WO2016040764A1

WO2016040764A1 - Carbonyl linked bicyclic heteroaryl n-benzimidazoles and analogs as antibiotic tolerance inhibitors

Info

Publication number: WO2016040764A1
Application number: PCT/US2015/049619
Authority: WO
Inventors: Robert Zahler; Dawei Cui; Ding Zhou
Original assignee: Spero Therapeutics, Inc.
Priority date: 2014-09-12
Filing date: 2015-09-11
Publication date: 2016-03-17

Abstract

The disclosure provides compounds and pharmaceutical compositions of includes carbonyl linked bicyclic heteroaryl N-benzimidazole compounds useful for treating chronic and acute bacterial infections. Certain of the compounds are compounds of general Formula (I) or a pharmaceutically acceptable salt or prodrug thereof. Certain compounds of this disclosure are MvfR inhibitors. MvfR inhibitors reduce the formation of antibiotic tolerant bacterial strains and are useful for treating Gram-negative bacterial infections and reducing the virulence of Pseudomonas aeruginosa. Methods of treating bacterial infections in a subject, including Pseudomonas aeruginosa infections, are also provided by the disclosure.

Description

CARBONYL LINKED BICYCLIC HETEROARYL N-BENZIMIDAZOLES AND ANALOGS AS

ANTIBIOTIC TOLERANCE INHIBITORS

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from US provisional application serial no. 62/049,670, filed September 12, 2014, which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

[0001] The present disclosure includes carbonyl linked bicyclic heteroaryl N-benzimidazole compounds and related compounds and methods of using such compounds. For example, the disclosure provides methods of using the compounds in treating acute and chronic bacterial infections.

BACKGROUND

[0002] Hard-to-eradicate, often unbeatable, infections including chronic wounds and infections associated with medical devices pose increasing threats to human health worldwide. Such infections are often refractory to antibiotics due to antibiotic resistant bacterial cells, and/or to antibiotic tolerance of a subpopulation of bacterial cells that are not antibiotic resistant mutants but rather "dormant" cells that survive antibiotic killing. Antibiotic tolerance is defined as the ability of a fraction of a susceptible bacterial population to survive exposure to normally lethal concentrations of bactericidal antibiotics. According to the existing paradigm, many chronic infections are therefore unbeatable.

[0003] The ligand activated transcriptional regulator, MvfR, plays a central role in controlling the pathology of acute bacterial infections, and the shift of Gram-negative bacteria from acute to chronic infection. MvfR inhibitors reduce virulence of Pseudomonas aeruginosa, a Gram-negative bacterial species, and reduce the formation of antibiotic resistant Pseudomonas strains in vitro.

SUMMARY

[0004] In a first embodiment, this disclosure includes compounds of Formula (I) and the pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof.

Formula (I) [0005] Within Formula I the variables, e.g. Y -Y¹², R^la, R^lb, V¹, V², X, W, and Z, carry the following definitions.

[0006] Each of Y¹, Y², Y³, Y⁴, Y⁹, Y¹⁰, Y¹¹ and Y¹² is independently selected from N, CH, and C(R²), wherein at least one of Y¹, Y², Y³, or Y⁴ is C(R²), and at least one of Y⁹, Y¹⁰, Y¹¹ and Y¹² is C(R²).

[0007] Each of Z, Y⁵, Y⁶, Y⁷, and Y⁸ is independently selected from N and C.

[0008] No more than three of Y¹, Y², Y³, Y⁴, Y⁵ and Y⁶ is N.

[0009] No more than three of Y⁷, Y⁸, Y⁹, Y¹⁰, Y¹¹ and Y¹² is N.

[0010] Each of V¹, V², and X and W is independently selected from N, N(R³), S, O, CH, and C(R²), wherein V¹ and V² are not simultaneously S or simultaneously O.

[0011] Each " " represents independently a single or a double bond, wherein at least one

===== in each ring is a double bond.

[0012] R^la and R^lb are independently selected from hydrogen, -CN, fluoro, and methyl, and, when Z is C, each of R^la and R^lb are additionally and independently selected from -OH and -NH₂; or R^la and R^lb are taken together with the carbon atom to which they are bound to form a cyclopropyl ring.

[0013] Each R² is independently selected from halogen, -OH, -N0₂, -CN, -Ci-C₆-alkyl, -C₂-C6-alkenyl, -C₂-C6-alkynyl, -(C₀-C₄-alkylene)-(heterocyclyl), -(C₂-C₄-alkenylene)- (heterocyclyl), -(C₂-C₄-alkynylene)-(heterocyclyl), -(C₀-C₄-alkylene)-(carbocyclyl),

-(C₂-C -alkenylene)-(carbocyclyl), -(C₂-C -alkynylene)-(carbocyclyl), or any two R² are optionally taken together with the carbon atoms to which they are bound to form an optionally substituted carbocyclyl or heterocyclyl.

[0014] Each R³ is independently selected from hydrogen, -Ci-C6-alkyl, -C₂-C6-alkenyl, -C₂-C6-alkynyl, -(C₀-C -alkylene)-(heterocyclyl), -(C₂-C -alkenylene)-(heterocyclyl),

-(C₂-C -alkynylene) -(heterocyclyl), -(C₀-C -alkylene)-(carbocyclyl), -(C₂-C -alkenylene)- (carbocyclyl), or -(C₂-C₄-alkynylene)-(carbocyclyl).

Or, R³ and a nitrogen atom to which it is bound is optionally taken together with an adjacent carbon atom and a R² bound to the carbon atom to form an optionally substituted heterocyclyl.

[0015] Each alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, heterocyclyl or carbocyclyl portion of R² and R³ is optionally and independently substituted; and one or more methylene units in the alkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene portion of R² and R³ is optionally and independently replaced with -0-, -S-, -N(R³)-, -S(=0)- or -S(=0)₂-.

[0016] Wherein the compound is other than:

[0017] The disclosure further includes a method of treating a bacterial infection in a subject, comprising administering a therapeutically effective amount of a compound, salt, solvate, or hydrate of Formula (I) or a prodrug thereof to a subject in need of such treatment. The compound of Formulae (I) may be administered as the only active agent or may be administered together with one or more additional active agents.

DETAILED DESCRIPTION

CHEMICAL DESCRIPTION AND TERMINOLOGY

[0018] Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. Unless clearly contraindicated by the context, each compound name includes the free acid or free base form of the compound as well as all pharmaceutically acceptable salts, solvates, and hydrates of the compound.

[0019] The term "Formula (I)" encompasses all compounds that satisfy Formula (I), including any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts, solvates, and hydrates of such compounds. "Formula (I)" includes all subgeneric groups of Formula (I) unless clearly contraindicated by the context in which this phrase is used.

[0020] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and/or". The open-ended transitional phrase "comprising" encompasses the intermediate transitional phrase "consisting essentially of and the close-ended phrase "consisting of." Claims reciting one of these three transitional phrases, or with an alternate transitional phrase such as "containing" or "including" can be written with any other transitional phrase unless clearly precluded by the context or art. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as"), is intended merely to for illustration and does not pose a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs.

[0021] Compounds of Formula (I) include all compounds of Formula (I) having isotopic substitutions at any position. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include ⁿC, ¹³C, and ¹⁴C. In some embodiments, any one or more hydrogen atoms are replaced with deuterium atoms.

[0022] An "active agent" means a compound (including a compound disclosed herein), element, or mixture that when administered to a subject, alone or in combination with another compound, element, or mixture, confers, directly or indirectly, a physiological effect on the subject. The indirect physiological effect may occur via a metabolite or other indirect mechanism.

[0023] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(0)NH2 is attached through carbon of the keto C(O) group.

[0024] An "aliphatic group" is a hydrocarbon group having the indicated number of carbon atoms in which the carbon atoms are covalently bound in single, double or triple covalent bonds in straight chains, branched chains, or non-aromatic rings. Aliphatic groups may be substituted.

[0025] "Alkyl" is a branched or straight chain saturated aliphatic hydrocarbon group, having the specified number of carbon atoms, generally from 1 to about 8 carbon atoms. The term Ci-C₆-alkyl as used herein indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms. Other embodiments include alkyl groups having from 1 to 6 carbon atoms, 1 to 4 carbon atoms or 1 or 2 carbon atoms, e.g. Ci-C₈-alkyl, Ci-C₄-alkyl, and Ci-C₂-alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, and sec-pentyl. [0026] "Alkenyl" is a branched or straight chain aliphatic hydrocarbon group having one or more double carbon-carbon bonds that may occur at any stable point along the chain, having the specified number of carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

[0027] "Alkynyl" is a branched or straight chain aliphatic hydrocarbon group having one or more triple carbon-carbon bonds that may occur at any stable point along the chain, having the specified number of carbon atoms. Examples of alkynyl include, but are not limited to, ethynyl and propynyl.

[0028] "Alkoxy" is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by an oxygen bridge (-0-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3- pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3- methylpentoxy.

[0029] "Alkylthio" indicates an alkyl group as defined above attached through a sulfur linkage, i.e. a group of the formula alkyl-S-. Examples include ethylthio and pentylthio.

[0030] "Alkanoyl" is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes through a carbonyl C(O) bridge. The carbonyl carbon is included in the number of carbons, that is C₂alkanoyl is a CH₃C(0)- group.

[0031] "Alkylester" is an alkyl group as defined herein covalently bound to the group it substitutes by an ester linkage. The ester linkage may be in either orientation, e.g., a group of the formula -OC(0)-alkyl or a group of the formula -C(0)0-alkyl.

[0032] "Aryl" indicates aromatic groups containing only carbon in the aromatic ring or rings. Typical aryl groups contain 1 to 3 separate, fused, or pendant rings and from 6 to about 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Aryl groups include, for example, phenyl, naphthyl, including 1- naphthyl, 2-naphthyl, and bi-phenyl.

[0033] A "carbocycle" is a monocyclic or bicyclic saturated, partially unsaturated, or aromatic ring system in which all ring atoms are carbon. Usually each ring of the carbocycle contains from 3-6 ring atoms and a bicyclic carbocycle contains from 7 to 10 ring atoms, but some other number of ring atoms may be specified. Unless otherwise indicated, the carbocycle may be attached to the group it substitutes at any carbon atom that results in a stable structure. When indicated the carbocyclic rings described herein may be substituted at any carbon atom if the resulting compound is stable. Examples of carbocycles include phenyl, naphthyl, tetrahydronaphthyl, cyclopropyl, cyclohexyl, and cyclohexenyl.

[0034] "Cycloalkyl" is a saturated hydrocarbon ring group, having the specified number of carbon atoms. Monocyclic cycloalkyl groups typically have from 3 to about 8 carbon ring atoms or from 3 to 6 (3, 4, 5, or 6) carbon ring atoms. Cycloalkyl substituents may be pendant from a substituted nitrogen, oxygen, or carbon atom, or a substituted carbon atom that may have two substituents may have a cycloalkyl group, which is attached as a spiro group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0035] "Halo" or "halogen" indicates any of fluoro, chloro, bromo, and iodo.

[0036] "Haloalkyl" indicates both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, and penta-fluoroethyl.

[0037] "Haloalkoxy" indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).

[0038] The term "heterocycle" indicates a monocyclic saturated, partially unsaturated, or aromatic ring containing from 1 to 4 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a bicyclic saturated, partially unsaturated, or aromatic heterocycle containing at least 1 heteroatom chosen from N, O, and S in one of the two rings of the two ring system and containing up to about 4 heteroatoms independently chosen from N, O, and S in each ring of the two ring system. Usually each ring of the heterocycle contains from 4-6 ring atoms but some other number of ring atoms may be specified. Unless otherwise indicated, the heterocycle may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. When indicated the heterocycles described herein may be substituted on carbon, sulfur, or nitrogen atom if the resulting compound is stable. It is preferred that the total number of heteroatoms in a heterocycle is not more than 4 and that the total number of S and O atoms in a heterocycle is not more than 2, more preferably not more than 1. Examples of heterocycles include, pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl,

benz[b]thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, dihydroisoindolyl, 5,6,7, 8-tetrahydroisoquinoline, pyrazolyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl. In certain embodiments a heterocycle is chosen from pyridinyl, pyrimidinyl, furanyl, thienyl, and pyrrolyl.

[0039] Additional examples of heterocycles include, but are not limited to, phthalazinyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzoisoxolyl,

dihydro-benzodioxinyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanonyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, benzotetrahydroiuranyl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, 5 pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl, coumarinyl, isocoumarinyl, chromanyl, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonyl, dihydrocoumarinyl,

dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, pyrirnidinyl N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide, indolyl N-oxide, indolinyl N oxide, isoquinolyl N-oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N- oxide, thiazolyl N-oxide, indolizinyl N oxide, indazolyl N-oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, tetrazolyl N- oxide, benzothiopyranyl S-oxide, and benzothiopyranyl S,S-dioxide.

[0040] "Heteroaryl" is a stable monocyclic aromatic ring having the indicated number of ring atoms which contains from 1 to 4, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5- to 7-membered aromatic ring which contains from 1 to 4, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Monocyclic heteroaryl groups typically have from 5 to 7 ring atoms. In some embodiments bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, that is, groups containing 9 or 10 ring atoms in which one 5- to

7-member aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heteroaryl group is not more than 2. It is particularly preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, oxazolyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridazinyl, pyridyl, pyrirnidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thiophenyl, triazolyl, benzo[i ]oxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxadiazolyl, dihydrobenzodioxynyl, furanyl, imidazolyl, indolyl, and isoxazolyl.

[0041] The term "mono- and/ or di-alkylamino" indicates secondary or tertiary alkyl amino groups, wherein the alkyl groups are independently chosen alkyl groups, as defined herein, having the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and

methyl-propyl-amino.

[0042] The term "substituted", as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When the substituent is oxo (i.e., =0) then 2 hydrogens on the atom are replaced. When an oxo group substitutes a heteroaromatic moiety, the resulting molecule can sometimes adopt tautomeric forms. For example a pyridyl group substituted by oxo at the 2- or 4-position can sometimes be written as a pyridine or hydroxypyridine. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture and subsequent formulation into an effective therapeutic agent. Unless otherwise specified, substituents are named into the core structure. For example, it is to be understood that aminoalkyl means the point of attachment of this substituent to the core structure is in the alkyl portion and alkylamino means the point of attachment is a bond to the nitrogen of the amino group.

[0043] Suitable groups that may be present on a "substituted" or "optionally substituted" position include, but are not limited to, e.g., halogen; cyano; -OH; oxo; -NH₂; nitro; azido; alkanoyl (such as a C₂-C₆ alkanoyl group); C(0)NH₂; alkyl groups (including cycloalkyl and (cycloalkyl) alkyl groups) having 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 8, or 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 8, or from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those having one or more thioether linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those having one or more sulfinyl linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those having one or more sulfonyl linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; aminoalkyl groups including groups having one or more N atoms and from 1 to about 8, or from 1 to about 6 carbon atoms; mono- or dialkylamino groups including groups having alkyl groups from 1 to about 6 carbon atoms; mono- or dialkylaminocarbonyl groups (i.e. alkylNHCO- or (alkyl l)(alkyl2)NCO-) having alkyl groups from about 1 to about 6 carbon atoms; aryl having 6 or more carbons and one or more rings, (e.g., phenyl, biphenyl, naphthyl, or the like, each ring either substituted or unsubstituted aromatic); arylalkyl having 1 to 3 separate or fused rings and from 6 to about 18 ring carbon atoms, with benzyl being an exemplary arylalkyl group; arylalkoxy having 1 to 3 separate or fused rings and from 6 to about 18 ring carbon atoms, with benzyloxy being an exemplary arylalkoxy group; or a saturated, unsaturated, or aromatic heterocycle having 1 to 3 separate or fused rings with 3 to about 8 members per ring and one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl,

tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl. Such heterocycles may be further substituted, e.g. with hydroxy, alkyl, alkoxy, halogen and amino. In certain embodiments "optionally substituted" includes one or more substituents independently chosen from halogen, hydroxyl, oxo, amino, cyano, -CHO, -C0₂H, -C(0)NH₂, Ci-C6-alkyl, C₂-C6-alkenyl, C₁-C6- alkoxy, C₂-C6-alkanoyl, Ci-C6-alkylester, (mono- and di-Ci-C6-alkylamino)C₀-C₂-alkyl, (mono- and di-Ci-C6-alkylamino)(CO)Co-C₂-alkyl, Ci-C₂-haloalkyl, Ci-C₂haloalkoxy, and heterocyclic substituents of 5-6 members and 1 to 3 N, O or S atoms, i.e. pyridyl, pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and pyrrolidinyl, each of which heterocycle can be substituted by amino, C₁-C6- alkyl, Ci-C₆-alkoxy,.or -CONH₂.

[0044] A "dosage form" means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like.

[0045] "Pharmaceutical compositions" are compositions comprising at least one active agent, such as a compound or salt, solvate, or hydrate of Formula (I) or a prodrug thereof, and at least one other substance, such as a carrier. Pharmaceutical compositions optionally contain one or more additional active agents. When specified, pharmaceutical compositions meet the U.S. FDA's GMP (good manufacturing practice) standards for human or non-human drugs. "Pharmaceutical combinations" are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat a disorder, such as a Gram-negative bacterial infection.

[0046] "Pharmaceutically acceptable salts" includes derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Salts of the present compounds further include solvates of the compounds and of the compound salts.

[0047] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines or nitrogen-containing heteroaryl rings (e.g. pyridine, quinoline, isoquinoline); alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, H0₂C-(CH₂)_n-C0₂H where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in G. Steffen Paulekuhn, et al, Journal of Medicinal Chemistry 2007, 50, 6665 and Handbook of

Pharmaceutically Acceptable Salts: Properties, Selection and Use, P. Heinrich Stahl and Camille G. Wermuth Editors, Wiley-VCH, 2002.

[0048] The term "carrier" applied to pharmaceutical compositions/combinations of the disclosure refers to a diluent, excipient, or vehicle with which an active compound is provided.

[0049] A "pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition/ combination that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the present application includes both one and more than one such excipient.

[0050] A "subject" is a human or non-human animal in need of medical treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment. In some embodiments the subject is a human patient.

[0051] "Providing" means giving, administering, selling, distributing, transferring (for profit or not), manufacturing, compounding, or dispensing.

[0052] "Treatment," as used herein includes providing a compound of this disclosure such as a compound of any of Formulae (I), either as the only active agent or together with at least one additional active agent sufficient to: (a) inhibiting the disease, i.e. arresting its development; and (b) relieving the disease, i.e., causing regression of the disease and in the case of a bacterial infection to eliminate or reduce the virulence of the infection in the subject. "Treating" and "treatment" also means providing a therapeutically effective amount of a compound of the disclosure as the only active agent or together with at least one additional active agent to a subject having or susceptible to a bacterial infection.

"Prophylactic treatment" includes administering an amount of a compound of the disclosure sufficient to significantly reduce the likelihood of a disease from occurring in a subject who may be predisposed to the disease but who does not have it.

[0053] A "therapeutically effective amount" of a pharmaceutical composition/ combination is an amount effective, when administered to a subject, to provide a therapeutic benefit, such as to decrease the morbidity and mortality associated with bacterial infection and/ or effect a cure. In certain circumstances a subject suffering from a microbial infection may not present symptoms of being infected. Thus a therapeutically effective amount of a compound is also an amount sufficient to significantly reduce the detectable level of microorganism in the subject's blood, serum, other bodily fluids, or tissues. The disclosure also includes, in certain embodiments, using compounds of the disclosure in prophylactic treatment and therapeutic treatment. In the context of prophylactic or preventative treatment, a "therapeutically effective amount" is an amount sufficient to significantly decrease the incidence of or morbidity and mortality associated with bacterial infection. For example, prophylactic treatment may be administered when a subject is known to be at enhanced risk of bacterial infection, such cystic fibrosis or ventilator patients. A significant reduction is any detectable negative change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p < 0.05.

[0054] The term "prodrug" refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms. For example, a disclosed compound may be released by metabolic action (such as by esterase, amidase, phosphatase, oxidative and or reductive metabolism) in various locations (such as in the intestinal lumen or upon transit of the intestine, blood or liver) or in the absence of metabolism (such as pH-sensitive, cyclization-dependent cleavage of the prodrug moiety in the lung or plasma). Prodrugs are well known in the art (for example, see Nature Reviews Drug Discovery 2008, 7, 255; Current Topics in Medicinal Chemistry 2011, 11, 2265; Molecules 2008, 13, 519 and Molecules 2007, 12, 2484).

[0055] For example, if a compound of the disclosure or its pharmaceutically acceptable salt, hydrate or solvate 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 group such as Ci-C₈-alkyl, (C₂-Ci₂ alkyl)carbonyloxymethyl, l-(alkylcarbonyloxy)ethyl having from 4 to 9 carbon atoms, 1 -methyl- 1- (alkylcarbonyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-l- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3- phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2-alkyl)amino(C₂-C₃-alkyl) (such as beta-dimethylaminoethyl), carbamoyl-(Ci-C₂-alkyl), N,N-di(Ci-C₂-alkyl)carbamoyl-(Ci-C₂-alkyl), and piperidino-, pyrrolidino- or morpholino-(C₂-C₃-aikyl).

[0056] Similarly, if a compound of the disclosure contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-C₆-alkyl)carbonyloxymethyl, l-((Ci-C₆-alkyl)carbonyloxy)ethyl, l-methyl-l-((Ci-C₆- alkyl)carbonyloxy)ethyl, (Ci-C₆-alkoxy)carbonyloxymethyl, N-(Ci-C₆-alkoxy)carbonylaminomethyl, succinoyl, (d-Cs-alkyFtcarbonyl, -P(0)(OH)₂, -P(0)(OH)(0-C_!-C₆-alkyl), _, -P(0)(0-Ci-C₆-alkyl)_2> glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate) or alpha-aminoacyl, wherein the alpha-aminoacyl is derived from the natural L-aminoacids. [0057] If a compound of the disclosure incorporates an amine functional group, a prodrug can be formed, for example, by creation of an amide or carbamate, an as (C₁-C6- alkyl)carbonyloxymethylcarbonyl derivative, a l-((Ci-C6-alkyl)carbonyloxyethylcarbonyl) derivative, an (oxodioxolenyl)methyl derivative, a N-Mannich base, imine or enamine. In addition, a secondary amine can be metabolically cleaved to generate a bioactive primary amine, or a tertiary amine can metabolically cleaved to generate a bioactive primary or secondary amine. In addition, for active agents that contain tertiary amines or aromatic amines (such a pyridine), the corresponding N-oxides can serve as prodrugs. For examples, see Simplicio, et al, Molecules 2008, 13, 519 and references therein; Boyd, S.A., et al, J. Med. Chem. 1994, 37, 2991 and WO 1997010223.

CHEMICAL DESCRIPTION

[0058] Formulae (I) include all subformulae thereof. In certain situations, the compounds of any of Formulae (I) may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g. asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For compounds having asymmetric centers, it should be understood that all of the optical isomers and mixtures thereof are encompassed. In these situations, single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. Resolution of the racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example using a chiral HPLC column. In addition, compounds with carbon-carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds being included in the present disclosure.

[0059] Where a compound exists in various tautomeric forms, the disclosure is not limited to any one of the specific tautomers, but rather includes all tautomeric forms.

[0060] Certain compounds are described herein using a general formula that includes variables, e.g. R4 - R₉. Unless otherwise specified, each variable within such a formula is defined independently of other variables. Thus, if a group is said to be substituted, e.g. with 0-2 R*, then the group may be substituted with up to two R* groups and R* at each occurrence is selected independently from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0061] In addition to compounds and salts of Formula (I) disclosed in the SUMMARY section, the disclosure includes embodiments in which any of the following conditions are met. 0062] (1) The portion of the compound represented by:

each R⁴ is independently selected from hydrogen and R²; and

each R ^c is independently selected from hydrogen and R ^a. 0063] (2) The portion of the compound represented by:

each R^4a is independently selected from hydrogen, chloro, cyano, fluoro, -CF₃, and -OCH₃, wherein at least one R^4a is chloro or cyano;

R^4b is selected from hydrogen, chloro, cyano, -CH₃, -C(0)NH₂, and -C(0)NH(CH₃); and R^4c is selected from hydrogen, cyano, -OH, -NH₂, and -CH₃. [0064] (3) In certain embodiments each R ^a is independently selected from hydi

chloro, -OCH₃, and cyano, wherein at least one R^4a is chloro or cyano;

R^4b is hydrogen or chloro; and

R^4c is selected from hydrogen, cyano, and -OH.

0065] (4) The portion of the compound represented by

0066] (5) The portion of the compound represented by

, wherein:

R^3a is selected from hydrogen and optionally substituted C1 -C4 alkyl; and

R⁵ is selected from halogen, cyano, optionally substituted -O-heterocyclyl and optionally substituted -O-carbocyclyl.

[0067] (6) In certain embodiments R⁵ is selected from halogen, cyano, optionally substituted pyridyloxy, optionally substituted pyrimidinyloxy, optionally substituted pyrazinyloxy, optionally substituted pyridazinyloxy, optionally substituted phenoxy and optionally substituted cyclohexyloxy.

[0068] (7) In certain embodiments R⁵ is selected from chloro, cyano, pyridin-3 -yloxy, pyridin-3- yloxy, pyrazin-2-yloxy, pyrimidin-2-yloxy, pyrimidin-5-yloxy, 2-me thy lpyridin-5 -yloxy, 6-aminopyridin- 2-yloxy, 2-aminopyridin-4-yloxy, 2-aminopyridin-4-yloxy, 2-methylpyridin-3-yloxy, 4-methylpyridin-3- yloxy, 5-methylpyridin-3-yloxy, 5-methoxypyridin-3-yloxy, 3-hydroxyphenyl, 4-hydroxyphenyl, 3- aminocarbonylphenyl, 4-aminocarbonylphenyl, 4-hydroxycyclohexyl, 3,4-dihydroxycyclohexyl, pyridazin-4-yloxy, pyridazin-3-yloxy, 2-methylpyridin-3-yloxy, and 2-aminopyridin-4-yloxy.

[0069] (8) In certain embodiments R⁵ is selected from chloro, cyano, pyridin-3 -yloxy, pyridin-3- yloxy, pyrazin-2-yloxy, pyrimidin-2-yloxy, pyrimidin-5-yloxy, 2-me thy lpyridin-3 -yloxy, 5- methylpyridin-3 -yloxy, 2-aminopyridin-4-yloxy, 5-methoxypyridin-3-yloxy and 2-methylpyridin-5- yloxy.

[0070] (9) In certain embodiments R^3a is selected from hydrogen, 2-hydroxy-2-methylpropyl, dimethylaminocarbonylmethyl, morpholin-4-ylethyl, pyrrolidin-l-ylethyl, dimethylaminoethyl, 2- hydroxyethyl, methyl, and 3-hydroxy-3-methylpropyl.

[0071] (10) In certain embodiments R^3a is selected from hydrogen, 2-hydroxy-2-methylpropyl, dimethylaminocarbonylmethyl, morpholin-4-ylethyl, and pyrrolidin-l-ylethyl.

[0072] In certain embodiments both R^la and R^lb are hydrogen.

[0073] (11) The disclosure includes a compound having Structural Formula la or salt thereof:

Any one of structures Ia-1 to Ia-8 is within this embodiment. In this embodiment: each R⁴ is independently selected from hydrogen and R² as defined in claim 1 ; and each R^4c is independently selected from hydrogen and R^2a as defined in claim 1.

[0074] (12) The disclosure also includes compounds having any one of structural Formulae Ia-1 to Ia-8, wherein

R² is cyano or R² is -O-heteroaryl (having five or 6 ring atoms with 1 , 2, or 3 ring atoms being independently chosen from N, O, and S) and -O-aryl, each of which is unsubstituted or substituted with 1 to 3 substituents independently chosen from halogen, cyano, hydroxyl, amino, -C(0)NH₂, -CHO, Q- C₄alkyl, Ci-C₄alkoxy, C₂-C₄alkanoyl, mono- and di-(d- C₄alkylamino)Co-C₂alkyl, (C3-C₆cycloalkyl)Co-C₂alkyl, and mono- and di-(d- C₄alkyl)carboxamide ;

R³ is hydrogen or R³ is Ci-C₄alkyl, which is unsubstituted or substituted with hydroxyl, amino, cyano, mono-or di-Ci-C₄alkylamino, mono- and di-(Ci-C₄alkyl)carboxamide, C₃-C₆cycloalkyl, C₄-C₇heterocycloalkyl (having 1 or 2 heteroatoms independently chosen from N, O, and S), R⁴ is independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -C(0)NH₂, d- C₄ alkyl, Ci-C alkoxy, mono- and di-(Ci-C alkylamino)C₀-C₂alkyl, (C₃-C₆cycloalkyl)C₀-C₂alkyl, and mono- and di-(Ci-C alkyl)carboxamide; and

R^4c is hydrogen, hydroxyl, cyano, or Ci-C₂alkyl.

0075] (13) The disclosure includes a compound having Structural Formula lb or salt thereof:

(Ib), wherein:

R^3a is selected from hydrogen and optionally substituted Ci-C alkyl; and

each R^4a is independently selected from hydrogen, halo, cyano, optionally substituted Ci- C alkyl and optionally substituted -O-C₁-C4 alkyl, wherein at least one R^4a is halo or cyano;

R^4b is selected from hydrogen, halo, cyano, optionally substituted Ci- C₄

alkyl, -C(0)NH₂, -C(0)NH(C C₄ alkyl) and -C(0)N(d- C₄ alkyl)₂;

R^4c is selected from hydrogen, cyano, -OH, -NH₂, d- C₄ alkyl, NH(d- C₄ alkyl), - N(d- C₄ alkyl)₂ and -CH₃; and

R⁵ is selected from cyano, optionally substituted -O-heterocyclyl and optionally

substituted -O-carbocyclyl.

[0076] Any of the above conditions or variable definitions may be combined so long as a stable compound results. [0077] The disclosure includes prodrugs of Formula I. For example the disclosure includes prodrugs of the following formulas:

where each of the variables, e.g. Y^Y¹¹, R^la, R^lb, and R⁵ may carry any of the definitions set forth in this disclosure.

[0078] L¹ is a bond or a Ci-C6-alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl linker, and one or more methylene units in the alkyl, alkenyl, or alkynyl portion are optionally and independently replaced with O , S, N(R⁶) , S(O) or S(0)₂;

L² is a Ci-C6-alkyl, C₂-C₆alkenyl, or C₂-Cealkynyl linker, and one or more methylene units in the alkyl, alkenyl, or alkynyl portion are optionally and independently replaced with O , S, N(R⁶) , S(O) or S(0)₂; and

PD is a water-solublizing prodrug well known in the art such as but not limited to P(0)(OH)₂ or an alpha-aminoacyl, wherein the alpha-aminoacyl is derived from the natural L-aminoacids.

[0079] The disclosure includes, but is not restricted to, the following prodrugs:

METHODS OF TREATMENT

[0080] The disclosure includes a method of treating a bacterial infection in a subject by administering an effective amount of one or more compounds of the disclosure to a subject at risk for a bacterial infection or suffering from a microbial infection. Treatment of human patients is particularly contemplated. However, treatment of non-human subjects is within the scope of the disclosure. The disclosure includes treatment or prevention of microbial infections in fish, amphibians, reptiles or birds, but a preferred embodiment of the disclosure includes treating mammals.

[0081] In some embodiments, the bacterial infection or antibiotic-tolerant or antibiotic -resistant infection is caused by a Gram-negative bacterium.

[0082] In an embodiment of any of the methods of this disclosure, the microbial infection is the result of a pathogenic bacterial infection. Examples of pathogenic bacteria include, without limitation, bacteria within the genera Aerobacter, Aeromonas, Acinetobacter, Agrobacterium, Bacillus, Bacteroides, Bartonella, Bordetella, Brucella, Burkholderia, Calymmatobacterium, Campylobacter, Citrobacter, Clostridium, Corynebacterium, Enterobacter, Enterococcus, Escherichia, Francisella, Haemophilus, Hafnia, Helicobacter, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Proteus, Providencia, Pseudomonas, Salmonella, Serratia, Shigella, Staphylococcus, Streptococcus, Treponema, Xanthomonas, Vibrio, and Yersinia. Specific examples of such bacteria include Vibrio harveyi, Vibrio cholerae, Vibrio parahemolyticus, Vibrio alginolyticus, Pseudomonas phosphoreum, Pseudomonas aeruginosa, Yersinia enterocolitica, Escherichia coli, Salmonella typhimurium, Haemophilus influenzae, Helicobacter pylori, Bacillus subtilis, Borrelia burgdorferi, Neisseria meningitidis, Neisseria gonorrhoeae, Yersinia pestis, Campylobacter jejuni, Mycobacterium tuberculosis, Enterococcus faecalis, Streptococcus pneumoniae, Streptococcus pyogenes, Klebsiella pneumoniae, Burkholderia cepacia, Acinetobacter baumannii, Staphylococcus epidermidis, and Staphylococcus aureus. [0083] In some embodiments, the Gram-negative bacterium is a Pseudomonas, e.g., P.

aeruginosa.

[0084] In some embodiments, the Gram-negative bacterium is Burkholderia species.

[0085] In some embodiments, the Gram-negative bacterium is Acinetobacter, e.g., A. baumannii.

[0086] In some embodiments, the Gram-negative bacterium is an Enterobacteriaceae, e.g., Klebsiella pneumonia, e.g., Escherichia coli, e.g., Enterobacter cloacae, e.g., Serratia marcescens, e.g., Salmonella typhimurium, e.g., Shigella dysenteriae, e.g., Proteus mirabilis, e.g., Citrobacter freundii, e.g., Yersinia pestis.

[0087] In some embodiments, the infection is a polymicrobial infection, e.g., an infection comprising more than one organism. In some embodiments, the infection comprises at least one of the organisms listed above, e.g., one or more oi Pseudomonas, e.g., P. aeruginosa, Klebsiella, e.g., Klebsiella pneumoniae, and/or Acinetobacter, e.g., A. baumannii.

[0088] In some embodiments, the methods further include administering an additional active agent in combination with a compound of the disclosure, such as an antibiotic selected from the group consisting of but not limited to: beta-lactams such as penicillins, cephalosporins, carbacephems, cephamycins, carbapenems, monobactams, quinolones including fluoroquinolones and similar DNA synthesis inhibitors, tetracyclines, aminoglycosides, macrolides, glycopeptides, chloramphenicols, glycylcyclines, lincosamides, lipopeptides, lipodepsipeptides, such as daptomycin, and oxazolidinones.

[0089] In some embodiments, the bacterial infection is an upper and lower respiratory tract infection, pneumonia, bacteremia, a systemic infection, sepsis and septic shock, a urinary tract infection, a gastrointestinal infection, endocarditis, a bone infection, central nervous system infections such as meningitis, or an infection of the skin and soft tissue.

[0090] In some embodiments, the subject is a mammal, e.g., a human or non-human mammal. In some embodiments, the methods include treating one or more cells, e.g., cells in a culture dish.

[0091] In one aspect, the present disclosure features a method of treating a Gram-negative infection in a subject, the method comprising administering to said subject in need of such treatment a therapeutically effective amount of a compound described herein.

[0092] In some embodiments, the Gram-negative infection is caused by Pseudomonas aeruginosa.

[0093] In other embodiments the disclosure includes treating an infection caused by Gram- positive bacteria, such as Staphylococcus epidermidis and Staphylococcus aureus.

[0094] In some embodiments, the subject is a trauma patient or a burn patient suffering from a burn or skin wound. [0095] In a further aspect, the present disclosure features a method of reducing bacterial tolerance in a subject, the method comprising administering to said subject a therapeutically effective amount of a compound described herein.

[0096] In some embodiments, the method further includes identifying said subject suffering from an infection with bacteria resistant to antimicrobial therapy.

[0097] The disclosure includes methods of treatment in which a compound or composition of the disclosure is administered orally, topically, intravenously, parenterally, or inhaled.

[0098] A compound of the disclosure may be administered about 1 to about 5 times per day. Daily administration or post-periodic dosing may be employed. Frequency of dosage may also vary depending on the compound used, the particular disease treated and the bacteria causing the disease. It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

AGRICULTURAL METHODS

[0099] The disclosure also includes methods of treating bacterial infection in plants and fungal crops (e.g. mushrooms) comprising contacting a compound of the Formula I with a plant or fungal organism.

[0100] The plant may be an agricultural crop plant, such as a tobacco plant or a tomato plant .For example Pseudomonas species also can be involved in agricultural damage. Some of Pseudomonas syringae's numerous pathovars can be plant pathogens. For example P. syringae pathovar tabacii, phaseolicola, and tomato are pathogenic to plants. Pseudomonas agarici and Pseudomonas

tolaasii are pathogens of cultivated mushrooms. The compounds of this disclosure can are useful for reducing or eliminating the virulence of such Pseudomonal pathovars to plant and fungal crops.

PHARMACEUTICAL COMPOSITIONS

[0101] The disclosure includes the process for making a pharmaceutical composition containing at least one compound of Formula I. An embodiment comprises mixing one or more of the present compounds and an optional pharmaceutically acceptable carrier; and includes those compositions resulting from such a process, which process includes conventional pharmaceutical techniques.

[0102] The compositions of the disclosure include ocular, oral, nasal, transdermal, topical with or without occlusion, intravenous (both bolus and infusion), inhalable, and injection (intraperitoneally, subcutaneously, intramuscularlyor parenterally) formulations. The composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto- injector device, or suppository; for administration ocularly, orally, intranasally, sublingually, parenterally, or rectally, or by inhalation or insufflation.

[0103] The dosage form containing the composition of the disclosure contains an effective amount of the active ingredient necessary to provide a therapeutic effect by the chosen route of administration. The composition may contain from about 5,000 mg to about 0.5 mg (preferably, from about 1,000 mg to about 0.5 mg) of a compound of the disclosure or salt form thereof and may be constituted into any form suitable for the selected mode of administration.

[0104] In one embodiment of the disclosure, the pharmaceutical composition may be a parenteral formulation suitable for parenteral administration via injection or infusion. A parenteral formulation may consist of the active ingredient dissolved in or mixed with an appropriate inert liquid carrier. Acceptable liquid carriers usually comprise aqueous solvents and other optional ingredients for aiding solubility or preservation. Such aqueous solvents include sterile water, Ringer's solution, or an isotonic aqueous saline solution. Other optional ingredients include vegetable oils (such as peanut oil, cottonseed oil, and sesame oil), and organic solvents (such as solketal, glycerol, and formyl). A sterile, non-volatile oil may be employed as a solvent or suspending agent. The parenteral formulation is prepared by dissolving or suspending the active ingredient in the liquid carrier whereby the final dosage unit contains from 0.005 to 10% by weight of the active ingredient. Other additives include preservatives, isotonizers, solubilizers, stabilizers, and smoothing agents. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.

[0105] In another embodiment, the pharmaceutical composition of this disclosure may be a composition formulated for administration directly to the lungs by inhalation, such as an aerosol formulation. Known aerosol drug delivery systems include, for example, a unit dose dry-powder inhaler, a dry powder pulmonary device, a pressurized metered dose inhaler, a metered-dose inhaler, a nebulizer, and the like.

[0106] In another embodiment, the pharmaceutical compositions of this disclosure may be formulated for oral administration. Compositions of the disclosure suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions.

[0107] In another embodiment, the pharmaceutical compositions of this disclosure may formulated for topical administration, including topical administration to the eye. For ocular administration, the composition is preferably in the form of an ophthalmic composition. The ophthalmic compositions are preferably formulated as eye -drop formulations and filled in appropriate containers to facilitate administration to the eye, for example a dropper fitted with a suitable pipette.

EXAMPLES ABBREVIATIONS

BIOLOGICAL METHODS

[0108] Experiments were performed to identify compounds that inhibit the MvfR regulon without altering growth, ultimately attenuating infection. MvfR is a LysR-type transcriptional regulator that directs 4-hydroxy-2-alkylquinolines (HAQs) synthesis, including that of its ligands,

4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS). MvfR regulates the production of many virulence factors including pyocyanin, one of the many toxins secreted by

Pseudomonas aeruginosa. Both MvfR and PQS have been demonstrated as essential for pathogenesis in several host models.

[0109] MvfR promotes the production of HAQs by binding to and activating the pqs operon, which encodes enzymes for HAQ synthesis. Anthranilic acid (AA), derived from the phnAB, kynABU, and trpEG pathways, is the precursor for HAQs. Pqs A encodes an anthranilate -coenzyme A ligase, which activates anthranilic acid and catalyzes the first committed step to HAQ production. The exact roles of PqsB and PqsC are unknown, though both show homology to acyl-carrier-proteins and both are required for HHQ and PQS production. PqsD is a condensing enzyme that along with PqsA has been shown to be necessary and sufficient for the production of 2,4-dihydroxyquinoline (DHQ), a molecule whose biological role has yet to be determined. The final gene of the operon, PqsE encodes for a putative hydrolase, and while the protein is not required for the synthesis of HAQs, it is necessary for pyocyanin production. See Melissa Starkey, et al., PLOS Pathogens 2014, 10(8), el004321 and references therein.

[0110] Inhibition of Pyocyanin production is correlated with reduced P. aeruginosa infectivity. HHQ and PQS inhibition is also correlated with reduced P. aeruginosa infectivity. PQS inhibition is correlated with reduced infectivity of other bacterial pathogens as PQS is known to affect oxygen consumption and cell to cell communication of other Gram-negative and Gram-positive bacteria (Toyofuku, M. et al., Microbes Environ. (2010) 25(1): 1-7).

EXAMPLE 1. SYNTHESIS OF 2-(5,6-DICHLORO-1H-BENZO[D]IMIDAZOL-1-YL)-1-(6-(PYRIDIN -3- YLOXY)-1H-INDOL-3-YL)ETHANONE (Compound 100)

[0111] Step A. 3-(4-Methyl-3-nitrophenoxy)pyridine. To a mixture of 4-fluoro-l -methyl -2- nitrobenzene (9.0 g, 58.0 mmol) in NMP (120 mL) were added pyridin-3-ol (6.1 g, 63.8 mmol) and K₂C0₃ (12 g, 87.0 mmol). The reaction mixture was stirred at 160°C for 21 hr and filtered. The filtrate was partitioned between EtOAc and H₂0. The organic layer was separated, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (2.3 g, 17% yield) as brown oil. LC-MS: m/z 231 (M+H)⁺.

[0112] Step B. 6-(pyridin-3-yloxy)-lH-indole. To a mixture of 3-(4-methyl-3-nitrophenoxy) pyridine (2.3 g, 10.0 mmol) in DMF (10 mL) were added l,l-dimethoxy-N,N-dimethylmethanamine (1.8 mL, 14.0 mmol) and pyrrolidine (1.2 mL, 14.0 mmol). The reaction mixture was stirred at 115°C for 4hr then concentrated under reduced pressure. The residue was dissolved in EtOAc (20 mL), followed by addition of Pd/C (400 mg) under N₂ atmosphere. The resulting mixture was stirred at r.t. under hydrogen (1 atm) overnight and filtered. The filtrate was partitioned between EtOAc and H₂0. The organic layer was separated, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (2.0 g, 95% yield) as brown solid. LC-MS: m z 211 (M+H)⁺. [0113] Step C. l-(Phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indole. To a mixture of 6-(pyridin-3- yloxy)-lH-indole (500 mg, 2.4 mmol) in anhydrous THF (8 mL) at 0°C was added NaH (115mg, 2.9 mmol, 40 wt). The reaction mixture was stirred at 0°C for 30 min, followed by addition of

benzenesulfonyl chloride (0.3 mL, 2.4 mmol). The resulting mixture was stirred at 0 °C for another 1 hr, then quenched with ice- water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (550 mg, 65% yield) as yellow oil. LC-MS: m/z 351 (M+H)⁺.

[0114] Step D. 2-Chloro-l-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone. To a mixture of l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol (500 mg, 1.4 mmol) in anhydrous DCM (8 mL) at 0°C was added A1C1₃ (370 mg, 2.8 mmol), followed by addition of a solution of 2-chloroacetyl chloride (0.22 mL, 2.8 mmol) in anhydrous DCM (1 mL). The mixture was stirred at 55 °C for 4 hr, then quenched with aq. HC1 (0.1 N, 10 drops) and partitioned between DCM and H₂0. The organic layer was separated, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified by gel column chromatography to afford the desired product (500 mg, 83% yield) as yellow solid. LC-MS: m/z 427 (M+H)⁺.

[0115] Step E. 2-(5,6^ichloro-lH-benzo[d]imidazol-l-yl)-l-(l-^henylsulfonyl)-6-^yridin -3- yloxy)-lH-indol-3-yl)ethanone . To a mixture of 2-chloro-l-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH- indol-3-yl)ethanone (100 mg, 0.23 mmol) in DMF (3 mL) were added 5,6-dichloro-lH- benzo[d] imidazole (44 mg, 0.23 mmol) and K₂C0₃ (95 mg, 0.69 mmol). The reaction mixture was stirred at r.t. for 2hr, then partitioned between EtOAc and H₂0. The organic layer was washed with aq. LiCl (10% wt) and brine, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure to afford the crude product (100 mg) which was used in the next step without further purification. LC-MS: m/z 577 (M+H)⁺.

[0116] Step F. 2-(5,6-Dichloro-lH-benzo[d]imidazol-l-yl)-l-(6-^yridin-3-yloxy)-lH-indol -3- yljethanone. To a mixture of 2-(5,6-dichloro-lH-benzo[d]imidazol-l -yl)-l-(l-(phenylsulfonyl)-6- (pyridin-3-yloxy)-lH-indol-3-yl)ethanone (100 mg, 0.17 mmol) in MeOH (1 mL) was added a solution of NaOH (21 mg, 0.54 mmol) in H₂0 (1 mL). The reaction mixture was stirred at r.t. for 1 hr and then partitioned between EtOAc and H₂0. The organic layer was separated, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford the desired product (15 mg, 20% yield) as brown solid. LC-MS: m/z 437 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 8.62 (s, 1H), 8.37 (d, = 13.3 Hz, 3H), 8.10 (d, = 8.6 Hz, 1H), 7.98 (s, 2H), 7.41 (s, 2H), 7.21 (d, = 1.9 Hz, 1H), 7.02 (dd, = 8.6, 2.1 Hz, 1H), 5.86 (s, 2H). [0117] The procedure set forth above in Example 1 was used to produce the following the compounds using the appropriate starting materials.

[0118] 2-(5,6-Dichloro-lH-benzo[d]imidazol-l-yl)-l-(6-(pyrazin-2-yloxy)-lH-indol-3- yl)ethanone (Compound 102)

[0119] LC-MS: m/z 438 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 8.65 (s, 1H), 8.54 (s, 1H), 8.46 - 8.30 (m, 2H), 8.20 (s, 1H), 8.10 (d, / = 8.6 Hz, 1H), 7.99 (s, 2H), 7.40 (d, = 1.5 Hz, 1H), 7.07 (dd, / = 8.6, 1.7 Hz, 1H), 5.87 (s, 2H).

[0120] 2-(5,6-Dichloro-lH-benzo[d]imidazol-l-yl)-l-(6-(pyrimidin-5-yloxy)-lH-indol-3-

[0121] LC-MS: m/z: 438 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 8.98 (s, 1H), 8.64 (s, 1H), 8.60 (s, 2H), 8.37 (s, 1H), 8.12 (d, = 8.7 Hz, 1H), 7.98 (d, = 2.5 Hz, 2H), 7.32 (d, = 2.2 Hz, 1H), 7.08 (dd, / = 8.6, 2.2 Hz, 1H), 5.86 (s, 2H).

[0122] 2-(5,6-Dichloro-lH-benzo[d]imidazol-l-yl)-l-(6-(pyrimidin-2-yloxy)-lH-indol-3-

[0123] LC-MS: m/z: 438 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.26 (d, = 2.3 Hz, 1H), 8.64 (t, J = 3.8 Hz, 3H), 8.39 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 0.5 Hz, 2H), 7.38 (d, J = 2.0 Hz, 1H), 7.26 (t, = 4.8 Hz, 1H), 7.05 (dd, = 8.6, 2.1 Hz, 1H), 5.87 (s, 2H). [0124] 3-(2-(5,6-Dichloro-lH-benzo[d]imidazol-l-yl)acetyl)-lH-indole-6-carbonitrile Compound 113)

[0125] LC-MS: m/z: 369 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 8.85 (s, IH), 8.37 (s, IH), 8.22 (d, = 8.3 Hz, IH), 8.10 (s, IH), 8.00 (d, = 7.1 Hz, 2H), 7.58 (d, = 8.3 Hz, IH), 5.89 (s, 2H).

[0126] 2-(lH-Benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone

[0127] LC-MS: m/z: 369 (M+H)⁺. NMR (400 MHz, DMSO-d₆) δ 12.18 (s, IH), 8.67 (s, IH), 8.39 (d, = 1.3 Hz, IH), 8.36 - 8.34 (m, IH), 8.25 (s, IH), 8.19 (s, IH), 8.10 (d, = 8.6 Hz, IH), 7.71 - 7.66 (m, IH), 7.53 - 7.47 (m, IH), 7.41 (d, J = 2.5 Hz, IH), 7.21 (dd, J = 9.8, 3.0 Hz, 3H), 7.01 (dd, J = 8.6, 2.2 Hz, IH), 5.80 (s, 2H).

[0128] 2-(5-chloro- IH-indazol- 1-yl)- l-(6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone

[0129] LC-MS: m/z 403 (M+H)⁺. H NMR (600 MHz, DMSO-d₆) δ 12.11 (s, IH), 8.58 (s, IH), 8.38 (s, IH), 8.36 - 8.31 (m, IH), 8.11 (s, IH), 8.08 (d, = 8.4 Hz, IH), 7.89 (d, = 1.8 Hz, IH), 7.66 (d, = 9.0 Hz, IH), 7.44 - 7.36 (m, 3H), 7.18 (d, = 1.8 Hz, IH), 6.99 (dd, = 9.0, 2.4 Hz, IH), 5.94 (s, 2H). EXAMPLE 2. SYNTHESIS OF 2-(6-CHLORO-1H-BENZO[D]IMIDAZOL-2-YLTHIO)-1-(1-(2-HYDROXY-2- 108)

[0130] Step A. 2-(5,6-Dichloro-lH-benzo[d]imidazol-l-yl)-l-(l-(2-hydroxy-2-methylpropyl)-6- (pyridin-3-yloxy)-lH-indol-3-yl)ethanone. A mixture of 2-(5,6-dichloro-lH-benzo[d]imidazol-l-yl)-l- (6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone (50 mg, 0.115 mmol), Cs₂C0₃ (37 mg, 0.114 mmol), and 2,2-dimethyloxirane (17 mg, 0.228 mmol) in DMF (2 mL) was stirred at 100°C for 1 hr then diluted with EtOAc. The resulting mixture was washed with aq. LiCl (10 wt). The organic layer was dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 2-(5,6-dichloro-lH-benzo[d]imidazol-l-yl)-l-(l-(2-hydroxy-2-methylpropyl)-6-(pyridin-3-yloxy)- lH-indol-3-yl)ethanone (4 mg, 7% yield ) as white solid. LC-MS: m/z 509 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.28 - 8.40 (m, 3H), 8.08 - 8.15 (m, 1H), 7.98 (br. s., 2H), 7.56 - 7.63 (m, 1H), 7.29 - 7.42 (m, 2H), 6.96 - 7.05 (m, 1H), 5.85 (s, 2H), 4.71 - 4.92 (m, 1H), 4.09 - 4.28 (m, 2H).

EXAMPLE 3. SYNTHESIS OF 2-(5,6-DICHLORO-1H-BENZO[D]IMIDAZOL-1-YL)-1-(1-METHYL-6- PYRIDIN-3-YLOXY)-1H-INDOL-3-YL)ETHANONE (Compound 135)

[0131] Step A. l-Methyl-6-(pyridin-3-yloxy)-lH-indole. To a mixture of 6-(pyridin-3-yloxy)- lH-indole (500 mg, 2.4 mmol) in anhydrous DCM (10 mL) at 0 °C was added NaH (114 mg, 2.9 mmol, 40 w/w). The reaction mixture was stirred at that temperature for 30 min, followed by addition of Mel (0.15 mL, 2.4 mmol). The resulting mixture was stirred at 0°C for another 1 hr, then quenched with ice- water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified by column chromatography to afford the desired product (300 mg, 56% yield) as yellow oil. LC-MS: m/z 225 (M+H)⁺.

[0132] Step B. 2-chloro-l-(l-methyl-6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone. To a mixture of l-methyl-6-(pyridin-3-yloxy)-lH-indole (300 mg, 1.3 mmol) in anhydrous DCM (5 mL) at 0 °C was added A1C1₃ (178mg, 1.3 mmol), followed by addition of a solution of 2-chloroacetyl chloride (0.09mL, 1.0 mmol) in anhydrous DCM (1 mL). The mixture was stirred at that temperature for 3hr, then quenched with aq. HC1 (0.1N, 10 drops) and extracted with DCM. The organic layer was separated, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified by gel column chromatography to afford the desired product (180 mg, 46% yield) as yellow solid. LC-MS: m/z 301 (M+H)⁺.

[0133] Step C. 2-(5,6-dichloro-lH-benzo[d]imidazol-l-yl)-l-(l-methyl-6-(pyridin-3-yloxy)-lH- indol-3-yl)ethanone. To a mixture of 2-chloro-l-(l-methyl-6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone (70 mg, 0.23 mmol) in DMF (3 mL) were added 5,6-dichloro-lH-benzo[d]imidazole (43 mg, 0.23 mmol) and K₂C0₃ (95 mg, 0.69 mmol). The reaction mixture was stirred at r.t. for 2hr, then quenched with H₂0 and extracted with EtOAc. The combined organic layers were washed with aq. LiCl (10% wt) and brine, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford the desired product (20 mg, 20% yield) as yellow solid. LC-MS: m/z 451 (M+H)⁺. LC-MS: m/z 451 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.38 (d, = 3.6 Hz, 2H), 8.34 (dd, = 4.3, 1.6 Hz, 1H), 8.11 (d, = 8.6 Hz, 1H), 7.98 (d, = 5.5 Hz, 2H), 7.44 (d, = 2.0 Hz, 1H), 7.39 (dd, / = 5.6, 3.6 Hz, 2H), 7.05 (dd, / = 8.6, 2.1 Hz, 1H), 5.82 (s, 2H), 3.91 (s, 3H).

EXAMPLE 4. SYNTHESIS OF 2-(5,6-DICHLORO-1H-BENZO[D]IMIDAZOL-1-YL)-1-(6-(PYRIDIN-3- -1H- INDAZOL-3-YL)ETHANONE (Compound 101)

[0134] Step A. l-(6-(Pyridin-3-yloxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl) ethanone. To a mixture of l-(6-(pyridin-3-yloxy)-lH-indazol-3-yl)ethanone (2.5 g, 9.87 mmol) and PTSA (2.08 g, 10.68 mmol) in THF (20 mL) was added 3,4-dihydro-2H-pyran (1.66 g, 19.74 mmol). The reaction mixture was stirred at r.t. for 2 hr till completion. The resulting mixture was partitioned between EtOAc and water. The organic layer was separated, washed with saturated aq. NaHC0₃, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified via flash column chromatography to give l-(6-(pyridin-3-yloxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)ethanone (3.2 g, 96.1 % yield) . LC-MS: m/z 338 (M+H)⁺.

[0135] Step B. 2-Chloro-l-(6-(pyridin-3-yloxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3- yljethanone. A mixture of l-(6-(pyridin-3-yloxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3- yl)ethanone (300 mg, 0.889 mmol) and TEA (117 mg, 1.16 mmol) in DCM (10 mL) was cooled to below -5°C, followed by addition of TMSOTf (396 mg, 1.78 mmol). The mixture was stirred at that temperature for 2 hr, followed by addition of NCS (119 mg, 0.889 mmol) in one portion. The resulting mixture was stirred at that temperature for anther lhr, then diluted with EtOAc and washed with saturated aq.

NaHC0₃. The organic layer was separated, dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to give 2-chloro-l-(6-(pyridin-3-yloxy)-l-(tetrahydro-2H- pyran-2-yl)-lH-indazol-3-yl)ethanone (200 mg, 60.5% crude yield) as yellow semi-solid which was used directly in the next step without further purification. LC-MS: m/z 372 (M+H)⁺.

[0136] Step C. 2-(5,6-Dichloro-lH-benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy)-l- (tetrahy dro-2H-pyran-2-yl)-lH-indazol-3-yl)ethanone. A mixture of 2-chloro-l-(6-(pyridin-3-yloxy)-l- (tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)ethanone (30 mg, 0.081mmol), 5,6-dichloro-lH- benzo[d] imidazole (15 mg, 0.081 mmol) and K₂C0₃ (22 mg, 0.162 mmol) in DMF (2 mL) was stirred at r.t. for 2 hr, then diluted with EtOAc and washed with aq. LiCl (10%wt). The organic layer was separated, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure to give 2-(5,6-dichloro-lH- benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)ethanone (35 mg, 83% crude yield) as yellow semi-solid which was used directly in the next step without further purification. LC-MS: m/z 522 (M+H)⁺.

[0137] Step D. 2-(5,6-Dichloro-lH-benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy)-lH-indazol- 3-yl)ethanone . A mixture of 2-(5,6-dichloro-lH-benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy)-l- (tetrahydro-2H-pyran-2-yl)-lH-indazol-3-yl)ethanone (35 mg, 0.067 mmol) in a mixed solvent of aq. HC1 (2N, 10 mL) and MeOH (10 mL) was stirred at 60°C for 3 hr, then quenched with saturated aq. NaHC0₃, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The residue was purified via prep-HPLC to give 2-(5,6-dichloro- lH-benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy)-lH-indazol-3-yl)ethanone (19 mg, 64.5% yield) as white solid. LC-MS: m/z 438 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, = 2 Hz, 1H), 8.43 (dd, J = 2, 4 Hz, 3H), 8.38 (s, 1H), 8.10 (d, / = 8 Hz, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.51 - 7.59 (m, 1H), 7.43 - 7.50 (m, 1H), 7.26 (d, = 2 Hz, 1H), 7.14 (dd, = 2, 8 Hz, 1H), 6.07 (s, 2H)

[0138] The procedure set forth above in Example 3 was used to produce the following compounds using the appropriate starting materials.

[0139] 2-(5,6-Dichloro-lH-benzo[d]imidazol-l-yl)-l-(l-methyl-6- (pyridin-3-yloxy)-lH-

[0140] LC-MS: m/z: 452 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 8.44 - 8.47 (m, 2H), 8.38 (s, 1H), 8.12 (d, = 8.8 Hz, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 7.46 - 7.56 (m, 3H), 7.17 - 7.20 (m, 1H), 6.05 (s, 2H), 4.21 (s, 3H)

[0141] 2-(5,6-Dichloro-lH-benzo[d]imidazol-l-yl)-l-(6-(pyridin -3-yloxy)imidazo[l,5- 37)

[0142] LC-MS: m/z 438 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 8.62 - 8.55 (m, 2H), 8.53 (d, = 2.8 Hz, 1H), 8.45 (dd, = 4.6, 1.2 Hz, 1H), 8.37 (s, 1H), 8.12 (d, = 9.7 Hz, 1H), 7.96 (m, 2H), 7.63 (m, 1H), 7.49 (dd, = 8.3, 4.7 Hz, 1H), 7.39 (dd, = 9.7, 2.0 Hz, 1H), 5.97 (s, 2H).

EXAMPLE 5. SYNTHESIS OF 5,6-DICHLORO-1-(2-OXO-2-(6-(PYRIDIN-3-YLOXY)-1H-INDOL-3-

[0143] Step A. 5,6-Dichloro-lH-indole-3-carbonitrile. To a mixture of 5,6-dichloro-lH-indole (279 mg, 1.5 mmol) in DMF (10 mL) at 0°C was added drop wise sulfurisocyanatidic chloride (426 mg, 3 mmol). The reaction mixture was slowly warmed to r.t. over 2 hr, then poured into ice -water (30 mL) and filtered. The solid was collected and purified by flash column chromatography to afford 5,6-dichloro-lH- indole-3-carbonitrile (180 mg, 57% yield) as yellow solid. LC-MS: m/z 211 (M+H) ⁺.

[0144] Step B. 5₎6-Dichloro-l-(2-oxo-2-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3- yl)ethyl)-lH-indole-3-carbonitrile. To a mixture of 5,6-dichloro-lH-indole-3-carbonitrile (53 mg, 0.25 mmol) in DMF (12 mL) were added 2-chloro-l-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3- yl)ethanone (106 mg, 0.25 mmol) and K₂C0₃ (69 mg, 0.5 mmol). The reaction mixture was stirred at r.t. for 1 hr then quenched with aq. LiCl (10%wt, 30 mL) and extracted with DCM (30 mL). The organic layer was separated, dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to afford 5,6- dichloro-l-(2-oxo-2-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3-yl)ethyl)-lH-indole-3- carbonitrile (150 mg, quant, crude yield) which was directly used in the next step without further purification. LC-MS: m/z 601 (M+H) ⁺.

[0145] Step C. 5₎6-Dichloro-l-(2-oxo-2-(6-(pyridin-3-yloxy)-lH-indol-3-yl)ethyl)-lH-indole-3- carbonitrile . To a suspension of 5,6-dichloro-l-(2-oxo-2-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH- indol-3-yl)ethyl)-lH-indole-3-carbonitrile (150 mg, 0.25 mmol) in THF/H₂0 (18 mL, 2/1) was added NaOH (50 mg, 1.25 mmol). The reaction mixture was stirred at r.t. for 2 hr then extracted with DCM (20 mL). The organic layer was separated, dried over anhydrous Na₂S0_4i and concentrated under reduced pressure. The residue was purified via prep-HPLC to give 5,6-dichloro-l-(2-oxo-2-(6-(pyridin-3-yloxy)- lH-indol-3-yl)ethyl)-lH-indole-3-carbonitrile (20 mg, 18% yield) as white solid. LC-MS: m/z: 461 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.19 (s, 1H), 8.61 (s, 1H), 8.43 (s, 1H), 8.39 (s, 1H), 8.35 (dd, = 3.8, 2.1 Hz, 1H), 8.10 (s, 1H), 8.08 (d, = 8.6 Hz, 1H), 7.97 (s, 1H), 7.44 - 7.38 (m, 2H), 7.21 (d, = 2.1 Hz, 1H), 7.01 (dd, = 8.6, 2.2 Hz, 1H), 5.88 (s, 2H).

EXAMPLE 6. SYNTHESIS OF 2-(6-CHLORO-1H-IMIDAZO[4,5-B]PYRIDIN-1-YL)-1-(6-(PYRIDIN-3- YLOXY)-1H-INDOL-3-YL)ETHANONE (Compound 110) AND 2-(6-CHLORO-3H-IMIDAZO[4,5-

[0146] Step A. 6-Chloro-3H-imidazo[4,5-b]pyridine. A mixture of 5-chloropyridine-2,3-diamine (288 mg, 2 mmol) in triethyl orthoformate (8 mL) was stirred at 100°C for 2 hr then concentrated under reduced pressure. The residue was purified by flash column chromatography to give 6-chloro-3H- imidazo[4,5-b]pyridine (190 mg, 63% yield) as yellow solid. LC-MS: m/z 154 (M+H)⁺.

[0147] Step B. 2-(6-Chloro-3H midazo[4,5-b]pyridin-3-yl)-l-(l-(phenylsulfonyl)-6-(pyridin-3- yloxy)-lH-indol-3-yl)ethanone and 2-(6-chloro-lH-imidazo[4,5-b ]pyridin-l-yl)-l-(l-(phenylsulfonyl)- 6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone. To a mixture of 6-chloro-3H-imidazo [4,5-b]pyridine (39 mg, 0.25 mmol) in DMF (10 mL) were added 2-chloro-l-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH- indol-3-yl)ethanone (106 mg, 0.25 mmol) and K₂C0₃ (69 mg, 0.5 mmol). The reaction mixture was stirred at r.t. for 2 hr then quenched with aq. LiCl solution (10%wt, 30 mL) and extracted with DCM (30 mL). The organic layer was separated, dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to afford a mixture of 2-(6-chloro-3H midazo[4,5-b]pyridin-3-yl)-l-(l-(phenylsulfonyl)-6- (pyridin-3-yloxy)-lH-indol-3-yl)ethanone and 2-(6-chloro-lH-imidazo[4,5-b]pyridin-l-yl)-l-(l- (phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone (135 mg, quant, crude yield) which were used in the next step without further purification. LC-MS: m/z 544 (M+H) ⁺.

[0148] Step C. 2-(6-Chloro-lH midazo[4,5-b]pyridin-l-yl)-l-(6-(pyridin-3-yloxy)-lH-indol-3- yljethanone and 2-(6-chloro-3H midazo[4,5-b]pyridin-3-yl)-l-(6-(pyridin-3-yloxy)-lH-indol-3- yljethanone. To a mixture of 2-(6-chloro-3H midazo[4,5-b]pyridin-3-yl)-l-(l-(phenylsulfonyl)-6- (pyridin-3-yloxy)-lH-indol-3-yl)ethanone and 2-(6-chloro-lH-imidazo[4,5-b]pyridin-l-yl)-l-(l- (phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone (135 mg, 0.25 mmol) in THF/H₂0 (18 mL, 2: 1) was added NaOH (50 mg, 1.25 mmol). The reaction mixture was stirred at r.t. for 2 hr then extracted with DCM (20 mL). The organic layer was separated, dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The residue was purified via prep-HPLC to give 2-(6-chloro-lH-imidazo[4,5- b]pyridin-l-yl)-l-(6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone (15 mg, 12% yield) as white solid. H NMR (400 MHz, DMSO-d₆) δ 12.20 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 8.44 (d, = 2.2 Hz, 1H), 8.39 (s, 1H), 8.37 - 8.33 (m, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.09 (d, = 8.6 Hz, 1H), 7.41 (d, J = 2.6 Hz, 2H), 7.21 (d, = 1.9 Hz, 1H), 7.01 (dd, / = 8.6, 2.0 Hz, 1H), 5.87 (s, 2H).

[0149] And 2-(6-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-l-(6-(pyridin-3-yloxy)-lH-indol-3- yl)ethanone (18 mg, 15% yield) as white solid. LC-MS: m/z: 404(M+H)⁺. H NMR (400 MHz, DMSO- d₆) δ 12.20 (s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 8.39 (s, 1H), 8.35 (dd, = 5.4, 2.5 Hz, 2H), 8.32 (d, = 2.1 Hz, 1H), 8.08 (d, = 8.6 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.19 (d, = 2.1 Hz, 1H), 7.00 (dd, = 8.6, 2.1 Hz, 1H), 5.82 (s, 2H).

EXAMPLE 7. SYNTHESIS OF 2-(5-CHLORO-1H-IMIDAZO[4,5-H]QUINOLIN-1-YL)-1-(6-(PYRIDIN-3- - 1H-INDOL-3-YL)ETHANONE (Compound 109)

[0150] Step A. 5-Chloro-8-nitroquinoline . Glycerol (11.4mL, 156.05mmol) was preheated to 160°C for lhr then cooled down to 110°C, followed by addition of 5-chloro-2-nitroanoline (10 g, 58 mmol) and sodium iodide (0.17 g, 1.2 mmol). The reaction mixture was vigorously stirred at 110°C to get a homogenous tar then heated to 150°C, followed by dropwise addition of cone, sulfuric acid (7.1 mL, 133.3 mmol). The mixture was stirred at 150°C for 45min then cooled to r.t. and partitioned between DCM and aq. H₂S0₄ (50 wt). The organic layer was dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to give the crude product (7.33 g, 61% yield). LC-MS: m/z 209 (M+H)⁺.

[0151] Step B. 5-Chloroquinolin-8-amine . A mixture of 5-chloro-8-nitroquinoline (5 g, 23.97 mmol), and Zn (14.4 g, 239.69 mmol) in DCM (200 mL) was cooled to 0°C, followed by dropwise addition of AcOH (15.7 g, 239.69 mmol). The reaction mixture was stirred at 0°C for 2 hr then filtered. The filtrate was concentration under reduced pressure. The residue was purified via flash column chromatography, yielding the desired product (3.5 g, 82% yield). LC-MS: m/z 179 (M+H)⁺.

[0152] Step C. N-(5-chloroquinolin-8-yl)acetamide. A mixture of 5-chloroquinolin-8-amine (3.5 g, 19.59 mmol) in AcOH (100 mL) was stirred at r.t. for 5 hr then concentrated under reduced pressure to give N-(5-chloroquinolin-8-yl)acetamide (3.5 g, 81% yield) as white solid. LC-MS: m/z 221 (M+H)⁺. [0153] Step D. N-(5-chloro-7-nitroquinolin-8-yl)acetamide. A mixture of N-(5-chloroquinolin- 8-yl)acetamide (1 g, 4.53 mmol) and KN03 (0.68 g, 6.8 mmol) in TFA (25 mL) was stirred at 80°C for 12 hr, then quenched with saturated aq. NaHC0₃ and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified via flash column chromatography to give N-(5-chloro-7-nitroquinolin-8-yl)acetamide (450 mg, 37.4% yield) as yellow solid. LC-MS: m/z 266 (M+H)⁺.

[0154] Step E. 5-Chloro-7-nitroquinolin-8-amine. A mixture of N-(5-chloro-7-nitroquinolin-8- yl)acetamide (0.150 g, 0.564 mmol) in aq. H₂SO₄ (50%wt, 25 mL) stirred 100°C for 12 hr then quenched with saturated aq. NaHC0₃ and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to give crude 5-chloro-7-nitroquinolin-8- amine (100 mg, 79% yield) as yellow solid which was used in the next step without further purification. LC-MS: m/z 224 (M+H)⁺.

[0155] Step F. 5-Chloroquinoline-7,8-diamine. A mixture of 5-chloro-7-nitroquinolin-8-amine (0.1 g, 0.447 mmol) and Zn (292 mg, 4.47 mmol) in DCM (20 mL) was cooled to 0°C, followed by dropwise addition of AcOH (0.269 mg, 4.47 mmol). The reaction mixture was stirred at 0°C for 2 hr, then filtered. The filtrate was concentrated under reduced pressure and the residue was purified via flash column chromatography to give the desired product (70 mg, 81 % yield). LC-MS: m/z 194(M+H)⁺.

[0156] Step G. 5-Chloro-lH-imidazo[4,5-h]quinoline. A mixture of 5-chloroquinoline-7,8- diamine (70 mg, 0. 361 mmol) in triethoxymethane (2 mL) was stirred at 100°C for 1 hr then purified via flash column chromatography to give 5-chloro-lH-imidazo[4,5-h]quinoline (30 mg, 41% yield) as yellow solid. LC-MS: m/z 204 (M+H)⁺.

[0157] Step H. 2-(5-Chloro-lH midazo[4,5-h]quinolin-l-yl)-l-(l-(phenylsulfonyl)-6-(pyridin- 3-yloxy)-lH-indol-3-yl)ethanone. A mixture of 5-chloro-lH-imidazo[4,5-h]quinoline (30 mg, 0.098 mmol), 2-chloro-l-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone (84 mg, 0.196 mmol), and K₂C0₃ (40 mg, 0.95 mmol) in DMF (5 mL) was stirred at r.t. for 1 hr then diluted with EtOAc. The organic layer was separated, wash with aq. LiCl (10% wt), dried over anhydrous Na₂S0₄, and concentrated under reduced pressure to give crude 2-(5-chloro-lH-imidazo[4,5-h]quinolin-l-yl)-l-(l- (phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone (40 mg, 68% crude yield) as black oil. LC-MS: m/z 595 (M+H)⁺.

[0158] Step I. 2-(5- Chloro-lH-imidazo[4,5-h]quinolin-l-yl)-l-(6-(pyridin-3-yloxy )-lH-indol-3- yljethanone. A mixture of the above 2-(5-chloro-lH-imidazo[4,5-h]quinolin-l-yl)-l-(l-(phenylsulfonyl)- 6- (pyridin-3-yloxy)-lH-indol-3-yl)ethanone (40 mg) and NaOH (20 mg, 0.491 mmol) in THF (5 mL) was stirred at r.t. for 1 hr then diluted with EtOAc. The organic layer was separated washed with brine, dried over anhydrous Na₂S0 , and concentrated under reduced pressure. The residue was purified via prep-HPLC to give 2-(5-chloro-lH-imidazo[4,5-h]quinolin-l-yl)-l-(6-(pyridin-3-yloxy)-lH-indol-3- yl)ethanone (4.4 mg, 10% yield over two steps) as white solid. LC-MS: m/z 454 (M+H)⁺. H NMR (DMSO-d₆ ,400MHz): δ = 8.76 - 8.80 (m, 1 H), 8.73 (s, 1 H), 8.66 (m, 1 H), 8.45 (s, 1 H), 8.38 (s, 1 H), 8.34 (t, = 2 Hz, 1 H), 8.19 (s, 1 H), 7.98 - 8.05 (m, 1 H), 7.59 - 7.65 (m, 1 H), 7.41 (s, 2 H), 7.18 - 7.22 (m, 1 H), 6.91 - 7.01 (m, 1 H), 6.41 ppm (s, 2 H).

EXAMPLE 8. SYNTHESIS OF 2-(5-CHLORO-1H-BENZO[D]IMIDAZOL-1-YL)-1-(6-(PYRIDIN-3-YLOXY)- -INDOL-3-YL)ETHANONE (Compound 112)

[0159] Step A. 2-(5-chloro-lH-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide. A mixture of 2- (5-chloro-lH-benzo[d]imidazol-l-yl)acetic acid (1.0 g, 4.75 mmol), dimethyl amine hydrochloride (0.465 g, 5.7 mmol), EDCI (1.19 g, 6.2 mmol), HOBt ( 0.84 g, 6.2 mmol) and triethylamine (2.5 mL) in DMF (10 mL) was stirred at r.t. for 16 hr then partitioned between EtOAc and water. The aqueous phase was extracted by EtOAc (2x10 mL). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM : MeOH = 1:0 to 20 : 1) to give the desired product ( 800 mg, 70% yield) as white solid. LC-MS: m/z 238 (M+H)⁺.

[0160] Step B. 2-(5-Chloro-lH-benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy)-lH-indol-3- yljethanone. A mixture of 2-(5-chloro-lH-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide (150 mg, 0.63 mmol) and POCl₃ (217.3 mg, 1.4 mol) in dioxane (5 mL) was stirred at 100°C for 1 hr then cooled to r.t., followed by addition of 6-(pyridin-3-yloxy)-lH-indole (146 mg, 0.69 mmol) in one portion. The resulting mixture was stirred at 95°C for 16 hr then poured into cold water. The mixture was adjusted pH 8 and heated to reflux for 10 min, then cooled to r.t. and extracted with DCM (3x 40 mL). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the product (15 mg, 5.9% yield) as white solid. LC-MS: m/z 403 (M+H)VH NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.31-8.37 (m, 3H), 8.08 (d, = 8.4 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.54 (d, = 8.4 Hz, 1H), 7.38-7.43 (m, 2H), 7.25-7.28 (m, 1H), 7.19 (d, = 2 Hz, 1H), 6.99-7.01 (m, 1H), 5.81 (s, 2H). [0161] The procedure set forth above in Example 8 was used to produce the following compounds using the appropriate starting materials.

[0162] 2-(5-Chloro-lH-benzo[d]imidazol-l-yl)-l-(6-((6-methylpyridin-3-yl)oxy)-lH-indol-3-

[0163] LC-MS: m/z 417 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.09 (s, 1H), 8.61 (s, 1H), 8.31 (s, 1H), 8.24 (d, / = 2.8 Hz, 1H), 8.06 (d, / = 8.8 Hz, 1H), 7.74 (d, / = 2.0 Hz, 1H), 7.54 (d, / = 6.8 Hz 1H), 7.32-7.35 (m, 1H), 7.24-7.27 (m, 2H), 7.11 (d, / = 2.0 Hz, 1H), 6.95-6.98 (m, 1H), 5.80 (s, 2H), 2.45 (s, 3H).

[0164] 2-(5-Chloro-lH-benzo[d]imidazol-l-yl)-l-(6-((2-methylpyridin-3-yl)oxy)-lH-indol-3-

[0165] LC-MS: m/z 417 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 1H), 8.62 (s, 1H), 8.32 (s, 1H), 8.26 (t, J = 3.0 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.55 (d, = 8.8 Hz, 1H), 7.24-7.28 (m, 3H), 7.03 (d, = 2.0 Hz, 1H), 6.93-6.96 (m, 1H), 5.81 (s, 2H), 2.43 (s, 3H).

[0166] 2-(5-Chloro-lH-benzo[d]imidazol-l-yl)-l-(6-((5-methylpyridin-3-yl)oxy)-lH-indol-3-

[0167] LC-MS: m/z 417 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 8.65 (s, 1H), 8.32 (s, 1H), 8.17-8.19 (m, 2H), 8.09 (d, = 8.4 Hz, 1H), 7.75 (d, = 2.0 Hz, 1H), 7.55 (d, = 8.4 Hz, 1H), 7.18-7.28 (m, 3H), 6.98-7.01 (m, 1H), 5.82 (s, 2H), 2.27 (s, 3H). [0168] 1^6-((2-Aminopyridin-4-yl)oxy)-lH-indol-3-yl)-2-(5-chloro-lH-benzo[d]imidazol-l-

[0169] LC-MS: m/z 418 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.26 (s, 1H), 8.67 (s, / = 2.8 Hz, 1H), 8.33 (s, 1H), 8.12 (d, = 8.8 Hz, 1H), 7.76-7.80 (m, 2H), 7.55 (d, = 8.4 Hz, 1H), 7.26-7.29 (m, 2H), 6.99-7.01 (m, 1H), 6.15-6.16 (m, 1H), 5.79-5.89 (m, 5H).

[0170] 2-(5-Chloro-lH-benzo[d]imidazol-l-yl)-l-(6-((5-methoxypyridin-3-yl)oxy)-lH-indol- -yl)ethanone (Compound 133)

[0171] LC-MS: m/z 433 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 8.65 (s, 1H), 8.33 (s, 1H), 8.09 (d, = 5.9 Hz, 2H), 7.93 (s, 1H), 7.76 (s, 1H), 7.55 (d, = 8.5 Hz, 1H), 7.36 - 7.16 (m, 2H), 7.03 (d, = 14.3 Hz, 2H), 5.83 (s, 2H), 3.80 (s, 3H).

[0172] 4-((3-(2-(5-Chloro-lH-benzo[d]imidazol-l-yl)acetyl)-lH-indol-6-yl)oxy)benzamide

[0173] LC-MS: m/z 445 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 8.65 (s, 1H), 8.33 (s, 1H), 8.10 (d, = 8.6 Hz, 1H), 7.90 (t, = 10.5 Hz, 3H), 7.76 (d, = 1.9 Hz, 1H), 7.55 (d, = 8.6 Hz, 1H), 7.33 - 7.19 (m, 3H), 7.00 (d, = 8.8 Hz, 3H), 5.83 (s, 2H).

[0174] l-(2-Oxo-2-(6-(pyridin-3-yloxy)-lH-indol-3-yl)ethyl)-lH-benzo[d]imidazole-5- carbonitrile (Compound 128)

[0175] LC-MS: m/z 394 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 8.65 (s, IH), 8.48 (s, IH), 8.45 (s, IH), 8.24-8.38 (m, IH), 8.33-8.35 (m, IH), 8.25 (d, = 0.8 Hz, IH), 8.08 (d, = 8.8 Hz, IH), 7.74 (d, = 8.4 Hz, IH), 7.63-7.65 (m, IH), 7.40-7.41 (m, IH), 7.20 (d, = 4.4 Hz, IH), 6.98-7.01 (m, IH), 5.90 (s, 2H).

[0176] l-(2-(6-Chloro-lH-indol-3-yl)-2-oxoethyl)-lH-benzo[d]imidazole-5-carbonitrile

[0177] LC-MS: m/z 335 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, IH), 8.47 (s, IH), 8.25 (s, IH), 8.05 (d, = 8.4 Hz, IH), 7.75 (d, = 8.0 Hz, IH), 7.60-7.65 (m, 2H), 7.21-7.24 (m, IH), 5.90 (s, 2H).

[0178] 2-(6-Chloro-5-methoxy-lH-benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy)-lH-indol-

[0179] LC-MS: m/z 433 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, IH), 8.62 (s, IH), 8.39 (s, IH), 8.36 - 8.33 (m, IH), 8.22 (s, IH), 8.10 (d, = 8.6 Hz, IH), 7.70 (s, IH), 7.41 (d, = 2.7 Hz, 3H), 7.20 (d, = 2.1 Hz, IH), 7.01 (dd, = 8.6, 2.2 Hz, IH), 5.78 (s, 2H), 3.89 (s, 3H).

[0180] 2-(4-Chloro-lH-benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy)-lH-indol-3- yl)ethanone (Compound 124)

[0181] LC-MS: m/z 403 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.18 (s, IH), 8.66 (s, IH), IH), 8.37 - 8.31 (m, 2H), 8.09 (d, = 8.6 Hz, IH), 7.51 (d, = 7.9 Hz, IH), 7.44 - 7.37 (m, 2H).

EXAMPLE 9. SYNTHESIS OF 2-(3-(2-(5-CHLORO-1H-BENZO[D]IMIDAZOL-1-YL)ACETYL)-6-(PYRIDIN-3-

[0182] Step A. 2-(3-(2-(5-Chloro-lH-benzo[d]imidazol-l-yl)acetyl)-6-(pyridin-3-yloxy)-lH- indol-l-yl)-N,N-dimethylacetamide. To a mixture of 2-(5-chloro-lH-benzo[d]imidazol-l-yl)-l-(6- (pyridin-3-yloxy)-lH-indol-3-yl)ethanone (6 mg, 0.015 mmol) in DMF (1 mL ) were added K₂C0₃ (2.0 mg, 0.06 mmol) and 2-chloro-N,N-dimethylacetamide (1.8 mg, 0.015 mmol). The reaction mixture was stirred at r.t. for 16 hr then filtered. The filtrate was purified by prep-HPLC to give the desired product (3.1 mg, 42% yield) as white solid. LC-MS: m/z 488 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 8.55 (s, 1H), 8.31-8.34 (m, 3H), 8.10 (d, = 8.8 Hz 1H), 7.75 (d, = 2 Hz, 1H), 7.55 (d, = 8.4Hz, 1H), 7.25- 7.43 (m, 4H), 6.99-7.02 (m, 1H), 5.80 (s, 2H), 5.32 (s, 2H), 3.11 (s, 3H), 2.88 (s, 3H).

[0183] The procedure set forth in Example 9 above was used to produce the following compounds using the appropriate starting materials.

[0184] 2 5-Chloro-lH-benzo[d]imidazol-l-yl)-l-(l-(2-(dimethylamino)ethyl)-6-(pyridin-3- ound 122)

[0185] LC-MS: m/z: 474(M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.40 - 8.30 (m, 3H), 8.11 (d, = 8.6 Hz, 1H), 7.75 (d, = 1.9 Hz, 1H), 7.54 (dd, = 17.1, 5.4 Hz, 2H), 7.45 - 7.32 (m, 2H), 7.27 (dd, / = 8.6, 2.0 Hz, 1H), 7.02 (dd, / = 8.6, 2.1 Hz, 1H), 5.80 (s, 2H), 4.36 (t, = 6.2 Hz, 2H), 2.69 (t, = 6.3 Hz, 2H), 2.20 (s, 6H).

[0186] 2-(5-Chloro-lH-benzo[d]imidazol-l-yl)-l-(l-(2-morpholinoethyl)-6-(pyridin-3- yloxy)-lH-indol-3-yl)ethanone (Compound 116)

[0187] LC-MS: m/z 516 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, IH), 8.33-8.36 (m, 3H), 8.10 (d, = 8.4 Hz IH), 7.75 (s, IH), 7.52-7.55 (m, 2H), 7.35-7.41 (m, 2H), 7.26 (d, / = 8.8 Hz ,1H), 7.0-7.03 (m, IH), 5.79 (s, 2H), 4.37-4.40 (m, 2H), 3.53 (s, 4H), 2.71-2.74 (m, 2H), 2.44 (s, 4H).

[0188] 2-(5-Chloro-lH-benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy)-l-(2-(pyrrolidin-l- yl)ethyl)-lH-indol- -yl)ethanone (Compound 117)

[0189] LC-MS: m/z 500 (M+H)VH NMR (400 MHz, DMSO-d₆) δ 8.70 (s, IH), 8.36 (d, = 2.4 Hz, IH), 8.32-8.33 (m, 2H), 8.10 (d, = 8.8 Hz, IH), 7.75 (d, = 2.0Hz, IH), 7.54 (d, = 8.8 Hz, IH), 7.49 (d, = 2.0 Hz , IH), 7.34-7.41 (m, 2H), 7.25-7.27 (m, IH), 7.00-7.03 (m, IH), 5.79 (s, 2H), 4.36- 4.39 (m, 2H), 3.36 (s, 4H), 2.84-2.87 (m, 2H), 1.62-1.68 (m, 4H).

[0190] 2-(5-Chloro-lH-benzo[d]imidazol-l-yl)-l-(l-(3-hydroxy-3-methylbutyl)-6-(pyridin- 3-yloxy)-lH-indol-3-yl)ethanone (Compound 121)

[0191] LC-MS: m/z: 489 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 8.75 (s, IH), 8.44 - 8.29 (m, 3H), 8.11 (d, = 8.6 Hz, IH), 7.94 (s, IH), 7.75 (d, = 1.9 Hz, IH), 7.56 (d, = 8.6 Hz, IH), 7.49 - 7.32 (m, 3H), 7.27 (dd, / = 8.6, 2.0 Hz, IH), 7.02 (dd, / = 8.6, 2.1 Hz, IH), 5.80 (s, 2H), 4.59 (s, IH), 4.43 - 4.26 (m, 2H), 2.04 - 1.86 (m, 2H), 1.20 (s, 6H). [0192] 2-(5-Chloro-lH-benzo[d]imidazol-l-yl)-l-(l-(2-hydroxy-2-methylpropyl)-6-(pyridin- pound 127)

[0193] LC-MS: m/z: 475 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 8.57 (s, 1H), 8.33 (dd, / = 12.6, 3.9 Hz, 3H), 8.10 (d, = 8.6 Hz, 1H), 7.75 (d, = 1.8 Hz, 1H), 7.57 (dd, / = 17.2, 5.3 Hz, 2H), 7.38 (dd, J = 8.2, 4.6 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.26 (dd, J = 8.6, 1.9 Hz, 1H), 7.00 (dd, J = 8.6, 2.1 Hz, 1H), 5.82 (s, 2H), 4.85 (s, 1H), 4.19 (s, 2H), 1.14 (s, 6H).

EXAMPLE 10. SYNTHESIS OF 2-(5-CHLORO-2-METHYL-1H-BENZO[D]IMIDAZOL-1-YL)-1-(6-(PYRIDIN- -YLOXY)-1H-INDOL-3-YL)ETHANONE (Compound 114)

[0194] Step A. 2-(4-Chloro-2-nitrophenylamino)-N,N-dimethylacetamide. To a mixture of 4- chloro-l-fluoro-2 -nitrobenzene (0.9 g, 5 mmol) in EtOH (20 mL) were added 2-amino-N,N- dimethylacetamide hydrochloride (0.7 g, 5 mmol) and Et₃N (1.5 g, 15 mmol). The reaction mixture was stirred at reflux for 4 hr then cooled and filtered. The solid was collected, washed with PE and dried under high vacuum to give pure 2-(4-chloro-2-nitrophenylamino)-N,N-dimethylacetamide (0.8 g, 62% yield) as yellow crystal. LC-MS: m/z 258 (M+H)⁺.

[0195] Step B. 2-(2-Amino-4-chlorophenylamino)-N,N-dimethylacetamide. To a mixture of 2-(4-chloro-2-nitrophenylamino)-N,N-dimethylacetamide (258 mg, 1 mmol) in EtOH (10 mL) were added Fe° (560 mg, 10 mmol), NH₄C1 (535 mg, 10 mmol) and H₂0 (10 mL). The reaction mixture was stirred at 70°C for 3 hr then cooled and filtered through Celite. The filtrate was partitioned between H₂0 and EtOAc. The organic layer was separated, washed with brine, dried over Na₂S0₄ and concentrated under reduced pressure to give crude 2-(2-armno-4-chlorophenylamino)-N,N-dimethylacetamide (230 mg, 100% yield) as yellow solid which was used directly in next step without further purification.

LC-MS: m/z 228 (M+H)⁺.

[0196] Step C. 2-(5-Chloro-2-methyl-lH-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide. A mixture of 2-(2-armno-4-chlorophenylamino)-N,N-dimethylacetamide (228 mg, 1 mmol) in Et(OMe)₃ (1.5 mL) was stirred at 100°C for 1.5 hr then concentrated in vacuo by oil pump. The residue was partitioned between H₂0 and EtOAc. The organic layer was separated, washed with brine, dried over Na₂S0₄ and concentrated under reduced pressure to afford crude 2-(5-chloro-2-methyl-lH- benzo[d]imidazol-l-yl)-N,N-dimethylacetamide (230 mg, 91.2% yield) as pale yellow solid which was used directly in the following step. LC-MS: m/z 252 (M+H)⁺.

[0197] Step D. 2-(5-Chloro-2-methyl-lH-benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy)-lH- indol-3-yl)ethanone. To a mixture of 2-(5-chloro-2-methyl-lH-benzo[d]imidazol-l-yl)-N,N- dimethylacetamide (125 mg, 0.5 mmol) in dry dioxane (3 mL) at r.t. was added POCl₃ (0.8 mL, 8.7 mmol). The reaction mixture stirred under an atmosphere of N₂ at 100°C for 2 hr then cooled to r.t., followed by addition of 6-(pyridin-3-yloxy)-lH-indole (105 mg, 0.5 mmol) in one portion. The resulting mixture was stirred under an atmosphere of N₂ at 100°C for another 18 hr then cooled to r.t., poured into ice -water, and basified to pH 8 with IN NaOH at 0°C. The resulting mixture was heated to reflux for 10 min then cooled to r.t. and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂S0₄ and concentrated under reduced pressure. The residue was purified by prep- TLC and repurified by prep-HPLC to give 2-(5-chloro-2-methyl-lH-benzo[d]imidazol-l-yl)-l-(6- (pyridin-3-yloxy)-lH-indol-3-yl)ethanone (12 mg, 5.7% yield) as white solid. LC-MS: m/z 417 (M+H)⁺. H NMR (400 MHz, DMSO-d₆) δ 12.21 (s, 1H), 8.66 (s, 1H), 8.34-8.3 (m, 2H), 8.09 (d, = 8.4 Hz, 1H), 7.61 (d, = 2.0 Hz, 1H), 7.47 (d, = 8.4 Hz, 1H), 7.39-7.41 (m, 2H), 7.17-7.21 (m, 2H), 6.99-7.02 (m, 1H), 5.78 (s, 2H), 2.47 (s, 3H).

EXAMPLE 11. SYNTHESIS OF 5-CHLORO-1-(2-OXO-2-(6-(PYRIDIN-3-YLOXY)-1H-INDOL-3-YL)ETHYL)- -BENZO[D]IMIDAZOL-2(3H)-ONE (Compound 118)

[0198] Step A. 2-(5-Chloro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-N,N- dimethylacetamide. To a mixture of 2-(2-amino-4-chlorophenylamino)-N,N-dimethylacetamide (460 mg, 2 mmol) in dry THF (10 mL) at r.t.was added CDI (648 mg, 4 mmol) in one portion. The reaction mixture was stirred at r.t for 18 hr, then filtered. The solid was collected, washed with n-hexane and dried under high vacuumto give pure 2-(5-chloro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-N,N- dimethylacetamide (410 mg, 82% yield) as white solid. LC-MS: m/z 254 (M+H)⁺.

[0199] Step B. 5-Chloro-l-(2-oxo-2-(6-(pyridin-3-yloxy)-lH-indol-3-yl)ethyl)-lH- benzo[d]imidazol-2(3H)-one. To a mixture of 2-(5-chloro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l- yl)-N,N-dimethylacetamide (125 mg, 0.5 mmol) in dry dioxane (3 mL) at r.t. was added POCl₃ (0.5 mL, 5.4 mmol). The reaction mixture stirred at 120°C under an atmosphere of N₂ for 3 hr then cooled to r.t., followed by addition of 6-(pyridin-3-yloxy)-lH-indole (126 mg, 0.6 mmol) in one portion. The resulting mixture was stirred at 90°C for another 16 hr, then cooled and concentrated under reduced pressure. The residue was dissolved in a MeOH/DCM (1 mL/10 mL) and then slowly poured into ice -water. The resulting mixture was basified to pH 8-9 with 1 N NaOH and extracted with DCM. The combined organic layers were dried and concentrated under reduced pressure. The residue was first purified by flash column chromatography then further purified by prep-HPLC to give 5-chloro-l-(2-oxo-2-(6-(pyridin-3-yloxy)- lH-indol-3-yl)ethyl)-lH-benzo[d]imidazol-2(3H)-one (50 mg, 23.9% yield) as white solid. LC-MS: m/z 419 (M+H)⁺. ^:H NMR (400 MHz, DMSO-d₆) δ 12.14 (br, 1H), 11.15 (br, 1H), 8.61 (s, 1H), 8.35-8.39 (m, 2H), 8.09 (d, = 8.8 Hz, 1H), 7.41 (s, 2H), 7.03-7.18 (m, 5H), 5.26 (s, 2H).

EXAMPLE 12. SYNTHESIS OF 2-(5-CHLORO-1H-BENZO[D]IMIDAZOL-1-YL)-1-(6-(4-HYDROXY PHENOXY)-1H-INDOL-3-YL)ETHANONE (Compound 139)

Step A. 6-(4-Methoxyphenoxy)-l-(phenylsulfonyl)-lH-indole. To a mixture of 1- (phenylsulfonyl)-lH-indol-6-ol (1.37 g, 5 mmol) and 4-methoxyphenylboronic acid (1.52g, 10 mmol) in dry DCM (15 mL) were added powdered activated 4A molecular sieves (2.0 g), Cu(OAc)₂ (0.9 g, 5 mmol) and Et₃N (0.5 g, 5 mmol). The reaction mixture was stirred at r.t. for 6 hr under air, then quenched with an excess of n-hexane and filtered. The filtrate was

concentrated under reduced pressure and the residue was purified by column chromatography to afford the desired product (1 g, 50% yield) as yellow solid. LC-MS: m/z: 380 (M+H)⁺.

Step B. 6-(4-Methoxyphenoxy)-lH-indole. To a suspension of 6-(3-methoxyphenoxy)- l-(phenylsulfonyl)-lH-indole (lg, 2.6mmol) in THF/H₂0 (21 ml, V:V=2:1) was added NaOH (0.16 g, 3.9 mmol). The reaction mixture was stirred at r.t for 1 hr, then extracted with DCM (20 mL). The organic layer was separated, dried over anhydrous Na₂S0_4i and concentrated under reduced pressure to give the desired product (0.5 g, 72% crude yield) as white solid which was used directly in the next step without any further purification. LC-MS: m/z: 240 (M+H)⁺.

Step C. 2-(5-Chloro-lH-benzo[d]imidazol-l-yl)-l-(6-(4-methoxy phenoxy)-lH-indol -3-yl)ethanone. To a mixture of 2-(5-chloro-lH-benzo[d]imidazol-l-yl)-N,N-dimethylacetamide (0.5g, 2.1mmol) in dry dioxane (10 mL) at r.t. under N₂ was added POCl₃ (2 mL, 20mmol). The reaction mixture was stirred at 120°C for 4 hr then cooled to r.t., followed by addition of 6-(4- methoxyphenoxy)-lH-indole (0.5 g, 2.1mmol) in one portion. The resulting mixture was stirred at 90°C under N₂ for another 16 hr then concentrated under reduced pressure. The residue was dissolved in MeOH (50 mL) then cooled to 0°C, followed by addition of H₂0 (10 mL). The resulting mixture was basified to pH 8-9 with aqueous NaOH (30%wt) then stirred at reflux for 20 min. After cooled to r.t., the mixture was concentrated under reduced pressure to about 10 mL then filtered. The precipitate was collected and purified by flash column chromatography to give the desired product (0.25 g, 30% yield). LC-MS: m/z: 432 (M+H)⁺.

Step D. 2-(5-Chloro-lH-benzo[d]imidazol-l-yl)-l-(6-(4-hydroxy phenoxy)-lH-indol - 3-yl)ethanone. A mixture of 2-(5-chloro-lH-benzo[d]imidazol-l-yl)-l-(6- (4-methoxyphenoxy)- lH-indol-3-yl)ethanone (100 mg, 0.23 mmol) in pyridine hydrochloride (500 mg) was stirred at 180°C for 6 hr then cooled to r.t. and extracted with DCM (10 mL). The organic layer was separated, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified via prep-HPLC to afford the desired product (30 mg, 31% yield) as white solid. LC-MS: m/z: 418(M+H) ⁺. 1H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 3H), 8.56 (s, 3H), 8.00 (d, J = 8.5 Hz, 3H), 7.69 (d, J = 69.2 Hz, 6H), 7.26 (d, J = 8.6 Hz, 4H), 6.98 - 6.68 (m, 18H), 5.78 (d, J = 19.2 Hz, 5H).

The procedure set forth above as Example 12 was used to produce the following compound from the appropriate starting materials.

2-(5-Chloro-lH-benzo[d]imidazol-l-yl)-l-(6-(3-hydroxyphenoxy)-lH-indol-3- yl)ethanone (Compound 140)

LC-MS: m/z: 418(M+H) ⁺. 1H NMR (400 MHz, DMSO-d₆) δ 9.61 (s, 1H), 8.63 (s, 1H), 8.33 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.76 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.19 - 7.08 (m, 2H), 6.95 (d, J = 8.5 Hz, 1H), 6.52 (d, J = 7.8 Hz, 1H), 6.47 - 6.32 (m, 2H), 5.82 (s, 2H). EXAMPLE 13. SYNTHESIS OF 4-((3-(2-(5-CHLORO-1H-BENZO[D]IMIDAZOL-1-YL)ACETYL)-1H - -6-YL)OXY)BENZAMIDE (Compound 138)

Step A. 4-(3-(2-(5-Chloro-lH-benzo[d]imidazol-l-yl)acetyl)-lH-indol-6-yloxy)benzo- nitrile. To a mixture of 2-(5-chloro-lH-benzo[d]imidazol-l-yl)-N,N-dimethylacet -amide (80 mg, 0.34 mmol) in dry dioxane (3 mL) at r.t. under N₂ was added POCI₃ (0.4 mL, 4.2 mmol). The reaction mixture was stirred at 120°C for 3 hr then cooled to r.t., followed by addition of a solution of 4-(lH-indol-6-yloxy)benzonitrile (80 mg, 0.34 mmol) in dioxane (1.5 mL) in one portion. The resulting mixture was stirred at 90°C under N₂ for another 18 hr then concentrated under reduced pressure. The residue was dissolved in MeOH/DCM (2 mL/10 mL) then slowly poured into ice- water. The mixture was basified to pH 8-9 with aqueous NaOH and then extracted with DCM. The combined organic layers were concentrated under reduced pressure and the residue was purified by prep-TLC to give the desired product (30 mg, 20.6% yield) as yellow solid. LC-MS: m/z 427 (M+H)⁺.

Step B. 4-(3-(2-(5-Chloro-lH-benzo[d]imidazol-l-yl)acetyl)-lH-indol-6-yloxy) benzamide. To a mixture of 4-(3-(2-(5-chloro-lH-benzo[d]imidazol-l-yl)acetyl)-lH-indol-6- yloxy)benzonitrile (30 mg, 0.0.07 mmol) in DMSO (3 mL) at r.t. were added K₂C0₃ (138 mg, 1 mmol) and aqueous H₂0₂ (30 mg, 0.26 mmol, 30%wt in H₂0). The reaction mixture was stirred at r.t. for 6 hr then poured into ice water, quenched with aqueous Na₂S₂0₃ and extracted with DCM. The combined organic layers were concentrated under reduced pressure and the residue was purified by prep-HPLC to give the desired product (7 mg, 6.3% yield) as white solid.

LC-MS: m/z 445 (M+H)⁺. 1HNMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 8.66 (s, 1H), 8.34- 8.44 (m, 3H), 8.09-8.17 (m, 2H), 7.83 (d, J= 2.0 Hz, 1H), 7.61-7.64 (m, 1H), 7.41-7.42 (m, 2H), 7.18 (d, J= 2.4 Hz, 1H), 7.00-7.03 (m, 1H), 5.48 (s, 2H). The procedure set forth above as Example 13 was used to produce the following compounds from the appropriate starting materials.

3-((3-(2-(5-Chloro-lH-benzo[d]imidazol-l-yl)acetyl)-lH-indol-6-yl)oxy)benzamide (Compound 141)

LC-MS: m/z 445 (M+H)⁺. 1H NMR (400 MHz, DMSO-d₆) δ 12.16 (s, 1H), 8.64 (s, 1H), 8.32 (s, 1H), 8.07 (s, 2H), 7.87 - 6.85 (m, 8H), 5.82 (s, 2H).

EXAMPLE 14. SYNTHESIS OF 2-(4,5-DICHLORO-1H-BENZO[D]IMIDAZOL-1-YL)-1-(6-(PYRIDIN-3 -YLOXY)-1H-INDOL-3-YL)ETHANONE AND 2-(6,7-DICHLORO-1H-BENZO[D]IMIDAZOL-1-YL)-1- (6-(PYRIDIN-3-YLOXY)-1H-INDOL-3-YL)ETHANONE (Compound 142)

83:17 Step A. 2,3-Dichloro-6-nitroaniline . To a mixture of l,2,3-trichloro-4-nitrobenzene (1.5 g, 6.64 mmol) in 1,4-dioxane (20 mL) at r.t. was added ammonium hydroxide (20 mL, 30%wt). The reaction mixture was stirred at 120 °C in a sealed tube for 20 hr then concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 2,3- dichloro-6-nitroaniline (1.1 g, 81% yield) as yellow solid. LC-MS: m/z 207 (M+H)⁺.

Step B. 3,4-Dichlorobenzene-l,2-diamine. To a mixture of 2,3-dichloro-6-nitroaniline (414 mg, 2 mmol) in EtOH/H₂O(30 mL, V:V=1:1) were added Fe (896 mg, 16 mmol) and NH₄C1 (848 mg, 16 mmol). The reaction mixture was stirred at reflux for 2 hr then filtered. The filtrate was extracted with DCM (30 mL). The organic layer was separated, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure to afford the desired product (330 mg, 93% crude yield) which was used in the next step without any further purification. LC-MS: m/z 177(M+H) ⁺.

Step C. 4,5-Dichloro-lH-benzo[d]imidazole. A mixture of 3,4-dichlorobenzene-l,2- diamine (330 mg, 1.8 mmol) in HCOOH (8 mL) was stirred at 100°C for 2 hr then concentrated under reduced pressure. T he residue was purified by flash column chromatography to give the desired product (140 mg, 42% yield) as yellow solid. LC-MS: m/z 187 (M+H) ⁺.

Step D. 2-(4,5-Dichloro-lH-benzo[d]imidazol-l-yl)-l-(l-(phenylsulfonyl) -6-(pyridin-3- yloxy )-lH-indol-3-yl)ethanone and 2-( 6, 7-dichloro-lH-benzo [d]imidazol-l-yl)-l-( 1- (phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone. To a mixture of 4,5-dichloro-lH- benzo[d] imidazole (75 mg, 0.4 mmol) in DMF (6 mL) were added 2-chloro-l-(l- (phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3-yl) ethanone (240 mg, 0.6 mmol) and K₂C0₃ (115 mg, 0.8 mmol). The reaction mixture was stirred at r.t. for 16 hr then quenched with aqueous LiCl (10%wt, 30 mL) and extracted with DCM (30 mL). The organic layer was separated, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford a mixture of 2-(4,5-dichloro-lH- benzo[d]imidazol-l-yl)-l-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone and

2- (6,7-dichloro-lH-benzo[d]imidazol-l-yl)-l-(l- (phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-

3- yl)ethanone (190 mg, 83% yield). LC-MS: m/z 577 (M+H)⁺.

Step E. 2-(4,5-dichloro-lH-benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy)-lH-indol -3- yl)ethanone and 2-(6,7-dichloro-lH-benzo[d]imidazol-l-yl)-l-(6-(pyridin-3 -yloxy)-lH-indol- 3-yl)ethanone . To a mixture of 2-(4,5-dichloro-lH-benzo[d]imidazol-l-yl)-l-(l- (phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone and 2-(6,7-dichloro-lH- benzo[d]imidazol-l-yl)-l-(l-(phenyl-sulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone (190 mg, 0.35 mmol) in THF/H₂0 (18 mL, V:V=2:1) was added NaOH (66 mg, 1.65 mmol). The reaction mixture was stirred at r.t. for 2 hr then extracted with DCM (20 mL). The organic layer was separated, dried over anhydrous Na₂S0_4i and concentrated under reduced pressure. The residue was purified via prep-HPLC to afford a mixture (83:17) of 2-(4,5-dichloro-lH- benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone and 2-(6,7-dichloro-lH- benzo[d]imidazol-l-yl)-l-(6-(pyridin-3-yloxy) -lH-indol-3-yl)ethanone (12 mg, 9% yield) as white solid. LC-MS: m/z 437 (M+H)⁺. 1H NMR (400 MHz, DMSO-d₆) δ 12.20 (s, 1H), 8.64 (d, J = 3.1 Hz, 1H), 8.38 (dd, J =6.4 Hz, 3H), 8.09 (d, J =8.6 Hz, 1H), 7.65 (dd, J = 8.6 Hz, 1H), 7.45 (dd, J =5.6 Hz, 3H), 7.21 (d, J = 2.0 Hz, 1H), 7.02 (dd, J =8.7, 2.1 Hz, 1H), 5.96 (s, 2H).

EXAMPLE 15. SYNTHESIS OF 2-(5-CHLORO-1H-INDOL-1-YL)-1-(6-(PYRIDIN-3-YLOXY)-1H - -3-YL)ETHANONE (Compound 143)

Step A. 2-( 5-Chloro-lH-indol-l-yl)-l-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy )-1Η- indol-3-yl)ethanone . To a mixture of 5-chloro-lH-indole (16 mg, 0.1 mmol) in DMF (2 mL) were added 2-chloro-l-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol-3-yl)ethanone (43mg, 0.1 mmol) and CS₂CO₃ (65 mg, 0.2 mmol). The reaction mixture was stirred at r.t. for 16 hr then quenched with aqueous LiCl (20 mL, 10 wt) and extracted with DCM (20 mL). The organic layer was separated, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford the desired product (27 mg, 50% yield). LC-MS: m/z: 542 (M+H)⁺. Step B. 2-(5-chloro-lH-indol-l-yl)-l-(6-(pyridin-3-yloxy)-lH-indol-3-yl) ethanone. To a suspension of 2-(5-chloro-lH-indol-l-yl)-l-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol- 3-yl)ethanone (27 mg, 0.5 mmol) in THF/H₂0 (6 mL, V:V=2:1) was added NaOH (60 mg, 1.5 mmol). The reaction mixture was stirred at r.t. for 1 hr then extracted with DCM (20 mL). The organic layer was separated, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified prep-HPLC to give the desired product as white solid.

LC-MS: m/z: 402(M+H)⁺. 1HNMR (400 MHz, DMSO-d₆) δ 12.11 (s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.34 (dd, J = 3.8, 2.2 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 3.1 Hz, 1H), 7.40 (dd, J = 5.4, 2.8 Hz, 3H), 7.18 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 8.7, 2.1 Hz, 1H), 6.99 (dd, J = 8.6, 2.2 Hz, 1H), 6.49 (d, J = 3.1 Hz, 1H), 5.68 (s, 2H).

EXAMPLE 16. SYNTHESIS OF 5-CHLORO-1-(2-OXO-2-(6-(PYRIDIN-3-YLOXY)-1H-INDOL- -YL) ETHYL)-1H-INDAZOL-3(2H)-ONE (Compound 144)

Step A. 5-Chloro-l-(2-oxo-2-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH -indol-3 -yl) ethyl)-lH-indazol-3(2H)-one. To a mixture of 5-chloro-lH-indazol-3(2H)-one (160 mg, 0.95 mmol) in DMF (5 ml) were added 2-chloro-l-(l-(phenylsulfonyl)-6-(pyridin-3-yloxy)-lH-indol- 3-yl)ethanone (400 mg, 0.95 mmol), Cs₂C0₃ (624 mg, 1.9 mmol), and Nal (136 mg, 0.95 mmol). The reaction mixture was stirred at r.t. for 2 hr then quenched with aqueous LiCl (10 wt, 80 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure to give the desired product (250 mg, 47.1% crude yield). The residue was used directly in the next step without any further

purification.. LC-MS: m/z 559 (M+H)⁺.

Step B. 5-Chloro-l-(2-oxo-2-( 6-(pyridin-3-yloxy)-lH-indol-3-yl)ethyl)-lH-indazol- 3(2H)-one. To a suspension of 5-chloro-l-(2-oxo-2-(l-(phenylsulfonyl) -6-(pyridin-3-yloxy)- lH-indol-3-yl)ethyl)-lH-indazol-3(2H)-one (250 mg, 0.45 mmol) in THF/H₂0 (10 mL,

V:V=4:1) was added NaOH (36 mg, 0.9 mmol). The reaction mixture was stirred at r.t. for 1 hr then extracted with DCM (20 mL). The organic layer was separated, dried over anhydrous Na₂S0₄, and concentrated under reduced pressure. The residue was purified via prep-HPLC to give the desired product (7mg, 3.7% yield) as white solid. LC-MS: m/z 419 (M+H)⁺. 1H NMR (400 MHz, DMSO-d₆) δ 12.07 (d, J = 31.1 Hz, 2H), 8.53 (d, J = 2.4 Hz, 1H), 8.36 (dd, J = 11.8, 8.3 Hz, 2H), 8.16 (d, J = 8.6 Hz, 1H), 7.76 (s, 1H), 7.47 - 7.31 (m, 4H), 7.16 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.6, 2.2 Hz, 1H), 5.54 (s, 2H).

TABLE 1. (TABLE OF COMPOUNDS)

EXAMPLE 12. PYOCYANIN INHIBITION ASSAY (TOPSEAL AND BREATHABLE SEAL)

[0200] Test compounds were dissolved in DMSO at 10 mM and stored at -20 °C until needed. Test concentrations from 0.0032 to 31.6 micromolar (topseal) or 0.001 micromolar to 31.6 micromolar (breathable seal) were used for each compound. Seven test concentrations were used for each compound in the topseal assay and eight test concentrations were used for each compound in the breathable seal assay.

[0201] P. aeruginosa, strain PA14, was inoculated into 5 mL of LB broth in a 15-mL sterile glass culture tube and incubated overnight at 37°C under shaking (~ 240 rpm). The overnight culture was then diluted in LB Broth to give an OD₆₀₀ = 0.04 (T₀ culture). Colony Forming Units (CFU)/mL of the overnight culture and T₀ culture were determined by a series of 1 : 10 serial dilutions in sterile saline. 4x20 of each dilution was seeded on LB agar plates and incubated at 35±2 °C for 20 hours. CFU/mL was determined from the dilution that gives 2 to 50 colonies/ 20μί.

[0202] For concentration response curve (CRC) experiments, internal standard, 2-((5-nitro-lH- indol-2-yl)thio)-N-(4-phenoxyphenyl)acetamide, a compound previously identified as an MvfR inhibitor (see Example 1 of US 2014-0066454 (WO 2012/116010)), and test compounds were serially diluted in DMSO to 200 times each final concentration (0.5% DMSO final), and ^L/well is dispensed in duplicate into 2 mL wells of a 96-well deep well plate. 200 μίΛνεΙΙ of T₀ culture were added to each internal standard/ test compound well. Wells containing only T₀ culture (200 200 μυν/εΙΙ) were used to determine pyocyanin control level and wells containing only LB broth (blank wells) were also included in the plate.

[0203] The topseal assay plate was sealed and incubated at 37°C under shaking (-700 rpm) using a microtiter shaker for 24 hours. In the breathable seal assay the plate was sealed with a breathable seal, covered with a lid, and incubated at 37°C under shaking (-700 rpm) using a microtiter shaker for 24 hours. At the end of the incubation period, the plate was centrifuged at 4,000g for 40 minutes at room temperature, 100 μυν/εΙΙ of the supernatant was transferred to a 96-microtiter PS flat-bottom plate, and absorbance at 690 nm was determined using SPECTROstar® Nano microplate reader. Pyocyanin concentration (M) is determined using the equation C = A₆₉₀/ (ε xd), where ε is the Pyocyanin extinction coefficient, at A₆₉₀ nm ε is 4,310 M cm and d is the experimentally derived pathlength. The level of pyocyanin in the presence of test compound was expressed as percentage of inhibition with respect to the control. Curve fitting and IC₅₀ determination were carried out using a four-parameter logistic model using GraphPad Prism v.5.

[0204] Pyocyanin inhibition data obtained in the topseal assay is provided in Table 2. Pyocyanin inhibition data obtained in the breathable assay is provided in Table 3. Three stars (***) indicates an IC₅₀ < 0.1 μΜ, two stars (**) indicates 0.1 μΜ < IC₅₀<1.0 μΜ, one star (*) indicates 1.0 μΜ < IC₅₀<10.0 μΜ, no stars beside a compound number indicates that compound has an IC₅₀ > 10 μΜ.

EXAMPLE 13. ASSAY FOR PQS AND HHQ INHIBITION (6 HOUR INCUBATION)

[0205] A concentration range with 7 test concentrations was chosen for each test compound. Typically concentration ranges for the PQS and HHQ assays were from 0.03 to 31.6 μΜ. Compounds were prepared in solvent, usually DMSO, at either 200 or 500 times the final test concentration. [0206] P. aeruginosa PA 14 wild-type strain was inoculated into 5 ml LB broth in a 15 ml sterile glass culture tube and incubated overnight at 37°C under shaking (~ 240 rpm). After overnight incubation, the bacterial culture was diluted in fresh LB broth to an OD600nm=0.04, and 5 mL aliquots of the diluted bacterial culture were distributed into 15-mL glass tubes. 10 of test compound at 500 times the final test concentration or 25μί of test compound at 200 times the final test concentration or solvent alone was added to each of the bacterial suspension tubes, and the tubes were incubated at 37°C under shaking (300rpm) for 6 hours. At the end of the incubation period, a 0.5 mL aliquot of bacterial suspension was transferred from each 15 mL glass tube, after shaking, to a 2 mL polypropylene vial. 0.5 mL of methanol-containing D4-PQS (deuterated-PQS), D4-HHQ (deuterated-HHQ) and 2% acetic acid were added to each 2 mL vial and each vial was vigorously shaken. The vials were then centrifuged for 5 minutes at 12,000g, and 200 of supernatant from each vial is transferred to a glass vial (vials crimp 0.2mL), and the sealed vials were kept at 4°C until LC-MS/MS analysis was performed. HAQs quantification is carried out analyzing samples in discrete batches together with spiked standards and blank samples. Calibration curves were constructed from HAQs standards, and respective deuterated forms were used as Internal Standards (IS), to calculate the concentration of analytes in the sample and improve the precision of the assay. The back-calculated concentrations of the calibration standards from the calibration curve are within ± 20% of the nominal values, the range of the analytical method was determined, and the lower and upper limit of quantification specified.

[0207] Liquid chromatography separations were performed using Agilent HP1100 system (Agilent Technologies) coupled with a CTC PAL Autos ampler (CTC Analytics AG). Chromatographic retention is obtained using a monolithic column (Chromolith® RP-18, 50 x 4.6 mm). The solvent system consists of water containing 0.1 % (v/v) formic acid (A) and acetonitrile containing 0.1 % (v/v) formic acid (B). The gradient elution profile was chosen as follows: 0 min: 70% A (1500 μί/ητϊη), 0.3 min: 70% A (1500 μί/ητίη), 1.3 min: 5% A (2500 μί/ητίη), 1.6 min: 5% A (2500 μί/ητίη).

[0208] The MS/MS analysis was performed with a API4000 series mass spectrometer (AB Sciex™) operating in Multiple Reaction Monitoring (MRM) mode and equipped with a TIS ion source. The specific ions monitored were PQS (m/z 260 -> m/z 175), D4-PQS (m/z 264 -> m/z 179), HHQ (m/z 244 -> m/z 159) and D4-HHQ (m/z 248 -> m/z 163). PQS and HHQ in presence of different test compound concentrations were expressed as percentage of inhibition of the basal level in control samples.

[0209] PQS 6 hour inhibition data is provided in Table 4. HHQ 6 hour inhibition data is provided in Table 5. Typically compounds that exhibited an IC₅₀ of less than 1 micromolar in the Pyocyanin inhibition assay were tested in the PQS and HHQ 6 hour inhibition assays. Three stars (***) indicates an IC₅₀ < 1.0 μΜ, two stars (**) indicates 1.0 μΜ < IC₅₀<5.0 μΜ, one star (*) indicates 5.0 μΜ ≤ IC₅o< 10.0 μΜ, no stars beside a compound number indicates that compound has an IC₅₀ > 10 μΜ. Table 4 PQS 6 hour inhibition

Cmp. No. PQS (6 hr) Cmp. No. PQS (6 hr)

IC₅₀ (μΜ) IC₅₀ (μΜ)

100 *** 108 ***

101 *** 112 ***

102 *** 135 ***

Table 5 HHQ 6 hour inhibition

Cmp. No. HHQ (6 hr) Cmp. No. HHQ (6 hr)

IC₅₀ (μΜ) IC₅₀ (μΜ)

100 *** 108 ***

101 *** 112 ***

102 *** 135 ***

Claims

What is claimed is:

1. A com ound having structural formula I:

, or a pharmaceutically acceptable salt thereof, wherein:

each of Y¹, Y², Y³, Y⁴, Y⁹, Y¹⁰, Y¹¹ and Y¹² is independently selected from N, CH, and C(R²), wherein at least one of Y¹, Y², Y³, or Y⁴ is C(R²), and at least one of Y⁹, Y¹⁰, Y¹¹ and Y¹² is C(R²); each of Z, Y⁵, Y⁶, Y⁷, and Y⁸ is independently selected from N and C;

no more than three of Y¹, Y², Y³, Y⁴, Y⁵ and Y⁶ is N;

no more than three of Y⁷, Y⁸, Y⁹, Y¹⁰, Y¹¹ and Y¹² is N;

each of V¹, V², and X and W is independently selected from N, N(R³), S, O, CH, and C(R²), wherein V¹ and V² are not simultaneously S or simultaneously O;

each " " represents independently a single or a double bond, wherein at least one ===== in each ring is a double bond;

R^la and R^lb are independently selected from hydrogen, -CN, fluoro, and methyl, and, when Z is C each of R^la and R^lb are additionally and independently selected from -OH and -NH₂; or R^la and R¹ are taken together with the carbon atom to which they are bound to form a cyclopropyl ring;

each R² is independently selected from halogen, -OH, -N0₂, -CN, -Ci-C6-alkyl,

-C₂-C6-alkenyl, -C₂-C6-alkynyl, -(C₀-C₄-alkylene)-(heterocyclyl), -(C₂-C₄-alkenylene)- (heterocyclyl), -(C₂-C₄-alkynylene)-(heterocyclyl), -(C₀-C₄-alkylene)-(carbocyclyl),

-(C₂-C -alkenylene)-(carbocyclyl), -(C₂-C -alkynylene)-(carbocyclyl), or

any two R² are optionally taken together with the carbon atoms to which they are bound to form an optionally substituted carbocyclyl or heterocyclyl;

each R³ is independently selected from hydrogen, -Ci-C₆-alkyl, -C₂-C₆-alkenyl,

-C₂-C₆-alkynyl, -(C₀-C₄-alkylene)-(heterocyclyl), -(C₂-C₄-alkenylene)-(heterocyclyl),

-(C₂-C₄-alkynylene) -(heterocyclyl), -(C₀-C₄-alkylene)-(carbocyclyl), -(C₂-C₄-alkenylene)- (carbocyclyl), or -(C₂-C₄-alkynylene)-(carbocyclyl); or

R³ and a nitrogen atom to which it is bound is optionally taken together with an adjacent carbon atom and a R² bound to the carbon atom to form an optionally substituted heterocyclyl; each alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, heterocyclyl or carbocyclyl portion of R² and R³ is optionally and independently substituted; and

one or more methylene units in the the alkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene portion of R² and R³ is optionally and independently replaced with -0-, -S-, -N(R₃)-, -S(=0)-, or -S(=0)₂-,

2. The com ound of claim 1 , wherein the portion of the compound represented by:

, wherein:

each R⁴ is independently selected from hydrogen and R²; and

each R^4c is independently selected from hydrogen and R^2a.

3. The com ound of claim 2, wherein the portion of the compound represented by:

R^4b is selected from hydrogen, chloro, cyano, -CH₃, -C(0)NH₂, and -C(0)NH(CH₃); and

R^4c is selected from hydrogen, cyano, -OH, -NH₂, and -CH₃.

4. The compound of claim 3, wherein:

each R^4a is independently selected from hydrogen, chloro, -OCH₃, and cyano, wherein at least one R^4a is chloro or cyano;

R^4b is hydro gen or chloro; and

R^4c is selected from hydrogen, cyano, and -OH.

5. The com ound of any one of claims 1-4, wherein the portion of the compound represented by

and , wherein each R⁴ is independently selected from hydrogen and

R^z

The compound of claim 5, wherein the portion of the compound represented by

is selected from:

, wherein:

R^3a is selected from hydrogen and optionally substituted Ci-C₄ alkyl; and

7. The compound of claim 6, wherein R⁵ is selected from halogen, cyano, optionally substituted pyridyloxy, optionally substituted pyrimidinyloxy, optionally substituted pyrazinyloxy, optionally substituted pyridazinyloxy, optionally substituted phenoxy and optionally substituted cyclohexyloxy.

8. The compound of claim 7, wherein R⁵ is selected from chloro, cyano, pyridin-3 -yloxy, pyridin-3- yloxy, pyrazin-2-yloxy, pyrimidin-2-yloxy, pyrimidin-5-yloxy, 2-me thy lpyridin-5 -yloxy, 6-aminopyridin- 2-yloxy, 2-aminopyridin-4-yloxy, 2-aminopyridin-4-yloxy, 2-methylpyridin-3-yloxy, 4-methylpyridin-3- yloxy, 5-methylpyridin-3-yloxy, 5-methoxypyridin-3-yloxy, 3-hydroxyphenyl, 4-hydroxyphenyl, 3- aminocarbonylphenyl, 4-aminocarbonylphenyl, 4-hydroxycyclohexyl, 3,4-dihydroxycyclohexyl, pyridazin-4-yloxy, pyridazin-3-yloxy, 2-methylpyridin-3-yloxy, and 2-aminopyridin-4-yloxy.

9. The compound of claim 8, wherein R⁵ is selected from chloro, cyano, pyridin-3 -yloxy, pyridin-3- yloxy, pyrazin-2-yloxy, pyrimidin-2-yloxy, pyrimidin-5-yloxy, 2-me thy lpyridin-3 -yloxy, 5- methylpyridin-3 -yloxy, 2-aminopyridin-4-yloxy, 5-methoxypyridin-3-yloxy and 2-methylpyridin-5- yloxy.

10. The compound of any one of claims 6-9, wherein R^3a is selected from hydrogen, 2-hydroxy-2- methylpropyl, dimethylaminocarbonylmethyl, mo holin-4-ylethyl, pyrrolidin-l-ylethyl,

dimethylaminoethyl, 2-hydroxyethyl, methyl, and 3-hydroxy-3-methylpropyl.

11. The compound of claim 10, wherein R^3a is selected from hydrogen, 2-hydroxy-2-methylpropyl, dimethylaminocarbonylmethyl, morpholin-4-ylethyl, and pyrrolidin-l-ylethyl.

12. The compound of any one of claim 1 to 11, wherein each of R^la and R^lb is hydrogen.

The compound of claim 1, having Structural Formula Ia-1

(Ia-1), wherein:

each R⁴ is independently selected from hydrogen and R² as defined in claim 1 ; and

each R^4c is independently selected from hydrogen and R^2a as defined in claim 1.

The compound of claim 13, having Structural Formula lb:

(lb), wherein:

R^3a is selected from hydrogen and optionally substituted Ci-C₄ alkyl; and

each R^4a is independently selected from hydrogen, halo, cyano, optionally substituted Ci- C₄ alkyl and optionally substituted -O-C₁-C4 alkyl, wherein at least one R^4a is halo or cyano;

R^4b is selected from hydrogen, halo, cyano, optionally substituted Ci- C₄ alkyl, -C(0)NH₂, -C(0)NH(C C₄ alkyl) and -C(0)N(d- C₄ alkyl)₂;

R^4c is selected from hydrogen, cyano, -OH, -NH₂, d- C₄ alkyl, NH(C C₄ alkyl), - N(C C₄ alkyl)₂ and -CH₃; and

substituted -O-carbocyclyl.

15. The compound of claim 1, selected from any one of compound numbers 100-138 in Table 1, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a therapeutically effective amount of compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

17. A method of treating a bacterial infection in a subject comprising administering to the subject in need thereof the composition of claim 16.

18. The method of claim 17, wherein the bacterial infection is a Pseudomonas aeruginosa infection.