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WO2016039936A2 - Monocyclic substituted 2-pyridinone antibacterial compounds - Google Patents

Monocyclic substituted 2-pyridinone antibacterial compounds Download PDF

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Publication number
WO2016039936A2
WO2016039936A2 PCT/US2015/045436 US2015045436W WO2016039936A2 WO 2016039936 A2 WO2016039936 A2 WO 2016039936A2 US 2015045436 W US2015045436 W US 2015045436W WO 2016039936 A2 WO2016039936 A2 WO 2016039936A2
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alkyl
amino
oxo
dihydropyridine
carboxylic acid
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PCT/US2015/045436
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French (fr)
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WO2016039936A3 (en
Inventor
Arthur A. Branstrom
Jana Narasimhan
Melissa L. DUMBLE
Marla L. Weetall
Gary Mitchell Karp
Aleksey Igorevich GERASYUTO
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PTC Therapeutics Inc
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PTC Therapeutics Inc
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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
    • A61K31/495—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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/435—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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/495—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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged 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
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present description relates to the use of substituted 2-pyridinone compounds and forms thereof for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae). More particularly, the present description relates to the use of monocyclic ring substituted 2- pyridinone compounds and forms thereof for treating or ameliorating a wild-type or drug- resistant form of N. gonorrhoeae.
  • Neisseria is a large genus of generally commensal Gram-negative bacteria that colonize the mucosal surfaces of many animals.
  • the facile ability of N. gonorrhoeae to develop drug resistance makes N. gonorrhoeae a rapidly emerging global health threat, and is considered to be an emerging superbug. 820,000 new cases of N. gonorrhoeae are estimated to occur in the United States every year. With more than 100 million cases of
  • N. gonorrhoeae reported worldwide, about 12% of drug-resistant N. gonorrhoeae is estimated to be penicillin resistant (penicillin R ), about 23% is estimated to be tetracycline resistant (tetracycline R ) and about 13% is estimated to be quinolone resistant (quinolone R ).
  • penicillin R penicillin resistant
  • 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 R ).
  • streptomycin-resistant streptomycin R
  • ciprofloxacin R ciprofloxacin R
  • ampicillin R ampicillin-resistant
  • ceftriaxone a cephalosporin
  • the present description relates to use of a substituted 2-pyridinone compound for treating or ameliorating Neisseria gonorrhoeae (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:
  • R 1 , R 2 or R 3 are as defined herein, and forms and compositions thereof.
  • 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. More particularly, 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 also 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 I R) or extensively drug resistant (XDR).
  • IR intermediate resistance
  • HLR high level resistance
  • MDR multi-drug resistant
  • MD I 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 I R or XDR forms of N. gonorrhoeae.
  • the present description also relates to a 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 a 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 use of a substituted 2-pyridinone compound for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae) in a subject in need thereof comprising, administering an effective amount of a compound of Formula (I) to the subject:
  • R 1 is a monocyclic ring system selected from the group consisting of:
  • R 2 is hydrogen, cyano, C 1-8 alkyl, hydroxyl-C 1-8 alkyl, formyl-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynl, carboxyl, amino-C 1-8 alkyl, aryl or C 3-14 cycloalkyl;
  • R 3 is hydrogen, hydroxyl or C 1-8 alkoxy;
  • R 5 is hydrogen, halogen, hydroxyl, oxo, cyano, nitro, C 1-8 alkyl, hydroxyl-C 1-8 alkyl,
  • halo-C 1-8 alkyl C 1-8 alkoxy, halo-C 1-8 alkoxy, C 1-8 alkyl-thio, carboxyl,
  • aryl-C 1-8 alkyl-amino-C 1-8 alkyl (aryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl,
  • aryl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-amino, heteroaryl-C 1-8 alkyl-amino, (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino,
  • heteroaryl-C 1-8 alkyl 2 -amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl,
  • heteroaryl,C 1-8 alkyl)amino-C 1-8 alkyl (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-oxy, heterocyclyl-C 1-8 alkoxy, heterocyclyl-amino, (heterocyclyl,C 1-8 alkyl)amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-C 1-8 alkyl, (heterocyclyl,C 1-8 alkyl)amino-C 1-8 alkyl,
  • heterocyclyl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, heterocyclyl-oxy-amino,
  • heterocyclyl-oxy,C 1-8 alkyl)amino (heterocyclyl-oxy) 2 -amino, (heterocyclyl-oxy-C 1-8 alkyl,C 1-8 alkyl)amino, heterocyclyl-carbonyl or heterocyclyl-carbonyl-oxy;
  • each instance of C 3-14 cycloalkyl, aryl, heterocyclyl is optionally substituted with one, two or three substituents each selected from R 6 ;
  • R 6 is azido, halogen, hydroxyl, oxo, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl,
  • halo-C 1-8 alkyl 2 -amino-C 1-8 alkyl, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl,C 1-8 alkyl]amino-C 1-8 alkyl, C 1-8 alkyl-thio, amino-carbonyl, C 1-8 alkyl-amino-carbonyl,
  • aryl-C 1-8 alkyl 2 -amino, aryl-C 1-8 alkyl-amino-C 1-8 alkyl,
  • heteroaryl-C 1-8 alkyl-amino (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino,
  • heteroaryl-C 1-8 alkyl 2 -amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl,
  • heteroaryl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-amino-C 1-8 alkyl or heterocyclyl-oxy;
  • R 9 is C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl or aryl-C 1-8 alkyl-amino; and, R 10 is halogen;
  • 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.
  • R 5 is hydrogen, halogen, hydroxyl, oxo, cyano, C 1-8 alkyl, hydroxyl-C 1-8 alkyl, C 1-8 alkoxy, carboxyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, (C 2-8 alkenyl) 2 -amino, amino-C 1-8 alkyl, C 1-10 alkyl-amino-C 1-8 alkyl, (C 1-10 alkyl) 2 -amino-C 1-8 alkyl,
  • aryl-C 1-8 alkyl-amino-C 1-8 alkyl (aryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl,
  • heteroaryl,C 1-8 alkyl (heteroaryl,C 1-8 alkyl)amino-C 1-8 alkyl, (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-oxy, heterocyclyl-amino-C 1-8 alkyl, (heterocyclyl,C 1-8 alkyl)amino-C 1-8 alkyl,
  • heterocyclyl-C 1-8 alkyl-amino-C 1-8 alkyl (heterocyclyl-oxy-C 1-8 alkyl,C 1-8 alkyl)amino or heterocyclyl-carbonyl;
  • each instance of C 3-14 cycloalkyl, aryl, heterocyclyl is optionally substituted with one, two or three substituents each selected from R 6 ;
  • R 6 is azido, halogen, hydroxyl, oxo, cyano, C 1-8 alkyl, halo-C 1-8 alkyl, hydroxyl-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl, C 1-8 alkoxy, carboxyl, C 1-8 alkyl-carbonyl, C 1-8 alkoxy-carbonyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl,C 1-8 alkyl]amino, amino-C 1-8 alkyl,
  • aryl-C 1-8 alkyl-amino-C 1-8 alkyl (aryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl,
  • aryl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, aryl-amino-C 1-8 alkyl, aryl-C 1-8 alkoxy,
  • R 9 is C 1-8 alkyl, amino, (C 1-8 alkyl) 2 -amino or aryl-C 1-8 alkyl-amino;
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • the present description further relates to use of a compound of Formula (I) or a form thereof wherein, when R 5 is C 3-14 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • C 3-14 cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
  • aryl is selected in each instance, when present, from phenyl
  • heteroaryl is selected in each instance, when present, from pyrrolyl, thiazolyl, 1H-1,2,3- triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1H-imidazolyl or pyridinyl; and,
  • heterocyclyl is selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-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][1,4]oxazinyl, 3,4- dihydroisoquinolin-(1H)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetra
  • the present description further relates to use of a compound of Formula (I) or a form thereof wherein, when R 5 is C 3-14 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • C 3-14 cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
  • aryl is selected in each instance, when present, from phenyl
  • heteroaryl is selected in each instance, when present, from 1H-pyrrol-1-yl, thiazol-2-yl, 1H- 1,2,3-triazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 1H-imidazol-1-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or, heterocyclyl is selected in each instance, when present, from azetidin-1-yl, tetrahydrofuran-2- yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-1-yl, 1,3-di
  • aryl selected in each instance, when present, from phenyl
  • heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H-1,2,3- triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1H-imidazolyl or pyridinyl; or,
  • heterocyclyl selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or 1,4-diazepanyl.
  • aryl selected in each instance, when present, from phenyl
  • heteroaryl selected in each instance, when present, from 1H-pyrrol-1-yl, thiazol-2-yl, 1H- 1,2,3-triazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 1H-imidazol-1-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
  • heterocyclyl selected in each instance, when present, from azetidin-1-yl, tetrahydrofuran-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan-1-yl.
  • the present description further relates to use of a compound of Formula (I), wherein the ring system R 1a is selected from a R 1a1 ring system:
  • R 1a1 wherein“*” represents a point of attachment; and, wherein R 5a , R 5b , R 5c , R 5d and R 5e , when present, are selected from the group consisting of:
  • aryl-C 1-8 alkyl-amino-C 1-8 alkyl (aryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl,
  • aryl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-amino, heteroaryl-C 1-8 alkyl-amino, (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino,
  • heteroaryl-C 1-8 alkyl 2 -amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl,
  • heteroaryl,C 1-8 alkyl)amino-C 1-8 alkyl (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-oxy, heterocyclyl-C 1-8 alkoxy, heterocyclyl-amino, (heterocyclyl,C 1-8 alkyl)amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-C 1-8 alkyl, (heterocyclyl,C 1-8 alkyl)amino-C 1-8 alkyl,
  • heterocyclyl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, heterocyclyl-oxy-amino,
  • heterocyclyl-oxy-C 1-8 alkyl,C 1-8 alkyl (heterocyclyl-oxy-C 1-8 alkyl,C 1-8 alkyl)amino, heterocyclyl-carbonyl or
  • each instance of C 3-14 cycloalkyl, aryl, heterocyclyl is optionally substituted with one, two or three substituents each selected from R 6 ;
  • R 6 is azido, halogen, hydroxyl, oxo, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl,
  • halo-C 1-8 alkyl 2 -amino, halo-C 1-8 alkyl-amino-C 1-8 alkyl, (halo-C 1-8 alkyl) 2 -amino-C 1-8 alkyl, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl,C 1-8 alkyl]amino-C 1-8 alkyl, C 1-8 alkyl-thio, amino-carbonyl, C 1-8 alkyl-amino-carbonyl,
  • aryl-C 1-8 alkyl 2 -amino, aryl-C 1-8 alkyl-amino-C 1-8 alkyl,
  • heteroaryl-C 1-8 alkyl-amino (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino,
  • heteroaryl-C 1-8 alkyl 2 -amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl,
  • heteroaryl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-amino-C 1-8 alkyl or heterocyclyl-oxy;
  • R 9 is C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, amino-C 1-8 alkyl,
  • 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), wherein the ring system R 1a is selected from the R 1a1 ring system, and R 5a , R 5b , R 5c , R 5d and R 5e , when present, are selected from the group consisting of:
  • heterocyclyl wherein each instance of heterocyclyl is optionally substituted with one, two or three
  • R 6 is azido, halogen, hydroxyl, oxo, cyano, C 1-8 alkyl, halo-C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl, C 1-8 alkoxy, carboxyl, C 1-8 alkoxy-carbonyl, amino, C 1-8 alkyl-amino,
  • aryl-C 1-8 alkyl-amino-C 1-8 alkyl (aryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl,
  • aryl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, aryl-C 1-8 alkoxy, aryl-C 1-8 alkoxy-carbonyl-amino, heteroaryl, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl or heterocyclyl-oxy;
  • R 9 is C 1-8 alkyl, amino, (C 1-8 alkyl) 2 -amino or aryl-C 1-8 alkyl-amino;
  • R 10 is halogen
  • 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, when R 5a , R 5b , R 5c , R 5d and R 5e substituted on the R 1a1 ring system is C 3-14 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C 3-14 cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
  • aryl is selected in each instance, when present, from phenyl
  • heteroaryl is selected in each instance, when present, from pyrrolyl, thiazolyl, 1H-1,2,3- triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1H-imidazolyl or pyridinyl; and,
  • heterocyclyl is selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-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][1,4]oxazinyl, 3,4- dihydroisoquinolin-(1H)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetra
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R 5a , R 5b , R 5c , R 5d and R 5e substituted on the R 1a1 ring system is C 3-14 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C 3-14 cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
  • aryl is selected in each instance, when present, from phenyl
  • heteroaryl is selected in each instance, when present, from 1H-pyrrol-1-yl, thiazol-2-yl, 1H- 1,2,3-triazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 1H-imidazol-1-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
  • heterocyclyl is selected in each instance, when present, from azetidin-1-yl, tetrahydrofuran-2- yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-1-yl, 1,3-dioxolan-2-yl, 2,5-dihydro-1H-pyrrol-1-yl, 4,5-dihydro-1H- imidazol-2-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R 5a , R 5b , R 5c , R 5d and R 5e substituted on the R 1a1 ring system is aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • aryl is selected in each instance, when present, from phenyl
  • heteroaryl is selected in each instance, when present, from pyrrolyl, 1H-tetrazolyl or
  • heterocyclyl is selected in each instance, when present, from azetidinyl, pyrrolidinyl,
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R 5a , R 5b , R 5c , R 5d and R 5e substituted on the R 1a1 ring system is aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • aryl selected in each instance, when present, from phenyl
  • heteroaryl selected in each instance, when present, from 1H-pyrrol-1-yl, 1H-tetrazol-5-yl or 1H-imidazol-1-yl; or,
  • heterocyclyl selected in each instance, when present, from azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,2,3,6- tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-6-yl, (6H)- pyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-4(4aH)-yl, hexahydro-1H- cyclopenta[c]pyrrol-2-yl,
  • heterocyclyl selected in each instance, when present, from pyrrolidinyl or morpholinyl.
  • C 3-14 cycloalkyl selected in each instance, when present, from cyclopropyl or cyclobutyl; aryl selected in each instance, when present, from phenyl;
  • heteroaryl selected in each instance, when present, from thiazol-2-yl, 1H-1,2,3-triazol-1-yl, 2H-tetrazol-2-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; and,
  • heterocyclyl selected in each instance, when present, from pyrrolidin-1-yl or morpholin-4-yl.
  • the present description further relates to use of a compound of Formula (I), wherein the ring system R 1a is selected from the R 1a1 ring system, and R 5a , R 5b , R 5c , R 5d and R 5e , when present, are selected from the group consisting of (where“--” indicates that one or more of R 5a , R 5b , R 5c , R 5d or R 5e 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 use of a compound of Formula (I), wherein the ring system R 1b , R 1c , R 1d and R 1e is selected from a R 1b1 , R 1c1 , R 1d1 and R 1e1 ring system, respectively:
  • R 5a , R 5b , R 5c , R 5d and R 5e when present, are selected from the group consisting of:
  • aryl-C 1-8 alkyl-amino-C 1-8 alkyl (aryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl,
  • aryl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-amino, heteroaryl-C 1-8 alkyl-amino, (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino,
  • heteroaryl-C 1-8 alkyl 2 -amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl,
  • heteroaryl,C 1-8 alkyl)amino-C 1-8 alkyl (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-oxy, heterocyclyl-C 1-8 alkoxy, heterocyclyl-amino, (heterocyclyl,C 1-8 alkyl)amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-C 1-8 alkyl, (heterocyclyl,C 1-8 alkyl)amino-C 1-8 alkyl,
  • heterocyclyl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, heterocyclyl-oxy-amino,
  • heterocyclyl-oxy-C 1-8 alkyl,C 1-8 alkyl (heterocyclyl-oxy-C 1-8 alkyl,C 1-8 alkyl)amino, heterocyclyl-carbonyl or
  • each instance of C 3-14 cycloalkyl, aryl, heterocyclyl is optionally substituted with one, two or three substituents each selected from R 6 ;
  • R 6 is azido, halogen, hydroxyl, oxo, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl,
  • halo-C 1-8 alkyl 2 -amino-C 1-8 alkyl, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl,C 1-8 alkyl]amino-C 1-8 alkyl, C 1-8 alkyl-thio, amino-carbonyl, C 1-8 alkyl-amino-carbonyl,
  • aryl-C 1-8 alkyl 2 -amino, aryl-C 1-8 alkyl-amino-C 1-8 alkyl,
  • heteroaryl-C 1-8 alkyl-amino (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino,
  • heteroaryl-C 1-8 alkyl 2 -amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl,
  • heteroaryl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-amino-C 1-8 alkyl or heterocyclyl-oxy;
  • R 9 is C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, amino-C 1-8 alkyl,
  • 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 use of a compound of Formula (I), wherein the ring system R 1b , R 1c , R 1d and R 1e is selected from the R 1b1 , R 1c1 , R 1d1 and R 1e1 ring system, respectively, and R 5a , R 5b , R 5c , R 5d and R 5e , when present, are selected from the group consisting of hydrogen, (C 1-8 alkyl) 2 -amino or heterocyclyl;
  • heterocyclyl is optionally substituted with a substituent selected from R 6 ; and, R 6 is amino or (C 1-8 alkyl) 2 -amino;
  • a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R 5a , R 5b , R 5c , R 5d and R 5e substituted on a R 1b1 , R 1c1 , R 1d1 or R 1e1 ring system is C 3-14 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • C 3-14 cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
  • aryl is selected in each instance, when present, from phenyl
  • heteroaryl is selected in each instance, when present, from pyrrolyl, thiazolyl, 1H-1,2,3- triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1H-imidazolyl or pyridinyl; and,
  • heterocyclyl is selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-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][1,4]oxazinyl, 3,4- dihydroisoquinolin-(1H)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetra
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R 5a , R 5b , R 5c , R 5d and R 5e substituted on a R 1b1 , R 1c1 , R 1d1 or R 1e1 ring system is C 3-14 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • C 3-14 cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
  • aryl is selected in each instance, when present, from phenyl
  • heteroaryl is selected in each instance, when present, from 1H-pyrrol-1-yl, thiazol-2-yl, 1H- 1,2,3-triazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 1H-imidazol-1-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
  • heterocyclyl is selected in each instance, when present, from azetidin-1-yl, tetrahydrofuran-2- yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-1-yl, 1,3-dioxolan-2-yl, 2,5-dihydro-1H-pyrrol-1-yl, 4,5-dihydro-1H- imidazol-2-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R 5a , R 5b , R 5c , R 5d and R 5e substituted on a R 1b1 , R 1c1 , R 1d1 or R 1e1 ring system is heterocyclyl alone or as a portion of a substituent, then:
  • heterocyclyl is selected in each instance, when present, from pyrrolidinyl, piperazinyl,
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R 5a , R 5b , R 5c , R 5d and R 5e substituted on a R 1b1 , R 1c1 , R 1d1 or R 1e1 ring system is heterocyclyl alone or as a portion of a substituent, then:
  • heterocyclyl is selected in each instance, when present, from pyrrolidin-1-yl, piperazin-1-yl, morpholin-4-yl or (1R,5S,6s)-3-azabicyclo[3.1.0]hexan-3-yl.
  • the present description further relates to use of a compound of Formula (I), wherein the ring system R 1b , R 1c , R 1d and R 1e is selected from the R 1b1 , R 1c1 , R 1d1 and R 1e1 ring system, respectively, and R 5a , R 5b , R 5c , R 5d and R 5e , when present, are selected from the group consisting of (where“Ring” in the table below indicates whether an R 1b1 , R 1c1 , R 1d1 or R 1e1 ring system is selected; and,“--” in the table below indicates that one or more of R 5a , R 5b , R 5c , R 5d or R 5e 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 use of a compound of Formula (I), wherein the ring system R 1f , R 1g , R 1h , R 1i and R 1j is selected from a R 1f1 , R 1g1 , R 1h1 , R 1i1 and R 1j1 ring system, respectively:
  • aryl-C 1-8 alkyl-amino-C 1-8 alkyl (aryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl,
  • aryl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heteroaryl-amino, heteroaryl-C 1-8 alkyl-amino, (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino,
  • heteroaryl-C 1-8 alkyl 2 -amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl,
  • heteroaryl,C 1-8 alkyl)amino-C 1-8 alkyl (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-oxy, heterocyclyl-C 1-8 alkoxy, heterocyclyl-amino, (heterocyclyl,C 1-8 alkyl)amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-C 1-8 alkyl, (heterocyclyl,C 1-8 alkyl)amino-C 1-8 alkyl,
  • heterocyclyl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, heterocyclyl-oxy-amino,
  • heterocyclyl-oxy-C 1-8 alkyl,C 1-8 alkyl (heterocyclyl-oxy-C 1-8 alkyl,C 1-8 alkyl)amino, heterocyclyl-carbonyl or
  • R 6 is azido, halogen, hydroxyl, oxo, cyano, nitro, C 1-8 alkyl, halo-C 1-8 alkyl,
  • halo-C 1-8 alkyl 2 -amino-C 1-8 alkyl, amino-C 1-8 alkyl, C 1-8 alkyl-amino-C 1-8 alkyl, (C 1-8 alkyl) 2 -amino-C 1-8 alkyl, [(C 1-8 alkyl) 2 -amino-C 1-8 alkyl,C 1-8 alkyl]amino-C 1-8 alkyl, C 1-8 alkyl-thio, amino-carbonyl, C 1-8 alkyl-amino-carbonyl,
  • aryl-C 1-8 alkyl 2 -amino, aryl-C 1-8 alkyl-amino-C 1-8 alkyl,
  • heteroaryl-C 1-8 alkyl-amino (heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino,
  • heteroaryl-C 1-8 alkyl 2 -amino, heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl,
  • heteroaryl-C 1-8 alkyl 2 -amino-C 1-8 alkyl, heterocyclyl, heterocyclyl-C 1-8 alkyl, heterocyclyl-amino-C 1-8 alkyl or heterocyclyl-oxy;
  • R 9 is C 1-8 alkyl, amino, C 1-8 alkyl-amino, (C 1-8 alkyl) 2 -amino, amino-C 1-8 alkyl,
  • 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 use of a compound of Formula (I), wherein the ring system R 1f , R 1g , R 1h , R 1i and R 1j is selected from the R 1f1 , R 1g1 , R 1h1 , R 1i1 and R 1j1 ring system, respectively, and R 5a , R 5b , R 5c and R 5d , when present, are selected from the group consisting of:
  • heterocyclyl-C 1-8 alkyl wherein each instance of heterocyclyl is optionally substituted with one (C 1-8 alkyl) 2 -amino substituent;
  • 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, when R 5a , R 5b , R 5c and R 5d substituted on a R 1f1 , R 1g1 , R 1h1 , R 1i1 and R 1j1 ring system is C 3-14 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • C 3-14 cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
  • aryl is selected in each instance, when present, from phenyl
  • heteroaryl is selected in each instance, when present, from pyrrolyl, thiazolyl, 1H-1,2,3- triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1H-imidazolyl or pyridinyl; and,
  • heterocyclyl is selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-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][1,4]oxazinyl, 3,4- dihydroisoquinolin-(1H)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetra
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R 5a , R 5b , R 5c and R 5d substituted on a R 1f1 , R 1g1 , R 1h1 , R 1i1 and R 1j1 ring system is C 3-14 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • C 3-14 cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
  • aryl is selected in each instance, when present, from phenyl
  • heteroaryl is selected in each instance, when present, from 1H-pyrrol-1-yl, thiazol-2-yl, 1H- 1,2,3-triazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 1H-imidazol-1-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
  • heterocyclyl is selected in each instance, when present, from azetidin-1-yl, tetrahydrofuran-2- yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-1-yl, 1,3-dioxolan-2-yl, 2,5-dihydro-1H-pyrrol-1-yl, 4,5-dihydro-1H- imidazol-2-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R 5a , R 5b , R 5c and R 5d substituted on a R 1f1 , R 1g1 , R 1h1 , R 1i1 and R 1j1 ring system is heterocyclyl alone or as a portion of a substituent, then:
  • heterocyclyl selected in each instance, when present, from pyrrolidinyl or piperidinyl.
  • the present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R 5a , R 5b , R 5c and R 5d substituted on a R 1f1 , R 1g1 , R 1h1 , R 1i1 and R 1j1 ring system is heterocyclyl alone or as a portion of a substituent, then:
  • heterocyclyl selected in each instance, when present, from pyrrolidin-1-yl or piperidin-1-yl.
  • the present description further relates to use of a compound of Formula (I), wherein the ring system R 1f , R 1g , R 1h , R 1i and R 1j is selected from the R 1f1 , R 1g1 , R 1h1 , R 1i1 and R 1j1 ring system, respectively, and R 5a , R 5b , R 5c and R 5d , when present, are selected from the group consisting of (where“Ring” in the table below indicates whether an R 1f1 , R 1g1 , R 1h1 , R 1i1 or R 1j1 ring system is selected; and,“--” in the table below indicates that 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.
  • a compound or a form thereof for the use described herein is a compound of Formula (I) or a form thereof 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.
  • a compound or a form thereof for the use described herein is a compound of Formula (I) or a form thereof (wherein compound number (# 1 ) indicates that the salt form was isolated) selected from the group consisting of: Cpd Name
  • 262 1 6- ⁇ 4-[(3aR,4R,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl ⁇ -5-ethyl-4-hydroxy- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
  • 353 6-(5-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-1-methyl-1H-pyrrol-2-yl)-5-ethyl- 2-oxo-1,2-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.
  • 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 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 of Formula (I) or a form thereof to the subject.
  • the compound or a form thereof is isolated for use.
  • the compound or a form thereof is isolated as a salt.
  • a compound salt or a form thereof for the use described herein is a compound salt of Formula (I) or a form thereof selected from the group consisting of:
  • 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 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.
  • C 1-10 alkyl 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.
  • C 1-10 alkyl includes C 1-8 alkyl, C 1-6 alkyl, C 1-4 alkyl and the like.
  • a C 1-10 alkyl radical may be optionally substituted where allowed by available valences.
  • C 2-8 alkenyl generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, without limitation, ethenyl, allyl, propenyl and the like.
  • C 2-8 alkenyl includes C 2-6 alkenyl, C 2-4 alkenyl and the like.
  • a C 2-8 alkenyl radical may be optionally substituted where allowed by available valences.
  • C 2-8 alkynyl generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon triple bonds therein, including, without limitation, ethynyl, propynyl and the like.
  • C 2-8 alkynyl includes C 2-6 alkynyl, C 2-4 alkynyl and the like.
  • a C 2-8 alkynyl radical may be optionally substituted where allowed by available valences.
  • C 1-8 alkoxy generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration of the formula: -O-C 1-8 alkyl, including, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like.
  • C 1-8 alkoxy includes C 1-6 alkoxy, C 1-4 alkoxy and the like.
  • a C 1-8 alkoxy radical may be optionally substituted where allowed by available valences.
  • C 3-14 cycloalkyl generally refers to a saturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indanyl, indenyl, tetrahydro-naphthalenyl and the like.
  • C 3-14 cycloalkyl includes C 3-8 cycloalkyl, C 5-8 cycloalkyl, C 3-10 cycloalkyl and the like.
  • a C 3-14 cycloalkyl radical may be optionally substituted where allowed by available valences.
  • aryl generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like.
  • An aryl radical may be optionally substituted where allowed by available valences.
  • heteroaryl generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S or N atom, including, without limitation, furanyl, thienyl (also referred to as thiophenyl), pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, benzofuranyl, benzothi
  • heterocyclyl generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with a heteroatom, such as an O, S or N atom, including, without limitation, oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl,
  • dihydro-triazinyl dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl, 1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl, dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl, dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl,
  • 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 .
  • C 2-8 alkenyl-amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 2-8 alkenyl.
  • (C 2-8 alkenyl) 2 -amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N(C 2-8 alkenyl) 2 .
  • C 1-8 alkoxy-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-O-C 1-8 alkyl.
  • C 1-8 alkoxy-C 1-8 alkyl-amino refers to a radical of the formula: -O-C 1-8 alkyl-NH-C 1-8 alkyl-O-C 1-8 alkyl.
  • (C 1-8 alkoxy-C 1-8 alkyl) 2 -amino” refers to a radical of the formula: -N(C 1-8 alkyl-O-C 1-8 alkyl) 2 .
  • C 1-8 alkoxy-C 1-8 alkyl-amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-8 alkyl-O-C 1-8 alkyl.
  • (C 1-8 alkoxy-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-O-C 1-8 alkyl) 2 .
  • the term“(C 1-8 alkoxy-C 1-8 alkyl,C 1-8 alkyl)-amino” refers to a radical of the formula: -N[(C 1-8 alkyl)(C 1-8 alkyl-O-C 1-8 alkyl)].
  • (C 1-8 alkoxy-C 1-8 alkyl,C 1-8 alkyl)-amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(C 1-8 alkyl-O-C 1-8 alkyl)].
  • C 1-8 alkoxy-carbonyl refers to a radical of the formula: -C(O)-O-C 1-8 alkyl.
  • C 1-8 alkyl-amino refers to a radical of the formula:
  • C 1-8 alkyl-amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-8 alkyl.
  • C 1-10 alkyl-amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-10 alkyl.
  • (C 1-10 alkyl) 2 -amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N(C 1-10 alkyl) 2 .
  • C 1-8 alkyl-amino-C 1-8 alkyl-amino refers to a radical of the formula: -NH-C 1-8 alkyl-NH-C 1-8 alkyl.
  • (C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino” refers to a radical of the formula: -NH-C 1-8 alkyl-N(C 1-8 alkyl) 2 .
  • C 1-8 alkyl-amino-C 1-8 alkyl-amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-8 alkyl-NH-C 1-8 alkyl.
  • the term“(C 1-8 alkyl) 2 -amino-C 1-8 alkyl-amino-C 1-8 alkyl” refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-8 alkyl-N(C 1-8 alkyl) 2 .
  • the term“(C 1-8 alkyl-amino-C 1-8 alkyl,C 1-8 alkyl)amino” refers to a radical of the formula: -N[(C 1-8 alkyl)(C 1-8 alkyl-NH-C 1-8 alkyl)].
  • the term“[(C 1-8 alkyl) 2 -amino-C 1-8 alkyl,C 1-8 alkyl]amino” refers to a radical of the formula: -N ⁇ (C 1-8 alkyl)[C 1-8 alkyl-N(C 1-8 alkyl) 2 ] ⁇ .
  • (C 1-8 alkyl-amino-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(C 1-8 alkyl-NH-C 1-8 alkyl)].
  • the term“[(C 1-8 alkyl) 2 -amino-C 1-8 alkyl,C 1-8 alkyl]amino-C 1-8 alkyl” refers to a radical of the formula: -C 1-8 alkyl-N ⁇ (C 1-8 alkyl)[C 1-8 alkyl-N(C 1-8 alkyl) 2 ] ⁇ .
  • (C 1-8 alkyl-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 .
  • C 1-8 alkyl-amino-carbonyl refers to a radical of the formula: -C(O)-NH-C 1-8 alkyl.
  • (C 1-8 alkyl) 2 -amino-carbonyl refers to a radical of the formula:–C(O)-N(C 1-8 alkyl) 2 .
  • C 1-8 alkyl-carbonyl refers to a radical of the formula:
  • C 1-8 alkyl-carbonyl-amino refers to a radical of the formula: -NH-C(O)-C 1-8 alkyl.
  • (C 1-8 alkyl-carbonyl,C 1-8 alkyl)amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(-C(O)-C 1-8 alkyl)].
  • C 1-8 alkyl-thio refers to a radical of the formula:
  • C 2-8 alkynyl-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-C 2-8 alkynyl.
  • C 2-8 alkynyl-amino refers to a radical of the formula:
  • (C 2-8 alkynyl) 2 -amino” refers to a radical of the formula: -N(C 2-8 alkynyl) 2 .
  • C 2-8 alkynyl-amino-C 1-8 alkyl refers to a radical of the formula:
  • (C 2-8 alkynyl) 2 -amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N(C 2-8 alkynyl) 2 .
  • the term“amino” refers to a radical of the formula: -NH 2 .
  • the term“amino-C 1-8 alkyl” refers to a radical of the formula:
  • amino-C 1-8 alkyl-amino refers to a radical of the formula: -NH-C 1-8 alkyl-NH 2 .
  • the term“(amino-C 1-8 alkyl) 2 -amino” refers to a radical of the formula: -N(C 1-8 alkyl-NH 2 ) 2 .
  • amino-C 1-8 alkyl,C 1-8 alkyl)amino refers to a radical of the formula: -N[(C 1-8 alkyl)(C 1-8 alkyl-NH 2 )].
  • amino-C 1-8 alkyl-amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-8 alkyl-NH 2 .
  • 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 2 ) 2 .
  • amino-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(C 1-8 alkyl-NH 2 )].
  • amino-carbonyl refers to a radical of the formula:
  • aryl-C 1-8 alkoxy refers to a radical of the formula:
  • aryl-C 1-8 alkoxy-carbonyl-amino refers to a radical of the formula: -NH-C(O)-O-C 1-8 alkyl-aryl.
  • aryl-C 1-8 alkyl refers to a radical of the formula:
  • aryl-C 1-8 alkyl-amino refers to a radical of the formula: -NH-C 1-8 alkyl-aryl.
  • aryl-C 1-8 alkyl) 2 -amino refers to a radical of the formula: -N[(C 1-8 alkyl-aryl) 2 ].
  • aryl-C 1-8 alkyl-amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-8 alkyl-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 1-8 alkyl-aryl) 2 ].
  • the term refers to a radical of the formula: -N[(C 1-8 alkyl)(aryl)].
  • the term“(aryl,C 1-8 alkyl)amino-C 1-8 alkyl” refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(aryl)].
  • aryl-C 1-8 alkyl,C 1-8 alkyl)amino refers to a radical of the formula: -N[(C 1-8 alkyl)(C 1-8 alkyl-aryl)].
  • aryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(C 1-8 alkyl-aryl)].
  • aryl-amino refers to a radical of the formula: -NH-aryl.
  • the term“(aryl) 2 -amino” refers to a radical of the formula: -N[(aryl) 2 ].
  • the term“aryl-amino-C 1-8 alkyl” refers to a radical of the formula: -C 1-8 alkyl-NH-aryl.
  • (aryl) 2 -amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N[(aryl) 2 ].
  • aryl-amino-carbonyl refers to a radical of the formula: -C(O)-NH-aryl.
  • carboxyl refers to a radical of the formula: -COOH, -C(O)OH or -CO 2 H.
  • the term“(carboxyl-C 1-8 alkyl,C 1-8 alkyl)amino-carbonyl-amino” refers to a radical of the formula: -NH-C(O)-N[(C 1-8 alkyl)(C 1-8 alkyl-CO 2 H)].
  • C 3-14 cycloalkyl-C 1-8 alkoxy refers to a radical of the formula: -O-C 1-8 alkyl-C 3-14 cycloalkyl.
  • C 3-14 cycloalkyl-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-C 3-14 cycloalkyl.
  • C 3-14 cycloalkyl-amino refers to a radical of the formula: -NH-C 3-14 cycloalkyl.
  • C 3-14 cycloalkyl-amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 3-14 cycloalkyl.
  • (C 3-14 cycloalkyl) 2 -amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N[(C 3-14 cycloalkyl) 2 ].
  • C 3-14 cycloalkyl-C 1-8 alkyl-amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-8 alkyl-C 3-14 cycloalkyl.
  • the term“(C 3-14 cycloalkyl-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-C 3-14 cycloalkyl) 2 ].
  • the term“(C 3-14 cycloalkyl,C 1-8 alkyl)amino-C 1-8 alkyl” refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(C 3-14 cycloalkyl)].
  • the term“(C 3-14 cycloalkyl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl” refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(C 1-8 alkyl-C 3-14 cycloalkyl)].
  • C 3-14 cycloalkyl-oxy refers to a radical of the formula: -O-C 3-14 cycloalkyl.
  • 2-oxoethyl 2-formyl-ethyl (also referred to as 3-oxopropyl), 3-formyl-propyl (also referred to as 4-oxobutyl), 4-formyl-butyl (also referred to as 5-oxopentyl) and the like.
  • halo or“halogen” generally refers to a halogen atom radical, including fluoro, chloro, bromo and iodo.
  • halo-C 1-8 alkoxy refers to a radical of the formula:
  • halo-C 1-8 alkoxy includes halo-C 1-6 alkoxy, halo-C 1-4 alkoxy and the like.
  • halo-C 1-8 alkyl refers to a radical of the formula:
  • halo-C 1-8 alkyl includes halo-C 1-6 alkyl, halo-C 1-4 alkyl and the like.
  • halo-C 1-8 alkyl-amino refers to a radical of the formula: -NH-C 1-8 alkyl-halo.
  • halo-C 1-8 alkyl 2 -amino refers to a radical of the formula: -N(C 1-8 alkyl-halo) 2 .
  • halo-C 1-8 alkyl-amino-C 1-8 alkyl refers to a radical of the formula: -NH-C 1-8 alkyl-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 1-8 alkyl-halo) 2 .
  • heteroaryl-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-heteroaryl.
  • heteroaryl-amino refers to a radical of the formula:
  • heteroaryl-C 1-8 alkyl-amino refers to a radical of the formula: -NH-C 1-8 alkyl-heteroaryl.
  • heteroaryl-C 1-8 alkyl 2 -amino refers to a radical of the formula: -N[(C 1-8 alkyl-heteroaryl) 2 ].
  • heteroaryl-C 1-8 alkyl-amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-8 alkyl-heteroaryl.
  • heteroaryl-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-heteroaryl) 2 ].
  • heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino refers to a radical of the formula: -N[(C 1-8 alkyl)(C 1-8 alkyl-heteroaryl)].
  • heteroaryl,C 1-8 alkyl)amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(heteroaryl)].
  • heteroaryl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(C 1-8 alkyl-heteroaryl)].
  • heterocyclyl-C 1-8 alkoxy refers to a radical of the formula: -O-C 1-8 alkyl-heterocyclyl.
  • heterocyclyl-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-heterocyclyl.
  • 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-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-NH-heterocyclyl.
  • (heterocyclyl) 2 -amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N[(heterocyclyl) 2 ].
  • heterocyclyl-C 1-8 alkyl-amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-8 alkyl-heterocyclyl.
  • the term“(heterocyclyl-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-heterocyclyl) 2 ].
  • the term“(heterocyclyl,C 1-8 alkyl)amino” refers to a radical of the formula: -N[(C 1-8 alkyl)(heterocyclyl)].
  • heterocyclyl,C 1-8 alkyl)amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(heterocyclyl)].
  • heterocyclyl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(C 1-8 alkyl-heterocyclyl)].
  • the term“(heterocyclyl,C 3-14 cycloalkyl-C 1-8 alkyl)amino-C 1-8 alkyl” refers to a radical of the formula: -C 1-8 alkyl-N[(heterocyclyl)(C 1-8 alkyl-C 3-14 cycloalkyl)].
  • heterocyclyl-carbonyl refers to a radical of the formula: -C(O)-heterocyclyl.
  • heterocyclyl-carbonyl-oxy refers to a radical of the formula: -O-C(O)-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 refers to a radical of the formula: -N[(-O-heterocyclyl) 2 ].
  • heterocyclyl-oxy,C 1-8 alkyl)amino refers to a radical of the formula: -N[(C 1-8 alkyl)(-O-heterocyclyl)].
  • heterocyclyl-oxy-C 1-8 alkyl,C 1-8 alkyl)amino refers to a radical of the formula: -N[(C 1-8 alkyl)(C 1-8 alkyl-O-heterocyclyl)].
  • hydroxyl-C 1-8 alkoxy refers to a radical of the formula: -O-C 1-8 alkyl-OH, wherein C 1-8 alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
  • hydroxyl-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-OH, wherein C 1-8 alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxy radicals.
  • hydroxyl-C 1-8 alkyl-amino refers to a radical of the formula: -NH-C 1-8 alkyl-OH, wherein C 1-8 alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
  • the term“(hydroxyl-C 1-8 alkyl) 2 -amino” refers to a radical of the formula: -N(C 1-8 alkyl-OH) 2 , wherein C 1-8 alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
  • hydroxyl-C 1-8 alkyl-amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-NH-C 1-8 alkyl-OH, wherein C 1-8 alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
  • hydroxyl-C 1-8 alkyl-amino-C 1-8 alkyl-amino refers to a radical of the formula: -NH-C 1-8 alkyl-NH-C 1-8 alkyl-OH, wherein C 1-8 alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
  • hydroxyl-C 1-8 alkyl,C 1-8 alkyl)amino refers to a radical of the formula: -N[(C 1-8 alkyl)(C 1-8 alkyl-OH)], wherein C 1-8 alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
  • hydroxyl-C 1-8 alkyl,C 1-8 alkyl)amino-C 1-8 alkyl refers to a radical of the formula: -C 1-8 alkyl-N[(C 1-8 alkyl)(C 1-8 alkyl-OH)], wherein C 1-8 alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
  • the term“[(hydroxyl-C 1-8 alkyl,C 1-8 alkyl)amino- C 1-8 alkyl,C 1-8 alkyl]amino” refers to a radical of the formula: -N[(C 1-8 alkyl) ⁇ C 1-8 alkyl- N[(C 1-8 alkyl)(C 1-8 alkyl-OH)] ⁇ ], wherein C 1-8 alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
  • the term“(hydroxyl-C 1-8 alkyl-amino-C 1-8 alkyl,C 1-8 alkyl)amino” refers to a radical of the formula: -N[(C 1-8 alkyl)(C 1-8 alkyl-NH-C 1-8 alkyl-OH)], wherein C 1-8 alkyl 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.
  • a double bond was included within the scope of the substituent group showing only a single bond as the point of attachment to the core structure of Formula (I).
  • the term“and the like,” with reference to the definitions of chemical terms provided herein, means that variations in chemical structures that could be expected by one skilled in the art include, without limitation, isomers (including chain, branching or positional structural isomers), hydration of ring systems (including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations where allowed by available valences which result in a stable compound.
  • each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.
  • the terms“independently selected,” or“each selected” refer to functional variables in a substituent list that may occur more than once on the structure of Formula (I), 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“selected in each instance, when present,” or variations thereof, when used relative to a phrase such as“...C 3-14 cycloalkyl, C 3-14 cycloalkyl-C 1-8 alkyl, aryl, aryl-C 1-8 alkyl, heteroaryl, heteroaryl-C 1-8 alkyl, heterocyclyl and heterocyclyl-C 1-8 alkyl,” are intended to refer to the C 3-14 cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems either alone or as a portion of a substituent.
  • the term“optionally substituted” means optional substitution with the specified substituent variables, groups, radicals or moieties.
  • the terms“stable compound’ or“stable structure” mean a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulations thereof into an efficacious therapeutic agent.
  • the term“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.
  • the term“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.
  • the term“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.
  • 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.
  • a compound of Formula (I) or a form thereof contains both a basic moiety, such as, without limitation an amine moiety, and an acidic moiety, such as, but not limited to a carboxylic acid
  • zwitterions inner salts
  • inner salts inner salts
  • pharmaceutically acceptable salt(s) means those salts of compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful.
  • Salts of the compounds of the Formula (I) 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., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides) and the like.
  • lower alkyl halides e.g., methyl, ethyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g., decyl, lauryl,
  • Compounds of Formula (I) 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.
  • the term“substantially pure” refers to compounds consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.
  • 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%.
  • a“racemate” is any mixture of isometric forms that are not “enantiomerically 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
  • 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).
  • stereoisomers of the compounds described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as described supra.
  • the use of the terms “salt”, “solvate”,“ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or isotopologues of the instant compounds.
  • 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 O, 17 O, 31 P, 32 P, 35 S, 18 F, 35 Cl and 36 Cl, 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., 2 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.

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Abstract

The present description relates to the use of monocyclic ring substituted 2-pyridinone compounds and forms thereof for treating or ameliorating Neisseria gonorrhoeae.

Description

MONOCYCLIC SUBSTITUTED 2-PYRIDINONE ANTIBACTERIAL COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of U.S. Patent Provisional Application No.
62/048,085, filed September 9, 2014, the contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present description relates to the use of substituted 2-pyridinone compounds and forms thereof for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae). More particularly, the present description relates to the use of monocyclic ring substituted 2- pyridinone compounds and forms thereof for treating or ameliorating a wild-type or drug- resistant form of N. gonorrhoeae.
BACKGROUND
Neisseria is a large genus of generally commensal Gram-negative bacteria that colonize the mucosal surfaces of many animals. The facile ability of N. gonorrhoeae to develop drug resistance makes N. gonorrhoeae a rapidly emerging global health threat, and is considered to be an emerging superbug. 820,000 new cases of N. gonorrhoeae are estimated to occur in the United States every year. With more than 100 million cases of
N. gonorrhoeae reported worldwide, about 12% of drug-resistant N. gonorrhoeae is estimated to be penicillin resistant (penicillinR), about 23% is estimated to be tetracycline resistant (tetracyclineR) and about 13% is estimated to be quinolone resistant (quinoloneR). The level of quinolone resistance in Taiwan and China is about 90% (Morbidity and
Mortality Weekly, Feb 15, 2013). Other forms of drug-resistant N. gonorrhoeae include streptomycin-resistant (streptomycinR), ciprofloxacin-resistant (ciprofloxacinR) and ampicillin-resistant (ampicillinR). Currently, ceftriaxone (a cephalosporin) is the drug of last resort for treating N. gonorrhoeae. With few clinical trials underway for new drugs targeting N. gonorrhoeae, the discovery of new antibacterial agents to treat wild-type or drug-resistant forms of N. gonorrhoeae is urgently needed.
Although quinolones have been highly effective agents in the clinic, wide-scale deployment and generic usage of second generation quinolones (e.g., ciprofloxacin) has jeopardized their future long-term utility. Furthermore, fluoroquinolones had become the standard of care for treating N. gonorrhoeae in early 1999. As early as 2001, though, bacterial resistance to these agents was also on the rise. Within 6 years, N. gonorrhoeae resistance in certain patient populations went from less than 1% to greater than 40%. In 2007, the Centers for Disease Control (CDC) discontinued the use of ciprofloxacin as the standard of care for treating N. gonorrhoeae. Therefore, new drugs targeting wild-type or drug-resistant forms of N. gonorrhoeae would be expected to help address this important unmet medical need.
As resistance to marketed antibacterial agents continues to increase, and new antibacterial agents have not been readily forthcoming from the pharmaceutical industry, the availability of new agents is essential to overcome pre-existing and burgeoning resistance. More particularly, an effective, orally deliverable monotherapy and novel compounds active against wild-type or drug-resistant forms of N. gonorrhoeae are urgently needed. New compounds and new therapies with combinations of antibacterial and antibiotic agents having additive or synergistic activities, including combinations with current agents, would enable longer clinical lifetimes for proven agents against N. gonorrhoeae. Accordingly, the availability of such compounds and therapies would provide a significant current and future human health benefit with a high probability of success on several fronts for the control of wild-type or drug-resistant forms of N. gonorrhoeae for a number of years to come.
All other documents referred to herein are incorporated by reference into the present application as though fully set forth herein. SUMMARY
The present description relates to use of a substituted 2-pyridinone compound for treating or ameliorating Neisseria gonorrhoeae (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:
Figure imgf000003_0001
wherein R1, R2 or R3 are as defined herein, and forms and compositions thereof.
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. More particularly, 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 also 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 (MDIR) or extensively drug resistant (XDR).
More particularly, the present description relates to use of a compound of Formula (I) or a form thereof for treating or ameliorating IR, HLR, MDR, MDIR or XDR forms of N. gonorrhoeae.
The present description also relates to a 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 a 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 use of a substituted 2-pyridinone compound for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae) in a subject in need thereof comprising, administering an effective amount of a compound of Formula (I) to the subject:
Figure imgf000004_0001
or a form thereof, wherein
R1 is a monocyclic ring system selected from the group consisting of:
Figure imgf000005_0001
wherein“*” represents a point of attachment for R1 to the 2-pyridinone of Formula (I); and, wherein R1 is substituted on available valences with one to five substituents each selected from R5;
R2 is hydrogen, cyano, C1-8alkyl, hydroxyl-C1-8alkyl, formyl-C1-8alkyl, C1-8alkoxy-C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynl, carboxyl, amino-C1-8alkyl, aryl or C3-14cycloalkyl; R3 is hydrogen, hydroxyl or C1-8alkoxy;
R5 is hydrogen, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, hydroxyl-C1-8alkyl,
halo-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkyl-thio, carboxyl,
C1-8alkyl-carbonyl, C1-8alkoxy-carbonyl, amino-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C2-8alkenyl-amino, (C2-8alkenyl)2-amino, C2-8alkynyl-amino, (C2-8alkynyl)2-amino, amino-C1-8alkyl, C1-10alkyl-amino-C1-8alkyl,
(C1-10alkyl)2-amino-C1-8alkyl, C2-8alkenyl-amino-C1-8alkyl,
(C2-8alkenyl)2-amino-C1-8alkyl, C2-8alkynyl-amino-C1-8alkyl,
(C2-8alkynyl)2-amino-C1-8alkyl, halo-C1-8alkyl-amino, (halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl, (halo-C1-8alkyl)2-amino-C1-8alkyl,
C1-8alkoxy-C1-8alkyl-amino, (C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino,
(C1-8alkoxy-C1-8alkyl)2-amino, C1-8alkoxy-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, amino-C1-8alkyl-amino-C1-8alkyl, (amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (amino-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C1-8alkyl)2-amino-C1-8alkyl-amino-C1-8alkyl, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl)2-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino, (hydroxyl-C1-8alkyl)2-amino,
hydroxyl-C1-8alkyl-amino-C1-8alkyl, (hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl-amino,
[(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,C1-8alkyl]amino,
(C1-8alkyl-carbonyl,C1-8alkyl)amino-C1-8alkyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C3-14cycloalkyl, C3-14cycloalkyl-C1-8alkyl,
C3-14cycloalkyl-oxy, C3-14cycloalkyl-C1-8alkoxy, C3-14cycloalkyl-amino,
C3-14cycloalkyl-amino-C1-8alkyl, (C3-14cycloalkyl,C1-8alkyl)amino-C1-8alkyl,
(C3-14cycloalkyl)2-amino-C1-8alkyl, C3-14cycloalkyl-C1-8alkyl-amino-C1-8alkyl, (C3-14cycloalkyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C3-14cycloalkyl-C1-8alkyl)2-amino-C1-8alkyl, aryl, aryl-C1-8alkyl, aryl-C1-8alkoxy, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-amino-C1-8alkyl,
(aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino, (aryl-C1-8alkyl)2-amino,
aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(aryl-C1-8alkyl)2-amino-C1-8alkyl, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl,C1-8alkyl)amino-C1-8alkyl, (heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-oxy, heterocyclyl-C1-8alkoxy, heterocyclyl-amino, (heterocyclyl,C1-8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-C1-8alkyl, (heterocyclyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl)2-amino-C1-8alkyl,
(heterocyclyl,C3-14cycloalkyl-C1-8alkyl)amino-C1-8alkyl,
heterocyclyl-C1-8alkyl-amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl-oxy-amino,
(heterocyclyl-oxy,C1-8alkyl)amino, (heterocyclyl-oxy)2-amino, (heterocyclyl-oxy-C1-8alkyl,C1-8alkyl)amino, heterocyclyl-carbonyl or heterocyclyl-carbonyl-oxy;
wherein each instance of C3-14cycloalkyl, aryl, heterocyclyl is optionally substituted with one, two or three substituents each selected from R6;
R6 is azido, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, halo-C1-8alkyl,
hydroxyl-C1-8alkyl, C1-8alkoxy-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy,
hydroxyl-C1-8alkoxy, carboxyl, C1-8alkyl-carbonyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, halo-C1-8alkyl-amino,
(halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl,
(halo-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl, C1-8alkyl-thio, amino-carbonyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C1-8alkyl-carbonyl-amino,
(carboxyl-C1-8alkyl,C1-8alkyl)amino-carbonyl-amino, C3-14cycloalkyl,
C3-14cycloalkyl-amino, aryl, aryl-C1-8alkyl, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino,
(aryl-C1-8alkyl)2-amino, aryl-C1-8alkyl-amino-C1-8alkyl,
(aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (aryl-C1-8alkyl)2-amino-C1-8alkyl, aryl-amino-C1-8alkyl, (aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-amino-carbonyl, aryl-C1-8alkoxy, aryl-C1-8alkoxy-carbonyl-amino, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heteroaryl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-amino-C1-8alkyl or heterocyclyl-oxy;
wherein each instance of C3-14cycloalkyl is optionally substituted with one substituent
selected from R9; and,
wherein each instance of aryl is optionally substituted with one substituent selected from R10; R9 is C1-8alkyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl or aryl-C1-8alkyl-amino; and, R10 is halogen;
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 present description further relates to use of a compound of Formula (I), wherein: R5 is hydrogen, halogen, hydroxyl, oxo, cyano, C1-8alkyl, hydroxyl-C1-8alkyl, C1-8alkoxy, carboxyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, (C2-8alkenyl)2-amino, amino-C1-8alkyl, C1-10alkyl-amino-C1-8alkyl, (C1-10alkyl)2-amino-C1-8alkyl,
C2-8alkenyl-amino-C1-8alkyl, halo-C1-8alkyl-amino, halo-C1-8alkyl-amino-C1-8alkyl, C1-8alkoxy-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl-amino, amino-C1-8alkyl-amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkyl)2-amino-C1-8alkyl-amino-C1-8alkyl, (hydroxyl-C1-8alkyl,C1-8alkyl)amino, hydroxyl-C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl-carbonyl,C1-8alkyl)amino-C1-8alkyl, C3-14cycloalkyl-amino-C1-8alkyl, (C3-14cycloalkyl,C1-8alkyl)amino-C1-8alkyl,
C3-14cycloalkyl-C1-8alkyl-amino-C1-8alkyl,
(C3-14cycloalkyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, aryl, aryl-C1-8alkoxy, aryl-amino, (aryl,C1-8alkyl)amino, aryl-amino-C1-8alkyl,
aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl,C1-8alkyl)amino-C1-8alkyl, (heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-oxy, heterocyclyl-amino-C1-8alkyl, (heterocyclyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl,C3-14cycloalkyl-C1-8alkyl)amino-C1-8alkyl,
heterocyclyl-C1-8alkyl-amino-C1-8alkyl, (heterocyclyl-oxy-C1-8alkyl,C1-8alkyl)amino or heterocyclyl-carbonyl;
wherein each instance of C3-14cycloalkyl, aryl, heterocyclyl is optionally substituted with one, two or three substituents each selected from R6;
R6 is azido, halogen, hydroxyl, oxo, cyano, C1-8alkyl, halo-C1-8alkyl, hydroxyl-C1-8alkyl, C1-8alkoxy-C1-8alkyl, C1-8alkoxy, carboxyl, C1-8alkyl-carbonyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, amino-C1-8alkyl,
C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, (C1-8alkyl)2-amino-carbonyl, C1-8alkyl-carbonyl-amino, (carboxyl-C1-8alkyl,C1-8alkyl)amino-carbonyl-amino, C3-14cycloalkyl, C3-14cycloalkyl-amino, aryl, aryl-C1-8alkyl,
(aryl-C1-8alkyl,C1-8alkyl)amino, (aryl-C1-8alkyl)2-amino,
aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(aryl-C1-8alkyl)2-amino-C1-8alkyl, aryl-amino-C1-8alkyl, aryl-C1-8alkoxy,
aryl-C1-8alkoxy-carbonyl-amino, heteroaryl, heteroaryl-C1-8alkyl-amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl or heterocyclyl-oxy;
wherein each instance of C3-14cycloalkyl is optionally substituted with one substituent
selected from R9; and,
R9 is C1-8alkyl, amino, (C1-8alkyl)2-amino or aryl-C1-8alkyl-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
The present description further relates to use of a compound of Formula (I) or a form thereof wherein, when R5 is C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3-14cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
aryl is selected in each instance, when present, from phenyl;
heteroaryl is selected in each instance, when present, from pyrrolyl, thiazolyl, 1H-1,2,3- triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1H-imidazolyl or pyridinyl; and,
heterocyclyl is selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-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][1,4]oxazinyl, 3,4- dihydroisoquinolin-(1H)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][1,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][1,4]oxazin-(4aH)-yl, hexahydro-1H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, 3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-1H-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-1H-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- 1H-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-1H-carbazolyl, 1,2,3,4-tetrahydropyrazino[1,2-a]indolyl, 2,3-dihydro-1H- pyrrolo[1,2-a]indolyl, 1,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- 1,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-1H-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (1R,5S,6s)-3- azabicyclo[3.1.0]hexyl, (1R,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (1R,5S)-3- azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (1S,5R,6R)-3- azabicyclo[3.2.0]heptyl, (1S,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (1S,5R,6S)-3- azabicyclo[3.2.0]heptyl, (1S,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (1S,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptanyl, 2,6- diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7- diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decyl, 2- azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl.
The present description further relates to use of a compound of Formula (I) or a form thereof wherein, when R5 is C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3-14cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
aryl is selected in each instance, when present, from phenyl;
heteroaryl is selected in each instance, when present, from 1H-pyrrol-1-yl, thiazol-2-yl, 1H- 1,2,3-triazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 1H-imidazol-1-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or, heterocyclyl is selected in each instance, when present, from azetidin-1-yl, tetrahydrofuran-2- yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-1-yl, 1,3-dioxolan-2-yl, 2,5-dihydro-1H-pyrrol-1-yl, 4,5-dihydro-1H- imidazol-2-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-6-yl, indolinyl, 2,3-dihydrobenzo[d]oxazol-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl, 3,4-dihydroisoquinolin-2(1H)-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl, 1,2,3,4- tetrahydroquinoxalin-1-yl, (6H)-pyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,
hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][1,4]oxazin-4(4aH)-yl, hexahydro-1H-cyclopenta[c]pyrrol-2-yl, (cis)- octahydrocyclopenta[c]pyrrol-4-yl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-3a(1H)- yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-2(1H)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, 3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazin-4-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-1H-pyrrolo[3,4-b]pyridin- 6(2H,7H,7aH)-yl, hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin- 6-yl, 2,3,4,9-tetrahydro-1H-carbazolyl, 1,2,3,4-tetrahydropyrazino[1,2-a]indolyl, 2,3- dihydro-1H-pyrrolo[1,2-a]indolyl, 1,3-dihydro-2H-isoindol-2-yl, octahydro-2H- isoindol-2-yl, (3aS)-1,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-1H- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2- azabicyclo[2.2.1]hept-5-en-2-yl, 3-azabicyclo[3.1.0]hex-3-yl, 3- azabicyclo[3.1.0]hexan-3-yl, (1R,5S,6s)-3-azabicyclo[3.1.0]hex-3-yl, (1R,5S,6s)-3- azabicyclo[3.1.0]hexan-3-yl, (1R,5S)-3-azabicyclo[3.1.0]hex-6-yl, (1R,5S)-3- azabicyclo[3.1.0]hexan-6-yl, 3,6-diazabicyclo[3.1.0]hex-3-yl, 3,6- diazabicyclo[3.1.0]hexan-3-yl, (1S,5R,6R)-3-azabicyclo[3.2.0]hept-3-yl, (1S,5R,6S)- 3-azabicyclo[3.2.0]hept-3-yl, (1S,5R)-3-azabicyclo[3.2.0]heptan-3-yl, 5- azaspiro[2.4]hept-5-yl, 5-azaspiro[2.4]heptan-5-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,5-diazaspiro[3.4]octan-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 2,7- diazaspiro[3.5]nonan-2-yl, 2,7-diazaspiro[4.4]nonan-2-yl, 2-azaspiro[4.5]dec-2-yl, 2- azaspiro[4.5]decan-2-yl, 2,8-diazaspiro[4.5]dec-2-yl or 2,8-diazaspiro[4.5]decan-2-yl. The present description further relates to use of a compound of Formula (I) or a form thereof wherein, R6 is:
C3-14cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H-1,2,3- triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1H-imidazolyl or pyridinyl; or,
heterocyclyl selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or 1,4-diazepanyl.
The present description further relates to use of a compound of Formula (I) or a form thereof wherein, R6 is:
C3-14cycloalkyl 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 1H-pyrrol-1-yl, thiazol-2-yl, 1H- 1,2,3-triazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 1H-imidazol-1-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl selected in each instance, when present, from azetidin-1-yl, tetrahydrofuran-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan-1-yl.
The present description further relates to use of a compound of Formula (I), wherein the ring system R1a is selected from a R1a1 ring system:
Figure imgf000012_0001
R1a1 wherein“*” represents a point of attachment; and, wherein R5a, R5b, R5c, R5d and R5e, when present, are selected from the group consisting of:
hydrogen, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, hydroxyl-C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkyl-thio, carboxyl, C1-8alkyl-carbonyl,
C1-8alkoxy-carbonyl, amino-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C2-8alkenyl-amino, (C2-8alkenyl)2-amino, C2-8alkynyl-amino, (C2-8alkynyl)2-amino, amino-C1-8alkyl, C1-10alkyl-amino-C1-8alkyl, (C1-10alkyl)2-amino-C1-8alkyl,
C2-8alkenyl-amino-C1-8alkyl, (C2-8alkenyl)2-amino-C1-8alkyl,
C2-8alkynyl-amino-C1-8alkyl, (C2-8alkynyl)2-amino-C1-8alkyl, halo-C1-8alkyl-amino, (halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl,
(halo-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkoxy-C1-8alkyl-amino,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino, (C1-8alkoxy-C1-8alkyl)2-amino,
C1-8alkoxy-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, amino-C1-8alkyl-amino-C1-8alkyl, (amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (amino-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C1-8alkyl)2-amino-C1-8alkyl-amino-C1-8alkyl,
[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl)2-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino, (hydroxyl-C1-8alkyl)2-amino,
hydroxyl-C1-8alkyl-amino-C1-8alkyl, (hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl-amino,
[(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,C1-8alkyl]amino,
(C1-8alkyl-carbonyl,C1-8alkyl)amino-C1-8alkyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl,
Figure imgf000013_0001
C3-14cycloalkyl-oxy, C3-14cycloalkyl-C1-8alkoxy, C3-14cycloalkyl-amino, C3-14cycloalkyl-amino-C1-8alkyl, (C3-14cycloalkyl,C1-8alkyl)amino-C1-8alkyl,
(C3-14cycloalkyl)2-amino-C1-8alkyl, C3-14cycloalkyl-C1-8alkyl-amino-C1-8alkyl, (C3-14cycloalkyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C3-14cycloalkyl-C1-8alkyl)2-amino-C1-8alkyl, aryl, aryl-C1-8alkyl, aryl-C1-8alkoxy, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-amino-C1-8alkyl,
(aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino, (aryl-C1-8alkyl)2-amino,
aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(aryl-C1-8alkyl)2-amino-C1-8alkyl, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl,C1-8alkyl)amino-C1-8alkyl, (heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-oxy, heterocyclyl-C1-8alkoxy, heterocyclyl-amino, (heterocyclyl,C1-8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-C1-8alkyl, (heterocyclyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl)2-amino-C1-8alkyl,
(heterocyclyl,C3-14cycloalkyl-C1-8alkyl)amino-C1-8alkyl,
heterocyclyl-C1-8alkyl-amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl-oxy-amino,
(heterocyclyl-oxy,C1-8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-C1-8alkyl,C1-8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-carbonyl-oxy;
wherein each instance of C3-14cycloalkyl, aryl, heterocyclyl is optionally substituted with one, two or three substituents each selected from R6;
R6 is azido, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, halo-C1-8alkyl,
hydroxyl-C1-8alkyl, C1-8alkoxy-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy,
hydroxyl-C1-8alkoxy, carboxyl, C1-8alkyl-carbonyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, halo-C1-8alkyl-amino,
(halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl, (halo-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl, C1-8alkyl-thio, amino-carbonyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C1-8alkyl-carbonyl-amino,
(carboxyl-C1-8alkyl,C1-8alkyl)amino-carbonyl-amino, C3-14cycloalkyl,
C3-14cycloalkyl-amino, aryl, aryl-C1-8alkyl, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino,
(aryl-C1-8alkyl)2-amino, aryl-C1-8alkyl-amino-C1-8alkyl,
(aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (aryl-C1-8alkyl)2-amino-C1-8alkyl, aryl-amino-C1-8alkyl, (aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-amino-carbonyl, aryl-C1-8alkoxy, aryl-C1-8alkoxy-carbonyl-amino, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heteroaryl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-amino-C1-8alkyl or heterocyclyl-oxy;
wherein each instance of C3-14cycloalkyl and heterocyclyl is optionally substituted with one substituent selected from R9; and,
wherein each instance of aryl is optionally substituted with one substituent selected from R10; R9 is C1-8alkyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl,
C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl or aryl-C1-8alkyl-amino; and, R10 is halogen;
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 present description also relates to use of a compound of Formula (I), wherein the ring system R1a is selected from the R1a1 ring system, and R5a, R5b, R5c, R5d and R5e, when present, are selected from the group consisting of:
hydrogen, halogen, hydroxyl, cyano, C1-8alkyl, C1-8alkoxy, amino, C1-8alkyl-amino,
(C1-8alkyl)2-amino, (C2-8alkenyl)2-amino, (C1-10alkyl)2-amino-C1-8alkyl,
halo-C1-8alkyl-amino, C1-8alkyl-amino-C1-8alkyl-amino,
[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, (hydroxyl-C1-8alkyl,C1-8alkyl)amino, aryl-amino, (aryl,C1-8alkyl)amino, heterocyclyl or
(heterocyclyl-oxy-C1-8alkyl,C1-8alkyl)amino;
wherein each instance of heterocyclyl is optionally substituted with one, two or three
substituents each selected from R6;
R6 is azido, halogen, hydroxyl, oxo, cyano, C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy-C1-8alkyl, C1-8alkoxy, carboxyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino,
(C1-8alkyl)2-amino, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl,
(C1-8alkyl)2-amino-C1-8alkyl, (carboxyl-C1-8alkyl,C1-8alkyl)amino-carbonyl-amino, C3-14cycloalkyl, C3-14cycloalkyl-amino, aryl, aryl-C1-8alkyl, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino, (aryl-C1-8alkyl)2-amino,
aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(aryl-C1-8alkyl)2-amino-C1-8alkyl, aryl-C1-8alkoxy, aryl-C1-8alkoxy-carbonyl-amino, heteroaryl, heteroaryl-C1-8alkyl-amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl or heterocyclyl-oxy;
wherein each instance of C3-14cycloalkyl and heterocyclyl is optionally substituted with one substituent selected from R9; and,
wherein each instance of aryl is optionally substituted with one substituent selected from R10; R9 is C1-8alkyl, amino, (C1-8alkyl)2-amino or aryl-C1-8alkyl-amino; and,
R10 is halogen;
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 present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R5a, R5b, R5c, R5d and R5e substituted on the R1a1 ring system is C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C3-14cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
aryl is selected in each instance, when present, from phenyl;
heteroaryl is selected in each instance, when present, from pyrrolyl, thiazolyl, 1H-1,2,3- triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1H-imidazolyl or pyridinyl; and,
heterocyclyl is selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-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][1,4]oxazinyl, 3,4- dihydroisoquinolin-(1H)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][1,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][1,4]oxazin-(4aH)-yl, hexahydro-1H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, 3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-1H-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-1H-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- 1H-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-1H-carbazolyl, 1,2,3,4-tetrahydropyrazino[1,2-a]indolyl, 2,3-dihydro-1H- pyrrolo[1,2-a]indolyl, 1,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- 1,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-1H-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (1R,5S,6s)-3- azabicyclo[3.1.0]hexyl, (1R,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (1R,5S)-3- azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (1S,5R,6R)-3- azabicyclo[3.2.0]heptyl, (1S,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (1S,5R,6S)-3- azabicyclo[3.2.0]heptyl, (1S,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (1S,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptanyl, 2,6- diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7- diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decyl, 2- azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl. The present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R5a, R5b, R5c, R5d and R5e substituted on the R1a1 ring system is C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C3-14cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
aryl is selected in each instance, when present, from phenyl;
heteroaryl is selected in each instance, when present, from 1H-pyrrol-1-yl, thiazol-2-yl, 1H- 1,2,3-triazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 1H-imidazol-1-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl is selected in each instance, when present, from azetidin-1-yl, tetrahydrofuran-2- yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-1-yl, 1,3-dioxolan-2-yl, 2,5-dihydro-1H-pyrrol-1-yl, 4,5-dihydro-1H- imidazol-2-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-6-yl, indolinyl, 2,3-dihydrobenzo[d]oxazol-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl, 3,4-dihydroisoquinolin-2(1H)-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl, 1,2,3,4- tetrahydroquinoxalin-1-yl, (6H)-pyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,
hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][1,4]oxazin-4(4aH)-yl, hexahydro-1H-cyclopenta[c]pyrrol-2-yl, (cis)- octahydrocyclopenta[c]pyrrol-4-yl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-3a(1H)- yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-2(1H)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, 3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazin-4-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-1H-pyrrolo[3,4-b]pyridin- 6(2H,7H,7aH)-yl, hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin- 6-yl, 2,3,4,9-tetrahydro-1H-carbazolyl, 1,2,3,4-tetrahydropyrazino[1,2-a]indolyl, 2,3- dihydro-1H-pyrrolo[1,2-a]indolyl, 1,3-dihydro-2H-isoindol-2-yl, octahydro-2H- isoindol-2-yl, (3aS)-1,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-1H- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2- azabicyclo[2.2.1]hept-5-en-2-yl, 3-azabicyclo[3.1.0]hex-3-yl, 3- azabicyclo[3.1.0]hexan-3-yl, (1R,5S,6s)-3-azabicyclo[3.1.0]hex-3-yl, (1R,5S,6s)-3- azabicyclo[3.1.0]hexan-3-yl, (1R,5S)-3-azabicyclo[3.1.0]hex-6-yl, (1R,5S)-3- azabicyclo[3.1.0]hexan-6-yl, 3,6-diazabicyclo[3.1.0]hex-3-yl, 3,6- diazabicyclo[3.1.0]hexan-3-yl, (1S,5R,6R)-3-azabicyclo[3.2.0]hept-3-yl, (1S,5R,6S)- 3-azabicyclo[3.2.0]hept-3-yl, (1S,5R)-3-azabicyclo[3.2.0]heptan-3-yl, 5- azaspiro[2.4]hept-5-yl, 5-azaspiro[2.4]heptan-5-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,5-diazaspiro[3.4]octan-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 2,7- diazaspiro[3.5]nonan-2-yl, 2,7-diazaspiro[4.4]nonan-2-yl, 2-azaspiro[4.5]dec-2-yl, 2- azaspiro[4.5]decan-2-yl, 2,8-diazaspiro[4.5]dec-2-yl or 2,8-diazaspiro[4.5]decan-2-yl. The present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R5a, R5b, R5c, R5d and R5e substituted on the R1a1 ring system is aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
aryl is selected in each instance, when present, from phenyl;
heteroaryl is selected in each instance, when present, from pyrrolyl, 1H-tetrazolyl or
1H-imidazolyl; and,
heterocyclyl is selected in each instance, when present, from azetidinyl, pyrrolidinyl,
piperidinyl, piperazinyl, morpholinyl, 2,5-dihydro-1H-pyrrolyl, 1,2,3,6- tetrahydropyridinyl, tetrahydro-2H-pyranyl, (6H)-pyrrolo[3,4-b][1,4]oxazin-(2H)-yl, hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][1,4]oxazin-(4aH)-yl, hexahydro-1H-cyclopenta[c]pyrrolyl, (3aR,4R,6aS)- hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4S,6aS)-hexahydrocyclopenta[c]pyrrol- (1H)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,6aR)- hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- (1H)-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, octahydro-6H-pyrrolo[3,4- b]pyridinyl, 1,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-1,3,3a,4,5,6- hexahydro-2H-isoindolyl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S,6s)-3-azabicyclo[3.1.0]hexyl, (1R,5S,6s)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, (1S,5R,6R)-3-azabicyclo[3.2.0]heptyl, (1S,5R,6S)-3- azabicyclo[3.2.0]heptyl, 5-azaspiro[2.4]heptyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2- azaspiro[4.5]decyl or 2,8-diazaspiro[4.5]decanyl.
The present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R5a, R5b, R5c, R5d and R5e substituted on the R1a1 ring system is aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from 1H-pyrrol-1-yl, 1H-tetrazol-5-yl or 1H-imidazol-1-yl; or,
heterocyclyl selected in each instance, when present, from azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, 2,5-dihydro-1H-pyrrol-1-yl, 1,2,3,6- tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-6-yl, (6H)- pyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-4(4aH)-yl, hexahydro-1H- cyclopenta[c]pyrrol-2-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl, (3aR,4S,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl, (3aR,5r,6aS)- hexahydrocyclopenta[c]pyrrol-2(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol- 5(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, 5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl, octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, 1,3-dihydro-2H- isoindol-2-yl, octahydro-2H-isoindol-2-yl, (3aS)-1,3,3a,4,5,6-hexahydro-2H-isoindol- 2-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2- yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 2- azabicyclo[2.2.1]hept-5-en-2-yl, 3-azabicyclo[3.1.0]hex-3-yl, (1R,5S,6s)-3- azabicyclo[3.1.0]hex-3-yl, (1R,5S,6s)-3-azabicyclo[3.1.0]hexan-3-yl, 3,6- diazabicyclo[3.1.0]hex-3-yl, (1S,5R,6R)-3-azabicyclo[3.2.0]hept-3-yl, (1S,5R,6S)-3- azabicyclo[3.2.0]hept-3-yl, 5-azaspiro[2.4]hept-5-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,5-diazaspiro[3.4]octan-2-yl, 2,7-diazaspiro[3.5]nonan-2-yl, 2,7- diazaspiro[4.4]nonan-2-yl, 2-azaspiro[4.5]dec-2-yl or 2,8-diazaspiro[4.5]dec-2-yl. The present description further relates to use of a compound of Formula (I) or a form thereof wherein R6 is:
C3-14cycloalkyl selected in each instance, when present, from cyclopropyl or cyclobutyl; aryl selected in each instance, when present, from phenyl; heteroaryl selected in each instance, when present, from thiazolyl, 1H-1,2,3-triazolyl, 2H-tetrazolyl or pyridinyl; and,
heterocyclyl selected in each instance, when present, from pyrrolidinyl or morpholinyl.
The present description further relates to use of a compound of Formula (I) or a form thereof wherein R6 is:
C3-14cycloalkyl selected in each instance, when present, from cyclopropyl or cyclobutyl; aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from thiazol-2-yl, 1H-1,2,3-triazol-1-yl, 2H-tetrazol-2-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; and,
heterocyclyl selected in each instance, when present, from pyrrolidin-1-yl or morpholin-4-yl.
The present description further relates to use of a compound of Formula (I), wherein the ring system R1a is selected from the R1a1 ring system, and R5a, R5b, R5c, R5d and R5e, when present, are selected from the group consisting of (where“--” indicates that one or more of R5a, R5b, R5c, R5d or R5e are not present):
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0002
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 present description further relates to use of a compound of Formula (I), wherein the ring system R1b, R1c, R1d and R1e is selected from a R1b1, R1c1, R1d1 and R1e1 ring system, respectively:
Figure imgf000036_0001
wherein“*” represents a point of attachment; and, wherein R5a, R5b, R5c, R5d and R5e, when present, are selected from the group consisting of:
hydrogen, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, hydroxyl-C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkyl-thio, carboxyl, C1-8alkyl-carbonyl,
C1-8alkoxy-carbonyl, amino-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C2-8alkenyl-amino, (C2-8alkenyl)2-amino, C2-8alkynyl-amino, (C2-8alkynyl)2-amino, amino-C1-8alkyl, C1-10alkyl-amino-C1-8alkyl, (C1-10alkyl)2-amino-C1-8alkyl, C2-8alkenyl-amino-C1-8alkyl, (C2-8alkenyl)2-amino-C1-8alkyl,
C2-8alkynyl-amino-C1-8alkyl, (C2-8alkynyl)2-amino-C1-8alkyl, halo-C1-8alkyl-amino, (halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl,
(halo-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkoxy-C1-8alkyl-amino,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino, (C1-8alkoxy-C1-8alkyl)2-amino,
C1-8alkoxy-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, amino-C1-8alkyl-amino-C1-8alkyl, (amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (amino-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C1-8alkyl)2-amino-C1-8alkyl-amino-C1-8alkyl,
[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl)2-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino, (hydroxyl-C1-8alkyl)2-amino,
hydroxyl-C1-8alkyl-amino-C1-8alkyl, (hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl-amino,
[(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,C1-8alkyl]amino,
(C1-8alkyl-carbonyl,C1-8alkyl)amino-C1-8alkyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C3-14cycloalkyl, C3-14cycloalkyl-C1-8alkyl,
C3-14cycloalkyl-oxy, C3-14cycloalkyl-C1-8alkoxy, C3-14cycloalkyl-amino,
C3-14cycloalkyl-amino-C1-8alkyl, (C3-14cycloalkyl,C1-8alkyl)amino-C1-8alkyl, (C3-14cycloalkyl)2-amino-C1-8alkyl, C3-14cycloalkyl-C1-8alkyl-amino-C1-8alkyl, (C3-14cycloalkyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C3-14cycloalkyl-C1-8alkyl)2-amino-C1-8alkyl, aryl, aryl-C1-8alkyl, aryl-C1-8alkoxy, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-amino-C1-8alkyl, (aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino, (aryl-C1-8alkyl)2-amino,
aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(aryl-C1-8alkyl)2-amino-C1-8alkyl, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl,C1-8alkyl)amino-C1-8alkyl, (heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-oxy, heterocyclyl-C1-8alkoxy, heterocyclyl-amino, (heterocyclyl,C1-8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-C1-8alkyl, (heterocyclyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl)2-amino-C1-8alkyl,
(heterocyclyl,C3-14cycloalkyl-C1-8alkyl)amino-C1-8alkyl,
heterocyclyl-C1-8alkyl-amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl-oxy-amino,
(heterocyclyl-oxy,C1-8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-C1-8alkyl,C1-8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-carbonyl-oxy;
wherein each instance of C3-14cycloalkyl, aryl, heterocyclyl is optionally substituted with one, two or three substituents each selected from R6;
R6 is azido, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, halo-C1-8alkyl,
hydroxyl-C1-8alkyl, C1-8alkoxy-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy,
hydroxyl-C1-8alkoxy, carboxyl, C1-8alkyl-carbonyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, halo-C1-8alkyl-amino,
(halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl,
(halo-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl, C1-8alkyl-thio, amino-carbonyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C1-8alkyl-carbonyl-amino,
(carboxyl-C1-8alkyl,C1-8alkyl)amino-carbonyl-amino, C3-14cycloalkyl, C3-14cycloalkyl-amino, aryl, aryl-C1-8alkyl, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino,
(aryl-C1-8alkyl)2-amino, aryl-C1-8alkyl-amino-C1-8alkyl,
(aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (aryl-C1-8alkyl)2-amino-C1-8alkyl, aryl-amino-C1-8alkyl, (aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-amino-carbonyl, aryl-C1-8alkoxy, aryl-C1-8alkoxy-carbonyl-amino, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heteroaryl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-amino-C1-8alkyl or heterocyclyl-oxy;
wherein each instance of C3-14cycloalkyl and heterocyclyl is optionally substituted with one substituent selected from R9; and,
wherein each instance of aryl is optionally substituted with one substituent selected from R10; R9 is C1-8alkyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl,
C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl or aryl-C1-8alkyl-amino; and, R10 is halogen;
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 present description further relates to use of a compound of Formula (I), wherein the ring system R1b, R1c, R1d and R1e is selected from the R1b1, R1c1, R1d1 and R1e1 ring system, respectively, and R5a, R5b, R5c, R5d and R5e, when present, are selected from the group consisting of hydrogen, (C1-8alkyl)2-amino or heterocyclyl;
wherein heterocyclyl is optionally substituted with a substituent selected from R6; and, R6 is amino or (C1-8alkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
The present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R5a, R5b, R5c, R5d and R5e substituted on a R1b1, R1c1, R1d1 or R1e1 ring system is C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3-14cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
aryl is selected in each instance, when present, from phenyl;
heteroaryl is selected in each instance, when present, from pyrrolyl, thiazolyl, 1H-1,2,3- triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1H-imidazolyl or pyridinyl; and,
heterocyclyl is selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-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][1,4]oxazinyl, 3,4- dihydroisoquinolin-(1H)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][1,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][1,4]oxazin-(4aH)-yl, hexahydro-1H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, 3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-1H-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-1H-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- 1H-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-1H-carbazolyl, 1,2,3,4-tetrahydropyrazino[1,2-a]indolyl, 2,3-dihydro-1H- pyrrolo[1,2-a]indolyl, 1,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- 1,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-1H-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (1R,5S,6s)-3- azabicyclo[3.1.0]hexyl, (1R,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (1R,5S)-3- azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (1S,5R,6R)-3- azabicyclo[3.2.0]heptyl, (1S,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (1S,5R,6S)-3- azabicyclo[3.2.0]heptyl, (1S,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (1S,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptanyl, 2,6- diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7- diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decyl, 2- azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl.
The present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R5a, R5b, R5c, R5d and R5e substituted on a R1b1, R1c1, R1d1 or R1e1 ring system is C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3-14cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
aryl is selected in each instance, when present, from phenyl;
heteroaryl is selected in each instance, when present, from 1H-pyrrol-1-yl, thiazol-2-yl, 1H- 1,2,3-triazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 1H-imidazol-1-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl is selected in each instance, when present, from azetidin-1-yl, tetrahydrofuran-2- yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-1-yl, 1,3-dioxolan-2-yl, 2,5-dihydro-1H-pyrrol-1-yl, 4,5-dihydro-1H- imidazol-2-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-6-yl, indolinyl, 2,3-dihydrobenzo[d]oxazol-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl, 3,4-dihydroisoquinolin-2(1H)-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl, 1,2,3,4- tetrahydroquinoxalin-1-yl, (6H)-pyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,
hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][1,4]oxazin-4(4aH)-yl, hexahydro-1H-cyclopenta[c]pyrrol-2-yl, (cis)- octahydrocyclopenta[c]pyrrol-4-yl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-3a(1H)- yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-2(1H)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, 3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazin-4-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-1H-pyrrolo[3,4-b]pyridin- 6(2H,7H,7aH)-yl, hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin- 6-yl, 2,3,4,9-tetrahydro-1H-carbazolyl, 1,2,3,4-tetrahydropyrazino[1,2-a]indolyl, 2,3- dihydro-1H-pyrrolo[1,2-a]indolyl, 1,3-dihydro-2H-isoindol-2-yl, octahydro-2H- isoindol-2-yl, (3aS)-1,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-1H- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2- azabicyclo[2.2.1]hept-5-en-2-yl, 3-azabicyclo[3.1.0]hex-3-yl, 3- azabicyclo[3.1.0]hexan-3-yl, (1R,5S,6s)-3-azabicyclo[3.1.0]hex-3-yl, (1R,5S,6s)-3- azabicyclo[3.1.0]hexan-3-yl, (1R,5S)-3-azabicyclo[3.1.0]hex-6-yl, (1R,5S)-3- azabicyclo[3.1.0]hexan-6-yl, 3,6-diazabicyclo[3.1.0]hex-3-yl, 3,6- diazabicyclo[3.1.0]hexan-3-yl, (1S,5R,6R)-3-azabicyclo[3.2.0]hept-3-yl, (1S,5R,6S)- 3-azabicyclo[3.2.0]hept-3-yl, (1S,5R)-3-azabicyclo[3.2.0]heptan-3-yl, 5- azaspiro[2.4]hept-5-yl, 5-azaspiro[2.4]heptan-5-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,5-diazaspiro[3.4]octan-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 2,7- diazaspiro[3.5]nonan-2-yl, 2,7-diazaspiro[4.4]nonan-2-yl, 2-azaspiro[4.5]dec-2-yl, 2- azaspiro[4.5]decan-2-yl, 2,8-diazaspiro[4.5]dec-2-yl or 2,8-diazaspiro[4.5]decan-2-yl. The present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R5a, R5b, R5c, R5d and R5e substituted on a R1b1, R1c1, R1d1 or R1e1 ring system is heterocyclyl alone or as a portion of a substituent, then:
heterocyclyl is selected in each instance, when present, from pyrrolidinyl, piperazinyl,
morpholinyl or (1R,5S,6s)-3-azabicyclo[3.1.0]hexanyl.
The present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R5a, R5b, R5c, R5d and R5e substituted on a R1b1, R1c1, R1d1 or R1e1 ring system is heterocyclyl alone or as a portion of a substituent, then:
heterocyclyl is selected in each instance, when present, from pyrrolidin-1-yl, piperazin-1-yl, morpholin-4-yl or (1R,5S,6s)-3-azabicyclo[3.1.0]hexan-3-yl. The present description further relates to use of a compound of Formula (I), wherein the ring system R1b, R1c, R1d and R1e is selected from the R1b1, R1c1, R1d1 and R1e1 ring system, respectively, and R5a, R5b, R5c, R5d and R5e, when present, are selected from the group consisting of (where“Ring” in the table below indicates whether an R1b1, R1c1, R1d1 or R1e1 ring system is selected; and,“--” in the table below indicates that one or more of R5a, R5b, R5c, R5d or R5e are not present):
Figure imgf000043_0001
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof. The present description further relates to use of a compound of Formula (I), wherein the ring system R1f, R1g, R1h, R1i and R1j is selected from a R1f1, R1g1, R1h1, R1i1 and R1j1 ring system, respectively:
Figure imgf000044_0001
wherein“*” represents a point of attachment; and, wherein R5a, R5b, R5c and R5d, when
present, are selected from the group consisting of:
hydrogen, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, hydroxyl-C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkyl-thio, carboxyl, C1-8alkyl-carbonyl,
C1-8alkoxy-carbonyl, amino-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C2-8alkenyl-amino, (C2-8alkenyl)2-amino, C2-8alkynyl-amino, (C2-8alkynyl)2-amino, amino-C1-8alkyl, C1-10alkyl-amino-C1-8alkyl, (C1-10alkyl)2-amino-C1-8alkyl,
C2-8alkenyl-amino-C1-8alkyl, (C2-8alkenyl)2-amino-C1-8alkyl,
C2-8alkynyl-amino-C1-8alkyl, (C2-8alkynyl)2-amino-C1-8alkyl, halo-C1-8alkyl-amino, (halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl,
(halo-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkoxy-C1-8alkyl-amino,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino, (C1-8alkoxy-C1-8alkyl)2-amino,
C1-8alkoxy-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, amino-C1-8alkyl-amino-C1-8alkyl, (amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (amino-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C1-8alkyl)2-amino-C1-8alkyl-amino-C1-8alkyl,
[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl)2-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino, (hydroxyl-C1-8alkyl)2-amino,
hydroxyl-C1-8alkyl-amino-C1-8alkyl, (hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl-amino,
[(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,C1-8alkyl]amino,
(C1-8alkyl-carbonyl,C1-8alkyl)amino-C1-8alkyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C3-14cycloalkyl, C3-14cycloalkyl-C1-8alkyl,
C3-14cycloalkyl-oxy, C3-14cycloalkyl-C1-8alkoxy, C3-14cycloalkyl-amino,
C3-14cycloalkyl-amino-C1-8alkyl, (C3-14cycloalkyl,C1-8alkyl)amino-C1-8alkyl,
(C3-14cycloalkyl)2-amino-C1-8alkyl, C3-14cycloalkyl-C1-8alkyl-amino-C1-8alkyl, (C3-14cycloalkyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C3-14cycloalkyl-C1-8alkyl)2-amino-C1-8alkyl, aryl, aryl-C1-8alkyl, aryl-C1-8alkoxy, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-amino-C1-8alkyl,
(aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino, (aryl-C1-8alkyl)2-amino,
aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(aryl-C1-8alkyl)2-amino-C1-8alkyl, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl,C1-8alkyl)amino-C1-8alkyl, (heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-oxy, heterocyclyl-C1-8alkoxy, heterocyclyl-amino, (heterocyclyl,C1-8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-C1-8alkyl, (heterocyclyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl)2-amino-C1-8alkyl,
(heterocyclyl,C3-14cycloalkyl-C1-8alkyl)amino-C1-8alkyl,
heterocyclyl-C1-8alkyl-amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl-oxy-amino,
(heterocyclyl-oxy,C1-8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-C1-8alkyl,C1-8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-carbonyl-oxy;
wherein each instance of C3-14cycloalkyl, aryl, heterocyclyl is optionally substituted with one substituent selected from R6;
R6 is azido, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, halo-C1-8alkyl,
hydroxyl-C1-8alkyl, C1-8alkoxy-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy,
hydroxyl-C1-8alkoxy, carboxyl, C1-8alkyl-carbonyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, halo-C1-8alkyl-amino,
(halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl,
(halo-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl, C1-8alkyl-thio, amino-carbonyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C1-8alkyl-carbonyl-amino,
(carboxyl-C1-8alkyl,C1-8alkyl)amino-carbonyl-amino, C3-14cycloalkyl,
C3-14cycloalkyl-amino, aryl, aryl-C1-8alkyl, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino,
(aryl-C1-8alkyl)2-amino, aryl-C1-8alkyl-amino-C1-8alkyl,
(aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (aryl-C1-8alkyl)2-amino-C1-8alkyl, aryl-amino-C1-8alkyl, (aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-amino-carbonyl, aryl-C1-8alkoxy, aryl-C1-8alkoxy-carbonyl-amino, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heteroaryl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-amino-C1-8alkyl or heterocyclyl-oxy;
wherein each instance of C3-14cycloalkyl and heterocyclyl is optionally substituted with one substituent selected from R9; and,
wherein each instance of aryl is optionally substituted with one substituent selected from R10; R9 is C1-8alkyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl,
C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl or aryl-C1-8alkyl-amino; and, R10 is halogen;
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 present description further relates to use of a compound of Formula (I), wherein the ring system R1f, R1g, R1h, R1i and R1j is selected from the R1f1, R1g1, R1h1, R1i1 and R1j1 ring system, respectively, and R5a, R5b, R5c and R5d, when present, are selected from the group consisting of:
hydrogen, C1-8alkyl, (C1-8alkyl)2-amino, (C1-10alkyl)2-amino-C1-8alkyl, heterocyclyl or
heterocyclyl-C1-8alkyl; wherein each instance of heterocyclyl is optionally substituted with one (C1-8alkyl)2-amino substituent; and,
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 present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R5a, R5b, R5c and R5d substituted on a R1f1, R1g1, R1h1, R1i1 and R1j1 ring system is C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3-14cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
aryl is selected in each instance, when present, from phenyl;
heteroaryl is selected in each instance, when present, from pyrrolyl, thiazolyl, 1H-1,2,3- triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1H-imidazolyl or pyridinyl; and,
heterocyclyl is selected in each instance, when present, from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3-dioxolanyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydro-1H-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][1,4]oxazinyl, 3,4- dihydroisoquinolin-(1H)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][1,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][1,4]oxazin-(4aH)-yl, hexahydro-1H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, 3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-1H-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-1H-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- 1H-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-1H-carbazolyl, 1,2,3,4-tetrahydropyrazino[1,2-a]indolyl, 2,3-dihydro-1H- pyrrolo[1,2-a]indolyl, 1,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- 1,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-1H-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (1R,5S,6s)-3- azabicyclo[3.1.0]hexyl, (1R,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (1R,5S)-3- azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (1S,5R,6R)-3- azabicyclo[3.2.0]heptyl, (1S,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (1S,5R,6S)-3- azabicyclo[3.2.0]heptyl, (1S,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (1S,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptanyl, 2,6- diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7- diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decyl, 2- azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl.
The present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R5a, R5b, R5c and R5d substituted on a R1f1, R1g1, R1h1, R1i1 and R1j1 ring system is C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3-14cycloalkyl is selected in each instance, when present, from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
aryl is selected in each instance, when present, from phenyl;
heteroaryl is selected in each instance, when present, from 1H-pyrrol-1-yl, thiazol-2-yl, 1H- 1,2,3-triazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 1H-imidazol-1-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl is selected in each instance, when present, from azetidin-1-yl, tetrahydrofuran-2- yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-1-yl, 1,3-dioxolan-2-yl, 2,5-dihydro-1H-pyrrol-1-yl, 4,5-dihydro-1H- imidazol-2-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-6-yl, indolinyl, 2,3-dihydrobenzo[d]oxazol-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl, 3,4-dihydroisoquinolin-2(1H)-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl, 1,2,3,4- tetrahydroquinoxalin-1-yl, (6H)-pyrrolo[3,4-b][1,4]oxazin-6(2H)-yl,
hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][1,4]oxazin-4(4aH)-yl, hexahydro-1H-cyclopenta[c]pyrrol-2-yl, (cis)- octahydrocyclopenta[c]pyrrol-4-yl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-3a(1H)- yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-2(1H)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, 3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazin-4-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-1H-pyrrolo[3,4-b]pyridin- 6(2H,7H,7aH)-yl, hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-1H-pyrrolo[3,4-b]pyridin-6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin- 6-yl, 2,3,4,9-tetrahydro-1H-carbazolyl, 1,2,3,4-tetrahydropyrazino[1,2-a]indolyl, 2,3- dihydro-1H-pyrrolo[1,2-a]indolyl, 1,3-dihydro-2H-isoindol-2-yl, octahydro-2H- isoindol-2-yl, (3aS)-1,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-1H- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl, 2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2- azabicyclo[2.2.1]hept-5-en-2-yl, 3-azabicyclo[3.1.0]hex-3-yl, 3- azabicyclo[3.1.0]hexan-3-yl, (1R,5S,6s)-3-azabicyclo[3.1.0]hex-3-yl, (1R,5S,6s)-3- azabicyclo[3.1.0]hexan-3-yl, (1R,5S)-3-azabicyclo[3.1.0]hex-6-yl, (1R,5S)-3- azabicyclo[3.1.0]hexan-6-yl, 3,6-diazabicyclo[3.1.0]hex-3-yl, 3,6- diazabicyclo[3.1.0]hexan-3-yl, (1S,5R,6R)-3-azabicyclo[3.2.0]hept-3-yl, (1S,5R,6S)- 3-azabicyclo[3.2.0]hept-3-yl, (1S,5R)-3-azabicyclo[3.2.0]heptan-3-yl, 5- azaspiro[2.4]hept-5-yl, 5-azaspiro[2.4]heptan-5-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,5-diazaspiro[3.4]octan-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 2,7- diazaspiro[3.5]nonan-2-yl, 2,7-diazaspiro[4.4]nonan-2-yl, 2-azaspiro[4.5]dec-2-yl, 2- azaspiro[4.5]decan-2-yl, 2,8-diazaspiro[4.5]dec-2-yl or 2,8-diazaspiro[4.5]decan-2-yl. The present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R5a, R5b, R5c and R5d substituted on a R1f1, R1g1, R1h1, R1i1 and R1j1 ring system is heterocyclyl alone or as a portion of a substituent, then:
heterocyclyl selected in each instance, when present, from pyrrolidinyl or piperidinyl.
The present description also relates to use of a compound of Formula (I) or a form thereof wherein, when R5a, R5b, R5c and R5d substituted on a R1f1, R1g1, R1h1, R1i1 and R1j1 ring system is heterocyclyl alone or as a portion of a substituent, then:
heterocyclyl selected in each instance, when present, from pyrrolidin-1-yl or piperidin-1-yl.
The present description further relates to use of a compound of Formula (I), wherein the ring system R1f, R1g, R1h, R1i and R1j is selected from the R1f1, R1g1, R1h1, R1i1 and R1j1 ring system, respectively, and R5a, R5b, R5c and R5d, when present, are selected from the group consisting of (where“Ring” in the table below indicates whether an R1f1, R1g1, R1h1, R1i1 or R1j1 ring system is selected; and,“--” in the table below indicates that R5a, R5b, R5c or R5d are not present):
Figure imgf000050_0001
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In one embodiment of the present description, a compound or a form thereof for the use described herein is a compound of Formula (I) or a form thereof selected from the group consisting of:
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In one embodiment of the present description, a compound or a form thereof for the use described herein is a compound of Formula (I) or a form thereof (wherein compound number (#1) indicates that the salt form was isolated) selected from the group consisting of: Cpd Name
1 5-benzyl-6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid 2 5-benzyl-6-[4-(dimethylamino)phenyl]-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
3 6-(4-aminophenyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
4 6-[4-(dimethylamino)phenyl]-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5 6-[4-(dimethylamino)phenyl]-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6 5-cyclohexyl-6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid Cpd Name
7 5-cyclohexyl-6-[4-(dimethylamino)phenyl]-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
8 6-[4-(dimethylamino)phenyl]-2-oxo-5-propyl-1,2-dihydropyridine-3-carboxylic acid 9 6-[4-(dimethylamino)phenyl]-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridine-3- carboxylic acid
10 6-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxylic acid
11 6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3,5-dicarboxylic acid
12 5-cyclopropyl-6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid
13 5-cyclopropyl-6-[4-(dimethylamino)phenyl]-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
14 5-cyano-6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid 15 6-(4-cyanophenyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
16 5-ethyl-6-(4-{methyl[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino}phenyl)-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
17 5-ethyl-6-{4-[(2-hydroxyethyl)(methyl)amino]phenyl}-2-oxo-1,2-dihydropyridine-3- carboxylic acid
18 5-ethyl-4-hydroxy-6-{4-[(2-hydroxyethyl)(methyl)amino]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
19 6-[2-(dimethylamino)pyrimidin-5-yl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
20 6-[2-(dimethylamino)pyrimidin-5-yl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
21 4-hydroxy-2-oxo-6-[4-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid
221 5-(aminomethyl)-6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid Cpd Name
23 5-ethyl-2-oxo-6-[4-(1H-tetrazol-5-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid 24 5-ethyl-6-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
25 5-ethyl-4-hydroxy-6-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
26 5-ethyl-6-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
27 5-ethyl-6-(4-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
28 5-ethyl-4-hydroxy-6-(4-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 29 5-ethyl-4-hydroxy-2-oxo-6-[2-(piperidin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
30 5-ethyl-6-(2-fluoro-4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 31 5-ethyl-2-oxo-6-[2-(piperidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid 32 5-ethyl-4-hydroxy-6-(4-methoxy-2-methylphenyl)-2-oxo-1,2-dihydropyridine-3- carboxylic acid
33 5-ethyl-6-(4-methoxy-2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 34 6-(2,4-dimethoxyphenyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
35 5-ethyl-6-[4-methoxy-2-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
36 6-(2,4-dimethoxyphenyl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
37 5-ethyl-6-[2-methyl-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
38 5-ethyl-6-[2-fluoro-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
39 5-ethyl-4-hydroxy-6-[2-methyl-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid Cpd Name
40 6-[2-(dimethylamino)-4-methoxyphenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
41 5-ethyl-4-hydroxy-2-oxo-6-(2,4,6-trimethoxyphenyl)-1,2-dihydropyridine-3- carboxylic acid
43 5-ethyl-6-[2-fluoro-4-(piperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
44 5-ethyl-6-[2-fluoro-4-(piperidin-1-yl)phenyl]-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
45 5-ethyl-4-hydroxy-6-[2-methoxy-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
46 5-ethyl-2-oxo-6-[2-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid 47 5-ethyl-4-hydroxy-2-oxo-6-[2-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
48 5-ethyl-4-hydroxy-6-[4-methoxy-2-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
49 5-ethyl-4-hydroxy-6-[2-methoxy-4-(piperidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
50 5-ethyl-6-[2-methoxy-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
51 5-ethyl-4-hydroxy-6-[2-methyl-4-(piperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
52 5-ethyl-6-[2-methyl-4-(piperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
53 6-[4-(dimethylamino)-2-fluorophenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
54 6-[2-(dimethylamino)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid Cpd Name
55 6-[4-(dimethylamino)-2-fluorophenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
56 6-[4-(dimethylamino)-2-methylphenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
57 6-[4-(dimethylamino)-2-methylphenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
58 6-[2-(dimethylamino)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
59 5-ethyl-6-[2-methoxy-4-(piperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
60 6-[2-(dimethylamino)-4-methoxyphenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
61 6-[4-(dimethylamino)-2-methoxyphenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
62 6-[4-(dimethylamino)-2-methoxyphenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
63 6-[4-(dimethylamino)-3-methylphenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
64 6-[4-(dimethylamino)-3-methoxyphenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
65 6-[4-(dimethylamino)-3-methoxyphenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
66 5-ethyl-6-[3-methoxy-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
67 5-ethyl-4-hydroxy-6-[3-methoxy-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid Cpd Name
68 5-ethyl-6-[3-methoxy-4-(piperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
69 5-ethyl-4-hydroxy-6-[3-methoxy-4-(piperidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
70 5-ethyl-6-[3-methyl-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
71 5-ethyl-4-hydroxy-6-[3-methyl-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
72 5-ethyl-6-[3-methyl-4-(piperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
73 5-ethyl-4-hydroxy-6-[3-methyl-4-(piperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
74 5-ethyl-6-(4-fluorophenyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid 75 5-ethyl-2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid
76 6-(4-chlorophenyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
77 6-(4-chlorophenyl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid 78 6-(4-bromophenyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
79 6-(4-bromophenyl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid 80 5-ethyl-6-(4-iodophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
81 5-ethyl-4-hydroxy-6-(4-iodophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 82 5-ethyl-4-hydroxy-6-{4-[(3-iodopropyl)amino]phenyl}-2-oxo-1,2-dihydropyridine-3- carboxylic acid
83 6-[4-(azetidin-1-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
84 5-ethyl-6-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid Cpd Name
85 5-ethyl-6-{4-[(3S)-3-fluoropyrrolidin-1-yl]phenyl}-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
86 6-[6-(dimethylamino)pyridin-3-yl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
87 6-[6-(dimethylamino)pyridin-3-yl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
88 6-[4-(dimethylamino)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid 89 6-[3-fluoro-4-(morpholin-4-yl)phenyl]-5-methyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
90 6-[4-(dimethylamino)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
91 6-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-3-fluorophenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
921 5-ethyl-6-[3-fluoro-4-(piperazin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
93 6-[4-(dimethylamino)-3-fluorophenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
94 6-[4-(dimethylamino)-3-fluorophenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
95 6-[4-(dimethylamino)phenyl]-2-oxo-5-(propan-2-yl)-1,2-dihydropyridine-3- carboxylic acid
96 6-[4-(dimethylamino)phenyl]-4-hydroxy-2-oxo-5-(propan-2-yl)-1,2-dihydropyridine- 3-carboxylic acid
97 6-[4-(diethylamino)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid 98 6-[4-(diethylamino)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
99 5-ethyl-2-oxo-6-[4-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid Cpd Name
100 5-ethyl-4-hydroxy-2-oxo-6-[4-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
101 5-ethyl-2-oxo-6-[4-(1H-pyrrol-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid 102 6-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
1031 5-ethyl-2-oxo-6-[4-(piperazin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid 104 6-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
105 1 5-ethyl-4-hydroxy-2-oxo-6-[4-(piperazin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
106 5-ethyl-6-[4-(1H-imidazol-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid 107 5-ethyl-4-hydroxy-6-[4-(1H-imidazol-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
108 5-ethyl-2-oxo-6-[4-(piperidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid 109 5-ethyl-4-hydroxy-2-oxo-6-[4-(piperidin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
110 5-ethyl-6-[4-(morpholin-4-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid 111 6-[4-(azetidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid 112 5-ethyl-4-hydroxy-6-(5-morpholinopyridin-2-yl)-2-oxo-1,2-dihydropyridine-3- carboxylic acid
113 5-ethyl-4-hydroxy-2-oxo-6-[5-(piperazin-1-yl)pyridin-2-yl]-1,2-dihydropyridine-3- carboxylic acid
114 5-ethyl-2-oxo-6-[4-(2-oxopyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid
115 5-ethyl-4-hydroxy-2-oxo-6-[4-(2-oxopyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid Cpd Name
116 5-ethyl-6-[4-(2-methyl-5-oxopyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
117 5-ethyl-6-{4-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
118 5-ethyl-2-oxo-6-[4-(3-oxo-2-azaspiro[4.5]dec-2-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
119 5-ethyl-2-oxo-6-[4-(3-oxo-2-azabicyclo[2.2.1]hept-5-en-2-yl)phenyl]-1,2- dihydropyridine-3-carboxylic acid
120 5-ethyl-2-oxo-6-{4-[3-(tetrahydro-2H-pyran-2-yloxy)azetidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
121 5-ethyl-6-[4-(3-hydroxyazetidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
122 5-ethyl-6-{4-[(3R)-3-hydroxypiperidin-1-yl]phenyl}-2-oxo-1,2-dihydropyridine-3- carboxylic acid
123 5-ethyl-6-[4-(3-hydroxypyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
124 5-ethyl-4-hydroxy-6-{4-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
125 5-ethyl-4-hydroxy-6-{4-[(3R)-3-hydroxypiperidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
126 5-ethyl-4-hydroxy-6-[4-(3-hydroxypyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
128 6-{4-[3-(benzyloxy)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
129 6-[4-(3-azidopyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid Cpd Name
130 6-{4-[(3S)-3-azidopyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
1311 6-[4-(3-aminopyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
1321 6-{4-[(3S)-3-aminopyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
1331 6-{4-[(3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
134 1 6-{4-[(3R,4R)-3-amino-4-methoxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
1351 6-{4-[(3R,4S)-3-amino-4-methoxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
1361 6-{4-[(3R,4S)-3-amino-4-hydroxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
137 6-{4-[5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl}-5-ethyl-2- oxo-1,2-dihydropyridine-3-carboxylic acid
1381 6-[4-(2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
139 5-ethyl-6-[4-(2-methylpyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
1401 5-ethyl-6-{4-[3-(morpholin-4-yl)pyrrolidin-1-yl]phenyl}-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
141 5-ethyl-2-oxo-6-{4-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
142 5-ethyl-2-oxo-6-{4-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid Cpd Name
1431 5-ethyl-2-oxo-6-{4-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
144 6-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
145 5-ethyl-2-oxo-6-[4-(2-phenylpyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
146 5-ethyl-6-{4-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
147 5-ethyl-6-{4-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
148 6-{4-[(2S,5S)-2,5-bis(methoxymethyl)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
1491 6-{4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
150 1 6-{4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
1511 6-{4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
152 5-ethyl-6-[4-(3-fluoropyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
153 5-ethyl-6-{4-[(3S)-3-fluoropyrrolidin-1-yl]phenyl}-2-oxo-1,2-dihydropyridine-3- carboxylic acid
154 5-ethyl-6-{4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl}-2-oxo-1,2-dihydropyridine-3- carboxylic acid
155 5-ethyl-2-oxo-6-[4-(phenylamino)phenyl]-1,2-dihydropyridine-3-carboxylic acid 156 5-ethyl-2-oxo-6-{4-[2-(1,3-thiazol-2-yl)pyrrolidin-1-yl]phenyl}-1,2-dihydropyridine- 3-carboxylic acid Cpd Name
157 6-{4-[(2S)-2-carboxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
158 5-ethyl-6-{4-[methyl(phenyl)amino]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
159 6-(4-{[2-(dimethylamino)ethyl]amino}phenyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
160 5-ethyl-6-{4-[ethyl(methyl)amino]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
161 6-(4-{[2-(dimethylamino)ethyl](methyl)amino}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
162 6-[4-(1,3-dihydro-2H-isoindol-2-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
163 5-isopropyl-2-oxo-6-[4-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid
164 5-cyclopropyl-2-oxo-6-[4-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid
165 6-(4-{[2-(dimethylamino)ethyl](methyl)amino}phenyl)-2-oxo-5-(propan-2-yl)-1,2- dihydropyridine-3-carboxylic acid
1661 6-[4-(3-amino-3-methylpyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
167 6-[4-(3-{[(carboxymethyl)(methyl)carbamoyl]amino}azetidin-1-yl)phenyl]-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
168 5-ethyl-6-{4-[3-(5-methyl-2H-tetrazol-2-yl)azetidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
169 1 6-[4-(1-amino-3-azabicyclo[3.1.0]hex-3-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid Cpd Name
170 6-[4-(3-aminoazetidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
171 6-[4-(3-{[(benzyloxy)carbonyl]amino}azetidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
1721 6-{4-[3-(diethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
173 6-{4-[3-(cyclopropylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
174 1 6-{4-[3-(benzylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
175 6-[4-(1,3'-bipyrrolidin-1'-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
1761 6-{4-[(1R,5S,6s)-6-(dibenzylamino)-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-2- oxo-1,2-dihydropyridine-3-carboxylic acid
177 6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
178 6-{4-[(1R,5S,6s)-6-(benzylamino)-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-2- oxo-1,2-dihydropyridine-3-carboxylic acid
1791 5-ethyl-6-[4-(hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
1801 6-[4-(4-benzylhexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl]-5-ethyl-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
1811 6-(4-{3-[(dibenzylamino)methyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
182 1 6-(4-{3-[(benzylamino)methyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid Cpd Name
1831 6-[4-(3-{[benzyl(methyl)amino]methyl}pyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
1841 5-ethyl-6-(4-{3-[(methylamino)methyl]pyrrolidin-1-yl}phenyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
1851 6-(4-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
1861 5-ethyl-6-{4-[(4aR,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-4(4aH)-yl]phenyl}-2- oxo-1,2-dihydropyridine-3-carboxylic acid
187 1 5-ethyl-6-{4-[(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
1881 6-{4-[3-(aminomethyl)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
1891 6-{4-[(3aR,6aR)-1-benzylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
190 1 5-ethyl-6-{4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
191 5-ethyl-2-oxo-6-{4-[3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
192 6-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
1931 6-{4-[(3aR,4R,7aS)-4-(dimethylamino)octahydro-2H-isoindol-2-yl]phenyl}-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
1941 6-(4-{(3aR,4R,7aS)-4-[benzyl(methyl)amino]octahydro-2H-isoindol-2-yl}phenyl)-5- ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
195 1 5-ethyl-6-{4-[(3aR,4R,7aS)-4-(methylamino)octahydro-2H-isoindol-2-yl]phenyl}-2- oxo-1,2-dihydropyridine-3-carboxylic acid Cpd Name
1961 6-{4-[(3aR,4R,7aS)-4-(dibenzylamino)octahydro-2H-isoindol-2-yl]phenyl}-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
1971 6-{4-[(3aR,4R,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
1981 6-{4-[(3aR,4R,6aS)-4-(dimethylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
1991 6-{4-[(3aR,4R,6aS)-4-[benzyl(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
200 1 5-ethyl-6-{4-[(3aR,4R,6aS)-4-(methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2011 6-{4-[(3aR,4R,6aS)-4-(dibenzylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2021 6-{4-[(3aR,4R,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
203 1 6-{4-[(3aR,4S,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
2041 6-{4-[(3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2051 6-(4-{(3aR,7aS)-3a-[(dimethylamino)methyl]octahydro-2H-isoindol-2-yl}phenyl)-5- ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2061 6-{4-[(3aR,6aS)-5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}-5-ethyl-2- oxo-1,2-dihydropyridine-3-carboxylic acid
2071 5-ethyl-6-{4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
208 1 5-ethyl-6-{4-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}- 2-oxo-1,2-dihydropyridine-3-carboxylic acid Cpd Name
209 6-[4-(3,6-diazabicyclo[3.1.0]hex-3-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
2101 5-ethyl-6-{4-[(1S,5R,6R)-6-(methylamino)-3-azabicyclo[3.2.0]hept-3-yl]phenyl}-2- oxo-1,2-dihydropyridine-3-carboxylic acid
211 6-{4-[(1S,5R,6R)-6-amino-3-azabicyclo[3.2.0]hept-3-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
2121 6-{4-[(1S,5R,6S)-6-amino-3-azabicyclo[3.2.0]hept-3-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
213 1 5-ethyl-6-[4-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
2141 6-[4-(7-amino-5-azaspiro[2.4]hept-5-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
2151 5-ethyl-6-{4-[(3aR,5r,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
216 6-{4-[(3S,4R)-3-(aminomethyl)-4-methylpyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
2171 6-(4-{3-[1-(benzylamino)cyclopropyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
2181 6-{4-[3-(1-aminocyclobutyl)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
219 6-[4-(3a-cyanooctahydro-2H-isoindol-2-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
2201 2-[4-(5-carboxy-3-ethyl-6-oxo-1,6-dihydropyridin-2- yl)phenyl]hexahydrocyclopenta[c]pyrrole-3a(1H)-carboxylic acid
221 6-{4-[3-(dimethylamino)pyrrolidin-1-yl]-2-fluorophenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid Cpd Name
222 5-ethyl-6-[4-(4-hydroxypiperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
223 6-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
224 5-ethyl-6-[4-(4-methoxypiperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
225 5-ethyl-6-{2-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
226 5-ethyl-2-oxo-6-{4-[3-(pyridin-4-yl)pyrrolidin-1-yl]phenyl}-1,2-dihydropyridine-3- carboxylic acid
227 5-ethyl-2-oxo-6-{4-[3-(pyridin-2-yl)pyrrolidin-1-yl]phenyl}-1,2-dihydropyridine-3- carboxylic acid
228 6-[4-(4-aminopiperidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
230 5-ethyl-2-oxo-6-{4-[3-(1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
2311 6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-2-fluorophenyl}-5-ethyl-2- oxo-1,2-dihydropyridine-3-carboxylic acid
232 5-ethyl-6-[4-(3-ethyl-3-hydroxypyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
233 5-ethyl-6-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
234 6-[4-(3-{[(2-chlorobenzyl)amino]methyl}pyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
235 6-{4-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid Cpd Name
236 6-[4-(3-{[(3-chlorobenzyl)amino]methyl}pyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
237 6-[4-(3-{[(4-chlorobenzyl)amino]methyl}pyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
238 5-ethyl-6-[4-(3-{[(3-fluorobenzyl)amino]methyl}pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
239 5-ethyl-6-[4-(3-{[(4-fluorobenzyl)amino]methyl}pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
240 5-ethyl-6-[4-(3-{[(2-fluorobenzyl)amino]methyl}pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
241 5-ethyl-2-oxo-6-[4-(3-{[(pyridin-3-ylmethyl)amino]methyl}pyrrolidin-1-yl)phenyl]- 1,2-dihydropyridine-3-carboxylic acid
242 5-ethyl-2-oxo-6-[4-(3-{[(pyridin-4-ylmethyl)amino]methyl}pyrrolidin-1-yl)phenyl]- 1,2-dihydropyridine-3-carboxylic acid
243 5-ethyl-2-oxo-6-[4-(3-{[(pyridin-2-ylmethyl)amino]methyl}pyrrolidin-1-yl)phenyl]- 1,2-dihydropyridine-3-carboxylic acid
2441 6-{4-[(3aR,4S,7aS)-4-azidooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
2451 6-{4-[(3aR,4S,6aS)-4-azidohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
2461 5-ethyl-6-{4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}-4- hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
247 6-(4-{3-[1-(dimethylamino)cyclopropyl]pyrrolidin-1-yl}phenyl)-5-ethyl-4-hydroxy- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
248 6-{4-[(3aR,5r,6aS)-5-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5-ethyl- 4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid Cpd Name
249 6-(4-{(3S,4R)-3-[(dibenzylamino)methyl]-4-methylpyrrolidin-1-yl}phenyl)-5-ethyl- 4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
250 6-{4-[(3aR,5r,6aS)-5-(benzylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
251 6-{4-[(3aR,5r,6aS)-5-(dibenzylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2521 6-[4-(7-amino-5-azaspiro[2.4]hept-5-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
253 6-{4-[1-(tert-butoxycarbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]phenyl}-5- ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2541 5-ethyl-4-hydroxy-6-(4-{3-[(methylamino)methyl]pyrrolidin-1-yl}phenyl)-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
255 6-[4-(3-{[benzyl(methyl)amino]methyl}pyrrolidin-1-yl)phenyl]-5-ethyl-4-hydroxy-2- oxo-1,2-dihydropyridine-3-carboxylic acid
256 1 5-ethyl-4-hydroxy-6-{4-[(3aR,4R,6aS)-4- (methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
2571 6-[4-(1,3'-bipyrrolidin-1'-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
2581 6-{4-[(3aR,4S,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-4-hydroxy- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
259 1 6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-4-hydroxy-5-methyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
2601 4-hydroxy-5-methyl-6-{4-[(3aR,4R,7aS)-4-(methylamino)octahydro-2H-isoindol-2- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2611 6-{4-[(3aR,4R,7aS)-4-(dimethylamino)octahydro-2H-isoindol-2-yl]phenyl}-5-ethyl- 4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid Cpd Name
2621 6-{4-[(3aR,4R,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-4-hydroxy- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
2631 6-{4-[(3aR,4R,6aS)-4-(dimethylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2641 6-{4-[(3aR,4R,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2651 6-{4-[(3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
266 1 6-(4-{(3aR,7aS)-3a-[(dimethylamino)methyl]octahydro-2H-isoindol-2-yl}phenyl)-5- ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2671 5-ethyl-4-hydroxy-6-{4-[(3aR,4S,6aS)-4- (methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
2681 5-ethyl-4-hydroxy-6-{4-[(3aR,4S,7aS)-4-(methylamino)octahydro-2H-isoindol-2- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2691 6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-4-hydroxy-2- oxo-1,2-dihydropyridine-3-carboxylic acid
2701 5-ethyl-4-hydroxy-6-{4-[(1R,5S,6s)-6-(methylamino)-3-azabicyclo[3.1.0]hex-3- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2711 6-{4-[(1R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-4- hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
272 1 5-ethyl-4-hydroxy-6-[4-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)phenyl]-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
2731 5-ethyl-4-hydroxy-6-{4-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2741 5-ethyl-6-{4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}-4- hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid Cpd Name
2751 6-{4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
2761 6-[4-(3a-cyanooctahydro-2H-isoindol-2-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
2771 6-[4-(1-amino-3-azabicyclo[3.1.0]hex-3-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
2781 6-[4-(2,8-diazaspiro[4.5]dec-2-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
279 1 6-{4-[3-(2-aminopropan-2-yl)pyrrolidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
280 5-ethyl-4-hydroxy-6-[4-(4-hydroxypiperidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
281 6-{4-[4-(benzyloxy)piperidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
282 5-ethyl-4-hydroxy-6-[4-(4-methoxypiperidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
283 6-{4-[4-(dibenzylamino)piperidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
284 6-[4-(4-aminopiperidin-1-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
286 5-ethyl-4-hydroxy-2-oxo-6-{4-[3-(pyridin-2-yl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
287 5-ethyl-4-hydroxy-2-oxo-6-{4-[3-(1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
288 5-ethyl-6-[4-(3-ethyl-3-hydroxypyrrolidin-1-yl)phenyl]-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid Cpd Name
289 5-ethyl-4-hydroxy-6-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
290 6-{4-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
291 6-{4-[3-(dimethylamino)pyrrolidin-1-yl]-2-fluorophenyl}-5-ethyl-4-hydroxy-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
292 5-ethyl-6-{2-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl}-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
293 5-ethyl-6-{2-fluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl}-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
294 6-{4-[5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl}-5-ethyl-4- hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2951 6-[4-(2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
296 1 5-ethyl-4-hydroxy-6-{4-[(3aR,4R,7aS)-4-(methylamino)octahydro-2H-isoindol-2- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
2971 5-ethyl-6-{4-[(3aS)-1,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl]phenyl}-4-hydroxy-2- oxo-1,2-dihydropyridine-3-carboxylic acid
298 6-[4-(dimethylamino)phenyl]-5-ethyl-4-methoxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
299 6-{4-[di(prop-2-en-1-yl)amino]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
300 6-{4-[di(prop-2-en-1-yl)amino]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
301 6-[4-(2,5-dihydro-1H-pyrrol-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid Cpd Name
302 6-[4-(2,5-dihydro-1H-pyrrol-1-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
303 6-{4-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
304 6-{4-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
305 6-[5-(dimethylamino)thiophen-2-yl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
306 6-[5-(dimethylamino)thiophen-2-yl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
307 5-ethyl-4-hydroxy-2-oxo-6-[5-(pyrrolidin-1-yl)thiophen-2-yl]-1,2-dihydropyridine-3- carboxylic acid
308 5-ethyl-2-oxo-6-[5-(piperidin-1-yl)thiophen-2-yl]-1,2-dihydropyridine-3-carboxylic acid
309 5-ethyl-4-hydroxy-2-oxo-6-[5-(piperidin-1-yl)thiophen-2-yl]-1,2-dihydropyridine-3- carboxylic acid
310 6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid
311 6-(4-tert-butoxyphenyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
312 6-(5-(dimethylamino)pyrazin-2-yl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
313 5-ethyl-4-hydroxy-2-oxo-6-(5-(pyrrolidin-1-yl)pyrazin-2-yl)-1,2-dihydropyridine-3- carboxylic acid
314 6-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyrazin-2-yl)-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
315 4-hydroxy-5-methyl-2-oxo-6-(5-(pyrrolidin-1-yl)pyridin-2-yl)-1,2-dihydropyridine- 3-carboxylic acid Cpd Name
316 6-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)-4-hydroxy-5-methyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
317 6-(5-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-4-hydroxy-5- methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
318 6-(4-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-2-methylphenyl)-4- hydroxy-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
319 5-ethyl-4-hydroxy-6-(4-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
320 6-(4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
321 6-(4-(2,7-diazaspiro[4.4]nonan-2-yl)phenyl)-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
322 5-ethyl-4-hydroxy-6-(4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
323 6-(4-(2,5-diazaspiro[3.4]octan-2-yl)phenyl)-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
324 6-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
325 5-ethyl-6-(4-(ethylamino)phenyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
326 5-ethyl-4-hydroxy-6-(4-(methylamino)phenyl)-2-oxo-1,2-dihydropyridine-3- carboxylic acid
327 6-(4-(dimethylamino)phenyl)-4-hydroxy-2-oxo-5-(2-oxoethyl)-1,2-dihydropyridine- 3-carboxylic acid
328 6-(4-(dimethylamino)phenyl)-4-hydroxy-5-(2-hydroxyethyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid Cpd Name
329 5-(2,3-dihydroxypropyl)-6-(4-(dimethylamino)phenyl)-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
330 (E)-6-(4-(dimethylamino)phenyl)-4-hydroxy-2-oxo-5-(prop-1-enyl)-1,2- dihydropyridine-3-carboxylic acid
331 6-(4-(dimethylamino)phenyl)-4-hydroxy-5-(hydroxymethyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
332 6-(4-(dimethylamino)phenyl)-4-hydroxy-5-(methoxymethyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
333 6-(4-(dimethylamino)phenyl)-4-hydroxy-2-oxo-5-(prop-1-ynyl)-1,2-dihydropyridine- 3-carboxylic acid
334 5-ethyl-4-hydroxy-6-(4-hydroxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
335 6-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-yl)-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
336 5-ethyl-4-hydroxy-2-oxo-6-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1,2-dihydropyridine-3- carboxylic acid
337 6-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-yl)-4-hydroxy-5-methyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
338 5-ethyl-4-hydroxy-6-(4-(1-methylpiperidin-4-yl)phenyl)-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
339 5-ethyl-6-(4-(1-ethylpiperidin-4-yl)phenyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
340 5-ethyl-4-hydroxy-2-oxo-6-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1,2- dihydropyridine-3-carboxylic acid
341 5-ethyl-6-(4-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid Cpd Name
342 5-ethyl-4-hydroxy-6-(4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
343 6-(4-(2-(dimethylamino)ethyl)phenyl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
344 5-ethyl-6-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 345 5-ethyl-4-hydroxy-6-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1,2-dihydropyridine-3- carboxylic acid
346 5-ethyl-6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 347 5-ethyl-4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3- carboxylic acid
348 5-ethyl-6-(1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrrol-3-yl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
349 5-ethyl-6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrrol-3-yl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
350 5-ethyl-6-(1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrrol-2-yl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
351 6-(5-((dimethylamino)methyl)-1-methyl-1H-pyrrol-2-yl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
352 5-ethyl-6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrrol-2-yl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid, and
353 6-(5-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-1-methyl-1H-pyrrol-2-yl)-5-ethyl- 2-oxo-1,2-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.
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 or a form thereof to the subject.
In another embodiment, 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.
In another embodiment of the use of the present description, the compound or a form thereof is isolated for use.
In another embodiment of the present description, the compound or a form thereof is isolated as a salt.
In another embodiment of the present description, a compound salt or a form thereof for the use described herein is a compound salt of Formula (I) or a form thereof selected from the group consisting of:
Cpd Name
5-(aminomethyl)-6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic 22 acid hydrochloride
5-ethyl-6-[3-fluoro-4-(piperazin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic 92 acid trifluoroacetate
5-ethyl-2-oxo-6-[4-(piperazin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid
103 trifluoroacetate
5-ethyl-4-hydroxy-2-oxo-6-[4-(piperazin-1-yl)phenyl]-1,2-dihydropyridine-3- 105 carboxylic acid trifluoroacetate
6-[4-(3-aminopyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic 131 acid trifluoroacetate
6-{4-[(3S)-3-aminopyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- 132 carboxylic acid hydrochloride
6-{4-[(3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- 133 dihydropyridine-3-carboxylic acid hydrochloride Cpd Name
6-{4-[(3R,4R)-3-amino-4-methoxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- 134 dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(3R,4S)-3-amino-4-methoxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- 135 dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(3R,4S)-3-amino-4-hydroxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- 136 dihydropyridine-3-carboxylic acid trifluoroacetate
6-[4-(2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- 138 carboxylic acid trifluoroacetate
5-ethyl-6-{4-[3-(morpholin-4-yl)pyrrolidin-1-yl]phenyl}-2-oxo-1,2-dihydropyridine-3- 140 carboxylic acid trifluoroacetate
5-ethyl-2-oxo-6-{4-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]phenyl}-1,2- 143 dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- 149 carboxylic acid trifluoroacetate
6-{4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- 150 dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- 151 dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(3-amino-3-methylpyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- 166 carboxylic acid trifluoroacetate
6-[4-(1-amino-3-azabicyclo[3.1.0]hex-3-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine- 169 3-carboxylic acid hydrochloride
6-{4-[3-(diethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- 172 carboxylic acid trifluoroacetate
6-{4-[3-(benzylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- 174 carboxylic acid hydrochloride Cpd Name
6-{4-[(1R,5S,6s)-6-(dibenzylamino)-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-2- 176 oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-6-[4-(hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl]-2-oxo-1,2- 179 dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(4-benzylhexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl]-5-ethyl-2-oxo-1,2- 180 dihydropyridine-3-carboxylic acid trifluoroacetate
6-(4-{3-[(dibenzylamino)methyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- 181 dihydropyridine-3-carboxylic acid trifluoroacetate
6-(4-{3-[(benzylamino)methyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- 182 dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(3-{[benzyl(methyl)amino]methyl}pyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2- 183 dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-6-(4-{3-[(methylamino)methyl]pyrrolidin-1-yl}phenyl)-2-oxo-1,2- 184 dihydropyridine-3-carboxylic acid hydrochloride
6-(4-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- 185 dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-6-{4-[(4aR,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-4(4aH)-yl]phenyl}-2-oxo- 186 1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-6-{4-[(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}-2- 187 oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[3-(aminomethyl)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- 188 carboxylic acid trifluoroacetate
6-{4-[(3aR,6aR)-1-benzylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}-5-ethyl-2- 189 oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-6-{4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}-2-oxo-1,2- 190 dihydropyridine-3-carboxylic acid trifluoroacetate Cpd Name
6-{4-[(3aR,4R,7aS)-4-(dimethylamino)octahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2- 193 oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-(4-{(3aR,4R,7aS)-4-[benzyl(methyl)amino]octahydro-2H-isoindol-2-yl}phenyl)-5- 194 ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-6-{4-[(3aR,4R,7aS)-4-(methylamino)octahydro-2H-isoindol-2-yl]phenyl}-2- 195 oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4R,7aS)-4-(dibenzylamino)octahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2- 196 oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4R,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2-oxo-1,2- 197 dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4R,6aS)-4-(dimethylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- 198 yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(3aR,4R,6aS)-4-[benzyl(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)- 199 yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-6-{4-[(3aR,4R,6aS)-4-(methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- 200 yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(3aR,4R,6aS)-4-(dibenzylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- 201 yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4R,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5-ethyl-2- 202 oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4S,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2-oxo-1,2- 203 dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5-ethyl-2- 204 oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-(4-{(3aR,7aS)-3a-[(dimethylamino)methyl]octahydro-2H-isoindol-2-yl}phenyl)-5- 205 ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate Cpd Name
6-{4-[(3aR,6aS)-5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}-5-ethyl-2- 206 oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-6-{4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}-2-oxo-1,2- 207 dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-6-{4-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}-2- 208 oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-6-{4-[(1S,5R,6R)-6-(methylamino)-3-azabicyclo[3.2.0]hept-3-yl]phenyl}-2- 210 oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(1S,5R,6S)-6-amino-3-azabicyclo[3.2.0]hept-3-yl]phenyl}-5-ethyl-2-oxo-1,2- 212 dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-6-[4-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)phenyl]-2-oxo-1,2- 213 dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(7-amino-5-azaspiro[2.4]hept-5-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- 214 carboxylic acid trifluoroacetate
5-ethyl-6-{4-[(3aR,5r,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- 215 yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-(4-{3-[1-(benzylamino)cyclopropyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- 217 dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[3-(1-aminocyclobutyl)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- 218 dihydropyridine-3-carboxylic acid trifluoroacetate
2-[4-(5-carboxy-3-ethyl-6-oxo-1,6-dihydropyridin-2- 220 yl)phenyl]hexahydrocyclopenta[c]pyrrole-3a(1H)-carboxylic acid trifluoroacetate
6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-2-fluorophenyl}-5-ethyl-2-oxo- 231 1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4S,7aS)-4-azidooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2-oxo-1,2- 244 dihydropyridine-3-carboxylic acid trifluoroacetate Cpd Name
6-{4-[(3aR,4S,6aS)-4-azidohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5-ethyl-2- 245 oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-6-{4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}-4-hydroxy- 246 2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(7-amino-5-azaspiro[2.4]hept-5-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- 252 dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-4-hydroxy-6-(4-{3-[(methylamino)methyl]pyrrolidin-1-yl}phenyl)-2-oxo-1,2- 254 dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-4-hydroxy-6-{4-[(3aR,4R,6aS)-4-(methylamino)hexahydrocyclopenta[c]pyrrol- 256 2(1H)-yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(1,3'-bipyrrolidin-1'-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- 257 carboxylic acid hydrochloride
6-{4-[(3aR,4S,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-4-hydroxy-2- 258 oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-4-hydroxy-5-methyl-2- 259 oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
4-hydroxy-5-methyl-6-{4-[(3aR,4R,7aS)-4-(methylamino)octahydro-2H-isoindol-2- 260 yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(3aR,4R,7aS)-4-(dimethylamino)octahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-4- 261 hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(3aR,4R,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-4-hydroxy-2- 262 oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4R,6aS)-4-(dimethylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
263 hydrochloride
6-{4-[(3aR,4R,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5-ethyl-4- 264 hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride Cpd Name
6-{4-[(3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5-ethyl-4- 265 hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-(4-{(3aR,7aS)-3a-[(dimethylamino)methyl]octahydro-2H-isoindol-2-yl}phenyl)-5- 266 ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-4-hydroxy-6-{4-[(3aR,4S,6aS)-4-(methylamino)hexahydrocyclopenta[c]pyrrol- 267 2(1H)-yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-4-hydroxy-6-{4-[(3aR,4S,7aS)-4-(methylamino)octahydro-2H-isoindol-2- 268 yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-4-hydroxy-2- 269 oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-4-hydroxy-6-{4-[(1R,5S,6s)-6-(methylamino)-3-azabicyclo[3.1.0]hex-3- 270 yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(1R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-4- 271 hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-4-hydroxy-6-[4-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)phenyl]-2-oxo-1,2- 272 dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-4-hydroxy-6-{4-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)- 273 yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-6-{4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}-4-hydroxy-2- 274 oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- 275 dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(3a-cyanooctahydro-2H-isoindol-2-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- 276 dihydropyridine-3-carboxylic acid trifluoroacetate
6-[4-(1-amino-3-azabicyclo[3.1.0]hex-3-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- 277 dihydropyridine-3-carboxylic acid hydrochloride Cpd Name
6-[4-(2,8-diazaspiro[4.5]dec-2-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- 278 dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[3-(2-aminopropan-2-yl)pyrrolidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- 279 dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- 295 dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-4-hydroxy-6-{4-[(3aR,4R,7aS)-4-(methylamino)octahydro-2H-isoindol-2- 296 yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride, and
5-ethyl-6-{4-[(3aS)-1,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl]phenyl}-4-hydroxy-2- 297 oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride; wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
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 or a form thereof to the subject.
In another embodiment, 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.
In another embodiment of the present description, the compound salt or a form thereof is isolated for use.
Chemical Definitions
The chemical terms used above and throughout the description herein, unless specifically defined otherwise, shall be understood by one of ordinary skill in the art to have the following indicated meanings.
As used herein, the term“C1-10alkyl” generally refers to saturated hydrocarbon radicals having from one to ten carbon atoms in a straight or branched chain configuration, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. In some embodiments, C1-10alkyl includes C1-8alkyl, C1-6alkyl, C1-4alkyl and the like. A C1-10alkyl radical may be optionally substituted where allowed by available valences.
As used herein, the term“C2-8alkenyl” generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, without limitation, ethenyl, allyl, propenyl and the like. In some embodiments, C2-8alkenyl includes C2-6alkenyl, C2-4alkenyl and the like. A C2-8alkenyl radical may be optionally substituted where allowed by available valences.
As used herein, the term“C2-8alkynyl” generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon triple bonds therein, including, without limitation, ethynyl, propynyl and the like. In some embodiments, C2-8alkynyl includes C2-6alkynyl, C2-4alkynyl and the like. A C2-8alkynyl radical may be optionally substituted where allowed by available valences.
As used herein, the term“C1-8alkoxy” generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration of the formula: -O-C1-8alkyl, including, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like. In some embodiments, C1-8alkoxy includes C1-6alkoxy, C1-4alkoxy and the like. A C1-8alkoxy radical may be optionally substituted where allowed by available valences.
As used herein, the term“C3-14cycloalkyl” generally refers to a saturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indanyl, indenyl, tetrahydro-naphthalenyl and the like. In some embodiments, C3-14cycloalkyl includes C3-8cycloalkyl, C5-8cycloalkyl, C3-10cycloalkyl and the like. A C3-14cycloalkyl radical may be optionally substituted where allowed by available valences.
As used herein, the term“aryl” generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like. An aryl radical may be optionally substituted where allowed by available valences.
As used herein, the term“heteroaryl” generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S or N atom, including, without limitation, furanyl, thienyl (also referred to as thiophenyl), pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, 9H-purinyl, quinoxalinyl, isoindolyl, quinolinyl, isoquinolinyl, quinazolinyl, acridinyl and the like. A heteroaryl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.
As used herein, the term“heterocyclyl” generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with a heteroatom, such as an O, S or N atom, including, without limitation, oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl,
tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, dihydropyrazolyl, pyrazolinyl, pyrazolidinyl, 4,5- dihydro-1H-imidazolyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, dihydro-2H-pyranyl, dihydro-pyridinyl, tetrahydro-pyridinyl, 1,2,3,6- tetrahydropyridinyl, hexahydro-pyridinyl, dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, 1,4,5,6-tetrahydropyrimidinyl, dihydro-pyrazinyl, tetrahydro-pyrazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl,
dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl, 1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl, dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl, dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl,
tetrahydro-benzothienyl, dihydro-benzimidazolyl, tetrahydro-benzimidazolyl,
dihydro-benzooxazolyl, 2,3-dihydrobenzo[d]oxazolyl, tetrahydro-benzooxazolyl,
dihydro-benzooxazinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, tetrahydro-benzooxazinyl, benzo[1,3]dioxolyl, benzo[1,4]dioxanyl, dihydro-purinyl, tetrahydro-purinyl,
dihydro-quinolinyl, tetrahydro-quinolinyl, 1,2,3,4-tetrahydroquinolinyl,
dihydro-isoquinolinyl, 3,4-dihydroisoquinolin-(1H)-yl, tetrahydro-isoquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, dihydro-quinazolinyl, tetrahydro-quinazolinyl, dihydro-quinoxalinyl, tetrahydro-quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dioxolanyl, 2,5-dihydro-1H- pyrrolyl, 4,5-dihydro-1H-imidazolyl, tetrahydro-2H-pyranyl, hexahydropyrrolo[3,4- b][1,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-(4aH)-yl, 3,4-dihydro- 2H-pyrido[3,2-b][1,4]oxazinyl, (cis)-octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4- b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H- pyrrolo[3,4-b]pyridinyl, tetrahydro-1H-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro- 1H-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-1H-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9-tetrahydro-1H-carbazolyl, 1,2,3,4- tetrahydropyrazino[1,2-a]indolyl, 2,3-dihydro-1H-pyrrolo[1,2-a]indolyl, (3aR,6aR)- hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,4S,6aS)-hexahydrocyclopenta[c]pyrrol-(1H)-yl, (3aR,5r,6aS)- hexahydrocyclopenta[c]pyrrol-(1H)-yl, 1,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-1,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-1H-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexanyl, (1R,5S)-3-azabicyclo[3.1.0]hexanyl, (1S,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl and the like. A heterocyclyl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.
As used herein, the term“C2-8alkenyl-amino” refers to a radical of the formula:
-NH-C2-8alkenyl.
As used herein, the term“(C2-8alkenyl)2-amino” refers to a radical of the formula: -N(C2-8alkenyl)2.
As used herein, the term“C2-8alkenyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C2-8alkenyl.
As used herein, the term“(C2-8alkenyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C2-8alkenyl)2.
As used herein, the term“C1-8alkoxy-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-O-C1-8alkyl. As used herein, the term“C1-8alkoxy-C1-8alkyl-amino” refers to a radical of the formula: -O-C1-8alkyl-NH-C1-8alkyl-O-C1-8alkyl.
As used herein, the term“(C1-8alkoxy-C1-8alkyl)2-amino” refers to a radical of the formula: -N(C1-8alkyl-O-C1-8alkyl)2.
As used herein, the term“C1-8alkoxy-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-O-C1-8alkyl.
As used herein, the term“(C1-8alkoxy-C1-8alkyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C1-8alkyl-O-C1-8alkyl)2.
As used herein, the term“(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino” refers to a radical of the formula: -N[(C1-8alkyl)(C1-8alkyl-O-C1-8alkyl)].
As used herein, the term“(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(C1-8alkyl-O-C1-8alkyl)].
As used herein, the term“C1-8alkoxy-carbonyl” refers to a radical of the formula: -C(O)-O-C1-8alkyl.
As used herein, the term“C1-8alkyl-amino” refers to a radical of the formula:
-NH-C1-8alkyl.
As used herein, the term“(C1-8alkyl)2-amino” refers to a radical of the formula:
-N(C1-8alkyl)2.
As used herein, the term“C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl.
As used herein, the term“C1-10alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-10alkyl.
As used herein, the term“(C1-10alkyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C1-10alkyl)2.
As used herein, the term“C1-8alkyl-amino-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-NH-C1-8alkyl.
As used herein, the term“(C1-8alkyl)2-amino-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-N(C1-8alkyl)2.
As used herein, the term“C1-8alkyl-amino-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-NH-C1-8alkyl.
As used herein, the term“(C1-8alkyl)2-amino-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-N(C1-8alkyl)2. As used herein, the term“(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino” refers to a radical of the formula: -N[(C1-8alkyl)(C1-8alkyl-NH-C1-8alkyl)].
As used herein, the term“[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino” refers to a radical of the formula: -N{(C1-8alkyl)[C1-8alkyl-N(C1-8alkyl)2]}.
As used herein, the term“(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(C1-8alkyl-NH-C1-8alkyl)].
As used herein, the term“[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N{(C1-8alkyl)[C1-8alkyl-N(C1-8alkyl)2]}.
As used herein, the term“(C1-8alkyl-amino-C1-8alkyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C1-8alkyl-NH-C1-8alkyl)2.
As used herein, the term“C1-8alkyl-amino-carbonyl” refers to a radical of the formula: -C(O)-NH-C1-8alkyl.
As used herein, the term“(C1-8alkyl)2-amino-carbonyl” refers to a radical of the formula:–C(O)-N(C1-8alkyl)2.
As used herein, the term“C1-8alkyl-carbonyl” refers to a radical of the formula:
-C(O)-C1-8alkyl.
As used herein, the term“C1-8alkyl-carbonyl-amino” refers to a radical of the formula: -NH-C(O)-C1-8alkyl.
As used herein, the term“(C1-8alkyl-carbonyl,C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(-C(O)-C1-8alkyl)].
As used herein, the term“C1-8alkyl-thio” refers to a radical of the formula:
-S-C1-8alkyl.
As used herein, the term“C2-8alkynyl-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-C2-8alkynyl.
As used herein, the term“C2-8alkynyl-amino” refers to a radical of the formula:
-NH-C2-8alkynyl.
As used herein, the term“(C2-8alkynyl)2-amino” refers to a radical of the formula: -N(C2-8alkynyl)2.
As used herein, the term“C2-8alkynyl-amino-C1-8alkyl” refers to a radical of the formula:
Figure imgf000114_0001
As used herein, the term“(C2-8alkynyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C2-8alkynyl)2.
As used herein, the term“amino” refers to a radical of the formula: -NH2. As used herein, the term“amino-C1-8alkyl” refers to a radical of the formula:
-C1-8alkyl-NH2.
As used herein, the term“amino-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-NH2.
As used herein, the term“(amino-C1-8alkyl)2-amino” refers to a radical of the formula: -N(C1-8alkyl-NH2)2.
As used herein, the term“(amino-C1-8alkyl,C1-8alkyl)amino” refers to a radical of the formula: -N[(C1-8alkyl)(C1-8alkyl-NH2)].
As used herein, the term“amino-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-NH2.
As used herein, the term“(amino-C1-8alkyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C1-8alkyl-NH2)2.
As used herein, the term“(amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(C1-8alkyl-NH2)].
As used herein, the term“amino-carbonyl” refers to a radical of the formula:
-C(O)-NH2.
As used herein, the term“aryl-C1-8alkoxy” refers to a radical of the formula:
-O-C1-8alkyl-aryl.
As used herein, the term“aryl-C1-8alkoxy-carbonyl-amino” refers to a radical of the formula: -NH-C(O)-O-C1-8alkyl-aryl.
As used herein, the term“aryl-C1-8alkyl” refers to a radical of the formula:
-C1-8alkyl-aryl.
As used herein, the term“aryl-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-aryl.
As used herein, the term“(aryl-C1-8alkyl)2-amino” refers to a radical of the formula: -N[(C1-8alkyl-aryl)2].
As used herein, the term“aryl-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-aryl.
As used herein, the term“(aryl-C1-8alkyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl-aryl)2].
As used herein, the term
Figure imgf000115_0001
refers to a radical of the formula: -N[(C1-8alkyl)(aryl)]. As used herein, the term“(aryl,C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(aryl)].
As used herein, the term“(aryl-C1-8alkyl,C1-8alkyl)amino” refers to a radical of the formula: -N[(C1-8alkyl)(C1-8alkyl-aryl)].
As used herein, the term“(aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(C1-8alkyl-aryl)].
As used herein, the term“aryl-amino” refers to a radical of the formula: -NH-aryl. As used herein, the term“(aryl)2-amino” refers to a radical of the formula: -N[(aryl)2]. As used herein, the term“aryl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-aryl.
As used herein, the term“(aryl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(aryl)2].
As used herein, the term“aryl-amino-carbonyl” refers to a radical of the formula: -C(O)-NH-aryl.
As used herein, the term“azido” refers to a radical of the formula: -N=N+=N-.
As used herein, the term“carboxyl” refers to a radical of the formula: -COOH, -C(O)OH or -CO2H.
As used herein, the term“(carboxyl-C1-8alkyl,C1-8alkyl)amino-carbonyl-amino” refers to a radical of the formula: -NH-C(O)-N[(C1-8alkyl)(C1-8alkyl-CO2H)].
As used herein, the term“C3-14cycloalkyl-C1-8alkoxy” refers to a radical of the formula: -O-C1-8alkyl-C3-14cycloalkyl.
As used herein, the term“C3-14cycloalkyl-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-C3-14cycloalkyl.
As used herein, the term“C3-14cycloalkyl-amino” refers to a radical of the formula: -NH-C3-14cycloalkyl.
As used herein, the term“C3-14cycloalkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C3-14cycloalkyl.
As used herein, the term“(C3-14cycloalkyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C3-14cycloalkyl)2].
As used herein, the term“C3-14cycloalkyl-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-C3-14cycloalkyl.
As used herein, the term“(C3-14cycloalkyl-C1-8alkyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl-C3-14cycloalkyl)2]. As used herein, the term“(C3-14cycloalkyl,C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(C3-14cycloalkyl)].
As used herein, the term“(C3-14cycloalkyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(C1-8alkyl-C3-14cycloalkyl)].
As used herein, the term“C3-14cycloalkyl-oxy” refers to a radical of the formula: -O-C3-14cycloalkyl.
As used herein, the term“formyl” refers to a radical of the formula: -C(O)-H.
As used herein, the term“formyl-C1-8alkyl” refers to a radical of the formula:
-C1-8alkyl-C(O)-H, including, without limitation, formylmethyl (also referred to as
2-oxoethyl), 2-formyl-ethyl (also referred to as 3-oxopropyl), 3-formyl-propyl (also referred to as 4-oxobutyl), 4-formyl-butyl (also referred to as 5-oxopentyl) and the like.
As used herein, the term“halo” or“halogen” generally refers to a halogen atom radical, including fluoro, chloro, bromo and iodo.
As used herein, the term“halo-C1-8alkoxy” refers to a radical of the formula:
-O-C1-8alkyl-halo, wherein C1-8alkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms. In some embodiments, halo-C1-8alkoxy includes halo-C1-6alkoxy, halo-C1-4alkoxy and the like.
As used herein, the term“halo-C1-8alkyl” refers to a radical of the formula:
-C1-8alkyl-halo, wherein C1-8alkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms. In some embodiments, halo-C1-8alkyl includes halo-C1-6alkyl, halo-C1-4alkyl and the like.
As used herein, the term“halo-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-halo.
As used herein, the term“(halo-C1-8alkyl)2-amino” refers to a radical of the formula: -N(C1-8alkyl-halo)2.
As used herein, the term“halo-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -NH-C1-8alkyl-halo.
As used herein, the term“(halo-C1-8alkyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N(C1-8alkyl-halo)2.
As used herein, the term“heteroaryl-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-heteroaryl.
As used herein, the term“heteroaryl-amino” refers to a radical of the formula:
-NH-heteroaryl. As used herein, the term“(heteroaryl)2-amino” refers to a radical of the formula: -N[(heteroaryl)2].
As used herein, the term“heteroaryl-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-heteroaryl.
As used herein, the term“(heteroaryl-C1-8alkyl)2-amino” refers to a radical of the formula: -N[(C1-8alkyl-heteroaryl)2].
As used herein, the term“heteroaryl-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-heteroaryl.
As used herein, the term“(heteroaryl-C1-8alkyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl-heteroaryl)2].
As used herein, the term“(heteroaryl-C1-8alkyl,C1-8alkyl)amino” refers to a radical of the formula: -N[(C1-8alkyl)(C1-8alkyl-heteroaryl)].
As used herein, the term“(heteroaryl,C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(heteroaryl)].
As used herein, the term“(heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(C1-8alkyl-heteroaryl)].
As used herein, the term“heterocyclyl-C1-8alkoxy” refers to a radical of the formula: -O-C1-8alkyl-heterocyclyl.
As used herein, the term“heterocyclyl-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-heterocyclyl.
As used herein, the term“heterocyclyl-amino” refers to a radical of the formula: -NH-heterocyclyl.
As used herein, the term“(heterocyclyl)2-amino” refers to a radical of the formula: -N[(heterocyclyl)2].
As used herein, the term“heterocyclyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-heterocyclyl.
As used herein, the term“(heterocyclyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(heterocyclyl)2].
As used herein, the term“heterocyclyl-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-heterocyclyl.
As used herein, the term“(heterocyclyl-C1-8alkyl)2-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl-heterocyclyl)2]. As used herein, the term“(heterocyclyl,C1-8alkyl)amino” refers to a radical of the formula: -N[(C1-8alkyl)(heterocyclyl)].
As used herein, the term“(heterocyclyl,C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(heterocyclyl)].
As used herein, the term“(heterocyclyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(C1-8alkyl-heterocyclyl)].
As used herein, the term“(heterocyclyl,C3-14cycloalkyl-C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(heterocyclyl)(C1-8alkyl-C3-14cycloalkyl)].
As used herein, the term“heterocyclyl-carbonyl” refers to a radical of the formula: -C(O)-heterocyclyl.
As used herein, the term“heterocyclyl-carbonyl-oxy” refers to a radical of the formula: -O-C(O)-heterocyclyl.
As used herein, the term“heterocyclyl-oxy” refers to a radical of the formula:
-O-heterocyclyl.
As used herein, the term“heterocyclyl-oxy-amino” refers to a radical of the formula: -NH-O-heterocyclyl.
As used herein, the term“(heterocyclyl-oxy)2-amino” refers to a radical of the formula: -N[(-O-heterocyclyl)2].
As used herein, the term“(heterocyclyl-oxy,C1-8alkyl)amino” refers to a radical of the formula: -N[(C1-8alkyl)(-O-heterocyclyl)].
As used herein, the term“(heterocyclyl-oxy-C1-8alkyl,C1-8alkyl)amino” refers to a radical of the formula: -N[(C1-8alkyl)(C1-8alkyl-O-heterocyclyl)].
As used herein, the term“hydroxyl-C1-8alkoxy” refers to a radical of the formula: -O-C1-8alkyl-OH, wherein C1-8alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term“hydroxyl-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-OH, wherein C1-8alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxy radicals.
As used herein, the term“hydroxyl-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-OH, wherein C1-8alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals. As used herein, the term“(hydroxyl-C1-8alkyl)2-amino” refers to a radical of the formula: -N(C1-8alkyl-OH)2, wherein C1-8alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term“hydroxyl-C1-8alkyl-amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-NH-C1-8alkyl-OH, wherein C1-8alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term“hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino” refers to a radical of the formula: -NH-C1-8alkyl-NH-C1-8alkyl-OH, wherein C1-8alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term“(hydroxyl-C1-8alkyl,C1-8alkyl)amino” refers to a radical of the formula: -N[(C1-8alkyl)(C1-8alkyl-OH)], wherein C1-8alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term“(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl” refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(C1-8alkyl-OH)], wherein C1-8alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term“[(hydroxyl-C1-8alkyl,C1-8alkyl)amino- C1-8alkyl,C1-8alkyl]amino” refers to a radical of the formula: -N[(C1-8alkyl){C1-8alkyl- N[(C1-8alkyl)(C1-8alkyl-OH)]}], wherein C1-8alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term“(hydroxyl-C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino” refers to a radical of the formula: -N[(C1-8alkyl)(C1-8alkyl-NH-C1-8alkyl-OH)], wherein C1-8alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term“substituent” means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances one or more substituents having a double bond (e.g.,“oxo” or “=O”) as the point of attachment may be described, shown or listed herein as part of a substituent group having a single bond as the point of attachment to the core structure of Formula (I) with the understanding that it would be clear to a person of ordinary skill in the art that a double bond was included within the scope of the substituent group showing only a single bond as the point of attachment to the core structure of Formula (I).
As used herein, the term“and the like,” with reference to the definitions of chemical terms provided herein, means that variations in chemical structures that could be expected by one skilled in the art include, without limitation, isomers (including chain, branching or positional structural isomers), hydration of ring systems (including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations where allowed by available valences which result in a stable compound.
For the purposes of this description, where one or more substituent variables for a compound of Formula (I) or a form thereof encompass functionalities incorporated into a compound of Formula (I), each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.
As used herein, the terms“independently selected,” or“each selected” refer to functional variables in a substituent list that may occur more than once on the structure of Formula (I), the pattern of substitution at each occurrence is independent of the pattern at any other occurrence. Further, the use of a generic substituent variable on any formula or structure for a compound described herein is understood to include the replacement of the generic substituent with species substituents that are included within the particular genus, e.g., aryl may be replaced with phenyl or naphthalenyl and the like, and that the resulting compound is to be included within the scope of the compounds described herein.
As used herein, the terms“each instance of” or“selected in each instance, when present,” or variations thereof, when used relative to a phrase such as“…C3-14cycloalkyl, C3-14cycloalkyl-C1-8alkyl, aryl, aryl-C1-8alkyl, heteroaryl, heteroaryl-C1-8alkyl, heterocyclyl and heterocyclyl-C1-8alkyl,” are intended to refer to the C3-14cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems either alone or as a portion of a substituent.
As used herein, the term“optionally substituted” means optional substitution with the specified substituent variables, groups, radicals or moieties. As used herein, the terms“stable compound’ or“stable structure” mean a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulations thereof into an efficacious therapeutic agent.
Compound names used herein were obtained using the ACD Labs Index Name software provided by ACD Labs; and/or, were obtained using the naming function of ChemDraw Ultra provided by CambridgeSoft. When the compound name disclosed herein conflicts with the structure depicted, the structure shown will supercede the use of the name to define the compound intended.
Compound Forms
As used herein, the term“form” means a compound of Formula (I) having a form selected from the group consisting of a free acid, free base, prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In certain embodiments described herein, the form of the compound of Formula (I) is a free acid, free base or salt thereof.
In certain embodiments described herein, the form of the compound of Formula (I) is a salt thereof.
In certain embodiments described herein, the form of the compound of Formula (I) is an isotopologue thereof.
In certain embodiments described herein, the form of the compound of Formula (I) is a stereoisomer, racemate, enantiomer or diastereomer thereof.
In certain embodiments described herein, the form of the compound of Formula (I) is a tautomer thereof.
In certain embodiments described herein, the form of the compound of Formula (I) is a pharmaceutically acceptable form.
In certain embodiments described herein, the compound of Formula (I) or a form thereof is isolated for use.
As used herein, the term“isolated” means the physical state of a compound of Formula (I) or a form thereof after being isolated and/or purified from a synthetic process (e.g., from a reaction mixture) or natural source or combination thereof according to an isolation or purification process or processes described herein or which are well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
As used herein, the term“protected” means that a functional group in a compound of Formula (I) or a form thereof is in a form modified to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T.W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.
Prodrugs and solvates of the compounds described herein are also contemplated. As used herein, the term“prodrug” means a form of an instant compound (e.g., a drug precursor) that is transformed in vivo to yield an active compound of Formula (I) or a form thereof. The transformation may occur by various mechanisms (e.g., by metabolic and/or non-metabolic chemical processes), such as, for example, by hydrolysis and/or metabolism in blood, liver and/or other organs and tissues. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella,“Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
In one example, when a compound of Formula (I) or a form thereof contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a functional group such as alkyl and the like. In another example, when a compound of Formula (I) or a form thereof contains a hydroxyl functional group, a prodrug form can be prepared by replacing the hydrogen atom of the hydroxyl with another functional group such as alkyl, alkylcarbonyl or a phosphonate ester and the like. In another example, when a compound of Formula (I) or a form thereof contains an amine functional group, a prodrug form can be prepared by replacing one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl.
Pharmaceutically acceptable prodrugs of compounds of Formula (I) or 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.
As used herein, the term“solvate” means a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. As used herein, “solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
One or more compounds described herein may optionally be converted to a solvate. Preparation of solvates is generally known. The preparation of solvates of the antifungal fluconazole in ethyl acetate as well as from water has been described (see, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004)). Similar preparations of solvates, hemisolvate, hydrates and the like have also been described (see, E.C. van Tonder et al, AAPS
PharmSciTech., 5(1), article 12 (2004); and A.L. Bingham et al, Chem. Commun., 603-604 (2001)). A typical, non-limiting process involves dissolving a compound in a desired amount of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example infrared spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
As used herein, the term“hydrate” means a solvate wherein the solvent molecule is water.
The compounds of Formula (I) 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. In addition, when a compound of Formula (I) or a form thereof contains both a basic moiety, such as, without limitation an amine moiety, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. The term "pharmaceutically acceptable salt(s)", as used herein, means those salts of compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful. Salts of the compounds of the Formula (I) 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.
Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in compounds described herein. Embodiments of acid addition salts include, and are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate, di-trifluoroacetate (also referred to as bis-trifluoroacetate), tri-trifluoroacetate (also referred to as tris-trifluoroacetate) salts and the like. Certain embodiments of acid addition salts include chloride, bromide, acetate or trifluoroacetate salts.
Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium and zinc salts. Certain compounds described herein can also form pharmaceutically acceptable salts with organic bases (for example, organic amines) such as, but not limited to, dicyclohexylamines, t-butyl amines and the like, and with various amino acids such as, but not limited to, arginine, lysine and the like. Basic nitrogen- containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides) and the like.
All such acid salts and base salts are intended to be included within the scope of pharmaceutically acceptable salts as described herein. In addition, all such acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of this description.
Compounds of Formula (I) 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.
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). In one embodiment, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer. In another embodiment, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer. As one of skill in the art will recognize, when more than one chiral center is present, the compounds described herein may also exist as a (R,R), (R,S), (S,R) or (S,S) isomer, as defined by IUPAC Nomenclature Recommendations.
As used herein, the term“substantially pure” refers to compounds consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.
In one aspect of the description, a compound of Formula (I) or 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%.
In one aspect of the description, 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%.
As used herein, a“racemate” is any mixture of isometric forms that are not “enantiomerically pure”, including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, or about 80/20.
In addition, the present description embraces all geometric and positional isomers. For example, if a compound of Formula (I) or a form thereof incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the description. Diastereomeric mixtures can be separated into their individual
diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by use of chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this description.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this description, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as described supra. The use of the terms "salt", "solvate",“ester”, "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or isotopologues of the instant compounds.
The term "isotopologue" refers to isotopically-enriched compounds described herein which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 35Cl and 36Cl, respectively, each of which are also within the scope of this description.
Certain isotopically-enriched compounds described herein (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
Polymorphic crystalline and amorphous forms of the compounds of Formula (I) and of the salts, solvates, hydrates, esters and prodrugs of the compounds of Formula (I) are further intended to be included in the present description.
Compound Uses
The present description relates to a method of use for a compound of Formula (I) or 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. gonorrhoeae that are azithromycin- resistant, and the like), quinolone-resistant (including drug-resistant forms of N. gonorrhoeae that are ciprofloxacin-resistant, and the like) or tetracycline-resistant N. gonorrhoeae (including drug-resistant forms of N. gonorrhoeae that are tetracycline-resistant).
The present description also relates to use of the compound of Formula (I) or 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
N. gonorrhoeae.
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. The instant compounds possess in vitro activity against a wide spectrum of N. gonorrhoeae which have developed resistance to almost all known treatments and are expected to successfully treat wild-type or drug-resistant forms of N. gonorrhoeae compared to current antibacterial agents. The compounds are also effective in vivo and lack cellular toxicity. In addition to monotherapeutic use, the instant compounds are useful in a combination therapy with current standard of care antibacterial or antibiotic agents, having additive or synergistic activity with one or more known antibacterial or antibiotic agents.
A combination therapy comprising compounds described herein in combination with one or more known antibacterial or antibiotic drugs may be used to treat wild-type or drug- resistant forms of N. gonorrhoeae regardless of whether N. gonorrhoeae is resistant or responsive to the known antibacterial or antibiotic drug.
Embodiments of the present description include the use of a compound of Formula (I) or 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
antibacterial agent(s).
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
antibacterial agent(s) in a combination therapy for treating or ameliorating N. gonorrhoeae in a subject in need thereof.
In one embodiment, the agents used in the combination therapy may include, without limitation, one or more agents selected from Amikacin, Amoxicillin, Ampicillin,
Arsphenamine, Azithromycin, Azlocillin, Aztreonam, Bacitracin, Capreomycin,
Carbenicillin, Cefaclor, Cefadroxil, Cefalexin, Cefalotin, Cefamandole, Cefazolin, Cefdinir, Cefditoren, Cefixime, Cefoperazone, Cefotaxime, Cefoxitin, Cefpodoxime, Cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Chloramphenicol, Cilastatin, Ciprofloxacin, Clarithromycin, Clavulanate, Clindamycin, Clofazimine, Cloxacillin, Colistin, Cycloserine, Dalfopristin, Dapsone, Daptomycin, Dicloxacillin, Dirithromycin, Doripenem, Doxycycline, Enoxacin, Erythromycin, Ethambutol, Ethionamide, Flucloxacillin,
Fosfomycin, Furazolidone, Fusidic acid, Gatifloxacin, Gemifloxacin, Gentamicin, Imipenem, Isoniazid, Kanamycin, Levofloxacin, Lincomycin, Linezolid, Lomefloxacin, Loracarbef, Mafenide, Meropenem, 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, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Tazobactam, Teicoplanin, Telavancin, Telithromycin, Temocillin, Tetracycline, Thiamphenicol, Ticarcillin,
Tigecycline, Tinidazole, Tobramycin, Trimethoprim, Troleandomycin or Vancomycin. In another embodiment, the agents used in the combination therapy may include, without limitation, one or more agents selected from Amikacin, Amoxicillin, Arsphenamine, Azlocillin, Aztreonam, Bacitracin, Capreomycin, Carbenicillin, Cefaclor, Cefadroxil, Cefalexin, Cefalotin (Cefalothin), Cefamandole, Cefazolin, Cefdinir, Cefditoren,
Cefoperazone, Cefotaxime, Cefoxitin, Cefpodoxime, Cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Cefuroxime, Chloramphenicol, Cilastatin, Clarithromycin, Clavulanate, Clindamycin, Clofazimine, Cloxacillin, Colistin, Cycloserine, Dalfopristin, Dapsone, Daptomycin, Dicloxacillin, Dirithromycin, Doripenem, Doxycycline, Enoxacin,
Erythromycin, Ethambutol, Ethionamide, Flucloxacillin, Fosfomycin, Furazolidone, Fusidic acid, Gatifloxacin, Gemifloxacin, Gentamicin, Imipenem, Isoniazid, Kanamycin,
Levofloxacin, Lincomycin, Linezolid, Lomefloxacin, Loracarbef, Mafenide, Meropenem, Methicillin, Metronidazole, Mezlocillin, Minocycline, Moxifloxacin, Mupirocin, Nafcillin, Nalidixic acid, Neomycin, Netilmicin, Nitrofurantoin, Norfloxacin, Ofloxacin, Oxacillin, Oxytetracycline, Paromomycin, Piperacillin, Platensimycin, Polymyxin B, Pyrazinamide, Quinupristin, Rapamycin, Rifabutin, Rifampicin, Rifampin, Rifapentine, Rifaximin,
Roxithromycin, Silver sulfadiazine, Solithromycin, Sulbactam, Sulfacetamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Tazobactam, Teicoplanin, Telavancin, Telithromycin, Temocillin, Thiamphenicol, Ticarcillin, Tigecycline, Tinidazole, Tobramycin, Trimethoprim, Troleandomycin or Vancomycin.
In another embodiment, the agents used in the combination therapy may include, without limitation, one or more agents selected from Amoxicillin, Ampicillin, Azithromycin, Ciprofloxacin, Doxycycline, Enoxacin, Erythromycin, Gatifloxacin, Gemifloxacin,
Gentamicin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Rapamycin, Solithromycin, Spectinomycin, Streptomycin, Tetracycline or Vancomycin.
In another embodiment, the agents used in the combination therapy may particularly include one or more agents selected from Amoxicillin, Azithromycin, Ciprofloxacin, Doxycycline, Enoxacin, Erythromycin, Gatifloxacin, Gemifloxacin, Gentamicin,
Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin,
Rapamycin, Solithromycin or Vancomycin.
In another embodiment, the agents used in the combination therapy may include, without limitation, one or more agents selected from Ampicillin, Azithromycin, Cefixime, Ceftriaxone, Ciprofloxacin, Penicillin G, Penicillin V, Spectinomycin, Streptomycin or Tetracycline.
Accordingly, the present description relates to use of a compound of Formula (I) or a form thereof for treating or ameliorating wild-type forms of N. gonorrhoeae, for treating or ameliorating drug-resistant forms of N. gonorrhoeae or for treating or ameliorating multi- drug resistant forms of N. gonorrhoeae.
One embodiment of the use of the present description relates to use of a compound of Formula (I) or 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.
An 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.
An 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.
An 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.
An 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.
An 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.
An 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.
An 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.
An 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 drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (I) or 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.
An 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.
An 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 the medicament to the subject.
In one respect, for each of such embodiments, the subject is treatment naive. In another respect, for each of such embodiments, the subject is not treatment naive. As used herein, the term“treating” refers to: (i) preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having the disease, disorder and/or condition; (ii) inhibiting a disease, disorder or condition, i.e., arresting the development thereof; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
As used herein, the term“subject” refers to an animal or any living organism having sensation and the power of voluntary movement, and which requires oxygen and organic food. Nonlimiting examples include members of the human, primate, equine, porcine, bovine, murine, rattus, canine and feline specie. In some embodiments, the subject is a mammal or a warm-blooded vertebrate animal. In other embodiments, the subject is a human. As used herein, the term“patient” may be used interchangeably with“subject” and “human”.
Another aspect of the description particularly relates to a method of use for a compound of Formula (I) or 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. gonorrhoeae clinical isolates and their derivatives selected from ATCC penicillin-sensitive wild-type N. gonorrhoeae FA19 (ATCC BAA- 1838), ATCC streptomycin-resistant (streptomycinR) N. gonorrhoeae FA1090 (ATCC 700825; GenBank Acc. No. AE004969), ATCC N. gonorrhoeae MS11 (ATCC BAA-1833) and ATCC wild-type N. gonorrhoeae 49226 (ATCC 49226) (see, http://www.atcc.org).
Another aspect of the description relates to a method of use for a compound of Formula (I) or 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 FA19 to contain mutations in gyrA and parC, including those selected from ciprofloxacin-resistant (ciprofloxacinR) N. gonorrhoeae AK1 (gyrA91/95) and
ciprofloxacinR N. gonorrhoeae AK2 (gyrA91/95, parC86) (see, Anjali N. Kunz, Afrin A.
Begum, Hong Wu, Jonathan A. D’Ambrozio, James M. Robinson, William M. Shafer, Margaret C. Bash and Ann E. Jerse. Impact of Fluoroquinolone Resistance Mutations on Gonococcal Fitness and In Vivo Selection for Compensatory Mutations. J. Infect Dis., 2012, Jun 15; 205(12):1821-9).
Another aspect of the description relates to a method of use for a compound of Formula (I) or 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
Organization (WHO) isolates selected from: tetracyclineIR N. gonorrhoeae 13477 (WHO tetracycline intermediate resistant isolate F), ciprofloxacinIR/tetracyclineR N. gonorrhoeae 13478 (WHO ciprofloxacin intermediate resistant and tetracycline resistant isolate G), quinoloneHLR N. gonorrhoeae 13479 (WHO quinolone high level resistant isolate K), MDR N. gonorrhoeae 13480 (WHO multi-drug resistant isolate L) and MDIR N. gonorrhoeae 13481 (WHO multi-drug intermediate resistant isolate M) (see, Unemo M, Fasth O, Fredlund H, Limnios A, Tapsall J. Phenotypic and genetic characterization of the 2008 WHO Neisseria gonorrhoeae reference strain panel intended for global quality assurance and quality control of gonococcal antimicrobial resistance surveillance for public health purposes. J.
Antimicrobial Agents Chemother., 2009, Jun; 63(6): 1142-51).
Another aspect of the description relates to a method of use for a compound of Formula (I) or 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
ciprofloxacinXDR/cefiximeXDR/ceftriaxoneXDR extensively drug resistant N. gonorrhoeae F89 (see, Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. J. Antimicrobial Agents Chemother., 2012, Mar; 56(3): 1273-80). Another aspect of the description relates to a method of use for a compound of Formula (I) or 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 streptomycinR determinant. The resulting isolate SP1364 is streptomycinR at >1250 µg/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.
Phenotypic and genotypic analyses of Neisseria gonorrhoeae isolates that express frequently recovered PorB PIA variable region types suggest that certain P1a porin sequences confer a selective advantage for urogenital tract infection. Infect Immun., 2008, Aug;76(8):3700-9).
Another aspect of the description relates to a method of use for a compound of Formula (I) or 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 (penicillinR) N. gonorrhoeae LGB3, tetracycline-resistant
(tetracyclineR) N. gonorrhoeae LGB24 and ampicillin-resistant (ampicillinR) N. gonorrhoeae LGB50 (see, McKnew DL, Lynn F, Zenilman JM, Bash MC. Porin variation among clinical isolates of N. gonorrhoeae over a 10-year period, as determined by Por variable region typing. J. Infect Dis., 2003, Apr 15;187(8):1213-22).
An embodiment of the use of a compound of Formula (I) or 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
N. gonorrhoeae MS11 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 ampicillinR 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 streptomycinR N. gonorrhoeae FA1090 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 ciprofloxacinR 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 tetracyclineR 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 ciprofloxacinXDR/cefiximeXDR/ceftriaxoneXDR 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.
As used herein, 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 approximately a 24 hour period), twice (once in approximately a 12 hour period) or thrice (once in approximately an 8 hour period) daily according to subject weight.
In certain embodiments, the effective amount will be in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.1 mg to about 500 mg/kg/day, or about 1.0 mg/day to about 500 mg/kg/day, in single, divided, or a continuous dose for a patient or subject having a weight in a range of between about 40 to about 200 kg (which dose may be adjusted for patients or subjects above or below this range, particularly children under 40 kg). The typical adult subject is expected to have a median weight in a range of about 70 kg.
In another embodiment, where daily doses are adjusted based upon the weight of the subject or patient, compounds described herein may be formulated for delivery at about 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.20, 0.25, 0.30, 0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0, 3.0, 5.0, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400 or 500 mg/kg/day. Daily doses adjusted based upon the weight of the subject or patient may be administered as a single, divided, or continuous dose. In embodiments where a dose of compound is given more than once per day, the dose may be administered twice, thrice, or more per day.
Within the scope of the present description, the“effective amount” of a compound of Formula (I) or a form thereof for use in the manufacture of a medicament, the preparation of a pharmaceutical kit or in a method of treating or ameliorating N. gonorrhoeae in a subject in need thereof, is intended to include an amount in a range of from about 0.001 mg to about 3500 mg administered daily; 1.0 mg to about 3500 mg administered daily; 1.0 mg to about 1500 mg administered daily; 1.0 mg to about 1000 mg administered daily; 10.0 mg to about 600 mg administered daily; 0.5 mg to about 2000 mg administered daily; or, an amount in a range of from about 5.0 mg to about 300 mg administered daily.
For example, the effective amount may be the amount required to treat
N. gonorrhoeae, or the amount required to inhibit N. gonorrhoeae replication in a subject or, more specifically, in a human. In some instances, the desired effect can be determined by analyzing the presence of bacterial DNA. The effective amount for a subject will depend upon various factors, including the subject’s body weight, size and health. Effective amounts for a given patient can be determined by routine experimentation that is within the skill and judgment of the clinician.
For any compound, the effective amount can be estimated initially either in cell culture assays or in relevant animal models, such as a mouse, chimpanzee, marmoset or tamarin animal model. Relevant animal models may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is therapeutic index, and can be expressed as the ratio, LD50/ED50. In some embodiments, the effective amount is such that a large therapeutic index is achieved. In further embodiments, the dosage is within a range of circulating concentrations that include an ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
More specifically, the concentration-biological effect relationships observed with regard to a compound of Formula (I) or a form thereof indicate a target plasma concentration ranging from approximately 0.001 µg/mL to approximately 50 µg/mL, from approximately 0.01 µg/mL to approximately 20 µg/mL, from approximately 0.05 µg/mL to approximately 10 µg/mL, or from approximately 0.1 µg/mL to approximately 5 µg/mL. To achieve such plasma concentrations, the compounds described herein may be administered at doses that vary, such as, for example, without limitation, from 0.1 ng to 10,000 mg, depending upon the route of administration in single, divided, or continuous doses for a patient weighing between about 10 to about 100 kg (which dose may be adjusted for patients within this weight range, particularly for children under 40 kg).
The exact dosage will be determined by the practitioner, in light of factors related to the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, ethinicity, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, experience with other antibacterial therapies, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 2, 3 or 4 days, once every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
The compounds and compositions described herein may be administered to the subject via any drug delivery route known in the art. Nonlimiting examples include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration. Metabolites of the Compounds
Also included within the scope of the present description are the use of in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the description includes the use of compounds produced by a process comprising contacting a compound described herein with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof.
Such products typically are identified by preparing a radio-labeled isotopologue (e.g., 14C or 3H) of a compound described herein, administering the radio-labeled compound in a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal such as a rat, mouse, guinea pig, dog, monkey or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to about 30 hours), and identifying the metabolic conversion products from urine, bile, blood or other biological samples. The conversion products are easily isolated since they are“radiolabeled” by virtue of being isotopically-enriched (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds described herein even if they possess no biological activity of their own.
Pharmaceutical Compositions
Embodiments of the present description include the use of a compound of Formula (I) or 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
pharmaceutically acceptable excipient(s).
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).
An embodiment of the present description includes the use of a pharmaceutical composition of the compound of Formula (I) or a form thereof in the preparation of a kit comprising the pharmaceutical composition of 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.
As used herein, the term“composition” means a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical composition may be formulated to achieve a physiologically compatible pH, ranging from about pH 3 to about pH 11. In some embodiments, the pharmaceutical composition is formulated to achieve a pH of from about pH 3 to about pH 7. In other embodiments, the pharmaceutical composition is formulated to achieve a pH of from about pH 5 to about pH 8. The term“pharmaceutically acceptable excipient” refers to an excipient for administration of a pharmaceutical agent, such as the compounds described herein. The term refers to any pharmaceutical excipient that may be administered without undue toxicity. Pharmaceutically acceptable excipients may be determined in part by the particular composition being administered, as well as by the particular mode of administration and/or dosage form. Nonlimiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, etc. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions for the instant compoounds described herein (see, e.g., Remington’s Pharmaceutical Sciences).
Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive antibodies. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA;
carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose (e.g., hydroxypropylmethylcellulose, also known as HPMC), stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting or emulsifying agents; pH buffering substances; and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.
The pharmaceutical compositions described herein may be formulated in any form suitable for the intended use described herein. Suitable formulations for oral administration include solids, liquid solutions, emulsions and suspensions, while suitable inhaleable formulations for pulmonary administration include liquids and powders. Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids which can be reconstituted with a physiologically compatible solvent prior to administration.
When intended for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
Pharmaceutically acceptable excipients suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross- linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including
microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
In other embodiments, pharmaceutical compositions described herein may be formulated as suspensions comprising a compound of Formula (I) or a form thereof in admixture with one or more pharmaceutically acceptable excipient(s) suitable for the manufacture of a suspension. In yet other embodiments, pharmaceutical compositions described herein may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of one or more excipient(s).
Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
The pharmaceutical compositions described herein may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids;
hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
Additionally, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propane-diol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
The compounds described herein may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but generally soluble in medium-chain fatty acids (e.g., caprylic and capric acids) or triglycerides and in propylene glycol esters of medium-chain fatty acids. Thus, contemplated in the description are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, etc.
In some embodiments, the compound described herein is formulated for oral administration in a lipid-based composition suitable for low solubility compounds. Lipid- based formulations can generally enhance the oral bioavailability of such compounds. As such, pharmaceutical compositions described herein may comprise a effective amount of a compound of Formula (I) or a form thereof, together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants, such as polysorbate 20 or 80 (also referred to as Tween 20 or Tween 80, respectively) or polyoxyl 40 hydrogenated castor oil.
In other embodiments, the bioavailability of low solubility compounds may be enhanced using particle size optimization techniques including the preparation of
nanoparticles or nanosuspensions using techniques known to those skilled in the art. The compound forms present in such preparations include amorphous, partially amorphous, partially crystalline or crystalline forms.
In alternative embodiments, the pharmaceutical composition may further comprise one or more aqueous solubility enhancer(s), such as a cyclodextrin. Nonlimiting examples of cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin, and hydroxypropyl-β-cyclodextrin (HPBC). In some embodiments, the pharmaceutical composition further comprises HPBC in a range of from about 0.1% to about 20%, from about 1% to about 15%, or from about 2.5% to about 10%. The amount of solubility enhancer employed may depend on the amount of the compound in the composition.
Preparation of Compounds
Methods for synthesizing certain compounds described herein have been disclosed in International Application PCT/US2012/052898, published as International Application Number WO2013/033240, and United States Patent Application U.S.S.N.14/241,372, published as United States Patent Application Publication Number US2015/0080362.
Biological Examples
The following in vitro biological examples demonstrate the usefulness of the compounds of the present description for treating Neisseria gonorrhoeae.
The antibacterial activity from a microbroth dilution method in either or both
Fastidious Broth (FB) and FB containing 40 mg/mL Human Serum Albumin (HSA), as indicated, may be represented by the minimum inhibitory concentration (MIC in µg/mL). The MIC value is the lowest concentration of drug which prevents macroscopically visible growth under test conditions.
In the following tables, a MIC value between > 12.5 µg/mL and≤ 150 µg/mL is indicated by a single star (*), a MIC value between > 3.5 µg/mL and≤ 12.5 µg/mL is indicated by two stars (**), a MIC value between > 1.0 µg/mL and≤ 3.5 µg/mL is indicated by three stars (***) and a MIC value of≤ 1.0 µg/mL is indicated by four stars (****). Example 1
Antibacterial activity of test compounds against N. gonorrhoeae WHO isolate F (13477) is shown in Table 1.
Figure imgf000147_0001
Example 2
Antibacterial activity of test compounds against N. gonorrhoeae WHO isolates G, K, L and M (13478, 13479, 13480 and 13481, respectively) is shown in Table 2.
Figure imgf000147_0002
Figure imgf000148_0001
Example 3
Antibacterial activity of test compounds against streptomycin-resistant
N. gonorrhoeae FA1090 isolate is compared in FB (Table 3) and FB containing 40 mg/mL HSA (Table 4). Table 3
Figure imgf000149_0001
Example 4
Antibacterial activity of test compounds against penicillin-sensitive wild-type N. gonorrhoeae FA19 and ciprofloxacin-resistant AK1 and AK2 isolates and the LG24 clinical isolate is shown in Table 5.
Figure imgf000149_0002
Example 5
Antibacterial activity of test compounds against N. gonorrhoeae tetracycline-resistant LGB24, penicillin-resistant LGB3 and ampicillin-resistant LGB50 isolates and an MS11 isolate is shown in Table 6.
Table 6
Figure imgf000149_0003
Figure imgf000150_0001
Example 6
Antibacterial activity of test compounds against the wild-type N. gonorrhoeae isolate 49226 is shown in Table 7.
Figure imgf000150_0002
Example 7
The antibacterial activity of Compound 269 against the SP1364 N. gonorrhoeae isolate was obtained as **** (four stars).
Example 8
In Vivo Mouse Model
Background
The usefulness of the compounds of the present description for treating Neisseria gonorrhoeae may be demonstrated in an in vivo mouse model developed by the adaptation of several published protocols (see, Jerse, A.E., Experimental Gonococcal Genital Tract Infection and Opacity Protein Expression in estradiol-treated mice. Infection and Immunity, 1999, 67(11):5699-5708; and, Cole, J.E. et al., Opacity Proteins Increase Neisseria gonorrhoeae Fitness in the Female Genital Tract Due to a Factor Under Ovarian Control. Infection and Immunity, 2010, 78(4):1629-1641).
Compound efficacy is demonstrated when all mice in a treatment group are completely clear of N. gonorrhoeae after 5 full days post-treatment (100% clearance).
Bacterial clearance is defined as the number of mice in the treatment group free of
N. gonorrhoeae expressed as a percentage of the total. Complete bacterial clearance (100% clearance) for the treatment group equates to an approximate log 4 reduction in bacterial count for the group. Compounds that achieve less than 100% clearance for the treatment group have an average maximal log drop value calculated by the following equation:
Maximal Log Drop = log(average Day 2 bacterial count for all mice) - log(average lowest bacterial count post dose for all mice) Study Conduct
On Day -2 of the study, ovariectomized Balb/c female mice (5 weeks old - Charles River Laboratory) are implanted with a single 17β-estradiol pellet (0.5 mg, 21 day release) subcutaneously and begin treatment with a combination of vancomycin HCl, streptomycin sulfate (0.6 mg and 0.3 mg, respectively, IP, BID) and trimethoprim sulfate (0.8 mg, PO, BID). The antibiotic combination is administered to control commensal flora induced by the high level of 17β-estradiol resulting from the implanted pellet. Combined antibiotic treatment continues from Day -2 to Day 1 of the study. After Day 1, mice are dosed with streptomycin only (0.6 mg, IP, QD).
On Day 0 of the study, mice are inoculated with a form of N. gonorrhoeae (target 1 x 108 CFU) suspended in saline. Following inoculation, and for the 7 days of the study, the bacterial count is determined by daily vaginal swabbing using sterile swabs.
On Day 1 of the study, mice are randomized into treatment groups according to bacterial count. The treatment groups (n=10) included a vehicle control, a positive control (such as ciprofloxacin, 30 mg/kg) and test compound group. The treatment groups are dosed with a single dose (mg/kg) either orally or IP. The vehicle control, positive control and test compound oral dose is administered in a mixture of HPMC (0.5%) and Tween 80 (0.1%) and the IP dose is administered in a mixture of DMSO (3%) in saline.
Example 9
Combinations with Antibacterial Agents
The in vitro effects of compounds described herein in combination with a known antibacterial or antibiotic agent may be investigated in various organisms using the microdilution checkerboard method for the measurement of additive or synergistic effect. Assays can be performed in a 96-well checkerboard titration format, with serial dilutions of each compound to identify the lowest MIC value (µg/mL) at which the combination completely inhibits colony formation. The ability of a combination of one or more compounds described herein with known agents to either act synergistically, additively, indifferently or antagonistically can be determined. A synergistic effect is demonstrated when the activity of the separate agents are combined and the result is greater than the expected arithmetic sum of each agents activity alone. The fractional inhibitory
concentration (FIC) is a quantitative measure of such drug interactions, where the fractional inhibition indices are calculated using the checkerboard method in a 96-well microtiter plate. Combined activity is synergistic when the FIC value is≤ 0.5; combined activity is additive when the FIC value is > 0.5 and < 2; combined activity that is not different from the agents alone when the FIC value is≥ 2 and≤ 4; and, combined activity is antagonistic when the FIC value is > 4.
Without regard to whether a document cited herein was specifically and individually indicated as being incorporated by reference, all documents referred to herein are incorporated by reference into the present application for any and all purposes to the same extent as if each individual reference was fully set forth herein.
Having now fully described the subject matter of the claims, it will be understood by those having ordinary skill in the art that the same can be performed within a wide range of equivalents without affecting the scope of the subject matter or embodiments described herein. It is intended that the appended claims be interpreted to include all such equivalents.

Claims

What is claimed is:
1. A use of a compound for treating or ameliorating Neisseria gonorrhoeae
(N. gonorrhoeae) in a subject in need thereof comprising, administering an effective amount of a compound of Formula (I) to the subject:
or a form thereof, wherein
Figure imgf000153_0001
R1 is a monocyclic ring system selected from the group consisting of:
Figure imgf000153_0002
wherein“*” represents a point of attachment for R1 to the 2-pyridinone of Formula (I); and, wherein R1 is substituted on available valences with from one to five substituents each
selected from R5;
R2 is hydrogen, cyano, C1-8alkyl, hydroxyl-C1-8alkyl, formyl-C1-8alkyl, C1-8alkoxy-C1-8alkyl, C1-8alkoxy, C2-8alkenyl, C2-8alkynl, carboxyl, amino-C1-8alkyl, aryl or C3-14cycloalkyl; R3 is hydrogen, hydroxyl or C1-8alkoxy;
R5 is hydrogen, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, hydroxyl-C1-8alkyl,
halo-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkyl-thio, carboxyl,
C1-8alkyl-carbonyl, C1-8alkoxy-carbonyl, amino-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C2-8alkenyl-amino, (C2-8alkenyl)2-amino, C2-8alkynyl-amino, (C2-8alkynyl)2-amino, amino-C1-8alkyl, C1-10alkyl-amino-C1-8alkyl,
(C1-10alkyl)2-amino-C1-8alkyl, C2-8alkenyl-amino-C1-8alkyl,
(C2-8alkenyl)2-amino-C1-8alkyl, C2-8alkynyl-amino-C1-8alkyl,
(C2-8alkynyl)2-amino-C1-8alkyl, halo-C1-8alkyl-amino, (halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl, (halo-C1-8alkyl)2-amino-C1-8alkyl,
C1-8alkoxy-C1-8alkyl-amino, (C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino,
(C1-8alkoxy-C1-8alkyl)2-amino, C1-8alkoxy-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, amino-C1-8alkyl-amino-C1-8alkyl, (amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (amino-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C1-8alkyl)2-amino-C1-8alkyl-amino-C1-8alkyl,
[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl)2-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino, (hydroxyl-C1-8alkyl)2-amino,
hydroxyl-C1-8alkyl-amino-C1-8alkyl, (hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl-amino,
[(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,C1-8alkyl]amino,
(C1-8alkyl-carbonyl,C1-8alkyl)amino-C1-8alkyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C3-14cycloalkyl, C3-14cycloalkyl-C1-8alkyl,
C3-14cycloalkyl-oxy, C3-14cycloalkyl-C1-8alkoxy, C3-14cycloalkyl-amino,
C3-14cycloalkyl-amino-C1-8alkyl, (C3-14cycloalkyl,C1-8alkyl)amino-C1-8alkyl, (C3-14cycloalkyl)2-amino-C1-8alkyl, C3-14cycloalkyl-C1-8alkyl-amino-C1-8alkyl, (C3-14cycloalkyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C3-14cycloalkyl-C1-8alkyl)2-amino-C1-8alkyl, aryl, aryl-C1-8alkyl, aryl-C1-8alkoxy, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-amino-C1-8alkyl,
(aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino, (aryl-C1-8alkyl)2-amino,
aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(aryl-C1-8alkyl)2-amino-C1-8alkyl, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino, (heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl,C1-8alkyl)amino-C1-8alkyl, (heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-oxy, heterocyclyl-C1-8alkoxy, heterocyclyl-amino, (heterocyclyl,C1-8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-C1-8alkyl, (heterocyclyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl)2-amino-C1-8alkyl,
(heterocyclyl,C3-14cycloalkyl-C1-8alkyl)amino-C1-8alkyl,
heterocyclyl-C1-8alkyl-amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl-oxy-amino,
(heterocyclyl-oxy,C1-8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-C1-8alkyl,C1-8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-carbonyl-oxy;
wherein each instance of C3-14cycloalkyl, aryl, heterocyclyl is optionally substituted with one, two or three substituents each selected from R6;
R6 is azido, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, halo-C1-8alkyl,
hydroxyl-C1-8alkyl, C1-8alkoxy-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy,
hydroxyl-C1-8alkoxy, carboxyl, C1-8alkyl-carbonyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, halo-C1-8alkyl-amino,
(halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl,
(halo-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl, C1-8alkyl-thio, amino-carbonyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C1-8alkyl-carbonyl-amino,
(carboxyl-C1-8alkyl,C1-8alkyl)amino-carbonyl-amino, C3-14cycloalkyl,
C3-14cycloalkyl-amino, aryl, aryl-C1-8alkyl, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino,
(aryl-C1-8alkyl)2-amino, aryl-C1-8alkyl-amino-C1-8alkyl,
(aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (aryl-C1-8alkyl)2-amino-C1-8alkyl, aryl-amino-C1-8alkyl, (aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-amino-carbonyl, aryl-C1-8alkoxy, aryl-C1-8alkoxy-carbonyl-amino, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heteroaryl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-amino-C1-8alkyl or heterocyclyl-oxy;
wherein each instance of C3-14cycloalkyl is optionally substituted with one substituent
selected from R9; and,
wherein each instance of aryl is optionally substituted with one substituent selected from R10; R9 is C1-8alkyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl,
C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl or aryl-C1-8alkyl-amino; and, R10 is halogen;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
2. The use of claim 1, wherein the ring system R1a is selected from a R1a1 ring system:
Figure imgf000156_0001
wherein“*” represents a point of attachment; and, wherein R5a, R5b, R5c, R5d and R5e, when present, are selected from the group consisting of:
hydrogen, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, hydroxyl-C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkyl-thio, carboxyl, C1-8alkyl-carbonyl,
C1-8alkoxy-carbonyl, amino-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C2-8alkenyl-amino, (C2-8alkenyl)2-amino, C2-8alkynyl-amino, (C2-8alkynyl)2-amino, amino-C1-8alkyl, C1-10alkyl-amino-C1-8alkyl, (C1-10alkyl)2-amino-C1-8alkyl,
C2-8alkenyl-amino-C1-8alkyl, (C2-8alkenyl)2-amino-C1-8alkyl,
C2-8alkynyl-amino-C1-8alkyl, (C2-8alkynyl)2-amino-C1-8alkyl, halo-C1-8alkyl-amino, (halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl,
(halo-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkoxy-C1-8alkyl-amino, (C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino, (C1-8alkoxy-C1-8alkyl)2-amino,
C1-8alkoxy-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, amino-C1-8alkyl-amino-C1-8alkyl, (amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (amino-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C1-8alkyl)2-amino-C1-8alkyl-amino-C1-8alkyl,
[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl)2-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino, (hydroxyl-C1-8alkyl)2-amino,
hydroxyl-C1-8alkyl-amino-C1-8alkyl, (hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl-amino,
[(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,C1-8alkyl]amino,
(C1-8alkyl-carbonyl,C1-8alkyl)amino-C1-8alkyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C3-14cycloalkyl, C3-14cycloalkyl-C1-8alkyl,
C3-14cycloalkyl-oxy, C3-14cycloalkyl-C1-8alkoxy, C3-14cycloalkyl-amino,
C3-14cycloalkyl-amino-C1-8alkyl, (C3-14cycloalkyl,C1-8alkyl)amino-C1-8alkyl, (C3-14cycloalkyl)2-amino-C1-8alkyl, C3-14cycloalkyl-C1-8alkyl-amino-C1-8alkyl, (C3-14cycloalkyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C3-14cycloalkyl-C1-8alkyl)2-amino-C1-8alkyl, aryl, aryl-C1-8alkyl, aryl-C1-8alkoxy, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-amino-C1-8alkyl,
(aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino, (aryl-C1-8alkyl)2-amino,
aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(aryl-C1-8alkyl)2-amino-C1-8alkyl, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl, (heteroaryl,C1-8alkyl)amino-C1-8alkyl, (heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-oxy, heterocyclyl-C1-8alkoxy, heterocyclyl-amino, (heterocyclyl,C1-8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-C1-8alkyl, (heterocyclyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl)2-amino-C1-8alkyl,
(heterocyclyl,C3-14cycloalkyl-C1-8alkyl)amino-C1-8alkyl,
heterocyclyl-C1-8alkyl-amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl-oxy-amino,
(heterocyclyl-oxy,C1-8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-C1-8alkyl,C1-8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-carbonyl-oxy;
wherein each instance of C3-14cycloalkyl, aryl, heterocyclyl is optionally substituted with one, two or three substituents each selected from R6;
R6 is azido, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, halo-C1-8alkyl,
hydroxyl-C1-8alkyl, C1-8alkoxy-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy,
hydroxyl-C1-8alkoxy, carboxyl, C1-8alkyl-carbonyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, halo-C1-8alkyl-amino,
(halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl,
(halo-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl, C1-8alkyl-thio, amino-carbonyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C1-8alkyl-carbonyl-amino,
(carboxyl-C1-8alkyl,C1-8alkyl)amino-carbonyl-amino, C3-14cycloalkyl,
C3-14cycloalkyl-amino, aryl, aryl-C1-8alkyl, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino,
(aryl-C1-8alkyl)2-amino, aryl-C1-8alkyl-amino-C1-8alkyl,
(aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (aryl-C1-8alkyl)2-amino-C1-8alkyl, aryl-amino-C1-8alkyl, (aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-amino-carbonyl, aryl-C1-8alkoxy, aryl-C1-8alkoxy-carbonyl-amino, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heteroaryl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-amino-C1-8alkyl or heterocyclyl-oxy;
wherein each instance of C3-14cycloalkyl and heterocyclyl is optionally substituted with one substituent selected from R9; and,
wherein each instance of aryl is optionally substituted with one substituent selected from R10; R9 is C1-8alkyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl,
C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl or aryl-C1-8alkyl-amino; and, R10 is halogen;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
3. The use of claim 2, wherein R5a, R5b, R5c, R5d and R5e, when present, are selected from the group consisting of:
hydrogen, halogen, hydroxyl, cyano, C1-8alkyl, C1-8alkoxy, amino, C1-8alkyl-amino,
(C1-8alkyl)2-amino, (C2-8alkenyl)2-amino, (C1-10alkyl)2-amino-C1-8alkyl,
halo-C1-8alkyl-amino, C1-8alkyl-amino-C1-8alkyl-amino,
[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, (hydroxyl-C1-8alkyl,C1-8alkyl)amino, aryl-amino, (aryl,C1-8alkyl)amino, heterocyclyl or
(heterocyclyl-oxy-C1-8alkyl,C1-8alkyl)amino;
wherein each instance of heterocyclyl is optionally substituted with one, two or three
substituents each selected from R6;
R6 is azido, halogen, hydroxyl, oxo, cyano, C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy-C1-8alkyl, C1-8alkoxy, carboxyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino,
(C1-8alkyl)2-amino, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl,
(C1-8alkyl)2-amino-C1-8alkyl, (carboxyl-C1-8alkyl,C1-8alkyl)amino-carbonyl-amino, C3-14cycloalkyl, C3-14cycloalkyl-amino, aryl, aryl-C1-8alkyl, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino, (aryl-C1-8alkyl)2-amino,
aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(aryl-C1-8alkyl)2-amino-C1-8alkyl, aryl-C1-8alkoxy, aryl-C1-8alkoxy-carbonyl-amino, heteroaryl, heteroaryl-C1-8alkyl-amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl or heterocyclyl-oxy;
wherein each instance of C3-14cycloalkyl and heterocyclyl is optionally substituted with one substituent selected from R9; and,
wherein each instance of aryl is optionally substituted with one substituent selected from R10; R9 is C1-8alkyl, amino, (C1-8alkyl)2-amino or aryl-C1-8alkyl-amino; and,
R10 is halogen;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
4. The use of claim 1, wherein the ring system R1b, R1c, R1d and R1e is selected from a R1b1, R1c1, R1d1 and R1e1 ring system, respectively:
Figure imgf000160_0001
wherein“*” represents a point of attachment; and, wherein R5a, R5b, R5c, R5d and R5e, when present, are selected from the group consisting of:
hydrogen, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, hydroxyl-C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkyl-thio, carboxyl, C1-8alkyl-carbonyl,
C1-8alkoxy-carbonyl, amino-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C2-8alkenyl-amino, (C2-8alkenyl)2-amino, C2-8alkynyl-amino, (C2-8alkynyl)2-amino, amino-C1-8alkyl, C1-10alkyl-amino-C1-8alkyl, (C1-10alkyl)2-amino-C1-8alkyl,
C2-8alkenyl-amino-C1-8alkyl, (C2-8alkenyl)2-amino-C1-8alkyl,
C2-8alkynyl-amino-C1-8alkyl, (C2-8alkynyl)2-amino-C1-8alkyl, halo-C1-8alkyl-amino, (halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl,
(halo-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkoxy-C1-8alkyl-amino,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino, (C1-8alkoxy-C1-8alkyl)2-amino,
C1-8alkoxy-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino, (C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, amino-C1-8alkyl-amino-C1-8alkyl, (amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (amino-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C1-8alkyl)2-amino-C1-8alkyl-amino-C1-8alkyl,
[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl)2-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino, (hydroxyl-C1-8alkyl)2-amino,
hydroxyl-C1-8alkyl-amino-C1-8alkyl, (hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl-amino,
[(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,C1-8alkyl]amino,
(C1-8alkyl-carbonyl,C1-8alkyl)amino-C1-8alkyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C3-14cycloalkyl, C3-14cycloalkyl-C1-8alkyl,
C3-14cycloalkyl-oxy, C3-14cycloalkyl-C1-8alkoxy, C3-14cycloalkyl-amino,
C3-14cycloalkyl-amino-C1-8alkyl, (C3-14cycloalkyl,C1-8alkyl)amino-C1-8alkyl,
(C3-14cycloalkyl)2-amino-C1-8alkyl, C3-14cycloalkyl-C1-8alkyl-amino-C1-8alkyl, (C3-14cycloalkyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C3-14cycloalkyl-C1-8alkyl)2-amino-C1-8alkyl, aryl, aryl-C1-8alkyl, aryl-C1-8alkoxy, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-amino-C1-8alkyl,
(aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino, (aryl-C1-8alkyl)2-amino,
aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(aryl-C1-8alkyl)2-amino-C1-8alkyl, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl,C1-8alkyl)amino-C1-8alkyl, (heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-oxy, heterocyclyl-C1-8alkoxy, heterocyclyl-amino, (heterocyclyl,C1-8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-C1-8alkyl, (heterocyclyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl)2-amino-C1-8alkyl, (heterocyclyl,C3-14cycloalkyl-C1-8alkyl)amino-C1-8alkyl,
heterocyclyl-C1-8alkyl-amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl-oxy-amino,
(heterocyclyl-oxy,C1-8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-C1-8alkyl,C1-8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-carbonyl-oxy;
wherein each instance of C3-14cycloalkyl, aryl, heterocyclyl is optionally substituted with one, two or three substituents each selected from R6;
R6 is azido, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, halo-C1-8alkyl,
hydroxyl-C1-8alkyl, C1-8alkoxy-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy,
hydroxyl-C1-8alkoxy, carboxyl, C1-8alkyl-carbonyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, halo-C1-8alkyl-amino,
(halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl,
(halo-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl, C1-8alkyl-thio, amino-carbonyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C1-8alkyl-carbonyl-amino,
(carboxyl-C1-8alkyl,C1-8alkyl)amino-carbonyl-amino, C3-14cycloalkyl,
C3-14cycloalkyl-amino, aryl, aryl-C1-8alkyl, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino,
(aryl-C1-8alkyl)2-amino, aryl-C1-8alkyl-amino-C1-8alkyl,
(aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (aryl-C1-8alkyl)2-amino-C1-8alkyl, aryl-amino-C1-8alkyl, (aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-amino-carbonyl, aryl-C1-8alkoxy, aryl-C1-8alkoxy-carbonyl-amino, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (heteroaryl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-amino-C1-8alkyl or heterocyclyl-oxy;
wherein each instance of C3-14cycloalkyl and heterocyclyl is optionally substituted with one substituent selected from R9; and,
wherein each instance of aryl is optionally substituted with one substituent selected from R10; R9 is C1-8alkyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl,
C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl or aryl-C1-8alkyl-amino; and, R10 is halogen;
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.
5. The use of claim 4, wherein R5a, R5b, R5c, R5d and R5e, when present, are selected from the group consisting of:
hydrogen, (C1-8alkyl)2-amino or heterocyclyl;
wherein heterocyclyl is optionally substituted with a substituent selected from R6; and, R6 is amino or (C1-8alkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
6. The use of claim 1, wherein the ring system R1f, R1g, R1h, R1i and R1j is selected from a R1f1, R1g1, R1h1, R1i1 and R1j1 ring system, respectively:
Figure imgf000163_0001
wherein“*” represents a point of attachment; and, wherein R5a, R5b, R5c and R5d, when
present, are selected from the group consisting of:
hydrogen, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, hydroxyl-C1-8alkyl, halo-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C1-8alkyl-thio, carboxyl, C1-8alkyl-carbonyl,
C1-8alkoxy-carbonyl, amino-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C2-8alkenyl-amino, (C2-8alkenyl)2-amino, C2-8alkynyl-amino, (C2-8alkynyl)2-amino, amino-C1-8alkyl, C1-10alkyl-amino-C1-8alkyl, (C1-10alkyl)2-amino-C1-8alkyl, C2-8alkenyl-amino-C1-8alkyl, (C2-8alkenyl)2-amino-C1-8alkyl,
C2-8alkynyl-amino-C1-8alkyl, (C2-8alkynyl)2-amino-C1-8alkyl, halo-C1-8alkyl-amino, (halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl,
(halo-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkoxy-C1-8alkyl-amino,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino, (C1-8alkoxy-C1-8alkyl)2-amino,
C1-8alkoxy-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl,C1-8alkyl)-amino-C1-8alkyl,
(C1-8alkoxy-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, amino-C1-8alkyl-amino-C1-8alkyl, (amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (amino-C1-8alkyl)2-amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl-amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C1-8alkyl)2-amino-C1-8alkyl-amino-C1-8alkyl,
[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl,
(C1-8alkyl-amino-C1-8alkyl)2-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino, (hydroxyl-C1-8alkyl)2-amino,
hydroxyl-C1-8alkyl-amino-C1-8alkyl, (hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino,
(hydroxyl-C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino,
(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl-amino,
[(hydroxyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,C1-8alkyl]amino,
(C1-8alkyl-carbonyl,C1-8alkyl)amino-C1-8alkyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C3-14cycloalkyl, C3-14cycloalkyl-C1-8alkyl,
C3-14cycloalkyl-oxy, C3-14cycloalkyl-C1-8alkoxy, C3-14cycloalkyl-amino,
C3-14cycloalkyl-amino-C1-8alkyl, (C3-14cycloalkyl,C1-8alkyl)amino-C1-8alkyl, (C3-14cycloalkyl)2-amino-C1-8alkyl, C3-14cycloalkyl-C1-8alkyl-amino-C1-8alkyl, (C3-14cycloalkyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(C3-14cycloalkyl-C1-8alkyl)2-amino-C1-8alkyl, aryl, aryl-C1-8alkyl, aryl-C1-8alkoxy, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-amino-C1-8alkyl,
(aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino, (aryl-C1-8alkyl)2-amino,
aryl-C1-8alkyl-amino-C1-8alkyl, (aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(aryl-C1-8alkyl)2-amino-C1-8alkyl, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl,C1-8alkyl)amino-C1-8alkyl, (heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-oxy, heterocyclyl-C1-8alkoxy, heterocyclyl-amino, (heterocyclyl,C1-8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-C1-8alkyl, (heterocyclyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl)2-amino-C1-8alkyl,
(heterocyclyl,C3-14cycloalkyl-C1-8alkyl)amino-C1-8alkyl,
heterocyclyl-C1-8alkyl-amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heterocyclyl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl-oxy-amino,
(heterocyclyl-oxy,C1-8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-C1-8alkyl,C1-8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-carbonyl-oxy;
wherein each instance of C3-14cycloalkyl, aryl, heterocyclyl is optionally substituted with one substituent selected from R6;
R6 is azido, halogen, hydroxyl, oxo, cyano, nitro, C1-8alkyl, halo-C1-8alkyl,
hydroxyl-C1-8alkyl, C1-8alkoxy-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy,
hydroxyl-C1-8alkoxy, carboxyl, C1-8alkyl-carbonyl, C1-8alkoxy-carbonyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl-amino,
(amino-C1-8alkyl,C1-8alkyl)amino, C1-8alkyl-amino-C1-8alkyl-amino,
(C1-8alkyl-amino-C1-8alkyl,C1-8alkyl)amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino, halo-C1-8alkyl-amino,
(halo-C1-8alkyl)2-amino, halo-C1-8alkyl-amino-C1-8alkyl,
(halo-C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, [(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1-8alkyl, C1-8alkyl-thio, amino-carbonyl, C1-8alkyl-amino-carbonyl,
(C1-8alkyl)2-amino-carbonyl, C1-8alkyl-carbonyl-amino,
(carboxyl-C1-8alkyl,C1-8alkyl)amino-carbonyl-amino, C3-14cycloalkyl,
C3-14cycloalkyl-amino, aryl, aryl-C1-8alkyl, aryl-amino, (aryl,C1-8alkyl)amino, (aryl)2-amino, aryl-C1-8alkyl-amino, (aryl-C1-8alkyl,C1-8alkyl)amino,
(aryl-C1-8alkyl)2-amino, aryl-C1-8alkyl-amino-C1-8alkyl,
(aryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl, (aryl-C1-8alkyl)2-amino-C1-8alkyl, aryl-amino-C1-8alkyl, (aryl,C1-8alkyl)amino-C1-8alkyl, (aryl)2-amino-C1-8alkyl, aryl-amino-carbonyl, aryl-C1-8alkoxy, aryl-C1-8alkoxy-carbonyl-amino, heteroaryl, heteroaryl-C1-8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-C1-8alkyl-amino, (heteroaryl-C1-8alkyl,C1-8alkyl)amino,
(heteroaryl-C1-8alkyl)2-amino, heteroaryl-C1-8alkyl-amino-C1-8alkyl,
(heteroaryl-C1-8alkyl,C1-8alkyl)amino-C1-8alkyl,
(heteroaryl-C1-8alkyl)2-amino-C1-8alkyl, heterocyclyl, heterocyclyl-C1-8alkyl, heterocyclyl-amino-C1-8alkyl or heterocyclyl-oxy;
wherein each instance of C3-14cycloalkyl and heterocyclyl is optionally substituted with one substituent selected from R9; and,
wherein each instance of aryl is optionally substituted with one substituent selected from R10; R9 is C1-8alkyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl,
C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl or aryl-C1-8alkyl-amino; and, R10 is halogen;
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.
7. The use of claim 6, wherein R5a, R5b, R5c and R5d, when present, are selected from the group consisting of:
hydrogen, C1-8alkyl, (C1-8alkyl)2-amino, (C1-10alkyl)2-amino-C1-8alkyl, heterocyclyl or
heterocyclyl-C1-8alkyl; wherein each instance of heterocyclyl is optionally substituted with one (C1-8alkyl)2-amino substituent; and,
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.
8. A method of use for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of claim 1 or a form thereof to the subject.
9. The method of claim 8, wherein the compound or a form thereof is selected from the group consisting of:
5-benzyl-6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5-benzyl-6-[4-(dimethylamino)phenyl]-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-(4-aminophenyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-[4-(dimethylamino)phenyl]-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-[4-(dimethylamino)phenyl]-4-hydroxy-5-methyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-cyclohexyl-6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-cyclohexyl-6-[4-(dimethylamino)phenyl]-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
6-[4-(dimethylamino)phenyl]-2-oxo-5-propyl-1,2-dihydropyridine-3-carboxylic acid 6-[4-(dimethylamino)phenyl]-4-hydroxy-2-oxo-5-propyl-1,2-dihydropyridine-3- carboxylic acid
6-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarboxylic acid
6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3,5-dicarboxylic acid 5-cyclopropyl-6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-cyclopropyl-6-[4-(dimethylamino)phenyl]-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
5-cyano-6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid 6-(4-cyanophenyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-(4-{methyl[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino}phenyl)-2-oxo- 1,2-dihydropyridine-3-carboxylic acid 5-ethyl-6-{4-[(2-hydroxyethyl)(methyl)amino]phenyl}-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
5-ethyl-4-hydroxy-6-{4-[(2-hydroxyethyl)(methyl)amino]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[2-(dimethylamino)pyrimidin-5-yl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[2-(dimethylamino)pyrimidin-5-yl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
4-hydroxy-2-oxo-6-[4-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid
5-(aminomethyl)-6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-2-oxo-6-[4-(1H-tetrazol-5-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-6-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-(4-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-(4-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-4-hydroxy-2-oxo-6-[2-(piperidin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-(2-fluoro-4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-2-oxo-6-[2-(piperidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-4-hydroxy-6-(4-methoxy-2-methylphenyl)-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-(4-methoxy-2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 6-(2,4-dimethoxyphenyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-6-[4-methoxy-2-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-(2,4-dimethoxyphenyl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-[2-methyl-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-[2-fluoro-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-4-hydroxy-6-[2-methyl-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[2-(dimethylamino)-4-methoxyphenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-4-hydroxy-2-oxo-6-(2,4,6-trimethoxyphenyl)-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-[2-fluoro-4-(piperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-[2-fluoro-4-(piperidin-1-yl)phenyl]-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
5-ethyl-4-hydroxy-6-[2-methoxy-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-2-oxo-6-[2-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-4-hydroxy-2-oxo-6-[2-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-4-hydroxy-6-[4-methoxy-2-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-[2-methoxy-4-(piperidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid 5-ethyl-6-[2-methoxy-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-4-hydroxy-6-[2-methyl-4-(piperidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-[2-methyl-4-(piperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[4-(dimethylamino)-2-fluorophenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[2-(dimethylamino)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid 6-[4-(dimethylamino)-2-fluorophenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(dimethylamino)-2-methylphenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(dimethylamino)-2-methylphenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[2-(dimethylamino)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-[2-methoxy-4-(piperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[2-(dimethylamino)-4-methoxyphenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(dimethylamino)-2-methoxyphenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(dimethylamino)-2-methoxyphenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[4-(dimethylamino)-3-methylphenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid 6-[4-(dimethylamino)-3-methoxyphenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[4-(dimethylamino)-3-methoxyphenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-[3-methoxy-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-4-hydroxy-6-[3-methoxy-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-[3-methoxy-4-(piperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-4-hydroxy-6-[3-methoxy-4-(piperidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-[3-methyl-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-4-hydroxy-6-[3-methyl-4-(pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-[3-methyl-4-(piperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-4-hydroxy-6-[3-methyl-4-(piperidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-(4-fluorophenyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-2-oxo-6-phenyl-1,2-dihydropyridine-3-carboxylic acid
6-(4-chlorophenyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-(4-chlorophenyl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid 6-(4-bromophenyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-(4-bromophenyl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-6-(4-iodophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-4-hydroxy-6-(4-iodophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-4-hydroxy-6-{4-[(3-iodopropyl)amino]phenyl}-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
6-[4-(azetidin-1-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-{4-[(3S)-3-fluoropyrrolidin-1-yl]phenyl}-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[6-(dimethylamino)pyridin-3-yl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-[6-(dimethylamino)pyridin-3-yl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[4-(dimethylamino)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid 6-[3-fluoro-4-(morpholin-4-yl)phenyl]-5-methyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[4-(dimethylamino)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-3-fluorophenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-[3-fluoro-4-(piperazin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[4-(dimethylamino)-3-fluorophenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[4-(dimethylamino)-3-fluorophenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(dimethylamino)phenyl]-2-oxo-5-(propan-2-yl)-1,2-dihydropyridine-3- carboxylic acid 6-[4-(dimethylamino)phenyl]-4-hydroxy-2-oxo-5-(propan-2-yl)-1,2- dihydropyridine-3-carboxylic acid
6-[4-(diethylamino)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid 6-[4-(diethylamino)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-2-oxo-6-[4-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-4-hydroxy-2-oxo-6-[4-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-2-oxo-6-[4-(1H-pyrrol-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid 6-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-2-oxo-6-[4-(piperazin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid 6-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-2-oxo-6-[4-(piperazin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-[4-(1H-imidazol-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-[4-(1H-imidazol-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-2-oxo-6-[4-(piperidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-4-hydroxy-2-oxo-6-[4-(piperidin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-[4-(morpholin-4-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid 6-[4-(azetidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-4-hydroxy-6-(5-morpholinopyridin-2-yl)-2-oxo-1,2-dihydropyridine-3- carboxylic acid 5-ethyl-4-hydroxy-2-oxo-6-[5-(piperazin-1-yl)pyridin-2-yl]-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-2-oxo-6-[4-(2-oxopyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-2-oxo-6-[4-(2-oxopyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-[4-(2-methyl-5-oxopyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-{4-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-2-oxo-6-[4-(3-oxo-2-azaspiro[4.5]dec-2-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-2-oxo-6-[4-(3-oxo-2-azabicyclo[2.2.1]hept-5-en-2-yl)phenyl]-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-2-oxo-6-{4-[3-(tetrahydro-2H-pyran-2-yloxy)azetidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-[4-(3-hydroxyazetidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-{4-[(3R)-3-hydroxypiperidin-1-yl]phenyl}-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-[4-(3-hydroxypyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-4-hydroxy-6-{4-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-{4-[(3R)-3-hydroxypiperidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-[4-(3-hydroxypyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid 6-{4-[3-(benzyloxy)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[4-(3-azidopyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-{4-[(3S)-3-azidopyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[4-(3-aminopyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-{4-[(3S)-3-aminopyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-{4-[(3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(3R,4R)-3-amino-4-methoxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(3R,4S)-3-amino-4-methoxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(3R,4S)-3-amino-4-hydroxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl}-5-ethyl-2- oxo-1,2-dihydropyridine-3-carboxylic acid
6-[4-(2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
5-ethyl-6-[4-(2-methylpyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-{4-[3-(morpholin-4-yl)pyrrolidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-2-oxo-6-{4-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid 5-ethyl-2-oxo-6-{4-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-2-oxo-6-{4-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
6-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-2-oxo-6-[4-(2-phenylpyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-{4-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-{4-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(2S,5S)-2,5-bis(methoxymethyl)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-[4-(3-fluoropyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-{4-[(3S)-3-fluoropyrrolidin-1-yl]phenyl}-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-{4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl}-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-2-oxo-6-[4-(phenylamino)phenyl]-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-2-oxo-6-{4-[2-(1,3-thiazol-2-yl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(2S)-2-carboxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-{4-[methyl(phenyl)amino]phenyl}-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-(4-{[2-(dimethylamino)ethyl]amino}phenyl)-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
5-ethyl-6-{4-[ethyl(methyl)amino]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-(4-{[2-(dimethylamino)ethyl](methyl)amino}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(1,3-dihydro-2H-isoindol-2-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-isopropyl-2-oxo-6-[4-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid
5-cyclopropyl-2-oxo-6-[4-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid
6-(4-{[2-(dimethylamino)ethyl](methyl)amino}phenyl)-2-oxo-5-(propan-2-yl)-1,2- dihydropyridine-3-carboxylic acid
6-[4-(3-amino-3-methylpyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
6-[4-(3-{[(carboxymethyl)(methyl)carbamoyl]amino}azetidin-1-yl)phenyl]-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-{4-[3-(5-methyl-2H-tetrazol-2-yl)azetidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(1-amino-3-azabicyclo[3.1.0]hex-3-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid 6-[4-(3-aminoazetidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-[4-(3-{[(benzyloxy)carbonyl]amino}azetidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[3-(diethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
6-{4-[3-(cyclopropylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[3-(benzylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[4-(1,3'-bipyrrolidin-1'-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(1R,5S,6s)-6-(dibenzylamino)-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-2- oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(1R,5S,6s)-6-(benzylamino)-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-2- oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-[4-(hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(4-benzylhexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl]-5-ethyl-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
6-(4-{3-[(dibenzylamino)methyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-(4-{3-[(benzylamino)methyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(3-{[benzyl(methyl)amino]methyl}pyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid 5-ethyl-6-(4-{3-[(methylamino)methyl]pyrrolidin-1-yl}phenyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-(4-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-{4-[(4aR,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-4(4aH)-yl]phenyl}-2- oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-{4-[(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[3-(aminomethyl)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
6-{4-[(3aR,6aR)-1-benzylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-{4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
5-ethyl-2-oxo-6-{4-[3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
6-[4-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4R,7aS)-4-(dimethylamino)octahydro-2H-isoindol-2-yl]phenyl}-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-(4-{(3aR,4R,7aS)-4-[benzyl(methyl)amino]octahydro-2H-isoindol-2-yl}phenyl)- 5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-{4-[(3aR,4R,7aS)-4-(methylamino)octahydro-2H-isoindol-2-yl]phenyl}-2- oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4R,7aS)-4-(dibenzylamino)octahydro-2H-isoindol-2-yl]phenyl}-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4R,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid 6-{4-[(3aR,4R,6aS)-4-(dimethylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4R,6aS)-4-[benzyl(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-{4-[(3aR,4R,6aS)-4-(methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4R,6aS)-4-(dibenzylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4R,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4S,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-(4-{(3aR,7aS)-3a-[(dimethylamino)methyl]octahydro-2H-isoindol-2-yl}phenyl)- 5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,6aS)-5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-{4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-{4-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-[4-(3,6-diazabicyclo[3.1.0]hex-3-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-{4-[(1S,5R,6R)-6-(methylamino)-3-azabicyclo[3.2.0]hept-3-yl]phenyl}-2- oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(1S,5R,6R)-6-amino-3-azabicyclo[3.2.0]hept-3-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid 6-{4-[(1S,5R,6S)-6-amino-3-azabicyclo[3.2.0]hept-3-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-[4-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(7-amino-5-azaspiro[2.4]hept-5-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
5-ethyl-6-{4-[(3aR,5r,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3S,4R)-3-(aminomethyl)-4-methylpyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-(4-{3-[1-(benzylamino)cyclopropyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[3-(1-aminocyclobutyl)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(3a-cyanooctahydro-2H-isoindol-2-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
2-[4-(5-carboxy-3-ethyl-6-oxo-1,6-dihydropyridin-2- yl)phenyl]hexahydrocyclopenta[c]pyrrole-3a(1H)-carboxylic acid
6-{4-[3-(dimethylamino)pyrrolidin-1-yl]-2-fluorophenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-[4-(4-hydroxypiperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-{4-[4-(dimethylamino)piperidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
5-ethyl-6-[4-(4-methoxypiperidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-{2-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid 5-ethyl-2-oxo-6-{4-[3-(pyridin-4-yl)pyrrolidin-1-yl]phenyl}-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-2-oxo-6-{4-[3-(pyridin-2-yl)pyrrolidin-1-yl]phenyl}-1,2-dihydropyridine-3- carboxylic acid
6-[4-(4-aminopiperidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-2-oxo-6-{4-[3-(1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-2-fluorophenyl}-5-ethyl-2- oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-[4-(3-ethyl-3-hydroxypyrrolidin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
5-ethyl-6-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(3-{[(2-chlorobenzyl)amino]methyl}pyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(3-{[(3-chlorobenzyl)amino]methyl}pyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(3-{[(4-chlorobenzyl)amino]methyl}pyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-[4-(3-{[(3-fluorobenzyl)amino]methyl}pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-[4-(3-{[(4-fluorobenzyl)amino]methyl}pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-[4-(3-{[(2-fluorobenzyl)amino]methyl}pyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid 5-ethyl-2-oxo-6-[4-(3-{[(pyridin-3-ylmethyl)amino]methyl}pyrrolidin-1-yl)phenyl]- 1,2-dihydropyridine-3-carboxylic acid
5-ethyl-2-oxo-6-[4-(3-{[(pyridin-4-ylmethyl)amino]methyl}pyrrolidin-1-yl)phenyl]- 1,2-dihydropyridine-3-carboxylic acid
5-ethyl-2-oxo-6-[4-(3-{[(pyridin-2-ylmethyl)amino]methyl}pyrrolidin-1-yl)phenyl]- 1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4S,7aS)-4-azidooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4S,6aS)-4-azidohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-{4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}-4- hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-(4-{3-[1-(dimethylamino)cyclopropyl]pyrrolidin-1-yl}phenyl)-5-ethyl-4-hydroxy- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,5r,6aS)-5-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-(4-{(3S,4R)-3-[(dibenzylamino)methyl]-4-methylpyrrolidin-1-yl}phenyl)-5-ethyl- 4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,5r,6aS)-5-(benzylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,5r,6aS)-5-(dibenzylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-[4-(7-amino-5-azaspiro[2.4]hept-5-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[1-(tert-butoxycarbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]phenyl}-5- ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-(4-{3-[(methylamino)methyl]pyrrolidin-1-yl}phenyl)-2-oxo- 1,2-dihydropyridine-3-carboxylic acid 6-[4-(3-{[benzyl(methyl)amino]methyl}pyrrolidin-1-yl)phenyl]-5-ethyl-4-hydroxy- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-{4-[(3aR,4R,6aS)-4- (methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(1,3'-bipyrrolidin-1'-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
6-{4-[(3aR,4S,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-4- hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-4-hydroxy-5- methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
4-hydroxy-5-methyl-6-{4-[(3aR,4R,7aS)-4-(methylamino)octahydro-2H-isoindol-2- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4R,7aS)-4-(dimethylamino)octahydro-2H-isoindol-2-yl]phenyl}-5-ethyl- 4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4R,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-4- hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4R,6aS)-4-(dimethylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4R,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-(4-{(3aR,7aS)-3a-[(dimethylamino)methyl]octahydro-2H-isoindol-2-yl}phenyl)- 5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-{4-[(3aR,4S,6aS)-4- (methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid 5-ethyl-4-hydroxy-6-{4-[(3aR,4S,7aS)-4-(methylamino)octahydro-2H-isoindol-2- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-4-hydroxy- 2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-{4-[(1R,5S,6s)-6-(methylamino)-3-azabicyclo[3.1.0]hex-3- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[(1R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl- 4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-[4-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)phenyl]-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-{4-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-{4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}-4- hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-{4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(3a-cyanooctahydro-2H-isoindol-2-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(1-amino-3-azabicyclo[3.1.0]hex-3-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(2,8-diazaspiro[4.5]dec-2-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[3-(2-aminopropan-2-yl)pyrrolidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-[4-(4-hydroxypiperidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[4-(benzyloxy)piperidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid 5-ethyl-4-hydroxy-6-[4-(4-methoxypiperidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[4-(dibenzylamino)piperidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(4-aminopiperidin-1-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
5-ethyl-4-hydroxy-2-oxo-6-{4-[3-(pyridin-2-yl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-2-oxo-6-{4-[3-(1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl]phenyl}- 1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-[4-(3-ethyl-3-hydroxypyrrolidin-1-yl)phenyl]-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-[4-(3-hydroxy-3-methylpyrrolidin-1-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[3-(aminomethyl)-3-methylpyrrolidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
6-{4-[3-(dimethylamino)pyrrolidin-1-yl]-2-fluorophenyl}-5-ethyl-4-hydroxy-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-{2-fluoro-4-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl}-4-hydroxy-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
5-ethyl-6-{2-fluoro-4-[(3R)-3-fluoropyrrolidin-1-yl]phenyl}-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]phenyl}-5-ethyl-4- hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-[4-(2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-{4-[(3aR,4R,7aS)-4-(methylamino)octahydro-2H-isoindol-2- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-6-{4-[(3aS)-1,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl]phenyl}-4-hydroxy-2- oxo-1,2-dihydropyridine-3-carboxylic acid
6-[4-(dimethylamino)phenyl]-5-ethyl-4-methoxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-{4-[di(prop-2-en-1-yl)amino]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-{4-[di(prop-2-en-1-yl)amino]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[4-(2,5-dihydro-1H-pyrrol-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[4-(2,5-dihydro-1H-pyrrol-1-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-{4-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-[5-(dimethylamino)thiophen-2-yl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-[5-(dimethylamino)thiophen-2-yl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
5-ethyl-4-hydroxy-2-oxo-6-[5-(pyrrolidin-1-yl)thiophen-2-yl]-1,2-dihydropyridine- 3-carboxylic acid
5-ethyl-2-oxo-6-[5-(piperidin-1-yl)thiophen-2-yl]-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-2-oxo-6-[5-(piperidin-1-yl)thiophen-2-yl]-1,2-dihydropyridine-3- carboxylic acid
6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-(4-tert-butoxyphenyl)-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid 6-(5-(dimethylamino)pyrazin-2-yl)-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-4-hydroxy-2-oxo-6-(5-(pyrrolidin-1-yl)pyrazin-2-yl)-1,2-dihydropyridine-3- carboxylic acid
6-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyrazin-2-yl)-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
4-hydroxy-5-methyl-2-oxo-6-(5-(pyrrolidin-1-yl)pyridin-2-yl)-1,2-dihydropyridine- 3-carboxylic acid
6-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)-4-hydroxy-5-methyl-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
6-(5-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-4-hydroxy-5- methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-(4-((1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-2-methylphenyl)-4- hydroxy-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-(4-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-(4-(2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-(4-(2,7-diazaspiro[4.4]nonan-2-yl)phenyl)-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-(4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-(4-(2,5-diazaspiro[3.4]octan-2-yl)phenyl)-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-(4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-(4-(ethylamino)phenyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid 5-ethyl-4-hydroxy-6-(4-(methylamino)phenyl)-2-oxo-1,2-dihydropyridine-3- carboxylic acid
6-(4-(dimethylamino)phenyl)-4-hydroxy-2-oxo-5-(2-oxoethyl)-1,2-dihydropyridine- 3-carboxylic acid
6-(4-(dimethylamino)phenyl)-4-hydroxy-5-(2-hydroxyethyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-(2,3-dihydroxypropyl)-6-(4-(dimethylamino)phenyl)-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
(E)-6-(4-(dimethylamino)phenyl)-4-hydroxy-2-oxo-5-(prop-1-enyl)-1,2- dihydropyridine-3-carboxylic acid
6-(4-(dimethylamino)phenyl)-4-hydroxy-5-(hydroxymethyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-(4-(dimethylamino)phenyl)-4-hydroxy-5-(methoxymethyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-(4-(dimethylamino)phenyl)-4-hydroxy-2-oxo-5-(prop-1-ynyl)-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-(4-hydroxyphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid
6-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-yl)-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-2-oxo-6-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1,2-dihydropyridine-3- carboxylic acid
6-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-yl)-4-hydroxy-5-methyl-2-oxo- 1,2-dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-(4-(1-methylpiperidin-4-yl)phenyl)-2-oxo-1,2-dihydropyridine- 3-carboxylic acid
5-ethyl-6-(4-(1-ethylpiperidin-4-yl)phenyl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3- carboxylic acid 5-ethyl-4-hydroxy-2-oxo-6-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-(4-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-4-hydroxy-6-(4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-(4-(2-(dimethylamino)ethyl)phenyl)-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-4-hydroxy-6-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid 5-ethyl-4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridine-3- carboxylic acid
5-ethyl-6-(1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrrol-3-yl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrrol-3-yl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-(1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrrol-2-yl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid
6-(5-((dimethylamino)methyl)-1-methyl-1H-pyrrol-2-yl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid
5-ethyl-6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrrol-2-yl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid, and
6-(5-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-1-methyl-1H-pyrrol-2-yl)-5-ethyl- 2-oxo-1,2-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.
10. The method of claim 9, wherein a compound salt or a form thereof is selected from the group consisting of:
5-(aminomethyl)-6-[4-(dimethylamino)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid hydrochloride
5-ethyl-6-[3-fluoro-4-(piperazin-1-yl)phenyl]-2-oxo-1,2-dihydropyridine-3- carboxylic acid trifluoroacetate
5-ethyl-2-oxo-6-[4-(piperazin-1-yl)phenyl]-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-4-hydroxy-2-oxo-6-[4-(piperazin-1-yl)phenyl]-1,2-dihydropyridine-3- carboxylic acid trifluoroacetate
6-[4-(3-aminopyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid trifluoroacetate
6-{4-[(3S)-3-aminopyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid hydrochloride
6-{4-[(3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(3R,4R)-3-amino-4-methoxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(3R,4S)-3-amino-4-methoxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(3R,4S)-3-amino-4-hydroxypyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
6-[4-(2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid trifluoroacetate
5-ethyl-6-{4-[3-(morpholin-4-yl)pyrrolidin-1-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-2-oxo-6-{4-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]phenyl}-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate 6-{4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(3-amino-3-methylpyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid trifluoroacetate
6-[4-(1-amino-3-azabicyclo[3.1.0]hex-3-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[3-(diethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid trifluoroacetate
6-{4-[3-(benzylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid hydrochloride
6-{4-[(1R,5S,6s)-6-(dibenzylamino)-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-2- oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-6-[4-(hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(4-benzylhexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)phenyl]-5-ethyl-2-oxo- 1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-(4-{3-[(dibenzylamino)methyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
6-(4-{3-[(benzylamino)methyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(3-{[benzyl(methyl)amino]methyl}pyrrolidin-1-yl)phenyl]-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-6-(4-{3-[(methylamino)methyl]pyrrolidin-1-yl}phenyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride 6-(4-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-6-{4-[(4aR,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-4(4aH)-yl]phenyl}-2- oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-6-{4-[(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}- 2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[3-(aminomethyl)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid trifluoroacetate
6-{4-[(3aR,6aR)-1-benzylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-6-{4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}-2-oxo- 1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4R,7aS)-4-(dimethylamino)octahydro-2H-isoindol-2-yl]phenyl}-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-(4-{(3aR,4R,7aS)-4-[benzyl(methyl)amino]octahydro-2H-isoindol-2-yl}phenyl)- 5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-6-{4-[(3aR,4R,7aS)-4-(methylamino)octahydro-2H-isoindol-2-yl]phenyl}-2- oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4R,7aS)-4-(dibenzylamino)octahydro-2H-isoindol-2-yl]phenyl}-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4R,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4R,6aS)-4-(dimethylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride 6-{4-[(3aR,4R,6aS)-4-[benzyl(methyl)amino]hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride 5-ethyl-6-{4-[(3aR,4R,6aS)-4-(methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride 6-{4-[(3aR,4R,6aS)-4-(dibenzylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate 6-{4-[(3aR,4R,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4S,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-(4-{(3aR,7aS)-3a-[(dimethylamino)methyl]octahydro-2H-isoindol-2-yl}phenyl)- 5-ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,6aS)-5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}-5-ethyl- 2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-6-{4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}-2-oxo- 1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-6-{4-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}- 2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-6-{4-[(1S,5R,6R)-6-(methylamino)-3-azabicyclo[3.2.0]hept-3-yl]phenyl}-2- oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(1S,5R,6S)-6-amino-3-azabicyclo[3.2.0]hept-3-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-6-[4-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)phenyl]-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(7-amino-5-azaspiro[2.4]hept-5-yl)phenyl]-5-ethyl-2-oxo-1,2-dihydropyridine- 3-carboxylic acid trifluoroacetate
5-ethyl-6-{4-[(3aR,5r,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-(4-{3-[1-(benzylamino)cyclopropyl]pyrrolidin-1-yl}phenyl)-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate 6-{4-[3-(1-aminocyclobutyl)pyrrolidin-1-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
2-[4-(5-carboxy-3-ethyl-6-oxo-1,6-dihydropyridin-2- yl)phenyl]hexahydrocyclopenta[c]pyrrole-3a(1H)-carboxylic acid trifluoroacetate 6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-2-fluorophenyl}-5-ethyl-2- oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4S,7aS)-4-azidooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4S,6aS)-4-azidohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-6-{4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]phenyl}-4- hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(7-amino-5-azaspiro[2.4]hept-5-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-4-hydroxy-6-(4-{3-[(methylamino)methyl]pyrrolidin-1-yl}phenyl)-2-oxo- 1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-4-hydroxy-6-{4-[(3aR,4R,6aS)-4- (methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(1,3'-bipyrrolidin-1'-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylic acid hydrochloride
6-{4-[(3aR,4S,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-4- hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-4-hydroxy-5- methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
4-hydroxy-5-methyl-6-{4-[(3aR,4R,7aS)-4-(methylamino)octahydro-2H-isoindol-2- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(3aR,4R,7aS)-4-(dimethylamino)octahydro-2H-isoindol-2-yl]phenyl}-5-ethyl- 4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride 6-{4-[(3aR,4R,7aS)-4-aminooctahydro-2H-isoindol-2-yl]phenyl}-5-ethyl-4- hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate
6-{4-[(3aR,4R,6aS)-4-(dimethylamino)hexahydrocyclopenta[c]pyrrol-2(1H)- yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(3aR,4R,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride 6-{4-[(3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-5- ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid trifluoroacetate 6-(4-{(3aR,7aS)-3a-[(dimethylamino)methyl]octahydro-2H-isoindol-2-yl}phenyl)- 5-ethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride 5-ethyl-4-hydroxy-6-{4-[(3aR,4S,6aS)-4- (methylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl]phenyl}-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-4-hydroxy-6-{4-[(3aR,4S,7aS)-4-(methylamino)octahydro-2H-isoindol-2- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl-4-hydroxy- 2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-4-hydroxy-6-{4-[(1R,5S,6s)-6-(methylamino)-3-azabicyclo[3.1.0]hex-3- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[(1R,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]phenyl}-5-ethyl- 4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-4-hydroxy-6-[4-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)phenyl]-2-oxo- 1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-4-hydroxy-6-{4-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride
5-ethyl-6-{4-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]phenyl}-4- hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride 6-{4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(3a-cyanooctahydro-2H-isoindol-2-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
6-[4-(1-amino-3-azabicyclo[3.1.0]hex-3-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(2,8-diazaspiro[4.5]dec-2-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
6-{4-[3-(2-aminopropan-2-yl)pyrrolidin-1-yl]phenyl}-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid hydrochloride
6-[4-(2,5-diazabicyclo[2.2.1]hept-2-yl)phenyl]-5-ethyl-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylic acid trifluoroacetate
5-ethyl-4-hydroxy-6-{4-[(3aR,4R,7aS)-4-(methylamino)octahydro-2H-isoindol-2- yl]phenyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride, and
5-ethyl-6-{4-[(3aS)-1,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl]phenyl}-4-hydroxy-2- oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride; wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
11. The method of any of claims ,8 ,9 or10, wherein the effective amount of the
compound is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.
12. The use of claim 1, wherein the compound of claim 1 or a form thereof is used for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof.
13. The use of claim 1, wherein the compound of claim 1 or a form thereof is used in the manufacture of a medicament for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
14. The use of claim 1, wherein the compound of claim 1 or a form thereof is used in a pharmaceutical composition for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of claim 1 or a form thereof in admixture with one or more pharmaceutically acceptable excipient(s).
15. The use of claim 1, wherein the compound of claim 1 or a form thereof is used in a combination therapy for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of claim 1 or a form thereof and an effective amount of one or more antibiotic or antibacterial agent(s).
16. The use of any of claims 12 to 16, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.
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