Attorney's Docket 2882.023B

(l-AZINONE) -SUBSTITUTED PYRIDOINDOLES AS MCH ANTAGONISTS

Cross-Reference to Related Application

This application claims the benefit of priority from U.S. Provisional Application Serial No. 61/020,530, filed January 11, 2008, and U.S. Provisional Application Serial No. 61/048,677, filed April 29, 2008, the disclosures of which are incorporated herein by reference.

Field of the Invention

The invention relates to human melanin-concentrating hormone (MCHi) receptor- selective antagonists substituted pyridoindoles that are useful for treating obesity, to pharmaceutical compositions comprising these compounds, and to methods for the treatment of obesity, anxiety, depression, and psychiatric disorders in a mammal.

Background of the Invention

Obesity and the multitude of co-morbidities associated with obesity such as diabetes, dyslipidemia, coronary heart disease, and certain cancers are a major concern for public health. The currently available pharmaceutical therapies for the treatment of obesity have limited efficacy and side effects that limit their use. Thus, there is a significant medical need for better pharmacotherapy for obesity.

Melanin-concentrating hormone (MCH) has been identified as an orexigenic peptide that exerts an effect on food intake and body weight regulation. MCH is a cyclic 19 amino acid neuropeptide expressed in the zona incerta and lateral hypothalamus in response to both energy restriction and leptin deficiency. MCH is known to stimulate feeding when injected into the lateral ventricle of rats and the mRNA for MCH is upregulated in the hypothalamus of genetically obese mice (ob/ob) and in fasted control and ob/ob animals. In addition, animals treated with MCH show increases in glucose, insulin and leptin levels, mimicking human metabolic syndrome (Gomori, A. Chronic infusion of MCH causes obesity in mice Am. J. Physiol. Endocrinol. Metab. 284, E583, 2002). Mice lacking MCH are hypophagic and lean with increased metabolic rate,

Attorney's Docket 2882.023B whereas animals over-expressing MCH gain excess weight on both standard and high fat diets. MCH is thought to have effects on other nervous system functions as well (Rocksz, L. L. Biological Examination of Melanin Concentrating Hormone 1: Multi-tasking from the hypothalamus Drug News Perspect 19(5), 273, 2006). An orphan G-protein coupled receptor (GPCR) was recently identified as a receptor for MCH. Disruption of the binding between MCH and the MCH receptor, i.e. MCH antagonism, may thus be used to counteract the effects of MCH (McBriar, M. D. Recent advances in the discovery of melanin-concentrating hormone receptor antagonists Curr. Opin. Drug Disc. & Dev. 9(4), 496, 2006).

Summary of the Invention

In accordance the present invention, there is provided a compound of formula (I)

(I) wherein

R ¹ is H or optionally substituted alkyl;

R ² , R ³ , R ⁴ are each independently selected from H, -O-alkyl, -S-alkyl, alkyl, halo, -CF ₃ , and -CN;

G is -CR ¹² R ¹³ -NR ⁵ - or -NR ⁵ -CR ¹² R ¹³ ;

R ⁵ is H, optionally substituted alkyl, optionally substituted heterocycle, -C(=O)-R ⁶ ,

-C(=O)-O-R ⁷ , or -C(=O)-NR ¹⁹ R ²⁰ ;

R and R are each optionally substituted alkyl or optionally substituted heterocycle; RR ⁸⁸ ,, RR ⁹⁹ ,, RR ¹¹⁰⁰ ,, RR ¹¹¹¹ ,, F R ¹² , R ¹³ , R ¹⁹ and R ²⁰ are each independently selected from H or optionally substituted alkyl;

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R ¹⁴ and R ¹⁵ are each independently H or halogen;

L is -CH ₂ -O-, -CH ₂ CH ₂ -, -CH=CH- or a bond; and

B is aryl or heteroaryl or cycloalkyl; with the proviso that, when L is a direct bond, B cannot be unsubstituted heteroaryl or heteroaryl monosubstituted with fluorine.

Detailed Description of the Invention

In accordance with the present invention, compounds represented by formula (I) above may be substituted derivatives either of tetrahydro-β-carboline, where G is - CR ¹² R ¹³ -NR ⁵ -, or of tetrahydro-γ-carboline, where G is -NR ⁵ -CR ¹² R ¹³ -. In some embodiments of the invention, G is -CH ₂ -NR ⁵ -; in other embodiments, G is -NR ⁵ -CH ₂ -. In accordance with some embodiments of the invention, R ¹ is H.

In accordance with other embodiments of the invention, R ¹ is alkyl, for example, methyl or ethyl.

In accordance with some embodiments of the invention, R ⁵ is H. In other embodiments, R ⁵ is optionally substituted alkyl. In some embodiments, R ⁵ is selected from methyl, ethyl, 2-propyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2- oxo-2-(pyrrolidin-l-yl)ethyl, 2-(pyrrolidin-l-yl)ethyl and (5)-pyrrolidin-2-ylmethyl. In other embodiments, R ⁵ is optionally substituted heterocycle. In some embodiments, R ⁵ is selected from piperidin-4-yl and l-methylpiperidin-4-yl. In other embodiments, R ⁵ is - C(=O)-R ⁶ . In other embodiments, R ⁵ is -C(=O)-O-R ⁷ .

In some embodiments, R ⁶ and R ⁷ are each optionally substituted alkyl, for example, methyl, 2-propyl, 2-(pyrrolidin-l-yl)-ethyl, pyrrolidin-1-ylmethyl, and dimethylaminomethyl. In some embodiments, R ⁶ is optionally substituted heterocycle, for example, pyrrolidin-3-yl, (i?)-pyrrolidin-2-yl, (5)-pyrrolidin-2-yl, l-methylpyrrolidin-3-yl, (i?)-l-methylpyrrolidin-2-yl and (5)-l-methylpyrrolidin-2-yl.

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In accordance with some embodiments of the invention, the compound has the

structure

In accordance with other embodiments of the invention, the compound has the

In accordance with some embodiments of the invention, the L is a bond. In accordance with other embodiments of the invention, L is -CH ₂ -O-. In accordance with some embodiments of the invention, L is -CH ₂ CH ₂ -. In accordance with other embodiments of the invention, L is -CH=CH-.

In accordance with some embodiments of the invention, B is aryl, for example, phenyl. In accordance with other embodiments of the invention, B is heteroaryl, for example, pyridinyl. In some embodiments, B is pyridin-2-yl or pyridin-3-yl. In other embodiments, B is pyridazinyl, for example, pyridazin-3-yl. In some other embodiments, B is pyrimidinyl, for example, pyrimidin-5-yl or pyrimidin-2-yl. In accordance with other embodiments of the invention, B is cycloalkyl, for example, cyclohexyl.

In accordance with some embodiments of the invention, R ² , R ³ and R ⁴ are each H. In accordance with other embodiments of the invention, two of R ² , R ³ and R ⁴ are H, and the other of R ² , R ³ and R ⁴ is selected from trifluoromethyl, chloro, fluoro, methyl, methoxy and methanethio.

In accordance with other embodiments of the invention, one of R ² , R ³ and R ⁴ is H, another of R ² , R ³ and R ⁴ is Cl, and the third of R ² , R ³ and R ⁴ is F, Cl or methoxy. In accordance with other embodiments of the invention, one of R ² , R ³ and R ⁴ is H, another of R ² , R ³ and R ⁴ is F, and the third of R ² , R ³ and R ⁴ is methoxy. In accordance with other

Attorney's Docket 2882.023B embodiments of the invention, one of R ² , R ³ and R ⁴ is H, another of R ² , R ³ and R ⁴ is methoxy, and the third of R ² , R ³ and R ⁴ is methyl.

In accordance with some embodiments of the invention, B, together with R ² , R ³ and R ⁴ , is selected from phenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 2,4- dichlorophenyl, 4-fluorophenyl, 4-chloro-2-fluorophenyl, 2-fluoro-4-methoxyphenyl, pyridin-2-yl, 5-chloropyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 5-fluoropyridin-2-yl, 6- (trifluoromethyl)pyridazin-3-yl, 6-methylpyridazin-3-yl, 4-fluoro-2-methoxyphenyl, 6- (trifluoromethyl)pyridin-3-yl, 2-(trifluoromethyl)pyrimidin-5-yl, 5- (trifluoromethyl)pyrimidin-2-yl, 5-methylpyridin-2-yl, 6-methylpyridin-3-yl, cyclohexyl, 4-chloro-2-methoxyphenyl, pyrimidin-2-yl, imidazo[l,2-α]pyridin-6-yl, imidazo[l,2- α]pyridin-2-yl, 4-methoxyphenyl, 4-methanethiophenyl and 4-methoxy-2-methylphenyl.

In accordance with some embodiments of the invention, at least one of R , R , R 10 R ¹¹ , R ¹² , R ¹³ , R ¹⁹ and R ²⁰ is H. In other embodiments, at least one of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² ,

R ¹³ , R ¹⁹ and R ²⁰ is optionally substituted alkyl, for example, methyl, ethyl, or hydroxymethyl.

In accordance with some embodiments of the invention, the compound is selected

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In accordance with some embodiments of the invention, the compound is a pharmaceutically acceptable salt thereof. In some embodiments, the salt is an HCl salt. There is also provided, in accordance with embodiments of the invention, a pharmaceutical composition comprising a compound as described herein, and a pharmaceutically acceptable carrier, excipient or diluent therefore.

There is also provided, in accordance with embodiments of the invention, a method of treating obesity, comprising administering to a patient in need of obesity reduction an obesity-reducing effective amount of a compound as described herein.

There is also provided, in accordance with embodiments of the invention, a method of treating anxiety, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound as described herein.

There is also provided, in accordance with embodiments of the invention, a method of treating depression, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound as described herein.

There is also provided, in accordance with embodiments of the invention, a method of treating non-alcoholic fatty liver disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound as described herein.

There is also provided, in accordance with embodiments of the invention, a method of treating a disease or condition which is susceptible to treatment with an MCHi receptor modulator, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as described herein.

Attorney's Docket 2882.023B

Definitions

Throughout this specification the terms and substituents retain their definitions. Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. When not otherwise restricted, the term refers to alkyl of 20 or fewer carbons. Lower alkyl refers to alkyl groups of 1, 2, 3, 4, 5 and 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t- butyl and the like. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3, 4, 5, 6, 7, and 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c- butyl, c-pentyl, norbornyl, adamantyl and the like.

Ci to C ₂ O Hydrocarbon (e.g. C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , Ci ₀ , Cn, Ci ₂ , Ci ₃ , C ₁₄ , C ₁₅ , Ci6, Ci ₇ , C ₁₈ , Ci9, C ₂ o) includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. The term "phenylene" refers to ortho, meta or para residues of the formulae:

Alkoxy or alkoxyl refers to groups of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purposes of the present patent application alkoxy also includes methylenedioxy and ethylenedioxy in which each oxygen atom is bonded to the atom, chain or ring from which the methylenedioxy or ethylenedioxy group is pendant so as to form a ring. Thus, for example, phenyl substituted by alkoxy may be, for example,

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Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like. The term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 1(196, but without the restriction of ]|127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds). Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.

Acyl refers to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include formyl, acetyl, propionyl, isobutyryl, t-butoxycarbonyl, benzoyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to four carbons.

Aryl and heteroaryl refer to aromatic or heteroaromatic rings, respectively, as substituents. Heteroaryl contains one, two or three heteroatoms selected from O, N, or S. Both refer to monocyclic 5- or 6-membered aromatic or heteroaromatic rings, bicyclic 9- or 10-membered aromatic or heteroaromatic rings and tricyclic 13- or 14-membered aromatic or heteroaromatic rings. Aromatic 6, 7, 8, 9, 10, 11, 12, 13 and 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5, 6, 7, 8, 9 and 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.

Arylalkyl means an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl and the like.

Substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with alkyl, halogen, halo alkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as

Attorney's Docket 2882.023B alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "prodrug" refers to a compound that is made more active in vivo. Commonly the conversion of prodrug to drug occurs by enzymatic processes in the liver or blood of the mammal. Many of the compounds of the invention may be chemically modified without absorption into the systemic circulation, and in those cases, activation in vivo may come about by chemical action (as in the acid-catalyzed cleavage in the stomach) or through the intermediacy of enzymes and microflora in the gastrointestinal GI tract.

In the characterization of some of the substituents, it is recited that certain substituents may combine to form rings. Unless stated otherwise, it is intended that such rings may exhibit various degrees of unsaturation (from fully saturated to fully unsaturated), may include heteroatoms and may be substituted with lower alkyl or alkoxy.

It will be recognized that the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, iodine and chlorine include ³ H, ¹⁴ C, ³⁵ S, ¹⁸ F, ³² P, ³³ P, ¹²⁵ I, and ³⁶ Cl, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Radiolabeled compounds described herein and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non- radio labeled reagent.

The terms "methods of treating or preventing" mean amelioration, prevention or relief from the symptoms and/or effects associated with lipid disorders. The term "preventing" as used herein refers to administering a medicament beforehand to forestall or obtund an acute episode or, in the case of a chronic condition to diminish the likelihood or seriousness of the condition. The person of ordinary skill in the medical art (to which the

Attorney's Docket 2882.023B present method claims are directed) recognizes that the term "prevent" is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended in applicants' claims. As used herein, reference to "treatment" of a patient is intended to include prophylaxis.

Throughout this application, various references are referred to. Each of the patents, patent applications, patent publications, and references mentioned herein is hereby incorporated by reference in its entirety.

The term "mammal" is used in its dictionary sense. The term "mammal" includes, for example, mice, hamsters, rats, cows, sheep, pigs, goats, and horses, monkeys, dogs (e.g., Canis familiaris), cats, rabbits, guinea pigs, and primates, including humans.

Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration; thus a carbon-carbon double bond depicted arbitrarily herein as E may be Z, E, or a mixture of the two in any proportion. Likewise, all tautomeric forms are also intended to be included.

As used herein, and as would be understood by the person of skill in the art, the recitation of "a compound" is intended to include salts, solvates and inclusion complexes of that compound as well as any stereoisomeric form, or a mixture of any such forms of that compound in any ratio. Thus, in accordance with some embodiments of the invention, a compound as described herein, including in the contexts of pharmaceutical compositions,

Attorney's Docket 2882.023B methods of treatment, and compounds per se, is provided as the salt form. In accordance with some embodiments of the invention, the salt is a hydrochloride salt.

The term "enantiomeric excess" is well known in the art and is defined for a resolution of ab into a + b as

e _ea = ( ^COnC - ° ^{f a ' C} ° ^nC - ° ^{f b} ) x WO yconc. of a + cone, of b)

The term "enantiomeric excess" is related to the older term "optical purity" in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, zero being racemic and 100 being pure, single enantiomer. A compound which in the past might have been called 98% optically pure is now more precisely described as 96% ee; in other words, a 90% ee reflects the presence of 95% of one enantiomer and 5% of the other in the material in question.

Terminology related to "protecting", "deprotecting" and "protected" functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes which involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as "protecting groups". Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W.Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference. Particular attention is drawn to the chapters entitled "Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols" (pages 10-86).

The following abbreviations and terms have the indicated meanings throughout: Ac = acetyl; Bu = butyl; c- = eye Io ; DIEA = N,N-diisopropylethyl amine; TEA = triethylamine; HOAc = acetic acid; mesyl = methanesulfonyl; rt = room temperature; sat'd

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= saturated; s- = secondary; t- = tertiary; TMS = trimethylsilyl; tosyl = p-toluenesulfonyl; TFA = trifluoroacetic acid; HATU = 0-(7-azabenzotriazol-l-yl)-7V,jV,iVW'- tetramethyluronium hexafluorophosphate. The abbreviations HPLC, THF, DCM and DMSO represent high performance liquid chromatography, tetrahydrofuran, dichloromethane and dimethylsulfoxide, respectively. The abbreviations Me, Et, Ph, Tf, Ts, Boc and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, toluenesulfonyl, butyloxycarbonyl and methanesulfonyl respectively. The term dppf refers to 1,1 '-Bis- (diphosphenylphosphino)ferrocene. A comprehensive list of abbreviations utilized by organic chemists (i.e. persons of ordinary skill in the art) appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations" is incorporated herein by reference.

While it may be possible for the compounds of the invention to be administered as the raw chemical, it is preferable to present them as a pharmaceutical composition. In accordance with an embodiment of the present invention there is provided a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Furthermore, notwithstanding the statement above regarding the term "compound" including salts thereof as well, so that independent claims reciting "a compound" will be understood as referring to salts thereof as well, if in an independent claim reference is made to a compound or a pharmaceutically acceptable salt thereof, it will be understood that claims which depend from that independent claim which refer to such a compound also include pharmaceutically acceptable salts of the compound, even if explicit reference is not made to the salts in the dependent claim.

The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods

Attorney's Docket 2882.023B well known in the art of pharmacy. Such methods include the step of bringing into association a compound of formula I or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.

The pharmaceutical compositions may include a "pharmaceutically acceptable inert carrier", and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, "Pharmaceutically acceptable carrier" also encompasses controlled release means.

Pharmaceutical compositions may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient must be compatible with the compound of formula I to insure the stability of the formulation. The composition may contain other additives as needed, including for example lactose,

Attorney's Docket 2882.023B glucose, fructose, galactose, trehalose, sucrose, maltose, raffÏŠnose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino acids, for example alanine, glycine and betaine, and peptides and proteins, for example albumen.

Examples of excipients for use as the pharmaceutically acceptable carriers and the pharmaceutically acceptable inert carriers and the aforementioned additional ingredients include, but are not limited to binders, fillers, disintegrants, lubricants, anti-microbial agents, and coating agents.

The dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of formula I which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. A dosage unit (e.g. an oral dosage unit) can include from, for example, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g. 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg) of a compound described herein.

For additional information about pharmaceutical compositions and their formulation, see, for example, Remington: The Science and Practice of Pharmacy, 20 ^th Edition, 2000.

The agents can be administered, e.g., by intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, topical, sublingual, intraarticular (in the joints), intradermal, buccal, ophthalmic (including intraocular), intranasaly (including using a cannula), or by other routes. The agents can be administered orally, e.g., as a tablet or cachet containing a predetermined amount of the active ingredient, gel, pellet, paste,

Attorney's Docket 2882.023B syrup, bolus, electuary, slurry, capsule, powder, granules, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, as an oil-in-water liquid emulsion or a water-in- oil liquid emulsion, via a micellar formulation (see, e.g. WO 97/11682) via a liposomal formulation (see, e.g., EP 736299,WO 99/59550 and WO 97/13500), via formulations described in WO 03/094886 or in some other form. The agents can also be administered transdermally (i.e. via reservoir-type or matrix-type patches, microneedles, thermal poration, hypodermic needles, iontophoresis, electroporation, ultrasound or other forms of sonophoresis, jet injection, or a combination of any of the preceding methods (Prausnitz et al. 2004, Nature Reviews Drug Discovery 3:115)). The agents can be administered locally, for example, at the site of injury to an injured blood vessel. The agents can be coated on a stent. The agents can be administered using high- velocity transdermal particle injection techniques using the hydrogel particle formulation described in U.S. 20020061336. Additional particle formulations are described in WO 00/45792, WO 00/53160, and WO 02/19989. An example of a transdermal formulation containing plaster and the absorption promoter dimethylisosorbide can be found in WO 89/04179. WO 96/11705 provides formulations suitable for transdermal administration.

The agents can be administered in the form a suppository or by other vaginal or rectal means. The agents can be administered in a transmembrane formulation as described in WO 90/07923. The agents can be administered non-invasively via the dehydrated particles described in U.S. 6,485,706. The agent can be administered in an enteric-coated drug formulation as described in WO 02/49621. The agents can be administered intranasaly using the formulation described in U.S. 5,179,079. Formulations suitable for parenteral injection are described in WO 00/62759. The agents can be administered using the casein formulation described in U.S. 20030206939 and WO 00/06108. The agents can be administered using the particulate formulations described in U.S. 20020034536.

The agents, alone or in combination with other suitable components, can be administered by pulmonary route utilizing several techniques including but not limited to intratracheal instillation (delivery of solution into the lungs by syringe), intratracheal delivery of liposomes, insufflation (administration of powder formulation by syringe or

Attorney's Docket 2882.023B any other similar device into the lungs) and aerosol inhalation. Aerosols (e.g., jet or ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry-Powder inhalers (DPIs)) can also be used in intranasal applications. Aerosol formulations are stable dispersions or suspensions of solid material and liquid droplets in a gaseous medium and can be placed into pressurized acceptable propellants, such as hydrofluoroalkanes (HFAs, i.e. HFA- 134a and HFA-227, or a mixture thereof), dichlorodifluoromethane (or other chlorofluorocarbon propellants such as a mixture of Propellants 11, 12, and/or 114), propane, nitrogen, and the like. Pulmonary formulations may include permeation enhancers such as fatty acids, and saccharides, chelating agents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat), preservatives (e.g., benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5% but possibly up to 20%, by weight). Ethanol is commonly included in aerosol compositions as it can improve the function of the metering valve and in some cases also improve the stability of the dispersion.

Pulmonary formulations may also include surfactants which include but are not limited to bile salts and those described in U.S. 6,524,557 and references therein. The surfactants described in U.S. 6,524,557, e.g., a Cs-Ci ₆ fatty acid salt, a bile salt, a phospholipid, or alkyl saccharide are advantageous in that some of them also reportedly enhance absorption of the compound in the formulation.

Also suitable in the invention are dry powder formulations comprising a therapeutically effective amount of active compound blended with an appropriate carrier and adapted for use in connection with a dry-powder inhaler. Absorption enhancers that can be added to dry powder formulations of the present invention include those described in U.S. 6,632,456. WO 02/080884 describes new methods for the surface modification of powders. Aerosol formulations may include U.S. 5,230,884, U.S. 5,292,499, WO 017/8694, WO 01/78696, U.S. 2003019437, U. S. 20030165436, and WO 96/40089 (which includes vegetable oil). Sustained release formulations suitable for inhalation are described in U.S. 20010036481A1, 20030232019Al, and U.S. 20040018243A1 as well as in WO 01/13891, WO 02/067902, WO 03/072080, and WO 03/079885.

Attorney's Docket 2882.023B

Pulmonary formulations containing microparticles are described in WO 03/015750, U.S. 20030008013, and WO 00/00176. Pulmonary formulations containing stable glassy state powder are described in U.S. 20020141945 and U.S. 6,309,671. Other aerosol formulations are described in EP 1338272A1 WO 90/09781, U. S. 5,348,730, U.S. 6,436,367, WO 91/04011, and U.S. 6,294,153 and U.S. 6,290,987 describes a liposomal based formulation that can be administered via aerosol or other means.

Powder formulations for inhalation are described in U.S. 20030053960 and WO 01/60341. The agents can be administered intranasally as described in U.S. 20010038824. Solutions of medicament in buffered saline and similar vehicles are commonly employed to generate an aerosol in a nebulizer. Simple nebulizers operate on Bernoulli's principle and employ a stream of air or oxygen to generate the spray particles. More complex nebulizers employ ultrasound to create the spray particles. Both types are well known in the art and are described in standard textbooks of pharmacy such as Sprowls' American Pharmacy and Remington's The Science and Practice of Pharmacy.

Other devices for generating aerosols employ compressed gases, usually hydrofluorocarbons and chlorofluorocarbons, which are mixed with the medicament and any necessary excipients in a pressurized container, these devices are likewise described in standard textbooks such as Sprowls and Remington.

The agent can be incorporated into a liposome to improve half-life. The agent can also be conjugated to polyethylene glycol (PEG) chains. Methods for pegylation and additional formulations containing PEG-conjugates (i.e. PEG-based hydrogels, PEG modified liposomes) can be found in Harris and Chess, Nature Reviews Drug Discovery 2:214-221 and the references therein. The agent can be administered via a nanocochleate or cochleate delivery vehicle (BioDelivery Sciences International). The agents can be delivered transmucosally (i.e. across a mucosal surface such as the vagina, eye or nose) using formulations such as that described in U.S. 5,204,108. The agents can be formulated in microcapsules as described in WO 88/01165. The agent can be administered intra-orally using the formulations described in U.S. 20020055496, WO 00/47203, and U.S. 6,495,120. The agent can be delivered using nanoemulsion formulations described in WO 01/91728A2.

Attorney's Docket 2882.023B

TABLE 1 lists compounds representative of embodiments of the invention. In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.

Processes for obtaining the compounds of the invention are presented below. Other compounds of the invention may be prepared in analogous fashion to those whose synthesis is exemplified herein. The procedures below illustrate such methods. Furthermore, although the syntheses depicted herein may result in the preparation of enantiomers having a particular stereochemistry, included within the scope of the present invention are compounds of formula I in any stereoisomeric form, and preparation of compounds of formula I in stereoisomeric forms other than those depicted herein would be obvious to one of ordinary skill in the chemical arts based on the procedures presented herein.

Synthetic Methods Scheme 1

2

Compounds of formula 3 (wherein R ¹⁴ is H or halogen; R ¹ is H; R ⁵ is a protecting group such as te/t-butoxycarbonyl or benzyloxycarbonyl; R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected from H or optionally substituted alkyl) can be prepared from 3- or 4-bromo phenylhydrazine 1 (or a salt thereof) and piperidinone 2 under heated acidic conditions. Optional N5-alkylation or N5-protection of compound 3 can provide compounds of formula 3 wherein R ¹ is alkyl or a protecting group such as tert- butoxycarbonyl, benzyloxycarbonyl or/?-toluenesulfonyl. Optional removal of N2-

Attorney's Docket 2882.023B protecting group R ⁵ and reductive amination, alkylation or acylation can provide compounds of formula 3 wherein R ⁵ is alkyl or acyl.

Scheme 2

Compounds of formula 1 (wherein R ¹⁴ is H or halogen) can be treated with compounds of formula 4 (wherein R ¹² and R ¹³ are each independently selected from H or optionally substituted alkyl and R ¹⁶ is alkyl) and a Lewis acid such as ZnCl ₂ under heated conditions to give compounds of formula 5. Treatment of compounds of formula 5 with ethyl glyoxylate under heated acidic conditions can provide compounds of formula 6 wherein R ¹⁰ and R ¹¹ are H. Alternatively, compounds of formula 5 can be treated with a ketone under heated acidic conditions to provide compounds of formula 6 wherein R ¹⁰ and R ¹¹ are optionally substituted alkyl. Compounds of formula 5 also can be treated with an acid chloride under basic conditions, followed by heating with POCI3 and finally by treatment with a reducing agent such as NaBH ₄ to provide compounds of formula 6 wherein R ¹⁰ is H and R ¹¹ is optionally substituted alkyl. Protection of the N2 -position on the tetrahydrocarboline ring can provide compounds of formula 7 (wherein R ⁵ is a protecting group such as te/t-butoxycarbonyl or benzyloxycarbonyl). Protection of the N9-position on the tetrahydrocarboline ring can provide compounds of formula 8 (wherein R ¹ is a protecting group such as te/t-butoxycarbonyl, benzyloxycarbonyl oxp- toluenesulfonyl). Alternatively, treatment of compound 7 with a base such as sodium hydride and an alkylating agent can provide compounds of formula 8 wherein R ¹ is optionally substituted alkyl. Optional removal of N2 -protecting group R ⁵ and reductive

Attorney's Docket 2882.023B animation, alkylation or acylation can provide compounds of formula 8 wherein R ⁵ is alkyl or acyl.

Scheme 3

Compounds of formula 12 (wherein B is aryl or heteroaryl; R ² , R ³ , R ⁴ are each independently selected from H, -O-alkyl, S-alkyl, alkyl, halo, -CF ₃ , and -CN; and Y is CH) can be prepared by treating compounds of formula 9 (wherein X ¹ is chlorine, bromine or iodine and Y is CH) with compounds of formula 10 (wherein B is aryl or heteroaryl; R ² , R ³ , R ⁴ are each independently selected from H, -O-alkyl, alkyl, halo, -CF ₃ , and -CN; Z ¹ is B(OH) ₂ , B(OR ¹⁷ ) ₂ , SnR ¹⁷ S or the like and R ¹⁷ is alkyl), a catalyst such as palladium(O), and a base such as potassium carbonate to give compounds of formula 11, wherein L is a direct bond. Alternatively, in the case where Z ¹ is -CH ₂ OH and B is aryl, heteroaryl or cycloalkyl, compounds of formula 10 can be treated with a base such as sodium hydride and compounds of formula 9 under heated conditions to give compounds of formula 11, wherein L is -CH ₂ O-. In turn, compounds of formula 11 can be treated with acetic anhydride under heated conditions followed by methanol and water or methanol and sodium hydroxide under ambient to heated conditions to provide compounds of formula 12, wherein L is -CH ₂ O- or a direct bond.

Scheme 4

Attorney's Docket 2882.023B

Alternatively, compounds of formula 12 (wherein B is aryl or heteroaryl; R ² , R ³ , R ⁴ are each independently selected from H, -O-alkyl, S-alkyl, alkyl, halo, -CF ₃ , and -CN; and Y is CH) can be prepared by treating compounds of formula 13 (wherein X is chlorine, bromine or iodine and Y is CH) with compounds of formula 10 (wherein Z ¹ is -CH=CH- B(OR ¹⁷ ) ₂ , B(OR ¹⁷ ) ₂ , SnR ¹⁷ S or the like and R ¹⁷ is H or alkyl), a catalyst such as palladium(O), and a base such as potassium carbonate to give compounds of formula 14, wherein L is -CH=CH- or a direct bond, in accordance with Z ¹ . In the case where L is - CH=CH-, compounds of formula 14 can be treated with palladium on carbon under an atmosphere of hydrogen to give compounds of formula 14, wherein L is -CH ₂ CH ₂ -. Alternatively, in the case where Z ¹ is -CH ₂ OH, compounds of formula 10 can be treated with compounds of formula 13, a catalyst such as copper iodide, a ligand such as 3,4,7,8- tetramethylphenanthroline and a base such as cesium carbonate under heated conditions to give compounds of formula 14, wherein L is -CH ₂ O-. In turn, when L is -CH=CH-, - CH ₂ CH ₂ -, -CH ₂ O- or a direct bond, compounds of formula 14 can be heated under acid conditions to provide compounds of formula 12, wherein L is -CH=CH-, -CH ₂ CH ₂ -, - CH ₂ O- or a direct bond, respectively.

Scheme 5

Alternatively, compounds of formula 12 (wherein B is aryl or heteroaryl; R ² , R ³ , R ⁴ are each independently selected from H, -O-alkyl, S-alkyl, alkyl, halo, -CF ₃ , and -CN; and Y is N) can be prepared from compounds of formula 15 (wherein Y is N and R ¹⁸ is a protecting group such as tetrahydropyran-2-yl). The hydroxyl group on compound 15 can

Attorney's Docket 2882.023B be converted to an appropriate activating group to give compounds of formula 16. In the case where Z ² is triflate, compounds of formula 15 can be treated with trifluoromethylsulfonic anhydride or JV-phenyl trifluoromethanesulfonamide and a base such as triethylamine, pyridine or lithium bis(trimethylsilyl)amide under cooled conditions to give compounds of formula 16. Treatment of compounds of formula 16 with compounds of formula 10 (wherein B is aryl or heteroaryl; R ² , R ³ , R ⁴ are each independently selected from H, -O-alkyl, S-alkyl, alkyl, halo, -CF ₃ , and -CN; Z ¹ = - CH=CH-B(OR ¹⁷ ) ₂ , B(OH) ₂ , B(OR ¹⁷ ) ₂ , SnR ¹⁷ ₃ or the like, and R ¹⁷ = alkyl), a catalyst such as palladium(O), and a base such as potassium carbonate under heated conditions can provide compounds of formula 17, wherein L is -CH=CH- or a direct bond. Removal of the protecting group R ¹⁸ on compound 17 can provide compounds of formula 12.

Scheme 6

Compounds of formula 18 (wherein B is aryl, heteroaryl or cycloalkyl; R ² , R ³ , R ⁴ are each independently selected from H, -O-alkyl, -S-alkyl, alkyl, halo, -CF ₃ , and -CN; L is -CH ₂ - O-, -CH=CH-, -CH ₂ CH ₂ -, or a bond; Y is CH or N; R ¹⁴ is H or halogen; R ⁵ is alkyl, acyl or a protecting group such as te/t-butoxycarbonyl or benzyloxycarbonyl; R ¹ is alkyl or a protecting group such as te/t-butoxycarbonyl, benzyloxycarbonyl or/?-toluenesulfonyl; and R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected from H or optionally substituted alkyl) can be prepared by treating compounds of formula 3 (wherein R ⁵ is alkyl, acyl or a protecting group such as te/t-butoxycarbonyl or benzyloxycarbonyl and R ¹ is alkyl or a protecting group such as te/t-butoxycarbonyl, benzyloxycarbonyl or p- toluenesulfonyl) under heated conditions with a catalyst such as copper iodide, a ligand such as trans- 1,2-diaminocyclohexane or 8-hydroxyquinoline, a base such as potassium carbonate, cesium carbonate or potassium phosphate and compounds of formula 12

Attorney's Docket 2882.023B

(wherein B is aryl, heteroaryl or cycloalkyl; R ² , R ³ , R ⁴ are each independently selected from H, -O-alkyl, -S-alkyl, alkyl, halo, -CF ₃ , and -CN; L is -CH ₂ -O-, -CH=CH-, -CH ₂ CH ₂ - , or a bond; and Y is CH or N). Removal of the N2 -protecting group R ⁵ followed by reductive amination or alkylation can provide compounds of formula 18, wherein R ⁵ is an optionally substituted alkyl group.

Alternatively, following deprotection, N2 can be acylated to give compounds of formula 18 wherein R ⁵ is -C(=O)-R ⁶ or -C(=O)-O-R ⁷ , and R ⁶ and R ⁷ are each optionally substituted alkyl or optionally substituted heterocycle. Additionally, in the case where R ¹ is a protecting group, the protecting group can be removed to give compounds of formula 18 wherein R ¹ is H.

Alternatively, following removal of the R ¹ protecting group, N5 can be alkylated to give compounds of formula 18 wherein R ⁵ is an optionally substituted alkyl.

Scheme 7

Compounds of formula 19 (wherein B is aryl, heteroaryl or cycloalkyl; R , R , R are each independently selected from H, -O-alkyl, -S-alkyl, alkyl, halo, -CF ₃ , and -CN; L is -CH ₂ -O-, -CH=CH-, -CH ₂ CH ₂ -, or a bond; Y is CH or N; R ¹⁴ is H or halogen; R ⁵ is alkyl, acyl or a protecting group such as te/t-butoxycarbonyl or benzyloxycarbonyl; R ¹ is alkyl or a protecting group such as te/t-butoxycarbonyl, benzyloxycarbonyl or/?-toluenesulfonyl; and R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected from H or optionally substituted alkyl) can be prepared by treating compounds of formula 3 (wherein R ⁵ is alkyl, acyl or a protecting group such as te/t-butoxycarbonyl or benzyloxycarbonyl and R ¹ is alkyl or a protecting group such as te/t-butoxycarbonyl, benzyloxycarbonyl or p- toluenesulfonyl) under heated conditions with a catalyst such as copper iodide, a ligand such as trans- 1,2-diaminocyclohexane or 8-hydroxyquinoline, a base such as potassium

Attorney's Docket 2882.023B carbonate, cesium carbonate or potassium phosphate and compounds of formula 12 (wherein B is aryl, heteroaryl or cycloalkyl; R ² , R ³ , R ⁴ are each independently selected from H, -O-alkyl, -S-alkyl, alkyl, halo, -CF ₃ , and -CN; L is -CH ₂ -O-, -CH=CH-, -CH ₂ CH ₂ - , or a bond; and Y is CH or N). Removal of the N2 -protecting group R ⁵ followed by reductive amination or alkylation can provide compounds of formula 18, wherein R ⁵ is an optionally substituted alkyl group.

Alternatively, following deprotection, N2 can be acylated to give compounds of formula 18 wherein R ⁵ is -C(=O)-R ⁶ or -C(=O)-O-R ⁷ , and R ⁶ and R ⁷ are each optionally substituted alkyl or optionally substituted heterocycle. Additionally, in the case where R ¹ is a protecting group, the protecting group can be removed to give compounds of formula 18 wherein R ¹ is H.

Alternatively, following removal of the R ¹ protecting group, N5 can be alkylated to give compounds of formula 18 wherein R ⁵ is an optionally substituted alkyl. Scheme 8

Compounds of formula 20 (wherein Y is CH or N; R ¹⁴ is H or halogen; R ⁵ is alkyl, acyl or a protecting group such as te/t-butoxycarbonyl or benzyloxycarbonyl; R ¹ is alkyl or

Attorney's Docket 2882.023B a protecting group such as te/t-butoxycarbonyl, benzyloxycarbonyl or/?-toluenesulfonyl; and R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected from H or optionally substituted alkyl) can be treated with hydrogen and a catalyst such as palladium on carbon to provide compounds of formula 21. The hydroxyl group on compounds of formula 21 can be converted to an appropriate activating group to give compounds of formula 22. In the case where Z ² is triflate, compounds of formula 21 can be treated with trifluoromethylsulfonic anhydride or JV-phenyl trifluoromethanesulfonamide and a base such as pyridine or lithium bis(trimethylsilyl)amide under cooled conditions to give compounds of formula 22. Treatment of compounds of formula 22 with compounds of formula 10 (wherein B is aryl or heteroaryl; R ² , R ³ , R ⁴ are each independently selected from H, -O-alkyl, -S-alkyl, alkyl, halo, -CF ₃ , and -CN; Z ¹ = -CH=CH-B(OR ¹⁷ ) ₂ , B(OH) ₂ , B(OR ¹⁷ ) ₂ , SnR ¹⁷ 3 or the like and R ¹⁷ = alkyl), a catalyst such as palladium(O), and a base such as potassium carbonate under heated conditions can provide compounds of formula 18, wherein L is -CH=CH- or a direct bond. In the case where L is -CH=CH-, compounds of formula 18 can be treated with palladium on carbon under an atmosphere of hydrogen to give compounds of formula 18, where L is -CH ₂ CH ₂ -. Scheme 9

Attorney's Docket 2882.023B

Compounds of formula 23 (wherein Y is CH or N; R ¹⁴ is H or halogen; R ⁵ is alkyl, acyl or a protecting group such as te/t-butoxycarbonyl or benzyloxycarbonyl; R ¹ is alkyl or a protecting group such as te/t-butoxycarbonyl, benzyloxycarbonyl or/?-toluenesulfonyl; and R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected from H or optionally substituted alkyl) can be treated with hydrogen and a catalyst such as palladium on carbon to provide compounds of formula 24. The hydroxyl group on compounds of formula 24 can be converted to an appropriate activating group to give compounds of formula 25. In the case where Z ² is triflate, compounds of formula 24 can be treated with trifluoromethylsulfonic anhydride or //-phenyl trifluoromethanesulfonamide and a base such as pyridine or lithium bis(trimethylsilyl)amide under cooled conditions to give compounds of formula 25.

Treatment of compounds of formula 25 with compounds of formula 10 (wherein B is aryl or heteroaryl; R ² , R ³ , R ⁴ are each independently selected from H, -O-alkyl, -S-alkyl, alkyl, halo, -CF ₃ , and -CN; Z ¹ = -CH=CH-B(OR ¹⁷ ) ₂ , B(OH) ₂ , B(OR ¹⁷ ) ₂ , SnR ¹⁷ ₃ or the like and R ¹⁷ = alkyl), a catalyst such as palladium(O), and a base such as potassium carbonate

Attorney's Docket 2882.023B under heated conditions can provide compounds of formula 19, wherein L is -CH=CH- or a direct bond. .

In the case where L is -CH=CH-, compounds of formula 18 can be treated with palladium on carbon under an atmosphere of hydrogen to give compounds of formula 18, where L is -CH ₂ CH ₂ -.

Scheme 10

Compounds of formula 26 (wherein B is aryl or heteroaryl; R ² , R ³ , R ⁴ are each independently selected from H, -O-alkyl, -S-alkyl, alkyl, halo, -CF ₃ , and -CN; L is -CH ₂ - O-, -CH=CH-, -CH ₂ CH ₂ -, or a bond; G is -CR ¹² R ¹³ -NH- or -NH-CR ¹² R ¹³ -; R ¹ is alkyl; and R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each independently selected from H or optionally substituted alkyl) can be treated under halogenation conditions such as 2-bromopropane under heated conditions to provide compounds of formula 27 wherein R ¹⁵ is a halogen such as bromine.

Examples

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on Bruker spectrometers at 300, 400 or 500 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Mass spectra were collected using either a Finnigan LCQ Duo LCMS ion trap electrospray ionization (ESI) or a mass Varian 1200L single quadrapole mass spectrometer (ESI). High performace liquid chromatograph (HPLC) analyses were obtained using a Luna C 18(2) column (250 x 4.6 mm, Phenomenex) or a Gemini C 18

Attorney's Docket 2882.023B column (250 x 4.6 mm, Phenomenex) with UV detection at 254 nm or 223 nm using a standard solvent gradient program (Method A or Method B).

Method A:

A = Water with 0.025% Trifluoroacetic Acid

B = Acetonitrile with 0.025% Trifluoroacetic Acid

Method B:

A = Water with 0.025% Trifluoroacetic Acid

B = Acetonitrile with 0.025% Trifluoroacetic Acid

Example 1

Preparation of 4-(Benzyloxy)- 1 -(5-methyl-2,3,4,5-tetrahydiO- lH-pyrido[4,3-& ^" |indol-7- yl)pyridin-2(l//)-one hydrochloride

a) te/t-Butyl 7-bromo-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylat e

3-Bromophenylhydrazine (40.0 g, 0.179 mol) and JV-Boc-4-oxo-piperidine (35.4 g, 0.179 mol) were dissolved in ethanol (368 mL), and cone. HCl (72 mL) was added. The reaction mixture was then heated to reflux for 18 h, concentrated and basifÏŠed using 10% NH ₄ OH in methanol (10%, 100 mL). The solvent was removed, and the residue was suspended in CH ₂ Cl ₂ (1.2 L). BoC ₂ O (39.2 g, 0.179 mol) followed by DMAP (195 mg, 1.6 mmol) and

Attorney's Docket 2882.023B triethylamine (46.4 niL, 0.358 mol) were then added, and the reaction progressed at room temperature for 18 h. The mixture was washed with 0.5 N HCl, and the organic phase was removed, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The resulting mixture of regioisomers was purified by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 then 25:75) to give the more polar title compound (26.2 g, 42%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.16 (br s, IH), 7.42 (s, IH), 7.28 (d, J= 8.1 Hz, IH, partially masked by solvent), 7.18 (d, J= 8.1 Hz, IH), 4.60 (s, 2H), 3.80 (t, J= 5.5 Hz, 2H), 2.79 (t, J= 5.6 Hz, 2H), 1.51 (s, 9H).

b) tert-Butyl 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-c arboxylate

Sodium hydride (60% weight dispersion in mineral oil, 4.19 g, 0.105 mol) was added portionwise to a solution of tert-butyi 7-bromo-3,4-dihydro-lH-pyrido[4,3-δ]indole- 2(5H)-carboxylate (23.6 g, 0.07 mol) in DMF (300 mL) at room temperature under N ₂ . After 1 h, methyl iodide (14.8 g, 6.47 mL, 0.105 mol) was added, and the reaction was allowed to proceed for an additional 2 h. The mixture was quenched with H ₂ O, upon which a solid precipitated out of solution. The suspension was therefore diluted to 2 L with H ₂ O and filtered. The solids were washed thoroughly with water, then dissolved in CH ₂ Cl ₂ , dried over Na ₂ SO ₄ , filtered and concentrated to dryness. This provided the title compound (22.4g, 91%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.41 (s, IH), 7.30 (d, J= 8.3 Hz, IH), 7.17 (d, J= 8.4 Hz, IH), 4.60 (s, 2H), 3.81 (br t, 2H), 3.58 (s, 3H), 2.77 (t, J= 5.4 Hz, 2H), 1.50 (s, 9H).

Attorney's Docket 2882.023B c) tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-dihydro -lH- pyrido[4,3-δ]indole-2(5H)-carboxylate

tert-Butyl 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-c arbox- ylate (7.0 g, 19 mmol), 4-benzyloxypyridone (3.85 g, 19.2 mmol), K ₂ CO ₃ (2.91 g, 21.1 mmol) and 8-hydroxyquinoline (418 mg, 2.88 mmol) were suspended in DMSO (50 mL) and the air removed under vacuum for 15 min. The system was then flushed with N ₂ . This process was repeated and then copper iodide (547 mg, 2.88 mmol) was added. The evacuation/N ₂ flushing process was repeated twice more, and the reaction mixture was heated to 100-120 ⁰ C for 18 h. The mixture was cooled, partitioned between EtOAc and sat. NH ₄ Cl and the organic phase removed, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. Purification by flash column chromatography (silica gel, CH ₂ Cl ₂ /Me0H, 100:0 to 98:2 to 95:5 to 92:8 then 90:10) gave the title compound (4.71 g, 51%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.50 (d, J= 8.2 Hz, IH), 7.43-7.35 (m, 5H), 7.32-7.29 (m, 2H), 7.01 (d, J= 7.9 Hz, IH), 6.10-6.03 (m, 2H), 5.06 (s, 2H), 4.64 (s, 2H), 3.89 (br t, 2H), 3.63 (s, 3H), 2.82 (br t, 2H), 1.50 (s, 9H).

d) 4-(Benzylo xy)-l -(5-methyl-2, 3,4, 5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)pyridin- 2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₄ ClN ₃ O ₂

Exact Mass: 421.16 Molecular Weight: 421.92 tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-dihydro -lH-pyrido[4,3- 6]indole-2(5H)-carboxylate (12.0 g, 24.7 mmol) was dissolved in MeOH (100 mL), and 2

Attorney's Docket 2882.023B

N HCl in Et ₂ O (300 niL) was added. The reaction was allowed to proceed for 18 h. The mixture was concentrated, and the residue was partitioned between CH ₂ Cl ₂ and sat. Na ₂ CO ₃ solution. The organic phase was removed, and the aqueous phase was back extracted with CH ₂ Cl ₂ . The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated to dryness providing the free base of the title compound (8.1 g, 85%) as a yellow solid. A portion of the free base was converted to the HCl salt for biological testing. Free base: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.47-7.34 (m, 6H), 7.32-7.28 (m, 2H), 6.98 (d, J= 7.1 Hz, IH), 6.07 (d, J= 2.6 Hz, IH), 6.04 (dd, J= 7.5, 2.6 Hz, IH), 5.05 (s, 2H), 4.15 (s, 2H), 3.61 (s, 3H), 3.34 (br s, 2H), 2.78 (br s, 2H). HCl salt: melting point (mp) 296-302 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.61-7.57 (2 x d, 2H), 7.47-7.46 (m, 3H), 7.43-7.40 (m, 2H), 7.37-7.34 (m, IH), 7.05 (dd, J= 8.3, 1.7 Hz, IH), 6.33 (dd, J = 7.5, 2.7 Hz, IH), 6.16 (d, J= 2.6 Hz, IH), 5.19 (s, 2H), 4.57 (s, 2H), 3.73 (s, 3H), 3.67 (t, J = 6.2 Hz, 2H), 3.20 (t, J= 6.1 Hz, 2H); ESI MS m/z 386 [M + H] ⁺ ; HPLC (Method A) 95.7% (AUC), t _R = 13.6 min.

Example 2

Preparation of 4-(Benzyloxy)- 1 -(2,5-dimethyl-2,3,4,5-tetrahydro- lH-pyrido| ^" 4,3-& ^" |indol-7- yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₅ H ₂₆ ClN ₃ O ₂

Exact Mass: 435.17 Molecular Weight: 435.95

4-(Benzyloxy)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-Î ´]indol-7-yl)pyridin-2(lH)- one (8.1 g, 21.0 mmol) and 37% aqueous formaldehyde (2.56 niL, 31.5 mmol) were dissolved in MeOH (200 mL) and stirred at room temperature for 2 h. Sodium triacetoxyborohydride (8.9 g, 42.0 mmol) was then added, and the reaction was stirred at room temperature for an additional 1 h. The mixture was concentrated, and the residue was partitioned between CH ₂ Cl ₂ and sat. Na ₂ CO ₃ solution. The organic phase was removed and the aqueous phase was back extracted with CH ₂ Cl ₂ . The combined organics were dried over Na ₂ SO ₄ , filtered and concentrated to dryness. Purification by column

Attorney's Docket 2882.023B chromatography (120 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 85% methylene chloride over 60 min) provided the free base of the title compound. This was converted to the HCl salt using 2 N HCl in Et ₂ O providing the title compound (5.57 g, 61%) as a yellow solid: mp 268-274°C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.57 (dd, J= 7.6, 1.7 Hz, 2H), 7.47-7.46 (m, 3H) 7.43-7.34 (m, 3H), 7.06 (dd, J= 8.4, 1.9 Hz, IH), 6.29 (dd, J= 7.6, 2.7 Hz, IH), 6.13 (d, J= 2.6 Hz, IH), 5.18 (s, 2H), 4.75 (d, J= 14.3 Hz, IH), 4.38 (d, J= 14.2 Hz, IH), 3.90 (m, IH), 3.73 (s, 3H), 3.64-3.58 (m, IH), 3.29-3.26 (m, 2H, partially masked by solvent), 3.13 (s, 3H); ESI MS m/z 400 [M + H] ⁺ ; HPLC (Method B) 97.4% (AUC), t _R = 14.7 min.

Example 3

Preparation of 4-(Benzyloxy)- 1 -(2-(2-hydroxyethyl)-5-methyl-2,3,4,5-tetrahydro- IH- pyrido[4,3-&lindol-7-yl)pyridin-2(lH)-one dihydrochloride

hemical Formula: C ₂₆ H ₂₉ Cl ₂ N ₃ O ₃

Exact Mass: 501.16 Molecular Weight: 502.43

4-(Benzyloxy)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-Î ´]indol-7-yl)pyridin-2(lH)- one (75 mg, 0.16 mmol), 2-iodoethanol (17 μL, 36 mg, 0.21 mmol) and triethylamine (105 μL, 0.82 mmol) were dissolved in MeCN (2 mL) and heated to reflux for 3 h. The mixture was then concentrated and purified by flash column chromatography (4 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 85% methylene chloride over 30 min) providing the free base. This was converted to the HCl salt (2 N ηCl/Et ₂ O) providing the title compound (22 mg, 27%) as a yellow solid: mp 162-168°C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.63 (dd, J= 7.6, 2.0 Hz, 2H), 7.51-7.50 (m, 3H) 7.46-7.43 (m, 2H), 7.41-7.38 (m, IH), 7.09 (dd, J= 8.3, 1.7 Hz, IH), 6.36 (dd, J= 7.6, 2.7 Hz, IH), 6.18 (d, J= 2.7 Hz, IH), 5.23 (s, 2H), 4.82 (d, IH,

Attorney's Docket 2882.023B partially masked by solvent), 4.520 (d, J= 14.3 Hz, IH), 4.06-4.02 (m, 3H), 3.77 (s, 3H), 3.70-3.68 (m, IH), 3.55-3.51 (m, 2H), 3.33-3.31 (m, 2H, partially masked by solvent); ESI MS m/z 430 [M + H] ⁺ ; HPLC (Method B) 95.1% (AUC), t _R = 12.4 min.

Example 4

Preparation of 4-(Benzyloxy)- 1 -(5-methyl-2-(2-(pyrrolidin- 1 -yl)acetyl)-2,3,4,5-tetrahydro- lH-pyrido[4,3-&lindol-7-yl)pyridin-2(lH)-one dihydrochloride

a) 4-(Benzyloxy)-l-(2-(2-chloroacetyl)-5-methyl-2,3,4,5-tetrahy dro-lH-pyrido[4,3- δ]indol-7-yl)pyridin-2(lH)-one

4-(Benzyloxy)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-Î ´]indol-7-yl)pyridin-2(lH)- one (75 mg, 0.16 mmol) was dissolved in a mixture Of CH ₂ Cl ₂ (1 mL) and sat. NaHCO ₃ solution (1 mL) and chloroacetyl chloride (28 mg, 0.25 mmol) was added. The reaction mixture was vigorously stirred for 1 h then the phases were separated. The aqueous phase was extracted with CH ₂ Cl ₂ and the combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated to dryness providing the title compound (74 mg, 97%) as a beige solid which was a mixture of rotamers: ESI MS m/z 462 [M + H] ⁺ .

b) 4-(Benzyloxy)- 1 -(5-methyl-2-(2-(pyrrolidin- 1 -yl)acetyl)-2,3 ,4,5-tetrahydro- IH- pyrido[4,3-δ]indol-7-yl)pyridin-2(lH)-one dihydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₃₀ H ₃₄ Cl ₂ N ₄ O ₃

Exact Mass: 568.20 Molecular Weight: 569.52

4-(Benzyloxy)-l-(2-(2-chloroacetyl)-5-methyl-2,3,4,5-tetrahy dro-l/f-pyrido[4,3- δ]indol-7-yl)pyridin-2(lH)-one (70 mg, 0.15 mmol) was dissolved in MeCN (0.5 niL) and pyrrolidine (54 mg, 0.76 mmol) was added. The reaction mixture was refluxed for 2 h, concentrated and the residue purified by preparative HPLC. The fractions were concentrated, and the residue was converted to the free base by partitioning between CH ₂ Cl ₂ and sat. Na ₂ CO ₃ solution. The organic phase was removed, and the aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated to dryness. Conversion to the HCl salt (2 N HCl/Et ₂ O) provided the title compound (74 mg, 97%) as a beige solid: ¹ U NMR (500 MHz, CD ₃ OD) δ 7.62 (dd, J= 7.7, 1.9 Hz, IH), 7.53 (d, J= 8.0 Hz, IH) 7.46-7.44 (m, 2H), 7.41-7.35 (m, 4H), 7.06 (dd, J= 8.0, 1.7 Hz, IH), 6.36 (d, J= 7.6 Hz, IH), 6.18 (s, IH), 5.25 (s, 2H), 4.90 (m, IH, masked by solvent), 4.82 (s, IH), 4.53 (d, J= 14.2 Hz, 2H), 4.09 (t, J= 6.5 Hz, IH), 3.91 (t, J= 6.4 Hz, IH), 3.89-3.86 (m, 2H), 3.77 (s, 3H), 3.20-3.18 (m, 2H), 3.05-3.03 (m, IH), 2.99-2.97 (m, IH), 2.12-2.10 (m, 2H), 2.08-2.05 (m, 2H); ESI MS m/z 497 [M + H] ⁺ ; HPLC (Method B) 95.0% (AUC), t _R = 13.1 min.

Example 5

Preparation of 4-(Benzyloxy)- 1 -(5-methyl-2-(2.2.2-trifluoroethvQ-2.3 A5-tetrahydro- IH-

Pyridor4,3-άlindol-7-yl)pyridin-2(lH)-one dihydrochloride

Attorney's Docket 2882.023B

4-(Benzyloxy)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-Î ´]indol-7-yl)pyridin- 2(lH)-one (75 mg, 0.16 mmol) and triethylamine (105 μL, 0.753 mmol) were dissolved in MeCN (2 rnL) and l,l,l-trifluoro-2-bromoethane (32 mg, 0.20 mmol) was added. The reaction mixture was heated to reflux for 4 h, but no reaction occurred. The mixture was concentrated, DMF (2 mL) and NaI (5 mg) were added, and the reaction mixture was heated to reflux. Again, no reaction occurred. 1,1,1-trifluoroethyl triflate (76 mg, 0.328 mmol) was then added, and the mixture was heated to reflux. After 1.5 h, the mixture was concentrated and purified by flash column chromatography (4 g ISCO column eluting with methylene chloride and a methano I/ammo nia mixture (10:1); gradient 100% methylene chloride to 85% methylene chloride over 30 min). Further purification by preparative HPLC, followed by conversion to the HCl salt (2 N HCl/Et ₂ O) provided the title compound (6 mg, 7%) as a white solid: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.48 (d, J= 7.5 Hz, IH), 7.40-7.24 (m, 7H), 6.87 (dd, J= 8.3, 1.9 Hz, IH), 6.19 (dd, J= 7.6, 2.7 Hz, IH), 6.03 (d, J= 2.7 Hz, IH), 5.08 (s, 2H), 3.96 (s, 2H), 3.58 (s, 3H), 3.37 (q, J= 9.7 Hz, 2H), 3.15-3.14 (m, 2H, partially masked by solvent), 2.87 (t, J= 5.5 Hz, 2H); ESI MS m/z 468 [M + H] ⁺ ; HPLC (Method B) 98.9% (AUC), t _R = 17.3 min.

Example 6

Preparation of 4-(Benzyloxy)- 1 -(5-methyl-2-(3 ,3 ,3-trifluoropropyl)-2,3 ,4,5-tetrahydro- IH- pyridor4,3-άlindol-7-yl)pyridin-2(lH)-one dihydrochloride

Attorney's Docket 2882.023B

4-(Benzyloxy)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-Î ´]indol-7-yl)pyridin- 2(lH)-one (63 mg, 0.14 mmol) and K ₂ CO ₃ (97 mg, 0.70 mmol) were suspended in DMF (1 rnL) and l,l,l-trifluoro-3-bromopropane (50 mg, 0.28 mmol) was added. The reaction mixture was heated to 80 ⁰ C for 18 h, cooled and partitioned between ethyl acetate and water. The aqueous phase was removed and the organic phase washed with 5% LiCl (5 ^χ ), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. Purification by flash column chromatography (4 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 85% methylene chloride over 30 min) followed by conversion to the HCl salt (2 N HCl/Et ₂ O) provided the title compound (12 mg, 16%) as a yellow solid: ¹ U NMR (500 MHz, CD ₃ OD) δ 7.66 (d, J = 8.3 Hz, IH), 7.63 (d, J= 7.6 Hz, IH), 7.52-7.51 (m, 3H), 7.48-7.45 (m, 2H), 7.43 (d, J = 7.2 Hz, IH), 7.11 (dd, J= 8.3, 1.7 Hz, IH), 6.36 (dd, J= 7.6, 2.7 Hz, IH), 6.19 (d, J= 2.7 Hz, IH), 5.24 (s, 2H), 4.96 (m, 6H, masked by solvent), 3.79-3.74 (m, 5H), 3.03-3.02 (m, 2H); ESI MS m/z 482 [M + H] ⁺ ; HPLC (Method B) 95.6% (AUC), t _R = 14.3 min.

Example 7

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-yl)-4 -(4-

(trifluoromethyl)benzyloxy)pyridin-2( lHVone dihydrochloride

a) tert-Butyl 5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)benzyloxy)pyridin-l( 2H)-yl)-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

Attorney's Docket 2882.023B

The compound was prepared from tert-hvXy\ 7-bromo-5-methyl-3,4-dihydro-lH- pyrido[4,3-6]indole-2(5H)-carboxylate (250 mg, 0.701 mmol) and 4-(4- (trifluoromethyl)benzyloxy)pyridin-2(lH)-one (142 mg, 0.526 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (73 mg, 19%) as a solid, that contained an impurity: ESI MS m/z 554 [M + H] ⁺ .

b) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4 -(4- (trifluoromethyl)benzyloxy)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₅ H ₂₄ Cl ₂ F ₃ N ₃ O ₂

Exact Mass: 525.12 Molecular Weight: 526.38 te/t-Butyl 5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)benzyloxy)pyridin- 1 (2H)-yl)- 3,4-dihydro-l/f-pyrido[4,3-δ]indole-2(5H)-carboxylate (73 mg, 0.13 mmol) was dissolved in MeOH (0.5 mL) and 2 N HCl in Et ₂ O (3 mL) was added. The reaction was allowed to proceed for 3 h. The mixture was concentrated and purified by preparative HPLC. Converion to the HCl salt (2 N HCl/Et ₂ O) provided the title compound (26 mg, 38%) as a yellow solid: mp 311-315 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.77 (d, J= 8.3 Hz, 2H), 7.71 (d, J= 8.2 Hz, 2H), 7.65 (d, J= 7.6 Hz, IH), 7.62 (d, J= 8.3 Hz, IH), 7.50 (s, IH), 7.09 (dd, J= 8.3, 1.8 Hz, IH), 6.38 (dd, J= 7.6, 2.7 Hz, IH), 6.17 (d, J= 2.7 Hz, IH), 5.33

Attorney's Docket 2882.023B

(s, 2H), 4.51 (s, 2H), 3.77 (s, 3H), 3.71 (t, J= 6.2 Hz, 2H), 3.24 (t, J= 6.1 Hz, 2H); ESI MS m/z 454 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 14.2 min.

Example 8

Preparation of 4-(4-Chlorobenzyloxy)- 1 -(5-methyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-

&1indol-7-yl)pyridin-2(lH)-one dihydrochloride

a) tert-Butyl 7-(4-(4-chlorobenzyloxy)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4 -dihydro-lH- pyrido[4,3-δ]indole-2(5H)-carboxylate

The compound was prepared from tert-butyi 7-bromo-5-methyl-3,4-dihydro-lH- pyrido[4,3-6]indole-2(5H)-carboxylate (200 mg, 0.548 mmol) and 4-(4- chlorobenzyloxy)pyridin-2(lH)-one (129 mg, 0.548 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (143 mg, 50%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.51 (d, J = 8.0 Hz, IH), 7.43-7.29 (m, 6H), 7.01 (d, J = 7.9 Hz, IH), 6.05-6.02 (m, 2H), 5.02 (s, 2H), 4.64 (br s, 2H), 3.84 (br s, 2H), 3.63 (s, 3H), 2.82 (br s, 2H), 1.50 (s, 9H).

b) 4-(4-Chlorobenzyloxy)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyri do[4,3-δ]indol-7- yl)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₄ H ₂₄ Cl ₃ N ₃ O ₀ Exact Mass: 491.09

Molecular Weight: 492.83

Attorney's Docket 2882.023B tert-Butyl-7-(4-(4-chlorobenzyloxy)-2-oxopyridin-l(2H)-yl)-5 -methyl-3,4-dihydro- lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (143 mg, 0.275 mmol) was dissolved in MeOH (1 niL) and 2 N HCl in Et ₂ O (5 niL) was added. The reaction was allowed to proceed for 3 h. The resulting precipitate was collected by filtration and washed with Et ₂ O to provide the title compound (95 mg, 71%) as a yellow solid: mp 305-310 ⁰ C dec; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.54 (br s, 2H), 7.57 (m, 2H), 7.51 (s, 5H), 6.99 (d, J= 7.8 Hz, IH), 6.12 (dd, J= 7.8, 2.7 Hz, IH), 5.99 (d, J= 2.7 Hz, IH), 5.16 (s, 2H), 4.33 (br s, 2H), 3.68 (s, 3H), 3.52-3.48 (m, 2H), 3.12-3.08 (m, 2H); ESI MS m/z 420 [M + H] ⁺ ; HPLC (Method B) 97% (AUC), t _R = 13.99 min.

Example 9

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-yl)-4 - phenethylpyridin-2( lHVone dihydrochloride

a) tert-Butyl 5-methyl-7-(2-oxo-4-phenethylpyridin-l(2H)-yl)-3,4-dihydro-l H-pyrido[4,3- δ]indole-2(5H)-carboxylate

The compound was prepared from tert-bvXy\ 7-bromo-5-methyl-3,4-dihydro-lH- pyrido[4,3-δ]indole-2(5H)-carboxylate (200 mg, 0.548 mmol) and 4-phenethylpyridin- 2(lH)-one (109 mg, 0.548 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (126 mg, 48%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.52 (d, J= 8.2 Hz, IH), 7.34-7.30 (m, 4H), 7.24-7.20 (m, 3H, partially masked by solvent), 7.03 (d, J= 7.8 Hz, IH), 6.52 (s, IH), 6.10 (dd, J= 7.9,

Attorney's Docket 2882.023B

1.7 Hz, IH), 4.65 (br s, 2H), 3.84 (br s, 2H), 3.63 (s, 3H), 2.98-2.93 (m, 2H), 2.84-2.81 (m, 4H), 1.51 (s, 9H).

b) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)- 4-phenethylpyridin-2(lH)- one dihydrochloride

Chemical Formula: C ₂₅ H ₂₇ Cl ₂ N ₃ O Exact Mass: 455.15

Molecular Weight: 456.41 tert-Butyl 5-methyl-7-(2-oxo-4-phenethylpyridin-l(2H)-yl)-3,4-dihydro-l H- pyrido[4,3-δ]indole-2(5H)-carboxylate (120 mg, 0.248 mmol) was dissolved in MeOH (1.5 niL) and 2 N HCl in Et ₂ O (5 niL) was added. The reaction was allowed to proceed for 3 h. The resulting precipitate was collected by filtration and washed with Et ₂ O to provide the title compound (90 mg, 80%) as a yellow solid: mp 282-286°C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.70 (d, J= 6.9 Hz, IH), 7.62 (d, J= 8.3 Hz, IH), 7.52 (s, IH), 7.33-7.26 (m, 4H), 7.22 (t, J= 7.2 Hz, IH), 7.09 (dd, J= 8.3, 1.6 Hz, IH), 6.59-6.56 (m, 2H), 4.50 (s, 2H), 3.76 (s, 3H), 3.70 (t, J= 6.2 Hz, 2H), 3.24 (t, J= 6.0 Hz, 2H), 3.04-3.01 (m, 2H), 2.98-2.95 (m, 2H); ESI MS m/z 384 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 13.3 min.

Example 10

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-yl)-4 -(4-

(trifluoromethyl)phenyl)pyridin-2( lHVone dihydrochloride

a) tert-Butyl 5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-l(2H) -yl)-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

Attorney's Docket 2882.023B

The compound was prepared from tert-hvXy\ 7-bromo-5-methyl-3,4-dihydro-lH- pyrido[4,3-6]indole-2(5H)-carboxylate (153 mg, 0.418 mmol) and 4-(4- (trifluoromethy)phenyl)pyridine-2(lH)-one (100 mg g, 0.418 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (98 mg, 45%) as a yellow/green solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.75 (s, 4H), 7.57- 7.53 (m, 2H), 7.37 (s, IH), 7.09 (d, J= 8.0 Hz, IH), 6.92 (s, IH), 6.50 (d, J= 6.7 Hz, IH), 4.67 (s, 2H), 3.86 (br s, 2H), 3.60 (s, 3H), 2.84 (br s, 2H), 1.51 (s, 9H).

b) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4 -(4- (trifluoromethyl)phenyl)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₄ H ₂₂ Cl ₂ F ₃ N ₃ O

Exact Mass: 495.1 1 Molecular Weight: 496.35 tert-Butyl 5 -methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin- 1 (2H)-yl)-3 ,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (95 mg, 0.18 mmol) was dissolved in MeOH (2 mL) and 2 N HCl in Et ₂ O (10 mL) was added. The reaction was allowed to proceed for 3 h. The resulting precipitate was collected by filtration and washed with Et ₂ O to provide the title compound (45 mg, 50%) as a pale yellow solid: mp 318-323 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.95 (d, J= 8.2 Hz, 2H), 7.84 (d, J= 8.2 Hz, 2H), 7.81 (d, J = 7.1 Hz, IH), 7.63 (d, J= 8.3 Hz, IH), 7.57 (s, IH), 7.14 (dd, J= 8.3, 1.3 Hz, IH), 6.96 (d, J= 1.6 Hz, IH), 6.87 (dd, J= 7.1, 1.7 Hz, IH), 4.50 (s, 2H), 3.76 (s, 3H), 3.68 (t, J= 6.1

Attorney's Docket 2882.023B

Hz, 2H), 3.22 (t, J= 6.1 Hz, 2H); ESI MS m/z 424 [M + H] ⁺ ; HPLC (Method B) 97.6% (AUC), t _R = 13.9 min.

Example 11

Preparation of 4-(4-Chlorophenyl)- 1 -(5-methyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-& ^" |indol-

7-yl)pyridin-2( lHVone dihydrochloride

a) 4-(4-Chlorophenyl)pyridine 1 -oxide

Beilstein Registry Number 5510914

Chemical Formula: C ₁₁ H ₈ ClNO

Exact Mass: 205.03 Molecular Weight: 205.64

4-Chloropyridine-iV-oxide (1.5 g, 12 mmol), 4-chlorophenylboronic acid (2.7 g, 17 mmol) and K ₂ CO ₃ (4.78 g, 34.6 mmol) were suspended in DMSO (15 mL) and [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl ₂ (dppf)) (225 mg, 0.276 mmol) was added. The reaction mixture was placed under vacuum for 20 min and then flushed with N ₂ . This process was repeated, and the reaction mixture was heated to 120 ⁰ C for 3 h, cooled and partitioned between ethyl acetate and brine. The aqueous phase was removed, and the organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 then 25:75 followed by methylene chloride/MeOH 100:0 to 95:5 then 90:10) provided the title compound (1.05 g, 44%) as a grey solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.26 (d, J= 7.1 Hz, 2H), 7.58-7.43 (m, 6H).

b) 4-(4-Chlorophenyl)pyridin-2( lH)-one

Chemical Formula: C ₁₁ H ₈ ClNO

Exact Mass: 205.03 Molecular Weight: 205.64

Attorney's Docket 2882.023B

4-(4-Chlorophenyl)pyridine 1 -oxide (1.04 g, 5.07 mmol) and acetic anhydride (25 rnL) were heated to reflux for 24 h. The mixture was then concentrated, and 1 N NaOH (10 rnL) in MeOH (10 mL) was added. The reaction mixture was heated to reflux for 1 h, then cooled, concentrated, and purified by flash column chromatography (silica gel, methylene chloride/MeOH 100:0 to 98:2 to 95:5 then 90:10) providing the title compound (500 mg, 48%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 11.64 (s, IH), 7.73 (d, J= 8.6 Hz, 2H), 7.54 (d, J= 8.6 Hz, 2H), 7.46 (d, J= 6.8 Hz, IH), 6.60 (d, J= 1.4 Hz, IH), 6.50 (dd, J= 6.9, 1.8 Hz, IH).

c) tert-Butyl 7-(4-(4-chlorophenyl)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-di hydro-lH- pyrido[4,3-δ]indole-2(5H)-carboxylate

The compound was prepared from tert-Butyl 7-bromo-5-methyl-3,4-dihydro-lH- pyrido[4,3-6]indole-2(5H)-carboxylate (250 mg, 0.685 mmol) and 4-(4- chlorophenyl)pyridine-2(lH)-one (100 mg, 0.418 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (59 mg, 18%) as a solid, that contained an impurity: ESI MS m/z 490 [M + H] ⁺ .

d) 4-(4-Chlorophenyl)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[ 4,3-δ]indol-7-yl)pyridin- 2(lH)-one dihydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₃ H ₂₂ Cl ₃ N ₃ O

Exact Mass: 461.08 Molecular Weight: 462.80 tert-Butyl 7-(4-(4-chlorophenyl)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-di hydro-l/f- pyrido[4,3-δ]indole-2(5H)-carboxylate (59 mg, 0.12 mmol) was dissolved in MeOH (0.5 niL) and 2 N HCl in Et ₂ O (3 niL) was added. The reaction was allowed to proceed for 3 h. The mixture was concentrated and purified by preparative HPLC. Conversion to the HCl salt (2 N HCl in Et ₂ O) provided the title compound (22 mg, 40%) as a pale yellow solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.80-7.78 (m, 3H), 7.66 (d, J= 8.5 Hz, IH), 7.58-7.57 (m, 3H), 7.16 (dd, J= 8.3, 1.7 Hz, IH), 6.94 (d, J= 1.8 Hz, IH), 6.87 (dd, J= 7.1, 1.9 Hz, IH), 6.17 (d, J= 2.7 Hz, IH), 4.53 (s, 2H), 3.79 (s, 3H), 3.72 (t, J= 5.9 Hz, 2H), 3.25 (t, J= 5.9 Hz, 2H); ESI MS m/z 390 [M + H] ⁺ ; HPLC (Method B) 98.2% (AUC), t _R = 16.3 min.

Example 12

Preparation of 4-(2,4-DichlorophenyD- 1 -(5-methyl-2,3 ,4,5-tetrahydro- lH-pyrido| ^" 4,3-

&1indol-7-yl)pyridin-2(lH)-one dihydrochloride

a) tert-Butyl 7-(4-(2,4-dichlorophenyl)-2-oxopyridin-l(2H)-yl)-5-methyl-3, 4-dihydro-lH- pyrido[4,3-δ]indole-2(5H)-carboxylate

The compound was prepared from tert-butyl 7-bromo-5-methyl-3,4-dihydro-lH- pyrido[4,3-6]indole-2(5H)-carboxylate (200 mg, 0.548 mmol) and 4-(2,4- dichlorophenyl)pyridine-2(lH)-one (132 mg, 0.548 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel,

Attorney's Docket 2882.023B hexanes/EtOAc, 100:0 to 80:20 to 50:50 then 25:75) provided the title compound (56 mg, 20%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.56-7.52 (m, 2H), 7.47 (d, J= 7.0 Hz, IH), 7.39-7.32 (m, 3H), 7.10 (br s, IH), 6.69 (s, IH), 6.35 (d, J= 5.7 Hz, IH), 4.66 (s, 2H), 3.85 (br s, 2H), 3.65 (s, 3H), 2.84 (br s, 2H), 1.51 (s, 9H).

b) 4-(2,4-Dichlorophenyl)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyr ido[4,3-δ]indol-7- yl)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₃ H ₂₁ Cl ₄ N ₃ O

Exact Mass: 495.04 Molecular Weight: 497.24 tert-Butyi 7-(4-(2,4-dichlorophenyl)-2-oxopyridin-l(2H)-yl)-5-methyl-3, 4-dihydro- lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (56 mg, 0.11 mmol) was dissolved in MeOH (1 mL) and 2 N HCl in Et ₂ O (5 mL) was added. The reaction was allowed to proceed for 3 h. The mixture was concentrated and purified by preparative ηPLC. Conversion to the HCl salt (2 N HCl in Et ₂ O) provided the title compound (22 mg, 42%) as a yellow solid: mp 321-324 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.80 (d, J= 7.0 Hz, IH), 7.70 (s, IH), 7.68 (d, J= 7.9 Hz, IH), 7.62 (s, IH), 7.54 (s, 2H), 7.13 (d, J= 7.0 Hz, IH), 6.73 (s, IH), 6.61 (d, J= 7.2 Hz, IH), 4.54 (s, 2H), 3.80 (s, 3H), 3.72 (t, J= 6.0 Hz, 2H), 3.26 (t, J= 5.9 Hz, 2H); ESI MS m/z 424 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 14.1 min.

Example 13

Preparation of 4-(Benzyloxy)- 1 -(5-methyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-& ^" |indol-8- yl)pyridin-2(lH)-one hydrochloride

a) tert-Butyl 8-bromo-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylat e

Chemical Formula: C ₁₆ H ₁₉ BrN ₂ O ₂ Exact Mass: 350.0630 Molecular Weight: 351.2383

Attorney's Docket 2882.023B

To a mixture of 4-bromophenylhydryzine hydrochloride (1.00 g, 4.47 mmol) and tert-butyl 4-oxopiperidine-l-carboxylate (0.89 g, 4.5 mmol) were added EtOH (10 mL) and cone. HCl (3 mL). The reaction mixture was heated to 90 ⁰ C and stirred at 90 ⁰ C until the reaction was complete. Then the mixture was concentrated and the residue was dissolved in CH ₂ Cl ₂ (10 mL) and CH3OH (5 mL). To the above solution were added BoC ₂ O (1.46 g, 6.69 mmol), TEA (0.94 mL, 6.7 mmol) and DMAP (55 mg, 0.45 mmol). The reaction mixture was stirred at room temperature until it was complete. The mixture was concentrated and the residue was dissolved in CH ₂ Cl ₂ , washed with H ₂ O and brine, dried with Na ₂ SO ₄ , filtered and concentrated. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 1 :1) gave the title compound (1.12 g, 72%) as a yellow foam: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.89 (br s, IH), 7.57 (s, IH), 7.17-7.24 (m, 2H), 4.58 (s, 2H), 3.81 (m, 2H), 2.83 (m, 2H), 1.5 (s, 9H); ESI MS m/z 351 [M + H] ⁺ .

b) tert-Butyl 8-4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-dihydro- lH- pyrido[4,3-δ]indole-2-(5H)-carboxylate

Chemical Formula: C ₂₉ H ₃₁ N ₃ O ₄ Exact Mass: 485.2315 Molecular Weight: 485.5741

To a solution of tert-butyl 8-bromo-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)- carboxylate (0.53g, 1.5 mmol) in DMF (6 mL) was added NaH (60% weight dispersion in mineral oil, 91 mg, 2.3 mmol) and CH3I (0.14 mL, 2.3 mmol). The reaction mixture was stirred at room temperature until the reaction was complete. Then the reaction was quenched with H ₂ O and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and 5% LiCl, dried WkIi Na ₂ SO ₄ , filtered and concentrated to give tert-butyl 8-bromo-5- methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate , which was used directly without purification.

To a mixture of tert-butyl 8-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole- 2(5H)-carboxylate (0.48 g, 1.3 mmol), 4-(benzyloxy)pyridin-2(lH)-one (264 mg, 1.31 mmol), 8-hydroxyquinoline (29 mg, 0.20 mmol), K ₂ CO ₃ (217 mg, 1.57 mmol) and CuI (38

Attorney's Docket 2882.023B mg, 0.20 mmol) was added DMSO (5 mL). The reaction mixture was degassed and backfilled with N ₂ . The reaction mixture was heated to 130 ⁰ C and stirred at 130 ⁰ C overnight. After it was cooled, the mixture was filtered through a layer of Celite. The filtrate was diluted with CH ₂ Cl ₂ , washed with H ₂ O and 5% LiCl, dried with Na ₂ SO ₄ , filtered, and concentrated. Purification by flash column chromatography (silica gel, 5% CH ₃ OH in CH ₂ Cl ₂ ) gave the title compound (0.28 g, 44%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.36-7.29 (m, 8H), 7.13 (d, J= 8.0 Hz, IH), 6.09 (d, J= 2.0 Hz, IH), 6.03 (dd, J = 7.5, 2.0 Hz, IH), 5.05 (s, 2H), 4.61 (s, 2H), 3.84 (m, 2H), 3.66 (s, 3H), 2.82 (m, 2H), 1.49 (s, 9H); ESI MS m/z 486 [M + H] ⁺ .

c) 4-(Benzyloxy)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-Î ´]indol-8-yl)pyridin- 2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₄ ClN ₃ O ₂

Exact Mass: 421.16 Molecular Weight: 421.92

To a solution of tert-butyi 8-4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4- dihydro-lH-pyrido[4,3-6]indole-2-(5H)-carboxylate (180 mg, 0.37 mmol) in CH ₃ OH (2 mL) was added 1 N HCl in Et ₂ O (2 mL). The reaction mixture was stirred at room temperature until the reaction was complete. The resulting solid was dried under vacumn to give the title compound (142 mg, 91%) as a yellow solid: mp 280-285 ⁰ C (decompose); ¹ H NMR (500 MHz, CD ₃ OD) δ 7.59 (d, J= 7.5 Hz, IH), 7.54 (d, J= 9.0 Hz, IH), 7.48- 7.40 (m, 5H), 7.38-7.36 (m, IH), 7.17 (dd, J= 8.5, 1.5 Hz, IH), 6.33 (dd, J= 7.5, 2.5 Hz, IH), 6.16 (d, J = 2.5 Hz, IH), 5.20 (s, 2H), 4.45 (s, 2H), 3.77 (s, 3H), 3.67 (t, J = 6.0 Hz, 2H), 3.21 (t, J= 6.0 Hz, 2H); ESI MS m/z 386 [M + H] ⁺ ; HPLC (Method B) 98.8% (AUC), t _R = 12.9 min.

Example 14

Preparation of 4-(Benzyloxy)- 1 -(2,5-dimethyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-&]indol-8- yl)pyridin-2(lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₅ H ₂₆ ClN ₃ O ₂

Exact Mass: 435.17 Molecular Weight: 435.95

To a solution of 4-(benzyloxy)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3- 6]indol-8-yl)pyridin-2(lH)-one (100 mg, 0.26 mmol) in CH ₃ OH (3 niL) was added formaldehyde (30 μL, 0.29 mmol) and NaBH(OAc) ₃ (110 mg, 0.52 mmol). The reaction mixture was stirred at room temperature until the reaction was complete. Then the mixture was concentrated and the residue was dissolved in CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and 5% LiCl, dried with Na ₂ SO ₄ , filtered and concentrated. Purification by flash column chromatography (silica gel, 10% CH ₃ OH in CH ₂ Cl ₂ ) gave 4-(benzyloxy)-l-(2,5- dimethyl-2,3,4,5-tetrahydro-l/f-pyrido[4,3-δ]indol-8-yl)pyr idin-2(lH)-one (102 mg, 98%) as a yellow solid. The free base was converted to the HCl salt to give the title compound (100 mg, 90%) as a yellow solid: mp 264-268 ⁰ C (decompose); ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 10.26 (s, IH), 7.56-7.36 (m, 8H), 7.10 (dd, J= 8.5, 1.5 Hz, IH), 6.10 (dd, J = 7.5, 3.0 Hz, IH), 5.97 (d, J= 3.0 Hz, IH), 5.15 (s, 2H), 4.58 (m, IH), 4.27 (m, IH), 3.78 (m, IH), 3.72 (s, 3H), 3.50 (m, IH), 3.18 (m, 2H), 2.97 (s, 3H); ESI MS m/z 400 [M + H] ⁺ ; HPLC (Method B) > 99% (AUC), t _R = 12.9 min.

Example 15

Preparation of 2-(Pyrrolidin- 1 -yl)ethyl-7-4-(benzyloxy)-2-oxopyridin- 1 (2H)-5 -methyl- 3 A- dihydro- lH-pyridor4,3-& ^" |indole-2(5H)-carboxylate hydrochloride

Attorney's Docket 2882.023B

To a solution of 4-benzyloxy-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3- 6]indol-7-yl)pyridin-2(lH)-one hydrochloride (100 mg, 0.24 mmol) in DMSO (2 mL) was added l-(2-chloroethyl)pyrrolidine hydrochloride (53 mg, 0.29 mmol) and CS2CO3 (313 mg, 1.06 mmol). The reaction mixture was stirred at room temperature under Ar until the reaction was complete. The reaction was quenched with water and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and 5% LiCl, dried with Na ₂ SO ₄ , filtered, and concentrated. Purification by flash column chromatography (silica gel, 5% CH ₃ OH in CH ₂ Cl ₂ ) gave 2-(pyrrolidin- 1 -yl)ethyl-7-4-(benzyloxy)-2-oxopyridin- 1 (2H)-5-methyl-3 ,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (56 mg, 44%) as a yellow foam. The free base was converted to the HCl salt to give the title compound (44 mg, 73%) as a yellow solid: mp 95-97 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.78-7.75 (m, IH), 7.57-7.54 (m, IH), 7.49-7.37 (m, 6H), 7.04-7.01 (m, IH), 6.55-6.52 (m, IH), 6.33-6.31 (m, IH), 5.26 (s, 2H), 4.80-4.73 (m, 2H), 4.49-4.48 (m, 2H), 3.94-3.93 (m, 2H), 3.82-3.72 (m, 2H), 3.69 (s, 3H), 3.58-3.57 (m, 2H), 3.20-3.14 (m, 2H), 2.98-2.94 (m, 2H), 2.15-1.99 (m, 4H); ESI MS m/z 527 [M + H] ⁺ ; HPLC (Method B) > 99 % (AUC), t _R = 13.8 min.

Example 16

Preparation of 4-(Benzyloxy)-l-(2-(2-(dimethylamino)acetyl)-5-methyl-2,3,4, 5-tetrahydro- lH-pyridor4,3-άlindol-7-yl)pyridin-2(lH)-one hydrochloride

To a solution of 4-benzyloxy-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3- 6]indol-7-yl)pyridin-2(lH)-one (100 mg, 0.26 mmol) in CH ₂ Cl ₂ (2 mL) was added 2- chloroacetyl chloride (29 μL, 0.36 mmol) and Et ₃ N (0.1 mL, 0.7 mmol). The reaction mixture was stirred at room temperature until the reaction was complete. After the solvent was removed, the residue was dissolved in DMF. To the DMF solution was added

Attorney's Docket 2882.023B

(CHs) ₂ NH (64 μL, 1.2 mmol) and K2CO3 (166 mg, 1.2 mmol). The reaction mixture was heated to 70 ⁰ C and stirred at 70 ⁰ C until the reaction was complete. After it was cooled, the reaction was quenched with water and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and 5% LiCl, dried with Na ₂ SO ₄ , filtered, and concentrated. Purification by flash column chromatography (silica gel, 10% CH3OH in CH ₂ Cl ₂ ) gave 4-(benzyloxy)- l-(2-(2-(dimethylamino)acetyl)-5-methyl-2,3,4,5-tetrahydro-l H-pyrido[4,3-δ]indol-7- yl)pyridin-2(lH)-one (58 mg, 51%) as a yellow foam. The free base was converted to the HCl salt to give the title compound (31 mg, 50%) as a yellow solid and as a mixture of rotamers: mp 135-140 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.75-7.71 (m, IH), 7.59-7.55 (m, IH), 7.49-7.37 (m, 6H), 7.05-7.01 (m, IH), 6.49-6.45 (m, IH), 6.28-6.26 (m, IH), 5.24 (s, 2H), 4.87 (br s, IH), 4.69 (br s, IH), 4.44^1.41 (m, 2H), 4.11-4.07 (m, IH), 3.85- 3.82 (m, IH), 3.70 (2 x s, 3H), 3.06-2.92 (m, 2H), 2.97-2.94 (2 x s, 6H); ESI MS m/z All [M + H] ⁺ ; HPLC (Method B) 97.0 % (AUC), to = 13.2 min.

Example 17

Preparation of 4-(Benzyloxy)- 1 -(5-methyl-2-(2-oxo-2-(pyrrolidin- 1 -yl)ethyl)-2, 3,4,5- tetrahvdro-lH-pyridor4,3-άlindol-7-yl)pyridine-2(lH)-one hydrochloride

Chemical Formula: C ₃₀ H ₃₃ ClN ₄ O ₃

Exact Mass: 532.22 Molecular Weight: 533.06

To a solution of 4-benzyloxy-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3- 6]indol-7-yl)pyridin-2(lH)-one (100 mg, 0.26 mmol) in DMF (3 mL) was added 2-chloro- l-(pyrrolidin-l-yl)ethanone (77 mg, 0.52 mmol) and K ₂ CO ₃ (72 mg, 0.52 mmol). The reaction mixture was heated to 70 ⁰ C and stirred at 70 ⁰ C until the reaction was complete. After it was cooled, the reaction was quenched with water and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and 5% LiCl, dried with Na ₂ SO ₄ , filtered, and

Attorney's Docket 2882.023B concentrated. Purification by flash column chromatography (silica gel, 5% CH ₃ OH in CH ₂ Cl ₂ ) gave 4-(benzyloxy)- 1 -(5-methyl-2-(2-oxo-2-(pyrrolidin- 1 -yl)ethyl)-2,3,4,5- tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)pyridine-2(lH)-one (35 mg, 27%) as a yellow foam. The free base was converted to the HCl salt to the give title compound (30 mg, 80%) as a yellow solid: mp 162-166 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.60 (d, J= 7.5 Hz, IH), 7.56 (d, J= 8.0 Hz, IH), 7.49-7.35 (m, 6H), 7.06 (dd, J= 8.5, 1.5 Hz, IH), 6.33 (dd, J= 7.5, 3.0 Hz, IH), 6.16 (d, J= 3.0 Hz, IH), 5.20 (s, 2H), 4.80 (d, J= 14.5 Hz, IH), 4.54 (d, J= 14.5 Hz, IH), 4.36 (s, 2H), 4.00-3.98 (m, IH), 3.75 (s, 3H), 3.68-3.65 (m, IH), 3.54 (t, J= 7.0 Hz, 2H), 3.49-3.45 (m, 2H), 3.35-3.33 (m, 2H), 2.05-1.92 (m, 4H); ESI MS m/z 497 [M + H] ⁺ ; HPLC (Method B) 97.9 % (AUC), t _R = 13.4 min.

Example 18

Preparation of 4-(Benzyloxy)- 1 -(5-methyl-2-(3-(pyrrolidin- 1 -yPpropano yl)-2, 3,4,5- tetrahvdro-lH-pyridor4,3-άlindol-7-yl)pyridine-2(lH)-one hydrochloride

To a solution of 4-benzyloxy-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3- 6]indol-7-yl)pyridin-2(lH)-one (100 mg, 0.26 mmol) in DMF (3 mL) was added 0-(7- azabenzotriazol-l-yl)-N,N,NW-tetramethyluronium hexafluorophosphate (ηATU) (148 mg, 0.389 mmol), 3-(pyrrolidin-l-yl)propanoic acid hydrochloride (56 mg, 0.31 mmol), and Et ₃ N (73 μL, 0.52 mmol). The reaction mixture was stirred at room temperature under Ar until the reaction was complete. The reaction was quenched with water and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and 5% LiCl, dried with Na ₂ SO ₄ , filtered and concentrated. Purification by flash column chromatography (silica gel, 5% CH ₃ OH in CH ₂ Cl ₂ ) gave 4-(benzyloxy)-l-(5-methyl-2-(3-(pyrrolidin-l-yl)propanoyl)- 2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)pyridine-2(lH )-one as a yellow foam. The

Attorney's Docket 2882.023B free base was converted to the HCl salt to give the title compound (75 mg, 86%) as a yellow solid: mp 110-115 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.79-7.76 (m, IH), 7.61- 7.55 (m, IH), 7.49-7.36 (m, 6H), 7.05-7.02 (m, IH), 6.55-6.52 (m, IH), 6.33-6.32 (m, IH), 5.26 (s, 2H), 4.06 (t, J= 5.5 Hz, IH), 3.94 (t, J= 5.5 Hz, IH), 3.70-3.69 (m, 5H), 3.54-3.50 (m, 2H), 3.18-2.89 (m, 8H), 2.18-2.04 (m, 4H); ESI MS m/z 511 [M + H] ⁺ ; HPLC (Method B) 97.7 % (AUC), t _R = 13.6 min.

Example 19

Preparation of 4-(Benzyloxy)-l-(5-methyl-2-(pyrrolidine-3-carbonyl)-2,3,4,5 -tetrahydro- lH-pyridor4,3-άlindol-7-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₉ H ₃₁ ClN ₄ O ₃

Exact Mass: 518.21 Molecular Weight: 519.03

Following the procedure of Example 18, but substituting \-{tert- butoxycarbonyl)pyrrolidine-3-carboxylic acid for 3-(pyrrolidin-l-yl)propanoic acid hydrochloride, a yellow solid was obtained in 78% yield (118 mg). The yellow solid was dissolved in CH ₃ OH (3 mL) and was treated with 1 N HCl in Et ₂ O (2 mL). The resulting solid was isolated by filtration and dried under vacuum to give the title compound (90 mg, 90%) as a green-yellow powder: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.75-7.72 (m, IH), 7.63-7.55 (m, IH), 7.49-7.36 (m, 6H), 7.05-7.02 (m, IH), 6.51-6.46 (m, IH), 6.29-6.27 (m, IH), 5.25 (s, 2H), 4.79-4.76 (m, 2H), 4.14-3.97 (m, 2H), 3.87-3.82 (m, IH), 3.71- 3.69 (m, 4H), 3.60-3.50 (m, IH), 3.45-3.36 (m, 3H), 3.04-3.03 (m, IH), 2.94-2.92 (m, IH), 2.52-2.36 (m, IH), 2.18-2.00 (m, IH); ESI MS m/z 483 [M + H] ⁺ ; HPLC (Method B) 98.1 % (AUC), t _R = 13.2 min.

Example 20

Attorney's Docket 2882.023B

Preparation of (7?)-4-(Benzylo xy)-l-(5-methyl-2-(pyrrolidine-2-carbonyl)-2, 3,4,5- tetrahvdro-lH-pyridor4,3-άlindol-7-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₉ H ₃₁ CDST ₄ O ₃

Exact Mass : 518.21 Molecular Weight: 519.03

Following the procedure of Example 19, but substituting (R)-l-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid for l-(te/t-butoxycarbonyl)pyrrolidine-3- carboxylic acid, the title compound (67 mg, 50%) was obtained as a yellow solid and as a mixture of rotamers: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.82-7.79 (m, IH), 7.66-7.56 (m, IH), 7.49-7.36 (m, 6H), 7.07-7.03 (m, IH), 6.59-6.56 (m, IH), 6.36 (dd, J= 5.0, 2.5 Hz, IH), 5.28 (s, 2H), 4.82-4.81 (m, 2H), 4.14-4.05 (m, IH), 3.97-3.95 (m, IH), 3.71-3.69 (2 x s, 3H), 3.58-3.34 (m, 3H), 3.07-2.94 (m, 2H), 2.70-2.57 (m, IH), 2.17-1.85 (m, 3H); ESI MS m/z 483 [M + H] ⁺ ; HPLC (Method B) >99 % (AUC), t _R = 13.3 min.

Example 21

Preparation of (61-4-(Benzyloxy)- 1 -(5-methyl-2-(pyrrolidine-2-carbonyl)-2, 3,4,5- tetrahvdro-lH-pyridor4,3-άlindol-7-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₉ H ₃₁ ClN ₄ O ₃

Exact Mass: 518.21 Molecular Weight: 519.03

Following the procedure of Example 20, but substituting (S)-\-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid for (i?)-l-(te/t-butoxycarbonyl)pyrrolidine- 2-carboxylic acid, the title compound (47 mg, 72%) was obtained as a yellow solid and as

Attorney's Docket 2882.023B a mixture of rotamers: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.82-7.79 (m, IH), 7.66-7.56 (m, IH), 7.49-7.36 (m, 6H), 7.07-7.03 (m, IH), 6.59-6.56 (m, IH), 6.36 (dd, J= 5.0, 2.5 Hz, IH), 5.28 (s, 2H), 4.82-4.81 (m, 2H), 4.14-4.05 (m, IH), 3.97-3.95 (m, IH), 3.71-3.69 (2 x s, 3H), 3.58-3.34 (m, 3H), 3.07-2.94 (m, 2H), 2.70-2.57 (m, IH), 2.17-1.85 (m, 3H); ESI MS m/z 483 [M + H] ⁺ ; HPLC (Method B) >99 % (AUC), ^ = 13.3 min.

Example 22

Preparation of 4-(Benzyloxy)-l -(5-methyl-2-(l-methylpyrrolidine-3-carbonyl)-2, 3,4,5- tetrahydro-lH-pyrido[4,3-^lindol-7-yl)pyridin-2(lH)-one hydrochloride

To a solution of 4-(benzyloxy)-l-(5-methyl-2-(pyrrolidine-3-carbonyl)-2, 3,4,5- tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)pyridin-2(lH)-one hydrochloride (105 mg, 0.197 mmol) in CH ₃ OH (3 mL) was added Et ₃ N (40 μL, 0.29 mmol), formaldehyde (23 μL, 0.29 mmol), and NaBH(OAc) ₃ (86 mg, 0.41 mmol). The reaction mixture was stirred at room temperature until the reaction was complete. Then the mixture was concentrated and the residue was dissolved in CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and 5% LiCl, dried with Na ₂ SO ₄ , filtered and concentrated. Purification by flash column chromatography (silica gel, 10% CH ₃ OH in CH ₂ Cl ₂ ) gave 4-(benzyloxy)-l-(5-methyl-2-(l- methylpyrrolidine-3-carbonyl)-2,3,4,5-tetrahydro-lH-pyrido[4 ,3-δ]indol-7-yl)pyridin- 2(lH)-one (60 mg, 60%) as a yellow solid. The free base was converted to the HCl salt to give the title compound (43 mg, 80%) as a yellow solid and as a mixture of rotamers: mp 132-136 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.61-7.33 (m, 8H), 7.02-6.98 (m, IH), 6.29- 6.27 (m, IH), 6.12-6.11 (m, IH), 5.17 (s, 2H), 4.79-4.76 (m, 2H), 4.09-3.97 (m, 2H), 3.81-3.79 (m, IH), 3.69-3.67 (m, 4H), 3.49-3.42 (m, IH), 3.22-3.16 (m, 2H), 3.00 (m,

Attorney's Docket 2882.023B

IH), 2.92-2.91 (m, IH), 2.81-2.78 (2 x s, 3H), 2.52-2.36 (m, IH), 2.18-2.00 (m, IH); ESI MS m/z 497 [M + H] ⁺ ; HPLC (Method B) 98.7 % (AUC), t _R = 13.6 min.

Example 23

Preparation of (i?)-4-(Benzyloxy)- l-(5-methyl-2-(l -methylpyrro lidine-2-carbonyl)-2, 3,4,5- tetrahydro-lH-pyrido[4,3-&lindol-7-yl)pyridin-2(lH)-one hydrochloride

CH ₃

Chemical Formula: C ₃₀ H ₃₃ ClN ₄ O ₃

Exact Mass: 532.22 " ^HC1 Molecular Weight: 533.06

Following the procedure of Example 22, but substituting (i?)-4-(benzyloxy)-l-(5- methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,5-tetrahydro-lH-pyri do[4,3-δ]indol-7-yl)pyridin- 2(lH)-one hydrochloride for 4-(benzyloxy)-l-(5-methyl-2-(pyrrolidine-3-carbonyl)- 2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)pyridin-2(lH) -one hydrochloride, the title compound (80 mg, 67%) was obtained as a yellow solid and as a mixture of rotamers: mp 158-162 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.61-7.33 (m, 8H), 7.03-6.99 (m, IH), 6.30 (dd, J= 7.5, 2.5 Hz, IH), 6.13 (d, J= 2.5 Hz, IH), 5.18 (s, 2H), 4.80-4.70 (m, 2H), 4.12- 4.09 (m, IH), 3.92-3.90 (m, IH), 3.78-3.72 (m, IH), 3.69-3.68 (2s, 3H), 3.49-3.42 (m, IH), 3.28-3.20 (m, IH), 3.07-3.00 (m, 2H), 2.96-2.94 (2s, 3H), 2.79-2.65 (m, IH), 2.21- 2.09 (m, IH), 2.09-1.86 (m, 2H); ESI MS m/z 497 [M + H] ⁺ ; HPLC (Method B) > 99 % (AUC), t _R = 13.4 min.

Example 24

Preparation of (61-4-(Benzyloxy)- l-(5-methyl-2-(l -methylpyrro lidine-2-carbonyl)-2, 3,4,5- tetrahvdro-lH-pyrido[4,3-ά1indol-7-yl)pyridin-2(lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₃₀ H ₃₃ ClN ₄ O ₃

Exact Mass: 532.22 Molecular Weight: 533.06

Following the procedure of Example 22, but substituting (5)-4-(benzyloxy)-l-(5- methyl-2-(pyrrolidine-2-carbonyl)-2,3,4,5-tetrahydro-lH-pyri do[4,3-δ]indol-7-yl)pyridin- 2(lH)-one hydrochloride for 4-(benzyloxy)-l-(5-methyl-2-(pyrrolidine-3-carbonyl)- 2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)pyridin-2(lH) -one hydrochloride, the title compound (40 mg, 61%) was obtained as a yellow solid and as a mixture of rotamers: mp 154-160 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.61-7.33 (m, 8H), 7.03-6.99 (m, IH), 6.30 (dd, J= 7.5, 2.5 Hz, IH), 6.13 (d, J= 2.5 Hz, IH), 5.18 (s, 2H), 4.80-4.70 (m, 2H), 4.12- 4.09 (m, IH), 3.92-3.90 (m, IH), 3.78-3.72 (m, IH), 3.69-3.68 (2s, 3H), 3.49-3.42 (m, IH), 3.28-3.20 (m, IH), 3.07-3.00 (m, 2H), 2.96-2.94 (2 x s, 3H), 2.79-2.65 (m, IH), 2.21-2.09 (m, IH), 2.09-1.86 (m, 2H); ESI MS m/z 497 [M + H] ⁺ ; HPLC (Method B) 98.9 % (AUC), to = 13.3 min.

Example 25

Preparation of l-(2.5-Dimethyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-y l)-4-(4- fluorophenyl)pyridine-2( lHVone hydrochloride

a) tert-Butyl 5-methyl-7-(2-oxo-4-(trifluoromethylsulfonyloxy)pyridine-l(2 H)-yl)3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

Boc

Chemical Formula: C ₂₃ H ₂₄ F ₃ N ₃ O ₆ S

Exact Mass: 527.13 Molecular Weight: 527.51

Attorney's Docket 2882.023B

To a solution of tert-butyl 7-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4- dihydro-lH-pyrido[4,3-6]indole-2(5H)-carboxylate (0.98g, 2.0 mmol) in CH ₃ OH (30 mL) was added 5% Pd/C (0.3g) and ammonium formate (0.32g, 5 mmol) under Ar atmosphere. The reaction mixture was heated to 9O ⁰ C and stirred at 9O ⁰ C until the reaction was complete. After it was cooled, the reaction mixture was filtered through a layer of Celite. The solvent was concentrated to give tert-butyl 7-(4-hydroxy-2-oxopyridin-l(2H)-yl)-5- methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate , which was used directly without purification.

To a solution of tert-butyl 7-(4-hydroxy-2-oxopyridin-l(2H)-yl)-5-methyl-3,4- dihydro-lH-pyrido[4,3-6]indole-2(5H)-carboxylate (800 mg, 2.02 mmol) in TηF (10 mL) was added LiN(SiMe ₃ ) ₂ (2.6 mL, 2.6 mmol) followed by PhN(Tf) ₂ (0.94g, 2.6 mmol) under Ar atmosphere. The reaction mixture was stirred at room temperature until the reaction was complete. Then the mixture was concentrated and the residue was purified by flash column chromatography (silica gel, hexanes/EtOAc, 1 :1) to give the title compound (0.42 g, 40%) as a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.57-7.53 (m, 2H), 7.30 (d, J= 1.5 Hz, IH), 7.02-6.99 (m, IH), 6.60 (d, J= 2.7 Hz, IH), 6.27 (dd, J= 7.8, 2.7 Hz, IH), 4.65 (s, 2H), 3.85 (m, 2H), 3.65 (s, 3H), 2.84 (m, 2H), 1.51 (s, 9H); ESI MS m/z 528 [M + H] ⁺ .

b) l-(2,5-Dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7- yl)-4-(4- fluorophenyl)pyridine-2( lH)-one hydrochloride

CH,

Chemical Formula: C ₂₄ H ₂₃ ClFN ₃ O

Exact Mass: 423.15 Molecular Weight: 423.91

To a solution of tert-butyl 5-methyl-7-(2-oxo-4-(trifluloromethylsulfonyloxy) pyridine-l-(2H)-yl)3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H) -carboxylate (100 mg, 0.19 mmol) in DMSO (2 mL) was added 4-fluorophenylboronic acid (66 mg, 0.48 mmol), K ₂ CO ₃ (66 mg, 0.48 mmol), and PdCl ₂ (dppf) (14 mg, 0.019 mmol). The reaction mixture

Attorney's Docket 2882.023B was degassed, then back-filled with N ₂ . The reaction mixture was stirred at 80 ⁰ C in a preheated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and 5% LiCl, dried with Na ₂ SO ₄ , filtered and concentrated. Purification by flash column chromatography (silica gel, 5% CH ₃ OH in CH ₂ Cl ₂ ) gave a yellow solid (120 mg, >100%). The solid was dissolved in CH ₃ OH (2 mL) and treated with 1 N HCl in Et ₂ O (1.9 mL). The reaction mixture was stirred at room temperature until the reaction was complete. After the solvent was removed, the resulting solid was dissolved in CH ₃ OH (3 mL). Et ₃ N (40 μL), formaldehyde (22 μL, 0.29 mmol), and NaBH(OAc) ₃ were added sequentially. The reaction mixture was stirred at room temperature until the reaction was was complete. The solvent was removed and the residue was dissolved in CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and 5% LiCl, dried with Na ₂ SO ₄ , filtered and concentrated. Purification by flash column chromatography (silica gel, 5% CH ₃ OH in CH ₂ Cl ₂ ) gave l-(2,5-dimethyl- 2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)-4-(4-fluorop henyl)pyridine-2(lH)-one (37 mg 50% yield over three steps) as a yellow solid. The free base was converted to the HCl salt to give the title compound (36.5 mg, 91%) as a yellow solid: mp 276-280 ⁰ C (decompose); ¹ H NMR (500 MHz, CD ₃ OD) δ 7.82-7.79 (m, 2H), 7.75 (d, J= 7.0 Hz, IH), 7.61 (d, J= 8.5 Hz, IH), 7.56 (d, J= 1.5 Hz, IH), 7.29-7.25 (m, 2H), 7.14 (dd, J= 8.5, 1.5 Hz, IH), 6.88 (d, J= 2.0 Hz, IH), 6.82 (dd, J= 7.0, 2.0 Hz, IH), 4.77 (d, J= 14.0 Hz, IH), 4.41 (d, J= 14.0 Hz, IH), 3.93-3.90 (m, IH), 3.76 (s, 3H), 3.66-3.60 (m, IH), 3.27 (m, 2H), 3.15 (s, 3H); ESI MS m/z 388 [M + H] ⁺ ; HPLC (Method B) 98.1 % (AUC), t _R = 12.8 min.

Example 26

Preparation of l-(2.5-Dimethyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-y l)-4-(4-

(trifluoromethylphenyl)pyridin-2( lHVone hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₅ H ₂₃ ClF ₃ N ₃ O

Exact Mass: 473.15 Molecular Weight: 473.92

Following the procedure of Example 25 (step b), but substituting A- trifluoromethylphenylboronic acid for 4-fluorophenylboronic acid, the title compound (47 mg, 53%) was obtained as a yellow solid: mp 270-274 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.95 (d, J= 8.5 Hz, 2H), 7.84 (d, J= 8.5 Hz, 2H), 7.80 (d, J= 7.5 Hz, IH), 7.62 (d, J = 8.0 Hz, IH), 7.57 (d, J= 1.5 Hz, IH), 7.15 (dd, J= 8.5, 2.0 Hz, IH), 6.96 (d, J= 1.5 Hz, IH), 6.87 (dd, J= 7.5, 2.0 Hz, IH), 4.78 (d, J= 14.0 Hz, IH), 4.41 (d, J= 14.0 Hz, IH), 3.93-3.90 (m, IH), 3.77 (s, 3H), 3.66-3.60 (m, IH), 3.27 (m, 2H), 3.15 (s, 3H); ESI MS m/z 438 [M + H] ⁺ ; HPLC (Method B) >99 % (AUC), t _R = 13.8 min.

Example 27

Preparation of 4-(4-ChlorophenyP)- 1 -(2.5-dimethyl-2.3 A5-tetrahydro- lH-pyridor4.3- άlindol-7-yl)- pyridin-2(l/-/)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₃ Cl ₂ N ₃ O

Exact Mass: 439.12 Molecular Weight: 440.36

Following the procedure of Example 25 (step b), but substituting A- chlorophenylboronic acid for 4-fluorophenylboronic acid, the title compound (55 mg, 65%) was obtained as a yellow solid: mp 276-280 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.77-7.75 (m, 3H), 7.62 (d, J= 8.5 Hz, IH), 7.57 (d, J= 2.0 Hz, IH), 7.56-7.54 (m, 2H), 7.15 (dd, J= 8.5, 2.0 Hz, IH), 6.91 (d, J= 2.0 Hz, IH), 6.84 (dd, J= 7.0, 2.0 Hz, IH), 4.78 (d, J= 14.0 Hz, IH), 4.41 (d, J= 14.0 Hz, IH), 3.93-3.90 (m, IH), 3.77 (s, 3H), 3.66-3.60

Attorney's Docket 2882.023B

(m, IH), 3.27 (m, 2H), 3.15 (s, 3H); ESI MS m/z 404 [M + H] ⁺ ; HPLC (Method B) 98 % (AUC), t _R = 13.4 min.

Example 28

Preparation of 4-(4-Chloro-2-fluorophenvO- 1 -(2.5-dimethyl-2.3 A5-tetrahydro- IH- pyrido[4,3-&lindol-7-yl)- pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₂ Cl ₂ FN ₃ O

Exact Mass: 457.11 Molecular Weight: 458.36

Following the procedure of Example 25 (step b), but substituting 4-chloro-2- fluorophenylboronic acid for 4-fluorophenylboronic acid, the title compound (20 mg, 32%) was obtained as a yellow solid: mp 270-274 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.76 (d, J = 7.0 Hz, IH), 7.66-7.57 (m, 2H), 7.57 (d, J= 2.0 Hz, IH), 7.42-7.39 (m, 2H), 7.15 (dd, J = 8.5, 2.0 Hz, IH), 6.84 (s, IH), 6.73-6.71 (m, IH), 4.77 (d, J= 14.0 Hz, IH), 4.41 (d, J = 14.0 Hz, IH), 3.93-3.90 (m, IH), 3.76(s, 3H), 3.64-3.61 (m, IH), 3.27 (m, 2H), 3.15 (s, 3H); ESI MS m/z 422 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 12.9 min.

Example 29

Preparation of l-(2.5-Dimethyl-2.3.4.5-tetrahvdro-lH-pyrido[4.3-^1indol-7-y l)-4-(2- fluoro-4-methoxyphenyl)pyridin-2( lH)-one hydrochloride

Chemical Formula: C ₂₅ H ₂₅ ClFN ₃ O ₂

Exact Mass: 453.16 Molecular Weight: 453.94

Attorney's Docket 2882.023B

Following the procedure of Example 25 (step b), but substituting 2-fluoro-4- methoxyphenylboronic acid for 4-fluorophenylboronic acid, the title compound (46 mg, 53%) was obtained as a yellow solid: mp 280-282 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.72 (d, J= 7.0 Hz, IH), 7.63-7.56 (m, 3H), 7.15 (dd, J= 8.5, 1.5 Hz, IH), 6.92 (dd, J = 8.5, 2.5 Hz, IH), 6.87 (dd, J= 13.0, 2.0 Hz, IH), 6.83 (s, IH), 6.76 (d, J= 7.0 Hz, IH), 4.77 (d, J= 14.0 Hz, IH), 4.41 (d, J= 14.0 Hz, IH), 3.94-3.90 (m, IH), 3.88 (s, 3H), 3.76 (s, 3H), 3.66-3.60 (m, IH), 3.27 (m, 2H), 3.15 (s, 3H); ESI MS m/z 418 [M + H] ⁺ ; HPLC (Method B) >99 % (AUC), t _R = 12.9 min.

Example 30

Preparation of 4-(Benzyloxy)-l-(2.9-dimethyl-2.3.4.9-tetrahvdro-lH-pyridor3 .4-^1indol-7- yl)pyridin-2(lH)-one hydrochloride

a) 2-(6-Bromo- lH-indol-3-yl)ethanamine Beilstein Registry Number 6056308

Chemical Formula: C ₁₀ H _n BrN ₂ Exact Mass: 238.01 Molecular Weight: 239.1 1

3-Bromophenylhydrazine hydrochloride (20.0 g, 85.8 mmol) was reacted according to the procedure of Mascal et al. (Rinehart, Kenneth L.; Kobayashi, Jun'ichi; Harbour, Gary C; Gilmore, Jeremy; Mascal, Mark; et al. J. Am. Chem. Soc. 1987, 109, 3378-3387) to provide the title compound as a 1 :1 mixture of the 6-bromo and 7-bromo-regioisomers (13.2 g, 65%), obtained as an orange solid: ESI MS m/z 239 [M + H] ⁺ .

b) 7-Bromo-2,3,4,9-tetrahydro-lH-pyrido[3,4-6]indole Beilstein Registry Number 5935540 Chemical Formula: C ₁₁ H ₁₁ BrN ₂

Exact Mass: 250.01 Molecular Weight: 251.12

2-(6-Bromo-lH-indol-3-yl)ethanamine (13.2 g, 55.2 mmol) was reacted according to the procedure of Mascal et al. (Rinehart, Kenneth L.; Kobayashi, Jun'ichi; Harbour,

Attorney's Docket 2882.023B

Gary C; Gilmore, Jeremy; Mascal, Mark; et al. J Am. Chem. Soc. 1987, 109, 3378-3387) to provide the title compound as a 1 :1 mixture of the 7-bromo and 8-bromo-regioisomers (8.8 g, 63%), obtained as an orange solid: ESI MS m/z 251 [M + H] ⁺ .

c) tert-Butyi 7-bromo-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylat e Chemical Formula: C ₁₆ H ₁₉ BrN ₂ O ₂ Exact Mass: 350.06 Molecular Weight: 351.24

7-Bromo-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indole (8.81 g, 35.1 mmol, present as a mixture with the 8-bromo regioisomer) was suspended in CH ₂ Cl ₂ (100 mL) and THF (10 mL). Boc anhydride (7.83 g, 38.6 mmol) and a catalytic amount of 4- (dimethylamino)pyridine (DMAP) were added. After 24 h, the mixture was concentrated. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 70:30) separated the 7- and 8-regioisomers and gave the title compound (3.37 g, 27%) as a white powder: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.94 (br s, IH), 7.45 (d, J = 1.6 Hz, IH), 7.32 (d, J = 8.3 Hz, IH), 7.19 (dd, J= 8.3, 1.3 Hz, IH), 4.61 (br s, 2H), 3.75 (br s, 2H), 2.76 (br s, 2H), 1.50 (s, 9H).

d) tert-Butyl 7-bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-c arboxylate chemical Formula: C ₁₇ H ₂₁ BrN ₂ O ₂

Exact Mass: 364.08 Molecular Weight: 365.26 tert-Butyl 7-bromo-3,4-dihydro-lH-pyrido[3,4-6]indole-2(9H)-carboxylate (1.96 g, 5.58 mmol) was dissolved in DMF (20 mL), and sodium hydride (60% weight dispersion in mineral oil, 330 mg, 8.37 mmol) was added. After 30 minutes, methyl iodide (0.52 mL, 8.4 mmol) was added, and the reaction stirred for a further 2 h. The mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5 ^χ ), dried and concentrated. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) gave the title compound (1.75 g, 86%) as a white powder: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.41 (d, J= 1.5 Hz, IH), 7.32 (d, J= 8.3 Hz, IH), 7.18 (dd, J= 8.4, 1.6 Hz, IH), 4.60 (br s, 2H), 3.73 (br s, 2H), 3.59 (s, 3H), 2.76 (br s, 2H), 1.50 (s, 9H).

Attorney's Docket 2882.023B

e) 7-Bromo-9-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-6]indole

Chemical Formula: C ₁₂ H ₁₃ BrN ₂ Exact Mass: 264.03 Molecular Weight: 265.15 tert-Butyl-7-bromo-9-methyl-3,4-dihydro-7H-pyrido[3,4-δ]ind ole-2(9H)- carboxylate (1.75 g, 4.79 mmol) was dissolved in CH ₂ Cl ₂ (10 mL) and trifluoroacetic acid (TFA) (10 mL) was added. After stirring for 1 h, the mixture was diluted with methylene chloride (50 mL), washed with saturated Na ₂ CO ₃ solution, dried over sodium sulfate and concentrated to provide the title compound (1.24 g, 97%) as a yellow oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.41 (d, J= 1.4 Hz, IH), 7.32 (d, J= 8.3 Hz, IH), 7.17 (dd, J= 8.3, 1.4 Hz, IH), 4.01 (s, 2H), 3.55 (s, 3H), 3.15 (t, J= 6.0 Hz, 2H), 2.72 (t, J= 5.7 Hz, 2H).

f) 7-Bromo-2,9-dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]ind ole

Chemical Formula: C ₁₃ H ₁₅ BrN ₂ Exact Mass: 278.04 Molecular Weight: 279.18

7-Bromo-9-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-6]indole (1.24 g, 4.68 mmol) was dissolved in a mixture of MeOH (20 mL) and CH ₂ Cl ₂ (5 mL) and formaldehyde (0.56 mL, 37% aqueous solution) was added. After stirring for 1 h, NaBH(OAc) ₃ (1.98 g, 9.34 mmol) was added and the mixture stirred for a further 10 minutes. The mixture was diluted with methylene chloride (50 mL), washed with saturated Na ₂ CO ₃ solution, concentrated and purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) to provide the title compound (1.15 g, 88%) as a white powder: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.40 (d, J = 1.6 Hz, IH), 7.32 (d, J= 8.4 Hz, IH), 7.16 (dd, J= 8.3, 1.7 Hz, IH), 3.61 (s, 2H), 3.55 (s, 3H), 2.86-2.76 (m, 4H), 2.56 (s, 3H).

g) 4-(Benzyloxy)-l-(2,9-dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3 ,4-δ]indol-7-yl)pyridin- 2(lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₅ H ₂₆ ClN ₃ O ₂

Exact Mass: 435.17 Molecular Weight: 435.95

A stirred solution of 7-bromo-2,9-dimethyl-2,3,4,9-tetrahydro-l/f-pyrido[3,4- δ]indole (250 mg, 0.895 mmol) in DMSO (4 rnL) under nitrogen was treated sequentially with 4-(benzyloxy)pyridin-2(lH)-one (180 mg, 0.895 mmol), 8-hydroxyquinoline (20 mg, 0.14 mmol), CuI (196 mg, 1.04 mmol) and K ₂ CO ₃ (142 mg, 1.04 mmol). The mixture was placed under vacuum for 30 minutes and then flushed with nitrogen. After stirring overnight at 130 ⁰ C, the mixture was allowed to cool to room temperature, diluted with CH ₂ Cl ₂ , washed with brine, dried over Na ₂ SO ₄ and concentrated. Purification by flash column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 25 mL/min) provided the free-base. This was dissolved in methylene chloride (2 mL) and treated with 2 N HCl in Et ₂ O (1 equivalent) and the mixture was concentrated to provide the title compound (131 mg, 33%) as a yellow solid: mp 270-274 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.67-7.63 (m, 2H), 7.50-7.40 (m, 3H), 7.43-7.35 (m, 3H), 7.08 (dd, J= 8.3, 1.6 Hz, IH), 6.40 (dd, J= 7.5, 2.6 Hz, IH), 6.21 (d, J = 2.6 Hz, IH), 5.22 (s, 2H), 4.81-4.80 (m, IH), 4.58 (d, J= 15.3 Hz, IH), 3.88-3.84 (m, IH), 3.72 (s, 3H), 3.55-3.49 (m, IH), 3.21-3.16 (m, 5H); ESI MS m/z 400 [M + H] ⁺ ; HPLC (Method B) >98.9% (AUC), t _R = 13.0 min.

Example 31

Preparation of 1 -(2.9-Dimethyl-2.3A9-tetrahvdro-lH-pyrido [3.4-61indol-7-ylV4- phenethylpyridin-2( lHVone hydrochloride

a) (£)-2-Methoxy-4-styrylpyridine

Attorney's Docket 2882.023B

Chemical Formula: C ₁₄ H ₁₃ NO

Exact Mass: 21 1.10 Molecular Weight: 21 1.26

4-Bromo-2-methoxypyridine (1.85 g, 9.84 mmol), (E)-phenylvinylboronic acid (4.3 g, 30 mmol), K ₂ CO ₃ (4.0 g, 30 mmol) and PdCl ₂ (dppf) (400 mg, 0.5 mmol) were stirred in DMSO (15 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated to 90 ⁰ C for 30 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5 ^χ ), dried, concentrated, and the residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) to provide the title compound (1.93 g, 93%) as an orange oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.12 (d, J= 5.2 Hz, IH), 7.51 (m, 2H), 7.40- 7.22 (m, 4H), 7.02-6.94 (m, 2H), 6.78 (s, IH), 3.95 (s, 3H).

b) 2-Methoxy-4-phenethylpyridine

Chemical Formula: C ₁₄ H ₁₅ NO

Exact Mass: 213.12 Molecular Weight: 213.28

(E)-2-Methoxy-4-styrylpyridine (22.15 g, 104.8 mmol) was dissolved in MeOH (400 mL) and degassed with a nitrogen stream for 10 minutes. Palladium on charcoal (10%, wet, 5 g) was added and the reaction mixture was stirred under an atmosphere of hydrogen for 24 h. The reaction mixture was degassed again, and the catalyst was removed by filtration. Concentration of the filtrate provided the title compound (22 g, 98%) as a green oil: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.04 (d, J= 5.3 Hz, IH), 7.29-7.24 (m, 2H), 7.21-7.15 (m, 3H), 6.69-6.67 (m, IH), 6.54 (s, IH), 3.91 (s, 3H), 2.91-2.89 (m, 2H), 2.87-2.84 (m, 2H).

Attorney's Docket 2882.023B c) 4-Phenethylpyridin-2(lH)-one

Chemical Formula: C ₁₃ H ₁₃ NO

Exact Mass: 199.10 Molecular Weight: 199.25

2-Methoxy-4-phenethylpyridine (22.0 g, 102 mmol) was stirred in concentrated hydrochloric acid (200 rnL) at 120 ⁰ C for 18 h and then concentrated. The residue was dissolved in MeOH (100 mL) and made basic with aqueous 6 N NaOH and re- concentrated until most of the solvent had been removed. The solids were filtered off, washed with water and dried under vacuum to provide the title compound (21.3 g, 95%) as a beige solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 11.31 (br s, IH), 7.28-7.21 (m, 5H), 7.17 (t, J= 7.1 Hz, IH), 6.10-6.08 (m, 2H), 2.85-2.82 (m, 2H), 2.70-2.67 (m, 2H).

d) l-(2,9-Dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7- yl)-4-phenethylpyridin- 2(lH)-one hydrochloride

4-Phenethylpyridin-2(lH)-one (82 mg, 0.41 mmol) and 7-bromo-2,9-dimethyl- 2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indole (115 mg, 0.412 mmol) were reacted following the procedure for Example 30 (step g) to provide the title compound (54 mg, 30%) as a yellow solid: mp 299-304 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.67-7.64 (m, 2H), 7.51 (d, J= 1.8 Hz, IH), 7.30-7.24 (m, 4H), 7.20-7.17 (m, IH), 7.08 (dd, J= 8.4, 1.9 Hz, IH), 6.56 (dd, J= 6.9, 1.9 Hz, IH), 6.53 (s, IH), 4.85 (m, IH), 4.49 (d, J= 15.3 Hz, IH), 3.89- 3.84 (m, IH), 3.72 (s, 3H), 3.55-3.50 (m, IH), 3.21-3.19 (m, 2H), 3.16 (s, 3H), 3.02-2.99 (m, 2H), 2.96-2.93 (m, 2H); ESI MS m/z 398 [M + H] ⁺ ; HPLC (Method B) 98.1% (AUC), tκ = 13.5 min.

Attorney's Docket 2882.023B

Example 32

Preparation of l-(2.9-Dimethyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^1indol-7-y l)-4-(4-

(trifluoromethyl)benzyloxy)pyridin-2( lHVone hydrochloride

a) 4-(4-(Trifluoromethyl)benzyloxy)pyridine 1 -oxide

4-Trifluoromethylbenzylalcohol (4.2 g, 23 mmol) was dissolved in DMF (20 rnL) and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol) was added. After stirring for 30 minutes, 4-chloropyridine-iV-oxide (1.5 g, 11.5 mmol) was added and the reaction mixture was heated for 1 h at 120 ⁰ C. Upon cooling the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5 ^χ ), dried and concentrated. Purification by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) provided the title compound (0.6 g, 19%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.14 (d, J = 7.8 Hz, 2H), 7.68 (d, J= 8.1 Hz, 2H), 7.52 (d, J= 8.1 Hz, 2H), 6.86 (d, J= 7.8 Hz, 2H), 5.15 (s, 2H).

b) 4-(4-(Trifluoromethyl)benzyloxy)pyridin-2( lH)-one

Chemical Formula: C ₁₃ H ₁₀ F ₃ NO ₂ Exact Mass: 269.07 Molecular Weight: 269.22

4-(4-(Trifluoromethyl)benzyloxy)pyridine 1 -oxide (600 mg, 2.22 mmol) was heated to 140 ⁰ C in acetic anhydride (20 mL) for 2 h. The mixture was concentrated and then heated at 80 ⁰ C for 1 h in a mixture of MeOH (10 mL) and aqueous 1 N NaOH (1OmL). The resultant black solution was concentrated to a volume of 10 mL and extracted with CHCl ₃ ZEtOH (3:1). The organic layer was removed and concentrated to

Attorney's Docket 2882.023B provide the title compound (550 mg, 91%) as a tan solid: ¹ U NMR (300 MHz, CD ₃ OD) δ 7.70-7.60 (m, 4H), 7.41 (d, J= 7.0 Hz, IH), 6.17 (dd, J= 7.0, 2.5 Hz, IH), 5.96 (d, J= 2.4 Hz, IH), 5.18 (s, 2H).

c) l-(2,9-Dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7- yl)-4-(4- (trifluoromethyl)benzyloxy)pyridin-2( lH)-one hydrochloride

4-(4-(Trifluoromethyl)benzyloxy)pyridin-2(lH)-one (100 mg, 0.37 mmol) and 7- bromo-2,9-dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol e (103 mg, 0.47 mmol) were reacted following the procedure for Example 30 (step g) to provide the title compound (67 mg, 36%) as a light-brown solid: mp 280-285 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.78- 7.73 (m, 3H), 7.69-7.64 (m, 3H), 7.52 (d, J= 1.8 Hz, IH), 7.18-7.08 (m, IH), 6.55-6.52 (m, IH), 6.28 (d, J= 2.6 Hz, IH), 5.35 (s, 2H), 4.82-4.80 (m, IH), 4.50 (d, J= 15.4 Hz, IH), 3.89-3.85 (m, IH), 3.73 (s, 3H), 3.55-3.50 (m, IH), 3.22-3.16 (m, 5H); ESI MS m/z 468 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 14.4 min.

Example 33

Preparation of 4-(4-Chlorobenzyloxy)- 1 -(2,9-dimethyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 A-

&1indol-7-yl)pyridin-2(lH)-one hydrochloride

a) 4-(4-Chlorobenzyloxy)pyridine 1 -oxide Beilstein Registry Number 7707045

Chemical Formula: C ₁₂ H ₁₀ ClNO ₂

Exact Mass: 235.04 Molecular Weight: 235.67

Attorney's Docket 2882.023B

4-Chlorobenzylalcohol (5.0 g, 35 mmol) was dissolved in DMF (25 mL) and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol) was added. After stirring for 30 minutes, 4-chloropyridine-iV-oxide (2.27 g, 17.5 mmol) was added and the reaction mixture was heated for 1 h at 120 ⁰ C. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5 ^χ ), dried and concentrated. Purification by flash column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 25 mL/min) provided the title compound (1.9 g, 47%) as an orange solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.11 (d, J = 7.7 Hz, 2H), 7.40 (d, J= 8.6 Hz, 2H), 7.34 (d, J= 8.6 Hz, 2H), 6.86 (d, J= 7.7 Hz, 2H), 5.06 (s, 2H).

b) 4-(4-Chlorobenzyloxy)pyridin-2(lH)-one Beilstein Registry Number 7707762

Chemical Formula: C ₁₂ H ₁₀ ClNO ₂ Exact Mass: 235.04 Molecular Weight: 235.67

4-(4-Chlorobenzyloxy)pyridine 1-oxide (1.95 g, 8.24 mmol) was reacted according to the procedure of Example 32 (step b), and the crude product was purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) to provide the title compound (1.0 g, 51%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 12.70 (br s, IH), 7.37 (d, J= 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 7.22 (d, J= 7.3 Hz, IH), 6.02 (dd, J= 7.3, 2.5 Hz, IH), 5.93 (d, J= 2.5 Hz, IH), 4.98 (s, 2H).

c) 4-(4-Chlorobenzyloxy)-l-(2,9-dimethyl-2,3,4,9-tetrahydro-lH- pyrido[3,4-δ]indol-7- yl)pyridin-2(lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₅ H ₂₅ Cl ₂ N ₃ O ₂

Exact Mass: 469.13 Molecular Weight: 470.39

4-(4-Chlorobenzyloxy)pyridin-2(lH)-one (82 mg, 0.34 mmol) and 7-bromo-2,9- dimethyl-2,3,4,9-tetrahydro-l/f-pyrido[3,4-δ]indole (97 mg, 0.34 mmol) were reacted following the procedure for Example 30 (step g) to provide the title compound (28 mg, 17%) as a yellow solid: mp 290-296 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.83 (d, J= 7.6 Hz, IH), 7.68 (d, J= 8.3 Hz, IH), 7.50-7.46 (m, 3H), 7.44-7.42 (m, 2H), 7.08 (dd, J= 8.3, 1.8 Hz, IH), 6.41 (dd, J= 7.6, 2.6 Hz, IH), 6.21 (d, J= 2.6 Hz, IH), 5.21 (s, 2H), 4.86- 4.84 (m, IH), 4.49 (d, J= 15.4 Hz, IH), 3.88-3.84 (m, IH), 3.72 (s, 3H), 3.55-3.50 (m, IH), 3.21-3.16 (m, 5H); ESI MS m/z A3A [M + H] ⁺ ; HPLC (Method B) 98.6% (AUC), t _R = 14.0 min.

Example 34

Preparation of l-(2,9-Dimethyl-2,3,4,9-tetrahydro-l/-f-pyrido[3,4-&lind ol-7-yl)-4-(pyridin-

2-ylmethoxy)pyridin-2( lHVone dihydrochloride

a) 4-(Pyridin-2-ylmethoxy)pyridine 1 -oxide

Chemical Formula: C ₁₁ H ₁₀ N ₂ O ₂ Exact Mass: 202.07

Molecular Weight: 202.21

2-Pyridylbenzylalcohol (1.67 g, 15.3 mmol) was dissolved in 1,4-dioxane (25 mL) and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol) was added. After stirring for 30 minutes, 4-chloropyridine-iV-oxide (2.27 g, 17.5 mmol) was added and the reaction mixture was heated for 1 h at 120 ⁰ C. Upon cooling, the mixture was purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 40 mL/min) to provide the title compound (600 mg, 38%) as a brown solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.62-8.61 (m, IH), 8.13-8.10 (m, 2H), 7.74

Attorney's Docket 2882.023B

(overlapping ddd, J= 7.8, 1.4 Hz, IH), 7.44 (d, J= 7.8 Hz, IH), 7.30 (d, J= 4.8 Hz, IH), 6.92-6.89 (m, 2H), 5.23 (s, 2H).

b) 4-(Pyridin-2-ylmethoxy)pyridin-2( lH)-one

Chemical Formula: C ₁₁ H ₁₀ N ₂ O ₂ Exact Mass: 202.07

Molecular Weight: 202.21

4-(Pyridin-2-ylmethoxy)pyridine 1-oxide (9.0 g, 45 mmol) was heated to 140 ⁰ C in acetic anhydride (100 rnL) for 2 h. The solution was concentrated and then heated at 80 ⁰ C for 1 h in a mixture of MeOH (50 mL) and H ₂ O (50 rnL). The resultant black solution was concentrated and the residue was dissolved in hot /-PrOH (40 ml). Et ₂ O (250 mL) was added and the mixture was placed in the freezer for 16 h. The solid was filtered off to provide the title compound (1.9 g, 21%) as a brown solid: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 11.13 (br s, IH), 8.58 (d, J= 4.7 Hz, IH), 7.85 (overlapping ddd, J= 7.9, 1.6 Hz, IH), 7.49 (d, J= 7.9 Hz, IH), 7.38-7.34 (m, IH), 7.26 (d, J= 7.3 Hz, IH), 5.96 (dd, J= 7.3, 2.5 Hz, IH), 5.76 (d, J= 3.4 Hz, IH), 5.12 (s, 2H).

c) l-(2,9-Dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7- yl)-4-(pyridin-2- ylmethoxy)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₄ H ₂₆ Cl ₂ N ₄ O ₂ Exact Mass: 472.14

Molecular Weight: 473.39

4-(Pyridin-2-ylmethoxy)pyridin-2(lH)-one (109 mg, 0.539 mmol) and 7-bromo- 2,9-dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indole (97 mg, 0.34 mmol) were reacted following the procedure for Example 30 (step g) to provide the title compound (28 mg, 11%) as a yellow solid: mp 160-175 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.90 (dd, J= 5.8, 1.8 Hz, IH), 8.65 (overlapping ddd, J= 7.9, 1.6 Hz, IH), 8.20 (d, J= 8.0 Hz, IH), 8.07 (overlapping dd, J= 6.4 Hz, IH), 7.70 (d, J= 7.6 Hz, IH), 7.65 (d, J= 6.4 Hz, IH), 7.49

Attorney's Docket 2882.023B

(d, J= 1.7 Hz, IH), 7.07 (dd, J= 6.8, 1.8 Hz, IH), 6.63 (dd, J= 7.6, 2.7 Hz, IH), 6.21 (d, J = 2.7 Hz, IH), 5.59 (s, 2H), 4.80 (m, IH), 4.50 (d, J= 15.3 Hz, IH), 3.88-3.85 (m, IH), 3.73 (s, 3H), 3.55-3.50 (m, IH), 3.21-3.16 (m, 5H); ESI MS m/z 401 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 9.3 min.

Example 35

Preparation of 4-((5-Chloropyridin-2-yl)methoxy)- 1 -(2,9-dimethyl-2,3 ,4,9-tetrahydro- IH- pyrido [3 ,4-& ^" |indo l-7-yl)pyridin-2( lH)-one dihydrochloride

a) 4-((5-Chloropyridin-2-yl)methoxy)pyridine 1 -oxide

Chemical Formula: C ₁₁ H ₉ ClN ₂ O ₂ Exact Mass: 236.04 Molecular Weight: 236.65

5-Chloro-2-pyridylbenzylalcohol (4.9 g, 34 mmol) and 4-chloropyridine-iV-oxide (2.94 g, 22.7 mmol) were reacted according to Example 34 (step a) to provide the title compound (2.2 g, 40%) as a tan solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.58 (d, J= 2.2 Hz, IH), 8.13 (d, J= 7.7 Hz, 2H), 7.74 (dd, J= 8.4, 2.5 Hz, IH), 7.43 (d, J= 8.4 Hz, IH), 6.90 (d, J= 7.7 Hz, 2H), 5.20 (s, 2H).

Chemical Formula: C ₁₁ H ₉ ClN ₂ O ₂ Exact Mass: 236.04 Molecular Weight: 236.65

5-Chloro-2-pyridylbenzylalcohol (4.9 g, 34 mmol) and 4-chloropyridine-iV-oxide (2.94 g, 22.7 mmol) were reacted according to Example 34 (step a) to provide the title compound (2.2 g, 40%) as a tan solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.58 (d, J= 2.2 Hz, IH), 8.13 (d, J= 7.7 Hz, 2H), 7.76-7.72 (dd, J= 8.4, 2.5 Hz, IH), 7.43 (d, J= 8.4 Hz, IH), 6.90 (d, J= 7.7 Hz, 2H), 5.20 (s, 2H).

b) 4-((5-Chloropyridin-2-yl)methoxy)pyridin-2(7H)-one

Attorney's Docket 2882.023B

Chemical Formula: C ₁₁ H ₉ ClN ₂ O ₂ Exact Mass: 236.04

Molecular Weight: 236.65

4-((5-Chloropyridin-2-yl)methoxy)pyridine 1 -oxide (2.2 g, 9.2 mmol) was reacted according to Example 34 (step b) to provide the title compound (1.52 g, 69%) as a tan solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.56 (d, J= 2.3 Hz, IH), 7.91-7.89 (dd, J= 8.4, 2.5 Hz, IH), 7.56 (d, J= 8.4 Hz, IH), 7.34 (d, J= 8.3 Hz, IH), 6.21-6.19 (dd, J= 7.2, 2.5 Hz, IH), 5.97 (d, J= 2.4 Hz, IH), 5.18 (s, 2H).

c) tert-Butyl 7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-l(2H)-yl)- 9-methyl-3,4- dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate

4-((5-Chloropyridin-2-yl)methoxy)pyridin-2(l/-/)-one (259 mg, 1.09 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-c arboxylate (400 mg, 1.1 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (145 mg, 25%) as a yellow solid: ESI MS m/z 521 [M + H] ⁺ .

d) 4-((5-Chloropyridin-2-yl)methoxy)-l-(9-methyl-2,3,4,9-tetrah ydro-lH-pyrido[3,4- δ]indol-7-yl)pyridin-2(lH)-one dihydrochloride

Chemical Formula: C ₂₃ H ₂₃ Cl ₃ N ₄ O ₂ Exact Mass: 492.09 Molecular Weight: 493.81 tert-Butyl 7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin- 1 (2H)-yl)-9-methyl- 3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9/-/)-carboxylate (145 mg, 0.278 mmol) was

Attorney's Docket 2882.023B deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (114 mg, 94%) as a yellow solid: mp 275-280 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.61 (s, IH), 7.77 (dd, J= 8.3, 3.8 Hz, IH), 7.64-7.62 (m, 3H), 7.47 (d, J= 1.6 Hz, IH), 7.03 (dd, J= 8.4, 1.8 Hz, IH), 6.37 (dd, J= 7.6, 3.8 Hz, IH), 6.15 (d, J= 2.7 Hz, IH), 5.28 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.60 (t, J= 6.1 Hz, 2H), 3.12 (t, J= 6.0 Hz, 2H); ESI MS m/z 421 [M + H] ⁺ ; HPLC (Method B) 98.5% (AUC), t _R = 12.1 min

Example 36

Preparation of 4-((5-Chloropyridin-2-yl)methoxy)- 1 -(2.9-dimethyl-2.3 A9-tetrahydro- IH- p yrido [3 ,4-&1indo 1-7- yl)pyridin-2( lH)-one dihydrochloride

4-((5-Chloropyridin-2-yl)methoxy)- 1 -(9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido[3,4- δ]indol-7-yl)pyridin-2(lH)-one (80 mg, 0.19 mmol) was dissolved a mixture of MeOH (3 mL) and CH ₂ Cl ₂ (1 mL) and formaldehyde (9.0 mg, 0.29 mmol, 37% aqueous solution) was added. After stirring for 45 minutes, NaBH(OAc) ₃ (80 mg, 0.38 mmol) was added and the reaction mixture was stirred for a further 10 minutes. The mixture was diluted with CH ₂ Cl ₂ , washed with saturated Na ₂ CO ₃ solution and concentrated to provide the free base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (83 mg, 86%) as an orange solid: mp 202-210 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.68 (br s, IH), 8.05 (dd, J= 8.0, 2.4 Hz, IH), 7.76 (d, J= 8.4 Hz, IH), 7.71 (d, J= 8.4 Hz, IH), 7.65 (d, J= 8.3 Hz, IH), 7.51 (d, J= 1.6 Hz, IH), 7.09 (dd, J = 8.3, 1.8 Hz, IH), 6.53 (dd, J= 7.6, 1.7 Hz, IH), 6.28 (d, J= 1.6 Hz, IH), 5.36 (s, 2H), 4.85-4.80 (m, IH), 4.49 (d, J= 15.3 Hz, IH), 3.89-3.84 (m, IH), 3.72 (s, 3H), 3.53-3.47 (m, IH), 3.22-3.19 (m, 2H), 3.16 (s, 3H); ESI MS m/z 435 [M + H] ⁺ ; HPLC (Method B) 97.8% (AUC), t _R = 12.2 min.

Attorney's Docket 2882.023B

Example 37

Preparation of 4-(4-ChlorophenvO- 1 -(2.9-dimethyl-2.3 A9-tetrahydro- lH-pyridor3 A- άlindol-7-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₃ Cl ₂ N ₃ O

Exact Mass: 439.12 Molecular Weight: 440.36

4-(4-Chlorophenyl)pyridin-2(lH)-one (80 mg, 0.33 mmol) and 7-bromo-2,9- dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indole (49 mg, 0.33 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (28 mg, 19%) as a yellow-green solid: mp 316-323 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 11.0 (br s, IH), 7.83 (dd, J= 6.8, 1.9 Hz, 2H), 7.76 (d, J= 7.1 Hz, IH), 7.62-7.57 (m, 4H), 7.07 (dd, J= 8.3, 1.8 Hz, IH), 6.81 (d, J= 2.0 Hz, IH), 6.69 (dd, J= 7.2, 2.1 Hz, IH), 4.79 (d, J = 15.2 Hz, IH), 4.44 (dd, J= 15.2, 6.0 Hz, IH), 3.74-3.68 (m, 4H), 3.48-3.38 (m, IH), 3.10-2.99 (m, 5H); ESI MS m/z 404 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 13.5 min.

Example 38

Preparation of 4-(4-ChlorophenyD- 1 -(9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido| ^" 3,4-& ^" |indol-

7-yl)pyridin-2( lH)-one hydrochloride

a) tert-Butyi 7-(4-(4-chlorophenyl)-2-oxopyridin- 1 (2H)-yl)-9-methyl-3 ,4-dihydro- IH- pyrido[3,4-δ]indole-2(9H)-carboxylate

Attorney's Docket 2882.023B

4-(4-Chlorophenyl)pyridin-2(lH)-one (74 mg, 0.32 mmol) and tert-butyl 7-bromo- 9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxyla te (74 mg, 0.36 mmol) were coupled following the procedure of Example 30 (step g) to provide the title compound (85 mg, 54%) as a yellow solid: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.58-7.55 (m, 3H), 7.51-7.44 (m, 3H), 7.35 (s, IH), 7.07 (dd, J= 8.2, 1.6 Hz, IH), 6.87 (d, J= 1.8 Hz, IH), 6.47 (dd, J = 7.1, 1.8 Hz, IH), 4.65 (br m, 2H), 3.75 (br m, 2H), 3.64 (s, 3H), 2.81 (br m, 2H), 1.52 (s, 9H).

b) 4-(4-Chlorophenyl)-l-(9-methyl-2,3,4,9-tetrahydro-lH-pyrido[ 3,4-δ]indol-7-yl)pyridin- 2(lH)-one hydrochloride

Chemical Formula: C ₂₃ H ₂₁ Cl ₂ N ₃ O

Exact Mass: 425.11 Molecular Weight: 426.34 tert-Butyl 7-(4-(4-chlorophenyl)-2-oxopyridin- 1 (2H)-yl)-9-methyl-3 ,4-dihydro- lH-pyrido[3,4-δ]indole-2(9H)-carboxylate (85 mg, 0.17 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (38 mg, 52%) as a yellow solid: mp 310-315 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.78-7.75 (m, 3H), 7.67 (d, J= 8.3 Hz, IH), 7.55-7.53 (m, 3H), 7.13 (dd, J= 8.3, 1.8 Hz, IH), 6.91 (d, J= 1.9 Hz, IH), 6.84 (dd, J= 7.1, 2.0 Hz, IH), 4.56 (s, 2H), 3.74 (s, 3H), 3.61 (t, J= 6.0 Hz, 2H), 3.14 (t, J= 6.0 Hz, 2H); ESI MS m/z 390 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 13.6 min.

Example 39

Preparation of l-(9-Methyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^1indol-7-yl)-4 -(4-

(trifluoromethyl)phenyl)pyridin-2( lHVone hydrochloride hydrochloride

a) 4-(4-(Trifluoromethyl)phenyl)pyridine 1 -oxide

Attorney's Docket 2882.023B

Chemical Formula: C ₁₂ H ₈ F ₃ NO

Exact Mass: 239.06 Molecular Weight: 239.19

4-Chloropyridine-iV-oxide (3.0 g, 23 mmol), 4-trifluoromethylphenylboronic acid (6.57 g, 34.6 mmol), K ₂ CO ₃ (4.8 g, 35 mmol) and PdCl ₂ (dppf) (470 mg, 0.57 mmol) were stirred in DMSO (40 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated to 80 ⁰ C for 10 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5 ^χ ), dried, concentrated and the residue was purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 40 mL/min) to provide the title compound (1.90 g, 34%) as a tan solid: ESI MS m/z 240 [M + H] ⁺ .

b) 4-(4-(Trifluoromethyl)phenyl)pyridin-2( lH)-one

Chemical Formula: C ₁₂ H ₈ F ₃ NO

Exact Mass: 239.06 Molecular Weight: 239.19

4-(4-(Trifluoromethyl)phenyl)pyridine-l -oxide (1.9 g, 7.9 mmol) was reacted according to the procedure of Example 32 (step b) to provide the title compound (1.26 g, 66%) as a brown solid: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.80-7.74 (br m, 5H), 6.85-6.66 (br m, 2H).

c) tert-Butyl 9-methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin- 1 (2H)-yl)-3 ,4- dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate

Chemical Formula: C ₂₉ H ₂₈ F ₃ N ₃ O ₃

Exact Mass: 523.21 Molecular Weight: 523.55

Attorney's Docket 2882.023B

4-(4-(Trifluoromethyl)phenyl)pyridin-2(lH)-one (86 mg, 0.36 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-c arboxylate (120 mg, 0.32 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (97 mg, 58%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.74 (s, 4H), 7.58-7.52 (m, 2H), 7.36 (s, IH), 7.08 (dd, J= 8.2, 1.8 Hz, IH), 6.92 (d, J= 1.9 Hz, IH), 6.50 (dd, J= 7.2, 2.0 Hz, IH), 4.65 (br m, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.81 (br m, 2H), 1.52 (s, 9H).

d) l-(9-Methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)- 4-(4- (trifluoromethyl)phenyl)pyridin-2( lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₁ ClF ₃ N ₃ O

Exact Mass: 459.13 Molecular Weight: 459.89 tert-Butyl 9-methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin- 1 (2H)-yl)-3 ,4- dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate (97 mg, 0.19 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (53 mg, 62%) as a yellow solid: mp 316-321 ⁰ C; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.97 (d, J= 8.1 Hz, 2H), 7.87-7.80 (m, 3H), 7.68 (d, J= 8.2 Hz, IH), 7.57 (d, J= 1.5 Hz, IH), 7.14 (dd, J= 8.3, 1.8 Hz, IH), 6.96 (d, J= 1.8 Hz, IH), 6.87 (dd, J= 7.2, 1.8 Hz, IH), 4.56 (s, 2H), 3.74 (s, 3H), 3.61 (t, J= 6.0 Hz, 2H), 3.14 (t, J = 6.0 Hz, 2H); ESI MS m/z 424 [M + H] ⁺ ; HPLC (Method B) 96.3% (AUC), t _R = 14.0 min.

Example 40

Preparation of l-(2.9-Dimethyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^1indol-7-y l)-4-(4-

(trifluoromethyl)phenyl)pyridin-2( lHVone hydrochloride

Attorney's Docket 2882.023B

4-(4-(Trifluoromethyl)phenyl)pyridin-2(lH)-one (100 mg, 0.42 mmol) and 7- bromo-2,9-dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-6]indole (117 mg, 0.419 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (70 mg, 35%) as a yellow-brown solid: mp 294-299 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.96 (d, J= 8.2 Hz, 2H), 7.85-7.83 (m, 3H), 7.68 (d, J= 8.3 Hz, IH), 7.58 (d, J= 1.6 Hz, IH), 7.16 (dd, J= 8.3, 1.7 Hz, IH), 6.98 (d, J= 1.8 Hz, IH), 6.90 (dd, J= 7.1, 1.9 Hz, IH), 4.87-4.86 (m, IH), 4.51 (d, J= 15.3 Hz, IH), 3.90-3.86 (m, IH), 3.74 (s, 3H), 3.57-3.51 (m, IH), 3.23-3.20 (m, 2H), 3.17 (s, 3H); ESI MS m/z 438 [M + H] ⁺ ; HPLC (Method B) 95.6% (AUC), t _R = 14.1 min.

Example 41

Preparation of 4-(2.4-DichlorophenvO- 1 -(2.9-dimethyl-2.3 A9-tetrahydro- l/f-pyridoB A-

&lindol-7-yl)pyridin-2(lH)-one hydrochloride

a) 4-(2,4-Dichlorophenyl)pyridine 1 -oxide

Chemical Formula: C ₁₁ H ₇ Cl ₂ NO

Exact Mass: 238.99 Molecular Weight: 240.09

4-Chloropyridine-iV-oxide (1.5 g, 12 mmol), 2,4-dichlorophenylboronic acid (5.4 g, 29 mmol) were reacted according to the procedure of Example 39 (step a) to provide the title compound (1.40 g, 50%) as a grey solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.26 (d, J = 6.9 Hz, 2H), 7.53 (d, J= 2.0 Hz, IH), 7.37-7.35 (m, 3H), 7.29 (d, J= 8.3 Hz, IH).

b) 4-(2,4-Dichlorophenyl)pyridin-2( lH)-one

Attorney's Docket 2882.023B

Chemical Formula: C ₁₁ H ₇ Cl ₂ NO

Exact Mass: 238.99 Molecular Weight: 240.09

4-(2,4-Dichlorophenyl)pyridine 1 -oxide (1.4 g, 5.8 mmol) was reacted according to the procedure of Example 32 (step b) to provide the title compound (0.95 g, 67%) as a brown solid: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 11.75 (br m, IH), 7.75 (s, IH), 7.51-7.46 (m, 3H), 6.31-6.22 (m, 2H).

c) 4-(2,4-Dichlorophenyl)-l-(2,9-dimethyl-2,3,4,9-tetrahydro-l/ f-pyrido[3,4-δ]indol-7- yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₂ Cl ₃ N ₃ O

Exact Mass: 473.08 Molecular Weight: 474.81

4-(2,4-Dichlorophenyl)pyridin-2(lH)-one (103 mg, 0.429 mmol) and 7-bromo-2,9- dimethyl-2,3,4,9-tetrahydro-l/f-pyrido[3,4-δ]indole (120 mg, 0.43 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (44 mg, 21%) as a yellow solid: mp 308-313 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.77 (d, J= 7.0 Hz, IH), 7.68 (d, J= 8.4 Hz, IH), 7.65 (overlapping dd, J= 1.1 Hz, IH), 7.58 (d, J= 1.7 Hz, IH), 7.49 (s, 2H), 7.16 (dd, J= 8.3, 1.8 Hz, IH), 6.70 (d, J= 1.5 Hz, IH), 6.62 (dd, J = 7.0, 1.9 Hz, IH), 4.86 (m, IH), 4.50 (d, J= 15.3 Hz, IH), 3.89-3.85 (m, IH), 3.74 (s, 3H), 3.56-3.55 (m, IH), 3.23-3.20 (m, 2H), 3.16 (s, 3H); ESI MS m/z 438 [M + H] ⁺ ; HPLC (Method B) 98.5% (AUC), t _R = 14.3 min.

Example 42

Preparation of 4-(Benzyloxy)-l-(9-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-^ lindol-7- yl)pyridin-2(lH)-one hydrochloride

Attorney's Docket 2882.023B a) tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin- 1 (2H)-yl)-9-methyl-3 ,4-dihydro- IH- pyrido[3,4-δ]indole-2(9H)-carboxylate

Chemical Formula: C ₂₉ H ₃₁ N ₃ O ₄

Exact Mass: 485.23 Molecular Weight: 485.57

4-(Benzyloxy)pyridin-2(lH)-one (580 mg, 0.28 mmol) and tert-bvXy\ 7-bromo-9- methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate (850 mg, 0.23 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (700 mg, 62%) as a green solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.52 (d, J= 8.2 Hz, IH), 7.44- 7.39 (m, 4H), 7.38-7.35 (m, IH), 7.31-7.28 (m, 2H), 7.01 (dd, J= 8.3, 1.8 Hz, IH), 6.09 (d, J= 2.6 Hz, IH), 6.04 (dd, J= 7.6, 2.6 Hz, IH), 5.05 (s, 2H), 4.64 (br m, 2H), 3.74 (br m, 2H), 3.62 (s, 3H), 2.79 (br m, 2H), 1.47 (s, 9H).

b) 4-(Benzyloxy)- 1 -(9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido [3 ,4-6]indol-7-yl)pyridin- 2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₄ ClN ₃ O ₂

Exact Mass: 421.16 Molecular Weight: 421.92 tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin- 1 (2H)-yl)-9-methyl-3 ,4-dihydro- IH- pyrido[3,4-δ]indole-2(9H)-carboxylate (700 mg, 1.44 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (530 mg, 83%) as a yellow solid: mp 251-257 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.71 (br s, 2H), 7.56 (d, J= 7.6 Hz, IH), 7.54 (d, J= 8.3 Hz, IH), 7.50-7.47 (m, 3H), 7.44-7.41 (m, 2H), 7.38-7.37 (m, IH), 6.99 (dd, J= 8.3, 1.8 Hz, IH), 6.11 (dd, J= 7.6, 2.8 Hz, IH), 5.97 (d, J= 2.6 Hz, IH), 5.15 (s, 2H), 4.45 (s, 2H), 3.81 (s, 3H), 3.42-3.41 (m, 2H), 2.98-2.97 (m, 2H); ESI MS m/z 386 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 12.9 min.

Attorney's Docket 2882.023B

Example 43

Preparation of 4-(Benzyloxy)- 1 -(2-(2-hydroxyethyl)-9-methyl-2,3 ,4,9-tetrahydro- IH- pyrido [3 ,4-& ^" |indo 1-7- yl)pyridin-2( lH)-one hydrochloride

Chemical Formula: C ₂₆ H ₂₈ ClN ₃ O ₃

Exact Mass: 465.18 Molecular Weight: 465.97

4-(Benzyloxy)- 1 -(9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido [3 ,4-6]indol-7-yl)pyridin- 2(lH)-one (70 mg, 0.18 mmol), 2-iodoethanol (156 mg, 0.907 mmol) and K ₂ CO ₃ (250 mg, 1.8 mmol) were combined in DMF (3 mL) and heated to 80 ⁰ C for 1 h. Upon cooling, the product was purified by preparative ηPLC and then flash column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 25 mL/min) to provide the free-base. This was converted to the hydrochloride salt as of Example 30 (step g) to provide the title compound (14.8 mg, 18%) as a yellow solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.63 (d, J= 8.4 Hz, IH), 7.61 (d, J= 7.5 Hz, IH), 7.47-7.46 (m, 3H), 7.42-7.39 (m, 2H), 7.36 (d, J= 7.1 Hz, IH), 7.06 (dd, J= 8.3, 1.8 Hz, IH), 6.33 (dd, J = 7.6, 2.6 Hz, IH), 6.15 (d, J= 2.6 Hz, IH), 5.19 (s, 2H), 4.81-4.79 (m, IH), 4.59 (d, J = 15.3 Hz, IH), 4.01 (t, J= 5.1 Hz, 2H), 3.97-3.94 (m, IH), 3.73 (s, 3H), 3.58-3.50 (m, 3H), 3.21-3.16 (m, 2H); ESI MS m/z 430 [M + H] ⁺ ; HPLC (Method B) 97.2% (AUC), t _R = 12.8 min.

Example 44

Preparation of 4-(Benzyloxy)- 1 -(9-methyl-2-(2-(pyrrolidin- 1 -yl)acetyl)-2,3 ,4,9-tetrahydro- lH-pyrido [3 ,4-& ^" |indol-7-yl)pyridin-2( lH)-one hydrochloride

a) 4-(Benzyloxy)-l-(2-(2-chloroacetyl)-9-methyl-2,3,4,9-tetrahy dro-lH-pyrido[3,4- δ]indol-7-yl)pyridin-2(lH)-one

Attorney's Docket 2882.023B

Chemical Formula: C ₂₆ H ₂₄ ClN ₃ O ₃

Exact Mass: 461.15 Molecular Weight: 461.94

4-(Benzyloxy)- 1 -(2-(2-hydroxyethyl)-9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,4- δ]indol-7-yl)pyridin-2(lH)-one hydrochloride (100 mg, 0.23 mmol) was stirred in a mixture of CH ₂ Cl ₂ (2 mL) and saturated NaHCCh solution (2 mL) and chloroacetyl chloride (32 mg, 0.28 mmol) was added. After 1.5 h, the organic layer was removed and concentrated to provide the title compound (120 mg, 100%) as a yellow oil: ESI MS m/z 462 [M + H] ⁺ .

b) 4-(Benzyloxy)- 1 -(9-methyl-2-(2-(pyrrolidin- 1 -yl)acetyl)-2,3 ,4,9-tetrahydro- IH- pyrido [3 ,4-δ]indo l-7-yl)pyridin-2( lH)-one hydrochloride

Chemical Formula: C ₃₀ H ₃₃ ClN ₄ O ₃

Exact Mass: 532.22 Molecular Weight: 533.06

4-(Benzylo xy)- 1 -(2-(2-chloroacetyl)-9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,4- δ]indol-7-yl)pyridin-2(lH)-one (120 mg. 0.23 mmol), pyrrolidine (85 mg, 1.2 mmol) and K ₂ CO ₃ (331 mg, 2.39 mmol) were combined in DMF (3 mL) and heated to 80 ⁰ C for 1 h. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5 ^χ ), dried over Na ₂ SO ₄ and concentrated. The residue was converted to the hydrochloride salt as of Example 30 (step g) to provide the title compound (110 mg, 60%) as a yellow solid: mp 190-200 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.86 (d, J= 7.5 Hz, IH), 7.62 (dd, J= 8.2, 2.7 Hz, IH), 7.51-7.50 (m, 3H), 7.46-7.43 (m, 2H), 7.41-7.40 (m, IH), 7.08-7.06 (m, IH), 6.63 (dd, J= 7.8, 2.6 Hz, IH), 6.40 (d, J= 1.4 Hz, IH), 5.31 (s, 2H), 4.93 (s, 1.3H), 4.77 (s, 0.7H), 4.56-4.55 (m, 2H), 4.04-4.02 (m, 0.6H), 3.81-3.78 (m, 3.4H), 3.76 (s, 3H), 3.24-3.19 (m, 2H), 2.79-2.97 (m, 1.3H), 2.92-2.85 (m,

Attorney's Docket 2882.023B

0.7H), 2.22-2.19 (m, 2H), 2.11-2.19 (m, 2H); ESI MS m/z 497 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 13.7 min.

Example 45

Preparation of (61-4-(Benzyloxy)-l-(9-methyl-2-(pyrrolidine-2-carbonyl)-2,3 ,4,9- tetrahydro-lH-pyrido[3,4-^lindol-7-yl)pyridin-2(lH)-one hydrochloride

a) (S)-tert-Buiyl 2-(7-(4-(benzyloxy)-2-oxopyridin- 1 (2H)-yl)-9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido [3 ,4-δ]indole-2-carbonyl)pyrro lidine- 1 -carboxylate

Chemical Formula: C ₃₄ H ₃₈ N ₄ O ₅ Exact Mass: 582.28 Molecular Weight: 582.69

4-(Benzyloxy)- 1 -(9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido [3 ,4-6]indol-7-yl)pyridin-2( IH)- one hydrochloride (50 mg, 0.12 mmol) was stirred in DMF (1 rnL) and saturated Boc-L- proline (30 mg, 0.14 mmol), ηATU (68 mg, 0.18 mmol) and Et ₃ N (36 mg, 0.36 mmol) were added. After 16 h, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5 ^χ ), dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 90% methylene chloride over 30 min at 25 niL/min) to provide the title compound (55 mg, 78%) as a colorless oil: ESI MS m/z 583 [M + H] ⁺ .

b) (5)-4-(Benzyloxy)- 1 -(9-methyl-2-(pyrrolidine-2-carbonyl)-2,3 ,4,9-tetrahydro- IH- pyrido [3 ,4-δ]indo l-7-yl)pyridin-2( lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₉ H ₃₁ ClN ₄ O ₃

Exact Mass: 518.21 Molecular Weight: 519.03

(5)-tert-Butyl 2-(7-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-9-methyl-2,3,4,9- tetrahydro-lH-pyrido[3,4-δ]indole-2-carbonyl)pyrrolidine-l- carboxylate (55 mg, 0.094 mmol) was stirred in a mixture of MeOH (2 mL) and 2 N HCl in Et ₂ O (8 rnL) for 5 h. The reaction mixture was concentrated to provide the title compound (42 mg, 85%) as a yellow-green solid: mp 220-226 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.79 (dd, J= 7.5, 1.4 Hz, IH), 7.47 (d, J= 8.3 Hz, IH), 7.49-7.46 (m, 3H), 7.44-7.46 (m, 2H), 7.39-7.36 (m, IH), 7.04 (dd, J= 8.3, 1.6 Hz, IH), 6.57-6.55 (m, IH), 6.34 (d, J= 2.5 Hz, IH), 5.27 (s, 2H), 4.96-4.87 (m, 2H), 3.90-8.86 (m, 2H), 3.77 (s, 3H), 3.48-3.34 (m, 3H), 3.00-2.86 (m, 2H), 2.67-2.61 (m, IH), 2.17-2.02 (m, 3H); ESI MS m/z 483 [M + H] ⁺ ; HPLC (Method B) 95.5% (AUC), t _R = 13.5 min.

Example 46

Preparation of 4-(Benzyloxy)-l-(9-methyl-2,3,4,9-tetrahydro-l/-f-pyrido[3,4 -^lindol-6- yl)pyridin-2(lH)-one hydrochloride

a) 2-(5-Bromo- l/-f-indol-3-yl)ethanamine Beilstein Registry Number 143491

Chemical Formula: C ₁₀ H ₁₁ BrN ₂ Exact Mass: 238.01 Molecular Weight: 239.1 1

4-Bromophenylhydrazine hydrochloride (20.0 g, 85.8 mmol) was reacted according to the procedure of Mascal et al. (Rinehart, Kenneth L.; Kobayashi, Jun'ichi; Harbour, Gary C; Gilmore, Jeremy; Mascal, Mark; et al. J. Am. Chem. Soc. 1987, 109, 3378-3387) to provide the title compound (5.2 g, 25%) as an orange solid: ESI MS m/z 239 [M + H] ⁺ .

Attorney's Docket 2882.023B b) 6-Bromo-2,3,4,9-tetrahydro-lH-pyrido[3,4-6]indole Beilstein Registry Number 911238

Chemical Formula: C _{j j} η _{j j} BrN ₂

Exact Mass: 250.01 Molecular Weight: 251.12

2-(5-Bromo-lH-indol-3-yl)ethanamine (5.2 g, 22 mmol) was reacted according to the procedure of Mascal et al. (Rinehart, Kenneth L.; Kobayashi, Jun'ichi; Harbour, Gary C; Gilmore, Jeremy; Mascal, Mark; et al. J. Am. Chem. Soc. 1987, 109, 3378-3387) to provide the title compound (2.6 g, 48%) as an orange solid: ESI MS m/z 251 [M + H] ⁺ .

c) tert-Butyl 6-bromo-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylat e

6-Bromo-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indole (2.6 g, 10 mmol) was suspended in CH ₂ Cl ₂ (50 mL) and THF (7.5 mL) and BoC ₂ O (2.3 g, 11 mmol) was added. After 2.5 h, the mixture was concentrated. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 70:30) gave the title compound (1.15 g, 30%) as an orange powder: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.59 (s, IH), 7.23 (d, J= 8.5 Hz, IH), 7.18 (d, J= 8.5 Hz, IH), 4.68-4.59 (br m, 2H), 3.80-3.70 (br m, 2H), 2.78-2.71 (br m, 2H), 1.50 (s, 9H).

d) tert-Butyi 6-bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-c arboxylate Chemical Formula: C ₁₇ H ₂₁ BrN ₂ O ₂

Exact Mass: 364.08 Molecular Weight: 365.26 tert-Butyl 6-bromo-3,4-dihydro-lH-pyrido[3,4-6]indole-2(9H)-carboxylate (1.15 g, 3.26 mmol) was dissolved in DMF (20 mL) and sodium hydride (60% weight dispersion in mineral oil, 196 mg, 4.89 mmol) was added. After 1 h, methyl iodide (0.30 mL, 4.9 mmol) was added and the reaction mixture was stirred for a further 30 min. The mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5 ^χ ), dried

Attorney's Docket 2882.023B over Na ₂ SO ₄ and concentrated. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 97:3 to 75:25) gave the title compound (740 mg, 36%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.58 (s, IH), 7.24 (d overlapped by solvent, J= 8.5, IH), 7.14 (d, J= 8.5, IH), 4.67-4.53 (br m, 2H), 3.79-3.67 (br m, 2H), 3.60 (s, 3H), 2.78- 2.66 (br m, 2H), 1.51 (s, 9H).

e) tert-Butyl 6-(4-(benzyloxy)-2-oxopyridin- 1 (2H)-yl)-9-methyl-3 ,4-dihydro- IH- pyrido[3,4-δ]indole-2(9H)-carboxylate

Chemical Formula: C ₂₉ H ₃₁ N ₃ O ₄ Exact Mass: 485.23

Molecular Weight: 485.57

A solution of tert-Butyl-6-bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]ind o Ie- 2(9H)-carboxylate (750 mg, 2.03 mmol) in DMSO (10 mL) was stirred under nitrogen and treated sequentially with 4-(benzyloxy)pyridin-2(lH)-one (448 mg, 2.23 mmol), 8- hydroxyquinoline (44 mg, 0.305 mmol), CuI (58 mg, 0.305 mmol) and K ₂ CO ₃ (308 mg, 2.23 mmol). After stirring overnight at 130 ⁰ C, the mixture was allowed to cool to room temperature and a mixture of MeOH and NH ₄ OH (10:1, 10 mL) was added. After stirring for 15 min, the mixture was diluted with CH ₂ Cl ₂ , washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. Purification by flash column chromatography (40 g ISCO column eluting with a 1 :1 ethylacetate/hexanes and a methanol/ammonia mixture (10:1); gradient 100% 1 :1 ethylacetate/hexanes to 90% 1 :1 ethylacetate/hexanes/ 10% methanol/ammonia mixture (10:1) over 30 min at 25 mL/min) provided the title compound (340 mg, 33%) as a yellow solid; ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.50-7.36 (m, 8H), 7.13 (d, J= 7.8, Hz, IH), 6.09 (d, J= 2.6 Hz, IH), 6.03 (dd, J=7.5, 2.7 Hz, IH), 5.05 (s, 2H), 4.65 (br s, 2H), 3.73 (br s, 2H), 3.66 (s, 3H), 2.77 (br s, 2H), 1.51 (s, 9H).

f) 4-(Benzyloxy)- 1 -(9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido [3 ,4-6]indol-6-yl)pyridin- 2(lH)-one hydrochloride

Attorney's Docket 2882.023B ClN V ₃ oOW ₉₂ tert-BvXyl 6-(4-(benzyloxy)-2-oxopyridin- 1 (2H)-yl)-9-methyl-3 ,4-dihydro- IH- pyrido[3,4-δ]indole-2(9H)-carboxylate (0.340 g, 0.70 mmol) was dissolved in MeOH (5 niL) and 2 N HCl in ether (15 mL) was added. After stirring for 1 h, the liquid was decanted off and the resultant solid was filtered and washed with ether (3 ^χ ). This provided the title compound (267 mg, 98%) as a light yellow solid: mp 290-300 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.66 (d, J= 7.5 Hz, IH), 7.57-7.52 (m, 2H), 7.46 (d, J= 7.7 Hz, 2H), 7.41 (overlapping dd, J= 7.3 Hz, 2H), 7.36 (d, J= 7.5 Hz, IH), 7.19 (dd, J= 8.6, 2.0 Hz, IH), 6.42 (dd, J= 7.5, 2.7 Hz, IH), 6.22 (d, J= 2.6 Hz, IH), 5.22 (s, 2H), 4.55 (s, 2H), 3.75 (s, 3H), 3.58 (t, J= 6.0 Hz, 2H), 3.10 (t, J= 6.0 Hz, 2H); ESI MS m/z 386 [M + H] ⁺ ; HPLC (Method B) 98.8% (AUC), t _R = 12.8 min.

Example 47

Preparation of 4-(Benzyloxy)-l-(2,9-dimethyl-2,3,4,9-tetrahydro-l/-f-pyrido [3,4-^lindol-7- yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C _2J H ₂₆ ClN ₃ O ₂

Exact Mass: 435.17 Molecular Weight: 435.95

4-(Benzyloxy)-l-(9-methyl-2,3,4,9-tetrahydro-lH-pydido[3,4-6 ]indol-6- yl)pyridine-2(l/-/)-one hydrochloride (126 mg, 0.325 mmol) was dissolved in MeOH (2 mL) and CH ₂ Cl ₂ (0.5 mL) and formaldehyde (0.036 mL, 37% aqueous solution) was added. After stirring for 1 h, NaBH(OAc) ₃ (138 mg, 0.651 mmol) was added and the mixture was stirred for a further 40 min. The mixture was diluted with methylene chloride (50 mL), washed with saturated Na ₂ CO ₃ solution, concentrated and purified by flash column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 85% methylene

Attorney's Docket 2882.023B chloride over 30 min at 40 rnL/min), and further purified by preparative HPLC to provide the title compound (55.5 mg, 43%) as a white powder: mp 260-270 ⁰ C; ¹ U NMR (500 MHz, CD ₃ OD) δ 7.56-7.53 (m, 2H), 7.51 (d, J= 1.8, IH), 7.46 (d, J= 7.3 Hz, 2H), 7.41 (overlapping dd, J= 7.4 Hz, 2H), 7.36 (d, J= 7.2 Hz, IH), 7.19 (dd, J= 8.6, 2.0 Hz, IH), 6.27 (dd, J= 7.6, 2.7 Hz, IH), 6.11 (d, J= 2.6 Hz, IH), 5.18 (s, 2H), 4.64 (br s, 2H), 3.75 (s, 3H), 3.67 (br s, 2H), 3.18-3.13 (m, 5H); ESI MS m/z 400 [M + H] ⁺ ; HPLC (Method B) >99 % (AUC), t _R = 12.9 min.

Example 48

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-yl)-4 -(5-

(trifluoromethyl)pyridin-2-yl)pyridin-2( lHVone dihydrochloride

a) 2'-Methoxy-5-(trifluoromethyl)-2,4'-bipyridine

Chemical Formula: C ₁₂ H ₉ F ₃ N ₂ O

Exact Mass : 254.07 Molecular Weight: 254.21

2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol) and 2-methoxy-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (500 mg, 1.81 mmol) were reacted according to Example 31 (step a) to provide the title compound (337 mg, 62%) as a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.96 (s, IH), 8.31 (d, J= 5.4 Hz, IH), 8.04 (dd, J = 8.3, 2.1 Hz, IH), 7.87 (d, J= 8.3 Hz, IH), 7.51 (dd, J= 5.4, 1.4 Hz, IH), 7.36 (s, IH), 3.52 (s, 3H).

b) 4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(lH)-one

Chemical Formula: C ₁₁ H ₇ F ₃ N ₂ O

Exact Mass: 240.05 Molecular Weight: 240.18

Attorney's Docket 2882.023B

2'-Methoxy-5-(trifluoromethyl)-2,4'-bipyridine (337 mg, 1.32 mmol) was reacted reacted according to Example 31 (step c) to provide the title compound (289 mg, 89%) as a white solid: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 11.08 (s, IH) 9.10 (s, IH), 8.35 (dd, J = 8.4, 2.1 Hz, IH), 8.25 (d, J = 8.3 Hz, IH), 7.53 (d, J= 6.8, IH), 7.09 (d, J= 1.3 Hz, IH), 6.90 (dd, J= 6.8, 1.6 Hz, IH).

c) te/t-Butyl 5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin -l(2H)-yl)-3,4- dihydro-lH-pyrido[4,3-b]indole-2(5H)-carboxylate

4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(lH)-one (100 mg, 0.41 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-c arboxylate (152 mg, 0.416 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (83 mg, 38%) as a green solid: ¹ U NMR (500 MHz, CDCl ₃ ) δ 9.00 (s, IH), 8.06 (dd, J= 8.3, 2.1 Hz, IH), 7.91 (d, J= 8.3 Hz, IH), 7.58 (d, J= 7.2 Hz, IH), 7.55 (d, J= 8.2 Hz, IH), 7.37 (d, J= 1.6 Hz, IH), 7.25 (d, J= 1.6 Hz, IH), 7.08 (d, J= 7.5 Hz, IH), 7.03 (dd, J= 7.1, 1.8 Hz, IH), 4.66 (s, 2H), 3.85 (br m, 2H), 3.66 (s, 3H), 2.84 (br m, 2H), 1.51 (s, 9H).

d) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4 -(5- (trifluoromethyl)pyridin-2-yl)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₃ H ₂₁ Cl ₂ F ₃ N ₄ O

Exact Mass: 496.10 Molecular Weight: 497.34

Attorney's Docket 2882.023B tert-Butyi 5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin - 1 (2H)-yl)- 3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (83 mg, 0.16 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (51 mg, 78%) as a yellow solid: mp 320-330 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 9.06 (s, IH), 8.28 (dd, J= 8.4, 2.1 Hz, IH), 8.23 (d, J= 8.2 Hz, IH), 7.87 (d, J= 7.1 Hz, IH), 7.64 (d, J= 8.3 Hz, IH), 7.58 (d, J = 1.6 Hz, IH), 7.43 (d, J= 1.6 Hz, IH), 7.29 (dd, J= Hz, IH), 7.17 (dd, J= 8.3, 1.8 Hz, IH), 4.50 (s, 2H), 3.76 (s, 3H), 3.69 (t, J= 6.0 Hz, 2H), 3.22 (t, J= Hz, 2H); ESI MS m/z 425 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 12.5 min.

Example 49

Preparation of 4-((5-Fluoropyridin-2-yl)methoxy)- 1 -(9-methyl-2,3 ,4,9-tetrahydro- IH- pyrido [3 ,4-& ^" |indo l-7-yl)pyridin-2( lH)-one dihydrochloride

a) 4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1 -oxide

Chemical Formula: C ₁₁ H ₉ FN ₂ O ₂ Exact Mass: 220.06 Molecular Weight: 220.20

5-Fluoro-2-pyridylbenzylalcohol (3.00 g, 23.6 mmol) and 4-chloropyridine-iV- oxide (2.03 g, 15.7 mmol) were reacted according to Example 34 (step a) to provide the title compound (1.76 g, 50%) as a tan solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.48 (s, IH), 8.12 (d, J= 7.7 Hz, 2H), 7.48-7.46 (m, 2H), 6.90 (d, J= 7.7 Hz, 2H), 5.20 (s, 2H).

b) 4-((5-Fluoroyridin-2-yl)methoxy)pyridin-2(7H)-one

Chemical Formula: C ₁₁ H ₉ FN ₂ O ₂ Exact Mass: 220.06 Molecular Weight: 220.20

Attorney's Docket 2882.023B

4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide (1.76 g, 7.99 mmol) was reacted according to Example 34 (step b) to provide the title compound (1.29 g, 73%) as a yellow solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 11.12 (s, IH), 8.59 (d, J= 2.9 Hz, IH), 7.79 (dt, J= 8.7, 2.9 Hz, IH), 7.60 (dd, J= 8.7, 4.5 Hz, IH), 7.26 (d, J= 7.3 Hz, IH), 5.95 (dd, J= 7.4, 2.6 Hz, IH), 5.78 (d, J= 2.5 Hz, IH), 5.12 (s, 2H).

c) tert-Butyi 7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-l(2H)-yl)- 5-methyl-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

4-((5-Fluoropyridin-2-yl)methoxy)pyridin-2(lH)-one (275 mg, 1.25 mmol) and tert-butyi 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-c arboxylate (456 mg, 1.25 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (420 mg, 66%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.15 (d, J= 2.1 Hz, IH), 7.50 (m, 3H), 7.36 (d, J= 7.8 Hz, IH), 7.31 (d, J= 1.6 Hz, IH), 7.01 (d, J= 8.9 Hz, IH), 6.11-6.08 (m, 2H), 5.18 (s, 2H), 4.65 (s, 2H), 3.87 (t, J= 5.3 Hz, 2H), 3.65 (s, 3H), 2.84 (t, J= 4.2 Hz, 2H), 1.60 (s, 9H).

d) 4-((5-Fluoropyridin-2-yl)methoxy)-l-(5-methyl-2,3,4,5-tetrah ydro-lH-pyrido[4,3- δ]indol-7-yl)pyridin-2(7H)-one dihydrochloride

Chemical Formula: C ₂₃ H ₂₃ Cl ₂ FN ₄ O ₂

Exact Mass: 476.12 Molecular Weight: 477.36 tert-Butyl 7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin- 1 (2H)-yl)-5-methyl- 3,4-dihydro-lH-pyrido[4,3-6]indole-2(5H)-carboxylate (415 mg, 0.823 mmol) was deprotected and converted to the dihydrochloride according to procedure of Example 30

Attorney's Docket 2882.023B

(steps e and g) to provide the title compound (328 mg, 84%) as a white solid: mp 174-180 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.70 (s, IH), 8.00 (dt, J= 8.4, 2.8 Hz, IH), 7.91-7.88 (m, 2H), 7.63 (d, J= 8.4 Hz, IH), 7.55 (s, IH), 7.11 (dd, J= 8.3, 1.7 Hz, IH), 6.69 (dd, J = 7.5, 2.7 Hz, IH), 6.45 (d, J= 2.6 Hz, IH), 5.46 (s, 2H), 4.49 (s, 2H), 3.75 (s, 3H), 3.68 (t, J= 6.1 Hz, 2H), 3.22 (t, J= 6.1 Hz, 2H); ESI MS m/z 405 [M + H] ⁺ ; HPLC (Method B) 95.5% (AUC), t _R = 10.9 min.

Example 50

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-yl)-4 -(6-

(trifluoromethyl)pyridazin-3-yl)pyridin-2(lH)-one hydrochloride

a) 3 -(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine

Chemical Formula: C ₁₁ H ₈ F ₃ N ₃ O

Exact Mass : 255.06

Molecular Weight: 255.20

3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol) and 2-methoxy-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (176 mg, 0.749 mmol) were reacted according to Example 31 (step a) to provide the title compound (115 mg, 60%) as a white solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.39 (d, J= 5.8 Hz, IH), 8.05 (d, J= 8.8 Hz, IH), 7.94 (d, J= 8.8 Hz, IH), 7.62 (dd, J= 5.4, 1.5 Hz, IH), 7.45 (s, IH), 4.03 (s, 3H).

b) 4-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2(lH)-one

Chemical Formula: C ₁₀ H ₆ F ₃ N ₃ O

Exact Mass: 241.05 Molecular Weight: 241.17

3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine (115 mg, 0.451 mmol) was reacted according to Example 31 (step c) to provide the title compound (120 mg, quant) as a white solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 11.87 (s, IH), 8.61 (d, J= 8.9

Attorney's Docket 2882.023B

Hz, IH), 8.42 (d, J= 8.9 Hz, IH), 7.62 (d, J= 6.8 Hz, IH), 7.19 (s, IH), 7.01 (dd, J= 6.8, 1.6 Hz, IH).

c) tert-Butyi 5-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyrid in- 1 (2H)-yl)- 3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

5O 3,

4-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2(lH)-one (60 mg, 0.25 mmol) and tert-hvXy\ 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-c arboxylate (90 mg, 0.25 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (60 mg, 46%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.10 (d, J= 8.8 Hz, IH), 7.79 (d, J= 8.8 Hz, IH), 7.66 (d, J= 7.0 Hz, IH), 7.56 (d, J= 8.2 Hz, IH), 7.38 (d, J= 1.3 Hz, IH), 7.26-7.24 (m, 2H), 7.10 (d, J= 7.8 Hz, IH), 4.66 (s, 2H), 3.66 (t, J= 3.3 Hz, 2H), 3.86 (s, 3H), 2.84 (t, J= 3.3 Hz, 2H), 1.51 (s, 9H).

d) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4 -(6- (trifluoromethyl)pyridazin-3-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₂ H ₁₉ ClF ₃ N ₅ O

Exact Mass: 461.12 Molecular Weight: 461.87 tert-Butyi 5 -methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3 -yl)pyridin- 1 (2H)- yl)-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (60 mg, 0.11 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (44 mg, 88%) as a yellow solid: mp 315-

Attorney's Docket 2882.023B

320 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.54 (d, J= 8.8 Hz, IH), 8.28 (d, J= 8.9 Hz, IH), 7.91 (d, J= 7.0 Hz, IH), 7.64 (d, J= 8.4 Hz, IH), 7.60 (d, J= 1.5 Hz, IH), 7.44 (d, J= 1.5 Hz, IH), 7.35 (dd, J= 7.2, 1.9 Hz, IH), 7.16 (dd, J= 8.3, 1.8 Hz, IH), 4.50 (s, 2H), 3.77 (s, 3H), 3.69 (t, J= 6.1 Hz, 2H), 3.22 (t, J= 6.0 Hz, 2H); ESI MS m/z 426 [M + H] ⁺ ; HPLC (Method B) 95.9% (AUC), to = 11.7 min.

Example 51

Preparation of 4-((5-Chloropyridin-2-yl)methoxy)-l-(5-methyl-2,3,4,5-tetrah ydro-lH- pyrido[4,3-^lindol-7-yl)pyridin-2(lH)-one dihydrochloride

a) tert-Butyl 7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-l(2H)-yl)- 5-methyl-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

4-((5-Chloropyridin-2-yl)methoxy)pyridin-2(lH)-one (127 mg, 0.537 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-c arboxylate (200 mg, 1.1 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (113 mg, 40%) as a white solid: ¹ U NMR (300 MHz, CDCl ₃ ) δ 8.59 (d, J = 2.4 Hz, IH), 7.73 (dd, J= 8.4, 2.4 Hz, IH), 7.51 (d, J= 8.3 Hz, IH), 7.45 (d, J= 8.3 Hz, IH), 7.33 (d, J= 7.5 Hz, IH), 7.29 (d, J= 1.5 Hz, IH), 7.01 (d, J= 7.9 Hz, IH), 6.09 (dd, J = 7.5, 2.7 Hz, IH), 6.05 (d, J= 2.5 Hz, IH), 5.17 (s, 2H), 4.64 (s, 2H), 3.84 (t, J= 5.4 Hz, 2H), 3.63 (s, 3H), 2.82 (t, J= 5.4 Hz, 2H), 1.50 (s, 9H).

b) 4-((5-Chloropyridin-2-yl)methoxy)-l-(5-methyl-2,3,4,5-tetrah ydro-lH-pyrido[4,3- δ]indol-7-yl)pyridin-2(lH)-one dihydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₃ H ₂₃ Cl ₃ N ₄ O ₂

Exact Mass: 492.09 Molecular Weight: 493.81 tert-Butyi 7-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin- 1 (2H)-yl)-5-methyl- 3,4-dihydro-lH-pyrido[4,3-b]indole-2(5H)-carboxylate (108 mg, 0.207 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (99 mg, 97%) as a white solid: mp 290-320 ⁰ C dec; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.61 (d, J= 2.1 Hz, IH), 7.95 (dd, J = 8.4, 2.4 Hz, IH), 7.62 (d, J= 7.6 Hz, 2H), 7.58 (d, J= 8.4 Hz, IH), 7.47 (d, J= 1.6 Hz, IH), 7.05 (dd, J= 8.3, 1.8 Hz, IH), 6.36 (dd, J= 7.6, 2.2 Hz, IH), 6.13 (d, J= 2.6 Hz, IH), 5.28 (s, 2H), 4.48 (s, 2H), 3.73 (s, 3H), 3.67 (t, J= 6.2 Hz, 2H), 3.02 (t, J= 6.2 Hz, 2H); ESI MS m/z 421 [M + H] ⁺ ; HPLC (Method B) 98.2% (AUC), t _R = 12.0 min.

Example 52

Preparation of 4-((5-Chloropyridin-2-yl)methoxy)-l-(2.5-dimethyl-2.3.4.5-te trahvdro-lH- pyrido[4,3-^lindol-7-yl)pyridin-2(lH)-one dihydrochloride

Chemical Formula: C ₂₄ H ₂₅ Cl ₃ N ₄ O ₂

EExxaacctt MMaassss:: 506.10 MMoolleeccuullaarr W Weeiigaht: 507.84

4-((5-Chloropyridin-2-yl)methoxy)- 1 -(5-methyl-2,3 ,4,5-tetrahydro- lH-pyrido[4,3- δ]indol-7-yl)pyridin-2(l/-/)-one (50 mg, 0.12 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (39 mg, 64%) as a white solid: mp 278-282 ⁰ C; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.60 (d, J= 2.0 Hz, IH), 7.96-7.92 (m, IH), 7.61 (d, J= 7.7 Hz, 2H), 7.57 (d, J= 8.3 Hz, IH), 7.47 (d, J= 1.4 Hz, IH), 7.06 (dd, J= 8.4, 1.7 Hz, IH), 6.34 (dd, J= 7.6, 2.6 Hz, IH), 6.12 (d, J= 2.6 Hz, IH), 5.27 (s, 2H), 4.75 (d, J= 14.2 Hz, IH), 4.38 (d, J= 14.1 Hz, IH), 3.95-3.85 (m, IH),

Attorney's Docket 2882.023B

3.73 (s, 3H), 3.63 (m, IH), 3.31 (m overlapping with solvent, 2H), 3.13 (s, 3H); ESI MS m/z 435 [M + H] ⁺ ; HPLC (Method B) 98.9% (AUC), t _R = 12.1 min.

Example 53

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-ά1indol-7-yl)- 4-(pyridin-2- ylmethoxy)pyridin-2( lHVone dihydrochloride

a) tert-Butyl 5-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-l(2H)-yl)-3 ,4-dihydro- lH-pyrido[4,3-6]indole-2(5H)-carboxylate

Chemical Formula: C ₂₈ H ₃₀ N ₄ O ₄

Exact Mass: 486.23 Molecular Weight: 486.56

4-(Pyridin-2-ylmethoxy)pyridin-2(lH)-one (110 mg, 0.54 mmol) and tert-butyl 7- bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-car boxylate (200 mg, 0.54 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (113 mg, 43%) as a yellow oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.63 (ddd, J = 4.9, 1.6, 0.9 Hz, IH), 7.75 (overlapping ddd, J= 7.6, 1.8 Hz, IH), 7.49 (t, J= 7.3 Hz, 2H), 7.33 (d, J= 7.5 Hz, IH), 7.29 (d, J= 1.4 Hz, IH), 7.26 (m overlapping with solvent, IH), 7.01 (d, J= 7.9 Hz, IH), 6.12-6.07 (m, 2H), 5.19 (s, 2H), 4.64 (s, 2H), 3.84 (t, J= 5.4 Hz, 2H), 3.62 (s, 3H), 2.82 (t, J= 5.4 Hz, 2H), 1.52 (s, 9H).

b)l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7 -yl)-4-(pyridin-2- ylmethoxy)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₃ H ₂₄ Cl ₂ N ₄ O ₂ Exact Mass: 458.13

Molecular Weight: 459.37

Attorney's Docket 2882.023B tert-Butyi 5-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin-l(2H)-yl)-3 ,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (113 mg, 0.23 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (81 mg, 77%) as a white solid: mp 206-211 ⁰ C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.88 (d, J= 5.2 Hz, IH), 8.59 (dd, J= 7.9, 1.5 Hz, IH), 8.15 (d, J= 8.0 Hz, IH), 8.01 (overlapping dd, J= 6.6 Hz, IH), 7.69 (d, J= 7.6 Hz, IH), 7.60 (d, J = 8.4 Hz, IH), 7.48 (d, J= 1.6 Hz, IH), 7.06 (dd, J= 8.4, 1.8 Hz, IH), 6.44 (dd, J= 7.6, 2.7 Hz, IH), 6.21 (d, J= 2.7 Hz, IH), 5.57 (s, 2H), 4.48 (s, 2H), 3.74 (s, 3H), 3.68 (t, J = 6.2 Hz, 2H), 3.21 (t, J= 6.2 Hz, 2H); ESI MS m/z 387 [M + H] ⁺ ; HPLC (Method B) 98% (AUC), t _R = 9.3 min.

Example 54

Preparation of l-(2,5-Dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-&lindol -7-yl)-4-(pyridin-

2-ylmethoxy)pyridin-2( lHVone dihydrochloride

Chemical Formula: C ₂₄ H ₂₆ Cl ₂ N ₄ O ₂ Exact Mass: 472.14

Molecular Weight: 473.39 l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)- 4-(pyridin-2- ylmethoxy)pyridin-2(lH)-one (45 mg, 0.116 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (54 mg, 98%) as a white solid: mp 260-265 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.87 (d, J= 5.7 Hz, IH), 8.58 (overlapping dd, J= 8.2 Hz, IH), 8.14 (d, J= 7.9 Hz, IH), 8.00 (overlapping dd, J = 6.6 Hz, IH), 7.69 (d, J= 7.6 Hz, IH), 7.59 (d, J= 8.3 Hz, IH), 7.49 (s, IH), 7.07 (dd, J = 8.3, 1.7 Hz, IH), 6.44 (dd, J= 7.5, 2.6 Hz, IH), 6.20 (d, J= 2.0 Hz, IH), 5.56 (s, 2H), 4.76 (d, J= 14.2 Hz, IH), 4.40 (d, J= 14.2 Hz, IH), 3.91 (m, IH), 3.74 (s, 3H), 3.61 (m, IH), 3.29-3.17 (m overlapping with solvent, 2H), 3.13 (s, 3H); ESI MS m/z 401 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 9.2 min.

Attorney's Docket 2882.023B

Example 55

Preparation of 1 -(9-Methyl-2.3.4.9-tetrahvdro- lH-pyrido [3.4-&lindol-7-ylV4-(pyridin-2- ylmethoxy)pyridin-2( lH)-one dihydrochloride

a) tert-Butyi 9-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin- 1 (2H)-yl)-3 ,4-dihydro- lH-pyrido [3 ,4-6]indole-2(9H)-carboxylate

4-(Pyridin-2-ylmethoxy)pyridin-2(lH)-one (138 mg, 0.682 mmol) and tert-butyl 7- bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-car boxylate (250 mg, 0.68 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (170 mg, 51%) as a white foam: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.63 (d, J= 4.1 Hz, IH), 7.76 (overlapping ddd, J= 7.7, 1.7 Hz, IH), 7.53 (d, J= 8.3 Hz, IH), 7.48 (d, J = 7.8 Hz, IH), 7.33 (d, J= 7.4 Hz, IH), 7.29-7.26 (m overlapping with solvent, 2H), 7.01 (dd, J= 8.2, 1.8 Hz, IH), 6.12-6.07 (m, 2H), 5.19 (s, 2H), 4.63 (s, 2H), 3.74 (br s, 2H), 3.62 (s, 3H), 2.79 (s, 2H), 1.51 (s, 9H).

b)l-(9-Methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7 -yl)-4-(pyridin-2- ylmethoxy)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₃ H ₂₄ Cl ₂ N ₄ O ₂

Exact Mass: 458.13 Molecular Weight: 459.37 tert-Butyi 9-methyl-7-(2-oxo-4-(pyridin-2-ylmethoxy)pyridin- 1 (2H)-yl)-3 ,4- dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate (167 mg, 0.34 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (124 mg, 79%) as a yellow solid: mp 226-231 ⁰ C;

Attorney's Docket 2882.023B

¹ H NMR (500 MHz, CD ₃ OD) δ 8.89 (d, J= 5.4 Hz, IH), 8.61 (overlapping ddd, J= 8.0, 1.6 Hz, IH), 8.16 (d, J= 8.0 Hz, IH), 8.02 (overlapping dd, J= 6.6 Hz, IH), 7.70 (d, J = 7.6 Hz, IH), 7.63 (d, J= 8.4 Hz, IH), 7.47 (d, J= 1.6 Hz, IH), 7.06 (dd, J= 8.4, 1.8 Hz, IH), 6.44 (dd, J= 7.6, 2.7 Hz, IH), 6.21 (d, J= 2.6 Hz, IH), 5.57 (s, 2H), 4.56 (s, 2H), 3.73 (s, 3H), 3.60 (t, J= 6.0, 2H), 3.13 (t, J= 6.0, 2H); ESI MS m/z 387 [M + H] ⁺ ; HPLC (Method B) 98.6% (AUC), t _R = 9.2 min.

Example 56

Preparation of l-(9-Methyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^1indol-7-yl)-4 - phenethylpyridin-2( lHVone dihydrochloride

a) tert-Butyl 9-methyl-7-(2-oxo-4-phenethylpyridin- 1 (2H)-yl)-3 ,4-dihydro- lH-pyrido[3 ,4- δ]indole-2(9H)-carboxylate

Chemical Formula: C ₃₀ H ₃₃ N ₃ O ₃

Exact Mass: 483.25 Molecular Weight: 483.60

4-Phenethylpyridin-2(lH)-one (817 mg, 4.10 mmol) and tert-bvXy\ 7-bromo-9- methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate (1.5 g, 4.1 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (1.2 g, 60%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53 (d, J= 8.1 Hz, IH), 7.34- 7.29 (m, 4H), 7.26-7.20 (m, 3H), 7.03 (dd, J= 8.2, 1.5 Hz, IH), 6.50 (s, IH), 6.09 (dd, J = 6.9, 1.6 Hz, IH), 4.63 (br s, 2H), 3.74 (br s, 2H), 3.63 (s, 3H), 2.98-2.91 (m, 2H), 2.84- 2.79 (m, 4H), 1.51 (s, 9H).

b) l-(9-Methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)- 4-phenethylpyridin-2(lH)- one dihydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₅ H ₂₇ Cl ₂ N ₃ O

Exact Mass: 455.15 Molecular Weight: 456.41 tert-BvXy\ 9-methyl-7-(2-oxo-4-phenethylpyridin- 1 (2H)-yl)-3 ,4-dihydro- IH- pyrido[3,4-δ]indole-2(9H)-carboxylate (1.2 g, 2.4 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (550 mg, 51%) as a yellow solid: mp 280-295 ⁰ C; ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 9.67 (s, 2H), 7.59-7.52 (m, 3H), 7.35-7.27 (m, 4H), 7.24-7.17 (m, IH), 7.01 (dd, J= 7.4, 2.0 Hz, IH), 6.38-6.27 (m, 2H), 4.45 (s, 2H), 3.67 (s, 3H), 3.42 (t, J= 6.4 Hz, 2H), 2.97-2.89 (m, 4H), 2.81-2.76 (m, 2H); ESI MS m/z 384 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 13.3 min.

Example 57

Preparation of 4-(5-Chloropyridin-2-yl)- 1 -(5-methyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-

&lindol-7-yl)pyridin-2(lH)-one dihydrochloride

a) tert-Butyl 7-(4-(5-chloropyridin-2-yl)-2-oxopyridin-l(2H)-yl)-5-methyl- 3,4-dihydro- lH-pyrido[4,3-6]indole-2(5H)-carboxylate

Chemical Formula: C ₂₇ H ₂₇ CDST ₄ O ₃

Exact Mass: 490.18 Molecular Weight: 490.98

4-(5-Chloropyridin-2-yl)pyridin-2(lH)-one (111 mg, 0.537 mmol) and tert-butyi 7- bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-car boxylate (200 mg, 0.54 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (80 mg, 30%) as a green solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.69 (d, J= 2.2 Hz, IH), 7.79 (dd, J= 8.5, 2.4 Hz, IH), 7.74 (d, J= 8.5 Hz, IH), 7.53 (d, J= 7.2 Hz, 2H),

Attorney's Docket 2882.023B

7.36 (d, J= 1.5 Hz, IH), 7.17 (d, J= 1.5 Hz, IH), 7.07 (d, J= 7.4 Hz, IH), 6.98 (dd, J = 7.1, 1.8 Hz, IH), 4.65 (br s, 2H), 3.85 (br s, 2H), 3.65 (s, 3H), 2.83 (br s, 2H), 1.50 (s, 9H).

b) 4-(5-Chloropyridin-2-yl)-l-(5-methyl-2,3,4,5-tetrahydro-lH-p yrido[4,3-δ]indol-7- yl)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₂ H ₂₁ Cl ₃ N ₄ O Exact Mass: 462.08

Molecular Weight: 463.79 tert-Butyl 7-(4-(5-chloropyridin-2-yl)-2-oxopyridin-l(2H)-yl)-5-methyl- 3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (80 mg, 0.16 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (40 mg, 54%) as a white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.74 (d, J= 2.4 Hz, IH), 8.06 (d, J= 8.5 Hz, IH), 8.02 (dd, J= 8.7, 2.4 Hz, IH), 7.86 (d, J= 7.2 Hz, IH), 7.64 (d, J= 8.3 Hz, IH), 7.58 (d, J= 1.9 Hz, IH), 7.37 (d, J = 1.5 Hz, IH), 7.27 (dd, J= 8.5, 1.8 Hz, IH), 7.15 (dd, J= 8.4, 1.8 Hz, IH), 4.50 (s, 2H), 3.75 (s, 3H), 3.68 (t, J= 6.5 Hz, 2H), 3.22 (t, J= 6.5 Hz, 2H); ESI MS m/z 391 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 12.2 min.

Example 59

Preparation of l-(2.5-Dimethyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-y l)-4-((5- fluoropyridin-2-yl)methoxy)pyridin-2( lHVone dihydrochloride

Chemical Formula: C ₂₄ H ₂₅ Cl ₂ FN ₄ O ₂

EExxaacctt MMaassss:: 449900..1133 Molecular Weight: 491.39

4-((5-Fluoropyridin-2-yl)methoxy)-l-(5-methyl-2,3,4,5-tet rahydro-lH-pyrido[4,3- δ]indol-7-yl)pyridin-2(7H)-one (75 mg, 0.19 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt

Attorney's Docket 2882.023B using the procedure of Example 30 (step g) provided the title compound (71 mg, 78%) as a white solid: mp 215-230 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.65 (d, J= 2.6 Hz, IH), 7.91 (overlapping ddd, J= 9.6, 2.1 Hz, IH), 7.83-7.20 (m, 2H), 7.61 (d, J= 8.4 Hz, IH), 7.53 (d, J= 1.8 Hz, IH), 7.09 (dd, J= 8.4, 1.8 Hz, IH), 6.59 (dd, J= 7.5, 2.6 Hz, IH), 6.36 (d, J= 2.6 Hz, IH), 5.41 (s, 2H), 4.76 (d, J= 14.2 Hz, IH), 4.39 (d, J= 14.2 Hz, IH), 3.94-3.82 (m, 2H), 3.74 (s, 3H), 3.65-3.58 (m, 2H), 3.13 (s, 3H); ESI MS m/z 419 [M + H] ⁺ ; HPLC (Method B) 95.8% (AUC), t _R = 11.0 min.

Example 60

Preparation of 4-(5-Chloropyridin-2-yl)- 1 -(2.5-dimethyl-2.3 A5-tetrahydro- lH-pyridor4.3-

&1indol-7-yl)pyridin-2(lH)-one dihydrochloride

Chemical Formula: C ₂₃ H ₂₃ Cl ₃ N ₄ O

Exact Mass: 476.09 Molecular Weight: 477.81

4-(5-Chloropyridin-2-yl)-l-(5-methyl-2,3,4,5-tetrahydro-lH-p yrido[4,3-δ]indol-7- yl)pyridin-2(lH)-one (57 mg, 0.14 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (54.5 mg, 81%) as a yellow solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.72 (d, J= 1.7 Hz, IH), 8.03 (d, J= 7.9 Hz, IH), 7.99 (dd, J= 8.2, 2.2 Hz, IH), 7.79 (d, J= 7.1 Hz, IH), 7.61 (d, J= 8.3 Hz, IH), 7.56 (d, J = 1.3 Hz, IH), 7.34 (d, J= 1.5 Hz, IH), 7.19 (dd, J= 7.2, 1.8 Hz, IH), 7.14 (dd, J= 8.3, 1.8 Hz, IH), 4.80^1.72 (br m, IH), 4.46-4.34 (m, IH), 3.96-3.86 (m, IH), 3.75 (s, 3H), 3.65-3.55 (br m, IH), 3.28 (s, 2H), 3.14 (s, 3H); ESI MS m/z 405 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 12.0 min.

Example 61

Preparation of 4-(Benzyloxy)- 1 -(5-methyl-2-(2-(pyrrolidin- 1 -yl)ethyl)-2,3,4,5-tetrahydro- lH-pyrido[4,3-ά]indol-7-yl)pyridin-2(lH)-one dihydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₃₀ H ₃₆ Cl ₂ N ₄ O ₂

Exact Mass: 554.22 Molecular Weight: 555.54

4-(Benzyloxy)-l-(5-methyl-2,3,4,5-tetrahydro-l/f-pyrido[4,3- δ]indol-7-yl)pyridin- 2(lH)-one (180 mg, 0.46 mmol), l-(2-chloroethyl)pyrrolidine hydrochloride (95 mg, 0.56 mmol), (/-Pr) ₂ EtN (0.25 mL, 1.4 mmol) were combined in ethanol (2 mL) and heated at 60 ⁰ C for 2 h. Purification by preparative HPLC and conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound as a white solid: mp 285-289 ⁰ C; ¹ H NMR (300 MHz, D ₂ O) δ 7.50 (d, J= 8.3 Hz, IH), 7.46 (d, J= 7.7 Hz, IH), 7.42-7.31 (m, 6H), 6.96 (dd, J= 8.3, 1.6 Hz, IH), 6.27 (dd, J= 7.7, 2.6 Hz, IH), 6.10 (d, J= 2.6 Hz, IH), 5.90 (s, 2H), 4.59 (br s, 2H), 3.81-3.59 (m, 8H), 3.55 (s, 3H), 3.20 (t, J = 5.7 Hz, 2H), 3.18-3.05 (br m, 2H), 2.15-1.90 (m, 4H); ESI MS m/z 483 [M + H] ⁺ ; HPLC (Method B) 98.8% (AUC), t _R = 11.3 min.

Example 62

Preparation of l-(2.5-Dimethyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-y l)-4-(5-

(trifluoromethyl)pyridin-2-yl)pyridin-2( lHVone dihydrochloride

Chemical Formula: C ₂₄ H ₂₃ Cl ₂ F ₃ N ₄ O

Exact Mass: 510.12 Molecular Weight: 51 1.37 l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4 -(5- (trifluoromethyl)pyridin-2-yl)pyridin-2(l/-/)-one (68 mg, 0.16 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (39.6 mg, 48%) as a brown solid: mp 274-280 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 9.04 (s, IH), 8.28 (dd, J = 8.7, 1.9 Hz, IH), 8.21 (d, J= 2.1 Hz, IH), 7.83 (d, J

Attorney's Docket 2882.023B

= 7.1 Hz, IH), 7.62 (d, J= 8.3 Hz, IH), 7.58 (d, J= 1.3 Hz, IH), 7.39 (d, J= 1.6 Hz, IH), 7.24 (dd, J= 7.1, 1.9 Hz, IH), 7.15 (dd, J= 8.3, 1.7 Hz, IH), 4.80-4.71 (br m, IH), 4.44- 4.35 (br m, IH), 3.96-3.86 (br m, IH), 3.75 (s, 3H), 3.67-3.57 (br m, IH), 3.28 (s, 2H), 3.14 (s, 3H); ESI MS m/z 439 [M + H] ⁺ ; HPLC (Method B) 96.4% (AUC), t _R = 12.6 min.

Example 63

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-yl)-4 -(6- methylpyridazin-3-yl)pyridin-2(lH)-one dihydrochloride

a) 3-(2-Methoxypyridin-4-yl)-6-methylpyridazine

Chemical Formula: C ₁₁ H ₁₁ N ₃ O

Exact Mass: 201.09 Molecular Weight: 201.22

3-Chloro-6-methylpyridazine (343 mg, 2.67 mmol) and 2-methoxy-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (470 mg, 2.0 mmol) were reacted according to Example 31 (step a) to provide the title compound (183 mg, 45%) as a cream solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.31 (d, J= 5.3 Hz, IH), 7.62 (d, J= 8.7 Hz, IH), 7.59 (dd, J = 5.3, 1.5 Hz, IH), 7.43 (d, J= 8.6 Hz, IH), 7.38 (s, IH), 4.00 (s, 3H), 2.79 (s, 3H).

b) 4-(6-Methylpyridazin-3-yl)pyridin-2(lH)-one

Chemical Formula: C ₁₀ H ₉ N ₃ O

Exact Mass: 187.07 Molecular Weight: 187.20

3-(2-Methoxypyridin-4-yl)-6-methylpyridazine (183 mg, 0.909 mmol) was reacted according to Example 31 (step c) to provide the title compound (133 mg, 75%) as a white solid: ¹ H NMR (300 MHz, CD ₃ OD) δ 8.12 (d, J= 8.8 Hz, IH), 7.73 (d, J= 8.8 Hz, IH), 7.59 (d, J= 6.6 Hz, IH), 7.17-7.14 (m, 2H), 2.75 (s, 3H).

Attorney's Docket 2882.023B

c) tert-Butyl 5-methyl-7-(4-(6-methylpyridazin-3-yl)-2-oxopyridin-l(2H)-yl )-3,4-dihydro- lH-pyrido[4,3-6]indole-2(5H)-carboxylate

3-(2-Methoxypyridin-4-yl)-6-methylpyridazine (133 mg, 0.710 mmol) and tert- butyl 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-c arboxylate (259 mg, 0.71 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (200 mg, 59%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.83 (d, J = 8.7 Hz, IH), 7.60 (d, J= 7.2 Hz, IH), 7.56 (d, J= 8.3 Hz, IH), 7.48 (d, J= 8.8 Hz, IH), 7.39 (d, J= 1.6 Hz, IH), 7.29 (overlapping ddd, J= 7.3, 1.8 Hz, IH), 7.17 (d, J= 1.8 Hz, IH), 7.11 (d, J= 7.6 Hz, IH), 4.67 (br s, 2H), 3.91-3.83 (br m, 2H), 3.67 (s, 3H), 2.89- 2.83 (br m, 2H), 2.53 (s, 3H), 1.52 (s, 9H).

d) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)- 4-(6-methylpyridazin-3- yl)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₂ H ₂₃ Cl ₂ N ₅ O

Exact Mass: 443.13 Molecular Weight: 444.36 tert-Butyl 5 -methyl-7-(4-(6-methylpyridazin-3-yl)-2-oxopyridin-l(2H)-yl) -3, A- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (200 mg, 0.42 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (57 mg, 33%) as an orange solid: mp 310-315 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.47 (d, J= 8.8 Hz, IH), 8.03 (d, J= 8.8 Hz, IH), 7.89 (d, J= 7.4 Hz, IH), 7.64 (d, J= 8.4 Hz, IH), 7.58 (d, J= 1.6 Hz, IH), 7.35 (d, J= 1.6 Hz,

Attorney's Docket 2882.023B

IH), 7.25 (dd, J= 7.1, 1.9 Hz, IH), 7.15 (dd, J= 8.3, 1.9 Hz, IH), 4.49 (s, 2H), 3.75 (s, 3H), 3.68 (t, J= 6.2 Hz, 2H), 3.24 (t, J= 6.2 Hz, 2H), 2.85 (s, 3H); ESI MS m/z 372 [M + H] ⁺ ; HPLC (Method B) 98% (AUC), t _R = 9.3 min.

Example 64

Preparation of l-(2.5-Dimethyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-y l)-4-(6- methylpyridazin-3-yl)pyridin-2(lH)-one dihydrochloride

Chemical Formula: C ₂₃ H ₂₅ Cl ₂ N ₅ O

Exact Mass: 457.14 Molecular Weight: 458.38 l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)- 4-(6-methylpyridazin- 3-yl)pyridin-2(lH)-one (77 mg, 0.21 mmol) was reacted according to the procdure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (60 mg, 74%) as a yellow solid: mp 285-288 ⁰ C; ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 10.9 (s, IH), 8.32 (d, J= 8.8 Hz, IH), 7.85 (d, J= 7.2 Hz, IH), 7.79 (d, J= 8.8 Hz, IH), 7.64 (d, J= 1.5 Hz, IH), 7.56 (d, J = 8.3 Hz, IH), 7.25 (d, J= 1.7 Hz, IH), 7.14-7.11 (m, 2H), 4.65 (d, J= 12.1 Hz, IH), 4.31 (dd, J= 14.2, 7.5 Hz, IH), 3.81-3.74 (m, IH), 3.71 (s, 3H), 3.55-3.45 (m, IH), 3.26-3.15 (m, 2H), 2.98 (s, 3H), 2.72 (s, 3H); ESI MS m/z 386 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 9.4 min.

Example 65

Preparation of 4-(4-Fluoro-2-methoxyphenyD- 1 -(5-methyl-2,3,4,5-tetrahydro- IH- pyrido[4,3-ά]indol-7-yl)pyridin-2(lH)-one hydrochloride

a) 4-(4-Fluoro-2-methoxyphenyl)pyridine 1 -oxide

Attorney's Docket 2882.023B

Chemical Formula: C ₁₂ H ₁₀ FNO ₂

Exact Mass: 219.07 Molecular Weight: 219.21

4-Chloropyridine-iV-oxide (305 mg, 2.35 mmol), 4-fluoro-2-methoxyphenylboronic acid (1.0 g, 8.8 mmol) were reacted according to the procedure of Example 39 (step a) to provide the title compound (450 mg, 87%) as a purple solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.21 (d, J= 7.2 Hz, 2H), 7.45 (d, J= 7.2 Hz, 2H), 7.31 (d, J= 6.5 Hz, IH), 6.80-6.71 (m, 2H), 3.85 (s, 3H).

b) 4-(4-Fluoro-2-methoxyphenyl)pyridin-2( lH)-one

Chemical Formula: C ₁₂ H ₁₀ FNO ₂ Exact Mass: 219.07 Molecular Weight: 219.21

4-(4-Fluoro-2-methoxyphenyl)pyridine 1 -oxide (450 mg, 2.05 mmol) was reacted according to the procedure of Example 32 (step b) to provide the title compound (291 mg, 66%) as a brown solid: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 11.4 (br s, IH), 7.39-7.31 (m, 2H), 7.03 (d, J= 10.2 Hz, IH), 6.85 (overlapping dd, J= 7.4 Hz, IH), 6.35 (s, IH), 6.27 (d, J= 6.1 Hz, IH), 3.80 (s, 3H).

c) tert-Butyl 7-(4-(4-fluoro-2-methoxyphenyl)-2-oxopyridin-l(2/-/)-yl)-5-m ethyl-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5/-/)-carboxylate

Chemical Formula: C ₂₉ H ₃₀ FN ₃ O ₄

Exact Mass: 503.22 Molecular Weight: 503.56

4-(4-Fluoro-2-methoxyphenyl)pyridin-2(lH)-one (100 mg, 0.45 mmol) and tert- butyl 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-c arboxylate (166 mg, 0.454 mmol) were reacted following the procedure of Example 30 (step g) to provide the

Attorney's Docket 2882.023B title compound (106 mg, 46%) as a yellow oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53 (d, J = 8.2 Hz, IH), 7.41 (d, J= 7.1 Hz, IH), 7.39-7.32 (m, 2H), 7.08 (d, J= 8.0 Hz, IH), 6.80- 6.70 (m, 3H), 6.46 (dd, J= 7.1, 1.9 Hz, IH), 4.66 (br s, 2H), 3.87 (s, 3H), 3.86-3.78 (m, 2H), 3.64 (s, 3H), 2.83 (t, J= 6.1 Hz, 2H), 1.50 (s, 9H).

d) 4-(4-Fluoro-2-methoxyphenyl)-l-(5-methyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-δ]indol-7- yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₃ ClFN ₃ O ₂ Exact Mass: 439.15 Molecular Weight: 439.91 tert-EvXy\ 7-(4-(4-fluoro-2-methoxyphenyl)-2-oxopyridin-l(2H)-yl)-5-met hyl-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (106 mg, 0.211 mmol) was deprotected according to the procedure of Example 30 (step e) to provide the free base (74 mg, 88%). The free-base (37 mg, 0.092 mmol) was converted to the hydrochloride salt according to the procedure of Example 30 (steps g) to provide the title compound (35 mg, 89%) as a yellow solid: mp 296-300 ⁰ C; ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 9.56 (br s, 2H), 7.64 (d, J = 7.1 Hz, IH), 7.62-7.55 (m, 2H), 7.47 (dd, J= 8.4, 6.9 Hz, IH), 7.12-7.06 (m, 2H), 6.90 (overlapping ddd, J= 8.4, 2.4 Hz, IH), 6.55 (d, J= 1.6 Hz, IH), 6.47 (dd, J= 7.1, 1.8 Hz, IH), 4.37-4.30 (br m, 2H), 3.81 (s, 3H), 3.69 (s, 3H), 3.56-3.45 (br m, 2H), 3.10 (t, J= 5.5 Hz, 2H); ESI MS m/z 404 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 12.5 min.

Example 66

Preparation of l-(2.5-Dimethyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-ά1indol-7- yl)-4-(4-fluoro- 2-methoxyphenyl)pyridin-2( lHVone hydrochloride

Chemical Formula: C ₂₅ H ₂₅ ClFN ₃ O ₂

Exact Mass: 453.16 Molecular Weight: 453.94

Attorney's Docket 2882.023B

4-(4-Fluoro-2-methoxyphenyl)-l-(5-methyl-2,3,4,5-tetrahydro- lH-pyrido[4,3- δ]indol-7-yl)pyridin-2(lH)-one (37 mg, 0.092 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (21 mg, 52%) as a yellow solid: mp 294-298°C; ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 10.83 (br s, IH), 7.65 (d, J= 7.1 Hz, IH), 7.61 (d, J= 1.4 Hz, IH), 7.54 (d, J= 8.3 Hz, IH), 7.46 (dd, J= 8.4, 6.9 Hz, IH), 7.12-7.10 (m, IH), 7.08 (d, J= 1.4 Hz, IH), 6.91 (overlapping ddd, J= 8.4, 2.4 Hz, IH), 6.55 (d, J= 1.6 Hz, IH), 6.48 (dd, J= 7.1, 1.6 Hz, IH), 4.62 (d, J= 12.2 Hz, IH), 4.30 (dd, J= 14.2, 7.5 Hz, IH), 3.86 (s, 3H), 3.80-3.76 (m, IH), 3.75 (s, 3H), 3.52-3.42 (m, IH), 3.24-3.15 (m, 2H), 2.79 (d, J= 4.6 Hz, 3H); ESI MS m/z 418 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 12.6 min.

Example 67

Preparation of 4-(Benzyloxy)- 1 -(5-methyl-2-(piperidin-4-yl)-2,3 ,4,5-tetrahydro- IH- pyrido[4,3-&lindol-7-yl)pyridin-2(lH)-one dihydrochloride

a) tert-Butyl 4-(7-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-dihy dro-lH- pyrido[4,3-δ]indol-2(5H)-yl)piperidine-l-carboxylate

4-(Benzyloxy)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4, 3-δ]indol-7-yl)pyridin- 2(lH)-one (100 mg, 0.26 mmol) and tert-bvXy\ 4-oxopiperidine-l-carboxylate (27 mg, 0.26 mmol) were stirred in methylene chloride (1 mL) and AcOH (0.1 mL), and picoline borane complex (27 mg, 0.26 mmol) was added. After stirring for 16 h, the mixture was diluted with methylene chloride, washed with sodium carbonate solution and concentrated. The

Attorney's Docket 2882.023B obtained residue was purified by flash column chromatography (silica gel, (1 :1 EtOAc/hexanes)/(10:l methanol/ammonia), 10:0 to 9:1) to provide the title compound (90 mg, 61%) as a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.45-7.36 (m, 5H), 7.32-7.30 (m, IH), 7.32-7.27 (m, 2H), 6.99 (dd, J= 8.2, 1.6 Hz, IH), 6.05-6.01 (m, 2H), 5.05 (s, 2H), 4.20 (s, 2H), 3.85 (s, 2H), 3.60 (s, 3H), 3.04-2.93 (m, 2H), 2.88-2.66 (m, 5H), 1.98- 1.87 (m, 2H), 1.60-1.54 (m, 2H), 1.47 (s, 9H).

b) 4-(Benzyloxy)-l-(5-methyl-2-(piperidin-4-yl)-2,3,4,5-tetrahy dro-lH-pyrido[4,3-δ]indol-

7-yl)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₉ H ₃₄ Cl ₂ N ₄ O ₂

Exact Mass: 540.21 Molecular Weight: 541.51

tert-Butyl 4-(7-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-dihy dro-lH- pyrido[4,3-δ]indol-2(5H)-yl)piperidine-l-carboxylate (90 mg, 0.16 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (85 mg, 100%) as an orange solid: ¹ H NMR (500 MHz, D ₂ O) δ 7.56-7.53 (m, 2H), 7.48-7.40 (m, 6H), 7.02 (dd, J= 8.4, 1.4 Hz, IH), 6.33 (dd, J= 7.5, 2.4 Hz, IH), 6.17 (d, J= 2.4 Hz, IH), 5.16 (s, 2H), 4.63 (br s, 2H), 4.09-3.79 (br m, 2H), 3.69-3.53 (m, 6H), 3.26-3.23 (m, 2H), 3.14 (t, J= 12.8 Hz, 2H), 2.49 (d, J = 1.3 Hz, 2H), 2.16-2.04 (m, 2H); ESI MS m/z 469 [M + H] ⁺ ; HPLC (Method B) 98.1% (AUC), to = 11.4 min.

Example 68

Preparation of 4-(Benzyloxy)-l-(5-methyl-2-(l-methylpiperidin-4-yl)-2,3,4,5 -tetrahydro- lH-Pwidor4,3-&1indol-7-yl)pyridin-2(lH)-one dihydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₃₀ H ₃₆ Cl ₂ N ₄ O ₂

Exact Mass: 554.22 Molecular Weight: 555.54

4-(Benzyloxy)-l-(5-methyl-2-(piperidin-4-yl)-2,3,4,5-tetrahy dro-lH-pyrido[4,3- δ]indol-7-yl)pyridin-2(lH)-one (50 mg, 0.11 mmol) was methylated according to the procedure of Example 47 to provide the title compound (30 mg, 51%) as a white solid: ¹ H NMR (500 MHz, D ₂ O) δ 7.56-7.52 (m, 2H), 7.48-7.38 (m, 6H), 7.02 (dd, J= 8.3, 1.6 Hz, IH), 6.33 (dd, J= 7.5, 2.6 Hz, IH), 6.16 (d, J= 2.5 Hz, IH), 5.16 (s, 2H), 4.63 (s, 2H), 3.85-3.83 (m, 2H), 3.74-3.71 (m, 2H), 3.62 (s, 3H), 3.26-3.14 (m, 5H), 2.89 (s, 3H), 2.55- 2.50 (m, 2H), 2.19-2.12 (m, 2H); ESI MS m/z 483 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = U.4 min.

Example 69

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-yl)-4 -(6-

(trifluoromethyl)pyridin-3-yl)pyridin-2(l/-/)-one dihydrochloride

a) 2'-Methoxy-6-(trifluoromethyl)-3 ,4'-bipyridine

Chemical Formula: C ₁₂ H ₉ F ₃ N ₂ O

Exact Mass: 254.07 Molecular Weight: 254.21

2-Methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyridine (1.24 g, 0.53 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (2.4 g, 11 mmol) were reacted according to the procedure of Example 31 (step a) to provide the title compound (1.1 g, 81%) as a white solid: ESI MS m/z 255 [M + H].

b) 4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(l/-/)-one

Attorney's Docket 2882.023B

Chemical Formula: C ₁₁ H ₇ F ₃ N ₂ O

Exact Mass: 240.05 Molecular Weight: 240.18

2'-Methoxy-6-(trifluoromethyl)-3,4'-bipyridine (1.1 g, 4.3 mmol) was reacted according to the procedure of Example 31 (step c) to provide the title compound (522 mg, 50%) as a white solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 11.8 (br s, IH), 9.10 (s, IH), 8.40 (dd, J= 8.1, 1.2 Hz, IH), 8.00 (d, J= 8.2 Hz, IH), 7.56 (d, J= 6.7 Hz, IH), 6.81 (s, IH), 6.63 (dd, J= 6.7, 1.3 Hz, IH).

c) tert-Butyl 5-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin -l(2H)-yl)-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(l/-/)-one (131 mg, 0.54 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-c arboxylate (200 mg, 0.54 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (167 mg, 59%) as a green solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.99 (d, J= 2.0 Hz, IH), 8.10 (dd, J= 8.1, 1.8 Hz, IH), 7.84 (d, J= 8.2 Hz, IH), 7.60-7.54 (m, 2H), 7.32 (d, J= 1.9 Hz, IH), 7.07 (d, J= 8.0 Hz, IH), 6.93 (d, J= 1.8 Hz, IH), 6.49 (dd, J = 7.1, 2.0 Hz, IH), 4.66 (s, 2H), 3.85 (br m, 2H), 3.65 (s, 3H), 2.84 (s, 2H), 1.50 (s, 9H).

d) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4 -(6- (trifluoromethyl)pyridin-3-yl)pyridin-2(l/-/)-one dihydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₃ H ₂₁ Cl ₂ F ₃ N ₄ O

Exact Mass: 496.10 Molecular Weight: 497.34 tert-BvXyl 5 -methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridin-3 -yl)pyridin- 1 (2H)-yl)- 3,4-dihydro-l/f-pyrido[4,3-δ]indole-2(5H)-carboxylate (165 mg, 0.315 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (40 mg, 26%) as a yellow solid: ¹ H NMR (300 MHz, CD ₃ OD) δ 9.10 (d, J= 2.0 Hz, IH), 8.41 (dd, J= 8.2, 1.7 Hz, IH), 7.98 (d, J= 8.2 Hz, IH), 7.85 (d, J= 7.2 Hz, IH), 7.61 (d, J= 8.2 Hz, IH), 7.57 (d, J= 1.6 Hz, IH), 7.14 (dd, J= 8.3, 1.9 Hz, IH), 7.02 (d, J= 1.6 Hz, IH), 6.89 (dd, J= 7.1, 2.0 Hz, IH), 4.49 (s, 2H), 3.76 (s, 3H), 3.68 (t, J= 6.2 Hz, 2H), 3.22 (t, J= 6.2 Hz, 2H); ESI MS m/z 425 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 12.3 min.

Example 70

Preparation of l-(2.5-Dimethyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-y l)-4-(6-

(trifluoromethyl)pyridin-3-yl)pyridin-2(l/-/)-one

Chemical Formula: C ₂₄ H ₂₃ Cl ₂ F ₃ N ₄ O

Exact Mass: 510.12 Molecular Weight: 51 1.37 l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4 -(6- (trifluoromethyl)pyridin-3-yl)pyridin-2(l/-/)-one (77 mg, 0.18 mmol) was reacted according to the procedure of Example 47 and converted to the dihydrochloride to provide the title compound (27 mg, 29%) as a yellow solid: mp 295-300 ⁰ C; ¹ U NMR (500 MHz, CD ₃ OD) δ 9.09 (d, J= 1.7 Hz, IH), 8.42 (dd, J= 8.1, 2.0 Hz, IH), 7.97 (d, J= 8.2 Hz, IH), 7.85 (d, J= 7.1 Hz, IH), 7.62 (d, J= 8.3 Hz, IH), 7.58 (d, J= 1.5 Hz, IH), 7.15 (dd, J

Attorney's Docket 2882.023B

= 8.3, 1.8 Hz, IH), 7.02 (d, J= 1.8 Hz, IH), 6.89 (dd, J= 7.1, 2.0 Hz, IH), 4.79-4.37 (br m, 2H), 3.90-3.60 (br m, 5H), 3.30 (br m, 2H), 3.14 (s, 3H); ESI MS m/z 439 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 12.4 min.

Example 71

Preparation of l-(2.3.4.5-Tetrahvdro-lH-pyridor4.3-άlindol-7-yl)-4-(5-

(trifluoromethyl)pyridin-2-yl)pyridin-2( lHVone dihydrochloride

a) tert-Butyl 7-bromo-5-tosyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-ca rboxylate

Chemical Formula: C ₂₃ H ₂₅ BrN ₂ O ₄ S

Exact Mass: 504.07 Molecular Weight: 505.42 tert-&vXy\ 7-bromo-3,4-dihydro-lH-pyrido[4,3-6]indole-2(5H)-carboxylate (1.07 g, 3.04 mmol) was reacted according to the procedure of Example 87 (step a) to provide the title compound (1.39 g, 91%) as a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.35 (s, IH), 7.66 (d, J= 6.6 Hz, 2H), 7.35 (d, J= 8.2 Hz, IH), 7.28-7.21 (m, 2H), 7.18 (d, J= 8.1 Hz, IH), 4.47 (s, 2H), 3.77-3.65 (br m, 2H), 3.11-3.03 (br m, 2H), 2.36 (s, 3H), 1.48 (s, 9H).

b) tert-Butyl 7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-l(2H)-yl )-5-tosyl-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(lH)-one (131 mg, 0.545 mmol) and tert-butyl 7-bromo-5-tosyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-ca rboxylate (255 mg, 0.505 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (125 mg, 34%) as a yellow oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.01 (s, IH), 8.29 (d, J= 1.6 Hz, IH), 8.08 (dd, J= 8.3, 1.9 Hz, IH), 7.92 (d, J= 8.3 Hz, IH), 7.74

Attorney's Docket 2882.023B

(d, J= 8.3 Hz, IH), 7.57 (d, J= 7.2 Hz, IH), 7.46 (d, J= 8.2 Hz, IH), 7.33 (dd, J= 8.2, 1.6 Hz, IH), 7.29-7.23 (m, 4H), 7.09 (dd, J= 7.2, 1.8 Hz, IH), 4.52 (s, 2H), 3.80-3.73 (br m, 2H), 3.18-3.09 (br m, 2H), 2.35 (s, 3H), 1.50 (s, 9H).

b) l-(5-Tosyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4- (5- (trifluoromethyl)pyridin-2-yl)pyridin-2(lH)-one trifluoroacetic acid salt

Chemical Formula: C ₁ H ₂₃ F ₆ N ₄ O ₄ S

Exact Mass: 661.13 Molecular Weight: 661.59 tert-Butyi 7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin- 1 (2H)-yl)-5-tosyl- 3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (165 mg, 0.248 mmol) was stirred in TFA (3 rnL) and methylene chloride (1 mL) for 3 h. Concentration of the solution under reduced pressure provided the title compound (164 mg, 100%) as a yellow oil; ESI MS m/z 565 [M + H] ⁺ .

c) l-(2,3,4,5-Tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)-4-(5-(tri fluoromethyl)pyridin-2- yl)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₂ H ₁₉ Cl ₂ F ₃ N ₄ O

Exact Mass: 482.09

Molecular Weight: 483.31 l-(5-Tosyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4- (5-

(trifluoromethyl)pyridin-2-yl)pyridin-2(lH)-one trifluoroacetic acid salt (163 mg, 0.248 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 106 (step b) to provide the title compound (30 mg, 25%) as an orange solid: mp 308-313 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 9.04 (s, IH), 8.28 (dd, J = 8.3, 2.2 Hz, IH), 8.22 (d, J= 8.2 Hz, IH), 7.81 (d, J= 7.0 Hz, IH), 7.62 (d, J= 8.3 Hz, IH), 7.46 (d, J= 1.8 Hz, IH), 7.38 (d, J= 1.8 Hz, IH), 7.24 (dd, J= 7.1, 2.0 Hz, IH), 7.11

Attorney's Docket 2882.023B

(dd, J= 8.3, 2.0 Hz, IH), 4.49 (s, 2H), 3.65 (t, J= 6.2 Hz, 2H), 3.21 (t, J= 6.2 Hz, 2H); ESI MS m/z 411 [M + H] ⁺ ; HPLC (Method B) 97.6% (AUC), t _R = 12.4 min.

Example 72

Preparation of l-(2.3.4.5-Tetrahvdro-lH-pyridor4.3-άlindol-7-yl)-4-(6-

(trifluoromethyl)pyridazin-3-yl)pyridin-2(lH)-one hydrochloride

a) tert-Butyl 7-bromo-5-(triisopropylsilyl)-3,4-dihydro-lH-pyrido[4,3-δ]i ndole-2(5H)- carboxylate

Chemical Formula: C ₂₅ H ₃₉ BrN ₂ O ₂ Si

Exact Mass: 506.20 Molecular Weight: 507.58 tert-Butyl 7-bromo-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylat e (300 mg, 0.85 mmol) was dissolved in DMF (3 niL), and NaH (60% weight dispersion in mineral oil, 40 mg, 1.02 mmol) and TIPSCl (164 mg, 1.02 mmol) were added. After stirring for 1 h, the mixture was poured into water and extracted with EtOAc. Concentration of the organic extracts and purification of the residue by flash column chromatography (silica gel, EtOAc/hexanes) provided the title compound (262 mg, 61%) as a clear oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.70 (s, IH), 7.25 (d, J= 8.2 Hz, IH), 7.19 (dd, J= 8.2, 1.4 Hz, IH), 4.59 (s, 2H), 3.76-3.71 (br m, 2H), 2.96-2.90 (br m, 2H), 1.81- 1.71 (m, 3H), 1.51 (s, 9H), 1.15 (d, J= 7.5 Hz, 18H).

b) tert-Butyl 7-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-l(2H)- yl)-3,4-dihydro- lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

Chemical Formula: C ₂₆ H ₂₄ F ₃ N ₅ O ₃

Exact Mass: 511.18 Molecular Weight: 51 1.50

Attorney's Docket 2882.023B tert-Butyl 7-bromo-5-(triisopropylsilyl)-3,4-dihydro-lH-pyrido[4,3-δ]i ndole- 2(5H)-carboxylate (260 mg, 0.51 mmol) and 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin- 2(lH)-one (123 mg, 0.510 mmol) were reacted according to the procedure of Example 30 (step g) to provide the title compound (80 mg, 30%) as a yellow solid: ESI MS m/z 512 [M + H] ⁺ .

c) l-(2,3,4,5-Tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)-4-(6-(tri fluoromethyl)pyridazin-3- yl)pyridin-2(lH)-one hydrochloride

tert-Butyl 7-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-l(2H)- yl)-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (80 mg, 0.15 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (30 mg, 44%) as an orange solid: mp 314-318 ⁰ C; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.52 (d, J= 8.9 Hz, IH), 8.28 (d, J= 8.9 Hz, IH), 7.89 (d, J = 7.2 Hz, IH), 7.62 (d, J= 8.3 Hz, IH), 7.48 (d, J= 1.5 Hz, IH), 7.43 (d, J= 1.5 Hz, IH), 7.33 (dd, J= 7.2, 2.0 Hz, IH), 7.14 (dd, J= 7.4, 2.0 Hz, IH), 4.49 (s, 2H), 3.65 (t, J= 6.2 Hz, 2H), 3.21 (t, J= 6.2 Hz, 2H); ESI MS m/z 412 [M + H] ⁺ ; HPLC (Method B) 96.0% (AUC), to = l l.ÏŒ min.

Example 73

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyrido[4.3-^1indol-7-yl)-4 -(2-

(trifluoromethyl)pyrimidin-5-yl)pyridin-2(lH)-one hydrochloride

a) 5 -(2-Methoxypyridin-4-yl)-2-(trifluoromethyl)pyrimidine

Attorney's Docket 2882.023B

Chemical Formula: C ₁₁ H ₈ F ₃ N ₃ O

Exact Mass: 255.06 Molecular Weight: 255.20

2-Methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyr idine (2.0 g, 8.5 mmol) and 5-chloro-2-(trifluoromethyl)pyrimidine (2.3 g, 13 mmol) were reacted according to the procedure of Example 31 (step a) to provide the title compound (1.0 g, 46 %) as a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.10 (s, 2H), 8.35 (d, J= 5.5 Hz, IH), 7.11 (dd, J= 5.5, 1.6 Hz, IH), 6.98 (d, J= 1.6 Hz, IH), 4.02 (s, 3H).

b) 4-(2-(Trifluoromethyl)pyrimidin-5-yl)pyridin-2(l/-/)-one

Chemical Formula: C ₁₀ H ₆ F ₃ N ₃ O

Exact Mass : 241.05 Molecular Weight: 241.17

5-(2-Methoxypyridin-4-yl)-2-(trifluoromethyl)pyrimidine (900 mg, 3.5 mmol) was reacted according to the procedure of Example 31 (step c) to provide the title compound (470 mg, 56%) as an orange solid: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 11.6 (br s, IH), 9.41 (s, 2H), 7.61 (d, J= 6.8 Hz, IH), 6.91 (s, IH), 6.68 (dd, J= 6.8, 1.6 Hz, IH).

c) tert-Butyl 5-methyl-7-(2-oxo-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyrid in- 1 (2H)-yl)- 3,4-dihydro-lH-pyrido[4,3-6]indole-2(5H)-carboxylate

Chemical Formula: C ₂₇ H ₂₆ F ₃ N ₅ O ₃

Exact Mass : 525.20 Molecular Weight: 525.52

4-(2-(Trifluoromethyl)pyrimidin-5-yl)pyridin-2(l/-/)-one (100 mg, 0.42 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-c arboxylate (116

Attorney's Docket 2882.023B mg, 0.32 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (41 mg, 24%) as a yellow oil: ESI MS m/z 526 [M + H] ⁺ .

d) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4 -(2-

(trifluoromethyl)pyrimidin-5-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₂ H ₁₉ ClF ₃ N ₅ O

Exact Mass: 461.12 Molecular Weight: 461.87 tert-Butyl 5 -methyl-7-(2-oxo-4-(2-(trifluoromethyl)pyrimidin-5 -yl)pyridin- 1 (2H)- yl)-3,4-dihydro-lH-pyrido[4,3-6]indole-2(5H)-carboxylate (41 mg, 0.078 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (29 mg, 80%) as a yellow solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.51 (s, 2H), 9.37 (br s, 2H), 7.90 (d, J= 7.2 Hz, IH), 7.62-7.60 (m, 2H), 7.13 (d, J= 1.9 Hz, IH), 7.10 (dd, J= 8.3, 1.7 Hz, IH), 6.88 (dd, J= 7.1, 2.0 Hz, IH), 4.38-4.34 (br m, 2H), 3.70 (s, 3H), 3.56-3.50 (br m, 2H), 3.11 (t, J= 5.8 Hz, 2H); ESI MS m/z 426 [M + H] ⁺ ; HPLC (Method B) >100% (AUC), t _R = 12.2 min.

Example 74

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyrido[4.3-^1indol-7-yl)-4 -(5-

(trifluoromethyl)pyrimidin-2-yl)pyridin-2( lH)-one hydrochloride

a) 2-(2-Methoxypyridin-4-yl)-5 -(trifluoromethyl)pyrimidine

Chemical Formula: C ₁₁ H ₈ F ₃ N ₃ O

Exact Mass: 255.06 Molecular Weight: 255.20

2-Methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyridine (1.66 g, 7.06 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine (1.3 g, 7.1 mmol) were reacted

Attorney's Docket 2882.023B according to the procedure of Example 31 (step a) to provide the title compound (307 mg, 16%) as a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.08 (s, 2H), 8.34 (d, J= 5.3 Hz, IH), 7.89 (dd, J= 5.3, 1.4 Hz, IH), 7.81 (s, IH), 4.01 (s, 3H).

b) 4-(5-(Trifluoromethyl)pyrimidin-2-yl)pyridin-2(lH)-one

Chemical Formula: C ₁₀ H ₆ F ₃ N ₃ O

Exact Mass : 241.05 Molecular Weight: 241.17

2-(2-Methoxypyridin-4-yl)-5-(trifluoromethyl)pyrimidine (400 mg, 1.56 mmol) was reacted according to the procedure of Example 31 (step c) to provide the title compound (200 mg, 63 %) as a white solid: ¹ U NMR (300 MHz, DMSO-J ₆ ) δ 11.9 (br s, IH), 9.43 (s, 2H), 7.58 (d, J= 6.8 Hz, IH), 7.34 (s, IH), 7.06 (dd, J= 6.8, 1.7 Hz, IH).

c) tert-Butyl 5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)pyrid in- 1 (2H)-yl)- 3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

Chemical Formula: C ₂₇ H ₂₆ F ₃ N ₅ O ₃

Exact Mass : 525.20 Molecular Weight: 525.52

4-(5-(Trifluoromethyl)pyrimidin-2-yl)pyridin-2(lH)-one (100 mg, 0.34 mmol) and tert-butyi 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5η)- carboxylate (124 mg, 0.339 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (70 mg, 39%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.11 (s, 2H), 7.86 (s, IH), 7.59-7.53 (m, 2H), 7.38 (s, IH), 7.28-7.26 (m, IH), 7.08 (d, J= 8.4 Hz, IH), 4.89-4.63 (br m, 2H), 3.90-3.80 (br m, 2H), 3.65 (s, 3H), 2.88-2.79 (br m, 2H), 1.50 (s, 9H).

Attorney's Docket 2882.023B d) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4 -(5- (trifluoromethyl)pyrimidin-2-yl)pyridin-2( lH)-one hydrochloride

Chemical Formula: C ₂₂ H ₁₉ ClF ₃ N ₅ O

Exact Mass: 461.12 Molecular Weight: 461.87 tert-Butyl 5-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyrimidin-2-yl)pyrid in- 1 (2H)- yl)-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (70 mg, 0.13 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (51 mg, 87%) as a yellow solid: mp 301- 309 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.48 (s, 2H), 9.37 (br s, 2H), 7.89 (d, J= 7.2 Hz, IH), 7.65 (d, J= 1.6 Hz, IH), 7.61 (d, J= 8.3 Hz, IH), 7.50 (d, J= 1.6 Hz, IH), 7.21 (dd, J= 7.6, 1.9 Hz, IH), 7.12 (dd, J= 8.3, 1.8 Hz, IH), 4.41-4.31 (br m, 2H), 3.71 (s, 3H), 3.51-3.48 (br m, 2H), 3.10 (t, J= 5.6 Hz, 2H); ESI MS m/z 426 [M + H] ⁺ ; HPLC (Method B) 97.9% (AUC), t _R = 12.6 min.

Example 75

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-yl)-4 -((6-

(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(lH)-one hydrochloride

a) 2-Methoxy-4-((6-(trifluoromethyl)pyridin-3 -yl)methoxy)pyridine

Chemical Formula: C ₁₃ H ₁₁ F ₃ N ₂ O ₂ Exact Mass: 284.08

Molecular Weight: 284.23

4-BromoBromo-2-methoxypyridine (3.06 g, 16.2 mmol), (6- (trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol), 3,4,7,8- tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g, 0.74 mmol) and Cs ₂ CO ₃ (7.57 g, 23.2 mmol) were combined in toluene (15 mL) and heated to reflux under a nitrogen

Attorney's Docket 2882.023B atmosphere for 16 h. Upon cooling the mixture was purified by flash column chromagraphy (silica gel, hexanes/EtOAc, 1 :0 to 1 :1) to provide the title compound (3.19 g, 72%) as a red oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.78 (s, IH), 8.02 (d, J= 5.9 Hz, IH), 7.95 (d, J= 8.1 Hz, IH), 7.32 (d, J= 8.0 Hz, IH), 6.55 (dd, J= 5.9, 2.2 Hz, IH), 6.26 (d, J = 2.2 Hz, IH), 5.16 (s, 2H), 3.93 (s, 3H).

b) 4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(lH)-on e

Chemical Formula: C ₁₂ H ₉ F ₃ N ₂ O ₂ Exact Mass: 270.06

Molecular Weight: 270.21

2-Methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridi ne (3.19 g, 11.2 mmol) was reacted according to the procedure of Example 31 (step c) to provide the title compound (2.04 g, 67%) as a white solid: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 11.2 (br s, IH), 8.84 (s, IH), 8.14 (d, J= 8.5 Hz, IH), 7.96 (d, J= 8.0 Hz, IH), 7.28 (d, J= 7.3 Hz, IH), 5.95 (dd, J= 7.3, 2.5 Hz, IH), 5.82 (d, J= 2.4 Hz, IH), 5.25 (s, 2H).

c) te/t-Butyl 5-methyl-7-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methox y)pyridin- l(2H)-yl)-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxyl ate

Chemical Formula: C ₂₉ H ₂₉ F ₃ N ₄ O ₄ Exact Mass: 554.21

Molecular Weight: 554.56

4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(lH)-on e (177 mg, 0.655 mmol) and tert-bvXy\ 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)- carboxylate (200 mg, 0.54 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (120 mg, 40%) as a yellow oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.80 (s, IH), 7.95 (d, J= 8.1 Hz, IH), 7.76 (d, J= 8.0 Hz, IH), 7.51 (d, J= 7.9 Hz, IH), 7.35 (d, J= 8.0 Hz, IH), 7.28 (m, IH), 7.01 (d, J= 8.1 Hz, IH), 6.06-6.04 (m,

Attorney's Docket 2882.023B

2H), 5.16 (s, 2H), 4.65-4.60 (br m, 2H), 3.89-3.79 (br m, 2H), 3.63 (s, 3H), 2.87-2.78 (br m, 2H), 1.50 (s, 9H).

d) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4 -((6- (trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(lH)-one dihydrochloride

Chemical Formula: C ₂₄ H ₂₃ Cl ₂ F ₃ N ₄ O ₂

Exact Mass: 526.12 Molecular Weight: 527.37 tert-Butyi 5 -methyl-7-(2-oxo-4-((6-(trifluoromethy l)pyridin-3 -yl)methoxy)pyridin- l(2H)-yl)-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxyl ate (120 mg, 0.21 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (90 mg, 81%) as a white solid: mp 286-291 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.54 (br s, 2H), 8.89 (s, IH), 8.19 (dd, J= 7.9, 1.4 Hz, IH), 8.00 (d, J= 8.0 Hz, IH), 7.60 (d, J= 7.6 Hz, IH), 7.55 (d, J= 8.3 Hz, IH), 7.50 (d, J= 1.7 Hz, IH), 6.98 (dd, J= 8.3, 1.8 Hz, IH), 6.15 (dd, J= 7.5, 2.7 Hz, IH), 6.02 (d, J= 2.7 Hz, IH), 5.35 (s, 2H), 4.35-4.30 (br m, 2H), 3.67 (s, 3H), 3.53-3.47 (br m, 2H), 3.09 (t, J= 5.8 Hz, 2H); ESI MS m/z 455 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), tR = 12.7 min.

Example 76

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-yl)-4 -((5-

(trifluoromethyl)pyridin-2-yl)methoxy)pyridin-2(lH)-one

a) tert-Butyi 5-methyl-7-(2-oxo-4-((5-(trifluoromethyl)pyridin-2-yl)methox y)pyridin- l(2H)-yl)-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxyl ate

Attorney's Docket 2882.023B

Chemical Formula: C ₂₉ H ₂₉ F ₃ N ₄ O ₄

Exact Mass: 554.21 Molecular Weight: 554.56

2-(Bromomethyl)-5-(trifluoromethyl)pyridine (140 mg, 0.58 mmol), tert-hvXy\ 7- (4-hydroxy-2-oxopyridin4(2H)-yl)-5-methyl-3,4-dihydro-l/f-py rido[4,3-δ]indole-2(5H)- carboxylate (230 mg, 0.58 mmol) and K2CO3 (160 mg, 1.16 mmol) were stirred in acetonitrile/DMF (3 mL/0.5mL) for 72 h. The mixture was diluted with methylene chloride, washed with water and concentrated to provide the title compound (96 mg, 29%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.88 (s, IH), 8.00 (dd, J= 8.2, 2.0 Hz, IH), 7.63 (d, J= 8.2 Hz, IH), 7.51 (d, J= 8.2 Hz, IH), 7.36 (d, J= 7.6 Hz, IH), 7.28-7.26 (m, IH), 7.00 (d, J= 7.7 Hz, IH), 6.12 (dd, J= 7.6, 2.7 Hz, IH), 6.04 (d, J= 2.7 Hz, IH), 5.26 (s, 2H), 4.63-4.58 (br m, 2H), 3.87-3.76 (br m, 2H), 3.63 (s, 3H), 2.86-2.76 (br m, 2H), 1.50 (s, 9H).

b) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4 -((5- (trifluoromethyl)pyridin-2-yl)methoxy)pyridin-2(l/-/)-one dihydrochloride

Chemical Formula: C ₂₄ H ₂₃ Cl ₂ F ₃ N ₄ O ₂

Exact Mass: 526.12 Molecular Weight: 527.37

te/t-Butyl 5 -methyl-7-(2-oxo-4-((5 -(trifluoromethyl)pyridin-2-yl)methoxy)pyridin- l(2H)-yl)-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxyl ate (90 mg, 0.16 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (76 mg, 90%) as a white solid: mp 296-300 ⁰ C; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.93 (s, IH), 8.23 (dd, J= 8.2, 2.1 Hz, IH), 7.82 (d, J= 8.2 Hz, IH), 7.70 (d, J= 7.5 Hz, IH), 7.59 (d, J= 8.3 Hz, IH), 7.49 (d, J = 1.7 Hz, IH), 7.06 (dd, J= 8.3, 1.8 Hz, IH), 6.47 (dd, J= 7.5, 2.7 Hz, IH), 6.20 (d, J =

Attorney's Docket 2882.023B

2.6 Hz, IH), 5.42 (s, 2H), 4.48 (s, 2H), 3.73 (s, 3H), 3.67 (t, J= 6.1 Hz, 2H), 3.20 (t, J = 6.1 Hz, 2H); ESI MS m/z 455 [M + H] ⁺ ; HPLC (Method B) 97.6% (AUC), t _R = 12.6 min.

Example 77

Preparation of 5-(Benzyloxy)-2-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-^ lindol-7- yl)pyridazin-3 (2H)-one hydrochloride

a) 5-(Benzyloxy)pyridazin-3(2H)-one

CAS Registry Number 1008517-73-4

Chemical Formula: C ₁₁ H ₁₀ N ₂ O ₂ Exact Mass: 202.07 Molecular Weight: 202.21

This compound was prepared in accordance with the procedure of Stenkamp et al, WO 2008/022979.

b) tert-Butyl 7-(4-(benzyloxy)-6-oxopyridazin- 1 (6H)-yl)-5-methyl-3 ,4-dihydro- IH- pyrido[4,3-δ]indole-2(5H)-carboxylate

Chemical Formula: C ₂₈ H ₃₀ N ₄ O ₄

Exact Mass: 486.23 Molecular Weight: 486.56

5-(Benzyloxy)pyridazin-3(2H)-one (100 mg, 0.5 mmol) and tert-butyl 7-bromo-5- methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (180 mg, 0.5 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (106 mg, 43%) as a solid: ESI MS m/z 487 [M + H] ⁺ .

c) 5-(Benzyloxy)-2-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-Î ´]indol-7-yl)pyridazin- 3(2H)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₃ H ₂₃ CDST ₄ O ₂

Exact Mass: 422.15 Molecular Weight: 422.91 tert-BvXyl 7-(4-(benzyloxy)-6-oxopyridazin-l(6H)-yl)-5-methyl-3,4-dihyd ro-lH- pyrido[4,3-δ]indole-2(5H)-carboxylate (100 mg, 0.2 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (30 mg, 35%) as a white solid: mp 261-265 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.23 (s, 2H), 7.96 (d, J= 2.8 Hz, IH), 7.59 (d, J= 1.6 Hz, IH), 7.54 (d, J= 8.4 Hz, IH), 7.51-7.48 (m, 2H), 7.46-7.42 (m, 2H), 7.40 (d, J= 7.5 Hz, IH), 7.13 (dd, J= 8.4, 1.7 Hz, IH), 6.51 (d, J= 2.8 Hz, IH), 5.22 (s, 2H), 4.34 (s, 2H), 3.69 (s, 3H), 3.52 (t, J= 5.8 Hz, 2H), 3.09 (t, J= 5.8 Hz, 2H); ESI MS m/z 387 [M + H] ⁺ ; HPLC (Method B) 97.7% (AUC), t _R = 12.8 min.

Example 78

Preparation of 2-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-yl)-5 -(4-

(trifluoromethyl)phenyl)pyridazin-3 (2H)-one hydrochloride

a) 5-Hydroxy-2-(tetrahydro-2/-f-pyran-2-yl)pyridazin-3(2H)-one

CAS Registry Number 1008517-74-5

Chemical Formula: C ₉ H ₁₂ N ₂ O ₃

Exact Mass: 196.08 Molecular Weight: 196.20

This compound was prepared in accordance with the procedure of Stenkamp et al., WO 2008/022979.

b) 6-Oxo- 1 -(tetrahydro-2/-f-pyran-2-yl)- 1 ,6-dihydropyridazin-4-yl trifluoromethanesulfonate

Attorney's Docket 2882.023B

Chemical Formula: C ₁₀ H ₁₁ F ₃ N ₂ O ₅ S

Exact Mass: 328.03 Molecular Weight: 328.26

5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.4 g, 13 mmol) dissolved in methylene chloride (75 mL) and cooled to 0 ⁰ C. Triethylamine (3.5 rnL, 25 mmol) and Tf ₂ O (2.3 mL, 14 mmol) were added and the mixture stirred for a further 2.5 h. Saturated NaHCCh solution was added and the organic phase removed, dried over Na ₂ SO ₄ and concentrated. Purification by flash column chromaotgraphy (silica gel, EtOAc/hexanes) provided the title compound (2.47 g, 60%) as a yellow oil: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.85 (d, J= 2.8 Hz, IH), 6.86 (d, J= 2.7 Hz, IH), 6.01 (dd, J= 10.2, 2.2 Hz, IH), 4.15-4.12 (m, IH), 3.75 (dt, J= 11.6, 2.5 Hz, IH), 2.18-2.02 (m, 2H), 1.78-1.66 (m, 3H), 1.62-1.55 (m, IH).

c) 2-(Tetrahydro-2/-f-pyran-2-yl)-5-(4-(trifluoromethyl)phenyl) pyridazin-3(2/-/)-one

Chemical Formula: C ₁₆ H ₁₅ F ₃ N ₂ O ₂ Exact Mass: 324.1 1

Molecular Weight: 324.30

6-Oxo- 1 -(tetrahydro-2/-f-pyran-2-yl)- 1 ,6-dihydropyridazin-4-yl trifluoromethanesulfonate (2.47 g, 7.5 mmol) and 4-trifluoromethylphenylboronic acid (2.56 g, 15 mmol) were reacted according to the procedure of Example 31 (step a) to provide the title compound (500 mg, 20%) as a white solid: ESI MS m/z 325 [M + H] ⁺ .

d) 5 -(4-(Trifluoromethyl)phenyl)pyridazin-3 (2H)-one

Chemical Formula: C ₁₁ H ₇ F ₃ N ₂ O Exact Mass : 240.05

Molecular Weight: 240. 18

Attorney's Docket 2882.023B

2-(Tetrahydro-2H-pyran-2-yl)-5-(4-(trifluoromethyl)phenyl)py ridazin-3(2H)-one (500 mg, 1.54 mmol) was reacted according to the procedure of Example 31 (step c) to provide the title compound (100 mg, 27%) as a solid: ESI MS m/z 241 [M + H] ⁺ .

e) te/t-Butyl 5-methyl-7-(6-oxo-4-(4-(trifluoromethyl)phenyl)pyridazin-l(6 H)-yl)-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

Chemical Formula: C ₂₈ H ₂₇ F ₃ N ₄ O ₃

Exact Mass : 524.20 Molecular Weight: 524.53

5-(4-(Trifluoromethyl)phenyl)pyridazin-3(2H)-one (100 mg, 0.41 mmol) and tert- butyl 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-c arboxylate (151 mg, 0.41 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (65 mg, 30%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.20 (s, IH), 7.81 (d, J= 8.4 Hz, 2H), 7.76 (d, J= 8.4 Hz, 2H), 7.59 (d, J= 1.6 Hz, IH), 7.54 (d, J = 8.4 Hz, IH), 7.31 (d, J= 6.9 Hz, IH), 7.26-7.24 (m, IH), 4.62 (s, 2H), 3.89-3.80 (br m, 2H), 3.66 (s, 3H), 2.84 (br m, 2H), 1.51 (s, 9H).

f) 2-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-5 -(4- (trifluoromethyl)phenyl)pyridazin-3 (2H)-one hydrochloride

Chemical Formula: C ₂₃ H ₂₀ ClF ₃ N ₄ O

Exact Mass: 460.13 Molecular Weight: 460.88 tert-Butyl 5-methyl-7-(6-oxo-4-(4-(trifluoromethyl)phenyl)pyridazin- 1 (6H)-yl)- 3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (65 mg, 0.12 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (47 mg, 80%) as an orange solid: mp

Attorney's Docket 2882.023B

315-320 ⁰ C; ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 9.37 (s, 2H), 8.56 (d, J= 2.2 Hz, IH), 8.13 (d, J= Hz, 2H), 7.93 (d, J= 8.2 Hz, 2H), 7.72 (d, J= 1.6 Hz, IH), 7.61 (d, J= 8.4 Hz, IH), 7.48 (d, J= 2.2 Hz, IH), 7.25 (dd, J= 8.4, 1.8 Hz, IH), 4.36 (s, 2H), 3.70 (s, 3H), 3.58- 3.48 (br m, 2H), 3.11 (t, J= 5.7 Hz, 2H); ESI MS m/z 425 [M + H] ⁺ ; HPLC (Method A) 96.6% (AUC), t _R = 15.7 min.

Example 79

Preparation of 4-(5-Chloropyridin-2-yl)-l-(9-methyl-2.3.4.5-tetrahvdro-lH-p yridor3.4-

& ^" |indol-7-yl)pyridin-2(lH)-one hydrochloride:

a) tert-Butyl 7-(4-(5-chloropyridin-2-yl)-2-oxopyridin-l(2H)-yl)-9-methyl- 3,4-dihydro- lH-pyrido [3 ,4-6]indole-2(9H)-carboxylate

tert-Butyl 7-bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)- carboxylate (200 mg, 0.549 mmol) and 4-(5-chloropyridin-2-yl)pyridin-2(lH)-one (87 mg, 0.42 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (97 mg, 47%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.69 (d, J = 2.0 Hz, IH), 7.80 (dd, J= 8.5, 2.3 Hz, IH), 7.75 (d, J= 8.4 Hz, IH), 7.55 (overlapping dd, J= 7.4 Hz, 2H), 7.36 (s, IH), 7.18 (d, J= 1.7 Hz, IH), 7.08 (dd, J= 8.3, 1.6 Hz, IH), 7.00 (dd, J= 7.1, 1.8 Hz, IH), 4.65 (s, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 1.52 (s, 9H).

b) 4-(5-Chloropyridin-2-yl)-l-(9-methyl-2,3,4,5-tetrahydro-lH-p yrido[3,4-δ]indol-7- yl)pyridin-2(lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₂ H ₂₀ Cl ₂ N ₄ O

Exact Mass: 426.10 Molecular Weight: 427.33 tert-Butyl 7-(4-(5-chloropyridin-2-yl)-2-oxopyridin-l(2H)-yl)-5-methyl- 3,4- dihydro-l/f-pyrido[3,4-δ]indole-2(5H)-carboxylate (97 mg, 0.20 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound as a orange solid (68 mg, 88%): mp 310-320 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.73 (dd, J= 2.4, 0.6 Hz, IH), 8.03 (dd, J= 8.5, 0.5 Hz, IH), 8.00 (dd, J= 8.5, 2.4 Hz, IH), 7.80 (d, J= 7.1 Hz, IH), 7.67 (d, J= 8.3 Hz, IH), 7.56 (d, J = 1.7 Hz, IH), 7.31 (d, J= 1.7 Hz, IH), 7.19 (dd, J= 7.1, 2.0 Hz, IH), 7.14 (dd, J= 8.4, 1.8 Hz, IH), 4.56 (s, 2H), 3.74 (s, 3H), 3.61 (t, J= 6.1 Hz, 2H), 3.14 (t, J= 6.1 Hz, 2H); ESI MS m/z 391 [M + H] ⁺ ; HPLC (Method A) >99% (AUC), to = 11.9 min.

Example 80

Preparation of l-(2.9-Dimethyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^1indol-7-y l)-4-(5- chloropyridin-2-yl)pyridin-2( lHVone hydrochloride

Chemical Formula: C ₂₃ H ₂₂ Cl ₂ N ₄ O

Exact Mass: 440.12 Molecular Weight: 441.35

4-(5-Chloropyridin-2-yl)-l-(5-methyl-2,3,4,5-tetrahydro-lH-p yrido[3,4-δ]indol-7- yl)pyridin-2(l/-/)-one (104 mg, 0.266 mmol) was reacted following the procedure of Example 47 to provide the title compound (75 mg, 70%) as a yellow solid: mp 283- 295°C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.73 (d, J= 2.3 Hz, IH), 8.03 (d, J= 8.5 Hz, IH) 7.99 (dd, J= 8.5, 2.3 Hz, IH), 7.79 (d, J= 7.2 Hz, IH), 7.67 (d, J= 8.3 Hz, IH), 7.57 (s, IH), 7.31 (d, J= 1.6 Hz, IH), 7.19 (dd, J= 7.1, 1.8 Hz, IH), 7.15 (dd, J= 8.3, 1.7 Hz, IH), 4.65 (br s, 2H), 3.74 (m, 5H), 3.21 (t, J= 5.7 Hz, 2H), 3.17 (s, 3H); ESI MS m/z 405 [M + H] ⁺ ; HPLC (Method B) 98.7% (AUC), t _R = 12.1 min.

Attorney's Docket 2882.023B

Example 81

Preparation of 4-(5-(Trifluoromethyl)pyridin-2-yl)- 1 -(9-methyl-2,3,4,5-tetrahydro- IH- pyrido[3,4-&lindol-7-yl)pyridin-2(lH)-one hydrochloride:

a) tert-Butyl 9-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin -l(2H)-yl)-3,4- dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate

tert-Butyl 7-bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)- carboxylate (100 mg, 0.417 mmol) and 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(lη)- one (197 mg, 0.542 mmol), were reacted following the procedure of Example 30 (step g) to provide the title compound (168 mg, 66%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.00 (s, IH), 8.07 (dd, J= 8.3, 1.9 Hz, IH), 7.90 (d, J= 8.3 Hz, IH), 7.58 (overlapping dd, J= 7.1 Hz, 2H), 7.37 (s, IH), 7.26 (d, IH under solvent), 7.08 (dd, J = 8.3, 1.7 Hz, IH), 7.03 (dd, J= 7.1, 1.9 Hz, IH), 4.66 (s, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 1.52 (s, 9H).

b) 4-(5-(Trifluoromethyl)pyridin-2-yl)-l-(9-methyl-2,3,4,5-tetr ahydro-lH-pyrido[3,4- δ]indol-7-yl)pyridin-2(lH)-one hydrochloride

tert-EvXy\ 9-methyl-7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin - 1 (2H)-yl)- 3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate (168 mg, 0.321 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example

Attorney's Docket 2882.023B

30 (steps e and g) to provide the title compound as an orange solid (73 mg, 54%): mp 305-315 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 9.05 (s, IH), 8.28 (dd, J= 8.3, 2.2 Hz, IH), 8.22 (d, J= 8.3, Hz, IH), 7.84 (d, J= 7.1 Hz, IH), 7.67 (d, J= 8.4 Hz, IH), 7.58 (d, J= 1.8 Hz, IH), 7.40 (d, J= 1.8 Hz, IH), 7.25 (dd, J= 7.2, 2.0 Hz, IH), 7.15 (dd, J= 8.4, 1.8 Hz, IH), 4.57 (s, 2H), 3.74 (s, 3H), 3.62 (t, J= 6.1 Hz, 2H), 3.15 (t, J= 5.9 Hz, 2H); ESI MS m/z 425 [M + H] ⁺ ; HPLC (Method A) 96.4% (AUC), t _R = 12.6 min.

Example 82

Preparation of l-(2.9-Dimethyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^1indol-7-y l)-4-(5-

(trifluoromethyl) pyridin-2-yl)pyridin-2(lH)-one hydrochloride:

4-(5-(Trifluoromethyl)pyridin-2-yl)-l-(9-methyl-2,3,4,5-tetr ahydro-lH-pyrido[3,4- δ]indol-7-yl)pyridin-2(lH)-one (125 mg, 0.294 mmol) was reacted following the procedure of Example 47 to provide the title compound (97.9 g, 78%) as a yellow solid: mp 280-290 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 9.05 (s, IH), 8.28 (dd, J= 8.3, 2.1 Hz, IH) 8.22 (d, J= 8.4, Hz, IH), 7.84 (d, J= 7.1 Hz, IH), 7.68 (d, J= 8.3 Hz, IH), 7.59 (d, J = 1.6, IH), 7.40 (d, J= 1.7 Hz, IH), 7.25 (dd, J= 7.2, 1.9 Hz, IH), 7.16 (dd, J= 8.3, 1.8 Hz, IH), 4.87 (s, IH), 4.51 (s, IH), 3.87 (s, IH), 3.75 (br s, 3H), 3.55 (br s, IH), 3.21-3.17 (m, 5H); ESI MS m/z 439 [M + H] ⁺ ; HPLC (Method B) 98.3% (AUC), t _R = 12.8 min.

Example 84

Preparation of 4-((5-Fluoropyridin-2-yl)methoxy)- 1 -(9-methyl-2,3 ,4,9-tetrahydro- IH- pyrido[3,4-&1indol-7-yl)pyridin-2(lH)-one hydrochloride:

Attorney's Docket 2882.023B a) tert-Butyl 7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-l(2H)-yl)- 9-methyl-3,4- dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate

Chemical Formula: C ₂₈ H ₂₉ FN ₄ O ₄

Exact Mass: 504.22 Molecular Weight: 504.55 tert-Butyl 7-bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)- carboxylate (306 mg, 0.840 mmol) and 4-(4-fluorobenzyloxy)pyridin-2(lH)-one (142 mg, 0.640 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (157 mg, 49%) as a yellow/green solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.49 (d, J= 2.0 Hz, IH), 7.54-7.46 (m, 3H), 7.34-7.28 (m, 2H), 7.01 (dd, J= 8.2, 1.8 Hz, IH), 6.10 (d, J= 2.7 Hz, IH), 6.07 (s, IH), 5.17 (s, 2H), 4.63 (br m, 2H), 3.74 (br m, 2H), 3.62 (s, 3H), 2.80 (br m, 2H), 1.51 (s, 9H).

b) 4-((5-Fluoropyridin-2-yl)methoxy)-l-(9-methyl-2,3,4,9-tetrah ydro-lH-pyrido[3,4- δ]indol-7-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₃ H ₂₂ ClFN ₄ O ₂ Exact Mass: 440.14 Molecular Weight: 440.90 tert-Butyi 7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin- 1 (2H)-yl)-9-methyl- 3,4-dihydro-lH-pyrido[3,4-6]indole-2(9H)-carboxylate (157 mg, 0.312 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound as a yellow solid (72.7 mg, 54%): mp 285-295 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.51 (s, IH), 7.72-7.59 (m, 4H), 7.46 (d, J = 1.0 Hz, IH), 7.05 (dd, J= 8.3, 1.5 Hz, IH), 6.32 (dd, J= 7.6, 2.6 Hz, IH), 7.05 (d, J= 2.6 Hz, IH), 5.26 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.60 (t, J= 6.0 Hz, 2H), 3.12 (t, J= 5.8 Hz, 2H); ESI MS m/z 405 [M + H] ⁺ ; HPLC (Method B) 98.3% (AUC), t _R = 12.0 min.

Attorney's Docket 2882.023B

Example 85

Preparation of l-(2.9-Dimethyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^1indol-7-y l)-4-((5- fluoropyridin-2-yl)methoxy)pyridin-2( lHVone hydrochloride

4-((5-Fluoropyridin-2-yl)methoxy)-l-(9-methyl-2,3,4,9-tetrah ydro-lH-pyrido[3,4- δ]indol-7-yl)pyridin-2(lH)-one (76 mg, 0.19 mmol) was reacted following the procedure of Example 47 to provide the title compound (61 mg, 79%) as a yellow solid: mp 287-300 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.51 (d, J= 2.6 Hz, IH), 7.72-7.59 (m, 4H), 7.47 (s, IH), 7.06 (dd, J= 8.3, 1.7 Hz, IH), 6.32 (dd, J= 7.6, 2.6 Hz, IH), 6.13 (d, J= 2.6 Hz, IH), 5.26 (s, 2H), 4.68 (m, 2H), 3.71 (m, 5H), 3.18 (t, J= 5.9 Hz, 2H), 3.15 (s, 3H); ESI MS m/z 419 [M + H] ⁺ ; HPLC (Method B) 98.4% (AUC), to = 11.1 min.

Example 86

Preparation of l-(9-Methyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^1indol-7-yl)-4 -(6-

(trifluoromethyl)pyridin-3-yl)pyridin-2(lH)-one hydrochloride

a) tert-Butyi 9-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin -l(2H)-yl)-3,4- dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate

Chemical Formula: C ₂₈ H ₂₇ F ₃ N ₄ O ₃

Exact Mass: 524.20 Molecular Weight: 524.53

4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(lH)-one (145 mg, 0.604 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-c arboxylate (200 mg, 0.549 mmol) were coupled following the procedure of Example 30 (step g) to provide the title compound (129 mg, 45%) as a yellow/green solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ

Attorney's Docket 2882.023B

9.00 (s, IH), 8.10 (dd, J= 8.1, 2.0 Hz, IH), 7.82 (d, J= 8.2 Hz, IH), 7.60-7.57 (m, 2H), 7.36 (s, IH), 7.08 (dd, J= 8.3, 1.8 Hz, IH), 6.93 (d, J= 1.8 Hz, IH), 6.49 (dd, J= 7.1, 2.0 Hz, IH), 4.66 (br m, 2H), 3.76 (br m, 2H), 3.66 (s, 3H), 2.82 (br m, 2H), 1.52 (s, 9H).

b) l-(9-Methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-6]indol-7-yl)-4 -(6- (trifluoromethyl)pyridin-3-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₃ H ₂₀ ClF ₃ N ₄ O

Exact Mass: 460.13 Molecular Weight: 460.88 tert-Butyi 9-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin - 1 (2H)-yl)- 3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate (129 mg, 0.25 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (67 mg, 58%) as a yellow/brown solid: mp 315-320 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 9.10 (d, J= 1.9 Hz, IH), 8.41 (dd, J = 8.2, 2.2 Hz, IH), 7.97 (d, J= 8.3 Hz, IH), 7.85 (d, J= 7.0 Hz, IH), 7.68 (d, J= 8.3 Hz, IH), 7.57 (d, J= 1.7 Hz, IH), 7.15 (dd, J= 8.3, 1.8 Hz, IH), 7.03 (d, J= 1.8 Hz, IH), 6.89 (dd, J= 7.1, 2.0 Hz, IH), 4.57 (br m, 2H), 3.75 (s, 3H), 3.62 (br m, 2H), 3.15 (br m, 2H); ESI MS m/z 425 [M + H] ⁺ ; HPLC (Method B) 97.4% (AUC), t _R = 12.3 min.

Example 87

Preparation of l-(2.3.4.9-Tetrahvdro-lH-pyridor3.4-άlindol-7-yl)-4-(5-

(trifluoromethyl)pyridin-2-yl)pyridin-2( lHVone hydrochloride

a) tert-Butyl 7-bromo-9-tosyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-ca rboxylate Chemical Formula: C ₂₃ H ₂₅ BrN ₂ O ₄ S Exact Mass: 504.07 Molecular Weight: 505.42

6 N NaOH solution (6 mL), (Bu ₄ N) ₂ SO ₄ (50% wt. solution in H ₂ O, 0.20 mL), and TsCl (646 mg, 3.39 mmol) were added to a suspension of tert-butyl 7-bromo-3,4-dihydro-

Attorney's Docket 2882.023B lH-pyrido[3,4-6]indole-2(9H)-carboxylate (991 mg, 2.82 mmol) in toluene (20 mL) and the resulting suspension was stirred at 25 ⁰ C for 1.5 h. H ₂ O and EtOAc were added to the suspension and the phases were separated. The organic phase was washed with H ₂ O, dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford the title compound (1.285 g, 90%) as a white foam: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.32 (d, J= 1.5 Hz, IH), 7.78- 7.66 (m, 2H), 7.36 (dd, J= 8.4, 1.5 Hz, IH), 7.25-7.21 (m, 2H), 7.21-7.13 (m, IH), 4.92- 4.81 (m, 2H), 3.74-3.63 (m, 2H), 2.70-2.61 (m, 2H), 2.37 (s, 3H), 1.50 (s, 9H).

b) tert-Evλy\ 7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin- 1 (2H)-yl)-9-tosyl-3 ,4- dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate

Chemical Formula: C ₃₄ H ₃₁ F ₃ N ₄ O ₅ S

Exact Mass: 664.20 Molecular Weight: 664.69

4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(lH)-one (200 mg, 0.830 mmol) and tert-butyl 7-bromo-9-tosyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-ca rboxylate (419 mg, 0.830 mmol) were coupled following the procedure of Example 30 (step g) to provide the title compound (222 mg, 40%) as a yellow solid: ¹ U NMR (500 MHz, CDCl ₃ ) δ 9.02 (s, IH), 8.26 (s, IH), 8.08 (d, J= 7.6 Hz, IH), 7.80 (br s, 2H), 7.57 (d, J= 7.2 Hz, IH), 7.47 (d, J= 7.2 Hz, IH), 7.47 (d, J= 8.0 Hz, IH), 7.32 (d, J= 7.9 Hz, IH), 7.27 (3H, under solvent peak), 7.07 (d, J= 6.8 Hz, IH), 4.91 (br m, 2H), 3.71 (br m, 2H), 2.71 (br m, 2H), 2.36 (s, 3H), 1.52 (s, 9H).

c) l-(9-Tosyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-6]indol-7-yl)-4- (5- (trifluoromethyl)pyridin-2-yl)pyridin-2(lH)-one

Chemical Formula: C ₂₉ H ₂₃ F ₃ N ₄ O ₃ S

Exact Mass: 564.14 Molecular Weight: 564.58

Attorney's Docket 2882.023B tert-Butyl 7-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin- 1 (2H)-yl)-9-tosyl- 3,4-dihydro-lH-pyrido[3,4-6]indole-2(9H)-carboxylate (222 mg, 0.334 mmol) was deprotected according to the procedure of Example 30 (step e) to provide the title compound (131 mg, 58%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.02 (s, IH), 8.25 (d, J= 1.6 Hz, IH), 8.08 (dd, J= 8.3, 1.9 Hz, IH), 7.93 (d, J= 8.3 Hz, IH), 7.75 (d, J = 8.4 Hz, 2H), 7.58 (d, J= 7.2 Hz, IH), 7.48 (d, J= 8.3 Hz, IH), 7.32 (dd, J= 8.3, 1.8 Hz, IH), 7.28-7.24 (3H, under solvent peak), 7.08 (dd, J= 7.2, 2.0 Hz, IH), 4.30 (br s, 2H), 3.13 (t, J= 5.6 Hz, 2H), 3.61 (br m, 2H), 2.36 (s, 3H).

d) l-(2,3,4,9-Tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)-4-(5-(tri fluoromethyl)pyridin-2- yl)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₂ H ₁₉ Cl ₂ F ₃ N ₄ O

Exact Mass: 482.09 Molecular Weight: 483.31 l-(9-Tosyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-6]indol-7-yl)-4- (5-

(trifluoromethyl)pyridin-2-yl)pyridin-2(lH)-one (130 mg, 0.23 mmol) was deprotected according to the procedure of Example 106 (step b) to provide the title compound (39.5 mg, 36%) as a yellow solid: mp 320-330 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 9.05 (s, IH), 8.28 (dd, J= 8.4, 2.1 Hz, IH), 8.22 (d, J= 8.4 Hz, IH), 7.82 (d, J= 7.2 Hz, IH), 7.66 (d, J = 8.4 Hz, IH), 7.48 (d, J= 7.1 Hz, IH), 7.39 (d, J= 1.7 Hz, IH), 7.24 (dd, J= 7.2, 1.9 Hz, IH), 7.13 (dd, J= 8.4, 1.8 Hz, IH), 4.50 (s, 2H), 3.63 (t, J= 6.1 Hz, 2H), 3.14 (t, J= 6.1 Hz, 2H); ESI MS m/z 411 [M + H] ⁺ ; HPLC (Method B) 98.4% (AUC), t _R = 12.6 min.

Example 88

Preparation of 5-(Benzyloxy)-2-(9-methyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^ 1indol-7- yl)pyridazin-3 (2H)-one hydrochloride

a) tert-Butyl 7-(4-(benzyloxy)-6-oxopyridazin- 1 (6H)-yl)-9-methyl-3 ,4-dihydro- IH- pyrido[3,4-δ]indole-2(9H)-carboxylate

Attorney's Docket 2882.023B

Chemical Formula: C ₂₈ H ₃₀ N ₄ O ₄

Exact Mass: 486.23 Molecular Weight: 486.56

5-(Benzyloxy)pyridazin-3(2H)-one (197 mg, 0.974 mmol) and tert-bvXy\ 7-bromo- 9-methyl-3,4-dihydro-lH-pyrido[3,4-6]indole-2(9H)-carboxylat e (353 mg, 0.966 mmol) were coupled following the procedure of Example 30 (step g) to provide the title compound (130 mg, 28%) as a yellow/green solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.77 (d, J= 2.7 Hz, IH), 7.52 (d, J= 8.2 Hz, IH), 7.45-7.40 (m, 7H), 7.21 (dd, J= 8.4, 1.5 Hz, IH), 5.08 (s, 2H), 4.64 (br m, 2H), 3.75 (br m, 2H), 3.63 (s, 3H), 2.80 (br m, 2H), 1.52 (s, 9H).

b) 5-(Benzyloxy)-2-(9-methyl-2,3,4,9-tetrahydro-l/-f-pyrido[3,4 -δ]indol-7-yl)pyridazin- 3(2H)-one hydrochloride

Chemical Formula: C ₂₃ H ₂₃ CDST ₄ O ₂

Exact Mass: 422.15 Molecular Weight: 422.91 tert-Butyl 7-(4-(benzyloxy)-6-oxopyridazin- 1 (6H)-yl)-9-methyl-3 ,4-dihydro- IH- pyrido[3,4-δ]indole-2(9H)-carboxylate (130 mg, 0.27 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (55.7, 48%) as a yellow solid: mp 235-245 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.93 (d, J= 2.7 Hz, IH), 7.59 (d, J= 8.4 Hz, IH), 7.56 (d, J= 1.5 Hz, IH), 7.50-7.48 (m, 2H), 7.43 (overlapping dd, J= 7.8 Hz, 2H), 7.39 (d, J= 1.7 Hz, IH), 7.18 (dd, J= 8.4, 1.7 Hz, IH), 6.48 (d, J= 2.7 Hz, IH), 5.22 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.59 (t, J= 5.6 Hz, 2H), 3.12 (t, J= 5.9 Hz, 2H); ESI MS m/z 387 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), to = 11.7 min.

Attorney's Docket 2882.023B

Example 89

Preparation of l-(9-Methyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-άlindol-7-yl)- 4-((6-

(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(lH)-one hydrochloride

a) tert-Butyi 9-methyl-7-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methox y)pyridin- l(2H)-yl)-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxyl ate

Chemical Formula: C ₂₉ H ₂₉ F ₃ N ₄ O ₄

Exact Mass: 554.21 Molecular Weight: 554.56

4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(lH)-on e (100 mg, 0.37 mmol) and tert-butyi 7-bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)- carboxylate (135 mg, 0.370 mmol) were coupled following the procedure of Example 30 (step g) to provide the title compound (44 mg, 21%) as a yellow/brown solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.81 (s, IH), 7.96 (d, J= 8.6 Hz, IH), 7.75 (d, J= 8.0 Hz, IH), 7.54 (d, J= 8.3 Hz, IH), 7.37-7.34 (m, IH), 7.27 (IH, under solvent peak), 7.02 (dd, J= 8.3, 1.7 Hz, IH), 6.07-6.04 (m, 2H), 5.16 (s, 2H), 4.64 (br m, 2H), 3.75 (br m, 2H), 3.63 (s, 3H), 2.80 (br m, 2H), 1.52 (s, 9H).

b) l-(9-Methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-6]indol-7-yl)-4 -((6- (trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₂ ClF ₃ N ₄ O ₂

Exact Mass: 490.14 Molecular Weight: 490.91 tert-Butyl 9-methyl-7-(2-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methox y)pyridin- l(2H)-yl)-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxyl ate (44 mg, 0.079 mmol) was deprotected and converted to the hydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (28 mg, 65%) as a yellow solid:

Attorney's Docket 2882.023B mp 285-295 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.75 (s, IH), 8.08 (d, J= 7.9 Hz, IH), 7.79 (d, J= 8.1 Hz, IH), 7.53 (dd, J= 7.9, 2.0 Hz, 2H), 7.38 (d, J= 1.7 Hz, IH), 6.97 (dd, J= 8.4, 1.8 Hz, IH), 6.25 (dd, J= 7.6, 2.7 Hz, IH), 6.08 (d, J= 2.6 Hz, IH), 5.26 (s, 2H), 4.46 (s, 2H), 3.63 (s, 3H), 3.51 (t, J= 6.1 Hz, 2H), 3.03 (t, J= 6.1 Hz, 2H); ESI MS m/z 455 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 12.8 min.

Example 90

Preparation of l-(9-Methyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^1indol-7-yl)-4 -(5- methylpyridin-2-yl)pyridin-2( lHVone dihydrochloride

a) 2'-Methoxy-5-methyl-2,4'-bipyridine

Chemical Formula: C ₁₂ H ₁₂ N ₂ O

Exact Mass: 200.09 Molecular Weight: 200.24

2-Bromo-5-methylpyridine (2.93 g, 17.0 mmol) and 2-methoxy-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (3.34 g, 14.2 mmol) were reacted according to Example 31 (step a) to provide the title compound (1.2 g, 42%) as a brown solid: ESI MS m/z 201 [M + H] ⁺ .

b) 4-(5-Methylpyridin-2-yl)pyridin-2(lH)-one

Chemical Formula: C _n H ₁₀ N ₂ O

Exact Mass: 186.08 Molecular Weight: 186.21

2'-Methoxy-5-methyl-2,4'-bipyridine (1.2 g, 6.0 mmol) was reacted according to Example 31 (step c) to provide the title compound (301 mg, 27%) as a white solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 11.58 (s, IH) 8.53 (s, IH), 7.88 (overlapping dd, J= 8.2 Hz, IH), 7.71 (d, J= 6.0 Hz, IH), 7.43 (d, J= 7.7, IH), 6.95 (d, J= 1.5 Hz, IH), 6.84 (dd, J= 6.9, 1.7 Hz, IH), 2.34 (s, 3H).

Attorney's Docket 2882.023B

c) tert-Butyl 9-methyl-7-(4-(5-methylpyridin-2-yl)-2-oxopyridin-l(2H)-yl)- 3,4-dihydro- 1 η-pyrido [3 ,4-6]indole-2(9H)-carboxylate

Chemical Formula: C ₂₈ H ₃₀ N ₄ O ₃

Exact Mass : 470.23 Molecular Weight: 470.56

4-(5-methylpyridin-2-yl)pyridin-2(lH)-one (150 mg, 0.81 mmol) and tert-bvXy\ 7- bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-car boxylate (294 mg, 0.805 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (138 mg, 36%) as a yellow/green solid: ¹ U NMR (500 MHz, CDCl ₃ ) δ 8.56 (s, IH), 7.71 (d, J= 8.2 Hz, IH), 7.63-7.61 (m, IH), 7.56 (d, J= 8.3 Hz, IH), 7.52 (d, J= 7.2 Hz, IH), 7.37 (s, IH), 7.17 (d, J= 1.6 Hz, IH), 7.09 (dd, J= 8.3, 1.7 Hz, IH), 7.04 (dd, J = 7.2, 1.9 Hz, IH), 4.65 (br m, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 2.42 (s, 3H), 1.51 (s, 9H).

d) l-(9-Methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)- 4-(5-methylpyridin-2- yl)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₃ H ₂₄ Cl ₂ N ₄ O

Exact Mass: 442.13 Molecular Weight: 443.37 tert-Butyl 9-methyl-7-(4-(5-methylpyridin-2-yl)-2-oxopyridin-l(2H)-yl)- 3,4- dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate (138 mg, 0.27 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (18 mg, 15%) as a yellow solid: mp 303-310 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.59 (s, IH), 7.95 (d, J= 8.1Hz, IH), 7.87 (d, J= 6.5 Hz, IH), 7.80 (d, J= 7.0 Hz, IH), 7.67 (d, J= 8.4 Hz, IH), 7.56 (d, J= 1.4 Hz, IH), 7.24 (d, J

Attorney's Docket 2882.023B

= 1.6 Hz, IH), 7.15-7.12 (m, 2H), 4.57 (s, 2H), 3.74 (s, 3H), 3.61 (t, J= 6.0 Hz, 2H), 3.14 (t, J= 6.1 Hz, 2H), 2.46 (s, 3H); ESI MS m/z 371 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), to = 11.0 min.

Example 91

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-yl)-4 -(5- methylpyridin-2-yl)pyridin-2( lHVone dihydrochloride

a) tert-Butyl 5-methyl-7-(4-(5-methylpyridin-2-yl)-2-oxopyridin-l(2H)-yl)- 3,4-dihydro- lη-pyrido[4,3-6]indole-2(5H)-carboxylate

Chemical Formula: C ₂₈ H ₃₀ N ₄ O ₃

Exact Mass: 470.23 Molecular Weight: 470.56

4-(5-Methylpyridin-2-yl)pyridin-2(lH)-one (150 mg, 0.81 mmol) and tert-bv&y\ 7- bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-car boxylate (294 mg, 0.805 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (245 mg, 64%) as a yellow/green solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.57 (d, J= 2.0 Hz, IH), 7.71 (d, J= 8.0 Hz, IH), 7.64-7.60 (m, IH), 7.55-7.51 (m, 2H), 7.37 (d, J = 1.6 Hz, IH), 7.17 (d, J= 1.6 Hz, IH), 7.10-7.03 (m, 2H), 4.66 (br m, 2H), 3.85 (br m, 2H), 3.65 (s, 3H), 2.84 (br m, 2H), 2.42 (s, 3H), 1.51 (s, 9H).

b) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)- 4-(5-methylpyridin-2- yl)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₃ H ₂₄ Cl ₂ N ₄ O

Exact Mass: 442.13 Molecular Weight: 443.37

Attorney's Docket 2882.023B tert-Butyl 5 -methyl-7-(4-(5 -methylpyridin-2-yl)-2-oxopyridin- 1 (2H)-yl)-3 ,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (245 mg, 0.520 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (57 mg, 30%) as a yellow solid: mp 295-305 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.76 (d, J= 1.8 Hz, IH), 8.34 (d, J= 6.9 Hz, IH), 8.24 (d, J= 8.2 Hz, IH), 7.94 (d, J= 7.2 Hz, IH), 7.67 (d, J= 8.3 Hz, IH), 7.61 (d, J= 1.7 Hz, IH), 7.23 (d, J= 1.8 Hz, IH), 7.17 (dd, J= 8.3, 1.8 Hz, IH), 7.04 (dd, J= 7.1, 2.1 Hz, IH), 4.53 (s, 2H), 3.79 (s, 3H), 3.71 (t, J= 6.2 Hz, 2H), 3.25 (t, J= 6.2 Hz, 2H), 2.61 (s, 3H); ESI MS m/z 371 [M + H] ⁺ ; HPLC (Method B) 97.3% (AUC), t _R = 10.9 min.

Example 92

Preparation of l-(5-Methyl-2.3.4.9-tetrahvdro-lH-pyridor4.3-^1indol-7-yl)-4 -(6- methylpyridin-3-yl)pyridin-2(lH)-one dihydrochloride

a) 2'-Methoxy-6-methyl-3 ,4'-bipyridine

Chemical Formula: C ₁₂ H ₁₂ N ₂ O

Exact Mass: 200.09 Molecular Weight: 200.24

2-Methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyri dine (3.5 g, 16 mmol) and 4-bromo-2-methoxypyridine (2.0 g, 11 mmol) were reacted according to Example 31 (step a) to provide the title compound (2.1 g, 98%) as a brown solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.75 (d, J= 2.1 Hz, IH), 8.23 (d, J= 5.4 Hz, IH), 7.78 (dd, J= 8.0, 2.4 Hz, IH), 7.24 (d, J= 8.1, IH), 7.08 (dd, J= 5.4, 1.5 Hz, IH), 6.84 (d, J= 1.0, IH), 3.98 (s, 3H), 2.61 (s, 3H).

b) 4-(6-Methylpyridin-3-yl)pyridin-2(lH)-one

Attorney's Docket 2882.023B

Chemical FoÏ€nula: C ₁₁ H ₁₀ N ₂ O

Exact Mass: 186.08 Molecular Weight: 186.21

2'-Methoxy-6-methyl-3,4'-bipyridine (2.1 g, 10.4 mmol) was reacted according to Example 31 (step c) to provide the title compound (1.36 mg, 68%) as a white solid: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 11.65 (s, IH) 8.78 (d, J= 2.1 Hz, IH), 8.01 (dd, J= 8.1, 2.5 Hz, IH), 7.47 (d, J= 6.9 Hz, IH), 7.36 (d, J= 8.1, IH), 6.66 (d, J= 1.4 Hz, IH), 6.55 (dd, J= 6.9, 1.8 Hz, IH), 2.5 l (s, 3H).

c) tert-Butyl 5-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-l(2/-/)-yl )-3,4-dihydro- lH-pyrido[4,3-6]indole-2(5H)-carboxylate

Chemical Formula: C _2S H ₃₀ N ₄ O ₃

Exact Mass: 470.23 Molecular Weight: 470.56

4-(6-Methylpyridin-3-yl)pyridin-2(lH)-one (150 mg, 0.81 mmol) and tert-butyl 7- bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-car boxylate (294 mg, 0.805 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (220 mg, 58%) as a yellow/green solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.79 (d, J= 8.2 Hz, IH), 7.83 (dd, J= 8.1, 2.4 Hz, IH), 7.56-7.51 (m, 2H), 7.37 (d, J= 1.4 Hz, IH), 7.30 (IH, partially under solvent), 7.08 (d, J= 8.7 Hz, IH), 6.90 (d, J= 1.6 Hz, IH), 6.50 (dd, J= 7.1, 1.9 Hz, IH), 4.66 (br s, 2H), 3.85 (br m, 2H), 3.65 (s, 3H), 2.84 (br m, 2H), 2.64 (s, 3H), 1.51 (s, 9H).

d) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)- 4-(6-methylpyridin-3- yl)pyridin-2( lH)-one dihydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₃ H ₂₄ Cl ₂ N ₄ O

Exact Mass: 442.13 Molecular Weight: 443.37 tert-Evλy\ 5 -methyl-7-(4-(6-methylpyridin-3 -yl)-2-oxopyridin- 1 (2H)-yl)-3 ,A- dihydro-l/f-pyrido[4,3-δ]indole-2(5H)-carboxylate (220 mg, 0.47 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (50.2 mg, 29%) as a yellow solid: mp 295-305 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.80 (d, J= 2.2 Hz, IH), 8.12 (dd, J= 8.1, 2.5 Hz, IH), 7.79 (d, J= 7.0 Hz, IH), 7.59 (d, J= 8.3 Hz, IH), 7.52 (d, J= 1.7 Hz, IH), 7.47 (d, J= 8.2 Hz, IH), 7.10 (dd, J= 8.3, 1.9 Hz, IH), 6.93 (d, J= 1.8 Hz, IH), 6.85 (dd, J= 7.1, 2.0 Hz, IH), 4.34 (s, 2H), 3.73 (s, 3H), 3.52 (t, J= 6.1 Hz, 2H), 3.10 (t, J= 6.1 Hz, 2H), 2.62 (s, 3H); ESI MS m/z 371 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 8.7 min.

Example 93

Preparation of l-(9-Methyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^1indol-7-yl)-4 -(6- methylpyridin-3-yl)pyridin-2(l/-/)-one dihydrochloride

a) tert-Butyi 9-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-l(2/-/)-yl )-3,4-dihydro- lH-pyrido [3 ,4-δ]indole-2(9H)-carboxylate

Chemical Formula: C ₂₈ H ₃₀ N ₄ O ₃

Exact Mass: 470.23 Molecular Weight: 470.56

4-(6-Methylpyridin-3-yl)pyridin-2(lH)-one (150 mg, 0.81 mmol) and tert-bv&y\ 7- bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-car boxylate (294 mg, 0.805 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (208 mg, 55%) as a yellow/green solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.79 (d, J= 8.2 Hz, IH), 7.83 (dd, J= 8.0, 2.3 Hz, IH), 7.58-7.51 (m, 2H), 7.36 (s, IH), 7.30 (IH,

Attorney's Docket 2882.023B partially under solvent), 7.08 (dd, J= 8.3, 1.8 Hz, IH), 6.90 (d, J= 1.7 Hz, IH), 6.50 (dd, J = 7.1, 2.0 Hz, IH), 4.65 (br s, 2H), 3.76 (br m, 2H), 3.65 (s, 3H), 2.82 (br m, 2H), 2.64 (s, 3H), 1.52 (s, 9H).

b) l-(9-Methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)- 4-(6-methylpyridin-3- yl)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₃ H ₂₄ Cl ₂ N ₄ O

Exact Mass: 442.13 Molecular Weight: 443.37 tert-Butyl 9-methyl-7-(4-(6-methylpyridin-3-yl)-2-oxopyridin-l(2H)-yl)- 3,4- dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate (208 mg, 0.442 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (40.6 mg, 23%) as a yellow solid: mp 305-313 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 8.80 (d, J= 8.1Hz, IH), 8.11 (dd, J= 8.2, 2.5 Hz, IH), 7.79 (d, J= 7.0 Hz, IH), 7.64 (d, J= 8.3 Hz, IH), 7.52 (d, J= 1.7 Hz, IH), 7.47 (d, J= 8.2 Hz, IH), 7.11 (dd, J= 8.3, 1.8 Hz, IH), 6.93 (d, J= 1.9 Hz, IH), 6.85 (dd, J= 7.1, 2.0 Hz, IH), 4.40 (s, 2H), 3.71 (s, 3H), 3.46 (t, J= 5.9 Hz, 2H), 3.04 (t, J= 5.9 Hz, 2H), 2.62 (s, 3H); ESI MS m/z 371 [M + H] ⁺ ; HPLC (Method B) >99% (AUC), t _R = 8.9 min.

Example 94

Preparation of 4-(Benzyloxy)-l-(1.9-dimethyl-2.3.4.9-tetrahvdro-iH-pyridor3 .4-^1indol-7- yl)pyridin-2(7H)-one hydrochloride

a) tert-Butyl 7-bromo-l,9-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indole-2(9H )- carboxylate

Chemical Formula: C ₁₈ H ₂₃ BrN ₂ O ₂ Exact Mass: 378.0943 Molecular Weight: 379.2914

Attorney's Docket 2882.023B

To a solution of 2-(6-bromo-lH-indol-3-yl)ethanamine (1.9 g, 8.0 mmol) in TηF (30 niL) at 0 ⁰ C was added saturated aqueous NaHCO ₃ (30 mL) and acetyl chloride (0.56 rnL, 7.95 mmol). The reaction was warmed up to room temperature and stirred at room temperature until complete. The solution was concentrated, and the residue was dissolved in CH ₂ Cl ₂ , washed with H ₂ O and brine and dried with Na ₂ SO ₄ . The organic solution was filtered and concentrated to give a pale yellow foam. The foam was suspended in benzene (70 mL) and treated with POCI3 (3.52 mL, 38.4 mmol). The reaction was heated and stirred at 85 ⁰ C for one hour. After the solution was concentrated, the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH ₂ Cl ₂ ) to give a brown solid (1.83 g 91%). The solid was suspended in EtOH (20 mL) and CHCl ₃ (20 mL) and cooled to 0 ⁰ C. NaBH ₄ (0.26 g, 6.95 mmol) was added, and the reaction was stirred from 0 ⁰ C to room temperature for one hour. The reaction was quenched with H ₂ O, extracted with CH ₂ Cl ₂ , washed with H ₂ O and brine and dried over Na ₂ SO ₄ . The organic solution was filtered and concentrated to give a yellow foam (1.44 g, 78%). The foam was dissolved in /-PrOH (15 mL) and H ₂ O (10 mL) and treated with BoC ₂ O (1.36 g, 6.24 mmol) and K ₂ CO ₃ (0.86 g, 6.2 mmol). The reaction was stirred at room temperature for one hour and then concentrated under reduced pressure. The resulting residue was dissolved in CH ₂ Cl ₂ , washed with H ₂ O and brine and dried over Na ₂ SO ₄ . After filtration and concentration, the residue was purified by flash column chromatography (silica gel, hexanes/EtOAc, 4:1) to give a yellow foam (0.92 g, 46 %). The foam was dissolved in DMF (6 mL) and cooled to 0 ⁰ C. The solution was treated with NaH (60% weight dispersion in mineral oil, 108 mg, 2.68 mmol) followed by CH ₃ I (0.17 mL, 0.69 mmol). The reaction was stirred at 0 ⁰ C until complete. The reaction was quenched with H ₂ O, extracted with CH ₂ Cl ₂ , washed with H ₂ O and brine and dried over Na ₂ SO ₄ . The organic solution was filtered and concentrated, and the residue was purified by flash column chromatography (silica gel, hexanes/EtOAc, 4: 1) to give the title compound as a white foam (0.82 g, 89%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.42 (s, IH), 7.31 (d, J= 8.0 Hz, IH), 7.18 (d, J= 8.0 Hz, IH), 5.43-5.20 (m, IH), 4.48-4.26 (m, IH), 3.62 (s, 3H), 3.24-3.13 (m, IH), 2.78-2.66 (m, 2H), 1.49 (s, 9H), 1.47 (d, J= 6.5 Hz, 3H); MS (ESI) m/z 380 [M + H] ⁺ .

Attorney's Docket 2882.023B b) 4-(Benzyloxy)-l-(l,9-dimethyl-2,3,4,9-tetrahydro-iH-pyrido[3 ,4-δ]indol-7-yl)pyridin- 2(1H)-OTiQ hydrochloride

Chemical Formula: C ₂₅ H ₂₆ CDST ₃ O ₂

Exact Mass: 435.17 Molecular Weight: 435.95

To a mixture of tert-butyi 7-bromo-l,9-dimethyl-3,4-dihydro-lH-pyrido[4,3- δ]indole-2(9H)-carboxylate (0.57g, 1.6 mmol), 4-(benzyloxy)pyridin-2(lH)-one (0.32 g, 1.6 mmol), 8 -hydroxy quilinine (46 mg, 0.32 mmol), K2CO3 (0.26 g, 1.9 mmol) and CuI (0.15 g, 0.79 mmol) was added DMSO (4 mL). The reaction mixture was degassed and back-filled with N ₂ . The reaction was stirred at 130 ⁰ C overnight. The mixture was cooled and filtered through a layer of Celite. The filtrate was diluted with CH ₂ Cl ₂ , washed with H ₂ O and 5% aqueous LiCl and dried over Na ₂ SO ₄ . The organic solution was filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 5% CH3OH in CH ₂ Cl ₂ ) to give a yellow solid (0.5 g, 64%). The solid was dissolved in CH3OH (8 mL) and treated with 1 N HCl in Et ₂ O (5 mL). The reaction was stirred at room temperature until complete. The solvent was removed under reduced pressure and the resulting solid was dried under vacumn to give the title compound (0.44 g, 100%) as a yellow powder: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.79 (d, J= 7.0 Hz, IH), 7.66 (d, J= 8.0 Hz, IH), 7.53 (s, IH), 7.48-7.36 (m, 5H), 7.10 (d, J= 8.5 Hz, IH), 6.55 (d, J= 6.5 Hz, IH), 6.33 (s, IH), 5.27 (s, 2H), 4.98 (q, J= 6.5 Hz, IH), 3.76 (s, 3H), 3.67-3.59 (m, 2H), 3.13-3.08 (m, 2H), 1.76 (d, J= 7.0 Hz, 3H); ESI MS m/z 400 [M + H] ⁺ ; HPLC (Method A) >99 % (AUC), t _R = 12.9 min.

Example 95

Preparation of 4-(Benzyloxy)-l-(l,2,9-trimethyl-2,3,4,9-tetrahydro-iH-pyrid o[3,4-^lindol-

7-yl)pyridin-2(7H)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₆ H ₂₈ ClN ₃ O ₂

Exact Mass: 449.19 Molecular Weight: 449.97

To a solution of 4-(benzyloxy)-l-(l,9-dimethyl-2,3,4,9-tetrahydro-iH-pyrido[3 ,4- 6]indol-7-yl)pyridin-2(7H)-one hydrochloride (205 mg, 0.470 mmol) in CH ₃ OH (8 niL) was added formaldehyde (53 μL, 0.71 mmol) and NaBH(OAc) ₃ (200 mg, 0.94 mmol). The reaction was stirred at room temperature until complete and then concentrated under reduced pressure. The residue was dissolved in CH ₂ Cl ₂ and washed with H ₂ O and 5% aqueous LiCl and dried over Na ₂ SO ₄ . The organic solution was filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 10% CH ₃ OH in CH ₂ Cl ₂ ) to give 4-(benzyloxy)-l-(l,2,9-trimethyl-2,3,4,9-tetrahydro-i/f-pyri do[3,4- δ]indol-7-yl)pyridin-2(7H)-one as a white solid (0.15 g, 77 %). The free base was converted to the HCl salt to give the title compound (147 mg, 90 %) as an off-white powder: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.58-7.55 (m, 2H), 7.47-7.34 (m, 6H), 6.99 (d, J = 8.5, 1.0 Hz, IH), 6.28 (dd, J= 7.5, 2.5 Hz, IH), 6.11 (d, J= 2.5 Hz, IH), 5.18 (s, 2H), 4.27 (q, J= 6.5 Hz, IH), 3.69 (s, 3H), 3.36-3.33 (m, IH), 3.10-2.96 (m, 2H), 2.84-2.80 (m, IH), 2.65 (s, 3H), 1.51 (d, J= 6.5 Hz, 3H); ESI MS m/z 414 [M + H] ⁺ ; HPLC (Method A) >99 % (AUC), t _R = 13.0 min.

Example 96

Preparation of 4-(Benzyloxy)-l-(5-(ethoxymethyl)-2,3,4,5-tetrahydro-i/-f-py rido[4,3-

&1indol-7-yl)pyridin-2(i/-/)-one hydrochloride

a) te/t-Butyl 7-(4-(benzyloxy)-2-oxopyridin-l(2/-/)-yl)-5-(ethoxymethyl)-3 ,4-dihydro-iH- pyrido[4,3-δ]indole-2(5H)-carboxylate

Attorney's Docket 2882.023B

Chemical Formula: C ₃₄ H ₄₃ N ₃ O ₅ Si

Exact Mass: 601.30 Molecular Weight: 601.81

To a solution of tert-bv&y\ 7-bromo-3,4-dihydro-i/f-pyrido[4,3-δ]indole-2(5H)- carboxylate (0.66 g, 1.9 mmol) in DMF (8 niL) was added NaH (60% weight dispersion in mineral oil, 113 mg, 2.82 mmol) followed by SEMCl (0.50 mL, 2.8 mmol). The reaction was stirred at room temperature until complete. The reaction was quenched with H ₂ O, and the aqueous mixture was extracted with CH ₂ Cl ₂ . The organic phase was washed with H ₂ O and brine and dried over Na ₂ SO ₄ . After filtration and concentration, the residue was dried under vacuum to give tert-hvXy\ 7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4- dihydro-iH-pyrido[4,3-δ]indole-2(5H)-carboxylate, which and used directly in the next step. To a mixture of tert-hvXy\ 7-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydro- i/f-pyrido[4,3-δ]indole-2(5H)-carboxylate (0.75 g, 1.6 mmol), 4-benzyloxypyridone (0.31 g, 1.6 mmol), 8 -hydroxy quilinine (34 mg, 0.23 mmol), K3CO3 (0.26 g, 1.9 mmol) and CuI (45 mg, 0.23 mmol) was added DMSO (6 mL). The reaction mixture was degassed and back-filled with N ₂ . The reaction was stirred at 130 ⁰ C overnight. The mixture was cooled and filtered through a layer of Celite. The filtrate was diluted with CH ₂ Cl ₂ , washed with H ₂ O and 5% aqueous LiCl and dried over Na ₂ SO ₄ . The organic solution was filtered and concentrated, and the residue was purified by flash column chromatography (silica gel, 5% CH ₃ OH in CH ₂ Cl ₂ ) to give the title compound as a yellow oil (0.12 g, 13%): ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.60 (d, J= 8.5 Hz, IH), 7.44-7.37 (m, 6H), 7.31 (d, J= 7.5 Hz, IH), 7.09 (m, IH), 6.12 (s, IH), 6.07 (d, J= 6.5 Hz, IH), 5.40 (s, 2H), 5.07 (s, 2H), 4.65 (m, 2H), 3.86 (m, 2H), 3.51 (t, J= 8.0 Hz, 2H), 2.73 (m, 2H), 1.53 (s, 9H), 0.89 (t, J= 8.0 Hz, 2H), -0.04 (s, 9H); ESI MS m/z 602 [M + H] ⁺ .

b) 4-(Benzyloxy)-l-(5-(ethoxymethyl)-2,3,4,5-tetrahydro-7H-pyri do[4,3-δ]indol-7- yl)pyridin-2(i/-/)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₆ H ₂₈ CDST ₃ O ₃

Exact Mass: 465.18 Molecular Weight: 465.97

To a solution of tert-butyl 7-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-5- (ethoxymethyl)-3,4-dihydro-i/f-pyrido[4,3-δ]indole-2(5H)-ca rboxylate (120 mg, 0.20 mmol) in EtOH (2 mL) was added 1 N HCl in Et ₂ O (1 niL). The reaction was stirred at 60 ⁰ C until complete. The solvent was concentrated and the residue was purified by preparative HPLC (Phenomenex Luna Cl 8 (2), 250 x 50 mm, 15 micron, H ₂ O with 0.05% TFA and CH ₃ CN with 0.05% TFA) to give 4-(benzyloxy)-l-(5-(ethoxymethyl)-2,3,4,5- tetrahydro-iH-pyrido[4,3-δ]indol-7-yl)pyridin-2(7H)-one as a white solid (54 mg, 73 %). The free base was converted to the HCl salt to give the title compound (35 mg, 65 %) as a white powder: mp 148-149 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.12 (s, 2H), 7.66 (d, J = 2.0 Hz, IH), 7.59-7.56 (m, 2H), 7.49-7.37 (m, 5H), 7.08-7.05 (m, IH), 6.14-6.12 (m, IH), 5.99 (d, J= 2.5 Hz, IH), 5.57 (s, 2H), 5.17 (s, 2H), 4.38 (m, 2H), 3.55 (m, 2H), 3.45- 3.40 (m, 2H), 3.13 (m, 2H), 1.08-1.05 (m, 3H); ESI MS m/z 430 [M + H] ⁺ ; HPLC (Method A) >99 % (AUC), t _R = 12.8 min.

Example 97

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-l/f-pyridor4.3-^1indol-7-yl)- 4- phenylpyridin-2( lHVone hydrochloride

a) tert-Butyl 5-methyl-7-(2-oxo-4-(trifluoromethylsulfonyloxy)pyridine-l(2 H)-yl)3,4- dihydro-l/f-pyrido[4,3-δ]indole-2(5H)-carboxylate

Chemical Formula: C ₂₃ H ₂₄ F ₃ N ₃ O ₆ S Exact Mass: 527.13

Molecular Weight: 527.51

To a solution of tert-butyl 7-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4- dihydro-l/f-pyrido[4,3-δ]indole-2(5H)-carboxylate (0.98 g, 2.0 mmol) in CH ₃ OH (30 mL)

Attorney's Docket 2882.023B was added 5% Pd/C (0.3 g) and ammonium formate (0.32 g, 5.1 mmol) under an atmosphere of argon. The reaction was stirred at 90 ⁰ C until complete. The reaction mixture was cooled and filtered through a layer of Celite. The solvent was removed under reduced pressure to give tert-butyi 7-(4-hydroxy-2-oxopyridin-l(2H)-yl)-5-methyl-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate, which was used directly in the next step. To a solution of tert-butyi 7-(4-hydroxy-2-oxopyridin-l(2H)-yl)-5-methyl-3,4- dihydro-lH-pyrido[4,3-6]indole-2(5H)-carboxylate (800 mg, 2.02 mmol) in TηF (10 mL) was added LiN(SiMe ₃ ) ₂ (1.0 M in TηF, 2.6 mL, 2.6 mmol) followed by PhN(Tf) ₂ (0.94 g, 2.6 mmol) under an atmosphere of argon. The reaction was stirred at room temperature until complete. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (silica gel, hexanes/EtOAc, 1 :1) to give the title compound (0.42g, 40% yield) as a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.57-7.53 (m, 2H), 7.30 (d, J= 1.5 Hz, IH), 7.02-6.99 (m, IH), 6.60 (d, J= 2.7 Hz, IH), 6.27 (dd, J = 7.8, 2.7 Hz, IH), 4.65 (s, 2H), 3.85 (m, 2H), 3.65 (s, 3H), 2.84 (m, 2H), 1.51 (s, 9H); ESI MS m/z 528 [M + H] ⁺ .

b) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)- 4-phenylpyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₃ H ₂₂ ClN ₃ O Exact Mass: 391.15

Molecular Weight: 391.89

Following the procedure of Example 25 (step b), but substituting phenylboronic acid for 4-fluorophenylboronic acid and eliminating the methylation step, the title compound (37 mg, 46%) was obtained as a yellow solid: mp 275-280 ⁰ C (decompose); ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.26 (s, 2H), 7.79 (dd, J= 8.0, 1.5 Hz, 2H), 7.75 (d, J= 7.5 Hz, IH), 7.62 (d, J= 1.5 Hz, IH), 7.59 (d, J= 8.5 Hz, IH), 7.55-7.50 (m, 3H), 7.10 (dd, J = 8.5, 2.0 Hz, IH), 6.78 (d, J= 1.5 Hz, IH), 6.70 (dd, J= 7.0, 2.0 Hz, IH), 4.37 (m, 2H), 3.71 (s, 3H), 3.54-3.53 (m, 2H), 3.10 (t, J= 6.0 Hz, 2H); ESI MS m/z 356 [M + H] ⁺ ; HPLC (Method A) >99 % (AUC), t _R = 12.3 min.

Attorney's Docket 2882.023B

Example 98

Preparation of l-(2.5-Dimethyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-y l)-4- phenylpyridin-2( lHVone hydrochloride

Chemical Formula: C ₂₄ H ₂₄ ClN ₃ O

Exact Mass : 405.16 Molecular Weight: 405.92

Following the procedure of Example 25 (step b), but substituting phenylboronic acid for 4-fluorophenylboronic acid, the title compound (56 mg, 83%) was obtained as an off-white solid: mp 290-295 ⁰ C (decompose); ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 10.46 (s, IH), 7.80-7.74 (m, 3H), 7.63 (s, IH), 7.56-7.52 (m, 4H), 7.11 (d, J= 8.0 Hz, IH), 6.78 (s, IH), 6.70 (d, J= 7.0 Hz, IH), 4.68-4.65 (m, IH), 4.34-4.30 (m, IH), 3.82-3.79 (m, IH), 3.71 (s, 3H), 3.53-3.51 (m, IH), 3.20 (m, 2H), 3.00 (d, J= 4.0 Hz, 3H); ESI MS m/z 370 [M + H] ⁺ ; HPLC (Method A) 98% (AUC), t _R = 12.5 min.

Example 99

Preparation of 4-(2-Fluoro-4-methoxyphenyl)-l-(5-methyl-2,3,4,5-tetrahydro- 7H- pyrido[4,3-&lindol-7-yl)pyridin-2(iH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₃ ClFN ₃ O ₂ Exact Mass: 439.15

Molecular Weight: 439.91

Following the procedure of Example 25 (step b), but substituting 2-fluoro-4- methoxyphenylboronic acid for 4-fluorophenylboronic acid and eliminating the

Attorney's Docket 2882.023B methylation step, the title compound (34 mg, 19%) was obtained as a green powder: mp 270-274 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.72 (d, J= 7.0 Hz, IH), 7.63-7.56 (m, 3H), 7.14 (dd, J= 8.5, 1.5 Hz, IH), 6.92 (dd, J= 8.5, 2.5 Hz, IH), 6.87 (dd, J= 13.0, 2.5 Hz, IH), 6.84 (s, IH), 6.77-6.75 (m, IH), 4.50 (s, 2H), 3.88 (s, 3H), 3.76 (s, 3H), 3.68 (t, J = 6.0 Hz, 2H), 3.22 (t, J= 6.0 Hz, 2H); ESI MS m/z 404 [M + H] ⁺ ; HPLC (Method A) >99 % (AUC), t _R = 12.3 min

Example 100

Preparation of l-(2-Acetyl-5-methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indo l-7-yl)-4-

(benzyloxy)pyridin-2( lHVone

Chemical Formula: C ₂₆ H ₂₅ N ₃ O ₃

Exact Mass : 427.19 Molecular Weight: 427.50

To a solution of 4-(benzyloxy)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3- 6]indol-7-yl)pyridin-2(lH)-one (0.2 g, 0.5 mmol) in CH ₂ Cl ₂ (6 mL) was added triethylamine (0.20 mL, 1.4 mmol) followed by acetyl chloride (50 μL, 0.71 mmol). The reaction was stirred at room temperature until complete. After the solvent was removed under reduced pressure, the residue was purified by flash column chromatography (silica gel, 5 % CH ₃ OH in CH ₂ Cl ₂ ) to give the title compound (72.2 mg, 36%) as a yellow solid and as a mixture of rotamers: mp 225-230 ⁰ C; ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.53-7.36 (m, 6H), 7.32-7.30 (m, 2H), 7.06-7.00 (m, IH), 6.09 (d, J= 3.0 Hz, IH), 6.07-6.04 (m, IH), 5.06 (s, 2H), 4.82 (s, IH), 4.67 (s, IH), 4.03 (t, J= 5.5 Hz, IH), 3.84 (t, J= 5.5 Hz, IH), 3.64 (s, 3H), 2.90 (t, J= 5.5 Hz, IH), 2.84 (t, J= 5.5 Hz, IH), 2.24, 2.22 (2 x s, 3H); ESI MS m/z 428 [M + H] ⁺ ; HPLC (Method A) 95.7 % (AUC), t _R = 16.8 min.

Attorney's Docket 2882.023B

Example 101

Preparation of l-(2-Acetyl-5-methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indo l-7-yl)-4-((5- fluoropyridin-2-yl)methoxy)pyridin-2(lH)-one

Chemical Formula: C ₂₅ H ₂₃ FN ₄ O ₃

Exact Mass: 446.18 Molecular Weight: 446.47

Following the procedure of Example 100, but substituting 4-((5-fluoropyridin-2- yl)methoxy)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-δ] indol-7-yl)-pyridin-2(lH)- one for 4-(benzyloxy)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-Î ´]indol-7-yl)pyridin- 2(lH)-one, the title compound (71 mg, 61%) was obtained as a yellow solid and as a mixture of rotamers: mp 220-224 ⁰ C; ¹ U NMR (500 MHz, CDCl ₃ ) δ 8.50 (d, J= 1.5 Hz, IH), 7.54-7.46 (m, 3H), 7.35 (d, J= 7.5 Hz, IH), 7.32 (d, J= 2.0 Hz, IH), 7.03 (ddd, J = 20, 8.0, 1.5 Hz, IH), 6.15-6.08 (m, 2H), 5.18 (s, 2H), 4.83, 4.70 (2 x s, 2H), 4.04 (t, J = 5.5 Hz, IH), 3.85 (t, J= 5.5 Hz, IH), 3.65, 3.64 (2 x s, 3H), 2.91 (t, J= 5.5 Hz, IH), 2.85 (t, J= 5.5 Hz, IH), 2.23, 2.25 (2 x s, 3H); ESI MS m/z 447 [M + H] ⁺ ; HPLC (Method A) 96.4 % (AUC), t _R = 14.5 min.

Example 102

Preparation of 4-(Cyclohexylmethoxy)- 1 -(9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 A-

&1indol-7-yl)pyridin-2(lH)-one hydrochloride

a) 4-(Cyclohexylmethoxy)pyridin-2( lH)-one

Chemical Formula: C ₁₂ H ₁₇ NO ₂ Exact Mass : 207.1259 Molecular Weight: 207.2689

Attorney's Docket 2882.023B

To a solution of cyclohexylmethanol (1.1 mL, 9.3 mmol) in DMF (8 niL) was added NaH (60% weight dispersion in mineral oil, 0.37 g, 9.3 mmol) in one portion. After the bubbles disappeared, 4-chloropyridine JV-oxide (1.0 g, 7.7 mmol) was added. The reaction was stirred at room temperature under Ar until complete. The reaction was quenched with water and the aqueous mixture was extracted with CH ₂ Cl ₂ . The combined organic extracts were washed with H ₂ O and 5% aqueous LiCl and dried over Na ₂ SO ₄ . After filtration and concentration, the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH ₂ Cl ₂ ) to give a yellow solid. The yellow solid was suspended in Ac ₂ O (5 mL) and heated at 140 ⁰ C for 4 h. The reaction mixture was cooled, diluted with CH _S OHZH ₂ O (10 mL, 1 :1) and stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH ₂ Cl ₂ ) to give the title compound (0.92 g, 58%) as a brown solid: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 11.03 (s, IH), 7.21 (d, J= 7.2 Hz, IH), 5.83 (dd, J= 7.2, 2.4 Hz, IH), 5.64 (d, J= 2.4 Hz, IH), 3.72 (d, J= 6.0 Hz, 2H), 1.84-1.68 (m, 6H), 1.30-1.01 (m, 5H).

Chemical Formula: C ₂₄ H ₃₀ ClN ₃ O ₂

Exact Mass: 427.20 Molecular Weight: 427.97

Following the procedure of Example 1 (steps c and d), but substituting A- (cyclohexylmethoxy)pyridin-2(i/-/)-one for 4-benzyloxypyridone, the title compound (56 mg, 81 %) was obtained as a yellow solid: mp 256-260 ⁰ C; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.67-7.65 (m, 2H), 7.50 (s, IH), 7.09 (d, J= 8.5 Hz, IH), 6.35 (d, J= 6.0 Hz, IH), 6.10 (s, IH), 4.58 (s, 2H), 3.92 (d, J= 5.5 Hz, 2H), 3.75 (s, 3H), 3.63 (t, J= 6.0 Hz, 2H), 3.15 (d, J= 6.0 Hz, 2H), 1.92-1.74 (m, 6H), 1.39-1.19 (m, 5H); ESI MS m/z 392 [M + H] ⁺ ; HPLC (Method A) 97.8 % (AUC), t _R = 14.4 min.

Example 103

Attorney's Docket 2882.023B

Preparation of 4-(Cyclohexylmethoxy)- 1 -(5-methyl-2,3A5-tetrahydro- lH-pyrido[4,3- &lindol-7-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₃₀ ClN ₃ O ₂ Exact Mass: 427.20 Molecular Weight: 427.97

Following the procedure of Example 102, but substituting substituting tert-butyl 7- bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-car boxylate for tert-butyl 7- bromo-9-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(9H)-car boxylate, the title compound (197 mg, 100 %) was obtained as a pale green solid: mp 245-250 ⁰ C (decompose); ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.21 (s, 2H), 7.55 (d, J= 8.5 Hz, IH), 7.52 (d, J= 7.5 Hz, IH), 7.50 (s, IH), 6.99 (dd, J= 8.5, 1.5 Hz, IH), 6.04 (dd, J= 7.5, 2.5 Hz, IH), 5.85 (d, J= 2.5 Hz, IH), 4.35 (s, 2H), 3.82 (d, J= 6.0 Hz, 2H), 3.68 (s, 3H), 3.54-3.53 (m, 2H), 3.09 (t, J= 5.5 Hz, 2H), 1.80-1.65 (m, 6H), 1.30-1.01 (m, 5H); ESI MS m/z 392 [M + H] ⁺ ; HPLC (Method A) >99 % (AUC), t _R = 14.3 min.

Example 104

Preparation of 4-(Cyclohexylmethoxy)- 1 -(2,5-dimethyl-2,3A5-tetrahydro- lH-pyrido[4,3-

&1indol-7-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₅ H ₃₂ ClN ₃ O ₂

Exact Mass: 441.22 Molecular Weight: 441.99

To a solution of 4-(cyclohexylmethoxy)-l-(5-methyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-δ]indol-7-yl)pyridin-2(lH)-one hydrochloride (110 mg, 0.26 mmol) in Cη3Oη (5 mL) was added triethylamine (90 μL, 2.5 mmol), formaldehyde (30 μL, 0.39 mmol) and NaBH(O Ac) ₃ (110 mg, 0.52 mmol). The reaction was stirred at room temperature until complete. The solvent was removed under reduced pressure, and the residue was

Attorney's Docket 2882.023B dissolved in CH ₂ Cl ₂ . The organic solution was washed with H ₂ O and 5% aqueous LiCl and dried over Na ₂ SO ₄ . After filtration and concentration, the residue was purified by flash column chromatography (silica gel, 10% CH ₃ OH in CH ₂ Cl ₂ ) to give 4- (cyclohexylmethoxy)-l-(2,5-dimethyl-2,3,4,5-tetrahydro-lH-py rido[4,3-δ]indol-7- yl)pyridin-2(lH)-one as a white solid (73 mg, 69 %). The free base was converted to the HCl salt to give the title compound (84 mg, 100 %) as a white powder: mp 270-272 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 10.53 (s, IH), 7.53 (d, J= 7.5 Hz, IH), 7.51 (d, J= 8.0 Hz, IH), 7.50 (d, J= 1.5 Hz, IH), 7.00 (dd, J= 8.5, 1.5 Hz, IH), 6.04 (dd, J= 7.5, 2.5 Hz, IH), 5.85 (d, J= 3.0 Hz, IH), 4.64 (d, J= 13 Hz, IH), 4.30 (dd, J= 14, 7.5 Hz, IH), 3.82 (d, J= 6.0 Hz, 2H), 3.80-3.78 (m, IH), 3.69 (s, 3H), 3.51-3.47 (m, IH), 3.18 (t, J= 5.5 Hz, 2H), 2.98 (d, J= 4.5 Hz, 3H), 1.80-1.65 (m, 6H), 1.30-1.01 (m, 5H); ESI MS m/z 406 [M + H] ⁺ ; HPLC (Method A) >99 % (AUC), t _R = 14.4 min.

Example 105

Preparation of 4-(Benzyloxy)- 1 -( 1 -(hydroxymethyl)-9-methyl-2,3 ,4,9-tetrahydro- IH- pyrido [3 ,4-δ]indo l-7-yl)pyridin-2( lH)-one hydrochloride

a) 7-Bromo-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indole-l-carboxy lic acid Chemical Formula: C ₁₂ H ₁₁ BrN ₂ O ₂

Exact Mass: 294.00 Molecular Weight: 295.13

Glyoxylic acid monohydrate (3.69 g, 40.1 mmol) was added to a solution of a 2:1 mixture of 2-(6-bromo-lH-indol-3-yl)ethanamine and 2-(4-bromo-lH-indol-3- yl)ethanamine (7.38 g, 30.9 mmol) in 0.4 N HCl (50 mL), and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was adjusted to pη 3.5 with 6 N NaOH solution, and the resulting tan suspension was stirred at 25 ⁰ C for 22 h. The suspension was adjusted to pη 5 with 6 N NaOH solution, and the resulting suspension was filtered. The filtered solid was dried under reduced pressure to afford 3.85 g (42%) of a 2:1 mixture of the title compound and an undesired regioisomer as a tan solid: ¹ H NMR (300 MHz,

Attorney's Docket 2882.023B

DMSO-J ₆ ) δ 10.90 (s, IH), 9.00 (br s, IH), 7.63 (s, IH), 7.33 (d, J= 8.4 Hz, IH), 7.12- 7.04 (m, IH), 4.66 (s, IH), 3.50-2.70 (m, 4H).

Undesired regioisomer: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 11.09 (s, IH), 9.00 (br s, IH), 7.47 (d, J= 8.0 Hz, IH), 7.12-7.04 (m, IH), 6.91 (overlapping dd, J= 8.0 Hz, IH), 4.66 (s, IH), 3.50-2.70 (m, 4H).

b) 7-Bromo- 1 -((tert-butyldimethylsilyloxy)methyl)-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,4- b] indole Chemical Formula: C ₁₈ H ₂₇ BrN ₂ OSi Exact Mass: 394.11 Molecular Weight: 395.41

A 1.0 M solution Of LiAlH ₄ in THF (26 rnL, 26.1 mmol) was added to a solution of a 2:1 mixture of 7-bromo-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indole-l-carboxy lic acid and the undesired regioisomer (3.85 g, 13.1 mmol) in TηF (50 mL) under N ₂ , and the resulting solution was heated at reflux for 1 h. The solution was cooled to 0 ⁰ C and H ₂ O, 6 N NaOH in H ₂ O and H ₂ O were added carefully in succession. The resulting suspension was filtered through celite. The filtrate was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded 2.48 g of a tan foam. Et ₃ N (6.2 mL, 44.3 mmol) was added to a suspension of TBSCl (6.68 g, 44.3 mmol) and the above tan foam in CH ₂ Cl ₂ (50 mL) under N ₂ , and the resulting suspension was stirred at 25 ⁰ C overnight. H ₂ O was added to the suspension, and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 Et ₂ O/MeOH/NH ₄ OH), 100:0 to 75:25) yielded the title compound (1.186 g, 32%) as a clear oil: ¹ U NMR (300 MHz, CDCl ₃ ) δ 8.50 (s, IH), 7.45 (d, J= 1.7 Hz, IH), 7.35 (d, J= 8.4 Hz, IH), 7.18 (dd, J= 8.4, 1.7 Hz, IH), 4.19-4.10 (m, IH), 3.92 (dd, J= 9.2, 5.0 Hz, IH), 3.69 (dd, J= 9.2, 9.2 Hz, IH), 3.32 (ddd, J= 12.6, 4.2, 4.2 Hz, IH), 3.11-3.01 (m, IH), 2.75-2.62 (m, 2H), 0.97 (s, 9H), 0.13 (s, 6H).

Attorney's Docket 2882.023B c) tert-Butyl 7-bromo- 1 -((tert-butyldimethylsilyloxy)methyl)-9-methyl-3 ,4-dihydro- IH- pyrido[3,4-δ]indole-2(9H)-carboxylate Chemical Formula: C ₂₄ H ₃₇ BrN ₂ O ₃ Si

Exact Mass: 508.18 Molecular Weight: 509.55

BoC ₂ O (752 mg, 3.45 mmol) was added to a suspension of 7-Bromo-l-((tert- butyldimethyl-silyloxy)methyl)-2,3,4,9-tetrahydro-lH-pyrido[ 3,4-δ]indole (1.239 g, 3.14 mmol) and K ₂ CO ₃ (476 mg, 3.45 mmol) in a 1:1 mixture of η ₂ 0/z-Pr0η (80 mL), and the resulting suspension was stirred at 25 ⁰ C for 2 h. The suspension was filtered, and the solid was concentrated under reduced pressure. MeI (0.19 mL, 3.1 mmol) was added to a suspension of the above solid and Cs ₂ CO ₃ (1.34 g, 4.12 mmol) in DMSO (20 mL) under N ₂ , and the resulting suspension was stirred at 25 ⁰ C for 4 h. H ₂ O was added to the suspension, and the resulting suspension was filtered. The solid was dried under reduced pressure to afford the title compound (728 mg, 46%) as a white solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.44 (br s, IH), 7.37-7.28 (m, IH), 7.23-7.15 (m, IH), 5.49-5.43 (m, 0.6H), 5.37-5.32 (m, 0.4H), 4.56-4.48 (m, 0.4H), 4.35-4.24 (m, 0.6H), 3.98-3.84 (m, 2H), 3.68 (s, 3H), 3.43-3.35 (m, 0.6H), 3.30-3.21 (m, 0.4H), 2.90-2.75 (m, IH), 2.72-2.63 (m, IH), 1.50 (s, 9H), 0.90-0.82 (m, 9H), 0.14-0.02 (m, 6H).

d) 4-(Benzyloxy)- 1 -( 1 -(hydroxymethyl)-9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,4- δ]indol-7-yl)pyridin-2(lH)-one

Chemical Formula: C ₂₅ H ₂₅ N ₃ O ₃

Exact Mass: 415.19 Molecular Weight: 415.48

A suspension of tert-butyi 7-bromo- l-((tert-butyldimethylsilyloxy)methyl)-9- methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate (727 mg, 1.47 mmol), 4- (benzyl-oxy)pyridin-2(lH)-one (591 mg, 2.94 mmol), CuI (110 mg, 0.576 mmol), 8- hydroxyquinoline (84 mg, 0.58 mmol) and Cs ₂ CO ₃ (720 mg, 2.21 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar

Attorney's Docket 2882.023B and heated at 135 ⁰ C with stirring for 14 h. The suspension was cooled, 1 : 1 MeOHZNH ₄ OH (40 rnL) was added, and the resulting suspension was stirred for 30 min. CH ₂ Cl ₂ was added and the phases were separated. The aqueous phase was extracted with CH ₂ Cl ₂ , and the combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 Et ₂ O/MeOH/NH ₄ OH) 100:0 to 0:100) afforded the amine as a yellow amorphous solid. A 1.0 M solution of TBAF in THF (0.57 mL, 0.57 mmol) was added to a solution of the above yellow semi-solid in THF (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 1.5 h. H ₂ O and CH ₂ Cl ₂ were added to the solution and the phases were separated. The aqueous phase was extracted with CH ₂ Cl ₂ , and the combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 Et ₂ O/MeOH/NH ₄ OH) 100:0 to 0:100) yielded a yellow amorphous solid. TFA (2 mL) was added to a solution of the above amorphous solid in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 1 h. The solution was concentrated under reduced pressure. The resulting residue was diluted with CH ₂ Cl ₂ and neutralized with a saturated aqueous NaHCO ₃ solution. The phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH) 100:0 to 0:100) yielded the title compound (56 mg, 9%) as a viscous oil: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.56 (d, J = 8.0 Hz, IH), 7.46-7.37 (m, 5H), 7.32 (d, J= 7.5 Hz, IH), 7.30 (d, J= 1.5 Hz, IH), 7.03 (dd, J= 8.0, 1.5 Hz, IH), 6.11 (d, J= 2.5 Hz, IH), 6.06 (dd, J= 7.5, 2.5 Hz, IH), 5.08 (s, 2H), 4.14 (dd, J= 10.0, 4.5 Hz, IH), 3.80 (dd, J= 10.0, 4.5 Hz, IH), 3.69-3.62 (m, 4H), 3.23 (ddd, J= 14.0, 4.5, 4.5 Hz, IH), 3.12-3.05 (m, IH), 2.78-2.73 (m, 2H); ESI MS m/z 416 [M + H] ⁺ .

e) 4-(Benzyloxy)- 1 -( 1 -(hydroxymethyl)-9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,4- δ]indol-7-yl)pyridin-2(lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₅ H ₂₆ ClN ₃ O ₃ Exact Mass: 451.17

Molecular Weight: 451.95

A 1.0 M solution of HCl in Et ₂ O (0.13 niL, 0.13 mmol) was added to a solution of 4-(benzyloxy)- 1 -( 1 -(hydroxymethyl)-9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,4-ÏŒ]indol- 7-yl)pyridin-2(lH)-one (55 mg, 0.13 mmol) in CH ₂ Cl ₂ (10 mL) under N ₂ and stirred at 25 ⁰ C for 1 h. The solution was concentrated to afford the title compound (32 mg, 54%) as an off-white powder: mp 168-170 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.48 (br s, IH), 9.10 (br s, IH), 7.56 (overlapping dd, J= 8.5 Hz, 2H), 7.52 (s, IH), 7.49-7.41 (m, 4H), 7.40-7.36 (m, IH), 7.01 (dd, J= 7.0, 1.5 Hz, IH), 6.12 (dd, J= 7.5, 1.5 Hz, IH), 5.98 (d, J = 1.5 Hz, IH), 5.72 (t, J= 3.3 Hz, IH), 5.16 (s, 2H), 4.89-4.82 (m, IH), 4.07-4.01 (m, IH), 3.80-3.71 (m, IH), 3.72 (s, 3H), 3.61-3.50 (m, IH), 3.49-3.43 (m, IH), 3.02-2.94 (m, 2H); ESI MS m/z 416 [M + H] ⁺ .

Example 106

Preparation of 4-(Benzyloxy)-l -(2,3,4, 9-tetrahydro-lH-pyrido[3,4-^lindol-7-yl)pyridin-

2(lH)-one hydrochloride

a) tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin- 1 (2H)-yl)-9-tosyl-3 ,4-dihydro- l/f-pyrido[3 ,A- δ]indole-2(9H)-carboxylate

Chemical Formula: C ₃₅ H ₃₅ N ₃ O ₆ S

Exact Mass: 625.22 Molecular Weight: 625.73

A suspension of 4-(benzyloxy)pyridin-2(lH)-one (426 mg, 2.12 mmol), tert-hvXy\ 7-bromo-9-tosyl-3,4-dihydro-l/f-pyrido[3,4-δ]indole-2(9H)-c arboxylate (1.28 g, 2.54 mmol), CuI (484 mg, 2.54 mmol), 8-hydroxyquinoline (369 mg, 2.54 mmol) and Cs ₂ COs (760 mg, 2.33 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min.

Attorney's Docket 2882.023B

The suspension was put under Ar and heated at 135 ⁰ C with stirring for 1.5 h. The suspension was cooled, 4:1 CH ₂ C1 ₂ /(9:1 MeOH/NH ₄ OH) (50 niL) was added and the resulting suspension was stirred at 25 ⁰ C for 10 min. The suspension was passed through a plug of silica gel and the filtrate was washed with brine. The solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford an amorphous solid. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH) 100:0 to 0:100) yielded the title compound (715 mg, 54%) as an off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.18 (br s, IH), 7.82-7.73 (m, 2H), 7.48-7.35 (m, 6H), 7.33-7.23 (m, 4H), 6.12-5.97 (m, 2H) 5.07 (s, 2H), 4.90 (br s, 2H), 3.72-3.64 (m, 2H), 2.73-2.63 (m, 2H), 2.34 (s, 3H), 1.51 (s, 9H).

b) 4-(Benzyloxy)-l-(2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7 -yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₃ H ₂₂ ClN ₃ O ₂

Exact Mass: 407.14 Molecular Weight: 407.89

TFA (2 mL) was added to a solution of tert-butyl 7-(4-(benzyloxy)-2-oxopyridin- l(2H)-yl)-9-tosyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)- carboxylate (678 mg, 1.09 mmol) in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 1 h. Saturated NaHCO ₃ solution and EtOAc were added, and the phases were separated. The aqueous phase was extracted with CH ₂ Cl ₂ , and the combined organic phases were dried over Na ₂ SO ₄ . The organic solution was concentrated under reduced pressure to afford 510 mg of an off-white solid. NaOH (469 mg, 11.7 mmol) was added to a solution of the off- white solid (123 mg) in CH ₂ Cl ₂ /Me0H (10 mL) that had been degassed with N ₂ . The resulting solution was heated at 40 ⁰ C with stirring for 5 h under N ₂ . The solution was allowed to cool, saturated NH ₄ Cl solution and CH ₂ Cl ₂ were added, and the phases were separated. The organic phase was washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure to yield an off-white solid. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH) 100:0

Attorney's Docket 2882.023B to 0:100) afforded a white solid. 1 M HCl in Et ₂ O (0.28 ml, 0.28 mmol) was added to a solution of the white solid in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 30 min. The resulting suspension was filtered. The solid was washed with CH ₂ Cl ₂ and dried under reduced pressure to afford the title compound (26 mg, 24%) as a white solid: mp 246-248 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 11.22 (s, IH), 9.29 (br s, 2H), 7.54 (dd, J= 12.0, 8.0 Hz, 2H), 7.50-7.41 (m, 4H), 7.40-7.33 (m, 2H), 6.96 (dd, J= 8.0, 1.5 Hz, IH), 6.09 (dd, J= 7.5, 2.5 Hz, IH), 5.97 (d, J= 2.5 Hz, IH), 5.15 (s, 2H), 4.38 (s, 2H), 3.50-3.42 (m, 2H) 3.00-2.92 (m, 2H); ESI MS m/z 372 [M + H] ⁺ .

Example 107

Preparation of 4-(Benzyloxy)-l-(2-methyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^ 1indol-7- yl)pyridin-2(lH)-one hydrochloride

a) 4-(Benzyloxy)-l-(2-methyl-9-tosyl-2,3,4,9-tetrahydro-lH-pyri do[3,4-δ]indol-7- yl)pyridin-2( lH)-one

TFA (2 mL) was added to a solution of tert-butyl 7-(4-(benzyloxy)-2-oxopyridin- l(2H)-yl)-9-tosyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)- carboxylate (678 mg, 1.09 mmol) in CH ₂ Cl ₂ (10 mL) under N ₂ and the resulting solution was stirred at 25 ⁰ C for 1 h. Saturated NaHCO ₃ solution and EtOAc were added to the solution and the phases were separated. The aqueous phase was extracted with CH ₂ Cl ₂ and the combined organic phases were dried over Na ₂ SO ₄ . The organic solution was concentrated under reduced pressure to afford 510 mg of an off-white solid. Formaldehyde (37% in H ₂ O, 0.04 mL, 0.49 mmol) was added to a solution of the off-white solid (170 mg) in 1:1 MeOH/CH ₂ Cl ₂ (10 mL) and the resulting solution was stirred at 25 ⁰ C for 45 min. NaBH(OAc) ₃ (137 mg, 0.648 mmol) was added to the solution and the resulting suspension was stirred at 25 ⁰ C for 30 min. The suspension was concentrated under reduced pressure and the resulting

Attorney's Docket 2882.023B residue was diluted with CH ₂ Cl ₂ and saturated NaHCO ₃ solution. The phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to yield the title compound (174 mg, 89%) as a viscous oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.14 (d, J= 1.5 Hz, IH), 7.72 (d, J= 8.4 Hz, 2H), 7.47-7.35 (m, 6H), 7.33-7.28 (m, IH), 7.26-7.21 (m, 3H), 6.12-6.05 (m, 2H), 5.07 (s, 2H), 3.92 (br s, 2H), 2.79-2.70 (m, 4H), 2.56 (s, 3H), 2.33 (s, 3H).

b) 4-(Benzyloxy)- 1 -(2-methyl-2,3 ,4,9-tetrahydro- lH-pyrido [3 ,4-6]indol-7-yl)pyridin- 2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₄ ClN ₃ O ₂

Exact Mass : 421.16 Molecular Weight: 421.92

NaOH (644 mg, 16.1 mmol) was added to a solution of the 4-(benzyloxy)-l-(2- methyl-9-tosyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7-y l)pyridin-2(lH)-one (174 mg, 0.322 mmol) in Cη ₂ Cl ₂ /Me0η (10 mL) that had been degassed with N ₂ . The resulting solution was heated at reflux with stirring for 2 h under N ₂ . The solution was allowed to cool, saturated NH ₄ Cl solution and CH ₂ Cl ₂ were added, and the phases were separated. The organic phase was washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure to yield a white solid. 1 M HCl in Et ₂ O (0.38 ml, 0.38 mmol) was added to a solution of the white solid in 9:1 CH ₂ Cl ₂ /Me0H (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was concentrated, and the residue was diluted with a small amount of CH ₂ C1 ₂ /CH ₃ CN. The resulting suspension was filtered, and the solid was dried under reduced pressure to yield the title compound (46 mg, 34%) as a white solid: mp 168-170 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 11.30 (s, IH), 10.50-10.41 (m, IH), 7.58-7.52 (m, 2H), 7.49-7.40 (m, 4H), 7.39-7.35 (m, 2H), 6.96 (br d, J= 8.0 Hz, IH), 6.09 (br d, J= 7.5 Hz, IH), 5.97 (br s, IH), 5.15 (s, 2H), 4.60 (br d, J= 15.0 Hz, IH), 4.41 (dd, J= 15.0, 7.5 Hz, IH), 3.78-3.71 (m, IH), 3.45-3.38 (m, IH), 3.09-2.98 (m, 5H); ESI MS m/z 386 [M + H] ⁺ .

Attorney's Docket 2882.023B

Example 108

Preparation of l-(2.3.4.9-Tetrahvdro-lH-pyridor3.4-&1indol-7-yl)-4-(4-( trifluoro- methyl)phenyl)pyridin-2( lHVone hydrochloride

a) tert-Butyi 7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin- 1 (2H)-yl)-9-tosyl-3 ,4-dihydro- lH-pyrido [3 ,4-6]indole-2(9H)-carboxylate

Chemical Formula: C ₃₅ H ₃₂ F ₃ N ₃ O ₅ S

Exact Mass: 663.20 Molecular Weight: 663.71

A suspension of 4-(4-(trifluoromethyl)phenyl)pyridin-2(lH)-one (121 mg, 0.504 mmol), tert-butyi 7-bromo-9-tosyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-ca rboxylate (305 mg, 0.605 mmol), CuI (115 mg, 0.605 mmol), 8-hydroxyquinoline (88 mg, 0.605 mmol) and CS2CO3 (181 mg, 0.605 mmol) in DMSO (5 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and heated at 135 ⁰ C with stirring for 2.5 h. The suspension was cooled, 4:1 Cη ₂ C1 ₂ /(9:1 MeOH/NH ₄ OH) (25 mL) was added and the resulting suspension was stirred at 25 ⁰ C for 10 min. The suspension was passed through a plug of silica gel and the filtrate was washed with brine. The solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford an amorphous solid. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH) 100:0 to 0:100) gave the title compound (170 mg, 51%) as a pink foam: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.26 (br s, IH), 7.83-7.74 (m, 6H), 7.53 (d, J= 7.2 Hz, IH), 7.51-7.45 (m, IH), 7.35-7.23 (m, 3H), 6.93 (d, J= 1.8 Hz, IH), 6.54 (dd, J= 7.2, 1.8 Hz, IH), 4.91 (br s, 2H), 3.75-3.65 (m, 2H), 2.73-2.68 (m, 2H), 2.36 (s, 3H), 1.52 (s, 9H).

b) l-(2,3,4,9-Tetrahydro-lH-pyrido[3,4-6]indol-7-yl)-4-(4- (trifluoromethyl)phenyl)pyridin-2( lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₃ H ₁₉ ClF ₃ N ₃ O

Exact Mass: 445.12 Molecular Weight: 445.86

TFA (1 niL) was added to a solution of tert-bvXy\ 7-(2-oxo-4-(4-(trifluoro- methyl)phenyl)pyridin-l(2H)-yl)-9-tosyl-3,4-dihydro-l/f-pyri do[3,4-δ]indole-2(9H)- carboxylate (170 mg, 0.256 mmol) in CH ₂ Cl ₂ (5 niL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 30 min. Saturated NaHCO ₃ solution and CH ₂ Cl ₂ were added to the solution, and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford 145 mg of a pink solid. NaOH (227 mg, 5.67 mmol) was added to a solution of the pink solid (64 mg) in CH ₂ Cl ₂ /Me0H (10 mL) that had been degassed with N ₂ . The resulting solution was heated at reflux with stirring for 7 h under N ₂ . The solution was allowed to cool, saturated NH ₄ Cl solution and CH ₂ Cl ₂ were added, and the phases were separated. The organic phase was washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure to yield a yellow powder. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH) 100:0 to 0:100) afforded a yellow solid. 1 M HCl in Et ₂ O (0.07ml, 0.06 mmol) was added to a solution of the yellow solid in 9:1 CH ₂ Cl ₂ /Me0H (10 mL) under N ₂ and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was concentrated under reduced pressure to yield the title compound (27 mg, 54%) as a yellow solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 11.28 (s, IH), 9.21 (br s, 2H), 8.01 (d J= 8.3 Hz, 2H), 7.88 (d, J= 8.3 Hz, 2H), 7.80 (d, J= 7.0 Hz, IH), 7.58 (d, J= 8.0 Hz, IH), 7.49 (d, J = 1.5 Hz, IH), 7.07 (dd, J= 8.0, 1.5 Hz, IH), 6.87 (d, J= 2.0 Hz, IH), 6.72 (dd, J= 7.0, 2.0 Hz, IH), 4.40 (s, 2H), 3.52-3.48 (m, 2H), 2.99 (t, J= 6.0 Hz, 2H); ESI MS m/z 410 [M + H] ⁺ .

Attorney's Docket 2882.023B

Example 109

Preparation of 1 -(2-Methyl-2.3 A9-tetrahydro- lH-pyrido [3.4-61indol-7-ylV4-(4-(trifluoro- methyl)phenyl)pyridin-2( lH)-one hydrochloride

a) l-(2-Methyl-9-tosyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indo l-7-yl)-4-(4- (trifluoromethyl)phenyl)pyridin-2(lH)-one

Chemical Formula: C ₃₁ H ₂₆ F ₃ N ₃ O ₃ !;

Exact Mass: 577.16 Molecular Weight: 577.62

TFA (1 mL) was added to a solution of tert-butyi 7-(2-oxo-4-(4-(trifluoro- methyl)phenyl)pyridin- 1 (2H)-yl)-9-tosyl-3 ,4-dihydro- lH-pyrido [3 ,4-6]indo le-2(9H> carboxylate (170 mg, 0.256 mmol) in CH ₂ Cl ₂ (5 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 30 min. Saturated NaHCO ₃ solution and CH ₂ Cl ₂ were added to the solution, and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford 145 mg of a pink solid. Formaldehyde (37% in H ₂ O, 0.02 mL, 0.2 mmol) was added to a solution of the pink solid (80 mg) in 1 :1 MeOH/CH ₂ Cl ₂ (4 mL) and the resulting solution was stirred at 25 ⁰ C for 45 min. NaBH(O Ac)3 (60 mg, 0.28 mmol) was added to the solution and the resulting suspension was stirred at 25 ⁰ C for 30 min. The suspension was concentrated under reduced pressure. The residue was diluted with CH ₂ Cl ₂ and saturated NaHCO ₃ solution. The phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to yield the title compound (61 mg, 74%) as a pink foam: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.23 (d, J= 1.8 Hz, IH), 7.79-7.71 (m, 6H), 7.53 (d, J= 7.2 Hz, IH), 7.47 (d, J = 8.4 Hz, IH), 7.32 (dd, J= 8.4, 1.8 Hz, IH), 7.27-7.22 (m, 2H), 6.93 (d, J= 1.8 Hz, IH), 6.53 (dd, J= 7.2, 1.8 Hz, IH), 3.93 (br s, 2H), 2.80-2.60 (m, 4H), 2.57 (s, 3H), 2.34 (s, 3H).

Attorney's Docket 2882.023B b) l-(2-Methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)- 4-(4-(trifluoro- methyl)phenyl)pyridin-2( lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₁ ClF ₃ N ₃ O

Exact Mass: 459.13 Molecular Weight: 459.89

NaOH (211 mg, 5.28 mmol) was added to a solution of l-(2-methyl-9-tosyl- 2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)-4-(4-(triflu oromethyl)phenyl)pyridin- 2(lH)-one (61 mg, 0.11 mmol) in Cη ₂ Cl ₂ /Me0η (10 mL) that had been degassed with N ₂ . The resulting solution was heated at reflux with stirring for 7 h under N ₂ . The solution was allowed to cool, saturated NH ₄ Cl solution and CH ₂ Cl ₂ were added, and the phases were separated. The organic phase was washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure to yield a yellow solid. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH) 100:0 to 0:100) afforded a yellow solid. 1 M HCl in Et ₂ O (0.06 ml, 0.06 mmol) was added to a solution of the yellow solid in 9:1 CH ₂ Cl ₂ /Me0H (10 mL) under N ₂ and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was concentrated under reduced pressure to yield the title compound (28 mg, 58%) as a yellow solid: mp 200-204 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 11.36 (s, IH), 10.35 (br s, IH), 8.02 (d, J= 8.3 Hz, 2H), 7.88 (d, J= 8.3 Hz, 2H), 7.80 (d, J= 7.0 Hz, IH), 7.59 (d, J= 8.0 Hz, IH), 7.49 (br s, IH), 7.07 (dd, J= 8.0, 1.5 Hz, IH), 6.87 (d, J= 1.5 Hz, IH), 6.72 (d, J= 7.0, 1.5 Hz, IH), 4.62 (br d, J= 16.0 Hz, IH), 4.49-4.40 (m, IH), 3.81-3.73 (m, IH), 3.49-3.39 (m, IH), 3.12- 3.00 (m, 5H); ESI MS m/z 424 [M + H] ⁺ .

Example 110

Preparation of 4-(Benzyloxy)- 1-(U ,9-trimethyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,4-& ^" |indol-

7-yl)pyridin-2( lHVone hydrochloride

a) 7-Bromo-l,l-dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]ind ole

Attorney's Docket 2882.023B

Chemical Formula: C ₁₃ H ₁₅ BrN ₂ Exact Mass: 278.04 Molecular Weight: 279.18

Concentrated HCl (10 rnL) was added to a suspension of a 2:1 mixture of 2-(6- bromo-lH-indol-3-yl)ethanamine and 2-(4-bromo-lH-indol-3-yl)ethanamine (9.90 g, 41.4 mmol) and Na ₂ SO ₄ (30 g) in 1 :1 acetone//? -butanol (100 mL). The resulting suspension was heated at 60 ⁰ C with stirring for 4 d. The suspension was cooled and concentrated under reduced pressure. The residue was diluted with EtOAc, and the suspension was filtered. The filtrate was washed with saturate NaHCOs solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH) 100:0 to 0:100) yielded the title compound (1.68 g, 15%) as a red foam: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.66 (br s, IH), 7.45 (d, J= 1.5 Hz, IH), 7.32 (d, J= 8.5 Hz, IH), 7.19 (dd, J= 8.5, 1.5 Hz, IH), 3.20 (t, J = 5.5 Hz, 2H), 2.68 (t, J= 5.5 Hz, 2H), 1.47 (s, 6H).

b) tert-Butyl 7-bromo- 1 , 1 ,9-trimethyl-3 ,4-dihydro- lH-pyrido [3 ,4-ÏŒ]indole-2(9H> carboxylate Chemical Formula: C ₁₉ H ₂₅ BrN ₂ O ₂ Exact Mass: 392.11 Molecular Weight: 393.32

BoC ₂ O (7.88 g, 36.1 mmol) was added to a suspension of 7-bromo- 1,1 -dimethyl- 2,3,4,9-tetrahydro-lH-pyrido[3,4-6]indole (1.68 g, 6.02 mmol) and K ₂ CO ₃ (1.66 g, 12.0 mmol) in 1 :1 H ₂ O/z-PrOH (80 mL), and the resulting suspension was stirred at 25 ⁰ C for 2 h. The suspension was filtered. The solid was washed with H ₂ O and dried under reduced pressure to afford 1.285 g of a white solid. NaH (60% dispersion in oil, 152 mg, 3.80 mmol) was added to a solution of the white solid (720 mg) in DMF (10 mL) under N ₂ and the resulting suspension was stirred at 25 ⁰ C for 30 min. MeI (0.18 mL, 2.9 mmol) was added to the suspension, and the resulting suspension was stirred at 25 ⁰ C for 30 min. The suspension was cooled to 0 ⁰ C, and H ₂ O was added slowly. Hexanes was added and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under

Attorney's Docket 2882.023B reduced pressure. Flash chromatography (silica gel, hexanes/(l :l EtOAc/hexanes) 100:0 to 60:40) yielded the title compound (471 mg, 36%) as a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.43 (d, J= 1.5 Hz, IH), 7.33 (d, J= 8.4 Hz, IH), 7.20 (dd, J= 8.4, 1.5 Hz, IH), 3.79-3.72 (m, 5H), 2.73 (t, J= 5.4 Hz, 2H), 1.88 (s, 6H), 1.53 (s, 9H).

c) tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin- 1 (2H)-yl)- 1 , 1 ,9-trimethyl-3 ,4-dihydro- IH- pyrido[3,4-δ]indole-2(9H)-carboxylate

Chemical Formula: C ₃₁ H ₃₅ N ₃ O ₄ Exact Mass: 513.26 Molecular Weight: 513.63

A suspension of 4-(benzyloxy)pyridin-2(lH)-one (107 mg, 0.532 mmol), tert-butyi 7-bromo-l,l,9-trimethyl-3,4-dihydro-lH-pyrido[3,4-δ]indole- 2(9H)-carboxylate (251 mg, 0.639 mmol), CuI (122 mg, 0.639 mmol), 8-hydroxyquinoline (93 mg, 0.639 mmol) and Cs ₂ CO ₃ (190 mg, 0.585 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and heated at 135 ⁰ C with stirring overnight. The suspension was cooled, 40:9:1 CH ₂ CVMeOHZNH ₄ OH was added and the resulting suspension was stirred at 25 ⁰ C for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford an amorphous solid. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH) 100:0 to 1 :1) yielded the title compound (74 mg, 27%) as a white powder: ¹ U NMR (300 MHz, CDCl ₃ ) δ 7.54 (d, J= 8.1 Hz, IH), 7.46-7.35 (m, 4H), 7.33-7.25 (m, 3H), 7.12 (dd, J= 8.1, 2.1 Hz, IH), 6.09 (d, J= 2.6 Hz, IH), 6.04 (dd, J= 7.5, 2.6 Hz, IH), 5.06 (s, 2H), 3.80 (s, 3H), 3.77 (t, J = 4.8 Hz, 2H), 2.77 (t, J= 4.8 Hz, 2H), 1.89 (s, 6H), 1.54 (s, 9H).

d) 4-(Benzyloxy)- 1 -( 1 , 1 ,9-trimethyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,4-6]indol-7- yl)pyridin-2(lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₆ H ₂₈ ClN ₃ O ₂

Exact Mass : 449.19 Molecular Weight: 449.97

TFA (1 niL) was added to a solution of tert-bvXy\ 7-(4-(benzyloxy)-2-oxopyridin- l(2H)-yl)-l,l,9-trimethyl-3,4-dihydro-l/f-pyrido[3,4-δ]indo le-2(9H)-carboxylate (72 mg, 0.14 mmol) in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 30 min. Saturated NaHCO ₃ solution and CH ₂ Cl ₂ were added to the solution and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Purification by semi-preparative HPLC (Phenomenex Luna C18 (2), 250.0 x 21.20 mm, 10 micron, H ₂ O with 0.05% TFA and CH ₃ CN with 0.05% TFA) afforded 14 mg of clear crystals. 1 M HCl in Et ₂ O (0.04 ml, 0.04 mmol) was added to a solution of the clear crystals in CH ₂ Cl ₂ (10 mL) under N ₂ and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was concentrated under reduced pressure to yield the title compound (15 mg, 24%) as an off-white powder: mp 296-298; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.59 (s, 2H), 7.58-7.51 (m, 3H), 7.49-7.41 (m, 4H), 7.40-7.35 (m, IH), 7.01 (dd, J= 8.5, 1.5 Hz, IH), 6.10 (dd, J= 7.5, 2.8 Hz, IH), 5.97 (d, J= 2.8 Hz, IH), 5.16 (s, 2H), 3.80 (s, 3H), 3.52-3.48 (m, 2H), 2.99 (t, J= 6.0 Hz, 2H), 1.81 (s, 6H); ESI MS m/z 414 [M + H] ⁺ .

Example 111

Preparation of (61-4-(Benzyloxy)- 1 -(9-methyl-2-(pyrrolidin-2-ylmethyl)-2,3 ,4,9- tetrahvdro-lH-pyridor3,4-άlindol-7-yl)pyridin-2(lH)-one dihydrochloride

a) (S)-tert-Buty\ 2-(bromomethyl)pyrrolidine-l-carboxylate Beilstein Registry Number 6325435

^Br '-, Chemical Formula: C ₁₀ H ₁₈ BrNO ₂

O Exact Mass: 263.05

Molecular Weight: 264.16

Attorney's Docket 2882.023B

This compound was prepared in accordance with the procedure of Kawara et al., Tetrahedron Lett., 1994, 55, 8805-8808.

b) (5)-4-(Benzyloxy)- 1 -(9-methyl-2-(pyrrolidin-2-ylmethyl)-2,3 ,4,9-tetrahydro- IH- pyrido [3 ,4-δ]indo l-7-yl)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₉ H ₃₄ Cl ₂ N ₄ O ₂ Exact Mass: 540.21 Molecular Weight: 541.51

A suspension of 4-(benzyloxy)- 1 -(9-methyl-2, 3 ,4,9-tetrahydro- lH-pyrido[3 ,A- 6]indol-7-yl)pyridin-2(lH)-one (250 mg, 0.646 mmol), (S)-tert-butyl 2- (bromomethyl)pyrrolidine-l-carboxylate (342 mg, 1.29 mmol) and CS2CO3 (841 mg, 2.58 mmol) in DMSO (10 mL) under N ₂ was stirred at 25 ⁰ C for 16 h. The suspension was heated at 60 ⁰ C for 1 d. The suspension was cooled, and H ₂ O was added. The suspension was filtered. The solid was washed with H ₂ O and dried under reduced pressure. Flash chromatograph (silica gel, hexanes/(9:0.9:0.1 Et ₂ O/MeOH/NH ₄ OH), 100:0 to 0:100) afforded 18 mg of a yellow solid. TFA (1 mL) was added to a solution of the yellow solid in CH ₂ Cl ₂ (5 mL) under N ₂ and the resulting solution was stirred at 25 ⁰ C for 3.5 h. Saturated NaHCO ₃ solution and CH ₂ Cl ₂ were added and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatograph (silica gel,(l :l EtOAc/hexanes)/(9:0.9:0.1 Et ₂ O/MeOH/NH ₄ OH), 100:0 to 0:100) yielded 10 mg of a yellow solid. 1 M HCl in Et ₂ O (0.04 ml, 0.04 mmol) was added to a solution of the yellow solid in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was concentrated under reduced pressure to yield the title compound (10 mg, 3%) as an off-white powder: mp 160-162 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.25 (br s, IH), 7.56 (d, J= 7.5 Hz, IH), 7.54-7.40 (m, 6H), 7.39-7.34 (m, IH), 7.04-6.93 (m, IH), 6.11 (dd, J= 7.5, 2.5 Hz, IH), 5.97 (d, J= 2.5 Hz, IH), 5.16 (s, 2H), 3.98-3.45 (m, HH), 3.39 (s, IH), 3.30-3.21 (m, 2H), 2.25-2.10 (m, IH), 2.05-1.74 (m, 2H), 1.73-1.60 (m, IH); ESI MS m/z 469 [M + H] ⁺ .

Attorney's Docket 2882.023B

Example 112

Preparation of 4-(4-Chloro-2-methoxyphenyD- 1 -(5-methyl-2,3A5-tetrahydro- IH- pyrido[4,3-&lindol-7-yl)pyridin-2(lH)-one hydrochloride

a) 4-(4-Chloro-2-methoxyphenyl)pyridine 1 -oxide

Chemical Formula: C _{] 2} HJ ₀ CINO ₂

Exact Mass: 235.04 Molecular Weight: 235.67

4-Chloropyridine-jV-oxide (500 mg, 3.85 mmol), 2-methoxy-4- chlorophenylboronic acid (862 mg, 4.63 mmol) and K2CO3 (1.59 g, 11.55 mmol) were suspended in DMSO (5 mL) and PdCl ₂ (dppf) (314 mg, 0.385 mmol) was added. The reaction mixture was placed under vacuum for 20 min and flushed with N ₂ . This process was repeated, and the reaction mixture was heated at 120 ⁰ C for 3 h. The reaction mixture was cooled to 25 ⁰ C and partitioned between methylene chloride and 5% lithium chloride. The aqueous phase was removed, and the organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. Flash chromatography (ISCO 40 g column, methylene chloride/MeOH 100:0 to 90:10) provided the title compound (673 mg, 74%) as a tan solid: ¹ H NMR (300 MHz, CD ₃ OD) δ 8.21 (dd, J= 5.4, 1.8 Hz, 2H), 7.47 (dd, J= 5.6, 1.6 Hz, 2H), 7.26 (d, J= 8.2 Hz, IH), 7.06 (dd, J = 8.3, 2.4 Hz, IH), 7.00 (d, J= 1.7 Hz, IH), 3.87 (s, 3H); ESI MS m/z 235 [M + H] ⁺ .

b) 4-(4-Chloro-2-methoxyphenyl)pyridin-2( lH)-one

Chemical Formula: C _{] 2} H _]Q C1NO ₂ Exact Mass: 235.04

Molecular Weight: 235.67

4-(4-Chloro-2-methoxyphenyl)pyridine 1 -oxide (673 mg, 2.86 mmol) and acetic anhydride (10 mL) were heated at reflux for 3 h. The mixture was concentrated under reduced pressure, and a 1:1 solution of H ₂ O/MeOH (20 mL) was added. The reaction mixture was heated to reflux for 1 h, cooled to 25 ⁰ C and concentrated under reduced pressure. The

Attorney's Docket 2882.023B resulting residue was dissolved in hot 2-propanol (3 mL), triturated with Et ₂ O, sonicated for 30 min then placed in the freezer. The solid was filtered off providing the title compound (550 mg, 91%) as a tan solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 11.54 (s, IH), 7.35-7.33 (m, 2H), 7.01 (s, IH), 7.08 (d, J= 6.6 Hz, IH), 6.36 (s, IH), 6.28 (s, IH), 3.82 (s, 3H); ESI MS m/z 235 [M + H] ⁺ .

c) tert-Butyi 7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin-l(2H)-yl)-5-met hyl-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

Chemical Formula: C ₂₉ H ₃₀ ClN ₃ O ₄

Exact Mass: 519.19 Molecular Weight: 520.02

A suspension of 4-(4-chloro-2-methoxyphenyl)pyridin-2(lH)-one (126 mg, 0.534 mmol), tert-butyl 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)- carboxylate (234 mg, 0.641 mmol), CuI (122 mg, 0.641 mmol), 8-hydroxyquinoline (93 mg, 0.64 mmol) and CS2CO3 (191 mg, 0.587 mmol) in DMSO (5 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and heated at 135 ⁰ C with stirring overnight. The suspension was cooled, 40:9:1 CH ₂ Cl ₂ ZMeOHZNH ₄ OH was added, and the resulting suspension was stirred at 25 ⁰ C for 10 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The solution was dried over Na ₂ SO ₄ and concentrate under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAcZhexanes)Z(9:0.9:0.1 CH ₂ Cl ₂ ZMeOHZNH ₄ OH) 100:0 to 0:100) gave the title compound (123 mg, 44%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.54 (d, J = 8.1 Hz, IH), 7.42-7.35 (m, 2H), 7.31 (d, J= 8.1 Hz, IH), 7.12-7.02 (m, 2H), 6.99 (d, J = 1.8 Hz, IH), 6.81 (d, J= 1.8 Hz, IH), 6.44 (dd, J= 7.2, 1.8 Hz, IH), 4.65 (br s, 2H), 3.88 (s, 3H), 3.90-3.81 (m, 2H), 3.65 (s, 3H), 2.87-2.79 (m, 2H), 1.51 (s, 9H).

d) 4-(4-Chloro-2-methoxyphenyl)-l-(5-methyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-δ]indol- 7-yl)pyridin-2( lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₄ H ₂₃ Cl ₂ N ₃ O ₂ Exact Mass: 455.12 Molecular Weight: 456.36

TFA (2 niL) was added to a solution of tert-bvXy\ 7-(4-(4-chloro-2- methoxyphenyl)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-dihydro-l /f-pyrido[4,3-δ]indole- 2(5H)-carboxylate (124 mg, 0.238 mmol) in CH ₂ Cl ₂ (10 niL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 1 h. Saturated NaHCO ₃ solution and CH ₂ Cl ₂ were added to the solution, and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH) 100:0 to 0:100) yielded 70 mg of an off- white solid. 1 M HCl in Et ₂ O (0.03 ml, 0.03 mmol) was added to a solution of the off- white solid (10 mg) in CH ₂ Cl ₂ (10 mL) under N ₂ and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was concentrated under reduced pressure to yield the title compound (9 mg, 26%) as an off-white powder: mp 290-292 ⁰ C; ¹ U NMR (500 MHz, DMSO-J ₆ ) δ 9.17 (br s, 2H), 7.65 (d, J= 7.0 Hz, IH), 7.62 (d, J= 1.8 Hz, IH), 7.59 (d, J = 8.5 Hz, IH), 7.44 (d, J= 8.0 Hz, IH), 7.26 (d, J= 1.8 Hz, IH), 7.14 (dd, J= 8.0, 1.8 Hz, IH), 7.09 (dd, J= 8.5, 1.8 Hz, IH), 6.57 (d, J= 2.0 Hz, IH), 6.47 (dd, J= 7.0, 2.0 Hz, IH), 4.37 (br s, 2H), 3.87 (s, 3H), 3.70 (s, 3H), 3.57-3.52 (m, 2H), 3.10 (t, J= 6.0 Hz, 2H); ESI MS m/z 420 [M + H] ⁺ .

Example 113

Preparation of 4-(4-Chloro-2-methoxyphenyD- 1 -(2,5-dimethyl-2,3,4,5-tetrahydro- IH- pyrido[4,3-&lindol-7-yl)pyridin-2(lH)-one hydrochloride

a) 4-(4-Chloro-2-methoxyphenyl)-l-(2,5-dimethyl-2,3,4,5-tetrahy dro-lH-pyrido[4,3- δ]indol-7-yl)pyridin-2(lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₅ H ₂₅ Cl ₂ N ₃ O ₂

Exact Mass: 469.13 Molecular Weight: 470.39

TFA (2 niL) was added to a solution of tert-bvXy\ 7-(4-(4-chloro-2- methoxyphenyl)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-dihydro-l /f-pyrido[4,3-δ]indole- 2(5H)-carboxylate (124 mg, 0.238 mmol) in CH ₂ Cl ₂ (10 niL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 1 h. Saturated NaHCO ₃ solution and CH ₂ Cl ₂ were added to the solution, and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) yielded 70 mg of an off-white solid. Formaldehyde (37% in H ₂ O, 0.02 mL, 0.2 mmol) was added to a solution of the off-white solid (43 mg) in 1:1 MeOH/CH ₂ Cl ₂ (5 mL) and the resulting solution was stirred at 25 ⁰ C for 45 min. NaBH(OAc) ₃ (43 mg, 0.20 mmol) was added to the solution, and the resulting suspension was stirred at 25 ⁰ C for 30 min. The suspension was concentrated under reduced pressure, and the resulting residue was diluted with CH ₂ Cl ₂ and saturated NaHCO ₃ solution. The phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Purification by semi-preparative HPLC (Phenomenex Luna Cl 8 (2), 250.0 x 21.20 mm, 10 micron, H ₂ O with 0.05% TFA and CH ₃ CN with 0.05% TFA) afforded 13 mg of an off-white solid. 1 M HCl in Et ₂ O (0.03 ml, 0.03 mmol) was added to a solution of the off-white solid in CH ₂ Cl ₂ (10 mL) under N ₂ and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was concentrated under reduced pressure to yield the title compound (14 mg, 17%) as an off- white powder: mp 270-272 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 10.15 (br s, IH), 7.66 (d, J= 7.0 Hz, IH), 7.63 (d, J= 1.5 Hz, IH), 7.55 (d, J= 8.0 Hz, IH), 7.44 (d, J= 8.5 Hz, IH), 7.26 (d, J= 1.8 Hz, IH), 7.14 (dd, J= 8.5, 1.5 Hz, IH), 7.11 (dd, J= 8.0, 1.8 Hz, IH), 6.57 (d, J= 2.0 Hz, IH), 6.47 (dd, J= 7.0, 2.0 Hz, IH), 4.67 (d, J= 13.5 Hz, IH), 4.33 (dd, J= 14.3, 6.0 Hz, IH), 3.87 (s, 3H), 3.86-3.79 (m, IH), 3.71 (s, 3H), 3.55-3.47 (m, IH), 3.24-3.15 (m, 2H), 3.01 (s, 3H); ESI MS m/z A3A [M + H] ⁺ .

Attorney's Docket 2882.023B

Example 114

Preparation of l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-&lindol-7-y l)-4-(pyrimidin-2- ylmethoxy)pyridin-2( lHVone dihydrochloride

a) 4-(Pyrimidin-2-ylmethoxy)pyridine 1 -oxide Chemical Formula: C ₁₀ H ₉ N ₃ O ₂

Exact Mass : 203.07 Molecular Weight: 203.20

Following the procedure of Example 137 (step a), but substituting pyrimidin- 2ylmethanol (3.0 g, 27 mmol) for imidazo[l,2-α]pyridine-2-ylmethanol, the title compound (0.95 g, 17%) was prepared as an orange solid: ¹ H NMR (300 MHz, CD ₃ OD) δ 8.81 (d, J= 5.1 Hz, 2H), 8.23-8.21 (m, 2H), 7.45 (t, J= 4.8 Hz, IH), 7.24-7.21 (m, 2H), 5.46 (s, 2H).

b) 4-(Pyrimidin-2-ylmethoxy)pyridin 2(lH)-one

Chemical Formula: C ₁₀ H ₉ N ₃ O ₂ Exact Mass: 203O7 Molecular Weight: 203.20

Following the procedure of Example 137 (step b), but substituting 4-(pyrimidin-2- ylmethoxy)pyridine 1-oxide (0.95 g, 4.6 mmol) for 4-(imidazo[l,2-α]pyridin-2- ylmethoxy)pyridine 1-oxide, the title compound (0.55 g, 58%) was prepared as a dark brown solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 11.09 (br s, IH), 8.84 (d, J= 4.5 Hz, 2H), 7.48 (t, J= 5.0 Hz, IH), 7.25-7.23 (m, IH), 5.92 (dd, J= 7.0, 2.5 Hz, IH), 5.66 (d, J= 8.0, 2.5 Hz, IH), 5.23 (s, 2H).

c) tert-Butyl 5-methyl-7-(2-oxo-4-(pyrimidin-2-ylmethoxy)pyridin-l(2H)-yl) -3,4-dihydro- lH-pyrido[4,3-6]indole-2(5H)-carboxylate

Attorney's Docket 2882.023B

Chemical Formula: C ₂₇ H ₂₉ N ₅ O ₄

Exact Mass: 487.22 Molecular Weight: 487.55

A suspension of 4-(pyrimidin-2-ylmethoxy)pyridin-2(lH)-one (242 mg, 1.19 mmol), tert-butyl 7-bromo-5-methyl-3,4-dihydro-l/f-pyrido[4,3-δ]indole-2(5H)- carboxylate (522 mg, 1.43 mmol), CuI (272 mg, 1.43 mmol), 8-hydroxyquinoline (35 mg, 0.24 mmol) and CS2CO3 (426 mg, 1.31 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and heated at 135 ⁰ C with stirring overnight. The suspension was cooled, 40:9:1 CH ₂ Cl ₂ /MeOH/NH ₄ OH (50 mL) was added, and the resulting suspension was stirred at 25 ⁰ C for 1 h. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(4:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) yielded the title compound (256 mg, 44%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) 5 8.81 (d, J= 4.5 Hz, IH), 7.50 (d, J= 8.0 Hz, IH), 7.32 (d, J= 7.5 Hz, IH), 7.31-7.27 (m, 3H), 7.01 (br d, J= 8.0 Hz, IH), 6.17 (dd, J= 7.5, 2.8 Hz, IH), 6.00 (d, J= 2.8 Hz, IH), 5.32 (s, 2H), 4.64 (br s, 2H), 3.88-3.79 (m, 2H), 3.62 (s, 3H), 2.84-2.78 (m, 2H), 1.50 (s, 9H).

d) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)- 4-(pyrimidin-2- ylmethoxy)pyridin-2( lH)-one dihydrochloride

Chemical Formula: C ₂₂ H ₂₃ Cl ₂ N ₅ O ₂

Exact Mass: 459.12 Molecular Weight: 460.36

TFA (2 mL) was added to a solution of tert-butyl 5-methyl-7-(2-oxo-4-(pyrimidin- 2-ylmethoxy)pyridin- 1 (2H)-yl)-3 ,4-dihydro- lH-pyrido [4,3-6]indole-2(5H)-carboxylate (256 mg, 0.525 mmol) in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred

Attorney's Docket 2882.023B at 25 ⁰ C for 1 h. Saturated NaHCO ₃ solution and CH ₂ Cl ₂ were added to the solution, and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 : 1 EtOAc/hexanes)/(4:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) yielded 35 mg of a yellow foam. 1 M HCl in Et ₂ O (0.08 ml, 0.08 mmol) was added to a solution of the yellow foam (16 mg) in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was concentrated under reduced pressure to yield the title compound (16 mg, 14%) as an off-white powder: mp 234-236 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.10 (br s, 2H), 8.88 (d, J= 5.0 Hz, 2H), 7.58-7.52 (m, 4H), 6.99 (dd, J= 8.0, 1.8 Hz, IH), 6.14 (dd, J= 7.5, 2.5 Hz, IH), 5.86 (d, J= 2.5 Hz, IH), 5.33 (s, 2H), 4.36 (br s, 2H), 3.68 (s, 3H), 3.57-3.52 (m, 2H), 3.11-3.05 (m, 2H); ESI MS m/z 388 [M + H] ⁺ .

Example 115

Preparation of 4-(Imidazo[l,2-αlpyridin-6-ylmethoxy)-l-(5-methyl-2,3,4,5-t etrahydro-lH- pyrido[4,3-^lindol-7-yl)pyridin-2(lH)-one dihydrochloride

a) tert-Butyl 7-(4-(imidazo[l,2-α]pyridin-6-ylmethoxy)-2-oxopyridin-l(2H) -yl)-5-methyl-

3,4-dihydro-lH-pyrido[4,3-6]indole-2(5H)-carboxylate

Chemical Formula: C ₃₀ H ₃₁ N ₅ O ₄

Exact Mass: 525.24 Molecular Weight: 525.60

A suspension of 4-(imidazo[l,2-α]pyridin-6-ylmethoxy)pyridin-2(lH)-one (270 mg, 1.12 mmol), tert-butyl 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)- carboxylate (493 mg, 1.35 mmol), CuI (257 mg, 1.35 mmol), 8-hydroxyquinoline (98 mg, 0.67 mmol) and Cs ₂ CO ₃ (401 mg, 1.23 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and heated at 135 ⁰ C with stirring for 4.5 h. The suspension was cooled, 40:9:1 Cη ₂ Cl ₂ /MeOη/Nη ₄ Oη (50 mL) was added, and the resulting suspension was stirred at 25 ⁰ C for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The solution

Attorney's Docket 2882.023B was dried over Na ₂ SO ₄ and concentrate under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(4:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) yielded the title compound (167 mg, 28%) as a yellow solid: ¹ U NMR (300 MHz, CDCl ₃ ) δ 8.34-8.25 (m, IH), 7.79-7.61 (m, 3H), 7.58-7.50 (m, IH), 7.40-7.25 (m, 3H), 7.07-6.69 (m, IH), 6.17-6.10 (m, IH), 6.09-6.02 (m, IH), 5.11 (s, 2H), 4.65 (br s, 2H), 3.92-3.80 (m, 2H), 3.65 (s, 3H), 2.89-2.80 (m, 2H), 1.52 (s, 9H); ESI MS m/z 526 [M + H] ⁺ .

b) 4-(Imidazo[ 1 ,2-α]pyridin-6-ylmethoxy)- 1 -(5-methyl-2,3,4,5-tetrahydro- lH-pyrido[4,3- δ]indol-7-yl)pyridin-2(lH)-one dihydrochloride

Chemical FoÏ€nula: C ₂₅ H ₂₅ Cl ₂ N ₅ O ₂ Exact Mass: 497.14 Molecular Weight: 498.40

TFA (2 mL) was added to a solution of tert-butyi 7-(4-(imidazo[l,2-α]pyridin-6- ylmethoxy)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-dihydro-lH-py rido[4,3-δ]indole-2(5H)- carboxylate (167 mg, 0.317 mmol) in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 1 h. Saturated NaHCO ₃ solution and CH ₂ Cl ₂ were added to the solution, and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(4:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) yielded 51 mg of a yellow solid. Purification by semi-preparative HPLC (Phenomenex Luna C18 (2), 250.0 x 21.20 mm, 10 micron, H ₂ O with 0.05% TFA and CH ₃ CN with 0.05% TFA) afforded 7 mg of a white solid. 1 M HCl in Et ₂ O (0.03 ml, 0.03 mmol) was added to a solution of the white solid (7 mg) in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was concentrated under reduced pressure to yield the title compound (8 mg, 5%) as a white powder: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.28 (br s, 2H), 9.06 (s, IH), 8.38 (s, IH), 8.19 (s, IH), 8.05-7.94 (m, 2H), 7.62 (d, J= 7.5 Hz, IH), 7.56 (d, J= 8.0 Hz, IH), 7.50 (d, J= 1.5 Hz, IH), 6.99 (dd, J= 8.0, 1.5 Hz, IH), 6.13 (dd, J= 7.5, 2.5 Hz, IH), 6.09 (d, J= 2.5 Hz, IH), 5.33 (s, 2H), 4.35 (br s, 2H), 3.69 (s, 3H), 3.56-3.50 (m, 2H), 3.12-3.05 (m, 2H); ESI MS m/z 426 [M + H] ⁺ .

Attorney's Docket 2882.023B

Example 116

Preparation of 4-(Imidazo[l,2-αlpyridin-2-ylmethoxy)-l-(5-methyl-2,3,4,5-t etrahydro-lH- pyrido[4,3-^lindol-7-yl)pyridin-2(lH)-one dihydrochloride

a) te/t-Butyl 7-(4-(imidazo[l,2-α]pyridin-2-ylmethoxy)-2-oxopyridin-l(2H) -yl)-5 -methyl-

3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

Chemical Formula: C ₃₀ H ₃₁ N ₅ O ₄

Exact Mass: 525.24 Molecular Weight: 525.60

A suspension of 4-(imidazo[l,2-α]pyridin-2-ylmethoxy)pyridin-2(lH)-one (231 mg, 0.960 mmol), tert-bvXy\ 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole- 2(5H)-carboxylate (421 mg, 1.15 mmol), CuI (219 mg, 1.15 mmol), 8-hydroxyquinoline (84 mg, 0.576 mmol) and Cs ₂ CO ₃ (345 mg, 1.06 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and heated at 135 ⁰ C with stirring overnight. The suspension was cooled, 40:9:1 Cη ₂ Cl ₂ /MeOη/Nη ₄ Oη (50 mL) was added, and the resulting suspension was stirred at 25 ⁰ C for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine and 10% CuSO ₄ solution. The solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtO Ac/hexanes)/(4:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) gave the title compound (132 mg, 26%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.12 (d, J= 6.9 Hz, IH), 7.70 (br s, IH), 7.62 (d, J= 8.7 Hz, IH), 7.50 (d, J= 8.4 Hz, IH), 7.33-7.18 (m, 3H), 7.02 (d, J= 7.5 Hz, IH), 6.82 (dd, J= 6.9, 6.9 Hz, IH), 6.17 (d, J= 2.1 Hz, IH), 6.08 (dd, J= 7.5, 2.1 Hz, IH), 5.25 (s, 2H), 3.84 (br s, 2H), 3.63 (s, 3H), 2.84-2.79 (m, 2H), 1.72-1.60 (m, 2H), 1.50 (s, 9H).

b) 4-(Imidazo[l,2-α]pyridin-2-ylmethoxy)-l-(5-methyl-2,3,4,5-t etrahydro-lH-pyrido[4,3- δ]indol-7-yl)pyridin-2(lH)-one dihydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₅ H ₂₅ Cl ₂ N ₅ O ₂

Exact Mass: 497.14 Molecular Weight: 498.40

TFA (1 niL) was added to a solution of tert-bvXy\ 7-(4-(imidazo[l,2-α]pyridin-2- ylmethoxy)-2-oxopyridin4(2H)-yl)-5-methyl-3,4-dihydro-l/f-py rido[4,3-δ]indole-2(5H)- carboxylate (132 mg, 0.251 mmol) in CH ₂ Cl ₂ (10 niL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 1 h. Saturated NaHCO ₃ solution and CH ₂ Cl ₂ were added to the solution, and the phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(4:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) yielded 42 mg of an off-white solid. 1 M HCl in Et ₂ O (0.07 ml, 0.07 mmol) was added to a solution of the off- white solid (15 mg) in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was concentrated under reduced pressure to yield the title compound (15 mg, 34%) as a white powder: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.30 (br s, 2H), 8.84 (s, IH), 8.37 (s, IH), 7.89-7.70 (m, 2H), 7.64-7.53 (m, 2H), 7.50 (s, IH), 7.37-7.29 (m, IH), 7.03- 6.97 (m, IH), 6.20-6.09 (m, 2H), 5.41 (s, 2H), 4.35 (br s, 2H), 3.69 (s, 3H), 3.58-3.50 (m, 2H), 3.13-3.07 (m, 2H); ESI MS m/z 426 [M + H] ⁺ .

Example 117

Preparation of l-(2.5-Dimethyl-2.3.4.5-tetrahvdro-l/f-pyridor4.3-^1indol-7- yl)-4-

(imidazo[l,2-αlpyridin-2-ylmethoxy)pyridin-2(l//)-one dihydrochloride

a) l-(2,5-Dimethyl-2,3,4,5-tetrahydro-l/f-pyrido[4,3-δ]indol-7 -yl)-4-(imidazo[l,2- α]pyridin-2-ylmethoxy)pyridin-2( lH)-one dihydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₆ H ₂₇ Cl ₂ N ₅ O ₂

Exact Mass: 511.15 Molecular Weight: 512.43

TFA (1 niL) was added to a solution of tert-butyl 7-(4-(imidazo[l,2-α]pyridin-2- ylmethoxy)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-dihydro-lH-py rido[4,3-δ]indole-2(5H)- carboxylate (132 mg, 0.251 mmol) in CH ₂ Cl ₂ (10 niL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 1 h. Saturated NaHCO ₃ solution and CH ₂ Cl ₂ were added to the solution, and the phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(4:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) yielded 42 mg of an off-white solid. Formaldehyde (37% in H ₂ O, 0.01 mL, 0.12 mmol) was added to a solution of the off-white solid (27 mg) in 1 :1 MeOH/CH ₂ Cl ₂ (5 mL), and the resulting solution was stirred at 25 ⁰ C for 45 min. NaBH(O Ac) ₃ (27 mg, 0.13 mmol) was added to the solution, and the resulting suspension was stirred at 25 ⁰ C for 30 min. The suspension was concentrated under reduced pressure, and the residue was diluted with CH ₂ Cl ₂ and saturated NaHCO ₃ solution. The phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure to afford 25 mg of a viscous oil. 1 M HCl in Et ₂ O (0.11 ml, 0.11 mmol) was added to a solution of the off-white solid in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was concentrated under reduced pressure to yield the title compound (25 mg, 30%) as an off-white powder: 1H NMR (500 MHz, DMSO-J ₆ ) 10.79 (br s, IH), 8.87 (d, J= 6.5 Hz, IH), 8.41 (s, IH), 7.90-7.78 (m, 2H), 7.61 (d, J= 7.5 Hz, IH), 7.53-7.49 (m, 2H), 7.42-7.35 (m, IH), 7.00 (dd, J= 8.5, 1.5 Hz, IH), 6.15 (d, J= 2.5Hz, IH), 6.12 (dd, J= 7.5, 2.5 Hz, IH), 5.43 (s, 2H), 4.62 (d, J= 14.0 Hz, IH), 4.29 (dd, J= 14.0, 7.5 Hz, IH), 3.80-3.75 (m, IH), 3.69 (s, 3H), 3.55-3.46 (m, IH), 3.23-3.16 (m, 2H), 2.97 (s, 3H); ESI MS m/z 440 [M + H] ⁺ .

Example 118

Attorney's Docket 2882.023B

Preparation of l-(2-Acetyl-9-methyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^1indo l-7-yl)-4- (benzyloxy)pyridin-2( lHVone

Chemical Formula: C ₂₆ H ₂₅ N ₃ O ₃

Exact Mass: 427.19 Molecular Weight: 427.50

AcCl (0.023 mL, 0.32 mmol) was added to a solution of 4-(benzyloxy)-l-(9- methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)pyridi n-2(lH)-one dihydrochloride (100 mg, 0.216 mmol), DMAP (5 mg, 0.04 mmol) and Et ₃ N (0.09 mL, 0.6 mmol) in CH ₂ Cl ₂ (20 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 4 h. H ₂ O was added to the solution, and the phases were separated. The organic phase was washed with saturated NH4CI solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded the title compound (61 mg, 66%) as a mixture of rotomers as a white powder: mp 80-82 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 7.56 (d, J= 7.5 Hz, IH), 7.52-7.35 (m, 7H), 6.94 (dd, J= 8.0, 1.5 Hz, IH), 6.12-6.08 (m, IH), 5.97 (d, J= 3.0 Hz, IH), 5.15 (s, 2H), 4.77-4.72 (m, 2H), 3.82-3.72 (m, 2H), 3.69- 3.65 (m, 3H), 3.82-2.78 (m, 1.3H), 2.71-2.68 (m, 0.7H), 2.16 (s, 3H); ESI MS m/z 428 [M + H] ⁺ .

Example 119

Preparation of l-(2-Acetyl-5-methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indo l-7-yl)-4-(5-

(trifluoromethyl)pyridin-2-yl)pyridin-2(lH)-one

Attorney's Docket 2882.023B

AcCl (0.03 mL, 0.4 mmol) was added to a solution of l-(5-methyl-2, 3,4,5- tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)-4-(5-(trifluoromethy l)pyridin-2-yl)pyridin-2(lH)- one (125 mg, 0.294 mmol), DMAP (7 mg, 0.06 mmol) and Et ₃ N (0.08 mL, 0.6 mmol) in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 17 h. H ₂ O was added to the solution, and the phases were separated. The organic phase was washed with saturated NH4CI solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded the title compound (116 mg, 84%) as a mixture of rotomers as a white powder: mp 232-236 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.15 (s, IH), 8.38 (d, J= 8.3 Hz, IH), 8.35 (d, J= 8.3 Hz, IH), 7.84 (d, J= 7.5 Hz, IH), 7.59-7.54 (m, 2H), 7.28 (d, J= 1.5 Hz, IH), 7.08-7.03 (m, 2H), 4.70 (s, 0.8H), 4.68 (s, 1.2H), 3.88 (t, J= 5.5 Hz, 0.8H), 3.83 (t, J= 5.5 Hz, 1.2 H), 3.67 (s, 3H), 2.97-2.91 (m, 1.2H), 2.86-2.81 (m, 0.8H), 2.15 (s, 1.8H), 2.13 (s, 1.2H); ESI MS m/z 467 [M + H] ⁺ .

Example 120

Preparation of l-(2-Ethyl-5-methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol -7-yl)-4-(5-

(trifluoromethyl)pyridin-2-yl)pyridin-2( lHVone dihvdrochloride

Chemical Formula: C ₂₅ Fl ₂₅ Cl ₂ F ₃ N ₄ O Exact Mass: 524.14 Molecular Weight: 525.39

2-Picoline borane (63 mg, 0.59 mmol) was added to a suspension of l-(5-methyl- 2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)-4-(5-(triflu oromethyl)pyridin-2-yl)pyridin- 2(lH)-one dihydrochloride (98 mg, 0.20 mmol) and acetylaldhyde (0.03 mL, 1 mmol) in 9:1 CH ₂ Cl ₂ / AcOH (10 mL) under N ₂ , and the resulting solution was stirred under N ₂ for 4 h. Acetylaldhyde (0.03 mL, 1 mmol) was added to the solution under N ₂ and the resulting solution was stirred at 25 ⁰ C for 15 min. The solution was neutralized with saturated NaHCO ₃ solution, and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 : 1

Attorney's Docket 2882.023B

EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded 67 mg of a yellow powder. 2 N HCl in Et ₂ O (0.15 rnL, 0.330 mmol) was added to a solution of the yellow powder in 1 : 1 MeOH/CH ₂ Cl ₂ (10 rnL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 15 min. Et ₂ O was added to the solution, and the resulting suspension was filtered under N ₂ to afford the title compound (78 mg, 75%) as a yellow powder: mp 300-302 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 10.16 (br s, IH), 9.15 (s, IH), 8.42-8.35 (m, 2H), 7.85 (d, J= 7.0 Hz, IH), 7.65 (d, J= 1.5 Hz, IH), 7.61 (d, J= 8.5 Hz, IH), 7.30 (d, J= 2.0 Hz, IH), 7.13 (dd, J= 8.5, 1.5 Hz, IH), 7.08 (dd, J= 7.5, 2.0 Hz, IH), 4.70 (d, J = 12.5 Hz, IH), 4.32 (dd, J= 14.5, 8.0 Hz, IH), 3.91-3.83 (m, IH), 3.72 (s, 3H), 3.52-3.43 (m, IH), 3.41-3.30 (m, 2H), 3.24-3.16 (m, 2H), 1.38 (t, J= 7.3 Hz, 3H); ESI MS m/z 453 [M + H] ⁺ .

Example 121

Preparation of l-(2-Isopropyl-5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-^li ndol-7-yl)-4- (5-(trifluoromethyl)pyridin-2-yl)pyridin-2(lH)-one dihydrochloride

Chemical Formula: C ₂₆ H ₂₇ Cl ₂ F ₃ N ₄ O

Exact Mass: 538.15 Molecular Weight: 539.42

2-Picoline borane (87 mg, 0.81 mmol) was added to a suspension of l-(5-methyl- 2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)-4-(5-(triflu oromethyl)pyridin-2-yl)pyridin- 2(lH)-one dihydrochloride (134 mg, 0.27 mmol) and acetone (0.10 mL, 1.4 mmol) in 9:1 CH ₂ Cl ₂ / AcOH (10 mL) under N ₂ , and the resulting solution was stirred for 24 h. Acetone (1 mL) was added to the solution and the resulting solution was stirred at 25 ⁰ C for 24 h. Acetone (1 mL) and 2-picoline borane (87 mg, 0.81 mmol) were added to the solution, and the resulting solution was stirred at reflux for 24 h. The solution was cooled, H ₂ O was added, and the reaction mixture was neutralized with saturated NaHCO ₃ solution. The phases were separated, and the organic phase was dried over Na ₂ SO ₄ and concentrated

Attorney's Docket 2882.023B under reduced pressure. Flash chromatography (silica gel, (1 : 1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded 88 mg of a yellow powder. 2 N HCl in Et ₂ O (0.15 rnL, 0.330 mmol) was added to a solution of the yellow powder in 1 :1 MeOH/CH ₂ Cl ₂ (10 rnL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 30 min. Et ₂ O was added to the solution, and the resulting solid was collected by filtration under N ₂ . The solid was washed with Et ₂ O to afford the title compound (25 mg, 17%) as a yellow powder: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.80 (br s, IH), 9.15 (d, J= 2.0 Hz, IH), 8.42-8.35 (m, 2H), 7.85 (d, J= 7.5 Hz, IH), 7.66 (d, J= 1.5 Hz, IH), 7.62 (d, J= 8.5 Hz, IH), 7.30 (d, J= 2.0 Hz, IH), 7.14 (dd, J= 8.5, 1.5 Hz, IH), 7.08 (dd, J= 7.5, 2.0 Hz, IH), 4.58 (d, J= 13.0 Hz, IH), 4.48-4.40 (m, IH), 3.90-3.82 (m, IH), 3.78-3.70 (m, 4H), 3.51-3.42 (m, IH), 3.38-3.15 (m, 2H), 1.45-1.36 (m, 6H); ESI MS m/z 467 [M + H] ⁺ .

Example 122

Preparation of 4-(4-MethoxyphenyD- 1 -(9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 A-

&1indol-7-yl)pyridin-2(lH)-one hydrochloride

a) 4-(4-Methoxyphenyl)pyridin-2( lH)-one

Chemical Formula: C ₁₂ H ₁₁ NO ₂

Exact Mass: 201.08 Molecular Weight: 201.22

A suspension of 4-bromo-2-methoxypyridine (1.22 g, 6.49 mmol), 4- methoxyphenyl boronic acid (1.97 g, 13.0 mmol), PdCl ₂ (dppf) (530 mg, 0.649 mmol) and K ₂ Cθ3 (1.79 g, 13.0 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and stirred at 95 ⁰ C for 2 h. The suspension was cooled, H ₂ O was added, and the suspension was filtered to afford a light colored solid. Flash chromatography (silica gel, hexanes/(l :l EtOAc/hexanes), 100:0 to 0:100) afforded 1.10 g of a white powder. The white powder was diluted with concentrated HCl solution (50 mL) and stirred at reflux for 12 h. The reaction was cooled and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1

Attorney's Docket 2882.023B

CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded the title compound (313 mg, 24%) as a white powder: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 11.47 (s, IH), 7.65 (d, J= 8.7 Hz, 2H), 7.38 (d, J= 6.8 Hz, IH), 7.01 (d, J= 8.7 Hz, 2H), 6.51 (br s, IH), 6.47 (d, J= 6.8 Hz, IH), 3.79 (s, 3H).

b) tert-Butyl 7-(4-(4-methoxyphenyl)-2-oxopyridin- 1 (2H)-yl)-9-methyl-3 ,4-dihydro- IH- pyrido[3,4-δ]indole-2(9H)-carboxylate

A suspension of 4-(4-methoxyphenyl)pyridin-2(lH)-one (103 mg, 0.510 mmol), tert-butyi 7-bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-c arboxylate (223 mg, 0.612 mmol), CuI (116 mg, 0.612 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and CS2CO3 (183 mg, 0.561 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and stirred at 135 ⁰ C overnight. The suspension was cooled, 9:0.9:0.1 Cη ₂ Cl2/MeOη/Nη ₄ Oη was added, and the resulting suspension was stirred at 25 ⁰ C for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 : 1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded the title compound (98 mg, 40%) as a yellow powder: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.64-7.53 (m, 3H), 7.46 (d, J= 7.2 Hz, IH), 7.36 (br s, IH), 7.08 (dd, J= 8.1, 1.5 Hz, IH), 7.01 (d, J = 8.7 Hz, 2H), 6.87 (d, J= 1.8 Hz, IH), 6.51 (dd, J= 7.2, 1.8 Hz, IH), 4.68-4.60 (m, 2H), 3.88 (s, 3H), 3.82-3.73 (m, 2H), 3.65 (s, 3H), 2.85-2.78 (m, 2H), 1.52 (s, 9H).

c) 4-(4-Methoxyphenyl)-l-(9-methyl-2,3,4,9-tetrahydro-lH-pyrido [3,4-δ]indol-7- yl)pyridin-2(lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₄ H ₂₄ CDST ₃ O ₂

Exact Mass: 421. 16 Molecular Weight: 421.92

TFA (1 ml) was added to a solution of tert-bvXy\ 7-(4-(4-methoxyphenyl)-2- oxopyridin- 1 (2H)-yl)-9-methyl-3 ,4-dihydro- 1/f-pyrido [3 ,4-6]indole-2(9H)-carboxylate (98 mg, 0.20 mmol) in CH ₂ Cl ₂ (10 mL) under N ₂ and the resulting solution was stirred for 2.5 h at 25 ⁰ C. Saturated NaHCO ₃ solution was added, and the phases were separated. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded 49 mg of a white powder. 1 N HCl in Et ₂ O (0.07 mL, 0.07 mmol) was added to a solution of the white powder in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 1 h. The solution was concentrated under reduced pressure to yield the title compound (47 mg, 55%) as a yellow powder: mp 306-308 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.43 (br s, 2H), 7.76 (d, J= 9.0 Hz, 2H), 7.70 (d, J= 7.0 Hz, IH), 7.61-7.58 (m, 2H), 7.11-7.05 (m, 3H), 6.73 (d, J= 2.0 Hz, IH), 6.68 (dd, J= 7.0, 2.0 Hz, IH), 4.51^1.45 (m, 2H), 3.83 (s, 3H), 3.70 (s, 3H), 3.48-3.42 (m, 2H), 2.99 (t, J = 6.0 Hz, 2H); ESI MS m/z 386 [M + H] ⁺ .

Example 123

Preparation of l-(5-Methyl-2.3.4.5-tetrahvdro-lH-pyridor4.3-^1indol-7-yl)-4 -(4-

(methylthio)phenyl)pyridin-2( lHVone hydrochloride

a) 4-(4-(Methylthio)phenyl)pyridin-2( lH)-one

Chemical Formula: C ₁₂ H ₁₁ NOS

Exact Mass: 217.06 Molecular Weight: 217.29

A suspension of 4-bromo-2-methoxypyridine (1.225 g, 6.511 mmol), A- methylthiophenyl boronic acid (2.188 g, 13.02 mmol), PdCl ₂ (dppf) (531 mg, 0.651 mmol)

Attorney's Docket 2882.023B and K ₂ CO ₃ (1.797 g, 13.02 mmol) in DMSO (10 niL) was degassed under reduced pressure for 25 min. The suspension was put under N ₂ and stirred at 95 ⁰ C for 16 h. The suspension was cooled, H ₂ O was added, and the suspension was filtered to afford a light colored solid. Flash chromatography (silica gel, hexanes/(l :l EtOAc/hexanes), 100:0 to 0 : 100) afforded 1.10 g of a white powder. The white powder was diluted with concentrated HCl solution (50 rnL) and stirred at reflux for 24 h. The reaction was cooled and concentrated under reduced pressure. The residue was neutralized with saturated NaHCO ₃ solution, and the solid was collected by filtration. The solid was washed with H ₂ O to afford the title compound (1.103 g, 71%) as a tan solid: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 7.65 (d, J= 8.4 Hz, 2H), 7.43 (d, J= 6.9 Hz, IH), 7.34 (d, J= 8.4 Hz, 2H), 6.57 (d, J= 1.7 Hz, IH), 6.50 (dd, J= 6.9, 1.7 Hz, IH), 3.34 (s, 3H).

b) l-(5-Methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-6]indol-7-yl)-4 -(4- (methylthio)phenyl)pyridine-2( lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₄ ClN ₃ OS Exact Mass: 437.13

Molecular Weight: 437.98

A suspension of 4-(4-(methylthio)phenyl)pyridine-2(lH)-one (134 mg, 0.615 mmol), tert-butyl 7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)- carboxylate (247 mg, 0.676 mmol), CuI (140 mg, 0.738 mmol), 8-hydroxyquinoline (18 mg, 0.12 mmol) and Cs ₂ CO ₃ (220 mg, 0.676 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N ₂ and stirred at 135 ⁰ C overnight. The suspension was cooled, 9:0.9:0.1 Cη ₂ Cl ₂ /MeOη/Nη ₄ θη was added, and the resulting suspension was stirred at 25 ⁰ C for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded 179 mg of a yellow powder. 2 N HCl in Et ₂ O (300 mL) was added to a solution

Attorney's Docket 2882.023B of the yellow powder in 1 : 1 CH ₂ Cl ₂ ZMeOH (8 rnL) under N ₂ , and the resulting suspension was stirred at 25 ⁰ C for 17 h. The suspension was filtered and the solid was washed with CH ₂ Cl ₂ and 99:1 CH ₂ Cl ₂ /Me0H to afford the title compound (41 mg, 15%) as an off-white solid: mp 306-310 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.27 (br s, 2H), 7.77-7.71 (m, 3H), 7.61-7.58 (m, 2H), 7.39 (d, J= 8.5 Hz, 2H), 7.09 (dd, J= 8.5, 2.0 Hz, IH), 6.78 (d, J = 2.0 Hz, IH), 6.69 (dd, J= 7.5, 2.0 Hz, IH), 4.36 (br s, 2H), 3.70 (s, 3H), 3.56-3.51 (m, 2H), 3.10 (t, J= 5.5 Hz, 2H), 2.54 (s, 3H); ESI MS m/z 402 [M + H] ⁺ .

Example 124

Preparation of l-(9-Methyl-2.3.4.9-tetrahvdro-lH-pyridor3.4-^1indol-7-yl)-4 -(4-

(methylthio)phenyl)pyridine-2( lHVone hydrochloride

a) tert-Butyl 9-methyl-7-(4-(4-(methylthio)phenyl)-2-oxopyridin- 1 (2H)-yl)-3 ,4-dihydro- lH-pyrido [3 ,4-6]indole-2(9H)-carboxylate

Chemical Formula: C ₂₉ H ₃₁ N ₃ O ₃ S

Exact Mass: 501.21 Molecular Weight: 501.64

A suspension of 4-(4-(methylthio)phenyl)pyridine-2(lH)-one (110 mg, 0.505 mmol), tert-butyl 7-bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)- carboxylate (203 mg, 0.555 mmol), CuI (115 mg, 0.606 mmol), 8-hydroxyquinoline (15 mg, 0.10 mmol) and Cs ₂ CO ₃ (181 mg, 0.555 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N ₂ and stirred at 135 ⁰ C overnight. The suspension was cooled, 9:0.9:0.1 Cη ₂ Cl ₂ /MeOη/Nη4θη was added, and the resulting suspension was stirred at 25 ⁰ C for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded the title compound (97 mg, 38%) as an off-white powder: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.61-7.54 (m, 3H), 7.48 (d, J= 7.5 Hz, IH), 7.38-7.32 (m, 3H), 7.08 (dd, J= 8.5,

Attorney's Docket 2882.023B

2.0 Hz, IH), 6.89 (d, J= 2.0 Hz, IH), 6.50 (dd, J= 7.5, 2.0 Hz, IH), 4.70-4.61 (m, 2H), 3.81-3.73 (m, 2H), 3.65 (s, 3H), 2.84-2.78 (m, 2H), 2.54 (s, 3H), 1.52 (s, 9H).

b) l-(9-Methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-6]indol-7-yl)-4 -(4- (methylthio)phenyl)pyridine-2( lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₄ ClN ₃ OS

Exact Mass: 437.13 Molecular Weight: 437.98

TFA (1 ml) was added to a solution of tert-butyl 9-methyl-7-(4-(4- (methylthio)phenyl)-2-oxopyridin- 1 (2H)-yl)-3 ,4-dihydro- lH-pyrido [3 ,4-6]indole-2(9H)- carboxylate (97 mg, 0.19 mmol) in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred for 1.5 h at 25 ⁰ C. Saturated NaHCO ₃ solution was added to the reaction mixture, and the resulting suspension was filtered. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded 35 mg of a yellow powder. 2 N HCl in Et ₂ O (0.09 mL, 0.09 mmol) was added to a solution of the yellow solid in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 15 min. Et ₂ O was added to the solution, and the resulting suspension was filtered under N ₂ . The solid was washed with Et ₂ O to afford the title compound (37 mg, 17%) as a yellow powder: mp 300-304 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.32 (br s, 2H), 7.75 (d, J= 8.5 Hz, 2H), 7.73 (d, J= 7.3 Hz, IH), 7.62-7.58 (m, 2H), 7.38 (d, J= 8.5 Hz, 2H), 7.10 (dd, J= 8.5, 2.0 Hz, IH), 6.78 (d, J= 2.0 Hz, IH), 6.69 (dd, J= 7.3, 2.0 Hz, IH), 4.49 (br s, 2H), 3.70 (s, 3H), 3.60-3.32 (m, 2H), 2.99 (t, J= 5.5 Hz, 2H), 2.54 (s, 3H); ESI MS m/z 402 [M + H] ⁺ .

Example 125

Preparation of 4-(Benzyloxy)- 1 -(3 ,3 ,9-trimethyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,4-6 ^" |indol-

7-yl)pyridine-2( lH)-one hydrochloride

a) 4-(l ,3-Dioxolan-2-yl)-2-methylbutan-2-amine

Attorney's Docket 2882.023B

Beilstein Registry Number 9387059 Chemical Formula: C _a H ₁₇ NO ₂ Exact Mass: 159.13 Molecular Weight: 159.23

This compound was prepared in accordance with the procedure of Hinderaker, et al, Protien ScL 2003, 12, 1188-1194.

b) tert-Qutyl 7-bromo-3 ,3-dimethyl-3 ,4-dihydro- 1/f-pyrido [3 ,4-6]indole-2(9H)- carboxylate

Chemical Formula: C ₁₈ H ₂₃ BrN ₂ O ₂

Exact Mass: 378.09 Molecular Weight: 379.29

A mixture of 4-(l,3-dioxolan-2-yl)-2-methylbutan-2-amine (3.28 g, 20.4 mmol), 3- bromophenylhydrazine hydrochloride (4.34 g, 19.4 mmol) and ZnCl ₂ (2.90 g, 21.3 mmol) was stirred at 180 ⁰ C for 2.5 h. The mixture was cooled to 120 ⁰ C, MeOH was added, and the resulting suspension was concentrated on silica gel. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded 4.20 g of a red amorphous solid. Glyoxylic acid (1.87 g, 20.4 mmol) was added to a suspension of the red amorphous solid in 4:2:1 H ₂ O/MeOH/(concentrated HCl solution) (70 mL), and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was adjusted to pH 3.5 with 6 N NaOH in H ₂ O, and the resulting solution was stirred at 25 ⁰ C overnight. The solution was adjusted to pH 5 with saturated NaHCO ₃ solution and the suspension was filtered. The solid was diluted with 2 N HCl in H ₂ O, and the resulting suspension was stirred at reflux for 2.5 h. The solution was concentrated under reduced pressure and neutralized with saturated NaHCO ₃ solution. The resulting suspension was filtered, and the solid was dissolved in CH ₂ Cl ₂ . The resulting solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded 577 mg of a white solid. BoC ₂ O (2.71 g, 12.4 mmol) was added to a suspension of the white solid and K ₂ CO ₃ (571 mg, 4.14 mmol) in 1:1 H ₂ O/z-PrOH (40 mL), and the resulting suspension was

Attorney's Docket 2882.023B stirred at 25 C for 5.5 h. The suspension was concentrated under reduced pressure, and the residue was diluted with water. The solid was collected by filtration, and flash chromatography (silica gel, hexanes/(l :l EtOAc/hexanes), 100:0 to 0:100) afforded the title compound (200 mg, 3%) as a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.83 (br s, IH), 7.47 (br s, IH), 7.31 (br d, J= 8.7 Hz, IH), 7.20 (br d, J= 8.7 Hz, IH), 4.62 (br s, 2H), 2.77 (br s, 2H), 1.53 (s, 6H), 1.48 (s, 9H).

c) tert-Butyl 7-bromo-3 ,3 ,9-trimethyl-3 ,4-dihydro- lH-pyrido [3 ,4-6]indole-2(9H)- carboxylate

Chemical Formula: C ₁₉ H ₂₅ BrN ₂ O ₂

Exact Mass: 392.11 Molecular Weight: 393.32

NaH (60% dispersion in oil, 42 mg, 1.1 mmol) was added to a solution of tert-butyi 7-bromo-3,3-dimethyl-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9 H)-carboxylate (200 mg, 0.528 mmol) in DMF (10 mL) under N ₂ , and the resulting suspension was stirred at 25 ⁰ C for 30 min. MeI (0.05 mL, 0.8 mmol) was added to the suspension, and the resulting suspension was stirred at 25 ⁰ C for 1 h. H ₂ O was added, and the resulting solid was collected by fÏŠlteration. Flash chromatography (silica gel, hexanes/(l:l EtOAc/hexanes), 100:0 to 0:100) afforded the title compound (145 mg, 70%) as a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.43 (d, J= 1.5 Hz, IH), 7.30 (d, J= 8.3 Hz, IH), 7.18 (dd, J= 8.3, 1.5 Hz, IH), 4.62 (s, 2H), 3.61 (s, 3H), 2.77 (s, 2H), 1.52 (s, 6H), 1.49 (s, 9H).

d) 4-(Benzyloxy)- 1 -(3 ,3 ,9-trimethyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,4-6]indol-7- yl)pyridine-2(lH)-one hydrochloride

Chemical Formula: C ₂₆ H ₂₈ CDST ₃ O ₂

Exact Mass: 449.19 Molecular Weight: 449.97

Attorney's Docket 2882.023B

A suspension of 4-(benzyloxy)pyridine-2(lH)-one (67 mg, 0.34 mmol), tert-butyl 7-bromo-3,3,9-trimethyl-3,4-dihydro-lH-pyrido[3,4-δ]indole- 2(9H)-carboxylate (145 mg, 0.369 mmol), CuI (76 mg, 0.40 mmol), 8-hydroxyquinoline (10 mg, 0.07 mmol) and CS2CO3 (120 mg, 0.369 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and stirred at 135 ⁰ C overnight. The suspension was cooled, 9:0.9:0.1 Cη ₂ Cl ₂ /MeOη/Nη ₄ Oη (10 mL) was added, and the resulting suspension was stirred at 25 ⁰ C for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded 28 mg of a white solid. TFA (1 ml) was added to a solution of the white solid in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred for 1 h at 25 ⁰ C. Saturated NaHCOs solution was added to the solution, and the phases were separated. The aqueous phase was extracted with CH ₂ Cl ₂ , and the combined organic extracts were dried over Na ₂ SO ₄ . The resulting solution was concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded 14 mg of a white powder. 2 N HCl in Et ₂ O (0.01 mL, 0.02 mmol) was added to a solution of the white solid in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was concentrated under reduced pressure to afford the title compound (5.2 mg, 3%) as a white powder: mp 184-186 ⁰ C; ¹ H NMR (500 MHz, DMSO- dβ) δ 9.34 (br s, 2H), 7.57 (d, J= 7.5 Hz, IH), 7.53-7.50 (m, 2H), 7.49-7.41 (m, 4H), 7.40-7.35 (m, IH), 6.99 (dd, J= 8.0, 2.0 Hz, IH), 6.11 (dd, J= 8.0, 2.5 Hz, IH), 5.98 (d, J = 2.5 Hz, IH), 5.16 (s, 2H), 4.50 (br s, 2H), 3.70 (s, 3H), 2.89 (s, 2H), 1.42 (s, 6H); ESI MS m/z 414 [M + H] ⁺ .

Example 126

Preparation of 4-(4-Methoxy-2-methylphenyl)- 1 -(9-methyl-2,3 ,4,9-tetrahydro- IH- pyrido [3 ,4-δ]indo l-7-yl)pyridin-2( lH)-one hydrochloride

a) 4-(4-Methoxy-2-methylphenyl)pyridin-2( lH)-one

Attorney's Docket 2882.023B

Chemical Formula: C ₁₃ H ₁₃ NO ₂

Exact Mass: 215.09 Molecular Weight: 215.25

A suspension of 4-bromo-2-methoxypyridine (341 mg, 1.82 mmol), 4-methyloxy- 2-methylphenyl boronic acid (452 mg, 2.72 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (133 mg, 0.182 mmol) and K2CO3 (503 mg, 3.64 mmol) in DMSO (10 mL) was degassed under reduced pressure for 1 h. The suspension was put under Ar and stirred at 90 ⁰ C for 2 h. The suspension was cooled, H ₂ O was added, and the suspension was filtered to afford a light colored solid. Flash chromatography (silica gel, hexanes/(l :l EtOAc/hexanes), 100:0 to 0:100) afforded 235 mg of a white powder. The white powder was diluted with concentrated HCl solution (20 mL) and stirred at reflux for 24 h. The reaction was cooled and concentrated under reduced pressure. The residue was neutralized with saturated NaHCO ₃ solution, and the solid was collected by filtration. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded the title compound (62 mg, 16%) as a white powder: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 11.54 (br s, IH), 7.35 (d, J= 6.9 Hz, IH), 7.13 (d, J= 8.4 Hz, IH), 6.87-6.76 (m, 2H), 6.15-6.09 (m, 2H), 3.75 (s, 3H), 1.97 (s, 3H).

b) 4-(4-Methoxy-2-methylphenyl)-l-(9-methyl-2,3,4,9-tetrahydro- l/f-pyrido[3,4-δ]indol- 7-yl)pyridin-2( lH)-one hydrochloride

Chemical Formula: C ₂₅ H ₂₆ ClN ₃ O ₂

Exact Mass: 435.17 Molecular Weight: 435.95

A suspension of 4-(4-methoxy-2-methylphenyl)pyridin-2(lH)-one (62 mg, 0.29 mmol), tert-butyl 7-bromo-3,3,9-trimethyl-3,4-dihydro-l/f-pyrido[3,4-δ]indole -2(9H)- carboxylate (126 mg, 0.344 mmol), CuI (66 mg, 0.34 mmol), 8-hydroxyquinoline (8 mg, 0.06 mmol) and CS2CO3 (103 mg, 0.316 mmol) in DMSO (10 mL) was degassed under

Attorney's Docket 2882.023B reduced pressure for 45 min. The suspension was put under Ar and stirred at 135 ⁰ C overnight. The suspension was cooled, 9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH (10 niL) was added, and the resulting suspension was stirred at 25 ⁰ C for 1 h. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. The resulting solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded 52 mg of a yellow amorphous solid. TFA (1 ml) was added to a solution of the yellow amorphous solid in CH ₂ Cl ₂ (10 mL) under N ₂ and the resulting solution was stirred for 1 h at 25 ⁰ C. Saturated NaHCO ₃ solution was added to the solution, and the phases were separated. The aqueous phase was extracted with CH ₂ Cl ₂ , and the combined organic extracts were dried over Na ₂ SO ₄ . The resulting solution was concentrated under reduced pressure. Flash chromatography (silica gel, (1 :1 EtOAc/hexanes)/(9:0.9:0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) afforded 19 mg of a viscous oil. 1 N HCl in Et ₂ O (0.05 mL, 0.05 mmol) was added to a solution of the viscous oil in CH ₂ Cl ₂ (10 mL) under N ₂ , and the resulting solution was stirred at 25 ⁰ C for 30 min. The solution was concentrated under reduced pressure to afford the title compound (16 mg, 13%) as a white powder: mp 308-310 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.44 (br s, 2H), 7.67 (d, J= 7.0 Hz, IH), 7.63 (d, J= 1.5 Hz, IH), 7.60 (d, J= 8.0 Hz, IH), 7.25 (d, J = 8.5 Hz, IH), 7.11 (dd, J= 8.5, 1.5 Hz, IH), 6.92 (d, J= 2.5 Hz, IH), 6.88 (dd, J= 8.5, 2.5 Hz, IH), 6.37 (s, IH), 6.34 (dd, J= 7.5, 1.5 Hz, IH), 4.89 (br s, 2H), 3.79 (s, 3H), 3.70 (s, 3H), 3.49-3.43 (m, 2H), 2.99 (t, J= 6.0 Hz, 2H), 2.36 (s, 3H); ESI MS m/z 400 [M + H] ⁺ .

Example 127

Preparation of 4-(Benzyloxy)- 1 -(9-methyl-2-(2-(pyrrolidin- 1 -yl)ethyl)-2,3 ,4,9,-tetrahydro- lH-pyrido [3 ,4-& ^" |indol-7-yl)pyridine-2( lH)-one hydrochloride

a) 4-(Benzyloxy)- 1 -(9-methyl-2-(2-(pyrrolidin- 1 -yl)ethyl)-2,3 ,4,9,-tetrahydro- IH- pyrido [3 ,4-δ]indo l-7-yl)pyridine-2( lH)-one

Attorney's Docket 2882.023B

Chemical Formula: C ₃₀ H ₃₄ N ₄ O ₂

Exact Mass: 482.27 Molecular Weight: 482.62

l-(2-Chloroethyl)pyrrolidine hydrochloride (50 mg, 0.29 mmol) was added to a solution of 4-(benzyloxy)-l-(9-methyl-2, 3,4,9, -tetrahydro-l/f-pyrido[3,4-δ]indo 1-7- yl)pyridine-2(lH)-one (0.10 g, 0.27 mmol) and diisoproylethyl amine (0.14 mL) in EtOH (4 mL), and the resulting solution was heated at 65 ⁰ C for 2 h. The reaction mixture was concentrated to dryness under reduced pressure. Purification by flash column chromatography (40 g ISCO column, CH ₂ C1 ₂ /(8O:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 hold 5 column volumes increased to to 0:100 over 20 column volumes) followed by preparative TLC (Analtech, 20 x 20 cm, 1000 microns, uV 254, 80:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0 x 21.2 mm, 10 micron, H ₂ O with 0.05% TFA and CH ₃ CN with 0.05% TFA) and filtration through SCX-2 column gave the title compound (10 mg, 7%) as a yellow solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.54 (d, J= 7.5 Hz, IH), 7.51 (d, J= 8.5 Hz, IH), 7.46- 7.33 (m, 6H), 6.96 (dd, J= 8.0, 1.5 Hz, IH), 6.26 (dd, J= 7.5, 2.5, Hz, IH), 6.11 (d, J = 3.0 Hz, IH), 5.16 (s, 2H), 3.82 (s, 2H), 3.64 (s, 3H), 3.01-2.99 (m, 2H), 2.94-2.85 (m, 10H), 1.91-1.90 (m, 4H); HPLC (Method A) 95.1% (AUC), t _R = 13.8 min.

b) 4-(Benzyloxy)- 1 -(9-methyl-2-(2-(pyrrolidin- 1 -yl)ethyl)-2,3 ,4,9,-tetrahydro- IH- pyrido [3 ,4-δ]indo l-7-yl)pyridine-2( lH)-one hydrochloride

Chemical Formula: C ₃₀ H ₃₅ ClN ₄ O ₂

Exact Mass: 518.24 Molecular Weight: 519.08

2 N HCl in Et ₂ O (20 μL, 0.04 mmol) was added to a solution of 4-(benzyloxy)-l- (9-methyl-2-(2-(pyrrolidin-l-yl)ethyl)-2,3,4,9,-tetrahydro-l H-pyrido[3,4-δ]indol-7-

Attorney's Docket 2882.023B yl)pyridine-2(lH)-one (10 mg, 0.020 mmol) in CH ₂ Cl ₂ (3 niL) and the reaction was stirred at ambient temperature for 1 h under N ₂ . The reaction was concentrated to dryness under reduced pressure to provide the title compound (10 mg, quantitative) as a yellow solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.62-7.57 (m, 2H), 7.47-7.34 (m, 6H), 7.03 (dd, J= 8.5, 1.5 Hz, IH), 6.29 (dd, J= 7.5, 2.5 Hz, IH), 6.12 (d, J= 2.5 Hz, IH), 5.18 (s, 2H), 4.55-4.43 (m, 2H), 3.72 (s, 3H), 3.38-3.14 (m, 12H), 2.14 (m, 4H); ESI MS m/z 483 [M + H] ⁺ ; HPLC (Method A) 92.8% (AUC), t _R = 13.6 min.

Example 128

Preparation of 4-(4-Chloro-2-methoxyphenyD- 1 -(9-methyl-2,3 ,4,9-tetrahydro- IH- pyrido [3 ,4-& ^" |indo l-7-yl)pyridin-2( lH)-one hydrochloride

a) tert-Butyl-7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin- 1 (2H)-yl)-9-methyl-3 ,4- dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate

Chemical Formula: C ₂₉ H ₃₀ ClN ₃ O ₄

Exact Mass : 519.19 Molecular Weight: 520.02 tert-Butyl-7-bromo-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]ind ole-2(9H)- carboxylate (0.19 g, 0.81 mmol), 4-(4-chloro-2-methoxyphenyl)pyridin-2(lH)-one (0.30 g, 0.81 mmol), Cs ₂ CO ₃ (0.29 g, 0.89 mmol) were diluted with DMSO (3.3 mL), and argon was bubbled through the suspension for 10 min. 8-ηydroxyquinoline (59 mg, 0.41 mmol) and copper iodide (0.18 g, 0.97 mmol) were added, and the resulting suspension was placed under vacuum for 15 min. The system was flushed with argon, and the degassing/argon flushing process was repeated a total of three times. The reaction mixture was heated at 130 ⁰ C for 18 h and stirred under argon. The suspension was cooled. A solution of 20% NH ₄ OH in MeOH (40 mL) was added, and the resulting mixture was stirred for 1 h. The mixture was diluted with CH ₂ Cl ₂ and filtered through celite. The filtrate was washed with brine (2 x 50 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure. Flash chromatography (4Og ISCO (1 :1 hexanes/EtOAc)/(80:18:2

Attorney's Docket 2882.023B

CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 for 3 column volumnes then increase to 50:50 over 10 column volumnes and hold for 10 column volumes) gave the title compound (0.23 g, 54%) as an olive-green film: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 7.65 (d, J= 7.0 Hz, IH), 7.54 (d, J= 2.0 Hz, IH), 7.50 (d, J= 8.0 Hz, IH), 7.44 (d, J= 8.0 Hz, IH), 7.25 (d, J= 1.5 Hz, IH), 7.13 (dd, J= 8.0, 1.5 Hz, IH), 7.02 (dd, J= 8.0, 1.5 Hz, IH), 6.55 (d, J= 2.0 Hz, IH), 6.54 (dd, J= 7.0, 1.5 Hz, IH), 4.64 (s, 2H), 3.87 (s, 3H), 3.68-3.66 (m, 5H), 2.74-2.72 (m, 2H), 1.46 (s, 9H).

b) 4-(4-Chloro-2-methoxyphenyl)-l-(9-methyl-2,3,4,9-tetrahydro- lH-pyrido[3,4-δ]indol- 7-yl)pyridin-2( lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₃ Cl ₂ N ₃ O ₂

Exact Mass: 455.12 Molecular Weight: 456.36

Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl-7-(4-(4-chloro- 2-methoxyphenyl)-2-oxopyridin-l(2H)-yl)-9-methyl-3,4-dihydro -lH-pyrido[3,4-δ]indole- 2(9H)-carboxylate (0.23 g, 0.44 mmol) in CH ₂ Cl ₂ (2 mL) under argon and stirred for 1 h. The mixture was concentrated under reduced pressure, and the residue was partitioned between CH ₂ Cl ₂ and saturated NaHCO ₃ solution. The organic phase was removed, and the aqueous phase was extracted with CH ₂ Cl ₂ (10 x 25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na ₂ SO ₄ , and concentrated under reduced pressure. Flash column chromatography (12 g ISCO CH ₂ C1 ₂ /(8O:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 for 2 column volumes to 0:100 over 20 column volumes and hold for 10 column volumes) provided the free base of the title compound. The free base was converted to the HCl salt using 2 N HCl in Et ₂ O as of Example 129 (step b), providing the title compound (0.13 g, 33%) as a yellow solid: mp 294-300 ⁰ C; ¹ H NMR (500 MHz, DMSO-de) δ 9.43 (br s, 2H), 7.65 (d, J= 7.0 Hz, IH), 7.61 (d, J=1.5 Hz, IH), 7.59 (d, J= 8.0 Hz, IH), 7.44 (d, J= 8.5 Hz, IH), 7.26 (d, J= 2.0 Hz, IH), 7.13 (dd, J = 8.5, 2.0 Hz, IH), 7.09 (dd, J= 8.0, 2.0 Hz, IH), 6.56 (d, J= 2.0 Hz, IH), 6.47 (dd, J= 7.0,

Attorney's Docket 2882.023B

1.5 Hz, IH), 4.49^1.47 (m, 2H), 3.87 (m, 3H), 3.69 (s, 3H), 3.47-3.43 (m, 2H), 3.00-2.97 (m, 2H); ESI MS m/z 420 [M + H] ⁺ ; HPLC (Method A) 96.7% (AUC), t _R = 15.5 min.

Example 129

Preparation of 4-(4-Chloro-2-methoxyphenyl)- 1 -(2,9-dimethyl-2,3 ,4,9-tetrahydro- IH- pyrido[3,4-&lindol-7-yl)pyridin-2(lH)-one hydrochloride

a) 4-(4-Chloro-2-methoxyphenyl)- 1 -(2,9-dimethyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,4- δ]indol-7-yl)pyridin-2(lH)-one

Chemical Formula: C ₂₅ H ₂₄ ClN ₃ O ₂

Exact Mass: 433.16 Molecular Weight: 433.93

4-(4-Chloro-2-methoxyphenyl)- 1 -(9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,A- δ]indol-7-yl)pyridin-2(lH)-one (83 mg, 0.20 mmol) and 37% aqueous formaldehyde (24 μL, 0.30 mmol) were dissolved in 1 :1 MeOHZCH ₂ Cl ₂ (1.4 mL) and stirred at room temperature for 45 min. Sodium triacetoxyborohydride (84 mg, 0.40 mmol) was added, and the reaction was stirred at ambient temperature for 30 min. The reaction mixture was neutralized with saturated NaHCO ₃ solution and extracted with CH ₂ Cl ₂ (3 x 25 mL). The combined organics were washed with brine (25mL), dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. Purification by flash column chromatography (12 g ISCO (1 :1 hexanes/EtOAc)/(80:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 95:5 to 10:90 over 20 column volumes, hold for 10 column volumes) provided the title compound (77 mg, 89%) as a yellow film: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.55 (d, J= 8.0 Hz, IH), 7.41 (d, J= 7.0 Hz, IH), 7.35-7.34 (m, IH), 7.31 (d, J= 8.0 Hz, IH), 7.07-7.03 (m, 2H), 7.00-6.99 (m, IH), 6.81-6.80 (m, IH), 6.43-6.42 (m, IH), 3.87 (s, 3H), 3.66- 3.65 (m, 2H), 3.48 (s, 3H), 2.87-2.86 (m, 2H), 2.81-2.80 (m, 2H), 2.58 (s, 3H).

b) 4-(4-Chloro-2-methoxyphenyl)- 1 -(2,9-dimethyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,A- δ]indol-7-yl)pyridin-2(lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₅ H ₂₅ Cl ₂ N ₃ O ₂

Exact Mass: 469.13 Molecular Weight: 470.39

2 N HCl in Et ₂ O (0.17 niL, 0.34 mmol) was added to a solution of 4-(4-chloro-2- methoxyphenyl)-l-(2,9-dimethyl-2,3,4,9-tetrahydro-l/f-pyrido [3,4-δ]indol-7-yl)pyridin- 2(lH)-one (74 mg, 0.17 mmol) in CH ₂ Cl ₂ (2 mL) and the reaction was stirred at ambient temperature for 1.5 h under N ₂ . The solids were collected by filtration, washed with Et ₂ O and dried under reduced pressure to yield the title compound (54 mg, 68%) as a yellow powder: mp 272-280 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 10.82 (br s, IH), 7.65 (d, J = 7.0 Hz, IH), 7.62 (d, J= 1.5 Hz, IH), 7.60 (d, J= 8.5 Hz, IH), 7.44 (d, J= 8.5 Hz, IH), 7.26 (d, J= 1.5 Hz, IH), 7.14-7.09 (m, 2H), 6.56 (d, J= 1.5 Hz, IH), 6.47 (dd, J= 7.0, 1.5 Hz, IH), 4.79-4.76 (m, IH), 4.53-4.42 (m, IH), 3.87 (s, 3H), 3.72-3.68 (m, 4H), 3.42- 3.40 (m, IH), 3.08-3.06 (m, 2H), 3.00 (s, 3H); ESI MS m/z 434 [M + H] ⁺ ; HPLC (Method A) 96.5% (AUC), t _R = 15.3 min.

Example 130

Preparation of (61-4-(Benzyloxy)-l-(5-methyl-2-pyrrolidin-2-ylmethyl)-2,3,4 ,5-tetrahydro-

1/f-pyrido [4, 3-άlindol-7yl)pyridine-2(l//)-one hydrochloride

a) (5)-tert-Butyl 2-((7-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-dih ydro-l/f- pyrido[4,3-δ]indol-2(5H)-yl)methyl)pyrrolidine-l-carboxylat e oc

Chemical Formula: C ₃₄ H ₄₀ N ₄ O ₄

Exact Mass: 568.30 Molecular Weight: 568.71

Attorney's Docket 2882.023B

A solution of (5)-tert-butyl-2-(bromomethyl)pyrrolidine-l-carboxylate (0.45 g, 1.7 mmol) in DMSO (1.5 mL) was added to a solution of 4-(benzyloxy)-l -(9-methyl-2, 3,4,9, - tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)pyridine-2(lH)-one (0.33 g, 0.85 mmol), and CS2CO3 (1.10 g, 3.4 mmol) in DMSO (2.8 mL), and the resulting solution was heated at 60 ⁰ C for 18 h. The reaction mixture was diluted with H ₂ O and extracted with CH ₂ Cl ₂ (3 x 25 mL). The combined organic extracts were washed with brine (2 x 25 mL), dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure. Purification by flash column chromatography (40 g ISCO column, CH ₂ C1 ₂ /(8O:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 hold 5 column volumes, increased to 0:100:0 over 20 column volumes) provided a clear film. The film was diluted with EtOAc and washed with brine (4 x 10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to provide the title compound (19 mg, 3%) as a clear film: ESI MS m/z 569 [M + H] ⁺ .

b) (5)-4-(Benzyloxy)-l-(5-methyl-2-pyrrolidin-2-ylmethyl)-2,3,4 ,5-tetrahydro-lH- pyrido[4,3-δ]indol-7yl)pyridine-2(lH)-one

Chemical Formula: C ₂₉ H ₃₂ N ₄ O ₂

Exact Mass: 468.25 Molecular Weight: 468.59

Trifluoroacetic acid (1.0 mL) was added to a solution of (S)-tert-butyl 2-((7-(4- (benzyloxy)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-dihydro-lH-p yrido[4,3-δ]indol-2(5H)- yl)methyl)pyrrolidine-l-carboxylate (19 mg, 0.033 mmol) in 2:1 CDCl ₃ /MeOη (1.5 mL) under argon and stirred for 30 min. The mixture was concentrated to dryness under reduced pressure. Flash column chromatography (4 g ISCO CH ₂ C1 ₂ /(8O:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 95:5 for 20 column volumes to 0:100 over 40 column volumes and hold for 100 column volumnes) yielded the title compound (10 mg, 65%) as a clear film: ESI MS m/z 469 [M + H] ⁺

Attorney's Docket 2882.023B c) (5)-4-(Benzyloxy)-l-(5-methyl-2-pyrrolidin-2-ylmethyl)-2,3,4 ,5-tetrahydro-lH- pyrido[4,3-δ]indol-7yl)pyridine-2(lH)-one hydrochloride

Chemical Formula: C _2P H ₃₃ ClN ₄ O ₂

Exact Mass: 504.23 Molecular Weight: 505.05

2 N HCl in Et ₂ O (0.12 μL, 0.024 mmol) was added to a solution oÏŠ [S)-A- (benzyloxy)-l-(5-methyl-2-pyrrolidin-2-ylmethyl)-2,3,4,5-tet rahydro-lH-pyrido[4,3- 6]indol-7yl)pyridine-2(lH)-one) (10 mg, 0.021 mmol) in CH ₂ Cl ₂ (0.6 mL), and the solution was stirred at ambient temperature for 1.5 h under N ₂ . The reaction mixture was concentrated under reduced pressure to provide the title compound (6.0 mg, 56%) as a white solid: ¹ H NMR (500 MHz, CD ₃ OD) δ 7.59-7.56 (m, 2H), 7.47-7.45 (m, 3H), 7.42- 7.39 (m, 2H), 7.37-7.34 (m, IH), 7.06 (dd, J= 8.5, 2.0 Hz, IH), 6.29 (dd, J= 7.5, 2.5 Hz, IH), 6.12 (d, J= 3.0 Hz, IH), 5.18 (s, 2H), 4.70-4.49 (br m, 2H), 4.28-4.26 (m, IH), 3.75- 3.73 (m, 7H), 3.46-3.43 (m, 2H), 3.34-3.33 (m, 2H), 2.46-2.43 (m, IH), 2.21-2.08 (m, 2H), 1.91-1.86 (m, IH); ESI MS m/z 469 [M + H] ⁺ ; HPLC (Method A) 93.8% (AUC), t _R = 13.5 min.

Example 131

Preparation of 4-(4-MethoxyphenyD- 1 -(5-methyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-

& ^" |indol-7-yl)pyridin-2(lH)-one hydrochloride

c) tert-Butyi 7-(4-(4-methoxyphenyl)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-d ihydro-lH- pyrido[4,3-δ]indole-2(5H)-carboxylate

Attorney's Docket 2882.023B

Chemical Formula: C ₂₉ H ₃₁ N ₃ O ₄

Exact Mass: 485.23 Molecular Weight: 485.57 tert-Butyl-7-bromo-5-methyl-3,4-dihydro-l/f-pyrido[4,3-δ]in dole-2(5H)- carboxylate (0.19 g, 0.54 mmol), 4-(4-methoxyphenyl)pyridin-2(lH)-one (90 mg, 0.45 mmol) and CS2CO3 (0.16 g, 0.49 mmol) were suspensed in DMSO (2.0 mL) and degassed under vacuum for 15 min. The system was then flushed with Ar and 8-hydroxyquinoline (19 mg, 0.13 mmol) and copper iodide (0.10 g, 0.54 mmol) were added. The degassing/Ar flushing process was repeated twice more, and the reaction mixture was heated at 133 ⁰ C for 18 h under N ₂ . The suspension was cooled, diluted with 20% NH ₄ OHMeOH (25mL) and stirred at ambient temperature for 30 min. The suspension was further diluted with CH ₂ Cl ₂ (100 mL). The solution was filtered through silica gel and concentrated under reduced pressure. The concentrate was diluted with CH ₂ Cl ₂ and washed with brine (3 x 25 mL). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to dryness. Flash column chromatography (12 g ISCO column, (1 :1 hexanes/ EtOAc)/(80:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 for 10 column volumes, increased to 50:50 over 20 column volumes and then hold for 5 column volumes) gave the title compound (75 mg, 34%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.60 (d, J= 9.0 Hz, 2H), 7.53 (d, J= 8.0 Hz, IH), 7.46 (d, J= 7.5 Hz, IH), 7.37 (d, J= 1.5 Hz, IH), 7.08 (d, J= 7.5 Hz, IH), 7.00 (d, J = 9.0 Hz, 2H), 6.86 (d, J= 2.0 Hz, IH), 6.50 (dd, J= 7.0, 2.0 Hz, IH), 4.66-4.64 (m, 2H), 3.87 (s, 3H), 3.85-3.84 (m, 2H), 3.64 (s, 3H), 2.84-2.83 (m, 2H), 1.50 (s, 9H).

b) 4-(4-Methoxyphenyl)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido [4,3-δ]indol-7- yl)pyridin-2( lH)-one

Chemical Formula: C ₂₄ H ₂₃ N ₃ O ₂

Exact Mass: 385.18 Molecular Weight: 385.46

Attorney's Docket 2882.023B

Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl 7-(4-(4- methoxyphenyl)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4-dihydro-l H-pyrido[4,3-δ]indole- 2(5H)-carboxylate (74 mg, 0.15 mmol) in CH ₂ Cl ₂ (1 mL) under N ₂ and stirred for 2 h at ambient temperature. The mixture was concentrated, and the residue was partitioned between CH ₂ Cl ₂ and saturated NaHCO ₃ solution. The organic phase was removed, and the aqueous phase was extracted with CH ₂ Cl ₂ (4 x 25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash column chromatography (12 g ISCO CH ₂ C1 ₂ /(8O:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 for 5 column volumes to 0:100 over 20 column volumes and hold for 5 column volumnes) yielded the title compound (46 mg, 78%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.60 (d, J= 9.0 Hz, 2H), 7.50-7.46 (m, 2H), 7.36 (d, J= 2.0 Hz, IH), 7.05 (dd, J= 8.5, 2.0 Hz, IH), 7.00 (d, J= 8.5 Hz, 2H), 6.86 (d, J= 1.5 Hz, IH), 6.49 (dd, J= 7.0, 2.0 Hz, IH), 4.08 (s, 2H), 3.87 (s, 3H), 3.63 (s, 3H), 3.27 (t, J = 6.0 Hz, 2H), 2.77 (t, J= 5.5 Hz, 2H).

c) 4-(4-Methoxyphenyl)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido [4,3-δ]indol-7- yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₄ ClN ₁ O _o

Exact Mass: 421.16 Molecular Weight: 421.92

2 N HCl in Et ₂ O (0.12 mL, 0.24 mmol) was added to a solution of 4-(4- methoxyphenyl)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3- δ]indol-7-yl)pyridin- 2(lH)-one (45 mg, 0.12 mmol) in CH ₂ Cl ₂ (2.0 mL), and the solution was stirred at ambient temperature for 2.5 h under N ₂ . The reaction mixture was concentrated, partially diluted with H ₂ O and lyophilized to provide the title compound (46 mg, 95%) as a yellow powder: ¹ H NMR (500 MHz, DMSO-de) δ 9.26 (br s, 2H), 7.76 (d, J= 9.0 Hz, 2H), 7.70 (d, J= 7.0 Hz, IH), 7.60-7.57 (m, 2H), 7.09-7.06 (m, 3H), 6.73 (d, J= 2.0 Hz, IH), 6.68 (dd, J= 7.5, 2.0 Hz, IH), 4.37^1.35 (m, 2H), 3.83 (s, 3H), 3.70 (s, 3H), 3.54-3.53 (m, 2H), 3.10 (t, J = 6.0 Hz, 2H); ESI MS m/z 386 [M + H] ⁺ .

Attorney's Docket 2882.023B

Example 132

Preparation of 4-(4-Methoxy-2-methylphenyD- 1 -(5-methyl-2,3A5-tetrahydro- IH- pyrido[4,3-&lindol-7-yl)pyridin-2(lH)-one hydrochloride

a) te/t-Butyl 7-(4-(4-methoxy-2-methylphenyl)-2-oxopyridin-l(2H)-yl)-5-met hyl-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate

Chemical Formula: C ₃₀ H ₃₃ N ₃ O ₄

Exact Mass: 499.25 Molecular Weight: 499.60 tert-Butyl-7-bromo-5-methyl-3,4-dihydro-lH-pyrido[4,3-δ]ind ole-2(5H)- carboxylate (0.35 g, 0.96 mmol), 4-(4-methoxy-2-methylphenyl)pyridin-2(lH)-one (0.21 g, 0.96 mmol) and CS2CO3 (0.35 g, 1.1 mmol) were suspensed in DMSO (5.6 mL), and the resulting suspension was degassed under vacuum for 15 min. The system was then flushed with Ar, and 8-hydroxyquinoline (42 mg, 0.29 mmol) and copper iodide (0.22 g, 1.2 mmol) were added. The evacuation/ Ar flushing process was repeated twice more, and the reaction mixture was heated at 130 ⁰ C for 18 h under N ₂ . The suspension was cooled, diluted with 20% Nη ₄ Oη/MeOη (1OmL) and stirred at ambient temperature for 30 min. The reaction was further diluted with CH ₂ Cl ₂ (100 mL). The solution was filtered through silica gel and concentrated. The concentrate was diluted with CH ₂ Cl ₂ and washed with brine (4 x 20 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure. Flash column chromatography (12 g ISCO column, (1 :1 hexanes/ EtOAc)/(80:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and then hold for 5 column volumes, increase to 0:100 over 10 column volumes and hold for 5 column volumes) gave the title compound (0.25 g, 52%) as a yellow film: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.54 (d, J= 8.0 Hz, IH), 7.42 (d, J= 6.5 Hz, IH), 7.39 (d, J= 1.5 Hz, IH), 7.22 (d, J= 8.0 Hz, IH), 7.10 (d, J= 7.0 Hz, IH), 6.82-6.80

Attorney's Docket 2882.023B

(m, 2H), 6.60 (d, J= 1.5 Hz, IH), 6.24 (dd, J= 6.5, 1.5 Hz, IH), 4.67-4.65 (m, 2H), 3.86- 3.83 (m, 5H), 3.65 (s, 3H), 2.93 (m, 3H), 2.82-2.84 (m, 2H), 1.50 (s, 9H).

b) 4-(4-Methoxy-2-methylphenyl)-l-(5-methyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-δ]indol- 7-yl)pyridin-2( lH)-one

Chemical Formula: C ₂₅ H ₂₅ N ₃ O ₂

Exact Mass: 399.19 Molecular Weight: 399.48

Trifluoroacetic acid (1.0 mL) was added to a solution of tert-bvXy\ 7-(4-(4- methoxy-2-methylphenyl)-2-oxopyridin-l(2H)-yl)-5-methyl-3,4- dihydro-lH-pyrido[4,3- 6]indole-2(5H)-carboxylate (0.25 g, 0.50 mmol) in CH ₂ Cl ₂ (2.0 mL) under N ₂ and stirred for 1 h. The reaction mixture was made basic with saturated NaHCO ₃ solution and the resultion solution was extracted with CH ₂ Cl ₂ (3 x 25 mL). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash column chromatography (12 g ISCO CH ₂ C1 ₂ /(8O:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 for 5 column volumes to 0:100 over 20 column volumes and hold for 40 column volumes) yielded the title compound (0.16 g, 80%) as an off-white film: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.50 (d, J= 8.0 Hz, IH), 7.42 (d, J= 7.0 Hz, IH), 7.38 (m, IH), 7.22 (d, J= 8.0 Hz, IH), 7.07 (dd, J= 8.5, 2.0 Hz, IH), 6.82-6.80 (m, 2H), 6.60 (d, J= 1.5 Hz, IH), 6.23 (dd, J= 7.0, 1.5 Hz, IH), 4.09 (s, 2H), 3.84 (s, 3H), 3.64 (s, 3H), 2.77 (t, J= 5.5 Hz, 2H), 2.27 (t, J= 6.0 Hz, 2H), 2.39 (s, 3H).

c) 4-(4-Methoxy-2-methylphenyl)-l-(5-methyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-δ]indol- 7-yl)pyridin-2( lH)-one hydrochloride

Chemical Formula: C ₂₅ H ₂₆ ClN ₃ O ₂

Exact Mass: 435.17 Molecular Weight: 435.95

Attorney's Docket 2882.023B

2 N HCl in Et ₂ O (0.40 niL, 0.80 mmol) was added to a solution of 4-(4-methoxy-2- methylphenyl)-l-(5-methyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-Î ´]indol-7-yl)pyridin-2(lH)- one (0.16 g, 0.40 mmol) in CH ₂ Cl ₂ (1.5 mL), and the solution was stirred at ambient temperature for 1 h under N ₂ . The solids were collected by filtration, washed with Et ₂ O and dried to yield the title compound (0.15 g, 85% ) as an off-white powder: ¹ H NMR (500 MHz, DMSO-de) δ 9.39 (br s, 2H), 7.67 (d, J= 7.0 Hz, IH), 7.59 (d, J= 8.0 Hz, IH), 7.27 (d, J= 2.0 Hz, IH), 7.25 (d, J= 8.5 Hz, IH), 7.10 (dd, J= 8.5, 2.0 Hz, IH), 6.92 (d, J = 2.5 Hz, IH), 6.88 (dd, J= 8.0, 2.5 Hz, IH), 6.37 (d, J= 2.0 Hz, IH), 6.34 (dd, J= 7.0, 2.0 Hz, IH), 4.36^1.34 (m, 2H), 3.79 (s, 3H), 3.71 (s, 3H), 3.53-3.52 (m, 2H), 3.10 (t, J = 6.0 Hz, 2H), 2.35 (s, 3H); ESI MS m/z 400 [M + H] ⁺ ; HPLC (Method A) 95.8 % (AUC), t _R = 14.5 min.

Example 133

Preparation of (4-Benzyloxy)-l-(9-(difluoromethyl)-2,3,4,9-tetrahydro-lH-py rido[4,3-

&1indol-7-yl)pyridin-2(lH)-one hydrochloride

a) tert-Butyl 7-bromo-9-(difluoromethyl)-3,4-dihydro-lH-pyrido[4,3-δ]indo le-2(9H)- carboxylate Chemical Formula: C ₁₇ H ₁₉ BrF ₂ N ₂ O ₂

Exact Mass: 400.06 Molecular Weight: 401.25

Sodium hydride (60% in mineral oil, 0.347 g, 8.71 mmol) was added to a solution oftert-butyl 7-bromo-3,4-dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylat e (2.04 g, 5.81 mmol) in DMF (20 mL) at room temperature under N ₂ and stirred for 30 minutes. Difluoroiodomethane (~1.5 mL), which had been condensed with a cold finger into a separate flask, was added via syringe. The reaction was sealed with a rubber septum and stirred overnight at ambient temperature. The mixture was quenched with H ₂ O. EtOAc was added and the mixture was stirred for 40 minutes. The mixture was extracted with EtOAc (3 x 40 mL), and the combined organic extracts were washed with brine (2 x 20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography

Attorney's Docket 2882.023B

(40+M Biotage column, hexanes/(4:l hexanes /EtOAc), 100:0 to 0:100) provided the title compound (0.93 g, 40%) as a white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.62 (s, IH), 7.17 (t, J= 56.0 Hz, IH), 7.33 (m, 2H), 4.71 (s, 2H), 3.75 (m, 2H), 2.74 (s, 2H), 1.50 (s, 9H).

b) tert-Butyl 7-(4-benzyloxy)-2-oxopyridin- 1 (2H)-yl)-9-(difluoromethyl)-3 ,4-dihydro- IH- pyrido[4,3-δ]indole-2(9H)-carboxylate

Chemical Formula: C ₂₉ H ₂₉ F ₂ N ₃ O ₄

Exact Mass: 521.21 Molecular Weight: 521.56 tert-Butyl 7-bromo-9-(difluoromethyl)-3,4-dihydro-lH-pyrido[4,3-δ]indo le-2(9H)- carboxylate (0.936 g, 2.33 mmol), 4-benzyloxypyridone (0.469 g, 2.33 mmol), Cs ₂ CO ₃ (0.834 g, 2.57 mmol) and H ₂ O (1 drop) were diluted with DMSO (10.4 mL) and argon was bubbled through the suspension for 10 minutes. 8 -Hydroxy quino line (0.101 g, 0.699 mmol) and copper iodide (133 mg, 0.699 mmol) were added, and the resulting suspension was placed under vacuum for 15 min. The system was flushed with argon. The degassing/argon flushing process was repeated a total of three times. The reaction mixture was heated to 130 ⁰ C for 18 h and stirred under argon. The suspension was cooled. A solution of 20% NH ₄ OH in MeOH (40 mL) was added, and the resulting mixture was stirred for 1 h. The mixture was diluted with CH ₂ Cl ₂ and filtered through celite. The filtrate was washed with brine (3 x 25mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (40+M Biotage column, (20% EtOAc in hexanes)/(50% EtOAc in hexanes)/(80:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0:0 to 0:100:0 over 1.2 L then 0:100:0 to 0:0:100 over 1.2 L) gave the title compound (0.41 g, 33%) as a yellow foam: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 8.10 (t, J= 58.0 Hz, IH), 7.74 (d, J= 1.4 Hz, IH), 7.60 (d, J= 3.2 Hz, IH), 7.58 (d, J= 3.9 Hz, IH), 7.47-7.35 (m, 5H), 7.16 (dd, J = 8.3, 1.7 Hz, IH), 6.12 (dd, J= 7.6, 2.6 Hz, IH), 5.99 (d, J= 2.7 Hz, IH), 5.15 (s, 2H), 4.72 (m, 2H), 4.03 (s, 2H), 3.70 (m, 2H), 1.44 (s, 9H).

Attorney's Docket 2882.023B c) (4-Benzyloxy)-l-(9-(difluoromethyl)-2,3,4,9-tetrahydro-lH-py rido[4,3-δ]indol-7- yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₂ ClF ₂ N ₃ O ₂

Exact Mass: 457.14 Molecular Weight: 457.90

2 N HCl in Et ₂ O (15.0 rnL) was added to a solution of tert-bvλy\ 7-(4-benzyloxy)-2- oxopyridin-l(2H)-yl)-9-(difluoromethyl)-3,4-dihydro-lH-pyrid o[4,3-δ]indole-2(9H)- carboxylate (0.39 g, 0.75 mmol) in 1 :1 MeOη/Cη ₂ Cl ₂ (5 rnL). The reaction was stirred at ambient temperature for 2 h under N ₂ . The reaction was diluted with Et ₂ O, and the resulting solids were collected by filtration to yield the title compound (0.31 g, 92%) as a yellow solid: mp 220-230 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.60 (br s, 2H), 8.11 (t, J = 58.0 Hz, IH), 7.78 (d, J= 1.5 Hz, IH), 7.68 (d, J= 8.0 Hz, IH), 7.60 (d, J= 7.5 Hz, IH), 7.48-7.36 (m, 5H), 7.22 (dd, J= 8.5, 1.5 Hz, IH), 6.14 (dd, J= 7.5, 2.5 Hz, IH), 5.99 (d, J = 2.5 Hz, IH), 5.16 (s, 2H), 4.52 (m, 2H), 3.49-3.48 (m, 2H), 2.99 (m, 2H); ESI MS m/z 422 [M + H] ⁺ ; HPLC (Method A) 96.5% (AUC), t _R = 14.4 min.

Example 134

Preparation of (4-Benzyloxy)- 1 -(9-(difluoromethyl)-2-methyl-2,3 ,4,9-tetrahydro- IH- pyrido [3 ,4-&1indo 1-7- yl)pyridin-2( lH)-one hydrochloride

a) (4-Benzyloxy)- 1 -(9-(difluoromethyl)-2-methyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,4- δ]indol-7-yl)pyridin-2(lH)-one

Chemical Formula: C ₂₅ H ₂₃ F ₂ N ₃ O ₂

Exact Mass: 435.18 Molecular Weight: 435.47

(4-Benzyloxy)-l-(9-(difluoromethyl)-2,3,4,9-tetrahydro-lH-py rido[4,3-δ]indol-7- yl)pyridin-2(lH)-one (83 mg, 20 mmol) and 37% aqueous formaldehyde (22 μL, 0.30 mmol) were dissolved in 1 :1 Cη ₂ Cl ₂ /Me0η (1.0 mL) and stirred at ambient temperature

Attorney's Docket 2882.023B for 45 min. Sodium triacetoxyborohydride (83 mg, 0.39 mmol) was added, and the resulting suspension was stirred at ambient temperature for 15 min. The suspension was concentrated, and the residue was diluted with saturated NaHCCh solution. The aqueous solution was extracted with CH ₂ Cl ₂ . The combined organic extracts were dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (1O g Biotage SNAP column, CH ₂ Cl ₂ /(80:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100) gave the title compound (57 mg, 67%) as a clear oil. ESI MS m/z 436 [M + H] ⁺ ; HPLC (Method A) 98.9% (AUC), t _R = 14.3 min.

b) (4-Benzyloxy)- 1 -(9-(difluoromethyl)-2-methyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 ,4- δ]indol-7-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₅ H ₂₄ ClF ₂ N ₃ O ₂

Exact Mass: 471.15 Molecular Weight: 471.93

A solution of (4-benzyloxy)-l-(9-(difluoromethyl)-2-methyl-2,3,4,9-tetrahy dro-lH- pyrido[3,4-6]indol-7-yl)pyridin-2(lH)-one (58 mg, 0.13 mmol) in CH ₂ Cl ₂ (1.0 mL) was treated with anhydrous 1.0 M HCl in diethyl ether (0.13 mL, 0.13 mmol). The reaction was stirred at ambient temperature for 1 h, and the solids were collected and dried to yield the title compound (53 mg, 86%) as a yellow solid: mp 250-256 ⁰ C; ¹ U NMR (500 MHz, DMSO-J ₆ ) δ 10.89 (br s, IH), 8.15 (t, J= 58.0 Hz, IH), 7.82 (d, J= 1.5 Hz, IH), 7.69 (d, J = 8.3 Hz, IH), 7.60 (d, J= 7.6 Hz, IH), 7.47-7.36 (m, 5H), 7.23 (dd, J= 8.4, 1.5 Hz, IH), 6.14 (dd, J= 7.6, 2.7 Hz, IH), 6.00 (d, J= 2.7 Hz, IH), 5.16 (s, 2H), 4.77 (m, IH), 4.55 (m, IH), 3.76-3.75 (m, IH), 3.45-3.40 (m, IH), 3.07-3.02 (m, 5H); ESI MS m/z 436 [M + H] ⁺ ; HPLC (Method A) 98.9% (AUC), t _R = 14.4 min.

Example 135

Preparation of 4-(2-Fluoro-4-methoxyphenyD- 1 -(9-methyl-2,3 ,4,9-tetrahydro- IH- p yrido [3 ,4-&]indo 1-7- yl)pyridin-2( lH)-one hydrochloride

Attorney's Docket 2882.023B

a) 4-(2-Fluoro-4-methoxyphenyl)-2-methoxypyridine

Chemical Formula: C ₁₃ H ₁₂ FNO ₂

Exact Mass: 233.09 Molecular Weight: 233.24

4-Bromo-2-methoxypyridine (1.39 g, 7.42 mmol), 2-fluoro- 4methoxyphenylboronic acid (2.40 g, 14.1 mmol), K ₂ CO ₃ (2.05 g, 14.8 mmol) and bis(triphenylphosphine) palladium(II)chloride (Pd(PPhS) ₂ Cl ₂ ) (52 mg, 0.74 mmol) were stirred in DMSO (8.5 mL) under vacuum for 20 min. The flask was flushed with argon and the mixture was heated to 90 ⁰ C for 3 h. Upon cooling, the mixture was diluted with brine, and the aqueous solution was extracted with CH ₂ Cl ₂ (3 x 50 mL). The combined organic extracts were washed with water (3 x 20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. Flash chromatography (40+M Biotage column, CH ₂ C1 ₂ /(8O:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 80:20) provided the title compound (0.98 g, 57%) as a yellow oil: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.20 (d, J= 5.4 Hz, IH), 7.42-7.38 (m, IH), 7.07 (d, J= 5.4 Hz, IH), 6.93 (s, IH), 6.80 (dd, J= 8.6, 2.5 Hz, IH), 6.74 (dd, J= 12.6, 2.5 Hz, IH), 3.99 (s, 3H), 3.85 (s, 3H).

b) 4-(2-Fluoro-4-methoxyphenyl)pyridin-2( lH)-one

Chemical Formula: C ₁₂ H ₁₀ FNO ₂

Exact Mass: 219.07 Molecular Weight: 219.21

4-(2-Fluoro-4-methoxyphenyl)-2-methoxypyridine (1.34 g, 5.72 mmol) was stirred in concentrated hydrochloric acid (25.5 mL) at reflux for 18 h. The reaction was cooled to 0 ⁰ C and neutralized with solid NaOH. The resulting solids were collected by filtration and dried under vacuum to yield the title compound (1.09 g, 87%) as a light brown solid: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 7.52-7.38 (m, 2H), 6.97-6.85 (m, 2H), 6.42-6.33 (m, 2H), 3.80 (s, 3H); ESI MS m/z 220 [M + H] ⁺ .

Attorney's Docket 2882.023B

c) tert-Butyl-7(4(2-fluoro-4-methoxyphenyl)-2-oxopyridin-2( lH)-yl)-9-methyl-3 ,4- dihydro-lH-pyrido[3,4-δ]indole-2(9H)-carboxylate

Chemical Formula: C ₂₉ H ₃₀ FN ₃ O ₄

Exact Mass: 503.22 Molecular Weight: 503.56

Following the procedure of Example 133 (step b), but substituting 4-(2-fluoro-4- methoxyphenyl)pyridin-2(lH)-one (359 mg, 1.64 mmol) for 4-benzyloxypyridone, the title compound (288 mg, 41%) was prepared as a yellow foam: ¹ H NMR (500 MHz, DMSO- J ₆ ) δ 7.71 (d, J= 7.1 Hz, IH), 7.61 (m, IH), 7.55 (d, J= 1.6 Hz, IH), 7.51 (d, J= 8.3 Hz, IH), 7.04-6.99 (m, 2H), 6.94 (dd, J= 6.9, 2.5 Hz, IH), 6.61 (s, IH), 6.51-6.50 (m, IH), 4.64 (s, 2H), 3.84 (s, 3H), 3.69-3.67 (m, 5H), 2.74-2.72 (m, 2H), 1.45 (s, 9H).

d) 4-(2-Fluoro-4-methoxyphenyl)-l-(9-methyl-2,3,4,9-tetrahydro- lH-pyrido[3,4-δ]indol-7- yl)pyridin-2( lH)-one

Chemical Formula: 0 ₂₄ H ₂₂ FN ₃ O ₂

Exact Mass: 403.17 Molecular Weight: 403.45

Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl-7(4(2-fluoro-4- methoxyphenyl)-2-oxopyridin-2(lH)-yl)-9-methyl-3,4-dihydro-l H-pyrido[3,4-δ]indole- 2(9H)-carboxylate (0.28 g, 0.56 mmol) in CH ₂ Cl ₂ (5 mL) under argon and stirred for 1 h. The mixture was concentrated, and the residue was partitioned between CH ₂ Cl ₂ and saturated NaHCO ₃ solution. The organic phase was removed, and the aqueous phase was extracted with CH ₂ Cl ₂ . The combined organic extracts were dried over Na ₂ SO ₄ and concentrated under reduced pressure. Preparative HPLC (Phenomenex Luna C18 (2), 250.0 x 50.0 mm, 10 micron, H ₂ O with 0.05% TFA and CH ₃ CN with 0.05% TFA) provided the title compound (87 mg, 39%) as a yellow solid: ¹ U NMR (500 MHz, DMSO-

Attorney's Docket 2882.023B dβ) δ 7.71 (d, J= 7.1 Hz, IH), 7.61 (m, IH), 7.49-7.46 (m, 2H), 7.02-6.99 (m, 2H), 6.93 (dd, J= 8.7, 2.1 Hz, IH), 6.60 (s, IH), 6.50 (d, J= 7.1 Hz, IH), 3.96 (m, 2H), 3.84 (s, 3H), 3.61 (s, 3H), 3.01-2.99 (m, 2H), 2.66 (m, 2H); ESI MS m/z 404 [M + H] ⁺ .

e) 4-(2-Fluoro-4-methoxyphenyl)-l-(9-methyl-2,3,4,9-tetrahydro- lH-pyrido[3,4-δ]indol-7- yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₃ ClFN ₃ O ₂

Exact Mass: 439.15 Molecular Weight: 439.91

A solution of 4-(2-fluoro-4-methoxyphenyl)- 1 -(9-methyl-2,3 ,4,9-tetrahydro- IH- pyrido[3,4-6]indol-7-yl)pyridin-2(lH)-one (80 mg, 0.20 mmol) in CH ₂ Cl ₂ (2.6 mL) was treated with anhydrous 1.0 M HCl in diethyl ether (0.22 mL, 0.22 mmol). The reaction was stirred at ambient temperature for 1 h, and then the solids were collected by filtration and dried to yield the title compound (68 mg, 77%) as a yellow solid: mp 290-292 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.54 (s, 2H), 7.71 (d, J= 7.2 Hz, IH), 7.62-7.58 (m, 3H), 7.10 (dd, J= 8.3, 1.8 Hz, IH), 7.01 (dd, J= 13.2, 2.4 Hz, IH), 6.94 (dd, J= 8.6, 2.3 Hz, IH), 6.62 (s, IH), 6.53-6.52 (m, IH), 4.48 (s, 2H), 3.95 (s, 3H), 3.69 (s, 3H), 3.45-3.44 (m, 2H), 3.00-2.97 (m, 2H); ESI MS m/z 404 [M + H] ⁺ ; HPLC (Method A) >99% (AUC), ÏŠ _R = 14.6 min.

Example 136

Preparation of 1 -(2.9-Dimethyl-2.3A9-tetrahvdro-lH-pyrido [3.4-&lindol-7-vP)-4-(2- fluoro-4-methoxyphenyl)pyridin-2( lH)-one hydrochloride a) l-(2,9-Dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7- yl)-4-(2-fiuoro-4- methoxyphenyl)pyridin-2( lH)-one

Attorney's Docket 2882.023B

Chemical Formula: C ₂₅ H ₂₄ FN ₃ O ₂

Exact Mass: 417.19 Molecular Weight: 417.48

Following the procedure of Example 134 (step a), but substituting 4-(2-fluoro-4- methoxyphenyl)- 1 -(9-methyl-2,3 ,4,9-tetrahydro- 1/f-pyrido [3 ,4-δ]indol-7-yl)pyridin- 2(lH)-one (57 mg, 0.14 mmol) for (4-benzyloxy)-l-(9-(difluoromethyl)-2,3,4,9- tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)pyridin-2(lH)-one, the title compound (35 mg, 59%) was provided as an off-white solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 7.71 (d, J = 7.0 Hz, IH), 7.61 (m, IH), 7.51 (d, J= 1.8 Hz, IH), 7.48 (d, J= 8.3 Hz, IH), 7.02-6.99 (m, 2H), 6.94 (dd, J= 8.6, 2.4 Hz, IH), 6.60 (s, IH), 6.53-6.52 (m, IH), 3.84 (s, 3H), 3.62 (m, 5H), 2.74-2.70 (m, 4H), 2.46 (s, 3H).

Attorney's Docket 2882.023B b) l-(2,9-Dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7- yl)-4-(2-fluoro-4- ethoxyphenyl)pyridin-2( lH)-one hydrochloride

Chemical Formula: C ₂₅ H ₂₅ ClFN ₃ O ₂

Exact Mass: 453.16 Molecular Weight: 453.94

Following the procedure of Example 134 (step b), but substituting l-(2,9-dimethyl- 2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)-4-(2-fluoro- 4-methoxyphenyl)pyridin- 2(lH)-one (35 mg, 0.84 mmol) for (4-benzyloxy)-l-(9-(difluoromethyl)-2-methyl-2,3,4,9- tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)pyridin-2(lH)-one, the title compound (33 mg, 87%) was provided as a yellow solid: mp 290-294 ⁰ C; ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 10.71 (s, IH), 7.71 (d, J= 7.2 Hz, IH), 7.63-7.59 (m, 3H), 7.11 (dd, J= 8.3, 1.6 Hz, IH), 7.01 (dd, J= 13.2, 2.4 Hz, IH), 6.94 (dd, J= 8.7, 2.4 Hz, IH), 6.62 (s, IH), 6.53-6.52 (m, IH), 4.80-4.77 (m, IH), 4.45-4.43 (m, IH), 3.84 (s, 3H), 3.73 (br s, IH), 3.68 (s, 3H), 3.42-3.34 (m, IH), 3.07-3.06 (m, 2H), 3.00 (s, 3H); ESI MS m/z 418 [M + H] ⁺ ; HPLC (Method A) 97.0% (AUC), t _R = 14.0 min.

Example 137

Preparation of 4-(Imidazo[ 1 ,2-α ^" |pyridin-2-ylmethoxy)- 1 -(9-methyl-2,3 ,4,9-tetrahydro- IH- pyrido [3 ,4-& ^" |indo l-7-yl)pyridin-2( lH)-one hydrochloride

a) 4-(Imidazo[l,2-α]pyridin-2-ylmethoxy)pyridine 1 -oxide Chemical Formula: C ₁₃ H ₁₁ N ₃ O ₂ Exact Mass: 241.09 Molecular Weight: 241.25

Imidazo[l,2-α]pyridine-2-ylmethanol (3.01 g, 20.3 mmol) was partially dissolved in 5:1 dioxane/DMF (30 mL) and the resulting slurry was added slowly to a stirring suspension of NaH (60% in mineral oil, 0.812 g, 16.9 mmol) in dioxane (29 mL). The resulting mixture was heated to 60 ⁰ C for 15 min. 4-Chloropyridine-iV-oxide (1.5 g, 11.5

Attorney's Docket 2882.023B mmol) was added and the reaction mixture was heated for 1 h at 110 ⁰ C. Upon cooling, the mixture was diluted with methylene chloride and a 20% NH ₄ OH in MeOH solution. The resulting suspension was filtered through a silica gel plug using CH ₂ Cl ₂ (200 mL) and 20% 4:1 MeOH/ NH ₄ OH in CH ₂ Cl ₂ (500 mL). The filtrate was collected and concentrated under reduced pressure. Flash chromatography (120 g ISCO column, CH ₂ C1 ₂ /(8O:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 100:0 to 0:100 over 60 min) provided the title compound (1.5 g, 30%) as an orange-brown solid: ¹ H NMR (300 MHz, CD ₃ OD) δ 8.42 (m, IH), 8.24-8.22 (m, 2H), 7.97 (d, J= 0.5 Hz, IH), 7.54 (dd, J= 9.1, 0.7 Hz, IH) 7.37-7.32 (m, IH), 7.27- 7.25 (m, 2H), 6.94 (m, IH), 5.37 (s, 2H).

b) 4-(Imidazo[l ,2-α]pyridin-2-ylmethoxy)pyridine-2(lH)-one

Chemical Formula: C ₁₃ H ₁₁ N ₃ O ₂ Exact Mass: 241.09 Molecular Weight: 241.25

4-(Imidazo[l,2-α]pyridin-2-ylmethoxy)pyridine 1-oxide (1.50 g, 6.25 mmol) was heated at 140 ⁰ C in acetic anhydride (18 mL) for 2 h. The mixture was concentrated and heated at 80 ⁰ C for 2 h in 1 :1 MeOH/ H ₂ O ( 50 mL). The resulting black solution was concentrated. The material was then partially dissolved in zPrOH (20 mL). Et ₂ O (70 mL) was added, and the mixture was allowed to sit at ambient temperature for 1 h. The resulting solids were collected by filtration and washed with Et ₂ O to yield the title compound (951 mg, 63%) as a dark brown solid: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 11.08 (br s, IH), 8.54 (m, IH), 8.01 (s, IH), 7.53 (d, J= 9.0 Hz, IH), 7.26-7.23 (m, 2H), 6.90 (m, IH), 5.89-5.87 (m, 2H), 5.14 (s, 2H).

c) tert-Butyl-7-(4-(imidazo[l,2-α]pyridin-2-ylmethoxy)-2-oxopy ridin-l(2H)-yl)-9-methyl- 3,4-dihydro-lH-pyrido[3,4-6]indole-2(9H)-carboxylate

Attorney's Docket 2882.023B

Chemical Formula: C ₃₀ H ₃₁ N ₅ O ₄

Exact Mass: 525.24 Molecular Weight: 525.60 tert-Butyl-7-bromo-9-methyl-3,4-dihydro-l/f-pyrido[3,4-δ]in dole-2(9H)- carboxylate (0.328 g, 0.898 mmol), 4-(imidazo[l,2-α]pyridin-2-ylmethoxy)pyridine- 2(lH)-one (0.240 g, 0.998 mmol) and Cs ₂ CO ₃ (0.358 g, 1.09 mmol) were suspended in DMSO (4.0 mL), and argon was bubbled through the system for 10 minutes. 8- Hydroxyquinoline (43.4 mg, 0.299 mmol) and copper iodide (228 mg, 1.20 mmol) were added, and resulting suspension was placed under vacuum for 15 min. The system was flushed with argon. The evacuation/argon flushing process was repeated a total of three times. The reaction mixture was heated at 130 ⁰ C for 18 h under argon. The mixture was cooled, and a solution of 20% NH ₄ OH in MeOH (40 mL) was added. The resulting mixture was stirred for 1 h. The mixture was diluted with CH ₂ Cl ₂ and filtered through a silica gel plug. The filtrate was collected and concentrated. The residue was diluted with CH ₂ Cl ₂ , washed with brine (3 x 25 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. Purification by flash column chromatography (80 g ISCO column, (1 :1 hexanes/ EtOAc)/(80:18:2 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 80:20 to 0:100:0 over 10 column volumes and then hold for 8 column volumes) gave the title compound (0.190 g, 40%) as a yellow foam: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 8.12 (d, J= 6.8 Hz, IH), 7.69 (s, IH), 7.61 (d, J= 9.1 Hz, IH), 7.52 (d, J= 8.3 Hz, IH), 7.31-7.29 (m, 2H), 7.22-7.19 (m, IH), 7.02 (dd, J= 8.3, 1.7 Hz, IH), 6.83-6.80 (m, IH), 6.17 (d, J= 2.7 Hz, IH), 6.07 (dd, J = 7.6, 2.7 Hz, IH), 5.25 (s, 2H), 4.64 (m, 2H), 3.75 (m, 2H), 3.63 (s, 3H), 2.80 (m, 2H), 1.52 (s, 9H); ESI MS m/z 526 [M + H] ⁺ _.

d) 4-(Imidazo[l,2-α]pyridin-2-ylmethoxy)-l-(9-methyl-2,3,4,9-t etrahydro-lH-pyrido[3,4- δ]indol-7-yl)pyridin-2(lH)-one

Attorney's Docket 2882.023B

Chemical Formula: C ₂₅ H ₂₃ N ₅ O ₂

Exact Mass: 425.19 Molecular Weight: 425.48

Following the procedure of Example 135 (step d), but subsituting tert-hvXy\-l -{4- (imidazo[ 1 ,2-α]pyridin-2-ylmethoxy)-2-oxopyridin- 1 (2H)-yl)-9-methyl-3 ,4-dihydro- IH- pyrido[3,4-6]indole-2(9H)-carboxylate (190 mg, 362 mmol) for tert-butyl-7(4(2-fiuoro-4- methoxyphenyl)-2-oxopyridin-2(lH)-yl)-9-methyl-3,4-dihydro-l H-pyrido[3,4-δ]indole- 2(9H)-carboxylate, the title compound (0.105 g, 68%) was prepared as a yellow film: ¹ H NMR (500 MHz, CD ₃ OD) δ 8.45-8.43 (m, IH), 7.98 (s, IH), 7.59-7.54 (m, 3H), 7.41 (d, J = 1.8 Hz, IH), 7.37-7.33 (m, IH), 7.02 (dd, J= 8.3, 1.8 Hz, IH), 6.96-6.94 (m, IH), 6.29 (dd, J= 7.6, 2.7 Hz, IH), 6.21 (d, J= 2.7 Hz, IH), 5.31 (s, 2H), 3.96 (s, 2H), 3.68 (s, 3H), 3.42 (t, J= 6.0 Hz, 2H), 3.00 (t, J= 6.0 Hz, 2H); ESI MS m/z 426 [M + H] ⁺ .

e) 4-(Imidazo[l,2-α]pyridin-2-ylmethoxy)-l-(9-methyl-2,3,4,9-t etrahydro-lH-pyrido[3,4- δ]indol-7-yl)pyridin-2(lH)-one -hydrochloride

Chemical Formula: C ₂₅ H ₂₄ ClN ₅ O ₂

Exact Mass: 461.16 Molecular Weight: 461.94

Following the procedure of Example 134 (step b), but substituting 4-(imidazo[l,2- α]pyridin-2-ylmethoxy)-l-(9-methyl-2,3,4,9-tetrahydro-lH-py rido[3,4-δ]indol-7- yl)pyridin-2(lH)-one (102 mg, 0.240 mmol) for (4-benzyloxy)-l-(9-(difluoromethyl)-2- methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)pyridi n-2(lH)-one, the title compound (95 mg, 86%) was prepared as a yellow solid: ¹ U NMR (500 MHz, CD ₃ OD) δ 8.81 (d, J= 7.0, 1.0 Hz, IH), 8.38 (s, IH), 8.02-7.99 (m, IH), 7.92 (d, J= 9.5 Hz, IH), 7.66-7.62 (m, 2H), 7.52-7.49 (m, IH), 7.46 (s, IH), 7.05 (d, J= 7.0 Hz, IH), 6.33 (dd, J = 7.5, 3.0 Hz, IH), 6.23 (d, J= 3.0 Hz, IH), 5.50 (s, 2H), 4.55 (s, 2H), 3.72 (s, 3H), 3.60 (t, J

Attorney's Docket 2882.023B

= 6.0 Hz, 2H), 3.14-3.12 (m, 2H); ESI MS m/z 426 [M + H] ⁺ ; HPLC (Method A) 98.5% (AUC), t _R = 9.2 min.

Example 138

Preparation of l-(2.9-Dimethyl-2.3A9-tetrahvdro-lH-pyrido [3.4-&lindol-7-vD-4-

(imidazo[l,2-αlpyridin-2-ylmethoxy)pyridin-2(lH)-one hydrochloride

a) l-(2,9-Dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7- yl)-4-(imidazo[l,2- α]pyridin-2-ylmethoxy)pyridin-2(lH)-one

Chemical Formula: C ₂₆ H ₂₅ N ₅ O ₂

Exact Mass: 439.20 Molecular Weight: 439.51

Following the procedure of Example 134 (step a), but substituting 4-(imidazo[l,2- α]pyridin-2-ylmethoxy)-l-(9-methyl-2,3,4,9-tetrahydro-lH-py rido[3,4-δ]indol-7- yl)pyridin-2(lH)-one (57 mg, 0.14 mmol) for (4-benzyloxy)-l-(9-(difluoromethyl)-2,3,4,9- tetrahydro-lH-pyrido[4,3-δ]indol-7-yl)pyridin-2(lH)-one, the title compound (25 mg, 62%) was prepared as a yellow solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 7.54 (d, J= 7.5 Hz, IH), 7.47-7.36 (m, 7H), 6.95 (dd, J= 8.5, 1.5 Hz, IH), 6.10 (dd, J= 7.5, 2.5 Hz, IH), 5.96 (d, J = 3.0 Hz, IH), 5.15 (s, 2H), 3.64 (m, 4H), 3.18-3.16 (m, IH), 3.05-3.02 (m, IH), 2.90-2.84 (m, 4H), 2.42-2.39 (m, IH), 2.00-1.92 (m, IH).

b) l-(2,9-Dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7- yl)-4-(imidazo[l,2- α]pyridin-2-ylmethoxy)pyridin-2( lH)-one hydrochloride

Chemical Formula: C~ 26,η _o 26,ClN 5 ₅ 0~ 2

Exact Mass: 475.18 Molecular Weight: 475.97

Attorney's Docket 2882.023B

Following the procedure of Example 134 (step b), but substituting l-(2,9-dimethyl- 2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)-4-(imidazo[l ,2-α]pyridin-2- ylmethoxy)pyridin-2(lH)-one (25 mg, 0.056 mmol) for (4-benzyloxy)-l-(9- (difluoromethyl)-2-methyl-2,3 ,4,9-tetrahydro- lH-pyrido [3 ,4-6]indol-7-yl)pyridin-2( IH)- one, the title compound (27 mg, 98%) was prepared as a yellow solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 10.91 (br s, IH), 8.86 (d, J= 6.0 Hz, IH), 8.39 (s, IH), 7.87-7.79 (m, 2H), 7.61 (d, J= 7.5 Hz, IH), 7.57 (d, J= 8.0 Hz, IH), 7.51 (s, IH), 7.37-7.35 (m, IH), 7.01 (dd, J= 8.5, 1.0 Hz, IH), 6.15-6.11 (m, 2H), 5.42 (s, 2H), 4.77 (d, J= 15.0 Hz, IH), 4.43 (dd, J= 14.0, 6.0 Hz, IH), 3.80-3.77 (m, IH), 3.66 (s, 3H), 3.41-3.39 (m, IH), 3.08- 3.04 (m, 2H), 2.99 (s, 3H); ESI MS m/z 440 [M + H] ⁺ ; HPLC (Method A) 97.1% (AUC), t _R = 9.8 min.

Example 139

Preparation of 1 -(2.9-Dimethyl-2.3.4.9-tetrahvdro-lH-pyrido [3.4-&1indol-7-yl)-4-(4-

(trifluoromethyl)benzyloxy)pyridin-2( lH)-one hydrochloride

a) 4-(Imidazo[l,2-α]pyridin-6-ylmethoxy)pyridine 1 -oxide

Chemical Formula: C ₁₃ H ₁₁ N ₃ O ₂

Exact Mass: 241.09 Molecular Weight: 241.25

Following the procedure of Example 137 (step a), but substituting imidazo[l,2- α]pyridine-6-ylmethanol (2.91 g, 19.6 mmol) for imidazo[l,2-α]pyridine-2-ylmethanol, the title compound (1.69 g, 42%) was prepared as an orange solid: ¹ H NMR (300 MHz, DMSO-de) δ 8.70 (s, IH), 8.13-8.10 (m, 2H), 7.97 (s, IH), 7.60-7.59 (m, 2H), 7.30 (dd, J = 9.3, 1.7 Hz, IH), 7.14-7.11 (m, 2H), 5.18 (s, 2H).

b) 4-(Imidazo[l ,2-α]pyridin-6-ylmethoxy)pyridine-2(lH)-one

Attorney's Docket 2882.023B

Chemical Formula: C ₁₃ H ₁₁ N ₃ O ₂

Exact Mass: 241.09 Molecular Weight: 241.25

4-(Imidazo[l,2-α]pyridin-6-ylmethoxy)pyridine 1-oxide (1.69 g, 7.04 mmol) was heated at 140 ⁰ C in acetic anhydride (20 rnL) for 4 h. The mixture was concentrated and heated at 80 ⁰ C for 3 h in a mixture of 1 : 1 MeOHZH ₂ O (50 mL). The resulting solution was concentrated. The residue was partially dissolved in zPrOH (75 mL). Et ₂ O (200 mL) was added, and the mixture was allowed to sit at ambient temperature for 1 h. The resulting solids were collected by filtration, washed with Et ₂ O and dried under reduced pressure. The solids were again subjected to zPrOH and Et ₂ O, and the solids were removed by filtration. The filtrate was concentrated to afford the title compound (0.47 g, 28%) as a dark brown solid: ¹ H NMR (300 MHz, CD ₃ OD) δ 8.60 (d, J= 0.7 Hz, IH), 7.87 (d, J = 0.6 Hz, IH), 7.59 (d, J= 1.4 Hz, IH), 7.57 (s, IH), 7.40-7.27 (m, 2H), 6.18 (dd, J= 7.3, 2.5 Hz, IH), 6.05 (d, J= 2.5 Hz, IH), 5.13 (s, 2H).

c) tert-Butyl-7-(4-(imidazo[l,2-α]pyridin-6-ylmethoxy)-2-oxopy ridin-l(2/-/)-yl)-9-methyl- 3,4-dihydro-lH-pyrido[3,4-6]indole-2(9H)-carboxylate

Chemical Formula: C ₃₀ H ₃₁ N ₅ O ₄

Exact Mass: 525.24 Molecular Weight: 525.60

Following the procedure of Example 133 (step b), but substituting 4-(imidazo[l,2- α]pyridin-6-ylmethoxy)pyridine-2(l/-/)-one (218 mg, 0.901 mmol) for 4- benzyloxypyridone, the title compound (112 mg, 26%) was prepared as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.25 (s, IH), 7.68-7.65 (m, 2H), 7.64-7.61 (m, IH), 7.53-7.52 (m, IH), 7.33 (d, J= 7.6 Hz, IH), 7.28-7.26 (m, IH), 7.22 (dd, J= 9.3, 1.5 Hz, IH), 7.01 (dd, J= 8.2, 1.8 Hz, IH), 6.11 (d, J= 2.7 Hz, IH), 6.03 (dd, J= 7.5, 2.7 Hz, IH), 5.06- 5.04 (m, 2H), 4.70-4.57 (m, 2H), 3.75 (m, 2H), 3.62 (s, 3H), 2.79 (m, 2H), 1.51 (s, 9H).

Attorney's Docket 2882.023B d) 4-(Imidazo[l,2-α]pyridin-6-ylmethoxy)-l-(9-methyl-2,3,4,9-t etrahydro-lH-pyrido[3,4- δ]indol-7-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C _2J H ₂₃ N ₅ O ₂

Exact Mass: 425.19 Molecular Weight: 425.48

Following the procedure of Example 135 (step d), but substituting tert-butyl-7-(4- (imidazo[ 1 ,2-α]pyridin-6-ylmethoxy)-2-oxopyridin- 1 (2H)-yl)-9-methyl-3 ,4-dihydro- IH- pyrido[3,4-6]indole-2(9H)-carboxylate (112 mg, 0.213 mmol) for tert-butyl-7(4(2-fiuoro- 4-methoxyphenyl)-2-oxopyridin-2(lH)-yl)-9-methyl-3,4-dihydro -lH-pyrido[3,4-δ]indole- 2(9H)-carboxylate, the crude title compound was prepared. Preparative ηPLC (Phenomenex Luna Cl 8 (2), 250.0 x 21.2 mm, 10 micron, H ₂ O with 0.05% TFA and CH ₃ CN with 0.05% TFA) yielded the title compound (12 mg, 13%) as an off-white film: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.24 (s, IH), 7.67-7.65 (m, 2H), 7.59 (s, IH), 7.53 (d, J = 8.3 Hz, IH), 7.34 (d, J= 7.6Hz, IH), 7.26 (m, IH overlapping with solvent), 7.22 (dd, J = 9.3, 1.6 Hz, IH), 7.00 (dd, J= 8.3, 1.8 Hz, IH), 6.11 (d, J= 2.7 Hz, IH), 6.03 (dd, J= 7.6, 2.7 Hz, IH), 5.04 (s, 2H), 4.04 (s, 2H), 3.57 (s, 3H), 3.17 (t, J= 5.6 Hz, 2H), 2.76 (t, J = 5.6 Hz, 2H).

e) 4-(Imidazo[l,2-α]pyridin-6-ylmethoxy)-l-(9-methyl-2,3,4,9-t etrahydro-lH-pyrido[3,4- δ]indol-7-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₅ H ₂₄ ClN ₅ O ₂ Exact Mass: 461.16

Molecular Weight: 461.94

Following the procedure of Example 134 (step b), but substituting 4-(imidazo[l,2- α]pyridin-6-ylmethoxy)-l-(9-methyl-2,3,4,9-tetrahydro-lH-py rido[3,4-δ]indol-7- yl)pyridin-2(lH)-one (12 mg, 0.028 mmol) for (4-benzyloxy)-l-(9-(difluoromethyl)-2- methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)pyridi n-2(lH)-one, the title compound (14 mg, 100%) was prepared as a light yellow solid: ¹ H NMR (500 MHz,

Attorney's Docket 2882.023B

DMSO-de) δ 9.55 (br s, 2H), 9.01 (s, IH), 8.33 (s, IH), 8.11 (s, IH), 7.97 (d, J= 9.2 Hz, IH), 7.89 (d, J= 9.2 Hz, IH), 7.61 (d, J= 7.6 Hz, IH), 7.56 (d, J= 8.4 Hz, IH), 7.50 (d, J = 1.6 Hz, IH), 7.00 (dd, J= 8.4, 1.7 Hz, IH), 6.13 (dd, J= 7.6, 2.7 Hz, IH), 6.08 (d, J = 2.7 Hz, IH), 5.31 (s, 2H), 4.46 (m, 2H), 3.67 (s, 3H), 3.44 (m, 2H), 2.97 (t, J= 5.7 Hz, 2H); ESI MS m/z 426 [M + H] ⁺ ; HPLC (Method A) >99% (AUC), t _R = 9.7 min.

Example 140

Preparation of 4-(Benzyloxy)- 1 -(8-fluoro-2,5-dimethyl-2,3,4,5-tetrahydro- lH-pyrido[4,3- blindol-7-yl)pyridin-2(lH)-one hydrochloride

a) (3-Bromo-4-fluorophenyl)hydrazine hydrochloride

Chemical Formula: C ₆ H ₇ BrClFN ₂

Exact Mass: 239.95 Molecular Weight: 241.49

A solution of sodium nitrite (4.2 g , 60 mmol) was added drop-wise to a mixture of 3-bromo-4-fluoroaniline (11.2 g, 58.9 mmol) and concentrated HCl (30 mL, 0.36 M) at 0 ⁰ C over 30 min. The resulting clear solution was stirred for 45 min, and a solution of SnCl ₂ *2H ₂ O (27 g, 120 mmol) in concentrated HCl (30 mL) was added drop-wise at 0 ⁰ C over 1.5 h. The mixture was stirred for 18 h at room temperature. The resulting precipitate was collected by filtration and crystallized from ethanol to provide the title compound (6.2 g, 42 %) as a yellow powder: ¹ H NMR (300 MHz, DMSO-J ₆ ) δ 10.24 (s, 3H), 8.42 (s, IH), 7.36-7.30 (m, 2H), 7.03-6.98 (m, IH).

b) 7-Bromo-8-fluoro-3,4-dihydro-lH-pyrido[4,3-b]indole-2(5H)-ca rboxylate Chemical Formula: C ₁₆ H ₁₈ BrFN ₂ O ₂

Exact Mass: 368.05 Molecular Weight: 369.23

A mixture of (3-bromo-4-fluorophenyl)hydrazine hydrochloride (3.0 g, 12 mmol), tert-butyl 4-oxopiperidine-l-carboxylate (2.48 g, 12.5 mmol) and concentrated HCl (6.0 mL, 72 mmol) in ethanol (40 mL) was stirred for 18 h at reflux. The solvent was removed under reduced pressure, the residue was suspended in dichloromethane (50 mL), and di-

Attorney's Docket 2882.023B tert-butyl dicarbonate (3.3 g, 15 mmol) and triethylamine (2.1 niL, 30 mmol) were added. The mixture was stirred for 18 h at ambient temperature. The resulting clear solution was concentrated, and the residue was purified by flash chromatography (silica gel, hexanes/ethyl acetate, 1 :0 to 1 : 1) to afford the title compound (0.9 g, 20%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.94 (br s, IH), 7.45 (d, J= 5.5 Hz, IH), 7.14 (br s, IH), 4.56 (br s 2H), 3.81 (br m 2H), 2.81 (br m 2H), 1.57 (s, 9H); ESI MS m/z 369 [M + H] ⁺ .

c) tert-Butyl 7-bromo-8-fluoro-5-methyl-3,4-dihydro-lH-pyrido[4,3-b]indole -2(5H)- carboxylate

Chemical Formula: C ₁₇ H ₂₀ BrFN ₂ O ₂

Exact Mass: 382.07 Molecular Weight: 383.26

Sodium hydride (60% weight dispersion in mineral oil, 150 mg, 3.66 mmol) was added to a solution of tert-butyl 7-bromo-8-fluoro-3,4-dihydro-lH-pyrido[4,3-b]indole- 2(5H)-carboxylate (0.9 g, 2.44 mmol) in 20 ml of DMF, and the mixture was stirred for 40 min at ambient temperature. Iodomethane (0.25 mL, 3.66 mmol) was added, and the resulting suspension was stirred for 2 h. The resulting mixture was concentrated under reduced pressure to ~ 1/3 of initial volume and treated with water (20 mL). The resulting precipitate was collected by filtration, sequentially washed with water and diethyl ether and dried under vacuum to afford the title compound (0.75 g, 83%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.42 (d, J= 5.4 Hz, IH), 7.17 (d, J= 9.3 Hz, IH), 4.45 (br s, 2H), 3.81 (br m, 2H), 3.60 (s, 3H), 2.78 (br m, 2H), 1.52 (s, 9H); ESI MS m/z 383 [M + H] ⁺ .

d) 4-(Benzyloxy)-l-(8-fluoro-5-methyl-2,3,4,5-tetrahydro-lH-pyr ido[4,3-δ]indol-7- yl)pyridin-2( lH)-one

Attorney's Docket 2882.023B

Chemical Formula: C ₂₄ H ₂₂ FN ₃ O ₂

Exact Mass : 403.17 Molecular Weight: 403.45 tert-Butyl 7-bromo-8-fluoro-5-methyl-3,4-dihydro-l/f-pyrido[4,3-δ]indo le-2(5H)- carboxylate (720 mg, 1.88 mmol), 4-benzyloxypyridone (380 mg, 1.9 mmol) and CS2CO3 (680 mg, 2.1 mmol) were suspended in DMSO (8.0 mL) and the resulting suspension was degassed for 15 min. The system was flushed with Ar. Then 8-hydroxyquinoline (87 mg, 0.60 mmol) and copper iodide (114 mg, 0.599 mmol) were added. The degassing/ Ar flushing process was repeated twice more, and the reaction mixture was heated at 133 ⁰ C for 18 h under argon. The reaction mixture was cooled, diluted with 15% solution of concentrated ammonium hydroxide in methanol (25 mL) and stirred at ambient temperature for 30 min. The reaction was further diluted with dichloromethane (75 mL). The solution was filtered through silica gel and concentrated under reduced pressure. The residue was diluted with CH ₂ Cl ₂ and washed with H ₂ O (25 mL) and brine (3 x 50 mL). The combined organics were dried over Na ₂ SO ₄ and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, (1 :1 hexanes/EtOAc)/(10: 1 :0.1 dichloromethane/methanol/concentrated ammonium hydroxide), 1 :0 to 0:1) to afford crude tert-bvXy\ 7-(4-(benzyloxy)-2-oxopyridin- 1 (2H)-yl)-8-fluoro-5-methyl-3 ,4-dihydro- IH- pyrido[4,3-δ]indole-2(5H)-carboxylate (280 mg) as a yellow oil. This oil was dissolved in dichloromethane (3 mL) and TFA (1 mL) was added. The reaction mixture was stirred at ambient temperature for 1 h, concentrated and dried under vacuum overnight to provide the title compound (200 mg), which was used in the next step without further purification: ESI MS m/z 404 [M + H] ⁺ .

Attorney's Docket 2882.023B e) 4-(Benzyloxy)-l-(8-fluoro-2,5-dimethyl-2,3,4,5-tetrahydro-lH -pyrido[4,3-δ]indol-7- yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₅ H ₂₅ ClFN ₃ O ₂

Exact Mass: 453.16 Molecular Weight: 453.94

To a solution of 4-(benzyloxy)-l-(8-fluoro-5-methyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-δ]indol-7-yl)pyridin-2(lH)-one (100 mg, 0.26 mmol) in dichloromethane/acetic acid (1% acetic acid, 10 rnL) were sequentially added formaldehyde (37% aqueous solution, 22 μL, 0.74 mmol) and NaBH(OAc) ₃ (316 mg, 1.49 mmol). The reaction mixture was stirred at room temperature for 2.5 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in CH ₂ Cl ₂ . The organic layer was washed with H ₂ O and 5% aqueous LiCl, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by flash chromatography (silica gel, CH ₂ Cl ₂ /(10:l :0.1 CH ₂ Cl ₂ /MeOH/NH ₄ OH), 0:1 to 1 :1) gave 4-(benzylo xy)-l -(8-fluoro-2,5-dimethyl-2, 3,4, 5-tetrahydro-lH-pyrido[4,3-δ]indo 1-7- yl)pyridin-2(lH)-one (78 mg, 38%) as a yellow solid. The free base was converted to the HCl salt using 1.25M HCl in methanol providing the title compound (75 mg, 95%) as a off-white solid: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.53-7.33 (m, 7H), 7.27 (d, J= 10.5 Hz, IH), 7.28 (dd, J= 7.8, 2.4 Hz, IH), 6.10 (d, J= 2.7 Hz, IH), 5.17 (s, 2H), 3.79 (br s, 2H), 3.67 (s, 3H), 3.03-3.00 (m, 4H), 2.64 (s, 3H); ESI MS m/z 418 [M + H] ⁺ ; HPLC (Method A) 95.7% (AUC), t _R = 14.5 min.

Example 141

Preparation of 4-(Benzyloxy)- 1 -(6-fluoro-9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 A-

&1indol-7-yl)pyridin-2(lH)-one hydrochloride.

Attorney's Docket 2882.023B

a) 2-(6-Bromo-5-fluoro-lH-indol-3- yl)ethanamine

Chemical Formula: C ₁₀ H ₁₀ BrFN ₂

Exact Mass: 256.00 Molecular Weight: 257.10

4,4-Diethoxybutan-l -amine (4.72 g, 29.3 mmol) was added to (3-bromo-4- fluorophenyl)hydrazine hydrochloride (6.4 g, 27 mmol) . The resulting mixture in an open round bottom flask was placed into a preheated oil bath at 180 ⁰ C. The mixture was stirred at 180 ⁰ C for 2.5 h and then cooled to 120 ⁰ C. Methanol (30OmL) was added, and the mixture was stirred at ambient temperature for 18h. The resulting suspension was filtered through a silica gel plug, and the silica gel was then washed with methanol (5 x 300 mL). The combined methanol fractions were concentrated under vacuum to provide the crude title compound (8.1 g) as a yellow solid, which was used in the next step without further purification: ESI MS m/z 257 [M + H] ⁺ .

b) tert-Butyi 7-bromo-6-fluoro-3,4-dihydro-lH-pyrido[3,4-b]indole-2(9H)-ca rboxylate Chemical Formula: C ₁₆ H ₁₈ BrFN ₂ O ₂

Exact Mass: 368.05 Molecular Weight: 369.23

Glyoxylic acid (8.6 g, 95 mmol) was added to a solution of 2-(6-bromo-5-fluoro- lH-indol-3-yl)ethanamine (8.1 g 31 mmol) in 2 N HCl (150 ml), and the pη of the resulting solution was adjusted to pη 3.5 with 6 N NaOH solution. The reaction mixture was stirred at ambient temperature for 18 h. The solution was adjusted to pη 5.5 with 6 N NaOH solution. The resulting precipitate was collected by filtration and dried under vacuum to afford a yellow solid. The yellow solid was suspended in 2 N HCl (100 mL), and the resulting mixture was stirred at reflux for 4.5 h. The reaction mixture was cooled to ambient temperature and was adjusted to pη 10 by addition of 2 N sodium hydroxide solution. The resulting precipitate was collected by filtration and dried under vacuum to afford a crude mixture of 7-bromo-6-fluoro-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indole and

Attorney's Docket 2882.023B

6-bromo-7-fluoro-2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indole (2.0 g, 23%) as a yellow solid. The mixture (1.9 g, 7.1 mmol) was suspended in dichloromethane (100 mL) and di- tert-butyl carbonate (1.85 g, 8.7 mmol) was added, followed by addition of DMAP (100 mg, 0.82 mmol). The reaction mixture was stirred at ambient temperature for 18 h and concentrated under vacuum. The residue was purified twice by column chromatography (silica gel, hexanes/ethyl acetate, 0:1 to 1:1) to afford the title compound (300 mg, 12%) as a pale yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.46 (d, J= 5.7 Hz, IH), 7.18 (d, J = 9.0 Hz, IH), 4.61 (s, 2H), 3.75 (br m, 2H), 2.73 (br m, 2H), 1.56 (s, 9H); ESI MS m/z 369 [M + H] ⁺ .

c) tert-Butyl 7-bromo-6-fluoro-9-methyl-3,4-dihydro-lH-pyrido[3,4-δ]indol e-2(9H)- carboxylate Chemical Formula: C ₁₇ H ₂₀ BrFN ₂ O ₂

Exact Mass: 382.07

Molecular Weight: 383.26

Sodium hydride (60% weight dispersion in mineral oil, 25 mg, 0.60 mmol) was added to a solution of tert-butyl 7-bromo-6-fluoro-3,4-dihydro-lH-pyrido[3,4-δ]indole- 2(9H)-carboxylate (150 mg, 0.40 mmol) in DMF (10 mL) at room temperature under N ₂ and stirred for 1 h at ambient temperature. Methyl iodide (230 mg, 0.16 mL, 0.60 mmol) was added, and the reaction mixture was stirred for 1 h. The resulting mixture was concentrated under reduced pressure to approximately 1/3 of initial volume and treated with water (20 mL). The resulting precipitate was collected by filtration, washed with water and diethyl ether and dried under vacuum to afford the title compound (140 mg, 91%) as a yellow powder: ESI MS m/z 383 [M + H] ⁺ .

d) 4-(Benzyloxy)-l-(6-fluoro-9-methyl-2,3,4,9-tetrahydro-lH-pyr ido[3,4-δ]indol-7- yl)pyridin-2(lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₄ H ₂₃ ClFN ₃ O ₂

Exact Mass: 439.15 Molecular Weight: 439.91 tert-Butyl 7-bromo-6-fluoro-9-methyl-3,4-dihydro-l/f-pyrido[3,4-δ]indo le-2(9H)- carboxylate (160 mg, 0.40 mmol), 4-benzyloxypyridone (80 mg, 0.33 mmol) and CS2CO3 (390 mg, 0.38 mmol) were suspended in DMSO (8.0 mL) and degassed under vacuum for 15 min. The system was then flushed with Ar, and 8-hydroxyquinoline (30 mg, 0.18 mmol) and copper iodide (80 mg, 0.40 mmol) were added. The degassing/ Ar flushing process was repeated twice, and the reaction mixture was heated at 133 ⁰ C for 18 h under argon. The mixture was cooled, diluted with 15% solution of concentrated ammonium hydroxide in methanol (25mL) and stirred at ambient temperature for 30 min. The reaction was further diluted with CH ₂ Cl ₂ (75mL) and filtered through silica gel and concentrated. The concentrate was diluted with CH ₂ Cl ₂ and washed with H ₂ O (25 mL) and brine (3 x 5OmL). The combined organics were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to dryness. The crude material was purified by flash chromatography (silica gel, (1 :1 hexanes/EtOAc)/(l 0:1 :0.1 dichloromethane/methanol/concentrated ammonium hydroxide), 1 :0 to 0:1) to afford 75 mg of crude material containing the desired product. The crude mixture was dissolved in a mixture of dichloro methane and methanol (1 :1, 5 mL), treated with TFA (2 mL) and stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure, and the residue was neutralized by ion- exchange chromatography (SCX-2 column, 5g). Purification by preparatory TLC (silica gel, 10:1 :0.1 dichloromethane/methanol/concentrated ammonium hydroxide) provided the free base of the title compound (12 mg, 10%) as a white foam: ESI MS m/z 404 [M + H] ⁺ . The free base was dissolved in methanol (25 mL) and treated with a solution of HCl (1.25 M in methanol, 0.1 mL, 0.13 mmol). The reaction mixture was sonicated for 5 min at ambient temperature. The mixture was concentrated, and the resulting residue was lyophilized from water (5 mL) to afford the title compound (14 mg, 8%) as a white powder: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 9.56 (br s, 2H), 7.61 (d, J= 6.0 Hz, IH), 7.54 (d, J= 7.5 Hz, IH), 7.50-7.37 (m, 6H), 6.14-6.12 (m, IH), 5.99 (s, IH), 5.16 (s, 2H), 4.46

Attorney's Docket 2882.023B

(br s, 2H), 3.67 (s, 3H), 3.43 (br m, 2H), 2.94 (m, 2H); ESI MS m/z 404 [M + H] ⁺ ; HPLC (Method A) 95.7% (AUC), t _R = 14.8 min

Example 142

Preparation of 4-(Benzyloxy)- 1 -(2-ethyl-9-methyl-2,3 ,4,9-tetrahydro- lH-pyrido[3 A-

&1indol-7-yl)pyridin-2(lH)-one hydrochloride

Chemical Formula: C ₂₆ H ₂₈ ClN ₃ O ₂

Exact Mass: 449.19 Molecular Weight: 449.97

To a solution of 4-(benzyloxy)-l-(9-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4- δ]indol-7-yl)pyridin-2(lH)-one hydrochloride (120 mg, 0.28 mmol) in dichloromethane/acetic acid (1% acetic acid, 10 rnL) were sequentially added acetaldehyde (0.50 mL, 13 mmol) and NaBH(O Ac) ₃ (1.0 g, 4.7 mmol). The reaction mixture was stirred at ambient temperature for Ih. The mixture was concentrated, and the residue was purified by flash chromatography (silica gel silica gel, (1 :1 hexanes/EtOAc)/(l 0:1 :0.1 dichloromethane/methanol/concentrated ammonium hydroxide), 1 :0 to 0:1) to provide 4- (benzyloxy)-l-(2-ethyl-9-methyl-2,3,4,9-tetrahydro-lH-pyrido [3,4-δ]indol-7-yl)pyridin- 2(lH)-one (120 mg, 72%) as a white solid. The free base was converted to the HCl salt using 1.25 M HCl in methanol, providing the title compound (120 mg, 95%) as an off- white solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 7.57 (d, J= 7.5 Hz, IH), 7.54-7.34 (m, 7H), 6.97 (d, J= 8.0 Hz, IH), 6.10 (dd, J= 7.5, 2.0 Hz, IH), 5.97 (s, IH), 5.16 (s, 2H), 3.67 (s, 3H), 3.45-3.18 (4H, overlapping with solvent peak), 3.26 (br m, 2H), 2.96 (m, 2H), 1.33 (br m, 3H); ESI MS m/z 414 [M + H] ⁺ ; HPLC (Method A) 95.7% (AUC), t _R = 14.6 min.

Example 143

Preparation of 4-(Benzyloxy)- 1 -(2-isopropyl-9-methyl-2, 3 ,4,9-tetrahydro- lH-pyrido[3 A-

&1indol-7-yl)pyridin-2(lH)-one hydrochloride

Attorney's Docket 2882.023B

Chemical Formula: C ₂₇ H ₃₀ ClN ₃ O ₂

Exact Mass: 463.20 Molecular Weight: 464.00

2-Bromopropane (1.5 mL, 16 mmol) was added to a mixture of 4-(benzyloxy)-l-(9- methyl-2, 3,4, 9-tetrahydro-l/f-pyrido[3,4-δ]indol-7-yl)pyridin-2(lH)-one hydrochloride (138 mg, 0.327 mmol) and CS2CO3 (1.2 g, 3.7 mmol) in acetonitrile (25 mL). The mixture was stirred at 55 ⁰ C for 72 h. The resulting mixture was cooled, and the precipitate was filtered off. The mother liquor was concentrated under vacuum. The residue was purified by preparatory TLC (silica gel, 10:1 :0.1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford 4-(benzyloxy)-l-(2-isopropyl-9-methyl-2, 3,4,9- tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)pyridin-2(lH)-one. The free base was converted to the HCl salt using 1.25 M HCl in methanol to provide the title compound (26 mg, 19%) as a off white solid: ¹ H NMR (500 MHz, DMSO-J ₆ ) δ 10.50 (s, IH), 7.56 (d, J= 4.5 Hz, 2H), 7.52-7.38 (m, 6H), 7.01 (dd, J= 4.5, 1.0 Hz, IH), 6.11 (dd, J= 4.5, 1.0 Hz, IH), 5.97 (s, IH), 5.16 (s, 2H), 4.60-4.53 (m, 2H), 3.78-3.70 (m, 2H), 3.70 (s, 3H), 3.40-3.28 (m, IH), 3.18-2.98 (m, 2H), 1.44-1.39 (m, 6H); ESI MS m/z 428 [M + H] ⁺ ; HPLC (Method A) 95.7% (AUC), t _R = 15.1 min.

Example 144

Preparation of Isopropyl 7-(4-(benzyloxy)-2-oxopyridin- 1 (2H)-yl)-9-methyl-3 ,4-dihydro- l/f-pyridor3.4-^1indole-2(9//)-carboxylate

Chemical Formula: C ₂₈ H ₂₉ N ₃ O ₄

Exact Mass: 471.22 Molecular Weight: 471.55

Following the procedure of Example 143, the title compound (12 mg, 8%) was obtained as a second product as an off-white powder after lyophilization from acetonitrile/water: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.48 (d, J= 8.5 Hz, IH), 7.50-7.32 (m,

Attorney's Docket 2882.023B

7H), 6.99 (d, J= 8.5 Hz, IH), 6.90 (s, IH), 6.34 (d, J= 6.5 Hz, IH), 5.17 (s, 2H), 5.05- 5.00 (m, IH), 4.72-4.58 (m, 2H), 3.79 (br m, 2H), 3.76 (s, 3H), 2.82 (m, 2H), 1.42-1.32 (m, 6H); ESI MS m/z All [M + H] ⁺ ; HPLC (Method A) 95.7% (AUC), t _R = 19.9 min.

Example 145

Preparation of 4-(Benzyloxy)-3-bromo-l-(9-methyl-2,3,4,9-tetrahydro-lH-pyri do[3,4-

&1indol-7-yl)pyridine-2(lH)-one hydrochloride

Chemical Formula: C ₂₄ H ₂₃ BrClN ₃ O ₂

Exact Mass: 499.07 Molecular Weight: 500.82

2-Bromopropane (0.25 mL, 2.7 mmol) was added to a solution of 4-(benzyloxy)-l- (9-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-δ]indol-7-yl)pyr idin-2(lH)-one in DMSO (5 mL). The reaction mixture was stirred at 55 ⁰ C for 3 d. The mixture was diluted with a saturated solution of sodium bicarbonate and extracted with dichloro methane (3 x 50 mL). The combined organics were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by preparatory TLC (silica gel, 10:1 :0.1 dichloromethane/methanol/concentrated ammonium hydroxide) provided the free base of the title compound. The free base was converted to the HCl salt using 2.5 M HCl in methanol to afford, after lyophilization from acetonitrile/water, the title compound (15 mg, 14%) as a yellow solid: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.71 (d, J= 7.8 Hz, IH), 7.63 (d, J= 8.4, Hz, IH), 7.53-7.30 (m, 6H), 7.05 (dd, J= 7.8, 1.2 Hz, IH), 6.60 (d, J= 7.6 Hz, IH), 5.40 (s, 2H), 4.54 (s, 2H), 3.71 (s, 3H), 3.62-3.55 (m, 2H), 3.22-3.02 (m, 2H); ESI MS m/z 465 [M + H] ⁺ ; HPLC (Method A) 95.7% (AUC), t _R = 15.3 min.

Example 146

Preparation of 4-(Benzyloxy)- 1 -(2,3,4,5-tetrahydro- lH-pyrido[4,3-ά]indol-7-yl)pyridin-

2(lH)-one dihydrochloride

a) Di-tert-buty{ 7-bromo-3,4-dihydro-lH-pyrido[4,3-δ]indole-2,5-dicarboxylat e

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Chemical Formula: C ₂₁ H ₂₇ BrN ₂ O ₄

Exact Mass: 450.12 Molecular Weight: 451.35

To a solution of tert-bvXy\ 7-bromo-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)- carboxylate (1.00 g, 2.85 mmol), BoC ₂ O (683 mg, 3.13 mol) and triethylamine (0.73 niL, 5.7 mmol) in methylene chloride (30 mL) at room temperature was added DMAP (50 mg, 0.41 mmol), and the reaction progressed for 18 h. The mixture was washed with 0.5 N HCl, and the organic phase was removed, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude title product (1.25 g, 98%) was recovered as an orange solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.37 (br s, IH), 7.34 (dd, J= 8.2, 1.6 Hz, IH), 7.24 (d, J= 8.25 Hz, IH), 4.54 (br s, 2H), 3.73 (m, 2H), 3.07 (t, J= 5.6 Hz, 2H), 1.66 (s, 9H), 1.50 (s, 9H).

b) tert-&vXy\ 7-(4-(benzyloxy)-2-oxopyridin- 1 (2H)-yl)-3,4-dihydro- lH-pyrido[4,3- b]indole-2(5H)-carboxylate

Chemical Formula: C ₂₈ H ₂₉ N ₃ O ₄

Exact Mass: 471.22 Molecular Weight: 471.55

Prepared from di-tert-butyl 7-bromo-3,4-dihydro-lH-pyrido[4,3-δ]indole-2,5- dicarboxylate (1.24 g, 2.72 mmol) and 4-benzyloxypyridone (547 mg, 2.72 mmol) according to the procedure of Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) gave the title compound (155 mg, 10%) as a yellow solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.40 (br s, IH), 7.44-7.38 (m, 5H), 7.30 (d, J= 7.5 Hz, IH), 7.22 (d, J= 8.2 Hz, IH), 7.16 (s, IH), 6.82 (dd, J= 8.2, 1.4 Hz, IH), 6.12-6.09 (m, 2H), 5.09 (s, 2H), 4.46 (br s, 2H), 3.70 (br m, 2H), 2.54 (br m, 2H), 1.50 (s, 9H).

c) 4-(Benzyloxy)-l-(2,3,4,5-tetrahydro-lH-pyrido[4,3-δ]indol-7 -yl)pyridin-2(lH)-one dihydrochloride

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Chemical Formula: C ₂₃ H ₂₃ Cl ₂ N ₃ O ₂

Exact Mass: 443.12 Molecular Weight: 444.35

Prepared from tert-bvXy\ 7-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-3,4-dihydro-lH- pyrido[4,3-δ]indole-2(5H)-carboxylate (150 mg, 0.32 mmol) according to the procedure of Example 1 (step d). Purification by flash column chromatography (4 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 85% methylene chloride over 30 min) provided the free-base as a yellow solid. This was converted to the bis-HCl salt (2 N HCl/Et ₂ O in CH ₂ Cl ₂ ) providing the title compound (36 mg, 26%) as a yellow solid: mp 240 ⁰ C dec; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.65 (d, J= 7.5 Hz, IH), 7.57 (d, J= 8.2 Hz, IH), 7.47 (d, J= 7.2 Hz, 2H), 7.42-7.36 (m, 4H), 7.03 (d, J= 8.5 Hz, IH), 6.39 (dd, J= 7.6, 2.5 Hz, IH), 6.21 (d, J= 2.5 Hz, IH), 5.21 (s, 2H), 4.47 (s, 2H), 3.64 (t, J= 6.0 Hz, 2H), 3.20 (t, J= 6.1 Hz, 2H); ESI MS m/z 372 [M + H] ⁺ ; HPLC (Method A) 95.0% (AUC), t _R = 12.2 min.

Example 147

Preparation of 4-(Benzyloxy)- 1 -(5-ethyl-2,3A5-tetrahydro- l/-/-pyrido[4,3-&]indol-7- yl)pyridin-2( lHVone dihydrochloride

a) tert-Butyl 7-bromo-5-ethyl-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)-ca rboxylate

Chemical Formula: C ₁₈ H ₂₃ BrN ₂ O ₂

Exact Mass: 378.09 Molecular Weight: 379.29

Prepared from tert-butyi 7-bromo-3,4-dihydro-lH-pyrido[4,3-δ]indole-2(5H)- carboxylate (500 mg, 1.43 mmol) according to the procedure of Example 1 (step b). This provided the title compound (520 mg, 96%) as a yellow/orange solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.36 (s, IH), 7.23 (d, J= 8.3 Hz, IH), 7.10 (d, J= 8.2 Hz, IH), 4.54 (s, 2H), 3.96 (q, J= 7.2 Hz, 2H), 3.76 (br m, 2H), 2.71 (br m, 2H), 1.43 (s, 9H), 1.25 (t, J= 7.2 Hz, 3H).

Attorney's Docket 2882.023B b) tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-5-ethyl-3,4-dihydro- lH-pyrido[4,3- δ]indole-2(5H)-carboxylate

Chemical Formula: C ₃₀ H ₃₃ N ₃ O ₄

Exact Mass: 499.25 Molecular Weight: 499.60

Prepared from tert-butyl 7-bromo-5-ethyl-3,4-dihydro-lH-pyrido[4,3-δ]indole- 2(5H)-carboxylate (500 mg, 1.32 mmol) and 4-benzyloxypyridone (265 mg, 1.32 mmol), according to the procedure of Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) gave the title compound (317 mg, 48%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53 (d, J= 8.2 Hz, IH), 7.44-7.37 (m, 5H), 7.32-7.29 (m, 2H), 7.04 (d, J= 8.0 Hz, IH), 6.10-6.03 (m, 2H), 5.08 (s, 2H), 4.66 (br s, 2H), 4.10 (q, J= 7.1 Hz, 2H), 3.86 (br m, 2H), 2.84 (br m, 2H), 1.53 (s, 9H), 1.25 (t, J= 7.1 Hz, 3H).

c) 4-(Benzyloxy)-l-(5-ethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3-δ ]indol-7-yl)pyridin-2(lH)- one dihydrochloride

Chemical Formula: C ₂₅ H ₂₇ Cl ₂ N ₃ O ₂

EExxaacctt MMaassss:: 447711..1155 Molecular Weight: 472.41

Prepared from tert-butyi 7-(4-(benzyloxy)-2-oxopyridin-l(2H)-yl)-5-ethyl-3,4- dihydro-lH-pyrido[4,3-δ]indole-2(5H)-carboxylate (315 mg, 0.631 mmol) according to the procedure of Example 1 (step d) providing the title compound (207 mg, 74%) as a yellow solid: mp 176-181 ⁰ C; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.83 (d, J = 7.5 Hz, IH), 7.62- 7.57 (m, 2H), 7.45-7.40 (m, 5H), 7.09 (dd, J= 8.4, 1.6 Hz, IH), 6.59 (dd, J= 7.5, 2.3 Hz, IH), 6.36 (d, J= 2.3 Hz, IH), 5.28 (s, 2H), 4.49 (s, 2H), 4.23 (q, J= 7.2 Hz, 2H), 3.68 (t, J = 6.1 Hz, 2H), 3.22 (t, J= 5.9 Hz, 2H), 1.35 (t, J= 7.1 Hz, 3H); ESI MS m/z 400 [M + H] ⁺ ; HPLC (Method A) >99% (AUC), to = 13.2 min.

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In accordance with further embodiments of the invention, there are provided the following compounds, which may be synthesized by analogy by the methods shown and described above:

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Binding Assay I for Human Melanin-Concentrating Hormone (MCHi) receptor

Evaluation of the affinity of compounds for the human MCHi receptor was accomplished in transfected Chinese Hamster Ovary (CHO) cells determined in a radioligand binding assay, as described in MacDonald et al., "Molecular characterization of the melanin- concentrating hormone/receptor complex: identification of critical residues involved in binding and activation", MoI Pharmacol., 58:217 (2000). Cell membrane homogenates (5 μg protein) were incubated for 60 min at 22°C with 0.1 nM [ ¹²⁵ I][Phe ¹³ ,Tyr ¹⁹ ]-MCH in the absence or presence of the test compound in a buffer containing 25 mM Hepes/Tris (pH 7.4), 5 mM MgCl ₂ , 1 mM CaCl ₂ and 0.5% bovine serum albumin (BSA). Nonspecific binding was determined in the presence of 0.1 μM MCH. Following incubation, the samples were filtered rapidly under vacuum through glass fiber filters (GF/B, Packard) and rinsed several times with an ice-cold buffer containing 25 mM Hepes/Tris (pH 7.4), 500 mM NaCl, 5 mM MgCl ₂ , 1 mM CaCl ₂ and 0.1% BSA using a 96-sample cell harvester (Unifilter, Packard). The filters were dried, then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard).

The results are expressed as a percent inhibition of the control radioligand specific binding. The IC ₅₀ value (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficient (TI _H ) were determined by non-linear regression analysis of the competition curve using Hill equation curve fitting. The inhibition constant (K ₁ ) was calculated from the Cheng Prusoff equation: (K ₁ = IC ₅₀ /(1+(L/K _D )), where L = concentration of radioligand in the assay, and K _D = affinity of the radioligand for the receptor).

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Binding Assay II for Human Melanin-Concentrating Hormone (MCHi) receptor

Evaluation of the affinity of compounds for the human MCHi receptor was accomplished using 4-(3 ,4,5-tritritiumbenzyloxy)- 1 -( 1 -(2-(pyrrolidin- 1 -yl)ethyl)- IH- indazol-5-yl)pyridin-2(lH)-one and membranes prepared from stable CηO-K1 cells expressing the human MCηi receptor obtained from Euroscreen (Batch 1138). Cell membrane homogenates (8.92 μg protein) were incubated for 60 min at 25 ⁰ C with 1.4 nM of the [ ³ η]-labeled compound in the absence or presence of the test compound in 50 mM Tris-HCl buffer, pH 7.4. Nonspecific binding was determined in the presence of 50 μM 1- (5-(4-cyanophenyl)bicyclo[3.1.0]hexan-2-yl)-3-(4-fluoro-3-(t rifluoromethyl)phenyl)- 1 -(3- (4-methylpiperazin-l-yl)propyl)urea. Following incubation, the samples were filtered rapidly under vacuum through Skatron 11731 filters, pre-soaked in 0.5% polyethylenimine, and washed with ice-cold 50 mM Tris-HCl buffer, pH 7.4, (wash setting 9,9,0) using a Skatron cell harvester. The filters were counted for radioactivity in a liquid scintillation counter (Tri-Carb 2100TR, Packard) using a scintillation cocktail (Ultima Gold MV, Perkin Elmer).

The results are expressed as a percent inhibition of the control radioligand specific binding. The IC ₅₀ value (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficient (H _H ) were determined by non-linear regression analysis of the competition curve using Hill equation curve fitting. The inhibition constant (K ₁ ) was calculated from the Cheng Prusoff equation: (K ₁ = IC _SO /(1+(L/K _D )), where L = concentration of radioligand in the assay, and K _D = affinity of the radioligand for the receptor.

By methods as described above, the compounds listed in TABLE 1 were synthesized and tested for biological activity. All of the compounds in TABLE 1 exhibited K ₁ of less than or equal to 3.5 μM in MCHi binding assays I or II.

TABLE 1

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As compounds that bind strongly to MCHi, compounds of formula I are expected to be effective in reducing obesity.

The present invention is not limited to the compounds found in the above examples, and many other compounds falling within the scope of the invention may also be prepared using the procedures set forth in the above synthetic schemes. The preparation of additional compounds of formula (I) using these methods will be apparent to one of ordinary skill in the chemical arts.

The invention has been described in detail with particular reference to some embodiments thereof, but it will be understood by those skilled in the art that variations and modifications can be effected within the spirit and scope of the invention.