WO2016039938A1 - Polycyclic 2-pyridinone antibacterial compounds - Google Patents

Polycyclic 2-pyridinone antibacterial compounds Download PDF

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Publication number
WO2016039938A1
WO2016039938A1 PCT/US2015/045438 US2015045438W WO2016039938A1 WO 2016039938 A1 WO2016039938 A1 WO 2016039938A1 US 2015045438 W US2015045438 W US 2015045438W WO 2016039938 A1 WO2016039938 A1 WO 2016039938A1
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methyl
oxo
carboxylic acid
hydroxy
indole
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PCT/US2015/045438
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French (fr)
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Arthur Branstrom
Jana Narasimhan
Melissa L. DUMBLE
Jean Hedrick
Marla L. Weetall
Gary Mitchell Karp
Aleksey Igorevich GERASYUTO
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Ptc Therapeutics, Inc.
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Publication of WO2016039938A1 publication Critical patent/WO2016039938A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present description relates to the use of polycyclic compounds and forms thereof for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae). More particularly, the present description relates to the use of polycyclic 2-pyridinone compounds and forms thereof for treating or ameliorating a wild- type or drug-resistant form of N. gonorrhoeae.
  • Neisseria is a large genus of generally commensal Gram-negative bacteria that colonize the mucosal surfaces of many animals.
  • the facile ability of N. gonorrhoeae to develop drug resistance makes N. gonorrhoeae a rapidly emerging global health threat, and is considered to be an emerging superbug. 820,000 new cases of N. gonorrhoeae are estimated to occur in the United States every year. With more than 100 million cases of
  • N. gonorrhoeae reported worldwide, about 12% of drug-resistant N. gonorrhoeae is estimated to be penicillin resistant (penicillin ), about 23% is estimated to be tetracycline resistant (tetracycline R ) and about 13% is estimated to be quinolone resistant (quinolone R ).
  • penicillin penicillin
  • tetracycline R tetracycline resistant
  • quinolone R quinolone resistant
  • the level of quinolone resistance in Taiwan and China is about 90% (Morbidity and
  • N. gonorrhoeae Other forms of drug-resistant N. gonorrhoeae include streptomycin-resistant (streptomycin R ), ciprofloxacin-resistant (ciprofloxacin R ) and ampicillin-resistant (ampicillin ).
  • streptomycin-resistant streptomycin R
  • ciprofloxacin R ciprofloxacin R
  • ampicillin-resistant ampicillin-resistant
  • the present description relates to use of substituted polycyclic compounds for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae) in a subject in need thereof comprising, administering an effective amount of the compound to the subject, wherein the compound is selected from a compound of Formula (I) or Formula (II):
  • the present description further relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae.
  • the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating wild-type forms of
  • the present description also relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating drug-resistant forms of N. gonorrhoeae.
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae resistant to one or more known antibacterial or antibiotic agents, wherein drug resistance may be classified as intermediate resistance (IR), high level resistance (HLR), multi-drug resistant (MDR), multi- drug intermediate resistant (MD ⁇ R) or extensively drug resistant (XDR).
  • IR intermediate resistance
  • HLR high level resistance
  • MDR multi-drug resistant
  • MD ⁇ R multi- drug intermediate resistant
  • XDR extensively drug resistant
  • the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating IR, HLR, MDR, MD ⁇ R or XDR forms of N. gonorrhoeae .
  • the present description also relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating an aminoglycoside-resistant, beta-lactam- resistant, cephalosporin-resistant, macrolide-resistant, quinolone-resistant or tetracycline- resistant form of N. gonorrhoeae.
  • the present description further relates to use of a compound of Formula (I) or Formula (II) or a form thereof in combination with known agents having additive or synergistic activity, thus providing a combination product for the treatment of
  • the present description relates to use of substituted polycyclic compounds for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae) in a subject in need thereof comprising, administering an effective amount of the compound to the subject, wherein the compound is selected from a compound of Formula (I) or Formula (II):
  • Z is -CH(R 9 )-
  • Ri is hydrogen, halogen, Ci-galkyl-amino, amino-Ci-galkyl,
  • Ci-ioalkyl-amino-Ci-galkyl (Ci-salkyl amino-Ci-galkyl, C 2 - 8 alkenyl-amino-C 1 _ 8 alkyl, C 2 - 8 alkynyl-amino-Ci_ 8 alkyl, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
  • each instance of C 3 _i 4 cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R ⁇ ;
  • each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn;
  • R 2 is hydrogen, halogen or Ci-galkyl
  • R 3 is hydrogen, hydroxyl or C h alky!;
  • R 4 is hydrogen, Ci-galkyl or aryl-Ci_galkyl, wherein aryl is optionally substituted with one substituent selected from Ci_galkyl, halo-Ci_galkyl, Ci_galkoxy or
  • R 5 is hydrogen or Ci-galkyl
  • R 6 is hydrogen or hydroxyl
  • R 7 is hydrogen or halogen
  • Rg is hydrogen or halogen
  • R9 is hydrogen or Ci-galkyl
  • R 10 is halogen, hydroxyl, Ci-galkyl, Ci_galkoxy, amino, Ci_galkyl-amino, (Ci_galkyl)2-amino, Ci-galkyl-amino-Ci-galkyl, (C 1 _galkyl) 2 -amino-C 1 _galkyl or Ci_galkyl-carbonyl-amino; and,
  • Rn is aryl-Ci-galkyl-amino, (aryl-Ci-galkyl, ⁇ galkyl)amino or (aryl-Ci-galkyl) 2 -amino;
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • One embodiment of the present description includes the use of a compound of Formula (I):
  • Z is -CH(R 9 )-
  • Ri is hydrogen, halogen, Ci_galkyl-amino, (Ci_galkyl) 2 -amino, amino-Ci_galkyl,
  • Ci-ioalkyl-amino-Ci-galkyl (C 1 _galkyl) 2 -amino-C 1 _galkyl, C 2 -galkenyl-amino-C 1 _galkyl, C 2 -galkynyl-amino-Ci_galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl,
  • each instance of C 3 _ 14 cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R ⁇ ;
  • each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn;
  • R 2 is hydrogen, halogen or Ci-galkyl
  • R 3 is hydrogen, hydroxyl or Ci-galkyl
  • R 4 is hydrogen, Ci-galkyl or aryl-Ci_galkyl, wherein aryl is optionally substituted with
  • Ci-galkyl halo-Ci_galkyl, Ci_galkoxy or
  • R 6 is hydrogen or hydroxyl
  • Rg is hydrogen or halogen
  • R 9 is hydrogen or Ci-galkyl
  • R 10 is halogen, hydroxyl, Ci_galkyl, Ci-galkoxy, amino, Ci-galkyl-amino, (C 1 _galkyl) 2 -amino, Ci-galkyl-amino-Ci-galkyl, (C 1 _galkyl) 2 -amino-C 1 _galkyl or Ci-galkyl-carbonyl-amino; and,
  • Rn is aryl-Ci-galkyl-amino, or (aryl-C 1 _galkyl) 2 -amino; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein:
  • X is a O, -CH(R 3 )-, -CH(R 3 )-CH(R 3 )-, -CH(R 3 )-CH(R 3 )-CH(R 3 )-, -0-CH(R 3 )-,
  • Z is -CH(R 9 )-; Ri is hydrogen, halogen, Ci_galkyl-amino, (C 1 _ 8 alkyl) 2 -amino,
  • heterocyclyl wherein each instance of heterocyclyl is optionally substituted with one, two or three
  • heterocyclyl is optionally substituted with one substituent selected from Rii;
  • R 2 is hydrogen or halogen
  • R 3 is hydrogen or hydroxyl
  • R 4 is hydrogen or aryl-Ci_galkyl, wherein aryl is optionally substituted with one
  • Ci_galkyl halo-Ci_galkyl, Ci_galkoxy or
  • R 6 is hydrogen or hydroxyl
  • R 8 is hydrogen or halogen
  • R 9 is hydrogen or Ci_galkyl
  • R 10 is Ci-galkyl, amino or (C 1 _galkyl) 2 -amino;
  • Rn is or (aryl-C 1 _galkyl) 2 -amino.
  • Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein:
  • Ri is hydrogen, halogen, Ci-galkyl-amino, (Ci_galkyl) 2 -amino, amino-Ci-galkyl,
  • Ci-ioalkyl-amino-Ci-galkyl (C 1 _galkyl) 2 -amino-C 1 _galkyl, C 2 -galkenyl-amino-Ci_galkyl,
  • Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein:
  • Ri is C 3 _i 4 cycloalkyl-amino-Ci_galkyl, C ⁇ H cycloalkyl-Ci-galkyl-amino-Ci-galkyl,
  • aryl-Ci-galkyl-amino-Ci-galkyl heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci_galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
  • each instance of C 3 _i 4 cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R ⁇ ;
  • One embodiment of the present description includes the use of a compound of Formula (II):
  • Z is -CH(R 9 )-
  • Ri is hydrogen, halogen, Ci-galkyl-amino, (Ci_galkyl) 2 -amino, amino-Ci-galkyl,
  • Ci-ioalkyl-amino-Ci-galkyl (C 1 _galkyl) 2 -amino-C 1 _galkyl, C 2 -galkenyl-amino-Ci_galkyl, C 2 -galkynyl-amino-Ci_galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl,
  • each instance of C 3 _i 4 cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R ⁇ ;
  • each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn;
  • R 3 is hydrogen, hydroxyl or Ci-galkyl
  • R 4 is hydrogen, Ci-galkyl or aryl-Ci_galkyl
  • R 5 is Ci-galkyl
  • R 6 is hydrogen or hydroxyl
  • R 7 is hydrogen or halogen
  • R9 is hydrogen or Ci-galkyl
  • Rio is halogen, hydroxyl, Ci_galkyl, Ci_galkoxy, amino, (Ci_galkyl) 2 -amino or
  • Ci_galkyl-carbonyl-amino
  • Rn is (aryl-Ci-galkyl,Ci_galkyl)amino or (aryl-Ci_galkyl) 2 -amino;
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein:
  • Z is -CH(R 9 )-
  • Ri is hydrogen, amino-Ci-galkyl, Ci_ioalkyl-amino-Ci_galkyl, (Ci_galkyl) 2 -amino-Ci_galkyl, C 2 _galkenyl-amino-Ci_galkyl, C 2 _galkynyl-amino-Ci_galkyl,
  • each instance of C 3 _ 14 cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R ⁇ ;
  • R 3 is hydrogen, hydroxyl or Ci-galkyl
  • R 4 is hydrogen or Ci_galkyl
  • R 5 is Ci-galkyl
  • R 6 is hydrogen or hydroxyl
  • R 7 is hydrogen or halogen
  • R9 is hydrogen or Ci-galkyl
  • Rio is halogen, hydroxyl, Ci-galkyl, Ci_galkoxy, amino, (Ci_galkyl) 2 -amino or
  • Ci-galkyl-carbonyl-amino Ci-galkyl-carbonyl-amino.
  • Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein:
  • Ri is hydrogen, halogen, Ci-galkyl-amino, (Ci_galkyl) 2 -amino, amino-Ci-galkyl,
  • Ci-ioalkyl-amino-Ci-galkyl Ci-ioalkyl-amino-Ci-galkyl, (Ci-galkyl) 2 -amino-Ci_galkyl, C 2 -galkenyl-amino-Ci_galkyl, C 2 -galkynyl-amino-Ci_galkyl, Ci_galkoxy-Ci_galkyl-amino-Ci_galkyl,
  • Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein:
  • Ri is C 3 _i 4 cycloalkyl-amino-Ci_galkyl, C 3 _i 4 cycloalkyl-Ci_galkyl-amino-Ci_galkyl,
  • aryl-Ci-galkyl-amino-Ci-galkyl heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
  • each instance of C 3 _ 14 cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R ⁇ ; and, wherein each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn-
  • One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein X is a bond, O, -CH(R 3 )-,
  • Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein X is a O, -CH(R 3 )-, -CH(R 3 )-CH(R 3 )-,
  • One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein Z is -CH(R 9 )-.
  • One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein Ri is hydrogen, halogen,
  • C 1 -galkyl 2 -amino-C 1 _galkyl, C ⁇ galkenyl-amino-Ci-galkyl, C ⁇ galkynyl-amino-Ci-galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, (C 1 _galkyl) 2 -amino-C 1 _galkyl-amino,
  • Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein Ri is hydrogen, halogen, Ci-galkyl-amino,
  • Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein Ri is hydrogen, amino-Ci_galkyl,
  • Ci-ioalkyl-amino-Ci-galkyl (C 1 _galkyl) 2 -amino-C 1 _galkyl, C 2 -galkenyl-amino-Ci_galkyl, C 2 _galkynyl-amino-Ci_galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl,
  • One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein R is Cs-wcycloalkyl-amino-Ci-galkyl, Cs- H cycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl,
  • heterocyclyl-amino heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl, wherein each instance of Cs- ⁇ cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R 10 ; and,
  • each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from R ⁇ ⁇ ;
  • Rio is halogen, hydroxyl, Ci-galkyl, Ci-galkoxy, amino, Ci-galkyl-amino, (C 1 _galkyl) 2 -amino,
  • Ci-galkyl-amino-Ci-galkyl Ci-galkyl-amino-Ci-galkyl, (C 1 _galkyl) 2 -amino-C 1 _galkyl or Ci-galkyl-carbonyl-amino; and,
  • Rn is aryl-Ci-galkyl-amino, (aryl-Ci-galkyl, ⁇ galkyl)amino or (aryl-C 1 _galkyl) 2 -amino.
  • Another embodiment of the present description includes the use of a compound of
  • heterocyclyl wherein each instance of heterocyclyl is optionally substituted with one, two or three
  • heterocyclyl is optionally substituted with one substituent selected from Rn;
  • Rio Ci-galkyl, amino or (Ci_galkyl) 2 -amino
  • Rn is or (aryl-Ci_galkyl) 2 -amino.
  • Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein Ri is Cs-ncycloalkyl-amino-Ci-galkyl,
  • One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein
  • Ri is hydrogen, halogen, Ci-galkyl-amino, amino-Ci-galkyl,
  • Ci-ioalkyl-amino-Ci-galkyl (Ci-galkyl amino-Ci-galkyl, C ⁇ galkenyl-amino-Ci-galkyl, C ⁇ galkynyl-amino-Ci-galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl,
  • each instance of Cs- ⁇ cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R 10 ;
  • each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn ;
  • Rio is halogen, hydroxyl, Ci-galkyl, Q-galkoxy, amino, Ci-galkyl-amino, (C 1 _galkyl) 2 -amino, Ci-galkyl-amino-Ci-galkyl, (C 1 _galkyl) 2 -amino-C 1 _galkyl or Ci-galkyl-carbonyl-amino; and,
  • Rn is aryl-Ci-galkyl-amino, (aryl-Ci-galkyl,Ci-galkyl)amino or (aryl-C 1 _galkyl) 2 -amino.
  • Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein
  • Ri is hydrogen, halogen, Ci-galkyl-amino, (Ci_galkyl) 2 -amino,
  • each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn ;
  • Rio Ci-galkyl, amino or (C 1 _ 8 alkyl) 2 -amino
  • Rn is aryl-Ci-galkyl-amino, or (aryl-C 1 _galkyl) 2 -amino.
  • Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein
  • Ri is hydrogen, amino-Ci_galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C 1 _galkyl) 2 -amino-C 1 _galkyl, C ⁇ galkenyl-amino-Ci-galkyl, C ⁇ galkynyl-amino-Ci-galkyl,
  • heterocyclyl-Ci-galkyl heterocyclyl-amino-Ci-galkyl or
  • each instance of C 3 _i 4 cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R 10 ;
  • Rio is halogen, hydroxyl, Ci-galkyl, Q-galkoxy, amino, Ci-galkyl-amino, (C 1 _galkyl) 2 -amino,
  • Ci-galkyl-amino-Ci-galkyl (C 1 _galkyl) 2 -amino-C 1 _galkyl or Ci-galkyl-carbonyl-amino.
  • One embodiment of the present description includes the use of a compound of
  • C 3 _i 4 cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
  • aryl selected in each instance, when present, from phenyl
  • heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, imidazolyl or pyridinyl; heterocyclyl selected in each instance, when present, from azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3- dioxolanyl, 2,5-dihydro- lH-pyrrolyl, dihydro-lH-imidazolyl, 1,4,5,6- tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, 3,4-d
  • Another embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein Ri is
  • heteroaryl selected in each instance, when present, from pyrrol- 1-yl, thiazol-2-yl, 1 H- 1,2,3- triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; heterocyclyl selected in each instance, when present, from azetidin- l-yl, pyrrolidin- l-yl, tetrahydrofuran-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin- l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan- l-yl, l,
  • Another embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein Ri is
  • Cs- ⁇ cycloalkyl selected in each instance, when present, from cyclopropyl or cyclobutyl; aryl selected in each instance, when present, from phenyl;
  • Another embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein R is
  • Cs-ncycloalkyl selected in each instance, when present, from cyclopropyl or cyclobutyl; aryl selected in each instance, when present, from phenyl;
  • heteroaryl selected in each instance, when present, from pyridin-3-yl or pyridin-4-yl;
  • heterocyclyl selected in each instance, when present, from azetidin-l-yl, pyrrolidin-l-yl, tetrahydrofuran-2-yl, piperidin-l-yl, piperidin-4-yl, piperazin-l-yl, morpholin-4-yl, 1,4-diazepan-l-yl, (cis)-octahydrocyclopenta[c]pyrrol-4-yl, hexahydropyrrolo[3,4- b]pyrrol-5(lH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, (cis,cis)-3-azabicyclo[3.1.0]hexan-3- yl, 2,6-diazaspir
  • One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein R is
  • Cs- ⁇ cycloalkyl-amino-Ci-galkyl wherein Cs- ⁇ cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • aryl-Ci-8 alkyl-amino-Ci-8 alkyl wherein aryl is selected from phenyl;
  • heteroaryl wherein heteroaryl is selected from pyrrolyl, thiazolyl, lH-l,2,3-triazolyl,
  • heteroaryl-Ci-galkyl-amino-Ci-galkyl wherein heteroaryl is selected from pyridin-2-yl, pyridin-3-yl or pyridin-4-yl;
  • heterocyclyl wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl,
  • heterocyclyl-Ci-galkyl wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl,
  • heterocyclyl-amino wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl,
  • heterocyclyl-amino-Ci-galkyl wherein heterocyclyl is selected from azetidin-l-yl or
  • heterocyclyl-Ci-galkyl-amino-Ci-galkyl wherein heterocyclyl is selected from pyrrolidin-l-yl, pyrrolidin-2-yl, tetrahydrofuran-2-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl or tetrahydro-2H-pyran-4-yl.
  • Another embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein Ri is
  • Cs-Hcycloalkyl-amino-Ci-galkyl wherein C 3 _i 4 cycloalkyl is selected from cyclopropyl or cyclobutyl;
  • aryl-Ci-g alkyl-amino-Ci_g alkyl wherein aryl is selected from phenyl;
  • heteroaryl- ⁇ galkyl-amino-Ci-galkyl wherein heteroaryl is selected from pyridin-3-yl or pyridin-4-yl;
  • heterocyclyl wherein heterocyclyl is selected from pyrrolidinyl, piperidinyl, piperazinyl, 1,4- diazepanyl, hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- 1H- pyrrolo[3,4-b]pyridin-(2H)-yl, (cis,cis)-3-azabicyclo[3.1.0]hexanyl, 2,6- diazaspiro[3.4]octanyl or 2,7-diazaspiro[4.4]nonanyl;
  • heterocyclyl-Ci-galkyl wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl,
  • heterocyclyl-amino wherein heterocyclyl is selected from piperidinyl, (cis)- octahydrocyclopenta[c]pyrrolyl;
  • heterocyclyl-amino-Ci-galkyl wherein heterocyclyl is piperidin-4-yl; and,
  • heterocyclyl-Ci-galkyl-amino-Ci-galkyl wherein heterocyclyl is selected from pyrrolidin-l-yl or tetrahydrofuran-2-yl.
  • One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein
  • R 2 is hydrogen, halogen or Ci-galkyl
  • R 3 is hydrogen, hydroxyl or Ci-galkyl
  • R 4 is hydrogen, Ci_galkyl or aryl-Ci_galkyl, wherein aryl is optionally substituted with one substituent selected from Ci_galkyl, halo-Ci_galkyl, Ci_galkoxy or
  • R 5 is hydrogen or Ci-galkyl
  • R 6 is hydrogen or hydroxyl
  • R 7 is hydrogen or halogen
  • Rg is hydrogen or halogen
  • R9 is hydrogen or Ci-galkyl.
  • Another embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein
  • R 2 is hydrogen or halogen
  • R 3 is hydrogen, hydroxyl or Ci-galkyl
  • R 4 is hydrogen, Ci_galkyl or aryl-Ci-galkyl
  • R 5 is Ci-galkyl
  • R 6 is hydrogen or hydroxyl
  • R 7 is hydrogen or halogen
  • Rg is hydrogen or halogen
  • R 9 is hydrogen or Ci_galkyl.
  • Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein
  • R 2 is hydrogen or halogen
  • R 3 is hydrogen, hydroxyl or Ci_galkyl
  • R 4 is hydrogen or aryl-Ci-galkyl
  • R 6 is hydrogen or hydroxyl
  • Rg is hydrogen or halogen
  • R 9 is hydrogen or Ci_galkyl.
  • Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein
  • R 3 is hydrogen, hydroxyl or Ci_galkyl
  • R 4 is hydrogen, Ci-galkyl or aryl-Ci_galkyl
  • R 5 is Ci-galkyl
  • R 6 is hydrogen or hydroxyl
  • R 7 is hydrogen or halogen
  • R 9 is hydrogen or Ci-galkyl.
  • the use of the compound of Formula (I) or Formula (II) or a form thereof includes a use of a form selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form of the compound of Formula (I) or Formula (II).
  • the use of the compound of Formula (I) or Formula (II) or a form thereof includes a use of an isotopologue form of the compound of Formula (I) or Formula (II) wherein, when present as hydrogen, one or more R 1 ; R 2 , R 3 , R4, R5, R 6 , R 7 , Rs and R 9 hydrogen atoms are independently replaced with deuterium.
  • the compound or a form thereof is selected from the group consisting of:
  • R 1 ; X, Z, R 6 , R 4 , R % and R 2 are selected from:
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • the compound or a form thereof is a compound of Formula (Ila) selected from the group consisting of:
  • R 1; R 7 , X, Z, R 6 and R 4 are selected from:
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • a compound or a form thereof is selected from the group consisting of:
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound or a form thereof for treating or
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • Another embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound salt or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound salt or a form thereof to the subject, wherein a compound salt or a form thereof is selected from the group consisting of:
  • hydrochloride wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • the compound or a form thereof is isolated for use.
  • Ci-ioalkyl generally refers to saturated hydrocarbon radicals having from one to ten carbon atoms in a straight or branched chain configuration, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • Ci-ioalkyl includes Ci ⁇ alkyl, C 1-6 alkyl, Ci ⁇ alkyl and the like.
  • a Ci-ioalkyl radical may be optionally substituted where allowed by available valences.
  • C 2 - 8 alkenyl generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, without limitation, ethenyl, allyl, propenyl and the like.
  • C 2 - 8 alkenyl includes C 2 - 6 alkenyl, C 2 - 4 alkenyl and the like.
  • a C 2 - 8 alkenyl radical may be optionally substituted where allowed by available valences.
  • C 2 - 8 alkynyl generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon triple bonds therein, including, without limitation, ethynyl, propynyl and the like.
  • C 2 - 8 alkynyl includes C 2 - 6 alkynyl, C 2 - 4 alkynyl and the like.
  • a C 2 - 8 alkynyl radical may be optionally substituted where allowed by available valences.
  • Ci-salkoxy generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration of the formula: -O-Ci-galkyl, including, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like.
  • Ci ⁇ alkoxy includes Ci ⁇ alkoxy, Ci- ⁇ alkoxy and the like.
  • Ci- 8 alkoxy radical may be optionally substituted where allowed by available valences.
  • C 3 _ 14 cycloalkyl generally refers to a saturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, lH-indanyl, indenyl, tetrahydro-naphthalenyl and the like.
  • C 3 _ 14 cycloalkyl includes C 3 _gcycloalkyl, Cs-gcycloalkyl, Cs-iocycloalkyl and the like.
  • a C 3 _ 14 cycloalkyl radical may be optionally substituted where allowed by available valences.
  • aryl generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like.
  • An aryl radical may be optionally substituted where allowed by available valences.
  • heteroaryl generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S or N atom, including, without limitation, furanyl, thienyl (also referred to as thiophenyl), pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, benzofuranyl, benzothi
  • heterocyclyl generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with a heteroatom, such as an O, S or N atom, including, without limitation, oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl,
  • dihydro-triazinyl dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl, 1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl, dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl, dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl,
  • the term refers to a radical of the formula: -C 1-8 alkyl-NH-C 2-8 alkenyl.
  • C 1-8 alkoxy-C 1-8 aLky ' refers to a radical of the formula: -Ci_ 8 alkyl-0-Ci_ 8 alkyl.
  • C 1-8 alkoxy-C 1-8 alkyl-anu ⁇ o-C 1-8 alky ' refers to a radical of the formula: -Ci-8alk l-NH-Ci- 8 alkyl-0-Ci- 8 alkyl.
  • Ci-galkoxy-carbonyl refers to a radical of the formula:
  • Ci-galkyl-amino refers to a radical of the formula:
  • (C 1-8 alkyl) 2 -amino refers to a radical of the formula:
  • Ci-galkyl-amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl.
  • Ci-ioalkyl-amino-Ci-galkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-10 alkyl.
  • (C 1 _galkyl) 2 -amino-C 1 _galkyl refers to a radical of the formula: -C 1 _galkyl-N(C 1 _galkyl) 2 .
  • (C 1 _galkyl) 2 -amino-C 1 _galkyl-amino refers to a radical of the formula: -NH-C 1 _galkyl-N(C 1 _galkyl) 2 .
  • the term "Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl” refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-8 alkyl-NH-C 1-8 alkyl.
  • (Ci-galkyl amino- ⁇ galkyl-amino-Ci-galkyl) refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-8 alkyl-N(C 1-8 alkyl) 2 .
  • the term "[(C 1 _ 8 alkyl) 2 -amino-C 1 _ 8 alkyl,C 1 _ 8 alkyl]amino-C 1 _ 8 alkyl” refers to a radical of the formula: -C 1 _ 8 alkyl-N ⁇ (C 1 _ 8 alkyl)[C 1 _ 8 alkyl-N(C 1 _ 8 alkyl) 2 ] ⁇ .
  • (C 1 - 8 alkyl) 2 -amino-carbonyl-C 1 - 8 alkyl-amino-C 1 _ 8 alkyl refers to a radical of the formula: -C 1 - 8 alkyl-NH-C 1 _ 8 alkyl-C(0)-N(C 1 - 8 alkyl) 2 .
  • Ci-galkyl-carbonyl-amino refers to a radical of the formula: -NH-C(0)-Ci_ 8 alkyl.
  • Ci-salkyl-thio refers to a radical of the formula:
  • C ⁇ galkynyl-amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-NH-C ⁇ galkynyl.
  • amino refers to a radical of the formula: -NH 2 .
  • amino-Ci-salkyl refers to a radical of the formula:
  • amino-Ci-galkyl-amino-Ci-galkyl refers to a radical of the formula: -C 1 - 8 alkyl-NH-C 1 _ 8 alkyl-NH 2 .
  • aryl-Ci-salkoxy refers to a radical of the formula:
  • aryl-Ci-galkyl refers to a radical of the formula:
  • aryl-Ci-salkyl-amino refers to a radical of the formula: -NH-Ci-galkyl-aryl.
  • (aryl-C 1 _galkyl) 2 -amino refers to a radical of the formula: -N[(Ci_ 8 alkyl-aryl) 2 ].
  • aryl-Ci-galkyl-amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-aryl.
  • aryl-Ci-galky ⁇ Ci-galky ⁇ amino refers to a radical of the formula: -N[(Ci- 8 alkyl)(Ci- 8 alkyl-aryl)] .
  • carboxyl refers to a radical of the formula: -COOH, -C(0)OH or -C0 2 H.
  • Cs- M cycloalkyl-amino-Ci-galkyl refers to a radical of the formula:
  • Cs- H cycloalkyl-Ci-galkyl-amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-Cs- H cycloalkyl.
  • halo or halogen generally refers to a halogen atom radical, including fluoro, chloro, bromo and iodo.
  • halo-Ci-galkoxy refers to a radical of the formula:
  • halo-Ci-galkoxy includes halo-C i ⁇ alkoxy, halo-Ci ⁇ alkoxy and the like.
  • halo-Ci-galkyl refers to a radical of the formula:
  • Ci-galkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms.
  • halo-Ci-galkyl includes halo-Ci-ealkyl, halo-C 1 _ 4 alkyl and the like.
  • heteroaryl-Ci-galkyl-amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-heteroaryl.
  • heterocyclyl-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-heterocyclyl.
  • heterocyclyl-amino refers to a radical of the formula: -NH-heterocyclyl.
  • heterocyclyl-amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-NH-heterocyclyl.
  • heterocyclyl-Ci-galkyl-amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-heterocyclyl.
  • heterocyclyl-oxy refers to a radical of the formula:
  • hydroxyl-Ci-galkyl-amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-OH, wherein Ci-galkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
  • hydroxyl-Ci-galky ⁇ Ci-galky ⁇ amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-N Ci-galkylXCi-galkyl-OH)], wherein Ci-galkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
  • substituted means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown.
  • the term "and the like,” with reference to the definitions of chemical terms provided herein, means that variations in chemical structures that could be expected by one skilled in the art include, without limitation, isomers (including chain, branching or positional structural isomers), hydration of ring systems (including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations where allowed by available valences which result in a stable compound.
  • each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.
  • the terms "independently selected,” or “each selected” refer to functional variables in a substituent list that may occur more than once on the structure of Formula (I) or Formula (II) or a form thereof, the pattern of substitution at each occurrence is independent of the pattern at any other occurrence.
  • a generic substituent variable on any formula or structure for a compound described herein is understood to include the replacement of the generic substituent with species substituents that are included within the particular genus, e.g., aryl may be replaced with phenyl or naphthalenyl and the like, and that the resulting compound is to be included within the scope of the compounds described herein.
  • each instance of or “in each instance, when present,” when used preceding a phrase such as "...aryl, aryl-Ci-galkyl, heterocyclyl and heterocyclyl-Ci-galkyl, are intended to refer to the aryl and heterocyclyl ring systems and the like when each are present either alone or as a substituent.
  • stable compound' or stable structure mean a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulations thereof into an efficacious therapeutic agent.
  • the term "form” means a compound of Formula (I) or Formula (II) having a form selected from the group consisting of a free acid, free base, prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • the form of the compound of Formula (I) or Formula (II) is a free acid, free base or salt thereof.
  • Formula (II) is a salt thereof.
  • the form of the compound of Formula (I) or Formula (II) is an isotopologue thereof.
  • the form of the compound of Formula (I) or Formula (II) is a stereoisomer, racemate, enantiomer or diastereomer thereof.
  • the form of the compound of Formula (I) or Formula (II) is a tautomer thereof.
  • the form of the compound of Formula (I) or Formula (II) is a pharmaceutically acceptable form.
  • isolated means the physical state of a compound of Formula (I) or Formula (II) or a form thereof after being isolated and/or purified from a synthetic process (e.g., from a reaction mixture) or natural source or combination thereof according to an isolation or purification process or processes described herein or which are well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • protecting means that a functional group in a compound of Formula (I) or Formula (II) or a form thereof is in a form modified to preclude undesired side reactions at the protected site when the compound is subjected to a reaction.
  • Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T.W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.
  • Prodrugs and solvates of the compounds described herein are also contemplated.
  • the term "prodrug” means a form of an instant compound (e.g., a drug precursor) that is transformed in vivo to yield an active compound of Formula (I) or Formula (II) or a form thereof. The transformation may occur by various mechanisms (e.g., by metabolic and/or non-metabolic chemical processes), such as, for example, by hydrolysis and/or metabolism in blood, liver and/or other organs and tissues.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug when a compound of Formula (I) or Formula (II) or a form thereof contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a functional group such as alkyl and the like.
  • a prodrug form when a compound of Formula (I) or Formula (II) or a form thereof contains a hydroxyl functional group, a prodrug form can be prepared by replacing the hydrogen atom of the hydroxyl with another functional group such as alkyl, alkylcarbonyl or a phosphonate ester and the like.
  • a prodrug form can be prepared by replacing one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl.
  • a functional group such as alkyl or substituted carbonyl.
  • Formula (I) or Formula (II) or a form thereof include those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid esters, phosphonate esters and mono-, di- or triphosphate esters or alkyl substituents, where appropriate. As described herein, it is understood by a person of ordinary skill in the art that one or more of such substituents may be used to provide a compound of Formula (I) or Formula (II) or a form thereof as a prodrug.
  • One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to embrace both solvated and unsolvated forms.
  • solvate means a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. As used herein, “solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • One or more compounds described herein may optionally be converted to a solvate.
  • Preparation of solvates is generally known. The preparation of solvates of the antifungal fluconazole in ethyl acetate as well as from water has been described (see, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004)). Similar preparations of solvates, hemisolvate, hydrates and the like have also been described (see, E.C. van Tonder et al, AAPS
  • a typical, non-limiting process involves dissolving a compound in a desired amount of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example infrared spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • hydrate means a solvate wherein the solvent molecule is water.
  • the compounds of Formula (I) or Formula (II) can form salts, which are intended to be included within the scope of this description.
  • Reference to a compound of Formula (I) or Formula (II) or a form thereof herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • a compound of Formula (I) or Formula (II) or a form thereof contains both a basic moiety, such as, without limitation an amine moiety, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term “salt(s)" as used herein.
  • salts of the compounds of the Formula (I) or Formula (II) may be formed, for example, by reacting a compound of Formula (I) or Formula (II) or a form thereof with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • compositions include one or more salts of acidic or basic groups present in compounds described herein.
  • Embodiments of acid addition salts include, and are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), triflu
  • Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium and zinc salts.
  • Certain compounds described herein can also form pharmaceutically acceptable salts with organic bases (for example, organic amines) such as, but not limited to, dicyclohexylamines, t-butyl amines and the like, and with various amino acids such as, but not limited to, arginine, lysine and the like.
  • Basic nitrogen- containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides) and the like.
  • lower alkyl halides e.g., methyl, ethyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g., decyl, lauryl,
  • Compounds of Formula (I) or Formula (II) and forms thereof may further exist in a tautomeric form (for example, the 4-hydroxy-2-pyridinone core of Formula (I) and Formula (II) may exist in either the 2,4-dihydroxy-pyridine or the 2-hydroxy-4-pyridinone form). All such tautomeric forms are contemplated and intended to be included within the scope of the compounds of Formula (I) or Formula (II) or a form thereof as described herein.
  • the compounds of Formula (I) or Formula (II) or a form thereof may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms.
  • the present description is intended to include all stereoisomeric forms of the compounds of Formula (I) or Formula (II) as well as mixtures thereof, including racemic mixtures.
  • the compounds described herein may include one or more chiral centers, and as such may exist as racemic mixtures (R/S) or as substantially pure enantiomers and diastereomers.
  • the compounds may also exist as substantially pure (R) or (S) enantiomers (when one chiral center is present).
  • the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer.
  • the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer.
  • the compounds described herein may also exist as a (R,R), (R,S), (S,R) or (S,S) isomer, as defined by IUPAC Nomenclature Recommendations.
  • substantially pure refers to compounds consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.
  • a compound of Formula (I) or Formula (II) or a form thereof is a substantially pure (S) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
  • a compound of Formula (I) or Formula (II) or a form thereof is a substantially pure (R) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
  • racemate is any mixture of isometric forms that are not
  • “enantiomeric ally pure” including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, or about 80/20.
  • the present description embraces all geometric and positional isomers.
  • a compound of Formula (I) or Formula (II) or a form thereof incorporates a double bond or a fused ring
  • both the cis- and trans-forms, as well as mixtures are embraced within the scope of the description.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by use of chiral HPLC column or other chromatographic methods known to those skilled in the art.
  • Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher' s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher' s acid chloride
  • converting e.g., hydrolyzing
  • some of the compounds of Formula (I) or Formula (II) or a form thereof may be atropisomers (e.g. , substituted biaryls) and are considered as part of this description.
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this description, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as described supra.
  • isotopologue refers to isotopically-enriched compounds described herein which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 35 C1 and 36 C1, respectively, each of which are also within the scope of this description.
  • Certain isotopically-enriched compounds described herein are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • the present description relates to a method of use for a compound of Formula (I) or
  • the present description further relates to use of the compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof.
  • the present description further relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity toward wild-type or drug-resistant
  • the present description also relates to use of a compound of Formula (I) or Formula (II) or a form thereof having activity against aminoglycoside-resistant, beta-lactam-resistant, cephalosporin-resistant, macrolide-resistant, quinolone-resistant or tetracycline-resistant N. gonorrhoeae .
  • the present description also relates to use of a compound of Formula (I) or Formula (II) or a form thereof having activity against aminoglycoside-resistant (including drug- resistant forms of N. gonorrhoeae that are spectinomycin-resistant, streptomycin-resistant, and the like), beta-lactam-resistant (including drug-resistant forms of N. gonorrhoeae that are ampicillin-resistant, penicillin-resistant, and the like), cephalosporin-resistant (including drug-resistant forms of N. gonorrhoeae that are ceftriaxone-resistant, cefixime-resistant, and the like), macrolide-resistant (including drug-resistant forms of N.
  • aminoglycoside-resistant including drug- resistant forms of N. gonorrhoeae that are spectinomycin-resistant, streptomycin-resistant, and the like
  • beta-lactam-resistant including drug-resistant forms of N. gonorrhoeae that are ampicillin
  • gonorrhoeae that are azithromycin-resistant, and the like
  • quinolone-resistant including drug-resistant forms of N. gonorrhoeae that are ciprofloxacin-resistant, and the like
  • tetracycline-resistant N. gonorrhoeae including drug-resistant forms of N. gonorrhoeae that are tetracycline- resistant.
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against ampicillin-resistant, azithromycin-resistant, ceftriaxone-resistant, cefixime-resistant, ciprofloxacin-resistant, penicillin-resistant, spectinomycin-resistant, streptomycin-resistant and tetracycline-resistant forms of
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against aminoglycoside-resistant forms of
  • N. gonorrhoeae The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against beta-lactam-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against cephalosporin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against macrolide-resistant forms of N. gonorrhoeae.
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against quinolone-resistant forms of N. gonorrhoeae.
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against tetracycline-resistant forms of N. gonorrhoeae .
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against ampicillin-resistant forms of N. gonorrhoeae.
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against azithromycin-resistant forms of N. gonorrhoeae.
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against ceftriaxone-resistant forms of N. gonorrhoeae.
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against cefixime-resistant forms of N.
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against ciprofloxacin-resistant forms of N. gonorrhoeae.
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against penicillin-resistant forms of N. gonorrhoeae.
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against spectinomycin-resistant forms of N. gonorrhoeae.
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against streptomycin-resistant forms of N. gonorrhoeae.
  • the present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against tetracycline-resistant forms of N. gonorrhoeae.
  • the present description further relates to use of the compound of Formula (I) or Formula (II) or a form thereof in a combination therapy with known antibacterial or antibiotic agents to provide additive or synergistic activity, thus enabling the development of a combination product for the treatment of a wild-type or drug-resistant form of
  • the compounds of the present description have demonstrated an ability to inhibit the replication of a wide variety of N. gonorrhoeae isolates.
  • the instant compounds possess in vitro activity against a wide spectrum of N. gonorrhoeae isolates which have developed resistance to almost all known treatments and are expected to successfully treat wild-type or drug-resistant forms of N. gonorrhoeae compared to current antibacterial agents.
  • the compounds are also effective in vivo and lack cellular toxicity.
  • the instant compounds are useful in a combination therapy with current standard of care antibacterial or antibiotic agents, having additive or synergistic activity with one or more known antibacterial or antibiotic agents.
  • a combination therapy comprising compounds described herein in combination with one or more known antibacterial or antibiotic drugs may be used to treat wild-type or drug- resistant forms of N. gonorrhoeae regardless of whether N. gonorrhoeae is resistant or responsive to the known antibacterial or antibiotic drug.
  • Embodiments of the present description include the use of a compound of Formula (I) or Formula (II) or a form thereof in a combination therapy for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof and an effective amount of one or more antibiotic or antibacterial agent(s).
  • Embodiments of the present description include the use of a compound of Formula (I) or Formula (II) or a form thereof in a combination therapy for treating or ameliorating wild- type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof and an effective amount of one or more antibiotic or antibacterial agent(s).
  • An embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof in the preparation of a kit comprising the compound of Formula (I) or Formula (II) or a form thereof and instructions for administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof and an effective amount of one or more antibiotic or antibacterial agent(s) in a combination therapy for treating or ameliorating N. gonorrhoeae in a subject in need thereof.
  • the agents used in the combination therapy may include, without limitation, one or more agents selected from Amikacin, Amoxicillin, Ampicillin,
  • Carbenicillin Cefaclor, Cefadroxil, Cefalexin, Cefalotin, Cefamandole, Cefazolin, Cefdinir, Cefditoren, Cefixime, Cefoperazone, Cefotaxime, Cefoxitin, Cefpodoxime, Cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Chloramphenicol, Cilastatin, Ciprofloxacin, Clarithromycin, Clavulanate, Clindamycin, Clofazimine, CloxaciUin, Colistin, Cycloserine, Dalfopristin, Dapsone, Daptomycin, Dicloxacillin, Dirithromycin, Doripenem, Doxycycline, Enoxacin, Erythromycin, Ethambutol, Ethionamide, Flucloxacillin,
  • Fosfomycin Furazolidone, Fusidic acid, Gatifloxacin, Gemifloxacin, Gentamicin, Imipenem, Isoniazid, Kanamycin, Levofloxacin, Lincomycin, Linezolid, Lomefloxacin, Loracarbef, Mafenide, Meropenem, MethiciUin, Metronidazole, Mezlocillin, Minocycline, Moxifloxacin, Mupirocin, Nafcillin, Nalidixic acid, Neomycin, Netilmicin, Nitrofurantoin, Norfloxacin, Ofloxacin, Oxacillin, Oxytetracycline, Paromomycin, Penicillin G, Penicillin V, Piperacillin, Platensimycin, Polymyxin B, Pyrazinamide, Quinupristin, Rapamycin, Rifabutin, Rifampicin, Rifampin, Rifapentine, Rifaximin, Roxithromycin, Silver
  • Tigecycline Tinidazole, Tobramycin, Trimethoprim, Troleandomycin or Vancomycin.
  • the agents used in the combination therapy may include, without limitation, one or more agents selected from Amikacin, Amoxicillin, Arsphenamine, Azlocillin, Aztreonam, Bacitracin, Capreomycin, Carbenicillin, Cefaclor, Cefadroxil, Cefalexin, Cefalotin (Cefalothin), Cefamandole, Cefazolin, Cefdinir, Cefditoren,
  • Cefoperazone Cefotaxime, Cefoxitin, Cefpodoxime, Cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Cefuroxime, Chloramphenicol, Cilastatin, Clarithromycin, Clavulanate, Clindamycin, Clofazimine, Cloxacillin, Colistin, Cycloserine, Dalfopristin, Dapsone, Daptomycin, Dicloxacillin, Dirithromycin, Doripenem, Doxycycline, Enoxacin,
  • Roxithromycin Silver sulfadiazine, Solithromycin, Sulbactam, Sulfacetamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfanamide, Sulfasalazine, Sulfisoxazole, Tazobactam, Teicoplanin, Telavancin, Telithromycin, Temocillin, Thiamphenicol, TicarciUin, Tigecycline, Tinidazole, Tobramycin, Trimethoprim, Troleandomycin or Vancomycin.
  • the agents used in the combination therapy may include, without limitation, one or more agents selected from Amoxicillin, Ampicillin, Azithromycin, Ciprofloxacin, Doxycycline, Enoxacin, Erythromycin, Gatifloxacin, Gemifloxacin,
  • Gentamicin Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Rapamycin, Solithromycin, Spectinomycin, Streptomycin, Tetracycline or Vancomycin.
  • the agents used in the combination therapy may particularly include one or more agents selected from Amoxicillin, Azithromycin, Ciprofloxacin, Doxycycline, Enoxacin, Erythromycin, Gatifloxacin, Gemifloxacin, Gentamicin,
  • the agents used in the combination therapy may include, without limitation, one or more agents selected from Ampicillin, Azithromycin, Cefixime, Ceftriaxone, Ciprofloxacin, Penicillin G, Penicillin V, Spectinomycin, Streptomycin or Tetracycline.
  • the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating wild-type forms of
  • N. gonorrhoeae for treating or ameliorating drug-resistant forms of N. gonorrhoeae or for treating or ameliorating multi-drug resistant forms of N. gonorrhoeae.
  • One embodiment of the use of the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
  • One embodiment of the use of the present description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound to the subject.
  • One embodiment of the use of the present description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating wild- type or drug-resistant forms N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound to the subject.
  • An embodiment of the use of the present description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating wild- type forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound to the subject.
  • An embodiment of the use of the present description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating drug- resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound to the subject.
  • An embodiment of the use of the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof in the manufacture of a medicament for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
  • An embodiment of the use of the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof in the manufacture of a medicament for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
  • An embodiment of the use of the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof in the manufacture of a medicament for treating or ameliorating wild-type forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
  • An embodiment of the use of the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof in the preparation of a kit comprising the compound of Formula (I) or Formula (II) or a form thereof and instructions for administering the compound for treating or ameliorating N. gonorrhoeae in a subject in need thereof.
  • An embodiment of the use of the present description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I) or Formula (II) or a form thereof to the subject.
  • the subject is treatment naive. In another respect, for each of such embodiments, the subject is not treatment naive.
  • treating refers to: (i) preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having the disease, disorder and/or condition; (ii) inhibiting a disease, disorder or condition, i.e., arresting the development thereof; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
  • the term "subject” refers to an animal or any living organism having sensation and the power of voluntary movement, and which requires oxygen and organic food.
  • Nonlimiting examples include members of the human, primate, equine, porcine, bovine, murine, rattus, canine and feline specie.
  • the subject is a mammal or a warm-blooded vertebrate animal. In other embodiments, the subject is a human.
  • the term “patient” may be used interchangeably with “subject” and "human”.
  • Another aspect of the description particularly relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae resulting from wild type forms of N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof.
  • Another aspect of the description particularly relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating
  • N. gonorrhoeae resulting from drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof.
  • One aspect of the description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against N. gonorrhoeae clinical isolates and their derivatives selected from ATCC penicillin-sensitive wild-type N.
  • gonorrhoeae FA19 ATCC BAA-1838
  • N. gonorrhoeae FA1090 ATCC 700825; GenBank Acc. No. AE004969
  • ATCC 700825 GenBank Acc. No. AE004969
  • N. gonorrhoeae MS 11 (ATCC BAA- 1833) and ATCC wild- type N. gonorrhoeae 49226 (ATCC 49226) (see, http://www.atcc.org).
  • Another aspect of the description relates to a method of use for a compound of
  • Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against
  • Another aspect of the description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against
  • N. gonorrhoeae World Health Organization (WHO) isolates selected from: tetracycline ER N. gonorrhoeae 13477 (WHO tetracycline intermediate resistant isolate F),
  • ciprofloxacin ER /tetracycline R N. gonorrhoeae 13478 (WHO ciprofloxacin intermediate resistant and tetracycline resistant isolate G), quinoline HLR N. gonorrhoeae 13479 (WHO quinolone high level resistant isolate K), MDR N. gonorrhoeae 13480 (WHO multi-drug resistant isolate L) and MD ⁇ R N. gonorrhoeae 13481 (WHO multi-drug intermediate resistant isolate M) (see, Unemo M, Fasth O, Fredlund H, Limnios A, Tapsall J.
  • Another aspect of the description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against the ciprofloxacin XDR /cefixime XDR /ceftriaxone XDR extensively drug resistant N. gonorrhoeae F89 (see, Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P.
  • Another aspect of the description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against a
  • N. gonorrhoeae isolate engineered from WHO isolate F (N. gonorrhoeae 13477), where DNA from FA 1090 was isolated and used to transform 13477 with the streptomycin determinant.
  • the resulting isolate SP1364 is streptomycin at >1250 ⁇ g/mL.
  • Another aspect of the description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against a
  • N. gonorrhoeae clinical isolate LG24 see, Garvin LE, Bash MC, Keys C, Warner DM, Ram S, Shafer WM and Jerse AE. Phenotypic and genotypic analyses of Neisseria gonorrhoeae isolates that express frequently recovered PorB PIA variable region types suggest that certain Pla porin sequences confer a selective advantage for urogenital tract infection. Infect Immun., 2008, Aug;76(8):3700-9).
  • Another aspect of the description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against
  • N. gonorrhoeae clinical isolates selected from penicillin-resistant (penicillin )
  • N. gonorrhoeae LGB3, tetracycline-resistant (tetracycline ) N. gonorrhoeae LGB24 and ampicillin-resistant (ampicillin ) N. gonorrhoeae LGB50 see, McKnew DL, Lynn F, Zenilman JM, Bash MC. Porin variation among clinical isolates of N. gonorrhoeae over a 10- year period, as determined by Por variable region typing. J. Infect Dis., 2003, Apr
  • An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate wild-type N. gonorrhoeae 49226 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate clinical isolate N. gonorrhoeae LG24 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate N. gonorrhoeae MSI 1 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate ampicillin N. gonorrhoeae LGB50 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate penicillin-sensitive N. gonorrhoeae FA 19 or LGB3 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate streptomycin N. gonorrhoeae FA 1090 or SP1364 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate ciprofloxacin N. gonorrhoeae AK1 or AK2 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate N. gonorrhoeae caused by an isolate selected from 13477, 13478, 13479, 13480 or 13481 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.

Abstract

The present description relates to the use of polycyclic 2-pyridinone compounds and forms thereof for treating or ameliorating Neisseria gonorrhoeae. The present description relates to use of substituted polycyclic compounds for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae) in a subject in need thereof comprising, administering an effective amount of the compound to the subject, wherein the compound is selected from a compound of Formula (I) or Formula (II): wherein R1, R2, R4, R5, R6, R7, R8, X and Z are as defined herein, and forms and compositions thereof.

Description

POLYCYCLIC 2-PYRIDINONE ANTIBACTERIAL COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of U.S. Patent Provisional Application No.
62/048,151, filed September 9, 2014, the contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present description relates to the use of polycyclic compounds and forms thereof for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae). More particularly, the present description relates to the use of polycyclic 2-pyridinone compounds and forms thereof for treating or ameliorating a wild- type or drug-resistant form of N. gonorrhoeae.
BACKGROUND
Neisseria is a large genus of generally commensal Gram-negative bacteria that colonize the mucosal surfaces of many animals. The facile ability of N. gonorrhoeae to develop drug resistance makes N. gonorrhoeae a rapidly emerging global health threat, and is considered to be an emerging superbug. 820,000 new cases of N. gonorrhoeae are estimated to occur in the United States every year. With more than 100 million cases of
N. gonorrhoeae reported worldwide, about 12% of drug-resistant N. gonorrhoeae is estimated to be penicillin resistant (penicillin ), about 23% is estimated to be tetracycline resistant (tetracycline R ) and about 13% is estimated to be quinolone resistant (quinolone R ). The level of quinolone resistance in Taiwan and China is about 90% (Morbidity and
Mortality Weekly, Feb 15, 2013). Other forms of drug-resistant N. gonorrhoeae include streptomycin-resistant (streptomycin R ), ciprofloxacin-resistant (ciprofloxacin R ) and ampicillin-resistant (ampicillin ). Currently, ceftriaxone (a cephalosporin) is the drug of last resort for treating N. gonorrhoeae. With few clinical trials underway for new drugs targeting N. gonorrhoeae, the discovery of new antibacterial agents to treat wild-type or drug-resistant forms of N. gonorrhoeae is urgently needed.
Although quinolones have been highly effective agents in the clinic, wide-scale deployment and generic usage of second generation quinolones (e.g., ciprofloxacin) has jeopardized their future long-term utility. Furthermore, fluoroquinolones had become the standard of care for treating N. gonorrhoeae in early 1999. As early as 2001, though, bacterial resistance to these agents was also on the rise. Within 6 years, N. gonorrhoeae resistance in certain patient populations went from less than 1% to greater than 40%. In 2007, the Centers for Disease Control (CDC) discontinued the use of ciprofloxacin as the standard of care for treating N. gonorrhoeae. Therefore, new drugs targeting wild-type or drug-resistant forms of N. gonorrhoeae would be expected to help address this important unmet medical need.
As resistance to marketed antibacterial agents continues to increase, and new antibacterial agents have not been readily forthcoming from the pharmaceutical industry, the availability of new agents is essential to overcome pre-existing and burgeoning resistance. More particularly, an effective, orally deliverable monotherapy and novel compounds active against wild-type or drug-resistant forms of N. gonorrhoeae are urgently needed. New compounds and new therapies with combinations of antibacterial and antibiotic agents having additive or synergistic activities, including combinations with current agents, would enable longer clinical lifetimes for proven agents against N. gonorrhoeae. Accordingly, the availability of such compounds and therapies would provide a significant current and future human health benefit with a high probability of success on several fronts for the control of wild-type or drug-resistant forms of N. gonorrhoeae for a number of years to come.
All other documents referred to herein are incorporated by reference into the present application as though fully set forth herein.
SUMMARY
The present description relates to use of substituted polycyclic compounds for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae) in a subject in need thereof comprising, administering an effective amount of the compound to the subject, wherein the compound is selected from a compound of Formula (I) or Formula (II):
Figure imgf000003_0001
(I) (Π) wherein R1; R2, R4, R5, R6, R7, Rs, and Z are as defined herein, and forms and compositions thereof.
The present description further relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae.
More particularly, the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating wild-type forms of
N. gonorrhoeae.
The present description also relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating drug-resistant forms of N. gonorrhoeae.
The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae resistant to one or more known antibacterial or antibiotic agents, wherein drug resistance may be classified as intermediate resistance (IR), high level resistance (HLR), multi-drug resistant (MDR), multi- drug intermediate resistant (MD∑R) or extensively drug resistant (XDR).
More particularly, the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating IR, HLR, MDR, MD∑R or XDR forms of N. gonorrhoeae .
The present description also relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating an aminoglycoside-resistant, beta-lactam- resistant, cephalosporin-resistant, macrolide-resistant, quinolone-resistant or tetracycline- resistant form of N. gonorrhoeae.
The present description further relates to use of a compound of Formula (I) or Formula (II) or a form thereof in combination with known agents having additive or synergistic activity, thus providing a combination product for the treatment of
N. gonorrhoeae.
DETAILED DESCRIPTION
The present description relates to use of substituted polycyclic compounds for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae) in a subject in need thereof comprising, administering an effective amount of the compound to the subject, wherein the compound is selected from a compound of Formula (I) or Formula (II):
Figure imgf000005_0001
(I) (Π) or a form thereof, wherein,
X is a bond, O, -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-,
-0-CH(R3)-, -N(R9)-CH(R3)-, -S-CH(R3)- or -N(R9)-CH(R3)-CH(R3)-;
Z is -CH(R9)-;
Ri is hydrogen, halogen, Ci-galkyl-amino,
Figure imgf000005_0002
amino-Ci-galkyl,
Ci-ioalkyl-amino-Ci-galkyl, (Ci-salkyl amino-Ci-galkyl, C2-8alkenyl-amino-C1_8alkyl, C2-8alkynyl-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci-galky^i-amino-Ci-galkyl-amino, amino-Ci-salkyl-amino-Ci-galkyl,
Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1_8alkyl)2-amino-C1_8alkyl-amino-C1_8alkyl,
[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1_8alkyl,
hydroxyl-Ci-salkyl-amino-Ci-salkyl, (hydroxyl-Ci-salky^Ci-salky^amino-Ci-salkyl, (C1_8alkyl)2-amino-carbonyl-C1_8alkyl-amino-C1_8alkyl,
C^Hcycloalkyl-amino-Ci-salkyl, C^wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-salkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci_8alkyl, heterocyclyl-amino, heterocyclyl-amino-Ci_8alkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C3_i4cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R^; and,
wherein each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn;
R2 is hydrogen, halogen or Ci-galkyl;
R3 is hydrogen, hydroxyl or Chalky!; R4 is hydrogen, Ci-galkyl or aryl-Ci_galkyl, wherein aryl is optionally substituted with one substituent selected from Ci_galkyl, halo-Ci_galkyl, Ci_galkoxy or
Ci-galkoxy-Ci-galkyl;
R5 is hydrogen or Ci-galkyl;
R6 is hydrogen or hydroxyl;
R7 is hydrogen or halogen;
Rg is hydrogen or halogen;
R9 is hydrogen or Ci-galkyl;
R10 is halogen, hydroxyl, Ci-galkyl, Ci_galkoxy, amino, Ci_galkyl-amino, (Ci_galkyl)2-amino, Ci-galkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl or Ci_galkyl-carbonyl-amino; and,
Rn is aryl-Ci-galkyl-amino, (aryl-Ci-galkyl,^galkyl)amino or (aryl-Ci-galkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
One embodiment of the present description includes the use of a compound of Formula (I):
Figure imgf000006_0001
or a form thereof, wherein,
X is a bond, O, -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -0-CH(R3)-, -N(R9)-CH(R3)-, -S-CH(R3)- or -N(R9)-CH(R3)-CH(R3)-;
Z is -CH(R9)-;
Ri is hydrogen, halogen, Ci_galkyl-amino, (Ci_galkyl)2-amino, amino-Ci_galkyl,
Ci-ioalkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl, C2-galkenyl-amino-C1_galkyl, C2-galkynyl-amino-Ci_galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl,
(C1-galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1_8alkyl)2-amino-C1_8alkyl-amino-C1_8alkyl,
[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1_8alkyl,
hydroxyl-Ci-salkyl-amino-Ci-salkyl, (hydroxyl-Ci-salky^Ci-salky^amino-Ci-salkyl, (C1_8alkyl)2-amino-carbonyl-C1_8alkyl-amino-C1_8alkyl,
Cs-Hcycloalkyl-amino-Ci-salkyl, C^wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-^galkyl-amino-Ci-galkyl, heteroaryl-^galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C3_14cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R^; and,
wherein each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn;
R2 is hydrogen, halogen or Ci-galkyl;
R3 is hydrogen, hydroxyl or Ci-galkyl;
R4 is hydrogen, Ci-galkyl or aryl-Ci_galkyl, wherein aryl is optionally substituted with
one substituent selected from Ci-galkyl, halo-Ci_galkyl, Ci_galkoxy or
Ci-galkoxy-Ci.galkyl;
R6 is hydrogen or hydroxyl;
Rg is hydrogen or halogen;
R9 is hydrogen or Ci-galkyl;
R10 is halogen, hydroxyl, Ci_galkyl, Ci-galkoxy, amino, Ci-galkyl-amino, (C1_galkyl)2-amino, Ci-galkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl or Ci-galkyl-carbonyl-amino; and,
Rn is aryl-Ci-galkyl-amino,
Figure imgf000007_0001
or (aryl-C1_galkyl)2-amino; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein:
X is a O, -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -0-CH(R3)-,
-N(R9)-CH(R3)- or -S-CH(R3)-;
Z is -CH(R9)-; Ri is hydrogen, halogen, Ci_galkyl-amino, (C1_8alkyl)2-amino,
(C1_8alkyl)2-amino-C1_8alkyl-amino, heterocyclyl or heterocyclyl-amino,
wherein each instance of heterocyclyl is optionally substituted with one, two or three
substituents each selected from R^; and,
wherein each instance of heterocyclyl is optionally substituted with one substituent selected from Rii;
R2 is hydrogen or halogen;
R3 is hydrogen or hydroxyl;
R4 is hydrogen or aryl-Ci_galkyl, wherein aryl is optionally substituted with one
substituent selected from Ci_galkyl, halo-Ci_galkyl, Ci_galkoxy or
Ci-galkoxy-Ci-galkyl;
R6 is hydrogen or hydroxyl;
R8 is hydrogen or halogen;
R9 is hydrogen or Ci_galkyl;
R10 is Ci-galkyl, amino or (C1_galkyl)2-amino; and,
Rn is
Figure imgf000008_0001
or (aryl-C1_galkyl)2-amino.
Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein:
Ri is hydrogen, halogen, Ci-galkyl-amino, (Ci_galkyl)2-amino, amino-Ci-galkyl,
Ci-ioalkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl, C2-galkenyl-amino-Ci_galkyl,
C2_galkynyl-amino-Ci_galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl,
(C1_galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl,
Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1_galkyl)2-amino-C1_galkyl,C1_galkyl]amino-C1_galkyl,
hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl or
(C1-galkyl)2-amino-carbonyl-C1-galkyl-amino-C1_galkyl.
Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein:
Ri is C3_i4cycloalkyl-amino-Ci_galkyl, C^Hcycloalkyl-Ci-galkyl-amino-Ci-galkyl,
aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci_galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C3_i4cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R^; and,
wherein each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn-
One embodiment of the present description includes the use of a compound of Formula (II):
Figure imgf000009_0001
(Π) or a form thereof, wherein,
X is a bond, O, -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -0-CH(R3)-, -N(R9)-CH(R3)-, -S-CH(R3)- or -N(R9)-CH(R3)-CH(R3)-;
Z is -CH(R9)-;
Ri is hydrogen, halogen, Ci-galkyl-amino, (Ci_galkyl)2-amino, amino-Ci-galkyl,
Ci-ioalkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl, C2-galkenyl-amino-Ci_galkyl, C2-galkynyl-amino-Ci_galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl,
(C1-galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl,
Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1_galkyl)2-amino-C1_galkyl-amino-C1_galkyl,
[(C1_galkyl)2-amino-C1_galkyl,C1_galkyl]amino-C1_galkyl,
hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1-galkyl)2-amino-carbonyl-C1-galkyl-amino-C1_galkyl,
Cs-Hcycloalkyl-amino-Ci-galkyl, C^wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci_galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C3_i4cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R^; and,
wherein each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn;
R3 is hydrogen, hydroxyl or Ci-galkyl;
R4 is hydrogen, Ci-galkyl or aryl-Ci_galkyl;
R5 is Ci-galkyl;
R6 is hydrogen or hydroxyl;
R7 is hydrogen or halogen;
R9 is hydrogen or Ci-galkyl;
Rio is halogen, hydroxyl, Ci_galkyl, Ci_galkoxy, amino, (Ci_galkyl)2-amino or
Ci_galkyl-carbonyl-amino; and,
Rn is (aryl-Ci-galkyl,Ci_galkyl)amino or (aryl-Ci_galkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein:
X is a bond, -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-,
-0-CH(R3)-, -N(R9)-CH(R3)- or -N(R9)-CH(R3)-CH2-;
Z is -CH(R9)-;
Ri is hydrogen, amino-Ci-galkyl, Ci_ioalkyl-amino-Ci_galkyl, (Ci_galkyl)2-amino-Ci_galkyl, C2_galkenyl-amino-Ci_galkyl, C2_galkynyl-amino-Ci_galkyl,
Ci_galkoxy-Ci_galkyl-amino-Ci_galkyl, amino-Ci_galkyl-amino-Ci_galkyl,
Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(Ci-galkyl)2-amino-Ci-galkyl-amino-Ci_galkyl,
[(Ci_galkyl)2-amino-Ci_galkyl,Ci_galkyl]amino-Ci_galkyl,
hydroxyl-Ci_galkyl-amino-Ci_galkyl, (hydroxyl-Ci_galkyl,Ci_galkyl)amino-Ci_galkyl,
(Ci-galkyl)2-amino-carbonyl-Ci-galkyl-amino-Ci_galkyl,
C3-i4cycloalkyl-amino-Ci_galkyl, C3-i4cycloalkyl-Ci_galkyl-amino-Ci_galkyl, aryl-Ci_galkyl-amino-Ci_galkyl, heteroaryl-Ci_galkyl-amino-Ci_galkyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino-Ci_galkyl or
heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C3_14cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R^;
R3 is hydrogen, hydroxyl or Ci-galkyl;
R4 is hydrogen or Ci_galkyl;
R5 is Ci-galkyl;
R6 is hydrogen or hydroxyl;
R7 is hydrogen or halogen;
R9 is hydrogen or Ci-galkyl; and,
Rio is halogen, hydroxyl, Ci-galkyl, Ci_galkoxy, amino, (Ci_galkyl)2-amino or
Ci-galkyl-carbonyl-amino.
Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein:
Ri is hydrogen, halogen, Ci-galkyl-amino, (Ci_galkyl)2-amino, amino-Ci-galkyl,
Ci-ioalkyl-amino-Ci-galkyl, (Ci-galkyl)2-amino-Ci_galkyl, C2-galkenyl-amino-Ci_galkyl, C2-galkynyl-amino-Ci_galkyl, Ci_galkoxy-Ci_galkyl-amino-Ci_galkyl,
(C1_galkyl)2-amino-C1_galkyl-amino, amino-Ci_galkyl-amino-Ci_galkyl,
Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1_galkyl)2-amino-C1_galkyl,C1_galkyl]amino-C1_galkyl,
hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci_galkyl,Ci_galkyl)amino-Ci_galkyl or (C1-galkyl)2-amino-carbonyl-C1-galkyl-amino-C1_galkyl.
Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein:
Ri is C3_i4cycloalkyl-amino-Ci_galkyl, C3_i4cycloalkyl-Ci_galkyl-amino-Ci_galkyl,
aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C3_14cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R^; and, wherein each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn-
One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein X is a bond, O, -CH(R3)-,
-CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -0-CH(R3)-, -N(R9)-CH(R3)-, -S-CH(R3)- or -N(R9)-CH(R3)-CH2-.
Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein X is a O, -CH(R3)-, -CH(R3)-CH(R3)-,
-CH(R3)-CH(R3)-CH(R3)-, -0-CH(R3)-, -N(R9)-CH(R3)- or -S-CH(R3)-. Another embodiment of the present description includes the use of a compound of
Formula (II) or a form thereof, wherein X is a bond, -CH(R3)-, -CH(R3)-CH(R3)-,
-CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -0-CH(R3)-, -N(R9)-CH(R3)- or
-N(R9)-CH(R3)-CH(R3)-.
One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein Z is -CH(R9)-.
One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein Ri is hydrogen, halogen,
Ci-galkyl-amino, (C1_galkyl)2-amino, amino-Ci_galkyl, Ci_ioalkyl-amino-Ci_galkyl,
(C1-galkyl)2-amino-C1_galkyl, C^galkenyl-amino-Ci-galkyl, C^galkynyl-amino-Ci-galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl-amino,
amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1_galkyl)2-amino-C1_galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl or
(C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl.
Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein Ri is hydrogen, halogen, Ci-galkyl-amino,
(Ci_galkyl)2-amino or (C1_galkyl)2-amino-C1_galkyl-amino.
Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein Ri is hydrogen, amino-Ci_galkyl,
Ci-ioalkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl, C2-galkenyl-amino-Ci_galkyl, C2_galkynyl-amino-Ci_galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl,
amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(Ci-galky^i-amino-Ci-galkyl-amino-Ci-galkyl,
[(Ci-galky^i-amino-Ci-galky^Ci-galky^amino-Ci-galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl or
(C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl.
One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein R is Cs-wcycloalkyl-amino-Ci-galkyl, Cs-Hcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl,
heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci_galkyl,
heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl, wherein each instance of Cs-^cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R10; and,
wherein each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from R \ \ ;
Rio is halogen, hydroxyl, Ci-galkyl, Ci-galkoxy, amino, Ci-galkyl-amino, (C1_galkyl)2-amino,
Ci-galkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl or Ci-galkyl-carbonyl-amino; and,
Rn is aryl-Ci-galkyl-amino, (aryl-Ci-galkyl,^galkyl)amino or (aryl-C1_galkyl)2-amino. Another embodiment of the present description includes the use of a compound of
Formula (I) or a form thereof, wherein R\ is heterocyclyl or heterocyclyl-amino,
wherein each instance of heterocyclyl is optionally substituted with one, two or three
substituents each selected from R^; and,
wherein each instance of heterocyclyl is optionally substituted with one substituent selected from Rn;
Rio is Ci-galkyl, amino or (Ci_galkyl)2-amino; and,
Rn is
Figure imgf000013_0001
or (aryl-Ci_galkyl)2-amino.
Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein Ri is Cs-ncycloalkyl-amino-Ci-galkyl,
Cs-Hcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl,
heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl, wherein each instance of C3_i4cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R10; and,
Rio is halogen, hydroxyl, Ci_galkyl,
Figure imgf000014_0001
^galkyl-amino-Ci-galkyl, (Ci-galkyl amino-Ci-galkyl or Ci-galkyl-carbonyl-amino.
One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein
Ri is hydrogen, halogen, Ci-galkyl-amino,
Figure imgf000014_0002
amino-Ci-galkyl,
Ci-ioalkyl-amino-Ci-galkyl, (Ci-galkyl amino-Ci-galkyl, C^galkenyl-amino-Ci-galkyl, C^galkynyl-amino-Ci-galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl,
(C1_galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl,
Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1_galkyl)2-amino-C1_galkyl,C1_galkyl]amino-C1_galkyl,
hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1-galkyl)2-amino-carbonyl-C1-galkyl-amino-C1_galkyl,
Cs-^cycloalkyl-amino-Ci-galkyl, Cs-wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci_galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of Cs-^cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R10; and,
wherein each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn ;
Rio is halogen, hydroxyl, Ci-galkyl, Q-galkoxy, amino, Ci-galkyl-amino, (C1_galkyl)2-amino, Ci-galkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl or Ci-galkyl-carbonyl-amino; and,
Rn is aryl-Ci-galkyl-amino, (aryl-Ci-galkyl,Ci-galkyl)amino or (aryl-C1_galkyl)2-amino.
Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein
Ri is hydrogen, halogen, Ci-galkyl-amino, (Ci_galkyl)2-amino,
(C1-galkyl)2-amino-C1_galkyl-amino, heterocyclyl or heterocyclyl-amino, wherein each instance of heterocyclyl is optionally substituted with one, two or three substituents each selected from R10; and,
wherein each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn ;
Rio is Ci-galkyl, amino or (C1_8alkyl)2-amino; and,
Rn is aryl-Ci-galkyl-amino,
Figure imgf000015_0001
or (aryl-C1_galkyl)2-amino.
Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein
Ri is hydrogen, amino-Ci_galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl, C^galkenyl-amino-Ci-galkyl, C^galkynyl-amino-Ci-galkyl,
Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, amino-Ci-galkyl-amino-Ci-galkyl,
Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1_galkyl)2-amino-C1_galkyl-amino-C1_galkyl,
[(C1_galkyl)2-amino-C1_galkyl,C1_galkyl]amino-C1_galkyl,
hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl,
(C1-galkyl)2-amino-carbonyl-C1-galkyl-amino-C1_galkyl,
Cs-Hcycloalkyl-amino-Ci-galkyl, Cs-wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl,
heterocyclyl-Ci-galkyl, heterocyclyl-amino-Ci-galkyl or
heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C3_i4cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R10; and,
Rio is halogen, hydroxyl, Ci-galkyl, Q-galkoxy, amino, Ci-galkyl-amino, (C1_galkyl)2-amino,
Ci-galkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl or Ci-galkyl-carbonyl-amino. One embodiment of the present description includes the use of a compound of
Formula (I) or Formula (II) or a form thereof, wherein Ri is
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, imidazolyl or pyridinyl; heterocyclyl selected in each instance, when present, from azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3- dioxolanyl, 2,5-dihydro- lH-pyrrolyl, dihydro-lH-imidazolyl, 1,4,5,6- tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3-dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b] [l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, hexahydropyrrolo[3,4-b] [l,4]oxazin-(2H)-yl, (4aR,7aS)- hexahydropyrrolo[3,4-b][l,4]oxazin-(4aH)-yl, 3,4-dihydro-2H-pyrido[3,2- b] [l,4]oxazinyl, (cis)-octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4- b]pyrrol-(lH)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro- lH-carbazolyl, 1 ,2,3,4-tetrahydropyrazino[ 1 ,2-a]indolyl, 2,3-dihydro- 1H- pyrrolo[l,2-a]indolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl,
(3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-l,3,3a,4,5,6- hexahydro-2H-isoindolyl, (3aR,4R,7aS)- lH-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl,
(3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2- azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexanyl, (cis,cis)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexanyl, (lS,5R)-3-azabicyclo[3.2.0]heptanyl, 5- azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2,6- diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2- azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl.
Another embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein Ri is
heteroaryl selected in each instance, when present, from pyrrol- 1-yl, thiazol-2-yl, 1 H- 1,2,3- triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; heterocyclyl selected in each instance, when present, from azetidin- l-yl, pyrrolidin- l-yl, tetrahydrofuran-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin- l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan- l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol- l-yl, dihydro-lH-imidazol- 2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H- pyran-2-yl, tetrahydro-2H-pyran-4-yl, 3,4-dihydroisoquinolin-2(lH)-yl, 1,2,3,4- tetrahydroisoquinolin- l-yl, hexahydropyrrolo[3,4-b] [l,4]oxazin-6(2H)-yl, (4aR,7aS)- hexahydropyrrolo[3,4-b][l,4]oxazin-4(4aH)-yl, (cis)-octahydrocyclopenta[c]pyrrol-4- yl, hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, (3aR,6aR)-hexahydropyrrolo[3,4- b]pyrrol-5(lH)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl, 5H- pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-lH-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4- b]pyridin-6(2H)-yl, (4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol- 3a(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, l,3-dihydro-2H-isoindol-2-yl, octahydro-2H-isoindol-2-yl, (3aS)- l,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-lH-isoindol- 2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl,
(3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2-azabicyclo[2.2.1]hept-5-en-2-yl, 3- azabicyclo[3.1.0]hexan-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hexan-3-yl, (cis,cis)-3- azabicyclo[3.1.0]hexan-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hexan-6-yl, (cis,cis)-3- azabicyclo[3.1.0]hexan-6-yl, 3,6-diazabicyclo[3.1.0]hexan-3-yl, (lS,5R)-3- azabicyclo[3.2.0]heptan-3-yl, 5-azaspiro[2.4]heptan-5-yl, 2,6-diazaspiro[3.3]heptan- 2-yl, 2,5-diazaspiro[3.4]octan-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 2,7- diazaspiro[3.5]nonan-2-yl, 2,7-diazaspiro[4.4]nonan-2-yl, 2-azaspiro[4.5]decan-2-yl or 2,8-diazaspiro[4.5]decan-2-yl.
Another embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein Ri is
Cs-^cycloalkyl selected in each instance, when present, from cyclopropyl or cyclobutyl; aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from pyridinyl; heterocyclyl selected in each instance, when present, from azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, (cis)- octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4-b]pyrrol-( lH)-yl, hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin- (2H)-yl, (cis,cis)-3-azabicyclo[3.1.0]hexanyl, 2,6-diazaspiro[3.4]octanyl or 2,7- diazaspiro [4.4] nonanyl .
Another embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein R is
Cs-ncycloalkyl selected in each instance, when present, from cyclopropyl or cyclobutyl; aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from pyridin-3-yl or pyridin-4-yl;
heterocyclyl selected in each instance, when present, from azetidin-l-yl, pyrrolidin-l-yl, tetrahydrofuran-2-yl, piperidin-l-yl, piperidin-4-yl, piperazin-l-yl, morpholin-4-yl, 1,4-diazepan-l-yl, (cis)-octahydrocyclopenta[c]pyrrol-4-yl, hexahydropyrrolo[3,4- b]pyrrol-5(lH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, (cis,cis)-3-azabicyclo[3.1.0]hexan-3- yl, 2,6-diazaspiro[3.4]octan-6-yl or 2,7-diazaspiro[4.4]nonan-2-yl.
One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein R is
Cs-^cycloalkyl-amino-Ci-galkyl, wherein Cs-^cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
Cs-Hcycloalkyl-Ci-galkyl-amino-Ci-galkyl, wherein Cs-^cycloalkyl is selected from
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
aryl-Ci-8 alkyl-amino-Ci-8 alkyl, wherein aryl is selected from phenyl;
heteroaryl, wherein heteroaryl is selected from pyrrolyl, thiazolyl, lH-l,2,3-triazolyl,
lH-tetrazolyl, 2H-tetrazolyl, imidazolyl or pyridinyl;
heteroaryl-Ci-galkyl-amino-Ci-galkyl, wherein heteroaryl is selected from pyridin-2-yl, pyridin-3-yl or pyridin-4-yl;
heterocyclyl, wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3- dioxolanyl, 2,5-dihydro-lH-pyrrolyl, dihydro-lH-imidazolyl, 1,4,5,6- tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, hexahydropyrrolo[3,4- b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4-b][l,4]oxazin-(4aH)-yl, (cis)- octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aR)- hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- (lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4- b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-l,3,3a,4,5,6- hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl,
(3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2- azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexanyl, (cis,cis)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexanyl, (lS,5R)-3-azabicyclo[3.2.0]heptanyl, 5- azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2,6- diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2- azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl;
heterocyclyl-Ci-galkyl, wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3- dioxolanyl, 2,5-dihydro-lH-pyrrolyl, dihydro-lH-imidazolyl, 1,4,5,6- tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, hexahydropyrrolo[3,4- b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4-b][l,4]oxazin-(4aH)-yl, (cis)- octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aR)- hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- (lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4- b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-l,3,3a,4,5,6- hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl,
(3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2- azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexanyl, (cis,cis)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (lS,5R,6S)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl;
heterocyclyl-amino, wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3- dioxolanyl, 2,5-dihydro-lH-pyrrolyl, dihydro-lH-imidazolyl, 1,4,5,6- tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, hexahydropyrrolo[3,4- b] [ 1 ,4] oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3 ,4-b] [ 1 ,4] oxazin-(4aH)-yl, (cis)- octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aR)- hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- (lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4- b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-l,3,3a,4,5,6- hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl,
(3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2- azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexanyl, (cis,cis)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (lS,5R,6S)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl;
heterocyclyl-amino-Ci-galkyl, wherein heterocyclyl is selected from azetidin-l-yl or
piperidin-4-yl; and,
heterocyclyl-Ci-galkyl-amino-Ci-galkyl, wherein heterocyclyl is selected from pyrrolidin-l-yl, pyrrolidin-2-yl, tetrahydrofuran-2-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl or tetrahydro-2H-pyran-4-yl.
Another embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein Ri is
Cs-Hcycloalkyl-amino-Ci-galkyl, wherein C3_i4cycloalkyl is selected from cyclopropyl or cyclobutyl;
Cs-^cycloalkyl-Ci-galkyl-amino-Ci-galkyl, wherein C3_i4cycloalkyl is selected from
cyclopropyl or cyclobutyl;
aryl-Ci-g alkyl-amino-Ci_g alkyl, wherein aryl is selected from phenyl;
heteroaryl-^galkyl-amino-Ci-galkyl, wherein heteroaryl is selected from pyridin-3-yl or pyridin-4-yl;
heterocyclyl, wherein heterocyclyl is selected from pyrrolidinyl, piperidinyl, piperazinyl, 1,4- diazepanyl, hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- 1H- pyrrolo[3,4-b]pyridin-(2H)-yl, (cis,cis)-3-azabicyclo[3.1.0]hexanyl, 2,6- diazaspiro[3.4]octanyl or 2,7-diazaspiro[4.4]nonanyl;
heterocyclyl-Ci-galkyl, wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, hexahydropyrrolo[3,4-b]pyrrol- (lH)-yl;
heterocyclyl-amino, wherein heterocyclyl is selected from piperidinyl, (cis)- octahydrocyclopenta[c]pyrrolyl;
heterocyclyl-amino-Ci-galkyl, wherein heterocyclyl is piperidin-4-yl; and,
heterocyclyl-Ci-galkyl-amino-Ci-galkyl, wherein heterocyclyl is selected from pyrrolidin-l-yl or tetrahydrofuran-2-yl.
One embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein
R2 is hydrogen, halogen or Ci-galkyl;
R3 is hydrogen, hydroxyl or Ci-galkyl; R4 is hydrogen, Ci_galkyl or aryl-Ci_galkyl, wherein aryl is optionally substituted with one substituent selected from Ci_galkyl, halo-Ci_galkyl, Ci_galkoxy or
Ci-galkoxy-Ci-galkyl;
R5 is hydrogen or Ci-galkyl;
R6 is hydrogen or hydroxyl;
R7 is hydrogen or halogen;
Rg is hydrogen or halogen; and,
R9 is hydrogen or Ci-galkyl.
Another embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof, wherein
R2 is hydrogen or halogen;
R3 is hydrogen, hydroxyl or Ci-galkyl;
R4 is hydrogen, Ci_galkyl or aryl-Ci-galkyl;
R5 is Ci-galkyl;
R6 is hydrogen or hydroxyl;
R7 is hydrogen or halogen;
Rg is hydrogen or halogen; and,
R9 is hydrogen or Ci_galkyl.
Another embodiment of the present description includes the use of a compound of Formula (I) or a form thereof, wherein
R2 is hydrogen or halogen;
R3 is hydrogen, hydroxyl or Ci_galkyl;
R4 is hydrogen or aryl-Ci-galkyl;
R6 is hydrogen or hydroxyl;
Rg is hydrogen or halogen; and,
R9 is hydrogen or Ci_galkyl.
Another embodiment of the present description includes the use of a compound of Formula (II) or a form thereof, wherein
R3 is hydrogen, hydroxyl or Ci_galkyl;
R4 is hydrogen, Ci-galkyl or aryl-Ci_galkyl;
R5 is Ci-galkyl;
R6 is hydrogen or hydroxyl; R7 is hydrogen or halogen; and,
R9 is hydrogen or Ci-galkyl.
In another embodiment, the use of the compound of Formula (I) or Formula (II) or a form thereof includes a use of a form selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form of the compound of Formula (I) or Formula (II).
In another embodiment, the use of the compound of Formula (I) or Formula (II) or a form thereof includes a use of an isotopologue form of the compound of Formula (I) or Formula (II) wherein, when present as hydrogen, one or more R1 ; R2, R3, R4, R5, R6, R7, Rs and R9 hydrogen atoms are independently replaced with deuterium.
In one embodiment of the use of a compound of Formula (I) of the present description, the compound or a form thereof is selected from the group consisting of:
Figure imgf000023_0001
wherein R1 ; X, Z, R6, R4, R% and R2 are selected from:
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In one embodiment of the use of a compound of Formula (II) of the present description, the compound or a form thereof is a compound of Formula (Ila) selected from the group consisting of:
Figure imgf000027_0001
(Ila) wherein R1; R7, X, Z, R6 and R4 are selected from:
Figure imgf000027_0002
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof. In one embodiment of the use of the present description, a compound or a form thereof is selected from the group consisting of:
Figure imgf000032_0001
11 12
10
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
55 56 57
Figure imgf000036_0001
Figure imgf000037_0001
87 88 89
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000043_0002
Figure imgf000043_0003
Figure imgf000043_0004
Figure imgf000043_0005
173 174 175
Figure imgf000044_0001
Figure imgf000044_0002
Figure imgf000044_0003
Figure imgf000044_0004
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound or a form thereof for treating or
ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound or a form thereof to the subject, wherein the compound or a form thereof is selected from the group consisting of (where compound number (#*) indicates that the salt form was isolated):
Cpd Name
1 8-(dimethylamino)-2-oxo- 1 ,2,5,6-tetrahydrobenzo[h]quinoline-3-carboxylic acid
2 9-(dimethylamino)-2-oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid
3 9-(dimethylamino)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4 10-(dimethylamino)-2-oxo- 1,2,5, 6,7, 8-hexahydrobenzo[7,8]cycloocta[ 1,2- b]pyridine-3-carboxylic acid
5 10-(dimethylamino)-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydrobenzo[7,8]cycloocta[l,2-b]pyridine-3-carboxylic acid
61 9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
7 4-hydroxy-2-oxo-9-(pyrrolidin-l-yl)-2,5,6,7-tetrahydro- lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
81 4-hydroxy-9-(3-(methylamino)pyrrolidin-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
91 9-((cis,cis)-6 -amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo-2,5,6,7- tetrahydro- lH-benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid
101 9-((cis,cis)-6-(benzyl(methyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2- oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid ll1 4-hydroxy-9-((cis,cis)-6-(methylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxo- 2,5,6,7-tetrahydro- lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
121 9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-5-methyl-2-oxo-2,5,6,7-tetrahydro- lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
131 9-((cis,cis)-6 -amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl-2-oxo- 2,5,6,7-tetrahydro- lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid Cpd Name
141 9-((cis,cis)-6 -amino-3-azabicyclo[3.1.0]hexan-3-yl)-4,7-dihydroxy-2-oxo-2,5,6,7- tetrahydro- lH-benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid
151 9-(3-(dimethylamino)pyrrolidin-l-yl)-4,7-dihydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
16 4-hydroxy-9-methyl-2-oxo-l,2,5,9-tetrahydropyrido[3',2':6,7]cyclohepta[l,2- f]indole-3-carboxylic acid
17 4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2- f]indole-3-carboxylic acid
18 8-fluoro-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
191 2-((ethylamino)methyl)-8-hydroxy-l-methyl-6-oxo- 1,5,6,9- tetrahydropyrido[3',2':4,5]cyclopenta[l,2-f]indole-7-carboxylic acid
201 4-hydroxy-8-methyl-9-((methylamino)methyl)-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
211 9-(azetidin-l-ylmethyl)-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
221 4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
231 10-((cyclobutylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
241 10-(azetidin-l-ylmethyl)-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
251 10-((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
261 4-hydroxy-10-((isopropylamino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid Cpd Name
271 10-((tert-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
281 4-hydroxy-10-((4-hydroxypiperidin-l-yl)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9- exahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
291 10-((4-aminopiperidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- exahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
301 10-((4-(dimethylamino)piperidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
311 10-((3-aminopiperidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
321 10-(((cyclopropylmethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
331 4-hydroxy-9-methyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
341 10-((benzylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
351 10-(aminomethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
361 10-((cyclopropylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
371 10-(((cyclobutylmethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
381 4-hydroxy-9-methyl-10-((((2-methylcyclopropyl)methyl)amino)methyl)-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
391 4-hydroxy-9-methyl-2-oxo-10-(((pyridin-4-ylmethyl)amino)methyl)- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid Cpd Name
401 4-hydroxy-9-methyl-2-oxo- 10-(piperidin- 1-ylmethyl)- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
411 4-hydroxy-9-methyl-10-(morpholinomethyl)-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
421 4-hydroxy-9-methyl-10-((4-methylpiperazin-l-yl)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
431 10-((diethylamino)methyl)-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
441 4-hydroxy-9-methyl-2-oxo-10-((propylamino)methyl)- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
451 4-hydroxy-9-methyl-2-oxo-10-((prop-2-yn-l-ylamino)methyl)- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
461 (R)-10-((3-fluoropyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
471 10-((3-(dimethylamino)pyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
481 10-((dimethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
491 (S)-10-((3-aminopyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
501 4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin- 1-ylmethyl)- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
511 4-hydroxy-10-((3-hydroxypyrrolidin-l-yl)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
521 4-hydroxy-9-methyl-2-oxo-10-(((pyridin-3-ylmethyl)amino)methyl)- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid Cpd Name
531 9-methyl-10-((methylamino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
541 10-((ethylamino)methyl)-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
551 10-((isopropylamino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
561 10-((tert-butylamino)methyl)-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
571 10-(azetidin-l-ylmethyl)-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
581 4-hydroxy-10-methyl-l l-((methylamino)methyl)-2-oxo-2,5,6,7,8,10-hexahydro-lH- pyrido[3',2':7,8]cycloocta[l,2-f]indole-3-carboxylic acid
591 l l-((ethylamino)methyl)-4-hydroxy-10-methyl-2-oxo-2,5,6,7,8,10-hexahydro-lH- pyrido[3',2':7,8]cycloocta[l,2-f]indole-3-carboxylic acid
621 4-hydroxy-7,9-dimethyl-10-((methylamino)methyl)-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
631 10-((ethylamino)methyl)-4-hydroxy-7,9-dimethyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
641 4-hydroxy-10-((isopropylamino)methyl)-7,9-dimethyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
651 10-((tert-butylamino)methyl)-4-hydroxy-7,9-dimethyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
661 4-hydroxy-7,9-dimethyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
671 10-((ethylamino)methyl)-4-hydroxy-5,9-dimethyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid Cpd Name
681 4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo- 1,2,5,9- tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
691 10-((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo-l,2,5,9- tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
701 10-((ethylamino)methyl)-4-hydroxy-7,9-dimethyl-2-oxo-l,2,5,9- tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
711 (cis)-10-((ethylamino)methyl)-4,6,7-trihydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
72 l-benzyl-8-chloro-5-methyl-2-oxo-2,5-dihydro-lH-chromeno[4,3-b]pyridine-3- carboxylic acid
73 5-methyl-2-oxo-2,5-dihydro-lH-chromeno[4,3-b]pyridine-3-carboxylic acid
74 5-methyl-2-oxo-8-(pyrrolidin-l-yl)-2,5-dihydro-lH-chromeno[4,3-b]pyridine-3- carboxylic acid
751 8-(3-(dimethylamino)pyrrolidin-l-yl)-5-methyl-2-oxo-2,5-dihydro-lH- chromeno[4,3-b]pyridine-3-carboxylic acid
76 9-(dimethylamino)-4-hydroxy-2-oxo- 1,2,5, 6-tetrahydrobenzo[2,3]oxepino[4,5- b]pyridine-3-carboxylic acid
77 4-hydroxy-2-oxo-9-(pyrrolidin-l-yl)- 1,2,5, 6-tetrahydrobenzo[2,3]oxepino[4,5- b]pyridine-3-carboxylic acid
781 9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-2-oxo- 1,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
791 9-((cis,cis)-6-(dibenzylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo- l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
801 9-((cis,cis)-6 -amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo- 1 ,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
81 2-oxo-9-(pyrrolidin-l-yl)-l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3- carboxylic acid Cpd Name
821 9-(3-(dimethylamino)pyrrolidin- 1 -yl)-2-oxo- 1 ,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
83 4-hydroxy-5-methyl-2-oxo-9-(pyrrolidin-l-yl)-l,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
841 9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-5-methyl-2-oxo- 1,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
851 9-((cis,cis)-6-(dibenzylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl- 2-oxo-l, 2,5, 6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
861 9-((cis,cis)-6 -amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl-2-oxo- l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
87 4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2- f]indole-3-carboxylic acid
881 4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
891 10-((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
901 4-hydroxy-10-((isopropylamino)methyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
911 10-(azetidin-l-ylmethyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
921 10-((ethylamino)methyl)-4-hydroxy-5,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
93 4-hydroxy-7-methyl-2-oxo-9-(pyrrolidin-l-yl)-2,5,6,7-tetrahydro-lH- benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid
94 4-hydroxy-2-oxo-9-(pyrrolidin-l-yl)-2,5,6,7-tetrahydro-lH-benzo[b]pyrido[2,3- d]azepine-3-carboxylic acid Cpd Name
951 9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid
961 4-hydroxy-9-(4-methylpiperazin-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH- benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid
971 9-((cis,cis)-6 -amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo-2,5,6,7- tetrahydro-lH-benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid
981 9-(hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-4-hydroxy-2-oxo-2,5,6,7- tetrahydro-lH-benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid
991 4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo-l,2,5,6,7,9- hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid
1001 10-((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid
1011 4-hydroxy-10-((isopropylamino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid
1021 10-((tert-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid
1031 4-hydroxy-10-methyl-l l-((methylamino)methyl)-2-oxo-2,5, 6,7,8, 10-hexahydro-lH- pyrido[2',3':4,5]azocino[3,2-f]indole-3-carboxylic acid
1041 l l-((ethylamino)methyl)-4-hydroxy-10-methyl-2-oxo-2,5, 6,7,8, 10-hexahydro-lh- pyrido[2',3':4,5]azocino[3,2-f]indole-3-carboxylic acid
1051 4-hydroxy-l l-((isopropylamino)methyl)-10-methyl-2-oxo-2,5, 6,7,8, 10-hexahydro- lH-pyrido[2',3':4,5]azocino[3,2-f]indole-3-carboxylic acid
107 4-hydroxy-5-methyl-2-oxo-8-(pyrrolidin-l-yl)- 1,2,5, 6-tetrahydrobenzo[h]quinoline- 3-carboxylic acid
108 8-(dimethylamino)-4-hydroxy-5-methyl-2-oxo- 1 ,2,5,6-tetrahydrobenzo[h]quinoline- 3-carboxylic acid Cpd Name
1091 8-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-5-methyl-2-oxo- 1,2,5,6- tetrahydrobenzo[h]quinoline-3-carboxylic acid
HO1 8-((cis,cis)-6 -amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl-2-oxo-
1.2.5.6- tetrahydrobenzo[h]quinoline-3-carboxylic acid
1111 9-(l,4-diazepan-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
1121 4-hydroxy-9-(4-methyl-l,4-diazepan-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
1131 9-((2-(dimethylamino)ethyl)amino)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
1141 9-((4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-4-hydroxy-2-oxo-
2.5.6.7- tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
1151 4-hydroxy-9-((4aR,7aR)-l-methylhexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2- oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
1161 9-(4-(dimethylamino)piperidin- l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1H- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
1171 9-(3-(dimethylamino)piperidin- l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- 1H- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
1181 4-hydroxy-2-oxo-9-(piperidin-4-ylamino)-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
1191 4-hydroxy-2-oxo-9-(piperazin- l-yl)-2,5,6,7-tetrahydro- 1H- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
1201 4-hydroxy-9-(4-methylpiperazin-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
1211 4-hydroxy-2-oxo-9-(2,6-diazaspiro[3.4]octan-6-yl)-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid Cpd Name
1221 4-hydroxy-2-oxo-9-(2,7-diazaspiro[4.4]nonan-2-yl)-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
1231 4-hydroxy-9-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
1241 9-((cis,cis)-6 -amino-3-azabicyclo[3.1.0]hexan-3-yl)-10, 1 l-difluoro-4-hydroxy-2- oxo-2,5, 6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
1251 9-((cis,cis)-6 -amino-3-azabicyclo[3.1.0]hexan-3-yl)-l l-fluoro-4-hydroxy-2-oxo- 2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
126 4-hydroxy-2-oxo-10-(pyrrolidin-l-yl)-l,2,5,6,7,8- hexahydrobenzo[7,8]cycloocta[l,2-b]pyridine-3-carboxylic acid
1271 10-((cis,cis)-6 -amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo- 1 ,2,5,6,7,8- hexahydrobenzo[7,8]cycloocta[l,2-b]pyridine-3-carboxylic acid
128 4-hydroxy-2-oxo-10-(propylamino)- 1,2,5, 6,7, 8-hexahydrobenzo[7,8]cycloocta[ 1,2- b]pyridine-3-carboxylic acid
129 10-(ethylamino)-4-hydroxy-2-oxo- 1,2,5,6,7, 8-hexahydrobenzo[7,8]cycloocta[ 1,2- b]pyridine-3-carboxylic acid
130 l,9-dimethyl-2-oxo-l,2,5,9-tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3- carboxylic acid
131 4-hydroxy-l,9-dimethyl-2-oxo-l,2,5,9-tetrahydropyrido[3',2':6,7]cyclohepta[l,2- f]indole-3-carboxylic acid
132 l-ethyl-4-hydroxy-9-methyl-2-oxo- 1,2,5, 9-tetrahydropyrido[3',2':6,7]cyclohepta[ 1,2- f]indole-3-carboxylic acid
133 l,9-dimethyl-2 -oxo-l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3- carboxylic acid
134 4-hydroxy-l,9-dimethyl-2-oxo-l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2- f]indole-3-carboxylic acid Cpd Name
1361 10-((butylamino)methyl)-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1371 4-hydroxy-9-methyl-2-oxo-10-((pentylamino)methyl)- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1381 10-((hexylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1391 10-((heptylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1401 4-hydroxy-9-methyl- 10-((octylamino)methyl)-2-oxo- 1 ,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1411 4-hydroxy-9-methyl- 10-((nonylamino)methyl)-2-oxo- 1 ,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1421 10-(((2-(dimethylamino)ethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1431 4-hydroxy-9-methyl-10-(((2-(methylamino)ethyl)amino)methyl)-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1441 10-(((2-aminoethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1451 10-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1461 10-((sec-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1471 4-hydroxy-10-(((2-hydroxyethyl)amino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1481 4-hydroxy-10-(((2-methoxyethyl)amino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid Cpd Name
1491 4-hydroxy-10-(((2-hydroxyethyl)(methyl)amino)methyl)-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1501 4-hydroxy-10-(((l-methoxypropan-2-yl)amino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1511 4-hydroxy-10-(((l-hydroxypropan-2-yl)amino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1521 4-hydroxy-9-methyl-2-oxo-10-(((2-(pyrrolidin-l-yl)ethyl)amino)methyl)- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1531 10-((allylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
4-hydroxy-10-((isobutylamino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1551 4-hydroxy-9-methyl-10-((neopentylamino)methyl)-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid j^gi 4-hydroxy-9-methyl- 10-((4-methyl- 1 ,4-diazepan- 1 -yl)methyl)-2-oxo- 1 ,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid j^yi 4-hydroxy-9-methyl-10-(((l-methylpiperidin-4-yl)amino)methyl)-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1581 4-hydroxy-10-((3-methoxypyrrolidin-l-yl)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1591 10-((3-acetamidopyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1601 10-(((l-(dimethylamino)propan-2-yl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid j^ji 4-hydroxy-9-methyl-2-oxo-10-((((tetrahydrofuran-2-yl)methyl)amino)methyl)- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid Cpd Name
4-hydroxy-9-methyl-10-((l-methylhexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl)methyl)- 2-oxo- 1,2,5, 6,7, 9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
1631 10-(((2-(dimethylamino)-2-oxoethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
10-(2-(ethylamino)ethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,9- tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
1651 10-(2-(ethylamino)ethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid j^gi 4-hydroxy-9-(((cis)-octahydrocyclopenta[c]pyrrol-4-yl)-(cis)-amino)-2-oxo- 1,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid j^yi 4-hydroxy-9-methyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
1681 10-((sec-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo- 10-((propylamino)methyl)-2,5,6,9-tetrahydro- 1H- pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid 10-(((2,4-dimethoxybenzyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid 10-((cyclopropylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
10-((cyclobutylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid yjT^ 10-((dimethylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
1741 4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid Cpd Name j ^i 10-((tert-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid j gi 4-hydroxy-9-methyl-10-((4-methylpiperazin-l-yl)methyl)-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-10-(((2-hydroxyethyl)amino)methyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
1781 4-hydroxy-10-(((l-hydroxypropan-2-yl)amino)methyl)-9-methyl-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo- 10-(((2-(pyrrolidin- l-yl)ethyl)amino)methyl)-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid jgQi 10-(((2-aminoethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid jgji 4-hydroxy-9-methyl-10-(((2-(methylamino)ethyl)amino)methyl)-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
1821 10-(((2-(dimethylamino)ethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
1831 4-hydroxy-10-(((2-methoxyethyl)amino)methyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
1841 4-hydroxy-10-(((l-methoxypropan-2-yl)amino)methyl)-9-methyl-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
185 9-(dimethylamino)-4-hydroxy-2-oxo- 1,2,5, 6-tetrahydrobenzo[2,3]thiepino[4,5- b]pyridine-3-carboxylic acid, and
186 4-hydroxy-2-oxo-9-(pyrrolidin-l-yl)- 1,2,5, 6-tetrahydrobenzo[2,3]thiepino[4,5- b]pyridine-3-carboxylic acid; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof. Another embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound salt or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound salt or a form thereof to the subject, wherein a compound salt or a form thereof is selected from the group consisting of:
Cpd Name
9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 6 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-(3-(methylamino)pyrrolidin-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH-
8 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo-2,5,6,7- tetrahydro- lH-benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid
9 trifluoroacetate
9-((cis,cis)-6-(benzyl(methyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2- oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
10 hydrochloride
4-hydroxy-9-((cis,cis)-6-(methylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxo- 2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
11 hydrochloride
9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-5-methyl-2-oxo-2,5,6,7-tetrahydro-
12 lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl-2-oxo- 2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
13 hydrochloride
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4,7-dihydroxy-2-oxo-2,5,6,7- tetrahydro- lH-benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid
14 trifluoroacetate
9-(3-(dimethylamino)pyrrolidin-l-yl)-4,7-dihydroxy-2-oxo-2,5,6,7-tetrahydro-lH-
15 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride Cpd Name
2-((ethylamino)methyl)-8-hydroxy-l-methyl-6-oxo-l,5,6,9-
19 tetrahydropyrido[3',2':4,5]cyclopenta[l,2-f]indole-7-carboxylic acid hydrochloride
4-hydroxy-8-methyl-9-((methylamino)methyl)-2-oxo-2,5,6,8-tetrahydro-lH-
20 indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
9- (azetidin-l-ylmethyl)-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH-
21 indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo- 1,2,5, 6,7,9-
22 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10- ((cyclobutylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
23 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-(azetidin-l-ylmethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
24 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9-
25 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-10-((isopropylamino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9-
26 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-((tert-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
27 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-10-((4-hydroxypiperidin-l-yl)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9-
28 exahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((4-aminopiperidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9-
29 exahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid dihydrochloride
10-((4-(dimethylamino)piperidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
30 dihydrochloride
10-((3-aminopiperidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9-
31 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid dihydrochloride Cpd Name
10-(((cyclopropylmethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
32 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo- 1,2,5,6,7,9-
33 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-((benzylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
34 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-(aminomethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
35 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-((cyclopropylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
36 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-(((cyclobutylmethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9-
37 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((((2-methylcyclopropyl)methyl)amino)methyl)-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
38 hydrochloride
4-hydroxy-9-methyl-2-oxo-10-(((pyridin-4-ylmethyl)amino)methyl)- 1,2,5,6,7,9-
39 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo- 10-(piperidin- 1-ylmethyl)- 1,2,5,6,7,9-
40 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-(morpholinomethyl)-2-oxo- 1,2,5,6,7,9-
41 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((4-methylpiperazin-l-yl)methyl)-2-oxo- 1,2,5,6,7,9-
42 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid dihydrochloride
10-((diethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9-
43 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-((propylamino)methyl)- 1,2,5, 6,7,9-
44 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride Cpd Name
4-hydroxy-9-methyl-2-oxo-10-((prop-2-yn-l-ylamino)methyl)- 1,2,5,6,7,9-
45 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
(R)-10-((3-fluoropyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
46 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-((3-(dimethylamino)pyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
47 dihydrochloride
10-((dimethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
48 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
(S)-10-((3-aminopyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9-
49 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid dihydrochloride
4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,9-
50 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-10-((3-hydroxypyrrolidin-l-yl)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9-
51 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-(((pyridin-3-ylmethyl)amino)methyl)- 1,2,5,6,7,9-
52 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
9- methyl-10-((methylamino)methyl)-2-oxo- 1,2,5,6,7,9-
53 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10- ((ethylamino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9-
54 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-((isopropylamino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9-
55 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-((tert-butylamino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9-
56 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-(azetidin-l-ylmethyl)-9-methyl-2-oxo- 1,2,5, 6,7,9-
57 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride Cpd Name
4-hydroxy- 10-methyl- 11 -((methylam
58 pyrido[3',2':7,8]cycloocta[l,2-f]indole-3-carboxylic acid hydrochloride l l-((ethylamino)methyl)-4-hydroxy-10-methyl-2-oxo-2,5, 6,7,8, 10-hexahydro-lH-
59 pyrido[3',2':7,8]cycloocta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-7,9-dimethyl-10-((methylamino)methyl)-2-oxo- 1,2,5, 6,7,9-
62 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-((ethylamino)methyl)-4-hydroxy-7,9-dimethyl-2-oxo- 1,2,5, 6,7,9-
63 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy- 10-((isopropylamino)methyl)-7,9-dimethyl-2-oxo- 1,2,5, 6,7,9-
64 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-((tert-butylamino)methyl)-4-hydroxy-7,9-dimethyl-2-oxo- 1,2,5, 6,7,9-
65 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-7,9-dimethyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
66 hydrochloride
10-((ethylamino)methyl)-4-hydroxy-5,9-dimethyl-2-oxo- 1,2,5, 6,7,9-
67 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo- 1,2,5,9-
68 tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,9-
69 tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((ethylamino)methyl)-4-hydroxy-7,9-dimethyl-2-oxo- 1,2,5,9-
70 tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
(cis)-10-((ethylamino)methyl)-4,6,7-trihydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9-
71 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
8-(3-(dimethylamino)pyrrolidin-l-yl)-5-methyl-2-oxo-2,5-dihydro-lH- 75 chromeno[4,3-b]pyridine-3-carboxylic acid hydrochloride Cpd Name
9-(3-(dimethylamino)pyrrolidin- 1 -yl)-4-hydroxy-2-oxo- 1 ,2,5,6-
78 tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid hydrochloride
9-((cis,cis)-6-(dibenzylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo- l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
79 trifluoroacetate
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo- 1,2,5,6-
80 tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid hydrochloride
9-(3-(dimethylamino)pyrrolidin- 1 -yl)-2-oxo- 1 ,2,5,6- 82 tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid hydrochloride
9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-5-methyl-2-oxo- 1,2,5,6-
84 tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid hydrochloride
9-((cis,cis)-6-(dibenzylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl- 2-oxo-l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
85 hydrochloride
9- ((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl-2-oxo-
86 l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo-2,5,6,9-tetrahydro-lH-
88 pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
10- ((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-
89 pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-10-((isopropylamino)methyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-
90 pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
10-(azetidin-l-ylmethyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-
91 pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
10-((ethylamino)methyl)-4-hydroxy-5,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH-
92 pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- 95 benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid hydrochloride Cpd Name
4-hydroxy-9-(4-methylpiperazin-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH-
96 benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid hydrochloride
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo-2,5,6,7-
97 tetrahydro-lH-benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid hydrochloride
9- (hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-4-hydroxy-2-oxo-2,5,6,7-
98 tetrahydro-lH-benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo- 1,2,5, 6,7,9-
99 hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid hydrochloride
10- ((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7, 9-
100 hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-((isopropylamino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9-
101 hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid hydrochloride
10- ((tert-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
102 hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-methyl-l l-((methylamino)methyl)-2-oxo-2,5,6,7,8,10-hexahydro-lH-
103 pyrido[2',3':4,5]azocino[3,2-f]indole-3-carboxylic acid hydrochloride
11- ((ethylamino)methyl)-4-hydroxy-10-methyl-2-oxo-2,5, 6,7,8, 10-hexahydro-lh-
104 pyrido[2',3':4,5]azocino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-l l-((isopropylamino)methyl)-10-methyl-2-oxo-2,5, 6,7,8, 10-hexahydro-
105 lH-pyrido[2',3':4,5]azocino[3,2-f]indole-3-carboxylic acid hydrochloride
8-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-5-methyl-2-oxo- 1,2,5,6-
109 tetrahydrobenzo[h]quinoline-3-carboxylic acid hydrochloride
8- ((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl-2-oxo-
110 l,2,5,6-tetrahydrobenzo[h]quinoline-3-carboxylic acid trifluoroacetate
9- (l,4-diazepan-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH-
111 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride Cpd Name
4-hydroxy-9-(4-methyl-l,4-diazepan-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH-
112 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9-((2-(dimethylamino)ethyl)amino)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH-
113 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9-((4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-4-hydroxy-2-oxo- 2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
114 hydrochloride
4-hydroxy-9-((4aR,7aR)-l-methylhexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2- oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
115 hydrochloride
9-(4-(dimethylamino)piperidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH-
116 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9-(3-(dimethylamino)piperidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH-
117 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-9-(piperidin-4-ylamino)-2,5,6,7-tetrahydro-lH-
118 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-9-(piperazin- l-yl)-2,5,6,7-tetrahydro- 1H-
119 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-(4-methylpiperazin-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH-
120 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-9-(2,6-diazaspiro[3.4]octan-6-yl)-2,5,6,7-tetrahydro-lH-
121 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-9-(2,7-diazaspiro[4.4]nonan-2-yl)-2,5,6,7-tetrahydro-lH-
122 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-oxo-2,5,6,7-tetrahydro-lH-
123 benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride Cpd Name
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-10,l l-difluoro-4-hydroxy-2- oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
124 hydrochloride
9- ((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-l l-fluoro-4-hydroxy-2-oxo- 2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
125 hydrochloride
10- ((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo- 1,2,5,6,7, 8- 127 hexahydrobenzo[7,8]cycloocta[l,2-b]pyridine-3-carboxylic acid hydrochloride
10-((butylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7, 9-
136 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-((pentylamino)methyl)- 1,2,5,6,7, 9-
137 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-((hexylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
138 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((heptylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
139 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((octylamino)methyl)-2-oxo- 1,2,5,6,7,9-
140 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((nonylamino)methyl)-2-oxo- 1,2,5,6,7,9-
141 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-(((2-(dimethylamino)ethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
142 dihydrochloride
4-hydroxy-9-methyl-10-(((2-(methylamino)ethyl)amino)methyl)-2-oxo-l,2,5,6,7,9-
143 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid dihydrochloride
10-(((2-aminoethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9-
144 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid dihydrochloride Cpd Name
10-(((2-(dimethylamino)ethyl)(m
l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
145 dihydrochloride
10-((sec-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9-
146 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-10-(((2-hydroxyethyl)amino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9-
147 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-10-(((2-methoxyethyl)amino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9-
148 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-10-(((2-hydroxyethyl)(methyl)amino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7, 9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
149 hydrochloride
4-hydroxy-10-(((l-methoxypropan-2-yl)amino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9-
150 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-(((l-hydroxypropan-2-yl)amino)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9-
151 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-(((2-(pyrrolidin-l-yl)ethyl)amino)methyl)- 1,2,5,6,7,9-
152 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid dihydrochloride
10-((allylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
153 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-10-((isobutylamino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9-
154 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((neopentylamino)methyl)-2-oxo- 1,2,5,6,7,9-
155 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl- 10-((4-methyl- 1 ,4-diazepan- 1 -yl)methyl)-2-oxo- 1 ,2,5,6,7,9-
156 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid dihydrochloride
4-hydroxy-9-methyl-10-(((l-methylpiperidin-4-yl)amino)methyl)-2-oxo-l,2,5,6,7,9-
157 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid dihydrochloride Cpd Name
4-hydroxy-10-((3-methoxypyrrolidin-l-yl)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9-
158 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-((3-acetamidopyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9-
159 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-(((l-(dimethylamino)propan-2-yl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
160 dihydrochloride
4-hydroxy-9-methyl-2-oxo-10-((((tetrahydrofuran-2-yl)methyl)amino)methyl)- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
161 hydrochloride
4-hydroxy-9-methyl-10-((l-methylhexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl)methyl)- 2-oxo- 1,2,5, 6,7, 9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic
162 acid dihydrochloride
10-(((2-(dimethylamino)-2-oxoethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
163 hydrochloride
10-(2-(ethylamino)ethyl)-4-hydroxy-9-methyl-2-oxo-l,2,5,9-
164 tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid trifluoroacetate
10-(2-(ethylamino)ethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7, 9-
165 hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid trifluoroacetate
4-hydroxy-9-(((cis)-octahydrocyclopenta[c]pyrrol-4-yl)-(cis)-amino)-2-oxo- 1,2,5,6-
166 tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo-2,5,6,9-
167 tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-((sec-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-
168 pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-((propylamino)methyl)-2,5,6,9-tetrahydro-lH-
169 pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride Cpd Name
10-(((2,4-dimethoxybenzyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-
170 tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-((cyclopropylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-
171 pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
10-((cyclobutylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-
172 pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
10-((dimethylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-
173 pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-2,5,6,9-tetrahydro-lH-
174 pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
10-((tert-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-
175 pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((4-methylpiperazin-l-yl)methyl)-2-oxo-2,5,6,9-tetrahydro- J7g lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid dihydrochloride
4-hydroxy-10-(((2-hydroxyethyl)amino)methyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-10-(((l-hydroxypropan-2-yl)amino)methyl)-9-methyl-2-oxo-2,5,6,9- J78 tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-(((2-(pyrrolidin-l-yl)ethyl)amino)methyl)-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
J79 dihydrochloride
10-(((2-aminoethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro- J80 lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid dihydrochloride
4-hydroxy-9-methyl-10-(((2-(methylamino)ethyl)amino)methyl)-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
J81 dihydrochloride Cpd Name
10-(((2-(dimethylamino)ethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
182 dihydrochloride
4-hydroxy-10-(((2-methoxyethyl)amino)methyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro-
183 lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride, and
4-hydroxy-10-(((l-methoxypropan-2-yl)amino)methyl)-9-methyl-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
184 hydrochloride; wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In another embodiment of the use of the present description, the compound or a form thereof is isolated for use.
Chemical Definitions
The chemical terms used above and throughout the description herein, unless specifically defined otherwise, shall be understood by one of ordinary skill in the art to have the following indicated meanings.
As used herein, the term "Ci-ioalkyl" generally refers to saturated hydrocarbon radicals having from one to ten carbon atoms in a straight or branched chain configuration, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. In some embodiments, Ci-ioalkyl includes Ci^alkyl, C1-6alkyl, Ci^alkyl and the like. A Ci-ioalkyl radical may be optionally substituted where allowed by available valences.
As used herein, the term "C2-8alkenyl" generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, without limitation, ethenyl, allyl, propenyl and the like. In some embodiments, C2-8alkenyl includes C2-6alkenyl, C2-4alkenyl and the like. A C2-8alkenyl radical may be optionally substituted where allowed by available valences. As used herein, the term "C2-8alkynyl" generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon triple bonds therein, including, without limitation, ethynyl, propynyl and the like. In some embodiments, C2-8alkynyl includes C2-6alkynyl, C2-4alkynyl and the like. A C2-8alkynyl radical may be optionally substituted where allowed by available valences.
As used herein, the term "Ci-salkoxy" generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration of the formula: -O-Ci-galkyl, including, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like. In some embodiments, Ci^alkoxy includes Ci^alkoxy, Ci-^alkoxy and the like. A
Ci-8alkoxy radical may be optionally substituted where allowed by available valences.
As used herein, the term "C3_14cycloalkyl" generally refers to a saturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, lH-indanyl, indenyl, tetrahydro-naphthalenyl and the like. In some embodiments, C3_14cycloalkyl includes C3_gcycloalkyl, Cs-gcycloalkyl, Cs-iocycloalkyl and the like. A C3_14cycloalkyl radical may be optionally substituted where allowed by available valences.
As used herein, the term "aryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like. An aryl radical may be optionally substituted where allowed by available valences.
As used herein, the term "heteroaryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S or N atom, including, without limitation, furanyl, thienyl (also referred to as thiophenyl), pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, 9H-purinyl, quinoxalinyl, isoindolyl, quinolinyl, isoquinolinyl, quinazolinyl, acridinyl and the like. A heteroaryl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences. As used herein, the term "heterocyclyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with a heteroatom, such as an O, S or N atom, including, without limitation, oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl,
tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, dihydropyrazolyl, pyrazolinyl, pyrazolidinyl, dihydroimidazolyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, dihydro-2H-pyranyl, dihydro-pyridinyl, tetrahydro-pyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydro-pyridinyl, dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, 1,4,5,6- tetrahydropyrimidinyl, dihydro-pyrazinyl, tetrahydro-pyrazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl,
dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl, 1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl, dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl, dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl,
tetrahydro-benzothienyl, dihydro-benzimidazolyl, tetrahydro-benzimidazolyl,
dihydro-benzooxazolyl, 2,3-dihydrobenzo[d]oxazolyl, tetrahydro-benzooxazolyl,
dihydro-benzooxazinyl, 3,4-dihydro-2H-benzo[b] [ 1 ,4] oxazinyl, tetrahydro-benzooxazinyl, benzo[l,3]dioxolyl, benzo[l,4]dioxanyl, dihydro-purinyl, tetrahydro-purinyl,
dihydro-quinolinyl, tetrahydro-quinolinyl, 1 ,2,3,4-tetrahydroquinolinyl,
dihydro-isoquinolinyl, 3,4-dihydroisoquinolin-(lH)-yl, tetrahydro-isoquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, dihydro-quinazolinyl, tetrahydro-quinazolinyl, dihydro-quinoxalinyl, tetrahydro-quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dioxolanyl, 2,5-dihydro-lH- pyrrolyl, dihydro-lH-imidazolyl, tetrahydro-2H-pyranyl, hexahydropyrrolo[3,4- b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4-b][l,4]oxazin-(4aH)-yl, 3,4-dihydro- 2H-pyrido [3, 2-b][ 1,4] oxazinyl, (cis)-octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4- b]pyrrol-(lH)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H- pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9-tetrahydro-lH-carbazolyl, 1,2,3,4- tetrahydropyrazino[ 1 ,2-a]indolyl, 2,3-dihydro- lH-pyrrolo[ 1 ,2-a]indolyl, (3aR,6aR)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-l,3,3a,4,5,6-hexahydro- 2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)- octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro- 2H-isoindolyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]hept-5-enyl, 3- azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexanyl, (cis,cis)-3-azabicyclo[3.1.0]hexanyl, (lS,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl and the like. A heterocyclyl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.
As used herein, the term
Figure imgf000074_0001
refers to a radical of the formula: -C1-8alkyl-NH-C2-8alkenyl.
As used herein, the term "C1-8alkoxy-C1-8aLky ' refers to a radical of the formula: -Ci_8alkyl-0-Ci_8alkyl.
As used herein, the term "C1-8alkoxy-C1-8alkyl-anu^o-C1-8alky ' refers to a radical of the formula: -Ci-8alk l-NH-Ci-8alkyl-0-Ci-8alkyl.
As used herein, the term "Ci-galkoxy-carbonyl" refers to a radical of the formula:
-C(0)-0-Ci_8alkyl.
As used herein, the term "Ci-galkyl-amino" refers to a radical of the formula:
-NH-Ci-galkyl.
As used herein, the term "(C1-8alkyl)2-amino" refers to a radical of the formula:
-N(C1_8alkyl)2.
As used herein, the term "Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl.
As used herein, the term "Ci-ioalkyl-amino-Ci-galkyl" refers to a radical of the formula: -C1-8alkyl-NH-C1-10alkyl.
As used herein, the term "(C1_galkyl)2-amino-C1_galkyl" refers to a radical of the formula: -C1_galkyl-N(C1_galkyl)2.
As used herein, the term "(C1_galkyl)2-amino-C1_galkyl-amino" refers to a radical of the formula: -NH-C1_galkyl-N(C1_galkyl)2. As used herein, the term "Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-NH-C1-8alkyl.
As used herein, the term "(Ci-galkyl amino-^galkyl-amino-Ci-galkyl" refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-N(C1-8alkyl)2.
As used herein, the term "[(C1_8alkyl)2-amino-C1_8alkyl,C1_8alkyl]amino-C1_8alkyl" refers to a radical of the formula: -C1_8alkyl-N{ (C1_8alkyl)[C1_8alkyl-N(C1_8alkyl)2] }.
As used herein, the term "(C1-8alkyl)2-amino-carbonyl-C1-8alkyl-amino-C1_8alkyl" refers to a radical of the formula: -C1-8alkyl-NH-C1_8alkyl-C(0)-N(C1-8alkyl)2.
As used herein, the term "Ci-galkyl-carbonyl-amino" refers to a radical of the formula: -NH-C(0)-Ci_8alkyl.
As used herein, the term "Ci-salkyl-thio" refers to a radical of the formula:
-S-Ci-ealkyl.
As used herein, the term "C^galkynyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-C^galkynyl.
As used herein, the term "amino" refers to a radical of the formula: -NH2.
As used herein, the term "amino-Ci-salkyl" refers to a radical of the formula:
-Ci_8alkyl-NH2.
As used herein, the term "amino-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -C1-8alkyl-NH-C1_8alkyl-NH2.
As used herein, the term "aryl-Ci-salkoxy" refers to a radical of the formula:
-O-Ci-salkyl-aryl.
As used herein, the term "aryl-Ci-galkyl" refers to a radical of the formula:
-Ci-salkyl-aryl.
As used herein, the term "aryl-Ci-salkyl-amino" refers to a radical of the formula: -NH-Ci-galkyl-aryl.
As used herein, the term "(aryl-C1_galkyl)2-amino" refers to a radical of the formula: -N[(Ci_8alkyl-aryl)2].
As used herein, the term "aryl-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-aryl.
As used herein, the term "(aryl-Ci-galky^Ci-galky^amino" refers to a radical of the formula: -N[(Ci-8alkyl)(Ci-8alkyl-aryl)] .
As used herein, the term "azido" refers to a radical of the formula: -N=N+=N". As used herein, the term "carboxyl" refers to a radical of the formula: -COOH, -C(0)OH or -C02H.
As used herein, the term "Cs-Mcycloalkyl-amino-Ci-galkyl" refers to a radical of the formula:
Figure imgf000076_0001
As used herein, the term "Cs-Hcycloalkyl-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-Cs-Hcycloalkyl.
As used herein, the term "halo" or "halogen" generally refers to a halogen atom radical, including fluoro, chloro, bromo and iodo.
As used herein, the term "halo-Ci-galkoxy" refers to a radical of the formula:
-O-Ci-galkyl-halo, wherein Ci-galkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms. In some embodiments, halo-Ci-galkoxy includes halo-C i^alkoxy, halo-Ci^alkoxy and the like.
As used herein, the term "halo-Ci-galkyl" refers to a radical of the formula:
-Ci-galkyl-halo, wherein Ci-galkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms. In some embodiments, halo-Ci-galkyl includes halo-Ci-ealkyl, halo-C 1_4alkyl and the like.
As used herein, the term "heteroaryl-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-heteroaryl.
As used herein, the term "heterocyclyl-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-heterocyclyl.
As used herein, the term "heterocyclyl-amino" refers to a radical of the formula: -NH-heterocyclyl.
As used herein, the term "heterocyclyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-heterocyclyl.
As used herein, the term "heterocyclyl-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-heterocyclyl.
As used herein, the term "heterocyclyl-oxy" refers to a radical of the formula:
-O-heterocyclyl.
As used herein, the term "hydroxyl-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-OH, wherein Ci-galkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term "(hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-N Ci-galkylXCi-galkyl-OH)], wherein Ci-galkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term "substituent" means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown.
As used herein, the term "and the like," with reference to the definitions of chemical terms provided herein, means that variations in chemical structures that could be expected by one skilled in the art include, without limitation, isomers (including chain, branching or positional structural isomers), hydration of ring systems (including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations where allowed by available valences which result in a stable compound.
For the purposes of this description, where one or more substituent variables for a compound of Formula (I) or Formula (II) encompass functionalities incorporated into a compound of Formula (I) or Formula (II), each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.
As used herein, the terms "independently selected," or "each selected" refer to functional variables in a substituent list that may occur more than once on the structure of Formula (I) or Formula (II) or a form thereof, the pattern of substitution at each occurrence is independent of the pattern at any other occurrence. Further, the use of a generic substituent variable on any formula or structure for a compound described herein is understood to include the replacement of the generic substituent with species substituents that are included within the particular genus, e.g., aryl may be replaced with phenyl or naphthalenyl and the like, and that the resulting compound is to be included within the scope of the compounds described herein.
As used herein, the terms "each instance of or "in each instance, when present," when used preceding a phrase such as "...aryl, aryl-Ci-galkyl, heterocyclyl and heterocyclyl-Ci-galkyl, are intended to refer to the aryl and heterocyclyl ring systems and the like when each are present either alone or as a substituent.
As used herein, the term "optionally substituted" means optional substitution with the specified substituent variables, groups, radicals or moieties.
As used herein, the terms "stable compound' or "stable structure" mean a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulations thereof into an efficacious therapeutic agent.
Compound names used herein were obtained using the ACD Labs Index Name software provided by ACD Labs; and/or, were obtained using the naming function of ChemDraw Ultra provided by CambridgeSoft. When the compound name disclosed herein conflicts with the structure depicted, the structure shown will supercede the use of the name to define the compound intended.
Compound Forms
As used herein, the term "form" means a compound of Formula (I) or Formula (II) having a form selected from the group consisting of a free acid, free base, prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In certain embodiments described herein, the form of the compound of Formula (I) or Formula (II) is a free acid, free base or salt thereof.
In certain embodiments described herein, the form of the compound of Formula (I) or
Formula (II) is a salt thereof.
In certain embodiments described herein, the form of the compound of Formula (I) or Formula (II) is an isotopologue thereof.
In certain embodiments described herein, the form of the compound of Formula (I) or Formula (II) is a stereoisomer, racemate, enantiomer or diastereomer thereof.
In certain embodiments described herein, the form of the compound of Formula (I) or Formula (II) is a tautomer thereof.
In certain embodiments described herein, the form of the compound of Formula (I) or Formula (II) is a pharmaceutically acceptable form.
In certain embodiments described herein, the compound of Formula (I) or Formula
(II) or a form thereof is isolated for use.
As used herein, the term "isolated" means the physical state of a compound of Formula (I) or Formula (II) or a form thereof after being isolated and/or purified from a synthetic process (e.g., from a reaction mixture) or natural source or combination thereof according to an isolation or purification process or processes described herein or which are well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
As used herein, the term "protected" means that a functional group in a compound of Formula (I) or Formula (II) or a form thereof is in a form modified to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T.W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.
Prodrugs and solvates of the compounds described herein are also contemplated. As used herein, the term "prodrug" means a form of an instant compound (e.g., a drug precursor) that is transformed in vivo to yield an active compound of Formula (I) or Formula (II) or a form thereof. The transformation may occur by various mechanisms (e.g., by metabolic and/or non-metabolic chemical processes), such as, for example, by hydrolysis and/or metabolism in blood, liver and/or other organs and tissues. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
In one example, when a compound of Formula (I) or Formula (II) or a form thereof contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a functional group such as alkyl and the like. In another example, when a compound of Formula (I) or Formula (II) or a form thereof contains a hydroxyl functional group, a prodrug form can be prepared by replacing the hydrogen atom of the hydroxyl with another functional group such as alkyl, alkylcarbonyl or a phosphonate ester and the like. In another example, when a compound of Formula (I) or Formula (II) or a form thereof contains an amine functional group, a prodrug form can be prepared by replacing one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl. Pharmaceutically acceptable prodrugs of compounds of
Formula (I) or Formula (II) or a form thereof include those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid esters, phosphonate esters and mono-, di- or triphosphate esters or alkyl substituents, where appropriate. As described herein, it is understood by a person of ordinary skill in the art that one or more of such substituents may be used to provide a compound of Formula (I) or Formula (II) or a form thereof as a prodrug.
One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to embrace both solvated and unsolvated forms.
As used herein, the term "solvate" means a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. As used herein, "solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
One or more compounds described herein may optionally be converted to a solvate. Preparation of solvates is generally known. The preparation of solvates of the antifungal fluconazole in ethyl acetate as well as from water has been described (see, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004)). Similar preparations of solvates, hemisolvate, hydrates and the like have also been described (see, E.C. van Tonder et al, AAPS
PharmSciTech., 5(1), article 12 (2004); and A.L. Bingham et al, Chem. Commun., 603-604 (2001)). A typical, non-limiting process involves dissolving a compound in a desired amount of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example infrared spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
As used herein, the term "hydrate" means a solvate wherein the solvent molecule is water.
The compounds of Formula (I) or Formula (II) can form salts, which are intended to be included within the scope of this description. Reference to a compound of Formula (I) or Formula (II) or a form thereof herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula (I) or Formula (II) or a form thereof contains both a basic moiety, such as, without limitation an amine moiety, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein.
The term "pharmaceutically acceptable salt(s)", as used herein, means those salts of compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful. Salts of the compounds of the Formula (I) or Formula (II) may be formed, for example, by reacting a compound of Formula (I) or Formula (II) or a form thereof with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in compounds described herein. Embodiments of acid addition salts include, and are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate salts and the like. Certain embodiments of acid addition salts include chloride, bromide, acetate or trifluoroacetate salts.
Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International ], of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium and zinc salts. Certain compounds described herein can also form pharmaceutically acceptable salts with organic bases (for example, organic amines) such as, but not limited to, dicyclohexylamines, t-butyl amines and the like, and with various amino acids such as, but not limited to, arginine, lysine and the like. Basic nitrogen- containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides) and the like.
All such acid salts and base salts are intended to be included within the scope of pharmaceutically acceptable salts as described herein. In addition, all such acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of this description.
Compounds of Formula (I) or Formula (II) and forms thereof, may further exist in a tautomeric form (for example, the 4-hydroxy-2-pyridinone core of Formula (I) and Formula (II) may exist in either the 2,4-dihydroxy-pyridine or the 2-hydroxy-4-pyridinone form). All such tautomeric forms are contemplated and intended to be included within the scope of the compounds of Formula (I) or Formula (II) or a form thereof as described herein.
The compounds of Formula (I) or Formula (II) or a form thereof may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. The present description is intended to include all stereoisomeric forms of the compounds of Formula (I) or Formula (II) as well as mixtures thereof, including racemic mixtures.
The compounds described herein may include one or more chiral centers, and as such may exist as racemic mixtures (R/S) or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (when one chiral center is present). In one embodiment, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer. In another embodiment, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer. As one of skill in the art will recognize, when more than one chiral center is present, the compounds described herein may also exist as a (R,R), (R,S), (S,R) or (S,S) isomer, as defined by IUPAC Nomenclature Recommendations.
As used herein, the term "substantially pure" refers to compounds consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.
In one aspect of the description, a compound of Formula (I) or Formula (II) or a form thereof is a substantially pure (S) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
In one aspect of the description, a compound of Formula (I) or Formula (II) or a form thereof is a substantially pure (R) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
As used herein, a "racemate" is any mixture of isometric forms that are not
"enantiomeric ally pure", including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, or about 80/20.
In addition, the present description embraces all geometric and positional isomers. For example, if a compound of Formula (I) or Formula (II) or a form thereof incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the description. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by use of chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher' s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) or Formula (II) or a form thereof may be atropisomers (e.g. , substituted biaryls) and are considered as part of this description.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this description, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as described supra.
The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, isotopologues or prodrugs of the instant compounds.
The term "isotopologue" refers to isotopically-enriched compounds described herein which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, 35C1 and 36C1, respectively, each of which are also within the scope of this description.
Certain isotopically-enriched compounds described herein (e.g., those labeled with H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon- 14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
Polymorphic crystalline and amorphous forms of the compounds of Formula (I) or Formula (II) and of the salts, solvates, hydrates, esters and prodrugs of the compounds of Formula (I) or Formula (II) are further intended to be included in the present description. Compound Uses
The present description relates to a method of use for a compound of Formula (I) or
Formula (II) or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound or a form thereof to the subject.
The present description further relates to use of the compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof. The present description further relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity toward wild-type or drug-resistant
N. gonorrhoeae .
The present description also relates to use of a compound of Formula (I) or Formula (II) or a form thereof having activity against aminoglycoside-resistant, beta-lactam-resistant, cephalosporin-resistant, macrolide-resistant, quinolone-resistant or tetracycline-resistant N. gonorrhoeae .
The present description also relates to use of a compound of Formula (I) or Formula (II) or a form thereof having activity against aminoglycoside-resistant (including drug- resistant forms of N. gonorrhoeae that are spectinomycin-resistant, streptomycin-resistant, and the like), beta-lactam-resistant (including drug-resistant forms of N. gonorrhoeae that are ampicillin-resistant, penicillin-resistant, and the like), cephalosporin-resistant (including drug-resistant forms of N. gonorrhoeae that are ceftriaxone-resistant, cefixime-resistant, and the like), macrolide-resistant (including drug-resistant forms of N. gonorrhoeae that are azithromycin-resistant, and the like), quinolone-resistant (including drug-resistant forms of N. gonorrhoeae that are ciprofloxacin-resistant, and the like) or tetracycline-resistant N. gonorrhoeae (including drug-resistant forms of N. gonorrhoeae that are tetracycline- resistant).
The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against ampicillin-resistant, azithromycin-resistant, ceftriaxone-resistant, cefixime-resistant, ciprofloxacin-resistant, penicillin-resistant, spectinomycin-resistant, streptomycin-resistant and tetracycline-resistant forms of
N. gonorrhoeae .
The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against aminoglycoside-resistant forms of
N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against beta-lactam-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against cephalosporin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against macrolide-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against quinolone-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against tetracycline-resistant forms of N. gonorrhoeae .
The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against ampicillin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against azithromycin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against ceftriaxone-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against cefixime-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against ciprofloxacin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against penicillin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against spectinomycin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against streptomycin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I) or Formula (II) or a form thereof having activity against tetracycline-resistant forms of N. gonorrhoeae.
The present description further relates to use of the compound of Formula (I) or Formula (II) or a form thereof in a combination therapy with known antibacterial or antibiotic agents to provide additive or synergistic activity, thus enabling the development of a combination product for the treatment of a wild-type or drug-resistant form of
N. gonorrhoeae.
The compounds of the present description have demonstrated an ability to inhibit the replication of a wide variety of N. gonorrhoeae isolates. The instant compounds possess in vitro activity against a wide spectrum of N. gonorrhoeae isolates which have developed resistance to almost all known treatments and are expected to successfully treat wild-type or drug-resistant forms of N. gonorrhoeae compared to current antibacterial agents. The compounds are also effective in vivo and lack cellular toxicity. In addition to
monotherapeutic use, the instant compounds are useful in a combination therapy with current standard of care antibacterial or antibiotic agents, having additive or synergistic activity with one or more known antibacterial or antibiotic agents.
A combination therapy comprising compounds described herein in combination with one or more known antibacterial or antibiotic drugs may be used to treat wild-type or drug- resistant forms of N. gonorrhoeae regardless of whether N. gonorrhoeae is resistant or responsive to the known antibacterial or antibiotic drug.
Embodiments of the present description include the use of a compound of Formula (I) or Formula (II) or a form thereof in a combination therapy for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof and an effective amount of one or more antibiotic or antibacterial agent(s).
Embodiments of the present description include the use of a compound of Formula (I) or Formula (II) or a form thereof in a combination therapy for treating or ameliorating wild- type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof and an effective amount of one or more antibiotic or antibacterial agent(s).
An embodiment of the present description includes the use of a compound of Formula (I) or Formula (II) or a form thereof in the preparation of a kit comprising the compound of Formula (I) or Formula (II) or a form thereof and instructions for administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof and an effective amount of one or more antibiotic or antibacterial agent(s) in a combination therapy for treating or ameliorating N. gonorrhoeae in a subject in need thereof.
In one embodiment, the agents used in the combination therapy may include, without limitation, one or more agents selected from Amikacin, Amoxicillin, Ampicillin,
Arsphenamine, Azithromycin, Azlocillin, Aztreonam, Bacitracin, Capreomycin,
Carbenicillin, Cefaclor, Cefadroxil, Cefalexin, Cefalotin, Cefamandole, Cefazolin, Cefdinir, Cefditoren, Cefixime, Cefoperazone, Cefotaxime, Cefoxitin, Cefpodoxime, Cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Chloramphenicol, Cilastatin, Ciprofloxacin, Clarithromycin, Clavulanate, Clindamycin, Clofazimine, CloxaciUin, Colistin, Cycloserine, Dalfopristin, Dapsone, Daptomycin, Dicloxacillin, Dirithromycin, Doripenem, Doxycycline, Enoxacin, Erythromycin, Ethambutol, Ethionamide, Flucloxacillin,
Fosfomycin, Furazolidone, Fusidic acid, Gatifloxacin, Gemifloxacin, Gentamicin, Imipenem, Isoniazid, Kanamycin, Levofloxacin, Lincomycin, Linezolid, Lomefloxacin, Loracarbef, Mafenide, Meropenem, MethiciUin, Metronidazole, Mezlocillin, Minocycline, Moxifloxacin, Mupirocin, Nafcillin, Nalidixic acid, Neomycin, Netilmicin, Nitrofurantoin, Norfloxacin, Ofloxacin, Oxacillin, Oxytetracycline, Paromomycin, Penicillin G, Penicillin V, Piperacillin, Platensimycin, Polymyxin B, Pyrazinamide, Quinupristin, Rapamycin, Rifabutin, Rifampicin, Rifampin, Rifapentine, Rifaximin, Roxithromycin, Silver sulfadiazine, Solithromycin, Spectinomycin, Streptomycin, Sulbactam, Sulfacetamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfanamide, Sulfasalazine, Sulfisoxazole, Tazobactam, Teicoplanin, Telavancin, Telithromycin, Temocillin, Tetracycline, Thiamphenicol, TicarciUin,
Tigecycline, Tinidazole, Tobramycin, Trimethoprim, Troleandomycin or Vancomycin.
In another embodiment, the agents used in the combination therapy may include, without limitation, one or more agents selected from Amikacin, Amoxicillin, Arsphenamine, Azlocillin, Aztreonam, Bacitracin, Capreomycin, Carbenicillin, Cefaclor, Cefadroxil, Cefalexin, Cefalotin (Cefalothin), Cefamandole, Cefazolin, Cefdinir, Cefditoren,
Cefoperazone, Cefotaxime, Cefoxitin, Cefpodoxime, Cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Cefuroxime, Chloramphenicol, Cilastatin, Clarithromycin, Clavulanate, Clindamycin, Clofazimine, Cloxacillin, Colistin, Cycloserine, Dalfopristin, Dapsone, Daptomycin, Dicloxacillin, Dirithromycin, Doripenem, Doxycycline, Enoxacin,
Erythromycin, Ethambutol, Ethionamide, Flucloxacillin, Fosfomycin, Furazolidone, Fusidic acid, Gatifloxacin, Gemifloxacin, Gentamicin, Imipenem, Isoniazid, Kanamycin,
Levofloxacin, Lincomycin, Linezolid, Lomefloxacin, Loracarbef, Mafenide, Meropenem, MethiciUin, Metronidazole, Mezlocillin, Minocycline, Moxifloxacin, Mupirocin, Nafcillin, Nalidixic acid, Neomycin, Netilmicin, Nitrofurantoin, Norfloxacin, Ofloxacin, Oxacillin, Oxytetracycline, Paromomycin, Piperacillin, Platensimycin, Polymyxin B, Pyrazinamide, Quinupristin, Rapamycin, Rifabutin, Rifampicin, Rifampin, Rifapentine, Rifaximin,
Roxithromycin, Silver sulfadiazine, Solithromycin, Sulbactam, Sulfacetamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfanamide, Sulfasalazine, Sulfisoxazole, Tazobactam, Teicoplanin, Telavancin, Telithromycin, Temocillin, Thiamphenicol, TicarciUin, Tigecycline, Tinidazole, Tobramycin, Trimethoprim, Troleandomycin or Vancomycin.
In another embodiment, the agents used in the combination therapy may include, without limitation, one or more agents selected from Amoxicillin, Ampicillin, Azithromycin, Ciprofloxacin, Doxycycline, Enoxacin, Erythromycin, Gatifloxacin, Gemifloxacin,
Gentamicin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Rapamycin, Solithromycin, Spectinomycin, Streptomycin, Tetracycline or Vancomycin.
In another embodiment, the agents used in the combination therapy may particularly include one or more agents selected from Amoxicillin, Azithromycin, Ciprofloxacin, Doxycycline, Enoxacin, Erythromycin, Gatifloxacin, Gemifloxacin, Gentamicin,
Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin,
Rapamycin, Solithromycin or Vancomycin.
In another embodiment, the agents used in the combination therapy may include, without limitation, one or more agents selected from Ampicillin, Azithromycin, Cefixime, Ceftriaxone, Ciprofloxacin, Penicillin G, Penicillin V, Spectinomycin, Streptomycin or Tetracycline.
Accordingly, the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating wild-type forms of
N. gonorrhoeae, for treating or ameliorating drug-resistant forms of N. gonorrhoeae or for treating or ameliorating multi-drug resistant forms of N. gonorrhoeae.
One embodiment of the use of the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
An embodiment of the use of the present description relates to use of a compound of
Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae resulting from wild-type forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
An embodiment of the use of the present description relates to use of a compound of
Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae resulting from drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
One embodiment of the use of the present description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound to the subject. One embodiment of the use of the present description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating wild- type or drug-resistant forms N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound to the subject.
An embodiment of the use of the present description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating wild- type forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound to the subject.
An embodiment of the use of the present description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating drug- resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof in the manufacture of a medicament for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof in the manufacture of a medicament for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof in the manufacture of a medicament for treating or ameliorating wild-type forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
An embodiment of the use of the present description relates to use of a compound of
Formula (I) or Formula (II) or a form thereof in the manufacture of a medicament for treating or ameliorating drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (I) or Formula (II) or a form thereof in the preparation of a kit comprising the compound of Formula (I) or Formula (II) or a form thereof and instructions for administering the compound for treating or ameliorating N. gonorrhoeae in a subject in need thereof. An embodiment of the use of the present description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I) or Formula (II) or a form thereof to the subject.
An embodiment of the use of the present description relates to use of a compound of
Formula (I) or Formula (II) or a form thereof in the manufacture of a medicament for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the the medicament to the subject.
In one respect, for each of such embodiments, the subject is treatment naive. In another respect, for each of such embodiments, the subject is not treatment naive.
As used herein, the term "treating" refers to: (i) preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having the disease, disorder and/or condition; (ii) inhibiting a disease, disorder or condition, i.e., arresting the development thereof; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
As used herein, the term "subject" refers to an animal or any living organism having sensation and the power of voluntary movement, and which requires oxygen and organic food. Nonlimiting examples include members of the human, primate, equine, porcine, bovine, murine, rattus, canine and feline specie. In some embodiments, the subject is a mammal or a warm-blooded vertebrate animal. In other embodiments, the subject is a human. As used herein, the term "patient" may be used interchangeably with "subject" and "human".
Another aspect of the description particularly relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae resulting from wild type forms of N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof.
Another aspect of the description particularly relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating
N. gonorrhoeae resulting from drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof. One aspect of the description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against N. gonorrhoeae clinical isolates and their derivatives selected from ATCC penicillin-sensitive wild-type N. gonorrhoeae FA19 (ATCC BAA-1838), ATCC streptomycin-resistant (streptomycinR) N. gonorrhoeae FA1090 (ATCC 700825; GenBank Acc. No. AE004969), ATCC
N. gonorrhoeae MS 11 (ATCC BAA- 1833) and ATCC wild- type N. gonorrhoeae 49226 (ATCC 49226) (see, http://www.atcc.org).
Another aspect of the description relates to a method of use for a compound of
Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against
N. gonorrhoeae isolates engineered from clinical isolate FA 19 to contain mutations in gyrA and parC, including those selected from ciprofloxacin-resistant (ciprofloxacin )
N. gonorrhoeae AK1 (gyrAgws) and ciprofloxacin N. gonorrhoeae AK2 (gyrAgws, parC%e) (see, Anjali N. Kunz, Afrin A. Begum, Hong Wu, Jonathan A. D'Ambrozio, James M.
Robinson, William M. Shafer, Margaret C. Bash and Ann E. Jerse. Impact of
Fluoroquinolone Resistance Mutations on Gonococcal Fitness and In Vivo Selection for Compensatory Mutations. J. Infect Dis., 2012, Jun 15; 205(12): 1821-9).
Another aspect of the description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against
N. gonorrhoeae World Health Organization (WHO) isolates selected from: tetracycline ER N. gonorrhoeae 13477 (WHO tetracycline intermediate resistant isolate F),
ciprofloxacin ER /tetracycline R N. gonorrhoeae 13478 (WHO ciprofloxacin intermediate resistant and tetracycline resistant isolate G), quinoline HLR N. gonorrhoeae 13479 (WHO quinolone high level resistant isolate K), MDR N. gonorrhoeae 13480 (WHO multi-drug resistant isolate L) and MD∑R N. gonorrhoeae 13481 (WHO multi-drug intermediate resistant isolate M) (see, Unemo M, Fasth O, Fredlund H, Limnios A, Tapsall J. Phenotypic and genetic characterization of the 2008 WHO Neisseria gonorrhoeae reference strain panel intended for global quality assurance and quality control of gonococcal antimicrobial resistance surveillance for public health purposes. J. Antimicrobial Chemother., 2009, Jun; 63(6): 1142-51).
Another aspect of the description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against the ciprofloxacin XDR /cefixime XDR /ceftriaxone XDR extensively drug resistant N. gonorrhoeae F89 (see, Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother., 2012, Mar; 56(3): 1273-80).
Another aspect of the description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against a
N. gonorrhoeae isolate engineered from WHO isolate F (N. gonorrhoeae 13477), where DNA from FA 1090 was isolated and used to transform 13477 with the streptomycin determinant. The resulting isolate SP1364 is streptomycin at >1250 μg/mL.
Another aspect of the description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against a
N. gonorrhoeae clinical isolate LG24 (see, Garvin LE, Bash MC, Keys C, Warner DM, Ram S, Shafer WM and Jerse AE. Phenotypic and genotypic analyses of Neisseria gonorrhoeae isolates that express frequently recovered PorB PIA variable region types suggest that certain Pla porin sequences confer a selective advantage for urogenital tract infection. Infect Immun., 2008, Aug;76(8):3700-9).
Another aspect of the description relates to a method of use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof having activity against
N. gonorrhoeae clinical isolates selected from penicillin-resistant (penicillin )
N. gonorrhoeae LGB3, tetracycline-resistant (tetracycline ) N. gonorrhoeae LGB24 and ampicillin-resistant (ampicillin ) N. gonorrhoeae LGB50 (see, McKnew DL, Lynn F, Zenilman JM, Bash MC. Porin variation among clinical isolates of N. gonorrhoeae over a 10- year period, as determined by Por variable region typing. J. Infect Dis., 2003, Apr
15;187(8): 1213-22).
An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate wild-type N. gonorrhoeae 49226 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate clinical isolate N. gonorrhoeae LG24 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate N. gonorrhoeae MSI 1 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate ampicillin N. gonorrhoeae LGB50 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate penicillin-sensitive N. gonorrhoeae FA 19 or LGB3 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate streptomycin N. gonorrhoeae FA 1090 or SP1364 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate ciprofloxacin N. gonorrhoeae AK1 or AK2 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate N. gonorrhoeae caused by an isolate selected from 13477, 13478, 13479, 13480 or 13481 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I) or Formula (II) or a form thereof includes a method of use for a compound of Formula (I) or Formula (II) or a form thereof to treat or ameliorate tetracycline N. gonorrhoeae LGB24 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof to the subject.
As used herein, the terms "effective amount" or "therapeutically effective amount" mean an amount of compound of Formula (I) or Formula (II) or a form, composition or medicament thereof effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect in a subject in need thereof.
The dose administered to achieve an effective target plasma concentration may also be administered based upon the weight of the subject or patient. Doses administered on a weight basis may be in the range of about 0.001 mg/kg/day to about 3500 mg/kg/day, or about 0.01 mg/kg/day to about 2000 mg/kg/day, or about 0.01 mg/kg/day to about 1500 mg/kg/day, or about 0.01 mg/kg/day to about 1000 mg/kg/day, or about 0.01 mg/kg/day to about 600 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 300 mg/kg/day, or about 0.015 mg/kg/day to about 200 mg/kg/day, or about 0.02 mg/kg/day to about 100 mg/kg/day, or about 0.025 mg/kg/day to about 100 mg/kg/day, or about 0.03 mg/kg/day to about 100 mg/kg/day, wherein said amount may be orally administered once (once in approximately a 24 hour period), twice (once in approximately a 12 hour period) or thrice (once in approximately an 8 hour period) daily according to subject weight.
In certain embodiments, the effective amount will be in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.1 mg to about 500 mg/kg/day, or about 1.0 mg/day to about 500 mg/kg/day, in single, divided, or a continuous dose for a patient or subject having a weight in a range of between about 40 to about 200 kg (which dose may be adjusted for patients or subjects above or below this range, particularly children under 40 kg). The typical adult subject is expected to have a median weight in a range of about 70 kg.
In another embodiment, where daily doses are adjusted based upon the weight of the subject or patient, compounds described herein may be formulated for delivery at about 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.20, 0.25, 0.30, 0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0, 3.0, 5.0, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400 or 500 mg/kg/day. Daily doses adjusted based upon the weight of the subject or patient may be administered as a single, divided, or continuous dose. In embodiments where a dose of compound is given more than once per day, the dose may be administered twice, thrice, or more per day.
Within the scope of the present description, the "effective amount" of a compound of Formula (I) or Formula (II) or a form thereof for use in the manufacture of a medicament, the preparation of a pharmaceutical kit or in a method of treating or ameliorating N. gonorrhoeae in a subject in need thereof, is intended to include an amount in a range of from about 0.001 mg to about 3500 mg administered daily; 1.0 mg to about 3500 mg administered daily; 1.0 mg to about 1500 mg administered daily; 1.0 mg to about 1000 mg administered daily; 10.0 mg to about 600 mg administered daily; 0.5 mg to about 2000 mg administered daily; or, an amount in a range of from about 5.0 mg to about 300 mg administered daily.
For example, the effective amount may be the amount required to treat
N. gonorrhoeae, or the amount required to inhibit N. gonorrhoeae replication in a subject or, more specifically, in a human. In some instances, the desired effect can be determined by analyzing the presence of bacterial DNA. The effective amount for a subject will depend upon various factors, including the subject's body weight, size and health. Effective amounts for a given patient can be determined by routine experimentation that is within the skill and judgment of the clinician. For any compound, the effective amount can be estimated initially either in cell culture assays or in relevant animal models, such as a mouse, chimpanzee, marmoset or tamarin animal model. Relevant animal models may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g. , ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is therapeutic index, and can be expressed as the ratio, LD50/ED50. In some embodiments, the effective amount is such that a large therapeutic index is achieved. In further embodiments, the dosage is within a range of circulating concentrations that include an ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
More specifically, the concentration-biological effect relationships observed with regard to a compound of Formula (I) or Formula (II) or a form thereof indicate an trough target plasma concentration ranging from approximately 0.001 μg/mL to approximately 50 μg/mL, from approximately 0.01 μg/mL to approximately 20 μg/mL, from approximately 0.05 μg/mL to approximately 10 μg/mL, or from approximately 0.1 μg/mL to approximately 5 μg/mL. To achieve such plasma concentrations, the compounds described herein may be administered at doses that vary, such as, for example, without limitation, from 0.1 ng to 10,000 mg, depending upon the route of administration in single, divided, or continuous doses for a patient weighing between about 10 kg to about 100 kg (which dose may be adjusted for patients within this weight range, particularly for children under 40 kg).
The exact dosage will be determined by the practitioner, in light of factors related to the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, ethinicity, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, experience with other antibacterial therapies, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 2, 3 or 4 days, once every week, or once every two weeks depending on half-life and clearance rate of the particular formulation. The compounds and compositions described herein may be administered to the subject via any drug delivery route known in the art. Nonlimiting examples include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration. Metabolites of the Compounds
Also included within the scope of the present description are the use of in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the description includes the use of compounds produced by a process comprising contacting a compound described herein with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof.
Such products typically are identified by preparing a radio-labeled isotopologue (e.g., 14C or 3H) of a compound described herein, administering the radio-labeled compound in a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal such as a rat, mouse, guinea pig, dog, monkey or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to about 30 hours), and identifying the metabolic conversion products from urine, bile, blood or other biological samples. The conversion products are easily isolated since they are "radiolabeled" by virtue of being isotopically-enriched (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds described herein even if they possess no biological activity of their own.
Pharmaceutical Compositions
Embodiments of the present description include the use of a compound of Formula (I) or Formula (II) or a form thereof in a pharmaceutical composition for treating or ameliorating N. gonorrhoeae in a subject in need thereof comprising administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof in admixture with a pharmaceutically acceptable excipient.
An embodiment of the present description includes the use of a pharmaceutical composition of the compound of Formula (I) or Formula (II) or a form thereof in the preparation of a kit comprising the pharmaceutical composition of the compound of Formula (I) or Formula (II) or a form thereof and instructions for administering the compound for treating or ameliorating N. gonorrhoeae in a subject in need thereof.
As used herein, the term "composition" means a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical composition may be formulated to achieve a physiologically compatible pH, ranging from about pH 3 to about pH 11. In some embodiments, the pharmaceutical composition is formulated to achieve a pH of from about pH 3 to about pH 7. In other embodiments, the pharmaceutical composition is formulated to achieve a pH of from about pH 5 to about pH 8.
The term "pharmaceutically acceptable excipient" refers to an excipient for administration of a pharmaceutical agent, such as the compounds described herein. The term refers to any pharmaceutical excipient that may be administered without undue toxicity. Pharmaceutically acceptable excipients may be determined in part by the particular composition being administered, as well as by the particular mode of administration and/or dosage form. Nonlimiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, etc. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions for the instant compoounds described herein {see, e.g., Remington's Pharmaceutical Sciences).
Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive antibodies. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA;
carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose {e.g., hydroxypropylmethylcellulose, also known as HPMC), stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting or emulsifying agents; pH buffering substances; and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.
The pharmaceutical compositions described herein may be formulated in any form suitable for the intended use described herein. Suitable formulations for oral administration include solids, liquid solutions, emulsions and suspensions, while suitable inhaleable formulations for pulmonary administration include liquids and powders. Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids which can be reconstituted with a physiologically compatible solvent prior to administration.
When intended for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
Pharmaceutically acceptable excipients suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross- linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including
microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
In other embodiments, pharmaceutical compositions described herein may be formulated as suspensions comprising a compound of Formula (I) or Formula (II) or a form thereof in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension. In yet other embodiments, pharmaceutical compositions described herein may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of one or more excipient(s).
Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g. , lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g. , polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g. , heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
The pharmaceutical compositions described herein may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids;
hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
Additionally, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propane-diol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer' s solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
The compounds described herein may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but generally soluble in medium-chain fatty acids (e.g. , caprylic and capric acids) or triglycerides and in propylene glycol esters of medium-chain fatty acids. Thus, contemplated in the description are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, etc.
In some embodiments, the compound described herein is formulated for oral administration in a lipid-based composition suitable for low solubility compounds. Lipid- based formulations can generally enhance the oral bioavailability of such compounds. As such, pharmaceutical compositions described herein may comprise a effective amount of a compound of Formula (I) or Formula (II) or a form thereof, together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or propylene glycol esters thereof (e.g. , propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants, such as polysorbate 20 or 80 (also referred to as Tween 20 or Tween 80, respectively) or polyoxyl 40 hydrogenated castor oil.
In other embodiments, the bioavailability of low solubility compounds may be enhanced using particle size optimization techniques including the preparation of
nanoparticles or nanosuspensions using techniques known to those skilled in art. The compound forms present in such preparations include amorphous, partially amorphous, partially crystalline or crystalline forms.
In alternative embodiments, the pharmaceutical composition may further comprise one or more aqueous solubility enhancer(s), such as a cyclodextrin. Nonlimiting examples of cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin, and hydroxypropyl- β-cyclodextrin (HPBC). In some embodiments, the pharmaceutical composition further comprises HPBC in a range of from about 0.1% to about 20%, from about 1% to about 15%, or from about 2.5% to about 10%. The amount of solubility enhancer employed may depend on the amount of the compound in the composition.
Preparation of Compounds Methods for synthesizing certain compounds described herein have been disclosed in
International Application PCT/US2012/052882, published as International Application Number WO2013/033228, and United States Patent Application U.S.S.N. 14/241,649, published as United States Patent Application Number US2015/0038438. Biological Examples
The following in vitro biological examples demonstrate the usefulness of the compounds of the present description for treating Neisseria gonorrhoeae.
The antibacterial activity from a microbroth dilution method in either or both Fastidious Broth (FB) and FB containing 40 mg/mL Human Serum Albumin (HSA), as indicated, may be represented by the minimum inhibitory concentration (MIC in μg/mL). The MIC value is the lowest concentration of drug which prevents macroscopically visible growth under test conditions.
In the following tables, a MIC value between > 12.5 μg/mL and < 150 μg/mL is indicated by a single star (*), a MIC value between > 3.5 μg/mL and < 12.5 μg/mL is indicated by two stars (**), a MIC value between > 1.0 μg/mL and < 3.5 μg/mL is indicated by three stars (***) and a MIC value of < 1.0 μg/mL is indicated by four stars (****).
Example 1
Antibacterial activity of test compounds against N. gonorrhoeae WHO isolate F (13477) is compared in FB (Table 1) and in FB containing 40 mg/mL HSA (Human Serum Albumin) (Table 2).
Table 1
Cpd 13477 Cpd 13477 Cpd 13477
2 **** 47 **** 119 ***
3 **** 48 **** 120 ***
4 **** 50 **** 121 ***
5 **** 51 **** 122 **
6 **** 52 **** 123 ****
7 **** 59 **** 124 ****
9 **** 63 **** 125 ****
10 ** 64 **** 126 **
11 **** 67 **** 127 ****
12 **** 68 **** 128 *
13 **** 69 **** 129 ***
14 * 70 **** 131 *** Cpd 13477 Cpd 13477 Cpd 13477
15 71 132
16 **** 76 134 **** 17 **** 77 142 **** 18 **** 78 146 **** 19 79 148 **** 20 **** 80 150 **** 22 **** 83 152 **** 23 **** 84 153 **** 25 **** 85 154 **** 26 **** 86 156 **** 27 **** 87 **** 158 **** 28 **** 89 **** 159 **** 32 **** 90 **** 161 **** 33 **** 102 **** 163 **** 34 **** 107 **** 165 **** 35 **** 108 **** 166
36 **** 109 167 **** 37 **** 110 168 **** 38 **** 111 **** 169 **** 39 **** 112 **** 171 **** 40 **** 113 172 **** 43 **** 114 173 **** 44 **** 115 175 **** 45 **** 116 183 **** 46 **** 117 Table 2
Cpd 13477 Cpd 13477
17 **** 45 **** 28 **** 68 **** 37 **** 150 **** 38 **** 154 **** 40 **** 161 **** 43 ****
Example 2
Antibacterial activity of test compounds against N. gonorrhoeae WHO isolates G, K, L and M (13478, 13479, 13480 and 13481, respectively) is shown in Table 3.
Table 3
Cpd 13478 13479 13480 13481 Cpd 13478 13479 13480 13481
2 84
3 85
4 86
5 87
6 89
7 90
8 102
9 107
10 108
11 109
12 110
13 111
14 112
15 113
16 114 Cpd 13478 13479 13480 13481 Cpd 13478 13479 13480 13481
17 115
18 116
19 117
20 119
22 120
23 121
25 122
26 123
27 124
28 125
32 126
33 127
34 128
35 129
36 131
37 132
38 134
39 142
40 146
41 147
43 148
44 149
45 150
46 151
47 152
48 153
50 154
51 155 Cpd 13478 13479 13480 13481 Cpd 13478 13479 13480 13481
52 156
59 158
63 159
64 161
67 163
68 165
69 166
70 167
71 168
76 169
77 171
78 172
79 173
80 175
83 183
Example 3
Antibacterial activity of test compounds against a streptomycin-resistant
onorrhoeae FA1090 isolate is compared in FB (Table 4) and in FB containing 40 mg/mL (Table 5). Table 4
Cpd FA1090 Cpd FA1090 Cpd FA1090
5 **** 40 **** J24 ****
6 **** 43 **** 125 ****
9 **** 44 **** 127 ****
11 **** 45 **** 1 2 ****
12 **** 46 **** 146 ****
13 **** 47 **** 1 g **** Cpd FA1090 Cpd FA1090 Cpd FA1090
16 **** 48 **** 150 **** 17 **** 50 **** 152 **** 18 **** 51 **** 153 **** 20 **** 52 **** 154 **** 22 **** 54 **** 156 **** 23 **** 59 **** 158 **** 25 **** 63 161 **** 26 **** 64 163 **** 27 **** 67 **** 165 **** 28 **** 68 **** 167 **** 32 **** 87 **** 168 **** 33 **** 89 **** 169 **** 34 **** 92 171 **** 35 **** 102 173 **** 36 **** 107 **** 175 **** 37 **** 108 **** 182
38 **** 114 183 **** 39 ****
Table 5
Cpd FA1090 Cpd FA1090 Cpd FA1090
5 36 **** 107
6 **** 37 **** 108
9 **** 38 **** 124
11 **** 39 125 ****
12 **** 40 **** 127 ****
13 **** 43 **** 146 ****
16 45 **** 148 **** Cpd FA1090 Cpd FA1090 Cpd FA1090
**** *** 150 ****
18 * *** 153 ****
20 **** **** 154 ****
22 **** **** 156
23 **** **** 158 ****
22 **** *** 161 ****
33 **** **** 163
34 *** *** 165
35 ****
Example 4
Antibacterial activity of test compounds against penicillin-sensitive wild-type N. gonorrhoeae FA19 and ciprofloxacin-resistant AKl and AK2 isolates and the LG24 clinical isolate is shown in Table 6.
Table 6
Cpd AKl AK2 FA19 LG24 Cpd AKl AK2 FA19 LG24
16 g7 **** **** 17 g9 **** **** 20 92 *** ***
22 102 **** ****
23 ii^ *** *** 25 127 **** ****
26 142 **** ****
27 146 **** ****
32 j g **** **** 33 152 **** ****
34 153 **** ****
35 156 **** **** Cpd AK1 AK2 FA19 LG24 Cpd AK1 AK2 FA19 LG24
36 158
44 165
47 167
48 168
54 169
55 171
59 173
63 175
64 182
67 183
Example 5
Antibacterial activity of test compounds against N. gonorrhoeae tetracycline-resistant LGB24, penicillin-resistant LGB3, ampiciUin-resistant LGB50 isolates and an MS 11 isolate is shown in Table 7.
Table 7
Cpd LGB24 LGB3 LGB50 MS11 Cpd LGB24 LGB3 LGB50 MS11
16 89 **** 17 92
20 102
22 114
23 127 **** 25 142
26 146 **** 27 148 **** 32 152
33 153 ****
34 156 **** Cpd LGB24 LGB3 LGB50 MS11 Cpd LGB24 LGB3 LGB50 MS11
35 158
36 165
44 167
47 168
48 169
54 171
59 173
63 175
64 182
67 183
87
Example 6
Antibacterial activity of test compounds against the wild-type N. gonorrhoeae isolate 49226 is shown in Table 8 and the SP1364 isolate is shown in Table 9.
Table 8
Cpd 49226 Cpd 49226
17 **** 48 ****
22 **** 167 ****
25 **** 168 ****
26 **** 175 ****
33 ****
Table 9
Cpd SP1364
****
25 ****
5Q **** Example 7
In Vivo Mouse Model Background
The usefulness of the compounds of the present description for treating Neisseria gonorrhoeae was demonstrated in an in vivo mouse model developed by the adaptation of several published protocols {see, Jerse, A.E., Experimental Gonococcal Genital Tract Infection and Opacity Protein Expression in estradiol-treated mice. Infection and Immunity, 1999, 67(l l):5699-5708; and, Cole, J.E. et al., Opacity Proteins Increase Neisseria gonorrhoeae Fitness in the Female Genital Tract Due to a Factor Under Ovarian Control. Infection and Immunity, 2010, 78(4): 1629- 1641).
Compound efficacy is demonstrated when all mice in a treatment group are completely clear of N. gonorrhoeae after 5 full days post-treatment (100% clearance).
Bacterial clearance is defined as the number of mice in the treatment group free of
N. gonorrhoeae expressed as a percentage of the total. Complete bacterial clearance (100% clearance) for the treatment group equates to an approximate log 4 reduction in bacterial count for the group. Compounds that achieve less than 100% clearance for the treatment group have an average maximal log drop value calculated by the following equation:
Maximal Log Drop = log(average Day 2 bacterial count for all mice) - log(average lowest bacterial count post dose for all mice)
Study Conduct
On Day -2 of the study, ovariectomized Balb/c female mice (5 weeks old - Charles River Laboratory) were implanted with a single 17 -estradiol pellet (0.5 mg, 21 day release) subcutaneously and began treatment with a combination of vancomycin HC1, streptomycin sulfate (0.6 mg and 0.3 mg, respectively, IP, BID) and trimethoprim sulfate (0.8 mg, PO, BID). The antibiotic combination was administered to control commensal flora induced by the high level of 17 -estradiol resulting from the implanted pellet. Combined antibiotic treatment continued from Day -2 to Day 1 of the study. After Day 1, mice were dosed with streptomycin only (0.6 mg, IP, QD).
On Day 0 of the study, mice were inoculated with SP1364 N. gonorrhoeae (target 1 x 10 CFU) suspended in saline. Following inoculation, and for the 7 days of the study, the bacterial count was determined by daily vaginal swabbing using sterile swabs. On Day 1 of the study, mice were randomized into treatment groups according to bacterial count. The treatment groups (n=10) included a vehicle control, a positive control (ciprofloxacin, 30 mg/kg) and test compound group. The treatment groups were dosed with a single dose (mg/kg) either orally or IP. The vehicle control, positive control and test compound oral dose was administered in a mixture of HPMC (0.5%) and Tween 80 (0.1%) and the IP dose was administered in a mixture of DMSO (3%) in saline. Routes of administration for each compound tested are shown in Table 10.
Results
Antibacterial efficacy of test compounds (Cpd) against SP1364 N. gonorrhoeae is shown in Table 10, where percent clearance (%) and maximal log drop value (Drop) for each treatment group (n) administered (Route) a particular dose (Dose in mg/kg) is indicated.
Table 10
Cpd Dose Route n % Drop
12 30 IP 7 57 0.26
12 60 IP 9 100 3.39
13 60 IP 10 80 1.8
25 100 IP 9 100 4.48
33 30 PO 8 38 0.032
33 60 PO 9 50 0.26
48 60 IP 10 100 4.53
125 60 IP 9 33 0.42
Example 8
Combinations with Antibacterial Agents The in vitro effects of compounds described herein in combination with a known antibacterial or antibiotic agent may be investigated in various organisms using the microdilution checkerboard method for the measurement of additive or synergistic effect. Assays can be performed in a 96- well checkerboard titration format, with serial dilutions of each compound to identify the lowest MIC value ^g/mL) at which the combination completely inhibits colony formation. The ability of a combination of one or more compounds described herein with known agents to either act synergistically, additively, indifferently or antagonistically can be determined. A synergistic effect is demonstrated when the activity of the separate agents are combined and the result is greater than the expected arithmetic sum of each agents activity alone. The fractional inhibitory
concentration (FIC) is a quantitative measure of such drug interactions, where the fractional inhibition indices are calculated using the checkerboard method in a 96-well microtiter plate. Combined activity is synergistic when the FIC value is < 0.5; combined activity is additive when the FIC value is > 0.5 and < 2; combined activity that is not different from the agents alone when the FIC value is > 2 and < 4; and, combined activity is antagonistic when the FIC value is > 4.
Without regard to whether a document cited herein was specifically and individually indicated as being incorporated by reference, all documents referred to herein are
incorporated by reference into the present application for any and all purposes to the same extent as if each individual reference was fully set forth herein.
Having now fully described the subject matter of the claims, it will be understood by those having ordinary skill in the art that the same can be performed within a wide range of equivalents without affecting the scope of the subject matter or embodiments described herein. It is intended that the appended claims be interpreted to include all such equivalents.

Claims

What is claimed is:
A use of a compound for treating or ameliorating Neisseria gonorrhoeae
(N. gonorrhoeae) in a subject in need thereof comprising, administering an effective amount of the compound to the subject, wherein the compound is selected from a compound of Formula (I) or Formula (II):
Figure imgf000115_0001
(I) (Π) or a form thereof, wherein,
X is a bond, O, -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -0-CH(R3)-, -N(R9)-CH(R3)-, -S-CH(R3)- or -N(R9)-CH(R3)-CH2-;
Z is -CH(R9)-;
Ri is hydrogen, halogen, Ci_8alkyl-amino, (Ci_8alkyl)2-amino, amino-Ci_8alkyl,
Ci-ioalkyl-amino-Ci-galkyl, (C1_8alkyl)2-amino-C1_8alkyl, C^galkenyl-amino-Ci-galkyl,
Figure imgf000115_0002
Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl,
(C1_galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl,
Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1_galkyl)2-amino-C1_galkyl,C1_galkyl]amino-C1_galkyl,
hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl,
Cs-^cycloalkyl-amino-Ci-galkyl, Cs-wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci_galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl, wherein each instance of C3_14cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R10; and,
wherein each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn;
R2 is hydrogen, halogen or Ci-galkyl;
R3 is hydrogen, hydroxyl or Ci-galkyl;
R4 is hydrogen, Ci-galkyl or aryl-Ci-galkyl, wherein aryl is optionally substituted with
one substituent selected from Ci-galkyl, halo-Ci-galkyl, Ci_galkoxy or
Ci-galkoxy-Ci.galkyl;
R5 is hydrogen or Ci-galkyl;
R6 is hydrogen or hydroxyl;
R7 is hydrogen or halogen;
R8 is hydrogen or halogen;
R9 is hydrogen or Ci_galkyl;
R10 is halogen, hydroxyl, Ci-galkyl, Ci-galkoxy, amino, Ci-galkyl-amino, (C1_galkyl)2-amino,
Ci-galkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl or Ci-galkyl-carbonyl-amino; and,
Rn is aryl-Ci-galkyl-amino,
Figure imgf000116_0001
or (aryl-C1_galkyl)2-amino; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
2. The use of claim 1, wherein the compound is selected from a compound of Formula (I):
Figure imgf000116_0002
(I) or a form thereof, wherein,
X is a bond, O, -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -0-CH(R3)-, -N(R9)-CH(R3)-, -S-CH(R3)- or -N(R9)-CH(R3)-CH2-;
Z is -CH(R9)-; Ri is hydrogen, halogen, Ci_galkyl-amino, (C1_galkyl)2-amino, amino-Ci_galkyl,
Ci-ioalkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl, C2_galkenyl-amino-Ci_galkyl, C^galkynyl-amino-Ci-galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl,
(C1-galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl,
Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1_galkyl)2-amino-C1_galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl,
hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci_galkyl,^galkyl)amino-^galkyl,
(C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl,
C3_i4cycloalkyl-amino-Ci_galkyl, C3_i4cycloalkyl-Ci_galkyl-amino-Ci_galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C3_i4cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from Rio; and,
wherein each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn;
R2 is hydrogen, halogen or Ci_galkyl;
R3 is hydrogen, hydroxyl or Ci-galkyl;
R4 is hydrogen, Ci-galkyl or aryl-Ci_galkyl, wherein aryl is optionally substituted with
one substituent selected from Ci-galkyl, halo-Ci_galkyl, Ci_galkoxy or
Ci_galkoxy-Ci_galkyl;
R6 is hydrogen or hydroxyl;
Rg is hydrogen or halogen;
R9 is hydrogen or Ci-galkyl;
Rio is halogen, hydroxyl, Ci_galkyl, Ci_galkoxy, amino, Ci_galkyl-amino, (Ci_galkyl)2-amino, Ci-galkyl-amino-Ci-galkyl, (Ci_galkyl)2-amino-Ci_galkyl or Ci-galkyl-carbonyl-amino; and, Rn is aryl-Ci-galkyl-amino,
Figure imgf000118_0001
or (aryl-C1_8alkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
3. The use of claim 1, wherein the compound is selected from a compound of Formula (II):
Figure imgf000118_0002
(ID or a form thereof, wherein,
X is a bond, O, -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -0-CH(R3)-, -N(R9)-CH(R3)-, -S-CH(R3)- or -N(R9)-CH(R3)-CH(R3)-;
Z is -CH(R9)-;
Ri is hydrogen, halogen, Ci_galkyl-amino, (Ci_8alkyl)2-amino, amino-Ci_galkyl,
Ci-ioalkyl-amino-Ci-galkyl, (C1_8alkyl)2-amino-C1_8alkyl, C^galkenyl-amino-Ci-galkyl, C2-8alkynyl-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(C1_8alkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl,
Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl,
hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl,
Cs-^cycloalkyl-amino-Ci-galkyl, Cs-wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl, wherein each instance of C3_14cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R10; and,
wherein each instance of aryl or heterocyclyl is optionally substituted with one substituent selected from Rn;
R3 is hydrogen, hydroxyl or Ci-galkyl;
R4 is hydrogen, Ci-galkyl or aryl-Ci-galkyl;
R5 is Ci-galkyl;
R6 is hydrogen or hydroxyl;
R7 is hydrogen or halogen;
R9 is hydrogen or Ci-galkyl;
Rio is halogen, hydroxyl, Ci-galkyl, Ci-galkoxy, amino, (Ci-galkyl amino or
Ci-galkyl-carbonyl-amino; and,
Rn is
Figure imgf000119_0001
or (aryl-C1_galkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
4. A method of use for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of claim 1 or a form thereof to the subject. 5. The method of claim 4, wherein the compound or a form thereof is selected from the group consisting of:
8- (dimethylamino)-2-oxo- 1 ,2,5,6-tetrahydrobenzo[h]quinoline-3-carboxylic acid
9- (dimethylamino)-2-oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid
9- (dimethylamino)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
10- (dimethylamino)-2-oxo- 1,2,5,6,7, 8-hexahydrobenzo[7,8]cycloocta[ 1,2- b]pyridine-3-carboxylic acid
10-(dimethylamino)-4-hydroxy-2-oxo- 1,2,5,6,7, 8- hexahydrobenzo[7,8]cycloocta[l,2-b]pyridine-3-carboxylic acid 9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-2-oxo-9-(pyrrolidin-l-yl)-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-9-(3-(methylamino)pyrrolidin-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo-2,5,6,7- tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9-((cis,cis)-6-(benzyl(methyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2- oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-9-((cis,cis)-6-(methylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxo- 2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-5-methyl-2-oxo-2,5,6,7-tetrahydro- lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl-2-oxo- 2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4,7-dihydroxy-2-oxo-2,5,6,7- tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9-(3-(dimethylamino)pyrrolidin-l-yl)-4,7-dihydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo- 1,2,5, 9-tetrahydropyrido[3',2':6,7]cyclohepta[ 1,2- f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 9-hexahydropyrido[3',2':6,7]cyclohepta[ 1,2- f]indole-3-carboxylic acid
8-fluoro-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
2-((ethylamino)methyl)-8-hydroxy-l-methyl-6-oxo-l,5,6,9- tetrahydropyrido[3',2':4,5]cyclopenta[l,2-f|indole-7-carboxylic acid 4-hydroxy-8-methyl-9-((methylamino)methyl)-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
9- (azetidin-l-ylmethyl)-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10- ((cyclobutylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-(azetidin-l-ylmethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-10-((isopropylamino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((tert-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-10-((4-hydroxypiperidin-l-yl)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- exahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
10-((4-aminopiperidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- exahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
10-((4-(dimethylamino)piperidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2' :6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((3-aminopiperidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-(((cyclopropylmethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid 10-((benzylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-(aminomethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((cyclopropylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-(((cyclobutylmethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-((((2-methylcyclopropyl)methyl)amino)methyl)-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-(((pyridin-4-ylmethyl)amino)methyl)- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-(piperidin-l-ylmethyl)- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-(morpholinomethyl)-2-oxo- 1,2,5,6,7, 9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-((4-methylpiperazin-l-yl)methyl)-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((diethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-((propylamino)methyl)- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-((prop-2-yn-l-ylamino)methyl)- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
(R)-10-((3-fluoropyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((3-(dimethylamino)pyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid 10-((dimethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
(S)-10-((3-aminopyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-10-((3-hydroxypyrrolidin-l-yl)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-(((pyridin-3-ylmethyl)amino)methyl)- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
9- methyl-10-((methylamino)methyl)-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10- ((ethylamino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((isopropylamino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((tert-butylamino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10- (azetidin-l-ylmethyl)-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy- 10-methyl- 1 l-((methylamino)methyl)-2-oxo-2,5,6,7,8, 10-hexahydro- 1H- pyrido[3',2':7,8]cycloocta[l,2-f|indole-3-carboxylic acid
11- ((ethylamino)methyl)-4-hydroxy-10-methyl-2-oxo-2,5,6,7, 8, 10-hexahydro- 1H- pyrido[3',2':7,8]cycloocta[l,2-f|indole-3-carboxylic acid
4-hydroxy-7,9-dimethyl-10-((methylamino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((ethylamino)methyl)-4-hydroxy-7,9-dimethyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid 4-hydroxy-10-((isopropylamino)methyl)-7,9-dimethyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((tert-butylamino)methyl)-4-hydroxy-7,9-dimethyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-7,9-dimethyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((ethylamino)methyl)-4-hydroxy-5,9-dimethyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4- hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo- 1,2,5,9- tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
10-((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,9- tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
10-((ethylamino)methyl)-4-hydroxy-7,9-dimethyl-2-oxo- 1,2,5,9- tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
(cis)-10-((ethylamino)methyl)-4,6,7-trihydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid l-benzyl-8-chloro-5-methyl-2-oxo-2,5-dihydro-lH-chromeno[4,3-b]pyridine-3- carboxylic acid
5- methyl-2-oxo-2,5-dihydro-lH-chromeno[4,3-b]pyridine-3-carboxylic acid
5-methyl-2-oxo-8-(pyrrolidin-l-yl)-2,5-dihydro-lH-chromeno[4,3-b]pyridine-3- carboxylic acid
8- (3-(dimethylamino)pyrrolidin-l-yl)-5-methyl-2-oxo-2,5-dihydro-lH- chromeno[4,3-b]pyridine-3-carboxylic acid
9- (dimethylamino)-4-hydroxy-2-oxo-l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5- b]pyridine-3-carboxylic acid
4-hydroxy-2-oxo-9-(pyrrolidin-l-yl)-l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5- b]pyridine-3-carboxylic acid 9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-2-oxo-l,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
9-((cis,cis)-6-(dibenzylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo- l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo-l,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
2-oxo-9-(pyrrolidin-l-yl)- 1,2,5, 6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3- carboxylic acid
9-(3-(dimethylamino)pyrrolidin-l-yl)-2-oxo- 1,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
4-hydroxy-5-methyl-2-oxo-9-(pyrrolidin-l-yl)-l,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-5-methyl-2-oxo-l,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
9-((cis,cis)-6-(dibenzylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl- 2-oxo- l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
9- ((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl-2-oxo- l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2- f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10- ((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-10-((isopropylamino)methyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10-(azetidin-l-ylmethyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid 10-((ethylamino)methyl)-4-hydroxy-5,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-7-methyl-2-oxo-9-(pyrrolidin-l-yl)-2,5,6,7-tetrahydro-lH- benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid
4-hydroxy-2-oxo-9-(pyrrolidin-l-yl)-2,5,6,7-tetrahydro-lH-benzo[b]pyrido[2,3- d]azepine-3-carboxylic acid
9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid
4-hydroxy-9-(4-methylpiperazin-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH- benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo-2,5,6,7- tetrahydro- lH-benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid
9- (hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-4-hydroxy-2-oxo-2,5,6,7- tetrahydro- lH-benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid
4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid
10- ((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-10-((isopropylamino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid
10- ((tert-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid
4-hydroxy- 10-methyl- 1 l-((methylamino)methyl)-2-oxo-2,5,6,7,8, 10-hexahydro- 1H- pyrido[2',3':4,5]azocino[3,2-f|indole-3-carboxylic acid
11- ((ethylamino)methyl)-4-hydroxy-10-methyl-2-oxo-2,5,6,7, 8, 10-hexahydro- lh- pyrido[2',3':4,5]azocino[3,2-f|indole-3-carboxylic acid
4-hydroxy- l l-((isopropylamino)methyl)-10-methyl-2-oxo-2,5,6,7, 8, 10-hexahydro- lH-pyrido[2',3':4,5]azocino[3,2-f|indole-3-carboxylic acid 4-hydroxy-5-methyl-2-oxo-8-(pyrrolidin-l-yl)- 1,2,5, 6-tetrahydrobenzo[h]quinoline- 3-carboxylic acid
8-(dimethylamino)-4-hydroxy-5-methyl-2-oxo- 1,2,5, 6-tetrahydrobenzo[h]quinoline-
3- carboxylic acid
8-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-5-methyl-2-oxo-l,2,5,6- tetrahydrobenzo [h] quinoline- 3 -c arboxylic acid
8- ((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl-2-oxo-
1.2.5.6- tetrahydrobenzo[h]quinoline-3-carboxylic acid
9- (l,4-diazepan-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4- hydroxy-9-(4-methyl-l,4-diazepan-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9-((2-(dimethylamino)ethyl)amino)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9-((4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-4-hydroxy-2-oxo-
2.5.6.7- tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-9-((4aR,7aR)-l-methylhexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2- oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9-(4-(dimethylamino)piperidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9-(3-(dimethylamino)piperidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-2-oxo-9-(piperidin-4-ylamino)-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-2-oxo-9-(piperazin-l-yl)-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-9-(4-methylpiperazin-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid 4-hydroxy-2-oxo-9-(2,6-diazaspiro[3.4]octan-6-yl)-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-2-oxo-9-(2,7-diazaspiro[4.4]nonan-2-yl)-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-9-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-oxo-2,5,6,7-tetrahydro- lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-10,l l-difluoro-4-hydroxy-2- oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9- ((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-l l-fluoro-4-hydroxy-2-oxo- 2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-2-oxo-10-(pyrrolidin-l-yl)- 1,2,5,6,7, 8- hexahydrobenzo[7,8]cycloocta[l,2-b]pyridine-3-carboxylic acid
10- ((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydrobenzo[7,8]cycloocta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-2-oxo-10-(propylamino)- 1,2,5,6,7, 8-hexahydrobenzo[7,8]cycloocta[ 1,2- b]pyridine-3-carboxylic acid
10-(ethylamino)-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydrobenzo[7,8]cycloocta[ 1,2- b]pyridine-3-carboxylic acid l,9-dimethyl-2-oxo- 1,2,5, 9-tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3- carboxylic acid
4-hydroxy-l,9-dimethyl-2-oxo- 1,2,5, 9-tetrahydropyrido[3',2':6,7]cyclohepta[ 1,2- f]indole-3-carboxylic acid l-ethyl-4-hydroxy-9-methyl-2-oxo- 1,2,5,9- tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid l,9-dimethyl-2-oxo- 1,2,5, 6,7, 9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3- carboxylic acid
4-hydroxy- 1 ,9-dimethyl-2-oxo- 1 ,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid 10-((butylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-((pentylamino)methyl)- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((hexylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((heptylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-((octylamino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-((nonylamino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-(((2-(dimethylamino)ethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-(((2-(methylamino)ethyl)amino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-(((2-aminoethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((sec-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-10-(((2-hydroxyethyl)amino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-10-(((2-methoxyethyl)amino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-10-(((2-hydroxyethyl)(methyl)amino)methyl)-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid 4-hydroxy-10-(((l-methoxypropan-2-yl)amino)methyl)-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-10-(((l-hydroxypropan-2-yl)amino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-(((2-(pyrrolidin-l-yl)ethyl)amino)methyl)- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((allylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-10-((isobutylamino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-((neopentylamino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl- 10-((4-methyl- 1 ,4-diazepan- l-yl)methyl)-2-oxo- 1 ,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-(((l-methylpiperidin-4-yl)amino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-10-((3-methoxypyrrolidin-l-yl)methyl)-9-methyl-2-oxo- 1,2,5,6,7, 9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-((3-acetamidopyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-(((l-(dimethylamino)propan-2-yl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-((((tetrahydrofuran-2-yl)methyl)amino)methyl)- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-((l-methylhexahydropyrrolo[3,4-b]pyrrol-5(lH)- yl)methyl)-2-oxo- 1,2,5, 6,7, 9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3- carboxylic acid
10-(((2-(dimethylamino)-2-oxoethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid 10-(2-(ethylamino)ethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,9- tetrahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
10-(2-(ethylamino)ethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-(((cis)-octahydrocyclopenta[c]pyrrol-4-yl)-(cis)-amino)-2-oxo-l,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
10-((sec-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-((propylamino)methyl)-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10-(((2,4-dimethoxybenzyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
10-((cyclopropylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10-((cyclobutylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10-((dimethylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10-((tert-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-((4-methylpiperazin-l-yl)methyl)-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-10-(((2-hydroxyethyl)amino)methyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid 4-hydroxy-10-(((l-hydroxypropan-2-yl)amino)methyl)-9-methyl-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-(((2-(pyrrolidin-l-yl)ethyl)amino)methyl)-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10-(((2-aminoethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-(((2-(methylamino)ethyl)amino)methyl)-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10-(((2-(dimethylamino)ethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-10-(((2-methoxyethyl)amino)methyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-10-(((l-methoxypropan-2-yl)amino)methyl)-9-methyl-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
9-(dimethylamino)-4-hydroxy-2-oxo-l,2,5,6-tetrahydrobenzo[2,3]thiepino[4,5- b]pyridine-3-carboxylic acid, and
4-hydroxy-2-oxo-9-(pyrrolidin-l-yl)-l,2,5,6-tetrahydrobenzo[2,3]thiepino[4,5- b]pyridine-3-carboxylic acid; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
6. The method of claim 5, wherein a compound salt or a form thereof is selected from the group consisting of:
9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-(3-(methylamino)pyrrolidin-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride 9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo-2,5,6,7- tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
trifluoroacetate
9-((cis,cis)-6-(benzyl(methyl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2- oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-((cis,cis)-6-(methylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxo- 2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-5-methyl-2-oxo-2,5,6,7-tetrahydro- lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl-2-oxo- 2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4,7-dihydroxy-2-oxo-2,5,6,7- tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
trifluoroacetate
9-(3-(dimethylamino)pyrrolidin-l-yl)-4,7-dihydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
2-((ethylamino)methyl)-8-hydroxy-l-methyl-6-oxo-l,5,6,9- tetrahydropyrido[3',2':4,5]cyclopenta[ 1 ,2-f]indole-7-carboxylic acid hydrochloride
4-hydroxy-8-methyl-9-((methylamino)methyl)-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
9- (azetidin-l-ylmethyl)-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10- ((cyclobutylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride 10-(azetidin-l-ylmethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-((isopropylamino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((tert-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-((4-hydroxypiperidin-l-yl)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- exahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride
10-((4-aminopiperidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- exahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid dihydrochloride
10-((4-(dimethylamino)piperidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid dihydrochloride
10-((3-aminopiperidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
dihydrochloride
10-(((cyclopropylmethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((benzylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-(aminomethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((cyclopropylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride 10-(((cyclobutylmethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((((2-methylcyclopropyl)methyl)amino)methyl)-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-(((pyridin-4-ylmethyl)amino)methyl)- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-(piperidin-l-ylmethyl)- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-(morpholinomethyl)-2-oxo- 1,2,5,6,7, 9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((4-methylpiperazin-l-yl)methyl)-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
dihydrochloride
10-((diethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-((propylamino)methyl)- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-((prop-2-yn-l-ylamino)methyl)- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
(R)-10-((3-fluoropyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((3-(dimethylamino)pyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid dihydrochloride
10-((dimethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride (S)-10-((3-aminopyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
di ydrochloride
4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-((3-hydroxypyrrolidin-l-yl)methyl)-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-(((pyridin-3-ylmethyl)amino)methyl)- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
9- methyl-10-((methylamino)methyl)-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10- ((ethylamino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride 10-((isopropylamino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride 10-((tert-butylamino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10- (azetidin-l-ylmethyl)-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy- 10-methyl- 1 l-((methylamino)methyl)-2-oxo-2,5,6,7, 8, 10-hexahydro- 1H- pyrido[3',2':7,8]cycloocta[l,2-f|indole-3-carboxylic acid hydrochloride
11- ((ethylamino)methyl)-4-hydroxy-10-methyl-2-oxo-2,5,6,7, 8, 10-hexahydro- 1H- pyrido[3',2':7,8]cycloocta[l,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-7,9-dimethyl-10-((methylamino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((ethylamino)methyl)-4-hydroxy-7,9-dimethyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy- 10-((isopropylamino)methyl)-7,9-dimethyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride 10-((tert-butylamino)methyl)-4-hydroxy-7,9-dimethyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-7,9-dimethyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((ethylamino)methyl)-4-hydroxy-5,9-dimethyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo- 1,2,5,9- tetrahydropyrido[3',2':6,7]cyclohepta[ 1 ,2-f]indole-3-carboxylic acid hydrochloride
10-((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,9- tetrahydropyrido[3',2':6,7]cyclohepta[ 1 ,2-f]indole-3-carboxylic acid hydrochloride
10-((ethylamino)methyl)-4-hydroxy-7,9-dimethyl-2-oxo- 1,2,5,9- tetrahydropyrido[3',2':6,7]cyclohepta[ 1 ,2-f]indole-3-carboxylic acid hydrochloride
(cis)-10-((ethylamino)methyl)-4,6,7-trihydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
8- (3-(dimethylamino)pyrrolidin-l-yl)-5-methyl-2-oxo-2,5-dihydro-lH- chromeno[4,3-b]pyridine-3-carboxylic acid hydrochloride
9- (3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-2-oxo-l,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid hydrochloride
9-((cis,cis)-6-(dibenzylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo- l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid
trifluoroacetate
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo-l,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid hydrochloride
9-(3-(dimethylamino)pyrrolidin-l-yl)-2-oxo- 1,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid hydrochloride
9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-5-methyl-2-oxo-l,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid hydrochloride 9-((cis,cis)-6-(dibenzylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl- 2-oxo-l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid hydrochloride
9- ((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl-2-oxo- l,2,5,6-tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10- ((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-((isopropylamino)methyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-(azetidin-l-ylmethyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-((ethylamino)methyl)-4-hydroxy-5,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
9-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid hydrochloride
4-hydroxy-9-(4-methylpiperazin-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH- benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid hydrochloride
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo-2,5,6,7- tetrahydro- lH-benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid hydrochloride
9- (hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-4-hydroxy-2-oxo-2,5,6,7- tetrahydro- lH-benzo[b]pyrido[2,3-d]azepine-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((methylamino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid hydrochloride
10- ((ethylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-((isopropylamino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid hydrochloride 10- ((tert-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[2',3':4,5]azepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy- 10-methyl- 1 l-((methylamino)methyl)-2-oxo-2,5,6,7, 8, 10-hexahydro- 1H- pyrido[2',3':4,5]azocino[3,2-f|indole-3-carboxylic acid hydrochloride
11- ((ethylamino)methyl)-4-hydroxy-10-methyl-2-oxo-2,5,6,7, 8, 10-hexahydro- lh- pyrido[2',3':4,5]azocino[3,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy- l l-((isopropylamino)methyl)-10-methyl-2-oxo-2,5,6,7, 8, 10-hexahydro- lH-pyrido[2',3':4,5]azocino[3,2-f|indole-3-carboxylic acid hydrochloride
8-(3-(dimethylamino)pyrrolidin-l-yl)-4-hydroxy-5-methyl-2-oxo-l,2,5,6- tetrahydrobenzo[h]quinoline-3-carboxylic acid hydrochloride
8- ((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-5-methyl-2-oxo-
1.2.5.6- tetrahydrobenzo[h]quinoline-3-carboxylic acid trifluoroacetate
9- (l,4-diazepan-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-(4-methyl-l,4-diazepan-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
9-((2-(dimethylamino)ethyl)amino)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
9-((4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-4-hydroxy-2-oxo-
2.5.6.7- tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-((4aR,7aR)-l-methylhexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-2- oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9-(4-(dimethylamino)piperidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
9-(3-(dimethylamino)piperidin-l-yl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride 4-hydroxy-2-oxo-9-(piperidin-4-ylamino)-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-9-(piperazin-l-yl)-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-(4-methylpiperazin-l-yl)-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-9-(2,6-diazaspiro[3.4]octan-6-yl)-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-9-(2,7-diazaspiro[4.4]nonan-2-yl)-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)-2-oxo-2,5,6,7-tetrahydro- lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9-((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-10,l l-difluoro-4-hydroxy-2- oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9- ((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-l l-fluoro-4-hydroxy-2-oxo- 2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
10- ((cis,cis)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-4-hydroxy-2-oxo- 1,2,5, 6,7,8- hexahydrobenzo[7,8]cycloocta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
10-((butylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-((pentylamino)methyl)- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((hexylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((heptylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride 4-hydroxy-9-methyl-10-((octylamino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((nonylamino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-(((2-(dimethylamino)ethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid dihydrochloride
4-hydroxy-9-methyl-10-(((2-(methylamino)ethyl)amino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
dihydrochloride
10-(((2-aminoethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
dihydrochloride
10-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid dihydrochloride
10-((sec-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-(((2-hydroxyethyl)amino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-(((2-methoxyethyl)amino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-(((2-hydroxyethyl)(methyl)amino)methyl)-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-(((l-methoxypropan-2-yl)amino)methyl)-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-(((l-hydroxypropan-2-yl)amino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride 4-hydroxy-9-methyl-2-oxo-10-(((2-(pyrrolidin-l-yl)ethyl)amino)methyl)- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid di ydrochloride
10-((allylamino)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-((isobutylamino)methyl)-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((neopentylamino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((4-methyl-l,4-diazepan-l-yl)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
dihydrochloride
4-hydroxy-9-methyl-10-(((l-methylpiperidin-4-yl)amino)methyl)-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
dihydrochloride
4-hydroxy-10-((3-methoxypyrrolidin-l-yl)methyl)-9-methyl-2-oxo- 1,2,5,6,7, 9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-((3-acetamidopyrrolidin-l-yl)methyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-(((l-(dimethylamino)propan-2-yl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid dihydrochloride
4-hydroxy-9-methyl-2-oxo-10-((((tetrahydrofuran-2-yl)methyl)amino)methyl)- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((l-methylhexahydropyrrolo[3,4-b]pyrrol-5(lH)- yl)methyl)-2-oxo- 1,2,5, 6,7, 9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3- carboxylic acid dihydrochloride 10-(((2-(dimethylamino)-2-oxoethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-(2-(ethylamino)ethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,9- tetrahydropyrido[3',2':6,7]cyclohepta[ 1 ,2-f]indole-3-carboxylic acid trifluoroacetate
10-(2-(ethylamino)ethyl)-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid trifluoroacetate
4-hydroxy-9-(((cis)-octahydrocyclopenta[c]pyrrol-4-yl)-(cis)-amino)-2-oxo-l,2,5,6- tetrahydrobenzo[2,3]oxepino[4,5-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-(((l-methylcyclopropyl)amino)methyl)-2-oxo-2,5,6,9- tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
10-((sec-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-((propylamino)methyl)-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-(((2,4-dimethoxybenzyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9- tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
10-((cyclopropylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-((cyclobutylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-((dimethylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-((tert-butylamino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-((4-methylpiperazin-l-yl)methyl)-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid dihydrochloride 4-hydroxy-10-(((2-hydroxyethyl)amino)methyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-10-(((l-hydroxypropan-2-yl)amino)methyl)-9-methyl-2-oxo-2,5,6,9- tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-(((2-(pyrrolidin-l-yl)ethyl)amino)methyl)-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
dihydrochloride
10-(((2-aminoethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid dihydrochloride
4-hydroxy-9-methyl-10-(((2-(methylamino)ethyl)amino)methyl)-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
dihydrochloride
10-(((2-(dimethylamino)ethyl)amino)methyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
dihydrochloride
4-hydroxy-10-(((2-methoxyethyl)amino)methyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride, and
4-hydroxy-10-(((l-methoxypropan-2-yl)amino)methyl)-9-methyl-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
hydrochloride; wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
7. The method of any of claims 4, 5 or 6, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.
8. The use of claim 1, wherein the compound of claim 1 or a form thereof is used for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof. The use of claim 1, wherein the compound of claim 1 or a form thereof is used in the manufacture of a medicament for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
The use of claim 1, wherein the compound of claim 1 or a form thereof is used in a pharmaceutical composition for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of claim 1 or a form thereof in admixture with one or more pharmaceutically acceptable excipient(s).
The use of claim 1, wherein the compound of claim 1 or a form thereof is used in a combination therapy for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of claim 1 or a form thereof and an effective amount of one or more antibiotic or antibacterial agent(s).
The use of any of claims 8 to 11, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.
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