WO2011140009A1 - Methods of using semi-synthetic glycopeptides as antibacterial agents - Google Patents

Methods of using semi-synthetic glycopeptides as antibacterial agents Download PDF

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Publication number
WO2011140009A1
WO2011140009A1 PCT/US2011/034885 US2011034885W WO2011140009A1 WO 2011140009 A1 WO2011140009 A1 WO 2011140009A1 US 2011034885 W US2011034885 W US 2011034885W WO 2011140009 A1 WO2011140009 A1 WO 2011140009A1
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compound
substituted
alkoxy
alkyl
group
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PCT/US2011/034885
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French (fr)
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Daniel Chu
Bing Wang
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Biomarin Pharmaceutical Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Naturally occurring and semi-synthetic glycopeptide antibiotics used to combat bacterial infections include compounds such as vancomycin, desmethylvancomycin, eremomycin, teicoplanin (complex of five compounds), dalbavancin, oritavancin, telavancin, and A82846B (LY264826) having structures A, B, C, D, E, F, G and H:
  • Staphylococcus aureus (S. aureus), a spherical bacterium, is the most common cause of staph infections.
  • S. aureus has been known to cause a range of illnesses from minor skin infections, such as pimples, impetigo, boils, cellulitis folliculitis, furuncles, carbuncles, scalded skin syndrome, abscesses, to life-threatening diseases such as pneumonia, meningitis, osteomyelitis endocarditis, toxic shock syndrome, and septicemia.
  • S. aureus is one of the most common causes of nosocomial infections, often causing postsurgical wound infections.
  • Methicillin was introduced in the late 1950s to treat infections caused by penicillin-resistant S. aureus. It has been reported previously that S. aureus isolates had acquired resistance to methicillin (methicillin-resistant S. aureus, MRSA).
  • the methicillin resistance gene (mecA) encodes a methicillin-resistant penicillin-binding protein that is not present in susceptible strains. mecA is carried on a mobile genetic element, the staphylococcal cassette chromosome mec (SCCmec), of which four forms have been described that differ in size and genetic composition.
  • SCCmec staphylococcal cassette chromosome mec
  • Vancomycin-intermediate Staphylococcus aureus and vancomycin-resistant staphylococcus aureus are specific types of antimicrobial-resistant Staph bacteria that are refractory to vancomycin treatment.
  • S. aureus isolates for which vancomycin ICs are 4-8 ⁇ g/mL ⁇ are classified as vancomycin-intermediate and isolates for which vancomycin MICs are >16 ⁇ /mL are classified as vancomycin-resistant (Clinical and Laboratory Standards Institute/NCCLS. Performance Standards for Antimicrobial Susceptibility Testing. Sixteenth informational supplement. M100-S 16. Wayne, PA: CLSI, 2006).
  • Enterococci are bacteria that are normally present in the human intestines and in the female genital tract and are often found in the environment. These bacteria sometimes cause infections. In some cases, enterococci have become resistant to vancomycin (also known as vancomycin-resistant enterococci or VRE.) Common forms of resistance to vancomycin occur in enterococcal strains that involve the acquisition of a set of genes endoding proteins that direct peptidoglycan precursors to incorporate D-Ala-D-Lac instead of D-Ala-D-Ala. The six different types of vancomycin resistance shown by enterococcus are: Van-A, Van-B, Van-C, Van-D, Van-E and Van-F.
  • Van-A VRE is resistant to both vancomycin and teicoplanin
  • Van-B VRE is resistant to vancomycin but sensitive to teicoplanin
  • Van-C is partly resistant to vancomycin, and sensitive to teicoplanin.
  • Described 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.
  • compositions formed by modification of Compound A, Compound B, Compound C or Compound H scaffolds to provide 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 are used, in some embodiments, as antibacterial agents for the treatment of bacterial infections with superior microbiology and pharmacokinetic properties than currently available glycopeptide antibacterial agents.
  • a method of treating a bacterial infection in a mammal where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia comprising administering a therapeutically acceptable amount of a com X, XI, XII, XIII, or XIV:
  • RA is hydrogen, methyl, or C 2 -Ci 2 -alkyl
  • R) and R 2 are each independently selected from the group consisting of
  • R 8 , R 9 and R 10 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R 8 and R 10 or R 9 and R 10 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C r C 3 -alkoxy, C r C 3 - alkoxy-Ci-C 3 -alkoxy, oxo, Ci-C 3 -alkyl, halo-Ci-C 3 -alkyl, and Ci-C 3 -alkoxy-C r C 3 -alkyl; or R] and R 2 taken together with the atom to which they are attached form a substituted heteroaryl or 3-10 membered heterocycl
  • R 7 is selected from the group consisting of
  • C r Ci2-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C r Ci 2 -alkoxy, Ci-C 3 -alkoxy-C C 3 -alkoxy, amino, C r Ci 2 - dialkylamino, alkenyl, alkynyl, and Ci-Ci 2 -thioalkoxy,
  • X is hydrogen or chlorine
  • Y is oxygen or NRi
  • Z is oxygen or sulfur
  • R E is halo or -OR where R is selected from the group consisting of
  • R 5 and 3 ⁇ 4 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R 5 and Re taken together with the atom to which they are attached form a 3- 10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C r C 3 -alkoxy, Ci-C 3 -alkoxy-Ci-C3-alkoxy, oxo, halo-C r Ci2-alkyl, and Ci- C 3 -alkoxy-C r C
  • R u is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and
  • R 12 is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or R n and Ri 2 together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C 3 -alkoxy, C r C 3 -alkoxy-C r C 3 -alkoxy, oxo, CrC l2 -alkyl, substituted loweralkyl, halo-C r C i2-alkyl, amino, alkylamino, dialkylamino, and Ci-C 3 -alkoxy-Ci-Ci 2 -alkyl; or
  • R 3 is selected from the group consisting of
  • aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy;
  • R B is selected from the group consisting of
  • C r C 12 -alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C r Ci 2 -alkoxy, C r C 3 -alkoxy- C r C 3 -alkoxy, amino, C Ci 2 -alkylamino, C r C
  • C r C 12 -alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C Ci 2 -alkoxy, C C 3 -alkoxy- C r C 3 -alkoxy, amino, C]-C 12 -alkylamino, C C 12 - dialkylamino, alkenyl, alkynyl, and C r Ci 2 -thioalkoxy,
  • R 8 , R 9 and Ri 0 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R 8 and Rio or R 9 and R 10 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, d-C 3 -alkoxy, C r C 3 - alkoxy-CpCs-alkoxy, oxo, C r C 3 -alkyl, halo-C r C 3 -alkyl, Ci-CValkoxy-CpCs-alkyl;
  • R D is each selected from the group consisting of
  • R 8 , R 9 and Ri 0 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R 8 and R 10 or R 9 and R 10 taken together with the atom to which they are attached form a 3- 10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C r C 3 -alkoxy, C1-C3- alkoxy-Ci-C 3 -alkoxy, oxo, Ci-C 3 -alkyl, halo-C r C 3 -alkyl, and Ci-C 3 -alkoxy-C r C 3 -alkyl;
  • At least two of Al , A2, and A3 are hydrogen and the other is -C(Z)-NH-R B , -C(Z)NHCHRi 5 -(CH 2 ) m -NHCONHR B ,
  • X, XI, XII, XIII, or XIV or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, in the formulation of a medicament for the treatment of a bacterial infection in a mammal where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia.
  • compositions, compounds, methods and uses described herein are described in conjunction with these embodiments, it should be understood that the compositions, compounds, methods and uses described herein are not to be limited to these embodiments. On the contrary, the compositions, compounds, methods and uses described herein cover alternatives, modifications, and equivalents as are 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, methods and uses described herein are optionally 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, methods and uses described herein.
  • the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula I
  • Embodiment 1 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula II
  • Embodiment 2 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula III
  • Embodiment 3 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula IV
  • Embodiment 4 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula V
  • Embodiment 5 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula VI
  • Embodiment 6 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula VII
  • Embodiment 7 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula VIII
  • Embodiment 8 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula IX
  • Embodiment 9 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula X
  • Embodiment 10 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula XI
  • Embodiment 11 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula XII
  • Embodiment 12 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula XIII
  • the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula XIV
  • Embodiment 14 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R A is methyl and R4 is hydrogen. In embodiment, R A is hydrogen and R4 is hydrogen. In another embodiment, X is hydrogen and R4 is hydrogen. In a further embodiment, X is chlorine and R4 is hydrogen. In yet a further embodiment, R A is methyl and R4 is
  • R A is hydrogen and R4 IS CH2NHCH2PO3H2.
  • R A is hydrogen and R( is CH 2 NH-CHR 15 -(CH 2 ) M -NHS02RB, where m is 1 to 6 and R 15 is H or loweralkyl.
  • R A is hydrogen and R4 is CH 2 NR F -CHR 15 -(CH 2 ) Q -NRGS0 2 RB, where q is 2 to 4, R 15 , R F , and RQ is H or loweralkyl, R F and RQ together represents -CH 2 -.
  • R A is hydrogen and R4 is CH 2 NH- CHR 15 -(CH 2 ) P -CONHS0 2 RB, where p is 0 to 6 and R 15 is H or loweralkyl.
  • Al and A2 are both hydrogen and R4 is CH 2 NH-CHR 15 - (CH 2 ) p -CONHR B , where p is 0 to 6 and R IS is H or loweralkyl.
  • R is CH 2 NH-(CH 2 ) 2 . 6 CONHR B .
  • Al and A2 are both hydrogen and R, is CH 2 NH- CHR 15 -(CH 2 ) M -0-(CH 2 ) r NHCONHR B , where m is 1 to 6, f is 1 to 6 and R 15 is H or loweralkyl.
  • R4 is CH 2 NH-(CH 2 ) 2 -0-CH 2 -NHCONHR B .
  • Al and A2 are both hydrogen and R, is CH 2 NH-CHR 15 -(CH 2 ) p -NHCOR B , where p is 0 to 6 and R 15 is H or loweralkyl.
  • R is CH 2 NH-(CH 2 ) 2 . 6 NHCOR B .
  • Embodiment 15 In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R A is hydrogen and R, is CH 2 NH- CHR 15 -(CH 2 ) p -COOH, where p is 0 to 6 and R [5 is H or loweralkyl. In yet a further embodiment, R A is methyl and R( is CH 2 NH-CHR 15 -(CH 2 ) m -NHS0 2 RB, where m is 1 to 6 and R 15 is H or loweralkyl.
  • R A is methyl and R, is CH 2 NH- CHR 15 -(CH 2 ) p -CONHS0 2 R B , where p is 0 to 6 and R 15 is H or loweralkyl.
  • R A is methyl and R, is CH 2 NH- CHRi 5 -(CH 2 ) p -COOH, where p is 0 to 6 and R 15 is H or loweralkyl.
  • R A is methyl and R, is CH 2 NR F -CHR 15 -(CH 2 ) Q -NRGS0 2 R B , where q is 2 to 4, R 15 , R F , and R Q is H or loweralkyl, R F and R Q together represents -CH 2 -.
  • R A is hydrogen and Al is CONH- CHR 15 -(CH 2 ) P -NHS0 2 R B , where p is 0 to 6 and R 15 is H or loweralkyl.
  • R A is methyl and Al is CONH- CHR 15 -(CH 2 ) p -NHS0 2 R B , where p is 0 to 6 and R 15 is H or loweralkyl.
  • R A is hydrogen and Al is -CONHCHR 15 -(CH 2 ) m - NHCONHR B , where m is 1 to 6 and R [5 is H or loweralkyl.
  • R A is methyl and Al is
  • R A is hydrogen and A2 is CONH- CHR 15 -(CH 2 ) P -NHS0 2 R B , where p is 0 to 6 and R 15 is H or loweralkyl.
  • R A is methyl and A2 is CONH- CHR I5 -(CH2)P-NHS0 2 RB, where p is 0 to 6 and R 15 is H or loweralkyl.
  • R A is hydrogen and A2 is -CONHCHR 15 -(CH 2 ) m -NHCONHR B , where m is 1 to 6 and R !5 is H or loweralkyl.
  • R A is methyl and A2 is -CONHCHRi 5 -(CH 2 ) m -NHCONHR B , where m is 1 to 6 and Ri5 is H or loweralkyl.
  • R A is hydrogen and A3 is CONH- CHRi 5 -(CH 2 ) p -NHS0 2 R B , where p is 0 to 6 and R i5 is H or loweralkyl.
  • R A is methyl and A3 is CONH- CHR 1 5-(CH 2 ) p -NHS0 2 R B , where p is 0 to 6 and Ri 5 is H or loweralkyl.
  • R A is hydrogen and A3 is -CONHCHR 15 -(CH 2 ) m - NHCONHR B , where m is 1 to 6 and Ri 5 is H or loweralkyl.
  • R A is methyl and A3 is
  • Embodiment 16 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R 3 is selected from the group consisting of
  • R )3 and R 14 are each independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl, aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy; or Ri 3 and R M together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C 3 -alkoxy, Ci-C 3 -alkoxy-C r C 3 -alkoxy, oxo, C Ci 2 -alkyl, substituted loweralkyl, hal
  • Embodiment 17 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R 3 is OH. In another embodiment, R 3 is 2-adamantanamino. In yet another embodiment, R 3 is dimethylamino. In one embodiment, R 3 is dimethylaminoethylamino. In another embodiment, R 3 is N-methylpiperazino.
  • Embodiment 18 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R] and R 2 are each independently selected from the group consisting of
  • R 8 , R 9 and R 10 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or
  • R 8 and Ri 0 or R 9 and Ri 0 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C r C 3 -alkoxy, VC 3 - alkoxy-Ci-C 3 -alkoxy, oxo, C r C 3 -alkyl, halo-C r C 3 -alkyl, and C r C 3 -alkoxy-C C 3 -alkyl; or Ri and R 2 taken together with the atom to which they are attached form a substituted heteroaryl or 3-10 membered
  • heterocycloalkyl ring optionally having one or two hetero functionalities selected from the group consisting of -0-, -N-, -NH, -N(C r C 6 -alkyl)-, -N(aryl)-, -N(aryl- C C 6 -alkyl-)-, -N(substituted-aryl- C r C 6 -alkyl-)-, -N(heteroaryl)-,
  • n 1 or 2 and the 3-10 membered heterocycloalkyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C r C 3 -alkoxy, C C 3 -alkoxy-CrC 3 -alkoxy, oxo, C C 3 -alkyl, halo-C r C 3 -alkyl, and C r C 3 -alkoxy-Ci-C 3 -alkyl.
  • Embodiment 19 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where Ri and R 2 are hydrogen.
  • R ( is C r C 12 -alkyl and R 2 is hydrogen.
  • Ri is Ci-C
  • R t is and R 2 is hydrogen.
  • Ri is C Ci 2 -alkyl substituted C r C 12 -alkoxy and R 2 is hydrogen. In another embodiment, Ri is CVCi 2 - alkyl substituted C r C 12 -thioalkoxy and R 2 is hydrogen. In yet another embodiment, Ri is C C 12 -alkyl substituted CpC ⁇ - alkylamino and R 2 is hydrogen.
  • Embodiment 20 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where RE is halo or -OR where R is selected from the group consisting of
  • Ci-Ci2-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy,
  • R 5 and R are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R 5 and 3 ⁇ 4 are taken 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 halogen, hydroxy, C r C 3 -aIkoxy, Ci-C 3 -alkoxy-Ci-C 3 -alkoxy, oxo, Ci-Ci 2 -alkyl, halo-C r Ci 2 -alkyl, and C C 3 -alkoxy-C C 12 -alkyl,
  • Rn is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and
  • Ri 2 is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or Rn and R i2 together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C 3 -alkoxy, C r C 3 -alkoxy-Ci-C 3 -alkoxy, oxo, substituted loweralkyl, halo-Ci-Ci 2 -alkyl, amino, alkylamino, dialkylamino, and Ci-C 3 -alkoxy-C r Ci 2 -alkyl.
  • Embodiment 21 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R E is -OR and R is hydrogen. In another embodiment, R E is -OR and R is C C 12 -alkyl. In one embodiment, R E is -OR and R is C r Ci 2 -alkyl substituted with aryl or substituted aryl. In a further embodiment, R E is -OR and R is substituted with aryl or substituted aryl. In one embodiment, R E is -OR and R is In another embodiment, R E is -OR and R is substituted with heteroaryl or substituted heteroaryl.
  • Embodiment 22 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R B is selected from the group consisting of
  • C r C 12 -alkyl b) C r C 12 -alkyl, c) C r C I2 -alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C r C l2 -alkoxy, C r C 3 -alkoxy- C r C 3 -alkoxy, amino, CpCn-alkylamino, C r C 12 - dialkylamino, alkenyl, alkynyl, and C r Ci 2 -thioalkoxy,
  • substituents selected from the group consisting of halogen, hydroxy, C C
  • Embodiment 23 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R B is C r C 12 -alkyl. In another embodiment, R B is C Ci 2 -alkyl substituted with aryl or substituted aryl. In yet another embodiment, R B is C Ci 2 -alkyl substituted with heteroaryl or substituted heteroaryl. In another embodiment, R B is aryl substituted with one or more halogens. In another embodiment, R B is aryl substituted one or more C Ci 2 -alkoxy.
  • R B is aryl substituted with one or more Q-Cn-alkylamino- C r C 12 -alkoxy. In another embodiment, R B is aryl substituted with one or more amino- Q-Cn-alkoxy. In another embodiment, R B is aryl substituted with one or more C Ci 2 -alkylamino. In another embodiment, R B is aryl substituted one or more C r C 12 -dialkylamino- C C 12 -alkoxy. In another embodiment, R B is aryl substituted one or more C r C Ci 2 -substituted alkyl. In another embodiment, R B is heteroaryl substituted one or more Ci-Ci 2 -alkoxy.
  • R B is heteroaryl substituted with one or more C Ci 2 -alkylamino- Ci-C 12 -alkoxy. In another embodiment, R B is heteroaryl substituted with one or more amino- C r Ci2-alkoxy. In another embodiment, R B is heteroaryl substituted with one or more C r Ci 2 -alkylamino. In another embodiment, R B is heteroaryl substituted one or more C Ci 2 -dialkylamino- C Ci 2 -alkoxy. In another embodiment, R B is heteroaryl substituted one or more C r C 12 -substituted alkyl.
  • Embodiment 24 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where Rc is each selected from the group consisting of
  • R 8 , R9 and R l0 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or R 8 and Ri 0 or R 9 and Ri 0 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, CpCValkoxy, C r C 3 - alkoxy-C r C 3 -alkoxy, oxo, Ci-C 3 -alkyl, halo-C C 3 -alkyl, and Ci-C 3 -alkoxy-C r C 3 -alkyl.
  • Embodiment 26 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R D is each selected from the group consisting of
  • Ci 2 -alkyl substituted with one or more substituents selected from the group consisting of
  • R 8 , R 9 and R 10 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or R 8 and R !0 or R 9 and R !0 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C C 3 -alkoxy, C r C 3 - alkoxy-CrC 3 -alkoxy, oxo, C r C 3 -alkyl, halo-C r C 3 -alkyl, and C r C 3 -alkoxy-Ci-C 3 -alkyl.
  • R D is C r Ci 2 -alkyl substituted C r C 12 -alkoxy. In a further embodiment, R D is C r C 12 -alkyl substituted C r Ci 2 -thioalkoxy. In yet a further embodiment, R D is C r Ci 2 -alkyl substituted C r C 12 -alkylamino. In yet a further embodiment, R D is alkyl.
  • Embodiment 28 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where Y is oxygen and R4 is hydrogen. In another embodiment, Z is oxygen and R4 is hydrogen. In yet another embodiment, Y is NH and R4 is hydrogen. In a further embodiment, Z is sulfur and R4 is hydrogen. In yet a further embodiment, Z is oxygen and R4 is CH 2 NHCH 2 P0 3 H 2 . In one embodiment, Y is oxygen and R4 is CH 2 NHCH 2 P0 3 H 2 . In another embodiment, Y is NH and R4 is CH 2 NHCH 2 P0 3 H 2 .
  • Embodiment 29 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R] is hydrogen and R 2 is COCHR 8 NHR ]5 where R 15 is substituted arylalkyl.
  • Embodiment 30 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula VII or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where Al, A2, and A3 are each hydrogen. In a further embodiment of any of the aforementioned embodiments is the method of use where for the Compound of Formula (VIII) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, where Al, A2, and A3 are each hydrogen.
  • any of the aforementioned embodiments is the method or use where for the Compound of Formula (IX) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where Al, A2, and A3 are each hydrogen.
  • any of the aforementioned embodiments is the method or use where for the Compound of Formula (XI) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where Al, A2, and A3 are each hydrogen.
  • Embodiment 31 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula X
  • Rc is hydrogen
  • R 8 is C r C 3 alkyl.
  • R 7 is amino, amino-cycloalkyl, or C r Ci 2 alkyl.
  • Al, A2, and A3 are hydrogen and R4 is CH 2 NH- CHRi 5 -(CH 2 ) m -NHS0 2 R B or CH 2 NH-CHRi 5 -(CH 2 ) m -NHCONHR B , m is 1 to 6 and R 15 is H or loweralkyl.
  • R B is aryl substituted with one or more Ci-Ci 2 alkyl.
  • C r C 12 alkyl is selected from n-butyl, n-pentyl, n-hexyl, n-heptyl, or n-octyl.
  • R B is phenyl substituted with n-hexyl at the para position.
  • A2, A3 and R4 are hydrogen and Al is -C(Z)-NH-R B , -C(Z)NHCHRi 5 -(CH 2 ) m -NHCONHR B , C(Z)NHCHR 15 -(CH 2 ) m -R B or -C(Z)NHCHR 15 -(CH 2 ) m -NHS0 2 R B .
  • R B is C C 12 alkyl.
  • C[-C 12 alkyl is n-hexyl, n-heptyl, n-octyl, or n-nonyl.
  • Al is m is 4 or 5, R 15 is hydrogen, and R B is aryl substituted with C Ci 2 alkoxy or C r C 12 alkyl.
  • R A is methyl
  • R D is hydrogen
  • R 3 is OH
  • A2, A3 and R4 are each hydrogen.
  • Embodiment 34 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula (XIII) where R A is methyl, Rc is hydrogen and R 3 is OH.
  • R A is methyl
  • Rc is hydrogen
  • R 3 is OH.
  • Al, A2, and A3 are hydrogen and R4 is CH 2 NH-CHR l5 -(CH 2 ) m -NHS0 2 R B or CH 2 NH-CHR 15 -(CH 2 ) m -NHCONHR B , m is 1 to 6 and R 15 is H or loweralkyl.
  • R B is selected from aryl substituted with one or more C r Ci 2 alkyl, aryl substituted with one or more C r C I2 alkoxy, or aryl substituted with one or more C r Ci 2 alkylamino.
  • Embodiment 35 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is com licated skin and skin structure infection or bacterial pneumonia and the compound is of Formula II, III, VIII or IX, where Ri is hydrogen and R 2 are 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 or more optionally substituted aryl, heteroaryl, or condensed rings, or Ri and R 2 together with the atom to which they are attached form a substituted heteroaryl or cycloheterocyclic ring which optionally contains additional heteroatom selected from the group consisting of optionally substituted O, N, and S.
  • R is hydrogen and R 2 are selected
  • Embodiment 36 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII, where R A is methyl or hydrogen and V, XI, and XIV and R B is selected from the group consisting of
  • substituents selected from the group consisting of halogen, hydroxy, C Ci 2 -alkoxy, C r Ci 2 -alkoxy- C Ci 2 -alkoxy, amino, amino-Ci-Ci 2 -alkoxy, CpCn- alkylamino, C r Ci
  • Embodiment 37 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula II - V and VIII - XI or XIII where R 7 is selected from the group consisting of
  • Ci 2 -alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, Ci-C 3 -alkoxy-C C3-alkoxy, amino, C r Ci 2 -alkylamino, C r C 12 -dialkylamino, alkenyl, alkynyl,
  • Embodiment 38 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I where R E is halo or -OR where R is selected from the group consisting of
  • R 5 and e are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R 5 and Re are taken together with the atom to which they are attached form a 3 - 10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C r C 3 -alkoxy, C r C 3 -alkoxy-CrC 3 -alkoxy, oxo, C r Ci2-alkyl, halo-C C 12 -alkyl, and C r C3-alkoxy-C C l2 -alkyl,
  • R u is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and
  • R ]2 is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or R u and R 12 together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C r C 3 -alkoxy, C r C 3 -alkoxy-C]-C 3 -alkoxy, oxo, C C 12 -alkyl, substituted loweralkyl, halo-C r Ci 2 -alkyl, amino, alkylamino, dialkylamino, and C r C 3 - alkoxy-C r C 12-alkyl.
  • Embodiment 39 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula VII - XII where at least two of Al, A2, and A3 are hydrogen and where when two of Al, A2, and A3 are hydrogen, the other is -C(Z)-NH-R B , -C(Z)NHCHRi 5 -(CH 2 ) m -NHCONHR B , -C(Z)NHCHR 15 -(CH 2 ) m -R B or -C(Z)NHCHRi 5 -(CH 2 ) m - NHS0 2 R B where m is 1 to 6, and Ri 5 is H or loweralkyl.
  • Al and A2 are hydrogen and A3 is-C(Z)-NH-R B .
  • Al and A2 are hydrogen and A3 is -C(Z)NHCHR ]5 - (CH 2 ) m -NHS0 2 R B .
  • Al and A2 are hydrogen and A3 is -C(Z)NHCHR, 5 -(CH 2 ) m -NHCONHR B .
  • Al and A2 are hydrogen and A3 is -C(Z)NHCHRi 5 -(CH 2 ) m -R B .
  • Al and A3 are hydrogen and A2 is-C(Z)-NH-R B .
  • Al and A3 are hydrogen and A2 is -C(Z)NHCHRi5-(CH 2 ) m -NHS0 2 RB.
  • Al and A3 are hydrogen and A2 is -C(Z)NHCHRi 5 - (CH 2 ) m -NHCONHR B .
  • Al and A3 are hydrogen and A2 is -C(Z)NHCHR 15 -(CH 2 ) m -RB .
  • A2 and A3 are hydrogen and Al is-C(Z)-NH-R B .
  • A2 and A3 are hydrogen and Al is -C(Z)NHCHR 15 -(CH 2 ) m -NHS0 2 R B .
  • A2 and A3 are hydrogen and Al is -C(Z)NHCHR 15 -(CH 2 ) m -NHCONHR B .
  • A2 and A3 are hydrogen and Al is - C(Z)NHCHR 15 -(CH 2 ) m -R B .
  • Embodiment 40 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula V or XI where X is chlorine and » is hydrogen.
  • Embodiment 41 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula V or XI where X is hydrogen and R4 is hydrogen..
  • Embodiment 42 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula VI where Y is oxygen and R4 is hydrogen.
  • Embodiment 43 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula VI where Y is NH and R4 is hydrogen.
  • Embodiment 44 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XII where Z is oxygen and R4 is hydrogen.
  • Embodiment 45 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XII where Z is sulfur and R4 is hydrogen.
  • Embodiment 46 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII where R A is methyl and R4 is hydrogen.
  • Embodiment 47 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII where R A is hydrogen and R4 is hydrogen.
  • Embodiment 48 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII where R A is methyl or hydrogen and R 3 is selected from the group consisting of
  • R ]3 and R, 4 are each independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl, aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy; or R ]3 and R M together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C 3 -alkoxy, Ci-C 3 -alkoxy-Ci-C 3 -alkoxy, oxo, C r Ci2-alkyl, substituted loweralkyl
  • Embodiment 49 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII where R A is methyl or hydrogen and R4 is selected from the group consisting of
  • aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy,
  • Embodiment 50 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula XIII or XIV where R4 is selected from the group consisting of hydrogen, CH 2 NH-CHR 15 -(CH 2 ) m -NHS0 2 R B , where m is 1 to 6 and R 15 is H or loweralkyl, hydrogen, CH 2 NH-CHR 15 -(CH 2 ) m -NHCONHR B , where m is 1 to 6 and R L5 is H or loweralkyl, CH 2 NR F -CHR 15 -(CH 2 ) q -NR G S0 2 R B where q is 2 to 4 and R L5 is H or loweralkyl, or CH 2 NH-CHR 15 -(CH 2 ) m -0- (CH 2 ) r NHS0 2 R B , where m is 1 to 6 and f
  • Embodiment 51 In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is selected from Compound (23). Compound (24). Compound (25). Compound (26). Compound (27). Compound (28). Compound (29). Compound (30). Compound (31). Compound (32). Compound (33). Compound (34). Compound (47). Compound (49).
  • Compound (201) Compound (202). Compound (203). Compound (204). Compound (205). Compound (206). Compound (207). Compound (208). Compound (209). Compound (210). Compound (211). Compound (212). Compound (213).
  • Embodiment 52 In a further embodiment of any embodiments 1-31, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the bacterial strain is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL-137. In a further embodiment, the method or use is where the bacterial strain is Staphylococcus aureus 2E5 CFU ATCC 13709 and the compound is
  • the method or use is where the bacterial strain is methicillin-resistant Staphylococcus aureus VL-137 and the compound is
  • a method of treating a bacterial infection in a mammal where the bacterial strain to be treated is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL-137 comprising administering a therapeutically acceptable amount of a compound having a structure of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV as described in the Summary of the Invention or in any of embodiments 1-52 as a pharmaceutical composition comprising the Compound of any of Formula I-XIV together with a pharmaceutically acceptable carrier.
  • a compound having a structure of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV as described in the Summary of the Invention or in any of embodiments 1-52 as a pharmaceutical composition comprising the Compound of any of Formula I-XIV together with a pharmaceutically acceptable carrier, for treating a bacterial infection in a mammal where the bacterial strain to be treated is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL- 137.
  • a compound having a structure of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV as described in the Summary of the Invention or in any of embodiments 1-52 as a pharmaceutical composition
  • a pharmaceutical composition comprising the Compound of any of Formula I-XIV together with a pharmaceutically acceptable carrier, in the formulation of a medicment for the treatment of a bacterial infection in a mammal where the bacterial strain to be treated is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL-137.
  • articles of manufacture comprising packaging material, a compound of any of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII or Formula XIV as described in the Summary of the Invention or in any of embodiments 1-52 which is effective for treatment, prevention or amelioration of one or more symptoms of a bacterial- mediated disease or condition where the bacterial strain to be treated is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL-137, 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
  • Embodiment 53 In another embodiment is a method of treating a gram-positive bacterial infection in a mammal comprising f
  • [0078] is use of a compound (303). (309). or (311). for treating a mammal having a gram-positive bacterial infection.
  • [0079] is use of a compound (303). (309). or (311). in the formulation of a medicament for the treatment of a mammal having a gram-positive bacterial infection.
  • Embodiment 54 In an further embodiment of embodiment 53, the method or use is that where the infection is bacteremia, complicated intra-abdominal infection, complicated skin and skin structure infection, or bacterial pneumonia.
  • a futher embodiment is that where the infection is complicated skin and skin structure infection or bacterial pneumonia.
  • a further embodiment is that where t he bacterium to be treated is resistant or refractory to a beta-lactam antibiotic, vancomycin, desmethylvancomycin, eremomycin, teicoplanin, dalbavancin, oritavancin, telavancin, or A82846B
  • Embodiment 55 A further embodiment of any of the embodiments in embodiments 53 and 54 is that where the compound is administered as a pharmaceutical composition which comprises a therapeutically effective amount of a compound, together with a pharmaceutically acceptable carrier, diluent or excipient.
  • the bacterium is a Gram-positive bacteria.
  • the Gram-positive bacterium is S. aureus.
  • the S. aureus is resistant or refractory to a beta-lactam antibiotic.
  • the beta-lactam antibiotic belongs to the class of penicillins.
  • the beta-lactam antibiotic is methicillin.
  • the subject has a methicillin-resistant S. aureus bacteria.
  • the beta-lactam antibiotic is flucloxacillin.
  • a method for treating a subject having a dicloxacillin-resistant bacteria comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to dicloxacillin.
  • a method for treating a subject having a methicillin-resistant bacteria comprising administering compound (303). (309).
  • the subject is screened for methicillin-resistant bacteria.
  • the subject screening is performed through a nasal culture.
  • the methicillin-resistant bacteria is detected by swabbing the nostril(s) of the subject and isolating the bacteria.
  • Real-time PCR and/or Quantitative PCR is employed to determine whether the subject has a methicillin- resistant bacteria.
  • a method for treating a subject having a first-generation cephalosporin-resistant bacteria comprising administering compound (303). (309), or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to a first-generation cephalosporin.
  • the bacteria is resistant to a first-generation cephalosporin.
  • the bacteria is resistant to cefacetrile.
  • the bacteria is resistant to cefadroxil.
  • the bacteria is resistant to cefalexin.
  • the bacteria is resistant to cefaloglycin.
  • the bacteria is resistant to cefalonium. In another embodiment, the bacteria is resistant to cefaloridine. In yet another embodiment, the bacteria is resistant to cefalotin. In a further embodiment, the bacteria is resistant to cefapirin. In yet a further embodiment, the bacteria is resistant to cefatrizine. In one embodiment, the bacteria is resistant to cefazaflur. In another embodiment, the bacteria is resistant to cefazedone. In yet another embodiment, the bacteria is resistant to cefazolin. In a further embodiment, the bacteria is resistant to cefradine. In yet a further embodiment, the bacteria is resistant to cefroxadine. In one embodiment, the bacteria is resistant to ceftezole.
  • the bacteria is resistant to a second-generation cephalosporin.
  • the bacteria is resistant to cefaclor.
  • the bacteria is resistant to cefonicid.
  • the bacteria is resistant to cefprozil.
  • the bacteria is resistant to cefuroxime.
  • the bacteria is resistant to cefuzonam.
  • the bacteria is resistant to cefmetazole.
  • the bacteria is resistant to cefotetan.
  • the bacteria is resistant to cefoxitin.
  • a method for treating a subject having a third-generation cephalosporin-resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to a third-generation cephalosporin.
  • the bacteria is resistant to a third-generation cephalosporin.
  • the bacteria is resistant to cefcapene.
  • the bacteria is resistant to cefdaloxime.
  • the bacteria is resistant to cefdinir.
  • the bacteria is resistant to cefditoren.
  • the bacteria is resistant to cefixime. In another embodiment, the bacteria is resistant to cefmenoxime. In yet another embodiment, the bacteria is resistant to cefodizime. In a further embodiment, the bacteria is resistant to cefotaxime. In yet a further embodiment, the bacteria is resistant to cefpimizole. In one embodiment, the bacteria is resistant to cefpodoxime. In another embodiment, the bacteria is resistant to cefteram. In yet another embodiment, the bacteria is resistant to ceftibuten. In a further embodiment, the bacteria is resistant to ceftiofur. In yet a further embodiment, the bacteria is resistant to ceftiolene. In one embodiment, the bacteria is resistant to ceftizoxime. In another embodiment, the bacteria is resistant to ceftriaxone. In yet another embodiment, the bacteria is resistant to cefoperazone. In yet a further embodiment, the bacteria is resistant to ceftazidime.
  • a method for treating a subject having a fourth-generation cephalosporin-resistant bacteria comprising administering compound (303), (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to a fourth-generation cephalosporin.
  • the bacteria is resistant to a fourth-generation cephalosporin.
  • the bacteria is resistant to cefclidine.
  • the bacteria is resistant to cefepime.
  • the bacteria is resistant to cefluprenam.
  • the bacteria is resistant to cefoselis.
  • the bacteria is resistant to cefozopran.
  • the bacteria is resistant to cefpirome.
  • the bacteria is refractory to cefquinome.
  • a method for treating a subject having a carbapenem-resistant bacteria comprising administering compound (303), (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to a carbapenem.
  • the bacteria is resistant to a carbapenem.
  • a method for treating a subject having a imipenem-resistant bacteria comprising administering compound (303). (309).
  • a method for treating a subject having a meropenem-resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to imipenem.
  • a method for treating a subject having a meropenem-resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to meropenem.
  • a method for treating a subject having a ertapenem -resistant bacteria comprising administering compound (303). (309).
  • a method for treating a subject having a faropenem-resistant bacteria comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to faropenem.
  • a method for treating a subject having a doripenem -resistant bacteria comprising administering compound (303). (309).
  • a method for treating a subject having a panipenem -resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to doripenem.
  • a method for treating a subject having a panipenem -resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to panipenem.
  • a method for treating a subject having a biapenem -resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where
  • Vancomycin-Intermediate and Vancomycin-Resistant Staphylococcus aureus Vancomycin-Intermediate and Vancomycin-Resistant Staphylococcus aureus
  • MIC minimum inhibitory concentration
  • a common method for determining the MIC of an antibiotic is to prepare several tubes containing serial dilutions of the antibiotic, that are then inoculated with the bacterial isolate of interest. The MIC of an antibiotic is determined from the tube with the lowest concentration that shows no turbidity (no growth).
  • [0091] in one aspect is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacterial infection comprises a vancomycin-intermediate Staphylococcus aureus bacterium.
  • a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309).
  • a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309).
  • a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309).
  • a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309).
  • a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309).
  • is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309).
  • [0092] in another aspect is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacterial infection comprises a vancomycin-resistant
  • the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of between about 16 ⁇ / ⁇ ⁇ ,. In another embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of about > 16 ⁇ g/mL. In yet another embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of about 20 ⁇ / ⁇ ⁇ . In a further embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of about 25 ⁇ g/mL.
  • conditions treated by the compounds described herein include, but are not limited to, endocarditis, osteomyelitis, neningitis, skin and skin structure infections, genitourinary tract infections, abscesses, and necrotizing infections.
  • the compounds disclosed herein are used to treat conditions, such as, but not limited to, diabetic foot infections, decubitus ulcers, burn infections, animal or human bite wound infections, synergistic- necrotizing gangrene, necrotizing fascilitis, intra-abdominal infection associated with breeching of the intestinal barrier, pelvic infection associated with breeching of the intestinal barrier, aspiration pneumonia, and post-operative wound infections.
  • the conditions listed herein are caused by, contain, or result in the presence of VISA and/or VRSA.
  • a method of treating a subject having a vancomycin-resistant enterococci comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the enterococci has developed resistance to vancomycin.
  • the subject has been previously treated with vancomycin for a sustained period of time.
  • the subject has been hospitalized.
  • the subject has a weakened immune system such as patients in Intensive Care Units or in cancer or transplant wards.
  • the subject has undergone surgical procedures such as, for example, abdominal or chest surgery.
  • the subject has been colonized vith VRE.
  • the subject has a medical device such that an infection has developed.
  • the medical device is a urinary catheter or central intravenous (IV) catheter.
  • [0097] in another embodiment is a method of treating a subject having a vancomycin-resistant enterococci comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the enterococcus has Van-A resistance.
  • [0098] in another embodiment is a method of treating a subject having a vancomycin-resistant enterococci comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the enterococcus has Van-B resistance.
  • [0099] in another embodiment is a method of treating a subject having a vancomycin-resistant enterococci comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the enterococcus has Van-C resistance.
  • [00 00] in another aspect, is use of a compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, for treating a subject having a vancomycin- resistant enterococci.
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom.
  • substituted alkyl refers to alkyl substituted by one, two or three groups consisting of halogen, alkoxy, amino, alkylamino, dialkylamino, hydroxy, aryl, heteroaryl, alkenyl or alkynyl group.
  • alkenyl refers to unsaturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between two and twenty carbon atoms by removal of a single hydrogen atom.
  • cycloalkyl 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.
  • substituted cycloalkyl refers to cycloalkyl substituted by one, two or three groups consisting of halogen, alkoxy, amino, alkylamino, dialkylamino, hydroxy, aryl, heteroaryl, alkenyl or alkynyl groups.
  • cycloalkenyl 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.
  • C r C 3 -alkyl refers 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 Ci-C 3 -alkyl radicals include methyl, ethyl, propyl and isopropyl.
  • C C 6 -alkyl radicals include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl.
  • Ci-Ci 2 -alkyl 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.
  • loweralkyl refers to Ci-Ci2-alkyl as defined above.
  • substituted loweralkyl refers to C r Ci 2 -alkyl substituted by one, two or three groups consisting of halogen, alkoxy, amino, alkylamino, dialkylamino, hydroxy, aryl, heteroaryl, alkenyl or alkynyl groups.
  • C 3 -Ci 2 -cycloalkyl denoted a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by removal of a single hydrogen atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.
  • Ci-C 3 -alkoxy refers to the C C 3 -alkyl group and Ci-C 6 -alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • C C 6 -alkoxy radicals include, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
  • loweralkylamino refers to Ci-Ci2-alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom.
  • loweralkylamino include, but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, propylamino and decylamino.
  • oxo denotes a group where 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).
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like and is optionally un- substituted or substituted (including bicyclic aryl groups) with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, Ci-Ci2-alkoxy, thioalkoxy, C r C 12 -thioalkoxy, aryloxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • substituted aryl groups include tetrafluorophenyl and pentafluoroph
  • substituted aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like substituted (including bicyclic aryl groups) with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, C r Ci 2 -alkoxy, thioalkoxy, C r Ci 2 -thioalkoxy, alkoxyalkylalkoxy, aryloxy, amino, aminoalkyl, aminoalkylalkoxy, alkylamino, alkylaminoalkyl, alkylaminoalkylalkoxy, dialkylamino, dialkylaminoalkyl,
  • substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
  • arylalkyl refers to an aryl group as defined above attached to the parent molecular moiety through an alkyl group where the alkyl group is of one to twelve carbon atoms.
  • substituted arylalkyl refers to a substituted aryl group as defined above attached to the parent molecular moiety through an alkyl group where the alkyl group is of one to twelve carbon atoms.
  • alkylaryl refers to an alkyl group as defined above attached to the parent molecular moiety through an aryl group.
  • halo and "halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • alkylamino refers to a group having the structure -NHR' where R' is alkyl, as previously defined.
  • alkylamino include methylamino, ethylamino, iso-propylamino, and the like.
  • dialkylamino refers to a group having the structure -NHR'R" where R' and R" are independently selected from alkyl, as previously defined. Additionally, R' and R" taken together optionally be -(CH 2 ) k - where k is an integer of from 2 to 6. Examples of dialkylamino include dimethylamino, diethylamino, methylpropylamino, piperidino, and the like.
  • 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.
  • 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.
  • thioalkoxy refers to an alkyl group previously defined attached to the parent molecular moiety through a sulfur atom.
  • carboxamide refers to a group of formula -CONHR'R" where R' and R" are independently selected from hydrogen, alkyl, substituted loweralkyl, or R' and R" taken together optionally be -(CH 2 ) k - where k is an integer of from 2 to 6.
  • heteroaryl refers to a cyclic or bicyclic aromatic radical having from five to ten ring atoms in each ring 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 ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, naphthyridinyl;
  • substituted heteroaryl refers to a cyclic or bicyclic aromatic radical having from five to ten ring atoms in each ring 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 ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, naphthyridiny
  • heterocycloalkyl refers to a non-aromatic partially unsaturated or fully saturated 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- or tri-cyclic ring systems which includes aromatic six-membered aryl or heteroaryl rings fused to a non-aromatic ring.
  • 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 be oxidized and the nitrogen heteroatom optionally be quaternized.
  • heterocycloalkyl rings include, but not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • heteroarylalkyl refers to a heteroaryl group as defined above attached to the parent molecular moiety through an alkylene group where the alkylene group is of one to four carbon atoms.
  • 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. 2nd edition, John Wiley & Sons, New York (1991).
  • hydroxy-protecting groups include, but not limited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, ethers such as methoxymethyl, and esters including acetyl, benzoyl, and the like.
  • 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.
  • amine protecting groups include, but are not limited to, tert-butoxycarbonyl (Boc) and carbobenzyloxy (Cbz).
  • a term "protected-hydroxy” refers to a hydroxy group protected with a hydroxy protecting group, as defined above.
  • amino acid refers to amino acids having D or L stereochemistry, and also refers to synthetic, non-natural amino acids having side chains other than those found in the 20 common amino acids.
  • Non-natural amino acids are commercially available or are optionally prepared according to US 5,488,131 and references therein.
  • Amino acids are optionally further substituted to contain modifications to their amino, carboxy, or side-chain groups. These modifications include the numerous protecting group commonly used in peptide synthesis (T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley & Sons, New York, 1991).
  • substituted heteroaryl refers to a heteroaryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with CI, Br, F, I, OH, CN, C C 12 - alkoxy, C r C 12 -alkoxy substituted with aryl, haloalkyl, thioalkyl, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • any one substituent is optionally an aryl, heteroaryl, or heterocycloalkyl group.
  • substituted heterocycloalkyl refers to a heterocycloalkyl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with CI, Br, F, I, OH, CN, C r C, 2 - alkyl, C Ci 2 -alkoxy, C r C 12 -alkoxy substituted with aryl, haloalkyl, thioalkyl, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • any one substituent is optionally aryl, heteroaryl, or heterocycloalkyl group.
  • phenolic regioiosmer refers to either of the three possible isomers of a compound having the same molecular weight with the substituent attached to one of the phenolic alcohols of the glycopeptide derivatives illustrated by either structure (A), (B) or (C).
  • stereoisomer 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. If asymmetric centers exist in the described compounds, except where otherwise noted, the compounds described herein include 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 present.
  • tautomer refers to either of the two forms of a chemical compound that exhibits tautomerism, 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.
  • salts 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.
  • S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference for this purpose.
  • the salts are prepared in situ during the final isolation and purification of the compounds described herein, 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, succinic acid or malonic acid or by using other documented methodologies such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other documented methodologies such as ion exchange.
  • 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, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • 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 counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • 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.
  • solvate refers to a compound formed by salvation, the combination of solvent molecules with molecules or ions of solute composed of a compound described herein.
  • 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.
  • alkylated quaternary ammonium salt refers to a compound formed by alkylation of the nitrogen atom of the primary, secondary or tertiary amine of the molecule with alkyl halide to form alkyl quaternary ammonium salt.
  • prodrugs refers to those prodrugs of the compounds described herein 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 zwitterionic forms, where possible, of the compounds described herein.
  • 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 in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 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 for this purpose.
  • a "beta-lactam antibiotic” includes, but is not limited to, penicillin, methicillin, dicloxacillin, flucloxacillin, first generation cephalosporins (such as cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefradine, cefroxadine, and ceftezole), second generation cephalosporins (such as cefaclor, cefonicid, cefprozil, cefuroxime, cefuzonam, cefmetazole, cefotetan, and cefoxitin), third generation cephalosporins (such as cefcapene, cefdaloxime, cefdinir, cefditoren, cefixime, cefmenoxime,
  • the semi-synthetic glycopeptides described herein are based on hydrolysis of the disaccharide moiety of the amino acid-4 of the parent glycopeptide to monosaccharide; conversion of the monosaccharide to the amino-sugar; acylation of the amino substituent on the amino-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.
  • Key reaction is the treatment of properly protected intermediate compound with isocyanate or carrying a Hofmann degradation of the primary amide of the 3 rd amino acid asparagines with phenyl-bis-trifluoroacetate to give the primary amine.
  • the compounds described herein are made, for example, by coupling the amino-sugar moiety of functionalized or unfunctionalized 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 substituent on the amino-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, a-amino acid or ⁇ -amino acids or derivatives thereof, and conversion of the acid moiety on the macrocyclic ring of this scaffold to certain substituted amides.
  • the compounds described herein are made, for example, by chemical modifications of the Compound A, Compound B, Compound H and Compound C scaffolds.
  • the semi-synthetic glycopeptides described herein are made by chemical modification of Compound A, Compound B, Compound H and Compound C or of the monosaccharide of the about glycopeptides made by subjecting the appropriate protected glycopeptide to a Mannich reaction with formaldehyde and an amine followed by de-protection.
  • synthesis of compounds also involves the use of protecting or blocking groups in order to maximize yields, minimize unwanted side products, or improve purification.
  • the semi-synthetic glycopeptides of the compounds described herein are made, for example, 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 CH2NHCH2PO3H2, or aminoloweralkyl as defined herein.
  • compound of Formulas I-XIV, described herein are made by where R A is hydrogen or methyl, X is chlorine or hydrogen, R 3 is alkoxy, 2-adamantanamino, or loweralkylamino, or R4 is hydrogen or properly protected CH 2 NHCH 2 P0 3 H2, or Boc-aminoloweralkyl, or PG is nitrogen protecting group by a technique selected from the group consisting of,
  • R, R h R 2 , R 3 , R4, R A , RB, RC, 3 ⁇ 4>, Al, A2, A3, X , Y, and Z are as defined herein.
  • the semi-synthetic glycopeptides described herein are made, for example, by modifying Compound A, Compound B, Compound H or Compound C scaffolds.
  • These natural glycopeptide starting materials are optionally unsubstituted or substituted at R4 with CH2NHCH2PO3H2, or aminoloweralkyl as defined herein.
  • Substitutions at R4 are introduced, for example, via a Mannich reaction where the glycopeptide is treated with an amine and formaldehyde under basic conditions (for example, as described in The Journal of Antibiotics, Vol. 50, No. 6, p. 509-513).
  • compositions described herein comprise a therapeutically effective amount of a compound described herein formulated together with one or more pharmaceutically acceptable carriers.
  • a pharmaceutically acceptable carrier 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.
  • materials which serve as pharmaceutically acceptable carriers 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; isotonic saline; 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 are also present in the composition, according to the judgment of the formulator.
  • compositions described herein are administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, 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.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms optionally contain inert diluents such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, 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.
  • the oral compositions optionally also include adjuvants such as wetting agents,
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions are formulated using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation are 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.
  • acceptable vehicles and solvents that are optionally employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are optionally employed as a solvent or suspending medium.
  • any bland fixed oil is optionally employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations are sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which is dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • biodegradable polymers examples include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared, for example, by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which are optionally prepared by mixing the compounds described herein 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.
  • 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.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium 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, polyvinylpyrrolidinone, 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, acety
  • 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 and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules are prepared, for example, with coatings and shells such as enteric coatings and other documented coatings. They optionally contain opacifying agents and also are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which are used include polymeric substances and waxes.
  • 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 and the like.
  • the active compounds are optionally in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules are optionally prepared with coatings and shells such as enteric coatings, release controlling coatings and other documented coatings.
  • the active compound is admixed, for example, with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms optionally comprise additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms optionally comprise buffering agents. They optionally contain opacifying agents and are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • 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 required. Ophthalmic formulations, ear drops, and the like are also contemplated.
  • the ointments, pastes, creams and gels optionally 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, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder.
  • Liquid aerosol formulations are nebulized, for example, predominantly into particle sizes that are 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 in 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.
  • Aerosolized formulations described herein are delivered, for example, 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 ⁇ . Further, the formulation preferably has balanced osmolality ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the compounds described herein 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.
  • an aerosol forming device such as a jet, vibrating porous plate or ultrasonic nebulizer
  • Aerosolization devices suitable for administration of aerosol formulations described 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 ⁇ . Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 ⁇ 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, AeroNebTM and AeroDoseTM vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California),
  • Compounds described herein are formulated, for example, 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.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms made, for example, by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers are optionally used to increase the flux of the compound across the skin.
  • the rate is controlled, for example, by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • 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.
  • 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.
  • the total daily usage of the compounds and compositions described 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 severity 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 in combination or coincidental with the specific compound employed; and like factors known in the medical arts.
  • the total daily dose of the compounds described herein administered to a human or other mammal in single or in divided doses is in amounts, for example, from about 0.01 to about 50 mg/kg body weight or more usually from about 0.1 to about 25 mg kg body weight.
  • Single dose compositions contain, for example, such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens described herein comprise administration to a patient in need of such treatment from about 10 mg to about 2000 mg of the compound(s) described herein per day in single or multiple doses.
  • LiN(TMS)2 for lithium bis(trimethylsilyl)amide
  • MCPBA for /Meta-chloroperbenzoic acid
  • MeOH for methanol
  • MsCl for methanesulfonyl chloride
  • NaHMDS or NaN(TMS)2 for sodium bis(trimethylsilyl)amide
  • MTBE for methyl tert-butyl ether
  • NMO for N-methylmorpholine N-oxide
  • pNZ-OSu for 2,5-dioxopyrrolidin-l-yl 4-nitrobenxyl carbonate
  • Boc for tert- W 201 butoxycarbonyl group
  • pNZ or p-nitrocarbobenzyloxy for carbo-(4-nitro)benzyloxy group
  • PE for petroleum ether
  • SOCl 2 for thionyl chloride
  • PPTS for pyridium -toluene sulfonate
  • Pd(OAc) 2 for palladium (II) acetate
  • PPh 3 for triphenylphosphine
  • Py for pyridine
  • TFA for trifluoroacetic acid
  • TEA for triethylamine
  • THF for tetrahydrofuran
  • TMSC1 for trimethylsilyl chloride
  • TMSCF 3 for trimethyl(trifluoromethyl)-silane

Abstract

Methods of using semi-synthetic glycopeptides of formula I-XIV having antibacterial activity are described.

Description

METHODS OF USING SEMI-SYNTHETIC GLYCOPEPTIDES AS ANTIBACTERIAL AGENTS
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 61/33 1,285, filed May 4, 2010, which is incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] Described herein are semi-synthetic glycopeptides having antibacterial activity, pharmaceutical compositions comprising these compounds, and methods of treatment using semi-synthetic glycopeptides.
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 bacterial infections include compounds such as vancomycin, desmethylvancomycin, eremomycin, teicoplanin (complex of five compounds), dalbavancin, oritavancin, telavancin, and A82846B (LY264826) having structures A, B, C, D, E, F, G and H:
Figure imgf000003_0001
R = B-2-Acetylamido-glucopyranosyl- D
Figure imgf000004_0001
Figure imgf000004_0002
[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.
[0005] Staphylococcus aureus (S. aureus), a spherical bacterium, is the most common cause of staph infections. S. aureus has been known to cause a range of illnesses from minor skin infections, such as pimples, impetigo, boils, cellulitis folliculitis, furuncles, carbuncles, scalded skin syndrome, abscesses, to life-threatening diseases such as pneumonia, meningitis, osteomyelitis endocarditis, toxic shock syndrome, and septicemia. Further, S. aureus is one of the most common causes of nosocomial infections, often causing postsurgical wound infections.
[0006] Methicillin was introduced in the late 1950s to treat infections caused by penicillin-resistant S. aureus. It has been reported previously that S. aureus isolates had acquired resistance to methicillin (methicillin-resistant S. aureus, MRSA). The methicillin resistance gene (mecA) encodes a methicillin-resistant penicillin-binding protein that is not present in susceptible strains. mecA is carried on a mobile genetic element, the staphylococcal cassette chromosome mec (SCCmec), of which four forms have been described that differ in size and genetic composition. The methicillin-resistant penicillin-binding protein allows for resistance to β-lactam antibiotics and obviates their clinical use during MRSA infections.
[0007] Vancomycin-intermediate Staphylococcus aureus and vancomycin-resistant staphylococcus aureus are specific types of antimicrobial-resistant Staph bacteria that are refractory to vancomycin treatment. S. aureus isolates for which vancomycin ICs are 4-8 μg/mL· are classified as vancomycin-intermediate and isolates for which vancomycin MICs are >16 μβ/mL are classified as vancomycin-resistant (Clinical and Laboratory Standards Institute/NCCLS. Performance Standards for Antimicrobial Susceptibility Testing. Sixteenth informational supplement. M100-S 16. Wayne, PA: CLSI, 2006).
[0008] Enterococci are bacteria that are normally present in the human intestines and in the female genital tract and are often found in the environment. These bacteria sometimes cause infections. In some cases, enterococci have become resistant to vancomycin (also known as vancomycin-resistant enterococci or VRE.) Common forms of resistance to vancomycin occur in enterococcal strains that involve the acquisition of a set of genes endoding proteins that direct peptidoglycan precursors to incorporate D-Ala-D-Lac instead of D-Ala-D-Ala. The six different types of vancomycin resistance shown by enterococcus are: Van-A, Van-B, Van-C, Van-D, Van-E and Van-F. In some cases, Van-A VRE is resistant to both vancomycin and teicoplanin, while in other cases, Van-B VRE is resistant to vancomycin but sensitive to teicoplanin; in further cases Van-C is partly resistant to vancomycin, and sensitive to teicoplanin.
[0009] 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.
SUMMARY OF THE INVENTION
[0010] Described 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.
[0011] In one aspect described herein are compounds formed by modification of Compound A, Compound B, Compound C or Compound H scaffolds to provide 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 are used, in some embodiments, as antibacterial agents for the treatment of bacterial infections with superior microbiology and pharmacokinetic properties than currently available glycopeptide antibacterial agents.
[0012] In one aspect described herein is a method of treating a bacterial infection in a mammal where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia comprising administering a therapeutically acceptable amount of a com X, XI, XII, XIII, or XIV:
Figure imgf000005_0001
Figure imgf000006_0001
-4-
where,
RA is hydrogen, methyl, or C2-Ci2-alkyl;
R) and R2 are each independently selected from the group consisting of
a) hydrogen,
b) Ci-C,2-alkyl,
c) C|-Ci2-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, Ci-C12-alkoxy, Ci-C3-alkoxy- CrC3-alkoxy, amino, CrCi2-alkylamino, CrC12- dialkylamino, alkenyl, alkynyl, and CrCi2-thioalkoxy,
d) C i-C 12-alkyl substituted with aryl,
e) C i -C i2-alkyl substituted with substituted aryl,
f) Ci-Ci2-alkyl substituted with heteroaryl,
g) Ci-Ci2-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) cycloalkenyl,
j) heterocycloalkyl,
k) -C(=0)R7, and
1) -C(=O)CHR8NR9R10where R8, R9 and R10 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R8 and R10 or R9 and R10 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, CrC3-alkoxy, CrC3- alkoxy-Ci-C3-alkoxy, oxo, Ci-C3-alkyl, halo-Ci-C3-alkyl, and Ci-C3-alkoxy-CrC3-alkyl; or R] and R2 taken together with the atom to which they are attached form a substituted heteroaryl or 3-10 membered heterocycloalkyl ring optionally having one or two hetero functionalities selected from the group consisting of -0-, -N-, -NH, -N(CrC6-alkyl)-, -N(aryl)-, -N(aryl- C,-C6-alkyl-)-, -N(substituted-aryl- CrC6-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl- C C6-alkyl-)-, -N(substituted-heteroaryl- CrC6-alkyl-)-, and -S- or S(0)n- where n is 1 or 2 and the 3-10 membered heterocycloalkyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, CpC3-alkoxy, CrC3- alkoxy-CrC3-alkoxy, oxo, CrC3-alkyl, halo-CrC3-alkyl, and Ci-C3-alkoxy-Ci-C3-alkyl,
R7 is selected from the group consisting of
a) hydrogen,
b) C,-C12-alkyl,
c) CrCi2-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CrCi2-alkoxy, Ci-C3-alkoxy-C C3-alkoxy, amino,
Figure imgf000008_0001
CrCi2- dialkylamino, alkenyl, alkynyl, and Ci-Ci2-thioalkoxy,
d) C Ci2-alkyl substituted with aryl,
e) C Ci2-alkyl substituted with substituted aryl,
f) CrCi2-alkyl substituted with heteroaryl,
g) CrC12-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) cycloalkenyl,
j) heterocycloalkyl,
k) amino;
1) CrC12-alkylamino, and
m) amino-cycloalkyl;
X is hydrogen or chlorine;
Y is oxygen or NRi;
Z is oxygen or sulfur;
RE is halo or -OR where R is selected from the group consisting of
(1) hydrogen,
(2) cycloalkyl,
(3) cycloalkenyl,
(4) CrC12-alkyl,
(5)
Figure imgf000008_0002
substituted with one or more substituents selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) CrCi2-alkoxy,
(d) CrC3-alkoxy- CrC3-alkoxy,
(e) -COOR5 where R5 is hydrogen or loweralkyl,
(f) -C(0)NR5R6 where Re is hydrogen or loweralkyl,
(g) amino, (h) - R5R6, where R5 and ¾ are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R5 and Re taken together with the atom to which they are attached form a 3- 10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, CrC3-alkoxy, Ci-C3-alkoxy-Ci-C3-alkoxy, oxo,
Figure imgf000009_0001
halo-CrCi2-alkyl, and Ci- C3-alkoxy-CrC|2-alkyl,
(i) aryl,
(j) substituted aryl,
(k) heteroaryl,
(1) substituted heteroaryl,
(m) mercapto, and
(n) C Ci2-thioalkoxy,
(6) -C(=0)ORn, where Ru is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and
(7)
Figure imgf000009_0002
where R12 is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or Rn and Ri2 together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C3-alkoxy, CrC3-alkoxy-CrC3-alkoxy, oxo, CrCl2-alkyl, substituted loweralkyl, halo-CrC i2-alkyl, amino, alkylamino, dialkylamino, and Ci-C3-alkoxy-Ci-Ci2-alkyl; or
R3 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 -loweralkylamino- 1 -adamantanamino,
(7) l-loweralkylamino-3 -adamantanamino,
(8) amino, and
(9) -NR13Ri4 where R13 and R14 are each independently selected from the group consisting of
hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl, aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted and substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy; or Rn and RM together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C3- alkoxy, Ci-Ca-alkoxy-CpQ-alkoxy, oxo, CrCi2-alkyl, substituted loweralkyl, halo-C C12-alkyl, amino, alkylamino, dialkylamino, and Ci-C3-alkoxy-C Ci2-alkyl; R4 is selected from the group consisting of
(1 ) -CH2NH-CHR15-(CH2)m-NHS02RB, where m is 1 to 6 and RI5 is H or loweralkyl,
(2) -CH2NH- CHR15 -(CH2)p-CONHS02RB, where p is 0 to 6 and RL5 is H or loweralkyl,
(3) -CH2NH- CHR,5-(CH2)m-0-(CH2)rNHS02RB, where m is 1 to 6, f is 1 to 6 and R15 is H or loweralkyl,
(4) -CH2NRF-CHR,5-(CH2)q-NRGS02RB, where q is 2 to 4 and RI5 is H or loweralkyl, RF and RQ are independently hydrogen, lower alkyl or taken together represents a -CH2-,
(5) H,
(6) -CH2NH-CHR15-(CH2)m-NHCONHRB, where m is 1 to 6 and R15 is H or loweralkyl,
(7) -CH2NHCH2P03H2,
(8) aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy;
(9) -CH2NH-CHR,5-(CH2)p-NHCORB, where p is 0 to 6 and R15 is H or loweralkyl,
(10) -CH2NH-CHR15-(CH2)p-CONHRB, where p is 0 to 6 and R!5 is H or loweralkyl, and
(1 1) -CH2NH- CHR15-(CH2)m-0-(CH2)rNHCONHRB, where m is 1 to 6, f is 1 to 6 and RI5 is H or loweralkyl;
RB is selected from the group consisting of
a) aryl,
b) CrC12-alkyl,
c) CrC12-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CrCi2-alkoxy, CrC3-alkoxy- CrC3-alkoxy, amino, C Ci2-alkylamino, CrC|2- dialkylamino, alkenyl, alkynyl, and CrC12-thioalkoxy,
d) Ci-C12-alkyl substituted with aryl,
e) Ci-C12-alkyl substituted with substituted aryl,
f) CrC12-alkyl substituted with heteroaryl,
g) Ci-C12-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) heteroaryl,
j) heterocycloalkyl,
k) aryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, Ci-Ci2-alkoxy, Ci-Ci2-alkoxy- C C12-alkoxy, amino, amino-CrCi2-alkoxy, CrCi2- alkylamino, Ci-C12-alkylamino- C Ci2-alkoxy, C C12-dialkylamino, Ci-Ci2-dialkylamino- Cr Ci2-alkoxy, alkenyl, alkynyl, CrCi2-thioalkoxy, CrCi2-alkyl, CrCi2-substituted alkyl, CrC12- alkoxy-morpholino, C C12-alkoxy-Ci-C12-dialkoxyamino, C1-C12-alkoxy-NHS02C1-C6alkyl, and C ,-C 12-alkoxy-NHCOC i-Qalkyl, and
1) heteroaryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CpCn-alkoxy, CrCi2-alkoxy- CrCi2-alkoxy, amino, amino-CrCi2-alkoxy, CrCi2- alkylamino, CrC12-alkylamino- CrCI2-alkoxy, CVC^-dialkylamino, C|-C12-dialkylamino- Cr Ci2-alkoxy, alkenyl, alkynyl, CrCi2-thioalkoxy, CrC12-alkyl, and
Figure imgf000011_0001
alkyl; Rc is each selected from the group consisting of
a) hydrogen,
b) C,-C12-alkyl,
c) CrC12-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C Ci2-alkoxy, C C3-alkoxy- CrC3-alkoxy, amino, C]-C12-alkylamino, C C12- dialkylamino, alkenyl, alkynyl, and CrCi2-thioalkoxy,
d) CrCi2-alkyl substituted with aryl,
e) CrCi2-alkyl substituted with substituted aryl,
f) CpCn-alkyl substituted with heteroaryl,
g) Ci-Ct2-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) cycloalkenyl,
j) heterocycloalkyl,
k) -C(=0)R7, and
1) -C(=O)CHR8NR9R10 where R8, R9 and Ri0 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R8 and Rio or R9 and R10 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, d-C3-alkoxy, CrC3- alkoxy-CpCs-alkoxy, oxo, CrC3-alkyl, halo-CrC3-alkyl, Ci-CValkoxy-CpCs-alkyl;
RD is each selected from the group consisting of
a) hydrogen,
b) CrC12-alkyl,
c) CrC12-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CrCi2-alkoxy, C C3-alkoxy- C C3-alkoxy, amino, CrC12-alkylamino, C C12- dialkylamino, alkenyl, alkynyl, and CrCI2-thioalkoxy,
d) C !-C 12-alkyl substituted with aryl,
e) C Ci2-alkyl substituted with substituted aryl,
f) Ci-C12-alkyl substituted with heteroaryl,
g) CrCi2-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) cycloalkenyl,
j) heterocycloalkyl,
k) -C(=0)R7, and
1) -C(=O)CHR8NR9R10 where R8, R9 and Ri0 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R8 and R10 or R9 and R10 taken together with the atom to which they are attached form a 3- 10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, CrC3-alkoxy, C1-C3- alkoxy-Ci-C3-alkoxy, oxo, Ci-C3-alkyl, halo-CrC3-alkyl, and Ci-C3-alkoxy-CrC3-alkyl;
at least two of Al , A2, and A3 are hydrogen and the other is -C(Z)-NH-RB , -C(Z)NHCHRi5-(CH2)m-NHCONHRB ,
-C(Z)NHCHRl5-(CH2)m-RB or -C(Z)NHCHR15-(CH2)m-NHS02RB;
and where for compounds having the structure of Formula X or XI, when A 1, A2, A3, Rc and RD are hydrogen, then R4 is not hydrogen;
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0013] In another aspect is described a method of treating a bacterial infection in a mammal comprising administering a therapeutically acceptable amount of a compound having a structure of
Figure imgf000012_0001
[00141 In another aspect is described the use of a compound having a structure of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV, or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, for treating a bacterial infection in a mammal where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia.
[00151 In another aspect is described the use of a compound having a structure of Formula I, II, III, IV, V, VI, VII, VIII, IX,
X, XI, XII, XIII, or XIV, or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, in the formulation of a medicament for the treatment of a bacterial infection in a mammal where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia.
[0016] In another aspect is described the use of compound (303), (309). or (311) for treating a bacterial infection in a mammal.
[0017| In another aspect is described the use of compound (303), (309). or (311) in the formulation of a medicament for the treatment of a bacterial infection in a mammal.
DETAILED DESCRIPTION
[0018] 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, methods and uses described herein are described in conjunction with these embodiments, it should be understood that the compositions, compounds, methods and uses described herein are not to be limited to these embodiments. On the contrary, the compositions, compounds, methods and uses described herein cover alternatives, modifications, and equivalents as are 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, methods and uses described herein. The compositions, compounds, methods and uses described herein are optionally 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, methods and uses described herein.
[0019] Described herein are semi-synthetic glycopeptides that have antibacterial activity.
[0020] In a further embodiment, the method or use is wherethe bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula I
Figure imgf000013_0001
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0021] Embodiment 1 ; In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula II
Figure imgf000014_0001
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0022] Embodiment 2: In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula III
Figure imgf000014_0002
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0023] Embodiment 3: In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula IV
Figure imgf000014_0003
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0024] Embodiment 4: In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula V
Figure imgf000015_0001
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0025] Embodiment 5: In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula VI
Figure imgf000015_0002
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0026] Embodiment 6: In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula VII
Figure imgf000015_0003
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0027] Embodiment 7: In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula VIII
Figure imgf000016_0001
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0028] Embodiment 8: In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula IX
Figure imgf000016_0002
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0029] Embodiment 9: In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula X
Figure imgf000016_0003
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0030] Embodiment 10: In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula XI
Figure imgf000017_0001
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0031] Embodiment 11 : In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula XII
Figure imgf000017_0002
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0032] Embodiment 12: In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula XIII
Figure imgf000017_0003
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof. |0033| Embodiment 13: In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound has the structure of Formula XIV
Figure imgf000018_0001
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0034] Embodiment 14: In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where RA is methyl and R4 is hydrogen. In embodiment, RA is hydrogen and R4 is hydrogen. In another embodiment, X is hydrogen and R4 is hydrogen. In a further embodiment, X is chlorine and R4 is hydrogen. In yet a further embodiment, RA is methyl and R4 is
CH2NHCH2PO3H2. In another embodiment, RA is hydrogen and R4 IS CH2NHCH2PO3H2. In one embodiment, RA is hydrogen and R( is CH2NH-CHR15-(CH2)M-NHS02RB, where m is 1 to 6 and R15 is H or loweralkyl. In another embodiment, RA is hydrogen and R4 is CH2NRF-CHR15-(CH2)Q-NRGS02RB, where q is 2 to 4, R15, RF, and RQ is H or loweralkyl, RF and RQ together represents -CH2-. In yet another embodiment, RA is hydrogen and R4 is CH2NH- CHR15-(CH2)P-CONHS02RB, where p is 0 to 6 and R15 is H or loweralkyl. In one embodiment, Al and A2 are both hydrogen and R4 is CH2NH-CHR15- (CH2)p-CONHRB, where p is 0 to 6 and RIS is H or loweralkyl. In one embodiment, R, is CH2NH-(CH2)2.6CONHRB. In another embodiment, Al and A2 are both hydrogen and R, is CH2NH- CHR15-(CH2)M-0-(CH2)rNHCONHRB, where m is 1 to 6, f is 1 to 6 and R15 is H or loweralkyl. In a further embodiment, R4 is CH2NH-(CH2)2-0-CH2-NHCONHRB. In yet another embodiment, Al and A2 are both hydrogen and R, is CH2NH-CHR15-(CH2)p-NHCORB, where p is 0 to 6 and R15 is H or loweralkyl. In one embodiment, R, is CH2NH-(CH2)2.6NHCORB.
[0035] Embodiment 15: In a further embodiment, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where RA is hydrogen and R, is CH2NH- CHR15-(CH2)p-COOH, where p is 0 to 6 and R[5 is H or loweralkyl. In yet a further embodiment, RA is methyl and R( is CH2NH-CHR15-(CH2)m-NHS02RB, where m is 1 to 6 and R15 is H or loweralkyl. In one embodiment, RA is methyl and R, is CH2NH- CHR15-(CH2)p-CONHS02RB, where p is 0 to 6 and R15 is H or loweralkyl. In another embodiment, RA is methyl and R, is CH2NH- CHRi5-(CH2)p-COOH, where p is 0 to 6 and R15 is H or loweralkyl. In another embodiment, RA is methyl and R, is CH2NRF-CHR15-(CH2)Q-NRGS02RB, where q is 2 to 4, R15, RF, and RQ is H or loweralkyl, RF and RQ together represents -CH2-. In yet another embodiment, RA is hydrogen and Al is CONH- CHR15-(CH2)P-NHS02RB, where p is 0 to 6 and R15 is H or loweralkyl. In yet another embodiment, RA is methyl and Al is CONH- CHR15-(CH2)p-NHS02RB, where p is 0 to 6 and R15 is H or loweralkyl. In yet another embodiment, RA is hydrogen and Al is -CONHCHR15-(CH2)m- NHCONHRB, where m is 1 to 6 and R[5 is H or loweralkyl. In yet another embodiment, RA is methyl and Al is
-CONHCHR15-(CH2)m-NHCONHRB, where m is 1 to 6 and Ri5 is H or loweralkyl. In yet another embodiment, RA is hydrogen and A2 is CONH- CHR15-(CH2)P-NHS02RB, where p is 0 to 6 and R15 is H or loweralkyl. In yet another embodiment, RA is methyl and A2 is CONH- CHRI5-(CH2)P-NHS02RB, where p is 0 to 6 and R15 is H or loweralkyl. In yet another embodiment, RA is hydrogen and A2 is -CONHCHR15-(CH2)m-NHCONHRB, where m is 1 to 6 and R!5 is H or loweralkyl. In yet another embodiment, RA is methyl and A2 is -CONHCHRi5-(CH2)m-NHCONHRB, where m is 1 to 6 and Ri5 is H or loweralkyl. In yet another embodiment, RA is hydrogen and A3 is CONH- CHRi5-(CH2)p-NHS02RB, where p is 0 to 6 and Ri5 is H or loweralkyl. In yet another embodiment, RA is methyl and A3 is CONH- CHR15-(CH2)p-NHS02RB, where p is 0 to 6 and Ri5 is H or loweralkyl. In yet another embodiment, RA is hydrogen and A3 is -CONHCHR15-(CH2)m- NHCONHRB, where m is 1 to 6 and Ri5 is H or loweralkyl. In yet another embodiment, RA is methyl and A3 is
-CONHCHR,5-(CH2)m-NHCONHRB, where m is 1 to 6 and R15 is H or loweralkyl.
[00361 Embodiment 16: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R3 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 -loweralkylamino- 1 -adamantanamino,
(7) 1 -loweralkylamino-3 -adamantanamino,
(8) amino
(9) -NR13Ri4 where R)3 and R14 are each independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl, aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy; or Ri3 and RM together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C3-alkoxy, Ci-C3-alkoxy-CrC3-alkoxy, oxo, C Ci2-alkyl, substituted loweralkyl, halo-CrCi2-alkyl, amino, alkylamino, dialkylamino, and Ci-C3-alkoxy-CrC12-alkyl.
[0037] Embodiment 17: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R3 is OH. In another embodiment, R3 is 2-adamantanamino. In yet another embodiment, R3 is dimethylamino. In one embodiment, R3 is dimethylaminoethylamino. In another embodiment, R3 is N-methylpiperazino.
[0038] Embodiment 18: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R] and R2 are each independently selected from the group consisting of
a) hydrogen,
b) CrC12-alkyl,
c) C Ci2-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CrC12-alkoxy, CrC3-alkoxy- C C3-alkoxy, amino, CrC12-alkylamino, CrCi2- dialkylamino, alkenyl, alkynyl, CrC12-thioalkoxy, d) C,-C12-alkyl substituted with aryl,
e) CrCi2-alkyl substituted with substituted aryl,
f) C i-C i2-alkyl substituted with heteroaryl,
g) CrCi2-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) cycloalkenyl,
j) heterocycloalkyl,
k) -C(=0)R7, and
1)
Figure imgf000020_0001
where R8, R9 and R10 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or
R8 and Ri0 or R9 and Ri0 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, CrC3-alkoxy, VC3- alkoxy-Ci-C3-alkoxy, oxo, CrC3-alkyl, halo-CrC3-alkyl, and CrC3-alkoxy-C C3-alkyl; or Ri and R2 taken together with the atom to which they are attached form a substituted heteroaryl or 3-10 membered
heterocycloalkyl ring optionally having one or two hetero functionalities selected from the group consisting of -0-, -N-, -NH, -N(CrC6-alkyl)-, -N(aryl)-, -N(aryl- C C6-alkyl-)-, -N(substituted-aryl- CrC6-alkyl-)-, -N(heteroaryl)-,
-N(heteroaryl- C C6-alkyl-)-, -N(substituted-heteroaryl- Ci-C6-alkyl-)-, and -S- or S(0)n- where n is 1 or 2 and the 3-10 membered heterocycloalkyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, CrC3-alkoxy, C C3-alkoxy-CrC3-alkoxy, oxo, C C3-alkyl, halo-CrC3-alkyl, and CrC3-alkoxy-Ci-C3-alkyl.
[0039] Embodiment 19: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where Ri and R2 are hydrogen. In another embodiment, R( is CrC12-alkyl and R2 is hydrogen. In yet another embodiment, Ri is Ci-C|2-alkyl substituted with aryl or substituted aryl and R2 is hydrogen. In a further embodiment, Rt is
Figure imgf000020_0002
and R2 is hydrogen. In yet a further embodiment, R[ is C(=0) CH2 NH C Ci2-alkyl and R2 is hydrogen. In one embodiment, Ri is C Ci2-alkyl substituted CrC12-alkoxy and R2 is hydrogen. In another embodiment, Ri is CVCi2- alkyl substituted CrC12-thioalkoxy and R2 is hydrogen. In yet another embodiment, Ri is C C12-alkyl substituted CpC^- alkylamino and R2 is hydrogen.
[0040] Embodiment 20: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where RE is halo or -OR where R is selected from the group consisting of
(1) hydrogen,
(2) cycloalkyl,
(3) cycloalkenyl,
(4) C C12-alkyl,
(5) Ci-Ci2-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy,
(c) CrCi2-alkoxy,
(d) CrC3-alkoxy- C C3-alkoxy,
(e) -COOR5 where R5 is hydrogen or loweralkyl,
(f) -C(0)NR5R6 where R6 is hydrogen or loweralkyl,
(g) amino,
(h) -NR5R6, where R5 and R,; are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R5 and ¾ are taken 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 halogen, hydroxy, CrC3-aIkoxy, Ci-C3-alkoxy-Ci-C3-alkoxy, oxo, Ci-Ci2-alkyl, halo-CrCi2-alkyl, and C C3-alkoxy-C C12-alkyl,
(i) aryl,
(j) substituted aryl,
(k) heteroaryl,
(1) substituted heteroaryl,
(m) mercapto, and
(n) CrCi2-thioalkoxy,
(6) -C(=0)ORn, where Rn is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and
(7) -C(=0)NRnR12, where Ri2 is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or Rn and Ri2 together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C3-alkoxy, CrC3-alkoxy-Ci-C3-alkoxy, oxo,
Figure imgf000021_0001
substituted loweralkyl, halo-Ci-Ci2-alkyl, amino, alkylamino, dialkylamino, and Ci-C3-alkoxy-CrCi2-alkyl.
[0041] Embodiment 21 : In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where RE is -OR and R is hydrogen. In another embodiment, RE is -OR and R is C C12-alkyl. In one embodiment, RE is -OR and R is CrCi2-alkyl substituted with aryl or substituted aryl. In a further embodiment, RE is -OR and R is
Figure imgf000021_0002
substituted with aryl or substituted aryl. In one embodiment, RE is -OR and R is
Figure imgf000021_0003
In another embodiment, RE is -OR and R is
Figure imgf000021_0004
substituted with heteroaryl or substituted heteroaryl.
[0042] Embodiment 22: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where RB is selected from the group consisting of
a) aryl,
b) CrC12-alkyl, c) CrCI2-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CrCl2-alkoxy, CrC3-alkoxy- CrC3-alkoxy, amino, CpCn-alkylamino, CrC12- dialkylamino, alkenyl, alkynyl, and CrCi2-thioalkoxy,
d) CrC|2-alkyl substituted with aryl,
e) CrCi2-alkyl substituted with substituted aryl,
f) Cj-C12-alkyl substituted with heteroaryl,
g) Cj-CI2-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) heteroaryl,
j) heterocycloalkyl,
k) aryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C rCi2-alkoxy, Ci-C12-alkoxy- C|-Q2-alkoxy, amino, amino-Ci-C12-alkoxy, CrC12- alkylamino, CrC12-alkylamino- C Ci2-alkoxy, CrCi2-dialkylamino, CrC12-dialkylamino- Cr C12-alkoxy, alkenyl, alkynyl, CrCi2-thioalkoxy, C Ci2-alkyl, C Ci2-substituted alkyl, C Ci2- alkoxy-morpholino, CrC12-alkoxy-Ci-Ci2-dialkoxyamino, Ci-Ci2-alkoxy-NHS02CrC6alkyl, and CrCI2-alkoxy-NHCOCrC6alkyl, and
1) heteroaryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C C|2-alkoxy, CrCi2-alkoxy- CrC|2-alkoxy, amino, amino-Ci-Ci2-alkoxy, CrCi2- alkylamino, C Cl2-alkylamino- CVC12-alkoxy, CrCi2-dialkylamino, CrCi2-dialkylamino- Cr C [2-alkoxy, alkenyl, alkynyl, C[-Ci2-thioalkoxy, C C12-alkyl, and Ci-C ^-substituted alkyl.
[0043] Embodiment 23 : In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where RB is CrC12-alkyl. In another embodiment, RB is C Ci2-alkyl substituted with aryl or substituted aryl. In yet another embodiment, RB is C Ci2-alkyl substituted with heteroaryl or substituted heteroaryl. In another embodiment, RB is aryl substituted with one or more halogens. In another embodiment, RB is aryl substituted one or more C Ci2-alkoxy. In yet another embodiment, RB is aryl substituted with one or more Q-Cn-alkylamino- CrC12-alkoxy. In another embodiment, RB is aryl substituted with one or more amino- Q-Cn-alkoxy. In another embodiment, RB is aryl substituted with one or more C Ci2-alkylamino. In another embodiment, RB is aryl substituted one or more CrC12-dialkylamino- C C12-alkoxy. In another embodiment, RB is aryl substituted one or more Cr C Ci2-substituted alkyl. In another embodiment, RB is heteroaryl substituted one or more Ci-Ci2-alkoxy. In yet another embodiment, RB is heteroaryl substituted with one or more C Ci2-alkylamino- Ci-C12-alkoxy. In another embodiment, RB is heteroaryl substituted with one or more amino- Cr Ci2-alkoxy. In another embodiment, RB is heteroaryl substituted with one or more CrCi2-alkylamino. In another embodiment, RB is heteroaryl substituted one or more C Ci2-dialkylamino- C Ci2-alkoxy. In another embodiment, RB is heteroaryl substituted one or more CrC12-substituted alkyl.
[0044] Embodiment 24: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where Rc is each selected from the group consisting of
a) hydrogen,
b) CrC12-alkyl, c) CrC i2-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C]-Ci2-alkoxy, C]-C3-alkoxy- C]-C3-alkoxy, amino, Ci-Ci2-alkylamino, CrCi2- dialkylamino, alkenyl, alkynyl, and Ci-C]2-thioalkoxy,
d) CrCi2-alkyl substituted with aryl,
e) CrCi2-alkyl substituted with substituted aryl,
f) C i-C i2-alkyl substituted with heteroaryl,
g) Ci-C]2-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) cycloalkenyl,
j) heterocycloalkyl,
k) -C(=0)R7, and
1)
Figure imgf000023_0001
R8, R9 and Rl0 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or R8 and Ri0 or R9 and Ri0 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, CpCValkoxy, CrC3- alkoxy-CrC3-alkoxy, oxo, Ci-C3-alkyl, halo-C C3-alkyl, and Ci-C3-alkoxy-CrC3-alkyl.
[0045] Embodiment 25: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where Rc is hydrogen. In another embodiment, Rc is CrCi2-alkyl. In yet another embodiment, Rc is CrCi2- alkyl substituted with aryl or substituted aryl. In a further embodiment, Rc is C,-Ci2-alkyl substituted with heteroaryl or substituted heteroaryl. In one embodiment, Rc is C(=0)CrC12-alkyl. In another embodiment, Rc is C(=0) CH2 NH C C2- alkyl. In yet another embodiment, Rc is CpCn-alkyl substituted Ci-Ci2-alkoxy. In a further embodiment, Rc is C Ci2-alkyl substituted CrCi2-thioalkoxy. In yet a further embodiment, Rc is CrC,2-alkyl substituted C Ci2-alkylamino. In yet a further embodiment, Rc is C(=0)NH2. In yet a further embodiment, Rc is
Figure imgf000023_0002
alkyl.
[0046] Embodiment 26: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where RD is each selected from the group consisting of
a) hydrogen,
b) CrC12-alkyl,
c) C Ci2-alkyl substituted with one or more substituents selected from the group consisting of
halogen, hydroxy, Ci-Ci2-alkoxy, CrC3-alkoxy- CrC3-alkoxy, amino, CrC12-alkylamino, CrC12- dialkylamino, alkenyl, alkynyl, and CrC12-thioalkoxy,
d) CrCi2-alkyl substituted with aryl,
e) Ci-Ci2-alkyl substituted with substituted aryl,
f) CrCi2-alkyl substituted with heteroaryl,
g) Ci-Ci2-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) cycloalkenyl, j) heterocycloalkyl,
k) -C(=0)R7, and
1) -C(=O)CHR8NR9RI0where R8, R9 and R10 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or R8 and R!0 or R9 and R!0 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, C C3-alkoxy, CrC3- alkoxy-CrC3-alkoxy, oxo, CrC3-alkyl, halo-CrC3-alkyl, and CrC3-alkoxy-Ci-C3-alkyl.
[0047] Embodiment 27: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where RD is hydrogen. In another embodiment, RD is Ci-Ci2-alkyl. In yet another embodiment, RD is CrC12- alkyl substituted with aryl or substituted aryl. In a further embodiment, RD is
Figure imgf000024_0001
substituted with heteroaryl or substituted heteroaryl. In one embodiment, RD is
Figure imgf000024_0002
In another embodiment, RD is C(=0) CH2 NH Ci-C2- alkyl. In yet another embodiment, RD is CrCi2-alkyl substituted CrC12-alkoxy. In a further embodiment, RD is CrC12-alkyl substituted CrCi2-thioalkoxy. In yet a further embodiment, RD is CrCi2-alkyl substituted CrC12-alkylamino. In yet a further embodiment, RD is
Figure imgf000024_0003
alkyl.
[0048] Embodiment 28: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where Y is oxygen and R4 is hydrogen. In another embodiment, Z is oxygen and R4 is hydrogen. In yet another embodiment, Y is NH and R4 is hydrogen. In a further embodiment, Z is sulfur and R4 is hydrogen. In yet a further embodiment, Z is oxygen and R4 is CH2NHCH2P03H2. In one embodiment, Y is oxygen and R4 is CH2NHCH2P03H2. In another embodiment, Y is NH and R4 is CH2NHCH2P03H2.
[0049] Embodiment 29: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XIV where R] is hydrogen and R2 is COCHR8NHR]5 where R15 is substituted arylalkyl.
[0050] Embodiment 30: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula VII or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where Al, A2, and A3 are each hydrogen. In a further embodiment of any of the aforementioned embodiments is the method of use where for the Compound of Formula (VIII) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, where Al, A2, and A3 are each hydrogen. In a further embodiment of any of the aforementioned embodiments is the method or use where for the Compound of Formula (IX) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where Al, A2, and A3 are each hydrogen. In a further embodiment of any of the aforementioned embodiments is the method or use where for the Compound of Formula (X) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where Al, A2, and A3 are each hydrogen. In a further embodiment of any of the aforementioned embodiments is the method or use where for the Compound of Formula (XI) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where Al, A2, and A3 are each hydrogen. In a further embodiment of any of the aforementioned embodiments is the method or use where for the Compound of Formula (XII) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where Al, A2, and A3 are each hydrogen.
[00511 Embodiment 31 : In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula X
Figure imgf000025_0001
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0052] Embodiment 32: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula (X) where RA is methyl, RD is hydrogen or C(=0)NH2, and R3 is OH or 2-adamantamino. In another embodiment, Rc is hydrogen,
Figure imgf000025_0002
In a further embodiment, R8 is CrC3alkyl. In yet a further embodiment, R7 is amino, amino-cycloalkyl, or CrCi2alkyl. In another embodiment, Al, A2, and A3 are hydrogen and R4 is CH2NH- CHRi5-(CH2)m-NHS02RB or CH2NH-CHRi5-(CH2)m-NHCONHRB, m is 1 to 6 and R15 is H or loweralkyl. In yet another embodiment, RB is aryl substituted with one or more Ci-Ci2alkyl. In one embodiment, CrC12alkyl is selected from n-butyl, n-pentyl, n-hexyl, n-heptyl, or n-octyl. In a further embodiment, RB is phenyl substituted with n-hexyl at the para position. In another embodiment, A2, A3 and R4 are hydrogen and Al is -C(Z)-NH-RB, -C(Z)NHCHRi5-(CH2)m-NHCONHRB, C(Z)NHCHR15-(CH2)m-RB or -C(Z)NHCHR15-(CH2)m-NHS02RB. In one embodiment, Al is -C(=0)-NH-RB, and RB is C C12alkyl. In yet another embodiment, C[-C12alkyl is n-hexyl, n-heptyl, n-octyl, or n-nonyl. In a further embodiment, Al is C(=0)NHCHR15-(CH2)m-RB, m is 1 or 2 and RB is CrCi2alkyl substituted with C C12alkoxy, CrC3-alkoxy-Ci-C3-alkoxy, or aryl substituted with CrCi2alkoxy. In yet a further embodiment, Al is
Figure imgf000025_0003
m is 4 or 5, R15 is hydrogen, and RB is aryl substituted with C Ci2alkoxy or CrC12alkyl. In one embodiment, Al is C(=0)NHCHR15- (CH2)m-NHCONHRB, m is 4 or 5, Rl5 is hydrogen, and RB is aryl substituted with C Ci2alkyl. In yet a further embodiment, RA is methyl, RD is hydrogen, R3 is OH, A2, A3 and R4 are each hydrogen. [0053] Embodiment 33 : In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula XIII
Figure imgf000026_0001
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
[0054] Embodiment 34: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula (XIII) where RA is methyl, Rc is hydrogen and R3 is OH. In another embodiment, Al, A2, and A3 are hydrogen and R4 is CH2NH-CHRl5-(CH2)m-NHS02RB or CH2NH-CHR15-(CH2)m-NHCONHRB, m is 1 to 6 and R15 is H or loweralkyl. In a further embodiment, RB is selected from aryl substituted with one or more CrCi2alkyl, aryl substituted with one or more Cr CI2alkoxy, or aryl substituted with one or more CrCi2alkylamino.
[0055] Embodiment 35: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is com licated skin and skin structure infection or bacterial pneumonia and the compound is of Formula II, III, VIII or IX, where Ri is hydrogen and R2 are 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 or more optionally substituted aryl, heteroaryl, or condensed rings,
Figure imgf000026_0002
or Ri and R2 together with the atom to which they are attached form a substituted heteroaryl or cycloheterocyclic ring which optionally contains additional heteroatom selected from the group consisting of optionally substituted O, N, and S. In specific embodiments, R2 is hydrogen or methyl substituted with an unsubstituted or substituted biphenyl, for example biphenyl or chloro-biphenyl.
[0056] Embodiment 36: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII, where RA is methyl or hydrogen and V, XI, and XIV and RB is selected from the group consisting of
a) aryl,
b) CrC12-alkyl,
c) C Ci2-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C Ci2-alkoxy, Ci-C3-alkoxy- Ci-C3-alkoxy, amino, C Ci2-alkylamino, Cr dialkylamino, alkenyl, alkynyl, CrCi2-thioalkoxy, d) CrC i2-alkyl substituted with aryl,
e) C i-C i2-alkyl substituted with substituted aryl,
f) CrCi2-alkyl substituted with heteroaryl,
g) C i -C 12-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) heteroaryl,
j) heterocycloalkyl,
k) aryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy,
Figure imgf000027_0001
CrCi2-alkoxy- C Ci2-alkoxy, amino, amino-C C12-alkoxy, CrCi2- alkylamino, Ci-Ci2-alkylamino- C Ci2-alkoxy, Ci-Ci2-dialkylamino, Ci-Ci2-dialkylamino- CrCi2-alkoxy, alkenyl, alkynyl, Ci-Ci2-thioalkoxy, C Ci2-alkyl, C Ci2-substituted alkyl, C Ci2- alkoxy-morpholino, C i -C 12-alkoxy-C C i2-dialkoxyamino, C rC i2-alkoxy-NHS02C rC6alkyl, CrC12-alkoxy-NHCOC C6alkyl, and
1) heteroaryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C Ci2-alkoxy, CrCi2-alkoxy- C Ci2-alkoxy, amino, amino-Ci-Ci2-alkoxy, CpCn- alkylamino, CrCi2-alkylamino-
Figure imgf000027_0002
Ci-Ci2-dialkylamino, C Ci2-dialkylamino- CrCi2-alkoxy, alkenyl, alkynyl, Ci-Ci2-thioalkoxy, C Ci2-alkyl, and C C12-substituted alkyl.
[0057] Embodiment 37: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula II - V and VIII - XI or XIII where R7 is selected from the group consisting of
a) hydrogen,
b) C C12-alkyl,
c) C Ci2-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy,
Figure imgf000027_0003
Ci-C3-alkoxy-C C3-alkoxy, amino, CrCi2-alkylamino, CrC12-dialkylamino, alkenyl, alkynyl,
Figure imgf000027_0004
d) CrC12-alkyl substituted with aryl,
e) CrCi2-alkyl substituted with substituted aryl,
f) C Ci2-alkyl substituted with heteroaryl,
g) < CrC12-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) cycloalkenyl,
j) heterocycloalkyl,
k) amino;
1) CrCi2-alkylamino; and
m) amino-cycloalkyl.
[0058] Embodiment 38: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I where RE is halo or -OR where R is selected from the group consisting of
(1) hydrogen, (2) cycloalkyl,
(3) cycloalkenyl,
(4) C C12-alkyl,
(5) CrCi2-alkyl substituted with one or more substituents selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) CrC12-alkoxy,
(d) CrC3-alkoxy- CrC3-alkoxy,
(e) -COORs where R5 is hydrogen or loweralkyl,
(f) -C(0)NR5R6 where R6 is hydrogen or loweralkyl,
(g) amino,
(h) -NR5R6, where R5 and e are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R5 and Re are taken together with the atom to which they are attached form a 3 - 10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, CrC3-alkoxy, CrC3-alkoxy-CrC3-alkoxy, oxo, CrCi2-alkyl, halo-C C12-alkyl, and CrC3-alkoxy-C Cl2-alkyl,
(i) aryl,
0) substituted aryl,
(k) heteroaryl,
(1) substituted heteroaryl,
(m) mercapto, and
(n) Ci-C)2-thioalkoxy,
(6) -C(=0)ORu, where Ru is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and
(7)
Figure imgf000028_0001
where R]2 is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or Ru and R12 together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, CrC3-alkoxy, CrC3-alkoxy-C]-C3-alkoxy, oxo, C C12-alkyl, substituted loweralkyl, halo-CrCi2-alkyl, amino, alkylamino, dialkylamino, and CrC3- alkoxy-C rC 12-alkyl.
[0059] Embodiment 39: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula VII - XII where at least two of Al, A2, and A3 are hydrogen and where when two of Al, A2, and A3 are hydrogen, the other is -C(Z)-NH-RB, -C(Z)NHCHRi5-(CH2)m-NHCONHRB, -C(Z)NHCHR15-(CH2)m-RB or -C(Z)NHCHRi5-(CH2)m- NHS02RB where m is 1 to 6, and Ri5 is H or loweralkyl. In one embodiment are compounds of Formula VII - XII where Al and A2 are hydrogen and A3 is-C(Z)-NH-RB. In another embodiment, Al and A2 are hydrogen and A3 is -C(Z)NHCHR]5- (CH2)m-NHS02RB. In another embodiment, Al and A2 are hydrogen and A3 is -C(Z)NHCHR,5-(CH2)m-NHCONHRB. In another embodiment, Al and A2 are hydrogen and A3 is -C(Z)NHCHRi5-(CH2)m-RB . In one embodiment are compounds of Formula VII - XII where Al and A3 are hydrogen and A2 is-C(Z)-NH-RB. In another embodiment, Al and A3 are hydrogen and A2 is -C(Z)NHCHRi5-(CH2)m-NHS02RB. In another embodiment, Al and A3 are hydrogen and A2 is -C(Z)NHCHRi5- (CH2)m-NHCONHRB. In another embodiment, Al and A3 are hydrogen and A2 is -C(Z)NHCHR15-(CH2)m-RB . In one embodiment are compounds of Formula VII - XII where A2 and A3 are hydrogen and Al is-C(Z)-NH-RB. In another embodiment, A2 and A3 are hydrogen and Al is -C(Z)NHCHR15-(CH2)m-NHS02RB. In another embodiment, A2 and A3 are hydrogen and Al is -C(Z)NHCHR15-(CH2)m-NHCONHRB. In another embodiment, A2 and A3 are hydrogen and Al is - C(Z)NHCHR15-(CH2)m-RB.
[0060] Embodiment 40: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula V or XI where X is chlorine and » is hydrogen.
[0061] Embodiment 41 : In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula V or XI where X is hydrogen and R4 is hydrogen..
[0062] Embodiment 42: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula VI where Y is oxygen and R4 is hydrogen.
[0063] Embodiment 43 : In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula VI where Y is NH and R4 is hydrogen.
[0064] Embodiment 44: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XII where Z is oxygen and R4 is hydrogen.
[0065] Embodiment 45: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-XII where Z is sulfur and R4 is hydrogen.
[0066] Embodiment 46: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII where RA is methyl and R4 is hydrogen.
[0067] Embodiment 47: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII where RA is hydrogen and R4 is hydrogen.
[0068] Embodiment 48: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII where RA is methyl or hydrogen and R3 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 -loweralky lamino- 1 -adamantanamino,
(7) 1 -loweralky lamino-3 -adamantanamino,
(8) amino, and
(9) -NR13R14 where R]3 and R,4 are each independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl, aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy; or R]3 and RM together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C3-alkoxy, Ci-C3-alkoxy-Ci-C3-alkoxy, oxo, CrCi2-alkyl, substituted loweralkyl, halo-C Ci2-alkyl, amino, alkylamino, dialkylamino, and CrC3- alkoxy-Ci-Ci2-alkyl.
[0069] Embodiment 49: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula I-IV, VI-X, XII or XIII where RA is methyl or hydrogen and R4 is selected from the group consisting of
(1) -CH2NH-CHR15-(CH2)m-NHS02RB, where m is 1 to 6 and R15 is H or loweralkyl,
(2) -CH2NH- CHR15 -(CH2)p-CONHS02RB, where p is 0 to 6 and R)5 is H or loweralkyl,
(3) -CH2NH- CHRi5-(CH2)m-0-(CH2)r HS02 B, where m is 1 to 6, f is 1 to 6 and R15 is H or loweralkyl,
(4) -CH2NRF-CHR15-(CH2)q-NRGS02RB, where q is 2 to 4, RL5 is H or loweralkyl, RF and RQ are independently hydrogen, lower alkyl or taken together represents a -CH2-,
(5) H,
(6) -CH2NH-CHR15-(CH2)m-NHCONHRB, where m is 1 to 6 and R15 is H or loweralkyl,
(7) -CH2NHCH2P03H2,
(8) aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy,
(9) -CH2NH-CHR,5-(CH2)p-NHCORB, where p is 0 to 6 and R15 is H or loweralkyl,
( 10) -CH2NH-CHR,5-(CH2)p-CONHRB, where p is 0 to 6 and R15 is H or loweralkyl, and
(11) -CH2NH- CHR15-(CH2)m-0-(CH2)rNHCONHRB, where m is 1 to 6, f is 1 to 6 and R15 is H or loweralkyl.
[0070] Embodiment 50: In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is of Formula XIII or XIV where R4 is selected from the group consisting of hydrogen, CH2NH-CHR15-(CH2)m-NHS02RB, where m is 1 to 6 and R15 is H or loweralkyl, hydrogen, CH2NH-CHR15-(CH2)m-NHCONHRB, where m is 1 to 6 and RL5 is H or loweralkyl, CH2NRF-CHR15-(CH2)q-NRGS02RB where q is 2 to 4 and RL5 is H or loweralkyl, or CH2NH-CHR15-(CH2)m-0- (CH2)rNHS02RB, where m is 1 to 6 and f is 1 to 6 and R15 is H or loweralkyl, RF and RQ are independently hydrogen, lower alkyl or taken together represents a -CH2-.
[0071] Embodiment 51 : In a further embodiment of any of the aforementioned embodiments, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the compound is selected from Compound (23). Compound (24). Compound (25). Compound (26). Compound (27). Compound (28). Compound (29). Compound (30). Compound (31). Compound (32). Compound (33). Compound (34). Compound (47). Compound (49).
Compound (64). Compound (64A). Compound (65). Compound (66). Compound (67). Compound (68). Compound (69).
Compound (70). Compound (71). Compound (72). Compound (73). Compound (74). Compound (75). Compound (76).
Compound (77). Compound (78). Compound (79). Compound (80). Compound (81). Compound (82). Compound (83).
Compound (84). Compound (85). Compound (86). Compound (87). Compound (88). Compound (104). Compound (105).
Compound (106). Compound (107). Compound (108). Compound (109). Compound (110). Compound (111). Compound (112). Compound (113). Compound (114). Compound (115). Compound (116). Compound (117). Compound (118).
Compound (120). Compound (121). Compound (122). Compound (123). Compound (125). Compound (131). Compound (132). Compound (133). Compound (134). Compound (135). Compound (136). Compound (137). Compound (138).
Compound (139). Compound (140). Compound (141). Compound (143). Compound (144). Compound (145). Compound (146). Compound (147). Compound (148). Compound (149). Compound (150). Compound (151). Compound (152).
Compound (153). Compound (154). Compound (155). Compound (156). Compound (157). Compound (158). Compound (159). Compound (160). Compound (161). Compound (184). Compound (185). Compound (186). Compound (187).
Compound (188). Compound (188). Compound (190). Compound (191). Compound (192). Compound (193). Compound (194). Compound (195). Compound (196). Compound (197). Compound (198). Compound (199). Compound (200).
Compound (201). Compound (202). Compound (203). Compound (204). Compound (205). Compound (206). Compound (207). Compound (208). Compound (209). Compound (210). Compound (211). Compound (212). Compound (213).
Compound (214). Compound (215). Compound (216). Compound (217). Compound (218). Compound (219). Compound (220). Compound (221). Compound (222). Compound (248). Compound (249). Compound (250). Compound (251).
Compound (252). Compound (253). Compound (254). Compound (255). Compound (256). Compound (257). Compound (258). Compound (259). Compound (260). Compound (261). Compound (262). Compound (263). Compound (264).
Compound (265). Compound (266). Compound (267). Compound (268). Compound (269). Compound (270). Compound (271). Compound (272). Compound (273). Compound (274). Compound (275). Compound (276). Compound (277).
Compound (279). Compound (280). Compound (281). Compound (282). Compound (283). Compound (284). Compound (285). Compound (286). Compound (287). Compound (289). Compound (290). Compound (291). Compound (292).
Compound (293). Compound (294). Compound (295). Compound (296). Compound (299). Compound (301). Compound (302). Compound (303). Compound (304). Compound (305). Compound (306). Compound (307). Compound (308).
Compound (309). Compound (310). Compound (311). Compound (312). Compound (313). Compound (314). Compound (315). Compound (316). Compound (317). Compound (218). Compound (319). Compound (320). Compound (321).
Compound (322). Compound (323). Compound (324). Compound (325). Compound (326). Compound (327). Compound (328). Compound (329). Compound (330). Compound (331 . Compound (332). Compound (333). Compound (334).
Compound (335). Compound (336). Compound (337). Compound (338). Compound (339). Compound (340). Compound (341). Compound (342). Compound (343). Compound (344). Compound (345). Compound (346). Compound (347).
Compound (348). Compound (349). Compound (350). Compound (351). Compound (352). Compound (353). Compound (354). Compound (355). Compound (356). Compound (357). Compound (358). Compound (359). Compound (360).
Compound (361). Compound (362). Compound (363). Compound (365). Compound (366). Compound (367). Compound (368). and Compound (370).
[0072] Embodiment 52: In a further embodiment of any embodiments 1-31, the method or use is where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia and the bacterial strain is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL-137. In a further embodiment, the method or use is where the bacterial strain is Staphylococcus aureus 2E5 CFU ATCC 13709 and the compound is
Figure imgf000032_0001
. In a further embodiment, the method or use is where the bacterial strain is methicillin-resistant Staphylococcus aureus VL-137 and the compound is
Figure imgf000032_0002
[0073] In another embodiment is a method of treating a bacterial infection in a mammal where the bacterial strain to be treated is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL-137 comprising administering a therapeutically acceptable amount of a compound having a structure of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV as described in the Summary of the Invention or in any of embodiments 1-52 as a pharmaceutical composition comprising the Compound of any of Formula I-XIV together with a pharmaceutically acceptable carrier.
[0074] In another aspect, is use of a compound having a structure of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV as described in the Summary of the Invention or in any of embodiments 1-52 as a pharmaceutical composition comprising the Compound of any of Formula I-XIV together with a pharmaceutically acceptable carrier, for treating a bacterial infection in a mammal where the bacterial strain to be treated is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL- 137.
[0075] In another aspect, is use of a compound having a structure of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV as described in the Summary of the Invention or in any of embodiments 1-52 as a pharmaceutical composition comprising the Compound of any of Formula I-XIV together with a pharmaceutically acceptable carrier, in the formulation of a medicment for the treatment of a bacterial infection in a mammal where the bacterial strain to be treated is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL-137.
|0076] In another aspect, described herein are articles of manufacture, comprising packaging material, a compound of any of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII or Formula XIV as described in the Summary of the Invention or in any of embodiments 1-52 which is effective for treatment, prevention or amelioration of one or more symptoms of a bacterial- mediated disease or condition where the bacterial strain to be treated is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL-137, 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.
[0077] Embodiment 53: In another embodiment is a method of treating a gram-positive bacterial infection in a mammal comprising f
Figure imgf000033_0001
Figure imgf000034_0001
[0078] In another aspect, is use of a compound (303). (309). or (311). for treating a mammal having a gram-positive bacterial infection.
[0079] In another aspect, is use of a compound (303). (309). or (311). in the formulation of a medicament for the treatment of a mammal having a gram-positive bacterial infection.
[0080] Embodiment 54: In an further embodiment of embodiment 53, the method or use is that where the infection is bacteremia, complicated intra-abdominal infection, complicated skin and skin structure infection, or bacterial pneumonia. A futher embodiment is that where the infection is complicated skin and skin structure infection or bacterial pneumonia. A further embodiment is that where t he bacterium to be treated is resistant or refractory to a beta-lactam antibiotic, vancomycin, desmethylvancomycin, eremomycin, teicoplanin, dalbavancin, oritavancin, telavancin, or A82846B
(LY264826).
[0081] Embodiment 55: A further embodiment of any of the embodiments in embodiments 53 and 54 is that where the compound is administered as a pharmaceutical composition which comprises a therapeutically effective amount of a compound, together with a pharmaceutically acceptable carrier, diluent or excipient.
Methicillin-Resistant Staphylococcus aureus
[0082] In one aspect is a method for treating a subject having a resistant bacterium comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof. In one embodiment, the bacterium is a Gram-positive bacteria. In another embodiment, the Gram-positive bacterium is S. aureus. In further embodiment, the S. aureus is resistant or refractory to a beta-lactam antibiotic. In yet a further embodiment, the beta-lactam antibiotic belongs to the class of penicillins. In a further embodiment, the beta-lactam antibiotic is methicillin. In yet another embodiment, the subject has a methicillin-resistant S. aureus bacteria. In one embodiment the beta-lactam antibiotic is flucloxacillin. In another embodiment is a method for treating a subject having a dicloxacillin-resistant bacteria comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to dicloxacillin. Also disclosed herein is a method for treating a subject having a methicillin-resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject has been determined to have a methicillin-resistant bacteria. In one embodiment the subject is screened for methicillin-resistant bacteria. In another embodiment, the subject screening is performed through a nasal culture. In a further embodiment the methicillin-resistant bacteria is detected by swabbing the nostril(s) of the subject and isolating the bacteria. In another embodiment, Real-time PCR and/or Quantitative PCR is employed to determine whether the subject has a methicillin- resistant bacteria.
[0083] In one embodiment is a method for treating a subject having a first-generation cephalosporin-resistant bacteria comprising administering compound (303). (309), or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to a first-generation cephalosporin. In one embodiment, the bacteria is resistant to a first-generation cephalosporin. In a further embodiment, the bacteria is resistant to cefacetrile. In another embodiment, the bacteria is resistant to cefadroxil. In yet another embodiment, the bacteria is resistant to cefalexin. In one embodiment, the bacteria is resistant to cefaloglycin. In another embodiment, the bacteria is resistant to cefalonium. In another embodiment, the bacteria is resistant to cefaloridine. In yet another embodiment, the bacteria is resistant to cefalotin. In a further embodiment, the bacteria is resistant to cefapirin. In yet a further embodiment, the bacteria is resistant to cefatrizine. In one embodiment, the bacteria is resistant to cefazaflur. In another embodiment, the bacteria is resistant to cefazedone. In yet another embodiment, the bacteria is resistant to cefazolin. In a further embodiment, the bacteria is resistant to cefradine. In yet a further embodiment, the bacteria is resistant to cefroxadine. In one embodiment, the bacteria is resistant to ceftezole.
[0084] In one embodiment is a method for treating a subject having a second-generation cephalosporin-resistant bacteria comprising administering compound (303), (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to a second-generation cephalosporin. In another embodiment, the bacteria is resistant to a second-generation cephalosporin. In a further embodiment, the bacteria is resistant to cefaclor. In another embodiment, the bacteria is resistant to cefonicid. In yet another embodiment, the bacteria is resistant to cefprozil. In one embodiment, the bacteria is resistant to cefuroxime. In another embodiment, the bacteria is resistant to cefuzonam. In another embodiment, the bacteria is resistant to cefmetazole. In yet another embodiment, the bacteria is resistant to cefotetan. In a further embodiment, the bacteria is resistant to cefoxitin.
[0085] In one embodiment is a method for treating a subject having a third-generation cephalosporin-resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to a third-generation cephalosporin. In another embodiment, the bacteria is resistant to a third-generation cephalosporin. In a further embodiment, the bacteria is resistant to cefcapene. In another embodiment, the bacteria is resistant to cefdaloxime. In yet another embodiment, the bacteria is resistant to cefdinir. In one embodiment, the bacteria is resistant to cefditoren. In another embodiment, the bacteria is resistant to cefixime. In another embodiment, the bacteria is resistant to cefmenoxime. In yet another embodiment, the bacteria is resistant to cefodizime. In a further embodiment, the bacteria is resistant to cefotaxime. In yet a further embodiment, the bacteria is resistant to cefpimizole. In one embodiment, the bacteria is resistant to cefpodoxime. In another embodiment, the bacteria is resistant to cefteram. In yet another embodiment, the bacteria is resistant to ceftibuten. In a further embodiment, the bacteria is resistant to ceftiofur. In yet a further embodiment, the bacteria is resistant to ceftiolene. In one embodiment, the bacteria is resistant to ceftizoxime. In another embodiment, the bacteria is resistant to ceftriaxone. In yet another embodiment, the bacteria is resistant to cefoperazone. In yet a further embodiment, the bacteria is resistant to ceftazidime.
[0086] In one embodiment is a method for treating a subject having a fourth-generation cephalosporin-resistant bacteria comprising administering compound (303), (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to a fourth-generation cephalosporin. In another embodiment, the bacteria is resistant to a fourth-generation cephalosporin. In a further embodiment, the bacteria is resistant to cefclidine. In another embodiment, the bacteria is resistant to cefepime. In yet another embodiment, the bacteria is resistant to cefluprenam. In one embodiment, the bacteria is resistant to cefoselis. In another embodiment, the bacteria is resistant to cefozopran. In another embodiment, the bacteria is resistant to cefpirome. In yet another embodiment, the bacteria is refractory to cefquinome.
[0087] In one embodiment is a method for treating a subject having a carbapenem-resistant bacteria comprising administering compound (303), (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the subject is refractory to a carbapenem. In another embodiment, the bacteria is resistant to a carbapenem. In a further embodiment, is a method for treating a subject having a imipenem-resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to imipenem. In another embodiment, is a method for treating a subject having a meropenem-resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to meropenem. In yet another embodiment, is a method for treating a subject having a ertapenem -resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to ertapenem. In one embodiment, is a method for treating a subject having a faropenem-resistant bacteria comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to faropenem. In another embodiment, is a method for treating a subject having a doripenem -resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to doripenem. In another embodiment, is a method for treating a subject having a panipenem -resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to panipenem. In yet another embodiment, is a method for treating a subject having a biapenem -resistant bacteria comprising administering compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacteria is resistant to biapenem.
[0088] In another aspect, is use of a compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, for treating a subject having a methicillin- resistant bacteria.
[0089] In another aspect, is use of a compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, in the formulation of a medicament for the treatment of a subject having a methicillin-resistant bacteria. Vancomycin-Intermediate and Vancomycin-Resistant Staphylococcus aureus
[0090] As used herein, the term "minimum inhibitory concentration" (MIC) refers to the lowest concentration of an antibiotic that is needed to inhibit growth of a bacterial isolate in vitro. A common method for determining the MIC of an antibiotic is to prepare several tubes containing serial dilutions of the antibiotic, that are then inoculated with the bacterial isolate of interest. The MIC of an antibiotic is determined from the tube with the lowest concentration that shows no turbidity (no growth).
[0091] In one aspect is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacterial infection comprises a vancomycin-intermediate Staphylococcus aureus bacterium. In one embodiment, is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the vancomycin-intermediate Staphylococcus aureus bacterium has a MIC of between about 4 to about 8 μg/mL. In another embodiment, is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the vancomycin- intermediate Staphylococcus aureus bacterium has a MIC of about 4 μg/mL. In yet another embodiment, is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the vancomycin-intermediate Staphylococcus aureus bacterium has a MIC of about 5 μg/mL. In a further embodiment, is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the vancomycin-intermediate Staphylococcus aureus bacterium has a MIC of about 6 μg/mL. In yet a further embodiment, is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the vancomycin-intermediate Staphylococcus aureus bacterium has a MIC of about 7 μg/mL. In one embodiment, is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the vancomycin-intermediate Staphylococcus aureus bacterium has a MIC of about 8 μg/mL.
[0092] In another aspect is a method of treating a subject having a bacterial infection comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the bacterial infection comprises a vancomycin-resistant
Staphylococcus aureus bacterium. In one embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of between about 16 μξ/ι ί,. In another embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of about > 16 μg/mL. In yet another embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of about 20 μξ/ηύ^. In a further embodiment, the vancomycin-resistant Staphylococcus aureus bacterium has a MIC of about 25 μg/mL.
[0093] In another aspect, is use of a compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, for treating a subject having a bacterial infection, where the bacterial infection comprises a vancomycin-intermediate or vancomycin-resistant Staphylococcus aureus bacterium.
[0094] In another aspect, is use of a compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, in the formulation of a medicament for the treatment of a subject having a bacterial infection, where the bacterial infection comprises a vancomycin-intermediate or vancomycin-resistant Staphylococcus aureus bacterium.
[0095] In one embodiment, conditions treated by the compounds described herein include, but are not limited to, endocarditis, osteomyelitis, neningitis, skin and skin structure infections, genitourinary tract infections, abscesses, and necrotizing infections. In another embodiment, the compounds disclosed herein are used to treat conditions, such as, but not limited to, diabetic foot infections, decubitus ulcers, burn infections, animal or human bite wound infections, synergistic- necrotizing gangrene, necrotizing fascilitis, intra-abdominal infection associated with breeching of the intestinal barrier, pelvic infection associated with breeching of the intestinal barrier, aspiration pneumonia, and post-operative wound infections. In another embodiment, the conditions listed herein are caused by, contain, or result in the presence of VISA and/or VRSA.
Vancomycin-Resistant Enterococci
[0096] In one aspect, is a method of treating a subject having a vancomycin-resistant enterococci comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the enterococci has developed resistance to vancomycin. In one embodiment, the subject has been previously treated with vancomycin for a sustained period of time. In another embodiment, the subject has been hospitalized. In yet another embodiment, the subject has a weakened immune system such as patients in Intensive Care Units or in cancer or transplant wards. In a further embodiment, the subject has undergone surgical procedures such as, for example, abdominal or chest surgery. In yet a further embodiment, the subject has been colonized vith VRE. In one embodiment, the subject has a medical device such that an infection has developed. In another embodiment, the medical device is a urinary catheter or central intravenous (IV) catheter.
[0097] In another embodiment, is a method of treating a subject having a vancomycin-resistant enterococci comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the enterococcus has Van-A resistance.
[0098] In another embodiment, is a method of treating a subject having a vancomycin-resistant enterococci comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the enterococcus has Van-B resistance.
[0099] In another embodiment, is a method of treating a subject having a vancomycin-resistant enterococci comprising administering to the subject compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof where the enterococcus has Van-C resistance.
[00 00] In another aspect, is use of a compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, for treating a subject having a vancomycin- resistant enterococci.
[00101] In another aspect, is use of a compound (303). (309). or (311) or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof, in the formulation of a medicament for the treatment a subject having a vancomycin-resistant enterococci. Definitions
[00102] Unless otherwise noted, terminology used herein should be given its normal meaning as understood by one of skill in the art.
[00103] The term "alkyl" as used herein refers to saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom.
[00104] The term substituted alkyl as used herein refers to alkyl substituted by one, two or three groups consisting of halogen, alkoxy, amino, alkylamino, dialkylamino, hydroxy, aryl, heteroaryl, alkenyl or alkynyl group.
[00105] The term "alkenyl" as used herein refers to unsaturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between two and twenty carbon atoms by removal of a single hydrogen atom.
[00106] 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.
[00107] The term substituted cycloalkyl as used herein refers to cycloalkyl substituted by one, two or three groups consisting of halogen, alkoxy, amino, alkylamino, dialkylamino, hydroxy, aryl, heteroaryl, alkenyl or alkynyl groups.
[00108] 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.
[00109] The terms "CrC3-alkyl", "CrC6-alkyl", and "CrCi2-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 Ci-C3-alkyl radicals include methyl, ethyl, propyl and isopropyl. Examples of C C6-alkyl radicals include, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl. Examples of Ci-Ci2-alkyl 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.
[00110] The term loweralkyl as used herein refers to Ci-Ci2-alkyl as defined above.
[00111] The term substituted loweralkyl as used herein refers to CrCi2-alkyl substituted by one, two or three groups consisting of halogen, alkoxy, amino, alkylamino, dialkylamino, hydroxy, aryl, heteroaryl, alkenyl or alkynyl groups.
[00112] The term "C3-Ci2-cycloalkyl" denoted a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by removal of a single hydrogen atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.
[00113] The terms "Ci-C3-alkoxy", "CrC6-alkoxy" as used herein refers to the C C3-alkyl group and Ci-C6-alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples of C C6-alkoxy radicals include, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
[00114] The term "loweralkylamino" as used herein refers to Ci-Ci2-alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. Examples of loweralkylamino include, but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, propylamino and decylamino.
[00115] The term "oxo" denotes a group where 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).
[00116] The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like and is optionally un- substituted or substituted (including bicyclic aryl groups) with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, Ci-Ci2-alkoxy, thioalkoxy, CrC12-thioalkoxy, aryloxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
[00117] The term "substituted aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like substituted (including bicyclic aryl groups) with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, CrCi2-alkoxy, thioalkoxy, CrCi2-thioalkoxy, alkoxyalkylalkoxy, aryloxy, amino, aminoalkyl, aminoalkylalkoxy, alkylamino, alkylaminoalkyl, alkylaminoalkylalkoxy, dialkylamino, dialkylaminoalkyl,
dialkylaminoalkylalkoxy, acylamino, cyano, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, aryl, heteroaryl, heterocycloaryl and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
[00118] The term "arylalkyl" as used herein refers to an aryl group as defined above attached to the parent molecular moiety through an alkyl group where the alkyl group is of one to twelve carbon atoms.
[00119] The term "substituted arylalkyl" as used herein refers to a substituted aryl group as defined above attached to the parent molecular moiety through an alkyl group where the alkyl group is of one to twelve carbon atoms.
[00120] The term "alkylaryl" as used herein refers to an alkyl group as defined above attached to the parent molecular moiety through an aryl group.
[00121] The term "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
[00122] The term "alkylamino" refers to a group having the structure -NHR' where R' is alkyl, as previously defined. Examples of alkylamino include methylamino, ethylamino, iso-propylamino, and the like.
[00123] The term "dialkylamino" refers to a group having the structure -NHR'R" where R' and R" are independently selected from alkyl, as previously defined. Additionally, R' and R" taken together optionally be -(CH2)k- where k is an integer of from 2 to 6. Examples of dialkylamino include dimethylamino, diethylamino, methylpropylamino, piperidino, and the like.
[00124] 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.
[00125] 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.
[00126] The term "thioalkoxy" refers to an alkyl group previously defined attached to the parent molecular moiety through a sulfur atom.
[00127] The term "carboxaldehyde" as used herein refers to a group of formula -CHO.
[00128] The term "carboxy" as used herein refers to a group of formula -C02H.
[00129] The term "carboxamide" as used herein refers to a group of formula -CONHR'R" where R' and R" are independently selected from hydrogen, alkyl, substituted loweralkyl, or R' and R" taken together optionally be -(CH2)k- where k is an integer of from 2 to 6.
[00130] The term "heteroaryl", as used herein, refers to a cyclic or bicyclic aromatic radical having from five to ten ring atoms in each ring 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 ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, naphthyridinyl; and the like.
[00131] The term "substituted heteroaryl" as used herein refers to a cyclic or bicyclic aromatic radical having from five to ten ring atoms in each ring 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 ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, naphthyridinyl; and the like substituted with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, C C12-alkoxy, thioalkoxy, CrCi2-thioalkoxy, alkoxyalkylalkoxy, aryloxy, amino, aminoalkyl, aminoalkylalkoxy, alkylamino, alkylaminoalkyl, alkylaminoalkylalkoxy, dialkylamino, dialkylaminoalkyl, dialkylaminoalkylalkoxy, acylamino, cyano, hydroxy, halogen, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, aryl, heteroaryl, heterocycloaryl and carboxamide.
[00132] The term "heterocycloalkyl" as used herein, refers to a non-aromatic partially unsaturated or fully saturated 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- or tri-cyclic ring systems which includes 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 be oxidized and the nitrogen heteroatom optionally be quaternized. Representative heterocycloalkyl rings include, but not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
[00133] The term "heteroarylalkyl" as used herein, refers to a heteroaryl group as defined above attached to the parent molecular moiety through an alkylene group where the alkylene group is of one to four carbon atoms.
[00134] "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. 2nd edition, John Wiley & Sons, New York (1991). Examples of hydroxy-protecting groups include, but not limited to, methylthiomethyl, 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).
[00135] A term "protected-hydroxy" refers to a hydroxy group protected with a hydroxy protecting group, as defined above.
[00136] The term amino acid refers to amino acids having D or L stereochemistry, and also refers to synthetic, non-natural amino acids having side chains other than those found in the 20 common amino acids. Non-natural amino acids are commercially available or are optionally prepared according to US 5,488,131 and references therein. Amino acids are optionally further substituted to contain modifications to their amino, carboxy, or side-chain groups. These modifications include the numerous protecting group commonly used in peptide synthesis (T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley & Sons, New York, 1991).
[00137] 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 CI, Br, F, I, OH, CN, C C12- alkoxy, CrC12-alkoxy substituted with aryl, haloalkyl, thioalkyl, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substituent is optionally an aryl, heteroaryl, or heterocycloalkyl group.
[00138] 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 CI, Br, F, I, OH, CN, CrC,2- alkyl, C Ci2-alkoxy, CrC12-alkoxy substituted with aryl, haloalkyl, thioalkyl, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substituent is optionally aryl, heteroaryl, or heterocycloalkyl group.
[00139] The term "phenolic regioiosmer" as used herein, refers to either of the three possible isomers of a compound having the same molecular weight with the substituent attached to one of the phenolic alcohols of the glycopeptide derivatives illustrated by either structure (A), (B) or (C).
rest of glycopeptide skeleton rest of glycopeptide skeleton rest of glycopeptide skeleton
Figure imgf000042_0001
[00140] 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. If asymmetric centers exist in the described compounds, except where otherwise noted, the compounds described herein include 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 present.
[00141] The term "tautomer" as used herein refers to either of the two forms of a chemical compound that exhibits tautomerism, 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.
[00142] 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 herein by reference for this purpose. The salts are prepared in situ during the final isolation and purification of the compounds described herein, 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, succinic acid or malonic acid or by using other documented methodologies 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, nicotinate, 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 counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
[00143| 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.
[00144] 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.
[00145] 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 halide to form alkyl quaternary ammonium salt.
[00146] The term "pharmaceutically acceptable prodrugs" refers to those prodrugs of the compounds described herein 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 zwitterionic 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 in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 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 for this purpose.
[00147] A "beta-lactam antibiotic" includes, but is not limited to, penicillin, methicillin, dicloxacillin, flucloxacillin, first generation cephalosporins (such as cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefradine, cefroxadine, and ceftezole), second generation cephalosporins (such as cefaclor, cefonicid, cefprozil, cefuroxime, cefuzonam, cefmetazole, cefotetan, and cefoxitin), third generation cephalosporins (such as cefcapene, cefdaloxime, cefdinir, cefditoren, cefixime, cefmenoxime, cefodizime, cefotaxime, cefpimizole, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, cefoperazone, and ceftazidime), fourth generation cephalosporins (such as cefclidine, cefepime, cefluprenam, cefoselis, cefozopran, cefpirome, and cefquinome), and carbapenem antibiotics (such as imipenem, meropenem, ertapenem, faropenem, doripenem, panipenem, and biapenem). Synthetic Methods
[00148] The semi-synthetic glycopeptides described herein are based on hydrolysis of the disaccharide moiety of the amino acid-4 of the parent glycopeptide to monosaccharide; conversion of the monosaccharide to the amino-sugar; acylation of the amino substituent on the amino-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. Key reaction is the treatment of properly protected intermediate compound with isocyanate or carrying a Hofmann degradation of the primary amide of the 3 rd amino acid asparagines with phenyl-bis-trifluoroacetate to give the primary amine.
[00149] Synthesis of the compounds described herein is broadly summarized as follows. The compounds described herein are made, for example, 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 chemical modification of Compound A, Compound B, Compound H and Compound C or of the monosaccharide of glycopeptides made by subjecting the parent glycopeptide in acidic medium to hydrolyze the disaccharide moiety of the amino acid-4 of the parent glycopeptide to give the monosaccharide; protection of the amino function by t-butoxycarbonyl group, carbobenzyloxy group, p- nitrocarbobenzyloxy group or allyloxycarbonyl group; conversion of the acid moiety on the macrocyclic ring of these scaffolds to certain substituted amides and treatment of the compound with isocyante. Alternatively, if amino function on the monosaccharide is required, in some embodiments, conversion of the monosaccharide to the amino-sugar derivative;
acylation of the amino substituent on the amino-substituted sugar moiety on these scaffolds with certain acyl groups;
protection of the amino function by t-butoxycarbonyl group, carbobenzyloxy group, p-nitrocarbobenzyloxy group or allyloxycarbonyl group; conversion of the acid moiety on the macrocyclic ring of these scaffolds to certain substituted amides and treatment of the compound with isocyante. The compounds described herein are made, for example, by coupling the amino-sugar moiety of functionalized or unfunctionalized 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 substituent on the amino-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, a-amino acid or β-amino acids or derivatives thereof, and conversion of the acid moiety on the macrocyclic ring of this scaffold to certain substituted amides. In another series, the compounds described herein are made, for example, 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 chemical modification of Compound A, Compound B, Compound H and Compound C or of the monosaccharide of the about glycopeptides made by subjecting the appropriate protected glycopeptide to a Mannich reaction with formaldehyde and an amine followed by de-protection. In some embodiments, synthesis of compounds also involves the use of protecting or blocking groups in order to maximize yields, minimize unwanted side products, or improve purification.
[00150] In particular, the semi-synthetic glycopeptides of the compounds described herein are made, for example, by modifying Compound A, Compound B, Compound H and Compound C scaffolds. The glycopeptide starting material is optionally unsubstituted or substituted at the 7th amino acid at the 4' position of the phenyl ring with CH2NHCH2PO3H2, or aminoloweralkyl as defined herein.
[00151] Selective hydrolysis of Compound A, Compound B, Compound H or Compound C in which the 7th amino acid at the 4' position of the phenyl ring substituted with hydrogen, CH2NHCH2PO3H2, or aminoloweralkyl as defined herein with acid gives the monosaccharide intermediate.
[00152] In general, compound of Formulas I-XIV, described herein are made by
Figure imgf000045_0001
where RA is hydrogen or methyl, X is chlorine or hydrogen, R3 is alkoxy, 2-adamantanamino, or loweralkylamino, or R4 is hydrogen or properly protected CH2NHCH2P03H2, or Boc-aminoloweralkyl, or PG is nitrogen protecting group by a technique selected from the group consisting of,
(a) acylating the primary amide group of the 3rd amino acid asparagine with an RB-isocyanate or RB- thioisocyanate in the presence of a base such as 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and the like; or acylating the phenolic alcohol with an RB-isocyanate or RB-thioisocyanate or OCN-CHR15- (CH2)m-NHS02RB, in the presence of a base such as dimethylaminopyridine (DMAP) and the like; or performing a Mannich reaction with the phenolic alcohol in the presence of formaldehyde and NH2 -CHRl5-(CH2)m-NHS02RB,
(b) removing the Boc protecting group with mild acid such as trifluoroacetic acid, or other nitrogen
protecting group with appropriate deprotection methodology,
(c) removing the alkoxy group by mild base or acid hydrolysis to give the carboxylic acid derivative when R3 is alkoxy,
(d) reducing the azide functional group to an amine,
(e) alkylating the primary alcohol of the mono-sugar or the amino substituent on the amino-substituted sugar moiety of the 4th amino acid of the compound with an alkyl halide having the structure RrJ where J is a halogen or Rc-J where J is a halogen
(f) acylating the primary alcohol of the mono-sugar or the amino substituent on the amino-substituted sugar moiety of the 4th amino acid of the compound with an acyl group having the structure -C(=0)R7,
(g) acylating the primary alcohol of the mono-sugar or the amino substituent on the amino-substituted sugar moiety of the 4th amino acid of the compound with an acyl group having the structure, C(=O)CHR8NR9R10,
(h) reacting the amino substituent on the amino-substituted sugar moiety of the 4th amino acid of the compound with an aldehyde or ketone followed by reductive amination of the resulting imine,
(i) converting the acid moiety on the macrocyclic ring of the compound with substituted amide as defined by R3,
(j) performing a phosgene reaction on the primary alcohol or primary amine of the mono- sugar moiety of the 4 h amino acid of the compound with the adjacent hydroxyl group,
(k) performing a dipolar cycloaddition of the azide with alkyne to form a 1,2,3-trizole,
(1) a combination of (a) and (b),
(m) a combination of (a), (b) and (c),
(n) a combination of (a), (c), (i) and (b),
(o) a combination of (a), (e), and (b),
(p) a combination of (a), (f) and (b),
(q) a combination of (a), (g) and (b),
(r) a combination of (a), (h) and (b),
(s) a combination of (a), (d) and (b),
(t) a combination of (a), (d), (c) and (b), (u) a combination of (a .'), (c), (i), (d)and(b), (v) a combination of (a .), (c), (d) and(b),
(w) a combination of (a^ ), (c), (i),(d), (e)and(b),
(x) a combination of (a^ ), (c), (i), (d), (f)and(b),
(y) a combination of (a^ ), (c), (i),(d), (g)and(b),
(z) a combination of (a ), (c), (i), (d), (h) and (b),
(aa) a combination of (a ), (c), (d), (e)and(b),
(bb)a combination of (a^ ), (c), (d), (f)and(b),
(cc) a combination of (a ), (c), (d), (g) and (b),
(dd)a combination of (a ), (c), (d), (h)and(b),
(ee) a combination of (a^ ),G), and(b),
(ff) a combination of (a ),0), (c), (i)and(b),
(gg) a combination of (a ), (d),(j),and(b),
(hh) a combination of (a^ ), (d),0), (c), (i)and(b),
(ii) a combination of (a ), (k),and(b),
(jj) a combination of (a ),(k), (c), (i) and(b),
a compound having a formula selected from the group consisting of:
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
where R, Rh R2, R3, R4, RA, RB, RC, ¾>, Al, A2, A3, X , Y, and Z are as defined herein.
[00153] In particular, the semi-synthetic glycopeptides described herein are made, for example, by modifying Compound A, Compound B, Compound H or Compound C scaffolds. These natural glycopeptide starting materials are optionally unsubstituted or substituted at R4 with CH2NHCH2PO3H2, or aminoloweralkyl as defined herein.
[00154] Substitutions at R4 are introduced, for example, via a Mannich reaction where the glycopeptide is treated with an amine and formaldehyde under basic conditions (for example, as described in The Journal of Antibiotics, Vol. 50, No. 6, p. 509-513).
Pharmaceutical Compositions
[00155] Pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein 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 serve as pharmaceutically acceptable carriers 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; isotonic saline; 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 are also present in the composition, according to the judgment of the formulator. The pharmaceutical compositions described herein are administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, 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.
[00156] 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 such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, 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 optionally also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[00157] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions are formulated using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation are 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 optionally employed as a solvent or suspending medium. For this purpose any bland fixed oil is optionally employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[00158] The injectable formulations are sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which is dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
[00159] 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 accomplished, for example, 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, depends upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is 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-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release is optionally controlled.
Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared, for example, by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
[00160| Compositions for rectal or vaginal administration are preferably suppositories which are optionally prepared by mixing the compounds described herein 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.
[00161] 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 dicalcium 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, polyvinylpyrrolidinone, 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 bentonite 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 comprises buffering agents.
[00162] 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 and the like.
[00163] The solid dosage forms of tablets, dragees, capsules, pills, and granules are prepared, for example, with coatings and shells such as enteric coatings and other documented coatings. They optionally contain opacifying agents and also are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which are used include polymeric substances and waxes.
[00164] 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 and the like.
[00165] The active compounds are optionally in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules are optionally prepared with coatings and shells such as enteric coatings, release controlling coatings and other documented coatings. In such solid dosage forms the active compound is admixed, for example, with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms optionally comprise additional substances other than inert diluents, e.g., tableting lubricants and other tableting 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 contain opacifying agents and are of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which are used include polymeric substances and waxes.
[00166] 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 required. Ophthalmic formulations, ear drops, and the like are also contemplated.
[00167] The ointments, pastes, creams and gels optionally 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, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
[00168] Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are nebulized, for example, predominantly into particle sizes that are 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 in 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.
[00169 ] Aerosolized formulations described herein are delivered, for example, 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 osmolality ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the compounds described herein 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.
[00170] Aerosolization devices suitable for administration of aerosol formulations described 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™ and AeroDose™ vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California),
Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic™ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.
[00171] Compounds described herein are formulated, for example, 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.
[00172] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms made, for example, by dissolving or dispensing the compound in the proper medium. Absorption enhancers are optionally used to increase the flux of the compound across the skin. The rate is controlled, for example, by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
[00173] 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. The total daily usage of the compounds and compositions described 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 severity 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 in combination or coincidental with the specific compound employed; and like factors known in the medical arts.
[00174] The total daily dose of the compounds described herein administered to a human or other mammal in single or in divided doses is in amounts, for example, from about 0.01 to about 50 mg/kg body weight or more usually from about 0.1 to about 25 mg kg body weight. Single dose compositions contain, for example, 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 compound(s) described herein per day in single or multiple doses.
Abbreviations
[00175] Abbreviations which may have been used in the descriptions of the schemes and the examples that follow are: AcOH for acetic acid; AIBN for azobisisobutyronitrile; nBu for normal butyl; (Boc)20 for di-te -butyl dicarbonate, BU3S11H for tributyltin hydride; CDI for carbonyldiimidazole; DBU for l,8-diazabicyclo[5.4.0]undec-7-ene; DCC for dicyclohexyl carbodiimide; DCM for dichloromethane; DEAD for diethyl azodicarboxylate; DIAD for diisopropyl azodicarboxylate; DMF for dimethylformamide; DIEA or DIPEA for Ν,Ν-diisopropylethylamine; DMP for 2,2-dimethoxypropane; DMSO for dimethylsulfoxide (or methylsulfoxide); DPPA for diphenylphosphoryl azide; Et3N for triethylamine; EtOAc or EA for ethyl acetate; Et20 for diethyl ether; EtOH for ethanol; HO Ac for acetic acid; HOSu for N-hydroxysuccinimide; LiHMDS or
LiN(TMS)2 for lithium bis(trimethylsilyl)amide; MCPBA for /Meta-chloroperbenzoic acid; MeOH for methanol; MsCl for methanesulfonyl chloride; NaHMDS or NaN(TMS)2 for sodium bis(trimethylsilyl)amide; MTBE for methyl tert-butyl ether;
NMO for N-methylmorpholine N-oxide; pNZ-OSu for 2,5-dioxopyrrolidin-l-yl 4-nitrobenxyl carbonate; Boc for tert- W 201 butoxycarbonyl group; pNZ or p-nitrocarbobenzyloxy for carbo-(4-nitro)benzyloxy group; PE for petroleum ether; SOCl2 for thionyl chloride; PPTS for pyridium -toluene sulfonate; Pd(OAc)2 for palladium (II) acetate; PPh3 for triphenylphosphine; Py for pyridine; TFA for trifluoroacetic acid; TEA for triethylamine; THF for tetrahydrofuran; TMSC1 for trimethylsilyl chloride; TMSCF3 for trimethyl(trifluoromethyl)-silane; TPP for triphenylphosphine; TPAP for tetra-n-propylammonium perruthenate; DMAP for 4-dimethylamino pyridine; TsOH for p-toluene sulfonic acid; MsOH for methanesulfonic 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 0-benzotriazol-l -yl-N,N,N',N',-bis(tetramethylene)uronium hexafluorophosphate; PyBOP for benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate; HATU for Ν,Ν,Ν', /V'-tetramethyl-0-(7- azabenzotriazol- 1 -yl)uranium hexafluorophosphate.
EXAMPLES
[00176] The following examples provide details concerning the synthesis, properties and activities and applications of semisynthetic glycopeptides described herein. It should be understood the following is representative only.
Example 1
Synthesis of Compound (1)
Figure imgf000053_0001
Hi
[00177] Vancomycin (30 g) was added slowly to a mixture solution (300 ml, TFA: H20 = 9: 1) at 10 "C. Then the reaction mixture was stirred at 10 °C for 2hrs (with reaction progress checked by HPLC). The reaction mixture was quenched with 1500 ml cold diethyl ether, the precipitate was filtered and washed by ether several times, then dried under vacuum. The crude product was purified by reverse phase column (MeCN:H2O=10%~20%) to afford Compound £1} as a white solid (yield = 45%).
Example 2
Figure imgf000053_0002
[00178] Using a procedure similar to the preparation of Compound £1}, and replacing vancomycin with
desmethylvancomycin, Compound £2} is made. Example 3
Synthesis of Compound (3)
Figure imgf000054_0001
[00179] Using a procedure similar to the preparation of Compound £1), and replacing vancomycin with LY264826, Compound {3 is made.
Example 4
Synthesis of Compound (4)
Figure imgf000054_0002
[00180] Using a procedure similar to the preparation of Compound £1}, and replacing vancomycin with eremomycin, Compound (4} is made.
Example 5
Figure imgf000054_0003
[00181] Compound £1} (5.0g, 3.72 mmol) was dissolved in THF/ H20 (35 ml/ 35 ml). TEA (0.77 ml, 5.58 mmol) was then added. The reaction mixture was cooled down to 15 °C and then (Boc)20 (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 (MeCN:H2O=l :5-3: 10). 3g of Compound (5) was obtained as a white solid (yield = 60%). Example 6
Synthesis of Compound (6)
Figure imgf000055_0001
|00182] Using a procedure similar to the preparation of Compound £5), and replacing Compound £1} with Compound £2), Compound (6) is made.
Example 7
Synthesis of Compound (7)
Figure imgf000055_0002
100183] Using a procedure similar to the preparation of Compound £5}, and replacing Compound £1} with Compound £3), Compound (7} is made.
Example 8
Synthesis of Compound (8)
Figure imgf000055_0003
[00184] Using a procedure similar to the preparation of Compound £5), and replacing Compound £1} with Compound (4), Compound (8 is made. Example 9
Synthesis of Compound £9}
Figure imgf000056_0001
[00185] Using a procedure similar to the preparation of Compound £5), and replacing Compound £1} with vancomycin, Compound (9} was made.
Example 10
Synthesis of Compound (10)
Figure imgf000056_0002
[00186] Using a procedure similar to the preparation of Compound £5), and replacing Compound £1} with
desmethylvancomycin Compound (10) is made.
Example 11
Synthesis of Compound (11)
Figure imgf000056_0003
[00187] Compound £5} (lg, 0.712 mmol) and 2-adamantylamine hydrochloride (0.4g, 2.1 mmol) were dissolved in anhydrous DMSO (12ml). 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: CH2C12 = 1 :7-1 :3) gave the Compound £111 as white solid (850 mg, yield = 77%).
Example 12
Synthesis of Compound (12)
Figure imgf000057_0001
[00188] Using a procedure similar to the preparation of Compound (11). and replacing Compound £5) with Compound £6), Compound (12) is made.
Example 13
Synthesis of Compound (13)
Figure imgf000057_0002
[00189] Using a procedure similar to the preparation of Compound (11). and replacing Compound £5 with Compound £7}, Compound (13) is made.
Example 14
Synthesis of Compound (14)
Figure imgf000057_0003
[00190] Using a procedure similar to the preparation of Compound (11). and replacing Compound £5} with Compound (8).
Figure imgf000058_0001
[00191] Using a procedure similar to the preparation of Compound (11), and replacing Compound £5} with Compound £9), Compound (15) was made.
Example 16
Synthesis of Compound (16)
Figure imgf000058_0002
[00192] Using a procedure similar to the preparation of Compound (11). and replacing Compound £5} with Compound (10).
Compound (16) is made.
Example 17
Synthesis of Compound (17)
Figure imgf000058_0003
[00193] To a suspension of Compound (11) (380 mg) in CH2Cl2(4ml) at 0 °C , was added TFA (0.5 ml) dropwise. The reaction mixture was stirred at 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 (17) as TFA salt.
Example 18
Synthesis of Compound (18)
Figure imgf000059_0001
(18)
[00194] Using a procedure similar to the preparation of Compound (17). and replacing Compound (11) with Compound (12).
Compound (18) as TFA salt is made.
Example 19
Synthesis of Compound (19)
Figure imgf000059_0002
[00195] Using a procedure similar to the preparation of Compound (17). and replacing Compound (11) with Compound (13).
Compound (19) as TFA salt is made.
Example 20
Synthesis of Compound (20)
Figure imgf000059_0003
[00196] Using a procedure similar to the preparation of Compound (17). and replacing Compound (11) with Compound (14).
Compound (20) as TFA salt is made. Example 21
Synthesis of Compound (21)
Figure imgf000060_0001
[00197] Using a procedure similar to the preparation of Compound (17), and replacing Compound (11) with Compound (15).
Compound (21) as TFA salt was made.
Example 22
Figure imgf000060_0002
[00198] Using a procedure similar to the preparation of Compound (17). and replacing Compound (11) with Compound (16). Compound (22) as TFA salt is made.
Example 23
Synthesis of Compound (23) or phenolic regioisomer
Figure imgf000060_0003
[00199] To Compound Oil (1 -0 g, 0.65 mmol) and DMAP (0.25 g, 2.0 mmol) in dry DMF (15 ml) at room temperature, was added slowly C8H17NCO (0.20 g, 1.30 mmol). After stirring at room temperature for 15 hours, the reaction mixture was precipitated in ether and the solid was washed with water and collected to yield Compound (23) or phenolic regioisomer ( 1.0 g, 91% yield) as a white solid. Example 24
Synthesis of Compound (24) or phenolic regioisomer
Figure imgf000061_0001
[00200] Using a procedure similar to the preparation of Compound (23), and replacing Compound (11) with Compound (12), Compound (24) or phenolic regioisomer is made.
Example 25
Synthesis of Compound (25) or phenolic regioisomer
Figure imgf000061_0002
[00201] Using a procedure similar to the preparation of Compound (23), and replacing Compound (11) with Compound (13).
Compound (25) or phenolic regioisomer is made.
Example 26
Synthesis of Compound (26) or phenolic regioisomer
Figure imgf000061_0003
[00202] Using a procedure similar to the preparation of Compound (23). and replacing Compound (11) with Compound (14). Compound (26) or phenolic regioisomer is made.
Example 27
Synthesis of Compound (27) or phenolic regioisomer
Figure imgf000062_0001
[00203] Using a procedure similar to the preparation of Compound (23). and replacing Compound (11) with Compound (IS).
Compound (27) or phenolic regioisomer was made.
Example 28
Synthesis of Compound (28) or phenolic regioisomer
Figure imgf000062_0002
[00204] Using a procedure similar to the preparation of Compound (23). and replacing Compound (11) with Compound (16).
Compound (28) or phenolic regioisomer is made.
Example 29
Synthesis of Compound (29) or phenolic regioisomer
Figure imgf000062_0003
[00205] To a suspension of Compound £23} (1.0 g, 0.58 mmol) in CH2C12 (16 ml) at 0 °C, was added TFA (4 ml) dropwise. The reaction mixture was stirred at 0 °C for 1 hour. Ether (80 ml) was added and the forming solid was collected and washed with ether 3 times. The collected white solid was dried and purified by preparative HPLC to yield Compound (29) or phenolic regioisomer as TFA salt ( 150 mg, 15%) as a white solid. Preparation HPLC conditions: Eluent:65/35 of MeCN/H20 (with 0.1 % TFA); Flow rate: 10 ml/min; Column size: 250* 22 mm; Retention time: approximately 10 min.
Example 30
Synthesis of Compound (30) or phenolic regioisomer
Figure imgf000063_0001
[00206] Using a procedure similar to the preparation of Compound (29). and replacing Compound (23) with Compound (24).
Compound (30) or phenolic regioisomer as TFA salt is made.
Example 31
Synthesis of Compound (31) or phenolic regioisomer
Figure imgf000063_0002
[00207] Using a procedure similar to the preparation of Compound (29). and replacing Compound (23) with Compound (25).
Compound (31) or phenolic regioisomer as TFA salt is made.
Example 32
Synthesis of Compound (32) or phenolic regioisomer
Figure imgf000064_0001
[00208] Using a procedure similar to the preparation of Compound (29), and replacing Compound (23) with Compound (26).
Compound (32) or phenolic regioisomer as TFA salt is made.
Example 33
Synthesis of Compound (33) or phenolic regioisomer
[00209] Using a procedure similar to the preparation of Compound (29). and replacing Compound (23) with Compound (27). Compound (33) or phenolic regioisomer as TFA salt was made.
Example 34
Synthesis of Compound (34) or phenolic regioisomer
Figure imgf000064_0003
[00210] Using a procedure similar to the preparation of Compound (29). and replacing Compound (23) with Compound (28).
Compound (34) or phenolic regioisomer as TFA salt is made. Example 35
Synthesis of Compound (35) or phenolic regioisomer
Figure imgf000065_0001
[00211] Using a procedure similar to the preparation of Compound (23). and reacting Compound (11) with the appropriate isocyanate or thioisocyanate (RB-NCO or RB-NCS), and treating the resulting product with TFA following the procedure as outlined in Example 29 to yield Compound (35) or phenolic regioisomer as a TFA salt where Z is O or S and RB is loweralkyl, substituted loweralkyl, phenyl, pyridyl, substituted aryl or substituted heteroaryl is made.
Example 36
Synthesis of Compound (36) or phenolic regioisomer
Figure imgf000065_0002
[00212] Using a procedure similar to the preparation of Compound (23). and reacting Compound (12) with the appropriate isocyanate or thioisocyanate (RB-NCO or RB-NCS), and treating the resulting product with TFA following the procedure as outlined in Example 29 to yield Compound (36) or phenolic regioisomer as a TFA salt where Z is O or S and RB is loweralkyl, substituted loweralkyl, phenyl, pyridyl, substituted aryl or substituted heteroaryl is made.
Example 37
Synthesis of Compound (37) or phenolic regio isomer
Figure imgf000066_0001
[00213] Using a procedure similar to the preparation of Compound (23), and reacting Compound (13) with the appropriate isocyanate or thioisocyanate (RB-NCO or RB-NCS), and treating the resulting product with TFA following the procedure as outlined in Example 29 to yield Compound (37) or phenolic regioisomer as a TFA salt where Z is O or S and RB is loweralkyl, substituted loweralkyl, phenyl, pyridyl, substituted aryl or substituted heteroaryl is made.
Example 38
Synthesis of Compound (38) or phenolic regioisomer
Figure imgf000066_0002
[00214] Using a procedure similar to the preparation of Compound (23). and reacting Compound (14) with the appropriate isocyanate or thioisocyanate (RB-NCO or RB-NCS), and treating the resulting product with TFA following the procedure as outlined in Example 29 to yield Compound (38) or phenolic regioisomer as a TFA salt where Z is O or S and RB is loweralkyl, substituted loweralkyl, phenyl, pyridyl, substituted aryl or substituted heteroaryl is made.
W
Example 39
Synthesis of Compound (39) or phenolic regioisomer
Figure imgf000067_0001
[00215] Using a procedure similar to the preparation of Compound (23), and reacting Compound (15) with the appropriate isocyanate or thioisocyanate (RB-NCO or RB-NCS), and treating the resulting product with TFA following the procedure as outlined in Example 29 to yield Compound (39) or phenolic regioisomer as a TFA salt where Z is O or S and RB is loweralkyl, substituted loweralkyl, phenyl, pyridyl, substituted aryl or substituted heteroaryl is made.
Example 40
Synthesis of Compound (40) or phenolic re ioisomer
Figure imgf000067_0002
[00216] Using a procedure similar to the preparation of Compound (23). and reacting Compound (16) with the appropriate isocyanate or thioisocyanate (RB-NCO or RB-NCS), and treating the resulting product with TFA following the procedure as outlined in Example 29 to yield Compound (40) or phenolic regioisomer as a TFA salt where Z is O or S and RB is loweralkyl, substituted loweralkyl, phenyl, pyridyl, substituted aryl or substituted heteroaryl is made. W
Example 41
Synthesis of Compound (41)
Figure imgf000068_0001
[00217] Compound (11) (1 g, 0.649 mmol) was azeotroped with toluene 3 times and then dissolved in anhydrous pyridine. Mesitylenesulfonyl chloride (426 mg, 1.95 mmol) in 1 ml of anhydrous pyridine was added to the solution dropwise at 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 (41) as a white solid (500 mg, yield =50%). LC-MS (ESI): 1620(M++1-Boc).
Example 42
Figure imgf000068_0002
[00218] Using a procedure similar to the preparation of Compound (41), and replacing Compound (11) with Compound (12), Compound (42) is prepared.
Example 43
Synthesis of Compound (43)
Figure imgf000068_0003
[00219] A solution of Compound (41) (lg, 0.581 mmol) and sodium azide (377mg, 5.81 mmol, lOeq.) in anhydrous DMF was heated to 70 °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 (43) as a pale yellow solid (500 mg, yield = 50%). LC-MS (ESI): 1463(M++l-Boc).
Example 44
Synthesis of Compound (44)
Figure imgf000069_0001
[00220] To a solution of Compound (43) (1 g, 0.639 mmol) in 5 ml THF containing a few drops of water was added n-Bu3P (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/ H20=l/9~l/3) to afford Compound (44) as a pale yellow solid (100 mg, yield = 10%). LC-MS (ESI): 1537(M++1).
Example 45
Synthesis of Compound (45)
Figure imgf000069_0002
[00221] To a solution of Compound (44) (380 mg) in 2 ml of THF containing 10 drops of water was added di-tert butyl dicarbonate (1.05 eq) and TEA (2.0 eq). The mixture was stirred at room temperature for 5 hours. The reaction was checked for completion by HPLC-MS. The solvent was evaporated to afford Compound (45) upon purification by prep-HPLC.
Example 46
Synthesis of Compound (46)
Figure imgf000069_0003
[00222] Using Compound (45) (100 mg) was azeotroped with toluene for three times. It was the dissolved in 1 ml dry DMF. DBU (3.0 equivalent) in 1 ml dry DMF was added under argon atmosphere in an ice bath followed by the addition of isocyanate C8Hi7NCO (2.0 equivalent) in 1 ml DMF. The mixture was stirred at room temperature overnight. The reaction was checked for completion by HPLC-MS. The reaction was quenched by adding water, and then filled. The cake was washed three times with water. The crude compound was purified by preparative HPLC to afford Compound (46).
Example 47
Synthesis of Compound (47)
Figure imgf000070_0001
[00223] Compound (46) in 2 ml of TEA/DCM (1/1) was stirred for 1 hour in an ice-bath. The reaction was checked for completion by HPLC-MS. The solvent was removed under reduced pressure at 0 °C. The residue was washed with ether and filtered to give Compound (47) as a TFA salt.
Example 48
Synthesis of Compound (48)
Figure imgf000070_0002
(48)
[00224] To a mixture of Compound (44) (0.10 mmol) and pyridine (24 mg, 0.30 mmol) in dry DMF (0.5 ml) at room temperature under nitrogen atmosphere was slowly added a solution of acetyl chloride (8 mg, 0.10 mmol)vin dry DMF (0.5 ml). After stirring at room temperature for 1 hour, the reaction mixture was precipiptated in ether and the solid was washed with ether and collected to yield Compound (48). Example 49
Figure imgf000071_0001
I00225] Using a procedure similar to the preparation of Compound £29}, and replacing Compound £23} with Compound (48).
Compound (49) is prepared.
Example 50
Synthesis of carboxamide glycopeptides derivatives (50-55)
Figure imgf000071_0002
NH2 hydrochloride and reacting it with Compound (5-10). Compound (50-55) where R|3 is as defined, is prepared.
Example 51
Synthesis of carboxamide glycopeptides derivatives (56-61
Figure imgf000072_0001
[00227] Following the synthetic methodology as Example 46 followed with the removal of the protecting group with a procedure similar to Example 47. Compound (56-61). where R13 is as defined, is prepared from Compound (50-55).
Example 52
Synthesis of Compound (62 & 63) or phenolic regioisomers
Figure imgf000072_0002
[00228] Using a procedure similar to the preparation of Compound (23), and replacing C8H17NCO with (1- isocyanatoethyl)benzene, Compound (62) and also Compound (63) or phenolic regioisomers were made.
Example 53
Figure imgf000073_0001
[00229] Using a procedure similar to the preparation of Compound (29), and replacing Compound (23) with a mixture of Compounds (62 & 63), Compounds (64 &_64A) or phenolic regioisomers were prepared as a TFA salt.
Example 54
Synthesis of Compound (65) or phenolic regioisomer
Figure imgf000073_0002
[00230] Using a procedure similar to the preparation of Compound (23) (Example 23), replacing C8H17NCO with reagent C6H13NCO, nitrogen protected Boc-65 was produced. Subsequent de-protection of Boc-65 by treatment with TFA with a procedure similar to the preparation of Compound (29) (Example 29), Compound (65) or phenolic regioisomer was prepared as a TFA salt.
Example 55
Synthesis of Compound (66) or phenolic regio isomer
Figure imgf000074_0001
[00231] Using a procedure similar to the preparation of Compound (65) (Example 54), and replacing reagent C6H13NCO with reagent C7H|5NCO, Compound (66) or phenolic regioisomer was prepared as a TFA salt.
Example 56
Figure imgf000074_0002
[00232J Using a procedure similar to the preparation of Compound (65) (Example 54), and replacing reagent C6H13NCO with reagents l-butyl-4-isocyanatobenzene, l-methoxy-4- isocyanatobenzene, l-ethoxy-4- isocyanatobenzene, l-butoxy-4- isocyanatobenzene and 2-adamantyl isocyanate, Compounds (67), (68), (69), (70) and (71), respectively, or phenolic regioisomers were prepared as a TFA salt. LC-MS (M+ + 1): Compound (67): 1613.5; Compound (68): 1587.5; Compound (69): 1601.5; Compound (70J: 1629.5; Compound (71): 1615.6. Example 57
Synthesis of Compounds (72), (73), (74), (75), (76) and (77)
Figure imgf000075_0001
[00233] Using a procedure similar to the preparation of Compound (11) (Example 1 1), and replacing reagent 2- adamantylamine with N1, N'-dimethylpropane-l^-diamine, 1-methylpiperazine, cyclopropanamine, propan-2-amine, O-methylhydroxylamine and 2-methylpropan-2-amine, Compounds (72), (73), (74), (75), (76) and (77), respectively, were prepared.
Example 58
Synthesis of Compounds (78) and (79) or phenolic regioisomers
Figure imgf000075_0002
[00234] Using a procedure similar to the preparation of Compound (23) (Example 23), replacing Compound (11) with Compound (92), and substituting the isocyanate C8H17NCO with various isocyanate, nitrogen protected acylureas were prepared. Subsequent de-protection of acylamides by treatment with TFA with a procedure similar to the preparation of Compound (29) (Example 29), Compounds (98) and (99) or phenolic regioisomers were prepared as a TFA salt. LC-MS (M+ + 1): Compound (98): 1544.6; Compound (99): 1516.5. Example 59
Synthesis of Compounds (80) and (81) or phenolic regioisomers
Figure imgf000076_0001
[00235] Using a procedure similar to the preparation of Compound (23) (Example 23), replacing Compound (11) with Compound (73). and substituting the isocyanate C8H17NCO with various isocyanates, nitrogen protected acylureas were prepared. Subsequent de-protection of acylamides by treatment with TFA with a procedure similar to the preparation of Compound (29) (Example 29), Compounds (80) and (81) or phenolic regioisomers were prepared as a TFA salt. LC-MS (M+ + 1): Compound (80): 1514.5; Compound (81): 1542.5.
Example 60
Synthesis of Compounds (82) and (83) or phenolic regioisomers
Figure imgf000076_0002
[00236] Using a procedure similar to the preparation of Compound (23) (Example 23), replacing Compound (11) with Compound (74), and substituting the isocyanate C8H17NCO with various isocyanates, nitrogen protected acylureas were prepared. Subsequent de-protection of acylamides by treatment with TFA with a procedure similar to the preparation of Compound (29) (Example 29), Compounds (82) and (83) or phenolic regioisomers were prepared as a TFA salt. LC-MS (M+ + 1): Compound (82): 1471.5; Compound (83): 1499.5. Example 61
Synthesis of Compound (84) or phenolic regioisomer
Figure imgf000077_0001
[00237] Using a procedure similar to the preparation of Compound (23) (Example 23), replacing Compound (11) with Compound (75), and substituting the isocyanate C8H17NCO with C6H13NCO, nitrogen protected acylureas were prepared. Subsequent de-protection of acylamides by treatment with TFA with a procedure similar to the preparation of Compound (29) (example 29), Compound (84) or phenolic regioisomer was prepared as a TFA salt. LC-MS (M+ + 1): 1473.5.
Example 62
Synthesis of Compounds (85) and (86) or phenolic regioisomers
Figure imgf000077_0002
[00238] Using a procedure similar to the preparation of Compound (23) (Example 23), replacing Compound (11) with Compound (76), and substituting the isocyanate C8HnNCO with various isocyanates, nitrogen protected acylureas were prepared. Subsequent de-protection of acylamides by treatment with TFA with a procedure similar to the preparation of Compound (29) (example 29), Compounds (85) and (86) or phenolic regioisomers were prepared as a TFA salt. LC-MS (M+ + 1): Compound (85): 1461.5.; Compound (86): 1489.5.
Example 63
Synthesis of Compounds (87) and (88) or phenolic regioisomers
Figure imgf000078_0001
[00239] Using a procedure similar to the preparation of Compound (23) (Example 23), replacing Compound (11) with Compound (77), and substituting the isocyanate C8H17NCO with various isocyanates, nitrogen protected acylureas were prepared. Subsequent de-protection of acylamides by treatment with TFA with a procedure similar to the preparation of Compound (29) (Example 29), Compounds (87) and (88) or phenolic regioisomers were prepared as a TFA salt. LC-MS (M+ + 1): Compound (87): 1515.5.; Compound (88): 1478.5.
Example 64
Synthesis of tert-butyl 2-(4-isocyanatophenoxy)ethyl(methyl)carbamate
[00240] To a mixture 2-(methylamino) ethanol (5.0 g, 66.5 mmol) in 15ml of ethyl acetate was added a solution of (Boc)20 (14.5 g, 66.5 mmol) in 5 ml of ethyl acetate dropwise with cooling in an ice bath. The resulting mixture was stirred at room temperature for 2 hours, and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over Na2S04 and filtered. After removing the solvent, the crude tert-butyl 2- hydroxyethyl(methyl)carbamate was used without further purification for the next reaction (10.5 g, 90%) A solution of diisopropyl azodicarboxylate (5.22 g, 25.9 mmol) in 5 ml of THF was added dropwise to a solution of 4-nitryl phenol (3.0 g, 21.56 mmol), tert-butyl 2-hydroxyethyl(methyl)carbamate (4.53 g, 25.9 mmol) and triphenylphosphine (6.78 g, 25.9 mmol) in 60 ml of THF with ice-bath cooling under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure by evaporation. The residue was mixed with ether and filtered. The filtrate was concentrated and purified by flashing silica gel column (Petroleum ether/Ethyl acetate= 10/ 1-8/1) to afford the intermediate ieri-butyl methyl(2-(4-nitrophenoxy)ethyl)carbamate (2.48 g, 39%). To a solution of this intermediate tert- butyl methyl(2-(4-nitrophenoxy)ethyl)carbamate (2.48 g, 8.4 mmol) in methanol was added Pd/C under hydrogen atmosphere. The mixture was heated to 50 °C for 1 hour, and then cooled down to room temperature and filtered. The filtrate was concentrated to give the crude tert-butyl 2-(4-aminophenoxy)ethyl(methyl)carbamate which was used without further purification for the next reaction (2.10 g, 95%). To a solution of triphosgene (206 mg, 0.695 mmol) in DCM was added tert- butyl 2-(4-aminophenoxy)ethyl(methyl)carbamate (500 mg, 1.88 mmol) with ice-bath cooling followed by dropwise addition of TEA (380 mg, 3.76 mmol). After that, the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure without heating. The residue mixed with ether and filtered. The filtrate was concentrated to give tert- butyl 2-(4-isocyanatophenoxy)ethyl(methyl)carbamate (500 mg). Example 65
Synthesis of ter/-butyl 2-(4-isocyanatophenoxy)ethyl(ethyl)carbamate
[002411 Using a procedure similar to the preparation of iert-butyl 2-(4-isocyanatophenoxy)ethyl(methyl)carbamate (Example 64), replacing 2-(methylamino)ethanol with 2-(ethylamino)ethanol, the isocyanate, iert-butyl 2-(4- isocyanatophenoxy)ethyl(ethyl)carbamate were made.
Example 66
Sy (lOT), (102) and (103)
Figure imgf000079_0001
Figure imgf000080_0001
[00242] Using a procedure similar to the preparation of Compound (46) as in Example 46 and replacing the isocyanate C8Hi7 NCO with an appropriate isocyanate, Compounds (89), (20), (21), (2?J, (23), (24), (95), (26), (2D, (98), (22), OM), (Ml), (102) and (103) were made.
Example 67
Synthesis of terf-butyl 2-(4-isocyanatophenoxy)ethyl(propyl)carbamate
[00243] Using a procedure similar to the preparation of tert-butyl 2-(4-isocyanatophenoxy)ethyl(methyl)carbamate (example 64), replacing 2-(methylamino)ethanol with 2-(propylamino)ethanol, the isocyanate, teri-butyl 2-(4- isocyanatophenoxy)ethyl(propyl)carbamate is made.
Example 68
Synthesis of Compounds (104), Q ), Q06), (MI), OM), (M), (1M), Oil), Oil), OM), Q14), (115), (116), (112) and
Figure imgf000080_0002
Figure imgf000081_0001
[00244] Using a procedure similar to the preparation of Compound (47) as in Example 47 and replacing Compound (47) with Compounds (89), (90), (21), (2D, (2D, (24), (25), (26), (2D, (2*0, (22), OOO), (ΙΜ), ϋ - and (103) the acylurea derivatives Compounds (104), (105), Qj ), (lliD, Q ), (M2), OM), Oil), Oil), Q ), Oil), (115), 016), Oil) and (118) were made as TFA salts.
Example 69
Alternate Synthesis of Compound (21)
Figure imgf000081_0002
[00245] To a solution of vancomycin hydrochloride (100.0 g) in DMSO (800 mL) was added 2-adamantylamine hydrochloride (20.0 g), DIPEA (35.0 g) and HATU (28.1 g) with stirring at ambient temperature. The reaction mixture was stirred overnight. Analytical HPLC showed the reaction completed. DMSO was removed under vacuum. The residue was subjected to purification by reverse phase silica gel column chromatography (CI 8 silica gel, CH3CN-H2O:5%-30%). The collected fraction was condensed to give Compound (21) (45 g) as a white powder. Example 70
Figure imgf000082_0001
[00246] To a solution of Compound (21) (35.0 g) in 1,4-dioxane (50 mL) and water (50 mL) was added Fmoc-OSu (9- fluorenylmethyloxycarbonyl-O-succinimide) (11.0 g) with stirring at room temperature. After the reaction mixture was stirred at ambient temperature for 2 hr, the solvent was removed under reduced pressure. The resulting solid was collected by filtration under vacuum and was purified by silica gel column chromatography (silica gel, MeOH-CH2C12: 10%-20%) to give Compound (119), (20 g) as a white solid.
Example 71
Figure imgf000082_0002
[00247] Using a procedure similar to the preparation of Compound (46) as in Example 46 and replacing Compound (45) with Compound (119), and isocyanate C8Hi7NCO with l-isocyanato-4-methoxybenzene, Compound (120) was made.
Example 72
Figure imgf000082_0003
[00248] Compound (120) obtained from Example 71 was dissolved into DMF (9 mL) and then diethylamine (3 eq.) was added at ambient temperature. After stirring at room temperature for 2 hr, the reaction mixture was poured into ether. The formed solid was applied on preparative HPLC to give Compound (121).
Example 73
Synthesis of Compound (122) & (123)
Figure imgf000083_0001
[00249] Using a procedure provided in Examples 71 and 72 in the preparation of Compound (121) and replacing l-isocyanato-4-methoxybenzene with l-isocyanato-4-butoxybenzene or l-isocyanato-4-ethoxybenzene, Compound (122) and Compound (123) were prepared, respectively.
Example 74
Figure imgf000083_0002
(124)
[00250] Using a procedure similar to the preparation of Compound (120) as in Example 71 and replacing l-isocyanato-4- methoxybenzene with l-isocyanato-4-(2-(9-fluorenylmethyloxycarbonylamino)ethoxy)benzene , Compound (124) was prepared.
Example 75
Figure imgf000084_0001
(125)
[00251| Using a procedure similar to the preparation of Compound (121) as in Example 72 and replacing Compound (120) with Compound (124), Compound ( 125) was made.
Example76
Synthesis of Compounds (126), (127), (128). (129) and (130)
Figure imgf000084_0002
[00252] Using a procedure similar to the preparation of Compound (120) as in Example 71 and replacing l-isocyanato-4- methoxybenzene with other appropriate isocyanates, Compounds (126), (127), (128), (129) and (130) are prepared. Example 77
Figure imgf000085_0001
[00253] Using a procedure similar to the preparation of Compound (121) as in Example 72 and replacing Compound (120) with Compounds (126), (127), (128). (129) and (130). Compounds (131). (132). (133), (134). and (135) are prepared, respectively.
Example 78
Synthesis of Compounds (136), (137), (138). (139). (140) and (141)
Figure imgf000085_0002
[00254] Using a procedure provided in Examples 66 and 68 in the preparation of various acyiurea derivatives such as Compounds (104). and using appropriate isocyanates, acyiurea Compounds (136). (137). (138). (139). (140). and (141) are prepared. Example 79
Figure imgf000086_0001
(142)
[00255] To a solution of mixture of N-(2-aminoethyl)-4-(pentyloxy)benzenesulfonamide (151 mg, 0.53 mmol) and Compound (119) (1 g, 0.53 mmol) in acetonitrile (30 mL) and water (30 mL) was added 37% aqueous formaldehyde (1.2 g, 14.8 mmol) and acetic acid (640 mg, 10.7 mmol) at room temperature. The reaction mixture was stirred for an additional 20 hr at room temperature. The volatile solvents were removed under reduced pressure. The formed solid was collected by filtration and washed with EtOAc. The crude product was dissolved into DMF (5 mL). After diethylamine (22 mg) was added, the reaction mixture was stirred at room temperature for 40 minutes and then was poured into ether (20 mL). The formed solid was applied on preparative HPLC to give Compound (142) as a white powder.
Example 80
Sy
Figure imgf000086_0002
[00256] Using a procedure similar to the preparation of Compound (142) as in Example 79 and replacing Compound (119) with Compound (126), Compound (143) is made.
Example 81
(149)
Figure imgf000086_0003
Figure imgf000087_0001
|00257] Using a procedure similar to the preparation of Compound (142) as in Example 79 and replacing Compound (119) with Compound (126), and N-(2-aminoethyl)-4-(pentyloxy)benzenesulfonamide with various aminoalkyl sulfonamide, Compounds (144), (145). (146). (147). (148) and (149) are prepared.
Example 82
Syn
Figure imgf000087_0002
[002581 Using a procedure similar to the preparation of Compound (142) as in Example 79 and replacing Compound (119) with Compound (120). Compound (150) is made.
Example 83
Synthesis of Compounds (151). (152). (153). (154). (155) (156). (157). (158). (159). (160) and (161)
Figure imgf000087_0003
Figure imgf000088_0001
[00259] Using a procedure similar to the preparation of Compound (142) as in Example 79 and replacing Compound (119) with Compound (120). and N-(2-aminoethyl)-4-(pentyloxy)benzenesulfonamide with various aminoalkyl sulfonamide or aminoalkylacetamide, Compounds (151). (152). (153). (154). (155) (156). (157). (158). (159). (160) and (161) are prepared.
Example 84
Figure imgf000088_0002
[00260] To a mixture solution of vancomycin hydrochloride (100.0 g, 67.3 mmol) and NaHC03 (28.3g, 336.9 mmol) in THF (700 ml) and water (500 ml) was added a solution of pNZ-OSu (56.2 g, 191.2 mmol) in THF (200ml) with stirring at 0 °C for lh. The reaction mixture was stirred at room temperature for 2 hr. and the organic layer was separated and the volatile was removed under reduce pressure. The resulting solid was collected by filtration under vacuum and washed with EtOAc and ether, dried under vacuum at 40 °C giving 130 g of compound (162) as a solid. ESI-MS: m/z: calcd for C92H1 i6C|2N14027 [M+H] + 1921.89; Found: 1921.5 (33.1%), 1281.1 (28.5%), 961.1(100%); [M+CF3COO]- 2033.5; Found: 2033.6 (100%) .
Example 85
Synthesis of Compound (163)
Figure imgf000089_0001
[00261] To a solution of compound (162) from the previous experiment (130 g) in DMSO (1000 ml) was added 2- adamantylamine hydrochloride (24.3 g, 129.5 mmol), DIPEA (46.47 g, 360.2 mmol) and HATU (54.69 g, 143.8 mmol) with stirring at room temperature. The reaction mixture was stirred overnight. Analytical HPLC showed the reaction completed. The reaction mixture was poured into ice-water (2000ml). A precipitate was formed and collected by filtration. The solid was purified by column chromatography (silica gel, CH3OH-DCM=l :9-l :5). The collected fraction was condensed to provide compound (163) (76 g, 58.2 % yield from vancomycin hydrochloride) as white powder. ESI-MS: m/z: calcd for
C92H1ooCi2N12031 [M+H]+ 1941.75; Found: 1941.8 ( 100%); [M+CF3COO]- 2053.75; Found: 2053.8 (100%) .
Example 86
Synthesis of Compound (164)
Figure imgf000089_0002
[00262] Using a procedure similar to the preparation of Compound (162) as in Example 84 and replacing vancomycin hydrochloride with Compound (1), Compound (164) was prepared. Example 87
Synthesis of Compound (165)
Figure imgf000090_0001
[00263] Using a procedure similar to the preparation of Compound (163) as in Example 85 and replacing Compound (162) with Compound (164). Compound (165) was made.
Example 88
Synthesis of 4-nitrobenzyl 2-hydroxyethyl(methyI)carbamate
[00264] To a mixture of 2-(methylamino) ethanol ( 100 g, 1.33 mol) and TEA (161 g, 1.60 mol) in DCM (250ml) was added a solution of pNZ-Cl (258.3 g, 1.20 mmol) in DCM (500 ml) dropwise within an ice bath. The reaction mixture was stirred overnight at room temperature. The formed solid was filtered. The filtrate was washed with water and brine, dried over Na2S04. Hexane was added and the precipitate was collected. The crude was purified by chromatography on silica gel (EtOAc) to provide 225 g of 4-nitrobenzyl 2-hydroxyethyl(methyl)carbamate. Ή NMR:(CDC13): 3.0(3H),
3.5(2H),3.85(2H),5.2(2H), 7.5(2H),8.1(2H).
Example 89
Synthesis of 4-nitrobenzyl ethyl(2-liydroxyethyl)carbamate
[00265] Using a procedure similar to the preparation of 4-nitrobenzyl 2-hydroxyethyl(methyl)carbamate as in Example 88 and replacing 2-(methylamino) ethanol with 2-(ethylamino) ethanol, 4-nitrobenzyl ethyl(2-hydroxyethyl)carbamate was made. Ή NMR:(CDC13): 1.1(3H), 3.7(2H),3.85(2H),4.03(2H),5.32(2H),7.45(2H),8.1(2H).
Example 90
Synthesis of 4-nitrobenzyl 2-hydroxyethyl(propyl)carbamate
[00266] Using a procedure similar to the preparation of 4-nitrobenzyl 2-hydroxyethyl(methyl)carbamate as in Example 88 and replacing 2-(methylamino) ethanol with 2-(ethylamino) ethanol, 4-nitrobenzyl 2-hydroxyethyl(propyl)carbamate was made.
Example 91
Synthesis of Compound (166)
Figure imgf000090_0002
(166) |00267] To a solution of methyl 3,4,5-trihydroxybenzoate (18.4 g, O. lmol), 4-nitrobenzyl 2-hydroxyethyl(methyl)carbamate ( 1 14.4 g, 0.45mol) and triphenylphosphine ( 1 18 g, 0.45mol) in 100 ml of THF was added dropwise DIAD (91 g, 0.45 mol) with ice-bath cooling under nitrogen atmosphere. The resulting mixture was stirred at room temperature over night. The solvent was evaporated. The residue was mixed with ether and filtered. The filtrate was concentrated and purified by flash silica gel column (hexanes: EtOAc=6: l) to give the methyl benzoate derivative (38g) as colorless oil. To the solution of this methyl benzoate derivative (38g) in THF 500mL was added NaOH (350ml, 10N). The solution was stirred at room temperature overnight. The solvent was removed, and the residue was dissolved in water. To the water layer was added 10% H2S04 dropwise until pH~4. The mixture was extracted with EtOAc. The organic layers was combined and washed with brine, dried over Na2S04. The filtrate was concentrated and purified by flash silica gel column
(hexanes:EtOAc.HOAc=3: 1 :0.05) to give the triethoxy benzoic acid derivative (10.8g) as off-white solid. lH NMR:(CDC13): 3.0(9H), 3.71-3.80(6H),4.1 1-4.19(6H),5.2(6H),7.25(2H),7.5(6H), 8.1-8.2(6H). To a mixture solution of this acid (700mg) and TEA (0.34ml) in THF (40ml) at 0 °C, and ethyl chlorocarbonate (130mg) was added. The mixture was stirred for 20min at room temperature NaN3 (78mg) was added. The reaction was monitored by TLC. The solvent was removed under reduce pressure. The residue was dissolved in EtOAc and was washed with brine, dried over Na2S04. After the solvent was concentrated, the triethoxybenzoyl azide derivative (400mg) which was dissolved in 5 ml toluene and heated to reflux for 4 h under nitrogen atmosphere. The solvent was removed to give the isocyanate derivative Compound (166)
Example 92
Synthesis of various isocyanate Compounds (167), (168). (169). (170) and (171)
Figure imgf000091_0001
(167) (.168)
[00268] Using a procedure similar to the preparation of compound (166) as in Example 91 and replacing methyl 3,4,5- trihydroxybenzoate with methyl 3,4-dihydroxybenzoate, methyl 3,5-dihydroxybenzoate, methyl 2,5-dihydroxybenzoate, methyl 2,4-dihydroxybenzoate or methyl 4-hydroxybenzoate, the various isocyanates Compounds (167). (168). (169) and (170). respectively, were prepared, and Compound (171) is made.
Example 93
Synthesis of Compound (172)
Figure imgf000091_0002
(1Z2)
[00269] Using a procedure similar to the preparation of Compound (166) as in Example 91 and replacing 4-nitrobenzyl 2- hydroxyethyl(methyl)carbamate with 4-nitrobenzyl ethyl(2-hydroxyethyl)carbamate, the isocyanate Compound (172) was prepared.
Example 94
Synthesis of various isocyanate Compounds (173). (174). (175). (176) and (177)
Figure imgf000092_0001
[00270] Using a procedure similar to the preparation of Compound (172) as in Example 93 and replacing methyl 3,4,5- trihydroxybenzoate with methyl 3,4-dihydroxybenzoate, methyl 3,5-dihydroxybenzoate, methyl 2,5-dihydroxybenzoate, methyl 2,4-dihydroxybenzoate or methyl 4-hydroxybenzoate, the various isocyanates Compounds (173). (174). (175) and (176) respectively were prepared and Compound (177) is made.
Example 95
Synthesis of Compound (178)
Figure imgf000092_0002
(ITS)
[00271] To a procedure similar to the preparation of Compound (166) as in Example 91 and replacing 4-nitrobenzyl 2-hydroxyethyl(methyl)carbamate with 4-nitrobenzyl 2-hydroxyethyl(propyl)carbamate, the isocyanate Compound (178) was prepared.
Example 96
Synthesis of various isocyanate Compounds (179). (180). (181). (182) and (183)
Figure imgf000092_0003
[00272] Using a procedure similar to the preparation of Compound (178) as in Example 95 and replacing methyl 3,4,5- trihydroxybenzoate with methyl 3,4-dihydroxybenzoate, methyl 3,5-dihydroxybenzoate, methyl 2,5-dihydroxybenzoate, methyl 2,4-dihydroxybenzoate or methyl 4-hydroxybenzoate, the various isocyanates Compounds (179). (180). (181). (182) and (183). respectively,are prepared. Example 97
Synthesis of Compound (184)
Figure imgf000093_0001
(! )
[00273] To a solution of Compound (163) (1.37 g, 0.708 mmol) in DMF (7 ml) was added a solution of isocyanate Compound (175) (400mg) in DMF (5 ml) at room temperature under Argon, followed by addition of DBU (269 mg, 1.77 mmol).The mixture was stirred for 1.5 h at room temperature and the starting material was completely consumed. The resulted mixture was poured into EtOAc (200 ml), and a precipitate was formed and collected by filtration. The solid (the nitrogen protected derivative of Compound (184) (2.0 g) was dried under vacuum. A solution of this compound in DMF (20 ml) was poured into a buffer (60 ml) (DMF-H20 (3/2)) containing N-methylmorpholine (2.04 g) and acetic acid (0.84 g) (pH 6.0) .The resulting biphasic reaction mixture was hydrogenated over 5% Pd/C (0.8g) at 40-50 overnight under 1 atm. The reaction was monitored by analytical HPLC. The reaction mixture was filtered and washed with DMF. The filtrate was concentrated and the residue was solidified with EtOAc. The solid was collected by filtration and purified by RP-HPLC to provide Compound (184) (65mg). ESI-MS: m z: calcd for QuHnsClzNuOze [M+H] + 1876.85; Found: 1876.6 (41.1%), 1251.1 (46.4%), 938.7(100%); [M+CF3COO]" 1988.85; Found: 1988.8 (100%).
Example 98
Synthesis of Compounds (185). (186). (187). (188) and (189)
Figure imgf000093_0002
Figure imgf000094_0001
[00274] Using a procedure similar to the preparation of Compound (184) as in Example 97 and replacing isocyanate Compound (175) with various isocyanate Compound (172), Compound (173). Compound (174). Compound (176). or Compound (177). Compounds (185), (186). (187) and (188). respectively, were prepared and Compound (189) is made.
Example 99
Synthesis of Compound (190)
Figure imgf000094_0002
(190)
[00275] Using a procedure similar to the preparation of Compound (184) as in Example 97 and replacing isocyanate Compound (175) with isocyanate Compound (169). Compounds (190) was prepared. ESI-MS: m/z: calcd for
C89H,09Cl2N13O26 [M+H] + 1848.80; Found: 1848.5 (32.6%), 1232.4 (47.7%), 924.3(100%); [M+CF3COO]" 1960.80; Found: 1960.6 (100%).
Example 100
Synthesis of Compounds (191), (192), (193), (194) and (195)
Figure imgf000095_0001
[00276] Using a procedure similar to the preparation of Compound (190) as in Example 99 and replacing isocyanate Compound (169) with various isocyanate Compound (166), Compound (167). Compound (168). Compound (170). or Compound (171). Compounds (191), (192). (193) and (194). respectively, were made and Compound (195) is made.
Example 101
Figure imgf000095_0002
[00277] Using a procedure similar to the preparation of Compound (184) as in Example 97 and replacing isocyanate Compound (175) with isocyanate Compound (178). Compounds (196) was prepared. Example 102
Figure imgf000096_0001
[00278] Using a procedure similar to the preparation of Compound (196) as in Example 101 and replacing isocyanate Compound (178) with various isocyanate Compound (179). Compound (180). Compound (181). Compound (182). or Compound (183). Compounds (197), (198), (200) and (201) are made and Compounds (199) was prepared.
Example 103
Synthesis of Compounds (202). (203), (204), (205). (206). (207). (208). (209). (210). (211). (212). (213). (214). (215) and
Figure imgf000096_0002
Figure imgf000097_0001
[00279] Using a procedure similar to the preparation of Compound (184) as in Example 97 and replacing isocyanate Compound (175) with various pNZ nitrogen protected isocyanates, Compounds (202), (203). (204), (205) (206), (207), (208), (209), (210), (211), (212), (213), (214), (215) and (216) are prepared. Example 104
Synthesis of Compound (217), (208), (219), (220). (221) and (222)
Figure imgf000098_0001
[00280] Using a procedure similar to the preparation of Compound (184) as in Example 97 and replacing Compound (163) with Compound (165) and isocyanate Compound (175) with various pNZ nitrogen protected isocyanates, Compounds (217). (218). (219). (220). (221) and (222) are prepared.
Example 105
Synthesis of nitro derivative Compound (223)
Figure imgf000098_0002
(223)
[00281] A solution of 1, 2-dibromoethane (36 g, 192 mmol) in DMF (100 ml) was added drop wise to a mixture of 4- nitrophenol (8.9 g, 64 mmol) and Cs2C03 (21 g, 64 mmol) in DMF (500 ml). After stirring for 15 h at room temperature, the reaction mixture was filtered. After evaporating of solvent, the residue was dissolved in DCM, washed with water and brine, dried over Na2S04. After filtering and evaporating, the crude product was purified with column using PE/EA/CH2C12 = 5/1/1 as eluent to give l-(2-bromoethoxy)-4-nitrobenzene as white solid (10 g, 64%). To a solution of l-(2-bromoethoxy)-4- nitrobenzene (2.46 g, 10 mmol) in DMF (50 ml) was added tert-but l 2-aminoacetate (1.935 g, 15 mmol), and followed by Cs2C03 (3.26 g, 10 mmol) and KI (1.66 g, 10 mmol). After heating for 5 h at 50 °C, the stirring was continued for another 12 h at room temperature, and then, the reaction mixture was filtered. After evaporating of solvent, the residue was dissolved in CHC13, washed with water and brine, dried over Na2S04. After filtering and evaporating, the crude product was purified with column using PE/EA/CH2C12 = 1 : 1 : 1 as eluent to give compound (223) as yellow thick oil (237 mg, 8%). Example 106
Synthesis of N-Boc nitro derivative Compounds (224)
Figure imgf000099_0001
(224)
[002821 To a solution of compound (223) (237 mg, 0.8 mmol) in DCM (4 ml) was added Boc20 (0.28 ml, 1.2 mmol), and followed by DIEA (0.2 ml, 1.2 mmol) and DMAP (20 mg). The reaction mixture was stirred at room temperature for 3 h until the conversion of the starting material compound (233) was completed. After evaporating of solvent, the residue was purified with column using PE/EA = 8/1 as eluent to give compound (224) as a yellow thick oil (208 mg, 66%).
Example 107
Synthesis of isocyanate Compound (225)
Figure imgf000099_0002
(225)
[00283] To a solution of compound (224) (98 mg, 0.25 mmol) in MeOH (3 ml) was added Pd-C (20 mg). The reaction mixture was stirred for 2 h at 40 °C under hydrogen atmosphere until the conversion of the starting material compound (224) was complete. After filtering, the filtrate was concentrated in vacuum to give amino derivative as a pink solid (61 mg, 67%). To a solution of triphosgene ( 16 mg, 0.055 mmol) in DCM ( 1 ml) was added drop wise a solution of the amine (54 mg, 0.148 mmol) in DCM (1 ml) at 0 °C, and followed by TEA (0.04 ml, 0.296 mmol). After stirring for 2 h at room temperature, the reaction mixture was concentrated in vacuum at room temperature. The residue was dissolved in ether (10 ml), and the suspension was filtered. After concentrating of filtrate, the crude product was purified with column using PE/EA = 4/1 as eluent to give the isocyanate compound (225) as a colorless oil (39 mg, 67%).
Example 108
Synthesis of N-Boc nitro derivative Compounds (226)
Figure imgf000099_0003
(226)
[00284] l-(2-Bromoethoxy)-4-nitrobenzene was dissolved in ethanol and ethanolamine was added (lOeq). It was stirred at 80°C for 6 h, and the organic solvents were evaporated. The crude product was purified by flash column chromatography (5% MeOH/DCM to 15% MeOH/DCM). This residue (950 mg) was dissolved in DCM and 843 mg of DIEA was added, followed by addition of (Boc)20 (1 g) in DCM. And then the mixture was stirred at room temperature for 1 h. Product formation was monitored by TLC. The reaction was quenched by water and extracted with DCM. The organic layer was dried over Na2S04> filtered and concentrated. The crude product was purified by flashing column chromatography. To a suspension of NaH in dry THF was added a solution of the above product in dry THF at 0 °C. The mixture was stirred for 30 min, and then Mel in dry THF was added. The resulting mixture was stirred at room temperature for 3hrs. Check completion by TLC. The reaction was quenched by water. Organic solvent was evaporated under vacuum, and the residue was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give Compound (226). Example 109
Synthesis of isocyanate Compound (227'
Figure imgf000100_0001
(227)
[00285] Using a procedure similar to the preparation of Compound (225) as in Example 107 and replacing Compound (224) with Compound (226). the isocyanate Compound (227) was prepared.
Example 1 10
Synthesis of N-Boc nitro derivative Compounds (228)
Figure imgf000100_0002
(228)
[00286] To a solution of l-(2-bromoethoxy)-4-nitrobenzene (934 mg, 3.8 mmol) in acetonitrile (20 ml) was added an aqueous solution of ethyl amine (60-70%, 5 ml). The reaction mixture was heated at 80 with stirring for 7 h until the conversion of starting reactant was complete. After evaporating of solvent, the residue was dissolved in ethyl acetate, and dried over Na2S04. After filtering and evaporating, the crude product was purified with column using PE/ EA = 2/1 as eluent to give ethylamino derivative as a yellow oil (750 mg, 94%). To a solution of this ethylamino derivative (750 mg, 3.6 mmol) in DCM (20 ml) was added Boc20 (1.17 ml, 5.1 mmol), and followed by TEA (0.7 ml, 5.1 mmol) and DMAP (80 mg). The reaction mixture was stirred for 1.5 h at room temperature until the conversion of starting reactant was complete. After evaporating of solvent, the crude product was purified with column using PE/EA = 5/1 as eluent to give N-Boc nitro derivative Compounds (228") as a yellow solid (1.08 g, 97%).
Example 1 1 1
Synthesis of isocyanate Compound (229)
N
Boc
NCO
(229)
[00287] Using a procedure similar to the preparation of Compound (225) as in Example 107 and replacing Compound (224) with Compound (228). the isocyanate Compound (229) was prepared.
Example 112
Synthesis of 4-2-morpholinoethoxy)benzoyl azide Compound (230)
Figure imgf000100_0003
(230)
[00288] 1, 2-Dibromoethane (15 g, 79.7 mmol) was dissolved in anhydrous DMF, Cs2C03 (13 g, 39.5 mmol) was added. Methyl 4-hydroxybenzoate (2 g, 21 mmol) was added slowly. After addition, the reaction mixture was allowed to stir at 60 °C overnight. Check completion by TLC, the resulting mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The crude was purified by silica gel column to give methyl 4-(2-bromoethoxy)benzoate (0.95 g, 90%). Methyl 4-(2-bromoethoxy)benzoate (0.95 g, 3.7 mmol) in 2ml DMF was added drop-wise to 7 ml morphine. Stirring was continued overnight at room temperature. Check completion by TLC. The reaction mixture was mixed with water, extracted by ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give methyl 4-(2-morpholinoethoxy)benzoate (0.9 g, 92%). To a solution of methyl 4-(2-morpholinoethoxy)benzoate (0.9 g, 3.4 mmol) in MeOH (2ml) was added 2ml of 2N NaOH in water. Stirring was continued at 40°C for 2hrs. TLC showed no starting material left. The solvent was removed under reduce pressure. The residue was acidified to pH 4. The solid that was formed was filtered and washed with ice-water to give 4-(2-morpholinoethoxy)benzoic acid (0.85 g, 97%). 4-(2- Morpholinoethoxy)benzoic acid (0.3 g, 1.2 mmol) was dissolved in SOCl2. The resulting mixture was refluxed for 4 hrs. The solvent was evaporated to give 4-(2-morpholinoethoxy)benzoyl chloride (0.3 g, 93%). 4-(2-Morpholinoethoxy)benzoyl chloride (0.3 g, 1.1 mmol) in acetone was added drop-wise to a solution of NaN3 (0.29 g, 0.44 mmol) in water. The reaction mixture was allowed to stir at rroom temperature overnight. The solvent was evaporated and the residue was extracted by ethyl acetate. The combined organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give 4-2- morpholinoethoxy)benzoyl azide Compound (230) (0.24 g, 80%).
Example 1 13
Synthesis of 4-(2-(4-isocyanatop enoxy)ethyI)morpholine Compound (231)
Figure imgf000101_0001
(231)
[00289] A solution of 4-2-morpholinoethoxy)benzoyl azide Compound (230) (0.24 g, 0.87 mmol) in anhydrous toluene was refluxed under nitrogen atmosphere for 3hrs. Check completion by TLC. The solvent was evaporated to give 4-(2-(4- isocyanatophenoxy)ethyl)morpholine Compound (231) (0.2 g, 91%).
Example 1 14
Synthesis of tert-butyl methyl(4-nitrophenethyl)carbamate Compound (232)
Figure imgf000101_0002
(232)
[00290] To a solution of 4-nitrophenyl acetic acid (5 g, 27.6 mmol) in DCM ( 100ml) was added HATU (1 1.5 g, 30.3 mmol) followed by DIEA ( 10.9 g, 84.5 mmol). It was cooled down to 0°C and methylamine hydrochloride salt (2.8 g, 41.5 mmol) was added. It was stirred at room temperature for 16 hrs. The product formation was followed by TLC. After the reaction was complete, it was quenched by water, organic layer was extracted by DCM and followed by ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash column chromatography to obtain pure N-methyl-2-(4-nitrophenyl)acetamide as yellow solid (4 g, 75%). To a solution of this acetamide (2.2 g, 1 1.3 mmol) in dry THF (50ml) was added 3M Borane-methyl sulfide complex ( 18.8ml, 56.7 mmol) at 0 °C. The reaction mixture was refluxed for 16 hrs. After cooling, the reaction mixture was quenched by ice/water; organic solvents were removed by vacuum. The residue was extracted with ethyl acetate and it was purified by acid base extraction. Organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to obtained pure N-methyl-2-(4- nitrophenyl)ethanamine (1.6 g, 78%). To a solution of this ethanamine (600 mg, 3.33 mmol) in DCM (25 ml) was added DIEA (645 mg, 5 mmol). It was cooled down to 5 °C; (Boc)20 (800 mg, 3.66 mmol) in DCM (5 ml) was added. The W 201 resulting mixture was stirred at room temperature for 3 hrs. Product formation was followed by TLC. Upon completion, it was quenched by water. The organic layer was evaporated under vacuum. The residue was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under vacuum. The crude was purified by flashing column chromatography to obtained pure tert-butyl methyl(4-nitrophenethyl)carbamate, Compound (232) (500 mg, 53.5%).
Example 1 15
Synthesis of tert-butyl 4-isocyanatophenethyl(methyl)carbamate Compound (233)
Figure imgf000102_0001
(233)
100291] Using a procedure similar to the preparation of Compound (225) as in Example 107 and replacing Compound (224) with Compound (232), tert-butyl 4-isocyanatophenethyl(methyl)carbamate Compound (233) was prepared.
Example 1 16
Synthesis of tert-butyl methyl(2-(2-(4-nitrophenoxy)ethoxy)ethyl)carbamate Compound (234)
Figure imgf000102_0002
(234)
[00292) To a solution of 2-(4-nitrophenoxy)ethanol (1.5 g, 8.19 mmol) in THF was added NaH (0.33 g, 9.0 mmol) at 0 °C. The mixture was stirred at room emperature for 10 min, and then methyl a-bromoacetate (1.37 g, 8.19mmol) was added drop- wise. The resulting mixture was stirred at room temperature for 3hrs. Organic solvent was removed and water was added, followed by EA. The organic layer was washed with water and brine, dried over Na2S04, filtered and concentrated to give methyl 2-(2-(4-nitrophenoxy)ethoxy)acetate (1.5 g, 68%). Methyl 2-(2-(4-nitrophenoxy)ethoxy)acetate (1.5 g, 5.6 mmol) was dissolved in ethanol and then LiOH.H20 (1.0 g, 23.8 mmol) was added. The mixture was heated to reflux for 30 min. Ethanol was removed, and then ether and water were added. The aqueous layer was washed with ether for three times, and then acidified to pH value 2 with IN HCl, extracted with DCM for three times. The combined organic layer was dried over Mg2S04, filtered and concentrated to give 2-(2-(4-nitrophenoxy)ethoxy)acetic acid (0.96 g, 71%). To a solution of 2-(2-(4- nitrophenoxy)ethoxy)acetic acid (0.85 g, 3.4 mmol) in THF was added CH3NH2 (27% in alcohol, 800 mg, 6.97 mmol) followed by addition of HATU (1.41 g, 3.71 mmol). The mixture was stirred at room temperature for 3 hrs. The solvent was removed, and then water and EA were added. The organic layer was washed with 0.1N HCl and NaHC03 (aq), dried over Na2S04, filtered and concentrated to give N-methyl-2-(2-(4-nitrophenoxy)ethoxy)acetamide (800 mg, 80%). To a solution of N-methyl-2-(2-(4-nitrophenoxy)ethoxy)acetamide (800 mg, 2.85 mmol) in THF was added BH3 THF. The solution was heated to reflux for 2 hours. Organic solvent was removed. The residue was partitioned between IN HCl and DCM. The organic layer was washed with IN HCl for several times. The combine aqueous layer was adjusted to pH value 10 with LiOH and extracted with DCM for 3 times. The organic layers was collected and dried. The solvent was removed to give N-methyl- 2-(2-(4-nitrophenoxy)ethoxy)ethanamine (400 mg, 59%). To a solution of this ethanamine in DCM, 1.5 mole equivalent of Boc20 was added followed by the addition of DIEA and DMAP. The reaction was reacted for 3 hrs until the conversion was completed. Evaporation of solvent, the residue was purified by chromatography to give iert-butyl methyl(2-(2-(4- nitrophenoxy)ethoxy)ethyl)carbamate Compound (234). Example 1 17
Synthesis of tert-butyl 2-(2-(4-isocyanatopheno y)ethoxy)ethyI(methyl)carbamate Compound (235)
Figure imgf000103_0001
(235)
[00293] Using a procedure similar to the preparation of Compound (225) as in Example 107 and replacing Compound (224) with Compound (234), tert-butyl 2-(2-(4-isocyanatophenoxy)ethoxy)ethyl(methyl)carbamate Compound (235) was made.
Example 1 18
tert-Butyl 2,2'-(4-(azidocarbonyl)-l,2-phenylene)bis(oxy)bis(ethane-2,l-diyl)bis(methylcarbamate) Compound (236)
Figure imgf000103_0002
(2
[00294] A solution of DIAD (9.6, 47.6 mmol) in 5 ml of THF was added drop-wise to a solution of methyl
3,4-dihydorxybenzoate (2.0g, 11.9 mmol), iert-butyl 2-hydroxyethyl(methyl)carbamate (8.3g, 47.6mmol) and
triphenylphosphine ( 12.5g, 47.6mmol) in 60 ml of THF with ice-bath cooling under nitrogen atmosphere. The resulting mixture was stirred at 40°C overnight. The solvent was evaporated. The residue was mixed with ether and filtered. The filtrate was concentrated and purified by flashing silica gel column to give methyl 3,4-bis(2-(teri- butoxycarbonyl(methyl)amino)ethoxy)benzoate as colorless oil. This crude benzoate was stirred with Petroleum ether, and filtered. The filtrate was concentrated to afford the pure product (1.7 g, 30%). To a solution of methyl 3,4-bis(2-(tert- butoxycarbonyl(methyl)amino)ethoxy)benzoate (1.7 g, 3.5 mmol) in methanol was added IN NaOH solution 2.5 ml. The solution was stirred at room temperature overnight. The solvent was removed, and the residue was dissolved in water. To the water layer was added 0.5N HCl/water drop-wise until pH~4. The mixture was extracted with DCM for 3 times. The organic layers was combined and washed with brine and concentrated to give 3,4-bis(2-(te - butoxycarbonyl(methyl)amino)ethoxy)benzoic acid (1.4 g, 85%). 300 mg (0.640 mmol) of 3,4-bis(2-(terf- butoxycarbonyl(methyl)amino)ethoxy)benzoic acid was dissolved in 5 ml DCM under nitrogen atmosphere, and then DMF (3 drops) was added, followed by addition of oxalyl chloride (98 mg, 0.768 mmol). The solution was stirred at room temperature for 3 minutes. DCM was removed under reduced pressure at a low temperature to afford the corresponding acid chloride (300 mg), which was dissolved in acetone and was added drop-wise to a solution of NaN3 (125 mg, 1.92 mmol). The resulting solution was stirred for another 5 minutes. Acetone was removed, and DCM was added. The organic layer was washed with brine and concentrated. The crude was purified by Prep.TLC to afford tert-butyl 2,2'-(4-(azidocarbonyl)-l,2- phenylene)bis(oxy)bis(ethane-2, l-diyl)bis(methylcarbamate) Compound (236) (280mg, 89%). Example 1 19
tert-Butyl 2,2'-(4-isocyanato-l,2-phenylene)bis(oxy)bis(ethane-2,l-diyl)bis(methylcarbamate) Compound (237)
Figure imgf000104_0001
(237)
[00295] Using a procedure similar to the preparation of Compound (231) as in Example 1 13 and replacing Compound (230) with Compound (236). teri-butyl 2,2'-(4-isocyanato-l,2-phenylene)bis(oxy)bis(ethane-2,l-diyl)bis(methylcarbamate) Compound (237) was prepared.
Example 120
Synthesis of isocyanate Compounds (238), (239), (240), (241), (242) (243), (244), (245), (246) and (247)
Figure imgf000104_0002
Figure imgf000104_0003
[00296] Using synthetic procedures similar to Examples 105. 106 and 107 in the preparation of isocyanate Compound (225) and various mono- or multi-hydroxy nitrobenzene or synthetic procedures similar to Examples 112 and 1 13 in the preparation of isocyanate Compound (231) and various mono- or multi-hydroxy benzoate, various isocyanate Compounds (238), (239), (240), (241), (242) (243J, (244), (245), (246) and (247) were prepared.
Example 121
Synthesis of Compound (248)
Figure imgf000105_0001
[00297] To a solution of Compound (45) (76 mg, 0.046 mmol) in DMF (1 ml) was added a solution of DBU (23 mg, 0.15 mmol, 3.0 eq) in DMF (0.5 ml) at 0 °C under Argon, and followed by the addition of a solution of Compound (225) (39 mg, 0.099 mmol, 2.0 eq) in DMF (1.5 ml). The reaction mixture was stirred at room temperature for 15 h. The reaction was quenched with two drops of water. After evaporating of DMF, the residue was dissolved in MeOH, and the solution was filtered. After concentrating of filtrate, the residue was purified with Prep.HPLC to give Compound (248) as a white solid (22 mg, 23%).
Example 122
Synthesis of Compound (249)
Figure imgf000105_0002
[00298] Compound (248) (22 mg, 0.0108 mmol) was dissolved in a mixture solution of DCM (2 ml) and TFA (2 ml). After stirring for 6 h at room temperature, the reaction mixture was concentrated in vacuum. The residue of yellow powder (22 mg) was washed with ether and filtered to give Compound (249) (13.5 mg, 62%). Example 123
Figure imgf000106_0001
(00299| Using synthetic procedures similar to the preparation of Compound (249) as in Examples 121 and 122 and replacing Compound (225) with Compound (227), Compound (250) was prepared.
Example 124
Synthesis of Compound (116)
Figure imgf000106_0002
[00300] Using synthetic procedures similar to the preparation of Compound (249) as in Examples 121 and 122 and replacing Compound (225) with Compound (229), Compound (116) was made.
Example 125
Figure imgf000106_0003
[00301] Using synthetic procedures similar to the preparation of Compound (249) as in Examples 121 and 122 and replacing Compound (225) with Compound (231), Compound (117) was prepared. Example 126
Synthesis of Compound (251)
Figure imgf000107_0001
[00302] Using synthetic procedures similar to the preparation of Compound (249) as in Examples 121 and 122 and replacing Compound (225) with Compound (233). Compound (251) was made.
Example 127
Figure imgf000107_0002
[00303] Using synthetic procedures similar to the preparation of Compound (249) as in Examples 121 and 122 and replacing Compound (225) with Compound (235), Compound (252) was prepared.
Example 128
Figure imgf000107_0003
[00304] Using synthetic procedures similar to the preparation of Compound (249) as in Examples 121 and 122 and replacing Compound (225) with Compound (237), Compound (253) was prepared.
Example 128a
Synthesis of Compound (254)
Figure imgf000108_0001
[00305] Using synthetic procedures similar to the preparation of Compound (249) as in Examples 121 and 122 and replacing Compound (225) with Compound (238), Compound (254) was made.
Example 129
Synthesis of Compounds (255). (256). (257). (258). (259). (260). (261). (262). (263). (264). (265). (266). (267) and (268J
Figure imgf000108_0002
Figure imgf000109_0001
[00306] Using synthetic procedures similar to the preparation of Compound (249) as in Examples 121 and 122 and replacing Compound (225) with various isocyanates such as Compounds (239). (240). and other similar cisocyantes, Compounds (255), (256), (257), (258), (259), (260), (261), (262), (263), (264), (265), (266), (267) and (268) were prepared.
Example 130
and (277)
Figure imgf000109_0002
Figure imgf000110_0001
[00307] Using synthetic procedures similar to the preparation of Compound (249) as in Examples 121 and 122 and replacing Compound (225) with various isocyanates, Compounds (269). (270). (271). (272). (273). (274). (275). (276) and (277) are made.
Example 131
Synthesis of Compound (278)
Figure imgf000110_0002
(2Z§)
[00308] To a mixture solution of vancomycin hydrochloride (100.0 g) and NaHC03 (28.3g) in THF (700 ml) and water (500 ml) was added a solution of pNZ-OSu (56.2 g) in THF (200ml) with stirring at 0 °C for lh. The reaction mixture was then stirred at room temperature for 2 hr. The organic layer was separated and the volatile was removed under reduce pressure. The resulting solid was collected by filtration under vacuum and washed with EtOAc and ether, dried under vacuum at 40 °C to give a solid. To a solution of this solid (2g, 1.106 mmol, leq) in DMF (20ml) was added solid NaHC03 ( 1.12 g, 13.27 mmol, 13.27 mmol) with stirring at 0 °C for lh, followed by the addition of l-(bromomethyl)-4-nitrobenzene (2.39g, 11.06 mmol, 10 eq) in one portion. The reaction mixture was stirred at room temperature for lh. The reaction was monitored by analytical HPLC and the starting material was completely consumed. The insoluble solid was filtered away. The filtrate was poured into MTBE (150 ml). The formed solid was collected by filtration washed with EtOAc (20mL*3), dried under vacuum. The solid will be purified by silica gel column chromatography to afford Compound (278). ESI-MS: m/z: calcd for Cg9H9oCl2N12034 [M+H]+ 1943.63; Found: 1843.3 (100%); [M+CF3COO]" 2055.63; Found: 2055.5 (100%).
Example 132
and (287)
Figure imgf000111_0001
[00309] Using a procedure similar to the preparation of Compound (184) as in Example 97 and replacing Compound (163) with Compound (278) and isocyanate Compound (175) with various pNZ nitrogen protected isocyanates, Compounds (279). (280). (281). (282). (283). (284). (285). (286) and (287) are made. Example 133
Synthesis of Compound (288)
Figure imgf000112_0001
[00310] To a solution of Compound (44) (100 mg) in 3 ml of DMF was added CDI (15.8 mg, 1.5 eq) and TEA (19.7 mg, 3 eq). The mixture was stirred at 50 °C for 3 hours. Check completion by HPLC-MS. Then the solvent was removed under reduced pressure. The residue was purified by Prep-HPLC to afford Compound (288) (68 mg, yield=68%). LC- MS: 1563.5 (M+l).
Example 134
(296)
Figure imgf000112_0002
|003111 Using a synthetic procedures similar to the preparation of Compound (249) as in Examples 121 and 122 and replacing Compound (45) with Compound (288) and also replacing Compound (225) with various isocyanates, Compounds (289), (291) and (292) were prepared and (290), (293), (294), (295) and (296) are made.
Example 135
Alternate synthesis of Compound (33) or phenolic regioisomer
Figure imgf000113_0001
[00312] A solution of Compound (163) (4.0g, 2.06 mmol) in anhydrous DMF (15 ml) was treated with C8H17NCO (640 mg, 4.12 mmol) in the presence of DMAP (250 mg, 2.06 mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by analytical HPLC and the starting material was completely consumed. The reaction mixture was poured into 200 ml of MTBE and a precipitate was formed. The solid (4.2g) was collected by filtration and dried under vacuum. The solid (350 mg) was dissolved in DMF (10 ml) and poured into a buffer (30 ml) (DMF-H20 (3/2)) containing N-methylmorpholine (0.68 g) and acetic acid (0.28 g) (pH 6.0) .The resulting biphasic reaction mixture was hydrogenated over 5% Pd/C (500 mg) at room temperature overnight under latm. The reaction was monitored by analytical HPLC. The reaction mixture was filtered and washed with DMF. The filtrate was concentrated and the residue was solidified with MTBE. The solid was collected by filtration and purified by RP-HPLC to afford Compound (33) or phenolic regioisomer. ESI-MS: m/z: calcd for C85H107Cl2NI 1O24 [M+H] + 1738.72; Found: 1738.4 (100%), 1 159.2 (46.4%), 869.7(41.7%); [M+CF3COO]" 1850.72; Found: 1850.5 (100%). +MS2(1738.0):
1593 A( 100%), 1431.3 (34.2%).
Example 136
N-(2-(3-aminopropylamino)ethyl)-4-(pentyloxy)benzenesulfonamide, Compound (297)
Figure imgf000113_0002
(297)
[00313] To a solution of pentoxybenzene (5.0 g, 30.8 mmol) in chloroform was added chlorosulfuric acid (7.2 g, 61.7 mmol) dropwise at 0 °C. Stirring was continued overnight at room temperature. The solvent was removed under reduced pressure. Ether was added to the residue, followed by crushed ice. The organic layer was dried over Mg2S04, filtered and concentrated to give 4-(pentyloxy)benzene-l-sulfonyl chloride (6.7 g, yield: 85%). To a solution of 1 ,2-diaminoethane (1.38 g, 23 mmol) in 15ml THF was added a solution of 4-(pentyloxy)benzene-l-sulfonyl chloride ( 1.0 g, 3.8 mmol) in 50ml THF dropwise at 0 °C. The mixture was stirred at room temperature for 2h. The solvent was removed and EA/water was added. To the mixture was added IN NaOH dropwise until pH=10. The organic layer was washed with water for 6 times and brine for 2 times, dried
- I l l - over sodium sulfate, filtered and concentrated to give N-(2-aminoethyl)-4-(pentyloxy)benzenesulfonamide (1.1 g, yield: 85%). To a solution of N-(2-aminoethyl)-4-(pentyloxy)benzenesulfonamide (1.1 g, 3.8 mmol) in acetonitrile was added t- butyl 2-bromoethylcarbamate (1.3 g, 5.7 mmol) and potassium carbonate (1.3 g, 9.5 mmol). The mixture was heated to 95 °C overnight. The resulting mixture was cooled down to r.t. and filtered. The filtrate was concentrated and purified by chromatography to give a mixture of ieri-butyl 3-(2-(4-(pentyloxy)phenylsulfonamido)ethylamino)propylcarbamate. A solution of ieri-butyl 3-(2-(4-(pentyloxy)phenylsulfonamido)ethylamino)propylcarbamate (600 mg, not pure) in 6 ml of TFA/DCM (1/1) was stirred at 0°C for lh. The solvent was evaporated and the residue was mixed with water. The mixture was adjusted to pH 10 with sodium hydroxide (2N) and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The crude was purified by Prep.TLC to give N-(2-(3- aminopropylamino)ethyl)-4-(pentyloxy)benzenesulfonamide, compound (297) (358 mg).
Example 137
Figure imgf000114_0001
(298)
[00314] To a solution of vancomycin (20.0 g, 13.5 mmol) and DIEA (3.83 g, 29.7 mmol) in DMSO (300 ml) was added CDI (2.21 g, 13.5 mmol). The mixture was stirred at 45 °C overnight, and then another batch of CDI (0.66 g, 4.0 mmol) was added. The mixture was stirred for another 3h. The reaction was quenched by water, and DMSO was removed under reduced pressure at 70 °C. The residue was purified by reverse flash column (ACN/water, 5-20%, 0.5% acetic acid) to give compound (298) as a white powder (6.7g, yield: 33%).
Example 138
Figure imgf000115_0001
[00315] N-(2-(3-aminopropylamino)ethyl)-4-(pentyloxy)benzenesulfonamide (156 mg, 0.475 mmol) and DIEA (62 mg, 0.475 mmol) were combined in 2ml of water/acetonitrile(l/l). Formaldehyde (60 mg, 3.7% water solution) was added. To the mixture that was obtained was added a mixture of compound (298) (100 mg, 0.068mmol) and DIEA (62 mg, 0.475 mmol). Stirring was continued overnight. The solvent was evaporated, and the residue was washed with
acetonitrile/methanol/ether (10/1/1) and filtered. The solid was purified by Prep.HPLC to give compound (299) (3.5 mg).
Example 139
Synthes (305), (306), (307), (308), (309), (310), and (311)
Figure imgf000115_0002
Figure imgf000116_0001
[00316] Using a procedure similar to the preparation of Compound (299) as in Example 138 and replacing N-(2-(3- aminopropylamino)ethyl)-4-(pentyloxy)benzenesulfonamide with various amines, compounds (300), (301), (302). (303). (304), (305), (306), (307), (308), (309), (310), and (311) were prepared. Example 140
Figure imgf000117_0001
[00317] Using synthetic procedures similar to the preparation of Compound (33) as in Examples 135 and replacing isocyanate C8Hi7NCO with various isocyanate or N-p-nitrocarbobenzyloxy isocyanate derivatives, Compounds (312). (313) and (317) were prepared and Compounds (314), (315), and (316) or phenolic regioisomers are made.
Example 141
regioisomers
Figure imgf000118_0001
[00318] Using synthetic procedures similar to the preparation of Compound (33) as in Examples 135 and replacing isocyanate C8Hl7NCO with various isocyanate or N-p-nitrocarbobenzyloxy isocyanate derivatives, and also Compound (163) with Compound (278). Compounds (318). (321) and (322) were prepared and Compounds (319). (320). and (323) or phenolic regioisomers are made.
Example 142
Figure imgf000119_0001
[00319] Using synthetic procedures similar to the preparation of Compound (299) as in Examples 138 and replacing N-(2-(3- aminopropylamino)ethyl)-4-(pentyloxy)benzenesulfonamide with N-(2-aminoethyl)-4-(pentyloxy)benzenesulfonamide and also replacing Compound (298) with Compounds (318), Compound (319) or Compound (322), Compounds (324), (325), and (326) or phenolic regioisomers are prepared.
Example 143
Synthesis of Compound (313) or phenolic re ioisomer
Figure imgf000119_0002
[00320] A solution of Compound (163) (3.0g, 1.546 mmol) in anhydrous DMF (10 ml) was treated with l-butoxy-4- isocyanatobenzene (592 mg, 3.092 mmol) in the presence of DMAP (188 mg, 1.546 mmol) at room temperature under nitrogen. The resulting mixture was stirred for 2h at room temperature. The reaction was monitored by analytical HPLC and the starting material was completely consumed. The reaction mixture was poured into 250 ml of methyl tert-butyl ether and a precipitate was formed. The solid (2.8 g) was collected by filtration and dried under vacuum. The solid (2.8g) was dissolved in DMF (10 ml) and poured into a buffer (60 ml)(DMF-H20 (3/2)) containing N-methylmorpholine (1.36 g) and acetic acid (0.56 g) (pH~6.0) .The resulting biphasic reaction mixture was hydrogenated over 5% Pd/C (800 mg) at room temperature overnight under lata. The reaction was monitored by analytical HPLC. The reaction mixture was filtered and washed with DMF. The filtrate was concentrated and the residue was solidified with methyl tert-butyl ether. The solid was collected by filtration and purified by RP-HPLC to afford Compound (313) or phenolic regioisomer (70 mg). HPLC Ret time 1 1.612 min, purity: 91.682%. ESI-MS: Compound (313) m z: calcd for
Figure imgf000120_0001
[M+H] + 1774.71 ; Found: 1774.4 (100%), 1 183.1 (77.2%), 887.7(48.7%); [M+CF3COO]" 1886.71 ; Found: 1886.5 (100%) +MS2(1774.0):
1629.4( 100%), 1467.3(48.9%).
Example 144
Figure imgf000120_0002
[00321] A solution of Compound (163) (2.0 g, 1 eq) in anhydrous DMF ( 15 ml) was treated with TV-butyl-JV-/?- nitrocarbobenzyloxy-4-isocyanatoaniline (1 g, 2 eq) in the presence of DBU (0.2 ml, 1.5 eq) at room temperature under nitrogen. The resulting mixture was stirred for 3h at room temperature. The reaction was monitored by analytical HPLC and the starting material was completely consumed. The reaction mixture was poured though a pad of silica gel, the filtrate was removed away. The cake was washed with a solution of 50% CH2C12 in MeOH. The filtrate was concentrated and dried under vacuum to afford a solid (2.6 g). The solid (2.6g) was dissolved in DMF (20ml) and poured into a buffer (60ml) (DMF-H20 (3/2)) containing N-methylmorpholine (1.36 g) and acetic acid (0.56 g) (pH~6.0) .The resulting biphasic reaction mixture was hydrogenated over 5% Pd/C (2.5 g) at room temperature overnight under 1 atm. The reaction was monitored by analytical HPLC. The reaction mixture was filtered and washed with DMF. The filtrate was concentrated and the residue was solidified with methyl tert-butyl ether. The solid was collected by filtration and purified by RP-HPLC to afford Compound (327) or phenolic regioisomer (20 mg). HPLC Ret time 9.025 min, purity 95.619%. ESI-MS: m/z: calcd for QvH^ClzNnC^ [M+H] + 1773.73; Found: 1773.4 (100%), 1182.0 (10%), 887.1(42.4%); [M+CF3COO]" 1885.73; Found: 1885.5 (100%). +MS2(1773.0): 1654.4(100%), 1276.2(88.8%).
Example 145
Synthesis of Compound (328)
Figure imgf000121_0001
[00322] To a mixture solution of vancomycin (15 g, leq) in DMF/DMSO (10/1) 165 ml was added DIPEA (5.2 ml, 3eq) at room temperature, followed by addition of benzaldehyde (3.2 ml, 3eq). The resulting mixture was stirred for 3 h at room temperature. The forming water was removed away under reduce pressure. To the resulted mixture solution a solution of pNZOSu (3.2 g) in 20 ml DMF was added at 0 . The reaction was stirred for 4 h at room temperature. The reaction mixture was poured into a mixture solution of HOAc/H20 (1/1) and stirred for 4h. The solution was concentrated to 100 ml under vacuum. The residue was washed with EtOAc (3> 200 ml). The formed solid was collected by filtration and washed with water (50 ml) and EtOAc (100 ml), dried in vacuum to provided Compound (328).
Example 146
Synthesis of Compound (312) or phenolic regioisomer
Figure imgf000121_0002
[00323] A solution of compound (163) ( 1.2 g, 0.618mmol) in anhydrous DMF (7ml) was treated with 2-isocyanatononane (125.6 mg, 0.742 mmol) in the presence of DMAP (82.58 mg, 0.68 mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 4 h. The reaction was monitored by analytical HPLC and the starting material was completely consumed. The solvent was removed away under vacuum. 100 ml of methyl tert-butyl ether was added. A formed solid was collected by filtration and washed with EtOAc (3x20 ml). The solid (1.3 g) was dried under vacuum, which was used without further purification. The solid (1.3g) was dissolved in DMF (5 ml) and poured into a buffer (30ml) (DMF- H20=3:2, pH= 6.0) .The resulting reaction mixture was hydrogenated over 5% Pd/C (0.2g) at room temperature under latm overnight. The reaction was monitored by analytical HPLC. The reaction mixture was filtered and washed with DMF. The filtrate was concentrated under reduce pressure. The residue was solidified with EtOAc (100 ml). The solid was collected by filtration and washed with ethyl acetate (3 x20 ml), which was purified by RP-HPLC to provide compound (312) (50mg). ESI-MS: V625 (PL0142) m/z: calcd for C86H1o9Cl2N11024 [M+H] + 1752.75; Found: 1751.3, 1606.3, 1444.3, 1 167.5
Example 147
Synthes phenolic regioisomer
Figure imgf000122_0001
[00324] Using synthetic procedures similar to the preparation of Compound (312) as in Examples 146 and replacing compound (163) with compound (278) as well as 2- isocyanatononane with l-isocyanato-4-propoxybenzene Compound (329) or phenolic regioisomers was prepared. Compound (329) m/z: calcd for C76H86Cl2N10O26 [M+H] + 1627.45; Found: 1626.2, 1554.1, 1390.3, 1078.7
Example 148
Synthesis of Compound (317)
Figure imgf000122_0002
[00325] A solution of compound (163) (2.0 g, 1.03 mmol, leq) in anhydrous DMF (10 ml) was treated with N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide (759 mg, 2.06 mmol, 2eq) in the presence of DMAP ( 125 mg, 1.03 mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by analytical HPLC and the starting material was completely consumed. The solvent was removed away under vacuum. The residue was dissolved in 10 ml MeOH and poured into 200 ml of methyl tert-butyl ether. A precipitate was collected by filtration and washed with EtOAc (3 x20 ml). The solid (1.6g) was dried under vacuum, which was used without further purification. The solid ( 1.6g) was dissolved in DMF (10 ml) and poured into a buffer (20 ml) (DMF-H20=3 :2, pH=6.0). The resulting biphasic reaction mixture was hydrogenated over 5% Pd/C ( l .Og) at room temperature under latm for 3 h. The reaction was monitored by analytical HPLC. The reaction mixture was filtered and washed with DMF. The filtrate was concentrated under reduce pressure. The residue was dissolved in 10 ml MeOH and poured into methyl tert-butyl ether (200ml). The solid was collected by filtration and washed with ethyl acetate (3x20 ml), which was purified by RP-HPLC to provide compound (317) (89mg). ESI-MS: m/z: calcd for C94H118C12N12027S [M+H] + 1951.98; Found: 1951.6, 1806.5,
1646.5.
Example 149
Synthesis phenolic regioisomer
Figure imgf000123_0001
[00326] A solution of compound (278) (2.0 g, 1.03 mmol, 1 eq) in anhydrous DMF (10 ml) was treated with /V-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide (759 mg, 2.06 mmol, 2 eq) in the presence of DMAP (125 mg, 1.03 mmol) at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by analytical HPLC and the starting material was completely consumed. The solvent was removed away under vacuum. The residue was dissolved in 10 ml MeOH and poured into 200 ml of methyl tert-butyl ether. A precipitate was collected by filtration and washed with EtOAc (3 χ 20ml), and dried under vacuum yielding 1.2 g carbamate derivative as a solid. The solid (1.2g) was dissolved in DMF (10 ml) and poured into a buffer (30ml)(DMF-H2O=3 :2, pH=6.0) .The resulting biphasic reaction mixture was hydrogenated over 5% Pd/C (l .Og) at room temperature under 1 arm for 3 h. The reaction was monitored by analytical HPLC. The reaction mixture was filtered and washed with DMF. The filtrate was concentrated under reduce pressure. The residue was dissolved in 10 ml MeOH and poured into methyl tert-butyl ether (200 ml). The solid (l . lg) was collected by filtration and washed with ethyl acetate (3x20 ml), which was purified by RP-HPLC to afford Compound (322) (82mg). ESI-MS: m/z: calcd for C84H103Cl2NuO28S [M+H] + 1818.74; Found: 1818.5, 1673.4, 1513.4. Example 150
Synthes phenolic regioisomer
Figure imgf000124_0001
[00327] Using synthetic procedures similar to the preparation of Compound (317) as in Examples 148 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with 1 -ethoxy-4-isocyanatobenzene, Compound (330) or phenolic regioisomers was prepared. Compound (330): ESI-MS: m/z: calcd for C85H99CI2N11O25 [M+H] + 1746.66; Found: 1746.4, 1745.41276.
Example 151
Synthes phenolic regioisomer
Figure imgf000124_0002
[00328] Using synthetic procedures similar to the preparation of Compound (317) as in Examples 148 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with l-butyl-4-isocyanatobenzene, Compound (331) or phenolic regioisomers was prepared. Compound (331) : ESI-MS: m/z: calcd for
Figure imgf000124_0003
[M+H] + 1758.71 ; Found: 1759.0(100%); [M+CF3COO]' 1870.71 ; Found: 1870.8(100%).
Example 152
Synthes phenolic regioisomer
Figure imgf000125_0001
[00329] Using synthetic procedures similar to the preparation of Compound (317) as in Examples 148 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with l-hexyl-4-isocyanatobenzene, Compound (332) or phenolic regioisomers was prepared. Compound (332): ESI-MS: m/z: calcd for C89H107Cl2Ni1O24 [M+H] + 1786.77; Found:
1787.0(100%); [M+CFjCOO]- 1898.77; Found: 1898.9(100%).
Example 153
Synthes phenolic regioisomer
Figure imgf000125_0002
[00330] Using synthetic procedures similar to the preparation of Compound (317) as in Examples 148 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with 4-nitrobenzyl 3-(4-isocyanatophenoxy)propyl(methyl)carbamate, Compound (333) or phenolic regioisomers was prepared. Compound (333): ESI-MS: m/z: calcd for ΰ87Ηιο4¾Ν12θ25 [M+H] + 1789.73; Found: 1789.7(100%), 1646.9(59.9%), 895.2(26.3%); [M+CF3COO]" 1901.73; Found: 1901.8(100%).
Example 154
Synthes phenolic regioisomer
Figure imgf000126_0001
[00331] Using synthetic procedures similar to the preparation of Compound (317) as in Examples 148 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with N-(4-isocyanatobutyl)-4-(pentyloxy)benzenesulfonamide, Compound (334) or phenolic regioisomers was prepared. Compound (334): ESI-MS: m/z: calcd for C92H114Cl2Ni2027S [M+H] + 1923.92; Found: 1924.8(100%); [M+CF3COO]" 2035.92; Found: 2036.6(100%).
Example 155
Synthes phenolic regioisomer
Figure imgf000126_0002
[00332] Using synthetic procedures similar to the preparation of Compound (317) as in Examples 148 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with 4-nitrobenzyl 2-(4-isocyanatophenoxy)ethyl(methyl)carbamate, Compound (335) or phenolic regioisomers was prepared. Compound (335): ESI-MS: m/z: calcd for
Figure imgf000126_0003
[M+H] + 1803.75; Found: 1805.1(100%); [M+CF3COO]- 1915.75; Found: 1958.9(100%). Example 156
Synthes phenolic regioisomer
Figure imgf000127_0001
[00333] Using synthetic procedures similar to the preparation of Compound (317) as in Examples 148 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with 4-nitrobenzyl 5-isocyanatopentyl (methyl)carbamate, Compound (336) or phenolic regioisomers was prepared. Compound (336): m/z: calcd for C83H104CI2N12O24 [M+H] + 1725.69; Found: 1725.6(100%), 791.4(53.0%); [M+CF3COO]_ 1837.69; Found: 1837.8(100%).
Example 157
Synthes phenolic regioisomer
Figure imgf000127_0002
[00334] Using synthetic procedures similar to the preparation of Compound (317) as in Examples 148 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with 4-nitrobenzyl ethyl(2-(4-(2-isocyanatoethyl)phenoxy)ethyl- carbamate, Compound (337) or phenolic regioisomers was prepared. Compound (337): ESI-MS: m/z: calcd for
C89H108Cl2Ni2O25 [M+H] + 1817.78; Found: 1817.9(100%), 837.9(16.9%); [M+CF3COO]_ 1929.78; Found: 1930.0(100%). Example 158
Synthe phenolic regio isomer
Figure imgf000128_0001
[00335] Using synthetic procedures similar to the preparation of Compound (317) as in Examples 148 and rep lacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with l-(2-isocyanatoethyl)-4-(pentyloxy)benzene, Compound (338) or phenolic regioisomers was prepared. Compound (338): ESI-MS: m/z: calcd for C90H109CI2N11O25 [M+H] + 1816.79; Found: 1818.5(100%); [M+CF3COO]" 1928.79; Found: 1928.9(100%).
Example 159
Synthe phenolic regio isomer
Figure imgf000128_0002
[00336] Using synthetic procedures similar to the preparation of Compound (317) as in Examples 148 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with l-butoxy-4-(2-isocyanatoethyl)benzene, Compound (339) or phenolic regioisomers was prepared. Compound (339): ESI-MS: m/z: calcd for C89H107Cl2 11O25 [M+H] + 1802.77; Found: 1802.8(100%), 1202.9(64.0%), 902.8(48.5%); [M+CF3COO]" 1914.77; Found: 1914.9(100%). Example 160
Synthes phenolic regioisomer
Figure imgf000129_0001
[00337] Using synthetic procedures similar to the preparation of Compound (317) as in Examples 148 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with l-(2-isocyanatoethoxy)pentane, Compound (340) or phenolic regioisomers was prepared. Compound (340): ESI-MS: m/z: calcd for C84H105CI2N11O25 [M+H] + 1740.7; Found:
1740.8( 100%), 1162.1(21.4%), 872.1(15.2%); [M+CF3COO]" 1852.7; Found: 1852.9( 100%).
Example 161
Synthes phenolic regioisomer
Figure imgf000129_0002
[00338J Using synthetic procedures similar to the preparation of Compound (317) as in Examples 148 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with l -ethoxy-2-(2-isocyanatoethoxy)ethane, Compound (341) or phenolic regioisomers was prepared. Compound (341): ESI-MS: m/z: calcd for C80H94CI2N10O26 [M+H] + 1683.56; Found: 1683.6(100%); [M+CF3COO]- 1795.56; Found: 1796.4(100%). Example 162
Figure imgf000130_0001
[00339] To a mixture solution of compound (328) (1.5 g, 1 eq) and K2C03 (0.5 g, 4 eq) in 15 ml DMF was added a solution of ( ?)-N-pNZ-alanine-OSu (0.55 g) in 5 ml DMF with stirring at 0 °C. The resulting mixture was stirred for overnight at room temperature. 100 ml of MTBE was added and a precipitate was formed. The solid was collected by filtration and washed with EtOAc (2> 50 ml), dried in vacuum giving the vancomycin alanine derivative as a solid (1.2 g). To a solution of this solid (1.2 g) in MeCN-H20 (2: 1) 12 ml at RT, DIPEA (5eq) was added, followed by addition of the N-(6-aminohexyl)-4- hexylbenzenesulfonamide (0.4g) and 1% aqueous HCHO (3 ml). The resulting mixture was stirred for 5 h at RT. The reaction was monitored by analytical HPLC. The solvent was removed under reduce pressure. The residue was washed with EtOAc (2x 10 ml) and dried under vacuum. 1.1 g of the crude Mannich condensed product was obtained as a solid and used in the next step without further purification. The solid (1.1 g) was dissolved in DMF (20 ml) and poured into a buffer (20ml) (DMF-H20=3 :2, pH= 6.0). The resulting biphasic reaction mixture was hydrogenated over 5% Pd/C (1.0 g) at room temperature under 1 atm for 14 h. The reaction was monitored by analytical HPLC. The reaction mixture was filtered and washed with DMF. The filtrate was concentrated under reduce pressure. Methyl tert-butyl ether (MTBE) (100 ml) was added. The formed solid was collected by filtration and applied to RP-HPLC, All the suitable fractions of the product were combined and 3 drops of aqueous NH40H was added until the pH 8-9. The solvent was concentrated to 50 ml and applied to a chromatographic column with reverse phase silica gel (5 g) that was preequilibrated with H20. The column was eluted firstly with H20 (10 ml) under reduce pressure. The column was then eluted with DCM-MeOH (1/1) under reduce pressure and monitored by analytical HPLC. All the fractions containing the desired compound were collected and concentrated in vacuum to provide Compound (342) (70mg). ESI-MS: m/z: calcd for C88Hi12Cl2Ni2027S [M+H] + 1873.87; Found:
1873.9( 100%), 1659.8(21%), 1249.3( 15.6%); [M+CF3COO]" 1985.87; Found: 1986.1(100%). Example 163
Figure imgf000131_0001
[003401 Using synthetic procedures similar to the preparation of Compound (342) as in Examples 162 and replacing (R)-N- pNZ-alanine-OSu with (R)-N-pNZ-valine-OSu, Compound (343) was prepared. Compound (343): ESI-MS: m/z: calcd for C9oH116Cl2N12027S [M+H] + 1901.92; Found: 1902.4(100%); [M+CF3COO]' 2013.92; Found: 2014.6(100%).
Example 164
Synthesis of Compound (344)
Figure imgf000131_0002
[00341] Using synthetic procedures similar to the preparation of Compound (342) as in Examples 162 and replacing (R)-N- pNZ-alanine-OSu with 2,5-dioxopyrrolidin-l-yl 6-((4-nitrobenzyloxy)carbonylamino)hexanoate, Compound (344) was prepared. Compound (344): ESI-MS: m/z: calcd for
Figure imgf000131_0003
[M+H] + 1915.95; Found: 1916.5(100%);
[M+CF3COO]- 2027.95; Found: 2028.1(100%). Example 165
Figure imgf000132_0001
[00342] Using synthetic procedures similar to the preparation of Compound (342) as in Examples 162 and replacing (R)-N- pNZ-alanine-OSu with N-pNZ-glycine-OSu,and also N-(6-aminohexyl)-4-hexylbenzenesulfonamide with N-(6-aminohexyl)- 4-pentyloxy)benzenesulfonamide, Compound (345) was prepared. Compound (345): ESI-MS: V656 (PL0148) m/z: calcd for C86H108Cl2N12O28S [M+H] + 1861.81; Found: 1862.5(100%), 1662.6(33.8%), 440.7(71.9%);[M-H]' 1973.81 ; Found:
1859.9(33.5%), 1239.9(38.5%),930.1 ( 100%).
Example 166
Synthesis of Compound (346)
Figure imgf000132_0002
[00343] Using synthetic procedures similar to the preparation of Compound (342) as in Examples 162 and replacing (7?)-N- pNZ-alanine-OSu with N-pNZ-glycine-OSu,and also N-(6-aminohexyl)-4-hexylbenzenesulfonamide with N-(4-aminobutyl)- 4-pentyloxy)benzenesulfonamide, Compound (346) was prepared. Compound (346): ESI-MS: m/z: calcd for
C84H104Cl2N12O28S [M+H] + 1833.76; Found: 1833.7 (100%), 1633.8 (39.1%), 817.7(10%); [M+CF3COO]- 1945.76; Found: 1945.7( 100%). Example 167
Synthesis of Compound (347)
Figure imgf000133_0001
[00344] Using synthetic procedures similar to the preparation of Compound (342) as in Examples 162 and replacing (/?)-N- pNZ-alanine-OSu with N-pNZ-glycine-OSu, and also N-(6-aminohexyl)-4-hexylbenzenesulfonamide with N-(2-aminoethyl)- 4-pentyloxy)benzenesulfonamide, Compound (347) was prepared. Compound (347): ESI-MS: V652 (PL0149) m/z: calcd for C82H,ooCl2N12028S [M+H] + 1805.71 ; Found: 1805.7(100%), 1605.7(36.7%); [M+CFjCOOV 1917.71; Found:
1917.9(100%).
Example 168
Synthesis phenolic regioisomer
Figure imgf000133_0002
[00345] Using synthetic procedures similar to the preparation of Compound (322) as in Examples 149 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with l-(2-isocyanatoethoxy)pentane, Compound (348) or phenolic regioisomers was prepared. Compound (348): ESI-MS: m/z: calcd for C74H90O2 10O26 [M+H] + 1607.46; Found:
1608.2(100%), 1073.5(13.4%), 805.5(16.7%); [M+CF3COO]- 1719.46; Found: 1719.7(100%). Example 169
Synthe phenolic regioisonter
Figure imgf000134_0001
[00346] Using synthetic procedures similar to the preparation of Compound (322) as in Examples 149 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with 4-(hexyloxy)-N-(6-isocyanatohexyl) benzenesulfonamide, Compound (349) or phenolic regioisomers was prepared. Compound (349): ESI-MS: m/z: calcd for
Figure imgf000134_0002
[M+H] + 1832.77; Found: 1832.8(100%); [M+CF3COO]" 1944.77; Found: 1945.5(100%).
Example 170
Synthe phenolic regioisonter
Figure imgf000134_0003
[00347] Using synthetic procedures similar to the preparation of Compound (322) as in Examples 149 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with 4-hexyl-N-(5-isocyanatopentyl) benzenesulfonamide, Compound (350) or phenolic regioisomers was prepared. Compound (350): ESI-MS: m/z: calcd for
Figure imgf000134_0004
[M+H] + 1802.75; Found: 1802.8(100%); [M+CF3COO]" 1914.75; Found: 1915.1(100%). Example 171
Synthesis of regioisomer
Figure imgf000135_0001
[00348] Using synthetic procedures similar to the preparation of Compound (322) as in Examples 149 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with l-butoxy-4-(2-isocyanatoethyl)benzene, Compound (351) or phenolic regioisomers was prepared. Compound (351): ESI-MS: m/z: calcd for
Figure imgf000135_0002
[M+H] + 1669.53; Found: 1670.1(100%); [M+CF3COO]" 1781.53; Found: 1781.8(100%).
Example 172
Synthesis of Compound (352) or phenolic regioisomer
Figure imgf000135_0003
[00349] Using synthetic procedures similar to the preparation of Compound (322) as in Examples 149 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with 4-hexyl-N-(6-isocyanatohexyl) benzenesulfonamide, Compound (352) or phenolic regioisomers was prepared. Compound (352): ESI-MS: m/z: calcd for
Figure imgf000135_0004
[M+H] + 1816.77; Found: 1816.8(100%), 1116.1(76.2%), 908.9(46.9%); [M+CF3COO]" 1928.77; Found: 1928.9(100%). Example 173
Synthesis of Compound (353) or phenolic regioisomer
Figure imgf000136_0001
(352)
[00350] Using synthetic procedures similar to the preparation of Compound (322) as in Examples 149 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with lethoxy-2-(2-isocyanatoethoxy)ethane, Compound (353) or phenolic regioisomers was prepared. Compound (353): ESI-MS: m/z: calcd for C73H88CI2 10O27 [M+H] + 1609.44; Found: 1609.6(100%), 1073.3(65.2%), 805.3(43.8%); [M+CF3COO]" 1721.44; Found: 1721.8(100%).
Example 174
Synthesis of Compound (354) or phenolic regioisomer
Figure imgf000136_0002
[00351] Using synthetic procedures similar to the preparation of Compound (322) as in Examples 149 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with l-(4-hexylphenyl)-3-(6-isocyanatohexyl)urea, Compound (354) or phenolic regioisomers was prepared. Compound (354): ESI-MS: m/z: calcd for C^ ^Cy^C^ [M+H] + 1795.73; Found: 1795.8(100%); [M+CF3COO]" 1907.8; Found: 1908.0(100%). Example 175
Synthesis of Compound (355) or phenolic regioisomer
Figure imgf000137_0001
[00352] Using synthetic procedures similar to the preparation of Compound (322) as in Examples 149 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with 4-(heptoxy)-N-(6-isocyanatohexyl)benzenesulfonamide, Compound (355) or phenolic regioisomers was prepared. Compound (355): ESI-MS: m/z: calcd for Ο86Ηΐ07¾ΝπΟ288 [M+H] + 1846.8; Found: 1846.9(100%); [M+CF3COO]" 1958.8; Found: 1959.1(100%).
Example 176
Synthesis of Compound (356) or phenolic regioisomer
Figure imgf000137_0002
(356)
[00353] Using synthetic procedures similar to the preparation of Compound (322) as in Examples 149 and replacing N-(6- isocyanatohexyl)-4-(pentyloxy)benzenesulfonamide with l-(2-isocyanatoethyl)-4-(pentyloxy)benzene, Compound (356) or phenolic regioisomers was prepared. Compound (356): ESI-MS: m/z: calcd for
Figure imgf000137_0003
[M+H] + 1683.56; Found: 1683.6(100%); [M+CF3COO]- 1795.56; Found: 1796.4(100%). Example 177
Figure imgf000138_0001
[00354] Using synthetic procedures similar to the preparation of Compound (342) as in Examples 162 and replacing N-(6- aminohexyl)-4-hexylbenzenesulfonamide with N-(6-aminohexyl)-4-(pentyloxy)benzenesulfonamide, Compound (357) was prepared. Compound (357): ESI-MS: m/z: calcd for C87H110Cl2N12O28S [M+H] + 1875.84; Found: 1876.2(100%), 1662.5(54.4%), 832.9(47.6%); [M+CF3COO]" 1987.84; Found: 1988.0(100%).
Example 178
(361)
Figure imgf000138_0002
[00355] Using a procedure similar to the preparation of Compound (299) as in Example 138 and replacing N-(2-(3- aminopropylamino)ethyl)-4-(pentyloxy)benzenesulfonamide with various amines, compounds (358). (359). (360). and (361) were prepared.
Example 179
Synthesis of Compound (362)
Figure imgf000139_0001
[00356] Using synthetic procedures similar to the preparation of Compound (342) as in Examples 162 and replacing (R)-N- pNZ-alanine-OSu with N-pNZ-glycine-OSu, Compound (362) was prepared.
Example 180
Figure imgf000139_0002
[00357] Using synthetic procedures similar to the preparation of Compound (342) as in Examples 162 and replacing (R)-N- pNZ-alanine-OSu with 2,5-dioxopyrrolidin-l-yl acetate, Compound (363) was prepared.
Example 181
Figure imgf000140_0001
[00358] To a solution of compound (328) (2.0 g, 1.2 mmol) in dry DMF was added DIEA (600 mg) and cyclopropyl isocyanate (500 mg). It was stirred at room temperature for 2 days. The mixture was dissolved in methanol (100 ml), and then 2C03 (600 mg) was added. It was stirred at room temperature for 2 hrs. The organic solvent was evaporated and the residue was suspended in water, neutralized with acetic acid to pH 6-7 and concentrated. The crude was purified by reverse phase column chromatography to afford compound (364) (800 mg, 39%).
Example 182
(368)
Figure imgf000140_0002
[00359] Using synthetic procedures similar to the preparation of Compound (342) as in Examples 162 and replacing compound (328) with compound (364) and skipping the addition of (^)-N-pNZ-alanine-OSu and K2C03 in DMF but following the rest of the procedure and also replaing the N-(6-aminohexyl)-4-hexylbenzenesulfonamide with various amines, compounds (365), (366). (367), and (368) were prepared. Example 183
Figure imgf000141_0001
[00360] .... To a solution of compound (328) (325 mg, 0.2 mmol) in DMSO ( 10 ml) was added NaNCO (325 mg, 5.0 mmol). The mixture was stirred for 20 min. Acetic acid (60 mg, 1.0 mmol) in DMSO (2 ml) was added. The resulting mixture was stirred for 4 days (conversion >90%) and then the reaction was quenched by pouring into water and extracted with n-butane. The organic layer was washed with brine for 2 times and the solvent was removed to give compound (369) (260 mg, 76%).
Example 184
Synthesis of Compound (370)
Figure imgf000141_0002
[00361] Using synthetic procedures similar to the preparation of Compound (342) as in Examples 162 and replacing compound (328) with compound (369) and skipping the addition of (R)-N-pNZ-alanine-OSu and K2C03 in DMF but following the rest of the procedure, compounds (370) was prepared.
Antibacterial Evaluation
[00362] 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 C LSI-recommended broth microdilution procedure (Clinical and Laboratory Standards Institute, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard- Seventh Edition.). Automated liquid handlers (Multidrop 384, Labsystems, Helsinki, Finland; Biomek 2000 and Multimek 96, Beckman Coulter, Fullerton CA) were used to conduct serial dilutions and liquid transfers. MIC data for representative glycopeptides derivatives made and described in this application are summarized in Tables 1, 2, 3 and 4. The MIC value for vancomycin is given for comparison. The abbreviations for organisms tested are as follow: SA 100 - Staphylococcus aureus 100 (ATCC 29213); SA 757 - Staphylococcus aureus 757 (MRSA); SA 2012 - Staphylococcus aureus 2012 (VISA); SE 835 - Staphylococcus epidermidis 835; SE 831 - Staphylococcus epidermidis 831 (MRSE); EFc 101 - Enterococcus faecalis 101 (ATCC 29212); EFc 848 - Enterococcus faecalis 848 (VRE, Van A); EFcm 800 - Enterococcus faecium 800; EFcm 752 - Enterococcus faecium 752 (VRE, Van A); SPNE 1 195 - Streptococcus pneumoniae 1 195 (ATCC 49619); SPY 712 - Streptococcus pyogenes 712.
Biological data
[00363] Most of the glycopeptides derivatives in Tables 1, 2, 3, and 4 are very potent and have activity against
Streptococcus pneumoniae and MRSA, clinical important pathoges. Many derivatives have activity against vancomycin resistant bacteria such as VISA (vancomycin intermediate-resistant Staphylococcus aureus), and vancomycin resistant enterococci.
Table 1
Figure imgf000142_0001
Table 2
Figure imgf000142_0002
Table 3
Figure imgf000143_0001
Table 4
Figure imgf000143_0002
MIC (μΒ/mL
0.01 < A < 0.5
0.5 < B < 1.0
1.0 < C < 2.0
2.0 < D < 4.0
4.0 < E < 8.0
8.0 < F < 16.0
16.0 < G
Neutropenic Mouse Pulmonary Infection Model
[00364] Female Balb/C mice weighing 18 to 20 grams were pre-treated with cyclophosphamide to render the mice neutropenic. Mice were infected with methicillin-resistant S. aureus (MRSA) VL-137, via intranasal inoculation of 0.05 mL per mouse. Mice were intravenously injected with either vehicle as a control, the trifluoroacetic acid salt (designated "a") of a test compound, the trifluoroacetic acid (TFA) salt of telavancin as a comparison, or vancomycin as a comparison at 12, 24 and 36 hours post infection. Six mice were treated with each drug concentration. All test and comparison compounds were formulated in a solution of 10% DMSO and 2.5% Cremophor EL in deionized water. Forty-eight hours post infection, mice were euthanized by C02 inhalation. One group of mice was euthanized at two hours post infection and their lungs were processed to confirm infectivity. The lungs of the mice were aseptically removed, weighed, homogenized, serially diluted, and plated on TSA medium. The plates were incubated overnight at 37 °C in 5% C02. The number of colony forming units (CFUs) per gram of lung was calculated by enumerating the plated colonies and then adjusting for serial dilutions and the weight of the lungs. The minimum inhibitory concentration (MIC) was determined for test and comparison compounds using standard CLSI broth microdilution methods, where the broth was supplemented with 0.002% Tween 80. Results from the mouse lung infection model are presented below according to experiments that generated the results.
Table 5. Infection inoculum: 4.03 x 107 CFU/mouse
Figure imgf000144_0001
[00365] Table 5 shows that Compounds 33, 303 and 305, as their trifluoroacetic acid salt, markedly reduced the number of CFUs of MRSA VL-137 compared to vehicle-treated mice and vancomycin-treated mice.
Table 6. Infection inoculum: 4.28 x 107 CFU/mouse
Figure imgf000144_0002
[00366] Table 6 demonstrates that Compound 305 and the trifluoroacetic acid salts of Compounds 33, 309 and 311 markedly reduced the number of CFUs of MRSA VL-137 compared to vehicle-treated mice and vancomycin-treated mice.
Table 7. Infection inoculum: 3.78 x 107 CFU/mouse
Figure imgf000144_0003
Compound Dose n Logio CFU/ Standard Log Change MIC
(mg/kg) g of Lung Deviation from Control ^g/mL)
(TFA salt)
Vancomycin 50 6 9.22 0.33 -0.09 0.25
[00367] Table 7 shows that the trifluoroacetic acid salts of Compounds 322, 345 and 362 markedly reduced the number of CFUs of MRS A VL-137 compared to vehicle-treated mice and vancomycin-treated mice.
Table 8. Infection inoculum: 3.37 x 107 CFU/mouse
Figure imgf000145_0001
[00368] All 1 1 test compounds listed in Table 8, as their trifluoroacetic acid salt (except for Compound 352), exhibited reduction in (logi0 CFU/gram of lung) greater than 2 when dosed at 10 mg/kg compared to vehicle-treated mice.
Table 9. Infection inoculum: 3.55 x 107 CFU/mouse
Figure imgf000145_0002
[00369] Table 9 shows that the TFA salt of Compound 33 was more potent than the TFA salt of telavancin, and much more potent than vancomycin, in the mouse lung infection model. The TFA salt of Compound 33 achieved 1, 2 and 3 log10 reductions in the number of CFUs of MRSA VL-137 per gram of lung, compared to vehicle-treated mice, at doses of 3.5, 4.5 and 9.7 mg/kg, respectively. The TFA salt of telavancin achieved 1 and 2 logi0 CFU reductions at doses of 4.0 and 17.7 mg/kg, respectively, but failed to achieve a 3 log10 CFU reduction at its maximum administered dose of 25 mg/kg.
Vancomycin was evaluated at a single dose of 50 mg/kg and failed to achieve a 1 logio CFU reduction at that dose. Table 10. Infection inoculum: 5.75 x 107 CFU/mouse
Figure imgf000146_0001
[00370] Table 10 demonstrates that the TFA salt of Compound 352 was more potent than the TFA salt of telavancin, and much more potent than vancomycin, in the mouse lung infection model. The TFA salt of Compound 352 achieved 1 , 2 and 3 log10 reductions in the number of CFUs of MRSA VL-137 per gram of lung, compared to vehicle-treated mice, at doses of 2.0, 4.0 and 10.6 mg/kg, respectively. In comparison, the TFA salt of telavancin achieved 1, 2 and 3 logi0 CFU reductions at doses of 4.0, 1 1.6 and 19.5 mg/kg, respectively. Vancomycin was evaluated at a single dose of 50 mg/kg and failed to achieve a 1 logio CFU reduction at that dose.
Neutropenic Mouse Thigh Infection Model
[00371] Seven week-old female CD-I mice were made neutropenic with 2 x i.p. injections of cyclophosphamide (150 mg/kg, the first injection at 4 days before inoculation, the second injection at 1 day before inoculation). Mice were inoculated with S. aureus 2E5 CFU ATCC 13709 (methicillin-sensitive S. aureus (MSSA)) in both legs. Vehicle and the trifluoroacetic acid (TFA) salt of Compound 33 were administered i.v. at 1 hr post inoculation, with Compound 33 being dosed at 3.2, 10.0 or 32.0 mg/kg. Vancomycin was administered at 1 hr and 6 hr post inoculation at a dose of 1.6, 5.0 or 16.0 mg/kg to compensate for its short half-life. Thigh tissues were collected at 1 hr post inoculation (the time of drug treatment, vehicle only), and 25 hr post inoculation. The number of colony forming units (CFUs) per gram of thigh tissue was determined from colony counts and plotted.
[00372] The TFA salt of Compound 33 was more potent than vancomycin in the mouse thigh infection model. At 25 hr post inoculation, The TFA salt of Compound 33 at 1 x 32 mg/kg achieved a 6.45 logio reduction in the number of CFUs of MSSA per gram of thigh tissue relative to vehicle-treated mice, whereas vancomycin at 2 x 16 mg/kg achieved a 4.54 logio CFU reduction. The TFA salt of Compound 33 at 1 x 10 mg/kg achieved a 3.99 logio CFU reduction compared to a 3.17 logio CFU reduction with vancomycin at 2 x 5 mg/kg.
Pharmacokinetics Studies
[00373] A test compound was dissolved in DMSO/saline/Cremophore (10:85:5) to yield a final concentration of 1.25 mg/mL for i.v. administration. Male CD-I mice weighing 20 to 25 grams were used in the study. Blood was collected by retro-orbital puncture from each mouse into tubes containing sodium heparin anticoagulant at 0, 15, 30, 60, 120, 240, 480 and 1440 minutes after dose administration. Plasma was separated from the blood before analysis.
[00374] Pharmacokinetic parameters of the TFA salt of Compound 33 and vancomycin in CD-I mice, each administered i.v. at 5 mg/kg, are given in Table 11. The TFA salt of Compound 33 has a much greater AUC than vancomycin (> 88-fold) and a longer half-life (2.83 hr vs. 0.55 hr). The TFA salt of Compound 33 also has a much lower clearance than vancomycin (12 vs. 1052 mL/hr/kg), and a substantially smaller Vss than vancomycin (36 vs 472 mL/kg). Table 11. Pharmacokinetics in CD-I mice
Figure imgf000147_0001
Clinical Trial of the Safety and Efficacy of Compounds of Formula (I) - (XIV) in Patients with C. Difficile-Associated Diarrhea
[00375] Purpose: This study aims to determine the safety and efficacy of glycopeptide compounds presented herein for the treatment of symptoms of C. difficile-associated diarrhea and lowering the risk of repeat episodes of diarrhea. The compounds are evaluated in comparison to current standard antibiotic treatment, so all patients will receive active medication. All study-related care is provided including doctor visits, physical exams, laboratory tests and study medication.
Total length of participation is approximately 10 weeks.
Patients: Eligible subjects will be men and women 18 years and older.
Criteria:
Inclusion Criteria:
Be at least 18 years old;
Have active mild to moderate C. difficile- Associated Diarrhea (CDAD);
Be able to tolerate oral medication;
Not be pregnant or breast-feeding; and
Sign and date an informed consent form.
[00376] Study Design: This is a randomized, double-blind, active control study of the efficacy, safety, and tolerability of a compound of Formula (I) - (XIV) in patients with C. difficile-associated diarrhea.
Clinical Trial Comparing a Compound of Formula (I) - (XIV) with Vancomycin for the Treatment of MRSA
Osteomyleitis
[00377] Purpose: This study aims to determine the efficacy of glycopeptide compounds presented herein as compared to vancomycin for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis.
Patients: Eligible subjects will be men and women 18 years and older.
Criteria:
Inclusion Criteria:
Culture-proven MRSA, obtained in operating room or sterile biopsy procedure from bone site. The infection and sampling site is either within the bone or a deep soft-tissue site that is contiguous with bone; OR radiographic abnormality consistent with osteomyelitis in conjunction with a positive blood culture for MRSA;
Surgical debridement of infection site, as needed;
Subject is capable of providing written informed consent; and
Subject capable of receiving outpatient parenteral therapy for 12 weeks.
Exclusion Criteria:
Hypersensitivity to a compound of Formula (I) - (XIV) or vancomycin;
S. aureus resistant to a compound of Formula (I) - (XIV) or vancomycin;
Osteomyelitis that develops directly from a chronic, open wound; Polymicrobial culture (the only exception is if coagulase-negative staphylococcus is present in the culture and the clinical assessment is that it is a contaminant);
Subject has a positive pregnancy test at study enrollment;
Baseline renal or hepatic insufficiency that would preclude administration of study drugs;
Active injection drug use without safe conditions to administer intravenous antibiotics for 3 months; and
Anticipated use of antibiotics for greater than 14 days for an infection other than osteomyelitis.
[00378] Study Design: This is a randomized, open-label, active control, efficacy trial comparing vancomycin with a compound of Formula (I) - (XIV) for the treatment of MRS A Osteomyelitis.
Clinical Trial Evaluating a Compound of Formula (I) - (XIV) in Selected Serious Infections Caused by Vancomycin- Resistant Enterococcus (VRE)
[00379] Purpose: This study aims to determine the safety and efficacy of a compound of Formula (I) - (XIV) in the treatment of selected serious infections caused by VRE.
Patients: Eligible subjects will be men and women 18 years and older.
Criteria:
Inclusion Criteria:
Isolation of one of the following multi-antibiotic resistant bacteria: vancomycin-resistant Enterococcus faecium, vancomycin-resistant Enterococcus faecalis alone or as part of a polymicrobial infection; and
Have a confirmed diagnosis of a serious infection (eg, bacteremia [unless due to an excluded infection], complicated intra-abdominal infection, complicated skin and skin structure infection, or pneumonia) requiring administration of intravenous (IV) antibiotic therapy.
Exclusion Criteria:
Subjects with any concomitant condition or taking any concomitant medication that, in the opinion of the investigator, could preclude an evaluation of a response or make it unlikely that the contemplated course of therapy or follow-up assessment will be completed or that will substantially increase the risk associated with the subject's participation in this study
Anticipated length of antibiotic therapy less than 7 days
[00380] Study Design: This is a randomized, double-blind, safety and efficacy study of a compound of Formula (I) - (VI) in the treatment of selected serious infections caused by VRE.
[00381] Although the foregoing embodiments have been described in some detail for purposes of clarity of understanding, it will be apparent that in some embodiments, certain changes and modifications are 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 aspects described herein are not to be limited to the details given herein, but in some embodiments are modified within the scope and equivalents of the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A method of treating a bacterial infection in a mammal where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia comprising administering a therapeutically acceptable amount of a compound having a structure VIII, IX, X, XI, XII, XIII, or XIV
Figure imgf000149_0001
Figure imgf000150_0001
where,
RA is hydrogen, methyl, or C2-C12-alkyl;
R! and R2 are each independently selected from the group consisting of
a) hydrogen,
b) C Cz-alkyl,
c) CrCi2-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, Ci-C12-alkoxy, C C3-alkoxy- CrC3-alkoxy, amino, CrC12-alkylamino, CpCn-dialkylamino, alkenyl, alkynyl, and Q-Cn-thioalkoxy,
d) CrCi2-alkyl substituted with aryl,
e) C Ci2-alkyl substituted with substituted aryl,
f) C C12-aIkyl substituted with heteroaryl,
g) Ci-C12-alkyl substituted with substituted heteroaryl,
h) cycloalkyl, i) cycloalkenyl, and
j) heterocycloalkyl;
k) -C(=0)R7, and
1)
Figure imgf000151_0001
R8, R9 and R10 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R8 and R10 or R9 and R10 taken together with the atom to which they are attached form a 3- 10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, CrC3-alkoxy, C C3-alkoxy-Ci-C3-alkoxy, oxo, CrC3-alkyl, halo- CrC3-alkyl, and CrC3-alkoxy-CrC3-alkyl; or
Ri and R2 taken together with the atom to which they are attached form a substituted heteroaryl or 3-10 membered
heterocycloalkyl ring optionally having one or two hetero functionalities selected from the group consisting of -0-, -N-, -NH, -N(CrC6-alkyl)-, -N(aryl)-, -N(aryl- C C6-alkyl-)-, -N(substituted-aryl- C,-C6-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl- CrC6-alkyl-)-, -N(substituted-heteroaryl- CrC6-alkyl-)-, and -S- or S(0)„- where n is 1 or 2 and the 3-10 membered heterocycloalkyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, CrC3-alkoxy, C!-C3-alkoxy-Ci-C3-alkoxy, oxo, Q-Q-alkyl, halo- C C3-alkyl, and CrC3-alkoxy-CrC3-alkyl;
R7 is selected from the group consisting of
a) hydrogen,
b) CrC12-alkyl,
c) Q-Cn-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C Ci2-alkoxy, C1-C3-alkoxy-C1-C3-alkoxy, amino, CrC12-alkylamino, C C12-dialkylamino, alkenyl, alkynyl, and CrC12-thioalkoxy,
d) CrC12-alkyl substituted with aryl,
e) CrC12-alkyl substituted with substituted aryl,
f) CrCi2-alkyl substituted with heteroaryl,
g) CrC12-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) cycloalkenyl,
j) heterocycloalkyl,
k) amino,
1) CrCi2-alkylamino, and
m) amino-cycloalkyl;
X is hydrogen or chlorine;
Y is oxygen or NR^
Z is oxygen or sulfur;
RE is halo or -OR where R is selected from the group consisting of
(1) hydrogen,
(2) cycloalkyl,
(3) cycloalkenyl, (4) CrC,2-aIkyl,
(5) C,-C12-aIkyl substituted with one or more substituents selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) CrC12-alkoxy,
(d) CrC3-alkoxy- CrC3-alkoxy,
(e) -COOR5 where R5 is hydrogen or loweralkyl,
(f) -C(0)NR5R6 where R¾ is hydrogen or loweralkyl,
(g) amino,
(h) -N 5R6, where R5 and Re are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R5 and R6 are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, Ci-C3-alkoxy, Ci-C3-alkoxy-CrC3-alkoxy, oxo, Ci-C12-alkyl, halo-Ci-Ci2-alkyl, and C rC3-alkoxy-C i-C 12-alkyl;
(i) aryl,
(j) substituted aryl,
(k) heteroaryl,
(1) substituted heteroaryl,
(m) mercapto,
(n) CrC]2-thioalkoxy,
(6) -C(=0)ORn, where Rn is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl,
(7)
Figure imgf000152_0001
is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; or Rn and Ri2 together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C C3-alkoxy, Ci-C3-alkoxy-C C3-alkoxy, oxo, CrCi2-alkyl, substituted loweralkyl, halo-CrCi2-alkyl, amino, alkylamino, dialkylamino, and C C3- alkoxy-CrCi2-alkyl; or
R3 is selected from the group consisting of
(1) OH,
(2) 1 -adamantanamino,
(3) 2-adamantanamino,
(4) 3 -amino- 1 -adamantanamino,
(5) 1 -amino-3 -adamantanamino,
(6) 3 -loweralkylamino- 1 -adamantanamino,
(7) 1 -loweralky lamino-3 -adamantanamino,
(8) amino, (9) -NR13R14 where R13 and R)4 are each independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl, alkoxy, aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy; or Rl3 and R14 together with the atom to which they are attached form a 3- 10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, CrC3-alkoxy, CrC3-alkoxy-CrC3-alkoxy, oxo, CrCi2-alkyl, substituted loweralkyl, halo-CrC12-alkyl, amino, alkylamino, dialkylamino, and CrC3- alkoxy-C i-C] 2-alky 1;
R4 is selected from the group consisting of
( 1 ) -CH2NH-CHR15-(CH2)M-NHS02RB, where m is 1 to 6 and R15 is H or loweralkyl,
(2) -CH2NH- CHR15 -(CH2)P-CONHS02RB, where p is 0 to 6 and R15 is H or loweralkyl,
(3) -CH2NH- CHRi5-(CH2)M-0-(CH2)RNHS02RB, where m is 1 to 6, f is 1 to 6 and R15 is H or loweralkyl,
(4) -CH2NRF-CHR,3-(CH2)q-NRoS02RB, where q is 2 to 4, R15 is H or loweralkyl, RF and RQ are independently hydrogen, lower alkyl or taken together represent a -CH2- ,
(5) hydrogen,
(6) -CH2NH-CHR,5-(CH2)M-NHCONHRB, where m is 1 to 6 and R15 is H or loweralkyl,
(7) -CH2NHCH2P03H2,
(8) aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy;
(9) -CH2NH-CHR,5-(CH2)P-NHCORB, where p is 0 to 6 and R15 is H or loweralkyl,
( 10) -CH2NH-CHR15-(CH2)P-CONHRB, where p is 0 to 6 and R15 is H or loweralkyl,
( 1 1) -CH2NH- CHR15-(CH2)M-0-(CH2)RNHCONHRB, where m is 1 to 6, f is 1 to 6 and R15 is H or loweralkyl; RB is selected from the group consisting of
a) aryl,
b) C-Ciz-alkyl,
c) CrC12-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CpCn-alkoxy, CrC3-alkoxy- CrC3-alkoxy, amino, CrC12-alkylamino, CrCi2-dialkylamino, alkenyl, alkynyl, and CrCi2-thioalkoxy,
d) C i-C 12-alkyl substituted with aryl,
e) Ci-C 12-alkyl substituted with substituted aryl,
f) Ci-C12-alkyl substituted with heteroaryl,
g) Q-C12-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) heteroaryl,
j) heterocycloalkyl,
k) aryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CV Ci2-alkoxy, CrC12-alkoxy- CrC12-alkoxy, amino, amino-C C12-alkoxy, CrCi2-alkylamino, CpCn- alkylamino- CrCi2-alkoxy, CrCi2-dialkylamino, Ci-C:2-dialkylamino- Ci-C12-alkoxy, alkenyl, alkynyl,
Figure imgf000154_0001
CrCi2-alkyl, C Ci2-substituted alkyl, C|-Cl2-alkoxy-mo holίno, Ci-C12-alkoxy-C C12-dialkoxyamino, CrC12-alkoxy-NHS02C,-C6alkyl, and C,-Ci2-alkoxy-NHCOC C6alkyl, 1) heteroaryl substituted with one or more substituents selected from the group consisting of halogen,
hydroxy, Ci-Ci2-alkoxy, CrC12-alkoxy- Ci-C,2-alkoxy, amino, amino-CrCi2-alkoxy, CrCi2-alkylamino, CrCi2-alkylamino- CrCi2-alkoxy, CrCi2-dialkylamino, CrCi2-dialkylamino- CrCi2-alkoxy, alkenyl, alkynyl, C(-Ci2-thioalkoxy, Ci-C12-alkyl, and C C ^-substituted alkyl;
Rc is selected from the group consisting of
a) hydrogen,
b) C,-C12-alkyl,
c) CrCi2-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CrC12-alkoxy, CrC3-alkoxy- CrC3-alkoxy, amino, CrCi2-alkylamino, C C12-dialkylamino, alkenyl, alkynyl, and C Ci2-thioalkoxy,
d) C Ci2-alkyl substituted with aryl,
e) C Ci2-alkyl substituted with substituted aryl,
f) Ci-C12-alkyl substituted with heteroaryl,
g) CrCi2-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) cycloalkenyl,
j) heterocycloalkyl,
k) -C(=0)R7,
1) -C(=O)CHR8NR9R10 where Rg, R9 and Ri0 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R8 and Ri0 or R9 and R10 taken together with the atom to which they are attached form a 3- 10 membered heterocycloalkyl ring which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, Ci-C3-alkoxy, Ci-C3-alkoxy-CrC3-alkoxy, oxo, CrC3- alkyl, halo-CrC3-alkyl, and CrC3-alkoxy-CrC3-alkyl;
RD is selected from the group consisting of
a) hydrogen,
b) C,-C12-alkyl,
c) C C12-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, Ci-C)2-alkoxy, CrC3-alkoxy- C|-C3-alkoxy, amino, CrC12-alkylamino, CrC12-dialkylamino, alkenyl, alkynyl, and Ci-C]2-thioalkoxy,
d) C Ci2-alkyl substituted with aryl,
e) C C12-alkyl substituted with substituted aryl,
f) CrC12-alkyl substituted with heteroaryl,
g) CrCi2-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) cycloalkenyl, j) heterocycloalkyl,
k) -C(=0)R7,
1)
Figure imgf000155_0001
where R8, R9 and R10 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R8 and R!0 or R9 and R)0 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, CrC3-alkoxy, Ci-C3-alkoxy-CVC3-alkoxy, oxo, Ci-C3- alkyl, halo-CrC3-alkyl, and C,-C3-alkoxy-CrC3-alkyl;
at least two of Al, A2, and A3 are hydrogen and the other is -C(Z)-NH-RB , -C(Z)NHCHR15-(CH2)m-NHCONHRB ,
-C(Z)NHCHR15-(CH2)m-RB or -C(Z)NHCHR15-(CH2)m-NHS02RB;
and where for compounds having the structure of Formula X or XI, when Al, A2, A3, Rc and RD are hydrogen, then R4 is not hydrogen;
a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
The method of claim 1 where the compound has the structure of Formula I
Figure imgf000155_0002
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
3. The method of claim 1 where the compound has the structure of Formula II
Figure imgf000155_0003
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof. The method of claim 1 where the compound has the structure of Formula III
Figure imgf000156_0001
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
5. The method of claim 1 where the compound has the structure of Formula IV
Figure imgf000156_0002
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
6. The method of claim 1 where the compound has the structure of Formula V
Figure imgf000156_0003
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
7. The method of claim 1 where the compound has the structure of Formula VI
Figure imgf000157_0001
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
8. The method of claim 1 where the compound has the structure of Formula VII
Figure imgf000157_0002
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
9. The method of claim 1 where the compound has the structure of Formula VIII
Figure imgf000157_0003
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof. The method of claim 1 where the compound has the structure of Formula IX
Figure imgf000158_0001
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
1 1. The method of claim 1 where the compound has the structure of Formula X
Figure imgf000158_0002
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
12. The method of claim 1 where the compound has the structure of Formula XI
Figure imgf000158_0003
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof. The method of claim 1 where the compound has the structure of Formula XII
Figure imgf000159_0001
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
14. The method of claim 1 where the compound has the structure of Formula XIII
Figure imgf000159_0002
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
15. The method of claim 1 where the compound has the structure of Formula XIV
Figure imgf000159_0003
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
16. The method of claim 2, 3, 4, 5, 7, 8, 9, 10, 1 1, 13, or 14 where RA is methyl and R, is hydrogen.
17. The method of claim 2, 3, 4, 5, 7, 8, 9, 10, 1 1, 13, or 14 where RA is hydrogen and R4 IS hydrogen.
18. The method of claim 6, 12, or 15, where X is chlorine and R, is hydrogen.
19. The method of claim 6, 12, or 15, where X is hydrogen and R4 is hydrogen.
20. The method of claim 14, where RA is methyl and R4 is CH2NH-CHR15-(CH2)m-NHS02RB, where m is 1 to 6 and R,5 is H or loweralkyl.
21. The method of claim 14, where RA is methyl and R, is CH2NH-CHR15-(CH2)m-NHCONHRB, where m is 1 to 6 and R)5 is H or loweralkyl.
22. The method of any one of claims 16-21 where each R3 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-loweralkylamino-l-adamantanamino,
(7) 1 -loweralkylamino-3 -adamantanamino,
(8) amino, and
(9) -NR13R.14 where R13 and R)4 are each independently selected from the group consisting of hydrogen, loweralkyl, substituted loweralkyl, cycloalkyl, substituted cycloalkyl, aminoloweralkyl where the amino portion of the aminoloweralkyl group is further optionally substituted with unsubstituted or substituted alkyl, alkenyl, cycloalkyl, cycloalkenyl, arylaryl, alkoxy, aryloxy, substituted alkoxy, and substituted aryloxy; or R13 and Ru together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, CrC3-alkoxy, CrC3-alkoxy-Ci-C3-alkoxy, oxo, CrCi2-alkyl, substituted loweralkyl, halo-CrC12-alkyl, amino, alkylamino, dialkylamino, and CrC3-alkoxy-Ci-C12-alkyl.
23. The method of any one of claims 16-21 where each RB is selected from group consisting of
a) aryl,
b) C,-Cl2-alkyl,
c) Ci-C,2-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CrCi2-alkoxy, CrC3-alkoxy- CrC3-alkoxy, amino, CrCi2-alkylamino, CrCi2-dialkylamino, alkenyl, alkynyl, and d-C12-thioalkoxy,
d) C C12-alkyl substituted with aryl,
e) CpCn-alkyl substituted with substituted aryl,
f) Ci-C,2-alkyl substituted with heteroaryl,
g) Ci-C,2-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) heteroaryl,
j) heterocycloalkyl,
k) aryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C C12-alkoxy, CrCi2-alkoxy- C Ci2-alkoxy, amino, amino-C Ci2-alkoxy, Ci-Ci2-alkylamino, CrC)2- alkylamino- C Ci2-alkoxy, Ci-C12-dialkylamino, C Ci2-dialkylamino- CrC12-alkoxy, alkenyl, alkynyl, CrCi2-thioalkoxy, CrCi2-alkyl,
Figure imgf000161_0001
alkyl, Ci-C i2-alkoxy-morpholino, CrC12-alkoxy-Ci- C,2-dialkoxyamino, Ci-Cl2-alkoxy-NHS02C,-C6alkyl, C,-Ci2-alkoxy-NHCOC,-C6alkyl, and
1) heteroaryl substituted with one or more substituents selected from the group consisting of halogen,
hydroxy, CrC12-alkoxy, C C12-alkoxy- C C12-alkoxy, amino, amino-CrC12-alkoxy, CrCi2-alkylamino, Ci-Ci2-alkylamino- Ci-C12-alkoxy,
Figure imgf000161_0002
CrCi2-dialkylamino- Ci-Ci2-alkoxy, alkenyl, alkynyl, CrCi2-thioalkoxy, C Ci2-alkyl, Ct-Ci2-substituted alkyl.
The method of claim 1 where the compound is according to Formula I or VII where RA is methyl and R4 is hydrogen hydrogen and R4 is hydrogen; and RE is halo or -OR where R is selected from the group consisting of
( 1 ) hydrogen,
(2) cycloalkyl,
(3) cycloalkenyl,
(4) CrC12-alkyl,
(5) Ci-C12-alkyl substituted with one or more substituents selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) C Ci2-alkoxy,
(d) C,-C3-alkoxy- C,-C3-alkoxy,
(e) -COOR5 where R5 is hydrogen or loweralkyl,
(f) -C(0)NR5R6 where Rg is hydrogen or loweralkyl,
(g) amino,
(h) -NR5R6, where R5 and Re are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or R5 and ¾ are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, CrC3-alkoxy, CrC3-alkoxy-CrC3-alkoxy, oxo, CrC12-alkyl, halo-CrC12-alkyl, and CrC3-alkoxy-CrC12-alkyl,
(i) aryl,
(j) substituted aryl,
(k) heteroaryl,
(1) substituted heteroaryl,
(m) mercapto, and
(n) C Ci2-thioalkoxy,
(6) -C(=0)ORu, where Ru is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and
(7) -C(=0)NRuR12, where R12 is hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; Rn and R12 together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, CrC3-alkoxy, CrC3-alkoxy-CrC3-alkoxy, oxo, CrCi2-alkyl, substituted loweralkyl, halo-CrCi2-alkyl, amino, alkylamino, dialkylamino, and CpC3- alkoxy-C ] -C i2-alky 1.
25. The compound of claim 1 where the compound is according to Formula II, III, VIII, or IX and RA is methyl and R4 is hydrogen or RA is hydrogen and R4 is hydrogen; and Ri and R2 are each independently selected from the group consisting of
a) hydrogen,
b) CrCi2-alkyl,
c) Ci-Ci2-alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, CrCi2-alkoxy, CrC3-alkoxy- CrC3-alkoxy, amino, Ci-Ci2-alkylamino, CrC12-dialkylamino, alkenyl, alkynyl, and Ci-C12-thioalkoxy,
d) CrCi2-alkyl substituted with aryl,
e) C C12-alkyl substituted with substituted aryl,
f) Ci-Ci2-alkyl substituted with heteroaryl,
g) CrC12-alkyl substituted with substituted heteroaryl,
h) cycloalkyl,
i) cycloalkenyl,
j) heterocycloalkyl,
k) -C(=0)R7, and
1) -C(=O)CHR8NR9RI0where R8, R9 and R10 are each independently selected from a group consisting of hydrogen, loweralkyl, substituted loweralkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl, or R8 and Ri0 or R9 and Ri0 taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, Ci-C3-alkoxy, Ci-C3-alkoxy-CrC3-alkoxy, oxo, CrC3-alkyl, halo- C C3-alkyl, C C3-alkoxy-C C3-alkyl;
Ri and R2 taken together with the atom to which they are attached form a substituted heteroaryl or 3-10 membered
heterocycloalkyl ring optionally having one or two hetero functionalities selected from the group consisting of -0-, -N-, -NH, -N(CrC6-alkyl)-, -N(aryl)-, -N(aryl- C C6-alkyl-)-, -N(substituted-aryl- CrC6-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl- C C6-alkyl-)-, -N(substituted-heteroaryl- Ci-C6-alkyl-)-, and -S- or S(0)„- where n is 1 or 2 and the 3-10 membered heterocycloalkyl ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, CrC3-alkoxy, C C3-alkoxy-C C3-alkoxy, oxo, CrC3-alkyl, haIo-C C3-alkyl, CrC3-alkoxy-C C3-alkyl.
26. The method of any one of claims 16-25 where Z is each selected from the group consisting of oxygen and sulfur.
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
or a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
28. The method of claim 1 where the compound is
Figure imgf000176_0002
Figure imgf000177_0001
- 175 -
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000181_0002
- 179- includes the phenolic regioisomer structure (B) or (C) as shown below:
rest of glycopeptide skeleton rest of glycopeptide skeleton
Figure imgf000182_0001
where R4 is H or for compounds 324, 325, and 326 is the corresponding alkyl amino substituent; or
a pharmaceutically acceptable salt, ester, solvate, alkylated quaternary ammonium salt, stereoisomer, tautomer or prodrug thereof.
29. The method of claim 1 where the compound is
Figure imgf000182_0002
Figure imgf000183_0001
- 181 -
Figure imgf000184_0001
- 182-
Figure imgf000185_0001
Figure imgf000185_0002
Figure imgf000186_0001
31. The method of any of claims 1-30 where the bacterial strain is Staphylococcus aureus 2E5 CFU ATCC 13709 or methicillin-resistant Staphylococcus aureus VL-137.
32. The method of claim 1 where the bacterial strain is Staphylococcus aureus 2E5 CFU ATCC 13709 and the compound is
Figure imgf000186_0002
33. The method of claim 1 where the bacterial strain is methicillin-resistant Staphylococcus aureus VL-137 and the compound is
Figure imgf000187_0001
34. The method of any of claims 1-33 where the compound is administered as a pharmaceutical composition which comprises a therapeutically effective amount of a compound of any of claims 1 to 32, together with a pharmaceutically acceptable carrier, diluent or excipient.
35. A method of treating a bacterial infection in a mammal comprising administering a therapeutically acceptable
Figure imgf000188_0001
36. The method of claim 35 where the bacterial infection is gram-positive.
37. The method of claim 35 or 36 where the infection is bacteremia, complicated intra-abdominal infection, complicated skin and skin structure infection, or bacterial pneumonia.
38. The method of claim 35 or 36 where the infection is complicated skin and skin structure infection or bacterial pneumonia.
39. The method of any of claims 35-38 where the bacterium to be treated is resistant or refractory to a beta-lactam antibiotic, vancomycin, desmethylvancomycin, eremomycin, teicoplanin, dalbavancin, oritavancin, telavancin, or A82846B (LY264826).
40. The method of any of claims 35-39 where the compound is administered as a pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 34 or 35, together with a pharmaceutically acceptable carrier, diluent or excipient.
41. Use of a compound of any of claims 1-40 for the treatment of a bacterial infection in a mammal, optionally where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia.
42. Use of a compound of any of claims 1-40 in the formulation of a medicament for the treatment of a bacterial infection in a mammal, optionally where the bacterial infection is complicated skin and skin structure infection or bacterial pneumonia.
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