylamino-3 -adamantanamino,

(8) amino

(9) NR ₃ R ₉ wherein R ₈ and R ₉ are independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl or

Rg and Rg together with the atom to which they are attached from a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of

(a) halogen

(b) hydroxy,

(c) C _r C ₃ -alkoxy,

(d) C _r C ₃ -alkoxy- C,-C ₃ -alkoxy,

(e) oxo,

(f) C _r C ₁₂ -alkyl,

(g) substituted loweralkyl,

(h) halo-C,-C ₁₂ -alkyl, and

(i) d-Cs-alkoxy-Ci-Ciz-alkyl

[0014] In a i further embodiment, R ₃ is OH In an alternative embodiment, R ₃ is 2-adamantanammo

[0015] In a further or alternative embodiment of any of the aforementioned embodiments, Rj and R ₂ are each independently selected from the group consisting of a) hydrogen, b) C ₁ -C ■ ₁₂ alkyl, c) C _r C ₁₂ -alkyl substituted with one or more substituents selected from the group consisting of

(a) halogen,

(b) hydroxy,

(c) C _r C ₃ -alkoxy,

(d) C ₁ -C ₃ -BIkOXy- C _r C ₃ -alkoxy,

(e) amino,

(f) C ] -C ₁₂ -alkylamino,

GO alkenyl,

(0 alkynyl, d) C ₁ -C n-alkyl substituted with aryl, e) C ₁ -C ₁₂ -alkyl substituted with substituted aryl, f) C ₁ -C ₁₂ -alkyl substituted with heteroaryl,

g) C _r Ci ₂ -alkyl substituted with substituted heteroaryl, h) cycloalkyl, i) cycloalkenyl, J) heterocycloalkyl, or

Ri and R ₂ taken together with the atom to which they are attached from a 3-10 membered heterocycle πng which optionally contains one to three heteroatom or hetero functionalities selected from the group consisting of-O-, -NH, -N(C _r C ₃ -alkyl)-, -N(aryl)-, -N(aryl- C _r C ₆ -alkyl-

)-, -N(substituted-aryl- C]-C ₆ -alkyl-)-, -N(heteroaryl)-, -N(heteroaryl- C _r C ₆ -alkyl-)-, -

N(substituted-heteroaryl- Ci-Cβ-alkyl-)-, and -S- or S(O) _n - wherein n is 1 or 2 and the 3-10 membered heterocycle ring optionally is substituted with one or more substituents independently selected from the group consisting of

(a) halogen,

(b) hydroxy],

(c) C _r C ₃ -alkoxy,

(d) C ₁ -C ₃ -alkoxy- C , -C ₃ -alkoxy,

(e) oxo,

(f) C _r C ₃ -alkyl,

(g) halo-CrCj-alkyl,

(h) Q-Q-alkoxy- C _r C ₃ -alkyl, and k) C(=O) R ₇ ,

1) C(=O) CHRNR ₁ R ₂ ,

[0016] In a further or alternative embodiment of any of the aforementioned embodiments, R ₁ and R ₂ are hydrogen [0017] In a further embodiment are compounds having a structure selected from the group consisting of

Formulas (I and J)

wherein R _A IS hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or ammoloweralkyl as defined herein and L is a leaving group such as OMs, OTs, OTf, halogen and the like [0018] In a further embodiment are compounds having a structure selected from the group consisting of

Formulas (K and LJ

wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ POsH ₂ , or aminoloweralkyl as defined herein, R ₃ is previous defined with the proviso R ₃ is not OH, and L is a leaving group such as OMs, OTs, halogen and the like [0019] In a further or alternative embodiment of any of the aforementioned embodiments, R ₁ is hydrogen and R ₂ is COCHRNHRio wherein R^ is substituted arylalkyl and R is previous defined

[0020] In another aspect are compounds selected from Desvancosaminyl vancomycin (1),

Desvancosaminyl desmethylvancomycm (2), Des-4-epivancosammyl A82846B £3}, Des-4-epivancosaminyl eremomycin (4), Boc-desvancosaminyl vancomycin £5}, Boc-desvancosaminyl desmefhylvancomycm £6), Boc-des- 4-epivancosaminyl A82846B £7), Boc-des-4-eρivancosammyl eremomycin £8), Boc-desvancosaminyl vancomycin mesylate £9}, Boc-desvancosaminyl desmethylvancomycm mesylate (10), Boc- des-4-eρivancosaminyl A82846B mesylate (11), Boc- des-4-epivancosaminyl eremomycin mesylate (12), Desvancosaminyl vancomycin mesylate (13), Desvancosaminyl desmethylvancomycm mesylate (14). Des-4-epivancosaminyl A82846B mesylate (15), Des-4- epivancosammyl eremomycin mesylate (16). Desvancosaminyl vancomycin azide (17), Desvancosaminyl desmethylvancomycm azide (18), Des-4-epivancosaminyl A82846B azide (19), Des-4-epivancosaminyl eremomycin azide (20), Desvancosaminyl vancomycin amine (21), Desvancosaminyl desmethylvancomycm amine (22), Des-4- epivancosaminyl A82846B amine (23), Des-4-eptvancosaminyl eremomycin amine (24), Nitro-desvancosaminyl vancomycin (25). Nitro-desvancosaminyl demethylvancomycm (26). Nitro-des-4-epivancosamrnyl A82846B (27), Nitro-des-4-epivancosaminyl eremomycin (28), Amino-desvancosaminyl vancomycin (29), Ammo-desvancosaminyl demethylvancomycm (30), Amino-des-4-epivancosammyl A82846B (31), Amino-des-4-epivancosaminyl eremomycin (32), Adamantyl-2-ammo desvancosaminyl vancomycin amide (33). Adamantyl-2-amino- desvancosaminyl desmethylvancomycm amide (34). Adamantyl-l-ammo-des-4-eρivancosaminyl A82846B amide (35), Adamantyl-2-amino-Des-4-epivancosammyl eremomycin amide (36), Desvancosaminyl vancomycin nitrile (37), Desvancosaminyl desmethylvancomycm mtrile (3_8), Des-4-epivancosaminyl A82846B nitrile (39), Des-4- epivancosaminyl eremomycin (40), Adamantyl-2-ammo desvancosaminyl vancomycin amide (41). Adamantyl-2- amino-desvancosaminyl desmethylvancomycm amide (42), Adamantyl-l-amino-des-4-epivancosaminyl A82846B amide (43), Adamantyl-2-amino-Des-4-epivancosammyl eremomycin amide (44), Desvancosaminyl vancomycin Ci ₂ amide (45), N'-(p-OctylOPhCH ₂ NHCH ₂ CO)- desvancosaminyl vancomycin (46), N'-(p- OcIyIOPhCH ₂ NHCH(CH ₃ )CO)- desvancosaminyl vancomycin (47), Biphenyl desvancosaminyl vancomycin (51) [0021] In another aspect are pharmaceutical compositions comprising a therapeutically effective amount of any of the aforementioned compounds, together with a pharmaceutically acceptable carrier

[0022] In another aspect are methods of treating a mammal in need of such treatment comprising administering to the mammal an antibacteπally effective amount of any of the aforementioned compounds together with a pharmaceutically acceptable carrier

[0023] In another aspect, described herein is the use of a compound descπbed herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) m the manufacture of a medicament for the treatment of a bacterial-related disease or condition

[0024] In another aspect, described herein is the use of a compound described herein (i e , a compound of any of Formula I, Formula H, Formula III or Formula IV) as a non-medicament or non-pharmaceutical antibacterial product Non-limiting examples include antibacterial soaps and cleaning products

[0025] In another aspect, described herein is the use of a compound described herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) as an intermediate in the synthesis of an antibacterial compound [0026] In any of the antibacterial uses descπbed herein, a compound descπbed herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) is used m combination with another antibacterial agent, including a different compound descπbed herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) or any other antibacterial agent (e g , Amdinocillm, Amikacin, Amoxicillin, Ampicillm, Atovaquone, Azithromycin, Aztreonam, Bacampicillin, Bacitracin, Capreomycin, Carbenicillm mdanyl sodium, Cefaclor, Cefadroxil, Cefamandole, Cefazolm, Cefdinir, Cefditoren, Cefepime, Cefixime, Cefmetazole, Cefomcid, Cefoperazone, Cefotaxime, Cefotetan, Cefoxitin, Cefpodoxime Proxetil, Cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime and Cefuroxime axetil, Cephalexin, Cephalotmn, Cephapinn, Cephradine, Chloramphenicol, Cmoxacin, Ciprofloxacin, Clarithromycin, Clindamycin, Cloxacillm, Colistimethate, Cycloserine, Daptomycm, Demeclocyclme, Dicloxacillm, Dinthromycin, Doπpenem, Doxycychne, Enoxacm, Ertapenem, Erythromycin, Fosfomycin, Gatifloxacin, Gemifloxacm, Gentamicm, Grepafloxacin, Imipenem/Cilastatin, Imiquimod, Kanamycin, Levofloxacrn, Lincomycrn, Lmezohd, Lomefloxacm, Loracarbef, Mafenide, Malathion, Meropenem, Methacyclme, Methenamrne mandelate and Methenamine hippurate, Methicilhn, Metronidazole, Mezlocillin, Minocycline, Moxifloxacrn, Mupirocm, Nafcilhn, Nalidixic Acid, Neomycin, Netihnycin, Nitrofurantoin, Nitrofurazone, Norfloxacin, Novobiocin, Ofloxacin, Oxacillin, Oxytetracyclme, Penicillin, Piperacillin, Piperacillin + Tazobactam, Podophylhn, Polymyxin B, Quinupπstin + Dalfopristin, Retapamulin, Rifapentine, Rifaximin, Saturated Solution of Potassium Iodide (SSKI), Sparfloxacin, Spectmomycm, Streptomycin, Sulfadiazine, Sulfamethoxazole, Sulfϊsoxazole, Sulphur, precipitated in petrolatum, TCA (trichloroacetic acid), BCA (bichloroacetic acid) , Teicoplanm, Telithromycin, Terbmafϊne, Tetracycline, Ticarcillm, Ticarcillin + Clavulamc Acid, Tigecycline, Tobramycin, Trimethoprim, Tnmethopπm + Sulfamethoxazole, Trovafioxacm, and Vancomycin)

[0027] In another aspect, described herein are articles of manufacture, comprising packaging material, a compound of any of Formula I, Formula II, Formula III or Formula IV, which is effective for treatment, prevention or amelioration of one or more symptoms of a bacterial-mediated disease or condition, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically acceptable acyl glucuroide metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for treatment, prevention or amelioration of one or more symptoms of a bacterial-mediated disease or condition, are provided [0028] In another aspect are methods of making a compound of Formulas I-IV, comprising modifying a compound from the group consisting of Formulas i, ii, iii and iv,

wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or ammoloweralkyl as defined herein, by a technique selected from the group consisting of, (a) alkylation of the amino substituent on the amino-substituted sugar moiety of the 4 ^th ammo acid of the compound with an alkyl halide having structure Rj-J where J is a halogen,

(b) acylation of the amino substituent on the ammo-substituted sugar moiety of the 4 ^th amino acid of the compound with an acyl group having the structure, C(=O) R ₇ ,

(c) acylation of the amino substituent on the amino-substituted sugar moiety of the 4 ^th amino acid of the compound with an acyl group having the structure, C(=O) CHRNR ₁ R ₂ ,

(d) reaction of the ammo substituent on the ammo-substituted sugar moiety of the 4 ^th amino acid of the compound with an aldehyde or ketone followed by reductive amination of the resulting lmine,

(e) conversion of the acid moiety on the macrocyclic ring of the compound with substituted amide as defined by R ₃ ,

(f) removal of the Boc protectmg group by use of mild acid,

(g) a combination of (a), (b), and (f), (h) a combination of (a), (c), and (f), (1) a combination of (a), (d), and (f), (]) a combination of (a), (e), and (f),

(k) a combination of (b), (e), and (f),

(1) a combination of (c), (e), and (f),

(m) a combmation of (d), (e), and (f),

(n) a combmation of (a), (b), (e), and (f), (o) a combination of (a), (c), (e), and (f),

(p) a combmation of (a), (d) , (e), and (f), to form a compounds having a formula selected from the group consisting of:

wherein R, R ₁ , R ₂ , R ₃ , R ₄ , R _A , and X are as defined herein

[0029] It will be observed above that in the disclosure that numerous asymmetric centers may exist in the described compounds which will be found in the R or S configurations Excepted where otherwise noted, the compounds described herein compound described herein (1 e , a compound of any of Formula I, Formula II, Formula III or Formula IV) include the various stereoisomers and mixtures thereof

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION [0030] The materials and associated techniques and apparatuses described herein will now be described with reference to several embodiments Important properties and characteristics of the described embodiments are illustrated in the structures in the text While the compositions, compounds and methods described herein are described in conjunction with these embodiments, it should be understood that the compositions, compounds and methods described herein are not to be limited to these embodiments On the contrary, the compositions, compounds and methods described herein cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the appended claims In the following description, numerous specific details are set forth in order to provide a thorough understanding of the compositions, compounds and methods described herein The compositions, compounds and methods described herein maybe practiced without some or all of these specific details Well known process operations have not been described in detail in order not to unnecessarily obscure the compositions, compounds and methods described herein [0031] There is a continuing need to identify new derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess improved effectiveness bacterial infections that resist treatment with currently available antibiotics, or which possess unexpected selectivity against target microorganisms. [0032] Therefore, described herein are novel semi-synthetic glycopeptides that have antibacterial activity The semi-synthetic glycopeptides described herein are based on hydrolysis of the disacchaπde moiety of the amino acid-4 of the parent glycopeptide to monosaccharide, conversion of the monosaccharide to the ammo-sugar,

acylation of the amino substituent on the ammo-substituted sugar moiety on these scaffolds with certain acyl groups, and conversion of the acid moiety on the macrocyclic ring of these scaffolds to certain substituted amides Also provided are methods for synthesis of the compounds, pharmaceutical compositions containing the compounds, and methods of use of the compounds for the treatment and/or prophylaxis of diseases, especially bacterial infections

Compounds

[0033] Described herein are compounds having a structure selected from the group consisting of Formulas

I, II, III and IV

wherein,

R _A is selected from the group consisting of a) hydrogen, b) methyl, c) C ₂ -C ₁₂ -alkyl, Ri and R ₂ are each independently selected from the group consisting of a) hydrogen, b) C _r C ₁₂ -alkyl, c) C]-C ₁₂ -alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy,

(c) CrCj-alkoxy,

(d) C,-C ₃ -alkoxy- C ₁ -C ₃ ^IkOXy,

(e) amino,

(f) Ci-Ci ₂ -alkylamino, (g) Ci-C] ₂ -dialkylamino,

(h) alkenyl,

(l) alkynyl, d) C _r Ci ₂ -alkyl substituted with aryl, e) C _r C ₁₂ -alkyl substituted with substituted aryl, f) C _r C ₁₂ -alkyl substituted with heteroaryl, g) Ci-Cn-alkyl substituted with substituted heteroaryl, h) cycloalkyl, i) cycloalkenyl, j) heterocycloalkyl, or Ri and R ₂ taken together with the atom to which they are attached form a 3- 10 membered heterocycle ring which optionally contains one to three heteroatom or hetero functionalities selected from the group consisting of-O-, -NH, -N(C _r C ₆ -alkyl)-, -N(aryl)-, -N(aryl- C _r C _β -alkyl- )-, -N(substituted-aryl- Ci-C ₆ -alkyl-)-, -N(heteroaryl)-, -N(heteroaryl- Q-Q-alkyl-)-, - N(substituted-heteroaryl- Ci-Cβ-alkyl-)-, and -S- or S(O) ₁₁ - wherein n is 1 or 2 and the 3-10 membered heterocycle ring optionally is substituted with one or more substituents independently selected from the group consisting of (a) halogen,

(b) hydroxyl,

(c) C _r C ₃ -alkoxy,

(d) Q-Cs-alkoxy-Q-Q-alkoxy,

(e) OXO,

(0 Ci-Cs-alkyl,

(g) halo-C _r C ₃ -alkyl,

(h) CrCs-alkoxy-C^Ca-alkyl, and k) C(=O) R ₇ ,

1) C(-O) CHRNR ₁ R ₂ ,

R ₇ is selected from the group consisting of a) hydrogen, b) C]-Ci2 -alkyl, c) C]-Ci2 -alkyl substituted with one or more substituents selected from the group consisting of

(a) halogen,

(b) hydroxy,

(c) Ci-C ₃ -alkoxy,

(d) C ₁ -C ₃ -BIkOXy-C ₁ C ₃ -alkoxy,

(e) ammo,

(f) Ci-C ₁₂ -alkylammo,

(g) Ci-Ci ₂ -dialkylamino,

(h) alkenyl,

(i) alkynyl, d) C rC i ₂ -alkyl substituted with aryl,

e) C _r C ₁₂ -alkyl substituted with substituted aryl, f) Ci-Ci ₂ -alkyl substituted with heteroaryl, g) C _r Ci ₂ -alkyl substituted with substituted heteroaryl, h) cycloalkyl, i) cycloalkeny], j) heterocycloalkyl,

X is selected from the group consisting of

(1) hydrogen,

(2) chlorine, R is selected from the group consisting of

(1) hydrogen,

(2) cycloalkyl,

(3) cycloalkenyl,

(4) Ci-Ci2-alkyl, (5) Ci-Ci ₂ -alkyl substituted with one or more substituents selected from the group consisting of

(a) halogen,

(b) hydroxy,

(c) C _r C ₃ -alkoxy,

(d) C _r C ₃ -alkoxy- C,-C ₃ -alkoxy, (e) -COOR ₅ wherein R ₅ is hydrogen or loweralkyl,

(f) -C(O)NR ₅ R ₆ wherein R ₅ is as previously defined and R ₆ is hydrogen or loweralkyl,

(g) amino,

(h) -NR ₅ R^ wherein R ₅ and R^ are as previously defined, or R ₅ and R ₆ are taken together with the atom to which they are attached from a 3-

10 membered heterocycloalkyl ring which optionally is substituted with one or more substituents independently selected from the group consisting of

(I) halogen

(II) hydroxy, (111) Ci-Cs-alkoxy,

(iv) Ci-C ₃ -alkoxy-Ci-C ₃ -alkoxy, (v) oxo,

(vi) C _r C ₁₂ -alkyl, (vii) halo-Ci-C ₁₂ -alkyl, and

(vin) Ci-C ₃ -alkoxy-C,-Ci ₂ -alkyl, (1) aryl

(j) substituted aryl,

(k) heteroaryl (1) substituted heteroaryl,

(m) mercapto,

(n) C ₁ -C ₃ -UiIOaIkOXy, R ₃ is selected from the group consisting of

(1) OH,

(2) 1-adamantanamino, (3) 2-adamantanammo,

(4) 3-amino-l-adamantanamino,

(5) l-amino-3-adamantanamino,

(6) 3-loweralkylammo- 1 -adamantanamino,

(7) 1 -loweralkylarrano-3-adamantanamino, (8) amino

(9) NR ₈ R ₉ wherein R ₈ and R ₉ are independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl or

R ₈ and R ₉ together with the atom to which they are attached from a 3-10 membered heterocycloalkyl ring, which optionally is substituted with one or more substituents independently selected from the group consisting of

(a) halogen

(b) hydroxy,

(c) Ci-C ₃ -alkoxy,

(d) C _r C ₃ -alkoxy-CrC ₃ -alkoxy, (e) oxo,

(f) C _r C ₁₂ -alkyl,

(g) substituted loweralkyl, (h) halo-C _r C, ₂ -alkyl, and (i) Q-Cs-alkoxy-Q-Qz-alkyl,

R ₄ is selected from the group consisting of

(1) H,

(2) CH ₂ NHCH ₂ PO ₃ H ₂ ,

(3) aminoloweralkyl wherein the amino portion of the aminoloweralkyl group is further substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy, or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof [0034] It will be observed above that in the disclosure that numerous asymmetric centers may exist in the compounds provided herein which will be found in the R or S configurations Excepted where otherwise noted, the the compounds provided herein include the various stereoisomers and mixtures thereof

[0035] Also provided herein are pharmaceutical compositions which comprise a therapeutically effective amount of a compound as defined above in combination with a pharmaceutically acceptable carrier [0036] According to the methods of treatment provided herein, bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound provided herein, in such amounts and for such time as is necessary to achieve the desired

result

[0037] In a further aspect are provided processes and intermediates for the preparation of semi-synthetic glycopeptides of Formulas I, II, III and IV above

[0038] In another embodiment are provided compounds of Formulas I - IV wherein R ₁ is hydrogen and R ₂ is selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, arylalkyl, alkylaryl, and heteroaryl, and said aryl, alkylaryl, arylalkyl or heteroaryl group optionally containing one ore more optionally substituted aryl, heteroaryl, or condensed rings,

C(=O) R ₇ C(=O) CHRNR ₁ R ₂ or R ₁ and R ₂ together with the atom to which they are attached form a cycloheterocyclic ring which optionally contains additional heteroatom selected from the group consisting of optionally substituted O, N, and S In specific embodiments, R ₂ is hydrogen or methyl substituted with an unsubstituted or substituted biphenyl, for example biphenyl or chloro-biphenyl

[0039] In another embodiment are provided compounds of Formulas I - IV wherein R ₇ is selected from the group consisting of a) hydrogen, b) C _r C ₁₂ -alkyl, c) Q-C^-alkyl substituted with one or more substituents selected from the group consisting of

(a) halogen,

(b) hydroxy,

(c) C _r C ₃ -alkoxy, (d) d-Cj-alkoxy- C ₁ -C ₃ ^IkOXy,

(e) amino,

(h) alkenyl, (i) alkynyl, d) C i-Ci ₂ -alkyl substituted with aryl, e) C _r Ci ₂ -alkyl substituted with substituted aryl, f) Ci-C ₁₂ -alkyl substituted with heteroaryl, g) Ci-C ₁₂ -alkyl substituted with substituted heteroaryl, h) cycloalkyl, i) cycloalkenyl, j) heterocycloalkyl

[0040] In another embodiment are provided compounds of Formulas I — IV wherein R is selected from the group consisting of (1) hydrogen,

(2) cycloalkyl,

(3) cycloalkenyl,

(4) d-Cπ-alkyl.

(5) Ci-C ₁₂ -alkyl substituted with one or more substituents selected from the group consisting of (a) halogen,

(b) hydroxy,

(c) C _r C ₃ -alkoxy,

(d) d-Cs-alkoxy-

(e) -COOR ₅ wherein R ₅ is hydrogen or loweralkyl,

(f) -C(O)N R ₅ R ₆ wherein R ₅ is as previously defined and R ₆ is hydrogen or loweralkyl,

(g) amino,

(h) — NRsRe wherein R ₅ and Re are as previously defined, or

R ₅ and R ₆ are taken together with the atom to which they are attached from a 3- 10 membered heterocycloalkyl ring which optionally is substituted with one or more substituents independently selected from the group consisting of

(I) halogen

(II) hydroxy,

(111) C _r C ₃ -alkoxy,

(IV) Ci-C ₃ -alkoxy- Ci-C ₃ -alkox3

(v) oxo,

(Vl) C ₁ C ₁₂ alkyl,

(VIl) halo-C,-C ₁₂ -alkyl ₃ and

(vm) CrC ₃ -alkoxy

(1) aryl

0) substituted aryl,

(k) heteroaryl

(1) substituted heteroaryl,

(m) mercapto,

C i-Cj-thioalkoxy,

[0041] In another embodiment are provided compounds of Formulas III - IV wherein X is chlorine and R ₄ is hydrogen

[0042] In another embodiment are provided compounds of Formulas III - IV wherein X is hydrogen and R ₄ is hydrogen

[0043] In another embodiment are provided compounds of Formulas I - II wherein R _A is methyl and R ₄ is hydrogen

[0044] In another embodiment are provided compounds of Formulas I - II wherein R _A is hydrogen and R ₄ is hydrogen [0045] In another embodiment are provided compounds of Formulas I - IV wherein R _A is methyl or hydrogen, X is chlorine or hydrogen, R ₄ is hydrogen and R ₃ is selected from the group consisting of (I) OH,

(2) 1-adamantanarmno,

(3) 2-adamantanamino, (4) 3-amino-l-adamantanammo,

(5) l-ammo-3-adamantanamino,

(6) 3-loweralkylarmno- 1-adamantanaiπino,

(7) l-loweralkylamino-3-adamantanamino,

(8) amino

(9) NR ₈ R ₉ wherein R ₃ and R ₉ are independently selected from the group consisting of hydrogen, loweralkyl or substituted loweralkyl, cycloalkyl, substituted cycloalkyl or

R ₈ and R ₉ together with the atom to which they are attached from a 3-10 membered heterocycloalkyl rmg, which optionally is substituted with one or more substituents independently selected from the group consisting of

(a) halogen (b) hydroxy,

(c) C ₁ -C ₃ alkoxy,

(d) Ci-Cs-alkoxy- C,-C ₃ -alkoxy,

(e) oxo,

(f) CrCj-alkyl, (g) substituted loweralkyl,

(h) halo-C _r C ₁₂ -alkyl, and

(i) C _r C ₃ -alkoxy -C _r C ₁₂ -alkyl

[0046] In another embodiment are provided compounds of Formulas I - IV wherein R ₄ is selected from the group consisting of hydrogen,

CH ₂ NHCH ₂ PO ₃ H ₂ , and aminoloweralkyl wherein the aminoloweralkyl amino group is further substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy [0047] In another embodiment are provided intermediate compounds of Formulas I, EI, HI and IV for the synthesis of antibacterial agents wherern R _A is hydrogen or methyl, X is chlorme or hydrogen, R ₄ is hydrogen, CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl, R ₃ is OH and Ri and R ₂ are hydrogen

[0048] In another embodiment are provided pharmaceutically acceptable salts of compounds of Formulas

I, II, III, and IV By way of example only, are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobrormc acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid Further salts include those in which the counteπon is an anion, such as adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethane sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, mcotmate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylproρionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate Further salts include those m which the counteπon is an cation, such as sodium, lithium, potassium, calcium, magnesium, ammonium, and quaternary ammonium (substituted with at least one organic moiety) cations [0049] In another embodiment are pharmaceutically acceptable esters of compounds of Formulas I, II, III, and IV, including those in which the ester group is selected from a formate, acetate, propionate, butyrate, acrylate

and ethylsuccinate.

[0050] In another embodiment are pharmaceutically acceptable carbamates of compounds of Formulas I,

II, III, and IV. In another embodiment are pharmaceutically acceptable N-acyl derivatives of compounds of Formulas I, II, III, and IV Examples of N-acyl groups include N-acetyl and N-ethoxycarbonyl groups. Definitions

[0051] Unless otherwise noted, terminology used herein should be given its normal meanmg as understood by one of skill in the art.

[0052] The term "alkyl" as used herein refers to saturated, straight- or branched-cham hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom

[0053] The term "alkenyl" as used herein refers to unsaturated, straight- or branched-cham hydrocarbon radicals derived from a hydrocarbon moiety containing between two and twenty carbon atoms by removal of a single hydrogen atom [0054] The term "cycloalkyl" as used herein refers to a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound containing between three and twenty carbon atoms by removal of a single hydrogen atom.

[0055] The term substituted cycloalkyl as used herein refers to cycloalkyl substituted by one, two or three groups consisting of halogen, alkoxy, amino, alkylammo, dialkylarmno, hydroxy, aryl, heteroaryl, alkenyl or alkynyl groups [0056] The term "cycloalkenyl" as used herein refers to a monovalent group derived from a monocyclic or bicyclic unsaturated carbocyclic ring compound containing between three and twenty carbon atoms by removal of a single hydrogen atom.

[0057] The terms "C _r C ₃ -alkyl", "C _r C ₆ -alkyl", and "C _r C, ₂ -alkyl" as used herein refer to saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and three, one and six, and one and twelve carbon atoms, respectively, by removal of a single hydrogen atom. Examples of C _! -C ₃ -alkyl radicals include methyl, ethyl, propyl and isopropyl Examples of C _r C ₆ -alkyl radicals include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl Examples of radicals include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl , n-hexyl. N-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-docecyl. [0058] The term loweralkyl as used herein refers to Ci-Ci ₂ -alkyl as defined above

[0059] The term substituted loweralkyl as used herein refers to C]-Ci ₂ -alkyl substituted by one, two or three groups consisting of halogen, alkoxy, amino, alkylammo, dialkylarmno, hydroxy, aryl, heteroaryl, alkenyl or alkynyl groups [0060] The term "Cj-Ci ₂ -cycloalkyl" denoted a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic rmg compound by removeal of a single hydrogen atom Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1 ]heptyl, and bicyclo[2 2.2]octyl

[0061] The terms "C _r C ₃ -alkoxy", "Q-Q-alkoxy" as used herein refers to the C _r C ₃ -alkyl group and C ₁ -

C _δ -alkyl group, as previously defined, atttached to the parent molecular moiety through an oxygen atom Examples of CpCβ-alkoxy radicals include, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.

[0062] The term "loweralkylamino" as used herein refers to C _r C ₁₂ -alkyl groups, as previously defined,

attached to the parent molecular moiety through a nitrogen atom Examples of loweralkylamrno include, but are not limited to methylamino, dimethylamino, ethylaimno, diethylamino, propylamino and decylamino [0063] The term "oxo" denotes a group wherein two hydrogen atoms on a single carbon atom in an alkyl group as defined above are replaced with a single oxygen atom (i e a carbonyl group) [0064] The term "aryl" as used herein refers to a mono- or bicychc carbocylic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, mdenyl and the like and can be un- substituted or substituted (including bicychc aryl groups) with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, C _r C ₁₂ -alkoxy, thioalkoxy, C ₁ -C ₁₂ - thioalkoxy, aryloxy, amino, alkylamino, dialkylamino, acylarmno, cyano, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl

[0065] The term "substituted aryl" as used herein refers to a mono- or bicychc carbocylic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, mdenyl and the like substituted (including bicychc aryl groups) with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, C _r C ₁₂ -alkoxy, thioalkoxy, aryloxy, amino, alkylamino, dialkylamino, acylarmno, cyano, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl,aryl, heteroaryl, heterocyclaryl and carboxamide In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl [0066] The term "arylalkyl" as used herein refers to an aryl group as defined above attached to the parent molecular moiety through an alkyl group wherein the alkyl group is of one to twelve carbon atoms.

[0067] The term "substituted arylalkyl" as used herein refers to an substituted aryl group as defined above attached to the parent molecular moiety through an alkyl group wherein the alkyl group is of one to twelve carbon atoms

[0068] The term "alkylaryl" as used herein refers to an alkyl group as defined above attached to the parent molecular moiety through an aryl group

[0069] The term "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodme

[0070] The term "alkylamino" refers to a group having the structure -NHR' wherein R' is alkyl, as previously defined Examples of alkylamino include methylamino, ethylamino, lso-propylamino, and the like [0071] The term "dialkylamino" refers to a group having the structure -NR'R" wherein R' and R" are independently selected from alkyl, as previously defined Additionally, R' and R" taken together optionally is - (CH ₂ ) _k - where k is an integer of from 2 to 6 Examples of dialkylamino include dimethylamino, diethylamino, methylpropylammo, pipeπdmo, and the like [0072] The term "haloalkyl" denotes an alkyl group, as defined above, having one, two or three halogen atoms attached thereto and is exemplified by such group as chloromethyl, bromoethyl , trifluoromethyl, and the like [0073] The term "alkoxycarbonyl" represents as ester group, i e an alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like [0074] The term "thioalkoxy" refers to an alkyl group previously defined attached to the parent molecular moiety through a sulfur atom [0075] The term "carboxaldehyde" as used herein refers to a group of formula -CHO

[0076] The term "carboxy" as used herein refers to a group of formula -CO ₂ H

[0077] The term "carboxamide" as used herein refers to a group of formula -CONR'R" wherein R' and

R" are independently selected from hydrogen, alkyl, substituted loweralkyl, or R' and R" taken together optionally is — (CH ₂ ) _k - where k is an integer of from 2 to 6

[0078] The term "heteroaryl", as used herein, refers to a cyclic or bicyclic aromatic radical having from five to ten ring stoms in each rmg of which at least one atom of the cyclic or bicyclic ring is selected from optionally substituted S, O, and N, zero, one or two ring atoms are additional heteroatoms independently selected from optionally substituted S, O, and N, and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the rmg atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, lmidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, qurnolinyl, isoqumolinyl, naphthyπdinyl, and the like

[0079] The term "heterocycloalkyl" as used herein, refers to a non-aromatic partially unsaturated or fully saturated 3- to 10-membered rmg system, which includes single rings of 3 to 8 atoms in size and bi- or tri-cyclic ring systems which may include aromatic six-membered aryl or heteroaryl rings fused to a non-aromatic ring These heterocycloalkyl rings include those having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms optionally is oxidized and the nitrogen heteroatom optionally is quaternized Representative heterocycloalkyl rings include, but not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, lrmdazolinyl, lmidazolidinyl, pipendmyl, prperazrnyl, oxazolidinyl, lsoxazolidmyl, morpholinyl, thiazohdinyl, lsothiazolidinyl, and tetrahydrofuryl [0080] The term "heterocycle ring" as used herein, refers to an aromatic or a non-aromatic partially unsaturated or fully saturated 3- to 10-membered ring system consisting of one to three heteroatom independently selected from oxygen, sulfur and nitrogen Represaentative heterocycle ring include, but not limited to, triazole, pyridyl, piperazinyl and morpholinyl

[0081] The term "heteroarylalkyl" as used herein, refers to a heteroaryl group as defined above attached to the parent molecular moiety through an alkylene group wherein the alkylene group is of one to four carbon atoms [0082] "Protecting group" refers to an easily removable group which is known in the art to protect a functional group, for example, a hydroxyl, ketone or amine against undesirable reaction during synthetic procedures and to be selectively removable Examples of such protecting groups are known, cf , for example, T H Greene and P G M Wuts, Protective Groups in Organic Synthesis, 2 nd edition, John Wiley & Sons, New York (1991) Examples of hydroxy-protecting groups include, but not limited to, mefhylfhiomethyl, tert-dimethylsilyl, tert- butyldiphenylsilyl, ethers such as methoxymethyl, and esters including acetyl, benzoyl, and the like Examples of ketone protecting groups include, but not limited to, ketals, oximes, O-substituted oximes for example O-benzyl oxime, O-phenylthiomethyl oxime, 1-isopropoxycyclohexyl oxime, and the like Examples of amine protecting groups include, but are not limited to, tert-butoxycarbonyl (Boc) and carbobenzyloxy (Cbz) [0083] A term "protected-hydroxy" refers to a hydroxy group protected with a hydroxy protecting group, as defined above

[0084] The term ammo acid refers to ammo acids having D or L stereochemistry, and also refers to synthetic, non-natural ammo acids having side chains other than those found in the 20 common amino acids Non- natural amino acids are commercially available or are prepared according to US 5,488, 131 and references therein Amino acids are further substituted to contain modifications to their amino, carboxy, or side-cham groups These modifications include the numerous protecting group commonly used in peptide synthesis (T H Greene and P G M Wuts, Protective Groups m Organic Synthesis. 2 nd edition, John Wiley & Sons, New York, 1991)

[0085J The term "substituted heteroaryl" as used herein, refers to a heteroaryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, Ci-Cπ-alkyl, C _r Ci ₂ -alkoxy, C _r Ci ₂ -alkoxy substituted with aryl, haloalkyl, thioalkyl, amino, alkylamino, dialkylamino, mercapto, mtro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide In addition, any one substituent is optionally an aryl, heteroaryl, or hetercycloalkyl group

[0086] The term "substituted heterocycloalkyl" as used herein, refers to a heterocycloalkyl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C _r C ₁₂ -alkyl, CpCπ-alkoxy, Q-C^-alkoxy substituted with aryl, haloalkyl, thioalkyl, amino, alkylamino, dialkylamino, mercapto, mtro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide In addition, any one substituent is optionally an aryl, heteroaryl, or hetercycloalkyl group

[0087] The term "stereoisomer" as used herein, refers to either of two forms of a compound having the same molecular formula and having their constituent atoms attached in the same order, but having different arrangement if their atoms in space about an asymmetric center. Numerous asymmetric centers may exist in the compounds described herein Except where otherwise noted, the compounds described herem mclude the various stereoisomers and mixtures thereof Accordingly, except where otherwise noted, it is intended that a mixture of stereo orientations or an individual isomer of assigned or unassigned orientation is optionally present [0088] The term "tautomer" as used herein refers to either of the two forms of a chemical compound that exhibits tautomensm, which is the ability of certain chemical compounds to exist as a mixture of two interconvertible isomers in equilibrium via proton transfer The keto and enol forms of carbonyl compounds are examples of tautomers They are interconvertible in the presence of traces of acids and bases via a resonance stabilized anion, the enolate ion

[0089] The term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio For example, S. M Berge, et al describes pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 66 1-19 (1977), incorporated heτein by reference The salts can be prepared in situ during the final isolation and purification of the compounds described herem compound described herem (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV), or separately by reacting the free base function with a suitable organic acid Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succmic acid or malonic acid or by using other methods used in the art such as ion exchange Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotmate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counteπons such as

hahde, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate [0090] The term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down in the human body to leave the parent compound or a salt thereof Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms Representative examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates

[0091] The term "solvate" as used herein refers to a compound formed by salvation, the combination of solvent molecules with molecules or ions of solute composed of a compound described herein The term "pharmaceutically acceptable solvate" refers to those solvates which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lover animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio

[0092] The term "alkylated quaternary ammonium salt" as used herein refers to a compound formed by alkylation of the nitrogen atom of the primary, secondary or tertiary amine of the molecule with alkyl hahde to form alkyl quaternary ammonium salt

[0093] The term "pharmaceutically acceptable prodrugs" refers to those prodrugs of the compounds described herein compound described herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitteπomc forms, where possible, of the compounds described herein The term "prodrug" refers to compounds that are transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood A thorough discussion is provided m T Higuchi and V Stella, Pro-drugs as Novel Delivery Systems, VoI 14 of the A C S Symposium Series, and in Edward B Roche, ed , Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference Synthetic Methods

[0094] Synthesis of the compound described herein (i e , a compound of any of Formula I, Formula II,

Formula III or Formula IV) can be broadly summarized as follows The compounds described herein are optionally made by chemical modifications of the Compound A, Compound B, Compound H and Compound C scaffolds In particular, the semi-synthetic glycopeptides described herein are made by subjecting the parent glycopeptide in acidic medium to hydrolyze the disacchaπde moiety of the amino acid-4 of the parent glycopeptide to give the monosaccharide, conversion of the monosaccharide to the amino-sugar derivative, acylation of the amino substituent on the ammo-substituted sugar moiety on these scaffolds with certain acyl groups, and conversion of the acid moiety on the macrocyclic ring of these scaffolds to certain substituted amides The compounds described herein are optionally made by coupling the ammo-sugar moiety of functionalized or unfunctionahzed glycopeptides from the above scaffolds with the appropriate acyl and/or amino groups under amide formation conditions and conversion of the acid moiety on the macrocyclic ring of the resulting glycopeptide derivative to certain substituted amides, or a combination of an alkylation modification of the substitutent on the ammo-substituted sugar moiety on this scaffold with certain alkyl groups or acylation modification of the ammo substituent on the amino-subsntuted sugar moiety on this scaffold with certain acyl groups, α-ammo acid or /3-amino acids or deπvatives thereof, and conversion of the acid moiety on the macrocyclic ring of this scaffold to certain substituted amides Synthesis of compounds optionally

involves the use of protecting or blocking groups in order to maximize yields, minimize unwanted side products, or improve the ease purification

[0095] In particular, the symi-synthetic glycopeptides of the compounds described herein are optionally made by modifying Compound A, Compound B, Compound H and Compound C scaffolds The glycopeptide starting material is optionally unsubstituted or substituted at the 7 ^th amino acid at the 4' position of the phenyl ring with CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl as defined herein

[0096] Selective hydrolysis of Compound A, Compound B, Compound H or Compound C in which the 7* amino acid at the 4' position of the phenyl ring substituted with hydrogen, CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl as defined herein with acid gives the monosaccharide intermediate [1], [2], [3] or [4], respectively, wherein R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl as defined herein

[0097] Conversion of the monosaccharides [1, 2, 3 and 4] to the synthetic intermediate ammo-sugar derivatives of Formulas I and III can be achieved as follow 1) temporary protection of the amino grouρ(s) of the molecules with t-butoxycarbonyl group, 2) activating the primary alcohol of the monosaccharide to a leaving group, such as mesylate, tosylate, Inflate and the like, to give glycopeptides [5 and 6] wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl as defined herein, R ₃ is OH, and L is a leaving group such as OMs, OTs, halogen and die like, 4) displacement of the leaving group with sodium azide to form the azido deπvative and 5) reduction of the azide group to give the corresponding synthetic intermediate amino-sugar derivatives of Formulas I and III for the synthesis of antibacterial semi-synthetic glycopeptides, wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl as defined herein, R ₃ is OH, Ri and R ₂ are hydrogen

[0098} Alternatively, the compounds described herein can be prepared by direct displacement of the leaving group in compounds of Formula [5 and 6] with an appropriate R)NH ₂ to yield compounds of Formulas I and III wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or armnoloweralkyl as defined herein, Rj is OH, R ₂ is hydrogen and R ₁ is defined wherein with the proviso that R ₁ is not hydrogen, C(=O) CRNR ₁ R ₂ or C(=O) R ₇

[0099] Conversion of the monosaccharides [1, 2, 3 and 4] to the synthetic intermediate amino sugar derivatives of Formulas II and IV can be achieved as follow 1) temporary protection of the ammo group(s) of the molecules with t-butoxycarbonyl group, 2) activating the primary alcohol of the monosaccharide to a leaving group, such as mesylate, tosylate, tπfiate and the like, to give glycopeptides [5 and 6] wherem R _A IS hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or armnoloweralkyl as defined herein, R ₃ is OH, and L is a leaving group, 4) displacement of the leaving group with mtromethane in basic condition to form the mtro- deπvative and 5) reduction of the nitro group to give the corresponding synthetic intermediate ammo-sugar derivatives of Formulas II and IV for the synthesis of antibacterial semi-synthetic glycopeptides, wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl as defined herein, R ₃ is OH, R ₁ and R ₂ are hydrogen

[00100] Alternately, replacing mtromethane with sodium cyanide, the glycopeptides [5 and 6] wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl as defined herein, R ₃ is OH, and L is a leaving group yield the corresponding nitrile derivatives Catalytic reduction of these mtriles may give the corresponding synthetic intermediate ammo-sugar derivatives of Formulas II and IV for the synthesis of antibacterial semi-synthetic glycopeptides, wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or armnoloweralkyl as defined herein, R ₃ is OH, R ₁ and R ₂ are hydrogen [00101] Modification of the above intermediates ammo-sugar scaffolds of Formulas I, II, III and IV, wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl as defined herein, R ₃ is OH, R ₁ and R ₂ are hydrogen, to achieve semi-synthetic glycopeptides is by acylation or alkylation or reaction with aldehyde followed by reductive amination of the resulting imine of the amino substituent on the amino-sugar moiety of the 4 ^th amino acid of on these scaffolds with certain acyl or alkyl groups or aldehydes or ketones, and /or conversion of the acid moiety on the macrocyclic ring of these scaffolds to certain substituted amides In specific embodiments, the compounds described herein may generally be made by coupling a suitably functionahzed or un-functionalized mono-sugar scaffolds of Formulas I, II, III and IV, wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl as defined herein, R ₃ is OH, R ₁ and R ₂ are hydrogen with the appropπate starting materials using known alkylation, reductive amination, ammo acid coupling, or acylation procedures Synthesis of compounds optionally involves the use of

protecting groups in order to maximize yields, minimize unwanted side products, or improve the ease of purification [00102] The Ri alkyl groups are optionally formed by contacting the ammo-sugar derivatives with an aldehyde or ketone followed by reductive animation of the resulting imme The Ri groups linked to the glycopeptide with an amide bond are optionally formed by reacting the glycopeptide with the appropπate startmg material containing a carboxyhc acid or activated carboxyhc acid moiety under known amide forming conditions A second alkyl R ₂ is optionally formed by contacting the ammo-sugar derivatives having substituent Ri with an aldehyde or ketone followed by reductive armnation of the resulting imrne The R ₂ groups linked to the glycopeptide with an amide bond are optionally formed by reaction of the glycopeptide having R ₁ alkyl group with the appropriate startmg material containing a carboxyhc acid or activated carboxyhc acid moiety under known amide forming conditions [00103] Substitutions at R ₃ are optionally introduced by coupling an appropπate amine with the carboxyhc acid group of the amrno-sugar glycopeptide under known amide forming conditions

[00104] Substitutions at R ₄ are optionally introduced via Mannich reaction wherein the glycopeptide is treated with an amine and formaldehyde under basic conditions (for example, as described in The Journal of Antibiotics, VoI 50, No 6, p 509-513)

[00105] Specific examples of synthesis for the compounds described herein are provided in the Examples, below Other compounds that fall within the scope of the claims can be prepared in an analogous manner [00106] In general, compounds describe herein are optionally made by modifying compound having

Formulas i, ii, iii, and iv,

wherem R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or amrnoloweralkyl as defined herein, by a technique selected from the group consisting of,

(a) alkylation of the amino substituent on the ammo-substituted sugar moiety of the 4 ^th ammo acid of the compound with an alkyl halide having structure R)-J where J is a halogen, (b) acylation of the ammo substituent on the ammo-substituted sugar moiety of the 4 ^th ammo acid of the compound with an acyl group having the structure, C(=O) R ₇ ,

(C) acylation of the amino substituent on the ammo-substituted sugar moiety of the 4 ^th ammo acid of the compound with an acyl group having the structure, C(=O) CHRNR,R ₂ ,

(d) reaction of the amino substituent on the amino-substituted sugar moiety of the 4 ^th amino acid of the compound with an aldehyde or ketone followed by reductive armnation of the resulting imine,

(e) conversion of the acid moiety on the macrocyclic ring of the compound with substituted amide as defined by R ₃ ,

(f) removal of the Boc protecting group by the use of mild acid,

(g) a combination of (a), (b), and (f), (h) a combination of (a), (c), and (f), (i) a combination of (a), (d), and (f), (j) a combination of (a), (e), and (f), (k) a combination of (b), (e), and (f), (1) a combination of (c), (e), and (f), (m) a combination of (d),(e), and (f),

(n) a combination of (a), (b), (e), and (f),

(o) a combination of (a), (c), (e), and (f),

(p) a combination of (a), (d), (e), and (f), to form a compounds having a formula selected from the group consisting of

wherein R, Ri, R ₂ , R ₃ , R ₄ , R _A , and X are as defined herein.

[00107] The compounds described herein are optionally made by chemical modifications of the Compound

A, Compound B, Compound H, and Compound C amides In particular, the semi-synthetic glycopeptides described herein are made by firstly conversion of the acid moiety on the macrocyclic ring of the parent glycopeptide (Compound A, Compound B, Compound H or Compound C) to certain substituted amides. Treatment of the glycopeptide amide in acidic medium to hydrolyze the disacchaπde moiety of the amino acid-4 of the parent glycopeptide amide to give the monosaccharide derivative; conversion the monosaccharide to the amino-sugar derivative, acylation of the ammo substituent on the amino-substituted sugar moiety of the 4* amino acid on these

scaffolds with certain acyl groups The compounds descπbed herein are optionally made by coupling the amrno- sugar moiety of functionalized or unfunctionalized glycopeptides from the above scaffolds with the appropriate acyl and/or amino groups under amide formation conditions; or a combination of an alkylation modification of the substitutent on the ammo-substituted sugar moiety on this scaffold with certain alkyl groups or acylation modification of the amino substituent on the amino-substituted sugar moiety on this scaffold with certain acyl groups, α-amino acid or j3-ammo acids or derivatives thereof. Synthesis of compounds optionally involves the use of protecting or blocking groups in order to maximize yields, minimize unwanted side products, or improve the ease purification.

[00108] In particular, the symi-synthetic glycopeptides described herein are optionally made by modifying

Compound A, Compound B, Compound H or Compound C scaffolds These natural glycopeptide starting materials are optionally unsubstituted or substituted at R ₄ with CH ₂ NHCH ₂ PO ₃ H ₂ , or ammoloweralkyl as defined herein [00109] Treatment of Compound A and Compound B, scaffolds with appropriate amines in the presence of amide forming coupling reagent provides the glycopeptide amides [7] wherein R _A is methyl or hydrogen, R ₄ is hydrogen, CH ₂ NHCH ₂ PO ₃ H ₂ , or ammoloweralkyl as defined herem and R ₃ is previous defined with the proviso R ₃ is not OH Treatment of Compound H and Compound C scaffolds with appropriate amines rn the presence of amide forming couplmg reagent provides the glycopeptide amides [8] wherein X is hydrogen or chlorine, R ₄ is hydrogen, CH ₂ NHCH ₂ PO ₃ H ₂ , or ammoloweralkyl as defined herein and R ₃ is previous defined with the proviso R ₃ is not OH

[00110] Selective hydrolysis of glycopeptide amide [7] or [8] wherein R _A is methyl or hydrogen, X is hydrogen or chlorine, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl as defined herein and R ₃ is previous defined with the proviso R ₃ is not OH with acid gives the amino acid-4 monosaccharide intermediates [9] or [10] wherein R _A IS methyl or hydrogen, X is chorine of hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or ammoloweralkyl as defined herein and R ₃ is previous defined with the proviso R ₃ is not OH.

[00111] Conversion the amino acid -4 monosacchaπdes derivatives [9] and [10] to the synthetic intermediate ammo acid-4 ammo-sugar derivatives can be achieved as follow 1) temporary protection of the amino group(s) of the molecules with t-butoxycarbonyl group, 2) activating the primary alcohol of the monosaccharide to a

leaving group, such as mesylate, tosylate, triflate and the like, to give glycopeptides [11] and [12], respectively, wherein R _A IS hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ POsH ₂ , or armnoloweralkyl as defined herein, R ₃ is previous defined with the proviso R ₃ is not OH, and L is a leaving group such as OMs, OTs, halogen and the like, 4) displacement of the leaving group with sodium azide to form the azido derivative and 5) reduction of the azide group to give the corresponding synthetic intermediate amino-sugar derivatives of Formulas I and III for the synthesis of antibacterial semi-synthetic glycopeptides, wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl as defined herein, R ₃ is as defined with the proviso that R ₃ is not OH, and JL ₁ and R ₂ are hydrogen.

[00112] Alternatively, the compounds described herein can be prepared by direct displacement of the leaving group m compounds of Formulas [11] and [12] with an appropriate R ₁ NH ₂ to yield compounds of Formulas I and III wherein R _A IS hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or armnoloweralkyl as defined herein, R ₃ is defined wherem with the proviso that R ₃ is not OH, R ₁ is defined wherein with the proviso that R ₁ is not C(=O) R ₇ or Q=O)CHRNR ₁ R ₂ [00113] Conversion the [11] and [12] to the synthetic intermediate amino acid-4 ammo-sugar derivatives of

Formulas II and IV can be achieved as follow. 1) displacement of the leaving group in compounds of Formulas [11] and [12] with nitromethane in basic condition to form the mtro-derivatives and 2) reduction of the nitro group to give the corresponding synthetic intermediate ammo acid-4 amino-sugar derivatives of Formulas II and IV for the synthesis of antibacterial semi-synthetic glycopeptides, wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or armnoloweralkyl as defined herein, R ₃ is as defined wherein with the proviso that R ₃ is not OH, and R ₁ and R ₂ are hydrogen

[00114] Alternatively, conversion the [11] and [12] to the synthetic intermediate amino acid-4 amino-sugar derivatives of Formulas II and IV can be achieved as follow 1) displacement of the leaving group in compounds of Formulas [11] and [12] with sodium cyanide to form the nitrile-denvatives and 2) catalytic reduction of the nitrile group to give the corresponding synthetic intermediate amino acid-4 amino sugar derivatives of Formulas II and IV for the synthesis of antibacterial semi-synthetic glycopeptides, wherein R _A IS hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or armnoloweralkyl as defined herein, R ₃ is as defined wherein with the proviso that R ₃ is not OH, and R ₁ and R ₂ are hydrogen [00115] Modification of the above intermediates amino acid-4 ammo sugar scaffolds of Formulas I, II, III and IV, wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or armnoloweralkyl as defined herein, R ₃ is as defined wherein with the proviso that R ₃ is not OH, and R ₁ and R ₂ are hydrogen, to achieve semi-synthetic glycopeptides is by acylation or alkylation or reaction with aldehyde followed by reductive animation of the resulting imine of the ammosubstituent on the amino-sugar moiety of the 4 ^th amino acid of on these scaffolds with certain acyl or alkyl groups or aldehydes or ketones In specific embodiments, the compounds descπbed herein are generally be made by coupling a suitably functionalized or un-functionalized amino

acid-4 mono-sugar scaffolds of Formulas I, II, III and IV, wherein R _A is hydrogen or methyl, X is chlorine or hydrogen, R ₄ is hydrogen oi CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl as defined herein, R ₃ is as defined wherein with the proviso that R ₃ is not OH, and R ₁ and R ₂ are hydrogen, with the appropriate starting materials using known alkylation, reductive amination procedure, amino acid coupling, or acylation procedures. Synthesis of compounds optionally involves the use of protecting groups in order to maximize yields, minimize unwanted side products, or improve the ease of purification.

[00116] The R ₁ alkyl groups are optionally formed by contacting the above ammo acid-4 amino-sugar derivatives with an aldehyde or ketone followed by reductive amination of the resulting irrune. The R ₁ groups linked to the glycopeptide with an amide bond are optionally formed by reaction of the glycopeptide with the appropriate starting material containing a carboxylic acid or activated carboxylic acid moiety under known amide forming conditions A second alkyl R ₂ is optionally formed by contacting the amino acid-4 ammo-sugar derivatives having substituent Ri with an aldehyde or ketone followed by reductive animation of the resulting lmme. The R ₂ groups linked to the glycopeptide with an amide bond are optionally formed by reaction of the glycopeptide having R ₁ alkyl group with the appropriate starting material containing a carboxylic acid or activated carboxylic acid moiety under known amide forming conditions

[00117] Substitutions at R ₄ are optionally introduced via Mannich reaction wherein the glycopeptide is treated with an amine and formaldehyde under basic conditions (for example, as descπbed m The Journal of Antibiotics, Vol. 50, No. 6, p. 509-513). [00118] In general, compounds descπbed herein are optionally made by modifying compounds having

methyl, X is chlorine or hydrogen, R ₄ is hydrogen or CH ₂ NHCH ₂ PO ₃ H ₂ , or aminoloweralkyl as defined herein, R ₃ is as defined wherein with the proviso that R ₃ is not OH, Ri and R ₂ are hydrogen, by a technique selected from the group consisting of,

(a) alkylation of the amino substituent on the amino acid-4 amino-substituted sugar moiety of the compound with an alkyl hahde having structure Ri-J where J is a halogen,

(b) acylation of the amino substituent on the amino acid-4 amino-substituted sugar moiety of the compound with an acyl group havmg the structure, C(=O) R ₇ ,

(c) acylatioπ of the amino substituent on the amino acid-4 amino-substituted sugar moiety of the compound with an acyl group havmg the structure, C(=O) CHRNRiR ₂ ,

(d) reaction of the amino substituent on the amino-substituted sugar moiety of the 4 ^th amino acid of the compound with an aldehyde or ketone followed by reductive armnation of the resulting imine

(e) removal of the protecting Boc group by use of mild acid,

(f) a combination of (a), (b), and (e),

(g) a combination of (a), (c), and (e), (h) a combination of (a), (d), and (e), to form a compounds of Formulas I, II, III, and VI, wherein R, R ₁ , R ₂ , R ₃ , R ₄ , R _A , and X are as defined herein with the proviso R ₃ is not OH

Pharmaceutical Compositions

[00119] Pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) formulated together with one or more pharmaceutically acceptable carriers As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type Some examples of materials which can serve as pharmaceutically acceptable earners are sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil; safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols, such a propylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffering agents such as magnesium hydroxide and aluminum hydroxide, alginic acid; pyrogen-free water, isotomc salme; Ringer's solution, ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator The pharmaceutical compositions described herein can be administered to humans and other animals orally, rectally, parenterally, mtracisternally, intravaginally, mtrapeπtoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray, or a liquid aerosol or dry powder formulation for inhalation [00120] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs In addition to the active compounds, the liquid dosage forms optionally contain inert diluents commonly used in the art such as, for example, water or other solvents, solubihzmg agents and emulsifϊers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof Besides inert diluents, the oral compositions can also include ad _j uvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [00121] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions are optionally formulated according to the known art using suitable dispersing or wetting agents and suspending agents The sterile injectable preparation is optionally a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol Among the acceptable

vehicles and solvents that are optionally employed are water, Ringer's solution, U S P and isotonic sodium chloride solution In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides In addition, fatty acids such as oleic acid are used in the preparation of injectables [00122] The injectable formulations can be sterilized, for example, by filtration through a bacteπal- retaimng filter, or by incorporating sterilizing agents in the form of steπle solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use

[00123] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection This is optionally accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form Alternatively, delayed absorption of a parenterally administered drug form is optionally accomplished by dissolving or suspending the drug in an oil vehicle Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycohde Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled Examples of other biodegradable polymers include poly(orthoesters) and poly( anhydrides) Depot injectable formulations are optionally prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues

[00124] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compound described herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound

[00125] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules

In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcmm phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose mannitol, and silicic acid, b) binders such as, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrohdinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentomte clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof In the case of capsules, tablets and pills, the dosage form optionally comprise buffering agents [00126] Solid compositions of a similar type are optionally employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols

[00127] The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings known in the pharmaceutical formulating art They optionally contains opacifying agents and can also be of a composition that they release the active mgredient(s) only, or preferentially, in a certain part of the mtestmal tract, optionally, in a delayed manner Examples of embedding compositions which can be used include polymeric substances and waxes

[00128] Solid compositions of a similar type are optionally employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols

[00129] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings known m the pharmaceutical formulating art In such solid dosage forms the active compound is optionally admixed with at least one inert diluent such as sucrose, lactose or starch Such dosage forms optionally comprise, as is normal practice, additional substances other than inert diluents, e g , tableting lubπcants and other tabletmg aids such a magnesium stearate and microcrystalline cellulose In the case of capsules, tablets and pills, the dosage forms optionally comprise buffering agents They optionally contains opacifying agents and can also be of a composition that they release the active mgredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner Examples of embedding compositions which can be used include polymeric substances and waxes [00130] Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as are optionally required Ophthalmic formulations, ear drops, and the like are also contemplated [00131] The ointments, pastes, creams and gels may contain, in addition to an active compound described herein, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentomtes, silicic acid, talc and zinc oxide, or mixtures thereof

[00132] Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles where bacteria reside in patients with bronchial infections, such as chronic bronchitis and pneumonia Pathogenic bacteria are commonly present throughout airways down to bronchi, bronchioli and lung parenchema, particularly in terminal and respiratory bronchioles During exacerbation of infection, bacteria can also be present m alveoli Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue [00133] Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of a aerosol particles having with a mass medium average diameter predominantly between 1 to 5 μ Further, the formulation preferably has balanced osmolaπty ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the compounds described herein compound described herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) to the site of the infection Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects

[00134] Aerosolization devices suitable for administration of aerosol formulations descπbed herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 μ Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 μ range A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets Vibrating porous

plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets A variety of suitable devices are available, including, for example, AeroNeb TM and AeroDose TM

(S) vibrating porous plate nebulizers (AeroGen, Inc , Sunnyvale, California), Sidestream nebulizers (Medic-Aid Ltd ,

® ® West Sussex, England), Pan LC and Pan LC Star jet nebulizers (Pan Respiratory Equipment, Inc., Richmond,

TM

Virginia), and Aerosomc (DeVilbiss Medizmische Produkte (Deutschland) GmbH, Heiden, Germany) and

® UltraAire (Omron Healthcare, Inc , Vernon Hills, Illinois) ultrasonic nebulizers

[00135] In some embodiments, compounds described herein compound described herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) are formulated for use as topical powders and sprays that contain, in addition to the compounds described herein, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances Sprays optionally contain customary propellants such as chlorofluorohydrocarbons

[00136] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body Such dosage forms can be made by dissolving or dispensing the compound in the proper medium Absorption enhancers can also be used to increase the flux of the compound across the skm The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel

[00137] According to the methods of treatment described herein, bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound described herein, in such amounts and for such time as is necessary to achieve the desired result By a "therapeutically effective amount" of a compound described herein is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment It will be understood, however, that the total daily usage of the compounds and compositions descnbed herein will be decided by the attending physician within the scope of sound medical judgment The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the seventy of the disorder, the activity of the specific compound employed, the specific composition employed, the age, body weight, general health, sex and diet of the patient, the time of administration, route of administration, and rate of excretion of the specific compound employed, the duration of the treatment, drugs used m combination or coincidental with the specific compound employed, and like factors known in the medical arts [00138] The total daily dose of the compounds described herein compound described herein (i e , a compound of any of Formula I, Formula II, Formula III or Formula IV) administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0 01 to 50 mg/kg body weight or more usually from 0 1 to 25 mg/kg body weight Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose In general, treatment regimens described herein comprise administration to a patient in need of such treatment from about 10 mg to about 2000 mg of the comρound(s) described herein per day in single or multiple doses Abbreviations

[00139] Abbreviations which may have been used in the descriptions of the schemes and the examples that follow are AcOH for acetic acid, AIBN for azobisisobutyromtnle, BU3S11H for tπbutyltm hydride, CDI for

carbonyldπmidazole, DBU for l,8-diazabicyclo[5 4 0]undec-7-ene; DCM for dichloromethane, DEAD for diethylazodicarboxylate, DMF for dimethylformamide, DMP for 2,2-dimethoxypropane DMSO for dimethylsulfoxide (or methylsulfoxide), DPPA for diphenylphosphoryl azide, Et _β N for tπethylamine, EtOAc for ethyl acetate, Et2θ for diethyl ether, EtOH for ethanol, HOAc for acetic acid, LiHMDS or LiN(TMS)2 for lithium bis(tπmethylsilyl)amide, MCPBA for meta-chloroperbenzoic acid, MeOH for methanol, MsCl for methanesulfonyl chloride, NaHMDS or NaN(TMS)2 for sodium bis(trimethylsilyl)amide, NMO for N-methylmorphohne N-oxide,

SOCl ₂ for thionyl chloride, PPTS for pyridmm p- toluene sulfonate, Py for pyridine, TEA for tπethylamme, THF for tetrahydrofuran, TMSCl for tπmethylsilyl chloride, TMSCF ₃ for trimethyl(trifluoromethyl) silane, TPP for tπphenylphosphine, TPAP for tetra-n-propylammonium perruthenate, DMAP for 4-dirnethylarnino pyridine, TsOH for /7-toluene sulfonic acid, MsOH for methanesulfomc acid, OMs for mesylate, OTs for tosylate, OTf for triflate, Boc for tert-butoxycarbonyl, Fmoc for N-fluorenylmethoxycarbonyl, Su for succinimide, Ph for phenyl, HBPyU for O-benzotriazol-l-yl-N,N,N',N',-bis(tetramethylene)uronium hexafluorophosphate, PyBOP for benzotriazol 1 yloxytripyrrolidinophosphomum hexafluorophosphate

EXAMPLES

[00140] The following examples provide details concerning the synthesis, properties and activities and applications of semi-synthetic glycopeptides described herein It should be understood the following is representative only

Example 1 Synthesis of Compound (1)

[00141] To 0 5 mmol of Compound A (base) in a round bottom flask is added 10 mL of tπfluoroacetic acid The mixture is stirred at -15 ⁰ C for 6 hours yielding Compound (1)

Example 2 Synthesis of Compound (2)

[00142] To 0 55 mmol of Compound B (base) in a round bottom flask is added 10 mL of trifluoroacetic acid The mixture is stirred at - 15 ⁰ C for 6 hours yielding Compound {2}

Example 3 Synthesis of Compound £3}

[00143] To 0.45 mmol of Compound H (base) in a round bottom flask is added 10 mL of tiifluoroacetic acid. The mixture is stirred at -15 °C for 6 hours yielding Compound (3).

Example 4 Synthesis of Comound (4}

[00144] To 0.48 mmol of Compound C (base) in a round bottom flask is added 10 mL of trifluoroacetic acid. The mixture is stirred at -15 ⁰ C for 6 hours yielding Compound (4).

Example 5 Synthesis of Compound {5}

151

[00145] To 0.10 mmol of Compound £1), 0.15 mmol of di-t-butyl-dicarbonate and 0.20 mmol of sodium bicarbonate in a round bottom flask is added 10 mL of 1:1 solution of water/ 1,4 dioxane. The mixture is heated at 80 °C with stirring for 20 hours yielding Compound (5).

Example 6 Synthesis of Compound £6i

M

[00146] To of 0.11 rranol of Compound £2}, 0.15 mmol of di-t-butyl-dicarbonate and 0.20 mmol of sodium bicarbonate in a round bottom flask is added 10 mL of 1"1 solution of water/1,4 dioxane. The mixture is heated at 80 ⁰ C with stirring for 20 hours yielding Compound (6).

Example 7 Synthesis of Compound (7)

[00147] To 0.10 mmol of Compound £3}, 0.25 mmol of di-t-butyl-dicarbonate and 0.40 mmol of sodium bicarbonate in a round bottom flask is added 10 mL of 1 :1 solution of water/ 1,4 dioxane. The mixture is heated at 80 ^C C with stirring for 20 hours yielding Compound (7).

Example 8 Synthesis of Compound [8J

[00148] To of 0.11 mmol of Compound £4), 0.28 mmol of di-t-butyl-dicarbonate and 0.40 mmol of sodium

bicarbonate in a round bottom flask is added 10 mL of 1 1 solution of water/1,4 dioxane The mixture is heated at 80 ⁰ C with stirring for 20 hours yielding Compound ( 8)

Example 9 Synthesis of Compound £9}

[00149] To 0 10 mmol of Compound £5} in 10 mL 1,4 dioxane in a round bottom flask is added O i l mmol of methanesulfonyl chloride and 0 20 mmol of tπethylamine The mixture is stirred at 25 ⁰ C with stirring for 20 hours yielding Compound (9)

Example 10 Synthesis of Compound (10)

(10)

[00150] To 0 11 mmol of Compound £6} in 10 mL 1,4 dioxane in a round bottom flask is added 0 12 mmol of methanesulfonyl chloride and 0 20 mmol of triethylamme The mixture is stirred at 25 °C with stirring for 20 hours yielding Compound (10)

Example 11 Synthesis of Compound (11)

[00151 J To 0 10 mmol of Compound (21 in 10 mL 1,4 dioxane in a round bottom flask is added 0 11 mmol of methanesulfonyl chloride and 0 20 mmol of tπethylamine The mixture is stirred at 25 ⁰ C with stirring for 20 hours yielding Compound (11)

Example 12 Synthesis of Compound (12)

[00152] To 0 11 mmol of Compound £8} m 10 mL 1,4 dioxane in a round bottom flask is added 0 12 mmol of methanesulfonyl chloride and 0 20 mmol of tπethylamme The mixture is stirred at 25 ⁰ C with stirring for 20 hours yielding Compound (12)

Example 13 Synthesis of Compound (13)

(13)

[00153] To 0 10 mmol of Compound £9} in 10 mL dichloromethane in a round bottom flask is added 2 mL

of trifluoroacetic acid dropwise. The mixture is stirred at ambient temperature with stirring for 20 minutes yielding Compound (13).

Example 14 Synthesis of Compound (14)

[00154] To 0 11 mmol of Compound (10) in 10 mL dichloromethane in a round bottom flask is added 2 mL of trifluoroacetic acid dropwise. The mixture is stirred at ambient temperature with stirring for 20 minutes yielding Compound (14).

Example 15 Synthesis of Compound (15)

[00155] To 0.10 mmol of Compound (11) mesylate m 10 mL dichloromethane in a round bottom flask is added 2 mL of trifluoroacetic acid dropwise. The mixture is stirred at ambient temperature with stirring for 20 minutes yielding Compound (15).

Example 16 Synthesis of Compound (16)

[00156] To 0.11 mmol of Compound (12) in 10 mL dichloromethane in a round bottom flask is added 2 mL of trifluoroacetic acid dropwise. The mixture is stirred at ambient temperature with stirring for 20 minutes

yielding Compound (16)

Example 17 Synthesis of Compound (17)

LLZi

[00157] To 0 10 mmol of Compound (13) in 10 mL of DMF in a round bottom flask is added 0 20 mmol of sodium azide The mixture is heated at 85 ⁰ C with stirring for 20 hours yielding Compound (17)

Example 18 Synthesis of Compound (18)

(18)

[00158] To 0 11 mmol of Compound (14) in 10 mL of DMF in a round bottom flask is added 0 25 mmol of sodium azide. The mixture is heated at 85 ⁰ C with stirring for 20 hours yielding Compound (18)

Example 19 Synthesis of Compound (19)

[00159] To 0 10 mmol of Compound (15) in 10 mL of DMF in a round bottom flask is added 0 25 mmol of sodium azide The mixture is heated at 85 ⁰ C with stirring for 20 hours yielding Compound (19)

Example 20 Synthesis of Compound (20)

[00160] To 0 10 mmol of Compound (16) in 10 mL of DMF in a round bottom flask is added 0 25 mmol of sodium azide. The mixture is heated at 85 ⁰ C with stirring for 20 hours yielding Compound (20)

Example 21 Synthesis of Compound (21)

(21 )

[00161] To 0 12 mmol of Compound (17) in 10 mL of methanol in a round bottom flask is added 0 60 mmol of hydrazine It is followed immediately by addition of 20% Pd(OH) ₂ on carbon (~ 10 mg, Degussa type) The reaction mixture is heated at reflux with stirring for 20 hours yielding Compound (21)

Example 22 Synthesis of Compound (22)

[00162] To 0.11 mmol of Compound (18) in 10 mL of methanol in a round bottom flask is added 0.58 mmol of hydrazme. It is followed immediately by addition of 20% Pd(OH) ₂ on carbon (~ 10 mg, Degussa type) The reaction mixture is heated at reflux with stirring for 20 hours yielding Compound (22)

Example 23 Synthesis of Compound (23)

[00163] To 0 10 mmol of Compound (19) m 10 mL of methanol in a round bottom flask is added 0 60 mmol of hydrazine It is followed immediately by addition of 20% Pd(OH) ₂ on carbon (~ 10 mg, Degussa type). The reaction mixture is heated at reflux with stirring for 20 hours yielding Compound (23)

Example 24 Synthesis of Compound (24)

[00164] To 0 10 mmol of Compound (20) in 10 mL of methanol m a round bottom flask is added 0 60 mmol of hydrazine It is followed immediately by addition of 20% Pd(OH) ₂ on carbon (~ 10 mg, Degussa type) The reaction mixture is heated at reflux with stirring for 20 hours yielding Compound (24)

Example 25 Synthesis of Compound (25)

[00165] To 0 10 mmol of Compound (13) in 5 mL of dry tert-butyl alcohol in a round bottom flask is

added 0 2 mmol of nitromethane and 0 15 mmol of sodium t-butoxide. The mixture is heated to reflux with stirring for 20 hours yielding Compound (25).

Example 26 Synthesis of Compound (26)

(26)

[00166] To 0 11 mmol of Compound (14) in 5 mL of dry tert-butyl alcohol in a round bottom flask is added 0.2 mmol of nitromethane and 0 15 mmol of sodium t-butoxide The mixture is heated to reflux with stirring for 20 hours yielding Compound (26).

Example 27 Synthesis of Compound (27)

[00167] To 0 10 mmol of Compound (15) in 5 mL of dry tert-butyl alcohol in a round bottom flask is added 0.2 mmol of nitromethane and 0.15 mmol of sodium t-butoxide. The mixture is heated to reflux with stirring for 20 hours yielding Compound (27).

Example 28 Synthesis of Compound (28)

[00168] To 0 10 mmol of Compound (16 ^" ) in 5 mL of dry tert-butyl alcohol in a round bottom flask is added 0 2 mmol of nitromethane and 0 15 mmol of sodium t-butoxide The mixture is heated to reflux with stirring for 20 hours yielding Compound (28).

Example 29 Synthesis of Compound (29)

(29)

[00169] A mixture of 0 10 mmol of Compound (25) in 15 mL of ethanol and 50mg 10% palladium on activated carbon (Degussa type) m a round bottom flask is stirred at ambient temperature under hydrogen for 16 hours yielding Compound (29)

Example 30 Synthesis of Compound (30)

[00170] A mixture of 0.11 mmol of Compound (26) in 15 mL of ethanol and 50mg 10% palladium on activated carbon (Degussa type) in a round bottom flask is stirred at ambient temperature under hydrogen for 16 hours yielding Compound (30)

Example 31 Synthesis of Compound (31)

[00171] A mixture of 0 10 mmol of Compound (27) in 15 mL of ethanol and 50mg 10% palladium on activated carbon (Degussa type) in a round bottom flask is stirred at ambient temperature under hydrogen for 16 hours yielding Compound (31)

Example 32 Synthesis of Compound (32)

^K 3

[00172] A mixture of 0 10 mmol of Compound (28) m 15 mL of ethanol and 50mg 10% palladium on activated carbon (Degussa type) in a round bottom flask is stirred at ambient temperature under hydrogen for 16 hours yielding Compound (32)

Example 33 Synthesis of Compound (33)

(33)

[00173] To a solution of 0 12 mmol of Compound (21) in 5 mL DMSO in a round bottom flask is added

0 60 mmol of 2-amino-adamantan, I mmol of triethylamine HBPyU (0 2 mmol) is then added at room temperature in three portion with stirring over 1 hour. After an additional of 4 hours, acetone (10OmL) is added to give a solid

which is further washed with acetone yielding Compound (33).

Example 34 Synthesis of Compound (34)

(34)

[00174] To a solution of 0.11 mmol of Compound (22). in 5 mL DMSO in a round bottom flask is added

0.60 mmol of 2-amino-adamantan, 1 mmol of triethylamine. PyBOP (0.2 mmol) is then added at room temperature in three portion with stirring over 1 hour. After an additional of 4 hours, acetone ( 10OmL) is added to give a solid which is further washed with acetone yielding Compound (34).

Example 35 Synthesis of Compound (35)

[00175] To a solution of 0.10 mmol of Compound (23) m 5 mL DMSO in a round bottom flask is added

0.60 mmol of 1-amino-adamantan, 1 mmol of triethylamine. PyBOP (0.2 mmol) is then added at room temperature in three portion with stirring over 1 hour. After an additional of 4 hours, acetone (10OmL) is added to give a solid which is further washed with acetone yielding Compound (35).

Example 36 Synthesis of Compound (36)

[00176] To 0 10 of Compound (24) in 5 mL DMSO in a round bottom flask is added 0 60 mmol of 2- ammo-adamantan, 1 mmol of tπethylamine HBPyU (0 2 mmol) is then added at room temperature in three portion with stirring over 1 hour After an additional of 4 hours, acetone (10OmL) is added to give a solid which is further washed with acetone yielding Compound (36)

Example 37

Alternate Preparation of Glycopeptide amines (21., 22, 23 and 24)

[00177J Using a procedure similar to Example 29. the glycopeptide azides (17-20) are treated with either

10% palladium on active carbon (Degussa type) or 20% Pd(OH) ₂ on activated carbon (Degussa type) under hydrogen giving the corresponding glycopeptide amines 21., 22, 23 and 24

Example 38 Synthesis of Compound (37)

(37)

[00178) To 0 10 mmol of Compound (13) in 5mL of DMSO in a round bottom flask is added 0 15 mmol of sodium cyanide The mixture is heated at 90 ⁰ C for 20 hours yielding Compound (37)

Example 39 Synthesis of Compound (38)

(38)

[00179] To 0 10 mmol of Compound (14) in 5mL of DMSO in a round bottom flask is added 0 15 mmol of sodium cyanide The mixture is heated at 90 ⁰ C for 20 hours yielding Compound (38)

Example 40 Synthesis of Compound (39)

[00180] To 0.10 mmol of Compound (15) m 5mL of DMSO in a round bottom flask is added 0 15 mmol of sodium cyanide. The mixture is heated at 90 °C for 20 hours yielding Compound e (39).

Example 41 Synthesis of Compound (40)

[00181] To 0 10 mmol of Compound (16) in 5mL of DMSO in a round bottom flask is added 0 15 mmol of sodium cyanide The mixture is heated at 90 ⁰ C for 20 hours yielding Compound (40)

Example 42

Alternate Preparation of Aminoglycopeptides (29 - 32)

[00182] Using a procedure similar to example 29, glycopeptide nitπles (37 - 40) can be catalytic reduced to their corresponding aminoglycopeptides (29 - 32) in the presence of catalytic amount of Raney nickel active catalyst under hydrogen atmosphere

Example 43 Synthesis of Compound (41)

(41)

[00183] To a solution of 0 12 mmol of Compound (29) in 5 mL DMSO in a round bottom flask is added

0 60 mmol of 2-ammo-adamantan, 1 mmol of tπethylamine HBPyU (0 2 mmol) is then added at room temperature in three portion with stirring over 1 hour After an additional of 4 hours, acetone (10OmL) is added to give a solid which is further washed with acetone yielding Compound (41)

Example 44 Synthesis of Compound (42)

(42)

[00184] To a solution of 0 11 mmol of Compound (30) in 5 mL DMSO in a round bottom flask is added

0 60 mmol of 2-amino-adamantan, 1 mmol of tπethylamine PyBOP (0 2 mmol) is then added at room temperature m three portion with stirring over 1 hour After an additional of 4 hours, acetone (10OmL) is added to give a solid which is further washed with acetone yielding Compound (42)

Example 45 Synthesis of Compound (43)

[00185] To a solution of 0 10 mmol of Compound (31) in 5 mL DMSO in a round bottom flask is added

0 60 mmol of 1-amino-adamantan, 1 mmol of triethylarmne PyBOP (0 2 mmol) is then added at room temperature in three portion with stirring over 1 hour After an additional of 4 hours, acetone (10OmL) is added to give a solid which is further washed with acetone yielding Compound (43).

Example 46 Synthesis of Compound (44)

[00186] To 0 10 of Compound (32) m 5 mL DMSO in a round bottom flask is added 0 60 mmol of 2- amino-adamantan, 1 mmol of tπethylamine HBPyU (0 2 mmol) is then added at room temperature in three portion with stirring over 1 hour After an additional of 4 hours, acetone (10OmL) is added to give a solid which is further washed with acetone yielding Compound (44)

Example 47 Synthesis of Compound (45)

(45)

[00187] To a stirred solution of 0 12 mmol of Compound (21) in a 5 mL DMSO H ₂ O (4 1) mixture, 0 13 mmol of triethylamme and 0 2 mmol of CH ₃ CH(CH ₃ )C ₈ H ₁₆ COOSU are added The reaction mixture is stirred at ambient temperature for 5 hours. 40 mL of acetone is then added into the mixture A solid precipitate is filtered and washed with acetone and dried under vacuum The resulting dry precipitate is then dissolved in a H ₂ O-THF (1 1) mixture and evaporated with a small amount of silamzed silica gel under vacuum This solution was applied to a chromatographic column on silanized silica gel to yield Compound (45)

Example 48 Synthesis of Compound (46)

NNHHCCHH ₃

(46)

[00188] To a stirred solution of 0 12 mmol of Compound (21) in a 5 mL DMSO H ₂ O (4 1) mixture, 0.15 mmol of triethylamme and 0 2 mmol of p-octylOPhCH ₂ N(Fmoc)CH ₂ COOSu are added The reaction mixture is stirred at ambient temperature for 5 hours 0 45 mL of diethylamme is then added The reaction mixture is then stirred for an additional one hour 30 mL of acetone is then added into the mixture A solid precipitate is filtered and washed with acetone and dried under vacuum The resulting dry precipitate is then dissolved in a H ₂ O THF (1 1) mixture and evaporated with a small amount of silamzed silica gel under vacuum This solution was applied to a chromatographic column on silamzed silica gel to yield Compound (46)

Example 49 Synthesis of Compound (47)

[00189] To a stirred solution of 0 12 mmol of Compound QD in a 5 mL DMSO H ₂ O (4 1) mixture, 0 15 mmol of tnethylamme and 0 2 mmol of p-octylOPhCH ₂ N(Fmoc)CH(CH ₃ )COOSu are added The reaction mixture is stirred at ambient temperature for 5 hours 0 45 mL of diethylamine is then added The reaction mixture is then stirred for an additional one hour 30 mL of acetone is then added into the mixture. A solid precipitate is filtered and washed with acetone and dried under vacuum The resulting dry precipitate is then dissolved in a H ₂ O THF (1 1) mixture and evaporated with a small amount of silamzed silica gel under vacuum This solution was applied to a chromatographic column on silamzed silica gel to yield Compound (47)

Example 50

Synthesis of N'-aminoacyl desvancosaminyl glycopeptides derivatives (48)

[00190] N-acylated derivatives substituted with amino acid or N alkylated ammo acid of desvancosaminyl glycopeptides 21_, 22, 29 and 30_represented by the general formula (48) wherein R _A is hydrogen or methyl, n is 0 or 1 and R and Ri are previously defined, can be prepared by the treatment of the desvancosaminyl glycopeptides 21, 22, 29 and 30_with N-hydroxy succinimide ester of N-Fmoc- derivatives of the amino acid or N-alkylated amino acid followed by deprotection with 10% diethylamine in DMSO to give the desired product (48) The following is a general preparation procedure

[00191] To a stirred solution of 0 5 mmol of desvancosaminyl glycopeptides 21, 22, 29 or 30 m 15 mL

DMSO H ₂ O (4 1) mixture 0 5 mmol of tπethylamine and 0 75 mmol of starting N-Fmoc-amrno acid-succrnimide ester derivative are added The reaction mixture was stirred at room temperature for 5 h, then 1 5 mL of Et ₂ NH weas added The reaction mixture is stirred at ambient temperature for 1 hour The reaction mixture is then added to 100 mL of acetone A solid precipitated is filtered off, washed with acetone and dried under vacuum It is then dissolved

in a H ₂ OiTHF (1.1) mixture, evaporated with a small amount of silanized silica gel under vacuum and applied to a chromatographic column with silanized silica to purify the desired product (48).

Example 51 Synthesis of N'-aminoacyl desvancosaminyl glycopeptides adamantylamino amide derivatives (49)

[00192] Using a similar procedure as example 50 and using desvancosaminyl glycopeptide adamantylamino amide 35, 36, 43 and 44 instead of desvancosaminyl glycopeptides 21_, 22, 29 and 30 adamantylamino amides derivatives (49), wherein R _A is hydrogen or methyl, n is 0 or 1 and R, R ₁ and X are previously defined, are prepared.

Example 52

Synthesis of Amino acid-4-monosaccharide glycopeptide carboxamides (50)

[00193] The amino acid-4-monosaccharide glycopeptide carboxamides (50) wherein R _A is hydrogen or methyl, n is 0 or 1 , Y is hydrogen or epi-vancosammyl and R, Ri, X and R ₃ are previously defined, can be prepared by the following procedure. To a mixture of 0.1 mmol of (21), (22), (23), (24), (29), (30), (31) or (32) and 1 mmol of an amine hydrochloride (R ₃ NH ₂ .HC1) in 5 mL of DMSO is added portion-wise triethylamine to adjust to a pH 8.5 to 9. 0.2 mmol of PyBOP or HBPyU reagent is then added over a period of 1 hour. The reaction mixture is stirred at ambient for 3 hours to give the titled compound the amino acid-4-monosaccharide glycopeptide carboxamides (50).

Example 53 Synthesis of Compound (51)

[00194] To a solution of 0 2 mmol Compound QD in 15 mL of DMSO-DMF-MeOH 1 1 1 (v/v/v) is added 0 4 mmol of p-(p-chlorophenyl)-benzaldehyde The reaction mixture is stirred at ambient temperature for 2 hours To the resulting solution, NaBH ₃ CN (0 6 mmol) is added portion-wise for 4 hours The reaction mixture is further stirred for 2 hours 100 mL acetone is then added The precipitate solid is filtered and washed with acetone and dried yielding Compound (51)

Example 54 Antibacterial evaluation

[00195] Antibacterial activity in vitro is investigated by broth microdilution method in Meuller-Hinton broth as recommended by NCCLS All strains tested are clinical isolates either sensitive or resistant to natural glycopeptides MIC values were determined using the CLSI-recommended broth microdilution procedure (Clinical and Laboratory Standard Institute, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically Approved Standard-Seveth Edition) Automated liquid handlers (Mutidrop 384, Labsystems, Helsinki, Finland, Biomek 2000 and Multimek 96, Beckman Couter, Fullerton CA) were used to conduct serial dilutions and liquid transfers The in vitro antiacteπal activity data (MIC) in μg/ml for representative examples is given in Table 1 having antibacterial activity superior to vancomycin against resistant strains

SA 100 = Staphylococcus aureus 100 (MSSA), SA 757 = Staphylococcus aureus 757 (MRSA); SA2012 = Staphylococcus aureus 2012 (VISA); SE 835 = Staphylococcus epidermidis 835 (MSSE); SE 831 = Staphylococcus epidermidis 831 (MRSE), EFC 101 = Enterococcus faecalis 101 (vancomycin sensitive); EFC 848 = Enterococcus faecahs 848 (VRE), EFCM 750 = Enterococcus faecium 750 (vancomycin sensitive), EFCM 752 = Enterococcus faecium 752 (VRE), SPNE 1195 = Streptococcus pneumoniae 1195 (penicillin sensitive), SPYO 712 = Streptococcus pyogenes 712 (penicillin sensitive)

Example 55 Synthesis of Compound (1 ^" )

[00196] Vancomycin (30 g) was added slowly to a mixture solution (300 ml, TFA H ₂ O = 9 1) at 1O ⁰ C. Then the reaction mixture was stirred at 10 ⁰ C for 2hrs (with reaction progress checked by HPLC) The reaction mixture was quenched to 1500 ml cold diethyl ether, the precipitate was filtered and washed by ether several times, dried under vacuum The crude product was purified by reverse phase column (MeCN H ₂ O=10%~20%) to afford Compound £1} as a white solid (yield = 45%) Example 56

Synthesis of Compound £2)

[00197] Using a procedure similar to the preparation of Compound (JJ as in example 55, and replacing vancomycin with desmethylvancomycm, Compound £2} is made

Example 57 Synthesis of Compound £3}

[00198] Using a procedure similar to the preparation of Compound £1} as in example 55, and replacing vancomycin with LY264826, Compound £3} is made

Example 58 Synthesis of Compound £4}

[00199] Using a procedure similar to the preparation of Compound £lj as in example 55, and replacing vancomycin with eremomycin, Compound (4} is made.

Example 59 Synthesis of Compound (5)

[00200] Compound £11(5. Og, 3.72 mmol) was dissolved in THF/ H ₂ O (35 ml/ 35 ml). TEA (0.77 ml, 5 58 mmol) was then added. The reaction mixture was cooled down to 15 ⁰ C. and then (BoC) ₂ O (0.89 g, 4 08 mmol) was added slowly. After the addition, the reaction mixture was allowed to be stirred at 15 °C for 7 hrs. It was concentrated and the crude was purified by reverse phase column (MeCNrH ₂ O=I :5-3: 10). 3g of Compound £5} was obtained as a white solid (yield = 60%).

Example 60 Synthesis of Compound (6)

[00201] Using a procedure similar to the preparation of Compound £5) as in example 59, and replacing Compound (1) with Compound £2), Compound (6) is made.

Example 61 Synthesis of Compound (7)

[00202] Using a procedure smulaτ to the preparation of Compound £5) as in example 59, and replacing Compound (1) with Compound £3), Compound (7) is made

Example 62 Synthesis of Compound (8)

[00203] Using a procedure similar to the preparation of Compound £5} as in example 59, and replacing Compound fl) with Compound £4), Compound (8) is made.

Example 63 Synthesis of Compound (52)

[00204] Compound {5} from example 59, (Ig, 0.712 mmol) and 2-adamantylamine hydrochloride (0.4g, 2 1 mniol) were dissolved in anhydrous DMSO (12ml). Dusopropylethylamine (DIEA) was added the solution to adjust the pH of reaction mixture to 8. HATU (0.3g, 0.789 mmol) was then added in the presence of DIEA. Stirring was continued for about 1 hr, checking the progress of the reaction to completion by TLC. The resulting mixture was then added to 120 ml of water and filtered The cake was washed for two times with water and dried in vacuum. Purification by running a normal phase silica column (MeOH: CH ₂ Cl ₂ = 1:7-1 3) gave the Compound (52) as white solid (850 mg, yield = 77%)

Example 64 Synthesis of Compound (53)

[00205] Using a procedure similar to the preparation of Compound (52) as in example 63, and replacing Compound (5) with Compound (6), Compound (53} is made

Example 65 Synthesis of Compound (54)

[00206] To a suspension of Compound (52) (380 mg) in CH ₂ Cl ₂ (4ml) at 0 ⁰ C , was added TFA (0 5 ml) dropwise The reaction mixture was stirred at 0 ⁰ C for 1 hour and then at room temperature for another hour The reaction was follow by HPLC until the analysis showed no starting material present Ether (30 ml) was added and the forming solid was collected and washed with ether twice The collected white solid was dried and purified by preparative HPLC to yield Compound (5Jl as TFA salt LC-MS(ESI) 1438 5 (M ⁺ +l)

Example 66 Synthesis of Compound (55)

[00207] Using a procedure similar to the preparation of Compound (54) as m example 65, and replacing Compound (52) with Compound (53), Compound (55) as TFA salt is made

Example 67 Synthesis of Compound (56)

[00208] Compound (52) (1 g, 0 649 mmol) was azeotroped with toluene 3 times and then dissolved in anhydrous pyridine Mesitylenesulfonyl chloride (426 mg, 1 95 mmol) m 1 ml of anhydrous pyridine was added m to the solution dropwise at O ⁰ C, and the mixture was kept stirring for 2 hour The reaction mixture was poured into water and filtered The solid was purified by flashing normal phase column (MeOH/DCM=l/10~l/5) to give Compound (561as a white solid (500 mg, yield =5 0%) LC-MS (ESI) 1620(M ⁺ +1-Boc),

Example 68 Synthesis of Compound (57)

[00209] Using a procedure similar to the preparation of Compound (561 as in example 67, and replacing Compound (52) with Compound (53 ^" ). Compound (57) is prepared.

Example 69 Synthesis of Compound (58)

[00210] A solution of Compound (56) (Ig, 0 581 mmol) and sodium azide (377mg, 5.81 mmol, 10eq.) in anhydrous DMF was heated to 70 ⁰ C overnight. The reaction mixture was cooled and added to water. The solid was filtered, washed with water, and purified by flashing normal phase column (MeOH/DCM =1/12—1/9) to give Compound (58) as a pale yellow solid (500 mg, yield = 50%). LC-MS (ESI): 1463(M ⁺ +1-Boc).

Example 70 Synthesis of Compound (59)

[00211] Using a procedure similar to the preparation of Compound (58) as in example 69, and replacing Compound (56) with Compound (57), Compound (59) is prepared.

Example 71 Synthesis of Compound (60)

[00212] To a solution of Compound (58) (1 g, 0 639 mmol) in 5 ml THF containing a few drops of water was added n-Bu ₃ P (905 mg, 4.47 mmol). The mixture was heated to reflux overnight, then cooled to room temperature, and poured into water. The solid was filtered, washed with water, and purified by flashing reverse phase column (MeCN/ H ₂ O=l/9~l/3) to afford Compound (60) as a pale yellow solid (100 mg, yield = 10%). LC-MS (ESI): 1537(M ⁺ +1)

Example 72 Synthesis of Compound (61)

[00213] Using a procedure similar to the preparation of Compound (60) as in example 71, and replacing Compound (58) with Compound (59), Compound (61} is prepared

Example 73 Synthesis of Compound (62)

(621

[00214] A solution of Compound (60) (25 mg, 0 0162 mmol) m 2 mL of trifluoroacetic acid (TFA)/dichloromethane (1/1) was stirred for about 1 hour at 0 ⁰ C, until the HPLC-MS analysis showed no starting material left. The solvent was evaporated under reduced pressure at 0 ⁰ C The residue was added some ether and filtered to give Compound (62) as a white solid (20 mg, yield = 74%). LC-MS (ESI). 1438 (M ⁺ + 1).

Example 74 Synthesis of Compound (63)

(63)

[00215] Using a procedure similar to the preparation of Compound (62) as in example 73, and replacing Compound (60) with Compound (61), Compound (63) is made.

Example 75 Synthesis of Compound (64)

[00216] To a stirred solution of N-hydroxysuccmimide (84 mg, 0 73 mmol) and triethylamine (92 5μL, 0.66 mmol) m 1 3 mL acetomtπle/0 5 dichloromethane under argon atmosphere at 4 ⁰ C was added nonanoyl chloride (117 mg,

0.66 mmol) in 0 3 ml acetonitrile After 2 hours of stirring, the reaction was stopped and the triethylammomum chloride was allowed to settle and filtered to give a 0 3M solution of the N-hydroxysuccmimide active ester (2,5- dioxopyrrohdin-1-yl nonanoate). This 2,5-dioxopyrrolidm-l-yl nonanoate solution (0 5 mL, 0 15 mmol) was added to a solution of Compound (60) (80 mg, 0 052 mmol) in 1 mL of anhydrous DMF The mixture was stirred at room temperature overnight The mixture was precipitated by addition of 10 mL diethyl ether. It was filtered. The solid was purified by preparative TLC to afford 25 mg (29% yield) t-Boc protected Compound (64) LC-MS (ESI).

1577.6 (M ⁺ + 1- Boc) A solution of this compound in 2 mL of rrifluoroacetic acid (TFA)/dichloromethane (1/1) was stirred for about 1 hour at 0 ⁰ C, until the HPLC-MS analysis showed no starting material left The solvent was evaporated under reduced pressure at 0 ⁰ C . The residue was added some ether and filtered to give Compound (64) as a white solid as TFA salt (15 mg, 60% yield), LC-MS (ESI): 1577 6 (M ⁺ + 1)

Example 76 Synthesis of Compound (65)

[00217] Using a procedure similar to the preparation of Compound (64) as in example 75, and replacing nonanoyl chloride with undecanoyl chloride, t-Boc protected Compound (65) was made as a white solid (45 mg, 51% yield). LC-MS (ESI): 1605.6 (M ⁺ + 1- Boc). The compound was further converted to Compound (65} with the same procedure described in example 75 giving a Compound (65) as TFA salt (39 mg, yield = 86%). LC-MS (ESI): 1605.6 (M ⁺ + 1).

Example 77 Synthesis of Compound (66)

<ββ>

[00218] Using a procedure similar to the preparation of Compound (64) as in example 75, and replacing nonanoyl chloride with 8-methylnonanoyl chloride, t-Boc protected Compound (66} was made as a white solid (45 mg, 51% yield). LC-MS (ESI): 1591.6 (M ⁺ + 1- Boc). The compound was further converted to Compound (66} with the same procedure described in example 75 giving a Compound (66) as TFA salt (38 mg, 84% yield). LC-MS (ESI): 1591 6(M ⁺ + 1).

Example 78 Synthesis of Compound (67)

[00219] Using a procedure similar to the preparation of Compound (64) as in example 75, and replacing 2,5- dioxopyrrolidin-l-yl nonanoate with 2,5-dioxopyrrohdin-l-yl 4'-chlorobiphenyl-4-carboxylate, t-Boc protected Compound (67) was made as a white solid (27 mg, 26% yield) LC-MS (ESI): 1651.5 (M ⁺ + 1- Boc) The compound was further converted to Compound (67) with the same procedure described in example 75 giving a Compound (67) as TFA salt (20 mg, 73% yield). LC-MS (ESI): 1651.5 (M ⁺ + 1)

Example 79 Synthesis of Compound (68)

[00220] Using a procedure similar to the preparation of Compound (64) as in example 75, and replacing 2,5- dioxopyrrolidin-1-yl nonanoate with 2,5 dioxopyrrolidm-1-yl 2-(tert-butoxycarbonyl(4-

(octyloxy)benzyl)amino)acetate, t-Boc protected Compound (68) was made as a white solid (50 mg, 65% yield). LC- MS (ESI) 1912 7 (M ⁺ + 1). The compound was further converted to Compound (68) with the same procedure described in example 75 giving a Compound (68} as TFA salt(15 mg, 34% yield). LC-MS (ESI): 1712.7 (M ⁺ + 1).

Example 80 Synthesis of Compound (69)

(69)

[00221] To a solution of Compound (60) (700 mg, 0.455 mmol) in 3 mL of methanol was added acetic anhydride (0.2 mL, 2 27 mmol) and NaHCO ₃ (199 mg, 2 27 mmol). The reaction mixture was stirred for 2 hours and the reaction was monitored by HPLC-MS for completion. The solvent was the evaporated under reduced pressure. 100 mg of thecrude material was purified by flashing a reverse phase column to give the t-Boc protected Compound (69) as a white solid (15 mg). The compound was further converted to Compound (69) with the same procedure described in example 75 giving a Compound (69} as TFA salt (6 mg, 43% yield). LC-MS (ESI): 1479.5 (M ⁺ + 1).

Example 81 Synthesis of 2,5-dioxopyrrolidin-l-yl 4'-chlorobiphenyl-4-carboxyIate (70)

(70)

[00222] Pd(PPh ₃ ) ₄ (1.68 g, 1.45 mmol) was added to a solution of 4-bromobenzoic zcid (5 83 g, 29.0 mmol) and 4- chlorophenylboiomc acid (4.53 g, 29 0 mmol) in 50 mL of 1 ,4-dioxane and 29 mL of 2M NaCO ₃ (58.0 mmol) under argon atmosphere. Then the mixture was refluxed for 6 hours. The reaction was monitored by LC-MS to check for completion. The hot reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The aqueous phase was acidified with citric acid and stirred for 1 hour with ice-bath, and then filtered. The cake was washed with water and dried in vacumm. The crude was recrystallized in 2-methoxyethanol to give 4-chlorophenyl-4-carboxyhc acid as white solid (0 51 g pure, 4.5 g crude). A mixture of 4-chlorophenyl-4-carboxyhc acid (150 mg, 0.645 mmol),

N-hydroxysuccmimide (82 mg, 0.709 mmol), triethylamine (85 mg, 0.838 mmol) and l-(3-dimethylammopropyl)-3- ethylcarbodimide hydrochloride (EDCI) (136 mg, 0 709 mmol) in 10 mL of DCM was stirred at room temperature overnight Checked for completion by TLC The reaction was quenched by adding water and separated. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water for three times, dried over Na ₂ SO ₄ and evaporated to give 2,5-dioxopyrrolidin-l-yl 4'-chlorobiphenyl-4-carboxylate (70) as white solid (210 mg)

Example 82 Synthesis of 2,5 dioxopyrrolidin-1-yl 2-(tert-butoxycarbonyl(4-(octyloxy)benzyl)amino)acetate (71)

mi [00223] To a mixture of glycine methyl ester hydrochloride (3.21 g, 26 0 mmol) and 4-hydroxybenzaldehyde (2 44 g, 20.0 mmol) in 100 mL of methanol was added NaCNBH ₃ (2.76 g, 44 0 mmol) portion-wise. The reaction mixture stirred at room temperature overnight, and then evaporated under reduced pressure The residue was dissolved in water and extracted with ethyl acetate. The combined organic layer was dried over Na ₂ SO ₄ and evaporated under reduced pressure The crude material was purified by flashing chromatography to afford methyl 2-(4- hydroxybenzylamme)acetate (1.2 g). To a solution of methyl 2-(4-hydroxybenzylamine)acetate (940 mg, 4 8 mmol) in 10 mL of methanol was added di-yert-bytyl dicarbonate followed by addition of triethylamine (730 mg, 7.2 mmol). The mixture stirred at room temperature overnight and evaporated The residue was dissolved m water and extracted with ethyl acetate. The combined organic layer was dried over Na ₂ SO ₄ and evaporated. The crude was purified by flashing chromatography to afford methyl 2-tert-butoxycarbonyl(4-hydroxybenzyl)ammo)acetate (620 mg). To a solution of methyl 2-tert-butoxycarbonyl(4-hydroxybenzyl)amino)acetate (620 mg, 2.1 mmol) in 10 mL of DMF was added Cs ₂ CO ₃ (684 mg, 2.1 mmol) followed by addition of 1-iodooctane (505 mg, 2.1 mmol) The mixture stirred at room temperature overnight The resulting mixture was partitioned between water and ethyl

acetate. The combined organic layer was dried Na ₂ SO ₄ and evaporated. The crude material was purified by flashing chromatography to afford methyl 2-tert-butoxycarbonyl(4-(octyloxy)henzyl)amino)acetate ( 644 mg). To a solution of this acetate (644 mg, 1.58 mmol) in 8 mL of ethanol was added 1 8 mL of IM LiOH. The mixture stirred at room temperature overnight. The solvent was evaporated. The residue was dissolved in water and extracted with ether. The aqueous layer was acidified to pH 1—2, and extracted with ether. The combined orgamc layer was dried over Na ₂ SO ₄ and evaporated to give 2-tert-butoxycarbonyl(4-(octyloxy)benzyl)amino)acetic acid (594 mg). A mixture of 2-tert- butoxycarbonyl(4-(octyloxy)benzyl)amino)acetic acid ( (594 mg, 1.51 mmol), N-hydroxysuccimmide (191 mg, 1.66 mmol), EDCI (318 mg, 0.1.66 mmol) and tnethylamine (200 mg, 1.96 mmol) in 10 mL of dichloromethnae was stirred at room temperature overnight. The reaction was checked for completion by TLC. The reaction was quenched by adding water and separated. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water for three times, dried over Na ₂ SO ₄ and evaporated under reduced pressure. The crude material was purified by flashing chromatography to give 2,5 dioxopyrrolidin-1-yl 2-(tert-butoxycarbonyl(4- (octyloxy)benzyl)amino)acetate (71) (680 mg).

Example 83

Synthesis of 4'-chlorobiphenyl-4-carbaldehyde (72)

(72)

[00224] Pd(PPh ₃ ) ₄ (1.16 g, 1.0 mmol) was added to a solution of 4-bromobenzaldehyde (1 85 g, 10.0 mmol) and A- chlorophenylboionic acid (1 56 g, 10 0 mmol) in 20 mL of 1,4-dioxane and 10 mL of 2M NaCO ₃ (20.0 mmol) under argon atmosphere Then the mixture was refluxed overnight The reaction was checked for completion by LC-MS The solvent was evaporated. The residue was extracted with ethyl acetate. The combined orgamc layer was dried over Na ₂ SO ₄ and evaporated. The crude material was purified by flashing chromatography to give 4'- chlorobiphenyl-4-carbaldehyde £72} (0 735 g).

Example 84 Synthesis of Compound (731

[00225] Compound (60) (50 mg, 0.032 mmol) and 4-n-octyloxybenzaldehyde (9 mg, 0.0390 mmol) were dissolved m 2 mL of anhydrous (N,N-dimethylformamide (DMF), and the mixture was stirred at room temperature for several hours under argon atmosphere. After addition of NaCNBH ₃ (4 mg, 0.064 mmol), the mixture was kept stirring for 2 hours. The solvent was removed under reduced pressure The residue was precipitated by adding 20 mL of ether, and the solid was filtered, purified by preparative TLC to afford t-Boc protected Compound (73) as a white solid (5 mg, 9% yield). LC-MS (ESI)- 1755 6 (M ⁺ +l). The compound was further converted to Compound (73) with the same procedure described in example 75 giving a Compound (73} as TFA salt (2.9 mg, 54% yield). LC-MS (ESI): 1655.6

(M ⁺ +l)

Example 85 Synthesis of Compound (74)

[00226] Using a procedure similar to the preparation of Compound (73) as in example 84, and replacing 4-n- octyloxybenzaldehyde with 4-butylbenzaldehyde, t-Boc protected Compound (74} was made as a white solid (10 mg, 11 4% yield) LC-MS (ESI) 1683 6 (M ⁺ + 1) The compound was further converted to Compound (74} with the same procedure described in example 75 giving a Compound (74) as TFA salt (I I mg, 99% yield) LC-MS (ESI) 1583 6 (M ⁺ + 1)

Example 86 Synthesis of Compound (75)

[00227] Using a procedure similar to the preparation of Compound (73) as m example 84, and replacing 4-n- octyloxybenzaldehyde with 4'-chlorobiρhenyl-4-carbaldehyde, t-Boc protected Compound (75} was made as a white solid (7 mg, 8 6% yield) LC-MS (ESI) 1737 5 (M ⁺ + 1) The compound was further converted to Compound (75) with the same procedure described in example 75 giving a Compound (75) as TFA salt (8 2 mg, 99% yield) LC-MS (ESI) 1637 5 (M ⁺ + 1)

Example 87 Synthesis of 2,5-dioxopyrrolidin-l-yl 2-(4-octyl-l.fl ^r -l,2,3-triazol-l-yl)acetate (76)

[00228] A solution of ethyl 2-bromoacetate ( 14 2 g, 85 mmol and sodium azide (5 86 g, 90 1 mmol) in 20 niL of DMF was stirred at room temperature for 2 5 hours After a white solid formed, 20 mL of water was added and the resulting solution was extracted three times with ether The orgamc layer was washed six times with water and dried over Na ₂ SO ₄ The solvent was removed under reduced pressure to give ethyl 2-azidoacetate (9 1 g, 83%) To a stirred mixture of 2-azidoacetate (300 mg, 2 3 mmol) and CuI (2 2 g, 11 6 mmol) in 10 mL of THF was added 1-

decyne (643 mg, 4 6 mmol) The mixture was heated to reflux overnight, and then cooled down to room temperature and filtered. The filtrate was evaporated Water was added to the residue which was extracted with ethyl acetate three times The combined organic layer was dried over Na ₂ SO ₄ and evaporated The crude was purified by flashing chromatography to give ethyl 2-(4-octyl-l i/-l,2,3-triazol-l-yl)acetate as colorless oil (593 mg) To a solution of ethyl 2-(4-octyl-l #-l,2,3-tnazol-l-yl)acetate (300 mg, 1 12 mmol) m 5 mL of ethanol was added 1 5 mL of IM LiOH The mixture stirred at room temperature overnight The solvent was evaporated The residue was dissolved in water and extracted with ether The aqueous layer was acidified to pH 1—2, and extracted with ether The latter combined organic layer was dried over Na ₂ SO ₄ . and evaporated to give 2-(4-octyl-l i/-l,2,3-tπazol-l-yi)acetic acid (200 mg, 80%) A mixture of 2-(4-octyl-l //-l,2,3-tπazol-l-yl)acetic acid (78 mg, 0 326 mmol), N- hydroxysuccmimide (82 mg, 0 709 mmol) and 1,3-dicyclohexylcarbodiimide (DCC) (74 mg, 0358 mmol) in 5 mL of dichloromethane was stirred at room temperature overnight The resulting mixture was filtered and evaporated to yield 2,5-dioxopyrrolidin-l-yl 2-(4-octyl-l//-l,2,3-triazol-l-yl)acetate (76) (lOOmg)

Example 88 Synthesis of Compound (771

[00229] Using a procedure similar to the preparation of Compound (64) as in example 75, and replacing 2,5- dioxopyrrolidin- 1 -yl nonanoate with 2,5-dioxopyrrolidin-l-yl 2-(4-octyl-l//-l,2,3-tπazol-l yl)acetate (76), t-Boc protected Compound (22} was made as a white solid (21 mg, 23% yield) LC-MS (ESI) 1758 6(M ⁺ + 1) The compound was further converted to Compound (77) with the same procedure descπbed in example 75 giving a Compound (771 as TFA salt (14 mg, 67% yield) LC-MS (ESI) LC-MS (ESI) 1658 6 (M ⁺ + 1)

Example 89 Synthesis of Compound (78)

[00230] A solution of Compound (59) (70 mg, 0 045 mmol) and 1 -decyne (928 mg, 6 71 mmol) in 10 mL of THF was added CuI (43 mg, 0 226 mmol) The reaction mixture was heated to reflux overnight, and then cooled down to room temperature, filtered and concentrated The residue was purified by preparative TLC (MeOH/DCM = 1/5) to afford the t-Boc protected compound (78) as a white sohde (40 mg, 52% yield) LC-MS (ESI) 1701 6 (M ⁺ + 1) The compound was further converted to Compound (78) with the same procedure described in example 75 giving a

Compound (78). as TFA salt (28 mg, 69% yield) LC-MS (ESI) 1601 6 (M ⁺ + 1)

Example 90

Mouse Model for Bacterial Biofilm Infection

[00231] The procedure described in Antimicrobial Agents and Chemotherapy, October 2003, p 3130- 3137, VoI 47, No 10 is used Briefly, seven days after implantation of a 1-cm segment of a precolonized catheter carrying 10 ⁴ CFU of S aureus (made bio luminescent by inserting a modified lux operon into the bacterial chromosome), groups of mice are treated with a compound of Formula I, II, III or IV Three doses of each antibiotic (30, 20, and 10 mg/kg of body weight) are tested by administering the compound in 0.1 ml of saline The antibiotics are given every 12 h for 4 consecutive days An infected control group is treated with saline A sterile catheter is implanted in another group of animal to serve as a negative control group The mice are maintained in an anesthetized state with 1 5% isoflurane gas and are imaged for at vaπous time points after inoculation by using an IVIS Imaging System Total photon emissions from defined regions of interest within the images of each mouse are quantified by using the Living Image software package (Xenogen Corp ) The photon signals from the catheter are quantified from the dorsal image of each mouse During the treatment and after the final imaging time point, mice are euthanized, and the infected catheter is surgically removed for enumeration of bacteria by both biolummescence imaging and the conventional viable count method The bioluminescence of the bacteria recovered at the end of the experimental period is compared with that of the inoculating strain

Example 91 Pharmaceutical Compositions Example 91a Parenteral Composition

[00232] To prepare a parenteral pharmaceutical composition suitable for administration by injection, 50 mg of a water-soluble salt of a compound of any of Formula I, II, III or IV, is dissolved m PEG 400 and then mixed with 10 mL of 0 9% sterile saline The mixture is incorporated into a dosage unit form suitable for administration by injection Alteratively, the compound can form a l l complex with sulfo-butylether-β-cyclodextrm (Captisol) and the complex is reconstituted with salme to a 12 % w/v Captisol solution

Example 91b- Oral Composition

[00233] To prepare a pharmaceutical composition for oral delivery, 50 mg of a compound of any of

Formula I, II, III or IV, is mixed with 950 mg of starch The mixture is incorporated into an oral dosage unit for, such as a hard gelatin capsule, which is suitable for oral administration Example 91c Topical Gel Composition

[00234] To prepare a pharmaceutical topical gel composition, 50 mg of a compound of any of Formula I,

II, III or IV, is mixed with 1 75 g of hydroxymethyl celluose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topicl administration Example 9 Id Ophthalmic Solution Composition

[00235] To prepare a pharmaceutical opthalmic solution composition, 50 mg of a compound of any of

Formula I, II, III or IV, is mixed with 0 9 g of NaCl m 100 mL of purified water and filtered using a 0 2 micron filter The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration

[00236] Although the foregoing inventions have been described in some detail for purposes of clarity of understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. It should be noted that there are many alternative ways of implementing both the processes and compositions described herein. Accordingly, the present embodiments are to be considered as illustrative and not restrictive, and the inventions are not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.