WO2016025933A2

WO2016025933A2 - Substituted polycyclic antibacterial compounds

Info

Publication number: WO2016025933A2
Application number: PCT/US2015/045433
Authority: WO
Inventors: Jiashi WANG; Aleksey Igorevich GERASYUTO; Michael A. ARNOLD; Gary Mitchell Karp; Hongyan Qi; Matthew G. WOLL; Nanjing Zhang; Arthur A. Branstrom; Jana Narasimhan; Melissa L. DUMBLE; Jean Hedrick; Maria L. WEETALL
Original assignee: Ptc Therapeutics, Inc.
Priority date: 2014-08-15
Filing date: 2015-08-15
Publication date: 2016-02-18
Also published as: WO2016025933A3

Abstract

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 and Neisseria meningiditis.

Description

SUBSTITUTED POLYCYCLIC ANTIBACTERIAL COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Patent Provisional Application No.

62/038,135, 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) or Neisseria meningitidis (N. meningitidis). More particularly, the present description relates to substituted 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 or N. meningitidis.

BACKGROUND

Neisseria is a large genus of generally commensal Gram-negative bacteria that colonize the mucosal surfaces of many animals, with N. gonorrhoeae and N. meningitidis being two of the more well-known pathogenic Neisseria species. The facile ability of N. gonorrhoeae to develop drug resistance makes N. gonorrhoeae a rapidly emerging global health threat, and is considered to be an emerging superbug. 820,000 new cases of

N. gonorrhoeae are estimated to occur in just the United States every year. 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 ) and about 13% is estimated to be quinolone resistant (quinolone ). 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 ), ciprofloxacin-resistant

(ciprofloxacin R ) and ampicillin-resistant (ampicillin R ). 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.

An exclusively human pathogen, N. meningitidis is commonly associated with the flora of the nasopharynx. Although usually considered non-pathogenic, it is opportunistic, having the ability to cause meningitis and sepsis. Individuals who are immunocomprised are most at risk of infection. One in every 100,000 individuals in the United States are estimated to become infected every year, with children under the age of five being especially vulnerable. An infected individual requires rapid antibiotic intervention before potentially fatal bacterial dissemination occurs. There remains a need for effective, orally deliverable therapies and novel compounds active against forms of N. meningitidis. 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), Formula Formula (IV):

wherein the dashed line "— " represents an optional double bond and R_1; R₂, R5, 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), Formula (III) or Formula (IV) or a form thereof and methods for treating or ameliorating Neisseria gonorrhoeae (N. gonorrhoeae) or

Neisseria meningitidis (N. meningitidis) in a subject in need thereof, comprising,

administering an effective amount of the compound to the subject.

In particular, the present description relates to a compound of Formula (I), Formula

(II), Formula (III) or Formula (IV) and forms and compositions thereof, and to uses of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) and forms and compositions thereof, and methods for treating or ameliorating N. gonorrhoeae in a subject in need thereof, comprising, administering an effective amount of the compound, and forms and compositions thereof, to the subject.

In particular, the present description relates to a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) and forms and compositions thereof, and to uses of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) and forms and compositions thereof, and methods for treating or ameliorating N. meningitidis in a subject in need thereof, comprising, administering an effective amount of the compound, and forms and compositions thereof, to the subject. The present description further relates to a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof having activity against wild-type or drug- resistant forms of N. gonorrhoeae or N. meningitidis.

More particularly, the present description relates to a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof having activity against wild- type forms of N. gonorrhoeae or N. meningitidis.

The present description also relates to a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof having activity against drug-resistant forms of N. gonorrhoeae or N. meningitidis.

The present description also relates to a compound of Formula (I), Formula (II),

Formula (III) or Formula (IV) or a form thereof having activity against N. gonorrhoeae resistant to one or more known antibacterial or antibiotic agents, wherein drug resistance may be classified as intermediate resistance (IR), high level resistance (HLR), multi-drug resistant (MDR), multi-drug intermediate resistant (MD^∑R) or extensively drug resistant (XDR).

More particularly, the present description relates to a compound of Formula (I),

Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof in combination with known agents having additive or synergistic activity, thus providing a combination product for the treatment of N. gonorrhoeae or N. meningitidis.

The present description further relates to use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating wild- type or drug-resistant forms of N. gonorrhoeae or N. meningitidis.

More particularly, the present description relates to use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating wild- type forms of N. gonorrhoeae or N. meningitidis. The present description also relates to use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating drug- resistant forms of N. gonorrhoeae or N. meningitidis.

The present description also relates to use of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof in combination with known agents having additive or synergistic activity, thus providing a combination product for the treatment of N. gonorrhoeae or N. meningitidis.

DETAILED DESCRIPTION

The present description relates to substituted polycyclic compounds selected from a compound of Formula (I), Formula (II), Formula (III) or Formula (IV):

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(R₄)-, 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, (Ci_galkyl)₂-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (Ci-ioalkyl amino-Ci-galkyl,

C^galkenyl-amino-Ci-galkyl, C^galkynyl-amino-Ci-galkyl,

Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, (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, 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;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci-galkyl;

R₄ is hydrogen or Ci-galkyl;

R5 is hydrogen, Ci-galkyl, amino, Ci_galkyl-amino, (Ci_galkyl)₂-amino,

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;

with the proviso that a compound of Formula (I) is other than:

7-hydroxy-l-methyl-2-((methylamino)methyl)-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid; and, 2-((ethylamino)methyl)-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-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.

One embodiment of the present description includes a compound of Formula (I):

or a form thereof, wherein,

the dashed line represents an optional double bond;

Z is O or -CH(R₄)-, provided that, when Z is O, then X is selected

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, (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-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 C₃_₁₄cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R₆;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci-galkyl;

R₄ is hydrogen or Ci-galkyl;

R₅ is hydrogen, C_1-8alkyl, amino, Ci-galkyl-amino, (C₁_galkyl)₂-amino,

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;

with the proviso that a compound of Formula (I) is other than:

7-hydroxy-l-methyl-2-((methylamino)methyl)-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid; and, 2-((ethylamino)methyl)-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid;

One embodiment of the present descri tion includes a compound of Formula (la):

(la)

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(R₄)-, provided that, when Z is O, then X is selected

C^galkenyl-amino-Ci-galkyl, C^galkynyl-amino-Ci-galkyl,

substituted with one, two or three substituents each selected from R₆;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci-galkyl;

R₄ is hydrogen or Ci-galkyl;

R5 is hydrogen, Ci-galkyl, amino, Ci_galkyl-amino, (Ci_galkyl)₂-amino,

(Ci_galkyl)₂-amino;

with the proviso that a compound of Formula (I) is other than:

7-hydroxy-l-methyl-2-((methylamino)methyl)-9-oxo- 1,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid; and,

2-((ethylamino)methyl)-7-hydroxy-l-methyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-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. One embodiment of the present description includes a compound of Formula (lb):

or a form thereof, wherein,

Z is O or -CH(R₄)-, provided that, when Z is O, then X is selected

C^galkynyl-amino-Ci-galkyl,

Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, (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,

substituted with one, two or three substituents each selected from R₆;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci-galkyl; R₄ is hydrogen or Ci-galkyl;

R₅ is hydrogen, Ci-galkyl, amino, Ci-galkyl-amino, (C₁_₈alkyl)₂-amino,

amino-Ci-galkyl, C oalkyl-amino-Ci-galkyl, (C₁_₁oalkyl)₂-amino-C₁_₈alkyl or hydroxyl-Ci-galkyl; and,

(C₁_galkyl)₂-amino;

One embodiment of the present descri tion includes a compound of Formula (II)

or a form thereof, wherein,

the dashed line represents an optional double bond;

Z is O or -CH(R₄)-, provided that, when Z is O, then X is selected

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,

C₃-₁₄cycloalkyl-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,

substituted with one, two or three substituents each selected from R₆;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci-galkyl;

R₄ is hydrogen or Ci-galkyl;

R₅ is hydrogen, Ci-galkyl, amino, Ci-galkyl-amino, (Ci_galkyl)₂-amino,

(Ci-galkyl)₂-amino;

One embodiment of the present descri tion includes a compound of Formula (Ila):

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(R₄)-, provided that, when Z is O, then X is selected

Ri is selected from hydrogen, halogen, Ci-galkyl-amino,

amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (Ci-ioalkyl amino-Ci-galkyl,

C^galkenyl-amino-Ci-galkyl, C^galkynyl-amino-Ci-galkyl,

C₃-₁₄cycloalkyl-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,

substituted with one, two or three substituents each selected from R₆;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci_galkyl;

R₄ is hydrogen or Ci_galkyl;

R5 is hydrogen, Ci_galkyl, amino, Ci-galkyl-amino, (C₁_galkyl)₂-amino,

(C₁_galkyl)₂-amino;

One embodiment of the present description includes a compound of Formula (lib)

(lib)

or a form thereof, wherein,

Z is O or -CH(R₄)-, provided that, when Z is O, then X is selected

Ri is selected from hydrogen, halogen, Ci_₈alkyl-amino, (Ci_₈alkyl)₂-amino, amino-Ci_₈alkyl, Ci-ioalkyl-amino-Ci-galkyl, (Ci-ioalkyl amino-Ci-galkyl,

C₂-galkenyl-amino-C₁_galkyl, C₂-galkynyl-amino-C₁_galkyl,

Ci-salkoxy-Ci-salkyl-amino-Ci-salkyl, (C₁_₈alkyl)₂-amino-C₁_₈alkyl-amino, amino-Ci-salkyl-amino-Ci-salkyl, ^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, hydroxyl-Ci-salkyl-amino-Ci-salkyl, (hydroxyl-Ci-galky^Ci-galky^amino-Ci-galkyl, (C₁-₈alkyl)₂-amino-carbonyl-C₁-₈alkyl-amino-C₁_₈alkyl,

C₃-₁₄cycloalkyl-amino-Ci-₈alkyl, 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,

substituted with one, two or three substituents each selected from R₆;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci_galkyl;

R₄ is hydrogen or Ci-galkyl; R5 is hydrogen, Ci_galkyl, amino, Ci_galkyl-amino, (C₁_₈alkyl)₂-amino,

(C₁_₈alkyl)₂-amino;

One embodiment of the present descri tion includes a compound of Formula (III):

or a form thereof, wherein,

the dashed line represents an optional double bond;

Z is O or -CH(R₄)-, provided that, when Z is O, then X is selected

Ri is selected from 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,

[(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,

substituted with one, two or three substituents each selected from R₆;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci-galkyl;

R₄ is hydrogen or C_1-8alkyl;

R₅ is hydrogen, C_1-8alkyl, amino, Ci_galkyl-amino, (C₁_galkyl)₂-amino,

R₆ is halogen, hydroxyl, cyano, Ci-galkyl, Ci-galkoxy, amino, Ci_galkyl-amino or

(Ci_galkyl)₂-amino;

One embodiment of the present descri tion includes a compound of Formula (Ilia):

(Ilia)

or a form thereof, wherein,

Z is O or -CH(R₄)-, 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, (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,

Cs-Hcycloalkyl-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,

substituted with one, two or three substituents each selected from R₆;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci_galkyl;

R₄ is hydrogen or Ci_galkyl;

R₅ is hydrogen, Ci-galkyl, amino, Ci-galkyl-amino, (C₁_galkyl)₂-amino,

R₆ is halogen, hydroxyl, cyano, Ci_galkyl, Ci-galkoxy, amino, Ci-galkyl-amino or

(Ci-galkyl)₂-amino;

One embodiment of the present description includes a compound of Formula (Illb):

(nib)

or a form thereof, wherein,

Z is O or -CH(R₄)-, provided that, when Z is O, then X is selected

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, (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,

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,

substituted with one, two or three substituents each selected from R₆;

R₂ is hydrogen or halogen;

R is hydrogen or Ci-galkyl;

R₄ is hydrogen or Ci-galkyl; R5 is hydrogen, Ci_galkyl, amino, Ci-galkyl-amino, (C₁_₈alkyl)₂-amino,

amino-Ci-galkyl, Ci_ioalkyl-amino-Ci_galkyl, (C₁_₁oalkyl)₂-amino-C₁_galkyl or

R₆ is halogen, hydroxyl, cyano, Ci-galkyl, Q-galkoxy, amino, Ci-galkyl-amino or

(C₁_galkyl)₂-amino; and,

One embodiment of the present descri tion includes a compound of Formula (IV):

or a form thereof, wherein,

the dashed line represents an optional double bond;

Z is O or -CH(R₄)-, provided that, when Z is O, then X is selected

Ri is selected from 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,

[(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,

substituted with one, two or three substituents each selected from R₆;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci-galkyl;

R₄ is hydrogen or C_1-8alkyl;

R₅ is hydrogen, C_1-8alkyl, amino, Ci_galkyl-amino, (C₁_galkyl)₂-amino,

(Ci_galkyl)₂-amino;

One embodiment of the present descri tion includes a compound of Formula (IVa):

(IVa)

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(R₄)-, provided that, when Z is O, then X is selected

C₂-galkenyl-amino-Ci_galkyl, C₂-galkynyl-amino-Ci-galkyl,

(C₁_galkyl)₂-amino-C₁_galkyl-amino-C₁_galkyl,

substituted with one, two or three substituents each selected from R₆;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci_galkyl;

R₄ is hydrogen or Ci_galkyl;

R₅ is hydrogen, Ci-galkyl, amino, Ci-galkyl-amino, (C₁_galkyl)₂-amino,

(Ci-galkyl)₂-amino;

One embodiment of the present description includes a compound of Formula (IVb):

(IVb)

or a form thereof, wherein,

Z is O or -CH(R₄)-, provided that, when Z is O, then X is selected

C^galkenyl-amino-Ci-galkyl, C^galkynyl-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,

substituted with one, two or three substituents each selected from R₆;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci-galkyl;

R₄ is hydrogen or C_halky!; R5 is hydrogen, Ci_galkyl, amino, Ci-galkyl-amino, (C₁_₈alkyl)₂-amino,

(C₁_galkyl)₂-amino;

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein,

Z is O or -CH(R₄)-, provided that, when Z is O, then X is selected

C₂_galkenyl-amino-Ci_galkyl, C₂_galkynyl-amino-Ci_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,

C₃-₁₄cycloalkyl-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,

substituted with one, two or three substituents each selected from R₆;

wherein C₃_₁₄cycloalkyl is selected in each instance, when present, from cyclopropyl,

cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

wherein aryl is selected in each instance, when present, from phenyl; wherein heteroaryl is selected in each instance, when present, from pyrrolyl, thiazolyl, 1H-

1,2,3-triazolyl, lH-tetrazolyl, 2H-tetrazolyl, imidazolyl or pyridinyl; and,

wherein heterocyclyl is 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]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl;

R₂ is hydrogen or halogen;

R₃ is hydrogen or C^aUcyl;

R₄ is hydrogen or C_halky!; R5 is hydrogen, Ci_galkyl, amino, Ci_galkyl-amino, (C₁_₈alkyl)₂-amino,

(C₁_₈alkyl)₂-amino;

with the proviso that a compound of Formula (I) is other than:

7-hydroxy-l-methyl-2-((methylamino)methyl)-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid; and,

2-((ethylamino)methyl)-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid;

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(R₄)-, 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 hydrogen, (C₁_₈alkyl)₂-amino, amino-Ci-galkyl, C oalkyl-amino-Ci-galkyl,

(C₁_₁oalkyl)₂-amino-C₁_galkyl, C^galkenyl-amino-Ci-galkyl, hydroxyl-Ci-galkyl, C₃_₁₄cycloalkyl-amino-Ci_galkyl, heterocyclyl or heterocyclyl-Ci_galkyl,

wherein each instance of C₃_₁₄cycloalkyl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R₆;

wherein C₃_₁₄cycloalkyl is selected in each instance, when present, from cyclopropyl or cyclobutyl; and,

wherein heterocyclyl is selected in each instance, when present, from pyrrolidinyl;

R₂ is hydrogen or halogen;

R is hydrogen or Ci-galkyl;

R₄ is hydrogen or Ci_galkyl;

R5 is hydrogen, Ci-galkyl, amino, Ci-galkyl-amino, (Ci_galkyl)₂-amino,

amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-galkyl, (C₁_₁oalkyl)₂-amino-C₁_galkyl or hydroxyl-Ci-galkyl; and, R₆ is Ci-galkyl, amino, Ci-galkyl-amino or (C₁_₈alkyl)₂-amino;

with the proviso that a compound of Formula (I) is other than:

One embodiment of the present description includes a compound of Formula (I), (II),

(III) or (IV) or a form thereof, wherein,

-0-CH(R₃)-, -0-CH(R₃)-CH(R₃)-, -CH(R₃)-0-CH(R₃)- or -S-CH(R₃)-;

Z is O or -CH(R₄)-, provided that, when Z is O, then X is selected

Ri is hydrogen, Ci-ioalkyl-amino-Ci-galkyl, (C₁_₁oalkyl)₂-amino-C₁_₈alkyl,

or heterocyclyl-Ci-galkyl,

wherein heterocyclyl is in each instance, when present, pyrrolidinyl;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci-galkyl;

R₄ is hydrogen or Ci-galkyl;

R5 is hydrogen, Ci_galkyl, amino, Ci_galkyl-amino, (C₁_galkyl)₂-amino,

R₆ is Ci-galkyl, amino, Ci_galkyl-amino or (C₁_galkyl)₂-amino;

with the proviso that a compound of Formula (I) is other than:

7-hydroxy- 1 -methyl-2-((methylamino)methyl)-9-oxo- 1,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid; and, 2-((ethylamino)methyl)-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid;

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) 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), (II),

(III) or (IV) or a form thereof, wherein X is -CH(R₃)-, -CH(R₃)-CH(R₃)-, - -CH(R₃)-CH(R₃)-CH(R₃)-, -C(R₃)=C(R₃)- or -0-CH(R₃)-CH(R₃)-.

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein X is -CH(R₃)-, -CH(R₃)-CH(R₃)-, - -CH(R₃)-CH(R₃)-CH(R₃)-, -C(R₃)=C(R₃)- or -CH(R₃)-0-.

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein Z is O or -CH(R₄)-, 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), (II), (III) or (IV) 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), (II), (III) or (IV) or a form thereof, wherein Z is -CH(R₄)-.

X is -CH(R₃)-, -CH(R₃)-CH(R₃)-, -CH(R₃)-CH(R₃)-CH(R₃)-, -C(R₃)=C(R₃)- or -CH(R₃)-0-; Z is O or -CH(R₄)-, 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^alkenyl-amino-Ci-salkyl, C^alkynyl-amino-Ci-salkyl, Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, (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,

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 Cs-^cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally

substituted with one, two or three substituents each selected from R₆;

wherein Cs-ncycloalkyl is selected in each instance, when present, from cyclopropyl,

cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

wherein aryl is selected in each instance, when present, from phenyl;

wherein heteroaryl is selected in each instance, when present, from pyrrolyl, thiazolyl, 1H- 1,2,3-triazolyl, lH-tetrazolyl, 2H-tetrazolyl, imidazolyl or pyridinyl; and,

wherein heterocyclyl is 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] [ 1 ,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, l,2,3,4-tetrahydropyrazino[l,2-a]indolyl, 2,3-dihydro-lH- pyrrolo[l,2-a]indolyl, (3aR,6aR)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4R,6aS)-hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,4S,6aS)- hexahydrocyclopenta[c]pyrrol-(lH)-yl, (3aR,5r,6aS)-hexahydrocyclopenta[c]pyrrol- (lH)-yl, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-l,3,3a,4,5,6- hexahydro-2H-isoindolyl, (3aR,4R,7aS)- lH-isoindol-(3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)-octahydro-2H-isoindolyl,

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci-galkyl;

R₄ is hydrogen or Ci-galkyl;

R₅ is hydrogen, Ci-galkyl, amino,

(C₁_₈alkyl)₂-amino,

R₆ is halogen, hydroxyl, cyano, Ci-galkyl, Ci_galkoxy, amino, Ci_galkyl-amino or

(C₁_galkyl)₂-amino;

with the proviso that a compound of Formula (I) is other than:

7-hydroxy-l-methyl-2-((methylamino)methyl)-9-oxo- 1,4,5,6, 9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid; and,

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) 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, (C₁_galkyl)₂-amino-C₁_galkyl-amino,

amino-Ci-galkyl-amino-Ci-galkyl, Ci-galkyl-amino-Ci-galkyl-amino-Ci-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-galky^Ci-galky^amino-Ci-galkyl,

(C₁-₈alkyl)₂-amino-carbonyl-C₁-₈alkyl-amino-C₁_₈alkyl, Cs-wcycloalkyl-amino-Ci-galkyl, Cs-Hcycloalkyl-Ci-salkyl-amino-Ci-salkyl, 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

(C₁_galkyl)₂-amino;

with the proviso that a compound of Formula (I) is other than 7-hydroxy- l-methyl-2-

((methylamino)methyl)-9-oxo- 1,4,5, 6,9, 10-hexahydropyrido[2',3':3,4]cyclohepta[ 1,2- e]indole-8-carboxylic acid; and,

2-((ethylamino)methyl)-7-hydroxy-l-methyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid.

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;

2-((ethylamino)methyl)-7-hydroxy-l-methyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid. One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein R is selected from Cs-_Hcycloalkyl-amino-Ci-galkyl, Cs-^cycloalkyl-Ci-galkyl-amino-Ci-galkyl, aryl-Ci-salkyl-amino-Ci-galkyl,

heteroaryl-Ci-galkyl-amino-Ci-galkyl, heterocyclyl, heterocyclyl-Ci-salkyl,

heterocyclyl-amino, heterocyclyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl-amino-Ci-galkyl; wherein each instance of Cs-ncycloalkyl, aryl, heteroaryl or heterocyclyl is optionally

substituted with one, two or three substituents each selected from R₆; and, wherein R₆ is halogen, hydroxyl, Ci^alkyl, Ci^alkoxy, amino, Ci-salkyl-amino or,

(C₁_₈alkyl)₂-amino. One embodiment of the present description includes a compound of Formula (I), (II),

(III) or (IV) or a form thereof, wherein R is selected from hydrogen, (C₁_₈alkyl)₂-amino, amino-Ci-galkyl, Ci-ioalkyl-amino-Ci-salkyl, (C₁_₁oalkyl)₂-amino-C₁_₈alkyl,

or hydroxyl-Ci-galkyl;

with the proviso that a compound of Formula (I) is other than 7-hydroxy-l-methyl-2- ((methylamino)methyl)-9-oxo- 1,4,5, 6,9, 10-hexahydropyrido[2',3':3,4]cyclohepta[ 1,2- e]indole-8-carboxylic acid; and,

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein R is selected from Cs-wcycloalkyl-amino-Ci-salkyl, heterocyclyl or heterocyclyl-Ci-galkyl;

wherein each instance of Cs-ncycloalkyl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R₆; and,

wherein R₆ is halogen, hydroxyl, Ci^alkyl, Ci^alkoxy, amino, Ci-salkyl-amino or

(C₁_galkyl)₂-amino.

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein R is selected from:

Cs-^cycloalkyl selected in each instance, when present, from cyclopropyl, cyclobutyl,

cyclopentyl, cyclohexyl or cycloheptyl;

aryl selected in each instance, when present, from phenyl;

heteroaryl selected in each instance, when present, from 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]hexanyl, (lR,5S)-3- azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.0]hexanyl, (lS,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl.

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein Ri is 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]hexan-3-yl, (lR,5S)-3- azabicyclo[3.1.0]hexan-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hexan-6-yl, 3,6- diazabicyclo[3.1.0]hexan-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.

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]hexanyl.

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein R is

heteroaryl selected in each instance, when present, from pyridin-2-yl, pyridin-3-yl or

pyridin-4-yl;

heterocyclyl selected in each instance, when present, from azetidin-l-yl, pyrrolidin-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, tetrahydrofuran-2-yl, piperidin-l-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-l-yl, piperazin-2-yl, morpholin-4-yl, 1,4- diazepan-l-yl, l,3-dioxolan-2-yl, 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]hexan-3-yl or (lR,5S)-3- azabicyclo[3.1.0]hexan-6-yl.

heteroaryl selected in each instance, when present, from pyrrolyl, imidazolyl, IH-tetrazolyl or 2H-tetrazolyl; or,

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]hexanyl, 3,6- diazabicyclo[3.1.0]hexanyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, (lS,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl.

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]hexan-3-yl, 3,6- diazabicyclo[3.1.0]hexan-3-yl, (lR,5S)-3-azabicyclo[3.1.0]hexan-3-yl, (lR,5S)-3- azabicyclo[3.1.0]hexan-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.

Cs-_Hcycloalkyl-amino-Ci-galkyl, wherein Cs-ncycloalkyl is selected from cyclopropyl,

cyclobutyl, cyclopentyl or cyclohexyl;

Cs-^cycloalkyl-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;

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,

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,

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] [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,

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.

heteroaryl selected in each instance, when present, from IH-tetrazolyl, imidazolyl, pyrrolyl or 2H-tetrazolyl; or,

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]hexanyl, 3,6- diazabicyclo[3.1.0]hexanyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, (lS,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl or 2,8-diazaspiro[4.5]decanyl.

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein Ri is selected from C3_i₄cycloalkyl selected, in each instance, when present, from cyclopropyl or cyclobutyl; and, heterocyclyl selected, in each instance, when present, from pyrrolidinyl.

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein R₂ is hydrogen or halogen.

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein R₂ is hydrogen.

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein R₂ is halogen.

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein R₃ is hydrogen or Ci_₈alkyl. One embodiment of the present description includes a compound of Formula

(I), (II), (III) or (IV) or a form thereof, wherein R₃ is hydrogen.

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein R₃ is C^ancyl.

One embodiment of the present description includes a compound of Formula (I), (II), (III) or (IV) or a form thereof, wherein R4 is hydrogen or Ci-galkyl. One embodiment of the present description includes a compound of Formula

(I), (II), (III) or (IV) or a form thereof, wherein R₄ is hydrogen.

One embodiment of the present description includes a compound of Formula

(I), (II), (III) or (IV) or a form thereof, wherein R₄ is Ci-galkyl. One embodiment of the present description includes a compound of Formula

(I), (II), (III) or (IV) or a form thereof, wherein R5 is hydrogen, Ci-galkyl, amino,

(Ci-galkyl amino, amino-Ci-galkyl, C oalkyl-amino-Ci-galkyl,

(Ci-ioalkyl amino-Ci-galkyl or hydroxyl-Ci-galkyl.

One embodiment of the present description includes a compound of Formula

(I), (II), (III) or (IV) or a form thereof, wherein R5 is hydrogen, Ci_galkyl,

(Ci-ioalkyl amino-Ci-galkyl or hydroxyl-Ci-galkyl.

One embodiment of the present description includes a compound of Formula

(I), (II), (III) or (IV) or a form thereof, wherein R₆ is halogen, hydroxyl, cyano,

Ci-galkyl, Ci_galkoxy, amino, Ci_galkyl-amino or (C₁_₈alkyl)₂-amino. One embodiment of the present description includes a compound of Formula

(I), (II), (III) or (IV) or a form thereof, wherein R₆ is Ci-galkyl, amino,

Ci-galkyl-amino or (C₁_galkyl)₂-amino.

In another embodiment, the compound of Formula (I), (II), (III) or (IV) 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), (II), (III) or (IV).

In another embodiment, the compound of Formula (I), (II), (III) or (IV) or a form thereof includes an isotopologue form of the compound of Formula (I), (II), (III) or (IV) wherein, when present as hydrogen, one or more Ri, R₂, R3, R₄ and R5 hydrogen atoms are independently replaced with deuterium.

Embodiments of the compound of Formula (I) or a form thereof described herein include a compound of Formula (la):

or a form thereof, wherein R_1; X, Z, R₂ and R5 are selected from:

Embodiments of the use of a compound of Formula (I) or a form thereof described herein include the use of a compound of Formula (la):

or a form thereof, wherein R_1; X, Z, R₂ and R₅ are selected from:

Embodiments of the compound of Formula (I) or a form thereof described herein include a compound of Formula (lb):

or a form thereof, wherein R_{1 ;} X, Z, R₂ and R5 are selected from:

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 use of a compound of Formula (lb) or a form thereof described herein include the use of a compound of Formula (lb):

or a form thereof, wherein R_{1 ;} X, Z, R₂ and R5 are selected from:

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) or a form thereof described herein include a compound of Formula (Ila):

(Ila) or a form thereof, wherein R_{1 ;} X, Z, R₂ and R₅ are selected from:

Embodiments of the use of a compound of Formula (II) or a form thereof described herein include the use of a compound of Formula (Ila):

(Ila) or a form thereof, wherein R_{1 ;} X, Z, R₂ and R5 are selected from:

Embodiments of the compound of Formula (III) or a form thereof described herein include a compound of Formula (Ilia):

or a form thereof, wherein R_1; X, Z, R₂ and R5 are selected from:

Embodiments of the use of a compound of Formula (III) or a form thereof described herein include the use of a compound of Formula (Ilia):

(Ilia) or a form thereof, wherein R_1; X, Z, R₂ and R₅ are selected from:

In one embodiment of the present description, a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof is selected from the group consisting of:

38 39 40 41

54 55 56 57

58 59 60 61

64 65 66 67

88; 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 use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae or N. meningitidis 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:

1 2 3 4

86 87, and 88; 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), Formula (II), Formula (III) or Formula (IV) or a form thereof (wherein compound number (#*) indicates that the salt form was isolated) is selected from the group consisting of:

Cpd Name

1 6-hydroxy-8-oxo-4,5,8,9-tetrahydro- lH-indolo[4,5-h]quinoline-7-carboxylic acid

2 6-hydroxy-l-methyl-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5-h]quinoline-7- carboxylic acid

3 7 -hydroxy- l-methyl-9-oxo- 1,4,5, 6,9, 10-hexahydropyrido[2',3':3,4]cyclohepta[ 1,2- e]indole-8-carboxylic acid

4 7-hydroxy-3-methyl-9-oxo-3,4,5,6,9,10-hexahydropyrido[3',2':6,7]cyclohepta[l,2- g]indole-8-carboxylic acid

5 7-hydroxy-l-(2-hydroxyethyl)-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

6 7-hydroxy-9-oxo-4,5,9,10-tetrahydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole-8- carboxylic acid

7 7-hydroxy-l-methyl-9-oxo-4,5,9,10-tetrahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid Cpd Name

8 7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydropyrido[3',2':6,7]cyclohepta[l,2-g]indole- 8-carboxylic acid

9 7-hydroxy-9-oxo- 1,4,5, 6,9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole- 8-carboxylic acid

10 7-hydroxy-9-oxo-4,6,9,10-tetrahydro-lH-pyrido[2',3':5,6]oxepino[3,4-e]indole-8- carboxylic acid

ll¹ 7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

12¹ 2-[(dimethylamino)methyl]-7 -hydroxy- l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

13¹ 7 -hydroxy- l-methyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

14¹ 7 -hydroxy- l-methyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

15¹ 2-[(butan-2-ylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

16¹ 2-[(cyclobutylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

17¹ l-[2-(dimethylamino)ethyl]-7-hydroxy-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

18¹ 7-hydroxy- l-methyl-2- { [(l-methylcyclopropyl)amino]methyl}-9-oxo-

1,4,5, 6,9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

19¹ 2-[(tert-butylamino)methyl]-7-hydroxy-l-methyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

20¹ 7-hydroxy- l-methyl-2- { [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

21¹ 7-hydroxy-2-[(methylamino)methyl]-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid Cpd Name

22¹ 2-[(dimethylamino)methyl]-7-hydroxy-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

23¹ 6-hydroxy-2-[(methylamino)methyl]-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid

24¹ 2-[(dimethylamino)methyl]-6-hydroxy-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid

25¹ 6-hydroxy-8-oxo-2-[(propylamino)methyl]-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid

26¹ 6-hydroxy-8-oxo-2-(pyrrolidin-l-ylmethyl)-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid

27¹ 6-hydroxy-8-oxo-2-[(propan-2-ylamino)methyl]-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid

29¹ 2-[(dimethylamino)methyl] -7 -hydroxy- 1 -methyl-9-oxo- 1,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

30¹ 2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l-methyl-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

31¹ 7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

32¹ 7-hydroxy-l-methyl-2-[(methylamino)methyl] -9-oxo-l,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

33¹ 2-[(ethylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

34¹ 7-hydroxy-l-methyl-9-oxo-2-[(propylamino)methyl]-l,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

35¹ 7-hydroxy-l-methyl-9-oxo-2-[(propan-2-ylamino)methyl] -1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

36¹ 2-[(cyclobutylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid Cpd Name

37¹ 2-[(tert-butylamino)methyl] -7 -hydroxy- 1 -methyl-9-oxo- 1,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

38¹ 7-hydroxy-l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

39¹ 7-hydroxy-l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

40¹ 7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

41¹ 2-[(dimethylamino)methyl]-7 -hydroxy- l,6-dimethyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

42¹ 2-[(ethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

43¹ 7-hydroxy- l,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

44¹ 2-[(tert-butylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

45¹ 7-hydroxy- l,6-dimethyl-2-[(methylamino)methyl]-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

46¹ 2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

47¹ 7-hydroxy- l,6-dimethyl-9-oxo-2-[(propylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

48¹ 2-[(dimethylamino)methyl]-8-hydroxy-l -methyl- lO-oxo-4,5, 6,7, 10,11-hexahydro- 1 H-pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

49 8-hydroxy-10-oxo-l,4,5,6,10,l l-hexahydropyrido[3',2':2,3]oxocino[5,4-e]indole- 9-carboxylic acid

50 8-hydroxy-l-methyl-10-oxo-l,4,5,6,10,l l-hexahydropyrido[3',2':2,3]oxocino[5,4- e]indole-9-carboxylic acid Cpd Name

51¹ 2-[(diethylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

52¹ 7-hydroxy- l-methyl-2-[(2-methylpyrrolidin-l-yl)methyl]-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

53¹ 2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

54¹ 7-hydroxy- l-methyl-2-{ [(2-methylpropyl)amino]methyl}-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

55¹ 2-[(butylamino)methyl]-7-hydroxy-l-methyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

56¹ 2-[(ethylamino)methyl]-8-hydroxy- 1-methyl- lO-oxo-4,5, 6,7, 10,11-hexahydro-lH- pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

57¹ 2-{ [ethyl(methyl)amino]methyl}-8-hydroxy-l-methyl-10-oxo-4,5,6,7,10,l 1- hexahydro- 1 H-pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

58¹ 8-hydroxy- 1 -methyl- 10 -oxo-2-(pyrrolidin- l-ylmethyl)-4,5, 6,7, 10,11 -hexahydro- 1 H-pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

59¹ 8-hydroxy- 1 -methyl- 10 -oxo-2-[(propan-2-ylamino)methyl]-4,5,6,7,10,l l- hexahydro- 1 H-pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

60¹ 8-hydroxy- 1 -methyl-2- { [( 1 -methylcyclopropyl)amino] methyl } - 10-oxo-

4,5,6,7,10,1 l-hexahydro-lH-pyrido[2',3':3,4]cycloocta[l,2-e]indole-9-carboxylic acid

61¹ 8-hydroxy- 1-methyl- 10-oxo-2-[(propylamino)methyl]-4,5,6,7, 10, 11-hexahydro- 1 H-pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

64¹ (6R)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

65¹ (6R)-2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo-

66¹ (6R)-7-hydroxy-l,6-dimethyl-9-oxo-2-[(propylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid Cpd Name

67¹ (6R)-7-hydroxy-l,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

68¹ (6R)-2-[(ethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

69¹ (6R)-2-[(dimethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

70¹ (6S)-2-[(ethylamino)methyl] -7-hydroxy- 1 ,6-dimethyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

71¹ (6S)-2-[(dimethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

72¹ (6S)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

73¹ (6S)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-[(propylamino)methyl] - 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

74¹ (6S)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl] - 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

75¹ (6S)-2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

76¹ 2-[(dimethylamino)methyl]-12-fluoro-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

77¹ 12-fluoro-7-hydroxy-l-methyl-9-oxo-2-[(propylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

78¹ 12-fluoro-7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

79 4-hydroxy-2-oxo- 1,2,5, 6,7, 10-hexahydropyrido[3',2':6,7]cyclohepta[l,2-e]indole- 3-carboxylic acid

80¹ 7-hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid Cpd Name

81¹ 7-hydroxy-l-methyl-9-oxo-2,3,4,5,9,10-hexahydro-lH- pyrido[2',3':6,7]oxepino[4,5-e]indole-8-carboxylic acid

82¹ 7-hydroxy-9-oxo-2,3,4,6,9,10-hexahydro-lH-pyrido[2',3':5,6]oxepino[3,4- e]indole-8-carboxylic acid

83¹ l-ethyl-7-hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid

84¹ 7-hydroxy-l-methyl-9-oxo-2,3,4,6,9,10-hexahydro-lH- pyrido[2',3':5,6]oxepino[3,4-e]indole-8-carboxylic acid

85¹ 6-hydroxy-8 -oxo-l,2,3,4,8,9-hexahydropyrido[2',3':5,6]pyrano[3,4-e]indole-7- carboxylic acid

86¹ 8-hydroxy-10-oxo-l,2,3,4,5,6,10,l l-octahydropyrido[3',2':2,3]oxocino[5,4- e]indole-9-carboxylic acid

87¹ 8-hydroxy-l-methyl-10-oxo-l,2,3,4,5,6,10,l l- octahydropyrido[3',2':2,3]oxocino[5,4-e]indole-9-carboxylic acid, and

88¹ 2-[(dimethylamino)methyl]-7-hydroxy-l-methyl-9-oxo-l,2,3,4,5,6,9,10- octahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-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.

A use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a use for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae or N. meningitidis 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

1 6-hydroxy-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5-h]quinoline-7-carboxylic acid

2 6-hydroxy-l-methyl-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5-h]quinoline-7- carboxylic acid Cpd Name

3 7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9, 10-hexahydropyrido[2',3':3,4]cyclohepta[ 1,2- e]indole-8-carboxylic acid

5 7-hydroxy- 1 -(2-hydroxyethyl)-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

7 7-hydroxy- l-methyl-9-oxo-4,5, 9, 10-tetrahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid

8 7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydropyrido[3',2':6,7]cyclohepta[l,2-g]indole-8- carboxylic acid

9 7-hydroxy-9-oxo- 1,4,5,6, 9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8- carboxylic acid

ll¹ 7-hydroxy- l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

12¹ 2-[(dimethylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

13¹ 7-hydroxy- l-methyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

14¹ 7-hydroxy- l-methyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

15¹ 2-[(butan-2-ylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

16¹ 2-[(cyclobutylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid Cpd Name

17¹ l-[2-(dimethylamino)ethyl]-7-hydroxy-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

18¹ 7 -hydroxy- l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-9-oxo- 1,4,5,6, 9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

19¹ 2-[(tert-butylamino)methyl]-7-hydroxy-l-methyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

20¹ 7 -hydroxy- l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,4,5,6, 9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

21¹ 7-hydroxy-2-[(methylamino)methyl]-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

22¹ 2-[(dimethylamino)methyl]-7-hydroxy-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

29¹ 2-[(dimethylamino)methyl]-7-hydroxy- l-methyl-9-oxo- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

30¹ 2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l-methyl-9-oxo- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

31¹ 7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid Cpd Name

32¹ 7 -hydroxy- l-methyl-2-[(methylamino)methyl]-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

33¹ 2-[(ethylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

34¹ 7 -hydroxy- l-methyl-9-oxo-2-[(propylamino)methyl]- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

35¹ 7 -hydroxy- l-methyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

36¹ 2-[(cyclobutylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

37¹ 2-[(tert-butylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

39¹ 7-hydroxy-l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

40¹ 7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

41¹ 2-[(dimethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

42¹ 2-[(ethylamino)methyl] -7-hydroxy- 1 ,6-dimethyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

43¹ 7-hydroxy- 1 ,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl] - 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

44¹ 2-[(tert-butylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

45¹ 7-hydroxy- l,6-dimethyl-2-[(methylamino)methyl]-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid Cpd Name

46¹ 2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

47¹ 7-hydroxy- 1 ,6-dimethyl-9-oxo-2-[(propylamino)methyl] - 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

48¹ 2-[(dimethylamino)methyl]-8-hydroxy-l-methyl-10-oxo-4,5,6,7,10,l l-hexahydro- 1 H-pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

49 8-hydroxy-10-oxo-l,4,5,6,10,l l-hexahydropyrido[3',2':2,3]oxocino[5,4-e]indole-9- carboxylic acid

50 8-hydroxy- 1 -methyl- 10-oxo- 1,4,5,6, 10, l l-hexahydropyrido[3',2':2,3]oxocino[5,4- e]indole-9-carboxylic acid

51¹ 2-[(diethylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

52¹ 7-hydroxy- l-methyl-2-[(2-methylpyrrolidin-l-yl)methyl]-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

53¹ 2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l-methyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

54¹ 7-hydroxy- l-methyl-2-{ [(2-methylpropyl)amino]methyl}-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

55¹ 2-[(butylamino)methyl]-7-hydroxy-l-methyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

56¹ 2-[(ethylamino)methyl]-8-hydroxy-l-methyl-10-oxo-4,5,6,7,10,l l-hexahydro-lH- pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

57¹ 2-{ [ethyl(methyl)amino]methyl}-8-hydroxy-l-methyl-10-oxo-4,5,6,7,10,l 1- hexahydro- 1 H-pyrido [2',3': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

58¹ 8-hydroxy- 1 -methyl- 10 -oxo-2-(pyrrolidin-l-ylmethyl)-4,5,6,7,10,l l-hexahydro-lH- pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

59¹ 8-hydroxy- 1 -methyl- 10 -oxo-2-[(propan-2-ylamino)methyl]-4,5,6,7, 10,11- hexahydro- 1 H-pyrido [2',3': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid Cpd Name

61¹ 8-hydroxy- l-methyl-10-oxo-2-[(propylamino)methyl]-4,5, 6,7, 10,11-hexahydro-lH- pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

62¹ 7-hydroxy-l-methyl-2-((methylamino)methyl)-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

63¹ 2-((ethylamino)methyl)-7-hydroxy-l-methyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

64¹ (6R)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

65¹ (6R)-2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

66¹ (6R)-7-hydroxy-l,6-dimethyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

67¹ (6R)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl] - 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

68¹ (6R)-2-[(ethylamino)methyl] -7-hydroxy- 1 ,6-dimethyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

69¹ (6R)-2-[(dimethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

70¹ (6S)-2-[(ethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

71¹ (6S)-2-[(dimethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

72¹ (6S)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

73¹ (6S)-7-hydroxy-l,6-dimethyl-9-oxo-2-[(propylamino)methyl]-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid Cpd Name

74¹ (6S)-7-hydroxy-l,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl]-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

75¹ (6S)-2- { [ethyl(methyl)amino]methyl } -7-hydroxy- 1 ,6-dimethyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

76¹ 2-[(dimethylamino)methyl]-12-fluoro-7 -hydroxy- l-methyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

77¹ 12-fluoro-7-hydroxy-l-methyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

78¹ 12-fluoro-7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

79 4-hydroxy-2-oxo- 1,2,5,6,7, 10-hexahydropyrido[3',2':6,7]cyclohepta[l,2-e]indole-3- carboxylic acid

80¹ 7-hydroxy-9 -oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole- 8-carboxylic acid

81¹ 7-hydroxy-l-methyl-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid

82¹ 7-hydroxy-9-oxo-2,3,4,6,9,10-hexahydro-lH-pyrido[2',3':5,6]oxepino[3,4-e]indole-

8- carboxylic acid

84¹ 7-hydroxy-l-methyl-9-oxo-2,3,4,6,9,10-hexahydro-lH-pyrido[2',3':5,6]oxepino[3,4- e]indole-8-carboxylic acid

85¹ 6-hydroxy-8 -oxo- 1,2,3,4,8, 9-hexahydropyrido[2',3':5,6]pyrano[3,4-e]indole-7- carboxylic acid

86¹ 8-hydroxy-10 -oxo- 1,2,3,4,5, 6, 10, l l-octahydropyrido[3',2':2,3]oxocino[5,4-e]indole-

9- carboxylic acid

87¹ 8-hydroxy-l-methyl-10-oxo-l,2,3,4,5,6,10,l l- octahydropyrido [3',2' :2,3 ] oxocino [5 ,4-e] indole-9-carboxylic acid, and Cpd Name

88¹ 2-[(dimethylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,2,3,4,5,6,9, 10- octahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole- 8 -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), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae or N. meningitidis 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

8 7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydropyrido[3',2':6,7]cyclohepta[l,2-g]indole-8- carboxylic acid Cpd Name

ll¹ 7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

13¹ 7 -hydroxy- l-methyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

14¹ 7 -hydroxy- l-methyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

16¹ 2-[(cyclobutylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

18¹ 7-hydroxy- l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

20¹ 7-hydroxy- l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

21¹ 7-hydroxy-2-[(methylamino)methyl]-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

22¹ 2-[(dimethylamino)methyl]-7-hydroxy-9-oxo- 1,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid Cpd Name

31¹ 7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

37¹ 2-[(tert-butylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid Cpd Name

38¹ 7-hydroxy-l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-9-oxo-l,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

39¹ 7-hydroxy-l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo-l,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

45¹ 7-hydroxy- l,6-dimethyl-2-[(methylamino)methyl]-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

51¹ 2-[(diethylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid Cpd Name

52¹ 7-hydroxy-l-methyl-2-[(2-methylpyrrolidin-l-yl)methyl]-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

54¹ 7-hydroxy-l-methyl-2-{ [(2-methylpropyl)amino]methyl}-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

58¹ 8-hydroxy-l -methyl- 10 -oxo-2-(pyrrolidin-l-ylmethyl)-4,5,6,7,10,l l-hexahydro-lH- pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

59¹ 8-hydroxy-l -methyl- 10 -oxo-2-[(propan-2-ylamino)methyl]-4,5,6,7, 10,11- hexahydro- 1 H-pyrido [2',3': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

63¹ 2-((ethylamino)methyl)-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

65¹ (6R)-2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid Cpd Name

73¹ (6S)-7-hydroxy-l,6-dimethyl-9-oxo-2-[(propylamino)methyl]-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

79 4-hydroxy-2-oxo- 1,2,5,6,7, 10-hexahydropyrido[3',2':6,7]cyclohepta[l,2-e]indole-3- carboxylic acid Cpd Name

8- carboxylic acid

9- carboxylic acid

87¹ 8-hydroxy-l-methyl-10-oxo-l,2,3,4,5,6,10,l l- octahydropyrido [3',2' :2,3 ] oxocino [5 ,4-e] indole-9-carboxylic acid, and

In another embodiment of the present description, the compound or a form thereof is isolated as a salt.

In other embodiments of the present description, the compound salt or a form thereof is isolated as a chloride, bromide, acetate or trifluoroacetate salt.

In other embodiments of the present description, the compound salt or a form thereof is isolated as a chloride salt. In another embodiment of the present description, a compound salt or a form thereof is selected from the group consisting of: Cpd Name

11 7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

12 2-[(dimethylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

13 7 -hydroxy- l-methyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

14 7 -hydroxy- l-methyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

15 2-[(butan-2-ylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

16 2-[(cyclobutylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

17 l-[2-(dimethylamino)ethyl]-7-hydroxy-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

18 7-hydroxy- l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

19 2-[(tert-butylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

20 7-hydroxy- l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

21 7-hydroxy-2-[(methylamino)methyl]-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

22 2-[(dimethylamino)methyl]-7-hydroxy-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

23 6-hydroxy-2-[(methylamino)methyl]-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid hydrochloride

24 2-[(dimethylamino)methyl]-6-hydroxy-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid hydrochloride Cpd Name

25 6-hydroxy-8-oxo-2-[(propylamino)methyl]-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid hydrochloride

26 6-hydroxy-8-oxo-2-(pyrrolidin-l-ylmethyl)-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid hydrochloride

27 6-hydroxy-8-oxo-2-[(propan-2-ylamino)methyl]-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid hydrochloride

29 2-[(dimethylamino)methyl]-7-hydroxy- l-methyl-9-oxo- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride

30 2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l-methyl-9-oxo- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride

31 7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride

32 7 -hydroxy- l-methyl-2-[(methylamino)methyl]-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride

33 2-[(ethylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride

34 7 -hydroxy- l-methyl-9-oxo-2-[(propylamino)methyl]- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride

35 7 -hydroxy- l-methyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride

36 2-[(cyclobutylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride

37 2-[(tert-butylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride

38 7-hydroxy-l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride

39 7-hydroxy-l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride Cpd Name

40 7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

41 2-[(dimethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

42 2-[(ethylamino)methyl] -7-hydroxy- 1 ,6-dimethyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

43 7-hydroxy- 1 ,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl] - 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

44 2-[(tert-butylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

45 7-hydroxy- l,6-dimethyl-2-[(methylamino)methyl]-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

46 2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

47 7-hydroxy- 1 ,6-dimethyl-9-oxo-2-[(propylamino)methyl] - 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

48 2-[(dimethylamino)methyl]-8-hydroxy-l-methyl-10-oxo-4,5,6,7,10,l l-hexahydro- 1 H-pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

51 2-[(diethylamino)methyl]-7-hydroxy- l-methyl-9-oxo-l ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

52 7-hydroxy- l-methyl-2-[(2-methylpyrrolidin-l-yl)methyl]-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

53 2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l-methyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

54 7-hydroxy- l-methyl-2-{ [(2-methylpropyl)amino]methyl}-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

55 2-[(butylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride Cpd Name

56 2-[(ethylamino)methyl]-8-hydroxy-l-methyl-10-oxo-4,5,6,7,10,l l-hexahydro-lH- pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

57 2-{ [ethyl(methyl)amino]methyl}-8-hydroxy-l-methyl-10-oxo-4,5,6,7,10,l 1- hexahydro- 1 H-pyrido [2',3': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

hydrochloride

58 8-hydroxy-l-methyl-10-oxo-2-(pyrrolidin-l-ylmethyl)-4,5,6,7,10,l l-hexahydro-lH- pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

59 8-hydroxy- l-methyl-10-oxo-2-[(propan-2-ylamino)methyl]-4,5, 6,7, 10,11-hexahydro- 1 H-pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

60 8-hydroxy- l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-10-oxo-4,5, 6,7, 10,11- hexahydro- 1 H-pyrido [2',3': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

hydrochloride

61 8-hydroxy- l-methyl-10-oxo-2-[(propylamino)methyl]-4,5, 6,7, 10,11-hexahydro-lH- pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

64 (6R)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

65 (6R)-2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

66 (6R)-7-hydroxy-l,6-dimethyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

67 (6R)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl] - 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

68 (6R)-2-[(ethylamino)methyl] -7-hydroxy- 1 ,6-dimethyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

69 (6R)-2-[(dimethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

70 (6S)-2-[(ethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride Cpd Name

71 (6S)-2-[(dimethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

72 (6S)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

73 (6S)-7-hydroxy-l,6-dimethyl-9-oxo-2-[(propylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

74 (6S)-7-hydroxy-l,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

75 (6S)-2- { [ethyl(methyl)amino]methyl } -7-hydroxy- 1 ,6-dimethyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

76 2-[(dimethylamino)methyl]-12-fluoro-7 -hydroxy- l-methyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

77 12-fluoro-7-hydroxy-l-methyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

78 12-fluoro-7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

80 7-hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole-8- carboxylic acid hydrochloride

81 7-hydroxy- l-methyl-9-oxo-2,3,4,5, 9, 10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid hydrochloride

82 7-hydroxy-9-oxo-2,3,4,6,9,10-hexahydro-lH-pyrido[2',3':5,6]oxepino[3,4-e]indole-8- carboxylic acid hydrochloride

83 l-ethyl-7-hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid hydrochloride

84 7-hydroxy- l-methyl-9-oxo-2,3,4,6, 9, 10-hexahydro-lH-pyrido[2',3':5,6]oxepino[3,4- e]indole-8-carboxylic acid hydrochloride

85 6-hydroxy-8-oxo- 1,2,3,4,8, 9-hexahydropyrido[2',3':5,6]pyrano[3,4-e]indole-7- carboxylic acid hydrochloride Cpd Name

86 8-hydroxy- 10-oxo- 1,2,3,4,5, 6, 10, l l-octahydropyrido[3',2':2,3]oxocino[5,4-e]indole- 9-carboxylic acid hydrochloride

87 8-hydroxy-l-methyl-10-oxo-l,2,3,4,5,6,10,l l-octahydropyrido[3',2':2,3]oxocino[5,4- e]indole-9-carboxylic acid hydrochloride, and

88 2-[(dimethylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,2,3,4,5,6,9, 10- octahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole- 8 -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.

A use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a use for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae or N. meningitidis 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

12 2-[(dimethylamino)methyl]-7-hydroxy- l-methyl-9-oxo- 1,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

13 7 -hydroxy- l-methyl-9-oxo-2-[(propylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

17 l-[2-(dimethylamino)ethyl]-7-hydroxy-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride Cpd Name

18 7-hydroxy-l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

20 7-hydroxy-l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

24 2-[(dimethylamino)methyl]-6-hydroxy-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid hydrochloride

32 7 -hydroxy- l-methyl-2-[(methylamino)methyl]-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride Cpd Name

39 7-hydroxy-l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride

46 2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride Cpd Name

47 7 -hydroxy- l,6-dimethyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

52 7-hydroxy-l-methyl-2-[(2-methylpyrrolidin-l-yl)methyl]-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

54 7-hydroxy-l-methyl-2-{ [(2-methylpropyl)amino]methyl}-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

55 2-[(butylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

hydrochloride

58 8-hydroxy-l-methyl-10-oxo-2-(pyrrolidin-l-ylmethyl)-4,5,6,7,10,l l-hexahydro- 1 H-pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

59 8-hydroxy- 1-methyl- 10-oxo-2-[(propan-2-ylamino)methyl]-4,5, 6,7, 10,11- hexahydro- 1 H-pyrido [2',3': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

hydrochloride

60 8-hydroxy- 1 -methyl-2- { [( 1 -methylcyclopropyl)amino] methyl } - 10-oxo- 4,5,6,7,10,1 l-hexahydro-lH-pyrido[2',3':3,4]cycloocta[l,2-e]indole-9-carboxylic acid hydrochloride

61 8-hydroxy- 1-methyl- 10-oxo-2-[(propylamino)methyl]-4,5, 6,7, 10,11-hexahydro-lH- pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride Cpd Name

62 7-hydroxy-l-methyl-2-((methylamino)methyl)-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

63 2-((ethylamino)methyl)-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

70 (6S)-2-[(ethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

75 (6S)-2- { [ethyl(methyl)amino]methyl } -7-hydroxy- 1 ,6-dimethyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride Cpd Name

80 7-hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole- 8-carboxylic acid hydrochloride

81 7-hydroxy-l-methyl-9-oxo-2,3,4,5,9,10-hexahydro-lH- pyrido[2',3':6,7]oxepino[4,5-e]indole-8-carboxylic acid hydrochloride

82 7-hydroxy-9-oxo-2,3,4,6,9,10-hexahydro-lH-pyrido[2',3':5,6]oxepino[3,4-e]indole- 8-carboxylic acid hydrochloride

84 7-hydroxy-l-methyl-9-oxo-2,3,4,6,9,10-hexahydro-lH- pyrido [2',3' : 5 ,6] oxepino [3 ,4-e] indole- 8-carboxylic acid hydrochloride

85 6-hydroxy-8-oxo- 1,2,3,4,8, 9-hexahydropyrido[2',3':5,6]pyrano[3,4-e]indole-7- carboxylic acid hydrochloride

86 8-hydroxy- 10-oxo- 1,2,3,4,5, 6, 10, l l-octahydropyrido[3',2':2,3]oxocino[5,4- e]indole-9-carboxylic acid hydrochloride

87 8-hydroxy-l-methyl-10-oxo-l,2,3,4,5,6,10,l l- octahydropyrido [3',2' :2,3 ] oxocino [5 ,4-e] indole-9-carboxylic acid hydrochloride, and

88 2-[(dimethylamino)methyl]-7-hydroxy-l-methyl-9-oxo-l,2,3,4,5,6,9,10- octahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole- 8 -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), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound salt or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae or N. meningitidis 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

21 7-hydroxy-2-[(methylamino)methyl]-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride Cpd Name

22 2-[(dimethylamino)methyl]-7-hydroxy-9-oxo- 1,4,5,6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

36 2-[(cyclobutylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride Cpd Name

47 7-hydroxy- l,6-dimethyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

52 7-hydroxy- l-methyl-2-[(2-methylpyrrolidin-l-yl)methyl]-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride Cpd Name

hydrochloride

61 8-hydroxy- 1-methyl- 10-oxo-2-[(propylamino)methyl]-4,5, 6,7, 10,11-hexahydro-lH- pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

65 (6R)-2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride Cpd Name

80 7-hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole- 8-carboxylic acid hydrochloride Cpd Name

88 2-[(dimethylamino)methyl]-7-hydroxy-l-methyl-9-oxo-l,2,3,4,5,6,9,10- octahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole- 8 -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, C₂-₈alkynyl includes C₂-₆alkynyl, C₂-₄alkynyl and the like. A C₂-₈alkynyl radical may be optionally substituted where allowed by available valences.

As used herein, the term "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-galkoxy 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,

tetrahydro thienyl, pyrrolinyl, pyrrolidinyl, dihydropyrazolyl, pyrazolinyl, pyrazolidinyl, dihydroimidazolyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, dihydro-2H-pyranyl, dihydro-pyridinyl, tetrahydro-pyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydro-pyridinyl, dihydro-pyrimidinyl, tetrahydro-pyrimidinyl, 1,4,5,6- tetrahydropyrimidinyl, dihydro-pyrazinyl, tetrahydro-pyrazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl,

dihydro-triazinyl, tetrahydro-triazinyl, hexahydro-triazinyl, 1,4-diazepanyl, dihydro-indolyl, indolinyl, tetrahydro-indolyl, dihydro-indazolyl, tetrahydro-indazolyl, dihydro-isoindolyl, dihydro-benzofuranyl, tetrahydro-benzofuranyl, dihydro-benzothienyl,

tetrahydro-benzothienyl, dihydro-benzimidazolyl, tetrahydro-benzimidazolyl,

dihydro-benzooxazolyl, 2,3-dihydrobenzo[d]oxazolyl, tetrahydro-benzooxazolyl,

dihydro-benzooxazinyl, 3,4-dihydro-2H-benzo[b] [ 1 ,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, l,3-dihydro-2H-isoindolyl, octahydro-2H-isoindolyl, (3aS)-l,3,3a,4,5,6-hexahydro-2H-isoindolyl, (3aR,4R,7aS)-lH-isoindol- (3H,3aH,4H,5H,6H,7H,7aH)-yl, (3aR,7aS)-octahydro-2H-isoindolyl, (3aR,4R,7aS)- octahydro-2H-isoindolyl, (3aR,4S,7aS)-octahydro-2H-isoindolyl, 2,5- diazabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]hept-5-enyl, 3-azabicyclo[3.1.0]hexanyl, 3,6- diazabicyclo[3.1.0]hexanyl, (lR,5S)-3-azabicyclo[3.1.0]hexanyl, (lS,5R)-3- azabicyclo[3.2.0]heptanyl, 5-azaspiro[2.4]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 2,5- diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl and the like. A heterocyclyl radical may be optionally substituted on a carbon or nitrogen atom ring member where allowed by available valences.

As used herein, the term

refers to a radical of the formula:

As used herein, the term "Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci.galkyl-NH-^galkyl-O-Ci.galkyl.

As used herein, the term "Ci-galkyl-amino" refers to a radical of the

formula: -NH-Ci-galkyl.

As used herein, the term "(C₁_galkyl)₂-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-Ci-ioalkyl. As used herein, the term "(C₁_₁oalkyl)₂-amino-C₁_₈alkyl" refers to a radical of the formula: -C₁_galkyl-N(C₁_₁oalkyl)₂.

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 "Ci-galkyl-amino-Ci-galkyl-amino-Ci-galkyl" refers to a radical of the formula: -C_1-8alkyl-NH-C_1-8alkyl-NH-C_1-8alkyl.

As used herein, the term "(C₁-₈alkyl)₂-amino-C₁-₈alkyl-amino-C₁_₈alkyl" refers to a radical of the formula: -C_1-8alkyl-NH-C_1-8alkyl-N(C_1-8alkyl)₂.

As used herein, the term "[(C₁_₈alkyl)₂-amino-C₁_₈alkyl,C₁_₈alkyl]amino-C₁_₈alkyl" refers to a radical of the formula: -Ci-galkyl-Nj (C₁_₈alkyl)[C₁_galkyl-N(C₁_galkyl)₂] } .

As used herein, the term "(C₁-galkyl)₂-amino-carbonyl-C₁-galkyl-amino-C₁_galkyl" refers to a radical of the formula: -C₁-galkyl-NH-C₁-₈alkyl-C(0)-N(C₁-galkyl)₂.

As used herein, the term

refers to a radical of the formula: -Ci-salkyl-NH-C^salkynyl.

As used herein, the term "amino" refers to a radical of the formula: -NH₂.

As used herein, the term "amino-Ci-salkyl" refers to a radical of the

formula: -C₁_₈alkyl-NH₂.

As used herein, the term "amino-Ci-salkyl-amino-Ci-salkyl" refers to a radical of the formula: -C₁-₈alkyl-NH-C₁_₈alkyl-NH₂.

As used herein, the term "aryl-Ci-salkyl-amino-Ci-salkyl" refers to a radical of the formula: -Ci-salkyl-NH-Ci-salkyl-aryl.

As used herein, the term "Cs-_Hcycloalkyl-amino-Ci-salkyl" refers to a radical of the formula: -C^alkyl-NH-Cs-wcycloalkyl.

As used herein, the term "Cs-wcycloalkyl-Ci-salkyl-amino-Ci-salkyl" refers to a radical of the formula: -Ci-salkyl-NH-Ci-salkyl-Cs-_Hcycloalkyl.

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-salkyl-amino-Ci-salkyl" refers to a radical of the formula: -Ci-salkyl-NH-Ci-salkyl-heteroaryl.

As used herein, the term "heterocyclyl-Ci-salkyl" refers to a radical of the formula: -Ci-salkyl-heterocyclyl.

As used herein, the term "heterocyclyl-amino" refers to a radical of the

formula: -NH-heterocyclyl. As used herein, the term "heterocyclyl-amino-Ci-galkyl" refers to a radical of the formula: -Ci-galkyl-NH-heterocyclyl.

As used herein, the term "heterocyclyl-Ci-galkyl-amino-^galkyr refers to a radical of the formula: -Ci-galkyl-NH-^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-^galkyl-amino-Ci-galkyr refers to a radical of the formula: -Ci-galkyl-NH-Ci-galkyl-OH, wherein Ci-galkyl may be partially or completely substituted where allowed by available valences with one or more hydroxyl radicals.

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), Formula (II), Formula (III) or Formula (IV) or a form thereof encompass functionalities incorporated into a compound of Formula (I), Formula (II), Formula (III) or Formula (IV), 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), Formula (II), Formula (III) or Formula (IV), 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-ncycloalkyl, Cs-ncycloalkyl-Ci-galkyl, aryl, aryl-Ci-galkyl, heteroaryl, heteroaryl-Ci-galkyl, heterocyclyl and heterocyclyl-Ci-galkyl," are intended to refer to the Cs-^cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems when each are present either alone or as a substituent.

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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) is a free acid, free base or salt thereof. In certain embodiments described herein, the form of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) is a salt thereof.

In certain embodiments described herein, the form of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) is an isotopologue thereof.

In certain embodiments described herein, the form of the compound of Formula (I),

Formula (II), Formula (III) or Formula (IV) is a stereoisomer, racemate, enantiomer or diastereomer thereof.

In certain embodiments described herein, the form of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) is a tautomer thereof.

Formula (II), Formula (III) or Formula (IV) is a pharmaceutically acceptable form.

In certain embodiments described herein, the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) can form salts, which are intended to be included within the scope of this description. Reference to a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof herein is understood to include reference to salt forms thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) may be formed, for example, by reacting a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) and forms thereof, may further exist in a tautomeric form (for example, the 4-hydroxy-2-pyridinone core of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof as described herein. The compounds of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof is a substantially pure (S) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

In one aspect of the description, a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof is a substantially pure (R) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

As used herein, a "racemate" is any mixture of isometric forms that are not

"enantiomerically pure", including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, or about 80/20. In addition, the present description embraces all geometric and positional isomers. For example, if a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) may be atropisomers (e.g. , substituted biaryls) and are considered as part of this description.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this description, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as described supra.

The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or isotopologues of the instant compounds.

The term "isotopologue" refers to isotopically-enriched compounds described herein which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁵C1 and ³⁶C1, respectively, each of which are also within the scope of this description.

Certain isotopically-enriched compounds described herein (e.g., those labeled with 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), Formula (III) or Formula (IV) and of the salts, solvates, hydrates, esters and prodrugs of the compounds of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae or N. meningitidis 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), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae or N. meningitidis in a subject in need thereof.

The present description further relates to use of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof having activity toward wild- type or drug-resistant N. gonorrhoeae or N. meningitidis.

The present description also relates to use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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.

(II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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 or N. meningitidis.

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 or N. meningitidis regardless of whether N. gonorrhoeae or N. meningitidis 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), Formula (III) or Formula (IV) or a form thereof in a combination therapy for treating or ameliorating N. gonorrhoeae or N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof in a combination therapy for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae or

N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof in the preparation of a kit comprising the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof and instructions for administering an effective amount of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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 or N. meningitidis 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, CloxaciUin, 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, Sulfanamide, 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), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating wild-type forms of N. gonorrhoeae or N. meningitidis, for treating or ameliorating drug- resistant forms of N. gonorrhoeae or N. meningitidis or for treating or ameliorating multidrug resistant forms of N. gonorrhoeae or N. meningitidis. In accordance with the use of the present description, compounds that are useful in selectively treating or ameliorating

N. gonorrhoeae or N. meningitidis, lacking potent broad- spectrum antibacterial activity, have been identified and use of these compounds for treating or ameliorating N. gonorrhoeae or N. meningitidis have been provided.

One embodiment of the use of the present description relates to use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating N. gonorrhoeae or N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II), Formula

(III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating N. gonorrhoeae or N. meningitidis resulting from wild-type forms of

N. gonorrhoeae or N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II), Formula (III) or Formula

(IV) 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), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating N. gonorrhoeae or N. meningitidis resulting from drug-resistant forms of N. gonorrhoeae or N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating N. gonorrhoeae or N. meningitidis 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), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating wild-type or drug-resistant forms N. gonorrhoeae or N. meningitidis 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), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating wild-type forms of N. gonorrhoeae or N. meningitidis 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), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating drug-resistant forms of N. gonorrhoeae or N. meningitidis 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), Formula (III) or Formula (IV) or a form thereof in the manufacture of a medicament for treating or ameliorating N. gonorrhoeae or N. meningitidis 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), Formula (III) or Formula (IV) or a form thereof in the manufacture of a medicament for treating or ameliorating wild-type or drug-resistant forms of

N. gonorrhoeae or N. meningitidis 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), Formula (III) or Formula (IV) or a form thereof in the manufacture of a medicament for treating or ameliorating wild-type forms of N. gonorrhoeae or N. meningitidis 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), Formula (III) or Formula (IV) or a form thereof in the manufacture of a medicament for treating or ameliorating drug-resistant forms of N. gonorrhoeae or

N. meningitidis 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), Formula (III) or Formula (IV) or a form thereof in the preparation of a kit comprising the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof and instructions for administering the compound for treating or

ameliorating N. gonorrhoeae or N. meningitidis 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), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating N. gonorrhoeae or N. meningitidis in a subject in need thereof, comprising administering an effective amount of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof in the manufacture of a medicament for treating or ameliorating N. gonorrhoeae or N. meningitidis 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), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating N. gonorrhoeae or N. meningitidis resulting from wild type forms of N. gonorrhoeae or N. meningitidis in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof.

Another aspect of the description particularly relates to a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof for treating or ameliorating N. gonorrhoeae or N. meningitidis resulting from drug-resistant forms of N. gonorrhoeae or N. meningitidis in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof.

One aspect of the description relates to a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof having activity against N. gonorrhoeae clinical isolates and their derivatives selected from ATCC penicillin- sensitive wild- type N. gonorrhoeae FA 19 (ATCC BAA- 1838), ATCC streptomycin-resistant (streptomycin ) N. gonorrhoeae FA1090 (ATCC 700825; GenBank Acc. No. AE004969), ATCC N. gonorrhoeae MS11 (ATCC BAA-1833) and ATCC wild-type N. gonorrhoeae 49226 (ATCC 49226) (see, http://www.atcc.org).

Another aspect of the description relates to a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof having activity against N. gonorrhoeae isolates engineered from clinical isolate FA 19 to contain mutations in gyrA and parC, including those selected from ciprofloxacin-resistant (ciprofloxacin ) N. gonorrhoeae AK1 (gyrAgi_/gs) and

ciprofloxacin N. gonorrhoeae AK2 (gyrAgi/g₅, parCge) (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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof having activity against a N. gonorrhoeae isolate engineered from WHO isolate F (N. gonorrhoeae 13477), where DNA from FA1090 was isolated and used to transform 13477 with the streptomycin determinant. The resulting isolate SP1364 is streptomycin at > 1250 μg/mL.

Another aspect of the description relates to a method of use for a compound of

Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof having activity against N. gonorrhoeae clinical isolates selected from penicillin-resistant (penicillin ) N. gonorrhoeae LGB3, tetracycline -resistant (tetracycline R ) N. gonorrhoeae LGB24 and ampicillin-resistant (ampicillin R ) 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), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof to the subject.

An embodiment of the use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof to the subject.

An embodiment of the use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof to treat or ameliorate

N. gonorrhoeae MS 11 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof to the subject.

An embodiment of the use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof to the subject.

An embodiment of the use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof to treat or ameliorate penicillin- sensitive N. gonorrhoeae FA19 or LGB3 in a subject in need thereof, comprising

administering an effective amount of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof to the subject.

An embodiment of the use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof to the subject.

An embodiment of the use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof to the subject. An embodiment of the use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof to the subject.

An embodiment of the use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form thereof to the subject.

An embodiment of the use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof to treat or ameliorate ciprofloxacin XDR /cefixime XDR /ceftriaxone XDR N. gonorrhoeae F89 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof to the subject.

An embodiment of the use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof includes a method of use for a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof to treat or ameliorate or N. meningitidis 13090 in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) 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), Formula (III) or Formula (IV) or a form, composition or medicament thereof effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect in a subject in need thereof.

The dose administered to achieve an effective target plasma concentration may also be administered based upon the weight of the subject or patient. Doses administered on a weight basis may be in the range of about 0.001 mg/kg/day to about 3500 mg/kg/day, or about 0.01 mg/kg/day to about 2000 mg/kg/day, or about 0.01 mg/kg/day to about 1500 mg/kg/day, or about 0.01 mg/kg/day to about 1000 mg/kg/day, or about 0.01 mg/kg/day to about 600 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 300 mg/kg/day, or about 0.015 mg/kg/day to about 200 mg/kg/day, or about 0.02 mg/kg/day to about 100 mg/kg/day, or about 0.025 mg/kg/day to about 100 mg/kg/day, or about 0.03 mg/kg/day to about 100 mg/kg/day, wherein said amount is orally administered once (once in approximately a 24 hour period), twice (once in approximately a 12 hour period) or thrice (once in approximately an 8 hour period) daily according to subject weight.

In certain embodiments, the effective amount will be in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.1 mg to about 500 mg/kg/day, or about 1.0 mg/day to about 500 mg/kg/day, in single, divided, or a continuous dose for a patient or subject having a weight in a range of between about 40 to about 200 kg (which dose may be adjusted for patients or subjects above or below this range, particularly children under 40 kg). The typical adult subject is expected to have a median weight in a range of about 70 kg.

In another embodiment, where daily doses are adjusted based upon the weight of the subject or patient, compounds described herein may be formulated for delivery at about 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.20, 0.25, 0.30, 0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0, 3.0, 5.0, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400 or 500 mg/kg/day. Daily doses adjusted based upon the weight of the subject or patient may be administered as a single, divided, or continuous dose. In embodiments where a dose of compound is given more than once per day, the dose may be administered twice, thrice, or more per day.

Within the scope of the present description, the "effective amount" of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof for use in the manufacture of a medicament, the preparation of a pharmaceutical kit or in a method of treating or ameliorating N. gonorrhoeae or N. meningitidis in a subject in need thereof, is intended to include an amount in a range of from about 0.001 mg to about 3500 mg administered daily; 1.0 mg to about 3500 mg administered daily; 1.0 mg to about 1500 mg administered daily; 1.0 mg to about 1000 mg administered daily; 10.0 mg to about 600 mg administered daily; 0.5 mg to about 2000 mg administered daily; or, an amount in a range of from about 5.0 mg to about 300 mg administered daily. For example, the effective amount may be the amount required to treat N. gonorrhoeae or N. meningitidis, or the amount required to inhibit N. gonorrhoeae or N. meningitidis replication in a subject or, more specifically, in a human. In some instances, the desired effect can be determined by analyzing the presence of bacterial DNA. The effective amount for a subject will depend upon various factors, including the subject's body weight, size and health. Effective amounts for a given patient can be determined by routine experimentation that is within the skill and judgment of the clinician.

For any compound, the effective amount can be estimated initially either in cell culture assays or in relevant animal models, such as a mouse, chimpanzee, marmoset or tamarin animal model. Relevant animal models may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED₅₀ (the dose therapeutically effective in 50% of the population) and LD₅₀ (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is therapeutic index, and can be expressed as the ratio, LD₅₀/ED₅₀. In some embodiments, the effective amount is such that a large therapeutic index is achieved. In further embodiments, the dosage is within a range of circulating concentrations that include an ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

More specifically, the concentration-biological effect relationships observed with regard to a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof indicate a target plasma concentration ranging from approximately 0.001 μg/mL to approximately 50 μg/mL, from approximately 0.01 μg/mL to approximately 20 μg/mL, from approximately 0.05 μg/mL to approximately 10 μg/mL, or from approximately 0.1 μg/mL to approximately 5 μg/mL. To achieve such plasma concentrations, the compounds described herein may be administered at doses that vary, such as, for example, without limitation, from 0.1 ng to 10,000 mg, depending upon the route of administration in single, divided, or continuous doses for a patient weighing between about 10 to about 100 kg (which dose may be adjusted for patients within this weight range, particularly for children under 40 kg).

The exact dosage will be determined by the practitioner, in light of factors related to the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, ethinicity, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, experience with other antibacterial therapies, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 2, 3 or 4 days, once every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

The compounds and compositions described herein may be administered to the subject via any drug delivery route known in the art. Nonlimiting examples include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration.

Metabolites of the Compounds

Also included within the scope of the present description are the use of in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the description includes the use of compounds produced by a process comprising contacting a compound described herein with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof.

Such products typically are identified by preparing a radio-labeled isotopologue (e.g., ¹⁴C or ³H) of a compound described herein, administering the radio-labeled compound in a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal such as a rat, mouse, guinea pig, dog, monkey or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to about 30 hours), and identifying the metabolic conversion products from urine, bile, blood or other biological samples. The conversion products are easily isolated since they are "radiolabeled" by virtue of being isotopically-enriched (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds described herein even if they possess no biological activity of their own. Pharmaceutical Compositions

Embodiments of the present description include the use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof in a pharmaceutical composition for treating or ameliorating N. gonorrhoeae or N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof in admixture with one or more pharmaceutically acceptable excipient(s).

Embodiments of the present description include the use of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof in a pharmaceutical composition for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae or N. meningitidis in a subject in need thereof, comprising administering an effective amount of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof in admixture with one or more pharmaceutically acceptable excipient(s).

An embodiment of the present description includes the use of a pharmaceutical composition of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof in the preparation of a kit comprising the pharmaceutical composition of the compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof and instructions for administering the compound for treating or ameliorating N. gonorrhoeae or N. meningitidis 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), Formula (III) or Formula (IV) or a form thereof in admixture with one or more pharmaceutically acceptable excipient(s) suitable for the manufacture of a suspension. In yet other

embodiments, pharmaceutical compositions described herein may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of one or more excipient(s).

Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g. , lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g. , polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g. , heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

The pharmaceutical compositions described herein may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids;

hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

Additionally, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propane-diol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer' s solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

The compounds described herein may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but generally soluble in medium-chain fatty acids (e.g. , caprylic and capric acids) or triglycerides and in propylene glycol esters of medium-chain fatty acids. Thus, contemplated in the description are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, etc.

In some embodiments, the compound described herein is formulated for oral administration in a lipid-based composition suitable for low solubility compounds. Lipid- based formulations can generally enhance the oral bioavailability of such compounds. As such, pharmaceutical compositions described herein may comprise a effective amount of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) or a form thereof, together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants, such as polysorbate 20 or 80 (also referred to as Tween 20 or Tween 80, respectively) or polyoxyl 40 hydrogenated castor oil. In other embodiments, the bioavailability of low solubility compounds may be enhanced using particle size optimization techniques including the preparation of

nanoparticles or nanosuspensions using techniques known to those skilled in the art. The compound forms present in such preparations include amorphous, partially amorphous, partially crystalline or crystalline forms.

In alternative embodiments, the pharmaceutical composition may further comprise one or more aqueous solubility enhancer(s), such as a cyclodextrin. Nonlimiting examples of cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin, and hydroxypropyl- β-cyclodextrin (HPBC). In some embodiments, the pharmaceutical composition further comprises HPBC in a range of from about 0.1% to about 20%, from about 1% to about 15%, or from about 2.5% to about 10%. The amount of solubility enhancer employed may depend on the amount of the compound in the composition.

Preparation of Compounds As disclosed herein, many of the starting materials used are commercially available or can be prepared using the routes described below using techniques known to those skilled in the art.

General Schemes

Compounds of Formula (I), Formula (II), Formula (III) or Formula (IV) can be prepared as described in the Schemes below.

Starting material ketones used in Scheme 3 were prepared via the routes depicted in Scheme 1 and Scheme 2:

Scheme 1

General Procedure for Scheme 1

Halogenated anilines of Type lb (where Hal represents a halogen such as I or Br) are prepared from bicyclic anilinoketones of Type la via electrophilic halogenation with a suitable halogen source (such as NIS or NBS and the like).

Tricyclic indoles of Type lc are prepared from the respective halogenated anilines of Type lb via Sonogashira coupling with a substituted alkyne (where Rx represents a protecting group, a reactive group or R 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).

Ketones of Type Id are prepared from the respective tricyclic indoles of Type lc via 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).

Scheme 2

Xa: C(R₃), CHR₃-C(R₃), CHR₃-CHR₃-C(R₃)

Za: C(R₄)

General Procedure for Scheme 2

Vinyl aldehydes of Type 2b are prepared from chlorobenzaldehydes of Type 2a via Pd catalyzed Suzuki coupling with a suitable vinylation reagent (such as potassium vinyl trifluoroborate and the like), in the presence of a suitable phosphine ligand (such as 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl and the like) in a suitable biphasic mixture (such as a mixture of dioxane/H₂0 and the like).

Diene intermediates of Type 2c are prepared from the respective vinyl aldehydes of Type 2b via reaction with alkenyl metal halides (where Mg(Hal) represents a magnesium halide).

Unsaturated ketones of Type 2d are prepared from the respective diene intermediates of Type 2c by reaction with suitable oxidative reagents (where [Ox] represents a mixture of reagents such as TPAP and NMO and the like).

Ring closing metathesis (RCM) of the respective unsaturated ketones of Type 2d to provide olefin intermediates of Type 2e is accomplished in the presence of Grubbs' catalyst (such as a second generation Grubbs' catalyst) in a suitable organic solvent (such as toluene and the like).

Tricyclic ketones of Type Id are prepared from the respective olefin intermediates of Type 2e by hydrogenation in the presence of suitable Pd or Pt catalysts (such as Pd/C, Pt0₂ and the like).

Scheme 3

General Procedure for Scheme 3

Ketones of Type Id may be 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-pyridone esters of Type 3b may be 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) Scheme 4

General Procedure for Scheme 4

Substituted pyridones of Type 3b (where Rx represents CH₂OTBS (CH₂-0-tert- butyldimethylsilyl)) can be converted into aldehydes of Type 4a via a three step process: Step 1. TBS-group deprotection with a suitable fluoride containing reagent, such as TBAF and the like; Step 2. Ester cleavage with a suitable nucleophilic reagent, such as Lil and the like; and, Step 3. Conversion of the benzylic hydroxyl to an aldehyde with a suitable oxidant, such as Mn0₂ and the like.

Compounds of Formula (la) can be prepared from the respective aldehydes via a two step process: Step 1. Reaction with primary or secondary amine in the presence of a suitable reducing reagent, such as NaBH(OAc)₃ and the like; and, Step 2. Protecting group cleavage (such as cleavage of the 2,4-dimethoxybenzyl group) in the presence of a suitable acid (such as TF A and the like).

Compounds of Formula (lb) can be prepared from compounds of Formula (la) 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 5

General Procedure for Scheme 5

Compounds of Formula (la) can also be prepared from the respective substituted pyridones of Type 3b (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 in the presence of a suitable acid (such as TFA and the like).

Scheme 6

General Procedure for Scheme 6

Boronic ester intermediates of Type 6b are prepared from bromoindolines of Type 6a (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 alkylated pinacol boronate (such as 2-isopropoxy-4,4,5,5- tetramethyl-l,3,2-dioxaborolane and the like).

Biaryl intermediates of Type 6d are prepared from the respective boronic esters of Type 6b via Pd catalyzed Suzuki coupling with functionalized pyridines of Type 6c (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) in a suitable biphasic mixture (such as a mixture of THF and water and the like).

Tetracyclic indoles of Type 6e are prepared from the respective biaryl intermediates of Type 6d via a two step process: Step 1. TBS-group deprotection with a suitable fluoride containing reagent, such as TBAF and the like; Step 2. Intramolecular Mitsunobu reaction with a suitable dialkyl azodicarboxylate (such as diisopropyl azodicarboxylate and the like).

4-hydroxy-2-pyridone compounds of Type 6f are prepared from the respective tetracyclic indolines of Type 6e 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 6g representative of a Compound Formula (lb), wherein Z is O, are prepared from the respective 4-hydroxy-2-pyridone compounds of Type 6f by reductive amination with an R₅ substituted aldehyde in the presence of a suitable reducing reagent, such as NaBH(OAc)₃ and the like.

Scheme 7

General Procedure for Scheme 7

Alternatively, indoline intermediates of Type 6e are converted to tetracyclic indoles of Type 7a via a three step process: Step 1. Indoline moiety oxidation with a suitable oxidant, such as Mn0₂ and the like; Step 2. Protecting group cleavage (such as via thermal cleavage of a Boc-group); and, Step 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 7b representative of a Compound Formula (la), wherein Z is O, are prepared from the respective tetracyclic indoles of Type 7a by global deprotection via suitable methods (such as hydrogenation in the presence of a suitable Pd catalyst, e.g., Pd/C and the like).

Compounds of Type 6g representative of a Compound Formula (lb), wherein Z is O, can also be prepared from compounds of Type 7b by reduction with a suitable reducing reagent (such as Et₃SiH and the like) in a presence of a suitable acid (such as TFA and the like).

Scheme 8

General Procedure for Scheme 8

Biaryl intermediates of Type 8c are prepared by Suzuki-type coupling reaction between boronic esters of Type 8a with orthogonally protected halogenated pyridines of Type 8b 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).

Tetracyclic intermediates of Type 8d are prepared from the respective biaryl intermediates of Type 8c by TBS-groups cleavage with a suitable fluoride containing reagent (such as TBAF and the like) followed by intramolecular cyclization promoted by a suitable aminosulfur trifluoride reagent (such as DAST and the like).

4-hydroxy-2-pyridone compounds of Type 8e are prepared from the respective tetracyclic intermediates of Type 8d by global protecting group cleavage (such as cleavage of benzyl- and Boc-groups) in the presence of a suitable acid (such as HC1 and the like).

Compounds of Type 8f representative of a compound of Formula (lb), wherein X is -CH(R )-0- and Z is CH(R₄), are prepared from the respective 4-hydroxy-2-pyridone compounds of Type 8e by reductive amination with an R5 substituted aldehyde in the presence of a suitable reducing reagent, such as NaBH(OAc)₃ and the like.

Scheme 9

General Procedure for Scheme 9

Alternatively, tetracyclic intermediates of Type 8d are converted to indole compounds of Type 9a by indoline moiety oxidation with a suitable oxidant (such as Mn0₂ and the like), followed by protecting group cleavage (such as via thermal cleavage of a Boc-group).

Compounds of Type 9b representative of a Compound Formula (la), wherein X is

CH(R₃)-0 and Z is CH(R₄), are prepared from the respective indole compounds of Type 9a 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 protecting group cleavage (such as cleavage of benzyl groups) by hydrogenation in the presence of a suitable Pd catalyst (such as Pd/C and the like).

Scheme 10

General Procedure for Scheme 10

Tetracyclic indoles of Type 10b are prepared from nitroketals of Type 10a via reaction with vinyl metal halides (where Mg(Hal) represents a magnesium halide).

Tricyclic ketones of Type 10c are prepared from their respective tetracyclic indoles of Type 10b via 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 protecting group cleavage in the presence of a suitable acid (such as HC1 and the like). 4-Hydroxy-2-pyridone esters of Type lOd are prepared from their respective tricyclic ketones of Type 10c by a two step process: Step 1. Imine formation by reaction with a suitable amine (such as t-butyl amine and the like) in the presence of a suitable dehydrating agent (such as titanium tetrachloride and the like); and, Step 2. Cyclization via 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 (Ila) can be prepared from the respective ester substituted 4- hydroxy-2-pyridones of Type lOd by reaction with a suitable nucleophilic reagent (where Nu^" represents a nucleophilic reagent such as Lil and the like).

Compounds of Formula (lib) can be prepared from compounds of Formula (Ila) via reduction with a suitable reducing reagent (such as EtsSiH and the like) in the presence of a suitable acid (such as TFA and the like).

Scheme 11

General Procedure for Scheme 11

Tricyclic 4-hydroxy-2-pyridones of Type 1 lb are prepared from nitroketones of Type 1 la by a two step process: Step 1. Imine formation by reaction with a suitable amine (such as t-butyl amine and the like) in the presence of a suitable dehydrating agent (such as titanium tetrachloride and the like); and, Step 2. Cyclization via reaction with a trialkylmethane tricarboxylate (such as trimethylmethane tricarboxylate and the like), in a suitable organic solvent (such as diphenyl ether and the like).

Nitro pyridines of Type 1 lc are prepared from their respective tricyclic 4-hydroxy-2- pyridones of Type 1 lb by treatment with a suitable alcohol (such as benzyl alcohol and the like) under Mitsunobu reaction conditions with a suitable dialkyl azodicarboxylate (such as diisopropyl azodicarboxylate and the like).

Bromoanilines of Type 1 Id are prepared from their respective nitro pyridines of Type 1 lc via reduction of the nitro-group with a suitable reducing reagent (such as iron metal and the like) in the presence of a suitable acid (such as AcOH and the like), followed by bromination with a suitable brominating reagent (such as NBS and the like).

Tetracyclic indoles of Type l ie can be prepared from the respective bromoanilines of Type 1 Id via Sonogashira coupling with a substituted alkyne 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 (Ilia) can be prepared from the respective tetracyclic indoles of Type 1 le via a three step process: Step 1. 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); Step 2. Protecting group cleavage (such as cleavage of a benzyl group) by hydrogenation in the presence of a suitable Pd catalyst (such as Pd/C and the like); and, Step 3. 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).

Compounds of Formula (Illb) can be prepared from respective compounds of

Formula (Ilia) by reduction with a suitable reducing reagent (such as Et SiH and the like) in the presence of a suitable acid (such as TFA and the like). Scheme 12

General Procedure for Scheme 12

Halogenated anilines of Type 12b (where Hal represents a halogen such as Br or I) can be prepared from bicyclic anilinoketones of Type 12a via electrophilic halogenation with a suitable halogen source (such as NBS or NIS and the like).

Tricyclic indoles of Type 12c can be prepared from the respective iodoanilines of Type 12b via Sonogashira coupling with a substituted alkyne 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).

Ketones of Type 12d can be prepared from the respective tricyclic indoles of Type 12c via 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).

Tetracyclic 4-hydroxy-2-pyridones of Type 12e can be prepared from their respective ketones of Type 12d by a two step process: Step 1. Imine formation by reaction with a suitable amine (such as t-butyl amine and the like) in the presence of a suitable dehydrating agent (such as titanium tetrachloride and the like); and, Step 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 (IVa) can be prepared their respective tetracyclic 4-hydroxy- 2-pyridones of Type 12e by ester group hydrolysis to the corresponding carboxylic acid by reaction with a suitable nucleophilic reagent (where Nu^" represents a nucleophilic reagent such as Lil and the like).

Compounds of Formula (IVb) can be prepared from their respective compounds of Formula (IVa) by reduction with a suitable reducing reagent (such as EtsSiH and the like) in the presence of a suitable acid (such as TFA and the like). Specific Examples

To assist in understanding the present description, the following specific examples are included. The specific examples for synthesizing Compounds 62 and 63 have been disclosed in International Application Publication Number WO2013/033228 and United States Patent Application Publication Number US2015/0038438, found therein as Compounds 60 and 61. The experiments relating to representative compounds described herein should not, of course, be construed as specifically limiting the scope of compounds intended to be included, as well as variations thereof, now known or later developed, which would be within the purview of one skilled in the art. Such actual and possible equivalents are considered to fall within the scope of the compound genera and variations thereof 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.

The following method was used to obtain LC-MS characterization for the compounds described herein, 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 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 Abbreviation Meaning

ACN or MeCN acetonitrile

4A MS 4 Angstrom Molecular Sieves

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

DAST diethylamino sulfur trifluoride

DCE dichloroethane

DCM dichloromethane (CH₂C1₂)

DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone

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 Abbreviation Meaning

HPLC high performance liquid chromatography

h/hr/hrs/min/s hour(s)(h, hrs or hrs)/minute(s)(min/mins)/second(s)

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

Pin pinacol

PPA polyphosphoric acid

PPh₃ triphenylpho sphine

Psi pounds per square inch pressure

PTFE polytetrafluoroethylene Abbreviation Meaning

RT retention time

RCM ring closing methathesis

S-Phos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl

TBAF tetra-n-butylammonium fluoride

TBS tert-butyldimethylsilyl

TBSC1 tert-butyldimethylsilyl chloride

t-BuOK potassium tert-butoxide

t-Bu₃P tert-butyl phosphine

TEA or NEt 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

Intermediate 1

3 ,7, 8 ,9-Tetrahydro-6H-benzo [e] indol-6-

Step 1: 6-Amino-5-iodo-3,4-dihydronaphthalen-l(2H)-one

To a solution of 6-amino-3,4-dihydronaphthalen-l(2H)-one (1.0 g, 6.2 mmol) in CH₂CI₂ (20 mL) was added NIS (1.6 g, 6.8 mmol) along with AcOH (500 μί). The reaction mixture was stirred for 1 hr at 25 °C and then partitioned between CH₂CI₂ (40 mL) and aqueous saturated Na₂S₂0₃. The organic layer was separated, dried over Na₂S0₄, filtered and concentrated to afford 1.2 g (67%) of desired product.

LC-MS: 288.0 [M+H]⁺, RT 1.47 min. 1H NMR (500 MHz, CDC1₃) δ ppm 2.13 (quin, J=6.40 Hz, 2H), 2.53 - 2.63 (m, 2H), 2.94 (t, J=6.19 Hz, 2H), 6.65 - 6.74 (m, 1H), 7.88 - 7.97 (m, 1H).

Step 2: 6-Amino-5-((trimethylsilyl)ethynyl)-3,4-dihydronaphthalen- 1 (2H)-one

A mixture of 6-amino-5-iodo-3,4-dihydronaphthalen-l(2H)-one (4.0 g, 13.9 mmol), copper(I) iodide (106 mg, 0.56 mmol), bis(triphenylphosphine)palladium(II) dichloride (195 mg, 0.28 mmol), ethynyltrimethylsilane (2.2 mL, 15.3 mmol), triethylamine (3.9 mL, 27.8 mmol), and acetonitrile (28 mL) was stirred under argon at 75 °C for 1 hr. The reaction mixture was then allowed to cool to room temperature, concentrated, and the crude residue was

chromato graphed on silica gel, eluting with 20% EtOAc in hexanes to afford 3.38 g (94%) of product.

1H NMR (500 MHz, DMSO- ₆) δ ppm 0.26 (s, 9H), 1.93 - 2.00 (m, 2H), 2.40 - 2.44 (m, 2H), 2.87 - 2.92 (m, 2H), 5.76 (s, 2H), 6.65 (d, J=8.67 Hz, 1H), 7.63 (d, J=8.67 Hz, 1H).

Step 3: 3 ,7 , 8 ,9-Tetrahydro-6H-benzo [e] indol-6-one

A mixture of 6-amino-5-((trimethylsilyl)ethynyl)-3,4-dihydronaphthalen-l(2H)-one (3.38 g, 13.2 mmol), copper(I) iodide (2.76 g, 14.5 mmol), and DMF (26 mL) was stirred under argon at 100 °C for 16 hrs. The reaction mixture was then diluted with Et₂0 (100 mL) and filtered through Celite. The residue was rinsed with another portion of Et₂0 (50 mL) and the combined filtrates were washed with H₂0 (100 mL) and then brine (100 mL). The organic layer was separated, dried over MgS0₄, filtered, and concentrated. The crude residue was chromato graphed on silica gel, eluting with 20% EtOAc in hexanes to afford 800 mg (33%) of product.

1H NMR (500 MHz, DMSO- ₆) δ ppm 2.11 (quin, J=6.32 Hz, 2H), 2.58 (dd, J=7.25, 5.75 Hz, 2H), 3.13 (t, J=6.11 Hz, 2H), 6.64 (ddd, J=3.05, 1.99, 0.87 Hz, 1H), 7.32 (dd, J=8.59, 0.79 Hz, 1H), 7.41 - 7.46 (m, 1H), 7.68 (d, J=8.59 Hz, 1H), 11.50 (br. s, 1H). Intermediate 2

3-Methyl-3 ,7 ,8 ,9-tetrahydro-6H-benzo [e] indol-6-one

To a solution of 3,7,8, 9-tetrahydro-6H-benzo[e]indol-6-one (Intermediate 1, 0.33 g, 1.78 mmol) in DMF (5 mL), cooled to 0 °C, was added NaH (72 mg, 60%, 1.78 mmol). The mixture was stirred at 0 °C for 30 min, then iodomethane (0.11 mL, 1.78 mmol) was added and the ice bath was removed. The mixture was stirred an additional 2 hrs at 25 °C, then quenched with aqueous saturated NH₄C1 and diluted with H₂0 (25 mL). The precipitate was filtered, rinsed with H₂0 (50 mL) and dried under a N₂ stream to afford 265 mg (73%) of product.

1H NMR (500 MHz, DMSO- d₆) δ ppm 2.11 (quin, J=6.31 Hz, 2H), 2.55 - 2.62 (m, 2H), 3.12 (t, J=6.11 Hz, 2H), 3.81 (s, 3H), 6.65 (dd, J=3.11, 0.67 Hz, 1H), 7.39 (d, J=8.67 Hz, 1H), 7.42 (d, J=3.15 Hz, 1H), 7.72 (d, J=8.67 Hz, 1H).

Intermediate 3

7,8,9, 10-Tetrahydrocyclohepta[e]indol-6(3H)-one

Step 1 : 2-Amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one

A mixture of 2-chloro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (11.3 g, 58 mmol), tert- butyl carbamate (8.83 g, 75.4 mmol), CS₂CO₃ (37.8 g, 116 mmol), tris(dibenzylideneacetone) dipalladium(O) (800 mg, 0.87 mmol) and tri-ieri-butylphosphonium tetrafluoroborate (1.0 g, 3.5 mmol) in 1,4-dioxane (200 mL) was stirred under N₂ at 90 °C for 18 h. The mixture was partitioned between EtOAc (800 mL) and H₂0 (800 mL). The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-25% EtOAc in hexanes to afford 13.5 g of oil that was dissolved in trifluoroacetic acid (20 mL). The solution was stirred at room temperature for 20 min before removing all volatiles with a stream of nitrogen. The residue was partitioned in CH₂C1₂ (500 mL) and aqueous saturated NaHC0₃ (500 mL). The organic layer was dried over Na₂S0₄, filtered and concentrated to afford 8.0 g (79%) of product.

LC-MS: 176.1 [M+H]⁺, RT 0.95 min.

Step 2: 2-Amino-l-iodo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one To a solution of 2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (8.0 g, 46 mmol) and AcOH (2.6 mL, 46 mmol) in CH₂C1₂ (200 mL) at 0 °C was added N-iodosuccinimide (10.4 g, 46 mmol) portion wise over 5 min. The mixture stirred at room temperature for 1 hr, and then was washed with aqueous saturated NaHC0₃. The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-5% EtOAc in CH₂C1₂ to afford 4.5 g (33%) of product, the minor isomer of the iodination reaction (6.3 g of major isomer collected).

LC-MS: 301.9 [M+H]⁺, RT 1.21 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 1.61 (m, 2H), 1.71 (m, 2H), 2.57 (m, 2H), 3.06 (m, 2H), 5.97 (br. s, 2H), 6.65 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H). Step 3: 7,8,9, 10-Tetrahydrocyclohepta[e]indol-6(3H)-one

To a mixture of 2-amino-l-iodo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.51 g, 5 mmol), copper(I) iodide (48 mg, 0.25 mmol), bis(triphenylphosphine)palladium(II) dichloride (175 mg, 0.25 mmol), triethylamine (1.4 mL, 10 mmol) and THF (25 mL) was added trimefhylsilylacetylene (1.07 mL, 7.5 mmol). The mixture was stirred at room temperature for 48 h. The mixture was diluted with EtOAc (50 mL), filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-20% EtOAc in hexanes to affording 1.45 g of an intermediate alkyne. The alkyne intermediate was combined with copper(I) iodide (285 mg, 1.5 mmol) in DMF (10 mL) and heated with stirring at 120 °C for 2 hrs. The mixture was partitioned in EtOAc (80 mL) and H₂0 (80 mL). The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-40% EtOAc in hexanes to afford 450 mg of the title product (45%).

LC-MS: 200.1 [M+H]⁺, RT 1.13 min. Intermediate 4

7,8,9, 10-Tetrahydrocyclohepta[g]indol-6(lH)-

Step 1: l-Nitro-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,2'-[l,3]dioxolane] To a mixture of l-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (0.44 g, 2.2 mmol), toluene (20 mL) and ethylene glycol (185 μί, 3.3 mmol) was added p-toluenesulfonic acid (84 mg, 0.44 mmol). The mixture was stirred at reflux for 8 h under a Dean-Stark apparatus. The mixture was diluted with EtOAc (100 mL) and washed with aqueous saturated NaHC0₃. 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% EtOAc in hexanes to afford the desired product (0.47 g) in 86% yield.

Step 2: 7,8,9, 10-Tetrahydrocyclohepta[g]indol-6(lH)-one

To a solution of l-nitro-6,7,8,9-tetrahydrospiro[benzo[7]annulene-5,2'-[l,3]dioxolane] (0.47 g, 1.88 mmol) in THF (10 mL) at -40 °C was added vinyl magnesium bromide (7.5 mL, 7.5 mmol, 1 M in THF). The mixture was stirred at -40 °C for 3 hrs. Excess reagent was quenched by the addition of aqueous saturated NH₄C1 (5 mL). The mixture was partitioned between EtOAc (50 mL) and H₂0 (50 mL). The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was dissolved in 1,4-dioxane (8 mL) and aqueous 6 M HC1 (1 mL). The resulting mixture was stirred vigorously at room temperature for 20 min. The mixture was partitioned between EtOAc (50 mL) and H₂0 (50 mL). The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromato graphed on silica gel, eluting with 0-30% EtOAc in hexanes to afford the desired product (135 mg) in 36% yield.

LC-MS: 200.1 [M+H]⁺, RT 1.12 min. Intermediate 5

2-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methyl-7,8-dihydrocyclohepta[e]indol-6(3H)

Step 1 : N-(4-Bromo-3-chloro-2-iodophenyl)-2,2,2-trifluoroacetamide To a solution of 4-bromo-3-chloro-2-iodoaniline (14.95 g, 45 mmol) in CH₂CI₂ (200 mL) at 0 °C was added pyridine (4.0 mL, 49.5 mmol) followed by TFAA (6.9 mL, 49.5 mmol). The mixture was stirred at 0 °C for 1 hr, then washed with 1 N HC1 (2X), satd. NaHC0₃ and water. The organics were dried over Na₂S0₄ then concentrated to give the title compound (19.26 g, quant.) as a brownish solid which was used in the next step without further purification.

Step 2: 5-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloro-lH-indole

A mixture of N-(4-bromo-3-chloro-2-iodophenyl)-2,2,2-trifluoroacetamide (19.26 g, 45 mmol), PdCl₂(PPh₃)₂ (1.58 g, 2.25 mmol) and Cul (0.807 g, 4.5 mmol) was degassed and back-filled with N₂. To the mixture was added DMF (150 mL), tert-butyldimethyl(prop-2-yn- l-yloxy)silane (22.8 mL, 112.5 mmol) followed by Et₃N (31.4 mL, 225 mmol). The mixture was heated at 65 °C for 8 h then cooled to room temperature, diluted with ether and washed with water (3X). The organics were concentrated and dried over Na₂S0₄. The black oily residue was chromato graphed (0-5% EtOAc/hexanes). The combined product fractions were concentrated to give a light brown solid. The solid was stirred in hexanes and filtered. The filtrate was concentrated and the washing process was repeated a few times to give the title product as an off-white solid (12.44 g, 73%).

LC-MS 374.2/376.2 [M+H]⁺, RT 1.78 min. 1H NMR (500 MHz, CDC1₃) δ ppm 0.13 (s, 6H), 0.95 (s, 9H), 4.89 (d, J=0.9 Hz, 2H), 6.40 (dd, J=22, 0.9 Hz, 1H), 7.16 (dd, J=8.5, 0.9 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 8.48 (br. s, 1H) Step 3: 5-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloro-l-methyl-lH-indole

To a solution of 5-bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloro-lH-indole (20.24 g, 54 mmol) in DMF (150 mL) at 0 °C was added NaH (2.59 g, 64.8 mmol) in portions. The mixture was stirred at room temperature for 0.5 hrs, then cooled to 0 °C before Mel (5.0 mL, 81 mmol) was added. The mixture was stirred at room temperature for 1 hr, then cooled to 0 °C and the reaction quenched with ice- water (approx.. 450 mL). The solid was collected by filtration and washed with water (3x150 mL), hexanes (2x30 mL) and dried to give the title compound as an off-white solid (13.383 g). The hexanes filtrate was concentrated and the solid was stirred in a minimal amount of hexanes and filtered. The process was repeated 2 more times to give an additional 4.56 g of title compound. The last filtrate was concentrated and chromatographed (0-3% EtOAc/hexanes) to give 1.5 g of title compound. The combined yield was 19.44 g, 93%.

1H NMR (500 MHz, CDC1₃) δ ppm 0.08 (s, 6H), 0.91 (s, 9H), 3.77 (s, 3H), 4.82 (s, 2H), 6.47 (s, 1H), 7.09 (d, J=8.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H).

Step 4: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-4-chloro-l -methyl- lH-indole-5- carbaldehyde

5-Bromo-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloro-l -methyl- lH-indole (19.44 g, 50 mmol) in a 1 L flask was degassed and back-filled with N₂. Anhydrous THF (180 mL) was added and the solution was cooled to -95 °C (MeOH and liquid N₂). To the reaction mixture was added w-BuLi (23.0 mL, 57.5 mmol, 2.5 M in hexanes) over 40 min via a syringe pump. 5 min later DMF (8.94 mL, 115 mmol) in THF (20 mL) was added. The solution was warmed to -60 °C in 30 min, and then quenched with satd. NH₄C1, extracted with ether, and washed with water. The organics were dried over Na₂S0₄ and concentrated. The solid was stirred in 45 mL of ether, filtered, and washed with cold ether (10 mL x 2) to give the title compound (13.15 g) as an off-white solid. The filtrate was concentrated to about 1/3 volume, cooled, and the resulting precipitate was collected by filtration, then washed with a minimal amount of cold ether (2X) to give the title compound (0.94 g). The combined yield was 14.02 g, 83%. LC-MS 338.2/340.2 [M+H]⁺, RT 1.76 min. 1H NMR (500 MHz, CDC1₃) δ ppm 0.10 (s, 6H) 0.92 (s, 9H) 3.83 (s, 3H) 4.85 (s, 2H) 6.66 (s, 1H) 7.27 (d, J=8.5 Hz, 1H) 7.81 (d, J=8.5 Hz, 1H) 10.58 (s, 1H).

Step 5: 2-(((tert-Butyldimethylsilyl)oxy)methyl)- l-methyl-4-vinyl- lH-indole-5-carbaldehyde

A mixture of 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloro-l -methyl- lH-indole-5- carbaldehyde (14.02 g, 41.5 mmol), potassium trifluoroborate (11.12 g, 83 mmol), palladium acetate (0.279 g, 1.245 mmol), S-Phos ligand (1.022 g, 2.49 mmol) and K₂C0₃ (17.18 g, 124.5 mmol) in a 1 L flask was degassed and back-filled with nitrogen. 1,4-Dioxane (334 mL) and water (66 mL) were added and the mixture was heated at 75 °C for 1 hr. The reaction was then cooled to room temperature, extracted with ether and washed with water. The organics were dried and concentrated to give crude product which was purified by a filtration column (160 g silica) with 0-5% EtOAc/hexanes to afford the title compound (13.01 g, 95%) as an off-white solid.

LC-MS 330.3 [M+H]⁺, RT 1.72 min. 1H NMR (500 MHz, acetone- ₆) δ ppm 0.12 (s, 6H), 0.92 (s, 9H), 3.89 (s, 3H), 4.97 (d, J=0.6 Hz, 2H), 5.70 (dd, J=17.5, 1.6 Hz, IH), 5.76 (dd, J=11.2, 1.6 Hz, IH), 6.77 (s, IH), 7.49 (d, J=8.8 Hz, IH), 7.60 (dd, J=17.5, 11.2 Hz, IH), 7.74 (d, J=8.8 Hz, IH), 10.34 (s, IH). Step 6: l-(2-(((tert-Butyldimethylsilyl)oxy)methyl)-l-methyl-4-vinyl-lH-indol-5-yl)pent-4- en-l-ol

To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-l-methyl-4- vinyl- lH-indole-5- carbaldehyde (3.60 g, 10.93 mmol) in THF (30 mL) at -78 °C was added 3- butenylmagnesium bromide (0.5M in THF, 35.0 mL, 17.5 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 and stirred for 1 hr before the reaction was quenched with NH₄C1 (aq. satd, approx.. 30 mL) at -78 °C. The mixture was extracted with Et₂0:EtOAc (9: 1, 3x50 mL). The combined organics were washed with brine (50 mL), dried over Na₂S0₄ and then

concentrated to afford the title compound (approx.. 4.74 g) which was carried over to the next step without further purification.

LC-MS 386.3 [M+H]⁺, RT 1.78 min. 1H NMR (500 MHz, CDC1₃) δ ppm 0.07 (s, 3H), 0.08 (s, 3H), 0.91 (s, 9H), 1.81 - 1.91 (m, IH), 1.93 - 2.01 (m, IH), 2.07 - 2.17 (m, IH), 2.18 - 2.28 (m, IH), 3.79 (s, 3H), 4.83 (s, 2H), 4.97 (ddt, J=10.2, 2.1, 1.1 Hz, IH), 5.05 (dq, J=17.0, 1.7 Hz, IH), 5.16 (dd, J=7.9, 5.4 Hz, IH), 5.60 (dd, J=11.3, 1.9 Hz, IH), 5.68 (dd, J=17.7, 1.9 Hz, IH), 5.86 (ddt, J=17.0, 10.2, 6.6 Hz, IH), 6.55 (s, IH), 7.13 (dd, J=17.7, 11.3 Hz, IH), 7.26 (d, J=8.5 Hz, IH), 7.39 (d, J=8.5 Hz, IH).

Step 7: l-(2-(((tert-Butyldimethylsilyl)oxy)methyl)-l-methyl-4-vinyl-lH-indol-5-yl)pent-4- en-l-one

To a solution of crude l-(2-(((tert-butyldimethylsilyl)oxy)methyl)-l-methyl-4- vinyl- 1H- indol-5-yl)pent-4-en-l-ol (4.74 g, 11 mmol) in CH₂C1₂ (50 mL) was added 4A MS (5 g) followed by NMO (2.88 g, 24.58 mmol) at room temperature. The mixture was cooled to 0 °C then TPAP (387 mg, 1.10 mmol) was added in one portion. The reaction was stirred at 0 °C for 30 min, then allowed to warm to room temperature and stirred for 1 hr. The reaction progress was monitored by TLC analysis. Upon the completion of the reaction, the mixture was filtered through a Celite column (10 g) and washed with CH₂CI₂ (3x50 mL). The filtrate was concentrated to give crude product which was purified by column chromatography (80 g, EtOAc/hexanes, 0-10% gradient) to afford the title compound (3.33 g, 79%) as a yellow solid.

Step 8: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methyl-7,8-dihydrocyclohepta[e]indol- 6(3H)-one

To a solution of l-(2-(((tert-butyldimethylsilyl)oxy)methyl)-l-methyl-4-vinyl-lH-indol-5- yl)pent-4-en-l-one (3.33 g, 8.68 mmol) in toluene (200 mL, 0.043M) under an argon atmosphere was added Grubbs' 2^nd generation catalyst (180 mg, 0.21 mmol, 2.4 mol%). The reaction mixture was heated at 80 °C for 1 hr then cooled to room temperature before a second portion of Grubbs' catalyst (160 mg, 0.19 mmol, 2.2 mol%) was added. The reaction mixture was heated at 80 °C for 1 hr until starting material was completely consumed as indicated by TLC. Upon cooling the reaction to room temperature toluene was removed under reduced pressure and the residue was purified by column chromatography (80 g, EtOAc/hexanes, 0-10% gradient) to afford the title compound (2.805 g, 91%) as light tan solid.

1H NMR (500 MHz, acetone- d₆) δ ppm 0.11 (s, 6H), 0.92 (s, 9H), 2.43 - 2.52 (m, 2H), 2.84 - 2.90 (m, 2H), 3.86 (s, 3H), 4.95 (s, 2H), 6.36 - 6.46 (m, 1H), 6.75 (s, 1H), 7.07 (dt, J=11.5, 1.3 Hz, 1H), 7.36 (dd, J=8.8, 0.6 Hz, 1H), 7.78 - 7.87 (m, 1H).

Intermediate 6

2-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methyl-7,8,9,10-tetrahydrocyclohepta[e]indol-

6(3H)-one

To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-7,8- dihydrocyclohepta[e]indol-6(3H)-one (Intermediate 5, 2.805 g, 7.89 mmol) in EtOAc (30 mL) was added 10% Pd/C (Degussa type, 300 mg, 10%). The reaction mixture was evacuated and then back-filled with H₂ (1 atm) in three cycles. The reaction mixture was stirred at room temperature for 1.5 hrs until starting material was completely consumed as indicated by TLC. The reaction mixture was filtered and washed with EtOAc. The filtrate was concentrated and the residue was purified by column chromatography (80 g, EtOAc/hexanes, 0-10% gradient) to afford the title compound (2.68 g, 95 %) as an off-white solid.

LC-MS 358.3 [M+H]⁺, RT 1.75 min. 1H NMR (500 MHz, CDC1₃) 5 ppm 0.10 (s, 6H), 0.92 (s, 9H), 1.77 - 1.89 (m, 2H), 1.91 - 1.99 (m, 2H), 2.80 (t, J=6.0 Hz, 2H), 3.21 (t, J=6.6 Hz, 2H), 3.80 (s, 3H), 4.84 (s, 2H), 6.55 (s, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H).

Intermediate 7

2-(((tert-Butyldimethylsilyl)oxy)methyl)-3,8-dimethyl-7,8,9,10-tetrahydrocyclohepta[e]indol-

6(3H)-one

Steps 1-2: l-(2-(((tert-Butyldimethylsilyl)oxy)methyl)-l-methyl-4- vinyl- lH-indol-5-yl)-3- methylpent-4-en- 1 -one To a solution of 4-iodo-3-methylbut-l-ene (1.8 g, 9.2 mmol) in diethylether (16 mL) was added ί-BuLi (1.7M in pentane, 11.9 mL, 20.2 mmol) at -78 °C dropwise via syringe pump over 15 min. The resulting mixture was stirred at -78 °C for 1 hr before a solution of 2-(((tert- butyldimethylsilyl)oxy)methyl)- 1 -methyl-4-vinyl- lH-indole-5-carbaldehyde (Intermediate 5, Step 5, 2.2 g, 6.6 mmol) in THF (9 mL) was added. The reaction was stirred at -78 °C for 15 min then quenched by NH₄C1 (aq. satd., lOmL). The mixture was extracted with Et₂0/EtOAc (9/1, 3x20mL). The combined organics were washed with brine (50mL) and dried over Na₂S0₄ and then concentrated to afford the desired alcohol (approx.. 2.7 g) which was carried over to the next step without further purification.

To a solution of the crude alcohol (2.7 g, 6.6 mmol) in CH₂C1₂ (40 mL) was added 4A MS (3 g) followed by NMO (1.5 g, 13.2 mmol) at room temperature. The mixture was cooled to 0 °C then TPAP (232 mg, 0.66 mmol) was added in one portion. The reaction was stirred at 0 °C for 30 min, allowed to warm to room temperature then stirred for 1 hr. The reaction progress was monitored by TLC analysis. Upon the completion of the reaction, the mixture was filtered through Celite (10 g) and washed with CH₂CI₂ (3x50mL). The filtrate was concentrated to give crude product which was purified by column chromatography

(EtOAc/hexanes, 0-10% gradient) to afford the title compound (2.0 g, 77%) as a light yellow oil.

1H NMR (500 MHz, acetone- d₆) δ ppm 0.11 (s, 6H), 0.91 (s, 9H), 1.04 (d, J=6.6 Hz, 3H), 2.77 - 2.85 (m, IH), 2.86 - 2.94 (m, IH), 3.00 (dd, J=15.8, 6.6 Hz, IH), 3.86 (s, 3H), 4.86 - 4.92 (m, IH), 4.95 (d, J=0.6 Hz, 2H), 4.98 (dt, J=17.1, 1.5 Hz, IH), 5.50 (dd, J=11.3, 1.9 Hz, IH), 5.59 - 5.65 (m, IH), 5.85 (ddd, J=17.3, 10.4, 6.9 Hz, IH), 6.75 (d, J=0.6 Hz, IH), 7.28 (dd, J=18.0, 11.3 Hz, IH), 7.40 (d, J=8.2 Hz, IH), 7.59 (d, J=8.8 Hz, IH) Step 3: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-3,8-dimethyl-7,8- dihydrocyclohepta[e]indol-6(3H)-one

To a solution of l-(2-(((tert-butyldimethylsilyl)oxy)methyl)-l-methyl-4-vinyl-lH-indol-5-yl)- 3-methylpent-4-en-l-one (2.6 g, 6.5 mmol) in toluene (130 mL) under an argon atmosphere was added Grubbs' 2^nd generation catalyst (160 mg, 0.19 mmol). The reaction mixture was heated at 85 °C for 1 hr then cooled to room temperature before second portion of Grubbs' catalyst (160 mg, 0.19 mmol) was added. The reaction mixture was at heated at 85 °C for 2 hrs. The solvent was concentrated and then the residue was purified by column

chromatography (EtOAc/hexanes, 0-10% gradient) to afford the title compound (1.83 g, 76%) as a light tan solid.

1H NMR (500 MHz, acetone- ₆) δ ppm 0.11 (s, 6H), 0.91 (s, 9H), 1.16 (d, J=6.9 Hz, 3H), 2.75 - 2.80 (m, IH), 2.83 - 2.86 (m, 2H), 3.86 (s, 3H), 4.95 (d, J=0.6 Hz, 2H), 6.20 (dd, J=11.8, 4.6 Hz, IH), 6.76 (s, IH), 6.99 (dd, J=11.5, 1.9 Hz, IH), 7.36 (dd, J=8.8, 0.9 Hz, IH), 7.79 - 7.81 (m, IH)

Step 4: 2-(((tert-Butvldimethvlsilvl)oxv)methvl)-3,8-dimethyl-7,8,9,10- tetrahydrocyclohepta[e]indol-6(3H)-one

To a solutionof 2-(((tert-butyldimethylsilyl)oxy)methyl)-3,8-dimethyl-7,8- dihydrocyclohepta[e]indol-6(3H)-one (1.83 g, 4.95 mmol) in EtOAc (30 mL) was added 10% Pd/C (Degussa type, 200 mg). The reaction mixture was evacuated and then back-filled with H₂ (1 atm) in three cycles. The reaction was stirred at room temperature for 1.5 hrs until starting material was completely consumed as indicated by TLC. The heterogeneous mixture was filtered and washed with EtOAc. The filtrate was concentrated and the residue was purified by column chromatography (EtOAc/hexanes, 0-10% gradient) to afford the title compound (1.8 g, 98 %) as an off-white solid.

LC-MS 372.1 [M+H]⁺, RT 1.77 min. 1H NMR (500 MHz, acetone- ₆) δ ppm 0.11 (s, 3H), 0.12 (s, 3H), 0.92 (s, 9H), 1.06 (d, J=6.7 Hz, 3H), 1.52 - 1.58 (m, 1H), 2.04 - 2.11 (m, 2H), 2.60 - 2.65 (m, 1H), 2.75 - 2.80 (m, 1H), 3.22 - 3.25 (m, 2H), 3.84 (s, 3H), 4.94 (d, J=0.6 Hz, 2H), 6.66 (d, J=0.6 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H).

Intermediate 8a

(S)-4-Iodo-3-methylbut- 1-ene

Step 1 : Methyl (R)-2-methyl-3-(tosyloxy)propanoate

To a solution of methyl (R)-3-hydroxy-2-methylpropanoate (25.0 g, 0.21 mol) in CH₂CI₂ (300 mL) cooled to 0 °C were subsequently added NEt₃ (34.5 mL, 0.25 mol, 1.2 eq), DMAP (1.3 g, 5 mol%) and TsCl (44.5 g, 0.23 mol, 1.1 eq). The reaction mixture was stirred at 0 °C for 1 hr and then overnight at room temperature. The reaction mixture was washed with water (150 mL) and the aqueous phase was extracted with CH₂CI₂ (2x). The combined organics were dried over Na₂S0₄, concentrated and the residue was purified by column

chromatography (EtOAc/hexanes, 0-40% gradient) to afford the title compound (53.4 g, 93%) as a white solid.

1H NMR (500 MHz, acetone- d₆) δ ppm 1.12 (d, J=7.3 Hz, 3H), 2.47 (s, 3H), 2.84 (ddq, J=5.5, 7.2, 7.2 Hz, 1H), 3.59 (s, 3H), 4.13 (dd, J=5.5, 9.5 Hz, 1H), 4.18 (dd, J=6.6, 9.5 Hz, 1H), 7.48 - 7.52 (m, 2H), 7.78 - 7.82 (m, 2H).

Step 2: (_lS')-2-Methylbut-3-en-l-yl 4-methylbenzenesulfonate

To a solution of methyl (R)-2-methyl-3-(tosyloxy)propanoate (27.0 g, 99.1 mmol) in toluene (135 mL) cooled to -95 °C (MeOH/N₂) was added a solution of DIBAL-H (1M hexanes, 114.0 mL, 114.0 mmol, 1.15 eq) over 30 min via syringe pump. The reaction was stirred at -95 °C for 1.5 hrs then excess DIBAL-H was quenched by addition of EtOAc (3 mL). A citric acid solution (1M ¾0, 330 mL) was subsequently added in one portion to the mixture still kept at -95 °C with vigorous stirring of the reaction to avoid local overheating. The cooling bath was removed 5 min later and the mixture was allowed to stir at room

temperature for 1 hr. Et₂0 was added to the mixture and the organic phase was separated. The aqueous layer was then extracted with Et₂0 (2x). The combined organics were dried over MgS0₄ and Et₂0 was removed under reduced pressure. A toluene solution of the

intermediate aldehyde was immediately used in the Wittig reaction below without purification.

To a suspension of methyltriphenylphosphonium bromide (53.1 g, 149.0 mmol, 1.5 eq) in THF (400 mL) at 0 °C was added n-BuLi solution (2.5M hexanes, 52.0 mL, 130.0 mmol, 1.3 eq) dropwise via syringe pump over 15 min. The reaction mixture was stirred at 0 °C for 15 min then cooled to -78 °C. A toluene solution of the aldehyde obtained above was added to the mixture via syringe pump over 30 min with efficient stirring. The stirred mixture was allowed to slowly (approx.. 4-5 hrs) warm to 0 °C before being quenched with H₂0. Et₂0 was added to the mixture and the organic phase was separated. The aqueous layer was extracted with Et₂0 (2x). The combined organics were dried over MgS0₄ and the solvents were concentrated. A mixture of Et₂0:pentane (1: 1, 500 mL) was added to the residue and the PPh₃ by-product was filtered off. The mother liquor was concentrated and the residue was purified by column chromatography (EtOAc/hexanes, 5-10% gradient) to afford the title compound (14.8 g, 62%) as a colorless oil.

1H NMR (500 MHz, CDC1₃) δ ppm 1.02 (d, J=6.8 Hz, 3H), 2.46 (s, 3H), 2.48 - 2.57 (m, 1H), 3.85 (dd, J=9.5, 6.9 Hz, 1H), 3.93 (dd, J=9.5, 6.4 Hz, 1H), 5.03 - 5.08 (m, 2H), 5.64 (ddd, J=17.3, 10.4, 7.0 Hz, 1H), 7.35 (d, J=7.9 Hz, 2H), 7.80 (d, J=8.3 Hz, 2H). Step 3: ( )-4-Iodo-3-methylbut-l-ene

To a solution of (S)-2-methylbut-3-en-l-yl 4-methylbenzenesulfonate (8.9 g, 36.9 mmol) in Et₂0 (100 mL) was added Lil (9.9 g, 74.0 mmol, 2.0 eq) at room temperature. The reaction mixture was heated to 40 °C and monitored by TLC analysis for 3 hrs. The mixture was cooled to room temperature and the reaction was quenched with water (ca. 50 mL). n-Pentane was added to the mixture and the organic phase was separated. The aqueous layer was extracted with n-pentane (2x). The combined organics were dried over MgS0₄ then filtered through a pad of silica gel by gravity. The filtrate was carefully concentrated under vacuum to afford a solution of the title compound in n-pentane/Et₂0 (23.1 g, 32% wt.) which was used immediately in the next step without further purification.

1H NMR (500 MHz, acetone- d₆) δ ppm 1.10 (d, J=6.6 Hz, 3H), 2.32 - 2.41 (m, 1H), 3.24 (dd, J=6.0, 9.5 Hz, 1H), 3.28 (dd, J=5.8, 9.5 Hz, 1H), 5.02 - 5.06 (m, 1H), 5.06 - 5.11 (m, 1H), 5.75 (ddd, J=6.9, 10.2, 17.2 Hz, 1H). Intermediate 8b

(R)-4-Iodo-3-methylbut- 1-

.(R).

Ί

The title compound was prepared from methy (_lS')-3-hydroxy-2-methylpropanoate according to the procedures described for Intermediate 8a

Intermediate 9

(R)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-3,8-dimethyl-7,8,9, 10- tetrahydrocyclohepta[e]indol-6(3H)-one

Intermediate 9 was prepared starting from (R)-4-iodo-3-methylbut-l-ene (Intermediate 8b) according to procedures for Intermediate 7.

Chiral HPLC: (R)-enantiomer RT 5.70 min (100%), ADH column, 5% IPA/hexanes, 10-min method.

Intermediate 10

(5)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-3,8-dimethyl-7,8,9, 10- tetrahydrocyclohepta[e]indol-6(3H)-one

Intermediate 10 was prepared starting from (S)-4-iodo-3-methylbut- l-ene (Intermediate 8a) according to procedures for Intermediate 7.

Chiral HPLC: (S)-enantiomer RT 5.00 min (99.3%), (R)-enantiomer RT 5.67 min (0.7%), ADH column, 5% IPA/hexanes 10-min method. Intermediate 11

2-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methyl-3,7,8,9,10,l l-hexahyd]

cycloocta[e]indol-6-one

Step 1: 4-Allyl-2-(((tert-butyldimethylsilyl)oxy)methyl)- 1 -methyl- lH-indole-5-carbaldehyde

A mixture of 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloro-l -methyl- lH-indole-5- carbaldehyde (Intermediate 5, Step 4, 2.8 g, 8.3 mmol), potassium allyltrifluoroborate (1.44 g, 9.8 mmol), palladium acetate (25 mg, 0.11 mmol), 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (107 mg, 0.23 mmol), K₂C0₃ (3.1 g, 22.5 mmol), dioxane (30 mL), and H₂0 (10 mL) was stirred under an Ar atmosphere at 50 °C for 4 hrs. The mixture was partitioned between EtOAc (100 mL) and H₂0 (100 mL). The organic layer was washed with brine (100 mL), dried over MgS0₄, filtered, and concentrated. The crude residue was chromato graphed on silica gel, eluting with 0-20% EtOAc in hexanes to afford 2.53 g of product (89%).

1H NMR (500 MHz, CDC1₃) δ ppm 0.09 (s, 6H), 0.91 (s, 9H), 3.81 (s, 3H), 4.06 - 4.12 (m, 2H), 4.85 (s, 2H), 4.98 - 5.08 (m, 2H), 6.03 - 6.16 (m, 1H), 6.58 (d, J=0.63 Hz, 1H), 7.29 (d, J=8.70 Hz, 1H), 7.78 (d, J=8.67 Hz, 1H), 10.35 (s, 1H).

Step 2: l-(4-Allyl-2-(((tert-butyldimethylsilyl)oxy)methyl)- 1 -methyl- lH-indol-5-yl)pent-4- en-l-one To a solution of 4-allyl-2-(((tert-butyldimethylsilyl)oxy)methyl)-l-methyl-lH-indole-5- carbaldehyde (3.18 g, 9.3 mmol) in THF (25 mL), cooled to 0 °C, was added but-3-en-l- ylmagnesium bromide (20.4 mL, 0.5 M in THF, 10.2 mmol). The mixture was stirred at 0 °C for 1.5 hrs and then quenched with an aqueous saturated solution of NH₄C1. The reaction mixture was then partitioned between Et₂0 (100 mL) and H₂0 (100 mL). The organic layer was separated, dried over MgS0₄, then filtered and concentrated. The crude residue was dissolved in CH₂C1₂ (25 mL), activated 4 A molecular sieves (2.3 g) were added along with TPAP (100 mg, 0.28 mmol) and NMO (1.6 g, 14 mmol). The mixture was stirred at 25 °C for 5 hrs, then filtered through Celite, eluting with CH₂CI₂. The filtrate was concentrated and the resulting crude residue was chromato graphed on silica gel, eluting with 0-10% EtOAc in hexanes to afford 2.6 g of product (70% yield over 2 steps).

1H NMR (500 MHz, CDC1₃) δ ppm 0.08 (s, 6H), 0.90 (s, 9H), 2.45 - 2.53 (m, 2H), 3.04 - 3.10 (m, 2H), 3.80 (s, 3H), 3.92 (d, J=6.23 Hz, 2H), 4.84 (s, 2H), 4.95 - 5.11 (m, 4H), 5.86 - 5.97 (m, 1H), 6.04 - 6.14 (m, 1H), 6.55 (s, 1H), 7.20 (d, J=9.14 Hz, 1H), 7.60 (d, J=8.67 Hz, 1H).

Step 3: (Z)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methyl-3,7,8, 1 l-tetrahydro-6H- cycloocta[e]indol-6-one A mixture of l-(4-allyl-2-(((tert-butyldimethylsilyl)oxy)methyl)-l-methyl-lH-indol-5- yl)pent-4-en-l-one (2.0 g, 5 mmol) and [l,3-Bis-(2,4,6-trimethylphenyl)-2- imidazolidinylidene]dichloro(isopropoxyphenylmethylene)ruthenium (HG2) (300 mg, 0.48 mmol) in toluene (150 mL) was heated at 70 °C for 2 hr. The reaction mixture was then concentrated and the crude residue was chromatographed on silica gel, eluting with 0-10% EtOAc in hexanes to afford 600 mg of product (32%).

1H NMR (500 MHz, CDC1₃) δ ppm 0.10 (s, 6H), 0.92 (s, 9H), 2.57 - 2.63 (m, 2H), 3.22 (t, J=7.13 Hz, 2H), 3.79 (s, 3H), 3.97 (d, J=8.43 Hz, 2H), 4.85 (s, 2H), 5.64 - 5.69 (m, 1H), 5.84 - 5.91 (m, 1H), 6.58 (s, 1H), 7.18 (d, J=8.59 Hz, 1H), 7.71 (d, J=8.67 Hz, 1H).

Step 4: 2-(((tert-Butvldimethvlsilvl)oxv)methvl)-3-methyl-3,7,8,9,10,l l-hexahydro-6H- cycloocta[e]indol-6-one

A mixture of (Z)-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-3,7,8,l l-tetrahydro-6H- cycloocta[e]indol-6-one (1.1 g, 3 mmol) and platinum (IV) oxide (20 mg, 0.09 mmol) in EtOAc (30 mL) was stirred under an atmosphere of ¾ (1 atm) for 1 hr. The mixture was then filtered through Celite and concentrated to afford 1.1 g of product (99%).

1H NMR (500 MHz, CDCI₃) δ ppm 0.10 (s, 6H), 0.91 (s, 9H), 1.45 - 1.55 (m, 2H), 1.82 -

1.92 (m, 4H), 3.07 (t, J=7.01 Hz, 2H), 3.37 - 3.45 (m, 2H), 3.79 (s, 3H), 4.84 (s, 2H), 6.53 (s, 1H), 7.21 (d, J=8.75 Hz, 1H), 7.81 (d, J=8.75 Hz, 1H).

Intermediate 12

2-(((tert-Butyldimethylsilyl)oxy)methyl)-4-fluoro-3-methyl-7,8,9,10- tetrahydrocyclohepta[e]indol-6(3H)-one

Step 1: Ethyl (5-bromo-2-fluorophenyl)carbamate

To a solution of 5-bromo-2-fluoroaniline (21.3 g, 112 mmol) and pyridine (12.8 mL, 134.4 mmol) in CH₂C1₂ (560 mL) at 0 °C was added ethyl chloroformate (18.0 mL, 224 mmol). The mixture was stirred for 1 hr at room temperature, then washed with aqueous 1 N HC1 and brine. The organic layer was dried over Na₂S0₄, filtered and concentrated to afford the desired product (29.3 g) in quantitative yield.

LC-MS: 260.1/262.1 [M-H]⁺, RT 1.27 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 1.71 (t, J=6.9 Hz, 3H), 4.64 (q, J=7.2 Hz, 2H), 7.60 (dd, J=10.8, 8.8 Hz, 1H), 7.69 (m, 1H), 8.72 (m, 1H), 8.98 (br. s, 1H).

Step 2: 5-(3-((Ethoxycarbonyl)amino)-4-fluorophenyl)pentanoic acid

A solution of ethyl (5-bromo-2-fluorophenyl)carbamate (29.3 g, 112 mmol), 4-pentenoic acid (12.0 mL, 118 mmol), triethylamine (31.2 mL, 224 mmol), palladium(II) acetate (0.75 g, 3.4 mmol) and tri(o-tolyl)phosphine (2.0 g, 6.7 mmol) in CH₃CN (250 mL) was heated at 70 °C for 6 hr. Volatiles were removed by rotary evaporation. The residue was partitioned in aqueous 0.1 N NaOH (500 mL) and EtOAc (500 mL). The aqueous layer was washed with EtOAc (500 mL) and then acidified with 1 M HC1 (pH <2). The aqueous mixture was extracted with EtOAc (2 x 500 mL). The combined organics were washed with brine, dried over Na₂S0₄ and filtered. To the solution was added 10% Pd/C (1.5 g). The mixture was stirred under H₂ (1 atm) for 24 hrs and then filtered through Celite. The filtrate was concentrated to afford a colorless oil that was carried on to the next step without further purification.

LC-MS: 284.2 [M+H]⁺, RT 1.11 min.

Step 3: Ethyl (3-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)carbamate A mixture of 5-(3-((ethoxycarbonyl)amino)-4-fluorophenyl)pentanoic acid (31.7 g, 112 mmol) and Eaton's reagent (320 g) stirred at room temperature for 16 h. To the mixture was added 500 mL of H₂0. The aqueous mixture was extracted with EtOAc (2 x 500 mL). The combined organics were washed with aqueous saturated NaHC0₃ and brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromato graphed on silica gel, eluting with CH₂C1₂ to afford the desired product (23.0 g) in 77% yield.

1H NMR (500 MHz, acetone- d₆) δ ppm 1.29 (t, J=7.0 Hz, 3H), 1.80 (m, 2H), 1.90 (m, 2H), 2.73 (m, 2H), 3.00 (m, 2H), 4.23 (q, J=7.0 Hz, 2H), 7.44 (d, J=11.9 Hz, 1H), 8.05 (d, J=7.6 Hz, 1H), 8.59 (br. s, 1H).

Step 4: 2-Amino-3-fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one

A mixture of ethyl (3-fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)carbamate (7.96 g, 30 mmol) and potassium hydroxide (5.05 g, 90 mmol) in EtOH:H₂0 (98:2, 100 mL) was stirred at reflux for 38 h. Volatiles were removed. To the residue was added H₂0 (100 mL). The solid material was collected by vacuum filtration, washed with H₂0, and dried giving the desired product (5.8 g).

LC-MS: 194.4 [M+H]⁺, RT 0.93 min.

Step 5: 2,2,2-Trifluoro-N-(3-fluoro-l-iodo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2- yl)acetamide

To a solution of 2-amino-3-fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.16 g, 6 mmol) in l,4-dioxane:H₂0 (4: 1, 24 mL) was added iodic acid (1.16 g, 6 mmol) and iodine (0.76 g, 3 mmol). The mixture was stirred at room temperature for 16 h, and then was diluted with H₂0 (100 mL) and aqueous saturated NaHC0₃ (100 mL). The mixture was extracted with EtOAc (2 x 100 mL). The combined organics were washed with aqueous 5% Na₂S₂0₃ and brine, dried over Na₂S0₄, filtered, and concentrated. The crude residue was dissolved in CH₂C1₂ (24 mL) with pyridine (0.96 mL, 12 mmol) and cooled to 0 °C. To the solution was added trifluoroacetic anhydride (1.02 mL, 7.2 mmol). The mixture was stirred at 0 °C for 30 min, and then was washed with aqueous 1 M HCl and brine. The organic layer was dried over Na₂S0₄, filtered and concentrated. The residue was chromato graphed on silica gel, eluting with 0-30% EtOAc in hexanes to afford the desired product (1.7 g) in 68% yield.

LC-MS: 414.4 [M-H]⁺, RT 1.11 min.

Step 6: 2-(((tert-Butvldimethvlsilvl)oxv)methyl)-4-fluoro-7.8.9.10- tetrahydrocyclohepta[e]indol-6(3H)-one To a mixture of 2,2,2-trifluoro-N-(3-fluoro-l-iodo-5-oxo-6,7,8,9-tetrahydro-5H- benzo[7]annulen-2-yl)acetamide (1.7 g, 4.1 mmol), copper(I) iodide (0.78 g, 0.41 mmol), bis(triphenylphosphine)palladium(II) dichloride (140 mg, 0.2 mmol), triethylamine (1.14 mL, 8.2 mmol) and DMF (20 mL) was added tert-butyldimethyl(prop-2-yn-l-yloxy)silane (1.66 mL, 8.2 mmol). The mixture was heated at 80 °C for 48 h. The mixture was partitioned in EtOAc (200 mL) and aqueous saturated NH₄C1 (200 mL). The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-30% EtOAc in hexanes to afford the desired product (1.0 g) in 67% yield.

LC-MS: 362.4 [M+H]⁺, RT 1.62 min.

Step 7: 2-(((tert-Butvldimethvlsilvl)oxv)methvl)-4-fluoro-3-methyl-7,8,9,10- tetrahydrocyclohepta[e]indol-6(3H)-one

To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-4-fluoro-7,8,9,10- tetrahydrocyclohepta[e]indol-6(3H)-one (1.0 g, 2.8 mmol) and DMF (14 mL) was added sodium hydride (60% dispersion in mineral oil, 170 mg, 4.2 mmol). The mixture was stirred at room temperature for 5 min before iodomethane (0.26 mL, 4.2 mmol) was added. The mixture was stirred an additional 10 min before being quenched with aqueous saturated

NH₄C1 (10 mL). The mixture was partitioned between EtOAc (100 mL) and H₂0 (100 mL). The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-30% EtOAc in hexanes to afford the desired product (0.45 g) in 43% yield.

LC-MS: 376.4 [M+H]⁺, RT 1.72 min. 1H NMR (500 MHz, acetone- ₆) δ ppm 0.13 (s, 6H), 0.92 (s, 9H), 1.79 (m, 2H), 1.89 (m, 2H), 2.74 (m, 2H), 3.20 (m, 2H), 4.02 (s, 3H), 4.94 (s, 2H), 6.74 (d, J=2.6 Hz, 1H), 7.27 (d, J=13.9 Hz, 1H).

Intermediate 13

10-(2,4-Dimethoxybenzyl)-2-formyl-7-hydroxy-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

Step 1: 2-Amino-l-(3-((tert-butyldimethylsilyl)oxy)prop-l-yn-l-yl)-6,7,8,9-tetrahydro-5H- benzo [7 ] annulen-5 - one

To a mixture of 2-amino-l-iodo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (Intermediate 3, Step 2, 1.5 g, 5 mmol), copper(I) iodide (190 mg, 1 mmol),

bis(triphenylphosphine)palladium(II) dichloride (350 mg, 0.5 mmol), triethylamine (2.1 mL, 15 mmol) and DMF (25 mL) was added tert-butyldimethyl(prop-2-yn-l-yloxy)silane (1.52 mL, 7.5 mmol). The mixture was heated at 80 °C for 6 h. The mixture was partitioned in EtOAc (200 mL) and aqueous saturated NH₄C1 (200 mL). The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-40% EtOAc in hexanes to afford the desired product (0.79 g) in 46% yield.

LC-MS: 344.1 [M+H]⁺, RT 1.55 min.

Step 2: 2-(Hydroxymethyl)-3-tosyl-7,8,9,10-tetrahydrocyclohepta[e]indol-6(3H)-one

To a mixture of 2-amino-l-(3-((tert-butyldimethylsilyl)oxy)prop-l-yn-l-yl)-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-one (0.79 g, 2.3 mmol) and pyridine (5 mL) was added p- toluenesulfonyl chloride (0.66 g, 3.45 mmol). The mixture stirred at room temperature for 18 h. The mixture 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 0-30% EtOAc in hexanes to afford 745 mg of intermediate. The intermediate was dissolved in THF (8 mL) with tetrabutylammonium fluoride (3 mmol, 3 mL, 1 M in THF). The mixture was stirred for 12 hrs at room

temperature and then partitioned between EtOAc (50 mL) and aqueous saturated NaHC0₃. The organic layer was washed with brine, dried over Na₂S0₄, then filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-80% EtOAc in hexanes to afford 0.55 g of product (62%).

LC-MS: 384.2 [M+H]⁺, RT 1.30 min.

Step 3: 2-(((tert-Butvldimethvlsilvl)oxv)methvl)-3-tosyl-7,8,9,10- tetrahydrocyclohepta[e]indol-6(3H)-one

To a mixture of 2-(hydroxymethyl)-3-tosyl-7,8,9,10-tetrahydrocyclohepta[e]indol-6(3H)-one (550 g, 1.4 mmol) and imidazole (120 mg, 1.75 mmol) in CH₂C1₂ (7 mL) was added tert- butyldimethylsilyl chloride (253 mg, 1.68 mmol). The mixture stirred for 1 hr at room temperature, and then was washed with H₂0 (5 mL). The organic layer was concentrated and chromato graphed on silica gel, eluting with 0-40% EtOAc in hexanes to afford 0.65 g of product (93%).

LC-MS: 498.2 [M+H]⁺, RT 1.88 min. Step 4: Methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)- 10-(2,4-dimethoxybenzyl)-7- hydroxy-9-oxo-l-tosyl- 1,4,5,6, 9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8- carboxylate

To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-tosyl-7,8,9,10- tetrahydrocyclohepta[e]indol-6(3H)-one (650 mg, 1.3 mmol) in CH₂C1₂ (6 mL) was added 2- ,4-dimethoxybenzylamine (0.22 mL, 1.43 mmol) and triethylamine (0.54 mL, 3.9 mmol). The mixture was cooled to 0 °C. To the mixture was added a TiCl₄ solution (1 M CH₂C1₂, 0.85 mL, 0.85 mmol) dropwise via syringe over 5 min. The mixture was allowed to warm to room temperature and was stirred overnight. The excess reagent was quenched with aqueous saturated NaHC0₃ (3 mL). The organic phase was separated with vigorous shaking using a PTFE phase separator, dried over Na₂S0₄, filtered, and concentrated. The residue was combined with trimethyl methanetricarboxylate (342 mg, 1.8 mmol) in Ph₂0 (2.6 mL). The mixture was placed in a pre-heated aluminum block at 230 °C and stirred for 15 minutes. The reaction vessel was removed from the heating block and allowed to cool to room temperature. The crude reaction mixture was loaded directly onto a silica gel column, eluting with 0-60% EtOAc in hexanes to yield a yellow powder (0.52 g, 52%).

LC-MS: 773.4 [M+H]⁺, RT 1.97 min. 1H NMR (500 MHz, acetone- ₆) δ ppm 0.18 (s, 6H), 0.98 (s, 9H), 1.34 (m, 1H), 1.92 (m, 1H), 2.01 (m, 1H), 2.26 (m, 1H), 2.39 (s, 3H), 2.90 (m, 2H), 3.38 (s, 3H), 3.68 (s, 3H), 3.90 (s, 3H), 4.96 (d, J=15.6 Hz, 2H), 5.17 (m, 2H), 6.16 (d, J=8.3 Hz, 1H), 6.30 (d, J=2.3 Hz, 1H), 6.61 (d, J=8.3 Hz, 1H), 6.91 (s, 1H), 7.25 (d, J=8.6 Hz, 1H), 7.43 (d, J=7.8 Hz, 2H), 7.94-8.00 (m, 3H), 13.79 (br. s, 1H).

Step 5: Methyl 10-(2,4-dimethoxybenzyl)-7-hydroxy-2-(hydroxymethyl)-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylate

To a solution of methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-10-(2,4-dimethoxybenzyl)- 7-hydroxy-9-oxo-l-tosyl- 1,4,5, 6,9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8- carboxylate (410 mg, 0.53 mmol) in THF (2.5 mL) was added a solution of

tetrabutylammonium fluoride (1 M in THF, 1 mL, 1 mmol). The mixture was stirred 15 min at room temperature and then was concentrated. The residue was partitioned in CH₂C1₂ (20 mL) and aqueous saturated NaHC0₃ (20 mL). The organic layer was collected and concentrated. The residue was combined with K₂C0₃ (138 mg, 1 mmol) in MeOH (4 mL) in a microwave vial. The mixture was heated at 130 °C under μ-wave irradiation for 10 min. The mixture was partitioned in CH₂C1₂ (20 mL) and aqueous saturated NaHC0₃ (20 mL). The organic layer was collected, concentrated and chromatographed on silica gel, eluting with 0-10% MeOH in CH₂C1₂ to afford 270 mg of white powder (99%).

LC-MS: 505.1 [M+H]⁺, RT 1.22 min.

Step 6: 10-(2,4-Dimethoxybenzyl)-2-formyl-7-hydroxy-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid To a solution of methyl 10-(2,4-dimethoxybenzyl)-7-hydroxy-2-(hydroxymethyl)-9-oxo-

1,4,5,6, 9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate (270 mg, 0.53 mmol) in EtOAc (5 mL) was added lithium iodide (134 mg, 1 mmol). The mixture was heated at 70 °C for 1 hr. The volatiles were removed with a stream of nitrogen. The residue was suspended in aqueous 1 M HC1. The solid was collected, washed with H₂0, and dried, yielding 220 mg of a white solid. The solid was suspended in CH₂C1₂ (10 mL) with Mn0₂ (650 mg). The mixture was stirred for 48 hrs at room temperature and then filtered through Celite. The filtrate was concentrated to afford 188 mg of an off white powder (73%).

LC-MS: 489.1 [M+H]⁺, RT 1.33 min. 1H NMR (500 MHz, DMSO- ₆) 5 ppm 1.48 (m, IH), 2.09 (m, 2H), 2.37 (m, IH), 2.94 (m, IH), 3.14 (m, IH), 3.52 (s, 3H), 3.71 (s, 3H), 5.13 (d, J=15.7 Hz, IH), 5.30 (d, J=15.7 Hz, IH), 6.37 (d, J=8.1 Hz, IH), 6.43 (s, IH), 6.65 (d, J=8.3 Hz, IH), 7.33-7.44 (2H), 7.68 (s, IH), 9.91 (s, IH), 12.30 (s, IH), 13.91 (br. s, IH), 16.21 (br s, IH).

Intermediate 14

9-(2,4-Dimethoxybenzyl)-2-formyl-6-hydroxy-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid

Intermediate 14 was prepared from 6-amino-5-iodo-3,4-dihydronaphthalen-l(2H)-one (Intermediate 1, Step 1) according to procedures for Intermediate 13.

LC-MS: 474.9 [M+H]⁺, RT 1.42 min. 1H NMR (500 MHz, CDC1₃) δ ppm 2.48 - 2.63 (m, 2H), 2.78 (m, 2H), 3.69 (s, 3H), 3.86 (s, 3H), 6.29 - 6.38 (m, 2H), 6.68 (s, IH), 6.96 (d, J=8.91 Hz, IH), 7.29 (d, J=8.99 Hz, IH), 7.38 (m, 2H), 7.68 (d, J=8.98 Hz, IH), 9.1 (s, IH), 11.77 (br. s, IH), 12.7 (br. s, IH), 13.49 - 13.61 (br. s, IH).

Intermediate 15

Methyl 7-hydroxy-9-oxo-l-tosyl- 1,4,5, 6,9, 10-hexahydropyrido[2',3':3,4]cyclohepta[ 1,2- e]indole-8-carboxylate

Step 1: 3-Tosyl-7,8,9,10-tetrahydrocyclohepta[e]indol-6(3H)-one

To a solution of 7,8,9, 10-tetrahydrocyclohepta[e]indol-6(3H)-one (Intermediate 3, 450 mg, 2.25 mmol) in DMF (10 mL) was added sodium hydride (135 mg, 3.38 mmol, 60% dispersion in mineral oil). The mixture was stirred at room temperature for 10 min. To the mixture was added p-toluenesulfonyl chloride (0.52 g, 2.7 mmol). The mixture stirred at room temperature for 1 hr. The mixture 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 chromato graphed on silica gel, eluting with 0-10% EtOAc in CH₂C1₂ to afford 670 mg of product (85%).

LC-MS: 354.0 [M+H]⁺, RT 1.47 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 1.69 (p, J=6.1 Hz, 2H), 1.80 (p, J=6.6 Hz, 2H), 2.32 (s, 3H), 2.71 (m, 2H), 3.15 (m, 2H), 7.14 (m, IH), 7.41 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.8 Hz, IH), 7.86-7.93 (4H).

Step 2: Methyl 10-(2,4-dimethoxybenzyl)-7-hydroxy-9-oxo-l-tosyl-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylate To a solution of 3-tosyl-7,8,9,10-tetrahydrocyclohepta[e]indol-6(3H)-one (670 mg, 1.9 mmol) in CH₂C1₂ (10 mL) was added 2-,4-dimethoxybenzylamine (0.32 mL, 2.1 mmol) and triethylamine (0.79 mL, 5.7 mmol). The mixture was cooled to 0 °C. To the mixture was added a TiCl₄ solution (1 M CH₂C1₂, 1.24 mL, 1.24 mmol) dropwise via syringe over 5 min. The mixture was allowed to warm to room temperature and was stirred overnight. The excess reagent was quenched with aqueous saturated NaHC0₃ (5 mL). The organic phase was separated with vigorous shaking using a PTFE phase separator, dried over Na₂S0₄, filtered, and concentrated. The residue was combined with trimethyl methanetricarboxylate (650 mg, 3.4 mmol) in Ph₂0 (3.8 mL). The mixture was placed in a pre-heated aluminum block at 220 °C and stirred for 15 min. The reaction vessel was removed from the heating block and allowed to cool to room temperature. The crude reaction mixture was loaded directly onto a silica gel column, eluting with 0-100% EtOAc in hexanes to yield a yellow powder (0.58 g, 49%).

LC-MS: 629.1 [M+H]⁺, RT 1.47 min. 1H NMR (500 MHz, acetone- ₆) δ ppm 1.33 (m, 1H), 1.87-2.03 (m, 2H), 2.25 (m, 1H), 2.39 (s, 3H), 2.92 (m, 2H), 3.32 (s, 3H), 3.67 (s, 3H), 3.90 (s, 3H), 4.95 (d, J=15.6 Hz, 1H), 5.28 (d, J=15.2 Hz, 1H), 6.15 (m, 1H), 6.27 (m, 1H), 6.62 (d, J=8.2 Hz, 1H), 6.96 (m, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.46 (m, 2H), 7.81 (d, J=8.6 Hz, 1H), 7.91 (d, J=3.8 Hz, 1H), 7.98 (m, 2H), 13.77 (br. s, 1H).

Step 3: Methyl 7-hydroxy-9-oxo-l-tosyl-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylate

To methyl 10-(2,4-dimethoxybenzyl)-7-hydroxy-9-oxo-l-tosyl- 1,4,5,6, 9,10- hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate (580 mg, 0.92 mmol) was added trifluoroacetic acid (4 mL) and triisopropylsilane (0.57 mL, 2.8 mmol). The mixture was stirred 3 hrs at room temperature, and then was concentrated. The residue was suspended in CH₃CN (3 mL). The solid was collected and dried, affording 402 mg of white powder (91%).

LC-MS: 479.0 [M+H]⁺, RT 1.38 min. Intermediate 16

Methyl l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-hydroxy-9-oxo-l,4,5,6,9,10- hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate

The title compound was prepared from 7,8,9, 10-tetrahydrocyclohepta[e]indol-6(3H)-one (Intermediate 3) and (2-bromoethoxy) (tert-butyl)dimethylsilane according to procedures for Intermediate 2 and Example 1 (Step 2).

Intermediate 17

tert-Butyl 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)indoline- 1 -carboxylate

c

Step 1: tert-Butyl 4-vinylindoline-l -carboxylate

A mixture of tert-butyl 4-chloroindoline- 1 -carboxylate (1.0 g, 3.95 mmol), potassium vinyltrifluoroborate (0.69 g, 5.14 mmol), Pd(OAc)₂ (27 mg, 0.12 mmol), S-Phos ligand (98 mg, 0.24 mmol), aqueous K₂C0₃ (2.0 M x 6.0 mL, 12 mmol) and dioxane (12 mL) was stirred at 80 °C under an Ar 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 to 10% gradient) to give the title compound (0.92 g, 95%).

1H NMR (CDC1₃) δ: 7.15-7.20 (m, 2H), 7.10-7.14 (m, 1H), 6.73 (dd, J=17.7, 11.0 Hz, 1H), 5.73 (dd, J=17.7, 0.9 Hz, 1H), 5.34 (d, J=11.0 Hz, 1H), 3.96-4.08 (m, 2H), 3.14 (t, J=8.7 Hz, 2H), 1.59 (br. s, 9H).

Step 2: tert-Butyl 4-(2-hydroxyethyl)indoline-l-carboxylate To a solution of the product of Step 1 (0.92 g, 3.76 mmol) in THF (9.0 mL) was added a solution of 9-BBN in THF (0.5 M, 9.0 mL, 4.5 mmol) dropwise. The mixture was stirred at room temperature overnight then cooled to 0 °C. To the mixture was added an aqueous NaOH solution (1.0 M, 15 mL) followed by 30% H₂0₂ (15 mL). The mixture was 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 CH₂C1₂ (0 to 20% gradient) to give the title compound (0.65 g, 66%). 1H NMR (CDCI₃) δ: 7.29-7.89 (m, 1H), 7.14 (t, J=7.7 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 3.99 (t, J=8.5 Hz, 2H), 3.84 (t, J=6.8 Hz, 2H), 3.07 (t, J=8.7 Hz, 2H), 2.81 (t, J=6.6 Hz, 2H), 1.53- 1.61 (s, 9H).

Step 3: tert-Butyl 5-bromo-4-(2-hydroxyethyl)indoline-l-carboxylate To a solution of the product of Step 2 (0.65 g, 2.47 mmol) in CH₂CI₂ (8.0 mL) was added NBS (0.48 g, 2.72 mmol) portionwise. The mixture was stirred at room temperature overnight, then partitioned between saturated NaHC0₃ and CH₂CI₂. The aqueous layer was extracted with CH₂CI₂. The CH₂CI₂ layers were combined, dried over Na₂S0₄ and evaporated. The residue was purified by silica gel column chromatography with CH₂CI₂ to give the title compound (0.8 g, 95%).

1H NMR (CDCI₃) δ: 7.65 (br. s, 1H), 7.37 (d, J=8.5 Hz, 1H), 4.01 (br. s, 2H), 3.88 (t, J=6.8 Hz, 2H), 3.16 (t, J=8.7 Hz, 2H), 2.98 (t, J=6.9 Hz, 2H), 1.53-1.65 (br. s, 9H).

Step 4: tert-Butyl 5-bromo-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)indoline- 1-carboxylate

To a solution of the product of Step 3 (0.8 g, 2.34 mmol), imidazole (0.476 g, 7.0 mmol) in DMF (7.0 mL) at 0 °C was added TBSCl (0.42 g, 2.8 mmol). The mixture was stirred at room temperature for 1 hr, then treated with water (20 mL) and extracted with ether (3x). 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 to 10% gradient) to give the title compound (0.82 g, 77%).

1H NMR (CDCI₃) δ: 7.62 (br. s, 1H), 7.34 (d, J=8.5 Hz, 1H), 3.93-4.06 (m, 2H), 3.83 (s, 2H), 3.13-3.19 (m, 2H), 2.92 (s, 2H), 1.58 (br. s, 9H), 0.88 (s, 9H), 0.00 (s, 6H).

Step 5: tert-Butyl 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)indoline- 1-carboxylate

To a solution of the product of Step 4 (0.82 g, 1.8 mmol) in THF (15 mL) cooled at -78 °C was added n-BuLi (1.6 M x 1.35 mL, 2.16 mmol). To the mixture 2-isopropoxy-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (0.5 g, 0.55 mL, 2.7 mmol) was added 1 hr later. The cooling bath was removed and the temperature was allowed to rise to room temperature. The reaction was quenched with aqueous NH₄C1 solution, then 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 to 10% gradient) to give the title compound (0.95 g, 100%). 1H NMR (CDCI₃) δ: 7.69-7.77 (m, 1H), 7.28-7.34 (m, 1H), 3.96-4.08 (m, 2H), 3.77-3.85 (m, 2H), 3.06-3.22 (m, 4H), 1.61 (br. s, 9H), 1.38 (s, 12H), 0.85-0.93 (s, 9H), -0.05-0.07 (s, 6H).

Intermediate 18

Benzyl 2,4-bis(benzyloxy)-6-bromo-5-hydroxynicotinate

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 NH₄CI 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 benzoxide 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. 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-bis(benzyloxy)-5-iodonicotinate (2.55 g, 51%). LC-MS 552.1 [M+H]⁺, RT 1.80 min. 1H NMR (500 MHz, CDCI₃) 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. The mixture was stirred at -45 °C for 15 minutes, then was allowed to warm to room temperature slowly. The mixture was stirred at room temperature for 1.5 hrs, cooled to -20 °C, then 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). The mixture was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, then evaporated and purified by silica 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 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, CDCI₃) δ ppm 5.15 (s, 2H), 5.30 (s, 2H), 5.34 (s, 2H), 7.24 - 7.40 (m, 15H). Intermediate 19

8-Benzyl l-(tert-butyl) 7,9-bis(benzyloxy)-2,3,4,5-tetrahydro- pyrido[2',3':6,7]oxepino[4,5-e]indole-l,8-dicarboxylate

Step 1: tert-Butyl 5-(4,6-bis(benzyloxy)-5-((benzyloxy)carbonyl)-3-hydroxypyridin-2-yl)-4- (2-((tert-butyldimethylsilyl)oxy)ethyl)indoline-l-carboxylate

A mixture of tert-butyl 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)indoline-l-carboxylate (Intermediate 17, 0.48 g, 0.95 mmol), benzyl 2,4- bis(benzyloxy)-6-bromo-5-hydroxynicotinate (Intermediate 18, 0.36 g, 0.69 mmol), Pd₂(dba)₃ (31 mg, 0.0345 mmol), i-Bu P HBF4 (20 mg, 0.069 mmol), aqueous potassium carbonate (2.0 M, 1.4 mL) and THF (2.8 mL) was stirred at 65 °C for 60 min under an argon

atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate (3X). The organic phases were combined, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0 to 30% gradient) to give the title compound (1.02 g, 91%).

¹H NMR (CDC1₃) δ: 7.37-7.47 (m, 16H), 7.17 (d, J=8.2 Hz, 1H), 5.44 (s, 2H), 5.43 (s, 2H), 5.27 (s, 2H), 4.07-4.16 (m, 2H), 3.72 (t, J=7.1 Hz, 2H), 3.26 (t, J=8.5 Hz, 2H), 2.84 (t, J=7.1 Hz, 2H), 1.68 (br. s, 9H), 0.88 (s, 9H), 0.01 (s, 6H).

Step 2: tert-Butyl 5-(4,6-bis(benzyloxy)-5-((benzyloxy)carbonyl)-3-hydroxypyridin-2-yl)-4- (2-hydroxyethyl)indoline- 1 -carboxylate

To a solution of the product of Step 1 (0.92 g, 1.125 mmol) in THF (4.5 mL) cooled at 0 °C was added a solution of TBAF in THF (1.0 M, 2.25 mL). The reaction mixture was stirred at room temperature for 2 hrs, quenched with saturated ammonium chloride aqueous solution, then extracted with ethyl acetate (3X), dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0 to 50%) to give the title compound (0.74 g, 93%). LC-MS 703.2 [M+H]⁺, RT 1.60 min. 1H NMR (CDC1₃) δ: 7.66-7.80 (m, 16H), 7.47 (d, J=8.5 Hz, 1H), 5.80 (s, 2H), 5.74 (s, 2H), 5.59 (s, 2H), 4.43 (t, J=8.4 Hz, 2H), 4.06 (t, J=6.3 Hz, 2H), 3.52 (t, J=8.7 Hz, 2H), 3.08 (t, J=6.3 Hz, 2H), 1.90-2.03 (br. s, 9H).

Step 3: 8-Benzyl l-(tert-butyl) 7,9-bis(benzyloxy)-2,3,4,5-tetrahydro-lH- pyrido[2',3':6,7]oxepino[4,5-e]indole-l,8-dicarboxylate

To a solution of the product from Step 2 (100 mg, 0.14 mmol), triphenylphosphine (49 mg, 0.185 mmol) in THF (1.0 mL) cooled at 0 °C was added a solution of DEAD in toluene (40%, 84 μί, 0.185 mmol). The mixture was stirred at 0 °C for 15 minutes then the ice-bath was removed. The mixture was stirred at room temperature overnight then evaporated. The residue was purified by silica gel column chromatography with dichloromethane and ethyl acetate (0 to 5% gradient) to give the desired title compound (78 mg, 80%).

LC-MS 685.2 [M+H]⁺, RT 1.74 min. 1H NMR (CDC1₃) δ: 7.64 (d, J=7.9 Hz, 1H), 7.27-7.53 (m, 16H), 5.50 (s, 2H), 5.34 (s, 2H), 5.30 (s, 2H), 4.48-4.66 (m, 2H), 4.11 (br. s., 2H), 3.10- 3.26 (m, 2H), 2.77-2.93 (m, 2H), 1.63 (br. s, 9H). Intermediate 20

Benzyl 7,9-bis(benzyloxy)-4,5-dihydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole-8- carboxylate

Step 1: 8-Benzyl l-(tert-butyl) 7,9-bis(benzyloxy)-4,5-dihydro-lH- pyrido[2',3':6,7]oxepino[4,5-e]indole-l,8-dicarboxylate

A mixture of 8-benzyl l-(tert-butyl) 7,9-bis(benzyloxy)-2,3,4,5-tetrahydro-lH- pyrido[2',3':6,7]oxepino[4,5-e]indole-l,8-dicarboxylate (Intermediate 19, 0.53 g, 0.77 mmol) and Μη(¾ (3.4 g, 38.7 mmol) in dichloromethane (25 mL) was stirred at room temperature overnight, then filtered and washed with a large amount of dichloromethane. The filtrate was combined and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0 to 15% gradient) to give the title compound (0.41 g, 77%). LC-MS 683.2 [M+H]⁺, RT 1.76 min. 1H NMR (CDC1₃) δ: 8.21 (d, J=8.2 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.70 (d, J=3.8 Hz, 1H), 7.29-7.47 (m, 15H), 6.69 (d, J=3.8 Hz, 1H), 5.52 (s, 2H), 5.34 (s, 2H), 5.31 (s, 2H), 4.65 (t, J=6.3 Hz, 2H), 3.14 (t, J=6.3 Hz, 2H), 1.73 (s, 9H).

Step 2: Benzyl 7,9-bis(benzyloxy)-4,5-dihydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole-8- carboxylate

A solution of the product of Step 1 (0.2 g, 0.29 mmol) in diphenyl ether (2.0 mL) was heated at 210 °C for 2 hrs. The mixture was cooled and directly loaded onto a silica gel loading cartridge and purified by silica gel column chromatography with EtOAc in hexanes (5 to 35% gradient) to give the title compound (0.17 g, 99%).

LC-MS 581.2 [M-H]⁺, RT 1.59 min. 1H NMR (CDC1₃) δ: 8.40 (br. s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.24-7.49 (m, 16H), 6.65 (dd, J=2.5, 1.6 Hz, 1H), 5.54 (s, 2H), 5.34 (s, 2H), 5.33 (s, 2H), 4.69 (t, J=6.3 Hz, 2H), 3.19 (t, J=6.1 Hz, 2H).

Intermediate 21

tert-Butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)indoline- 1 -carboxylate

Step 1: Methyl indoline-4-carboxylate

To a solution of methyl lH-indole-4-carboxylate (5.0 g, 28.6 mmol) in dichloromethane (150 mL) and TFA (36 mL) was added triethylsilane (7.0 mL, 43.9 mmol). The mixture was stirred at room temperature for 16 hrs, then additional dichloromethane (350 mL) and water (200 mL) were added. The mixture was neutralized with concentrated ammonium hydroxide (approx.. 50 mL) and extracted with ethyl acetate (3X). 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), then 4N HC1 in dioxane (8 mL) was added. The resulting precipitate 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 desired compound as a solid (3.63 g, 73%), which was used in the next step without purification. LC-MS 178.4 [M+H]⁺, RT 0.77 min. 1H NMR (CDC1₃) δ: 7.47 (dd, J=7.9, 0.6 Hz, 1H), 7.16 (t, J=7.9 Hz, 1H), 6.96 (d, J=7.6 Hz, 1H), 3.87-3.92 (s, 3H), 3.64-3.71 (m, 2H), 3.47 (t, J=8.4 Hz, 2H).

Step 2: l-(tert-Butyl) 4-methyl indoline-l,4-dicarboxylate A mixture of the product of Step 1 (3.63 g, 20.5 mmol), Boc₂0 (4.9 g, 22.6 mmol), DIREA (5.3 g, 41 mmol) and DMAP (0.25 g, 2.05 mmol) in THF (60 mL) was stirred at room temperature overnight. Water was then added and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (2 to 35%) to give the title compound (1.5 g, 26%).

1H NMR (CDC1₃) δ: 8.10 (br. s, 1H), 7.61 (dd, J=7.9, 1.3 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 4.03 (t, J=8.7 Hz, 2H), 3.92 (s, 3H), 3.47 (t, J=8.7 Hz, 2H), 1.54-1.66 (br. s, 9H).

Step 3: tert-Butyl 4-(hydroxymethyl)indoline-l-carboxylate

To a solution of product of Step 2 (1.5 g, 5.4 mmol) in dichloromethane (20 mL) at -78 °C was added a 1.0 M solution of DIBAL-H in toluene (13.5 mL, 13.5 mmol). The temperature was allowed to rise to room temperature over 2 hrs. The reaction was carefully quenched with methanol followed by addition of water and acidification with IN HCl. The mixture was stirred at room temperature for 30 min then extracted with dichloromethane (3X). The organic extracts were combined, dried over sodium sulfate and evaporated to give the title compound (1.21 g, 90%), which was used in the next step without further purification.

LC-MS 250.1 [M+H]⁺, RT 1.16 min. 1H NMR (CDC1₃) δ: 7.34-7.93 (br. s, 1H), 7.20 (t, J=7.7 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 4.66 (s, 2H), 4.03 (t, J=8.5 Hz, 2H), 3.13 (t, J=8.7 Hz, 2H), 1.59 (br. s., 9H).

Step 4: tert-Butyl 5-bromo-4-(hydroxymethyl)indoline-l-carboxylate A mixture of the product of Step 3 (1.21 g, 4.86 mmol) and NBS (0.95 g, 5.35 mmol) in dichloromethane (15 mL) was stirred at room temperature overnight. Aqueous potassium carbonate (15 mL) was then added and the mixture was extracted with dichloromethane (3X). The organic extracts were combined, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and evaporated to give the title compound (1.68 g), which was used in the next step without further purification. 1H NMR (CDCI₃) δ: 7.71 (br. s, 1H), 7.38 (d, J=8.5 Hz, 1H), 4.73 (s, 2H), 4.03 (t, J=8.4 Hz, 2H), 3.24 (t, J=8.7 Hz, 2H), 1.87 (br. s, 1H), 1.58 (br. s, 9H).

Step 5: tert-Butyl 5-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)indoline- 1-carboxylate

A mixture of product of Step 4 (1.68 g, 5.1 mmol), TBSC1 (0.84, 5.6 mmol) and imidazole (1.04 g, 15.3 mmol) in dichloromethane (20 mL) was stirred at room temperature overnight. Water was added and the mixture was extracted with dichloromethane (3X). The organic extracts were combined, dried over sodium sulfate and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0 to 6% gradient) to provide the title compound (1.76 g, 78% over 2 steps).

1H NMR (CDCI₃) δ: 7.67 (br. s, 1H), 7.33 (d, J=8.5 Hz, 1H), 4.79 (s, 2H), 3.99 (t, J=8.2 Hz, 2H), 3.21 (t, J=8.7 Hz, 2H), 1.56 (br. s, 9H), 0.92 (s, 9H), 0.11 (s, 6H).

Step 6: tert-Butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)indoline- 1-carboxylate

To a solution of the product of Step 5 (1.76 g, 4.0 mmol) in THF (24 mL) at -78 °C was added a solution of BuLi in hexane (1.6 M x 3.0 mL, 4.8 mmol) dropwise. Then 2- isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.12 g, 6.0 mmol) was added 30 minutes later. The cooling bath was removed and the temperature was allowed to rise to room temperature, then saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted with ether. The organic extracts were combined, dried over sodium sulfate and evaporated. The residue was purified by silica gel column

chromatography with EtOAc in hexanes to give the title compound (0.22 g, 11 ).

1H NMR (CDCI₃) δ: 7.68 (br. s, 1H), 7.59 (d, J=7.9 Hz, 1H), 4.91 (s, 2H), 3.91 (t, J=8.7 Hz, 2H), 3.12 (t, J=8.8 Hz, 2H), 1.49 (s, 9H), 1.26 (s, 12H), 0.84 (s, 9H), 0.00 (s, 6H).

Intermediate 22

tert-Butyl 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)indoline- 1 -carboxylate

c Step 1: tert-Butyl 4-bromoindoline- 1 -carboxylate

To a solution of 4-bromoindoline (12.2 g, 61.6 mmol) in dichloromethane (200 mL) was added Boc₂0 (14.8 g, 67.8 mmol) and DMAP (0.75 g, 6.16 mmol). The mixture was stirred at room temperature for 48 h and then evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0 to 10% gradient) to provide the title compound (11.5 g, 62.5%).

1H NMR (CDC1₃) δ: 7.80 (br. s, 1H), 6.98-7.12 (m, 2H), 4.00 (t, J=8.7 Hz, 2H), 3.08 (t, J=8.7 Hz, 2H), 1.50-1.66 (s, 9H).

Step 2: tert-Butyl 4-allylindoline-l -carboxylate A mixture of the product of Step 1 (1.5 g, 5.0 mmol), allyltributylstannane (2.48 g, 7.5 mmol) and Pd(PPh₃)₄ (0.58 g, 0.5 mmol) in toluene (20 mL) was stirred at 100 °C overnight under a nitrogen atmosphere. The mixture was loaded directly to a silica gel loading cartridge and purified by silica gel column chromatography with EtOAc in hexanes (0 to 10% gradient) to give the title compound (0.88 g, 68%).

1H NMR (CDC1₃) δ: 7.76 (br. s, 1H), 7.15 (t, J=7.7 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 5.88- 5.98 (m, 1H), 5.01-5.11 (m, 2H), 3.93-4.09 (m, 2H), 3.32 (d, J=6.3 Hz, 2H), 3.04 (t, J=8.7 Hz, 2H), 1.57 (s, 9H).

Step 3: tert-Butyl 4-(3-hydroxypropyl)indoline-l-carboxylate

A solution of 9-BBN in THF (0.5 M, 10.0 mL, 5.0 mmol) was added to the product of Step 2 (0.88 g, 3.4 mmol) at 0 °C. The mixture was stirred at room temperature overnight, cooled to 0 °C, then an aqueous NaOH solution (1.0 M, 15 mL) was added followed by 30% H₂0₂ (15 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 CH₂C1₂ and ethyl acetate (10 to 50% gradient) to give the desired compound (1.0 g, 100%).

1H NMR (CDC1₃) δ: 7.30-8.08 (m, 2H), 7.11-7.18 (m, 1H), 6.81 (d, J=7.6 Hz, 1H), 4.01 (br. s., 2H), 3.72 (t, J=6.3 Hz, 2H), 3.06 (t, J=8.7 Hz, 2H), 2.61-2.68 (m, 2H), 1.84-1.92 (m, 2H), 1.58 (s, 9H).

Step 4: tert-Butyl 4-(3-((tert-butyldimethylsilyl)oxy)propyl)indoline-l-carboxylate To a solution of the product of Step 3 (1.0 g, 3.6 mmol), imidazole (0.49 g, 7.2 mmol) in dichloromethane (18.0 mL) was added TBSC1 (0.59 g, 3.8 mmol). 3 hrs later, the mixture was treated with water (20 mL) and extracted with ether (3x). The organic extracts were combined, dried over Na₂S0₄ and evaporated. The residue was purified by silica gel column chromatography with hexane and ethyl acetate (0 to 10% gradient) to give the title compound (1.13 g, 80%).

1H NMR (CDC1₃) δ: 7.65 (br. s, 1H), 7.05 (t, J=7.9 Hz, 1H), 6.72 (d, J=7.6 Hz, 1H), 3.92 (br. s., 2H), 3.58 (t, J=6.3 Hz, 2H), 2.97 (t, J=8.7 Hz, 2H), 2.50-2.56 (m, J=7.9 Hz, 2H), 1.68-1.76 (m, 2H), 1.51 (br. s, 9H), 0.86 (s, 9H), 0.00 (s, 6H).

Step 5: tert-Butyl 5-bromo-4-(3-((tert-butyldimethylsilyl)oxy)propyl)indoline-l-carboxylate

To a solution of the product of Step 4 (1.13 g, 2.9 mmol) in CH₂C1₂ (9.0 mL) was added NBS (0.57 g, 3.2 mmol) portionwise. The mixture was stirred at room temperature overnight and then partitioned between saturated NaHC0₃ and ether. The aqueous layer was extracted with ether. The organic extracts were combined, dried over Na₂S0₄ and evaporated. The residue was purified by silica gel column chromatography with EtOAc in hexanes (0 to 8% gradient) to give the desired compound (1.3 g, 96%).

1H NMR (CDCI₃) δ: 7.38-7.63 (br. s, 1H), 7.25 (d, J=8.5 Hz, 1H), 3.91 (br. s, 2H), 3.60 (t,

J=6.1 Hz, 2H), 3.00 (t, J=8.7 Hz, 2H), 2.59-2.68 (m, 2H), 1.62-1.72 (m, 2H), 1.45 (m, 9H),

0.83-0.86 (m, 9H), 0.00 (s, 6H).

Step 6: tert-Butyl 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)indoline-l-carboxylate To a solution of the product of Step 5 (1.3 g, 2.76 mmol) in THF (11 mL) cooled at -78 °C was added n-BuLi (1.6 M x 2.1 mL, 3.32 mmol). 2-isopropoxy-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane (0.77 g, 0.84 mL, 4.14 mmol) was added 15 min later. The cooling bath was removed and the temperature was allowed to rise to room temperature. The reaction was quenched with aqueous NH₄C1 solution then extracted with ether (3x). The organic extracts were combined, dried over Na₂S0₄ and evaporated. The residue was purified by silica gel column chromatography with EtOAc and hexanes (0 to 10% gradient) to give the title compound (1.31 g, 92%).

1H NMR (CDCI₃) δ: 7.60 (d, J=7.9 Hz, 1H), 3.90 (br. s, 2H), 3.60 (t, J=6.6 Hz, 2H), 2.99 (t, J=8.8 Hz, 2H), 2.74-2.80 (m, 2H), 1.61-1.68 (m, 2H), 1.49 (br. s, 9H), 1.26 (s, 12H), 0.85 (s, 9H), 0.00 (s, 6H). Intermediate 23

Benzyl 2,4-bis(benzyloxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloronicotinate

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 then 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 was quenched with H₂0 and the mixture was partitioned between H₂0 and EtOAc. The EtOAc layer was washed with H₂0 and brine. The organic layer was dried over MgS0₄ and filtered. The filtrate was concentrated under vacuum, then 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 mixture was stirred at -78° C for 10 minutes then quenched with saturated NH₄C1. The mixture was then partitioned between EtOAc and H₂0. The organic layer was dried over MgS0₄, filtered, and concentrated under vacuum. The product was filtered through a short plug of silica gel eluting with CH₂C1₂. A crude 4-(benzyloxy)-2,6-dichloronicotinaldehyde (19.65 g) was obtained as a 5:3 molar ratio of product : starting material (based on NMR).

The crude product was dissolved in CH₂C1₂ (215 mL) at -78° C. DIBAL-H (50.5 mL, 1M in CH₂C1₂, 50.5 mmol) was added dropwise. The reaction mixture was stirred at -78° C for 30 minutes then quenched with a sodium potassium tartrate solution (25 g in 80 mL of H₂0). The bilayer was filtered through Celite. The filtrate was then separated and the organic layer was dried over MgS0₄, then 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 hours. 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. The reaction mixture was stirred at room temperature for 15 hrs, then the mixture was partitioned between H₂0 and EtOAc. The organic layer was dried over MgS0₄, then 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 mixture was stirred at - 78° C for 30 minutes after the addition was complete. Dry C0₂ was bubbled through the mixture for 30 minutes, then 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 partitioned between aqueous HC1 and EtOAc. The organic layer was dried over MgS0₄, then 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

A mixture of 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) was stirred at room temperature for 15 hours. The mixture was partitioned between H₂0 and EtOAc. The organic layer was dried over MgS0₄, then 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 24

tert-Butyl 5-(4,6-bis(benzyloxy)-5-((benzyloxy)carbonyl)-3-(hydroxymethyl)pyridin-2-yl)-4-

(hydroxymethyl)indoline- 1 -carboxylate

Step 1: tert-Butyl 5-(4,6-bis(benzyloxy)-5-((benzyloxy)carbonyl)-3-(((tert- butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-4-(((tert- butyldimethylsilyl)oxy)methyl)indoline- 1 -carboxylate

Following the procedure described for Intermediate 19 (Step 1), benzyl 2,4-bis(benzyloxy)-5- (((tert-butyldimethylsilyl)oxy)methyl)-6-chloronicotinate (Intermediate 23, 132 mg, 0.218 mmol) was coupled with tert-butyl 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)indoline-l-carboxylate (Intermediate 21, 160 mg, 0.327 mmol) to afford the title compound (210 mg) in quantitative yield, which was used directly in the next step without further purification. Step 2: tert-Butyl 5-(4,6-bis(benzyloxy)-5-((benzyloxy)carbonyl)-3-(hydroxymethyl)pyridin- 2-yl)-4-(hydroxymethyl)indoline-l-carboxylate

To a solution of the product of Step 1 (105 mg, 0.113 mmol) in THF (2.0 mL) at 0 °C was added a solution of TBAF in THF (1.0 M, 0.45 mL, 0.45 mmol). The mixture reacted for 1 hr at room temperature then was quenched with saturated aqueous ammonium chloride. The mixture was extracted with ether, dried overs sodium sulfate and evaporated. The residue was purified by silica gel column chromatography with EtOAc in dichloromethane (5 to 30% gradient) to provide the title compound (71 mg, 90%).

LC-MS 703.2 [M+H]⁺, RT 1.63 min.

Example 1

6-Hydroxy-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5-h]quinoline-7-carboxylic acid (Cpd 1)

Step 1: tert-Butyl 6-oxo-6,7,8,9-tetrahydro-3H-benzo[e]indole-3-carboxylate

A mixture of 3,7,8,9-tetrahydro-6H-benzo[e]indol-6-one (Intermediate 1, 0.33 g, 1.78 mmol), di-tert-butyl dicarbonate (450 mg, 2.06 mmol), N,N-dimethylpyridin-4-amine (10 mg), and THF (5 mL) was stirred under argon at 25 °C for 2 h. The reaction mixture was then concentrated and the crude residue was chromatographed on silica gel, eluting with 20% EtOAc in hexanes to afford 0.425 g of product as a light yellow solid.

1H NMR (500 MHz, DMSO- ₆) δ ppm 1.64 (s, 9H) 2.13 (t, J=6.27 Hz, 2H) 2.63 (dd, J=7.25, 5.75 Hz, 2H) 3.14 (t, J=6.11 Hz, 2H) 6.92 (dd, J=3.78, 0.71 Hz, 1H) 7.76 (d, J=3.78 Hz, 1H) 7.86 (d, J=8.75 Hz, 1H) 8.00 (d, J=8.83 Hz, 1H). Step 2: Methyl 6-hydroxy-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5-h]quinoline-7-carboxylate

To a solution of tert-butyl 6-oxo-6,7,8,9-tetrahydro-3H-benzo[e]indole-3-carboxylate (0.425 g, 1.49 mmol) and 2-methylpropan-2-amine (0.475 mL, 4.5 mmol) in CH₂CI₂ (7.5 mL) was added a solution of titanium(IV) tetrachloride (0.9 mL, 1M in CH₂CI₂, 0.9 mmol) dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at 25 °C for 16 h. The mixture was then diluted with CH₂CI₂ (20 mL) and quenched with aqueous saturated

NaHCC"3 (20 mL). The organic phase was separated using a PTFE phase separator, dried over Na₂S0₄, filtered, and concentrated to afford a crude residue which was added to a solution of trimethyl methanetricarboxylate (0.4 g, 2.1 mmol) in Ph₂0 (3.0 mL). The mixture was heated at 230 °C for 15 minutes. The cooled reaction mixture was loaded directly onto silica gel, eluting with 0-100% EtOAc in hexanes to afford the title compound (100 mg, 22% over 2 steps).

1H NMR (500 MHz, DMSO- ₆) δ ppm 2.68 (dd, J=8.51, 6.94 Hz, 2H) 3.06 (t, J=7.72 Hz, 2H) 3.85 (s, 3H) 6.60 - 6.66 (m, 1H) 7.33 (d, J=8.59 Hz, 1H) 7.42 - 7.47 (m, 1H) 7.80 (d, J=8.67 Hz, 1H) 11.36 (br. s, 1H) 11.42 (br. s, 1H) 13.54 (br. s, 1H).

Step 3: 6-Hydroxy-8-oxo-4,5,8,9-tetrahydro- lH-indolo[4,5-h]quinoline-7-carboxylic acid A mixture of methyl 6-hydroxy-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5-h]quinoline-7- carboxylate (100 mg, 0.3 mmol), lithium(I) iodide (130 mg, 0.9 mmol), and EtOAc (3 mL) was stirred at 60 °C for 1.5 h. The reaction mixture was partitioned between CH₂C1₂ (50 mL) and 1M HC1 (10 mL). The organic layer was separated, dried over Na₂S0₄, filtered, and concentrated to afford 22 mg (23%) of product.

LC-MS: 297.0 [M+H]⁺, RT 0.68 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 2.73 (dd,

J=8.59, 6.94 Hz, 2H) 3.10 (dd, J=8.60, 6.90 Hz, 2H) 6.66 (ddd, J=3.03, 2.01, 0.79 Hz, 1H) 7.39 (d, J=8.51 Hz, 1H) 7.45 - 7.49 (m, 1H) 7.81 (d, J=8.67 Hz, 1H) 11.48 (br. s, 1H) 12.62 (br. s, 1H) 13.63 (s, 1H).

Using the procedure described for Example 1 above, additional compounds described herein may be prepared by using the indicated intermediate, obtaining compounds such as those selected from:

Cpd Materials and Data

Intermediate 2: LC-MS: 311.1 [M+H]⁺, RT 0.67 min. 1H NMR (500 MHz, DMSO-

2 d_e) δ ppm 2.66 - 2.77 (m, 2H), 3.01 - 3.15 (m, 2H), 3.82 (s, 3H), 6.60 - 6.71 (m, 1H), 7.44 (br. s, 2H), 7.83 - 7.95 (m, 1H).

Intermediate 3 was used and functionalized according to the procedure for preparing Intermediate 2: LC-MS: 325.0 [M+H]⁺, RT 1.29 min. 1H NMR (500 MHz, DMSO-

3 <k) δ ppm 2.17-2.35 (m, 4H), 2.85 (br. s, 2H), 3.84 (s, 3H), 6.70 (m, 1H), 7.33 (d, J=8.7 Hz, 1H), 7.45 (d, J=3.3 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 12.87 (br. s, 1H), 13.90 (br. s, 1H), 16.40 (br. s, 1H). Cpd Materials and Data

Intermediate 4 was used and functionalized according to the procedure for preparing Intermediate 2: LC-MS: 325.0 [M+H]⁺, RT 1.27 min H NMR (500 MHz, DMSO- ₆)

4 δ ppm 2.17-2.35 (m, 4H), 2.91 (br. s, 2H), 4.07 (s, 3H), 6.51 (d, J=3.2 Hz, 1H), 7.19 (d, J=8.2 Hz, 1H), 7.46 (d, J=3.3 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 12.92 (br. s, 1H), 13.99 (br. s, 1H), 16.33 (br. s, 1H).

Intermediate 4: LC-MS: 311.0 [M+H]⁺, RT 1.18 min. 1H NMR (500 MHz, DMSO-

8 d₆) δ ppm 2.17-2.35 (m, 4H), 2.91 (br. s, 2H), 6.56 (m, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.55-7.59 (2H), 11.53 (br. s, 1H), 12.86 (br. s, 1H), 13.88 (s, 1H), 16.41 (br. s, 1H).

Example 2

2-[(Dimethylamino)methyl]-7 -hydroxy- l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride (Cpd 12)

Step 1: 2-(((tert-Butyldimethylsilyl)oxy)methyl)-N-(2,4-dimethoxybenzyl)-3-methyl- 7,8,9, 10-tetrahydrocyclohepta[e]indol-6(3H)-imine

To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-7,8,9,10- tetrahydrocyclohepta[e]indol-6(3H)-one (Intermediate 6, 3.66 g, 10.24 mmol) in CH₂CI₂ (30 mL) was added 2,4-dimethoxybenzylamine (1.60 mL, 10.65 mmol) and NEt₃ (3.70 mL, 26.55 mmol) at room temperature. The reaction mixture was cooled to 0 °C then T1CI₄ (1M in CH₂CI₂, 6.70 mL, 6.70 mmol) was added via a syringe pump over 30 min. The reaction mixture was allowed to warm to room temperature with stirring overnight. The mixture was diluted with CH₂CI₂ (30 mL) then quenched with NaHC0₃ (aq. satd., 20 mL). Vigorous shaking separated the organic phase using a PTFE phase separator. The product was dried over Na₂SC"4 and the solvent concentrated to give the title compound (approx.. 5.2 g) as a brown foam, which was taken directly into the next step without purification.

Step 2: Methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-10-(2,4-dimethoxybenzyl)-7- hydroxy-l-methyl-9-oxo- 1,4,5, 6,9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8- carboxylate

2-(((tert-Butyldimethylsilyl)oxy)methyl)-N-(2,4-dimethoxybenzyl)-3-methyl-7, 8,9,10- tetrahydrocyclohepta[e]indol-6(3H)-imine was divided into two batches for the annulation reaction. The crude imine (2.6 g, 5.12 mmol) and trimethyl methanetricarboxylate (1.66 g, 8.73 mmol) were mixed together in Ph₂0 (10 mL). The stirred mixture was placed onto a heat block pre-heated to 230 °C and heated for 10 minutes. Initial bubbling of MeOH was observed (occuring at approx.. 160 °C internal reaction temperature). The reaction mixture was cooled to room temperature, loaded directly on a column, eluted first with hexanes to separate Ph₂0 and then an EtOAc/hexanes gradient (0-50%) to yield the title compound as a yellow foam (3.093 g, 48% 2 steps).

LC-MS 633.5 [M+H]⁺, RT 1.85 min. 1H NMR (500 MHz, CDC1₃ δ ppm 0.09 (s, 3H), 0.12 (s, 3H), 0.92 (s, 9H), 1.49 (td, J=13.6, 7.3 Hz, IH), 1.97 - 2.17 (m, 2H), 2.41 (td, J=12.9, 7.9 Hz, IH), 2.99 (dd, J=13.9, 6.0 Hz, 2H), 3.48 (s, 3H), 3.75 (s, 3H), 3.78 (s, 3H), 3.99 (s, 3H), 4.84 (d, J=13.2 Hz, IH), 4.84 (d, J=13.2 Hz, IH), 5.18 (br. s, 2H), 6.27 (d, J=2.4 Hz, IH), 6.35

(dd, J=8.2, 2.4 Hz, IH), 6.45 (s, IH), 6.82 (d, J=8.2 Hz, IH), 7.00 (d, J=8.8 Hz, IH), 7.11 (d, J=8.8 Hz, IH), 13.68 (s, IH).

Step 3: Methyl 10-(2,4-dimethoxybenzyl)-7-hydroxy-2-(hydroxymethyl)-l-methyl-9-oxo-

I, 4,5,6, 9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate To a solution of methyl 2-(((tert-butyldimethylsilyl)oxy)methyl)-10-(2,4-dimethoxybenzyl)- 7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8- carboxylate (3.093 g, 4.89 mmol) in THF (20 mL) was added a TBAF solution (1M THF,

I I.0 mL, 11.0 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 minutes, then allowed to warm to room temperature and stirred for 1 hour. The solvent was concentrated and the residue was purified by column chromatography (EtOAc/CH₂Cl₂, 0-30% gradient) to yield the title compound (approx. 2.661 g) as a yellow solid.

LC-MS 517.3 [M-H]⁺, 519.2 [M+H]⁺, RT 1.22 min. 1H NMR (500 MHz, CDC1₃) δ ppm 1.49 (dt, J=13.6, 6.8 Hz, IH), 1.96 - 2.18 (m, 2H), 2.42 (td, J=12.8, 7.7 Hz, IH), 2.99 (dt, J=13.6, 4.5 Hz, 2H), 3.49 (s, 3H), 3.75 (s, 3H), 3.81 (s, 3H), 3.99 (s, 3H), 4.83 (s, 2H), 5.17 (br. s, 2H), 6.28 (d, J=2.4 Hz, IH), 6.36 (dd, J=8.4, 2.4 Hz, IH), 6.54 (s, IH), 6.82 (d, J=8.4 Hz, IH), 7.02 (d, J=8.8 Hz, IH), 7.13 (d, J=8.8 Hz, IH), 13.68 (br. s, IH).

Step 4: 10-(2,4-Dimethoxybenzyl)-7-hydroxy-2-(hydroxymethyl)-l-methyl-9-oxo- 1,4,5,6, 9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

To a suspension of methyl 10-(2,4-dimethoxybenzyl)-7-hydroxy-2-(hydroxymethyl)-l- methyl-9-oxo- 1,4,5, 6,9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate (2.66 g, 4.89 mmol) in EtOAc (25 mL) was added Lil (2.30 g, 17.18 mmol). The reaction mixture was stirred and heated at 60 °C for 1.5 hours until complete consumption of starting material was observed. The reaction mixture was cooled to room temperature and acidified with aqueous HC1 (0.1 M, 50 mL). The product was extracted with a EtOAc:MeOH mixture (9: 1, 3x40 mL). The combined organics were washed with Na₂S203 (aq. satd., 40 mL), followed by brine (50 mL) and dried over Na₂S0₄. The solvent was removed under reduced pressure to afford the title compound (2.43 g, 98%) as a yellow solid.

LC-MS 503.1 [M-H]⁺, 505.2 [M+H]⁺, RT 1.33 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 1.41 (td, J=13.5, 7.1 Hz, IH), 1.86 - 2.15 (m, 2H), 2.38 (td, J=12.8, 8.0 Hz, IH), 2.88 (dd, J=13.6, 5.7 Hz, IH), 3.01 (dd, J=13.6, 6.0 Hz, IH), 3.33 (br. s, IH), 3.53 (s, 3H), 3.69 (s, 3H), 3.75 (s, 3H), 4.64 (s, 2H), 5.12 - 5.32 (m, 2H), 6.37 (dd, J=8.4, 2.4 Hz, IH), 6.43 (d, J=2.4 Hz, IH), 6.57 (s, IH), 6.64 (d, J=8.4 Hz, IH), 7.10 (d, J=8.5 Hz, IH), 7.36 (d, J=8.5 Hz, IH), 13.82 (s, IH), 16.17 (s, IH).

Step 5: 10-(2,4-Dimethoxybenzyl)-2-formyl-7-hydroxy-l-methyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid To a solution of 10-(2,4-dimethoxybenzyl)-7-hydroxy-2-(hydroxymethyl)-l-methyl-9-oxo- 1,4,5,6, 9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid (2.43 g, 4.82 mmol) in CH₂C1₂ (40 mL) was added activated Mn0₂ (8.51 g, 97.9 mmol) at 0 °C in one portion. The reaction was allowed to warm to room temperature with stirring overnight. After 12 hours, additional Mn0₂ was added in 2 portions (first portion: 2.2 g, 25.3 mmol; second portion: 2.2 g, 25.3 mmol) with a 60 min interval. The reaction was monitored by LC/MS until complete consumption of starting material. The mixture was filtered and washed with CH₂C1₂ and the filtrate concentrated to yield the title compound (1.85 g, 77%) as a dark brown foam which was used in the next step without further purification.

LC-MS 501.1 [M-H]⁺, RT 1.47 min. 1H NMR (500 MHz, DMSO- ₆) 5 ppm 1.43 (td, J=13.6, 7.3 Hz, IH), 1.92 - 2.15 (m, 2H), 2.29 - 2.40 (m, IH), 2.89 (dd, J=13.6, 5.4 Hz, IH), 3.11 (dd, J=13.4, 5.8 Hz, IH), 3.48 (s, 3H), 3.67 (s, 3H), 4.06 (s, 3H), 5.10 (d, J=15.8 Hz, IH), 5.24 (d, J=16.1 Hz, IH), 6.34 (dd, J=8.5, 2.2 Hz, IH), 6.39 (d, J=2.2 Hz, IH), 6.65 (d, J=8.2 Hz, IH), 7.42 (d, J=8.8 Hz, IH), 7.58 (d, J=8.8 Hz, IH), 7.70 (s, IH), 9.93 (s, IH), 13.86 (s, IH), 16.14 (br. s, IH). Steps 6-8: 2-((Dimethvlamino)methvl)-7-hvdroxv-l-methyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride To a solution of 10-(2,4-dimethoxybenzyl)-2-formyl-7-hydroxy-l-methyl-9-oxo-l,4,5,6,9,10- hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid (220 mg, 0.44 mmol) in DCE (3 mL) was added HNMe₂-HCl salt (90 mg, 1.10 mmol) followed by Et₃N (0.15 mL, 1.08 mmol) and AcOH (0.06 mL, 1.04 mmol). The reaction mixture was stirred for 15 minutes at room temperature then NaBH(OAc) (250 mg, 1.18 mmol) was added. The reaction mixture was then stirred at room temperature overnight and monitored by LC/MS until the starting aldehyde was completely consumed. The DCE was concentrated and the residue dissolved in MeOH (6 mL). Several drops of TFA were added to generate a homogeneous mixture that was filtered through a PTFE micron filter and purified directly by preparative HPLC (30-90% ACN/H₂0). The product (218 mg) was obtained as a TFA salt and taken directly into the DMB group deprotection step.

To the product (218 mg) was added i-Pr SiH (2.5 mL) followed by TFA (2.2 mL). The mixture was heated at 60 °C for 2 hours and monitored by LC/MS until complete consumption of starting material. TFA was then concentrated under reduced pressure to provide an oily residue. Addition of HC1 (2M in Et₂0, 10 mL) to the residue resulted in precipitate formation. The mixture was diluted with Et₂0 (5 mL) and stirred for 30 minutes at room temperature. The solid was filtered and thoroughly washed with Et₂0 (3x5 mL) to afford the title compound (112 mg, 61% overall yield) as an off white solid.

LC-MS 380.1 [M-H]⁺, 382.1 [M+H]⁺, RT 0.85 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 2.14 - 2.26 (m, 4H), 2.77 - 2.91 (m, 2H), 2.82 (s, 6H), 3.89 (s, 3H), 4.59 (s, 2H), 7.01 (s, 1H), 7.41 (d, J=8.83 Hz, 1H), 7.58 (d, J=8.20 Hz, 1H), 10.40 (br. s, 1H), 12.94 (br. s, 1H), 13.86 (br. s, 1H).

Using the procedure described for Example 2 (Steps 6-8) above, additional compounds described herein may be prepared by using the appropriate amine, obtaining compounds such as those selected from:

Cpd Data

LC-MS 406.0 [M-H]⁺, 408.1 [M+H]⁺, RT 0.90 min. 1H NMR (500 MHz, DMSO- ₆) 5 ppm 1.92 (br. s, 2H), 1.99 - 2.12 (m, 2H), 2.14 - 2.25 (m, 4H), 2.85 (br. s., 2H),

11 3.20 (br. s, 2H), 3.51 (br. s, 2H), 3.90 (s, 3H), 4.66 (s, 2H), 7.02 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 10.64 (br. s, 1H), 12.91 (br. s, 1H), 13.86 (s, 1H) Cpd Data

LC-MS 394.2 [M-H]⁺, 396.2 [M+H]⁺, RT 0.89 min. 1H NMR (500 MHz, DMSO- ₆) δ ρρηι 0.94 (t, J=7.4 Hz, 3H), 1.67 - 1.74 (m, 2H), 2.10 - 2.25 (m, 4H), 2.84 (br. s,

13

2H), 2.99 (br. s, 2H), 3.85 (s, 3H), 4.44 (br. s, 2H), 6.93 (s, IH), 7.38 (d, J=8.8 Hz, IH), 7.56 (d, J=8.8 Hz, IH), 9.14 (br. s, 2H), 12.90 (s, IH), 13.86 (s, IH)

LC-MS 394.2 [M-H]⁺, 396.3 [M+H]⁺, RT 0.85 min. 1H NMR (500 MHz, DMSO- ₆) δ ρρηι 1.36 (d, J=6.6 Hz, 6H), 2.10 - 2.35 (m, 4H), 2.84 (br. s, 2H), 3.40 - 3.55 (m,

14

IH), 3.86 (s, 3H), 4.44 (t, J=6.0 Hz, 2H), 6.93 (s, IH), 7.38 (d, J=8.8 Hz, IH), 7.57 (d, J=8.8 Hz, IH), 9.10 (br. s, 2H), 12.90 (s, IH), 13.87 (s, IH)

LC-MS 408.2 [M-H]⁺, 410.3 [M+H]⁺, RT 0.94 min. 1H NMR (500 MHz, DMSO- ₆) 5 ppm 0.95 (t, J=7.4 Hz, 3H), 1.33 (d, J=6.6 Hz, 3H), 1.56 (ddd, J=13.6, 9.5, 7.6 Hz,

15 IH), 1.92 (ddd, J=13.4, 7.7, 3.8 Hz, IH), 2.10 - 2.35 (m, 4H), 2.84 (br. s, 2H), 3.36 - 3.42 (m, IH), 3.85 (s, 3H), 4.45 (br. s, 2H), 6.94 (s, IH), 7.38 (d, J=8.8 Hz, IH), 7.57 (d, J=8.2 Hz, IH), 9.01 (br. s, IH), 9.09 (br. s, IH), 12.89 (s, IH), 13.86 (s, IH)

LC-MS 406.2 [M-H]⁺, 408.3 [M+H]⁺, RT 0.93 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 1.76 - 1.86 (m, 2H), 2.08 - 2.29 (m, 8 H), 2.84 (br. s, 2H), 3.79 - 3.86 (m,

16

IH), 3.85 (s, 3H), 4.32 (br. s., 2H), 6.92 (s, IH), 7.38 (d, J=8.8 Hz, IH), 7.56 (d, J=8.5 Hz, IH), 9.41 (br. s, 2H), 12.90 (br. s, IH), 13.87 (br. s, IH)

LC-MS 406.2 [M-H]⁺, 408.4 [M+H]⁺, RT 0.90 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 0.72 - 0.75 (m, 2H), 1.14 - 1.18 (m, 2H), 1.53 (s, 3H), 2.10 - 2.35 (m, 4H),

18

2.84 (br. s, 2H), 3.87 (s, 3H), 4.53 (br. s, 2H), 6.93 (s, IH), 7.38 (d, J=8.5 Hz, IH), 7.57 (d, J=8.5 Hz, IH), 9.46 (br. s, 2H), 12.90 (br. s, IH), 13.86 (br. s, IH)

LC-MS 408.2 [M-H]⁺, 410.4 [M+H]⁺, RT 0.92 min. 1H NMR (500 MHz, DMSO- ₆) 5 ppm 1.43 (s, 9H), 2.10 - 2.35 (m, 4H), 2.84 (br. s, 2H), 3.86 (s, 3H), 4.38 - 4.43

19

(m, 2H), 6.94 (s, IH), 7.38 (d, J=8.5 Hz, IH), 7.58 (d, J=8.8 Hz, IH), 9.15 (br. s, 2H), 12.91 (s, IH), 13.87 (s, IH)

LC-MS 420.2 [M-H]⁺, 422.4 [M+H]⁺, RT 0.91 min. 1H NMR (500 MHz, DMSO- ₆) 5 ppm 1.61 (s, 3H), 1.83 - 1.98 (m, 6H), 2.10 - 2.34 (m, 4H), 2.84 (br. s, 2H), 3.87

20

(s, 3H), 4.32 (br. s, 2H), 6.95 (s, IH), 7.38 (d, J=8.8 Hz, IH), 7.58 (d, J=8.5 Hz, IH), 9.51 (br. s, 2H), 12.90 (s, IH), 13.87 (s, IH) Cpd Data

LC-MS 408.1 [M-H]⁺, RT 0.89 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 1.30 (t, J=6.9 Hz, 6H), 2.10 - 2.35 (m, 4H), 2.86 (br. s, 2H), 3.20 (br. s, 4H), 3.89 (s, 3H),

51

4.57 (br. s, 2H), 7.05 (s, IH), 7.40 (d, J=8.2 Hz, IH), 7.58 (d, J=8.5 Hz, IH), 10.09 (br. s, IH), 12.92 (br. s, IH), 13.85 (br. s, IH)

LC-MS 420.1 [M-H]⁺, 422.2 [M+H]⁺, RT 0.88 min. 1H NMR (500 MHz, DMSO- ₆) 5 ppm 1.45 (d, J=6.3 Hz, 3H), 1.62 - 1.75 (m, IH), 1.86 - 2.09 (m, 2H), 2.11 - 2.32 (m, 5H), 2.85 (br. s, 2H), 3.21 - 3.30 (m, IH), 3.41 - 3.51 (m, IH), 3.55 - 3.65 (m,

52

IH), 3.90 (s, 3H), 4.49 (dd, J=14.8, 7.9 Hz, IH), 4.80 (d, J=14.5 Hz, IH), 7.05 (s, IH), 7.39 (d, J=8.5 Hz, IH), 7.58 (d, J=8.5 Hz, IH), 10.33 (br. s, IH), 12.91 (s, IH) 13.86 (s, IH)

LC-MS 394.1 [M-H]⁺, RT 0.86 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 1.32 (t, J=7.3 Hz, 3H), 2.11 - 2.35 (m, 4H), 2.69 - 2.80 (m, 3H), 2.85 (br. s, 2H), 3.10 - 3.20

53 (m, 2H), 3.89 (s, 3H), 4.43 - 4.58 (m, IH), 4.66 (d, J=13.2 Hz, IH), 7.04 (s, IH), 7.40 (d, J=8.5 Hz, IH), 7.57 (d, J=8.5 Hz, IH), 10.32 (br. s, IH), 12.92 (br. s, IH), 13.86 (s, IH)

LC-MS 408.1 [M-H]⁺, RT 0.92 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 0.98 (d, J=6.6 Hz, 6H), 2.07 (dt, J=13.6, 6.8 Hz, IH), 2.13 - 2.35 (m, 4H), 2.85 (br. s., 2H),

54

2.85 - 2.95 (m, 2H), 3.85 (s, 3H), 4.44 (br. s, 2H) 6.97 (s, IH), 7.38 (d, J=8.8 Hz, IH), 7.57 (d, J=8.5 Hz, IH), 9.07 (br. s, 2H), 12.91 (s, IH), 13.86 (s, IH)

LC-MS 408.1 [M-H]⁺, RT 0.92 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 0.91 (t, J=7.4 Hz, 3H), 1.36 (dq, J=14.9, 7.4 Hz, 2H), 1.67 (dt, J=15.6, 7.6 Hz, 2H), 2.10 -

55 2.35 (m, 4H), 2.84 (br. s, 2H), 2.95 - 3.08 (m, 2H), 3.85 (s, 3H), 4.33 - 4.48 (m, 2H), 6.94 (s, IH), 7.38 (d, J=8.5 Hz, IH), 7.56 (d, J=8.5 Hz, IH), 9.16 (br. s, 2H), 12.91 (s, IH), 13.86 (s, IH)

LC-MS 366.1 [M-H]⁺, 368.2 [M+H]⁺, RT 0.76 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 2.08 - 2.35 (m, 4H), 2.64 (br. s, 3H), 2.84 (br. s, 2H), 3.86 (s, 3H), 4.43 (br. s,

62

2H), 6.92 (s, IH), 7.38 (d, J=8.5 Hz, IH), 7.56 (d, J=8.5 Hz, IH), 9.25 (br. s, 2H), 12.90 (br. s, IH), 13.87 (s, IH) Cpd Data

LC-MS 380.1 [M-H]⁺, 382.2 [M+H]⁺, RT 0.78 min. 1H NMR (500 MHz, DMSO- ₆) 5 ppm 1.28 (t, J=7.3 Hz, 3H), 2.12 - 2.35 (m, 4H), 2.84 (br. s, 2H), 3.01 - 3.16 (m,

63

2H), 3.86 (s, 3H), 4.43 (t, J=5.0 Hz, 2H), 6.93 (s, IH), 7.38 (d, J=8.5 Hz, IH), 7.56 (d, J=8.5 Hz, IH), 9.21 (br. s, 2H), 12.89 (s, IH) 13.87 (s, IH)

Using the procedure described for Example 2 (Steps 6-8) above, additional compounds described herein may be prepared by using the indicated aldehyde intermediate, obtaining compounds such as those selected from:

Cpd Materials and Data

Intermediate 13: LC-MS: 354.1 [M+H]⁺, RT 0.83 min. 1H NMR (500 MHz, DMSO- de) 5 ppm 2.15-2.34 (4H), 2.62 (s, 3H), 2.85 (br. s, 2H), 4.32 (s, 2H), 6.84 (s, IH),

21

7.33 (d, J=8.6 Hz, IH), 7.48 (d, J=8.6 Hz, IH), 9.15 (br. s, 2H), 11.61 (br. s, IH), 12.88 (br. s, IH), 13.88 (br. s, IH) 16.40 (br. s, IH)

Intermediate 13: LC-MS: 368.1 [M+H]⁺, RT 0.84 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 2.15-2.34 (4H), 2.80 (s, 6H), 2.86 (br. s, 2H), 4.47 (s, 2H), 6.84 (s, IH),

22

7.33 (d, J=8.6 Hz, IH), 7.48 (d, J=8.6 Hz, IH), 10.45 (br. s, IH), 11.73 (s, IH), 12.88 (br. s, IH), 13.88 (s, IH), 16.40 (br. s, IH)

Intermediate 14: LC-MS: 340.2 [M+H]⁺, RT 0.79 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 2.58 (t, J=5.32 Hz, 3H), 2.71 - 2.77 (m, 2H), 3.05 - 3.11 (m, 2H), 4.27 -

23

4.34 (m, 2H), 6.82 (d, J=1.10 Hz, IH), 7.44 (d, J=8.70 Hz, IH), 7.87 (d, J=8.75 Hz, IH), 9.28 (br. s, IH), 11.76 (br. s, IH), 12.68 (br. s, IH), 13.64 (br. s, IH)

Intermediate 14: LC-MS: 354.2 [M+H]⁺, RT 0.80 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 2.78 (d, J=3.31 Hz, 8 H), 3.07 - 3.14 (m, 2H), 4.45 (br. s, 2H), 6.89 (s,

24

IH), 7.47 (d, J=8.70 Hz, IH), 7.89 (d, J=8.70 Hz, IH), 10.39 (br. s, IH), 11.79 (br. s, IH), 12.70 (br. s, IH), 13.65 (br. s, IH) Cpd Materials and Data

Intermediate 14: LC-MS: 368.3 [M+H]⁺, RT 0.84 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 0.93 (t, J=7.60 Hz, 3H), 1.61 - 1.71 (m, 2H), 2.71 - 2.77 (m, 2H), 2.86 -

25 2.95 (m, 2H), 3.05 - 3.13 (m, 2H), 4.29 - 4.36 (m, 2H), 6.83 (s, 1H), 7.45 (d, J=8.70 Hz, 1H), 7.87 (d, J=8.70 Hz, 1H), 9.23 (br. s, 1H), 11.72 (br. s, 1H), 12.68 (br. s, 1H), 13.64 (br. s, 1H)

Intermediate 14: LC-MS: 380.2 [M+H]⁺, RT 0.83 min. 1H NMR (500 MHz, DMSO- de) 5 ppm 1.81 - 1.95 (m, 2H), 1.96 - 2.10 (m, 2H), 2.69 - 2.79 (m, 2H), 3.05 - 3.13

26 (m, 2H), 3.14 - 3.22 (m, 2H), 3.42 - 3.49 (m, 2H), 4.48 - 4.58 (m, 2H), 6.84 - 6.95 (m, 1H), 7.40 - 7.53 (m, 1H), 7.82 - 7.94 (m, 1H), 11.77 (br. s, 1H), 12.70 (br. s, 1H), 13.63 (br. s, 1H)

Intermediate 14: LC-MS: 368.3 [M+H]⁺, RT 0.82 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 1.30 (d, J=6.54 Hz, 6H), 2.70 - 2.80 (m, 2H), 3.04 - 3.12 (m, 2H), 3.27 -

27

3.33 (m, 1H), 4.30 - 4.37 (m, 2H), 6.82 - 6.90 (m, 1H), 7.40 - 7.50 (m, 1H), 7.84 - 7.91 (m, 1H), 9.20 (br. s, 1H), 11.75 (br. s, 1H), 12.68 (br. s, 1H), 13.64 (br. s, 1H)

Using the procedure described for Example 2 above, additional compounds described herein may be prepared by using the indicated ketone intermediate, obtaining compounds such as those selected from:

Cpd Materials and Data

Intermediate 5: LC-MS: 380.2 [M+H]⁺, RT 0.85 min. 1H NMR (500 MHz, DMSO- d₆) δ ppm 2.80 (br. s, 6H), 3.32-3.3.50 (br. s, 2 H, obscured by H₂0), 3.95 (s, 3H),

29

4.60 (br. s, 2H), 6.40-6.44 (m, 1H), 6.90 - 7.19 (m, 2H), 7.62-7.70 (m, 2H), 10.80 (br. s, 1H), 12.78 (br. s, 1H), 13.94 (br. s, 1H)

Intermediate 5: LC-MS: 394.2 [M+H]⁺, RT 0.86 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 1.32 (t, J=7.3 Hz, 3H), 2.70-2.76 (m, 3H), 3.09 - 3.22 (m, 1H), 3.22 - 3.35

30 (m, 1H), 3.32-3.55 (br. s, 2 H, obscured by H₂0), 3.95 (s, 3H), 4.48 - 4.75 (m, 2H), 6.40-6.46 (m, 1H), 7.07 - 7.13 (m, 2H), 7.61 - 7.76 (m, 2H), 10.43 - 10.62 (br. s, 1H), 12.78 (br. s, 1H), 13.95 (s, 1H) Cpd Materials and Data

Intermediate 5: LC-MS: 406.2 [M+H]⁺, RT 0.87 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 1.86 - 2.11 (m, 4H), 3.18 (br. s, 2H), 3.48 (br. s, 2H), 3.38-3.59 (br. s, 2 H,

31

obscured by H₂0), 4.02 (br. s, 3H), 4.67 (br. s, 2H), 6.40-6.45 (m, 1H), 7.02 - 7.15 (m, 2H), 7.60 - 7.74 (m, 2H), 11.25 (br. s, 1H), 12.77 (br. s, 1H), 13.94 (br. s, 1H)

Intermediate 5: LC-MS: 366.2 [M+H]⁺, RT 0.83 min. 1H NMR (500 MHz, DMSO- d₆) δ ppm 2.63 (br. s, 3H), 3.38-3.59 (br. s, 2 H, obscured by H₂0), 3.86 - 3.95 (m,

32

3H), 4.44 (br. s, 2H), 6.40-6.45 (m, 1H), 6.93 - 7.11 (m, 2H), 7.58 - 7.77 (m, 2H), 9.40 (br. s, 2H), 12.77 (br. s, 1H), 13.94 (br. s, 1H)

Intermediate 5: LC-MS: 380.2 [M+H]⁺, RT 0.85 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 1.27 (t, J=7.1 Hz, 3H), 3.05-3.09 (m, 2H), 3.36-3.59 (br. s, 2 H, obscured

33

by H₂0), 3.93 (s, 3H), 4.44 (br. s, 2H), 6.40-6.6-46 (m, 1H), 6.93 - 7.11 (m, 2H), 7.59 - 7.76 (m, 2H), 9.34 (br. s, 2H), 12.77 (br. s, 1H), 13.95 (br. s, 1H)

Intermediate 5: LC-MS: 394.3 [M+H]⁺, RT 0.88 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 0.94 (t, J=7.4 Hz, 3H), 1.70 (q, J=7.4, 2H), 3.00 (br. s, 2H), 3.32-3.50 (br.

34 s, 2 H, obscured by H₂0), 3.89 (s, 3H), 4.41 - 4.51 (m, 2H), 6.38 - 6.49 (m, 1H), 6.97 (s, 1H), 7.03 - 7.10 (m, 1H), 7.60-7.74 (m, 2H), 9.04 (br. s, 2H), 12.77 (br. s, 1H), 13.95 (br. s, 1H)

Intermediate 5: LC-MS: 394.3 [M+H]⁺, RT 0.87 min. 1H NMR (500 MHz, DMSO- d₆) δ ppm 1.36 (d, J=6.3 Hz, 6H), 3.50-3.75 (br. s, 2 H, obscured by H₂0), 3.42 -

35

3.49 (m, 1H), 3.92 (s, 3H), 4.40-4.47 (m, 2H), 6.38 - 6.49 (m, 1H), 6.94 - 7.12 (m, 2H), 7.61 - 7.77 (m, 2H), 9.26 (br. s, 2H), 12.77 (br. s, 1H), 13.95 (br. s, 1H)

Intermediate 5: LC-MS: 406.3 [M+H]⁺, RT 0.88 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 1.74 - 1.86 (m, 2H), 2.15 - 2.34 (m, 4H), 3.50-3.75 (br. s, 2 H, obscured

36 by H₂0), 3.76 - 3.85 (m, 1H), 3.91 (s, 3H), 4.30-4.36 (m, 2H), 6.38 - 6.49 (m, 1H), 6.97 (s, 1H), 7.06 (d, J=10.1 Hz, 1H), 7.61 - 7.74 (m, 2H), 9.64 (br. s, 2H), 12.76 (br. s, 1H), 13.95 (br. s, 1H) Cpd Materials and Data

Intermediate 5: LC-MS: 408.4 [M+H]⁺, RT 0.89 min. 1H NMR (500 MHz, DMSO- d₆) δ ppm 1.44 (s, 9H), 3.50-3.75 (br. s, 2H, obscured by H₂0), 3.93 (s, 3H), 4.41

37

(br. s, 2H), 6.38 - 6.49 (m, IH), 6.95 - 7.11 (m, 2H), 7.58 - 7.78 (m, 2H), 9.37 (br. s, 2H), 12.81 (br. s, IH), 13.95 (br. s, IH)

Intermediate 5: LC-MS: 406.3 [M+H]⁺, RT 0.88 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 0.67 - 0.77 (m, 2H), 1.13 - 1.24 (m, 2H), 1.53 (s, 3H), 3.50-3.75 (br. s, 2H,

38

obscured by H₂0), 3.93 (s, 3H), 4.54 (br. s, 2H), 6.33 - 6.52 (m, IH), 6.95 - 7.08 (m, 2H), 7.57 - 7.80 (m, 2H), 9.63 (br. s, 2H), 12.76 (br. s, IH), 13.95 (br. s, IH)

Intermediate 5: LC-MS: 420.3 [M+H]⁺, RT 0.90 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 1.61 (s, 3H), 1.80 - 2.00 (m, 4H), 3.50-3.98 (br. s, 2H, obscured by H₂0),

39

3.93 (s, 3H), 3.60 - 4.10 (m, 2H), 4.32 (br. s, 2H), 6.32 - 6.48 (m, IH), 6.93 - 7.15 (m, 2H), 7.58 - 7.83 (m, 2H), 9.71 (br. s, 2H), 12.77 (br. s, IH), 13.95 (br. s, IH)

Intermediate 7: LC-MS 420.3 [M-H]⁺, RT 0.90 min. 1H NMR (500 MHz, DMSO- ₆) 5 ppm 0.57 (br. s, 3H), 1.91 (br. s, 3H), 2.06 (br. s, 2H), 2.45 - 2.55 (m, 2H), 2.76

40 (br. s, IH), 2.99 (br. s, IH), 3.20 (br. s, 2H), 3.52 (br. s, 2H), 3.89 (s, 3H), 4.62 - 4.70 (m, 2H), 7.02 (s, IH), 7.37 (d, J=8.5 Hz, IH), 7.56 (d, J=8.5 Hz, IH), 10.58 (br. s, IH), 12.82 (br. s, IH), 14.13 (s, IH)

Intermediate 7: LC-MS 394.3 [M-H]⁺, RT 0.87 min. 1H NMR (500 MHz, DMSO- ₆) 5 ppm 0.56 (br. s, 3H), 1.92 (br. s, IH), 2.45 - 2.55 (m, 2H), 2.70 - 2.90 (m, IH),

41 2.82 (s, 6H), 2.99 (br. s, IH), 3.89 (s, 3H), 4.54 - 4.61 (m, 2H), 7.00 (s, IH), 7.38 (d, J=8.8 Hz, IH), 7.57 (d, J=8.5 Hz, IH), 10.36 (br. s, IH), 12.83 (br. s, IH), 14.13 (s, IH)

Intermediate 7: LC-MS 394.1 [M-H]⁺, 396.2 [M+H]⁺, RT 0.57 min. 1H NMR (500 MHz, DMSO- ) 5 ppm 0.54 (br. s, 3H), 1.27 (t, J=6.8 Hz, 3H), 1.90 (br. s, IH),

42 2.45 - 2.55 (m, 2H), 2.75 (br. s, IH), 2.97 (br. s, IH), 3.03 - 3.20 (m, 2H), 3.85 (s, 3H), 4.42 (br. s, 2H), 6.91 (s, IH), 7.35 (d, J=8.8 Hz, IH), 7.56 (d, J=8.5 Hz, IH), 9.15 (br. s, 2H), 12.81 (br. s, IH), 14.13 (br. s, IH) Cpd Materials and Data

Intermediate 7: LC-MS 408.1 [M-H]⁺, RT 0.59 min. 1H NMR (500 MHz, DMSO- ₆) 5 ppm 0.52 (br. s, 3H), 1.35 (dd, J=6.5, 2.0 Hz, 6H), 1.89 (br. s, IH), 2.45 - 2.55 (m,

43 2H), 2.75 (br. s, IH), 2.99 (br. s, IH), 3.44 - 3.55 (m, IH), 3.85 (s, 3H), 4.44 (t, J=6.1 Hz, 2H), 6.92 (s, IH), 7.35 (d, J=8.8 Hz, IH), 7.57 (d, J=8.2 Hz, IH), 9.03 (br. s, IH), 9.09 (br. s, IH), 12.81 (s, IH), 14.13 (br. s, IH)

Intermediate 7: LC-MS 422.1 [M-H]⁺, RT 0.58 min. 1H NMR (500 MHz, DMSO- ₆) 5 ppm 0.53 (br. s, 3H), 1.43 (s, 9H), 1.89 (br. s, IH), 2.45 - 2.55 (m, 2H), 2.76 (br. s,

44 IH), 2.98 (br. s, IH), 3.86 (s, 3H), 4.40 (br. s, 2H), 6.94 (s, IH), 7.35 (m, J=8.2 Hz, IH), 7.57 (m, J=8.2 Hz, IH), 9.11 (br. s, IH), 9.24 (br. S, IH), 12.81 (br. s, IH), 14.13 (br. s, IH)

Intermediate 7: LC-MS 380.1 [M-H]⁺, 382.1 [M+H]⁺, RT 0.56 min. 1H NMR (500 MHz, DMSO- ) 5 ppm 0.54 (br. s, 3H), 1.89 (br. s, IH), 2.45 - 2.55 (m, 2H), 2.65

45 (br. s, 3H), 2.74 (br. s, IH), 2.97 (br. s, IH), 3.84 (s, 3H), 4.42 (br. s, 2H), 6.90 (s, IH), 7.35 (d, J=8.5 Hz, IH), 7.55 (d, J=8.8 Hz, IH), 9.15 (br. s, 2H), 12.81 (br. s, IH), 14.13 (br. s, IH)

Intermediate 7: LC-MS 408.1 [M-H]⁺, RT 0.57 min. 1H NMR (500 MHz, DMSO- ₆) 5 ppm 0.57 (br. s, 3H), 1.32 (t, J=7.3 Hz, 3H), 1.93 (br. s, IH), 2.45 - 2.55 (m, 2H),

46 2.76 (br. s, 4H), 2.99 (br. s, IH), 3.17 (br. s, 2H), 3.89 (s, 3H), 4.51 (br. s, IH), 4.64 (br. s, IH), 7.03 (s, IH), 7.38 (d, J=8.5 Hz, IH), 7.57 (d, J=8.8 Hz, IH), 10.16 (br. s, IH), 12.81 (br. s, IH), 14.14 (s, IH)

Intermediate 7: LC-MS 408.1 [M-H]⁺, 410.2 [M+H]⁺, RT 0.57 min. 1H NMR (500 MHz, DMSO- ) 5 ppm 0.54 (br. s, 3H), 0.94 (t, J=7.4 Hz, 3H), 1.72 (dt, J=15.1, 7.3

47 Hz, 2H), 1.90 (br. s, IH), 2.45 - 2.55 (m, 2H), 2.76 (br. s, IH), 2.99 (br. s, 3H), 3.86 (s, 3H), 4.43 (br. s, 2H), 6.94 (s, IH), 7.35 (d, J=8.5 Hz, IH), 7.56 (d, J=8.8 Hz, IH), 9.22 (br. s, 2H), 12.81 (br. s, IH), 14.13 (s, IH)

Intermediate 11 : LC-MS: 396.3 [M+H]⁺, RT 0.98 min. 1H NMR (500 MHz, DMSO- de) 5 ppm 1.31 - 1.48 (m, 4H), 1.86 - 1.95 (m, IH), 2.05 - 2.15 (m, IH), 2.33 - 2.38

48

(m, IH), 2.82 (br. s, 6H), 3.17 - 3.24 (m, IH), 3.90 (s, 3H), 4.55 - 4.64 (m, 2H), 6.94 (s, IH), 7.24 - 7.31 (m, IH), 7.51 - 7.56 (m, IH), 12.86 (br. s, IH), 13.93 (br. s, IH). Cpd Materials and Data

Intermediate 11 : LC-MS: 396.3 [M+H]⁺, RT 1.00 min. 1H NMR (500 MHz, DMSO- de) 5 ppm 1.27 (s, 3H), 1.33 - 1.47 (m, 3H), 1.85 - 1.96 (m, 1H), 2.05 - 2.15 (m, 1H),

56 2.33 - 2.39 (m, 1H), 2.78 - 2.88 (m, 1H), 3.02 - 3.13 (m, 2H), 3.14 - 3.21 (m, 1H), 3.86 (s, 3H), 4.40 - 4.48 (m, 2H), 6.85 (s, 1H), 7.20 - 7.27 (m, 1H), 7.48 - 7.55 (m, 1H), 9.12 (br. s, 1H), 12.86 (br. s, 1H), 13.93 (br. s, 1H).

Intermediate 11 : LC-MS: 410.3 [M+H]⁺, RT 1.00 min. 1H NMR (500 MHz, DMSO- de) 5 ppm 1.28 - 1.47 (m, 7 H), 1.86 - 1.96 (m, 1H), 2.06 - 2.16 (m, 1H), 2.61 - 2.68

57 (m, 1H), 2.78 - 2.87 (m, 1H), 3.16 - 3.24 (m, 2H), 3.86 (s, 3H), 3.90 (s, 3H), 4.40 - 4.47 (m, 2H), 6.96 (s, 1H), 7.22 - 7.29 (m, 1H), 7.49 - 7.55 (m, 1H), 12.86 (br. s, 1H), 13.92 (br. s, 1H).

Intermediate 11 : LC-MS: 422.3 [M+H]⁺, RT 1.01 min. 1H NMR (500 MHz, DMSO- de) 5 ppm 1.33 - 1.47 (m, 4H), 1.84 - 1.96 (m, 3H), 1.99 - 2.14 (m, 3H), 2.77 - 2.88

58 (m, 1H), 3.16 - 3.25 (m, 3H), 3.46 - 3.57 (m, 2H), 3.91 (s, 3H), 4.64 - 4.71 (m, 2H), 6.95 (s, 1H), 7.21 - 7.29 (m, 1H), 7.48 - 7.56 (m, 1H), 12.86 (br. s, 1H), 13.92 (br. s, 1H).

Intermediate 11 : LC-MS: 410.3 [M+H]⁺, RT 1.01 min. 1H NMR (500 MHz, DMSO- 6) 5 ppm l .32 - 1.45 (m, 10H), 1.88 - 1.94 (m, 1H), 2.08 - 2.15 (m, 1H), 2.79 - 2.87

59 (m, 1H), 3.14 - 3.21 (m, 1H), 3.46 - 3.52 (m, 1H), 3.86 (s, 3H), 4.42 - 4.49 (m, 2H), 6.86 (s, 1H), 7.22 - 7.27 (m, 1H), 7.50 - 7.55 (m, 1H), 12.86 (br. s, 1H), 13.93 (br. s, 1H).

Intermediate 11 : LC-MS: 422.3 [M+H]⁺, RT 1.03 min. 1H NMR (500 MHz, DMSO- d₆) δ ppm 0.70 - 0.77 (m, 2H), 1.12 - 1.18 (m, 2H), 1.32 - 1.45 (m, 4H), 1.53 (s, 3H),

60 1.86 - 1.95 (m, 1H), 2.07 - 2.16 (m, 1H), 2.79 - 2.88 (m, 1H), 3.12 - 3.20 (m, 1H), 3.86 (s, 3H), 4.51 - 4.59 (m, 2H), 6.87 (s, 1H), 7.20 - 7.28 (m, 1H), 7.49 - 7.56 (m, 1H), 9.40 (br. s, 1H), 12.87 (br. s, 1H), 13.93 (br. s, 1H). Cpd Materials and Data

Intermediate 11: LC-MS: 410.3 [M+H]⁺, RT 1.03 min. 1H NMR (500 MHz, DMSO- <k) δ ρρηι 0.94 (t, J=7.45 Hz, 3H), 1.33 - 1.46 (m, 4H), 1.69 (dd, J=15.72, 7.53 Hz,

61 4H), 2.79 - 2.87 (m, IH), 2.95 - 3.05 (m, 2H), 3.13 - 3.22 (m, IH), 3.85 (s, 3H), 4.41 - 4.50 (m, 2H), 6.86 (s, IH), 7.20 - 7.28 (m, IH), 7.50 - 7.55 (m, IH), 9.01 (br. s, IH), 12.87 (br. s, IH), 13.93 (br. s, IH).

Intermediate 9: LC-MS 420.3 [M-H]⁺, 422.2 [M+H]⁺, RT 0.95 min. 1H NMR (500 MHz, DMSO- ) 5 ppm 0.57 (br. s, 3H), 1.92 (br. s, 3H), 2.05 (br. s, 2H), 2.45 -

64 2.55 (m, 2H), 2.75 (br. s, IH), 2.98 (br. s, IH), 3.20 (br. s, 2H) 3.50 (br. s, 2H), 3.90 (s, 3H), 4.63 - 4.68 (m, 2H), 7.03 (s, IH), 7.36 (d, J=8.5 Hz, IH), 7.56 (d, J=8.5 Hz, IH), 10.84 (br. s, IH), 12.81 (br. s, IH), 14.13 (s, IH)

Intermediate 9: LC-MS 408.3 [M-H]⁺, 410.2 [M+H]⁺, RT 0.91 min. 1H NMR (500 MHz, DMSO- ) 5 ppm 0.58 (br. s, 3H), 1.32 (t, J=6.9 Hz, 3H), 1.93 (br. s, IH),

65 2.45 - 2.55 (m, 2H), 2.76 (br. s, 4H), 2.99 (br. s, IH), 3.17 (br. s, 2H), 3.89 (s, 3H), 4.51 (d, J=7.3 Hz, IH), 4.63 - 4.68 (m, IH), 7.03 (s, IH), 7.38 (d, J=8.5 Hz, IH), 7.57 (d, J=8.5 Hz, IH), 10.29 (br. s, IH), 12.82 (br. s, IH), 14.13 (s, IH)

Intermediate 9: LC-MS 408.2 [M-H]⁺, 410.3 [M+H]⁺, RT 0.95 min. 1H NMR (500 MHz, DMSO- ) 5 ppm 0.55 (br. s, 3H), 0.94 (t, J=7.4 Hz, 3H), 1.66 - 1.82 (m, 2H),

66 1.91 (br. s, IH), 2.45 - 2.55 (m, 2H), 2.75 (br. s, IH), 3.00 (br. s, 3H), 3.85 (s, 3H), 4.44 (br. s, 2H), 6.93 (s, IH), 7.36 (d, J=8.5 Hz, IH), 7.56 (d, J=8.5 Hz, IH), 9.11 (br. s, 2H), 12.80 (br. s, IH), 14.14 (br. s, IH)

Intermediate 9: LC-MS 408.3 [M-H]⁺, 410.1 [M+H]⁺, RT 0.93 min. 1H NMR (500 MHz, DMSO- ) 5 ppm 0.55 (br. s, 3H), 1.37 (dd, J=6.5, 2.0 Hz, 6H), 1.86 - 1.95

67 (m, IH), 2.45 - 2.55 (m, 2H), 2.70 - 2.85 (m, IH), 2.99 (br. s, IH), 3.44 - 3.55 (m, IH), 3.87 (s, 3H), 4.44 (t, J=5.7 Hz, 2H), 6.94 (s, IH), 7.36 (d, J=8.5 Hz, IH), 7.57 (d, J=8.8 Hz, IH), 9.09 (br. s, IH), 9.15 (br. s, IH), 12.80 (s, IH), 14.15 (s, IH) Cpd Materials and Data

Intermediate 9: LC-MS 394.3 [M-H]⁺, 396.2 [M+H]⁺, RT 1.02 min. 1H NMR (500 MHz, DMSO- ) 5 ppm 0.54 (br. s, 3H), 1.27 (br. s, 3H), 1.89 (br. s, IH), 2.45 -

68 2.55 (m, 2H), 2.75 (br. s, IH), 2.96 (br. s, IH), 3.08 (br. s, 2H), 3.85 (br. s, 3H), 4.41 (br. s, 2H), 6.92 (br. s, IH), 7.34 (d, J=7.3 Hz, IH), 7.55 (d, J=7.6 Hz, IH), 9.23 (br. s, 2H), 12.79 (br. s, IH), 14.13 (br. s, IH)

Intermediate 9: LC-MS 394.3 [M-H]⁺, 396.2 [M+H]⁺, RT 1.00 min. 1H NMR (500 MHz, DMSO- ) 5 ppm 0.56 (br. s, 3H), 1.93 (br. s, IH), 2.45 - 2.55 (m, 2H), 2.70 -

69 2.90 (m, IH), 2.82 (s, 6H), 2.99 (br. s, IH), 3.89 (s, 3H), 4.49 - 4.67 (m, 2H), 7.01 (s, IH), 7.38 (d, J=8.5 Hz, IH), 7.57 (d, J=8.5 Hz, IH), 10.48 (br. s, IH), 12.81 (br. s, IH), 14.14 (s, IH)

Intermediate 10: LC-MS 394.1 [M-H]⁺, 396.1 [M+H]⁺, RT 0.98 min. 1H NMR (500 MHz, DMSO- ) 5 ppm 0.55 (br. s, 3H), 1.28 (t, J=7.3 Hz, 3H), 1.90 (br. s, IH),

70 2.45 - 2.55 (m, 2H), 2.76 (br. s, IH), 2.97 (br. s, IH), 3.03 - 3.14 (m, 2H), 3.86 (s, 3H), 4.42 (br. s, 2H), 6.93 (s, IH), 7.35 (d, J=8.8 Hz, IH), 7.56 (d, J=8.8 Hz, IH), 9.22 (br. s, 2H), 12.80 (br. s, IH), 14.14 (br. s, IH)

Intermediate 10: LC-MS 394.2 [M-H]⁺, 396.2 [M+H]⁺, RT 0.97 min. 1H NMR (500 MHz, DMSO- ) 5 ppm 0.57 (br. s, 3H), 1.92 (br. s, IH), 2.45 - 2.55 (m, 2H), 2.77

71 (br. s, IH), 2.82 (s, 6H), 2.98 (br. s, IH), 3.89 (s, 3H), 4.52 - 4.66 (m, 2H), 7.00 (s, IH), 7.38 (d, J=8.5 Hz, IH), 7.57 (d, J=8.5 Hz, IH), 10.36 (br. s, IH), 12.83 (br. s, IH), 14.13 (s, IH)

Intermediate 10: LC-MS 420.2 [M-H]⁺, 422.5 [M+H]⁺, RT 1.00 min. 1H NMR (500 MHz, DMSO- ) 5 ppm 0.57 (br. s, 3H), 1.92 (br. s, 3H), 2.06 (br. s, 2H), 2.45 -

72 2.55 (m, 2H), 2.76 (br. s, IH), 2.98 (br. s, IH), 3.20 (br. s, 2H), 3.51 (br. s, 2H), 3.89 (s, 3H), 4.58 - 4.75 (m, 2H), 7.02 (s, IH), 7.37 (d, J=8.5 Hz, IH), 7.55 (d, J=8.8 Hz, IH), 10.64 (br. s, IH), 12.80 (br. s, IH), 14.13 (s, IH) Cpd Materials and Data

Intermediate 10: LC-MS 408.2 [M-H]⁺, 410.0 [M+H]⁺, RT 1.01 min. 1H NMR (500 MHz, DMSO- d₆) δ ppm 0.54 (br. s., 3H) 0.94 (t, J=7.4 Hz, 3H) 1.67 - 1.83 (m, 2H)

73 1.90 (br. s., IH) 2.45 - 2.55 (m, 2H) 2.76 (br. s., IH) 3.00 (br. s., 3H) 3.85 (s, 3H) 4.43 (br. s., 2H) 6.93 (s, IH) 7.36 (d, J=8.8 Hz, IH) 7.56 (d, J=8.5 Hz, IH) 9.18 (br. s., 2H) 12.79 (br. s., IH) 14.14 (s, IH)

Intermediate 10: LC-MS 408.3 [M-H]⁺, 410.2 [M+H]⁺, RT 1.04 min. 1H NMR (500 MHz, DMSO- d₆) δ ppm 0.54 (br. s, 3H), 1.36 (dd, J=6.3, 2.2 Hz, 6H), 1.90 (br. s,

74 IH), 2.45 - 2.55 (m, 2H), 2.76 (br. s, IH), 2.98 (br. s, IH), 3.43 - 3.63 (m, IH), 3.86 (s, 3H), 4.43 (t, J=5.8 Hz, 2H), 6.94 (s, IH), 7.36 (d, J=8.5 Hz, IH), 7.56 (d, J=8.5 Hz, IH), 9.13 (br. s, IH), 9.20 (br. s, IH), 12.79 (s, IH), 14.14 (s, IH)

Intermediate 10: LC-MS 408.2 [M-H]⁺, 410.2 [M+H]⁺, RT 0.98 min. 1H NMR (500 MHz, DMSO- ) 5 ppm 0.57 (br. s, 3H), 1.32 (t, J=7.3 Hz, 3H), 1.93 (br. s, IH),

75 2.45 - 2.55 (m, 2H), 2.76 (br. s, 4H), 2.99 (br. s, IH), 3.17 (br. s, 2H), 3.89 (s, 3H), 4.51 (br. s, IH), 4.64 (br. s, IH), 7.03 (s, IH), 7.38 (d, J=8.5 Hz, IH), 7.57 (d, J=8.8 Hz, IH), 10.16 (br. s, IH), 12.81 (br. s, IH), 14.14 (s, IH)

Intermediate 12: LC-MS: 400.3 [M+H]⁺, RT 0.71 min. 1H NMR (500 MHz, DMSO- de) δ ppm 2.15-2.34 (4H), 2.73-2.88 (8 H), 4.05 (s, 3H), 4.57 (s, 2H), 7.08 (d, J=1.8

76

Hz, IH), 7.28 (d, J=13.6 Hz, IH), 10.58 (br. s, IH), 12.91 (br. s, IH), 13.90 (s, IH), 16.32 (br. s, IH)

Intermediate 12: LC-MS: 414.3 [M+H]⁺, RT 0.78 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 0.95 (d, J=7.6 Hz, 3H), 1.72 (m, 2H), 2.15-2.34 (4H), 2.80 (2H), 3.00

77

(2H), 4.01 (s, 3H), 4.44 (s, 2H), 7.01 (d, J=1.8 Hz, IH), 7.25 (d, J=13.6 Hz, IH), 9.19 (br.s, IH), 12.91 (br. s, IH), 13.90 (s, IH), 16.32 (br. s, IH)

Intermediate 12: LC-MS: 426.3 [M+H]⁺, RT 0.74 min. 1H NMR (500 MHz, DMSO- d₆) 5 ppm 1.93 (m, 2H), 2.06 (m, 2H), 2.15-2.34 (4H), 2.80 (m, 2H), 3.20 (m, 2H),

78

3.54 (m, 2H), 4.05 (s, 3H), 4.67 (s, 2H), 7.10 (d, J=1.8 Hz, IH), 7.26 (d, J=13.6 Hz, IH), 10.63 (br. s, IH), 12.91 (br. s, IH), 13.90 (s, IH), 16.34 (br. s, IH) Example 3

7-Hydroxy-9-oxo- 1,4,5,6,9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8- carboxylic acid (Cpd 9)

A mixture of methyl 7-hydroxy-9-oxo-l-tosyl-l,4,5,6,9,10- hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate (Intermediate 15, 50 mg, 0.1 mmol) and K₂C0₃ (28 mg, 0.2 mmol) in MeOH (3 mL) was heated at 150 °C with stirring for 10 min in a microwave reactor. To the mixture was added aqueous 1M HCl (1 mL). The solid precipitate was collected, washed with H₂0 and dried. The solid was suspended in EtOAc (2 mL) with lithium iodide (27 mg, 0.2 mmol). The mixture was stirred at 70 °C for 30 min, then cooled to room temperature and filtered. The solid was suspended in aqueous 1M HCl (1 mL) and CH₃CN (0.5 mL). The solid was collected and dried to afford the product (17 mg, 52%) as a white powder.

LC-MS: 311.0 [M+H]⁺, RT 1.17 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 2.14-2.37 (4H), 2.86 (br. s, 2H), 6.69 (m, 1H), 7.26 (d, J=8.6 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.47 (m, 1H), 11.42 (br. s, 1H), 12.84 (br. s, 1H), 13.86 (s, 1H), 16.43 (br. s, 1H).

Example 4

l-[2-(Dimethylamino)ethyl]-7-hydroxy-9-oxo-l,4,5,6,9,10- hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride (Cpd 17)

Step 1: Methyl 7,9-bis(benzyloxy)-l-tosyl- 1,4,5, 6-tetrahydropyrido[2',3':3,4]cyclohepta[ 1,2- e]indole-8-carboxylate

To a mixture of diisopropyl azodicarboxylate (0.56 mL, 2.84 mmol) and triphenylphosphine (747 mg, 2.84 mmol) in THF(3.5 mL) at 0 °C, was added methyl 7-hydroxy-9-oxo-l-tosyl- 1,4,5,6, 9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate (Intermediate 15, 340 mg, 0.71 mmol). The mixture was stirred vigorously for 5 min at 0 °C. Benzyl alcohol (0.29 mL, 2.84 mmol) was added to the mixture, and the mixture was allowed to warm to room temperature while stirring. After stirring at room temperature for 16 h, the mixture was concentrated. The residue was chromatographed on silica gel, eluting with 0- 20% EtOAc in hexanes to yield 0.44 g of a colorless oil (94 %).

LC-MS: 659.2 [M+H]⁺, RT 1.80 min. Step 2: Methyl 7,9-bis(benzyloxy)-l,4,5,6-tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole- 8-carboxylate A mixture of methyl 7, 9-bis(benzyloxy)-l-tosyl- 1,4,5,6- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate (440 mg, 0.67 mmol) and K₂C0₃ (185 mg, 1.34 mmol) in MeOH (6 mL) was heated at 140 °C with stirring for 10 min in a microwave reactor. The mixture was partitioned between EtOAc (50 mL) and aqueous saturated NaHC0₃ (50 mL). The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-50% EtOAc in hexanes to afford 175 mg of white powder (52%).

LC-MS: 505.2 [M+H]⁺, RT 1.57 min.

Step 3: Methyl 7,9-bis(benzyloxy)-l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-l,4,5,6- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate

To a mixture of methyl 7,9-bis(benzyloxy)-l,4,5,6-tetrahydropyrido[2',3':3,4]cyclohepta[l,2- e]indole-8-carboxylate (175 mg, 0.35 mmol) and DMF (1 mL) was added sodium hydride (28 mg, 0.7 mmol, 60% dispersion in mineral oil). The mixture stirred 5 min at room

temperature, before the addition of (2-bromoethoxy)-ieri-butyldimethylsilane (110 μί, 0.53 mmol). The mixture was stirred at room temperature for 1 hr, and was then was partitioned between EtOAc (10 mL) and aqueous saturated NaHC0₃ (10 mL). The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-30% EtOAc in hexanes to afford 135 mg of a colorless oil (58%).

LC-MS: 663.4 [M+H]⁺, RT 2.08 min.

Step 4: Methyl 7,9-bis(benzyloxy)-l-(2-((methylsulfonyl)oxy)ethyl)-l,4,5,6- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate

To a solution of methyl 7,9-bis(benzyloxy)-l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-l,4,5,6- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate (135 mg, 0.20 mmol) and THF (1 mL) was added a solution of tetrabutylammonium fluoride (0.4 mL, 0.4 mmol, 1 M in THF). The mixture was stirred for 30 min at room temperature and then was concentrated. The residue was chromatographed on silica gel, eluting with 0-100% EtOAc in hexanes to afford an alcohol intermediate (110 mg). The intermediate was dissolved in CH₂C1₂ (1.0 mL) with diisopropylethylamine (70 μί, 0.4 mmol) and cooled to 0 °C. To the mixture was added methanesulfonyl chloride (30 μί, 0.4 mmol). The mixture was stirred 15 min at room temperature and then was loaded onto silica gel, eluting with 0-50% EtOAc in hexanes to afford 92 mg of a white powder (73%). LC-MS: 627.3 [M+H]⁺, RT 1.61 min.

Step 5: Methyl 7,9-bis(benzyloxy)-l-(2-(dimethylamino)ethyl)-l,4,5,6- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate

To a mixture of methyl 7,9-bis(benzyloxy)-l-(2-((methylsulfonyl)oxy)ethyl)-l,4,5,6- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate (90 mg, 0.14 mmol) and DMF (1 mL) was added dimethylamine (2 M in THF, 0.5 mL, 1 mmol). The mixture stirred for 48 h at room temperature. The mixture was partitioned between EtOAc (10 mL) and aqueous 1 M K₂CO₃ (10 mL). The organic layer was concentrated and chromato graphed on silica gel, eluting with 0-10% MeOH in CH₂C1₂ to afford 50 mg of product (62%).

LC-MS: 576.3 [M+H]⁺, RT 1.28 min.

Step 6: l-[2-(dimethylamino)ethyl]-7-hydroxy-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid hydrochloride

To a mixture of methyl 7,9-bis(benzyloxy)-l-(2-(dimethylamino)ethyl)-l,4,5,6- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate (50 mg, 0.08 mmol) and MeOH (2 mL) was added 10% Pd/C (10 mg). The mixture stirred under H₂ (1 atm) at room temperature for 2 hrs. The mixture was filtered and the filtrate was concentrated. The residue was combined with lithium iodide (48 mg, 0.36 mmol) in EtOAc (2 mL) and heated to 70 °C for 16 hours. The mixture was then cooled and filtered. The solid was suspended in aqueous 1 M HC1 (1 mL), collected, washed with CH₃CN and dried to afford the desired product (25 mg, 73%) as a tan powder.

LC-MS: 382.2 [M+H]⁺, RT 0.90 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 2.12-2.37 (m, 4H), 2.84 (s, 6H), 2.87 (br. s, 2H), 3.50 (m, 2H), 4.65 (m, 2H), 6.81 (d, J=3.3 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.57 (d, J=3.1 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 10.24 (br. s, 1H), 12.92 (br. s, 1H), 13.88 (s, 1H), 16.37 (br. s, 1H). Example 5

7-Hydroxy-l-(2-hydroxyethyl)-9-oxo- 1,4,5, 6,9, 10-hexahydropyrido[2',3':3,4]cyclohepta[ 1,2- e]indole-8-carboxylic acid (Cpd 5)

Step 1: l-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-7-hydroxy-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid A mixture of methyl l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-hydroxy-9-oxo-l,4,5,6,9,10- hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylate (Intermediate 16, 20 mg, 0.04 mmol) and lithium iodide (11 mg, 0.08 mmol) in EtOAc (1 mL) was heated at 70 °C for 1 hr and then the volatiles were removed. The residue was suspended and triturated in aqueous 1 N HC1. The solid was collected and dried (12 mg, 64%).

LC-MS: 469.1 [M+H]⁺, RT 1.71 min. Step 2: 7-Hydroxy-l-(2-hydroxyethyl)-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid

To a solution of l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-hydroxy-9-oxo-l,4,5,6,9,10- hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid (12 mg, 0.025 mmol) and THF (1 mL) was added a solution of tetrabutylammonium fluoride (0.05 mL, 1 M in THF). The mixture was stirred 30 min at room temperature. The volatiles were removed and the residue was suspended and triturated in aqueous 1 N HC1. The solid was collected, washed with CH₃CN and dried to give 8 mg (90%) of the title compound.

LC-MS: 355.0 [M+H]⁺, RT 1.13 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 2.17-2.35 (m, 4H), 2.84 (br, s, 2H) 3.74 (q, J=5.4 Hz, 2H), 4.27 (t, J=5.5 Hz, 2H), 4.91 (t, J=5.2 Hz, 1H), 6.68 (d, J=3.3 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.47 (d, J=3.3 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 12.83 (br. s, 1H), 14.02 (br. s, 1H), 16.13 (br. s, 1H).

Example 6

4-Hydroxy-2-oxo- 1,2,5,6,7, 10-hexahydropyrido[3',2':6,7]cyclohepta[l,2-e]indole-3- carboxylic acid (Cpd 79) Step 1: Methyl 4-hydroxy-10-nitro-2-oxo-2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2- b]pyridine-3-carboxylate

To a solution of 3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (16.4 g, 80 mmol) in CH₂CI₂ (400 mL) was added t-butylamine (25.2 mL, 240 mmol). The mixture was cooled to 0 °C. To the mixture was added a TiCl₄ solution (1 M CH₂CI₂, 52 mL, 52 mmol) drop wise via an addition funnel over 30 min. The mixture was allowed to warm to room temperature and was stirred overnight. The excess reagent was quenched with aqueous saturated NaHC0₃ (50 mL). After vigorous shaking, the organic phase was separated using a PTFE phase separator, dried over Na₂S0₄, filtered, and concentrated. The residue was combined with trimethyl methanetricarboxylate (33.4 g, 144 mmol) in PI1₂O (160 mL). The mixture was placed in a pre-heated aluminum block at 220 °C and stirred for 15 minutes. The reaction vessel was removed from the heating block and allowed to cool to room temperature. The crude reaction mixture was loaded directly onto a silica gel column, eluting with 0-10% MeOH in CH₂C1₂ to yield a tan powder (3.0 g, 11%).

LC-MS: 331.0 [M+H]⁺, RT 1.16 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 2.05-2.33 (4H), 2.64-2.74 (2H), 3.86 (s, 3H), 7.69 (d, J=8.3 Hz, 1H), 8.31 (dd, J=8.3, 2.6 Hz, 1H), 8.36 (d, J=2.4 Hz, 1H), 11.85 (br. s, 1H), 13.39 (br. s, 1H).

Step 2: Methyl 2,4-bis(benzyloxy)-10-nitro-6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2- b]pyridine-3-carboxylate

To a mixture of diisopropyl azodicarboxylate (7.2 mL, 36.4 mmol) and triphenylphosphine (9.6 g, 36.4 mmol) in THF(45 mL) at 0 °C, was added methyl 4-hydroxy-10-nitro-2-oxo- 2,5,6,7-tetrahydro-lH-benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylate (3.0 g, 9.1 mmol). The mixture was stirred vigorously for 5 min at 0 °C. Benzyl alcohol (3.77 mL, 36.4 mmol) was added to the mixture, and the mixture was allowed to warm to room temperature while stirring. After stirring at room temperature for 16 h, the mixture was concentrated. The residue was chromato graphed on silica gel, eluting with 0-20% EtOAc in hexanes to yield 4.6 g of tan powder (100 %).

1H NMR (500 MHz, acetone- d₆) δ ppm 2.26 (p, J=7.1 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.73 (t, J=7.2 Hz, 2H), 3.91 (s, 3H), 5.17 (s, 2H), 5.55 (s, 2H), 7.24-7.55 (10H), 7.63 (d, J=8.2 Hz, 1H), 8.25 (dd, J=8.2, 2.5 Hz, 1H), 8.46 (d, J=2.5 Hz, 1H).

Step 3: Methyl 10-amino-2,4-bis(benzyloxy)-l l-bromo-6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylate

To a mixture of methyl 2,4-bis(benzyloxy)-10-nitro-6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylate (4.8 g, 9.4 mmol) and AcOH:EtOH (1: 1, 50 mL) was added iron powder (2.62 g, 47 mmol). The mixture was stirred at 60 °C for 2 hrs and then filtered through Celite. The filtrate was partitioned between EtOAc (200 mL) and 0.2 M KOH (200 mL). The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was dissolved in CH₂C1₂ (45 mL) with AcOH (1.61 mL, 28.2 mmol). To the mixture was added N-bromosuccinimide (1.67 g, 9.4 mmol). The mixture was stirred at room temperature for 15 min, and then diluted with CH₂C1₂ (100 mL). The mixture was washed with aqueous saturated NaHC0₃, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-30% EtOAc in hexanes to afford the desired product (1.1 g, 21% yield) as the major bromination isomer (0.77 g of minor isomer collected). 1H NMR (500 MHz, acetone- ₆) δ ppm 1.57 (m, 2H), 1.88-1.97 (4H), 3.73 (s, 3H), 4.61 (s, 2H), 4.86 (s, 2H), 5.02 (s, 2H), 6.68 (s, 1H), 6.87-7.01 (11H).

Step 4: Methyl 2,4-bis(benzyloxy)-5,6,7,10-tetrahydropyrido[3',2':6,7]cyclohepta[l,2- e]indole-3-carboxylate To a mixture of methyl 10-amino-2,4-bis(benzyloxy)-l l-bromo-6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-b]pyridine-3-carboxylate (1.12 g, 2 mmol), copper(I) iodide (152 mg, 0.8 mmol), bis(triphenylphosphine)palladium(II) dichloride (280 mg, 0.4 mmol), triethylamine (1.4 mL, 10 mmol) and DMF (10 mL) was added trimethylsilylacetylene (0.57 mL, 4 mmol). The mixture was heated at 80 °C for 3 hrs, then diluted with EtOAc (20 mL), filtered and concentrated. The residue was chromato graphed on silica gel, eluting with 0-30% EtOAc in hexanes to afford an intermediate (200 mg). The intermediate was combined with copper(I) iodide (76 mg, 0.4 mmol) in DMF (5 mL) and heated with stirring at 120 °C for 2 hrs. The mixture was diluted with EtOAc (20 mL), then filtered and concentrated. The residue was chromato graphed on silica gel, eluting with 0-30% EtOAc in hexanes to afford the title compound (40 mg).

LC-MS: 505.2 [M+H]⁺, RT 1.65 min.

Step 5: 4-Hydroxy-2-oxo- 1,2,5,6,7, 10-hexahydropyrido[3',2':6,7]cyclohepta[l,2-e]indole-3- carboxylic acid

To a mixture of methyl 2,4-bis(benzyloxy)-5,6,7,10- tetrahydropyrido[3',2':6,7]cyclohepta[l,2-e]indole-3-carboxylate (40 mg, 0.08 mmol) and MeOH (2 mL) was added 10% Pd/C (5 mg). The mixture was stirred under H₂ (1 atm) at room temperature for 2 hrs. The mixture was filtered and the filtrate was concentrated. The residue was combined with lithium iodide (32 mg, 0.24 mmol) in EtOAc (2 mL). The mixture was stirred at 75 °C for 16 h. Volatiles were removed with a stream of nitrogen. The residue was suspended in aqueous 0.5 M HC1. The solid precipitate was collected, washed with CH₃CN and dried to afford the desired product (7 mg, 28%) as a tan powder.

LC-MS: 311.0 [M+H]⁺, RT 1.17 min. 1H NMR (500 MHz, DMSO- ₆) δ ppm 1.63 (m, 1H), 2.09 (m, 2H), 2.53 (m, 1H), 2.73 (m, 1H), 2.87 (m, 1H), 6.43 (m, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.50 (d, J=2.8 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 11.39 (br. s, 1H), 12.90 (br. s, 1H), 13.96 (br. s, 1H), 16.45 (br. s, 1H). Example 7

7-Hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole-8- carboxylic acid hydrochloride (Cpd 80)

Step 1: l-(tert-Butoxycarbonyl)-7-hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH- pyrido[2',3':6,7]oxepino[4,5-e]indole-8-carboxylic acid

A mixture of 8-benzyl l-(tert-butyl) 7,9-bis(benzyloxy)-2,3,4,5-tetrahydro-lH- pyrido[2',3':6,7]oxepino[4,5-e]indole-l,8-dicarboxylate (Intermediate 19, 78 mg, 0.11 mmol) and 10% Pd/C (15 mg) in dichloromethane (1.0 mL) and methanol (1.0 mL) was stirred at room temperature under a hydrogen atmosphere. After 4 h, the mixture was filtered and the cake was washed with dichloromethane and methanol. The filtrate was combined and evaporated to give the title compound (42 mg, 89%).

Step 2: 7-Hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole- 8-carboxylic acid

A solution of the product of Step 1 (42 mg, 0.10 mmol) in TFA (1.5 mL) and

dichloromethane (1.5 mL) was stirred at room temperature for 30 min. The mixture was then evaporated. A portion of the residue (20 mg) was triturated with 1 N HCl in ether. The solid was collected to give the title compound as an HCl salt (12 mg).

LC-MS 315.0 [M+H]⁺, RT 0.93 min. 1H NMR (DMSO- ₆) δ: 12.71 (br. s, IH), 7.25 (d, J=8.2 Hz, IH), 6.64 (d, J=5.7 Hz, IH), 4.47 (t, J=6.5 Hz, 2H), 3.61 (t, J=8.5 Hz, 2H), 3.08 (t, J=8.5 Hz, 2H), 2.78 (t, J=6.3 Hz, 2H).

Using the procedure described for Example 7 above, additional compounds described herein may be prepared by using the indicated intermediate, obtaining compounds such as those selected from:

Cpd Materials and Data

Intermediate 21 was functionalized according to the procedure for preparing Intermediate 19 for use in preparing Compound 85. LC-MS 301.1 [M+H]⁺, RT 0.95

85

min. 1H NMR (DMSO- ₆) δ: 12.64 (br. s, IH), 7.69 (d, J=8.5 Hz, IH), 6.52 (d, J=8.2 Hz, IH), 5.04 (s, 2H), 3.61 (t, J=8.7 Hz, 2H), 2.97 (t, J=8.7 Hz, 2H) Cpd Materials and Data

Intermediate 22 was functionalized according to the procedure for preparing Intermediate 19 for use in preparing Compound 86. LC-MS 329.1 [M+H]⁺, RT 0.96

86 min. 1H NMR (DMSO- ₆) δ: 13.74 (s, IH), 12.74 (br. s, IH), 7.01-7.12 (m, IH), 6.58-6.68 (m, IH), 4.36-4.44 (m, IH), 3.68-3.78 (m, IH), 3.57-3.64 (m, 2H), 2.99- 3.08 (m, 2H), 2.80-2.90 (m, IH), 2.35-2.42 (m, IH), 1.69-1.90 (m, 2H)

Example 8

7-Hydroxy-l-methyl-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid hydrochloride (Cpd 81)

Method A: The product (24 mg) obtained in Step 2 of Example 7 was dissolved in TFA (0.5 mL) and then cooled to -15 °C, into which was added 37% aqueous formaldehyde (14 μί, 0.168 mmol) followed by NaBH(OAc)3 (36 mg, 0.168 mmol). The reaction was complete after 5 min. The mixture was evaporated and the residue was purified by preparative HPLC using a CI 8 column to give the title compound.

Method B: To a solution of Compound 7 (Example 10, 17 mg) in dichloromethane (0.75 mL) and TFA (0.25 mL) was added triethylsilane (0.25 mL). The mixture was then stirred at room temperature overnight, after which the organic volatiles were removed by a stream of nitrogen. The residue was treated with 1.0 N HC1 in ether, stirred at room for 30 min then filtered. The solid was collected and washed with ether to give the title compound as the HC1 salt (20 mg).

LC-MS 329.0 [M+H]⁺, RT 1.09 min. 1H NMR (DMSO- ₆) δ: 12.69 (br. s, IH), 7.29 (d, J=8.2 Hz, IH), 6.53 (d, J=8.5 Hz, IH), 4.44 (t, J=6.5 Hz, 2H), 3.46 (t, J=8.5 Hz, 2H), 3.01 (t, J=8.5 Hz, 2H), 2.82 (s, 3H), 2.76 (t, J=6.6 Hz, 2H).

Example 8a

l-Ethyl-7-hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole- 8-carboxylic acid hydrochloride (Cpd 83)

Compound 83 was prepared according to the procedure for Example 8 (Method A) by replacing formaldehyde with acetaldehyde to give the title compound.

LC-MS 365.1 [M+Na]⁺, RT 0.72 min. 1H NMR (DMSO- ₆) δ: 12.67 (br. s., IH), 7.27 (d, J=8.2 Hz, IH), 6.52 (d, J=8.2 Hz, IH), 4.44 (t, J=6.5 Hz, 2H), 3.51 (t, J=8.5 Hz, 2H), 3.25 (q, J=7.3 Hz, 2H), 3.02 (t, J=8.5 Hz, 2H), 2.75 (t, J=6.5 Hz, 2H), 1.12 (t, J=7.1 Hz, 3H). Using the procedures described for Examples 7 & 8 (Method A) above, additional compounds described herein may be prepared by using the indicated intermediate, obtaining compounds such as those selected from:

Example 9

7-Hydroxy-9-oxo-4,5,9,10-tetrahydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole-8-carboxylic acid (Cpd 6)

A mixture of benzyl 7,9-bis(benzyloxy)-4,5-dihydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylate (Intermediate 20, 50 mg, 0.086 mmol) and 10% Pd/C (10 mg) in dichloromethane (1.0 mL) and methanol (1.0 mL) was stirred at room temperature under a hydrogen atmosphere for 1 hr and then filtered. The solid cake was treated with DMSO (5.0 mL) and filtered. The filtrate was combined and concentrated, to which was added ether (5.0 mL) and hexane (5.0 mL). The mixture was allowed to sit for 30 min before being filtered. The solid was washed with ether and collected to provide the title compound (14 mg).

LC-MS 313.0 [M+H]⁺, RT 1.00 min. 1H NMR (DMSO- ₆) δ: 16.34 (br. s, IH), 13.67 (br. s, IH), 12.86 (br. s, IH), 11.48 (br. s, IH), 7.49-7.51 (t, J=2.6 Hz, IH), 7.47 (d, J=8.5 Hz, IH), 7.32 (d, J=8.5 Hz, IH), 6.74 (d, J=2.2 Hz, IH), 4.58 (t, J=6.5 Hz, 2H), 3.19 (t, J=6.5 Hz, 2H).

Using the procedure described for Example 9 above, additional compounds described herein may be prepared by using the indicated intermediate, obtaining compounds such as those selected from: Cpd Materials and Data

Intermediate 22 was functionalized according to the procedures for preparing Intermediates 19 and 20 for use in preparing Compound 49. LC-MS 325.0 [M-H]⁺, RT 1.04 min. 1H NMR (DMSO- ₆) δ: 13.82 (br. s, 1H), 12.86 (br. s, 1H), 11.41 (br.

49

s, 1H), 7.46-7.50 (m, 1H), 7.39 (dd, J=8.5, 0.6 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.65 (br. s, 1H), 4.36-4.47 (m, 1H), 3.74-3.84 (m, 1H), 2.55-2.69 (m, 2H), 1.92-2.01 (m, 1H), 1.67-1.79 (m, 1H).

Example 10

7-Hydroxy-l-methyl-9-oxo-4,5,9,10-tetrahydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole-8- carboxylic acid (Cpd 7)

Step 1: Benzyl 7,9-bis(benzyloxy)-l-methyl-4,5-dihydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylate

To a solution of benzyl 7,9-bis(benzyloxy)-4,5-dihydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylate (Intermediate 20, 129 mg, 0.22 mmol) in DMF (1.0 mL) at 0 °C was added 60% NaH (13 mg, 0.33 mmol). After 30 min, iodomethane (47 mg, 0.33 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was quenched with aqueous ammonium chloride. The mixture was extracted with ether (3X). The organic layers were combined, washed with water and brine, dried and evaporated. The residue was purified by silica gel column chromatography with hexane and ethyl acetate (0 to 50% gradient) to provide the title compound (82 mg, 62%).

LC-MS 597.1 [M+H]⁺, RT 1.66 min. 1H NMR (CHLOROFORM-d) δ: 7.71 (d, J=8.8 Hz, 1H), 7.29-7.48 (m, 16H), 7.13-7.15 (m, 1H), 6.59 (d, J=2.5 Hz, 1H), 5.55 (s, 2H), 5.33 (s, 2H), 5.32 (s, 2H), 4.68 (t, J=6.3 Hz, 2H), 3.87 (s, 3H), 3.19 (t, J=6.3 Hz, 2H).

Step 2: 7-Hydroxy-l-methyl-9-oxo-4,5,9,10-tetrahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid

The title compound was prepared utilizing the procedure described for Example 9.

LC-MS 327.0 [M+H]⁺, RT 1.07 min. 1H NMR (DMSO- ₆) δ: 16.32 (br. s, 1H), 13.67 (br. s, 1H), 12.89 (br. s, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.48 (d, J=3.2 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 6.74 (dd, J=3.2, 0.9 Hz, 1H), 4.57 (t, J=6.3 Hz, 2H), 3.86 (s, 3H), 3.19 (t, J=6.3 Hz, 2H). Using the procedure described for Example 10 above, additional compounds described herein may be prepared by using the indicated intermediate, obtaining compounds such as those selected from:

Example 11

7-Hydroxy-9-oxo-2,3,4,6,9,10-hexahydro-lH-pyrido[2',3':5,6]oxepino[3,4-e]indole-8- carboxylic acid hydrochloride (Cpd 82)

A mixture of Intermediate 24 (32 mg, 0.046 mmol), 6 N HC1 (2.0 mL) and THF (2.0 mL) was stirred at 50 °C overnight. Water (20 mL) was added and organic volatiles were removed on the rotovap. The mixture was filtered and the resulting solid was washed with acetonitrile and collected to give the title compound (8 mg).

LC-MS 315.0 [M+H]⁺, RT 0.98 min. 1H NMR (DMSO- ₆) δ: 15.99 (br. s, 1H), 13.81 (s, 1H), 12.85 (br. s, 1H), 7.36 (d, J=8.2 Hz, 1H), 6.62 (d, J=8.2 Hz, 1H), 4.29 (s, 2H), 4.15 (s, 2H), 3.56-3.64 (t, J=8.7 Hz, 2H), 3.08 (t, J=8.7 Hz, 2H).

Example 12

7-Hydroxy-l-methyl-9-oxo-2,3,4,6,9,10-hexahydro-lH-pyrido[2',3':5,6]oxepino[3,4- e]indole-8-carboxylic acid hydrochloride (Cpd 84)

To a solution of Compound 82 (Example 11, 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, 0.15 mmol) followed by NaBH(OAc)₃ (34 mg, 0.15 mmol). 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. The desired fractions were lyophilized and treated with 2N HC1 in ether to provide the title compound as an HC1 salt.

LC-MS 329.0 [M+H]⁺, RT 1.10 min. 1H NMR (DMSO-d₆) δ: 13.81 (s, 1H), 12.88 (br. s, 1H), 7.45 (d, J=8.5 Hz, 1H), 6.64 (d, J=7.3 Hz, 1H), 4.29 (s, 2H), 4.15 (s, 2H), 3.50-3.54 (m, 2H), 3.03-3.08 (m, 2H), 2.85 (s, 3H). Example 13

7-Hydroxy-9-oxo-4,6,9,10-tetrahydro-lH-pyrido[2',3':5,6]oxepino[3,4-e]indole-8-carboxylic acid (Cpd 10)

Step 1: 8-Benzyl l-(tert-butyl) 7,9-bis(benzyloxy)-2,3,4,6-tetrahydro-lH- pyrido[2',3':5,6]oxepino[3,4-e]indole-l,8-dicarboxylate

To a solution of Intermediate 24 (76 mg, 0.11 mmol) in dichloromethane (5.0 mL) cooled at -78 °C was added a solution of DEOXO-FLUOR^® (brand of bis(2- methoxyethyl) amino sulfur trifluoride) in dichloromethane (1.0 M, 0.27 mL, 0.27 mmol) and cooled using a cooling bath for 1 hr. The bath was removed and the temperature was allowed to rise to 0 °C over approximately 1 hr. LC/MS indicated the reaction was completed. The mixture was treated with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3X). The organic extracts were combined, washed with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel column

chromatography with hexane and ethyl acetate (5 to 30% gradient) to provide the title compound (54 mg, 74%).

LC-MS 685.2 [M+H]⁺, RT 1.78 min. ¹H NMR (CDC1₃) δ: 7.75 (d, J=7.9 Hz, 1H), 7.43-7.48 (m, 2H), 7.29-7.42 (m, 14H), 5.56 (s, 2H), 5.36 (s, 2H), 5.17 (s, 2H), 4.39 (s, 2H), 4.35 (s, 2H), 4.06-4.14 (m, 2H), 3.25 (t, J=8.7 Hz, 2H), 1.62 (br. s, 9H).

Step 2: 8-Benzyl l-(tert-butyl) 7,9-bis(benzyloxy)-4,6-dihydro-lH- pyrido[2',3':5,6]oxepino[3,4-e]indole-l,8-dicarboxylate

A mixture of the product of Step 1 (54 mg, 0.08 mmol) and Mn0₂ (350 mg, 4.0 mmol) in dichloromethane (3.0 mL) was stirred at room temperature for 4 h, the filtered, evaporated and purified by silica gel column chromatography with EtOAc in hexanes (2 to 30% gradient) to give the title compound (29 mg, 53%).

1H NMR (CDC1₃) δ: 7.88 (d, J=8.5 Hz, 1H), 7.73 (d, J=3.8 Hz, 1H), 7.46 (d, J=0.6 Hz, 2H), 7.30-7.42 (m, 14H), 6.82 (d, J=3.8 Hz, 1H), 5.59 (s, 2H), 5.37 (s, 2H), 5.21 (s, 2H), 4.70 (s, 2H), 4.37 (s, 2H), 1.73 (s, 9H).

Step 3: 7-Hydroxy-9-oxo-4,6,9,10-tetrahydro-lH-pyrido[2',3':5,6]oxepino[3,4-e]indole-8- carboxylic acid A mixture of the product of Step 2 (29 mg) and 10% Pd/C (10 mg) in dichloromethane (1.0 mL) and methanol (1.0 mL) was stirred at room temperature under a hydrogen atmosphere for 1.5 h then evaporated. The residue was treated with a mixed solvent of dichloromethane and TFA (1: 1) and filtered. The filtrate was concentrated and triturated with ether. The solid was collected by filtration to provide the title compound (5 mg).

LC-MS 313.1 [M+H]⁺, RT 1.33 min. 1H NMR (DMSO-d₆) δ: 16.04 (br. s, IH), 13.90 (s, IH), 13.10 (br. s, IH), 11.63 (s, IH), 7.61 (d, J=7.9 Hz, IH), 7.55-7.59 (m, IH), 7.47 (d, J=8.5 Hz, IH), 6.81-6.85 (m, IH), 4.70 (s, 2H), 4.12 (s, 2H).

Example 14

2-[(Dimethylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,2,3,4,5,6,9, 10- octahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid hydrochloride (Cpd 88) To a solution of Compound 12 (Example 2, 10 mg) in TFA (2.0 mL) was added NaBH₃CN (40 mg). The mixture was stirred at room temperature overnight then diluted with methanol, treated with Celite and evaporated to dryness. The resultant solid mixture was put into a solid loading cartridge and purified by CI 8 column chromatography. The desired fractions were combined, lyophilized and treated with IN HCl in ether to provide the title compound as the HCl salt.

LC-MS 384.1, [M+H]⁺, RT 0.90 min. 1H NMR (DMSO- ₆) δ: 16.33 (br. s, IH), 13.79 (s, IH), 12.72 (s, IH), 10.43 (br. s, IH), 7.28 (d, J=8.2 Hz, IH), 6.56 (d, J=8.2 Hz, IH), 3.88- 4.01 (m, 2H), 3.40-3.47 (m, IH), 3.26-3.36 (m, 2H), 2.97-3.09 (m, IH), 2.79-2.89 (m, 11H), 2.39-2.46 (m, IH), 2.00-2.12 (m, 2H). Biological Examples

The following in vitro biological examples demonstrate the usefulness of the compounds of the present description for treating Neisseria gonorrhoeae or Neisseria meningitidis.

The antibacterial activity from a microbroth dilution method in either or both

Fastidious Broth (FB) and FB containing 40 mg/mL Human Serum Albumin (HSA), as indicated, may be represented by the minimum inhibitory concentration (MIC in μg/mL). The MIC value is the lowest concentration of drug which prevents macroscopically visible growth under test conditions.

In the following tables, a 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 **** 32 **** 60 ****

2 **** 33 **** 61 ****

3 **** 34 **** 62 ****

4 **** 35 **** 63 ****

5 **** 36 **** 64 ****

7 **** 37 **** 65 ****

8 **** 38 **** 66 ****

9 **** 39 **** 67 ****

11 **** 40 **** 68 ****

12 **** 41 **** 69 ****

13 **** 42 **** 70 ****

14 **** 43 **** 71 ****

15 **** 44 **** 72 ****

16 **** 45 **** 73 ****

17 **** 46 **** 74 ****

18 **** 47 **** 75 ****

19 **** 48 **** 76 ****

20 **** 49 **** 77 ****

21 **** 50 **** 78 ****

22 **** 51 **** 79 **** Cpd 13477 Cpd 13477 Cpd 13477

23 **** 52 **** 80 ****

24 **** 53 **** 81 ***

25 **** 54 **** 83 ****

26 **** 55 **** 84 ****

27 **** 56 **** 85 **

29 **** 57 **** 86 ****

30 **** 58 **** 87 ****

31 **** 59 **** 88 ****

Table 2

Cpd 13477 Cpd 13477 Cpd 13477

1 * 34 **** 58 ****

3 * 35 **** 59 ****

7 *** 36 **** 60 ***

8 *** 37 **** 61 ****

9 *** 38 **** 64 ****

11 **** 39 **** 65 ****

12 **** 40 **** 66 ****

13 **** 41 **** 67 ***

14 **** 42 **** 68 ****

15 **** 43 **** 69 ****

16 **** 44 **** 70 ****

17 *** 45 **** 71 ****

18 **** 46 **** 72 ****

19 **** 47 **** 73 ****

20 **** 48 **** 74 ****

21 **** 49 *** 75 **** Cpd 13477 Cpd 13477 Cpd 13477

22 **** 50 76 **** 24 **** 51 **** 77 **** 25 **** 52 **** 78 **** 26 **** 53 **** 79 29 **** 54 **** 81 30 **** 55 **** 86 31 **** 56 **** 87 32 **** 57 **** 88 **** 33 ****

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

1 46

2 47

3 48

4 49

5 50

6 51

7 52

8 53

9 54

10 55

11 56

12 57

13 58 Cpd 13478 13479 13480 13481 Cpd 13478 13479 13480 13481

14 59

15 60

16 61

17 62

18 63

19 64

20 65

21 66

22 67

23 68

24 69

25 70

26 71

27 72

29 73

30 74

31 75

32 76

33 77

34 78

35 79

36 80

37 81

38 82

39 83

40 84

41 85 Cpd 13478 13479 13480 13481 Cpd 13478 13479 13480 13481

42 86

43 87

44 88

45

Example 3

Antibacterial activity of test compounds against a streptomycin-resistant

onorrhoeae FA1090 isolate is compared in FB (Table 4) and in FB containing 40 mg/mLA (Table 5).

Table 4

Cpd FA1090 Cpd FA1090 Cpd FA1090

1 **** 8 **** 15 ****

2 **** 9 **** 16 ****

3 **** 11 **** 62 ****

4 **** 12 **** 63 ****

5 **** 13 **** 80 ****

7 **** 14 **** 81 ****

Table 5

Cpd FA1090 Cpd FA1090 Cpd FA1090

1 9 **** 16 ****

2 11 **** 62 ****

4 12 **** 63 ****

5 13 **** 80

7 **** 14 **** 81 ****

8 15 **** 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 AKl AK2 FA19 LG24

63

Example 5

Antibacterial activity of test compounds against N. gonorrhoeae tetracycline-resistant LGB24, penicillin-resistant LGB3, ampiciUin-resistant LGB50 and MS 11 isolates is shown in Table 7.

Table 7

Cpd LGB24 LGB3 LGB50 MS11

63

Example 6

Antibacterial activity of test compounds against the N. gonorrhoeae SP1364 isolate is shown in Table 8.

Table 8

Cpd SP1364 Cpd SP1364

**** ****

**** ^2 ****

29 ****

Example 7

Antibacterial activity of test compounds against N. meningitidis isolate 13090 is compared in FB (Table 9) and in FB containing 40 mg/mL HSA (Table 10).

Table 9

Cpd 13090 Cpd 13090

j2 **** 72 ****

^2 **** γ5 **** Cpd 13090 Cpd 13090

71 ****

Table 10

Cpd 13090 Cpd 13090

12 **** 72 ****

62 75 ****

71 ****

Example 8

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 began treatment with a combination of vancomycin HC1, streptomycin sulfate (0.6 mg and 0.3 mg, respectively, IP, BID) and trimethoprim sulfate (0.8 mg, PO, BID). The antibiotic combination was administered to control commensal flora induced by the high level of 17 -estradiol resulting from the implanted pellet. Combined antibiotic treatment continued from Day -2 to Day 1 of the study. After Day 1, mice were dosed with streptomycin only (0.6 mg, IP, QD).

On Day 0 of the study, mice were inoculated with 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 (ciprofloxacin, 30 mg/kg) and test compound group. The treatment groups were orally dosed with a single dose (mg/kg) with either vehicle control, positive control or test compound, each administered in a mixture of HPMC (0.5%) and Tween 80 (0.1%).

Results

Antibacterial efficacy of test compounds (Cpd) against SP1364 N. gonorrhoeae is shown in Table 10, 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 10

Cpd Dose % Drop

12 10 70 2.32

40 60 100 4.86

70 10 60 2.31

71 10 100 4.56

72 10 100 4.27

73 10 60 2.13

74 10 20 1.44

75 10 100 4.33 Example 9

Combinations with Antibacterial Agents

The in vitro effects of compounds described herein in combination with a known antibacterial or antibiotic agent may be investigated in various organisms using the microdilution checkerboard method for the measurement of additive or synergistic effect. Assays can be performed in a 96-well checkerboard titration format, with serial dilutions of each compound to identify the lowest MIC value ^g/mL) at which the combination completely inhibits colony formation. The ability of a combination of one or more compounds described herein with known agents to either act synergistically, additively, indifferently or antagonistically can be determined. A synergistic effect is demonstrated when the activity of the separate agents are combined and the result is greater than the expected arithmetic sum of each agents activity alone. The fractional inhibitory

concentration (FIC) is a quantitative measure of such drug interactions, where the fractional inhibition indices are calculated using the checkerboard method in a 96-well microtiter plate. Combined activity is synergistic when the FIC value is < 0.5; combined activity is additive when the FIC value is > 0.5 and < 2; combined activity that is not different from the agents alone when the FIC value is > 2 and < 4; and, combined activity is antagonistic when the FIC value is > 4.

Results

Compound 12 was tested in combination with certain antibiotic agents. Table 11 provides the FIC value and resulting activity for each combination.

Table 11

Agent FIC Activity

Ceftriaxone 0.6 Additive

Ciprofloxacin 0.7 Additive

Azithromycin 0.7 Additive

Without regard to whether a document cited herein was specifically and individually indicated as being incorporated by reference, all documents referred to herein are

incorporated by reference into the present application for any and all purposes to the same extent as if each individual reference was fully set forth herein. Having now fully described the subject matter of the claims, it will be understood by those having ordinary skill in the art that the same can be performed within a wide range of equivalents without affecting the scope of the subject matter or embodiments described herein. It is intended that the appended claims be interpreted to include all such equivalents.

Claims

What is claimed is:

1. A compound of Formula (I), Formula (II), Formula (III) or Formula (IV):

(I) (Π) (HI) (IV) or a form thereof, wherein,

the dashed line represents an optional double bond;

Z is O or -CH(R₄)-, provided that, when Z is O, then X is selected

C^galkenyl-amino-Ci-galkyl, C^galkynyl-amino-Ci-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 C₃_₁₄cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one, two or three substituents each selected from R₆;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci_galkyl;

R₄ is hydrogen or Ci_galkyl;

R5 is hydrogen, Ci_galkyl, amino, Ci_galkyl-amino, (C₁_galkyl)₂-amino,

R₆ is halogen, hydroxyl, cyano, Ci_galkyl, Ci_galkoxy, amino, Ci_galkyl-amino or

(C₁_galkyl)₂-amino;

with the proviso that a compound of Formula (I) is other than:

2. The compound of claim 1, wherein X is -CH(R₃)-, -CH(R₃)-CH(R₃)-, - -CH(R₃)-CH(R₃)-CH(R₃)-, -C(R₃)=C(R₃)-, -CH(R₃)-0- or -0-CH(R₃)-CH(R₃)-;

Z is O or -CH(R₄)-, 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,

C₂_galkenyl-amino-Ci_galkyl, C₂_galkynyl-amino-Ci_galkyl,

Ci-galkoxy-Ci-galkyl-amino-Ci-galkyl, (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,

substituted with one, two or three substituents each selected from R₆;

cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

wherein aryl is selected in each instance, when present, from phenyl;

wherein heterocyclyl is 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,

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci-galkyl;

R₄ is hydrogen or Ci-galkyl;

R₅ is hydrogen, Ci-galkyl, amino-Ci-galkyl, C oalkyl-amino-Ci-galkyl,

(C₁-₁oalkyl)₂-amino-C₁_₈alkyl or hydroxyl-Ci-galkyl; and,

(C₁_galkyl)₂-amino;

with the proviso that a compound of Formula (I) is other than:

3. The compound of claim 1, wherein,

-0-CH(R₃)-, -0-CH(R₃)-CH(R₃)-, -CH(R₃)-0-CH(R₃)- or -S-CH(R₃)-;

Z is O or -CH(R₄)-, 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 hydrogen, Ci-ioalkyl-amino-Ci-galkyl, (C₁_₁oalkyl)₂-amino-C₁_galkyl,

or heterocyclyl-Ci_galkyl,

wherein heterocyclyl is in each instance, when present, pyrrolidinyl;

R₂ is hydrogen or halogen;

R₃ is hydrogen or Ci-galkyl;

R₄ is hydrogen or C_halky!; R5 is hydrogen, Ci_galkyl, (C₁_₁oalkyl)₂-amino-C₁_₈alkyl or hydroxyl-Ci_galkyl; and,

R₆ is Ci-galkyl, amino, Ci_galkyl-amino or (C₁_galkyl)₂-amino;

with the proviso that a compound of Formula (I) is other than:

4. The compound of claim 1, wherein R 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,

(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;

with the proviso that a compound of claim 1 is other than 7-hydroxy-l-methyl-2-

5. The compound of claim 1, wherein,

Z is O or -CH(R₄)-, provided that, when Z is O, then X is selected

Ri is selected from hydrogen, (C₁_galkyl)₂-amino, amino-Ci-galkyl,

Ci-ioalkyl-amino-Ci-galkyl, (C₁_₁oalkyl)₂-amino-C₁_galkyl, C^galkenyl-amino-Ci-galkyl, hydroxyl-Ci-galkyl, C^_Hcycloalkyl-amino-Ci-galkyl, heterocyclyl or heterocyclyl-Ci-galkyl,

wherein each instance of C₃_₁₄cycloalkyl 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;

with the proviso that a compound of claim 1 is other than 7-hydroxy-l-methyl-2-

2-((ethylamino)methyl)-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid.

6. The compound of claim 1, wherein,

-0-CH(R₃)-, -0-CH(R₃)-CH(R₃)-, -CH(R₃)-0-CH(R₃)- or -S-CH(R₃)-;

Z is O or -CH(R₄)-, provided that, when Z is O, then X is selected

Cs-_Hcycloalkyl-amino-Ci-galkyl or heterocyclyl-Ci-galkyl,

wherein C₃_₁₄cycloalkyl is selected in each instance, when present, from cyclopropyl or

cyclobutyl; and,

wherein heterocyclyl is in each instance, when present, pyrrolidinyl; and,

R₆ is Ci-galkyl, amino, Ci-galkyl-amino or (C₁_galkyl)₂-amino;

with the proviso that a compound of Formula (I) is other than:

7-hydroxy- 1 -methyl-2-((methylamino)methyl)-9-oxo- 1,4,5,6,9,10- hexahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-carboxylic acid; and,

7. A compound or a form thereof selected from the group consisting of:

6-hydroxy-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5-h]quinoline-7-carboxylic acid

6- hydroxy-l-methyl-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5-h]quinoline-7- carboxylic acid

7- hydroxy-l-methyl-9-oxo- 1,4,5, 6,9, 10-hexahydropyrido[2',3':3,4]cyclohepta[ 1,2- e]indole-8-carboxylic acid

7-hydroxy-3-methyl-9-oxo-3,4,5,6,9,10-hexahydropyrido[3',2':6,7]cyclohepta[l,2- g]indole-8-carboxylic acid

7-hydroxy-l-(2-hydroxyethyl)-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7-hydroxy-9-oxo-4,5,9,10-tetrahydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole-8- carboxylic acid

7-hydroxy-l-methyl-9-oxo-4,5,9,10-tetrahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid

7-hydroxy-9-oxo-3,4,5,6,9,10-hexahydropyrido[3',2':6,7]cyclohepta[l,2-g]indole-8- carboxylic acid

7-hydroxy-9-oxo- 1,4,5, 6,9, 10-hexahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8- carboxylic acid

7-hydroxy-9-oxo-4,6,9,10-tetrahydro-lH-pyrido[2',3':5,6]oxepino[3,4-e]indole-8- carboxylic acid

7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-[(dimethylamino)methyl]-7 -hydroxy- l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7-hydroxy-l-methyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7-hydroxy-l-methyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-[(butan-2-ylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid 2-[(cyclobutylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

1- [2-(dimethylamino)ethyl]-7-hydroxy-9-oxo- 1,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7-hydroxy- l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2- [(tert-butylamino)methyl]-7 -hydroxy- l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7-hydroxy- l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7-hydroxy-2-[(methylamino)methyl]-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-[(dimethylamino)methyl]-7-hydroxy-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

6-hydroxy-2-[(methylamino)methyl]-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid

2-[(dimethylamino)methyl]-6-hydroxy-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid

6-hydroxy-8-oxo-2-[(propylamino)methyl]-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid

6-hydroxy-8-oxo-2-(pyrrolidin-l-ylmethyl)-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid

6- hydroxy-8-oxo-2-[(propan-2-ylamino)methyl]-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid

2-[(dimethylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l-methyl-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

7- hydroxy- l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid 7-hydroxy-l-methyl-2-[(methylamino)methyl] -9-oxo-l,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

2-[(ethylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

7-hydroxy-l-methyl-9-oxo-2-[(propylamino)methyl]-l,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

7-hydroxy-l-methyl-9-oxo-2-[(propan-2-ylamino)methyl] -1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

2-[(cyclobutylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

2-[(tert-butylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

7-hydroxy- l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

7-hydroxy- l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-[(dimethylamino)methyl]-7 -hydroxy- l,6-dimethyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-[(ethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7-hydroxy- l,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-[(tert-butylamino)methyl]-7 -hydroxy- l,6-dimethyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7-hydroxy- l,6-dimethyl-2-[(methylamino)methyl]-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid 7- hydroxy-l,6-dimethyl-9-oxo-2-[(propylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-[(dimethylamino)methyl]-8-hydroxy-l -methyl- lO-oxo-4,5, 6,7, 10,11-hexahydro- 1 H-pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

8- hydroxy-10-oxo-l,4,5,6,10,l l-hexahydropyrido[3',2':2,3]oxocino[5,4-e]indole-9- carboxylic acid

8-hydroxy-l-methyl-10-oxo-l,4,5,6,10,l l-hexahydropyrido[3',2':2,3]oxocino[5,4- e]indole-9-carboxylic acid

2-[(diethylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7-hydroxy- l-methyl-2-[(2-methylpyrrolidin-l-yl)methyl]-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7- hydroxy- l-methyl-2-{ [(2-methylpropyl)amino]methyl}-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-[(butylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-[(ethylamino)methyl]-8-hydroxy- l-methyl-10-oxo-4,5, 6,7, 10,11-hexahydro-lH- pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

2-{ [ethyl(methyl)amino]methyl}-8-hydroxy-l-methyl-10-oxo-4,5, 6,7, 10,11- hexahydro- 1 H-pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

8- hydroxy- 1-methyl- 10-oxo-2-(pyrrolidin- l-ylmethyl)-4,5, 6,7, 10,11-hexahydro- 1H- pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

8-hydroxy- 1-methyl- 10-oxo-2-[(propan-2-ylamino)methyl]-4,5,6,7, 10, 11-hexahydro- 1 H-pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

8-hydroxy- l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-10-oxo-4,5,6,7, 10,11- hexahydro- 1 H-pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

8-hydroxy- 1-methyl- 10-oxo-2-[(propylamino)methyl]-4,5,6,7, 10, 11-hexahydro- 1H- pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid (6R) -7 -hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

(6R)-2- { [ethyl (methyl)amino]methyl } -7-hydroxy- 1 ,6-dimethyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

(6R)-7-hydroxy-l,6-dimethyl-9-oxo-2-[(propylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

(6R)-7-hydroxy-l,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

(6R)-2-[(ethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

(6R)-2-[(dimethylamino)methyl] -7-hydroxy- l,6-dimethyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

(6S)-2-[(ethylamino)methyl] -7-hydroxy- 1 ,6-dimethyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

(6S)-2-[(dimethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

(6S)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

(6S)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-[(propylamino)methyl] - 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

(6S)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl] - 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

(6S)-2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-[(dimethylamino)methyl]-12-fluoro-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

12-fluoro-7-hydroxy-l-methyl-9-oxo-2-[(propylamino)methyl]-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

12-fluoro-7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid 4-hydroxy-2-oxo- 1,2,5, 6,7, 10-hexahydropyrido[3',2':6,7]cyclohepta[l,2-e]indole-3- carboxylic acid

7- hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5-e]indole-

8- carboxylic acid

7-hydroxy-l-methyl-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid

7- hydroxy-9-oxo-2,3,4,6,9,10-hexahydro-lH-pyrido[2',3':5,6]oxepino[3,4-e]indole-

8- carboxylic acid

1- ethyl-7-hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid

7- hydroxy-l-methyl-9-oxo-2,3,4,6,9,10-hexahydro-lH-pyrido[2',3':5,6]oxepino[3,4- e]indole-8-carboxylic acid

6- hydroxy-8-oxo-l,2,3,4,8,9-hexahydropyrido[2',3':5,6]pyrano[3,4-e]indole-7- carboxylic acid

8- hydroxy- 10-oxo- 1,2,3,4,5,6, 10, l l-octahydropyrido[3',2':2,3]oxocino[5,4-e]indole-

9- carboxylic acid

8-hydroxy- 1-methyl- 10-oxo- 1,2,3,4,5, 6, 10, l l-octahydropyrido[3',2':2,3]oxocino[5,4- e]indole-9-carboxylic acid, and

2- [(dimethylamino)methyl]-7 -hydroxy- l-methyl-9-oxo- 1,2,3,4,5,6, 9,10- octahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-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:

7- hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-[(dimethylamino)methyl]-7 -hydroxy- l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride 7-hydroxy-l-methyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

7-hydroxy-l-methyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-[(butan-2-ylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-[(cyclobutylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

1- [2-(dimethylamino)ethyl]-7-hydroxy-9-oxo- 1,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

7-hydroxy- l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2- [(tert-butylamino)methyl]-7 -hydroxy- l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

7-hydroxy- l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

7-hydroxy-2-[(methylamino)methyl]-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride 2-[(dimethylamino)methyl]-7-hydroxy-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

6-hydroxy-2-[(methylamino)methyl]-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid hydrochloride

2-[(dimethylamino)methyl]-6-hydroxy-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid hydrochloride

6-hydroxy-8-oxo-2-[(propylamino)methyl]-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid hydrochloride

6-hydroxy-8-oxo-2-(pyrrolidin-l-ylmethyl)-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid hydrochloride

6-hydroxy-8-oxo-2-[(propan-2-ylamino)methyl]-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid hydrochloride 2-[(dimethylamino)methyl] -7 -hydroxy- 1 -methyl-9-oxo- 1,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l-methyl-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

7-hydroxy-l-methyl-2-[(methylamino)methyl] -9-oxo-l,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

2-[(ethylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

7-hydroxy-l-methyl-9-oxo-2-[(propylamino)methyl] -1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

7-hydroxy-l-methyl-9-oxo-2-[(propan-2-ylamino)methyl] -1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

2-[(cyclobutylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

2-[(tert-butylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

7-hydroxy- l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

7-hydroxy- l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-[(dimethylamino)methyl]-7 -hydroxy- l,6-dimethyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-[(ethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

7-hydroxy- l,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride 2-[(tert-butylamino)methyl]-7 -hydroxy- 1 ,6-dimethyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

7-hydroxy-l,6-dimethyl-2-[(methylamino)methyl]-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

7-hydroxy-l,6-dimethyl-9-oxo-2-[(propylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-[(dimethylamino)methyl]-8-hydroxy-l -methyl- lO-oxo-4,5, 6,7, 10,11-hexahydro- 1 H-pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

2-[(diethylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

7-hydroxy- l-methyl-2-[(2-methylpyrrolidin-l-yl)methyl]-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

7- hydroxy- l-methyl-2-{ [(2-methylpropyl)amino]methyl}-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-[(butylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-[(ethylamino)methyl]-8-hydroxy- l-methyl-10-oxo-4,5, 6,7, 10,11-hexahydro-lH- pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

hydrochloride

8- hydroxy- 1-methyl- 10-oxo-2-(pyrrolidin- l-ylmethyl)-4,5, 6,7, 10,11-hexahydro- 1H- pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

8-hydroxy- 1-methyl- 10-oxo-2-[(propan-2-ylamino)methyl]-4,5,6,7, 10, 11-hexahydro- 1 H-pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride 8-hydroxy-l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-10-oxo-4,5,6,7, 10,11- hexahydro- 1 H-pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

hydrochloride

8-hydroxy- 1-methyl- 10-oxo-2-[(propylamino)methyl]-4,5,6,7,10, 11-hexahydro- 1H- pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

(6R) -7 -hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

(6R)-2- { [ethyl (methyl)amino]methyl } -7-hydroxy- 1 ,6-dimethyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

(6R)-7-hydroxy-l,6-dimethyl-9-oxo-2-[(propylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

(6R)-7-hydroxy-l,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

(6R)-2-[(ethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

(6R)-2-[(dimethylamino)methyl] -7-hydroxy- l,6-dimethyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

(6S)-2-[(ethylamino)methyl] -7-hydroxy- 1 ,6-dimethyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

(6S)-2-[(dimethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

(6S)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

(6S)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-[(propylamino)methyl] - 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

(6S)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl] - 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

(6S)-2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride 2-[(dimethylamino)methyl]-12-fluoro-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

12-fluoro-7-hydroxy-l-methyl-9-oxo-2-[(propylamino)methyl]-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

12-fluoro-7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

8- carboxylic acid hydrochloride

7-hydroxy-l-methyl-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid hydrochloride

8- carboxylic acid hydrochloride

1- ethyl-7-hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid hydrochloride

7- hydroxy-l-methyl-9-oxo-2,3,4,6,9,10-hexahydro-lH-pyrido[2',3':5,6]oxepino[3,4- e]indole-8-carboxylic acid hydrochloride

6-hydroxy-8-oxo-l,2,3,4,8,9-hexahydropyrido[2',3':5,6]pyrano[3,4-e]indole-7- carboxylic acid hydrochloride

9- carboxylic acid hydrochloride

8-hydroxy- 1-methyl- 10-oxo- 1,2,3,4,5, 6, 10, l l-octahydropyrido[3',2':2,3]oxocino[5,4- e]indole-9-carboxylic acid hydrochloride, and

2- [(dimethylamino)methyl]-7 -hydroxy- l-methyl-9-oxo- 1,2,3,4,5,6, 9,10- octahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-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 use of a compound of claim 1 or a form thereof in a method for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae and N. meningiditis in a subject in need thereof, comprising administering an effective amount of the compound or a form thereof to the subject. 10. A use of a compound or a form thereof in a method of use for treating or ameliorating wild-type or drug-resistant forms of N. gonorrhoeae in a subject in need thereof, comprising administering an effective amount of the compound or a form thereof to the subject, wherein the compound or a form thereof is selected from the group consisting of:

6-hydroxy-8-oxo-4,5,8,9-tetrahydro-lH-indolo[4,5-h]quinoline-7-carboxylic acid

7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid 2-[(dimethylamino)methyl]-7 -hydroxy- 1 -methyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7-hydroxy- l-methyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7-hydroxy- l-methyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-[(butan-2-ylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-[(cyclobutylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

6-hydroxy-8-oxo-2-(pyrrolidin-l-ylmethyl)-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid 6- hydroxy-8-oxo-2-[(propan-2-ylamino)methyl]-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid

2-[(dimethylamino)methyl] -7 -hydroxy- 1 -methyl-9-oxo- 1,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

7- hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

7-hydroxy-l-methyl-2-[(methylamino)methyl] -9-oxo-l,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[l,2-e]indole-8-carboxylic acid

2-[(ethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid 7-hydroxy-l,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7-hydroxy-l,6-dimethyl-2-[(methylamino)methyl]-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7- hydroxy-l,6-dimethyl-9-oxo-2-[(propylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

7-hydroxy- l-methyl-2-{ [(2-methylpropyl)amino]methyl}-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-{ [ethyl(methyl)amino]methyl}-8-hydroxy-l-methyl-10-oxo-4,5, 6,7, 10,11- hexahydro- 1 H-pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid 8-hydroxy- 1-methyl- 10-oxo-2-(pyrrolidin- l-ylmethyl)-4,5, 6,7, 10,11-hexahydro- 1H- pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

8-hydroxy- 1-methyl- 10-oxo-2-[(propan-2-ylamino)methyl]-4,5,6,7, 10,11-hexahydro- 1 H-pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

8-hydroxy- l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-10-oxo-4,5,6,7, 10, 11- hexahydro- 1 H-pyrido [2',3' : 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

8-hydroxy- 1-methyl- 10-oxo-2-[(propylamino)methyl]-4,5,6,7, 10, 11-hexahydro- 1H- pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid

7-hydroxy-l-methyl-2-((methylamino)methyl)-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-((ethylamino)methyl)-7-hydroxy-l-methyl-9-oxo- 1,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

(6R) -7 -hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

(6S)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-(pyrrolidin- 1 -ylmethyl)- 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid (6S)-7-hydroxy- 1 ,6-dimethyl-9-oxo-2-[(propylamino)methyl] - 1 ,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

2-[(dimethylamino)methyl]-12-fluoro-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

12-fluoro-7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid

4-hydroxy-2-oxo- 1,2,5, 6,7, 10-hexahydropyrido[3',2':6,7]cyclohepta[l,2-e]indole-3- carboxylic acid

8- carboxylic acid

l-ethyl-7-hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid

6-hydroxy-8-oxo-l,2,3,4,8,9-hexahydropyrido[2',3':5,6]pyrano[3,4-e]indole-7- carboxylic acid

9- carboxylic acid

8-hydroxy- 1-methyl- 10-oxo- 1,2,3,4,5, 6, 10, l l-octahydropyrido[3',2':2,3]oxocino[5,4- e]indole-9-carboxylic acid, and 2-[(dimethylamino)methyl]-7 -hydroxy- l-methyl-9-oxo- 1,2,3,4,5,6, 9,10- octahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-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 use of claim 10, wherein a compound salt or a form thereof is selected from the group consisting of:

7-hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-[(dimethylamino)methyl]-7 -hydroxy- l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

7-hydroxy-l-methyl-9-oxo-2-[(propylamino)methyl]- 1,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

6- hydroxy-8-oxo-2-[(propan-2-ylamino)methyl]-4,5,8,9-tetrahydro-lH-indolo[4,5- h]quinoline-7-carboxylic acid hydrochloride

2-[(dimethylamino)methyl] -7 -hydroxy- 1 -methyl-9-oxo- 1,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

7- hydroxy-l-methyl-9-oxo-2-(pyrrolidin-l-ylmethyl)- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

2-[(tert-butylamino)methyl] -7-hydroxy- 1 -methyl-9-oxo- 1,6,9,10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride 7-hydroxy-l-methyl-2-{ [(l-methylcyclopropyl)amino]methyl}-9-oxo- 1,6, 9,10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

7-hydroxy-l-methyl-2-{ [(l-methylcyclobutyl)amino]methyl}-9-oxo- 1,6,9, 10- tetrahydropyrido[2',3':3,4]cyclohepta[ 1 ,2-e]indole-8-carboxylic acid hydrochloride

7-hydroxy- l,6-dimethyl-9-oxo-2-[(propan-2-ylamino)methyl]- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-[(tert-butylamino)methyl]-7 -hydroxy- l,6-dimethyl-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

7-hydroxy- l,6-dimethyl-2-[(methylamino)methyl]-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

7-hydroxy- l,6-dimethyl-9-oxo-2-[(propylamino)methyl]- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

7-hydroxy- l-methyl-2-{ [(2-methylpropyl)amino]methyl}-9-oxo- 1,4,5, 6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride 2-[(butylamino)methyl]-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

hydrochloride

8-hydroxy- 1-methyl- 10-oxo-2-(pyrrolidin- l-ylmethyl)-4,5, 6,7, 10,11-hexahydro- 1H- pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

8-hydroxy- 1-methyl- 10-oxo-2-[(propan-2-ylamino)methyl]-4,5,6,7, 10, 11-hexahydro- 1 H-pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

hydrochloride

8-hydroxy- 1-methyl- 10-oxo-2-[(propylamino)methyl]-4,5,6,7,

10,

11-hexahydro- 1H- pyrido [2',3 ': 3 ,4] cycloocta[ 1 ,2-e] indole-9-carboxylic acid hydrochloride

7-hydroxy-l-methyl-2-((methylamino)methyl)-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-((ethylamino)methyl)-7-hydroxy-l-methyl-9-oxo- 1,4,5,6,9, 10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

(6R)-2-[(ethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride (6R)-2-[(dimethylamino)methyl]-7-hydroxy-l,6-dimethyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

(6S)-2-{ [ethyl(methyl)amino]methyl}-7-hydroxy-l,6-dimethyl-9-oxo-l,4,5,6,9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

2-[(dimethylamino)methyl]-12-fluoro-7-hydroxy-l-methyl-9-oxo- 1,4,5,6, 9,10- hexahydropyrido [2',3' : 3 ,4] cyclohepta[ 1 ,2-e] indole-8 -carboxylic acid hydrochloride

8- carboxylic acid hydrochloride

7-hydroxy- l-methyl-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid hydrochloride

8- carboxylic acid hydrochloride

l-ethyl-7-hydroxy-9-oxo-2,3,4,5,9,10-hexahydro-lH-pyrido[2',3':6,7]oxepino[4,5- e]indole-8-carboxylic acid hydrochloride

7-hydroxy- l-methyl-9-oxo-2,3,4,6,9,10-hexahydro-lH-pyrido[2',3':5,6]oxepino[3,4- e]indole-8-carboxylic acid hydrochloride 6-hydroxy-8-oxo-l,2,3,4,8,9-hexahydropyrido[2',3':5,6]pyrano[3,4-e]indole-7- carboxylic acid hydrochloride

9- carboxylic acid hydrochloride

2-[(dimethylamino)methyl]-7 -hydroxy- l-methyl-9-oxo- 1,2,3,4,5,6, 9,10- octahydropyrido [2',3 ': 3 ,4] cyclohepta[ 1 ,2-e] indole- 8-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 use 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 and N. meningiditis 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 and N. meningiditis in a subject in need thereof, comprising administering an effective amount of the compound or a form thereof to the subject.

15. 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 and N. meningiditis in a subject in need thereof, comprising administering an effective amount of the medicament to the subject.

16. 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 and N. meningiditis 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).

17. 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 and N. meningiditis 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).

18. 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.