Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed 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
  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • 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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines 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
  • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present description relates to compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof for treating or ameliorating a bacterial infection. More particularly, the present description relates to compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof for treating or ameliorating a bacterial infection, or for treating or ameliorating a multi-drug resistant (MDR) bacterial infection.
• MDR multi-drug resistant
• the DNA gyrase and topoisomerase IV enzymes are both type II topoisomerases, consisting of two protein subunits active as heterodimers (A 2 B 2 ).
• the ATPase domain resides on one polypeptide (GyrB in DNA gyrase, ParE in topoisomerase IV), while the DNA cleavage core lies on a second polypeptide (GyrA in DNA gyrase, ParC in topoisomerase IV).
• Current therapies including the aminocoumarin novobiocin, function as competitive inhibitors of energy transduction of DNA gyrase by binding to the ATPase active site in GyrB (see, Maxwell, A. The interaction between coumarin drugs and DNA gyrase. Mol. Microbiol. 1993, 9 (4), 681-686; Flatman, R. H.; Eustaquio, A.; Li, S. M.; Heide, L.;
• topoisomerase IV inhibitors obtained by combinatorial biosynthesis. Antimicrob. Agents Chemother. 2006, 50 (4), 1 136-1 142).
• nalidixic acid ciprofloxacin and moxifloxacin preferentially bind these enzymes at the cleavage core (GyrA and ParC) and prevent decatenation of replicating DNA (see, Hooper, D. C. Quinolone mode of action. Drugs 1995, 49 Suppl 2, 10-15).
• Bacterial DNA synthesis inhibitors e.g. fluoroquinolones
• fluoroquinolones have been used to treat primarily Gram-negative infections and have historically achieved outstanding clinical outcomes (see, Emmerson, A.M.; Jones, A.M. The quinolones: decades of development and use. J. Antimicrobial Chemotherapy, 2003, 51 (SI), 13-20).
• a wealth of knowledge exists for the quinolone class of compounds see, Hooper, D. C; Rubinstein, E. Quinolone
• quinolone antibiotics possess a bicyclic (ciprofloxacin and moxifloxacin) or tricyclic ring structure (levofloxacin) with an aryl side chain containing an acyclic ring incorporating an amine functionality.
• the monocyclic 4-pyridone class of molecules generally exhibited poor activity against quinolone-resistant (quin R ) strains, possessed attendant CNS side effects, and in most cases, had only limited in vivo efficacy.
• quin R quinolone-resistant
• Recent studies on monocyclic-4-pyridone analogs see, Laursen, J. B.; Nielsen, J.; Haack, T.; Pusuluri, S.; David, S.; Balakrishna, R.; Zeng, Y.; Ma, Z.; Doyle, T. B.; Mitscher, L. A. Further exploration of antimicrobial
• ketodihydronicotinic acid derivatives by multiple parallel syntheses.
• Comb. Chem. High Throughput. Screen. 2006, 9 (9), 663-681) demonstrate that these compounds elicit cross- resistance to ciprofloxacin and possess poor antibacterial activity against E. coli.
• QPT-1 antibacterial spiro-tricyclic barbituric acid derivatives
• MRSA MRSA
• J. Med. Chem., 2010, 54(9), 3268-3282 have been described as new classes of bacterial topoisomerase inhibitors.
• the X-ray crystallographic structure of GSK299423 bound to DNA gyrase has also been reported (Bax, B. D., et al, 2010).
• Quinolones have been shown to be highly effective in the clinic, but wide-scale deployment of these current drugs, partly due to generic usage of the effective second generation quinolones (e.g., ciprofloxacin), jeopardizes their future long-term utility.
• the effective second generation quinolones e.g., ciprofloxacin
• 6-methoxyquinoline based compounds for use as antibacterial topoisomerase inhibitors possessing Gram-negative activities have been reported by Glaxo-SmithKline, Johnson & Johnson and Novexel. Achillion and Rib-x Pharmaceuticals have also reported isothiazoloquinolones and quinolone (delafloxacin), respectively, that possess activity against resistant Gram-positive strains, including MRSA.
• Other examples in the literature include AM- 1954 (Kyorin), DC- 159a and DX-619 (Diaiichi), JNJ-Q2 (Johnson & Johnson), WQ- 3813 (Wakunaga). However, all these compounds are derived from a quinolone moiety.
• Pfizer, Astra Zeneca, Achaogen and Targanta further describe quinolone-based compounds that possess an expanded spectrum of activity, especially against Gram-positive strains.
• the present description relates to compounds having activity toward wild-type and MDR bacteria.
• the present description also relates to compounds having activity against quinolone-resistant Gram-negative strains (including MDR strains) as well as antibacterial activity to MDR resistant Gram-positive pathogens (including MRSA strains).
• the present description also relates to compounds with selectivity between bacterial topoisomerase IV and DNA gyrase enzyme inhibition compared to human topoisomerase II enzyme inhibition.
• the present description further relates to compounds that may be combined with known antibacterial agents to provide additive or synergistic activity, thus enabling the development of a combination product for the treatment of Gram-negative (especially MDR strains) and Gram-positive infections.
• Ri, R 2 , R3 and R4 are as defined herein, and forms and compositions thereof, and also relates to uses of the compound of Formula (I) and methods of treating or ameliorating a bacterial infection, or for treating or ameliorating a multi-drug resistant (MDR) bacterial infection.
• MDR multi-drug resistant
• the present description further relates to a compound of Formula (I) having activity toward wild-type and MDR bacteria.
• the present description also relates to a compound of Formula (I) having activity against quinolone-resistant Gram-negative strains (including MDR strains) as well as antibacterial activity to MDR resistant Gram-positive pathogens (including MRSA strains).
• the present description also relates to a compound of Formula (I) having selectivity between bacterial topoisomerase IV and DNA gyrase enzyme inhibition compared to human topoisomerase II enzyme inhibition.
• the present description further relates to a compound of Formula (I) that may be combined with known antibacterial agents to provide additive or synergistic activity, thus enabling the development of a combination product for the treatment of Gram-negative (especially MDR strains) and Gram-positive infections.
• Ri is aryl, heterocyclyl and heteroaryl each optionally substituted with one, two or three substituents each selected from R 5 and one additional substituent selected from R 6 , wherein aryl, heterocyclyl and heteroaryl are selected from a bicyclic or tricyclic ring system;
• R2 is hydrogen, halogen, cyano, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl,
• R3 is hydrogen, halogen, hydroxyl, Ci-salkyl, Ci-salkoxy, carboxyl, amino, Ci-salkyl-amino, (Ci- 8 alkyl)2-amino or Ci_ 8 alkyl-S02-amino;
• R4 is hydrogen or Ci-salkyl
• R5 is halogen, hydroxyl, oxo, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl, Ci-salkyl-carbonyl,
• C3-i4cycloalkyl-Ci- 8 alkoxy C3_i4cycloalkyl-amino, C3-i4cycloalkyl-amino-Ci_ 8 alkyl, (C3-i4cycloalkyl,Ci- 8 alkyl)amino-Ci- 8 alkyl, (C3_i4cycloalkyl)2-amino-Ci_ 8 alkyl, C3-i4cycloalkyl-Ci- 8 alkyl-amino-Ci- 8 alkyl,
• aryl-Ci- 8 alkyl-amino-Ci_ 8 alkyl (aryl-Ci- 8 alkyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl,
• aryl-Ci- 8 alkyl 2-amino-Ci_ 8 alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci-salkyl-amino, (heteroaryl-Ci-8alkyl,Ci-8alkyl)amino, (heteroaryl-Ci_ 8 alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl, (heteroaryl-Ci- 8 alkyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-Ci-salkoxy, heterocyclyl-amino,
• heterocyclyl,Ci- 8 alkyl (heterocyclyl,Ci- 8 alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci-salkyl, (heterocyclyl,Ci- 8 alkyl)amino-Ci- 8 alkyl, (heterocyclyl)2-amino-Ci_ 8 alkyl,
• heterocyclyl-Ci- 8 alkyl 2-amino-Ci- 8 alkyl, heterocyclyl-oxy-amino
• heterocyclyl-oxy-Ci- 8 alkyl,Ci- 8 alkyl (heterocyclyl-oxy-Ci- 8 alkyl,Ci- 8 alkyl)amino, heterocyclyl-carbonyl or
• heterocyclyl wherein each instance of heterocyclyl is optionally substituted with one, two or three
• R7 is azido, halogen, hydroxyl, oxo, cyano, nitro, Ci-salkyl, halo-Ci-salkyl,
• Ci-salkyl-carbonyl Ci-salkoxy-carbonyl, amino, Ci_ 8 alkyl-amino, (Ci_ 8 alkyl)2-amino, halo-Ci-salkyl-amino, (halo-Ci- 8 alkyl)2-amino, halo-Ci- 8 alkyl-amino-Ci- 8 alkyl, (halo-Ci- 8 alkyl)2-amino-Ci- 8 alkyl, amino-Ci-salkyl, Ci- 8 alkyl-amino-Ci_ 8 alkyl, (Ci_ 8 alkyl)2-amino-Ci_ 8 alkyl,
• Ci-salkyl-amino-carbonyl Ci-salkyl-amino-carbonyl, (Ci_ 8 alkyl)2-amino-carbonyl,
• Ci_ 8 alkyl-carbonyl-amino (carboxyl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino-carbonyl-amino, C3-i4cycloalkyl, C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino,
• aryl-Ci- 8 alkyl-amino-Ci_ 8 alkyl (aryl-Ci- 8 alkyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl,
• heteroaryl-Ci-8alkyl,Ci-8alkyl)amino (heteroaryl-Ci-8alkyl)2-amino, heteroaryl-Ci- 8 alkyl-amino-Ci_ 8 alkyl, (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl,
• heteroaryl-Ci- 8 alkyl 2 -amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci_ 8 alkyl or heterocyclyl-oxy;
• each instance of aryl is optionally substituted with one substituent selected from R 10 ;
• Rs is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, Ci-salkoxy,
• R9 is amino, Ci-salkyl-amino, (Ci_ 8 alkyl)2-amino, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci- 8 alkyl)2-amino-Ci- 8 alkyl or aryl-Ci-salkyl-amino;
• R11 is halogen, hydroxyl, Ci-salkyl, halo-Ci-salkyl, Ci-salkoxy, Ci-salkoxy-Ci-salkyl,
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein Ri is
• aryl selected from naphthalenyl
• heterocyclyl selected from indolinyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H- benzo[b][l,4]oxazinyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3,4,9-tetrahydro-lH- carbazolyl, 1,2,3,4-tetrahydroquinoxalinyl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, 6,7,8,9-tetrahydropyrido[l,2-a]indolyl, 2,3,4,9-tetrahydro-lH- pyrido[3,4-b]indolyl, 2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indolyl, 1,2,3,4- tetrahydropyrazino[l,2-a]indolyl
• aryl selected from naphthalen-2-yl
• heterocyclyl selected from indolin-5-yl, l,2,3,4-tetrahydroquinolin-6-yl, 3,4-dihydro-2H- benzo[b][l,4]oxazin-7-yl, 2,3-dihydrobenzo[d]oxazol-6-yl, 2,3,4,9-tetrahydro-lH- carbazol-6-yl, l,2,3,4-tetrahydroquinoxalin-6-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-7-yl, 6,7,8,9-tetrahydropyrido[l,2-a]indol-2-yl, 2,3,4,9-tetrahydro-lH- pyrido[3,4-b]indol-7-yl, 2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-7-
• heteroaryl selected from lH-indol-2-yl, lH-indol-3-yl, lH-indol-4-yl, lH-indol-5-yl, 1H- indol-6-yl, lH-indazol-4-yl, lH-indazol-5-yl, lH-indazol-6-yl, 2H-indazol-5-yl, 2H- indazol-6-yl, indolizin-6-yl, benzofuran-5-yl, benzo[b]thien-5-yl, benzo[d]oxazol-6- yl, quinolin-6-yl, quinoxalin-6-yl, 9H-carbazol-2-yl, lH-pyrrolo[2,3-b]pyridin-5-yl, lH-pyrrolo[2,3-b]pyridin-5-yl, lH-pyrrolo
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R 2 , R6, R7 and Rs is
• C3_i 4 cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
• aryl selected in each instance, when present, from phenyl
• heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H-1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, imidazolyl or pyridinyl;
• heterocyclyl selected in each instance, when present, from azetidinyl, pyrrolidinyl,
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R 6 , R7 and Rs is
• heteroaryl selected in each instance, when present, from pyrrol-l-yl, thiazol-2-yl, 1H-1,2,3- triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl;
• heterocyclyl selected in each instance, when present, from azetidin-l-yl, pyrrolidin- 1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl, tetrahydrofuran-2-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, dihydro-lH-imidazol- 2-yl, 1,4,5, 6-tetrahydropyrimidin-2-yl, l,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H- pyran-2-yl, tetrahydro-2H
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R 6 , R7 and Rs is
• heteroaryl selected in each instance, when present, from pyridinyl
• heterocyclyl selected in each instance, when present, from azetidinyl, pyrrolidinyl,
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R 6 , R7 and Rs is
• heteroaryl selected in each instance, when present, from pyridin-2-yl, pyridin-3-yl or
• pyridin-4-yl heterocyclyl selected in each instance, when present, from azetidin-l-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, tetrahydrofuran-2-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, dihydro-lH-imidazol-2-yl, 1,4,5,6- tetrahydropyrimidin-2-yl, l,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, 3 ,
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein, R 6 , R7 and Rs is
• heteroaryl selected in each instance, when present, from pyrrolyl, imidazolyl, IH-tetrazolyl or 2H-tetrazolyl;
• heterocyclyl selected in each instance, when present, from azetidinyl, pyrrolidinyl,
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R 2 , R6, R7 and Rs is
• heteroaryl selected in each instance, when present, from lH-tetrazol-5-yl, imidazol-l-yl, pyrrol- 1-yl or 2H-tetrazol-2-yl;
• heterocyclyl selected in each instance, when present, from azetidin-l-yl, pyrrolidin- 1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl, tetrahydrofuran-2-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, dihydro-lH-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, 3 ,4-dihydrois
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein
• R2 is hydrogen, cyano, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, formyl-Ci-salkyl,
• Ci-salkoxy-Ci-salkyl Ci-salkoxy, C2-salkenyl, C2-salkynl, carboxy, C3_i 4 cycloalkyl, aryl or aryl-Ci-salkyl, wherein each instance of aryl is optionally substituted with one halogen substituent;
• R3 is hydrogen, hydroxyl, carboxyl or amino
• R4 is hydrogen or Ci-salkyl
• R5 is halogen, oxo, cyano, Ci-salkyl, hydroxyl-Ci-salkyl, carboxyl,
• R6 is C3-i4cycloalkyl-amino-Ci- 8 alkyl, (C3-i4cycloalkyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl,
• heteroaryl-Ci- 8 alkyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci_ 8 alkyl, (heterocyclyl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl,
• heterocyclyl wherein each instance of heterocyclyl is optionally substituted with one, two or three
• heteroaryl wherein each instance of heteroaryl is optionally substituted with one, two or three
• R7 is azido, halogen, hydroxyl, cyano, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl,
• Ci-salkoxy-Ci-salkyl Ci-salkoxy, carboxyl, Ci-salkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_ 8 alkyl)2-amino, amino-Ci-salkyl,
• each instance of aryl is optionally substituted with one substituent selected from R 10 ;
• Rs is Ci-salkyl;
• R9 is amino, (Ci_ 8 alkyl) 2 -amino or aryl-Ci-salkyl-amino;
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein
• R 2 is Ci-salkyl selected from methyl, ethyl, propyl or isopropyl; hydroxyl-Ci-salkyl selected from hydroxyl-methyl, hydroxyl-ethyl or hydroxyl-propyl; formyl-Ci-salkyl selected from formylmethyl, formylethyl or formylpropyl; C3_i 4 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; aryl selected from phenyl; and, aryl-Ci-salkyl selected from benzyl;
• R3 is Ci-salkoxy selected from methoxy, ethoxy, propoxy or isopropoxy; or,
• Ci_ 8 alkyl-S0 2 -amino selected from methyl-S0 2 -amino, ethyl-S0 2 -amino, propyl-S0 2 -amino or isopropyl-SCVamino; and,
• R4 is Ci-salkyl selected from methyl, ethyl, propyl or isopropyl.
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein
• R 2 is C3-i 4 cycloalkyl selected from cyclopropyl or cyclobutyl and aryl selected from phenyl;
• R3 is Ci-salkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R 2 is
• Ci-salkyl selected from methyl, ethyl, propyl or isopropyl
• C3-i 4 cycloalkyl selected from cyclopropyl, cyclopentyl or cyclohexyl; or,
• aryl-Ci-salkyl selected from benzyl.
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R 2 is C3_i 4 cycloalkyl selected from cyclopropyl.
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R3 is Ci-salkoxy selected from methoxy or ethoxy .
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R4 is Ci-salkyl selected from methyl.
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein I3 ⁇ 4 is
• C3-i 4 cycloalkyl-amino-Ci_ 8 alkyl wherein C3_i 4 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
• aryl wherein aryl is selected from phenyl
• aryl-amino wherein aryl is selected from phenyl
• aryl,Ci- 8 alkyl (aryl,Ci- 8 alkyl)amino, wherein aryl is selected from phenyl;
• aryl-amino-Ci_ 8 alkyl wherein aryl is selected from phenyl;
• aryl-Ci- 8 alkyl-amino-Ci- 8 alkyl wherein aryl is selected from phenyl;
• aryl-Ci- 8 alkyl 2 -amino-Ci_ 8 alkyl, wherein aryl is selected from phenyl;
• heteroaryl wherein heteroaryl is selected from pyrrolyl, thiazolyl, lH-l,2,3-triazolyl,
• heteroaryl-Ci- 8 alkyl-amino-Ci- 8 alkyl wherein heteroaryl is selected from pyridin-2-yl, pyridin-3-yl or pyridin-4-yl;
• heterocyclyl wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl,
• heterocyclyl-Ci-salkyl wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl,
• heterocyclyl-amino-Ci_ 8 alkyl wherein heterocyclyl is selected from azetidin-l-yl or
• heterocyclyl,Ci- 8 alkyl (heterocyclyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl, wherein heterocyclyl is selected from piperidin-3-yl or piperidin-4-yl;
• heterocyclyl (heterocyclyl,C3-i 4 cycloalkyl-Ci- 8 alkyl)amino-Ci- 8 alkyl, wherein heterocyclyl is selected from piperidin-3-yl or piperidin-4-yl; or,
• heterocyclyl-Ci- 8 alkyl-amino-Ci_ 8 alkyl wherein heterocyclyl is selected from pyrrolidin-2-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl or tetrahydro-2H-pyran-4-yl; and, (heterocyclyl-oxy-Ci-8alkyl,Ci-8alkyl)amino selected from tetrahydro-2H-pyran-2-yl-oxy-
• Ci- 8 alkyl,Ci- 8 alkyl)amino
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein I3 ⁇ 4 is
• heteroaryl wherein heteroaryl is selected from IH-tetrazolyl, imidazolyl, pyrrolyl or
• heterocyclyl selected in each instance, when present, from azetidinyl, pyrrolidinyl,
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R6 is
• heteroaryl wherein heteroaryl is selected from lH-tetrazol-5-yl, imidazol- 1 -yl, pyrrol- 1-yl or 2H-tetrazol-2-yl; and,
• heterocyclyl selected in each instance, when present, from azetidin-l-yl, pyrrolidin- 1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl, tetrahydrofuran-2-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, dihydro-lH-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, 3 ,4-dihydrois
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R 6 is
• heteroaryl wherein heteroaryl is selected from pyridinyl;
• heterocyclyl selected in each instance, when present, from azetidinyl, pyrrolidinyl,
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R 6 is
• heteroaryl selected in each instance, when present, from pyridin-2-yl, pyridin-3-yl or
• heterocyclyl selected in each instance, when present, from azetidin-l-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, tetrahydrofuran-2-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, dihydro-lH-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, 3 ,4-dihydroiso
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R7 is
• C3_i 4 cycloalkyl wherein C3_i 4 cycloalkyl is selected from cyclopropyl or cyclobutyl;
• C3_i 4 cycloalkyl-amino wherein C3_i 4 cycloalkyl is selected from cyclopropyl;
• aryl wherein aryl is selected from phenyl
• aryl-Ci-salkyl wherein aryl is selected from phenyl
• aryl-amino wherein aryl is selected from phenyl
• aryl,Ci- 8 alkyl (aryl,Ci- 8 alkyl)amino, wherein aryl is selected from phenyl;
• aryl-Ci_ 8 alkyl-amino wherein aryl is selected from phenyl;
• aryl-Ci- 8 alkyl,Ci- 8 alkyl)amino wherein aryl is selected from phenyl;
• aryl-Ci_ 8 alkyl 2 -amino, wherein aryl is selected from phenyl;
• aryl-Ci- 8 alkyl-amino-Ci- 8 alkyl wherein aryl is selected from phenyl;
• aryl-Ci- 8 alkyl 2 -amino-Ci_ 8 alkyl, wherein aryl is selected from phenyl;
• aryl-amino-Ci_ 8 alkyl wherein aryl is selected from phenyl;
• aryl-Ci-salkoxy wherein aryl is selected from phenyl
• aryl-Ci_ 8 alkoxy-carbonyl-amino, wherein aryl is selected from phenyl;
• heteroaryl wherein heteroaryl is selected from pyridin-2-yl, pyridin-4-yl, thiazol-2-yl or 1H- 1,2,3-triazol-l-yl;
• heteroaryl-Ci- 8 alkyl-amino-Ci- 8 alkyl wherein heteroaryl is selected from pyridin-2-yl,
• heterocyclyl wherein heterocyclyl is selected from pyrrolidin-l-yl, piperidin-l-yl or
• heterocyclyl-Ci-salkyl wherein heterocyclyl is selected from pyrrolidin-l-yl;
• heterocyclyl-amino-Ci-salkyl wherein heterocyclyl is selected from (lR,5S,6s)-3- azabicyclo[3.1.0]hexan-6-yl; and,
• heterocyclyl-oxy wherein heterocyclyl is selected from tetrahydro-2H-pyran-2-yloxy.
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R7 is
• C3-i 4 cycloalkyl wherein C3-i 4 cycloalkyl is selected from cyclopropyl or cyclobutyl; C3_i 4 cycloalkyl-amino, wherein C3_i 4 cycloalkyl is selected from cyclopropyl;
• aryl wherein aryl is selected from phenyl
• aryl-Ci-salkyl wherein aryl is selected from phenyl
• aryl-amino wherein aryl is selected from phenyl
• aryl,Ci_ 8 alkyl (aryl,Ci_ 8 alkyl)amino, wherein aryl is selected from phenyl;
• aryl-Ci_ 8 alkyl-amino wherein aryl is selected from phenyl;
• aryl-Ci- 8 alkyl,Ci- 8 alkyl)amino wherein aryl is selected from phenyl;
• aryl-Ci_ 8 alkyl 2 -amino, wherein aryl is selected from phenyl;
• aryl-Ci- 8 alkyl-amino-Ci- 8 alkyl wherein aryl is selected from phenyl;
• aryl-Ci- 8 alkyl 2 -amino-Ci_ 8 alkyl, wherein aryl is selected from phenyl;
• aryl-Ci-8alkoxy wherein aryl is selected from phenyl
• aryl-Ci_ 8 alkoxy-carbonyl-amino, wherein aryl is selected from phenyl;
• heteroaryl wherein heteroaryl is selected from pyridin-2-yl, pyridin-4-yl, thiazol-2-yl or 1H- 1,2,3-triazol-l-yl;
• heteroaryl-Ci- 8 alkyl-amino-Ci- 8 alkyl wherein heteroaryl is selected from pyridin-2-yl, pyridin-3-yl or pyridin-4-yl;
• heterocyclyl wherein heterocyclyl is selected from pyrrolidin-l-yl or morpholin-4-yl;
• heterocyclyl-Ci-salkyl wherein heterocyclyl is selected from pyrrolidin-l-yl; and, heterocyclyl-oxy, wherein heterocyclyl is selected from tetrahydro-2H-pyran-2-yloxy.
• One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R7 is
• aryl wherein aryl is selected from phenyl
• aryl-Ci-8alkyl,Ci-8alkyl)amino wherein aryl is selected from phenyl;
• aryl-Ci_ 8 alkyl 2 -amino, wherein aryl is selected from phenyl;
• aryl-amino-Ci_ 8 alkyl wherein aryl is selected from phenyl;
• heteroaryl wherein heteroaryl is selected from pyridin-2-yl or pyridin-4-yl;
• heterocyclyl wherein heterocyclyl is selected from piperidin-l-yl; and,
• heterocyclyl-amino-Ci-salkyl wherein heterocyclyl is selected from (lR,5S,6s)-3- azabicyclo[3.1.0]hexan-6-yl.
• a compound or a form thereof is selected from:
• a compound or a form thereof is selected from:
• the form of the compound is selected from a free acid, free base, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer,
• the compound or a form thereof is isolated for use.
• a compound or a form thereof is selected from:
• the form of the compound is selected from a free acid, free base, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph or tautomer form thereof.
• the compound or a form thereof is isolated for use.
• Ci_i 0 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.
• Ci-ioalkyl includes Ci-salkyl, Ci- 6 alkyl, Ci_ 4 alkyl and the like.
• a Ci-ioalkyl radical may be optionally substituted where allowed by available valences.
• C2- 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.
• C2-salkenyl includes C2- 6 alkenyl, C2- 4 alkenyl and the like.
• a C2-salkenyl radical may be optionally substituted where allowed by available valences.
• C2- 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.
• C2-salkynyl includes C2- 6 alkynyl, C2- 4 alkynyl and the like.
• a C2-salkynyl radical may be optionally substituted where allowed by available valences.
• Ci_ 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-Ci-salkyl, including, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like.
• Ci-salkoxy includes Ci- 6 alkoxy, Ci_ 4 alkoxy and the like.
• a Ci-salkoxy radical may be optionally substituted where allowed by available valences.
• C 3 _i 4 cycloalkyl generally refers to a saturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, lH-indanyl, indenyl, tetrahydro-naphthalenyl and the like.
• C3_i 4 cycloalkyl includes C3_ 8 cycloalkyl, Cs-scycloalkyl, C3_iocycloalkyl and the like.
• a C3_i 4 cycloalkyl radical may be optionally substituted where allowed by available valences.
• C3_i 4 cycloalkenyl generally refers to a partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon radical having one or more chemically stable carbon-carbon double bonds therein, including, without limitation, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the like.
• C3_i 4 cycloalkenyl includes C3_ 8 cycloalkenyl, Cs-scycloalkenyl,
• a C3-iocycloalkenyl 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,
• C2- 8 alkenyl-amino refers to a radical of the formula:
• (C2- 8 alkenyl)2-amino refers to a radical of the formula: -N(C 2 - 8 alkenyl) 2 .
• the term refers to a radical of the formula: -Ci_ 8 alkyl-NH-C 2 - 8 alkenyl.
• (C2- 8 alkenyl)2-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci-8alkyl-N(C2-8alkenyl)2.
• Ci_ 8 alkoxy-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-0-Ci_ 8 alkyl.
• Ci_ 8 alkoxy-Ci_ 8 alkyl-amino refers to a radical of the formula: -0-Ci_ 8 alkyl-NH-Ci_ 8 alkyl-0-Ci_ 8 alkyl.
• (Ci_ 8 alkoxy-Ci_ 8 alkyl)2-amino refers to a radical of the formula: -N(C 1-8 alkyl-0-C 1-8 alkyl) 2 .
• Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl refers to a radical of the formula: -d-galkyl- H-d-galkyl-O-d-galkyl.
• (Ci- 8 alkoxy-Ci- 8 alkyl)2-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci-8alkyl-N(Ci-8alkyl-0-Ci_8alkyl)2.
• (Ci- 8 alkoxy-Ci- 8 alkyl,Ci_ 8 alkyl)-amino refers to a radical of the formula: -N[(Ci_ 8 alkyl)(-Ci_ 8 alkyl-0-Ci_ 8 alkyl)].
• (Ci- 8 alkoxy-Ci- 8 alkyl,Ci- 8 alkyl)-amino-Ci- 8 alkyl refers to a radical of the formula: -Ci- 8 alkyl-N[(Ci- 8 alkyl)(-Ci- 8 alkyl-0-Ci_ 8 alkyl)].
• Ci_ 8 alkoxy-carbonyl refers to a radical of the formula: -C(0)-0-Ci_ 8 alkyl.
• Ci-salkyl-amino refers to a radical of the formula:
• (Ci_ 8 alkyl) 2 -amino refers to a radical of the formula:
• Ci_ 8 alkyl-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci-salkyl-NH-Ci-salkyl.
• (Ci- 8 alkyl) 2 -amino-Ci- 8 alkyl refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl) 2 .
• Ci_ 8 alkyl-amino-Ci_ 8 alkyl-amino refers to a radical of the formula: -NH-C 1-8 alkyl-NH-C 1-8 alkyl.
• (Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl-amino refers to a radical of the formula: -NH-Ci_ 8 alkyl-N(Ci_ 8 alkyl) 2 .
• Ci-salkyl-amino-Ci-salkyl-amino-Ci-salkyl refers to a radical of the formula: -Ci-salkyl-NH-Ci-salkyl-NH-Ci-salkyl.
• (Ci- 8 alkyl) 2 -amino-Ci_ 8 alkyl-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci- 8 alkyl-NH-Ci- 8 alkyl-N(Ci- 8 alkyl) 2 .
• (Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino refers to a radical of the formula: -N[(C 1-8 alkyl)(-C 1-8 alkyl- H-C 1-8 alkyl)].
• the term ' 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-N(C 1-8 alkyl) 2 )].
• Ci_ 8 alkyl-amino-carbonyl refers to a radical of the formula: -C(0)-NH-Ci_ 8 alkyl.
• (Ci_ 8 alkyl) 2 -amino-carbonyl refers to a radical of the formula: -C(0)-N(C 1-8 alkyl) 2 .
• Ci_ 8 alkyl-carbonyl refers to a radical of the formula:
• Ci_ 8 alkyl-carbonyl-amino refers to a radical of the formula: -NH-C(0)-Ci_ 8 alkyl.
• (Ci_ 8 alkyl-carbonyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-N[(Ci_ 8 alkyl)(-C(0)-Ci_ 8 alkyl)].
• C h alky 1-thio refers to a radical of the formula:
• C2- 8 alkynyl-Ci- 8 alkyl refers to a radical of the formula:
• C2- 8 alkynyl-amino refers to a radical of the formula:
• (C2- 8 alkynyl)2-amino refers to a radical of the formula: -N(C 2 -8alkynyl) 2 .
• C2- 8 alkynyl-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-NH-C2- 8 alkynyl.
• (C2- 8 alkynyl)2-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_8alkyl- (C2-8alkynyl)2.
• amino refers to a radical of the formula: -NH2.
• amino-Ci-salkyl refers to a radical of the formula:
• amino-Ci-salkyl-amino refers to a radical of the formula: -NH-Ci_ 8 alkyl-NH 2 .
• amino-Ci_ 8 alkyl refers to a radical of the formula:
• amino-Ci-salkyl-amino-Ci-salkyl refers to a radical of the formula: -Ci_ 8 alkyl-NH-Ci_ 8 alkyl-NH 2 .
• amino-Ci- 8 alkyl,Ci_ 8 alkyl)amino refers to a radical of the formula: -N[(Ci_8alkyl)(-Ci_8alkyl-NH 2 )].
• amino-Ci- 8 alkyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-N[(Ci_ 8 alkyl)(-Ci_ 8 alkyl-NH 2 )].
• amino-carbonyl refers to a radical of the formula:
• aryl-Ci-salkoxy refers to a radical of the formula:
• aryl-Ci-salkoxy-carbonyl-amino refers to a radical of the formula: -NH-C(0)-0-C 1-8 alkyl-aiyl.
• aryl-Ci-salkyl refers to a radical of the formula:
• aryl-Ci-salkyl-amino refers to a radical of the formula: -NH-Ci_ 8 alkyl-aryl.
• (aryl-Ci_ 8 alkyl) 2 -amino refers to a radical of the formula: -N[(-Ci_ 8 alkyl-aryl) 2 ].
• aryl-Ci-salkyl-amino-Ci-salkyl refers to a radical of the formula: -Ci-salkyl-NH-Ci-salkyl-aryl.
• (aryl-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_8alkyl-N[(-Ci_8alkyl-aryl) 2 ].
• (aryl,Ci-8alkyl)amino refers to a radical of the formula:
• (aryl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci- 8 alkyl-N[(Ci- 8 alkyl)(aryl)].
• (aryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino refers to a radical of the formula: -N[(C 1-8 alkyl)(-C 1-8 alkyl-aiyl)].
• (aryl-Ci- 8 alkyl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci- 8 alkyl-N[(Ci_ 8 alkyl)(-Ci_ 8 alkyl-aryl)].
• aryl-amino refers to a radical of the formula: -NH-aryl.
• aryl 2 -amino refers to a radical of the formula: -N[(aryl) 2 ].
• aryl-amino-Ci-salkyl refers to a radical of the formula:
• (aryl) 2 -amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci -8 alkyl-N[(aiyl) 2 ].
• aryl-amino-carbonyl refers to a radical of the formula: -C(0)-NH-aryl.
• carboxyl refers to a radical of the formula: -COOH, -C(0)OH or -C0 2 H.
• (carboxyl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino-carbonyl-amino refers to a radical of the formula: - H-C(0)-N[(C 1-8 alkyl)(-C 1-8 alkyl-C02H)].
• C3_i4cycloalkyl-Ci_ 8 alkoxy refers to a radical of the formula: -0-Ci_ 8 alkyl-C3_i4cycloalkyl.
• C3_i4cycloalkyl-Ci_ 8 alkyl refers to a radical of the formula: -Ci- 8 alkyl-C3_i4cycloalkyl.
• C3_i4cycloalkyl-amino refers to a radical of the formula:
• C3_i4cycloalkyl-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-NH-C3_i4cycloalkyl.
• (C3_i4cycloalkyl)2-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci-8alkyl-N[(C3-i4cycloalkyl)2].
• C3_i4cycloalkyl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci- 8 alkyl-NH-Ci_ 8 alkyl-C3_i4cycloalkyl.
• (C3_i4cycloalkyl-Ci- 8 alkyl) 2 -amino-Ci- 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-N[(-Ci_ 8 alkyl-C3_i4cycloalkyl)2].
• (C3-i4cycloalkyl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci- 8 alkyl-N[(Ci_ 8 alkyl)(C 3 _i4cycloalkyl)].
• (C3_i4cycloalkyl-Ci- 8 alkyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci- 8 alkyl-N[(Ci_ 8 alkyl)(-Ci- 8 alkyl-C3_i4cycloalkyl)].
• C3_i4cycloalkyl-oxy refers to a radical of the formula: -0-C3_i4cycloalkyl.
• -Ci_ 8 alkyl-C(0)-H including, without limitation, formylmethyl (also referred to as 2-oxoethyl or formylmethyl), 2-formyl-ethyl (also referred to as 3-oxopropyl or formylethyl), 3-formyl-propyl (also referred to as 4-oxobutyl or formylpropyl), 4-formyl-butyl (also referred to as 5-oxopentyl or formylpropyl) and the like.
• formylmethyl also referred to as 2-oxoethyl or formylmethyl
• 2-formyl-ethyl also referred to as 3-oxopropyl or formylethyl
• 3-formyl-propyl also referred to as 4-oxobutyl or formylpropyl
• 4-oxobutyl or formylpropyl also referred to as 5-oxopentyl or formylpropyl
• halo or halogen generally refers to a halogen atom radical, including fluoro, chloro, bromo and iodo.
• halo-Ci-salkoxy refers to a radical of the formula:
• Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms, including, without limitation, fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy or trifluoroethoxy and the like.
• difluoroethoxy includes 2,2- difluoroethoxy, 1 ,2-difluoroethoxy or 1, 1-difluoroethoxy and the like.
• halo-Ci-salkoxy includes halo-Ci- 6 alkoxy, halo-Ci-4alkoxy and the like.
• halo-Ci-salkyl refers to a radical of the formula:
• Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms, including, without limitation, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, fluoroisopropyl, difluoroisopropyl, trifluoroisopropyl, fluoro-tert-butyl, difluoro-tert-butyl, trifluoro-tert-butyl and the like.
• difluoroethyl includes 2,2- difluoroethyl, 1,2-difluoroethyl or 1, 1 -difluoroethyl and the like; difluoroisopropyl includes l,3-difluoropropan-2-yl and the like; trifluoroisopropyl includes l, l,l-trifluoropropan-2-yl and the like; trifluoro-tert-butyl includes l, l, l-trifluoro-2-methylpropan-2-yl and the like.
• halo-Ci-salkyl includes halo-Ci- 6 alkyl, halo-Ci-4alkyl and the like.
• halo-Ci-salkyl-amino refers to a radical of the formula: -NH-Ci_ 8 alkyl-halo.
• (halo-C h alky l)2-amino refers to a radical of the formula: -N(Ci_ 8 alkyl-halo) 2 .
• halo-Ci-salkyl-amino-Ci-salkyl refers to a radical of the formula: -NH-Ci-salkyl-halo.
• halo-Ci_ 8 alkyl)2-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl-halo)2.
• heteroaryl-Ci-salkyl refers to a radical of the formula:
• heteroaryl-amino refers to a radical of the formula:
• (heteroaryl) 2 -amino refers to a radical of the formula: -N[(heteroaryl) 2 ].
• heteroaryl-Ci-salkyl-amino refers to a radical of the formula: -NH-Ci-salkyl-heteroaryl.
• heteroaryl-Ci_ 8 alkyl 2 -amino refers to a radical of the formula: -N[(-Ci_8alkyl-heteroaryl)2].
• heteroaryl-Ci-salkyl-amino-Ci-salkyl refers to a radical of the formula: -Ci-salkyl-NH-Ci-salkyl-heteroaryl.
• heteroaryl-Ci- 8 alkyl 2 -amino-Ci- 8 alkyl refers to a radical of the formula: -Ci_8alkyl-N[(-Ci_8alkyl-heteroaryl)2].
• heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino refers to a radical of the formula: -N[(Ci_ 8 alkyl)(-Ci_ 8 alkyl-heteroaryl)].
• heteroaryl-Ci- 8 alkyl,Ci- 8 alkyl)amino-Ci- 8 alkyl refers to a radical of the formula: -Ci- 8 alkyl-N[(Ci_ 8 alkyl)(-Ci_ 8 alkyl-heteroaryl)].
• heterocyclyl-Ci-salkoxy refers to a radical of the formula: -0-Ci-8alkyl-heterocyclyl.
• heterocyclyl-Ci-salkyl refers to a radical of the formula: -Ci_ 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-Ci-salkyl refers to a radical of the formula: -Ci-salkyl-NH-heterocyclyl.
• (heterocyclyl) 2 -amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_8alkyl-N[(heterocyclyl)2].
• heterocyclyl-Ci-salkyl-amino-Ci-salkyl refers to a radical of the formula: -Ci-salkyl-NH-Ci-salkyl-heterocyclyl.
• (heterocyclyl-Ci_ 8 alkyl)2-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_8alkyl-N[(-Ci_8alkyl-heterocyclyl)2].
• heterocyclyl,Ci_ 8 alkyl)amino refers to a radical of the formula: -N[(Ci_ 8 alkyl)(heterocyclyl)].
• heterocyclyl,Ci- 8 alkyl)amino-Ci- 8 alkyl refers to a radical of the formula: -Ci- 8 alkyl-N[(Ci_ 8 alkyl)(heterocyclyl)].
• heterocyclyl-Ci- 8 alkyl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci- 8 alkyl-N[(Ci- 8 alkyl)(-Ci_ 8 alkyl-heterocyclyl)].
• heterocyclyl,C3-i4cycloalkyl-Ci- 8 alkyl)amino-Ci- 8 alkyl refers to a radical of the formula: -Ci- 8 alkyl-N[(heterocyclyl)(-Ci- 8 alkyl-C3_i4cycloalkyl)].
• heterocyclyl-carbonyl refers to a radical of the formula: -C(0)-heterocyclyl.
• heterocyclyl-carbonyl-oxy refers to a radical of the formula: -0-C(0)-heterocyclyl.
• heterocyclyl-oxy refers to a radical of the formula:
• heterocyclyl-oxy-amino refers to a radical of the formula: -NH-O-heterocyclyl.
• heterocyclyl-oxy refers to a radical of the formula: -N[(-0-heterocyclyl)2].
• heterocyclyl-oxy,Ci_ 8 alkyl)amino refers to a radical of the formula: -N[(Ci_ 8 alkyl)(-0-heterocyclyl)].
• heterocyclyl-oxy-Ci_ 8 alkyl,Ci_ 8 alkyl)amino refers to a radical of the formula: -N[(Ci_ 8 alkyl)(-Ci_ 8 alkyl-0-heterocyclyl)].
• hydroxyl-Ci-salkoxy refers to a radical of the formula:
• Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
• hydroxyl-Ci-salkyl refers to a radical of the formula: -Ci-salkyl-OH, wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
• hydroxyl-amino refers to a radical of the formula:
• hydroxyl-Ci-salkyl-amino refers to a radical of the formula: -NH-Ci-salkyl-OH, wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
• (hydroxyl-Ci_ 8 alkyl) 2 -amino refers to a radical of the formula: -N(Ci_ 8 alkyl-OH) 2 , wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
• hydroxyl-Ci-salkyl-amino-Ci-salkyl refers to a radical of the formula: -Ci-salkyl-NH-Ci-salkyl-OH, wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
• hydroxyl-Ci-salkyl-amino-Ci-salkyl-amino refers to a radical of the formula: -NH-Ci-salkyl-NH-Ci-salkyl-OH, wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
• hydroxyl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino refers to a radical of the formula: -N[(Ci_ 8 alkyl)(Ci_ 8 alkyl-OH)], wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
• hydroxyl-Ci- 8 alkyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci- 8 alkyl-N[(Ci- 8 alkyl)(Ci- 8 alkyl-OH)], wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
• hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl-amino refers to a radical of the formula: -NH-Ci- 8 alkyl-N[(Ci- 8 alkyl)(Ci_ 8 alkyl-OH)], wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
• Ci- 8 alkyl,Ci_ 8 alkyl)amino- Ci- 8 alkyl,Ci- 8 alkyl)amino refers to a radical of the formula: -N[(Ci_ 8 alkyl)(-Ci_ 8 alkyl- N[(Ci- 8 alkyl)(Ci_ 8 alkyl-OH)])], wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
• hydroxyl-Ci- 8 alkyl-amino-Ci- 8 alkyl,Ci_ 8 alkyl)amino refers to a radical of the formula: -N[(Ci- 8 alkyl)(-Ci- 8 alkyl-NH-Ci_ 8 alkyl-OH)], wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
• substituted means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
• any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown.
• the term "and the like,” with reference to the definitions of chemical terms provided herein, means that variations in chemical structures that could be expected by one skilled in the art include, without limitation, isomers (including chain, branching or positional structural isomers), hydration of ring systems (including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations where allowed by available valences which result in a stable compound.
• each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.
• the terms "independently selected,” or “each selected” refer to functional variables in a substituent list that may occur more than once on the structure of Formula (I), 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 when used in a phrase such as "...aryl, aryl-Ci_ 8 alkyl, heterocyclyl and heterocyclyl-Ci-salkyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one or two substituents" (emphasis added) is intended to optionally include substitution on each appearance of aryl and heterocyclyl, whether the ring is a primary or secondary substituent, that is, where the the aryl and heterocyclyl rings are the primary (first) substituent or where the primary substituent is Ci-salkyl and the aryl and heterocyclyl rings are the secondary (second) substituent, as in, for example, aryl-Ci-salkyl and heterocyclyl-Ci-salkyl.
• 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.
• a compound of Formula (la) refers to a sub-genus of the compound of Formula (I) or a form thereof. Rather than repeat embodiments for a compound of Formula (la), in certain embodiments, the term "a compound of Formula (I) or a form thereof is used to refer to a compound of Formula (la) or a form thereof. Thus, embodiments and references to "a compound of Formula (I)" are intended to include compounds of Formula (la).
• form means a compound of Formula (I) isolated for use selected from a free acid, free base, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph or 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 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. In certain embodiments described herein, the form of the compound of Formula (I) is a pharmaceutically acceptable form.
• the compound of Formula (I) or a form thereof is isolated for use.
• isolated means the physical state of a compound of
• Formula (I) 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.
• a synthetic process e.g., from a reaction mixture
• natural source or combination thereof e.g., chromatography, recrystallization and the like
• protected means that a functional group in a compound of Formula (I) 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.
• 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.
• metabolic and/or non-metabolic chemical processes e.g., by hydrolysis and/or metabolism in blood, liver and/or other organs and tissues.
• 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 when a compound of Formula (I) or a form thereof contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a functional group such as alkyl or carbonyloxy and the like.
• a prodrug when a compound of Formula (I) or a form thereof contains an amine functional group, a prodrug can be formed by the replacement of one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl.
• 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.
• solvate encompasses both solution-phase and isolatable solvates.
• 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), 601-61 1 (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) herein is understood to include reference to salts thereof, unless otherwise indicated.
• salt(s) 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) contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts”) may be formed and are included within the term “salt(s)" as used herein.
• salts of the compounds of the Formula (I) may be formed, for example, by reacting a compound of Formula (I) 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, acid phosphate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, hydrobromide,
• hydrochloride dihydrochloride, hydroiodide, isonicotinate, lactate, maleate,
• acid addition salts include chloride, hydrobromide, hydrochloride, dihydrochloride, acetate or trifluoroacetic acid salts.
• Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
• Certain compounds of 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 others.
• 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
• 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.
• the compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms.
• the present description is intended to include all stereoisomeric forms of the compounds of Formula (I) 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 (5) enantiomers (when one chiral center is present).
• the compounds described herein are (5) isomers and may exist as enantiomerically pure compositions substantially comprising only the (5) 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) is a substantially pure (S) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
• a compound of Formula (I) is a substantially pure (R) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
• racemate is any mixture of isometric forms that are not
• “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.
• the present description embraces all geometric and positional isomers.
• a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the description.
• Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by use of chiral HPLC column or other chromatographic methods known to those skilled in the art.
• Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
• an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
• converting e.g., hydrolyzing
• some of the compounds of Formula (I) 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
• 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).
• 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 H 2 , H 3 , C 13 , C 14 , N 15 , O 18 , O 17 , P 31 , P 32 , S 35 , F 18 , CI 35 and CI 36 , 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., H 3 ) and carbon- 14 (i.e., C 14 ) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., H 2 ) 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 further relates to uses of the compound of Formula (I) and methods of treating or ameliorating a bacterial infection, or of treating or ameliorating a multi-drug resistant (MDR) bacterial infection.
• MDR multi-drug resistant
• the present description further relates to uses of the compound of Formula (I) having activity toward wild-type and MDR bacteria.
• the present description also relates to uses of the compound of Formula (I) having activity against quinolone-resistant Gram-negative strains (including MDR strains) as well as antibacterial activity to MDR resistant Gram- positive pathogens (including MRSA strains).
• the present description also relates to uses of the compound of Formula (I) having selectivity between bacterial topoisomerase IV and
• DNA gyrase enzyme inhibition compared to human topoisomerase II enzyme inhibition.
• the present description further relates to uses of the compound of Formula (I) that may be combined with known antibacterial agents to provide additive or synergistic activity, thus enabling the development of a combination product for the treatment of Gram-negative (especially MDR strains) and Gram-positive infections.
• the compounds of the present description inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV, and, thus, may be used for the treatment of infections caused by Gram-negative and Gram-positive pathogens.
• the instant compounds possess in vitro antibacterial activity against a wide spectrum of bacteria which have developed resistance to almost all known treatments, including MDR Gram-negative and MDR Gram-positive pathogens and successfully effect the treatment of bacterial infections compared to current antibacterial agents that target the same enzymes.
• the compounds are also effective in vivo and lack cellular toxicity.
• the instant compounds are amenable to combination therapy with current standards of care, having demonstrated additive and synergistic activity with one or more fluoroquinolone based antibacterial agents.
• the demonstrated additive and synergistic activity of the compounds indicates a mechanistically alternate binding in conjunction with the DNA gyrase and topoisomerase IV targets.
• the present description relates to methods of using a compound of Formula (I) for treating or ameliorating a bacterial infection, or for using a compound of Formula (I) for treating or ameliorating a multidrug resistant bacterial infection.
• compounds that selectively treat or ameliorate a bacterial infection have been identified and methods of using these compounds for treating or ameliorating a bacterial infection or disorders or symptoms associated therewith are provided.
• One embodiment of the present description relates to a method of treating or ameliorating a bacterial infection 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 present description relates to a method of treating or ameliorating a bacterial infection resulting from a bacteria that is a Gram-negative or Gram- positive type 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 present description relates to a method of treating or ameliorating a bacterial infection resulting from a bacteria that is a resistant Gram-negative or Gram-positive type 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 present description relates to a use of a compound of Formula (I) or a form thereof for treating or ameliorating a bacterial infection in a subject in need thereof comprising administering an effective amount of the compound to the subject.
• (I) or a form thereof for treating or ameliorating a bacterial infection resulting from a bacteria that is a Gram-negative or Gram-positive type in a subject in need thereof comprising administering an effective amount of the compound to the subject.
• An embodiment of the present description relates to a use of a compound of Formula (I) or a form thereof for treating or ameliorating a bacterial infection resulting from a bacteria that is a resistant Gram-negative or Gram-positive type in a subject in need thereof comprising administering an effective amount of the compound to the subject.
• An embodiment of the present description relates to a use of a compound of Formula (I) or a form thereof in the manufacture of a medicament for treating or ameliorating a bacterial infection in a subject in need thereof comprising administering an effective amount of the medicament to the subject.
• An embodiment of the present description relates to a use of a compound of Formula (I) or a form thereof in the manufacture of a medicament for treating or ameliorating a bacterial infection resulting from a bacteria that is a Gram-negative or Gram-positive type in a subject in need thereof comprising administering an effective amount of the compound to the subject.
• An embodiment of the present description relates to a use of a compound of Formula (I) or a form thereof in the manufacture of a medicament for treating or ameliorating a bacterial infection resulting from a bacteria that is a resistant Gram-negative or Gram-positive type in a subject in need thereof comprising administering an effective amount of the compound to the subject.
• An embodiment of the present description relates to a use of a compound of Formula (I) or a form thereof in the preparation of a pharmaceutical kit comprising the compound of Formula (I) or a form thereof and instructions for administering the compound for treating or ameliorating a bacterial infection in a subject in need thereof.
• Another embodiment of the present description relates to the use of a compound of Formula (I) or a form thereof for treating or ameliorating a bacterial infection by selectively inhibiting DNA gyrase and topoisomerase IV compared to human topoisomerase II.
• An embodiment of the present description relates to a method of treating or ameliorating a bacterial infection or disorders or symptoms associated therewith in a subject in need thereof comprising administering an effective amount of a compound of Formula (I) or a form thereof to the subject.
• Formula (I) or a form thereof in the manufacture of a medicament for treating or ameliorating bacterial infection or disorders or symptoms associated therewith in a subject in need thereof comprising administering an effective amount of the medicament to the subject.
• An embodiment of the present description relates to the use of a compound of Formula (I) or a form thereof in the preparation of a pharmaceutical kit comprising the compound of Formula (I) or a form thereof and instructions for administering the compound for treating or ameliorating a bacterial infection or disorders or symptoms associated therewith in a subject in need thereof.
• the subject is treatment naive. In another respect, for each of such embodiments, the subject is not treatment naive.
• treating refers to: (i) preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having the disease, disorder and/or condition; (ii) inhibiting a disease, disorder or condition, i.e., arresting the development thereof; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
• the term "subject” refers to an animal or any living organism having sensation and the power of voluntary movement, and which requires oxygen and organic food. Nonlimiting examples include members of the human, equine, porcine, bovine, murine, 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 relates to a method of treating or ameliorating a bacterial infection resulting from a bacteria that is a Gram-negative or Gram-positive type.
• Another aspect of the description relates to a method of treating or ameliorating a bacterial infection resulting from bacteria that is a resistant Gram-negative or Gram-positive type.
• Another aspect of the description particularly relates to a method of treating or ameliorating a bacterial infection by a wild type bacteria that is resistant to a currently available antibacterial agent, in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I) or a form thereof.
• bacterial infections intended to be included within the scope of the description include bacterial infections resulting from a bacteria of the phyla including, but not limited to, Acidobacteria; Actinobacteria; Aquificae; Bacteroidetes; Caldiserica;
• Chlamydiae Chlorobi; Chloroflexi; Chrysiogenetes; Cyanobacteria; Deferribacteres;
• Spirochaetes Synergistetes; Tenericutes; Firmicutes; Thermodesulfobacteria;
• Thermomicrobia Thermotogae; or Verrucomicrobia.
• the listing of phyla is obtained from the List of Prokaryotic Names with Standing in Nomenclature (LPSN) (see,

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