WO2016039939A1 - Composés 2-pyridinone antibactériens à substitution bicyclique et tricyclique - Google Patents

Composés 2-pyridinone antibactériens à substitution bicyclique et tricyclique Download PDF

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WO2016039939A1
WO2016039939A1 PCT/US2015/045440 US2015045440W WO2016039939A1 WO 2016039939 A1 WO2016039939 A1 WO 2016039939A1 US 2015045440 W US2015045440 W US 2015045440W WO 2016039939 A1 WO2016039939 A1 WO 2016039939A1
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amino
galkyl
galky
ethyl
oxo
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PCT/US2015/045440
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English (en)
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Michael A. ARNOLD
Guangming Chen
Gary Mitchell Karp
Hongyan Qi
Anthony A. Turpoff
Jiashi WANG
Matthew G. WOLL
Nanjing Zhang
Xiaoyan Zhang
Aleksey Igorevich GERASYUTO
Arthur A. Branstrom
Jana Narasimhan
Melissa L. DUMBLE
Marla L. Weetall
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Ptc Therapeutics, Inc.
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Publication of WO2016039939A1 publication Critical patent/WO2016039939A1/fr

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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
    • A61K31/435—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 or sparfloxacin
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present description relates to substituted 2-pyridinone compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae). More particularly, the present description relates to bicyclic and tricyclic ring substituted 2-pyridinone compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions 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
  • R 1; R 2 and R 3 are as defined herein, and forms and compositions thereof, and also relates to uses of a compound of Formula (I) or a form thereof and methods 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.
  • N. gonorrhoeae Neisseria gonorrhoeae
  • the present description relates to a compound of Formula (I), and forms and compositions thereof, and to uses of a compound of Formula (I), and forms and compositions thereof, and methods for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising, administering an effective amount of the compound, and forms and compositions thereof, to the subject.
  • the present description also relates to a compound of Formula (I) or a form thereof having activity against wild- type or drug-resistant forms of N. gonorrhoeae.
  • the present description relates to a compound of Formula (I) or a form thereof having activity against wild-type or drug-resistant forms of N. gonorrhoeae.
  • the present description also relates to a compound of Formula (I) or a form thereof having activity against wild- type forms of N. gonorrhoeae.
  • the present description relates to a compound of Formula (I) or a form thereof having activity against wild- type forms of N. gonorrhoeae.
  • the present description also relates to a compound of Formula (I) or a form thereof having activity against drug-resistant forms of N. gonorrhoeae.
  • the present description relates to a compound of Formula (I) or a form thereof having activity against drug-resistant forms of N. gonorrhoeae.
  • the present description also relates to a compound of Formula (I) or a form thereof having activity against 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 a compound of Formula (I) or a form thereof having activity against a IR, HLR, MDR, MD ⁇ R or XDR form of
  • the present description also relates to a compound of Formula (I) or a form thereof having activity against 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 a compound of Formula (I) 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.
  • the present description further relates to use of a compound of Formula (I) 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 a form thereof for treating or ameliorating wild- type forms of N. gonorrhoeae.
  • the present description relates to use of a compound of Formula (I) 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 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 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 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 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 substituted 2-pyridinone compounds selected from a compound of Formula (I):
  • Ri is a bicyclic or tricyclic ring system selected from the group consisting of
  • R 2 is hydrogen, cyano, Ci_ 8 alkyl, hydroxyl-Ci_ 8 alkyl, formyl-Ci_ 8 alkyl, Ci-galkoxy-Ci-galkyl,
  • Ci-galkoxy C 2 _galkenyl, C 2 _galkynl, carboxyl, amino-Ci_galkyl, aryl or C3_i 4 cycloalkyl;
  • R 3 is hydrogen, hydroxyl, Ci_galkoxy or amino;
  • R 5 is hydrogen, halogen, hydroxyl, oxo, cyano, nitro, Ci_galkyl, hydroxyl-Ci-galkyl,
  • halo-Ci-galkyl Ci-galkoxy, halo-Ci-galkoxy, Ci-galkyl-thio, carboxyl, Ci-galkyl-carbonyl, Ci-galkoxy-carbonyl, amino-carbonyl, amino, Ci-galkyl-amino, (C 1 _galkyl) 2 -amino, C 2 _galkenyl- amino, (C 2 _galkenyl) 2 -amino, C 2 _galkynyl-amino, (C 2 _galkynyl) 2 -amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl,
  • Ci-galkoxy-Ci-galkyl-amino (Ci-galkoxy-Ci-galky ⁇ Ci-galky ⁇ -amino,
  • aryl-C 1 _galkyl 2 -amino-C 1 _galkyl, heteroaryl, heteroaryl-Ci-galkyl, heteroaryl-amino, heteroaryl-Ci-galkyl-amino, (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino,
  • heteroaryl-C 1 _galkyl 2 -amino
  • heteroaryl-Ci-galkyl-amino-Ci-galkyl
  • heteroary ⁇ Ci-galky ⁇ amino-Ci-galkyl (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-oxy, heterocyclyl-Ci-galkoxy, heterocyclyl-amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-Ci-galkyl, (heterocycly ⁇ Ci-galky ⁇ amino-Ci-galkyl,
  • heterocyclyl-C 1 _galkyl 2 -amino-C 1 _galkyl, heterocyclyl-oxy-amino
  • R 6 is azido, halogen, hydroxyl, cyano, nitro, Ci-galkyl, halo-Ci-galkyl, hydroxyl-Ci-galkyl, Ci-galkoxy-Ci-galkyl, Ci-galkoxy, halo-Ci-galkoxy, hydroxyl-Ci-galkoxy, carboxyl, Ci-galkyl-carbonyl, Ci-galkoxy-carbonyl, amino, Ci-galkyl-amino, (C 1 _galkyl) 2 -amino, amino-Ci-galkyl-amino, (amino-Ci-galky ⁇ Ci-galky ⁇ amino,
  • heteroaryl-Ci-galkyl-amino (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino,
  • heteroaryl-C 1 _galkyl 2 -amino
  • heteroaryl-Ci-galkyl-amino-Ci-galkyl
  • heteroaryl-C 1 -galkyl 2 -amino-C 1 _galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino-Ci-galkyl or heterocyclyl-oxy;
  • R 9 is Ci-galkyl, amino, Ci_galkyl-amino, (C 1 _galkyl) 2 -amino, amino-Ci_galkyl,
  • 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, lH-imidazolyl or pyridinyl; and,
  • heterocyclyl selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl,
  • Cs- ⁇ cycloalkyl 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H-
  • heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-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, 4,5-dihydro-lH- imidazol-2-yl, 1 ,4,5,6-tetrahydropyrimidin-2-yl, 1 ,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, te
  • the present description further relates to a compound of Formula (I) or a form thereof, wherein:
  • R 2 is hydrogen, cyano, Ci-galkyl, hydroxyl-Ci_galkyl, formyl-Ci_galkyl, Ci-galkoxy-Ci-galkyl, Ci-galkoxy, C 2 _galkenyl, C 2 _galkynl, carboxyl, amino-Ci-galkyl, aryl or C 3 -i 4 cycloalkyl;
  • R 3 is hydrogen, hydroxyl, Ci-galkoxy or amino;
  • R5 is hydrogen, halogen, cyano, Ci-galkyl, hydroxyl-Ci_galkyl, halo-Ci_galkyl,
  • heterocyclyl is optionally substituted with one, two or three substituents each
  • R9 is Ci-galkyl, amino, Ci-galkyl-amino, (Ci_galkyl) 2 -amino, amino-Ci-galkyl,
  • the present description further relates to a compound of Formula (I) or a form thereof, wherein the ring system R la , and R lc is selected from a R lal , Ri b i and R lcl ring system, respectively:
  • R 5a , R 5b , R 5c and R 5d when present, are selected from the group consisting of: hydrogen, halogen, hydroxyl, cyano, nitro, Ci-galkyl, hydroxyl-Ci-galkyl, halo-Ci-galkyl, Ci-galkoxy, halo-Ci-galkoxy, Ci-galkyl-thio, carboxyl, Ci-galkyl-carbonyl,
  • Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl
  • C 1 _galkyl 2 -amino-carbonyl, Ci-galkyl-amino-Ci-galkyl-carbonyl, (C 1 _ 8 alkyl) 2 -amino-C 1 _ 8 alkyl-carbonyl, Cs-ncycloalkyl, Cs-ncycloalkyl-Ci-galkyl, Cs-ncycloalkyl-oxy, Cs-ncycloalkyl-Ci-galkoxy, Cs-wcycloalkyl-amino,
  • aryl-C 1 -galkyl 2 -amino-C 1 _galkyl, heteroaryl, heteroaryl-Ci-galkyl, heteroaryl-amino, heteroaryl-Ci-galkyl-amino, (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino,
  • heteroaryl-C 1 _galkyl 2 -amino
  • heteroaryl-Ci-galkyl-amino-Ci-galkyl
  • heteroary ⁇ Ci-galky ⁇ amino-Ci-galkyl (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-oxy, heterocyclyl-Ci-galkoxy, heterocyclyl-amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-Ci-galkyl, (heterocycly ⁇ Ci-galky ⁇ amino-Ci-galkyl,
  • heterocyclyl-C 1 _galkyl 2 -amino-C 1 _galkyl, heterocyclyl-oxy-amino
  • R 6 is azido, halogen, hydroxyl, cyano, nitro, Ci-galkyl, halo-Ci-galkyl, hydroxyl-Ci-galkyl, Ci-galkoxy-Ci-galkyl, Ci-galkoxy, halo-Ci-galkoxy, hydroxyl-Ci-galkoxy, carboxyl, Ci-galkyl-carbonyl, Ci-galkoxy-carbonyl, amino, Ci-galkyl-amino, (C 1 _galkyl) 2 -amino, amino-Ci-galkyl-amino, (amino-Ci-galky ⁇ Ci-galky ⁇ amino,
  • aryl-C 1 _galkyl 2 -amino, aryl-Ci-galkyl-amino-Ci-galkyl,
  • heteroaryl-Ci-galkyl-amino (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino,
  • heteroaryl-C 1 _galkyl 2 -amino
  • heteroaryl-Ci-galkyl-amino-Ci-galkyl
  • heteroaryl-C 1 _galkyl 2 -amino-C 1 _galkyl, heterocyclyl, heterocyclyl-Ci_galkyl, heterocyclyl-amino-Ci-galkyl or heterocyclyl-oxy;
  • R 9 is Ci-galkyl, amino, Ci_galkyl-amino, (C 1 _galkyl) 2 -amino, amino-Ci_galkyl,
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein R 5a , R 5 b, R 5c and R 5 d substituted on a R lal , Ribi and R lcl ring system is: 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, lH-imidazolyl or pyridinyl; and, heterocyclyl selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl, 2,5-dihydro- IH-pyrrolyl, 4,5-dihydro- IH-imidazolyl, 1 ,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein R 5a , R 5c and R 5 d substituted on a R lal , Ribi and R lcl ring system is:
  • Cs-ncycloalkyl 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H-
  • heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-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, 4,5-dihydro-lH- imidazol-2-yl, 1 ,4,5,6-tetrahydropyrimidin-2-yl, 1 ,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, te
  • the present description further relates to a compound of Formula (I) or a form thereof, wherein the ring system R la , R 3 ⁇ 4 and R lc is selected from the R lal , Ri b i and R lcl ring system, respectively, and R 5a , R 5b , R 5c and R 5d , when present, are selected from the group consisting of:
  • Ci-ioalkyl-amino-Ci-galkyl (Ci-ioalkyl amino-Ci-galkyl,
  • Ci-galkyl-amino-Ci-galkyl-carbonyl (Ci-galkyl amino-Ci-galkyl-carbonyl or heterocyclyl-Ci-galkyl;
  • heterocyclyl is optionally substituted with one, two or three substituents each
  • R 9 is Ci-galkyl, amino, Ci-galkyl-amino, (Ci-galkyl amino, amino-Ci-galkyl,
  • 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 present description also relates to use of a compound of Formula (I) or a form thereof wherein Rs a , Rs , R 5c and Rsa substituted on a R lal , R ⁇ i and R lcl ring system is:
  • heterocyclyl selected in each instance, when present, from pyrrolidin-l-yl.
  • the present description further relates to a compound of Formula (I) or a form thereof, wherein the ring system R la , and R lc is selected from the R lal , R ⁇ i and R lcl ring system, respectively, and Rs a , Rs b , R 5c and Rsa, when present, are selected from the group consisting of (where "Ring” in the table below indicates whether an R lal , R ⁇ i or R lcl ring system is selected; and, "— " indicates that one or more of R 5a , R 5b , R 5c or R 5d are not present):
  • 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 present description further relates to a compound of Formula (I) or a form thereof, wherein the ring system R ⁇ , Rn and R lm is selected from a Rm, Rni and R lml ring system, respectively:
  • R 5a , R 5 b, R 5c , Rsa, R 5e and R5 when present are selected from the group consisting of:
  • Ci-galkyl-carbonyl hydrogen, halogen, hydroxyl, cyano, nitro, Ci-galkyl, hydroxyl-Ci-galkyl, halo-Ci-galkyl, Ci- 8 alkoxy, halo-Ci-galkoxy, Ci-galkyl-thio, carboxyl, Ci-galkyl-carbonyl,
  • Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl
  • aryl-C 1 -galkyl 2 -amino-C 1 _galkyl, heteroaryl, heteroaryl-Ci-galkyl, heteroaryl-amino, heteroaryl-Ci-galkyl-amino, (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino,
  • heteroaryl-C 1 _galkyl 2 -amino
  • heteroaryl-Ci-galkyl-amino-Ci-galkyl
  • heteroary ⁇ Ci-galky ⁇ amino-Ci-galkyl (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-oxy, heterocyclyl-Ci-galkoxy, heterocyclyl-amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-Ci-galkyl, (heterocycly ⁇ Ci-galky ⁇ amino-Ci-galkyl,
  • R 6 is azido, halogen, hydroxyl, cyano, nitro, Ci-galkyl, halo-Ci-galkyl, hydroxyl-Ci-galkyl, Ci-galkoxy-Ci-galkyl, Ci- 8 alkoxy, halo-Ci-galkoxy, hydroxyl-Ci-galkoxy, carboxyl, Ci-galkyl-carbonyl, Ci-galkoxy-carbonyl, amino, Ci-galkyl-amino, (C 1 _galkyl) 2 -amino, amino-Ci-galkyl-amino, (amino-Ci-galky ⁇ Ci-galky ⁇ amino,
  • aryl-C 1 _galkyl 2 -amino, aryl-Ci-galkyl-amino-Ci-galkyl,
  • heteroaryl-Ci-galkyl-amino (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino,
  • heteroaryl-C 1 _galkyl 2 -amino
  • heteroaryl-Ci-galkyl-amino-Ci-galkyl
  • heteroaryl-C 1 _galkyl 2 -amino-C 1 _galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino-Ci-galkyl or heterocyclyl-oxy;
  • R9 is Ci-galkyl, amino, Ci-galkyl-amino, (C 1 _ 8 alkyl) 2 -amino, amino-Ci-galkyl,
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein R 5a , Rs c , R 5d , R 5e and R 5f substituted on a R , R 111 and R lml ring system is:
  • Cs-ncycloalkyl 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, lH-imidazolyl or pyridinyl; and,
  • heterocyclyl selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl, 2,5-dihydro- lH-pyrrolyl, 4,5-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,
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein R 5a , R 5 b, R 5c , R 5 d, R 5e and R 5 f substituted on a R , Rin and R lml ring system is:
  • Cs-ncycloalkyl 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H-
  • heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-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, 4,5-dihydro-lH- imidazol-2-yl, 1 ,4,5,6-tetrahydropyrimidin-2-yl, 1 ,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, te
  • the present description further relates to a compound of Formula (I) or a form thereof, wherein the ring system Ri k , Rn and R lm is selected from the R , Rin and R lml ring system, respectively, and Rs a , Rs , R 5c , R 5d , R 5e and Rs f , when present, are selected from the group consisting of:
  • the present description further relates to a compound of Formula (I) or a form thereof, wherein the ring system R ⁇ , Rn and R lm is selected from a Rm, Rni and R lml ring system, respectively, and Rs a , Rs , R 5c , R 5 d, R 5e and R5 when present, are selected from the group consisting of (where "Ring” in the table below indicates whether an Rm, Rm or R lml ring system is selected; and, "— " indicates that one or more of R 5a , R 5 b, R 5c , Rsa, R 5e or R 5 f are not present):
  • 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 present description further relates to a compound of Formula (I) or a form thereof, wherein the ring system R ⁇ , Rn and Ry is selected from a Rm, Rm and R ⁇ ring system, respectively:
  • Rs a and Rs when present, are selected from the group consisting of: hydrogen, halogen, hydroxyl, cyano, nitro, Ci-galkyl, hydroxyl-Ci-galkyl, halo-Ci-galkyl, Ci-galkoxy, halo-Ci-galkoxy, Ci-galkyl-thio, carboxyl, Ci-galkyl-carbonyl,
  • Ci-galkoxy-carbonyl amino-carbonyl, amino, Ci-galkyl-amino,
  • Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl
  • aryl-C 1 -galkyl 2 -amino-C 1 _galkyl, heteroaryl, heteroaryl-Ci-galkyl, heteroaryl-amino, heteroaryl-Ci-galkyl-amino, (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino,
  • heteroaryl-C 1 _galkyl 2 -amino
  • heteroaryl-Ci-galkyl-amino-Ci-galkyl
  • heteroary ⁇ Ci-galky ⁇ amino-Ci-galkyl (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-oxy, heterocyclyl-Ci-galkoxy, heterocyclyl-amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-Ci-galkyl, (heterocycly ⁇ Ci-galky ⁇ amino-Ci-galkyl,
  • heterocyclyl-C 1 -galkyl 2 -amino-C 1 _galkyl, heterocyclyl-oxy-amino
  • R 6 is azido, halogen, hydroxyl, cyano, nitro, Ci-galkyl, halo-Ci-galkyl, hydroxyl-Ci-galkyl, Ci-galkoxy-Ci-galkyl, Ci-galkoxy, halo-Ci-galkoxy, hydroxyl-Ci-galkoxy, carboxyl, Ci-galkyl-carbonyl, Ci-galkoxy-carbonyl, amino, Ci-galkyl-amino, (C 1 _galkyl) 2 -amino, amino-Ci-galkyl-amino, (amino-Ci-galky ⁇ Ci-galky ⁇ amino,
  • aryl-C 1 _galkyl 2 -amino, aryl-Ci-galkyl-amino-Ci-galkyl,
  • heteroaryl-Ci-galkyl-amino (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino,
  • heteroaryl-C 1 _galkyl 2 -amino
  • heteroaryl-Ci-galkyl-amino-Ci-galkyl
  • heteroaryl-C 1 _galkyl 2 -amino-C 1 _galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino-Ci-galkyl or heterocyclyl-oxy;
  • R9 is Ci-galkyl, amino, Ci-galkyl-amino, (C 1 _galkyl) 2 -amino, amino-Ci-galkyl,
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein Rs a and Rs substituted on a Rmi, Rm and R 1j1 ring system is:
  • Cs-ncycloalkyl 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, lH-imidazolyl or pyridinyl; and,
  • heterocyclyl selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl, 2,5-dihydro- lH-pyrrolyl, 4,5-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,
  • Cs- ⁇ 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H-
  • heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-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, 4,5-dihydro-lH- imidazol-2-yl, 1 ,4,5,6-tetrahydropyrimidin-2-yl, 1 ,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, te
  • the present description further relates to a compound of Formula (I) or a form thereof, wherein the ring system Rm Rn and Ry is selected from the Ri h i, Rm and R 1j1 ring system, respectively, and Rs a and Rs , when present, are 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.
  • the present description further relates to a compound of Formula (I) or a form thereof, wherein the ring system Rm Rn and Ry is selected from the R ⁇ i, Rm and R 1j1 ring system, respectively, and Rs a and Rs , when present, are selected from the group consisting of (where "Ring” in the table below indicates whether an Rm, Rm and R ⁇ ring system is selected; and, "— " indicates that one or more of R 5a or R 5b are not present):
  • 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 present description further relates to a compound of Formula (I) or a form thereof, wherein the ring system R 1(1 , Ri e , Ri f and R lg is selected from a R 1( JI, R le i, Rin and R lgl ring system, respectively:
  • Rs a , Rs t ,, R 5c and Rsa when present, are selected from the group consisting of: hydrogen, halogen, hydroxyl, , cyano, nitro, Ci-galkyl, hydroxyl-Ci-galkyl, halo-Ci-galkyl, Ci- 8 alkoxy, halo-Ci-galkoxy, Ci-galkyl-thio, carboxyl, Ci-galkyl-carbonyl,
  • Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl
  • aryl-C 1 -galkyl 2 -amino-C 1 _galkyl, heteroaryl, heteroaryl-Ci-galkyl, heteroaryl-amino, heteroaryl-Ci-galkyl-amino, (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino,
  • heteroaryl-C 1 _galkyl 2 -amino
  • heteroaryl-Ci-galkyl-amino-Ci-galkyl
  • heteroary ⁇ Ci-galky ⁇ amino-Ci-galkyl (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-oxy, heterocyclyl-Ci-galkoxy, heterocyclyl-amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-Ci-galkyl, (heterocycly ⁇ Ci-galky ⁇ amino-Ci-galkyl,
  • R 6 is azido, halogen, hydroxyl, cyano, nitro, Ci-galkyl, halo-Ci-galkyl, hydroxyl-Ci-galkyl, Ci-galkoxy-Ci-galkyl, Ci- 8 alkoxy, halo-Ci-galkoxy, hydroxyl-Ci-galkoxy, carboxyl, Ci-galkyl-carbonyl, Ci-galkoxy-carbonyl, amino, Ci-galkyl-amino, (C 1 _galkyl) 2 -amino, amino-Ci-galkyl-amino, (amino-Ci-galky ⁇ Ci-galky ⁇ amino,
  • aryl-C 1 _galkyl 2 -amino, aryl-Ci-galkyl-amino-Ci-galkyl,
  • heteroaryl-Ci-galkyl-amino (heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino,
  • heteroaryl-C 1 _galkyl 2 -amino
  • heteroaryl-Ci-galkyl-amino-Ci-galkyl
  • heteroaryl-C 1 _galkyl 2 -amino-C 1 _galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino-Ci-galkyl or heterocyclyl-oxy;
  • R9 is Ci-galkyl, amino, Ci-galkyl-amino, (C 1 _ 8 alkyl) 2 -amino, amino-Ci-galkyl,
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein R 5a , R 5c and R 5d substituted on a R 1( JI, R le i, Rin and R lgl ring system is: Cs- ⁇ 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, lH-imidazolyl or pyridinyl; and,
  • heterocyclyl selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl, 2,5-dihydro- lH-pyrrolyl, 4,5-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,
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein R 5a , R 5b , R 5c and R 5d substituted on a R 1( JI, R le i, Rin and R lgl ring system is: Cs- ⁇ 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 IH-pyrrol- l-yl, thiazol-2-yl, 1H-
  • heterocyclyl selected in each instance, when present, from azetidin- l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-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, 4,5-dihydro- lH- imidazol-2-yl, 1 ,4,5,6-tetrahydropyrimidin-2-yl, 1 ,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-y
  • the present description further relates to a compound of Formula (I) or a form thereof, wherein the ring system R 1(1 , Ri e , Ri f and R lg is selected from the R 1( JI, Ri e i, Rin and R lgl ring system, respectively, and R 5a , R 5b , R 5c and R 5d , when present, are 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.
  • the present description further relates to a compound of Formula (I) or a form thereof, wherein the ring system R 1(1 , Ri e , Ri f and R lg is selected from the R 1( JI, Riei , Rin and R lgl ring system, respectively, and R 5a , R 5 b, R 5c and R 5 d, when present, are selected from the group consisting of (where "Ring” in the table below indicates whether an R 1( JI, R le i, Rin or R lgl ring system is selected; and, "— " indicates that one or more of Rs a , Rs , R 5c or Rsa are not present):
  • 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 of Formula (I) 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.
  • the compound of Formula (I) or a form thereof (wherein compound number (#*) indicates that the salt form was isolated) is selected from the group consisting of:
  • 53 5-amino-4-hydroxy-6-(l-methyl-lH-indol-5-yl)-2-oxo-l,2-dihydropyridine-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.
  • the compound or a form thereof is isolated as a salt.
  • the present description includes 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 Formula (I) or a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) 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 of Formula (I) or a form thereof (wherein compound number (#*) indicates that the salt form was isolated) to the subject, selected from the group consisting of:
  • 53 5-amino-4-hydroxy-6-(l-methyl-lH-indol-5-yl)-2-oxo-l,2-dihydropyridine-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 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 of Formula (I) or a form thereof to the subject, selected from the group consisting of:
  • the present description includes 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 Formula (I) or a form thereof to the subject.
  • the present description includes 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 salt of Formula (I) or a form thereof to the subject.
  • the compound salt 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-galkyl, Ci_ 6 alkyl, C 1 _ 4 alkyl and the like.
  • a Ci-ioalkyl radical may be optionally substituted where allowed by available valences.
  • C 2 -galkenyl 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 -galkenyl includes C 2 - 6 alkenyl, C 2 - 4 alkenyl and the like.
  • a C 2 -galkenyl 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 -galkynyl 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-salkoxy includes Ci ⁇ alkoxy, Ci_ 4 alkoxy and the like.
  • a Ci-salkoxy radical may be optionally substituted where allowed by available valences.
  • C 3 _i 4 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, C 3 _iocycloalkyl and the like.
  • a C3_ 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,
  • C 2 - 8 alkenyl-amino refers to a radical of the formula:
  • (C 2 - 8 alkenyl) 2 -amino refers to a radical of the formula: -N(C 2 _ 8 alkenyl) 2 .
  • the term refers to a radical of the formula: -Ci-salkyl-NH-C ⁇ alkenyl.
  • the term ' C 2 - 8 alkenyl) 2 -amino-C 1 _ 8 alkyr refers to a radical of the formula: -C 1 _ 8 alkyl-N(C 2 - 8 alkenyl) 2 .
  • Ci-salkoxy-Ci-salkyl refers to a radical of the formula: -Ci-galkyl-O-Ci-galkyl.
  • Ci-galkoxy-Ci-galkyl-amino refers to a radical of the formula: -O-Ci.galkyl-NH-C ⁇ alkyl-O-C ⁇ alkyl.
  • (C 1 _galkoxy-C 1 _galkyl) 2 -amino refers to a radical of the formula: -N(C 1 _galkyl-0-C 1 -galkyl) 2 .
  • Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl refers to a radical of the formula: -Ci.galkyl-NH-C ⁇ alkyl-O-Ci.galkyl.
  • (C 1 _galkoxy-C 1 -galkyl) 2 -amino-C 1 -galkyl refers to a radical of the formula: -C 1 -galkyl-N(C 1 - 8 alkyl-0-C 1 -galkyl) 2 .
  • (Ci-galkoxy-Ci-galky ⁇ Ci-galky ⁇ -amino) refers to a radical of the formula: -NK ⁇ galkylX ⁇ galkyl-O-Ci.galkyl)].
  • (Ci-galkoxy-Ci-galky ⁇ Ci-galky ⁇ -amino-Ci-galkyl) refers to a radical of the formula: -Ci-galkyl-NfCCi-galky CCi-galkyl-O-Ci-galkyl)].
  • Ci-galkoxy-carbonyl refers to a radical of the formula: -C(0)-0-Ci_ 8 alkyl.
  • Ci-galkyl-amino refers to a radical of the formula:
  • (C 1 _galkyl) 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: -Ci.galkyl-NH-C oalkyl.
  • (C 1 _ 1 oalkyl) 2 -amino-C 1 -galkyl refers to a radical of the formula: -C 1 _galkyl-N(C 1 _ 1 oalkyl) 2 .
  • Ci-galkyl-amino-Ci-galkyl-amino refers to a radical of the formula: -NH-Ci.galkyl-NH-Ci.galkyl.
  • (C 1 -galkyl) 2 -amino-C 1 _galkyl-amino refers to a radical of the formula: -NH-C 1 - 8 alkyl-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-salky ⁇ i-amino-Ci-salkyl-amino-Ci-salkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-8 alkyl-N(C 1-8 alkyl) 2 .
  • (Ci-salkyl-amino-Ci-salky ⁇ Ci-salky ⁇ amino refers to a radical of the formula: -NKC ⁇ alkylXCi.galkyl-NH-C ⁇ alkyl)].
  • (Ci-galkyl-amino-Ci-galky ⁇ Ci-galky ⁇ amino-Ci-galkyl) refers to a radical of the formula: -Ci- 8 alkyl-N[(Ci- 8 alkyl)(Ci- 8 alkyl-NH-Ci- 8 alkyl)] .
  • [(C 1-8 alkyl) 2 -aiidno-C 1-8 alkyl,C 1-8 alkyl]amino-C 1-8 alky ' 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-amino-C 1 _ 8 alkyl) 2 -amino-C 1 _ 8 alkyl refers to a radical of the formula: -C 1 _ 8 alkyl-N(C 1 _ 8 alkyl-NH-C 1 _ 8 alkyl) 2 .
  • Ci-salkyl-amino-carbonyl refers to a radical of the formula:
  • (C 1 _galkyl) 2 -amino-carbonyl refers to a radical of the formula: -C(0)-N(C 1 _ 8 alkyl) 2 .
  • C ⁇ alkyl-amino-C ⁇ alkyl-carbonyr refers to a radical of the formula: -C(0)-C 1 - 8 alkyl-NH-C 1 _ 8 alkyl.
  • (C 1 _ 8 alkyl) 2 -amino-C 1 _ 8 alkyl-carbonyl refers to a radical of the formula: -C(0)-C 1 _ 8 alkyl-N(C 1 _ 8 alkyl) 2 .
  • Ci-salkyl-carbonyl refers to a radical of the formula:
  • Ci-salkyl-carbonyl-amino refers to a radical of the formula:
  • (Ci-salkyl-carbony ⁇ Ci-salky ⁇ amino-Ci-salkyl) refers to a radical of the formula: -C 1 - 8 alkyl-N[(C 1 _ 8 alkyl)(-C(0)-C 1 - 8 alkyl)].
  • Ci-salkyl-thio refers to a radical of the formula:
  • C ⁇ salkynyl-Ci-salkyl refers to a radical of the formula: -Ci-salkyl-C ⁇ salkynyl.
  • C 2 _galkynyl- amino refers to a radical of the formula:
  • (C 2 - 8 alkynyl) 2 -amino refers to a radical of the formula: -N(C 2 -8alkynyl) 2 .
  • the term refers to a radical of the formula: -C 1 _ 8 alkyl-NH-C 2 - 8 alkynyl.
  • (C 2 - 8 alkynyl) 2 -amino-C 1 - 8 alkyl refers to a radical of the formula: -C 1 _8alkyl-N(C 2 -8alkynyl) 2 .
  • amino refers to a radical of the formula: -NH 2 .
  • amino-Ci-galkyl refers to a radical of the formula:
  • amino-Ci-galkyl-amino refers to a radical of the formula: -NH-C 1 _ 8 alkyl-NH 2 .
  • (amino-C 1 _galkyl) 2 -amino) refers to a radical of the formula: -N(C 1 _ 8 alkyl-NH 2 ) 2 .
  • amino-C 1 _ 8 alkyl refers to a radical of the formula: -C 1 _ 8 alkyl-N(C 1 _ 8 alkyl-NH 2 ) 2 .
  • amino-Ci-galkyl-amino-Ci-galkyl refers to a radical of the formula: -C 1 - 8 alkyl-NH-C 1 - 8 alkyl-NH 2 .
  • amino- ⁇ galky ⁇ Ci-galky ⁇ amino refers to a radical of the formula: -N[(C 1 _ 8 alkyl)(C 1 _ 8 alkyl-NH 2 )] .
  • amino-Ci-galky ⁇ Ci-galky ⁇ amino-Ci-galkyl refers to a radical of the formula: -C 1 - 8 alkyl-N[(C 1 - 8 alkyl)(C 1 - 8 alkyl-NH 2 )].
  • amino-carbonyl refers to a radical of the formula:
  • aryl-Ci-galkoxy refers to a radical of the formula:
  • aryl- ⁇ galkoxy-carbonyl-amino refers to a radical of the formula: -NH-C(0)-0-C 1 _ 8 alkyl-aryl.
  • aryl-Ci-galkyl refers to a radical of the formula:
  • the term refers to a radical of the formula: -NH-Ci-galkyl-aryl.
  • (aryl-C 1 _ 8 alkyl) 2 -amino refers to a radical of the formula: -NtCd-galkyl-aryDJ.
  • aryl- ⁇ galkyl-amino-Ci-galkyl refers to a radical of the formula: - ⁇ galkyl-NH-Ci-galkyl-aryl.
  • (aryl-C 1 _ 8 alkyl) 2 -amino-C 1 _ 8 alkyl refers to a radical of the formula: -C 1 _ 8 alkyl-N[(C 1 _galkyl-aryl) 2 ].
  • the term refers to a radical of the formula: -N[(Ci_ 8 alkyl)(aryl)] .
  • ary ⁇ Ci-galky ⁇ amino-Ci-galkyl refers to a radical of the formula: -Ci. 8 alkyl-N[(Ci- 8 alkyl)(aryl)].
  • the term refers to a radical of the formula: -N[(Ci- 8 alkyl)(Ci- 8 alkyl-aryl)] .
  • aryl-Ci-galky ⁇ Ci-galky ⁇ amino-Ci-galkyl refers to a radical of the formula: -Ci- 8 alkyl-N[(Ci- 8 alkyl)(Ci- 8 alkyl-aryl)].
  • aryl-amino refers to a radical of the formula: -NH-aryl.
  • (aryl) 2 -amino refers to a radical of the formula: -N[(aryl) 2 ].
  • aryl-amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-NH-aryl.
  • (aryl) 2 -amino-C 1 _galkyl refers to a radical of the formula: -Ci. 8 alkyl-N[(aryl) 2 ].
  • aryl-amino-carbonyl refers to a radical of the formula: -C(0)-NH-aryl.
  • carboxyl refers to a radical of the formula: -COOH, -C(0)OH or -C0 2 H.
  • (carboxyl-Ci-galky ⁇ Ci-galky ⁇ amino-carbonyl-amino refers to a radical of the formula: -NH-C(0)-N[(C 1 _galkyl)(C 1 -galkyl-C0 2 H)].
  • Cs-wcycloalkyl-Ci-galkoxy refers to a radical of the formula:
  • Cs- ⁇ cycloalkyl-amino refers to a radical of the formula: -NH-C 3-14 cycloalkyl.
  • Cs- H cycloalkyl-amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-NH-Cs-wcycloalkyl.
  • (Cs- M cycloalkyl amino-Ci-galkyl) refers to a radical of the formula: - ⁇ galkyl-N[(C 3 -i 4 cycloalkyl) 2 ] .
  • Cs- H cycloalkyl-Ci-galkyl-amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-Cs- H cycloalkyl.
  • (Cs- M cycloalkyl-Ci-galkyl amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-N ⁇ galkyl-Cs-wcycloalkyl) ⁇ .
  • (Cs- H cycloalky ⁇ Ci-galky ⁇ amino-Ci-galkyl) refers to a radical of the formula: -Ci-galkyl-N Ci-galkylXCs- H cycloalkyl)].
  • (Cs-wcycloalkyl-Ci-galky ⁇ Ci-galky ⁇ amino-Ci-galkyl) refers to a radical of the formula: -Ci-galkyl-NfiCi-galky ⁇ iCi-galkyl-Cs- ⁇ cycloalkyl)].
  • C 3 _i 4 cycloalkyl-oxy refers to a radical of the formula: -O-Cs-ncycloalkyl.
  • 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:
  • halo-Ci-galkyl includes halo-Ci_ 6 alkyl, halo-C i ⁇ alkyl and the like.
  • halo-Ci-galkyl-amino refers to a radical of the formula: -NH-Ci-galkyl-halo.
  • halo-Ci-galkyl ⁇ -amino refers to a radical of the formula:
  • halo-Ci-galkyl-amino-Ci-galkyl refers to a radical of the formula: -NH-Ci_galkyl-halo.
  • (halo-C 1 _ 8 alkyl) 2 -amino-C 1 _ 8 alkyl refers to a radical of the formula: -C 1 _ 8 alkyl-N(C 1 _galkyl-halo) 2 .
  • heteroaryl-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-heteroaryl.
  • heteroaryl- amino refers to a radical of the formula:
  • (heteroaryl) 2 -amino refers to a radical of the formula: -N[(heteroaryl) 2 ].
  • heteroaryl-Ci-galkyl-amino refers to a radical of the formula: -NH-Ci-galkyl-heteroaryl.
  • heteroaryl-C 1 _ 8 alkyl) 2 -amino refers to a radical of the formula: -N[(C 1 _ 8 alkyl-heteroaryl) 2 ] .
  • heteroaryl-Ci-galkyl-amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-heteroaryl.
  • heteroaryl-C 1 -galkyl) 2 -amino-C 1 _galkyl refers to a radical of the formula: -C 1 _galkyl-N[(C 1 _galkyl-heteroaryl) 2 ].
  • heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino refers to a radical of the formula: -N Ci-galkylXCi-galkyl-heteroaryl)].
  • heteroary ⁇ Ci-galky ⁇ amino-Ci-galkyl refers to a radical of the formula: -Ci- 8 alkyl-N[(Ci- 8 alkyl)(heteroaryl)].
  • heteroaryl-Ci-galky ⁇ Ci-galky ⁇ amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-N Ci-galkylXCi-galkyl -heteroaryl)].
  • heterocyclyl-Ci-galkoxy refers to a radical of the formula: -O-Ci-galkyl-heterocyclyl.
  • heterocyclyl-Ci-galkyl refers to a radical of the formula:
  • heterocyclyl-amino refers to a radical of the formula: -NH-heterocyclyl.
  • (heterocyclyl) 2 -amino refers to a radical of the formula: -N[(heterocyclyl) 2 ].
  • heterocyclyl-amino-Ci-galkyl refers to a radical of the formula: -Ci-galkyl-NH-heterocyclyl.
  • (heterocyclyl) 2 -amino-C 1 _ 8 alkyl refers to a radical of the formula: -C 1 _galkyl-N[(heterocyclyl) 2 ] .
  • heterocyclyl-Ci-salkyl-amino-C ⁇ alkyl refers to a radical of the formula: -Ci-salkyl-NH-C ⁇ alkyl-heterocyclyl.
  • heterocyclyl-C 1 _ 8 alkyl) 2 -amino-C 1 _galkyl refers to a radical of the formula: -C 1 _ 8 alkyl-N[(C 1 _galkyl-heterocyclyl) 2 ].
  • heterocyclyl,C ⁇ alkyl)amino refers to a radical of the formula: -NIXCi-salkylXheterocyclyl)] .
  • heterocycly ⁇ Ci-galky ⁇ amino-Ci-galkyl refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(heterocyclyl)].
  • heterocyclyl-Ci-salky ⁇ Ci-salky ⁇ amino-Ci-salkyl refers to a radical of the formula: -C ⁇ alkyl-N Ci-salkylXC ⁇ alkyl-heterocyclyl)].
  • heterocycly ⁇ Cs- H cycloalkyl-Ci-salky ⁇ amino-Ci-salkyl refers to a radical of the formula: -Ci-salkyl-Nfiheterocycly ⁇ iCi-salkyl-Cs-wcycloalkyl)].
  • heterocyclyl-carbonyl refers to a radical of the formula:
  • heterocyclyl-carbonyl-oxy refers to a radical of the formula: -0-C(0)-heterocyclyl.
  • heterocyclyl-oxy refers to a radical of the formula:
  • heterocyclyl-oxy-amino refers to a radical of the formula: -NH-O-heterocyclyl.
  • heterocyclyl-oxy) 2 -amino refers to a radical of the formula: -N[(-0-heterocyclyl) 2 ].
  • heterocyclyl-oxy ⁇ i-salky ⁇ amino refers to a radical of the formula: -N[(C 1-8 alkyl)(-0-heterocyclyl)] .
  • heterocyclyl-oxy-Ci-salky ⁇ C ⁇ alky ⁇ amino refers to a radical of the formula: -N C ⁇ alkylXCi-salkyl-O-heterocyclyl)].
  • hydroxyl-Ci-salkoxy refers to a radical of the formula: -O-Ci-salkyl-OH, wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
  • ''hydroxyl-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 hydroxy radicals.
  • hydroxyl-Ci-salkyl-amino refers to a radical of the formula: -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-galkyl amino refers to a radical of the formula: -N(Ci-galkyl-OH)2, wherein Ci-galkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
  • '3 ⁇ 4ydroxyl-Ci_galkyl-amino-Ci_galkyr 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-galkyl-amino-Ci-galkyl-amino refers to a radical of the formula: -NH-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_galkyl,Ci_galkyl)amino refers to a radical of the formula: -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.
  • hydroxyl-Ci-galkyl,Ci-galkyl)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.
  • Ci-galkylXCi-galkyl-OH 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.
  • hydroxyl-Ci-galkyl-amino-Ci-galkyl,Ci_galkyl)amino refers to a radical of the formula: -N Ci-galkylXCi-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.
  • 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 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 "...Cs-ncycloalkyl, Cs-ncycloalkyl-Ci-galkyl, aryl, aryl-Ci-galkyl, heteroaryl, heteroaryl-Ci-galkyl, heterocyclyl and heterocyclyl-Ci-galkyl,” are intended to refer to the Cs- ⁇ cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems 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.
  • form means a compound of Formula (I) 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) is a free acid, free base or salt thereof.
  • the form of the compound of Formula (I) is a salt thereof.
  • the form of the compound of Formula (I) is an isotopologue thereof.
  • the form of the compound of Formula (I) is a stereoisomer, racemate, enantiomer or diastereomer thereof.
  • the form of the compound of Formula (I) is a tautomer thereof.
  • the form of the compound of Formula (I) is a pharmaceutically acceptable form.
  • the compound of Formula (I) or a form thereof is isolated for use.
  • isolated means the physical state of a compound of Formula (I) 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.
  • protected means that a functional group in a compound of Formula (I) 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 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 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 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 when a compound of Formula (I) 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.
  • prodrugs of compounds of Formula (I) 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 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.
  • solvates 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) can form salts, which are intended to be included within the scope of this description.
  • Reference to a compound of Formula (I) or a form thereof herein is understood to include reference to salt forms 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.
  • salts of the compounds of the Formula (I) may be formed, for example, by reacting a compound of Formula (I) 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.
  • 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
  • Compounds of Formula (I) and forms thereof may further exist in a tautomeric form (for example, the 4-hydroxy-2-pyridinone core of Formula (I) 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 a form thereof as described herein.
  • a tautomeric form for example, the 4-hydroxy-2-pyridinone core of Formula (I) 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 a form thereof as described herein.
  • the compounds of Formula (I) or a form thereof may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms.
  • the present description is intended toinclude all stereoisomeric forms of the compounds of Formula (I) 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 a form thereof is a substantially pure (S) enantiomer form 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 a form thereof is a substantially pure (R) enantiomer form 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.
  • 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) may be atropisomers (e.g. , substituted biaryls) and are considered as part of this description.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher' s acid chloride
  • 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 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 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 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 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 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- resistant, pen
  • 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 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 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 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 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 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 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 a form thereof having activity against tetracycline-resistant forms of
  • the present description also relates to use of the compound of Formula (I) 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 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 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 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 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 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 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 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 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 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.
  • 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 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 a form thereof and an effective amount of one or more antibiotic or
  • Embodiments of the present description include the use of a compound of Formula (I) 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 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 a form thereof in the preparation of a kit comprising the compound of Formula (I) or a form thereof and instructions for administering an effective amount of the compound of Formula (I) or a form thereof and an effective amount of one or more antibiotic or
  • 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,
  • Mafenide Meropenem, Methicillin, 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, Sulf
  • 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, Sulfanilimide, 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 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 multidrug resistant forms of N. gonorrhoeae.
  • One embodiment of the use of the present description relates to use of a compound of Formula (I) 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 a form thereof to the subject.
  • One embodiment of the use of the present description relates to use of a compound of Formula (I) 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 a form thereof to the subject.
  • One embodiment of the use of the present description relates to use of a compound of Formula (I) 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 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 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 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.
  • One embodiment of the use of the present description relates to a method of use for a compound of Formula (I) 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.
  • One embodiment of the use of the present description relates to a method of use for a compound of Formula (I) 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.
  • One embodiment of the use of the present description relates to a method of use for a compound of Formula (I) 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.
  • One embodiment of the use of the present description relates to a method of use for a compound of Formula (I) 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.
  • One embodiment of the use of the present description relates to use of a compound of Formula (I) 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.
  • One embodiment of the use of the present description relates to use of a compound of Formula (I) 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.
  • One embodiment of the use of the present description relates to use of a compound of Formula (I) 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.
  • One embodiment of the use of the present description relates to use of a compound of Formula (I) or a form thereof in the preparation of a kit comprising the compound of Formula (I) or a form thereof and instructions for administering the compound for treating or ameliorating N. gonorrhoeae in a subject in need thereof.
  • One embodiment of the use of the present description relates to a method of use for a compound of Formula (I) 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 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 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 a form thereof.
  • Another aspect of the description particularly relates to a method of use for a compound of Formula (I) 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 a form thereof.
  • One aspect of the description relates to a method of use for a compound of Formula (I) 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 a form thereof having activity against N.
  • Another aspect of the description relates to a method of use for a compound of Formula (I) 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 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 (gyrAgi / g 5 ) and
  • Another aspect of the description relates to a method of use for a compound of
  • Formula (I) 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 a form thereof having activity against N. gonorrhoeae World Health
  • WHO World Health Organization
  • 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 N. gonorrhoeae 13479 (WHO quinolone high level resistant isolate K), MDR N. gonorrhoeae 13480 (WHO multi-drug resistant isolate L) and MD ⁇ R N.
  • WHO tetracycline ER N. gonorrhoeae 13477
  • ciprofloxacin ER /tetracycline R N. gonorrhoeae 13478 WHO ciprofloxacin intermediate resistant and tetracycline resistant isolate G
  • gonorrhoeae 13481 WHO multi-drug intermediate resistant isolate M
  • 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.
  • Another aspect of the description relates to a method of use for a compound of Formula (I) 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 a form thereof having activity against the
  • Another aspect of the description relates to a method of use for a compound of
  • Formula (I) 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 a form thereof having activity against a N. gonorrhoeae isolate engineered from WHO isolate F (N. gonorrhoeae 13477), where DNA from FA1090 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 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 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.
  • Another aspect of the description relates to a method of use for a compound of
  • Formula (I) 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 a form thereof having activity against N. gonorrhoeae clinical isolates selected from penicillin-resistant (penicillin ) N. gonorrhoeae LGB3, tetracycline-resistant
  • An embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use for a compound of Formula (I) 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 a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use for a compound of Formula (I) 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 a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use for a compound of Formula (I) or a form thereof to treat or ameliorate
  • An embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use for a compound of Formula (I) 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 a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use for a compound of Formula (I) or a form thereof to treat or ameliorate penicillin-sensitive N. gonorrhoeae FA19 or LGB3 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use for a compound of Formula (I) 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 a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use for a compound of Formula (I) 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 a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use for a compound of Formula (I) 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 a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use for a compound of Formula (I) 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 a form thereof to the subject.
  • An embodiment of the use of a compound of Formula (I) or a form thereof includes a method of use for a compound of Formula (I) or a form thereof to treat or ameliorate ciprofloxacin XDR /cefixime XDR /ceftriaxone XDR N. gonorrhoeae F89 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I) or a form thereof to the subject.
  • the terms "effective amount” or “therapeutically effective amount” mean an amount of compound of Formula (I) 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 is orally administered once (once in
  • 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.
  • 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.
  • the "effective amount" of a compound of Formula (I) 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.
  • the effective amount may be the amount required to treat
  • 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.
  • 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., ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 (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, LD 50 /ED 50 .
  • the effective amount is such that a large therapeutic index is achieved.
  • the dosage is within a range of circulating concentrations that include an ED 50 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.
  • concentration-biological effect relationships observed with regard to a compound of Formula (I) or a form thereof indicate a target plasma concentration ranging from approximately 0.001 ⁇ g/mL to approximately 50 ⁇ g/mL, from approximately 0.01 ⁇ g/mL to approximately 20 ⁇ g/mL, from approximately 0.05 ⁇ g/mL to approximately 10 ⁇ g/mL, or from approximately 0.1 ⁇ g/mL to approximately 5 ⁇ g/mL.
  • 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 to about 100 kg (which dose may be adjusted for patients within this weight range, particularly for children under 40 kg).
  • 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 include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration.
  • 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.,
  • a detectable dose e.g., greater than about 0.5 mg/kg
  • a mammal such as a rat, mouse, guinea pig, dog, monkey or human
  • sufficient time for metabolism to occur typically about 30 seconds to about 30 hours
  • 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.
  • Embodiments of the present description include the use of a compound of Formula (I) 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 a form thereof in admixture with one or more
  • Embodiments of the present description include the use of a compound of Formula (I) or a form thereof 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 Formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipient(s).
  • 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.
  • 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;
  • 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.
  • 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.
  • 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.
  • compositions 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.
  • 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.
  • an inert solid diluent for example celluloses, lactose, calcium phosphate or kaolin
  • non-aqueous or oil medium such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
  • compositions described herein may be formulated as suspensions comprising a compound of Formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipient(s) suitable for the manufacture of a suspension.
  • 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.
  • 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
  • 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
  • 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.
  • compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous emulsion or oleaginous suspension.
  • 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.
  • acceptable vehicles and solvents that may be employed are water, Ringer' s solution, and isotonic sodium chloride solution.
  • sterile fixed oils may be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • 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.
  • medium-chain fatty acids e.g. , caprylic and capric acids
  • propylene glycol esters of medium-chain fatty acids e.g., caprylic and capric acids
  • 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.
  • 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.
  • pharmaceutical compositions described herein may comprise a effective amount of a compound of Formula (I) 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.
  • 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
  • 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 the art.
  • the compound forms present in such preparations include amorphous, partially amorphous, partially crystalline or crystalline forms.
  • the pharmaceutical composition may further comprise one or more aqueous solubility enhancer(s), such as a cyclodextrin.
  • a cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -, ⁇ -, and ⁇ -cyclodextrin, and hydroxypropyl- ⁇ -cyclodextrin (HPBC).
  • HPBC hydroxypropyl- ⁇ -cyclodextrin
  • 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.
  • Rx2 Rsb or CH 2 OTBS
  • Halogenated pyridones of Type lc (where Hal represents a halogen such as CI) are prepared through the reaction of nitriles of Type lb with malonyl halides of Type la.
  • Pyridines of Type Id are prepared from pyridones of Type lc via Mitsunobu reaction with a suitable dialkyl azodicarboxylate (such as diisopropyl azodicarboxylate and the like) and benzyl alcohol.
  • a suitable dialkyl azodicarboxylate such as diisopropyl azodicarboxylate and the like
  • Functionalized pyridines of Type le are prepared from pyridines of Type Id via deprotonation of pyridine of Type Id with an appropriate alkyl lithium species (such as n- BuLi and the like) followed by reaction with benzylchloroformate.
  • an appropriate alkyl lithium species such as n- BuLi and the like
  • Boronic ester intermediates of Type lg are prepared from aryl halides of Type If (where Hal represents a halogen such as Br or I, R xl is either Rs a or a suitable protecting group such as Boc, and R x2 is R 5b or CH 2 OTBS (CH 2 -0-tert-butyldimethylsilyl)) via a Miyaura borylation reaction with a suitable Pd catalyst (such as PdCl 2 (dppf) and the like) and an appropriate diboron ester (such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2- dioxaborolane and the like).
  • a suitable Pd catalyst such as PdCl 2 (dppf) and the like
  • diboron ester such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2- dioxaborolane and the
  • Biaryl intermediates of Type lh are prepared from the respective boronic esters of Type lg via Pd catalyzed Suzuki coupling with functionalized pyridines of Type le in the presence of a suitable phosphine ligand (such as t-Bu 3 P and the like) in a suitable biphasic mixture (such as a mixture of THF and water and the like).
  • a suitable phosphine ligand such as t-Bu 3 P and the like
  • a suitable biphasic mixture such as a mixture of THF and water and the like.
  • Compounds of Type li are prepared from biaryl intermediates of Type lh by global benzyl group deprotection via suitable methods (such as hydrogenation in the presence of a suitable Pd catalyst (such as Pd/C and the like) or treatment with a suitable acid (such as TFA and the like).
  • suitable methods such as hydrogenation in the presence of a suitable Pd catalyst (such as Pd/C and the like) or treatment with a suitable acid (such as TFA and the like).
  • Boronic ester intermediates of Type 2b are prepared from 6-haloindoles of Type 2a (where Hal represents a halogen such as Br or I) via a Miyaura borylation reaction with a suitable Pd catalyst (such as PdCl 2 (dppf) and the like) and an appropriate diboron ester (such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane and the like).
  • a suitable Pd catalyst such as PdCl 2 (dppf) and the like
  • diboron ester such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane and the like.
  • Biaryl pyridines of Type 2c are prepared from the corresponding boronic esters of
  • Type 2b through a Pd catalyzed Suzuki coupling with functionalized pyridines of Type le in the presence of a suitable phosphine ligand (such as t-Bu 3 P and the like) in a suitable biphasic mixture (such as a mixture of THF and water and the like).
  • a suitable phosphine ligand such as t-Bu 3 P and the like
  • a suitable biphasic mixture such as a mixture of THF and water and the like.
  • Indoles of Type 2d are prepared from the corresponding N-Boc amines of Type 2c via Boc cleavage using a suitable acid (such as TFA and the like) followed by treatment with an appropriate aldehyde in the presence of a hydride source (such as NaBH(OAc) 3 and the like).
  • a suitable acid such as TFA and the like
  • an appropriate aldehyde in the presence of a hydride source (such as NaBH(OAc) 3 and the like).
  • Compounds of Type 2e are prepared via global benzyl group deprotection of pyridines of Type 2d with a suitable acid (such as TFA and the like).
  • Amides of Type 3b are prepared via treatment of oximes of Type 3a (where Hal represents a halogen such as Br or I) with an acid (such as PPA and the like).
  • Boc-protected amines of Type 3c are prepared via reduction of amides of Type 3b with a suitable hydride source (such as borane and the like) followed by treatment with Boc 2 0.
  • a suitable hydride source such as borane and the like
  • Boronic ester intermediates of Type 3d are prepared from amines of Type 3c via a Miyaura borylation reaction with a suitable Pd catalyst (such as PdCl 2 (dppf) and the like) and an appropriate diboron ester (such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2- dioxaborolane and the like).
  • a suitable Pd catalyst such as PdCl 2 (dppf) and the like
  • diboron ester such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2- dioxaborolane and the like.
  • Biaryl pyridines of Type 3e are prepared from the corresponding boronic esters of Type 3d through a Pd catalyzed Suzuki coupling with functionalized pyridines of Type le in the presence of a suitable phosphine ligand (such as t-Bu 3 P and the like) in a suitable biphasic mixture (such as a mixture of THF and water and the like).
  • a suitable phosphine ligand such as t-Bu 3 P and the like
  • a suitable biphasic mixture such as a mixture of THF and water and the like.
  • Substituted biaryl pyridines of Type 3f are prepared from the corresponding N-Boc amines of Type 3e via Boc cleavage using a suitable acid (such as TFA and the like) followed by treatment with an appropriate aldehyde in the presence of a hydride source (such as NaBH(OAc) 3 and the like).
  • a suitable acid such as TFA and the like
  • an appropriate aldehyde in the presence of a hydride source (such as NaBH(OAc) 3 and the like).
  • Compounds of Type 3g are prepared via global benzyl group deprotection of pyridines of Type 3f with a suitable acid (such as TFA and the like).
  • Boronic ester intermediates of Type 4b are prepared from 6-haloindoles of Type 4a (where Hal represents a halogen such as Br or I) via a Miyaura borylation reaction with a suitable Pd catalyst (such as PdCl 2 (dppf) and the like) and an appropriate diboron ester (such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane and the like).
  • a suitable Pd catalyst such as PdCl 2 (dppf) and the like
  • diboron ester such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane and the like.
  • Biaryl pyridines of Type 4c are prepared from the corresponding boronic esters of
  • Type 4b through a Pd catalyzed Suzuki coupling with functionalized pyridines of Type le in the presence of a suitable phosphine ligand (such as t-Bu 3 P and the like) in a suitable biphasic mixture (such as a mixture of THF and water and the like).
  • a suitable phosphine ligand such as t-Bu 3 P and the like
  • a suitable biphasic mixture such as a mixture of THF and water and the like.
  • Step 1 reductive amination with a primary alkylamine in the presence of a hydride source (such as NaBH 4 and the like);
  • Step 2 reductive amination with an appropriate aldehyde in the presence of a hydride source (such as NaBH(OAc) 3 and the like);
  • Step 3 global benzyl group deprotection with a suitable acid (such as TFA and the like).

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Abstract

La présente invention concerne l'utilisation de composés 2-pyridinone substitués par des anneaux bicycliques et tricycliques et des formes de ceux-ci pour traiter ou améliorer Neisseria gonorrhoeae.
PCT/US2015/045440 2014-09-09 2015-08-15 Composés 2-pyridinone antibactériens à substitution bicyclique et tricyclique WO2016039939A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018037223A1 (fr) * 2016-08-22 2018-03-01 Discuva Ltd. Composés antibiotiques
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4278681A (en) * 1979-03-12 1981-07-14 Warner-Lambert Co. Antibacterial amide compounds and means for using the same
WO2013033258A1 (fr) * 2011-08-29 2013-03-07 Ptc Therapeutics, Inc. Composés antibactériens et leurs méthodes d'utilisation
WO2013033240A1 (fr) * 2011-08-29 2013-03-07 Ptc Therapeutics, Inc. Composés antibactériens et procédés destinés à leur utilisation
WO2014022613A1 (fr) * 2012-08-01 2014-02-06 Musc Foundation For Research Development Compositions antibactériennes et procédés antibactériens

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4278681A (en) * 1979-03-12 1981-07-14 Warner-Lambert Co. Antibacterial amide compounds and means for using the same
WO2013033258A1 (fr) * 2011-08-29 2013-03-07 Ptc Therapeutics, Inc. Composés antibactériens et leurs méthodes d'utilisation
WO2013033240A1 (fr) * 2011-08-29 2013-03-07 Ptc Therapeutics, Inc. Composés antibactériens et procédés destinés à leur utilisation
WO2014022613A1 (fr) * 2012-08-01 2014-02-06 Musc Foundation For Research Development Compositions antibactériennes et procédés antibactériens

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018037223A1 (fr) * 2016-08-22 2018-03-01 Discuva Ltd. Composés antibiotiques
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same

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