WO2016109706A1 - Fused polycyclic 2-pyridinone antibacterial compounds - Google Patents

Fused polycyclic 2-pyridinone antibacterial compounds Download PDF

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WO2016109706A1
WO2016109706A1 PCT/US2015/068119 US2015068119W WO2016109706A1 WO 2016109706 A1 WO2016109706 A1 WO 2016109706A1 US 2015068119 W US2015068119 W US 2015068119W WO 2016109706 A1 WO2016109706 A1 WO 2016109706A1
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alkyl
amino
oxo
hydroxy
carboxylic acid
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PCT/US2015/068119
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French (fr)
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Aleksey I. GERASYUTO
Michael A. ARNOLD
Guangming Chen
Gary Mitchell Karp
Hongyan Qi
Anthony A. Turpoff
Jiashi WANG
Matthew G. WOLL
Arthur A. Branstrom
Jana Narasimhan
Melissa L. DUMBLE
Jean Hedrick
Maria L. WEETALL
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Ptc Therapeutics, Inc.
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Publication of WO2016109706A1 publication Critical patent/WO2016109706A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the present description relates to fused polycyclic 2-pyridinone compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof for treating or ameliorating Neisseria gonorrhoeae
  • N. gonorrhoeae Neisseria meningitidis
  • N. meningitidis Neisseria meningitidis
  • the present description relates to fused tricyclic and tetracyclic 2-pyridinone compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae or N. meningitidis.
  • Neisseria is a large genus of generally commensal Gram-negative bacteria that colonize the mucosal surfaces of many animals, with N. gonorrhoeae and N. meningitidis being two of the pathogenic Neisseria species.
  • 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 just the United States every year. An exclusively human pathogen, N.
  • meningitidis is commonly associated with the flora of the nasopharynx. Although usually considered non-pathogenic, it is opportunistic, having the ability to cause meningitis and sepsis. Individuals who are immunocompromised are most at risk of infection. One in every 100,000 individuals in the United States are estimated to become infected every year, with children under the age of five being especially vulnerable. An infected individual requires rapid antibiotic intervention before potentially fatal bacterial dissemination occurs.
  • N. gonorrhoeae 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 11 ) and about 13% is estimated to be quinolone resistant (quinolone R ). The level of quinolone resistance in Taiwan and China is about 90% (Morbidity and Mortality Weekly, Feb 15, 2013).
  • Other forms of drug-resistant N. gonorrhoeae include streptomycin-resistant (streptomycin 11 ), ciprofloxacin-resistant (ciprofloxacin 11 ) and ampicillin-resistant (ampicillin R ).
  • ceftriaxone (a)
  • cephalosporin is the drug of last resort for treating N. gonorrhoeae.
  • 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.
  • 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.
  • CDC Centers for Disease Control
  • fused polycyclic 2-pyridinone compounds selected from a fused tricyclic compound of Formula (la) or fused tetracyclic compounds of Formula (lb) or Formula (Ic):
  • X, Y, Ao, Ai, A 2 , A3 and A 4 are as defined herein, and forms and compositions thereof, and also relates to uses of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof and methods for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae) or Neisseria meningitidis (N. meningitidis) in a subject in need thereof, comprising, administering an effective amount of the compound to the subject.
  • N. gonorrhoeae Neisseria gonorrhoeae
  • Neisseria meningitidis Neisseria meningitidis
  • the present description relates to a compound of Formula (la), Formula (lb), and Formula (Ic) and forms and compositions thereof, and to uses of a compound of Formula (la), Formula (lb), or Formula (Ic) and forms and compositions thereof, and methods for treating or ameliorating N. meningitidis in a subject in need thereof, comprising, administering an effective amount of the compound, and forms and compositions thereof, to the subject.
  • the present description further relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof having activity against wild-type or drug-resistant forms of N. gonorrhoeae or N. meningitidis. More particularly, the present description relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof having activity against wild-type forms of N. gonorrhoeae or N. meningitidis.
  • the present description also relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof having activity against drug-resistant forms of N. gonorrhoeae or N. meningitidis.
  • the present description also relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof having activity against N. gonorrhoeae resistant to one or more known antibacterial or antibiotic agents, wherein drug resistance may be classified as intermediate resistance (IR), high level resistance (HLR), multi-drug resistant (MDR), multidrug intermediate resistant (MD R) or extensively drug resistant (XDR).
  • IR intermediate resistance
  • HLR high level resistance
  • MDR multi-drug resistant
  • MD R multidrug intermediate resistant
  • XDR extensively drug resistant
  • the present description relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof having activity against a IR, HLR, MDR, MD ! R or XDR form of N. gonorrhoeae.
  • the present description also relates to a compound of Formula (la), Formula (lb), and
  • the present description further relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof in combination with known agents having additive or synergistic activity, thus providing a combination product for the treatment of
  • the present description further relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating wild-type or drug- resistant forms of N. gonorrhoeae.
  • the present description relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating N. gonorrhoeae resistant to one or more known antibacterial or antibiotic agents, wherein drug resistance may be classified as intermediate resistance (IR), high level resistance (HLR), multi-drug resistant (MDR), multi-drug intermediate resistant (MD ! R) or extensively drug resistant (XDR).
  • IR intermediate resistance
  • HLR high level resistance
  • MDR multi-drug resistant
  • MD ! R multi-drug intermediate resistant
  • XDR extensively drug resistant
  • the present description relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating IR, HLR, MDR, MD ! R or XDR forms of N. gonorrhoeae.
  • the present description also relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating an aminoglycoside - resistant, beta-lactam-resistant, cephalosporin-resistant, macrolide-resistant, quinolone- resistant or tetracycline-resistant form of N. gonorrhoeae.
  • the present description further relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) 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 or N. meningitidis N. gonorrhoeae or N. meningitidis.
  • fused polycyclic 2-pyridinone compounds selected from a fused tricyclic compound of Formula (la) or fused tetracyclic compounds of Formula (lb) or Formula (Ic):
  • the dashed lines represent one or more double bonds optionally present where allowed by available valences
  • Ai, A 2 , A3, and A 4 are independently C or N; wherein, Ai and A2 are not simultaneously N; Ao is independently C(R 5 ), CH(Rs), N or N(R 5 ), where allowed by available valences;
  • Y is -CH(R 2 , -N(R 2 , -O- or -S-;
  • R 2 is hydrogen or Ci-salkyl
  • R5 is hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl Ci-salkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl,
  • Ci_ 8 alkyl-carbonyl Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
  • Ci- 8 alkoxy-carbonyl-Ci_ 8 alkyl Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
  • Ci- 8 alkoxy-Ci_ 8 alkyl-amino (Ci- 8 alkoxy-Ci_ 8 alkyl,Ci_ 8 alkyl)-amino,
  • 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_ 8 alkyl-amino, (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl 2 -amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
  • heteroaryl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_ 8 alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_ 8 alkyl)amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-Ci_ 8 alkyl, (heterocyclyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl, (heterocyclyl) 2 -amino, heterocyclyl-amino-Ci_ 8 alkyl, (
  • heterocyclyl-Ci- 8 alkyl 2 -amino-Ci_ 8 alkyl, heterocyclyl-oxy- amino
  • heterocyclyl-oxy,Ci_ 8 alkyl (heterocyclyl-oxy,Ci_ 8 alkyl)amino, (heterocyclyl-oxy) 2 -amino, (heterocyclyl-oxy-Ci- 8 alkyl,Ci_ 8 alkyl)amino, heterocyclyl-carbonyl or
  • R 6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci- 8 alkoxy-Ci_ 8 alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_ 8 alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_ 8 alkyl)2-amino, amino-Ci- 8 alkyl-amino, (amino-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci- 8 alkyl-amino (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci- 8 alkyl 2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
  • heteroaryl-Ci- 8 alkyl 2-amino-Ci- 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci- 8 alkyl or heterocyclyl-oxy;
  • each instance of C 3 _i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
  • Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_ 8 alkyl)2-amino, amino-Ci-salkyl,
  • the present description also relates to a fused tricyclic compound of Formula (la):
  • Ai and A2 are independently C or N; wherein, Ai and A2 are not simultaneously N;
  • Ao is independently QR5), CH(Rs), N or N(R 5 ), where allowed by available valences;
  • Y is -CH(R 2 , -N(R 2 )-, -O- or -S-;
  • R 2 is hydrogen or Ci-salkyl
  • R5 is hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci_ 8 alkoxy, hydroxyl-Ci_ 8 alkoxy, halo-Ci_ 8 alkoxy, Ci_ 8 alkyl-thio, carboxyl,
  • Ci_ 8 alkyl-carbonyl Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
  • Ci- 8 alkoxy-carbonyl-Ci_ 8 alkyl Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
  • Ci- 8 alkoxy-Ci_ 8 alkyl-amino (Ci_ 8 alkoxy-Ci_ 8 alkyl,Ci_ 8 alkyl)-amino,
  • aryl-Ci- 8 alkyl-amino-Ci_ 8 alkyl (aryl-Ci_ 8 alkyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl,
  • heteroaryl-Ci_ 8 alkyl 2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
  • heteroaryl,Ci- 8 alkyl (heteroaryl,Ci- 8 alkyl)amino-Ci_ 8 alkyl, (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_ 8 alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (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
  • R 6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci- 8 alkoxy-Ci_ 8 alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_ 8 alkyl-carbonyl, Ci_ 8 a]koxy-carbonyl, amino, Ci_ 8 alkyl-amino, (Ci_ 8 alkyl) 2 -amino, amino-Ci- 8 alkyl-amino, (amino-Ci- 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl-amino (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl 2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
  • heteroaryl-Ci- 8 alkyl 2-amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci_ 8 alkyl or heterocyclyl-oxy;
  • Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_ 8 alkyl)2-amino, amino-Ci-salkyl,
  • the present description also relates to a fused tetracyclic compound of Formula (lb):
  • dashed lines represent one or more double bonds optionally present where allowed by available valences
  • Ai, A 2 , A3, and A 4 are independently C or N; wherein, Ai and A2 are not simultaneously N; Ao is independently QR5), CH(Rs), N or N(R 5 ), where allowed by available valences;
  • Y is -CH(R 2 )-, -N(R 2 , -O- or -S-;
  • R 2 is hydrogen or Ci-salkyl
  • R5 is hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci_ 8 alkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl,
  • Ci_ 8 alkyl-carbonyl Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
  • Ci- 8 alkoxy-carbonyl-Ci_ 8 alkyl Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
  • Ci- 8 alkoxy-Ci_ 8 alkyl-amino (Ci- 8 alkoxy-Ci_ 8 alkyl,Ci_ 8 alkyl)-amino,
  • 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_ 8 alkyl-amino, (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl 2 -amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
  • heteroaryl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_ 8 alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_ 8 alkyl)amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-Ci_ 8 alkyl, (heterocyclyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl, (heterocyclyl) 2 -amino, heterocyclyl-amino-Ci_ 8 alkyl, (
  • heterocyclyl-Ci- 8 alkyl 2 -amino-Ci_ 8 alkyl, heterocyclyl-oxy- amino
  • heterocyclyl-oxy,Ci_ 8 alkyl (heterocyclyl-oxy,Ci_ 8 alkyl)amino, (heterocyclyl-oxy) 2 -amino, (heterocyclyl-oxy-Ci- 8 alkyl,Ci_ 8 alkyl)amino, heterocyclyl-carbonyl or
  • R 6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci- 8 alkoxy-Ci_ 8 alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_ 8 alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_ 8 alkyl)2-amino, amino-Ci- 8 alkyl-amino, (amino-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci- 8 alkyl-amino (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci- 8 alkyl 2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
  • heteroaryl-Ci- 8 alkyl 2-amino-Ci- 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci- 8 alkyl or heterocyclyl-oxy;
  • each instance of C 3 _i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
  • Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_ 8 alkyl)2-amino, amino-Ci-salkyl,
  • the present description also relates to a fused tetracyclic compound of Formula (Ic):
  • Ai, A 2 , A3, and A 4 are independently C or N; wherein, Ai and A2 are not simultaneously N; Ao is independently QR5), CH(Rs), N or N(R 5 ), where allowed by available valences;
  • Y is -CH(R 2 , -N(R 2 )-, -O- or -S-;
  • R 2 is hydrogen or Ci-salkyl
  • R5 is hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci_ 8 alkoxy, hydroxyl-Ci_ 8 alkoxy, halo-Ci_ 8 alkoxy, Ci_ 8 alkyl-thio, carboxyl,
  • Ci_ 8 alkyl-carbonyl Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
  • Ci- 8 alkoxy-carbonyl-Ci_ 8 alkyl Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
  • Ci- 8 alkoxy-Ci_ 8 alkyl-amino (Ci_ 8 alkoxy-Ci_ 8 alkyl,Ci_ 8 alkyl)-amino,
  • aryl-Ci- 8 alkyl-amino-Ci_ 8 alkyl (aryl-Ci_ 8 alkyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl,
  • heteroaryl-Ci_ 8 alkyl 2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
  • heteroaryl,Ci- 8 alkyl (heteroaryl,Ci- 8 alkyl)amino-Ci_ 8 alkyl, (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_ 8 alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (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
  • R 6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci- 8 alkoxy-Ci_ 8 alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_ 8 alkyl-carbonyl, Ci_ 8 a]koxy-carbonyl, amino, Ci_ 8 alkyl-amino, (Ci_ 8 alkyl) 2 -amino, amino-Ci- 8 alkyl-amino, (amino-Ci- 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl-amino (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl 2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
  • heteroaryl-Ci- 8 alkyl 2-amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci_ 8 alkyl or heterocyclyl-oxy;
  • each instance of C 3 _i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
  • Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_ 8 alkyl)2-amino, amino-Ci-salkyl,
  • the present description further relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof wherein, when R 5 is C 3 _i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • C 3 _i4cycloalkyl 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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- lH-pyrrolyl, 4,5-dihydro- lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b] [l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4
  • the present description further relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof wherein, when R5 is C 3 _i 4 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • C 3 _i 4 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
  • heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl,
  • the present description further relates to a compound of Formula (la), Formula (lb), and Formula (Ic), or a form thereof wherein, R 6 is:
  • C 3 _i 4 cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
  • aryl selected in each instance, when present, from phenyl
  • heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, lH-imidazolyl or pyridinyl; 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 a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof wherein, R 6 is:
  • C 3 _i 4 cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
  • aryl selected in each instance, when present, from phenyl
  • heteroaryl selected in each instance, when present, from IH-pyrrol-l-yl, thiazol-2-yl, 1H-
  • heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan-l-yl.
  • An embodiment of the present description includes a tricyclic compound of Formula (la) selected from a compound of Formula (Ial), Formula (Ia2), Formula (Ia3), Formula (Ia5), Formula (Ia6), Formula (Ia7), Formula (Ia8), Formula (lal l), Formula (Ial2), Formula (Ial5), Formula (Ial6), Formula (Ial7), Formula (Ial8), Formula (Ial9), Formula (Ia20), Formula (Ia21), Formula (Ia22), Formula (Ia23), Formula (Ia24), Formula (Ia25), Formula (Ia26), Formula (Ia27), Formula (Ia28), Formula (Ia29), Formula (Ia30), or Formula (Ia31) or a form thereof:
  • the 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 present description includes a compound of Formula (la), wherein the compound of Formula (lal), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), ( l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) is substituted with one or more Rs a , Rs b ,and Rs c substituents each, when present, selected from the group consisting of:
  • Ci-salkyl-sulfinyl Ci-salkyl-sulfonyl
  • Ci-salkyl-sulfonyl Ci-salkyl-sulfonyl
  • Ci- 8 alkoxy-Ci_ 8 alkyl-amino (Ci_ 8 alkoxy-Ci_ 8 alkyl,Ci_ 8 alkyl)-amino,
  • 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- 8 alkyl-amino, (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci- 8 alkyl 2 -amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
  • heteroaryl,Ci- 8 alkyl)amino-Ci_ 8 alkyl (heteroaryl-Ci- 8 alkyl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_ 8 alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_ 8 alkyl)amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-Ci-salkyl, (heterocyclyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl, (heterocyclyl) 2 -amino, heterocyclyl-amino-Ci-salkyl, (
  • heterocyclyl-Ci_ 8 alkyl 2 -amino-Ci_ 8 alkyl, heterocyclyl-oxy- amino
  • R 6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci- 8 alkoxy-Ci_ 8 alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_ 8 alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_ 8 alkyl)2-amino, amino-Ci- 8 alkyl-amino, (amino-Ci- 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci- 8 alkyl-amino (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci- 8 alkyl 2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
  • heteroaryl-Ci- 8 alkyl 2-amino-Ci- 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci- 8 alkyl or heterocyclyl-oxy;
  • each instance of C 3 _i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
  • Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_ 8 alkyl)2-amino, amino-Ci-salkyl,
  • the present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lall), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, when Rs a , Rs b or Rs c is C 3 _i 4 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion
  • C 3 _i 4 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-
  • the present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lall), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, when Rs a , Rs b or Rs c is C 3 _i 4 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • C 3 _i 4 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
  • heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl,
  • the present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lall), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31), or a form thereof wherein, R 6 is:
  • C3_i 4 cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
  • cyclopentyl cyclohexyl or cycloheptyl
  • aryl selected in each instance, when present, from phenyl
  • heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, lH-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 a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, R 6 is:
  • C 3 _i 4 cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
  • aryl selected in each instance, when present, from phenyl
  • heteroaryl selected in each instance, when present, from IH-pyrrol-l-yl, thiazol-2-yl, 1H-
  • heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan-l-yl.
  • Another embodiment of the present description includes a compound selected from a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) is substituted with one or more R 5a , R 5b and R 5c substituents each, when present, selected from the group consisting of:
  • C 3 _i 4 cycloalkyl, aryl-oxy-Ci-salkyl, aryl-Ci-salkoxy-Ci-salkyl, heteroaryl-Ci-salkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy-Ci-salkyl or heterocyclyl-Ci- 8 alkoxy-Ci_ 8 alkyl;
  • R 6 is (Ci- 8 alkyl) 2 -amino or (Ci-salkyl ⁇ -amino-Ci-salkyl.
  • the present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, when Rs a , Rs b or Rs c is C 3 _i 4 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • C 3 _i 4 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-
  • the present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lall), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, when Rs a , Rs b or Rs c is C 3 _i 4 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • C 3 _i 4 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
  • heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl,
  • the present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, R 6 is:
  • C 3 _i 4 cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
  • aryl selected in each instance, when present, from phenyl
  • heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, lH-imidazolyl or pyridinyl; 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 a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, R 6 is:
  • C 3 _i 4 cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
  • aryl selected in each instance, when present, from phenyl
  • heteroaryl selected in each instance, when present, from lH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
  • heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan-l-yl.
  • Another embodiment of the present description includes a compound selected from a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) is substituted with one or more Rs a , Rs b or Rs c substituents each, when present, selected from the group consisting of:
  • Ci-salkyl hydroxyl-Ci-salkyl
  • Ci-salkyl-carbonyl-oxy-Ci-salkyl
  • aryl-Ci- 8 alkoxy-Ci_ 8 alkyl heteroaryl-Ci-salkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy-Ci_ 8 alkyl, or heterocyclyl-Ci-salkoxy-Ci-salkyl;
  • R 6 is (Ci- 8 alkyl)2-amino or (Ci-salkyl ⁇ -amino-Ci-salkyl.
  • the present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, when Rs a , Rs b or Rs c is C 3 _i 4 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • C 3 _i 4 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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,
  • the present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lall), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, when Rs a , Rs b or Rs c is C 3 _i 4 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
  • C 3 _i 4 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or, heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-
  • the present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lall), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, R 6 is:
  • C 3 _i 4 cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
  • aryl selected in each instance, when present, from phenyl
  • heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, lH-imidazolyl or pyridinyl; 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 a compound of Formula (Ial), (Ia2), (Ia3),
  • R 6 is:
  • C 3 _i 4 cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
  • aryl selected in each instance, when present, from phenyl
  • heteroaryl selected in each instance, when present, from lH-pyrrol-l-yl, thiazol-2-yl, 1H-
  • heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan-l-yl.
  • An embodiment of the present description includes a tricyclic compound of Formula (la) selected from a compound of Formula (Ia3), Formula (Ia5), Formula (Ial2), Formula (Ial6), Formula (Ial7), Formula (Ial9), Formula (Ia20), Formula (Ia21), and Formula (Ia31) or a form thereof:
  • the form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • Another embodiment of the present description includes a tetracyclic compound of Formula (lb) selected from a compound of Formula (Ibl), Formula (Ib2), Formula (Ib3), Formula (Ib4), Formula (Ib5), Formula (Ib6), Formula (Ib7), Formula (Ib8), Formula (Ib9), Formula (IblO), Formula (Ibll), Formula (Ibl2), Formula (Ibl3), Formula (Ibl4), Formula (Ibl5), Formula (Ibl6), Formula (Ibl7), Formula (Ibl8), Formula (Ibl9), Formula (Ib20), Formula (Ib21), Formula (Ib22), Formula (Ib23), Formula (Ib24), Formula (Ib25), Formula (Ib26), Formula (Ib27), Formula (Ib28), Formula (Ib29), Formula (Ib30), Formula (Ib31), Formula (Ib32), Formula (Ib33), Formula (Ib34), Formula (Ib35), Formula (Ib36), Formula
  • An embodiment of the present description includes a compound of Formula (lb), wherein the compound of Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (
  • Ci-salkyl hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci_ 8 alkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl,
  • Ci_ 8 alkyl-carbonyl Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
  • Ci- 8 alkoxy-carbonyl-Ci_ 8 alkyl Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
  • Ci- 8 alkoxy-Ci_ 8 alkyl-amino (Ci_ 8 alkoxy-Ci_ 8 alkyl,Ci_ 8 alkyl)-amino,
  • Ci_ 8 alkoxy-Ci_ 8 alkyl 2 -amino
  • 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_ 8 alkyl-amino, (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl 2 -amino
  • heteroaryl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl
  • heteroaryl,Ci- 8 alkyl)amino-Ci_ 8 alkyl (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_ 8 alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_ 8 alkyl)amino, (heterocyclyl) 2 -amino, heterocyclyl-amino-Ci-salkyl, (heterocyclyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl, (heterocyclyl) 2 -amino, heterocyclyl-amino-Ci-salkyl, (
  • heterocyclyl-Ci- 8 alkyl-amino-Ci_ 8 alkyl (heterocyclyl-Ci- 8 alkyl,Ci- 8 alkyl)amino-Ci_ 8 alkyl,
  • heterocyclyl-Ci- 8 alkyl 2-amino-Ci_ 8 alkyl, heterocyclyl-oxy- amino
  • R 6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci- 8 alkoxy-Ci_ 8 alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_ 8 alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_ 8 alkyl)2-amino, amino-Ci- 8 alkyl-amino, (amino-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci- 8 alkyl-amino (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci- 8 alkyl 2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
  • heteroaryl-Ci- 8 alkyl 2-amino-Ci- 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci- 8 alkyl or heterocyclyl-oxy;
  • C 3 _i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and, R9 is Ci-salkyl, amino, Ci-salkyl-amino, (Ci_ 8 alkyl) 2 -amino, amino-Ci-salkyl,
  • the present description further relates to a compound of Formula Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (Ib45), (Ib46),
  • R 5a , R 5 b, Rsc, Rsd and R 5e is C 3 _i 4 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C 3 _i 4 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl,
  • the present description further relates to a compound of Formula (Ibl), (Ib2), (Ib3),
  • C 3 _i4cycloalkyl 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
  • heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl,
  • the present description further relates to a compound of Formula Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl 8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (Ib45), (Ib46),
  • C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
  • aryl selected in each instance, when present, from phenyl
  • heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1 ,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, lH-imidazolyl or pyridinyl; 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 a compound of Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (Ib45), (Ib46), (
  • 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 lH-pyrrol-l-yl, thiazol-2-yl, 1H-
  • heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan-l-yl.
  • An embodiment of the present description includes a compound of Formula (lb), wherein the compound of Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (
  • R 6 is (Ci- 8 alkyl)2-amino or (Ci-salkyl ⁇ -amino-Ci-salkyl.
  • the present description further relates to a compound of Formula Formula (Ibl),
  • 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-
  • the present description further relates to a compound of Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibll), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (Ib45), (Ib46), (Ib
  • C 3 _i 4 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent then: C 3 _i 4 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
  • heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, 1,2,3, 6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, tetra
  • An embodiment of the present description includes a compound of Formula (lb), wherein the compound of Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (
  • Ci-salkyl Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl) 2 -amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci_ 8 alkyl;
  • R 6 is amino, Ci-salkyl-amino, (Ci_ 8 alkyl) 2 -amino.
  • Another embodiment of the present description includes a tetracyclic compound of Formula (lb) selected from a compound of Formula (Ibl), Formula (Ib2), Formula (Ibl6), and Formula (Ib76), or a form thereof;
  • the form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • Another embodiment of the present description includes a tetracyclic compound of Formula (Ic) selected from a compound of Formula (Icl), Formula (Ic2), Formula (Ic3), Formula (Ic4), Formula (Ic5), Formula (Ic6), Formula (Ic7), Formula (Ic8), Formula (Ic9), Formula (IclO), Formula (Icl l), Formula (Icl2), Formula (Icl3), Formula (Icl4), Formula (Icl5), Formula (Icl6), Formula (Icl7), Formula (Icl8), Formula (Icl9), Formula (Ic20), Formula (Ic21), Formula (Ic22), Formula (Ic23), Formula (Ic24), Formula (Ic25), Formula (Ic26), Formula (Ic27), Formula (Ic28), Formula (Ic29), Formula (Ic30), Formula (Ic31), Formula (Ic32), Formula (Ic33), Formula (Ic34), Formula (Ic35), Formula (Ic36
  • the 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 present description includes a compound of Formula (Ic), wherein the compound of Formula (Icl), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Icl l), (Icl2), (Icl3), (Icl4), (Icl5), (Icl6), (Icl7), (Icl8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (
  • Ci- 8 alkoxy-Ci_ 8 alkyl-amino (Ci_ 8 alkoxy-Ci_ 8 alkyl,Ci_ 8 alkyl)-amino,
  • 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_ 8 alkyl-amino, (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl 2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
  • heteroaryl,Ci- 8 alkyl (heteroaryl,Ci- 8 alkyl)amino-Ci_ 8 alkyl, (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_ 8 alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (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
  • R 6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci- 8 alkoxy-Ci_ 8 alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_ 8 alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_ 8 alkyl)2-amino, amino-Ci- 8 alkyl-amino, (amino-Ci- 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl-amino (heteroaryl-Ci_ 8 alkyl,Ci_ 8 alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl 2 -amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
  • heteroaryl-Ci- 8 alkyl 2 -amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci_ 8 alkyl or heterocyclyl-oxy;
  • each instance of C 3 _i 4 cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg;
  • R9 is Ci_ 8 alkyl, amino, Ci-salkyl-amino, (Ci_ 8 alkyl) 2 -amino, amino-Ci-salkyl,
  • the present description further relates to a compound of Formula Formula (Icl), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Icl l), (Icl2), (Icl3), (Icl4), (Icl5), (Icl6), (Icl7), (Icl8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (Ic45), (Ic46),
  • 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl,
  • the present description further relates to a compound of Formula (Icl), (Ic2), (Ic3),
  • C 3 _i 4 cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent then: C 3 _i 4 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
  • heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl,
  • the present description further relates to a compound of Formula Formula (Icl), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Icll), (Icl2), (Icl3), (Icl4), (Icl5), (Icl6), (Icl7), (Icl8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (Ic45), (Ic46), (I
  • 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, lH-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 a compound of Formula (Icl), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Icl l), (Icl2), (Icl3), (Icl4), (Icl5), (Icl 6), (Icl7), (Ic l8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (Ic45), (Ic46),
  • C3_i4cycloalkyl 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 lH-pyrrol- l-yl, thiazol-2-yl, 1H-
  • heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin- l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin- l-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan- l-yl.
  • An embodiment of the present description includes a compound of Formula (Ic), wherein the compound of Formula (Ic l), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Ic l l), (Icl2), (Icl3), (Ic l4), (Icl5), (Icl 6), (Ic l7), (Icl8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (I
  • Ci-salkyl Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_ 8 alkyl, heterocyclyl, heterocyclyl-Ci_ 8 alkyl; wherein each instance of C 3 _i 4 cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R 6 ; and,
  • R 6 is amino, Ci-salkyl-amino, (Ci_ 8 alkyl) 2 -amino.
  • the present description further relates to a compound of Formula Formula (Icl), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Icll), (Icl2), (Icl3), (Icl4), (Icl5), (Icl6), (Icl7), (Icl8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (Ic45), (Ic46), (I
  • 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-
  • the present description further relates to a compound of Formula (Icl), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Icl l), (Icl2), (Icl3), (Icl 4), (Icl5), (Icl6), (Icl7), (Ic l8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (Ic45), (Ic46),
  • C 3 _i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent then: C 3 _i4cycloalkyl 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
  • heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl,
  • Another embodiment of the present description includes a tetracyclic compound of Formula (Ic) selected from a compound of Formula (Icl), or a form thereof:
  • the form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
  • Another embodiment of the present description includes a compound selected from a compound of Formula (la), Formula (lb), and Formula (Ic) substituted with one or more Rs a , R5b, R 5 c, R 5 d, and Rs e substituents wherein, the term "(Ixn)" in the tables below indicates whether the compound is selected from a compound of Formula (lal) to Formula (Ia31), Formula (Ibl) to Formula (Ib90), or Formula (Icl) to Formula (Ib90).
  • An embodiment of the present description includes a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof selected from the group consisting of:
  • Another embodiment of the present description includes a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof (wherein compound number (# ) indicates that the salt form was isolated) selected from the group consisting of:
  • the compound or a form thereof is isolated as a salt.
  • Another embodiment of the present description includes a compound salt of Formula (la), Formula (lb), and Formula (Ic) or a form thereof selected from the group consisting of:
  • An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
  • (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof (wherein compound number (# ) indicates that the salt form was isolated) to the subject, wherein the compound is selected from the group consisting of:

Abstract

The present description relates to fused polycyclic 2-pyridinone compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae or N. meningitides. A compound of Formula (la), Formula (lb) or Formula (Ic), or a form thereof, wherein the dashed lines represent one or more double bonds optionally present where allowed by available valences.

Description

FUSED POLYCYCLIC 2-PYRIDINONE ANTIBACTERIAL COMPOUNDS
The present description relates to fused polycyclic 2-pyridinone compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof for treating or ameliorating Neisseria gonorrhoeae
(N. gonorrhoeae) or Neisseria meningitidis (N. meningitidis). More particularly, the present description relates to fused tricyclic and tetracyclic 2-pyridinone compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae or N. meningitidis.
BACKGROUND
Neisseria is a large genus of generally commensal Gram-negative bacteria that colonize the mucosal surfaces of many animals, with N. gonorrhoeae and N. meningitidis being two of the pathogenic Neisseria species. 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 just the United States every year. An exclusively human pathogen, N.
meningitidis is commonly associated with the flora of the nasopharynx. Although usually considered non-pathogenic, it is opportunistic, having the ability to cause meningitis and sepsis. Individuals who are immunocompromised are most at risk of infection. One in every 100,000 individuals in the United States are estimated to become infected every year, with children under the age of five being especially vulnerable. An infected individual requires rapid antibiotic intervention before potentially fatal bacterial dissemination occurs.
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 (tetracycline11) 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 (streptomycin11), ciprofloxacin-resistant (ciprofloxacin11) 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 fused polycyclic 2-pyridinone compounds selected from a fused tricyclic compound of Formula (la) or fused tetracyclic compounds of Formula (lb) or Formula (Ic):
Figure imgf000004_0001
(la) (lb) (Ic)
wherein X, Y, Ao, Ai, A2, A3 and A4 are as defined herein, and forms and compositions thereof, and also relates to uses of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof and methods for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae) or Neisseria meningitidis (N. meningitidis) in a subject in need thereof, comprising, administering an effective amount of the compound to the subject.
In particular, the present description relates to a compound of Formula (la), Formula
(lb), or Formula (Ic) and forms and compositions thereof, and to uses of a compound of Formula (la), Formula (lb), or Formula (Ic) and forms and compositions thereof, and methods for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising, administering an effective amount of the compound, and forms and compositions thereof, to the subject.
In particular, the present description relates to a compound of Formula (la), Formula (lb), and Formula (Ic) and forms and compositions thereof, and to uses of a compound of Formula (la), Formula (lb), or Formula (Ic) and forms and compositions thereof, and methods for treating or ameliorating N. meningitidis in a subject in need thereof, comprising, administering an effective amount of the compound, and forms and compositions thereof, to the subject.
The present description further relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof having activity against wild-type or drug-resistant forms of N. gonorrhoeae or N. meningitidis. More particularly, the present description relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof having activity against wild-type forms of N. gonorrhoeae or N. meningitidis.
The present description also relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof having activity against drug-resistant forms of N. gonorrhoeae or N. meningitidis.
The present description also relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof having activity against N. gonorrhoeae resistant to one or more known antibacterial or antibiotic agents, wherein drug resistance may be classified as intermediate resistance (IR), high level resistance (HLR), multi-drug resistant (MDR), multidrug intermediate resistant (MD R) or extensively drug resistant (XDR).
More particularly, the present description relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof having activity against a IR, HLR, MDR, MD!R or XDR form of N. gonorrhoeae.
The present description also relates to a compound of Formula (la), Formula (lb), and
Formula (Ic) or a form thereof having activity against an aminoglycoside-resistant, beta- lactam-resistant, cephalosporin-resistant, macrolide-resistant, quinolone-resistant or tetracycline-resistant form of N. gonorrhoeae.
The present description further relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof in combination with known agents having additive or synergistic activity, thus providing a combination product for the treatment of
N. gonorrhoeae.
The present description further relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating N. gonorrhoeae resistant to one or more known antibacterial or antibiotic agents, wherein drug resistance may be classified as intermediate resistance (IR), high level resistance (HLR), multi-drug resistant (MDR), multi-drug intermediate resistant (MD!R) or extensively drug resistant (XDR).
More particularly, the present description relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating IR, HLR, MDR, MD!R or XDR forms of N. gonorrhoeae.
The present description also relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating an aminoglycoside - resistant, beta-lactam-resistant, cephalosporin-resistant, macrolide-resistant, quinolone- resistant or tetracycline-resistant form of N. gonorrhoeae.
The present description further relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) 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 or N. meningitidis.
DETAILED DESCRIPTION
The present description relates to fused polycyclic 2-pyridinone compounds selected from a fused tricyclic compound of Formula (la) or fused tetracyclic compounds of Formula (lb) or Formula (Ic):
Figure imgf000006_0001
(la) (lb) (Ic) or a form thereof, wherein
the dashed lines represent one or more double bonds optionally present where allowed by available valences;
Ai, A2, A3, and A4 are independently C or N; wherein, Ai and A2 are not simultaneously N; Ao is independently C(R5), CH(Rs), N or N(R5), where allowed by available valences; X is -CH(R2 , -CH(R2)-CH(R2 , -CH(R2)-CH(R2)-CH(R2)-, -C(R2)=C(R2)-, -CH(R2)-0-, -0-CH(R2 , -0-CH(R2)-CH(R2)-, -CH(R2)-0-CH(R2)-, -N(R2)-, -S-CH(R2)-, -O- or S-;
Y is -CH(R2 , -N(R2 , -O- or -S-;
wherein, when Y is -N(R2 , -O- or -S-, then X is not -CH(R2)-0-, -0-CH(R2 ,
-CH(R2)-0-CH(R2)-, -N(R2 , -S-CH(R2)-, -O- or -S-;
R2 is hydrogen or Ci-salkyl;
R5 is hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl Ci-salkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl,
Ci_8alkyl-carbonyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
Ci-8alkyl-sulfinyl-Ci_8alkyl, Ci-salkyl-sulfonyl-Ci-salkyl, amino-carbonyl, amino, Ci-8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2_8alkenyl-amino,
(C2_8alkenyl)2-amino, C2_salkynyl, C2_8alkynyl-amino, (C2_8alkynyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl,
C2-8alkenyl-amino-Ci_8alkyl, (C2_8alkenyl)2-amino-Ci_8alkyl,
C2-8alkynyl-amino-Ci_8alkyl, (C2_8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl,
hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci-8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci-8alkoxy-Ci_8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci_8alkyl-amino-Ci_8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino, amino-Ci-salkyl-amino-Ci-salkyl, (amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (amino-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci-8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,
(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci-8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino, (hydroxyl-Ci-8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino,
(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl-amino,
[(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-amino-Ci-salkyl-carbonyl,
(Ci-8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_8alkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3_i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino,
(aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl,
(aryl,Ci-8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-Ci-salkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci-8alkyl-amino-Ci_8alkyl, (aryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,
(aryl-Ci-8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl,Ci_8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci_8alkyl, (heterocyclyl,Ci-8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl,
(heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino, (heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci_8alkyl,Ci_8alkyl)amino,
Ci-8alkyl-amino-Ci-8alkyl-amino, (Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci-8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci_8alkyl, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci-8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl,
C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-Ci-salkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino,
(aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl, (aryl-Ci_8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_salkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci-8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci-8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci-8alkyl)2-amino-Ci-8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci-8alkyl or heterocyclyl-oxy;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci-8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci-salkyl-amino; wherein the 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 a fused tricyclic compound of Formula (la):
Figure imgf000010_0001
(la)
or a form thereof, wherein
wherein the dashed lines represent one or more double bonds optionally present where
allowed by available valences;
Ai and A2 are independently C or N; wherein, Ai and A2 are not simultaneously N;
Ao is independently QR5), CH(Rs), N or N(R5), where allowed by available valences;
X is -CH(R2 , -CH(R2)-CH(R2 , -CH(R2)-CH(R2)-CH(R2 , -C(R2)=C(R2 , -CH(R2)-0-, -0-CH(R2 , -0-CH(R2)-CH(R2 , -CH(R2)-0-CH(R2 , -N(R2 , -S-CH(R2 , -O- or -S-;
Y is -CH(R2 , -N(R2)-, -O- or -S-;
wherein, when Y is -N(R2 , -O- or -S-, then X is not -CH(R2)-0-, -0-CH(R2 ,
-CH(R2)-0-CH(R2)-, -N(R2)-, -S-CH(R2 , -O- or -S-;
R2 is hydrogen or Ci-salkyl;
R5 is hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci_8alkoxy, hydroxyl-Ci_8alkoxy, halo-Ci_8alkoxy, Ci_8alkyl-thio, carboxyl,
Ci_8alkyl-carbonyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
Ci_8alkyl-sulfinyl-Ci_8alkyl, Ci_8alkyl-sulfonyl-Ci_8alkyl, amino-carbonyl, amino, Ci-8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2_8alkenyl-amino,
(C2_8alkenyl)2-amino, C2_salkynyl, C2_8alkynyl-amino, (C2_8alkynyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl,
C2-8alkenyl-amino-Ci_8alkyl, (C2_8alkenyl)2-amino-Ci_8alkyl, C2-8alkynyl-amino-Ci_8alkyl, (C2-8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl,
hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci-8alkoxy-Ci_8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci-8alkoxy-Ci-8alkyl,Ci-8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci_8alkyl]amino, amino-Ci-salkyl-amino-Ci-salkyl, (amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (amino-Ci_8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci_8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino,
(hydroxyl-Ci-8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino,
(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl-amino,
[(hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-amino-Ci-salkyl-carbonyl,
(Ci_8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_salkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3_i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl, (C3-i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl, (aryl,Ci-8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-Ci-salkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci-8alkyl-amino-Ci_8alkyl, (aryl-Ci_8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(aryl-Ci-8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl,Ci-8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci-salkyl, (heterocyclyl,Ci-8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl,
(heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci_8a]koxy-carbonyl, amino, Ci_8alkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci-8alkyl,Ci_8alkyl)amino,
Ci-8alkyl-amino-Ci-8alkyl-amino, (Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci-8alkyl, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci-8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl,
C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-Ci-salkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (aryl-Ci_8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci_8alkyl or heterocyclyl-oxy;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci-8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci-salkyl-amino; wherein the 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 a fused tetracyclic compound of Formula (lb):
Figure imgf000013_0001
or a form thereof, wherein
wherein the dashed lines represent one or more double bonds optionally present where allowed by available valences;
Ai, A2, A3, and A4 are independently C or N; wherein, Ai and A2 are not simultaneously N; Ao is independently QR5), CH(Rs), N or N(R5), where allowed by available valences; X is -CH(R2 , -CH(R2)-CH(R2 , -CH(R2)-CH(R2)-CH(R2)-, -C(R2)=C(R2)-, -CH(R2)-0-, -0-CH(R2 , -0-CH(R2)-CH(R2)-, -CH(R2)-0-CH(R2)-, -N(R2)-, -S-CH(R2)-, -O- or -S-;
Y is -CH(R2)-, -N(R2 , -O- or -S-;
wherein, when Y is -N(R2 , -O- or -S-, then X is not -CH(R2)-0-, -0-CH(R2 ,
-CH(R2)-0-CH(R2)-, -N(R2)-, -S-CH(R2 , -O- or -S-;
R2 is hydrogen or Ci-salkyl;
R5 is hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci_8alkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl,
Ci_8alkyl-carbonyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
Ci-8alkyl-sulfinyl-Ci_8alkyl, Ci-salkyl-sulfonyl-Ci-salkyl, amino-carbonyl, amino, Ci-8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2_8alkenyl-amino,
(C2_8alkenyl)2-amino, C2_salkynyl, C2_8alkynyl-amino, (C2_8alkynyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl,
C2-8alkenyl-amino-Ci_8alkyl, (C2_8alkenyl)2-amino-Ci_8alkyl,
C2-8alkynyl-amino-Ci_8alkyl, (C2_8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl,
hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci-8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci-8alkoxy-Ci_8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci_8alkyl-amino-Ci_8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino, amino-Ci-salkyl-amino-Ci-salkyl, (amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (amino-Ci_8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci-8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,
(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci-8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino, (hydroxyl-Ci-8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino,
(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl-amino,
[(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-amino-Ci-salkyl-carbonyl,
(Ci-8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_8alkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3_i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino,
(aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl,
(aryl,Ci-8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-Ci-salkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci-8alkyl-amino-Ci_8alkyl, (aryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,
(aryl-Ci-8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl,Ci_8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci_8alkyl, (heterocyclyl,Ci-8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl,
(heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino, (heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci_8alkyl,Ci_8alkyl)amino,
Ci-8alkyl-amino-Ci-8alkyl-amino, (Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci-8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci_8alkyl, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci-8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl,
C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-Ci-salkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino,
(aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl, (aryl-Ci_8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_salkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci-8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci-8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci-8alkyl)2-amino-Ci-8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci-8alkyl or heterocyclyl-oxy;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci-8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci-salkyl-amino; wherein the 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 a fused tetracyclic compound of Formula (Ic):
Figure imgf000017_0001
(Ic)
or a form thereof, wherein
wherein the dashed lines represent one or more double bonds optionally present where
allowed by available valences;
Ai, A2, A3, and A4 are independently C or N; wherein, Ai and A2 are not simultaneously N; Ao is independently QR5), CH(Rs), N or N(R5), where allowed by available valences;
X is -CH(R2 , -CH(R2)-CH(R2 , -CH(R2)-CH(R2)-CH(R2 , -C(R2)=C(R2 , -CH(R2)-0-, -0-CH(R2 , -0-CH(R2)-CH(R2 , -CH(R2)-0-CH(R2 , -N(R2 , -S-CH(R2 , -O- or -S-;
Y is -CH(R2 , -N(R2)-, -O- or -S-;
wherein, when Y is -N(R2 , -O- or -S-, then X is not -CH(R2)-0-, -0-CH(R2 ,
-CH(R2)-0-CH(R2 , -N(R2)-, -S-CH(R2)-, -O- or -S-;
R2 is hydrogen or Ci-salkyl;
R5 is hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci_8alkoxy, hydroxyl-Ci_8alkoxy, halo-Ci_8alkoxy, Ci_8alkyl-thio, carboxyl,
Ci_8alkyl-carbonyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
Ci-8alkyl-sulfinyl-Ci_8alkyl, Ci-salkyl-sulfonyl-Ci-salkyl, amino-carbonyl, amino, Ci-8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2_8alkenyl-amino,
(C2_8alkenyl)2-amino, C2_salkynyl, C2_8alkynyl-amino, (C2_8alkynyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl,
C2-8alkenyl-amino-Ci_8alkyl, (C2_8alkenyl)2-amino-Ci_8alkyl, C2-8alkynyl-amino-Ci_8alkyl, (C2-8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl,
hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci-8alkoxy-Ci_8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci-8alkoxy-Ci-8alkyl,Ci-8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci_8alkyl]amino, amino-Ci-salkyl-amino-Ci-salkyl, (amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (amino-Ci_8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci_8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino,
(hydroxyl-Ci-8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino,
(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl-amino,
[(hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-amino-Ci-salkyl-carbonyl,
(Ci_8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_salkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3_i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl, (C3-i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl, (aryl,Ci-8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-Ci-salkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci-8alkyl-amino-Ci_8alkyl, (aryl-Ci_8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(aryl-Ci-8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl,Ci-8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci-salkyl, (heterocyclyl,Ci-8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl,
(heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci_8a]koxy-carbonyl, amino, Ci_8alkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci-8alkyl,Ci_8alkyl)amino,
Ci-8alkyl-amino-Ci-8alkyl-amino, (Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci-8alkyl, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci-8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl,
C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-Ci-salkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (aryl-Ci_8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci_8alkyl or heterocyclyl-oxy;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci-8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci-salkyl-amino; wherein the form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
The present description further relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof wherein, when R5 is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3_i4cycloalkyl 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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- lH-pyrrolyl, 4,5-dihydro- lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b] [l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][l,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b] [ 1 ,4]oxazin-(4aH)-yl, hexahydro- 1 H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro-lH- pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- l,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo [2.2.1 Jheptyl, 2,5 -diazabicyclo [2.2.1 Jheptanyl, 2-azabicyclo [2.2.1 ]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexyl, (lR,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.OJhexyl, ( lR,5S)-3-azabicyclo[3.1.OJhexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (lS,5R,6S)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (lS,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 or 2,8-diazaspiro[4.5]decanyl. The present description further relates to a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof wherein, when R5 is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3_i4cycloalkyl 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,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][l,4]oxazin-4-yl, 3 ,4-dihydroisoquinolin-2( lH)-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][l,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][l,4]oxazin-4(4aH)-yl, hexahydro-lH-cyclopenta[c]pyrrol-2-yl, (cis)- octahydrocyclopenta[c]pyrrol-4-yl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-3a(lH)- yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,4S,6aS
hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-4-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, (3aR,6aS hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- 6(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin- 6-yl, 2,3,4,9-tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3- dihydro-lH-pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindol-2-yl, octahydro-2H- isoindol-2-yl, (3aS)-l,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-lH- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl, 2,5-diazabicyclo[2.2.1]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, (lR,5S,6s)-3-azabicyclo[3.1.0]hex-3-yl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexan-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hex-6-yl, (lR,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, (lS,5R,6R)-3-azabicyclo[3.2.0]hept-3-yl, (1S,5R,6S)- 3-azabicyclo[3.2.0]hept-3-yl, (lS,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 a compound of Formula (la), Formula (lb), and Formula (Ic), or a form thereof wherein, R6 is:
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, lH-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 a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof wherein, R6 is:
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from IH-pyrrol-l-yl, thiazol-2-yl, 1H-
1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan-l-yl.
An embodiment of the present description includes a tricyclic compound of Formula (la) selected from a compound of Formula (Ial), Formula (Ia2), Formula (Ia3), Formula (Ia5), Formula (Ia6), Formula (Ia7), Formula (Ia8), Formula (lal l), Formula (Ial2), Formula (Ial5), Formula (Ial6), Formula (Ial7), Formula (Ial8), Formula (Ial9), Formula (Ia20), Formula (Ia21), Formula (Ia22), Formula (Ia23), Formula (Ia24), Formula (Ia25), Formula (Ia26), Formula (Ia27), Formula (Ia28), Formula (Ia29), Formula (Ia30), or Formula (Ia31) or a form thereof:
Figure imgf000024_0001
(Ial2) (Ial5) (Ial6) (Ial7)
Figure imgf000025_0001
(Ia23) (Ia24) (Ia25)
Figure imgf000025_0002
(Ia26) (Ia27) (Ia29)
Figure imgf000025_0003
(Ia30), and (Ia31);
wherein the 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 present description includes a compound of Formula (la), wherein the compound of Formula (lal), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), ( l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) is substituted with one or more Rsa, Rsb,and Rsc substituents each, when present, selected from the group consisting of:
hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci_8alkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl, Ci_8alkyl-carbonyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl, Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
Ci-8alkyl-sulfinyl-Ci_8alkyl, Ci-salkyl-sulfonyl-Ci-salkyl, amino-carbonyl, amino, Ci-8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2-8alkenyl-amino,
(C2-8alkenyl)2-amino, C2-salkynyl, C2-8alkynyl-amino, (C2-8alkynyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl, C2-8alkenyl-amino-Ci_8alkyl, (C2-8alkenyl)2-amino-Ci_8alkyl,
C2-8alkynyl-amino-Ci_8alkyl, (C2-8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl,
hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci-8alkoxy-Ci_8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci-8alkoxy-Ci-8alkyl,Ci-8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino, amino-Ci-salkyl-amino-Ci-salkyl, (amino-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, (amino-Ci_8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci-8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,
(Ci_8alkyl)2-amino-Ci_8alkyl-amino-Ci_8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino,
(hydroxyl-Ci-8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino,
(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl-amino, [(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-amino-Ci-salkyl-carbonyl,
(Ci-8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_8alkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3_i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino,
(aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl,
(aryl,Ci-8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-Ci-salkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci-8alkyl-amino-Ci_8alkyl, (aryl-Ci_8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(aryl-Ci-8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci-8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci-8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl,Ci-8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci-8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci-salkyl, (heterocyclyl,Ci-8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl,
(heterocyclyl,C3_i4cycloalkyl-Ci_8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci_8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci-8alkyl,Ci_8alkyl)amino,
Ci-8alkyl-amino-Ci-8alkyl-amino, (Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci-8alkyl)2-amino-Ci-8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci-8alkyl, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci-8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl,
C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-Ci-salkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino,
(aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl, (aryl-Ci_8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci-8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci-8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci-8alkyl)2-amino-Ci-8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci-8alkyl or heterocyclyl-oxy;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci_8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci_8alkyl-amino. The present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lall), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, when Rsa, Rsb or Rsc is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3_i4cycloalkyl 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][l,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b] [ 1 ,4]oxazin-(4aH)-yl, hexahydro- 1 H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro-lH- pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- l,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo [2.2.1 Jheptyl, 2,5 -diazabicyclo [2.2.1 Jheptanyl, 2-azabicyclo [2.2.1 ]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexyl, (lR,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (lS,5R,6S)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (lS,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 or 2,8-diazaspiro[4.5]decanyl.
The present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lall), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, when Rsa, Rsb or Rsc is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3_i4cycloalkyl 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,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][l,4]oxazin-4-yl, 3 ,4-dihydroisoquinolin-2( lH)-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][l,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][l,4]oxazin-4(4aH)-yl, hexahydro-lH-cyclopenta[c]pyrrol-2-yl, (cis)- octahydrocyclopenta[c]pyrrol-4-yl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-3a(lH)- yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,4S,6aS
hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-4-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, (3aR,6aS hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- 6(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin- 6-yl, 2,3,4,9-tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3- dihydro-lH-pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindol-2-yl, octahydro-2H- isoindol-2-yl, (3aS)-l,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-lH- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl, 2,5-diazabicyclo[2.2.1]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, (lR,5S,6s)-3-azabicyclo[3.1.0]hex-3-yl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexan-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hex-6-yl, (lR,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, (lS,5R,6R)-3-azabicyclo[3.2.0]hept-3-yl, (1S,5R,6S)- 3-azabicyclo[3.2.0]hept-3-yl, (lS,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 a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lall), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31), or a form thereof wherein, R6 is:
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl; aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, lH-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 a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, R6 is:
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from IH-pyrrol-l-yl, thiazol-2-yl, 1H-
1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan-l-yl.
Another embodiment of the present description includes a compound selected from a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) is substituted with one or more R5a, R5b and R5c substituents each, when present, selected from the group consisting of:
hydrogen, halogen, cyano, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl,
Ci_8alkyl-carbonyl-oxy-Ci_8alkyl, Ci_8alkyl-sulfinyl-Ci_8alkyl,
Ci-8alkyl-sulfonyl-Ci-8alkyl, (Chalky l)2-amino, C2-salkenyl, amino-Ci-salkyl, Ci-ioalkyl-amino-Ci_8alkyl, (Ci-ioalkyl)2-amino-Ci-8alkyl,Ci-8alkoxy-Ci_8aIkyl, hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkyl-amino-Ci-8alkyl-carbonyl, (Ci_8alkyl)2-amino-Ci_8alkyl-carbonyl,
C3_i4cycloalkyl, aryl-oxy-Ci-salkyl, aryl-Ci-salkoxy-Ci-salkyl, heteroaryl-Ci-salkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy-Ci-salkyl or heterocyclyl-Ci-8alkoxy-Ci_8alkyl;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is (Ci-8alkyl)2-amino or (Ci-salkyl^-amino-Ci-salkyl.
The present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, when Rsa, Rsb or Rsc is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3_i4cycloalkyl 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][l,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b] [ 1 ,4]oxazin-(4aH)-yl, hexahydro- 1 H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro-lH- pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- l,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo [2.2.1 Jheptyl, 2,5 -diazabicyclo [2.2.1 Jheptanyl, 2-azabicyclo [2.2.1 ]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexyl, (lR,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (1S,5R,6S 3- azabicyclo[3.2.0]heptyl, (lS,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 or 2,8-diazaspiro[4.5]decanyl.
The present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lall), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, when Rsa, Rsb or Rsc is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3_i4cycloalkyl 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,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][l,4]oxazin-4-yl,
3.4- dihydroisoquinolin-2(lH)-yl, 1,2,3,4-tetrahydroisoquinolin-l-yl, 1,2,3,4- tetrahydroquinoxalin- 1 -yl, (6H)-pyrrolo[3 ,4-b] [ 1 ,4]oxazin-6(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][l,4]oxazin-4(4aH)-yl, hexahydro-lH-cyclopenta[c]pyrrol-2-yl, (cis)- octahydrocyclopenta[c]pyrrol-4-yl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-3a(lH)- yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,4S,6aS
hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-4-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, (3aR,6aS hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- 6(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin- 6-yl, 2,3,4,9-tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3- dihydro-lH-pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindol-2-yl, octahydro-2H- isoindol-2-yl, (3aS)-l,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-lH- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl,
2.5- diazabicyclo[2.2.1]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, (lR,5S,6s)-3-azabicyclo[3.1.0]hex-3-yl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexan-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hex-6-yl, (lR,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, (lS,5R,6R)-3-azabicyclo[3.2.0]hept-3-yl, (1S,5R,6S)- 3-azabicyclo[3.2.0]hept-3-yl, (lS,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 a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, R6 is:
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, lH-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 a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, R6 is:
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from lH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan-l-yl.
Another embodiment of the present description includes a compound selected from a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) is substituted with one or more Rsa, Rsb or Rsc substituents each, when present, selected from the group consisting of:
hydrogen, halogen, Ci-salkyl, hydroxyl-Ci-salkyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl,
Ci-8alkyl-sulfinyl-Ci_8alkyl, Ci-salkyl-sulfonyl-Ci-salkyl, (Ci_8alkyl)2-amino, C2-8alkenyl, amino-Ci-salkyl, Ci-ioalkyl-amino-Ci-salkyl,
(Ci-ioalkyl)2-amino-Ci-8alkyl,Ci-8alkoxy-Ci_8alkyl, hydroxyl-Ci-salkoxy-Ci-salkyl, Ci-8alkoxy-Ci-8alkoxy-Ci_8alkyl, C3_i4cycloalkyl, aryl-oxy-Ci-salkyl,
aryl-Ci-8alkoxy-Ci_8alkyl, heteroaryl-Ci-salkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy-Ci_8alkyl, or heterocyclyl-Ci-salkoxy-Ci-salkyl;
wherein each instance of aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is (Ci-8alkyl)2-amino or (Ci-salkyl^-amino-Ci-salkyl.
The present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lal l), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, when Rsa, Rsb or Rsc is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3_i4cycloalkyl 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][l,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b] [ 1 ,4]oxazin-(4aH)-yl, hexahydro- 1 H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol-
(lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro-lH- pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- l,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo [2.2.1 Jheptyl, 2,5 -diazabicyclo [2.2.1 Jheptanyl, 2-azabicyclo [2.2.1 ]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexyl, (lR,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (lS,5R,6S)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (lS,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 or 2,8-diazaspiro[4.5]decanyl.
The present description further relates to a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lall), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, when Rsa, Rsb or Rsc is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3_i4cycloalkyl 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or, heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,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][l,4]oxazin-4-yl,
3.4- dihydroisoquinolin-2( lH)-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][l,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][l,4]oxazin-4(4aH)-yl, hexahydro-lH-cyclopenta[c]pyrrol-2-yl, (cis)- octahydrocyclopenta[c]pyrrol-4-yl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-3a(lH)- yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,4S,6aS
hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-4-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, (3aR,6aS hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- 6(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin- 6-yl, 2,3,4,9-tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3- dihydro-lH-pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindol-2-yl, octahydro-2H- isoindol-2-yl, (3aS)-l,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-lH- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl,
2.5- diazabicyclo[2.2.1]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, (lR,5S,6s)-3-azabicyclo[3.1.0]hex-3-yl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexan-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hex-6-yl, (lR,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, (lS,5R,6R)-3-azabicyclo[3.2.0]hept-3-yl, (1S,5R,6S)- 3-azabicyclo[3.2.0]hept-3-yl, (lS,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 a compound of Formula (Ial), (Ia2), (Ia3), (Ia5), (Ia6), (Ia7), (Ia8), (lall), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, R6 is:
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, lH-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 a compound of Formula (Ial), (Ia2), (Ia3),
(Ia5), (Ia6), (Ia7), (Ia8), (lall), (Ial2), (Ial5), (Ial6), (Ial7), (Ial8), (Ial9), (Ia20), (Ia21), (Ia22), (Ia23), (Ia24), (Ia25), (Ia26), (Ia27), (Ia28), (Ia29), (Ia30), and (Ia31) or a form thereof wherein, R6 is:
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from lH-pyrrol-l-yl, thiazol-2-yl, 1H-
1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan-l-yl. An embodiment of the present description includes a tricyclic compound of Formula (la) selected from a compound of Formula (Ia3), Formula (Ia5), Formula (Ial2), Formula (Ial6), Formula (Ial7), Formula (Ial9), Formula (Ia20), Formula (Ia21), and Formula (Ia31) or a form thereof:
Figure imgf000041_0001
(Ia3) (Ia5) (Ial2)
Figure imgf000041_0002
(Ial6) (Ial7) (Ial9)
Figure imgf000041_0003
(Ia20) (Ia21), and (Ia31);
wherein the form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Another embodiment of the present description includes a tetracyclic compound of Formula (lb) selected from a compound of Formula (Ibl), Formula (Ib2), Formula (Ib3), Formula (Ib4), Formula (Ib5), Formula (Ib6), Formula (Ib7), Formula (Ib8), Formula (Ib9), Formula (IblO), Formula (Ibll), Formula (Ibl2), Formula (Ibl3), Formula (Ibl4), Formula (Ibl5), Formula (Ibl6), Formula (Ibl7), Formula (Ibl8), Formula (Ibl9), Formula (Ib20), Formula (Ib21), Formula (Ib22), Formula (Ib23), Formula (Ib24), Formula (Ib25), Formula (Ib26), Formula (Ib27), Formula (Ib28), Formula (Ib29), Formula (Ib30), Formula (Ib31), Formula (Ib32), Formula (Ib33), Formula (Ib34), Formula (Ib35), Formula (Ib36), Formula (Ib37), Formula (Ib38), Formula (Ib39), Formula (Ib40), Formula (Ib41), Formula (Ib42), Formula (Ib43), Formula (Ib44), Formula (Ib45), Formula (Ib46), Formula (Ib47), Formula (Ib48), Formula (Ib49), Formula (Ib50), Formula (Ib51), Formula (Ib52), Formula (Ib53), Formula (Ib54), Formula (Ib55), Formula (Ib56), Formula (Ib57), Formula (Ib58), Formula (Ib59), Formula (Ib60), Formula (Ib61), Formula (Ib62), Formula (Ib63), Formula (Ib64), Formula (Ib65), Formula (Ib66), Formula (Ib67), Formula (Ib68), Formula (Ib69), Formula (Ib70), Formula (Ib71), Formula (Ib72), Formula (Ib73), Formula (Ib74), Formula (Ib75), Formula (Ib76), Formula (Ib77), Formula (Ib78), Formula (Ib79), Formula (Ib80), Formula (Ib81), Formula (Ib82), Formula (Ib83), Formula (Ib84), Formula (Ib85), Formula (Ib86), Formula (Ib87), Formula (Ib88), Formula (Ib89), or Formula (Ib90), or a form thereof;
Figure imgf000042_0001
(Ib6) (Ib7) (Ib8) (Ib9) (IblO)
Figure imgf000043_0001
(Ib26) (Ib27) (Ib28) (Ib29) (Ib30)
Figure imgf000044_0001
(Ib46) (Ib47) (Ib48) (Ib49) (Ib50)
Figure imgf000045_0001
(Ib66) (Ib67) (Ib68) (Ib69) (Ib70)
Figure imgf000046_0001
(Ib86) (Ib87) (Ib88) (lb 89), and (Ib90); wherein the 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 present description includes a compound of Formula (lb), wherein the compound of Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (Ib45), (Ib46), (Ib47), (Ib48), (Ib49), (Ib50), (Ib51), (Ib52), (Ib53), (Ib54), (Ib55), (Ib56), (Ib57), (Ib58), (Ib59), (Ib60), (Ib61), (Ib62), (Ib63), (Ib64), (Ib65), (Ib66), (Ib67), (Ib68), (Ib69), (Ib70), (Ib71), (Ib72), (Ib73), (Ib74), (Ib75), (Ib76), (Ib77), (Ib78), (Ib79), (Ib80), (Ib81), (Ib82), (Ib83), (Ib84), (Ib85), (Ib86), (Ib87), (Ib88), (Ib89) and (Ib90) is substituted with one or more Rsa, Rsb, 5c, R5d, and Rse substituents each, when present, selected from the group consisting of:
hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci_8alkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl,
Ci_8alkyl-carbonyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
Ci-8alkyl-sulfinyl-Ci_8alkyl, Ci-salkyl-sulfonyl-Ci-salkyl, amino-carbonyl, amino, Ci-8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2-8alkenyl-amino,
(C2-8alkenyl)2-amino, C2-salkynyl, C2-8alkynyl-amino, (C2-salkynyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl,
C2-8alkenyl-amino-Ci_8alkyl, (C2-8alkenyl)2-amino-Ci_8alkyl,
C2-8alkynyl-amino-Ci_8alkyl, (C2-8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci_8alkyl)2-amino-Ci_8alkyl, Ci_8alkoxy-Ci_salkyl,
hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci_8alkoxy-Ci_8alkyl)2-amino, Ci_8alkoxy-Ci_8alkyl-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl,Ci-8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino, amino-Ci-salkyl-amino-Ci-salkyl, (amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (amino-Ci_8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci-8alkyl, (Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci_8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino,
(hydroxyl-Ci-8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino,
(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl-amino,
[(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-amino-Ci-salkyl-carbonyl,
(Ci-8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_8alkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3_i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino,
(aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl,
(aryl,Ci-8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-Ci-salkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci_8alkyl-amino-Ci_8alkyl, (aryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,
(aryl-Ci-8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci_8alkyl-amino-Ci_8alkyl,
(heteroaryl,Ci-8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci-salkyl, (heterocyclyl,Ci-8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl,
(heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl, (heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci_8alkyl,Ci_8alkyl)amino,
Ci-8alkyl-amino-Ci-8alkyl-amino, (Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci-8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci_8alkyl, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci-8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl,
C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-Ci-salkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino,
(aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, (aryl-Ci_8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_salkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci-8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci-8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci-8alkyl)2-amino-Ci-8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci-8alkyl or heterocyclyl-oxy;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and, R9 is Ci-salkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci-8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci-salkyl-amino.
The present description further relates to a compound of Formula Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (Ib45), (Ib46), (Ib47), (Ib48), (Ib49), (Ib50), (Ib51), (Ib52), (Ib53), (Ib54), (Ib55), (Ib56), (Ib57), (Ib58), (Ib59), (Ib60), (Ib61), (Ib62), (Ib63), (Ib64), (Ib65), (Ib66), (Ib67), (Ib68), (Ib69), (Ib70), (Ib71), (Ib72), (Ib73), (Ib74), (Ib75), (Ib76), (Ib77), (Ib78), (Ib79), (Ib80), (Ib81), (Ib82), (Ib83), (Ib84), (Ib85), (Ib86),
(Ib87), (Ib88), (Ib89) and (Ib90) or a form thereof wherein, when R5a, R5b, Rsc, Rsd and R5e is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C3_i4cycloalkyl 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl,
1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][l,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b] [ 1 ,4]oxazin-(4aH)-yl, hexahydro- 1 H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro- lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro- lH- pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- l ,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)- lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo [2.2.1 Jheptyl, 2,5 -diazabicyclo [2.2.1 Jheptanyl, 2-azabicyclo [2.2.1 ]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexyl, (lR,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (lS,5R,6S)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (lS,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 or 2,8-diazaspiro[4.5]decanyl.
The present description further relates to a compound of Formula (Ibl), (Ib2), (Ib3),
(Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (Ib45), (Ib46), (Ib47), (Ib48), (Ib49), (Ib50), (Ib51), (Ib52), (Ib53), (Ib54), (Ib55), (Ib56), (Ib57), (Ib58), (Ib59), (Ib60), (Ib61), (Ib62), (Ib63), (Ib64), (Ib65), (Ib66), (Ib67), (Ib68), (Ib69), (Ib70), (Ib71), (Ib72), (Ib73), (Ib74), (Ib75), (Ib76), (Ib77), (Ib78), (Ib79), (Ib80), (Ib81), (Ib82), (Ib83), (Ib84), (Ib85), (Ib86), (Ib87), (Ib88), (Ib89) and (Ib90) or a form thereof wherein, when Rsa, Rsb, Rsc, R5d and Rse is
C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C3_i4cycloalkyl 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,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][l,4]oxazin-4-yl,
3.4- dihydroisoquinolin-2( lH)-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][l,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][l,4]oxazin-4(4aH)-yl, hexahydro-lH-cyclopenta[c]pyrrol-2-yl, (cis)- octahydrocyclopenta[c]pyrrol-4-yl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-3a(lH)- yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,4S,6aS
hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-4-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, (3aR,6aS hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- 6(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin- 6-yl, 2,3,4,9-tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3- dihydro-lH-pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindol-2-yl, octahydro-2H- isoindol-2-yl, (3aS)-l,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-lH- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl,
2.5- diazabicyclo[2.2.1]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, (lR,5S,6s)-3-azabicyclo[3.1.0]hex-3-yl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexan-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hex-6-yl, (lR,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, (lS,5R,6R)-3-azabicyclo[3.2.0]hept-3-yl, (1S,5R,6S)- 3-azabicyclo[3.2.0]hept-3-yl, (lS,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 a compound of Formula Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl 8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (Ib45), (Ib46), (Ib47), (Ib48), (Ib49), (Ib50), (Ib51), (Ib52), (Ib53), (Ib54), (Ib55), (Ib56), (Ib57), (Ib58), (Ib59), (Ib60), (Ib61), (Ib62), (Ib63), (Ib64), (Ib65), (Ib66), (Ib67), (Ib68), (Ib69), (Ib70), (Ib71), (Ib72), (Ib73), (Ib74), (Ib75), (Ib76), (Ib77), (Ib78), (Ib79), (Ib80), (Ib81), (Ib82), (Ib83), (Ib84), (Ib85), (Ib86), (Ib87), (Ib88), (Ib89) and (Ib90) or a form thereof wherein, R6 is:
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1 ,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, lH-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 a compound of Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (Ib45), (Ib46), (Ib47), (Ib48), (Ib49), (Ib50), (Ib51), (Ib52), (Ib53), (Ib54), (Ib55), (Ib56), (Ib57), (Ib58), (Ib59), (Ib60), (Ib61), (Ib62), (Ib63), (Ib64), (Ib65), (Ib66), (Ib67), (Ib68), (Ib69), (Ib70), (Ib71), (Ib72), (Ib73), (Ib74), (Ib75), (Ib76), (Ib77), (Ib78), (Ib79), (Ib80), (Ib81), (Ib82), (Ib83), (Ib84), (Ib85), (Ib86), (Ib87), (Ib88), (Ib89) and (Ib90) or a form thereof wherein, R6 is:
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from lH-pyrrol-l-yl, thiazol-2-yl, 1H-
1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan-l-yl.
An embodiment of the present description includes a compound of Formula (lb), wherein the compound of Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (Ib45), (Ib46), (Ib47), (Ib48), (Ib49), (Ib50), (Ib51), (Ib52), (Ib53), (Ib54), (Ib55), (Ib56), (Ib57), (Ib58), (Ib59), (Ib60), (Ib61), (Ib62), (Ib63), (Ib64), (Ib65), (Ib66), (Ib67), (Ib68), (Ib69), (Ib70), (Ib71), (Ib72), (Ib73), (Ib74), (Ib75), (Ib76), (Ib77), (Ib78), (Ib79), (Ib80), (Ib81), (Ib82), (Ib83), (Ib84), (Ib85), (Ib86), (Ib87), (Ib88), (Ib89), and (Ib90) is substituted with one or more Rsa, Rsb, 5c, R5d, and Rse substituents each, when present, selected from the group consisting of:
hydrogen, halogen, cyano, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl,
Ci-8alkyl-carbonyl-oxy-Ci_8alkyl, Ci-salkyl-sulfinyl-Ci-salkyl, Ci-8alkyl-sulfonyl-Ci_8alkyl, (Ci_8alkyl)2-amino, C2-salkenyl, amino-Ci-salkyl, Ci-ioalkyl-amino-Ci_8alkyl, (Ci_ioalkyl)2-amino-Ci-8alkyl,Ci-8alkoxy-Ci_8alkyl, hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl, C3_i4cycloalkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy-Ci-salkyl, heteroaryl-Ci-salkyl, heterocyclyl, heterocyclyl-Ci_8alkyl, heterocyclyl-oxy-Ci-salkyl or
heterocyclyl-Ci-8alkoxy-Ci_8alkyl;
wherein each instance of aryl and heterocyclyl is optionally substituted with one substituent selected from R6; and,
R6 is (Ci-8alkyl)2-amino or (Ci-salkyl^-amino-Ci-salkyl.
The present description further relates to a compound of Formula Formula (Ibl),
(Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (Ib45), (Ib46), (Ib47), (Ib48), (Ib49), (Ib50), (Ib51), (Ib52), (Ib53), (Ib54), (Ib55), (Ib56), (Ib57), (Ib58), (Ib59), (Ib60), (Ib61), (Ib62), (Ib63), (Ib64), (Ib65), (Ib66), (Ib67), (Ib68), (Ib69), (Ib70), (Ib71), (Ib72), (Ib73), (Ib74), (Ib75), (Ib76), (Ib77), (Ib78), (Ib79), (Ib80), (Ib81), (Ib82), (Ib83), (Ib84), (Ib85), (Ib86), (Ib87), (Ib88), (Ib89) and (Ib90) or a form thereof wherein, when R5a, R5b, Rsc, Rsd and R5e is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C3_i4cycloalkyl 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][l,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b] [ 1 ,4]oxazin-(4aH)-yl, hexahydro- 1 H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro-lH- pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- l,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo [2.2.1 Jheptyl, 2,5 -diazabicyclo [2.2.1 Jheptanyl, 2-azabicyclo [2.2.1 ]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexyl, (lR,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.OJhexyl, ( lR,5S)-3-azabicyclo[3.1.OJhexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (lS,5R,6S)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (lS,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 or 2,8-diazaspiro[4.5]decanyl.
The present description further relates to a compound of Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibll), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (Ib45), (Ib46), (Ib47), (Ib48), (Ib49), (Ib50), (Ib51), (Ib52), (Ib53), (Ib54), (Ib55), (Ib56), (Ib57), (Ib58), (Ib59), (Ib60), (Ib61), (Ib62), (Ib63), (Ib64), (Ib65), (Ib66), (Ib67), (Ib68), (Ib69), (Ib70), (Ib71), (Ib72), (Ib73), (Ib74), (Ib75), (Ib76), (Ib77), (Ib78), (Ib79), (Ib80), (Ib81), (Ib82), (Ib83), (Ib84), (Ib85), (Ib86), (Ib87), (Ib88), (Ib89) and (Ib90) or a form thereof wherein, when Rsa, Rsb, Rsc, R5d and Rse is
C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C3_i4cycloalkyl 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,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][l,4]oxazin-4-yl, 3,4-dihydroisoquinolin-2(lH)-yl, 1,2,3,4-tetrahydroisoquinolin-l-yl, 1,2,3,4- tetrahydroquinoxalin- 1 -yl, (6H)-pyrrolo[3 ,4-b] [ 1 ,4]oxazin-6(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][l,4]oxazin-4(4aH)-yl, hexahydro-lH-cyclopenta[c]pyrrol-2-yl, (cis)- octahydrocyclopenta[c]pyrrol-4-yl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-3a(lH)- yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,4S,6aS
hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-4-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, (3aR,6aS hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- 6(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin- 6-yl, 2,3,4,9-tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3- dihydro-lH-pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindol-2-yl, octahydro-2H- isoindol-2-yl, (3aS)-l,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-lH- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl, 2,5-diazabicyclo[2.2.1]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, (lR,5S,6s)-3-azabicyclo[3.1.0]hex-3-yl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexan-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hex-6-yl, (lR,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, (lS,5R,6R)-3-azabicyclo[3.2.0]hept-3-yl, (1S,5R,6S)- 3-azabicyclo[3.2.0]hept-3-yl, (lS,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.
An embodiment of the present description includes a compound of Formula (lb), wherein the compound of Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6), (Ib7), (Ib8), (Ib9), (IblO), (Ibl l), (Ibl2), (Ibl3), (Ibl4), (Ibl5), (Ibl6), (Ibl7), (Ibl8), (Ibl9), (Ib20), (Ib21), (Ib22), (Ib23), (Ib24), (Ib25), (Ib26), (Ib27), (Ib28), (Ib29), (Ib30), (Ib31), (Ib32), (Ib33), (Ib34), (Ib35), (Ib36), (Ib37), (Ib38), (Ib39), (Ib40), (Ib41), (Ib42), (Ib43), (Ib44), (Ib45), (Ib46), (Ib47), (Ib48), (Ib49), (Ib50), (Ib51), (Ib52), (Ib53), (Ib54), (Ib55), (Ib56), (Ib57), (Ib58), (Ib59), (Ib60), (Ib61), (Ib62), (Ib63), (Ib64), (Ib65), (Ib66), (Ib67), (Ib68), (Ib69), (Ib70), (Ib71), (Ib72), (Ib73), (Ib74), (Ib75), (Ib76), (Ib77), (Ib78), (Ib79), (Ib80), (Ib81), (Ib82), (Ib83), (Ib84), (Ib85), (Ib86), (Ib87), (Ib88), (Ib89), and (Ib90) is substituted with one or more Rsa, Rsb, R5c, R5d, and Rse substituents each, when present, selected from the group consisting of:
hydrogen, Ci-salkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci_8alkyl;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino. Another embodiment of the present description includes a tetracyclic compound of Formula (lb) selected from a compound of Formula (Ibl), Formula (Ib2), Formula (Ibl6), and Formula (Ib76), or a form thereof;
Figure imgf000059_0001
wherein the form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Another embodiment of the present description includes a tetracyclic compound of Formula (Ic) selected from a compound of Formula (Icl), Formula (Ic2), Formula (Ic3), Formula (Ic4), Formula (Ic5), Formula (Ic6), Formula (Ic7), Formula (Ic8), Formula (Ic9), Formula (IclO), Formula (Icl l), Formula (Icl2), Formula (Icl3), Formula (Icl4), Formula (Icl5), Formula (Icl6), Formula (Icl7), Formula (Icl8), Formula (Icl9), Formula (Ic20), Formula (Ic21), Formula (Ic22), Formula (Ic23), Formula (Ic24), Formula (Ic25), Formula (Ic26), Formula (Ic27), Formula (Ic28), Formula (Ic29), Formula (Ic30), Formula (Ic31), Formula (Ic32), Formula (Ic33), Formula (Ic34), Formula (Ic35), Formula (Ic36), Formula (Ic37), Formula (Ic38), Formula (Ic39), Formula (Ic40), Formula (Ic41), Formula (Ic42), Formula (Ic43), Formula (Ic44), Formula (Ic45), Formula (Ic46), Formula (Ic47), Formula (Ic48), Formula (Ic49), Formula (Ic50), Formula (Ic51), Formula (Ic52), Formula (Ic53), Formula (Ic54), Formula (Ic55), Formula (Ic56), Formula (Ic57), Formula (Ic58), Formula (Ic59), Formula (Ic60), Formula (Ic61), Formula (Ic62), Formula (Ic63), Formula (Ic64), Formula (Ic65), Formula (Ic66), Formula (Ic67), Formula (Ic68), Formula (Ic69), Formula (Ic70), Formula (Ic71), Formula (Ic72), Formula (Ic73), Formula (Ic74), Formula (Ic75), Formula (Ic76), Formula (Ic77), Formula (Ic78), Formula (Ic79), Formula (Ic80), Formula (Ic81), Formula (Ic82), Formula (Ic83), Formula (Ic84), Formula (Ic85), Formula (Ic86), Formula (Ic87), Formula (Ic88), Formula (Ic89), or Formula (Ic90), or a form thereof;
Figure imgf000060_0001
(Ic5) (Ic6) (Ic7) (Ic8)
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
(Ic89), and (Ic90);
wherein the 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 present description includes a compound of Formula (Ic), wherein the compound of Formula (Icl), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Icl l), (Icl2), (Icl3), (Icl4), (Icl5), (Icl6), (Icl7), (Icl8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (Ic45), (Ic46), (Ic47), (Ic48), (Ic49), (Ic50), (Ic51), (Ic52), (Ic53), (Ic54), (Ic55), (Ic56), (Ic57), (Ic58), (Ic59), (Ic60), (Ic61), (Ic62), (Ic63), (Ic64), (Ic65), (Ic66), (Ic67), (Ic68), (Ic69), (Ic70), (Ic71), (Ic72), (Ic73), (Ic74), (Ic75), (Ic76), (Ic77), (Ic78), (Ic79), (Ic80), (Ic81), (Ic82), (Ic83), (Ic84), (Ic85), (Ic86), (Ic87), (Ic88), (Ic89) and (Ic90) is substituted with one or more Rsa, Rsb, 5c, R5d, and Rse substituents each, when present, selected from the group consisting of:
hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl,
Ci_8alkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl, Ci_8alkyl-carbonyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl, Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
Ci_8alkyl-sulfinyl-Ci_8alkyl, Ci_8alkyl-sulfonyl-Ci_8alkyl, amino-carbonyl, amino, Ci-8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2-8alkenyl-amino,
(C2-8alkenyl)2-amino, C2-salkynyl, C2-8alkynyl-amino, (C2-8alkynyl)2-amino, amino-Ci_8alkyl, Ci_ioalkyl-amino-Ci_8alkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl, C2-8alkenyl-amino-Ci_8alkyl, (C2-8alkenyl)2-amino-Ci_8alkyl,
C2-8alkynyl-amino-Ci_8alkyl, (C2-8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl, hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci-8alkoxy-Ci_8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci-8alkoxy-Ci-8alkyl,Ci-8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci_8alkyl]amino, amino-Ci-salkyl-amino-Ci-salkyl, (amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (amino-Ci_8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,
(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci_8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino,
(hydroxyl-Ci-8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino,
(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl-amino,
[(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-amino-Ci-salkyl-carbonyl,
(Ci_8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_salkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3_i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl, (C3_i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl,
(aryl,Ci-8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-C i-salkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci-8alkyl-amino-Ci_8alkyl, (aryl-Ci-8alkyl,Ci_8alkyl)amino-Ci_8alkyl, (aryl-Ci-8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl,Ci-8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci-salkyl, (heterocyclyl,Ci-8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl,
(heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci-8alkyl,Ci_8alkyl)amino,
Ci-8alkyl-amino-Ci-8alkyl-amino, (Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci_8alkyl)2-amino-Ci_8alkyl, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci-8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl,
C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-Ci-salkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino,
(aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl, (aryl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci_8alkyl or heterocyclyl-oxy;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
R9 is Ci_8alkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci-8alkyl-amino-Ci-8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci-salkyl-amino.
The present description further relates to a compound of Formula Formula (Icl), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Icl l), (Icl2), (Icl3), (Icl4), (Icl5), (Icl6), (Icl7), (Icl8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (Ic45), (Ic46), (Ic47), (Ic48), (Ic49), (Ic50), (Ic51), (Ic52), (Ic53), (Ic54), (Ic55), (Ic56), (Ic57), (Ic58), (Ic59), (Ic60), (Ic61), (Ic62), (Ic63), (Ic64), (Ic65), (Ic66), (Ic67), (Ic68), (Ic69), (Ic70), (Ic71), (Ic72), (Ic73), (Ic74), (Ic75), (Ic76), (Ic77), (Ic78), (Ic79), (Ic80), (Ic81), (Ic82), (Ic83), (Ic84), (Ic85), (Ic86), (Ic87), (Ic88), (Ic89) and (Ic90) or a form thereof wherein, when Rsa, Rsb, Rsc, R5d and Rse is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C3_i4cycloalkyl 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl,
1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][l,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b] [ 1 ,4]oxazin-(4aH)-yl, hexahydro- 1 H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl,
(3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro-lH- pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- l,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo [2.2.1 Jheptyl, 2,5 -diazabicyclo [2.2.1 Jheptanyl, 2-azabicyclo [2.2.1 ]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexyl, (lR,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (lS,5R,6S)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (lS,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 or 2,8-diazaspiro[4.5]decanyl.
The present description further relates to a compound of Formula (Icl), (Ic2), (Ic3),
(Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Icl l), (Icl2), (Icl3), (Icl4), (Icl5), (Icl 6), (Icl7), (Icl8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (Ic45), (Ic46), (Ic47), (Ic48), (Ic49), (Ic50), (Ic51), (Ic52), (Ic53), (Ic54), (Ic55), (Ic56), (Ic57), (Ic58), (Ic59), (Ic60), (Ic61), (Ic62), (Ic63), (Ic64), (Ic65), (Ic66), (Ic67), (Ic68), (Ic69), (Ic70), (Ic71), (Ic72), (Ic73), (Ic74), (Ic75), (Ic76), (Ic77), (Ic78), (Ic79), (Ic80), (Ic81), (Ic82), (Ic83), (Ic84), (Ic85), (Ic86), (Ic87), (Ic88), (Ic89) and (Ic90) or a form thereof wherein, when Rsa, Rsb, Rsc, R5d and Rse is
C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C3_i4cycloalkyl 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,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][l,4]oxazin-4-yl, 3 ,4-dihydroisoquinolin-2( lH)-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][l,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][l,4]oxazin-4(4aH)-yl, hexahydro-lH-cyclopenta[c]pyrrol-2-yl, (cis)- octahydrocyclopenta[c]pyrrol-4-yl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-3a(lH)- yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,4S,6aS
hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-4-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, (3aR,6aS hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- 6(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin- 6-yl, 2,3,4,9-tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3- dihydro-lH-pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindol-2-yl, octahydro-2H- isoindol-2-yl, (3aS)-l,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-lH- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl, 2,5-diazabicyclo[2.2.1]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, (lR,5S,6s)-3-azabicyclo[3.1.0]hex-3-yl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexan-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hex-6-yl, (lR,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, (lS,5R,6R)-3-azabicyclo[3.2.0]hept-3-yl, (1S,5R,6S)- 3-azabicyclo[3.2.0]hept-3-yl, (lS,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 a compound of Formula Formula (Icl), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Icll), (Icl2), (Icl3), (Icl4), (Icl5), (Icl6), (Icl7), (Icl8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (Ic45), (Ic46), (Ic47), (Ic48), (Ic49), (Ic50), (Ic51), (Ic52), (Ic53), (Ic54), (Ic55), (Ic56), (Ic57), (Ic58), (Ic59), (Ic60), (Ic61), (Ic62), (Ic63), (Ic64), (Ic65), (Ic66), (Ic67), (Ic68), (Ic69), (Ic70), (Ic71), (Ic72), (Ic73), (Ic74), (Ic75), (Ic76), (Ic77), (Ic78), (Ic79), (Ic80), (Ic81), (Ic82), (Ic83), (Ic84), (Ic85), (Ic86), (Ic87), (Ic88), (Ic89) and (Ic90) or a form thereof wherein, R6 is:
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, lH-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 a compound of Formula (Icl), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Icl l), (Icl2), (Icl3), (Icl4), (Icl5), (Icl 6), (Icl7), (Ic l8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (Ic45), (Ic46), (Ic47), (Ic48), (Ic49), (Ic50), (Ic51), (Ic52), (Ic53), (Ic54), (Ic55), (Ic56), (Ic57), (Ic58), (Ic59), (Ic60), (Ic61), (Ic62), (Ic63), (Ic64), (Ic65), (Ic66), (Ic67), (Ic68), (Ic69), (Ic70), (Ic71), (Ic72), (Ic73), (Ic74), (Ic75), (Ic76), (Ic77), (Ic78), (Ic79), (Ic80), (Ic81), (Ic82), (Ic83), (Ic84), (Ic85), (Ic86), (Ic87), (Ic88), (Ic89) and (Ic90) or a form thereof wherein, R6 is:
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from lH-pyrrol- l-yl, thiazol-2-yl, 1H-
1,2,3-triazol- l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol- l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin- l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin- l-yl, piperazin-2-yl, morpholin-4-yl or 1,4- diazepan- l-yl.
An embodiment of the present description includes a compound of Formula (Ic), wherein the compound of Formula (Ic l), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Ic l l), (Icl2), (Icl3), (Ic l4), (Icl5), (Icl 6), (Ic l7), (Icl8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (Ic45), (Ic46), (Ic47), (Ic48), (Ic49), (Ic50), (Ic51), (Ic52), (Ic53), (Ic54), (Ic55), (Ic56), (Ic57), (Ic58), (Ic59), (Ic60), (Ic61), (Ic62), (Ic63), (Ic64), (Ic65), (Ic66), (Ic67), (Ic68), (Ic69), (Ic70), (Ic71), (Ic72), (Ic73), (Ic74), (Ic75), (Ic76), (Ic77), (Ic78), (Ic79), (Ic80), (Ic81), (Ic82), (Ic83), (Ic84), (Ic85), (Ic86), (Ic87), (Ic88), (Ic89) and (Ic90) is substituted with one or more Rsa, Rsb, 5c, R5d, and Rse substituents each, when present, selected from the group consisting of:
hydrogen, Ci-salkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci_8alkyl; wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino.
The present description further relates to a compound of Formula Formula (Icl), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Icll), (Icl2), (Icl3), (Icl4), (Icl5), (Icl6), (Icl7), (Icl8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (Ic45), (Ic46), (Ic47), (Ic48), (Ic49), (Ic50), (Ic51), (Ic52), (Ic53), (Ic54), (Ic55), (Ic56), (Ic57), (Ic58), (Ic59), (Ic60), (Ic61), (Ic62), (Ic63), (Ic64), (Ic65), (Ic66), (Ic67), (Ic68), (Ic69), (Ic70), (Ic71), (Ic72), (Ic73), (Ic74), (Ic75), (Ic76), (Ic77), (Ic78), (Ic79), (Ic80), (Ic81), (Ic82), (Ic83), (Ic84), (Ic85), (Ic86), (Ic87), (Ic88), (Ic89) and (Ic90) or a form thereof wherein, when Rsa, Rsb, Rsc, R5d, and Rse is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C3_i4cycloalkyl 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][l,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b] [ 1 ,4]oxazin-(4aH)-yl, hexahydro- 1 H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro- lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro- lH- pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- l ,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)- lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo [2.2.1 Jheptyl, 2,5 -diazabicyclo [2.2.1 Jheptanyl, 2-azabicyclo [2.2.1 ]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexyl, (lR,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (lS,5R,6S)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (lS,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 or 2,8-diazaspiro[4.5]decanyl.
The present description further relates to a compound of Formula (Icl), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6), (Ic7), (Ic8), (Ic9), (IclO), (Icl l), (Icl2), (Icl3), (Icl 4), (Icl5), (Icl6), (Icl7), (Ic l8), (Icl9), (Ic20), (Ic21), (Ic22), (Ic23), (Ic24), (Ic25), (Ic26), (Ic27), (Ic28), (Ic29), (Ic30), (Ic31), (Ic32), (Ic33), (Ic34), (Ic35), (Ic36), (Ic37), (Ic38), (Ic39), (Ic40), (Ic41), (Ic42), (Ic43), (Ic44), (Ic45), (Ic46), (Ic47), (Ic48), (Ic49), (Ic50), (Ic51), (Ic52), (Ic53), (Ic54), (Ic55), (Ic56), (Ic57), (Ic58), (Ic59), (Ic60), (Ic61), (Ic62), (Ic63), (Ic64), (Ic65), (Ic66), (Ic67), (Ic68), (Ic69), (Ic70), (Ic71), (Ic72), (Ic73), (Ic74), (Ic75), (Ic76), (Ic77), (Ic78), (Ic79), (Ic80), (Ic81), (Ic82), (Ic83), (Ic84), (Ic85), (Ic86), (Ic87), (Ic88), (Ic89) and (Ic90) or a form thereof wherein, when Rsa, Rsb, Rsc, R5d and Rse is
C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C3_i4cycloalkyl 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 IH-pyrrol-l-yl, thiazol-2-yl, 1H- 1,2,3-triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, lH-imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl is selected in each instance, when present, from azetidin-l-yl, tetrahydrofuran-2- yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,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][l,4]oxazin-4-yl,
3.4- dihydroisoquinolin-2( lH)-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][l,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][l,4]oxazin-4(4aH)-yl, hexahydro-lH-cyclopenta[c]pyrrol-2-yl, (cis)- octahydrocyclopenta[c]pyrrol-4-yl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-3a(lH)- yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,4S,6aS
hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazin-4-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, (3aR,6aS hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- 6(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)- hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin- 6-yl, 2,3,4,9-tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3- dihydro-lH-pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindol-2-yl, octahydro-2H- isoindol-2-yl, (3aS)-l,3,3a,4,5,6-hexahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-lH- isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl,
2.5- diazabicyclo[2.2.1]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, (lR,5S,6s)-3-azabicyclo[3.1.0]hex-3-yl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexan-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hex-6-yl, (lR,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, (lS,5R,6R)-3-azabicyclo[3.2.0]hept-3-yl, (lS,5R,6S)-3-azabicyclo[3.2.0]hept-3-yl, (lS,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.
Another embodiment of the present description includes a tetracyclic compound of Formula (Ic) selected from a compound of Formula (Icl), or a form thereof:
Figure imgf000076_0001
del);
wherein the form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Another embodiment of the present description includes a compound selected from a compound of Formula (la), Formula (lb), and Formula (Ic) substituted with one or more Rsa, R5b, R5c, R5d, and Rse substituents wherein, the term "(Ixn)" in the tables below indicates whether the compound is selected from a compound of Formula (lal) to Formula (Ia31), Formula (Ibl) to Formula (Ib90), or Formula (Icl) to Formula (Ib90).
Figure imgf000076_0002
Figure imgf000076_0003
Figure imgf000077_0001
Figure imgf000077_0004
Figure imgf000077_0002
Figure imgf000077_0005
Figure imgf000077_0003
Figure imgf000077_0006
Figure imgf000078_0001
Figure imgf000078_0003
(Ial9)
Figure imgf000078_0002
Figure imgf000078_0004
Figure imgf000079_0001
Figure imgf000079_0003
Figure imgf000079_0002
Figure imgf000079_0004
Figure imgf000080_0001
Figure imgf000080_0002
Figure imgf000081_0001
Figure imgf000081_0004
Figure imgf000081_0002
Figure imgf000081_0005
Figure imgf000081_0003
Figure imgf000081_0006
Figure imgf000082_0001
Figure imgf000082_0003
Figure imgf000082_0002
Figure imgf000082_0004
Figure imgf000083_0001
An embodiment of the present description includes a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof selected from the group consisting of:
Figure imgf000083_0002
Figure imgf000084_0001
83
Figure imgf000085_0001
84
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
87
Figure imgf000089_0001
Figure imgf000090_0001
111 112 113, and 114; wherein the form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof. Another embodiment of the present description includes a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof (wherein compound number (# ) indicates that the salt form was isolated) selected from the group consisting of:
Cpd Name
4-hydroxy-8,9-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
2 b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
3 b]pyridine-3-carboxylic acid
8-ethyl-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
4 b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-8-propyl- 1,2,5,6,7,8-
5 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid
8-cyclopropyl-4-hydroxy-9-methyl-2-oxo-l, 2,5, 6,7,8-
6 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid
7- hydroxy-2,3-dimethyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-
8 b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-
9 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
10 b]pyridine-3-carboxylic acid
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
11 b]pyridine-3-carboxylic acid
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9, 10- 121 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-2-oxo-2,5,6,7,9,10,l l, 12-octahydro-lH-
131 pyrido[3'\2'':6 7 cyclohepta[l\2 ,5]imidazo[l,2-a]pyridine-3-carboxylic acid
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic 141 acid
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7 , 8- 161 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 171 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8,9,10-trimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
19 b]pyridine-3-carboxylic acid
8- ethyl-4-hydroxy-9,10-dimethyl-2-oxo-l,2,5, 6,7,8-
20 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- 211 carboxylic acid Cpd Name
2- ethyl-7-hydroxy-3-methyl-9-oxo-3,4,5,6,9,10-
22 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2,3-diethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cycloliepta[l,2-
23 b]pyridine-8-carboxylic acid
7- hydroxy-l-methyl-9-oxo- 1,4,5,6,9, 10-hexahydropyrazolo[4',3':6,7]cyclohepta[l,2-
24 b]pyridine-8-carboxylic acid
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,9-hexaliydropyrrolo[3',4':6,7]cycloliepta[l,2-
25 b]pyridine-3-carboxylic acid
8- hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- 261 carboxylic acid
3- (2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-
281 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-(methoxymethyl)-9-oxo-3,4,5,6,9,10- 29 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
8-hydroxy-2,3-dimethyl-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 301 c]azepine-9-carboxylic acid
2-ethyl-7-hydroxy-9-oxo-2,4,5,6,9,10-hexahydro[l,2,3]triazolo[4',5':6,7]cyclohepta[l,2- 31 b]pyridine-8-carboxylic acid
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 321 c]azepine-9-carboxylic acid
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 331 c]azepine-9-carboxylic acid
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 341 c]azepine-9-carboxylic acid
3- ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine- 351 9-carboxylic acid
2- chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 361 c]azepine-9-carboxylic acid
3- ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo-3,4,5,6,9,10-
37 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2-[(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- 381 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-methyl-2-oxo-2,6,7,8-tetrahydro-lH-pyrazolo[4',3':4,5]oxepino[3,2-
39 b]pyridine-3-carboxylic acid
2- [(benzyloxy)methyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
40 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- 411 f][l,4]oxazepine-9-carboxylic acid Cpd Name
3-ethyl-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- 421 f][l,4]oxazepine-9-carboxylic acid
7-hydroxy-2-(methoxymethyl)-3-methyl-9-oxo-3,4,5,6,9,10- 43 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- 441 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- 451 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- 461 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10-
471 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-5,8-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
48 b]pyridine-3-carboxylic acid
3-ethyl-7-hydroxy-2- [(oxetan-3 -yloxy)methyl] -9-oxo-3 ,4, 5 ,6,9, 10-
49 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-9-oxo-3,4,5,6,9,10-
50 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-2,3-dimethyl-9-oxo-2,4,5,6,9,10-hexaliydropyrazolo[4',3':6,7]cycloliepta[l,2-
51 b]pyridine-8-carboxylic acid
7- hydroxy-3-(2-methoxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10-
52 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-(3-hydroxypropyl)-2-oxo-l, 2,5, 6,7,8-
53 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
541 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8-(2-methoxyethyl)-2-oxo-l,2,5,6,7,8-
55 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8-(3-methoxypropyl)-2-oxo-l, 2,5, 6,7,8-
56 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
7-hydroxy-3-(2-hydroxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10-
57 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-[(2-hydroxyethoxy)methyl]-9-oxo-3,4,5,6,9,10-
58 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-etliyl-7-liydroxy-9-oxo-3,4,5,6,9,10- 591 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- 601 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid Cpd Name
4-hydroxy-8-(2-hydroxyethyl)-2-oxo-l,2,5,6,7,8- 61 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- 621 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-2-[(ethylsulfonyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10-
63 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-2-[(ethylsulfinyl)methyl]-7-hydroxy-9-oxo-3,4,5, 6,9,10-
64 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [(acetyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
65 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-3-(3-methoxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10-
66 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-3-(3-hydroxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10-
67 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- [3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 681 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-(2-hydroxyethyl)-9-oxo-3,4,5,6,9,10-
69 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [2-(benzyloxy)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
70 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5S)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8-
71 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
3- ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10-
721 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-[(methylsulfinyl)methyl]-9-oxo-3,4,5,6,9,10- 73 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10- 741 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2-[3-(dimethylamino)propyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- 751 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5R)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8-
76 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(5S)-4-hydroxy-8-(3-methoxypropyl)-5-methyl-2-oxo-l, 2,5, 6,7,8-
77 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(5S)-4-hydroxy-5-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
78 b]pyridine-3-carboxylic acid
(5S)-8-ethyl-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8- 82 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid Cpd Name
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5, 6,9,10-
831 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-
85 carboxylic acid
4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-
86 b]indole-3-carboxylic acid
4-hydroxy-12-methyl-2-oxo-l,2,5,6,7,12-hexahydropyrido[3',2':6,7]cycloliepta[l,2-
87 b]indole-3-carboxylic acid
4-hydroxy-2-oxo- 1,2,5,6,7, 12-hexahydropyrido[3',2':6,7]cyclohepta[l,2-b]indole-3-
88 carboxylic acid
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-
89 3 -carboxylic acid
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1 ,2,5 , 6,7, 8- 901 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,8- 911 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)- 1,2,5,6,7,8- 921 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- 941 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 951 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8- 961 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo- 1,2,5,6,7,8- 971 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9-[3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- 981 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
ll-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 991 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-ll-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- 1001 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- 1011 carboxylic acid
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]indole-3- 102 carboxylic acid
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- 1031 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid Cpd Name
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8- 1041 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 1051 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 1061 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
10-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 1071 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- 1081 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- 1091 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
3-ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10- 1101 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9,10- lll1 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5S)-4-hydroxy-5-methyl-2-oxo-8-(propan-2-yl)-l,2,5,6,7,8- 112 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- 1131 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid, and
(6S)-3-ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-6-methyl-9-oxo-3,4,5, 6,9,10- 114 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; wherein the 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 another embodiment of the present description, the compound or a form thereof is isolated as a salt.
Another embodiment of the present description includes a compound salt of Formula (la), Formula (lb), and Formula (Ic) or a form thereof selected from the group consisting of:
Cpd Name
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-
12 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate
4- hydroxy-2-oxo-2,5 ,6,7,9, 10, 11 , 12-octahydro- 1H- pyrido[3'\2":6 7 cyclohepta[l\2 ,5]imidazo[l,2-a]pyridine-3-carboxylic acid
13 hydrochloride Cpd Name
4-hydroxy-2-oxo-l,5,6 -tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic 14 acid hydrochloride
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7, 8-
16 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
8- [2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
17 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- 21 carboxylic acid hydrochloride
8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- 26 carboxylic acid hydrochloride
3-(2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 28 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate
8-hydroxy-2,3-dimethyl-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 30 c]azepine-9-carboxylic acid hydrochloride
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
32 c]azepine-9-carboxylic acid hydrochloride
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
33 c]azepine-9-carboxylic acid hydrochloride
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
34 c]azepine-9-carboxylic acid hydrochloride
3- ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-
35 9-carboxylic acid hydrochloride
2-chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
36 c]azepine-9-carboxylic acid hydrochloride
2- [(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
38 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3-
41 f][l,4]oxazepine-9-carboxylic acid hydrochloride
3- ethyl-8-hydroxy-10-oxo-5,6,10,ll-tetrahydroimidazo[l,2-d]pyrido[2,3-
42 f][l,4]oxazepine-9-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10-
44 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10-
45 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10-
46 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10-
47 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride Cpd Name
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8-
54 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
59 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10-
60 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- 62 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-[3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 68 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10- 72 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
74 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2- [3-(dimethylamino)propyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
75 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5, 6,9,10-
83 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1,2,5,6,7,8-
90 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4- hydroxy-8-methyl-2-oxo-9-(pyrrolidin- 1-ylmethyl)- 1 ,2,5, 6,7,8-
91 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)-l,2,5,6,7,8-
92 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8-
94 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
9- [(ethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo-l, 2,5, 6,7,8-
95 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8-
96 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-
97 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
9- [3 -(diethylamino)pyrrolidin- 1 -yl] -4-hydroxy-8-methyl-2-oxo- 1,2,5,6,7,8-
98 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate ll-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8-
99 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8-
100 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride Cpd Name
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- 101 carboxylic acid hydrochloride
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8-
103 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8-
104 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8-
105 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
106 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
10-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8-
107 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-
108 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8-
109 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9, 10-
110 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride,
111 and
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- 113 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; wherein the 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.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula
(Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof (wherein compound number (# ) indicates that the salt form was isolated) to the subject, wherein the compound is selected from the group consisting of:
Cpd Name
4-hydroxy-8,9-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
2 b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
3 b]pyridine-3-carboxylic acid
8-ethyl-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
4 b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-8-propyl- 1,2,5,6,7,8-
5 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid
8-cyclopropyl-4-hydroxy-9-methyl-2-oxo-l, 2,5, 6,7,8-
6 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid
7- hydroxy-2,3-dimethyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-
8 b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-
9 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
10 b]pyridine-3-carboxylic acid
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
11 b]pyridine-3-carboxylic acid
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9, 10- 121 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-2-oxo-2,5,6,7,9,10,l l, 12-octahydro-lH-
131 pyrido[3'\2":6 7 cyclohepta[l\2 ,5]imidazo[l,2-a]pyridine-3-carboxylic acid
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic 141 acid
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7 , 8- 161 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 171 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8,9,10-trimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
19 b]pyridine-3-carboxylic acid
8- ethyl-4-hydroxy-9,10-dimethyl-2-oxo-l,2,5, 6,7,8-
20 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- 211 carboxylic acid Cpd Name
2- ethyl-7-hydroxy-3-methyl-9-oxo-3,4,5,6,9,10-
22 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2,3-diethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cycloliepta[l,2-
23 b]pyridine-8-carboxylic acid
7- hydroxy-l-methyl-9-oxo- 1,4,5,6,9, 10-hexahydropyrazolo[4',3':6,7]cyclohepta[l,2-
24 b]pyridine-8-carboxylic acid
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,9-hexaliydropyrrolo[3',4':6,7]cycloliepta[l,2-
25 b]pyridine-3-carboxylic acid
8- hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- 261 carboxylic acid
3- (2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-
281 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-(methoxymethyl)-9-oxo-3,4,5,6,9,10- 29 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
8-hydroxy-2,3-dimethyl-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 301 c]azepine-9-carboxylic acid
2-ethyl-7-hydroxy-9-oxo-2,4,5,6,9,10-hexahydro[l,2,3]triazolo[4',5':6,7]cyclohepta[l,2- 31 b]pyridine-8-carboxylic acid
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 321 c]azepine-9-carboxylic acid
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 331 c]azepine-9-carboxylic acid
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 341 c]azepine-9-carboxylic acid
3- ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine- 351 9-carboxylic acid
2- chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 361 c]azepine-9-carboxylic acid
3- ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo-3,4,5,6,9,10-
37 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2-[(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- 381 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-methyl-2-oxo-2,6,7,8-tetrahydro-lH-pyrazolo[4',3':4,5]oxepino[3,2-
39 b]pyridine-3-carboxylic acid
2- [(benzyloxy)methyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
40 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- 411 f][l,4]oxazepine-9-carboxylic acid Cpd Name
3-ethyl-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- 421 f][l,4]oxazepine-9-carboxylic acid
7-hydroxy-2-(methoxymethyl)-3-methyl-9-oxo-3,4,5,6,9,10- 43 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- 441 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- 451 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- 461 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10-
471 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-5,8-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
48 b]pyridine-3-carboxylic acid
3-ethyl-7-hydroxy-2- [(oxetan-3 -yloxy)methyl] -9-oxo-3 ,4, 5 ,6,9, 10-
49 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-9-oxo-3,4,5,6,9,10-
50 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-2,3-dimethyl-9-oxo-2,4,5,6,9,10-hexaliydropyrazolo[4',3':6,7]cycloliepta[l,2-
51 b]pyridine-8-carboxylic acid
7- hydroxy-3-(2-methoxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10-
52 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-(3-hydroxypropyl)-2-oxo-l, 2,5, 6,7,8-
53 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
541 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8-(2-methoxyethyl)-2-oxo-l,2,5,6,7,8-
55 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8-(3-methoxypropyl)-2-oxo-l, 2,5, 6,7,8-
56 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
7-hydroxy-3-(2-hydroxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10-
57 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-[(2-hydroxyethoxy)methyl]-9-oxo-3,4,5,6,9,10-
58 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-etliyl-7-liydroxy-9-oxo-3,4,5,6,9,10- 591 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- 601 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid Cpd Name
4-hydroxy-8-(2-hydroxyethyl)-2-oxo-l,2,5,6,7,8- 61 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- 621 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-2-[(ethylsulfonyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10-
63 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-2-[(ethylsulfinyl)methyl]-7-hydroxy-9-oxo-3,4,5, 6,9,10-
64 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [(acetyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
65 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-3-(3-methoxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10-
66 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-3-(3-hydroxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10-
67 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- [3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 681 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-(2-hydroxyethyl)-9-oxo-3,4,5,6,9,10-
69 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [2-(benzyloxy)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
70 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5S)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8-
71 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
3- ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10-
721 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-[(methylsulfinyl)methyl]-9-oxo-3,4,5,6,9,10- 73 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10- 741 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2-[3-(dimethylamino)propyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- 751 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5R)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8-
76 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(5S)-4-hydroxy-8-(3-methoxypropyl)-5-methyl-2-oxo-l, 2,5, 6,7,8-
77 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(5S)-4-hydroxy-5-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
78 b]pyridine-3-carboxylic acid
(5S)-8-ethyl-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8- 82 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid Cpd Name
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5, 6,9,10-
831 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-
85 carboxylic acid
4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-
86 b]indole-3-carboxylic acid
4-hydroxy-12-methyl-2-oxo-l,2,5,6,7,12-hexahydropyrido[3',2':6,7]cycloliepta[l,2-
87 b]indole-3-carboxylic acid
4-hydroxy-2-oxo- 1,2,5,6,7, 12-hexahydropyrido[3',2':6,7]cyclohepta[l,2-b]indole-3-
88 carboxylic acid
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-
89 3 -carboxylic acid
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1 ,2,5 , 6,7, 8- 901 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,8- 911 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)- 1,2,5,6,7,8- 921 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- 941 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 951 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8- 961 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo- 1,2,5,6,7,8- 971 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9-[3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- 981 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
ll-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 991 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-ll-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- 1001 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- 1011 carboxylic acid
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]indole-3- 102 carboxylic acid
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- 1031 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid Cpd Name
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8- 1041 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 1051 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 1061 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
10-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 1071 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- 1081 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- 1091 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
3-ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10- 1101 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9,10- lll1 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5S)-4-hydroxy-5-methyl-2-oxo-8-(propan-2-yl)-l,2,5,6,7,8- 112 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- 1131 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid, and
(6S)-3-ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-6-methyl-9-oxo-3,4,5, 6,9,10- 114 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; wherein the form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Another embodiment of the present description includes a method of use for a compound salt of Formula (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound salt of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to the subject, wherein the compound is selected from the group consisting of:
Cpd Name
3-[2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 12 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate Cpd Name
4-hydroxy-2-oxo-2,5 ,6,7,9, 10,11 , 12-octahydro- 1H- pyrido[3",2":6',7']cyclohepta[ ,2':4,5]imidazo[l,2-a]pyridine-3-carboxylic acid
13 hydrochloride
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic
14 acid hydrochloride
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7, 8-
16 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
8- [2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
17 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- 21 carboxylic acid hydrochloride
8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- 26 carboxylic acid hydrochloride
3-(2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 28 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate
8-hydroxy-2,3-dimethyl-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 30 c]azepine-9-carboxylic acid hydrochloride
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
32 c]azepine-9-carboxylic acid hydrochloride
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
33 c]azepine-9-carboxylic acid hydrochloride
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
34 c]azepine-9-carboxylic acid hydrochloride
3- ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-
35 9-carboxylic acid hydrochloride
2-chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
36 c]azepine-9-carboxylic acid hydrochloride
2- [(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
38 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3-
41 i][l,4]oxazepine-9-carboxylic acid hydrochloride
3- ethyl-8-hydroxy-10-oxo-5,6,10,ll-tetrahydroimidazo[l,2-d]pyrido[2,3-
42 i][l,4]oxazepine-9-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10-
44 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10-
45 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10-
46 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride Cpd Name
3-ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10- 47 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8-
54 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
59 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10-
60 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- 62 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-[3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 68 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10- 72 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
74 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2- [3-(dimethylamino)propyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
75 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5, 6,9,10-
83 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1,2,5,6,7,8-
90 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4- hydroxy-8-methyl-2-oxo-9-(pyrrolidin- 1-ylmethyl)- 1 ,2,5, 6,7,8-
91 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)-l,2,5,6,7,8-
92 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8-
94 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
9- [(ethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo-l, 2,5, 6,7,8-
95 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8-
96 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-
97 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
9- [3 -(diethylamino)pyrrolidin- 1 -yl] -4-hydroxy-8-methyl-2-oxo- 1,2,5,6,7,8-
98 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate ll-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8-
99 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride Cpd Name
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8-
100 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3-
101 carboxylic acid hydrochloride
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8-
103 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8-
104 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8-
105 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
106 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
10-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8-
107 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-
108 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8-
109 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9, 10-
110 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride,
111 and
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- 113 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; wherein the 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.
An embodiment of the use of a compound of Formula (la) or a form thereof includes a method of use for a compound of Formula (la) or a form thereof for treating or ameliorating a wild- type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la) or a form thereof
(wherein compound number (# ) indicates that the salt form was isolated) to the subject, selected from the group consisting of:
Cpd Name Cpd Name
4-hydroxy-8,9-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
2 b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexaliydropyrrolo[2',3':6,7]cycloliepta[l,2-
3 b]pyridine-3-carboxylic acid
8-ethyl-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexaliydropyrrolo[2',3':6,7]cycloliepta[l,2-
4 b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-8-propyl- 1,2,5,6,7,8-
5 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid
8-cyclopropyl-4-hydroxy-9-methyl-2-oxo-l, 2,5, 6,7,8-
6 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid
7- hydroxy-2,3-dimethyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-
8 b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-
9 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
10 b]pyridine-3-carboxylic acid
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
11 b]pyridine-3-carboxylic acid
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 121 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic 141 acid
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7 , 8- 161 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 171 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8,9,10-trimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
19 b]pyridine-3-carboxylic acid
8- ethyl-4-hydroxy-9,10-dimethyl-2-oxo-l,2,5, 6,7,8-
20 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- 211 carboxylic acid
2-ethyl-7-hydroxy-3-methyl-9-oxo-3,4,5,6,9,10-
22 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2,3-diethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-
23 b]pyridine-8-carboxylic acid Cpd Name
7- hydroxy-l-methyl-9-oxo- 1,4,5,6,9, 10-hexahydropyrazolo[4',3':6,7]cyclohepta[l,2-
24 b]pyridine-8-carboxylic acid
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,9-hexaliydropyrrolo[3',4':6,7]cycloliepta[l,2-
25 b]pyridine-3-carboxylic acid
8- hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- 261 carboxylic acid
3-(2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 281 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-(methoxymethyl)-9-oxo-3,4,5,6,9,10- 29 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
8-hydroxy-2,3-dimethyl-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 301 c]azepine-9-carboxylic acid
2-ethyl-7-hydroxy-9-oxo-2,4,5,6,9,10-hexahydro[l,2,3]triazolo[4',5':6,7]cyclohepta[l,2- 31 b]pyridine-8-carboxylic acid
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 321 c]azepine-9-carboxylic acid
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 331 c]azepine-9-carboxylic acid
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 341 c]azepine-9-carboxylic acid
3- ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- 351 carboxylic acid
2- chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 361 c]azepine-9-carboxylic acid
3- ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo-3,4,5,6,9,10-
37 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2-[(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- 381 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-methyl-2-oxo-2,6,7,8-tetrahydro-lH-pyrazolo[4',3':4,5]oxepino[3,2-
39 b]pyridine-3-carboxylic acid
2- [(benzyloxy)methyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
40 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- 411 f][l,4]oxazepine-9-carboxylic acid
3- ethyl-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3-f][l,4]oxazepine- 421 9-carboxylic acid Cpd Name
7-hydroxy-2-(methoxymethyl)-3-methyl-9-oxo-3,4,5,6,9,10- 43 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- 441 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- 451 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- 461 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10-
471 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-5,8-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
48 b]pyridine-3-carboxylic acid
3-ethyl-7-hydroxy-2- [(oxetan-3 -yloxy)methyl] -9-oxo-3 ,4, 5 ,6,9, 10-
49 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-9-oxo-3,4,5,6,9,10-
50 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-2,3-dimethyl-9-oxo-2,4,5,6,9,10-hexaliydropyrazolo[4',3':6,7]cycloliepta[l,2-
51 b]pyridine-8-carboxylic acid
7- hydroxy-3-(2-methoxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10-
52 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-(3-hydroxypropyl)-2-oxo-l, 2,5, 6,7,8-
53 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
541 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8-(2-methoxyethyl)-2-oxo-l,2,5,6,7,8-
55 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8-(3-methoxypropyl)-2-oxo-l, 2,5, 6,7,8-
56 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
7-hydroxy-3-(2-hydroxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10-
57 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-[(2-hydroxyethoxy)methyl]-9-oxo-3,4,5,6,9,10-
58 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-etliyl-7-liydroxy-9-oxo-3,4,5,6,9,10- 591 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- 601 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid Cpd Name
4-hydroxy-8-(2-hydroxyethyl)-2-oxo-l,2,5,6,7,8- 61 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- 621 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-2-[(ethylsulfonyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10-
63 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-2-[(ethylsulfinyl)methyl]-7-hydroxy-9-oxo-3,4,5, 6,9,10-
64 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [(acetyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
65 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-3-(3-methoxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10-
66 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-3-(3-hydroxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10-
67 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- [3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 681 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-(2-hydroxyethyl)-9-oxo-3,4,5,6,9,10-
69 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [2-(benzyloxy)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4,5 , 6,9, 10-
70 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5S)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8-
71 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
3- ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10-
721 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-[(methylsulfinyl)methyl]-9-oxo-3,4,5,6,9,10- 73 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10- 741 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2-[3-(dimethylamino)propyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- 751 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5R)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8-
76 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(5S)-4-hydroxy-8-(3-methoxypropyl)-5-methyl-2-oxo-l, 2,5, 6,7,8-
77 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(5S)-4-hydroxy-5-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
78 b]pyridine-3-carboxylic acid Cpd Name
(5S)-8-ethyl-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8- 82 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5, 6,9,10- 831 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10- 1101 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9,10- lll1 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5S)-4-hydroxy-5-methyl-2-oxo-8-(propan-2-yl)-l,2,5,6,7,8- 112 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- 1131 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid, and
(6S)-3-ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-6-methyl-9-oxo-3,4,5, 6,9,10- 114 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; wherein the 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 (lb) or a form thereof includes a method of use for a compound of Formula (lb) or a form thereof for treating or ameliorating a wild- type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (lb) or a form thereof
(wherein compound number (# ) indicates that the salt form was isolated) to the subject, selected from the group consisting of:
Cpd Name
4- hydroxy-2-oxo-2,5,6,7,9,10,l l, 12-octahydro-lH-
131 pyrido[3'\2'':6 7 cyclohepta[l\2 ,5]imidazo[l,2-a]pyridine-3-carboxylic acid
4-hydroxy-12-methyl-2-oxo-l,2,5,6,7,12-hexahydropyrido[3',2':6,7]cyclohepta[l,2-
87 b]indole-3-carboxylic acid
4-hydroxy-2-oxo- 1,2,5,6,7, 12-hexahydropyrido[3',2':6,7]cyclohepta[l,2-b]indole-3-
88 carboxylic acid
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- 1011 carboxylic acid, and
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]indole-3-carboxylic 102 acid; wherein the 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 (Ic) or a form thereof includes a method of use for a compound of Formula (Ic) or a form thereof for treating or ameliorating a wild- type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (Ic) or a form thereof
(wherein compound number (# ) indicates that the salt form was isolated) to the subject, selected from the group consisting of:
Cpd Name
4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-
85 carboxylic acid
4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-
86 3 -carboxylic acid
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3- 89 carboxylic acid
9- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7,8- 901 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,8- 911 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)- 1,2,5,6,7,8- 921 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- 941 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 951 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8- 961 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo- 1,2,5,6,7,8- 971 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9-[3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- 981 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
l l-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 991 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- 1001 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid Cpd Name
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- 1031 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8- 1041 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 1051 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 1061 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
10-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 1071 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- 1081 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid, and
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- 1091 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid; wherein the form of the compound is selected from the group consisting of a prodrug, salt,
hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Another embodiment of the present description includes a method of use for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of a compound salt of Formula (la) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (la) or a form thereof includes a method of use for a compound salt of Formula (la) or a form thereof for treating or
ameliorating a wild-type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound salt of Formula (la) or a form thereof to the subject, selected from the group consisting of:
Cpd Name
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-
12 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate
4- hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic 14 acid hydrochloride
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7, 8- 16 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride Cpd Name
8- [2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
17 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- 21 carboxylic acid hydrochloride
8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- 26 carboxylic acid hydrochloride
3-(2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 28 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate
8-hydroxy-2,3-dimethyl-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 30 c]azepine-9-carboxylic acid hydrochloride
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
32 c]azepine-9-carboxylic acid hydrochloride
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
33 c]azepine-9-carboxylic acid hydrochloride
2,3-diethyl-8-hydroxy-10-oxo-6,7 ,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
34 c]azepine-9-carboxylic acid hydrochloride
3- ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9-
35 carboxylic acid hydrochloride
2-chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
36 c]azepine-9-carboxylic acid hydrochloride
2- [(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
38 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3-
41 f][l,4]oxazepine-9-carboxylic acid hydrochloride
3- ethyl-8-hydroxy-10-oxo-5,6,10,ll-tetrahydroimidazo[l,2-d]pyrido[2,3-f][l,4]oxazepine-
42 9-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10-
44 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10-
45 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10-
46 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10-
47 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- 54 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
2-({4-[(dimethylamino)methyl]phenoxy}methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- 59 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride Cpd Name
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- 60 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- 62 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-[3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9, 10- 68 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9, 10- 72 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
74 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2- [3-(dimethylamino)propyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
75 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5, 6,9,10-
83 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9, 10-
110 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride,
111 and
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- 113 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; wherein the 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 present description includes a method of use for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of a compound salt of Formula (lb) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (lb) or a form thereof includes a method of use for a compound salt of Formula (lb) or a form thereof for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound salt of Formula (lb) or a form thereof to the subject, selected from the group consisting of:
Cpd Name
4-hydroxy-2-oxo-2,5 ,6,7,9, 10, 11 , 12-octahydro- 1H- pyrido[3'\2'':6 7 cyclohepta[l\2 ,5]imidazo[l,2-a]pyridine-3-carboxylic acid
13 hydrochloride, and
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- 101 carboxylic acid hydrochloride;
wherein the 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 present description includes a method of use for treating or ameliorating a wild-type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of a compound salt of Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (Ic) or a form thereof includes a method of use for a compound salt of Formula (Ic) or a form thereof for treating or
ameliorating a wild-type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound salt of Formula (Ic) or a form thereof to the subject, selected from the group consisting of:
Cpd Name
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1,2,5,6,7,8-
90 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,8-
91 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)-l,2,5,6,7,8-
92 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8-
94 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
9- [(ethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo-l, 2,5, 6,7,8-
95 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride Cpd Name
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8-
96 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-
97 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
9- [3 -(diethylamino)pyrrolidin- 1 -yl] -4-hydroxy-8-methyl-2-oxo- 1,2,5,6,7,8-
98 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate l l-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8-
99 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8-
100 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8-
103 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8-
104 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8-
105 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
106 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
10- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8-
107 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-
108 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride, and
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8-
109 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; wherein the 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.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating a wild-type or drug-resistant form of N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating a wild-type or drug-resistant form of N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof (wherein compound number (# ) indicates that the salt form was isolated) to the subject, wherein the compound is selected from the group consisting of:
Cpd Name
4-hydroxy-8,9-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
2 b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
3 b]pyridine-3-carboxylic acid
8-ethyl-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
4 b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-8-propyl- 1,2,5,6,7,8-
5 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid
8-cyclopropyl-4-hydroxy-9-methyl-2-oxo-l, 2,5, 6,7,8-
6 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid
7- hydroxy-2,3-dimethyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-
8 b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-
9 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
10 b]pyridine-3-carboxylic acid
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
11 b]pyridine-3-carboxylic acid
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9, 10- 121 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-2-oxo-2,5,6,7,9,10,l l, 12-octahydro-lH-
131 pyrido[3'\2'':6 7 cyclohepta[l\2 ,5]imidazo[l,2-a]pyridine-3-carboxylic acid
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic 141 acid
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7 , 8- 161 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 171 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8,9,10-trimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
19 b]pyridine-3-carboxylic acid
8-ethyl-4-hydroxy-9,10-dimethyl-2-oxo-l,2,5, 6,7,8-
20 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid Cpd Name
9-ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- 211 carboxylic acid
2- ethyl-7-hydroxy-3-methyl-9-oxo-3,4,5,6,9,10-
22 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2 -diethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-
23 b]pyridine-8-carboxylic acid
7- hydroxy-l-methyl-9-oxo- 1,4,5,6,9, 10-hexahydropyrazolo[4',3':6,7]cyclohepta[l,2-
24 b]pyridine-8-carboxylic acid
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,9-hexaliydropyrrolo[3',4':6,7]cycloliepta[l,2-
25 b]pyridine-3-carboxylic acid
8- hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- 261 carboxylic acid
3- (2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-
281 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-(methoxymethyl)-9-oxo-3,4,5,6,9,10- 29 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
8-hydroxy-2,3-dimethyl-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 301 c]azepine-9-carboxylic acid
2-ethyl-7-hydroxy-9-oxo-2,4,5,6,9,10-hexahydro[l,2,3]triazolo[4',5':6,7]cyclohepta[l,2- 31 b]pyridine-8-carboxylic acid
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 321 c]azepine-9-carboxylic acid
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 331 c]azepine-9-carboxylic acid
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 341 c]azepine-9-carboxylic acid
3- ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine- 351 9-carboxylic acid
2- chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 361 c]azepine-9-carboxylic acid
3- ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo-3,4,5,6,9,10-
37 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2-[(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- 381 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-methyl-2-oxo-2,6,7,8-tetrahydro-lH-pyrazolo[4',3':4,5]oxepino[3,2-
39 b]pyridine-3-carboxylic acid
2- [(benzyloxy)methyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
40 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid Cpd Name
2 -dichloro-8-hydroxy-10-oxo-5,6J0J l-tetrahydroimidazo[l,2-d]pyrido[2,3- 411 f][l,4]oxazepine-9-carboxylic acid
3-ethyl-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- 421 f][l,4]oxazepine-9-carboxylic acid
7-hydroxy-2-(methoxymethyl)-3-methyl-9-oxo-3,4,5,6,9,10- 43 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- 441 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- 451 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- 461 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10-
471 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-5,8-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
48 b]pyridine-3-carboxylic acid
3-ethyl-7-hydroxy-2- [(oxetan-3 -yloxy)methyl] -9-oxo-3 ,4, 5 ,6,9, 10-
49 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-9-oxo-3,4,5,6,9,10-
50 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-2,3-dimethyl-9-oxo-2,4,5,6,9,10-hexaliydropyrazolo[4',3':6,7]cycloliepta[l,2-
51 b]pyridine-8-carboxylic acid
7- hydroxy-3-(2-methoxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10-
52 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-(3-hydroxypropyl)-2-oxo-l, 2,5, 6,7,8-
53 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
541 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8-(2-methoxyethyl)-2-oxo-l,2,5,6,7,8-
55 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8-(3-methoxypropyl)-2-oxo-l, 2,5, 6,7,8-
56 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
7-hydroxy-3-(2-hydroxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10-
57 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-[(2-hydroxyethoxy)methyl]-9-oxo-3,4,5,6,9,10-
58 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2-({4-[(dimethylamino)methyl]phenoxy}methyl)-3-etliyl-7-liydroxy-9-oxo-3,4,5,6,9,10- 591 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid Cpd Name
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- 601 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-(2-hydroxyethyl)-2-oxo-l,2,5,6,7,8-
61 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- 621 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-2-[(ethylsulfonyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10-
63 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-2-[(ethylsulfinyl)methyl]-7-hydroxy-9-oxo-3,4,5, 6,9,10-
64 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [(acetyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
65 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-3-(3-methoxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10-
66 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-3-(3-hydroxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10-
67 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- [3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 681 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-(2-hydroxyethyl)-9-oxo-3,4,5,6,9,10-
69 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [2-(benzyloxy)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
70 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5S)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8-
71 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
3- ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10-
721 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-[(methylsulfinyl)methyl]-9-oxo-3,4,5,6,9,10- 73 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10- 741 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2-[3-(dimethylamino)propyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- 751 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5R)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8-
76 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(5S)-4-hydroxy-8-(3-methoxypropyl)-5-methyl-2-oxo-l, 2,5, 6,7,8-
77 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(5S)-4-hydroxy-5-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
78 b]pyridine-3-carboxylic acid Cpd Name
(5S)-8-ethyl-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8- 82 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5, 6,9,10-
831 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-
85 carboxylic acid
4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-
86 b]indole-3-carboxylic acid
4-hydroxy-12-methyl-2-oxo-l,2,5,6,7,12-hexahydropyrido[3',2':6,7]cycloliepta[l,2-
87 b]indole-3-carboxylic acid
4-hydroxy-2-oxo- 1,2,5,6,7, 12-hexahydropyrido[3',2':6,7]cyclohepta[l,2-b]indole-3-
88 carboxylic acid
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-
89 3 -carboxylic acid
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1 ,2,5 , 6,7, 8- 901 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,8- 911 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)- 1,2,5,6,7,8- 921 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- 941 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 951 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8- 961 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- 971 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9-[3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- 981 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
ll-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 991 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-ll-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- 1001 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- 1011 carboxylic acid
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]indole-3- 102 carboxylic acid Cpd Name
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- 1031 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8- 1041 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 1051 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 1061 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
10-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 1071 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
10-{[ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- 1081 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- 1091 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
3-ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10- 1101 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9,10- lll1 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5S)-4-hydroxy-5-methyl-2-oxo-8-(propan-2-yl)-l,2,5,6,7,8- 112 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- 1131 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid, and
(6S)-3-ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-6-methyl-9-oxo-3,4,5, 6,9,10- 114 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; wherein the form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Another embodiment of the present description includes a method of use for a
compound salt of Formula (la), Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating a wild-type or drug-resistant form of N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound salt of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to the subject, wherein the compound is selected from the group consisting of:
Cpd Name
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-
12 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate
4- hydroxy-2-oxo-2,5 ,6,7,9, 10, 11 , 12-octahydro- 1H- pyrido[3'\2'':6 7 cyclohepta[l\2 ,5]imidazo[l,2-a]pyridine-3-carboxylic acid
13 hydrochloride
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic
14 acid hydrochloride
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7, 8-
16 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
8- [2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
17 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- 21 carboxylic acid hydrochloride
8-hydroxy-10-oxo-6,7, 10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- 26 carboxylic acid hydrochloride
3-(2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 28 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate
8-hydroxy-2,3-dimethyl-10-oxo-6,7,10, l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 30 c]azepine-9-carboxylic acid hydrochloride
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
32 c]azepine-9-carboxylic acid hydrochloride
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
33 c]azepine-9-carboxylic acid hydrochloride
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
34 c]azepine-9-carboxylic acid hydrochloride
3- ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-
35 9-carboxylic acid hydrochloride
2-chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
36 c]azepine-9-carboxylic acid hydrochloride
2-[(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- 38 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride Cpd Name
2 -dichloro-8-hydroxy-10-oxo-5,6J0J l-tetrahydroimidazo[l,2-d]pyrido[2,3-
41 f][l,4]oxazepine-9-carboxylic acid hydrochloride
3-ethyl-8-hydroxy-10-oxo-5,6,10,ll-tetrahydroimidazo[l,2-d]pyrido[2,3-
42 f][l,4]oxazepine-9-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10-
44 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10-
45 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10-
46 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10-
47 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8-
54 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
59 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10-
60 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- 62 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-[3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 68 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10- 72 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
74 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2- [3-(dimethylamino)propyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
75 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5, 6,9,10-
83 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1,2,5,6,7,8-
90 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4- hydroxy-8-methyl-2-oxo-9-(pyrrolidin- 1-ylmethyl)- 1 ,2,5, 6,7,8-
91 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)-l,2,5,6,7,8-
92 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- 94 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride Cpd Name
9-[(ethylamino)methyl]-4-hydroxy-8-metliyl-2-oxo-l, 2,5, 6,7,8-
95 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8-
96 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-
97 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
9- [3 -(diethylamino)pyrrolidin- 1 -yl] -4-hydroxy-8-methyl-2-oxo- 1,2,5,6,7,8-
98 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate l l-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8-
99 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8-
100 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3-
101 carboxylic acid hydrochloride
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8-
103 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8-
104 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8-
105 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
106 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
10- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8-
107 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-
108 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8-
109 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9, 10-
110 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride,
111 and
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- 113 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; wherein the 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. An embodiment of the use of a compound of Formula (la) or a form thereof includes a method of use for a compound of Formula (la) or a form thereof for treating or ameliorating wild-type of N. meningitidis in a subject in need thereof, comprising administering an
effective amount of the compound of Formula (la) or a form thereof (wherein compound number (# ) indicates that the salt form was isolated) to the subject, selected from the group consisting of:
Cpd Name
4-hydroxy-8,9-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
2 b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
3 b]pyridine-3-carboxylic acid
8-ethyl-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
4 b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-8-propyl- 1,2,5,6,7,8-
5 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid
8-cyclopropyl-4-hydroxy-9-methyl-2-oxo-l, 2,5, 6,7,8-
6 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid
7- hydroxy-2,3-dimethyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-
8 b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-
9 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
10 b]pyridine-3-carboxylic acid
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
11 b]pyridine-3-carboxylic acid
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9, 10- 121 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic 141 acid
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7 , 8- 161 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 171 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8,9,10-trimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-
19 b]pyridine-3-carboxylic acid
8-ethyl-4-hydroxy-9,10-dimethyl-2-oxo-l,2,5, 6,7,8-
20 hexahydropyrrolo [2' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine-3 -carboxylic acid Cpd Name
9-ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- 211 carboxylic acid
2- ethyl-7-hydroxy-3-methyl-9-oxo-3,4,5,6,9,10-
22 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2 -diethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-
23 b]pyridine-8-carboxylic acid
7- hydroxy-l-methyl-9-oxo- 1,4,5,6,9, 10-hexahydropyrazolo[4',3':6,7]cyclohepta[l,2-
24 b]pyridine-8-carboxylic acid
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,9-hexaliydropyrrolo[3',4':6,7]cycloliepta[l,2-
25 b]pyridine-3-carboxylic acid
8- hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- 261 carboxylic acid
3- (2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-
281 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-(methoxymethyl)-9-oxo-3,4,5,6,9,10- 29 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
8-hydroxy-2,3-dimethyl-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 301 c]azepine-9-carboxylic acid
2-ethyl-7-hydroxy-9-oxo-2,4,5,6,9,10-hexahydro[l,2,3]triazolo[4',5':6,7]cyclohepta[l,2- 31 b]pyridine-8-carboxylic acid
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 321 c]azepine-9-carboxylic acid
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 331 c]azepine-9-carboxylic acid
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 341 c]azepine-9-carboxylic acid
3- ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- 351 carboxylic acid
2- chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 361 c]azepine-9-carboxylic acid
3- ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo-3,4,5,6,9,10-
37 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2-[(dimethylamino)methyl]-3-etliyl-7-liydroxy-9-oxo-3,4,5,6,9,10- 381 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-methyl-2-oxo-2,6,7,8-tetrahydro-lH-pyrazolo[4',3':4,5]oxepino[3,2- 39 b]pyridine-3-carboxylic acid Cpd Name
2- [(benzyloxy)methyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
40 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- 411 f][l,4]oxazepine-9-carboxylic acid
3- ethyl-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3-f][l,4]oxazepine- 421 9-carboxylic acid
7-hydroxy-2-(methoxymethyl)-3-methyl-9-oxo-3,4,5,6,9,10- 43 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- 441 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- 451 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- 461 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10-
471 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-5,8-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
48 b]pyridine-3-carboxylic acid
3-ethyl-7-hydroxy-2- [(oxetan-3 -yloxy)methyl] -9-oxo-3 ,4, 5 ,6,9, 10-
49 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-9-oxo-3,4,5,6,9,10-
50 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-2,3-dimethyl-9-oxo-2,4,5,6,9,10-hexaliydropyrazolo[4',3':6,7]cycloliepta[l,2-
51 b]pyridine-8-carboxylic acid
7- hydroxy-3-(2-methoxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10-
52 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-(3-hydroxypropyl)-2-oxo-l, 2,5, 6,7,8-
53 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
541 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8-(2-methoxyethyl)-2-oxo-l,2,5,6,7,8-
55 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-8-(3-methoxypropyl)-2-oxo-l, 2,5, 6,7,8-
56 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
7-hydroxy-3-(2-hydroxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10-
57 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid Cpd Name
3-ethyl-7-hydroxy-2-[(2-hydroxyethoxy)methyl]-9-oxo-3,4,5,6,9, 10- 58 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-etliyl-7-liydroxy-9-oxo-3,4,5,6,9,10- 591 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- 601 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
4- hydroxy-8-(2-hydroxyethyl)-2-oxo-l,2,5,6,7,8-
61 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- 621 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-2-[(ethylsulfonyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10-
63 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-2-[(ethylsulfinyl)methyl]-7-hydroxy-9-oxo-3,4,5, 6,9,10-
64 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [(acetyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9, 10-
65 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-3-(3-methoxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10-
66 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
7-hydroxy-3-(3-hydroxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10-
67 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- [3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 681 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-(2-hydroxyethyl)-9-oxo-3,4,5,6,9,10-
69 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [2-(benzyloxy)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
70 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5S)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8-
71 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
3- ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10-
721 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3-ethyl-7-hydroxy-2-[(methylsulfinyl)methyl]-9-oxo-3,4,5,6,9,10- 73 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10- 741 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
2-[3-(dimethylamino)propyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9, 10- 751 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid Cpd Name
(5R)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8-
76 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(5S)-4-hydroxy-8-(3-methoxypropyl)-5-methyl-2-oxo-l, 2,5, 6,7,8-
77 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(5S)-4-hydroxy-5-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-
78 b]pyridine-3-carboxylic acid
(5S)-8-ethyl-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8- 82 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5, 6,9,10- 831 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
3- ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10- 1101 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9,10- lll1 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
(5S)-4-hydroxy-5-methyl-2-oxo-8-(propan-2-yl)-l,2,5,6,7,8- 112 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- 1131 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid, and
(6S)-3-ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-6-methyl-9-oxo-3,4,5, 6,9,10- 114 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; wherein the 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 (lb) or a form thereof includes a method of use for a compound of Formula (lb) or a form thereof for treating or ameliorating wild-type of N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound of Formula (lb) or a form thereof (wherein compound number (# ) indicates that the salt form was isolated) to the subject, selected from the group consisting of:
Cpd Name
4- hydroxy-2-oxo-2,5,6,7,9,10,l l, 12-octahydro-lH-
131 pyrido[3'\2'':6 7 cyclohepta[l\2 ,5]imidazo[l,2-a]pyridine-3-carboxylic acid
4-hydroxy-12-methyl-2-oxo-l,2,5,6,7,12-hexahydropyrido[3',2':6,7]cyclohepta[l,2- 87 b]indole-3-carboxylic acid Cpd Name
4-hydroxy-2-oxo- 1,2,5,6,7, 12-hexahydropyrido[3',2':6,7]cyclohepta[l,2-b]indole-3-
88 carboxylic acid
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- 1011 carboxylic acid, and
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]indole-3-carboxylic 102 acid; wherein the 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 (Ic) or a form thereof includes a method of use for a compound of Formula (Ic) or a form thereof for treating or ameliorating wild-type of N. meningitidis in a subject in need thereof, comprising administering an
effective amount of the compound of Formula (Ic) or a form thereof (wherein compound number (# ) indicates that the salt form was isolated) to the subject, selected from the group consisting of:
Cpd Name
4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-
85 carboxylic acid
4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-
86 3 -carboxylic acid
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-
89 carboxylic acid
9- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7,8- 901 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,8- 911 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)- 1,2,5,6,7,8- 921 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- 941 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 951 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8- 961 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid Cpd Name
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo- 1,2,5,6,7,8- 971 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
9- [3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- 981 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
l l-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 991 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- 1001 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- 1031 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8- 1041 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 1051 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- 1061 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
10- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- 1071 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- 1081 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid, and
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- 1091 hexahydropyrido [2' ,3 ' : 3 ,4]cyclohepta[ 1 ,2-b]indole-3 -carboxylic acid; wherein the form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Another embodiment of the present description includes a method of use for treating or ameliorating wild-type N. meningitidis in a subject in need thereof, comprising administering an effective amount of a compound salt of Formula (la) or a form thereof to the subject. An embodiment of the use of a compound of Formula (la) or a form thereof includes a method of use for a compound salt of Formula (la) or a form thereof for treating or
ameliorating wild-type N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound salt of Formula (la) or a form thereof to the subject, selected from the group consisting of:
Cpd Name
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-
12 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate
4- hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic 14 acid hydrochloride
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7, 8-
16 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
8- [2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
17 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- 21 carboxylic acid hydrochloride
8-hydroxy-10-oxo-6,7, 10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- 26 carboxylic acid hydrochloride
3-(2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 28 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate
8-hydroxy-2,3-dimethyl-10-oxo-6,7,10, l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- 30 c]azepine-9-carboxylic acid hydrochloride
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
32 c]azepine-9-carboxylic acid hydrochloride
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
33 c]azepine-9-carboxylic acid hydrochloride
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
34 c]azepine-9-carboxylic acid hydrochloride
3- ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9-
35 carboxylic acid hydrochloride
2-chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-
36 c]azepine-9-carboxylic acid hydrochloride
2- [(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
38 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3-
41 f][l,4]oxazepine-9-carboxylic acid hydrochloride
3- ethyl-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3-f][l,4]oxazepine-
42 9-carboxylic acid hydrochloride Cpd Name
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10-
44 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10-
45 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10-
46 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10-
47 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- 54 hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
59 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10-
60 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- 62 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-[3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- 68 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10- 72 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10-
74 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
2- [3-(dimethylamino)propyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-
75 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5, 6,9,10-
83 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
3-ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10-
110 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride,
111 and
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- 113 hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; wherein the 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 present description includes a method of use for treating or ameliorating wild-type N. meningitidis in a subject in need thereof, comprising
administering an effective amount of a compound salt of Formula (lb) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (lb) or a form thereof includes a method of use for a compound salt of Formula (lb) or a form thereof for treating or ameliorating wild-type N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound salt of Formula (lb) or a form thereof to the subject, selected from the group consisting of:
Cpd Name
4-hydroxy-2-oxo-2,5 ,6,7,9, 10, 11 , 12-octahydro- 1H- pyrido[3'\2'':6 7 cyclohepta[l\2 ,5]imidazo[l,2-a]pyridine-3-carboxylic acid
13 hydrochloride, and
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- 101 carboxylic acid hydrochloride;
wherein the 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 present description includes a method of use for treating or ameliorating wild-type N. meningitidis in a subject in need thereof, comprising
administering an effective amount of a compound salt of Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (Ic) or a form thereof includes a method of use for a compound salt of Formula (Ic) or a form thereof for treating or
ameliorating wild-type N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound salt of Formula (Ic) or a form thereof to the subject, selected from the group consisting of:
Cpd Name
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1,2,5,6,7,8-
90 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,8-
91 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride Cpd Name
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)-l,2,5,6,7,8- 92 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8-
94 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8-
95 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8-
96 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-
97 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
9- [3 -(diethylamino)pyrrolidin- 1 -yl] -4-hydroxy-8-methyl-2-oxo- 1,2,5,6,7,8-
98 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate ll-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8-
99 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8-
100 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8-
103 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8-
104 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8-
105 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8-
106 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate
10- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8-
107 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
10-{[ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-
108 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride, and
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8-
109 hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; wherein the form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In another embodiment of the 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 "Ci-ioalkyl" generally refers to saturated hydrocarbon radicals having from one to ten carbon atoms in a straight or branched chain configuration, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. In some embodiments, Ci-ioalkyl includes Ci-salkyl, Ci_6alkyl, Ci^alkyl and the like. A Ci-ioalkyl radical may be optionally substituted where allowed by available valences.
As used herein, the term "C2-8alkenyl" generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, without limitation, ethenyl, allyl, propenyl and the like. In some embodiments, C2-salkenyl includes C2-6alkenyl, C2-4alkenyl and the like. A C2-salkenyl 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-salkynyl includes C2-6alkynyl, C2-4alkynyl and the like. A C2-salkynyl radical may be optionally substituted where allowed by available valences.
As used herein, the term "Ci-salkoxy" generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration of the formula: -O-Ci-salkyl, including, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like. In some embodiments, Ci-salkoxy includes Ci_6alkoxy, Ci^alkoxy and the like. A Ci-salkoxy radical may be optionally substituted where allowed by available valences.
As used herein, the term "C3_i4cycloalkyl" generally refers to a saturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, lH-indanyl, indenyl, tetrahydro-naphthalenyl and the like. In some embodiments, C3_i4cycloalkyl includes C3_8cycloalkyl, Cs-scycloalkyl, C3_iocycloalkyl and the like. A C3_i4cycloalkyl 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,
tetrahydro thienyl, pyrrolinyl, pyrrolidinyl, dihydropyrazolyl, pyrazolinyl, pyrazolidinyl, dihydroimidazolyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, dihydro-2H-pyranyl, dihydro-pyridinyl, tetrahydro-pyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydro-pyridinyl, dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, 1,4,5,6- tetrahydropyrimidinyl, dihydro-pyrazinyl, tetrahydro-pyrazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl,
dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl, 1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl, dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl, dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl,
tetrahydro-benzothienyl, dihydro-benzimidazolyl, tetrahydro-benzimidazolyl,
dihydro-benzooxazolyl, 2 , 3 -dihydrobenzo [d] oxazolyl, tetrahydro-benzooxazolyl , dihydro-benzooxazinyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, tetrahydro-benzooxazinyl, benzo[l,3]dioxolyl, benzo[l,4]dioxanyl, dihydro-purinyl, tetrahydro-purinyl,
dihydro-quinolinyl, tetrahydro-quinolinyl, 1,2,3,4-tetrahydroquinolinyl,
dihydro-isoquinolinyl, 3,4-dihydroisoquinolin-(lH)-yl, tetrahydro-isoquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, dihydro-quinazolinyl, tetrahydro-quinazolinyl, dihydro-quinoxalinyl, tetrahydro-quinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dioxolanyl, 2,5-dihydro-lH- pyrrolyl, 4,5-dihydro-lH-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][l,4]oxazinyl, (cis)-octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4- b]pyrrol-(lH)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS
hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H- pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro- 1 H-pyrrolo [3 ,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- 1 H-pyrrolo [3 ,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9-tetrahydro-lH-carbazolyl, 1,2,3,4- tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro-lH-pyrrolo[l,2-a]indolyl, (3aR,6aR)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-l,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexanyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, (lS,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl and the like. A heterocyclyl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences. As used herein, the term "C2-8alkenyl-amino" refers to a radical of the formula: -NH-C2-salkenyl.
As used herein, the term "(C2-8alkenyl)2-amino" refers to a radical of the
formula: -N(C2-salkenyl)2.
As used herein, the term "C2-8alkenyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-NH-C2-8alkenyl.
As used herein, the term "(C2-8alkenyl)2-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N(C2-8alkenyl)2.
As used herein, the term "Ci-salkoxy-Ci-salkyl" refers to a radical of the
formula: -Ci_8alkyl-0-Ci_8alkyl.
As used herein, the term "Ci-salkoxy-Ci-salkoxy-Ci-salkyl" refers to a radical of the formula: -Ci_8alkyl-0-Ci_8alkyl-0-Ci_8alkyl.
As used herein, the term "Ci-salkoxy-Ci-salkyl-amino" refers to a radical of the formula: -NH-Ci_8alkyl-0-Ci_8alkyl.
As used herein, the term "(Ci_8alkoxy-Ci_8alkyl)2-amino" refers to a radical of the formula: -N(Ci-8alkyl-0-Ci-8alkyl)2.
As used herein, the term "Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl" refers to a radical of the formula: -Ci_8alkyl-NH-Ci_8alkyl-0-Ci_8alkyl.
As used herein, the term "(Ci-salkoxy-Ci-salkyl^-amino-Ci-salkyl" refers to a radical of the formula: -C1_8alkyl-N(C1_8alkyl-0-C1_8alkyl)2.
As used herein, the term "(Ci-8alkoxy-Ci-8alkyl,Ci_8alkyl)-amino" refers to a radical of the formula: -N[(Ci_8alkyl)(Ci_8alkyl-0-Ci_8alkyl)].
As used herein, the term "(Ci-8alkoxy-Ci-8alkyl,Ci-8alkyl)-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N[(Ci_8alkyl)(Ci_8alkyl-0-Ci_8alkyl)].
As used herein, the term "Ci-salkoxy-carbonyl" refers to a radical of the
formula: -C(=0)-0-C1_8alkyl.
As used herein, the term "Ci-salkoxy-carbonyl-Ci-salkyl" refers to a radical of the formula:
Figure imgf000143_0001
As used herein, the term "Ci-salkyl-amino" refers to a radical of the formula: -NH-Ci_8alkyl.
As used herein, the term "(Ci_8alkyl)2-amino" refers to a radical of the
formula: -N(Ci_8alkyl)2.
As used herein, the term "Ci-salkyl-amino-Ci-salkyl" refers to a radical of the formula: -Ci-8a]kyl-NH-Ci-8alkyl.
As used herein, the term "Ci-ioalkyl-amino-Ci-salkyl" refers to a radical of the formula: -Ci-8alkyl-NH-Ci_ioalkyl.
As used herein, the term "(Ci-ioalkyl^-amino-Ci-salkyl" refers to a radical of the formula: -Ci_8alkyl-N(Ci_i0alkyl)2.
As used herein, the term "Ci-salkyl-amino-Ci-salkyl-amino" refers to a radical of the formula: -NH-C1-8alkyl-NH-C1-8alkyl.
As used herein, the term "(Ci_8alkyl)2-amino-Ci_8alkyl-amino" refers to a radical of the formula: -NH-Ci_8alkyl-N(Ci_8alkyl)2.
As used herein, the term "Ci-8alkyl-amino-Ci-8alkyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci-8alkyl-NH-Ci_8alkyl-NH-Ci_8alkyl.
As used herein, the term "(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci-8alkyl-NH-Ci-8alkyl-N(Ci-8alkyl)2.
As used herein, the term "(Ci_8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino" refers to a radical of the formula: -NtCd^alky^Cd^alkyl-NH-d^alkyl)].
As used herein, the term "[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci_8alkyl]amino" refers to a radical of the formula: -N{(Ci_8alkyl)[Ci_8alkyl-N(Ci_8alkyl)2] } .
As used herein, the term "(Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl" refers to a radical of the formula: -Ci_8alkyl-N[(Ci_8alkyl)(Ci_8alkyl-NH-Ci_8alkyl)].
As used herein, the term "[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N{(Ci_8alkyl)[Ci_8alkyl-N(Ci_8alkyl)2] } .
As used herein, the term "(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci-8alkyl" refers to a radical of the formula: -Ci-8alkyl-N(Ci_8alkyl-NH-Ci-8alkyl)2. As used herein, the term "Ci-salkyl-amino-carbonyl" refers to a radical of the formula: -C(=0)-NH-C1-8alkyl.
As used herein, the term "(Ci_8alkyl)2-amino-carbonyl" refers to a radical of the formula:
Figure imgf000145_0001
As used herein, the term "Ci-salkyl-amino-Ci-salkyl-carbonyl" refers to a radical of the formula: -C(=0)-Ci_8alkyl-NH-Ci_8alkyl.
As used herein, the term 'XCi_8alkyl)2-amino-Ci_8alkyl-carbonyr refers to a radical of the formula: -C(=0)-Ci_8alkyl-N(Ci_8alkyl)2.
As used herein, the term "Ci_8alkyl-carbonyl" refers to a radical of the
formula: -C(=0)-C1-8alkyl.
As used herein, the term "Ci-salkyl-carbonyl-oxy-Ci-salkyl" refers to a radical of the formula: -C1-8alkyl-0-C(=0)-C1-8alkyl.
As used herein, the term "Ci-salkyl-carbonyl-amino" refers to a radical of the formula: -NH-C(=0)-C1-8alkyl.
As used herein, the term "(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci-8alkyl" refers to a radical of the formula: -C1-8alkyl-N[(C1-8alkyl)(C(=0)-C1-8alkyl)].
As used herein, the term "Ci-8alkyl-sulfinyl" refers to a radical of the
formula: -S(=0)-C1-8alkyl.
As used herein, the term "Ci-8alkyl-sulfinyl-Ci-8alkyl" refers to a radical of the formula: -C1_8alkyl-S(=0)-C1_8alkyl.
As used herein, the term "Ci_8alkyl-sulfonyl" refers to a radical of the
formula: -S(=0)2-C1-8alkyl.
As used herein, the term "Ci_8alkyl-sulfonyl-Ci_8alkyl" refers to a radical of the formula:
Figure imgf000145_0002
As used herein, the term "Ci_8alkyl-thio" refers to a radical of the
formula: -S-Ci_8alkyl.
As used herein, the term "C2-8alkynyl-Ci_8alkyl" refers to a radical of the
formula: -Ci-8aLkyl-C2-8alkynyl. As used herein, the term "C2-8alkynyl-amino" refers to a radical of the
formula: -NH-C2-salkynyl.
As used herein, the term "(C2-8alkynyl)2-amino" refers to a radical of the formula: -N(C2-salkynyl)2.
As used herein, the term "C2-8alkynyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-NH-C2-8alkynyl.
As used herein, the term "(C2-8alkynyl)2-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_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-Ci-salkyl" refers to a radical of the
formula: -Ci_8alkyl-NH2.
As used herein, the term "amino-Ci-salkyl-amino" refers to a radical of the formula: -NH-Ci_8alkyl-NH2.
As used herein, the term "(amino-Ci_8alkyl)2-amino" refers to a radical of the formula: -N(Ci_8alkyl-NH2)2.
As used herein, the term "(amino-Ci-8alkyl)2-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl-NH2)2.
As used herein, the term "amino-Ci-salkyl-amino-Ci-salkyl" refers to a radical of the formula: -Ci_8alkyl-NH-Ci_8alkyl-NH2.
As used herein, the term "(amino-Ci-8alkyl,Ci_8alkyl)amino" refers to a radical of the formula: -N[(Ci_8alkyl)(Ci_8alkyl-NH2)].
As used herein, the term "(amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N[(Ci_8alkyl)(Ci_8alkyl-NH2)].
As used herein, the term "amino-carbonyl" refers to a radical of the
formula: -C(=0)-NH2.
As used herein, the term "aryl-Ci-salkoxy" refers to a radical of the
formula: -O-Ci-salkyl-aryl.
As used herein, the term "aryl-Ci-salkoxy-Ci-salkyl" refers to a radical of the formula: -Ci-salkyl-O-Ci-salkyl-aryl. As used herein, the term "aryl-Ci-salkoxy-carbonyl-amino" refers to a radical of the formula: -NH-C(=0)-0-Ci_8alkyl-aryl.
As used herein, the term "aryl-Ci_8alkyl" refers to a radical of the
formula: -Ci-salkyl-aryl.
As used herein, the term "aryl-Ci-salkyl-amino" refers to a radical of the
formula: -NH-Ci-salkyl-aryl.
As used herein, the term "(aryl-Ci_8alkyl)2-amino" refers to a radical of the formula: -N[(Ci_8alkyl-aryl)2].
As used herein, the term "aryl-Ci-salkyl-amino-Ci-salkyl" refers to a radical of the formula: -Ci-8a]kyl-NH-Ci-8alkyl-aryl.
As used herein, the term "(aryl-Ci-salkyl^-amino-Ci-salkyl" refers to a radical of the formula: -Ci_8alkyl-N[(Ci_8alkyl-aryl)2].
As used herein, the term "(aryl,Ci_8alkyl)amino" refers to a radical of the
formula: -N[(C1-8alkyl)(aryl)].
As used herein, the term "(aryl,Ci_8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N[(Ci_8alkyl)(aryl)].
As used herein, the term "(aryl-Ci-8alkyl,Ci_8alkyl)amino" refers to a radical of the formula: -N[(C1-8alkyl)(C1-8alkyl-aryl)].
As used herein, the term "(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_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-Ci_8alkyl" refers to a radical of the
formula: -Ci-8alkyl-NH-aryl.
As used herein, the term "(aryl)2-amino-Ci_8alkyl" refers to a radical of the formula: -Ci-8alkyl-N[(aryl)2].
As used herein, the term "aryl-amino-carbonyl" refers to a radical of the
formula: -C(=0)-NH-aryl. As used herein, the term "aryl-oxy-Ci-salkyl" refers to a radical of the formula: -Ci-salkyl-O-aryl.
As used herein, the term "azido" refers to a radical of the formula: -N=N+=N".
As used herein, the term "carboxyl" refers to a radical of the
formula: -COOH, -C(=0)OH or -C02H.
As used herein, the term "(carboxyl-Ci_8alkyl,Ci_8alkyl)amino-carbonyl-amino" refers to a radical of the formula: -NH-C(=0)-N[(Ci_8alkyl)(Ci_8alkyl-C02H)].
As used herein, the term "C3_i4cycloalkyl-Ci_8alkoxy" refers to a radical of the formula: -0-Ci_8alkyl-C3_i4cycloalkyl.
As used herein, the term "C3_i4cycloalkyl-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-C3_i4cycloalkyl.
As used herein, the term "C3_i4cycloalkyl-amino" refers to a radical of the formula: -NH-C3_i4cycloalkyl.
As used herein, the term "C3_i4cycloalkyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-NH-C3_i4cycloalkyl.
As used herein, the term "(C3_i4cycloalkyl)2-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N[(C3_i4cycloalkyl)2].
As used herein, the term "C3-i4cycloalkyl-Ci-8alkyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci-8alkyl-NH-Ci_8alkyl-C3_i4cycloalkyl.
As used herein, the term "(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N[(Ci_8alkyl-C3_i4cycloalkyl)2].
As used herein, the term "(C3-i4cycloalkyl,Ci-8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N[(Ci_8alkyl)(C3_i4cycloalkyl)].
As used herein, the term "(C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl" refers to a radical of the formula: -Ci-8alkyl-N[(Ci_8alkyl)(Ci-8alkyl-C3_i4cycloalkyl)].
As used herein, the term "C3_i4cycloalkyl-oxy" refers to a radical of the
formula: -0-C3_i4cycloalkyl.
As used herein, the term "formyl" refers to a radical of the formula: -C(=0)-H. As used herein, the term "formyl-Ci-salkyl" refers to a radical of the formula:
Figure imgf000149_0001
As used herein, the term "halo" or "halogen" generally refers to a halogen atom radical, including fluoro, chloro, bromo and iodo.
As used herein, the term "halo-Ci-salkoxy" refers to a radical of the
formula: -O-Ci-salkyl-halo, wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms. In some
embodiments, halo-Ci-salkoxy includes halo-Ci_6alkoxy, halo-Ci-4alkoxy and the like.
As used herein, the term "halo-Ci-salkyl" refers to a radical of the
formula: -Ci-salkyl-halo, wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more halogen atoms. In some embodiments, halo-Ci_8alkyl includes halo-Ci_6alkyl, halo-Ci-4alkyl and the like.
As used herein, the term "halo-Ci-salkyl-amino" refers to a radical of the formula: -NH-Ci-salkyl-halo.
As used herein, the term "(halo-Ci_8alkyl)2-amino" refers to a radical of the formula: -N(Ci_8alkyl-halo)2.
As used herein, the term "halo-Ci-salkyl-amino-Ci-salkyl" refers to a radical of the formula: -NH-Ci-salkyl-halo.
As used herein, the term "(halo-Ci-salkyl^-amino-Ci-salkyl" refers to a radical of the formula: -C1_8alkyl-N(C1_8alkyl-halo)2.
As used herein, the term "heteroaryl-Ci-salkyl" refers to a radical of the
formula: -Ci-salkyl-heteroaryl.
As used herein, the term "he teroaryl- 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-Ci-salkyl-amino" refers to a radical of the formula: -NH-Ci-salkyl-heteroaryl. As used herein, the term "(heteroaryl-Ci_8alkyl)2-amino" refers to a radical of the formula: -N[(Ci_8alkyl-heteroaryl)2].
As used herein, the term "heteroaryl-Ci_8alkyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci-salkyl-NH-Ci-salkyl-heteroaryl.
As used herein, the term "(heteroaryl-Ci-salkyl^-amino-Ci-salkyl" refers to a radical of the formula: -Ci_8alkyl-N[(Ci_8alkyl-heteroaryl)2].
As used herein, the term "(heteroaryl-Ci_8alkyl,Ci_8alkyl)amino" refers to a radical of the formula: -N[(Ci_8alkyl)(Ci_8alkyl-heteroaryl)].
As used herein, the term "(heteroaryl,Ci-8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci-8alkyl-N[(Ci-8alkyl)(heteroaryl)].
As used herein, the term "(heteroaryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N[(Ci_8alkyl)(Ci_8alkyl-heteroaryl)].
As used herein, the term "heterocyclyl-Ci-salkoxy" refers to a radical of the formula: -O-Ci-salkyl-heterocyclyl.
As used herein, the term "heterocyclyl-Ci-salkoxy-Ci-salkyl" refers to a radical of the formula: -Ci-salkyl-O-Ci-salkyl-heterocyclyl.
As used herein, the term "heterocyclyl-Ci-salkyl" refers to a radical of the formula: -Ci-salkyl-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-Ci-salkyl" refers to a radical of the formula: -Ci-salkyl-NH-heterocyclyl.
As used herein, the term "(heterocyclyl^-amino-Ci-salkyl" refers to a radical of the formula: -Ci_8alkyl-N[(heterocyclyl)2].
As used herein, the term "heterocyclyl-Ci-salkyl-amino-Ci-salkyl" refers to a radical of the formula: -Ci-salkyl-NH-Ci-salkyl-heterocyclyl. As used herein, the term "(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N[(Ci_8alkyl-heterocyclyl)2].
As used herein, the term "(heterocyclyl,Ci_8alkyl)amino" refers to a radical of the formula: -N [(C i -salkyl) (heterocy clyl) ] .
As used herein, the term "(heterocyclyl,Ci_8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N[(Ci_8alkyl)(heterocyclyl)].
As used herein, the term "(heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N[(Ci_8alkyl)(Ci_8alkyl-heterocyclyl)].
As used herein, the term "(heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N[(heterocyclyl)(Ci_8alkyl-C3_i4cycloalkyl)].
As used herein, the term "heterocyclyl-carbonyl" refers to a radical of the formula: -C(=0)-heterocyclyl.
As used herein, the term "heterocyclyl-carbonyl-oxy" refers to a radical of the formula: -0-C(=0)-heterocyclyl.
As used herein, the term "heterocyclyl-oxy" refers to a radical of the
formula: -O-heterocyclyl.
As used herein, the term "heterocyclyl-oxy-Ci-salkyl" refers to a radical of the formula: -C i _salkyl- 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[(-0-heterocyclyl)2].
As used herein, the term "(heterocyclyl-oxy,Ci_8alkyl)amino" refers to a radical of the formula: -N [(C i -salkyl) (-O-heterocyclyl) ] .
As used herein, the term "(heterocyclyl-oxy-Ci_8alkyl,Ci_8alkyl)amino" refers to a radical of the formula: -N[(Ci_8alkyl)(Ci_8alkyl-0-heterocyclyl)].
As used herein, the term "hydroxyl-Ci-salkoxy" refers to a radical of the
formula: -O-Ci-salkyl-OH, wherein Chalky 1 may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals. As used herein, the term "hydroxyl-Ci-salkoxy-Ci-salkyl" refers to a radical of the formula: -Ci-salkyl-O-Ci-salkyl-OH, wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term "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 hydroxy radicals.
As used herein, the term "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.
As used herein, the term "(hydroxyl-Ci_8alkyl)2-amino" refers to a radical of the formula: -N(Ci_8alkyl-OH)2, wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term "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.
As used herein, the term "hydroxyl-Ci-salkyl-amino-Ci-salkyl-amino" refers to a radical of the formula: -NH-Ci_8alkyl-NH-Ci_8alkyl-OH, wherein C^alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term "(hydroxyl-Ci_8alkyl,Ci_8alkyl)amino" refers to a radical of the formula: -N[(Ci_8alkyl)(Ci_8alkyl-OH)], wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term "(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N[(Ci_8alkyl)(Ci_8alkyl-OH)], wherein Ci-salkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term "[(hydroxyl-Ci_8alkyl,Ci_8alkyl)amino- Ci-8alkyl,Ci-8alkyl]amino" refers to a radical of the formula: -N[(Ci_8alkyl){Ci_8alkyl- N[(Ci-8alkyl)(Ci_8alkyl-OH)] }], wherein Ci^alkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals. As used herein, the term "(hydroxyl-Ci_8alkyl-amino-Ci_8alkyl,Ci_8alkyl)amino" refers to a radical of the formula: -N[(Ci-8a]kyl)(Ci-8alkyl-NH-Ci-8alkyl-OH)], wherein Ci_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 "=0") as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure of Formula (la), Formula (lb), and Formula (Ic). A person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.
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 (la), Formula (lb) and Formula (Ic) or a form thereof encompass functionalities incorporated into a compound of Formula (la), Formula (lb), and Formula (Ic), 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 (la), Formula (lb) and Formula (Ic), the pattern of substitution at each occurrence is independent of the pattern at any other occurrence. Further, the use of a generic substituent variable on any formula or structure for a compound described herein is understood to include the replacement of the generic substituent with species substituents that are included within the particular genus, e.g. , aryl may be replaced with phenyl or naphthalenyl and the like, and that the resulting compound is to be included within the scope of the compounds described herein.
As used herein, the terms "each instance of or "in each instance, when present," when used preceding a phrase such as "...C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_8alkyl, aryl, aryl-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heterocyclyl and heterocyclyl-Ci-salkyl," are intended to refer to the C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems when each are present either alone or as a substituent.
As used herein, the term "optionally substituted" means optional substitution with the specified substituent variables, groups, radicals or moieties.
As used herein, the terms "stable compound' or "stable structure" mean a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulations thereof into an efficacious therapeutic agent.
Compound names used herein were obtained using the ACD Labs Index Name software provided by ACD Labs; and/or, were obtained using the naming function of ChemDraw® Ultra provided by CambridgeSoft. When the compound name disclosed herein conflicts with the structure depicted, the structure shown will supercede the use of the name to define the compound intended.
Compound Forms
As used herein, the term "form" means a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) is a free acid, free base or salt thereof. In certain embodiments described herein, the form of the compound of Formula (la), Formula (lb), and Formula (Ic) is a salt thereof.
In certain embodiments described herein, the form of the compound of Formula (la), Formula (lb), and Formula (Ic) is an isotopologue thereof.
In certain embodiments described herein, the form of the compound of Formula (la),
Formula (lb), and Formula (Ic) is a stereoisomer, racemate, enantiomer or diastereomer thereof.
In certain embodiments described herein, the form of the compound of Formula (la), Formula (lb), and Formula (Ic) is a tautomer thereof.
In certain embodiments described herein, the form of the compound of Formula (la),
Formula (lb), and Formula (Ic) is a pharmaceutically acceptable form.
In certain embodiments described herein, the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof is isolated for use.
As used herein, the term "isolated" means the physical state of a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) can form salts, which are intended to be included within the scope of this description. Reference to a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) may be formed, for example, by reacting a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in compounds described herein. Embodiments of acid addition salts include, and are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate salts and the like. Certain embodiments of acid addition salts include chloride, bromide, acetate or trifluoroacetate salts.
Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International 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 Formula (la), Formula (lb), and Formula (Ic) and forms thereof, may further exist in a tautomeric form (for example, the 4-hydroxy-2-pyridinone core of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof as described herein.
The compounds of Formula (la), Formula (lb), and Formula (Ic) or a form thereof may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. The present description is intended to include all stereoisomeric forms of the compounds of Formula (la), Formula (lb), and Formula (Ic) 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). In one embodiment, the compounds described herein are (5) isomers and may exist as enantiomeric ally pure compositions substantially comprising only the (5) 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 (la), Formula (lb), and
Formula (Ic) or a form thereof is a substantially pure (5) 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 (la), Formula (lb), and
Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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, 180, 170, 31P, 32P, 35S, 18F, 35C1 and 36C1, respectively, each of which are also within the scope of this description.
Certain isotopically-enriched compounds described herein (e.g., those labeled with 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 (la),
Formula (lb), and Formula (Ic) and of the salts, solvates, hydrates, esters and prodrugs of the compounds of Formula (la), Formula (lb), and Formula (Ic) 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 (la),
Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae or N. meningiditis 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 (la),
Formula (lb), and Formula (Ic) or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae or N. meningiditis in a subject in need thereof.
The present description further relates to use of the compound Formula (la), Formula (lb), and Formula (Ic) or a form thereof having activity toward wild- type or drug-resistant N. gonorrhoeae or N. meningiditis. The present description also relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula
(lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof in a combination therapy with known antibacterial or antibiotic agents to provide additive or synergistic activity, thus enabling the development of a combination product for the treatment of a wild-type or drug-resistant form of N. gonorrhoeae.
The compounds of the present description have demonstrated an ability to inhibit the replication of a wide variety of N. gonorrhoeae isolates. The instant compounds possess in vitro activity against a wide spectrum of N. gonorrhoeae isolates which have developed resistance to almost all known treatments and are expected to successfully treat wild-type or drug-resistant forms of N. gonorrhoeae compared to current antibacterial agents. The compounds are also effective in vivo and lack cellular toxicity. In addition to
monotherapeutic use, the instant compounds are useful in a combination therapy with current standard of care antibacterial or antibiotic agents, having additive or synergistic activity with one or more known antibacterial or antibiotic agents.
A combination therapy comprising compounds described herein in combination with one or more known antibacterial or antibiotic drugs may be used to treat wild-type or drug- resistant forms of N. gonorrhoeae regardless of whether N. gonorrhoeae is resistant or responsive to the known antibacterial or antibiotic drug.
Embodiments of the present description include the use of a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof in the preparation of a kit comprising the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof and instructions for administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) 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, MethiciUin, Metronidazole, Mezlocillin, Minocycline, Moxifloxacin, Mupirocin, Nafcillin, Nalidixic acid, Neomycin, Netilmicin, Nitrofurantoin, Norfloxacin, Ofloxacin, Oxacillin, Oxytetracycline, Paromomycin, Penicillin G, Penicillin V, Piperacillin, Platensimycin, Polymyxin B, Pyrazinamide, Quinupristin, Rapamycin, Rifabutin, Rifampicin, Rifampin, Rifapentine, Rifaximin, Roxithromycin, Silver sulfadiazine, Solithromycin, Spectinomycin, Streptomycin, Sulbactam, Sulfacetamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, 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, Cef alexin, Cefalotin (Cefalothin), Cefamandole, Cefazolin, Cefdinir, Cefditoren,
Cefoperazone, Cefotaxime, Cefoxitin, Cefpodoxime, Cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Cefuroxime, Chloramphenicol, Cilastatin, Clarithromycin, Clavulanate, Clindamycin, Clofazimine, Cloxacillin, Colistin, Cycloserine, Dalfopristin, Dapsone, Daptomycin, Dicloxacillin, Dirithromycin, Doripenem, Doxycycline, Enoxacin,
Erythromycin, Ethambutol, Ethionamide, Flucloxacillin, Fosfomycin, Furazolidone, Fusidic acid, Gatifloxacin, Gemifloxacin, Gentamicin, Imipenem, Isoniazid, Kanamycin,
Levofloxacin, Lincomycin, Linezolid, Lomefloxacin, Loracarbef, Mafenide, Meropenem, MethiciUin, Metronidazole, Mezlocillin, Minocycline, Moxifloxacin, Mupirocin, Nafcillin, Nalidixic acid, Neomycin, Netilmicin, Nitrofurantoin, Norfloxacin, Ofloxacin, Oxacillin, Oxytetracycline, Paromomycin, Piperacillin, Platensimycin, Polymyxin B, Pyrazinamide, Quinupristin, Rapamycin, Rifabutin, Rifampicin, Rifampin, Rifapentine, Rifaximin,
Roxithromycin, Silver sulfadiazine, Solithromycin, Sulbactam, Sulfacetamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, 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 (la), Formula (lb), and Formula (Ic) 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. In accordance with the use of the present description, compounds that are useful in selectively treating or ameliorating N. gonorrhoeae, lacking potent broad-spectrum antibacterial activity, have been identified and use of these compounds for treating or ameliorating N. gonorrhoeae have been provided.
One embodiment of the use of the present description relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof in the preparation of a kit comprising the compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof.
Another aspect of the description particularly relates to a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof.
One aspect of the description relates to a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (streptomycin11) N. gonorrhoeae FA1090 (ATCC 700825; GenBank Acc. No. AE004969), ATCC N. gonorrhoeae MS 11 (ATCC BAA- 1833) and ATCC wild- type N. gonorrhoeae 49226 (ATCC 49226) (see, http://www.atcc.org).
Another aspect of the description relates to a method of use for a compound of
Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof having activity against N. gonorrhoeae isolates engineered from clinical isolate FA 19 to contain mutations in gyrA and parC, including those selected from ciprofloxacin-resistant (ciprofloxacin11) N. gonorrhoeae AK1 (gyrA91/95) and ciprofloxacin11 N. gonorrhoeae AK2 (gyrAgj/95, parCse) (see, Anjali Ν. 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof having activity against N. gonorrhoeae World Health Organization (WHO) isolates
IR
selected from: tetracycline N. gonorrhoeae 134ΊΊ (WHO tetracycline intermediate resistant
IR R
isolate F), ciprofloxacin /tetracycline N. gonorrhoeae 13478 (WHO ciprofloxacin intermediate resistant and tetracycline resistant isolate G), quinolone N. gonorrhoeae 13479 (WHO quinolone high level resistant isolate K), MDR N. gonorrhoeae 13480 (WHO multi-drug resistant isolate L) and MD!R N. gonorrhoeae 13481 (WHO multi-drug intermediate resistant isolate M) (see, Unemo M, Fasth O, Fredlund H, Limnios A, Tapsall J. Phenotypic and genetic characterization of the 2008 WHO Neisseria gonorrhoeae reference strain panel intended for global quality assurance and quality control of gonococcal antimicrobial resistance surveillance for public health purposes. J. Antimicrobial Chemother., 2009, Jun; 63(6): 1142-51).
Another aspect of the description relates to a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form
XDR XDR XDR
thereof having activity against the ciprofloxacin /cefixime /ceftriaxone extensively drug resistant N. gonorrhoeae F89 (see, Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother., 2012, Mar; 56(3): 1273-80).
Another aspect of the description relates to a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 streptomycin11 determinant. The resulting isolate SP1364 is streptomycin11 at >1250 μg/mL.
Another aspect of the description relates to a method of use for a compound of
Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof having activity against a N. gonorrhoeae clinical isolate LG24 (see, Garvin LE, Bash MC, Keys C, Warner DM, Ram S, Shafer WM and Jerse AE. Phenotypic and genotypic analyses of Neisseria gonorrhoeae isolates that express frequently recovered PorB PIA variable region types suggest that certain Pla porin sequences confer a selective advantage for urogenital tract infection. Infect Immun., 2008, Aug; 76(8):3700-9).
Another aspect of the description relates to a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof having activity against N. gonorrhoeae clinical isolates selected from penicillin- resistant (penicillinR) N. gonorrhoeae LGB3, tetracycline-resistant (tetracycline11)
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 (la), Formula (lb), and
Formula (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to treat or ameliorate N. gonorrhoeae MSI 1 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to treat or ameliorate ampicillin N. gonorrhoeae LGB50 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to treat or ameliorate penicillin-sensitive N. gonorrhoeae FA 19 or LGB3 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula
(Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to treat or ameliorate streptomycin11 N. gonorrhoeae FA1090 or SP1364 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to treat or ameliorate ciprofloxacin11 N. gonorrhoeae AK1 or AK2 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to treat or ameliorate tetracycline11 N. gonorrhoeae LGB24 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to treat or ameliorate
XDR XDR XDR
ciprofloxacin /cefixime /ceftriaxone N. gonorrhoeae F89 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (la), Formula (lb), and Formula
(Ic) or a form thereof includes a method of use for a compound of Formula (la), Formula (lb), and Formula (Ic) or a form thereof to treat or ameliorate or N. meningitidis 13090 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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. A dose 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 the daily dose is 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 (la), Formula (lb), and Formula (Ic) 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 or N. meningitidis 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 N. meningitidis, or the amount required to inhibit N. gonorrhoeae or N. meningitidis 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) or a form thereof in the preparation of a kit comprising the pharmaceutical composition of the compound of Formula (la), Formula (lb), and Formula (Ic) 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 (la), Formula (lb), and Formula (Ic) 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-propanediol. 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 (la), Formula (lb), and Formula (Ic) 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
As disclosed herein, many of the starting materials used are commercially available or can be prepared using the routes described below using techniques known to those skilled in the art.
General Schemes
Compounds of Formula (la), Formula (lb), and Formula (Ic) can be prepared as described in the Schemes below.
Starting materials used in Scheme 7 were prepared via the routes depicted in Scheme
1, Scheme 2, Scheme 3, Scheme 4, Scheme 5, and Scheme 6:
Scheme 1
Figure imgf000181_0001
General Procedure for Scheme 1
Imidazoles of Type lc can be prepared from tropolone- sulfonates of Type la via condensation with a suitable R5 substituted amidine of Type lb.
Ketones of Type Id can be prepared from the respective imidazoles by hydrogenation in the presence of a suitable Pd catalyst (such as Pd/C and the like).
Fused imidazoles of Type le can be prepared from the respective ketones by alkylation with a suitable R5 substituted alkylating reagent (where L represents a leaving group) in the presence of an appropriate base (such as NaH and the like).
Scheme 2
Figure imgf000182_0001
General Procedure for Scheme 2
Vinylogous amides of Type 2b can be prepared from β-diketones of Type 2a via condensation with a suitable dialkyl acetal (wherein R is d^alkyl, such as N,N- dimethylformamide dimethyl acetal and the like).
Fused pyrazoles of Type 2d can be prepared by condensation with suitable R5 substituted hydrazines of Type 2c.
Scheme 3
Figure imgf000182_0002
3e: W: C(R2)
Z: C(R2), CH(R2)-C(R2), CH(R2)-CH(R2)-C(R2)
3f: X: C(R2)
Y: C(R2), CH(R2)-C(R2), CH(R2)-CH(R2)-C(R2)
General Procedure for Scheme 3
Vinyl aldehydes of Type 3b can be prepared from iodoaldehydes of Type 3a via Pd catalyzed Suzuki coupling with a suitable vinylation reagent (such as potassium vinyl trifluoroborate and the like), in the presence of a suitable phosphine ligand (such as 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl and the like) in a suitable biphasic mixture (such as a mixture of dioxane/H20 and the like).
Diene intermediates of Type 3c can be prepared from the respective vinyl aldehydes via reaction with alkenyl metal halides (where Mg(Hal) represents a magnesium halide). Unsaturated ketones of Type 3d can be prepared from the respective diene intermediates by reaction with suitable oxidative reagents (where [Ox] represents a mixture of reagents such as TPAP and NMO and the like).
Ring closing metathesis (RCM) of the respective unsaturated ketones to provide olefin intermediates of Type 3e can be accomplished in the presence of Grubbs' catalyst (such as a second generation Grubbs' catalyst) in a suitable organic solvent (such as toluene and the like).
Ketones of Type 3f can prepared from the respective olefin intermediates by hydrogenation in the presence of suitable Pd or Pt catalysts (such as Pd/C, Pt02 and the like). Scheme 4
Figure imgf000183_0001
4a: W: C(R2)
4b: Z: C(R2), C(R2)-CH(R2), C(R2)-CH(R2)-CH(R2)
4c: W: C(R2)
Z: C(R2), C(R2)-CH(R2), C(R2)-CH(R2)-CH(R2)
General Procedure for Scheme 4
Esters of Type 4c can be prepared from aldehydes of Type 4a via a Wittig reaction with a suitable phosphorane of Type 4b followed by hydrogenation in the presence of a suitable Pd catalyst (such as Pd/C, Pd(OH)2/C and the like).
Ketones of Type 4d can be prepared from the respective esters via hydrolysis to carboxylic acids in the presence of a suitable base (such as LiOH and the like) followed by Friedel-Crafts condensation under suitable conditions (such as by thermal condensation in the presence of PPA or by intermediate acyl chloride formation, followed by Lewis acid catalyzed cyclization and the like).
Scheme
Figure imgf000184_0001
General Procedure for Scheme 5
Indole intermediates of Type 5c can be prepared via Fischer indole synthesis between aryl hydrazines of Type 5a and cyclic ketones of Type 5b.
Tricyclic ketones of Type 5d can be prepared by from the respective indole intermediates by alkylation with a suitable R5 substituted alkylating reagent (where L represents a leaving group) in the presence of an appropriate base (such as NaH and the like), followed by regioselective oxidation with a suitable oxidative reagent (such as DDQ and the like).
Scheme 6
Figure imgf000184_0002
General Procedure for Scheme 6
Intermediates of Type 6a can be prepared according to the literature procedure (Iwata, H. et al. ACS Med. Chem. Lett. 2012, 3(4), 342-346).
Tricyclic ketones of Type 6b can be prepared by N-alkylation with a suitable R5 substituted alkylating reagent (where L represents a leaving group) in the presence of an appropriate base (such as CS2CO3 and the like).
Scheme 7
Figure imgf000185_0001
General Procedure for Scheme 7
In the sequence above, ketones of types le, 2d, 3f, and 4d are represented by a ketone of Type 7a. Ketones of Type 7a can be converted into imines of Type 7b through reaction with an amine containing a suitable protecting group (such as 2,4-dimethoxybenzyl and the like), in the presence of a suitable dehydrating agent (such as titanium tetrachloride and the like).
4-Hydroxy-2-pyridone esters of Type 7b can be prepared from the respective imines through reaction with a trialkylmethane tricarboxylate (such as trimethylmethane
tricarboxylate and the like), in a suitable organic solvent (such as diphenyl ether and the like).
Compounds of Formula (la) can be prepared from the respective 4-hydroxy-2- pyridone esters converting the ester moiety to the corresponding carboxylic acid by reaction with a suitable nucleophilic reagent (where Nu" represents a nucleophilic reagent such as Lil and the like), followed by cleavage of the protecting group in the presence of a suitable acid (such as TFA and the like).
Compounds of Formula (lb) and (Ic) can be prepared from ketones of Type 6b and 5d, respectively, using the sequence described above for compounds of Formula (la).
Compounds of Formula (la), Formula (lb), and Formula (Ic) can alterntaviely be prepared as described in the Schemes below.
Scheme 8
Figure imgf000186_0001
General Procedure for Scheme 8
Substituted propargyl alcohols of Type 8b can be prepared from aryl iodides of Type 8a via Sonogashira coupling with a suitable alkyne in the presence of an appropriate Pd source (such as Pd(PPli3)2Cl2 and the like) and Cu1 salt (such as Cul and the like).
Malonates of Type 8c can be prepared from the respective substituted propargyl alcohols via a two-step process: Step 1. Conversion of a hydroxyl group to a sulfonate ester by reaction with a suitable sulfonyl chloride (such as MsCl and the like); Step 2. SN2 nucleophilic substitution reaction with a suitable alkyl benzyl malonate (such as methyl benzyl malonate and the like) in the presence of a suitable mild base (such as CsF and the like).
Diester intermediates of Type 8d can be prepared from the respective malonates by Bn-group cleavage under hydrogenation conditions in the presence of a suitable Pd catalyst (such as Pd/C and the like), followed by decarboxylation using thermal conditions (such as heating the reaction mixture in DMSO at 110 °C and the like).
β-Ketoesters of Type 8e can be prepared by intramolecular Dieckmann condensation of the respective diester intermediates in the presence of a suitable base (such as LiHMDS and the like).
Compounds of Formula (la) can be prepared from the respective β-ketoesters via a four- step sequence: Step 1. Formation of an enamine intermediate by reaction with a suitable ammonium salt (such as NH4OAc and the like); Step 2. Enamine acylation with a suitable mono malonate salt (such as methyl potassium malonate and the like) in the presence of a suitable activating reagent (such as propylphosphonic anhydride and the like); Step 3. Pyridone ring formation promoted by a suitable base (such as MeONa and the like); and, Step 4. Conversion of the ester moiety to the corresponding carboxylic acid by reaction with a suitable nucleophilic reagent (where Nu" represents a nucleophilic reagent such as Lil and the like).
Scheme 9
Figure imgf000187_0001
General Procedure for Scheme 9
Alkenyl intermediates of Type 9c can be prepared from halogenated pyridines of Type 9a by a halogen dance reaction promoted by treatment with a suitable base (such as 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride and the like), followed by transmetallation with a suitable Cu1 species (such as CuCN and the like) and finally by quenching of intermediate organocuprate with alkyl iodides of Type 9b.
Functionalized alcohols of Type 9d can be prepared from the respective alkenyl intermediates by a three-step process: Step 1. Hydroboration reaction with a suitable borane (such as 9-BBN and the like); Step 2. SNAT substitution reaction of pyridine 2,4-difluoride with a suitable alkoxide bearing a protecting group (such as t-BuOK and the like); and, 3. Oxidation of the intermediate borane with a suitable oxidative reagent (such as H2O2 and the like) in the presence of a suitable base (such as KOH and the like).
Heterocycle tethered pyridines of Type 9g and 9h can be prepared from the respective functionalized alcohols by hydroxyl-group activation with a suitable sulfonyl chloride (such as MsCl and the like) followed by reaction with the corresponding monocyclic or bicyclic heterocycles of Type 9e or 9f respectively.
Compounds of Formula (la) and (lb) can be prepared from the respective heterocycle tethered pyridines via a two-step process: Step 1. Intramolecular CH-activation/Suzuki coupling in the presence of a suitable Pd catalyst and ligand combination (such as a mixture of Pd(OAc)2 and DavePhos and the like); Step 2. Global cleavage of the protecting groups in the presence of a suitable acid (such as TFA and the like).
Scheme 10
Figure imgf000188_0001
General Procedure for Scheme 10
Boronic ester intermediates of Type 10b can be prepared from halogenated heterocycles of Type 10a via metal halogen exchange with a suitable alkyl metal species (such as i-PrMgCl and the like) followed by reaction with an appropriate pinacol boronate ester (such as 2-methoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane and the like).
Biaryl intermediates of Type lOd can be prepared from the respective boronic ester intermediates via Pd catalyzed Suzuki coupling with functionalized pyridines of Type 10c (where PG represents a protecting group such as benzyl and the like), in the presence of a suitable phosphine ligand (such as t-Bu3PHBF4 and the like) in a suitable biphasic mixture (such as a mixture of 1,4-dioxane and water and the like).
Tricyclic pyridines of Type lOe can be prepared from the respective biaryl intermediates via a two-step process: Step 1. TBS-group deprotection with a suitable fluoride containing reagent (such as TBAF and the like); and, Step 2. Intramolecular Mitsunobu reaction with a suitable dialkyl azodicarboxylate (such as diisopropyl azodicarboxylate and the like).
Compounds of Type lOf, representative of a compound of Formula (la), wherein Y is O, can be prepared from the respective tricyclic pyridines by global protecting group cleavage under hydrogenation conditions in the presence of a suitable Pd catalyst (such as Pd/C and the like).
Specific Examples
To assist in understanding the present description, the following specific examples are included. The experiments relating to this description should not, of course, be construed as specifically limiting the description and such variations of the description, now known or later developed, which would be within the purview of one skilled in the art are considered to fall within the scope of the description as described herein and hereinafter claimed.
Other than in the working examples, unless indicated to the contrary, all numbers expressing quantities of materials, reagents, reaction conditions, experimental data, and so forth used in the specification and claims are to be understood as being modified by the term "about". Accordingly, all such numbers represent approximations that may vary depending upon the desired properties sought to be obtained by a reaction or as a result of variable experimental conditions. Therefore, within an expected range of experimental
reproducibility, the term "about" in the context of the resulting data, refers to a range for data provided that may vary according to a standard deviation from the mean. As well, for experimental results provided, the resulting data may be rounded up or down to present data consistently, without loss of significant figures. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques.
While the numerical ranges and parameters setting forth the broad scope of the description are approximations, the numerical values set forth in the working examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
Synthetic Examples
Greater details of the present description are provided with reference to the following non-limiting examples, which are offered to more fully illustrate the description, but are not to be construed as limiting the scope thereof. The examples illustrate the preparation of certain compounds described herein, and the testing of these compounds in vitro and/or in vivo. Those of skill in the art will understand that the techniques described in these examples represent techniques described by the inventors to function well in the practice of the description, and as such constitute preferred modes for the practice thereof. However, those of skill in the art should appreciate in light of the present disclosure that many changes can be made to the specific methods that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the description. For example, various conditions were used to obtain LC-MS characterization for the compounds described herein.
Unless indicated otherwise for certain compounds, the 2 Minute Method was used, having the following column and mobile phase ratios:
Column: Acquity UPLC HSS C18 Column 2.1 x 50 mm, 1.8μιη
Mobile Phase A: H2O/0.1% HC02H
Mobile Phase B : Acetonitrile/0.1 % HC02H
Gradient Time (min) . T , . . %A %B
(mL/min)
Ϊ 0 08 100 0~
2 0.2 0.8 100 0
3 1.5 0.8 0 100
4 2.0 0.8 100 0
As indicated for certain compounds, the 1 Minute Method uses the following column and mobile phase ratios:
Column: Acquity UPLC HSS C18 Column 2.1 x 50 mm, 1.8μιη
Mobile Phase A: H2O/0.1% HC02H
Mobile Phase B : Acetonitrile/0.1 % HC02H
Figure imgf000190_0001
2 0.1 0.8 90 10 Gradient Time (min) . T , . . %A %B
(mL/min)
3 08 08 5 95"
4 1.0 0.8 90 10
As indicated for certain compounds, the Non-Polar Method uses the following column and mobile phase ratios:
Column: Acquity UPLC HSS C18 Column 2.1 x 50 mm, 1.8μιη
Mobile Phase A: H2O/0.1% HC02H
Mobile Phase B : Acetonitrile/0.1 % HC02H
Gradient Time (min) . T , . . %A %B
(mL/min)
Ϊ 0 08 80 20~
2 0.2 0.8 80 20
3 1.5 0.8 0 100
4 2.0 0.8 80 20
As used above, and throughout this description, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:
Abbreviation Meaning
AcOH or HOAc acetic acid
ACN or MeCN acetonitrile
4 A MS 4 Angstrom Molecular Sieves
Atm atmosphere
9-BBN 9-borabicyclo(3.3.1 )nonane
Bn benzyl
BnBr benzyl bromide
BnO or OBn benzyloxy
BnOH benzyl alcohol
Boc i<?ri-butoxycarbonyl
Boc20 or (Boc)20 di-i<?ri-butyl dicarbonate
BORSM based on recovered starting material
Cbz benzyloxycarbonyl
CDI 1 , 1 '-carbonyldiimidazole
DAST diethylaminosulfur trifluoride
DCE dichloroethane
DCM dichloromethane (CH2C12)
DDQ 2 , 3 -dichloro-5 , 6-dicy ano- 1 , 4-benzoquinone
DIAD diisopropyl azodicarboxylate Abbreviation Meaning
DIBAL-H diisobutylaluminium hydride
DMF dimethyl formamide
DMA dimethylacetamide
DMAP 4-dimethylaminopyridine
DMB 2,4-dimethoxybenzyl
DMSO dimethylsulf oxide
EA or EtOAc ethyl acetate
EtOH ethanol
Et20 diethyl ether
HPLC high performance liquid chromatography
h/hr/hrs/min/s hour(s)(h, hr or hrs)/minute(s)(min/mins)/second(s)
KOAc potassium acetate
LAH lithium aluminium hydride
LC/MS, LCMS or LC-MS liquid chromatographic mass spectroscopy
LDA lithium diisopropylamide
LiHMDS lithium bis(trimethylsilyl)amide
Mel methyl iodide
MeOH methanol
Me2NH or NHMe2 dimethyl amine
MS mass spectroscopy
NaBH(OAc)3 sodium triacetoxyborohydride
NaHMDS sodium bis(trimethylsilyl)amide
NBS N-bromosuccinimide
NIS N-iodosuccinimide
NMO N-methylmorpholine-N-oxide
n-BuLi n-butyl lithium
NMR nuclear magnetic resonance
Pd/C palladium on carbon
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
PdCl2dppf [1, l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II)
Pd(PPh3)4 tetrakis(triphenylphosphine)palladium
Ph20 diphenyl ether
Pin pinacol
PMB para-methoxybenzyl
PPA polyphosphoric acid
PPI13 triphenylphosphine
Psi pounds per square inch pressure Abbreviation Meaning
PTFE polytetrafluoroethylene
RT retention time
RCM ring closing methathesis
S-Phos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl
SEM 2-(trimethylsilyl)ethoxymethyl
SEM-C1 2-(trimethylsilyl)ethoxymethyl chloride
TBAF tetra-n-butylammonium fluoride
TBDPSC1 tert-butyldiphenylchlorosilane
TBS tert-butyldimethylsilyl
TBSC1 tert-butyldimethylsilyl chloride
t-BuOK potassium tert-butoxide
t-Bu3P tert-butyl phosphine
TEA or NEt3 triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
THP tetrahydro-2H-pyranyl
THPO or OTHP tetrahydro-2H-pyran-2-yl-oxy
TIPS-H or TIPSH triisopropyl silane
TLC thin layer chromatography
TMP 2,2,6,6-tetramethylpiperidinyl
„, T 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium TMPMgCl-LiCl , , · ,
chloride
TMSI trimethylsilyl iodide
TMSOK potassium trimethylsilanolate
TPAP tetra-n-propylammonium perruthenate
Intermediate 1
2,3-Dimethyl-5,6,7,8-tetrah dro-4H-cyclohepta[b]furan-4-one
Figure imgf000193_0001
Steps 1-2: Ethyl 5-(4,5-dimethylfuran-2-yl)pentanoate
To a suspension of (4-ethoxy-4-oxobutyl)triphenylphosphonium bromide (21.84 g, 47.75 mmol) in THF (75 mL) at -78 °C was added a solution of NaHMDS (1M THF, 50.0 mL, 50.0 mmol) dropwise over -10 min. The reaction mixture was stirred at -78 °C for 15 min before 4,5-dimethylfuran-2-carbaldehyde (4.0 mL, 32.73 mmol) was added dropwise. The reaction was allowed to slowly warm to room temperature. The reaction was stirred overnight then quenched with NH4C1 (aq. sat'd.). The product was extracted with EtOAc, and the combined organics were washed with NaCl (aq. sat'd.), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% EtOAc in hexanes gradient) to afford ethyl 5-(4,5-dimethylfuran-2- yl)pent-4-enoate (4.62 g, 69%) as a mixture of EIZ isomers.
A solution of the product obtained above in EtOH (80 mL) was hydrogenated under a ¾ balloon over a mixture of Pd/C (210 mg, 10% Degussa type) and Pd(OH)2/C (210 mg, 20%
Degussa type) catalysts. Upon complete consumption of the starting material, the catalysts were removed by filtration and washed with EtOH, and the mother liquor was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-
10% EtOAc in hexanes gradient) to afford the title compound (4.03 g, 86%) as an oil.
H NMR (500 MHz, CDC13) δ ppm 1.26 (t, 7=7.1 Hz, 3H), 1.58 - 1.73 (m, 4H), 1.89 (d, 7=0.6 Hz, 3H), 2.16 (s, 3H), 2.32 (t, 7=7.3 Hz, 2H), 2.55 (t, 7=7.1 Hz, 2H), 4.13 (q, 7=7.1 Hz, 2H), 5.76 (s, 1H)
Step 3: 5-(4,5-Dimethylfuran-2-yl)pentanoic acid
A mixture of ethyl 5-(4,5-dimethylfuran-2-yl)pentanoate (4.15 g, 18.53 mmol) and LiOH (1M in H20, 38.0 mL, 38.0 mmol) in THF (60 mL) was stirred overnight at room
temperature. The reaction was acidified to pH ~2 with 1M HC1 and extracted with EtOAc. The combined organic layers were washed with NaCl (aq. sat'd.), dried over Na2S04 and concentrated under reduced pressure to afford the title compound (3.52 g, 97%) as a white solid.
Steps 4-5: 2,3-Dimethyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-4-one
To a solution of 5-(4,5-dimethylfuran-2-yl)pentanoic acid (3.52 g, 17.96 mmol) in CH2CI2 (75 mL) at 0 °C was added oxalyl chloride (2.50 mL, 28.66 mmol, 1.6 eq) dropwise followed by addition of 3 drops of DMF. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The volatiles were removed under reduced pressure, and the intermediate acyl chloride was dissolved in CH2CI2 (100 mL). The mixture was cooled to 0 °C, and a solution of SnCl4 (3.20 mL, 27.34 mmol, 1.5 eq) in CH2C12 (20 mL) was added dropwise over - 10 min. Stirring was continued at 0 °C for 30 min before water (100 mL) was added. The organic layer was separated, washed with NaCl (aq. sat'd.) and dried over Na2S04. Removal of the solvent under reduced pressure afforded an oil which was purified by silica gel column chromatography (0-20% EtOAc in hexanes gradient) to afford the title compound (3.08 g, 95%) as a white solid.
!H NMR (500 MHz, CDC13) δ ppm 1.83 - 1.99 (m, 4H), 2.08 (d, 7=0.9 Hz, 3H), 2.16 (s, 3H), 2.65 - 2.73 (m, 2H), 2.94 (t, 7=6.3 Hz, 2H)
Intermediate 2
4-(Benzyloxy)butanimidamide hydrochloride
,NH2
BnO
. HCl NH
Step 1: Ethyl 4-(benzyloxy)butanimidate hydrochloride
4-Benzyloxybutyronitrile (31 g, 177 mmol) was dissolved in EtOH (435 mL) at 0 °C (ice bath). HCl gas was bubbled into the solution causing the internal temperature to rise to 25° C.
When the internal temperature subsided to 15 °C, HCl bubbling was ceased. The reaction mixture was stirred in an ice bath for an additional 4 h. The volatiles were removed under reduced pressure, and the resulting solid was triturated with ether to afford the title compound
(40.49 g, 89%) as a white solid.
H NMR (500 MHz, DMSO- ): δ ppm 1.31 (t, 7=7 Hz, 3H), 1.92 (pentet, 7=6 Hz, 2H), 2.69 (t, 7=7.5 Hz, 2H), 3.49 (t, 7=6 Hz, 2H), 4.31 (q, 7=7 Hz, 2H), 4.46 (s, 2H), 7.30 (m, 5H)
Step 2: 4-(Benzyloxy)butanimidamide hydrochloride
A mixture of ethyl 4-(benzyloxy)butanimidate hydrochloride (20 g, 77 mmol) and N¾ (7M in MeOH, 160 mL) was stirred at 0 °C and allowed to warm to room temperature over 90 min. The volatiles were removed under reduced pressure. Trituration of the residue afforded
4-(benzyloxy)butanimidamide hydrochloride (17.52 g, 99%) as a white solid.
H NMR (500 MHz, OMSO-d6): δ ppm 1.91 (pentet, 7=6.5 Hz, 2H), 2.47 (t, 7=7.5 Hz, 2H), 3.47 (t, 7=6.5 Hz, 2H), 4.48 (s, 2H), 7.33 (m, 5H), 8.72 (br. s, 1H), 9.03 (br. s, 1H)
Intermediate 3
l-Ethyl-2-methyl-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(lH)-one
Figure imgf000195_0001
Step 1: 2-Methylcyclohepta[d]imidazol-4(lH)-one
To a mixture of tropolone tosylate (33.1 g, 120 mmol), acetimidamide hydrochloride (34.0 g, 180 mmol) and toluene (300 mL), was added NaOH (30%, 84 mL), and the mixture was stirred for 5 h at 30 °C. Toluene was removed under reduced pressure, and the residue was treated with aqueous NH4C1 (500 mL). The mixture was concentrated to dryness under reduced pressure. The residue was suspended in CH2CI2 (1000 mL), and stirred for 0.5 h.
The precipitate was removed by filtration and washed with CH2CI2 until no product was detected by LC/MS analysis of the filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20 % MeOH in
EtOAc gradient) to afford the title compound (13.3 g, 83 mmol, 69%).
!H NMR (500 MHz, CDC13) δ ppm 2.75 (s, 3H), 7.12 (dd, 7=10.6, 9.0 Hz, 1H), 7.34 (d, 7=12.3 Hz, 1H), 7.47 (dd, 7=12.5, 8.7 Hz, 1H), 7.86 (d, 7=11.0 Hz, 1H)
Step 2: 2-Methyl-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(lH)-one
The product of step 1 (3.4 g, 21 mmol) was dissolved in methanol (80 mL) and hydrogenated at 60 psi in the presence of 10% Pd/C (0.7 g) for 72 h. The catalyst was removed by filtration and washed with methanol. The solvent was removed under reduced pressure to afford the title compound (3.3 g, 96%).
H NMR (500 MHz, CDC13) δ ppm 1.88 - 2.06 (m, 4H), 2.46 (s, 3H), 2.70 - 2.76 (m, 2H), 2.96 - 3.03 (m, 2H)
Step 3: l-Ethyl-2-methyl-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(lH)-one
The product of step 2 (0.82 g, 5.0 mmol) was suspended in THF (10 mL), treated with NaH (60% suspension in mineral oil, 0.24 g, 6.0 mmol) and stirred for 0.5 h. Etl (1.17 g, 0.6 mL, 7.5 mmol) was added, and the mixture was stirred overnight. The reaction was quenched with NaH2P04 (aq. sat'd.) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% gradient MeOH in CH2CI2) to afford the title compound as a white powder (0.68 g, 71%).
!H NMR (500 MHz, CDC13) δ ppm 1.31 (t, 7=7.4 Hz, 3H), 1.86 - 1.95 (m, 2H), 2.00 - 2.10 (m, 2H), 2.45 (s, 3H), 2.71 - 2.79 (m, 2H), 2.80 - 2.88 (m, 2H), 3.88 (q, 7=7.5 Hz, 2H)
Using the procedure described for Intermediate 2 and Intermediate 3 above, additional intermediates described herein may be prepared by substituting the appropriate starting material, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Int Structure Name and Data Int Structure Name and Data
l,2-Dimethyl-5,6,7,8-tetrahydrocyclohepta[d]imidazol- 4(lH)-one
4
H NMR (500 MHz, CDC13) δ ppm 1.86 - 1.95 (m, 2H), 2.02 - 2.10 (m, 2H), 2.43 (s, 3H), 2.73 - 2.78 (m, 2H), 2.79 - 2.85 (m, 2H), 3.47 (s, 3H)
2-Ethyl-l-methyl-5,6,7,8-tetrahydrocyclohepta[d]imidazol- 4(lH)-one
5
!H NMR (500 MHz, CDC13) δ ppm 1.33 (t, 7=7.6 Hz, 3H), 1.87 - 1.94 (m, 2H), 2.02 - 2.09 (m, 2H), 2.74 - 2.79 (m, 4H), 2.80 - 2.85 (m, 2H), 3.48 (s, 3H)
1 , 2-Diethyl- 5,6,7,8 -tetrahydrocyclohepta[d] imidazol-4( 1 H) - one
6
LC-MS 207.2 [M+H]+, RT 0.74 min
l-Ethyl-2-(methoxymethyl)-5,6,7,8- tetrahydrocyclohepta[d] imidazol-4( 1 H) -one
7 H NMR (500 MHz, CDC13) δ ppm 1.35 (t, 7=7.3 Hz, 3H),
1.87 - 1.99 (m, 2H), 2.02 - 2.11 (m, 2H), 2.74 - 2.81 (m, 2H), 2.84 - 2.92 (m, 2H), 3.35 (s. 3H), 4.03 (q, 7=7.4 Hz, 2H), 4.62 (s, 2H)
2-((Benzyloxy)methyl)-l-ethyl-5, 6,7,8- tetrahydrocyclohepta[d] imidazol-4( 1 H) -one
8 •■σ¾ LC-MS 299.3 [M+H]+, RT 1.03 min
2-(Methoxymethyl)-l-methyl-5,6,7,8- tetrahydrocyclohepta[d] imidazol-4( 1 H) -one
9
H NMR (500 MHz, CDC13) δ ppm 1.87 - 1.97 (m, 2H), 2.03 - 2.12 (m, 2H), 2.74 - 2.80 (m, 2H), 2.81 - 2.87 (m, 2H), 3.35 (s, 3H), 3.59 (s, 3H), 4.60 (s, 2H)
l-Ethyl-2-((2-methoxyethoxy)methyl)-5, 6,7,8- tetrahydrocyclohepta[d] imidazol-4( 1 H) -one
10 H NMR (500 MHz, CDC13) δ 1.36 (t, 7=7.3 Hz, 3H), 1.89- 1.98 (m, 2H), 2.02-2.10 (m, 2H), 2.74-2.81 (m, 2H), 2.85- 2.91 (m, 2H), 3.36 (s, 3H), 3.50-3.54 (m, 2H), 3.61-3.66 (m, 2H), 4.06 (q, 7=7.3 Hz, 2H),4.73 (s, 2H) Int Structure Name and Data
l-(2-Methoxyethyl)-2-methyl-5,6,7,8- tetrahydrocyclohepta[d] imidazol-4( 1 H) -one
11
lH NMR (500 MHz, CDC13) δ 1.86-1.96 (m, 2H), 1.99-2.09 (m, 2H), 2.48 (s, 3H), 2.73-2.79 (m, 2H), 2.84-2.90 (m, 2H), 3.31 (s, 3H), 3.57 (t, 7=5.4 Hz, 2H), 4.02 (t, 7=5.5 Hz, 2H) l-(3-Methoxypropyl)-2-methyl-5, 6,7,8- tetrahydrocyclohepta[d] imidazol-4( 1 H) -one
12 !H NMR (500 MHz, CDC13) δ 1.90-2.02 (m, 4H), 2.06-2.15
(m, 2H), 2.66 (s, 3H), 2.74-2.82 (m, 2H), 2.94 (t, 7=6.2 Hz, 2H), 3.35 (s, 3H), 3.39 (t, 7=5.5 Hz, 2H), 4.07 (t, 7=7.3 Hz, 2H)
2-(2-(Benzyloxy)ethyl)-l-ethyl-5,6,7,8-
0 tetrahydrocyclohepta[d] imidazol-4( 1 H) -one
13 H NMR (500 MHz, CDC13) δ ppm 1.27 (t, 7=7.4 Hz, 3H),
1.86 - 1.97 (m, 2H), 2.00 - 2.11 (m, 2H), 2.74 - 2.79 (m, 2H), 2.81 - 2.85 (m, 2H), 3.03 (t, 7=6.8 Hz, 2H), 3.90 - 3.96 (m, 4H), 4.51 (s, 2H), 7.24 - 7.40 (m, 5H)
2-(3 -(Benzyloxy)propyl)- 1 -ethyl-5 ,6,7 , 8- tetrahydrocyclohepta[d] imidazol-4( 1 H) -one
H NMR (500 MHz, acetone-d6): δ ppm 1.28 (t, 7=7 Hz,
14 3H), 1.86 (m, 2H), 2.00 (pentet, 7=6 Hz, 2H), 2.08 (m, 2H),
2.59 (m, 2H), 2.77 (t, 7=7.5 Hz, 2H), 2.92 (t, 7=6 Hz, 2H),
3.60 (t, 7=6 Hz, 2H), 3.99 (q, 7=7.5 Hz, 2H), 4.52 (s, 2H), 7.27-7.37 (m, 5H)
Intermediate 15
l-Ethyl-2-((oxetan-3-yloxy)methyl)-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(lH)-one
Figure imgf000198_0001
Step 1: 2-(Chloromethyl)- 1 -ethyl-5, 6,7, 8-tetrahydrocyclohepta[d]imidazol-4( lH)-one In a sealed high pressure vessel, a mixture of l-ethyl-2-(methoxymethyl)-5, 6,7,8- tetrahydrocyclohepta[d]imidazol-4(lH)-one (Intermediate 7, 4.7 g, 21.1 mmol) and HCl (concentrated, -37%, 40 mL) was stirred at 110 °C overnight. After cooling to room temperature, the reaction was neutralized with Na2C03 and concentrated under reduced pressure. The residue was suspended in CH2CI2, and the precipitate was removed by filtration. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (0-20% gradient MeOH in CH2CI2) to afford the title compound as a colorless oil (1.65 g).
lH NMR (500 MHz, CDC13) δ 1.25 (t, 7=7.09 Hz, 3H), 1.87-1.98 (m, 2H), 2.01-2.12 (m, 2H), 2.71-2.80 (m, 2H), 2.84-2.93 (m, 2H), 4.12 (q, 7=7.04 Hz, 2H), 5.30 (s, 2H)
Step 2: l-Ethyl-2-((oxetan-3-yloxy)methyl)-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(lH)- one
To a solution of oxetan-3-ol (96 mg, 1.3 mmol) in THF at 0 °C, was added NaH (60% suspension in mineral oil, 64 mg, 1.6 mmol). The mixture was stirred at room temperature for 0.5 h. The mixture was cooled to 0 °C and 2-(chloromethyl)-l-ethyl-5, 6,7,8- tetrahydrocyclohepta[d]imidazol-4(lH)-one (227 mg, 1.0 mmol) was added. The mixture was brought to room temperature and stirred overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% gradient MeOH in CH2CI2) to afford the title compound (34 mg, 13%).
LC-MS 265.4 [M+H]+, RT 0.69 min.
Intermediate 16
(l-Ethyl-4-oxo-l,4,5,6,7,8-hexahydrocyclohepta[d]imidazol-2-yl)methyl acetate
Figure imgf000199_0001
Step 1: l-Ethyl-2-(hydroxymethyl)-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(lH)-one In a sealed high pressure vessel, a mixture of l-ethyl-2-(methoxymethyl)-5, 6,7,8- tetrahydrocyclohepta[d]imidazol-4(lH)-one (Intermediate 7, 12.9 g, 58 mmol), and HC1 (30%, 80 mL) was stirred at 110 °C for 48 h. After cooling to room temperature, the reaction mixture was neutralized with Na2CC>3 and concentrated under reduced pressure. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (0-20% gradient MeOH in CH2CI2) to afford the title compound as a white solid (8.1 g, 67%). LC-MS 209.5 [M+H]+, RT 0.51 min. H NMR (500 MHz, CDC13) δ 1.42 (t, 7=7.3 Hz, 3H), 1.88-2.01 (m, 2H), 2.04-2.15 (m, 2H), 2.71-2.80 (m, 2H), 2.87-2.94 (m, 2H), 3.31 (br. s, 1H), 4.12 (q, 7=7.3 Hz, 2H), 4.77 (s, 2H)
Step 2: (l-Ethyl-4-oxo-l,4,5,6,7,8-hexahydrocyclohepta[d]imidazol-2-yl)methyl acetate To a solution of the product of step 1 (143 mg, 0.69 mmol) in DMF (1.5 mL) at 0 °C, was added NaH (60% suspension in mineral oil, 30 mg, 0.76 mmol). The mixture was stirred for
0.5 h followed and 2-bromoethyl acetate (184 mg, 0.12 mL, 1.1 mmol) was added. The reaction was brought to room temperature and stirred overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% gradient MeOH in CH2CI2) to afford the title compound (180 mg, 89%) as a colorless oil.
!H NMR (500 MHz, CDC13) δ 1.36 (t, 7=7.4 Hz, 3H), 1.89-2.00 (m, 2H), 2.03-2.15 (m, 5H), 2.75-2.82 (m, 2H), 2.89 (t, 7=6.3 Hz, 2H), 3.99 (q, 7=7.4 Hz, 2H), 5.25 (s, 2H)
Intermediate 17
10-(2,4-Dimethoxybenzyl)-3-ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5' dine-8-carboxylic acid
Figure imgf000200_0001
Step 1: 2-(((tert-Butvldimethvlsilvl)oxv)methvl)-l-ethyl-5,6,7,8- tetrahydrocyclohepta[d] imidazol-4( 1 H) -one
To a solution of l-ethyl-2-(hydroxymethyl)-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(lH)- one (Intermediate 16, step 1, 172 mg, 0.83 mmol) in DMF (3.0 mL) was added imidazole (67 mg, 0.99 mmol) and TBSC1 (149 mg, 0.99 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water and brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% gradient MeOH in CH2CI2) to afford the title compound as a colorless oil, which solidified on standing.
LC-MS 323.4 [M+H]+, RT 1.36 min. H NMR (500 MHz, CDC13) δ 0.11 (s, 6H), 0.90 (s, 9H), 1.38 (t, 7=7.3 Hz, 3H), 1.89-1.97 (m, 2H), 2.03-2.10 (m, 2H), 2.74-2.80 (m, 2H), 2.85- 2.91 (m, 7=6.6 Hz, 2H), 4.07 (q, 7=7.3 Hz, 2H), 4.86 (s, 2H) Steps 2-3: Methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)- 10-(2,4-dimethoxybenzyl)-3- ethyl-7-hydroxy-9-oxo-3,4,5,6,9J0-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8- carboxylate
To a solution of the product of step 1, triethylamine (324 mg, 0.45 mL, 3.21 mmol) and (2,4- dimethoxyphenyl)methanamine (195 mg, 0.18 mL, 1.17 mmol) in CH2CI2 at 0 °C (2.5 mL), was added TiCl4 (0.64 mL, 1.0 M in CH2C12, 0.64 mmol). The mixture was stirred at 0 °C for 15 min. The mixture was brought to room temperature and stirred overnight. The mixture was diluted with CH2CI2 and quenched at 0 °C with saturated NaHCC>3 solution. The organic layer was separated using a phase separator cartridge, and the aqueous layer was washed with additional CH2CI2. The CH2CI2 solution was concentrated under reduced pressure. To the residue, diphenyl ether (5.0 mL) and trimethyl methanetricarboxylate (380 mg, 2.0 mmol) were added. The mixture was stirred at 200 °C for 10 min and then cooled. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (0-100% gradient EtOAc in CH2CI2) to afford the title compound as a yellow oil (200 mg, 40%).
LC-MS 598.5 [M+H]+, RT 1.81 min.
Steps 4-5: 10-(2,4-Dimethoxybenzyl)-3-ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
A mixture of the product of steps 2-3 (200 mg, 0.34 mmol), Lil (180 mg, 1.34 mmol) and EtOAc (1.0 mL) was stirred at 60 °C for 3 h. EtOAc (10 mL) and NaH2P04 (aq. sat'd., 5 mL) were added, and the mixture was stirred for 10 min. The organic layer was separated, washed with water and brine, dried over Na2S04, and concentrated under reduced pressure. The residue was dissolved in THF (3.0 mL) and TBAF (3.0 mL, 3.0 mmol, 1.0 M in THF) was added. The mixture was stirred for 2 h at room temperature. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (0-20% gradient MeOH in CH2CI2) to afford the title compound as a yellow solid (601 mg, 58% yield over 2 steps).
LC-MS 470.3 [M+H]+, RT 1.33 min. Intermediate 18
Methyl 7-(benzyloxy)-2-(chloromethyl)-10-(2,4-dimethoxybenzyl)-3-ethyl-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
Figure imgf000202_0001
Step 1: 2-(((tert-Butyldiphenylsilyl)oxy)methyl)-l-ethyl-5,6,7,8- tetrahydrocyclohepta[d] imidazol-4( 1 H) -one
l-Ethyl-2-(hydroxymethyl)-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(lH)-one (Intermediate
16, step 1, 2.1 g, 10.1 mmol), imidazole (816 mg, 12 mmol), TBDPSC1 (2.9 mL, 11.1 mmol) and CH2CI2 (45 mL) were stirred at room temperature for 15 h. The mixture was filtered, and the filtrate was purified by silica gel column chromatography (30-50% EtOAc in CH2CI2 gradient) to afford the title compound (3.98 g, 88%) as a white solid.
H NMR (500 MHz, acetone-ifc): δ ppm 1.08 (s, 9H), 1.38 (t, 7=7.5 Hz, 3H), 1.88 (m, 2H), 2.02 (pentet, J=6 Hz, 2H), 2.62 (m, 2H), 2.97 (t, J=6 Hz, 2H), 4.18 (q, 7=7.5 Hz, 2H), 4.81 (s, 2H), 7.48 (m, 6H), 7.77 (m, 4H)
Step 2: Methyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-l-ethyl-4-oxo-l,4,5,6,7,8- hexahydrocyclohepta[d]imidazole-5-carboxylate
To a solution of the product of step 1 (3.8 g, 8.0 mmol) in dimethyl carbonate (83 mL) at room temperature, was added NaHMDS (2M in THF, 8.75 mL, 17.5 mmol). The mixture was stirred for 30 min after the addition was complete. The mixture was partitioned between aqueous HCl and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification of the residue by silica gel chromatography (30% EtOAc in CH2CI2) afforded the title compound (3.48 g, 86%) as a yellow oil.
Steps 3-5: Methyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-10-(2,4-dimethoxybenzyl)-3- ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8- carboxylate
The product of step 2 (3.48 g, 6.9 mmol), 2,4-dimethoxybenzylamine (2.5 mL, 16.9 mmol), Si(OEt)4 (2.6 mL, 11.2 mmol), and CHC13 (21 mL) were heated at 75 °C for 40 h. The mixture was loaded directly onto a silica gel column and was purified with 5-10% EtOAc in CH2CI2. The DMB-enamine was obtained as a crude semisolid (3.85 g, 85% yield). The crude DMB-enamine (3.2 g, 4.9 mmol) was dissolved in CH2C12 (20 mL) at 0 °C. To this mixture was sequentially added, pyridine (640 μΐ., 8.1 mmol), a solution of
monomethylmalonyl chloride (850 μΐ,, 7.9 mmol) in CH2C12 (15 mL), and DMAP (100 mg, 0.82 mmol). The reaction was stirred at room temperature for 1 h. The mixture was cooled to 0 °C, and the addition sequence above was repeated. The mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the resultant residue was partitioned between ether and aqueous KHSO4. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure to afford the crude N-malonyl intermediate as a yellow oil.
The intermediate obtained above was treated with NaOMe (0.5 M solution in MeOH, 29.5 mL, 14.75 mmol) at room temperature for 3 h. The reaction mixture was partitioned between aqueous NaH2P04 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification of the residue by silica gel chromatography (10-50% EtOAc in CH2C12) followed by trituration with 1:1 hexanes/ether afforded the title compound (2.49 g, 66% over 3 steps) as a white solid.
!H NMR (500 MHz, acetone-ifc): δ ppm 1.03 (s, 9H), 1.37 (t, 7= 7.5 Hz, 3H), 2.21 (m, 2H), 2.42 (br. s, 2H), 2.70 (t, 7=7.5 Hz, 2H), 3.64 (s, 3H), 3.70 (s, 3H), 3.86 (s, 3H), 4.23 (q, 7=7 Hz, 2H), 4.85 (s, 2H), 5.76 (s, 2H), 6.27 (dd, 7=8, 2 Hz, 1H), 6.38 (d, 7=2 Hz, 1H), 6.57 (d, 7= 8 Hz, 1H), 7.43 (m, 4H), 7.48 (m, 2H), 7.73 (m, 4H), 13.8 (s, 1H)
Step 6: Methyl 7-(benzyloxy)-2-(((tert-butyldiphenylsilyl)oxy)methyl 10-(2,4- dimethoxybenzyl)-3-ethyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylate
The product of steps 3-5 (2.15 g, 3.0 mmol), Cs2C03 (1.96 g, 6.0 mmol), BnBr (535 μί, 4.5 mmol), and DMF (11 mL) were stirred at room temperature for 30 min. The mixture was partitioned between H20 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification of the residue by silica gel chromatography
(20-50% EtOAc in CH2C12) afforded the title compound (2.0 g, 82%) as a white solid.
!H NMR (500 MHz, acetone-ifc): δ ppm 1.03 (s, 9H), 1.36 (t, 7=7.5 Hz, 3H), 2.17 (m, 2H), 2.35 (br. s, 2H), 2.63 (t, 7=7.5 Hz, 2H), 3.65 (s, 3H), 3.71 (s, 3H), 3.81 (s, 3H), 4.20 (q, 7=7.5 Hz, 2H), 4.85 (s, 2H), 5.14 (s, 2H), 5.78 (s, 2H), 6.28 (dd, 7= 8.5, 2.5 Hz, 1H), 6.38 (d, 7=2 Hz, 1H), 6.58 (d, 7=8.5 Hz, 1H), 7.35-7.52 (m, 11H), 7.49 (m, 4H)
Steps 7-8: Methyl 7-(benzyloxy)-2-(chloromethyl)-10-(2,4-dimethoxybenzyl)-3-ethyl-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
The product of the step 6 (2.0 g, 2.47 mmol), TBAF (1M in THF, 3.5 mL, 3.5 mmol), and THF (7 mL) was stirred at room temperature for 30 min. The reaction mixture was partitioned between aqueous NH4C1 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification of the residue by silica gel chromatography (10% acetone in CH2C12, followed by 10% MeOH in CH2C12), afforded the intermediate alcohol as a white solid in quantitative yield.
To a mixture of the alcohol intermediate (500 mg, 0.87 mmol), DIPEA (300 μί, 1.83 mmol), and CH2C12 (5 mL) at 0 °C, MsCl (150 μί, 1.83 mmol) was added dropwise. The mixture was stirred at 0 °C for 30 min. The mixture was partitioned between aqueous HC1 and
CH2C12. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Trituration with ether yielded the title compound (459 mg, 89%) as a white solid. H NMR (500 MHz, acetone-ifc): δ ppm 1.31 (t, 7=7.5 Hz, 3H), 2.15 (m, 2H), 2.32 (m, 2H), 2.55 (t, 7=7.5 Hz, 2H), 3.71 (s, 3H), 3.74 (s, 3H), 3.83 (s, 3H), 4.13 (q, 7= 7.5 Hz, 2H), 4.87 (s, 2H), 5.14 (s, 2H), 5.75 (s, 2H), 6.27 (dd, 7=8.5, 2.5 Hz, IH), 6.40 (d, 7=2 Hz, IH), 6.53 (d, 7=8.5 Hz, IH), 7.35-7.52 (m, 5H)
Intermediate 19
Methyl 7-(benzyloxy)-10-(2,4-dimethoxybenzyl)-3-ethyl-9-oxo-2-((pyridin-4-yloxy)methyl)- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
Figure imgf000204_0001
Methyl 7-(benzyloxy)-2-(chloromethyl)-10-(2,4-dimethoxybenzyl)-3-ethyl-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
(Intermediate 18, 200 mg, 0.34 mmol), Ag2CC>3 (55 mg, 0.2 mmol), 4-hydroxypyridine (55 mg, 0.58 mmol), and toluene (4 mL) were heated at 110 °C for 1 h. The mixture was diluted with CH2C12 and filtered through Celite. Purification of the filtrate by silica gel
chromatography (5% MeOH in CH2C12) afforded the title compound (94 mg, 42%) as a white solid.
!H NMR (500 MHz, acetone-ifc): δ ppm 1.31 (t, 7=7.5 Hz, 3H), 2.16 (pentet, 7=7 Hz, 2H), 2.33 (m, 2H), 2.62 (t, 7=7.5 Hz, 2H), 3.73 (s, 3H), 3.74 (s, 3H), 3.83 (s, 3H), 4.15 (q, 7=7.5 Hz, 2H), 5.15 (s, 2H), 5.32 (s, 2H), 5.75 (s, 2H), 6.30 (dd, 7=8.5, 2 Hz, IH), 6.43 (d, 7=2 Hz, IH), 6.57 (d, 7=8.5 Hz, IH), 7.08 (dd, 7=4.5, 1.5 Hz, 2H), 7.38-7.48 (m, 3H), 7.51 (m, 2H), 8.39 (dd, 7=4.5, 1.5 Hz, 2H) Intermediate 20
Methyl 7-(benzyloxy)- 10-(2,4-dimethoxybenzyl)-2-((4- ((dimethylamino)methyl)phenoxy)methyl)-3-ethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
Figure imgf000205_0001
Step 1: Methyl 7-(benzyloxy)-10-(2,4-dimethoxybenzyl)-3-ethyl-2-((4- formylphenoxy)methyl)-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylate
4-Hydroxybenzaldehyde (60 mg, 0.49 mmol) was dissolved in THF (1 mL) at 0 °C.
NaHMDS (2M in THF, 175 μί, 0.35 mmol) was added dropwise, followed by DMF (1.0 mL). The mixture was stirred at room temperature for 15 min and then cooled to 0 °C. Methyl 7-(benzyloxy)-2-(chloromethyl)-10-(2,4-dimethoxybenzyl)-3-ethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate (Intermediate 18, 100 mg, 0.17 mmol) was added. The mixture was stirred at room temperature for 15 min, and then at 50 °C for 20 min. The mixture was partitioned between H20 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (50% EtOAc in CH2CI2, followed by 50% acetone in CH2CI2) afforded the title compound (68 mg, 59%) as a white solid.
!H NMR (500 MHz, acetone-ifc): δ ppm 1.33 (t, 7=7.5 Hz, 3H), 2.16 (pentet, J=l Hz, 2H), 2.35 (m, 2H), 2.63 (t, 7=7.5 Hz, 2H), 3.73 (s, 3H), 3.4 (s, 3H), 3.82 (s, 3H), 4.17 (q, 7=7 Hz, 2H), 5.15 (s, 2H), 5.37 (s, 2H), 5.76 (s, 2H), 6.30 (dd /= 8.5, 2.5 Hz, 1H), 6.44 (d, J=2 Hz, 1H), 6.58 (d, /= 8.5 Hz, 1H), 7.31 (m, 2H), 7.35-7.5 (m, 3H), 7.52 (m, 2H), 7.85 (m, 2H), 9.91 (s, 1H)
Step 2: Methyl 7-(benzyloxy)-10-(2,4-dimethoxybenzyl)-2-((4- ((dimethylamino)methyl)phenoxy)methyl)-3-ethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
The product of step 1 (66 mg, 0.1 mmol), dimethylamine hydrochloride (19 mg, 0.23 mmol), DCE (0.5 mL), Et3N (28 μί, 0.2 mmol), HOAc (12 μί, 0.2 mmol), and NaBH(OAc)3 (43 mg, 0.2 mmol) were stirred at room temperature for 3 h. The mixture was partitioned between aqueous K2CO3 and CH2CI2. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (20% acetone in CH2C12, followed by 10-20% MeOH in CH2C12) afforded the title compound (57 mg, 81%) as a white solid.
!H NMR (500 MHz, acetone- ): δ ppm 1.32 (t, 7=7 Hz, 3H), 2.16 (m, 2H), 2.23 (br. s, 6H), 2.34 (m, 2H), 2.61 (t, 7=7 Hz, 2H), 3.42 (br. s, 2H), 3.72 (s, 3H), 3.73 (s, 3H), 3.82 (s, 3H), 4.14 (q, 7=7 Hz, 2H), 5.14 (s, 2H), 5.20 (s, 2H), 5.77 (s, 2H), 6.29 (dd, 7= 8.5, 2.5 Hz, 1H), 6.42 (d, 7= 2.5 Hz, 1H), 6.56 (d, 7= 8.5 Hz, 1H), 7.05 (m, 2H), 7.28 (br. s, 2H), 7.39 (m, 1H), 7.44 (m, 2H), 7.51 (m, 2H)
Intermediate 21
Methyl 7-(benzyloxy)-10-(2,4-dimethoxybenzyl)-3-ethyl-9-oxo-2-((pyridin-4- ylmethoxy)methyl)-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8- carboxylate
Figure imgf000206_0001
To a solution of 4-pyridinemethanol (12 mg, 0.11 mmol) in THF (200 μί) at room temperature, NaHMDS (2M in THF, 35 μί, 0.07 mmol) and DMF (200 μί) were added in succession. Methyl 7-(benzyloxy)-2-(chloromethyl)-10-(2,4-dimethoxybenzyl)-3-ethyl-9- oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate (Intermediate 18, 20 mg, 0.035 mmol) was added, and the mixture was stirred at room temperature for 15 min. The mixture was partitioned between aqueous NH4CI and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (5% MeOH in CH2CI2) afforded the title compound (13 mg, 56%) as a white solid.
H NMR (500 MHz, acetone-ifc): δ ppm 1.27 (t, 7=7.5 Hz, 3H), 2.17 (pentet, 7=7 Hz, 2H), 2.35 (br. s, 2H), 2.62 (t, 7=7 Hz, 2H), 3.70 (s, 6H), 3.82 (s, 3H), 4.12 (q, 7=7 Hz, 2H), 4.48 (s, 2H), 4.69 (s, 2H), 5.16 (s, 2H), 5.85 (s, 2H), 6.29 (dd, 7=8.5, 2.5 Hz, 1H), 6.38 (d, 7=2 Hz, 1H), 6.51 (d, 7=8.5 Hz, 1H), 7.26 (d, 7=5.5 Hz, 2H), 7.38-7.5 (m, 3H), 7.52 (m, 2H), 8.53 (d, 7=5.5 Hz, 2H) Intermediate 22
Methyl 2-((lH-pyrazol-l-yl)methyl)-7-(benzyloxy)-10-(2,4-dimethoxybenzyl)-3-ethyl-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
Figure imgf000207_0001
Pyrazole (40 mg, 0.59 mmol) was dissolved in DMF (2 mL) and NaH (60% suspension in mineral oil, 20 mg, 0.5 mmol) was added. The mixture was stirred at room temperature for 15 min then was cooled to 0 °C. Methyl 7-(benzyloxy)-2-(chloromethyl)-10-(2,4- dimethoxybenzyl)-3-ethyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylate (Intermediate 18, 100 mg, 0.17 mmol) was added. After 5 min at 0 °C, the mixture was quenched with aqueous NH4C1 and partitioned between ¾0 and EtOAc.
The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure.
Trituration with ether afforded the title compound (90 mg, 85%) as a white solid.
H NMR (500 MHz, acetone-ifc): δ ppm 1.01 (t, 7=7 Hz, 3H), 2.13 (pentet, 7=7 Hz, 2H), 2.33 (m, 2H), 2.55 (t, 7=7 Hz, 2H), 3.71 (s, 3H), 3.76 (s, 3H), 3.83 (s, 3H), 4.09 (q, 7=7 Hz, 2H), 5.15 (s, 2H), 5.45 (s, 2H), 5.82 (s, 2H), 6.24 (dd, 7=8.5 Hz, 2.5 Hz, IH), 6.28 (t, 7=2 Hz, IH), 6.44 (m, 2H), 7.39-7.46 (m, 5H), 7.52 (m, 2H)
Intermediate 23
Methyl 2-((lH-imidazol-l-yl)methyl)-7-(benzyloxy)-10-(2,4-dimethoxybenzyl)-3-ethyl-9- oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
Figure imgf000207_0002
Methyl 7-(benzyloxy)-2-(chloromethyl)-10-(2,4-dimethoxybenzyl)-3-ethyl-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
(Intermediate 18, 100 mg, 0.17 mmol), imidazole (38 mg, 0.56 mmol), and DMF (1.0 mL) were combined and stirred at 40 °C for 15 h. The mixture was partitioned between H20 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (10% MeOH in CH2CI2) afforded the title compound (72 mg, 68%) as a white solid.
!H NMR (500 MHz, acetone- ): δ ppm 0.96 (t, 7=7 Hz, 3H), 2.15 (pentet, 7=7 Hz, 2H), 2.35 (m, 2H), 2.59 (t, 7=7.5 Hz, 2H), 3.72 (s, 3H), 3.81 (s, 3H), 3.83 (s, 3H), 4.03 (q, 7=7 Hz, 2H), 5.16 (s, 2H), 5.35 (s, 2H), 5.85 (s, 2H), 6.28 (dd, 7=8.5, 2.5 Hz, 1H), 6.44 (d, 7=8.5 Hz, 1H), 6.47 (d, 7=2 Hz, 1H), 6.92 (d, 7=6.5 Hz, 2H), 7.38-7.47 (m, 3H), 7.50-7.57 (m, 3H)
Intermediate 24
Methyl 7-(benzyloxy)-10-(2,4-dimethoxybenzyl)-3-ethyl-2-((ethylthio)methyl)-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
Figure imgf000208_0001
Methyl 7-(benzyloxy)-2-(chloromethyl)-10-(2,4-dimethoxybenzyl)-3-ethyl-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
(Intermediate 18, 300 mg, 0.51 mmol), DIPEA (0.6 mL, 3.6 mmol), EtSH (300 μί, 4.06 mmol), and THF (3 mL) were combined and heated at 60 °C for 40 h. The mixture was loaded directly onto a silica gel column. Purification by silica gel column chromatography (50% EtOAc in CH2CI2) followed by trituration with ether afforded the title compound (256 mg, 81%).
H NMR (500 MHz, acetone-ifc): δ ppm 1.13 (t, 7=7.5 Hz, 3H), 1.32 (t, 7=7.5 Hz, 3H), 2.17 (pentet, 7= 7 Hz, 2H), 2.35 (m, 4H), 2.62 (t, 7= 7.5 Hz, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 3.83 (s, 2H), 4.10 (q, 7=7.5 Hz, 2H), 5.15 (s, 2H), 5.82 (s, 2H), 6.30 (dd, 7=8.5, 2.5 Hz, 1H), 6.44 (d, 7=2.5 Hz, 1H), 6.49 (d, 7= 8.5 Hz, 1H), 7.39 (m, 1H), 7.42 (m, 2H), 7.46 (m, 2H)
Intermediate 25
Methyl 7-(benzyloxy)-10-(2,4-dimethoxybenzyl)-3-ethyl-2-((ethylsulfinyl)methyl)-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
Figure imgf000209_0001
Methyl 7-(benzyloxy)- 10-(2,4-dimethoxybenzyl)-3-ethyl-2-((ethylthio)methyl)-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
(Intermediate 24, 20 mg, 0.032 mmol), NaI04 (8 mg, 0.037 mmol), MeOH (300 μί), and ¾0 (150 μ > were combined and heated at 55 °C for 40 min. The mixture was partitioned between ¾0 and EtOAc. The organic layer was dried over MgS04, filtered, and
concentrated under reduced pressure. Purification by silica gel column chromatography (5% MeOH in CH2CI2) followed by trituration with ether afforded the title compound (10 mg, 94%) as a white solid.
H NMR (500 MHz, acetone-ifc): δ ppm 1.19 (t, 7=7.5 Hz, 3H), 1.29 (t, 7=7 Hz, 3H), 2.18 (pentet, 7=6.5 Hz, 2H), 2.32 (m, IH), 2.38 (m, IH), 2.55-2.65 (m, 3H), 2.75 (m, IH), 3.72 (s, 3H), 3.78 (s, 3H), 3.82 (s, 3H), 4.07 (d, 7=14.5 Hz, IH), 4.12 (m, IH), 4.21 (m, IH), 4.30 (d, 7=14.5 Hz, IH), 5.15 (s, 2H), 5.71 (d, 7=15.5 Hz, IH), 5.80 (d, 7=15.5 Hz, IH), 6.31 (dd, 7=8.5, 2.5 Hz, IH), 6.44 (d, 7=2.5 Hz, IH), 6.56 (d, 7=8.5 Hz, IH), 7.38-7.46 (m, 3H), 7.51 (m, 2H)
Intermediate 26
Methyl 7-(benzyloxy)- 10-(2,4-dimethoxybenzyl)-3-ethyl-2-((methylthio)methyl)-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
Figure imgf000209_0002
Step 1: Methyl 7-(benzyloxy)-10-(2,4-dimethoxybenzyl)-2- (((ethoxycarbonothioyl)thio)methyl)-3-ethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
Methyl 7-(benzyloxy)-2-(chloromethyl)-10-(2,4-dimethoxybenzyl)-3-ethyl-9-oxo-
3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate (Intermediate 18, 200 mg, 0.34 mmol), potassium ethyl xanthogenate (230 mg, 1.4 mmol), and DMF (2 mL) were combined and stirred at room temperature for 90 min. The mixture was partitioned between ¾0 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (50% EtOAc in CH2C12) afforded the title compound (170 mg, 74%) as an off-white solid.
!H NMR (500 MHz, acetone- ): δ ppm 1.27 (t, 7=7.5 Hz, 3H), 1.43 (t, 7=7 Hz, 3H), 2.14 (pentet, 7=7 Hz, 2H), 2.33 (m, 2H), 2.56 (t, 7= 7.5 Hz, 2H), 3.72 (s, 3H), 3.76 (s, 3H), 3.82 (s, 3H), 4.07 (q, 7=7 Hz, 2H), 4.60 (s, 2H), 4.70 (q, 7=7 Hz, 2H), 5.14 (s, 2H), 5.77 (s, 2H), 6.28 (dd, 7=8.5, 2.5 Hz, 1H), 6.41 (d, 7=2 Hz, 1H), 6.50 (d, 7=8.5 Hz, 1H), 7.38-7.46 (m, 3H), 7.51 (m, 2H)
Steps 2-3: Methyl 7-(benzyloxy)-10-(2,4-dimethoxybenzyl)-3-ethyl-2-((methylthio)methyl)- 9-oxo-3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
The product of the step 1 (150 mg, 0.22 mmol), ethylenediamine (23 μΐ., 0.34 mmol), and
THF (2.6 mL) were combined and stirred at room temperature for 30 min. The mixture was partitioned between aqueous HC1 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under under reduced pressure. Purification by silica gel column chromatography (20-50% acetone in CH2CI2) afforded 58 mg of crude thiol intermediate, which was used directly in the next step.
The thiol intermediate (35 mg, 0.059 mmol), DIPEA (175 μί, 1.07 mmol), CH2C12 (0.35 mL), THF (0.35 mL), and Mel (88 μί, 1.41 mmol) were combined and stirred at room temperature for 30 min. The reaction mixture was partitioned between aqueous HC1 and CH2CI2. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (10-30% acetone in CH2CI2) afforded the title compound (27 mg, 33% yield over 2 steps) as a white solid.
H NMR (500 MHz, acetone-ifc): δ ppm 1.31 (t, 7=7.5 Hz, 3H), 1.90 (s, 3H), 2.18 (pentet, 7=7 Hz, 2H), 2.35 (m, 2H), 2.62 (t, 7=7 Hz, 2H), 3.72 (s, 3H), 3.76 (s, 3H), 3.80 (s, 2H), 3.82 (s, 3H), 4.08 (q, 7=7 Hz, 2H), 5.15 (s, 2H), 5.85 (s, 2H), 6.29 (dd, 7=8.5, 2.5 Hz, 1H), 6.42 (d, 7=2.5 Hz, 1H), 6.46 (d, 7=8.5 Hz, 1H), 7.38-7.47 (m, 3H), 7.52 (m, 2H)
Intermediate 27
l,2,3-Trimethyl-5,6,7,8- epta[c]pyrrol-4(2H)-one
Figure imgf000210_0001
Step 1: Ethyl 5-(2,5-dimethylfuran-3-yl)-5-oxopentanoate
Ethyl 5-chloro-5-oxopentanoate (4.9 mL, 31.2 mmol) was added dropwise to a suspension of A1C13 (4.45 g, 33.2 mmol) in CH2C12 (100 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. 2,5-Dimethylfuran (3.3 mL, 31.2 mmol) was added dropwise. This mixture was stirred at 0 °C for 30 min then quenched with aqueous HC1. The mixture was extracted with CH2CI2. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (20% EtOAc in CH2CI2) afforded the title compound (2.85 g, 38%) as an orange oil.
H NMR (500 MHz, acetone-ifc): δ ppm 1.23 (t, J=l Hz, 3H), 1.92 (pentet, J=l Hz, 2H), 2.26 (s, 3H), 2.38 (t, 7=7.5 Hz, 2H), 2.51 (s, 3H), 2.79 (t, 7=7.5 Hz, 2H), 4.10 (q, 7=7 Hz, 2H), 6.38 (s, 1H)
Steps 2-3: l,3-Dimethyl-5,6,7,8-tetrahydro-4H-cyclohepta[c]furan-4-one
The product obtained in step 1 (4.2 g, 17.6 mmol), hydrazine hydrate (2.6 mL, 53 mmol),
KOH (5 g, 89.3 mmol), and PEG-200 (110 mL) were combined. The mixture was heated at 165 °C for 1 h then heated at 195 °C for 3 h. The mixture was partitioned between ¾0 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure to afford the intermediate carboxylic acid as a crude black oil.
PPA (30 g) was added to the crude carboxylic acid intermediate. This mixture was heated at 80 °C for 15 min. The mixture was partitioned between ¾0 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (10% EtOAc in hexanes) afforded the title compound (1.33 g, 42%) as a yellow oil.
H NMR (500 MHz, acetone-ifc): δ ppm 1.80 (m, 4H), 2.19 (s, 3H), 2.41 (s, 3H), 2.57 (m, 2H), 2.64 (m, 2H)
Step 4: l,2,3-Trimethyl-5,6,7,8-tetrahydrocyclohepta[c]pyrrol-4(2H)-one
The product of step 3 (300 mg, 1.68 mmol), MeNH2 (40% w/w in H20, 1.0 mL, 11.6 mmol), and EtOH (1.0 mL) were combined and heated in a microwave reactor at 150 °C for 8 h. The volatiles were removed under a N2 stream. Purification by silica gel column chromatography
(20-30% EtOAc in hexanes) afforded the title compound (259 mg, 81%) as a clear oil.
H NMR (500 MHz, acetone-ifc): δ ppm 1.75 (m, 4H), 2.13 (s, 3H), 2.44 (s, 3H), 2.51 (m, 2H), 2.66 (m, 2H) Intermediate 28
l-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-5,6,7,8-tetrahydrocyclohepta[c]pyrazol^
Figure imgf000212_0001
Step 1: 2-((Dimethylamino)methylene)cycloheptane-l,3-dione
A mixture of cycloheptane-l,3-dione (5.0 g, 39.7 mmol) and l,l-dimethoxy-N,N- dimethylmethanamine (16 mL, 120 mmol) was heated at 90 °C for 1.5 h. The mixture was allowed to cool to room temperature and concentrated to afford 6.3 g of the title compound (88%).
H NMR (500 MHz, CDC13) 5 ppm 1.85-1.88 (m, 4H), 2.58-2.62 (m, 4H), 2.81 (s, 3H), 3.31 (s, 3H), 7.73 (s, 1H)
Step 2: l-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-5,6,7,8-tetrahydrocyclohepta[c]pyrazol- 4(lH)-one
A mixture of the product of step 1 (430 mg, 2.4 mmol), 2-hydrazinylethan-l-ol (0.2 mL, 2.6 mmol), and MeOH (10 mL) was stirred at room temperature for 1.5 h. The mixture was concentrated, and CH2C12 (10 mL), TBSC1 (0.54 g, 3.6 mmol), and imidazole (0.25 g, 3.6 mmol) were added. The mixture was stirred at room temperature for 1 h. The mixture was washed with ¾0 (50 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc in hexanes) to afford the title compound (578 mg, 78%).
LC-MS: 309.0 [M+H]+, RT 1.46 min. !H NMR (500 MHz, CDC13) δ ppm 0.00 (s, 6H), 0.89 (s, 9H), 1.95 - 2.01 (m, 2H), 2.06 - 2.11 (m, 2H), 2.80 (dd, 7=5.48, 1.06 Hz, 2H), 3.09 (t, 7=6.31 Hz, 2H), 4.06 (t, 7=6.30 Hz, 2H), 4.18 - 4.27 (m, 2H), 8.06 (s, 1H)
Using the procedure described for Intermediate 28, additional intermediates described herein may be prepared by substituting the appropriate hydrazine starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000212_0002
Int Structure Name and Data
l-Ethyl-5,6,7,8-tetrahydrocyclohepta[c]pyrazol-4(lH)-one
LC-MS: 179.0 [M+H]+,
30 •6b RT 0.91 min. 1H NMR (500 MHz, CDC13) δ ppm 1.40 (t, 7=7.29 Hz, 3H), 1.87 - 1.97 (m, 2H), 1.99 - 2.05 (m, 2H), 2.63 - 2.72 (m, 2H), 2.88 - 2.95 (m, 2H), 4.08 (q, 7=7.30 Hz, 2H), 7.91 (s, 1H)
l-(2-Methoxyethyl)-5,6,7,8-tetrahydrocyclohepta[c]pyrazol-4(lH)- one
31 LC-MS: 208.8 [M+H]+, RT 0.86 min. !H NMR (500 MHz, CDC13) δ ppm 1.89 - 1.97 (m, 2H), 1.97 - 2.07 (m, 2H), 2.70 - 2.75 (m, 2H), 2.96 - 3.00 (m, 2H), 3.30 (s, 3H), 3.75 (t, 7=5.28 Hz, 2H), 4.23 (t,
Me sO 7=5.24 Hz, 2H), 7.98 (s, 1H) l-(3-Methoxypropyl)-5,6,7,8-tetrahydrocyclohepta[c]pyrazol-4(lH)- one
-K LC-MS: 222.9 [M+H]+, RT 0.91 min. 1H NMR (500 MHz, CDC13) δ
32 ppm 1.90 - 1.96 (m, 2H), 2.01 - 2.08 (m, 2H), 2.08 - 2.15 (m, 2H),
2.71 - 2.78 (m, 2H), 2.91 - 2.97 (m, 2H), 3.33 (s, 3H), 3.32 (t, 7=5.75 Hz, 2H), 4.18 (t, 7=6.78 Hz, 2H), 7.98 - 8.00 (m, 1H)
^OMe
Intermediate 33
l-(3-((tert-Butyldimethylsilyl)oxy)propyl)-5,6,7,8-tetrahydrocyclohepta[c]pyrazol-4(lH)-one
Figure imgf000213_0001
A solution of 2-((dimethylamino)methylene)cycloheptane-l,3-dione (Intermediate 28, step 1, 3.03 g, 9.96 mmol), tert-butyl l-(3-((tert-butyldimethylsilyl)oxy)propyl)hydrazine-l- carboxylate (2.0g, 9.96 mmol), and MeOH (40 mL) was stirred at room temperature for 3 h. The mixture was concentrated, diphenylether (5 mL) was added, and the mixture was heated to 180 °C for 30 min. After cooling to room temperature, the mixture was purified by silica gel column chromatography (0-25% EtOAc in hexanes) to afford the title compound (3.14 g, 98%). LC-MS: 323.1 [M+H]+, RT 1.59 min. H NMR (500 MHz, CDC13) δ ppm 0.06 (s, 6H), 0.91 (s, 9H), 1.88 - 1.97 (m, 2H), 2.00 - 2.08 (m, 4H), 2.70 - 2.76 (m, 2H), 2.98 (t, 7=6.27 Hz, 2H), 3.59 (t, 7=5.67 Hz, 2H), 4.19 (br. s, 2H), 7.98 (s, 1H)
Intermediate 34
l-Methyl-4,5,6,7-tetrahydrocyclohepta[c]pyrazol-8(lH)-one
Figure imgf000214_0001
Step 1: 4-Iodo- 1 -methyl- lH-pyrazole-5-carbaldehyde
A mixture of l-methyl-lH-pyrazole-5-carbaldehyde (5.0 g, 45.4 mmol), N-iodosuccinimide (15.3 g, 68.1 mmol), and TFA (50 mL) was stirred at room temperature for 1.5 h. H20 (50 mL) was added, and the precipitate was filtered, rinsed with H20 (100 mL), and dried to afford the title compound (9.03 g, 84%).
H NMR (500 MHz, CDC13) δ ppm 4.19 (s, 3H), 7.58 (s, 1H), 9.80 (s, 1H)
Step 2: l-Methyl-4-vinyl-lH-pyrazole-5-carbaldehyde
A mixture of 4-iodo-l-methyl-lH-pyrazole-5-carbaldehyde (9.0 g, 38.1 mmol), potassium vinyltrifluoroborate (6.6 g, 49.5 mmol), PdCl2(dppf) (840 mg, 1.14 mmol), K2C03 (15.8 g, 114.3 mmol), dioxane (50 mL), and H20 (10 mL) was heated at 90 °C for 12 h. The mixture was allowed to cool to room temperature and poured into H20 (100 mL). The aqueous phase was extracted with Et20. The combined organic phases were washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc in hexanes) to afford the title compound (4.0 g, 77%).
LC-MS: 136.9 [M+H]+, RT 0.97 min. H NMR (500 MHz, CDC13) δ ppm 4.15 (s, 3H), 5.41 (dd, 7=11.03, 1.10 Hz, 1H), 5.70 (dd, 7=17.58, 1.10 Hz, 1H), 6.89 (dd, 7=17.50, 11.03 Hz, 1H), 7.66 (s, 1H), 10.03 (s, 1H)
Steps 3-4: l-(l-Methyl-4-vinyl-lH-pyrazol-5-yl)pent-4-en-l-one
3-Butenylmagnesium bromide (0.5M inTHF, 18.5 mL, 9.3 mmol) was added to a solution of l-methyl-4- vinyl- lH-pyrazole-5-carbaldehyde (0.97 g, 7.1 mmol) in THF (24 mL) at 0 °C. After stirring at 0 °C for 1.5 h, the mixture was quenched with saturated aqueous NH4C1 and poured into H20 (100 mL). The aqueous phase was extracted with Et20. The combined organic phases were washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure. The crude alcohol was used in the next step without further purification. The crude alcohol was dissolved in CH2CI2 (10 mL), and 4A molecular sieves (2.0 g), NMO
(1.25 g, 10.7 mmol), and TPAP (125 mg, 0.4 mmol) were added. The mixture was stirred at room temperature for 6 h then filtered through Celite and concentrated. The residue was purified by silica gel column chromatography (0-10% EtOAc in hexanes) to afford the title compound (0.8 g, 59%).
LC-MS: 191.0 [M+H]+, RT 1.26 min. !H NMR (500 MHz, CDC13) δ ppm 2.45 - 2.51 (m, 2H), 2.91 - 2.95 (m, 2H), 4.09 (s, 3H), 5.03 (dq, 7=10.24, 1.40 Hz, 1H), 5.08 (dq, 7=17.16, 1.61 Hz, 1H), 5.36 (dd, 7=10.88, 1.34 Hz, 1H), 5.61 (dd, 7=17.30, 1.38 Hz, 1H), 5.88 (dd, 7=17.02, 10.32 Hz, 1H), 6.84 (dd, 7=17.38, 10.92 Hz, 1H), 7.57 (s, 1H)
Step 5: l-Methyl-6,7-dihydrocyclohepta[c]pyrazol-8(lH)-one
Grubbs 2nd generation catalyst (60 mg, 0.09 mmol) was added to a solution of l-(l-methyl-4- vinyl-lH-pyrazol-5-yl)pent-4-en-l-one (0.7 g, 3.7 mmol) in CH2CI2 (80 mL, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography (20% EtOAc in hexanes) to afford the title compound (0.56 g, 94%).
!H NMR (500 MHz, CDC13) δ ppm 2.37 - 2.48 (m, 2H), 2.72 - 2.78 (m, 2H), 4.18 (s, 3H), 6.08 - 6.17 (m, 1H), 6.47 (dt, 7=10.88, 1.18 Hz, 1H), 7.40 (s, 1H)
Step 6: l-Methyl-4,5,6,7-tetrahydrocyclohepta[c]pyrazol-8(lH)-one
A mixture of l-methyl-6,7-dihydrocyclohepta[c]pyrazol-8(lH)-one (0.56 g, 3.5 mmol), PtC>2 (20 mg, 0.09 mmol), and EtOAc (20 mL) was stirred at room temperature under a ¾ atmosphere for 1 h. The mixture was filtered through Celite and concentrated to afford the title compound (0.54 g, 94%).
LC-MS: 165.0 [M+H]+, RT 0.73 min. H NMR (500 MHz, CDC13) δ ppm 1.85 - 1.92 (m, 4H), 2.70 - 2.76 (m, 2H), 2.80 (t, 7=6.07 Hz, 2H), 4.12 (s, 3H), 7.31 (s, 1H)
Intermediate 35
(5)-l,6-dimethyl-5,6,7,8-tetrahydrocyclohepta[c]pyrazol-4(lH)-one
Figure imgf000215_0001
Step 1: 5-Iodo-l-methyl-lH-pyrazole
n-BuLi (2.5M in hexane, 26.8 mL, 67 mmol) was added dropwise over 15 min to a solution of 1 -methyl- lH-pyrazole (5.0 mL, 61 mmol) in THF (100 mL) at -78 °C. After stirring at -78 °C for 1 h, a solution of I2 (17 g, 67 mmol) in THF (20 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 1 h. The mixture was quenched with saturated aqueous NH4CI and poured into ¾0 (100 mL). The aqueous phase was extracted with Et20. The combined organic phases were washed with saturated aqueous
Na2S2(¾, dried over MgS04, filtered, and concentrated under reduced pressure to afford the title compound (11.39 g, 90%).
LC-MS: 208.8 [M+H]+, RT 0.94 min. !H NMR (500 MHz, CDC13) δ ppm 3.94 (s, 3H), 6.43 (d, 7=1.97 Hz, 1H), 7.48 (d, 7=2.00 Hz, 1H)
Step 2: 5 -Iodo- 1 -methyl- lH-pyrazole-4-carbaldehyde
TFA (60 mL) was added to a mixture of 5-iodo- l-methyl- lH-pyrazole (10.3 g, 50 mmol) and 1,3,5,7-tetraazaadamantane (10.4 g, 75 mmol) at 0 °C. The mixture was stirred at 70 °C for 12 h. The mixture was cooled to 0 °C and neutralized with saturated aqueous NaHCC>3. The aqueous phase was extracted with CH2CI2, the organic phases were combined, dried over Na2S04, filtered, and concentrated under reduced pressure to afford the title compound (6.0 g, 51%).
LC-MS: 236.8 [M+H]+, RT 0.79 min. !H NMR (500 MHz, CDC13) δ ppm 4.01 (s, 3H), 8.00 (s, 1H), 9.70 (s, 1H)
Step 3: l-Methyl-5-vinyl-lH-pyrazole-4-carbaldehyde
A mixture of 5-iodo-l -methyl- lH-pyrazole-4-carbaldehyde (6.0 g, 25.4 mmol), potassium vinyltrifluoroborate (5.1 g, 38.1 mmol), PdCl2(dppf) (372 mg, 0.51 mmol), K2C03 (10.5 g, 76.2 mmol), dioxane (50 mL), and ¾0 (15 mL) was stirred at 90 °C for 12 h. After cooling to room temperature, the mixture was poured into ¾0 and extracted with Et20. The organic extracts were combined, washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0- 50% EtOAc in hexanes) to afford the title compound (2.9 g, 83%).
LC-MS: 137.1 [M+H]+, RT 0.74 min. !H NMR (500 MHz, DMSO- ) δ ppm 3.89 (s, 3H), 5.82 (dd, 7=11.78, 1.14 Hz, 1H), 6.20 (dd, 7=11.78, 1.18 Hz, 1H), 6.92 - 7.00 (m, 1H), 7.98 (s, 1H), 9.77 - 9.84 (m, 1H)
Steps 4-5: (R)-3-Methvl- l-(l-methvl-5-vinvl- lH-pvrazol-4-yl)pent-4-en-l-one
ί-BuLi (1.7M in pentane, 21.1 mL, 36 mmol) was added dropwise to a solution of (5)-4-iodo- 3-methylbut-l-ene (3.5 g, 18 mmol) in Et20 (90 mL) at -78 °C. After stirring at -78 °C for 1 h, a solution of l-methyl-5-vinyl- lH-pyrazole-4-carbaldehyde (2.9 g, 21.3 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at -78 °C for 15 min then quenched with NH4C1. The mixture was extracted with Et20. The organic extracts were combined, washed with brine, dried over Na2S04, filtered, and then concentrated under reduced pressure to afford the crude alcohol which was used without further purification. Μηθ2 (5.0 g, 57.5 mmol) was added to a solution of crude alcohol in CH2CI2 (20 mL). After stirring at room temperature for 16 h, additional MnC>2 (5.0 g, 57.5 mmol) was added, and the mixture was stirred at room temperature for an additional 2 h. The mixture was filtered through Celite, and the Celite was washed with CH2CI2. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (25-50% EtOAc in hexanes) to afford the title compound (1.4 g, 32%).
LC-MS: 205.5 [M+H]+, RT 1.19 min. H NMR (500 MHz, CDC13) δ ppm 1.04 - 1.12 (m, 3H), 2.64 - 2.74 (m, 1H), 2.79 - 2.91 (m, 2H), 3.94 (s, 3H), 4.90 - 5.08 (m, 2H), 5.75 - 5.89 (m, 3H), 7.09 (dd, 7=18.21, 11.98 Hz, 1H), 7.85 (s, 1H)
Step 6: (R)-l ,6-Dimethyl-5,6-dihydrocyclohepta[c]pyrazol-4(lH)-one
A mixture of (R)-3-methyl- l-(l-methyl-5-vinyl-lH-pyrazol-4-yl)pent-4-en-l-one (4.8 g, 23 mmol), Grubbs 2nd generation catalyst (488 mg, 0.58 mmol), and toluene (450 mL) was stirred at 80 °C. After stirring at 80 °C for 1 h, additional Grubbs 2nd generation catalyst (488 mg, 0.58 mmol) was added, and the reaction mixture was stirred at 80 °C for an additional 3 h. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% EtOAc in hexanes) to afford the title compound (2.84 g, 70%).
LC-MS: 176.9 [M+H]+, RT 0.90 min. H NMR (500 MHz, CDC13) δ ppm 1.22 (d, 7=7.17 Hz, 3H), 2.58 - 2.70 (m, 1H), 2.71 - 2.81 (m, 1H), 3.89 (s, 3H), 6.25 (dd, 7=11.47, 4.61 Hz, 1H), 6.41 - 6.47 (m, 1H), 7.97 (s, 1H)
Step 7: (5)-l ,6-Dimethyl-5,6,7,8-tetrahydrocyclohepta[c]pyrazol-4(lH)-one
A mixture of (R)-l ,6-dimethyl-5,6-dihydrocyclohepta[c]pyrazol-4(lH)-one (2.84 g, 16.1 mmol), 10% Pd/C (300 mg), and EtOAc (50 mL) was stirred at room temperature under a ¾ atmosphere for 1.5 h. The mixture was filtered through Celite. The filtrate was concentrated to afford the title compound (2.7 g, 94%).
LC-MS: 179.3 [M+H]+, RT 0.89 min. H NMR (500 MHz, CDC13) δ ppm 1.10 (d, 7=6.86 Hz, 3H), 1.74 - 1.87 (m, 1H), 2.06 - 2.18 (m, 2H), 2.55 (dd, 7=16.59, 9.81 Hz, 1H), 2.71 - 2.79 (m, 1H), 2.88 (dd, 7=10.13, 4.53 Hz, 1H), 2.95 (dd, 7=6.19, 4.22 Hz, 1H), 3.81 (s, 3H), 7.91 (s, 1H) Using the procedure described for Intermediate 35, the additional intermediate described herein may be prepared by substituting (5)-4-iodo-3-methylbut-l-ene with the racemic mixture in Steps 4-5 and suitable reagents and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000218_0002
Intermediate 37
5-Iodo-l-(3-methoxypropyl)-lH-pyrazole-4-carbaldehyde
Figure imgf000218_0001
Step 1: 1 -(3-Methoxypropyl)- lH-pyrazole
NaH (60% suspension in mineral oil, 0.7 g, 17.6 mmol) was added to a solution of 1H- pyrazole (1.0 g, 14.7 mmol) in THF (50 mL) at 0 °C. After stirring at 0 °C for 0.5 h, 1- bromo-3-methoxypropane (1.6 mL, 17.6 mmol) was added. The mixture was allowed to warm to room temperature. After stirring at room temperature for 16 h, the reaction was quenched with saturated aqueous NH4CI. The mixture was poured into H20 (50 mL), and the aqueous phase was extracted with Et20. The organic phases were combined, washed with aqueous NaOH (1M), dried over MgS04, filtered, and concentrated under reduced pressure to afford the title compound (1.8 g, 88%).
H NMR (500 MHz, CDC13) δ ppm 2.10 - 2.18 (m, 2H), 3.30 - 3.32 (m, 2H), 3.33 (s, 3H), 4.28 (t, 7=6.74 Hz, 2H), 6.27 (s, 1H), 7.42 (s, 1H), 7.55 (s, 1H) Steps 2-3: 5-Iodo-l-(3-methoxypropyl)-lH-pyrazole-4-carbaldehyde
The title compound was prepared according to steps 1-2 described in the preparation of Intermediate 35.
H NMR (500 MHz, CDC13) δ ppm 2.11 - 2.20 (m, 2H), 3.31 - 3.40 (m, 5H), 4.38 (t, 7=6.90 Hz, 2H), 8.04 (s, 1H), 9.71 (s, 1H) Intermediate 38
Methyl 5-iodo- l-(4-methoxybenzyl)- lH-pyrazole-4-carboxylate
Figure imgf000219_0001
Step 1: Methyl l-(4-methoxybenzyl)-lH-pyrazole-4-carboxylate
NaH (60% suspension in mineral oil, 810 mg, 20.1 mmol) was added in portions to a solution of methyl lH-pyrazole-4-carboxylate (2.3 g, 18.3 mmol) in DMF (18 mL) at 0 °C. After stirring at 0 °C for 0.5 h, l-(chloromethyl)-4-methoxybenzene (2.8 mL, 20.1 mmol) was added. The mixture was allowed to warm to room temperature and stirred for an additional 1 h. The reaction was quenched with saturated aqueous NH4C1 and poured into ¾0 (100 mL). The aqueous phase was extracted with EtOAc. The organic extracts were combined, washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% EtOAc in hexanes) to afford the title compound (4.39 g, 98%).
H NMR (500 MHz, DMSO-d6) δ ppm 3.72 (s, 3H), 3.72 (s, 3H), 5.27 (s, 2H), 6.88 - 6.93 (m, 2H), 7.22 - 7.28 (m, 2H), 7.86 (d, 7=0.71 Hz, 1H), 8.41 (d, 7=0.63 Hz, 1H)
Step 2: Methyl 5-iodo-l-(4-methoxybenzyl)-lH-pyrazole-4-carboxylate
TMPMgCl-LiCl (1M in THF, 14.9 mL, 14.9 mmol) was added to a solution of methyl l-(4- methoxybenzyl)-lH-pyrazole-4-carboxylate (3.34 g, 13.6 mmol) in THF at 0 °C. After stirring at 0 °C for 0.5 h, a solution of I2 (3.8 g, 14.9 mmol) in THF (20 mL) was added drop wise over 15 min. After stirring for an additional 1 h at 0 °C, the reaction was quenched with saturated aqueous NH4C1 and poured into H20 (100 mL). The aqueous phase was extracted with Et20. The organic phases were combined, washed with saturated aqueous Na2S2(¾, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc in hexanes) to afford the title compound (3.53 g, 70%).
lH NMR (500 MHz, CDC13) δ ppm 3.79 (s, 3H), 3.85 (s, 3H), 5.42 (s, 2H), 6.84 - 6.89 (m, 2H), 7.20 - 7.25 (m, 2H), 8.03 (s, 1H) Using the procedure described for Intermediate 38, additional intermediates described herein may be prepared by substituting the appropriate alkyl halide starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000220_0002
Intermediate 41
2-Ethyl-5,6,7,8-tetrahydrocyclohepta[d][l,2,3]triazol-4(2H)-one
Figure imgf000220_0001
A mixture of 2-(phenylsulfinyl)cyclohept-2-en-l-one (0.59 g, 2.59 mmol) and sodium azide (186 mg, 2.85 mmol) in water (5 mL) was stirred at 30 °C for 15 h. The mixture was acidified to pH ~ 3, extracted with EtOAc, dried over Na2S04 and concentrated under reduced pressure to give crude 5,6,7,8-tetrahydrocyclohepta[d][l,2,3]triazol-4(2H)-one (0.55 g, mixture of isomers) as a light brown solid, which was used in the next step without further purification. The product was taken up in DMF and K2CO3 and ethyl iodide were added. After stirring at room temperature for 5 h, the mixture was diluted with water and extracted with EtOAc. The organic phases were combined, washed with water, brine and dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to afford the title compound as an amber oil (40 mg, 8.6%, 2 steps).
H NMR (500 MHz, CDC13) δ ppm 1.60 (t, 7=7.3 Hz, 3H), 1.85-2.10 (m, 4H), 2.79-2.84 (m, 2H), 3.02-3.06 (m, 2H), 4.49 (q, 7=7.3 Hz, 2H) Intermediate 42
7,8,9, 10-Tetrahydrocyclohepta[b]indol-6(5H)-one
Figure imgf000221_0001
The title compound was prepared according to the literature procedure (Iwata, H. et al. ACS Med. Chem. Lett. 2012, 3(4), 342-346).
lH NMR (500 MHz, CDC13) δ ppm 1.96 - 2.05 (m, 2H), 2.07 - 2.15 (m, 2H), 2.82 - 2.90 (m, 2H), 3.12 - 3.21 (m, 2H), 7.14 (ddd, 7=8.0, 5.8, 2.2 Hz, IH), 7.32 - 7.40 (m, 2H), 7.67 (dd, 7=8.0, 0.8 Hz, IH), 8.91 (br. s, IH)
Intermediate 43
5-Methyl-7,8,9, 10-tetrahydrocyclohepta[b]indol-6(5H)-one
Figure imgf000221_0002
A mixture of 7,8,9, 10-tetrahydrocyclohepta[b]indol-6(5H)-one (Intermediate 42, 0.306 g, 1.54 mmol), Cs2C03 (1.0 g, 2 eq) and Mel (0.3 mL, 3 eq) in DMF was heated at 55 °C for 2 h. Upon cooling to room temperature the reaction mixture was diluted with ¾0 and acidified with 1M HC1. The product was then extracted with EtOAc. The combined organic layers were washed with NaCl (aq. sat'd.), dried over Na2S04 and concentrated. The residue was purified by silica gel column chromatography (0-10% EtOAc in hexanes gradient) to obtain the title compound (0.293 g, 89%) as a white solid.
!H NMR (500 MHz, DMSO- ) δ ppm 1.77 - 1.90 (m, 4H), 2.70 - 2.81 (m, 2H), 3.03 - 3.11
(m, 2H), 3.93 (s, 3H), 7.12 (ddd, 7=7.9, 6.9, 0.9 Hz, IH), 7.36 (ddd, 7=8.3, 7.0, 1.1 Hz, IH), 7.52 (dt, 7=8.5, 0.8 Hz, IH), 7.76 (dt, 7=8.0, 1.1 Hz, IH)
Intermediate 44
4,5-Dibromo-2-((2-methoxyeth
Figure imgf000222_0001
Step 1: 2,4,5-Tribromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole
NaH (60% suspension in mineral oil, 3.92 g, 98.0 mmol) was added to a solution of 2,4,5- tribromo-lH-imidazole (24.9 g, 81.7 mmol) in DMF (150 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was cooled to 0 °C before SEM-C1 (15.9 mL, 89.9 mmol) was added. The reaction was allowed to warm up to room temperature and then stirred for 1 h. The reaction was quenched by aqueous saturated
NH4CI and extracted with Et20. The organic layers were combined washed with aqueous saturated NaCl, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% EtOAc in hexanes) to afford the title compound (33.85 g, 95%) as a solid.
H NMR (500 MHz, acetone-ifc) δ ppm 0.01 (s, 9H) 0.92 - 0.98 (m, 2H) 3.67 - 3.73 (m, 2H) 5.44 (s, 2H)
Sterj_2j_4,5-Dibromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole-2-carbaldehyde ft-BuLi (2.5 M in hexanes, 5.2 mL, 13.0 mmol) was added over a 15 min to a solution of 2,4,5-tribromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole (5.59 g, 12.8 mmol) in THF (40 mL) at -78 °C. The mixture was stirred at -78 °C for 2 h then DMF (2.0 mL, 25.7 mmol) was added. The mixture was stirred at -78 °C for 1.5 h then allowed to warm to 0 °C and stirred for an addtional 30 min. The reaction was quenched with saturated aqueous NH4CI then extracted with Et20. The organic layers were combined, washed with brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% EtOAc in hexanes) to afford the title compound (4.55 g, 92%) as a light yellow oil.
H NMR (500 MHz, acetone-ifc) δ ppm -0.03 (s, 9H) 0.87 - 0.96 (m, 2H) 3.64 - 3.70 (m, 2H) 5.87 (s, 2H) 9.56 (s, 1H)
Step 3: (4,5-Dibromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)methanol NaBH4 (672 mg, 17.8 mmol) was added to a solution of 4,5-dibromo-l-((2-
(trimethylsilyl)ethoxy)methyl)-lH-imidazole-2-carbaldehyde (4.55 g, 11.8 mmol) in MeOH (48 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h then it was allowed to warm to room temperature. The mixutre was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was quenched with saturated aqueous NH4C1 and extracted with CH2CI2. The combined organic layers were washed with brine, dried over
Na2S04, and concentrated under reduced pressure to afford the title product (4.55 g, quant.) which was carried over to the next step without any further purification.
!H NMR (500 MHz, acetone-d6) δ ppm 0.00 (s, 9H) 0.90 - 0.96 (m, 2H) 3.64 - 3.70 (m, 2H) 4.53 (t, 7=6.0 Hz, 1H) 4.67 (d, 7=6.0 Hz, 2H) 5.52 (s, 2H)
Step 4: 4,5-Dibromo-2-((2-methoxvethoxv)methvl)-l-((2-(trimethvlsilvl)ethoxv)methyl)-lH- imidazole
NaH (60% suspension in mineral oil, 1.82 g, 45.5 mmol) to a solution of (4,5-dibromo-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)methanol (14.6 g, 37.8 mmol) in DMF (100 mL) at 0 °C. The mixture was allowed to warm to room temperature, and the mixture was stirred for 30 min. The mixture was cooled to 0 °C, and l-bromo-2-methoxy ethane (4.3 mL, 45.8 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4C1 and extracted with Et20. The organic layers were combined, washed with brine, dried over Na2S04, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc in hexanes) to afford the title compound (11.8 g, 70%) as a light yellow oil.
H NMR (500 MHz, acetone-ifc) δ ppm 0.01 (s, 9H) 0.90 - 0.97 (m, 2H) 3.29 (s, 3H) 3.47 - 3.53 (m, 2H) 3.60 - 3.64 (m, 2H) 3.64 - 3.69 (m, 2H) 4.62 (s, 2H) 5.50 (s, 2H)
Using the procedure described for Intermediate 44, the additional intermediate described herein may be prepared by using Mel as an alkylating reagent in step 4 and suitable reagents and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000223_0001
Intermediate 46
l-Ethyl-2,6-dimethyl-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(lH)-one
Step 1: 4,5-Dibromo-2-methyl-l-((2-(t -rim0ethy6lsilyl)e-thoxy)methyl)-lH-imidazole
NaH (60% suspension in mineral oil, 0.65 g, 16.3 mmol, 1.4 eq) was added to a solution of 4,5-dibromo-2-methyl-lH-imidazole (2.71 g, 11.3 mmol) in DMF (20 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was cooled to 0 °C before SEM-C1 (2.2 mL, 12.4 mmol, 1.1 eq) was added. The mixure was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with saturated aqueous NH4CI and extracted with ΈλτΟ. The organic layers were combined, washed brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-25% EtOAc in hexanes) to afford the title compound (4.15 g, 99%) as a solid.
H NMR (500 MHz, acetone-ifc) δ ppm 0.00 (s, 9H) 0.92 - 0.95 (m, 2H) 2.42 (s, 3H) 3.62 - 3.66 (m, 2H) 5.37 (s, 2H)
Step 2: 4-Bromo-2-methyl- 1 -((2-(trimethylsilyl)ethoxy)methyl)- lH-imidazole-5- carbaldehyde
ft-BuLi (2.5 M in hexanes, 7.1 mL, 17.8 mmol, 1.02 eq) was added over 15 min to a stirred solution of 4,5-dibromo-2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole (6.46 g, 17.4 mmol) in THF (42 mL) at -78 °C. The mixture was stirred at -78 °C for -10 min before DMF (2.7 mL, 34.7 mmol, 2.0 eq) was added. The mixture was warmed to 0 °C and stirred for 90 min. The reaction was quenched with saturated aqueous NH4C1 and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2S04> and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-25% EtOAc in hexanes) to afford the title compound (4.55 g, 82%) as a light yellow oil.
LC-MS 260.9/262.9 [M-TMS+H20-H]+, RT 1.44 min. H NMR (500 MHz, acetone-d6) δ ppm -0.02 (s, 9H) 0.87 - 0.95 (m, 2H) 2.48 (s, 3H) 3.58 - 3.67 (m, 2H) 5.77 (s, 2H) 9.69 (s, 1H)
Step 3: 2-Methyl- l-((2-(trimethylsilyl)ethoxy)methyl)-4-vinyl- lH-imidazole-5-carbaldehyde A mixture of 4-bromo-2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole-5- carbaldehyde (3.07 g, 9.6 mmol), potassium trifluoroborate (2.32 g, 17.3 mmol, 1.8 eq), palladium acetate (65 mg, 0.29 mmol, 3 mol%), S-Phos (237 mg, 0.58 mmol, 6 mol%), and K2C03 (2.66 g, 19.2 mmol, 2.0 eq), 1,4-dioxane (40 mL), and water (10 mL) was heated at 90 °C for 5 h. The mixture was cooled to room temperature, quenched with water, and extracted with CH2CI2. The organic layers were combined, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-35% EtOAc in hexanes) to afford the title compound (1.565 g, 61%) as a light yellow oil.
LC-MS 267.9 [M+H]+, RT 1.42 min. !H NMR (500 MHz, acetone-d6) 5 ppm -0.03 (s, 9H) 0.87 - 0.92 (m, 2H) 2.46 (s, 3H) 3.59 - 3.63 (m, 2H) 5.44 (dd, 7=10.9, 2.4 Hz, 1H) 5.74 (s, 2H) 6.20 (dd, 7=17.0, 2.2 Hz, 1H) 7.13 (dd, 7=17.0, 10.9 Hz, 1H) 9.98 (s, 1H)
Steps 4-5: 3 -Methyl- 1 -(2-methyl- 1 -((2-(trimethylsilyl)ethoxy)methyl)-4- vinyl- 1 H-imidazol- 5-yl)pent-4-en- 1 -one
ί-BuLi (1.7M in pentane, 8.4 mL, 14.3 mmol, 2.4 eq) was added over 15 in to a solution of 4- iodo-3-methylbut-l-ene (1.27 g, 6.5 mmol, 1.1 eq) in diethylether (25 mL) at -78 °C. The mixture was stirred at -78 °C for 1 h before a solution of 2-methyl- 1 -((2-
(trimethylsilyl)ethoxy)methyl)-4-vinyl-lH-imidazole-5-carbaldehyde (1.565 g, 5.9 mmol) in THF (9 mL) was added. The mixutre was stirred at -78 °C for 15 min then quenched with saturated aqueous NH4C1. The mixture was extracted with Et20/EtOAc (9: 1). The organic layers were combined, washed brine, dried over Na2S04, and concentrated under reduced pressure to afford the desired alcohol (-2.02 g, quant.).
The crude alcohol (-2.02 g, 5.9 mmol) was dissolved in CH2CI2 (30 mL), and 4A molecular sieves (2.4 g), NMO (1.34 g, 11.4 mmol) were added. The mixture was cooled to 0 °C and TPAP (190 mg, 0.54 mmol) was added in one portion. The reaction was stirred at 0 °C for 30 min. The mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 1 h then filtered through Celite. The Celite was washed with CH2CI2, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-25% EtOAc in hexanes) to afford the title compound (660 mg, 33% 2 steps) as a light yellow oil.
H NMR (500 MHz, acetone-ifc) δ ppm -0.03 (s, 9H) 0.85 - 0.90 (m, 2H) 1.07 (d, 7=6.6 Hz, 3H) 2.43 (s, 3H) 2.77 - 2.89 (m, 2H) 2.91 - 2.97 (m, 1H) 3.52 - 3.57 (m, 2H) 4.91 - 4.94 (m, 1H) 5.03 (dt, 7=17.3, 1.5 Hz, 1H) 5.39 (dd, 7=10.9, 2.7 Hz, 1H) 5.69 (s, 2H) 5.88 (ddd, 7=17.3, 10.5, 6.6 Hz, 1H) 6.18 (dd, 7=16.8, 2.8 Hz, 1H) 7.08 (dd, 7=16.8, 10.9 Hz, 1H) Step 6: 2,6-Dimethvl-3-((2-(trimethvlsilvl)ethoxv)methyl)-5,6- dihydrocyclohepta[d]imidazol-4(3H)-one
A mixture of 3-methyl-l-(2-methyl-l-((2-(trimethylsilyl)ethoxy)metliyl)-4-vinyl-lH- imidazol-5-yl)pent-4-en-l-one (660 mg, 1.97 mmol), Grubbs 2nd generation catalyst (50 mg, 0.059 mmol) and toluene (40 mL) was heated at 85 °C for 1 h. The mixture was cooled to room temperature, and a 2nd portion of Grubbs catalyst (50 mg, 0.059 mmol) was added. The mixture was heated at 90 °C for 2 h. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc in hexanes) to afford the title compound (405 mg, 67%) as a light tan solid.
H NMR (500 MHz, acetone-ifc) δ ppm -0.04 (s, 9H) 0.86 - 0.91 (m, 2H) 1.14 (d, 7=6.9 Hz, 3H) 2.42 (s, 3H) 2.52 - 2.68 (m, 3H) 3.55 - 3.63 (m, 2H) 5.75 (d, 7=10.7 Hz, 1H) 5.87 (d, 7=10.7 Hz, 1H) 6.06 - 6.11 (m, 1H) 6.45 (dd, 7=11.2, 1.9 Hz, 1H)
Step 7: 2,6-Dimethyl-3-((2-(trimethvlsilvl)ethoxv)methyl)-5,6,7,8- tetrahydrocyclohepta[d]imidazol-4(3H)-one
A mixture of 2,6-dimethyl-3-((2-(trimethylsilyl)ethoxy)methyl)-5,6- dihydrocyclohepta[d]imidazol-4(3H)-one (405 mg, 1.32 mmol) 10% Pd/C (Degussa type, 40 mg), and EtOAc (10 mL) was stirred at room temperature for 1.5 under ¾ (1 atm). The mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated under reduced pressure to afford the title compound (410 mg, quant.).
H NMR (500 MHz, acetone-ifc) δ ppm -0.04 (s, 9H) 0.83 - 0.88 (m, 2H) 1.03 (d, 7=6.9 Hz, 3H) 1.46 - 1.54 (m, 1H) 1.98 - 2.14 (m, 2H) 2.38 (s, 3H) 2.54 (dd, 7=14.5, 8.5 Hz, 1H) 2.66 (dd, 7=14.5, 3.7 Hz, 1H) 2.82 (ddd, 7=16.5, 8.6, 4.0 Hz, 1H) 2.90 (ddd, 7=16.5, 7.8, 4.0 Hz, 1H) 3.51 - 3.58 (m, 2H) 5.69 (d, 7=10.6 Hz, 1H) 5.73 (d, 7=10.6 Hz, 1H)
Step 8: 2,6-Dimethyl-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(3H)-one
TFA (2.5 mL, 32.6 mmol) was added to a solution of 2,6-dimethyl-3-((2-
(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(3H)-one (410 mg,
1.32 mmol) in CH2CI2 (5 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NaHC03 and extracted with CH2CI2. The organic layers were combined, dried over Na2S04, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% MeOH in CH2C12) to afford the title compound (224 mg, 95% over 2 steps) as a light tan solid.
LC-MS 178.9 [M+H]+, RT 0.31 min. H NMR (500 MHz, acetone-d6) 5 ppm 1.05 (d, 7=6.9 Hz, 3H) 1.74 (dtd, 7=13.9, 9.8, 9.8, 4.7 Hz, 1H) 1.93 - 2.02 (m, 1H) 2.05 - 2.09 (m, 1H) 2.32 (s, 3H) 2.45 (dd, 7=17.2, 10.2 Hz, 1H) 2.58 (ddd, 7=17.3, 3.1, 1.4 Hz, 1H) 2.79 - 2.92 (m, 2H) 11.12 (br. s, 1H) Step 9: l-Ethyl-2,6-dimethyl-5,6 ,8-tetrahydrocyclohepta[d]imidazol-4(lH)-one
NaH (60% suspension in mineral oil, 57 mg, 1.43 mmol) was added to a solution of 2,6- dimethyl-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(3H)-one (224 mg, 1.26 mmol) in THF (5 mL) at room temperature. The mixture was stirred for 20 min before a solution of EtI (0.13 mL, 1.6 mmol) in THF (1 mL) was added. The reaction was heated to 35 °C and stirred overnight. The mixture was quenched with saturated aqueous NH4C1 and extracted with
CH2CI2. The organic layers were combined, dried over Na2S04, and concentrated. The residue was purified by silica gel column chromatography (0-5% MeOH in CH2CI2) to afford the title compound (255 mg, 95%) as a light tan foam.
LC-MS 207.3 [M+H]+, RT 0.78 min. !H NMR (500 MHz, acetone-d6) δ ppm 1.03 (d, 7=6.9 Hz, 3H) 1.27 (t, 7=7.3 Hz, 3H) 1.64 - 1.73 (m, 1H) 2.02 - 2.10 (m, 2H) 2.30 (s, 3H) 2.43 (dd, 7=15.8, 9.5 Hz, 1H) 2.59 (ddd, 7=15.8, 3.4, 1.0 Hz, 1H) 2.81 - 2.89 (m, 1H) 2.94 (ddd, 7=16.9, 6.4, 4.3 Hz, 1H) 3.96 (q, 7=7.3 Hz, 2H)
Using the procedure described for Intermediate 46 above, additional intermediates described herein may be prepared by utilizing (5)-4-iodo-3-methylbut-l-ene in steps 4-5. Intermediates 44 and 45 were used as starting materials in synthesis of Intermediates 49 and
48, respectively, to obtain compounds such as those selected from:
Figure imgf000227_0001
Int Structure Name and Data
(S)-l-Ethyl-2-((2-methoxyethoxy)methyl)-6-methyl-5,6,7,8- tetrahydrocyclohepta[d]imidazol-4(lH)-one
LC-MS 281.9 [M+H]+, RT 0.84 min. !H NMR (500 MHz, acetone-d6) δ ppm 1.04 (d, 7=6.9 Hz, 3H) 1.33 (t, 7=7.3 Hz, 3H)
49 1.65 - 1.76 (m, 1H) 2.04 - 2.13 (m, 2H) 2.47 (dd, 7=15.8, 9.5 Hz,
1H) 2.62 (ddd, 7=15.8, 3.4, 1.0 Hz, 1H) 2.90 (ddd, 7=17.0, 9.6, 4.2 Hz, 1H) 2.99 (ddd, 7=17.0, 6.7, 4.2 Hz, 1H) 3.28 (s, 3H) 3.47 - 3.51 (m, 2H) 3.57 - 3.61 (m, 2H) 4.09 (q, 7=7.5 Hz, 2H) 4.54 (s, 2H)
Intermediate 50
2-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methyl-6,7,8,9-tetrahydrocyclohepta[b]indol- -one
Figure imgf000228_0001
Step 1: 2-Bromo-5-methyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole
NaH (60% suspension in mineral oil, 1.5 g, 37.5 mmol) was added in portions to a solution of
2-bromo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (5.1 g, 19.3 mmol) in DMF (80 mL).
The mixture was stirred at room temperature for 10 min, and Mel (2.5 mL, 40.1 mmol) was added dropwise. The mixture was stirred at room temperature for 30 min and was partitioned between ¾0 and EtOAc. The organic layer was dried over MgS04, filtered, and
concentrated under reduced pressure. Purification by silica gel column chromatography (20%
CH2CI2 in hexanes) gave the title compound (3.85 g, 53%) as a white solid.
H NMR (500 MHz, acetone-ifc): δ ppm 1.7-1.82 (m, 4H), 1.92 (m, 2H), 2.79 (m, 2H), 2.93 (m, 2H), 3.71 (s, 3H), 7.16 (dd, 7=8.5, 2 Hz, 1H), 7.26 (d, 7=8.5 Hz, 1H), 7.56 (d, 7=2 Hz, 1H)
Step 2: 5-Methyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole-2-carbaldehyde
n-BuLi (1.6 M in hexanes, 7.6 mL, 12.2 mmol) was added to a solution of the product of step 1 (2.6 g, 9.35 mmol) in THF (38 mL) at -78 °C. The mixture was stirred at -78 °C for 5 min, and DMF (2 mL, 25.7 mmol) was added. After stirring at -78 °C for 15 min, the reaction was quenched with saturated aqueous NH^Cl. The mixture was partitioned between ¾0 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (50-100% CH2CI2 in hexanes) afforded the title compound (2.0 g, 94%) as a white solid.
!H NMR (500 MHz, acetone- ): δ ppm 1.76-1.86 (m, 4H), 1.94 (m, 2H), 2.91 (m, 2H), 2.97 (m, 2H), 3.79 (s, 3H), 7.47 (d, 7=8.5 Hz, IH), 7.66 (dd, 7=8.5, 1.5 Hz, IH), 8.05 (d, 7=1.5 Hz, IH), 10.0 (s, IH)
Step 3: (5-Methyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indol-2-yl)methanol
NaBH4 (167 mg, 4.4 mmol) was added to a mixture of the product of step 2 (2.0 g, 8.8 mmol), EtOH (20 mL), H20 (10 mL), and NaOH (IN, 10 drops). The mixture was stirred at room temperature for 45 min. This mixture was partitioned between ¾0 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure to afford the title compound (1.95 g, 97%) as a white solid.
H NMR (500 MHz, acetone-ifc): δ ppm 1.71-1.80 (m, 4H), 1.90 (m, 2H), 2.79 (m, 2H), 2.88 (m, 2H), 3.67 (s, 3H), 3.83 (t, 7=6 Hz, IH), 4.66 (d, 7=6 Hz, 2H), 7.08 (dd, 7=8.5, 1.5 Hz, IH), 7.21 (d, 7=8.5 Hz, IH), 7.39 (s, IH)
Step 4: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methyl-5, 6,7,8,9, 10- hexahydrocyclohepta[b]indole
The product of step 3 (1.92 g, 8.5 mmol), imidazole (850 mg, 12.5 mmol), CH2CI2 (30 mL), and TBDMSC1 (1.5 g, 10 mmol) were stirred at room temperature for 15 h. The mixture was filtered, and the filtrate was purified by silica gel chromatography (20-40% CH2CI2 in hexanes) to afford the title compound as a white solid (2.58 g, 88%).
!H NMR (500 MHz, CDC13): δ ppm 0.12 (s, 6H), 0.95 (s, 9H), 1.75-1.81 (m, 4H), 1.91 (m, 2H), 2.81 (m, 2H), 2.92 (m, 2H), 3.69 (s, 3H), 4.83 (s, 2H), 7.09 (dd, 7=8, 1.5 Hz, IH), 7.24 (d, 7=8Hz, IH), 7.40 (s, IH)
Step_5: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methyl-6,7,8,9- tetrahydrocyclohepta[b]indol- 10(5H)-one
A solution of DDQ (3.15 g, 13.9 mmol) in THF (30 mL) was added dropwise over 10 min to a mixture of the product of step 4 (2.3 g, 6.7 mmol), THF (70 mL), and ¾0 (7 mL) at 0 °C.
The mixture was stirred at 0 °C for an additional 30 min. The solvent was then removed under reduced pressure. The crude solids were suspended in CH2CI2 and filtered. Purification of the filtrate by silica gel column chromatography (30-40% EtOAc in hexanes) followed by alumina column chromatography (5-50% EtOAc in CH2CI2) afforded the title compound
(450 mg, 20%) as a white solid.
!H NMR (500 MHz, acetone-ifc): δ ppm 0.13 (s, 6H), 0.97 (s, 9H), 1.92 (m, 2H), 2.07-2.10 (m, 2H, obscured by solvent peak), 2.73 (m, 2H), 3.20 (m, 2H), 3.81 (s, 3H), 4.87 (s, 2H), 7.26 (dd, 7=8, 1.5 Hz, IH), 7.40(d, 7=8.5 Hz, IH), 8.38 (m, IH) Using the procedure described for Intermediate 50, additional intermediates described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000230_0002
Intermediate 53
2-Bromo-3- 2-a]pyridine
Figure imgf000230_0001
Step 1: 2-Bromoimidazo[l,2-a]pyridine
A mixture of 2-aminopyridine (2.82 g, 30 mmol), ethyl 2-bromoacetate (3.33 mL, 30 mmol), and EtOH (30 mL) was heated at 90 °C for 1 h then N,N-Diisopropylethylamine (5.2 mL, 30 mmol) was added. The mixture was heated at 90 °C for 15 min. The volatiles were removed under a N2 stream. The residue was cooled to room temperature, and phosphorus oxybromide (9.5 g, 33 mmol) was added. The mixture was heated at 90 °C for 20 min. The mixture was cooled to room temperature and quenched with ice. The mixture was partitioned between CH2CI2 and aqueous saturated NaHCC>3. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20-80% EtOAc in hexanes) to afford the title compound as a tan powder (1.15 g, 20%).
LC-MS: 197.1/199.1 [M+H]+, RT 0.86 min. H NMR (500 MHz, acetone-d6) 5 ppm 6.98 (td, 7=6.8, 0.9 Hz, 1H), 7.34 (ddd, 7=9.1, 6.7, 1.3 Hz, 1H), 7.45 - 7.55 (m, 1H), 7.98 (s, 1H), 8.50 (dt, 7=6.8, 1.2 Hz, 1H) Step 2: 2-Bromo-3 -iodoimidazo[ 1 ,2-a]pyridine
A mixture of 2-bromoimidazo[l,2-a]pyridine (400 mg, 2 mmol), N-iodosuccinimide (495 mg, 2.2 mmol), and CH3CN (6 mL) was heated at 60 °C for 30 min. The volatiles were removed from the mixture under a N2 stream. The residue was purified by silica gel column chromatography (0-20% EtOAc in CH2CI2) to afford the title compound as a tan powder (610 mg, 94%).
LC-MS: 322.8/324.8 [M+H]+, RT 1.10 min. H NMR (500 MHz, OMSO-d6) δ ppm 7.09 - 7.13 (m, IH), 7.39 (ddd, 7=9.1, 6.9, 1.3 Hz, IH), 7.59 (dt, 7=9.0, 1.2 Hz, IH), 8.33 (dt, 7=6.9, 1.1Hz, IH)
Step 3: 2-Bromo-3-vinylimidazo[l,2-a]pyridine
Potassium carbonate (1 M, 1.5 mL, 1.5 mmol) was added to a mixture of 2-bromo-3- iodoimidazo[l,2-a]pyridine (244 mg, 0.75 mmol), potassium vinyltrifluoroborate (121 mg, 0.9 mmol), Pd(dppf)Cl2 (31 mg, 0.038 mmol), and CH3CN (3 mL). The mixture was stirred at 80 °C for 2 h. The mixture was partitioned between EtOAc and water. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to afford the title compound (64 mg, 38%) as an off-white powder.
LC-MS: 223.0/225.0 [M+H]+, RT 1.08 min. H NMR (500 MHz, acetone-d6) 5 ppm 5.55 (dd, 7=12.1, 0.8 Hz, IH), 6.07 (dd, 7=18.1, 0.5 Hz, IH), 7.00 (dd, 7=18.0, 12.2 Hz, IH), 7.09 (td, 7=6.8, 1.2, IH), 7.40 (ddd, 7=9.1, 6.7, 1.3 Hz, IH), 7.57 (dt, 7=9.1, 1.1 Hz, IH), 8.60 (dt, 7=6.9, 1.1 Hz, IH)
Intermediate 54
tert-Butyl 5-(3-(lH-imidazol-l-yl)propyl)-6-bromo-2,4-di-tert-butoxynicotinate
Figure imgf000231_0001
Step 1: tert-Butyl 5-allyl-6-bromo-2,4-difluoronicotinate
2,2,6,6-Tetramethylpiperidinylmagnesium chloride lithium chloride complex solution (1 M in THF, 32.5 mL, 32.5 mmol) was added to a solution of tert-butyl 5-bromo-2,4- difluoronicotinate (7.35 g, 25 mmol) in THF (125 mL) at -45 °C. After 20 min at -45 °C, Cu(I)CN (448 mg, 5 mmol) and allyl iodide (2.85 mL, 31.3 mmol) were added. The mixture was slowly warmed to room temperature over 1 h. The reaction was quenched with saturated aqueous NH4C1 and partitioned between EtOAc and water. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% CH2CI2 in hexanes) to afford the title compound as a colorless oil (5.9 g, 71%).
H NMR (500 MHz, acetone-ifc) δ ppm 1.60 (s, 9H), 3.58 (dd, 7=6.0, 1.6 Hz, 2H), 5.09 - 5.07 (m, 2H), 5.00 - 5.99 (m, 1H)
Step 2: tert-Butyl 6-bromo-2,4-di-tert-butoxy-5-(3-hydroxypropyl)nicotinate
9-BBN (0.5 M in THF, 9 mmol, 18 mL) was added to a solution of tert-butyl 5-allyl-6- bromo-2,4-difluoronicotinate (1.0 g, 3 mmol) in THF (15 mL) at 0 °C. The mixture was warmed to room temperature for 1 h. After cooling the mixture to 0 °C, a solution of potassium ten- butoxide (1 M in THF, 15 mmol, 15 mL) was added. The mixture was stirred for 1 h at room temperature. The mixture was cooled to 0 °C, and aqueous 1 M KOH (5 mL) and aqueous 35% H2O2 (4 mL) were added. The mixture was stirred for 30 min at room temperature before partitioning between EtOAc and ¾0. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc in CH2CI2) to afford of the title compound (880 mg, 64%).
H NMR (500 MHz, acetone-ifc) δ ppm 1.45 (s, 9H), 1.57 (s, 9H), 1.59 (s, 9H), 1.74 - 1.80 (m, 2H), 2.80 - 2.85 (m, 2H), 3.59 - 3.64 (m, 3H)
Step 3: tert-Butyl 5-(3-(lH-imidazol-l-yl)propyl)-6-bromo-2,4-di-tert-butoxynicotinate
Methanesulfonyl chloride (125 μί, 1.6 mmol) was added to the mixture of the product of step 2 (368 mg, 0.8 mmol), N,N-diisopropylethylamine (0.28 mL, 1.6 mmol), and CH2C12 (4 mL) at 0 °C. The mixture was allowed to warm to room temperature. The mixture was partitioned between EtOAc and saturated aqueous NaHC03. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was combined with imidazole (8 mmol), K2C03 (220 mg, 1.6 mmol), DMF (1.6 mL) and at 60 °C for 1 h. The mixture was partitioned between EtOAc and ¾0. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% MeOH in CH2CI2) to afford the title compound (380 mg, 93%).
LC-MS: 510.2/512.2 [M+H]+, RT 1.14 min. !H NMR (500 MHz, acetone-d6) 5 ppm 1.35 (s, 9H), 1.57 (s, 9H), 1.59 (s, 9H), 1.99 - 2.05 (m, 2H), 2.74 - 2.78 (m, 2H), 4.15 (t, 7=6.8 Hz, 2H), 6.93 (t, 7=1.1 Hz, 1H), 7.17 (t, 7=1.3 Hz, 1H), 7.61 (s, 1H) Using the procedure described for Intermediate 54, additional intermediates described herein may be prepared by substituting the appropriate starting heterocycle in Step 3, suitable reagents and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000233_0001
Figure imgf000234_0001
Intermediate 60
tert-Butyl 6-bromo-2,4-di-tert-butoxy-5-(2-(4,5-dichloro-lH-imidazol-l-yl)ethoxy)nicotinate
Figure imgf000234_0002
Step 1: 1 -(2- ((tert-B utyldimethylsilyl)oxy)ethyl) -4,5 -dichloro- 1 H-imidazole
NaH (60% dispersion in mineral oil, 240 mg, 6 mmol) was added to a solution of 4,5- dichloro-l H-imidazole (411 mg, 3 mmol) in DMF (10 mL). After 5 min, (2- bromoethoxy)(tert-butyl)dimethylsilane (718 mg, 3 mmol) was added to the mixture. The mixture was stirred at 60 °C for 1 h. The mixture was partitioned between EtOAc and ¾0. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-80% EtOAc in hexanes) to afford the title compound (274 mg, 31%).
H NMR (500 MHz, acetone-ifc) δ ppm 0.00 (s, 6H), 0.87 (s, 9H), 3.96 (t, 7=5.0 Hz, 2H), 4.20 (t, 7=5.2 Hz, 2H), 7.65 (s, 1H)
Step 2: 2-(4,5-Dichloro-lH-imidazol-l-vl)ethan-l-ol
TBAF (1 M in THF, 1.6mL, 1.6 mmol) was added to a solution of l-(2-((tert- butyldimethylsilyl)oxy)ethyl)-4,5-dichloro-lH-imidazole (236 mg, 0.8 mmol) in THF (2 mL). The mixture was stirred at room temperature for 15 min. The volatiles were removed, and the residue was purified by silica gel column chromatography (0-10% MeOH in CH2CI2) to afford the title compound (135 mg, 94%). H NMR (500 MHz, CDC13) δ ppm 3.95 - 4.00 (m, 2H), 4.24 - 4.28 (m, 2H), 8.47 (s, 1H)
Step 3: tert-Butyl 6-bromo-2,4-di-tert-butoxy-5-(2-(4,5-dichloro-lH-imidazol-l- yl)ethoxy)nicotinate
Triphenylphosphine (297 mg, 1.13 mmol) and tert-butyl 6-bromo-2,4-di-tert-butoxy-5- hydroxynicotinate (282 mg, 0.68 mmol) were sequentially added to a mixture of diisopropyl azodicarboxylate (0.22 mL, 1.13 mmol) and THF (4 mL) at 0 °C. 2-(4,5-Dichloro-lH- imidazol-l-yl)ethan-l-ol (135 mg, 0.75 mmol) was added to the mixture. The mixture was allowed to warm to room temperature and stirred for 2 h. The volatiles were removed, and the residue was purified by silica gel column chromatography (0-20% EtOAc in hexanes) to afford the title compound (350 mg, 93%).
LC-MS: 601.9/603.9/606.0 [M+Na]+, RT 1.68 min
Intermediate 61
tert-Butyl 8,10-di-tert-butoxy-2,3-dichloro-6,7-dihydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylate
Figure imgf000235_0001
A mixture of tert-butyl 6-bromo-2,4-di-tert-butoxy-5-(3-(4,5-dichloro-lH-imidazol-l- yl)propyl)nicotinate (Intermediate 58, 100 mg, 0.17 mmol), SPhos Pd G2 catalyst (12 mg, 0.017 mmol), K2CO3, (47 mg, 0.34 mmol), tetrabutylammonium bromide (5.5 mg, 0.017 mmol), and DMF (0.1 M) were stirred at 100 °C for 2 h. The mixture was cooled to room temperature, diluted with EtOAc, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% EtOAc in hexanes) to afford the title compound (14 mg, 17%).
H NMR (500 MHz, acetone-ifc) δ ppm 1.47 (s, 9H), 1.63 (s, 9H), 1.60 (s, 9H), 2.43 (m, 2H), 2.75 (t, 7=6.8 Hz, 2H), 4.13 (t, 7=6.8 Hz, 2H) Using the procedure described for Intermediate 61, an additional intermediate described herein may be prepared by substituting the Intermediate 59, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000236_0002
Intermediates 63 and 64
tert-Butyl 8,10-di-tert-butoxy-2-chloro-3-vinyl-6,7-dihydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylate
and
tert-Butyl 8,10-di-tert-butoxy-2,3-divinyl-6,7-dihydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylate
Figure imgf000236_0001
K2CO3 (1 M, 1 mL) was added to a mixture of tert-Butyl 8,10-di-tert-butoxy-2,3-dichloro- 6,7-dihydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9-carboxylate (Intermediate 61, 250 mg, 0.5 mmol), potassium vinyltriflouroborate (100 mg, 0.75 mmol), SPhos Pd G2 catalyst (18 mg, 0.025 mmol), and 1,4-dioxane (2.5 mL). The mixture was stirred at 80 °C for 1 h. The mixture was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc in CH2CI2) to afford tert-butyl 8,10-di-tert-butoxy-2-chloro-3-vinyl-6,7-dihydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylate (Intermediate 63, 183 mg, 73%) and tert-butyl 8,10-di-tert-butoxy-2,3-divinyl- 6,7-dihydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9-carboxylate (Intermediate 64, 40 mg, 17%).
Intermediate 63: H NMR (500 MHz, acetone-d6) δ ppm 1.47 (s, 9H), 1.60 (s, 9H), 1.64 (s, 9H), 2.40 - 2.46 (m, 2H), 2.73 (t, 7=6.8 Hz, 2H), 4.12 (t, 7=6.8 Hz, 2H), 5.52 (dd, 7=12.0, 1.3 Hz, 1H), 5.91 (dd, 7=17.8, 1.3 Hz, 1H), 6.73 (dd, 7=17.8, 12.0 Hz, 1H)
Intermediate 64: H NMR (500 MHz, acetone-d6) δ ppm 1.47 (s, 9H), 1.60 (s, 9H), 1.64 (s, 9H), 2.35 - 2.41 (m, 2H), 2.73 (t, 7=7.1 Hz, 2H), 4.06 (t, 7=6.6 Hz, 2H), 5.15 (dd, 7=10.9, 2.7 Hz, 1H), 5.50 - 5.57 (m, 2H), 6.03 (dd, 7=17.1, 1.6 Hz, 1H), 6.79 - 6.87 (m, 2H) Intermediate 65
tert-Butyl 8,10-di-tert-butoxy-2-chloro-3-vinyl-5,6-dihydroimidazo[l,2-d]pyrido[2,3- f] [ 1 ,4]oxazepine-9-carboxylate
Figure imgf000237_0001
The title compound was prepared from tert-butyl 6-bromo-2,4-di-tert-butoxy-5-(2-(4,5- dichloro-lH-imidazol-l-yl)ethoxy)nicotinate (Intermediate 60) using the intramolecular coupling procedure described in Example 19 (Step 1), followed by the vinylation reaction described in the synthesis of Intermediate 63.
LC-MS: 436.3/438.3 [M-56+H]+, RT 1.84 min (non-polar method)
Intermediate 66
4-Bromo-5-methyl-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one
Figure imgf000237_0002
Step 1: 4-Bromo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole
A mixture of (2-bromophenyl)hydrazine hydrochloride (1.80 g, 8.05 mmol) and
cycloheptanone (0.75 mL, 8.05 mmol) in AcOH (2.4 mL) was heated at 120 °C for 45 min. The mixture was cooled to room temperature and diluted with ¾0 and EtOH. The product was extracted with EtOAc. The organics were combined, washed with brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% EtOAc in hexanes gradient) to afford the title compound (1.35 g, 63%) as a white solid.
!H NMR (500 MHz, CDC13) δ ppm 1.72 - 1.84 (m, 4H), 1.88 - 1.96 (m, 2H), 2.77 - 2.82 (m, 2H), 2.85 - 2.91 (m, 2H), 6.96 (t, 7=7.9 Hz, 1H), 7.24 (dd, 7=7.6, 0.6 Hz, 1H), 7.41 (d, 7=7.9 Hz, 1H), 7.88 (br. s, 1H)
Step 2: 4-Bromo-5-methyl-5,6,7,8,9, 10-hexahydrocyclohepta[b]indole
NaH (60% suspension in mineral oil, 0.11 g, 1.5 eq) was added to a solution of 4-bromo-
5,6,7,8,9,10-hexahydrocyclohepta[b]indole (0.50 g, 1.89 mmol) in DMF (8 mL) at 0 °C. The mixture was stirred at room temperature for 10 min. The mixture was cooled to 0 °C, and Mel (0.25 mL, 2 eq) was added. After 10 min, the reaction was quenched with saturated aqueous NH4C1. The product was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% EtOAc in hexanes gradient) to afford the title compound (0.50 g, 96%) as a white solid.
!H NMR (500 MHz, CDC13) δ ppm 1.73 - 1.86 (m, 4H), 1.87 - 1.94 (m, 2H), 2.77 - 2.82 (m, 2H), 2.84 - 2.90 (m, 2H), 4.06 (s, 3H), 6.88 (t, 7=7.7 Hz, 1H), 7.26 (dd, 7=7.6, 0.9 Hz, 1H), 7.40 (dd, 7=7.9, 0.9 Hz, 1H)
Step 3: 4-Bromo-5-methyl-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one
A solution of DDQ (0.85 g, 3.74 mmol) in THF (8 mL) dropwise over 10 min to a solution of 4-bromo-5-methyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (0.523 g, 1.88 mmol) in THF (17 mL) and ¾0 (2 mL) at 0° C. The mixture was stirred at 0° C for 1 h. The solvent was removed under reduced pressure. The residue was suspended in CH2CI2, and the solids were removed by filtration. The supernatant was concentrated, and the residue was purified by silica gel column chromatography (10-50% EtOAc in hexanes gradient) to afford the title compound (0.43 g, 78%) as a white solid.
LC-MS: 292.0/294.0 [M+H]+, RT 1.32 min
Using the procedure described for Intermediate 66 above, additional intermediates described herein may be prepared by substituting the appropriate starting material, suitable rea ents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000238_0001
Figure imgf000239_0001
Example 1 (Compound 2)
4-Hydroxy-8,9-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid
Step 1: l,2-Dimethyl-5,6,7,8-tetrahydrocyclohepta[b]pyrrol-4(lH)-one
A mixture of 2-methyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-4-one (0.240 g, 1.46 mmol)
(prepared according to procedure described for Intermediate 1), MeN¾ (40% aq, 1.0 mL) and EtOH (1.0 mL) was microwaved at 150 °C for 4 h. The mixture was cooled to room temperature, diluted with ¾0, and extracted with CH2CI2. The organic layers were combined, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes (20-60% gradient) to give the title compound (0.212 g, 82%) as a colorless solid.
!H NMR (500 MHz, CDC13) δ ppm 1.82 - 1.93 (m, 2H) 1.95 - 2.05 (m, 2H) 2.20 (d, 7=0.9 Hz, 3 H) 2.73 - 2.78 (m, 2H) 2.83 - 2.90 (m, 2H) 3.40 (s, 3 H) 6.40 (q, 7=0.9 Hz, 1H)
Steps 2-3: Methyl l-(2,4-dimethoxybenzyl)-4-hydroxy-8,9-dimethyl-2-oxo-l,2,5,6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylate
2,4-Dimethoxybenzylamine (0.16 mL, 1.07 mmol) and NEt3 (0.40 mL, 2.87 mmol) were added to a solution of l,2-dimethyl-5,6,7,8-tetrahydrocyclohepta[b]pyrrol-4(lH)-one (0.172 g, 0.97 mmol) in CH2CI2 (4 mL) at room temperature. The mixture was cooled to 0 °C, and T1CI4 (1M in CH2CI2, 0.65 mL, 0.65 mmol) was added dropwise over 30 min. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was diluted with CH2CI2 and quenched with a saturated aqueous NaHCC>3. The organic phase was separated using a PTFE phase separator and dried over Na2S04. The solvent was
concentrated under reduced pressure to give the intermediate imine as a brown foam, which was used directly in the next step.
The crude imine (ca. 0.97 mmol) and trimethyl methanetricarboxylate (0.310 g, 1.63 mmol) were mixed together in PI12O (2 mL). The mixture was placed on a heat block pre-heated to 230 °C and stirred for 10 min after the initial bubbling of MeOH was observed. The mixture was cooled to room temperature, loaded directly onto a separation column, and eluted first with hexanes followed by EtOAc/hexanes (gradient 0-50%) to yield the title compound (0.140 g, 32% 2 steps) as a yellowish foam.
lH NMR (500 MHz, CDC13) δ ppm 2.09 - 2.22 (m, 4H) 2.14 (d, 7=0.9 Hz, 3H) 2.43 - 2.67 (m, 2H) 3.46 (s, 3H) 3.80 (s, 3H) 3.81 (s, 3H) 3.97 (s, 3H) 5.23 (br. s, 2H) 5.61 (s, 1H) 6.42 (dd, 7=8.4, 2.4 Hz, 1H) 6.47 - 6.50 (m, 1H) 6.71 (d, 7=8.4 Hz, 1H)
Step 4-5: 4-Hydroxy-8,9-dimethyl-2-oxo- l,2,5,6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
Lil (0.125 g, 0.93 mmol) was added to a suspension of methyl l-(2,4-dimethoxybenzyl)-4- hydroxy-8,9-dimethyl-2-oxo-l ,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylate (0.140 g, 0.31 mmol) in EtOAc (1.2 mL). The mixture was heated to 60 °C and stirred for 1.5 h. The mixture was cooled to room temperature and acidified with aqueous HC1 (0.1 M). The product was extracted with EtOAc, and the organic layers were combined, washed with a saturated aqueous Na2S2(¾, brine, and dried over Na2S04. The solvent was removed under reduced pressure. The residue was dissolved in CH2CI2 (1 mL), i-
PrsSiH (0.5 mL), and TFA (0.5 mL) and heated to 50 °C for 1 h. The mixture was concentrated under reduced pressure, and Et20 was added to the residue forming a precipitate. The resulting solid was filtered and washed with Et20 to afford the title compound (49.7 mg, 56% overall yield) as a brownish solid.
LC-MS: 287.1 [M-H]~, RT 1.17 min. !H NMR (500 MHz, DMSO- ) δ ppm 1.89 (dt, 7=10.5, 6.6 Hz, 2H) 2.19 (s, 3H) 2.55 - 2.65 (m, 2H) 2.89 (t, 7=6.6 Hz, 2H) 3.40 (s, 3H) 6.53 (s, 1H) 11.88 (s, 1H) 13.74 (s, 1H) 16.28 (br. s, 1H)
Using the procedure described for Example 1 above, additional compounds described herein may be prepared by using 2-methyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-4-one or Intermediate 1 and the appropriate amine in Step 1, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000241_0001
Cpd Intermediate and Data
Intermediate 3: LC-MS 304.5 [M+H]+, RT 1.21 min. H NMR (500 MHz, DMSO-
9 d6) δ 1.22 (t, J=7.3 Hz, 3H), 1.79-1.90 (m, 2H), 2.67-2.75 (m, 2H), 2.35 (s, 3H), 2.83 (t, J=6.2 Hz, 2H), 3.89 (q, J=7.0 Hz, 2H)
Intermediate 29: LC-MS: 274.1 [M-H]~, RT 0.99 min. H NMR (500 MHz, DMSO-
10 d6) δ ppm 1.92 (dt, 7=4.35, 2.12 Hz, 2H), 2.59 - 2.69 (m, 2H), 3.00 (m, 2H), 3.77 (s, 3H), 8.16 (s, IH), 12.44 (br. s, IH), 13.86 (s, IH)
Intermediate 30: LC-MS: 290.1 [M+H]+, RT 1.02 min. !H NMR (500 MHz, DMSO-rfe) δ ppm 1.33 (t, 7=7.25 Hz, 3H), 1.84 - 1.99 (m, 2H), 2.60 - 2.70 (m, 2H),
11
2.96 - 3.08 (m, 2H), 4.09 (q, 7=7.30 Hz, 2H), 8.20 (s, IH), 12.47 (br. s, IH), 13.84 (br. s, IH)
Intermediate 5: LC-MS 304.4 [M+H]+, RT 1.17 min. H NMR (500 MHz, DMSO- d6) δ 1.27 (t, J=7.4 Hz, 3H), 1.85-1.99 (m, 2H), 2.70-2.81 (m, 4H), 2.90 (t, J=6.2
22
Hz, 2H), 3.52 (s, 3H), 11.10 (br. s, IH), 14.14 (br. s, IH), 15.87 (br. s, IH)
Intermediate 6: LC-MS 318.3 [M+H]+, RT 1.33 min. !H NMR (500 MHz, DMSO-
23 d6) δ 1.14-1.39 (m, 6H), 1.94 (br. s, 2H), 2.74 (br. s, 2H), 2.84 (br. s, 2H), 2.97 (br. s, 2H), 4.03 (br. s, 2H), 11.37 (br. s, IH), 14.16 (br. s, IH), 16.02 (br. s, IH)
Intermediate 34: LC-MS: 276.3 [M+H]+, RT 0.65 min. H NMR (500 MHz,
24 DMSO- ) δ ppm 1.96 - 2.09 (m, 2H), 2.28 - 2.36 (m, 2H), 2.44 - 2.49 (m, 2H), 3.94 (s, 3H), 7.48 (s, IH), 13.97 (br. s, IH)
Intermediate 27: LC-MS: 301.5 [M-H]", RT 1.36 min. !H NMR (500 MHz, DMSO-
25 d6): δ ppm 1.89 (pentet, 7=7 Hz, 2H), 2.11 (s, 3H), 2.24 (s, 3H), 2.32 (m, 4H), 3.41 (s, 3H)
Intermediate 7: LC-MS 334.4 [M+H]+, RT 1.27 min. H NMR (500 MHz, DMSO- d6) δ 1.29 (t, J=7.1 Hz, 3H), 1.90-2.02 (m, 2H), 2.73-2.81 (m, 2H), 2.98 (t, J=6.2
29
Hz, 2H), 3.32 (s, 3H), 4.04 (q, J=7.3 Hz, 2H), 4.55 (s, 2H), 11.21 (br. s, IH), 13.97 (br. s, IH), 15.97 (br. s, IH)
Intermediate 41: LC-MS: 291.0 [M+H]+, RT 1.16 min. H NMR (500 MHz, DMSO- ) δ ppm 1.52 (t, 7=7.3 Hz, 3H), 1.91-1.99 (m, 2H), 2.72-2.80 (m, 2H),
31
3.00-3.04 (t, 7=6.4 Hz, 2H), 4.50 (q, 7=7.3 Hz, 2H), 12.37 (br.s, IH), 14.16 (s, IH), 16.20 (br. s, IH)
Intermediate 8: LC-MS 410.4 [M+H]+, RT 1.54 min. H NMR (500 MHz, DMSO- d6) δ 1.26 (t, J=7.3 Hz, 3H), 1.84-1.97 (m, J=4.7 Hz, 2H), 2.70-2.80 (m, 2H), 2.91
40
(t, J=5.8 Hz, 2H), 4.01 (q, J=6.9 Hz, 2H), 4.56 (s, 2H), 4.64 (s, 2H), 7.26-7.42 (m, 5H), 9.48 (br. s, IH), 14.16 (br. s, IH), 15.81 (br. s, IH) Cpd Intermediate and Data
Intermediate 9: LC-MS 320.3 [M+H]+, RT 1.20 min. H NMR (500 MHz, DMSO-
43 d6) δ 1.81-1.92 (m, 2H), 2.72 (d, J=10.4 Hz, 2H), 2.83 (t, J=6.2 Hz, 2H), 3.28 (s, 3H), 3.54 (s, 3H), 4.44-4.53 (m, 2H)
Intermediate 36: LC-MS: 290.0 [M+H]+, RT 1.04 min. H NMR (500 MHz, DMSO- ) δ ppm 0.94 (d, 7=7.25 Hz, 3H), 1.76 (td, 7=13.79, 3.86 Hz, IH), 2.08 -
48
2.19 (m, IH), 2.88 - 3.00 (m, IH), 3.01 - 3.10 (m, IH), 3.65 - 3.72 (m, IH), 3.80 (s, 3H), 8.29 (s, IH), 12.19 (br. s, IH), 13.97 (br. s, IH)
Intermediate 15: LC-MS 376.3 [M+H]+, RT 0.72 min. H NMR (500 MHz, DMSO- d6) δ 1.33 (t, J=7.3 Hz, 3H), 1.78 (s, IH), 2.08-2.20 (m, IH), 2.35 (s, IH), 2.90-3.08
49
(m, 3H), 3.66 (br. s, 2H), 3.92-4.17 (m, 3H), 4.24 (dd, J=10.3, 14.0 Hz, IH), 4.65 (dd, J=2.5, 14.2 Hz, IH), 5.07 (d, J=16.7 Hz, IH), 5.41 (d, J=16.4 Hz, IH)
Intermediate 10: LC-MS 378.4 [M+H]+, RT 1.20 min. H NMR (500 MHz, DMSO- d6) δ 1.30 (t, J=7.1 Hz, 3H), 1.89-1.99 (m, 2H), 2.72-2.81 (m, 2H), 2.96 (t, J=6.0
50
Hz, 2H), 3.24 (s, 3H), 3.43-3.50 (m, 2H), 3.60 (dd, J=3.9, 5.5 Hz, 2H), 4.04 (q, J=7.3 Hz, 2H), 4.61 (s, 2H), 11.12 (br. s, IH), 14.08 (br. s, IH), 15.99 (br. s, IH)
Intermediate 11: LC-MS 334.0 [M+H]+, RT 1.16 min. H NMR (500 MHz, DMSO- d6) δ ppm 1.92 (m, 7=6.0, 4.7 Hz, 2H), 2.45 (br. s, 3H), 2.71 - 2.78 (m, 2H), 2.95 (t,
52
7=6.3 Hz, 2H), 3.24 (s, 3H), 3.60 (t, 7=5.2 Hz, 2H), 4.14 (t, 7=4.7 Hz, 2H), 11.12 (br. s, 2H), 14.02 (br. s, IH), 15.86 (br. s, IH)
Intermediate 31: LC-MS: 320.0 [M+H]+, RT 1.03 min. H NMR (500 MHz, DMSO- ) δ ppm 1.87 - 1.97 (m, 2H), 2.61 - 2.69 (m, 2H), 3.04 (t, 7=6.66 Hz, 2H),
55
3.22 (s, 3H), 3.70 (t, 7=5.32 Hz, 2H), 4.24 (t, 7=5.36 Hz, 2H), 8.21 (s, IH), 12.44 (br. s, IH), 13.86 (br. s, IH)
Intermediate 32: LC-MS: 332.0 [M-H]~, RT 1.07 min. H NMR (500 MHz, DMSO- d6) δ ppm 1.89 - 1.96 (m, 2H), 1.96 - 2.04 (m, 2H), 2.64 - 2.69 (m, 2H), 3.01 (t,
56
7=6.66 Hz, 2H), 3.23 (s, 3H), 3.31 (t, 7=6.03 Hz, 2H), 4.10 (t, 7=7.09 Hz, 2H), 8.22 (s, IH), 12.43 (br. s, IH), 13.86 (br. s, IH)
Intermediate 16: LC-MS 361.7 [M+H]+, RT 1.16 min. H NMR (500 MHz, DMSO- d6) δ ppm 1.30 (t, 7=7.3 Hz, 3H), 1.92 - 2.00 (m, 2H), 2.08 (s, 3H), 2.74 - 2.81 (m,
65
2H), 2.99 (t, 7=6.3 Hz, 2H), 4.06 (q, 7=7.3 Hz, 2H), 5.20 (s, 2H), 11.26 (br. s, IH), 13.97 (s, IH), 16.02 (br. s, IH)
Intermediate 12: LC-MS 348.9 [M+H]+, RT 1.12 min. H NMR (500 MHz, DMSO- d6) δ 1.83-2.00 (m, 4H), 2.45 (s, 3H), 2.72-2.80 (m, 2H), 2.93 (t, J=6.2 Hz, 2H),
66
3.25 (s, 3H), 3.34 (t, J=5.8 Hz, 2H), 3.99 (t, J=7.4 Hz, 2H), 11.18 (br. s, IH), 14.27 (br. s, IH), 15.88 (br. s, IH) Cpd Intermediate and Data
Intermediate 13: LC-MS: 424.3 [M+H]+, RT 1.52 min. H NMR (500 MHz, DMSO- ) δ ppm 1.24 (t, 7=7.3 Hz, 3H), 1.89 - 1.98 (m, 2H), 2.72 - 2.80 (m, 2H),
70 2.94 (t, 7=6.3 Hz, 2H), 3.05 (t, 7=6.6 Hz, 2H), 3.88 (t, 7=6.6 Hz, 2H), 4.00 (q, 7=7.3 Hz, 2H), 4.53 (s, 2H), 7.23 - 7.37 (m, 5 H), 11.05 (br. s, IH), 14.02 (br. s, IH), 15.84 (br. s, IH)
Intermediate 35: LC-MS: 290.0 [M+H]+, RT 1.08 min. !H NMR (500 MHz, DMSO-i¾) δ ppm 0.93 (d, 7=7.33 Hz, 3H), 1.71 - 1.80 (m, IH), 2.12 (ddt, 7=11.68,
71
6.76, 2.68, 2.68 Hz, IH), 2.90 - 3.00 (m, IH), 3.01 - 3.09 (m, IH), 3.68 (dd, 7=7.37, 5.56 Hz, IH), 3.80 (s, 3H), 8.29 (s, IH), 12.19 (br. s, IH), 13.96 (s, IH)
Intermediate 67: LC-MS: 309.0 [M-H]", RT 1.45 min. !H NMR (500 MHz, DMSO- d6) δ ppm 2.10 - 2.21 (m, 2H), 2.46 - 2.50 (m, 2H), 3.00 (t, 7=7.4 Hz, 2H), 7.11 -
85
7.22 (m, 2H), 7.43 (dd, 7=7.1, 1.1 Hz, IH), 7.66 (d, 7=7.6 Hz, IH), 11.99 (s, IH), 12.50 (s, IH), 13.85 (s, IH), 16.35 (br. s, IH)
Intermediate 68: LC-MS: 323.2 [M-H]", RT 1.24 min. H NMR (500 MHz, DMSO- d6) δ ppm 2.11 - 2.20 (m, 2H), 2.47 - 2.49 (m, 2H), 3.05 (t, 7=7.3 Hz, 2H), 3.80 (s,
86
3H), 7.17 - 7.23 (m, IH), 7.26 (ddd, 7=8.2, 7.1, 1.1 Hz, IH), 7.59 (d, 7=8.2 Hz, IH), 7.69 (d, 7=7.9 Hz, IH), 12.55 (s, IH), 13.83 (s, IH), 16.36 (br. s, IH)
Intermediate 43: LC-MS: 323.0 [M-H]", RT 0.86 min (1 minute method). H NMR (500 MHz, DMSO-i¾) δ ppm 2.19 (quin, 7=7.0 Hz, 2H), 2.32 - 2.47 (m, 2H), 2.69 -
87 2.84 (m, 2H), 3.81 (s, 3H), 7.15 (ddd, 7=8.0, 7.1, 0.9 Hz, IH), 7.33 (ddd, 7=8.3, 7.0, 1.1 Hz, IH), 7.56 (d, 7=8.2 Hz, IH), 7.72 (dd, 7=7.9, 0.9 Hz, IH), 12.84 (br. s, IH), 13.95 (br. s, IH), 16.22 (br. s, IH)
Intermediate 42: LC-MS: 309.0 [M-H]", RT 0.78 min (1 minute method). !H NMR (500 MHz, DMSO-i¾) δ ppm 1.97 - 2.11 (m, 2H), 2.68 - 2.77 (m, 2H), 3.11 (t,
88 7=6.8 Hz, 2H), 7.11 (ddd, 7=8.0, 7.1, 0.9 Hz, IH), 7.30 (ddd, 7=8.1, 7.0, 0.9 Hz, IH), 7.46 (d, 7=8.2 Hz, IH), 7.64 (d, 7=7.9 Hz, IH), 11.40 (s, IH), 12.30 (br. s, IH), 13.91 (br. s, IH), 16.11 (br. s, IH)
Intermediate 69: LC-MS: 337.1 [M-H]", RT 0.77 min (1 minute method). H NMR (500 MHz, DMSO-i¾) δ ppm 1.29 (t, 7=7.1 Hz, 3H), 2.14 - 2.25 (m, 2H), 2.45 (dd,
89 7=7.4, 5.2 Hz, 2H), 3.01 (t, 7=7.4 Hz, 2H), 4.34 (q, 7=7.1 Hz, 2H), 7.17 - 7.22 (m, IH), 7.23 - 7.28 (m, IH), 7.61 (d, 7=8.2 Hz, IH), 7.68 (d, 7=7.6 Hz, IH), 12.55 (s, IH), 13.85 (s, IH), 16.35 (br. s, IH)
Example 2 (Compound 37)
3-Ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
A mixture of 10-(2,4-dimethoxybenzyl)-3-ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid (Intermediate 17, 50 mg, 0.11 mmol), triisopropylsilane, trifluoroacetic acid, and CH2CI2 was stirred at room temperature for 1 h. The volatiles were removed under reduced pressure, and the residue was triturated with MeOH. The precipitate was collected, washed with MeOH, and dried to afford the title compound as a white solid (20 mg, 59%).
LC-MS 320.3 [M+H]+, RT 1.13 min. !H NMR (500 MHz, OMSO-d6) δ 1.31 (t, 7=7.3 Hz, 3H), 1.90-2.02 (m, 2H), 2.71-2.83 (m, 2H), 2.97 (t, 7=6.15 Hz, 2H), 4.07 (q, 7=7.0 Hz, 2H), 4.60 (s, 2H), 5.52 (br. s, 1H), 11.09 (br. s, 1H), 14.06 (br. s, 1H), 15.91 (br. s, 1H)
Example 3 (Compound 57)
7-Hydroxy-3-(2-hydroxyethyl)-2-methyl-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
TMSI (242 mg, 1.192 mL, 1.2 mmol) was added to a solution of 7-hydroxy-3-(2- methoxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid (Compound 52, 20.1 mg, 0.06 mmol) in CH2CI2 (0.2 mL). The mixture was stirred at 60 °C in a sealed tube for 4 days. After cooling to room temperature, the volatiles were removed under reduced pressure, and the residue was triturated with
MeOH. The precipitate was collected and washed with MeOH to afford the title compound as a white powder (15.9 mg, 84%).
LC-MS 320.2 [M+H]+, RT 0.86 min. H NMR (500 MHz, DMSO-cfe) δ 1.84-1.98 (m, 2H), 2.47 (s, 3H), 2.70-2.79 (m, 2H), 2.96 (t, 7=6.2 Hz, 2H), 3.67 (t, 7=5.0 Hz, 2H), 4.02 (t, 7=5.0 Hz, 2H), 5.07 (br. s, 1H), 11.33 (br. s, 1H), 14.49 (br. s, 1H), 15.77 (br. s, 1H)
Using the procedure described for Example 3 above, an additional compound described herein may be prepared by substituting 7-hydroxy-3-(3-methoxypropyl)-2-methyl- 9-oxo-3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid (Compound 66), suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000245_0001
Example 4 (Compound 58)
3-Ethyl-7-hydroxy-2-((2-hydroxyethoxy)methyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
A mixture of 3-ethyl-7-hydroxy-2-((2-methoxyethoxy)methyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid (Compound 50, 14.0 mg, 0.037 mmol), CH2C12 (0.1 mL), and TMSI (149 mg, 0.106 mL, 0.74 mmol) was stirred at room temperature for 4 h. The mixture was cooled to 0 °C and quenched with MeOH. The mixture was diluted with CH2CI2, washed with Na2S203 solution, water, and brine. After drying over Na2S04, the solvent was evaporated and the residue was triturated with EtOAc. The precipitate was collected by filtration, washed with EtOAc, and dried under N2 to afford the title compound as a white powder (11.7 mg, 87%).
LC-MS 364.2 [M+H]+, RT 1.13 min. H NMR (500 MHz, DMSO-cfe) δ 1.31 (t, 7=7.3 Hz, 3H), 1.90-2.04 (m, 2H), 2.72-2.83 (m, 2H), 2.98 (br. s, 2H), 3.47-3.60 (m, 4H), 4.06 (q, 7=7.2 Hz, 2H), 4.63 (br. s, 3H), 11.23 (br. s, 1H), 13.98 (br. s, 1H), 15.96 (br. s, 1H)
Example 5 (Compound 38)
2-((Dimethylamino)methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
Step 1: 10-(2,4-Dimethoxybenzyl)-3-ethyl-2-formyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
Activated MnC>2 (1.02 g, 11.7 mmol) was added to a solution of 10-(2,4-dimethoxybenzyl)-3- ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid (Intermediate 17, 551 mg, 1.17 mmol) in CH2CI2 (10.0 mL). The mixture was stirred at room temperature for 24 h. The mixture was purified by silica gel column chromatography (0-20% gradient MeOH in CH2CI2) to afford the title compound as a yellow solid (215 mg, 39%).
LC-MS 468.3 [M+H]+, RT 1.55 min
Steps 2-3: 2-((Dimethylamino)methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
A mixture of the aldehyde obtained in step 1 (47 mg, 0.1 mmol), dimethylamine
hydrochloride (20.0 mg, 0.25 mmol), triethylamine (25 mg, 35 uL, 0.25 mmol), acetic acid
(15 mg, 14 uL, 0.25 mmol), and dichloroethane (0.5 mL) was stirred at room temperature for
0.5 h. NaBH(OAc)3 (42.4 mg, 0.20 mmol) was added, and the mixture was stirred overnight.
The mixture was diluted with CH2CI2, and washed with water, and over Na2S04. After the removal of the solvent, the residue was treated with CH2CI2 (0.5 mL) and TFA (0.5 mL) at room temperature for 1 h. The volatiles were removed under reduced pressure. The residue was purified using reverse phase preparative HPLC. The obtained TFA salt was converted to the HC1 salt by treatment with HC1 in ethyl ether (1.0 mL, 1.0 M) to afford the title compound as a white powder (4.3 mg, 11%).
LC-MS 347.4 [M+H]+, RT 0.90 min. !H NMR (500 MHz, DMSO-cfe) δ 1.27 (t, 7=6.3 Hz, 3H), 1.97 (br. s, 2H), 2.78 (br. s, 2H), 2.98 (br. s, 6H), 3.31-3.45 (m, 2H), 4.02-4.12 (m, 2H), 4.57 (br. s, 2H), 10.22-10.48 (m, 1H), 11.45 (br. s, 1H), 13.91 (br. s, 1H), 15.53-16.24 (br. s, 1H)
Using the procedure described for Example 5, steps 2-3 above, additional compounds described herein may be prepared by substituting the appropriate amine, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000247_0001
Example 6 (Compound 12)
3-(2-(Dimethylamino)ethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate Steps 1-2: Methyl 10-(2,4-dimethoxybenzyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
TiCl4 (1.0 M in CH2C12, 6.44 mL, 6.44 mmol) was added to a solution of 2-methyl-5,6,7,8- tetrahydrocyclohepta[d]imidazol-4(lH)-one (Intermediate 3, step 2, 0.96 g, 5.85 mmol), (2,4- dimethoxyphenyl)methanamine (1.08 g, 6.44 mmol), triethylamine (3.19 g, 4.39 mL, 31.61 mmol), and CH2CI2 (10.0 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The mixture was brought to room temperature and stirred overnight. The reaction was diluted with CH2CI2 and quenched with saturated aqueous NaHCC>3. The organic phase was separated using a phase separator cartridge. The aqueous layer was extracted with CH2CI2. The organic layers were combined and evaporated to dryness. The residue, trimethyl methanetricarboxylate
(2.22 g, 11.7 mmol), and diphenyl ether (25 mL) were stirred at 200 °C for 10 min. The mixture was cooled to room temperature and purified by silica gel column chromatography
(0-20% MeOH in CH2C12) followed by reversed phase C18 chromatography, (0-50% acetonitrile in water) to afford the title compound (0.36 g, 14%).
LC-MS 438.3 [M-H]~, RT 1.04 min
Step 3: Methyl 7-(benzyloxy)-10-(2,4-dimethoxybenzyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
DIAD (0.33g, 0.32 mL, 1.64 mmol) was added to a solution of the product of step 2 (0.36 g,
0.82 mmol), Ph3P (0.43 g, 1.64 mmol), and benzyl alcohol (0.18 g, 0.17 mL, 1.64 mmol) in CH2CI2 (5.0 mL) at 0 °C. The mixture was brought to room temperature and stirred overnight.
After removal of the solvent, the residue was purified by silica gel column chromatography
(0-100% EtOAc in CH2C12) to afford the title compound (0.35 g, 81%).
LC-MS 530.3 [M+H]+, RT 0.99 min
Step 4: 3-(2-(Dimethylamino)ethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate
NaH (60% suspension in mineral oil, 16.0 mg, 0.4 mmol) was added to a solution of the product of step 3 (53 mg, 0.1 mmol) in DMF (0.5 mL). The mixture was stirred for 0.5 h, followed by the addition of 2-bromo-N,N-dimethylethan-l-amine hydrochloride (37.6 mg,
0.2 mmol). The mixture was stirred at room temperature for 3 days. The mixture was diluted with EtOAc, dried over Na2S04, and concentrated under reduced pressure. The residue was treated with TFA at 60 °C for 0.5 h. TFA was removed under reduced pressure, and the residue was purified by reverse phase HPLC to afford the title compound as the TFA salt (2.5 mg).
LC-MS 347.2 [M+H]+, RT 0.76 min. H NMR (500 MHz, DMSO-cfe) δ 1.90-2.00 (m, 2H), 2.48 (s, 3H), 2.72-2.78 (m, 2H), 2.88 (s, 6H), 2.94-3.01 (m, 2H), 3.32-3.50 (br. s, 2H, obscured by H20), 4.22-4.38 (m, 2H), 10.28 (br. s, 1H), 14.16 (br. s, 1H), 16.40 (br. s, 1H) Using the procedure described for Example 6, additional compounds described herein may be prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000249_0001
Example 7 (Compound 62)
3-Ethyl-7-hydroxy-9-oxo-2-((pyridin-4-yloxy)methyl)-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
Step 1: 10-(2,4-Dimethoxybenzyl)-3-ethyl-7-hydroxy-9-oxo-2-((pyridin-4-yloxy)methyl)- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
Methyl 7-(benzyloxy)-10-(2,4-dimethoxybenzyl)-3-ethyl-9-oxo-2-((pyridin-4-yloxy)methyl)- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
(Intermediate 19, 92 mg, 0.14 mmol), TMSOK (120 mg, 0.9 mmol), and dioxane (0.5 mL) were heated to 80 °C for 30 min. The mixture was partitioned between aqueous HC1 and
EtOAc. The aqueous layer was neutralized with NaHCC>3, and was extracted with EtOAc.
The organic layer was dried over MgS04, filtered, and concentrated under vacuum.
Trituration with 1: 1 hexanes/acetone afforded the title compound (50 mg, 65%) as a white solid with -90% purity.
H NMR (500 MHz, MeOH-d4): δ ppm 1.30 (t, 7=7.5 Hz, 3H), 2.19 (pentet, 7=7 Hz, 2H), 2.47 (m, 2H), 2.52 (t, 7=7 Hz, 2H), 3.64 (s, 3H), 3.72 (s, 3H), 4.11 (q, 7= 7.5 Hz, 2H), 5.37 (s, 2H), 5.73 (s, 2H), 6.26 (dd, 7=8.5, 2.5 Hz, 1H), 6.40 (d, 7=2.5 Hz, 1H), 6.50 (d, 7=8.5 Hz, 1H), 7.20 (dd, 7=5, 1.5 Hz, 2H), 8.39 (dd, 7=5, 1.5 Hz, 2H)
Step 2: 3-Ethvl-7-hvdroxv-9-oxo-2-((pvridin-4-vloxv)methyl)-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
The product of step 1 (48 mg, 0.088 mmol) was treated with TFA (0.3 mmol) and TIPSH (0.1 mL) at room temperature for 30 min. The volatiles were removed under a N2 stream. The residue was triturated with 1M HC1 in ether, and the solid was removed by filtration. The solid was dissolved in MeOH (12 mL) and filtered to remove particulate matter. The filtrate was concentrated under reduced pressure. The solid was triturated with MeOH (2 mL) to afford the title compound (21 mg, 55%) as a white solid.
LC-MS: 395.0 [M-H]", RT 0.64 min. !H NMR (500 MHz, DMSO- ): δ ppm 1.31 (t, 7= 7.5 Hz, 3H), 1.98 (m, 2H), 2.51 (m, 2H), 3.01 (t, 7=6 Hz, 2H), 4.14 (q, 7=7.5 Hz, 2H), 5.67 (s, 2H), 7.76 (d, 7=7.5 Hz, 2H), 8.78 (d, 7 =7.5 Hz, 2H)
Using the procedure described for Example 7, additional compounds described herein may be prepared by substituting the indicated intermediate, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000250_0001
Example 8 (Compound 63)
3-Ethyl-2-((ethylsulfonyl)methyl)-7-hydroxy-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
Step 1: Methyl 7-(benzyloxy)- 10-(2,4-dimethoxybenzyl)-3-ethyl-2-((ethylsulfonyl)methyl)-9- oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate m-CPBA (131 mg, 0.76 mmol) was added to a mixture of methyl 7-(benzyloxy)-10-(2,4- dimethoxybenzyl)-3-ethyl-2-((ethylthio)methyl)-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate (Intermediate 24, 100 mg, 0.16 mmol) and CHCI3 (1.25 mL) at 0 °C and stirred at 0 °C for 20 min. The mixture was partitioned between aqueous NaHC03 and CH2CI2. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (20% acetone in CH2CI2) afforded the title compound. Step 2: Methyl 3-ethyl-2-((ethylsulfonyl)methyl)-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
The sulfone obtained in step 1 was treated with TFA (0.3 mL) and TIPSH (0.1 mL) at room temperature for 90 min. The volatiles were removed under a N2 stream. The residue was triturated with 1M HCl in ether, and filtered. The solid was dissolved in MeOH (6 mL), and the solution was filtered to remove particulate matter. The filtrate was concentrated under reduced pressure. Trituration with MeOH afforded the title compound (28 mg, 44% over 2 steps) as a white solid.
!H NMR (500 MHz, MeOH-d4): δ ppm 1.42 (m, 6H), 2.08 (m, 2H), 2.92 (m, 2H), 3.02 (t, 7=6 Hz, 2H), 3.3 (q, 7=7.5 Hz, 2H), 3.95 (s, 3H), 4.20 (q, 7=7.5 Hz, 2H), 4.73 (s, 2H)
Step 3: 3-Ethvl-2-((ethvlsulfonvl)methvl)-7-hydroxv-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
The product of step 2 (26 mg, 0.063 mmol), Lil (40 mg, 0.3 mmol), and EtOAc (0.5 mL) were heated at 40 °C for 2 h. EtOAc was removed under a N2 stream. The residue was triturated with H2O/HCI, and the solid was removed by filtration. The solid was washed with
H2O, followed by THF to afford the title compound (17 mg, 68%) as a white solid.
LC-MS: 394.0 [M-H]~, RT 0.93 min. H NMR (500 MHz, DMSO-cfe): δ ppm 1.30 (m, 6H), 1.97 (m, 2H), 2.66 (m, 2H), 2.99 (t, 7=6.5 Hz, 2H), 3.36 (q, 7=7.5 Hz, 2H), 4.13 (q, 7=7.5 Hz, 2H), 4.82 (s, 2H)
Using the procedure described for Example 8, steps 2-3, additional compounds described herein may be prepared by substituting the indicated intermediate, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000251_0001
Example 9 (Compound 76)
(R)-4-Hydroxy-5,8-dimethyl-2-oxo- 1,2, 5,6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid
Step 1 : 5-Iodo- l-methyl- lH-pyrazole-4-carboxylic acid
2-Methylbut-2-ene (60 mL, 550 mmol and a solution of NaH2P04 (26.4 g, 220 mmol) and
NaC102 (15.0 g, 165 mmol) in ¾0 (100 mL) were added to a suspension of 5-iodo-l- methyl- lH-pyrazole-4-carbaldehyde (Intermediate 35, step 2, 26.0 g, 110 mmol) in t-BuOH
(200 mL). After stirring at room temperature for 16 h, the volatiles were removed under reduced pressure. The aqueous phase was extracted with CH2CI2. The organic phases were combined, dried over Na2S04, filtered, and concentrated under reduced pressure to afford the title compound (16 g, 57%).
LC-MS: 252.6 [M+H]+, RT 0.72 min. H NMR (500 MHz, OMSO-d6) δ ppm 3.90 (s, 3H), 7.88 (s, 1H), 12.51 (br. s, 1H)
Step 2: Methyl 5-iodo-l-methyl- lH-pyrazole-4-carboxylate
A mixture of 5-iodo-l -methyl- lH-pyrazole-4-carboxylic acid (8.7 g, 34.5 mmol), concentrated ¾804 (0.6 mL), and MeOH (60 mL) were heated at reflux for 16 h. The mixture was cooled then concentrated under reduced pressure. The residue was dissolved in CH2CI2 and washed with saturated aqueous NaHCC>3. The organic phase was dried over Na2S04, filtered, and concentrated under reduced pressure to afford the title compound (9.2 g, 99%).
LC-MS: 266.9 [M+H]+, RT 1.0 min. !H NMR (500 MHz, CDC13) δ ppm 3.86 (s, 3H), 3.97 - 4.02 (m, 3H), 7.97 (s, 1H)
Step 3: Methyl (5)-5-(3-hydroxybut- 1 -yn- 1-yl)- 1 -methyl- lH-pyrazole-4-carboxylate
A mixture of methyl 5-iodo- l-methyl- lH-pyrazole-4-carboxylate (1.8 g, 6.8 mmol), (S)-but- 3-yn-2-ol (0.65 mL, 8.1 mmol), Cul (52 mg, 0.27 mmol), PdCl2(PPh3)2 (95 mg, 0.14 mmol), Et3N (2.1 mL, 15 mmol), and CH3CN (14 mL) was heated to 60 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column (20-50% EtOAc in hexanes) to afford the title compound (1.12 g, 80%).
LC-MS: 209.0 [M+H]+, RT 0.91 min. !H NMR (500 MHz, CDC13) δ ppm 1.62 (d, 7=6.70 Hz, 3H), 3.84 (s, 3H), 3.93 (s, 3H), 4.87 (q, 7=6.62 Hz, 1H), 7.90 (br. s, 1H)
Step 4: 1 -Benzyl 3-methyl 2-((5)-4-(4-(methoxycarbonyl)-l -methyl- lH-pyrazol-5-yl)but-3- yn-2-yl)malonate
Et3N (0.8 mL, 5.7 mmol) and MsCl (0.375 mL, 4.84 mmol) were added to a solution of methyl (5)-5-(3-hydroxybut- l-yn-l-yl)-l-methyl- lH-pyrazole-4-carboxylate (0.91 g, 4.4 mmol) in CH2CI2 (11 mL) at 0 °C. After stirring at 0 °C for 15 min, the reaction was allowed to warm to room temperature and stirred for an additional 1.5 h. The mixture was diluted with
CH2CI2 and washed with ¾0. The organic phase was dried over Na2S04, filtered, and concentrated under reduced pressure. Dioxane (20 mL), benzyl methyl malonate (1 mL, 5.3 mmol), and CsF (2.7 g, 17.7 mmol) were added to the crude residue. The mixture was heated at 80 °C for 16 h. The mixture was cooled to room temperature and poured into ¾0. The aqueous phase was extracted with EtOAc. The organic phases were combined, washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% EtOAc in hexanes) to afford the title compound (1.3 g, 74%) as a 1: 1 mixture of diastereomers.
LC-MS: 399.0 [M+H]+, RT 1.41 min
Step 5: Methyl (R)-5-(5-methoxy-3-methyl-5-oxopentyl)-l-methyl-lH-pyrazole-4- carboxylate
A mixture of 1-benzyl 3-methyl 2-((5)-4-(4-(methoxycarbonyl)-l-methyl-lH-pyrazol-5- yl)but-3-yn-2-yl)malonate (1.3 g, 3.3 mmol), 10% Pd/C (600 mg), and EtOAc (20 mL) was stirred under a ¾ atmosphere (50 psi) for 12 h. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was dissolved in DMSO (5 mL) and heated at 110 °C for 1.5 h. The mixture was cooled to room temperature and diluted with ¾0. The aqueous phase was extracted with EtOAc. The organic phases were combined, washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure to afford the title compound (0.73 g, 82%).
LC-MS: 267.1 [M-H]~, RT 1.04 min. !H NMR (500 MHz, CDC13) 5 ppm 1.07 (d, 7=6.70 Hz, 3H), 1.44 - 1.52 (m, 1H), 1.56 - 1.66 (m, 1H), 2.06 - 2.11 (m, 1H), 2.21 - 2.28 (m, 1H), 2.40 (dd, 7=15.05, 6.38 Hz, 1H), 2.94 (dd, 7=11.35, 5.36 Hz, 1H), 3.02 (dd, 7=11.43, 5.36 Hz, 1H), 3.68 (s, 3H), 3.82 (s, 3H), 3.88 (s, 3H), 7.85 (s, 1H)
Steps 6-7: Methyl (R)-4-amino-l,6-dimethyl- 1,6,7, 8-tetrahydrocyclohepta[c]pyrazole-5- carboxylate
LiHMDS (1M THF, 6.8 mL, 6.8 mmol) was added dropwise to a solution of methyl (R)-5-(5- methoxy-3-methyl-5-oxopentyl)-l -methyl- lH-pyrazole-4-carboxylate (0.73 g, 2.7 mmol) in THF (20 mL) at 0 °C. After stirring at 0 °C for 30 min, the ice bath was removed and the reaction was allowed to stir at room temperature for 2 h. The mixture was quenched with saturated aqueous NH4C1 and poured into ¾0. The aqueous phase was extracted with CH2CI2. The organic phases were combined, dried over Na2S04, filtered, and concentrated under reduced pressure. The crude β-ketoester was used directly in the next step. A mixture of the crude β-ketoester, NH4OAc (0.9 g, 12 mmol), tetraethyl orthosilicate (0.6 mL, 2.7 mmol), and ethanol (10 mL) was heated at 80 °C for 16 h. Upon cooling to room temperature, a precipitate formed. The precipitate was removed by filtration and rinsed with cold ethanol to afford the title compound (0.5 g, 78%).
LC-MS: 236.1 [M+H]+, RT 0.84 min. !H NMR (500 MHz, OMSO-d6) δ ppm 0.82 (d, 7=7.25 Hz, 3H), 1.62 - 1.73 (m, 1H), 1.99 (s, 1H), 2.72 - 2.83 (m, 1H), 2.87 (dd, 7=4.85, 2.56 Hz, 1H), 3.42 - 3.49 (m, 1H), 3.58 (s, 3H), 3.74 (s, 3H), 7.86 (s, 1H)
Steps 8-9: (R)-4-Hvdroxv-5.8-dimethvl-2-oxo- 1.2.5.6.7.8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
Propylphosphonic anhydride solution (50 wt% EtOAc, 2.9 mL, 5.0 mmol) was added to a suspension of methyl (R)-4-amino-l ,6-dimethyl-l ,6,7,8-tetrahydrocyclohepta[c]pyrazole-5- carboxylate (0.6 g, 2.5 mmol) and potassium 3-methoxy-3-oxopropanoate (0.6 g, 3.8 mmol) in DMF (5 mL). After stirring at room temperature for 1.5 h, NaOMe solution (5.4M MeOH, 1.9 mL, 10 mmol) was added. After stirring at room temperature for an additional 1 h, the mixture was diluted with methanol and neutralized with aqueous 4 N HC1 solution. The precipitate was removed by filtration, rinsed with cold methanol, and dried to afford the intermediate ester (0.32 g, 40%).
A mixture of the crude ester (320 mg, 1 mmol), Lil (565 mg, 4 mmol), and EtOAc (5 mL) was stirred at 60 °C for 2 h. The mixture was cooled to room temperature and poured into 1M HC1 . The aqueous phase was extracted with CH2CI2. The organic phases were combined, washed with saturated aqueous Na2S2(¾, dried over Na2S04, filtered, and concentrated under reduced pressure to afford the title compound (169 mg, 59%) as a white solid.
LC-MS: 290.0 [M+H]+, RT 1.08 min. H NMR (500 MHz, OMSO-d6) δ ppm 0.93 (d, 7=7.25 Hz, 3H), 1.70 - 1.80 (m, 1H), 2.08 - 2.18 (m, 1H), 2.89 - 3.00 (m, 1H), 3.01 - 3.10 (m, 1H), 3.64 - 3.72 (m, 1H), 3.80 (s, 3H), 8.28 (s, 1H), 12.21 (br. s, 1H), 13.98 (br. s, 1H)
Using the procedure described for Example 9, additional compounds described herein may be prepared by substituting the indicated intermediate and replacing (5)-but-3-yn-2-ol in the Step 3 with (R)-enantiomer, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000254_0001
Cpd Intermediate and Data
Intermediate 39 was used directly in step 3: LC-MS: 304.1 [M+H]+, RT 1.17 min. H NMR (500 MHz, CDC13) 5 ppm 1.06 (d, 7=7.25 Hz, 3H), 1.50 (t, 7=7.29 Hz, 3H), 1.87
82
- 1.96 (m, 1H), 2.18 - 2.25 (m, 1H), 2.93 - 3.05 (m, 2H), 3.85 (td, 7=7.11, 1.06 Hz, 1H), 4.11 - 4.24 (m, 2H), 8.00 (s, 1H), 10.28 (br. s, 1H), 14.00 (s, 1H)
Intermediate 40 was used directly in step 3: LC-MS: 318.0 [M+H]+, RT 1.18 min. lH NMR (500 MHz, DMSO-cfe) δ ppm 0.93 (d, 7=7.25 Hz, 3H), 1.39 (dd, 7=6.46, 5.04
112 Hz, 6H), 1.69 - 1.83 (m, 1H), 2.08 - 2.20 (m, 1H), 2.95 (ddd, 7=18.25, 13.24, 5.40 Hz, 1H), 3.05 - 3.14 (m, 1H), 3.67 (quin, 7=6.98 Hz, 1H), 4.59 (quin, 7=6.52 Hz, 1H), 8.35 (s, 1H), 12.20 (br. s, 1H), 13.96 (br. s, 2H)
Example 10 (Compound 78)
(5)-4-Hydroxy-5-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid
Step 1-6: Methyl (5)-4-hydroxy-8-(4-methoxybenzyl)-5-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylate
The title compound was be prepared from methyl 5-iodo-l-(4-methoxybenzyl)-lH-pyrazole-
4-carboxylate (Intermediate 38) using the procedures described for Example 9 (steps 3-8) by replacing (5)-but-3-yn-2-ol in Step 3 with the (R)-enantiomer.
LC-MS: 410.2 [M+H]+, RT 1.30 min. !H NMR (500 MHz, OMSO-d6) δ ppm 0.84 (d, 7=7.25 Hz, 3H), 1.64 - 1.77 (m, 1H), 1.99 - 2.11 (m, 1H), 2.76 - 2.87 (m, 1H), 2.95 - 3.05 (m, 1H), 3.59 - 3.68 (m, 1H), 3.72 (s, 3H), 3.84 (s, 3H), 5.29 (s, 2H), 6.90 (d, 7=8.67 Hz, 2H), 7.10 (d, 7=8.67 Hz, 2H), 8.36 (s, 1H), 10.93 - 11.01 (m, 1H), 13.79 - 13.89 (m, 1H)
Step 7: Methyl (S)-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylate
A mixture of methyl (S)-4-hydroxy-8-(4-methoxybenzyl)-5-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylate (300 mg, 0.72 mmol), TFA (1 mL), and triisopropylsilane (1 mL) was heated at 60 °C for 16 h then cooled to room temperature. The volatiles were then removed under reduced pressure. The residue was triturated with Et20. The precipitate was removed by filtration and rinsed with Et20 to afford the title compound (180 mg, 87%).
LC-MS: 289.9 [M+H]+, RT 1.03 min. !H NMR (500 MHz, OMSO-d6) δ ppm 0.94 (d, 7=7.25 Hz, 3H), 1.70 - 1.81 (m, 1H), 2.08 - 2.19 (m, 1H), 2.89 - 3.00 (m, 1H), 3.01 - 3.10 (m, 1H), 3.68 (quin, 7=7.07 Hz, 1H), 3.80 (s, 3H), 8.28 (s, 1H), 12.19 (br. s, 1H), 13.97 (br. s, 1H)
Step 8: (S)-4-Hvdroxv-5-methvl-2-oxo-l,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
A mixture of methyl (5)-4-hydroxy-5-methyl-2-oxo-l,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylate (180 mg, 0.62 mmol), lithium iodide (250 mg, 1.87 mmol), and EtOAc (3 mL) was heated at 60 °C for 2 h. The mixture was cooled to room temperature and poured into 1M HC1. The aqueous phase was extracted with CH2CI2. The organic layers were combined, washed with saturated aqueous
Na2S2(¾, dried over Na2S04, filtered, and concentrated under reduced pressure to afford the title compound (35 mg, 21%).
LC-MS: 276.2 [M+H]+, RT 1.05 min. !H NMR (500 MHz, OMSO-d6) δ ppm 0.96 (d, 7=7.17 Hz, 3H), 1.68 - 1.80 (m, 1H), 2.02 - 2.12 (m, 1H), 2.92 - 3.08 (m, 2H), 3.62 - 3.73 (m, 1H), 8.28 (s, 1H), 12.19 (br. s, 1H), 13.97 (br. s, 1H)
Example 11 (Compound 16)
4-Hydroxy-2-oxo-8-(2-(pyrrolidin-l-yl)ethyl)-l,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
Steps 1-2: Methyl 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-l-(2,4-dimethoxybenzyl)-4- hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3- carboxylate
The title compound was prepared using the 2-step procedure described for Example 1 (steps 2-3) starting from l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5, 6,7,8- tetrahydrocyclohepta[c]pyrazol-4(lH)-one (Intermediate 28).
LC-MS: 582.1 [M-H]~, RT 1.71 min. H NMR (500 MHz, CDC13) δ ppm 0.00 (s, 6H), 0.85 (s, 9H), 1.96 - 2.05 (m, 4H), 2.56 (br. s, 2H), 3.76 (s, 6H), 3.90 - 3.96 (m, 5 H), 4.13 - 4.18 (m, 2H), 5.15 (s, 2H), 6.36 - 6.46 (m, 2H), 6.68 (d, 7=8.35 Hz, 1H), 7.12 (s, 1H)
Steps 3-4: Methyl 4-(benzyloxy)-l-(2,4-dimethoxybenzyl)-8-(2-hydroxyethyl)-2-oxo- l,2,5,6,7,8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylate
A mixture of methyl 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-l-(2,4-dimethoxybenzyl)-4- hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3- carboxylate (0.1 g, 0.17 mmol), DMF (1 mL), K2C03 (30 mg, 0.21 mmol), and benzyl bromide (25 μί, 0.21 mmol) was stirred at room temperature for 2 h. The reaction mixture was diluted with ¾0 and extracted with Et20. The organic phases were combined, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was dissolved in THF and TBAF solution (1M THF, 0.2 mL) was added. The mixture was stirred at room temperature for 1 h then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc) to afford the title compound (63 mg, 66%).
LC-MS: 560.3 [M+H]+, RT 1.20 min. !H NMR (500 MHz, CDC13) δ ppm 1.96 - 2.05 (m, 4H), 2.56 (br. s, 2H), 3.76 (s, 6H), 3.90 - 3.96 (m, 5 H), 4.13 - 4.18 (m, 2H), 5.15 (s, 2H), 5.20 (s, 2H), 6.36 - 6.46 (m, 2H), 6.68 (d, 7=8.35 Hz, 1H), 7.12 (s, 1H), 7.34 - 7.42 (m, 5 H), 8.00 (br. s, 1H) Steps 5-7: 4-Hvdroxv-2-oxo-8-(2-(pvrrolidin-l-vl)ethyl)-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
Methanesulfonyl chloride (20 μί, 0.22 mmol) and Et3N (30 μΐ,, 0.22 mmol) were added to a solution of methyl 4-(benzyloxy)-l-(2,4-dimethoxybenzyl)-8-(2-hydroxyethyl)-2-oxo- l,2,5,6,7,8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylate (0.11 g, 0.2 mmol) in CH2CI2 (2 mL). The reaction was stirred at room temperature for 0.5 h. Pyrrolidine
(0.5 mL, 6.0 mmol) was added, and the mixture was heated to 40 °C and allowed to stir for
16 h. The mixture was cooled to room temperature and concentrated under reduced pressure.
The residue was dissolved in THF (2 mL) and TMSOK (65 mg, 0.5 mmol) was added. The mixture was heated at 70 °C for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with Et20, and the precipitate was removed by filtration. A mixture of the crude solid, TFA (1 mL), and triisopropyl silane (1 mL) was heated at 60 °C for 1 h. The mixture was cooled to room temperature, and the TFA was removed under reduced pressure. HCl solution (2.5 M Et20, 2 mL) was added to the crude residue. The precipitate was removed by filtration, rinsed with Et20, and dried to afford the title compound (14 mg, 30%).
LC-MS: 359.3 [M+H]+, RT 0.89 min. H NMR (500 MHz, OMSO-d6) δ ppm 1.80 - 1.90 (m, 2H), 1.92 - 2.01 (m, 4H), 2.62 - 2.71 (m, 2H), 2.93 - 3.05 (m, 2H), 3.11 (t, 7=6.62 Hz, 2H), 3.45 - 3.57 (m, 2H), 3.65 (m, 2H), 4.50 (t, 7=6.70 Hz, 2H), 8.29 (s, 1H), 12.51 (br. s, 1H), 13.87 (s, 1H)
Using the procedure described for Example 11, additional compounds described herein may be prepared by substituting the indicated intermediate, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000257_0001
Cpd Intermediate and Data
Intermediate 70: LC-MS: 366.1 [M-H]", RT 0.85 min. H NMR (500 MHz, DMSO-cfe) δ ppm 2.16 - 2.27 (m, 2H), 2.47 - 2.49 (m, 2H), 2.64 (t, 7=5.2 Hz, 3H), 3.02 (t, 7=7.3
103 Hz, 2H), 3.19 - 3.30 (m, 2H), 4.57 (t, 7=7.9 Hz, 2H), 7.25 (ddd, 7=8.0, 7.0, 1.1 Hz, 1H), 7.31 (ddd, 7=8.2, 7.1, 1.1 Hz, 1H), 7.69 (d, 7=8.2 Hz, 1H), 7.71 (d, 7=7.9 Hz, 1H), 8.85 (br. s, 2H), 12.65 (s, 1H), 13.87 (s, 1H), 16.33 (br. s, 1H)
Intermediate 71 : LC-MS: 380.1 [M-H]", RT 0.87 min. !H NMR (500 MHz, DMSO- ) δ ppm 1.98 - 2.09 (m, 2H), 2.20 - 2.28 (m, 2H), 2.43 - 2.48 (m, 2H), 2.54 (t, 7=5.5 Hz,
104 3H), 2.93 - 2.98 (m, 2H), 3.00 (t, 7=7.3 Hz, 2H), 4.41 (t, 7=7.6 Hz, 2H), 7.19 - 7.24 (m, 1H), 7.25 - 7.30 (m, 1H), 7.67 - 7.71 (m, 2H), 8.84 (br. s, 2H), 12.62 (s, 1H), 13.87 (s, 1H), 16.34 (br. s, 1H)
Intermediate 71 : LC-MS: 394.3 [M-H]", RT 0.87 min. !H NMR (500 MHz, CDC13) δ ppm 2.03 - 2.15 (m, 2H), 2.19 - 2.29 (m, 2H), 2.44 - 2.49 (m, 2H), 2.74 (d, 7=4.7 Hz,
105
6H), 3.02 (t, 7=7.3 Hz, 2H), 3.10 - 3.19 (m, 2H), 4.38 (t, 7=7.6 Hz, 2H), 7.20 - 7.24 (m, 1H), 7.28 (td, 7=7.6, 0.9 Hz, 1H), 7.66 - 7.71 (m, 2H), 10.39 (br. s, 1H).
Intermediate 70: LC-MS: 380.3 [M-H]", RT 0.85 min. H NMR (500 MHz, DMSO-cfe) δ ppm 2.20 - 2.27 (m, 2H), 2.45 - 2.49 (m, 2H), 2.90 (br. s, 6 H), 3.05 (t, 7=7.3 Hz, 2H),
106 3.34 - 3.41 (m, 2H), 4.68 - 4.74 (m, 2H), 7.23 - 7.27 (m, 1H), 7.29 - 7.34 (m, 1H), 7.70 (d, 7=7.6 Hz, 1H), 7.75 (d, 7=8.2 Hz, 1H), 10.71 (br. s, 1H), 12.65 (br. s, 1H), 13.87 (s, 1H), 16.30 (br. s, 1H)
Example 12 (Compound 53)
4-Hydroxy-8-(3-hydroxypropyl)-2-oxo-l, 2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
Steps 1-2: Methyl 8-(3-((tert-butyldimethylsilyl)oxy)propyl)- l-(2,4-dimethoxybenzyl)-4- hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3- carboxylate
The title compound was prepared using the 2-step procedure described for Example 1 (steps
2-3) starting from l-(3-((tert-butyldimethylsilyl)oxy)propyl)-5, 6,7,8- tetrahydrocyclohepta[c]pyrazol-4(lH)-one (Intermediate 33).
LC-MS: 598.3 [M+H]+, RT 1.74 min. H NMR (500 MHz, OMSO-d6) δ ppm 0.00 (s, 6H), 0.85 (s, 9H), 1.80 - 1.88 (m, 2H), 2.02 - 2.12 (m, 2H), 2.61 - 2.70 (m, 2H), 3.31 - 3.33 (m, 2H), 3.48 (t, 7=6.03 Hz, 2H), 3.72 (s, 3H), 3.76 (s, 3H), 3.82 (s, 3H), 4.16 (t, 7=6.00 Hz, 2H), 5.02 (s, 2H), 6.39 - 6.63 (m, 3H), 7.08 (s, 1H), 13.44 (s, 1H)
Steps 3-4: l-(2,4-Dimethoxybenzyl)-4-hydroxy-8-(3-hydroxypropyl)-2-oxo-l, 2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
TBAF (1 M THF, 1 mL, 1 mmol) was added to a solution of methyl 8-(3-((tert- butyldimethylsilyl)oxy)propyl)-l-(2,4-dimethoxybenzyl)-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylate (0.3 g, 0.5 mmol) in THF (5 mL). The mixture was stirred at room temperature for 1 h then concentrated under reduced pressure. The residue was then dissolved in EtOAc (5 mL), and lithium iodide (0.2 g, 1.5 mmol) was added. The mixture was stirred at 60 °C for 2 h then cooled to room temperature. The mixture was diluted with CH2CI2 and washed with 1 M HC1. The organic phase was dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50-100% EtOAc in hexanes) to afford the title compound (80 mg, 34%).
LC-MS: 470.4 [M+H]+, RT 1.24 min. !H NMR (500 MHz, OMSO-d6) δ ppm 1.51 - 1.61 (m, 4H), 1.71 - 1.81 (m, 2H), 1.86 - 1.96 (m, 2H), 3.28 (t, 7=5.83 Hz, 2H), 3.72 (s, 3H), 3.74 (s, 3H), 4.07 (t, 7=6.82 Hz, 2H), 4.55 (br. s, 2H), 6.36 - 6.59 (m, 3H), 6.79 - 6.88 (m, 2H)
Step 5: 4-Hydroxy- 8-(3 -hydroxypropyl)-2-oxo- 1 ,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
A mixture of l-(2,4-dimethoxybenzyl)-4-hydroxy-8-(3-hydroxypropyl)-2-oxo-l ,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid (80 mg, 0.17 mmol), triisopropylsilane (1 mL) and TFA (1 mL) was stirred at room temperature for 1 h.
The mixture was concentrated under reduced pressure. The residue was dissolved in methanol (2 mL) and stirred at room temperature for 3 h. The mixture was concentrated, and the crude residue was triturated with Et20. The precipitate was removed by filtration, rinsed with Et20, and dried to afford the title compound (18 mg, 33%).
LC-MS: 318.0 [M-H]~, RT 0.90 min. H NMR (500 MHz, DMSO-cfe) δ ppm 1.86 - 1.97 (m, 4H), 2.53 - 2.59 (m, 2H), 2.64 - 2.70 (m, 2H), 3.01 - 3.06 (m, 2H), 4.10 - 4.15 (m, 2H), 8.21 (s, 1H), 12.43 (br. s, 1H), 13.87 (br. s, 1H)
Using the procedure described for Example 12, additional compounds described herein may be prepared by substituting the indicated intermediate, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000259_0001
Example 13 (Compound 39)
4-Hydroxy-8-methyl-2-oxo-2,6,7,8-tetrahydro-lH-pyrazolo[4',3':4,5]oxepino[3,2-b]pyridine-
3-carboxylic acid
Step 1: 5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-l-methyl-lH-pyrazole
n-BuLi (2.5 M hexanes, 27 niL, 67 mmol) was added dropwise over 15 min to a solution of
1 -methyl- lH-pyrazole (5.0g, 60.9 mmol) in THF (100 mL) at -78 °C. After stirring at -78
°C for 1 h, (2-bromoethoxy)(tert-butyl)dimethylsilane (13 mL, 60.3 mmol) was added dropwise. After stirring at -78 °C for 0.5 h, the cooling bath was removed, and the mixture was allowed to warm to room temperature. After stirring at room temperature for 12 h, the reaction was quenched with saturated aqueous NH4C1 solution and poured into ¾0. The aqueous layer was extracted with Et20. The organic phases were combined, washed with brine, dried over MgS04, filtered, and concentrated. The residue purified by silica gel column chromatography (0-20% EtOAc in hexanes) to afford of the title compound (2.4 g, 16%). lH NMR (500 MHz, OMSO-d6) δ ppm -0.02 (s, 6H), 0.83 (s, 9H), 2.80 (t, 7=6.50 Hz, 2H), 3.73 (s, 3H), 3.79 (t, 7=6.54 Hz, 2H), 6.05 (d, 7=1.80 Hz, 1H), 7.27 (d, 7=1.81Hz, 1H)
Step 2: 5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-4-iodo- 1-methyl- lH-pyrazole
N-iodosuccinimide (94 mg, 0.42 mmol) was added to a solution of 5-(2-((tert- butyldimethylsilyl)oxy)ethyl)-l -methyl- lH-pyrazole (100 mg, 0.42 mmol) in DMF (1 mL).
After stirring at room temperature for 1 h, the solution was cooled to 0 °C, and ¾0 (5 mL) was added. The solid was filtered, rinsed with ¾0 and dried with under a N2 stream to afford the title compound (135 mg, 88%).
LC-MS: 367.6 [M+H]+, RT 1.67 min. !H NMR (500 MHz, OMSO-d6) δ ppm -0.06 (s, 6H), 0.76 - 0.82 (m, 9H), 2.86 (t, 7=6.40 Hz, 2H), 3.74 (t, 7=6.40 Hz, 2H), 3.83 (s, 3H), 7.42 (s, 1H)
Step 3: 5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole
i-PrMgCl (2M THF, 1.3 mL, 2.6 mmol) was added to a solution of 5-(2-((tert- butyldimethylsilyl)oxy)ethyl)-4-iodo-l -methyl- lH-pyrazole (0.89 g, 2.4 mmol) in THF (12 mL) at room temperature. After stirring for 30 min, 2-methoxy-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (0.5 mL, 2.6 mmol) was added. After stirring for 30 min, the reaction was quenched with saturated aqueous NH4CI and poured into ¾0. The aqueous layer was extracted with Et20. The organic extracts were combined, washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure to afford the title compound (0.81 g, 93%). H NMR (500 MHz, OMSO-d6) δ ppm -0.07 (s, 6H), 0.80 (s, 9H), 1.24 (s, 12H), 2.98 (t, 7=6.62 Hz, 2H), 3.76 (t, 7=6.60 Hz, 2H), 3.76 (s, 3H), 7.44 (s, 1H)
Step 4: Benzyl 2,4-bis(benzyloxy)-6-(5-(2-((tert-butyldimethylsilyl)oxy)ethyl) -methyl-lH- pyrazol-4-yl)-5-hydroxynicotinate
A solution of 5-(2-((tert-butyldimethylsilyl)oxy)ethyl) -methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (0.19 g, 0.52 mmol), benzyl 2,4-bis(benzyloxy)-6-bromo-5- hydroxynicotinate (0.25 g, 0.47 mmol), tris(dibenzylideneacetone)dipalladium (22 mg, 0.024 mmol), tri-i<?ri-butylphosphonium tetrafluoroborate (14 mg, 0.05 mmol), K2CO3 (1M, 1.5 mL, 1.5 mmol), and dioxane (1.5 mL) was heated at 90 °C for 12 h. The mixture was cooled to room temperature and partitioned between ¾0 and EtOAc. The organic phase was separated, washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% EtOAc in hexanes) to afford 0.21 g of the title compound.
LC-MS: 680.3 [M+H]+, RT 1.82 min. !H NMR (500 MHz, DMSO- ) δ ppm -0.12 (s, 6H), 0.75 (s, 9H), 3.25 - 3.30 (m, 2H), 3.76 - 3.81 (m, 2H), 3.84 (s, 3H), 5.11 (s, 2H), 5.24 (s, 2H), 5.31 (s, 2H), 7.22 - 7.41 (m, 15 H), 8.07 (s, 1H), 9.15 (s, 1H)
Steps 5-6: Benzyl 2,4-bis(benzyloxy)-8-methyl-7,8-dihydro-6H- pyrazolo[4',3':4,5]oxepino[3,2-b]pyridine-3-carboxylate
TBAF (1M THF, 1.5 mL, 1.5 mmol) was added to a solution of benzyl 2,4-bis(benzyloxy)-6- (5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-l-methyl-lH-pyrazol-4-yl)-5-hydroxynicotinate
(500 mg, 0.73 mmol) in THF (5 mL). The mixture was stirred at room temperature for 1 h then triphenylphosphine (185 mg, 0.73 mmol) and diisopropyl azodicarboxylate (0.13 mL,
0.73 mmol) were added. After stirring at room temperature for 1 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to afford the title compound (100 mg, 13%).
LC-MS: 548.1 [M+H]+, RT 1.62 min. H NMR (500 MHz, CDC13) δ ppm 3.16 (t, 7=5.24 Hz, 2H), 3.86 (s, 3H), 4.26 (t, 7=5.24 Hz, 2H), 5.23 (s, 2H), 5.29 (s, 2H), 5.47 (s, 2H), 7.28 - 7.51 (m, 15 H), 8.09 (s, 1H)
Step 7: 4-Hydroxy-8-methyl-2-oxo-2,6,7,8-tetrahydro-lH-pyrazolo[4',3':4,5]oxepino[3,2- b]pyridine-3-carboxylic acid
A mixture of benzyl 2,4-bis(benzyloxy)-8-methyl-7,8-dihydro-6H- pyrazolo[4',3':4,5]oxepino[3,2-b]pyridine-3-carboxylate (100 mg, 0.18 mmol), 10% Pd/C (20 mg), and EtOAc (4 mL) was stirred under an atmosphere of ¾ for 2 h. The mixture was filtered through Celite and concentrated under reduced pressure to afford the title compound (6 mg, 13%). LC-MS: 278.0 [M+H]+, RT 0.85 min. H NMR (500 MHz, OMSO-d6) δ ppm 3.25 - 3.30 (m, 2H), 3.82 (s, 3H), 4.26 - 4.32 (m, 2H), 8.31 (s, 1H)
Example 14 (Compound 51)
7-Hydroxy-2,3-dimethyl-9-oxo-2,4,5,6,9, 10-hexahydropyrazolo[4',3':6,7]cycloliepta[l,2- b]pyridine-8-carboxylic acid
Step 1: tert-Butyl 5-allyl-6-(4-bromo-l,5-dimethyl-lH-pyrazol-3-yl)-2,4-difluoronicotinate
TMPMgCl-LiCl (1M THF, 6.0 mL, 6 mmol) was added to a solution of 4-bromo-l,5- dimethyl-lH-pyrazole (0.9 g, 5.1 mmol) in THF (20 mL) at 0 °C. After stirring at 0 °C for 1 h, zinc (II) chloride (1M in Et20, 6 mL, 6.0 mmol) was added, and the reaction was allowed to warm to room temperature. After stirring at room temperature for 0.5 h, tert-butyl 5-allyl- 6-bromo-2,4-difluoronicotinate (1.7 g, 5.0 mmol), Pd2(dba)3 (234 mg, 0.25 mmol), and P(i- Bu)3 HBF4 (150 mg, 0.5 mmol) were added, and the mixture was stirred at 50 °C for 2.5 h. The mixture was cooled to room temperature and quenched with saturated aqueous NH4C1 (10 mL), poured into ¾0, and extracted with Et20. The organic extracts were combined, washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-60% EtOAc in hexanes) to afford the title compound (900 mg, 41%).
LC-MS: 428.2 [M+H]+, RT 1.64 min. !H NMR (500 MHz, CDC13) δ ppm 1.61 (s, 9H), 2.32 (s, 3H), 3.56 (d, 7=5.99 Hz, 2H), 3.86 (s, 3H), 4.95 - 5.04 (m, 2H), 5.79 - 5.92 (m, 1H)
Step 2: tert-Butyl 7,9-difluoro-2,3-dimethyl-2,4,5,6- tetrahydropyrazolo [4' ,3 ' : 6,7]cyclohepta[ 1 ,2-b]pyridine- 8-carboxylate
9-BBN (1M in Et20, 3 mL) was added to a solution of tert-butyl 5-allyl-6-(4-bromo-l,5- dimethyl-lH-pyrazol-3-yl)-2,4-difluoronicotinate (300 mg, 0.7 mmol) in THF (4 mL). After stirring at room temperature for 1 h, aqueous K2CO3 (1M, 4 mL) and PdCl2(dppf) (140 mg, 0.3 mmol) were added. The mixture heated at 50 °C for 2 h in a sealed vessel. The mixture was cooled to room temperature, poured into ¾0 and extracted with EtOAc. The organic extracts were combined washed with brine, dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-
50% EtOAc in hexanes) to afford the title compound (38 mg, 16%).
LC-MS: 350.3 [M+H]+, RT 1.40 min. !H NMR (500 MHz, CDC13) δ ppm 1.60 (s, 9H), 2.03 - 2.12 (m, 2H), 2.28 (s, 3H), 2.74 - 2.79 (m, 2H), 2.85 - 2.91 (m, 2H), 4.07 (s, 3H)
Step 3: 7-Hvdroxv-2,3-dimethvl-9-oxo-2,4,5,6,9,10- hexahydropyrazolo[4',3':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
KOtBu (1.7 M THF, 0.3 mL, 0.51 mmol) was added to a solution of tert-butyl 7,9-difluoro- 2,3-dimethyl-2,4,5,6-tetrahydropyrazolo[4',3':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate (38 mg, 0.11 mmol) in THF (2 mL) at 0 °C. After stirring at 0 °C for 1 h, the mixture was concentrated and TFA (1 mL) was added. After stirring at room temperature for 1 h, the mixture was concentrated under reduced pressure. The precipitate was removed by filtration and rinsed with Et20 to afford the title compound (28 mg, 81%).
LC-MS: 290.0 [M+H]+, RT 1.22 min. !H NMR (500 MHz, OMSO-d6) δ ppm 1.87 - 1.95 (m, 2H), 2.22 (s, 3H), 2.65 - 2.70 (m, 2H), 2.70 - 2.74 (m, 2H), 3.86 (s, 3H), 14.07 (br. s, 1H)
Example 15 (Compound 83)
3-Ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid Steps 1-3: Benzyl 10-(2,4-dimethoxybenzyl)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
2,4-Dimethoxybenzylamine (0.2 mL, 1.33 mmol) and NEt3 (0.67 mL, 4.8 mmol) was added to a solution of l-ethyl-2,6-dimethyl-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(lH)-one
(Intermediate 46, 255 mg, 1.24 mmol) in CH2CI2 (5 mL) at room temperature. The mixture was cooled to 0 °C before TiCl4 (1M in CH2CI2, 1.2 mL, 1.2 mmol) was added over 30 min. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with CH2CI2 then quenched with saturated aqueous NaHCC>3. The organic phase was separated using a PTFE phase separator and dried over Na2S04. The solvent was concentrated under reduced pressure to give the intermediate imine (-500 mg, -quant.) as a brown foam, which was taken directly into the next step.
N-(2,4-dimethoxybenzyl)-l-ethyl-2,6-dimethyl-5,6,7,8-tetrahydrocyclohepta[d]imidazol- 4(lH)-imine (-500 mg, 1.24 mmol) and trimethyl methanetricarboxylate (943 mg, 4.96 mmol) were mixed together in PI12O (4 mL). The mixture was placed onto a pre-heated heat block at 230 °C and heated for 10 min after initial bubbling of MeOH was observed. The mixture was cooled to room temperature and purified by silica gel column chromatography (0-10% MeOH in CH2CI2) to afford the cycloadduct as a light brown foam (-269 mg, mixed with starting imidazole ketone).
Methyl 10-(2,4-dimethoxybenzyl)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate (-269 mg, containing starting imidazole ketone) and benzyl alcohol (1.0 mL, 9.7 mmol) were heated to 135 °C for 1 h. The mixture was cooled to room temperature and purified by silica gel column chromatography (0-25% EtOAc in CH2CI2) to afford the title compound (187 mg, 27% over 3 steps) as a light tan foam. H NMR (500 MHz, acetone-ifc) δ ppm 0.73 (d, 7=7.3 Hz, 3H) 1.25 (t, 7=7.3 Hz, 3H) 2.04 - 2.11 (m, IH) 2.15 - 2.23 (m, IH) 2.36 (s, 3H) 2.66 (dt, 7=16.3, 6.7 Hz, IH) 2.74 (dt, 7=16.4, 7.6 Hz, IH) 3.68 (s, 3H) 3.69 - 3.75 (m, IH) 3.71 (s, 3H) 3.96 (q, 7=7.3 Hz, 2H) 5.39 (d, 7=13.8 Hz, IH) 5.42 (d, 7=13.8 Hz, IH) 5.68 (d, 7=15.7 Hz, IH) 6.02 (d, 7=15.7 Hz, IH) 6.28 (dd, 7=8.4, 2.4 Hz, IH) 6.39 (d, 7=2.5 Hz, IH) 6.56 (d, 7=8.2 Hz, IH) 7.28 - 7.44 (m, 3H) 7.54 - 7.63 (m, 2H) 13.90 (s, IH)
Step 4-5: 3-Ethvl-7-hydroxv-2,6-dimethvl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
i-Pr3SiH (2.0 mL) followed by TFA (1.5 mL) were added to benzyl 10-(2,4- dimethoxybenzyl)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,6a,9,10,10a- octahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate (187 mg, 0.34 mmol).
The mixture was heated at 60 °C for 90 min. Upon complete consumption of starting material, TFA was concentrated under reduced pressure. HC1 (2M in Et20, 3.0 mL) was added to the residue resulting in the formation of a precipitate. The mixture was diluted with Et20 and stirred for 30 min at room temperature. The solid was removed by filtration and washed with Et20 to afford the title compound (95 mg, 87%) as an off white solid.
LC-MS 316.2 [M-H]", RT 1.32 min. !H NMR (500 MHz, methanol-^) δ ppm 1.07 (d, 7=7.6 Hz, 3H) 1.42 (t, 7=7.4 Hz, 3H) 1.77 - 1.96 (m, IH) 2.24 - 2.39 (m, IH) 2.68 (s, 3H) 2.92 - 3.15 (m, 2H) 3.87 (quin, 7=6.8 Hz, IH) 4.21 (q, 7=7.4 Hz, 2H)
Using the procedure described for Example 15, additional compounds described herein may be prepared by substituting the indicated intermediate, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000264_0001
Example 16 (Compound 75)
2-(3-(Dimethylamino)propyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
Step 1: Methyl 2-(3-(benzyloxy)propyl)-l-ethyl-4-oxo-l,4,5, 6,7,8- hexahydrocyclohepta[d]imidazole-5-carboxylate
NaHMDS (2M in THF, 6.4 mL, 12.8 mmol) was added to a solution of 2-(3-
(benzyloxy)propyl)-l-ethyl-5,6,7,8-tetrahydrocyclohepta[d]imidazol-4(lH)-one (Intermediate
14, 2.2 g, 6.75 mmol) in dimethyl carbonate (22 mL) at 0 °C, and the mixture was stirred at 0
°C for 30 min. The reaction was quenched with dilute aqueous HC1. The mixture was then made basic with aqueous NaHCC>3 and extracted with EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under under reduced pressure to afford the title compound (2.64 g, 100%) as a yellow oil.
LC-MS: 385.0 [M+H]+, RT 1.02 min
Steps 2-3: Methyl 2-(3-((tert-butyldiphenylsilyl)oxy)propyl)-l-ethyl-4-oxo-l,4,5,6,7,8- hexahydrocyclohepta[d]imidazole-5-carboxylate
BBr3 (lM in CH2CI2, 19 mL, 19 mmol) was added to a solution of the product of step 1 (2.55 g, 6.64 mmol) in CH2C12 (90 mL) at -78 °C. After stirring at -78 °C for 40 min, a solution of
K2CO3 (10 g) in H2O (50 mL) was added. The solvents were removed under reduced pressure. The residue was extracted with CH2Cl2/EtOH (2:1) and filtered. The filtrate was concentrated under reduced pressure. The residue was suspended in CH2CI2 and filtered to remove any particulate matter. The filtrate was concentrated under reduced pressure to afford crude alcohol intermediate (2.56 g).
Imidazole (820 mg, 12 mmol) and TBDPSC1 (2.6 mL, 10 mmol) were added to a solution of the alcohol intermediate in CH2CI2 (30 mL). The mixture was stirred at room temperature for 30 min. The mixture was then filtered, and the filtrate was purified by silica gel column chromatography (20-50% EtOAc in CH2C12) to afford the title compound (2.73 g, 77%) as a yellow oil.
LC-MS: 534.4 [M+H]+, RT 1.37 min
Steps 4-6: Methyl 2- (3 - ((tert-butyldiphenylsilyl)oxy)propyl) - 10- (2, 4-dimethoxybenzyl)- 3 - ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8- carboxylate
The product of step 3 (2.73 g, 4.45 mmol), CHCI3 (13 mL), 2,4-dimethoxybenzylamine (DMB-NH2, 1.35 mL, 8.9 mmol), Si(OEt)4 (1.05 mL, 4.7 mmol), and HOAc (3 drops) were heated at 85 °C for 15 h. The mixture was loaded directly onto a basic alumina column and elution with (0-50% EtOAc in CH2C12) yielded the crude DMB-enamine (2.65 g) as an orange oil.
Pyridine (500 μί, 6.3 mmol), a solution of monomethylmalonyl chloride (640 μί, 5.9 mmol) in CH2CI2 (12 mL), and DMAP (50 mg, 0.41 mmol) were added, in sequence, to a solution of the crude enamine (2.45 g, 3.58 mmol) in CH2CI2 (15 mL) at 0 °C. The mixture was stirred at room temperature for 1 h. The mixture was cooled to 0 °C, and the addition sequence above was repeated. The mixture was stirred at room temperature for another hour and was concentrated under reduced pressure. The residue was partitioned between ether and aqueous KHSO4. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure to afford the crude intermediate as an orange oil.
The intermediate was stirred in NaOMe (0.5 M in MeOH, 50 mL, 25 mmol) at room temperature for 3 h. The mixture was partitioned between aqueous Na¾P04 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (20-50% EtOAc in CH2CI2) afforded the title compound (1.95 g, 63% over 3 steps) as an orange semi-solid.
!H NMR (500 MHz, acetone-ifc): δ ppm 1.11 (s, 9H), 1.21 (t, 7=7 Hz, 3H), 2.00 (m, 2H), 2.16 (m, 2H), 2.41 (m, 2H), 2.63 (t, 7=7 Hz, 2H), 2.80 (t, 7=7 Hz, 2H), 3.65 (s, 3H), 3.67 (s, 3H), 3.78 (t, 7=6 Hz, 2H), 3.86 (s, 3H), 3.94 (q, 7=7 Hz, 2H), 5.74 (s, 2H), 6.26 (dd, 7=8.5, 2.5 Hz, 1H), 6.35 (d, 7=2 Hz, 1H), 6.48 (d, 7=8.5 Hz, 1H), 7.4-7.5 (m, 6H), 7.70 (m, 4H), 13.83 (s, 1H)
Step 7: Methyl 7-(benzyloxy)-2-(3-((tert-butyldiphenylsilyl)oxy)propyl)-10-(2,4- dimethoxybenzyl)-3-ethyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylate
The product of step 6 (1.95 g, 2.6 mmol), CS2CO3 (1.7 g, 5.2 mmol), benzyl bromide (465 μί, 3.9 mmol), and DMF (10 mL) were stirred at room temperature for 30 min. The mixture was partitioned between ¾0 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (20-40% EtOAc in CH2CI2) afforded the title compound (1.67 g, 77%) as an orange semisolid.
H NMR (500 MHz, acetone-ifc): δ ppm 1.07 (s, 9H), 1.20 (t, 7=7.5 Hz, 3H), 2.00 (m, 2H), 2.13 (pentet, 7=6.5 Hz, 2H), 2.35 (m, 2H), 2.58 (t, 7=7.5 Hz, 2H), 2.80 (t, 7=7.5 Hz, 2H), 3.65 (s, 3H), 3.68 (s, 3H), 3.79 (t, 7=6 Hz, 2H), 3.81 (s, 3H), 3.94 (q, 7=7 Hz, 2H), 5.14 (s, 2H), 5.77 (s, 2H), 6.26 (dd, 7=8.5, 2.5 Hz, 1H), 6.35 (d, 7=2.5 Hz, 1H), 6.48 (d, 7=8.5 Hz, 1H), 7.4-7.55 (m, 11H), 7.70 (m, 4H) Step 8: Methyl 7-(benzyloxy)- 10-(2,4-dimethoxybenzyl)-3-ethyl-2-(3-hydroxypropyl)-9-oxo- 3,4,5,6,9, 10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
The product of step 7 (1.65 g, 1.95 mmol), THF (6 niL), and TBAF (1M in THF, 3 mL, 3 rnmol) were stirred at room temperature for 30 min. The reaction mixture was partitioned between aqueous NH4C1 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (5-
10% MeOH in CH2C12) afforded the title compound (1.115 g, 95%) as a semi-solid.
H NMR (500 MHz, acetone-ifc): δ ppm 1.22 (t, 7=7 Hz, 3H), 1.95 (pentet, 7=6.5 Hz, 2H), 2.13 (m, 2H), 2.35 (m, 2H), 2.56 (t, 7=7.5 Hz, 2H), 2.77 (t, 7=7.5 Hz, 2H), 3.60 (m, 2H), 3.71 (s, 3H), 3.76 (s, 3H), 3.82 (s, 3H), 3.97 (q, 7=7.5 Hz, 2H), 5.14 (s, 2H), 5.83 (s, 2H), 6.29 (dd, 7=8.5, 2Hz, IH), 6.42 (d, 7=2 Hz, IH), 6.47 (d, 7=8 Hz, IH), 7.38-7.46 (m, 3H), 7.52 (m, 2H)
Step 9: Methyl 7-(benzyloxy)-10-(2,4-dimethoxybenzyl)-3-ethyl-2-(3-
((methylsulfonyl)oxy)propyl)-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylate
The product of step 8 (300 mg, 0.5 mmol), MsCl (78 μί, 1.0 mmol), DIPEA (180 μί, 1.1 mmol), and CH2CI2 (3 mL) were stirred at 0 °C for 1 h. The mixture was partitioned between aqueous HC1 and CH2CI2. The organic layer was dried over MgS04, filtered, and
concentrated under reduced pressure to afford the title compound (290 mg, 85%) as a white solid.
H NMR (500 MHz, acetone-ifc): δ ppm 1.23 (t, 7=7 Hz, 3H), 2.17 (m, 4H), 2.36 (m, 2H),
2.60 (m, 2H), 2.82 (m, 2H, obscured by H20), 3.06 (s, 3H), 3.73 (s, 3H), 3.79 (s, 3H), 3.82 (s, 3H), 4.01 (m, 2H), 4.30 (t, 7=6.5 Hz, 2H), 5.14 (s, 2H), 5.76 (br. s, 2H), 6.31 (dd, 7=8.5, 2.5 Hz, IH), 6.45 (d, 7=2.5 Hz, IH), 6.51 (d, 7=8 Hz, IH), 7.38-7.46 (m, 3H), 7.52 (m, 2H)
Step 10: Methyl 7-(benzyloxy)- 10-(2,4-dimethoxybenzyl)-2-(3-(dimethylamino)propyl)-3- ethyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
The product of step 8 (100 mg, 0.15 mmol) and Me2NH (2M in THF, 1 mL, 2 mmol) were heated at 55 °C for 1 h. The mixture was partitioned between aqueous NaOH and CH2CI2.
The organic layer was dried over MgS04, filtered, and concentrated under vacuum.
Purification by silica gel column chromatography (0-2% NH4OH in 4:1 CH2Cl2/MeOH) afforded the title compound (46 mg, 49%) as a white solid.
!H NMR (500 MHz, acetone- ): δ ppm 1.22 (t, 7=7 Hz, 3H), 1.87 (pentet, 7=7 Hz, 2H), 2.15 (m, 8H), 2.25 (m, 2H), 2.36 (m, 2H), 2.60 (t, 7=7.5 Hz, 2H), 2.69 (t, 7=7.5 Hz, 2H), 3.71 (s, 3H), 3.77 (s, 3H), 3.81 (s, 3H), 3.98 (q, 7=7.5 Hz, 2H), 5.14 (s, 2H), 5.84 (s, 2H), 6.29 (dd, 7=8.5, 2.5 Hz, IH), 6.42 (d, 7=2.5 Hz, IH), 6.47 (d, 7=8 Hz, IH), 7.38-7.46 (m, 3H), 7.52 (m, 2H) Steps 11-12: 2-(3-(Dimethvlarnino)propvl)-3-ethvl-7-hydroxv-9-oxo-3,4,5,6,9J0- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride
The product of step 9 (45 mg, 0.071 mmol), TFA (0.3 mL), and TIPSH (0.1 mL) were stirred at room temperature for 90 min. The volatiles were removed under a N2 stream. The residue was triturated with 1M HC1 in ether. The volatiles were removed under a N2 stream. The residue was dissolved in MeOH and filtered to remove particulate impurities. The filtrate was dried under a N2 stream, and EtOAc (0.5 mL) and Lil (50 mg, 0.36 mmol) were added to the residue. The mixture was heated at 60 °C for 2 h. The mixture was partitioned between aqueous HC1 and ether. The aqueous layer was made basic with K2CO3 and filtered. After washing with THF, the solids were dissolved in MeOH and made acidic with HCl/ether. The particulate impurities were removed by filtration, and the filtrate was concentrated under a N2 stream. The resulting solid was washed with acetone to afford the title compound (6 mg,
20%) as an off-white solid.
LC-MS: 375.1 [M+H]+, RT 0.76 min. !H NMR (500 MHz, MeOH-<¾): δ ppm 1.41 (br. s, 3H), 2.1 (br. s, 2H), 2.36 (br. s, 2H), 2.90 (br. s, 2H), 3.06 (br. s, 6H), 3.15 (br. s, 4H), 3.37 (br. s, 2H), 4.15 (br. s, 2H)
Using the procedure described for Example 16, additional compounds described herein may be prepared by substituting the indicated intermediate, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000268_0001
Example 17 (Compound 99)
ll-((Dimethylamino)methyl)-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido [2' , 3 ' : 3 ,4] cyclohepta [ 1 ,2-b] indole- 3 -carboxylic acid hydrochloride
Steps 1-2: Methyl 1 l-(((tert-butyldimethylsilyl)oxy)methyl)-l-(2,4-dimethoxybenzyl)-4- hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3- carboxylate
2-(((tert-Butyldimethylsilyl)oxy)methyl)-5-methyl-6,7,8,9-tetrahydrocyclohepta[b]indol- 10(5H)-one (Intermediate 50, 335 mg, 0.92 mmol), 2,4-dimethoxybenzylamine (DMB-NH2, 150 μί, 0.97mmol), Et3N (0.4 mL, 2.87 mmol), CH2C12 (3.7 mmol), and T1CI4 (1M in CH2CI2, 0.6 mL, 0.6 mmol) were stirred at room temperature for 15 h. The reaction mixture was quenched with aqueous NaHC03. The mixture was partitioned between ether and ¾0. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure to afforde 468 mg of the crude DMB imine.
Trimethyl methanetricarboxylate (300 mg, 1.58 mmol) was added to a solution of the DMB imine in diphenyl ether (1.8 mL). The mixture was heated at 230 °C in a pre -heated bath for 8 min. The mixture was cooled to room temperature and purified by silica gel column chromatography (5-60% EtOAc in hexanes) followed by trituration with hexanes/ether (1 : 1) to afford the title compound (145 mg, 25%) as a white solid.
H NMR (500 MHz, acetone-ifc): δ ppm 0.14 (s, 3H), 0.16 (s, 3H), 0.98 (s, 9H), 1.59 (m, 1H), 2.23 (m, 2H), 2.61 (m, 1H), 3.01 (m, 2H), 3.50 (s, 3H), 3.71 (s, 3H), 3.84 (s, 3H), 3.89 (s, 3H), 4.86 (m, 2H), 5.13 (d, 7=15.5 Hz, 1H), 5.72 (d, 7=15.5 Hz, 1H), 6.35 (m, 2H), 6.59 (d, 7=9 Hz, 1H), 7.26 (dd, 7=8.5, 1.5 Hz, 1H), 7.43 (br. s, 1H), 7.49 (d, 7=8.5 Hz, 1H), 13.85 (s, 1H)
Step 3: Methyl l-(2,4-dimethoxybenzyl)-4-hydroxy-l l-(hydroxymethyl)-8-methyl-2-oxo- l,2,5,6,7,8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylate
The product of step 2 (143 mg, 0.22 mmol), THF (1 mL), and TBAF (1M in THF, 1 mL, 1 mmol) were stirred at room temperature for 1 h. The mixture was purified by silica gel column chromatography (50-100% EtOAc in CH2CI2) to afford the title compound (95 mg,
81%) as a white solid.
!H NMR (500 MHz, OMSO-d6): δ ppm 1.32 (sextet, 7=7.5 Hz, 1H), 2.16 (m, 2H), 2.91 (m, 2H), 3.02 (m, 1H), 3.49 (s, 3H), 3.66 (s, 3H), 3.77 (s, 3H), 3.83 (s, 3H), 4.56 (d, 7=5.5 Hz, 2H), 4.94 (d, 7=14.5 Hz, 1H), 5.15 (t, 7=5.5 Hz, 1H), 5.52 (d, 7=14.5 Hz, 1H), 6.36 (m, 2H), 6.44 (m, 1H), 7.19 (dd, 7=8.5, 1 Hz, 1H), 7.29 (br. s, 1H), 7.51 (d, 7=8.5 Hz, 1H), 13.49 (s, 1H)
Step 4: l-(2,4-Dimethoxvbenzvl)-4-hvdroxv-l l-(hvdroxvmethvl)-8-methvl-2-oxo- l,2,5,6,7,8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid
The product of step 3 (150 mg, 0.29 mmol), Lil (126 mg, 0.94 mmol), and EtOAc (1 mL) were heated at 60 °C for 1 h. The mixture was partitioned between EtOAc and aqueous HC1.
The organic layer was washed with aqueous Na2S203 and brine, dried over MgS04, filtered, and concentrated under reduced pressure to afford the title compound (146 mg, 100%) as a yellowish solid.
LC-MS: 503.0 [M-H]~, RT 1.26 min
Step 5: l-(2,4-Dimethoxybenzyl)-l l-formyl-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido [2' , 3 ' : 3 ,4] cyclohepta[ 1 , 2-b] indole- 3 -carboxylic acid
The product of step 4 (144 mg, 0.38 mmol) was dissolved in CH2CI2 (3 mL) at room temperature. Mn02 (825 mg, 9.6 mmol) was added in three portions every 30 min. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to afford the title compound (104 mg, 72%) as a gray solid. LC-MS: 501.1 [M-H]", RT 1.35 min
Step 6: l-(2,4-Dimethoxybenzyl)-ll-((dimethylamino)methyl)-4-hydroxy-8-methyl-2-oxo- l,2,5,6,7,8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid
The product of step 5 (40 mg, 0.08 mmol), DCE (1.0 mL), HO Ac (10 μί, 0.17 mmol), Me2NH (2M in THF, 80 μί, 0.16 mmol), and NaBH(OAc)3 (30 mg, 0.14 mmol) were stirred at room temperature for 15 h. The mixture was diluted in MeOH/TFA. Reverse phase preparatory HPLC yielded the trifluoroacetate salt of the title compound (33 mg, 64%).
LC-MS: 530.2 [M-H]", RT 1.03 min.
Step 7: l l-((Dimethylamino)methyl)-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride
The product of step 6 (33 mg, 0.051 mmol), TFA (0.35 mL), and TIPSH (0.35 mL) were heated at 60 °C for 90 min. The volatiles were removed under a N2 stream, and the residue was triturated with 1M HCl in ether. The solids were removed by filtration and washed with
CH2Cl2/MeOH (9:1) to afford the title compound (10 mg, 47%) as an off-white solid.
LC-MS: 380.1 [M-H]", RT 0.87 min. !H NMR (500 MHz, DMSO-cfe): δ ppm 2.16 (m, 2H), 2.48 (m, 2H), 2.54 (s, 3H), 2.73 (s, 3H), 3.04 (t, 7=7 Hz, 2H), 3.79 (d, 7=4.5 Hz, 3H), 4.21 (s, 1H), 4.35 (s, 1H), 7.34 (td, 7=8, 1.5 Hz, 1H), 7.65 (dd, 7=14.5, 8.5 Hz, 1H), 7.84 (m, 1H)
Using the procedure described for Example 17, steps 6-7, additional compounds described herein may be prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000270_0001
Using the procedure described for Example 17, additional compounds described herein may be prepared by substituting the indicated intermediate, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000270_0002
Cpd Intermediate and Data
Intermediate 51: LC-MS: 408.2 [M+H]+, RT 0.49 min (1 minute method). H NMR (500 MHz, DMSO- ) 5 pm 1.83 - 1.96 (m, 2H), 2.03 - 2.14 (m, 2H), 2.16 - 2.25 (m, 2H), 2.41 (dd, 7=7.3, 5.4 Hz, 2H), 3.00 (t, 7=7.3 Hz, 2H), 3.20 - 3.32 (m, 2H), 3.43 -
91
3.53 (m, 2H), 4.05 (s, 3H), 4.93 (d, 7=5.0 Hz, 2H), 7.26 (t, 7=7.7 Hz, IH), 7.40 (d, 7=7.3 Hz, IH), 7.78 (d, 7=7.9 Hz, IH), 10.17 (br. s, IH), 12.78 (br. s, IH), 13.87 (s, IH), 16.35 (br. s, IH)
Intermediate 51: LC-MS: 366.1 [M-H]", RT 0.85 min. !H NMR (500 MHz, OMSO-d6) δ ppm 2.20 (quin, 7=6.8 Hz, 2H), 2.38 - 2.44 (m, 2H), 2.70 (t, 7=5.2 Hz, 3H), 3.00 (t,
94 7=7.3 Hz, 2H), 4.04 (s, 3H), 4.69 (t, 7=5.8 Hz, 2H), 7.25 (t, 7=7.5 Hz, IH), 7.34 (d, 7=7.3 Hz, IH), 7.74 (d, 7=7.3 Hz, IH), 9.20 (br. s, 2H), 12.79 (s, IH), 13.86 (s, IH), 16.36 (br. s, IH).
Intermediate 51: LC-MS: 380.2 [M-H]", RT 0.86 min. !H NMR (500 MHz, OMSO-d6) δ ppm 1.29 (t, 7=7.3 Hz, 3H), 2.15 - 2.25 (m, 2H), 2.37 - 2.44 (m, 2H), 3.00 (t, 7=7.3 Hz,
95 2H), 3.10 - 3.21 (m, 2H), 4.04 (s, 3H), 4.68 (t, 7=5.7 Hz, 2H), 7.25 (t, 7=7.7 Hz, IH), 7.36 (d, 7=6.6 Hz, IH), 7.74 (d, 7=7.6 Hz, IH), 9.14 (br. s, 2H), 12.79 (s, IH), 13.86 (s, IH), 16.34 (br. s, IH)
Intermediate 51: LC-MS: 394.2 [M-H]", RT 0.90 min. H NMR (500 MHz, OMSO-d6) δ ppm 0.95 (t, 7=7.4 Hz, 3H), 1.73 (sextet, 7=7.7 Hz, 2H), 2.17 - 2.24 (m, 2H), 2.41 (dd,
96 7=7.1, 5.5 Hz, 2H), 3.00 (t, 7=7.3 Hz, 2H), 3.02 - 3.10 (m, 2H), 4.03 (s, 3H), 4.69 (t, 7=5.7 Hz, 2H), 7.25 (t, 7=7.6 Hz, IH), 7.37 (d, 7=6.9 Hz, IH), 7.74 (d, 7=7.9 Hz, IH), 9.12 (br. s, 2H), 12.80 (s, IH), 13.86 (s, IH), 16.35 (br. s, IH)
Intermediate 52: LC-MS: 382.4 [M+H]+, RT 0.91 min. H NMR (500 MHz, DMSO-cfe) δ ppm 2.13 - 2.22 (m, 2H), 2.47 - 2.49 (m, 2H), 2.72 (d, 7=4.4 Hz, 6H), 3.07 (t, 7=7.3
107 Hz, 2H), 3.82 (s, 3H), 4.39 (d, 7=4.7 Hz, 2H), 7.35 (dd, 7=8.4, 1.4 Hz, IH), 7.74 (d, 7=8.2 Hz, IH), 7.83 (s, IH), 10.47 (br. s, IH), 12.61 (br. s, IH), 13.85 (s, IH), 16.32 (br. s, IH).
Intermediate 52: LC-MS: 394.2 [M-H]", RT 0.94 min. H NMR (500 MHz, OMSO-d6) δ ppm 1.29 (t, 7=7.3 Hz, 3H), 2.14 - 2.22 (m, 2H), 2.47 - 2.50 (m, 2H), 2.66 (d, 7=5.0 Hz, 3H), 2.99 - 3.05 (m, IH), 3.07 (t, 7=7.3 Hz, 2H), 3.13 - 3.24 (m, IH), 3.82 (s, 3H), 4.33
108
(dd, 7=12.9, 6.1 Hz, IH), 4.48 (dd, 7=12.9, 4.4 Hz, IH), 7.35 (dd, 7=8.4, 1.4 Hz, IH), 7.75 (d, 7=8.2 Hz, IH), 7.83 (d, 7=0.9 Hz, IH), 10.06 (br. s, IH), 12.60 (br. s, IH), 13.85 (s, IH), 16.31 (br. s, IH)
Intermediate 52: LC-MS: 408.5 [M+H]+, RT 0.94 min. H NMR (500 MHz, DMSO-cfe) δ ppm 1.82 - 1.95 (m, 2H), 1.97 - 2.08 (m, 2H), 2.12 - 2.23 (m, 2H), 2.47 - 2.49 (m,
109 2H), 3.06 (t, 7=7.3 Hz, 2H), 3.08 - 3.16 (m, 2H), 3.29 - 3.37 (m, 2H), 3.82 (s, 3H), 4.45 (d, 7=5.7 Hz, 2H), 7.37 (dd, 7=8.4, 1.1 Hz, IH), 7.73 (d, 7=8.2 Hz, IH), 7.86 (s, IH), 10.53 (br. s, IH), 12.60 (br. s, IH), 13.85 (s, IH), 16.31 (br. s, IH) Example 18 (Compound 13)
4-Hydroxy-2-oxo-2,5,6,7,9,10,ll,12-octahydro-lH- pyrido[3' 2'':6\7']cyclohepta[ ,2':4,5]imidazo[l,2-a]pyridine-3-carboxylic acid
hydrochloride
Step 1: Benzyl 5-allyl-2,4-bis(benzyloxy)-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)nicotinate
Benzyl 5-allyl-2,4-bis(benzyloxy)-6-chloronicotinate (2.0 g, 4 mmol) was combined with bis(pinacolato)diboron (3.05 g, 12 mmol), Pd(dppf)Ci2 (81 mg, 0.1 mmol) and potassium acetate (1.18 g, 12 mmol) in 1,4-dioxane (2 mL), and the mixture was stirred at 120 °C for 10 min. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0-35%
EtOAc in hexanes) to afford a colorless oil (2.2 g, 74%) having 80% purity.
LC-MS: 510.2 [M+H]+ (boronic acid), RT 0.97 min. !H NMR (500 MHz, acetone-d6) 5 ppm 1.39 (s, 12H), 3.59 - 3.61 (m, 2H), 4.89 - 4.95 (m, 2H), 5.03 (s, 2H), 5.38 (s, 2H), 5.48 (s, 2H), 5.90 - 5.99 (m, 1H), 7.30 - 7.46 (m, 13H), 7.51 - 7.55 (m, 2H)
Step 2: Benzyl 5-allyl-2,4-bis(benzyloxy)-6-(3-vinylimidazo[l,2-a]pyridin-2-yl)nicotinate
K2CO3 (1 M, 0.75 mL) was added to a mixture of benzyl 5-allyl-2,4-bis(benzyloxy)-6-
(4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)nicotinate (206 mg, 0.35 mmol), 2-bromo-3- vinylimidazo[l,2-a]pyridine (Intermediate 53, 64 mg, 0.29 mmol), and Pd(dppf)Cl2 (24 mg, 0.03 mmol) in CH3CN (1.5 mL). The mixture was stirred at 60 °C for 3 h and partitioned between EtOAc and water. The organic layer was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to afford an off-white solid (20 mg, 11%).
LC-MS: 608.2 [M+H]+, RT 1.64 min
Step 3: Benzyl 2,4-bis(benzyloxy)-5H-pyrido[3",2":6',7']cyclohepta[l',2':4,5]imidazo[l,2- a]pyridine-3-carboxylate
A mixture of benzyl 5-allyl-2,4-bis(benzyloxy)-6-(3-vinylimidazo[l,2-a]pyridin-2- yl)nicotinate (20 mg, 0.033 mmol), Grubbs Catalyst (2nd generation) (3 mg, 0.003 mmol) and toluene (1 mL) was heated at 60 °C for 2 h. The mixture was cooled and purified by silica gel column chromatography (0-30% EtOAc in hexanes) to afford the title compound (10 mg, 50%).
LC-MS: 580.3 [M+H]+, RT 1.31 min Step_4: 4-hydroxy-2-oxo-2,5,6,7,9,10,ll,12-octahydro-lH- pyrido[3' 2'':6 7']cyclohepta[ ,2':4,5]imidazo[l,2-a]pyridine-3-carboxylic acid
hydrochloride
The product of step 3 was combined with 10% Pd/C (3 mg), 3 drops of 1.25 M HC1 in MeOH, and MeOH (1 mL). The mixture was stirred under ¾ (1 atm) for 3 h and was filtered. The filtrate was concentrated to afford of the title compound (3 mg, 50%) as a white powder.
LC-MS: 316.1 [M+H]+, RT 1.05 min. H NMR (500 MHz, methanol-^) δ ppm 2.06 - 2.16 (m, 4 H), 2.19 (dt, 7=5.9, 2.9 Hz, 2H), 2.84 - 2.89 (m, 2H), 3.05 (t, 7=6.8 Hz, 2H), 3.14 (t, 7=6.3 Hz, 2H), 4.10 (t, 7=6.0 Hz, 2H)
Example 19 (Compound 14)
4-Hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic acid hydrochloride
Step 1: tert-Butyl 2,4-di-tert-butoxy-6,7-dihydro-5H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- carboxylate
tert-Butyl 5-(3-(lH-imidazol-l-yl)propyl)-6-bromo-2,4-di-tert-butoxynicotinate (Intermediate 54, 255 mg, 0.5 mmol) was combined with palladium (II) acetate (28 mg, 0.13 mmol), DavePhos ligand (59 mg, 0.15 mmol) and K2C03 (138 mg, 1 mmol) in DMF (5 mL). The mixture was stirred at 120 °C for 30 min. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (0-50% acetone in CH2CI2) to afford 160 mg of 70% pure material.
LC-MS: 430.3 [M+H]+, RT 1.11 min
Step 2: 4-Hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- carboxylic acid hydrochloride
tert-Butyl 2,4-di-tert-butoxy-6,7-dihydro-5H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- carboxylate (60 mg, 70% purity, 0.1 mmol) was dissolved in TFA (1 mL). The mixture was stirred at room temperature for 10 min. The volatiles were removed under a stream of N2, and the residue was purified by reverse phase preparative HPLC. The purified material from the concentrated fractions was dissolved in 1.25 M HC1 in MeOH (0.25 mL). The volatiles were removed under reduced pressure to afford the title compound (13 mg, 9% over 2 steps).
LC-MS: 262.1 [M+H]+, RT 0.71 min. !H NMR (500 MHz, methanol-^) δ ppm 2.40 (t, 7=6.8 Hz, 2H), 2.75 (t, 7=7.1 Hz, 2H), 4.43 (t, 7=6.6 Hz, 2H), 8.04 (s, 1H), 9.18 (s, 1H) Using the procedure described for Example 19, additional compounds described herein may be prepared by substituting the indicated intermediate, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000274_0001
Example 20 (Compound 34)
2,3-Diethyl-8-hydroxy-10-oxo-6,7 ,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-
9-carboxylic acid hydrochloride
tert-Butyl 8,10-di-tert-butoxy-2,3-divinyl-6,7-dihydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylate (Intermediate 64, 40 mg, 0.08 mmol) was combined with 10% Pd/C
(Degussa type, 10 mg) in MeOH (1 mL) under ¾ (1 atm). After 2 h, the mixture was filtered and concentrated under reduced pressure. The residue was dissolved in TFA (1 mL). After 10 min, the volatiles were removed under reduced pressure. The residue was dissolved in 1.25 M
HC1 in MeOH. The volatiles were removed to afford a yellow powder which was suspended in CH3CN. The solids were collected by filtration to afford the title compound (18 mg, 71%).
LC-MS: 318.3 [M+H]+, RT 0.98 min. !H NMR (500 MHz, DMSO- ) δ ppm 1.14 (t, 7=7.5 Hz, 3H), 1.20 (t, 7=7.5 Hz, 3H), 2.20 - 2.26 (m, 2H), 2.67 (q, 7=7.6 Hz, 2H), 2.72 - 2.80 (m, 4H), 4.15 - 4.23 (m, 2H)
Using the procedure described for Example 20, additional compounds described herein may be prepared by substituting the indicated intermediate, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000275_0001
Example 21 (Compound 36)
2-Chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride
tert-Butyl 8,10-di-tert-butoxy-2-chloro-3-vinyl-6,7-dihydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylate (Intermediate 63, 20 mg, 0.04 mmol) was combined with Pt02 (4 mg) in EtOAc (1 mL) under ¾ (1 atm). After 2 h, the mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0- 40% EtOAc in hexanes). The intermediate was dissolved in TFA (1 mL). After 10 min, the volatiles were removed under reduced pressure. The residue was dissolved in 1.25 M HC1 in MeOH. The volatiles were removed to afford the title compound (11 mg, 85%) as a white powder.
LC-MS: 324.2/326.2 [M+H]+, RT 1.23 min. !H NMR (500 MHz, OMSO-d6) δ ppm 1.14 (t, 7=7.6 Hz, 3H), 2.18 - 2.24 (m, 2H), 2.64 - 2.68 (m, 2H), 2.72 (q, 7=7.6 Hz, 2H), 4.05 - 4.17 (m, 2H), 12.42 (br. s, 1H), 14.11 (br. s, 1H), 16.13 (br. s, 1H)
Example 22 (Compound 69)
3-Ethyl-7-hydroxy-2-(2-hydroxyethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
Steps 1-2: Methyl 2-(2-(benzyloxy)ethyl)-10-(2,4-dimethoxybenzyl)-3-ethyl-7-hydroxy-9- oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate
The title compound was prepared using the 2-step procedure described for Example 1 (steps
2-3) starting from 2-(2-(benzyloxy)ethyl)-l-ethyl-5,6,7,8-tetrahydrocyclohepta[d]imidazol-
4(lH)-one (Intermediate 13).
H NMR (500 MHz, CDC13) δ ppm 1.19 (t, 7=7.3 Hz, 3H), 2.15 (quin, 7=6.9 Hz, 2H), 2.39 - 2.52 (m, 4H), 2.93 (t, 7=6.8 Hz, 2H), 3.65 (s, 3H), 3.67 (s, 3H), 3.78 - 3.88 (m, 4H), 3.96 (s, 3H), 4.45 (s, 2H), 5.71 (s, 2H), 6.22 (dd, 7=8.5, 2.5 Hz, 1H), 6.28 (d, 7=2.5 Hz, 1H), 6.53 (d, 7=8.5 Hz, 1H), 7.17 - 7.36 (m, 6H), 13.75 (s, 1H)
Steps 3-5: 3-Ethyl-7-hydroxy-2-(2-hydroxyethyl)-9-oxo-3,4,5,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid
A solution of methyl 2-(2-(benzyloxy)ethyl)-10-(2,4-dimethoxybenzyl)-3-ethyl-7-hydroxy-9- oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylate (55 mg, 0.094 mmol) in MeOH (1.5 mL) was hydrogenated under 1 atm ¾ over a mixture of 10% Pd/C (10 mg, Degussa type) and 20% Pd(OH)2/C (10 mg, Degussa type) catalysts for 7 h. The catalysts were removed by filtration and washed with MeOH. The mother liquor was concentrated under reduced pressure. The residue was dissolved in EtOAc (1 mL) and treated with Lil (37 mg, 0.28 mmol) at 60 °C for 1.5 h. After cooling to room temperature, the reaction mixture was quenched with aqueous Na¾P04. The product was extracted with EtOAc, and the organic layers were combined, washed with aqueous Na2S203, dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% MeOH in CH2CI2 gradient) to afford 33 mg of the intermediate carboxylic acid. The intermediate carboxylic acid was treated with TIPSH (0.3 mL) and TFA (0.3mL) at room temperature for 48 h. TFA was removed under reduced pressure, and MeOH (1 mL) was added to the residue. The mixture was heated at 50 °C for 1 h. The volatiles were removed under reduced pressure, and the residue was treated with Et20 resulting in precipitate formation. The solid was removed by filtration and washed with Et20 to afford the title compound (14.9 mg, 47% overall) as a white solid.
LC-MS: 332.0 [M-H]", RT 1.01 min. !H NMR (500 MHz, DMSO-cfe) δ ppm 1.25 (t, 7=7.3 Hz, 3H), 1.86 - 2.01 (m, 2H), 2.71 - 2.78 (m, 2H), 2.87 (t, 7=5.4 Hz, 2H), 2.94 (t, 7=6.3 Hz, 2H), 3.85 (t, 7=5.8 Hz, 2H), 3.98 (q, 7=6.9 Hz, 2H), 4.92 (br. s, 1H), 11.54 (br. s, 1H), 14.03 (br. s, 1H), 16.01 (br. s, 1H)
Example 23 (Compound 92)
4-Hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate Steps 1-2: Methyl 9-bromo-l-(2,4-dimethoxybenzyl)-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido [2' , 3 ' : 3 ,4] cyclohepta[ 1 , 2-b] indole- 3 -carboxylate
The title compound was prepared in 28% yield using the 2-step procedure described for
Example 1 (steps 2-3) starting from 4-bromo-5-methyl-6,7,8,9-tetrahydrocyclohepta[b]indol-
10(5H)-one (Intermediate 66).
LC-MS: 565.0/567.0 [M-H]", RT 1.56 min
Steps 3-4: 4-Hvdroxv-8-methvl-2-oxo-9-(piperazin-l-yl)-l,2,5, 6,7,8- hexahydropyrido [2' , 3 ' : 3 ,4] cyclohepta[ 1 , 2-b] indole- 3 -carboxylic acid trifluoroacetate
Dioxane (1.1 mL) was added to a mixture of methyl 9-bromo-l-(2,4-dimethoxybenzyl)-4- hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3- carboxylate (70 mg, 0.123 mmol), tert-butyl piperazine-1 -carboxylate (35 mg, 0.188 mmol, 1.5 eq), t-BuONa (35 mg, 0.364 mmol, 3 eq), and RuPhos-Pd-G2 catalyst (10 mg, 0.012 mmol). The mixture was heated at 90 °C for 20 min under an argon atmosphere. After cooling to room temperature, the mixture was adjusted to pH ~2 with 1M HC1 and extracted with CH2CI2. The organic layers were combined, washed with brine, dried over Na2S04, and concentrated under reduced pressure. The residue was dissolved in CH2CI2 (0.5 mL) and treated with TIPSH (0.5 mL) and TFA (0.5 mL) at 50 °C for 1 h. The volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC (20-75%
ACN/H2O doped with 0.2% TFA) to afford the title compound (6.0 mg, 10%) as the TFA salt.
LC-MS: 407.3 [M-H]", RT 0.90 min. H NMR (500 MHz, DMSO-cfe) δ ppm 2.11 - 2.23 (m, 2H), 2.42 - 2.47 (m, 2H), 2.97 (t, 7=7.3 Hz, 2H), 3.01 - 3.10 (m, 2H), 3.24 - 3.44 (m, 6 H), 4.18 (s, 3H), 7.03 (d, 7=7.3 Hz, 1H), 7.15 (t, 7=7.9 Hz, 1H), 7.48 (d, 7=7.9 Hz, 1H), 8.72 (br. s, 1H), 8.98 (br. s, 1H), 12.55 (br. s, 1H), 13.85 (br. s, 1H), 16.32 (br. s, 1H) Using the procedure described for Example 23, additional compounds described herein may be prepared by substituting the appropriate starting materials, suitable reagents, and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000278_0001
Biological Examples
The following in vitro biological examples demonstrate the usefulness of the compounds of the present description for treating Neisseria gonorrhoeae or Neisseria meningitidis.
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, an MIC value between > 12.5 μg/mL and < 150 μg/mL is indicated by a single star (*), an MIC value between > 3.5 μg/mL and < 12.5 μg/mL is indicated by two stars (**), an MIC value between > 1.0 μg/mL and < 3.5 μg/mL is indicated by three stars (***) and an 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) was compared in FB (Table 1) and FB containing 40 mg/mL HSA (Table 2).
Table 1
Cpd 13477 Cpd 13477 Cpd 13477
2 **** 41 *** 76 ****
3 **** 42 **** 77 **** Cpd 13477 Cpd 13477 Cpd 13477
4 **** 43 **** 78 * * * *
5 **** 44 **** 82 * * * *
6 **** 45 **** 83 * * * *
8 **** 46 **** 85 * * * *
9 **** 47 **** 86 * * * *
10 **** 48 **** 87 * * * *
11 **** 49 *** 88 ***
12 **** 50 **** 89 ****
13 **** 51 **** 90 ****
14 ** 52 **** 92 ****
16 **** 53 **** 92 ****
17 **** 54 **** 94 ****
19 **** 55 **** 95 ****
20 **** 56 * * * * 96 **** 21 57 **** 97 ****
22 58 * * * * 98 **** 23 59 **** 99 ****
24 ** 60 **** 100 ****
25 **** 61 **** 101 ****
26 * * * * 62 * * * * 102 ****
28 * * * * 63 * * * * 103 ****
29 **** 64 **** 104 ****
30 **** 65 * * * * 105 ****
31 **** 66 * * * * 106 **** 32 67 * * * * 107 ****
33 **** 68 * * * * 108 ****
34 **** 69 **** 109 ****
35 **** 70 **** no ****
36 * * * * 71 **** in ****
37 **** 72 **** 112 ****
38 * * * * 73 **** 113 ****
39 ** 74 **** 114 ****
40 **** 75 **** Table 2
Cpd 13477 Cpd 13477 Cpd 13477
2 **** 41 ** 75 **** 3 *** 42 *** 76 **** 4 **** 43 **** 77 **** 5 **** 44 **** 78 *** 6 *** 45 **** 82 **** 8 **** 46 **** 83 **** 9 **** 47 **** 86 *** 10 **** 48 **** 87 * 11 **** 49 *** 88 * 12 **** 50 **** 89 ** 13 **** 51 *** 90 **** 14 * 52 **** 91 **** 16 **** 53 **** 92 **** 17 **** 54 **** 94 **** 19 ** 55 **** 95 **** 20 ** 56 **** 96 **** 21 **** 57 **** 97 **** 22 **** 58 **** 98 *** 23 **** 59 **** 99 *** 24 * 60 **** 100 *** 25 ** 61 *** 101 *** 26 *** 62 **** 102 *** 28 **** 63 **** 103 **** 29 **** 64 **** 104 **** 30 **** 65 **** 105 **** 31 ** 66 **** 106 *** 32 *** 67 **** 107 **** 33 *** 68 **** 108 **** 34 **** 69 **** 109 **** 35 **** 70 *** 110 •f**i~"1*"i* 36 **** 71 **** 111 **** 37 **** 72 **** 112 **** Cpd 13477 Cpd 13477 Cpd 13477
38 **** 73 **** 113 **** 39 * 74 **** 114 **** 40 ****
Example 2
Antibacterial activity of test compounds against N. gonorrhoeae WHO isolates G, K, L and M (13478, 13479, 13480 and 13481, respectively) is shown in Table 3.
Table 3
Cpd 13478 13479 13480 13481 Cpd 13478 13479 13480 13481
2 **** **** **** **** 58 **** **** **** ****
3 **** **** **** **** 59 **** **** **** ****
4 **** **** **** **** 60 **** **** **** ****
5 **** **** **** **** 61 *** *** *** ***
6 **** **** **** **** 62 **** **** **** ****
8 **** **** **** **** 63 **** **** **** ****
9 **** **** **** **** 64 **** **** **** ****
10 **** **** **** **** 65 **** **** **** ****
11 **** **** **** **** 66 **** **** **** ****
12 **** **** **** **** 67 **** **** **** ****
13 **** **** **** **** 68 **** *** **** ****
14 ** * ** ** 69 **** **** **** ****
16 **** *** **** **** 70 **** **** **** ****
17 **** **** **** **** 71 **** **** **** ****
19 **** **** **** **** 72 **** **** **** ****
20 **** **** **** **** 73 **** **** **** ****
21 **** *** *** *** 74 **** **** **** ****
22 **** **** **** **** 75 **** *** **** ****
23 **** **** **** **** 76 **** **** **** ****
24 * *** * * 77 **** **** **** ****
25 **** **** **** **** 78 *** *** **** ****
26 **** *** **** **** 82 **** **** **** ****
28 **** **** **** **** 83 **** **** **** ****
29 **** **** **** **** 85 **** *** **** **** Cpd 13478 13479 13480 13481 Cpd 13478 13479 13480 13481 30 **** **** **** **** 86 ^^^^ ^^^^ ^^^^
31 *** *** *** ***
32 **** **** **** **** 88 ### ^^^^ ^^^^ 33 **** **** **** ****
34 **** **** **** **** 90 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 35 **** **** **** ****
36 **** **** **** **** 92 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 37 **** **** **** **** 94 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 38 **** **** **** ****
39 ** * ** ** 96 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 40 **** **** **** **** 97 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 41 *** * ** *
42 **** *** *** **** 99 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 43 **** **** **** **** 100
44 **** **** **** **** 101 ^
45 **** **** **** **** 102 * * * * * * * * 46 **** **** **** **** 103 * * * * * * * * * * * * 47 **** **** **** **** 104 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 48 **** **** **** **** 105 * * * * * * * * * * * * 49 *** ** *** *** 106 *f* *f* *f* *f* *f* *f* *f* *f» *f» *f» *f» *f» *f» *f» *f» 50 **** **** **** **** 107 **** **** **** **** 51 **** **** **** **** 108 *f* *f* *f* *f*
52 **** **** **** **** 109 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 53 **** *** **** **** 110 ****
54 **** *** **** ****
55 **** **** **** **** 112 *f* *f* *f* *f*
56 **** **** **** ****
57 **** **** **** **** 114 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^
Example 3
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(l l):5699-5708; and, Cole, J.E. et al., Opacity Proteins Increase Neisseria gonorrhoeae Fitness in the Female Genital Tract Due to a Factor Under Ovarian Control. Infection and Immunity , 2010, 78(4): 1629-1641).
Compound efficacy is demonstrated when all mice in a treatment group are completely clear of N. gonorrhoeae after 5 full days post-treatment (100% clearance).
Bacterial clearance is defined as the number of mice in the treatment group free of
N. gonorrhoeae expressed as a percentage of the total. Complete bacterial clearance (100% clearance) for the treatment group equates to an approximate log 4 reduction in bacterial count for the group. Compounds that achieve less than 100% clearance for the treatment group have an average maximal log drop value calculated by the following equation:
Maximal Log Drop = log(average Day 2 bacterial count for all mice) - log(average lowest bacterial count post dose for all mice)
Study Conduct
On Day -2 of the study, ovariectomized Balb/c female mice (5 weeks old - Charles River Laboratory) were implanted with a single 17 -estradiol pellet (0.5 mg, 21 day release) subcutaneously and began treatment with a combination of vancomycin HC1, streptomycin sulfate (0.6 mg and 0.3 mg, respectively, IP, BID) and trimethoprim sulfate (0.8 mg, PO, BID). The antibiotic combination was administered to control commensal flora induced by the high level of 17 -estradiol resulting from the implanted pellet. Combined antibiotic treatment continued from Day -2 to Day 1 of the study. After Day 1, mice were dosed with streptomycin only (0.6 mg, IP, QD).
On Day 0 of the study, mice were inoculated with 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 was determined by daily vaginal swabbing using sterile swabs.
On Day 1 of the study, mice were randomized into treatment groups according to bacterial count. The treatment groups (n=10) included a vehicle control, a positive control (such as ciprofloxacin, 30 mg/kg) and test compound group. The treatment groups were dosed with a single dose (mg/kg) either orally or IP. The vehicle control, positive control and test compound oral dose was administered in a mixture of HPMC (0.5%) and Tween 80 (0.1%) and the IP dose was administered in a mixture of DMSO (3%) in saline. Results
Antibacterial efficacy of test compounds (Cpd) against SP1364 N. gonorrhoeae is shown in Table 4, where percent clearance (%) and maximal log drop value (Drop) for each treatment group orally administered a particular dose (Dose in mg/kg) is indicated.
Table 4
Cpd Dose % Drop
8 30 100 5.02
9 30 100 4.74
10 30 100 4.84
11 30 90.0 4.59
29 10 100 4.60
35 10 60.0 1.57
37 10 100 3.86
48 30 100 4.06
50 15 100 5.09
52 10 83.3 4.63
55 10 75.0 3.40
56 30 100 4.89
66 10 100 4.32
71 3 100 4.79
77 30 87.5 3.16
82 10 100 4.95
111 15 100 5.05
113 15 100 4.58
114 10 100 4.36
Example 4
Combinations with Antibacterial Agents
The in vitro effects of compounds described herein in combination with a known antibacterial or antibiotic agent may be investigated in various organisms using the microdilution checkerboard method for the measurement of additive or synergistic effect. Assays can be performed in a 96-well checkerboard titration format, with serial dilutions of each compound to identify the lowest MIC value ^g/mL) at which the combination completely inhibits colony formation. The ability of a combination of one or more compounds described herein with known agents to either act synergistically, additively, indifferently or antagonistically can be determined. A synergistic effect is demonstrated when the activity of the separate agents are combined and the result is greater than the expected arithmetic sum of each agents activity alone. The fractional inhibitory
concentration (FIC) is a quantitative measure of such drug interactions, where the fractional inhibition indices are calculated using the checkerboard method in a 96-well microtiter plate. Combined activity is synergistic when the FIC value is < 0.5; combined activity is additive when the FIC value is > 0.5 and < 2; combined activity that is not different from the agents alone when the FIC value is > 2 and < 4; and, combined activity is antagonistic when the FIC value is > 4.
Results
Compound 50 was tested in combination with certain antibiotic agents. Table 5 provides the FIC Value and resulting Activity for combinations tested:
Table 5
Agent FIC Value Activity
Azithromycin 1 Additive
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 compound of Formula (la), Formula (lb) or Formula (Ic):
Figure imgf000286_0001
or a form thereof, wherein
the dashed lines represent one or more double bonds optionally present where allowed by available valences;
Ai, A2, A3, and A4 are independently C or N; wherein, Ai and A2 are not simultaneously N; Ao is independently QR5), CH(Rs), N or N(R5), where allowed by available valences;
X is -CH(R2 , -CH(R2)-CH(R2 , -CH(R2)-CH(R2)-CH(R2 , -C(R2)=C(R2 , -CH(R2)-0-,
-0-CH(R2)-, -0-CH(R2)-CH(R2)-, -CH(R2)-0-CH(R2)-, -N(R2 , -S-CH(R2)-, -O- or -S-;
Y is -CH(R2 , -N(R2)-, -O- or -S-;
wherein, when Y is -N(R2 , -O- or -S-, then X is not -CH(R2)-0-, -0-CH(R2)-,
-CH(R2)-0-CH(R2 , -N(R2)-, -S-CH(R2)-, -O- or -S-;
R2 is hydrogen or Ci-salkyl;
R5 is hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci_8alkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl,
Ci_8alkyl-carbonyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
Ci-8alkyl-sulfinyl-Ci_8alkyl, Ci-salkyl-sulfonyl-Ci-salkyl, amino-carbonyl, amino, Ci-8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2_8alkenyl-amino,
(C2_8alkenyl)2-amino, C2_salkynyl, C2_8alkynyl-amino, (C2_8alkynyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl,
C2-8alkenyl-amino-Ci_8alkyl, (C2_8alkenyl)2-amino-Ci_8alkyl, C2-8alkynyl-amino-Ci_8alkyl, (C2-8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl,
hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci-8alkoxy-Ci_8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci-8alkoxy-Ci-8alkyl,Ci-8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci_8alkyl]amino, amino-Ci-salkyl-amino-Ci-salkyl, (amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (amino-Ci_8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,
(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci_8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino,
(hydroxyl-Ci-8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino,
(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl-amino,
[(hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-amino-Ci-salkyl-carbonyl,
(Ci_8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_salkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3_i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl, (C3-i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl, (aryl,Ci-8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-Ci-salkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci-8alkyl-amino-Ci_8alkyl, (aryl-Ci_8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(aryl-Ci-8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl,Ci-8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci-salkyl, (heterocyclyl,Ci-8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl,
(heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci_8a]koxy-carbonyl, amino, Ci_8alkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci-8alkyl,Ci_8alkyl)amino,
Ci-8alkyl-amino-Ci-8alkyl-amino, (Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci-8alkyl, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci-8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl,
C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-Ci-salkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino,
(aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (aryl-Ci_8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci_8alkyl or heterocyclyl-oxy;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci-8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci-salkyl-amino; wherein the 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 compound of claim 1, selected from a compound of Formula (la):
Figure imgf000289_0001
(la)
or a form thereof, wherein
wherein the dashed lines represent one or more double bonds optionally present where allowed by available valences;
Ai and A2 are independently C or N; wherein, Ai and A2 are not simultaneously N;
Ao is independently QR5), CH(Rs), N or N(R5), where allowed by available valences; X is -CH(R2 , -CH(R2)-CH(R2 , -CH(R2)-CH(R2)-CH(R2)-, -C(R2)=C(R2)-, -CH(R2)-0-, -0-CH(R2 , -0-CH(R2)-CH(R2)-, -CH(R2)-0-CH(R2)-, -N(R2)-, -S-CH(R2)-, -O- or -S-;
Y is -CH(R2)-, -N(R2 , -O- or -S-;
wherein, when Y is -N(R2 , -O- or -S-, then X is not -CH(R2)-0-, -0-CH(R2 ,
-CH(R2)-0-CH(R2)-, -N(R2)-, -S-CH(R2 , -O- or -S-;
R2 is hydrogen or Ci-salkyl;
R5 is hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci_8alkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl,
Ci_8alkyl-carbonyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
Ci-8alkyl-sulfinyl-Ci_8alkyl, Ci-salkyl-sulfonyl-Ci-salkyl, amino-carbonyl, amino, Ci-8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2_8alkenyl-amino,
(C2_8alkenyl)2-amino, C2_salkynyl, C2_8alkynyl-amino, (C2_8alkynyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl,
C2-8alkenyl-amino-Ci_8alkyl, (C2_8alkenyl)2-amino-Ci_8alkyl,
C2-8alkynyl-amino-Ci_8alkyl, (C2_8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl,
hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci-8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci-8alkoxy-Ci_8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci_8alkyl-amino-Ci_8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino, amino-Ci-salkyl-amino-Ci-salkyl, (amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (amino-Ci_8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci-8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,
(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci-8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino, (hydroxyl-Ci-8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino,
(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl-amino,
[(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-amino-Ci-salkyl-carbonyl,
(Ci-8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_8alkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3_i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino,
(aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl,
(aryl,Ci-8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-Ci-salkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci-8alkyl-amino-Ci_8alkyl, (aryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,
(aryl-Ci-8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl,Ci_8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci_8alkyl, (heterocyclyl,Ci-8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl,
(heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino, (heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci_8alkyl,Ci_8alkyl)amino,
Ci-8alkyl-amino-Ci-8alkyl-amino, (Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci-8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci_8alkyl, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci-8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl,
C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-Ci-salkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino,
(aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl, (aryl-Ci_8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_salkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci-8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci-8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci-8alkyl)2-amino-Ci-8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci-8alkyl or heterocyclyl-oxy;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci-8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci-salkyl-amino; wherein the 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 compound of claim 1, selected from a compound of Formula (lb):
Figure imgf000293_0001
(lb)
or a form thereof, wherein
wherein the dashed lines represent one or more double bonds optionally present where
allowed by available valences;
Ai, A2, A3, and A4 are independently C or N; wherein, Ai and A2 are not simultaneously N; Ao is independently QR5), CH(Rs), N or N(R5), where allowed by available valences;
X is -CH(R2 , -CH(R2)-CH(R2 , -CH(R2)-CH(R2)-CH(R2 , -C(R2)=C(R2 , -CH(R2)-0-, -0-CH(R2 , -0-CH(R2)-CH(R2 , -CH(R2)-0-CH(R2 , -N(R2)-, -S-CH(R2)-, -O- or -S-;
Y is -CH(R2 , -N(R2)-, -O- or -S-;
wherein, when Y is -N(R2 , -O- or -S-, then X is not -CH(R2)-0-, -0-CH(R2 ,
-CH(R2)-0-CH(R2)-, -N(R2)-, -S-CH(R2)-, -O- or -S-;
R2 is hydrogen or C^alkyl;
R5 is hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci-salkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl,
Ci_8alkyl-carbonyl, Ci_8alkyl-carbonyl-oxy-Ci_8alkyl, C^alkoxy-carbonyl,
Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
Ci-8alkyl-sulfinyl-Ci_8alkyl, Ci-salkyl-sulfonyl-Ci-salkyl, amino-carbonyl, amino, Ci-8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2_8alkenyl-amino,
(C2_8alkenyl)2-amino, C2_salkynyl, C2_8alkynyl-amino, (C2_8alkynyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl, C2-8alkenyl-amino-Ci_8alkyl, (C2-8alkenyl)2-amino-Ci_8alkyl,
C2-8alkynyl-amino-Ci_8alkyl, (C2-8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl,
hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci-8alkoxy-Ci_8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci-8alkoxy-Ci-8alkyl,Ci-8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci_8alkyl]amino, amino-Ci-salkyl-amino-Ci-salkyl, (amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (amino-Ci_8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,
(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci_8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino,
(hydroxyl-Ci-8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino,
(hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl-amino,
[(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci_8alkyl-amino-Ci_8alkyl-carbonyl,
(Ci-8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_8alkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3_i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl, (C3-i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl,
(aryl,Ci-8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-Ci-salkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci-8alkyl-amino-Ci_8alkyl, (aryl-Ci_8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(aryl-Ci-8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl,Ci-8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci-salkyl, (heterocyclyl,Ci-8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl,
(heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci_8alkoxy-Ci_8alkyl, Ci_8alkoxy, halo-Ci_salkoxy, hydroxyl-Ci_8alkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci-8alkyl,Ci_8alkyl)amino,
Ci_8alkyl-amino-Ci_8alkyl-amino, (Ci_8alkyl-amino-Ci_8alkyl,Ci_8alkyl)amino, (Ci-8alkyl)2-amino-Ci-8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci-8alkyl, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci-8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl, C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-Ci-salkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino,
(aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (aryl-Ci_8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci_8alkyl or heterocyclyl-oxy;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci-8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci-salkyl-amino; wherein the 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 compound of claim 1, selected from a compound of Formula (Ic):
Figure imgf000296_0001
or a form thereof, wherein
wherein the dashed lines represent one or more double bonds optionally present where allowed by available valences;
Ai, A2, A3, and A4 are independently C or N; wherein, Ai and A2 are not simultaneously N; Ao is independently QR5), CH(Rs), N or N(R5), where allowed by available valences; X is -CH(R2 , -CH(R2)-CH(R2 , -CH(R2)-CH(R2)-CH(R2)-, -C(R2)=C(R2)-, -CH(R2)-0-, -0-CH(R2 , -0-CH(R2)-CH(R2)-, -CH(R2)-0-CH(R2)-, -N(R2)-, -S-CH(R2)-, -O- or -S-;
Y is -CH(R2)-, -N(R2 , -O- or -S-;
wherein, when Y is -N(R2 , -O- or -S-, then X is not -CH(R2)-0-, -0-CH(R2 ,
-CH(R2)-0-CH(R2)-, -N(R2)-, -S-CH(R2 , -O- or -S-;
R2 is hydrogen or Ci-salkyl;
R5 is hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci_8alkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl,
Ci_8alkyl-carbonyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
Ci-8alkyl-sulfinyl-Ci_8alkyl, Ci-salkyl-sulfonyl-Ci-salkyl, amino-carbonyl, amino, Ci-8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2_8alkenyl-amino,
(C2_8alkenyl)2-amino, C2_salkynyl, C2_8alkynyl-amino, (C2_8alkynyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl,
C2-8alkenyl-amino-Ci_8alkyl, (C2_8alkenyl)2-amino-Ci_8alkyl,
C2-8alkynyl-amino-Ci_8alkyl, (C2_8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl,
hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci-8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci-8alkoxy-Ci_8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci_8alkyl-amino-Ci_8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino, amino-Ci-salkyl-amino-Ci-salkyl, (amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (amino-Ci_8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci-8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,
(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci-8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino, (hydroxyl-Ci-8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino,
(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl-amino,
[(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-amino-Ci-salkyl-carbonyl,
(Ci-8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_8alkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3_i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino,
(aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl,
(aryl,Ci-8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-Ci-salkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci-8alkyl-amino-Ci_8alkyl, (aryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,
(aryl-Ci-8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl,Ci_8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci_8alkyl, (heterocyclyl,Ci-8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl,
(heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino, (heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci_8alkyl,Ci_8alkyl)amino,
Ci-8alkyl-amino-Ci-8alkyl-amino, (Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci-8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci_8alkyl, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci-8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl,
C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-Ci-salkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino,
(aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl, (aryl-Ci_8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_salkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci-8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci-8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci-8alkyl)2-amino-Ci-8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci-8alkyl or heterocyclyl-oxy;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci-8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci-salkyl-amino; wherein the 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 compound of any of claims 1 to 4, wherein, when R5 is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3_i4cycloalkyl 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][l,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b] [ 1 ,4]oxazin-(4aH)-yl, hexahydro- 1 H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro-lH- pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- l,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo [2.2.1 Jheptyl, 2,5 -diazabicyclo [2.2.1 Jheptanyl, 2-azabicyclo [2.2.1 ]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexyl, (lR,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (lS,5R,6S)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (lS,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 or 2,8-diazaspiro[4.5]decanyl.
6. The compound of either of claims 1 or 2, wherein the compound of Formula (la) is selected from a compound of Formula (lal), Formula (Ia2), Formula (Ia3), Formula (Ia5), Formula (Ia6), Formula (Ia7), Formula (Ia8), Formula (Iall), Formula (Ial2), Formula (Ial5), Formula (Ial6), Formula (Ial7), Formula (Ial8), Formula (Ial9), Formula (Ia20), Formula (Ia21), Formula (Ia22), Formula (Ia23), Formula (Ia24), Formula (Ia25), Formula (Ia26), Formula (Ia27), Formula (Ia28), Formula (Ia29), Formula (Ia30), or Formula (Ia31) ( a form thereof:
Figure imgf000301_0001
(Ia6) (Ia7) (Ia8) (Ial l)
Figure imgf000302_0001
Figure imgf000303_0001
(Ia30), and (Ia31);
wherein the 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 compound of claim 6, wherein the compound is substituted with one or more Rsa, R5b,and Rsc substituents each, when present, selected from the group consisting of:
hydrogen, halogen, hydroxyl, cyano, nitro, Ci-galkyl, hydroxyl-C^alkyl, halo-Ci_8alkyl, Ci-salkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl,
Ci_8alkyl-carbonyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
Ci-8alkyl-sulfinyl-Ci_8alkyl, Ci-salkyl-sulfonyl-Ci-salkyl, amino-carbonyl, amino, Ci-8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2-8alkenyl-amino,
(C2-8alkenyl)2-amino, C2-salkynyl, C2-8alkynyl-amino, (C2-8alkynyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl,
C2-8alkenyl-amino-Ci_8alkyl, (C2-8alkenyl)2-amino-Ci_8alkyl,
C2-8alkynyl-amino-Ci_8alkyl, (C2-8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl,
hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci-8alkoxy-Ci_8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci-8alkoxy-Ci-8alkyl,Ci-8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino, amino-Ci-salkyl-amino-Ci-salkyl, (amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (amino-Ci_8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,
(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci_8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino,
(hydroxyl-Ci-8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino,
(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl-amino,
[(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-amino-Ci-salkyl-carbonyl,
(Ci-8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_8alkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3_i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino,
(aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl,
(aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-Ci_8alkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci-8alkyl-amino-Ci_8alkyl, (aryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,
(aryl-Ci_8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl,Ci-8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci-salkyl, (heterocyclyl,Ci-8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl, (heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci_8alkyl,Ci_8alkyl)amino,
Ci-8alkyl-amino-Ci-8alkyl-amino, (Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci-8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci_8alkyl, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci-8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl,
C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-Ci_8alkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino,
(aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl, (aryl-Ci_8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci-8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci-8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci-8alkyl)2-amino-Ci-8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci-8alkyl or heterocyclyl-oxy; wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
Rg is halogen, Ci-salkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci-8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci-salkyl-amino.
8. The compound of claim 7, wherein, when Rsa, Rsb or Rsc is C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then:
C3_i4cycloalkyl 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][l,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b] [ 1 ,4]oxazin-(4aH)-yl, hexahydro- 1 H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro-lH- pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- l,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo [2.2.1 Jheptyl, 2,5 -diazabicyclo [2.2.1 Jheptanyl, 2-azabicyclo [2.2.1 ]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexyl, (lR,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (lS,5R,6S)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (lS,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 or 2,8-diazaspiro[4.5]decanyl.
9. The compound of claim 6, wherein the compound is substituted with one or more Rsa, R5b and Rsc substituents each, when present, selected from the group consisting of:
hydrogen, halogen, cyano, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl,
Ci_8alkyl-carbonyl-oxy-Ci_8alkyl, Ci_8alkyl-sulfinyl-Ci_8alkyl,
Ci-8alkyl-sulfonyl-Ci-8alkyl, (Ci_8alkyl)2-amino, C2-salkenyl, amino-Ci-salkyl, Ci-ioalkyl-amino-Ci_8alkyl, (Ci-ioalkyl)2-amino-Ci-8alkyl,Ci-8alkoxy-Ci_8alkyl, hydroxyl-Ci_8alkoxy-Ci_salkyl, Ci_8alkoxy-Ci_8alkoxy-Ci_salkyl,
Ci-8alkyl-amino-Ci-8alkyl-carbonyl, (Ci_8alkyl)2-amino-Ci_8alkyl-carbonyl,
C3_i4cycloalkyl, aryl-oxy-Ci-salkyl, aryl-Ci-salkoxy-Ci-salkyl, heteroaryl-Ci-salkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy-Ci-salkyl or
heterocyclyl-Ci-8alkoxy-Ci_8alkyl;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is (Ci-8alkyl)2-amino or (Ci-salkyl^-amino-Ci-salkyl.
10. The compound of claim 6, wherein the compound is selected from a compound of Formula (Ia3), Formula (Ia5), Formula (Ial2), Formula (Ial6), Formula (Ial7), Formula (Ial9), Formula (Ia20), Formula (Ia21), and Formula (Ia31) or a form thereof:
Figure imgf000308_0001
(Ia3) (Ia5) (Ial2)
Figure imgf000308_0002
(Ia20) (Ia21), and (Ia31);
wherein the 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.
11. The compound of either of claims 1 or 3, wherein the compound of Formula (lb) is selected from a compound of Formula (Ibl), Formula (Ib2), Formula (Ib3), Formula (Ib4), Formula (Ib5), Formula (Ib6), Formula (Ib7), Formula (Ib8), Formula (Ib9), Formula (IblO), Formula (Ibll), Formula (Ibl2), Formula (Ibl3), Formula (Ibl4), Formula (Ibl5), Formula (Ibl6), Formula (Ibl7), Formula (Ibl8), Formula (Ibl9), Formula (Ib20), Formula (Ib21), Formula (Ib22), Formula (Ib23), Formula (Ib24), Formula (Ib25), Formula (Ib26), Formula (Ib27), Formula (Ib28), Formula (Ib29), Formula (Ib30), Formula (Ib31), Formula (Ib32), Formula (Ib33), Formula (Ib34), Formula (Ib35), Formula (Ib36), Formula (Ib37), Formula (Ib38), Formula (Ib39), Formula (Ib40), Formula (Ib41), Formula (Ib42), Formula (Ib43), Formula (Ib44), Formula (Ib45), Formula (Ib46), Formula (Ib47), Formula (Ib48), Formula (Ib49), Formula (Ib50), Formula (Ib51), Formula (Ib52), Formula (Ib53), Formula (Ib54), Formula (Ib55), Formula (Ib56), Formula (Ib57), Formula (Ib58), Formula (Ib59), Formula (Ib60), Formula (Ib61), Formula (Ib62), Formula (Ib63), Formula (Ib64), Formula (Ib65), Formula (Ib66), Formula (Ib67), Formula (Ib68), Formula (Ib69), Formula (Ib70), Formula (Ib71), Formula (Ib72), Formula (Ib73), Formula (Ib74), Formula (Ib75), Formula (Ib76), Formula (Ib77), Formula (Ib78), Formula (Ib79), Formula (Ib80), Formula (Ib81), Formula (Ib82), Formula (Ib83), Formula (Ib84), Formula (Ib85), Formula (Ib86), Formula (Ib87), Formula (Ib88), Formula (Ib89), or Formula (Ib90), or a form thereof;
Figure imgf000309_0001
(Ibl l) (Ibl2) (Ibl3) (Ibl4) (Ibl5)
Figure imgf000310_0001
(Ib21 (Ib22) (Ib23) (Ib24) (Ib25)
Figure imgf000310_0002
(Ib31) (Ib32) (Ib33) (Ib34). (Ib35)
Figure imgf000311_0001
(Ib51) (Ib52) (Ib53) (Ib54) (Ib55)
Figure imgf000312_0001
(Ib71) (Ib72) (Ib73) (Ib74) (Ib75)
Figure imgf000313_0001
(Ib86) (Ib87) (Ib88) (lb 89), and (Ib90); wherein the 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.
12. The compound of claim 11, wherein the compound is substituted with one or more R5a, R5b, R5c, R5d, and R5e substituents each, when present, selected from the group consisting of:
hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci_8alkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl,
Ci_8alkyl-carbonyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl, Ci-8alkyl-sulfinyl-Ci_8alkyl, Ci-salkyl-sulfonyl-Ci-salkyl, amino-carbonyl, amino, Ci_8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2-8alkenyl-amino,
(C2-8alkenyl)2-amino, C2-salkynyl, C2-8alkynyl-amino, (C2-8alkynyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl, C2-8alkenyl-amino-Ci_8alkyl, (C2-8alkenyl)2-amino-Ci_8alkyl,
C2-8alkynyl-amino-Ci_8alkyl, (C2-8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl,
hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci-8alkoxy-Ci_8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci-8alkoxy-Ci-8alkyl,Ci-8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci_8alkyl]amino, amino-Ci-salkyl-amino-Ci-salkyl, (amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (amino-Ci_8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci_8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino,
(hydroxyl-Ci_8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci_8alkyl-amino-Ci_8alkyl,Ci_8alkyl)amino,
(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl-amino,
[(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-amino-Ci-salkyl-carbonyl,
(Ci-8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_8alkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl, (C3-i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino,
(aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl,
(aryl,Ci-8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-Ci-salkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci-8alkyl-amino-Ci_8alkyl, (aryl-Ci_8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(aryl-Ci-8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci-8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci-8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl,Ci-8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci-8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci-salkyl, (heterocyclyl,Ci-8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl,
(heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is azido, halogen, hydroxyl, cyano, nitro, Ci_salkyl, halo-Ci_8alkyl, hydroxyl-Ci_salkyl, Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci-8alkyl,Ci_8alkyl)amino,
Ci-8alkyl-amino-Ci-8alkyl-amino, (Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci-8alkyl)2-amino-Ci-8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci_8alkyl, [(Ci-8alkyl)2-amino-Ci_8alkyl,Ci-8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl,
C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino,
(aryl)2-amino, aryl-Ci-salkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino,
(aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (aryl-Ci_8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci_8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-amino-Ci_8alkyl or heterocyclyl-oxy;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from Rg; and,
R9 is Ci_8alkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci-8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci-salkyl-amino.
13. The compound of claim 12, wherein, when Rsa, Rsb, Rsc, R5d and Rse is
C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C3_i4cycloalkyl 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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- lH-pyrrolyl, 4,5-dihydro- lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl,
1 ,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b] [l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][l,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b] [ 1 ,4]oxazin-(4aH)-yl, hexahydro- 1 H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro-lH- pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- l,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo [2.2.1 Jheptyl, 2,5 -diazabicyclo [2.2.1 Jheptanyl, 2-azabicyclo [2.2.1 ]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexyl, (lR,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (lS,5R,6S)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6S)-3-azabicyclo[3.2.0]heptanyl, (lS,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 or 2,8-diazaspiro[4.5]decanyl.
14. The compound of claim 11, wherein the compound is substituted with one or more R5a, R5b, R5c, R5d, and R5e substituents each, when present, selected from the group consisting of:
hydrogen, Ci-salkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci_8alkyl;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino.
15. The compound of claim 11, wherein the compound is selected from a compound of Formula (Ibl), Formula (Ib2), Formula (Ibl6), and Formula (Ib76), or a form thereof;
Figure imgf000318_0001
(Ibl) (Ib2) (Ibl6), and (Ib76); wherein the 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.
16. The compound of either of claims 1 or 4, wherein the compound of Formula (Ic) is selected from a compound of Formula (Icl), Formula (Ic2), Formula (Ic3), Formula (Ic4), Formula (Ic5), Formula (Ic6), Formula (Ic7), Formula (Ic8), Formula (Ic9), Formula (IclO), Formula (Icl l), Formula (Icl2), Formula (Icl3), Formula (Icl4), Formula (Icl5), Formula (Icl6), Formula (Icl7), Formula (Icl8), Formula (Icl9), Formula (Ic20), Formula (Ic21), Formula (Ic22), Formula (Ic23), Formula (Ic24), Formula (Ic25), Formula (Ic26), Formula (Ic27), Formula (Ic28), Formula (Ic29), Formula (Ic30), Formula (Ic31), Formula (Ic32), Formula (Ic33), Formula (Ic34), Formula (Ic35), Formula (Ic36), Formula (Ic37), Formula (Ic38), Formula (Ic39), Formula (Ic40), Formula (Ic41), Formula (Ic42), Formula (Ic43), Formula (Ic44), Formula (Ic45), Formula (Ic46), Formula (Ic47), Formula (Ic48), Formula (Ic49), Formula (Ic50), Formula (Ic51), Formula (Ic52), Formula (Ic53), Formula (Ic54), Formula (Ic55), Formula (Ic56), Formula (Ic57), Formula (Ic58), Formula (Ic59), Formula (Ic60), Formula (Ic61), Formula (Ic62), Formula (Ic63), Formula (Ic64), Formula (Ic65), Formula (Ic66), Formula (Ic67), Formula (Ic68), Formula (Ic69), Formula (Ic70), Formula (Ic71), Formula (Ic72), Formula (Ic73), Formula (Ic74), Formula (Ic75), Formula (Ic76), Formula (Ic77), Formula (Ic78), Formula (Ic79), Formula (Ic80), Formula (Ic81), Formula (Ic82), Formula (Ic83), Formula (Ic84), Formula (Ic85), Formula (Ic86), Formula (Ic87), Formula (Ic88), Formula (Ic89), or Formula (Ic90), or a form thereof;
Figure imgf000319_0001
(Icl3) (Icl4) (Icl5) (Icl6)
Figure imgf000320_0001
Figure imgf000320_0002
319
Figure imgf000321_0001
320
Figure imgf000322_0001
Figure imgf000323_0001
(Ic89), and (Ic90);
wherein the 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.
17. The compound of claim 16, wherein the compound is substituted with one or more R5a, R5b, R5c, R5d, and R5e substituents each, when present, selected from the group consisting of:
hydrogen, halogen, hydroxyl, cyano, nitro, Ci-salkyl, hydroxyl-Ci-salkyl, halo-Ci-salkyl, Ci-salkoxy, hydroxyl-Ci-salkoxy, halo-Ci-salkoxy, Ci-salkyl-thio, carboxyl,
Ci_8alkyl-carbonyl, Ci-salkyl-carbonyl-oxy-Ci-salkyl, Ci-salkoxy-carbonyl,
Ci-8alkoxy-carbonyl-Ci_8alkyl, Ci-salkyl-sulfinyl, Ci-salkyl-sulfonyl,
Ci-8alkyl-sulfinyl-Ci_8alkyl, Ci-salkyl-sulfonyl-Ci-salkyl, amino-carbonyl, amino, Ci-8alkyl-amino, (Ci_8alkyl)2-amino, C2-salkenyl, C2-8alkenyl-amino,
(C2-8alkenyl)2-amino, C2-salkynyl, C2-8alkynyl-amino, (C2-8alkynyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl,
C2-8alkenyl-amino-Ci_8alkyl, (C2-8alkenyl)2-amino-Ci_8alkyl,
C2-8alkynyl-amino-Ci_8alkyl, (C2-8alkynyl)2-amino-Ci_8alkyl, halo-Ci-salkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl,
(halo-Ci-8alkyl)2-amino-Ci_8alkyl, Ci-salkoxy-Ci-salkyl,
hydroxyl-Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy-Ci-salkoxy-Ci-salkyl,
Ci-8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl,Ci_8alkyl)-amino,
(Ci-8alkoxy-Ci_8alkyl)2-amino, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
(Ci-8alkoxy-Ci-8alkyl,Ci-8alkyl)-amino-Ci_8alkyl,
(Ci-8alkoxy-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl-amino,
(amino-Ci-8alkyl,Ci_8alkyl)amino, Ci-salkyl-amino-Ci-salkyl-amino,
(Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, amino-Ci_8alkyl-amino-Ci_8alkyl, (amino-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl, (amino-Ci_8alkyl)2-amino-Ci_8alkyl, Ci-8alkyl-amino-Ci-8alkyl-amino-Ci-8alkyl,
(Ci_8alkyl-amino-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,
(Ci-8alkyl)2-amino-Ci-8alkyl-amino-Ci_8alkyl,
[(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl,
(Ci-8alkyl-amino-Ci-8alkyl)2-amino-Ci_8alkyl, hydroxyl-Ci-salkyl-amino,
(hydroxyl-Ci-8alkyl,Ci_8alkyl)amino, (hydroxyl-Ci_8alkyl)2-amino,
hydroxyl-Ci-8alkyl-amino-Ci_8alkyl, (hydroxyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl, hydroxyl-C i -8 alkyl- amino-C i-8 alkyl- amino,
(hydroxyl-Ci-8alkyl-amino-Ci-8alkyl,Ci-8alkyl)amino, (hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl-amino,
[(hydroxyl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl,Ci_8alkyl]amino,
(Ci-8alkyl-carbonyl,Ci-8alkyl)amino-Ci_8alkyl, Ci-salkyl-amino-carbonyl,
(Ci_8alkyl)2-amino-carbonyl, Ci-salkyl-amino-Ci-salkyl-carbonyl,
(Ci-8alkyl)2-amino-Ci_8alkyl-carbonyl, C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_8alkyl, C3_i4cycloalkyl-oxy, C3_i4cycloalkyl-Ci_8alkoxy, C3_i4cycloalkyl-amino,
C3-i4cycloalkyl-amino-Ci_8alkyl, (C3_i4cycloalkyl,Ci_8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl)2-amino-Ci_8alkyl, C3_i4cycloalkyl-Ci_8alkyl-amino-Ci_8alkyl, (C3-i4cycloalkyl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(C3-i4cycloalkyl-Ci-8alkyl)2-amino-Ci_8alkyl, aryl, aryl-oxy, aryl-Ci-salkyl, aryl-oxy-Ci_8alkyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-Ci-salkyl, aryl-amino,
(aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-amino-Ci-salkyl,
(aryl,Ci-8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-Ci-salkyl-amino, (aryl-Ci-8alkyl,Ci_8alkyl)amino, (aryl-Ci_8alkyl)2-amino,
aryl-Ci-8alkyl-amino-Ci_8alkyl, (aryl-Ci_8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(aryl-Ci-8alkyl)2-amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci-salkyl, heteroaryl-amino, heteroaryl-Ci-8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci-8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl,Ci-8alkyl)amino-Ci_8alkyl, (heteroaryl-Ci-8alkyl,Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci-salkyl, heterocyclyl-oxy, heterocyclyl-oxy-Ci-salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-Ci-salkoxy-Ci-salkyl, heterocyclyl-amino, (heterocyclyl,Ci_8alkyl)amino, (heterocyclyl)2-amino, heterocyclyl-amino-Ci-salkyl, (heterocyclyl,Ci_8alkyl)amino-Ci_8alkyl, (heterocyclyl)2-amino-Ci_8alkyl,
(heterocyclyl,C3-i4cycloalkyl-Ci-8alkyl)amino-Ci_8alkyl,
heterocyclyl-Ci-8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci_8alkyl,Ci_8alkyl)amino-Ci_8alkyl,
(heterocyclyl-Ci-8alkyl)2-amino-Ci_8alkyl, heterocyclyl-oxy- amino,
(heterocyclyl-oxy,Ci_8alkyl)amino, (heterocyclyl-oxy)2-amino,
(heterocyclyl-oxy-Ci-8alkyl,Ci_8alkyl)amino, heterocyclyl-carbonyl or
heterocyclyl-c arbonyl-oxy ;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and, R6 is azido, halogen, hydroxyl, cyano, nitro, Ci-salkyl, halo-Ci-salkyl, hydroxyl-Ci-salkyl, Ci-8alkoxy-Ci_8alkyl, Ci-salkoxy, halo-Ci-salkoxy, hydroxyl-Ci-salkoxy, carboxyl, Ci_8alkyl-carbonyl, Ci-salkoxy-carbonyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-8alkyl-amino, (amino-Ci_8alkyl,Ci_8alkyl)amino,
Ci-8alkyl-amino-Ci-8alkyl-amino, (Ci-8alkyl-amino-Ci-8alkyl,Ci_8alkyl)amino, (Ci-8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl,Ci_8alkyl]amino, halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, halo-Ci-salkyl-amino-Ci-salkyl, (halo-Ci-8alkyl)2-amino-Ci_8alkyl, amino-Ci-salkyl, Ci-salkyl-amino-Ci-salkyl, (Ci-8alkyl)2-amino-Ci_8alkyl, [(Ci-8alkyl)2-amino-Ci-8alkyl,Ci-8alkyl]amino-Ci_8alkyl, Ci_8alkyl-thio, amino-carbonyl, Ci-salkyl-amino-carbonyl,
(Ci-8alkyl)2-amino-carbonyl, Ci-salkyl-carbonyl-amino,
(carboxyl-Ci-8alkyl,Ci_8alkyl)amino-carbonyl-amino, C3_i4cycloalkyl,
C3_i4cycloalkyl-amino, aryl, aryl-Ci-salkyl, aryl-amino, (aryl,Ci_8alkyl)amino, (aryl)2-amino, aryl-Ci-salkyl-amino, (aryl-Ci_8alkyl,Ci_8alkyl)amino,
(aryl-Ci_8alkyl)2-amino, aryl-Ci-salkyl-amino-Ci-salkyl,
(aryl-Ci-8alkyl,Ci-8alkyl)amino-Ci-8alkyl, (aryl-Ci_8alkyl)2-amino-Ci_8alkyl, aryl-amino-Ci_8alkyl, (aryl,Ci_8alkyl)amino-Ci_8alkyl, (aryl)2-amino-Ci_8alkyl, aryl-amino-carbonyl, aryl-Ci-salkoxy, aryl-Ci-salkoxy-carbonyl-amino, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-amino, (heteroaryl)2-amino,
heteroaryl-Ci-8alkyl-amino, (heteroaryl-Ci_8alkyl,Ci_8alkyl)amino,
(heteroaryl-Ci-8alkyl)2-amino, heteroaryl-Ci-salkyl-amino-Ci-salkyl,
(heteroaryl-Ci-8alkyl,Ci-8alkyl)amino-Ci_8alkyl,
(heteroaryl-Ci_8alkyl)2-amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci_salkyl, heterocyclyl-amino-Ci-8alkyl or heterocyclyl-oxy;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one, two or three substituents selected from R9; and,
R9 is Ci_8alkyl, amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino, amino-Ci-salkyl,
Ci-8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl or aryl-Ci-salkyl-amino; wherein the 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.
18. The compound of claim 17, wherein, when Rsa, Rsb, Rsc, R5d and Rse is
C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl alone or as a portion of a substituent, then: C3_i4cycloalkyl 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, lH-tetrazolyl, 2H-tetrazolyl, lH-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-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, indolinyl, 2,3- dihydrobenzo[d]oxazolyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, (6H)-pyrrolo[3,4-b][l,4]oxazin-(2H)-yl,
hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b] [ 1 ,4]oxazin-(4aH)-yl, hexahydro- 1 H-cyclopenta[c]pyrrolyl, (cis)- octahydrocyclopenta[c]pyrrolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro-lH-carbazolyl, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro-lH- pyrrolo[l,2-a]indolyl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)- l,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo [2.2.1 Jheptyl, 2,5 -diazabicyclo [2.2.1 Jheptanyl, 2-azabicyclo [2.2.1 ]hept- 5-enyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hexanyl, (lR,5S,6s)-3- azabicyclo[3.1.0]hexyl, (lR,5S,6s)-3-azabicyclo[3.1.0]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R,6R)-3- azabicyclo[3.2.0]heptyl, (lS,5R,6R)-3-azabicyclo[3.2.0]heptanyl, (1S,5R,6S 3- azabicyclo[3.2.0]heptyl, (lS,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 or 2,8-diazaspiro[4.5]decanyl.
19. The compound of claim 16, wherein the compound is substituted with one or more R5a, R5b, R5c, R5d, and R5e substituents each, when present, selected from the group consisting of:
hydrogen, Ci-salkyl, Ci-ioalkyl-amino-Ci-salkyl, (Ci_ioalkyl)2-amino-Ci_8alkyl, heterocyclyl, heterocyclyl-Ci_8alkyl;
wherein each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
R6 is amino, Ci-salkyl-amino, (Ci_8alkyl)2-amino.
20. The compound of claim 16, wherein the compound is a compound of Formula (Icl), or a form thereof;
Figure imgf000328_0001
(Icl);
wherein the 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.
21. A compound selected from the group consisting of:
4-hydroxy-8,9-dimethyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid; 8-ethyl-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
4-hydroxy-9-methyl-2-oxo-8-propyl- 1,2,5, 6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
8-cyclopropyl-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
7- hydroxy-2,3-dimethyl-9-oxo-3,4,5,6,9,10-hexaliydroimidazo[4',5':6,7]cycloliepta[l,2- b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
8- ethyl-4-hydroxy-2-oxo-l,2,5,6,7,8-hexahydropyrazolo[3',4':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid;
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-2-oxo-2,5, 6,7,9,10,11,12-octahydro-lH- pyrido[3",2":6',7']cyclohepta[ ,2':4,5]imidazo[l,2-a]pyridine-3-carboxylic acid;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic acid;
4-hydroxy-2-oxo-8-[2-(pyrrolidin-l-yl)ethyl]-l,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,8-hexaliydropyrrolo[2',3':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid;
8- ethyl-4-hydroxy-9,10-dimethyl-2-oxo-l,2,5,6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- carboxylic acid;
2-ethyl-7-hydroxy-3-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2,3-diethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid;
7- hydroxy-l-methyl-9-oxo- 1,4,5,6,9, 10-hexahydropyrazolo[4',3':6,7]cyclohepta[l, 2- b]pyridine-8-carboxylic acid;
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,9-hexaliydropyrrolo[3',4':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid;
8- hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid; 3-(2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-(methoxymethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
8- hydroxy-2 -dimethyl-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
2-ethyl-7-hydroxy-9-oxo-2,4,5,6,9,10-hexahydro[l,2,3]triazolo[4',5':6,7]cyclohepta[l,2- b] pyridine-8-carboxylic acid;
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c] azepine-9-carboxylic acid;
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
3- ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-
9- carboxylic acid;
2- chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
3- ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2-[(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-methyl-2-oxo-2,6,7,8-tetrahydro-lH-pyrazolo[4',3':4,5]oxepino[3,2- b]pyridine-3-carboxylic acid;
2- [(benzyloxy)methyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4,5 , 6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,ll-tetrahydroimidazo[l,2-d]pyrido[2,3- f] [ 1 ,4]oxazepine-9-carboxylic acid;
3- ethyl-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- f] [ 1 ,4]oxazepine-9-carboxylic acid;
7-hydroxy-2-(methoxymethyl)-3-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; 4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
3-ethyl-7-hydroxy-2-[(oxetan-3-yloxy)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-2,3-dimethyl-9-oxo-2,4,5,6,9,10-hexahydropyrazolo[4',3':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid;
7- hydroxy-3-(2-methoxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-(3-hydroxypropyl)-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8-(2-methoxyethyl)-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8-(3-methoxypropyl)-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
7-hydroxy-3-(2-hydroxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-[(2-hydroxyethoxy)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-(2-hydroxyethyl)-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-2-[(ethylsulfonyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-2-[(ethylsulfinyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2-[(acetyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-3-(3-methoxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-3-(3-hydroxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; 3-[3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-(2-hydroxyethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [2-(benzyloxy)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5S)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3- ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-[(methylsulfinyl)methyl]-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2-[2-(dimethylamino)ethyl]-3-ethyl-7-liydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [3-(dimethylamino)propyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5R)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
(5S)-4-hydroxy-8-(3-methoxypropyl)-5-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
(5S)-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8-hexaliydropyrazolo[3',4':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid;
(5S)-8-ethyl-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-2-oxo-l,2,5,6,7,8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3- carboxylic acid;
4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2- b]indole-3-carboxylic acid;
4-hydroxy-12-methyl-2-oxo-l,2,5,6,7,12-hexahydropyrido[3',2':6,7]cycloliepta[l,2- b]indole-3-carboxylic acid;
4-hydroxy-2-oxo-l,2,5,6,7,12-hexahydropyrido[3',2':6,7]cyclohepta[l,2-b]indole-3- carboxylic acid;
8- ethyl-4-hydroxy-2-oxo-l,2,5,6,7,8-hexahydropyrido[2',3':3,4]cycloliepta[l,2-b]indole-
3- carboxylic acid;
9- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4- hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid; 4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)- 1,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy- 8-methyl-9- [(methylamino)methyl] -2-oxo- 1 ,2, 5 ,6,7, 8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9- [3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
ll-[(dimethylamino)methyl]-4-hydroxy-8-metliyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-ll-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- carboxylic acid;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]indole-3- carboxylic acid;
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
10- [(dimethylamino)methyl]-4-hydroxy-8-metliyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
3-ethyl-7-hydroxy-2-( 1 H-imidazol- 1 -ylmethyl)-9-oxo-3 ,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-metliyl-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5S)-4-hydroxy-5-methyl-2-oxo-8-(propan-2-yl)-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid; (6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; and
(6S)-3-ethyl-7-hydroxy-2-[(2-methoxyethoxy)metliyl]-6-rnetliyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
wherein the 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.
22. The compound of claim 21, wherein a compound salt is selected from the group consisting of:
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate;
4- hydroxy-2-oxo-2,5, 6,7,9,10,11,12-octahydro-lH- pyrido[3' 2'':6 7']cyclohepta[l\2 ,5]imidazo[l,2-a]pyridine-3-carboxylic acid hydrochloride;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic acid hydrochloride;
4-hydroxy-2-oxo-8-[2-(pyrrolidin-l-yl)ethyl]-l,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
8- [2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- carboxylic acid hydrochloride;
8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid hydrochloride;
3-(2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate;
8- hydroxy-2,3-dimethyl-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
3- ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-
9- carboxylic acid hydrochloride;
2-chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride; 2- [(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,ll-tetrahydroimidazo[l,2-d]pyrido[2,3- f][l,4]oxazepine-9-carboxylic acid hydrochloride;
3- ethyl-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- f][l,4]oxazepine-9-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-[3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2-[2-(dimethylamino)ethyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2- [3-(dimethylamino)propyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
9- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4- hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 9-[(ethylamino)methyl]-4-hydroxy-8-metliyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
9- [3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate; ll-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-ll-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2\3':3,4]azepino[l,2-a]benzimidazole-3- carboxylic acid hydrochloride;
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 4-hydroxy-8-[3-(methylamino)propyl]-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
10- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-2-( 1 H-imidazol- 1 -ylmethyl)-9-oxo-3 ,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; and
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; wherein the 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.
23. A method of use for a compound of claim 1 for treating or ameliorating a wild- type or drug-resistant form 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.
24. The method of claim 23, wherein the compound is selected from the group consisting of:
4-hydroxy-8,9-dimethyl-2-oxo- 1,2, 5,6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
8-ethyl-4-hydroxy-9-methyl-2-oxo- 1,2, 5,6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
4-hydroxy-9-methyl-2-oxo-8-propyl-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
8-cyclopropyl-4-hydroxy-9-methyl-2-oxo- 1 ,2,5 , 6,7 , 8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
7- hydroxy-2,3-dimethyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid;
4- hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-2-oxo-2,5 ,6,7,9, 10,11 , 12-octahydro- 1H- pyrido[3",2":6',7']cyclohepta[ ,2':4,5]imidazo[l,2-a]pyridine-3-carboxylic acid;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic acid;
4-hydroxy-2-oxo-8-[2-(pyrrolidin-l-yl)ethyl]-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
8-ethyl-4-hydroxy-9,10-dimethyl-2-oxo-l,2,5,6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid; 9-ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- carboxylic acid;
2- ethyl-7-hydroxy-3-methyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid;
2 -diethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid;
7- hydroxy-l-methyl-9-oxo-l,4,5,6,9,10-hexahydropyrazolo[4',3':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid;
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,9-hexahydropyrrolo[3',4':6,7]cyclohepta[l,2- b] pyridine-3-carboxylic acid;
8- hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid;
3- (2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-(methoxymethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
8-hydroxy-2,3-dimethyl-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c] azepine-9-carboxylic acid;
2-ethyl-7-hydroxy-9-oxo-2,4,5,6,9,10-hexahydro[l,2,3]triazolo[4',5':6,7]cyclohepta[l,2- b] pyridine-8-carboxylic acid;
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c] azepine-9-carboxylic acid;
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
3- ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid;
2- chloro-3-ethyl-8-hydroxy-10-oxo-6 ,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
3- ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2-[(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-methyl-2-oxo-2,6,7,8-tetrahydro-lH-pyrazolo[4',3':4,5]oxepino[3,2- b]pyridine-3-carboxylic acid;
2-[(benzyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,ll-tetrahydroimidazo[l,2-d]pyrido[2,3- f] [1 ,4]oxazepine-9-carboxylic acid; 3-ethyl-8-hydroxy-10-oxo-5,6J0Jl-tetrahydroimidazo[l,2-d]pyrido[2,3-f][l,4]oxazepine- 9-carboxylic acid;
7-hydroxy-2-(methoxymethyl)-3-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
3-ethyl-7-hydroxy-2- [(oxetan-3 -yloxy)methyl] -9-OXO-3 ,4,5 , 6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-2,3-dimethyl-9-oxo-2,4,5,6,9,10-hexahydropyrazolo[4',3':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid;
7- hydroxy-3-(2-methoxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-(3-hydroxypropyl)-2-oxo- 1,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8-(2-methoxyethyl)-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8-(3-methoxypropyl)-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
7-hydroxy-3-(2-hydroxyethyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-[(2-hydroxyethoxy)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-(2-hydroxyethyl)-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid; 3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-2-[(ethylsulfonyl)methyl]-7-hydroxy-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-2-[(ethylsulfinyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [(acetyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-3-(3-methoxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-3-(3-hydroxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- [3 -(dimethylamino)propyl] -7-hydroxy-2-methyl-9-oxo-3 ,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-(2-hydroxyethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [2-(benzyloxy)ethyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5S)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3- ethyl-7-hydroxy-9-oxo-2-( 1 H-pyrazol- 1 -ylmethyl)-3 ,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-[(methylsulfinyl)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2-[2-(dimethylamino)ethyl]-3-ethyl-7-liydroxy-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [3-(dimethylamino)propyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5R)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
(5S)-4-hydroxy-8-(3-methoxypropyl)-5-methyl-2-oxo- 1,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
(5S)-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8-hexaliydropyrazolo[3',4':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid;
(5S)-8-ethyl-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-2-oxo- 1,2, 5,6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3- carboxylic acid; 4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-
3- carboxylic acid;
4- hydroxy-12-methyl-2-oxo- 1,2,5,6,7, 12-hexahydropyrido[3',2':6,7]cyclohepta[l,2- b]indole-3-carboxylic acid;
4-hydroxy-2-oxo- 1,2,5,6,7, 12-hexahydropyrido[3',2':6,7]cyclohepta[l,2-b]indole-3- carboxylic acid;
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3- carboxylic acid;
9- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin- 1-ylmethyl)- 1 ,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9-[3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
ll-[(dimethylamino)methyl]-4-hydroxy-8-metliyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- carboxylic acid;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]indole-3-carboxylic acid;
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid; 10-[(dimethylamino)methyl]-4-hydroxy-8-metliyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
10- {[ethyl(methyl)amino]methyl}-4-hydroxy-8-metliyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
3-ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-metliyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5S)-4-hydroxy-5-methyl-2-oxo-8-(propan-2-yl)-l,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; and
(6S)-3-ethyl-7-hydroxy-2-[(2-methoxyethoxy)metliyl]-6-metliyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
wherein the 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.
25. The method of claim 24, wherein a compound salt is selected from the group consisting of:
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate;
4- hydroxy-2-oxo-2,5 ,6,7,9, 10,11 , 12-octahydro- 1H- pyrido[3",2":6',7']cyclohepta[ ,2':4,5]imidazo[l,2-a]pyridine-3-carboxylic acid hydrochloride;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic acid hydrochloride;
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7, 8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
8- [2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- carboxylic acid hydrochloride;
8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid hydrochloride;
3-(2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate; 8- hydroxy-2 -dimethyl-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2,3-diethyl-8-hydroxy-10-oxo-6,7 ,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
3- ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid hydrochloride;
2-chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2- [(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- f][l,4]oxazepine-9-carboxylic acid hydrochloride;
3- ethyl-8-hydroxy-10-oxo-5,6,10,ll-tetrahydroimidazo[l,2-d]pyrido[2,3-f][l,4]oxazepine-
9- carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-[3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; 2- [3 -(dimethylamino)propyl] -3-ethyl-7-hydroxy-9-oxo-3 ,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4- hydroxy-8-methyl-2-oxo-9-(pyrrolidin- 1-ylmethyl)- 1 ,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
9- [(ethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
9- [3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate; ll-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- carboxylic acid hydrochloride;
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 4-hydroxy-8-[3-(methylamino)propyl]-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
10- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
10- { [ethyl(methyl) amino] methyl } -4-hydroxy-8-methyl-2-oxo- 1 ,2,5,6,7, 8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride ;
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 3- ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; and
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; wherein the 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.
26. The method of claim 23, wherein the compound is selected from the group consisting of:
4- hydroxy-8,9-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
8-ethyl-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
4-hydroxy-9-methyl-2-oxo-8-propyl- 1,2,5,6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
8-cyclopropyl-4-hydroxy-9-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
7- hydroxy-2,3-dimethyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-methyl-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic acid;
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7, 8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid; 4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
8- ethyl-4-hydroxy-9,10-dimethyl-2-oxo-l,2,5, 6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- carboxylic acid;
2- ethyl-7-hydroxy-3 -methyl-9-oxo-3 ,4,5 , 6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2,3-diethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid;
7- hydroxy-l-methyl-9-oxo-l,4,5,6,9,10-hexahydropyrazolo[4',3':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid;
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,9-hexahydropyrrolo[3',4':6,7]cyclohepta[l,2- b] pyridine-3-carboxylic acid;
8- hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid;
3- (2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-(methoxymethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
8-hydroxy-2,3-dimethyl-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c] azepine-9-carboxylic acid;
2-ethyl-7-hydroxy-9-oxo-2,4,5,6,9,10-hexahydro[l,2,3]triazolo[4',5':6,7]cyclohepta[l,2- b] pyridine-8-carboxylic acid;
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c] azepine-9-carboxylic acid;
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
3- ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid;
2- chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
3- ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2-[(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; 4-hydroxy-8-methyl-2-oxo-2,6,7,8-tetrahydro-lH-pyrazolo[4',3':4,5]oxepino[3,2- b]pyridine-3-carboxylic acid;
2- [(benzyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- f] [ 1 ,4]oxazepine-9-carboxylic acid;
3- ethyl-8-hydroxy- lO-oxo-5 ,6, 10, 11 -tetrahydroimidazo[ 1 ,2-d]pyrido[2,3-f] [ 1 ,4]oxazepine- 9-carboxylic acid;
7-hydroxy-2-(methoxymethyl)-3-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-5,8-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
3-ethyl-7-hydroxy-2- [(oxetan-3 -yloxy)methyl] -9-OXO-3 ,4, 5 ,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-2,3-dimethyl-9-oxo-2,4,5,6,9,10-hexaliydropyrazolo[4',3':6,7]cycloliepta[l,2- b]pyridine-8-carboxylic acid;
7- hydroxy-3-(2-methoxyethyl)-2-methyl-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-(3-hydroxypropyl)-2-oxo- 1,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8-(2-methoxyethyl)-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8-(3-methoxypropyl)-2-oxo- 1,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
7-hydroxy-3-(2-hydroxyethyl)-2-methyl-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; 3-ethyl-7-hydroxy-2-[(2-hydroxyethoxy)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-ethyl-7-hydroxy-9-oxo-: hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-(2-hydroxyethyl)-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-2-[(ethylsulfonyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-2-[(ethylsulfinyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [(acetyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-3-(3-methoxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-3-(3-hydroxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- [3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-(2-hydroxyethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [2-(benzyloxy)ethyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5S)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3- ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-[(methylsulfinyl)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [3 -(dimethylamino)propyl] -3-ethyl-7-hydroxy-9-oxo-3 ,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5R)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid; (5S)-4-hydroxy-8-(3-methoxypropyl)-5-methyl-2-oxo- 1,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
(5S)-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8-hexaliydropyrazolo[3',4':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid;
(5S)-8-ethyl-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-metliyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5S)-4-hydroxy-5-methyl-2-oxo-8-(propan-2-yl)-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; and
(6S)-3-ethyl-7-hydroxy-2-[(2-methoxyethoxy)metliyl]-6-rnetliyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; wherein the 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.
27. The method of claim 23, wherein the compound is selected from the group consisting of:
4- hydroxy-2-oxo-2,5 ,6,7,9, 10,11 , 12-octahydro- 1H- pyrido[3",2":6',7']cyclohepta[ ,2':4,5]imidazo[l,2-a]pyridine-3-carboxylic acid;
4-hydroxy-12-methyl-2-oxo- 1,2,5,6,7, 12-hexahydropyrido[3',2':6,7]cyclohepta[l,2- b]indole-3-carboxylic acid;
4-hydroxy-2-oxo- 1,2,5,6,7, 12-hexahydropyrido[3',2':6,7]cyclohepta[l,2-b]indole-3- carboxylic acid;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- carboxylic acid; and
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]indole-3-carboxylic acid; wherein the 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.
28. The method of claim 23, wherein the compound is selected from the group consisting of:
4-hydroxy-2-oxo- 1,2, 5,6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3- carboxylic acid;
4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-
3- carboxylic acid;
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3- carboxylic acid;
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4- hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9- [(ethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9-[3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
ll-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid; 8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
10-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid; and
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid; wherein the 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.
29. A method of use for a compound salt of claim 1 for treating or ameliorating a wild- type or drug-resistant form of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound salt of claim 1 or a form thereof to the subject.
30. The method of claim 29, wherein the compound salt is selected from the group consisting of:
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate;
4- hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic acid hydrochloride;
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7, 8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
8- [2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- carboxylic acid hydrochloride;
8-hydroxy-10-oxo-6,7, 10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid hydrochloride;
3-(2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate;
8-hydroxy-2,3-dimethyl-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride; 2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7 ,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
3- ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid hydrochloride;
2-chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2- [(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- f][l,4]oxazepine-9-carboxylic acid hydrochloride;
3- ethyl-8-hydroxy-10-oxo-5,6,10,ll-tetrahydroimidazo[l,2-d]pyrido[2,3-f][l,4]oxazepine- 9-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-[3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2- [3 -(dimethylamino)propyl] -3-ethyl-7-hydroxy-9-oxo-3 ,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; 3- ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; and
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; wherein the 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.
31. The method of claim 29, wherein the compound salt is selected from the group consisting of:
4- hydroxy-2-oxo-2,5 ,6,7,9, 10,11 , 12-octahydro- 1H- pyrido[3",2":6',7']cyclohepta[ ,2':4,5]imidazo[l,2-a]pyridine-3-carboxylic acid hydrochloride; and
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- carboxylic acid hydrochloride;
wherein the 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.
32. The method of claim 29, wherein the compound salt is selected from the group consisting of:
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
9- [(ethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate; 9- [3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate; l l-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
10- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; and
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
wherein the 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.
33. A method of use for a compound of claim 1 for treating or ameliorating a wild- type or drug-resistant form of N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound of claim 1 or a form thereof to the subject.
34. The method of claim 33, wherein the compound is selected from the group consisting of:
4-hydroxy-8,9-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
8-ethyl-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
4-hydroxy-9-methyl-2-oxo-8-propyl- 1,2,5,6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid; 8-cyclopropyl-4-hydroxy-9-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
7- hydroxy-2,3-dimethyl-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-methyl-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-hexaliydropyrazolo[3',4':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid;
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-2-oxo-2,5 ,6,7,9, 10,11 , 12-octahydro- 1H- pyrido[3",2":6',7']cyclohepta[ ,2':4,5]imidazo[l,2-a]pyridine-3-carboxylic acid;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic acid;
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7, 8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,8-hexaliydropyrrolo[2',3':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid;
8- ethyl-4-hydroxy-9,10-dimethyl-2-oxo-l,2,5, 6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- carboxylic acid;
2- ethyl-7-hydroxy-3 -methyl-9-oxo-3 ,4,5 , 6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2,3-diethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cycloliepta[l,2- b]pyridine-8-carboxylic acid;
7- hydroxy-l-methyl-9-oxo-l,4,5,6,9,10-hexaliydropyrazolo[4',3':6,7]cycloliepta[l,2- b]pyridine-8-carboxylic acid;
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,9-hexaliydropyrrolo[3',4':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid;
8- hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid;
3- (2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-(methoxymethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; 8- hydroxy-2,3-dimethyl-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
2-ethyl-7-hydroxy-9-oxo-2,4,5,6,9,10-hexahydro[l,2,3]triazolo[4',5':6,7]cyclohepta[l,2- b] pyridine-8-carboxylic acid;
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c] azepine-9-carboxylic acid;
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
3- ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-
9- carboxylic acid;
2- chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
3- ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2-[(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-methyl-2-oxo-2,6,7,8-tetrahydro-lH-pyrazolo[4',3':4,5]oxepino[3,2- b]pyridine-3-carboxylic acid;
2- [(benzyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- f] [ 1 ,4]oxazepine-9-carboxylic acid;
3- ethyl-8-hydroxy-10-oxo-5,6,10,ll-tetrahydroimidazo[l,2-d]pyrido[2,3- f] [ 1 ,4]oxazepine-9-carboxylic acid;
7-hydroxy-2-(methoxymethyl)-3-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-5,8-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
3-ethyl-7-hydroxy-2- [(oxetan-3 -yloxy)methyl] -9-OXO-3 ,4, 5 ,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; 3- ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-2,3-dimethyl-9-oxo-2,4,5,6,9,10-hexahydropyrazolo[4',3':6,7]cyclohepta[l,2- b]pyridine-8-carboxylic acid;
7- hydroxy-3-(2-methoxyethyl)-2-methyl-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-(3-hydroxypropyl)-2-oxo- 1,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8-(2-methoxyethyl)-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8-(3-methoxypropyl)-2-oxo- 1,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
7-hydroxy-3-(2-hydroxyethyl)-2-methyl-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-[(2-hydroxyethoxy)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-etliyl-7-liydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-(2-hydroxyethyl)-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-2-[(ethylsulfonyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-2-[(ethylsulfinyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [(acetyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-3-(3-methoxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-3-(3-hydroxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- [3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-(2-hydroxyethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; 2- [2-(benzyloxy)ethyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5S)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3- ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-[(methylsulfinyl)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [3 -(dimethylamino)propyl] -3-ethyl-7-hydroxy-9-oxo-3 ,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5R)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
(5S)-4-hydroxy-8-(3-methoxypropyl)-5-methyl-2-oxo- 1,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
(5S)-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8-hexaliydropyrazolo[3',4':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid;
(5S)-8-ethyl-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-2-oxo- 1,2, 5,6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3- carboxylic acid;
4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-hexaliydropyrido[2',3':3,4]cycloliepta[l,2- b]indole-3-carboxylic acid;
4-hydroxy-12-methyl-2-oxo- 1,2,5,6,7, 12-hexahydropyrido[3',2':6,7]cyclohepta[l,2- b]indole-3-carboxylic acid;
4-hydroxy-2-oxo- 1,2,5,6,7, 12-hexahydropyrido[3',2':6,7]cyclohepta[l,2-b]indole-3- carboxylic acid;
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-
3- carboxylic acid;
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4- hydroxy-8-methyl-2-oxo-9-(pyrrolidin- 1-ylmethyl)- 1 ,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid; 9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9- [3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
ll-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- carboxylic acid;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]indole-3- carboxylic acid;
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
10- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
10- { [ethyl(methyl) amino] methyl } -4-hydroxy-8-methyl-2-oxo- 1 ,2,5,6,7, 8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
3-ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-metliyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5S)-4-hydroxy-5-methyl-2-oxo-8-(propan-2-yl)-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; and
(6S)-3-ethyl-7-hydroxy-2-[(2-methoxyethoxy)metliyl]-6-metliyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; wherein the 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.
35. The method of claim 33, wherein a compound salt is selected from the group consisting of:
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate;
4- hydroxy-2-oxo-2,5 ,6,7,9, 10,11 , 12-octahydro- 1H- pyrido[3",2":6',7']cyclohepta[ ,2':4,5]imidazo[l,2-a]pyridine-3-carboxylic acid hydrochloride;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic acid hydrochloride;
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7, 8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
8- [2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- carboxylic acid hydrochloride;
8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid hydrochloride;
3-(2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate;
8- hydroxy-2,3-dimethyl-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
3- ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-
9- carboxylic acid hydrochloride;
2-chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2-[(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- f][l,4]oxazepine-9-carboxylic acid hydrochloride; 3-ethyl-8-hydroxy-10-oxo-5,6,10,ll-tetrahydroimidazo[l,2-d]pyrido[2,3- f][l,4]oxazepine-9-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-[3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2- [3 -(dimethylamino)propyl] -3-ethyl-7-hydroxy-9-oxo-3 ,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4- hydroxy-8-methyl-2-oxo-9-(pyrrolidin- 1-ylmethyl)- 1 ,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
9- [(ethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
9- [3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate; ll-[(dimethylamino)rnethyl]-4-hydroxy-8-metliyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- carboxylic acid hydrochloride;
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
10- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
10-{[ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
3- ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; and
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; wherein the 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.
36. The method of claim 33, wherein the compound is selected from the group consisting of:
4- hydroxy-8,9-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid; 4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
8-ethyl-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrrolo[2',3':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
4-hydroxy-9-methyl-2-oxo-8-propyl- 1,2,5,6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
8-cyclopropyl-4-hydroxy-9-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
7- hydroxy-2,3-dimethyl-9-oxo-3,4,5,6,9,10-hexaliydroimidazo[4',5':6,7]cycloliepta[l,2- b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-methyl-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-hexaliydropyrazolo[3',4':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid;
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic acid;
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7, 8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,8-hexaliydropyrrolo[2',3':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid;
8- ethyl-4-hydroxy-9,10-dimethyl-2-oxo-l,2,5, 6,7,8- hexahydropyrrolo[2',3':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- carboxylic acid;
2-ethyl-7-hydroxy-3 -methyl-9-oxo-3 ,4,5 , 6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2,3-diethyl-7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydroimidazo[4',5':6,7]cycloliepta[l,2- b]pyridine-8-carboxylic acid;
7-hydroxy- 1 -methyl-9-oxo- 1,4,5,6,9,10-hexahydropyrazolo [4' ,3 ' : 6,7]cyclohepta[ 1,2- b]pyridine-8-carboxylic acid;
4-hydroxy-8,9,10-trimethyl-2-oxo-l,2,5,6,7,9-hexaliydropyrrolo[3',4':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid; 8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid;
3-(2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-(methoxymethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
8- hydroxy-2,3-dimethyl-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
2-ethyl-7-hydroxy-9-oxo-2,4,5,6,9,10-hexahydro[l,2,3]triazolo[4',5':6,7]cyclohepta[l,2- b] pyridine-8-carboxylic acid;
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c] azepine-9-carboxylic acid;
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
3- ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid;
2- chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid;
3- ethyl-7-hydroxy-2-(hydroxymethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2-[(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-methyl-2-oxo-2,6,7,8-tetrahydro-lH-pyrazolo[4',3':4,5]oxepino[3,2- b]pyridine-3-carboxylic acid;
2- [(benzyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- f] [ 1 ,4]oxazepine-9-carboxylic acid;
3- ethyl-8-hydroxy-10-oxo-5,6,10,ll-tetrahydroimidazo[l,2-d]pyrido[2,3-f][l,4]oxazepine-
9- carboxylic acid;
7-hydroxy-2-(methoxymethyl)-3-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; 3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-5,8-dimethyl-2-oxo- 1,2,5, 6,7, 8-hexahydropyrazolo[3',4':6,7]cyclohepta[l,2- b]pyridine-3-carboxylic acid;
3-ethyl-7-hydroxy-2- [(oxetan-3 -yloxy)methyl] -9-OXO-3 ,4, 5 ,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-2-[(2-methoxyethoxy)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-2,3-dimethyl-9-oxo-2,4,5,6,9,10-hexaliydropyrazolo[4',3':6,7]cycloliepta[l,2- b]pyridine-8-carboxylic acid;
7- hydroxy-3-(2-methoxyethyl)-2-methyl-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-(3-hydroxypropyl)-2-oxo- 1,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
8- [3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8-(2-methoxyethyl)-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
4-hydroxy-8-(3-methoxypropyl)-2-oxo- 1,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
7-hydroxy-3-(2-hydroxyethyl)-2-methyl-9-oxo-3,4,5, 6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-[(2-hydroxyethoxy)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-etliyl-7-liydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
4- hydroxy-8-(2-hydroxyethyl)-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-2-[(ethylsulfonyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-2-[(ethylsulfinyl)methyl]-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; 2- [(acetyloxy)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-3-(3-methoxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
7-hydroxy-3-(3-hydroxypropyl)-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3- [3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-(2-hydroxyethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [2-(benzyloxy)ethyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5S)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3- ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-[(methylsulfinyl)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
2- [3 -(dimethylamino)propyl] -3-ethyl-7-hydroxy-9-oxo-3 ,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5R)-4-hydroxy-5,8-dimethyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
(5S)-4-hydroxy-8-(3-methoxypropyl)-5-methyl-2-oxo- 1,2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
(5S)-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8-hexaliydropyrazolo[3',4':6,7]cycloliepta[l,2- b]pyridine-3-carboxylic acid;
(5S)-8-ethyl-4-hydroxy-5-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid;
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
3-ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-metliyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid;
(5S)-4-hydroxy-5-methyl-2-oxo-8-(propan-2-yl)-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid; (6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; and
(6S)-3-ethyl-7-hydroxy-2-[(2-methoxyethoxy)metliyl]-6-rnetliyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid; wherein the 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.
37. The method of claim 33, wherein the compound is selected from the group consisting of:
4-hydroxy-2-oxo-2,5 ,6,7,9, 10,11 , 12-octahydro- 1H- pyrido[3",2":6',7']cyclohepta[ ,2':4,5]imidazo[l,2-a]pyridine-3-carboxylic acid;
4-hydroxy-12-methyl-2-oxo- 1,2,5,6,7, 12-hexahydropyrido[3',2':6,7]cyclohepta[l,2- b]indole-3-carboxylic acid;
4-hydroxy-2-oxo- 1,2,5,6,7, 12-hexahydropyrido[3',2':6,7]cyclohepta[l,2-b]indole-3- carboxylic acid;
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- carboxylic acid; and
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]indole-3-carboxylic acid; wherein the 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.
38. The method of claim 33, wherein the compound is selected from the group consisting of:
4-hydroxy-2-oxo- 1,2, 5,6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3- carboxylic acid;
4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-
3- carboxylic acid;
8- ethyl-4-hydroxy-2-oxo- 1,2,5, 6,7, 8-hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3- carboxylic acid;
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4- hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid; 4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
9- [3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
l l-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
10- [(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid;
10- { [ethyl(methyl) amino] methyl } -4-hydroxy-8-methyl-2-oxo- 1 ,2,5,6,7, 8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid; and
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid; wherein the 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.
39. A method of use for a compound salt of claim 1 for treating or ameliorating a wild- type or drug-resistant form of N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound salt of claim 1 or a form thereof to the subject.
40. The method of claim 39, wherein the compound salt is selected from the group consisting of:
3- [2-(dimethylamino)ethyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate;
4- hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3-carboxylic acid hydrochloride;
4-hydroxy-2-oxo- 8- [2-(pyrrolidin- 1 -yl)ethyl] - 1 ,2,5 , 6,7, 8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
8- [2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
9- ethyl-4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-imidazo[l,5-a]pyrido[2,3-c]azepine-3- carboxylic acid hydrochloride;
8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid hydrochloride;
3-(2-aminoethyl)-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid trifluoroacetate;
8- hydroxy-2,3-dimethyl-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2,3-dichloro-8-hydroxy-10-oxo-6,7,10,l l-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2- chloro-3-ethenyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2,3-diethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
3- ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3-c]azepine-9- carboxylic acid hydrochloride;
2-chloro-3-ethyl-8-hydroxy-10-oxo-6,7,10,ll-tetrahydro-5H-imidazo[l,2-a]pyrido[2,3- c]azepine-9-carboxylic acid hydrochloride;
2- [(dimethylamino)methyl]-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2,3-dichloro-8-hydroxy-10-oxo-5,6,10,l l-tetrahydroimidazo[l,2-d]pyrido[2,3- f][l,4]oxazepine-9-carboxylic acid hydrochloride;
3- ethyl-8-hydroxy-10-oxo-5,6,10,ll-tetrahydroimidazo[l,2-d]pyrido[2,3-f][l,4]oxazepine-
9- carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-(pyrrolidin-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; 3-ethyl-7-hydroxy-9-oxo-2-[(propan-2-ylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(propylamino)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-2-[(methylamino)methyl]-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrazolo[3',4':6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride;
2- ({4-[(dimethylamino)methyl]phenoxy}methyl)-3-ethyl-7-hydroxy-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3- ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-ylmethoxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-[(pyridin-4-yloxy)methyl]-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-[3-(dimethylamino)propyl]-7-hydroxy-2-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-9-oxo-2-(lH-pyrazol-l-ylmethyl)-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2- [2-(dimethylamino)ethyl] -3 -ethyl-7-hydroxy-9-oxo-3 ,4, 5 ,6,9, 10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
2- [3 -(dimethylamino)propyl] -3-ethyl-7-hydroxy-9-oxo-3 ,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3- ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
3-ethyl-7-hydroxy-2-(lH-imidazol-l-ylmethyl)-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride;
(6S)-3-ethyl-7-hydroxy-2-(methoxymethyl)-6-methyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; and
(6S)-3-ethyl-7-hydroxy-2,6-dimethyl-9-oxo-3,4,5,6,9,10- hexahydroimidazo[4',5':6,7]cyclohepta[l,2-b]pyridine-8-carboxylic acid hydrochloride; wherein the 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.
41. The method of claim 39, wherein the compound salt is selected from the group consisting of:
4-hydroxy-2-oxo-2,5 ,6,7,9, 10,11 , 12-octahydro- 1H- pyrido[3",2":6',7']cyclohepta[ ,2':4,5]imidazo[l,2-a]pyridine-3-carboxylic acid hydrochloride; and
4-hydroxy-2-oxo-l,5,6,7-tetrahydro-2H-pyrido[2',3':3,4]azepino[l,2-a]benzimidazole-3- carboxylic acid hydrochloride;
wherein the 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.
42. The method of claim 39, wherein the compound salt is selected from the group consisting of:
9- [(dimethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo- 1,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-9-(piperazin-l-yl)-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
4-hydroxy-8-methyl-9-[(methylamino)methyl]-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
9- [(ethylamino)methyl] -4-hydroxy- 8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]- 1,2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
9-[(3S)-3-aminopyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
9-[3-(diethylamino)pyrrolidin-l-yl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate; ll-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-methyl-2-oxo-l l-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
4-hydroxy-8-[2-(methylamino)ethyl]-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 4-hydroxy-8-[3-(methylamino)propyl]-2-oxo- 1,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 8-[3-(dimethylamino)propyl]-4-hydroxy-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; 8-[2-(dimethylamino)ethyl]-4-hydroxy-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid trifluoroacetate;
10-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride;
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-8-methyl-2-oxo-l,2,5,6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; and
4-hydroxy-8-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l, 2,5, 6,7,8- hexahydropyrido[2',3':3,4]cyclohepta[l,2-b]indole-3-carboxylic acid hydrochloride; wherein the 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.
43. The method of any of claims 23, 29, 33 or 39, 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.
44. A use of the compound of claim 1 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.
45. A use of the compound of claim 1 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.
46. A use of the compound of claim 1 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 claim 1 or a form thereof in admixture with one or more
pharmaceutically acceptable excipient(s).
47. A use of the compound of claim 1 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 claim 1 or a form thereof and an effective amount of one or more antibiotic or antibacterial agent(s).
48. The use of any of claims 44, 45, 46 or 47, 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.
49. A use of the compound of claim 1 or a form thereof for treating or ameliorating wild- type or drug-resistant forms of N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound or a form thereof to the subject.
50. A use of the compound of claim 1 or a form thereof in the manufacture of a
medicament for treating or ameliorating wild-type or drug-resistant forms of
N. meningitidis in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
51. A use of the compound of claim 1 or a form thereof in a pharmaceutical composition for treating or ameliorating wild-type or drug-resistant forms of N. meningitidis 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).
52. A use of the compound of claim 1 or a form thereof in a combination therapy for treating or ameliorating wild-type or drug-resistant forms of N. meningitidis 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).
53. The use of any of claims 49, 50, 51 or 52, 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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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020203763A1 (en) 2019-03-29 2020-10-08 住友化学株式会社 Heterocyclic compound and harmful arthropod pest control composition containing same
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same
WO2022071434A1 (en) 2020-09-30 2022-04-07 住友化学株式会社 Heterocyclic compound and harmful arthropod-controlling composition containing same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5155115A (en) * 1991-03-12 1992-10-13 Kyowa Hakko Kogyo Co., Ltd. Thienopyridine derivatives
WO2013033240A1 (en) * 2011-08-29 2013-03-07 Ptc Therapeutics, Inc. Antibacterial compounds and methods for use
WO2013033228A1 (en) * 2011-08-29 2013-03-07 Ptc Therapeutics, Inc. Antibacterial compounds and methods for use
WO2013033258A1 (en) * 2011-08-29 2013-03-07 Ptc Therapeutics, Inc. Antibacterial compounds and methods for use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5155115A (en) * 1991-03-12 1992-10-13 Kyowa Hakko Kogyo Co., Ltd. Thienopyridine derivatives
WO2013033240A1 (en) * 2011-08-29 2013-03-07 Ptc Therapeutics, Inc. Antibacterial compounds and methods for use
WO2013033228A1 (en) * 2011-08-29 2013-03-07 Ptc Therapeutics, Inc. Antibacterial compounds and methods for use
WO2013033258A1 (en) * 2011-08-29 2013-03-07 Ptc Therapeutics, Inc. Antibacterial compounds and methods for use

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same
WO2020203763A1 (en) 2019-03-29 2020-10-08 住友化学株式会社 Heterocyclic compound and harmful arthropod pest control composition containing same
WO2022071434A1 (en) 2020-09-30 2022-04-07 住友化学株式会社 Heterocyclic compound and harmful arthropod-controlling composition containing same

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