WO2015023898A1 - Linear peptide antibiotcs - Google Patents

Linear peptide antibiotcs Download PDF

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Publication number
WO2015023898A1
WO2015023898A1 PCT/US2014/051151 US2014051151W WO2015023898A1 WO 2015023898 A1 WO2015023898 A1 WO 2015023898A1 US 2014051151 W US2014051151 W US 2014051151W WO 2015023898 A1 WO2015023898 A1 WO 2015023898A1
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Prior art keywords
optionally substituted
formula
compound
alkyl
independently
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English (en)
French (fr)
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WO2015023898A8 (en
Inventor
Peter Andrew Smith
Tucker Curran ROBERTS
Robert I. Higuchi
Prasuna PARASELLI
Michael F. T. Koehler
James John Crawford
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RQx Pharmaceuticals Inc
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RQx Pharmaceuticals Inc
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Priority to EP14836261.9A priority Critical patent/EP3033352A4/en
Priority to KR1020167006533A priority patent/KR20160044512A/ko
Priority to JP2016534849A priority patent/JP2016528257A/ja
Priority to CA2921082A priority patent/CA2921082A1/en
Priority to RU2016107436A priority patent/RU2016107436A/ru
Priority to US14/911,823 priority patent/US20160194358A1/en
Application filed by RQx Pharmaceuticals Inc filed Critical RQx Pharmaceuticals Inc
Priority to MX2016001927A priority patent/MX2016001927A/es
Priority to CN201480056420.XA priority patent/CN105636978A/zh
Publication of WO2015023898A1 publication Critical patent/WO2015023898A1/en
Anticipated expiration legal-status Critical
Publication of WO2015023898A8 publication Critical patent/WO2015023898A8/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • 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
    • A61P31/08—Antibacterial agents for leprosy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • linear peptides for the treatment of microbial infections, such as for the treatment of bacterial infections.
  • the present disclosure provides lipopeptide compounds for the treatment of bacterial infections.
  • the lipopeptide compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria.
  • R is selected from:
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 C(0)OR 25 , -CH 2 CH 2 C(0)OH, -CH 2 CH 2 C(0)OR 25 , - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)N(H)C(H)(CH 3 )C0 2 H, - CH 2 CH 2 C(0)N(H)C(H)(C0 2 H)CH 2 C0 2 H, -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , -(CH 2 ) 4 N + (R 25 ) 3 , -(CH 2
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH
  • R x is H, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -Cgcycloalkyl; or R x and R 2 together with the nitrogen atom form optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R z is -NR 15 R 16 , -CH 2 -NR 15 R 16 , or -(CH 2 ) 2 -NR 15 R 16 ;
  • R 7 is optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heterocycloalkyl, or an optionally substituted , wherein Z is a bond, O, S, NH, CH 2 , NHCH 2 , or C ⁇ C;
  • R is a bond, -0-, or -N(R )-, optionally substituted Ci-C 6 alkyl, optionally substituted Ci- C 6 heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 9 is -CH 2 OH, -CH 2 CH(CH 3 ) 2 ,
  • R is Ci-Cealkyl, Ci-C 6 haloalky l, -C(0)OR , -CF 2 C(0)OH, or
  • R and R are each independently H, or Ci-C 4 alkyl
  • R is H, methyl, ethyl, isopropyl, or cyclopropyl
  • R 18 , R 19 , and 20 are each independently H, or methyl; each R 21 is independently H, or Ci-C 4 alkyl;
  • R 23 is H, Ci-C 4 alkyl, or Ci-C 4 alkoxy
  • R 24 is -H, -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -C(0)R 26 , -C(0)OR 26 , -C(0)NR 26 R 27 , CH 2 C(0)OH, -CH 2 C(0)OR 25 , -CH 2 CH 2 C(0)OH, -CH 2 CH 2 C(0)OR 25 , -CH 2 C(0)NH 2 , - CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)N(H)C(H)(CH 3 )C0 2 H, - CH 2 CH 2 C(0)N(H)C(H)(C0 2 H)CH 2 C0 2 H, -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , -(CH 2 ) 4 N + (R 25 ) 3 , -(CH 2
  • each R is independently Ci-Cealkyl
  • R 26 is H, or Ci-C 4 alkyl
  • R 27 is H, or Ci-C 4 alkyl
  • R 28 is Ci-C 6 alkyl
  • n 0 or 1 ;
  • p is 0 or 1 ;
  • q is 0 or 1 ;
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -
  • R 2 , R 4 , R 12 , and R 13 are each inde :ppeennddeennttllyy --HH,, --CCHH 33 ,, --CCHH 22 CCHH((CCHH 33 )) 22 , - CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , --
  • R 7 is a linear or branched alkyl chain of 1- 22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substitute , an optionally substituted heterocycloalkyl, or , wherein Z is a bond, O, S, NH,
  • R 7 is a linear or branched alkyl chain of 1 -22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted ⁇ , wherein Z is a bond.
  • R 7 is a linear or branched alkyl chain of 1 -22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted ⁇ , wherein Z is a bond.
  • R 7 is a compound of Formula (A) wherein R 7 is .
  • R is a compound of Formula (A) wherein R is a optionally substituted Ci-Ceheteroalkyl.
  • R 6 is a bond.
  • R is a compound of Formula (A) wherein R is -
  • R 14 is O .
  • R 23 is H or Ci-C 4 alkyl; and R 24 is H or optionally substituted Ci-Csalkyl.
  • R 23 and R 24 are each H.
  • R 23 is H and R 24 is CH 3 .
  • R 23 is CH 3 and R 24 is H.
  • R 14 is Ci- Cehaloalkyl.
  • R 14 is CF 3 .
  • n is 0.
  • R 1 is In another embodiment is a compound of Formula (A) wherein R 1 is In another embodiment is a compound of Formula (A) wherein R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), - CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -(CH 2 ) 4 NH 2 ,
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , - CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -
  • CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -(CH 2 ) 4 NH 2 , , or is a linear or branched alkyl chain of 1 -22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, or an optionally substituted , wherein Z is a bond, O, S, NH, CH 2 , NHCH 2 , or C C.
  • R 7 is a linear or branched alkyl chain of 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted .
  • R 7 is a linear or branched alkyl chain of 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted .
  • a compound of Formula (A) is a compound of Formula (A) wherein R 7 is a linear or branched alkyl chain of 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted .
  • R is a optionally substituted Ci-Ceheteroalkyl.
  • R is a compound
  • R is H or Ci-C 4 alkyl; and R is H or optionally substituted Ci-Csalkyl.
  • R 23 and R 24 are each H.
  • R 23 is H and R 24 is la (A) wherein R 23
  • Cehaloalkyl In another embodiment is a compound of Formula (A) wherein R 14 is CF 3 . In another embodiment is a compound of Formula (A) wherein n is 0.
  • composition comprising a compound of Formula
  • a method for treating a bacterial infection in a mammal comprising administering to the mammal a compound of Formula (A) or a pharmaceutically acceptable salt or prodrug thereof at afrequency and for a duration sufficient to provide a beneficial effect to the mammal.
  • the bacterial infection is an infection involving Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Pro
  • Acinetobacter baumannii Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae,
  • Haemophilus parainfluenzae Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella,
  • Gardnerella vaginalis Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile,
  • Mycobacterium tuberculosis Mycobacterium avium, Mycobacterium intracellulare
  • Mycobacterium leprae Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis,
  • Staphylococcus haemolyticus Staphylococcus hominis, or Staphylococcus saccharolyticus.
  • the bacterial infection is an infection involving a Gram-negative bacteria.
  • administering comprises a topical administration.
  • a further embodiment are methods of treating a mammal in need of such treatment comprising administering to the mammal a second therapeutic agent.
  • the second therapeutic agent is not an SpsB inhibitor.
  • the second therapeutic agent is an aminoglycoside antibiotic, fluoroquinolone antibiotic, ⁇ -lactam antibiotic, macrolide antibiotic, glycopeptide antibiotic, rifampicin, chloramphenicol, fluoramphenicol, colistin, mupirocin, bacitracin, daptomycin, or linezolid.
  • the second therapeutic agent is a ⁇ -lactam antibiotic.
  • the ⁇ -lactam antibiotic is selected from penicillins, monobactams, cephalosporins, and carbapenems.
  • a further embodiment comprises administering a ⁇ -lactamase inhibitor.
  • R 1 is selected from:
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , - CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 C(0)OR 25 , -CH 2 CH 2 C(0)OH, -CH 2 CH 2 C(0)OR 25 , -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)N(H)C(H)(CH 3 )C0 2 H, -CH 2 CH 2 C(0)N(H)C(H)(C0 2 H)CH 2 C0 2 H, - CH 2 NR 21 R 22 ,
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH; or R 5 and R 24 together with the boron atom form a 5- or
  • R x is H, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -Cgcycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R z is -NR 15 R 16 , -CH 2 -NR 15 R 16 , or -(CH 2 ) 2 -NR 15 R 16 ;
  • R 7 is unsubstituted Ci-Cioalkyl
  • R is optionally substituted Ci-Cioheteroalkyl
  • R is -CH 2 OH, -CH 2 CH(CH 3 ) 2 , , or
  • R 14 , R 15 , and R 16 are each independently H, or Ci-C 4 alkyl
  • R is H, methyl, ethyl, isopropyl, or cyclopropyl
  • R 18 , R 19 , and 20 are each independently H, or methyl
  • each R 21 is independently H, or Ci-C 4 alkyl
  • R 23 and 24 are each independently H, or Ci-C 4 alkyl; or R 23 and R 24 together with the boron atom form an optionally substituted 5- or 6-membered boron containing ring;
  • each R 25 is independently Ci-C 6 alkyl
  • R 26 is H, Ci-C 4 alkyl, Ci-C 4 alkoxy, -CH 2 C(0)OR 25 , or -OCH 2 C(0)OR 25 ;
  • n 0 or 1 ;
  • p is 0 or 1 ;
  • q is 0 or 1 ;
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , --
  • Another embodiment is a compound of Formula (XIV) wherein R is a substituted Ci-
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -
  • R 2 , R 4 , R 12 , and R 13 are each in iddeeppeennddeennttllyy --HH,, --CCHH 33 ,, --CCHH 22 CCHH((CCFH 3 ) 2 CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2
  • Another embodiment is a compound of Formula (XIV) wherein R is a substituted Ci-
  • ;iinn RR i iss .
  • R 6 is -B(OH) 2 .
  • n is 0.
  • composition comprising a compound of Formula (XIV) and a pharmaceutically acceptable excipient.
  • a method for treating a bacterial infection in a mammal comprising administering to the mammal a compound of Formula (XIV) or a pharmaceutically acceptable salt or prodrug thereof at afrequency and for a duration sufficient to provide a beneficial effect to the mammal.
  • the bacterial infection is an infection involving Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Pro
  • Haemophilus parainfluenzae Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella,
  • Gardnerella vaginalis Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile,
  • Mycobacterium tuberculosis Mycobacterium avium, Mycobacterium intracellulare
  • Mycobacterium leprae Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis,
  • Staphylococcus haemolyticus Staphylococcus hominis, or Staphylococcus saccharolyticus.
  • the bacterial infection is an infection involving a Gram-negative bacteria.
  • administering comprises a topical administration.
  • a further embodiment are methods of treating a mammal in need of such treatment comprising administering to the mammal a second therapeutic agent.
  • the second therapeutic agent is not an SpsB inhibitor.
  • the second therapeutic agent is an aminoglycoside antibiotic, fluoroquinolone antibiotic, ⁇ -lactam antibiotic, macrolide antibiotic, glycopeptide antibiotic, rifampicin, chloramphenicol, fluoramphenicol, colistin, mupirocin, bacitracin, daptomycin, or linezolid.
  • the second therapeutic agent is a ⁇ -lactam antibiotic.
  • the ⁇ -lactam antibiotic is selected from penicillins, monobactams, cephalosporins, and carbapenems.
  • a further embodiment comprises administering a ⁇ -lactamase inhibitor.
  • Figure 1 depicts synergy between Compound 217 and imipenem.
  • Figure 2 depicts the time-kill assay for Compound 217 and imipenem.
  • mammals as used herein, means both mammals and non-mammals.
  • Mammals include, for example, humans; non-human primates, e.g. apes and monkeys; and non-primates, e.g. dogs, cats, cattle, horses, sheep, and goats.
  • Non-mammals include, for example, fish and birds.
  • disease or “disorder” or “malcondition” are used interchangeably, and are used to refer to diseases or conditions wherein a bacterial SPase plays a role in the biochemical mechanisms involved in the disease or malcondition such that a therapeutically beneficial effect can be achieved by acting on the enzyme.
  • Acting on SPase can include binding to SPase and/or inhibiting the bioactivity of an SPase.
  • the expression "effective amount”, when used to describe therapy to an individual suffering from a disorder, refers to the amount of a compound described herein that is effective to inhibit or otherwise act on SPase in the individual's tissues wherein SPase involved in the disorder is active, wherein such inhibition or other action occurs to an extent sufficient to produce a beneficial therapeutic effect.
  • substantially as the term is used herein means completely or almost completely; for example, a composition that is "substantially free” of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is "substantially pure” is there are only negligible traces of impurities present.
  • Treating refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder, or curing the disease or disorder.
  • an "effective amount” or a “therapeutically effective amount” of a compound refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of compounds described herein are outweighed by the therapeutically beneficial effects.
  • chemically feasible is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim.
  • the structures disclosed herein, in all of their embodiments are intended to include only “chemically feasible” structures, and any recited structures that are not chemically feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein.
  • an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isotopically labeled form" of the molecule.
  • All isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated.
  • any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium ( 1 H), deuterium ( 2 H), or tritium ( 3 H) in any combination.
  • any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as U C, 12 C, 13 C, or 14 C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as 13 N, 14 N, or 15 N.
  • a molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected. In a multi-molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition. For example, a sample of a compound can include molecules containing various different isotopic
  • compositions such as in a tritium or 14 C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom. It is also understood that many elements that are not artificially isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as 14 N and 15 N, 32 S and 34 S, and so forth. A molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the molecule. As is well known in the art, isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled precursor molecule.
  • the isotopes can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry.
  • the isotopic forms are incorporated into precursors as required for use in any particular synthetic route.
  • 14 C and 3 H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, 14 C and 3 H are incorporated into precursor molecules, followed by further elaboration as needed.
  • amino protecting group or "N-protected” as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4- chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl
  • Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle.
  • amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
  • hydroxyl protecting group or "O-protected” as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used hydroxyl protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4- chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl,
  • substituted refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non- hydrogen atom such as, but not limited to, a halogen (i.e., F, CI, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups,
  • oxo(carbonyl) groups including carboxylic acids, carboxylates, and
  • carboxylate esters a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups.
  • Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, CI, Br, I, OR', OC(0)N(R * ) 2 , CN, NO, N0 2 , ON0 2 , azido, CF 3 , OCF 3 , R', O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R) 2 , SR * , SOR * , S0 2 R * , S0 2 N(R) 2 , S0 3 R * , C(0)R * ,
  • a substituent is monovalent, such as, for example, F or CI, it is bonded to the atom it is substituting by a single bond.
  • a divalent substituent such as O, S, C(O), S(O), or S(0) 2 can be connected by two single bonds to two different carbon atoms.
  • O a divalent substituent
  • any substituent can be bonded to a carbon or other atom by a linker, such as (CH 2 ) n or (CR' 2 ) n wherein n is 1, 2, 3, or more, and each R' is independently selected.
  • C(O) and S(0) 2 groups can be bound to one or two heteroatoms, such as nitrogen, rather than to a carbon atom.
  • a C(O) group is bound to one carbon and one nitrogen atom
  • the resulting group is called an "amide” or "carboxamide.”
  • the functional group is termed a urea.
  • a S(0) 2 group is bound to one carbon and one nitrogen atom
  • the resulting unit is termed a "sulfonamide.”
  • a S(0) 2 group is bound to two nitrogen atoms, the resulting unit is termed a "sulfamate.”
  • Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.
  • ring system as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic.
  • spirocyclic is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
  • any of the groups described herein, which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the compounds of this disclosed subject matter include all stereochemical isomers arising from the substitution of these compounds.
  • substituents within the compounds described herein are present to a recursive degree.
  • "recursive substituent” means that a substituent may recite another instance of itself or of another substituent that itself recites the first substituent. Because of the recursive nature of such substituents, theoretically, a large number may be present in any given claim.
  • One of ordinary skill in the art of medicinal chemistry and organic chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.
  • Recursive substituents are an intended aspect of the disclosed subject matter.
  • One of ordinary skill in the art of medicinal and organic chemistry understands the versatility of such substituents.
  • alkyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups.
  • alkyl encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • a group is an alkyl chain "optionally comprising within the alkyl chain or at an alkyl chain terminus", signifies that a moiety can be disposed between two subunits of the alkyl chain, or can be disposed at an unsubstituted end of the chain, or can be disposed between the chain and a point of attachment of the chain, for example to a carbonyl, NR, or O group.
  • alkylbenzoyl group is an alkyl chain with a phenyl group disposed between the alkyl and a carbonyl, fitting the above description;
  • N-alkylphenylcarboxamido is an alkyl chain with a phenyl group disposed between the alkyl and the aminocarbonyl group, filling within the above description.
  • alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of one to six carbon atoms unless otherwise stated, such as methylene, ethylene, propylene, 1 -methylpropylene, 2- methylpropylene, butylene, pentylene, and the like.
  • Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • cycloalkenyl alone or in combination denotes a cyclic alkenyl group.
  • carbocyclic denotes a ring structure wherein the atoms of the ring are carbon, such as a cycloalkyl group or an aryl group.
  • the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7.
  • the carbocyclic ring can be substituted with as many as N-l substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above.
  • a carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
  • a carbocyclyl can be monocyclic or polycyclic, and if polycyclic each ring can be independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
  • (Cycloalkyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
  • alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.
  • Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons.
  • cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups.
  • Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring.
  • Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • (Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
  • Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C ⁇ CH, -C ⁇ C(CH 3 ), -C ⁇ C(CH 2 CH 3 ),
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quatemized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -0-CH 2 -CH 2 -CH 3 , -CH 2 -CH 2 CH 2 -OH, -CH 2 -CH 2 -NH-CH 3 ,
  • -CH 2 CH 2 -0-CH 2 CH 2 -0-CH 3 Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH , or -CH 2 -CH 2 -S-S-CH .
  • a "cycloheteroalkyl” ring or “heterocycloalkyl” ring is a cycloalkyl ring containing at least one heteroatom.
  • a cycloheteroalkyl ring can also be termed a “heterocyclyl,” described below.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms in the ring.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain about 6 to about 14 carbons in the ring portions of the groups.
  • Aryl groups can be unsubstituted or substituted, as defined above.
  • Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.
  • Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4- ethyl-indanyl.
  • Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Heterocyclyl groups or the term "heterocyclyl” includes aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof.
  • heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • a heterocyclyl group designated as a C 2 -heterocyclyl can be a 5 -ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • a heterocyclyl ring can also include one or more double bonds.
  • a heteroaryl ring is an embodiment of a heterocyclyl group.
  • the phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups.
  • a dioxolanyl ring and a benzdioxolanyl ring system are both heterocyclyl groups within the meaning herein.
  • the phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquino
  • quinazolinyl groups Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members.
  • a heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure.
  • a heteroaryl group designated as a C 2 -heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6- ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl,
  • Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed above.
  • aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl
  • Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above.
  • Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
  • alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
  • cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
  • an allyloxy group is an alkoxy group within the meaning herein.
  • a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structures are substituted therewith.
  • thioalkoxy refers to an alkyl group previously defined attached to the parent molecular moiety through a sulfur atom.
  • glycosyloxyoxy refers to a glycoside attached to the parent molecular moiety through an oxygen atom.
  • alkoxycarbonyl represents as ester group; i.e. an alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl,
  • a "haloalkyl” group includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkyl include
  • a "haloalkoxy" group includes mono-halo alkoxy groups, poly-halo alkoxy groups wherein all halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
  • haloalkoxy include trifluoromethoxy, 1,1-dichloroethoxy, 1 ,2-dichloroethoxy, l,3-dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.
  • (C x -C y )perfluoroalkyl wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • x ⁇ y means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • Preferred is -(Ci-C 6 )perfluoroalkyl, more preferred is -(Ci-C 3 )perfluoroalkyl, most preferred is -CF 3 .
  • (C x -C y )perfluoroalkylene wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • x ⁇ y means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
  • aryloxy and “arylalkoxy” refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
  • acyl group refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like.
  • the group is a "formyl” group, an acyl group as the term is defined herein.
  • An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group.
  • An acyl group can include double or triple bonds within the meaning herein.
  • An acryloyl group is an example of an acyl group.
  • An acyl group can also include hetero atoms within the meaning here.
  • a nicotinoyl group (pyridyl-3 -carbonyl) group is an example of an acyl group within the meaning herein.
  • Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like.
  • the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group.
  • An example is a trifluoroacetyl group.
  • amine includes primary, secondary, and tertiary amines having, e.g., the formula N(group) 3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
  • Amines include but are not limited to R-NH 2 , for example, alkylamines, arylamines, alkylarylamines; R 2 NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R 3 N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
  • the term "amine” also includes ammonium ions as used herein.
  • An "amino” group is a substituent of the form -NH 2 , -NHR, -NR 2 , -NR 3 + , wherein each R is independently selected, and protonated forms of each, except for -NR 3 + , which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine.
  • An “amino group” within the meaning herein can be a primary, secondary, tertiary or quaternary amino group.
  • An "alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group.
  • An "ammonium” ion includes the unsubstituted ammonium ion NH 4 + , but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.
  • the term “amide” (or “amido”) includes C- and N-amide groups, i.e., -C(0)NR 2 , and - NRC(0)R groups, respectively. Amide groups therefore include but are not limited to primary carboxamide groups (-C(0)NH 2 ) and formamide groups (-NHC(O)H).
  • a "carboxamido" or “aminocarbonyl” group is a group of the formula C(0)NR 2 , wherein R can be H, alkyl, aryl, etc.
  • azido refers to an N 3 group.
  • An “azide” can be an organic azide or can be a salt of the azide (N 3 ⁇ ) anion.
  • nitro refers to an N0 2 group bonded to an organic moiety.
  • nitroso refers to an NO group bonded to an organic moiety.
  • nitrate refers to an ON0 2 group bonded to an organic moiety or to a salt of the nitrate (N0 3 ⁇ ) anion.
  • urethane (“carbamoyl” or “carbamyl”) includes N- and O-urethane groups, i.e., -NRC(0)OR and -OC(0)NR 2 groups, respectively.
  • sulfonamide includes S- and N-sulfonamide groups, i.e., -S0 2 NR 2 and -NRS0 2 R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (-S0 2 NH 2 ).
  • An organosulfur structure represented by the formula - S(0)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.
  • amidine or “amidino” includes groups of the formula -C(NR)NR 2 .
  • an amidino group is -C(NH)NH 2 .
  • guanidine or "guanidino” includes groups of the formula -NRC(NR)NR 2 .
  • a guanidino group is -NHC(NH)NH 2 .
  • a “salt” as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion.
  • acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH 4 + or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like.
  • “pharmacologically acceptable” salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt.
  • a “zwitterion” is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form.
  • a “zwitterion” is a salt within the meaning herein.
  • the compounds described herein may take the form of salts.
  • the term “salts" embraces addition salts of free acids or free bases which are compounds described herein. Salts can be “pharmaceutically-acceptable salts.” The term
  • “pharmaceutically-acceptable salt” refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present disclosure, such as for example utility in process of synthesis, purification or formulation of compounds of the present disclosure.
  • Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic,
  • Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates.
  • Suitable pharmaceutically acceptable base addition salts of compounds of the present disclosure include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N ⁇ -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts.
  • salts may be useful, for example as intermediates in the synthesis of Formula (A), ( ⁇ '), (I), ( ⁇ ), (II), (IF), (III), (IIF), (IV), (IV), (V), (V), (VI), (VF), (VII), (VIF), (VIII), (VIIF), (IX), (IX'), (X), ( ⁇ '), (XI), (XF), (XII), (XIF), (XIII), (XIIF), (XIV), (XIV), (XV), or (XV) compounds, for example in their purification by recrystallization.
  • All of these salts may be prepared by conventional means from the corresponding compound according to Formula (A), ( ⁇ '), (I), (F), (II), (IF), (III), (IIF), (IV), (IV), (V), (V), (VI), (VF), (VII), (VIF), (VIII), (VIIF), (IX), (IX'), (X), ( ⁇ '), (XI), (XF), (XII), (XIF), (XIII), (XIIF), (XIV), (XIV), (XV), or (XV) by reacting, for example, the appropriate acid or base with the compound according to Formula (A), ( ⁇ '), (I), (F), (II), (IF), (III), (IIF), (IV), (IV), (V), (VI), (VF), (VII), (VIF), (VIII), (VIIF), (IX), ( ⁇ '), (XI), ( ⁇ ), ( ⁇ ), (XIII), ( ⁇ ), (XIII), ( ⁇ ), (IX), ( ⁇ ),
  • pharmaceutically acceptable salts refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et al, Salt Selection for Basic Drugs (1986), IntJ. Pharm., 33, 201-217, incorporated by reference herein.
  • a "hydrate” is a compound that exists in a composition with water molecules.
  • the composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a "hydrate” refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.
  • a “solvate” is a similar composition except that a solvent other that water replaces the water.
  • a solvent other that water replaces the water.
  • methanol or ethanol can form an “alcoholate”, which can again be stoichiometic or non- stoichiometric.
  • a “solvate” refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.
  • a "prodrug” as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patients body, such as enzymes, to the active pharmaceutical ingredient.
  • Examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • a value of a variable that is necessarily an integer, e.g., the number of carbon atoms in an alkyl group or the number of substituents on a ring is described as a range, e.g., 0-4, what is meant is that the value can be any integer between 0 and 4 inclusive, i.e., 0, 1, 2, 3, or 4.
  • the compound or set of compounds, such as are used in the inventive methods can be any one of any of the combinations and/or sub -combinations of the above-listed embodiments.
  • a compound as shown in any of the Examples, or among the exemplary compounds is provided. Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of the other above disclosed embodiments or species may be excluded from such categories or embodiments.
  • the present disclosure further embraces isolated compounds according to Formula (A), ( ⁇ '), (I), (F), (II), (IF), (III), (IIF), (IV), (IV), (V), (V), (VI), (VF), (VII), (VIF), (VIII), (VIIF), (IX), ( ⁇ '), (X), ( ⁇ '), (XI), (XF), (XII), (XIF), (XIII), (XIIF), (XIV), (XIV), (XV), or (XV).
  • isolated compound refers to a preparation of a compound of Formula (A), ( ⁇ '), (I), (F), (II), (IF), (III), (IIF), (IV), (IV), (V), (V), (VI), (VF), (VII), (VIF), (VIII), (VIIF), (IX), ( ⁇ '), (X), ( ⁇ '), (XI), (XF), (XII), (XIF), (XIII), (XIIF), (XIV), (XIV), (XV), or (XV), or a mixture of compounds according to Formula (A), ( ⁇ '), (I), (F), (II), (IF), (III), (IIF), (IV), (IV), (V), (V), (VI), (VF), (VII), (VIF), (VIII), (VIIF), (IX), ( ⁇ '), (XI), (XF), (XII), (XIF), (XIII), (XIIF), (XIV), (XIV), (XV), or (XV),
  • an “isolated” does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically.
  • an “isolated compound” refers to a preparation of a compound of Formula (A), ( ⁇ '), (I), (F), (II), (IF), (III), (IIF), (IV), (IV), (V), (V), (VI), (VF), (VII), (VIF), (VIII), (VIIF), (IX), ( ⁇ '), (XI), (XF), (XII), (XIF), (XIII), (XIIF), (XIV), (XIV), (XV), or (XV) or a mixture of compounds according to Formula (A), ( ⁇ '), (I), (F), (II), (IF), (III), (IIF), (IV), (IV), (XIV), (XV), or (XV) or a mixture of compounds according to Formula (A), ( ⁇ '), (I), (F), (II
  • the preparation contains the named compound or mixture of compounds in an amount of at least 50 percent by weight of the total weight; more preferably at least 80 percent by weight of the total weight; and most preferably at least 90 percent, at least 95 percent or at least 98 percent by weight of the total weight of the preparation.
  • (XV) or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the present disclosure encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings.
  • Such tautomerism can also occur with substituted pyrazoles such as 3 -methyl, 5- methyl, or 3,5-dimethylpyrazoles, and the like.
  • Another example of tautomerism is amido- imido (lactam-lactim when cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a ring nitrogen atom.
  • the equilibrium is an example of tautomerism. Accordingly, a structure depicted herein as one tautomer is intended to also include the other tautomer.
  • the priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking.
  • the present disclosure is meant to encompass diastereomers as well as their racemic and resolved, diastereomerically and enantiomerically pure forms and salts thereof.
  • Diastereomeric pairs may be resolved by known separation techniques including normal and reverse phase chromatography, and crystallization.
  • isolated optical isomer means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula.
  • the isolated isomer is at least about 80%, more preferably at least 90%> pure, even more preferably at least 98%> pure, most preferably at least about 99% pure, by weight.
  • Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques. According to one such method, a racemic mixture of a compound described herein, or a chiral intermediate thereof, is separated into 99% wt.% pure optical isomers by HPLC using a suitable chiral column, such as a member of the series of DAICEL ® CHIRALPAK ® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer's instructions.
  • a suitable chiral column such as a member of the series of DAICEL ® CHIRALPAK ® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer's instructions.
  • the present disclosure therefore includes any possible stable rotamers of Formula (A), ( ⁇ '), (I), (F), (II), (IF), (III), (IIF), (IV), (IV), (V), (V), (VI), (VF), (VII), (VIF), (VIII), (VIIF), (IX), ( ⁇ '), (X), ( ⁇ '), (XI), (XF), (XII), (XIF), (XIII), (XIIF), (XIV), (XIV), (XV), or (XV) which are biologically active in the treatment of cancer or other proliferative disease states.
  • the compounds described herein have a particular spatial arrangement of substituents on the aromatic rings, which is related to the structure activity relationship demonstrated by the compound class. Often such substitution arrangement is denoted by a numbering system; however, numbering systems are often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature "para" for 1,4-substitution, "meta” for 1,3 -substitution and "ortho" for 1 ,2-substitution as shown below.
  • the compound or set of compounds such as are among the inventive compounds or are used in the inventive methods, can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
  • R 1 is selected from:
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 C(0)OR 25 , -CH 2 CH 2 C(0)OH, -CH 2 CH 2 C(0)OR 25 , - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)N(H)C(H)(CH 3 )C0 2 H, - CH 2 CH 2 C(0)N(H)C(H)(C0 2 H)CH 2 C0 2 H, -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , -(CH 2 ) 4 N + (R 25 ) 3 , -(CH 2
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH
  • R x is H, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -Cgcycloalkyl; or R x and R 2 together with the nitrogen atom form optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R z is -NR 15 R 16 , -CH 2 -NR 15 R 16 , or -(CH 2 ) 2 -NR 15 R 16 ;
  • R 7 is optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heterocycloalkyl, or an optionally substituted , wherein Z is a bond, O, S, NH, CH 2 , NHCH 2 , or C ⁇ C;
  • R is a bond, -0-, or -N(R )-, optionally substituted Ci-Cealkyl, optionally substituted Ci- Ceheteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 9 is -CH 2 OH, -CH 2 CH(CH 3 ) 2 ,
  • R is Ci-C 6 alkyl, Ci-C 6 haloalky l, -C(0)OR , -CF 2 C(0)OH, or
  • R 15 and R 16 are each independently H, or Ci-C 4 alkyl
  • R is H, methyl, ethyl, isopropyl, or cyclopropyl
  • R 18 , R 19 , and 20 are each independently H, or methyl; each R 21 is independently H, or Ci-C 4 alkyl;
  • R 23 is H, Ci-C 4 alkyl, or Ci-C 4 alkoxy
  • R 24 is -H, -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -C(0)R 26 , -C(0)OR 26 , -C(0)NR 26 R 27 , CH 2 C(0)OH, -CH 2 C(0)OR 25 , -CH 2 CH 2 C(0)OH, -CH 2 CH 2 C(0)OR 25 , -CH 2 C(0)NH 2 , - CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)N(H)C(H)(CH 3 )C0 2 H, - CH 2 CH 2 C(0)N(H)C(H)(C0 2 H)CH 2 C0 2 H, -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , -(CH 2 ) 4 N + (R 25 ) 3 , -(CH 2
  • each R is independently Ci-Cealkyl
  • R 26 is H, or Ci-C 4 alkyl
  • R 27 is H, or Ci-C 4 alkyl
  • R 28 is Ci-C 6 alkyl
  • n 0 or 1 ;
  • p is 0 or 1 ;
  • q is 0 or 1 ;
  • R 1 is selected from:
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 C(0)OR 25 , -CH 2 CH 2 C(0)OH, -CH 2 CH 2 C(0)OR 25 , - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)N(H)C(H)(CH 3 )C0 2 H, - CH 2 CH 2 C(0)N(H)C(H)(C0 2 H)CH 2 C0 2 H, -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , -(CH 2 ) 4 N + (R 25 ) 3 , -(CH 2
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH
  • R x is H, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -Cgcycloalkyl; or R x and R 2 together with the nitrogen atom form optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R z is -NR 15 R 16 , -CH 2 -NR 15 R 16 , or -(CH 2 ) 2 -NR 15 R 16 ;
  • R 7 is optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heterocycloalkyl, or an optionally substituted , wherein Z is a bond, O, S, NH, CH 2 , NHCH 2 , or C ⁇ C;
  • R is a bond, -0-, or -N(R )-, optionally substituted Ci-Cealkyl, optionally substituted Ci- Ceheteroalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 9 is -CH 2 OH, -CH 2 CH(CH 3 ) 2 ,
  • R is Ci-C 6 alkyl, Ci-C 6 haloalky l, -C(0)OR , -CF 2 C(0)OH, or
  • R 15 and R 16 are each independently H, or Ci-C 4 alkyl
  • R is H, methyl, ethyl, isopropyl, or cyclopropyl
  • R 18 , R 19 , and 20 are each independently H, or methyl; each R 21 is independently H, or Ci-C 4 alkyl;
  • R 23 is H, Ci-C 4 alkyl, or Ci-C 4 alkoxy
  • R 24 is -H, -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -C(0)R 26 , -C(0)OR 26 , -C(0)NR 26 R 27 , CH 2 C(0)OH, -CH 2 C(0)OR 25 , -CH 2 CH 2 C(0)OH, -CH 2 CH 2 C(0)OR 25 , -CH 2 C(0)NH 2 , - CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)N(H)C(H)(CH 3 )C0 2 H, - CH 2 CH 2 C(0)N(H)C(H)(C0 2 H)CH 2 C0 2 H, -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , -(CH 2 ) 4 N + (R 25 ) 3 , -(CH 2
  • each R is independently Ci-Cealkyl
  • R 26 is H, or Ci-C 4 alkyl
  • R 27 is H, or Ci-C 4 alkyl
  • R 28 is Ci-C 6 alkyl
  • n 0 or 1 ;
  • p is 0 or 1 ;
  • q is 0 or 1 ;
  • R 1 is a compound of Formula (A) or Formula ( ⁇ ') wherein R 1 is .
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , - CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , - .
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, - CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 ,
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -
  • Formula (A) or Formula ( ⁇ ') wherein R is an optionally substituted Ci-Ceheteroalkyl.
  • R 14 is -C(0)OR 28
  • C(0)OR 28 and R 28 is -CH 3 .
  • R 28 is -CH 3 .
  • C(0)OR 28 and R 28 is -CH 3 .
  • R 28 is -CH 3 .
  • Formula (A) or Formula ( ⁇ ') wherein R 14 is .
  • R 23 is H or Ci-C 4 alkyl; and R 24 is H or optionally substituted Ci-Csalkyl.
  • R 2 , R 4 , and R 12 are each independently -CH 2 CH(CH 3 ) 2 , -CH(OH)(CH 3 ), -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , or -(CH 2 ) 4 NH 2 ; and R 6 and R 7 are defined as above.
  • R 4 is -(CH 2 ) 4 NH 2
  • R 2 is -CH(OH)(CH 3 )
  • R 12 is -(CH 2 ) 2 NH 2
  • R 4 is -(CH 2 ) 4 NH 2
  • R 2 is -CH(OH)(CH 3 )
  • R 12 is -CH 2 NH 2
  • R 4 is -CH 2 C(0)NH 2
  • R 2 is - CH(OH)(CH 3 )
  • R 12 is -(CH 2 ) 4 NH 2 .
  • R 4 is -(CH 2 ) 4 NH 2
  • R 2 is -(CH 2 ) 4 NH 2
  • R 12 is -CH 2 NH 2
  • R 4 is -CH 2 C(0)NH 2
  • R 2 is -(CH 2 ) 4 NH 2
  • R 12 is - CH 2 NH 2
  • R 4 is - CH 2 CH(CH 3 ) 2
  • R 2 is -(CH 2 ) 2 NH 2
  • R 12 is -(CH 2 ) 2 NH 2 .
  • R 8 is an optionally substituted Ci-Ceheteroalkyl.
  • R 2 , R4 , R10 , R11 , R12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), - CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -(CH 2 ) 4 NH 2 ,
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , - CH 2 CH 2 C(0)NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -(CH 2 ) 4 NH 2 , , or .
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -(CH 2 ) 4 NH 2 , or .
  • n is 0 and p is 0.
  • n is 0 and p is 1.
  • n is 1 and p is 0.
  • R 2 , R 4 , and R 12 are each independently -CH 2 CH(CH 3 ) 2 , -(CH 2 ) 3 NH 2 , or - (CH 2 ) 4 NH 2 .
  • R 12 are each -(CH 2 ) 3 NH 2 .
  • R 4 is -CH 2 CH(CH 3 ) 2
  • R 2 is -(CH 2 ) 3 NH 2
  • R 12 is -(CH 2 ) 4 NH 2 .
  • R 4 is -CH 2 CH(CH 3 ) 2
  • R 2 is -(CH 2 ) 4 NH 2
  • R 12 is - (CH 2 ) 4 NH 2 .
  • R 5 is -H, or -CH 3 .
  • R 5 is -H, or -CH 3 .
  • R is an optionally substituted Ci-Ceheteroalkyl.
  • R , R , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , - CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -(CH 2 ) 4 NH 2 ,
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH,
  • n is 0 and p is 0.
  • n is 0 and p is 1.
  • n is 1 and p is 0.
  • R is -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, or -(CH 2 ) 4 NH 2 .
  • R 2 is -CH(OH)(CH 3 ).
  • R 2 is -CH 2 CH 2 C(0)OH.
  • R 2 is -(CH 2 ) 4 NH 2 .
  • a compound of Formula (AC) wherein R 4 is CH 2 CH(CH 3 ) 2 or -CH 2 C(0)NH 2 .
  • R 4 is CH 2 CH(CH ) 2 .
  • R 4 is -CH 2 C(0)NH 2 .
  • R 5 is H or -CH 3 .
  • R 4 is H.
  • R 4 is -CH 3 .
  • her embodiment is a compound of Formula (A) or Formula ( ⁇ ') wherein R 1 is
  • R 2 and R 4 are each independently -H, -CH 3 , -
  • q is 1 and R 8 is a bond.
  • R 8 is an optionally substituted Ci-Ceheteroalkyl.
  • R z is NH 2 ; and R 2 and R 4 are each independently -CH 2 CH(CH 3 ) 2 , -CH(OH)(CH 3 ), - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , or -(CH 2 ) 4 NH 2 .
  • [00128] in another embodiment is a compound of Formula (AD) wherein R is - CH(OH)(CH 3 ), and R 4 is -CH 2 C(0)NH 2 .
  • R 4 2 and R is -CH 2 CH(CH 3 ) 2 .
  • R is a compound of Formula (AD) wherein R is -(CH 2 ) 4 NH 2 and R 4 is -CH 2 C(0)NH 2 .
  • R is a bond.
  • R 8 is an optionally substituted Ci-Ceheteroalkyl.
  • R 2 , R 4 , R 10 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), - CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -
  • R are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , - CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -(CH 2 ) 2 NH 2 , - (CH 2 ) 3 NH 2 , -(CH 2 ) 4 NH 2 , , , , or
  • R 2 , R 4 , R 10 , R 12 , and R 13 are each independently -H, -CH 3 , CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -
  • n is 1.
  • R 5 is -H, or -CH 3 .
  • a compound of Formula (ADD) wherein R 10 is -CH 2 OH, and R 12 is -CH 3 .
  • R 10 is - CH 2 CH(CH 3 ) 2 , and R 12 is -CH(OH)(CH 3 ).
  • R 4 is -CH 2 C(0)NH 2 .
  • R 4 is a compound wherein R 4 is a compound wherein R 4 is a compound wherein R 4 is a compound wherein R 4 is
  • R 6 is a bond.
  • R 6 is an optionally substituted Ci-Ceheteroalkyl.
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , - CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , - CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -(CH 2 ) 4 NH 2 , , or .
  • R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , - CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, - CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 NH 2 ,
  • n is 1.
  • R 1 is in another embodiment, R is a bond.
  • R is an optionally substituted Ci-Ceheteroalkyl.
  • R 2 and R 4 are each independently -H, - CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 2 NH 2 , -
  • R 2 and R 4 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -
  • R 2 and R 4 are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH
  • R 5 is -H, or -CH 3 .
  • [00135] in another embodiment is a compound of Formula (AE) wherein R 10 and R 12 are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, or -CH(OH)(CH 3 ).
  • R 1 is selected from:
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 C(0)OR 25 , -CH 2 CH 2 C(0)OH, -CH 2 CH 2 C(0)OR 25 , - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)N(H)C(H)(CH 3 )C0 2 H, - CH 2 CH 2 C(0)N(H)C(H)(C0 2 H)CH 2 C0 2 H, -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , -(CH 2 ) 4 N + (R 25 ) 3 , -(CH 2
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R x is H, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -Cgcycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R z is -NR 15 R 16 , -CH 2 -NR 15 R 16 , or -(CH 2 ) 2 -NR 15 R 16 ;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, or an optionally substituted s wherein Z is a bond, O, S, NH, CH 2 , NHCH 2 , or C ⁇ C;
  • R is a bond, -0-, or -N(R )-, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R is -CH 2 OH, -CH 2 CH(CH 3 ) 2 ,
  • R 15 and R 16 are each independently H, or Ci-G t alkyl
  • R is H, methyl, ethyl, isopropyl, or cyclopropyl
  • R 18 , R 19 , and 20 are each independently H, or methyl; each R 21 is independently H, or Ci-C4alkyl;
  • R 23 is H, or Ci-C 4 alkyl
  • R 24 is optionally substituted Ci-Ceheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, -CH 2 C(0)OR 26 , or -CH 2 CH 2 R 27 ;
  • each R 25 is independently Ci-C 6 alkyl
  • R 26 is H, or optionally substituted Ci-C 6 alkyl
  • R 27 is optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • n 0 or 1 ;
  • p is 0 or 1 ;
  • q is 0 or 1 ;
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -
  • R 2 , R 4 , R 12 , and R 13 are each ind ieeppeennddeennttllyy --HH,, --CCHH 33 ,, --CCHH 22 CCHH((CCHH 33 )) 22 , - CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , --CH 2 NH 2 , -
  • R is a bond.
  • R 7 is a linear or branched alkyl chain of 1 -22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, or an optionally substituted wherein Z is a bond, O, S, NH, CH 2 , NHCH 2 , or
  • R 7 is a linear or branched alkyl chain of 1 -22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted s wherein Z is a bond.
  • R 7 is In a further embodiment of the aforementioned embodiments of Formula (I) is a compound wherein
  • R 23 is H; and R 24 is optionally substituted aryl.
  • R 6 is -
  • R 23 is H; and R 24 is optionally substituted heteroaryl.
  • R 6 is -
  • R 23 is H; and R 24 is -CH 2 C(0)OR 26 ; and R 26 is optionally substituted
  • R 1 is selected from:
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), CH 2 CF ? , -CH 2 C(0)OH, -CH 2 C(0)OR 25 , -CH 2 CH 2 C(0)OH, -CH 2 CH 2 C(0)OR 25 , - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)N(H)C(H)(CH 3 )C0 2 H, - CH 2 CH 2 C(0)N(H)C(H)(C0 2 H)CH 2 C0 2 H, -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , -(CH 2 ) 4 N + (R 25 ) 3 , -(CH 2 )
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R x is H, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -C 8 cycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R z is -NR 15 R 16 , -CH 2 -NR 15 R 16 , or -(CH 2 ) 2 -NR 15 R 16 ;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, or an optionally substituted , wherein Z is a bond, O, S, NH, CH 2 , NHCH 2 , or C ⁇ C;
  • R 8 is a bond, -0-, or -N(R 17 )-, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R and R are each independently H, or Ci-C 4 alkyl
  • R is H, methyl, ethyl, isopropyl, or cyclopropyl
  • R 18 , R 19 , and 20 are each independently H, or methyl
  • each R 21 is independently H, or Ci-C 4 alkyl
  • R 23 is H, or Ci-C 4 alkyl
  • R 24 is optionally substituted Ci-Ceheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, -CH 2 C(0)OR 26 , or -CH 2 CH 2 R 27 ;
  • each R 25 is independently Ci-Cealkyl
  • R 26 is H, or optionally substituted Ci-Cealkyl
  • R 27 is optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • n 0 or 1 ;
  • p is 0 or 1 ;
  • q is 0 or 1 ;
  • R 1 is a compound of Formula (I) or Formula ( ⁇ ) wherein R 1 is .
  • R 8 is a bond.
  • R 2 , R 4 , R 1Z , and R 1J are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), - CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -(CH 2 ) 4 NH 2 ,
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , - CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -(CH 2 ) 4 NH 2 ,
  • R are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -
  • n is 1.
  • R 2 , R 4 , and R 12 are each independently -CH 2 CH(CH 3 ) 2 , -CH(OH)(CH 3 ), -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , or -(CH 2 ) 4 NH 2 .
  • R 4 is -(CH 2 ) 4 NH 2
  • R 2 is -CH(OH)(CH 3 )
  • R 12 is -CH 2 NH 2
  • R 4 is -CH 2 C(0)NH 2
  • R 2 is -CH(OH)(CH 3 )
  • R 12 is - (CH 2 ) 4 NH 2
  • R 4 is -(CH 2 ) 4 NH 2
  • R 2 is -(CH 2 ) 4 NH 2
  • R 12 is -CH 2 NH 2
  • R 4 is -CH 2 C(0)NH 2
  • R 2 is -(CH 2 ) 4 NH 2
  • R 12 is -CH 2 NH 2
  • R 4 is -CH 2 CH(CH 3 ) 2
  • R 2 is -(CH 2 ) 2 NH 2
  • R 12 is - (CH 2 ) 2 NH 2
  • R 7 is a linear or branched alkyl chain of 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl,
  • Z is a bond, O, S, NH, CH 2 , NHCH 2 , or
  • R 7 is a linear or branched alkyl chain of 1-22 carbon atoms, optionall comprising
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , - CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -
  • R 11 , R 12 , and R 13 are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , - (CH 2 ) 4 NH 2 , or H .
  • n is 0 and p is 0.
  • n is 0 and p is 1.
  • n is 1 and p is 0.
  • R 2 , R 4 , and R 12 are each independently -CH 2 CH(CH 3 ) 2 , -(CH 2 ) 3 NH 2 , or - (CH 2 ) 4 NH 2 .
  • R 12 are each -(CH 2 ) 3 NH 2 .
  • R 4 is -CH 2 CH(CH 3 ) 2
  • R 2 is -(CH 2 ) 3 NH 2
  • R 12 is -(CH 2 ) 4 NH 2 .
  • R 4 is -CH 2 CH(CH 3 ) 2
  • R 2 is -(CH 2 ) 4 NH 2
  • R 12 is - (CH 2 ) 4 NH 2 .
  • R 5 is -H, or -CH 3 .
  • R 5 is -H, or -CH .
  • R 1 is n pio n R12 r>
  • R is a bond.
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , - CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 )
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , - CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -(CH 2 ) 4 NH 2 , , or .
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -(CH 2 ) 2 NH
  • n is 0 and p is 0.
  • n is 0 and p is 1.
  • n is 1 and p is 0.
  • R 2 , R 4 , and R 12 are each independently -CH 2 CH(CH 3 ) 2 , -CH(OH)(CH 3 ), - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , or -(CH 2 ) 4 NH 2 .
  • R 12 is -(CH 2 ) 2 NH 2 .
  • R 4 is -(CH 2 ) 4 NH 2
  • R 2 is -CH(OH)(CH 3 )
  • R 12 is -CH 2 NH 2 .
  • R 4 is -CH 2 C(0)NH 2
  • R 2 is -CH(OH)(CH 3 )
  • R 12 is - (CH 2 ) 4 NH 2 .
  • R 4 is -(CH 2 ) 4 NH 2 ,
  • R is -(CH 2 ) 4 NH 2 , and R is -CH 2 NH 2 .
  • R 4 is -CH 2 C(0)NH 2
  • R 2 is -(CH 2 ) 4 NH 2
  • R 12 is -CH 2 NH 2 .
  • R 4 is -CH 2 CH(CH 3 ) 2
  • R 2 is -(CH 2 ) 2 NH 2
  • R 12 is - (CH 2 ) 2 NH 2 .
  • R 5 is -H, or -CH 3 .
  • q is 1 and R is a bond.
  • R z is NH 2 ; and R 2 and R 4 are each independently -CH 2 CH(CH 3 ) 2 , -CH(OH)(CH 3 ), - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , or -(CH 2 ) 4 NH 2 .
  • R is -CH(OH)(CH 3 ), and R is -(CH 2 ) 3 NH 2 .
  • R is -CH(OH)(CH 3 ), and R is -(CH 2 ) 3 NH 2 .
  • R is a compound of
  • embodiment is a compound of Formula (Id) wherein R is -(CH 2 ) 4 NH 2 and R is -CH 2 C(0)NH 2 .
  • R is a bond.
  • R 2 , R 4 , R 10 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -(CH 2 ) 4 NH 2 ,
  • R 2 , R 4 , R 10 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -
  • R 2 , R 4 , R 10 , R 12 , and R 13 are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -
  • n is 1.
  • R 5 is -H, or -CH .
  • R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -(CH 2 ) 4 NH 2 , , or .
  • R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -
  • R 2 , R 4 , R 12 , and R are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 NH 2 , -CH 2 CH 2 C(0)NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -
  • n is 1.
  • R is a bond.
  • R and R are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -
  • R 2 and R 4 are each independently ⁇
  • R 2 and R 4 are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, - CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -(CH 2 ) 2 NH 2 , -
  • R 5 is -H, or -CH 3 .
  • [00161] in another embodiment is a compound of Formula (Ie) wherein R 10 and R 12 are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, or -CH(OH)(CH 3 ).
  • R 1 is selected from:
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 C(0)OR 25 , -CH 2 CH 2 C(0)OH, -CH 2 CH 2 C(0)OR 25 , - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)N(H)C(H)(CH 3 )C0 2 H, - CH 2 CH 2 C(0)N(H)C(H)(C0 2 H)CH 2 C0 2 H, -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , -(CH 2 ) 4 N + (R 25 ) 3 , -(CH 2
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH; or R 5 and R 24 together with the boron atom form a 5- or 6-membered boron containing ring;
  • R x is H, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C3-C 8 cycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R z is -NR 15 R 16 , -CH 2 -NR 15 R 16 , or -(CH 2 ) 2 -NR 15 R 16 ;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroaryl, an optionally
  • R is an optionally substituted heterocycloalkyl; R is -CH 2 OH, -CH 2 CH(CH 3 ) 2 ,
  • R 14 , R 15 , and R 16 are each independently H, or Ci-C 4 alkyl
  • R 18 , R 19 , and 20 are each independently H, or methyl
  • each R 21 is independently H, or Ci-C 4 alkyl
  • R 2"3 and 24 are each independently H, or Ci-C 4 alkyl; or R 23 and R 24 together with the boron atom form an optionally substituted 5- or 6-membered boron containing ring;
  • each R 25 is independently Ci-Cealkyl
  • R 26 is H, Ci-C 4 alkyl, Ci-C 4 alkoxy, -CH 2 C(0)OR 25 , or -OCH 2 C(0)OR 25 ;
  • n 0 or 1 ;
  • p is 0 or 1 ;
  • q is 0 or 1 ;
  • R 1 is selected from:
  • R 2 , R 4 , R 10 , R 11 , R 12 , and R 13 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 C(0)OR 25 , -CH 2 CH 2 C(0)OH, -CH 2 CH 2 C(0)OR 25 , - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)N(H)C(H)(CH 3 )C0 2 H, - CH 2 CH 2 C(0)N(H)C(H)(C0 2 H)CH 2 C0 2 H, -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , -(CH 2 ) 4 N + (R 25 ) 3 , -(CH 2
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH
  • R 5 and R 24 together with the boron atom form a 5- or 6-membered boron containing ring
  • R x is H, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -Cgcycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R z is -NR 15 R 16 , -CH 2 -NR 15 R 16 , or -(CH 2 ) 2 -NR 15 R 16 ;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, or an optionally substituted wherein Z is a bond, O, S, NH, CH 2 , NHCH 2 , or C ⁇ C;
  • R is an optionally substituted heterocycloalkyl
  • R 9 is -CH 2 OH, -CH 2 CH(CH 3 ) 2 ,
  • R 14 , R 15 , and R 16 are each independently H, or Ci-C 4 alkyl
  • R 18 , R 19 , and 20 are each independently H, or methyl
  • each R 21 is independently H, or Ci-C 4 alkyl
  • R 23 and 24 are each independently H, or Ci-C 4 alkyl; or R 23 and R 24 together with the boron atom form an optionally substituted 5- or 6-membered boron containing ring;
  • each R 25 is independently Ci-Cealkyl;
  • R b is H, Ci-C 4 alkyl, Ci-C 4 alkoxy, -CH 2 C(0)OR , or -OCH 2 C(0)OR 25 ;
  • n 0 or 1 ;
  • p is 0 or 1 ;
  • q is 0 or 1 ;
  • R 1 is a compound of Formula (II) or Formula (IF) wherein R 1 is .
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , - CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -
  • (CH 2 ) 4 NH 2 is a compound of Formula (II) or Formula (IF) wherein R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , -CH 2 OH, - CH(OH)(CH 3 ), -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 ,
  • R 2 , R 4 , R 12 , and R 13 are each independently -H, -CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NH 2 , -(CH 2 ) 2 NH 2 , -(CH 2 ) 3 NH 2 , -
  • aforementioned embodiments of Formula (II) or Formula (IF) is a compound wherein n is 0.
  • a compound wherein n is 1.
  • a compound wherein n is 1.
  • R 2 and R 4 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , optionally substituted Ci-Cgalkyl, optionally substituted Ci-Cgheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted -CH 2 -C 3 - Cgcycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH; or R 5 and R 24 together with the boron atom form a 5- or 6-membered boron containing ring;
  • R x is H, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -Cgcycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroar l, an optionally
  • substituted heterocycloalkyl or an optionally substituted s wherein Z is a bond, O, S, NH, CH 2 , NHCH 2 , or C ⁇ C; R is a bond, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
  • R 12 is -NR 21 R 22 ;
  • each R 14 is independently H, optionally substituted Ci-C 4 alkyl, optionally substituted Ci- Ceheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, -CH 2 C(0)OR 26 , or -CH 2 CH 2 R 27 ;
  • each R 21 is independently H, or Ci-C 4 alkyl
  • R 2"3 and 24 are each independently H, or Ci-C 4 alkyl
  • R 26 is H, or optionally substituted Ci-C 6 alkyl
  • R 27 is optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 28 is H, or optionally substituted Ci-C 6 alkyl
  • n 0 or 1 ;
  • R 2 and R 4 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , optionally substituted Ci-Cgalkyl, optionally substituted Ci-Cgheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted -CH 2 -C 3 - Cgcycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH
  • R 5 and R 24 together with the boron atom form a 5- or 6-membered boron containing ring
  • R x is H, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -C 8 cycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroar l, an optionally
  • R is a bond, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-Ceheteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
  • R 12 is -NR 21 R 22 ;
  • each R 14 is independently H, optionally substituted Ci-C 4 alkyl, optionally substituted Ci- Ceheteroalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, -CH 2 C(0)OR 26 , or -CH 2 CH 2 R 27 ;
  • each R 21 is independently H, or Ci-C 4 alkyl
  • R 2"3 and 24 are each independently H, or Ci-C 4 alkyl
  • R 26 is H, or optionally substituted Ci-Cealkyl
  • R 27 is optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 28 is H, or optionally substituted Ci-C 6 alkyl; and m is 0 or 1 ; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R and R 4 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), - CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , -(CH 2 ) 3 NR 21 R 22 , or -
  • (CH 2 ) 4 NR 21 R 22 is a compound of Formula (III) or Formula ( ⁇ ) wherein R 2 and R 4 are each independently -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , - CH 2 OH, -CH(OH)(CH 3 ), -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , -(CH 2 ) 3 NR 21 R 22 , or -(CH 2 ) 4 NR 21 R 22 .
  • [00170] in another embodiment is a compound of Formula (III) or Formula ( ⁇ ) wherein m is l, and R 12 is -NR 21 R 22. In another embodiment is a compound of Formula (III) or Formula ( ⁇ ) wherein m is l, and R 1 1 2 is -NH 2 .
  • R 2 and R 4 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , optionally substituted Ci-C 8 alkyl, optionally substituted Ci-C 8 heteroalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -CH 2 -C 3 - C 8 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R x is H, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted Cs-Cscycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroar l, an optionally
  • R is a bond, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
  • R 12 is H
  • each R 14 is independently H, optionally substituted Ci-C 4 alkyl, optionally substituted Ci- Ceheteroalkyl, optionally substituted C3-Cgcycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, -CH 2 C(0)OR 26 , or -CH 2 CH 2 R 27 ;
  • each R 21 is independently H, or Ci-C 4 alkyl
  • R 2"3 and 24 are each independently H, or Ci-C 4 alkyl
  • R 26 is H, or optionally substituted Ci-C 6 alkyl
  • R 27 is optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 28 is H, or optionally substituted Ci-C 6 alkyl
  • n 0;
  • R 2 and R 4 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , optionally substituted Ci-Cgalkyl, optionally substituted Ci-Cgheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted -CH 2 -C 3 - Cgcycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH; or R 5 and R 24 together with the boron atom form a 5- or 6-membered boron containing ring;
  • R x is H, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -Cgcycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycloalkyl, or an optionally substituted , wherein Z is a bond, O, S, NH, CH 2 , NHCH 2 , or C ⁇ C;
  • R is a bond, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
  • R is H
  • each R is independently H, optionally substituted Ci-C 4 alkyl, optionally substituted Ci- C 6 heteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, -CH 2 C(0)OR , or -CH 2 CH 2 R 2 / ;
  • each R 21 is independently H, or Ci-C 4 alkyl
  • 23 and 24 are each independently H, or Ci-C 4 alkyl
  • R 26 is H, or optionally substituted Ci-Cealkyl
  • R 27 is optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 28 is H, or optionally substituted Ci-C 6 alkyl
  • n 0; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • [00173] is a compound of Formula (IV) or Formula (IV) wherein R is a
  • R is an optionally substituted Ci-Ceheteroalkyl.
  • R and R 4 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), - CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , -(CH 2 ) 3 NR 21 R 22 , or -
  • (CH 2 ) 4 NR R is a compound of Formula (IV) or Formula (IV) wherein R 2 and R 4 are each independently -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , - CH 2 OH, -CH(OH)(CH 3 ), -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , -(CH 2 ) 3 NR 21 R 22 , or -(CH 2 ) 4 NR 21 R 22 .
  • R 2 and R 4 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , optionally substituted Ci-Cgalkyl, optionally substituted Ci-Cgheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted -CH 2 -C 3 - Cgcycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH; or R 5 and R 24 together with the boron atom form
  • R x is H, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -Cgcycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroaryl, an optionally
  • R is a bond, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-Ceheteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
  • R 12 is H or -NR 21 R 22 ; each R 14 is independently H, optionally substituted Ci-C 4 alkyl, optionally substituted Ci- Ceheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, -CH 2 C(0)OR 26 , or -CH 2 CH 2 R 27 ;
  • each R is independently H, or Ci-C 4 alkyl
  • R" and R" are each independently H, or Ci-C 4 alkyl
  • R 26 is H, or optionally substituted Ci-C 6 alkyl
  • R is optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R is H, or optionally substituted Ci-C 6 alkyl
  • n 2-4;
  • R 2 and R 4 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , optionally substituted Ci-Cgalkyl, optionally substituted Ci-Cgheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted -CH 2 -C 3 - Cgcycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R x is H, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted Cs-Cscycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroar l, an optionally
  • R is a bond, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-Ceheteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
  • R 12 is H or -NR 21 R 22 ;
  • each R 14 is independently H, optionally substituted Ci-C 4 alkyl, optionally substituted Ci- Ceheteroalkyl, optionally substituted C3-Cgcycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, -CH 2 C(0)OR 26 , or -CH 2 CH 2 R 27 ;
  • each R 21 is independently H, or Ci-C 4 alkyl
  • R 2"3 and 24 are each independently H, or Ci-C 4 alkyl
  • R 26 is H, or optionally substituted Ci-Cealkyl
  • R 27 is optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 28 is H, or optionally substituted Ci-Cealkyl
  • n is 2-4; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R and R 4 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), - CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , -(CH 2 ) 3 NR 21 R 22 , or -
  • (CH 2 ) 4 NR R is a compound of Formula (V) or Formula (V) wherein R 2 and R 4 are each independently -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , - CH 2 OH, -CH(OH)(CH 3 ), -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , -(CH 2 ) 3 NR 21 R 22 , or -(CH 2 ) 4 NR 21 R 22 .
  • R 12 is H.
  • R 12 is H.
  • R 12 is H.
  • a compound of Formula (V) or Formula (V) wherein m is 4 and R 12 is H.
  • R 1 1 2 is -NH 2 .
  • R 2 and R 4 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , optionally substituted Ci-Cgalkyl, optionally substituted Ci-Csheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted -CH 2 -C 3 - Cgcycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH; or R 5 and R 24 together with the boron atom form a 5- or 6-membered boron containing ring;
  • R x is H, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -Cgcycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroar l, an optionally
  • R is a bond, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
  • R 12 is -NR 21 R 22 ;
  • each R 14 is independently H, optionally substituted Ci-C 4 alkyl, optionally substituted Ci- Ceheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, -CH 2 C(0)OR 26 , or -CH 2 CH 2 R 27 ;
  • R 2"3 and 24 are each independently H, or Ci-C 4 alkyl
  • R 26 is H, or optionally substituted Ci-C 6 alkyl
  • R 27 is optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 28 is H, or optionally substituted Ci-Cealkyl
  • n 0-4;
  • R 2 and R 4 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , optionally substituted Ci-Cgalkyl, optionally substituted Ci-Cgheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted -CH 2 -C 3 - Cgcycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH; or R 5 and R 24 together with the boron atom form a 5- or 6-membered boron containing ring;
  • R x is H, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -Cgcycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring; R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroar l, an optionally
  • R is a bond, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-Ceheteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
  • R 12 is -NR 21 R 22 ;
  • each R 14 is independently H, optionally substituted Ci-C 4 alkyl, optionally substituted Ci- Ceheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, -CH 2 C(0)OR 26 , or -CH 2 CH 2 R 27 ;
  • each R 21 is independently H, or Ci-C 4 alkyl
  • R 2"3 and 24 are each independently H, or Ci-C 4 alkyl
  • R 26 is H, or optionally substituted Ci-Cealkyl
  • R 27 is optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 28 is H, or optionally substituted Ci-Cealkyl
  • n 0-4; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • [00182] is a compound of Formula (VI) or Formula (VI ') wherein R is a
  • R and R 4 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), - CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , -(CH 2 ) 3 NR 21 R 22 , or -
  • (CH 2 ) 4 NR R is a compound of Formula (VI) or Formula (VF) wherein R 2 and R 4 are each independently -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , - CH 2 OH, -CH(OH)(CH 3 ), -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , -(CH 2 ) 3 NR 21 R 22 , or -(CH 2 ) 4 NR 21 R 22 .
  • R 12 is -NH 2 .
  • R 2 and R 4 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, - CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , optionally substituted Ci-C 8 alkyl, optionally substituted Ci-C 8 heteroalkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted -CH 2 -C 3 - C 8 cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH; or R 5 and R 24 together with the boron atom form a 5- or 6-membered boron containing ring;
  • R x is H, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C 3 -C 8 cycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring; R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroar l, an optionally
  • R is a bond, optionally substituted Ci-C 6 alkyl, optionally substituted Ci-Ceheteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
  • R 12 is -NR 21 R 22 ;
  • each R 14 is independently H, optionally substituted Ci-C 4 alkyl, optionally substituted Ci- Ceheteroalkyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, -CH 2 C(0)OR 26 , or -CH 2 CH 2 R 27 ;
  • each R 21 is independently H, or Ci-C 4 alkyl
  • R 2"3 and 24 are each independently H, or Ci-C 4 alkyl
  • R 26 is H, or optionally substituted Ci-Cealkyl
  • R 27 is optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 28 is H, or optionally substituted Ci-Cealkyl
  • R 2 and R 4 are each independently -H, -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , - (CH 2 ) 3 NR 21 R 22 , -(CH 2 ) 4 NR 21 R 22 , optionally substituted Ci-Cgalkyl, optionally substituted Ci-Cgheteroalkyl, optionally substituted C3-Cgcycloalkyl, optionally substituted -CH 2 -C3- Cgcycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally
  • R is methyl, ethyl, isopropyl, or cyclopropyl
  • R 5 is H, methyl, ethyl, or -CH 2 OH; or R 5 and R 24 together with the boron atom form a 5- or 6-membered boron containing ring;
  • R x is H, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, or optionally substituted C3-Cgcycloalkyl; or R x and R 2 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R y is H or methyl; or R y and R 5 together with the nitrogen atom form an optionally substituted nitrogen containing ring;
  • R 7 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, or a linear or branched alkyl chain of about 1-22 carbon atoms, optionally comprising within the alkyl chain or at an alkyl chain terminus an optionally substituted aryl, an optionally substituted heteroaryl, an optionally
  • R is a bond, optionally substituted Ci-Cealkyl, optionally substituted Ci-Ceheteroalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
  • R 12 is -NR 21 R 22 ;
  • each R 14 is independently H, optionally substituted Ci-C 4 alkyl, optionally substituted Ci- C 6 heteroalkyl, optionally substituted C3-Cgcycloalkyl, optionally substituted
  • heterocycloalkyl optionally substituted aralkyl, optionally substituted aryl, optionally substituted heteroaryl, -CH 2 C(0)OR 26 , or -CH 2 CH 2 R 27 ; each R 21 is independently H, or Ci-C 4 alkyl;
  • R 2"3 and 24 are each independently H, or Ci-C 4 alkyl
  • R 26 is H, or optionally substituted Ci-C 6 alkyl
  • R 27 is optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R 28 is H, or optionally substituted Ci-C 6 alkyl
  • n 0-4; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  • R is an optionally substituted Ci-Ceheteroalkyl.
  • R and R 4 are each independently -H, -CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH(CH 3 )(CH 2 CH 3 ), - CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH(OH)(CH 3 ), -CH 2 CF 3 , -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, - CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , -(CH 2 ) 3 NR 21 R 22 , or -
  • (CH 2 ) 4 NR R is a compound of Formula (VII) or Formula (VIF) wherein R 2 and R 4 are each independently -CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 3 ) 2 , - CH 2 OH, -CH(OH)(CH 3 ), -CH 2 C(0)OH, -CH 2 CH 2 C(0)OH, -CH 2 C(0)NH 2 , -CH 2 CH 2 C(0)NH 2 , -CH 2 NR 21 R 22 , -(CH 2 ) 2 NR 21 R 22 , -(CH 2 ) 3 NR 21 R 22 , or -(CH 2 ) 4 NR 21 R 22 .

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