Compounds and methods for treating protein folding disorders

BACKGROUND OF THE INVENTION

[0001] Protein folding disorders include neurodegenerative conditions such as. e.g..

Alzheimer's disease, dementia. Huntington ^' s disease. Parkinson ^' s disease and prion-

based spongiform encephalopathy (e.g., Creutzfeldt-Jakob disease) and non-neural

protein folding disorders such as, e.g.. type II diabetes and systemic amyloidoses.

[0002] Alzheimer ^' s disease (AD) is a progressive neurodegenerative disease which first manifests with mild cognitive, memory and behavioral symptoms that gradually worsen in severity and eventually lead to dementia. It is the most common cause of

dementia, accounting for between 42 and 81% of cases, as determined in various

studies (Nussbaum. RL; Ellis. CE. N Engl J Med, 2003, 348: 1356-64). It affects 2.5

% of people 65-74 years of age, 4% of people aged 75-79. 1 1 % of those aged 80-84,

and 24% of those aged 85-93 years (Siegel. GJ; Agranoff, BW; Albers, RW;

Molinoff, PB, Basic Neurυchemislry. Fifth ed. 1994. New York: Raven Press, 1054

pp). Accounting for 100,000 deaths annually in North America alone. AD is the fourth leading cause of death in industrialized societies, preceded only by heart

disease, cancer and stroke (Schenk, DB; Rydel, RE: May, P; Little, S; Panetta, J; Lieberburg, I; Sinha, S. J Med Chem, 1995, 38: 4141-54). AD affects individuals in all races and ethnic groups, occurring slightly more commonly in females than males.

[0003] There is no remission in the progression of Alzheimer's disease, nor are there

any disease-stabilizing drugs currently available (Selkoe, DJ; Schenk, D. Annu Rev Pharmacol Toxicol, 2003, 43: 545-84). As such, onset of the disease is inevitably

followed by increasing mental and physical incapacitation, loss of independent living, institutionalization and death. There is usually an 8-10 year period from symptom onset until death, but patients can survive for 20 years or more after the initial

diagnosis of AD is made (Siegel).

[0004] A large body of evidence suggests Alzheimer's disease can be viewed as a

syndrome of protein misfolding and aggregation (Selkoe D.J. et al. Arch Neurol

(2005) 62: 192-5, Walsh D.M.. et al Protein Pept. Lett. (2004) 1 1 : 213-28 ). This syndrome accounts for the microscopic features recognized as the hallmarks of the

disease: extraneuronal plaques, composed primarily of Aβ peptide, and intraneuronal

neurofibrillary tangles (NFT), composed primarily of hyperphosphorylated tau protein (Mirra S. S., et al, Neurology (1991) 41 : 479-86). In addition to Aβ and tau,

aggregates of α-synuclein have also been implicated in AD pathogenesis (Duda J. E.,

et al,. J Neurosci. Res. (2000) 61 : 121 -7), and may contribute to the widespread cell loss, particularly of cholinergic neurons, in AD brain. Inhibiting the

misfolding/aggregation of these proteins, and particularly inhibiting all three at once,

is thus of great therapeutic interest.

[0005] Accordingly, there exists a need in the art for an agent which can be used for the treatment of Alzheimer's disease and other protein folding disorders.

[0006] U.S. Application Serial No. 1 1/443.396, U.S. Publication No. 2007-0015813, filed May 30, 2006 is hereby incorporated by reference in its entirey for all purposes. All other documents referred to herein are incorporated by reference in their entireties

for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

[0007] It is an object of the present invention to provide compounds and methods for

treating protein folding disorders.

(0008] It is an object of certain embodiments of the present invention to provide compounds and methods for treating neurodegenerative diseases such as, e.g.,

Alzheimer ^' s disease, tauopathies, cerebral amyloid angiopathy, Lewy body diseases

(e.g. Parkinson's disease), dementia, tauopathies, cerebral amyloid angiopathies, Huntington ^' s disease and prion-based spongiform encephalopathy.

[0009] It is an object of certain embodiments of the present invention to provide

compounds and methods for treating systemic amyloidoses such as, e.g.. secondary systemic amyloidosis, particularly those affecting the peripheral nerves, spleen,

kidney, heart, intestine, smooth muscle or pancreas, and type Il diabetes.

[0010] It is an object of the present invention to provide pharmaceutical compositions comprising an effective amount of a compound for treating protein folding disorders.

[0011] It is an object of certain embodiments of the present invention to provide pharmaceutical compositions comprising an effective amount of a compound for treating neurodegenerative diseases such as, e.g., Alzheimer ^' s disease, tauopathies,

cerebral amyloid angiopathy, Lewy body diseases (e.g. Parkinson's disease).

dementia, Huntington's disease, prion-based spongiform encephalopathy and a combination thereof.

[0012] It is an object of certain embodiments of the present invention to provide

pharmaceutical compositions comprising an effective amount of a compound for treating systemic amyloidoses, particularly those affecting the peripheral nerves,

spleen, kidney, heart, intestine, smooth muscle or pancreas.

[0013] It is an object of certain embodiments of the present invention to provide

compounds, methods and pharmaceutical compositions for inhibiting tau protein aggregation in a subject or patient.

[0014] It is an object of certain embodiments of the present invention to provide

compounds, methods and pharmaceutical compositions for inhibiting AB aggregation in a subject patient.

[0015] It is an object of certain embodiments of the present invention to provide compounds, methods and pharmaceutical compositions for inhibiting α-synuclein aggregation.

[0016] Other objects and advantages of the present invention will become apparent from the disclosure herein.

[0017] In certain embodiments, the present invention is directed to a compound of formula (I):

or a pharmaceutical acceptable salt thereof, wherein A and B are each

independently a substituted or unsubstituted mono-, bi- or tri-cyclic aromatic or

heteroaromatic substituent; wherein said substituted mono-, bi- or tri-cyclic aromatic or heteroaromatic substituent may each be independently substituted with at least one substituent

selected from the group consisting of alkyl. alkenyl. alkynyl, amide, cycloalkyl. heterocycloalkyl. cycloalkenyl, cycloalkynyl, aryl, arylalkyl, alkylaryl, alkylaryl

sulfonyl, alkylcarbonyl, alkyl ester, alkoxy. trihalomethoxy, aryloxy, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, thio, thioether, cyano, nitro. halogen, carboxylic acid, sulfonic acid, phenyl, benzyl, indolyl, methoxy or ethoxy

group; , wherein G is alkoxy (e.g., methoxy, ethoxy, propoxy), hydroxy,

carboxy, amino, amide, cyano;

wherein Z is a bond, carbon, or a diamino phenyl (e.g.

, wherein K is selected from the

group consisting of H, OH, OCH^,, COOH, and NO ₂ ; wherein ni and n ₂ are each independently an integer from O to 1 ; and

R ¹ and R are each independently selected from the group consisting of hydrogen, alkyl. cycloalkyl, alkoxy. hydroxy, halogen, and aryl. or together represent

the group =0 or =S.

[0018] As used herein, the term "alkyl" means a substituted or unsubstituted linear or

branched saturated aliphatic hydrocarbon group having a single radical and 1-10 carbon atoms. Examples of alkyl groups include methyl, propyl, isopropyl. butyl, n-

butyl, isobutyl. sec-butyl, tert-butyl, and pentyl. A branched alkyl means that one or

more alkyl groups such as, e.g., methyl, ethyl or propyl, replace one or both hydrogens in a -CH ₂ - group of a linear alkyl chain. The term "lower alkyl ^" ' means an alkyl of 1 -4 carbon atoms.

[0019] The term "haloalkyl" means an "alkyl' ^" as defined above connected to a halogen radical (e.g., fluorine, chlorine, iodine, bromine, or astatine).

[0020] The term ''alkoxy" means an "alkyl" as defined above connected to an oxygen

radical.

[0021] The term "cycloalkyl" means a substituted or unsubstituted non-aromatic mono- or multicyclic hydrocarbon ring system having a single radical and 3-12 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, and cyclohexyl. Exemplary multicyclic cycloalkyl rings include

adamantyl and norbornyl.

[0022] The term "alkenyl" means a substituted or unsubstituted linear or branched aliphatic hydrocarbon group containing a carbon-carbon double bond having a single

radical and 2-10 carbon atoms.

[0023] A "'branched" alkenyl means that one or more alkyl groups such as, e.g.. methyl, ethyl or propyl replace one or both hydrogens in a -CH ₂ - or -CH= linear

alkenyl chain. Exemplary alkenyl groups include ethenyl, 1 - and 2-propenyl. 1-. 2- and 3-butenyl. 3-methylbut-2-enyl, heptenyl, octenyl and decenyl.

[0024] The term "cycloalkenyl" means a substituted or unsubstituted non-aromatic monocyclic or multicyclic hydrocarbon ring system containing a carbon-carbon double bond having a single radical and 3 to 12 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopropenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. An exemplary multicyclic cycloalkenyl ring is norbornenyl.

[0025] The term "alkynyl" means a linear or branched aliphatic hydrocarbon group

containing a carbon-carbon triple bond having a single radical and 2-10 carbon atoms.

[0026] A "branched" alkynyl means that one or more alkyl groups such as, e.g., methyl, ethyl or propyl replace one or both hydrogens in a -CH ₂ - linear alkynyl chain.

[0027] The term "cycloalkynyl" means a non-aromatic monocyclic or multicyclic

hydrocarbon ring system containing a carbon-carbon triple bond having a single

radical and 3 to 12 carbon atoms.

[0028] The term "aryl" means a carbocyclic aromatic ring system containing one, two or three rings which may be attached together in a pendent manner or fused, and

containing a single radical. Exemplary aryl groups include phenyl, naphthyl and

acenaphthyl. "Aryl" includes heteroaryl.

[0029] The term "heteroaryl" means unsaturated heterocyclic radicals. Exemplary

heteroaryl groups include unsaturated 3 to 6 membered hetero-monocyclic groups

containing 1 to 4 nitrogen atoms, such as, e.g., pyrrolyl, pyridyl, pyrimidyl, and

pyrazinyl; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as, e.g., indolyl, quinolyl and isoquinolyl; unsaturated 3 to 6- membered hetero-monocyclic groups containing an oxygen atom, such as, e.g., furyl; unsaturated 3 to 6 membered hetero-monocyclic groups containing a sulfur atom, such as, e.g., thienyl; unsaturated 3 to 6 membered hetero-monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, e.g., oxazolyl; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen

atoms, such as, e.g., benzoxazolyl; unsaturated 3 to 6 membered hetero-monocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as, e.g.,

thiazolyl; and unsaturated condensed heterocyclic group containing 1 to 2 sulfur

atoms and 1 to 3 nitrogen atoms, such as, e.g.. benzothiazolyl. The term "heteroaryF ^* also includes unsaturated heterocyclic radicals, wherein "heterocyclic ^" ' is as previously described, in which the heterocyclic group is fused with an aryl group, in which aryl is as previously described. Exemplary fused radicals include benzofuran.

benzodioxole and benzothiophene.

[0030] The term "carbonyl", whether used alone or with other terms, such as, e.g.,

"alkoxycarbonyl", is (C=O).

[0031] The term "alkylcarbonyl" includes radicals having alkyl radicals, as defined above, attached to a carbonyl radical.

[0032] The term "carboxylic acid" is CO ₂ H.

[0033] All of the cyclic ring structures disclosed herein can be attached at any point

where such connection is possible, as recognized by one skilled in the art.

[0034] The terms "bi-indole' ^" and "bis-indole" are used interchangeably.

[0035] As used herein, the term ''subject" includes a human or an animal such as, e.g., a companion animal or livestock.

[0036] The term "effective amount" means that amount of a drug or pharmaceutical

agent that will elicit the biological or medical response of a tissue, system, animal, or

human that is being sought, for instance, by a researcher or clinician. Furthermore,

the term "therapeutically effective amount" means any amount which, as compared to

a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0037] Further, as used herein, "an effective amount" or "a therapeutically effective ^" '

amount is also intended to refer to the total amount of the active compound of the

method that is sufficient to show a meaningful patient benefit. This term is further

intended to refer to an amount that returns to normal, either partially or completely,

physiological or biochemical parameters associated with induced cellular damage. A

non-limiting example of an effective dose range for a pharmaceutical composition of

the invention is 0.01 -500 mg/kg of body weight per day. more preferably 0.01 -50

mg/kg of body weight per day. and still more preferably 0.05-50 mg/kg of body weight per day.

[0038] The term "patient" includes a subject in need of therapeutic treatment.

[0039] As used herein, the term "halogen"' or "halo ^" is interchangeable with the term '"halide" and includes fluoride, bromide, chloride, iodide or astatide.

[0040] For purposes of the present invention the abbreviation '"1Yp' ^" means tryptophan.

[0041] For purposes of the present invention the abbreviations "Aβ4CT and '"Aβ l -40 ^"

are synonymous, likewise. ^* 'Aβ42" and "Aβl-42'\

[0042] The invention disclosed herein is meant to encompass all pharmaceutically

acceptable salts thereof of the disclosed compounds. The pharmaceutically acceptable salts include, but are not limited to, metal salts such as, e.g., sodium salt,

potassium salt, cesium salt and the like; alkaline earth metals such as, e.g., calcium

salt, magnesium salt and the like; organic amine salts such as, e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like; inorganic acid salts such as, e.g.,

hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such

as. e.g., formate, acetate, trifluoroacetate, maleate, fumarate, tartrate and the like;

sulfonates such as. e.g., methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such as, e.g., arginate, asparginate, glutamate and the like.

[0043J The invention disclosed herein is also meant to encompass all prodrugs of the disclosed compounds (see Bundgaard, H. (ed.), "'Design of Prodrugs", published by Elsevier, Amsterdam (1985)). Prodrugs are considered to be any covalently bonded carriers which release the active parent drug in vivo. An example of a prodrug would be an ester which is processed in vivo to a carboxylic acid or salt thereof.

[0044] The invention disclosed herein is also meant to encompass the in vivo

metabolic products of the disclosed compounds. Such products may result for

example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes.

Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabeled compound of the invention, administering it parenterally

in a detectable dose to an animal such as. e.g., a rat, mouse, guinea pig, monkey, or to

man, allowing sufficient time for metabolism to occur and isolating its conversion

products from the urine, blood or other biological samples. One skilled in the art recognizes that interspecies pharmacokinetic scaling can be used to study the

underlining similarities (and differences) in drug disposition among species, to predict drug disposition in an untested species, to define pharmacokinetic equivalence in

various species, and to design dosage regimens for experimental animal models, as discussed in Mordenti, Man versus Beast: Pharmacokinetic Scaling in Mammals,

1028. Journal of Pharmaceutical Sciences, Vol. 75, No. 1 1 , November 1986.

[0045] The invention disclosed herein is also meant to encompass the disclosed

compounds being isotopically-labelled by having one or more atoms replaced by an

atom having a different atomic mass or mass number. Examples of isotopes that can

be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, e.g., ² H, ³ H. ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ 0, ³¹ P, ³² P, ³⁵ S. ¹⁸ F, and ³⁶ Cl. respectively. Some of the compounds disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present invention is also meant to encompass all such possible forms as well as their racemic and

resolved forms and mixtures thereof. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified

otherwise, it is intended to include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention as well.

[0046] As used herein, the term "stereoisomers" is a general term for all isomers of

individual molecules that differ only in the orientation of their atoms in space. It

includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

[0047] The term "chiral center" refers to a carbon atom to which four different groups

are attached.

[0048] The term "enantiomer" or "enantiomeric" refers to a molecule that is

nonsuperimposeable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image

rotates the plane of polarized light in the opposite direction.

[0049] The term "racemic" refers to a mixture of equal parts of enantiomers and which is optically inactive.

[0050] The term "resolution" refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.

BRIEF DESCRIPTION OF THE DRAWINGS

10051] Figure 1 is % cell viability graph for the cell viability assay performed on QR-

0161 in Example 50A.

[0052] Figures 2 and 3 are % cell viability graphs for the cell viability assay performed on QR-Ol 12 in Example 50A.

[0053] Figure 4 is a graph (ReI. Fluorescene v. Time) for QR-0292 for assays of

Example 52.

[0054] Figure 5 is a graph (ReI. Fluorescene v. Time) for QR-0319 for assays of Example 52.

[0055] Figure 6 is a graph (% aggregation v. cone.) for QR-0217 for assays of

Example 52.

[0056] Figure 7 is a graph (% aggregation v. cone.) for QR-0244 for assays of Example 52.

[0057] Figure 8 is a SDS PAGE technique showing the effect of QR-0273 on Aβl -42

self-assembly.

[0058] Figure 9 is a SDS PAGE technique showing the effects of compounds on

Aβl -40 self-assembly following ThT aggregation assay of Example 52.

[0059] Figure 10 a SDS PAGE technique showing the effects of compounds on Tau 441 self-assembly following ThS aggregation assay of Example 52.

[0060] Figure 1 1 is a TEM micrograph of Aβ 1-40 (20 μM) incubated in the absence

(a) and presence of compounds (b,c), taken following the ThT aggregation assay of

Example 52.

[0061] Figure 12 is a TEM micrograph of Aβ l-40 (20 μM) incubated in the absence

of ThT and in the absence (a) or presence (b,c) of compounds.

[0062] Figure 13 is a TEM micrograph of Aβ 1 -42 (20 μM) incubated in the absence

of ThT and in the absence (a) or presence (b,c) of compounds.

[0063] Figure 14 is a TEM micrograph of Tau 441 (6 μM) incubated in the absence

(a) and presence of compounds (b,c), taken following the ThS aggregation assay of Example 52.

[0064] Figure 15 is a graph of effects of compounds (QR-0244. QR-0263. QR-0281, and QR-0262, A-D, respectively) on Tau 441 aggregation after 24 hours incubation (37 ⁰ C) of Example 52.

[0065] Figure 16 is a graph of effects of compounds (QR-Ol 89. QR-0194, QR-0212,

QR-0217. QR-0176, A-E, respectively and resveratrol, F) on α-synuclein (4 μM)

aggregation at 100 μM (white bars) and 20 μM (black bars) after 96 hours incubation

(37 ⁰ C) of Example 52.

[0066] Figure 17 is a graph of compounds (QR-0164, QR-0147, and QR-0162. G-I,

resepectively) on α-synuclein aggregation (4 μM) at 50 μM (white bars) and 10 μM

(black bars) after 96 hours incubation (37 ⁰ C) of Example 52.

[0067] Figure 18 is a graph showing compound QR-0217 (50 μM) significantly

(P=O.022) rescuing impairment of LTP in APP/PS1 transgenic mice hippocampal

slices (capability of QR-0217 to reduce memory impairments caused by AB neurotoxicity).

DETAILED DESCRIPTION

[0068J Although the toxic species of protein aggregate are poorly characterized for

the proteins involved in AD, there is increasing evidence that "small-n' ^" oligomers, possibly trimers (Townsend M. et al, J. Physiol. f2006) 572(Pt 2): 477-92) or dodecamers (Lesne, S., el al, Nature (2006) 440: 352-7) in the case of Aβ, are the

primary mediators of neurotoxicity. Regardless of the size of Aβ, tau and α-synuclein

aggregates, compounds that bind to and/or alter the distribution of toxic aggregates are likely to disrupt the toxic action of these aggregates on neurons and may have potential to reduce toxicity of these aggregates.

[0069] This can happen in a number of different ways, for example: 1) compounds

can stabilize monomers or aggregates smaller than the one(s) that induce neurotoxicity, thereby reducing the pool of toxic aggregates; 2) compounds may bind

to toxic aggregates and block their detrimental interaction at neurons; 3) in binding to toxic aggregates, compounds may promote their breakdown into smaller, non-toxic aggregates; 4) metabolism/clearance of Aβ may be facilitated by compounds which promote a shift to smaller aggregate sizes, etc. Anti-Aβ drug candidates which may

function through one or more of these pathways include tramiprosate (Kisilvesky, Szarek & Weaver, 1997-2005; Gervais et al.. 2006), currently in Phase III human

clinical trials, and isomers of inositol (McLaurin, 2006).

COMPOUNDS

[0070] The compounds of the present invention are recently-developed small organic

molecules (e.g., "bi-aromatics") capable of binding to and modulating or altering, e.g.,

inhibiting, the aggregation of amyloidogenic proteins implicated in AD, i.e. Aβ, tau

and α-synuclein (Carter et al, US Patent Application No. 1 1/443,396. U.S.

Publication No. 2007-0015813.

[0071] It is believed that the compounds and methods of the present invention will

result in a therapeutic outcome by binding the Hisi3-Hisi4-Glnιs-Lysi ₆ region of Aβ

via cation-π interactions, rather than cationic-anionic interactions (See Giulian, D. et

al "The HHQK Domain of β-Amyloid Provides a Structural Basis for the

Immunopathology of Alzheimer's Disease," The Journal of Biological Chemistry, Vol. 274, No. 45. pp 29719-29726, 1988). Without being bound by theor>. it is

believed that, in certain embodiments, the compounds of the present invention (e.g.,

containing two aromatic groups as described herein) would form cation-π interactions

at two of the three cationic residues in the Hisi ₃ -Hisi4-Glni ₅ -Lysi ₆ region and thereby

interfere with Aβ aggregation.

[0072] Further, in certain embodiments, unlike tramiprosate (Gervais, F., et ai, "Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain

amyloidosis.' ^" Neurobiol Aging, online pre-publication. May 1 , 2006) and inositol (McLaurin, J., et ul., Nat. Med. (2006) 12: 801-8), which have been suggested to work

only against Aβ, the compounds of the present invention (e.g., bi-aromatics) in

addition to acting on Aβ may also act on tau and/or α-synuclein, thereby providing

additive or. in certain embodiments, synergistic effects (i.e. by acting at three different

targets in AD, the net effect of the compounds may be greater than the sum of the

individual effects). Further, in certain embodiments, because compounds of these embodiments are non-peptidic, small organic molecules, they are expected to

overcome deficiencies of peptidic compounds such as poor pharmacokinetics, e.g., degradation by proteases.

[0073] In certain embodiments, the present invention is directed to a compound of formula (I):

(D

or a pharmaceutically acceptable salt thereof, wherein A and B are each independently a substituted or unsubstited mono-, bi- or tri-cyclic aromatic or

heteroaromatic substituent; wherein said substituted mono-, bi- or tri-cyclic aromatic or heteroaromatic

substituent may each be independently substituted with at least one substituent selected from the group consisting of alkyl. alkenyl, alkynyl, amide, cycloalkyl. heterocycloalkyl, cycloalkenyl. cycloalkynyl, aryl. arylalkyl. alkylaryl,

alkylarylsulfonyl, alkylcarbonyl, alkyl ester, alkoxy. trihalomethoxy, aryloxy,

arylcarbonyl. alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, thio, thioether.

cyano, nitro, halogen, carboxylic acid, sulfonic acid, phenyl, benzyl, indolyl, methoxy

or ethoxy group, wherein any of these substituents are either substituted or

unsubstituted; wherein G is alkoxy (e.g., methoxy. ethoxy, propoxy),

hydroxy, carboxy. amino, amide, cyano;

wherein Z is a bond, carbon, or a

, wherein K is selected from the group consisting of H, OH, OCH ₃ , COOH. halogen, and NO ₂ ;

wherein ni and n ₂ are each independently an integer from O to 1 ; and

Ri and R ₂ are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, halogen, and aryl, or together represent

the group =0 or =S.

[0074] In certain embodiments. A and B of formula (I) are each independently

selected from the group consisting of substituted or unsubstituted indolyl,

benzofuranyl, naphalinyl. naphthyl, benzofuranyl. benzodiaxonyl. phenyl, benzol,

phenol, benzothiophenyl. benzopiperidim 1, pyridyl, pyrrolyl. thiophenyl, furanyl,

triazolyl, quinolinyl, isoquinolinyl, benzooxazolyl and benzimidazolyl, wherein said

substitution, if present, is with at least one substituent selected from the group

consisting of alkyl, haloalkyl, alkenyl. alk}nyl, cycloalkyl. heterocycloalkyl, cycloalkenyl, cycloalkynyl, aryl. arylalkyl. alkylaryl, alkylarylsulfonyl, alkylcarbonyl.

alkyl ester, aryl ester, alkoxy, trihalomethoxy. aryloxy, arylcarbonyl, alkoxycarbonyl,

aryloxycarbonyl, amino, hydroxy, thio, thioether, cyano. nitro. halogen, carboxylic acid, sulfonic acid, benzyl, methoxy or ethox} group.

[0075] In certain embodiments, at least one of A and B is selected from the group consisting of indolyl, benzofuranyl, naphthalinyl, benzofuranyl, benzodioxanyl,

benzopiperidinyl, phenolyl. methoxybenzyl. and ethoxybenzyl, all unsubstituted or substituted with the substituents as defined above.

[0076] In certain embodiments, both A and B of formula (I) are unsubstituted indolyl or an indolyl substituted with the substituents as defined above.

[0077] In certain embodiments, the present invention is directed to a compound of

formula (II):

or a pharmaceutically acceptable salt thereof wherein R ₃ , R _3a , R ₄ R ₅ Rs ₃ , R ₆ ,

R ₇ Rg, R8b, and R8 _C are each independently selected from the group consisting of hydrogen, halogen, nitro, alkoxy (e.g., methoxy. ethoxy, propoaxy, etc.), alkyl, amide

(p a

-CONH?), haloalkyl, aryl, alkylaryl, hydroxy, carboxy, cyano, carboxyalkyl (e.g., CH ₃ O ₂ C-. etc.). alkylcarbonyl, alkyl ester and carboxylic acid; wherein said halogen is fluorine, chlorine, iodine, bromine, or astatine;

Rsa is hydrogen, lower alkyl or carboxylic acid;

R9 is hydrogen, substituted or unsubstitued benzyl, or does not exist;

T is a bond, carbo wherein

K is selected from the group consisting of H, OH, OCH ₃ , COOH, and NO ₂ ;

L and Y are each independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur; and

Z is selected from the group consisting of carbon and nitrogen. It would be understood by a person skilled in the art that in a compound such as, for example, formula (II), when L is oxygen, its valency is complete and so R9 does not exist, and likewise when Z is nitrogen, R ₆ does not exist.

[0078] In certain embodiments, L and Y are both nitrogens, and R^ ₃ , R _4. and Rs are

each hydrogen.

[0079] In certain embodiments, the compound of formula (II) is 3-(2-

methoxynaphthalen-6->l)-l H-indole-5-carboxylic acid.

[0080] In certain embodiments, the compound of formula (II) is 3-(2- hydroxynaphthalen-6-yl)-l H-indole-5-carboxylic acid.

[0081 J In certain embodiments, the present invention is directed to a compound of

formula (III):

or a pharmaceutically acceptable salt thereof,

wherein R) ₀ , Rioa. Riob, Rn- R12, Rn, Ri 3a- Ri3b, Ri3c Rπd. Rue and R _]4 are each independently selected from the group consisting of hydrogen, halogen, nitro. alkoxy

(e.g., methoxy, ethoxy, propoxy. etc.), alkyl (e.g.. methyl, ethyl, propyl, etc.), amide (e.g., -CONH ₂ ); haloalkyl, hydroxy, carboxy, carboxyalkyl (e.g.. CH3O2C-, etc.), cyano, alkylcarbonyl. alkyl ester and carboxylic acid; wherein said halogen is fluorine, chlorine, iodine, bromine, or astatine;

Ri _Oc is hydrogen or substituted or unsubstitued benzyl,

Y and L are each independently selected from the group consisting of carbon,

nitrogen, oxygen and sulfur. In certain embodiments of the present invention, Rio _a is

carboxylic acid and Ri ₁ and R12 are each independently hydroxy.

[0082] In certain embodiments, L is oxygen or nitrogen, Y is carbon, and Rio, Rio _b ,

R13. Ri3a, Ri3b, Ri ₃ c- Rud, and Ri ₄ are each hydrogen.

[0083] In certain embodiments, the present invention is directed to a compound of

formula (IV):

or a pharmaceutically acceptable salt thereof.

wherein Ri ₆ , R _16a , R _16b , Ri ₇ , Ri ₈ , Ri _8a , Risb, R|9, Ri 9a, Ri%- Ri9c and R ₂₀ are each independently selected from the group consisting of hydrogen, halogen, nitro, alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), alkyl, amide (e.g., -CONH ₂ ), haloalkyl,

hydroxy, carboxy, carboxyalkyl (e.g.. CH ₃ O ₂ C-, etc.), cyano, alkylcarbonyl, alkyl

ester and carboxylic acid; wherein said halogen is fluorine, chlorine, iodine, bromine,

or astatine;

R ₁₅ is is hydrogen or substituted or unsubstituted benzyl; Y and L are each independently selected from the group consisting of carbon,

nitrogen, oxygen and sulfur.

[0084] In certain embodiments R ₁₅ is benzyl, and Rn is a hydroxy group.

[0085] In certain embodiments, the present invention is directed to a compound of formula (V):

or a pharmaceutically acceptable salt thereof,

wherein R ₂ 1 , R22, R22a, R-22b, R23. R24. R-25, R25a- R25b, R25C are each independently selected from the group consisting of hydrogen, halogen, nitro. alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), alkyl, amide (e.g., -CONH ₂ ). haloalkyl, hydroxy, carboxy. cyano, alkyl carbonyl, alkyl ester and carboxylic acid; wherein said halogen is

fluorine, chlorine, iodine, bromine, or astatine.

[0086] In certain embodiments, the present invention is directed to a compound of formula (VI):

or a pharmaceutically acceptable salt thereof, wherein R ₂₆ and R ₂₇ are are each independently selected from the group consisting of hydrogen, halogen, nitro, amino, amide, alkoxy (e.g., methoxy. ethoxy, propoxy, etc.). alkyl. amide (e.g., -CONH?), haloalkyl, hydroxy, carboxy, cyano, alkylcarbonyl, alkyl

ester and carboxylic acid; wherein said halogen is fluorine, chlorine, iodine, bromine, or astatine;

and mi and ni ₂ are each independently an integer from 0 to 5.

[0087] In certain embodiments, the present invention is directed to a compound of

formula (VlI):

or a pharmaceutically acceptable salt thereof,

wherein R2 _X and R ₂ 9 are each independently selected from the group consisting of

hydrogen, halogen, nitro, amino, amide (e.g., -CONH2). alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), alkyl, haloalkyl, hydroxy, carboxy, cyano, alkylcarbonyl, alkyl

ester and carboxylic acid; wherein said halogen is fluorine, chlorine, iodine, bromine,

or astatine;

J is oxygen or NH;

Ei and E2 are each independently carbon or nitrogen, provided that that Ei and E ₂ are not both nitrogens;

and mi and ni ₂ are each independently an integer from 0 to 5. In certain

embodiments, both Ei and E2 of formula (VII) are not nitrogen.

[0088] In certain embodiments, the present invention is directed to a compound of

formula (VIII):

or a pharmaceutically acceptable salt thereof,

wherein V and W are each independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur;

R30. R- ₃ 0a- R- ₃ 0b and R ₃ O ₀ are each independently selected from the group consisting of hydrogen, halogen, nitro, amide (e.g., -CONH2), alkoxy (e.g., methoxy, ethoxy,

propoxy, etc.), alkyl, haloalkyl, hydroxy, carboxy, cyano, alkylcarbonyl, alkyl ester

and carboxylic acid; wherein said halogen is fluorine, chlorine, iodine, bromine, or astatine;

and qi and q ₂ are each independently an integer from 0 to 4;

R ₃₁ and R _{3 I a} are each independently selected from the group consisting of hydrogen and unsubstituted or substituted benzyl.

[0089] In certain embodiments, the present invention is directed to a compound of formula (IX):

or a pharmaceutically acceptable salt thereof. wherein D and G are each independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur;

Rioo and R _1O i are each independently selected from the group consisting of hydrogen, halogen, nitro, amide (e.g.. -CONH ₂ ), alkoxy (e.g.. methoxy, ethoxy. propoxy, etc.), alkyl, haloalkyl, hydroxy, carboxy. cyano, alkylcarbonyl, alkyl ester and carboxylic

acid; wherein said halogen is fluorine, chlorine, iodine, bromine, or astatine; and

qi and q ₂ are each independently an integer from 1 to 4.

[0090] In certain embodiments, the present invention is directed to acompound of

formula (X):

wherein U is selected from the group consisting of carbon, nitrogen, oxygen and sulfur;

L is selected from the group consisting of carbon and nitrogen;

R32, R ₃ 2a and R ₃₂ b are each selected independently from the group of hydrogen, halogen, nitro, amide (e.g.. -CONH ₂ ). alkoxy (e.g., methoxy. ethoxy, propoxy, etc.), alkyl, haloalkyl, hydroxy, carboxy, cyano, alkylcarbonyl, alkyl ester and carboxylic acid; wherein said halogen is fluorine, chlorine, iodine, bromine, or astatine; and and q is an integer from 0 to 4.

[0091] In certain embodiments, the present invention is directed to a compound of formula (XI):

or a pharmaceutically acceptable salt thereof, wherein R ₂₀₀ is selected from the group

consisting of halogen, hydroxy, alkyl. alkoxy and carboxylic acid; and X is selected

from the group consisting of nitrogen, oxygen and sulfur. In certain embodiments,

R ₂₀₀ is carboxylic acid and X is nitrogen.

[0092] In certain embodiments, the present invention is directed to a compound of

formula (XIIa or XIIb):

or a pharmaceutically acceptable salt thereof.

[0093] In certain embodiments, the present invention is directed to a compound of formula (XIII):

or a pharmaceutically acceptable salt thereof, wherein R ₃₅ , R ₃₆ . R37, R ₃₈ , R ₃ 9. R ₄ 0, R ₄ I,

R ₄₂ , R ₄₃ , R ₄₄ , R ₄₅ . R ₄₆ , R ₄ 7. and R ₄₈ are each independently selected from the group

consisting of hydrogen, halogen, nitro, amide (e.g.. -CONH ₂ ), alkoxy (e.g., methoxy.

ethoxy. propoxy, etc.), alkyl, haloalkyl, hydroxy, carboxy, cyano. alkylcarbonyl, alkyl

ester and carboxylic acid; wherein said halogen is fluorine, chlorine, iodine, bromine,

or astatine. In certain embodiments, R ₃₅ , R ₃₉ and R ₄₈ are hydroxy groups, and R ₃₆ ,

R37, R ₃ 8, R40. R41. R42- R43, R44, R45, R46- and R47 are each hydrogen.

[0094] In certain embodiments, the present invention is directed to a compound of

formula (XIV):

or a pharmaceutically acceptable salt thereof, wherein R ₅₀ , R5 ₁ . R5 ₂ - R ₅₃ , R ₅₄ , R ₅₅ , R56-

R57, R58, R59, Rόo, Rόi, Rβ2, and R ₆₃ are each independently selected from the group

consisting of hydrogen, halogen, nitro, amide (e.g., -CONH ₂ ), alkoxy (e.g., methoxy,

ethoxy, propoxy. etc.), alkyl, haloalkyl, hydroxy, carboxy. cyano. alkylcarbonyl, alkyl ester and carboxylic acid; wherein said halogen is fluorine, chlorine, iodine, bromine, or astatine.

[0095] In certain embodiments, the present invention is directed to a compound of

formula (XV):

(XV) or a pharmaceutically acceptable salt thereof, wherein R ₆ ?, R^e, R07, Rό8, R-69, R70- R71.

R ₇ 2, R7 ₃ , R74, R75, R ₇₆ . R77. and R78 are each independently selected from the group consisting of hydrogen, halogen, nitro. amide (e.g., -CONH ₂ ). alkoxy (e.g., methoxy.

ethoxy, propoxy. etc.), alkyl, haloalkyl, hydroxy, carboxy. cyano, alkylcarbonyl, unsubstituted or substituted benzyl, alkyl ester and carboxylic acid; wherein said

halogen is fluorine, chlorine, iodine, bromine, or astatine;

L, Y and Z is each independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur;

R ₇ 9 is hydrogen, lower alkyl. or unsubstituted or substituted benzyl.

[0096] In certain embodiments, the present invention is directed to a compound of formula (XVI):

or a pharmaceutically acceptable salt thereof, wherein R ₈₀ , Rg i, R ₈ ?, Rs3- Rs4, Rg?, Rχ6, and R ₈₇ are each individialy selected from the group consisting of hydrogen, halogen,

nitro, amide (e.g., -CONH ₂ ), alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), alkyl, haloalkyl, hydroxy, carboxy, cyano, alkylcarbonyl, unsubstituted or substituted

benzyl, alkyl ester and carboxylic acid; wherein said halogen is fluorine, chlorine, iodine, bromine, or astatine. In certain embodiments, R ₈₃ is halogen, Ru and R ₈₅ are

both hydroxy groups, and Rgo, Rg ι, Rg2- Rgό. and R ₈₇ are all hydrogens. In certain

emdodiments, Rg ₄ and R ₈ , are both hydroxy groups, and R ₈ o, R ₈ 1. R ₈₂ , Rg3, R ₈₆ - and R ₈₇ are all hydrogens.

[0097] In certain embodiments, the present invention is directed to a compound of formula (XVII):

or a pharmaceutically acceptable salt thereof, wherein R9 ₀ , R9 ₁ , R ₉₂ , R ₉₃ are each

independently selected from the group consisting of hydrogen, halogen, nitro, amide

(e.g., -CONH2), alkoxy (e.g., methoxy, ethoxy, propoxy, etc.), alkyl, haloalkyl,

hydroxy, carboxy, cyano, alkylcarbonyl. unsubstituted or substituted benzyl, alkyl ester and carboxylic acid; wherein said halogen is fluorine, chlorine, iodine, bromine, or astatine;

R ₉₄ is hydrogen, unsubstituted or substituted benzyl, or ; wherein W is alkoxy (e.g., methoxy. ethoxy, propoxy), hydroxy, carboxy. amino, amide, cyano, and p is an integer 0 or 1 ;

R ₉₅ and R ₉₆ is hydrogen, , wherein G is alkoxy (e.g., methoxy. ethoxy,

propoxy). hydroxy, carboxy, amino, amide, cyano;

[0098] In certain embodiments, the present invention is directed to a compound of

formula (XVIII):

or a pharmaceutically acceptable salt thereof, wherein Q is a bond, substituted or

unsubstituted lower alkyl

METHODS OF PREPARING

[0099] The compounds of the present invention may be synthesized by a number of methods currently used in the chemical art.

[00100] For example, the compounds may be prepared by using a Suzuki- coupling reaction. The Suzuki-coupling reaction is the organic reaction of an aryl- or vinyl-boronic acid with an aryl- or vinyl-halide catalyzed by a palladium(O) complex. Potassium trifluoroborates and organoboranes or boronate esters may be used in place of boronic acids. Some pseudohalides (for example triflates) may also be used as

coupling partners.

[00101] The first step in the reaction is the oxidative addition of palladium to the halide to form an organo-palladium species. Generally, oxidative addition

proceeds with retention of stereochemistry with vinyl halides, while giving inversion

of stereochemistry with allylic and benzylic halides. The oxidative addition initially

forms the cis-palladium complex, which rapidly isomerizes to the trans-complex. The

next step in the reaction is a reaction with base, which gives an intermediate, which

via transmetallation with the boron-ate complex forms an organopalladium species. Finally, reductive elimination of a desired product restores the original palladium

catalyst and leaves a desired compound. Generally, it is believed that the reductive elimination proceeds with retention of stereochemistry.

[00102] The compounds of the present invention may also be synthesized by

Negishi coupling reaction. The Negishi coupling reaction is a cross coupling reaction involving an organozinc compound, an organic halide (i.e.. aryl. vinyl, benzyl, or allyl) and a nickel or palladium catalyst creating a new carbon-carbon covalent bond. Generically, the Negishi coupling reaction can be represented by the following

scheme.

= a Ik en v I ₁ arvl, a Hy I ₁ benzyl, ptopar g^l R' = akenvl, aiγl, a Iky ny I ₁ alky I ₁ benzyl, altøl

[00103] The active catalyst in this reaction is zerovalent (M ⁰ ) and the reaction

in general proceeds through an oxidative addition step of the organic halide followed

by transmetalation with the zinc compound and then reductive elimination.

[00104] The compounds of the present invention may also be synthesized by

Kumada coupling reaction, which is also a Pd or Ni-catalyzed cross coupling reaction.

This reaction is the direct coupling of Grignard reagents with alkyl, vinyl or aryl

halides, e.g., under Ni-catalysis. The reaction is represented by the following scheme:

= AyI, Vinyl, Alkyl

R ' = AyI ₁ Vin yl X = Cl > Br > I

[00105] In the Kumada coupling reaction, the coupling of Grignard reagents with alkyl, vinyl or aryl halides under Ni-catalysis provides an economic transformation. The Kumada coupling reaction may be the method of choice for the low-cost synthesis of unsymmetrical biaryls of the present invention.

[00106] The compounds of the present invention may also be synthesized by

Stille reaction. The Stille reaction is a chemical reaction coupling an organotin

compound with a sp '-hybridized organic halide catalyzed by palladium. The reaction is represented by the following scheme:

[00107] X is typically a halide, or a pseudohalide such as, e.g., a triflate.

CF ₃ SO ₃ . The reaction is usually performed under inert atmosphere using dehydrated

and degassed solvent. This is because oxygen causes the oxidation of the palladium catalyst and promotes homo coupling of organic stannyl compounds, and these side reactions lead to a decrease in the yield of the desired cross coupling reaction.

[00108] In certain embodiments, prior to conducting a coupling reaction (e.g..

Suzuki-coupling reaction), hydroxy substituent(s), if any, e.g., on the alkyl, vinyl or

aryl halides; an aryl- or vinyl-boronic acid; an organozinc compound; or Grignard

reagent may be protected, e.g., by converting the hydroxy substituent(s) to an alkoxy goup (i.e., methoxy-, -ethoxy, or -propoxy) prior to a coupling reaction, and, then,

once the coupling reaction is completed, converting the alkoxy- group back to

hydroxy group.

[00109] The specific reaction conditions (i.e., temperature, relative amounts of

the ingredients, etc.) will be apparent to one skilled in the art, e.g., from the Examples

given below and general knowledge available in the art.

METHODS OF TREATMENT

[00110] The compounds of the present invention can be administered to anyone requiring treatment of a protein folding disease or systemic amyloidoses. For

example, the compounds are useful for treating Alzheimer's disease, for helping prevent or delay the onset of Alzheimer's disease, for treating patients with MCI (mild

cognitive impairment) and preventing or delaying the onset of Alzheimer's disease in those who would progress from MCI to AD, for treating Down's syndrome, for

treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential

consequences, i.e. single and recurrent lobal hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative

origin, dementia associated with Parkinson's disease, dementia associated with

progressive supranuclear palsy, dementia associated with cortical basal degeneration, dementia associated with tauopathies, and diffuse Lewy body type Alzheimer's disease. Preferably, the compounds and compositions of the invention are particularly

useful for treating or preventing Alzheimer's disease.

[00111 ] In certain embodiments, the invention is directed to a method for treating a protein folding disorder comprising administering a compound or pharmaceutical composition as disclosed herein to a subject wherein the subject is treated for the protein folding disorder.

[00112 J In certain embodiments, the invention is directed to a method for treating a protein folding disorder comprising administering an effective amount of a

compound or pharmaceutical composition as disclosed herein to a patient in need

thereof.

[00113] Preferred doses of the compounds of the present invention are 0.01-

500 mg/kg of body weight per day, more preferably 0.01-50 mg/kg of body weight

per day, and still more preferably 0.05-50 mg/kg of body weight per day.

[00114] In certain embodiments, the present invention is directed to a method for treating a protein folding disorder comprising administering a compound of any of

formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII). (XIII).

(XIV), (XV), (XVI), (XVII) and (XVIII) as described above.

[00115] In certain embodiments, the compound of any of formulas (1), (II).

(Ill), (IV). (V). (VI), (VII), (VIII). (IX), (X), (XI), (XII), (XIII), (XIV). (XV). (XVI). (XVII) and (XVIII) is dosed, e.g.. at a dose of 0.01 -500 mg/kg of body weight per

day, more preferably 0.01-50 mg/kg of body weight per day, and still more preferably

0.05-50 mg/kg of body weight per day.

[00116] In certain embodiments of the present invention, the protein folding disorder being treated is a neurodegenerative disease.

[00117] In certain embodiments of the present invention, the neurodegenerative disease is selected from the group consisting of tauopathies, cerebral amyloid

angiopathy, Lewy body diseases, Alzheimer's disease, dementia, Huntington's

disease, Parkinson ^' s disease, prion-based spongiform encephalopathy and a

combination thereof.

[00118] In certain embodiments, the present invention is directed to a method

for inhibiting tau protein aggregation comprising administering to a subject a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII). (IX), (X). (XI),

(XII), (XIII). (XIV), (XV). (XVI), (XVII) and (XVIII) as disclosed herein, or a

pharmaceutically acceptable salt thereof.

[00119] In certain embodiments, the present invention is directed to a method

for inhibiting AB protein aggregation comprising administering to a subject a

compound of formula (I). (II). (III). (IV), (V). (VI), (VII), (VIII). (IX). (X). (XI), (XII), (XIII), (XIV), (XV). (XVl), (XVII) and (XVIII), as disclosed herein, or a

pharmaceutically acceptable salt thereof.

[00120] In certain embodiments, the present invention is directed to a method for inhibiting α-synuclein protein aggregation comprising administering to a subject a compound of formula (I), (II). (III). (IV), (V), (VI), (VII), (VIII). (IX), (X), (XI),

(XII), (XIII), (XIV), (XV), (XVI), (XVII) and (XVIII) as disclosed herein, or a pharmaceutically acceptable salt thereof.

[00121] In certain embodiments of the disclosed method, the neurodegenerative disease is selected from the group consisting of tauopathies, cerebral amyloid

angiopathy, Lewy body diseases (e.g. Parkinson's disease), Alzheimer ^' s disease,

dementia. Huntington's disease, prion-based spongiform encephalopathy and a

combination thereof.

[00122] In certain embodiments of the disclosed method, the neurodegenerative

disease is Alzheimer ^' s disease.

COMPOSITIONS

[00123] In certain embodiments, the present invention is directed to a

pharmaceutical composition comprising a pharmaceutically acceptable excipient(s)

and an effective amount of a compound of formula (I), (II). (III). (IV). (V), (VI), (VII), (VIII). (IX). (X), (XI), (XII), (XIII), (XIV), (XV), (XVI). (XVII) and (XVIII) to

treat a protein folding disorder, e.g., a neurodegenerative disease such as, tauopathies.

cerebral amyloid angiopathy. Lewy body diseases (e.g. Parkinson's disease).

Alzheimer's disease, dementia, Huntington's disease, prion-based spongiform

encephalopathy and a combination thereof.

[00124] In certain embodiments, the present invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and

an effective amount of a compound of formula (I), (II), (III), (IV), (V). (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII). (XIV), (XV), (XVI). (XVII) and (XVIII) to treat systemic amyloidoses, particularly those affecting the peripheral nerves, spleen and pancreas.

[00125] Various oral dosage forms can be used, including such solid forms as

tablets, gelcaps. capsules, caplets, granules, lozenges and bulk powders and liquid

forms such as, e.g., emulsions, solution and suspensions. The compounds of the

present invention can be administered alone or can be combined with various pharmaceutically acceptable carriers and excipients known to those skilled in the art.

including but not limited to diluents, suspending agents, solubilizers, binders, disintegrants. preservatives, coloring agents, lubricants and the like.

[00126] When the compounds of the present invention are incorporated into

oral tablets, such tablets can be compressed, tablet triturates, enteric-coated, sugar-

coated, film-coated, multiply compressed or multiply layered.

[00127] Liquid oral dosage forms include aqueous and nonaqueous solutions,

emulsions, suspensions, and solutions and/or suspensions reconstituted from non-

effervescent granules, containing suitable solvents, preservatives, emulsifying agents,

suspending agents, diluents, sweeteners, coloring agents, and flavoring agents.

[00128] Alternatively, when the compounds of the present invention are to be

inhaled, they may be formulated into a dry aerosol or may be formulated into an

aqueous or partially aqueous solution.

[00129] In addition, when the compounds of the present invention are incorporated into oral dosage forms, it is contemplated that such dosage forms may provide an immediate release of the compound in the gastrointestinal tract, or alternatively may provide a controlled and/or sustained release through the

gastrointestinal tract. A wide variety of controlled and/or sustained release

formulations are well known to those skilled in the art, and are contemplated for use

in connection with the formulations of the present invention. The controlled and/or

sustained release may be provided by, e.g.. a coating on the oral dosage form or by incorporating the compound(s) of the invention into a controlled and/or sustained

release matrix.

[00130] Specific examples of pharmaceutically acceptable carriers and

excipients that may be used to formulate oral dosage forms, are described in the

Handbook of Pharmaceutical Excipients. American Pharmaceutical Association

(1986). Techniques and compositions for making solid oral dosage forms are described in Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and

Schwartz, editors) 2nd edition, published by Marcel Dekker. Inc. Techniques and

compositions for making tablets (compressed and molded), capsules (hard and soft

gelatin) and pills are also described in Remington's Pharmaceutical Sciences (Arthur Osoi, editor). 1553B l 593 (1980). Techniques and composition for making liquid oral

dosage forms are described in Pharmaceutical Dosage Forms: Disperse Systems. (Lieberman, Rieger and Banker, editors) published by Marcel Dekker, Inc.

[00131] When the compounds of the present invention are incorporated for

parenteral administration by injection (e.g., continuous infusion or bolus injection), the formulation for parenteral administration may be in the form of suspensions, solutions, emulsions in oily or aqueous vehicles, and such formulations may further comprise pharmaceutically necessary additives such as. e.g., stabilizing agents, suspending agents, dispersing agents, and the like. The compounds of the invention may

also be in the form of a powder for reconstitution as an injectable formulation. The

compounds of the present invention may also be. e.g., in the form of an isotonic sterile solution.

[00132] In an aqueous composition, preferred concentrations for the active

compound are 10 M-500 mM, more preferably 10 M-100 niM, still more preferably

10 M-50 mM, and still more preferably 100 M-50 mM.

[00133] The compounds and compositions of the invention can be enclosed in

multiple or single dose containers. The enclosed compounds and compositions can be provided in kits, for example, including component parts that can be assembled for

use. The kit can also optionally include instructions for use in any medium. For

example, the instructions can be in paper or electronic form. For example, a

compound of the present invention in lyophilized form and a suitable diluent may be provided as separated components for combination prior to use. A kit may include a

compound of the present invention and a second therapeutic agent for co¬

administration. The compound of the present invention and second therapeutic agent

may be provided as separate component parts. A kit may include a plurality of

containers, each container holding one or more unit dose of the compound of the invention. The containers are preferably adapted for the desired mode of administration, including, but not limited to tablets, gel capsules, sustained-release capsules, and the like for oral administration; depot products, pre-filled syringes, ampules, vials, and the like for parenteral administration; and patches, medipads, creams, and the like for topical administration.

[00134] The concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors known to those of

skill in the art.

[00135] When treating or preventing these diseases, the compounds of the

invention can either be used individually or in combination. For example, administration may be orally, topically, by suppository, inhalation, subcutaneously,

intravenously, bucally. sublingually, or parenterally.

[00136] The active ingredient may be administered at once, or may be divided

into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being

treated and may be determined empirically using known testing protocols or by

extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and

dosage values may also vary with the severity of the condition to be alleviated. It is to

be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment

of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[00137] The compounds of the invention can be used in combination, with each

other or with other therapeutic agents or approaches used to treat or prevent the

protein folding conditions described above. Such agents include, for example,

cholinesterase inhibitors (such as. e.g., acetylcholinesterase inhibitors and butyrylcholinesterase inhibitors); gamma-secretase inhibitors/modulators; beta- secretase inhibitors; anti-inflammatory agents; anti-oxidants; immunological

approaches; NMDA antagonists; cholesterol lowering agents (such as, e.g., statins); and direct or indirect neurotropic agents.

[00138] Acetylcholinesterase inhibitors include compounds such as, e.g.. tacrine (tetrahydroaminoacridine. marketed as Cognex®), donepezil hydrochloride,

(marketed as Aricept®), rivastigmine (marketed as Exelon®) and galantamine

(Reminyl®).

[00139] Anti-oxidants include compounds such as, e.g., tocopherol, ascorbic acid, beta carotene, lipoic acid, selenium, glutathione, cysteine, coenzyme Q. vitamin

E and ginkolides.

[00140] NMDA (N-methyl-D-aspartate) antagonists include, for example, memantine (Namenda®).

[00141] Immunological approaches include, for example, immunization with beta-amyloid peptides (or fragments thereof) or administration of anti-beta-amyloid antibodies.

[00142] Direct or indirect neurotropics agents include, for example,

Cerebrolysin® and AIT-082 (Emilieu, 2000, Arch. Neurol. 57:454).

[00143] Anti-inflammatory agents include, for example, Cox-II inhibitors such as, e.g., rofecoxib, celecoxib, DUP-697. flosulide, meloxicam, 6-MNA, L-745337, nabumetone. nimesulide. NS-398, SC-5766, T-614, L-768277, GR-253035, JTE-522,

RS-57067-000, SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367. SC-5766.

PD-164387, etoricoxib. valdecoxib, parecoxib and pharmaceutically acceptable salts thereof. Other anti-inflammatory agents include, for example, aspirin, ibuprofen,

diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen. ketoprofen.

indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen,

suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin,

sulindac. tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac. clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid, diflurisal, flufenisal. piroxicam. sudoxicam, isoxicam and

pharmaceutically acceptable salts thereof.

[00144] Statins include, for example, atorvastatin. simvastatin, pravastatin,

cerivastatin, mevastatin, velostatin. fluvastatin. lovastatin, dalvastatin, rosuvastatin, fluindostatin, dalvastain and pharmaceutically acceptable salts thereof.

[00145] Other cholesterol reducing compounds include bile sequestration compounds (e.g., colestipol and cholestyramine); fibrin (e.g., gemfibrozil, fenofibrate, psyllium, wheat bran, oat bran, rice bran, corn bran, konjak flour. Jerusalem artichoke flour, fruit fiber and any other functional food products) and other agents such as, e.g., nicotinic acid (niacin).

[00146] In addition, the compounds of the invention can also be used with

inhibitors of P-glycoprotein (P-gp). The use of P-gp inhibitors is known to those skilled in the art. See for example, Cancer Research, 53, 4595-4602 (1993). Clin. Cancer Res., 2, 7-12 (1996). Cancer Research, 56, 4171 -4179 (1996), International

Publications WO99/64001 and WO01/10387. P-gp inhibitors are useful by inhibiting

P-gp from decreasing brain blood levels of the compounds of the invention. Suitable

P-gp inhibitors include cyclosporin A, verapamil, tamoxifen, quinidine, Vitamin E-

TGPS, ritonavir, megestrol acetate, progesterone, rapamycin, 10.1 1 -

methanodibenzosuberane, phenothiazines. acridine derivatives such as, e.g., GF120918, FK506, VX-710, LY335979, PSC-833, GF-102,918 and other steroids.

[00147] All of the additional agents disclosed above may be administered at the

same or different time and/or route of administration than the compounds of the

present invention.

[00148] The following examples illustrate various aspects of the present

invention, and are not to be construed to limit the claims in any manner whatsoever.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Example 1 Preparation by Suzuki-coupling reaction

[00149] Compounds QR-0159, QR-0160. and QR-0162 were prepared by

Suzuki-coupling reaction. The synthesis reaction is depicted in Scheme 1 below (Ts

is para-toluene sulfonic acid).

Scheme 1

[00150] The following general procedure was used.

General Procedure for Suzuki-coupling reaction

[00151] To a degassed solution of the aryl halide (84, 86, 87 or 90, Schemes 1

and 2) in DMF (4.0 - 6.0 mL) was added aryl boronic acid (53. 55. 63 or 85. 1.2 equiv.), Pd(OAc) ₂ (0.05 equiv.) and K2CO3 (2 equiv.) at room temperature. After degassing and purging with argon (done thrice), the reaction mixture was stirred at 9O ⁰ C. Reaction times varied from 1.5 hours to 12 hours. The mixture was allowed to cool to room temperature and diluted with H ₂ O ( 15 mL). The aqueous solution was

extracted with ethyl acetate (5 x 15 mL) and the combined organic layer was

concentrated under reduced pressure.

[00152] The residue was purified by flash column chromatography to yield the following compounds.

[00153] 6-[l-(Toluene-4-sulfonyl)-indol-6-yl)-nathalen-2-ol (QR-0158).

Beige solid. 40% Yield. ¹ H NMR (CDCl ₃ ) 6.69 (I H, d, J = 3.6), 7.16 (I H. dd, J = 2.4,

8.7), 7.19-7.25 (3H, m), 7.55-7.63 (3H. m). 7.72-7.81 (4H, m), 7.84 (IH, d, J = 8.8),

8.02 (1 H, s), 8.31 (I H, s).

[00154] 6-(Indol-6-yl)-naphthalen-2-ol (QR-0159). White solid. 83% Yield.

[00155] ¹ H NMR (DMSO) 6.47 (I H. s). 7.12 (I H. dd, J = 2.3, 8.7). 7.16 (IH, s). 7.40 (IH, t, J = 2.7), 7.43 (IH, dd. J = 1.3, 8.2), 7.65 (IH, d, J = 8.2), 7.76 (IH, d, J

= 13.5), 7.79 (I H, s), 7.87(1 H. d, J = 6.9), 8.07 (I H. s), 9.72 (IH, s), 1 1.16 ( IH, s); ¹³ C NMR 101.44. 108.95, 109.80, 1 18.86, 1 19.39, 120.91 , 125.17, 126.21. 126.51.

127.04, 127.42, 128.68, 130.10, 133.89, 134.02. 136.37, 137.13, 155.67.

[00156] 6'-Hydroxy-[l,2']-binaphthalenyl-8-carboxylic acid methyl ester

(QR-0160). White solid. 43% Yield. ¹ H NMR (CDCl ₃ ) 2.83 (3H, s), 7.1 1 ( I H. dd, J = 2.5, 8.8), 7.18 (IH, d, J = 2.4), 7.52 (IH. t, J = 7.3), 7.55-7.63 (3H. m), 7.68-7.78 (4H,

m). 7.9 (I H, dd, J = 1.9, 7.5), 8.30 (I H, d, J = 7.3). HRMS: calculated for C ₂₂ Hi ₆ O ₃ m/z [M] ⁺ = 328.1099, found [M] ⁺ = 328.1 107.

[00157] l-Benzyl-3-(6-methoxynaphthalen-2-yl)-indole-5-carboxylic methyl ester (88a). White solid. 22% Yield. ¹ H NMR (acetone-d ₆ ) 3.91 (3H, s), 3.96 (3H, s).

5.63 (2H, s), 6.90 (IH, s), 7.03 (2H, d. J = 6.8), 7.19-7.31 (4H, m), 7.37 (I H. s), 7.46

(I H, d, J = 8.2), 7.51 (IH, dd. J = 1.0, 8.2). 7.80 (IH, d, J = 8.7), 7.85 (IH, d, J =8.7),

7.89 (IH, d, J = 8.2), 7.99 (I H, s), 8.41 ( IH, s).

[00158] l-Benzyl-3-(6-hydroxynaphthalen-2-yI)-indole-5-carboxylic methyl ester (88b). White solid. 26% Yield. ¹ H NMR (CDCl ₃ ) 3.94 (3H. s). 5.40 (2H. s), 6.77 (I H. s), 7.0 (2H, d, J = 7.0), 7.13-7.30 (5H. m). 7.44 (IH, dd, J = 1.4, 8.4). 7.61- 7.67 (2H, m). 7.77 (IH, s). 7.87 (IH, dd. J = 1.42, 8.6), 8.03 (I H. s). 8.44 (I H, s); ¹³ C

NMR (CDCl ₃ ) 48.02, 51.96, 103.60, 109.40, 1 10.18, 1 18.96, 122.10, 123.26. 123.50.

125.99. 126.75, 127.30, 127.43. 128.0. 128.34. 128.45, 128.88. 130.03, 134.45.

137.73, 140.58, 143.62, 155.03, 168.47.

[00159] l-Benzyl-3-(6-hydroxynaphthalen-2-yl)-indole-5-carboxyIic acid

(QR-0162). White solid. 75% Yield. ¹ H NMR (DMSO) 5.58 (2H, s), 6.87 (IH, s).

6.92 (2H, d, J = 7.4), 7.1 1-7.28 (5H, m). 7.49 ( IH. d. J = 8.7). 7.53 (IH, d. J - 8.4),

7.72-7.80 (3H. m), 7.94 (IH, s). 8.31 (I H, s), 9.90 ( I H, s), 12.47 (l H.s); ¹³ C NMR 47.56, 103.90, 109.09, 1 1 1.04, 1 19.87, 122.98, 123.18 (2s). 126.38, 126.98, 127.23. 127.64, 127.88, 127.94, 128.47, 129.09. 130.27. 138.46, 140.49, 143.53, 156.59, 168.66; HRMS: calculated for C ₂₆ Hi ₉ NO ₃ m/z [M] ⁺ = 393.1365, found [M] ⁺ =

393.1373.

Example 2 Deprotection of O-methyl Goups

[00160] O-methyl groups were deprotected to give compounds QR-0164, QR-

0165 and QR-0166. Their syntheses are depicted in Scheme 2 below.

Scheme 2

[00161] The following general procedure was used.

General Procedure for deprotection of O-methyl groups

[00162] To a solution of 91, 92. or 93 (Scheme 2) in CH ₂ Cl ₂ at -78 ⁰ C. BBr ₃ (2-

4 equiv.) was added dropwise. The reaction mixture was stirred at -78 ⁰ C for 15 minutes and warmed up gradually to room temperature. Reaction times varied from 2

hours to 12 hours. The reaction was quenched with water. The organic solvent was evaporated under reduced pressure. HCl (1.0 N, 3 - 5 ml) was added and the mixture was stirred at room temperature for 24 hours. The product was extracted from the aqueous solution using ethyl acetate (3 x 5.0 ml). The combined organic layer was dried (MgSO ₄ ), filtered and concentrated under vacuum.

[00163] The residue was purified by flash chromatography to yield the

following compounds.

[00164] 2-(2,3-Dimethoxynaphthalen-l-yl)-benzofuran (91). White solid.

60% Yield. ¹ H NMR (CDCl ₃ ) 3.82 (3H. s), 4.03 (3H, s), 7.01 ( I H, s), 7.28-7.37 (4H, m), 7.42 (IH, t, J = 7.0). 7.58 (I H, d, J = 8.1 ). 7.69 (IH, d, J = 6.9), 7.75 (I H, d, J =

8.1), 7.82 (IH, d, J = 8.5); ¹³ C NMR (CDCl ₃ ): 55.86, 61.66, 108.22, 109.03, 1 1 1.38,

120.93, 121.06, 122.79, 124.09. 124.72. 125.39. 125.61, 126.76. 128.38. 128.90,

131.15, 149.04. 151.04. 151.98, 155.12,

[00165] 2-(2,3-Dihydroxynaphthalen-l-yl)-benzofuran (QR-0164). White

solid. 72% Yield. ¹ H NMR (DMSO): 7.09 (IH, s), 7.21 -7.37 (5H, m). 7.64 (2H, d. J = 7.96), 7.69 (I H, d, J = 7.9), 7.73 (I H, d. J = 7.3), 9.35 (IH, s), 10.4 (I H. s); ¹³ C NMR

(DMSO): 108.28, 1 1 1.22. 1 1 1.49, 121.34, 123.22, 123.87, 124.23, 124.31 , 124.38, 126.66, 128.14, 128.87, 129.15, 146.43. 147.0, 152.07, 152.07. 154.71 ; HRMS:

calculated for Ci ₈ Hi ₂ O ₃ m/∑ [M] ⁺ = 276.0786, found [M] ⁺ = 276.0789.

[00166] 2-(2,3-Dimethoxynaphthalen-l-yl)-benzothiophene (92). White solid. 58% Yield. ¹ H NMR (acetone-d ₆ ): 3.80 (s, 3H), 4.01 (3H, s), 7.34 ( I H, t, J = 7.6), 7.40-7.50 (411, m), 7.55 (IH, s). 7.68 (I H, d, J = 8.5). 7.88 (IH, d, J = 8.2), 7.96 (IH, d, J = 7.4), 8.15 (IH, d. J = 7.7); ¹³ C NMR (acetone-d ₆ ): 55.26, 60.60, 108.68. 121.99. 123.62, 123.84, 124.29, 124.33, 124.38. 125.05, 125.38, 126.82. 128.80, 131.37. 137.05, 140.16. 140.80. 148.20, 152.25.

[00167] 2-(2,3-Dihydroxynaphthalen-l-yl)-benzothiophene (QR-Ol 65).

White solid. 57% Yield. ¹ H NMR (DMSO): 7.16-7.30 (3H. m), 7.36-7.45 (3H, m), 7.52 (I H, d, J = 8.3). 7.69 (IH, d, J = 7.9), 7.92 ( I H, d, J = 7.3), 8.01 (IH. d, J = 7.8); ¹³ C NMR (DMSO): 1 10.48, 1 14.25, 122.60, 123.78. 123.97, 124.06, 124.14. 124.54,

124.68, 125.69, 126.52, 128.75, 128.88, 138.05, 140.38, 140.66. 145.99. 146.44.

HRMS: calculated for C ₈ Hi ₂ O ₂ S m/∑ [M] ⁺ = 292.0558, found [M] ⁺ = 292.0551.

[00168] 2,3,6'-Trimethoxy-[l,2']-binaphthalene (93). 51% Yield. ¹ H NMR

(CDCl ₃ ) 3.60 (3H, s), 3.97 (3H, s), 4.04 (3H, s). 7.16-7.26 (4H. m), 7.38 (I H, t, J = 7.5). 7.45-7.50 (2H, m), 7.75-7.79 (2H. m), 7.80 ( I H, s), 7.86 (I H, d, J = 8.3).

[00169] 2,3,6'-Trihydroxy-[l,2'|-binaphthalene (QR-0166). Purple oil. 63%

Yield. ¹ H NMR (acetone-d _ή ) 7.16 (I H, t, J = 7.0). 7.20 (2H. m). 7.33 (2H, s), 7.38 ( I H. d, J = 8.3), 7.43 (I H, dd, J = 1.5, 8.4), 7.82 ( I H. d. J = 8.1), 7.80-7.87 (3H, m);

¹³ C NMR (acetone-d ₆ ) 108.90, 1 18.52, 123.25, 123.29. 124.52. 126.20, 126.23,

128.67, 128.95, 129.49. 129.62, 129.81. 130.45. 134.37, 143.26, 145.81, 155.58.

HRMS: calculated for C ₂₀ Hi ₄ O ₃ m/z [M] ⁺ = 302.0943, found [M] ⁺ = 302.0947.

Example 3 Preparation by Negishi coupling reaction

[00170] Compounds QR-Ol 83, QR-0195, QR-0203, QR-0264, QR-0226, and

QR-0262 were prepared by Negishi coupling reaction. Their syntheses are depicted in Scheme 3 and 5 below.

Scheme 3

Scheme 5

[00171] The following general procedure was used:

General Procedure for Negishi coupling reaction

[00172] At -78 ⁰ C, /-BuLi (1.5 equiv) or π-BuLi (1.5 equiv) was added to the

solution of aryl halide (1 equiv) in THF. After stirring at -78 ⁰ C for 25 minutes, ZnCb solution (1.0 M, 1.5 equiv) was added dropwise. The resulting solution was stirred for 25 minutes and at room temperature for 30 minutes (Solution A).

[00173] Solution A (3 equiv) was then added to the degassed solution of substituted 3-iodoindole (1 equiv) and Pd(PPlVj) ₄ (0.05 equiv). The mixture was

stirred at 65 ⁰ C - 8O ⁰ C for 4 - 12 hours. After cooling to room temperature, the

reaction was quenched with brine. The aqueous layer was extracted with ethyl acetate

and the combined organic layer was dried (MgSO ₄ ), filtered and concentrated under

reduced pressure.

[00174] The crude product was purified by flash chromatography to yield the

following compounds.

[00175] Methyl 3-(2,3-dimethoxynathalen-l-yl)-l-tosyl-l//-indole-5- carboxylate, 94 (Scheme 3). White solid. 70% yield. ¹ H NMR (CDCl ₃ ): 2.38 (3H, s), 3.46 (3H, s). 3.79 (3H, s). 4.04 (3H. s), 7.18 (I H. t. J = 8.1). 7.24 - 7.32 (4H. m), 7.39

(IH, t, J = 7.0). 7.72 (IH, s). 7.77 (I H. d. J = 8.1), 7.81 - 7.87 (3H, m), 8.04 (IH. dd, J - 1.5, 8.8), 8.14 (IH, d. J = 8.8); ¹³ C NMR (CDCl ₃ ): 29.63, 52.00, 55.79, 61.09.

107.95, 1 13.66, 1 18.14, 121.54, 123.22, 124.34. 125.22, 125.58. 125.82. 126.15,

126.82, 126.90, 127.19, 128.68, 130.02. 131.33. 131.56, 135.14, 137.71, 145.39, 152.14, 167.10.

[00176] 3-(2,3-dimethoxynathalen-l-yl)-l-tosyl-l//-indole-5-carboxyl ic acid, QR-0183 (Scheme 3). White solid. 96% yield. ¹ H NMR (DMSO) 3.49 (3H, s),

4.00 (3H, s), 7.21 (IH, t, J = 7.39), 7.38 - 7.43 (2H. m), 7.51 (I H, s). 7.57 (IH, d, J = 8.53). 7.60 (IH, d, J = 2.26), 7.69 (I H, s). 7.77 (I H. dd. J = 8.57. 1.41 ), 7.88 (I H, d, J = 7.93), 1 1.73 (IH. s,), 12.30 (IH. s): ¹³ C NMR (DMSO) 56.10, 60.93, 107.67, 1 10.43, 1 1 1.95, 122.01, 122.33, 122.82, 124.20, 124.34, 125.57, 125.90. 127.24, 127.29. 127.91 , 129.33, 131.51, 138.98, 148.07, 152.51, 168.72.

[00177] 3-(2,3-dihydroxynathalen-l-yl)-l-tosyl-lH-indole-5-carboxyli c acid, QR-0194 (Scheme 3). Beige solid. 77% yield. ¹ H NMR (DMSO) 7.09 (IH. t, J= 6.9 ), 7.18-7.25 (2H, m). 7.37 (IH, d. J = 8.41), 7.51 (IH, d. J = 2.1 1). 7.55 (IH. d,

J = 8.50), 7.67 (I H. d, J = 8.06). 7.72-7.78 (2H. m). 8.49 (IH, s. br), 10.05 (IH, s, br), 1 1.64 (IH, s); ¹³ C NMR (DMSO) 109.07, 1 10.98, 1 1 1.76, 1 14.80, 121.61 , 122.62,

122.90, 123.22, 123.33, 124.94, 126.42. 127.56. 127.85, 129.20. 129.36, 139.15,

145.35, 146.70, 168.84; HRMS: measured = 319.0835, theoretical = 319.0844.

[00178] 3-(2,3-dimethoxynathalen-l-yl)-l-tosyl-lH-indole, 95 (Scheme 3).

Yellow solid. 72% yield. ¹ H NMR (CDCl ₃ ): 2.37 (3H, s), 3.44 (3H. s), 4.03 (3H, s),

7.10-7.20 (3H, m), 7.21 -7.28 (3H, m, overlapped with CDCl ₃ ). 7.32 - 7.41 (3H, m),

7.67 (I H, s). 7.75 (I H, d, J = 8.12), 7.82 (2H, d. J = 8.4). 8.1 1 ( I H, d, J = 8.4); ¹³ C

NMR (CDCl ₃ ): 21.60, 55.76, 61.03, 107.61, 1 13.90, 1 17.64, 121.1 1. 123.51 , 124.1 1,

124.79, 125.47, 125.56, 126.14, 126.74. 126.88. 128.67. 129.85, 131.30. 131.68.

135.19, 135.39, 144.92, 152.19.

[00179] 3-(2,3-dihydroxynathalen-l-yl)-l-tosyl-lH-indoIe, QR-0189

(Scheme 3). Yellow solid. 40% yield. ¹ H NMR (DMSO): 6.93 (I H, t. J = 7.6), 7.01- 7.09 (2H, m), 7.12 (IH, t, J = 7.6), 7.16-7.22 (2H. m), 7.37-7.42 (2H. m). 7.48 (IH, d, J = 8.2), 7.63 (I H, d, J = 8.1), 8.37 (IH, s). 9.98 (IH, s), 1 1.30 (IH. s); ¹³ C NMR (DMSO): 108.78. 109.37, 1 1 1.99. 1 15.68, 1 19.01 , 120.18, 121.25, 122.96. 123.21, 125.27, 126.06. 126.35, 128.20, 129.21 , 129.39, 136.65, 145.15. 146.73.

[00180] 3-(2,3-dimethoxynathalen-l-yl)-5-nitro-l-tosyl-lH-indole, 97

(Scheme 3). White solid. 67% yield. ¹ Il NMR (CDCl ₃ ): 2.40 (3H. s). 3.50 (311. s).

4.05 (3H, s), 7.20 (IH, t. J = 7.2), 7.27-7.34 (4H, m), 7.41 (IH, t, J = 6.9), 7.79 (IH. d.

J = 7.9), 7.83 (I H, s). 7.85 (2H, d, J = 8.6), 8.04 (I H, d, J= 1.8), 8.18 - 8.28 (2H, m); ¹³ C NMR (CDCl ₃ ): 21.69. 55.82, 61.13, 108.38, 1 14.08, 117.50, 118.29, 120.06. 120.49, 124.56, 124.83. 125.73, 126.96. 127.03, 128.34, 128.70, 130.24. 130.54. 131.42, 131.65, 134.82, 137.96. 1 14.57, 145.94. 148.21.

[00181] 3-(2,3-dimethoxynathalen-l-yl)-5-nitro~lH-indole , QR-0195

(Scheme 3). Yellow solid. 68% yield. ¹ H NMR (DMSO) 3.51 (3H, s). 4.02 (3H, s),

7.24 (IH, t, J = 7.5). 7.39 - 7.47 (2H, m), 7.54 (I H, s). 7.71 (I H. d, J = 9.0). 7.80 (IH.

s), 7.90 (IH. d, J = 8.1 ). 7.94 (IH. s), 8.06 (IH. d, J = 8.95), 12.16 (I H. s); ¹³ C NMR

(DMSO) 56.15, 60.97. 108.09. 1 1 1.77, 1 12.85, 1 16.47, 1 17.06, 123.24, 124.46.

125.61. 125.70. 127.36. 127.54, 129.04, 129.82, 131.60.

[00182] 5-methoxy-3-(2,3-dimethoxynathalen-l-yl)-l-tosyl-lH-indole, 98

(Scheme 3). Yellow solid. 99% yield. ¹ H NMR (CDCl ₃ ): 2.41 (3H. s). 3.48 (3H. s),

3.66(3H, s), 4.08 (3H. s), 6.56 (IH, d. J - 2.5). 7.0 (IH, dd. J = 2.5, 9.1). 7.21 (IH, t. J

= 8.0), 7.25 - 7.33 (3H. m), 7.36 (IH, d, J = 8.4). 7.43 (IH, t, J = 8.0). 7.65 (I H, s),

7.80 (IH, d. J = 8.1). 7.83 (2H, d, J = 8.3), 8.04 (IH, d, J = 9.0); ¹³ C NMR (CDCl ₃ ):

21.59, 55.60, 55.77. 61.04, 103.03, 107.59, 1 14.22, 1 14.89, 1 17.88, 122.25, 124.12, 125.51, 125.57, 126.71, 126.83. 126.96. 128.64, 129.79, 131.28. 132.77, 135.31, 144.81 , 152.19, 156.74.

[00183] 5-hydroxy-3-(2,3-dihydroxyynathalen-l-yl)-lH-indoIe , QR-0212

(Scheme 3). Gray solid. 89% yield. ¹ H NMR (DMSO) 6.38 (I H, d. J = ), 6.64 (IH,

dd, J = 2.3, 8.6), 7.08 (IH, t. J = 7.1), 7.16 - 7.23 (2H, m) 7.25 - 7.30 (2H. m), 7.41

(IH, d, J = 8.43), 7.64 (I H. d, J = 8.0). 8.28 (IH, s), 8.47 (IH, s), 9.91 (I H, s), 10.98 (IH. s); ¹³ C NMR (DMSO) 104.06, 108.42. 108.64, 1 12.25. 1 16.04, 122.92, 123.18, 125.46, 126.31, 126.45, 128.99, 129.20, 129.31, 131.17, 145.0, 146.74, 150.91 ;

HRMS: measured = 291.0894, theoretical = 291.0895.

[00184] 3-(2,3-dimethoxynaphthalen-l-yl)-l-tosyl-lH-pyrrolo|2,3-

Zφyridine, 100 (Scheme 3). White solid. 87% yield. ¹ H NMR (DMSO) 2.41 (3H, s). 3.58 (3H, s). 4.03 (3H, s), 7.26 - 7.36 (3H, m). 7.46 (IH. t. J = 6.77). 7.48 - 7.55 (3H.

m), 7.60 (I H. s). 7.93 (I H, d, J = 8.15). 8.06-8.13 (3H, m). 8.46 (I H, dd. J = 1.21 ,

4.65); ¹³ C NMR (DMSO) 21.63. 56.24. 61.22. 108.86, 1 14.22, 120.09. 121.28,

123.78. 124.88. 125.09, 125.91, 126.39, 127.49, 128.07, 128.41. 129.72, 130.60,

131.57, 135.15, 145.46, 146.19. 147.16, 148.23. 152.32.

[00185] 3-(2,3-dimethoxynaphthalen-l-yl)-li/-pyrrolo[2,3-λ]pyridine , QR-

0203 (Scheme 3). Yellow solid. 85% yield. ¹ H NMR (DMSO) 3.51 (3H, s), 3.99 (3H.

s), 7.03 (IH, dd, J = 4.6. 7.9), 7.24 (I H. t, J = 7.24), 7.40 (I H, t. J = 7.7). 7.44 - 7.51

(3H, m), 7.62 (I H, d. J = 2.4), 7.86 (I H, d, J = 8.1), 8.28 (IH, dd, J = 1.2, 4.6), 1 1.98 (I H, s); ¹³ C NMR (DMSO) 56.08, 60.87, 107.62, 107.81 , 1 16.05, 120.46, 124.22,

124.26, 125.55, 125.84, 126.39. 127.26. 127.85, 129.21, 131.55. 143.10, 148.00, 148.93, 152.51.

[00186] 3-(2,3-dihydroxynaphthalen-l-yl)-lH-pyrrolo[2,3-Z>]pyridi ne, QR-

0204 (Scheme 3). Beige solid. 65% yield. ¹ H NMR (MeOD): 7.04-7.10 (2H, m),

7.17-7.23 (2H, m). 7.43 ( I H, d, J=8.4), 7.48 (IH, s), 7.59 -7.64 (2H, m). 8.22 (IH, dd,

J = 1.3, 4.8); ¹³ C NMR (DMSO): 108.98, 1 14.81 , 1 15.74, 120.45, 123.26, 123.33,

124.90, 126.47, 126.65, 128.22, 129.18, 129.23. 142.80, 145.28, 146.64, 146.72, 149.1 1.

[00187] Methyl 3-(2,3-dimethoxynathalen-l-yl)-l-tosyl-lH-indole-7-

carboxylate, 101 (Scheme 3). White solid. 65% yield. ¹ H NMR (CDCl ₃ ): 2.36 (3H, s). 3.36 (3H, s), 4.00 (3H, s), 4.05 (3H, s), 6.91 (I H, d, J - 8.4), 7.06 (I H, t, J = 7.4),

7.13 - 7.26 (5H, m). 7.36 (IH, t, J = 7.4), 7.52 (IH, s). 7.57 - 7.63 (3H, m), 7.73 (I H. d, J = 8.1); ¹³ C NMR (CDCl ₃ ): 21.61 , 52.70, 55.74, 61.02. 107.84, 120.63, 121.28,

123.20, 123.83, 124.07, 124.24, 125.13. 125.50. 126.1 1. 126.75. 127.10, 128.36,

129.36. 129.62, 131.28, 132.53, 134.1 1. 134.79, 144.86, 148.50, 152.09. 169.15.

[00188] 3-(2,3-dimethoxynathalen-l-yl)-l-tosyl-lH-indole-7-carboxyli c acid, QR-0264 (Scheme 3). Light brown solid. 92% yield. ¹ H NMR (DMSO): 3.50

(3H, s), 4.0 (3H, s). 7.06 (IH, T. J = 7.6), 7.20 (IH. t. J - 8.1 ). 7.28 (I H, d, J = 7.8).

7.37 - 7.43 (2H. m), 7.45 - 7.51 (2H, m), 7.81 ( IH. d. J = 7.4). 7.86 (IH. d, J = 8.5), 1 1.35 (I H, s), 13.05 (IH, s); ¹³ C NMR (DMSO): 56.07. 60.91. 107.65. 109.49,

1 14.31, 1 19.08, 124.15, 124.37, 124.50, 124.57, 125.21. 125.52, 125.92. 127.23, 129.36, 129.85. 131.52, 135.19, 148.09. 152.52. 168.36.

[00189] 3-(2,3-dihydroxynathalen-l-yl)-l-tosyl-lH-indole-7-carboxyli c acid, QR- 0273 (Scheme 3). Yellow solid. 20% yield. ¹ H NMR (DMSO): 7.03 - 7.1 1 (2H, m). 7.18 - 7.23 (2H, m), 7.30 (IH, d, J - 7.8), 7.36 (I H, d. J = 8.4), 7.40 (I H. d. J = 2.3), 7.65 (I H, d, J = 8.0), 7.79 (I H. d. J = 7.4). 8.48 ( IH, s), 10.03 (IH, s).

1 1.25 (IH, s), 13.00 (I H, s); ¹³ C NMR (DMSO): 109.04, 109.94, 1 14.17, 1 14.86,

1 18.69, 123.17, 123.30, 124.26, 124.96, 125.67, 126.43, 127.54, 129.23, 129.32.

129.78, 135.40, 145.33, 146.73, 168.50.

[00190] 5-Methoxy-3-(2-methoxynaphthaIen-6-yl)-l-tosyl-l//-indole, 103

(Scheme 5). Light yellow solid. 70% yield. ¹ H NMR (acetone-d ₆ ): 2.37 (3H.s). 3.86 (3H. s), 3.97 (3H. s). 7.07 (IH, dd, J = 2.5. 9.0), 7.22 (I H. dd, J = 2.5, 8.9). 7.36 -

7.43 (4H, m), 7.81 (IH, dd, J = 1.7. 8.5). 7.91-7.98 (5H, m) 8.03 ( I H, d. J = 9.0), 8.18

(I H. s). ¹³ C NMR (acetone-d ₆ ): 20.53, 54.81 , 55.06, 103.06, 105.75, 1 13.82, 1 14.13,

1 14.75, 1 19.14, 124.22, 126.14, 126.48. 126.98. 127.49, 128.20, 129.27. 129.56.

130.04, 130.24. 130.43. 134.17, 135.07, 145.47. 157.12, 158.12.

[00191] 5-Methoxy-3-(2-methoxynaphthalen-6-yl)-lH-indoIe 104 (Scheme

5). Light yellow solid. 95% yield. ¹ H NMR (DMSO): 3.83 (3H, s), 3.90 (3H, s), 6.85

(IH, dd, J = 2.3, 8.8), 7.17 (I H, dd, J = 2.5, 8.9), 7.32 (IH, d, J = 2.3), 7.38 (I H. d. J =

8.8), 7.44 (I H, d, J = 2.2), 7.73 ( IH, d, J = 2.4). 7.80 - 7.94 (3H. m). 8.1 1 ( I H. s); ¹³ C NMR (DMSO) 55.65. 55.96, 101.75, 106.36, 1 1 1.90. 1 13.07. 1 15.94, 1 19.03, 123.93,

124.74, 125.86, 126.84. 127.56, 129.63. 129.68, 131.80, 132.63. 132.82.

[00192] 5-Hydroxy-3-(2-hydroxynaphthalen-6-yl)-li/-indole QR-0225

(Scheme 5). Yellow solid. 66% yield. ¹ H NMR (DMSO) 6.70 (I H, dd. J = 2.1 , 8.6), 7.06 -7.14 (2H, m). 7.26 ( I H, d. J = 8.6), 7.32( 1H. d, J = 1.99), 7,64 (IH, d, J = 2.5), 7.72 (2H, s), 7.78 (I H. d. J = 8.8), 7.98 (I H, s), 9.61 (IH, s), 1 1.05 (I H. s); ¹³ C NMR 103.62. 109.15, 1 12.19. 1 12.74. 1 15.45, 1 19.20, 123.69, 124.22, 126.27. 126.62, 126.80. 129.44, 131.19. 131.94, 133.09, 151.75, 155.08.

[00193] 3-(2-Methoxynaphthalen-6-yl)-l-tosyl-lH-pyrrolo[2,3-^lpyridi ne,

105 (Scheme 5). Yellow solid. 40% yield. ¹ H NMR (DMSO) 2.36 (3H, s), 3.91 (3H. s), 7.23 (IH, dd, J = 2.4, 8.9), 7.31-7.48 (4H, m), 7.88-7.99 (3H, m), 8.08 (2H, d. J =

8.3). 8.27 - 8.33 (2H. m), 8.44-8.51 (2H, m); ¹³ C NMR (DMSO) 21.6, 55.7. 106.4, 1 19.5, 120.0, 120.2, 121.2, 123.7, 126.0. 126.4, 127.7, 128.0, 128.2, 129.2, 130.1.

130.2. 130.5, 134.1 , 135.1, 145.5. 146.1 , 158.0.

[00194] 3-(2-Methoxynaphthalen-6-yl)-lH-pyrrolo[2,3-6]pyridine, QR-

0226 (Scheme 5). Yellow solid. 76% yield. ¹ H NMR (DMSO) 3.90 (3H. s), 7.16-7.22 (2H, m), 7.34 (IH, d. J = 2.3), 7.88 (2H. s). 7.92 (I H. d, J = 8.9), 7.98 (IH. d, J = 2.5).

8.19 (IH, s). 8.31 (I H, d. J = 4.5), 8.47 (I H. d, J = 7.9), 1 1.92 (I H, s): ¹³ C NMR

(DMSO): 55.66. 106.40. 1 14.76, 1 16.49. 1 17.86. 1 19.16, 124.02. 124.29. 126.37.

127.68, 128.27. 129.56. 129.74, 130.82, 133.08, 143.41. 149.65, 157.34.

[00195] 3-(2-Hydroxynaphthalen-6-yl)-lH-pyrrolo[2,3-Z>]pyridine, QR-

0257 (Scheme 5). Light yellow solid. ¹ H NMR (DMSO): 7.09 (IH. dd. J = 2.36,

8.75). 7.13 (I H, d. J = 2.19), 7.19 (I H, dd. J = 4.6, 7.9), 7.74 (I H, d, J = 8.6), 7.79

(IH, dd, J = 1.7, 8.5), 7.85 (IH, d, J = 8.8), 7.93 (IH. d, J = 2.5). 8.12 (IH. s), 8.30 (IH. dd, J = 1.4. 4.6). 8.43 (IH, d, J = 7.9), 9.66 (I H, s), 1 1.88 (IH. s); ¹³ C NMR (DMSO): 109.12. 1 14.94. 116.43, 117.89, 119.27, 124.05, 124.13, 126.20, 127.02, 128.22, 128.76, 129.75, 129.91 , 133.43. 143.36, 149.64. 1 15.37.

[00196] Methyl 3-(2-methoxynaphthalen-6-yl)-l-tosyl-lH-indole-7- carboxylate, 106 (Scheme 5). White solid. 45% yield. ¹ H NMR (CDCl ₃ ): 2.32 (3H, s), 3.95 (3H, s), 3.98 (3H, s), 7.14-7.21 (4H. m), 7.36 (IH. t. J = 7.7), 7.54 (I H. dd, J

= 1.7. 8.4), 7.58 (IH, dd, J = 1.0, 7.5), 7.61-7.65 (3H. m), 7.76 (IH, d, J = 8.9), 7.80

(I H, d, J = 8.5), 7.85 - 7.88 (2H. m); ¹³ C NMR (CDCl ₃ ): 21.60, 52.66, 55.40, 105.78. 1 19.50, 123.14, 124.18, 126.01, 126.50. 126.57, 126.60, 126.67, 126.96. 127.42, 127.49, 129.01, 129.49, 129.55, 132.08, 132.88. 134.12, 134.72, 144.88, 158.09,

169.00.

[00197] 3-(2-Methoxynaphthalen-6-yl)~l//-indole-7-carboxylic acid, QR-

0262 (Scheme 5). Yellow solid. 88% yield. ¹ H NMR (DMSO): 7.18 (IH, dd, J = 2.5.

8.9), 7.26 (IH. t, J = 7.69), 7.34 (I H, d. J = 2.3), 7.76 (I H, d, J = 2.4), 7.81 - 7.95 (4H, m), 8.17 (IH, s), 8.28 (IH, d, J = 7.9), 1 1.32 (I H, s). 13.1 1 (IH, s); ¹³ C NMR

(DMSO): 55.67, 106.37, 1 14.41 , 1 16.62. 1 19.16. 1 19.69, 124,71 , 124.85, 125.31.

125.42, 127.02, 127.26, 127.68, 129.57. 129.77. 130.78, 122.14, 136.14, 136.08, 157.37. 168.34.

[00198] 3-(2-Hydroxynaphthalen-6-yl)- l//-indole-7-carboxylic acid, QR-

0258 (Scheme 5). Yellow-orange solid. 83% yield. ¹ H NMR (DMSO): 7.1 1 (IH, dd,

J = 2.4, 8.8), 7.14 (I H, d, J = 2.3), 7.25 (I H, t, J = 7.7), 7.73 (I H, d, J = 2.5), 7.75 (2s, 2H), 7.85 (2H, d. J = 8.5), 8.10 (I H, s), 8.25 ( IH. d, J = 7.9), 9.68 (IH, br), 1 1.29

(I H. s), 13.07 (IH. br); ' ³ C NMR (DMSO): 109.08. 1 14.36, 1 16.78. 1 19.28, 1 19.62, 124.79, 124.82, 125.16, 125.20, 126.84. 127.02, 127.27, 128.77. 129.77. 129.88, 133.48, 136.09, 155.40, 168.45.

Example 4 Preparation by Suzuki coupling reaction

[00199] Compounds 102, 107. 108, 109, 1 1 1, 1 12, 1 13. 1 14, 115, 116, 1 18,

1 19, 121, QR-0220, QR-0221, QR-0223. QR-0242, QR-0234 were synthesized by

Suzuki coupling reaction. The reactions are depicted in Schemes 4, 6, 7, 8, 9, 10, and 1 1 below.

Scheme 4

Scheme 7

Scheme 8

Scheme 9

Scheme 10

Scheme 11

[00200] The following general procedure was followed. To a degassed solution of the aryl halide (1 equiv) in DMF was added aryl boronic acid (1.2 equiv.), K ₂ CO ₃ (2 equiv.) and boronic acid (1.2 equiv.) at room temperature. After degassing and purging with argon (done thrice), the reaction mixture was stirred at 9O ⁰ C. Reaction times varied from 2 hours to 12 hours. The reaction mixture was allowed to

cool to room temperature and diluted with water. The aqueous layer was extracted

with ethyl acetate several times, and the combined organic layer was dried (MgSO ₄ )

and concentrated under reduced pressure.

[00201] The residue was purified by flash chromatography to yield the

following compounds.

[00202] Methyl 4-benzo[Z>]thiophen-2-yl)naphthalene-l-carboxylate, 102

(Scheme 4). White solid. 95% yield. ¹ H NMR (CDCl ₃ ): 4.04 (3H, s), 7.36 -7.46 (2H.

m). 7.48 (IH. s). 7.55 (IH, t, J = 7.3). 7.62-7.69 (2H. m). 7.86 (I H. d, J = 7.6). 7.90 (I H, d, J = 7.9), 8.19 (IH, d, J = 7.6). 8.33 (I H. d, J = 8.4), 8.98 (I H. d, J = 8.7); ¹³ C

NMR (CDCl ₁ ): 52.33, 122.16. 123.84, 124.66. 124.70. 124.90. 126.15, 126.38,

126.83, 127.17. 127.63, 127.86, 129.21. 131.77, 132.29. 137.53, 140.05, 140.48,

141.21. 167.86..

[00203] 4-benzo[Z>]thiophen-2-yl)naphthalene-l-carboxylic acid, QR-0220

(Scheme 4). White solid. 96% yield. ¹ H NMR (DMSO): 7.43-7.52 (2H, m), 7.67 (IH,

t, J = 7.6), 7.71-7.81 (3H, m), 7.98 (I H, d, J = 7.3). 8.08 (IH, d, J = 7.8), 8.20 (IH, d. J = 7.5), 8.32 (I H. d, J = 8.4), 8.96 (1 , d. J = 8.5); ¹³ C NMR (DMSO): 122.81, 124.60, 125.39, 125.73. 126.26, 126.51. 127.64. 127.88, 128.28, 129.08. 129.39, 131.57, 131.82. 136.54. 140.08. 140.32. 140.67, 168.91.

[00204] Methyl 4-(benzofuran-2-yl)naphthalene-l-carboxylate , QR-0221

(Scheme 4). Light yellow solid. 97% yield. ¹ H NMR (CDCl ₃ ): 4.04 (3H, s), 7.17 (I H,

s). 7.31 (IH, t, J = 7.9), 7.38 (IH, t, J = 7.8), 7.58-7.72 (4H. m). 7.91 (IH, d. J = 7.6),

8.23 (IH, d, J = 7.6), 8.55 (IH, d, J = 8.2), 8.99 (I H, d. J = 8.2); ¹³ C NMR (CDCl ₃ ):

52.34, 107.55, 1 1 1.44, 1 1 1.71, 121.29, 123.21 , 124.95, 125.78, 125.99. 126.31 , 127.07, 127.81, 127.96. 128.83, 129.30. 131.07, 131.91 , 132.92, 167.83.

[00205] 4-(benzofuran-2-yI)naphthaIene-l-carboxylic acid, QR-0222

(Scheme 4). Yellow solid. 82% yield. ¹ H NMR (DMSO) 7.36 ( IH, t, J = 7.2). 7.43

(IH, t. J = 8.3). 7.52 (IH, s), 7.70-7.83 (4H, m), 8.03 (IH, d, J = 7.6), 8.23 ( I H, d. J = 7.6). 8.55 (I H, d, J = 7.72), 8.96 (IH, d, J - 7.9). 13.34 (IH, s); ¹³ C NMR (DMSO)

108.27. 1 1 1.84, 122.08, 123.89, 125.68, 126.12, 126.61 , 127.87. 128.23, 128.95,

129.41. 129.50, 130.66. 131.64, 131.89, 154.29, 155.04, 168.89.

[00206] Methyl 4-(2-hydroxynaphthalene-6-yl)naphthalene-l-carboxylate,

QR-0223 (Scheme 4). Light yellow solid. 85% yield. ¹ H NMR (CDCl ₃ ) 4.04 (3H. s),

5.04 ( 1 H, s). 7.18 ( 1 H, dd. J = 2.5), 7.23-7.28 ( 1 H. overlapped with CDCl ₃ ) 7.47 ( 1 H,

t, J = 8.2), 7,52 (IH, d, J = 7.5), 7.55 (IH. dd, J = 1.7, 8.4), 7.63 (I H, t, J = 7.0) 7.78-

7.84 (2H, m), 7.87 (I H, s). 8.24 (IH, d, J = 7.5), 9.00 (I H, d. J - 8.6); ¹³ C NMR

(CDCl ₃ ): 52.23, 109.48. 1 18.42, 125.97, 126.08, 126.28, 126.32, 126.51. 126.84.

127.54, 128.71 , 128.75, 129.66, 130.17, 131.85, 132.33, 134.01 , 135.50, 145.45, 153.89, 162.46.

[00207] 4-(2-hydroxynaphthalene-6-yl)naphthalene-l-carboxylic acid, QR-

0224 (Scheme 4). Yellow solid. 56% yield. ¹ H NMR (DMSO) 7.17 (I H, dd, J = 2.2, 8.7), 7.24 (IH. d. J = 1.98), 7.50-7.64 (3H, m), 7.69 (IH. t, J = 7.0), 7.82-8.0 (4H, m). 8.23 (IH, d, J = 7.5 ), 8.99 (IH, d, J = 8.5), 9.87 (I H, s), 13.15 (I H. s); ¹³ C NMR

(DMSO) 109.07, 1 19.74, 126.40, 126.61, 126.78, 126.93, 127.52, 127.82, 128.06,

128.46, 128.85, 129.84, 130.25. 131.73, 132.04, 134.19. 134.50. 144.94, 156.37.

169.12.

[00208] Methyl 4-(2,3-dihydrobenzo[*[[l,4]dioxin-7-yl)naphthaIene-l- carboxylate, 107 (Scheme 6). White solid. 65% yield. ¹ H NMR (CDCl ₃ ) 4.02 ( 3H, _s ). 4.34 (4H, s), 6.91 -7.01 (3H. m). 7.41 (I H, d. J = 7.5), 7.47 (I H, t. J = 7.6). 7.61

(IH, t, J = 7.7), 8.00 (IH, d, J = 8.4). 8.17 (1 H, d, J = 7.5), 8.96 (I H, d, J = 8.6); ¹³ C

NMR (CDCl ₃ ) 52.17, 64.52, 1 17.20, 1 18.82, 123.14, 125.63, 125.98, 126.17, 126.29.

126.79, 127.47, 129.61, 131.81. 132.19. 133.50, 143.39, 144.88, 168.08.

[00209] 2,3-D'hydro-6-(2-methoxynaphthalen-6-yl)benzon[6][l,4]dioxin e,

108 (Scheme 6). White solid. 99% yield. ¹ H NMR (CDCl ₃ ) 3.93 (3H, s), 4.31 (411, s).

6.96 (I H, d. J = 8.3). 7.12-7.23(4H, m), 7.64(1H, dd, J = 7.78, 8.53), 1.12-1.19 (2H.

m). 7.90 (I H. s); ¹³ C NMR (CDCl ₃ ) 55.36, 64.51. 105.63, 1 15.92, 1 17.63, 1 19.10.

120.25, 125.04, 125.85, 127.18, 129.23, 129.63. 133.57, 134.86, 135.83, 143.08,

143.80, 157.66.

[00210] 2,3-Dihydro-6-(2,3-dimethoxynaphthalen-4- yl)benzo[/>l[l,4]dioxine, 109 (Scheme 6). Yellow solid. 80% yield. ¹ H NMR (CDCl ₃ ) 3.66 (3H, s), 4.01 (3H. s). 4.38-4.45 (4H, m), 6.83 (I H, dd, J = 1.9. 8.2 ), 6.90 (I H, d, J = 1.9), 6.98 (I H, d, J = 8.2), 7.19 (IH. s), 7.22 (I H. t. J = 8.3), 7.37 ( I H, t. J = 7.9), 7.49 (I H, d. J = 8.2), 7.72 (IH, d. J = 8.0); ¹³ C NMR (CDCl ₃ ) 55.71 , 61.60. 64.44, 64.48, 106.73, 1 16.95, 1 19.41, 123.81 , 123.85, 125.18. 125.91 , 126.52.

128.88, 129.15, 131.21, 131.60. 142.91 , 143.23. 146.67, 152.22.

|00211] Methyl 4,7-dibromo-3-methoxynaphthalene-2-carboxylate, 110

(Scheme 7). Light yellow solid. ¹ H NMR (CDCl ₃ ) 3.99 (3H, s), 4.00 (3H, s), 7.72 (IH, dd, J = 1.92. 9.0), 8.04 (IH, s). 8.13 (IH, d. J = 9.06), 8.24 (IH, s); ¹³ C NMR (CDCl ₃ ) 52.72, 62.26, 1 17.84, 120.58. 126.47, 128.77, 130.90, 131.20, 132.78,

133.36, 153.78, 165.47.

[00212] 4-Bromo-7-(2-hydroxynaphthalen-6-yl)-3-methoxynaphthalene-2- carboxylic acid methyl ester, QR-0242 (Scheme 7). Yellow solid. ¹ H NMR

(DMSO) 3.94 (3H, s), 3.96 (3H, s), 7.14-7.21 (2H, m), 7.83-7.95 (3H, m), 8.25-8.32

(3H, m), 8.58 (2H, s), 9.89 (IH, s).

[00213] 4-Bromo-3-methoxy-7-(2-hydroxynaphthalen-6-yl)-3- methoxynaphthalene-2-carboxylic acid methyl ester, 111 (Scheme 7). White solid. 47% yield. ¹ H NMR (CDCl ₃ ): 3.96 (3H. s), 4.01(3H. s). 4.04 (3H, s), 7.17-7.23 (2H,

m), 7.8-7.89 (3H, m), 8.05 (IH. dd, J = 1.8. 8.8). 8.09 (I H. s). 8.17 (IH, d, J = 1.7).

8.35 (IH, d, J = 8.8), 8.45 (IH. s).

[00214] 4-Bromo-3-methoxy-7-(2-methoxynaphthalen-6-yl)naphthalene-2- carboxylic acid, QR-0243 (Scheme 7). White solid. 87% yield. ¹ H NMR ( DMSO) 3.92(3H, s), 3.94 (3H, s), 7.24 (IH, dd, J = 2.5, 8.9), 7.40 (IH, d. J = 2.2), 7.93 - 8.03 (3H, m), 8.27 (2H, 2s), 8.36 (IH, s), 8.56 (2H. m), 13.38 (IH, s); ¹³ C NMR (DMSO) 55.76. 62.35, 106.31. 1 16.54. 1 19.69, 125.91. 126.16, 126.96, 127.23, 127.59, 128.10, 129.25, 129.38, 130.35. 131.01. 132.44. 133.08, 134.21 , 134.39, 138.41. 153.32, 158.20, 166.81.

[00215] 4-bromo-3-hydroxy-7-(2-hydroxynaphthalen-6-yl)naphthaIene-2-

carboxylic acid, QR-0263 (Scheme 7). Bright yellow solid. 71% yield. ¹ H NMR (DMSO): 4.70 (3H, s, br), 7.16 (IH, dd, J = 2.3, 8.7), 7.19 ( I H. d, J = 2.1), 7.84 (IH,

d, J - 8.7), 7.90 (IH, d, J = 8.9), 7.94 (I H, dd, J = 1.6. 8.6), 8.15-8.21 (2H, m), 8.29 (IH, s), 8.55 (I H, s), 8.71 (IH, s); ' ³ C NMR (DMSO): 107.1 1. 109.02, 1 18.44,

1 19.63, 125.68, 125.82. 126.20, 127.35, 127.46, 128.53, 128.69. 129.57. 130.37,

131.76, 133/69, 134.49, 134.68, 136.33. 152.24, 156.15, 163.10.

[00216] Methyl 7-(benzofuran-2-y)-4-bromo-3-methoxynaphthalene-2-

carboxylate, 112 (Scheme 7). Light yellow solid. 58% yield. ¹ H NMR (CDCl ₃ ) 4.01

(3H, s), 4.07 (3H. s), 7.18 (IH, s), 7.28 (IH, t, J = 7.8), 7.33 (I H. td, J = 1.8, 7.8). 7,57

(IH, d, J = 7.7), 7.63 (I H, d, J = 7.3), 8.08 (I H, dd, J = 1.7. 8.9), 8.30 (IH, d, J = 8.9),

8.38 (I H, d, J = 1.45). 8.43 (I H, s); ¹³ C NMR (CDCl ₃ ) 52.65, 62.29, 102.85, 1 1 1.29. 1 17.83, 121.19. 123.24. 124.64. 124.91 , 126.03, 126.36. 127.57. 128.45. 129.07.

130.44, 132.72. 134.51, 153.93, 154.73, 155.18, 165.70.

[00217] 7-(Benzofuran-2-y)-4-bromo-3-methoxynaphthalene-2-carboxylic acid, QR-0237 (Scheme 7). Light yellow solid. 93% yield. ¹ H NMR (DMSO): 3.94

(3H, s), 7.32 (IH, t. J = 7.3), 7.39 (I H, t, J = 7.3), 7.64 (IH. s). 7.69 (IH, d, J = 8.2), 7.73 (IH. d, J = 7.5), 8.23-8.33 (2H, m), 8.51 (I H. s). 8.65 ( I H. s), 13.36 (I H, s); ¹³ C NMR (DMSO): 62.40, 104.16. 1 1 1.69, 1 16.74. 121.96, 123.94. 125.03, 125.64, 126.86, 127.44, 128.18, 128.30. 129.22. 130.69, 132.32, 133.72. 153.82, 154.72, 154.99, 166.77.

[00218] 7-(Benzofuran-2-y)-4-bromo-3-hydroxynaρhthalene-2-carboxyli c acid QR-0244 (Scheme 7). Bright yellow solid. 92% yield. ¹ H NMR 7.31 (IH. t, J =

7.3). 7.37 (I H, t, J - 7.4). 7.57 (I H, s). 7.67 (I H. d, J = 8.2), 7.71 (IH, d, J = 7.6),

8.15 (IH, d. J = 9.0). 8.25 (IH, d, J = 8.7), 8.63 (IH, s). 8.75 ( I H, s); ' ³ C NMR

(DMSO): 103.30, 106.1 1 , 1 1 1.61, 121.78. 123.86, 125.35, 125.93, 126.16, 127.62, 127.67, 129.32, 133.08, 135.33. 154.89, 155.02. 171.65. HRMS: measured =

382.9736. theoretical = 380.9768.

[00219] Methyl 7-(benzo[6]thiophen-2-yl-4-bromo-3-methoxynaphthalene-

2-carboxylate, 113 (Scheme 7). White solid. 84% yield. ¹ H NMR (CDCl ₃ ) 4.00 (3H,

s). 4.03 (3H, s), 7.32-7.41 (2H, m), 7.68 (IH. s). 7.81 (IH, d. J = 7.75). 7.86 (IH, d, J

= 7.75), 8.10 (IH. d, J = 8.1), 8.28 (IH, d, J = 8.9), 8.39 (IH. s): ¹³ C NMR (CDCh)

52.65, 62.29, 1 17.75, 120.66, 122.37. 123.86, 124.80, 124.86, 126.05. 126.13, 127.67.

127.88, 130.49, 132.41, 132.51. 134.36, 139.69. 140.63, 142.79, 153.84, 165.65.

[00220] 7-(Benzo[λ|thiophen-2-yl-4-bromo-3-methoxynaphthalene-2- carboxylic acid, QR-0245 (Scheme 7). Light yellow solid. 71% yield. ¹ H NMR

(DMSO) 7.38 - 7.47 (2H, m), 7.91 (I H, d. J = 7.2). 8.04 (IH. d, J = 7.5), 8.08 (I H, s), 8.24 ( 2H, 2s), 8.53 (2H, 2d overlapping), 13.41 (IH, s); ¹³ C NMR (DMSO) 62.39, 1 16.67, 121.92, 123.06, 124.49, 125.48, 125.57, 126.48. 127.51, 128.08, 128.21. 130.80, 132.09. 132.34, 133.60, 139.39, 140.86, 142.52, 153.72, 166.72.

[00221 J 7-(Benzo[6|thiophen-2-yI-4-bromo-3-hydroxynaphthalene-2- carboxylic acid, QR-02S5 (Scheme 7). Bright yellow solid. 77% yield. ¹ H NMR

(DMSO): 7.36-7.45 (2H, m). 7.89 (IH. d, J = 7.6), 8.0 - 8.06 (2H, m). 8.13 (IH, d, J =

8.9), 8.19 (IH, dd, J = 1.8. 8.9), 8.48 (IH. d, J = 1.7), 8.76 (I H, s); ¹³ C NMR (DMSO): 105.97, 1 17.43, 121.19, 123.01. 124.33, 125.41 (2s), 126.23, 127.30, 127.78, 129.01 , 130.04, 133, 135.17, 139.21. 140.93, 142.85, 154.70. 171.64.

[00222] Methyl 4-bromo-7-(2,3-dihydrobenzo[b][l,4]dioxin-7-yl)-3- methoxynaphthalene-2-carboxylate, 1 14 (Scheme 7). White solid. 57% yield. H

NMR (CDCl ₃ ): 3.98 (3H, s), 4.0 (3H. s). 4.33 (4H, s), 6.98 (I H. d, J = 8.35. 7.18-7.25

(2H, m), 7.86 (IH. dd, J 1.05, 8.86). 7.99 ( IH. s). 8.28 (IH, d. J = 8.8), 8.38 (IH. s);

¹³ C NMR (CDCl ₃ ): 52.59, 62.24. 64.49, 64.55. 1 16.10, 1 17.89, 120.37. 126.09.

127.43, 129.00, 130.63, 132.53. 138.59. 143.77. 143.98. 153.31 , 165.85.

[00223] 4-Bromo-7-(2,3-dihydrobenzo[b][l,4]dioxin-7-yl)-3- methoxynaphthalene-2-carboxylic acid, QR-0282 (Scheme 7). White, solid. 92%

yield. ¹ H NMR (DMSO): 3.92 (3H, s), 4.32 (4H. s). 7.01 (IH, d, J = 8.36), 7.30-7.40 (2H, m), 8.07 (I H, dd, J = 1.8, 8.9). 8.18 (I H, d. J = 8.9). 8.37 (I H, d. J = 1.55), 8.49

(I H. s), 13.32 (IH, s); ¹³ C NMR (DMSO): 62.32, 64.63, 64.72. 1 15.94, 1 16.45,

118.17, 120.34, 126.29, 127.07, 127.51 , 129.08, 130.92, 132.36, 132.45, 132.87, 137.88, 144.14, 144.35, 153.17, 166.85.

[00224] 4-Bromo-7-(2,3-dihydrobenzo[b][l,4]dioxin-7-yl)-3- hydroxyynaphthalene-2-carboxylic acid, QR-0281 (Scheme 7). Bright yellow solid. 70% yield. ¹ H NMR (DMSO): 4.31 (4H, s). 7.00 (1 H, d. J = 8.3), 7.29 - 7.35

(2H. m), 8.02 (IH, dd, J = 1.8, 8.9), 8.07 (I H, d, J = 8.8). 8.34 (IH, d, J = 1.4). 8.69 (IH, s); ¹³ C NMR (DMSO): 64.63, 64.69, 105.67, 1 15.73, 1 18.12, 120.12. 122.59,

125.85, 127.04, 128.03, 130.00. 132.66. 132.98, 134.47. 135.89, 143.89, 144.31,

144.71 , 153.92, 171.85.

100225) 3-Benzofuran-2-yl)-lH-indole-7-carboxylic acid, QR-0256 (Scheme

8). Light yellow solid. 50% yield ¹ H NMR (DMSO): 7.21- 7.29 (3 H, m), 7.33 (IH, t,

J = 7.7), 7.58-7.65 (2H, m), 7.89 (IH, d, J = 7.3), 7.95 (I H. d. J = 2.2), 8.38 (I H, d. J

= 7.9). 1 1.54 (IH, s), 13.23 (I H, s). ¹³ C NMR (DMSO): 99.77, 107.14. 1 1 1.07,

1 14.82, 120.45. 120.67, 123.41, 123.78. 125.40, 125.75, 125.92. 126.40, 129.85,

135.65, 152.95, 153.78, 168.07.

[00226] Methyl 3-benzo[61thiophen-2-yI)-l-tosyI-l//-indoIe-7-carboxyIate,

116 (Scheme 8). Light yellow solid. 44% yield ¹ H NMR (CDCl ₃ ): 2.32 (3H, s). 3.97

(3H, s). 7.17 (2H, d, J - 8.1 ), 7.34-7.38 (2H, m). 7.41 (I H. t, J = 7.7), 7.51 (IH, s). 7.60 (IH, dd, J - 1.0, 7.5), 7.62 (2H, d, J = 8.40). 7.76 (IH, s). 7.79 (IH, d, J = 8.2).

7.84 (IH. d, J = 7.8), 8.02 (IH. dd. J = 1.1. 8.0).

[00227J 3-Benzo[6]thiophen-2-yl)-li/-indole-7-carboxylic acid, QR-0261

(Scheme 8). Yellow solid. 67% yield ¹ H NMR (DMSO): 7.32 (2H. t, J = 7.6). 7.39

(IH. t, J = 7.9), 7.76 (I H, s), 7.79(1H, d. J = 2.4), 7.83 (I H, d, J = 7.8), 7.8 ( IH, d. J = 7.1), 7.94 (IH. d. J = 7.9), 8.33 (IH. d, J = 7.9), 11.48 (IH, s), 13.21 (IH, s); ¹³ C NMR (DMSO): 1 10.52, 114.77, 118.64. 120.34, 122.55, 123.40, 124.19, 12.5.05, 125.28, 125.38, 126.48, 126.70, 135.83. 137.83, 137.85. 141.18, 168.09.

[00228] Methyl l-benzyl-3-iodo-li/-indole-7-carboxylate, 117 (Scheme 9).

Yellow solid. 58% yield ¹ H NMR (CDCl ₃ ): 3.72 (3H. s), 5.59 (2H, s), 6.90 (2H. d, J =

6.35), 7.16 - 7.26 (5H. m), 7.61 (IH, d, J = 7.4). 7.65 (IH, d, J = 7.9); ¹³ C NMR (CDCl ₃ ): 52.22, 53.27, 1 17.31. 1 19.67. 125.85. 125.95, 126.69, 127.52. 128.58, 132.94, 133.05, 135.67, 137.35, 167.50.

[00229] Methyl S-benzofuran^-yl-l-benzyl-lH-indole^-carboxylate, 118

(Scheme 9). Light yellow solid. 51% yield ¹ H NMR (CDCl ₃ ) 3.74 (3H. s), 6.57 (2H, s). 6.93 (IH. s), 6.95 (2H. d, J = 6.5), 7.20 - 7.29 (6H, m). 7.49 (IH, d, J = 7.5), 7.57 -

7.60 ( I H. m), 7.62 (I H, dd. J = 0.93, 7.4), 7.75 (IH, s), 8.27 (I H, dd. J = 1.03, 8.0);

¹³ C NMR (CDCl ₃ ); 52.30, 53.39, 100.07, 107.96, 1 10.71 , 1 17.74, 1 19.99. 120.27.

122.81 , 123.44, 124.67, 125.54, 126.73, 127.57, 127.95, 128.64. 129.59. 130.48.

133.30, 137.26, 152.05, 154.01 , 167.85.

[00230] 3-Benzofuran-2-yl-l-benzyl-lH-indole-7-carboxylic acid, QR-0284

(Scheme 9). Beige solid. 76% yield ¹ H NMR (DMSO): 5.80 (2H, s). 6.98 (2H. d. J =

7.2), 7.18 - 7.31 (7H, m), 7.59 - 7.65 (3H, m), 8.31 (IH. s), 8.32 (I H. d. J = 8.0).

13.13 (IH, s. br); ¹³ C NMR (DMSO): 52.5, 100.36, 107.07, 1 1 1.05, 1 19.41. 120.57,

120.84, 123.48, 124.02, 124.45, 125.62, 127.17, 127.61, 127.81, 129.03, 129.77. 131.94, 133.1 1 , 138.24, 152.17, 153.75, 168.90.

[00231] Methyl 3-(benzo[£]thiophen-2-yl)-l-benzyl-17/-indole-7- carboxylate, 119 (Scheme 9). Light yellow solid. 53% yield ¹ H NMR (CDCl ₃ ): 3.73 (3H, s), 5.64 (2H, s), 6.95 (2H, d. J = 6.3), 7.20 - 7.25 (4H, m), 7.29 ( 1 H. t, J = 8.1 ), 7.36 (IH, t, J = 8.0). 7.50 (2H, d, J = 7.4), 7.61 (1 H, dd, J = 1.0, 7.4), 7.77 ( 1 H. d. J =

7.8), 7.82 (I H, d, J = 7.8), 8.26 (I H, dd, J = 1.0, 8.0); ¹³ C NMR (CDCl ₃ ): 52.25,

53.24, 1 1 1.35, 1 17.64, 1 19.08, 1 19.84, 122.03, 122.97. 123.74, 124.43. 125.58.

126.72, 127.55, 128.63, 128.93, 130.50. 133.41. 137.02, 137.34, 138.61, 140.80,

167.87.

[00232] S^Benzo^lthiophen^-ylH-benzyl-lH-indoIe-T-carboxylic acid,

QR-0287 (Scheme 9). Beige solid. 87% yield ¹ H NMR (DMSO): 5.78 (2H, s), 6.98 (2H, d, J =7.3), 7.18-7.42 (6H, m). 7.59 (I H. d, J = 6.6), 7.77 (I H, s). 7.85 ( I H, d. J =

7.8). 7.96 (IH, d, J = 7.9), 8.16 (I H. s). 8.28 (I H, d, J = 8.0); ¹³ C NMR (DMSO):

52.36. 1 10.49, 119.14, 1 19.44, 120.42. 122.58, 123.52, 123.99, 124.33. 125.09,

125.55. 127.13, 127.77, 128.48. 129.01. 132.14, 133.22. 137.10, 137.92, 138.33,

141.1 1 , 168.93.

[00233] 6-(3-(Pyridine-2-yloxy)phenyl)naphthalene-2-ol, QR-0234 (Scheme

1 1 ). White solid. 65% yield ¹ H NMR (DMSO) 7.07-7.18 (5H, m), 7.5-7.56 (2H. m).

7.64 (I H, d, J = 8.0), 7.72-7.80 (2H, m), 7.82-7.91 (2H, m), 8.13 (I H, s), 8.18 (I H,

dd, J = 1.8, 4.8), 9.82 (IH. s); ¹³ C NMR (DMSO) 108.92, 1 12.01 , 1 19.52. 1 19.59.

1 19.77, 120.36, 123.24. 125.57, 125.78, 127.23, 128.41 , 130.40, 130.66, 133.88, 134.52, 140.69, 142.49, 147.95. 154.95, 156.18, 163.60.

Example 4 General Procedure for deprotection of O-methyl groups

[00234] O-methyl groups were deprotected to give compounds QR-0229. QR-

0297, QR-0231, QR-0246, and QR-0247. Their synthesis reactions are depicted in Scheme 6 and Scheme 10 of Example 3 above, and Scheme 12 below.

Scheme 12

[00235] The following procedure was used to deprotect O-methyl groups. To

the solution of a methoxy-containing compound in CH ₂ Cl ₂ . BBr ₃ (2 - 4 equiv) was added dropwise at -78 ⁰ C. The reaction mixture was stirred at -78 ⁰ C for 20 minutes

and warmed up gradually to room temperature. Reaction time varied from 3 hours to

12 hours. The reaction was quenched with saturated NaHCO ₃ (aq). To make sure

that no boron complex remained, in some cases HCl (1.0 M, 2-3 ml) was added to the

mixture and stirred for 15-20 minutes. Layers were separated and the aqueous layer

was extracted thrice with CH ₂ CI2. The combined organic layer was dried (MgSO ₄ ). filtered and concentrated under vacuum.

[00236] The residue was purified by flash chromatography to yield the following compounds.

[00237] 4-(2,3-Dihydrobenzo[λ][l,4]dioxin-7-yI)naphthaIene-l-carbox ylic acid, QR-0228 (Scheme 6). White solid. 69% yield. ¹ H NMR (CDCl ₃ ) 4.35 (4H, s).

6.95-7.03 (3H, m), 7.46 ( 1 H, d, J= 7.5), 7.51 ( 1 H, t. J = 8.2). 7.66 ( 1 H, t, J = 8.2), 8.03

(IH, d, J = 8.4), 8.40 (IH, d, J = 7.5), 9.15 (I H, d, J = 8.7); ¹³ C NMR (CDCl ₃ ) 64.54,

1 17.26, 1 18.82. 123.13, 124.51 , 125.69, 126.07, 126.28, 126.98, 127.82, 131.17,

132.17. 132.30, 133.38, 143.43. 143.56, 146.13, 171.67.

[00238] 6-(2,3-Dihydrobenzo[Z>] |l,4]dioxin-7-yl)naphthalene-2-ol, QR-

0229 (Scheme 6). Beige solid. 97% yield. ¹ H NMR (CDCl ₁ ) 4.30 (4H. s), 5.07 (IH,

s), 6.96 (I H. d, J = 8.3), 7.08 - 7.23 (4H, m), 7.62 (IH. dd, J = 1.7. 8.5). 7.70 (IH, d, J

- 8.6), 7.76 (I H, d, J = 8.8), 7.89 (IH. s).

100239] l-(2,3-Dihydrobenzo[6]]l,4]dioxin-7-yl)-2,3- dihydroxynaphthalene, QR- 0231 (Scheme 6). Brown solid. ¹ H NMR (DMSO)

4.31 (4H, s. br), 6.71-6.77 (2H, m), 6.96 (IH, d, J = 8.1 ). 7.12 ( I H, t, J = 7.3), 7.16

(I H. s). 7.20 (IH, t, J = 7.6), 7.28 (I H. d. J = 8.2), 7.62 (I H. d. J = 7.6), 8.53 (IH, s),

10.20 ( I H. s); ¹³ C NMR (DMSO) 64.58. 108.87, 1 17.14. 1 19.85, 121.98, 123.33,

123.37, 124.18, 124.46, 126.40, 128.58. 129.00, 129.67. 142.81 , 143.47, 144.12, 146.54.

[00240] l,6-dibromo-2-methoxynaphtha!ene, 120 (Scheme 10). Light brown solid. 94.43% yield ¹ H NMR (CDCl ₃ ): 4.03 (3H, s), 7.28 (I H. d, J - 9.0), 7.61 (IH.

dd, J = 2.0, 9.1 ), 7.73 (IH, d. J = 9.0), 7.94 (I H, d, J = 1.94), 8.10 (IH, d, J = 9.1); ¹³ C NMR (CDCl ₃ ): 57.10. 108.74, 1 14.55, 1 18.22, 128.04, 128.1 1. 129.88, 130.68. 131.01 , 131.81, 154.07.

[00241] 2-(l-Bromo-2-methoxynaphthalen-6-yl)benzofuran, 121 (Scheme

10). White solid. 64% yield ¹ H NMR (CDCl ₃ ): 4.10 (3H, s), 7.18 (I H, s), 7.27 - 7.38

(311, m, overlapped with CDCl ₃ ), 7.59 ( IH, d, J = 8.2), 7.65 (I H, d, J = 7.1), 7.95

(IH. d, J = 8.9), 8.02(1H, dd, J = 1.7. 8.9). 8.31 (I H, d, J - 8.9), 8.36 (IH. d, J = 1.5): ' ³ C NMR (CDCl ₃ ): 57.08, 101.91 , 104.61. 1 1 1.16, 1 14.25, 120.99, 123.08, 123.89. 124.48, 124.73, 126.40. 126.86, 129.30, 129.50, 129.80, 133.40. 154.33, 155.06.

155.57.

[00242] 6-(Benzofuran-2-yl)-l-bromonaphthalen-2-ol, QR-0297 (Scheme

10). Light orange solid. 67% yield ¹ H NMR (DMSO): 7.28 (IH, t, J = 7.6), 7.32-7.38

(2H. m), 7.54 (IH, s). 7.66 (IH, d, J = 8.3), 7.69 (IH, d, J = 7.2), 7.98 (I H, d. J = 8.9).

8.12 (2H, s). 8.43 (IH, s); ¹³ C NMR (DMSO): 102.69, 104.97, 1 1 1.53, 1 19.59.

121.64, 123.78, 124.33, 124.99. 125.12, 125.29. 126.18. 129.06, 129.43. 130.05, 133.17, 153.71 , 154.81 , 155.54.

[00243] 1 -Bromo-2,3-dihydroxy-naphthalene (QR-0246) (Scheme 12).

Beige solid. 79% yield ¹ H NMR (DMSO): 7.19 (IH, s), 7.31 (I H, t, J = 7.94). 7.38 (I H. t, J = 7.79), 7.67 (I H, d, J = 8.39). 7.89 (I H. d. J = 8.24), 9.69 (IH, s). 10.49

(I H, s); ^π C NMR (DMSO): 105.46. 109.24, 124.33, 124.88, 125.08, 126.69, 127.52. 129.36, 145.41 , 146.91.

[00244] 2,3-Dihydroxy-naphthalene (QR-0247) (Scheme 12). Beige solid.

62% yield ¹ NMR (DMSO): 7.10 (2H, s), 7.15-7.20 (2H, s), 7.54 - 7.59 (2H, s), 9.48 ( 2H, s); ¹³ C NMR (DMSO) 109.98, 123.32, 125.99, 129.25, 147.30.

Example 5 Preparation of 5-methoxy-3-(tributylstannyl)-l-(toIuene-4-sulfonyl)-indole (217)

[00245] 5-methoxy-3-(tributylstannyl)- 1 -(toluene-4-sulfonyl)-indole (217) was

prepared by the reactions depicted in Scheme 13 below.

[00246] Procedure 206 of Example 7 of US Patent Application Serial No.

1 1/443.396, Publication No. US2007/0015813, was used.

Example 6

Preparation of 3-(5-methoxy-l-(toluene-4-sulfonyl)-indol-3-yl)-l-(toluene-4 - sulfonyl)-indole-2-earboxylie acid methyl ester (218)

[00247] 3-(5-methoxy-l -(toluene-4-sulfonyl)-indol-3-yl)-l-(toluene-4- sulfonyl)-indole-2-carboxylic acid methyl ester (218) (Scheme 4) was prepared using the same procedure as 207 in Example 7 of US Patent Application Serial No. 1 1/443,396, Publication No. US2007/0015813, with a yield of 80%.

[00248] The final product was obtained following flash chromatography. 3-(5-

methoxy-l-(toluene-4-sulfonyl)-indol-3-yl)-l-(toluene-4-sulf onyl)-indole-2- carboxylic acid methyl ester (218). ¹ H NMR (CDCl ₃ ): 2.32 (s, 3H), 2.34 (s, 3H). 3.70 (s, 3H), 3.81 (s, 3H), 6.73 (d, I H, }=2 A), 6.94-6.96 (m, IH), 7.21-7.28 (m, 5H), 7.36 (d, I H, J= 7.8), 7.43 (t, I H, J=7.6), 7.72 (s, I H). 7.80 (d, 2H. J=8.3), 7.88-7.92

(m. 3H), 8.10 (d, IH, J=8.4).

Example 7

Preparation of 3-(5-methoxy-indol-3-yl)-l-(toluenc-4-sulfonyl)-indole -2- carboxylie acid (OR-0169)

|00249] 3-(5-methoxy-indol-3-yl)-l-(toluene-4-sulfonyl)-indole -2-carboxylic

acid (QR-0169) (Scheme 14) was prepared using the same procedure as for 208 of Example 7 of US Patent Application Serial No. 1 1/443,396, Publication No.

US2007/0015813, with a yield of 76%.

[00250] The final product was obtained following flash chromatography. 3-(5-

methoxy-indol-3-yl)-l-(toluene-4-sulfonyl)-indole -2-carboxylic acid (QR-0169)

¹ H NMR (DMSO): 2.33 (s, 3H), 3.63 (s. 3H), 6.68 (d. IH, J=2.4), 6.96-6.98 (m, IH).

7.06-7.09 (m, 2H), 7.31 (d. 2H, J= 7.9), 7.40 (d, 2H, J=8.2), 7.52 (d, I H, J=8.4), 7.83

(s. I H). 7.86-7.89 (m, 2H), 1 1.98 (s, IH), 12.88 (s, IH); ¹³ C NMR (DMSO): 21.52, 55.75, 104.02, 1 1 1.75, 1 13.21, 1 13.92, 1 14.63. 1 16.30. 120.69. 121.22, 125.34,

125.67. 127.04, 127.24, 127.59, 129.31 , 130.66. 132.20, 134.60, 136.64, 145.77.

156.42. 163.14.

Example 8 Preparation of 3-(5-methoxy-indole-3-vi)-indole -2-carboxylic acid (QR-0168)

[00251] 3-(5-methoxy-indole-3-yl)-indole -2-carboxylic acid (QR-0168) was prepared by the reactions depicted in Scheme 14 below and using procedure 209 of Example 7 of US2007/0015813. with a yield of 82%.

[00252] The final product was obtained following flash chromatography. 3-(5-

methoxy-indole-3-yl)-indole -2-carboxylic acid (QR-0168). ¹ H NMR (DMSO).

3.64 (s, 3H), 6.75-6.78 (m, 2H). 7.04 (t, IH, J=7.5). 7.27 (t, IH, 5=7.6), 7.34 (d. IH,

J=8.6), 7.46-7.50 (m. 3H), 1 1.10 (s. 1 H), 1 1.65 (s, 1 H), 12.68 (s, 1 H); ' 'C NMR

(DMSO): 55.86, 102.49, 107.98. 1 1 1.65, 112.80, 1 13.09. 1 16.28. 120.08. 122.23.

124.37. 125.23, 126.75, 128.09. 128.31. 131.87. 136.91 , 153.76, 163.76.

Example 9

Preparation of 3-iodo-l-(toluene-4-sulfonyl)-indole-2-carboxylic Acid Methyl Ester (203)

[00253] 3-iodo-l-(toluene-4-sulfonyl)-indole-2-carboxylic acid methyl ester

(203) was prepared as follows.

[00254] To a mixture of 3-iodoindol-2-carboxylic acid methyl ester (202)

(0.604 g, 2 mmol) and NaH (60%, 0.192 g, 2.4 mmol) in DMF (20 mL) was added p- toluenesulfonylchloride (0.381 g, 2 mmol) at room temperature. After stirring for 1 hour, ethyl acetate (50 mL) was added to the reaction mixture. The mixture was washed with brine (3x30 mL). The organic layer was dried with MgSO ₄ , filtered and concentrated under vacuum. The residue was purified by flash chromatography (10%

ethyl acetate/hexane V: V) to afford 203 (0.68 g, 76%). ¹ H NMR (CDCl ₃ ): 2.35 (s,

3H). 4.05 (s, 3H), 7.23 (d. 2H. J=8.4), 7.33 (t. I H, J=7.2), 7.41, (m. 2H). 7.83 (d, 2H,

J=8.4), 7.98 (d, 1H, J=8.4).

Example 10 Preparation of 5-nitro-3-iodo-l-(tolucne-4-sulfonyl)-indole (222)

[00255] 5-nitro-3-iodo-l-(toluene-4-sulfonyl)-indole (222) was prepared by the

reaction depicted in Scheme 15 below, following procedure 212 of Example 7 of

US2007/0015813.

Scheme 15

Example 11

Preparation of 3-(l-(toluene-4-sulfonyl)-indole-3-yl)-5-nitro-l-(toluene-4- sulfonyQ-indole (223)

[00256] 3-(l -(toluene-4-sulfonyl)-indole-3-yl)-5-nitro-l-(toluene-4-sulf onyl)-

indole (223) was prepared as follows.

[00257] A solution of 222 (0.331 g, 0.748 mmol), crude 206 (0.42 g, 0.748 mmol), catalytic amount of CuI and tetrakis(triphenylphosphine)palladium in DMF (10 mL) was degassed with argon for 10 min (Scheme 16). The mixture was brought to 5O ⁰ C and stirred for 5 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (20% ethyl acetate/hexane V:V) to yield 223 (0.22

g. 50%). ¹ H NMR (CDCl ₃ ): 2.36 (s. 3H), 2.38 (s, 3H), 7.26-7.33 (m. 5H), 7.43 (t, I H.

J= 7.8), 7.56 (d, I H, J=7.8), 7.80 (s. IH), 7.84-7.87 (m, 4H), 7.92 (s. IH). 8.1 1 (d, I H, J=8.4), 8.17 (d, IH, J=9.1). 8.28 (d, IH. J=9.0), 8.48 (s, IH).

Example 12 Preparation of 3-(l-(toluene-4-sulfonyl)-indole-3-yl)-5-nitroindoIe (QR-0170)

[00258] 3-(l-(toluene-4-sulfonyl)-indole-3-yl)-5-nitroindole (QR-0170) was prepared by the reactions depicted in Scheme 16 below.

Scheme 16

[00259] The following procedure was used.

[00260] To a solution of 223 (0.2 g, 0.34 mmol) in THF/MeOH/H ₂ O (5:5:1)

was added LiOH (0.052 g, 2.2 mmol) (Scheme 16). The reaction mixture was stirred

at 5O ⁰ C for 0.5 h. The solution was cooled to room temperature and concentrated.

Water (10 mL) was added and pH was adjusted to 7 with IN HCl. T he aqueous phase was extracted with ethyl acetate (3 ^χ 1OmL). The combined organic phase was dried with MgSO ₄ . and the solvent was removed in vacuo. The residue was purified by

flash chromatography (ethyl acetate/hexane, 1 : 1 , V:V) to yield QR-0170 (0.13 g, 89%).'H NMR (DMSO): 2.30 (s, 3H), 7.33-7.39 (m. 3H), 7.45 (t, IH, J= 7.6), 7.66 (d, IH, J=9.0), 7.80 (d, I H, J=7.8), 7.96 (d, 2H. J=8.3), 8.06-8.10 (m. 3H), 8.13 (s, IH), 8.60 (d, IH. J=1.7), 12.18 (s, IH); ¹³ C NMR (DMSO): 21.49, 109.45, 1 12.89, 1 14.04, 1 16.56, 1 16.89, 1 17.64, 121.21. 123.24, 124.33. 125.48. 125.78, 127.29, 128.41, 129.84, 130.71, 134.52, 135.20. 139.97, 141.60, 146.03.

Example 13 Preparation of Bis(3-indolyl) methanone (229)

[00261] First, compound 226 (Scheme 17) was prepared using the same procedure as for 205 of Example 7 of US Patent Application Serial No. 11/443,396.

Publication No. US2007/0015813 by the reaction depicted in Scheme 17 below.

Scheme 17

Then, Bis(3-indolyl) methanone (229) was prepared by the reactions depicted in

Scheme 18 below.

Scheme 18

[00262] The following procedure was used.

[00263] To a solution of 205 (397 mg, 1 mmol) in dry THF (10 mL) was added n-BuLi (0.8 mL. 2.5 M) at - 78 ⁰ C over a period of 10 min (Scheme 18). After stirring for 15 min, 226 (400 mg. 1.5 mmol), dissolved in dry THF (10 mL). was added over a period of 5 min and the resulting mixture stirred for 5 h. Aqueous HCI

(1%, 40 mL) was added, and the mixture was extracted with ethyl acetate (3 x 2OmL).

The combined organic layers were washed with saturated NaHCO ₃ solution and brine

and dried over MgSO ₄ . The solvent was evaporated and the residue purified by

column chromatography (ethyl acetate/hexane, 3:7, V: V) to yield 227 (383 mg.

67%). ¹ H NMR (CDCl ₃ ): 2.35 (s. 6H). 6.23 (s, IH). 7.12 (t, 2H. J=7.6), 7.20 (d. 4H, J=8.1). 7.30 (t, 2H, J=7.8), 7.38 (d. 2H, J=7.9), 7.49 (s, 2H), 7.70 (d. 4H, J=8.3). 7.99

(d, 2H. J=8.4).

[00264] To a solution of 227 (285 mg. 0.5 mmol) in dry CH ₂ Cl ₂ ( 10 mL) was

added PDC (pyridinium dichromate) (940 mg. 2.5 mmol) and PTEA (pyridinium

trifluoroacetate) (190 mg, 1 mmol) (Scheme 18). The mixture was stirred for 2 h at

room temperature. The solid chromium waste was removed by filtration, the solvent

was evaporated, and the residue was purified by column chromatograph) on silica gel

with CH ₂ Cl ₂ /hexane, 2: 1, V: V) to yield 228 (263 mg. 93%). ¹ H NMR (CDCl ₃ ): 2.38

(s. 6H), 7.30 (d, 4H, J=8.2). 7.39 (t. 211. J=4.0), 7.42 (t, 2H, J=4.2), 7.85 (d. 4H.

J=8.4). 8.04 (d. 2H. J=8.3). 8.10 (s, 2H), 8.22 (d. 2H, J=7.8).

[00265] LiOH (12 mg. 0.5 mmol) and 228 (100 mg, 0.176 mmol) in

MeOH/THF/H ₂ O (1 :1 :1, 15 mL) were heated under reflux for 2 h (Scheme 18). The

resulting mixture was concentrated and the residue dissolved with ethyl acetate. The

solution was washed with brine and the organic layer dried over MgSO ₄ . The solvent was evaporated and the residue purified by column chromatography (ethyl acetate/CH ₂ Cl ₂ . 1 : 1 , V: V) to yield 229 (38 mg, 83%). ¹ H NMR (DMSO): 7.16-7.24 (m, 4H). 7.50 (d, 2H, J=7.9), 8.16 (d, 2H, J=2.9), 8.26 (2H. J=7.7), 1 1.80 (s, 2H); ' ¹ C NMR (DMSO): 1 12.36, 1 17.30. 121.45. 121.96, 122.99, 127.02. 132.40, 136.97. 185.04.

Example 14 Preparation of QR-Ol 74

[00266] QR-Ol 73 (Scheme 19) was prepared using the procedure to prepare

229 in the example above, by the reactions depicted in Scheme 19 below.

Scheme 19

The procedures yielded the following compounds:

|00267] 231 (58% yield). ¹ H NMR (DMSO): 2.33 (s. 6H), 3.79 (s, 3H), 7.07

(dd, I H, Ji=9.1, J ₂ =2.4), 7.39-7.42 (m, 5H), 7.47 (t. I H, J=7.7), 7.61 (d. IH, J=2.3),

7.91 (d, I H, J=9.1 ), 7.99-8.04 (m, 5H), 8.13 (d, I H, J=7.8). 8.62 (s. I H). 8.64 (s. IH).

[00268] QR-0173 (84% yield). ¹ H NMR (DMSO): 3.81 (s, 3H), 6.86 (dd. IH,

J,=8.8, J ₂ =2.5), 7.18 (t, I H, J=7.4), 7.22 (t, IH, J=8.0). 7.39 (d. I H, J=8.8), 7.50 (d, IH, J=7.9). 7.81 (d, I H, J=2.4), 8.12 (d, I H, J=3.0), 8.15 (d, I H. J=2.9), 8.27 (d, IH, J=7.7). 1 1.69 (s, IH), 1 1.78 (s. IH); ¹³ C NMR (DMSO): 55.74, 103.53, 1 12.35, 1 13.05, 1 13.13, 1 17.09, 1 17.28. 121.39, 121.95, 122.94, 127.05, 127.73. 131.89, 132.14, 132.74, 136.95, 155.38. 185.05.

[00269] QR-Ol 74 was then synthesized by deprotecting o-methyl group of QR-

0173 by using General Procedure A.

General Procedure A

[00270] To a solution of compound containing methoxy group in dry CH ₂ Cl ₂ was added BBr ₃ (2-10 equivalent) at - 78 ⁰ C. The mixture was stirred overnight and allowed to warm to room temperature. Water was added, and the mixture was

extracted with ethyl acetate. The organic layer was washed with brine and dried over

MgSO ₄ . The solvent was evaporated and the residue purified by column chromatography to yield the following compounds.

[00271] QR-0174 (87% yield). ¹ H NMR (DMSO): 6.72 (dd, I H. J,=8.6,

J ₂ =2.3), 7.18 (t, IH, J=7.2). 7.21 (t, IH, J=7.0), 7.29 (d, IH, J=8.6). 7.49 (d, I H,

J=7.9). 7.69 (d, I H, J=2.1). 8.04 (d, IH. J=2.9), 8.1 1 (d. IH. J=2.8). 8.24 (d, I H.

J=7.7), 8.91 (s, I H), 1 1.58 (s, I H), 1 1.78 (s. IH); ¹³ C NMR (DMSO): 106.28, 1 12.32, 1 12.67, 1 13.07. 1 16.76. 1 17.39. 121.3 1. 121.96. 122.90, 127.06. 128.03, 131.24,

131.90. 132.63. 136.92. 152.94, 185.01.

Example 15 Preparation of QR-0171

[00272] QR-0171 (Scheme 20) was synthesized using the same procedure as for 214 of Example 7 of US Patent Application Serial No. 1 1/443,396. Publication No. US2007/0015813. The reactions used are depicted in Scheme 20 below.

c eme

[00273] After column chromatography, the following compounds were

recovered:

[00274] 234 (64% yield). ¹ H NMR (CDCl ₃ ): 2.36 (s, 6H). 2.39 (s, 3H), 3.78 (s.

3H), 6.95 (d, IH, J=2.4). 7.03 (dd. I H, J,=9.1 , J ₂ =2.4), 7.24-7.32 (m, 4H), 7.73 (s, I H), 7.82-7.86 (m, 4H), 7.89 (s. I H). 8.00 (d, IH, J=9.1 ), 8.18 (d, IH. J=9.1 ). 8.28

(dd, I H, J, =9.2, J ₂ =2.2). 8.46 (d. IH. J=2.1).

[00275] QR-0171 (48% yield). ¹ H NMR (DMSO): 3.17 (s, 3H), 6.82 (dd, IH,

J,=8.8, J ₂ =2.3), 7.20 (d. IH, J=2.2), 7.38 (d, IH, J=8.8), 7.62 (d. IH, J=9.0), 7.68 (d. IH. J=2.4), 7.89 (d, IH, J=2.6), 8.05 (dd, I H, J,=9.0, J ₂ =I .8). 8.60 (d, I H, J=2.0).

1 1.16 (s, IH). 1 1.93 (s, I H); ¹³ C NMR (DMSO): 55.84, 101.44, 108.32, 1 12.21.

1 12.54, 1 12.95. 1 13.20, 1 17.12, 1 17.19, 123.88, 125.91, 126.60, 132.08. 139.93.

141.05. 154.15.

Example 16 Preparation of 4-methoxyl-3-(tributylstannyl)-l-(toluenc-4-sulfonyl)-indole (238)

[00276] 4-methoxyl-3-(tributylstannyl)-l-(toluene-4-sulfonyl)-indole (238)

(Scheme 21) was prepared using the same procedure as for 206 of Example 7 of US Patent Application Serial No. 1 1/443,396, Publication No. US2007/0015813. Reactions used are depicted in Scheme 21 below.

Scheme 21

Example 17 Preparation of QR-0179

[00277] QR-0179 (Scheme 22) was prepared using procedure 214 of Example

7 of US2007/0015813. Reactions used are depicted in Scheme 22 below.

Scheme 22

[00278] After column chromatography, the following compounds were

recovered:

[00279] 239 (73% yield). ¹ H NMR (CDCl ₃ ): 2.36 (s, 3H), 2.39 (s. 3H), 3.63 (s.

3H), 6.70 (d, IH, J=8.0), 7.28-7.34 (m, 5H), 7.61 (s. I H). 7.72 (d, I H. J=8.4), 7.83-

7.87 (m, 5H), 8.12 (d, I H, J=9.2), 8.22 (dd, IH. J,=9.2. J ₂ =2.2), 8.39 (d, IH, J=2.1).

[00280] QR-0179 (32% yield). ¹ H NMR (DMSO): 3.68 (s, 3H), 6.55 (t, IH,

.1=4.2), 7.08 (d, 2H, J=3.5). 7.43 (d, IH, J=2.2). 7.65 (d, IH, J=9.0), 7.64 (d. I H, .1=2.0), 8.00 (dd, 1 H, J _I =9.0, J ₂ =2.1 ), 8.52 (d, I H, J=I .8), 1 1.29 (s, IH), 1 1.75 (s, IH); ¹³ C NMR (DMSO): 55.19, 100.15, 105.63, 107.69. 1 12.19, 1 13.91 , 1 16.33, 1 16.59.

1 17.82, 122.73, 123.15, 127.26, 127.71 , 138.70, 139.58, 140.85, 154.37.

Example 18 Preparation of OR-0178

[00281 ] QR-O] 78 was prepared by the reaction depicted in Scheme 23 below.

Scheme 23

[00282] 1 , 1 '-Carbonyldiimidazole ('-CDI") (324 mg, 2 mmol ) was added to

the solution of indole-5-carboxyic acid (161 mg, 1 mmol) in dry DMF (5 mL) at 0 ⁰ C (Scheme 23). After the mixture was stirred for 1 h. concentrated aqueous ammonia

(0.4 mL) was added and the solution stirred overnight at room temperature. Water

(25 mL) was added to the mixture and the aqueous solution extracted with ethyl

acetate (3 ^χ 25 mL). The combined organic phase was dried with MgSO ₄ , filtered and concentrated under vacuum. The residue was purified by flash chromatography to yield the following compound.

[00283] QR-Ol 78 (60% yield). ¹ H NMR (DMSO): 6.5 ) (t, IH, .1=2.0), 7.06 (s,

IH). 7.39-7.41 (m, 2H), 7.65 (dd. IH, J,=8.5. J ₂ =1.7). 7.81 (s, I H), 8.15 (s. I H), 1 1.28 (s, I H); ¹³ C NMR (DMSO): 102.66, 1 1 1.25, 120.76, 121.43, 125.73, 126.92, 127.46, 137.92, 169.55.

Example 19 Preparation of QR-Ol 77

[00284] QR-Ol 77 (Scheme 24) was prepared using the procedure of Example

18 by the reaction depicted in Scheme 24 below.

Scheme 24

[00285] The following compound was afforded.

[00286] QR-Ol 77 (56% yield). ¹ H NMR (DMSO): 7.07 (t, 2H, J=7.4). 7.15 (t,

IH. J=7.5), 7.46 (t, 2H, J=7.8), 7.71-7.73 (m, 2H), 7.80-7.81 (m, 2H), 7.95 (s, IH).

8.37 (s, I H), 1 1.20 (s, IH). 1 1.37 (s, IH); ¹³ C NMR (DMSO): 109.63, 1 1 1.40. 1 1 1.44. 1 12.04. 1 19.42, 1 19.99, 120.24, 121.74, 122.83. 123.37. 125.76, 125.85. 126.45.

136.89, 138.40, 169.70.

Example 20 Preparation of methane linked bis-indoles

[00287] Compounds 243, QR-0192, QR-0193. QR-0182, QR-0181. QR-0191.

and QR-0190 were prepared by the reaction depicted in Scheme 25 below.

Scheme 25

[00288] The following General Procedure B was used to prepare methane linked bis-indoles.

General Procedure B

[00289] A mixture of 4-substituted benzaldehyde (1 mmol), 5-substituted

indole (2 mmol) and I ₂ (0.2 mmol) in acetonitrile (10 mL) was stirred at room temperature for 5-30 min. After completion of the reaction, the mixture was treated

with aqueous Na ₂ SO ₃ (5%, 10 mL). and the mixture was adjusted to pH 7 or 2 with

HCl (1 N) when required. The mixture was extracted with ethyl acetate and the

organic layer washed with brine and dried over MgSθ ₄ . The solvent was evaporated

and the residue purified by column chromatography to yield the following:

[00290] 243 (92% yield). ¹ H NMR (DMSO): 6.03 (s, IH), 6.89 (t. 2H, J=7.4).

6.90 (s, 2H), 7.06 (t, 2H, J=7.5). 7.30 (d. 2H. J=7.9), 7.37 (d, 2H, J=8.1). 7.61 (d, 2H,

J=8.7), 8.15 (d, 2H. .1=8.7), 10.92 (s. 2H); ¹³ C NMR (DMSO): 40.20. 1 12.07, 1 17.17, 1 18.90, 1 19.39, 121.58, 123.89, 124.34. 126.86, 129.93, 137.09. 146.26. 153.62.

[00291] QR-0192 (88% yield). ¹ H NMR (DMSO): 5.77 (s, IH), 6.57 (d, 2H,

J=2.2), 6.58 (s, 2H), 6.73 (d, 2H, J=2.1 ), 7.15 (d, 2H, J=9.3), 7.56 (d, 2H, J=8.7), 8.17 (d, 2H, J=8.7), 8.52, (s, 2H), 10.59 (s, 2H); ¹³ C NMR (DMSO): 40.26, 103.45, 1 1 1.90, 112.35, 1 16.17, 123.85, 124.76, 127.54, 129.95, 131.64, 146.21, 150.60, 153.65.

[00292] QR-0193 (75% yield). ¹ H NMR (DMSO): ¹ H NMR (DMSO): 3.61 (s.

6H), 5.96 (s, IH), 6.73 (dd, 2H, J,=8.7, J ₂ =2.4), 6.77 (d, 2H, J=2.2), 6.90 (d, 2H,

J=2.1), 7.27 (d, 2H, J=8.7). 7.62 (d. 2H, J=8.7). 8.16 (d, 2H, J=8.7). 10.77 (s. 2H); ¹³ C

NMR (DMSO): 39.86. 55.78, 101.70, 1 11.30, 1 12.66, 1 16.81 , 123.87, 125.05, 127.25.

129.90. 132.26, 146.20. 153.36, 153.74.

|00293] QR-0182 (89% yield). ¹ H NMR (DMSO): 6.25 (s. IH), 6.95 (d, 2H,

J-1.9), 7.45 (d, 2H. J=8.6), 7.64 (d. 2H, J=8.7), 7.72 (dd, 2H, J, =8.5, J ₂ =I .3), 8.04 (s. 2H), 8.20 (d, 2H. J=8.7). 1 1.31 (s, 2H), 12.33 (s. 2H); ¹³ C NMR (DMSO): 38.77,

1 1 1.37, 1 18.09, 121.1 1 , 121.64, 122.53. 123.58. 125.59, 125.89, 129.44. 129.13,

145.98, 152.44, 168.24.

[00294] QR-0181 (90% yield). ¹ H NMR (DMSO): 6.48 (s. I H). 7.22 (s, 2H).

7.56 (d, 2H, J=9.0). 7.67 (d, 2H, J=8.7), 7.99 (dd, 2H. J,=9.0, J ₂ =2.1), 8.20 (d. 2H,

J=8.7), 8.39 (d, 2H. J=2.0), 1 1.76 (s, 2H); ¹³ C NMR (DMSO): 38.47, 1 12.71, 1 16.53.

1 17.28, 1 19.77, 124.27. 126.10, 128.43. 129.89. 140.24, 140.88, 146.64, 152.30.

[00295] QR-0191 (65% yield). ¹ H NMR (DMSO): 5.66 (s, IH). 6.56-6.59 (m.

4H), 6.69 (s, 2H), 7.14 (d, 2H, J=8.4), 7.42 (d, 2H, J=7.8), 7.87 (d. 2H. J=7.8), 8.47 (s.

2H). 10.51 (s, 2H), 12.53 (s, IH); ¹³ C NMR (DMSO): 40.43, 103.56, 1 1 1.78, 1 12.25.

1 16.82, 124.62, 127.68, 128.83, 128.94, 129.69, 131.65. 150.50, 150.69, 167.83.

[00296] QR-Ol 90 (84% yield). ¹ H NMR (DMSO): 6.31 (s. I H). 7.16 (s, 2H),

7.49 (d. 2H, J=8.0). 7.56 (d, 2H. J=9.0), 7.90 (d, 2H. J=7.9), 7.98 (d. 2H. J=8.8), 8.34 (s, 2H), 1 1.78 (s. 2H); ¹³ C NMR (DMSO): 38.79, 1 12.65, 1 16.61 , 1 17.13, 120.43, 126.21 , 128.25, 128.68, 130.04, 130.76. 140.28, 140.75, 148.76, 168.01.

Example 21 Preparation of QR-0198, QR-0197 and QR-0206

[00297] Compounds QR-0198, QR-0197 and QR-0206 were prepared by the

reactions depicted in Scheme 26 below.

Scheme 26

[00298] The following procedure was used. A suspension of indole (1.17 g, 10 mmol) in THF (50 mL) was cooled to - 2O ⁰ C and ethylmagnesium bromide (3.7 mL. 3.0 M in THF) was added dropwise. The mixture was warmed to room temperature

for 3 h, and 4-anisolecarboxylic acid chloride (1.7O g, 10 mmol) in dry THF (30 mL)

was added dropwise. After stirring overnight, ethyl acetate ( 150 mL) was added and the mixture was washed with brine. After drying the organic layer over MgSO ₄ , the solvent was evaporated and the residue purified by column chromatography to yield the following:

[00299] QR-0198 (42% yield). ¹ H NMR (DMSO): 3.86 (s, 3H), 7.08 (d, 2H,

J=8.6), 7.20-7.26 (m, 2H). 7.52 (d, IH, J=7.6), 7.81 (d. 2H, J=8.6), 7.94 (d. I H,

J=2.9), 8.22 (d. 1H, J=7.6), 1 1.99 (s, IH); ¹³ C NMR (DMSO): 55.88, 1 12.62, 114.14, 1 15.54, 121.92, 122.13, 123.43. 126.93, 131.07, 133.44. 135.30, 137.10, 162.26.

189.22.

[00300] QR-0197 (38% yield). ¹ H NMR (CDCl ₃ ): 3.88 (s, 3H), 3.90 (s, 3H),

6.69 (d, 2H, J=8.8), 7.02 (d, 2H, .1=8.8), 7.40-7.45 (m, 2H), 7.77 (d, 2H, J=8.8), 7.83

(s, IH), 7.87 (d. 2H, J=8.8), 8.20-8.25 (m, 2H): ¹³ C NMR (CDCl ₃ ): 55.51 , 55.64,

1 13.80, 1 14.26, 1 15.69, 120.14, 122.37, 124.90. 125.35, 125.79, 128.62, 131.33.

132.05, 132.13, 133.98, 136.61 , 163.10. 163.50, 168.07, 189.85.

[00301] QR-0206 was prepared by deprotecting o-methyl group of QR-0198

using General Procedure A of Example 14. The following compound was afforded.

QR-0206 (76% yield). ¹ H NMR (DMSO): 6.89 (d, 2H, J=8.2). 7.18-7.25 (m, 2H),

7.51 (d, I H, J=7.8), 7.72 (d, 2H. J=8.0). 7.93, (d, IH, J=2.2). 8.21 (d. I H, J=7.5).

10.07 (s. I H), 1 1.94 (s, I H); ¹³ C NMR (DMSO): 1 12.57, 1 15.46, 1 15.56, 121.94. 122.00, 123.32, 126.99. 131.32, 131.94, 134.94, 137.05, 160.95. 189.24.

Example 22 Preparation of QR-0205

[00302] Compound 253 was prepared by the reactions depicted in Scheme 27 below, using procedure as that for QR-0198 in the Example 21.

Scheme 27

[00303] The following compound was recovered. 253 (72% yield). ¹ H NMR

(CDCl ₃ ): 3.87 (s, 3H), 3.88 (s, 3H). 6.94 (dd, I H, J,=8.8, J ₂ =2.5), 6.97 (d. 2H, J=8.7), 7.30 (d, IH, J=8.8). 7.62 (d. IH, J=3.1 ), 7.84 (d. 2H, J=8.7). 7.92 (d, IH, J=2.4). 9.02 (s, IH); ¹³ C NMR (CDCl ₃ ): 55.47, 55.79, 103.55, 1 12.20, 113.62, 1 14.51, 1 16.92,

127.40, 130.96. 131.25, 133.28, 133.44, 156.38, 162.35, 190.55.

[00304] Compound QR-0205 was then prepared following General Procedure

A of Example 14, to afford QR-0205 (70%). ¹ H NMR (DMSO): 6.74 (dd. 1 H.

Ji=8.6, J ₂ =2.0), 6.91 (d, 2H, J=8.4), 7.29 (d, 1 H. J=8.6), 7.62, (d, IH, J=I .6). 7.67, (d.

2H, J=8.4), 7.76 (d, 1 H, J=2.9), 8.99 (s, 1 H). 10.17 (s. 1 H), 1 1.86 (s, 1 H); ' ³ C NMR (DMSO): 106.31, 1 12.86, 1 13.27, 1 15.03. 1 15.40, 128.02, 131.05, 131.24, 132.12,

134.84, 153.41 , 160.85. 189.17.

Example 23 Preparation of QR-0196

[00305] Compound QR-0196 was prepared by the reaction depicted in Scheme

28 below.

Scheme 28 |00306] The following procedure was used.

[00307] 5-Nitroindole (162 mg, 1 mmol) was dissolved in dry THF (5 mL) and

added dropwise to a suspension of KH (137 mg. 35%. 1.2 mmol) in THF (10 mL)

cooled to -15°C. After 30 min., 4-anisolecarboxylic acid chloride ( 170 mg. 1 mmol) was added and the reaction stirred at room temperature for 4 h. Water (10 mL) was added and the aqueous layer was extracted with EtOAc (30 mL). The organic layer

was dried with MgSO ₄ and the product was purified by column chromatography to

yield the following compound.

[00308] QR-0196 (51% yield). ¹ H NMR (CDCl ₃ ): 3.93 (s. 3H). 6.77 (d. I H,

J=3.7), 7.05 (d, 2H, J=8.8), 7.56 (d. I H, J=3.7). 7.78 (d, 2H, J=8.8). 8.25 (dd, IH.

J,=9.1. J ₂ =2.2), 8.40 (d, IH, J=9.1 ), 8.54 (d, I H, J=2.2); ¹³ C NMR (CDCl ₃ ): 55.66, 108.32. 1 14.22, 1 16.25, 1 17.21, 1 19.90. 125.25, 130.47, 130.58. 132.08. 139.18, 144.25. 163.45, 167.94.

Example 24 Preparation of mcthylene-linked indole-tetrahydroisoquinoline compounds

100309] Compounds QR-0266, QR-0267, QR-0268, QR-0269. QR-0271. and

QR-0276 were prepared by the reaction depicted in Scheme 29 below.

Scheme 29 [00310] The following General Procedure C was used.

General Procedure C

[00311] To a solution of 1, 2, 3, 4-tetrahydronisoquinoline (4.4 mmol) in

AcOH-THF (1 :2, 6 mL) was added formaldehyde (0.327 mL, 4.4 mmol, 37% solution

in water). After the solution was stirred for 15 min, substituted indole (4 mmol) was

added. The resultant mixture was stirred at room temperature overnight. EtOAc (50

mL) was added to the mixture, and the mixture was washed with brine. After drying the organic phase with MgSθ4. solvents were removed under reduced pressure and flash chromatography, and the following compounds were recovered.

[00312] QR-0266 (88% yield). ¹ H NMR (DMSO): 2.72 (t, 2H, J=5.6). 2.80 (t,

2H, 3=5.6), 3.60 (s, 2H), 3.87 (s, 2H). 7.01 (d, IH, J=3.6), 7.06-7.12 (m, 3H), 7.55 (d,

IH. J=9.0), 7.59 (s. IH), 8.00 (dd, I H, J,=9.0, J ₂ =2.3), 8.65 (d, IH. 3=2.2). 1 1.72 (s, IH); ¹³ C NMR (DMSO): 29.25, 50.55. 53.22, 56.04, 1 12.39, 1 14.64. 1 16.89, 1 17.02, 125.92, 126.39, 126.88, 127.19, 128.84, 128.90, 134.71 , 135.40. 140.20. 140.77.

[00313] QR-0267 (59% yield). ¹ H NMR (DMSO): 3.04 (d. IH, J=15.8). 3.22-

3.33 (m, 2H), 3.68 (d, I H, J=9.6). 3.81 (s, 3H), 4.31-4.41 (m, 2H), 4.58 (d. 2H.

J=4.5), 6.81 (dd, I H, J,=8.8, J ₂ =2.2), 7.18 (d, IH, J=7.4), 7.22-7.29 (m. 3H). 7.35 (d.

1H, J=8.8), 7.41 (d, I H. J=I .9). 7.66 (d. 1 H, J=2.5), 1 1.03 (s, I H), 1 1.44 (s. I H); ¹³ C NMR (DMSO): 25.54, 47.99. 50.46. 51.28. 55.99, 101.13, 102.62, 1 12.38, 1 13.03.

127.03. 127.12, 128.05, 128.50. 128.98. 129.08, 129.95, 131.50, 132.12, 154.42.

[00314] QR-0268 (67% yield). ¹ H NMR (DMSO): 3.05 (d. I H, J=I 5.4), 3.20-

3.33 (m, 2H), 3.70 (s, IH. b), 4.41 (s, 2H). 4.68 (s, 2H), 7.18-7.29 (m, 4H). 7.54 (d. IH, J=8.5). 7.80 (d. I H, J=8.5), 7.85 (s. IH), 8.55 (s, IH), 10.79 (s, I H), 1 1.94 (s, IH), 12.53 (s, IH); ¹³ C NMR (DMSO): 25.12, 47.78, 49.66, 51.25, 103.99. 1 1 1.64,

121.59, 122.29, 122.92, 126.53, 126.60, 126.96, 127.59, 128.45, 128.53, 130.68,

131.60, 138.48, 168.28.

[00315] QR-0269 (91% yield). ¹ H NMR (DMSO): 2.68 (t, 2H, .1=5.6). 2.80 (t,

2H. J=5.6), 3.56 (s. 2H), 3.71 (s, 2H). 6.60 (dd, IH, J,=8.6. J ₂ =2.1), 7.00 (s, 2H). 7.07-7.10 (m, 3H). 7.16 (d. I H, J=8.6). 7.18 (d, I H, J=1.9), 8.55 (s, IH), 10.61 (s,

I H); ¹³ C NMR (DMSO): 29.36, 50.56, 53.98. 56.13, 103.65. 1 10.58, 1 1 1.82, 1 12.08,

125.43, 125.86, 126.31 , 126.83, 128.75. 128.86, 131.47, 134.84. 135.71 , 150.70.

[00316] QR-0271 (88% yield). ¹ H NMR (DMSO): 2.70 (t, 2H, J=5.6), 2.80 (t,

2H, J=5.6), 3.58 (s, 2H), 3.83 (s, 2H). 7.00 (d. I H, 6.8), 7.08-7.12 (m, 3H), 7.43 (dd,

IH, Ji=8.4, J ₂ =I .2), 7.53 (s, I H), 7.54 (d. I H, J=8.4), 8.17 (s. I H), 1 1.55 (s. IH); ¹³ C NMR (DMSO): 29.28, 50.51, 53.08, 55.88. 100.99, 1 12.80, 1 13.21 , 121.32. 124.23.

125.36, 125.89, 126.36, 126.86. 127.64. 127.83. 128.89, 134.71. 135.47, 138.67.

[00317] QR-0276 (82% yield). ¹ H NMR (DMSO): 2.68 (t, 2H, J=5.6), 2.79 (t.

2H, J=5.6), 3.57 (s. 2H), 3.77 (s, 2H), 7.00 (d. I H, 7.0), 7.08-7.12 (m, 3H), 7.19 (dd.

I H, J,=8.5, J ₂ =1.4). 7.35 (d. IH, J=8.5), 7.37 (d. IH, J=2.0), 7.81 (s, IH). 1 1 .17 (s, IH); ¹³ C NMR (DMSO): 29.28, 50.51 , 53.42. 55.99, 1 1 1.42. 1 1 1.55, 1 13.90. 121.86,

123.94, 125.89. 126.35, 126.68. 126.86. 128.88, 129.84, 134.75. 135.54, 135.63.

Example 25 Preparation of QR-0272

[00318] Compound QR-0272 was prepared by using reactions depicted in

Scheme 30 below.

Scheme 30 [00319] The following procedure was used.

|00320] 1 , 1 ⁿ -Carbonyldiimidazole ( 178 mg, 1.1 mmol ) was added to the solution of indole-2-carboxyic acid (161 mg. 1 mmol) in dry THF (10 mL) at 0 ⁰ C.

After the mixture was stirred for 1 h, 1. 2. 3, 4-tetrahydroisoquinoline (0.14 mL, 1.1

mmol) was added. The solution was stirred for 5 h at room temperature. The mixture

was concentrated under vacuum and the residue purified by flash chromatography to

yield the following.

[00321] QR-0272 (60% yield). ¹ H NMR (DMSO): 2.96 (s. 2H), 3.98-4.06 (m.

2H). 4.92 (s. 2H), 6.95 (s, IH), 7.07-7.09 (m, IH). 7.20-7.25 (m, 5H). 7.47 (d, IH,

J=8.2), 7.66 (d. IH. J=8.0). 1 1.63 (s. IH); ¹³ C NMR (DMSO): 104.62, 1 12.60, 120.22, 121.95. 123.80, 126.73, 126.91. 127.06. 127.43. 128.92. 130.58, 133.84. 135.25, 136.46. 162.83.

Example 26 Preparation of OR-274

[00322] Compound QR-274 was prepared by the reaction depicted in Scheme

31 below.

Scheme 31

[00323] The following procedure was used.

[00324] To a solution of 1, 2, 3, 4-tetrahydronisoquinoline (0.253 mL, 2 mmol)

in DMF (5 mL) was added K ₂ CO ₃ (552 mg. 4 mmol) and 4-methoxybenzylchloride

(0.288 mL. 2 mmol). The resultant mixture was stirred at room temperature overnight.

EtOAc (50 mL) was added to the mixture, and the mixture was washed with brine. After drying the organic layer with MgSθ ₄ , evaporation of the solvents and flash

chromatography yielded the following products.

[00325] QR-0274 (95% yield). ¹ H NMR (DMSO): 3.00-3.03 (m. I H), 3.23-

3.29 (2H), 3.57-3.62 (m, IH), 3.81 (s, 3H), 4.25-4.26 (m, 2H), 4.35-4.39 (m, 2H),

7.04 (d, 2H, J=8.7). 7.18 (d, IH, J=JA), 7.22-7.29 (m, 3H), 7.63 (d, 2H. J=8.6); ¹³ C

NMR (DMSO): 25.29, 48.42, 51.50, 55.72, 58.21 , 1 14.63. 122.00, 127.05, 127.10,

128.07. 128.82. 128.98, 132.07, 133.38, 160.54.

Example 27 Preparation of QR-259

[00326] Compound QR-0259 was prepared by the reaction depicted in Scheme

32 below.

Scheme 32 [00327] The following procedure was used.

[00328] To a solution of 1, 2, 3, 4-tetrahydronisoquinoline (0.253 mL, 2 mmol) in THF (15 mL) was added Et ₃ N (0.306 mL, 2.2 mmol) and />toluenesulfonylchloride (420 mg, 2.2 mmol). The resultant mixture was stirred at room temperature for 10 h.

EtOAc (20 mL) was added and the mixture washed with brine. After drying the

organic layer with MgSO ₄ , evaporation of the solvents and flash chromatography.

The following compounds were recovered.

[00329] QR-0259 (92% yield). ¹ H NMR (DMSO): 2.42 (s, 3H), 2.92 (t, 2H,

J=5.9), 3.35 (t, 2H, J=5.9), 4.25 (s, 2H). 7.02 (t, I H, J=4.5), 7.07 (t, I H, J=4.5), 7.12-

7.15 (m, 2H), 7.32 (d, 2H, J=8.0). 7.73 (d. 2H. J=8.2); ¹³ C NMR (DMSO): 21.53, 28.90, 43.73, 47.56, 126.35, 126.38, 126.75. 127.78, 128.83, 129.72, 131.70, 133.12.

133.41 , 143.67.

Example 28 Preparation of QR-0260

[00330] Compound QR-0260 was prepared by the reaction depicted in Scheme

33.

Scheme 33

[00331] The following procedure was used.

[00332] To a solution of 1. 2, 3. 4-tetrahydronisoquinoline (0.253 niL, 2 mmol) in THF (15 mL) was added Et ₃ N (0.306 mL. 2.2 mmol) and 4-anisolecarboxylic acid chloride (374 mg, 2.2 mmol). The resultant mixture was stirred at room temperature for 10 h. EtOAc (20 mL) was added and the mixture was washed with brine. After drying the organic layer with MgSO ₄ . evaporation of the solvents and flash

chromatography produced the following product.

[00333] QR-0260 (89% yield). ¹ H NMR (DMSO): 2.51 (t, 2H, J=5.8), 3.67 (s,

2H. b), 3.82 (s, 3H), 4.69 (s, 2H), 7.02 (d. 2H. J=8.6). 7.19 (m. 4H), 7.44 (d, 2H, J=8.6).

Example 29 Preparation of bisindole containing fused rings

[00334] Compunds QR-0278, QR-0288, QR-0279. QR-0291 , QR-0290, and

250 were prepared by the reaction depicted in Scheme 34 below.

Scheme 34

[00335] The following General Procedure D was used.

General Procedure D

[00336] A mixture of phthalaldehyde (1 mmol), 5-substituted indole (2 mmol)

and h (0.2 mmol) in acetonitrile (10 mL) was stirred at room temperature for 30 min.

to 10 hours. After completion of the reaction, aqueous Na^SO^ solution (5%. 10 mL) was added and the pH adjusted to 7 or 2 with HCl (1 N) when required. The mixture was extracted with ethyl acetate and the organic layer washed with brine and dried over MgSO ₄ . The solvent was evaporated and the residue purified by column chromatography to yield the following compounds.

[00337] QR-0278 (68% yield). ¹ H NMR (CDCl ₃ ): 3.60 (s, 3H), 3.96 (s, 3H).

6.70 (s, I H), 6.96 (d, IH, J-2.4), 7.05 (d, I H, J=2.4), 7.16 (s, IH), 7.36-7.45 (m, 4H),

7.74 (s, 2H), 8.00 (s, IH), 8.1 1 (d, I H, J=7.9), 8.43 (s, IH). 8.57 (s. IH); ¹ H NMR

(CDCl ₃ ): 55.84, 56.23, 101.51, 104.67, 110.92,111.30, 112.32, 113.42, 115.91, 118.04, 122.51.124.94, 125.19.127.86.128.61, 128.83, 131.49, 154.71.

[00338] QR-0288 (65% yield). ' H NMR (DMSO): 6.37 (d, 1 H. J=2.2).6.70

(dd, IH, J,=8.7, J ₂ =2.3), 6.94 (d, IH, J,=8.6, J ₂ =2.4), 7.27 (d, IH, J=8.5).7.32-7.35 (m, 2H), 7.38 (d. IH, J=8.7), 7.57 (d. IH..1=2.4), 7.62 (d. IH. J=2.3), 7.77-7.79 (m,

IH).8.10-8.12 (m, IH), 8.51 (s, IH), 8.59 (s, IH), 8.99 (s, IH).10.10 (s. IH).11.24 (s, IH); ¹³ CNMR(DMSO): 103.64, 106.42, 109.09, 111.81, 111.98, 112.15.112.63,

116.56, 117.57, 122.10, 123.51, 124.58, 125.18, 125.53, 126.41, 128.05, 128.67,

129.07.131.46, 136.84, 140.10, 150.85, 151.24.

[003391 QR-0279 (51% yield). ¹ HNMR(DMSO): 7.29 (t. IH, J=8.1).7.49-

7.53 (m, 3H), 7.65 (s, IH), 7.70s, IH).7.72. IH).7.81-8.84 (m.2H).7.97 (d, IH,

J=8.5), 8.04 (s, IH).8.12 (d, IH, J=8.3).11.75 (s, IH), 12.01 (s. IH), 12.23 (s, IH);

¹³ CNMR(DMSO): 106.13, 110.31, 112.28.112.98, 120.88.121.95.122.35.122.63,

123.21, 123.25, 124.73, 124.99, 125.52.126.33, 126.49.126.98.127.41.127.74,

128.73, 129.01, 132.99.139.46, 140.19.146.05.168.01, 168.59.

[00340] QR-0291 (72% yield). ¹ H NMR (DMSO): 6.91 (d, IH. J= 1.6), 6.96

(d, IH, J=1.5).7.28 (t, IH, J=7.6), 7.34 (d, IH, J=8.7).7.43-7.50 (m.3H), 7.65 (d, IH, J=8.7), 7.73 (d. IH, J=8.8), 7.75 (d, IH, J=2.3).7.99 (s, IH), 8.10 (d, IH, J=8.3), 11.49 (s, IH).11.88 (s, IH); ¹³ C NMR (DMSO): 105.88, 110.23, 111.24, 112.44, 112.69.114.67.121.33, 123.06, 123.86.124.67, 124.81, 125.00.125.56.126.22,

126.44, 127.17.127.69, 128.33, 129.40.129.60, 133.15, 135.60.140.01, 141.91.

[00341] QR-0290 (75% yield). ¹ H NMR (DMSO): 6.99 (s, IH), 7.33-7.36 (m.

2H), 7.55 (t, IH, J=7.5), 7.59-7.63 (m, 2H). 7.74-7.76 (m, 2H), 7.87 (d, IH. J=8.5). 7.97 (d, IH, J=2.3). 8.10 (s, I H), 8.16 (d. I H, J=8.3), 11.99 (s, IH), 12.29 (s, I H); ¹³ C

NMR (DMSO): 99.92, 102.18. 106.83. 1 1 1.98, 1 12.29, 1 14.12, 120.72, 120.77, 123.03, 123.53. 123.73, 124.84, 125.03, 125.96, 125.99, 126.36, 126.66, 127.22,

127.94, 128.47, 128.76, 130.70. 133.38. 138.71 , 139.84, 145.51.

[00342] 250 (74% yield). ¹ H NMR (DMSO): 7.37 (t. I H, J=7.5). 7.59 (t. IH.

J=7.5), 7.61 (d, IH, J=8.9), 7.72 (d. IH. J=2.3), 7.77 (d, IH, 3=22). 7.79 (d, IH.

J=8.7), 7.91 (d, IH, J=9.1 ), 8.08 (d. I H. 3=23), 8.14 (dd, IH, J,=9.1, J ₂ =2.3), 8.17 (s. IH), 8.20 (d, IH. J-=8.4). 8.28 (d. I H, J=8.9), 12.14 (s, IH), 12.52 (s, I H); ¹³ C NMR

(DMSO): 107.61. 1 10.95. 1 13.40. 1 13.66, 1 15.96, 1 17.70, 1 18.78, 122.42, 123.50.

124.06, 124.15, 125.94, 126.22, 126.33, 126.73, 128.12, 128.86, 129.74. 133.46, 139.48. 140.24, 140.41 , 141.60, 147.16.

Example 30 Preparation of QR-0209 and QR-0214

[00343] Compounds 251 , QR-0209 and QR-0214 were prepared by reactions depicted in Scheme 35 below.

Scheme 35

[00344] The following General Procedure E was used.

General Procedure E

[00345] A flask was charged with arylbromide (3 mmol) and dry THF (20 mL) under argon. The solution was cooled to -78 ⁰ C and then ?-BuLi (2.35 mL, 4 mmol,

1.7 M in hexanes) was added via a syringe through the septum, and the solution was

stirred at -78 ⁰ C for 20 min. ZnCb (4 mL, 4 mmol, 1 M in ether) was then added via a

syringe. The mixture was stirred for 30 min. at -78 ⁰ C and the flask was removed from

the cooling bath and stirred at room temperature for 30 min. This mixture was transferred to another flask containing Pd (PPh ₃ ) ₄ (0.05 mmol) catalyst and iodoindole

(1 mmol) under argon. Then the mixture was stirred at 50-70 ⁰ C for 3-5h. The

reaction mixture was then cooled to roomo temperature, diluted with water (15 mL),

and extracted with EtOAc(3 ^χ 15 mL). The combined organic phases were dried over

MgSO ₄ and concentrated under reduced pressure. The crude material was purified by

flash chromatography to yield 251. 251 (68% yield). ¹ H NMR (CDCl ₃ ): 2.33 (s, 3H),

3.81 (s, 3H). 3.86 (s, 3H), 6.96 (dd, IH. J,=9.0, J ₂ =2.4), 7.00 (d. 2H, J=8.6). 7.15 (d,

IH, J=2.4), 7.21 (d, 2H, J=8.2), 7.49 (d. 2H, J=8.6), 7.57 (s, I H), 7.76 (d, 2H. J=8.3),

7.94 (d, I H, J=9.0).

[00346] LiOH (2 mmol) and 251 (0.5 mmol) in methanol ( 10 mL) were heated under reflux for 2 h. The resulting mixture was concentrated and the residue was dissolved with ethyl acetate. The solution was washed with brine and dried over

MgSO ₄ . The solvent was then evaporated and the residue purified by column

chromatography to yield QR-0209 (90% yield). ¹ H NMR (CDCl ₃ ): 3.86 (s, 6H), 6.91

(dd, I H, Ji=8.8, J ₂ =2.4), 7.00-7.02 (m, 2H), 7.26 (d, I H. J=2.5), 7.31 (d, IH, J=5.6),

7.33 (d, IH, J=2.3), 7.55-7.57 (m, 2H). 8.07 (s. I H); ¹³ C NMR (CDCl ₃ ): 55.39, 56.02,

101.58, 1 12.03, 1 12.64, 1 14.33, 1 17.93, 122.01. 126.36, 128.24. 128.56, 131.76, 154.68, 158.10.

[00347] QR-0214 was prepared by General Procedure A of Example 14, to

deprotect O-methyl group of QR-0209 to obtain QR-0214 (83% yield). ¹ H NMR

(DMSO): 6.64 (dd. IH, J,=8.6, J ₂ =2.2), 6.82 (d. 2H. J=8.5), 7.12 (d. IH. J=2.0). 7.20

(d, I H, J=8.6), 7.38 (d, I H, J=2.5), 7.40 (d, 2H. J=8.5), 8.64 (s, I H). 9.22 (s, I H), 10.85 (s, I H); ¹³ C NMR (DMSO): 103.55, 1 1 1.97, 1 12.55. 1 15.55, 1 16.00, 122.98,

126.27, 127.56. 127.89, 131.74, 151.47. 155.55.

Example 31 Preparation of QR-0208 and QR-0215

[00348] Compounds QR-0208 and QR-0215 were prepared by reactions depicted in Scheme 36 below.

Scheme 36

[00349] General Procedure E of Example 30 was used to yield compound 252

(71% yield). ¹ H NMR (CDCl ₃ ): 2.32 (s, 3H), 3.82 (s. 3H), 3.85 (s, 3H), 7.10 (d, 2H,

J=8.7), 7.41 (d, 2H, J=8.2), 7.63 (d, 2H, J=8.7), 7.98-8.01 (m, 3H), 8.1 1 (s, IH), 8.14

(d, IH, J=8.7), 8.31 (d, IH, 0.9)

[00350] LiOH (2 mmol) and 252 (0.5 mmol) in MeOH/H ₂ O (1 : 1, 10 niL) were heated under reflux for 2 h. The resulting mixture was cooled to room temperature

and concentrated. The residue was adjusted to pH 2 with IN HCl. EtOAc (30 mL)

was added and the resultant mixture was washed with brine and dried over MgSO ₄ .

The solvent was evaporated and the residue purified by column chromatography to yield QR-0208 (89% yield). ¹ H NMR (DMSO): 3.81 (s, 3H). 7.07 (d, 2H. J=8.7).

7.51 (d. IH, .1=8.6), 7.60 (d, 2H. J=8.7), 7.69 (d, I H, .1=1.2), 7.78 (dd, IH, J,=8.6.

J ₂ =I .2), 8.48 (s, I H). 1 1.60 (s, IH), 12.47 (s, I H); ^π C NMR (DMSO): 55.60. 1 12.10.

1 14.91 , 1 17.34. 122.07, 122.36, 123.03. 124.55, 125.24, 127.97, 128.44, 139.65.

158.13, 168.83.

[00351] General Procedure A of Example 14 was used to prepare QR-0215

(82% yield). ¹ H NMR (DMSO): 6.88 (d, 2H, J=8.4). 7.47 (d, 2H, J=8.4). 7 48 (d. IH.

J=8.8). 7.61 (d. I H, J=2.1 ). 7.76 (d, I H. J=8.6), 8.44 (s. I H), 9.36 (s, I H), 1 1.52 (s.

IH), 12.42 (s, IH); ¹³ C NMR (DMSO): 1 1 1.52, 1 15.72, 1 17.28, 121.65, 121.71.

122.44, 123.63, 124.78. 125.79, 127.99, 139.1 1 , 155.75. 168.37.

Example 31A Preparation of OR-0216 and OR-0217

[00352] Compounds 254, QR-0216 and QR-0217 were prepared by reactions depicted in Scheme 37 below.

Scheme 37

[00353] The following procedure was used.

[00354] General Procedure E of Example 30 was used to prepare 254 (64%

yield). ¹ H NMR (CDCl ₃ ): 2.35 (s. 3H), 3.92 (s. 3H), 3.96 (s, 3H). 7.19-7.22 (m, 2H).

7.26 (d, 2H, J=8.2), 7.67 (dd, I H, J ₁ =SA J ₂ =1.6). 7.80-7.85 (m, 5H), 7.99 (s, IH), 8.06-8.12 (m, 2H), 8.55 (s, IH).

[00355] QR-0216 was prepared by the procedure of Example 31 for QR-0208

to yield QR-0216 (93% yield). ¹ H NMR (DMSO): 3.90 (s, 3H), 7.18 (dd, 1 H, J,=8.9. J ₂ =2.4). 7.34 (d, IH, J=2.1 ), 7.54 (d, I H, J=8.5), 7.80-7.83 (m, 2H), 7.87-7.92 (m.

3H). 8.10 (s, IH), 8.61 (s, IH), 1 1.72 (s. I H), 12.48 (s, IH); ¹³ C NMR (DMSO):

55.67, 106.42, 1 12.24. 1 17.60. 1 19.29. 122.21, 122.62. 123.23. 124.71, 125.26, 125.59. 127.01 , 127.76, 129.49, 129.69, 130.88, 133.20, 139.85, 157.40, 168.85.

[00356] General Procedure A of Example 14 was used to yield QR-0217 (86% yield). ¹ H NMR (DMSO): 7.10 (dd, IH. J,=8.8, J ₂ =2.3), 7.15 (d, I H, J=2.1 ), 7.53 (d,

IH, J=8.5), 7.73-7.84 (m, 5H), 8.04 (s, I H), 8.59 (s, I H). 9.68 (s, IH), 1 1.69 (s, IH),

12.41 (s, I H); ¹³ C NMR (DMSO): 108.66, 1 1 1.70, 1 17.27, 1 18.89, 121.73, 122.05.

122.68, 124.29, 124.80, 124.85, 126.34. 126.60. 128.19, 129.20, 129.45. 133.04,

139.32, 154.94, 168.35.

Example 32 Preparation of QR-0207

[00357] QR-0207 was prepared by reactions depicted in Scheme 38 below.

Scheme 38

[00358] General Procedure E of Example 30 was used to prepare QR-0207

(58% yield). ¹ H NMR (DMSO): 7.49 (t. IH, J=7.6). 7.57 (t. I H, J=7.4). 7.60-7.65 (m,

2H), 7.71 (d, 1H, J=9.O), 7.91 (d, I H, J=2.3), 7.94 (d, I H. .1=8.6), 7.99 (d, I H, .1=7,6).

8.04 (d, IH, J=8.1), 8.08 (dd, IH, J,=9.0. J ₂ =2.2). 8.19 (d, IH. J=2.0). 12.20 (s. IH);

13 C NMR (DMSO): 1 13.03, 1 16.39. 1 17.02, 1 17.36, 125.94. 126.29, 126.51, 126.74,

26.87, 127.94, 128.26, 128.92, 129.26, 131.68, 132.08, 134.18, 139.90, 141.43.

Example 33 Preparation of bisindoles containing 7-azaindole

[00359] Bisindoles containing 7-azaindole were prepared by reactions depicted

in Scheme 39 below.

Scheme 39 [00360] The following General Procedure F was used.

General Procedure F

[00361] A solution of 5-substituted isatin (5 mmol), 7-azaindole (5 mmol), and

piperidine (0.5 mmol) was stirred in ethanol at 45 ⁰ C overnight. When TLC indicated

the reaction was complete, the reaction mixture was concentrated and the product

rinsed with EtOAc/hexane. The product was used in the next step without further purification.

[00362] To a solution of the product (4 mmol) in dry THF at O ⁰ C was added

BH ₃ -THF (10 niL, 10 mmol) dropwise over 10 min. The solution was stirred at room

temperature overnight, and then quenched by the dropwise addition of MeOH (30 mL). The solvent was removed under vacuum and a solution of acetic acid and 1 M HCl (1 : 1. 30 mL) was added. The mixture was stirred for 2 h to remove any BH ₃ bonded at the pyridine nitrogen. K ₂ CO ₃ was added to adjust the pll to 7.0. and the aqueous solution was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was dried with MgSO ₄ . filtered and concentrated under vacuum. The residue was purified by flash chromatography to yield the following compounds.

Ill

[00363] QR-0218 (68% yield). ¹ H NMR (DMSO): 7.06-7.17 (m, 3H), 7.45 (d.

IH, J=8.1), 7.70 (d, IH, J=2.3), 7.75 (d, IH, J=2.3), 7.80 (d, IH. J=7.9), 8.18 (dd, IH, J,=7.8, J ₂ =0.8), 8.27 (dd, J,=4.6. J ₂ =I.3), 11.20 (s, IH), 11.67 (s, IH); ¹³ CNMR (DMSO): 109.24, 109.50.112.10, 115.81.118.72, 119.48, 119.97, 121.81, 122.39,

122.62.126.26, 128.27, 136.89, 143.17.149.18.

[00364] QR-0230 (65 % yield). ¹ H NMR (DMSO): 7.00 (t. IH. J=9.1).7.12

(q, IH. J=4.6, J=3.2), 7.45 (q. Ill, J=4.6. J=4.2), 7.46 (d. IH, J=10.2), 7.79 (s, 2H),

8.18 (d, IH, J=7.8), 8.27 (d.1H.J=4.6), 11.32 (s, IH), 11.71 (s, IH); ¹³ CNMR

(DMSO): 104.54, 104.73.108.70.109.84, 109.88, 110.08, 112.99, 113.07, 115.86,

118.56, 122.53.124.72.126.29, 126.36, 128.17, 133.56, 143.23, 149.18, 156.74.

158.58.

[00365] 255 (60% yield). ¹ H NMR (DMSO): 7.11-7.16 (m, 2H), 7.47 (d, IH,

J=8.6), 7.77-7.78 (m, 2H), 7.81 (d, IH. J=2.3).8.17 (d, IH, J=7.8), 8.27 (dd, IH,

Ji=4.6, J ₂ =U), 11.43, (s, IH).11.73 (s, IH); ¹³ C NMR (DMSO): 108.39, 109.43, 113.64, 115.91, 118.61, 119.05, 121.82, 122.81, 124.24, 124.48, 127.32, 128.10,

135.34.143.28, 149.19.

[00366] 256 (62% yield). ¹ HNMR(DMSO): 7.14 (t, IH, J=4.6, J=3.3), 7.28

(d, IH, J=8.6).7.44 (d, IH. J=8.6), 7.78 (d, IH, J=2.2), 7.82 (s, IH), 7.92 (d, IH. J=I.5), 8.17 (d, IH, J=7.8), 8.29 (d, IH, .1=4.5), 11.46 (s, IH), 11.75 (s, IH); ¹³ C NMR(DMSO): 108.35.109.32.112.20, 114.12, 115.92, 118.63, 122.03, 122.86, 124.33, 124.36, 128.08, 135.56, 143.29, 149.19.

Example 34 Preparation of OR-0241

[00367] Compound QR-0241 was prepared using the reaction depicted in

Scheme 40 below.

Scheme 40

[00368] The following General Procedure G was used.

General Procedure G

[00369] A bromoindole-containing compound ( 1 mmol). copper cyanide (2-4

mmol) and DMF (5 mL) were stirred under argon at 150 ⁰ C for 3-5 h. The mixture

was then cooled to room temperature and water (25 mL) added. The aqueous layer

was extracted with EtOAc (3 x 25 mL) and the combined organic layer dried with

MgSO ₄ , filtered and concentrated under vacuum. The residue was purified by flash

chromatography to yield QR-0241 (52% yield). ¹ H NMR (DMSO): 7.15 (q, I H,

J=7.5, J=4.6), 7.51 (dd. IH, J,=8.4, J ₂ =I .3), 7.62 (d, I H, J=8.4). 7.96 (d, IH, 3=2.2), 7.98 (d, IH, J=2.4), 8.23 (d, IH, J=7.5), 8.29 (dd. IH, J,=4.6, J ₂ =I .3). 8.35 (s, IH), 1 1.83 (s, 2H); ¹³ C NMR (DMSO): 101.62, 107.71 , 1 10.74. 1 13.34, 1 16.03, 1 18.45. 121.36. 123.36, 124.63, 125.00, 125.78, 125.91 , 128.12, 138.51, 143.37, 149.20.

Example 35 Preparation of OR-0239 and OR-0240

[00370] Compounds QR-0239 and QR-0240 were prepared by the reaction

depicted in Scheme 41 below.

Scheme 41

[00371] General Procedure G of Example 34 was used to yield the following compounds.

[00372] QR-239 (15% yield). ¹ H NMR (DMSO): 7.52 (dd. 2H. J,=8λ

J ₂ =I .4). 7.63 (d, 2H. J=8.4), 8.09 (d. 2H. J=2.3). 8.35 (s, 2H), 1 1.88 (s, 2H); ¹³ C NMR

(DMSO): 101.72, 109.97, 113.37, 121.36, 124.68, 125.56. 125.64. 125.95, 138.55.

[00373] QR-240 (37% yield). ¹ H NMR (DMSO): 7.28 (dd. IH. J,=8.6,

J ₂ =I .8). 7.44 (d. I H, J,=8.6), 7.50 (dd, IH. J,=8.4, J ₂ =I .4), 7.62 (d, I H, J=8.4), 7.91

(d, IH, J=2.4), 7.92 (d, I H, J=I.5), 7.94 (d. IH, J ₂ =2.3), 8.28 (s. IH), 1 1.51 (s. 2H),

1 1.79 (s, IH); ¹³ C NMR (DMSO): 101.53. 108.53. 1 10.56, 1 12.29, 1 13.36. 1 14.14,

121.38, 121.89, 124.42, 124.57, 124.82, 125.10. 125.61. 126.10. 128.03. 135.57,

138.51.

Example 36 Preparation of QR-0238 and QR-0276

[00374] Compounds QR-0238 and QR-0276 were prepared by reactions depicted in Scheme 42 below.

Scheme 42

[00375] General Procedure E of Example 30 was used to yield QR-0238 (55% yield). ¹ H NMR (DMSO): 3.80 (s, 3H), 6.83 (d, IH, J=7.7), 7.22 (s, IH).7.36 (d. IH..1=8.1), 7.50 (d, IH, J=7.5), 7.62 (d. IH, J=7.8), 7.77 (s. IH), 7.89 (s, IH).8.26 (s.

IH), 11.13 (s, IH), 11.73 (s, IH); ¹³ C NMR (DMSO): 55.89, 101.33, 101.65, 108.49.

111.55, 112.00, 112.79, 113.30.121.43.123.88, 124.44, 124.59, 125.74, 126.25.

126.56.132.05, 138.50.154.10.

[00376J General Procedure A of Example 14 was used to yield QR-0276 (53% yield). ¹ H NMR (DMSO): 6.69 (dd, IH, J,=8.6. J ₂ =2.0), 7.09 (d. IH, J=I.8), 7.26 (d,

IH. J=8.6).7.49 (dd. J,=8.4, J ₂ =Ll), 7.61 (d, IH, J=8.4).7.68 (s, IH.3=2.2).7.73 (d. IH. J=2.1), 8.22 (s, IH), 8.58 (s. IH), 10.97 (s, IH), 11.71 (s. IH); ¹³ C NMR

(DMSO): 101.25, 103.70.107.84.111.89, 112.18, 112.47, 113.31, 121.45.123.65.

124.25, 124.39, 125.79, 126.27.127.05, 131.43, 138.45, 151.38.

Example 37 Preparation of QR-0235 and QR-0236

[00377J Compounds QR-0235 and QR-0236 were prepared by reactions depicted in Scheme 43 below.

[00378] The following procedure was used.

[00379] A solution of 5-bromoisatin (5 mmol), 5-methoxy-2-methylindole (5 mmol), and piperidine (0.5 mmol) were stirred in ethanol at 45 ⁰ C overnight. When TLC indicated the reaction was complete, the reaction mixture was concentrated and

the product washed with EtOAc and hexane. The product was used in the next step

without further purification. To a solution of the product (3 mmol) in dry THF at O ⁰ C

was added BH ₃ -THF (7.5 mL, 7.5 mmol) dropwise over 10 min. The solution was

stirred at room temperature overnight, and then quenched by the dropwise addition of

MeOH (30 mL). The solvent was removed under reduced pressure and the residue

purified by flash chromatography to yield 257 (48% yield). ¹ H NMR (CDCl ₃ ): 2.42

(s. 3H). 3.76 (s, 3H), 6.83 (dd, IH, J,=8.7. J ₂ =2.5), 6.93 (d, IH. J=2.3). 7.25 (d. 2H,

J=4.0), 7.30-7.34 (m, 2H), 7.69 (s, IH), 7.90 (s. I H), 8.28 (s, I H).

[00380] Bromoindole species 257 (1.0 mmol) was dissolved in dry THF (10 mL) and added dropwise to a suspension of KH (2.2 eq., 35 wt.% in oil) in THF (10

mL) at O ⁰ C. After 20 min., the reaction was cooled to -78 ⁰ C and /-BuLi (3 eq.. 1.7M

in pentane) was added dropwise. After a further 20 min. of stirring, a large excess of CO ₂ gas was added via a balloon. After stirring 2 h, the reaction was quenched by adding water (10 mL) and HCl ( IN) until a pH of 2 was reached. The aqueous layer was extracted with EtOAc (2 x 20 mL) and the organic layer dried with MgSO ₄ . After concentration, product was purified by flash column chromatography to yield QR- 0235 (46% yield). ¹ H NMR (DMSO): 2.39 (s. 3H), 3.65 (s, 3H), 6.71 (dd. I H, J,=8.7.

J ₂ =2.4), 6.81 (d, I H, J=2.3), 7.25 (d, IH, J=8.7), 7.48 (d, IH, J=2.2), 7.52 (d, IH,

J=8.6), 7.77 (dd, IH, J,=8.6, J ₂ =Lo), 8.15 (s, I H). 10.94 (s, IH), 1 1.52 (s, IH), 12.28

(s. IH); ¹³ CNMR(DMSO): 11.92,55.60, 101.08, 105.72, 110.49, 110.98, 111.72, 111.85, 121.46, 122.69, 123.18, 125.28.127.07.128.98, 130.96.133.52.139.24, 153.66, 168.90.

[00381] General Procedure A of Example 14 was used to yield QR-0236 (67%

yield). ¹ H NMR (DMSO): 2.35 (s, 3H), 6.56 (d, IH, J=8.5).6.66 (d, IH, J=I.6), 7.14 (d. IH, J=8.5), 7.42 (d, IH. J-1.9), 7.50(d, IH, J=8.5), 7.76 (d, IH, J=8.5).8.08 (s,

111).8.45 (s, IH).10.76 (s, IH), 11.50 (s, IH), 12.32 (s, IH); ¹³ C NMR (DMSO):

12.84.103.16, 105.04, 110.67, 111.23, 111.31, 111.77, 121.47.122.64, 123.12. 125.22.127.26, 129.59, 130.31, 133.26.139.19, 150.97, 168.94.

Example 38 Preparation of QR-0252 and QR-0253

[00382] Compounds QR-0252 and QR-0253 were prepared by reactions

depicted in Scheme 44 below.

Scheme 44

[00383] Preparation of 258 followed the same procedure as that for 257 in

Example 37 to yield 258 (70% yield). ¹ H NMR (DMSO): 6.81 (dd, IH. J ,=8.7.

J ₂ =2.4), 7.18-7.20 (m, 2H).7.35 (d, IH, J=8.7), 7.59 (d, IH, J=2.4).7.64 (d, IH. J=I.7), 7.68 (d, IH. J=2.3).7.72 (d, IH, J ₂ =8.5).11.04 (s, 2H).11.27 (s, IH).

[00384] Preparation of QR-0252 followed the same procedure as that for QR-

0235 of Example 37 to yield QR-0252 (66% yield). ¹ H NMR (DMSO): 3.78 (s, 3H),

6.82 (dd, IH, J,=8.7. J ₂ =2.4), 7.20 (d, IH, J=2.3), 7.35 (d, IH, J=8.7).7.62 (d. IH, J=2.3), 7.67 (dd. IH. J, =8.4. J ₂ =I.4), 7.82 (d, IH, J=8.4), 7.88 (d, IH, J=2.4).8.11 (s,

IH), 11.05 (s, 2H).11.50(s. IH), 12.58 (IH); ¹³ C NMR (DMSO):55.86, 101.74. 109.30, 110.89, 111.92.112.74, 114.17.119.65, 120.21, 123.43, 123.78.125.92.

126.74, 129.69.132.02, 136.14, 153.97.168.84.

[00385] General Procedure A of Example 14 was used to prepare QR-0253

(70% yield). ¹ H NMR (DMSO): 6.68 (dd, IH, J,=8.6, J ₂ =2.2).7.08 (d.1H.J=2.1).

7.25 (d, IH, J=8.6).7.55 (d. IH, J=2.3), 7.67 (dd, IH, J,=8.4, J ₂ =1.4), 7.75 (d, IH,

J=2.3), 7.80 (d. IH. J=8.4).8.10 (s. IH), 8.64 (s, IH).10.90 (s, 2H), 11.48 (s. IH),

12.48(1H); ¹³ C NMR (DMSO): 103.87, 108.65, 111.21, 112.09, 112.39.114.14, 119.73, 120.15, 123.18.123.81, 125.56, 127.22, 129.68, 131.41, 136.09.151.25, 168.87.

Example 39 Preparation of QR-0303 and QR-0289

[00386] Compounds QR-0303 and QR-0289 were prepared by reactions depicted in Scheme 45 below.

Scheme 45

[00387] The procedure was as follows.

[00388] A solution of 5-substituted isatin (5 mmol), indole-7-carboxylic acid

methyl ester (5 mmol), and piperidine (0.5 mmol) were stirred in ethanol at room

temperature for 2-4 d. When TLC indicated the reaction was complete, the reaction

mixture was concentrated and the product washed with EtOAc and hexane. The

product was used in the next step without further purification. To a solution of the

product (4 mmol) in dry THF at O ⁰ C was added BH ₃ -THF (10 mL, 10 mmol)

dropwise over 10 min. The solution was stirred at room temperature overnight, and

then quenched by the dropwise addition of MeOH (30 mL). The solvent was

removed under vacuum, giving crude product which was stirred with LiOH (10 mmol) in MeOHZH ₂ O ( 1 : 1 , 40 mL) at 70 ⁰ C for 2h. The mixture was concentrated and the pH adjusted to 2 with IN HCl. The aqueous layer was extracted with EtOAc (2 x 20 mL) and the organic layer dried with MgSO ₄ . Final product was purified by flash column chromatography to yield the following compounds.

[00389] QR-0303 (32% yield). ¹ H NMR (DMSO): 7.19 (t, I H. J=7.7), 7.28

(d, I H, J=8.6), 7.45 (d, I H, J=8.6), 7.62 (d, I H, J=2.3). 7.76 (d, I H. J=2.3), 7.79 (d.

111..1=1.7).7.83 (d. IH, J=8.6), 8.02 (d, IH. J=7.8).11.15 (s, IH), 11.49 (s, IH), 13.12 (s, IH); ¹³ C NMR (DMSO): 109.09, 109.79, 112.07, 114.15, 114.22, 119.05.

121.74, 123.96, 124.30, 124.57, 124.78, 125.40.128.13, 128.33, 135.53, 135.55, 168.47.

[00390] QR-0289 (27% yield). ¹ H NMR (DMSO): 3.76 (s, 3H), 6.82 (d. IH,

J=8.7), 7.14 (d, IH. J=2.0), 7.19 (t, IH, J=7.6).7.36 (d, IH, J=8.7), 7.60 (d, IH,

J=2.2).7.63 (d, IH, J=2.2), 7.82 (d, IH, J=7.3), 8.03 (d, 1H,J=7.8), 11.11 (s, 2H), 13.10 (s, IH); ¹³ C NMR (DMSO): 55.82, 101.60.109.10, 110.72, 111.83, 112.81, 114.13, 118.85.123.58, 123.62, 124.64.125.54.126.87.128.31.132.06.135.56,

153.97,168.52.

Example 40 Preparation of QR-0254

[00391] Compound QR-0254 was prepared by reactions depicted in Scheme 46

below.

Scheme 46

[00392] The following procedure was used.

[00393] A solution of 5-nitroisatin (5 mmol). indole-5-carboxylic acid methyl

ester (5 mmol), and K ₂ CO ₃ (10 mmol) were stirred in ethanol at room temperature

overnight. When TLC indicated the reaction was complete, the reaction mixture was concentrated. The product was washed with EtOAc and hexane. The product was used in the next step without further purification. To a solution of the product (4

mmol) in dry THF at O ⁰ C was added BH ₃ THF (10 mL, 10 mmol) dropwise over 10

min. The solution was stirred at room temperature overnight, then quenched by the

dropwise addition of MeOH (30 mL). The solvent was removed under vacuum,

giving crude product which was stirred with LiOH (10 mmol) in MeOHZH ₂ O (1 : 1. 40

mL) at 70 ⁰ C for 2h. The mixture was concentrated and adjusted pH to 2 with IN

HCl. The aqueous layer was extracted with EtOAc (2 x 20 mL) and the organic layer

was dried with MgSO ₄ . Final product was purified by flash column chromatography

to yield QR-0254 (38% yield). ¹ H NMR (DMSO): 7.56 (d, I H, J=8.5). 7.67 (d, IH,

J=9.0), 7.81 (dd. I H, J,=8.6, J ₂ =I .4), 7.88 (d, I H, J=2.3), 7.93 (d. I H. J=2.2), 8.08 (dd. IH, Ji=9.0, J ₂ =2.2), 8.40 (s, IH), 8.65 (d, I H. J=2.1). 11.69 (s. I H), 12.02 (s.

IH). 12.46 (s, I H); ¹³ C NMR (DMSO): 109.80. 1 12.03. 1 12.22. 1 12.71. 1 16.94,

1 17.31 , 122.25. 122.28. 123.27, 124.88, 125.91. 126.06. 126.50, 139.36, 139.95, 141.25. 168.83.

Example 41 Preparation of QR-0251

[00394] Compound QR-0251 was prepared by reactions depicted in Scheme 47 below.

Scheme 47

[00395] Procedures of Example 40 were used to yield QR-0251 (18% yield).

¹ H NMR (DMSO): 6.70 (d, IH, J=8.6).7.06 (d, IH, J=2.0), 7.28 (d, IH, J=8.6), 7.61- 7.63 (m, 2H), 7.77 (d, IH, J=2.2).8.06 (d. IH. J=8.8), 8.63 (d, IH, J=2.1).8.7 (s, IH). 11.01 (s, IH), 11.92 (s, IH); ¹³ C NMR (DMSO): 103.54,107.61, 112.32.112.53,

112.57.113.51, 117.09, 117.21, 123.66, 125.60.125.94, 127.14, 131.44, 139.86,

141.00, 151.47.

Example 42 Preparation of QR-0327

[00396] Compound QR-0327 was prepared by reactions depicted in Scheme 48

below.

Scheme 48

[00397J The procedure of Example 40 was used to yield QR-0327 (36% yield).

¹ H NMR (DMSO): 7.64 (d, IH. J=9.0), 7.71 (dd. IH, J,=8.4, J ₂ =LO).7.83 (d, IH. J=8.4).7.95 (d. IH, J=1.6).8.00 (d, IH. J=2.4).8.07 (dd, IH, J,=9.0, J ₂ =2.1), 8.15 (s, IH), 8.67 (d. IH, J=2.0), 11.69 (s. IH).12.03 (s, IH), 12.57 (s. IH); ¹³ C NMR (DMSO): 109.02.112.38, 112.63.114.34.117.04, 117.25, 119.33, 120.62, 124.41, 125.81, 126.41, 126.77, 129.42, 136.25, 139.93, 141.23.168.79.

Example 43 Preparation of QR-0295

[00398] Compound QR-0295 was prepared by reactions depicted in Scheme 49

below.

Me

Scheme 49

[00399] Procedures of Example 40 were used to yield QR-0295 (5% yield). ¹ H

NMR (DMSO): 7.22 (t. IH, J=7.7), 7.64 (d, I H, J=9.0), 7.72(d, I H, J=2.5 ), 7.86 (d,

IH, J=7.0), 7.97 (d, I H, J=2.3), 8.05-8.09 (m. 2H). 8.62 (d, IH, J=2.1 ), 1 1.25 (s, IH),

12.02 (s, IH), 13.08 (s, I H); ¹³ C NMR (DMSO): 108.97, 1 12.16, 1 12.67. 1 14.31 ,

1 16.81, 1 17.29, 1 19.32, 124.49. 124.97. 125.29. 125.88, 126.55. 128.01. 135.59,

139.96. 141.22, 168.38.

Example 44 Preparation of QR-0311

[00400] Compound QR-031 1 was prepared by reactions depicted in Scheme 50 below.

[00401] The following General Procedure H was used.

General Procedure H

[00402] Arylbromide or aryliodide (1 mmol). boric acid ( 1.2 mmol) and

Pd(OAc) ₂ (0.05 mmol) in DMF (5 niL) were stirred under argon at 60-90 ⁰ C for 5-16 h. The mixture was then cooled to room temperature, ethyl acetate (50 mL) was added and the mixture washed with brine 3 times (50 mL). The organic layer was

dried with MgSO ₄ and concentrated. The residue was purified by flash column

chromatography.

100403] General Procedure H was used to yield 259 (63% yield). ¹ H NMR

(CDCl ₃ ): 2.38 (s, 3H). 7.30 (d, 2H. J=8.4). 7.37-7.41 (m, 2H), 7.55 (s, I H), 7.64 (d.

1 H. J=8.6), 7.82-8-7.86 (m, 4H), 7.96 (s. 1 H), 8.14 (d. 1 H, .1=8.6). 8.31 (s, 1 H).

[00404] LiOH (2 mmol) and 259 (0.5 mmol) in methanol ( 10 mL) were stirred

at room temperature for 2 h. The mixture was then concentrated and the residue dissolved in ethyl acetate. The solution was washed with brine and the organic layer

dried over MgSO ₄ . The solvent was evaporated and the residue purified by column

chromatography to yield QR-0311 (82% yield). ¹ H NMR (DMSO): 7.32 (t. I H,

J=7.2), 7.39 (t, IH. J=7.2). 7.58 (d, I H, J=8.4), 7.67 (d, IH, J=8.4). 7.85 (d, I H, 3=7.9). 7.87 (s. I H), 7.95 (d, IH. J=7.9). 8.06 (d, I H, J=2.5). 8.55 (s. IH). 1 1.12 (s, I II); ¹³ C NMR (DMSO): 102.94, 1 1 1.12, 1 14.04, 1 19.21, 120.96, 122.55. 123.53, 124.36, 124.83. 125.08, 125.35, 125.46, 127.72, 137.07, 137.83, 139.02. 141.26.

Example 45 Preparation of QR-0310

[00405] Compound QR-0310 was prepared by the reaction depicted in Scheme

51 below.

Scheme 51

[00406] General Procedure H of Example 44 was used to yield QR-0310 (50%

yield). ¹ H NMR (DMSO): 7.33-7.43 (m, 3H). 7.87-8.1 1 (m, 6H). 8.25 (s, I H). 10.72

(s. IH); ¹³ C NMR (DMSO): 104.85. 1 19.62, 120.67, 122.95. 124.21 , 125.18. 125.36.

125.71, 126.25. 126.28. 129.12. 129.20, 129.87, 133.01. 139.06. 141.03. 143.40,

153.56.

Example 46 Synthesis of QR-0292 and QR-0306

[00407] Compound QR-0292 was prepared by using the the reaction depicted in the following Scheme:

Scheme 52

[00408] The following procedure was used.

[00409] A mixture of 1 ,4-dibromobenzene (0.236 g, 1.00 mmol). 4-

methoxyaniline (0.369 g, 3.00 mmol), Pd(dba) ₂ (28.8 mg, 0.05 mmol), P(t-Bu) ₃ (8.1 mg, 0.04 mmol) and sodium /er/-butoxide (288 mg, 3.00 mmol) in dry toluene (10

mL) were refluxed together under an argon atmosphere. The reaction was monitored

by thin layer chromatography. Upon completion, the mixture was cooled to room

temperature, distilled water was added, and the mixture extracted with ethyl acetate (3

x 30 mL). The combined ethyl acetate extracts were washed with brine before being

dried over MgSO ₄ . The solution was concentrated under reduced pressure, and the

product purified by flash column chromatography (20% EtOAc/hexanes) to yield QR-

0292 (51 mg, 16%) as a colorless solid. ¹ H NMR (DMSO-d ₆ ): δ 7.46 (2H, s), 6.91

(4H, d, J= 8.9 Hz), 6.88 (4H, s). 6.80 (4H, d, J = 8.9 Hz) 3.68 (6H. s). ; ¹³ C NMR: δ

152.6, 138.3. 137.3, 1 18.2, 1 17.8, 1 14.5, 55.2.

[00410] Compound QR-0306 was prepared by the reaction depicted in the following Scheme:

QR-0306 Scheme 53

[00411] The same procedure as described above with regard to QR-0292 was

used to yield QR-0306 (Yield: 12%). ¹ H NMR (DMSO-d ₆ ): δ 7.89 (2H, s). 7.07 (2H,

t. J = 8.2 Hz), 7.04 (4H, s), 6.56 (2H, m), 6.50 (2H. m). 6.32(2H. m), 3.69 (6H, s); ¹³ C NMR (DMSO-d ₆ ): δ 160.2, 146.2, 136.4. 129.8. 120.0, 107.7, 103.8. 100.7, 54.7.

Example 47 Preparation of QR-0293, QR-0294, QR-0304

[00412] QR-0293, QR-0294 and QR-0304 were prepared by the reaction

depicted in the following Scheme:

Scheme 54

[00413] The following procedure was used. A solution of 3,6-

dichloropyridazine (0.298 g, 2.00 mmol), w-aminophenol (0.480 g. 4.40 mmol). potassium carbonate (0.414 g, 3.00 mmol) in DMF (10 mL) was re fluxed for 12 h.

Upon completion, the mixture was cooled to room temperature, distilled water (50

mL) was added, and the mixture was extracted with ethyl acetate (3 x 40 mL). The

combined organic extracts were washed with brine before being dried over MgSO ₄ . The solution was concentrated under reduced pressure, and the residue washed with Et ₂ θ (20 mL x 3) and hexane (20 mL x 2), yielding the following compounds.

[00414] QR-0293 (0.419 mg. 71%) as a colourless solid. ¹ H NMR (DMSO- d ₆ ): δ 7.42 (2H, s), 7.04 (2H, t, J = 8.1 Hz), 6.43 (2H, m), 6.34 (2H, t, J = 2.2 Hz),

6.26 (2H, m), 5.26 (4H, s); ¹³ C NMR(DMSO-d ₆ ): δ 163.1, 155.1, 150.4, 129.9, 122.3,

1 10.5. 107.0. 105.4.

[00415] QR-0294

[00416] Yield 39%; ¹ H NMR (DMSO-d ₆ ): δ 7.48 (2H, s), 7.1 1 (4H. d, J = 9.0

Hz), 6.96 (4H. d. J = 9.0 Hz), 3.75 (6H, s); ¹³ C NMR (DMSOd ₆ ): δ 163.2, 156.3.

147.0, 122.1 , 122.0, 1 14.7, 55.4.

[00417] QR-0304

[00418] Yield: 84%; ¹ H NMR (DMSO-d ₆ ): δ 7.32 (2H, s), 6.84 (4H. m), 6.59

(4H, m), 5.00 (4H, s); ¹³ C NMR (DMSOd ₆ ): 8163.4, 146.0. 143.8. 121.48. 121.46. 1 14.4.

Example 48 Preparation of QR-0315, OR-0316, QR-0317

[00419] Compounds QR-0315, QR-0316, and QR-0317 were prepared by the reaction depicted in the following Scheme:

Scheme 55

[00420] The following procedure was used. A mixture of 1 ,3-benezediamine

(0.216 g. 2.00 mmol), 3-bromoanisole (0.767 g. 4.1 mmol), tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ) (36.6 mg, 0.04 mmol), (R)-BINAP

(62.3 mg. 0.10 mmol), and sodium /er/-butoxide (0.499 g, 5.20 mmol) in THF (10 ml)

was refluxed for 12 h. a second portion of (Pd?(dba) ₃ (18.0 mg) was added and the

mixture refluxed for another 12 h. Upon completion, the reaction mixture was

concentrated and ethyl acetate (30 mL) and brine (20 mL) were added. The layers were separated and the aqueous layer extracted further with ethyl acetate (3 ^χ 20 mL).

The combined organic layers were washed with brine (20 mL), dried over MgSO ₄ .

and concentrated under vacuum. Flash column chromatography (20% EtOAc/hexane)

of the residue yielded the following compounds.

[00421] QR-0315 (0.486, 76%) as a colorless liquid. ¹ H NMR(CDCl ₃ ): δ 7.13

(3H, m), 6.75 (IH. m) 6.62 (6H. m). 6.46 (211. m). 5.67 (2H, m), 3.74(6H, s); ¹³ C

NMR(CDCl ₃ ): δ 160.9, 144.5, 144.3. 130.3, 130.2. 1 1 1.1 , 1 10.8. 107.5. 106.5, 104.0.

55.4.

[00422] QR-0316

[00423] Yield: 96%; ¹ H NMR(CDCl ₃ ): δ 7.31 (2H, d, J= 7.0 Hz). 7.12 (IH, t, J

= 8.0 Hz), 6.84 (7H, m), 6.68 (2H, m), 6.09 (2H, m), 3.79 (6H, s); ¹³ C NMR (CDCl ₃ ):

δ 148.5, 144.0, 133.0, 130.1 , 120.9. 120.1, 1 15.4, 1 1 1.4, 1 10.7. 108.1. 55.6.

[00424] QR-0318

[00425] Yield: 63%; ¹ H NMR (CDCl ₃ ): δ 7.04 (5H, m), 6.84 (4H, m), 6.43

(IH, m), 6.37 (2H, m), 5.41 (2H. s), 3.78 (6H, s); ¹³ C NMR (CDCl ₃ ): δ 155.5, 146.6,

135.9, 130.3. 122.7, 1 14.8, 107.4, 102.8. 55.8.

Example 49 Preparation of QR-0319, QR-0325, QR-0326

J00426] Compounds QR-0319. QR-0325, and QR-0326 were prepared by the

reaction depicted in the following Scheme:

Scheme 56

[00427] The following procedure was used. To a suspension of compound

QR-315 (0.215 g, 0.672 mmol) in dry CH ₂ Cl ₂ (50 mL) cooled to -78 ⁰ C was added BBr ₃ (0.38 mL, 4.03 mmol) dropwise. The reaction mixture was left to warm to room temperature overnight. The mixture was washed with saturated aqueous NaHCO ₃ (20

mL) the aqueous layer was extracted further with CH ₂ CI ₂ (3 x 30 mL), and the

combined CH ₂ Cl? extracts were washed with brine (30 mL). The organic layer was

dried over MgSO ₄ and concentrated under vacuum. Flash column chromatography (20% EtOAc/hexane) of the residue gave the following comounds.

[00428) Dihydroxyl compound QR-0319 (0.188 g, 96%) was obtained as a colorless solid. ¹ H NMR (CDCl ₃ ): 7.04 (2H. m), 7.02 (2H, m), 6.95 ( 1 H, t. J = 7.9 Hz), 6.93 (2H, m). 6.86 (2H. m). 6.24 (2H, dd, J = 8.0, 2.2 Hz). 6.12 ( I H. t, 2.2 Hz), 5.75 (2H, bs); ¹³ C NMR (CDCl ₃ ): 151.2, 146.9. 130.6, 129.0. 126.4. 125.3, 121.2,

1 15.6, 107.9. 103.1.

[00429] QR-0325

[00430] Yield: 78%; ¹ H NMR(CD ₃ OD): 6.94 (6H, m), 6.69 (5H, m), 6.50 (IH,

m), 6.30 (2H, m); ¹³ C NMR (CD ₃ OD): 153.3, 148.4, 137.1, 130.6. 123.2. 1 16.7, 107.6, 103.3.

[00431] QR-0326

[00432] Yield: 75%; ¹ H NMR (CD ₃ OD): 7.03 (5H, m), 6.86 ( 1 H, m) 6.57 (6H, m), 6.30 (2H, m); ¹³ C NMR (CD ₃ OD): 159.05, 146.53, 145.76. 145.69, 130.8, 130.7. 130.4, 1 10.2. 108.2, 105.2.

Example 50 Activity against Aβ aggregation

[00433] The compounds of the invention were evaluated for activity against Aβ

aggregation in a kinetic thioflavin T (ThT) fluorescence assay similar to that of

Chalifour, R.J., el al, J. Biol Chem. (2003) 278: 34874-81.

[00434] The following procedures were used. The compounds were examined by circular dichroism (CD) to confirm their anti-amyloidogenic activity and were further evaluated for inhibition of both tau and α-synuclein aggregation in Thioflavin S (ThS) and ThT dye-binding fluorescence assays, respectively. The compounds were also evaluated in a MTT [3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cell viability assay (Kaneko, L, et al., J. Neurochem. (1995) 65: 2585-93). Pharmacokinetic (PK) testing was also performed. Compounds administered to mice (IP or PO dosing) had no toxicity at doses up to 300 mg/kg and were present in brain more than four hours after administration.

[00435] Many of the in-vitro tests discussed above were performed in accordance with the methods disclosed in U.S. Patent Application Serial No. 1 1/443,396, U.S. Publication No. 2007-0015813, filed May 30. 2006. herein incorporated by reference.

[00436] The structure, in vitro activities and PK data for certain compounds are summarized below.

The compounds were found to inhibit aggregation of both Aβ40 and Aβ42, as well as

reverse the aggregation of both species when added to pre-formed aggregates.

Example 5OA Cell Viability Assay

[00437] The cell viability assay was performed for QR-Ol 12 and QR-0161 of

Example 50.

[00438] The assay was based on that reported by Conte and co-workers (Conte.

A., Pellegrini, s. & Tagliazucchi, D. 2Q03. Brain Res. Bull. 62, 29-38). Briefly, Aβl- 40 (1.0 mg) was dissolved directly in Tris base ( 15 mL. 20 microM, pH approximately 10). The pH was dropped to 7.4 using concentrated HCl and the

solution diluted ten-fold with growth medium consisting of Dulbecco's Modified Eagle Medium (high glucose) containing 10% fetal bovine serum. penicillin-G (10.000 units/mL) and streptomycin (10 mg/mL); giving 20 μM Aβ40. For non-Aβ -containing controls, growth medium was diluted 10% with Tris buffer (20 mM, pH 7.4). SH-SY5Y neuroblastoma cells were seeded at approximately 20,000 cells per well in a covered 96-well clear polystyrene plate and incubated at 37 ⁰ C, 5% CO ₂ for 24h. After discarding supernatant, growth medium (200 μL). containing either Aβ-40 or vehicle (controls), was added to the wells, followed by test compound in DMSO (0.5 μL) or DMSO alone (controls). Incubations all had 5 or more replicates. After incubating for 6-10 h (37 ⁰ C, 5% CO ₂ ), the dye 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT, 20 microL. 5 mg/mL in PBS) was added to each well and the plate incubated for another 2 h. Medium was discarded and the formazan product dissolved by adding DMSO (100 μL) and shaking. Absorbance was measured at 540 nm in a Tecan Genios microplate reader. Absorbance values for wells containing neither Aβ40 nor test compound at the beginning of the experiment were taken as 100 %, while wells to which was added 20 % Triton X-100 (0.5 μL) to lyse the cells were taken as a complete inhibition of cell function (0 %).

[00439] The results of the assay are graphically depicted in Figure 1 , Figure 2 and Figure 3.

[00440] It was concluded that QR-01 12 (p<0.05) is significantly protective at

50 μM and trends towards protection at the lower concentrations of 2 and 10 μM; and that QR-Ol 61 is significantly active at both 20 and 50 μM and protects SH-S Y5 Y cells from Aβ40 (20 μM).

Example 51 Inhibition of Aβl-40 aggregation in the ThT fluorescence assay

[00441] IC5 ₀ values for inhibition of Aβ 1-40 aggregation in the ThT

fluorescence assay for a number compounds of the present invention were

determined. Values were calculated by solving the equation y = (ITbV(I +

where y is percent aggregation, x is compound concentration, and ni ₃ is the concentration giving 50% aggregation (i e. ICs ₀ ). using KaleidaGraph 4.0 (Synergy Software). The data obtained is summarized in Table 1 below.

Table 1.

Example 52

Thioflavin T (ThT) and Thioflavin S (ThS) Aggregation Assays for Aβ, Tau and α-Synuclein

[00442] 1) Thioflavin T (ThT) and Thioflavin S (ThS) Aggregation Assays

for Aβ, Tau and α-Synuclein

[00443] Dye-binding ThTVThS protein aggregation assays for Aβ, tau and α-

synuclein were performed as described in Example 8 of US2007/0015813.

[00444J 2) Tris-Tricine SDS-PAGE:

[00445] Pre-cast polyacrylamide gels were purchased from NuSep (10-20%

Tris-tricine-SDS). These were chosen for their large separation range of 2.5 to 205

kDa. Molecular weight markers were purchased from Sigma Aldrich and diluted

twenty fold for individual use. Three buffers were used for this technique: 1) Sample

buffer (1.25 niL 0.5 M Tris-HCl (pH 6.8), 2.5 mL glycerol, 2.0 mL 10% SDS. 0.2 mL

0.5% bromophenol blue, 3.55 mL distilled water) which was used as the leading band

in the gel. 2) Cathode Buffer ( 12.1 1 g tris base, 17.92 g tricine, 1 g SDS. diluted to 1 L with distilled water) which was the inner buffer in the tank assembly. 3) Anode

Buffer (5X concentrated: 121.1 g tris base in 1 L of distilled water, pH 8.9 adjusted with concentrated HCl) which was the outer buffer and loaded at 1 X concentration.

Both Aβl-40 and Aβ l -42 were purchased from Anaspec.

[00446] Five solutions were required to stain the gels using the silver stain protocol: 1 ) Fixer 1 (40% methanol, 10% acetic acid, diluted to 1 L with Milli-Q water) 2) Fixer 2 (45 g anhydrous sodium acetate, 300 mL methanol, 5 mL 25%

glutaraldehyde, diluted to 1 L with Milli-Q water). 3) a) Silver stain A ( 15 mL of 25% ammonia solution. 0.8 g sodium hy ^H ™xide, diluted to 950 mL with Milli Q

water), b) Silver stain B (6 g of silver nitrate in 50 mL Milli Q water). Solution B was then slowly added to solution A. 4) Developer (0.1 g citric acid, 1 mL formaldehyde,

diluted to 1 L with Milli-Q water). 5) Stop solution (50 mL acetic acid, diluted to 1 L

with Milli-Q water).

[00447] Sample preparation: Aβl-40 and Tau 441

[00448] Following a ThT (Aβ 1 -40) or ThS (Tau 441 ) aggregation assay,

described in Example 8 of US2007/0015813. samples were immediately aspirated and stored in centrifuge tubes. lOμL of each sample was transferred to a micro fuge tube

and diluted 1 :1 with sample buffer before being incubated (37 ⁰ C) for 30 minutes and loaded in the precast gels (15 μL in each well). The gel was then run at 100 V for

approximately one hour or until the leading band reached the bottom of the gel.

[00449] Sample Preparation: Aβ l -42 treatment

[00450] Aβ 1 -42 was dissolved in 1.15 mL tris base (pH ~ 10). vortexed and

sonicated, giving a concentration of 200 μM. The pH was then dropped to 7.4 using

concentrated HCl and the solution diluted 10-fold with PBS and transferred as 20 μL aliquots to microfuge tubes. Compounds were added as 0.2 μL additions of DMSO stock solutions. Samples were then diluted 1 : 1 with sample buffer and incubated (37 ⁰ C) for 30 minutes before being loaded into precast gels. The load volume was 15 μL and the gel was run at 100 volts for approximately one hour or until the leading band reached the bottom of the gel.

[00451 J Silver staining

[00452] Once the gel had finished running, it was removed from its plastic case and placed in a tray for staining. Approximately 200-250 mL volume was used for all the solutions. The gel was first washed with distilled water briefly to rinse off the

excess buffer from the tank. It was then immersed in Fixer 1 for 30 minutes, followed by Fixer 2 for 30 minutes. Once the gel was fixed it then underwent three water

washes at 10 minutes per wash. After the water washes, the gel was stained for 30

minutes using the silver stain solution. Excess stain was removed using three four-

minute water washes. The gel was then immersed in the developer solution to

visualize the stain. This took place for approximately 5 minutes or until the desired

intensity was reached. To immediately stop the developing process the gel was

placed in the stop solution for 10 minutes.

[00453] 3) Transmission Electron Microscopy (TEM)

[00454| A modified version of the procedure of Cohen et al. (Biochemistry

2006, 45: 4727-35) was followed for TEM analysis. Uranylacetate was used as

negative stain (Electron Microscopy Sciences) and was made as a 3% solution and

stored at 5 ⁰ C in the dark to reduce photodecay. Aspirated samples from ThT ( Aβ 1 -

40) and ThS (Tau 441) aggregation assays, or Aβl-42 incubated (37 ⁰ C) for 30 min. in

the presence and absence of compounds were used in the TEM analyses. Samples were carefully loaded on Formvar-coated 400 mesh copper grids (Electron Microscopy Sciences) as a 10 μL drop. After sitting for 60 seconds, excess fluid was gently dabbed off with filter paper. Next, the 3% uranylacetate was added as a drop

onto the grid and left to stand for another 60 seconds. The excess fluid was again

dabbed off by filter paper. Samples were left to dry for at least 30 minutes prior to

being viewed on an electron microscope operating at 80 kV.

[00455] 4) Results

[00456] Effects of QR-0292 (0.08 - 10 microM) on ABetal -40 aggregation in the ThT fluorescence assay..

[00457] Effects of QR-0319 (0.16 - 100 μM) on Aβ 1 -40 aggregation in the

ThT fluorescence assay is graphically depicted in Figure 5.

[00458] IC ₅₀ curve for QR-0217 against aggregation of Aβ 1 -40 in the ThT

assay is graphically depicted in Figure 6. The IC ₅₀ value for QR-0217 is 7.5 μM. See

Table 1.

[00459] IC ₅₀ curve for QR-0244 against aggregation of Aβ 1 -40 in the ThT

assay is graphically depicted in Figure 7. The IC ₅₀ value for QR-0244 is 5.6 μM. See

Table 1.

[00460] SDS-PAGE technique showing the effect of QR-0273 on Aβ 1 -42 self-

assembly is shown in Figure 8. The compound caused an increase in the presence of monomer and pentamer as well as the appearance of a dimer and possibly a darker

higher molecular weight smear (lane 1) versus control (lane 2). Lane 3 is a molecular weight marker.

[00461] SDS-PAGE technique showing the effect of compounds on Aβl-40

self-assembly following ThT aggregation assay is depicted in Figure 9. QR-0276 and

QR-0279 (lanes 2 and 3) appeared to have little effect on the distribution of Aβ 1-40

among the various states of assembly when compared to control (lane 1 ). QR-0280,

QR-0282, QR-Ol 12, and QR-0142 (lanes 4-7). however, caused an increase in the

concentration of Aβ 1-40 monomer. QR-0280 and QR-0282 also caused the

appearance of a dimer band, further demonstrating their ability to modulate Aβl-40

aggregation.

[00462] SDS-PAGE technique showing the effect of compounds on Tau 441

self-assembly following ThS aggregation assay is depicted in Figure 10. Incubations containing QR-0244, QR-0263. and QR-0281 (lanes 3-6) had decreased

fragmentation of tau 441 monomer relative to control (lane 2) as well as the

appearance of dimer and trimer bands. Conversely, QR-0262 (lane 7) had no clear

effect on Tau 441 self-assembly in this assay. Lane 1 is a molecular weight marker.

The ability of compounds to inhibit Tau441 fragmentation is of particular interest given the implication of fragmentation in the protein's subsequent aggregation and

neurotoxicity (YP Wang et al., Proc Nat 7 Acad Sci USA 2007, 104: 10252-7).

[00463] TEM of Aβ 1-40 (20 μM) incubated in the absence (a) and presence of

compounds (b,c). taken following the ThT aggregation assay is depicted in Figure 1 1.

Compounds QR-Ol 12 (b) and QR-0194 (c), both at 20 μM, caused an increase in

fibril formation but of a different morphology than those present in the control

incubation (a). The incubation containing QR-0295 at 20 μM (d) had fibrils of similar

morphology to the control, however there appeared to be a reduction in the amount of

fibrils. The results collectively suggest that there are different mechanisms through

which the compounds disrupt Aβl-40 aggregation, with possibly more than one of the

mechanisms being of therapeutic benefit. Micrographs on left have scale bars of 1

μm, those on the right have scale bars of 200 nm.

[00464] TEM of Aβ 1 -40 (20 μM) incubated in the absence of ThT and in the

absence (a) or presence (b,c) of compounds is depicted in Figure 12. QR-0263 at 20

μM (b) appeared to cause a reduction in fibrils relative to control (a), while QR-0273

(c) at 100 μM showed an increase in the number of fibrils. The fibrils in the QR-0273

incubation, however, appeared to be of a different morphology when compared to control, suggesting the compound has a modulating effect on fibril formation.

Disrupting the normal aggregation of Aβ 1-40 by accelerating the formation of non-

native, non-toxic aggregates may be of therapeutic benefit. Micrographs on left have

scale bars of 1 μm, those on the right have scale bars of 200 nm.

[00465] TEM of Aβ 1 -42 (20 μM ) incubated in the absence of ThT and in the

absence (a) or presence (b,c) of compounds is depicted in Figure 13. QR-0185 at 100

μM (b) appeared to cause a decrease in fibrils relative to control (a), suggesting it may

inhibit Aβl -42 aggregation. QR-Ol 94 (c) at 20 μM caused an apparent increase in the

number of fibrils present relative to control (a). These fibrils, however, appeared to be of a different morphology when compared control suggesting the compound may

disrupt the normal aggregation of Aβ 1 -42 into toxic aggregates. Micrographs on left

have scale bars of 1 μm, those on the right have scale bars of 200 nm.

[00466] THM of Tau 441 (6 μM) incubated in the absence (a) and presence of

compounds (b.c), taken following the ThS aggregation assay is depicted in Figure 14.

QR-0281 (b) and QR-0262 (c), both at 20 μM, caused an increase in fibril formation

relative to the control (a) but gave fibrils of different morphology. Incubations

containing QR-0281 and QR-0262 also had spherical assemblies that were not present in the control. The results suggest that the compounds modulate Tau441 fibril

formation and may therefore disrupt pathological aggregation of the protein.

Micrographs on left have scale bars of 1 μm, those on the right have scale bars of 200

nm.

[00467] Referring to Figure 15, ThS fluorescence assay showing the effect of

compounds on Tau 441 aggregation after 24 hours incubation (37 ⁰ C). QR-0244. QR-

0263, and QR-0281 (A-C respectively) greatly inhibited aggregation of Tau 441 (6

μM) at 50 μM (white bars) and 10 μM (black bars) is depicted. QR-0262 (D) only

moderately inhibited Tau441 aggregation at these concentrations. Error bars represent standard deviation of n = 3 replicates.

[00468] Referring to Figure 16, ThT fluorescence assay showing the effect of

compounds on α-synuclein aggregation. QR-Ol 89, QR-0194, QR-0212, QR-0217,

QR-0176, and resveratrol (A-F, respectively) all showed inhibition of α-synuclein (4

μM) aggregation at 100 μM (white bars) and 20 μM (black bars) after 96 hours

incubation (37 ⁰ C) is depicted. Error bars represent standard deviation of n = 3

replicates. As α-synuclein aggregates have been implicated in the pathogenesis of a

number of neurodegenerative diseases, e.g. Parkinson's disease (AL Fink, Ace Chem

Res 2006, 39: 628-634) and Alzheimer's disease (JE Duda et al., J Neurosci Res 2000.

61 : 127-127), compounds that inhibit the protein's aggregation may be of therapeutic

benefit.

[00469] ThT fluorescence assay showing the effect of compounds on α-

synuclein aggregation. QR-0164. QR-0147. and QR-0162 (G-I) all showed inhibition

of α-synuclein (4 μM) aggregation at 50 μM (white bars) and 10 μM (black bars)

after 96 hours incubation (37 ⁰ C) is depicted in Figure 17. Error bars represent

standard deviation of n = 3 replicates.

[00470] Synaptic connections among neurons in cell cultures might undergo

long-lasting enhancement of synaptic strength that resembles long-term potentiation

(LTP) in slice preparations and in vivo in several critical ways (Malgaroli. A., et al.

Nature (1992) 357: 134-9; Arancio. O., et al, Nature (1995) 376: 74-80; Arancio, O.. et al. Cell (1996) 87: 1025-35; Arancio. O., et al. J. Physiol. (1994) 481( Pt 2): 395-

405; Arancio, O. et al, J. Neurophysiol. (1991 ) 65: 899-913) including: a) NMDA

receptor activation is necessary for LTP induction, b) Ca ^~+ influx through

postsynaptic NMDA receptor channels is required for LTP induction, c) high

frequency stimulation of the presynaptic neuron reliably induces LTP. d) potentiation can also be induced through pairing of low frequency stimulation of the presynaptic neuron with depolarization of the postsynaptic neuron. Thus, cell culture preparation is an excellent system to examine whether synaptic transmission is altered in transgenic models of AD, and to attempt rescuing changes of synaptic transmission through application of potential therapeutic agents. Towards this end, a model of

dissociated cell cultures derived from the hippocampus of APP/PS1 mice has been developed (Trinchese, F., el al, J. MoI. Neurosci. (2004) 24: 15-21) in order to look

at changes of synaptic transmission caused by Aβ elevation. These studies have demonstrated that cultured hippocampal neurons from APP/PS1 mice which release

into their medium two major types of Aβ peptides, Aβ40 and Aβ42, recapitulate the

in vivo localization and accumulation of Aβ42 and show an increase in number of

functional presynaptic release sites associated with lack of glutamate-induced long-

lasting increase in active release site number.

[00471] Electrophysiological analysis was performed on males (see detailed

description in Gong, B., el ah, Cell (2006) 126: 775-88). Hippocampal slices (400

μm) were cut with a tissue chopper and maintained in an interface chamber at 29°C

for 90 min prior to recording. Briefly. CAl fEPSPs were recorded by placing both the

stimulating and the recording electrodes in CA 1 stratum radiatum. Basal synaptic

transmission was assayed by plotting the stimulus voltages against slopes of fEPSP.

For LTP experiments, a 15 min baseline was recorded every min at an intensity that

evokes a response -35% of the maximum evoked response. LTP was induced using θ-

burst stimulation (4 pulses at 100 Hz, with the bursts repeated at 5 Hz and each tetanus including 3 ten-burst trains separated by 15 sec).

[00472] As seen in Figure 18. compound QR-0217 (50 μM) significantly

rescued impairment of LTP in the APP/PS 1 transgenic mice hippocampal slices. This

suggests the compound is able to reduce memory impairments caused by Aβ

neurotoxicity.

[00473] In the preceding specification, the invention has been described with

reference to specific exemplary embodiments. Those skilled in the art will recognize.

or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments to the methods described herein. Such equivalents are intended to be encompassed by the following claims.