WO2016025932A1 - Substituted polycyclic antibacterial compounds - Google Patents

Substituted polycyclic antibacterial compounds Download PDF

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Publication number
WO2016025932A1
WO2016025932A1 PCT/US2015/045432 US2015045432W WO2016025932A1 WO 2016025932 A1 WO2016025932 A1 WO 2016025932A1 US 2015045432 W US2015045432 W US 2015045432W WO 2016025932 A1 WO2016025932 A1 WO 2016025932A1
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Prior art keywords
galkyl
amino
methyl
hydroxy
oxo
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PCT/US2015/045432
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French (fr)
Inventor
Aleksey Igorevich GERASYUTO
Michael A. ARNOLD
Guangming Chen
Gary Mitchell Karp
Hongyan Qi
Anthony A. Turpoff
Jiashi WANG
Matthew G. WOLL
Nanjing Zhang
Xiaoyan Zhang
Arthur A. Branstrom
Jana Narasimhan
Melissa L. DUMBLE
Jean Hedrick
Marla L. Weetall
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Ptc Therapeutics, Inc.
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Publication of WO2016025932A1 publication Critical patent/WO2016025932A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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

Abstract

The present description relates to substituted polycyclic compounds of Formula (I), Formula (II) or Formula (III): wherein the dashed line represents an optional double bond and Rl, R2, R4, R5, R7, X and Z are as defined herein, and forms and compositions thereof, and also relates to uses of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof and methods for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae) in a subject in need thereof comprising, administering an effective amount of the compound to the subject.

Description

SUBSTITUTED POLYCYCLIC ANTIBACTERIAL COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of U.S. Patent Provisional Application No.
62/038,123, filed Augustl5, 2014, the contents of which are incorporated by reference herein. FIELD OF THE INVENTION
The present description relates to substituted polycyclic compounds and forms and pharmaceutical compositions thereof and methods of using such compounds, forms or compositions thereof for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae). More particularly, the present description relates to substituted tricyclic and tetracyclic 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.
BACKGROUND
Neisseria is a large genus of generally commensal Gram-negative bacteria that colonize the mucosal surfaces of many animals. The facile ability of N. gonorrhoeae to develop drug resistance makes N. gonorrhoeae a rapidly emerging global health threat, and is considered to be an emerging superbug. 820,000 new cases of N. gonorrhoeae are estimated to occur in the United States every year. With more than 100 million cases of
N. gonorrhoeae reported worldwide, about 12% of drug-resistant N. gonorrhoeae is estimated to be penicillin resistant (penicillin ), about 23% is estimated to be tetracycline resistant (tetracycline R ) and about 13% is estimated to be quinolone resistant (quinolone R ). The level of quinolone resistance in Taiwan and China is about 90% (Morbidity and
Mortality Weekly, Feb 15, 2013). Other forms of drug-resistant N. gonorrhoeae include streptomycin-resistant (streptomycin R ), ciprofloxacin-resistant (ciprofloxacin R ) and ampicillin-resistant (ampicillin ). Currently, ceftriaxone (a cephalosporin) is the drug of last resort for treating N. gonorrhoeae. With few clinical trials underway for new drugs targeting N. gonorrhoeae, the discovery of new antibacterial agents to treat wild-type or drug-resistant forms of N. gonorrhoeae is urgently needed.
Although quinolones have been highly effective agents in the clinic, wide-scale deployment and generic usage of second generation quinolones (e.g., ciprofloxacin) has jeopardized their future long-term utility. Furthermore, fluoroquinolones had become the standard of care for treating N. gonorrhoeae in early 1999. As early as 2001, though, bacterial resistance to these agents was also on the rise. Within 6 years, N. gonorrhoeae resistance in certain patient populations went from less than 1% to greater than 40%. In 2007, the Centers for Disease Control (CDC) discontinued the use of ciprofloxacin as the standard of care for treating N. gonorrhoeae. Therefore, new drugs targeting wild-type or drug-resistant forms of N. gonorrhoeae would be expected to help address this important unmet medical need.
As resistance to marketed antibacterial agents continues to increase, and new antibacterial agents have not been readily forthcoming from the pharmaceutical industry, the availability of new agents is essential to overcome pre-existing and burgeoning resistance. More particularly, an effective, orally deliverable monotherapy and novel compounds active against wild-type or drug-resistant forms of N. gonorrhoeae are urgently needed. New compounds and new therapies with combinations of antibacterial and antibiotic agents having additive or synergistic activities, including combinations with current agents, would enable longer clinical lifetimes for proven agents against N. gonorrhoeae. Accordingly, the availability of such compounds and therapies would provide a significant current and future human health benefit with a high probability of success on several fronts for the control of wild-type or drug-resistant forms of N. gonorrhoeae for a number of years to come. All other documents referred to herein are incorporated by reference into the present application as though fully set forth herein.
SUMMARY
The present description relates to a compound of Formula (I), Formula (II) or Formula
(HI):
Figure imgf000004_0001
(I) (Π) (HI) wherein the dashed line "— " represents an optional double bond and R1; R2, R4, R5, R7, X and Z are as defined herein, and forms and compositions thereof, and also relates to uses of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof and methods for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae) in a subject in need thereof comprising, administering an effective amount of the compound to the subject.
The present description further relates to a compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against wild-type or drug-resistant forms of N. gonorrhoeae .
More particularly, the present description relates to a compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against wild- type forms of N. gonorrhoeae .
The present description also relates to a compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against drug-resistant forms of
N. gonorrhoeae .
The present description also relates to a compound of Formula (I), Formula (II) or
Formula (III) 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 (I),
Formula (II) or Formula (III) 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 (I), Formula (II) or Formula (III) or a form thereof having activity against an aminoglycoside-resistant, beta- lactam-resistant, cephalosporin-resistant, macrolide-resistant, quinolone-resistant or tetracycline -resistant form of N. gonorrhoeae.
The present description further relates to a compound of Formula (I), Formula (II) or
Formula (III) or a form thereof in combination with known agents having additive or synergistic activity, thus providing a combination product for the treatment of
N. gonorrhoeae .
The present description further relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating wild- type or drug-resistant forms of N. gonorrhoeae .
More particularly, the present description relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating wild-type forms of N. gonorrhoeae.
The present description also relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating drug-resistant forms of
N. gonorrhoeae.
The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae resistant to one or more known antibacterial or antibiotic agents, wherein drug resistance may be classified as intermediate resistance (IR), high level resistance (HLR), multi-drug resistant (MDR), multi-drug intermediate resistant (MD∑R) or extensively drug resistant (XDR).
More particularly, the present description relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating IR, HLR, MDR, MD∑R or XDR forms of N. gonorrhoeae.
The present description also relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating an aminoglycoside-resistant, beta-lactam-resistant, cephalosporin-resistant, macrolide-resistant, quinolone-resistant or tetracycline -resistant form of N. gonorrhoeae.
The present description further relates to use of a compound of Formula (I), Formula
(II) or Formula (III) or a form thereof in combination with known agents having additive or synergistic activity, thus providing a combination product for the treatment of
N. gonorrhoeae. DETAILED DESCRIPTION
The present description relates to substituted polycyclic compounds selected from a compound of Formula (I), Formula (II) or Formula (III):
Figure imgf000006_0001
(I) (Π) (HI) or a form thereof, wherein,
the dashed line "— " represents an optional double bond;
X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-;
Z is O or -CH(R )-, provided that, when Z is O, then X is selected from -CH(R )-,
-CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-;
Ri and R2 are each, when present, selected from hydrogen, halogen, Ci-galkyl-amino, (C1_galkyl)2-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl,
(C1_1oalkyl)2-amino-C1_8alkyl, C2-galkenyl-amino-C1_galkyl,
C2-galkynyl-amino-C1-galkyl, Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl,
Ci-galkoxy-carbonyl-amino, (Ci-galkoxy-carbony^Ci-galky^amino,
(C1_8alkyl)2-amino-C1_8alkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl,
Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl,
Cs-^cycloalkyl-amino-Ci-galkyl, Cs-wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci_galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl, provided that, when R and R2 are both present, R is hydrogen when R2 is other than hydrogen and R2 is hydrogen when R is other than hydrogen,
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R6;
R3 is hydrogen or Ci-galkyl;
R4 is hydrogen, Ci-galkyl, amino, Ci-galkyl-amino, (Ci-galkyl)2-amino,
amino-Ci-galkyl, Ci_ioalkyl-amino-Ci_galkyl or (C1_1oalkyl)2-amino-C1_galkyl;
R5 is hydrogen, Ci-galkyl, amino, Ci_galkyl-amino, (Ci_galkyl)2-amino,
amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (Ci-ioalkyl)2-amino-Ci-galkyl or
Figure imgf000007_0001
R6 is halogen, hydroxyl, cyano, Ci-galkyl, Ci_galkoxy, amino, Ci-galkyl-amino or
(Ci_galkyl)2-amino; and,
R7 is hydrogen or Ci-galkyl;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
One embodiment of the present description includes a compound of Formula (I):
Figure imgf000007_0002
(I)
or a form thereof, wherein,
X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)- -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-;
Z is O or -CH(R )-, provided that, when Z is O, then X is selected from -CH(R )-,
-CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-; Ri and R2 are each selected from hydrogen, halogen, Ci_galkyl-amino, (C1_galkyl)2-amino, amino-Ci-galkyl, Ci_ioalkyl-amino-Ci_galkyl, (C1_1oalkyl)2-amino-C1_galkyl,
C2-galkenyl-amino-C1_galkyl, C2-galkynyl-amino-C1_galkyl,
Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, Ci-galkoxy-carbonyl-amino,
(Ci-galkoxy-carbony^Ci-galky^amino, (C1_galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl, (C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl,
Cs-^cycloalkyl-amino-Ci-galkyl, Cs-wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci_galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl, provided that, when Ri and R2 are both present, Ri is hydrogen when R2 is other than hydrogen and R2 is hydrogen when Ri is other than hydrogen,
wherein each instance of C3_i4cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R6;
R3 is hydrogen or Ci-galkyl;
R is halogen, hydroxyl, cyano, Ci-galkyl, Ci-galkoxy, amino, Ci-galkyl-amino or
(Ci_galkyl)2-amino; and,
R7 is hydrogen or Ci-galkyl;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
One embodiment of the present description includes a compound of Formula (II):
Figure imgf000009_0001
or a form thereof, wherein,
the dashed line "— " represents an optional double bond;
X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-;
Z is O or -CH(R3)-, provided that, when Z is O, then X is selected from -CH(R3)-,
-CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-;
Ri is selected from hydrogen, halogen, Ci-galkyl-amino, (C1_8alkyl)2-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C1_1oalkyl)2-amino-C1_galkyl,
C^galkenyl-amino-Ci-galkyl, C^galkynyl-amino-Ci-galkyl,
^galkoxy-^galkyl-amino-Ci-galkyl, ^galkoxy-carbonyl-amino,
(Ci-galkoxy-carbony^Ci-galky^amino, (C1_8alkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl, (C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl,
Cs-^cycloalkyl-amino-Ci-galkyl, Cs-wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C^wcycloalkyl, aryl, heteroaryl or heterocyclyl is optionally
substituted with one, two or three substituents each selected from R6;
R is hydrogen or Ci-galkyl; R5 is hydrogen, Ci-galkyl, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl,
(C1_1oalkyl)2-amino-C1_8alkyl or hydroxyl-Ci-galkyl; and,
R6 is halogen, hydroxyl, cyano, Ci-galkyl, Q-galkoxy, amino, Ci-galkyl-amino or
(C1_8alkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
One embodiment of the present description includes a compound of Formula (II) or a form thereof selected from a com ound of Formula (Ila) or Formula (lib):
Figure imgf000010_0001
or a form thereof, wherein,
X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-;
Z is O or -CH(R3)-, provided that, when Z is O, then X is selected from -CH(R3)-,
-CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-;
Ri is selected from hydrogen, halogen, Ci-galkyl-amino, (C1_galkyl)2-amino, amino-Ci_galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C1_1oalkyl)2-amino-C1_galkyl,
C^galkenyl-amino-Ci-galkyl, C^galkynyl-amino-Ci-galkyl,
Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, Ci-galkoxy-carbonyl-amino,
(Ci-galkoxy-carbony^Ci-galky^amino, (C1_galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl, (C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1_8alkyl)2-amino-carbonyl-C1_8alkyl-amino-C1_8alkyl,
Cs-Hcycloalkyl-amino-Ci-galkyl, C^wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-^galkyl-amino-Ci-galkyl, heteroaryl-^galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R6;
R3 is hydrogen or Ci-galkyl;
R5 is hydrogen, Ci-galkyl, amino-Ci_galkyl, Ci-ioalkyl-amino-Ci-galkyl,
(C1_1oalkyl)2-amino-C1_galkyl or hydroxyl-Ci_galkyl; and,
R6 is halogen, hydroxyl, cyano, Ci-galkyl, Ci-galkoxy, amino, Ci-galkyl-amino or
(C1_galkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
One embodiment of the present descri tion includes a compound of Formula (III):
Figure imgf000011_0001
(III)
or a form thereof, wherein,
the dashed line "— " represents an optional double bond;
X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-;
Z is O or -CH(R3)-, provided that, when Z is O, then X is selected from -CH(R3)-,
-CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-; Ri is selected from hydrogen, halogen, Ci_galkyl-amino, (C1_8alkyl)2-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C1_1oalkyl)2-amino-C1_galkyl,
C2-galkenyl-amino-Ci_galkyl, C2-galkynyl-amino-Ci_galkyl,
^galkoxy-^galkyl-amino-Ci-galkyl, ^galkoxy-carbonyl-amino,
(Ci-galkoxy-carbony^Ci-galky^amino, (C1_8alkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl, (C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl,
Cs-^cycloalkyl-amino-Ci-galkyl, C3_14cycloalkyl-^galkyl-amino-^galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci_galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C3_14cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally
substituted with one, two or three substituents each selected from R6;
R3 is hydrogen or Ci_galkyl;
R4 is hydrogen, Ci_galkyl, amino, Ci_galkyl-amino, (C1_galkyl)2-amino,
amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl or (C1_1oalkyl)2-amino-C1_galkyl;
R5 is hydrogen, Ci-galkyl, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl,
(C1_1oalkyl)2-amino-C1_galkyl or hydroxyl-Ci-galkyl; and,
R6 is halogen, hydroxyl, cyano, Ci_galkyl, Ci-galkoxy, amino, Ci_galkyl-amino or
(Ci_galkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
One embodiment of the present description includes a compound of Formula (III) or a form thereof selected from a compound of Formula (Ilia) or Formula (Illb):
Figure imgf000013_0001
(Ilia) (nib)
or a form thereof, wherein,
X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-;
Z is O or -CH(R )-, provided that, when Z is O, then X is selected from -CH(R )-,
-CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-;
Ri is selected from hydrogen, halogen, Ci-galkyl-amino,
Figure imgf000013_0002
amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C1_1oalkyl)2-amino-C1_8alkyl,
Figure imgf000013_0003
C^galkynyl-amino-Ci-galkyl,
Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, Ci-galkoxy-carbonyl-amino,
(Ci-galkoxy-carbony^Ci-galky^amino, (C1_galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl,
Cs-Hcycloalkyl-amino-Ci-galkyl, C^wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C^ncycloalkyl, aryl, heteroaryl or heterocyclyl is optionally
substituted with one, two or three substituents each selected from R6;
R3 is hydrogen or Ci-galkyl; R4 is hydrogen, Ci_galkyl, amino, Ci_galkyl-amino, (C1_8alkyl)2-amino,
amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl or (C1_1oalkyl)2-amino-C1_galkyl;
R5 is hydrogen, Ci-galkyl, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl,
(C1-1oalkyl)2-amino-C1_galkyl or hydroxyl-Ci-galkyl; and,
R6 is halogen, hydroxyl, cyano, Ci-galkyl, Ci-galkoxy, amino, Ci_galkyl-amino or
(Ci_galkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof. One embodiment of the present description includes a compound of Formula (I),
Formula (II) or Formula (III) or a form thereof, wherein X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-.
One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-,
-C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-.
One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein X is -CH(R3)-CH(R3)-, -CH(R3)-0-, -0-CH(R3)-CH(R3)- or
-CH(R3)-0-CH(R3)-.
One embodiment of the present description includes a compound of Formula (II), Formula (III) or a form thereof, wherein X is -CH(R3)-, -CH(R3)-CH(R3)-,
-CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-. One embodiment of the present description includes a compound of Formula (II),
Formula (III) or a form thereof, wherein X is -CH(R3)-, -CH(R3)-CH(R3)-,
-CH(R3)-CH(R3)-CH(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)- or -S-CH(R3)-.
One embodiment of the present description includes a compound of Formula (I), Formula (II) or Formula (III) or a form thereof, wherein Z is O or -CH(R )-, provided that, when Z is O, then X is selected from -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-. One embodiment of the present description includes a compound of Formula (I), Formula (II) or Formula (III) or a form thereof, wherein Z is O and X is selected from -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-.
One embodiment of the present description includes a compound of Formula (I), Formula (II) or Formula (III) or a form thereof, wherein Z is -CH(R )-.
One embodiment of the present description includes a compound of Formula (II), Formula (III) or a form thereof, wherein R is selected from hydrogen, halogen,
Figure imgf000015_0001
(Ci-galkyl amino, amino-Ci-galkyl, C oalkyl-amino-Ci-galkyl,
(C1_1oalkyl)2-amino-C1_8alkyl, C^galkenyl-amino-Ci-galkyl, C^galkynyl-amino-Ci-galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, Ci-galkoxy-carbonyl-amino,
(Ci-galkoxy-carbony^Ci-galky^amino, (C1_galkyl)2-amino-C1_galkyl-amino,
amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1_galkyl)2-amino-C1_galkyl-amino-C1_galkyl,
[(C1_galkyl)2-amino-C1_galkyl,C1_galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl,
(C1-galkyl)2-amino-carbonyl-C1-galkyl-amino-C1_galkyl, Cs-^cycloalkyl-amino-Ci-galkyl, Cs-Hcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl,
heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl,
heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl; wherein each instance of C^wcycloalkyl, aryl, heteroaryl or heterocyclyl is optionally
substituted with one, two or three substituents each selected from R6; and, wherein R6 is halogen, hydroxyl, Ci-galkyl, Ci-galkoxy, amino, Ci-galkyl-amino or
(C1_galkyl)2-amino.
One embodiment of the present description includes a compound of Formula (II), Formula (III) or a form thereof, wherein Ri is selected from hydrogen, halogen,
Ci-galkyl-amino, (C1_galkyl)2-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl,
(C1-1oalkyl)2-amino-C1_galkyl, C^galkenyl-amino-Ci-galkyl, C^galkynyl-amino-Ci-galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, Ci-galkoxy-carbonyl-amino,
(Ci-galkoxy-carbony^Ci-galky^amino, (C1_galkyl)2-amino-C1_galkyl-amino,
amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci_galkyl,Ci_galkyl)amino-Ci_galkyl or
(C1_8alkyl)2-amino-carbonyl-C1_8alkyl-amino-C1_8alkyl.
One embodiment of the present description includes a compound of Formula (II), Formula (III) or a form thereof, wherein Ri is selected from Cs-wcycloalkyl-amino-Ci-galkyl, Cs-Hcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl,
heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci_galkyl,
heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl; wherein each instance of Cs-^cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally
substituted with one, two or three substituents each selected from R6; and, wherein R6 is halogen, hydroxyl, Ci_galkyl, Ci_galkoxy, amino, Ci_galkyl-amino or,
(Ci_galkyl)2-amino.
One embodiment of the present description includes a compound of Formula (II), Formula (III) or a form thereof, wherein Ri is selected from hydrogen, (Ci_galkyl)2-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C1_1oalkyl)2-amino-C1_galkyl,
C2-galkenyl-amino-Ci_galkyl, (^galkoxy-carbonyl,Ci-galkyl)amino, hydroxyl-Ci_galkyl, Cs-^cycloalkyl-amino-Ci-galkyl, heterocyclyl or heterocyclyl-Ci-galkyl;
wherein each instance of C3_i4cycloalkyl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
wherein R6 is halogen, hydroxyl, Ci_galkyl, Ci_galkoxy, amino, Ci-galkyl-amino or,
(Ci_galkyl)2-amino.
One embodiment of the present description includes a compound of Formula (II), Formula (III) or a form thereof, wherein Ri is selected from hydrogen, (Ci_galkyl)2-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (Ci-ioalkyl)2-amino-Ci_galkyl,
C2-galkenyl-amino-Ci_galkyl, (^galkoxy-carbonyl,Ci-galkyl)amino or hydroxyl-Ci-galkyl. One embodiment of the present description includes a compound of Formula (II),
Formula (III) or a form thereof, wherein Ri is selected from Cs-wcycloalkyl-amino-Ci-galkyl, heterocyclyl or heterocyclyl-Ci-galkyl;
wherein each instance of C3_i4cycloalkyl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
wherein R6 is halogen, hydroxyl, Ci_galkyl, Ci_galkoxy, amino, Ci-galkyl-amino or,
(Ci-galkyl)2-amino. One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein Ri is hydrogen, halogen, Ci_galkyl-amino, (Ci_galkyl)2-amino, amino-Ci_8alkyl, C oalkyl-amino-Ci-galkyl, (C oalkyl)2-amino-Ci-galkyl,
C2-8alkenyl-amino-Ci_8alkyl, C2-galkynyl-amino-Ci-galkyl,
Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl, Ci-galkoxy-carbonyl-amino,
(Ci_galkoxy-carbonyl,Ci_galkyl)amino, (C1_8alkyl)2-amino-C1_8alkyl-amino,
amino-Ci-galkyl-amino-Ci-galkyl, ^galkyl-amino-Ci-galkyl-amino-^galkyl,
(C1-8alkyl)2-amino-C1-8alkyl-amino-C1_8alkyl,
[(C1_8alkyl)2-amino-C1_8alkyl,C1_8alkyl]amino-C1_8alkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-salky^Ci-salky^amino-Ci-salkyl,
(C1-8alkyl)2-amino-carbonyl-C1-8alkyl-amino-C1_8alkyl, Cs-wcycloalkyl-amino-Ci-galkyl, Cs-^cycloalkyl-Ci-salkyl-amino-Ci-salkyl, aryl-^galkyl-amino-Ci-galkyl,
heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci_galkyl,
heterocyclyl-amino, heterocyclyl-amino-Ci_galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl, provided that, when Ri and R2 are both present, R2 is hydrogen when Ri is other than
hydrogen;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally
substituted with one, two or three substituents each selected from R6; and, wherein R6 is halogen, hydroxyl, Ci-galkyl, Ci-galkoxy, amino, Ci-galkyl-amino or
(Ci-galkyl)2-amino.
One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein Ri is hydrogen, halogen, Ci_galkyl-amino, (Ci_galkyl)2-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C1_1oalkyl)2-amino-C1_galkyl,
C2-galkenyl-amino-Ci_galkyl, C2-galkynyl-amino-Ci_galkyl,
Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, Ci-galkoxy-carbonyl-amino,
(Ci_galkoxy-carbonyl,Ci_galkyl)amino, (C1_galkyl)2-amino-C1_galkyl-amino,
amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1_galkyl)2-amino-C1_galkyl,C1_galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl or
(C1-galkyl)2-amino-carbonyl-C1-galkyl-amino-C1_galkyl,
provided that, when Ri and R2 are both present, R2 is hydrogen when Ri is other than
hydrogen. One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein Ri is C3_i4cycloalkyl-amino-Ci_8alkyl,
Cs-^cycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-^galkyl-amino-Ci-galkyl,
heteroaryl-^galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci_8alkyl,
heterocyclyl-amino, heterocyclyl-amino-Ci_galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl, provided that, when Ri and R2 are both present, R2 is hydrogen when Ri is other than
hydrogen;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally
substituted with one, two or three substituents each selected from R6; and, wherein R6 is halogen, hydroxyl, Ci_galkyl, Ci_galkoxy, amino, Ci_galkyl-amino or,
(Ci-galkyl)2-amino.
One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein Ri is hydrogen, (Ci_galkyl)2-amino, amino-Ci_galkyl,
Ci-ioalkyl-amino-Ci-galkyl, (C1_1oalkyl)2-amino-C1_galkyl, C2-galkenyl-amino-C1_galkyl, (Ci-galkoxy-carbony^Ci-galky^amino, hydroxyl-Ci_galkyl, Cs-wcycloalkyl-amino-Ci-galkyl, heterocyclyl or heterocyclyl-Ci_galkyl;
provided that, when Ri and R2 are both present, R2 is hydrogen when Ri is other than
hydrogen;
wherein each instance of C3_i4cycloalkyl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
wherein R6 is halogen, hydroxyl, Ci_galkyl, Ci_galkoxy, amino, Ci_galkyl-amino or,
(Ci_galkyl)2-amino.
One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein Ri is hydrogen, (Ci_galkyl)2-amino, amino-Ci-galkyl,
Ci_ioalkyl-amino-Ci_galkyl, (C1_1oalkyl)2-amino-C1_galkyl, C2-galkenyl-amino-C1_galkyl, (Ci-galkoxy-carbony^Ci-galky^amino or hydroxyl-Ci_galkyl,
provided that, when Ri and R2 are both present, R2 is hydrogen when Ri is other than
hydrogen.
One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein Ri is C3_i4cycloalkyl-amino-Ci_galkyl, heterocyclyl or
heterocyclyl-Ci-galkyl, provided that, when Ri and R2 are both present, R2 is hydrogen when Ri is other than hydrogen;
wherein each instance of C3_i4cycloalkyl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
wherein R6 is halogen, hydroxyl, Ci_galkyl, Ci_galkoxy, amino, Ci-galkyl-amino or,
(Ci_8alkyl)2-amino.
One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R2 is hydrogen, halogen, Ci-galkyl-amino, (Ci-8alkyl)2-amino, amino-Ci-galkyl, Ci_ioalkyl-amino-Ci_galkyl, (C1_1oalkyl)2-amino-C1_8alkyl,
C2-galkenyl-amino-C1_galkyl, C2-galkynyl-amino-C1_galkyl,
Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl, Ci_8alkoxy-carbonyl-amino,
(Ci-galkoxy-carbonyl,^galkyl)amino, (C1-8alkyl)2-amino-C1_8alkyl-amino,
amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1_galkyl)2-amino-C1_galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl,
(C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl, Cs-Hcycloalkyl-amino-Ci-galkyl, Cs-Hcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl,
heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci_galkyl,
heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl; provided that, when Ri and R2 are both present, Ri is hydrogen when R2 is other than
hydrogen;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally
substituted with one, two or three substituents each selected from R6; and, wherein R6 is halogen, hydroxyl, Ci_galkyl, Ci_galkoxy, amino, Ci-galkyl-amino or
(Ci_galkyl)2-amino.
One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R2 is hydrogen, halogen, Ci-galkyl-amino, (Ci_galkyl)2-amino, amino-Ci-galkyl, Ci_ioalkyl-amino-Ci_galkyl, (C1_1oalkyl)2-amino-C1_galkyl,
C2-galkenyl-amino-C1_galkyl, C2-galkynyl-amino-C1_galkyl,
Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, Ci-galkoxy-carbonyl-amino,
(Ci-galkoxy-carbony^Ci-galky^amino, (C1-galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl, Ci_galkyl-amino-Ci_galkyl-amino-Ci_galkyl, (C1_galkyl)2-amino-C1_galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1-galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl or
(C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl,
provided that, when Ri and R2 are both present, Ri is hydrogen when R2 is other than
hydrogen;
One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R2 is C3_i4cycloalkyl-amino-Ci_galkyl,
Cs-Hcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl,
heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci_galkyl,
heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl, provided that, when Ri and R2 are both present, Ri is hydrogen when R2 is other than
hydrogen;
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally
substituted with one, two or three substituents each selected from R6; and, wherein R6 is halogen, hydroxyl, Ci_galkyl, Ci_galkoxy, amino, Ci_galkyl-amino or,
(Ci_galkyl)2-amino.
One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R2 is hydrogen, (Ci-galkyl)2-amino, amino-Ci-galkyl,
Ci-ioalkyl-amino-Ci-galkyl, (C1_1oalkyl)2-amino-C1_galkyl, C2-galkenyl-amino-C1_galkyl, (Ci-galkoxy-carbony^Ci-galky^amino, hydroxyl-Ci_galkyl, Cs-wcycloalkyl-amino-Ci-galkyl, heterocyclyl or heterocyclyl-Ci-galkyl,
provided that, when Ri and R2 are both present, Ri is hydrogen when R2 is other than
hydrogen;
wherein each instance of C3_i4cycloalkyl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
wherein R6 is halogen, hydroxyl, Ci-galkyl, Ci-galkoxy, amino, Ci-galkyl-amino or,
(Ci_galkyl)2-amino. One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R2 is hydrogen, (Ci-galkyl)2-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C1_1oalkyl)2-amino-C1_8alkyl, C2-8alkenyl-amino-C1_8alkyl, (Ci-galkoxy-carbony^Ci-galky^amino, or hydroxyl-Ci_galkyl,
provided that, when Ri and R2 are both present, Ri is hydrogen when R2 is other than
hydrogen.
One embodiment of the present description includes a compound of Formula (I) or a form thereof, wherein R2 is C3_i4cycloalkyl-amino-Ci_8alkyl, heterocyclyl or
heterocyclyl-Ci_8alkyl,
provided that, when Ri and R2 are both present, Ri is hydrogen when R2 is other than
hydrogen;
wherein each instance of C3_i4cycloalkyl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R6; and,
wherein R6 is halogen, hydroxyl, Ci_8alkyl, Ci-salkoxy, amino, Ci-salkyl-amino or,
(Ci_8alkyl)2-amino.
One embodiment of the present description includes a compound of Formula (I), Formula (II) or Formula (III) or a form thereof, wherein Ri and R2 are each, when present, selected from:
C3_i4cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl;
aryl selected in each instance, when present, from phenyl;
heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, imidazolyl or pyridinyl; and,
heterocyclyl selected in each instance, when present, from azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3- dioxolanyl, 2,5-dihydro-lH-pyrrolyl, 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, hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)- hexahydropyrrolo[3,4-b][l,4]oxazin-(4aH)-yl, 3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazinyl, (cis)-octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4- b]pyrrol-(lH)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7- dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin- (2H,7H,7aH)-yl, hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9- tetrahydro- lH-carbazolyl, 1 ,2,3,4-tetrahydropyrazino[ 1 ,2-a]indolyl, 2,3-dihydro- 1H- pyrrolo[l,2-a]indolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl,
(3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-l,3,3a,4,5,6- hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl,
(3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2- azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexyl, (lS,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl.
One embodiment of the present description includes a compound of Formula (I), Formula (II) or Formula (III) or a form thereof, wherein Ri and R2 are each, when present, selected from:
heteroaryl selected in each instance, when present, from pyrrol- 1-yl, thiazol-2-yl, 1 H- 1,2,3- triazol-l-yl, lH-tetrazol-5-yl, 2H-tetrazol-2-yl, imidazol-l-yl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or,
heterocyclyl selected in each instance, when present, from azetidin-l-yl, pyrrolidin-l-yl, tetrahydrofuran-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 2,5-dihydro-lH-pyrrol-l-yl, 4,5-dihydro-lH- imidazol-2-yl, 1 ,4,5,6-tetrahydropyrimidin-2-yl, 1 ,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, 3,4-dihydroisoquinolin-2(lH)- yl, 1 ,2,3, 4-tetrahydroisoquinolin- 1-yl, hexahydropyrrolo[3,4-b] [ 1 ,4]oxazin-6(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4-b][l,4]oxazin-4(4aH)-yl, (cis)- octahydrocyclopenta[c]pyrrol-4-yl, hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl,
(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(lH)-yl, (3aR,6aS)-hexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, 5,7-dihydro-6H-pyrrolo[3,4- b]pyridin-6-yl, tetrahydro-lH-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl, hexahydro-lH pyrrolo[3,4-b]pyridin-6(2H)-yl, (4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin- 6(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (3aR,6aR)- hexahydrocyclopenta[c]pyrrol-3a(lH)-yl, (3aR,4R,6aS)- hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,4S,6aS)-hexahydrocyclopenta[c]pyrrol 2(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl, l,3-dihydro-2H- isoindol-2-yl, octahydro-2H-isoindol-2-yl, (3aS)-l,3,3a,4,5,6-hexahydro-2H-isoindol- 2-yl, (3aR,4R,7aS)- lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)- octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4S,7aS) octahydro-2H-isoindol-2-yl, 2,5-diazabicyclo[2.2. l]heptan-2-yl, 2- azabicyclo[2.2.1]hept-5-en-2-yl, 3-azabicyclo[3.1.0]hex-3-yl, (lR,5S)-3- azabicyclo[3.1.0]hex-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hex-6-yl, 3,6- diazabicyclo[3.1.0]hex-3-yl, (lS,5R)-3-azabicyclo[3.2.0]heptan-3-yl, 5- azaspiro[2.4]heptan-5-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,5-diazaspiro[3.4]octan-2- yl, 2,6-diazaspiro[3.4]octan-6-yl, 2,7-diazaspiro[3.5]nonan-2-yl, 2,7- diazaspiro[4.4]nonan-2-yl, 2-azaspiro[4.5]decan-2-yl or 2,8-diazaspiro[4.5]decan-2- yi.
One embodiment of the present description includes a compound of Formula (I), Formula (II) or Formula (III) or a form thereof, wherein R and R2 are each, when present, selected from:
heteroaryl selected in each instance, when present, from pyridinyl;
heterocyclyl selected in each instance, when present, from azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3- dioxolanyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6-tetrahydropyrimidinyl, 1,2,3,6- tetrahydropyridinyl, tetrahydro-2H-pyranyl, 3,4-dihydroisoquinolin-(lH)-yl, 1,2,3,4- tetrahydroisoquinolinyl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, tetrahydro- 1H- pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, (3aR,4R,7aS)-lH-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, 2,5- diazabicyclo[2.2.1]heptanyl or (lR,5S)-3-azabicyclo[3.1.0]hexyl.
One embodiment of the present description includes a compound of Formula (I), Formula (II) or Formula (III) or a form thereof, wherein R and R2 are each, when present, selected from: heteroaryl selected in each instance, when present, from pyridin-2-yl, pyridin-3-yl or pyridin-4-yl;
heterocyclyl selected in each instance, when present, from azetidin-l-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, tetrahydrofuran-2-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 4,5-dihydro-lH-imidazol-2-yl, 1,4,5,6- tetrahydropyrimidin-2-yl, 1 ,2,3,6-tetrahydropyridin-4-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, 3,4-dihydroisoquinolin-2(lH)-yl, 1,2,3,4- tetrahydroisoquinolin- 1-yl, 5H-pyrrolo[3,4-b]pyridin-6(7H)-yl, tetrahydro- 1H- pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, (3aR,4R,7aS)-lH-isoindol-2(3H,3aH,4H,5H,6H,7H,7aH)-yl, 2,5- diazabicyclo[2.2.1]heptan-2-yl, (lR,5S)-3-azabicyclo[3.1.0]hex-3-yl or (lR,5S)-3- azabicyclo[3.1.0]hex-6-yl.
One embodiment of the present description includes a compound of Formula (I), Formula (II) or Formula (III) or a form thereof, wherein R and R2 are each, when present, selected from:
heteroaryl selected in each instance, when present, from pyrrolyl, imidazolyl, IH-tetrazolyl or 2H-tetrazolyl; or,
heterocyclyl selected in each instance, when present, from azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3- dioxolanyl, 2,5-dihydro-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6- tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, hexahydropyrrolo[3,4- b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4-b][l,4]oxazin-(4aH)-yl, (cis)- octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aR)- hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- (lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro- lH-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4- b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-l,3,3a,4,5,6- hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl,
(3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2- azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexyl, (lS,5R)-3-azabicyclo[3.2.0]heptanyl, 5- azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2,6- diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2- azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl.
One embodiment of the present description includes a compound of Formula (I), Formula (II) or Formula (III) or a form thereof, wherein Ri and R2 are each, when present, selected from:
heteroaryl selected in each instance, when present, from lH-tetrazol-5-yl, imidazol-l-yl, pyrrol- 1-yl or 2H-tetrazol-2-yl; or,
heterocyclyl selected in each instance, when present, from azetidin-l-yl, pyrrolidin-l-yl, tetrahydrofuran-2-yl, piperidin-l-yl, piperazin-l-yl, morpholin-4-yl, 2,5-dihydro-lH- pyrrol-l-yl, hexahydropyrrolo[3,4-b][l,4]oxazin-6(2H)-yl, (4aR,7aS)- hexahydropyrrolo[3,4-b][l,4]oxazin-4(4aH)-yl, (3aR,6aR)-hexahydropyrrolo[3,4- b]pyrrol-5(lH)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl, 5,7-dihydro- 6H-pyrrolo[3,4-b]pyridin-6-yl, octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (3aR,6aR)- hexahydrocyclopenta[c]pyrrol-3a(lH)-yl, (3aR,4R,6aS)- hexahydrocyclopenta[c]pyrrol-2(lH)-yl, (3aR,4S,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol-2(lH)-yl, l,3-dihydro-2H- isoindol-2-yl, octahydro-2H-isoindol-2-yl, (3aS)-l,3,3a,4,5,6-hexahydro-2H-isoindol- 2-yl, (3aR,7aS)-octahydro-2H-isoindol-2-yl, (3aR,4R,7aS)-octahydro-2H-isoindol-2- yl, (3aR,4S,7aS)-octahydro-2H-isoindol-2-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2- azabicyclo[2.2.1]hept-5-en-2-yl, 3-azabicyclo[3.1.0]hex-3-yl, 3,6- diazabicyclo[3.1.0]hex-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hex-3-yl, (lR,5S)-3- azabicyclo[3.1.0]hex-6-yl, (lS,5R)-3-azabicyclo[3.2.0]heptan-3-yl, 5- azaspiro[2.4]heptan-5-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,5-diazaspiro[3.4]octan-2- yl, 2,6-diazaspiro[3.4]octan-6-yl, 2,7-diazaspiro[3.5]nonan-2-yl, 2,7- diazaspiro[4.4]nonan-2-yl, 2-azaspiro[4.5]decan-2-yl or 2,8-diazaspiro[4.5]decan-2- yi. One embodiment of the present description includes a compound of Formula (I), Formula (II) or Formula (III) or a form thereof, wherein Ri and R2 are each, when present, selected from:
Cs-^cycloalkyl-amino-Ci-galkyl, wherein Cs-^cycloalkyl is selected from cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl;
Cs-Hcycloalkyl-Ci-galkyl-amino-Ci-galkyl, wherein Cs-^cycloalkyl is selected from
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;
aryl-Ci-galkyl-amino-Ci-galkyl, wherein aryl is selected from phenyl;
heteroaryl selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3- triazolyl, lH-tetrazolyl, 2H-tetrazolyl, imidazolyl or pyridinyl;
heteroaryl-Ci-galkyl-amino-Ci-galkyl, wherein heteroaryl is selected from pyridin-2-yl,
pyridin-3-yl or pyridin-4-yl;
heterocyclyl selected in each instance, when present, from azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, 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, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, hexahydropyrrolo[3,4- b] [ 1 ,4] oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3 ,4-b] [ 1 ,4] oxazin-(4aH)-yl, (cis)- octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aR)- hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- (lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4- b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-l,3,3a,4,5,6- hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl,
(3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2- azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexyl, (lS,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl;
heterocyclyl-Ci-galkyl, wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, 1,3- dioxolanyl, 2,5-dihydro-lH-pyrrolyl, 4,5-dihydro-lH-imidazolyl, 1,4,5,6- tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, hexahydropyrrolo[3,4- b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4-b][l,4]oxazin-(4aH)-yl, (cis)- octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aR)- hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- (lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4- b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-l,3,3a,4,5,6- hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl,
(3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2- azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexyl, (lS,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl;
heterocyclyl-amino, wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, 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, 3,4- dihydroisoquinolin-(lH)-yl, 1,2,3,4-tetrahydroisoquinolinyl, hexahydropyrrolo[3,4- b] [ 1 ,4] oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3 ,4-b] [ 1 ,4] oxazin-(4aH)-yl, (cis)- octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aR)- hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- (lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H-pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro-lH-pyrrolo[3,4- b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- 2(lH)-yl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-l,3,3a,4,5,6- hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl,
(3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2- azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexyl, (lR,5S)-3- azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexyl, (lS,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl;
heterocyclyl-amino-Ci-galkyl, wherein heterocyclyl is selected from azetidin-l-yl or
piperidin-4-yl; and,
heterocyclyl-Ci-galkyl-amino-Ci-galkyl, wherein heterocyclyl is selected from pyrrolidin-2-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl or tetrahydro-2H-pyran-4-yl.
One embodiment of the present description includes a compound of Formula (I), Formula (II) or Formula (III) or a form thereof, wherein Ri and R2 are each, when present, selected from:
heteroaryl selected in each instance, when present, from IH-tetrazolyl, imidazolyl, pyrrolyl or 2H-tetrazolyl; or,
heterocyclyl selected in each instance, when present, from azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, 2,5-dihydro-lH-pyrrolyl, hexahydropyrrolo[3,4-b][l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4- b][l,4]oxazin-(4aH)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl,
(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5,7-dihydro-6H-pyrrolo[3,4- b]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (3aR,6aR)- hexahydrocyclopenta[c]pyrrol-3a(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,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl,
(3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5-diazabicyclo[2.2. l]heptanyl, 2- azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexyl, (lS,5R)-3-azabicyclo[3.2.0]heptanyl, 5- azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5-diazaspiro[3.4]octanyl, 2,6- diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2- azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl.
One embodiment of the present description includes a compound of Formula (I), Formula (II) or Formula (III) or a form thereof, wherein Ri and R2 are each, when present, selected from C3_14cycloalkyl selected, in each instance, when present, from cyclopropyl or cyclobutyl; and, heterocyclyl selected, in each instance, when present, from pyrrolidinyl or (lR,5S)-3-azabicyclo[3.1.0]hexyl.
One embodiment of the present description includes a compound of Formula
(I), Formula (II) or Formula (III) or a form thereof, wherein R3 is hydrogen or
Ci_8alkyl.
One embodiment of the present description includes a compound of Formula
(I), Formula (II) or Formula (III) or a form thereof, wherein R is hydrogen.
One embodiment of the present description includes a compound of Formula
(I), Formula (II) or Formula (III) or a form thereof, wherein R3 is Ci_8alkyl.
One embodiment of the present description includes a compound of Formula
(III) or a form thereof, wherein R4 is hydrogen or Ci-galkyl.
One embodiment of the present description includes a compound of Formula
(III) or a form thereof, wherein R4 is hydrogen. One embodiment of the present description includes a compound of Formula
(III) or a form thereof, wherein R4 is Ci-galkyl.
One embodiment of the present description includes a compound of Formula
(III) or a form thereof, wherein R4 is hydrogen, Ci-salkyl, amino, Ci_8alkyl-amino,
(Ci_8alkyl)2-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl or
(C1_1oalkyl)2-amino-C1_8alkyl. One embodiment of the present description includes a compound of Formula
(III) or a form thereof, wherein R4 is hydrogen, Ci_galkyl or
(Ci-ioalkyl amino-Ci-galkyl.
One embodiment of the present description includes a compound of Formula
(II) or Formula (III) or a form thereof, wherein R5 is hydrogen, Ci_galkyl,
amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C1_1oalkyl)2-amino-C1_galkyl or
Figure imgf000030_0001
One embodiment of the present description includes a compound of Formula
(II) or Formula (III) or a form thereof, wherein R5 is hydrogen, Ci_galkyl,
(C1_1oalkyl)2-amino-C1_galkyl or hydroxyl-Ci_galkyl.
One embodiment of the present description includes a compound of Formula
(I), Formula (II) or Formula (III) or a form thereof, wherein R6 is halogen, hydroxyl, cyano, Ci_galkyl, Ci_galkoxy, amino, Ci_galkyl-amino or (C1_galkyl)2-amino.
One embodiment of the present description includes a compound of Formula
(I), Formula (II) or Formula (III) or a form thereof, wherein R6 is Ci-galkyl, amino,
Ci-galkyl-amino or (C1_galkyl)2-amino.
One embodiment of the present description includes a compound of Formula
(I) or a form thereof, wherein R7 is hydrogen or Ci-galkyl.
One embodiment of the present description includes a compound of Formula
(I) or a form thereof, wherein R7 is hydrogen.
One embodiment of the present description includes a compound of Formula
(I) or a form thereof, wherein R7 is Ci_galkyl.
In another embodiment, the compound of Formula (I), Formula (II) or Formula (III) or a form thereof includes a form selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form of the compound of Formula (I), Formula (II) or Formula (III).
In another embodiment, the compound of Formula (I), Formula (II) or Formula (III) or a form thereof includes an isotopologue form of the compound of Formula (I), Formula
(II) or Formula (III) wherein, when present as hydrogen, one or more R1; R2, R3, Rj, R5 and R7 hydrogen atoms are independently replaced with deuterium. Embodiments of the compound of Formula (I) described herein include a compound or a form thereof selected from a compound of Formula (la) or a form thereof:
Figure imgf000031_0001
wherein R1; X, R2 and R7 are selected from:
Figure imgf000031_0002
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Embodiments of the compound of Formula (II) described herein include a compound or a form thereof selected from a compound of Formula (Ila) or a form thereof:
Figure imgf000032_0001
wherein R1; R5, X and Z are selected from:
Cpd i R5 X Z
1 CH2-NH-C(CH3)2CH2CH3 CH3 0-CH2 CH2
2 CH2-NH-CH2CH=CH2 CH3 0-CH2 CH2
3 H H S-CH2 CH2
5 H CH3 S-CH2 CH2
6 CH2-N(CH3)2 H S-CH2 CH2
7 CH2-NH-CH2CH3 CH3 0-CH(CH3) CH2
8 CH2-N(CH3)2 CH3 0-CH(CH3) CH2
9 CH2-NH-CH(CH3)CH2CH3 CH3 0-CH(CH3) CH2
10 CH2-NH-cyclobutyl CH3 0-CH(CH3) CH2
11 CH2-NH-(l-CH3)-cyclopropyl CH3 0-CH(CH3) CH2
12 CH2-NH-(l-CH3)-cyclobutyl CH3 0-CH2 CH2
13 CH2-OH CH3 S-CH2 CH2
14 H H (CH2)2 0
15 CH2-NH2 CH3 0-CH2 CH2
16 H CH3 (CH2)2 0 Cpd i R5 X Z
17 CH2-N(CH3)2 CH3 S-CH2 CH2
18 CH2-NH-CH2CH3 CH3 S-CH2 CH2
19 CH2-NH-C(CH3)3 CH3 S-CH2 CH2
20 CH2-NH-cyclopropyl CH3 S-CH2 CH2
(CH2)3-
21 H (CH2)2 0
pyrrolidin-l-yl
(CH2)2-
22 H (CH2)2 0
pyrrolidin-l-yl
26 CH2-NH-CH(CH3)CH2CH3 CH3 0-(CH2)2 CH2
27 CH2-N(CH3)-CH2CH3 CH3 (CH2)2 CH2
28 CH2-NH-(l-CH3)-cyclobutyl CH3 (CH2)2 CH2
29 CH2-(2-CH3)-pyrrolidin-l-yl CH3 (CH2)2 CH2
30 CH2-[3,3-(CH3)2]-pyrrolidin-l-yl CH3 (CH2)2 CH2
31 CH2-[2,2-(CH3)2]-pyrrolidin-l-yl CH3 (CH2)2 CH2
32 CH2-NH-(l-CH3)-cyclobutyl CH3 0-(CH2)2 CH2
35 H CH3 CH2-0 CH2
37 CH2-NH-CH2CH3 CH3 CH2 CH2
38 CH2-NH-(CH2)2CH3 CH3 CH2 CH2
39 CH2-NH-(l-CH3)-cyclopropyl CH3 CH2 CH2
40 CH2-NH-(l-CH3)-cyclobutyl CH3 CH2 CH2
41 CH2-N(CH3)2 CH3 CH2 CH2
42 CH2-pyrrolidin- 1-yl CH3 CH2 CH2
43 CH2-NH-CH(CH3)2 CH3 CH2 CH2
44 CH2-NH-cyclobutyl CH3 CH2 CH2 Cpd i R5 X z
48 CH2-pyrrolidin- 1 -yl CH3 CH2-0 CH2 wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Embodiments of the compound of Formula (II) described herein include a compound a form thereof selected from a compound of Formula (lib) or a form thereof:
Figure imgf000034_0001
wherein R1; R5, X and Z are selected from:
Figure imgf000034_0002
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Embodiments of the compound of Formula (Ilia) described herein include a compound or a form thereof selected from a compound of Formula (Illal) or a form thereof:
Figure imgf000035_0001
(Illal) wherein R1; R4, X and Z are selected from:
Figure imgf000035_0002
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In one embodiment of the present description, a compound or a form thereof is selected from the group consisting of:
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000040_0003
46 47
Figure imgf000041_0001
Figure imgf000042_0001
58 59, and 60; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In one embodiment of the present description, a compound of Formula (I), (II) or (III) or a form thereof (wherein compound number (# ) indicates that the salt form was isolated) selected from the group consisting of:
Cpd Name
l1 4-hydroxy-9-methyl-10-{ [(2-methylbutan-2-yl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
21 4-hydroxy-9-methyl-2-oxo-10-[(prop-2-en-l-ylamino)methyl]-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
3 4-hydroxy-2-oxo-2,5,6,9-tetrahydro-lH-pyrido[2',3':4,5]thiepino[3,2-f]indole-3- carboxylic acid
41 10-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-2,5,6,7- tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
5 4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-pyrido[2',3':4,5]thiepino[3,2- f]indole-3-carboxylic acid
6 10-[(dimethylamino)methyl]-4-hydroxy-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
71 10-[(ethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid Cpd Name
81 10-[(dimethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
91 10-[(butan-2-ylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
101 10-[(cyclobutylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
ll1 4-hydroxy-6,9-dimethyl-10-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
121 4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
13 4-hydroxy- 10-(hydroxymethyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro- 1H- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
14 4-hydroxy-2-oxo-2,6,7,9-tetrahydro-lH-pyrido[3',2':2,3]oxepino[4,5-f|indole-3- carboxylic acid
151 10-(aminomethyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
16 4-hydroxy-9-methyl-2-oxo-2,6,7,9-tetrahydro-lH-pyrido[3',2':2,3]oxepino[4,5- f]indole-3-carboxylic acid
171 10-[(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
181 10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
191 10-[(tert-butylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
201 10-[(cyclopropylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
211 4-hydroxy-2-oxo-9-[3-(pyrrolidin- l-yl)propyl]-2,6,7,9-tetrahydro- 1H- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid Cpd Name
221 4-hydroxy-2-oxo-9-[2-(pyrrolidin-l-yl)ethyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid
231 9-(dimethylamino)-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
24 9-[(ethoxycarbonyl)(methyl)amino]-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro- lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
261 l l-[(butan-2-ylamino)methyl]-4-hydroxy-10-methyl-2-oxo- 1,2,5, 6,7, 10- hexahydropyrido[2',3':4,5]oxocino[3,2-f|indole-3-carboxylic acid
271 10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
281 4-hydroxy-9-methyl- 10- { [(l-methylcyclobutyl)amino]methyl}-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
291 4-hydroxy-9-methyl-10-[(2-methylpyrrolidin-l-yl)methyl] -2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
301 10-[(3,3-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
311 10-[(2,2-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
321 4-hydroxy-10-methyl-l l-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-l,2,5,6,7,10- hexahydropyrido[2',3':4,5]oxocino[3,2-f|indole-3-carboxylic acid
341 4-hydroxy- 10-[3-(methylamino)pyrrolidin- l-yl]-2-oxo-2,5,6,8-tetrahydro- 1H- [2]benzoxocino[6,5-b]pyridine-3-carboxylic acid
35 4-hydroxy-9-methyl-2-oxo- 1,5,7, 9-tetrahydro-2H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylic acid
371 9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH-indolo[6,5- h]quinoline-3-carboxylic acid
381 4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid Cpd Name
391 4-hydroxy-8-methyl-9-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid
401 4-hydroxy-8-methyl-9-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid
411 9-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
421 4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
431 4-hydroxy-8-methyl-2-oxo-9-[(propan-2-ylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
441 9-[(cyclobutylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
451 9-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid
461 9-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-l,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid
47 9-(dimethylamino)-4-hydroxy-2-oxo-l,2,5,7-tetrahydro[2]benzoxepino[5,4- b]pyridine-3-carboxylic acid
481 4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,5,7,9-tetrahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f]indole-3-carboxylic acid
491 4-hydroxy-2-oxo-l,5,7,9,10,l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3-f]indole-3- carboxylic acid
501 4-hydroxy-9-methyl-2-oxo-l,5,7,9,10,l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylic acid
511 4-hydroxy-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5-f|indole-3- carboxylic acid
521 4-hydroxy-9-methyl-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5- f]indole-3-carboxylic acid Cpd Name
53 4-hydroxy-2-oxo- 1,2,5, 6,7, l l-hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3- carboxylic acid
541 10-[(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid
55 4-hydroxy-2-oxo-2,5,6,l l-tetrahydro-lH-pyrido[2',3':4,5]oxepino[2,3-f|indole-3- carboxylic acid
561 10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid
571 10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,l 1- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid
581 4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-l,2,5,6,7,l 1- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid
591 l l-[(dimethylamino)methyl]-4-hydroxy-10-methyl-2-oxo-2,5,6,7,8,12-hexahydro-lH- pyrido[2',3':3,4]cycloocta[l,2-f]indole-3-carboxylic acid, and
601 9-[(dimethylamino)methyl]-4-hydroxy-2-oxo-l,2,5, 6,7,11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid; wherein a form of the compound is selected from the group consisting of a prodrug, salt,
hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
An embodiment of the use of a compound of Formula (I), (II) or (III) or a form thereof includes a method of use for a compound of Formula (I), (II) or (III) or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound or a form thereof to the subject, wherein the compound or a form thereof is selected from the group consisting of (where compound number (#*) indicates that the salt form was isolated):
Cpd Name
l1 4-hydroxy-9-methyl-10-{ [(2-methylbutan-2-yl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid Cpd Name
21 4-hydroxy-9-methyl-2-oxo-10-[(prop-2-en-l-ylamino)methyl]-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
3 4-hydroxy-2-oxo-2,5,6,9-tetrahydro-lH-pyrido[2',3':4,5]thiepino[3,2-f]indole-3- carboxylic acid
41 10-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-2,5,6,7- tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
5 4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-pyrido[2',3':4,5]thiepino[3,2- f]indole-3-carboxylic acid
6 10-[(dimethylamino)methyl]-4-hydroxy-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
71 10-[(ethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
81 10-[(dimethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
91 10-[(butan-2-ylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
101 10-[(cyclobutylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
ll1 4-hydroxy-6,9-dimethyl-10-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
121 4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
13 4-hydroxy- 10-(hydroxymethyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro- 1H- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
14 4-hydroxy-2-oxo-2,6,7,9-tetrahydro-lH-pyrido[3',2':2,3]oxepino[4,5-f|indole-3- carboxylic acid
151 10-(aminomethyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid Cpd Name
16 4-hydroxy-9-methyl-2-oxo-2,6,7,9-tetrahydro-lH-pyrido[3',2':2,3]oxepino[4,5- f]indole-3-carboxylic acid
171 10-[(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
181 10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
191 10-[(tert-butylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
201 10-[(cyclopropylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
211 4-hydroxy-2-oxo-9-[3-(pyrrolidin- l-yl)propyl]-2,6,7,9-tetrahydro- 1H- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid
221 4-hydroxy-2-oxo-9-[2-(pyrrolidin-l-yl)ethyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid
231 9-(dimethylamino)-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
24 9-[(ethoxycarbonyl)(methyl)amino]-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
261 l l-[(butan-2-ylamino)methyl]-4-hydroxy-10-methyl-2-oxo- 1,2,5, 6,7, 10- hexahydropyrido[2',3':4,5]oxocino[3,2-f|indole-3-carboxylic acid
271 10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
281 4-hydroxy-9-methyl- 10- { [(l-methylcyclobutyl)amino]methyl}-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
291 4-hydroxy-9-methyl-10-[(2-methylpyrrolidin-l-yl)methyl] -2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
301 10-[(3,3-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid Cpd Name
311 10-[(2,2-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
321 4-hydroxy-10-methyl-l l-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-l,2,5,6,7,10- hexahydropyrido[2',3':4,5]oxocino[3,2-f|indole-3-carboxylic acid
341 4-hydroxy- 10-[3-(methylamino)pyrrolidin- l-yl]-2-oxo-2,5,6,8-tetrahydro- 1H- [2]benzoxocino[6,5-b]pyridine-3-carboxylic acid
35 4-hydroxy-9-methyl-2-oxo- 1,5,7, 9-tetrahydro-2H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylic acid
371 9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH-indolo[6,5- h]quinoline-3-carboxylic acid
381 4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
391 4-hydroxy-8-methyl-9-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid
401 4-hydroxy-8-methyl-9-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid
411 9-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
421 4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
431 4-hydroxy-8-methyl-2-oxo-9-[(propan-2-ylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
441 9-[(cyclobutylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
451 9-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid
461 9-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-l,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid Cpd Name
47 9-(dimethylamino)-4-hydroxy-2-oxo-l,2,5,7-tetrahydro[2]benzoxepino[5,4-b]pyridine- 3-carboxylic acid
481 4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,5,7,9-tetrahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f]indole-3-carboxylic acid
491 4-hydroxy-2-oxo-l,5,7,9,10,l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3-f]indole-3- carboxylic acid
501 4-hydroxy-9-methyl-2-oxo-l,5,7,9,10,l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylic acid
511 4-hydroxy-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5-f|indole-3- carboxylic acid
521 4-hydroxy-9-methyl-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5- f]indole-3-carboxylic acid
53 4-hydroxy-2-oxo- 1,2,5, 6,7, l l-hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3- carboxylic acid
541 10-[(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid
55 4-hydroxy-2-oxo-2,5,6,l l-tetrahydro-lH-pyrido[2',3':4,5]oxepino[2,3-f|indole-3- carboxylic acid
561 10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid
571 10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,l 1- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid
581 4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-l,2,5,6,7,l 1- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid
591 l l-[(dimethylamino)methyl]-4-hydroxy-10-methyl-2-oxo-2,5,6,7,8,12-hexahydro-lH- pyrido[2',3':3,4]cycloocta[l,2-f|indole-3-carboxylic acid, and
601 9-[(dimethylamino)methyl]-4-hydroxy-2-oxo-l,2,5, 6,7,11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In one embodiment of the present description, the compound of Formula (I), (II) or (III) or a form thereof is isolated as a salt.
In another embodiment of the present description, a compound salt of Formula (I), (II) or (III) or a form thereof (wherein compound number (#x) indicates additional salt forms that were isolated for particular compounds) is selected from the group consisting of:
Cpd Name
1 4-hydroxy-9-methyl-10-{ [(2-methylbutan-2-yl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
2 4-hydroxy-9-methyl-2-oxo-10-[(prop-2-en-l-ylamino)methyl]-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
4 10-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-2,5,6,7- tetrahydro- lH-benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid trifluoroacetate
7 10-[(ethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
8 10-[(dimethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
9 10-[(butan-2-ylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10 10-[(cyclobutylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
11 4-hydroxy-6,9-dimethyl-10-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
12 4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
15 10-(aminomethyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride Cpd Name
17 10-[(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride
18a 10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid trifluoroacetate
18b 10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride
19a 10-[(tert-butylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid trifluoroacetate
19b 10-[(tert-butylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride
20a 10-[(cyclopropylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid trifluoroacetate
20b 10-[(cyclopropylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride
21 4-hydroxy-2-oxo-9-[3-(pyrrolidin- l-yl)propyl]-2,6,7,9-tetrahydro- 1H- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid hydrochloride
22 4-hydroxy-2-oxo-9-[2-(pyrrolidin-l-yl)ethyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid hydrochloride
23 9-(dimethylamino)-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
26 l l-[(butan-2-ylamino)methyl]-4-hydroxy-10-methyl-2-oxo- 1,2,5, 6,7, 10- hexahydropyrido[2',3':4,5]oxocino[3,2-f]indole-3-carboxylic acid hydrochloride
27 10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
28 4-hydroxy-9-methyl- 10- { [(l-methylcyclobutyl)amino]methyl}-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
29 4-hydroxy-9-methyl-10-[(2-methylpyrrolidin-l-yl)methyl]-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride Cpd Name
30 10-[(3,3-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
31 10-[(2,2-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
32 4-hydroxy-10-methyl-l l-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-l,2,5,6,7,10- hexahydropyrido[2',3':4,5]oxocino[3,2-f|indole-3-carboxylic acid hydrochloride
34 4-hydroxy- 10-[3-(methylamino)pyrrolidin- l-yl]-2-oxo-2,5,6,8-tetrahydro- 1H- [2]benzoxocino[6,5-b]pyridine-3-carboxylic acid trifluoroacetate
37 9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
38 4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
39 4-hydroxy-8-methyl-9-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
40 4-hydroxy-8-methyl-9-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
41 9-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
42 4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
43 4-hydroxy-8-methyl-2-oxo-9-[(propan-2-ylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
44 9-[(cyclobutylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
45 9-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid hydrochloride
46 9-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-l,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid hydrochloride Cpd Name
48 4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,5,7,9-tetrahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f]indole-3-carboxylic acid hydrochloride
49 4-hydroxy-2-oxo-l,5,7,9,10,l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3-f|indole- 3-carboxylic acid hydrochloride
50 4-hydroxy-9-methyl-2-oxo-l,5,7,9,10,l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylic acid hydrochloride
51 4-hydroxy-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5-f|indole- 3-carboxylic acid hydrochloride
52 4-hydroxy-9-methyl-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5- f]indole-3-carboxylic acid hydrochloride
54 10-[(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
56 10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
57 10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo-l,2,5, 6,7,11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
58 4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-l,2,5,6,7,l 1- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
59 l l-[(dimethylamino)methyl]-4-hydroxy-10-methyl-2-oxo-2,5,6,7,8,12-hexahydro- lH-pyrido[2',3':3,4]cycloocta[l,2-f|indole-3-carboxylic acid hydrochloride, and
60 9-[(dimethylamino)methyl]-4-hydroxy-2-oxo-l,2,5, 6,7,11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride; wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
Another embodiment of the use of a compound of Formula (I), (II) or (III) or a form thereof includes a method of use for a compound salt of Formula (I), (II) or (III) or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound salt or a form thereof to the subject, wherein the compound salt or a form thereof is selected from the group consisting of:
Cpd Name
1 4-hydroxy-9-methyl-10-{ [(2-methylbutan-2-yl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
2 4-hydroxy-9-methyl-2-oxo-10-[(prop-2-en-l-ylamino)methyl]-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
4 10-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-2,5,6,7- tetrahydro- lH-benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid trifluoroacetate
7 10-[(ethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
8 10-[(dimethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
9 10-[(butan-2-ylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10 10-[(cyclobutylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
11 4-hydroxy-6,9-dimethyl-10-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
12 4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
15 10-(aminomethyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
17 10-[(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride
18a 10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid trifluoroacetate
18b 10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride Cpd Name
19a 10-[(tert-butylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f|indole-3-carboxylic acid trifluoroacetate
19b 10-[(tert-butylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f|indole-3-carboxylic acid hydrochloride
20a 10-[(cyclopropylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f|indole-3-carboxylic acid trifluoroacetate
20b 10-[(cyclopropylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f|indole-3-carboxylic acid hydrochloride
21 4-hydroxy-2-oxo-9-[3-(pyrrolidin-l-yl)propyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f|indole-3-carboxylic acid hydrochloride
22 4-hydroxy-2-oxo-9-[2-(pyrrolidin-l-yl)ethyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f|indole-3-carboxylic acid hydrochloride
23 9-(dimethylamino)-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride
26 l l-[(butan-2-ylamino)methyl]-4-hydroxy-10-methyl-2-oxo- 1,2,5,6,7, 10- hexahydropyrido[2',3':4,5]oxocino[3,2-f]indole-3-carboxylic acid hydrochloride
27 10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
28 4-hydroxy-9-methyl- 10- { [(l-methylcyclobutyl)amino]methyl}-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
29 4-hydroxy-9-methyl-10-[(2-methylpyrrolidin-l-yl)methyl]-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
30 10-[(3,3-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
31 10-[(2,2-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
32 4-hydroxy-10-methyl-l l-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-l,2,5,6,7,10- hexahydropyrido[2',3':4,5]oxocino[3,2-f]indole-3-carboxylic acid hydrochloride Cpd Name
34 4-hydroxy-10-[3-(methylamino)pyrrolidin-l-yl]-2-oxo-2,5,6,8-tetrahydro-lH- [2]benzoxocino[6,5-b]pyridine-3-carboxylic acid trifluoroacetate
37 9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH-indolo[6,5- h]quinoline-3-carboxylic acid hydrochloride
38 4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
39 4-hydroxy-8-methyl-9-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
40 4-hydroxy-8-methyl-9-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
41 9-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
42 4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
43 4-hydroxy-8-methyl-2-oxo-9-[(propan-2-ylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
44 9-[(cyclobutylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
45 9-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid hydrochloride
46 9-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-l,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid hydrochloride
48 4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)- 1,5,7, 9-tetrahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f|indole-3-carboxylic acid hydrochloride
49 4-hydroxy-2-oxo-l,5,7,9,10,l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3-f]indole-3- carboxylic acid hydrochloride
50 4-hydroxy-9-methyl-2-oxo- 1,5,7,9, 10, l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylic acid hydrochloride Cpd Name
51 4-hydroxy-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5-f]indole-3- carboxylic acid hydrochloride
52 4-hydroxy-9-methyl-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5- f]indole-3-carboxylic acid hydrochloride
54 10-[(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7, 11- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-f] indole-3 -carboxylic acid hydrochloride
56 10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 11- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-f] indole-3 -carboxylic acid hydrochloride
57 10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,l 1- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-f] indole-3 -carboxylic acid hydrochloride
58 4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-l,2,5, 6,7,11- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-f] indole-3 -carboxylic acid hydrochloride
59 l l-[(dimethylamino)methyl]-4-hydroxy-10-methyl-2-oxo-2,5,6,7,8,12-hexahydro-lH- pyrido[2',3':3,4]cycloocta[l,2-f]indole-3-carboxylic acid hydrochloride, and
60 9-[(dimethylamino)methyl]-4-hydroxy-2-oxo-l,2,5,6,7,l 1- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-f] indole-3 -carboxylic acid hydrochloride; wherein a form of the compound salt is selected from the group consisting of a prodrug,
hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
In another embodiment of the present description, the compound or a form thereof is isolated for use.
Chemical Definitions
The chemical terms used above and throughout the description herein, unless specifically defined otherwise, shall be understood by one of ordinary skill in the art to have the following indicated meanings.
As used herein, the term "Ci-ioalkyl" generally refers to saturated hydrocarbon radicals having from one to ten carbon atoms in a straight or branched chain configuration, including, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. In some embodiments, Ci-ioalkyl includes Ci-galkyl, Ci_6alkyl, C1_4alkyl and the like. A Ci-ioalkyl radical may be optionally substituted where allowed by available valences.
As used herein, the term "C2-galkenyl" generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, without limitation, ethenyl, allyl, propenyl and the like. In some embodiments, C2-galkenyl includes C2-6alkenyl, C2-4alkenyl and the like. A C2-galkenyl 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-galkynyl includes C2-6alkynyl, C2-4alkynyl and the like. A C2-8alkynyl radical may be optionally substituted where allowed by available valences.
As used herein, the term "Ci-salkoxy" generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration of the formula: -O-Ci-galkyl, including, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like. In some embodiments, Ci-salkoxy includes Ci^alkoxy, Ci_4galkoxy and the like. A
Ci_8alkoxy radical may be optionally substituted where allowed by available valences.
As used herein, the term "C3_14cycloalkyl" generally refers to a saturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, lH-indanyl, indenyl, tetrahydro-naphthalenyl and the like. In some embodiments, C3_14cycloalkyl includes C3_gcycloalkyl, Cs-gcycloalkyl, C3_iocycloalkyl and the like. A C3_14cycloalkyl radical may be optionally substituted where allowed by available valences.
As used herein, the term "aryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including, without limitation, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like. An aryl radical may be optionally substituted where allowed by available valences.
As used herein, the term "heteroaryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S or N atom, including, without limitation, furanyl, thienyl (also referred to as thiophenyl), pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, 9H-purinyl, quinoxalinyl, isoindolyl, quinolinyl, isoquinolinyl, quinazolinyl, acridinyl and the like. A heteroaryl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.
As used herein, the term "heterocyclyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with a heteroatom, such as an O, S or N atom, including, without limitation, oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl,
tetrahydrothienyl, pyrrolinyl, pyrrolidinyl, dihydropyrazolyl, pyrazolinyl, pyrazolidinyl, dihydroimidazolyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, dihydro-2H-pyranyl, dihydro-pyridinyl, tetrahydro-pyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydro-pyridinyl, dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, 1,4,5,6- tetrahydropyrimidinyl, dihydro-pyrazinyl, tetrahydro-pyrazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl,
dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl, 1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl, dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl, dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl,
tetrahydro-benzothienyl, dihydro-benzimidazolyl, tetrahydro-benzimidazolyl,
dihydro-benzooxazolyl, 2,3-dihydrobenzo[d]oxazolyl, tetrahydro-benzooxazolyl,
dihydro-benzooxazinyl, 3,4-dihydro-2H-benzo[b][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] [l,4]oxazin-(2H)-yl, (4aR,7aS)-hexahydropyrrolo[3,4-b] [l,4]oxazin-(4aH)-yl, 3,4-dihydro- 2H-pyrido[3,2-b] [l,4]oxazinyl, (cis)-octahydrocyclopenta[c]pyrrolyl, hexahydropyrrolo[3,4- b]pyrrol-(lH)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, (3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, 5H-pyrrolo[3,4-b]pyridin-(7H)-yl, 5,7-dihydro-6H- pyrrolo[3,4-b]pyridinyl, tetrahydro-lH-pyrrolo[3,4-b]pyridin-(2H,7H,7aH)-yl, hexahydro- lH-pyrrolo[3,4-b]pyridin-(2H)-yl, (4aR,7aR)-hexahydro-lH-pyrrolo[3,4-b]pyridin-(2H)-yl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, 2,3,4,9-tetrahydro- lH-carbazolyl, 1,2,3,4- tetrahydropyrazino[ 1 ,2-a]indolyl, 2,3-dihydro- lH-pyrrolo[ 1 ,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, 1 ,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]hexyl, 3,6- diazabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexyl, (lS,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl and the like. A heterocyclyl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.
As used herein, the term
Figure imgf000061_0001
refers to a radical of the formula: -^8alkyl-NH-C2_8alkenyl.
As used herein, the term "Ci-salkoxy-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci.galkyl-NH-C^alkyl-O-Ci.galkyl.
As used herein, the term "Ci-galkoxy-carbonyl-amino" refers to a radical of the formula: -NH-C(0)-0-C1_galkyl.
As used herein, the term "(Ci-salkoxy-carbony^Ci-galky^amino" refers to a radical of the formula: -N{ (Ci_8alkyl)[C(0)-0-Ci_8alkyl] } .
As used herein, the term "Ci-galkyl-amino" refers to a radical of the formula:
-NH-Ci-galkyl.
As used herein, the term "(Ci-salkyl amino" refers to a radical of the formula:
-N(C1_8alkyl)2. As used herein, the term "Ci-ioalkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci.galkyl-NH-C oalkyl.
As used herein, the term "(Ci-ioalkyl amino-Ci-galkyl" refers to a radical of the formula:
Figure imgf000062_0001
As used herein, the term "(C1_8alkyl)2-amino-C1_8alkyl-amino" refers to a radical of the formula: -NH-C1_8alkyl-N(C1_8alkyl)2.
As used herein, the term "^galkyl-amino-^galkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-NH-^galkyl.
As used herein, the term "(C1_8alkyl)2-amino-C1_8alkyl-amino-C1_8alkyl" refers to a radical of the formula: -C1_8alkyl-NH-C1_8alkyl-N(C1_8alkyl)2.
As used herein, the term "[(C1-8alkyl)2-amino-C1-8alkyl,C1-8alkyl]amino-C1_8alkyl" refers to a radical of the formula: -C1-8alkyl-N{ (C1_8alkyl)[C1-8alkyl-N(C1_8alkyl)2] }.
As used herein, the term "(C1_8alkyl)2-amino-carbonyl-C1_8alkyl-amino-C1_8alkyl" refers to a radical of the formula: -C1_8alkyl-NH-C1_8alkyl-C(0)-N(C1_8alkyl)2.
As used herein, the term "C^galkynyl-amino-Ci-galkyl" refers to a radical of the formula:
Figure imgf000062_0002
As used herein, the term "amino" refers to a radical of the formula: -NH2.
As used herein, the term "amino-Ci-galkyl" refers to a radical of the formula:
-Ci.8alkyl-NH2.
As used herein, the term "amino-Ci-galkyl-amino-^galkyl" refers to a radical of the formula: -C1_8alkyl-NH-C1_8alkyl-NH2.
As used herein, the term "aryl-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -^galkyl-NH-Ci-galkyl-aryl.
As used herein, the term "Cs-Mcycloalkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-Cs-wcycloalkyl.
As used herein, the term "Cs-Hcycloalkyl-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-Cs-^cycloalkyl.
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 "heteroaryl-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-heteroaryl.
As used herein, the term "heterocyclyl-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-heterocyclyl. As used herein, the term "heterocyclyl-amino" refers to a radical of the formula: -NH-heterocyclyl.
As used herein, the term "heterocyclyl-amino-Ci-galkyr refers to a radical of the formula: -Ci-galkyl-NH-heterocyclyl.
As used herein, the term "heterocyclyl-Ci_galkyl-amino-Ci_galkyr refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-heterocyclyl.
As used herein, the term "hydroxyl-Ci-galkyl" refers to a radical of the formula:
-Ci-galkyl-OH, wherein Ci-galkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term "hydroxyl-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-OH, wherein Ci-galkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term "(hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-N Ci-galkylXCi-galkyl-OH)], wherein Ci-galkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.
As used herein, the term "substituent" means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown.
As used herein, the term "and the like," with reference to the definitions of chemical terms provided herein, means that variations in chemical structures that could be expected by one skilled in the art include, without limitation, isomers (including chain, branching or positional structural isomers), hydration of ring systems (including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations where allowed by available valences which result in a stable compound.
For the purposes of this description, where one or more substituent variables for a compound of Formula (I) or a form thereof or Formula (II) or a form thereof or Formula (III) or a form thereof encompass functionalities incorporated into a compound of Formula (I) or Formula (II) or Formula (III), each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.
As used herein, the terms "independently selected," or "each selected" refer to functional variables in a substituent list that may occur more than once on the structure of Formula (I) or Formula (II) or Formula (III), 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 "...Cs-^cycloalkyl, Cs-wcycloalkyl-Ci-salkyl, aryl, aryl-Ci^alkyl, heteroaryl, heteroaryl-Ci-salkyl, heterocyclyl and heterocyclyl-Ci-salkyl," are intended to refer to the Cs-ncycloalkyl, 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 (I), Formula (II) or
Formula (III) having a form selected from the group consisting of a free acid, free base, prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof. In certain embodiments described herein, the form of the compound of Formula (I), Formula (II) or Formula (III) is a free acid, free base or salt thereof.
In certain embodiments described herein, the form of the compound of Formula (I), Formula (II) or Formula (III) is a salt thereof.
In certain embodiments described herein, the form of the compound of Formula (I),
Formula (II) or Formula (III) is an isotopologue thereof.
In certain embodiments described herein, the form of the compound of Formula (I), Formula (II) or Formula (III) is a stereoisomer, racemate, enantiomer or diastereomer thereof.
In certain embodiments described herein, the form of the compound of Formula (I), Formula (II) or Formula (III) is a tautomer thereof.
In certain embodiments described herein, the form of the compound of Formula (I), Formula (II) or Formula (III) is a pharmaceutically acceptable form.
In certain embodiments described herein, the compound of Formula (I), Formula (II) or Formula (III) or a form thereof is isolated for use.
As used herein, the term "isolated" means the physical state of a compound of
Formula (I), Formula (II) or Formula (III) or a form thereof after being isolated and/or purified from a synthetic process (e.g., from a reaction mixture) or natural source or combination thereof according to an isolation or purification process or processes described herein or which are well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
As used herein, the term "protected" means that a functional group in a compound of Formula (I), Formula (II) or Formula (III) or a form thereof is in a form modified to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T.W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.
Prodrugs and solvates of the compounds described herein are also contemplated.
As used herein, the term "prodrug" means a form of an instant compound (e.g., a drug precursor) that is transformed in vivo to yield an active compound of Formula (I), Formula
(II) or Formula (III) or a form thereof. The transformation may occur by various mechanisms (e.g., by metabolic and/or non-metabolic chemical processes), such as, for example, by hydrolysis and/or metabolism in blood, liver and/or other organs and tissues. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
In one example, when a compound of Formula (I), Formula (II) or Formula (III) or a form thereof contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a functional group such as alkyl and the like. In another example, when a compound of Formula (I), Formula
(II) or Formula (III) or a form thereof contains a hydroxyl functional group, a prodrug form can be prepared by replacing the hydrogen atom of the hydroxyl with another functional group such as alkyl, alkylcarbonyl or a phosphonate ester and the like. In another example, when a compound of Formula (I), Formula (II) or Formula (III) or a form thereof contains an amine functional group, a prodrug form can be prepared by replacing one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl.
Pharmaceutically acceptable prodrugs of compounds of Formula (I), Formula (II) or Formula
(III) or a form thereof include those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid esters, phosphonate esters and mono-, di- or triphosphate esters or alkyl substituents, where appropriate. As described herein, it is understood by a person of ordinary skill in the art that one or more of such substituents may be used to provide a compound of Formula (I), Formula (II) or Formula (III) or a form thereof as a prodrug.
One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to embrace both solvated and unsolvated forms.
As used herein, the term "solvate" means a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. As used herein, "solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
One or more compounds described herein may optionally be converted to a solvate. Preparation of solvates is generally known. The preparation of solvates of the antifungal fluconazole in ethyl acetate as well as from water has been described (see, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004)). Similar preparations of solvates, hemisolvate, hydrates and the like have also been described (see, E.C. van Tonder et al, AAPS
PharmSciTech., 5(1), article 12 (2004); and A.L. Bingham et al, Chem. Commun., 603-604 (2001)). A typical, non-limiting process involves dissolving a compound in a desired amount of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example infrared spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
As used herein, the term "hydrate" means a solvate wherein the solvent molecule is water.
The compounds of Formula (I), Formula (II) or Formula (III) can form salts, which are intended to be included within the scope of this description. Reference to a compound of Formula (I), Formula (II) or Formula (III) or a form thereof herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula (I), Formula (II) or Formula (III) or a form thereof contains both a basic moiety, such as, without limitation an amine moiety, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein.
The term "pharmaceutically acceptable salt(s)", as used herein, means those salts of compounds described herein that are safe and effective {i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful. Salts of the compounds of the Formula (I), Formula (II) or Formula (III) may be formed, for example, by reacting a compound of Formula (I), Formula (II) or Formula (III) or a form thereof with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by
lyophilization.
Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in compounds described herein. Embodiments of acid addition salts include, and are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate salts and the like. Certain embodiments of acid addition salts include chloride, bromide, acetate or trifluoroacetate salts.
Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International ], of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium and zinc salts. Certain compounds described herein can also form pharmaceutically acceptable salts with organic bases (for example, organic amines) such as, but not limited to, dicyclohexylamines, t-butyl amines and the like, and with various amino acids such as, but not limited to, arginine, lysine and the like. Basic nitrogen- containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides) and the like.
All such acid salts and base salts are intended to be included within the scope of pharmaceutically acceptable salts as described herein. In addition, all such acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of this description.
Compounds of Formula (I), Formula (II) or Formula (III) and forms thereof, may further exist in a tautomeric form (for example, the 4-hydroxy-2-pyridinone core of Formula (I), Formula (II) and Formula (III) may exist in either the 2,4-dihydroxy-pyridine or the 2- hydroxy-4-pyridinone form). All such tautomeric forms are contemplated and intended to be included within the scope of the compounds of Formula (I), Formula (II) or Formula (III) or a form thereof as described herein. The compounds of Formula (I), Formula (II) or Formula (III) or a form thereof may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. The present description is intended toinclude all stereoisomeric forms of the compounds of Formula (I), Formula (II) or Formula (III) as well as mixtures thereof, including racemic mixtures.
The compounds described herein may include one or more chiral centers, and as such may exist as racemic mixtures (R/S) or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (when one chiral center is present). In one embodiment, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer. In another embodiment, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer. As one of skill in the art will recognize, when more than one chiral center is present, the compounds described herein may also exist as a (R,R), (R,S), (S,R) or (S,S) isomer, as defined by IUPAC Nomenclature Recommendations.
As used herein, the term "substantially pure" refers to compounds consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.
In one aspect of the description, a compound of Formula (I), Formula (II) or Formula (III) or a form thereof is a substantially pure (S) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
In one aspect of the description, a compound of Formula (I), Formula (II) or Formula (III) or a form thereof is a substantially pure (R) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
As used herein, a "racemate" is any mixture of isometric forms that are not
"enantiomerically pure", including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, or about 80/20. In addition, the present description embraces all geometric and positional isomers. For example, if a compound of Formula (I), Formula (II) or Formula (III) or a form thereof incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the description. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by use of chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher' s acid chloride), separating the diastereomers and converting (e.g. , hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I), Formula (II) or Formula (III) or a form thereof may be atropisomers (e.g., substituted biaryls) and are considered as part of this description.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this description, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as described supra.
The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, isotopologues or prodrugs of the instant
compounds.
The term "isotopologue" refers to isotopically-enriched compounds described herein which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, 35C1 and 36C1, respectively, each of which are also within the scope of this description.
Certain isotopically-enriched compounds described herein (e.g., those labeled with H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon- 14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
Polymorphic crystalline and amorphous forms of the compounds of Formula (I),
Formula (II) or Formula (III) and of the salts, solvates, hydrates, esters and prodrugs of the compounds of Formula (I), Formula (II) or Formula (III) are further intended to be included in the present description.
Compound Uses
The present description relates to a method of use for a compound of Formula (I),
Formula (II) or Formula (III) or a form thereof for treating or ameliorating wild-type or drug- resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound or a form thereof to the subject.
The present description further relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating wild-type or drug- resistant forms of N. gonorrhoeae in a subject in need thereof.
The present description further relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity toward wild-type or drug- resistant N. gonorrhoeae.
The present description also relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against aminoglycoside-resistant, beta- lactam-resistant, cephalosporin-resistant, macrolide-resistant, quinolone-resistant or tetracycline -resistant N. gonorrhoeae.
The present description also relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against aminoglycoside-resistant (including drug-resistant forms of N. gonorrhoeae that are spectinomycin-resistant, streptomycin- resistant, and the like), beta-lactam-resistant (including drug-resistant forms of
N. gonorrhoeae that are ampicillin-resistant, penicillin-resistant, and the like), cephalosporin- resistant (including drug-resistant forms of N. gonorrhoeae that are ceftriaxone-resistant, cefixime-resistant, and the like), macrolide-resistant (including drug-resistant forms of N. gonorrhoeae that are azithromycin-resistant, and the like), quinolone-resistant (including drug-resistant forms of N. gonorrhoeae that are ciprofloxacin-resistant, and the like) or tetracycline -resistant N. gonorrhoeae (including drug-resistant forms of N. gonorrhoeae that are tetracycline-resistant).
The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against ampicillin-resistant, azithromycin-resistant, ceftriaxone-resistant, cefixime-resistant, ciprofloxacin-resistant, penicillin-resistant, spectinomycin-resistant, streptomycin-resistant and tetracycline-resistant forms of N. gonorrhoeae .
The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against aminoglycoside-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against beta-lactam- resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against cephalosporin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against macrolide-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against quinolone-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against tetracycline-resistant forms of N. gonorrhoeae.
The present description also relates to use of the compound of Formula (I), Formula
(II) or Formula (III) or a form thereof having activity against ampicillin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against azithromycin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against ceftriaxone-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against cefixime-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against ciprofloxacin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against penicillin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against spectinomycin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against streptomycin-resistant forms of N. gonorrhoeae. The present description also relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against tetracycline-resistant forms of
N. gonorrhoeae.
The present description further relates to use of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof in a combination therapy with known antibacterial or antibiotic agents to provide additive or synergistic activity, thus enabling the development of a combination product for the treatment of a wild- type or drug-resistant form of N. gonorrhoeae.
The compounds of the present description have demonstrated an ability to inhibit the replication of a wide variety of N. gonorrhoeae isolates. The instant compounds possess in vitro activity against a wide spectrum of N. gonorrhoeae isolates which have developed resistance to almost all known treatments and are expected to successfully treat wild-type or drug-resistant forms of N. gonorrhoeae compared to current antibacterial agents. The compounds are also effective in vivo and lack cellular toxicity. In addition to
monotherapeutic use, the instant compounds are useful in a combination therapy with current standard of care antibacterial or antibiotic agents, having additive or synergistic activity with one or more known antibacterial or antibiotic agents.
A combination therapy comprising compounds described herein in combination with one or more known antibacterial or antibiotic drugs may be used to treat wild-type or drug- resistant forms of N. gonorrhoeae regardless of whether N. gonorrhoeae is resistant or responsive to the known antibacterial or antibiotic drug.
Embodiments of the present description include the use of a compound of Formula
(I), Formula (II) or Formula (III) or a form thereof in a combination therapy for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof and an effective amount of one or more antibiotic or antibacterial agent(s).
Embodiments of the present description include the use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof in a combination therapy for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof and an effective amount of one or more antibiotic or antibacterial agent(s).
An embodiment of the present description includes the use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof in the preparation of a kit comprising the compound of Formula (I), Formula (II) or Formula (III) or a form thereof and instructions for administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof and an effective amount of one or more antibiotic or antibacterial agent(s) in a combination therapy for treating or ameliorating N. gonorrhoeae in a subject in need thereof.
In one embodiment, the agents used in the combination therapy may include, without limitation, one or more agents selected from Amikacin, Amoxicillin, Ampicillin,
Arsphenamine, Azithromycin, Azlocillin, Aztreonam, Bacitracin, Capreomycin,
Carbenicillin, Cefaclor, Cefadroxil, Cefalexin, Cefalotin, Cefamandole, Cefazolin, Cefdinir, Cefditoren, Cefixime, Cefoperazone, Cefotaxime, Cefoxitin, Cefpodoxime, Cefprozil,
Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Chloramphenicol, Cilastatin, Ciprofloxacin, Clarithromycin, Clavulanate, Clindamycin, Clofazimine, Cloxacillin, Colistin, Cycloserine, Dalfopristin, Dapsone, Daptomycin, Dicloxacillin, Dirithromycin, Doripenem, Doxycycline, Enoxacin, Erythromycin, Ethambutol, Ethionamide, Flucloxacillin,
Fosfomycin, Furazolidone, Fusidic acid, Gatifloxacin, Gemifloxacin, Gentamicin, Imipenem, Isoniazid, Kanamycin, Levofloxacin, Lincomycin, Linezolid, Lomefloxacin, Loracarbef, Mafenide, Meropenem, Methicillin, Metronidazole, Mezlocillin, Minocycline, Moxifloxacin, Mupirocin, Nafcillin, Nalidixic acid, Neomycin, Netilmicin, Nitrofurantoin, Norfloxacin, Ofloxacin, Oxacillin, Oxytetracycline, Paromomycin, Penicillin G, Penicillin V, Piperacillin, Platensimycin, Polymyxin B, Pyrazinamide, Quinupristin, Rapamycin, Rifabutin, Rifampicin, Rifampin, Rifapentine, Rifaximin, Roxithromycin, Silver sulfadiazine, Solithromycin, Spectinomycin, Streptomycin, Sulbactam, Sulfacetamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfanamide, Sulfasalazine, Sulfisoxazole, Tazobactam, Teicoplanin, Telavancin, Telithromycin, Temocillin, Tetracycline, Thiamphenicol, TicarciUin,
Tigecycline, Tinidazole, Tobramycin, Trimethoprim, Troleandomycin or Vancomycin.
In another embodiment, the agents used in the combination therapy may include, without limitation, one or more agents selected from Amikacin, Amoxicillin, Arsphenamine, Azlocillin, Aztreonam, Bacitracin, Capreomycin, Carbenicillin, Cefaclor, Cefadroxil, Cefalexin, Cefalotin (Cefalothin), Cefamandole, Cefazolin, Cefdinir, Cefditoren,
Cefoperazone, Cefotaxime, Cefoxitin, Cefpodoxime, Cefprozil, Ceftazidime, Ceftibuten, Ceftizoxime, Cefuroxime, Chloramphenicol, Cilastatin, Clarithromycin, Clavulanate, Clindamycin, Clofazimine, Cloxacillin, Colistin, Cycloserine, Dalfopristin, Dapsone, Daptomycin, Dicloxacillin, Dirithromycin, Doripenem, Doxycycline, Enoxacin,
Erythromycin, Ethambutol, Ethionamide, Flucloxacillin, Fosfomycin, Furazolidone, Fusidic acid, Gatifloxacin, Gemifloxacin, Gentamicin, Imipenem, Isoniazid, Kanamycin,
Levofloxacin, Lincomycin, Linezolid, Lomefloxacin, Loracarbef, Mafenide, Meropenem, Methicillin, Metronidazole, Mezlocillin, Minocycline, Moxifloxacin, Mupirocin, Nafcillin, Nalidixic acid, Neomycin, Netilmicin, Nitrofurantoin, Norfloxacin, Ofloxacin, Oxacillin, Oxytetracycline, Paromomycin, Piperacillin, Platensimycin, Polymyxin B, Pyrazinamide, Quinupristin, Rapamycin, Rifabutin, Rifampicin, Rifampin, Rifapentine, Rifaximin,
Roxithromycin, Silver sulfadiazine, Solithromycin, Sulbactam, Sulfacetamide, Sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Tazobactam, Teicoplanin, Telavancin, Telithromycin, Temocillin, Thiamphenicol, TicarciUin, Tigecycline, Tinidazole, Tobramycin, Trimethoprim, Troleandomycin or Vancomycin.
In another embodiment, the agents used in the combination therapy may include, without limitation, one or more agents selected from Amoxicillin, Ampicillin, Azithromycin, Ciprofloxacin, Doxycycline, Enoxacin, Erythromycin, Gatifloxacin, Gemifloxacin,
Gentamicin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Rapamycin, Solithromycin, Spectinomycin, Streptomycin, Tetracycline or Vancomycin.
In another embodiment, the agents used in the combination therapy may particularly include one or more agents selected from Amoxicillin, Azithromycin, Ciprofloxacin, Doxycycline, Enoxacin, Erythromycin, Gatifloxacin, Gemifloxacin, Gentamicin,
Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin,
Rapamycin, Solithromycin or Vancomycin. In another embodiment, the agents used in the combination therapy may include, without limitation, one or more agents selected from Ampicillin, Azithromycin, Cefixime, Ceftriaxone, Ciprofloxacin, Penicillin G, Penicillin V, Spectinomycin, Streptomycin or Tetracycline.
Accordingly, the present description relates to use of a compound of Formula (I),
Formula (II) or Formula (III) or a form thereof for treating or ameliorating wild-type forms of N. gonorrhoeae, for treating or ameliorating drug-resistant forms of N. gonorrhoeae or for treating or ameliorating multi-drug resistant forms of N. gonorrhoeae.
One embodiment of the use of the present description relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating
N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae resulting from wild-type forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae resulting from drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof to the subject.
One embodiment of the use of the present description relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound to the subject.
One embodiment of the use of the present description relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating wild-type or drug-resistant forms N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound to the subject.
An embodiment of the use of the present description relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating wild-type forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound to the subject.
An embodiment of the use of the present description relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof in the manufacture of a medicament for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof in the manufacture of a medicament for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof in the manufacture of a medicament for treating or ameliorating wild-type forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
An embodiment of the use of the present description relates to use of a compound of
Formula (I), Formula (II) or Formula (III) or a form thereof in the manufacture of a medicament for treating or ameliorating drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.
An embodiment of the use of the present description relates to use of a compound of
Formula (I), Formula (II) or Formula (III) or a form thereof in the preparation of a kit comprising the compound of Formula (I), Formula (II) or Formula (III) or a form thereof and instructions for administering the compound for treating or ameliorating N. gonorrhoeae in a subject in need thereof.
An embodiment of the use of the present description relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof to the subject.
An embodiment of the use of the present description relates to use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof in the manufacture of a medicament for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the the medicament to the subject.
In one respect, for each of such embodiments, the subject is treatment naive. In another respect, for each of such embodiments, the subject is not treatment naive.
As used herein, the term "treating" refers to: (i) preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having the disease, disorder and/or condition;
(ii) inhibiting a disease, disorder or condition, i.e., arresting the development thereof; and/or
(iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
As used herein, the term "subject" refers to an animal or any living organism having sensation and the power of voluntary movement, and which requires oxygen and organic food. Nonlimiting examples include members of the human, primate, equine, porcine, bovine, murine, rattus, canine and feline specie. In some embodiments, the subject is a mammal or a warm-blooded vertebrate animal. In other embodiments, the subject is a human. As used herein, the term "patient" may be used interchangeably with "subject" and "human".
Another aspect of the description particularly relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae resulting from wild type forms of N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof.
Another aspect of the description particularly relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae resulting from drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof.
One aspect of the description relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), Formula (II) or Formula (III) 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 (streptomycin ) N. gonorrhoeae FA 1090 (ATCC 700825; GenBank Acc. No. AE004969), ATCC N. gonorrhoeae MS11 (ATCC BAA-1833) and ATCC wild- type N. gonorrhoeae 49226 (ATCC 49226) (see, http://www.atcc.org).
Another aspect of the description relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against N. gonorrhoeae isolates engineered from clinical isolate FA 19 to contain mutations in gyrA and parC, including those selected from ciprofloxacin-resistant
(ciprofloxacin R ) N. gonorrhoeae AK1 (gyrAgi/g5) and ciprofloxacin R N. gonorrhoeae AK2 (gyrAgi/95, parCse) (see, Anjali N. Kunz, Afrin A. Begum, Hong Wu, Jonathan A.
D'Ambrozio, James M. Robinson, William M. Shafer, Margaret C. Bash and Ann E. Jerse. Impact of Fluoroquinolone Resistance Mutations on Gonococcal Fitness and In Vivo
Selection for Compensatory Mutations. J. Infect Dis., 2012, Jun 15; 205(12): 1821-9).
Another aspect of the description relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against N. gonorrhoeae World Health Organization (WHO) isolates selected from: tetracycline ER N. gonorrhoeae 13477 (WHO tetracycline intermediate resistant isolate F), ciprofloxacin ER /tetracycline R N. gonorrhoeae 13478 (WHO ciprofloxacin intermediate resistant and tetracycline resistant isolate G), quinolone HLR N. gonorrhoeae 13479 (WHO quinolone high level resistant isolate K), MDR N. gonorrhoeae 13480 (WHO multi-drug resistant isolate L) and MD∑R N. gonorrhoeae 13481 (WHO multi-drug intermediate resistant isolate M) (see, Unemo M, Fasth O, Fredlund H, Limnios A, Tapsall J. Phenotypic and genetic characterization of the 2008 WHO Neisseria gonorrhoeae reference strain panel intended for global quality assurance and quality control of gonococcal antimicrobial resistance surveillance for public health purposes. J. Antimicrobial Chemother., 2009, Jun; 63(6): 1142-51). Another aspect of the description relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against the ciprofloxacin XDR /cefixime XDR /ceftriaxone XDR extensively drug resistant N. gonorrhoeae F89 (see, Unemo M, Golparian D, Nicholas R, Ohnishi M, Gallay A, Sednaoui P. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother., 2012, Mar; 56(3): 1273-80).
Another aspect of the description relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against a N. gonorrhoeae isolate engineered from WHO isolate F (N. gonorrhoeae 13477), where DNA from FA 1090 was isolated and used to transform
13477 with the streptomycin R determinant. The resulting isolate SP 1364 is streptomycin R at >1250 μg/mL.
Another aspect of the description relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against a N. gonorrhoeae clinical isolate LG24 (see, Garvin LE, Bash MC, Keys C, Warner DM, Ram S, Shafer WM and Jerse AE. Phenotypic and genotypic analyses of Neisseria gonorrhoeae isolates that express frequently recovered PorB PIA variable region types suggest that certain Pla porin sequences confer a selective advantage for urogenital tract infection. Infect Immun., 2008, Aug;76(8):3700-9).
Another aspect of the description relates to a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof having activity against N. gonorrhoeae clinical isolates selected from penicillin- resistant (penicillin R ) N. gonorrhoeae LGB3, tetracycline-resistant (tetracycline R )
N. gonorrhoeae LGB24 and ampicillin-resistant (ampicillin ) N. gonorrhoeae LGB50 (see, McKnew DL, Lynn F, Zenilman JM, Bash MC. Porin variation among clinical isolates of N. gonorrhoeae over a 10-year period, as determined by Por variable region typing. J. Infect Dis., 2003, Apr 15;187(8): 1213-22).
An embodiment of the use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof includes a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof to treat or ameliorate wild-type N. gonorrhoeae 49226 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof includes a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof to treat or ameliorate clinical isolate N. gonorrhoeae LG24 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof includes a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof to treat or ameliorate N. gonorrhoeae MSI 1 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof includes a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof to treat or ameliorate ampicillin N. gonorrhoeae LGB50 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof includes a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof to treat or ameliorate penicillin- sensitive N. gonorrhoeae FA 19 or LGB3 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof includes a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof to treat or ameliorate streptomycin N. gonorrhoeae FA 1090 or SP1364 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof includes a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof to treat or ameliorate ciprofloxacin N. gonorrhoeae AK1 or AK2 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof includes a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof to treat or ameliorate N. gonorrhoeae caused by an isolate selected from 13477, 13478, 13479, 13480 or 13481 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof to the subject.
An embodiment of the use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof includes a method of use for a compound of Formula (I), Formula (II) or Formula (III) or a form thereof to treat or ameliorate tetracycline N. gonorrhoeae LGB24 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof to the subject.
As used herein, the terms "effective amount" or "therapeutically effective amount" mean an amount of compound of Formula (I), Formula (II) or Formula (III) or a form, composition or medicament thereof effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect in a subject in need thereof.
The dose administered to achieve an effective target plasma concentration may also be administered based upon the weight of the subject or patient. Doses administered on a weight basis may be in the range of about 0.001 mg/kg/day to about 3500 mg/kg/day, or about 0.01 mg/kg/day to about 2000 mg/kg/day, or about 0.01 mg/kg/day to about 1500 mg/kg/day, or about 0.01 mg/kg/day to about 1000 mg/kg/day, or about 0.01 mg/kg/day to about 600 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 300 mg/kg/day, or about 0.015 mg/kg/day to about 200 mg/kg/day, or about 0.02 mg/kg/day to about 100 mg/kg/day, or about 0.025 mg/kg/day to about 100 mg/kg/day, or about 0.03 mg/kg/day to about 100 mg/kg/day, wherein said amount may be orally administered once (once in approximately a 24 hour period), twice (once in approximately a 12 hour period) or thrice (once in approximately an 8 hour period) daily according to subject weight.
In certain embodiments, the effective amount will be in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.1 mg to about 500 mg/kg/day, or about 1.0 mg/day to about 500 mg/kg/day, in single, divided, or a continuous dose for a patient or subject having a weight in a range of between about 40 to about 200 kg (which dose may be adjusted for patients or subjects above or below this range, particularly children under 40 kg). The typical adult subject is expected to have a median weight in a range of about 70 kg.
In another embodiment, where daily doses are adjusted based upon the weight of the subject or patient, compounds described herein may be formulated for delivery at about 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.20, 0.25, 0.30, 0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0, 3.0, 5.0, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400 or 500 mg/kg/day. Daily doses adjusted based upon the weight of the subject or patient may be administered as a single, divided, or continuous dose. In embodiments where a dose of compound is given more than once per day, the dose may be administered twice, thrice, or more per day.
Within the scope of the present description, the "effective amount" of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof for use in the manufacture of a medicament, the preparation of a pharmaceutical kit or in a method of treating or
ameliorating N. gonorrhoeae in a subject in need thereof, is intended to include an amount in a range of from about 0.001 mg to about 3500 mg administered daily; 1.0 mg to about 3500 mg administered daily; 1.0 mg to about 1500 mg administered daily; 1.0 mg to about 1000 mg administered daily; 10.0 mg to about 600 mg administered daily; 0.5 mg to about 2000 mg administered daily; or, an amount in a range of from about 5.0 mg to about 300 mg administered daily.
For example, the effective amount may be the amount required to treat
N. gonorrhoeae, or the amount required to inhibit N. gonorrhoeae replication in a subject or, more specifically, in a human. In some instances, the desired effect can be determined by analyzing the presence of bacterial DNA. The effective amount for a subject will depend upon various factors, including the subject's body weight, size and health. Effective amounts for a given patient can be determined by routine experimentation that is within the skill and judgment of the clinician. For any compound, the effective amount can be estimated initially either in cell culture assays or in relevant animal models, such as a mouse, chimpanzee, marmoset or tamarin animal model. Relevant animal models may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g. , ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is therapeutic index, and can be expressed as the ratio, LD50/ED50. In some embodiments, the effective amount is such that a large therapeutic index is achieved. In further embodiments, the dosage is within a range of circulating concentrations that include an ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
More specifically, the concentration-biological effect relationships observed with regard to a compound of Formula (I), Formula (II) or Formula (III) or a form thereof indicate an trough target plasma concentration ranging from approximately 0.001 μg/mL to approximately 50 μg/mL, from approximately 0.01 μg/mL to approximately 20 μg/mL, from approximately 0.05 μg/mL to approximately 10 μg/mL, or from approximately 0.1 μg/mL to approximately 5 μg/mL. To achieve such plasma concentrations, the compounds described herein may be administered at doses that vary, such as, for example, without limitation, from 0.1 ng to 10,000 mg, depending upon the route of administration in single, divided, or continuous doses for a patient weighing between about 10 kg to about 100 kg (which dose may be adjusted for patients within this weight range, particularly for children under 40 kg).
The exact dosage will be determined by the practitioner, in light of factors related to the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, ethinicity, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, experience with other antibacterial therapies, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 2, 3 or 4 days, once every week, or once every two weeks depending on half-life and clearance rate of the particular formulation. The compounds and compositions described herein may be administered to the subject via any drug delivery route known in the art. Nonlimiting examples include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration. Metabolites of the Compounds
Also included within the scope of the present description are the use of in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the description includes the use of compounds produced by a process comprising contacting a compound described herein with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof.
Such products typically are identified by preparing a radio-labeled isotopologue (e.g., 14C or 3H) of a compound described herein, administering the radio-labeled compound in a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal such as a rat, mouse, guinea pig, dog, monkey or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to about 30 hours), and identifying the metabolic conversion products from urine, bile, blood or other biological samples. The conversion products are easily isolated since they are "radiolabeled" by virtue of being isotopically-enriched (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds described herein even if they possess no biological activity of their own.
Pharmaceutical Compositions
Embodiments of the present description include the use of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof in a pharmaceutical composition for treating or ameliorating N. gonorrhoeae in a subject in need thereof comprising administering an effective amount of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof in admixture with a pharmaceutically acceptable excipient.
An embodiment of the present description includes the use of a pharmaceutical composition of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof in the preparation of a kit comprising the pharmaceutical composition of the compound of Formula (I), Formula (II) or Formula (III) or a form thereof and instructions for administering the compound for treating or ameliorating N. gonorrhoeae in a subject in need thereof.
As used herein, the term "composition" means a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The pharmaceutical composition may be formulated to achieve a physiologically compatible pH, ranging from about pH 3 to about pH 11. In some embodiments, the pharmaceutical composition is formulated to achieve a pH of from about pH 3 to about pH 7. In other embodiments, the pharmaceutical composition is formulated to achieve a pH of from about pH 5 to about pH 8.
The term "pharmaceutically acceptable excipient" refers to an excipient for administration of a pharmaceutical agent, such as the compounds described herein. The term refers to any pharmaceutical excipient that may be administered without undue toxicity. Pharmaceutically acceptable excipients may be determined in part by the particular composition being administered, as well as by the particular mode of administration and/or dosage form. Nonlimiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, etc. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions for the instant compoounds described herein {see, e.g., Remington's Pharmaceutical Sciences).
Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive antibodies. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA;
carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose {e.g., hydroxypropylmethylcellulose, also known as HPMC), stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting or emulsifying agents; pH buffering substances; and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.
The pharmaceutical compositions described herein may be formulated in any form suitable for the intended use described herein. Suitable formulations for oral administration include solids, liquid solutions, emulsions and suspensions, while suitable inhaleable formulations for pulmonary administration include liquids and powders. Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids which can be reconstituted with a physiologically compatible solvent prior to administration.
When intended for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
Pharmaceutically acceptable excipients suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross- linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including
microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
In other embodiments, pharmaceutical compositions described herein may be formulated as suspensions comprising a compound of Formula (I), Formula (II) or Formula (III) or a form thereof in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension. In yet other embodiments, pharmaceutical compositions described herein may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of one or more excipient(s).
Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g. , lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g. , polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g. , heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
The pharmaceutical compositions described herein may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids;
hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
Additionally, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propane-diol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer' s solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
The compounds described herein may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but generally soluble in medium-chain fatty acids (e.g. , caprylic and capric acids) or triglycerides and in propylene glycol esters of medium-chain fatty acids. Thus, contemplated in the description are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, etc.
In some embodiments, the compound described herein is formulated for oral administration in a lipid-based composition suitable for low solubility compounds. Lipid- based formulations can generally enhance the oral bioavailability of such compounds. As such, pharmaceutical compositions described herein may comprise a effective amount of a compound of Formula (I), Formula (II) or Formula (III) or a form thereof, together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or propylene glycol esters thereof (e.g. , propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants, such as polysorbate 20 or 80 (also referred to as Tween 20 or Tween 80, respectively) or polyoxyl 40 hydrogenated castor oil.
In other embodiments, the bioavailability of low solubility compounds may be enhanced using particle size optimization techniques including the preparation of
nanoparticles or nanosuspensions using techniques known to those skilled in art. The compound forms present in such preparations include amorphous, partially amorphous, partially crystalline or crystalline forms.
In alternative embodiments, the pharmaceutical composition may further comprise one or more aqueous solubility enhancer(s), such as a cyclodextrin. Nonlimiting examples of cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin, and hydroxypropyl- β-cyclodextrin (HPBC). In some embodiments, the pharmaceutical composition further comprises HPBC in a range of from about 0.1% to about 20%, from about 1% to about 15%, or from about 2.5% to about 10%. The amount of solubility enhancer employed may depend on the amount of the compound in the composition.
Preparation of Compounds General Synthetic Examples 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.
Compounds of Formula (I), (II) and (III) can be prepared as described in the Schemes below.
Starting material ketones used in Scheme 3 are prepared via the procedures described in Schemes 1 and 2.
Scheme 1
Figure imgf000090_0001
General Procedure for Scheme 1
Carboxylic acids of Type lc are prepared from substituted halogenated benzenes of Type la (where Hal is CI or Br) via a two-step process: 1),. Heck-type coupling reaction with alkenyl carboxylic acids of Type lb in the presence of a suitable Pd-catalyst/ligand combination (such as combination of Pd(OAc)2 and tri(o-tolyl)phosphine and the like); and, 2),. Hydro genation of the intermediate olefin in the presence of a suitable Pd catalyst (such as Pd/C and the like).
Ketones of Type Id are prepared from the carboxylic acids of Type lc via Friedel- Crafts acylation in the presence of a dehydrating reagent (such as polyphosphoric acid and the like). Scheme 2
Figure imgf000090_0002
General Procedures for Scheme 2
Alternatively, ketones of Type Id are prepared from phenols or thiophenols of Type 2a via alkylation with haloesters of Type 2b (where Hal is CI, Br or I) in the presence of a suitable base (such as NaH and the like), followed by intramolecular Friedel-Crafts acylation of intermediates of Type 2c in the presence of a dehydrating reagent (such as polyphosphoric acid and the like).
Scheme 3
Figure imgf000091_0001
1. [Nu"]
2. [H+]
Figure imgf000091_0002
substituted amine
General Procedures for Scheme 3
Ketones of Type Id are converted into imines of Type 3a 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-pyridones of Type 3b are prepared from the respective imines of Type 3a 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 (I) can be prepared directly from the respective 4-hydroxy-2- pyridones of Type 3b via a two step process: 1). 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); and, 2). Cleavage of the protecting group (such as 2,4-dimethoxybenzyl and the like) in the presence of a suitable acid (such as TFA and the like).
Alternatively, 4-hydroxy-2-pyridones of Type 3c can be first functionalized with optionally substituted amines (when Ri or R2 is halogen) in the presence of a suitable Pd- catalyst (such as 2-(2'-di-tert-butylphosphine)biphenylpalladium(II) acetate) to yield tricyclic intermediates of Type 3d. Compounds of Formula (I) are obtained from the respective tricyclic intermediates of Type 3d via the two-step process described above.
Starting material ketones used in Scheme 6 are prepared via the following routes:
Scheme 4
Figure imgf000092_0001
X = CH(R3) or CH(R3)-CH(R3)
Z = CH(R3)
General Procedures for Scheme 4
Vinyl aldehydes of Type 4b are prepared from chloroaldehydes of Type 4a via Pd- catalyzed Suzuki-type 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).
Dienes of Type 4c are prepared from the respective vinyl aldehydes via reaction with alkenyl metal halides (such as alkenyl magnesium bromides and the like).
Ring closing metathesis (RCM) of the respective dienes occurs in the presence of a Grubbs' catalyst (such as a second generation catalyst) followed by hydrogenation of the intermediate olefin in the presence of suitable Pd or Pt catalysts (such as Pd/C or Pt02 and the like) to obtain the tricyclic benzylic alcohols of Type 4d.
Ketones of Type 4e are obtained from the respective tricyclic benzylic alcohols by reaction with a suitable oxidative reagent (such as TPAP (tetrapropylammonium
perruthenate)/NMO (/V-methylmorpholine /V-oxide and the like)).
Scheme 5
Figure imgf000093_0001
General Procedures for Scheme 5
Hydroxy-aldehydes of Type 5a are treated with suitable alkenyl alkylating reagents
(where L represents a leaving group) and a suitable base (such as K2C03 and the like) to yield olefin intermediates of Type 5b.
Dienes of Type 5c are prepared from the respective olefin intermediates of Type 5b by reaction with a suitable vinyl metal species (such as vinyl magnesium halides and the like).
Ring closing metathesis (RCM) of the respective dienes in the presence of Grubbs' catalyst (such as a second generation catalyst) affords tricyclic benzylic alcohols of type 5d.
Ketones of type 4e are obtained from the respective tricyclic benzylic alcohols of Type 5d by reaction with a suitable oxidant (such as Mn02 and the like) followed by hydrogenation of the olefin intermediate of Type 5e in the presence of a suitable Pd or Pt catalyst (such as Pd/C or Pt02 and the like).
Scheme 6
Figure imgf000094_0001
General Procedures for Scheme 6
Ketones of Type 4e are converted into imines of Type 6a 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 6b are 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).
Scheme 7
Figure imgf000094_0002
General Procedure for Scheme 7
4-Hydroxy-2-pyridone esters of Type 6b (where Rx represents CH2OTBS) are converted into aldehydes of Type 7a via a three step process: 1). TBS-group deprotection with a suitable fluoride containing reagent (such as TBAF and the like); 2). Ester group cleavage with a suitable nucleophilic reagent (such as Lil and the like); and, 3). Conversion of the benzylic hydroxyl group to an aldehyde with a suitable oxidant (such as Mn02 and the like).
Compounds of Formula (Ila) are prepared from the respective aldehydes via a two- step process: 1). Reductive amination with a primary or secondary amine in the presence of a suitable reducing reagent (such as NaBH(OAc)3 and the like); and, 2). Protecting group cleavage (such as cleavage of the 2,4-dimethoxybenzyl group) in the presence of a suitable acid (such as TFA and the like).
Compounds of Formula (lib) can be prepared from compounds of Formula (Ila) via reduction with a suitable reducing reagent (such as NaBH CN and the like) in the presence of a suitable acid (such as TFA and the like).
Scheme 8
Figure imgf000095_0001
General Procedure for Scheme 8
Compounds of Formula (Ila) can also be prepared from the respective 4-hydroxy-2- pyridone esters of Type 6b (where Rx represents R directly, 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 (such as 2,4-dimethoxybenzyl and the like) in the presence of a suitable acid (such as TFA and the like).
Scheme 9
Figure imgf000095_0002
Figure imgf000096_0001
General Procedure for Scheme 9
Tricyclic pyridines of Type 9a are prepared from 4-hydroxy-2-pyridones of Type 3b by protecting group cleavage (such as cleavage of 2,4-dimethoxybenzyl group) under acidic conditions (such as TFA in DCM and the like), followed by reaction with a suitable alcohol bearing a protecting group (such as benzyl alcohol and the like) under Mitsunobu conditions.
Protected anilines of Type 9b are prepared by a Pd-catalyzed amination reaction of the respective tricyclic pyridines of Type 9a with an amine containing a suitable protecting group (such as a Boc-group and the like) followed by alkylation with a suitable alkylating reagent R5-L (where L represents a leaving group) in the presence of an appropriate base (such as NaH and the like).
Halogenated anilines of Type 9c are prepared from the respective protected anilines of Type 9b by thermal protecting group cleavage (such as cleavage of a Boc-group) followed by electrophilic halogenation with a suitable halogen source (such as NIS or NBS and the like).
Tetracyclic indoles of Type 9d are prepared from the respective halogenated anilines of Type 9c via Sonogashira coupling with propargyl alcohol in the presence of an appropriate Pd source (such as Pd(PPh3)2Cl2 and the like) followed by cyclization catalyzed by a suitable Cu1 salt (such as Cul and the like).
Compounds of Formula (Ila) are prepared from the respective tetracyclic indoles of
Type 9d via a three step process: 1). Benzylic alcohol oxidation with a suitable oxidant, such as Mn02 and the like; 2). Reaction with a primary or secondary amine in the presence of a suitable reducing reagent (such as NaBH(OAc)3 and the like); and, 3). Global protecting group cleavage (such as cleavage of the benzyl groups) accompanied by ester hydrolysis in the presence of a suitable halogenated trialkylsilane (such as TMSI and the like). Scheme 10
Figure imgf000097_0001
General Procedure for Scheme 10
Boronic ester intermediates of Type 10b are prepared from haloindolines of Type 10a
(where PGi represents a protecting group such as Boc and the like) via metal halogen exchange with a suitable alkyl lithium species (such as n-BuLi and the like) followed by reaction with an appropriate pinacol boronate (such as 2-isopropoxy-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane and the like).
Biaryl intermediates of Type lOd are prepared from the respective boronic esters via
Pd-catalyzed Suzuki coupling with functionalized pyridines of Type 10c (where PG2 represents a protecting group such as benzyl and the like), in the presence of a suitable phosphine ligand (such as t-Bu3P and the like).
Tetracyclic indolines of Type lOe are prepared from the respective biaryl
intermediates via a two-step process: 1). TBS-group deprotection with a suitable fluoride containing reagent (such as TBAF and the like); and, 2). Intramolecular Mitsunobu reaction with a suitable dialkyl azodicarboxylate (such as diisopropyl azodicarboxylate and the like).
4-Hydroxy-2-pyridone compounds of Type lOf are prepared from the respective tetracyclic indolines of Type lOe by global deprotection via suitable methods, such as hydrogenation in the presence of a suitable Pd catalyst (such as Pd/C and the like) followed by treatment with a suitable acid (such as TFA and the like).
Compounds of Type lOg (representative of a compound of Formula (lib), wherein Z is O) are prepared from the respective 4-hydroxy-2-pyridone compounds of Type lOf by reductive amination with an Rs-substituted aldehyde in the presence of a suitable reducing reagent (such as NaBH(OAc) and the like). Scheme 11
Figure imgf000098_0001
General Procedure for Scheme 11
Alternatively, indoline intermediates of Type lOe are converted to tetracyclic indoles of Type 11a via a three step process: 1). Indoline moiety oxidation with a suitable oxidant (such as Mn02 and the like); 2). Thermal protecting group cleavage (such as cleavage of a Boc-group); and, 3). Alkylation with a suitable alkylating reagent R5-L (where L represents a leaving group) in the presence of an appropriate base (such as NaH and the like).
Compounds of Type 1 lb (representative of a compound of Formula (Ila), wherein Z is O) are prepared from the respective tetracyclic indoles of Type 1 la by global deprotection via suitable methods (such as hydrogenation in the presence of a suitable Pd catalyst, such as Pd/C and the like). Additionally, compounds of Type lOg (representative of a compound of Formula (lib), wherein Z is O) can also be prepared from compounds of Type 1 lb by reduction with a suitable reducing reagent (such as Et3SiH and the like) in the presence of a suitable acid (such as TFA and the like). Scheme 12
Figure imgf000099_0001
General Procedure for Scheme 12
Biaryl intermediates of Type 12c are prepared via Suzuki-type coupling of boronic esters of Type 12a with protected halogenated pyridines of Type 12b in the presence of a suitable Pd source (such as Pd2dba3 and the like) and a suitable ligand (such as t-Bu PHBF4 and the like).
The tetracyclic intermediates of Type 12d are prepared via global protecting group cleavage (such as cleavage of benzyl, TBS and SEM groups) and accompanying
intramolecular cyclization by treatment of the respective biaryl intermediates of Type 12c with a suitable acid (such as HC1 and the like).
Compounds of Type 12e (representative of a compound of Formula (lib), wherein X is CH(R3)-0 and Z is CH(R3)) are prepared from the respective tetracyclic intermediates of Type 12d by reductive amination with an R5 substituted aldehyde in the presence of a suitable reducing reagent (such as NaBH(OAc) and the like). Scheme 13
Figure imgf000100_0001
General Procedure for Scheme 13
Biaryl intermediates of Type 13b are prepared by Suzuki-type coupling reaction of boronic esters of Type 13a with orthogonally protected halogenated pyridines of Type 12b in the presence of a suitable Pd source (such as Pd2dba3 and the like) and a suitable ligand (such as t-Bu3PHBF4 and the like).
Tetracyclic intermediates of Type 13c are prepared by TBS-groups cleavage of the respective biaryl intermediates of Type 13b with a suitable fluoride containing reagent (such as TBAF and the like), followed by intramolecular cyclization promoted by a suitable acid (such as TFA and the like).
Compounds of Type 13d (representative of a compound of Formula (Ila), wherein X is CH(R )-0 and Z is CH(R )) are prepared from the respective tetracyclic intermediates of Type 13c by global protecting group cleavage (such as cleavage of benzyl groups) via hydrogenation in the presence of a suitable Pd catalyst (such as Pd/C and the like). Scheme 14
Figure imgf000101_0001
X = CH(R3)-CH(R3)
Z = CH R3)
Figure imgf000101_0002
General Procedure for Scheme 14
Bicylic intermediates of Type 14c are prepared via hydroboration of protected chloropyridines of Type 14a with suitable borane reagents (such as 9-BBN and the like) followed by Suzuki-type coupling with halogenated indoles of Type 14b in presence of a suitable Pd-catalyst (such as Pd(dppf)Cl2 and the like).
Tetracyclic indoles of Type 14d are prepared from the respective intermediates of Type 14c via a two-step, one-pot sequence: 1). Regio selective formation of a boronic ester by reaction with a suitable pinacol boronate (such as 2-isopropoxy-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane and the like) in the presence of a suitable Pd-catalyst (such as Pd(dppf)Cl2 and the like); and, 2). Intramolecular Suzuki-type cyclization in the presence of a suitable Pd source/ligand combination (such as combination of Pd2dba3 and i-Bu3PHBF4 and the like).
Aldehydes of Type 14e are prepared from the respective tetracyclic indoles of Type 14d (where Rx represents CH2OTBS) via TBS-group deprotection with a suitable fluoride containing reagent (such as TBAF and the like), followed by oxidation of the benzylic hydroxyl group with a suitable oxidant (such as Mn02 and the like).
Compounds of Formula (Ilia) are prepared from the respective aldehydes of Type 14e via a two-step process: 1). Reductive amination with a primary or secondary amine in the presence of a suitable reducing reagent, such as NaBH(OAc)3 and the like; and, 2). Global protecting group cleavage (such as cleavage of the benzyl groups) by hydrogenation in the presence of a suitable Pd catalyst (such as Pd/C and the like).
Compounds of Formula (Illb) can be prepared from compounds of Formula (Ilia) via reduction with a suitable reducing reagent (such as NaBH3CN and the like) in the presence of a suitable acid (such as TFA and the like).
Scheme 15
Figure imgf000102_0001
Figure imgf000103_0001
General Procedure for Scheme 15
Protected anilines of Type 15b are prepared from nitroketones of Type 15a by a two- step sequence: 1). Ketal formation with a suitable diol (such as ethylene glycol and the like) in the presence of a suitable acid (such as p-TsOH and the like); and, 2). Nitro-group reduction by hydrogenation in the presence of a suitable Pd catalyst (such as Pd/C and the like).
Indoles of Type 15c are prepared from the respective protected anilines of Type 15b by halogenation with a suitable halogen source (such as NBS, NIS and the like), followed by Sonogashira coupling with a substituted alkyne in the presence of an appropriate Pd source (such as Pd(PPh3)2Cl2 and the like) and cyclization catalyzed by a suitable Cu1 salt (such as Cul and the like).
Tricyclic ketones of Type 15d are prepared from the respective indoles of Type 15c by alkylation with a suitable alkylating reagent R5-L (where L represents a leaving group) in the presence of an appropriate base (such as NaH and the like), followed by ketal cleavage by treatment with a suitable acid (such as HC1 and the like).
4-Hydroxy-2-pyridones of Type 15e are prepared from the respective tricyclic ketones of Type 15d by a two-step sequence: 1). Imine formation by 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); and, 2). Cyclization 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 (Ilia) are prepared from the respective 4-hydroxy-2- pyridones of Type 15e by cleavage of the protecting group in the presence of a suitable acid (such as TFA and the like), followed by 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). 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 ingredients, 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 CI 8 Column 2.1 x 50 mm, 1.8μπι
Mobile Phase A: H2O/0.1% HC02H
Mobile Phase B: Acetonitrile/0.1% HC02H
Flow
Gradient Time (min) %A %B
(mL/min)
1 0 0.8 100 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 Non-Polar Method uses the following column and mobile phase ratios:
Column: Acquity UPLC HSS CI 8 Column 2.1 x 50 mm, 1.8μπι
Mobile Phase A: H2O/0.1% HC02H
Mobile Phase B: Acetonitrile/0.1% HC02H
Flow
Gradient Time (min) %A %B
(mL/min)
1 0 0.8 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
4A MS 4 Angstrom Molecular Sieves Abbreviation Meaning
Atm atmosphere
Bn benzyl
BnBr benzyl bromide
BnO or OBn benzyloxy
BnOH benzyl alcohol
Boc ie/t-butoxycarbonyl
Boc20 or (Boc)20 di-iert-butyl dicarbonate
BORSM based on recovered starting material
Cbz benzyloxycarbonyl
CDI 1 , 1 '-carbonyldiimidazole
DCE dichloroethane
DCM dichloromethane (CH2C12)
DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone
DEAD diethyl azodicarboxylate
DIAD diisopropyl azodicarboxylate
DIBAL-H diisobutylaluminium hydride
DMF dimethyl formamide
DMA dimethylacetamide
DMAP 4-dimethylaminopyridine
DMB 2,4-dimethoxybenzyl
DMSO dimethylsulfoxide
EA or EtOAc ethyl acetate
EtOH ethanol
Et20 diethyl ether
HPLC high performance liquid chromatography h/hr/hrs/min/s hour(h or hr)/minute(min)/second(s) Abbreviation Meaning
KOAc potassium acetate
LAH lithium aluminium hydride
LC/MS, LCMS or : liquid chromatographic mass spectroscopy
LDA lithium diisopropylamide
Mel methyl iodide
MeOH methanol
Me2NH or NHMe2 dimethyl amine
MS mass spectroscopy
NaBH(OAc)3 sodium triacetoxyborohydride
NBS N-bromo succinimide
NIS N-iodo succinimide
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 [1,1 '-bis(diphenylphosphino)ferrocene] dichloropalladium(II)
Pd(PPh3)4 tetrakis(triphenylphosphine)palladium
Ph20 diphenyl ether
PPA polyphosphoric acid
PPh3 triphenylpho sphine
Psi pounds per square inch pressure
PTFE polytetrafluoroethylene
RT retention time
RCM ring closing methathesis
S-Phos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl Abbreviation Meaning
TBAF tetra-n-butylammonium fluoride
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 triisopropyl silane
TLC thin layer chromatography
TMSI trimethylsilyl iodide
TMSOK potassium trimethylsilanolate
TPAP tetra-n-propylammonium perruthenate
X-Phos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
Intermediate 1
2-((tert-Butyldimethylsilyloxy)methyl)-6-chloro-l-methyl-lH-indole-5-carbaldehyde
Figure imgf000108_0001
Step 1: 4-Amino-2-chloro-5-(3-hydroxyprop-l-ynyl)benzonitrile
To a solution of 4-amino-2-chloro-5-iodobenzonitrile prepared according to J. Med. Chem. 2001, 44, 3856 (51.73 g, 186 mmol) in CH3CN (270 mL) was added propargyl alcohol (13.3 mL, 223 mmol) and NEt (52 mL, 373 mmol). The mixture was degassed with argon before Pd(PPh3)2Cl2 (1.30 g, 1.85 mmol) and Cul (0.70 g, 3.67 mmol) were added. The reaction was heated at 70 °C for 2 hrs until the starting material was completely consumed. The mixture was cooled to room temperature and concentrated under reduced pressure. Water (300 mL) was added to the residue and the resulting precipitate was filtered, washed with H20 (2x200 mL) and dried under N2 flow. The crude product was obtained as a tan solid (40.00 g) and may be further purified by column chromatography using EtOAc/hexanes (gradient 50- 100%) or can be used directly in the next step without purification.
LC-MS: 205.1/207.1 [M-H]+, 207.1/209.1 [M+H]+, RT 0.92 min. 1H NMR (500 MHz, DMSO- ) δ ppm 4.33 (d, J=6.0 Hz, 2H), 5.29 (t, J=6.0 Hz, 1H), 6.67 (br. s, 2H), 6.86 (s, 1H), 7.64 (s, 1H)
Step 2: 6-Chloro-2-(hydroxymethyl)-lH-indole-5-carbonitrile
To a solution of crude 4-amino-2-chloro-5-(3-hydroxyprop-l-ynyl)benzonitrile (36.70 g, 178 mmol) in DMF (450 mL) was added t-BuOK (44.0 g, 392 mmol). The mixture was heated at 70 °C for 2 hrs under an argon atmosphere, cooled to room temperature and carefully poured into ice (approx. 800 mL) and HC1 (cone, 50 mL). The precipitate was filtered and washed with H20 (2x300 mL) and dried in a N2 flow. The product was obtained as a brownish solid (28.50 g, 77%, 2 steps) and was used directly in the next step without purification.
LC-MS: 205.1/207.1 [M-H]+, 207.1/209.1 [M+H]+, RT 0.92 min. 1H NMR (500 MHz,
DMSO- ) δ ppm 4.63 (d, J=5.7 Hz, 2H), 5.47 (t, J=5.7 Hz, 1H), 6.44 (s, 1H), 7.58 (s, 1H), 8.12 (s, 1H), 11.79 (br. s, 1H)
Step 3: 2-((tert-Butyldimethylsilyloxy)methyl)-6-chloro-lH-indole-5-carbonitrile
To a solution of crude 6-chloro-2-(hydroxymethyl)-lH-indole-5-carbonitrile (32.66 g, 158 mmol) in DMF (450 mL) was added imidazole (14.0 g, 205 mmol). The mixture was stirred at room temperature for 5 min before TBSC1 (29.0 g 192 mmol) was added in one portion. The reaction was stirred at room temperature for 1.5 hrs and then poured into ice/H20 (total final volume approx. 1700 mL) to provide a dark brown oil. Pentane (approx. 100 mL) was added and the resulting solid was filtered, washed with H20 (2x300 mL) and dried under a N2 flow overnight. The solid was washed with pentane (2x300 mL) and then suspended in 800 mL of CH2C12. The resulting mixture was stirred vigorously at room temperature for 1 hr, then filtered through Celite. The mother liquor was concentrated to yield the title compound as a brownish solid (37.42 g, 74%) which was used in the next step without purification. LC-MS: 319.3/321.3 [M-H]+, 321.2/323.2 [M+H]+, RT 1.62 min. 1H NMR (500 MHz, CDC13) δ ppm 0.13 (s, 6H), 0.94 (s, 9H), 4.88 (s, 2H), 6.36 (s, 1H), 7.49 (s, 1H), 7.89 (s, 1H), 8.63 (br. s, 1H) Step 4: 2-((tert-Butyldimethylsilyloxy)methyl)-6-chloro-l-methyl-lH-indole-5-carbonitrile
To a solution of crude 2-((tert-butyldimethylsilyloxy)methyl)-6-chloro-lH-indole-5- carbonitrile (37.50 g, 117 mmol) in DMF (400 mL) at 0 °C was added NaH (60%, 6.7 g, 168 mmol) in portions. The reaction mixture was allowed to warm to room temperature with stirring for 10 min, then cooled to 0 °C and Mel (10.5 mL, 169 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred 1.5 hrs, then poured into ice/H20 and 100 mL 1M HC1 (total final volume approx. 1600 mL). The precipitate which formed was filtered, washed with H20 (3x200 mL) and dried under a N2 flow overnight. The solid was then washed with pentane (2x200 mL). Crude product was obtained as a brownish solid (39.00 g), which was then further purified by column
chromatography with CH2Cl2/hexanes (gradient 50-100%) to yield the title compound as a pale orange solid (approx. 30.0 g, 76% yield).
LC-MS: 335.2/337.2 [M+H]+, RT 1.72 min. 1H NMR (500 MHz, CDC13) δ ppm 0.08 (s, 6H), 0.90 (s, 9H), 3.79 (s, 3H), 4.82 (s, 2H), 6.44 (s, IH), 7.41 (s, IH), 7.90 (s, IH) Step 5: 2-((tert-Butyldimethylsilyloxy)methyl)-6-chloro-l-methyl-lH-indole-5-carbaldehyde
To a solution of 2-((tert-butyldimethylsilyloxy)methyl)-6-chloro-l-methyl-lH-indole-5- carbonitrile (4.15 g, 12.4 mmol) in CH2C12 (50 mL) at -78 °C was added DIBAL-H (1M in CH2C12, 15.0 mL, 15.0 mmol) dropwise over approx. 10 min. The reaction was stirred at -78 °C for 10 min and slowly allowed to warm to -15 °C over about 2 hrs. LC/MS indicated complete consumption of starting material. The reaction mixture was cooled to -40 °C and then quenched by addition of the Rochelle salt (aq. satd., 20 mL). The resulting emulsion was allowed to warm to room temperature and vigorously stirred for about 1 hr. The organic phase was separated and the aqueous phase was extracted with CH2C12 (50 mL). The combined organics were washed sequentially with 1M HC1 (50 mL), NaHC03 (aq. satd., 50 mL) and finally NaCl (aq. satd., 50 mL) and then dried over Na2S04. The solvent was removed and the residue was purified by column chromatography (EtOAc/hexanes, 5-15% gradient), affording the title compound as an off-white solid (3.80 g, 91 %).
LC-MS: 338.2/340.3 [M+H]+, RT 1.76 min. 1H NMR (500 MHz, CDC13) δ ppm 0.08 (s, 6H), 0.90 (s, 9H), 3.79 (s, 3H), 4.82 (s, 2H), 6.49 (s, IH), 7.33 (s, IH), 8.21 (s, IH), 10.50 (s, IH) Intermediate 2
2-((tert-Butyldimethylsilyloxy)methyl)-l-methyl-6-vinyl-lH-indole-5-carbaldehyde
Figure imgf000111_0001
2-((tert-Butyldimethylsilyloxy)methyl)-6-chloro-l-methyl-lH-indole-5-carbaldehyde (Intermediate 1, 3.80 g, 11.24 mmol), potassium vinyltrifluoroborate (2.30 g, 17.17 mmol), Pd(OAc)2 (76 mg, 0.34 mmol, 3 mol%), S-Phos ligand (280 mg, 0.68 mmol, 6 mol%) and K2C03 (4.70 g, 34.0 mmol) were mixed together in a 100 mL round bottom flask. The flask was vacuumed and backfilled with argon before dioxane (45 mL) and H20 (7.5 mL) were added. The mixture was heated at 85-90 °C for 5 hrs and the reaction was monitored by LC/MS until the starting material was completely consumed. The reaction was cooled to room temperature and water (30 mL) was added. The product was extracted with CH2C12 (3x80 mL). The combined organics were washed with NaCl (aq. satd., 80 mL), dried over Na2S04 and concentrated. The residue was purified by column chromatography
(EtOAc/hexanes, 0-10% gradient) affording the product as a white solid (3.32 g, 89 %). LC-MS: 330.3 [M+H]+, RT 1.74 min. 1H NMR (500 MHz, CDC13) δ ppm 0.09 (s, 6H), 0.91 (s, 9H), 3.84 (s, 3H), 4.85 (s, 2H), 5.42 (dd, J=10.7, 1.7 Hz, 1H), 5.69 (dd, J=17.2, 1.7 Hz, 1H), 6.51 (s, 1H), 7.43 (s, 1H), 7.75 (dd, J=17.3, 10.7 Hz, 1H), 8.07 (s, 1H), 10.24 (s, 1H)
Intermediate 3
2-(((tert-Butyldimethylsilyl)oxy)methyl)-l-methyl-7,8-dihydro-lH-benzo[f]indol-5(6H)-one
Figure imgf000111_0002
Step 1: l-(2-(((tert-Butyldimethylsilyl)oxy)methyl)-l-methyl-6-vinyl-lH-indol-5-yl)but-3-en- l-ol
To a solution of 2-((tert-butyldimethylsilyloxy)methyl)-l-methyl-6-vinyl-lH-indole-5- carbaldehyde (Intermediate 2, 4.237 g, 12.86 mmol) in THF (50 mL) at -78 °C was added allylmagnesium chloride (2M in THF, 8.0 mL, 16.0 mmol) dropwise over approx. 10 min. The reaction was stirred at this temperature for 10 min and slowly allowed to warm to 0 °C, then quenched by addition of NH4C1 (aq. satd., 40 mL). The product was extracted with EtOAc (3x80 mL). The combined organics were washed with NaCl (aq. satd., 50 mL) and dried over Na2S04. The product was concentrated to obtain a pale-yellow oil (4.30 g, 90%) which solidified when triturated with pentane. The product was not very stable to silica gel but pure enough (>95%) to be used directly in the next step without purification.
1H NMR (500 MHz, acetone- 6) δ ppm 0.09 (s, 3H), 0.10 (s, 3H), 0.91 (s, 9H), 2.40 - 2.55 (m, 2H), 3.83 (s, 3H), 4.01 (d, J=4.1 Hz, 1H), 4.90 (s, 2H), 4.94 - 5.11 (m, 3H), 5.21 (dd, J=10.9, 1.7 Hz, 1H), 5.68 (dd, J=17.3, 1.6 Hz, 1H), 5.82 - 5.98 (m, 1H), 6.37 (s, 1H), 7.27 (dd, J=17.3, 11.0 Hz, 1H), 7.50 (s, 1H), 7.66 (s, 1H)
Step 2: 2-(((tert-Butyldimethylsilyl)oxy)methyl)- l-methyl-5,6,7,8-tetrahydro- 1H- benzo[f]indol-5-ol
Crude l-(2-(((tert-butyldimethylsilyl)oxy)methyl)- l-methyl-6-vinyl- lH-indol-5-yl)but-3-en- l-ol obtained above was dissolved in toluene (260 mL, 0.05M) under an argon atmosphere. Second generation Grubbs' catalyst (540 mg, 0.64 mmol, 5 mol %) was added and the mixture was stirred at room temperature overnight. Complete consumption of starting material was indicated by TLC. Pt02 (200 mg, 0.88 mmol, 7 mol %) was added to the mixture and the reaction was hydrogenated under 1 atm of H2 until the olefin intermediate was completely consumed. The catalyst was then filtered; toluene was concentrated and the residue was purified by column chromatography (EtOAc/hexanes, 0-15% gradient). The title compound was obtained as a solid (3.08 g, 69% 3 steps).
1H NMR (500 MHz, acetone- d6) δ ppm 0.07 (s, 3H), 0.07 (s, 3H), 0.90 (s, 9H), 1.67 - 1.78 (m, 1H), 1.81 - 1.90 (m, 1H), 1.92 - 2.09 (m, 2H), 2.81 - 2.88 (m, 1H), 2.94 (dt, J=16.4, 5.8 Hz, 1H), 3.72 (d, J=5.4 Hz, 1H), 3.75 (s, 3H), 4.80 (q, J=5.4 Hz, 1H), 4.88 (s, 2H), 6.31 (s, 1H), 7.04 (s, 1H), 7.56 (s, 1H)
Step 3: 2-(((tert-Butyldimethylsilyl)oxy)methyl)- l-methyl-7,8-dihydro- lH-benzo[f]indol- 5(6H)-one
To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-l-methyl-5,6,7,8-tetrahydro-lH- benzo[f]indol-5-ol (4.04 g, 11.69 mmol) in CH2C12 (120 mL) was added activated Mn02 (11.4 g + 11.4 g + 5.7 g, 118 + 118 + 59 mmol) in 3 portions with 20 min intervals. The reaction was monitored by TLC with KMn04 staining (due to much higher UV absorption of the product compared to the starting material) until the starting material was completely consumed. The Mn02 was filtered off and washed with CH2C12. The mother liquor was concentrated and the residue was purified by column chromatography (EtOAc/hexanes, 0- 15% gradient). The product was obtained as an off-white solid (2.580 g, 64%). LC-MS: 344.5 [M+H]+, RT 1.66 min. 1H NMR (500 MHz, CDC13) δ ppm 0.07 (s, 6H), 0.90 (s, 9H), 2.16 (quin, J=6.3 Hz, 2H), 2.68 (t, J=6.3 Hz, 2H), 3.10 (t, J=6.3 Hz, 2H), 3.78 (s, 3H), 4.82 (s, 2H), 6.45 (s, 1H), 7.09 (s, 1H), 8.37 (s, 1H)
Intermediate 4
2-((tert-Butyldimethylsilyloxy)methyl)- 1 -methyl-6,7,8,9-tetrahydrocyclohepta[f]indol-5( 1H)- one
Figure imgf000113_0001
Step 1 : l-(2-((tert-Butyldimethylsilyloxy)methyl)- l-methyl-6-vinyl- lH-indol-5-yl)pent-4-en- l-ol To a solution of 2-((tert-butyldimethylsilyloxy)methyl)-l-methyl-6-vinyl- lH-indole-5- carbaldehyde (Intermediate 2, 8.23 g, 24.98 mmol) in THF (50 mL) at -78 °C was added 3- butenylmagnesium bromide (0.5M in THF, 60.0 mL, 30.0 mmol) dropwise over approx. 10 min. The reaction was stirred at this temperature for 10 min and slowly allowed to warm to -10 °C. The reaction was quenched by the addition of NH4C1 (aq. sat., 80 mL). The product was extracted with EtOAc (4x150 mL). The combined organics were washed with NaCl (aq. satd., 100 mL), dried over Na2S04 and concentrated to obtain a pale yellow oil (9.60 g, quant.) which solidified under high vacuum. The product was not very stable to silica gel but was pure enough (>95 ) to be used directly in the next step without purification.
LC-MS: 386.3 [M+H]+, RT 1.80 min. 1H NMR (500 MHz, CDC13) 5 ppm 0.06 (s, 3H), 0.07 (s, 3H), 0.90 (s, 9 H), 1.86 - 1.99 (m, 2H), 2.11 - 2.31 (m, 2H), 3.80 (s, 3H), 4.82 (s, 2H), 4.95 - 5.16 (m, 3H), 5.29 (dd, J=10.4, 1.7 Hz, 1H), 5.65 (dd, J=17.2, 1.7 Hz, 1H), 5.83 - 5.93 (m, 1H), 6.34 (s, 1H), 7.23 (dd, J=17.2, 10.9 Hz, 1H), 7.40 (s, 1H), 7.66 (s, 1H)
Step 2: 2-((tert-Butyldimethylsilyloxy)methyl)- 1 -methyl- 1,5,6,7- tetrahydrocyclohepta[f]indol-5-ol l-(2-((tert-Butyldimethylsilyloxy)methyl)- l-methyl-6-vinyl- lH-indol-5-yl)pent-4-en-l-ol obtained above (ca. 24.98 mmol) was dissolved in toluene (500 mL, 0.05M) under an argon atmosphere. Second generation Grubbs' catalyst (640 mg, 0.75 mmol, 3 mol ) was added and the mixture was heated at 60 °C for 2-3 hrs until starting material was completely consumed as indicated by LC/MS. The reaction mixture was cooled to room temperature, toluene was removed under reduced pressure and the residue (approx. 8.9 g) was taken directly into the next step. The product can be purified by column chromatography
(EtOAc/hexanes, 0-20% gradient) to yield yellow solid material.
LC-MS: 358.3 [M+H]+, RT 1.66 min. 1H NMR (500 MHz, CDC13) 5 ppm 0.06 (s, 6H), 0.90 (s, 9H), 1.92 (br. s, 1H), 2.08 - 2.19 (m, 1H), 2.23 - 2.34 (m, 1H), 2.42 - 2.51 (m, 1H), 2.56 - 2.71 (m, 1H), 3.77 (s, 3H), 4.82 (s, 2H), 5.03 (d, J=8.2 Hz, 1H), 5.84 - 5.91 (m, 1H), 6.34 (s, 1H), 6.56 (d, J=12.3 Hz, 1H), 7.14 (s, 1H), 7.57 (s, 1H)
Step_3: 2-((tert-Butyldimethylsilyloxy)methyl)- 1 -methyl- 1 ,5,6,7,8,9- hexahydrocyclohepta[f]indol-5-ol A solution of 2-((tert-butyldimethylsilyloxy)methyl)-l -methyl- 1,5, 6,7- tetrahydrocyclohepta[f]indol-5-ol obtained above (ca. 24.98 mmol) in EtOAc (105 mL) and CH2C12 (15 mL) was hydrogenated over Pd/C (10%, 880 mg) with a H2-filled balloon (1 atm) until complete consumption of starting material as indicated by TLC (2x 10%
EtOAc/hexanes). After about 3 hrs, the catalyst was filtered and washed with EtOAc. The mother liquor was concentrated and the product was obtained as a brown solid (approx. 8.9 g) and was taken directly into the next step without purification. The product can be purified by column chromatography (EtOAc/hexanes, 0-25% gradient) to yield pale yellow solid material.
LC-MS: 360.3 [M+H]+, RT 1.71 min. 1H NMR (500 MHz, CDC13) 5 ppm 0.06 (s, 3H), 0.07 (s, 3H), 0.90 (s, 9H), 1.59 - 1.68 (m, 1H), 1.70 - 1.85 (m, 2H), 1.85 - 2.00 (m, 2H), 2.02 - 2.14 (m, 1H), 2.83 (dd, J=13.7, 10.6 Hz, 1H), 3.12 (dd, J=13.7, 9.3 Hz, 1H), 3.76 (s, 3H), 4.81 (s, 2H), 5.03 (d, J=9.1 Hz, 1H), 6.33 (s, 1H), 7.04 (s, 1H), 7.58 (s, 1H)
Step 4: 2-((tert-Butvldimethvlsilvloxv)methvl)-l-methyl-6,7,8,9- tetrahydrocyclohepta[f] indol-5 ( 1 H)-one To activated 4A molecular sieves (6.2 g, 250 mg/mmol) was added a solution of 2-((tert- butyldimethylsilyloxy)methyl)-l -methyl- 1, 5,6,7, 8,9-hexahydrocyclohepta[f]indol-5-ol obtained above (ca. 24.98 mmol) in CH2CI2 (125 mL). The mixture was cooled to 0 °C before NMO (4.45 g, 37.99 mmol) and TPAP (445 mg, 1.26 mmol, 5 mol%) were added
subsequently. The reaction was stirred at 0 °C and monitored by LC/MS until the starting material was completely consumed (approx. 1.5 hrs). The molecular sieves were filtered off through Celite and washed with CH2CI2. The mother liquor was concentrated and the residue was purified by column chromatography (EtOAc/hexanes, 0-25% gradient) to obtain an off- white solid (7.47 g, 84 % over 4 steps).
LC-MS: 358.3 [M+H]+, RT 1.73 min. 1H NMR (500 MHz, CDC13) 5 ppm 0.06 (s, 6H), 0.90 (s, 9H), 1.76 - 1.84 (m, 2H), 1.88 - 1.95 (m, 2H), 2.74 - 2.77 (m, 2H), 3.05 (t, J=6.6 Hz, 2H), 3.79 (s, 3H), 4.82 (s, 2H), 6.43 (s, 1H), 7.06 (s, 1H), 8.04 (s, 1H)
Intermediate 5
6-(But-3-en-2-yloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-l-methyl-lH-indole-5- carbaldeh de
Figure imgf000115_0001
SterjJj. 2-(((tert-Butyldimethylsilyl)oxy)methyl)-l-methyl-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-indole-5-carbaldehyde
2-((tert-Butyldimethylsilyloxy)methyl)-6-chloro-l-methyl-lH-indole-5-carbaldehyde (Intermediate 1, 21.5 g, 63.6 mmol), bis(pinacolato)diboron (25.0 g , 98.5 mmol, approx. 1.5 eq), Pd2dba3 (1.45 g, 1.65 mmol, 2.5 mol%), X-Phos ligand (1.51 g, 3.17 mmol, 5 mol%) and KOAc (18.7 g, 190.5 mmol, 3 eq) were mixed together in a 1L round bottom flask. The flask was vacuumed and backfilled with N2 and repeated twice. Dioxane (300 mL) was added and the mixture was heated at 75 °C for 2 hrs. The mixture was cooled to room temperature and filtered through a pad of Celite, washing with dioxane. The mother liquor was concentrated and hexanes (approx. 300 mL) were added to the residue. The mixture was cooled in an ice- bath and a solid was filtered yielding a first batch of the product (17.5 g). The mother liquor was concentrated and the residue was purified by column chromatography (0-20%
EtOAc/hexanes) to yield an additional batch of the product (4.7 g). Overall yield was 22.2 g (81%).
1H NMR (500 MHz, CDC13) 5 ppm 0.05 (s, 6H), 0.89 (s, 9H), 1.43 (s, 12H), 3.86 (s, 3H), 4.85 (s, 2H), 6.52 (s, 1H), 7.76 (s, 1H), 8.26 (s, 1H), 10.55 (s, 1H)
Step 2: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-6-hydroxy-l -methyl- lH-indole-5- carbaldehyde
The product of Step 1 (20.37 g, 47.48 mmol) was dissolved in dioxane (200 mL) and NMO (6.1 g, 1.1 eq) was added. The reaction mixture was heated at 80 °C for 1 hr. Additional NMO (0.61 g, approx. 10 mol%) was added and the mixture was heated for another 1 hr. The dioxane was concentrated and the residue was triturated with hexanes. The solid was filtered to provide a first batch of the product (8.00 g). The filtrate was concentrated and the residue was purified by column chromatography (0-10% EtOAc/ hexanes, containing 2.5% CH2CI2) to provide an additional batch of product (2.7 g). Overall yield was 10.7 g (71%).
1H NMR (500 MHz, CDCI3) δ ppm 0.08 (s, 6H), 0.91 (s, 9H), 3.71 (s, 3H), 4.79 (s, 2H), 6.40 (s, IH), 6.76 (s, IH), 7.72 (s, IH), 9.86 (s, IH), 11.04 (br. s, IH)
Step 3: 6-(But-3-yn-2-yloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)- 1-methyl- lH-indole-5- carbaldehyde To a solution of the product of Step 2 (0.25 g, 0.78 mmol) in THF (3 mL) was added CS2CO3 (0.33 g, 1.01 mmol) followed by but-3-yn-2-yl methanesulfonate (0.13 mL, 1.05 mmol). The reaction mixture was heated at 60 °C for 3 hrs before an additional batch of CS2CO3 (0.17 g, 0.52 mmol) and but-3-yn-2-yl methanesulfonate (0.05 mL, 0.40 mmol) was added. The reaction was heated at 60 °C until complete consumption of starting material was observed (approx. 5 hrs). THF was concentrated and the residue was loaded directly onto a silica gel column. The product was isolated by eluting with EtOAc/hexanes (0-20% gradient) to afford the title compound (0.114 g, 39%).
1H NMR (500 MHz, CDCI3) δ ppm 0.07 (s, 3H), 0.08 (s, 3H), 0.91 (s, 9H), 1.78 (d, J=6.5 Hz, 3H), 2.54 (d, J=2.0 Hz, IH), 3.77 (s, 3H), 4.79 (s, 2H), 5.00 (qd, J=6.5, 2.0 Hz, IH), 6.42 (d, J=0.6 Hz, IH), 6.98 (s, IH), 8.12 (s, IH), 10.48 (s, IH)
Step 4: 6-(But-3-en-2-yloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)- 1-methyl- lH-indole-5- carbaldehyde
A solution of the product of Step 3 (0.132 g, 0.36 mmol) in MeOH (3.5 mL) and CH2C12 (1.5 mL) was hydrogenated over Lindlar' s catalyst (25 mg) under a H2 balloon for approx. 1.5 hrs. The catalyst was filtered and washed with CH2CI2. The mother liquor was concentrated and the residue was purified by column chromatography (0-20% EtOAc/ hexanes) to afford the title compound (0.122 g, 93%).
1H NMR (500 MHz, acetone- d6) δ ppm 0.09 (s, 3H), 0.10 (s, 3H), 0.90 (s, 9H), 1.51 (d, J=6.4 Hz, 3H), 3.79 (s, 3H), 4.88 (s, 2H), 5.12 - 5.18 (m, IH), 5.20 (dt, J=10.6, 1.3 Hz, IH), 5.40 (dt, J=17.3, 1.3 Hz, IH), 6.04 (ddd, J=17.3, 10.6, 6.1 Hz, IH), 6.48 (s, IH), 7.10 (s, IH), 7.97 (s, IH), 10.49 (s, IH) Intermediate 6
8-((tert-Butyldimethylsilyloxy)methyl)-9-m^
one
Figure imgf000117_0001
Step 1 : 4-(Allyloxy)-3-bromobenzaldehyde
To a solution of 3-bromo-4-hydroxybenzaldehyde (10.0 g, 50 mmol) in DMF (50 mL) was added K2C03 (7.6 g, 55 mmol) and allylbromide (4.5 mL, 52.5 mmol). The reaction mixture was stirred at room temperature for 16 hrs until TLC showed complete consumption of starting material. The reaction mixture was then poured into H20 (100 mL) and extracted with Et20 (2 x 100 mL). The combined organic extracts were washed with brine, dried over MgS04, filtered, and concentrated to afford product (11.2 g, 93%) as a clear oil.
LC-MS: 243.1 [M+H]+, RT 1.46 min. 1H NMR (500 MHz, CDC13) δ ppm 4.62 (s, 2H), 5.32 (dq, J=10.60, 1.62 Hz, IH), 5.52 (dq, J=17.26, 1.79 Hz, IH), 6.10 (ddt, J=17.25, 10.61, 4.83, 4.83 Hz, IH), 7.01 (d, J=8.51 Hz, IH), 7.81 (dd, J=8.43, 2.05 Hz, IH), 8.04 - 8.15 (m, IH), 9.87 (s, IH)
Step 2: Ethyl 3-(4-(allyloxy)-3-bromophenyl)-2-azidoacrylate
To a solution of 4-(allyloxy)-3-bromobenzaldehyde (11.2 g, 46.5 mmol) and ethyl 2- azidoacetate (19.0 g, 140 mmol) in EtOH (100 mL), cooled to -10 °C, was added NaOEt (50 mL, 2.76 M) dropwise over 20 minutes. The reaction mixture was warmed to 5 °C and stirred for 16 hrs, then cooled to 0 °C and H20 was added. The precipitate was then filtered and washed with H20 to afford product (10.1 g, 62%) as a beige powder.
1H NMR (500 MHz, CDC13) δ ppm 1.41 (t, J=7.12Hz, 3H) 4.38 (q, J=7.15 Hz, 2H) 4.67 (dt, J=4.92, 1.53 Hz, 2H) 5.36 (dd, J=10.59, 1.38 Hz, IH) 5.52 (dq, J=17.25, 1.52 Hz, IH) 6.08 (ddt, J=17.22, 10.46, 5.07, 5.07 Hz, IH) 6.80 (s, IH) 6.86 - 6.93 (m, IH) 7.74 (dd, J=8.67, 2.06 Hz, IH) 8.11 (d, J=2.13 Hz, IH)
Step 3: Ethyl 6-(allyloxy)-5-bromo-lH-indole-2-carboxylate
A solution of ethyl 3-(4-(allyloxy)-3-bromophenyl)-2-azidoacrylate (6.5 g, 19 mmol) in xylenes (40 mL) was heated to 140 °C for 1 hr. The solution was then cooled to room temperature and concentrated. The crude residue was purified on silica gel (EtO Ac/Hex 1: 1) to afford the title compound (3.0 g, 47%) as a light yellow solid.
LC-MS: 326.1 [M+H]+ , RT 0.90 min. 1H NMR (500 MHz, DMSO- 6) δ ρρηι 1.33 (t, J=7.09 Hz, 3H), 4.33 (q, J=7.15 Hz, 2H), 4.66 (dt, J=4.79, 1.59 Hz, 2H), 5.32 (dq, J=10.60, 1.62 Hz, 1H), 5.52 (dq, J=17.26, 1.79 Hz, 1H), 6.10 (ddt, J=17.25, 10.61, 4.83, Hz, 1H), 7.01 (s, 1H), 7.07 (d, J=1.02 Hz, 1H), 7.91 (s, 1H), 11.88 (s, 1H)
Step 4: Ethyl 6-(allyloxy)-5-bromo-l -methyl- lH-indole-2-carboxylate
To a solution of ethyl 6-(allyloxy)-5-bromo-lH-indole-2-carboxylate (5.5 g, 16.9 mmol) in DMF (17 mL), cooled to 0 °C, was added NaH (60% in oil, 0.75g, 18.6 mmol). Gas evolution was observed and the mixture was stirred for 30 min at which point Mel (1.2 mL, 18.6 mmol) was added and the solution was allowed to warm to room temperature. After stirring at room temperature for 1 hr, saturated NH4C1 was added and the mixture was poured into H20 and extracted with Et20. The combined organic extracts were washed with brine, dried over MgS04, filtered, and concentrated to give the product (5.24 g, 92%) as a white solid.
LC-MS: 340.1 [M+H]+, RT 1.00 min. 1H NMR (500 MHz, CDCI3) δ ppm 1.31 (t, J=7.13 Hz, 3H), 3.86 - 3.91 (m, 3H), 4.26 (q, J=7.17 Hz, 2H), 4.55 (dt, J=4.95, 1.59 Hz, 2H), 5.25 (dq, J=10.63, 1.47 Hz, 1H), 5.46 (dq, J=17.26, 1.66 Hz, 1H), 5.97 - 6.08 (m, 1H), 6.63 (s, 1H), 7.05 (d, J=0.79 Hz, 1H), 7.71 (s, 1H)
Step 5: (6-(Allyloxy)-5-bromo-l-methyl-lH-indol-2-yl)methanol To a solution of ethyl 6-(allyloxy)-5-bromo-l-methyl-lH-indole-2-carboxylate (5.24 g, 15.4 mmol) in CH2C12 (40 mL), cooled to -78 °C, was added DIBAL-H (32.4 mL, 1M). After stirring at -78 °C for 30 min, TLC showed complete consumption of starting material. The reaction was then warmed to 0 °C and a saturated solution of Rochelle's Salt (30 mL) was added followed by CH2C12 (100 mL). The solution was warmed to room temperature and stirred for 1 hr. The organic layer was separated and washed with brine, dried over Na2S04, then filtered and concentrated to afford product (4.0 g, 87%) as a white solid.
LC-MS: 298.0 [M+H]+, RT 0.94 min. 1H NMR (500 MHz, CDC13) δ ppm 3.66 (s, 3H), 4.60 (dt, J=5.04, 1.62 Hz, 2H), 4.73 (s, 2H), 5.27 (dd, J=10.56, 1.50 Hz, 1H), 5.49 (dd, J=17.22, 1.62 Hz, 1H), 6.04 - 6.14 (m, 1H), 6.20 (d, J=0.63 Hz, 1H), 6.74 (s, 1H), 7.66 (s, 1H) Step 6: 6-(Allyloxy)-5-bromo-2-((tert-butyldimethylsilyloxy)methyl)-l-methyl-lH-indole To a solution of (6-(allyloxy)-5-bromo-l-methyl-lH-indol-2-yl)methanol (4.8 g, 16 mmol) was added imidazole (1.2 g, 17 mmol) and TBSC1 (2.6 g, 17 mmol). After stirring for 3 hrs, the solution was washed with H20, brine, dried with Na2S04, filtered, and concentrated. The crude residue was purified on silica gel (20% EtOAc/hexanes) to afford product (5.58 g, 85%) as a white solid.
LC-MS: 410.2 [M+H]+, RT 1.14 min.
Step 7: 6-(Allyloxy)-2-((tert-butyldimethylsilyloxy)methyl)-l-methyl-lH-indole-5- carbaldehyde
To a solution of 6-(allyloxy)-5-bromo-2-((tert-butyldimethylsilyloxy)methyl)-l-methyl-lH- indole (0.2 g, 0.5 mmol) in THF (5 mL), cooled to -78 °C) was added w-BuLi (300 μΐ,, 2.5M solution). After stirring at -78 °C for 30 min, DMF (100 μί) was added and the solution was warmed to room temperature. After stirring at room temperature for 30 min, the reaction was quenched with saturated NH4C1 (2 mL) and poured into H20. The aqueous layer was extracted with Et20 (2 x 20 mL) and the combined organics were washed with brine, dried with MgS04, filtered and concentrated to afford product (165 mg, 92%) as a white solid. LC-MS: 360.2 [M+H]+, RT 1.16 min. 1H NMR (500 MHz, CDC13) δ ppm -0.03 - 0.02 (m, 6H), 0.80 - 0.85 (m, 9H), 3.67 (s, 3H), 4.63 (dt, J=5.10, 1.55 Hz, 2H), 4.71 (d, J=0.32 Hz, 2H), 5.28 (dd, J=10.56, 1.42 Hz, 1H), 5.40 - 5.47 (m, 1H), 6.00 - 6.15 (m, 1H), 6.33 (d, J=0.55 Hz, 1H), 6.64 (s, 1H), 8.03 (s, 1H), 10.45 (s, 1H) Step 8: l-(6-(Allyloxy)-2-((tert-butyldimethylsilyloxy)methyl)- 1-methyl- lH-indol-5-yl)prop- 2-en-l-ol
To a solution of 6-(allyloxy)-2-((tert-butyldimethylsilyloxy)methyl)- 1-methyl- lH-indole-5- carbaldehyde (5.2 g, 14.6 mmol) in THF (60 mL) cooled to 0 °C was added vinylmagnesium bromide (16.0 mL, 1M). After stirring at 0 °C for 30 min, the solution was warmed to room temperature and stirred for an additional 30 min at which point saturated NH4C1 (10 mL) was added. The crude reaction mixture was poured into H20 and extracted with Et20 (2 x 100 mL). The combined organics were washed with brine, dried with MgS04, filtered, and concentrated to afford product (5.5 g, 98%) as a yellow oil which was used immediately in the subsequent step without further purification.
1H NMR (500 MHz, DMSO- 6) δ ppm -0.02 - 0.03 (m, 6H), 0.80 - 0.86 (m, 9H), 3.63 - 3.68 (m, 3H), 4.59 (dt, J=4.93, 1.60 Hz, 2H), 4.76 (s, 2H), 4.88 - 4.94 (m, 1H), 5.12 (d, J=4.81 Hz, 1H), 5.13 - 5.19 (m, 1H), 5.22 - 5.27 (m, 1H), 5.40 - 5.48 (m, 1H), 5.91 - 6.01 (m, 1H), 6.04 - 6.14 (m, 1H), 6.26 (s, 1H), 6.94 (s, 1H), 7.43 (s, 1H)
Step 9: 8-((tert-Butyldimethylsilyloxy)methyl)-9-methyl-5,9-dihydro-2H-oxepino[3,2- f]indol-5-ol To a solution of l-(6-(allyloxy)-2-((tert-butyldimethylsilyloxy)methyl)-l-methyl-lH-indol-5- yl)prop-2-en-l-ol (5.5 g, 14.3 mmol) in toluene (200 mL) was added Grubbs' catalyst second generation (350 mg) and the reaction mixture was heated at 60 °C for 3 hrs. The reaction mixture was then cooled to room temperature, concentrated, and the crude residue was purified on silica gel (20% EtOAc/hexanes) to afford the product as a light green solid (2.7 g, 51%).
LC-MS: 342.3 [M-H20]+, RT 1.00 min. 1H NMR (500 MHz, DMSO- 6) δ ppm -0.03 - 0.03 (m, 6H), 0.79 - 0.86 (m, 9H), 3.64 (s, 3H), 4.17 - 4.28 (m, 1H), 4.65 - 4.74 (m, 1H), 4.76 (s, 2H), 5.23 - 5.34 (m, 1H), 5.47 (d, J=5.60 Hz, 1H), 5.69 - 5.80 (m, 2H), 6.30 (d, J=0.55 Hz, 1H), 7.08 (s, 1H), 7.41 (d, J=0.63 Hz, 1H) Step 10: 8-((tert-Butvldimethvlsilvloxv)methvl)-9-methyl-2H-oxepinor3,2-flindol-5(9H)-one
To a solution of 8-((tert-butyldimethylsilyloxy)methyl)-9-methyl-5,9-dihydro-2H- oxepino[3,2-f]indol-5-ol (2.7 g, 7.5 mmol) in CH2C12 (40 mL) was added Mn02 in three batches over 2 hrs (1.5 g, 1.0 g, and 1.0 g). The reaction mixture was then filtered through Celite and concentrated to afford the product as an orange solid (2.0 g, 75%).
LC-MS: 358.8 [M+H]+, RT 1.02 min. 1H NMR (500 MHz, DMSO- 6) δ ppm -0.02 - 0.02 (m, 6H), 0.79 - 0.84 (m, 9H), 3.66 (s, 3H), 4.70 (dd, J=4.26, 1.66 Hz, 2H), 4.76 (s, 2H), 6.21 (d, J=11.82 Hz, 1H), 6.45 (d, J=0.63 Hz, 1H), 6.84 (d, J=11.82 Hz, 1H), 7.11 (s, 1H), 7.89 (s, 1H)
Step 11: 8-((tert-Butyldimethylsilyloxy)methyl)-9-methyl-3,4-dihydro-2H-oxepino[3,2- f]indol-5(9H)-one
To a solution of 8-((tert-butyldimethylsilyloxy)methyl)-9-methyl-2H-oxepino[3,2-f]indol- 5(9H)-one (2.0g, 5.6 mmol) in EtOH (30 mL) was added Pt02 (20 mg). The mixture was hydrogenated under a H2 balloon (1 atm) at room temperature for 3 hrs. The reaction mixture was filtered through Celite and concentrated to afford the title compound (1.9 g, 94%) as a tan solid. LC-MS: 360.8 [M+H]+, RT 1.03 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 0.00 (s, 6H), 0.81 (s, 9H), 1.92 - 2.01 (m, 2H), 2.65 - 2.72 (m, 2H), 3.65 (s, 3H), 4.11 (t, J=6.70 Hz, 2H), 4.76 (s, 2H), 6.43 (d, J=0.63 Hz, 1H), 7.10 (s, 1H), 7.81 (s, 1H)
Intermediate 7
8-(((tert-Butyldimethylsilyl)oxy)methyl)-2,9-dimethyl-3,4-dihydro-2H-oxepino[3,2-f]indol-
5(9H)-one
Figure imgf000121_0001
The title compound was prepared from Intermediate 5 according to the four-step procedure described for Intermediate 6 (steps 8-11).
1H NMR (500 MHz, CDC13) δ ppm 0.07 (s, 3H), 0.07 (s, 3H), 0.90 (s, 9H), 1.43 (d, J=6.2 Hz, 3H), 1.86 - 1.97 (m, 1H), 2.07 - 2.18 (m, 1H), 2.75 (ddd, J=14.3, 6.0, 4.0 Hz, 1H), 3.01 (ddd, J=14.3, 10.7, 4.9 Hz, 1H), 3.74 (s, 3H), 4.22 - 4.33 (m, 1H), 4.80 (s, 2H), 6.42 (s, 1H), 6.93 (s, 1H), 8.08 (s, 1H)
Intermediate 8
9-(((tert-Butyldimethylsilyl)oxy)methyl)-10-methyl-2,3,4,5-tetrahydrooxocino[3,2-f]indol-
6(10H)-one
Figure imgf000121_0002
Step 1: 6-(Allyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)- 1-methyl- lH-indole-5- carbaldehyde To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-6-hydroxy-l-methyl-lH-indole-5- carbaldehyde (Intermediate 5, Step 2, 5.0 g, 15.6 mmol) in DMF (10 mL) was added K2C03 (2.4 g, 17.4 mmol) and allyl bromide (1.5 mL, 17.4 mmol). After stirring at room temperature for 18 hrs, H20 (50 mL) was added. The precipitate was filtered, rinsed with H20 (100 mL), and dried under vacuum to afford 6-(allyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-l- methyl- lH-indole-5-carbaldehyde (5.6 g, 99%) as a light yellow solid. 1H NMR (500 MHz, CDC13) δ ppm 0.07 (s, 6H), 0.90 (s, 9H), 3.75 (s, 3H), 4.71 (dt, J=5.14, 1.61 Hz, 2H), 4.77 - 4.80 (m, 2H), 5.35 (dd, J=10.56, 1.42 Hz, 1H), 5.51 (dq, J=17.26, 1.60 Hz, 1H), 6.04 - 6.14 (m, 1H), 6.40 (s, 1H), 6.72 (s, 1H), 8.10 (s, 1H), 10.52 (s, 1H)
Step 2: l-(6-(Allyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)- 1 -methyl- lH-indol-5-yl)but- 3-en-l-one
To a solution of 6-(allyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-l-methyl-lH-indole-5- carbaldehyde (4.3 g, 12 mmol) in THF (60 mL), cooled to 0 °C, was added a solution of allylmagnesium chloride (7.2 mL, 2.0 M in THF, 14.4 mmol). After stirring at 0 °C for 1 hr, a saturated aqueous solution of NH4C1 (20 mL) was added. The reaction mixture was then poured into H20 (100 mL) and extracted with Et20 (2x100 mL). The combined organic extracts were washed with brine (100 mL), dried over MgS04, filtered, and concentrated. The residue was dissolved in CH2C12 (24 mL) and added to activated 4A molecular sieves (3.0 g, 250 mg/mmol). The mixture was cooled to 0 °C before NMO (2.1 g, 18 mmol) and TPAP (212 mg, 0.62 mmol) were added. The reaction was stirred at 0 °C for 10 min and slowly allowed to warm to room temperature. After stirring at room temperature for 1 hr, the crude reaction mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography (EtOAc/hexanes, 0-30% gradient) to afford the title compound (2.88 g, 60%).
LC-MS: 400.5, [M+H]+, RT 1.97 min. 1H NMR (500 MHz, CDC13) δ ppm 0.00 (s, 6H), 0.84 (s, 9H), 3.68 (s, 3H), 3.79 (dt, J=6.86, 1.38 Hz, 2H), 4.63 (dt, J=5.36, 1.42 Hz, 2H), 4.72 (s, 2H), 5.04 - 5.12 (m, 2H), 5.29 (dd, J=10.52, 1.38 Hz, 1H), 5.43 (dd, J=17.30, 1.46 Hz, 1H), 6.09 (s, 2H), 6.31 (s, 1H), 6.66 (s, 1H), 7.94 (s, 1H)
Step 3: (Z)-9-(((tert-Butyldimethylsilyl)oxy)methyl)-10-methyl-2,5-dihydrooxocino[3,2- f]indol-6(10H)-one To a solution of l-(6-(allyloxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-l-methyl-lH-indol- 5-yl)but-3-en-l-one (1.8 g, 4.5 mmol) in toluene (100 mL) was added second generation Grubbs catalyst (120 mg, 0.14 mmol) and the mixture was heated at 80 °C for 3 hrs. The crude reaction mixture was then allowed to cool to room temperature and concentrated. The crude residue was purified by column chromatography (EtOAc/hexanes, 0-20%) to afford the title compound (1.5 g, 89%). LC-MS: 372.4 [M+H]+, RT 1.72 min. 1H NMR (500 MHz, CDC13) δ ppm 0.00 (s, 6H), 0.83 (s, 9H), 3.69 (s, 3H), 3.79 - 3.86 (m, 2H), 4.73 (s, 2H), 4.76 - 4.83 (m, 2H), 5.39 - 5.47 (m, 1H), 5.69 - 5.77 (m, 1H), 6.37 (s, 1H), 6.92 (s, 1H), 8.14 (s, 1H)
Step 4: 9-(((tert-Butyldimethylsilyl)oxy)methyl)-10-methyl-2,3,4,5-tetrahydrooxocino[3,2- f]indol-6(10H)-one
A suspension of Pt02 (100 mg, .44 mmol) and (Z)-9-(((tert-butyldimethylsilyl)oxy)methyl)- 10-methyl-2,5-dihydrooxocino[3,2-f]indol-6(10H)-one (1.5 g, 4 mmol) in EtOAc (30 mL) was stirred under a H2 atmosphere (1 atm) for 1.5 hrs. The reaction mixture was then filtered through Celite and concentrated to afford the title compound (1.4 g, 93%).
LC-MS: 374.3 [M+H]+, RT 1.15 min. 1H NMR (500 MHz, CDC13) 5 ppm 0.00 (s, 6H), 0.83 (s, 9H), 1.60 (tdd, J=6.32, 6.32, 6.07, 4.93 Hz, 2H), 1.84 - 1.94 (m, 2H), 3.18 (t, J=7.09 Hz, 2H), 3.68 (s, 3H), 4.15 - 4.21 (m, 2H), 4.69 - 4.75 (m, 2H), 6.37 (s, 1H), 6.90 (s, 1H), 8.23 (s, 1H)
Intermediate 9
9-Tosyl-3,4-dihydro-2H-thiepino[3,2-f]indol-5(9H)-one
Figure imgf000123_0001
Step 1: Ethyl 4-((3-bromophenyl)thio)butanoate
To a solution of 3-bromothiophenol (50 g, 265 mmol) in dry DMF (500 mL) at 0 °C was added NaH (12.7 g, 318 mmol, 60% in mineral oil). The mixture was stirred for 10 min, followed by the addition of ethyl 4-bromobutanoate (45.5 mL, 318 mmol). The cooling bath was removed and the mixture was stirred overnight. This was then diluted with water (1.5 L) and extracted with ethyl ether (3 x 300 mL). The extracts were combined and washed with water (2 x 100 mL), brine (100 mL) and dried over anhydrous Na2S04. The volatiles were removed by vacuum to furnish ethyl 4-((3-bromophenyl)thio)butanoate as a light brown oil, which was used directly in the next step.
1H NMR (CDC13) δ: 7.46 (t, J=1.9 Hz, 1H), 7.29-7.32 (m, 1H), 7.23-7.27 (m, 1H), 7.15 (t, J=1.0 Hz, 1H), 4.15 (q, J=7.3 Hz, 2H), 2.98 (t, J=7.3 Hz, 2H), 2.47 (t, J=7.3 Hz, 2H), 1.97 (quin, J=7.2 Hz, 2H), 1.27 (t, J=1.0 Hz, 3H) Step 2: 8-Bromo-3,4-dihydrobenzo[b]thiepin-5(2H)-one
To preheated PPA (600 g) at 120 °C was added the intermediate obtained in Step 1. The mixture was well mixed at 120 °C for 2 hrs and then poured onto ice (1000 mL) and stirred for 0.5 hrs. The organic phase was extracted with CH2CI2 (3 x 300 mL). The CH2CI2 extracts were combined, washed with water (2 x 200 mL), satd. aqueous NaHC03 (300 mL) and dried over Na2S04. The solvent was then removed on a rotovap and the residue was
chromato graphed (silica gel, ethyl acetate in hexanes, 0-30% gradient) to provide
benzothiepinone intermediate as a light brown oil (39.9 g, 59% yield over two steps).
1H NMR (CDCI3) δ: 7.71 (d, J=8.5 Hz, 1H), 7.66 (d, J=1.9 Hz, 1H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 3.04 (t, J=6.6 Hz, 2H), 2.99 (t, J=6.8 Hz, 2H), 2.28 (quin, J=6.8 Hz, 2H)
Step 3: tert-Butyl (5-oxo-2,3,4,5-tetrahydrobenzo[b]thiepin-8-yl)carbamate
A mixture of the bromobenzothiepinone obtained in Step 2 (18.8 g, 73.2 mmol), BocN¾ (17.1 g, 146.3 mmol), K2C03 (25.3 g, 183 mmol), Cul (1.39 g, 7.3 mmol), N, N'- dimethylcyclohexane-l,2-diamine (2.07 g, 2.3 mL, 14.6 mmol) and toluene (100 mL) was stirred at 110 °C under a nitrogen atmosphere overnight. This was then diluted with ethyl acetate (200 mL) and filtered. The precipitates were washed with ethyl acetate and the filtrates were combined and concentrated to dryness. The residue was chromato graphed (silica gel, ethyl acetate in hexanes, 0-50 % gradient) to provide the title intermediate as a pale brown solid (11.55 g, 54%).
1H NMR (CDCI3) δ: 7.84 (d, J=8.5 Hz, 1H), 7.65 (d, J=1.9 Hz, 1H), 7.15 (dd, J=8.8, 2.2 Hz, 1H), 6.61 (br. s, 1H), 3.04 (t, J=6.8 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H), 2.25 (quin, J=6.8 Hz, 2H), 1.53 (s, 9H)
Step 4: 8-Amino-3,4-dihydrobenzo[b]thiepin-5(2H)-one
To a solution of benzothiepinone compound (11.5 g, 39.2 mmol) obtained in Step 3, in CH2CI2 (100 mL) was added TFA (50 mL). The solution was stirred at room temperature for 2 hrs. The volatiles were removed under vacuum and the residue was treated with water (100 mL) and basified to about pH 8. The precipitate was collected by filtration and washed with water and dried to furnish the title compound (6.73 g, 89%).
1H NMR (CDCI3) δ: 7.79 (d, J=8.5 Hz, 1H), 6.72 (d, J=2.2 Hz, 1H), 6.52 (dd, J=8.5, 2.2 Hz, 1H), 3.57 (br. s, 2H), 3.03 (t, J=6.8 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H), 2.21 (quin, J=6.8 Hz, 2H)
Step 5: 8-Amino-7-iodo-3,4-dihydrobenzo[b]thiepin-5(2H)-one A mixture of the product (6.6 g, 34.2 mmol) obtained in Step 4, NIS (7.77 g, 34.5 mmol) and DMF (100 mL) was stirred at room temperature overnight, then diluted with water (300 mL). The precipitate was collected by filtration, washed with water and dried. Column
chromatography purification (silica gel, ethyl acetate in CH2CI2 0-20 %, gradient) provided the title intermediate (7.80 g, 72%).
1H NMR (CDCI3) δ: 7.75 (d, J=8.5 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 2.99-3.05 (m, 4H), 2.31 (quin, J=6.8 Hz, 2H)
Step 6: 3 ,4-Dihydro-2H-thiepino [3 ,2-f] indol-5 (9H)-one
A mixture of the product obtained in Step 5 (7.80 g, 24.5 mmol), Cul (0.23 g, 1.2 mmol), Pd(Ph3P)2 Cl2 (0.86 g, 1.2 mmol), triethylamine (4.94 g, 6.8 mL, 48.9 mmol),
ethynyltrimethylsilane (2.87 g, 4.1 mL, 29.3 mmol) and acetonitrile (50 mL) was stirred at room temperature under an argon atmosphere for 6 hrs. The volatiles were removed on a rotovap and the residue was treated with water (50 mL) and ethyl acetate (100 mL). The organic phase was separated and the aqueous layer was extracted with ethyl acetate (2 x 25 mL). The combined organic phases were washed with water (20 mL), brine (20 mL) and dried over anhydrous Na2S04. The solvent was removed on a rotovap and the residue was chromato graphed (silica gel, ethyl acetate in hexanes, 0-50% gradient) to furnish the intermediate. The solid was dissolved in DMF (50 mL) and stirred at 90 °C for 3 hrs in the presence of Cul (9.31 g, 49 mmol). After cooling, the mixture was diluted with water. The precipitate was collected and dissolved in CH2CI2 (1 L) and washed with NH4OH (300 mL), water (200 mL) and dried over anhydrous Na2S04. After the removal of the solvent, the residue was chromato graphed (silica gel, ethyl acetate in CH2CI2, 0-30% gradient) to furnish the title compound as an oil (2.95 g, 56%, over two steps).
LC-MS: 218.0 [M+H]+, RT 1.08 min. Step 7: 9-Tosyl-3,4-dihydro-2H-thiepino[3,2-f]indol-5(9H)-one
To a mixture of the product obtained in Step 6 (2.95 g, 13.6 mmol), tetrabutylammonium bromide 0.45 g, 1.4 mmol), NaOH (5.44 g, 136 mmol), CH2C12 (24 mL) and water (12 mL) was added tosyl chloride (3.11 g, 16.3 mmol) with vigorous stirring. The mixture was stirred at room temperature overnight and diluted with CH2CI2 (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2CI2 (20 mL). The combined organic phases were washed with water (20 mL), brine (20 mL) and dried over Na2S04. After concentration, the residue was chromato graphed (silica gel, ethyl acetate in CH2CI2, 0-20% gradient) to provide the title intermediate as an oil, which solidified on standing (1.02 g, 20%).
1H NMR (CDC13) δ: 7.84-7.86 (m, 2H), 7.76-7.80 (m, 2H), 7.63 (d, J=3.8 Hz, 1H), 7.23-7.27 (m, 2H), 6.91 (dd, J=3.8, 0.6 Hz, 1H), 3.08 (t, J=6.8 Hz, 2H), 3.03 (t, J=6.8 Hz, 2H), 2.36 (s, 3H), 2.31 (quin, J=6.7 Hz, 2H)
Intermediate 10
Methyl 2,4-bis(benzyloxy)-10-(hydroxymethyl)-9-methyl-5,9-dihydro-6H- pyrido[2',3':4 thiepino[3,2-f]indole-3-carboxylate
Figure imgf000126_0001
Step 1: Methyl 9-bromo-l-(2,4-dimethoxybenzyl)-4-hydroxy-2-oxo-l,2,5,6- tetrahydrobenzo[2,3]thiepino[4,5-b]pyridine-3-carboxylate
To a stirring solution of 8-bromo-3,4-dihydrobenzo[b]thiepin-5(2H)-one (Intermediate 9, Step 2, 36.2 g, 141 mmol), (2,4-dimethoxyphenyl)methanamine (25.9 g, 23.3 mL, 155 mmol), triethylamine (42.7 g, 58.7 mL, 423 mmol) in CH2C12 (300 mL) at 0 °C was added T1CI4 (1M CH2C12, 71 mL, 71 mmol) dropwise. After the addition, the mixture was brought to room temperature and stirred overnight. The reaction was quenched with satd. NaHC03 solution (3 mL) and the mixture was diluted with CH2C12 (120 mL). The CH2C12 layer was separated using a phase separator cartridge and the aqueous layer was extracted with CH2C12 (2 x 30 mL). The combined organic phases were evaporated to dryness followed by the addition of trimethyl methanetricarboxylate (53.6 g, 282 mmol) and diphenyl ether (280 mL). The mixture was stirred at 230 °C for 15 min., then cooled and chromato graphed (ethyl acetate in hexanes, 0-100 % gradient) to obtain the title compoundas a light brown solid (47.6 g, 64%).
LC-MS: 532.0, 534.0 [M+H]+, RT 1.59 min. Step 2: Methyl 2,4-bis(benzyloxy)-9-bromo-5,6-dihydrobenzo[2,3]thiepino[4,5-b]pyridine-3- carboxylate
A mixture of the product obtained in Step 1 (47.6 g, 89.5 mmol) was dissolved in CH2C12 (100 mL) and treated with TFA (100 mL) for 1 hr at room temperature. The volatiles were removed on a rotovap and the residue was triturated with water (approx. 1 L). The precipitate was collected by filtration, washed with water and dried. The material was then dissolved in THF (600 mL) at 0 °C, followed by the addition of benzyl alcohol (40.6 g, 38.9 mL, 376 mmol), Ph3P (90.3 g, 344.4 mmol) and DIAD (69.6 g, 68.2 mL, 344.4 mmol). After the addition, the cooling bath was removed and the mixture was stirred for 4 hrs at room temperature. Chromatography of the crude material (silica gel, ethyl acetate in hexanes, 0- 50% gradient) provided the title compound (30.8 g, 61%).
LC-MS: 562.3, 564.3 [M-H]+, RT 1.73 min. 1H NMR (CDC13) δ: 7.78 (d, J=1.9 Hz, 1H), 7.59 (dd, J=8.4, 2.0 Hz, 1H), 7.28-7.51 (m, 11H), 5.48 (s, 2H), 5.13 (s, 2H), 3.93 (s, 3H), 3.24 (t, J=6.6 Hz, 2H), 2.71 (t, J=6.5 Hz, 2H)
Step 3: Methyl 2,4-bis(benzyloxy)-9-((tert-butoxycarbonyl)amino)-5,6- dihydrobenzo[2,3]thiepino[4,5-b]pyridine-3-carboxylate
A mixture of the product obtained in Step 2 (30.8 g, 54.8 mmol), BocNH2 (12.8 g, 110 mmol), K2C03 (18.9 g, 137 mmol), Cul (1.05 g, 5.5 mmol), N, N'-dimethylcyclohexane-l,2- diamine (1.56 g, 1.73 mL, 11.0 mmol) and toluene (100 mL) was stirred at 110 °C under a nitrogen atmosphere for 24 hrs. This was then diluted with ethyl acetate (200 mL) and filtered. The precipitates were washed with ethyl acetate and the filtrates were combined and concentrated to dryness. The residue was chromato graphed (silica gel, ethyl acetate in hexanes, 0-70 % gradient) to provide the title intermediate (30.3 g, 92%).
LC-MS: 599.2 [M+H]+, RT 1.75 min. 1H NMR (CDC13) δ: 7.64 (d, J=1.9 Hz, 1H), 7.55 (d, J=1.0 Hz, 1H), 7.33-7.51 (m, 10H), 7.28-7.32 (m, J=7.3 Hz, 1H), 6.56 (s, 1H), 5.50 (s, 2H), 5.12 (s, 2H), 3.92 (s, 3H), 3.23 (t, J=6.6 Hz, 2H), 2.71 (t, J=6.6 Hz, 2H), 1.55 (s, 9H)
Step 4: Methyl 2,4-bis(benzyloxy)-9-((tert-butoxycarbonyl)(methyl)amino)-5,6- dihydrobenzo[2,3]thiepino[4,5-b]pyridine-3-carboxylate To a solution of the product obtained in Step 3 (1.20 g, 2.0 mmol) in DMF (5.0 mL) was added NaH (0.12 g, 3.0 mmol, 60% in mineral oil) at room temperature. The mixture was stirred for 30 min followed by the addition of Mel (0.43 g, 0.19 mL, 3.0 mmol). The reaction was stirred for an additional 2 h. Water (5 mL) was added and product was extracted with CH2C12 (2 x 25 mL), washed with water and dried over Na2S04. Chromatography
purification of the crude material (silica gel, ethyl acetate in hexanes, 0-20% gradient) furnished the title compound (1.13 g, 94%). LC-MS: 613.2 [M+H]+, RT 1.82 min. 1H NMR (CDC13) δ: 7.58 (d, J=8.5 Hz, 1H), 7.53 (d, J=2.2 Hz, 1H), 7.35-7.47 (m, 10H), 7.29-7.33 (m, J=7.3 Hz, 1H), 5.50 (s, 2H), 5.13 (s, 2H), 3.92 (s, 3H), 3.31 (s, 3H), 3.25 (t, J=6.5 Hz, 2H), 2.74 (t, J=6.3 Hz, 2H), 1.50 (s, 9H)
Step 5: Methyl 2,4-bis(benzyloxy)-9-(methylamino)-5,6-dihydrobenzo[2,3]thiepino[4,5- b]pyridine-3-carboxylate
The product obtained in Step 4 (1.13 g, 1.85 mmol) was heated in diphenyl ether (20 mL) at 200 °C for 2 h under a nitrogen atmosphere. After cooling, the mixture was loaded on a silica gel column and eluted with ethyl acetate in hexanes (0-70%) to provide the title compound (0.90 g, 95%).
1H NMR (CDC13) δ: 7.51 (d, J=8.5 Hz, 1H), 7.34-7.47 (m, 8H), 7.28-7.33 (m, J=7.6 Hz, 1H), 6.97 (br. s, 1H), 6.78-6.84 (m, 1H), 5.50 (s, 2H), 5.11 (s, 2H), 3.91 (s, 3H), 3.25 (t, J=6.6 Hz, 2H), 2.92 (s, 3H), 2.75 (t, J=6.6 Hz, 2H)
Step 6: Methyl 2,4-bis(benzyloxy)-10-iodo-9-(methylamino)-5,6- dihydrobenzo[2,3]thiepino[4,5-b]pyridine-3-carboxylate A mixture of the product obtained in Step 5 (0.90g, 1.76 mmol), NIS (0.59 g, 2.64 mmol) and DMF (5.0 mL) was stirred at room temperature for 3 hrs. The mixture was diluted with water (30 mL) and the precipitate was collected by filtration, washed with water and dried. Column chromatography purification (silica gel, ethyl acetate in hexanes, 0-50% gradient) provided the title iodide intermediate (0.85 g, LC-MS: 639.5 [M-H]+, RT 1.66 min.), which contained approx. 33% of undesired isomer based on LC/MS (LC-MS: 639.5 [M+H]+, RT 1.64 min). This mixture was used directly in the next step.
Step 7: Methyl 2,4-bis(benzyloxy)- 10-(3-hydroxyprop- 1-yn- l-yl)-9-(methylamino)-5,6- dihydrobenzo[2,3]thiepino[4,5-b]pyridine-3-carboxylate
A mixture of the isomeric iodide intermediates obtained in Step 6 (0.85 g, 1.33 mmol), Cul (0.013 g, 0.07 mmol), Pd(Ph3P)2Cl2 (0.095 g, 0.07 mmol), triethylamine (0.27 g, 2.66 mmol), prop-2-yn-l-ol (0.15 g, 0.155 mL, 2.66 mmol) and acetonitrile (5.0 mL) was stirred at room temperature for 5 hrs under an argon atmosphere. The volatiles were removed on a rotovap and the residue was treated with water (5 mL) and ethyl acetate (10 mL). The organic phase was separated and the aqueous layer was extracted with ethyl acetate (2 x 5 mL). The combined organic phases were washed with water (5 mL), brine (5 mL) and dried over anhydrous Na2S04. The solvent was removed on a rotovap and the residue was chromatographed (silica gel, ethyl acetate in CH2CI2, 0-60% gradient) to furnish the title intermediate (0.38 g).
LC-MS: 567.5 [M+H]+, RT 1.49 min.
Step 8: Methyl 2,4-bis(benzyloxy)- 10-(hydroxymethyl)-9-methyl-5,9-dihydro-6H- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylate
The intermediate obtained in Step 7 (380 mg, 0.67 mmol) was dissolved in DMF (2.0 mL) and stirred at 100 °C overnight in the presence of Cul (154 mg, 0.81 mmol). After cooling, the mixture was diluted with saturated NH4CI (5.0 mL). The precipitate was collected by filtration, washed with water, dried, and chromatographed (silica gel, ethyl acetate in CH2CI2, 0-50% gradient) to furnish the title compound as an oil (330 mg, 87% over two steps).
LC-MS: 567.6 [M+H]+, RT 1.48 min. 1H NMR (CDC13) δ: 7.83 (d, J=0.6 Hz, 1H), 7.62 (s, 1H), 7.29-7.50 (m, 10H), 6.54 (s, 1H), 5.55 (s, 2H), 5.13 (s, 2H), 4.85 (s, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.21 (br. s, 2H), 2.73 (br. s, 2H)
Intermediate 11
l-Tosyl-5,6,7,8-tetrah drocyclohepta[f]indol-9(lH)-one
Figure imgf000129_0001
Step 1: 3-Nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one
To a stirred solution of HN03 (1.5 mL, 90%) and H2S04 (10 mL) at 0° C was added a solution of 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (4.02 g, 25.1 mmol) in 1¾804 (80 mL) dropwise over 30 min. The mixture was then poured onto ice and partitioned between H20 and CH2CI2. The organic layer was dried over MgS04, filtered, and concentrated under vacuum. Purification by silica gel chromatography (20% EtOAc in hexanes) yielded 3-nitro- 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (2.67 g, 52%) as a white solid, along with the less polar by-product l-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (478 mg, 9%). 1H NMR (acetone- 6): δ 1.85 (m, 2H), 1.99 (m, 2H), 2.75 (m, 2H), 3.00 (m, 2H), 7.61 (t, J = 8 Hz, 1H), 7.82 (dd, J = 8 Hz, 1.5 Hz, 1H), 8.02 (dd, J = 8 Hz, 1.5 Hz, 1H)
Step 2: 3-Nitro-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,2'-[l,3]dioxolane]
3-Nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.0 g, 4.9 mmol), toluene (10 mL), ethylene glycol (7.2 mmol) and p-TsOH monohydrate (100 mg, 0.52 mmol) were heated overnight under reflux with a Dean-Stark apparatus. The reaction mixture was partitioned between H20 and CH2C12. The organic layer was dried over MgS04, filtered, and
concentrated under vacuum. Purification by silica gel chromatography (10% EtOAc in hexanes) yielded 3-nitro-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,2'-[l,3]dioxolane] (948 mg, 77%) as a white solid.
1H NMR (acetone- d6): δ 1.68 (m, 2H), 1.97 (m, 4H), 3.12 (m, 2H), 3.94 (m, 2H), 4.11 (m, 2H), 7.44 (d, J = 8.5 Hz, 1H), 8.08 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 8.37 (d, J = 2.5 Hz, 1H)
Step 3: 6,7,8,9-Tetrahydrospiro[benzo[7]annulene-5,2'-[l,3]dioxolan]-3-amine
A mixture of 3-nitro-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,2'-[l,3]dioxolane] (935 mg, 3.75 mmol), Pd/C (10%, 53 mg), and EtOAc (6 mL) was hydrogenated at 1 atm of H2 for 15 hrs at ambient temperature. The reaction mixture was diluted in CH2C12 and was filtered through Celite. The filtrate was concentrated under vacuum. Purification by silica gel chromatography (5-20% EtOAc in CH2C12) yielded 6,7,8,9- tetrahydrospiro[benzo[7]annulene-5,2'-[l,3]dioxolan]-3-amine (807 mg, 98%) as a pink solid. 1H NMR (acetone- d6): δ 1.56 (m, 2H), 1.88 (m, 4H), 2.79 (m, 2H), 3.81 (m, 2H), 3.99 (m, 2H), 4.41 (br. s, 2H), 6.45 (dd, J = 8 Hz, 2.5 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.90 (d, J = 2.5 Hz, 1H)
Step 4: 2-Iodo-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,2'-[l,3]dioxolan]-3-amine
6,7,8,9-Tetrahydrospiro[benzo[7]annulene-5,2'-[l,3]dioxolan]-3-amine (570 mg, 2.6 mmol) was dissolved in CH3CN (400 mL). NIS (620 mg, 2.76 mmol) was added in portions over a 3 hrs period. The reaction mixture was quenched with aqueous NaHS03. The mixture was then partitioned between EtOAc and H20. The organic layer was dried over MgS04, filtered, and concentrated under vacuum. Purification by silica gel chromatography (0-5% EtOAc in CH2C12), followed by hexane trituration, yielded 2-iodo-6,7,8,9- tetrahydrospiro[benzo[7]annulene-5,2'-[l,3]dioxolan]-3-amine (428 mg, 48%) as an orange solid.
1H NMR (acetone- d6): δ 1.57 (m, 2H), 1.90 (m, 4H), 2.78 (m, 2H), 3.82 (m, 2H), 4.00 (m, 2H), 4.75 (br. s, 2H), 7.05 (s, 1H), 7.33 (s, 1H)
Step 5: 2-((Trimethylsilyl)ethynyl)-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,2'- [l,3]dioxolan]-3-amine A mixture of 2-iodo-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,2'-[l,3]dioxolan]-3-amine (395 mg, 1.14 mmol), Pd(PPh3)2Cl2 (40 mg, 0.057 mmol), Cul (20 mg, 0.1 mmol), Et3N (530 μί, 3.8 mmol), DMF (2.7 mL), and trimethylsilylacetylene (270 μί, 1.89 mmol) was stirred for 1 hr at room temperature under an argon atmosphere. The mixture was then partitioned between EtOAc and H20. The organic layer was dried over MgS04, filtered, and
concentrated under vacuum. Purification by silica gel chromatography (0-3% EtOAc in CH2C12), followed by hexane trituration, yielded gray solids. The solids were dissolved in ether and filtered to remove some gray insoluble impurities. 2-((Trimethylsilyl)ethynyl)- 6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,2'-[l,3]dioxolan]-3-amine (319 mg, 88%) was obtained as a gray solid.
1H NMR (acetone- d6): δ 0.24 (s, 9H), 1.57 (m, 2H), 1.88 (m, 4H), 2.78 (m, 2H), 3.80 (m, 2H), 3.99 (m, 2H), 4.89 (br. s, 2H), 6.93 (s, 1H), 6.99 (s, 1H)
Step 6: 5,6,7, 8-Tetrahydro-lH-spiro[cyclohepta[f]indole-9,2'-[l,3]dioxolane]
A mixture of 2-((trimethylsilyl)ethynyl)-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,2'- [l,3]dioxolan]-3-amine (280 mg, 0.89 mmol), Cul (350 mg, 1.84 mmol), and DMF (3.6 mL) was heated under argon at 100° C for 1 hr. The reaction mixture was diluted in EtOAc and was filtered through Celite. The filtrate was washed with H20. The organic layer was separated, dried over MgS04, filtered, and concentrated under vacuum. MeOH (25 mL) and Cs2C03 (320 mg, 1 mmol) were added to the crude intermediate and the mixture was stirred at room temperature for 15 min. The mixture was then partitioned between EtOAc and H20. The organic layer was dried over MgS04, filtered, and concentrated under vacuum.
Purification by silica gel chromatography (0-5% EtOAc in CH2C12) yielded 5,6,7,8- tetrahydro-lH-spiro[cyclohepta[f]indole-9,2'-[l,3]dioxolane] (138 mg, 64%) as an off-white solid.
1H NMR (acetone- d6): δ 1.65 (m, 2H), 1.96 (m, 4H), 3.04 (m, 2H), 3.84 (m, 2H), 4.02 (m, 2H), 6.37 (m, 1H), 7.29 (m, 2H), 7.64 (s, 1H)
Step 7: l-Tosyl-5,6,7,8-tetrahydrocyclohepta[f]indol-9(lH)-one
5,6,7,8-tetrahydro-lH-spiro[cyclohepta[f]indole-9,2'-[l,3]dioxolane] (136 mg, 0.56 mmol), CH2C12 (3 mL), tetrabutylammonium bisulfate (19 mg, 0.056 mmol), tosyl chloride (115 mg, 0.60 mmol), and NaOH (50% w/w solution, 300 μί) were stirred at room temperature for 30 minutes. The mixture was then partitioned between CH2C12 and H20. The organic layer was dried over MgS04, filtered, and concentrated under vacuum. Purification by silica gel chromatography (0-30% CH2CI2 in hexanes) yielded crude tosylate ketal which was treated with HCl (6N, 250 μί) and dioxane (600 μί) at room temperature for 1 hr. The mixture was then partitioned between EtOAc and ¾0. The organic layer was dried over MgS04, filtered, and concentrated under vacuum. Purification by silica gel chromatography (20% EtOAc in hexanes), followed by trituration with 2: 1 hexanes/ether, yielded l-tosyl-5, 6,7,8- tetrahydrocyclohepta[f]indol-9(lH)-one (123 mg, 87% overall) as a white solid.
1H NMR (acetone- d6): δ 1.76 (m, 2H), 1.86 (m, 2H), 2.37 (s, 3H), 2.75 (m, 2H), 3.04 (t, J = 6.5 Hz, 2H), 6.82 (dd, J = 3.5 Hz, 1 Hz, 1H), 7.41 (m, 2H), 7.48 (s, 1H), 7.84 (d, J = 3.5 Hz, 1H), 7.88 (m, 2H), 8.33 (s, 1H) Intermediate 12
Ethyl methyl(l-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)carbamate
Figure imgf000132_0001
Step 1 : Ethyl (3-bromo-2-methylphenyl)carbamate
To a solution of 3-bromo-2-methylaniline (1.86 g, 10 mmol) and ethyl chloroformate (1.05 mL, 11 mmol) in CH2CI2 (30 mL) at room temperature was added pyridine (3.2 mL, 40 mmol). After stirring at room temperature for 40 min, the mixture was washed with 1 N HCl, satd. NaHC03j water and brine, and dried over Na2S04. Removal of the solvents yielded the title compound, which was used in the next step without purification.
LC-MS: 258.2 [M+H]+, RT 1.43 min. Step 2: (E)-5-(3-((Ethoxycarbonyl)amino)-2-methylphenyl)pent-4-enoic acid
A mixture of the crude ethyl (3-bromo-2-methylphenyl)carbamate obtained in Step 1, pent-4- enoic acid (0.86 mL, 8.6 mmol), Pd(OAc)2 (193 mg, 0.86 mmol), P(o-Tol)3 (522 mg, 1.72 mmol) and triethylamine (2.4 mL, 17.2) in CH CN (20 mL) was degassed and heated at 90 °C for 7 hrs under N2 atmosphere. The mixture was concentrated, diluted with water, adjusted to pH 4-5 and extracted with EtOAc. The organics were washed with brine, dried over
Na2S04, filtered and concentrated to give the title compound, which was used in the next step without purification.
LC-MS: 278.3 [M+H]+, RT 1.13 min.
Step 3: 5-(3-((Ethoxycarbonyl)amino)-2-methylphenyl)pentanoic acid A mixture of (E)-5-(3-((ethoxycarbonyl)amino)-2-methylphenyl)pent-4-enoic acid from Step
2 and 10% Pd/C (900 mg) in MeOH (50 mL) was vigorously stirred under 1 atm of H2 for 15 hrs. The mixture was filtered through Celite and concentrated to give the title compound. The crude material was used in the next step without purification.
LC-MS: 280.1 [M+H]+, RT 1.11 min.
Step 4: Ethyl (l-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)carbamate
A mixture of 5-(3-((ethoxycarbonyl)amino)-2-methylphenyl)pentanoic acid obtained in Step
3 in P205-MsOH (Eaton' s reagent, 4 mL) was heated at 40 °C. After 1 hr, the mixture was treated with ice, neutralized with 6 N NaOH and extracted with EtOAc. The organics were washed with water and brine, dried over Na2S04, filtered and concentrated. The residue was chromato graphed on silica gel with EtOAc in hexanes (0-30%) to give the title compound (0.43 g, 38% over 4 steps).
LC-MS: 262.4 [M+H]+, RT 1.18 min. 1H NMR (500 MHz, CDC13) 5 ppm 1.32 (t, J=7.1 Hz, 3H), 1.71 - 1.77 (m, 2H), 1.78 - 1.85 (m, 2H), 2.24 (s, 3H), 2.61 - 2.70 (m, 2H), 2.86 - 2.93 (m, 2H), 4.24 (q, J=7.1 Hz, 2H), 6.51 (br. s., 1H), 7.49 (d, J=8.3 Hz, 1H), 7.76 (d, J=8.0 Hz,
1H)
Step 5: Ethyl methyl(l-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)carbamate
To a solution of ethyl (l-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2- yl)carbamate (261 mg, 1 mmol) and Mel (0.46 mL, 5 mmol) in DMF (3 mL) was added NaH (60 mg, 1.5 mmol, 60% in mineral oil) at 0 °C. After stirring for 10 min the mixture was allowed to warm to room temperature. After 1 hr, the mixture was cooled to 0 °C and treated with ice water and extracted with EtOAc. The organics were washed with water and brine, dried over Na2S04, filtered and concentrated. The residue was chromatographed on silica gel with EtOAc in hexanes (0-30%) to give the title compound (169 mg, 61%).
LC-MS: 276.3 [M+H]+, RT 1.26 min.
Intermediate 13
2-(Dimethylamino)- l-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one
Figure imgf000133_0001
Step 1 : 2- Amino- l-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one A mixture of ethyl (l-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)carbamate (Intermediate 12, Step 4, 158 mg, 0.6 mmol) and NaOH (120 mg, 3 mmol) in MeOH (1 mL), THF (3 mL) and H20 (3 mL) was heated at 70 °C for 20 hrs, then at 120 °C for 1.5 hrs. The mixture was cooled to room temperature, neutralized with 1 N HC1 and extracted with EtOAc. The organics were washed with water and brine, dried over Na2S04, filtered, and concentrated to give the title compound.
LC-MS: 190.2 [M+H]+, RT 1.01 min.
Step 2: 2-(Dimethylamino)-l-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one
To a mixture of 2-amino-l-methyl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (113 mg, 0.6 mmol), formaldehyde (0.58 mL, 7.2 mmol, 37% solution in water) and AcOH (0.14 mL,
2.4 mmol) in DCE (3 mL) was added NaBH(OAc)3 (509 mg, 2.4 mmol). After stirring at room temperature for 15 hrs, the mixture was treated with satd. NaHC03 and extracted with
EtOAc. The organic layers were washed with water and brine, dried over Na2S04, filtered and concentrated to give the title compound.
LC-MS: 218.5 [M+H]+, RT 1.12 min. 1H NMR (500 MHz, CDC13) 5 ppm 1.70 - 1.79 (m,
2H), 1.79 - 1.88 (m, 2H), 2.32 (br. s, 3H), 2.60 - 2.68 (m, 2H), 2.73 (br. s, 6H), 2.86 - 2.95
(m, 2H), 6.89 - 7.00 (m, 1H), 7.48 (d, J=8.5 Hz, 1H)
Intermediate 14
Benzyl 2,4-bis(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloronicotinate
Figure imgf000134_0001
Step 1: 4-Benzyloxy-2,6-dichloropyridine
Benzyl alcohol (13.8 mL, 133 mmol) was added dropwise to a suspension of NaH (60% mineral oil suspension, 6.0 g, 150 mmol) in THF (250 mL), resulting in a slight exotherm. The mixture was stirred at room temperature for 30 minutes before being cooled to 0° C. A solution of 2,6-dichloro-4-nitropyridine (25 g, 129 mmol) in THF (125 mL) was added dropwise over 45 minutes. The reaction mixture was stirred at 0° C for an additional 30 minutes after the addition was complete. The reaction mixture was quenched with H20, and the mixture was partitioned between H20 and EtOAc. The EtOAc layer was washed with H20, and then brine. The organic layer was dried over MgS04 and filtered. The filtrate was concentrated under vacuum. This was purified by dissolving the material in CH2Cl2/hexanes (1: 1) and filtering through a short plug of silica. Hexane trituration yielded 4-benzyloxy-2,6- dichlorpyridine (24.86 g, 75%) as an off-white solid.
1H NMR (acetone- d6): δ 5.35 (s, 2H), 7.16 (s, 2H), 7.39-7.49 (m, 3H), 7.53 (m, 2H)
Step 2: (4-(Benzyloxy)-2,6-dichloropyridin-3-yl)methanol
4-Benzyloxy-2,6-dichloropyridine (24.65 g, 97 mmol) was dissolved in THF (350 mL) at -78° C. A solution of n-BuLi (65.2 mL, 1.6 N, 104.3 mmol) was added dropwise. After completion of addition, DMF (11.8 mL, 152.8 mmol) was added in one portion. The reaction was stirred at -78° C for 10 minutes. The reaction mixture was quenched at this temperature with saturated NH4C1. The reaction mixture was then partitioned between EtOAc and H20. The organic layer was dried over MgS04, filtered, and concentrated under vacuum. This was filtered through a short plug of silica gel eluting with CH2C12. Crude 4-(benzyloxy)-2,6- dichloronicotinaldehyde (19.65 g) was obtained as a 5:3 molar ratio of product : starting material (based on NMR).
Crude product from the previous step was dissolved in CH2C12 (215 mL) at -78° C. DIBAL-H (50.5 mL, 1M in CH2C12, 50.5 mmol) was added dropwise. This was stirred at -78° C for 30 minutes. The reaction mixture was quenched with sodium potassium tartrate solution (25 g in 80 mL of H20). The bilayer was filtered through Celite. The filtrate was then separated. The organic layer was dried over MgS04, filtered, and concentrated under vacuum. Purification by silica gel chromatography (EtOAc in CH2C12, 0-10%), followed by ether trituration, yielded (4-(benzyloxy)-2,6-dichloropyridin-3-yl)methanol (9.91 g, 36% over 2 steps) as a white solid.
1H NMR (acetone- d6): δ 4.17 (t, J = 6 Hz, 1H), 4.77 (d, J = 6 Hz, 2H), 5.39 (s, 2H), 7.26 (s, 1H), 7.41 (m, 1H), 7.46 (m, 2H), 7.56 (m, 2H)
Step 3: 4-(Benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyridine
(4-(Benzyloxy)-2,6-dichloropyridin-3-yl)methanol (9.8 g, 34.5 mmol), TBDMSC1 (5.45 g, 36.2 mmol), imidazole (2.6 g, 38.2 mmol) and CH2C12 (140 mL) were stirred at room temperature for 2 hrs. The reaction mixture was filtered and the filtrate was concentrated under vacuum. Purification by silica gel chromatography (CH2C12 in hexanes, 50-100%) yielded 4-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyridine (13.66 g, 99%) as a white solid. 1H NMR (acetone- 6): δ 0.073 (s, 6H), 0.89 (s, 9H), 4.85 (s, 2H), 5.40 (s, 2H), 7.28 (s, 1H), 7.4-7.5 (m, 3H), 7.56 (m, 2H)
Step 4: 4,6-Bis(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyridine
4-(Benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dichloropyridine (13.1 g, 32.9 mmol), benzyl alcohol (6.8 mL, 65.4 mmol), and THF (130 mL) were stirred at 0° C.
NaHMDS (33 mL, 2M in THF, 66 mmol) was added dropwise. This was stirred at room temperature for 15 hrs. The reaction mixture was then partitioned between H20 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under vacuum.
Purification by silica gel chromatography (1: 1 CH2Cl2/hexanes) followed by trituration with ice-cold hexanes, yielded 4,6-bis(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2- chloropyridine (11.05 g, 71%) as a white solid.
1H NMR (acetone- 6): δ 0.076 (s, 6H), 0.90 (s, 9H), 4.82 (s, 2H), 5.30 (s, 2H), 5.35 (s, 2H), 6.52 (s, 1H), 7.32-7.48 (m, 6H), 7.51 (m, 2H), 7.56 (m, 2H)
Step 5: 2,4-Bis(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloronicotinic acid 4,6-Bis(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloropyridine (11.35 g, 24.1 mmol) was dissolved in THF (85 mL) at -78° C. A solution of n-BuLi (16.5 mL, 1.6 N, 26.4 mmol) was added via syringe pump over 15 minutes. The reaction was stirred at -78° C for 30 minutes after addition was complete. Dry C02 was bubbled through this mixture for 30 min. The C02 bubbling was ceased, and the cooling bath was removed. The reaction mixture was slowly warmed to room temperature, with an outlet tube of sufficient diameter to vent the C02 released from the warming reaction solution. The reaction mixture was then partitioned between aqueous HC1 and EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under vacuum. The crude solids were washed with hexanes/ether to obtain 2,4- bis(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloronicotinic acid (9.45 g, 75%) as a white solid.
1H NMR (acetone- d6): δ 0.12 (s, 6H), 0.90 (s, 9H), 4.80 (s, 2H), 5.30 (s, 2H), 5.47 (s, 2H), 7.3-7.45 (m, 6H), 7.52 (m, 4H)
Step 6: Benzyl 2,4-bis(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6- chloronicotinate 2,4-Bis(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloronicotinic acid (9.45 g, 18.4 mmol), K2C03 (5.3 g, 38.4 mmol), benzyl bromide (2.55 mL, 21.3 mmol), and DMF (35 mL) were stirred at room temperature for 15 hrs. The reaction mixture was then partitioned between H20 and EtOAc. The organic layer was dried over MgS04, filtered, and
concentrated under vacuum. Hexane trituration yielded the title product (10.38 g, 93%) as a white solid.
1H NMR (acetone- d6): δ 0.11 (s, 6H), 0.89 (s, 9H), 4.78 (s, 2H), 5.19 (s, 2H), 5.37 (s, 2H), 5.45 (s, 2H), 7.3-7.5 (m, 15H)
Intermediate 15
Benzyl 2,4-bis(benzyloxy)-6-bromo-5-hydroxynicotinate
Figure imgf000137_0001
Step 1 : Benzyl 2,4-dichloronicotinate
A mixture of 2,4-dichloronicotinic acid (5.0 g, 26 mmol), benzyl bromide (3.7 mL, 31 mmol) and K2C03 (7.2 g, 52 mmol) in DMF (50 mL) was stirred at room temperature overnight. Water was then added and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with water, brine, dried over sodium sulfate, evaporated and purified by silica chromatography (0-7% ethyl acetate in hexanes) to give benzyl 2,4-dichloronicotinate (7.0 g, 96%).
LC-MS: 282.0, 284.0 [M+H]+, RT 1.32 min. 1H NMR (500 MHz, CDC13) δ ppm 5.44 (s, 2H), 7.33 (d, J=5.4 Hz, 1H), 7.36 - 7.43 (m, 3H), 7.44 - 7.49 (m, 2H), 8.34 (d, J=5.4 Hz, 1H)
Step 2: Benzyl 2,4-dichloro-5-iodonicotinate Into a solution of benzyl 2,4-dichloronicotinate (4.35 g, 15.4 mmol) in THF (40 mL) at -78 °C was added LDA (1.5 M x 11.8 mL, 17.7 mmol) dropwise. The mixture was stirred at -78 °C for 30 min. Iodine (4.7 g, 18.5 mmol) was added portionwise. The temperature was then allowed to rise to room temperature slowly and the reaction was quenched with saturated NH4C1 solution. The mixture was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, evaporated and purified by silica chromatography (0-7% ethyl acetate in hexanes) to give benzyl 2,4-dichloro-5-iodonicotinate (3.8 g, 60%).
LC-MS: 408.0, 410.0 [M+H]+, RT 1.47 min. 1H NMR (500 MHz, CDC13) δ ppm 5.44 (s, 2H), 7.34 - 7.50 (m, 5H), 8.75 (s, 1H) Step 3: Benzyl 2,4-bis(benzyloxy)-5-iodonicotinate
Into a solution of benzyl 2,4-dichloro-5-iodonicotinate (3.7 g, 9.1 mmol) in THF (20 mL) was added a solution of sodium benzyloxide in THF (1.0 M x 20 mL, 20 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH4C1 and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, evaporated and purified by silica chromatography (0-7% ethyl acetate in hexanes) to give benzyl 2,4-bis(benzyloxy)-5-iodonicotinate (2.55 g, 51%).
LC-MS: 552.1 [M+H]+, RT 1.80 min. 1H NMR (500 MHz, CDC13) δ ppm 5.08 (s, 2H), 5.31 (s, 2H), 5.41 (s, 2H), 7.23 - 7.43 (m, 15H), 8.44 (s, 1H) Step 4: Benzyl 2,4-bis(benzyloxy)-5-hydroxynicotinate
Into a solution of benzyl 2,4-bis(benzyloxy)-5-iodonicotinate (1.0 g, 1.8 mmol) in THF (8.0 mL) at -45 °C was added a solution of i-PrMgCl-LiCl (1.3 M x 2.8 mL, 3.6 mmol) dropwise. The mixture was stirred at -45 °C for 30 min, then triisopropyl borate (0.87 mL, 3.78 mmol) was added dropwise. After stirring at -45 °C for 15 min, the temperature was allowed to rise to room temperature slowly. The mixture was stirred at room temperature for 1.5 hrs then cooled to -20 °C and peracetic acid (32%, 0.79 mL, 3.78 mmol) was added. The mixture was stirred at room temperature for another 30 min, then treated with water (50 mL) and extracted with ethyl acetate. The organic layers were combined then washed with brine, dried over sodium sulfate, evaporated, and purified by silica gel chromatography (0-30% ethyl acetate in hexanes) to give benzyl 2,4-bis(benzyloxy)-5-hydroxynicotinate (0.29 g, 36%).
1H NMR (500 MHz, CDC13) δ ppm 5.03 (s, 2H), 5.35 (s, 2H), 5.37 (s, 2H), 7.27 - 7.40 (m, 15H), 7.85 (s, 1H)
Step 5: Benzyl 2,4-bis(benzyloxy)-6-bromo-5-hydroxynicotinate
A mixture of benzyl 2,4-bis(benzyloxy)-5-hydroxynicotinate (0.29 g, 0.66 mmol) and NBS (0.13 g, 0.72 mmol) in DMF (1.2 mL) was stirred at room temperature for 5 min and then treated with water. The mixture was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, evaporated and purified by silica chromatography (0-30% ethyl acetate in hexanes) to give benzyl 2,4-bis(benzyloxy)-6- bromo-5-hydroxynicotinate (0.23 g, 68%).
1H NMR (500 MHz, CDC13) δ ppm 5.15 (s, 2H), 5.30 (s, 2H), 5.34 (s, 2H), 7.24 - 7.40 (m, 15H) Intermediate 16
Benzyl 9-amino-2,4-bis (benzyloxy)-5 ,7 -dihydrobenzo [5 ,6] oxepino [4,3-b]pyridine-3- carboxylate
Figure imgf000139_0001
Step 1: ((2-Bromo-5-nitrobenzyl)oxy)(tert-butyl)dimethylsilane
2-Bromo-5-nitrobenzoic acid (6.0 g, 24.4 mmol), THF (36 mL), and BH3-THF (1M solution, 72 mL, 72 mmol) were stirred at room temperature for 15 hrs. The reaction mixture was carefully quenched with H20. The reaction mixture was partitioned between aqueous HC1 and EtOAc. The organic layer was dried over MgS04j filtered, and concentrated under vacuum. Crude (2-bromo-5-nitrophenyl)methanol (6.3 g) was dissolved in CH2C12 (100 mL), and TBSC1 (4.68 g, 31.1 mmol) and imidazole (2.48 g, 36.5 mmol) were added. The mixture was stirred at room temperature for 1 hr and then filtered. The filtrate was concentrated under vacuum. Purification by silica gel chromatography (20-50% CH2C12 in hexanes) yielded ((2- bromo-5-nitrobenzyl)oxy)(tert-butyl)dimethylsilane (6.55 g, 77% yield over 2 steps) as a yellow oil.
1H NMR (acetone- 6): δ 0.23 (s, 6H), 1.03 (s, 9H), 4.88 (s, 2H), 7.91 (d, J = 9 Hz, 1H), 8.11 (dd, J = 8.5 Hz, 3 Hz, 1H), 8.44 (m, 1H)
Step 2: tert-Butyldimethyl((5-nitro-2-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)benzyl) oxy) silane ((2-Bromo-5-nitrobenzyl)oxy)(tert-butyl)dimethylsilane (6.55 g, 18.9 mmol),
bis(pinacolato)diboron (5.5 g, 21.6 mmol), KOAc (3.9 g, 39.8 mmol), Pd(dppf)Cl2 (300 mg, 0.41 mmol), and dioxane (40 mL) were heated at 100° C for 2 hrs. The reaction mixture was diluted in EtOAc and was filtered through Celite. The filtrate was concentrated under vacuum. Purification by silica gel chromatography (CH2C12) yielded tert-butyldimethyl((5- nitro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)oxy)silane (5.92 g, 80%) as a light tan solid.
1H NMR (acetone- 6): δ 0.18 (s, 6H), 1.01 (s, 9H), 1.41 (s, 12H), 5.14 (s, 2H), 7.98 (d, J = 8.5 Hz, 1H), 8.12 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 8.46 (m, 1H) Step 3: Benzyl 2,4-bis(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-(2-(((tert- butyldimethylsilyl)oxy)methyl)-4-nitrophenyl)nicotinate
A mixture of tert-butyldimethyl((5-nitro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)oxy)silane (3.55 g, 5.88 mmol), benzyl 2,4-bis(benzyloxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)-6-chloronicotinate (Intermediate 14, 3.46 g, 8.82 mmol), Pd2dba3 (710 mg, 0.77 mmol), P(t-Bu)3HBF4 (488 mg, 1.68 mmol), Cs2C03 (5.0 g, 15.3 mmol), dioxane (23 mL), and H20 (23 mL) were heated at 90° C under argon for 2 hrs. The reaction mixture was then partitioned between H20 and EtOAc. The organic layer was dried over MgS04> filtered, and concentrated under vacuum. Purification by silica gel
chromatography (50% CH2C12 in hexanes) yielded benzyl 2,4-bis(benzyloxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)-6-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4- nitrophenyl)nicotinate (5.0 g, 100%) as a light tan oil.
1H NMR (acetone- 6): δ -0.20 (s, 6H), 0.057 (s, 6H), 0.77 (s, 9H), 0.95 (s, 9H), 4.45 (br. s, 2H), 4.75 (br. s, 2H), 5.24 (s, 2H), 5.43 (m, 4H), 7.3-7.47 (m, 15H), 7.67 (d, J = 8.5 Hz, 1H), 8.26 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 8.58 (m, 1H)
Step 4: Benzyl 2,4-bis(benzyloxy)-9-nitro-5,7-dihydrobenzo[5,6]oxepino[4,3-b]pyridine-3- carboxylate
Benzyl 2,4-bis(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-(2-(((tert- butyldimethylsilyl)oxy)methyl)-4-nitrophenyl)nicotinate (4.96 g, 5.95 mmol), THF (100 mL), and TBAF (1M in THF, 25 mL, 25 mmol) were stirred at room temperature for 90 minutes. The reaction mixture was partitioned between aqueous NH4C1 and EtOAc. The organic layer was dried over MgS04> filtered, and concentrated under vacuum. Purification by silica gel chromatography (10% EtOAc in CH2C12) yielded crude benzyl 2,4-bis(benzyloxy)-5- (hydroxymethyl)-6-(2-(hydroxymethyl)-4-nitrophenyl)nicotinate (4.23 g) as a thick oil.
The oil was dissolved in CH2C12 (285 mL) and the solution was cooled to -78° C. To the mixture was added Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor, 2.8 mL, 15.2 mmol) in CH2C12 (15 mL) dropwise. The mixture was stirred at -78° C for 1 hr, then allowed to warm to 0° C over 45 min. The reaction was quenched with aqueous NaHC03. The organic layer was separated, dried over MgS04> filtered, and concentrated under vacuum. Purification by silica gel chromatography (0-30% CH2C12 in hexanes) yielded benzyl 2,4- bis(benzyloxy)-9-nitro-5,7-dihydrobenzo[5,6]oxepino[4,3-b]pyridine-3-carboxylate (2.44 g, 70%) as an orange semisolid. 1H NMR (acetone- 6): δ 4.41 (s, 2H), 4.62 (s, 2H), 5.24 (s, 2H), 5.42 (s, 2H), 5.62 (s, 2H), 7.3-7.5 (m, 15H), 8.25 (d, J = 8.5 Hz, 1H), 8.43 (m, 2H)
Step 5: Benzyl 9-amino-2,4-bis(benzyloxy)-5,7-dihydrobenzo[5,6]oxepino[4,3-b]pyridine-3- carboxylate Benzyl 2,4-bis(benzyloxy)-9-nitro-5,7-dihydrobenzo[5,6]oxepino[4,3-b]pyridine-3- carboxylate (2.44 g, 4.15 mmol), HOAc (60 mL), and Fe powder (3.3 g, 59.1 mmol) was vigorously stirred and heated at 50° C for 90 minutes. The reaction mixture was filtered through Celite and the filtrate was concentrated under vacuum. The crude product was partitioned between aqueous NaHC03 and CH2CI2. The biphasic mixture was filtered through Celite. The organic layer of the filtrate was separated, dried over MgS04> filtered, and concentrated under vacuum. Purification by silica gel chromatography (5% EtOAc in
CH2CI2) yielded benzyl 9-amino-2,4-bis(benzyloxy)-5,7-dihydrobenzo[5,6]oxepino[4,3- b]pyridine-3-carboxylate (1.877 g, 81%) as a semisolid.
1H NMR (acetone- 6): δ 4.33 (s, 2H), 4.34 (s, 2H), 5.20 (s, 2H), 5.22 (br. s, 2H), 5.37 (s, 2H), 5.57 (s, 2H), 6.78 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 7.3-7.55 (m, 15H), 7.75 (d, J = 8.5 Hz, 1H)
Intermediate 17
Benzyl 5-allyl-2,4-bis(benzyloxy)-6-chloronicotinate
Figure imgf000141_0001
Step 1: 5-Allyl-6-chloro-4-hydroxypyridin-2(lH)-one
A mixture of malonyl chloride (7.8 mL, 80 mmol) and 4-pentenenitrile (10.0 mL, 100 mmol) was stirred in a sealed high pressure vessel at room temperature for 3 d. The vessel was carefully vented to release excess HC1. The mixture was diluted with Et20 (100 mL) and filtered. The solid was washed with CH CN and dried giving 7.8 g of a tan powder, a 1.8: 1 mixture of desired product (27%) and 2-(but-3-en-l-yl)-6-chloropyrimidin-4-ol side product (15%).
LC-MS: 186.2 [M+H]+, RT 0.94 min. Step 2: 3-Allyl-4,6-bis(benzyloxy)-2-chloropyridine
The mixture obtained in Step 1 was added as a solid to a prestirred mixture of diisopropyl azodicarboxylate (17.1 mL, 86.8 mmol) and triphenylphosphine (22.0 g, 84 mmol) in THF (200 mL) at 0 °C. The mixture stirred vigorously for 5 min before the addition of benzyl alcohol (8.7 mL, 84 mmol). The mixture was stirred at room temperature for 1 hr. Volatiles were removed by rotary evaporation. The residue was suspended in Et20 (300 mL). Once a solid precipitate formed, hexanes was added (200 mL). The mixture was filtered. The solid was washed with hexanes. The combined filtrate was concentrated and chromato graphed on silica gel, eluting with 0-30% CH2C12 in hexanes to afford the product as a colorless oil (5.4 g, 53%).
1H NMR (500 MHz, acetone- 6) δ ppm 3.46 (m, 2H), 5.00 (m, 1H), 5.03 (m, 1H), 5.28 (s, 2H), 5.33 (s, 2H), 5.91 (m, 1H), 6.53 (s, 1H), 7.33-7.46 (6H), 7.48-7.53 (4H)
Step 3: Benzyl 5-allyl-2,4-bis(benzyloxy)-6-chloronicotinate
To a mixture of 3-allyl-4,6-bis(benzyloxy)-2-chloropyridine (5.0 g, 13.7 mmol) and THF (100 mL) at -78 °C was added a solution of w-BuLi in cyclohexane (14.3 mL, 28.7 mmol). After stirring the solution for 20 min at -78 °C, C02 was bubbled into the solution through a needle. The solution was allowed to slowly warm to room temperature over 30 min. Volatiles were removed by rotary evaporation. The residue was partitioned between EtOAc (400 mL) and aqueous 1 M HC1 (200 mL). The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The residue was combined with CS2CO3 (5.3 g, 16.4 mmol) and benzyl bromide (1.8 mL, 15 mmol) in DMF (30 mL). After stirring for 30 min at room temperature, the mixture was partitioned between EtOAc (400 mL) and H20 (200 mL). The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The residue was chromato graphed on silica gel, eluting with 20-60% CH2C12 in hexanes to provide the product as a colorless oil (3.8 g, 55%).
LC-MS: 500.5 [M+H]+, RT 1.78 min. 1H NMR (500 MHz, acetone- 6) δ ppm 3.44 (m, 2H), 4.97 (m, 1H), 5.02 (m, 1H), 5.09 (s, 2H), 5.39 (s, 2H), 5.43 (s, 2H), 5.88 (m, 1H), 7.31-7.49 (15H)
Intermediate 18
Benzyl 2,4-bis(benzyloxy)-5-(but-3-en-l-yl)-6-chloronicotinate
Figure imgf000143_0001
Following the three step procedure for Intermediate 17, malonyl chloride (40 mmol) and 5- hexenenitrile (44 mmol) yielded 960 mg of the title compound.
LC-MS: 514.1/516.1 [M+H]+, RT 1.76 min. 1H NMR (500 MHz, acetone- d6) δ ppm 2.25 (m, 2H), 2.77 (m, 2H), 4.93 (m, IH), 4.97 (m, IH), 5.10 (s, 2H), 5.40 (s, 2 H), 5.42 (s, 2 H), 5.82 (m, IH), 7.31-7.49 (15H)
Intermediate 19
6-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-iodo-3-methyl-lH-indole
Figure imgf000143_0002
Step 1: 3-Bromo-4-iodoaniline
To a mixture of 3-bromoaniline (6.88 g, 40 mmol) and CaC03 (5.21 g, 52 mmol) in CH2CI2 (520 mL) and MeOH (200 mL) was added benzyltrimethylammonium dichloroiodate (14.6 g, 42 mmol). The mixture was filtered after stirring at room temperature for 1 hr. The filtrate was concentrated. The residue was chromatographed on silica gel, eluting with 0-30% EtOAc in hexanes to provide 6.1 g of the title compound (51%).
LC-MS: 298.0/300.0 [M+H]+, RT 1.24 min.
Step 2: (3-Bromo-4-iodophenyl)hydrazine
A suspension of 3-bromo-4-iodoaniline (6.1 g, 20.5 mmol) and aqueous 4 N HC1 (30 mL) was stirred vigorously at room temperature for 2 hrs. The suspension was cooled to 0 °C, before slowly adding a solution of NaN02 (1.52 g, 22 mmol) in H20 (10 mL). The mixture stirred at 0 °C for 30 min, and then was added to a solution of SnCl2 (11.7 g, 61.5 mmol) in concentrated aqueous HC1 (12 mL). The mixture was stirred vigorously for 30 min and then filtered. The solid material was partitioned in EtOAc (200 mL) and saturated aqueous NaHC03 (100 mL). The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated. The residue was chromatographed on silica gel, eluting with 10-70% EtOAc in hexanes to provide 3.4 g of off-white powder (53%).
1H NMR (500 MHz, DMSO- d6) δ ppm 4.11 (br. s, 2H), 6.51 (dd, J=8.8, 2.5 Hz, 1H), 7.14 (d, J=2.5 Hz, 1H), 7.16 (br. s, 1H), 7.50 (d, J=8.5 Hz, 1H) Step 3: Ethyl 2-(2-(3-bromo-4-iodophenyl)hydrazono)butanoate
A mixture of (3-bromo-4-iodophenyl)hydrazine (3.4 g, 10.9 mmol), ethyl 2-oxobutanoate (1.7 g, 13.1 mmol) and acetic acid (60 μί, 1 mmol) in EtOH (20 mL) was stirred at 90 °C for 30 min. Volatiles were removed and the residue was chromatographed on silica gel, eluting with CH2CI2. A 3: 1 mixture of E and Z stereoisomers (4.4 g) was obtained and carried on without subsequent purification.
LC-MS: 423.1/425.1 [M+H]+, RT 1.54 and 1.82 min.
Step 4: Ethyl 6-bromo-5-iodo-3-methyl-lH-indole-2-carboxylate
To a mixture of ethyl 2-(2-(3-bromo-4-iodophenyl)hydrazono)butanoate (4.4 g, 10.4 mmol) in EtOH (50 mL) was added H2S04 (10 mL). The mixture was heated at 95 °C for 1 hr. The EtOH was removed by rotary evaporation. The remaining mixture was partitioned in CH2C12 (100 mL) and H20 (100 mL). The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated to give a crude 1: 1 mixture of regioisomeric indoles. The residue was chromatographed on silica gel, eluting with 0-20% EtOAc in hexanes to provide 1.1 g of the desired isomer (26%).
LC-MS: 406.2/408.2 [M+H]+, RT 1.60 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.36 (q, J=7.2 Hz, 3H), 2.49 (s, 3H), 4.36 (t, J=7.2 Hz, 2H), 7.77 (s, 1H), 8.28 (s, 1H), 11.71 (br. s, 1H)
Step 5: 6-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-iodo-3-methyl-lH-indole
To a solution of ethyl 6-bromo-5-iodo-3-methyl-lH-indole-2-carboxylate (1.1 g, 2.7 mmol) in CH2C12 (10 mL) at -78 °C was added a solution of DIBAL-H in cyclohexane (13.5 mL, 13.5 mmol). The mixture was allowed to warm to 0 °C with stirring over 1 hr. The excess reagent was quenched by the slow addition of 1 M aqueous HC1. The mixture was stirred vigorously for 1 hr, and then was filtered through Celite. The filter cake was washed successively with Et20 and EtOAc. The combined organics were concentrated. The residue was eluted through a pad of silica, eluting with EtOAc to provide 700 mg of crude intermediate. The intermediate was combined with imidazole (0.16 g, 2.3 mmol) and t- butyldimethylsilyl chloride (0.32 g, 2.1 mmol) in CH2CI2 (10 mL). The mixture stirred for 30 min at room temperature, and then was washed with water. The organic layer was concentrated and chromatographed on silica gel, eluting with 0-10% EtOAc in hexanes to provide 850 mg of the title compound (66%).
LC-MS: 478.2/480.2 [M+H]+, RT 1.83 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 0.00 (s, 6H), 0.81 (s, 9H), 2.12 (s, 3H), 4.70 (s, 2H), 7.63 (s, 1H), 7.97 (s, 1H), 10.99 (br. s, 1H)
Intermediate 20
tert-Butyl 5-bromo-6-((2-(trimeth lsilyl)ethoxy)methyl)indoline-l-carboxylate
Figure imgf000145_0001
Step 1: 6-Bromoindoline
To a solution of 6-bromo-lH-indole (11.0 g, 56.1 mmol) in dichloromethane (180 mL) and TFA (60 mL) was added triethylsilane (22.6 mL, 2.5 equiv.). The mixture was stirred at room temperature for 16 hrs, after which additional dichloromethane (180 mL), concentrated ammonium hydroxide (about 50 mL) and water (200 mL) were added. The mixture was then extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and evaporated. The residue was re-dissolved in a 1: 1 mixture of ether and hexane (100 mL), to which was added 4N HC1 in dioxane (14 mL). A precipitation was formed instantly, which was collected by filtration. The obtained solid was treated with saturated sodium bicarbonate. The mixture was extracted with dichloromethane. The organic phase was combined, dried over sodium sulfate and evaporated to give the title compound as a brownish oil (approx. 10.0 g), which was used in the next step without further purification. LC-MS: 195.9/197.9 [M-H]+, RT 0.98 min.
Step 2: tert-Butyl 6-bromoindoline-l-carboxylate
A mixture of the product from Step 1 (10.0 g, 50.5 mmol), Boc20 (11.0 g, 1.0 equiv.), diisopropylethylamine (16.5 mL, 2.0 equiv.) and DMAP (0.62 g, 0.1 equiv.) in
dichloromethane (100 mL) was stirred at room temperature overnight. Water was then added and the mixture was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography with hexane and ethyl acetate (0 to 30%) to give the title compound (8.1 g, 50% for two steps) as an off-white solid. 1H NMR (500 MHz, CDC13) δ ppm 1.58 (br. s, 9H), 3.05 (t, J=8.5 Hz, 2H), 4.00 (br. s, 2H), 7.00 (dd, J=7.5, 1 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 8.05 (br. s, 1H)
Step 3: tert-Butyl 6-((2-(trimethylsilyl)ethoxy)methyl)indoline-l-carboxylate
To a solution of the product from Step 2 (0.90 g, 3.0 mmol) in THF (12 mL) was added n- BuLi (2.0M in hexanes, 1.7 mL, 1.1 equiv.) dropwise at -78 °C, and stirred for 0.5 hrs. To the mixture was added (2-(chloromethoxy)ethyl)trimethylsilane (0.65 g, 1.3 equiv.) dropwise, and stirred at -78 °C for 0.5 hrs. The reaction mixture was warmed gradually to room temperature, then quenched by the addition of aqueous ammonium chloride solution at 0 °C, and extracted with ether. The organic layer was washed with brine, dried over anhydrous MgS04, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography with 0-30% dichloromethane in hexanes to give the desired product (0.76 g, 73%) as a brown foam.
1H NMR (500 MHz, CDC13) 5 ppm 0.00 (s, 9H), 0.96-1.00 (m, 2H), 1.53 (br. s, 9H), 3.06 (t, J=8.5 Hz, 2H), 3.55 (t, J=8.5 Hz, 2H), 3.97 (br. s, 2H), 4.43 (s, 2H), 6.93 (br. s, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.81 (br. s, 1H)
Step 4: tert-Butyl 5-bromo-6-((2-(trimethylsilyl)ethoxy)methyl)indoline- 1-carboxylate
A mixture of tert-butyl 6-((2-(trimethylsilyl)ethoxy)methyl)indoline- 1-carboxylate (0.76 g, 2.2 mmol) and NBS (0.43 g, 1.1 equiv.) in dichoromethane (10 mL) was stirred at room temperature overnight. Aqueous potassium carbonate (15 mL) was then added and the mixture was extracted with dichloromethane. The organic extracts were combined, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography with 0-20% dichloromethane in hexanes to give the desired product (0.70 g, 75%) as a white solid.
1H NMR (500 MHz, CDC13) δ ppm 0.00 (s, 9H), 0.99-1.01 (m, 2H), 1.54 (br. s, 9H), 3.03 (t, J=8.5 Hz, 2H), 3.60 (t, J=8.5 Hz, 2H), 3.96 (br. s, 2H), 4.46 (s, 2H), 7.22 (s, 1H), 7.93 (br. s, 1H)
Intermediate 21
tert-Butyl 5-bromo-6-((2-(trimethylsilyl)ethoxy)methyl)- lH-indole- 1 -carboxylate
Figure imgf000147_0001
A mixture of tert-butyl 5-bromo-6-((2-(trimethylsilyl)ethoxy)methyl)indoline-l-carboxylate (Intermediate 20, 0.80 g, 1.8 mmol) and Mn02 (7.8 g, 50 equiv.) in dichloromethane (25 mL) was stirred at room temperature overnight, then filtered and washed with large amount of dichloromethane. The filtrate was combined and evaporated to provide the desired product (0.65 g, 85%) as a white solid.
1H NMR (500 MHz, CDC13) δ ppm 0.00 (s, 9H), 1.01-1.05 (m, 2H), 1.65 (s, 9H), 3.63-3.66 (m, 2H), 4.52 (s, 2H), 6.45 (d, J=3.5 Hz, 1H), 7.55 (d, J=3.5 Hz, 1H), 7.70 (s, 1H), 8.25 (s, 1H)
Intermediate 22
tert-Butyl 5-bromo-6-(2-((tert-but ldimethylsilyl)oxy)ethyl)indoline-l-carboxylate
Figure imgf000147_0002
Step 1: tert-Butyl 6-vinylindoline-l-carboxylate
A mixture of tert-butyl 6-bromoindoline-l-carboxylate (Intermediate 20, Step 2, 0.59 g, 2.0 mmol), potassium vinyltrifluoroborate (0.40 g, 2.0 equiv.), tris(dibenzylideneacetone)- dipalladium(O) (82 mg, 0.05 equiv.), K2C03 (0.8 g, 3.0 equiv.) in THF (8 mL) and water (2 mL) was stirred at 80 °C under an argon atmosphere overnight. The mixture was then cooled and extracted with ethyl acetate (3x). The organic layers were combined, dried over Na2S04, and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0-30% gradient) to give the title compound (0.47 g, 96%) as a white solid.
1H NMR (500 MHz, CDC13) δ ppm 1.58 (br. s, 9H), 3.10 (t, J=8.5 Hz, 2H), 4.00 (br. s, 2H), 5.21 (d, J=l l Hz, 1H), 5.75 (br. s, 1H), 6.71 (dd, J=18, 11 Hz, 1H), 7.07 (br. s, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.79 (br. s, 1H)
Step 2: tert-Butyl 6-(2-hydroxyethyl)indoline-l-carboxylate
To a solution of tert-butyl 6-vinylindoline-l-carboxylate from Step 1 (0.47 g, 1.9 mmol) in THF (6.0 mL) was added a solution of 9-BBN (0.5M THF, 6.0 mL, 1.5 equiv.) dropwise. The mixture was then stirred at room temperature overnight and then was cooled to 0 °C. Aqueous NaOH solution (1.0 M, 8 mL) was added to the mixture, followed by 30% H202 (8 mL). The mixture was then stirred for 1 hr at room temperature and extracted with ethyl acetate (3x). The organic layers were combined, dried over Na2S04 and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0-60% gradient) to give the title compound (0.44 g, 88%).
1H NMR (500 MHz, CDC13) δ ppm 1.58 (br. s, 9H), 2.87 (t, J=6.5 Hz, 2H), 3.08 (t, J=9.0 Hz, 2H), 3.88 (t, J=6.5 Hz, 2H), 4.00 (br. s, 2H), 6.82 (dd, J=7.5, 1 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 7.79 (br. s, 1H)
Step 3: tert-Butyl 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)indoline- 1-carboxylate
To a solution of the product of Step 2 (263 mg, 1.0 mmol), imidazole (204 mg, 3.0 equiv.) in dichloromethane (1.0 mL) at 0 °C was added TBSC1 (1.0M in CH2C12, 1.1 mL, 1.1 equiv.). The mixture was stirred at room temperature for 2 hrs, then treated with NaHC03 (5% aq., 20 mL) and extracted with dichloromethane. The organic layers were combined, dried over Na2S04 and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0-15% gradient) to give the title compound (380 mg, quant.).
1H NMR (500 MHz, CDC13) 5 ppm 0.10 (s, 6H), 0.88 (s, 9H), 1.55 (br. s, 9H), 2.79 (t, J=6.5 Hz, 2H), 3.03 (t, J=9.0 Hz, 2H), 3.77 (t, J=6.5 Hz, 2H), 3.95 (br. s, 2H), 6.77 (d, J=7.5 Hz, 1H), 7.03 (d, J=7.5 Hz, 1H), 7.71 (br. s, 1H)
Step 4: tert-Butyl 5-bromo-6-(2-((tert-butyldimethylsilyl)oxy)ethyl)indoline- 1-carboxylate
To a solution of the product of Step 3 (380 mg, 1.0 mmol) in dichloromethane (10 mL) was added NBS (196 mg, 1.1 equiv.) portionwise. The mixture was stirred at room temperature for 2 hrs, then partitioned between aqueous saturated NaHC03 and dichloromethane. The aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over Na2S04 and evaporated. The residue was purified by silica gel column chromatography with ethyl acetate and hexanes (0-15% gradient) to give the title compound (410 mg, 90%). 1H NMR (500 MHz, CDC13) 5 ppm 0.10 (s, 6H), 0.85 (s, 9H), 1.53 (br. s, 9H), 2.93 (t, J=6.5 Hz, 2H), 3.02 (t, J=9.0 Hz, 2H), 3.78 (br. s, 2H), 3.95 (br. s, 2H), 7.29 (s, 1H), 7.78 (br. s, 1H)
Intermediate 23
3-Benzyl 9-(tert-butyl) 2,4-bis(benzyloxy)-6,7,10,l l-tetrahydro-9H- pyrido[3',2':2,3]oxepino[4,5-f]indole-3,9-dicarboxylate
Figure imgf000149_0001
Step 1: tert-Butvl 6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)indoline-l-carboxylate
A solution of tert-butyl 5-bromo-6-(2-((tert-butyldimethylsilyl)oxy)ethyl)indoline-l- carboxylate (Intermediate 22, 160 mg, 0.35 mmol), bis(pinacolato)diboron (134 mg, 1.5 equiv.), potassium acetate (13 mg, 3.0 eq.) and tris(dibenzylideneacetone)-dipalladium(0) (28 mg, 0.1 equiv.) in anhydrous dioxane (1 mL) was heated at 90° C under an argon atmosphere overnight. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with 0-20% dichloromethane in hexane to provide the desired product (130 mg, 74%) as a white foam.
1H NMR (500 MHz, CDC13) 5 ppm 0.10 (s, 6H), 0.88 (s, 9H), 1.28 (s, 12H), 1.57 (br. s, 9H), 3.03 (t, J=8.5 Hz, 2H), 3.13 (t, J=7.0 Hz, 2H), 3.75 (t, J=7.0 Hz, 2H), 3.95 (br. s, 2H), 7.57 (s, 1H), 7.76 (br. s, 1H) Step 2: tert-Butyl 5-(4,6-bis(benzyloxy)-5-((benzyloxy)carbonyl)-3-hydroxypyridin-2-yl)-6- (2-((tert-butyldimethylsilyl)oxy)ethyl)indoline-l-carboxylate
A mixture of the product of Step 1 (130 mg, 0.26 mmol), benzyl 2,4-bis(benzyloxy)-6- bromo-5-hydroxynicotinate (Intermediate 15, 80 mg, 0.15 mmol), Pd2(dba)3 (7 mg, 0.05 equiv.), P(i-Bu)3 HBF4 (4.4 mg, 0.1 equiv) in aqueous K2C03 (2.0 M, 0.5 mL) and THF (1 mL) was stirred at 65 °C for 1 hr under an argon atmosphere. The mixture was then cooled and extracted with ether. The organic layers were combined, dried over Na2S04 and evaporated. The residue was purified by silica gel column chromatography with hexane and ethyl acetate (0-50% gradient) to give the title compound (110 mg, 90%).
1H NMR (500 MHz, CDC13) 5 ppm 0.10 (s, 6H), 0.82 (s, 9H), 1.58 (br. s, 9H), 2.73 (t, J=8.5 Hz, 2H), 3.12 (t, J=7.0 Hz, 2H), 3.89 (br. s, 2H), 4.03 (br. s, 2H), 5.25 (s, 2H), 5.32 (s, 2H), 5.35 (s, 2H), 6.48 (br. s, 1H), 7.01 (s, 1H), 7.30-7.37 (m, 15H), 7.76 (br. s, 1H)
Step 3: tert-Butyl 5-(4,6-bis(benzyloxy)-5-((benzyloxy)carbonyl)-3-hydroxypyridin-2-yl)-6- (2-hydroxyethyl)indoline- 1 -carboxylate To a solution of the product of Step 2 (110 mg, 0.13 mmol) in THF (1 mL) was added a solution of TBAF in THF (1.0 M, 0.26 mL, 2 equiv.) at 0 °C. The mixture was stirred at room temperature for 1 hr, then the reaction was quenched with saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography with hexane and ethyl acetate (0-60%) to give the title compound (90 mg, quant.).
LC-MS: 703.4 [M+H]+, RT 1.61 min. 1H NMR (500 MHz, CDC13) 5 ppm 1.58 (br. s, 9H), 2.69 (t, J=6 Hz, 2H), 3.12 (t, J=7.0 Hz, 2H), 3.83 (br. s, 2H), 4.03 (br. s, 2H), 5.25 (s, 2H), 5.32 (s, 2H), 5.45 (s, 2H), 7.03 (s, 1H), 7.30-7.37 (m, 15H), 7.92 (br. s, 1H) Step 4: 3-Benzyl 9-(tert-butyl) 2,4-bis(benzyloxy)-6,7,10, l l-tetrahydro-9H- pyrido[3',2':2,3]oxepino[4,5-f]indole-3,9-dicarboxylate
To a solution of the product of Step 3 (90 mg, 0.13 mmol), triphenylphosphine (44 mg, 1.3 equiv.) in THF (1.5 mL) cooled to 0 °C was added a solution of DEAD in toluene (40%, 20 μί, 1.3 equiv.). The mixture was stirred at 0 °C for 15 min then the ice-bath was removed. The stirring was continued at room temperature for 3 hrs, after which the mixture was evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0-40% gradient) to give the title compound (78 mg, 86%).
1H NMR (500 MHz, CDC13) δ ppm 1.58 (br. s, 9H), 2.87 (br. s, 2H), 3.19 (t, J=9.0 Hz, 2H), 4.05 (br. s, 2H), 4.57 (t, J=6.0 Hz, 2H), 5.30 (s, 2H), 5.32 (s, 2H), 5.50 (s, 2H), 7.27-7.37 (m, 15H), 7.49 (s, 1H), 7.92 (br. s, 1H)
Intermediate 24
3-Benzyl 9-(tert-butyl) 2,4-bis(benzyloxy)-6,7-dihydro-9H-pyrido[3',2':2,3]oxepino[4,5- f]indole-3,9-dicarboxylate
Figure imgf000150_0001
Intermediate 24 was prepared starting from Intermediate 22 according to procedures described for Intermediate 21 and Intermediate 23.
1H NMR (500 MHz, CDC13) δ ppm 1.72 (br. s, 9H), 3.00 (t, J=6.0 Hz, 2H), 4.60 (t, J=6.0 Hz, 2H), 5.31 (s, 2H), 5.32 (s, 2H), 5.33 (s, 2H), 6.66 (d, J=3.5 Hz, 1H), 7.27-7.40 (m, 15H), 7.61 (d, J=3.5 Hz, 1H), 7.93 (s, 1H), 8.17 (br. s, 1H) Intermediate 25
Benzyl 2,4-bis(benzyloxy)-7,9-dihydro-6H-pyrido[3',2':2,3]oxepino[4,5-f]indole-3- carboxylate
Figure imgf000151_0001
A solution of 3-benzyl 9-(tert-butyl) 2,4-bis(benzyloxy)-6,7-dihydro-9H- pyrido[3',2':2,3]oxepino[4,5-f]indole-3,9-dicarboxylate (Intermediate 24, 140 mg, 0.21 mmol) in diphenyl ether (3 mL) was heated at 210 °C for 1 hr. The mixture was cooled to room temperature and loaded directly onto a silica gel cartridge and purified by silica gel column chromatography with EtOAc in hexanes (0-60% gradient) to give the title compound
(101 mg, 84%) as a white foam.
LC-MS: 583.2 [M+H]+, RT 1.65 min. 1H NMR (500 MHz, CDC13) δ ppm 2.77 (t, J=6.5 Hz, 2H), 4.56 (t, J=6.5 Hz, 2H), 5.31 (s, 2H), 5.32 (s, 4H), 6.66 (s, 1H), 7.25-7.39 (m, 15H), 7.45- 7.47 (m, 2H), 8.03 (s, 1H), 8.25 (br. s, 1H)
Intermediate 26
l-Tosyl-7,8-dihydro-lH-oxe ino[2,3-f]indol-9(6H)-one
Figure imgf000151_0002
Step 1: Ethyl 4-(4-bromophenoxy)butanoate
A solution of 4-bromophenol (34.6 g, 200 mmol), ethyl 4-bromobutyrate (31.5 mL, 220 mmol), and potassium carbonate (50 g, 360 mmol) in dimethylformamide (200 ml) was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was then diluted with diethyl ether, washed with water (3x), brine (50 mL), dried over sodium sulfate and concentrated. The crude product was used without further purification.
Step 2: 4-(4-Bromophenoxy)butanoic acid
To a solution of the crude product from Step 1 in methanol (100 mL) was added aqueous sodium hydroxide solution (3N, 200 mL). The mixture was heated to 70 °C for 1 hr then poured into ice followed by addition of aqueous HC1 solution (37%, 50 mL). The mixture was extracted with ethyl acetate and the combined organic phases were washed with water, dried over Na2S04 and evaporated. The crude product was triturated with diethyl ether to provide the title compound (41 g, 79% for two steps) as a white solid.
1H NMR (500 MHz, CDC13) δ ppm 2.12-2.16 (m, 2H), 2.61 (t, J=7.0 Hz, 2H), 4.02 (t, J=6.0 Hz, 2H), 6.78 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H)
Step 3: 7-Bromo-3 ,4-dihydrobenzo [b] oxepin-5 (2H)-one
To pre-heated PPA (200 g) at 120 °C was added 4-(4-bromophenoxy)butanoic acid from Step 2 (20 g, 77 mmol). The mixture was well mixed at 95 °C for 1 hr then poured onto ice and stirred for 0.5 hrs. The mixture was extracted with ethyl acetate and the organic layers were combined, washed with water, dried over Na2S04 and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0-30%) to give the title compound (12 g, 65%) as a yellow oil.
1H NMR (500 MHz, CDC13) δ ppm 2.23-2.27 (m, 2H), 2.92 (t, J=7.0 Hz, 2H), 4.26 (t, J=6.5 Hz, 2H), 6.99 (d, J=8.5 Hz, 1H), 7.52 (dd, J=8.5, 2.5 Hz, 1H), 7.90 (d, J=2.5 Hz, 1H) Step 4: 7-Bromo-3 ,4-dihydro-2H-spiro [benzo [b] oxepine-5 ,2'- [ 1 ,3] dioxolane]
To a mixture of 7-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one from Step 3 (5.0 g, 21 mmol), toluene (150 mL) and ethylene glycol (1.9 g, 1.5 equiv.) was added p-toluenesulfonic acid (400 mg, 0.1 equiv.). The mixture was stirred at reflux overnight with a Dean-Stark apparatus. The mixture was diluted with ethyl acetate and washed with aqueous saturated NaHC03 solution. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The residue was chromato graphed on silica gel, eluting with 0-20% ethyl acetate in hexanes to afford the title compound (5.1 g, 86%) as a yellow oil.
1H NMR (500 MHz, CDC13) δ ppm 2.07-2.11 (m, 4H), 3.95-3.98 (m, 2H), 4.07-4.15 (m, 4H), 6.92 (d, J=8.5 Hz, 1H), 7.34 (dd, J=8.5, 2.5 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H) Step 5: tert-Butyl (3,4-dihydro-2H-spiro[benzo[b]oxepine-5,2'-[l,3]dioxolan]-7-yl)carbamate
A mixture of 7-bromo-3,4-dihydro-2H-spiro[benzo[b]oxepine-5,2'-[l,3]dioxolane] from Step 4 (5.0 g, 17.5 mmol), tert-butyl carbamate (3.1 g, 26.3 mmol), palladium acetate (118 mg, 0.53 mmol), S-Phos ligand (430 mg, 1.1 mmol) and cesium carbonate (8.6 g, 26.3 mmol) in dioxane (80 mL) was degassed and back-filled with nitrogen. The mixture was heated at 100 °C overnight, then cooled to room temperature, extracted with ethyl acetate and washed with water. The organics were dried and concentrated to give crude product which was chromato graphed on silica gel, eluting with 0-30% ethyl acetate in hexanes to afford the title compound (5.0 g, 90%) as a colorless oil.
1H NMR (500 MHz, CDC13) 5 ppm 1.52, (s, 9H), 2.05-2.10 (m, 4H), 3.93-3.96 (m, 2H), 4.07- 4.11 (m, 4H), 6.56 (br. s, IH), 6.97 (d, J=8.5 Hz, IH), 7.37 (br. s, 2H) Step 6: 3 ,4-Dihydro-2H- spiro [benzo [b] oxepine-5 ,2'- [ 1 ,3] dioxolan] -7-amine
To a solution of tert-butyl (3,4-dihydro-2H-spiro[benzo[b]oxepine-5,2'-[l,3]dioxolan]-7- yl)carbamate from Step 5 (3.2 g, 10 mmol) in THF (50 mL) was added sodium tert-butoxide (1.9 g, 2.0 equiv.) and water (180 mg, 1.0 equiv.). The mixture was heated to 80 °C overnight then poured into ice and stirred for 1 hr. The mixture was extracted with ethyl acetate and the organic layers were combined, washed with water, dried over Na2S04 and evaporated. The crude product was triturated with diethyl ether to provide the title compound (1.5 g, 68%) as a white solid.
1H NMR (500 MHz, acetone- d6) δ ppm 1.97-1.99 (m, 4H), 3.85-3.90 (m, 2H), 3.97-4.00 (m, 4H), 4.37 (br. s, 2H), 6.50 (dd, J=8.0, 3.0 Hz, IH), 6.66 (d, J=8.0 Hz, IH), 6.84 (d, J=3.0 Hz, IH)
Step 7: 8-Bromo-3,4-dihydro-2H-spiro[benzo[b]oxepine-5,2'-[l,3]dioxolan]-7-amine
A mixture of the product of Step 6 (1.5 g, 6.8 mmol) and NBS (1.3 g, 1.05 equiv.) in dichloromethane (300 mL) was stirred at room for 3 hrs. The reaction was quenched with aqueous NaHC03 solution and extracted with dichloromethane. The organic extracts were combined, washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography with 0-20% ethyl acetate in dichloromethane to give the title compound (1.4 g, 69%) as a yellow solid.
1H NMR (500 MHz, acetone- d6) δ ppm 1.97-1.99 (m, 4H), 3.85-3.88 (m, 2H), 3.92-3.94 (m, 2H), 3.99-4.02 (m, 2H), 4.69 (br. s, 2H), 6.99 (s, IH), 7.05 (s, IH) Step 8: 8-((Trimethylsilyl)ethynyl)-3,4-dihydro-2H-spiro[benzo[b]oxepine-5,2'- [ 1 ,3]dioxolan] -7-amine
A mixture of 8-bromo-3,4-dihydro-2H-spiro[benzo[b]oxepine-5,2'-[l,3]dioxolan]-7-amine from Step 7 (450 mg, 1.5 mmol), copper(I) iodide (29 mg, 0.1 equiv.),
bis(triphenylphosphine)palladium(II) dichloride (105 mg, 0.1 equiv.), ethynyltrimethylsilane (220 mg, 1.5 equiv) in dimethylformamide (2 mL) and triethylamine (2 mL) was stirred under argon at 80 °C overnight. The reaction mixture was then allowed to cool to room temperature and then quenched by the addition of saturated NH4C1 aqueous solution. After stirring for 30 min the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over Na2S04 and evaporated. The residue was purified by silica gel column chromatography with EtOAc in dichloromethane (0-15% gradient) to give the title compound (375 mg, 79%).
1H NMR (500 MHz, CDCI3) δ ppm 0.00 (s, 9H), 1.78-1.83 (m, 4H), 3.37-3.70 (m, 2H), 3.72- 3.74 (m, 2H), 3.80-3.83 (m, 2H), 4.70 (br. s, 2H), 6.66 (s, 1H), 6.77 (s, 1H)
Step 9: 7,8-Dihydro-lH,6H-spiro[oxepino[2,3-f]indole-9,2'-[l,3]dioxolane]
A mixture of the product of Step 8 (375 mg, 1.2 mmol) and copper(I) iodide (450 mg, 2.0 equiv) in dimethylformamide (10 mL) was stirred under argon at 110 °C for 2 hrs. The reaction mixture was then diluted with ethyl acetate and filtered through Celite. The filtrate was treated with an equal volume of saturated NH4CI aqueous solution and stirred for 1 hr and then extracted with ethyl acetate. The organic layers were combined, washed with water, dried over Na2S04 and evaporated. The residue was purified by silica gel column
chromatography with methanol in dichloromethane (0-10% gradient) to give the title compound (167 mg, 58%) as an off-white solid.
1H NMR (500 MHz, DMSO- 6) 5 ppm 1.95-2.00 (m, 4H), 3.80-3.83 (m, 2H), 3.93-4.00 (m, 4H), 6.31 (br. s, 1H), 7.08 (s, 1H), 7.34-7.35 (m, 1H), 7.48 (s, 1H), 11.00 (br. s, 1H)
Step 10: l-Tosyl-7,8-dihydro-lH,6H-spiro[oxepino[2,3-f]indole-9,2'-[l,3]dioxolane] To a solution of 7,8-dihydro-lH,6H-spiro[oxepino[2,3-f]indole-9,2'-[l,3]dioxolane] from
Step 9 (167 mg, 0.68 mmol) in dimethylformamide (2.5 mL) at 0 °C was added NaH (33 mg, 1.2 equiv) and stirred at for 0.5 hrs. Then, p-toluenesulfonyl chloride (143 mg, 1.1 equiv.) was added and the reaction mixture was warmed gradually to room temperature and stirred overnight. The reaction was cooled to 0 °C and quenched with ice-water. The mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over Na2S04 and evaporated. The residue was purified by silica gel column chromatography with methanol in dichloromethane (0-5% gradient) to give the desired product (220 mg, 78%) as a white solid.
LC-MS: 400.4 [M+H]+, RT 1.43 min. 1H NMR (500 MHz, CDC13) δ ppm 2.12-2.13 (m, 4H), 2.38 (s, 3H), 3.90-3.93 (m, 2H), 4.05 (br. s, 2H), 4.10-4.14 (m, 2H), 6.58 (dd, J=3.5, 1.0 Hz, 1H), 7.18, (s, 1H), 7.25 (d, J=8.5 Hz, 2H), 7.59 (d, J=3.0 Hz, 1H), 7.80 (d, J=8.5 Hz, 2H), 8.13 (s, 1H) Step 11: l-Tosyl-7,8-dihydro-lH-oxepino[2,3-f]indol-9(6H)-one
To a solution of l-tosyl-7,8-dihydro-lH,6H-spiro[oxepino[2,3-f]indole-9,2'-[l,3]dioxolane] from Step 10 (220 mg, 0.55 mmol) in dioxane (2 mL) was added aqueous HC1 (6N, 0.2 mL) and the mixture was stirred at room temperature overnight. The mixture was diluted with water, then extracted with ethyl acetate, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography with EtOAc in dichloromethane (0-10%) to give the desired product (195 mg, quant.) as a colorless oil.
1H NMR (500 MHz, CDC13) δ ppm 2.17-2.19 (m, 2H), 2.38 (s, 3H), 2.92-2.95 (m, 2H), 4.22 (d, J=6.5 Hz, 2H), 6.62 (dd, J=3.5, 1.0 Hz, IH), 7.22, (s, IH), 7.27 (d, J=8.5 Hz, 2H), 7.71 (d, J=3.0 Hz, IH), 7.83 (d, J=8.5 Hz, 2H), 8.41 (s, IH)
Example 1
4-Hydroxy-2-oxo-2,5,6,9-tetrahydro-lH-pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid (Cpd 3)
Step 1: Methyl l-(2,4-dimethoxybenzyl)-4-hydroxy-2-oxo-9-tosyl-2,5,6,9-tetrahydro- 1H- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylate
To a stirring solution of Intermediate 9 (1.02 g, 2.75 mmol), (2,4- dimethoxyphenyl)methanamine (0.51 g, 0.45 mL, 3.03 mmol), triethylamine (0.83 g, 1.14 mL, 8.25 mmol) in CH2C12 (6.0 mL) at 0 °C was added a solution of TiCl4 (1M in CH2C12,
1.4 mL, 1.4 mmol) dropwise. After the addition, the mixture was brought to room
temperature and stirred overnight. The reaction was quenched with satd. NaHC03 solution (3 mL) and the mixture was diluted with CH2C12 (12 mL). The CH2C12 layer was separated and the aqueous layer was extracted with CH2C12 (2 x 3 mL). The combined organics were evaporated to dryness followed by the addition of trimethyl methanetricarboxylate (1.05 g,
5.5 mmol) and diphenyl ether (5.0 mL). The mixture was stirred at 230 °C for 10 min, then cooled to room temperature and loaded directly onto a silica gel column. The product was chromato graphed (ethyl acetate in CH2C12 0-50 %) to furnish the title compound as a light brown solid (1.10 g, 62%).
LC-MS: 647.2 [M+H]+, RT 1.57 min.
Step 2: Methyl 4-hydroxy-2-oxo-9-tosyl-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]thiepino[3,2- f]indole-3-carboxylate To a solution of the product of Step 1 (133 mg, 0.21 mmol) in CH2C12 (0.5 mL) was added TFA (0.5 mL). The solution was stirred at room temperature for 2 hrs. After removal of the volatiles, the residue was treated with water (2 mL). The precipitate was collected by filtration, washed with water and hexanes and dried under N2 to provide the title compound as a white solid which was used directly in the next step.
LC-MS: 497.0 [M+H]+, RT 1.41 min.
Step 3: Methyl 4-hydroxy-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]thiepino[3,2-f]indole- 3-carboxylate
A mixture of the 2-pyridone intermediate obtained in Step 2, K2C03 (276 mg, 2.0 mmol) and MeOH (2.0 mL) was stirred at 60 °C overnight. The solvent was removed on a rotovap and the residue was treated with NH4C1 solution (2 mL). The precipitate was collected, washed with water, CH2C12 and ethyl acetate, and then dried to furnish the title compound (64 mg, 91 % over two steps).
1H NMR (DMSO- 6) δ: 13.51 (br. s, 1H), 11.60 (br. s, 1H), 11.54 (br. s, 1H), 7.47-7.56 (m, 2H), 7.25 (d, J=8.2 Hz, 1H), 6.66 (ddd, J=3.1, 2.1, 0.8 Hz, 1H), 3.86 (s, 3H), 3.53 (br. s, 1H), 3.17 (br. s, 2H), 1.87 (br. s, 1H)
Sje _4^ 4-Hydroxy-2-oxo-2,5,6,9-tetrahydro-lH-pyrido[2',3':4,5]thiepino[3,2-f]indole-3- carboxylic acid
A mixture of the intermediate obtained in Step 3 (41 mg, 0.12 mmol), Lil (40 mg, 0.3 mmol) and ethyl acetate (0.5 mL) was stirred at 65 °C for 2 hrs. The solvent was evaporated and the residue was treated with water (1 mL) and acidified with acetic acid. The precipitate was collected and washed with water, ethyl acetate and dried to furnish the title compound as a white solid (32 mg, 82%).
LC-MS: 329.0 [M+H]+, RT 1.20 min. 1H NMR (DMSO- 6) δ: 16.22 (br. s, 1H), 13.85 (br. s, 1H), 12.94 (br. s, 1H), 11.61 (br. s, 1H), 7.52-7.62 (m, 2H), 7.32 (d, J=8.5 Hz, 1H), 6.69 (ddd, J=3.1, 2.1, 0.8 Hz, 1H), 3.61 (br. s, 1H), 3.19 (br. s, 2H), 1.97 (br. s, 1H)
Using the procedure described for Example 1 above, additional compounds described herein may be prepared by substituting the appropriate starting material, indicated
intermediate and suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Materials and Data
Intermediate 13: LC-MS: 329.4 [M+H]+, RT 1.31 min. lH NMR (500 MHz, DMSO-
23 d6) 5 ppm 2.03 - 2.14 (m, 2H), 2.39 (br. s, 3H), 2.84 (br. s, 6H), 4.50 - 5.13 (m, 4H), 7.29 - 7.46 (m, 2H), 12.92 (s, 1H), 13.85 (s, 1H)
Intermediate 12: LC-MS: 387.4 [M+H]+, RT 1.33 min. 1H NMR (500 MHz, CDC13)
24 5 ppm 1.00- 1.20 (m, 3H), 1.25-1.34 (m, 1H), 2.02 - 2.13 (m, 3H), 2.18 (s, 3H), 3.09- 3.19 (m, 4H), 3.87 - 4.21 (m, 3H), 7.30 (d, J=8.2 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H)
Intermediate 11 : LC-MS: 311.2 [M+H]+, RT 1.26 min. 1H NMR (DMSO- 6): δ 2.06
53 (m, 4H), 2.64 (m, 2H), 6.48 (m, 1H), 7.53 (m, 2H), 7.61 (s, 1H), 11.47 (s, 1H), 12.89 (br. s, 1H), 13.85 (s, 1H)
Intermediate 26: LC-MS: 313.2 [M+H]+, RT 1.12 min. 1H NMR (500 MHz, DMSO- d6) δ ppm 2.61 (t, J=6.5 Hz, 2H), 4.39 (t, J=6.5 Hz, 2H), 6.50 (br. s, 1H), 7.38 (s,
55
1H), 7.57 (d, J=3.0 Hz, 1H), 7.64 (s, 1H), 11.55 (s, 1H), 13.04 (br. s, 1H), 13.86 (br. s, 1H)
Example 2
4-Hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-pyrido[2',3':4,5]thiepino[3,2-f|indole-3- carboxylic acid (Cpd 5)
Step 1 : Methyl 4-(benzyloxy)-l-(2,4-dimethoxybenzyl)-2-oxo-9-tosyl-2,5,6,9-tetrahydro- lH- pyrido[2',3':4,5]thiepino[3,2-f|indole-3-carboxylate
To a solution of methyl l-(2,4-dimethoxybenzyl)-4-hydroxy-2-oxo-9-tosyl-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylate (Example 1, Step 1, 0.82 g, 1.27 mmol) in DMF (3.0 mL), at 0 °C, was added NaH (0.066 g, 1.65 mmol, 60% in mineral oil). After the addition, the mixture was warmed to room temperature and stirred for 0.5 hrs, followed by the addition of benzyl bromide (0.33 g, 0.23 mL, 1.91 mmol). The reaction mixture was stirred at 50 °C overnight and then diluted with ethyl acetate (25 mL), washed with water (2 x 10 mL), brine (10 mL) and dried over Na2S04. The crude product obtained after the removal of the solvent was chromatographed (silica gel, ethyl acetate in hexanes, 0-60 %) to provide the title compound as a white powder (0.84 g, 90%).
LC-MS: 737.3 [M+H]+, RT 1.64 min.
Step 2: Methyl 4-(benzyloxy)-l-(2,4-dimethoxybenzyl)-2-oxo-2,5,6,9-tetrahydro- lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylate A mixture of the intermediate obtained in Step 1 (450 mg, 0.61 mmol), K2C03 (193 mg, 1.4 mmol) and MeOH (4.0 mL) was stirred at 40 °C overnight. The solvent was removed on a rotovap and the residue was treated with NH4C1 solution (5 mL) and extracted with CH2C12 (10 mL). Column chromatography (silica gel, ethyl acetate in CH2C12, 0-60% gradient) provided the title compound as a white powder (210 mg, 59%).
LC-MS: 583.1 [M+H]+, RT 1.43 min.
Step 3: Methyl 4-(benzyloxy)-l-(2,4-dimethoxybenzyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylate
To a solution of the product obtained in Step 2 (210 mg, 0.36 mmol) in DMF (1.0 mL) was added NaH (22 mg, 0.54 mmol, 60% in mineral oil). The mixture was stirred for 30 min followed by the addition of Mel (77 mg, 34 uL, 0.54 mmol). The resulting mixture was then heated to 50 °C and stirred for 2 hr, diluted with water (5 mL) and extracted with CH2C12 (5 mL x 2). The crude material was chromato graphed (silica gel, ethyl acetate in hexanes, 0- 70%) to furnish the title intermediate which was directly used in the next step. Step 4: 4-Hvdroxv-9-methvl-2-oxo-2,5,6,9-tetrahvdro-lH-pvridor2',3':4,51thiepinor3,2- f]indole-3-carboxylic acid
The product obtained in Step 3 was dissolved in CH2C12 (1 mL) and treated with TFA (1 mL) at room temperature for 2 hrs. The mixture was then added to satd. NaHC03 solution (15 mL). Additional CH2C12 (5 mL) was added to extract the organic s from the water layer. After drying with anhydrous Na2S04, the solvent was removed under vacuum and the residue was treated with TMSI (216 mg, 0.15 mL, 1.08 mmol) and CH2C12 (2.0 mL) at room temperature for 24 hrs. MeOH (1.0 mL) was added to quench the reaction. The mixture was neutralized with NaHC03. The precipitate was collected by filtration, washed with water and further purified by preparative HPLC to furnish the title compound (9.2 mg).
LC-MS: 343.2 [M+H]+, RT 1.25 min. 1H NMR (DMSO- 6) δ: 16.20 (br. s, 1H), 13.86 (br. s, 1H), 12.95 (br. s, 1H), 7.67 (dd, J=8.5, 0.9 Hz, 1H), 7.53 (d, J=3.2 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 6.69 (dd, J=3.2, 0.6 Hz, 1H), 3.86 (s, 3H), 3.59 (br. s, 1H), 3.21 (br. s, 2H), 1.92 (br. s, 1H)
Example 3
4-Hydroxy-10-(hydroxymethyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid (Cpd 13) Step 1: 2,4-Bis(benzyloxy)-10-(hydroxymethyl)-9-methyl-5,9-dihydro-6H- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
Intermediate 10 (260 mg, 0.46 mmol) was stirred in THF (2.0 mL) with TMSOK (118 mg, 0.92 mmol) at 60 °C overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL) and acidified with HC1 (1M). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 mL). The combined organic phases were washed with water (2 mL), brine (2 mL) and dried over Na2S04. Chromatography of the crude material (silica gel, ethyl acetate in CH2C12, 0-40%) furnished the title intermediate (238 mg, 94%).
LC-MS: 553.5 [M+H]+, RT 1.34 min. 1H NMR (CDC13) δ: 7.87 (s, 1H), 7.63 (s, 1H), 7.35- 7.53 (m, 10H), 6.55 (s, 1H), 5.66 (s, 2H), 5.18 (s, 2H), 4.86 (s, 2H), 3.86 (s, 3H), 3.14 (br. s, 2H), 2.73 (br. s, 2H)
Step 2: 4-Hydroxy- 10-(hydroxymethyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro- 1H- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid The product obtained in Step 1 (110 mg, 0.2 mmol) was hydrogenated in MeOH (2.0 mL) in the presence of 10% Pd/C (35 mg) using a hydrogen balloon at room temperature overnight. The catalyst was removed by filtration through Celite and washed with DMSO (2 mL). Water (4 mL) was added to the filtrate and precipitate was collected by filtration, washed with ethyl acetate and dried. The title compound was obtained as a white solid (37 mg, 50%).
LC-MS: 373.3 [M+H]+, RT 1.12 min. 1H NMR (DMSO- 6) δ: 16.22 (br. s, 1H), 13.83 (br. s, 1H), 12.99 (br. s, 1H), 7.83 (s, 1H), 7.81 (s, 1H), 6.54 (d, J=0.6 Hz, 1H), 5.37 (t, J=5.0 Hz, 1H), 4.67 (d, J=5.0 Hz, 2H), 3.81 (s, 3H), 3.53 (br. s, 1H), 3.18 (br. s, 1H), 3.06 (br. s, 1H), 1.92 (br. s, 1H)
Example 4
10-[(Dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride (Cpd 17)
Step 1: Methyl 2,4-bis(benzyloxy)-10-formyl-9-methyl-5,9-dihydro-6H- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylate
Intermediate 10 (1.67 g, 2.95 mmol) was treated with activated Mn02 (1.31 g, 15 mmol) in CH2C12 (20 mL) at room temperature overnight. The solid material was filtered and washed thoroughly with CH2CI2. The filtrate was concentrated and chromatographed (silica gel, ethyl acetate in CH2C12, 0-10 %) to provide the title intermediate (1.2 g, 72%).
LC-MS: 565.4 [M+H]+, RT 1.62 min. 1H NMR (CDC13) δ: 9.94 (s, 1H), 7.96 (s, 1H), 7.72 (s, 1H), 7.31-7.51 (m, 11H), 5.54 (s, 2H), 5.14 (s, 2H), 4.13 (s, 3H), 3.94 (s, 3H), 3.21 (br. s, 2H), 2.76 (br. s, 2H)
Step 2: 10-[(Dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
To a solution of the aldehyde obtained in Step 1 (84.6 mg, 0.15 mmol) in DCE was added dimethylamine (0.23 mL, 0.45 mmol, 2.0 M in THF), NaBH(OAc)3 (82 mg, 0.39 mmol) and one drop of acetic acid. The mixture was stirred at room temperature for 1 hr, diluted with CH2CI2 (4 mL) and neutralized with NaHC03. The organic layer was dried and loaded onto a silica column and eluted with MeOH in CH2CI2 (0-20%) to provide the reductive amination product (LC-MS: 549.5 [M+H]+, RT 1.22 min.). This intermediate was dissolved in CH2C12 (1.0 mL) and treated with TMSI (600 mg, 0.43 mL, 3.0 mmol) at room temperature for 3 days. The reaction mixture was cooled on an ice- water bath and quenched with HC1 in methanol (1.0 mL, 1.25 M) and diluted with ethyl ether (1.5 mL). The precipitate was collected by filtration and purified by reverse phase preparative HPLC (0.2% TFA in acetonitrile / 0.2% TFA in water). The HC1 salt of the title compound was obtained by treating the material obtained from HPLC purification with HC1 in ethyl ether (1.0 mL, 2.0 M) at room temperature for 3 hrs (21 mg, 32%).
LC-MS: 398.4 [M-H]+, RT 0.90 min. 1H NMR (DMSO- 6) δ: 16.18 (br. s, 1H), 13.83 (br. s, 1H), 13.01 (br. s, 1H), 10.55 (br. s, 1H), 7.94 (s, 2H), 6.96 (s, 1H), 4.60 (br. s, 2H), 3.91 (s, 3H), 3.60 (br. s, 6H, obscured by H20), 3.55 (br. s, 1H), 3.21 (br. s, 1H), 3.09 (br. s, 1H), 1.93 (br. s, 1H)
Using the procedure described for Example 4 above, additional compounds described herein may be prepared by substituting the appropriate amine for Step 2 and suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data
LC-MS: 386.3 [M+H]+, RT 0.82 min. 1H NMR (methanol-^) δ: 7.80 (s, 1H), 7.75 (s,
6
1H), 6.66 (s, 1H), 4.58 (s, 2H), 4.00 (s, 2H), 2.55 (s, 6H), 2.16 (s, 2H)
LC-MS: 398.3 [M-H]+, RT 0.91 min. 1H NMR (DMSO- 6) δ: 16.19 (br. s, 1H), 13.82 (br. s, 1H), 13.02 (br. s, 1H), 9.12 (br. s, 2H), 7.93 (s, 1H), 7.92 (s, 1H), 6.85 (s, 1H),
18
4.45 (t, J=5.4 Hz, 2H), 3.87 (s, 3H), 3.50-3.59 (m, 1H), 3.15-3.26 (m, 1H), 3.00-3.14 (m, 3H), 1.86-1.98 (m, 1H), 1.27 (t, J=7.3 Hz, 3H)
LC-MS: 426.3 [M-H]+, RT 0.94 min. 1H NMR (DMSO- 6) δ: 16.18 (br. s, 1H), 13.82 (br. s, 1H), 13.05 (br. s, 1H), 9.02 (br. s, 2H), 7.94 (s, 1H), 7.93 (s, 1H), 6.85 (s, 1H),
19
4.34-4.52 (m, 2H), 3.87 (s, 3H), 3.50-3.60 (m, 1H), 3.16-3.25 (m, 1H), 3.03-3.15 (m, 1H), 1.85-1.97 (m, 1H), 1.42 (s, 9H)
LC-MS: 410.3 [M-H]+, RT 0.92 min. 1H NMR (DMSO- 6) δ: 16.19 (br. s, 1H), 13.82 (br. s, 1H), 13.02 (br. s, 1H), 9.42 (br. s, 2H), 7.93 (s, 1H), 7.91 (s, 1H), 6.85 (s, 1H),
20 4.55 (br. s, 2H), 3.88 (s, 3H), 3.50-3.60 (m, 1H), 3.14-3.24 (m, 1H), 3.01-3.14 (m, 1H), 2.76-2.87 (m, 1H), 1.83-1.98 (m, 1H), 0.88-0.97 (m, 2H), 0.75-0.85 (m, J=6.6 Hz, 2H)
Example 5
4-Hydroxy-9-methyl- 10- { [(l-methylcyclobutyl)amino]methyl}-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid hydrochloride (Cpd 28)
Step 1: N-(2-((tert-Butyldimethylsilyloxy)methyl)- l-methyl-6,7,8,9- tetrahydrocyclohepta[f]indol-5( lH)-ylidene)- 1 -(2,4-dimethoxyphenyl)methanamine
To solution of 2-((tert-butyldimethylsilyloxy)methyl)-l-methyl-6,7,8,9- tetrahydrocyclohepta[f]indol-5(lH)-one (Intermediate 4, 7.458 g, 20.86 mmol) in CH2C12 (65 mL) was added 2,4-dimethoxybenzylamine (3.30 mL, 21.97 mmol) and NEt3 (7.80 mL, 55.96 mmol). The mixture was cooled to 0 °C before TiCl4 solution (1M CH2C12, 13.60 mL, 13.60 mmol) was added dropwise via syringe pump over 30 min. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was diluted with CH2C12 (150 mL) and then quenched with NaHC03 (aq. satd., 50 mL). Upon vigorous shaking, the organic phase was separated with a PTFE phase separator and then dried over Na2S04. Removal of the solvent afforded the product (10.6 g, quant.) as yellow oil which was taken directly into next step without purification. Step 2: Methyl 10-(((tert-butyldimethylsilyl)oxy)methyl)- l-(2,4-dimethoxybenzyl)-4- hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3- carboxylate
Crude N-(2-((tert-butyldimethylsilyloxy)methyl)- l-methyl-6,7,8,9- tetrahydrocyclohepta[f]indol-5(lH)-ylidene)-l-(2,4-dimethoxyphenyl)methanamine (10.6 g, 20.91 mmol) and trimethyl methanetricarboxylate (6.80 g, 35.76 mmol) were mixed together in Ph20 (40 mL). The stirred mixture was placed onto a pre-heated heat block at 230 °C and heated for 10 min after initial bubbling of MeOH was observed (occurs at approx. 160 °C internal reaction temperature). The reaction mixture was cooled to room temperature, loaded directly on a silica column, eluted first with hexanes to separate Ph20 and then an
EtOAc/hexanes gradient (0-80%) to yield the product as a yellow foam (7.44 g, 56% 2 steps). LC-MS: 633.5 [M+H]+, RT 1.85 min. 1H NMR (500 MHz, CDC13) 5 ppm 0.08 (s, 3H), 0.09 (s, 3H), 0.90 (s, 9H), 1.45 - 1.55 (m, IH), 1.85 - 1.95 (m, IH), 1.96 - 2.05 (m, IH), 2.32 - 2.44 (m, IH), 2.58 (dd, J=13.4, 6.1 Hz, IH), 2.96 (dd, J=13.4, 5.4 Hz, IH), 3.33 (s, 3H), 3.76 (s, 3H), 3.78 (s, 3H), 4.00 (s, 3H), 4.80 (s, 2H), 5.13 - 5.37 (m, 2H), 6.22 (d, J=2.2 Hz, IH), 6.28 (s, IH), 6.34 (dd, J=8.4, 2.2 Hz, IH), 6.81 (d, J=8.4 Hz, IH), 7.06 (s, IH), 7.32 (s, IH), 13.66 (br. s, IH)
Step 3: Methyl l-(2,4-dimethoxybenzyl)-4-hydroxy- 10-(hydroxymethyl)-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylate To a solution of methyl 10-(((tert-butyldimethylsilyl)oxy)methyl)-l-(2,4-dimethoxybenzyl)- 4-hydroxy-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3- carboxylate (7.44 g, 11.76 mmol) in THF (40 mL) was added TBAF solution (1M THF, 30.0 mL, 30.0 mmol). The reaction mixture was stirred at room temperature for 2 hrs until starting material was completely consumed. THF was concentrated and the residue was purified by column chromatography (EtOAc/CH2Cl2, 0- 100% gradient). Product was obtained as a yellow solid (5.94 g, 97 %).
LC-MS: 517.4 [M-H]+, 519.3 [M+H]+, RT 1.27 min. 1H NMR (500 MHz, CDC13) δ ppm 1.49 (td, J=13.6, 6.9 Hz, IH), 1.84 - 1.95 (m, IH), 1.96 - 2.05 (m, IH), 2.38 (td, J=12.8, 7.6 Hz, IH), 2.59 (dd, J=13.2, 6.3 Hz, IH), 2.96 (dd, J=13.2, 5.2 Hz, IH), 3.33 (s, 3H), 3.75 (s, 3H), 3.81 (s, 3H), 4.00 (s, 3H), 4.80 (s, 2H), 5.11 - 5.30 (m, 2H), 6.22 (d, J=2.5 Hz, IH), 6.32 - 6.38 (m, 2H), 6.79 (d, J=8.5 Hz, IH), 7.07 (s, IH), 7.35 (s, IH), 13.72 (br. s, IH) Step 4: l-(2,4-Dimethoxybenzyl)-4-hydroxy-10-(hydroxymethyl)-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
To suspension of methyl l-(2,4-dimethoxybenzyl)-4-hydroxy-10-(hydroxymethyl)-9-methyl- 2-oxo- 1,2,5, 6,7, 9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylate (5.94 g, 11.45 mmol) in EtOAc (50 mL) was added Lil (4.60 g, 34.37 mmol). Reaction mixture was stirred and heated at 60 °C for 1.5 hrs until complete consumption of starting material was observed. The mixture was then cooled to room temperature and acidified with aqueous HC1 (1M, 20 mL) and diluted with H20. The product was extracted with EtOAc (4x100 mL). The organic phase was washed with Na2S203 (10% aq., 40 mL) and NaCl (aq. satd., 100 mL) then dried over Na2S04. The solvent was removed to obtain a yellow solid (5.24 g, 91%).
LC-MS: 503.1 [M-H]+, 505.2 [M+H]+, RT 1.34 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.45 (td, J=13.3, 7.4 Hz, IH), 1.85 - 1.98 (m, 2H), 2.29 - 2.40 (m, IH), 2.60 - 2.70 (m, IH), 2.86 (dd, J=13.2, 5.4 Hz, IH), 3.43 (s, 3H), 3.69 (s, 3H), 3.74 (s, 3H), 4.62 (s, 2H), 5.13 - 5.33 (m, 2H), 6.31 (s, IH), 6.36 (dd, J=8.4, 2.2 Hz, IH), 6.39 (d, J=2.2 Hz, IH), 6.59 (d, J=8.4 Hz, IH), 7.35 (s, IH), 7.52 (s, IH), 13.74 (s, IH)
Step 5: l-(2,4-Dimethoxybenzyl)-10-formyl-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
To solution of l-(2,4-dimethoxybenzyl)-4-hydroxy-10-(hydroxymethyl)-9-methyl-2-oxo- l,2,5,6,7,9-hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid (5.24 g, 10.39 mmol) in CH2C12 (100 mL) was added activated Mn02 (10.0 g + 10.0 g + 5.0 g, 103 + 103 + 52 mmol) in 3 portions in 30 min intervals. The reaction was monitored by LC/MS until the starting material was completely consumed. The Mn02 was filtered off and the mixture washed with CH2C12. The mother liquor was concentrated affording the product as a dark red foam (4.30 g, 73% 3 steps) which is used without purification.
LC-MS: 501.1 [M-H]+ RT 1.47 min. 1H NMR (500 MHz, CDC13) 5 ppm 1.55 (td, J=13.6, 6.6 Hz, IH), 1.90 - 2.10 (m, 2H), 2.20 - 2.33 (m, IH), 2.64 (dd, J=13.1, 5.8 Hz, IH), 3.03 (dd, J=14.0, 5.5 Hz, IH), 3.35 (s, 3H), 3.77 (s, 3H), 4.13 (s, 3H), 5.19 (d, J=15.4 Hz, IH), 5.39 (d, J=15.4 Hz, IH), 6.26 (s, IH), 6.33 (d, J=8.2 Hz, IH), 6.66 (d, J=8.2 Hz, IH), 7.20 (s, 2H), 7.56 (s, IH), 9.90 (s, IH), 13.97 (s, IH), 15.93 (s, IH) Steps 6-7: 4-Hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-l,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride To a solution of l-(2,4-dimethoxybenzyl)- 10-formyl-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid (100 mg, 0.20 mmol) in dichloroethane (2 mL) was added 1-methylcyclobutan- l -amine (45 μί, 0.40 mmol, 2 eq), followed by AcOH (23 μί, 0.40 mmol, 2 eq). The mixture was stirred at room temperature for 10 min and NaBH(OAc)3 (72 mg, 0.34 mmol, 1.7 eq) was added. The reaction was stirred at room temperature for 4-5 hrs and monitored by LC/MS until the starting aldehyde was completely consumed. The dichloroethane was concentrated and the residue dissolved in MeOH (5 mL) and several drops of TFA to generate a homogeneous mixture that was filtered through a PTFE filter and purified directly by preparative HPLC. The product was obtained as a TFA salt and was taken directly into the DMB group deprotection step.
To the reductive amination product (100.9 mg) obtained above was added i-Pr3SiH (1.0 mL) followed by TFA (1.0 mL). The mixture was heated at 60 °C for 2 hrs and
monitored by LC/MS until the starting material was completely consumed. The TFA was concentrated under reduced pressure and an HC1 solution (2M Et20, 1.0 mL) was added to the oily residue to obtain a precipitate. The mixture was diluted with Et20, and the solid was filtered and washed well with Et20 (4 x 5 mL) to obtain the title compound as a pale yellow solid (52.8 mg, 58% overall) HC1 salt.
LC-MS: 420.3 [M-H]+, 422.2 [M+H]+, RT 0.99 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.61 (s, 3H), 1.77 - 2.00 (m, 4H), 2.09 (quin, J=6.6 Hz, 2H), 2.51 - 2.57 (m, 2H), 2.71 (br. s, 2H), 3.29 - 3.37 (m, 2H), 3.86 (s, 3H), 4.30 (br. s, 2H), 6.82 (s, 1H), 7.55 (s, 1H), 7.81 (s, 1H), 9.59 (br. s, 2H), 12.91 (br. s, 1H), 13.84 (br. s, 1H), 16.37 (br. s, 1H)
Using the procedure described for Example 5 above, additional compounds described herein may be prepared by substituting the appropriate amine for Steps 6-7 and suitable reagents and reaction conditions, obtaining compounds such as those selected from:
Cpd Data
LC-MS: 394.2 [M-H]+, 396.2 [M+H]+, RT 0.94 min. lH NMR (500 MHz, DMSO- 6) δ ppm 1.32 (t, J=7.3 Hz, 3H), 2.09 (quin, J=6.4 Hz, 2H), 2.66 - 2.77 (m, 5H), 3.08 -
27 3.20 (m, 1H), 3.21 - 3.33 (m, 1H), 3.33 - 3.48 (m, 2H), 3.89 (s, 3H), 4.36 - 4.55 (m, 1H), 4.61 - 4.71 (m, 1H), 6.92 (s, 1H), 7.56 (s, 1H), 7.83 (s, 1H), 12.89 (br. s, 1H), 13.85 (s, 1H) Cpd Data
LC-MS: 420.3 [M-H]+, 422.2 [M+H]+, RT 0.97 min. lH NMR (500 MHz, DMSO- 6) δ ppm 1.44 (d, J=6.4 Hz, 3H), 1.62 - 1.78 (m, 1H), 1.83 - 2.04 (m, 2H), 2.09 (quin, J=6.6 Hz, 2H), 2.19 - 2.31 (m, 1H), 2.71 (br. s, 1H), 3.17 - 3.30 (m, 1H), 3.31 - 3.46
29
(m, 4H), 3.50 - 3.64 (m, 1H), 3.91 (s, 3H), 4.49 (dd, J=14.2, 6.0 Hz, 1H), 4.78 (d, J=14.2 Hz, 1H), 6.93 (s, 1H), 7.56 (s, 1H), 7.82 (s, 1H), 12.88 (br. s, 1H), 13.85 (s, 1H)
LC-MS: 434.1 [M-H]+, 436.2 [M+H]+, RT 0.90 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.13 (s, 3H), 1.17 (s, 3H), 1.44 - 1.46 (m, 1H), 1.76 - 1.85 (m, 1H), 1.86 - 1.99
30 (m, 1H), 2.01 - 2.23 (m, 2H), 2.45 - 2.55 (m, 2H), 2.70 (br. s, 2H), 3.01 (br. s, 1H), 3.26 (br. s, 1H), 3.58 (br. s, 1H), 3.89 (s, 3H), 4.66 (br. s, 2H), 6.94 (s, 1H), 7.55 (s, 1H), 7.82 (s, 1H), 10.90 (br. s, 1H), 12.88 (br. s, 1H), 13.85 (s, 1H)
LC-MS: 434.1 [M-H]+, 436.2 [M+H]+, RT 0.95 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.37 (s, 3H), 1.63 (s, 3H), 1.74 - 1.91 (m, 1H), 1.93 - 2.06 (m, 3H), 2.06 - 2.22
31 (m, 2H), 2.45 - 2.55 (m, 2H), 2.71 (br. s, 2H), 3.30 - 3.53 (m, 2H), 3.88 (s, 3H), 4.31 (dd, J=14.5, 9.1 Hz, 1H), 4.75 (d, J=14.5 Hz, 1H), 6.88 (s, 1H), 7.57 (s, 1H), 7.82 (s, 1H), 9.93 (br. s, 1H), 12.89 (s, 1H), 13.85 (s, 1H)
Using the procedure described for Example 5 above, additional compounds described herein may be prepared by using the indicated intermediate ketone in Steps 1-7 and suitable reagents and reaction conditions, obtaining compounds such as those selected from:
Cpd Materials and Data
Intermediate 6: LC-MS: 424.3 [M-H]+, 426.3 [M+H]+, RT 0.98 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 0.94 (t, J=7.4 Hz, 3H), 1.37 (s, 6H), 1.79 (q, J=7.6 Hz, 2H),
1 2.61 (t, J=6.5 Hz, 2H), 3.82 (s, 3H), 4.39 (br. s, 2H), 4.44 (t, J=6.5 Hz, 2H), 5.76 (s, 1H), 6.84 (s, 1H), 7.44 (s, 1H), 7.86 (s, 1H), 9.06 (br. s, 2H), 13.06 (br. s, 1H), 13.87 (br. s, 1H)
Intermediate 6: LC-MS: 394.0 [M-H]+, 396.0 [M+H]+, RT 0.89 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 2.61 (t, J=6.5 Hz, 2H), 3.69 (br. s, 2H), 3.81 (s, 3H), 4.39 (br.
2 s, 2H), 4.44 (t, J=6.5 Hz, 2H), 5.42 - 5.48 (m, 1H), 5.48 - 5.55 (m, 1H), 5.89 - 6.05 (m, 1H), 6.82 (s, 1H), 7.43 (s, 1H), 7.85 (s, 1H), 9.42 (br. s, 2H), 13.04 (br. s, 1H), 13.86 (br. s, 1H) Cpd Materials and Data
Intermediate 7: LC-MS: 396.4 [M-H]+, RT 0.83 min. lH NMR (500 MHz, DMSO- 6) δ ppm 1.27 (t, J=7.2 Hz, 3H), 1.32 (d, J=6.2 Hz, 3H), 2.36 (dd, J=14.6, 6.1 Hz, IH),
7 2.64 (dd, J=14.6, 5.4 Hz, IH), 2.96 - 3.15 (m, 2H), 3.82 (s, 3H), 4.41 (br. s, 2H), 4.70 - 4.80 (m, IH), 6.81 (s, IH), 7.38 (s, IH), 7.86 (s, IH), 9.15 (br. s, 2H), 12.89 - 13.12 (m, IH), 13.85 (s, IH)
Intermediate 7: LC-MS: 396.4 [M-H]+, RT 0.82 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.33 (d, J=6.2 Hz, 3H), 2.38 (dd, J=14.7, 5.8 Hz, IH), 2.65 (dd, J=14.7, 4.9 Hz,
8
IH), 2.80 (br. s, 6H), 3.86 (s, 3H), 4.57 (br. s, 2H), 4.70 - 4.82 (m, IH), 6.91 (s, IH), 7.39 (s, IH), 7.89 (s, IH), 13.02 (br. s, IH), 13.86 (s, IH)
Intermediate 7: LC-MS: 424.4 [M-H]+, RT 0.87 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 0.94 (t, J=7.4 Hz, 3H), 1.32 (d, J=5.4 Hz, 3H), 1.33 (d, J=6.0 Hz, 3H), 1.50 - 1.65 (m, IH), 1.83 - 2.00 (m, IH), 2.36 (dd, J=14.5, 5.8 Hz, IH), 2.64 (dd, J=14.5, 5.0
9
Hz, IH), 3.24 (br. s, IH), 3.83 (s, 3H), 4.42 (br. s, 2H), 4.70 - 4.80 (m, IH), 6.85 (s, IH), 7.38 (s, IH), 7.86 (s, IH), 9.18 (br. s, IH), 9.27 (br. s, IH), 13.03 (br. s, IH), 13.85 (s, IH)
Intermediate 7: LC-MS: 422.4 [M-H]+, RT 0.87 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.32 (d, J=6.2 Hz, 3H), 1.70 - 1.90 (m, 2H), 2.14 - 2.32 (m, 4H), 2.36 (dd,
10 J=14.6, 6.0 Hz, IH), 2.64 (dd, J=14.6, 5.0 Hz, IH), 3.75 - 3.80 (m, IH), 3.82 (s, 3H), 4.30 (br. s, 2H), 4.69 - 4.81 (m, IH), 6.81 (s, IH), 7.38 (s, IH), 7.85 (s, IH), 9.52 (br. s, 2H), 13.02 (br. s, IH), 13.85 (br. s, IH)
Intermediate 7: LC-MS: 422.5 [M-H]+, RT 0.86 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 0.69 - 0.76 (m, 2H), 1.13 - 1.20 (m, 2H), 1.32 (d, J=6.2 Hz, 3H), 1.52 (s, 3H),
11 2.36 (dd, J=14.7, 6.2 Hz, IH), 2.64 (dd, J=14.7, 5.1 Hz, IH), 3.83 (s, 3H), 4.51 (br. s,
2H), 4.71 - 4.80 (m, IH), 6.82 (s, IH), 7.38 (s, IH), 7.86 (s, IH), 9.49 (br. s, 2H), 13.02 (br. s, IH), 13.85 (br. s, IH)
Intermediate 6: LC-MS: 422.4 [M-H]+, RT 0.51 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.60 (s, 3H), 1.80 - 2.00 (m, 6H), 2.58 - 2.66 (m, 2H), 3.84 (s, 3H), 4.28 (t,
12
J=5.48 Hz, 2H), 4.44 (t, J=6.42 Hz, 2H), 6.84 (s, IH), 7.43 (s, IH), 7.85 (s, IH), 9.68 (br. s, 2H), 13.05 (br. s, IH), 13.86 (br. s, IH) Cpd Materials and Data
Intermediate 6: LC-MS: 354.3 [M-H]+, 356.4 [M+H]+, RT 0.84 min. lH NMR (500 MHz, DMSO- ) δ ppm 2.61 (t, J=6.3 Hz, 2H), 3.78 (s, 3H), 4.27 - 4.35 (m, 2H), 4.44
15
(t, J=6.3 Hz, 2H), 6.70 (s, IH), 7.42 (s, IH), 7.83 (s, IH), 8.46 (br. s, 3H), 13.04 (br. s, IH), 13.85 (br. s, IH)
Intermediate 8: LC-MS: 426.5 [M+H]+ , RT 0.56 min. 1H NMR (500 MHz, DMSO- d6) δ ppm 0.94 (t, J=7.49 Hz, 3H), 1.32 (d, J=6.46 Hz, 3H), 1.49 - 1.60 (m, IH), 1.66 -
26 1.86 (m, 4H), 1.90 (ddd, J=13.46, 7.70, 3.74 Hz, IH), 2.98 (dd, J=12.93, 7.25 Hz, IH), 3.81 (s, 3H), 3.89 - 3.98 (m, IH), 4.44 (br. s, 2H), 4.66 (dd, J=11.23, 4.77 Hz, IH), 6.77 (s, IH), 7.47 (s, IH), 7.72 (s, IH), 12.87 (s, IH), 13.89 (s, IH)
Intermediate 8: LC-MS: 438.4 [M+H]+, RT 0.55 min. 1H NMR (500 MHz, DMSO- 6) δ ρρηι 1.60 (s, 3H), 1.70 - 1.78 (m, 3H), 1.80 - 1.89 (m, 3H), 1.90 - 1.97 (m, 3H), 2.97
32 (dd, J=12.77, 7.25 Hz, IH), 3.84 (s, 3H), 3.89 - 3.99 (m, IH), 4.29 (t, J=6.23 Hz, 2H), 4.66 (dd, J=11.23, 5.00 Hz, IH), 6.80 (s, IH), 7.47 (s, IH), 7.71 (s, IH), 9.59 (br. s, IH), 9.64 (br. s, IH), 12.88 (s, IH), 13.90 (s, IH)
Intermediate 3: LC-MS: 366.1 [M-H]+, 368.1 [M+H]+, RT 1.12 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.27 (t, J=7.3 Hz, 3H), 2.68 (dd, J=8.2, 6.2 Hz, 2H), 2.98 (t,
37
J=7.2 Hz, 2H), 3.02 - 3.13 (m, 2H), 3.82 (s, 3H), 4.41 (br. s, 2H), 6.79 (s, IH), 7.54 (s, IH), 8.34 (s, IH), 9.15 (br. s, 2H), 12.72 (br. s, IH), 13.66 (br. s, IH)
Intermediate 3: LC-MS: 380.1 [M-H]+, 382.1 [M+H]+, RT 1.13 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 0.93 (t, J=7.4 Hz, 3H), 1.70 (sextet, J=7.6 Hz, 2H), 2.65 -
38
2.71 (m, 2H), 2.92 - 3.02 (m, 4H), 3.82 (s, 3H), 4.41 (br. s, 2H), 6.80 (s, IH), 7.54 (s, IH), 8.34 (s, IH), 9.18 (br. s, 2H), 12.72 (br. s, IH), 13.66 (br. s, IH)
Intermediate 3: LC-MS: 392.1 [M-H]+, 394.1 [M+H]+, RT 1.13 min. 1H NMR (500 MHz, DMSO- ) δ ρρηι 0.70 - 0.76 (m, 2H), 1.12 - 1.17 (m, 2H), 1.52 (s, 3H), 2.68
39
(dd, J=8.3, 6.3 Hz, 2H), 2.98 (t, J=7.2 Hz, 2H), 3.83 (s, 3H), 4.51 (br. s, 2H), 6.78 (s, IH), 7.55 (s, IH), 8.34 (s, IH), 12.72 (br. s, IH)
Intermediate 3: LC-MS: 406.1 [M-H]+, 408.1 [M+H]+, RT 1.14 min. 1H NMR (500 MHz, DMSO- ) δ ppm 1.60 (s, 3H), 1.77 - 2.00 (m, 4H), 2.44 - 2.50 (m, 2H), 2.68
40
(dd, J=8.3, 6.3 Hz, 2H), 2.98 (t, J=7.1 Hz, 2H), 3.83 (s, 3H), 4.31 (br. s, 2H), 6.79 (s, IH), 7.55 (s, IH), 8.34 (s, IH), 9.45 (br. s, 2H), 12.73 (br. s, IH) Cpd Materials and Data
Intermediate 3: LC-MS: 366.1 [M-H]+, RT 1.11 min. lH NMR (500 MHz, DMSO- 6) δ ppm 2.68 (dd, J=8.3, 6.2 Hz, 2H), 2.79 (s, 6H), 2.98 (t, J=7.1 Hz, 2H), 3.86 (s, 3H),
41
4.56 (s, 2H), 6.88 (s, 1H), 7.55 (s, 1H), 8.36 (s, 1H), 10.57 (br. s, 1H), 12.73 (br. s, 1H), 13.66 (s, 1H)
Intermediate 3: LC-MS: 392.1 [M-H]+, RT 1.12 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.86 - 1.97 (m, 2H), 2.00 - 2.09 (m, 2H), 2.68 (dd, J=8.3, 6.2 Hz, 2H), 2.98 (t,
42
J=7.1 Hz, 2H), 3.12 - 3.24 (m, 2H), 3.42 - 3.53 (m, 2H), 3.86 (s, 3H), 4.63 (br. s, 2H), 6.89 (s, 1H), 7.54 (s, 1H), 8.35 (s, 1H), 12.73 (br. s, 1H), 13.66 (s, 1H)
Intermediate 3: LC-MS: 380.1 [M-H]+, RT 1.13 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.35 (d, J=6.5 Hz, 6H), 2.68 (dd, J=8.3, 6.2 Hz, 2H), 2.98 (t, J=7.1 Hz, 2H),
43
3.41 - 3.51 (m, 1H), 3.83 (s, 3H), 4.41 (br. s, 2H), 6.79 (s, 1H), 7.54 (s, 1H), 8.34 (s, 1H), 9.14 (br. s, 2H), 12.73 (br. s, 1H), 13.66 (br. s, 1H)
Intermediate 3: LC-MS: 392.1 [M-H]+, 394.1 [M+H]+, RT 1.13 min. 1H NMR (500 MHz, DMSO- ) ppm 1.71 - 1.90 (m, 2H), 2.11 - 2.31 (m, 4H), 2.68 (dd, J=8.3, 6.2
44 Hz, 2H), 2.98 (t, J=7.1 Hz, 2H), 3.74 - 3.81 (m, 1H), 3.82 (s, 3H), 4.30 (br. s, 2H), 6.78 (s, 1H), 7.54 (s, 1H), 8.34 (s, 1H), 9.52 (br. s, 2H), 12.72 (br. s, 1H), 13.66 (br. s, 1H)
Example 6
9-(Dimethylamino)-4-hydroxy-2-oxo- l,2,5,7-tetrahydro[2]benzoxepino[5,4-b]pyridine-3- carboxylic acid (Cpd 47)
Step 1 : Benzyl 2,4-bis(benzyloxy)-9-(dimethylamino)-5,7-dihydrobenzo[5,6]oxepino[4,3- b]pyridine-3-carboxylate
Benzyl 9-amino-2,4-bis(benzyloxy)-5,7-dihydrobenzo[5,6]oxepino[4,3-b]pyridine-3- carboxylate (Intermediate 16, 50 mg, 0.09 mmol) was dissolved in a mixture of CH2CI2 (400 μν> and 37% aqueous formaldehyde (200 μί). NaBH(OAc)3 was added in 15 small portions over a period of 2 hrs. The reaction mixture was then partitioned between aqueous K2C03 and CH2CI2. The organic layer was dried over MgS04j filtered, and concentrated under vacuum. Purification by silica gel chromatography (0-2% EtOAc in CH2CI2) yielded the title compound (35 mg, 66%) as a white solid. 1H NMR (acetone- 6): δ 3.09 (s, 6H), 4.35 (s, 2H), 4.42 (s, 2H), 5.21 (s, 2H), 5.37 (s, 2H), 5.59 (s, 2H), 6.87 (d, J = 2.5 Hz, 1H), 6.93 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 7.3-7.55 (m, 15H), 7.86 (d, J = 8.5 Hz, 1H)
Step 2: 9-(Dimethylamino)-4-hydroxy-2-oxo-l,2,5,7-tetrahydro[2]benzoxepino[5,4- b]pyridine-3-carboxylic acid
The product obtained in Step 1 (33 mg, 0.056 mmol) was combined with 1: 1 CH2Cl2/MeOH (1 mL) and Pd/C (10%, 25 mg). The mixture was hydrogenated at 1 atm of H2 for 3 hrs, then diluted with 1: 1 CH2Cl2/MeOH (200 mL) and filtered through Celite. The filtrate was concentrated under vacuum and triturated with 4: 1 CH2Cl2/MeOH to yield the title compound (13 mg, 73%) as a yellow solid.
LC-MS: 317.1[M+H]+, RT 0.70 min. 1H NMR (DMSO- 6): δ 3.04 (s, 6H), 4.13 (s, 2H), 4.35 (s, 2H), 6.84 (dd, J = 8.5 Hz, 3 Hz, 1H), 6.90 (d, J = 3 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H)
Example 7
9-[(3S)-3-(Dimethylamino)pyrrolidin-l-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid hydrochloride (Cpd 45)
Step 1: Benzyl 2,4-bis(benzyloxy)-9-bromo-5,7-dihydrobenzo[5,6]oxepino[4,3-b]pyridine-3- carboxylate
Isoamyl nitrite (80 μΐ,, 0.68 mmol), CuBr2 (60mg, 0.27 mmol) and CH3CN (1.2 mL) were heated at 80 °C. A solution of benzyl 9-amino-2,4-bis(benzyloxy)-5,7- dihydrobenzo[5,6]oxepino[4,3-b]pyridine-3-carboxylate (Intermediate 16, 100 mg, 0.18 mmol) in CH CN (1.2 mL) was added dropwise to the heated solution. Heating was continued for an additional 10 min after the addition was complete. The reaction mixture was partitioned between EtOAc and H20 and the phases were separated. The organic layer was dried over MgS04, filtered, and concentrated under vacuum. Purification by silica gel chromatography (50-100% CH2C12 in hexanes) followed by hexane trituration yielded the title compound (41 mg, 37%) as a white solid.
1H NMR (acetone- 6): δ 4.36 (s, 2H), 4.46 (s, 2H), 5.22 (s, 2H), 5.40 (s, 2H), 5.59 (s, 2H), 7.3-7.55 (m, 15H), 7.78 (d, J = 2.5 Hz, 1H), 7.82 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H) Step 2: 9-[(3S)-3-(Dimethylamino)pyrrolidin-l-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid Benzyl 2,4-bis(benzyloxy)-9-bromo-5,7-dihydrobenzo[5,6]oxepino[4,3-b]pyridine-3- carboxylate (60 mg, 0.096 mmol), (S)-N,N-dimethylpyrrolidin-3-amine (21 μί, 0.16 mmol), S-Phos ligand (15 mg, 0.036 mmol, Pd2dba3 (15 mg, 0.016 mmol), Cs2C03 (78 mg, 0.24 mmol), and DME (0.5 mL) were heated under an argon atmosphere at 80° C for 15 hrs. The reaction mixture was diluted in CH2Cl2/MeOH and was filtered. The filtrate was concentrated under vacuum. Purification by silica gel chromatography (20% EtOAc in CH2C12, followed by 5-10% MeOH in CH2C12), followed by trituration of the resultant intermediate with 1: 1 hexanes/ether, yielded the crude mono-debenzylated amine product (48 mg).
The resulting crude product was dissolved in 1: 1 CH2Cl2/MeOH (1 mL) and Pd/C (10%, 52 mg) was added. The mixture was hydrogenated at 1 atm of H2 for 30 minutes, then diluted in CH2Cl2/MeOH (1: 1, 100 mL) and was filtered through Celite. Ethereal HC1 was added to the filtrate. The filtrate was concentrated under vacuum to yield the title compound (20 mg, 50% over 2 steps) as a light tan solid hydrochloride salt.
LC-MS: 384.3[M-H]+, RT 0.76 min. 1H NMR (DMSO- 6): δ 2.25 (m, 1H), 2.88 (s, 6H), 2.50 (m, 1H, obscured by DMSO), 3.60 (m, 2H, obscured by H20), 3.78 (m, 2H), 4.03 (m, 1H), 4.16 (m, 2H), 4.36 (s, 2H), 6.80 (m, 2H), 7.61 (d, J = 8.5 Hz, 1H)
Example 7a
9-[(lR,5S,6s)-6-Amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-l,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid hydrochloride (Cpd 46) Compound 46 was prepared according to procedures for Example 7, utilizing (lR,5S,6s)- N,N-dibenzyl-3-azabicyclo[3.1.0]hexan-6-amine in the Pd-catalyzed coupling step.
LC-MS: 368.3[M-H]+, RT 0.75 min. 1H NMR (DMSO- 6): δ 1.71 (s, 2H), 2.00 (s, 1H), 2.96 (m, 2H), 3.22 (d, J = 10 Hz, 2H), 3.67 (s, 2H), 3.89 (s, 2H), 6.29 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 6.34 (d, J = 2.5 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H) Example 8
10-[(lR,5S,6s)-6-Amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-2,5,6,7-tetrahydro- lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid hydrochloride (Cpd 4)
Step 1: Methyl 10-chloro-l-(2,4-dimethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylate 3-Chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (580 mg, 3 mmol), CH2C12 (11 mL), Et3N (1.25 mL, 9mmol) and 2,4-dimethoxybenzylamine (530 μί, 3.5 mmol) were stirred at 0° C. A solution of TiCl4 (190 μΐ,, 1M in CH2C12, 0.19 mmol) was added via syringe dropwise. The mixture was stirred at room temperature for 15 hrs, then the reaction was quenched with aqueous NaHC03. The mixture was then partitioned between ether and H20. The organic layer was dried over MgS04, filtered, and concentrated under vacuum to obtain 937 mg of crude imine.
The crude imine was combined with diphenyl ether (5 mL) and trimethyl
methanetricarboxylate (1.07 g, 5.63 mmol). The reaction was stirred in a pre-heated 190° C bath for 1 hr. After cooling to room temperature, the mixture was purified by silica gel chromatography (5-50% EtOAc in hexanes). Trituration with acetone yielded the title compound (620 mg, 49%) as an off-white solid.
1H NMR (acetone- d6): δ 1.45 (m, 1H), 1.85-2.05 (m, 2H), 2.26 (m, 1H), 2.53 (dd, J = 13 Hz, 6 Hz, 1H), 2.96 (dd, J = 14 Hz, 6 Hz, 1H), 3.61 (s, 3H), 3.75 (s, 3H), 3.94 (s, 3H), 5.05 (d, J = 16 Hz, 1H), 5.28 (d, J = 16 Hz, 1H), 6.41 (m, 2H), 6.81 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.37 (m, 1H), 7.41 (dd, J = 8 Hz, 2.5 Hz, 1H), 13.83 (s, 1H) Step 2: Methyl 10-((lR,5S,6s)-6-(dibenzylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-l-(2,4- dimethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2- b]pyridine-3-carboxylate
The product of the Step 1 (200 mg, 0.42 mmol), (lR,5S,6s)-N,N-dibenzyl-3- azabicyclo[3.1.0]hexan-6-amine (142 mg, 0.5 mmol), S-Phos ligand (32 mg, 0.078 mmol), Pd(OAc)2 (12 mg, 0.054 mmol), Cs2C03 (380 mg, 1.16 mmol), and dioxane (2.6 mL) were heated under argon at 100° C for 15 hrs. The reaction mixture was partitioned between aqueous NH4C1 and CH2C12. The organic layer was dried over MgS04, filtered, and concentrated under vacuum. Purification by silica gel chromatography (50% EtOAc in hexanes), followed by ether trituration, yielded the title compound (107 mg, 36%), as a white solid contaminated with 15% unreacted starting material (as indicated by LC/MS).
Step 3: 10-[(lR,5S,6s)-6-Amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-2,5,6,7- tetrahydro- lH-benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid
The crude product obtained in Step 2 (160 mg, 0.22 mmol), Lil (90 mg, 0.67 mmol), and EtOAc (0.75 mL) were heated at 60° C under argon for 1 hr. The reaction mixture was partitioned between aqueous HC1 and CH2Cl2/EtOH. The organic layer was dried over
MgS04, filtered, and concentrated under vacuum. Purification by silica gel chromatography (30% EtOAc in hexanes) yielded crude carboxylic acid (85 mg, 53%). The acid intermediate was mixed with Pd(OH)2/C (20%, 50 mg) and 1: 1:2
EtOAc/MeOH/ CH2C12 (1.2 mL), and was hydrogenated at 1 atm of H2 for 2 days. The reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum. Purification by silica gel chromatography (5-20% MeOH in CH2C12, with 2% NH4OH modifier), yielded 22 mg of crude de-benzylated intermediate (38%)
The above intermediate was treated with TFA (0.5 mL) and TIPSH (0.5 mL) at 50° C for 2 hrs. The volatiles were removed with a N2 stream. The solids were washed with EtOAc. The crude product was dissolved in MeOH and was filtered to remove black insoluble impurities. The filtrate was concentrated with a N2 stream to obtain the title compound (12 mg, 12% yield over 3 steps) as a yellow solid.
LC-MS: 368.3 [M+H]+, RT 0.89 min. 1H NMR (methanol-^): δ 2.08-2.23 (m, 4H), 2.50 (m, 2H), 2.55 (s, 1H), 3.30 (m, 4H, obscured by CD3OH), 3.76 (d, J = 11 Hz, 2H), 6.74 (m, 2H), 7.19 (m, 1H)
Example 9
10-[(Dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride (Cpd 54)
Step 1: Benzyl 2,4-bis(benzyloxy)-5-(3-(6-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-3- methyl-lH-indol-5-yl)propyl)-6-chloronicotinate
To a solution of benzyl 5-allyl-2,4-bis(benzyloxy)-6-chloronicotinate (Intermediate 17, 0.85 g, 1.7 mmol) in THF (10 mL) at 0 °C was added a solution of 9-borabicyclo(3.3.1)nonane in THF (6.8 mL, 3.4 mmol). The mixture was allowed to warm to room temperature with stirring for 1 hr. To the mixture was added aqueous 1 M K2C03 (5 mL), 6-bromo-2-(((tert- butyldimethylsilyl)oxy)methyl)-5-iodo-3-methyl-lH-indole (Intermediate 19, 0.72 g, 1.5 mmol), and Pd(dppf)Cl2 (60 mg, 0.075 mmol). The mixture was stirred vigorously for 2 hrs at 60 °C, and then partitioned in EtOAc (100 mL) and H20 (100 mL). The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The residue was chromato graphed on silica gel, eluting 0-15% EtOAc in hexanes to provide 910 mg of colorless oil (71%).
1H NMR (500 MHz, DMSO- 6) 5 ppm 0.05 (s, 6H), 0.86 (s, 9H), 1.73 (m, 2H), 2.17 (s, 3H), 2.66 (m, 2H), 2.73 (m, 2H), 4.74 (s, 2H), 4.95 (s, 2H), 5.33 (s, 2H), 5.35 (s, 2H), 7.23-7.39 (m, 16H), 7.46 (s, 1H), 10.77 (br. s, 1H) Step 2: Benzyl 2,4-bis(benzyloxy)-5-(3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-6- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indol-5-yl)propyl)-6-chloronicotinate
A mixture of benzyl 2,4-bis(benzyloxy)-5-(3-(6-bromo-2-(((tert- butyldimethylsilyl)oxy)methyl)-3-methyl- lH-indol-5-yl)propyl)-6-chloronicotinate (0.91 g, 1.06 mmol), bis(pinacolato)diboron (0.40 g, 1.6 mmol), KOAc (0.21 g, 2.1 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (40 mg, 0.05 mmol) in 1,4-dioxane (6 mL) was stirred under nitrogen at 100 °C for 4 hrs, and then was partitioned in EtOAc (50 mL) and H20 (50 mL). The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-20% EtOAc in hexanes to provide 400 mg of a colorless oil (42%).
1H NMR (500 MHz, DMSO- 6) δ ρρηι 0.05 (s, 6H), 0.87 (s, 9H), 1.21 (s, 12H), 1.72 (m, 2H), 2.17 (s, 3H), 2.63 (m, 2H), 2.90 (m, 2H), 4.77 (s, 2H), 4.92 (s, 2H), 5.32 (s, 2H), 5.34 (s, 2H), 7.13 (s, 1H), 7.18-7.38 (m, 15H), 7.68 (s, 1H), 10.66 (br. s, 1H)
Step 3: Benzyl 2,4-bis(benzyloxy)-10-(((tert-butyldimethylsilyl)oxy)methyl)-9-methyl- 5,6,7,1 l-tetrahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylate
A mixture of benzyl 2,4-bis(benzyloxy)-5-(3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-3- methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indol-5-yl)propyl)-6- chloronicotinate (400 mg, 0.44 mmol), tri-tert-butylphosphonium tetrafluoroborate (26 mg, 0.09 mmol), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.02 mmol), aqueous 1 M K2C03 (2 mL) and 1,4-dioxane (4 mL) was stirred under an argon atmosphere for 6 hrs at 90 °C. The mixture was partitioned in EtOAc (40 mL) and H20 (40 mL). The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The residue was
chromatographed on silica gel, eluting with 0-15% EtOAc in hexanes to provide 190 mg of colorless oil (58%).
LC-MS: 740.0 [M+H]+, RT 1.38 min (non-polar method).
Step 4: Benzyl 2,4-bis(benzyloxy)-10-formyl-9-methyl-5,6,7,l l- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylate
To a solution of benzyl 2,4-bis(benzyloxy)-10-(((tert-butyldimethylsilyl)oxy)methyl)-9- methyl-5,6,7,1 l-tetrahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylate (190 mg, 0.26 mmol) in THF (1.5 mL) was added a solution of tetrabutylammonium fluoride in THF (0.5 mL, 0.5 mmol). The mixture was stirred for 20 min, and then concentrated. The residue was passed through a pad of silica gel, eluting with 50% EtOAc in hexanes. The intermediate (110 mg, 0.18 mmol) was dissolved in CH2C12 (2 mL). Manganese dioxide (230 mg, 2.6 mmol) was added to the mixture. The mixture stirred at room temperature overnight, before being filtered over Celite. The filtrate was concentrated and chromato graphed on silica gel, eluting with 0-20% EtOAc in hexanes to provide 75 mg of white powder (46%).
LC-MS: 623.7 [M+H]+, RT 1.75 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 2.07 (m, 2H), 2.40 (m, 2H), 2.61 (m, 2H), 2.64 (s, 3H), 5.03 (s, 2H), 5.35 (s, 2H), 5.49 (s, 2H), 7.29-7.47 (m, 15H), 7.65 (s, 1H), 7.70 (s, 1H), 10.08 (s, 1H), 11.73 (s, 1H)
Step 5: Benzyl 2,4-bis(benzyloxy)-10-((dimethylamino)methyl)-9-methyl-5,6,7,l 1- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylate
A mixture of benzyl 2,4-bis(benzyloxy)-10-formyl-9-methyl-5,6,7,l l- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylate (25 mg, 0.04 mmol), dimethylamine hydrochloride (13 mg, 0.16 mmol), AcOH (10 μΐ, 0.16 mmol) and trimethylamine (22 μί, 0.16 mmol) in 1,2-dichloroethane (1 mL) was stirred at room temperature for 1 hr. To the mixture was added sodium triacetoxyborohydride (34 mg, 0.16 mmol). The mixture stirred at room temperature for 1 hr. The mixture was washed with aqueous 1 M K2C03 (1 mL). The organic layer was loaded directly onto silica gel, eluting with 0-10% MeOH in 9: 1 CH2Cl2:EtOAc to provide 18 mg of product (69%).
LC-MS: 652.9 [M+H]+, RT 0.79 min (non-polar method). Step 6: 10-[(Dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-l,2,5, 6,7,11- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-f] indole-3 -carboxylic acid hydrochloride
A mixture of benzyl 2,4-bis(benzyloxy)-10-((dimethylamino)methyl)-9-methyl-5,6,7,l l- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylate (18 mg, 0.028 mmol), 10% Pd/C (4 mg), 1 mL of MeOH and 0.1 mL of 1 M HCl in MeOH was stirred under H2 (1 atm) for 30 min. The mixture was filtered, washing the solid with 1: 1 CH2Cl2:MeOH several times. The combined organics were concentrated, giving the title compound (9 mg) as an off- white powder (85%).
LC-MS: 382.3 [M+H]+, RT 0.94 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 2.08 (m, 2H), 2.36 (s, 3H), 2.60-2.74 (4H), 2.78 (s, 6H), 4.46 (s, 2H), 7.55 (s, 1H), 7.63 (s, 1H), 10.33 (br. s, 1H), 11.39 (s, 1H), 12.94 (br. s, 1H), 13.85 (s, 1H) Using the procedure described for Example 9 above, additional compounds described herein may be prepared by substituting the appropriate amine for Steps 5-6 and suitable reagents and reaction conditions, obtaining compounds such as those selected from:
Figure imgf000175_0001
Example 9a l l-[(Dimethylamino)methyl]-4-hydroxy-10-methyl-2-oxo-2,5,6,7,8,12-hexahydro-lH- pyrido[2',3':3,4]cycloocta[l,2-f]indole-3-carboxylic acid hydrochloride (Cpd 59)
Compound 59 was prepared following procedures for Example 9: Benzyl 2,4-bis(benzyloxy)-
5-(but-3-en-l-yl)-6-chloronicotinate (Intermediate 18, 0.77 g, 1.5 mmol) and 6-bromo-2- (((tert-butyldimethylsilyl)oxy)methyl)-5-iodo-3-methyl-lH-indole (Intermediate 19, 0.72 g, 1.25 mmol) yielded the title compound (7 mg) over 6 steps.
LC-MS: 396.2 [M+H]+, RT 1.00 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.42 (m, 2H), 1.53 (m, IH), 1.91 (m, IH), 2.11 (m, IH), 2.31 (m, IH), 2.36 (s, 3H), 2.76-2.84 (7H), 2.96 (m, IH), 4.46 (m, 2H), 7.47 (s, IH), 7.57 (s, IH), 10.17 (br. s, IH), 11.22 (s, IH), 12.80 (br. s, IH), 13.93 (s, IH)
Example 10
4-Hydroxy-2-oxo- 1,5,7,9, 10, l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3-f|indole-3- carboxylic acid hydrochloride (Cpd 49) Step 1: tert-Butvl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6-((2- (trimethylsilyl)ethoxy)methyl)indoline- 1 -carboxylate
To a solution of tert-butyl 5-bromo-6-((2-(trimethylsilyl)ethoxy)methyl)indoline-l- carboxylate (Intermediate 20, 0.50 g, 1.2 mmol) in THF (10 mL) cooled at -78 °C was added n-BuLi (2.0 M, 0.64 mL, 1.1 equiv.). After 1 hr, 2-isopropoxy-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane (0.35 mL, 1.5 equiv.) was added. The cooling bath was removed and the mixture was allowed to warm to room temperature. The reaction was quenched with aqueous ammonium chloride solution, then the mixture was extracted with ethyl acetate. The organic layers were combined, dried over Na2S04 and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0-10% gradient) to give the title compound (0.32 g, 69%).
1H NMR (500 MHz, CDC13) 5 ppm 0.00 (s, 9H), 0.97-1.03 (m, 2H), 1.27 (s, 12H), 1.32 (s, 9H), 3.02-3.06 (m, 2H), 3.54-3.62 (m, 2H), 3.96 (br. s, 2H), 4.51 (br. s, 2H), 7.10 (s, 1H), 7.56 (s, 1H) Step 2: tert-Butyl 5-(4,6-bis(benzyloxy)-5-((benzyloxy)carbonyl)-3-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)indoline-l- carboxylate
A mixture of the product of Step 1 (0.32 g, 0.68 mmol), benzyl 2,4-bis(benzyloxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)-6-chloronicotinate (Intermediate 14, 0.21 g, 0.34 mmol), Pd2(dba)3 (31 mg, 0.1 equiv.), i-Bu PHBF4 (20 mg, 0.2 equiv.) and cesium carbonate (0.33 g, 3 equiv.) in dioxane (2.5 mL) and water (2.5 mL) was stirred at 90 °C for 1 hr under an argon atmosphere. The mixture was then cooled, diluted with water and extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography with 0-30% dichloromethane in hexane to give the desired product (0.29 g, 93%).
1H NMR (500 MHz, CDC13) 5 ppm 0.00 (s, 9H), 0.10 (s, 6H), 0.83 (s, 9H), 0.97-1.03 (m, 2H), 1.54 (br. s, 9H), 3.11 (br. s, 2H), 3.34 (br. s, 2H), 4.06 (br. s, 2H), 4.11 (br. s, 2H), 4.51 (br. s, 2H), 5.29 (s, 2H), 5.48 (s, 2H), 5.53 (s, 2H), 7.15 (dd, J=1.5 Hz, 1H), 7.29-7.34 (m, 15H), 7.42 (dd, J=1.5 Hz, 1H) Step_3: 4-Hydroxy-2-oxo-l,5,7,9,10,l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3-f]indole- 3-carboxylic acid The product of Step 2 (160 mg, 0.16 mmol) in 6 N HCl (9.0 mL) and THF (9.0 mL) was stirred at 50 °C overnight. The reaction mixture was cooled, diluted with ether and HCl (0.5N, aq.). The aqueous layer was washed with ether. The aqueous layer was separated and water was removed by lyophilization to provide the title compound (56 mg, 67%) as an HCl salt.
LC-MS: 315.0 [M+H]+, RT 0.96 min. 1H NMR (500 MHz, DMSO- 6) δ: 3.10 (t, J=8.7 Hz, 2H), 3.65 (t, J=8.7 Hz, 2H), 4.17 (br. s, 2H), 4.30 (s, 2H), 6.73 (s, IH), 7.67 (s, IH), 12.89 (br. s, IH), 13.87 (br. s, IH), 16.05 (br. s, IH)
Example 11
4-Hydroxy-9-methyl-2-oxo-l,5,7,9,10,l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylic acid hydrochloride (Cpd 50)
To a solution of Compound 49 (Example 10, 16 mg, 0.05 mmol) in dichloromethane (0.6 mL) and TFA (0.3 mL) cooled at 0 °C was added 37% aqueous formaldehyde (12 μί, 3 equiv.) followed by NaBH(OAc)3 (34 mg, 3 equiv.). The reaction was complete in a few minutes as indicated by LC/MS. The mixture was treated with Celite and evaporated to dryness and purified by C18 column chromatography eluting with H20:CH3CN (with 0.1%TFA). The desired fractions were lyophilized and then treated with IN HCl in ether to provide the title compound as an HCl salt.
LC-MS: 329.1 [M+H]+, RT 1.11 min. 1H NMR (500 MHz, DMSO- 6) δ: 2.91 (s, 3H), 3.08 (t, J=8.7 Hz, 2H), 3.56 (t, J=8.7 Hz, 2H), 4.17 (s, 2H), 4.33 (s, 2H), 6.75 (s, IH), 7.45 (s, IH), 12.89 (br. s, IH), 13.88 (br. s, IH), 16.05 (br. s, IH)
Example 11a
4-Hydroxy-9-methyl-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5- f]indole-3-carboxylic acid hydrochloride (Cpd 52) Compound 52 was prepared from Compound 51 (Example 13) according to procedure described for Example 11.
LC-MS: 329.1 [M+H]+, RT 1.00 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 2.81 (t, J=6.5 Hz, 2H), 2.96 (t, J=8.5 Hz, 2H), 3.37-3.44 (m, 5H), 4.46 (t, J=6.5 Hz, 2H), 6.58 (s, IH), 7.24 (s., IH), 12.65 (br. s, IH), 13.57 (br. s, IH) Example 12
4-Hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,5,7,9-tetrahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f|indole-3-carboxylic acid hydrochloride (Cpd 48)
Step 1: 5-Bromo-l-(tert-butoxycarbonyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-2- carboxylic acid
To a stirred solution of tert-butyl 5-bromo-6-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-l- carboxylate (Intermediate 21, 0.65 g, 1.5 mmol) in anhydrous THF (10 mL) under argon atmosphere at -78°C, was added LDA (2.0 M, 1.1 mL, 1.5 equiv.) dropwise. The mixture was stirred for 1 hr at -78°C, then allowed to warm to room temperature slowly over 2 hrs while C02 gas was bubbled through the solution. The reaction was quenched by the addition of saturated ammonium chloride solution and the mixture extracted with ethyl acetate. The aqueous layer was acidified to about pH 3.0 with HC1 (0.5N), and extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product was triturated with ether/hexane to provide the title compound (0.70 g, quant.) as a white solid, which was used in the next step without further purification.
LC-MS: 468.1/470.1 [M-H]+, RT 1.75 min. 1H NMR (500 MHz, CDC13) δ ppm 0.00 (s, 9H), 0.97 (t, J=8.0 Hz, 2H), 1.55 (s, 9H), 3.65 (t, J=8.0 Hz, 2H), 4.55 (s, 2H), 7.13 (s, 1H), 7.95 (s, 1H), 8.10 (s, 1H), 13.52 (br. s, 1H) Step 2: Methyl 5-bromo-l-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-2- carboxylate
5-Bromo-l-(tert-butoxycarbonyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-2- carboxylic acid from Step 1 (380 mg, 0.80 mmol) was treated with 4N HC1 in dioxane (2.0 mL) at 0°C. The mixture was stirred at room temperature and monitored by LC/MS until the starting material was completely consumed. The volatiles were removed in vacuo at room temperature to provide 5-bromo-6-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-2-carboxylic acid.
The crude acid was mixed with potassium carbonate (442 mg, 4 equiv.) in
dimethylformamide (2 mL). A solution of iodomethane (341 mg, 3 equiv.) in
dimethylformamide (1 mL) was added to the reaction mixture at room temperature. The reaction was stirred at 40°C overnight, then cooled and extracted with ethyl acetate. The organic layers were combined, washed with water, dried over Na2S04 and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0-20% gradient) to give the title compound (280 mg, 88%).
1H NMR (500 MHz, CDC13) 5 ppm 0.00 (s, 9H), 1.01-1.05 (m, 2H), 3.63-3.66 (m, 2H), 3.85 (s, 3H), 4.01 (s, 3H), 4.59 (s, 2H), 7.13 (s, 1H), 7.49 (s, 1H), 7.78 (s, 1H)
Step 3: (5-Bromo- l-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)- lH-indol-2-yl)methanol
To a solution of methyl 5-bromo-l-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-2- carboxylate (280 mg, 0.7 mmol) in dichloromethane (4 mL) at -78 °C was added DIBAL-H (1.0 M in dichloromethane, 1.7 mL, 2.4 equiv.) dropwise. The mixture was stirred at -78 °C for 1 hr, then quenched by addition of a saturated Rochelle's salt solution (4 mL) at -78 °C. The mixture was allowed to warm to room temperature, then diluted with dichloromethane. After stirring at room temperature for 30 min, the mixture was extracted with
dichloromethane. The organic extracts were combined, dried over sodium sulfate and evaporated to give the title compound (210 mg, 80%), which was used in the next step without further purific ation .
LC-MS: 370.0/372.1 [M+H]+, RT 1.55 min. 1H NMR (500 MHz, acetone- d6) δ ppm 0.00 (s, 9H), 1.03 (t, J=8.0 Hz, 2H), 3.71 (t, J=8.0 Hz, 2H), 3.81 (s, 3H), 4.59 (s, 2H), 4.75 (d, J=5.5 Hz, 2H), 6.35 (s, 1H), 7.53 (s, 1H), 7.70 (s, 1H)
Step 4: 5-Bromo- l-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-2-carbaldehyde A mixture of the product of Step 3 (210 mg, 0.57 mmol) and Mn02 (500 mg, 10 equiv.) in dichloromethane (6 mL) was stirred at room temperature overnight. The mixture was then filtered through a Celite pad and washed with dichloromethane. The filtrate was evaporated and the residue was purified by silica gel column chromatography with CH2C12 in hexanes (10-45% gradient) to give the title compound (200 mg, 96%) as an off-white solid.
LC-MS: 368.1/370.1 [M+H]+, RT 1.72 min. 1H NMR (500 MHz, acetone- d6) δ ppm 0.00 (s, 9H), 1.00 (t, J=8.0 Hz, 2H), 3.71 (t, J=8.0 Hz, 2H), 4.03 (s, 3H), 4.57 (d, J=1.0 Hz, 2H), 7.31 (s, 1H), 7.65 (s, 1H), 7.95 (s, 1H), 9.88 (s, 1H)
Step 5: l-Methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6-((2- (trimethylsilyl)ethoxy)methyl)-lH-indole-2-carbaldehyde A solution of 5-bromo-l-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-2- carbaldehyde from Step 4 (200 mg, 0.54 mmol), bis(pinacolato)diboron (166 mg, 1.2 equiv.), potassium acetate (160 mg, 3.0 eq.) and tris(dibenzylideneacetone)-dipalladium(0) (44 mg, 0.1 equiv.) in anhydrous dioxane (5 mL) was heated at 100° C under an argon atmosphere overnight. The reaction was cooled to room temperature, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with 0-50% dichloromethane in hexane to provide the title compound (200 mg, 89%) as a white foam.
1H NMR (500 MHz, acetone- d6) δ ppm 0.00 (s, 9H), 1.00 (t, J=8.0 Hz, 2H), 1.14 (s, 12H), 3.71 (t, J=8.0 Hz, 2H), 4.03 (s, 3H), 4.57 (d, J=1.0 Hz, 2H), 7.31 (s, 1H), 7.65 (s, 1H), 7.94 (s, 1H), 9.88 (s, 1H) Step 6: Benzyl 2,4-bis(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-(2-formyl-l- methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-lH-indol-5-yl)nicotinate
A mixture of the product of Step 5 (200 mg, 0.48 mmol), benzyl 2,4-bis(benzyloxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)-6-chloronicotinate (Intermediate 14, 195 mg, 0.32 mmol), Pd2(dba)3 (31 mg, 0.1 equiv.), i-Bu P HBF4 (20 mg, 0.2 equiv.) and potassium carbonate (132 g, 3 equiv.) in dioxane (2.4 mL) and water (0.8 mL) was stirred at 90 °C for 1 hr under an argon atmosphere. The reaction mixture was then cooled, diluted with water and extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography with 0-50% dichloromethane in hexanes to give the title compound (180 mg, 66%).
1H NMR (500 MHz, acetone- 6) δ ppm 0.00 (s, 9H), 0.10 (s, 6H), 0.76 (s, 9H), 0.97-1.03 (m, 2H), 3.71 (br. s, 2H), 4.03 (s, 3H), 4.13 (br. s, 2H), 4.51 (br. s, 2H), 5.29 (s, 2H), 5.48 (s, 2H), 5.53 (s, 2H), 7.29-7.34 (m, 15H), 7.31 (s, 1H), 7.63 (s, 1H), 7.72 (s, 1H), 9.88 (s, 1H)
Step 7: Benzyl 2,4-bis(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-(l-methyl-2- (pyrrolidin-l-ylmethyl)-6-((2-(trimethylsilyl)ethoxy)methyl)-lH-indol-5-yl)nicotinate To a mixture of the product of Step 6 (86 mg, 0.1 mmol) and pyrrolidine (14 mg, 2.0 equiv.) in dichloromethane (0.5 mL) was added NaBH(OAc)3 (65 mg, 3.0 equiv.). After 30 min, the reaction was quenched with aqueous K2C03. The mixture was extracted with ethyl acetate (3x). The organic phases were combined, dried over Na2S04 and evaporated. The residue was purified by silica gel column chromatography with 0-50% ethyl acetate in hexanes to give the desired product (35 mg, 40%).
1H NMR (500 MHz, acetone- 6) δ ppm 0.00 (s, 9H), 0.10 (s, 6H), 0.83 (s, 9H), 0.97-1.03 (m, 2H), 1.77-1.79 (m, 4H), 2.54 (br. s, 4H), 3.40 (br. s, 2H), 3.82 (s, 2H), 3.89 (s, 3H), 4.13 (br. s, 2H), 4.42 (s, 2H), 5.29 (s, 2H), 5.48 (s, 2H), 5.53 (s, 2H), 6.36 (s, 1H), 7.32-7.39 (m, 15H), 7.53 (s, 1H), 7.62 (s, 1H)
Step 8: 4-Hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)- 1,5,7, 9-tetrahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f]indole-3-carboxylic acid To a solution product of Step 7 (35 mg) in THF (1.0 mL) was added H2S04 (4N, 1 mL) at room temperature. The mixture stirred at 50 °C overnight, then cooled to room temperature, diluted with ether and HCl (0.5N, aq). The aqueous layer was washed with ether and water was removed via lyophilization. The crude product was re-dissolved in dichloromethane and methanol, and purified by flash column chromatography on C-18 reverse phase column eluting with H20: CH3CN (with 0.1%TFA). The desired fractions were lyophilized and treated with 2N HCl in ether to provide the title compound as an HCl salt.
LC-MS: 408.1 [M-H]+, RT 0.83 min. 1H NMR (500 MHz, methanol-^) δ ppm 1.97-2.11 (m, 4H), 3.55 (br. s, 4H), 3.86 (br. s, 5H), 4.20 (br. s, 2H), 4.52 (br. s, 2H), 6.95 (br. s, 1H), 7.67 (s, 1H), 7.96 (s, 1H) Example 13
4-Hydroxy-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5-f|indole-3- carboxylic acid hydrochloride (Cpd 51)
Step 1: 9-(tert-Butoxycarbonyl)-4-hydroxy-2-oxo-2,6,7,9,10,l l-hexahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid A mixture of 3-benzyl 9-(tert-butyl) 2,4-bis(benzyloxy)-6,7,10,l l-tetrahydro-9H- pyrido[3',2':2,3]oxepino[4,5-f]indole-3,9-dicarboxylate (Intermediate 23, 78 mg, 0.12 mmol) and 10% Pd/C (20 mg) in dichloromethane (2 mL) and methanol (2 mL) was stirred at room temperature under 1 atm of H2. After 4 hrs, the catalyst was filtered off and washed with dichloromethane and methanol. The filtrate was evaporated to give the desired product (30 mg, 58%).
LC-MS: 413.2 [M-H]+, RT 1.27 min
Step 2: 4-Hydroxy-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5-f]indole- 3-carboxylic acid
A solution of the product of Step 1 (10 mg) in 1 N HCl and diethyl ether was stirred at room temperature. The progress of the reaction was monitored by LC/MS. On completion of the reaction the volatiles were removed in vacuo at room temperature to provide the title compound as an HC1 salt.
LC-MS: 315.1 [M+H]+, RT 1.00 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 2.75 (t, J=6.5 Hz, 2H), 2.98 (t, J=8.5 Hz, 2H), 3.55 (t, J=8.5 Hz, 2H), 4.42 (t, J=6.5 Hz, 2H), 6.31 (br. s, 1H), 6.53 (s, 1H), 7.24 (s, 1H) Example 14
4-Hydroxy-2-oxo-9-[3-(pyrrolidin-l-yl)propyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f|indole-3-carboxylic acid hydrochloride (Cpd 21)
Step 1: Benzyl 2,4-bis(benzyloxy)-9-(3-((tert-butyldimethylsilyl)oxy)propyl)-7,9-dihydro- 6H-pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylate To a solution of benzyl 2,4-bis(benzyloxy)-7,9-dihydro-6H-pyrido[3',2':2,3]oxepino[4,5- f]indole-3-carboxylate (Intermediate 25, 100 mg, 0.17 mmol) in dimethylformamide (0.5 mL) was added cesium carbonate (112 mg, 2 equiv.) and (3-bromopropoxy)(tert- butyl)dimethylsilane (60 mg, 1.5 equiv.) and the mixture was stirred at 60 °C overnight. The reaction was then cooled to room temperature and extracted with ethyl acetate. The organic layers were combined, washed with water, dried over Na2S04 and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0-20% gradient) to give the desired product (127 mg, quant.).
1H NMR (500 MHz, CDC13) 5 ppm 0.10 (s, 6H), 0.95 (s, 9H), 1.99-2.03 (m, 2H), 2.95-2.98 (m, 2H), 3.56-3.59 (m, 2H), 4.25-4.29 (m, 2H), 4.53-4.55 (m, 2H), 5.31 (s, 2H), 5.32 (s, 4H), 6.66 (s, 1H), 7.25-7.39 (m, 15H), 7.45-7.47 (m, 2H), 8.03 (s, 1H)
Step 2: Benzyl 2,4-bis(benzyloxy)-9-(3-hydroxypropyl)-7,9-dihydro-6H- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylate
To the product of Step 1 (127 mg, 0.17 mmol) in THF (1 mL) was added a solution of TBAF in THF (1.0 M, 0.26 mL, 2 equiv.) at 0 °C. The mixture was stirred at room temperature for 1 hr, then the reaction was quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0-30%) to give the title compound (100 mg, 94%).
LC-MS: 641.5 [M+H]+, RT 1.69 min. Step 3: Benzyl 2,4-bis(benzyloxy)-9-(3-((methylsulfonyl)oxy)propyl)-7,9-dihydro-6H- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylate To a solution of the product of Step 2 (100 mg, 0.16 mmol) in dichloromethane (1 mL) was added a solution of methanesulfonyl chloride in dichloromethane (1.0 M, 0.25 mL, 1.5 equiv.) and trimethylamine (65 mg, 4 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hr then quenched with saturated NaHC03. The product was extracted with
dichloromethane, and the combined organics were dried over sodium sulfate and evaporated. The crude product (110 mg) was used in the next step without further purification.
LC-MS: 719.6 [M+H]+, RT 1.70 min. 1H NMR (500 MHz, CDC13) δ ppm 2.23 (t, J=6.0 Hz, 2H), 2.87-2.92 (m, 5H), 4.08 (t, J=6.0 Hz, 2H), 4.24-4.29 (m, 2H), 4.49 (t, J=6.5 Hz, 2H), 5.21-5.23 (m, 4H), 5.43 (s, 2H), 6.53 (d, J=2.0 Hz, IH), 7.06 (d, J=2.0 Hz, IH), 7.25-7.39 (m, 15H), 7.34 (s, IH), 7.92 (s, IH)
Step 4: Benzyl 2,4-bis(benzyloxy)-9-(3-(pyrrolidin- l-yl)propyl)-7,9-dihydro-6H- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylate
To a solution of the product of Step 3 (18 mg) in THF (0.1 mL) was added a solution of pyrrolidine in THF (1.0 M, 0.25 mL, 10 equiv.) and the mixture was stirred at 40 °C overnight. The reaction was then cooled and extracted with ethyl acetate. The organic layers were combined, washed with water, dried over Na2S04 and evaporated. The crude product (16 mg) was used in the next step without further purification.
LC-MS: 694.6 [M+H]+, RT 1.36 min.
Step 5: 4-Hydroxy-2-oxo-9-[3-(pyrrolidin- l-yl)propyl]-2,6,7,9-tetrahydro- 1H- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid
A mixture of the crude product from Step 4 and 10% Pd/C (5 mg) in dichloromethane (0.5 mL) and methanol (1 mL) was stirred at room temperature under 1 atm of H2. After 2 hrs, the catalyst was filtered off and washed with dichloromethane and methanol. The filtrate was evaporated to give the title compound as a yellow solid.
LC-MS: 424.4 [M+H]+, RT 0.90 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.76 (br. s, 2H), 1.92 (br. s, 2H), 20.8 (br. s, 2H), 2.91-2.94 (m, 8H), 4.24 (t, J=7.0 Hz, 2H), 4.39 (t, J=6.0 Hz, 2H), 6.56 (d, J=3.0 Hz, IH), 7.42 (d, J=3.0 Hz, IH), 7.54 (s, IH), 7.78 (s, IH), 9.43 (br. s, IH), 12.83 (br. s, IH)
Using the procedure described for Example 14 above, additional compounds described herein may be prepared starting from Intermediate 25 and using suitable reagents and reaction conditions, obtaining compounds such as those selected from: Cpd Data
LC-MS: 313.0 [M+H]+, RT 0.99 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 2.99 (t,
14 J=6.0 Hz, 2H), 4.46 (t, J=6.0 Hz, 2H), 6.56 (s, 1H), 7.45-7.47 (m, 2H), 7.84 (s, 1H), 11.42 (br. s, 1H), 12.87 (br. s, 1H), 13.64 (br. s, 1H)
LC-MS: 327.0 [M+H]+, RT 1.09 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 3.02 (t,
16 J=6.0 Hz, 2H), 3.85 (s, 3H), 4.47 (t, J=6.0 Hz, 2H), 6.56 (d, J=3.0 Hz, 1H), 7.44 (d, J=3.0 Hz, 1H), 7.56 (s, 1H), 7.84 (s, 1H), 12.89 (br. s, 1H), 13.65 (br. s, 1H)
LC-MS: 410.4 [M+H]+, RT 0.86 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.86 (br. s, 2H), 2.02 (br. s, 2H), 3.00-3.07 (m, 4H), 3.56-3.66 (m, 4H), 4.49 (t, J=7.0 Hz,
22
2H), 4.60 (t, J=6.0 Hz, 2H), 6.67 (d, J=3.0 Hz, 1H), 7.54 (d, J=3.0 Hz, 1H), 7.66 (s, 1H), 7.88 (s, 1H), 12.94 (br. s, 1H), 13.65 (br. s, 1H)
Example 15
4-Hydroxy-10-[3-(methylamino)pyrrolidin-l-yl]-2-oxo-2,5,6,8-tetrahydro-lH- [2]benzoxocino[6,5-b]pyridine-3-carboxylic acid hydrochloride (Cpd 34)
Step 1: (2-Bromo-5-chlorophenyl)methanol To a stirred suspension of 2-bromo-5-chlorobenzaldehyde (4.48 g, 20.4 mmol) in MeOH (50 mL) was added NaBH4 (1.16 g, 30.7 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 min, then allowed to warm to room temperature and stirred for an additional 30 min. TLC analysis indicated complete consumption of starting material. The solvent was removed and then NH4C1 (aq. satd., 30 mL) was added to quench the reaction. The mixture was extracted with CH2CI2 (3x50 mL). The combined organic phases were washed with NaCl (aq. satd.,
100 mL) and dried over Na2S04. The solvent was concentrated to yield the title compound as an oil (4.55 g, quant.) which was used in the next step without further purification.
1H NMR (500 MHz, acetone- 6) δ ppm 4.64 (br. s, 1H), 4.65 (s, 2H), 7.24 (dd, J=8.4, 2.7 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.62 (d, J=2.5 Hz, 1H) Step 2: 2-((Allyloxy)methyl)-l-bromo-4-chlorobenzene
To a stirred solution of (2-bromo-5-chlorophenyl)methanol (4.55 g, 20.4 mmol) in DMF (100 mL) was added NaH (1.18 g, 29.5 mmol, 1.4 eq) at 0 °C. The reaction as stirred at 0 °C for 30 min before allyl bromide (2.96 g, 24.4 mmol, 1.2 eq.) was added. After 12 hrs, the reaction was quenched by NH4C1 (aq. satd., 40 mL) then extracted with Et20 (3x50 mL). The combined organic phases were washed with NaCl (aq. satd., 100 mL) and dried over Na2S04. The solvent was concentrated to yield the crude product which was purified by flash column chromatography (0-10% EtOAc in hexanes) to afford the title product as an oil (5.09 g, 95%). 1H NMR (500 MHz, acetone- 6) δ ppm 4.16 (dt, J=5.4, 1.6 Hz, 2H), 4.55 (s, 2H), 5.18 - 5.24 (m, 1H), 5.36 (dq, J=17.2, 1.8 Hz, 1H), 5.96 - 6.08 (m, 1H), 7.26 - 7.38 (m, 1H), 7.43 - 7.56 (m, 1H), 7.60 (d, J=8.5 Hz, 1H)
Step 3: 2- ( ( Allyloxy)methyl) -4-chlorobenzaldehyde
To a stirred solution of 2-((allyloxy)methyl)-l-bromo-4-chlorobenzene (1.38 g, 5.3 mmol) in THF (20 mL) was added w-BuLi (2.3 mL, 5.75 mmol, 2.5 M in hexanes) at -78 °C over 15 min via syringe pump. The reaction was stirred at -78 °C for 30 min before DMF (0.8 mL, 10.3 mmol) was added to the reaction mixture. After 15 min the reaction was quenched by NH4C1 (aq. satd., 20 mL) then extracted with Et20 (3x40mL). The combined organics were washed with NaCl (aq. satd., 100 mL) and dried over Na2S04. The solvent was concentrated to yield the crude product which was purified by flash column chromatography (0-25% EtOAc in hexanes) to afford the title compound as an oil (0.84 g, 76%).
1H NMR (500 MHz, acetone- d6) δ ppm 4.16 (dt, J=5.4, 1.6 Hz, 2H), 4.95 (s, 2H), 5.07 - 5.23 (m, 1H), 5.34 (dq, J=17.2, 1.8 Hz, 1H), 5.94 - 6.05 (m, 1H), 7.57 (dd, J=8.2, 2.2 Hz, 1H), 7.70 - 7.83 (m, 1H), 7.95 (d, J=8.2 Hz, 1H), 10.22 (s, 1H)
Steps 4-6: (Z)-9-Chloro-lH-benzo[c]oxocin-6(3H)-one
To a stirred solution of 2-((allyloxy)methyl)-4-chlorobenzaldehyde (0.84 g, 4.0 mmol) in THF (10 mL) at -78 °C was added 1-propenylmagnesium bromide (10.5 mL, 0.5M in THF, 5.25 mmol) dropwise via syringe pump over 15 min. The reaction mixture was stirred at -78 °C for 15 min, then slowly allowed to warm to 0 °C with stirring for 1 hr. The reaction was quenched with NH4C1 (aq. satd., 10 mL) at -78 °C and then extracted with EtOAc (3x40 mL). The combined organic phases were washed with NaCl (aq. satd., 50 mL) and dried over Na2S04 and then concentrated to afford the desired alcohol (about 1.1 g, quant.) which was carried over to the next step without further purification.
To a solution of crude alcohol obtained above (approx. 1.1 g, ca. 4.0 mmol) in toluene (80 mL, 0.05M) under an argon atmosphere was added Grubbs' 2nd generation catalyst (102 mg, 0.12 mmol, 3 mol%). The reaction mixture was heated at 60 °C for 2 hrs and monitored by TLC analysis until the starting material was completely consumed. The mixture was cooled to room temperature, toluene was removed under reduced pressure and the crude RCM product was carried over to the next step without further purification. To a solution of the crude RCM product (ca. 4.0 mmol) in CH2CI2 (30 mL) was added Mn02 (3.5 g + 3.5 g, 40 + 40 mmol) in two portions with 30 min intervals. The reaction was stirred at room temperature for 2 hrs and the reaction progress was monitored by TLC analysis until the starting material was completely consumed. The mixture was filtered through Celite (10 g) and washed with CH2CI2 (3x40 mL). The filtrate was concentrated to give a crude product which was purified by column chromatography (0-20% EtOAc/hexanes) to afford the title compound (210 mg, 25% over 3 steps) as an oil.
1H NMR (500 MHz, acetone- 6) δ ppm 4.04 (dd, J=6.6, 0.9 Hz, 2H), 4.74 (s, 2H), 6.36 (dt, J=12.0, 6.5 Hz, 1H), 6.53 (dt, J=12.0, 0.9 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.52 (dd, J=8.2, 2.2 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H)
Step 7: 9-Chloro-4,5-dihydro- lH-benzo[c]oxocin-6(3H)-one
To a stirred solution of (Z)-9-chloro- lH-benzo[c]oxocin-6(3H)-one (210 mg, 1.0 mmol) in EtOAc (10 mL) was added 10% palladium on carbon (10 mg, Degussa type). The flask was evacuated and then back filled with H2. The reaction was then hydrogenated at 1 atm of H2 for 30 min and then was filtered through Celite (2.5 g) to remove the Pd catalyst. The filtrate was concentrated to afford the title compound (168 mg, 80%) as a light yellow solid.
1H NMR (500 MHz, acetone- d6) δ ppm 1.83 - 2.02 (m, 2H), 2.44 - 2.60 (m, 2H), 3.79 - 3.90 (m, 2H), 4.85 (s, 2H), 7.13 (dd, J=8.2, 0.6 Hz, 1H), 7.18 - 7.25 (m, 1H), 7.26 - 7.39 (m, 1H)
Step 8: 9-Chloro-N-(2,4-dimethoxybenzyl)-4,5-dihydro- lH-benzo[c]oxocin-6(3H)-imine To a solution of 9-chloro-4,5-dihydro-lH-benzo[c]oxocin-6(3H)-one (168 mg, 0.8 mmol) in CH2C12 (4 mL) was added 2,4-dimethoxybenzylamine (0.15 mL, 1.0 mmol) and NEt3 (0.45 mL, 3.2 mmol) at room temperature. The reaction mixture was cooled to 0 °C before TiCl4 (1M in CH2CI2, 0.8 mL, 0.8 mmol) was added over 5 min. The reaction was allowed to warm to room temperature and stirred overnight. The mixture was diluted with CH2CI2 (30 mL) then quenched with NaHC03 (aq. satd., 20 mL). Upon vigorous shaking, the organic phase was separated using a PTFE phase separator and dried over Na2S04. The solvent was concentrated to give the the title compound (approx. 0.3 g) as a brown oil which was taken directly into the next step without purification.
LC-MS: 360.1 [M+H]+, RT 1.04 min. Step 9: Methyl 10-chloro-l-(2,4-dimethoxybenzyl)-4-hydroxy-2-oxo-2,5,6,8-tetrahydro- lH- benzo[6,7]oxocino[5,4-b]pyridine-3-carboxylate 9-Chloro-N-(2,4-dimethoxybenzyl)-4,5-dihydro-lH-benzo[c]oxocin-6(3H)-imine (ca. 0.3 g, 0.8 mmol) and trimethyl methanetricarboxylate (0.35 g, 1.8 mmol) were mixed in Ph20 (5 mL). The stirred mixture was placed onto a pre-heated heat block at 230 °C and heated for 10 min after initial bubbling of MeOH was observed (occurs at approx. 160 °C internal reaction temperature). The reaction mixture was cooled to room temperature, loaded directly on a silica column, eluted first with hexanes to separate Ph20 and then EtOAc/hexanes gradient (0-50%) to yield the title compound (41 mg, 11% over 2 steps) as a yellow foam.
LC-MS: 484.1 [M-H]+, RT 1.45 min.
Steps 10-11: 4-Hvdroxv-10-r3-(methvlamino)pvrrolidin-l-vll-2-oxo-2,5,6,8-tetrahydro-lH- [2]benzoxocino[6,5-b]pyridine-3-carboxylic acid
To a flame-dried vial was added methyl 10-chloro-l-(2,4-dimethoxybenzyl)-4-hydroxy-2- oxo-2,5,6,8-tetrahydro-lH-benzo[6,7]oxocino[5,4-b]pyridine-3-carboxylate (41 mg, 0.084 mmol), iert-butyl pyrrolidin-3-ylcarbamate (40 mg, 0.2 mmol), 2-(2'-di-tert- butylphosphine)biphenylpalladium(II) acetate (4 mg, 0.0086 mmol), and sodium tert- butoxide (50 mg, 0.52 mmol). The vial was evacuated and then back-filled with argon.
Toluene (1.5 mL) was added to the solids and mixture was heated to 90 °C for 2 hrs. The reaction was quenched by IN HC1 (2 mL) then extracted with CH2C12 (3x10 mL). The combined organic phases were washed with NaCl (aq. satd., 10 mL) and dried over Na2S04. The solvent was concentrated to yield the crude product which was purified by flash column chromatography (0-5% MeOH in CH2C12) to afford the carboxylic acid coupling product as a tan solid (23 mg).
LC-MS: 634.4 [M-H]+, 636.4 [M+H]+, RT 1.61 min.
To a solution of the product (23 mg, 0.036 mmol) obtained above in CH2C12 (1 mL) was added TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 hrs. The volatiles were removed under reduced pressure and then the residue was dissolved in DMSO and purified by Prep-HPLC (30-95% MeCN in H20) to afford the title compound (11 mg, 26% over 2 steps) as a tan solid.
LC-MS: 384.2 [M-H]+, 386.2 [M+H]+, RT 0.85 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 1.74 (dd, J=14.2, 10.4 Hz, 1H), 2.12 - 2.22 (m, 1H), 2.32 - 2.42 (m, 1H), 2.66 (s, 3H), 2.98 (dd, J=14.8, 5.4 Hz, 1H), 3.32 - 3.42 (m, 2H), 3.46 - 3.56 (m, 2H), 3.59 - 3.67 (m, 1H), 3.92 (br. s, 1H), 3.96 - 4.03 (m, 2H), 4.60 (d, J=13.0 Hz, 1H), 6.62 - 6.82 (m, 2H), 7.36 (d, J=8.5 Hz, 1H), 8.73 (br. s, 2H), 12.76 (br. s, 1H), 13.91 (br. s, 1H), 16.25 (br. s, 1H) Example 16
4-Hydroxy-9-methyl-2-oxo- 1,5,7, 9-tetrahydro-2H-pyrido[2',3':5,6]oxepino[4,3-f]indole-3- carboxylic acid (Cpd 35)
Step 1 : 2-Bromo-4-methyl-5-nitrobenzonitrile To a solution of 2-bromo-4-methylbenzonitrile (15.0 g, 75.5 mmol) in H2S04 (30 mL) was added HN03 (30 mL) via an addition funnel at 0 °C over 30 min. The reaction mixture was allowed to warm to room temperature and stirred for 1 hr, then poured onto ice (ca. 200 mL) and the resulting precipitate was collected by filtration. The solid was dried under vacuum to afford the nitration products (17.6 g, 96%) as a 10.6: 1 mixture in favor of the title compound. LC-MS: 238.9/240.9 [M-H]+, RT 1.17 min. 1H NMR (500 MHz, CDC13) δ ppm 2.69 (s, 3H), 7.75 (s, 1H), 8.29 (s, 1H)
Step 2: (E)-2-Bromo-4-(2-(dimethylamino)vinyl)-5-nitrobenzonitrile
To a solution of 2-bromo-4-methyl-5-nitrobenzonitrile (2.4 g, 10.0 mmol) in DMF (6 mL) was added DMF-DMA (3.35 mL, 25.0 mmol) at room temperature. The reaction mixture was heated to 135 °C for 2 hrs and the volatiles were removed under reduced pressure to afford the title compound (2.5 g, 84%) which was used in the next step without further purification. 1H NMR (500 MHz, CDC13) δ ppm 3.06 (br. s, 3H), 3.41 (s, 3H), 5.98 (d, J=13.2 Hz, 1H), 7.23 (d, J=13.2 Hz, 1H), 7.68 (s, 1H), 8.15 (s, 1H)
Step 3: 5-Bromo-lH-indole-6-carbonitrile To a solution of (E)-2-bromo-4-(2-(dimethylamino)vinyl)-5-nitrobenzonitrile (approx. 2.5 g, 8.4 mmol) in acetic acid (10 mL) was added Zn dust (7.0 g, 107.0 mmol) at room temperature in three portions. The dark brown mixture was heated to 80 °C for 2 hrs. The reaction was monitored by LC-MS until the starting material was completely consumed. The resulting heterogeneous mixture was filtered through Celite (10 g) to remove the solids. The filtrate was neutralized with NaHC03 (aq. satd., approx. 200 mL) then extracted with CH2C12
(3x50mL). The combined organic phases were washed with NaCl (aq. satd., 100 mL) and dried over Na2S04. The solvent was concentrated to yield the crude product (1.22 g, 66%) which was carried over to the next step without further purification.
LC-MS: 218.9/220.9 [M-H]+, RT 1.27 min. 1H NMR (500 MHz, CDC13) δ ppm 6.58 - 6.62 (m, 1H), 7.42 - 7.47 (m, 1H), 7.78 (s, 1H), 7.92 (s, 1H), 8.60 (br. s, 1H) Step 4: 5-Bromo-l-methyl-lH-indole-6-carbonitrile
To a stirred solution of 5-bromo-lH-indole-6-carbonitrile (1.22 g, 5.5 mmol) in DMF (20 mL) was added NaH (60% suspension in mineral oil, 0.34 g, 8.5 mmol, 1.5 eq) at 0 °C. The reaction was stirred at 0 °C for 30 min before Mel (0.45 mL, 7.2 mmol, 1.3 eq.) was added. After 12 hrs, the reaction was quenched by NH4C1 (aq. satd., 40 mL) then extracted with Et20 (3x50 mL). The combined organics were washed with NaCl (aq. satd., 100 mL) and dried over Na2S04. The solvent was concentrated to yield the crude product which was triturated with hexanes to afford the title product as a tan solid (1.01 g, 78%).
LC-MS: 235.0/237.0 [M+H]+, RT 1.35 min. 1H NMR (500 MHz, CDC13) δ ppm 3.84 (s, 3H), 6.51 (dd, J=3.0, 0.8 Hz, 1H), 7.26 - 7.28 (m, 1H), 7.68 (d, J=0.9 Hz, 1H), 7.88 (d, J=0.6 Hz, 1H)
Step 5: 5-Bromo-l-methyl-lH-indole-6-carbaldehyde
To a stirred suspension of 5-bromo-l -methyl- lH-indole-6-carbonitrile (1.25 g, 5.3 mmol) in CH2C12 (20 mL) was added DIBAL-H (1.0M CH2C12, 6.4 mL, 6.4 mmol, 1.2 eq) at -78 °C over 15 min. The reaction was stirred at -78 °C for 1 hr then quenched at -78 °C with methanol, followed by addition of sodium potassium tartrate (aq. satd., 50 mL). The mixture was allowed to warm to room temperature and stirred vigorously for 2 hrs. The organic layer was separated from the aqueous phase and the aqueous phase was extracted with CH2C12 (3x40 mL). The combined organic phases were washed with NaCl (aq. satd., 100 mL) and dried over Na2S04. The solvent was concentrated to yield the crude imine which was dissolved in ethyl acetate (50 mL). To a stirred solution of the corresponding imine was added 6N HC1 (approx. 50 mL) and the resulting mixture was stirred for 1 hr at room temperature. The reaction mixture was extracted with EtOAc (3x50 mL). The combined organics were washed with NaCl (aq. satd., 100 mL) and dried over Na2S04. The solvent was concentrated to yield the title compound (1.25 g, 99%) which was used in the next step without further purification.
1H NMR (500 MHz, CDC13) δ ppm 3.87 (s, 3H), 6.48 (dd, J=3.2, 0.9 Hz, 1H), 7.27 - 7.29 (m, 1H), 7.85 (s, 1H), 8.02 (d, J=0.6 Hz, 1H), 10.47 (s, 1H)
Step 6: (5-Bromo-l-methyl-lH-indol-6-yl)methanol To a stirred suspension of 5-bromo-l -methyl- lH-indole-6-carbaldehyde (350 mg, 1.5 mmol) in MeOH (6 mL) was added NaBH4 (28 mg, 0.7 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then allowed to warm to room temperature and stirred for an additional 30 min. The TLC analysis indicated the complete consumption of starting material. The solvent was removed and then NH4C1 (aq sat, 30 mL) was added to quench the reaction. The mixture was extracted with CH2CI2 (3x25 mL). The combined organics were washed with NaCl (aq. satd., 100 mL) and dried over Na2S04. The solvent was concentrated to yield the title compound as a solid (356 mg, quant.) which was used in the next step without further purification.
LC-MS: 240.1/242.1 [M+H]+, RT 1.11 min. 1H NMR (500 MHz, CDC13) δ ppm 3.80 (s, 3H), 4.88 (s, 2H), 6.42 (dd, J=3.2, 0.9 Hz, 1H), 7.07 (d, J=3.2 Hz, 1H), 7.44 (s, 1H), 7.82 (s, 1H) Step 7: 5-Bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)-l-methyl-lH-indole
To a stirred solution of (5-bromo-l-methyl-lH-indol-6-yl)methanol (356 mg, 1.5 mmol) in CH2CI2 (6 mL) was added imidazole (143 mg, 2.1 mmol) followed by TBSC1 (271 mg, 1.8 mmol) at 0 °C. The reaction was allowed to warm to room temperature and then stirred overnight. The reaction was quenched by the addition of water and then extracted with CH2CI2 (3x25 mL). The combined organics were washed with NaCl (aq sat, 100 mL) and dried over Na2S04. The solvent was concentrated to yield the crude product which was purified by flash column chromatography (0-5% EtOAc/hexanes) to afford the title compound as an oil (477 mg, 92% over 2 steps).
1H NMR (500 MHz, CDCI3) δ ppm 0.17 (s, 6H), 1.01 (s, 9H), 3.79 (s, 3H), 4.87 (d, J=0.9 Hz, 2H), 6.40 (dd, J=3.2, 0.9 Hz, 1H), 7.04 (d, J=3.2 Hz, 1H), 7.54 (s, 1H), 7.76 (s, 1H)
Step 8: 6-(((tert-Butvldimethvlsilvl)oxv)methvl)-l-methvl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- lH-indole
To a flame-dried flask was added 5-bromo-6-(((tert-butyldimethylsilyl)oxy)methyl)-l- methyl-lH-indole (477 mg, 1.35 mmol), bis(pinacolato)diboron (513 mg, 2.0 mmol), KOAc (265 mg, 2.7 mmol) followed by Pd(dppf)Cl2 (49 mg, 0.07 mmol) at room temperature. The flask was evacuated and then back filled with argon. To the solids was added 1,4-dioxane (4 mL) and then reaction mixture was heated to 90 °C for 4 hrs. The LC-MS analysis indicated complete consumption of the starting material. The reaction was quenched by water then extracted with CH2CI2 (3x25 mL). The combined organic phases were washed with NaCl (aq. satd., 100 mL) and dried over Na2S04. The solvent was concentrated to yield the crude product which was purified by flash column chromatography (0-5% EtOAc/hexanes) to afford the title compound as an oil (approx. 480 mg, 89%). LC-MS: 402.5 [M+H]+, RT 1.86 min. 1H NMR (500 MHz, CDC13) 5 ppm 0.14 (s, 6H), 1.00 (s, 9H), 1.36 (s, 12H), 3.80 (s, 3H), 5.19 (d, J=0.9 Hz, 2H), 6.46 (dd, J=3.2, 0.9 Hz, 1H), 7.00 (d, J=3.2 Hz, 1H), 7.58 (s, 1H), 8.13 (s, 1H)
Steps 9-10: Benzyl 2,4-bis(benzyloxy)-5-(hydroxymethyl)-6-(6-(hydroxymethyl)- 1-methyl- lH-indol-5-yl)nicotinate
To a flame-dried flask was added 6-(((tert-butyldimethylsilyl)oxy)methyl)-l-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indole (97 mg, 0.24 mmol), Pd2(dba)3 (approx. 5 mg), iBu3PHBF4 (approx. 6 mg), K2C03 (28 mg, 0.20 mmol) and benzyl 2,4- bis(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloronicotinate (Intermediate 14, 61 mg, 0.10 mmol). To the solids was added DMSO (1 mL) and the reaction mixture was heated to 120 °C for 30 min. The LC-MS analysis indicated complete consumption of the starting material. The reaction was quenched by water and then extracted with CH2C12 (3x20 mL). The combined organics were washed with NaCl (aq. satd., 100 mL) and dried over Na2S04. The solvent was concentrated to yield the crude product which was purified by flash column chromatography (0-5% EtOAc/hexanes) to afford the desired coupling compound as an oil (34 mg).
To a solution of the coupling product (34 mg, 0.040 mmol) obtained above in THF (1 mL) was added TBAF (1M THF, 0.2 mL, 0.2 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then allowed to warm to room temperature and stirred for an additional 30 min. The solvent was concentrated and the crude mixture was purified by flash column chromatography (0-25% EtOAc/CH2Cl2) to afford the title compound as an oil (19 mg, 31% over 2 steps).
LC-MS: 615.2 [M+H]+, RT 1.58 min. 1H NMR (500 MHz, acetone- 6) δ ppm 3.90 (s, 3H), 4.18 (t, J=5.4 Hz, 1H), 4.36 (td, J=5.2, 1.6 Hz, 1H), 4.38 - 4.43 (m, 2H), 4.50 - 4.55 (m, 2H), 5.26 (br. s, 2H), 5.38 (br. s, 2H), 5.40 (s, 2H), 6.46 (dd, J=3.2, 0.9 Hz, 1H), 7.29 - 7.47 (m, 16H), 7.49 (s, 1H), 7.56 (s, 1H)
Step 11: Benzyl 2,4-bis(benzyloxy)-9-methyl-7,9-dihydro-5H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylate
To a solution of benzyl 2,4-bis(benzyloxy)-5-(hydroxymethyl)-6-(6-(hydroxymethyl)-l- methyl- lH-indol-5-yl)nicotinate (6 mg, 0.01 mmol) in CH2C12 (1 mL) was added TFA
(0.35M CH2C12, 0.3 mL, 0.1 mmol) at -40 °C. The reaction mixture was stirred at -40 °C for 2 hrs, then allowed to warm to room temperature and stirred for an additional 6 hrs. The reaction was quenched by NaHC03 (aq. satd., 10 mL) then extracted with CH2CI2 (3x20 mL). The combined organic phases were washed with NaCl (aq. satd., 50 mL) and dried over Na2S04. The solvent was concentrated to yield the crude product which was purified by flash column chromatography (0-20% EtOAc/hexanes) to afford the title compound as a solid (5 mg, 84%).
LC-MS: 597.2 [M+H]+, RT 1.76 min. 1H NMR (500 MHz, acetone- 6) δ ppm 3.94 (s, 3H), 4.35 (s, 2H), 4.57 (s, 2H), 5.23 (s, 2H), 5.38 (s, 2H), 5.62 (s, 2H), 6.62 (dd, J=3.2, 0.9 Hz, 1H), 7.31 - 7.46 (m, 14H), 7.50 - 7.53 (m, 2H), 7.58 (s, 1H), 8.20 (s, 1H)
Step 12: 4-Hydroxy-9-methyl-2-oxo- 1,5,7, 9-tetrahydro-2H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylic acid
To a solution of benzyl 2,4-bis(benzyloxy)-9-methyl-7,9-dihydro-5H- pyrido[2',3':5,6]oxepino[4,3-f]indole-3-carboxylate (44 mg, 0.074 mmol) in EtOAc (3 mL) and MeOH (2 mL) was added Pd/C (10% Degussa type, 11 mg). The reaction mixture was evacuated and then backfilled with H2 (1 atm balloon) in three cycles. Hydrogenation continued for 1 hr. The reaction mixture was filtered through Celite (2.5 g) and the Pd catalyst was washed with MeOH (3x50 mL). The filtrate was concentrated to afford the title compound as a light yellow solid (12 mg, 50%).
LC-MS: 325.0 [M-H]+, 327.1 [M+H]+, RT 1.12 min. 1H NMR (500 MHz, DMSO- 6) δ ppm 3.88 (s, 3H), 4.13 (s, 2H), 4.51 (s, 2H), 6.64 (dd, J=3.2, 0.6 Hz, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.74 (s, 1H), 7.99 (s, 1H), 13.10 (br. s, 1H), 13.91 (br. s, 1H), 15.99 (br. s, 1H)
Example 17
9-[(Dimethylamino)methyl]-4-hydroxy-2-oxo- 1,2,5,6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride (Cpd 60)
A mixture of Compound 53 (14 mg) and Ν,Ν-dimethylmethyleneiminium iodide (14 mg) in DMF (0.3 mL) was stirred at room temperature for 5 min and then purified by C18 preparative HPLC. The title compound was obtained as an HC1 salt (10 mg) after
lyophilization of the desired fraction and treatment of the residue with HCl/Et20.
LC-MS: 368.2, [M+H]+, RT 0.87 min. 1H NMR (DMSO- 6) δ: 16.33 (br. s, 1H), 13.87 (br. s, 1H), 12.94 (br. s, 1H), 11.86 (br. s, 1H), 9.49 (br. s, 1H), 7.78 (s, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.68 (s, 1H), 4.47 (s, 2H), 3.24-3.45 (m, 2H), 2.78 (s, 6H), 2.61-2.73 (m, 2H), 2.05-2.14 (m, 2H) Biological Examples
The following in vitro biological examples demonstrate the usefulness of the compounds of the present description for treating Neisseria gonorrhoeae.
The antibacterial activity from a microbroth dilution method in either or both Fastidious Broth (FB) and FB containing 40 mg/mL Human Serum Albumin (HSA), as indicated, may be represented by the minimum inhibitory concentration (MIC in μg/mL). The MIC value is the lowest concentration of drug which prevents macroscopically visible growth under test conditions.
In the following tables, 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) is compared in FB (Table 1) and in FB containing 40 mg/mL HSA (Human Serum Albumin) (Table 2).
Table 1
Cpd 13477 Cpd 13477 Cpd 13477
1 **** 20 **** 42 ****
2 **** 21 *** 43 ****
3 *** 22 *** 44 ****
4 *** 23 **** 45 ***
5 **** 24 *** 46 ***
6 **** 26 **** 47 ****
7 **** 27 **** 48 ****
8 **** 28 **** 49 **
9 **** 29 **** 50 ****
10 **** 30 **** 51 ***
11 **** 31 **** 52 **** Cpd 13477 Cpd 13477 Cpd 13477
12 **** 32 **** **** 13 **** 34 **** 14 35 **** *** 15 **** 37 **** **** 16 **** 38 **** ****
17 **** 39 **** **** 18 **** 40 **** *** 19 **** 41 ****
Table 2
Cpd 13477 Cpd 13477 Cpd 13477
14 30 **** 43 **** 16 **** 31 **** 44 **** 21 37 **** 45
22 38 **** 46
23 39 **** 47 ****
24 40 **** 48 **** 27 **** 41 **** 52
29 **** 42 ****
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
31
32
34 Cpd 13478 13479 13480 13481 Cpd 13478 13479 13480 13481
4 35
5 37
6 38
7 39
8 40
9 41
10 42
11 43
12 44
13 45
14 46
15 47
16 48
17 49
18 50
19 51
20 52
21 53
22 54
23 55
24 56
26 57
27 58
28 59
29 60
30 Example 3
Antibacterial activity of test compounds against a streptomycin-resistant
N. gonorrhoeae FA1090 isolate is compared in FB (Table 4) and in FB containing 40 mg/mL HSA (Table 5).
Table 4
Cpd FA1090 Cpd FA1090 Cpd FA1090
2 **** 13 **** 30 ****
3 15 **** 31 ****
5 **** 17 **** 35 ****
6 **** 18 **** 53 ****
7 **** 19 **** 54 ****
8 **** 20 **** 56 ****
9 **** 27 **** 57 ****
11 **** 28 **** 58 ****
12 **** 29 ****
Table 5
Cpd FA1090 Cpd FA1090 Cpd FA1090
5 30 **** 54 ***
27 **** 31 **** 56 ***
28 **** 35 5γ *** 29 **** 53 58 ***
Example 4
Antibacterial activity of test compounds against penicillin-sensitive wild-type N. gonorrhoeae FA19 and ciprofloxacin-resistant AKl and AK2 isolates and the LG24 clinical isolate is shown in Table 6. Table 6
Cpd AK1 AK2 FA19 LG24 Cpd AK1 AK2 FA19 LG24
2 13
3 15
5 17
6 18
7 19
8 20
9 53
11 54
12
Example 5
Antibacterial activity of test compounds against N. gonorrhoeae tetracycline-resistant LGB24, penicillin-resistant LGB3, ampicillin-resistant LGB50 and MS 11 isolates is shown in Table 7.
Table 7
Cpd LGB24 LGB3 LGB50 MS11 Cpd LGB24 LGB3 LGB50 MS11
2 13
3 15
5 17
6 18
7 19
8 20
9 53
11 54
12 Example 6
In Vivo Mouse Model Background
The usefulness of the compounds of the present description for treating Neisseria gonorrhoeae was demonstrated in an in vivo mouse model developed by the adaptation of several published protocols {see, Jerse, A.E., Experimental Gonococcal Genital Tract Infection and Opacity Protein Expression in estradiol-treated mice. Infection and Immunity, 1999, 67(l l):5699-5708; and, Cole, J.E. et al., Opacity Proteins Increase Neisseria gonorrhoeae Fitness in the Female Genital Tract Due to a Factor Under Ovarian Control. Infection and Immunity, 2010, 78(4): 1629- 1641).
Compound efficacy is demonstrated when all mice in a treatment group are completely clear of N. gonorrhoeae after 5 full days post-treatment (100% clearance).
Bacterial clearance is defined as the number of mice in the treatment group free of
N. gonorrhoeae expressed as a percentage of the total. Complete bacterial clearance (100% clearance) for the treatment group equates to an approximate log 4 reduction in bacterial count for the group. Compounds that achieve less than 100% clearance for the treatment group have an average maximal log drop value calculated by the following equation:
Maximal Log Drop = log(average Day 2 bacterial count for all mice) - log(average lowest bacterial count post dose for all mice)
Study Conduct
On Day -2 of the study, ovariectomized Balb/c female mice (5 weeks old - Charles River Laboratory) were implanted with a single 17 -estradiol pellet (0.5 mg, 21 day release) subcutaneously and begin treatment with a combination of vancomycin HC1, streptomycin sulfate (0.6 mg and 0.3 mg, respectively, IP, BID) and trimethoprim sulfate (0.8 mg, PO, BID). The antibiotic combination was administered to control commensal flora induced by the high level of 17 -estradiol resulting from the implanted pellet. Combined antibiotic treatment continued from Day -2 to Day 1 of the study. After Day 1, mice were dosed with streptomycin only (0.6 mg, IP, QD).
On Day 0 of the study, mice were inoculated with SP1364 N. gonorrhoeae (target 1 x 10 CFU) suspended in saline. Following inoculation, and for the 7 days of the study, the bacterial count was determined by daily vaginal swabbing using sterile swabs. On Day 1 of the study, mice were randomized into treatment groups according to bacterial count. The treatment groups (n=10) included a vehicle control, a positive control (such as ciprofloxacin, 30 mg/kg) and test compound group. The treatment groups were dosed IP with a single dose (mg/kg). The vehicle control, positive control and test compound were each administered in a mixture of DMSO (3%) in saline.
Results
Antibacterial efficacy of test compounds (Cpd) against SP1364 N. gonorrhoeae is shown in Table 8, 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 8
Cpd Dose % Drop
28 60 77.8 0.330
Example 7
Combinations with Antibacterial Agents
The in vitro effects of compounds described herein in combination with a known antibacterial or antibiotic agent may be investigated in various organisms using the microdilution checkerboard method for the measurement of additive or synergistic effect. Assays can be performed in a 96-well checkerboard titration format, with serial dilutions of each compound to identify the lowest MIC value ^g/mL) at which the combination completely inhibits colony formation. The ability of a combination of one or more compounds described herein with known agents to either act synergistically, additively, indifferently or antagonistically can be determined. A synergistic effect is demonstrated when the activity of the separate agents are combined and the result is greater than the expected arithmetic sum of each agents activity alone. The fractional inhibitory
concentration (FIC) is a quantitative measure of such drug interactions, where the fractional inhibition indices are calculated using the checkerboard method in a 96-well microtiter plate. Combined activity is synergistic when the FIC value is < 0.5; combined activity is additive when the FIC value is > 0.5 and < 2; combined activity that is not different from the agents alone when the FIC value is > 2 and < 4; and, combined activity is antagonistic when the FIC value is > 4. Without regard to whether a document cited herein was specifically and individually indicated as being incorporated by reference, all documents referred to herein are incorporated by reference into the present application for any and all purposes to the same extent as if each individual reference was fully set forth herein. Having now fully described the subject matter of the claims, it will be understood by those having ordinary skill in the art that the same can be performed within a wide range of equivalents without affecting the scope of the subject matter or embodiments described herein. It is intended that the appended claims be interpreted to include all such equivalents.

Claims

What is claimed is:
A compound of Formula (I), Formula (II) or Formula (III):
Figure imgf000201_0001
(I) (Π) (HI) or a form thereof, wherein,
the dashed line "— " represents the presence of an optional double bond;
X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-;
Z is O or -CH(R )-, provided that, when Z is O, then X is selected from -CH(R )-,
-CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-;
Ri and R2 are each, when present, selected from hydrogen, halogen, Ci-galkyl-amino, (C1_8alkyl)2-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl,
(C1_1oalkyl)2-amino-C1_8alkyl, C2-galkenyl-amino-C1_galkyl,
C2-galkynyl-amino-C1_galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl,
Ci-galkoxy-carbonyl-amino, (Ci-galkoxy-carbony^Ci-galky^amino,
(C1-galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl,
Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1_galkyl)2-amino-C1_galkyl-amino-C1_galkyl,
[(C1_galkyl)2-amino-C1_galkyl,C1_galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1-galkyl)2-amino-carbonyl-C1-galkyl-amino-C1_galkyl,
Cs-Hcycloalkyl-amino-Ci-galkyl, C^wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl, provided that, when Ri and R2 are both present, Ri is hydrogen when R2 is other than hydrogen and R2 is hydrogen when Ri is other than hydrogen,
wherein each instance of C3_i4cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally
substituted with one, two or three substituents each selected from R6;
R3 is hydrogen or Ci_galkyl;
R4 is hydrogen, Ci-salkyl, amino, ^salkyl- amino, (Ci-8alkyl)2-amino,
amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl or (C1-1oalkyl)2-amino-C1_8alkyl;
R5 is hydrogen, Ci-galkyl, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl,
(C1_1oalkyl)2-amino-C1_8alkyl or hydroxyl-Ci-galkyl;
R6 is halogen, hydroxyl, cyano, Ci^alkyl, Ci_8alkoxy, amino, Ci_8alkyl-amino or
(Ci-8alkyl)2-amino; and,
R7 is hydrogen or Ci-galkyl;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
2. The compound of claim 1, wherein the com ound is a compound of Formula (I):
Figure imgf000202_0001
(I)
or a form thereof, wherein,
X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-;
Z is O or -CH(R )-, provided that, when Z is O, then X is selected from -CH(R )-,
-CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-;
Ri and R2 are each selected from hydrogen, halogen, Ci_8alkyl-amino, (Ci_8alkyl)2-amino, amino-Ci_8alkyl, Ci-ioalkyl-amino-Ci-salkyl, (C1-8alkyl)2-amino-C1_8alkyl, C2-galkenyl-amino-Ci_galkyl, C2-galkynyl-amino-Ci_galkyl,
Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, Ci_galkoxy-carbonyl-amino,
(Ci-galkoxy-carbony^Ci-galky^amino, (^galkyl amino-Ci-galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl-amino-C1_galkyl,
[(C1_galkyl)2-amino-C1_galkyl,C1_galkyl]amino-C1_galkyl, hydroxyl-Ci_galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1-galkyl)2-amino-carbonyl-C1-galkyl-amino-C1-galkyl,
Cs-Hcycloalkyl-amino-Ci-galkyl, C^wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl, provided that, when Ri and R2 are both present, Ri is hydrogen when R2 is other than hydrogen and R2 is hydrogen when Ri is other than hydrogen,
wherein each instance of C3_i4cycloalkyl, aryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R6;
R3 is hydrogen or Ci-galkyl;
R6 is halogen, hydroxyl, cyano, Ci_galkyl, Ci_galkoxy, amino, Ci_galkyl-amino or
(Ci-galkyl)2-amino; and,
R7 is hydrogen or Ci-galkyl;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
3. The compound of claim 1, wherein the compound is a compound of Formula (II):
Figure imgf000204_0001
or a form thereof, wherein,
the dashed line "— " represents an optional double bond;
X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-;
Z is O or -CH(R )-, provided that, when Z is O, then X is selected from -CH(R )-,
-CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-;
Ri is selected from hydrogen, halogen, Ci-galkyl-amino,
Figure imgf000204_0002
amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C1_1oalkyl)2-amino-C1_8alkyl,
Figure imgf000204_0003
C^galkynyl-amino-Ci-galkyl,
Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, Ci-galkoxy-carbonyl-amino,
(Ci-galkoxy-carbony^Ci-galky^amino, (C1_galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl,
Cs-Hcycloalkyl-amino-Ci-galkyl, C^wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C^ncycloalkyl, aryl, heteroaryl or heterocyclyl is optionally
substituted with one, two or three substituents each selected from R6;
R3 is hydrogen or Ci-galkyl; R5 is hydrogen, Ci-galkyl, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl,
(C1_1oalkyl)2-amino-C1_8alkyl or hydroxyl-Ci-galkyl; and,
R6 is halogen, hydroxyl, cyano, Ci-galkyl, Q-galkoxy, amino, Ci-galkyl-amino or
(C1_8alkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
4. The compound of claim 3, wherein the compound of Formula (II) is selected from a compound of Formula (Ila) and Formula (lib):
Figure imgf000205_0001
or a form thereof, wherein,
X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-;
Z is O or -CH(R3)-, provided that, when Z is O, then X is selected from -CH(R3)-,
-CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-;
Ri is selected from hydrogen, halogen, Ci-galkyl-amino, (C1_galkyl)2-amino, amino-Ci_galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C1_galkyl)2-amino-C1_galkyl, C^galkenyl-amino-Ci-galkyl, C^galkynyl-amino-Ci-galkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl,
Ci-galkoxy-carbonyl-amino, (Ci-galkoxy-carbony^Ci-galky^amino,
(C1_galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl,
Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl,
(C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1_8alkyl)2-amino-carbonyl-C1_8alkyl-amino-C1_8alkyl,
Cs-Hcycloalkyl-amino-Ci-galkyl, C^wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-^galkyl-amino-Ci-galkyl, heteroaryl-^galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R6;
R3 is hydrogen or Ci-galkyl;
R5 is hydrogen, Ci-galkyl, amino-Ci_galkyl, Ci-ioalkyl-amino-Ci-galkyl,
(C1_galkyl)2-amino-C1_galkyl or hydroxyl-Ci_galkyl; and,
R6 is halogen, hydroxyl, cyano, Ci-galkyl, Ci-galkoxy, amino, Ci-galkyl-amino or
(C1_galkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
5. The compound of claim 1, wherein the com ound is a compound of Formula (III):
Figure imgf000206_0001
(III)
or a form thereof, wherein,
the dashed line "— " represents an optional double bond;
X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-;
Z is O or -CH(R )-, provided that, when Z is O, then X is selected from -CH(R )-,
-CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-; Ri is selected from hydrogen, halogen, Ci_galkyl-amino, (C1_8alkyl)2-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C1_1oalkyl)2-amino-C1_galkyl,
C2-galkenyl-amino-Ci_galkyl, C2-galkynyl-amino-Ci_galkyl,
^galkoxy-^galkyl-amino-Ci-galkyl, ^galkoxy-carbonyl-amino,
(Ci-galkoxy-carbony^Ci-galky^amino, (C1_8alkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl, (C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1-galkyl)2-amino-C1-galkyl,C1-galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1_galkyl)2-amino-carbonyl-C1_galkyl-amino-C1_galkyl,
Cs-^cycloalkyl-amino-Ci-galkyl, C3_14cycloalkyl-^galkyl-amino-^galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci_galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C3_14cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally
substituted with one, two or three substituents each selected from R6;
R3 is hydrogen or Ci_galkyl;
R4 is hydrogen, Ci_galkyl, amino, Ci_galkyl-amino, (C1_galkyl)2-amino,
amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl or (C1_1oalkyl)2-amino-C1_galkyl;
R5 is hydrogen, Ci-galkyl, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl,
(C1_1oalkyl)2-amino-C1_galkyl or hydroxyl-Ci-galkyl; and,
R6 is halogen, hydroxyl, cyano, Ci_galkyl, Ci-galkoxy, amino, Ci_galkyl-amino or
(Ci_galkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
6. The compound of claim 5, wherein the compound of Formula (III) is selected from a compound of Formula (Ilia) or Formula (Illb):
Figure imgf000208_0001
(Ilia) (nib)
or a form thereof, wherein,
X is -CH(R3)-, -CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)-, -C(R3)=C(R3)-, -CH(R3)-0-, -0-CH(R3)-, -0-CH(R3)-CH(R3)-, -CH(R3)-0-CH(R3)- or -S-CH(R3)-;
Z is O or -CH(R3)-, provided that, when Z is O, then X is selected from -CH(R3)-,
-CH(R3)-CH(R3)-, -CH(R3)-CH(R3)-CH(R3)- or -C(R3)=C(R3)-;
Ri is selected from hydrogen, halogen, Ci-galkyl-amino, (C1_8alkyl)2-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C1_1oalkyl)2-amino-C1_8alkyl,
C^galkenyl-amino-Ci-galkyl, C^galkynyl-amino-Ci-galkyl,
Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, Ci-galkoxy-carbonyl-amino,
(Ci-galkoxy-carbony^Ci-galky^amino, (C1_galkyl)2-amino-C1_galkyl-amino, amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl, (C1-galkyl)2-amino-C1-galkyl-amino-C1_galkyl,
[(C1_galkyl)2-amino-C1_galkyl,C1_galkyl]amino-C1_galkyl, hydroxyl-Ci-galkyl, hydroxyl-Ci-galkyl-amino-Ci-galkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C1-galkyl)2-amino-carbonyl-C1-galkyl-amino-C1_galkyl,
Cs-^cycloalkyl-amino-Ci-galkyl, Cs-wcycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-galkyl-amino-Ci-galkyl, heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-galkyl, heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl,
wherein each instance of C^wcycloalkyl, aryl, heteroaryl or heterocyclyl is optionally
substituted with one, two or three substituents each selected from R6;
R is hydrogen or Ci-galkyl; R4 is hydrogen, Ci_galkyl, amino, Ci_galkyl-amino, (C1_8alkyl)2-amino,
amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl or (C1_1oalkyl)2-amino-C1_galkyl;
R5 is hydrogen, Ci-galkyl, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl,
(C1-1oalkyl)2-amino-C1_galkyl or hydroxyl-Ci-galkyl; and,
R6 is halogen, hydroxyl, cyano, Ci-galkyl, Ci-galkoxy, amino, Ci_galkyl-amino or
(Ci_galkyl)2-amino;
wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof. 7. A compound or a form thereof selected from the group consisting of:
4-hydroxy-9-methyl-10-{ [(2-methylbutan-2-yl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-[(prop-2-en-l-ylamino)methyl]-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-2-oxo-2,5,6,9-tetrahydro-lH-pyrido[2',3':4,5]thiepino[3,2-f]indole-3- carboxylic acid
10-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-2,5,6,7- tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-pyrido[2',3':4,5]thiepino[3,2- f]indole-3-carboxylic acid
10-[(dimethylamino)methyl]-4-hydroxy-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
10-[(ethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10-[(dimethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10-[(butan-2-ylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10-[(cyclobutylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid 4-hydroxy-6,9-dimethyl-10-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
4-hydroxy-10-(hydroxymethyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-2-oxo-2,6,7,9-tetrahydro-lH-pyrido[3',2':2,3]oxepino[4,5-f|indole-3- carboxylic acid
10-(aminomethyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-2,6,7,9-tetrahydro-lH-pyrido[3',2':2,3]oxepino[4,5- f]indole-3-carboxylic acid
10-[(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
10-[(tert-butylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
10- [(cyclopropylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-2-oxo-9-[3-(pyrrolidin-l-yl)propyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid
4-hydroxy-2-oxo-9-[2-(pyrrolidin-l-yl)ethyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid
9-(dimethylamino)-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9-[(ethoxycarbonyl)(methyl)amino]-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro- lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
11- [(butan-2-ylamino)methyl]-4-hydroxy-10-methyl-2-oxo- 1,2,5, 6,7, 10- hexahydropyrido[2',3':4,5]oxocino[3,2-f|indole-3-carboxylic acid 10- { [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl- 10- { [(l-methylcyclobutyl)amino]methyl}-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-[(2-methylpyrrolidin-l-yl)methyl] -2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-[(3,3-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
10-[(2,2-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy- 10-methyl- 11 - { [( 1 -methylcyclobutyl)amino]methyl } -2-oxo- 1,2,5,6,7, 10-hexahydropyrido[2',3':4,5]oxocino[3,2-f]indole-3-carboxylic acid
4-hydroxy- 10-[3-(methylamino)pyrrolidin- l-yl]-2-oxo-2,5,6,8-tetrahydro- 1H- [2]benzoxocino[6,5-b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo- 1,5,7, 9-tetrahydro-2H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylic acid
9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
4-hydroxy-8-methyl-9-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid
4-hydroxy-8-methyl-9-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid
9-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-[(propan-2-ylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid 9-[(cyclobutylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
9-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid
9-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid
9- (dimethylamino)-4-hydroxy-2-oxo-l,2,5,7-tetrahydro[2]benzoxepino[5,4- b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,5,7,9-tetrahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f]indole-3-carboxylic acid
4-hydroxy-2-oxo-l,5,7,9,10,l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-l,5,7,9,10,l l-hexahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f]indole-3-carboxylic acid
4-hydroxy-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5- f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-2,6,7,9,10,l l-hexahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid
4-hydroxy-2-oxo- 1,2,5, 6,7, l l-hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3- carboxylic acid
10- [(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-2-oxo-2,5,6,l l-tetrahydro-lH-pyrido[2',3':4,5]oxepino[2,3-f|indole-3- carboxylic acid
10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid
10-{ [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,l l- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl- 10- { [(l-methylcyclobutyl)amino]methyl}-2-oxo- 1,2,5,6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid l l-[(dimethylamino)methyl]-4-hydroxy-10-methyl-2-oxo-2,5,6,7,8,12-hexahydro- lH-pyrido[2',3':3,4]cycloocta[l,2-f]indole-3-carboxylic acid, and
9- [(dimethylamino)methyl]-4-hydroxy-2-oxo- 1,2,5, 6,
7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
8. The compound of claim 7, wherein a compound salt or a form thereof is selected from the group consisting of:
4-hydroxy-9-methyl-10-{ [(2-methylbutan-2-yl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
hydrochloride
4-hydroxy-9-methyl-2-oxo-10-[(prop-2-en-l-ylamino)methyl]-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10- [(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-2,5,6,7- tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
trifluoroacetate
10-[(ethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(dimethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(butan-2-ylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(cyclobutylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-6,9-dimethyl-10-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
hydrochloride 4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
hydrochloride
10-(aminomethyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid trifluoroacetate
10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(tert-butylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid trifluoroacetate
10-[(tert-butylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(cyclopropylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid trifluoroacetate
10- [(cyclopropylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-9-[3-(pyrrolidin-l-yl)propyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-9-[2-(pyrrolidin-l-yl)ethyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid hydrochloride
9- (dimethylamino)-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
11- [(butan-2-ylamino)methyl]-4-hydroxy-10-methyl-2-oxo- 1,2,5, 6,7, 10- hexahydropyrido[2',3':4,5]oxocino[3,2-f]indole-3-carboxylic acid hydrochloride
10- { [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride 4-hydroxy-9-methyl- 10- { [(l-methylcyclobutyl)amino]methyl}-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-[(2-methylpyrrolidin-l-yl)methyl]-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-[(3,3-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-[(2,2-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy- 10-methyl- 11-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo- 1,2,5,6,7, 10- hexahydropyrido[2',3':4,5]oxocino[3,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy- 10-[3-(methylamino)pyrrolidin- l-yl]-2-oxo-2,5,6,8-tetrahydro- 1H- [2]benzoxocino[6,5-b]pyridine-3-carboxylic acid trifluoroacetate
9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-9-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-9-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
9-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-[(propan-2-ylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
9-[(cyclobutylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
9-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid hydrochloride 9- [(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,5,7,9-tetrahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-l,5,7,9,10,l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-l,5,7,9,10,l l-hexahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5- f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-2,6,7,9,10,l l-hexahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid hydrochloride
10- [(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10- { [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,l l- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl- 10- { [(l-methylcyclobutyl)amino]methyl}-2-oxo- 1,2,5,6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
11- [(dimethylamino)methyl]-4-hydroxy-10-methyl-2-oxo-2,5,6,7,8,12-hexahydro- lH-pyrido[2',3':3,4]cycloocta[l,2-f|indole-3-carboxylic acid hydrochloride, and
9-[(dimethylamino)methyl]-4-hydroxy-2-oxo- 1,2,5, 6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride; wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer,
diastereomer, stereoisomer, polymorph and tautomer form thereof.
9. A method of use for a 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.
10. The method of claim 9, wherein a compound or a form thereof is selected from the group consisting of:
4-hydroxy-9-methyl-10-{ [(2-methylbutan-2-yl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-[(prop-2-en-l-ylamino)methyl]-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-2-oxo-2,5,6,9-tetrahydro-lH-pyrido[2',3':4,5]thiepino[3,2-f]indole-3- carboxylic acid
10-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-2,5,6,7- tetrahydro- lH-benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH-pyrido[2',3':4,5]thiepino[3,2- f]indole-3-carboxylic acid
10-[(dimethylamino)methyl]-4-hydroxy-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid
10-[(ethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10-[(dimethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10-[(butan-2-ylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
10-[(cyclobutylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-6,9-dimethyl-10-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
4-hydroxy-10-(hydroxymethyl)-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid 4-hydroxy-2-oxo-2,6,7,9-tetrahydro-lH-pyrido[3',2':2,3]oxepino[4,5-f]indole-3- carboxylic acid
10-(aminomethyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f|indole-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-2,6,7,9-tetrahydro-lH-pyrido[3',2':2,3]oxepino[4,5- f]indole-3-carboxylic acid
10-[(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f|indole-3-carboxylic acid
10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f|indole-3-carboxylic acid
10-[(tert-butylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f|indole-3-carboxylic acid
10- [(cyclopropylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f|indole-3-carboxylic acid
4-hydroxy-2-oxo-9-[3-(pyrrolidin-l-yl)propyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f|indole-3-carboxylic acid
4-hydroxy-2-oxo-9-[2-(pyrrolidin-l-yl)ethyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f|indole-3-carboxylic acid
9-(dimethylamino)-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
9- [(ethoxycarbonyl)(methyl)amino]-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro- lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
11- [(butan-2-ylamino)methyl]-4-hydroxy-10-methyl-2-oxo- 1,2,5,6,7, 10- hexahydropyrido[2',3':4,5]oxocino[3,2-f]indole-3-carboxylic acid
10- { [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-l,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
4-hydroxy-9-methyl-10-[(2-methylpyrrolidin-l-yl)methyl]-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid 10-[(3,3-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
10-[(2,2-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f|indole-3-carboxylic acid
4-hydroxy- 10-methyl- 11 - { [( 1 -methylcyclobutyl)amino] methyl } -2-oxo- 1 ,2,5 ,6,7 , 10- hexahydropyrido[2',3':4,5]oxocino[3,2-f]indole-3-carboxylic acid
4-hydroxy- 10-[3-(methylamino)pyrrolidin-l-yl]-2-oxo-2,5, 6, 8-tetrahydro-lH- [2]benzoxocino[6,5-b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-l,5,7,9-tetrahydro-2H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylic acid
9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
4-hydroxy-8-methyl-9-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid
4-hydroxy-8-methyl-9-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid
9-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
4-hydroxy-8-methyl-2-oxo-9-[(propan-2-ylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
9-[(cyclobutylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid
9-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid
9-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid 9- (dimethylamino)-4-hydroxy-2-oxo-l,2,5,7-tetrahydro[2]benzoxepino[5,4- b]pyridine-3-carboxylic acid
4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)- 1,5,7, 9-tetrahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f|indole-3-carboxylic acid
4-hydroxy-2-oxo- 1,5,7,9, 10,1 l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3-f]indole-
3- carboxylic acid
4- hydroxy-9-methyl-2-oxo- 1,5,7,9, 10, l l-hexahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f|indole-3-carboxylic acid
4-hydroxy-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5-f]indole-
3- carboxylic acid
4- hydroxy-9-methyl-2-oxo-2,6,7,9,10,l l-hexahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f|indole-3-carboxylic acid
4-hydroxy-2-oxo- 1, 2,5,6,7, l l-hexahydropyrido[2',3':3,4]cyclohepta[l,2-f|indole-3- carboxylic acid
10- [(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7, 11- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-f] indole-3 -carboxylic acid
4-hydroxy-2-oxo-2,5,6,l l-tetrahydro-lH-pyrido[2',3':4,5]oxepino[2,3-f]indole-3- carboxylic acid
10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 11- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-f] indole-3 -carboxylic acid
10- { [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7, 11- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-f] indole-3 -carboxylic acid
4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-l,2,5,6,7,l l- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-f] indole-3 -carboxylic acid
11- [(dimethylamino)methyl]-4-hydroxy-10-methyl-2-oxo-2,5, 6,7,8, 12-hexahydro- lH-pyrido[2',3':3,4]cycloocta[l,2-f]indole-3-carboxylic acid, and
9-[(dimethylamino)methyl]-4-hydroxy-2-oxo- 1,2,5,6,7, 11- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-f] indole-3 -carboxylic acid; wherein a form of the compound is selected from the group consisting of a prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
11. The method of claim 10, wherein a compound salt or a form thereof is selected from the group consisting of:
4-hydroxy-9-methyl-10-{ [(2-methylbutan-2-yl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
hydrochloride
4-hydroxy-9-methyl-2-oxo-10-[(prop-2-en-l-ylamino)methyl]-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo-2,5,6,7- tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylic acid
trifluoroacetate
10-[(ethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(dimethylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(butan-2-ylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(cyclobutylamino)methyl]-4-hydroxy-6,9-dimethyl-2-oxo-2,5,6,9-tetrahydro- lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-6,9-dimethyl-10-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
hydrochloride
4-hydroxy-9-methyl-10-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,9- tetrahydro-lH-pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid
hydrochloride
10-(aminomethyl)-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]oxepino[3,2-f]indole-3-carboxylic acid hydrochloride 10-[(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid trifluoroacetate
10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(tert-butylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid trifluoroacetate
10-[(tert-butylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride
10-[(cyclopropylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid trifluoroacetate
10- [(cyclopropylamino)methyl]-4-hydroxy-9-methyl-2-oxo-2,5,6,9-tetrahydro-lH- pyrido[2',3':4,5]thiepino[3,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-9-[3-(pyrrolidin-l-yl)propyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-9-[2-(pyrrolidin-l-yl)ethyl]-2,6,7,9-tetrahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid hydrochloride
9- (dimethylamino)-4-hydroxy-8-methyl-2-oxo-2,5,6,7-tetrahydro-lH- benzo[6,7]cyclohepta[ 1 ,2-b]pyridine-3-carboxylic acid hydrochloride
11- [(butan-2-ylamino)methyl]-4-hydroxy-10-methyl-2-oxo- 1,2,5, 6,7, 10- hexahydropyrido[2',3':4,5]oxocino[3,2-f]indole-3-carboxylic acid hydrochloride
10- { [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl- 10- { [(l-methylcyclobutyl)amino]methyl}-2-oxo- 1,2,5,6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-10-[(2-methylpyrrolidin-l-yl)methyl]-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-[(3,3-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride 10-[(2,2-dimethylpyrrolidin-l-yl)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7,9- hexahydropyrido[3',2':6,7]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy- 10-methyl- 11-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo- 1,2,5,6,7, 10- hexahydropyrido[2',3':4,5]oxocino[3,2-f|indole-3-carboxylic acid hydrochloride
4-hydroxy- 10-[3-(methylamino)pyrrolidin- l-yl]-2-oxo-2,5,6,8-tetrahydro- 1H- [2]benzoxocino[6,5-b]pyridine-3-carboxylic acid trifluoroacetate
9-[(ethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-[(propylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-9-{ [(l-methylcyclopropyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-9-{ [(l-methylcyclobutyl)amino]methyl}-2-oxo-2,5,6,8- tetrahydro- lH-indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
9-[(dimethylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-(pyrrolidin-l-ylmethyl)-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
4-hydroxy-8-methyl-2-oxo-9-[(propan-2-ylamino)methyl]-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
9-[(cyclobutylamino)methyl]-4-hydroxy-8-methyl-2-oxo-2,5,6,8-tetrahydro-lH- indolo[6,5-h]quinoline-3-carboxylic acid hydrochloride
9-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid hydrochloride
9-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-4-hydroxy-2-oxo- 1,2,5,7- tetrahydro[2]benzoxepino[5,4-b]pyridine-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-10-(pyrrolidin-l-ylmethyl)-l,5,7,9-tetrahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-l,5,7,9,10,l l-hexahydro-2H-pyrido[2',3':5,6]oxepino[4,3- f]indole-3-carboxylic acid hydrochloride 4-hydroxy-9-methyl-2-oxo-l,5,7,9,10,l l-hexahydro-2H- pyrido[2',3':5,6]oxepino[4,3-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-2-oxo-2,6,7,9,10,l l-hexahydro-lH-pyrido[3',2':2,3]oxepino[4,5- f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl-2-oxo-2,6,7,9,10,l l-hexahydro-lH- pyrido[3',2':2,3]oxepino[4,5-f]indole-3-carboxylic acid hydrochloride
10-[(dimethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5, 6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10-[(ethylamino)methyl]-4-hydroxy-9-methyl-2-oxo- 1,2,5,6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
10- { [ethyl(methyl)amino]methyl}-4-hydroxy-9-methyl-2-oxo-l,2,5,6,7,l l- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
4-hydroxy-9-methyl- 10- { [(l-methylcyclobutyl)amino]methyl}-2-oxo- 1,2,5,6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride
11- [(dimethylamino)methyl]-4-hydroxy-10-methyl-2-oxo-2,5,6,7,8,12-hexahydro- lH-pyrido[2',3':3,4]cycloocta[l,2-f|indole-3-carboxylic acid hydrochloride, and
9-[(dimethylamino)methyl]-4-hydroxy-2-oxo- 1,2,5, 6,7, 11- hexahydropyrido[2',3':3,4]cyclohepta[l,2-f]indole-3-carboxylic acid hydrochloride; wherein a form of the compound salt is selected from the group consisting of a prodrug, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.
12. The method of any of claims 9 to 11, wherein the effective amount of the compound is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.
13. A use of a 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.
14. A use of a 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. 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.
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).
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).
The use of any of claims 13 to 17, 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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