CA2242579A1 - Benzimidzolyl neuropeptide y receptor antagonists - Google Patents

Benzimidzolyl neuropeptide y receptor antagonists Download PDF

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CA2242579A1
CA2242579A1 CA002242579A CA2242579A CA2242579A1 CA 2242579 A1 CA2242579 A1 CA 2242579A1 CA 002242579 A CA002242579 A CA 002242579A CA 2242579 A CA2242579 A CA 2242579A CA 2242579 A1 CA2242579 A1 CA 2242579A1
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alkylenyl
alkoxy
heterocyclic
phenyl
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Macklin Brian Arnold
Thomas Charles Britton
Robert Frederick Junior Bruns
Buddy Eugene Cantrell
Anne Marie Nunes
Philip Arthur Hipskind
James Jeffry Howbert
Karen Lynn Lobb
James Arthur Nixon
Paul Leslie Ornstein
Edward C. R. Smith
Hamideh Zarrinmayeh
Dennis Michael Zimmerman
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Eli Lilly and Co
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Abstract

This invention provides a series of substituted benzimidazoles which are useful in treating or preventing a condition associated with an excess of neuropeptide Y. This invention also provides methods employing these substituted benzimidazoles as well as pharmaceutical formulations which comprise as an active ingredient one or more of these compounds.

Description

W O 97/25041 PCT~US97/00511 BEN5~1MI~ZOLYLNEURO~ EYRE~;~l~RAl~TAGONl~IS

Neuropeptide Y i~ a peptide present in the central and 5 peripheral nervous systems. The peptide co-e~sts with noradrenaline in many neurons and acts as a neulo~ldn~ el per se or synergistically together with noradrenaline. Neuropeptide Y-cont~ining fibers are numerous around arteries in the heart, but are also found around the arteries in the respiratory tract, the 10 gastrointestinal tract, and the genitourinary tract. Neuropeptide Y is also present in the cerebrurn v~ith effects on blood pressure, feeding, and the release of different hormones. Alterations in central concentrations of neuropeptide Y have been imrlic~ted in the etiology of psyr.hi~t.ric disorders.
Neuropeptide Y was discovered, isolated and sec~uenced in 1982 from porcine brain as part of a general screening protocol to discover carboxy-terminal amidated peptides and was named neuropeptide Y due to its isolation from neural tissue and the presence of tyrosine as both the amino and carboxy terminal amino acid.
2 0 Neuropeptide Y is a member of the pancreatic family of peptides and shares si~nific~nt sequence homology with pancreatic polypeptide and peptide YY.
Neuropeptide Y and the other members of its family of peptides all feature a tertiary structure consisting of an N-terminal polyproline helix and an ~mphirhilic a-helix, connected with a ,13-turn, creating a hairpin-like loop, which is sometimes referred to as the pancreatic polypeptide (PP) fold. The helices are kept together by h~ vl hobic interactions. The amidated C-termin~l end projects away from the hairpin loop.
3~ Subsequent to its discovery neuropeptide Y was ~ntitied as being the most abllnl1~nt peptide in the central nervous system with widespread distribution including the corte~, brainstem, hippocampus, q . hypot~hl~m~ , amygdala, and t.h~l~qrnus as well as being present in the peripheral nervous system in symr~thetic neurons and adrenal " 3 5 chrom~ffin cells.

Neuropeptide Y seems to fulfill the main criteria for a role as a neurulldnsmitter, as it is stored in synaptic granules, is released upon electrical nerve stimlllAtion, and acts at specific receptors. It is clear that neuropeptide Y is an important messenger in its own right, probably in the brain, where neuropeptide Y potently inhibits the activity of adenylate cyclase and induces an increase in the intracellular levels of calcium. Central injection of neuropeptide Y results in blood pressure changes, increased feeding, increased fat storage, elevated blood sugar and insulin, decreased locomotor activity, reduced body 10 temperature, and catalepsy.
Neuropeptide Y (as well as its ~h~mic~sl relat*es) acts upon membrane receptors that are dependent on guanyl-nucleotide hin-lin~
proteins, known as G protein-coupled receptors. G proteins are a family of memhrane proteins that become activated only after hin-linE
15 gll~nosine triphosphate. Activated G proteins in turn activate an ~mpli~er enzyme on the inner face of a mçmhrane; the enzyme then converts precursor molecules into second messengers.
Neuropeptide Y appears to interact with a family of closely related receptors. These reGe~lols are generally rl~s~sifiefl into several 20 subtypes based upon the ability of different tissues and receptors to bind different frslEment~ of neuropeptide Y and other members of the PP
f~rnily of peptides. The Y1 receptor subtype appears to be the major vascular neuropeptide Y receptor. The Y2 receptor subtypes can also occur postjunctionally on vAsctll~r smooth muscle. The as-yet-25 llni.~ol~ted Y3 receptor subtype appears to be neuropeptide Y-specific, not hintling peptide YY. This receptor is likely to be present in the adrenal tissues, medulla, heart, and brain stem, ~mon~ other areas.
[For a review of neuropeptide Y and neuropeptide Y receptors, see. e.~., C. Wahlestedt and D. Reis, ~nnual Review of Ph~rmacolo~y and 30 Toxicolo~y, 33:309-352 ~1993); D. Gehlert and P. ~ir~kin~l, Current Ph~rm~ceutical Desi1Jn,1:29~;-304(1995)].
In view of the wide number of clinical m~ lies associated with an excess of neuropeptide Y, the development of neuropeptide Y ~
receptor antagonists will serve to control these clinical conditions. The 35 earliest such receptor antagonists, such as Patent Cooperation Treaty Patent Publication WO 91/08223, pllhli~hell dune 13, 1991, and Patent W O 97t25041 PCTrUS97/00511 Cooperation Treaty Patent Publication WO 94/00486, pllhli~hed January 6, 1994, were peptide del;vaLives. These antagonists are of limited h~ ceutical utility ~hecause of their metabolic instability.
This invention provides a class of potent non-peptide 5 neuropeptide Y receptor antagonists. By virtue of their non-peptide nature, the compounds of the present i~lvel~ion do not suffer from the shortcoming~, in terms of metabolic instability, of known peptide-based neuropeptide Y receptor antagonists.
This invention encomr~es methods for the tre~trn~nt or 10 l.level~tion of a physiological disorder associated with an excess of neuropeptide Y, which method co~ ises ~mini~tering to a m~mm~ql in need of said tre~tment an effect*e amount of a compound of Formula I

R5 ~ \ ~ R

I

wherein-RliS phenyl, C3-Cg cycloalkyl, C3-Cg cyclos~lkenyl, phenyl(Cl-C6 alkylenyl)-, phenyl(Cl-C6 alkoxy3, phenoxy(Cl-C6 alkylenyl)-, phenyl(Cl-C6 alkoxy)-(C1-C6 alkylenyl)-, nFIphthyl~ n~rhthyl(C1-C6 alkylenyl)-, naphthyl(Cl-C6 alkoxy), naphthyloxy(Cl-C6 alkylenyl)-, or n~phthyl~Cl-C6 alkoxy)-(C1-C6 alkylenyl)-, any one of which phenyl, C3-Cg cycloalkyl, phenoxy, n~phthyl, or n~phthyloxy moieties may be subs~i~u~ed with one or groups selected from the group consisting 3 0 of halo, trifluoromethyl, Cl-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, Cl-C6 alkoxy, Cl-C6 alkylthio, Cl-C6 CA 02242579 l998-07-08 W O 97/25041 PCTnUS97/OO511 alkyl~qmino, heterocyclic, unsaturated heterocyclic, C3-Cg cycloalkyl, C3-Cg cyclo~lkenyl, phenyl, phçno~y, phenyl(Cl-C6 alkylenyl)-, phenyl(Cl-C6 alko~y)-, benzoyl, phenyl(C2-C7 alk~qnQyl)-, and phenyl(C2-C7 ~lk~noyloxy)-;

R2 is Cl-Cl2 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 ~lk~noyl, Cl-C6 alkoxy, heterocyclic(Cl-C6 alkylenyl)-, C3-Cg cycloalkyl, C3-Cg cycloalkenyl, lm~tllrated heterocyclic(Cl-C6 alkylenyl)-, heterocyclic(Cl-C6 alko~y)-, unsaturated heterocyclic(C1-C6 alkoxy)-, phenyl, phenyl(C1-C6 alkylenyl)-, n~pht~yl,n~rht.~yl(C1-C6 alkylenyl)-, phenr~y(C1-C6 alkylenyl)-, n~pht~yloxy(Cl-C6 alkylenyl)-, benzoyl(Cl-C6 alkylenyl)-, C2-C7 alkenyl, C2-C7 carbPmoyl, C2-C7 amido, Cl-C6 alkolLyca,bonyl-, or Cl-C6 haloalkyl, any one of which Cl-C12 alkyl, phenyl, naphthyl, ph~no~y, n~pht~yloxy, benzoyl, C3-Cg cycloalkyl, C3-Cg cycloalkenyl, heterocyclic(Cl-C6 alkoxy)-, u~saturated heterocyclic(Cl-C6 alkoxy)-, heterocyclic, or lln~tllrated heterocyclic moieties may be substituted with one or more groups selected firom the group con~i~t;n~ of Cl-C6 alkyl, Cl-C6 alkoxy, phenyl, nslrh~yl, phenyl(Cl-C6 alkylenyl)-, n~phthyl(Cl-C6 a~ylenyl)-, halo, trifluoromethyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, heterocyclic, lln~atllrated heterocyclic, heterocyclic(Cl-C6 alkylenyl)-, lln~t~lrated heterocyclic(Cl-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(Cl-C6 alkoxy)-, C3-Cg cycloalkyl, C3-Cg cyr.loAlk~nyl, C2-C7 ~lk~nnyl, C2-C7 f~lk~noyloxy, Cl-C6 alkyl~mino, Cl-C6 alkylthio, Cl-C6 haloalkyl, amino, nitro, and hyd~O~y~
or R2 may also be -(CH2)n-NR7R8, where, nisOtolO,and R7 and R8 are indepen(l~ntly hydrogen, Cl-C6 alkyl, C2-C7 ~ 5 ~lkAntlyl, Cl-C6 alkogy, heterocyclic(Cl-C6 alkylenyl)-,nn~t~lrated heterocyclic(Cl-C6 alkylenyl)-, phenyl, phenyl(C1-C6 ~kylenyl)-, n~rht~yl, nApht.~yl(Cl-C6 alkylenyl)-, rh~nr~y(C1-C6 alkylenyl)-, n~I~ht.hyloxy(Cl-C6 alkylenyl)-, benzoyl(Cl-C6 Ikylenyl)-, heterocyclic(Cl-C6 alkoxy)-, lm~tllrated heterocyclic(Cl-C6 ~lkoxy)-, Cl-C6 h~lo~lkyl, C2-C7 alkenyl, C2-C7 ~kynyl, C3-Cg cycloAlk~nyl, or C3-Cg cycloalkyl, any one of which phenyl, nApht.hyl, phenogy, naphthyloxy, C3-Cg cycloalkyl, benzoyl, heterocyclic, llnfiAtllrated heterocyclic, heterocyclic(Cl-C6 alkoxy)-, or lm~Atllrated heterocyclic(Cl-C6 alkoxy)- moieties may be substituted with one or more groups selected from the group consisting of Cl-~6 alkyl, Cl-C6 alkoxy, halo, trifluoromethyl, alkoxy, C3-Cg cycloalkyl, C3-Cg cycloalkenyl, heterocyclic, lln~Atllrated heterocyclic, heterocyclic(Cl-C6 alkylenyl)-, lln~at.lrated heterocyclic(Cl-C6 alkylenyl)-, heterocyclic((: l-C6 alkoxy)-, ~n~Atnrated heterocyclictCl-C6 alkogy)-, C2-C7 ~lk~n~yl, C2-C7 Alk~noylogy, Cl-c6 alkylAmino, C1-C6 alkylthio, C2-C7 alkenyl, C2-C7 alkynyl, Cl-C6 hAloAlkyl, amino, nitro, and hydlv~y, and R3, R4, R5, and R6 are indepenclen~ly hydrogen, halo, Cl-C6 alkyl, 3 5 Cl-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 Alk~qn(~yl~
C2-C7 ~lk~noyloxy, Cl-C6 alkylArnino, Cl-C6 alkylthio, W O 97125041 PCT~US97/OOSll benzoyl, phqrlo~y, phenyl(Cl-C6 alkylenyl)-, C3-C8 cycloalkyl, C3-Cg cycloalkenyl, phenyl(cl-c6 alkoxy)-, phenyl(C1-C6 alkyl~ne~mino)-, phenyl(C1-C6 alkylenq~mino)-, phenyl(c2-c7 ~lk~noyl)-, phenyl(c2-c7 ~qlk~noyloxy)-~ heterocyclic, lln.~tllrated heterocyclic, heterocyclic(Cl-C6 alkylenyl)-, heterocyclic(C1-C6 alko~y)-, unsaturated heterocyclic(Cl-C6 alkylenyl)-, unsaturated heterocyclic(Cl-C6 alkoxy)-, amino, nitro, hyL~ y, tri~uoromethyl, ~o-(cH2)n-NR7R8~ or-(cH2)n-NR7R8;

or a pharmaceutically acceptable salt or solvate thereo~

This invention also çncolnpasses, in additional embo-liment~, the novel compounds of Formula I, and the salts and 15 solvates thereof, as well as pharmaceutical formulations co~ ising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in cnmhins~tion with one or more pharmaceutically acceptable carriers, excipients, or diluents therefor.
The current invention concerns the discovery that a select 20 group of substituted bçn~i7ni.1~7:0les, those of Formula I, are useful as neuropeptide Y receptor antagonists.
The terms and abbreviations used in the instant ~ mples have their normal me~nin~ unless otherwise ~lesign~ed. For example "~C" refers to degrees Celsius; aN" refers to normal or normality;
25 "mmol" refers to millimole or millimnles; "g" refers to gram or grams;
aml~ me~n~ milliliter or milliliters; "M" refers to molar or molarity;
"MS~ refers to mass spectrometry; aIRJJ refers to infrared spectroscopy;
and "NMR" refers to nuclear m:~Fnetic resonance ~pectroscopy.
As used herein, the term "Cl-Cl2 alkyl" refers to straight or 3 o branched, monovalent, saturated aliphatic chains of 1 to 12 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, iso~ro~yl, butyl, isobutyl, t-butylL, pentyl, isopentyl, and hexyl. The term "Cl-C12 alkyl" includes within its flqfinition the terms "Cl-C6 alkyl" and "C1-C4 alkyl".

W O 97/25041 PCT~US97/00511 "C2-C7 s~lk~n()yloxyn represents a straight or branched alkyl chain having from one to six carbon atoms attached to a carbonyl moiety joined through an o~y~en atom. Typical C2-C7 ~lk~noyloxy groups include acetoxy, propanoyloxy, isopropanoyloxy, butanoyloxy, 5 t-butanoyloxy, pentanoyloxy, hexanoyloxy, 3-methylp~nt~nnyloxy and the like.
"C3-Cg cycloalkyl" represents a saturated hydrocarbon ring structure cont~ining from three to eight carbon atoms. Typical C3-Cg cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, 10 cycloheptyl, and the like.
The term ~carbamoyl" as employed herein refers to a group of the structure -NH-C(O)-. The term aC2-C7 carbamoyl" as employed herein refers to a group of the structure (Cl-C6 alkyl)-NH-C(O~-"Halo" represents chloro, fluoro, bromo or iodo.
The term "C1-C6 h~lo~lkyl" refers to a straight or branched, monovalent, saturated ~ h~t.ic chains of 1 to 6 carbon atoms substituted with one or more halo groups.
"Cl-Clo alkylthio" represents a straight or br~nl~he~ alkyl chain having from one to ten carbon atoms ~tt~lh~fl to a sulfur atom.
Typical Cl-Clo ~lkylthio groups include methylthio, ethylthio, yl~l~io, iso~lo~ylthio, butylthio and the like. The term "Cl-Clo alkylthio" includes within its rl~finition the term "C1-C6 alkylthio" and aC1-C3 alkylthio".
"C1-Cl2 alkylenyl" refers to a straight or branched, divalent, saturated aliphatic chains of 1 to 12 carbon atoms and includes, but is not limited to, methylenyl, ethylenyl, propylenyl, iso~lo~ylenyl, butylenyl, isobutylenyl, t-butylenyl, pentylenyl, isopentylenyl, hexylenyl, octylenyl, 3-methyloctylenyl, decylenyl. The term "Cl-C6 alkylenyl" is encomr~.~sed within the term aCl-C~2 alkylenyl".
"C1-Clo alkyl~mino" represents a group of the formula -NH(Cl-Clo alkyl) wherein a chain having from one to ten carbon atoms is ~tt~ ed to an - amino group. Typical Cl-C4 alkyl~mino groups include methyl~mino, ethyl~mino, propyl~minn, iso~ yl~minn, butylamino, sec-butyl~minn 3 5 and the like.

CA 02242579 l998-07-08 W O 97/25041 PCT~US97/00511 The term "C2-Clo alkenyl" as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having s from two to ten carbon atoms. Typical C2-Clo alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, and the like.
The term ''C2-Clo alkynyln as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having firom two to ten carbon atoms with at least one triple bond. Typical C2-Clo alkynyl groups include ethynyl, 1-methylethenyl, 1-~lo~yl~y 1-butynyl, 1-hexynyl, 2-~ yllyl~ 2-butynyl, 2-pentynyl, and the like.
~C3-Cg cyclo~lk~nyl~ represents a hydrocarbon ring structure cont~ining from three to eight carbon atoms and having at least one double bond within that ring, which is unsubstituted or substituted with 1, 2 or 3 substituents indepen~n~ly selected from halo, halo(Cl-C4 alkyl), Cl-C4 alkyl, Cl-C4 alkoxy, carboxy, Cl-C4 alko,~y~;albonyl, carbamoyl, N-(Cl-C4 alkyl)carbamoyl, amino, Cl-C4 alkyl~mino, di(Cl-C4 alkyl)amino or ~(CH2)a-l~Y where a is 1, 2, 3 or 4 and RY is hy~ y~ Cl-C4 alkoxy, carboxy, Cl-C4 alk~yc~ll)onyl, amino, carbamoyl, Cl-C4 alkylamino or di(Cl-C4 alkyl)amino.
"Cl-C6 alkylzlmino" represents a straight or br~n-hefl alkyl~m;no chain having from one to six carbon atoms ~tt~ched to an amino group. Typical Cl-C6 alkyl-amino groups include methyl~mino, ethyl~minc-, propyl~mino, iso~lv~yl~mino, butyl~mino, sec-butylamino and the like. "Cl-C6 alkylamino~ ~ncomrasses within this term "Cl-C4 alkyl~m;no~.
~Cl-C6 alkoxy~ represents a straight or br~nohe~ alkyl chain having from one to six carbon atoms attached to an o~y~ell atom.
Typical Cl-C6 alkoxy groups include methoxy, ethoxy, propoxy, 3 o isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term ~Cl-C6 alkoxy" includes within its definition the term ~Cl-C3 alkoxy".
"C2-C7 alkanoyl~ represents a straight or branched alkyl chain having from one to six carbon atoms iqtt~hed to a carbonyl moiety. Typical C2-C7 ~lks~nf~yl groups include ethanoyl, propanoyl, W O 97/25041 PCT~US97/00511 isopropanoyl, butanoyl, t-butanoyl, pentP~noyl~ he~noyl, 3-methylpent~noyl and the like.
"C1-C6 alkoxycarbonyl" represents a straight or branched alkoxy chain having from one to six carbon atoms 2st~ hed to a carbonyl 5 moiety. Typical Cl-C6 alkoxycarbonyl groups include metho~yc~l~onyl, etho~y~ onyl, propo~y~bonyl, isopropo~yca.bonyl, buto~ycalbonyl, t-but~yc~Lbonyl and the like.
"C3-Cg cycloalkyl" represents a saturated hydrocarbon ring structure cont~inin~ from three to eight carbon atoms. Typical C3-Cg îO cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
In those substitl~*ons employing nAphthyl, naphthyloxy, n~I~ht.~nyl, or the like groups, the n~I ht.l~yl moiety may be attached at the one, two, or three position.
The term "heterocycle" represents an unsubstituted or substituted stable ~;- to 7-mPmhered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated and which consists o~
carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and 20 sulfur hetero~t~m~ may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized and including a bicyclic group in wh;ch any of the above-.lefinetl heterocyclic rings is fused to a b~n~ene ring. The heterocyclic ring may be ~tt~ch~d at any heteroatom or carbon atom which affords a stable structure. The hetero-cycle is unsubstituted 25 or substituted with 1, 2 or 3 subs+itllen+~ indep~n~ently selected from halo, halo(Cl-C4)-alkyl, Cl-C4 alkyl, Cl-C4 alkoxy, calbo~y, Cl-C4 alkoxy-carbonyl, carbamoyl, N-(C1-C4)-alkylcarbamoyl, amino, C1-C4 alkyl~mino, di(C1-C4)alkyl~mino or -(CH2)a-Rd where a is 1, 2, 3 or 4;
and Rd is hyJ~o~y, Cl-C4 alkoxy, carboxy, Cl-C4 alkoxycarbonyl, amino, 3 ~ carbamoyl, C1-C4 alkylAmino or di(C1-C4)alkyl~mino.
The term "llns~tllrated heterocycle" represents an unsubstituted or substituted stable ~i- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which has one or more double bonds and which consists of carbon atoms and from one to three 3 5 heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally W O 97/25041 PCT~US97/00511 be oxidized, and the nitrogen heteroatom may optionally be quarternized and including a bicyclic group in which any of the above-defined heterocyclic rings is fused to a bçn7ene ring. The lln.~Atllrated heterocyclic ring may be Att~-~he-l at any heteroatom or carbon atom 5 which affords a stable structure. The l1n~A~ a~ed heterocycle is unsubstituted or sul)~ u~ed with 1, 2 or 3 substitllen~ indepentl~ntly selected from halo, Cl-C6 haloalkyl, Cl-C4 alkyl, Cl-C4 alkoxy, carboxy, Cl-C4 alko~yc&ll,onyl, carbamoyl, N-(Cl-C4)alkylcarbamoyl, amino, Cl-C4 alkylAmin-~, di(Cl-C4)alkylAmino or -(CH2)a-Re where a is 1, 2, 3 or 4;
10 and Re is hyd~oxy, Cl-C4 alkoxy, carboxy, Cl-C4 A~kokyc~llbonyl, Amino, carbamoyl, Cl-C4 alkylArnino or di(Cl-C4)alkylAmino.
h'.~Amrles of such heterocycles and unsaturated heterocycles include piperidinyl, piperazinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, 15 imitlA7olinyl, imidazolidinyl, pyridyl, pyrazinyl, ~yl~idinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, t~i~7O1i~inyl~ isothiazolyl, quinl1rli~inyl, isothiA7oli(1inyl, indolyl, qninolinyl~ isoqninolinyl, ben7imidazolyl, thiAAiA70lyl, ben;~o~yl~lyl, benzothiA7olyl, ben7o~7olyl, furyl, 20 tetrahy~orulyl, tetrahyJlo~ylal-yl, thienyl, benzothienyl, thiAmorpholinyl, thiAmorpholinyl-sulfoxide, thiamorpholinylsul~one, o~A~ olyl, triazolyl, tetr~ydroqllinolinyl~ tetrahydrisoquinolinyl, 4,~-dihydrofhi~7Qlyl, 3-methylimi~A7olyl, 3-met~o~cy~y~;dyl, 4 chloroqllinolinyl, 4-aminothiA7.olyl, 8-methylqninolinyl, 6-25 chloroqlfino~Alinyl, 3-etLyl~y..dyl, 6-methoxyben7.imidazolyl, 4-hydiol~yrulyl, 4-methylisoqllinolinyl, 6~8-dibromoqllinolinyl~ 4,8-dimethyl-nArht~yl, 2-methyl-1,2,3,4-tetrahydroisoqllinolinyl, N-methyl-qllinolin-2-yl, 2-t-butoxycarbonyl-1,2,3,4-isoqllinolin-7-yl and 3 o the like.
The te~n "amino-protecting group" as used in the sper~ificAt;on refers to substituents of the amino group commnnly employed to block or protect the mino ~unctionality while reacting other functional groups on the compound. h'~Arnrles of such 35 amino-protecting groups include for_yl, trityl, ph~l~Alimi~lo, trichloroacetyl, chloroacetyl, br--moAcetyl, iodoacetyl, and urethane-type W O 97/2S041 PCT~US97/00511 blocking groups such as benzylo~ycall)onyl, 4-phenylbenzylo~y~ ~bonyl, 2-methylbenzylo~y~ onyl, 4-methoxybenzylo~ycdl l)onyl, 4-fluorobenzylo~y.,all,onyl, 4-chlorobenzylu~y~all,onyl, 3-chlorobenzylo~y~l)onyl, 2-chlorobenzylokyc~hlJonyl, 5 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzylo~ycall,onyl, 3-bromobenzyloxycarbonyl, ~nitrobenzylo~y~allJonyl, 4-cyanobenzylo~yc~bonyl, t-buto~yca~lJonyl, l,l-rliph~nyleth-l-ylo~ycall,onyl, l,~ phenyllJlo~-l-ylo~ycall)on 2-phellyl~ -2-ylo~y~l~onyl, 2-(p-toluyl)-prop-2-ylo~y. all~onyl, 10 cyclopentanyloxycarbonyl, l-methylcyclopentanyloxycarbonyl, cycl~hç~nylogycarbonyl, 1-methylcyr.lohe~nylo~yca~l~onyl, 2-methylcyclohe~nylu~yc~bonyl, 2-(4-toluylsulfonyl)-etho~y~;~lJonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphimo)-ethoxycarbonyl, fluorenylmethoxy-carbonyl 15 ("FMOC~), 2-(trimethylsilyl)etho~y~ onyl, allylo~y.a.l,onyl, 1-(trimethylsilylmethyl)prûp- 1-enylo~yca~ bonyl, ~;-benzisoxalylmethoxycarbonyl, 4-acetoxybenzylo~ycalbonyl, 2,2,2-trichloroetho~y~l)onyl, 2-ethynyl-2-propo~y~all)onyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, 2 o isobornylo,~y~all,onyl, 1-piperidylo~yca,bonyl and the like;
benzoylmethylsulfonyl group, 2-nitrophenylsulfenyl, diphenylphosphin o~ide and like amino-proteC~in~ groups. The species of ~mino-protecting group employed is usually not critical so long as the derivatized amino group is stable to the condition of subsequent 25 re~ction~ on other positions of the intermediate molecule and can be selectively removed at the a~ ol~l;ate point without di~. u~ g the r.qm~in~er of the molecule inr.lll~inE any other amino-protecting groups. r~felled amino-protec~inF groups are trityl, t-butu~yca~l)onyl (BoC), allylo~y. all,onyl and benzyloxycarbonyl. Further e~mrles of 3 0 groups 1 erellad to by the above terms are described by E. ~ m, "Protective Groups in Organic Chemist~, (J.G.W. McOmie, ed., 1973), at Chapter 2; and T.W. Greene and P.G.M. Wuts, PROTECTIVE GROUPS
IN ORGANI~ SYNTHESIS, (1991), at Chapter 7.
The term "carboxy-protect.in~ group" as used in the 3 5 specification refers to substituents of the carboxy group commonly employed to block or protect the carboxy functionality while re~ctinF

W O 97/25041 PCTnJS97/00511 other functional groups on the compound. F~Amrles of such carboxy-protecting groups include methyl, p-nitrobenzyl, p-methylbenzyl, p-methoxy-benzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, s p~nt~methylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-metho~y~ yl, 4,4'-dimetho~yl~;~yl, 4,4',4"-trimethoxy~rityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, 10 2-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, I~.innzlmyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl and like moieties. rle~e. led carboxy-protecting groups are allyl, benzyl and t-butyl. Further mples of these groups are found in E. ~lAm, sul?ra, at Chapter 5, 15 and T.W. Greene, ~, supra, at Chapter 5.
The term "hydroxy-protecting groups" as used herein refers to substitents of the hy~l~o~y group comm- nly employed to block or protect the hy~l~ol~y functionAlity while reActin~ other fi~nct;onAl groups on the compound. ~.~rAmples of such hy~ol~y-protecting groups include 20 methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methylf lti orn ethyl, 2,2-dichloro- 1,1-difluoroethyl, tetrahyd~ yl~nyl, phçn~cyl, cyclc,~ ylmethyl, allyl, Cl-C6 alkyl, 2,6-dimethylbenzyl, o-nitrobenzyl, 4-picolyl, dimethylsilyl, t-butyldimethylsilyl, levlllin~qte, pivaloate, benzoate, ~limet~ylsulfonate, 25 dimethylphosphinyl, isol)ul,y.ate, a~ nt~slte and tetrahyLo~ylallyl.
Further ç~mples of these groups may be found in T. W. Greene and P.G.M. Wuts, PROTECTrVE GROUPS IN OR~A~C SY1NTHESIS,(1991) at Chapter 3.
The compounds of the present invention may have one or 3 o more asymmetric centers. As a consequence of these chiral centers, those compounds of the present invention occur as r~c~m~tes, mixtures of çns~ntiomers and as individual enS~ntinmers~ as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual isomers and combinations thereof, are within the scope of the present 3 s invention.

W O 97~SO41 PCT~US97/00511 The terms "R" and "S" are used herein as commoIlly used in organic ~hemi~try to denote specific configuration of a chiral center.
The term "R" (rectus) refers to that configuration of a chiral center with a clockwise rel~t.ion~hip of group priorities ~highest to second lowest) 5 when viewed along the bond t~,v~d the lowest priority group. The term ''S~ (sinister) refers to that configuration of a chiral center with a counterclockwise rçl~*orl.~hip of group priolities thighest to second lowest) when viewed along the bond toward the lowest priority group.
The priority of groups is based upon their ~t~mic number (in order of 10 decreasing atom-ic number). A partial list of priorities and a discussion of stereoche_istry iB cont~in~rl in NOMENCLATURE OF ORGANIC
COMPOUNDS: PRINCIPLES AND PRACTICE, (J.H. Fletcher, et al., eds., 1974) at pages 103-12(?.
In ~iti~n to the (R)-(S) system, the older D-L system may 15 also be used in this docnment to denote absolute configuration, especially with reference to amino acids. In this system a Fischer projection formula is oriented so that the nlmnber 1 carbon of the main chain is at the top. The prefix ''D~iS used to represent the absolute configuration of the isomer in which the functional (determining) group 2 o is on the right side of the carbon atom at the chiral center and "L~, that of the isomer in which it is on the left.
In order to preferentially prepare one optical isomer over its enantiomer, the skilled practitioner can proceed by one of two routes.
The practitioner may first prepare the ...iX(..,e of en~ntiomers and then 25 separate the two en~ntiomers. A comml7I ly employed method for the resolution of the r~cem;c ,~;x~ e (or l~ ule of en~n*omçrs) into the individual çn~nti~mLers is to first convert the enantiomers to diastereomers by way of ~l....llg a salt with an optically active salt or base. These diastereomers can then be separated using differential 30 solubility, fractional cryst~ tion, chromatography, or ~ike methods.
Further details regarding resolution of enantiomeric ~i~ es can be found in J. Jacques, et al., ENANTIOMERS, RACEMATES, AND
RESOLUTIONS, (1991).
In addition to the srhçmes described above, the practitioner 3 5 of this i~lvel~ion may also choose an ~n~n1;Qspecific protocol for the preparation of the compounds of Formula I. Such a protocol employs a W O 97~5041 PCT~US97/00~11 synthetic reaction ~esi~n which m~int~in.q the chiral center present in the starting material in a desired orient~tion These reaction s-hemes usually produce compounds in which greater than 9~; percent of the title product is the desired enantiomer.
As noted sul~ra, this invention includes methods employing the pharmaceutically acceptable salts of the compounds defined by Formula I as well as salts of the compounds of Formula II. A
compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accoldillgly react with 10 any of a number of organic and inorganic bases, and inorganic and org~nic acids, to form a pharmaceutically acceptable salt.
The term "pharmaceutically acceptable salt~ as used herein, refers to salts of the compounds of the above forrn~ which are subst~n~i~lly non-toxic to living org~ni~mq. Typical pharmaceutically 15 acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or org~n;c acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
Acids commnnly employed to form acid addition salts are 20 inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. ~mples of such 2~ pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chlonde, bromide, iodide, acetate, propionate, rlec7lno~te, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, 30 heptanoate, propiolate, oxalate, m~lon~te, s~ cin~te, suberate, seh~c~te, fumarate, maleate, butyne-1,4-dioate, hexglle-1,6-~io~te, benzoate, chlorobenzoate, methylhen7o~te, hyJru2~yban~o~te~ methoxybenzoate, phthalate, sulfonate, xylenesnlfon~qte, phenylacetate, phenyl~ ionate, phenylbutyrate, citrate, lactate, ~-hy~o~yl~u~yl~lte~ glycolate, ta~ e, 35 methanesulfonate, propanesnlfor~S~te, n~phth~lene-1-~ulfonate~
napththalene-2-slllfon~te, m~n-lel~ta and the like. Preferred W O 97/25041 PCT~US97/00511 pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
Base addition ~alts include those derived from inorganic bases, such as ~qmmt nium or alkali or ~lk~line earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydro~ide, ~mmorium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcillm hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly ~ efelled.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, 80 long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute llnflesired qualities to the salt as a whole.
This invention further ~nComrA~ses methods employing the pharmaceutically acceptable solvates of the compounds of Formula I. Many of the compounds of Formula I can combine with solvents such as water, met~Anol, etl~nol and acetonitrile to form pharmaceutically acceptable solvates such as the correspon-ling hydrate, met~Anol~e, ethanolate and acetonitrilate.
This invention also çncomI-asses the pharmaceutically acceptable prodrugs of the compounds of Fo~mula I. A prodrug is a drug which has been çhemic~lly modified and may be biologically inactive at its site of Actinn, but which may be degraded or modified by one or more enzymatic or other ;n vivo processes to the parent hio~ctive form This prodrug should have a different pharmacokinetic profile 3 o than the parent, enabling easier absorption across the mucosal epithelium, better salt formation or solubility, or il~ oved syste~uc stability (an increase in plA~mA half-life, for ~Ample).
- Typically, such rh~mic~l mor~ificAt.ions include:
1) ester or amide del;va~ives which may be cleaved by 3 5 esterases or lipases;

CA 02242579 l998-07-08 W O 97/25041 PCTrUS97/OOSll 2) peptides which may be recognized by specific or nonspecific proteases; or 3) derivatives that accumulate at a site of action through memhrane selection of a prodrug form or a modified prodrug form;
or any comhin~tion of 1 to 3, $upra. ConventioTI~l procedures for the selection and preparation of suitable prodrug del;v~,ives are described, for ~mple, in H, Bllnrlg~s-rd, DESIGN OF PRODRUGS, (198~).
The compounds of the present invention are deliv2llives of ben7imi~ ole which are named and numbered accol lillg to the RING
INDEX, The American Chemical Society, as follows.
~>

The ~efel~ed methods of this invention employ those compounds of Formula I wherein.
a) R1 is phenyl, n~pht.hyl, phenyl(C1-C6 alkylenyl)-, naphthyl(Cl-C6 alkylenyl)-, phenyl(Cl-C6 alkoxy)-, n~ph+l~yl(cl-c6 alkoxy)-, phenoxy(C1-C6 alkylenyl)-, n~pht~yloxy(C1-C6 alkylenyl)-, or substituted de~;v~ives thereof;
b) R2 is phenyl, heterocyclic, lln.e$~t~lrated heterocyclic, phenyl(Cl-C6 alkylenyl)-, n~ph~llyl(Cl-C6 alkylenyl)-, phenyl(Cl-C6 alkoxy)-, heterocyclic(Cl-C6 alkylenyl)-, lln~t.lrated heterocyclic(Cl-C6 alkylenyl)-, heterocyclic(Cl-C6 alko~y)-, unsaturated heterocyclic(Cl-C6 alkoxy)-, -(CH2)n-NR7R8, or substituted deliv~ives thereof;
c) R3, R4, R5, and R6, are indepçn~enfly hydrogen, chloro, fluoro, bromo, C1-C6 alkyl, trifluoromethyl, Cl-c6 alkoxy, benzoyl, C2-C7 ~lk~noyl, phenyl(Cl-C6 alkylenyl)-, phenyl(Cl-C6 alkoxy)-, or -(CH2)n-NR7R8, or substituted del;v~lives thereof; and d) at least one of R3, R4, R5, and R6 is not hydrogen.
3 0 The preferred compounds of this invention are those compounds which are employed in the preferred methods of this invention.

W O 97/25041 PCT~US97/00511 In the s~ientific literature deliva~ives of b~n~irnidazole are already known to possess different biological activities, such as analgesic and ~ntiinfl~nmsltoly activity (Japan Kokai 7~,126,682; United States Patent 4,92~,853), gastric antise. let~l y activity OEuropean Patent p~lhlic~tiQn 246,126), ~nhhi~minic activity (United States Patents 4,200,641 and 5,182,280), dop~rninergic and andrenergic activity (United States Patent 4,92~,8~4), bronchodilatory activity, growth promotion (United States Pate~t 4,960,783), tachykinin receptor antagonist (United States Patent Application 08/235,401, filed April 29, 1994), and inhihitor of 10 ~-~myloid peptide production (United ~tates Patent Applic~ion 08/23~,400, f;led ApIil 29, 1994).
The compounds of Formula I can be prepared by processes known in the liteld~e. ~ee~ e.~., G.W.H. Cheeseman and R.F.
Cook~on, THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS, (A.
15 Weissberger, et al., eds. 1979).

W O 97~5041 PCT~US97/00511 Syntllefii.~ of the Ben~imitlAznle Nucleus R
R ~XNHHCl MeONa ,~N

NHo NC~ N~

Cl Syn~e~i~ of the N-l Substituted Ben7.imidazoles (Scheme I) R R
Br CH2)30H J ~ ~ O~r N~OAr 2. Br2/PPh3 >

R R
r\~ N r\~ N
~N~OAr HNR2 ~ N~OAr >

Br R2N

W O 97~5041 PCT~US97/00511 Synt~esi~ of the N-1 Substituted Ben~imirl~7:oles (Scheme II) R R
N Br(CH2)3NR2 ~
~OAr ~ ~OAr H ~>

W O 97/25041 PCT~US97/00511 Another m e~n.~ of preparing the compounds of Formula I
i8 by cy(~ stio~ of an aL)~ .iately substituted o-phenylene~ min~
such as the one depicted in Formula II

R5~NHR2 II

in a solvent or solvent mi~t.lre. It is generally ~lerelled ~hat the solvent or solvent l.n~uLe be heated, lJie~e~ably to the boiling point of the solvent. Suitable solvents include eth~nol, isopropanol, ~ 1 acetic acid, ben7ene, toluene, chloroben7ene, glycol, ethylene glycol, dimethyl ether, diethyl ether, dimethylform~ni~le~ chloroform, ethyl acetate, and the like. It is generally l~lefelfed to add a con~n~ on agent such as phosphorous oxychloride, thionyl chloride, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, phosphorous pentoxide, methanesulfonyl hydroxide, meth~nçsulfonyl chloride, and the like. The cyc~ tion re~ct.ion may also optionally be performed in the presence of a base such as sodium hydro~ide, sodium mesylate, or potassium tert-butylate.
In those compounds in which R2 is phenyl a d~livaliv~ of N-phenyl-o-phenylenerli~mine was used as the starting material for the cyc3ization re~ction The examples in~ provide sufficient guidance in the preparation of those compounds of Formula I wherein all of R3, R4, R5, and R6 are hydrogen.
Those compounds of Formula I wherein at least one of R3, R4, R5, and R6 is not hydrogen, can be prepared by methods t~llght. in the litela~ule. For ç~mIlle, the compounds of this invention wherein phenyl portion of the b~n~imidazole is substituted with C2-C7 ~lk~noyl can be prepared from the a~ .;ate keto o-phenylene~ nin~ of the 3 0 formula W O 97/25041 PCTAUS97/OOSll ~n~2 (C1-C6 alkyl)--C~NH2 by methods known in the b~n7imitlA~ole art such as the procedures described in U.S. Patent 4,401,817, issued August 30, 1983, the entire 5 cont,~nts of which are herein incorporated by reference. The method of preparation involves the Ammonolysis and reduction of a 4-halo-3-nitrophenyl ketone which is prepared by the Friedel-Crafts reaction of either a 4-halo-3-nitrobenzoyl chloride with an 2~ ;ate hydrocarbon or a halobenzene with an a~l lol liate acid chloride followed by aromAtic 10 nitration.
Alternatively, the keto bçn~imi~ ole re~ct~nts can be Jal ad from acetanilide by a Friedel-~rafts acylation with the ~. ol~,iate derivative of C2-C7 AlkAnoic acid. The resulting 4-keto acet~nili~le is nitrated to give a 2-nitro-4-ketoacet~nili~le. The acet~nilit1e 15 is hydrolyzed to give a 2-nitro-4-ketoAniline, which can then be catalytically hydrogenated to yield a 4-keto-o-phenylene~iAminç which can then be ring closed to provide the ~ or 6-substituted ben7imi~ ole.
Those compounds of Formula III wherein phenyl portion of the b~n~imirlA7:0le is substituted with alkyl or alkylenyl may be prepared 2 0 by meAn~ of a Friedel-Crafts alkylation with the a~ ;ate deriv2li ive of the sub~ ulillg moiety using standard procedures, usually employing an alkyl halide or an olefin in the presence of a catalyst such as aluinu_ chloride, alllminllm bromide or another Lewis acid.
An alternative strategy for preparing those compounds of 25 FnrrnlllA I wherein R~ is Cl-C6 alkoxy, R7R8N-(Cl-C6 alkoxy)-, or heterocyclic-(C~ 6 alkoxy)-, or a substituted del;v~ive thereof, involves first reAct.in~ a 3-nitro-4-a_inophennl with an acyl halide in the presence of a base CA 02242579 l998-07-08 W O 97~5041 PCT~US97/OOSII

E~OJ~( base ~¦~NO~

Rl,C~o to get substitution of the primary amine as well as substitution of the hydroxy group, the ester moiety serving as a hyLo~y-protecting group 5 for subsequent re~qc~;on~. In the next step of this syn+~esi~ the nitro group is then reduced to an amino group, usually by catalytic hydrogenation.

o,¢~ H2, Pd/C ~, Rl~ ~0 Rl_C~o The primary amine of the above compound is then substituted, usually using an aldehyde, such as benzaldehyde or a substituted der lva~ive thereof, followed by hydrog~n~tiPn, if necessary.
In an alternative embodiment, those compounds of Formula I in which 15 R2 is alkyl or substituted alkyl may be produced by alkylation of an aromatic amine with alkyl halide or tosylate, or the like, in the presence of a suitable base, such as t~ialkyl~mine, potassium carbonate, 1,8-hicyclo[~i.4.0]undec-7-ene (DBU), and the like.

,~N ,R

NH2 H2, Pd/C I NEI
2 o 1,C~O Rl,C~O R2 W O 97/25041 PCTrUS97/OOsll Cyclization of this substituted phenylene~i~mine is then performed as described supra, followed by cleavage of the ester group protecting the hy~o~y group at the 6-position of the ban~imirl~ole. Suitable cyclization catalysts include phosphorous oxychloride, thionyl chloride, 5 phosphorous pento~ide, phosphorous p~nt~hloride, and other like strong dehydrating agents.

~ 2 NaOH ,~CN\>--R
l'C~~ R2 R2 10 A preferred method of cleaving this ester is by incubation of the intermediate in a basic solution, such as lN sodium hydroxide, or a weaker base such as potassium carbonate. The hydroxy group at the 6-position is then substituted using an alkyl or aryl halide, resulting in a compound of Formula I.

HO~CNR>--Rl alkyl or alyl halide J~CRN\>--R

The skilled artisan understands that compounds of Formula I ~ubstitlltetl at the ~-position of the b~n7imidazole can be 20 prepared as described above by employing 3-amino-4-nitrophenol as the starting material instead of the 3-nitro-4-aminoph~nol shown supra.
Those compounds of Formula I wherein R2 is alkyl or substituted alkyl may alternatively be prepared by the direct alkylation of a benzirnidazole wherein the nitrogen at the 1-position is substituted 2 5 with a hydrogen. This type of alkylation is usually performed by the re~ction of the bçn~imitl~ 31e vwith an alkyl halide in the presence of a strong base, such as sodium hydride. This reaction is usually performed in a polar aprotic solvent, such as N,N-dimethylform~mi-le, W O 97/25041 PCT~US97/00511 dimethyl sulfoxide, dimethylacet~mi~, he~methylphosphoric triamide, and the like.

The following ~.~Ample~ filr~her illustrate the compounds of 5 the present invention and the methods for their synthesifi. The mples are not inten~e(1 to be l;..~;l.;..~ to the scope of the invention in any respect, and should not be so construed. All exp~r-mçnts were run under a positive pressure of dry nitrogen or argon. All solvents and reagents were purchased from commercial sources and used as 0 received, unless otherwise indicated. Dry tetrahy~l,o~ (THF) was obtained by distillAt.ion from sodiu_ or sodium benzophenon.q ketyl prior to use.
Proton nllr.le~r ms~gn~tic resonance (lH NMR) spectra were obtained on a GE QE-300 spectrometer at 300.15 MHz, a Bruker AM-600 spectrometer at 600 MHz, or a Bruker AC-200P spectrometer at 200 M HZ.
(Unless ~e~ign~ted otherwise, the term "NMR" as employed herein refers to proton nuclear Tn~gn~tic reson~nce.) Free atom bombardment mass spectroscopy (FAB) was performed on a VG ZAB-2SE instrllmen~
Field desorption mass spectroscopy (E'DMS) was performed using either a VG 70SE or a Varian MAT 731 instrllm-ont Optical rotations were measured with a Perkin-Elmer 241 polarimeter. Chromatographic separation on a Waters Prep 500 LC was generally carried out using a linear gradient of the solvents in-lic~terl in the text unless otherwise specified.
The reactions were generally monitored for completion using thin layer chromatography (TLC). Thin layer chromatography was performed using E. Merck Kieselgel 60 F2s4 plates, ~i cm x 10 cm, 0.25 mm thi~ kness. Spots were detected using a comhin~tion of W and ~.hemiç~l detection (plates dipped in a ceric ammonium molybdate 3 0 solution [75 g of ~mmonium molybdate and 4 g of ce. i~ (IV) sulfate in ~001 of 10% aqueous sulfuric acid~ and then he~te~l on a hot plate).
Preparative centrifugal thin layer chromatography was performed on a Harrison Model 7924A Chromatotron using Analtech silica gel GF
rotors.
3 5 Cation exchange chromatography was performed with Dowex(~) 50X8-100 ion e~rh~nge resin. Aniorl e~rrh~nFe W O 97~5041 PCTrUS97/00511 chromatography was performed with Bio-Rad AG~) l-X8 ~nion-e~çh~n~e resin (acetate form col~vel~ed to h~oxide form). Elash chromatography was performed a~ described by Still, .et al., Journal of Or~nic Chemistry,43:2923(1~78).
Optical rotations are reported at the sodium-D-line (3~4 nm) ~.lçment7~1 analyses for carbon, hydrogen, and nitrogen were determined on a Control Eq7lipmçnt Corporation 440 ~,lçmçnt~l Analyzer. Melting points were determined in open glass c~pill~ries on a Thomas Hoover ç~p;ll~ry melting point apparatus or a Buchi melting 10 point apparatus, and are uncoll~c~ed.

General Procedure for B~n~imidazole Synthesis R~ MeOH G~ NH2 HCl NH2 NHa-HCl NH2 HCl Cl~ ~o ,~} Cl NH2 HCl MeONa /MeOH H

To a 0.4 M solution of the optionally substituted 1,2-flis~minQben7:en~ in methanol, anhydrous hydrogen chloride gas was bubbled until saturation. The solution was permitted to cool to room tempe.d~,ule. The precipitate was collected, dried and then used in the 2 o next step.
A solution of 4-chloroI7heno~ynitrile (1.05 eq) in dry methanol (0.3 M) was treated with sodium methl)~i.1e (1.05 eq). The e was stirred at room tempeldLu~e. The mi~+nre was treated with the dihydrochloride salt of the ~i~mine (1.0 eqL) and stirred at room 2 5 tempeld~ul e for about one hour. In most of the cases the precipitate was observed upon addition. The crude cyrstals were washed with diethyl ether and dried in vacuo.

W O 97~5041 PCT~US97/00511 VVhne ~liAminotoluene was treated with 4-chlorophen-)xyl~iL,;le there was no pre~.ipit~te observed immediately.
The reaction ~ e was condensed under vacuum. The crude brownish solid was dissolved in ethyl acetate. The resulting solution 5 was washed with water, then brine, and then dried over sodium sulfate.
The solvents were then removed in vacuo to produce brown crystals with a good yield.

Pre~ar~tion 1 Preparation of 2-benzylb~n7imitl~7.01e ~ NH2 S HCl(g) ~ ~

A 1 M solution of benzyl cyanide in anhydrous methanol was treated with hydrogen chloride gas at 0~C for about thirty _inutes.
The ~ e was stirred for two hours at 0~C and then a 1 M solution of minobenzene was added and the resulting solution was stirred at 0~C. The progress of the reaction was monitored by thin layer 20 chromatography. The reaction ~ e was then poured into water.
The unreacted nitrile was extracted with ethyl acetate. The aqueous layer was neutralized with 1 N sodium hyd~ ide. The organic firaction was extracted with ethyl acetate and conllan.~ed. The desired title product was recryst~lli7:ed from meth~nol/water.

Pre~aration 2 Preparation of 2-(4-chlorophenyl)ben ~i mi dazole ;

W O 97/2~041 PCTAUS97/00511 ~ ~ MeOH 0~C ~ ~ Cl The title compound was prepared essent.i~lly as described in Preparation 1 except that an eq7limok7r amo7lnt of 4-cblorobenzonitrile was employed instead of the benzyl cyanide employed 5 therein.

Preparatio l 3 Preparation of 2-(4-chlorobenzyl)ben~imidazole 2 < HCl (g) ~ N

Cl HN
The title compo7lnd was prepared essentially as described in Preparation 1 except that an eqnimol~r amount of 4-cnlorobenzyl cyanide was employed instead of the benzyl cyanide employed therein.

Prep,7ration 4 Preparation of 2-(benzylogymethyl)-7-hydlo~y7l)~n~imidazole ~ NH2 ~ NaHCO3 r ~o ~ H

W O 97/25041 PCT~US97/OOSll A ~ u~e of the 2,3~ min~phenol (6 g, 40.3 mmol, 1 eq) and benzyloxyacetic acid (5.6 g, 48.3 ~nol, 1.2 eq) in 40 ml of a 10%
aqueous solution of sodium bicarbonate was stirred and re~u~ed at 140~C for one hour. The ..-;xl ..e was allowed to cool down to room 5 temperature. Ethyl acetate was poured into the ...; xl-.. e. The organic fraction was extracted with ethyl acetate, washed with water, and then dried over sodiu_ sulfate. The solvents were removed in vacuo. The crude product was further purified by flash chromatography to yield 6.87 grams (67% yield) of the desired title product.
The following interrne~ tes were prepared essentially as described above.

PreDaration 5 Preparation of 6-methyl-2-(4-chlorophenoxymethyl)beI~7imidazole H3C ~ ~ O ~
H

2 o :~ and NMR were consistent with the desired title product. FDMS 272 (M~).

Preparation 6 25 Preparation of 2-(4-chloropheI o~ymethyl)ben7.imidazole Cl N

IR and NMR were consistent with the desired tit~le product. FDMS 2~8 (M+).

Prepar~1ion 7 Preparation of 2 -(4-chlorophenoxymethyl )-7-nitrob~n ~i mi dazole ~ N ~ O

10 IR and NMR were consistent with the desired title product. FDMS 303 (M+).

Prep~ration 8 15 Preparation of 2-(4-chlorophenl)~ymethyl)-6-methoxyb~n~imidazole H3CO ~ ~ O ~ Cl H

IR and NMR were consistent with the desired title product. FDMS 288 20 (M+).

Pre~aration 9 Preparation of 2-(4-chloropheno~ymethyl)-6,7-dimethylben~imidazole H3C ~ ~ Cl .~ N

-3~-NME~ was consistent with the desired title product.

Pre;Daration 10 Preparation of 2-(4-chlorophenoxymethyl)-7-methylbçn7.imidazole ~ ~ Cl M

10 NMR was consistent with the desired title product.

Preparation 11 Preparation of 2-(4-chloroph~no~ymethyl)-6-15 methoxycarbonylben7:imidazole H3C' ~ N ~ O Cl 1.9 grams (67% yield).
Preparation 12 Preparation of 2-(4-chlorophenn~ymethyl)-7-hydroxybçn~imidazole ~ ~ Cl N

HO H

W O 97/25041 PCT~US97/00511 NMR was consistent with the desired title product. Yield ~.3 grams (91%).

Pre~aration 13 Preparation of 2-benzylben~ ole H ~

10 NMR was consistent with the desired title product. Yield 1.26 grams (14%).

Preparation 14 15 Preparation of 2-(3-chloropheno~rmethyl)berl~imidazole O~C 1 N

NMR was consistent with the desired title product. Yield 1.~ grams 2 o (>99%).

Preparation 15 Preparation of 2-(2-chlorophenoxymethyl)ben~imidazole N Cl W O 97/25041 PCT~US97/OOSII

NMR was consistent with the desired title product. Yield 1.36 grams (gl%).

Preparation 16 Preparation of 2-(4-chlorophenyl)ben ~i mi dazole ~ ~ Cl Prel?aration 17 Preparation of 2-(4-chlorobenzyl)ben~imid~ole ~ ~ Cl H
NMR was consistent with the desired title product.

Pre~aration 18 Preparation of 2-(phenoxymethyl)ben~imidazole ~ 0~

25 NMR was consistent with the desired title product. Yield 1.06 grams (65%).
Prel~aration 19 W O 97~5041 PCTAUS97/OOSII

Preparation of 2-(3,5-dichlorophenoxy~ethyl)ben~imi-1~7O1e Cl O~C 1 H

IR and NMR were consistent wi~h the desired t;tle product. Yield 0.28 grams (>99%). FDMS 292 (M+).
Analysis for Cl4HloCl2N20:
Theory: C, 57.36; H, 3.44; N, 9.56.
~ound: C, ~i7.46; H, 3.48; N, 9.41.

Preparation 20 Preparation of 2-(3,5-dichlorophenoxymethyl)-7-methylben7:imidazole O~C 1 ~3C H

IR and NMR were consistent with the desired title product. Yield 0.448 grams (75~). FDMS 306 (M+).
20 Analysis for ClsHl2Cl2N2O:
Theory: C, 58.65; H, 3.94; N, 9.12.
Found: C, 58.45; H, 3.95; N, 9.18.

Pre~aration 21 Preparation of 2-(3,5-dichlorophenoxy_ethyl)-7-hy~l~ o~yl)~n ~imi~ ole HO N

IR and NMR were consistent with the desired title product. Yield 0.46 graIns (78~). FDMS 308 (M+).
5 Analysis for C~ ocl2N2o2:
Theory: C, 54.39; H, 3.26; N, 9.06.
Fouund: C, 54.26; H, 3.22; N, 8.99.

Pre~aration 22 Preparation of 2-[4-(t~ ol-2-yl)phenogymethyl]-b~n~imidazole ~ 0~

15 NMR was con.~ tent with the desired title product. Yield 2.7 grams (>99%).

Preparation 23 2 o Preparation of 2-[3-chlorophenoxymethyl]-7-methylben ~mi dazole Cl ~0~ ~

W O 97/25041 PCT~US97/00511 NMR was consistent with the desired title product.

Pre~aratio~ 24 5 Preparation of 2-[3-chloropheno~ymethyl3-7-hydroxyberl7imidazole Cl N

HO H

NMR was consistent with the desired title product. Yield 1.5 gr~ms 10 (>99%).

Prel~aration 25 Preparation of 2-[1,6-dichloroI)heno~ymethyl]b~n~iTnidazole Cl H Cl IR and NMR were consistent with the desired title product. Yield 0.27 grAlns (~99%). FDMS 292 (M+).
20 Analysis for Cl4EloCl2N2O:

Theory: C, 57.36; H, 3.44; N, 9.50.
Found: C, 57.50; H, 3.43; N, 9.54.

r~ ; on 26 Preparation of 2-~l~6-dichlorophenoxymethyl~-7-methylben~iTn~ ol e W O 97/25041 PCT~US97/00511 ~ Cl H3C H Cl IR and NMR were consistent with the desired title product. Yield 0.5 grams (94%). FDMS 306 (M+).
5 Analysis for ClsHl2Cl2N2O:
Theory: C,58.65; H,3.94; N, 9.12.
Found: C,58.36; H,3.92; N, 9.32.

Preparation 27 Preparation of 2-[1,6-dichlorophenoxymethyl]-7-hy~o~ylJ~n7imidazole ~ Cl HO H Cl 15 IR and NMR were consistent with the desired title product. ~leld 0.52 grams (88%). FDMS 308 (M~).
Analysis for Cl4HloCl2N202:
Theory: C,64.39; H,3.26; N, 9.06.
Found: C,54.51; H,3.22; N, 9.22.
Prel~aration 28 Preparation of 2-~3-trifluoromethylpheno~ymethyl]-bçn7.imi~7ole ~ ~ G ~ CF3 N

H

W O 97~5041 PCT~US97/00511 N~ was consistent with the desired ti~e product. Yield 0.62 grams (ss~).

Pre}; arati--n 29 Preparation of 2-[3-trifluoromethylphenoxymethyl]-7-methylbe~ 7imi dazole NMR was consistent with the desired title product.

Prep~ration 30 15 Preparation of 2-[4-chlorophenoxymethyl] -6-chloroben 7.imi dazole Cl ~ ~ C
N

NMR and IR were consistent with the desired title product. Yield 8.20 20 grams (>99%). FDMS 292 (M~).

Preparation 31 Preparation of 2-[4-chloropheno~ymethyl]-~,6-dichloroben~imidazole X~ ~

W O 97/25041 PCTnUS97/00511 NMR and IR were consistent with the desired title product. Yield 9.20 grams (>99%). FDMS 328 (M+).

Preparation ~

Preparation of 2-~4-chlorophPno~ymethyl]-5,6-dimethylbçn7.imi~ ole E~ OJ~

NMR and IR were consistent with the desired title product. Yield 4,4 grams (52%). FDMS 286 (M+).

Preparation 33 Preparation of 2-[4-chlLoropheno~rymethyl~-4,5,6,7-tetramethylben 7.imi dazole H3C ~ ~ O
N

NMR was consi~tent with the desired title structure. Yield 0.~ grams (38%).

Prel; aration 33 Preparation of 2-[4-chlorophenoxymethyl]-6-(t-butyl)ben7im~ 7~ole CA 02242579 l998-07-08 W O 97/25041 PCTfUS97/00511 H3C ~ ~ Cl NMR was consistent with the desired title product. Yield 1.5 gra~
(40%).

Preparation 34 Preparation of 2-~,4-dichloropheno~ymethyl]bçn7.imidazole ~ ~ Cl H Cl IR and NMR were consistent with the desired title product. Yield 6.7 grams (96%). FDMS 292 (M+).
Analysis for C ~ oC12N20:
Theory: C, 57.36; H, 3.44; N, 9.56.
~ound: C, 57.11; H, 3.64; N, 9.31.

Preparatinn 35 2 o Preparation of 2-l[2,4-dichloropheno~rymethyl]-5,6-dichloroben7imidazole Cl ~ ~ Cl N cl ..
Nl~R and IR were consistent with the desired title product. Yield 3.2 2s grams (91%).

W O 97/2~041 PCT~US97/OOSll Prer~ration 36 Preparation of (3'R) ethyl 2-(piperidin-3-yl)acetate ~ ~ ~~" CH3 ~NJ
H
Ethyl-3-pyridylacetate (lOOg, 0.606 mol~ was dissolved in ethanol (1.8 liters), treated with 5% rhodium on all~mina (100 g) and hydrogenated at 60~C and 60 psi hydrogen gas overnight. The catalyst 10 was removed by fi~tration and the solvent evaporated to give a brown liquid (101.4 g, 98%). The brown liquid was dissolved in ethyl acetate (600 ml) and treated with L-(+)-m~n-lelic acid in warm ethyl acetate (600 ml).
After cooling in the refrigerator for four hours, the solid was collected and the cryst~ ion fluid reserved for processing to the other 15 enantiomer, infra. The solid was again recrystallized from ethyl acetate (1.5~;-1.6 liters, overnight at ambient tempe~a~u~e) to give the desired title product as white needles. ~leld: 81.6, 41%.
O.R. (EtOH) ~589 nm = +44.9~, ~365 nm = +173.73~. mp 118-119~C.

Pren~ration 37 Preparation of (3'S) ethyl 2-(pipendin-3-yl)acetate ~ O~_ " CH3 J
N

The cryst~ ;on fluid from Preparation 36, su;~ra, was evaporated to give a dark oil (100.3 g). This was dissolved in a cold solllt;on of potassium carbonate (52 g, 0.377 mol) in water (250 1) and extracted with ethyl acetate ~5 x 150 ml). The extracts were comhiner~
3 o and dried over m~nesium sulfate. The solvents were removed in vacuo W O 97/2S041 PCT~US97/00511 to give a dark liquid (40.2~i g3. The dark liquid was treat,ed wit~ a warm solution of D-(-)-mslntlelic acid (36 g) in ethyl acetate (650 ml) and cooled at a_bient tempe~ s overnight. The crystals were recrystallized twice more from ethyl acetate (1.2 liters and 1.1 liters, respectively) to give ~he desired title product as white needles. Yield: 48.7 g, 24.9%.
O.R. OEtOH) ~589 nm = -43.14~, ~365 nm = -164.31~. mp 115.5-117~C.

Chiral ~n~ l Methof~

Cold a~ueous potassium carbonate (0.15 g in 10 ml of water) was treated with 0.3 g ofthe m~nrle.lic acid salt and the ~;xl~..e was extracted with ethyl acetate (3 x ~ ml). The comhined extracts were dried over m~nesium sulfate and the solvents were removed in vacuo. The residue was dissolved in diethyl ether (10 ml~ and treated with S-(-)-a-methylbenzylisocyanate (0.121). After 2.5 hours, the re~ction was treated wtih 1 N hydrochloric acid (2 ml). The ether was separated and then washed seqllenti~lly with brine, a saturated aqueous sodium bicarbonate solution, and brine. The organic fiaction was dried over m,q~nesium sulfate and the solvents were removed hy evaporation. The residue was analyzed on a CHIRA(~EL OJTM high perform~nce liquid chromatography colulnn (4.6 x 250 mm), eluting with ~% et~l~nnl in he~nes at a flow rate of 2.~ ml/minllte. The slower component comes from the l-(+)-m~n~lelic acid salt and the faster from the d-(-)-m~n-lelic acid salt. ~lPLC analysis of the final crys~ tion products of both enantiomers show less than three percent of the opposite enantiomer.

Preparation 38 Preparation of (3'R) ethyl 2-[N-(t-butl ~yca~l~onyl)piperidin-3-yl]acetate ~ ~ O~_ " C~3 J
Boc W O 97/25041 PCT~US97/OOSll (3'R)-Ethyl-2-(piperidin-3-yl)acetate (10.9 g, 34 mmol) as prepared in Preparation 36 was dissolved in 60 ml of a 125b sodium carbonate in water solution and the resulting solution was extracted with chloroform. The extracts were dried and the solvents removed by evaporation. The residue was suspended in diethyl ether, filtered, and evaporated to give the free base (5.36 g). The liq~ud was dissolved in ether (50 ml) and treated L-)~wise with di-t-butyldicarbonate (7.9 g) in ether (10 ml). After stir~ing overnight, the solution was cooled in an ice water bath and treated Lv~wise with saturated aqueous citric acid (25 ml). The aqueous fraction was extracted with diethyl ether. The organic fractions were con~hine.l, washed with water, a saturated sodium bicarbonate solution, and then brine, and then dried over m~gnesium sulfate. The solvents were removed in vacuo to give the desired title product was a clear liquid. NMR was consistent with proposed title structure.

Preparation 39 Preparation of (3'S) ethyl 2-[N-(t-butoxycarbonyl)piperidin-3-yl]acetate ~ O~_ " CH3 ~ J
N
Boc (3'S)-Ethyl-2-(piperidin-3-yl)acetate (48.6 g, 1~iO m mol), as plelJaled in Preparation 37, was treated with a solution of potassium carbonate (30 g, 0.217 mol) in water (220 ml) and the resulting solution was extracted with chloroform (3 x 100 ml). The extracts were dried over sodium sulfate and the solvents were removed in vacuo. The residue was mixed with diethyl ether (200 ml) and filtered to remove some suspended solids. Evaporation of the e~er gave a L~lowl.-sh liquid (2~ g, 3 0 Theory = 25.7 g). The residue was dissolved in diethyl ether (200 ml), cooled in an ice water bath, and a solution of di-t-butyldicarbonate (31.8 g, 0.146 mol) in ether (25 ml) was added d~ wise with stiITing. Cooling W O 97/25041 PCT~US97/00511 was removed and reaction was stirred overnight. The solution was gain cooled ;n ice water and a solution of saturated aqueous citric acid (100 ml) was added dL~-vise. The organics were washed with brine, a saturated aqueous sodium bicarbonate solution, the brine, and then 5 dried over sodium sulfate. The solvents were removed in vacuo to give the desired title product as a clear liquid (38.6 g, >99%). NMR was consistent with desired title structure.

Preparation 40 Preparation of (RS) ethyl 3-[pyrid-3-yl]prop-2-enoate o A solution of ethylphosphinoacetate (98.6 g, 0.44 mol) in dry tetrahy~o~u.dll (1200 ml) was treated with 60% sodillm hydride (17.5 g, 0.44 mol). The ~l ule was stirred at room temperature for two hours and was then cooled down to 0~C. To this ~..i x 1-. . e 3-pyridine carboxaldehyde (38.9 g, 0.36 mol) was added and the resulting reaction 20 ~ e was stirred for 1'2 hours while warming to room temperature.
The progress of the reaction was monitored by thin layer chromatography.
Water (1000 ml) was added to the reaction ..~;xl ..e. The organic fraction was extracted with ethyl acetate (3 x 1000 ml). The organic fr~ction~ were comhined, washed with water (2 x 1000 ml), brine (1 x 1000 ml), and the dried over sodium sulfate. The solvents were removed in vacuo to yield 62.~; grams (97%) of the desired title product.

Preparation 41 Preparation of (RS) ethyl 3-[piperidin-3-yl}propionoate L

W O 97t25041 PCT~US97/00511 o ~CH3 A solution of (RS3 ethyl-1-[pyrid-3-yl]prop-1-enoate (60 g, 0.34 mol) in ethanol (600 ml) was treated with ~;% rhodil~m on alumina 5 powder (17.2 g). The ....~ e was placed under a hydrogen atmosphere (5~ psi) for five hours at 60~C. The reaction was stopped by removing the hydrogen and the reaciton ~uLe was filtered through a layer of CELITETM. The residue was washed with hot ethanol. The filtrate was concentrated and purified by flash chrom~tography to provide 39.6 10 grams (63%) of the desired title product.
lR, NMR, and IR were consistent with the proposed title structure.

Preparation 42 15 Preparation of (3'S) ethyl 3-[piperidin-3-yl]propionoate m~n~lic acid salt o ~'~ ~ o CH3 H ~mandelic acid A solution of (RS) ethyl 3-[piperidin-3-ylJpropionoate (62.0 g, 2 o 281 mmol) in hot ethyl acetate (300 ml3 was added to the hot solution of R-(-) m~nrlçlic acid (42.7 g, 281 mmol). The resulting mixture was then f;ltered and ~he clear solution was left at room temperature overnight.
The newly formed white crystals of the salt were filtered from the solution. These crystals were recryst~lli7:e-1 twice by dissolution in hot 2 5 ethyl acetate (300 ml3 and letting it cool dwon to room temperature each time. The final pure crystals were dried to yield 33.1 grams (70%).
NMR and IR were consistent with the desired title product. The conformAtion about the chiral center was con~ ned by X-ray crystallography.

W O 97/25041 PCT~US97/00511 Prep~ration 43 Preparation of (3'R3 ethyl 3-[piperidin-3-yl]propionoate m~n~lelic acid 5 salt o C~ ~ CH3 N .mandelic acid The title compound was prepared essentially as described 10 in Preparation 42, su~ra, except that S-(+) m~nfle.lic acid was employed instead of the R-(-) m~nrlalic acid employed therein.
NMR and IR were consistent with the desired title product.

Prel~aration 44 Preparation of (3'S) ethyl 3-[piperidin-3-yl]propionoate o ~ O ~ CH3 2 o A susr.qn~ion of (3'S) ethyl 3-[piperidin-3-yl3propiono~te rn~n~elic add salt (33.1 g, 98 mmol) in ethyl acetate (500 ml) was treated with a 30% aqueous solution of potassium carbonate until all the organic layer was clear. The mixture was poured into a separatory funnel and the organic fraction was extracted with ethyl acetate (3 x 300 ml). The combined organic fraction was washed with water (2 x 300 ml), then brine (1 x 300 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily product in nearly 100% yield.
NMR and IR were consistent with the desired title product.

W O 97/25041 PCT~US97/00511 Preparation ~6 Preparation of (3':~) ethyl 3-~piperidin-3-yl]propionoate o ~ ~ O ~ C~3 The title compound was prepared essentially as described in Preparation 44, sl~pra, except that (3'R) ethyl 3-[piperidin-3-yl]propionoate mandelic acid ~alt was employed instead of the (3'S) ethyl 10 3-[piperidin-3-yl]propionoate mandelic acid salt therein.
NMR and IR were consistent with the desired title product.

Pre~aration 46 15 Preparation of (3'S) ethyl 3-[1-(t-buto~ycalL)onyl)piperidin-3-ylJpropionoate o BoC

A solution of(3'S) ethyl 3-~piperidin-3-yl]propionoate (12.5 g, 67.5 mmol) in tetrahydrofuran:water (2:1, 33~:168 ml) was treated with potas~ium carbonate (14 g, 101 mmol) and di-tert-butyl dicarbonate (17.7 g, 81 mmol). The reaction ~ e was stirred at room temperature for five hours. The ~ e was then poured into water (200 ml). The organic fraction was extracted with ethyl acetate (3 x 200 ml). The organic fractions were comhined, washed with water (2 x 2001) and then brine (1 x 200 ml~, and then dlied over sodium sulfate. The solvents were removed in vacuo and the title product was fur~er purified by ~ash chromatography. Yield: 19.1 grams (99.2%).
NMR and IR were consistent with the desired title product.

Preparation 47 Preparation of(3'R) e1~hyl 3-~1-(t-buto~y~alluonyl)piperidin-3-yl]propionoate o J

BoC
The title product was prepared e~.~ent.i~lly as described in Preparation 46, supra. except that an eqllimol~r amount of (3'R) ethyl 3-[piperidin-3-yl}propionoate was employed instead of the (3'S) ethyl 3-~piperidin-3-yl]propionoate employed therein.

Preparation 48 Preparation of (3'S) 3-[1-(t-buto~y~a~bonyl)piperidin-3-yl]propanol OH

BoC

A solution of (3'S) ethyl 3-cl-(t-buto~yca~bonyl)piperidin-3-yl]propi~no~te (17.1 g, 60 m m ol) in dry diethyl acetate (600 ml) was cooled to 0~C. Lithium alu~num hydride powder (2.5 g, 65 ~ol) was gradually added to the ~ e. The resulting mi~tllre was stirred at 0~C and slowly warmed to room tempe. al~LL e within two hours. The reaciton was stopped by the slow addition of water (200 ml) and 15%

aqueous sodium hydroxide (60 ml). The organic fraction was extracted with diethyl e~her (3 x 300 ml). The comhined layer was washed with water (2 x 20Q ml) and then brine (1 x 200 ml) and then dried over sodium sulfate. The solvents were removed in vacuo to provide 13.2 grams (90%
5 yield) of the title product.
NMR and IR were consistent with the desired title product.

Preparation 49 10 Preparation of (3'S) 3-[1-(t-buto~y~aLl,onyl)piperidin-3-yl]propanol Q "' OH

BoC

The title product was prepared essentially as described in 15 Preparation 48, supra, except that an eqllimol~r amount of (3'S) ethyl 3-[1-(t-butoxycarbonyl)piperidin-3-yl~propionoate was employed instead of the (3'R) ethyl 3-[1-(t-buto~y~albonyl)piperidin-3-yl]propionoate employed therein.

Preparation ~;0 Preparation of ~3'S) 3-[1-(t-buto~ycall~onyl)piperidin-3-yl~propane bromide . ~ Br BoC
To a cold (0~C) solution of tnphenylphosphine (19.96 g, 76 mmol) in anhydrous methylene cbloride ~110 ml) was added bromine L~JlJwise until the solution turned pale yellow. A few crystals of CA 02242~79 1998-07-08 W O 97/25041 PCT~US97/OOSll triphenylphosphine were added to the ~--i x 1,.. ~ e to bring the color back to white. To this .~.;x~ e was added a suspension of (3'S) 3-[1-(t-buto~ycall~onyl)piperidin-3-yl]propanol (13.2 g, 54.4 mmol) and py~idine (8.0 g, 76 mmol) in dry methylene chloride (110 ml). The resulting 5 l.~ ,~e was stirred for f;ve hours while warming to room t~mperature.
The reaction was stopped by s~ nE water (2001). The organic fraction was extracted with methylene chloride (3 x 200 ml).
The comhined organic layer was washed with water (2 x 200 ml), then brine (1 x 100 ~), and then dried over sodium sulfate. The solvents 10 were removed in vacuo to provide a light brownish crude product, which was further purified by flash chrom~tography to yield 11.6 grams (70%) of the desired title product.
NMR and IR were consistent with the title product.

Pre~ration ~;1 Preparation of (3'R) 3-[ l-(t-buto~y cal bonyl)piperidin-3-yl~propane bromide ~ ~' ~ Br BoC
The title product was prepared eRs~n~i~lly as desclibed in Preparation ~0, supra~ except that an eql1imol~r amount of (3'R) 3-[1-(t-buto~ycall)onyl)pipelidin-3-yl]propanol was employed instead of the (3'S) 25 3-[1-(t-buto~y~ onyl)piperidin-3-yl]propanol employed therein.

(~Teneral ~rocedure for PreI~arin~ Cnn~ounds of the Formula DMF N C

HO
A solution of ben7.imidazole (1.0 g, 3.9 mmol, 1.0 eq~ in anhydrous N,N-dime~ylform~mi-le (10 ml) was treated with 60%
disperson of ~odium hydride (0.163 g, 4.1 mmol, 1.05 eq). The re~(~ion 5 mixture was stirred at room temperature for about thirty minutes.
Bromopropanol (0.6 g, 4.3 mmol, 1.1 eq) was added to the ..~;xI-..e and the resulting ..~ix~,...e was stirred at 70~C for five hours. The progress of the reaction was monitored by thin layer chrnm~to~raphy.
The reaction mixture was poured into water (20 ml). The 10 organic fraction was extracted wtih diethyl ether (3 x 60 ml). The organic fractions were comhined, washed with water (2 x 20 ml), and then brine (1 x 20 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield a white solid as a crude product. No further purification was pelrol...ed on this product.
The following e~mples were prepared essan*~lly as described above in the general procedure.

?le 1 Preparation of 2-[4-chlorophano~ymethyl]-1-(3-hydro~y~l o~yl )ban ~i mi dazole HO

W O 97/25041 PCTrUS97/00511 NMR was consistent with the desired title structure.

~ nn~l~ 2 Preparation of 2-[4-~hloropheno~ymethyl]-1-(3-llyLo~y~lo~yl~-5-chlorob~n 7i mi ~ ~ 701e HO
NMR was consistent with the desired title structure.
?le 3 Preparation of 2-[4-chloropheno~ymethyl]-1-(3-hydl o~y~. 01JY1)-~6 dichlorob~n7.irnidazole C l~N~ o~ C 1 HO

20 NMR was consistent with the desired title structure.
,. , F~"~ le 4 W O 97/2S041 PCTnUS97/OOSll ~62-Preparation of 2-[4-c7 lorophenoxymethyl]-1-(3-hyd~o~y~lo~yl)-6,6-dimethylben ~imi~ole H3C ~ N ~ ~ ~ Cl HO
NMR was consistent with the desired title structure.
T~le 5 Preparation of 2-[4-chloropheno~ymethyl]-1-(3-1lyd~ o~y~l o~yl)-4-_ethylben7.imi~ole N ~ ~

HO

15 NMR was consistent with the desired title structure.

(~eneral Procedure for Pre7~aration of Com1?ol7nds of the Formula W O 97/25041 PCT~US97/00511 -~3-R R

\ ~ N ~ Cl Br2/PPh3 f \ ~ N
O ~ pyr dine ~ ~ O ~ Cl EO Br To a solution of triphenylphosphine (1.62 g, ~.8 mmol, L5 eq) in dry ~ hl~romethane (101) at 0~C was added l~lo~le solution until it was pale yellow. To the resulting ,..ix~,... e as added additional 5 triphçnylphosphine until the solution was white. To this mi~tnre was then added the hydroxyalkyl-substituted ben~imidazole (1.2 g, 3.9 m m ol, 1.5 eq) and pyridine (0.~ 1, 5.8 m m ol, 1.5 eq) in dIy dichloromethane.
The resulting ~ ula was stirred at 0~(~ and then warmed to room tempe.d~ule at which temperature it was m~int~ined for about six 10 hours. The progress of the re~ction was m~ oled by thin layer chromatography .
White prel irit~te was removed by filtration, washed with dichloromethane, and dried in vacuo to provide the crude product.

The following compounds were prepared essentially as described above.

~,x~ le 6 2 0 Preparation of 2-[4-chlorophenoxymethyl]-1-(3-brom l3. o~yl)-ben~imi~ 0le C~ 0 N

Br W O 97/25041 PCT~US97/00511 NMR and IR were consistent with the desired title structure. FDMS 380 (M+).

F~m~le 7 Preparation of 2-[4-chlorophenoxymethyl]- 1-(3-bromo~l o~yl)-5-chlorobçn 7:i mitl~ole ~ ~ ~ Cl Br NMR was consistent with the desired title structure.

~ nnle 8 Preparation of 2-~4-chloroph~no~ymethyl~-1-(3-bromopro~yl)-5,6-dichloroben 7:imi dazole Cl Cl ~ ~ O ~ Cl N

NMR was consistent with the desired title structure.

~ple 9 CA 02242~79 1998-07-08 Preparation of 2-[4-chloroph~no~rymethyl]-1-(3-bromo~. o~yl)-5,6-dimethylbçn ~imi dazole H ] ~--0~ C 1 Br NMR was consistent with the desired title structure.
~.~ml?le 10 Preparation of 2-[4-chloroph en o~ymethyl]- 1-(3-bromo~l o~yl)-4-~ethylben7imi.1~7 ole Br 15 NMR was consistent with the desired title structure. FDMS 393 (M~).

(~T~neral Procedure for PreI)aration of Corr~ollnds of the Formula CA 02242~79 1998-07-08 WO 97/2s04l PCT~US97/OQ511 -5~-R R

f\~N /=\ Clhydrochloride f\s~N
N ~ O ~ K2C03 ~ ~ ~ ~ Cl ~ DMF, 70~C N

Br M
C>
A sollltion of the ben~imi~ole (100 mg,0.26 mmol, 1.0 eq) in anhydrous N~N-~imethylform~mi~le t2 ml) was treated with potassium carbonate (90 mg, 0.65 mmol, 2.5 eq) and piperidine hydrochloride (35 m g, 0.29 mn ol, 1.1 eq). The ~ ule was stirred at 70~C for about five hours. The resulting ~ ule was poured into water . The org~nic fraction was extracted with diethyl ether (3 x 10 ml).
The comhined ether layers were washed with water (3 x 5 ml), then brine, and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product. The desired title product was then further purified by flash chromatography.

The following compounds were prepared es~enti~lly as described above.
n~le 11 Preparation of 2-(4-chloropheno~ymethyl)-1-[3-(piperidin-1-yl~l opyl]ben~imifl~7:ole W O 97/25041 PCT~US97/00511 ~ ~ Cl IR and NMR were consistent with the desired title product. FDMS 384 (M+).
Analysis for C22H26ClN30:
Theory: C, 68.83; H, 6.83; N, 10.94.
Found: C, 68.21; H, 6.90; N, 10.98.
e 12 Preparation of 2-(4-chloropll~no~ymethyl)-1-[3-(piperidin-1-yl)~. olJyl]ben~imidazole ~ ~ Cl IR and NMR were consistent with the desired title product. FDMS 384 (M+).
Analysis for C22H26ClN30:

W O 97/2~041 PCT~US97/00511 Theory: C, 68.83; H, 6.83; N, 1û.94.
Found: C, 68.21; H, 6.90; N, 10.98.

ml~le 13 Preparation of 5-chloro-2-(4-chloroph~no~ymethyl)-1-[3-(piperidin-1-yl)~lopyl]ben7.imidazole Cl ~ ~ Cl IR and NMR were consistent with the desired title product. FDMS 418 (M+)-F.~m,l~le 14 Preparation of 5,6-dichloro-2-(4-chlorophenn~ymethyl)-1-[3-(piperidin-1-yl)~lo~yl~bçn7.imidazole W O 97/25041 PCTnJS97/00511 _~9_ Cl ~ ~ O

f ~

IR and NMR were consistent with the desired ti~le product. FDMS 452 (M+).

~n~le 15 Preparation of 2-(4-chlorophenoxymethyl)-5,6-dimethyl-1-[3-(piperidin-1-yl)propyl]ban 7i mi dazole H ~ ~ Cl O

~le 16 Preparation of 2-(4-chlorophenoxymethyl3-4-methyl-1-[3-(piperidin-1-Y1)L~1O~Y1]b~n7im; dazole W O 97/25041 PCT~US97/00511 C~3 Q ~ Cl IR and NMR were consistent with the desired title product. FDMS 397 (M+).

F.~mnle 17 Preparation of 2-(4-chlorophenoxymethyl)-5,6-dichloro-1-[3-~morpholin-l-yl)~. o~yl]ben7imidazole C ~ ~ O ~ Cl ~' ~ N ~

IR and NMR were consistent with the desired title product. FDMS 453, 454 (M+).
~m~le 18 W O 97/25041 PCT~US97/00511 Preparation of 2-(4-chlorophenoxy~nethyl )-5 -chloro- 1- ~3-(morpholin- 1-Y1)L~ Y1]b~n7; midazole Cl ~ ~ Cl ~1 ~ N ~

IR and NMR were consistent with the desired ti1~1e product. FDMS 419, 420 (M+).
m~le 19 Preparation of 2-(4-chloropheno~ymethyl~-1-[3-(morpholin-1-yl)~lo~yl]b~n ~imi~ ole Cl N ~

J

IR and NMR were consistent with the desired title product. FDMS 385, 386 (M+).

W O 97/25041 PCT~US97/00511 le 20 Preparation of 2-(4-chloroph~no~ymethyl)-1-[3-(piperazin-1-yl)propyl3ben7.imi~ ole Cl N ~

~le 21 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(piperazin-1-yl)~l ol~yl]bçn 7.imi~ ole ~ ~ Cl ~, N

5 IR and NMR were consistent with the desired t~tle product. FDMS 512 (M+).

W O 97/25041 PCT~US97/00511 rnrle 22 Preparation of 2-~4-chlorophenoxymethyl)-4-methyl-1-[3-[4-(pyrimidin-2-5 yl)piperazin-1-yl]propyl]ben7.;midazole ~N~--N ~ M

IR and NMR were consistent with the desired title product. FDMS 476.2 10 (M+).

ml?le 22 Preparation of 2-(4-chloroph~n()~ymethyl)-4-methyl-1-[3-[4-(pyrid-2-yl~piperazin-l-yl]~ yl]ben7,imi~1~7.01e W O 97/25041 PCTrUS97/00511 Cl ~ N

N

IR and Nl~R were consistent with the desired title product. FDMS 475.2 (M+).

m~le 23 Preparation of 2-(4-chloroph çn o7~ymethyl)- 1-[3-~4-(N,N-dimethyl~mino)piperidin-l-yl]~l0l,~13bçn7.imi~ole ~ ~ Cl ~, H3C'' CH3 :

?le 24 Preparation of 2-(4-chlorophen~ymethyl)-5,6-dichloro-1-[3-[4-(N,N-dimethy~mino)piperidin-l-yl]~l o~yl]bçn7imidazole Cl~ ~ Cl N

H3 C~ --CH3 IR and NMR were consistent with the desired title product. FDMS 49~.2 (M+).
Fx,~ 1e 25 Preparation of 2-(4-chloroph~no~ymethyl)-5-chloro-1-[3-[4-(N,N-dimethylamino)piperidin-l-yl]~lo,~yl]ben7.imidazole W O 97/25041 PCT~US97/00511 Cl ~ ~ Cl H3C'' CH3 IR and NMR were consistent with the desired ti~le product. FDMS 495.2 (M~).

F,~ ple 26 Preparation of 2-(4-chloroph~no~ymethyl)-5,6-dimethyl-1-[3-[4-(N,N-dimethyl~nnino)piperidin-1-yl]~,o~yl]ben7.imidazole H3 ~ ~ Cl ~1 ,,N

IR and NMR were consistent with the desired title product. FDMS 455.4 (M~).

W O 97/25041 PCT~US97/00511 ~ rnl?le ~7 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[4-(N,N-5 dimethyl~minn)piperidin-l-yl]~. o~yl]ben~imidazole ~ ~ Cl ~1 ~ N

IR and NMR were consistent with the desired title product. FDMS 441 lû ~M+).

?le 27 Preparation of 2-(4-chlorophçn o~ymethyl)-4-methyl- 1-[3-[4-(piperidin- 1-15 yl)piperidin-1-yl]propyl]benzimidazole N

~.~

IR and NMR were consistent with the desired title product. FDMS 481 (M+).

(~eneral Procedure for Pre~arin~ Com~ounds of the Followin~
Formulae R ~ ~ R ~ N

~) n and ~) n N~ APG ~ N~
APG
10 where n is 0, 1, or 2, and APG is an amino protecting group.

W O 97/25041 PCTrUS97/00511 R~ J~Cl ~N~O
N

H NaH
+ DMF, 80~C

Br~ ~ N~

BoC
A solution of the l-unsubstituted ben7imidazole (0.77 mmol, 1.0 eq) in anhydlous N,N-dimethylformamide (3 ml) was treated with a 60% disperson of sodium hydride (33 mg, 0.80 mmol, 1.~5 eq). The 5 mixture was stirred at room temperature for thirty minutes under a stream of nitrogen. To this ~i~ e was added [1-(t-buto~Ly~;aIl)onyl)piperidin-3-yl]l,lvlJyl bromide (260 mg, 0.85 mmol, 1.1 eq) and the resulting ..,;x4.~e was stirred at 80~C for about three hours.
The progress of the reaction was monitored by thin layer 1 0 chromatography.
The reaction l~.iX~ e was then poured into water (10 ml3.
The org~nic fraction was extracted with diethyl ether (3 x 15 ml). The organic fr~ on~ were comhine~, washed with water (2 x 10 ml), brine (1 x 10 ml), and then dried over sodium sulfate. The solvents were 15 removed in vacuo, leaving a light brown crude material which was further purified by flash chromatography to yield the desired title product as a white cryst~lline solid in 70-100% yield.

~mnle 28 Preparation of 2-(4-chloroph~nr ~ymethyl)-1-[3-[1-(t-butoxycarbonyl)piperidin-2-yl]~ Jyl]bçn~ 01e W O 97~S041 PCT~US97/00511 , BoC

IR and NMR were consistent with the desired title product. FDMS 483, 484 (M+).
Analysis for C27H34ClN303:
Theory: C, 67.00; H, 7.08; N, 8.60.
Found: C, 66.g3; H, 7.09; N, 8.43.

F~ l Preparation of 2-(4-chloroph~no~ymethyl)-5-methoxy-1-[3-[1-(t-butoxycarbonyl)piperidin-2-yl]propyl]ben~imir~ 01e and 2-(4-c~lorophenoxymethyl)-6-methoxy-1-[3-[1-(t-butoxycarbonyl)piperidin-2-yl]~l ol~yl~bçn 7.imi(1~ole H3C~ ~ ~ o ~ , BoC

W O 97/25041 PCT~US97/00511 IR and NMR were consistent with the desired title products. FDMS 513, ~14 (M+).
Analysis for C2gH30ClN3O4:
Theory: C, 6~.42; H, 7.06; N, 8.17.
Found: C, 65.12; H, 6.96; N, 8.29.
m,l7le 30 Preparation of 2-(4-chloroph~no~y~nethyl)-4,5-dimethyl-1-[3-~1-(t-10 butogycarbonyl)piperidin-2-yl]lJlol~yl]b~n~imidazole and 2-(4-chlororheno~ymethyl)-6,7-dimethyl-1-[3-[1-(t-buto~yca. l~onyl)piperidin-2-yl]~ yl~ben7imi~ ole H3C ~ ~ Cl < H3C

~ ~ BoC ~ , BoC

IR and NMR were consistent with the desired title products. FDMS 511, 512 (M~).
Analysis for C29H3gClN3O3:
Theory: C, 68.02; H, 7.48; N, 8.20.
Found: C, 68.32; H, 7.54; N, 8.36.
m~le 3 1 Preparation of 2-(4-chloroph~no~ymethyl)-5-methyl- 1-[3-[1-(~-2 5 butoxycarbonyl)piperidin-2-yl]lJl o~yl]ben7.imi dazole and 2-(4-W O 97/25041 PCT~US97/00511 cl310roI-h~no~y_ethyl)-6-methyl-1-[3-[1-(t-butoxycarbonyl)piperidin-2-yl]propyUben 7.imidazole H3C~/ ~ Cl ~ ~ BoC

IR and NMR were consistent with the desired title products. FDMS 497, 498 (M+). 3:2 mixture of the 6-methyl isomer to the 6-methyl isomer.
Analysis for C2gH36ClN3O3:
Theory: C, 67.62; H, 7.28; N, 8.44.
Found: C, 68.37; H, 7.40; N, 8.60.
h',~m,l~le 31 Preparation of 2-(4-chloroph~nc~rymethyl)-4-methyl 1 [3 [1-(t-butoxycarbonyl)piperidin-2-yl]propyl]ben~imidazole ~0 , BoC
N

W O 97/25041 PCT~US97/00511 IR and NMR were consistent with the desired title product. FDMS 497, 498 (M+).
Analysis for C2gH36C~lN3O3:
Theory: C, 67.52; H, 7.29; N, 8.44.
Found: C, 67.14; H, 7.65; N, 8.85.
le 32 0 Preparation of 2-(4-chloropheno~rymethyl)-5-benzoyl-1-[3-~1-(t-butoxycarbonyl)piperidin-2-yl]~l o~yl]bçn~;midazole o Cl N~ BoC
V

15 IR and NMR were consistent with the desired title product. FDMS ~87, 588 (M+).

~le 33 Preparation of 2-(4-chlorophenoxymethyl)-5,6-dichloro-1-[3-[1-(t-butoxycarbonyl)piperidin-2-yl]~L o~yuben~imitlsl7ole W O 97/25041 PCT~US97/00511 IR and NMR were consistent with the desired title product. FDMS 497, 498 (M+).
Analysis for C2gH36ClN3O3:
Theory: C, 67.52; H, 7.29; N, 8.44.
Found: C, 67.14; H, 7.65; N, 8.85.

~ m~le 32 10 Preparation of 2-(4-chlorophenn~ymethyl)-5-benzoyl-1-[3-[1-(t-butoxycarbonyl)piperidin-2-yl]~, vl~yl]bçn7:imidazole o Cl N~ BoC

15 IR and NMR were consistent with the desired title product. FDMS 587, ~88 (M+).

~m~le 33 Preparation of 2-(4-chloropheno~ymethyl)-5,6-dichloro-1-[3-[~-(t-butoxycarbonyl)piperidin-2-yl]l~.o~yl]ben7imifl~ole W O 97/25041 PCT~US97/00511 ~ C~ ~ N ~ Cl , BoC
~ N

IR and NMR were consistent with the desired title product FDMS 687, ~88 (M+).

F',~m~l~le 34 Preparation of 2-(2,4-dichlorophenoxymethyl)-1-[3-[1-(t-butoxycarbonyl)piperidin-2-yl]~i o~yl]b~n ~:i mi dazole ~N~

~N~ BoC

NMR was consistent with the desired title product.

h'.~ le 36 W O 97/2SQ41 PCT~US97/00511 Preparation of 2-(2,4-dichlorophenoxymethyl)-5,6-dichloro-1-[3-~ t-butoxycarbonyl)piperidin-2-yl],~ yl]ben~iTnidazole Cl~N~-- J~

NMR and IR were consistent with the desired title product. FDMS 587 (M+).
Analysi~ for C27H3lCl4N303:
Theory: C, 55.21; H, 5.32; N, 7.15.
Found: C, ~6.19; H, 5.69; N, 7.44.

F.~ le 36 Preparation of 2-(4-chloro~h~noxyInethyl)-5-methyl-1-[3-[1-(t-15 buto~y~;alllonyl)piperidin-3-yl]~. o~yl]benzimidazole and 2-(4-chloroph~no~ymethyl)-6-methyl-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]pl o~yl3ben ~i mi dazole , W O 97/25041 PCT~US97/00511 H3C ~ ~ Cl S and C' ~
N~ ~ N~
BoC BoC
NMR and IR were consistent with the desired title products. FDMS 497, 498 (M+).
Analysis for C2gH36ClN303:
Theory: C, 67.52; H, 7.28; N, 8.44.
Found: C, 67.58; H, 7.42; N, 8.52.

~"~ le 37 0 Preparation of 2-~4-chloroph en o~ymethyl)-5-methoxy- 1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl3propyl~ben7imi~ ole and 2-(4-chlorophenoxymethyl)-6-methoxy-1-[3-[1-(t-buto~y~al bonyl)piperidin-3-yl]~. o~yl]b~n7.imi~1~7.ole H3C ~ ~ Cl ~ Cl N N

and S

~ N~ ~ M~
BoC BoC

W O 97/25041 PCT~US97/00511 NMR and IR were consistent with the desired title products. FDMS 513, 514 (M+).
Analysis for C2gH36ClN3O4:
Theory: C, 65.42; H, 7.06; N, 8.17.
Found: C, 65.18; H, 7.22; N, 7.94.

~le 38 Preparation of 2-(4-chlorophenoxymethyl)-4,5-dimethyl-1-[3-[1-(t-10 butoxycarbonyl)piperidin-3-yl],~lul~yl]benzimidazole H3 ~ ~ Cl N~
BoC
NMR and IR were consistent with the desired title product. FDMS ~11, 512 (M+).
le 39 Preparation of 2-~4-chloroph~no~ymethyl)-4-methyl-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]~l v~yl~ben~irni(l~ole W O 97/25041 PCTnUS97/00511 N

N~
BoC

NMR and IR were consistent with the desired title product. FDMS 497, 498 (M+~.

~ m~ple 39a Preparation of 2-(4-chloropheno~rymethyl)-4-methyl-1-[5-[1-~t-buto~ bonyl)piperidin-3-yl3pentyl]b~n 7:i mi~ 701 e ~BoC

NMR was consistent with the desired tit~e product.

F"r~m~le 40 Preparation of 2-(4-chloroph~.nl)xy ,ethyl)-~;-benzoyl-1-[3-[1-(t-butoxycarbonyl)piperidin-3-ylJ~ l]ben7:imidazole ~o Cl N~
BoC

NMR and IR were consistent with the desired ti~le product. FDMS 497, 498 (M+).
F"~ ?le 41 Preparation of 2-(4-chlorophenoxymethyl)-6,6-dichloro-1-[3-~1-(t-butoxycarbonyl)piperidin-3-yl]~ ylJbens:imi~ ole Cl ~ ~ Cl N

N~
BoC

W O 97/25041 PCT~US97/00511 NMR and m were consistent with the desired title product. FDMS 552.5, 654.6 (M+).

m.~rle 42 Preparation of 2-(4-chloroph~n..~ymethyl)-5-chloro-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl3propyl]ber-~imifi~7.ole Cl ~ ~ Cl N

N~
BoC
NMR and IR were consistent with the desired title product. FDMS 518 (M+).

F'.~n~le 43 Preparation of 2-~4-chloroph~no~ymethyl)-5,6-dimethyl-1-[3-~1-(t-butoxycarbonyl)piperidin-3-yl]yio~yl]ben~imidazole CA 02242~79 1998-07-08 W O 97t25041 PCT~US97/00511 H3C ~ ~ O

N~
BoC

NMR and IR were consistent with the desired title product. FDMS 512.4 (M+).
m~?le 44 Preparation of 2-(2,4-dichlorophenoxylllethyl)-1-[3-~1-(t-butoxycarbonyl)piperidin-3-yl]l~lo~yl]ben7.imifl~ole N~
BoC

NMR and IR were consistent with the desired title product. FDMS 517, ~18 C~
Analysis for C27H33C12N303:
Theory: C, 62.58; H, 6.41; N, 8.10.
Found: C, 62.54; H, 6.39; N, 8.20.

W O 97/25041 PCT~US97/00511 ~"~ le 45 Preparation of 2-(2~4-dic-hlorophenn~ymethy~ 6-~lirhloro-l-c3-[l-(t butu~ycalbonyl)piperidin-3-yl]~ yl]ben7~ 7.0le Cl ~ N

M~
BoC

NMR and IR were consistent wit-h- the desired title product. FDMS 587 10 (M+).

~"~le 46 Preparation of 2-(4-ch~orophçno~ymethyl)-4,5-dimethyl-1-[3-[1-(t-15 butoxycarbonyl)piperidin-4-yl]~ro~yl~ben7.imidazole W O 97/25041 PCT~US97/00511 Cl M

BoC

~ le 47 5 Preparation of 2-(4-chlorophenosrymethyl)-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]~l o~yl]b~n~imidazole Cl N

BoC

10 NMR and IR were consistent with the desired title product. FDMS 484 {M+).

F.~ le 48 CA 02242~79 1998-07-08 W o 97/25041 pcTnJs97/oos Preparation of 2-(4-chlorophenoxymethyl)-4,5,6,7-tetr~met~yl- 1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]~ yl]ben7.imi(~s~7.01e H3 ~ ~ ~

BoC

~n~le 49 Preparation of 2-(4-chlorophenoxymethyl)-5-methogycarbonyl-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]~ yl]ben7imidazole and 2-(4-10 chlorophenoxymethyl)-6-metho~ycall)onyl-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]~l o~yl]b~n7:irnidazole H3C\ ~

--oJ~' ~OJ~

and BoC

NMR and IR were consistent with the desired title products. FDMS 541 (M+).
Analysis for C2gH36ClN30s:
Theory: C, 64.26; H, 6.69; N, 7.75.
Found: C, 64.07; H, 6.63; N, 7.96.

F,~m,l?le 50 Preparation of 2-(4-chloropheno~rymethyl)-4-methyl- 1-[3-[1-(t-10 butoxycarbonyl)piperidin-4-yl]~ yl]ben7imi-1~7ole N

BoC

NMR and IR were consistent with the desired title product. FDMS 497, 15 498 (M+).

F,~ml?le 50a Preparation of 2-(4-chloropheno~ymethyl)-4-met-h-yl-l-[5-[l-(t 20 butoxyca~bonyl)piperidin-4-yl]pentyl]ben7.imi/1~7ole ~ ~ Cl N
BoC

NMR was consistent with the desired title product.

~ ?le 51 Preparation of 2-(4-chlorophçno~ymethyl)-4-(t-butyl)-1-[3-[1-(t-buto~yca,l,onyl)piperidin-4-yl]propyl]ben7imidazole and 2-(4-chloropheno~ymethyl)-7-(t-butyl)-1-[3-{1-(t-buto,~y~ lJonyl)piperidin-4-10 yl]~io~yl]bçn7.imifl~q7.01e W O 97/25041 PCT~US97/00511 H3C\ ~CH3 Cl ~ ~ Cl < H3C / C\ <

and <

BoC BoC

NMR and IR were consistent with the desired title products. FDMS ~39, 540 (M+).

~ le 52 Preparation of 2-(4-chloroph~n o~ymethyl)-4-methyl- 1-~4-[ l-(t-butoxycarbonyl)piperidin-4-yl]butyl]ben 7.imi ~ ol e ~ ~ Cl -BoC

W O 97/2~041 PCT~US97/00511 NMR and IR were consistent with the desired title product. FDMS 511 (M+).
!

le 53 ~, Preparation of 2-(4-chloroI heno~yme1~hyl)-6,6-dimethyl-1 [4-[1 (t butol~yc~ bonyl)pipe~idin-4-ylJbutyl]ben Y.i mi ~ ol e rl ~ ~ Cl BoC

NMR and IR were consistent with the desired title product. FDMS 526 (M+).
rnl?le 54 Preparation of 2-(4-chloropheno~yme~hyl)-4,~-dimethyl-1-[4-[1-(t-buto~ycall)onyl)piperidin-4-yl]butyl]bçn~imi~ ole amd 2-(4-chloroph~nl ~ynnethyl)-6,7-dimethyl-1-[4-[1-(t-butokyca~l~onyl)piperidin-4-yl]butyl]b~n7.imi~ ole W O 97/25041 PCT~US97/00511 H3 ~ ~ O ~ Cl H3C ~ O ~ Cl N ~ N

< and BoC BoC
NMR and IR were consistent with the desired title products.

~ le ~

Preparation of 2-benzyl-1-[3-[1-(t-buto~yc~bonyl)piperidin-3-yl}~ o~yl~b~n7imidazole N

N
<

BoC

NMR and IR were consistent with the desired title product. FDMS 433 (M~).

le ~6 W O 97~5041 PCT~US97/00511 Preparation of Z-(4-chlorophenyl)-1-[3-[1-(t-buto,~y~all,onyl)piperidin-3-yl]~lo~l]ben 7imli~Sl 7:ole N~' C 1 N~
BoC

NMR and IR were consistent with the desired title product. FDMS 453 (M+).
Analysis for C26H32ClN302:
Theory: C, 68.78; H, 7.10; N, 9.25.
10 . Found: C, 68.56; H, 7.03; N, 9.54.

?le ~7 Preparation of 2-(2-chlorophen~ ~ymethyl)-1-[3-[1-(t-1~ bu~,o~ycall~onyl)piperidin-3-yl]~lo~yl]ben7:imidazole N
Cl N~
BoC

W O 97/25041 PCTnJS97/O0511 NMR and IR were consistent with the desired title product. FDMS 483 (M+).
Analysis for C27H34ClN303: ' Theory: C, 67.00; H, 7.08; N, 8.08.
Found: C, 67.25; H, 7.27; N, 8.81.

F.~s~rru?le 58 Preparation of 2-(3-chloropheno~ymethyl)-1-[3-Cl-(t-10 butoxycarbonyl)piperidin-3-yl]l~l v~yl]ben~imidazole N ~ ~

N~
BoC

NMR and IR were consistent with the desired title product. FDMS 483 15 (M+).

~le 59 Preparation of 2-(4-chlorobenzyl)-1-[3-[1-(t-buto~y-,~bonyl)piperidin-3-20 yl]~lo~yl3b~n~.imi(1~ole W O 97~5041 PCTnUS97/00511 N Cl N~
BoC

NMR ana IR were consistent with the desired title product. FDMS 467 (M+).
Analysis for C27H34ClN302:
Theory: C, 69.30; H, 7.32; N, 9.98.
Found: C, 69.54; H, 7.49; N, 9.08.

F,~rAm~I?le 60 Preparation of 2-(ph~no~rymethyl)-1-[3-[1-(t-buto~yL:~13onyl)piperidin-3-yl]~l o~yl]b~n ~imidazole N

N

N~
BoC

NMR and IR were consistent with the desired f;itle product. FDMS 449 (M+).

CA 02242579 l998-07-08 W O 97/25041 PCT~US97/00511 Analysis for C27H3sN3O3:
Theory: C, 72.13; H, 7.85; N, 9.35.
Found: C, 71.85; H, 7.81; N, 9.25.
le 61 Preparation of 2-(3,5-r~i~hlorophenoxymethyl)-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]~ yl]ben7:imi~7.ole ~,~ , 0 ~ N~
BoC
NMR and IR were consistent with the desired title product. FDMS 517 (M+).
Analysis for C27H33Cl2N3O3:
Theory: C, 62.65; H, 6.41; N,8.10.
Found: C, 62.33; H, 6.35; N,8.12.

~n~le 62 Preparation of 2-[4-(4,5-dihydrot~ ol-2-yl)pheno~rymethyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]~l o~yl]be~imi~ole W O 97/25041 PCT~US97/OOSII

., ~3 ~ o~N~

N~
BoC

NMR and IR were consistent with the desired ti~le product. FDMS 534 (M+).
5 Analysis ~or C30H3gN4O3S:
Theory: C, 67.38; H, 7.16; N, 10.48.
Found: C, 66.78; H, 7.0~; N, 10.00.

~ u?le 63 1~
Preparation of 2-(2,6-dichloropheno:~ymethyl)-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]~ v~l]ben~imidazole N

BoC

NMR and IR were con~istent with the desired title product. FDMS ~;17 (M+).

CA 02242579 l998-07-08 W O 97/25041 PCTnJS97/00511 Analysis for C27H33Cl2N303:
Theory: C, 62.55; H, 6.41; N, 8.10.
Found: C, 62.76; H, 6.44; N, 8.33.

m,~l-? 64 Preparation of 2-(3-trifluoromethylpher - ~rymethy~ -[3-~l-(t butoxycarbonyl)piperidin-3-yl]p~ o~yl]ben ~imi dazole ~~

~ N~
BoC
NMR and IR were consistent with the desired title product. FDMS 517 (M+).
Analysis for C~gH34F3N3O3:
Theory: C, 64.98; H, 6.42; N, 8.12.
Found: C, 64.89; H, 6.48; N, 8.31.

?le 65 Preparation of 2-(4-chloroph~no~Fymethyl)-4-methyl-1-(3-phenylpropyl)ben~imidazole W O 97/2~041 PCTAUS97/00511 -~ ~Cl '13 NMR and IR were consistent with the desired title product. FDM~3 390 (M+).
5 Analysis for C24H23clN2o:
Theory: C, 73.74; H, 5.93; N, 7.17.
Found: C, 73.87; H, ~;.99; N, 7.27.

~"~,~le 66 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-~3-cyclohe~yl~, o E,yl )ben 7i Tll~i dazole N ~ C

NMR and IR were consi~tent with the desired title product. FDMS 390 (M+).

W O 97/25041 PCT~US97/00511 ?le 67 Preparation of 2-~4-chlororhPno~ymethyl)-4-methyl-1-[3-(pyrid-3-5 yl)~lo~l]ban~imi~ le and 2-(4-chloroTheno~ymethyl)-7-methyl-1-[3-(pyrid-3-yl),~ yl]ben7~ 7.ole N Cl ~ N ~ ~ Cl / and ~ N ~ N

NMR and IR were consistent with the desired title products.
10Analysis for C23H22ClN30:
Theory: C, 70.49; H, 5.66; N, 10.72.
Found: C, 70.20; H, 5.76; N, 10.50.

G~n~ral Procedure for Removal of the t-Buto~ycall)onyl Protect.in~
15 ¢~Trour~

R ~ N ~ ~ Cl ~ N ~ ~ Cl trifluoroacetic acid S
dichloromethane ~ NH ~TFA
BoC

W O 97/25041 PCT~US97/00511 _ 99_ -To the amino-protected b~n7.imi~1S.sole was added a 1:1 e of trifluoroacetic acid in dichloromethane. The resulting e was stirred at room tempe~a~ule for about one hour. The progress of the reaction was monitored by thin layer chromatography.
5 The solvents were removed in vacuo and the residue was l,l~ ted with diethyl ether (3 x 10 ml) and dried under vAclllln to yield white crystalline hydroscopic ~olids.

~le 68 Preparation of 2-(4-chloropheno~ymethyl)-1-[3-(piperidin-3-yl)~lo~yl]ben7.imi~A7ole trifluoro~cet~t~ salt N ~ -Cl ~NH
~ ~TFA

NMR and IR were consistent with the desired title product. FDMS 383, 384 (M+).

le 69 Preparation of 2-(4-chloropheno~rymethyl)-5-metho2~y-1-[3-(piperidin-3-yl)~ yl]ben7imirlA~ole trifluoroacetate salt W O 97~5041 PCT~US97/00511 N

~NH
~ ~TFA

NMR and IR were consistent with the desired title product. FDMS 413, 414 (M+).
5 Analysis for C23H2gClN3O3:
Theory: C, 66.87; H, 5.54; N, 7.96.
Found: C, 55.93; H, 5.31; N, 8.01.

u?le 70 Preparation of 2-(4-chloroI~heno~ymethyl)-4,5-dimethyl-1-r3-(piperidin-3-yl)~lol3yl]ben7:imi~ole trifluoro~cet~te salt H3C ~ H3 N ~ Cl ~NH
~ ~TFA

NMR and IR were consistent with the desired title product. FDM~ 411, 412 (M+).

le 71 Preparation of 2-(4-chlorophenoxymethyl)-~-methyl-1-[3-(piperidin-3-yl)~ yl]b~n7imidazole trifluoroacetate salt and 2~(4-5 chlorophenoxymethyl)-6-~ethyl-1-r3-(piperidin-3-yl)~lo~yl]ben7imidazole trifluoroacetate salt H3C ~ ~ O ~ N ~ Cl ~ and ~NH ~NH
~ ~TFA ~ ~TF~

NMR and IR were consistent with the desired title products. FDMS 397 lo (M+).
A~alysis for C23H28ClN30:
Theory: C, 58.65; H, 5.54; N, 7.96.
Found: C, ~8.26; H, 6.~6; N, 9.17.

F',~on~le 72 Preparation of 2-(4-chlorophP.no~ymethyl)-4-methyl-1-[3-(piperidin-2-yl)~l~o~yl]bçn7.imidazole tlifluoroS.~etote salt W O 97/25041 PCT~US97/00511 C~~~CI

~N
~ ~TFA

NMR and IR were consistent with the desired title product. FDMS 397, 398 (M+).

~le 72a Preparation of 2-(4-chlorophçno~ymethyl)-4-methyl-1-r~-(piperidin-3-yl)pentyl3be~imi~ ole ~ ~ Cl H

NMR and IR were consistent with the desired title product. FDMS 427 (M+).

W O 97/25041 PCT~US97/00511 -Analysis for C2sH32ClN30:
Theory: C, 60.05; H, 6.16; N, 7.78.
Found: C, 59.75; H, 6.11; N, 7.78.

F"r~ le 73 Preparation of 2-(4-chlorophenoxy_ethyl)-~-benzoyl-1-[3-(piperidin-2-yl)~ yl]ben7imidazole trifluoroacetate salt ~, ~Cl ~27,N~
l J ~TFA

NMR and IR were consi~tent with the desired title product. FDMS 487, 488 (M+).

~ ml~le 74 Preparation of 2-(4-chlorophenoxy~..ethyl~-~,6-dichloro-1-[3-(piperidin-3-yl)~lo~yl]ben 7.i mi dazole trifluoroacetate salt W O 97/25041 PCT~US97/00511 C ~ ~ ~ ~ Cl ~NH
~ ~TFA

NMR and IR were consistent with the desired title product. FDMS 451, 452 (M+).

nu?le 76 Preparation of 2-(2,4-dichlorophenoxymethyl)-5,6-dichloro-1-[3-(piperidin-2-yl)~lo~yl]ben 7.imi~ 70le trifluoroacetate salt Cl ~ N ~
~TFA

NMR and IR were consistent with the desired title product. FDMS 487 (M+).
~,~m~ e 76 W O 97/25041 PCT~US97/00511 Preparation of 2-(2,4-dichloropheno~ymethyl)-1-~3-(piperidin-2-yl)~lo~yl]b~n~:imidazole trifluoroacetate salt Cl H
~27,N~
~TFA

NMR and IR were consistent with the desired title product. FDMS 418 (M+).

71e 78 Preparation of 2-(4-chloropheno~ymethyl)-~;-methoxy-1-[3-(piperidin-3-yl)~l o~yl]b~n 7 i mi dazole t, NMR and IR were consistent with the desired title product. FDMS 413 (M+).

~ u?le 79 W O 97/25041 PCT~US97/00511 Preparation of 2-(4-chlorophenoxymethyl)-6-methoxy-1-~3-(piperidin-3-yl)propyl]bçn ~irnirl~ole H3CO ~ N ~ ~ ~ Cl ~ NH

I \ J
NMR and IR were con.~i~t~nt, with the desired title product. FDMS 413 (M+).

F~nlr)le 80 Preparation of 2-(4-chlorophenoxymethyl)-4,5-dimethyl-1-[3-(piperidin-3-yl)propyl]ben ~imidazole H3C ~ H3 N ~ Cl ~ NH

~
NMR and IR were consistent with the desired title product. FDMS 411, 412 (M+).

W O 97/25041 PCT~US97/OOSll ,.
~le 81 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(piperidin-3-yl)~io~yl]ben7.imi~ ole and 2-(4-chloroph~no~ymethyl)-7-methyl-1-~3-5 (piperidin-3-yl)propyl]ben~imi~ ole N ~ O ~ H3C ~ Cl and ~J ~NH
~J
NMR and IR were consistent with the desired title products. FDMS 397, 3g8 ~M+).

h'.~nu?l.e 8~

Preparation of 2-(4-chlorophen o~rymethyl)-~i-benzoyl- 1-[3-(piperidin-3-yl~propyl]bçn ~:;mi dazole ~, N ~ Cl ~NH
~J

NM~ and IR were consistent with the desired title product. FDMS 487, 488 (M+) li',~ le 83 Preparation of 2-(4-chlorophenoxymethyl)-6,6-dichloro-1-[3-(piperidin-3-yl)propyl]ben7.imidazole Cl ~ ~ o ~ Cl _ ' NH
\J
NMR and IR were consistent with the desired title product. FDMS 4~;2.2 (M+).

F.~mJ le 84 Preparation of 2-(4-chlorophenoxymethyl)-6-chloro-1-[3-(piperidin-3-yl) ~l o ~yl]b~n ~i rni dazole Cl~s~

~ ~~Cl NMR and IR were consistent with the desired title product. FDMS 418.2 (M+).

ml~le 8~

Preparation of 2-(4-chloroph~no~rymethyl)-~,6-dimethyl-1-[3-(piperidin-3-yl)~lo~yl~ben7imi~ 0le H3C~
>g\

H3C~N~ ~--Cl ~GNH

NMR and IR were consistent with the desired title product. FDMS 418.2 (M+).
~rr~le 86 .

W O 97/25041 PCTnJS97/00511 Preparation of 2-(2,4-dichloroph~no~rymethyl)-1-[3-(piperidin-3-yl)~l o~yl3bçn7imirl~701e N ~ Cl NH

NMR and IR were consistent with the desired title product. FDMS 417, 418 (M+).
Analysis for C22H2sCl2N30:
Theory: C, 53.14; H, 4.92; N, 7.89.
Found: C, 63.02; H, 4.74; N, 7.59.

~"~ 87 Preparation of 2-(2,4-dichlorophenoxymethyl)-5,6-dichloro-1-[3-15 (piperidin-3-yl)~. o~yl]ben7.imidazole Cl ~ N
Cl~ ~~Cl ~ NH
~J ;

W O 97/25041 PCT~US97/00511 NMR and IR were consistent with the desired title product. FDMS 487 (M+).
n~le 88 Preparation of 2-(4-chloroph en o~ymethyl)-4,5-dimethyl- 1-[3-(piperidin-4-yl )1~, o ~yl]b ~.n 7:; mi dazole H3C ~

N ~ Cl ~ NH

NMR and IR were consistent with the desired title product. FDMS 411 (M+).

h~ n~E?le 89 Preparation of 2-(4-chloroph~no~y~ethyl)-1-[3-(piperidin-4-yl)~ro~yl]ben ~imi~7.ole N

N ~ Cl ~ NH

W O 97/25041 PCT~US97/00511 NMR and IR were consistent with the desired title product. FDMS 383 ;
(M+).
Analysis for C22E26ClN30:
Theory: C, 57.89; H, 5.46; N, 8.44.
Found: C, 57.06; H, 5.44; N, 8.31.
m,l~le 90 Preparation of 2-(4-chloropheno~yn ethyl)-4,5,6,7-tetramethyl-1-[3-(piperidin-4-yl)~l opyl]ben 7i miri~7.ole H3C ~ H3 H3C ~ O ~ Cl ~ NH

NMR and IR were consistent with the propsoed title structure.

~,~slmnle 91 Preparation of 2-(4-chloropheno~ymethyl)-5-methoxycarbonyl-1-[3-(piperidin-4-yl)propyl]b~n7imidazole and 2-(4-chlorophenoxymethylL)-6-methoxycarbonyl-1-[3-(piperidin-4-yl)~l~Juyl]benzimidazole W O 97/25041 PCT~US97/00511 H3C o ~ ~ N Cl NH

NH
NMR and IR were consistent with the desired title products. FDMS 541 (M+).
Analysis for C24H2gClN30:
Theory: C, 66.17; H, 5.26; N, 7.50.
Found: C, 55.91; H, 5.32; N, 7.68.

F,~mnle 92 Preparation of 2-(4-chlorop~ano~ymethyl)-4-methyl~ 3-(piperidin-4-yl)~l o~l]ben 7.irnidazole N ~ Cl NH

5 IR and NMR were consistent with the desired title structure. FDMS 397 (Mt).

W O 97/Z5041 PCT~US97/00511 F.~ ?le 92a Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[5-(piperidin-4-5 yl)pentyl]ben7imil1~701e N ~ Cl N

IR and NMR were consistent with ~he desired title structure. FDMS 426 10 (M+).
Analysis for C2~H32ClN30:
Theory: C, 60.06; H, 6.16; N, 7.78.
Found: C, 60.30; H, 6.19; N, 7.65.

~mlI7le 93 Preparation of 2-(4-chlorophenoxymethyl)-4-(t-butyl)-1-r3-(piperidin-4-yl)propyl]b~n 7.imi dazole and 2-(4-chlorophenoxymethyl~-7-(t-butyl)- 1-[3-(piperidin-4-yl)propyl]ben7.imi(1~ole - 1~--C'- CH3 N ~ Cl H3C~ Cl ~NH
IR and NMR were consistent with the desired title structures. FDMS
439 (M+).

~z3m~rle 94 Preparation of 2-(4-chloroph ~.n o~rymethyl)-4-methyl- 1-[4-(piperidin-4-yl)butyl]ben~imidazole N ~ Cl H

W O 97/25041 PCTnUS97/W511 IR and NMR were consistent with the desired title structure. FDMS 411 (M+).
F,~m~I?le 95 Preparation of 2-(4-chlorophenoxymethyl)-l ;,6-dimethyl- 1-[4-(piperidin-4-yl)butyl]ben7imitl~0le H3C ~ ~ ~ Cl 1~
IR and NMR were consistent with the desired title structure. FDMS 425 (M+ ).
m,~?le 96 ~5 Preparation of 2-(4-chlorophPno~ymethyl)-4,5-dimethyl-1-~4-(piperidin-4-yl)butyl]ben7.imidazole and 2-(4-chlorophenoxymethyl)-6,7--limethyl-1-~4-(piperidin-4-yl)butyl]ben ~i mi dazole CA 02242s79 l998-07-08 H3C ~ CH3 M ~ Cl and H3C ~ ~ Cl H

IR and NMR were consistent with the desired title struetures. FDMS
425 (M+).

F,~nu~le 97 Preparation of 2-benzyl-1-[3-(piperidin-3-yl)propyl]b~n7:imi~ ol~

N

IR and NMR were consistent with the desired title structure. FDMS 344 (M+).

F',~m~l?le 98 Preparation of 2-(4-chlorophenyl)-1-[3-(piperidin-3-yl)~l o~3yl]b~n 7.imidazole N ~
<> Cl M

IR and NMR were consistent with the desired title structure. FDMS 354 (M+).
~.~z~m~le 99 Preparation of 2-(2-ch~orophenoxymethyl)-1-[3-(piperidin-3-yl)~l ol~yl3ben 7imidazole N

N

IR and NMR were consistent with the desired title structure. FDMS 384 ~M+).

W O 97/25041 PCT~US97/00511 F~m,~le 100 Preparation of 2-(3-chloroph en o~ymethyl)- 1-r3 -(piperidin-3-5 yl)propyl]b~n7imi~A7ole ~N~\/

HN

IR and NMR were consistent with the desired title structure. FDMS 384 10 (~+).

F,~Anu~le 101 Preparation of 2-(4-chlorobenzyl)-1-[3-~piperidin-3-15 yl)~lo~yl]ben7imidazole N ~ Cl W O 97/25041 PCT~US97/00511 IR and NMR were consistent with the desired title structure. FDMS 368 (M+).

le 102 Preparation of 2-(pheno~rymethyl)-1-[3-(piperidin-3-yl)~ yl]bF~n~imi-1~7.ole Q ~

IR and NMR were consi~tent with the desired title structure. FDMS 349 (M+).
Analysis for C22H27N3O:
Theory: C, 62.19; H~ 6.09; N, 9.07.
Found: C, 61.08; H, 6.01; N, 9.01.

m}?le 103 Preparation of 2-(3,6-dichlorophenoxymethyl)-1-[3-(piperidin-3-2 0 yl)propyl]b~n7:imidazole N ~ C

H

IR and NMR were consistent with the desired title structure. FDMS 417 (M+).
5 Analysis for C22H2sCl2N3O:
Theory: C, 54.14; H, 4.92; N, 7.89.
Found: C, 54.06; H, 4.87; N, 7.82.

F,~ ?le 104 Preparation of 2-[4-(4,~;-diLyd~otl-i~7Ql-2-yl)~hen( ~ymethyl]-1-[3-(piperidin-3-yl)propyl]bçn ~i mi ~ ol e N
~ N ~ ~ /sN

IR and NMR were consistent with the desired title structure. FDMS 436 ~M~).

W O 97/25041 PCT~US97/00511 - 1~2-~,~Am~le 106 Preparation of 2-(2,6-dichlorophenoxymethyl)-1-[3-(piperidin-3-yl)~s o~yl]ben7:imidazole ~~

HN

IR and NMR were consistent with the desired title structure. FDMS 420 ~M+)-~A rr~,~l ~ 106 Preparation of 2-(3-~rifluoromethylphenoxymethyl)-1-[3-(piperidin-3-yl),~ yl]b~n7~imidazole ~~~

H

IR and NMR were consistent with the desired title structure. FDMS 418 ~M+).

W O 97/25041 PCT~US97/00511 Analysis for C23H26F3N30:
,~ Theory: C, ~6.60; H, ~.12; N, 7.91.
Found: C, 55.49; H, 5.03; N, 7.64.
,, F,~ 1?le 107 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[4-[3-(piperidin-1-yl)propylamino]-3-methylbutyl~ben7:imidazole ~ \>~ 0~

N
" ~

~rru?le 108 Preparation of 2-(4-chlorophçno~ymethyl)-4-methyl-1-[4-amino-3-methylbutyl]b~n 7imi dazole Cl ~.~ le 109 W O 97/25041 PCTnJS97/00511 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[4-dimethylAminQ
3-methylbutyl]ben7:imi dazole \>~ ~~

N(CH3)2 mple 110 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl- 1-[4-(1,2,3 ,4-tetrahydroisoquinolin-2-yl)-3-methylbutyl]benzimidazole ~ H3 ~b F,~mple 111 15 Preparation of 2-(4-chlorophenoxymethyl~-4-methyl-1-[3-[2-[2-(piperidin-1-yl)ethyl~piperidin-1-yl~carbonyl~butyl]b~n~irnidazole W O 97/25041 PCT~US97/00511 _ ~ _ .;
Cl _~ 3 0~1~
o mJ?le 112 Preparation o~ 2-(4-chlorophenoxymethyl)-4-methyl-1-{4-[2-[2-(piperidin-l-yl)ethyl]piperidin-l-yl]-3-methylbutyl~bçn7im;dazole ~ H3 1~

.. O

m~ple 113 Preparation of 2-(4-chlorop~eno~ymethyl)-4-methyl-1-~4-[(1,2,3,4-tetrahydronaphth-1-yl)amino~-3-methylbutyl}bçn7.imidazole W O 97/25041 PCT~US97/00511 Cl Y~

n~le 114 Preparation of 2-(4-chlorophçno~rymethyl)-4-methyl-1-l3-[3-~(2-methylpiperidin-1-yl)propylz~minl ]carbonyl~-3-methylpropyl}b~n 7:i mi dazole ~ CH3 0~

~ CH3 ?le 115 Preparation of 2-(4-chlorophenoxymethyl~-4-methyl-1-~4-[3-(2-15 methylpiperidin- 1-yl ~ ylamino] -3-methylbutyl}bçn ~i mi dazole W O 97/Z5041 PCTnUS97/00511 F,~le 116 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[1-(3-ethoxycarbonylbutyl)piperidin-3-yl]~lo~yl}ben7,imidazole Cl N ~

~ ~ O~_ " CH3 ~0 le 1 17 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[1-(3-ethoxycarbonyl4-phenylbutyl)piperidin-3-yl]~ v~yl}ben7.imidazole W O 97~5041 PCT~US97/00511 N

~ N O~_,,CH3 o Anlple 118 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[1-(2-ethoxycarbonyl-4-phenylbutyl)piperidin-3-yl]propyl~b~n7:imidazole ~ ~ Cl ~ ;
o O~

0 ~Am~le ~19 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[1-(3-carbo2~ylJu~yl~piperidin-3-yl]propyl~ben7imidazole ;

- lL29-r ~C \>~OJ~

N

C ~
OH
rn;ble 120 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[4-[2-~2-~piperidin-l-yl)ethyl]piperidin-l-yl3-3-methyl]butyl]ben~imidazole \>~~~
N
\_~H3 C~

~ ~le 121 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-phenyl-3-carboxyl,ro~yl)piperidin-3-yl]~,o~yl]benzimidazole .

W O 97/25041 PCT~US97/00511 \>~~~

HO O
rr~le 122 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[1-(4-phenyl-3-carboxybutyl)piperidin-3-yl]propyl]ben7.;mi-1~7ole HO ~

h~mnle 123 Preparation of 2-(4-chlorophenoxy_ethyl)-4-methyl-1-t3-[1-(3-benzoylbutyl)piperidin-3-yl]~ yl]ben7imidazole W O 97t25041 PCTAUS97/00511 Cl N

N

m~le 124 Preparation of 2-~4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-benzoyl-3-phenylpropyl)piperidin-3-yl]~ro~yl]ben7imidazole ~ >/~

~n~le 12~

Preparation of 2-(4-chloropheno:~ymethyl)-4-methyl-1-[3-r1-(3-benzoyl-3-phenylpropyl)piperidin-3-yl]propyl]be~imi dazole ,C1 ~le 126 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[1-(3-benzoyl-3-ben;~yl~l o~yl)piperidin-3-yl]~l o~yl]ben 7.imi dazole ~3~C 1 N

~ ~le 127 W O 97/25041 PCT~US97/00511 Preparation of 2-(4-chlorophenoxymethy1)-4-methyl-1-C3-[1-[4-(piperidin-1-yl)-3-methylbutyl]piperidin-3-yl]~l o IJyl]ben ~imi dazole ~ ~ Cl CJ~

~ml?le 128 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[4-(piperidin-1-yl)-3-phenylbutyl]piperidin-3-yl]~ yl3ben ~imi dazole ~ N

rnnle 130 W O 97/25041 PCT~US97/00511 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[4-(piperidin-l-yl)-3-benzylbutyl]piperidin-3-yl~lo~l]be~imidazole ~ ~ Cl GN ~N

F,~ml?le 131 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-ethoxycarbonyl-4-phenylbutyl)piperidin-3-yl]~l o~yl]ben7imitl~7:ole Cl N ~
~, H3C ~ O N
~13 ..

- 13~;-le 132 Preparation of 2-(4-chlorophe~o~ymethyl)-4-methyl-l-c3-[l-(3-carboxy-4 phenylbutyl)piperidin-4-yl]~l opyl]b~n7.i midazole ~\y~ 0 HO ~ N

mple 133 Preparation of 2-~4-chlorophenoxymethyl)-4-methyl-lL-[3-[1-[3-~piperidin-1-ylcarbonyl)-4-phenylbutyl]piperidin-4-yl]~ ~ o~yl]be~ 7i mi dazole W O 97/25041 PCT~US97/005tl CH3 ~ Cl M ~ ~

C~ ' ~13 F.~ny?le 134 5Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[1-[3-(piperidin-l-ylmethyl)-4-phenylbutyl3piperidin-4-yl]~ yl]b~n7:imidazole CH3 ~ Cl ~~~
N ~

C N
'3 :

13F~nl~le 135 W O 97/25041 PCTnUS97/00511 ..
Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-C1-L3-(ethoxycarbonyl)butyl]piperidin-4-yl~propyl]benzimidazole Cl m~;?le 136 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-L1-r3-(ethoxycarbonyl~propyl]piperidin-4-yl]propyl]b~n 7:imi dazole ~''~
1o \~ N ~ o~ CH3 F!~mnle 137 Preparation of 2-(4-chlorophenoxymethyl3-4-methyl-1-[3-~1-[3-(carboxy)butyl]piperidin-4-yl]~ o~yl]ben7:imidazole CA 02242579 l998-07-08 W O 97/25041 PCT~US97/00511 ~m~le 138 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-carbo2~yl,. o~yl)piperidin-4-yl]l3l ol~yl~b~n7imidazole CH3 ~ Cl ~ N ~

h~ m~I?le 139 Preparation of 2-~4-chloro~heno~ymethyl)-4-methyl-1-[3-[1-[3-(piperid~n-l-ylcarbonyl)butyl]piperidin-4-yl] ~l o~yl]ben 7.imidazole ;c & \>~~~

Cll~

mnle 140 5Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-L1-[3-(piperidin-1-ylcarbonyl)propyl]piperidin-4-yl]~ ol~yl]b~n 7i mi dazole ~ ~ Cl ~ O

10h~ rn~le 141 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-methyl-4-(piperidin- 1-yl )butyl3piperidin-4-yl]~l vllyl~ben ~i rni dazole W O 97/25041 PC~US97/00511 ~C \>~'0 N ~

m~le 142 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl- 1-L3-[l-[4-(piperidin l-yl)butyl]piperidin-4-yl]propyl]benzimidazole h~mrlle 143 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(ethoxycarbonyl~piperidin-4-yl]~ vlJyl]b~n~imidazole CA 02242579 l998-07-08 Cl N ~ O~_" CH3 F.~m~le 144 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[3-(aminocarbonyl)l,l o~yl]piperidin-4-yl]propyl]-ben 7imi dazole ~~ O
J'--NH2 F,~ml;le 145 Preparation of 2-(4-chloroph~no~ylllethyl)-4-methyl-1-~3-~4-[3-~benzyl~mino)~ yl]piperidin-l-yl]propyl]-bqn7:;mi~ 01e PCT~US97/00511 Cl N

m,l7le 146 Preparation of 2-~4-chlorophenoxymethyl)-4-methyl-1-[3-[4-r2-[(benzylamino)carbonyl]ethyl]piperidin-l-yl]propyl]-b~n7imidazole N~ N~C3 lo ~m~le 147 Preparation of 2-(4-chloroph~n o~ymethyl)-4-methyl- 1-~3-~4-[2-[(4-methoxybenzylamino)carbonyl]ethyl]piperidin-1-yl]~ yl]-bçn7imi~1~701e W O 97/25041 PCT~US97/00511 Cl N ~
\_~ f H3 H

?le 147 Preparation of 2-(4-ch~oropheno~ymethyl)-4-methyl-1-[3-[4-[2-(benzyloxycarbonyl~mino)ethyl]piperidin- 1 -yl]propyl]-ber- 7:irni dazole C

H

0 F:~nn~le 148 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[4-~4-phenylpiperidin-l-yl)butyl]ben~;midazole W O 97/25041 PCT~US97/00511 N

N

:F"~ ?le 149 Preparation of 2-(4-chloroI~h~no~ymethyl)-4-methyl-1-[3-methyl-4-~4-phenyl-4-(acetamidomethyl)piperidin- 1-yl]butyl]ben ~i m; dazole >~ o N ~ HN CH3 ~ le 160 Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-[3-[4-(propyl~minocarbonylethyl)piperidin-1-yl]propyl3b~n7imidazole CA 02242579 l998-07-08 W O 97/25041 PCTnJS97/OOSll Cl M~ O

N ~ ~ CH3 n~ple 151 Preparal;ion of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-~3-(piperidin-1-yl)propy~mino]~. o~yl]b~n7.imidazole \~ 0 N

N

h',~mple 152 Preparation of 2-(4-chloroIlheno~ymethyl)-4-methyl-1-[3-(4-phenylpiperidin-1-yl)propyl]ben7imidazole \~ 0 _ 15 N ~ N
F.~mple 1~;3 Preparation of 2-(4-chlorophenQ~rymethyl)-4-methyl-1-[4-phenyl-4-(4-20 phenyl-4-methyl~nninocarbonylpiperidin-1-yl)butyl]ben7imidazole CH, ~ C l N

N
,CH3 ~3 F,~m;l?le 1~;4 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl- 1-[3-[3-~piperidin- 1-yl)propyl~mino]propyl]ben7.imidazole \~ 0 N ~N

~mnle 15~;

Preparation of 2-(4-ch~oropheno~ymethyl)-4-methyl-1-[3-(4-benzylpiperidin-l-yl)~lo~yl]b~n7imi(1~7.01e CH ~ ,~ C l ~ N~ ~3 CA 02242579 l998-07-08 F,~r~m,ple 1~6 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[N-benzoyl-N-[3-(piperdin-l-yl)plopyl]~mino]propyl}ben7imidazole \~ ~~
N ~ N
6~

F,~n~le 157 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-{3-[4-(ethoxycarbonylethyl~piperidin-l-yl]l,l.,pyl}b~n7.imi~7Qle Cl N ~ ~ CH3 ~,~ ?le 158 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-l3-~4-hydroxy-4-benzylpiperidin-l-yl]~ro~yl}ben7.imidazole OH
N

l~a~ple 1~;9 Preparation of 2-(4-chlorophen-)~ymethyl)-4-methyl-1-{4-(1,2,3,4-tetrahydroisoqllin-~lin-l-yl)butyl}ben7.imi~7.01e ~ ~ Cl ~3 h~ m,ple 160 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{4-(4-propoxy-4-phenylpiperidin-1-yl)pentyl~b~,n7imidazole & \~~~
N ~ CH3 N ~
~ - CH3 ~

W O 97/25041 PCT~US97/00511 F,~ le 161 Preparation of 2-(4-chloroph çn o~ymethyl)-4-methyl- 1- ~3-[N-benzyl-N-(3-piperidin-1-ylpropyl)amino]propyl}ben~imidazole CH3 ~ Cl F.~m~le 162 Preparation of 2-(4-chloropheno~ymethyl3-4-methyl-1-{3-[N-(benzyloxycarbonylmethyl)-N-(3-piperidin-1-ylpropyl)amino]propyl}ben zimi dazole CH3 ~ Cl ~0~
o f - ~3 F~n~le 163 W O 97/25041 PCT~US97/00511 - 1~0-Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-{3-methyl-4-[4-phenyl-4-(etho~ycal llonyl)piperidin- 1-yl]butyl}b~n ~imi dazole N ~ ~

H3C N ~ ~ CH3 mI?le 164 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[(1,2,3,4-tetrahydronaphth-1-yl)amino]~ yl}ben~imidazole ~

N

mple 165 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(benzyl~mino)propyl~benzimidazole W O 97~5041 PCT~US97/00511 ,;~ - 151-C l H

?le 166 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[4-(piperidin-1-ylcarbonylethyl)piperidin-l-yl]propyl]ben~imi~ ole ~
N ~ N
/ /

F,~ml?le 167 Preparation of 2-(4-chloroph~nQ~ymethyl)-4-methyl-1-[3-(piperidin-1-yl)~l o~l]b~n 7 i mi dazole ~C >~ o N

F,~mnle 168 W O 97/2S041 PCT~US97/00511 Preparation of 2-(4-chloropherloxymethyl)-4-methyl-1-[3-(4-phenyl-1,2,~16-tetrahydl o~ylldin-l-yl~propyl]ben~imidazole ~C ~ ~

N

~ e 169 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-r3-(4-phenyl-4-etho~ycall,onylpiperidin-l-yl)propyl]ban7.imitl~7Qle CH3 ~ Cl ~C \>~~~

N ~ ~ CH3 /~

n~;~le 170 Preparation of 2-(4-chlorophenoxymethyl3-1-[2-(4-dimethylaminopiperidin- 1-yl)ethyl]ben 7imi dazole CA 02242579 l998-07-08 W O 97~5041 PCT~US97/00511 ~C >~ ~
~ ~N

N(CH3)2 .~An~l~ 171 5 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-~3-hydroxypropyl)ben 7i mi dazole Cl N ~

OH

~,~Am~le 172 Preparation of 2-(4-chlorophenc.~ymethyl)-4-methyl-1-(3-cyanopropyl)ben 7.i mi~l A 7ole Cl . N ~

mp 112~. NMR, IR and W were consistent with the desired title structure. FDMS 339 (M+).

WO 97n5041 PCTnJS97/00511 - ~54-Analysis calculated for ClgHlgClN3O:
Theory: C, 67.16; H, 5.34; N, 12.37.
Found: C, 66.95; H, 5.26; N, 12.16.

e 173 Preparation of 2-(4-chlorophen o~ymethyl)-4-methyl- 1-(3-azidopropyl)ben~imidazole \>~~~
N

M~

mp 68~. NMR, IR and W were consistent w;th the desired title structure. FDMS 355 (M+).
Analysis calculated for Cl8Hl8N5~3:
Theory: C, 60.76; H, ~.10; N, 19.68.
Found: C, 61.00; H, 5.13; N, 19.70.
h'"~le 174 Preparation of 2-(4-chlorophçno~ymethyl)-4-methyl-1-~3-[N-methyl-N-(7-dimethyl~minoheptyl)amino]propyl]ben~imidazole W O 97/25041 PCT~US97/00511 Cl N ~
\
\ N ~ 3 nu?le 175 Preparation of 2-(4-chloroph~nn~ymethyl3-4-methyl-1-[3-[4-(2-phenylethyl)piperazin- l-yl]propyl]b.3n 7:i mi dazole ~C \>~o N

M
~ M
~' lQ ~.~m;~;?le 176 Preparation of 2-(4-chlorophçno~ymethyl)-4-methyl-1-[3-[(4-cyclohexylpiperazin- l-yl~acetoxy]propyl]bçn~ilnidazole ..

WO 97/2S041 PCT~US97/00511 N ~

o~o ~ \ ~
~ N ~

NMR was consistent with the the desired title structure.
FAB e~act _ass calculated for C30H40ClN4O3:
Theory: ~39.2803 Found: ~39.2789 u?le 177 10 Preparation of (RS) 2-(4-chlorophenoxyethyl)-4-methyl-1-[3-(pyrrolidin-3-yloxy)~ vpyl]ben7.imidazole.

/~N
~ ~ ~~0~

0~ .

15 NMR was consistent with the desired title structure. FDMS 399 (M+).

-1~7-FAB exact mass calculated for ~22H27clN3o2:
Theory: 400.1792 Found: 400.1805 ..
F',~m~le 178 Preparation of 2-(4-ch~loropheno~ymethyl)-4-methyl-1-[3-~1-[3-~1-benzoyl)propyl]piperidin-4-yl]~l o~yl]ben ~i mi dazole /~N

~-Cl 10 ~
NMR, IR and UV were consistent with the desired title structure.
FDMS 544 (M~.
Analysis calculated for C33~I38ClN302:
Theory: C, 72.84; H, 7.04; N, 7.72.
Found: C, 72.58; H, 7.22: N, 7.72.
rnr)le 179 2 0 r~ dtion of 2-~4-chloropheno~ymethyl)-4-methyl-1-~3-~[4-2-phenylethyl)piperazin- 1-yl]carbonyl]butyl]ben 7 i mi dazole W O 97/25041 PCT~US97/Q0511 N ~

o~ N N

mple 180 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-methyl-4-~4-(2-phenylethyl)piperazin- 1 -yl]butyl]ben 7:imi dazole ~C ~

N N
\
lo ~,~mnle 181 Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-C3-(1-benzylpiperidin-4-yl)propyl]benzimidazole W O 97/25041 PCTfUS97/00511 - ~,59-~ ~ Cl ~ N

N

~,~m ~ e 182 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(2-phenylethyl)piperidin-4-yl]~lv,uyl~ben7imidazole >~ o F.~m~le 183 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-~3-[1-(3-lphenylpropyl)piperidin-4-yl]~lo~yl]bçn7.imidazole CA 02242579 l998-07-08 Cl N

M

MP 59~. NMR was consistent with the desired title structure.
FDMS 515 (M+).
5 Analysis calculated for C32H3gClN30:
Theory: C, 74.47; H, 7.42; N, 8.14.
Found: C, 74.20; H, 7.23; N, 8.17.

~ ,m~le 184 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[1-(benzoylmethyl)piperidin-4-yl]propyl]b~n 7.i mi dazole ~ o NMR and IR were consistent with the desired title structure.
Analysis calculated for C31H34C~N302:

W O 97/25041 PCT~US97/00511 .i Theory:C, 72.1~; H, 6.64; N, 8.14.
Found: C, 72.35; H, 6.61; N, 8.34.
, ?le 185 Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-[3-[1-(2-benzoylethyl)piperidin-4-yl]propyl]b~n ~i mi dazole ~Cl --~N> ~3 NMR was consistent with the desired title structure.
~AB exact mass calculated for C32H37ClN302:
Theory: 530.2574 Found: 530.2584 h'.~m~;?le 186 Preparation of 2-(4-chlorophenr~y_ethyl)-4-methyl-1-[3-[1-(3-hyd~o,.y-3-phenylpropyl)piperidin-4-yl]~. olJyl]ben~imidazole W O 97/25041 PCT~US97/00511 - 1~2-N

N

OH

NMR was consistent with the desired title s~ructure.
FAB exact mass calculated for C32E3sclN3o2:
Theory: ~32.2731 Found: 532.2738 F,~-~m~le 187 Preparation of 2-(4-chloropheno~ymethyl~-4-methyl-1-[2-formylethyl]bçn7.;m;dazole Cl CHO

F.~m,~le 188 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-(prop-1-en-3-yl)ben~im; dazole r ~ \ ~ O
N ~

~ m~le 189 Preparation of 2-(4-chlorophçno~ymethyl)-7-methyl-1-(prop-1-en-3-yl)bçn~imi~ole ~ Cl ~r ~~~
\~~ N~
CH3 \~ CH2 ~ mr)le 190 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[4-phenyl-4-acetamidomethyl)piperidin-1-yl]propyl]ben~imidazole & J~,Cl ~ CH3 m~?le 191 W O 97/25041 PCT~US97/00511 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-(4-aminobutyl)b~.n7.imidazole CH3 ~ Cl N ~
~nH2 ~ m~le 192 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-(piperidin-1-y~)propyl)b~n7.imidazole Cl N ~

~,~r~m.I~le 193 15 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[[2-(phenylethylcarbamoyl)ethyl]piperidin-1-yl]propyl]ben~irni dazole W O 97/25041 PCT~US97/00511 \>~0~

H
.~ ~ N

rnl?le 194 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[[N-[3-(piperidin-l-yl)~ol~yl]-N-2-phenylethyl]amino]~lo~yl]berl~im;~ ole "
~ N ~ N

~ ~le 195 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[N-[3-(piperidin-l-yl)~l o~yl]-N-(2-phenylethyl)amino]propyl]bçn7.irn;dazole CA 02242579 l998-07-08 \>~~~
N ~

N ~ N

~n~ple 196 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[N-(2-phenylethyl)amino~propyl]b~n7:irni dazole \>~~~
N

HN

~ n~le 197 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(1,2,3,4-tetrahydroisoquinolin-l-yl)~ yl]ben7:imidazole W O 97/25041 PCT~US97/00511 i, ~, N

F~ nple 198 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-(4-phenylpiperazin-l-yl)propyl]ben~imirl~ole ~C \>~0 N
b h',~n~le 199 Preparation of 2-(4-c~lorophenoxymethyl)-4-methyl-1-~3-[N-[3-(piperidin-l-yl)propyl]-N-(biphenylacetyl)amino]propyl]ben7:innidazole PCT~US97/00511 \>~~~

N
O

Tr~le 200 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl- 1-[3-tN-[3-(piperidin-l-yl)propyl]-N-(hirhenylacetyl~arnino3~ yl3ben7imidazole Cl H3C ~ N ~ N
o ~rr~le 201 Preparation of 2-(4-chloroI heno~ymethyl)-4-methyl-1-[3-(4-etho~yc~l~onylpiperidin-l-yl)propyl]ber-7:imi~ ole W O 97/25041 PCTnJS97/00511 Cl N ~
\_~

, ~ O~_ " CH3 F,~ ?le 202 5 Preparation of 2-(4-chlorophenoxymethyl~-4-methyl-1-(3-aminopropyl)b~n s~ i dazole Cl F~ le 203 Preparation of 2-(4-clhlorophenoxymethyl)-4-methyl-1-(4-hy dl O~YIJ uLyl)ben 7.i mi dazole 1~ '>'' ~
c N ~

OH
F,~ le 204 W O 97/25041 PCTrUS97/00511 Preparation of 2-(4-chloroph~no~rymethyl)-5-[2-(piperidin-1-yl)ethylcarbamoyl]-1-[3-(piperidin-4-yl~ol yl]ben~imidazole ~ N ~ ~ ~ Cl ~ NH

~ml?le 205 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-(3-0 bromopropyl )ben ~:i m i dazole Br h~m~le 206 Preparation of 2-(4-chlorophenoxymethyl )-4-methyl- 1-[3 -(ethoxycarbonyl~propyl]ben7:imi dazole CA 02242579 l998-07-08 W O 97/25041 PCT~US97/00~11 N ~

~ CH3 m~l~le 207 5 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-(3-hydro~Ly~l o~yl)ben7.imidazole Cl N ~

OH

F',x~n~le 208 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-{3-[N-ethyl-N-(3-piperidin-1-ylpropyl)amino]propyl}b.o.n7.imidazole ., ~ ~ O

W O 97/25041 PCT~US97/00511 m~le 209 Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-{3-[N-acetyl-N-(3-piperidin-1-ylpropyl)amino~propyl}b~n~im;dazole Cl m~ le ~10 Preparation of 2-(4-chlorophçno~rymethyl)-4-methyl-1-{3-[N-(benzoylmethyl)-N-(3-piperidin-1-ylpropyl)amino]propyl}ben~imidazole ~ ~ N ~ - N ~

~"r~rr~le ~11 Preparation of 2-(4-chlorophçno~rymethyl)-4-methyl~ 3-~N-(benzylo~y~a. bonylmethyl)-N-(3-piperidin- 1-ylpropyl)amino]plo~yl~berl~imi~ ole CA 02242579 l998-07-08 WO 97/25041 PCT/US97/OOSll N ~Cl o_~~ N~>
o ~3 F/~mI?le 212 Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-{3-[4-benzoylpiperidin-l-yl]l,lo~yl}ber~7.imirl~Qle ,Cl .

0 F,~ml;?le 212A

Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-{3-[2-(piperidin-1-ylethyl)piperid~n- 1-yl]propyl}ben 7.imi ~ ole ..

N

F.~m;l?le 213 S Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-{3-[4-~propylcarbamoylethyl)piperidin-1-yl]propyl}ben7imidazole ~ H
N ~ N CH3 ~ ml-le 214 Preparation of 2-(4-chlorophen()~rymethyl)-4-methyl-1-{3-[4-[2-(phenylethylcarbamoyl)ethyl]piperidin-1-yl~io~yl}be~7~imidazole CH3 ~ Cl ~ >~ o N N3~,N O

W O 97/25041 PCT~US97/00511 ~ n~le 215 Preparation of 2-(4-cl~lorophenoxymethyl)-4-methyl-1-(4-methyl~minO 3 5 methylbutyl)b~n7.imidazole NH

~ le 216 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-(4-methyl~minn-3-benzylbutyl)benzimidazole Cl N

NH

mJr~le 217 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-r4-(piperidin-1-yl)-2 0 3-methylbutyl]bçn~irnidazole W O 97~5041 PCT~US97/00511 N ~

N

~ e 218 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-~4-(piperidin-1-yl)-3-benzylbutyl]ban~:irnidazole h~r~ le 219 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[3-~(piperidin-1-yl)amino]carbonyl]-3-methylpropyl]ber-7.imidazole W O 97/25041 PCT~US97/00511 Cl - ~ ~3 M

le 220 Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-[3-[3-[(piperidin-1-yl)amino~carbonyl~-3-benzylpropyl]ben~imidazole N ~

F',~ ?Ie 221 Preparation of 2-(4-nitrophenoxymethyl)-4-methyl-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yU~lo~yl]be~imidazole W O 97/25041 PCT~US97/00511 N ~

N- BoC

NMR and IR were consistent with the desired title product. FDMS 508 (M+).
5 Analysis for C2gH36N4Os:
Theory: (~, 66.12; H, 7.13; N, 11.01.
Found: C, 6~.86; H, 7.09; N, 10.98.

~ le 222 1~
Preparation of 2-(4-~rninoph~n o~ymethyl)-4-me~hyl- 1-~3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]ben~imidazole ~~~

~ ~N--BoC

A mi sFtl1re of 2-(4-nitrophenoxymethyl)-4-methyl-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]ben~imidazole (396 mg, 0.78 mmol) and 10% palladium on activated carbon (400 mg) in 10 ml of ethanol was stirred under a hydrogen atmosphere at room temperature. After two 20 hours, the re~ction mixture was filtered through a CELITETM cake. The filtrate was cnn~len~ed on a rotoevaporator to yield 310 mg (83%) of the desired title product.
NMR and IR were consistent with the desired title product. FDMS 478 (M+).
Analysis for C2gH3gN4O3:
Theory: C, 70.26; H, 8.00; N, 11.70.
Found: C, 70.00; H, 7.97; N, 11.60.

~m~le 223 Preparation of 2-r4-(t-buto~ycall)ony1~qmino)phenoxymethyl~-4-methyl-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl],L,~o,~yl3bçn~imidazole ~ \~ OJ~ N BoC

~, ~ N--BoC

A solution of 2-(4-aminophenoxymethyl)-4-methyl-1-r3-[1-(t-buto~yca~lJonyl)piperidin-3-yl]lJ o~yl]b~n7.imi~ole (160 mg, 0.33 m m ol, 1.0 eq.) in a 1~ e of anhydrous tetrahydrofuran and water (2 ml total) was treated wtih pot~.c.cillm carbonate (56 mg, 0.4 m m ol, 1.2 eq.) and di-t-butyl dicarbonate (90 mg, 0.4 mmol, 1.2 eq.). The mixture was stirred at room temperature for two hours. Water (10 ml) was added to the mi~Lu~ e. The organic fraction was extracted with ethyl acetate (3 x ~- 10 ml). The combined organic fraction was washed with water (10 ml), brine (1 x 101), and then dried over sodium sulfate. The solvents were removed in vacuo. The title product was further purified by flash chromatography. Yield: 190 mg (>99%).
,.
Preparation 52 W O 97/25041 PCT~US97/00511 Preparation of a-benzyl-~-butyrol~ctone (3-benzyl-3,4-dihydrofuran-2-one) ~ ~0 O
To a solution of diiso~lo~ylamine tl5.18 g, 0.15 mol) in dry tetrahydrofuran (200 ml) at -78~C under a nitrogen atmosphere, n-butyllithium (1.6 M in he~nes, 94 ml, 0.15 mol) was added d~ wise.
10 After twenty rninlltes of stirring at -78~C, ~-butyrolactone (12.91 g, 0.15 mol) was added d~ wise, such that the reaction temperature was m~;nt~ined below -70~C. After twenty minutes of stirring at -78~C, a u e of benzyl bromide (25.66 g, 0.15 mol) and he~methylphosphoramide (26.85 g, 0.15 mol) was added dropwise to the 15 reaction mixture. The re~ctior~ ule was then permitted to warm to -30~C and stirred at this temperature for two hours.
The reaction mixture was partitioned between a saturated ammonium chloride solution (500 ml) and diethyl ether (600 ml). The organic fraction was dried over potassium car~onate and the solvents 20 were removed in vacuo to yield 36.13 grams of the desired intermerii~tes as a dark yellow oil.
The crude material was further purified by flash silica gel chromatography eluting with a solvent gradient be~innin~ at 19:1 hç~nes/ethyl acetate and enllin~ with 3:1 hexanes/ethyl acetate. The 25 fractions cont~ining desired product were combined and concentrated under reduced pressure to yield 20.1 grams (76%) as a pale yellow oil.
IR and NMR were consistent with the proposed title structure.
FDMS 177 (M+1) Analysis for CllHl202:

W O 97/25041 PCT~US97/00511 Theory: C, 74.98; H, 6.86.
Found: C, 74.76; H, 6.73.

Preparation 53 Preparation of ethyl 2-benzyl-4-bromob~ no~te ~3 Br, ~O~CH3 In absolute ethanol (78 ml), a-benzyl-~-butyrolactone (14 g, 80 mmol) was added and then saturated for thirty minutes with gaseous hydrogen bromide, m~int.~ining the temperature below 50~C. The reaction was then heated to 45~C and stirred a~ this temperature for 16 hours. The solution was concentrated under reduced pressure and the 15 resulting oil was taksn into ethyl acetate (500 ml), washed once with water, and then dried over magnesinm sulfate. The solvents were removed in vacuo to yield 15.13 grams of tan oil.
The crude ...; xl. . . e was further purified by flask silica gel chromatography, eluting with a gradient solvent of hexanes to a 1:1 mixture of h~ne.~/methylene chloride. The fractions c~nt~ining the desired intermediate were comhined and concentrated under reduced pressure to yield 13.47 grams (67%~.
IR and NMR were consistent with the proposed title structure.
FDMS 286.1 (M+1) Analysis for C13H17O2Br:
Theory: C, 54.75; H, 6.01.
Found: C, 54.99; H, 6.02.

Pre~aration 54 W O 97/25041 PCT~US97/00511 Preparation of ethyl 2-methyl-4-bromobllt~no~te Br ~O~CH3 In absolute ethanol (78 ml), a-methyl-y-butyrolactone (8 g, 8 mmol) was added and then saturated for t~irty minutes with gaseous hydrogen bromide, m~int~ining the temperature below ~0~~. The reaction was then h~te-l to 4~~C and stirred at this temperature for 16 hours. The solution was concentrated under reduced pressure and the 10 resulting oil was taken into ethyl acetate (500 ml), washed once with water, and then dried over magnesium sulfate. The solvents were removed in vacuo.
The crude ..~ u~e was further purified by flask silica gel chromatography, eluting with a gradient solvent of hç~r~n~s to a 1:1 15 ~ e of h~nes/methylene chloride. The fractions cont~in;ng the desired intermediate were cornhin~d and concentrated under reduced pressure to yield 7.1 grams (44%).
IR and NMR were consistent with the proposed title structure.
FDMS 208, 209, 210~0 Analysis for C7H13O2Br:
Theory: C, 40.21; H, 6.27.
Found: C, 39.24; H, 6.19.

Prel?aration 5 Preparation of ~RS) ethyl 2-phenyl-4-chlorobllt~no~te Cl~O~CH3 W O 97/25041 PCT~US97/00511 To a solution of diiso~lo~yl~mine (23 1, 0.16 mol) in dry tetrahydrofuran (100 ml) at -78~C, under a nitrogen atmosphere, was added dLop~vise n-butyllithium (100 ml of a 1.6 M solution, 160 mmol).
After stirring for thirty minutes at -78~C, ethyl phenylacetate ~25 g, 0.15 mol) in dry tetrahyd~ or~n (172 ml) was added dropwise to the reaction .,~;xI.-.e. The resulting ~ e was perm7tted to warm to -30~C. After stirring for fifteen minlltes at -30~C, N,N'-dimetllyl~lol~ylene urea (18 ml, 0.15 mol) in dry tetrahyLo~uLan (30 ml) was added L~l~wise and the resulting mi~ e was stirred for ten minlltes.
The reaction ...i~ e was added via cannula under nitrogen atmosphere into a flask cont5~in;ng 1-bromo-2-chloroethane (63 ml, 0.7~ mol~ in diethyl ether (200 ml) at -15~C. This re~c~ n ...;Y~ule was then stirred at -15~C for three hours. The reaction mixture was 15 partitioned between a saturated ~mm()nium chloride in water solution (~;00 ml) and diethyl ether (1 L). The organic fraction was dried over potassium carbonate and the solvents were removed in vacuo to yield 41.37 grams of oil.
The crude material was further purified by ~ash solica gel 20 chromatography, eluting with a solvent gradient of hç~nes to 1:1 h~nes:methylene chloride. Fractions cont~;nin~ the desired title product were comhined and concentrated under reduced pressure to yield 1~.û grams (44%) as a clear oil.
NMR was consistent with the proposed title structure.
FDMS 226.1 (M+) Analysis for C12H1sO2Cl:
Theory: C, 63.~;8; H, 6.67.
Found: C, 63.29; H, 6.80.

3 0 Pre~aration 56 ,, Preparation of 4-(cyclohexyl)piperidine and 4-phenylpiperidine ;

W O 97~5041 PCTAJS97/00511 - 1~4-¢~ and N

3-Phenylpyridine (25 g, 0.16 mol) was placed in ethanol (470 ~1) along with rhodium (5% on alllmin~, 5.0 g) and was subjected to 5 hydrogenation at room tempeld~u~e for four hours at 60 psi. The resulting solution was then filtered, and the resulting oil was taken into ethyl acetate (500 ml), washed with water, and then dired over potassium carbonate. The solvents were removed in vacuo to yield 24.41 gr~ms of a tan oil. The ....~ .e of compounds was further purifed by lo flash chromatography, eluting with methanol. The fractions cont~ining the desired title intermediates were cornhined and concentrated in vacuo to yield 22.41 grams (86%) of a clear oil.
NMR and FDMS were consistent with the proposed title structures.

Preparation 57 Preparation of 4-(cyclohexylmethyl)piperidine and 4-benzylpiperidine and N
H H
3-Benzylpyridine (5 g, 0.029 mol) was placed in ethanol (145 ml) along with rhodium (5% on aluminaJ 0.125 g) and was subjected to hydrogenation at room temp~rature for four hours at 60 psi. The resulting solution was then filtered, and the resulting oil was taken into ethyl acetate (~00 ml), washed with water, and then dired over potassium carbonate. The solvents were removed in vacuo to yield 4.71 5 grams of a tan oil. The ~lule of compounds was further purifed by flash chromatography, eluting with methanol. The fractions cont~ining the desired title intermediates were c mhined and concentrated in vacuo to yield 3.64 gr~rns (71%) of a clear oil.
NMR and FDMS were consistent with the proposed title structures.
ml;~le 224 Preparation of l-r3-(ethoxycarbonyl)butyl~-2-~(4-chlorophenoxy)methyl]-4-methylbçn 7imi dazole Cl >--CH3 O=~

A sodillm hydride solution (60~o in oil, 810 mg, 20.3 mmol) was washed with he~n~s (2 x 50 ml) and then diluted with N,N-20 dimethylformamide (100 ml) At room temperature, under a nitrogenatmosphere, 2-[t4-chlorophenoxy)methyl]-4-methylben7imidazole (5 g, 18.3 mmol) was then added in one portion. The resulting mixture was then stirred at room tempe~dl,ul~ for thirty minlltes, and then 3-(etho~yc~bonyl)butyl bromide (4.25 g, 20.3 mmol) in N,N-W O 97/Z5041 PCT~US97/00511 - ~86-dimethylform~mi-le (10 ml) was added dropwise. Upon compl~tion of this addition, the reaction ~ ula was stirred for about six hours at a temperature of 70-80~C. The reaction mixture was then cooled to room temperature, poured into water (500 ml), and then extracted with ethyl 5 acetate (500 ml). The organic fraction was washed once with water (500 ml) and then dried over potassium car~onate. The solvents were removed in vacuo, yielding 8.01 grams of a dark oil. The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of methylene chloride to 3:1 methylene chloride:ethyl 10 acetate. The fractions col t,$~inin~ the desired title product were comhineA and cnncP-ntrated in vacuo to yield 7.21 grams (98%) of a viscous yellow oil.
NMR and IR were consistent with the proposed title structure.
FDMS 401 (M+) Analysis for C22H2sN2O3Cl:
Theory: C, 65.91; H, 6.29; N, 6.99.
Found: C, 66.13; H, 6.50; N, 7.11.

n U?l e 225 Preparation of 1-[3-(ethoxycarbonyl3-4-phenylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylben7imidazole ~cN ~3' o <O

W O 97/25041 PCTnJS97/00511 A sodium hydride solution (60% in oil, 810 mg, 20.3 mmol) was washed with h~nes (2 x ~0 ml) and then diluted with N,N-dimethylform~mi~e (100 ml). At room temperature, under a nitrogen 5 atmosphere, 2-[(4-chlorophenoxy)methyl]-4-methylb.qn~imidazole (~.0 g, 18.3 mmol) was then added in one portion. The resulting mi~tllre was then stirred at room temperature for thirty minutes, and then 3-(etho2~yc~ bony~)-4-phenylbutyl bromide (5.7g g, 20.3 mmol) in N,N-dimethylformamide (10 ml) was added dropwise. Upon completion of 10 this addition, the reaction ~Lu~ was stirred for about six hours at a temperature of 70-80~C. The reaction ~u~e was then cooled to room temperature, poured into water (500 ml), and then extracted with ethyl acetate (500 ml). The organic fraction was washed once with water (500 ml) and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 10.28 grams of a dark oil. The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of methylene chloride to 9:1 methylene chloride:ethyl acetate. The fractions cont~inin~ the desired title product were cornhined and concentrated in vacuo to yield 8.08 grams (93%) of a 2 o viscous yellow oil.
NMR and IR were consistent with the proposed title structure.
FDMS 476, 477 (M+) Analysis for C2gH2gN2O3Cl:
Theory: C, 70.50; H, 6.13; N, ~.87.
Found: C, 67.~6; H, 6.22; N, 6.37.

F'x~mple 226 Preparation of 1-~3-(ethoxycarbonyl)~i~)L)yl]-2-[(4-chlorophenoxy)methyl]-3 o 4-methylbçn~:imirl~7 ole CA 02242579 l998-07-08 N

A sodium hydride solution (60% in oil, 325 mg, 8.1 mmol) was washed with h~nes (2 x 50 ml) and then diluted with N,N-dimethylform~ (100 ml). At room temperature, under a nitrogen atmosphere, 2-[(4-chlorophenoxy)methyl]-4-methylbçn~imidazole (2.0 g, 7.3 mmol) was then added in one portion. The resulting ll~i~ule was then stirred at room temperature for thirty minutes, and then 3-(etho~yca~l,onyl)~o~yl bromide (1.58 g, 8.1 mmol) in N,N-0 dimethylform~ 1e (10 ml) was added d~o~wise. Upon completion of this addition, the reaction mixture was stirred for about six hours at a tempela~ule of 70-80~C. The reaction ~ uie was then cooled to room temperature, poured into water (500 ml), and then extracted with ethyl acetate (500 ml). The organic fraction was washed once with water (500 15 ml) and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 3.16 grams of a semi-solid material. The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of methylene chloride to 1:1 methylene chloride:ethyl acetate. The fractions cont~inin~ the desired title product 20 were combined and conc~ntrated in vacuo to yield 2.21 grams (78%) of a viscous yellow oil.
mp 78.~-80~C
NMR was consistent with the proposed title structure.
FDMS 386 (M+) Analysis for C2lH23N203Cl:
Theory: C, 65.20; H, 5.99; N, 7.24.
Found: C, 64.97; H, 6.05; N, 7.23.

F',~z~m~ 7 Preparation of 1-(3-carbo~ybu~yl)-2-~(4-chlorophenogy)methyl]-4-methylben7.imil1~701e ~ CEI3 O=~
OH
To a ~i2~ e of tetrahydrofuran (42 ml), methanol (14 ml), and water (14 ml), were added 1-~3-(ethoxycarbonyl)butyl]-2-[(4-chlorophenoxy)methyl3-4-methylb~n~imidazole (1.3 g, 3.2 mmol) and 15 lithium ll~o~de (403 mg, 3 eq.~. The resulting mi~tllre was stirred overnight at room temperature and was then concentrated in vacuo to yield a white solid. This residue was taken into 250 ml of a 3:1 bllt~nol toluene solution. The organic fraction was washed once with 200 ml of water and then dried over m~gnefiillm sulfate. The solvents 2 o were removed in vacuo to yield 1.22 grams of tan solid, which was further purified by f~ash chromatography, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acetate:meth~n-ll. The fractions cont~ining the desired material were combined and concentrated under reduced pressure to yield 1.12 grams (94%) of the 25 desired title product as a white solid.
mp 149-161~C
NMR and IR were consistent with the proposed title structure.

W O 97/2~041 PCT~US97/00511 FDMS 373 (M+) Analysis for C2oH21N2O3CI:
Theory: C, 64.43; H, ~.68; N, 7.51.
Found: C, 64.62; H, 5.91; N, 7.26.

~"~m~le 228 Preparation of 1-(4-phenyl-3-carbo~ybu~yl~-2-[(4-chlorophenoxy)methyl]-4-methylb~,n 7:i mi dazole '/r- O
OH

To a ~ L~ll e of tetrahydrofuran (84 ml), meth~nol (28 ml), and water (28 ml), were added 1-[3-(ethoxycarbonyl)-4-phenylbutyl]-2-[(4-chlorophen--~y)methyl]-4-methylbenzimidazole (3.05 g, 6.4 mmol) and lithium lly~oxide (788 mg, 3 eq.). The resulting ~.~ixl,...e was stirred overnight at room temperature and was then conc~ntrated in vacuo to yield a white solid. This residue was taken into 2~0 ml of a 3:1 bllt~nr~l toluene solution. The organic fraction was washed once vwith 2 o 200 ml of water and then dried over magnesill~n sulfate. The solvents were removed in vacuo to yield 4.17 grams of tan solid, which was further purified by flash chromatography, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acetate:methanol. The fractions cont~ining the desired material were combined and ~' concentrated under reduced pressure to yield 2.71 grams (94~o) of the desired title product as a white solid.
mp 190-191.~;~C

., NMR and IR were consistent with the proposed title structure.
FDMS 448 (M+) Analysis for C26H2sN2O3Cl:
Theory: C, 6g.~6; H, 5.61; N, 6.24.
Found: (:, 69.77; H, 5.68; N, 6.46.
ny le 2~9 Preparation of 1-(3-carbo~y~ yl)-2-~(4-chlorophenoxy)methyl]-4-methylbe~7imi~7.01e ~, ~ \Y'~~

0~
0~

To a ~ ul e of tetrahy~L oîu~ dll (72 ml), methanol ~24 ml), and water (24 ml), were added 1-[3-(ethoxycarbonyl)~lo~y~]-2-[~4-chlorophenoxy)methyl3-4-methylben7.imitl~7O1e (2.0 g, ~.2 mmol) and lithium hydroxide (642 mg, 3 eq.). The resulting ...; x 1. . . e was stirred overnight at room temperature and was then concentrated in vacuo to yield a white solid. This residue was taken into 2~0 ml of a 3-1 butanol:toluene solution. The org~nic fraction was washed once with 200 ml of water and then dried over m~gn~.qium sulfate. The solvents ~ were removed in vacuo to yield 1.~6 gr~m.q of tan solid, which was further purified by flash chromatography, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acetate:met.h~nol The fractions cont~ining the desired material were combined and concentrated under reduced pressure to yield 1.31 grams (70%~ of the desired title product as a white solid.

- lg2-NMR was consistent with the proposed title structure.
FDMS 3~9 (M+) Analysis for ClgH1gN2O3Cl:
Theory: C, 63.60; H, 5.34; N, 7.81.
Found: C, 63.32; H, 6.26; N, 7.82.

le 230 Preparation of 1-[3-~N-methylcarbamoyl)butyl]-2-~(4-10 chlorophenoxy)methyl]-4-methylben~im~ ole ~CH3 NH

In methylamine (40% in water, 20 ml), 1-[3-15 (etho~ycall/onyl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbqn~imidazole (1.60 g, 3.7 m mol) was placed. To this ,..ixl l.e 10 ml of methanol were added, to enh~nce solubility. The resulting mi~t lre was stirred at room tempel~ule for about 64 hours, after which time the reaction ~ ule was concentrated in vacuo. The 2 o residue was taken up in 200 ml of methylene chloride. The organic fraction was washed once with 200 ml of water. The organic fraction was dried over potassium carbonate and the solvents were removed in vacuo to yield 1.61 grams of a dark oil. The crude material was further purified by flash silica gel chrornatography, eluting with a gradient of 25 methylene chloride to a 1:1 methylene chloride:ethyl acetate ~i~ e.

CA 02242~79 l998-07-08 W O 97/25041 PCT~US97/00511 The fractions cont~inin~ the desired material were comhined and concentrated under reduced pressure to yield ~10 mg(36%) of the desired title product as a white solid.
mp 167.6-168.5~C
NMR and IR were consistent with the proposed title structure.
FDMS 386 (M+) Analysis for C21H24N3O2Cl:
Theory: C, 65.36; H, 6.27; N, 10.89.
Found: C, 65.10; H, 6.46; N, 10.96.
~ n~le 231 Preparation of 1-[3-(N-methylcarbamoyl)-4-phenylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylben7imidazole 0~

In methyl~mine (40% in water, 10 ml), 1-[3-(ethoxycarbonyl)-4-phenylbutyl]-2-~(4-chloroI~h~n o~y)methyl]-4-20 methylbçn7imi~ (1.0 g, 2.5 rnmol) was placed. To this mi~tl1re 10 ml of methanol were added, to enhance solubility. The resulting mixture was stirred at room temperature for about 64 hours, after which time the reaction ~ e was conc~ntrated in vacuo. The residue was taken up in 200 ml of methylene chloride. The organic 25 fraction was washed once with 200 ml of water. The organic fraction W O 97/25041 PCTfUS97/00511 - 1~4-was dried over potas~ium carbonate and the solvents were removed in vacuo to yield 0.967 grams of a viscous oil. The crude material was further purified by flash silica gel chromatography, eluting with a gradient of methylene chloride to a 1:1 methylene chloride:ethyl acetate 5 mixture. The fractions cont~inin~ the desired mslterial were combined and concçnt.rated under reduced pressure to yield 306 mg (26%) of the desired title product as a crystalline material.
mp 169-170.5~C
NMR and IR were consistent with the proposed title structure.
FDMS 461, 462 (M+) Analysis for C27H2gN3O2Cl:
Theory: C, 70.20; H, 6.11; N, 9.09.
Fou~d: C, 6g.91; H, 5.85; N, 9.09.

~ mnle ~.~2 Preparation of 1-[3-(chlorocarbonyl)butyl~-2-[(4-chlorophenoxy)methyl]-4-methylben 7:i mi dazole >--CH3 O=~
Cl Under a nitrogen atmosphere at room temperature 1-[3-(carboxy)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbel~imirl~7:ole (1.2 g, 3.2 mmol) was added in one portion to oxalyl chloride ~ ml) in 25 methylene chloride (1~0 ml). After the material solubilized, one drop of N,N-dimethylformamide was added to initiate the reaction. Bubbling of the solution began and was visible for ~p~ xi~ tely fifteen minutes.

W O 97~5041 PCTAJS97/00511 The reaction .~ixl~l~e was stirred at room temperature for two hours.
The reaction m;~tllre was then concentrated under reduced pressure, reuslting in the formation of a white solid. The solid was triturated in . 100 ml of h~n~s, ~ltered and dried in a vacuum oven at ~0~C for one 5 hours to yield the title product (1.3 g, 91%) as a white solid.
mp 140-142~C
NMR was consistent with the proposed title structure.
FDMS 39Q, 391 (M~) Analysis for C2oH2oN2o2cl:
Theory: C, 61.39; H, 5.15; N, 7.16.
Found: C, ~;6.11; H, 5.00; N, 6.61.

le 233 5 Preparation of 1-r3-(carbamoyl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylben~imi~ ole ~CH3 In an ammonium hydroxide solutiorl (28%, 10 rnl) was placed 1-[3-(chlorocarbonyl)but~rl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (400 mg, 1.0 mmol). To this ~ 10 ml of methanol were added, to çnh~nce solubility and the ~ e was stirred for about 64 hours at room temperature. The reaction mixture was then 25 concentrated under reduced pressure to produce a tan foam. The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl W O 97/25041 PCT~US97/00511 acetate:methanol. The fractions cont~ining the desired material were comhined and concentrated in vacuo to yield 300 mg (73%) of the desired title compound as a white foam.
NMR was consistent with the proposed title structure.
5 FDMS 371.3 (M+) F,~ml?le ~4 Preparation of 1-[3-(N,N-dimethylcarbamoyl)butyl]-2-[(4-10 chlorophenoxy)methyl]-4-methylbe~7.imi~ ole >/~

=~CH3 ~N--CH3 In an dimethylamine (40% in water, 101) was placed 1-[3-15 (chlorocarbonyl)butyl~-2-~(4-chlorophenoxy)methyl~-4-methylb~n~imidazole (600 mg, 1.5 mmol). To this ~ 10 ml of methanol were added, to ~nh~nce solubility and the ~ u~e was stirred for about 64 hours at room tempeldl,-L~e. The reaction mixture was then concentrated under reduced pressure to produce 600 mg as a tan foam.
2 o The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acet~te meth~nol The fractions cont~inin~ the desired material were combined and concentrated in vacuo to yield 37~ mg (63%) of the desired title compound as a white 2 5 foam.
NMR was consistent with the proposed title structure.

W O 97/2S041 PCT~US97/~0511 F~ 23~

Preparation of 1-[4-(methyl~mino)-3-methylbutyl]-2-[(4-5 chloroph çn o~y)meth~rl]-4-methylb~n 7i mi dazole dihydrochloride salt monohydrate ~[~N
~2 HCl ~CH3 NH

lo Under a nitrogen atmosphere 1-~3-~(methylamino)carbonyl]butyl~-2-~(4-chloroph en o~y)methyl] -4-methylben7.inlidazole (100 mg, 0.26 mmol) was added via spatual to a solution of RED-ALTM (2 ml) in 10 ml dry toluene at room tempe. a~
The reaction ~ ,ul~ was then heated to 56~C for fifteen minutes. The 15 reaction ~ ule was cooled to room temperature and poured into 100 ml of water, and was then extracted with 200 ml ethyl acetate. The org~nic fraction was washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo to yield 107 mg of a viscous oil. The crude material was further purified by flash 2 0 chromatography, eluting with 2% ethyl~mine in methanol. The - fractions cont~inin~ the desired title product were combined andconcentrated under reduced pressure to yield 30 mg of a viscous oil ~Yield 31%).
The title desired product was collvel ~ed to the 2 5 dihydrochloride salt by placing the free base in 10 ml ethyl acetate and ~tling a saturated solution of hydrochloric acid in diethyl ether, until W O 97/25041 PCT~US97/00511 solution turned congo red litmus slightly blue. The solvents were removed in vacuo and the resulting white residue was triturated in diethyl ether. Drying at 60~C for one hour yield 32 mg of the dihydrochloride salt as a white solid.
mp 79-81~C
FDMS 371 (M+) Analysis for C21H2gN3OCl ~ 2 HCl ~ H20:
Theory: C,64.49; H, 6.63; N, 9.08.
Found: C,54.65; H, 6.23; N, 8.97.
~ ?le 236 Preparation of 1-[4-(methylamino)-3-benzylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylben7.imidazole dihydrochloride salt lS

~" C 'Y'o~3 ~2 HCl NH

Under a nitrogen atmosphere 1-[3-[(methyl~mino)carbonyl]-4-phenylbutyl~-2-~(4-chlorophenoxy)methyl]-4-20 methylbenzimidazole (470 mg, 0.87 mmol) was added via spatual to a solution of RED-ALTM (3 ml) in 10 ml dry toluene at room temperature.
The reaction mi~l ule was then heated to 55~C~ for fifteen minutes. The reaction mixture was cooled to room temperature and poured into 100 ml of water, and was then extracted with 200 ml ethyl acetate. The 25 organic fraction was washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo to yield 161 mg of a viscous oil. The crude m~teIi~l was further purified by flash chromatography, elnting with 2% ethyl~mine in methanol. The f~ction~ cont~inin~ the desired title product were combined and concentrated under reduced pressure to yield 117 mg of a viscous oil 5 (Yield 30%).
The title desired product was collvel led to the dihydrochloride salt by rl~;n~ the free base in 10 ml ethyl acetate and ~lrlin~ a saturated solution of hydrochloric acid in diethyl ether, until solution turned congo red litmus slightly blue. The solvents were 10 removed in vacuo and the resulting white residue was triturated in diethyl ether. Drying at 60~C for one hour yield 104 mg of the dihydrochloride salt as a white solid.
mp 106-109~C
NMR was consistent with the proposed title structure.
FDMS 448 (M+) Analysis for C27H32N30Cl ~ 2 HCl:
Theory: C, 62.25; H, 6.19; N, 8.07.
Found: C, 63.77; H, 6.33; N, 8.30.

2 o F~n~rle ~-~7 Preparation of 1-[4-(piperidin-1-yl)-3-methylbutyl3-2-[(4-chlorophenoxy)methyl]-4-methylben~imi~ole dihydrochloride salt ~N

~2 HCl <
~ CH3 Under a nitrogen atmosphere 1-[3-[(piperidin-1-yl)carbonyl]butyl~-2-[(4-chlorophenoxy)methyl~-4-methylb~n7imidazole (800 mg, 1.80 mmol) was added via spatual to a solution of RED-ALTM (~;
ml) in 10 ml dry toluene at room temperature. The reaction mixture was then heated to 55~C for fifteen minutes. The reaction ~ e was cooled to room tempe~ and poured into 100 ml of water, and was then extracted with 200 ml ethyl acetate. The organic fraction was lo washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo to yield 700 mg of a viscous oil. The crude material was further purified by flash chromatography, eluting with 2% ethyl~mine in methanol. The fractions contSIining the desired title product were combined and concen~tated under reduced pressure to 15 yield 200 mg of a light yellow oil (Yield 27%).
The title desired product was converted to the dihydrochloride salt by pl~ing the free base in 10 ml ethyl acetate and ing a saturated solution of hydrochloric acid in diethyl ether, until solution turned congo red litmus slightly blue. The solvents were 2 o removed in vacuo and the resulting white residue was triturated in diethyl ether. Drging at 60~C for one hour yielded the dihydrochloride salt as a white solid.
mp 98-102~C
NMR was consistent with the proposed title structure.

W O 97/25041 PCT~US97/00511 FDMS 42~, 426 (M+) Analysis for C2sH34N3OCl ~ 2 HCl:
Theory: C, 60.19; H, 6.87; N, 8.42.
Found: C, 60.33; ~I, 6.88; N, 8.69.

~ m~?le ~.~8 Preparation of 1-[3-[(piperidin-~-yl)carbonyl}-4-phenylbutyl]-2-~(4-chlorophenoxy~methyl]-4-methylbçn7:imi~ 01e ~ \y~O~

To a stirring solution of 1-[3-carboxy-4-phenylbutyl]-2-[~4-chlorophenoxy)methyl]-4-methylb~n~midazole (1.0 g, 2.2 mmol) in N,N-dimethylforms~mi-l~ (75 ml) were added seql1P.nti~lly piperidine (206 mg, 1.1 eq), l-hydlo~y-benzotriazole (327 mg, 1.1 eq), and dicyclohexylcarbodiimide (600 mg, 1.1 eq). The resulting .~ e was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mi~t~lre was then filtered and the resulting filtrate - 20 was concntrated under reduced pressure. This residue was taken into ethyl acetate ~200 ml) and washed once with water (200 ml), dried over potassium carbonate~ The solvents were removed in vacuo to yield 1.84 grams of a tan foam.

W O 97/25041 PCT~US97/OOSll This crude material was purif;ed by flash silica gel chromatography, eluting with a gradient solvent of 9:1 h~ nes:ethyl acetate to 1:1 he~nes:ethyl acetate. The fractions cont~ining the desired material were combined and concentrated under reduced pressure to yield 880 mg (77%) of the desired title product as a VlSCOU8 oil.
The slowly cryst~ ing oil was recrystallized from 10: hq~r~nes:eth acetate to yield 710 mg as a white solid.
mp 93.5-95~C
NMR and IR were consistent with the proposed title structure.
10 FDMS ~i15, ~16 (M+) Analysis for C31H34N3O2Cl:
Theory: C, 72.15; H, 6.64; N, 8.14.
Found: C, 71.88; H, 6.73; N, 7.98.

~ le 239 Preparation of 1-[3-[(piperidin-1-yl)carbonyl]butylJ-2-[(4-chlorophenoxy)methyl]-4-methylbf~n7:irnidazole > CH3 0~
N~

~
To a stirring solution of l-r3-carboxybutyl]-2-~(4-chlorophçno~y)methyl]-4-methylb~n~imidazole (1.2 g, 3.2 mmol) in N,N-dimethylformamide (75 ml) were added sequentially piperidine (299 mg, W O 97/25041 PCT~US97/00511 1.1 eq), 1-lly~o~ybenzotriazole (475 mg, 1.1 eq), and dicyclohexylcarbotliimi~le (726 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The re~ctit~n mi~ re was then filtered and the resulting filtrate 5 was coPl.nt.rated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potas~ium carbonate. The solvents were removed in vacuo to yield 1.78 grams of a tan fo~m.
This crude material was purified by flash silica gel 10 chromatography, eluting with a gradient solvent of 1:1 he~ne,q:ethyl acetate to ethyl acetate. The fractions cont,~ining the desired material were comhined and coI-centrated under reduced pressure to yield 910 mg (65%) of the desired title product as a white foam.
~MR was consistent with the proposed title structure.
FDMS 439.3 (M+) Analysis for C2~H30N3O2Cl:
Theory: C, 68.25; H, 6.87; N, 9.55.
Found: C, 68.54; H, 6.97; N, 9.52.

~.~m~le 240 Preparation of 1-[3-[3-(piperidin-1-yl)~ ylcarb~moyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbçn7imi~1~7.01e W O 97/25041 PCT~US97/00511 ~ N

,) CH3 ~<
N~

To a stirring solution of 1-[3-carboxybutyl]-2-[(4-chlorophenoxy)methyl~-4-methylb~n~imidazole (1.2 g, 3.2 mmol) in N,N-5 dimethylformamide (75 ml) were added sequentially 1-~mino-3-(piperidin-l-y~)propane (500 mg, 1.1 eq), 1-hydroxybenzotriazole (475 mg, 1.1 eq), and dicyclohexylcarbodiimide (726 mg, 1.1 eq). The resulting u~e was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and 10 the resulting f;ltrate was concntrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 2.00 grams of a semi-solid material.
This crude material was purified by flash silica gel 15 chromatography, eluting with a gradient solvent of 9:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate. The fractions cont~;ning the desired material were combined and concentrated under reduced pressure to yield 1.04 g (65%) of the desired title product as a white fo m.
The title product was recrystallized from a 9:1 hexanes:ethyl acetate 20 Ill;Y~ule to yield 800 mg as crystals.

W O 97/25041 PCT~US97/00511 mp 102-103~C
NMR and IR were consistent with the proposed title structure.
FDMS 496, 497 ~M+) s Analysis for C2gH37N4O2Cl:
Theory: C, 67.66; H, 7.~;0; N, 11.27.
Found: C, 67.41; H, 7.79; N, 11.22.
r~le 241 Preparation of 1-[3-[3-(piperidin-1-yl)propylcarbamoyl~-4-phenylbutyl]-2-[(4-chlorophenoxy)methyl~-4-methylben7irnidazole CH3 ~\~Cl \>~~~
$~3 NH

N
\

To a stirring solution of 1-[3-carboxy-4-phenylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylb~n7.imi~7.0le (1.0 g, 2.2 mmol) in N,N-dimethylform~qmi~e (75 ml) were added sequentially 1-amino-3-(piperidin-1-yl)propane (345 mg, 1.1 eq), l-hydlo~yl)enzotriazole (327 mg, 1.1 eq), and dicyclohexylcarbodiimide (500 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room W O 97/25041 PCTnJS97/OQ511 tempe, ~uie for 64 hours. The reaction mi~ was then filtered and the resulting filtrate was conc~nt7~ated under reduced pressure. Tnis residue was taken into ethyl acetate ~200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 1.3~ grams of an orange foam.
Tnis crude material was purified by flash silica gel cllromatography, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to ethyl acetate:methanol. The fractions conts~inin~
the desired material were comhined and concentrated under reduced 10 pressure to yield 960 mg (75%) ofthe desired title product as a slowly cryst~lli7.in~ oil. The title product was recrystallized from a 19:1 h~7nes:ethyl acetate ...;x~ e to yield 800 mg as crystals.
mp 91-93~C
NMR and IR were consistent with the proposed title structure.
FDMS 672-673 ~M+) Analysis for C34H4lN4O2Cl:
Theory: C, 71.25; H, 7.21; N, 9.78.
Found: C, 71.15; H, 7.39; N, 9.67.

F:~7~1e 242 Preparation of 1-~3-~(1,2,3,4-tetrahydroisoql7inolin-l-yl)carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylben 7:imi dazole W O 97/25041 PCTnJS97/00511 -1~ 'Y'~

~CH3 To a stirring solution of 1-[3-carboxybutyl]-2-t(4-chloroph~n--~y)methyl]-4-methylbeIl~imi~ ole (0.800 g, 2.2 mmol) in 5 N,N-dimethylformamide (~0 ml) were added sequentially 1,2,3,4-tetrahydroisoqllinnline (322 mg, 1.1 eq), 1-hydlv~y~enzotriazole (327 mg, 1.1 eq), and dicyclohexylcarbodiimide (500 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction ~ e was then filtered and 10 the resulting filtrate wa~ concntrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in ~racuo to yield 1.24 grams of a dark oil.
This crude material was purified by flash silica gel 15 chromatography, eluting with a gradient solvent of 1:1 hç~nes ethyl acetate to ethyl acetate. The fr~ctionq con~inin~ the desired material were comhine-l and concentrated under reduced pressure to yield 1.04 g of the desired title product as a white foam. The title product was - recrystallized from a 9:1 he~r~nes:ethyl acetate mixture to yield 734 mg 20 (69%) as a white foam.
NMR was consistent with the proposed title structure.
iFl}MS 487, 488 (M+) Analysis for C2gH30N302Cl:
Theory: C, 71.37; H, 6.20; N, 8.61.
Found: C, 70.97; H, 6.20; N, 8.52.

F~mnl e 243 Preparation of 1-[3-~(1,2,3,4-tetrahydronaphth-1-yl~mino)carbonyl]butyl]-2- [(4-chlorophenoxy)methyU-4-methylben ~i mi dazole CE3 ~C~l ~,~ \>/\~~

6~

To a stirring solution of 1-[3-carboxybutyl]-2-[(4-chloropheno~y)methyl]-4-methylben~tmtdazole (0.800 g, 2.2 mmol) in N,N-dimethylformamide (50 ml) were added sequentially 1,2,3,4-1~ tetrahydronaphthalene (356 mg, 1.1 eq), 1-hy~o~ylJenzotriazole (327 mg, 1.~ eq), and dicyclohexylcarbodiimide (~00 mg, 1.1 eq). The resulting ~i~1u~e was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concntrated under reduced pressure. This 2 0 residue was taken into ethyl acetate ~200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were re~noved in vacuo to yield 1.3 grams of a semi-solid. This crude material W O 97125041 PCT~US97/00511 was purified by recrystallization from 9:1 ethyl acetate:ethanol to yield 741 mg (67%) as a white solid.
mp 192-194~C
.. NMR was consistent with the proposed title structure.
FDMS ~01, ~02 (M+) Analy~is for C3OH32N3O2Cl:
Theory: C, 71.77; H, ~.43; N, 8.37.
Found: C, 71.43; H, 6.52; N, 8.22.

~m~les ?.44 and 245 Preparation of (R) 1-[3-[[2-[(2-piperidin- 1-yl)ethyl]piperidin- 1-yl] carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylb~n ~i mi dazole dihydrochloride salt monohydrate[A] and (S~ 1-[3-[[2-[(2-piperidin-1-15 yl)ethyl]piperidin-1-yl]carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylb~n7.imi-1~7.01e dihydrochloride salt [B]

CH3 I~Cl ~N\~ ,CI

~2 HCl ~CH ~ ~2 HCl 0~ and N--~ ,~ CH3 f ~> ~N (R) ~J (S) ~

To a ~tirring solution of 1-[3-carboxybutyl]-2-[(4-chlorophenoxy)methyl]-4-meth;ylbRn~imidazole (0.800 g, 2.2 mmol) in N,N-dimethylformamide (50 ml) were added seq~ f.i~lly (RS) 2-[(piperidin-1-yl)ef~yl]piperidine (475 mg, 1.1 eq), 1-hydlo~ybenzotriazole ~32~ mg, 1.1 eq), and dicyclohexylcarbodiimide (~00 mg, 1.1 eq). The CA 02242579 l998-07-08 W O 97/25041 PCT~US97/00511 resulting mi~ule was then stirred under a nitrogen atmosphere at room tempelatule for 64 hours. The reaction ~;x~u~e was then filtered and the resulting filtrate was concntrated under reduced pressure.
This residue was taken into ethyl acetate (200 ml) and washed once with 5 water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 1.3 gr~ms of the r~c,emP~te as a yellow foam.
The isomers were separated and purified by flash silica gel chromatography, eluting with a solvent gradient of 9:1 ethyl acetaet:methanol to 1:1 ethyl acetate:methanol. Fractions cont.zlining 10 each isomer were then conc~ntrated under reduced pressure and converted to the dihydrochloride salt as a white solid.
Yield: (R) isomer -- 335 mg; (S) isomer 164 mg.
[A]
mp 106-109~C
15 NMR was consistent with the proposed title structure.
FDMS 550, 551 (M+) Analysis for C32H43N4O2Cl ~ 2HCl, ~ H2O:
Theory: C, 59.85; H, 7.38; N, 8.73.
Found: C, 59.89; H, 7.32; N, g.l1.
E~
mp >146~C
N~aR was consistent with the proposed title structure.
FDMS 551 (M+) Analysis for C32H43N4O2Cl ~ 2ECl:
Theory: C, 61.59; H, 7.27; N, 8.98.
Found: C, 61.39; H, 7.05; N, 8.78.

le 246 Preparation of (RS) 1-[3-[[3-(2-methylpiperidin-1-yl~propylamino]carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylb~n~imidazole dihydrochloride salt monohydrate CA 02242579 l998-07-08 W O 97~25041 PCT~US97/00511 CH3 ~Cl ., ~ \>~0 ~2HCl ~ CH3 O-~
NH

~CH3 To a stir{ing solution of 1-[3-carboxybutyl]-2-[(4-chloropheno~y)methyl]-4-methylbçn7.;midazole (1.00 g, 2.7 m~nol) in N,N-dimethylfo~n~ e (60 ml) were added sequentially (RS) 3-(2-met~ylpiperidin-l-yl)propyl~mine (464 mg, 1.1 eq), 1-ll~dl.~Lyl,enzotriazole (402 mg, 1.1 eq), and dicyclohexylcarbodiimide (61 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction ll~i~ule was then filtered and the resulting filtrate was concentrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate.
The solvents were removed in vacuo to yield 1.17 grams of the racemate as an orange solid.
The material was further purified by flash silica gel chron~tography, eluting with a solvent gradient of 1:1 ethyl acetaet:methanol to methanol. Fractions cont7lin;ng the desired title product were then concentrated under reduced pressure and converted to the dihydrochloride salt as a white solid.
~leld 500 mg ofthe free base (36%) mp 8~-87.~~~

W O 97/25041 PCT~US97/00511 NMR was consistent with the proposed title structure.
FDMS 510, ~;11 (M+) Analysis for C32H43N4O2Cl ~ 2HCl ~H20:
Theory: C, 57.8~; H, 7.20; N, 9.31.
Found: C, 58.01; H, 7.1~; N, 9.02.
le 247 Preparation of 1-[3-[~phenylpiperidin-1-yl]carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylberl ~imi dazole hemihydrate CH3 ~ Cl ~C \y'~~

,~ CH3 To a stirring solution of 1-[3-carboxybutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbens:imifl~ole (0.800 g, 2.2 mmol) in N,N-dimethylformamide (50 ml) were added sequentially 4-phenylpiperidine (390 mg, 1.1 eq), 1-hy~o~y~enzotriazole (327 mg, 1.1 eq), and dicyclohexylcarbodiimide (~00 mg, 1.1 eq). The resulting ..-;x~...e was then stirred under a nitrogen at~nosphere at room 2 o temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concentrated under reduced pressure. This residue wa~ taken into ethyl acetate (200 ml) and washed once with r water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 1.04 grams of the title product as an orange foam.
The mAteri~l was fi~rther purified by flash silica gel 5 chromatography, eluting with a solvent gradient of 9:1 ethyl acetate:met~anol to 1:1 ethyl acetate:meth~n..l Fractions cont~inin~
the desired title product were then concentrated under reduced pressure.
Yield: 641 mg (56%) 10 NMR was consistent with the proposed title structure.
FDMS 515, 516 (M+) Analysis for C31H34N3O2Cl ~ 1/2 H2O:
Theory: C, 70.90; H, 6.70; N, 8.00.
Found: C, 70.43; H, 6.96; N, 7.75.
e 248 Preparation of 1-[3-~[3-(piperidin-1-yl)propyl~min~]carbonyl]propyl]-2-[(4-chlorophenoxy)methyl]-4-methylb~n~imidazole dihydrochloride salt ~~

NH

',' ~

W O 97/25041 PCTnJS97/00511 To a stirring solution of 1-[3-carboxypropyl~-2-[(4-chloroph~noxy)methyl]-4-methylben~imi-1~7O1e (0.540 g, 1.5 mmol) in N,N-dimethylformamide (60 ml) were added sequentially 3-(piperidin-1-yl)propyl~mine (23~ mg, 1.1 eq), 1-hydroxybenzotriazole (223 mg, 1.1 eq), and dicyclohexylcarbodiimide (340 mg, 1.1 eq). The resulting ..~ e was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and the resulting filtrate was concentrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 0.731 grams of the title compound as an orange solid.
The material was further purified by flash silica gel chromatography, eluting with methanol. Fractions cont~ining the desired title product were then concentrated under reduced pressure to yield a slowly cryst~lli7:in~ oil.
Yield: 471 mg (6~;%) mp 92-94~C
NMR was consistent with the proposed title structure.
FDMS 482,483 (M+) Analysis for C27H3sN4O2Cl:
Theory: C, 67.14; H, 7.30; N, 11.60.
~ound: C, 66.94; H, 7.23; N, 11.37.

F'~ les 249 and 2~0 Preparation of (RS) 1-[3-[[3-phenylpiperidin- 1-yl]carbonyl~butyl]-2-[(4-chlorophenoxy)methyl]-4-methylb~n7imidazole and (RS) 1-[3-[[3-cyclohe~ylpi~eridin-l-yl]carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4 30 methylbçn~imidazole W O 97t25041 PCT~USg7/00511 ~, Cl C~3 >
~=C and ~ o~CH3 ~ G~

To a stirring solution of 1-[3-carboxyl,ulyl]-2-[(4-chlorophenoxy)methyl]-4-methylber.~imidazole (1.00 g, 2.7 mmol) in 5 N,N-dimethylform~mi-le (50 ml) were added seqllenti~lly a ~0:50 mixture of 3-phenylpiperidine and 3-cyclohexylpiperidine (496 mg total, 1.1 eq), 1-hy~o~yl enzotriazole (402 mg, 1.1 eq), and dicyclohexylcarbodiimide (615 mg, 1.1 eq). The resulting ~ x ~-.. e was then stirred under a nitrogen atmosphere at room tempeIdtule for 64 10 hours. The re~ction mi~t~lre was then filtered and the resulting filtrate was con~ nt.rated under reduced pressure. This residue was taken into ethyl acetate (200 Tnl) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 1.43 grams of a~pl o~ tely a 50:50 ~ u~ e of the title products.
Separation and purification of this mix was ~tt~mpted using a chromatotron with a 4000 micron rotor and eluting with a gradient solvent of he~r~nes to 1:1 ethyl acetate l~ nes. Early fractions cont,~ining an 80:20 mixture of the 3-cyclohexyl derivatives:3-phenyl derivatives were then concentrated under reduced pressure, yi~.lrling 641 2 o mg. Later fractions c~-nt~ining substantially purified 3-phenyl derivatives were combined and coIlGentrated under reduced pressure to yield 200 mg as a white foz~m.
NMR was consistent with the proposed title structures.

~ n~les 251 and 252 Preparation of (RS) 1-[3-[[4-benzylpiperidin- 1-yl]carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylben7imidazole and (RS) 1-[3-[[4-(cyclohexylmethyl)piperidin- 1-yl]carbonyl]butyl]-2-[(4-1 Q chl orophenoxy)methyl] -4-methylbçn 7i m i dazole ~N>~ ~ , ~Cl ~CH3 and >
O

~3 ~~ C

To a stirring solution of 1-[3-carbu~ybu~yl]-2-[(4-chloroph~no~y)methyl]-4-methylben7imi~ ole (1.00 g, 2.7 mmol) in N,N-dimethylformamide (60 ml) were added sequentially a 50:60 u~ e of 4-benzylpiperidine and 4-(cyclohexylmethyl)piperidine (620 mg total, 1.1 eq), l-hydroxybenzotriazole (402 mg, 1.1 eq), and dicyclohexylcarbodiimide (615 mg, 1.1 eq). The resulting ~uLe was 20 then stirred under a nitrogen atmosphere at room tempeld~u~e for 64 ~ hours. The reaction .. ~ix~ e was then filtered and the resulting filtrate was concntrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 1.~1 grams of ~ ox;..~tely a 50:50 ~Ul~ of the title products.
Separation and pl~rif;c~ion of this mix was attempted ~ using a chrom~ollon with a 4000 micron rotor and eluting with a gradient solvent of hç2An~s to 2:1 ethyl acetate h~q~Anes. Early fractions cont~ining substantially purified the 4-benzyl derivatives were then cor centrated under reduced pressure, yielding 481 mg as a white foam.
Later fractions contAining subst~ntiAlly purif;ed 4-cyclohexylmethyl de~iva~iv~s were combined and concentrated under reduced pressure to yield 356 mg as a white foam.
NMR was consistent with the proposed title structures.

F,~A~le 253 Preparation of (RS) 1-[3-~2-phenylethyl~mino]carbonyUbutyl]-2-~(4-chlorophenoxy)methyl]-4-methylben~imillA~ole >~O

>~CH3 O-~
NH

~ 2 o To a stirring solution of (RS) 1-[3-carbo~ylJu~yl]-2-[(4-chlorophenoxy)methyl]-4-methylben7imi~lA~ole (0.~00 g, 1.4 mmol) in N,N-dimethylformamide (40 ml) were added seqllenti~lly 2-W O 97/25041 PCT~US97/00511 phenylethyl~mine (187 mg, 1.1 eq), l-hyd~ ybenzotriazole (208 mg, 1.1 eq), and dicyclohexylcarbodiimide (317 mg, 1.1 eq). The resulting mixture was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction mixture was then filtered and 5 the resulting filtrate was c--ncentrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 0.731 gr~ms of the title product as a white foam.
The material was further purified by flash silica gel chromatography, eluting with a solvent gradient of 1:1 ethyl acetate h~nes to ethyl acetate. Fractions cont~ining the desired title product were then concentrated under reduced pressure, yielding 581 mg (8Q%) as a white solid.
F.~ml?le ~54 Preparation of (RS) 1-[3-~[benzyl~rninoamino]carbonyl~butyl]-2-[(4-chlorophenoxy)methyl~-4-methylbçn~imidazole >~o >~CH3 O-~
NH

W O 97/25041 PCT~US97/00511 ..
To a stirring solution of (RS) 1-[3-carbu~ybulyl]-2-~(4-chlorophenoxy)methyl3-4-methylb~n~imifl~7.ole (0.500 g, 1.4 mmol~ in N,N-dimethylformamide (40 ml) were added sequentially benzylamine (16~ mg, 1.1 eq), 1-hydto~ylJenzotriazole (208 mg, 1.1 eq), and dicyclohexylcarbodiimide (317 mg, 1.1 eq). The resulting ~ e was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction . . . i x ~ . . . e was then filtered and the resulting filtrate was crncentrated under reduced pressure. This residue was taken into ethyl acetate (2()0 ml) and washed once with water (200 ml), dried over 0 potassium carbonate. The solvents were removed in vacuo to yield 0.714 gr~ms of the title product as a white foam.
The material was further purified by flash silica gel chromatography, eluting with a solvent gradient of hexanes to 1:1 ethyl acetate he~nes. Fractions cont~inin~ the desired title product were then concentrated under reduced pressure, yielding 437 mg (68%) as a white solid.
mp 145-146~C
NMR was consistent with the proposed title structure.
FDMS 461, 462 (M+) 2 o Analysis for C27H2gN302Cl:
Theory: C, 70.20; H, 6.11; N, 9.10.
Found: C, 70.44; H, 6.33; N, 8.7881 u?le 25 Preparation of (RS) 1-[3-[(pyrrolidin-1-yl)carbonyl}butyl]-2-[(4-chlorophenoxy)methyl]-4-methylben~imidazole ~N

>~CH3 O-~

To a stirring solution of (RS) 1-[3-carbo~yl~ulyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (0.700 g, 1.9 mmol) in 5 N,N-dimethylformamide (40 ml) were added ~equentially pyrroldine (165 mg, 1.1 eq), l-hydroxybenzotriazole (282 mg, 1.1 eq), and dicyclohexylcarbodiimide (431 mg, 1.1 eq). The resulting llLi~u,e was then stirred under a nitrogen atmosphere at room temperature for 64 hours. The reaction ...i~e was then filtered and the resulting filtrate 10 was concentrated under reduced pressure. This residue was taken into ethyl acetate (200 ml) and washed once with water (200 ml), dried over potassium carbonate. The solvents were removed in vacuo to yield 0.835 grams of the title product as a white foam.
The material was further purified by flash silica gel 15 chromatography, eluting with a solvent gradient of 1:1 ethyl acet,~te:he~n~s to ethyl acetate. Fractions cont~ining the desired title product were then concentrated under reduced pressure, yielding 560 mg (69%) as a white solid.
mp 140-142~C
2 0 NMR was consistent with the proposed title structure.
FDMS 42~ (M+) Analysis for C24H2gN3O2Cl:
Theory: C, 67.67; H, 6.63; N, 9.87.
Found: C, 67.76; H, 6.73; N, 9.84.
~"~zlrnrle 256 W O 97/25041 PCT~US97/00511 -Preparation of (RS) 1-[3-(methyl)-4-[3-(piperidin-1-yl)propyl~mine]butyl]-2-[(4-chloroph en f)~y)methyl~-4-methylban 7i mi dazole trihydrochloride ~ salt monohydrate ~H3 ~3 HCl NEI

N~

~ solution of 1-~3-[3-(piperidin-1-yl)propylcarbamoyl]butyl]-2-~(4-chlorophenoxy)methyl]-4-methylben~imitl~ole (300 mg, 0.6 mmol) 10 in dry tetrahyLoruldn (5 ml) was stirred at room temperature under a nitrogen atmosphere. To this solution borane-tetrahydrofuran complex (3.8 ml of a lM solution in tetrafuran, 6 eq) was syringed dropwise over a two minute period. The solution was then stirred overnight at room tempeld~u~e. To the reaction mi~t~lre was then slowly added, by 15 syringe, a 1:1 solution of tetrahydrofuran and methanol. After the f(!~ming subsided, ~ N sodium hydroxide (2 m-l) was then added by syrine and the resulting mixture was stirred for about sixteen hours under a nitrogen atmosphere at ~;0-60~C. The reaction ~ e was cooled to room temperature and was then diluted with methylene 20 chloride ~10 ml).
The organic fraction was separated and concentrated in vacuo to yield a semi-solid. This residue was taken up into ethyl acetate (50 ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 200 mg of a viscous oil. This oil was further purified using a chromatotron with a 2000 micron rotor, eluting with a gradient solvent of 9:1 ethyl 5 acet~te:m~thanol (with 1 % ammonium hydroxide) to 1:1 ethyl acetate:methanol (with 1 % ~n~monium hydroxide3. Fractions contSIinin~ the desired title product (170 mg, 59%) were collected and the compound was converted to the tri-hydrochloride salt, yielding a white solid.
mp 98-100.5~C
NMR was consistent with the proposed title structure.
FDMS 483 (M+) Analysis for C2gH3gN4OCl ~ 3HCl ~ H2O:
Theory: C, 55.09; H, 7.26; N, 9.18.
Found: C, 55.47; H, 7.12; N, 9.33.

F,~r~mnle ~-~7 Preparation of (RS) 1-~3-(benzyl)-4-[3-(piperidin-1-yl)~opyl~rn;ne]butyl]-20 2-~(4-chlorophenoxy)methyl]-4-methylbçn~imidazole trihydrochloride salt monohydrate Cl ~ '~
~3 HCl N

A solution of 1-[4-phenyl-3-[3-(piperidin-1-yl)~ ylcarbamoyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylben7:imidazole (450 mg, 0.78 mmol) in dry tetrahydl~r udll (5 ml) was stirred at room tempelal ule under a nitrogen atmosphere. To this solution borane-tetrah~dlorulan complex (4.7 ml of a lM solution in tetrafuran, 6 eq) was syringed dl~J~wise over a two minute period. The solution was then stirred overnight at room temperature. To the 0 reaction ~ ule was then slowly added, by syringe, a 1:1 solution of tetrahy ll.~ruldn and met~n-~l . After the fos~ming subsided, 5 N sodium hydroxide (2 ml) was then added by syrine and the resulting .-.;x~...e was stirred for about sixteen hours under a nitrogen atmosphere at 50-60~C. The re~ctio~ Ule was cooled to room tempela~u~e and was 15 then diluted with methylene chloride (10 ml).
The organic fraction was separated and concentrated in - vacuo to yield a semi-solid. This residue was taken up into ethyl acetate ({;O ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 200 mg of a 20 viscous oil. This oil was further purified using a chromatotron with a 2000 micron rotor, eluting with a 9:1 ethyl acetate:methanol (with 1 ~?o ammonium hydroxidle) solution. Fractions cor t~inin~ the desired title W O 97/25041 PCT~US97/00511 product (185 mg, 42%) were collected and the compound was converted to the tri-hydrochloride salt, yielding a white solid.
mp 96-98~C
NMR was consistent with the proposed title structure.
FDMS 559.1 (M+) Analysis for C34H43N40Cl ~ 3H~1 ~ H20:
Theory: C, 59.47; H, 7.04; N, 8.16.
Found C, 59.39; H, 6.87; N, 8.12.

~mnle 258 Preparation of (RS) 1-~3-benzyl-4-~piperidin-1-yl)butyl]-2-[(4-chlorophenoxy)methyl}-4-methylben~imidazole trihydrochloride salt >/~o ~2 HCl <~
A solution of 1-[4-phenyl-3-[~piperidin-1-yl)carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylben~imidazole (400 mg, 0.7 mmol) in dry tetrahyd.oru~dll (5 ml) was stirred at room tempeld~ule under a 20 nitrogen atmosphere. To this solution borane-tetrahyd.ofLI.dll complex (4.5 ml of a lM solution in te~ldru~ , 6 eq) was syringed d-~)~wise over a two minute period. The solution was then stirred overnight at room tempe.d~u~e. To the reaction ~ e was then slowly added, by syringe, a 1:1 solution of tetrahydrofuran and methanol. After the 25 fo~rnin~ subsided, 5 N sodium hydroxide (2 ml) was then added by W O 97/25041 PCT~US97/00511 syrine and the resulting l.~;xl~l~e was stirred for about sixteen hours under a nitrogen atmosphere at ~0-60~C. The reaction mixture was cooled to room tempe~tule and was then diluted with methylene chloride (10 ml).
The organic fraction was ~eparated and concentrated in vacuo to yield a semi-solid. This residue was taken up into ethyl acetate (50 ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 350 mg of a viscous oil. This oil was further purified using a chromatotron with a 10 2000 micron rotor, eluting with a gradient solvent of 9:1 ethyl acetate:methanol (with 1 % ~mmon;um hydroxide) to 1:1 ethyl acetate:methanol (with 1 % ammonium hyLo~ide). Fractions conkiining the desired title product (195 mg, ~6~o) were collected and the compound was converted to the di-hydrochloride salt, yielding a white 15 solid.
mp 120-123~C
NMR was consistent with the proposed title structure.
FDMS ~01, ~02 (M+) Analysis for C31H36N30Cl ~ 2HCl:
Theory: C, 64.76; H, 6.66; N, 7.31.
Found: C, 64.60; H, 6.36; N, 7.31.
h',~sln~le 2~9 25 Preparation of (RS~ 1-[3-(methyl)-4-a_inobutyl]-2-[(4-chlorophenoxy)methyl3-4-methylbçn~imidazole dihydrochloride salt monohydrate CH3 ,~\,,Cl ~N

~CH3 < ~2 HCl A solution of 1-~3-carbamoylbutyl]-2-U4-chlorophenoxy)methyl]-4-methylben7imidazole (350 mg, 0.94 mrnol) in 5 dry tetrahyd. or~dn (~ ml) was stirred at room tempela~u~e under a nitrogen atmosphere. To this solution borane-tetrahydrofuran complex (~.7 ml of a lM solution in tetrafuran, 6 eq) was syringed d~ wise over a two minute period. The solution was then stirred overnight at room temperature. To the reaction mixture was then slowly added, by lQ syringe, a 1:1 solution of tetrahy~oru.dn and methanol. After the foaming subsided, 5 N sodium hydroxide (2 ml) was then added by syrine and the resulting ..~ e was stirred for about sixteen hours under a nitrogen atrnosphere at 50-60~C. The reaction mixture was cooled to room temperature and was then diluted with methylene 15 chloride (10 ml).
The organic fraction was separated and concentrated in vacuo to yield a semi-solid. This residue was taken up into ethyl acetate (~0 ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 260 mg of a 20 viscous oil. This oil was further purified using a chromatotron with a 2000 micron rotor, eluting with a gradient solvent of 1:1 ethyl acetate:methanol to methanol. Fractions Cont~ining the desired 1itle product (69 mg, 21%) were collected and the compound was converted to the dihydrochloride salt, yielding a white solid.
25 mp >1~0~C
NMR was consistent with the proposed title structure.
FDMS 3~7.2 (M+) W O 97/25041 PCTnJS97/00511 Analysis for C20H24N3OCI ~ 2H(~l ~ H20:
Theory: C, 63.51; H, 6.29; N, 9.36.
Found: C, 53.22; H, 6.10; N, 9.28.

F'.~AmI?le 260 Preparation of (RS) 1-[3-(methyl)-4-dimethyl~minobutyl]-2-[(4-chlorophenoxy)methyl]-4-methylben7imidazole ~~

~CH3 N(CH3)2 A solution of 1-~3-[(N,N-dimethylzlmino)carbonyl]butyl]-2-[(4-chloroph~noxy)methyl]-4-methylben7imidazole (350 mg, 0.88 mmol) in dry tetrahydlofuldn (5 ml) was stirred at room temperature under a nitrogen atmosphere. To this solution borane-tetrahydrofuran complex (5.3 ml of a lM solution in te~la~uldll, 6 eq) was syringed dro~wise over a two _inute period. The solution was then stirred overnight at room temperature. To the reaction ~ ule wa~ then slowly added, by syringe, a 1:1 solution of tetrahyJ~ofulall and methanol. After the 2 o fo~ming subsided, 5 N sodium hydro~ide (2 ml) was then added by syrine and the resulting .l~;xl~lle was stirred for about sixteen hours under a nitrogen atmosphere at 50-60~C. The re~c*o~ mixture was - cooled to room temperature and was then diluted with methylene chloride (10 ml).
The organic fraction was separated and concentrated in vacuo to yield a semi-solid. This residue was taken up into ethyl acetate (50 ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo~ yielding 295 mg of a W O 97/25041 PCTnJS97/00511 viscous oil. This oil was further purified using a chromatotron with a 2000 micron rotor, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 1:1 ethyl acetate:metll~nol Fractions Cont.SIining the desired title product (200 mg, 21%) were collected.
mp 80-82~C
NMR was consistent with the proposed title structure.
FDMS 385.2 (M+) Analysis for C22H2gN3OCl:
Theory: C, 68.47; H, 7.31; N, 10.89.
0 Found: C, 68.~ I, 7.45;N, 11.07.

F~r~ ?le 261 Preparation of (R) 1-[4-~2-[(2-piperidin- 1-yl~ethyl]piperidin-1-yl]-3-15 methylbutyl]-2-[(4-chlorophenoxy)methyl]-4-methylbçn~imidazole trihydrochloride salt hemihydrate ~ >~o ~3 HCl ~CH

N--~
G~>

2 o A solution of (R) 1-[4-[[2-[(2-piperidin-1-yl)ethyl]piperidin-1-yl~carbonyl]butyl]-2-[(4-chloroph~no}~y)methyl]-4-methylben7imidazole dihydrochloride salt monohydrate (13~ mg, 0.2~ mmol) in dry tetrahydrofuran (5 ml) was stirred at room temperature under a nitrogen atmosphere. To this solution borane-tetrahy~loful~n complex (1.8 ml of a lM solution in te~ldru~dn, 6 eq) was syringed dropwise over a two minute period. The solution was then stirred overnight at room temperature. To the reaction ~ u~e was then slowly added, by - syringe, a 1:1 solution of tetrahy~roruldn and methanol. After the 5 ~min~ subsided, ~ N sodium hydro~ide (2 ml) was then added by syrine and the resulting ~i~e was stirred for about sixteen hours under a nitrogen atmosphere at ~i0-60~C. The reaction mixture was cooled to room temperature and was then diluted with methylene chloride (10 ml).
The org~nic fraction was separated and concentrated in vacuo to yield a sem;-solid. This residue was taken up into ethyl acetate (50 ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 105 mg of a viscous oil. This oil was further purified using a chromatotron with a 2000 micron rotor, eluting with metll~n.~l. Fractions cont~ininf~ the desired title product (73 mg, 55%) were collected and converted to the trihydrochloride salt, yielding a white solid.
mp 103-106~C
NMR was consistent with the proposed title structure.
FDMS 537 (M+) Analysis for C32H4sN4OCl ~ 3 HCl ~ 1/2 H2O:
Theory: C, 58.62; H, 7.53; N,8.55.
Found: C, 58.32; H, 7.22; N, 7.93.

Analysis for C32H4sN4OCl:
Theory: C, 71.55; H, 8.44; N, 10.43.
Found: C, 71.25; H, 8.49; N, 10.19.

~mnle 262 Preparation of (S) 1-~4-t2-[(2-piperidin-1-yl)ethyl]piperidin-1-yl]-3-methylbutyl]-2-[(4-chloroph~nc)~y)methyl]-4-methylben7:imidazole trihydrochloIide salt hemihydrate W O 97/25041 PCTAJS97/OOSll CH3 ~,Cl ~C Y'~

~3 HCl (~
<~ CH3 N~
GN \ "" <

The title compound was prepared essentially as described for the R siomer, except that (S) 1-[4-[[2-[(2-piperidin-1-yl)ethyl]piperidin-5 1-yl]carbonyl]butyl]-2-[(4-chlorophen oxy)methyl]-4-methylben 7.imi dazole dihydrochloride salt monohydrate was employed as a starting material.
le 263 Preparation of (RS) 1-[3-(methyl)-4-(1,2,3,4-tetrahydroisoquinolin-1-yl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylben ~imi dazole [~N>~O

<~CH3 W O 97/25041 PCT~US97/00511 .;

A solution of 1-[3-[(1,2,3,4-tetrahydroisoqllinolin-1-yl)carbonyl]butyl~-2-[(4-chloropheno~y)methyl]-4-methylbçn7imitlsl7Ole (37~ mg, 0.76 mmol) in dry tetrahydro~uran (5 ml~ was stirred at room 5 temperature under a nitrogen atmosphere. To this solution borane-tetrah~oru~all complex (4.6 ml of a lM solution in tetrafuran, 6 eq) was syringed dro~wise over a two minute period. The solution was then stirred overnight at room temperature. To the reaction ~ ule was then 810wly added, by syringe, a 1:1 solution of tetrahydrofuran and 10 methanol. After the fo~min~ subsided, 6 N sodium hydroxide (21) was then added by syrine and the resulting ~ e was stirred for about sixteen hours under a nitrogen atmLosphere at 50-60~C. The react,ion mixture was cooled to room temperature and was then diluted with methylene chloride (10 ml).
The organic fraction was separated and concentrated in vacuo to yield a semi-solid. This residue was taken up into ethyl acetate (60 ml), washed once with water, and then dried over potassi7~n carbonate. The solvents were removed in vacuo, yielding 340 mg of a slowly c~yst~lli7.in~ viscous oil. This oil was further purified by 2 o recryst,~lli7.~tio~ from ethyl acetate to yield the desired title product (183 mg, 52%) as white crystals.
mp 114.6-116~C
NMR was consistent with the proposed title structure.
FDMS 474 (M+) 25 Analysis for C2gH32N3OCl:
Theory: C, 73.48; H, 6.80; N, 8.86.
Found: C, 73.18; H, 6.82; N, 8.67.

~mJ le 264 Preparation of (RS) 1-[3-(methyl~-4-(1,2,3,4-tetrahydronaphth-1-yl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylb~n7imidazole dihydrochloride salt W O 97/25041 PCT~US97/00511 \>~~~

>~CH3 ~2 HCl A solution of 1-[3-[(1,2,3,4-tetrahydronaphth-1-yl)carbonyl]butyl]-2-[(4-chlorophenoxy)methyU-4-methylb~n~imidazole (52~ mg, 1.05 mmol) in dry tetrahydrofu~ (5 ml) was stirred at room temperature under a nitrogen atmosphere. To this solution borane-tetrahydrofuran complç~ (6.3 ml of a lM solution in tetl~uran~ 6 eq) was syringed dropwise over a two minute period. The solution was then stirred overnight at room temperature. To the reaction mixture was 10 then slowly added, by syringe, a 1:1 solution of tetrahydrofuran and methanol. ~fter the fo~rning subsided, ~ N sodium hydroxide ~2 ml) was then added by syrine and the resulting ~il~u~e was stirred for about sixteen hours under a nitrogen atmosphere at 50-60~C. The reaction mixture was cooled to room tempe~a~ule and was then diluted with 15 methylene chloride (10 ml).
The organic fraction was separated and concentrated in vacuo to yield a semi-solid. This residue was taken up into ethyl acetate (~0 ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 487 mg of a 20 viscous oil. This oil was further purified via a chromatotron using a 4000 micron rotor, eluting with ethyl acetate to yield the desired title product (325 mg, 64%) as a clear viscous oil. The title product was then converted to the dihydrochloride salt, yielding a white solid.
mp 116-118.5~C

W O 97/2~041 PCT~US97/00511 -NMR was consistent with the proposed title ~tructure.
FDMS 487, 488 (M+) Analysis for C30H34N3OCl ~ 2 HCl:
Theory: C, 64.23; H, 6.47; N, 7.49.
Found: C, 64.04; H, 6.3~; N, 7.35.

~ Tn}?1e 265 Preparation of (RS) 1-~3-(methyl)-~(4-phenylpiperidin-1-yl)butyl]-2-[(4-10 chl orophenoxy)methyl]-4-methylb~n ~i mi dazole dihydrochloride salt ~~

~CH3 A solution of 1-[3-[(4-phenylpiperidin-1-yl)carbonyl]butyl~-2-[(4-chlorophenoxy)methyl]-4-methylb~n~imidazole (560 mg, 1.07 mmol) in dry tetrahyd~or~lan (5 ml) was stirred at room temperature under a nitrogen atmosphere. To this solution borane-tetrahydrofuran complex - (6.7 ml of a lM solution in tetrafuran, 6 eq) was syringed dlo~wise over a two minute period. The solution was then stirred overnight at room 20 temperature. To the reaction ~ure was then slowly added, by syringe, a 1:1 solution of tetrahydrofuran and methanol. After the foaming subsided, ~; N sodium hydroxide (2 ml) was then added by syrine and the resulting ...,~ e was stirred for about sixteen hours W O 97/25041 PCT~US97/00511 under a nitrogen atmosphere at 50-60~C. The reaction I~ ule was cooled to room temperature and was then diluted with methylene chloride (10 ml).
The organic fraction was separated and crnc.qntrated in 5 vacuo to yield a ~emi-solid. This residue was taken up into ethyl acetate (50 ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 531 mg of a a white solid. This material was further purified by recryst~ tion from 5:1 he~ne,s:ethyl acetate, yielding a white solid (385 mg, 72~o).
mp 124-125~C
NMR was consistent with the proposed title structure.
FDMS 501, 502 (M+) Analysis for C31H36N3OCl:
Theory: C, 74.16; H, 7.23; N, 8.37.
Found: C, 74.42; ~I, 7.35; N, 8.41.

F.~rr~le 266 Preparation of (RS) 1-~3-(methyl)-4-(3-phenylpiperidin-1-yl)butyl]-2-[(4-20 chlorophenoxy)methyl]-4-methylb~n~imidazole dihydrochloride salt CH3 I~C

\>~~~

< ~2 HCl <~CH3 <~

A solution of 1-[3-[(3-phenylpiperidin-1-yl)carbonyl]butyl]-2-~(4-chlorophenoxy)methyl]-4-methylben7imidazole (200 mg, 0.380 mmol) in dry tetrahydlo~u~ (5 ml) was stirred at room temperature under a nitrogen atmosphere. To this solution borane-tetrahy~h~rul~l comple~
(6.3 ml of a lM solution in tetrafuran, 6 eq) was syringed dropwise over a two minute period. The solution was then stirred overnight at room temperature. To the reaction ~i~ was then slowly ~ lefl~ by 5 syringe, a 1:1 solution of tetrah~ orulan and methanol. A~ter the fo~rnin~ subsided, 5 N sodium hydroxide (2 ml) was then added by syrine and the resulting ...;xI...e was stirred for about sixteen hours under a nitrogen atmosphere at 50-60~C. The reaction ~ a was cooled to room temperature and was then diluted with methylene lo chloride (10 ml).
The organic fraction was separated and concentrated in vacuo to yield a semi-solid. This residue was taken up into ethyl acetate (50 ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 176 mg of a 15 yellow oil. T~is oil was further purified via a chromatotron using a 2000 micron rotor, eluting with ethyl acetate to yield the desired title product ~113 mg, 59%) as a clear viscous oil. The title product was then converted to the dihydrochloride salt, yielding a white solid.
mp 84-86.5~C
2 o NMR was consistent with the proposed title structure.
FDMS 501, ~;02 (M+) Analysis for C3~H36N30Cl ~ 2 HCl ~ 1 1/2 H20:
Theory: (:, 6L83; H, 6.86; N, 6.98.
Found: C, 61.98; H, 6.46; N, 6.81.
le Z67 Preparation of (RS) l-r3-(met~yl)-4-(2-phenylethyl~mino)butyl]-2-[(4-chloroph ~n o~y)methyl]-4-methylben 7.i mi dazole dihydrochloride salt ,, W O 97/25041 PCT~US97/00511 ~N

~CH3 ~2 HCl N

6~

A solution of 1-[3-t(2-phenylethyl~min~ )carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbçn7.iminz~7O1e (62~ mg, 1.06 mmol) 5 in dry tetrahydloru.,m (6 ml) was stirred at room temperat7ure 7lnder a nitrogen atmosphere. To this solution borane-tetrahydrofuran complex (6.3 ml of a lM solution in tetrafuran, 6 eq) was syringed dlopwise over a two minute period. The solution was then stirred overnight at room te..l~elalu~e. To the reaction mixture was then slowly added, by 10 syringe, a 1:1 solution of tetrahydl~)ru~ and methanol. After the fo~min~ subsided, 5 N sodil7m hydroxide (2 ml) was then added by syrine and the resulting ~;x~ l~e was stirred for about sixteen hours under a nitrogen atmosphere at 60-60~C. The reaction mixture was cooled to room temperature and was then diluted with methylene 15 cnloride (10 ml).
The organic fraction was separated and concentrated in vacuo to yield a semi-solid. This residue was taken up into ethyl acetate (50 ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yiçl~in~ 370 mg of a 20 viscous oil. This oil was further purified via a chromatotron using a 2000 micron rotor~ eluting with ethyl acetate to yield the desired title W O 97125041 PCT~US97/00511 product (160 mg, 31%) as a clear viscous oil. The title product was then converted to the dihydrochloride salt, yielding a white solid.
mp 84-87.5~C
NMR was consistent with the proposed title struc~ure.
5 FDMS 462 (M+) Analysis for C2gH32N3OCl ~ 2 HC: l ~ 1/2 H20:
Theory: C, 61.81; H, 6.49; N, 7.72.
Found: C, 61.98j H, 6.35; N, 7.79.

~ m~le 268 Preparation of (RS) 1-r3-(methyl)-4-(3-(piperidin-1-yl)propylamino)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylben~imidazole trihydrochloride salt >~o <?~rCH3 ~3 HCl NH

A solution of 1-[3-[~3-(piperidin-1-yl)~ro~ylamino)carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylben~imi~ ole (400 mg, 0.85 mmol) in dry tetrahydrofuran (~; ml) was stirred at room tempe~a~uLe under a nitrogen atmosphere. To this solution borane-tetrahy~ rllran complex (6.3 nnl of a lM solution in W O 97/25041 PCT~US97/00511 tetrafuran, 6 eq) was syringed dlol~wise over a two minute period. The solution was then stirred overnight at room temperature. To the reaction ~ ule was then slowly added, by syringe, a 1:1 solution of tetrahyLoru~n and methanol. After the fo:~min~ subsided, 6 N sodium 5 hydroxide (2 ml) was then added by syrine and the resulting ~;xL~--e was stirred for about sixteen hours under a nitrogen atmosphere at 50-60~C. The reaction mixture was cooled to room tempel~ e and was then diluted with methylene chloride (10 ml).
The organic fraction was ~eparated and concentrated in vacuo to yield a semi-solid. This residue was taken up into ethyl acetate (~;() ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 380 mg of a viscous oil. This oil was further purified via a chromatotron using a 2000 micron rotor, eluting with a gradient of ethyl acetate to 1:1 ethyl acetate:methanol (with 1% ~mmonium hydro~ide) to yield the desired title product (113 mg, 28%) as a clear viscous oil. The title product was then col~velled to the trihydrochloride salt, yielding a white solid.
NMR was consistent with the proposed title structure.
FDMS 469 (M+) Analysis for C27H37N40Cl ~ 3 HCl ~ 1/2 H20.
Theory: C, 67.82; H, 8.01; N, 11.72.
Found: C, 67.73; H, 8.20; N, 11.59.

Preparation of (RS) 1-[3-(methyl)-4-(benzyl~mino)butyl]-2-[(4-chlorophenoxy~methyl]-4-methylb~n7.imidazole W O 97n5041 PCT/US97/00511 \>~0 ~CH3 NH
<3 A solution of 1-[3-[(benzyl~mino)carbonyl]butyl]-2-[(4-chloroph~no~y)methyU-4-methylben~imidazole (500 mg, 1.05 mmol) in 5 dry tetrahydrofuran (5 ml ) was stirred at room tempel a~ e under a nitrogen atmosphere. To this solution borane-tetrahydrofuran complex (6.0 ml of a lM solution in tetrafuran, 6 eq) was sy~inged d~o~wise over a two minute period. The solution was then stirred overnight at room temperature. To the reaction ~l u~e was then slowly added, by 10 syringe, a 1:1 solution of tetrahydrofuu~n and methanol. After the foaming subsided, 5 N sodium hydroxide (2 ml) was then added by syrine and the resulting ~i~luLe was stirred for about sixteen hours under a nitrogen atmosphere at 50-60~C. The reaction ~u~e was cooled to room temperature and was then diluted with methylene 15 chloride (10 ml).
The organic fraction was separated and concentrated in vacuo to yield a semi-solid. This residue was taken up into ethyl acetate (50 ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 315 mg of a 20 semi-solid. This oil was fur~her purified via a chromatotron using a 2000 micron rotor, eluting with ethyl acetate to yield the desired title product (190 mg, 4()%) as a slowly cryst~ in~ oil.
mp 84.~-87~C
NMR was consistent with the proposed title structure.

W O 97/25041 PCT~US97/00511 FDMS 447, 448 (M~) Analysis for C27H3~N3OCl:
Theory: C, 72.37; H, 6.75; N, 9.38.
Found: C, 72.67; H, 6.75; N, 9.25.

~ rru?le 270 Preparation of (RS) 1-[34methyl)-4-(pyrrolidin-1-yl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylb~n~imidazole CH3 ~ Z Cl \>~~~

~CH3 A solution of 1-[3-[(pyrrolidin-1-yl)carbonyl~butyl]-2-[(4-chlorophenoxy)methyl]-4-methylben7imidazole (500 mg, 1.17 mmol) in 15 dry tetrahydfo~uran (5 ml) was stirred at room tempelalule under a nitrogen atmosphere. To this solution borane-tetral~dl.3rlllan complex (6.2 ml of a lM solution in tetrafuran, 6 eq) was syringed dropwise over a two minute period. The solution was then stirred overnight at room tempeltl~ule. To the reaction mixture was then slowly added, by 20 syringe, a 1:1 solution of tetrahydrofuran and methanol. After the foaming subsided, 5 N sodium hydroxide (2 ml) was then added by syrine and the resulting l~ ,Ule was stirred for about sixteen hours under a nitrogen atmosphere at 50-60~C. The reaction mixture was cooled to room temperature and was then diluted with methylene 25 chloride (10 ml).

The organic fraction was separated and concentrated in vacuo to yield a semi-solid. This residue was taken up into ethyl acetate (50 ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 326 mg of a 5 semi-solid. This oil was filrther purified v~a a chromatotron using a 2000 micron rotor, eluting with a gradient of ethyl acetate to 1:1 ethyl acetate:methanol to yield the desired title product (225 mg, 47%) as a white solid.
mp 8~-87~C
10 NMR was consistent with the proposed title structure.
FDMS 411 (M~) Analysis for C24H30N3OCl:
Theory: C, 69.97; H, 7.34; N, 10.20.
Found: C, 69.78; H, 7.29; N, 10.31.
m.l?l e 271 Preparation of (RS) 1-[3-(methyl~-4-(3-benzylpiperidin-1-yl)butylJ-2-[(4-chlorophenoxy)methyl]-4-methylbçn 7:i mi~ ole dihydrochloride salt \>~0 ~rCH3 f~

solution of 1-[3-[(3-benzylpiperidin-1-yl)carbonyl~butyl3-2-~4-chloroph~no~y)methyl]-4-methylbcn~imi(l~ole (360 mg, 0.68 mmol) 25 in dry tetrahydrofuran (~ ml) was stirred at room temperature under a nitrogen atmosphere. To this solution borane-tetrahydrofuran complex W O 97/2504} PCTnUS97/00511 - 2~2-(4.1 ml of a lM solution in tetrafuran, 6 eq) was syringed L~wise over a two minute period. The solution was then stirred overnight at room tempelaLule. To the reaction ~ u~e was then slowly added, by syringe, a 1:1 solution of tetrahydrofuran and methanol. After the 5 foaming subsided, 5 N sodium hydroxide (2 ml) was then added by syrine and the resulting ~i2~u- e was stirred for about sixteen hours under a nitrogen atmosphere at ~0-60~C. The reaction ..~ ~e was cooled to room tempe~al u~e and was then diluted with methylene chloride (10 nnl), The organic fraction was separated and concentrated in ~acuo to yield a semi-solid. This residue was taken up into ethyl acetate (50 ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 330 mg of a viscous oil. This oil was further purified via a chromatotron using a 15 2000 micron rotor, eluting with ethyl acetate to yield the desired title product (250 mg, 71%) as a slowly cryst~ inF oil.
mp 95-97~C
NMR was consistent with the proposed title structure.
FDMS 515,516 ~M+)~0 Analysis for C32H3gN3OCl:
Theory: C, 74.46; H, 7.42; N,8.14.
Found: C, 74.74; H, 7.62; N, 8.03.

F~3rr~l?1e 272 Preparation of (RS) 1-[3-(methyl)-4-(3-cyclohexylmethylpiperidin-1-yl)butyl]-2-[~4-chlorophenoxy)methyl]-4-methylben ~i mi ~ ole dihydrochloride salt trihydrate WO 97~5041 PCT~US97/00511 -CH3 ~Cl ~C \Y'~~

~CH3 ~2 HCl N--~

A solution of 1-~3-~(3-cyclohexylmethylpiperidin-1-yl)carbonyl]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylben~imidazole (360 mg, 0.67 mmol) in dry tetrahyd~o~u~an (5 ml) was stirred at room temperature under a nitrogen atmosphere. To this solution borane-tetrahydl,Jru~ complex (4.0 ml of a lM solution in tetrafuran, 6 eq) was syringed (Lo~wise over a two minllte period. The solution was then stirred overnight at room temperature. To the reaction mixture was then slowly added, by syringe, a 1:1 solution of tetrahydrofuran and met~nol After the foaming subsided, 5 N sodium hydroxide (2 ml) was then added by syrine and the resulting mixture was stirred for about sixteen hours undLer a nitrogen atmosphere at 50-60~C. The reaction mixture was cooled to room temperature and was then diluted with methylene chloride (10 ml).
The organic fraction was separated and concentrated in vacuo to yield a semi-solid. This residue was taken up into ethyl acetate (~0 ml), washed once with water, and then dried over potassium carbonate. The solvents were removed in vacuo, yielding 232 mg of a viscous oil. This oil was further purified via a chromatotron using a 2000 micron rotor, eluting with ethyl acetate to yield the desired title product (160 mg, 46%) as a clear viscous oil. The title product was then converted to the dihydrochloride salt, yielding a white solid.
mp 52-56~C

NMR was consistent with the proposed title structure.
FDMS 521,522 ~M+) Analysis for C32H44N3OCl ~ 2 HCl ~ 3 H20:
Theory: C, 59.20; H, 8.08; N, 6.47.
Found: C, 59.43; H, 7.60; N, 6.37.

Analysis for C32H44N30Cl ~ 1/2 H20:
Theory: C, 72.35; H, 8.54; N, 7.9L
Found: C, 72.7~; H, 8.57; N, 7.86.~0 m~le ~73 Preparation of ~RS) 1-[3-~methyl)-4-t3-(2-methylpiperidin-1-yl)propylamino]butyl] -2-[(4-chlorophenoxy)methyl]-4-15 methylben7:imidazole trihydrochloride salt monohydrate >~o ~CH3 ~3 HCl NH

A solution of 1-[3-[3-(2-methylpiperidin-1-20 yl)propyl~mino]butyl]-2-[(4-chlorophenoxy)methyl]-4-methylb~n7imi~7ole (350 mg, 0.69 mmol) in dry tetrahydror~dn (5 ml) was stirred at room temperature under a nitrogen atmosphere. To this W O 97/25041 PCTrUS97/00511 solution borane-tetrahy~oru~an complex (4.3 ml of a lM solution in tetrafuran, 6 eq) was ~y~inged dropwise over a two minute period. The solution was then stirred overnight at room temperature. To the reaction ~ ,Ul'e was then slowly added, by syringe, a 1:1 solution of 5 tetrahydrofuran and methanol. After the foaming subsided, 5 N sodium hydroxide (2 ml) was then added by syrine and the resulting ..,ixl.l~
was stirred for about sixteen hours under a nitrogen atmosphere at ~0-60~C. The reaction mixture was cooled to room temperature and was then diluted with methylene chloride (10 ml).
The organic fraction was separated and concentrated in vacuo to yield a semi-solid. This residue was taken up into ethyl acetate (50 ml), washed once with water, and then dried over potassium carbonate. The ~olvents were removed in vacuo, yielding 320 mg of a viscous oil. This oil was filrther purified via a chromatotron using a 2000 micron rotor, eluting with 1:1 ethyl acetate:methanol (with 1%
~n~m~nium llyLo~de) to yield the desired title product (151 mg, 44%) as a clear viscous oil. The title product was then converted to the trihydrochloride salt, yielding a white solid.
NMR was consistent with the proposed title structure.
2 o FDMS 497 ~M+) Analysis for C2gH44N4OCl ~ 3 HCl ~ H2O:
Theory: C, 55.76; H, 7.42; N, 8.97.
Found: C, 55.70; H, 7.21; N, 9.04.

l~ ?le ~74 Preparation of 2-(4-chloroph~no~ymethyl)-4-[3-[1-(t-buto~y~ onyl)piperidin-4-yl]propoxy]-1-[3-~1-(~-butoxycarbonyl)piperidin-4-yl]~l v~l]ben~;midazole WO 97/25041 PCTnJS97/00511 BoC
o N ~Cl ~ BoC

A solution of 4-hyd~o~y-2-(4-chlorophçno~ymethyl)ben7:imidazole (500 mg, 1.82 mmol) in dry N,N-5 dimethylform~mide (8 ml) was treated with sodium hydride (60% inmineral oil, 162 mg, 4.0 mrnol, 2.2 eq). The resulting mi~ e was stirred at room temperature under a stream of nitrogen for about one hour. To this reaction mi~tllre 3-[1-(t-buto~ycalbonyl~piperidin-4-yl)propyl bromide (4.0 mmol, 2.2 eq) was added and the resulting 10 mixture was stirred for three hours at 70~C. The reaction was quenched by the addition of 10 ml of water. The aqueous fraction was extracted with ethyl acetate (3 x 10 ml). The organic fractions were comhined and washed with water (2 x 10 ml), and then brine (1 x 10 ml), and then dried over magnesium sulfate. The solvents were removed in vacuo to yield a 15 light b.~w.~ish crude material. The desired title product was fi~rther purified by flash chromatography. There is some substitution at the 7-position of the bçn~imidazole present, although the 4-substituted is the major isomer.
NMR was consistent with the proposed title structure.

W O 97/25041 PCT~US97/00511 -FDMS (M+) 72~.

~"~m,ple 276 Preparation of 2-(4-chloropheno~ymethyl)-4-[3-(piperidin-4-yl)propoxy~-1-[3-(piperidin-4-yl)propyl]ben7.imi~ ole ~~~Cl ~,NH

The title compound is prepared from 2-(4-chloroph~no~ymethyl)-4-[3-~1-(t-buto~yca~l~onyl3piperidin-4-yl]propoxy~-1-[3-~1-(t-buto~yca bonyl)piperidin-4-yl]propyl]b.3n~imidazole by standard deprotection techniques using trifluoroacetic acid.
NMR and IR were consistent with the proposed title structure.
FDMS (M+) !i2~;
Ar~alysis for C30H4lClN4O2:
Theory: C, 54.22; H, ~.7~; N, 7.44.
Found: C, 53.97; H, ~.48; N, 7.26.

~"~ le 276 Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[3-[1-(t-buto~ycal l~onyl)piperidin-3-yl]propoxy]- 1-[3-[1-(t-5 butoxycarbonyl)piperidin-3-yl]~l o~yl]b~n ~im; dazole S N--BoC

N~ V~ Cl <~GN~BoC

A solution of 4-hydlo~y-2-(4-chloropheno~ymethyl)bçn~imidazole (~00 mg, 1.82 mrnol) in dry N,N-dimethylformamide (8 ml) was treated with sodium hydride (60% in mineral oil, 162 mg, 4.0 mmol, 2.2 eq). The resulting ~i~u~e was stilred at room temperature under a stream of nitrogen for about one hour. To this reaction mixture (RS) 3-[1-(t-butoxycarbonyl)piperidin-3-15 yl)propyl bromide (4.0 mmol, 2.2 eq) was added and the resulting ll~i~ule was stirred for three hours at 70~C. The reaction was qll~nrh~d by the addition of 10 ml of water The aqueous fraction was extracted with ethyl acetate (3 x 10 ml). The org~nic fractions were combined and washed with water (2 x 10 ml), and then brine (1 x 10 ml), and then dried 20 over magnesium sulfate. The solvents were removed in vacuo to yield a W O 97/2~041 PCT~US97/OOSll light brownish crude material. The desired title product was further purified by flash chromatography.
NMR and IR were consistent with the proposed title st~ucture.
FDMS (M+) 724.
5 Analysis for C40Hs7clN4o6:
Theory: C, 66.23; H, 7.92; N, 7.72.
Found: C, 66.49; H, 8.04; N, 7.79.
r~ 1e 277 Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[3-(piperidin-3-yl)propoxy]-1-[3-(piperidin-3-yl)~ yl]b~n~ ole ~NH

~<

~N~ --~~--~1 ~NH

The title compound is prepared from (RS) 2-(4-chlorophenoxymethyl)-4-[3-[1-(t-butoxycarbonyl~piperidin-3-yl]propogy]-1-[3-[1-~t-butoxycarbonyl)piperidin-3-yl]~ yl]b~n~in~idazole by standard deprotection techniques using trifluoroacetic acid.
2 0 NMR and IR were consistent with the proposed title structure.
FDMS (M+) ~i2~

- 2~0 -Analysis for C30H4~clN4o2:
Theory: C, 54.22; H, 5.75; N, 7.44.
Found: C, 53.97; H, 5.48; N, 7.26.

nu?le 278 Preparation of (R) 2-(4-chlorophenoxymethyl)-4-[3-[1-(t-buto~ycall)onyl)piperidin-3-yl]propoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl] lll olJyl]be~ ~imi dazole ~BoC

~~-~Cl ~'GN~ BoC

A solution of 4-hydl oxy-2-~4-chlorop~eno~ymethyl)b~n7imidazole (~;00 mg, 1.82 mmol) in dry N,N-15 dimethylformamide (8 ml) was treated with sodium hydride (60% inmineral oil, 162 mg, 4.0 mmol, 2.2 eq). The resulting ~ e was stiITed at room tempel a~u~e under a stream of nitrogen for about one hour. To this reaction ~..ix~ e (R) 3-[1-(t-butoxycarbonyl)piperidin-3-yl)propyl bromide (4.0 mmol, 2.2 eq) was added and the resulting 20 mixture was stirred for three hours at 70~C. The reaction was quenched by the addition of 10 ml of water. The aqueous fraction was extracted W O 97~41 PCT~US97/00511 - 2~--with ethyl acetate (3 x 10 ml). The organic fractions were c~mhin~d and washed with water (2 x 10 ml), and then brine (1 x 10 ml), and then dried over m~gnesium sulfate. The solvents were removed in vacuo to yield a light brownish crude m aterial. The desired title product was further 5 purified by flash chromatography.
NMR and IR were consistent with the proposed title structure.
FDMS (M~) 724.
Analysis for C4oHs7clN4o6:
Theory: C, 66.23; H, 7.92; Nt 7.72.
Found: C, 66.23; H, 7.86; N, 7.69.

F,~slrn,rle 279 Preparation of ~R) 2-(4-chlorophenoxymethyl)-4-[3-(piperidin-3-1~ yl)propoxy~-1-[3-(piperidin-3-yl)l~lo~yl]ben7:imidazole ~<

~~~Cl The title compound is prepared from (R) 2-(4-2 o chlorophenoxymethyl)-4-[3-[1-(t-butoxycarbonyl)piperidin-3-yl~propoxy]-1-[3-[1-(t-buto~y~all onyl)piperidin-3-yl]~ yl]be~imidazole by standard deprotection techniques using trifluoroacetic acid.
NMR and IR were consistent with the proposed title structure.
FDMS (M+) 525 5 Analysis for C30H4lclN4o2:
Theory: C, 54.22; H, 5.75; N, 7.44.
Found: C, 54.12; H, 5.86; N, 7.47.

~T~le 280 Preparation of (S) 2-(4-chloropheno~y~nethyl)-4-[3-[1-(t-buto~ycal l)onyl)piperidin-3-yl]propoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]ben~im; dazole ~N--BoC

N~~~ GC1 ",.~/~N,BoC

~J

A solution of 4-hy l~oky-2-(4-chloropheno~Fymethyl)ben~imidazole (~00 mg, 1.82 mmol) in dry N,N-dimethylformamide (8 ml) was treated with sodium hydride (60% in mineral oil~ 162 mg, 4.0 mmol, 2.2 eq). The resulting ~ e was stirred at room temperature under a stream of nitrogen for about one W O 97/25041 PCT~US97/00511 -2~3-hour. To ~his reaction ..~ e (S) 3-[1-(t-butoxycarbonyl)piperidin-3-yl)propyl bromide (4.0 mmol, 2.2 eq) wa6 added and the resulting , mixture was stirred for three hours at 70~C. The re~ctior- was ~n~,hed by the addition of 10 ml of water. The aqueous fraction was extracted 5 with ethyl acetate (3 X 10 ml). The organic fractions were cnmh;ned and washed with water (2 x 10 ml), and then brine (1 x 10 ml)~ and then dried over m~ne~ium sulfate. The solvents were removed in vacuo to yield a light brownish crude material. The desired title product was fi~rther purified by flash chromatography.
10 NMR and IR were consistent with the proposed title structure.
FDMS (M+) 724.
Analysis for C40H57ClN4~6:
Theory: C, 66.23; H, 7.92; N, 7.72.
Found: C, 65.51; H, 7.94; N, 7.80.~5 n~l e 281 Preparation of (S) 2-(4-chloropheno~ymethyl)-4-[3-~piperidin-3-yl)propoxy}-1-[3-(piperidin-3-yl)~l o~l]b~n7imidazole "'~/~NH

W O 97/25041 PCT~US97/OOSII

The title compound is prepared from (S) 2-(4-chlorophenoxymeth~l)-4-[3-[1-~t-butoxycarbonyl)piperidin-3-yl]propoxy]-1-[3-[1-(t-buto~ycall~onyl)piperidin-3-yl]propyl]benzi_idazole by standard 5 deprotection techniques using trifluoroacetic acid.
NMR and IR were consistent with the proposed title structure.
FDMS (M+) 525 Analysis for C30H4lclN4o2:
Theory: C, 54.22; H? 5.75; N, 7.44.
Found: C, 53.96; H, 5.74; N, 7.40.
le 282 Preparation of 2-(4-chlorophenoxymethyl)-4-~5-[1-(t-butoxycarbonyl)piperidin-4-yl3pentoxy]- 1-[5-r 1-(t-buto~yca~l~onyl)piperidin-4-yl]pentyl~ben7imidazole W O 97/250~1 PCT~US97/00511 - 2~5 --BoC

N ~Cl ~ BoC

A solution of 4-hyL o~y-2-(4-chlorophenoxymethyl)ben7:imidazole (~;00 mg, 1.82 mmol) in dry N,N-dimethylformamidLe (8 ml) was treated with sodium hydride (60% in mineral oil, 162 mg, 4.0 mmol, 2.2 eq). The resulting ~ ul.2 was stirred at room temperature under a stream of nitrogen for about one hour. To this reaction ~;x~ e 5-Ll-(t-butoxycarbonyl)piperidin-4 yl)pentyl bromide (4.0 mmol, 2.2 eq) was added and t~e resulting ~ 10 mi~t~lre was stirred for three hours at 70~C. The reaction was ql1~nr.h~d by the addition of 10 ml of water. The aqueous fraction was extracted c with ethyl acetate (3 x 10 ml). The organic fractions were comh;ned and washed with water (2 x 10 ml), and then brine (1 x 10 ml), and then dried over m~nesium sulfate. The solvents were removed in vacuo to yield a light blowllish crude materialL. The desired title product was further W O 97/25041 PCT~US97/00511 -2~6-purified by flash chromatography. There is some substitution at the 7-position of the ben7imidazole present, although the 4-substituted is the maJor ~somer.
NMR was consistent with the proposed title structure.
5 FDMS (M+) 781.
le 283 Preparation of 2-(4-chlorophenoxymethyl)-4-[5-(piperidin-4-yl)pentoxy]-1-lo ~5-~piperidin-4-yl]pentyl]b~n7.imidazole >

~0<
~~~Cl ~N'BoC

The title compound is prepared from 2-(4-15 chlorophenn~ymethyl)-4-[5-[1-(t-butoxycarbonyl)piperidin-4-yl]peIltogy]--1-[5-[1-(t-butoxycarbonyl)piperidin-4-yl]pentyl]ben7imidazole by standard deprotection techniques using trifluoroacetic acid.
NMR and IR were consistent with the proposed title structure.
FDMS (M+) !i81 Analysis for C34H4sClN402:
Theory: C, ~i6.40; H, 6.35; N, 6.92.
Found: C, 56.22; H, 6.37; N, 6.90.

Preparation 58 Preparation of 2-(4-chloropheno~ymethyl)-4-benzyloxy-ben7imi~ ole <O

N
~N~~~Cl A solution of 4-hydro~yl~e~imi(l~Qle (7.28 mmol, 1.0 eq) and triphenylphosphine (2.30 mg, 8,74 mmol, 1.2 eq ) in dry tetrahydro~uran (72 ml, 0.1 M) was treated with a solution of ~enzyl alcohol (0.9 ml, 8.74 mmol, 1.2 eq) and diethyl azodicarboxylate (1.4 ml, 8.74 mmol, 1.2 eq). The resulting ~ u~e was stirred at 0~C and was then waImed to room tempela~ule. After five hours, the tetrahydrofuran was removed in vacuo. The residue was further purified using flash chromatography to provide the title intermediate in - ~;-70% yield.
NMR and IR were consistent with the proposed title structure.
- 25 FDMS 364 (M+) Analysis for C21H16ClN20:
Theory: C, 69.14; H, 4.70; N, 7.68.

W O 97/25041 PCTfUS97/OQ511 -2~8-Found: C, 69.35; H, 4.89; N, 7.74.
m~;~le 284 Preparation of 2-(4-chloropheno~ymethyl)-4-benzyloxy-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]~ yl]-b~?n7.imidazole ~N~O~ Cl N--BoC

A solution of 2-(4-chlorophenoxymethyl)-4-benzyloxy-bçn~imitl~ole (720 mg, 1.97 mn~ol, 1.0 eq) in dry N,N-dimetllylrlJ....Ami(l~ (8 ml, 0.25 M) was treated with sodium hydride (60% in milleral oil, ~;7 mg, 2.30 mmol, 1.2 eq). The resulting l~ LLe was stirred at room temperature for thirty minutes and then 3-[1-(t-butoxyc~ll)onyl)piperidin-4-yl]LJlo~yl bromide (7.24 mg, 2.36 mmol, 1.2 eq) was added to the reaction .. i~ e. The resulting mi~ e was stirred at 70~C for three hours. The reaction was quenched by the addition of water (1 x 30 ml). The aqueous fraction was extracted with diethyl ether (1 x 30 ml). The organic fractions were combined, washed with water (1 x 30 ml), then ~rine (1 x 30 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product W O 97/2S041 PCTnUS97/00511 -2~9--was further purified by flash chromatography to provide a white foam in 38% yield.
s NMR and IR were consistent with the proposed title structure.
FDMS 589 (M+) Tr~le 285 Preparation of (RS) 2-(4-chloropheno~ymethyl)-4-benzyloxy-1-[3-[1-(t-buto~ycall)onyl)piperidin-3-yl~propyl]-ben ~mi dazole <O

~~~ Cl BoC

A solution of 2-(4-chloropheno~ymethyl)-4-benzylogy-bçn7;mi~ole (720 mg, 1.97 mmol, 1.0 eq) in dry N,N-dimethylform~mirle (8 ml, 0.2~ M) was treated with sodium hydride (60% in mineral oil, 57 mg, 2.30 mmol, 1.2 eq). The resulting l~ ,UI e was stirred at room tempel dlure for thirty minutes and then (RS) 3-[1-(t-but(J~ycall~onyl)piperidin-3-yl]~lo~yl bromide (7.24 mg, 2.36 mmol, 1.2 eq) was added to the re~c*on ~ ure. The resulting mixture was 2 0 stirred at 70~C for three hours. The reaction was quenched by the t addition of water (1 x 30 ml). The aqueous fraction was extracted with W O 97/25041 PCT~US97/00511 diethyl ether (1 x 30 ml). The organic fractions were comhined, washed with water tl x 3Q ml~, then brine (1 x 30 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by flash chromatography to provide a white foam in 38% yield.
NMR and IR were consistent with the proposed title structure.
FDMS 589 (M+) Arlalysis for C34H40ClN304:
Theory: C, 69.20; H, 6.83; N, 7.12.
Found: C, 69.20; H, 6.90; N, 7.28.

F,~m,ple 286 Preparation of (R) 2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]-ben 7.i mi dazole N~ ~Cl BoC

A solution of 2-(4-chloroph~noxymethyl)-4-benzyloxy-2 o ben~imidazole (720 mg, 1.97 mrnol, 1.0 eq) in dry N,N-dimethylformamide (8 ml, 0.25 M) was treated with sodium hydride CA 02242579 l998-07-08 (60% in mineral oil, 57 mg, 2.30 m m ol, 1.2 eq). The resulting mixture was stirred at room temperature for thirty minllte~ and then (R) 3-[1-(t-buto~y~.bonyl)piperidin-3-yl]~lo~yl bromide (7.24 mg, 2.36 mmol, 1.2 - eq) was added to the reaction mixture. The resulting ~ e was 5 stirred at 70~C for three hours. The reaction was qllenr.he-l by the addition of water (1 x 30 ml). The aqueous fraction was extracted with diethyl ether (1 x 30 ml). The org~niC fractions were combined, washed with water (1 x 30 ml), then brine (1 x 30 ml), and then dried over sodium sulfate. The solvents were removed im vacuo. The desired title product 10 was further purified by flash chromatography to provide a white foam in 38% yield.
IR was consistent with the proposed title structure.
FDMS 589 (M+) Analysis for C34H40ClN304:
Theory: ~, 69.20; H, 6.83; N, 7.12.
Found: C, 70.15; H, 7.17; N, 7.07.

?le ?87 Preparation of (S) 2-(4-chloroph~no~ymethyl)-4-benzyloxy-1-[3-[1-(t-buto~yca~ bonyl~piperidin-3-yl]propyl]-ben ~i mi dazole O

~~~C

N~
~oC

A solution of 2-(4-chlorophenQ~ymethyl)-4-benzyloxy-b~n~imidazole (720 mg, 1.97 mmol, 1.0 eq) in dry N,N-dimethylformamide (8 ml, 0.25 M) was treated with sodium hyd~ide (60~o in mineral oil, 57 mg, 2.30 mmol, 1.2 eq). The resulting llli~Lu~e was stirred at room temperature for thirty minutes and then (S) 3-[1-(t-buto~yc~lbonyl)piperidin-3-yl]~ro~yl bromide (7.24 mg, 2.36 mmol, 1.2 eq) was added to the reaction mixture. The resulting ~ u~ e was 10 stirred at 7Q~C for three hours. The reaction was quenched by the addition of water (1 x 30 ml). The aqueous fraction was extracted with diethyl ether (1 x 30 ml). The organic fractions were combined, washed with water (1 x 30 ml), then brine (1 x 30 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product 15 was further purified by flash chromatography to provide a white foam in 38% yield.
IR was consistent with the proposed title structure.
FDMS 589 (M+) Analysis for C34H40ClN304:
Theory: C, 69.20; H, 6.83; N, 7.12.

W O 97/25041 PCTnJS97/00511 -F ou n d: C, 68.26; H, 7.01; N, 7.25.

~ ml?le 288 Preparation of (:~) 2-(4-chlorophçno~ymethyl)-4-benzyloxy-1-[2-[1-~t-butu~yca~bonyl)piperidin-3-yl]ethyl]-ben~imidazole ~3 o N~ ~ Cl <~ N--BoC

A solution of 2-(4-chloropheno~ymethyl)-4-benzyloxy-bqn7.imi~0le (720 mg, 1.97 mmol, 1.0 eq) in dry N,N-dimethylformamide (8 ml, 0.25 M) was treated with sodium hydride (60% in mineral oil, 57 mg, 2.30 mmol, 1.2 eq). The resulting ~ e was stirred at room tempe- d~ e for thirty minutes and then (R) 2-[1-(t-butoxycarbonyl)piperidin-3-yl]ethyl bromide (2.36 mmol, 1.2 eq) was added to the reaction ~ e. The resulting mixture was stirred at 70~C for three hours. The reaction was quenched by the addition of water (1 x 30 ml). The aqueous fraction was extracted with diethyl ether (1 x 30 ml). The organic fractions were comhin~d, washed with water (1 - 20 x 30 ml), then brine (1 x 30 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by flash chromatography to provide a white foam in 40-60%
t yield.

W O 97/Z5041 PCT~US97/00511 lR and NMR were consistent with the proposed 1itle structure.
FDMS 575 (M+) Analysis for C33H3gClN3O4:
Theory: C, 68.80; ~I,6.65; N, 7.29.
Found: C, 68.35; H, 7.47; N,8.08.

mrle ~9 Preparation of (S) 2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[2-[1-(t-10 buto~ycal l~onyl )piperidin-3-yl]ethyl]-b~n 7 i mi dazole ~<

~~~Cl < N--BoC
\

A solution of 2-(4-chlorophenoxymethyl)-4-benzyloxy-b~n7imi~ ole (720 mg, 1.97 mmol, 1.Q eq) in dry N,N-~imethylform~mi~e (8 ml, 0.25 M) was treated with sodillm hydride (60% in mineral oil, 57 mg, 2.30 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for thirty minutes and then (S) 2-[1-(t-butoxycarbonyl)piperidin-3-yl]ethyl bromide (2.36 mmol, 1.2 eq) was 20 added to the reaction mi~ e. The resulting mixture was stirred at 70~C for three hours. The reaction was qll~nl h~d by the addition of water (1 x 30 ml). The aqueous fraction was extracted with diethyl ether (1 x 30 1). The organic fractions were combined, washed with water (1 W O 97~5041 PCTnUS97/00511 x 30 ml), then brine (1 x 30 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by flash chromatography to provide a white foam in 40-50%
yield.
5 IR and NMR were consistent with the proposed title structure.
FDMS 575 (M+) Analysis for C33H38ClN304:
Theory: C, 68.80; H, 6.65; N, 7.29.
Found: C, 68.03; H, 7.39; N, 7.86.
~ le 290 Preparation of (RS) 2-(4-chloroph~n-)~ymethyl)-4-hyd~o~y-1-[3-~1-(t-butoxycarbonyl )piperidin-3 -yl]propyl~-ben ~.i mi dazole OH

~' ~~Cl BoC

A solution of (RS) 2-~4-chloroph~n-~ymethyl)-4-benzyloxy-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]-ben~i~nidazole (24~ mg, 0.42 20 mmol, 1.0 eq) in ethyl acetate (4.2 ml) was degassed and then treated wit,h 5% palladium on carbon (250 mg). The resulting ~u.e was stirred under a hydrogen atmosphere. The reaction mixture was then filtered through a CELITETM cake layer. The catalyst was washed thoroughly with ethyl ~cet~te and et~l~n~l. The filtrate was con-1en~ed 2 5 on a rotoevaporator to yield the desired title product in 78% yield.

W O 97/25041 PCT~US97/00511 NMR was consistent with the proposed title structure.
FDMS 589 (M+) m~le ~91 Preparation of (RS3 2-(4-chlorophenoxyrnethyl)-4-[2-[1-(t-butoxycarbonyl)piperidin-3-yl]ethoxy]- 1-[3-tl-(t-butol~ycall)onyl)p;peridin 3-yl]propyl]-benzimidazole ,BoC

N~ ~ Cl N~
Bo~
A solution of (RS) 2-(4-chlorophenoxymethyl)-4-hyLo~y-1-~3-[l-(~-buto~ycalbonyl)piperidin-3-yl]~v~yl]b~n7.imitl~l)1e (76 mg, 0.1~
mmol, 1.0 eq) in dry N~N-llimethylformamide (1.0 ml) was treated with sodium hydride (60% in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting ~ mixture was stirred at room temperature for thirty m-inutes, after which time 2-[1-(t-butoxycarbonyl)piperidin-3-yl3ethyl bromide (0.18 mmol, 1.2 eq) was added. The resulting ~ u~e was stirred for three hours at 70~C. The reaction was quçn~hçd by the addition of water (10 W O 97/25041 PCT~US97/OOS11 ml). The aqueous fraction was extracted with diethyl ether (3 x 101).
The organic fractions were comhined, washed with water (2 x 10 ml), then brine (1 x 10 1), and then dried over sodium sulfate. The solvents were removed in vacuo to give a crude product. The title product wa~
5 further purified by flash chromatography to provide a crystalline product. Yield: 92%
NMR was consistent with the proposed ~tle structure.
FDMS 711 (M+) F.~ml le ?~2 Preparation of (RS) 2-(4-chlorophen-l~ymethyl)-4-[[1-(t-butoxycarbonyl)piperidin-3-yl]methoxy]- 1-[3-~1-(t-butoxycarbonyl)piperidin-3-yl~lo~yl]-b~n~imidazole ~\N--BoC
o ~<

N~ ~Cl N~
BoC

- A solution of (RS) 2-(4-chloroph~no~ymethyl)-4-hydroxy-1-[3-[1-(t-butoxycarbonyl~piperidin-3-yl]propyl]ben~imidazole (76 mg, 0.16 20 mmol, 1.0 eq) in dry N,N-dimethylformamide (1.0 ml) was treated with sodium hydride (60% in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting W O 97/25041 PCT~US97/00511 I 1~ il~LIUl 13 was stirred at room tempel a~ ul e for thirty minutes, after which time 1-(t-butoxycarbonyl)piperidin-3-yl)methyl bro_ide (0.18 mmol, 1.2 eq) wa~ added. The resulting ...i~ e was stirred for three hours at 70~C. The reaction was ql~anched by the A~ tion of water (10 5 ml). The aqueous fraction was extracted with diethyl ether (3 x 10 ml).
The organic fractions were comhined, washed with water (2 x 10 ml), then brine (1 x 10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to give a crude product. The title product was further purified by flash chromatography to provide a crystalline 1 o product.
NMR and IR were consistent with the proposed title structure.
FDMS 696 (M~) ~ m~le 293 Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[(piperidin-3-yl)methoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]propyl]-ben7.im;dazole ~<

~N~O~ Cl H

=

The title product is prepared from (RS~ 2-(4-chloropheno~ymethyl)-4-[[1-(t-butoxycarbonyl)piperidin-3-yl]methoxy]-1-v [3-[1-(t-buto~yca~l)onyl)piperidin-3-yl]~l~pyl]-benzimidazole using a standard trifluoroacetic acid deprotection protocol.
NMR and IR were consistent with the proposed title structure.
FDMS 497 (M+) F.~z~m~le 294 0 Preparation of (~S) 2-~4-chloror)heno~ymethyl)-4-[3-[1-(t-buto~ycarl)onyl)piperidin-4-yl]propoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]~l v~yl]-bçn 7:i mi dazole BoC

~~<~

~N~O~ Cl C~
N~
BoC
A solution of (RS) 2-(4-chloropheno~nethyl)-4-lly~o~y-1-[3-[1-(t-buto~ycallJonyl)piperidin-3-yl]~o~yl3benzimidazole (75 mg, 0.15 WO 97/2~041 PCT/US97/00511 mmol, 1.0 eq) in dry N,N-d;rr~ll~ylfc.~ amide (1.0 ml) was treated with sodium hydride (60~o in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting mixture was stirred at room tempela~ule for thirty minutes, after which time 3-[1-(t-butoxycarbonyl)piperidin-4-yl)]propyl bromide (0.18 5 mmol, 1.2 eq) was added. The resulting ...ix~,... e was stirred for three hours at 70~C. The reaction was qll~n~h~l by the addition of water (10 ml). The aqueous fraction was extracted with diethyl e~er (3 x 10 ml).
The organic fractions were cornhined, washed with water ~2 x 10 ml), then brine (1 x 10 ml~, and then dried over sodium sulfate. The solvents 10 were removed in vacuo to give a crude product. The title product was further purified by flash chromatography to provide a crystalline product.
NMR and IR were consistent with the proposed title structure.
FDMS 724 (M+) Analysis for C40Hs7ClN4O6:
Theory: C, 66.23; E, 7.92; N, 7.72.
Found: C, 66.51; H, 7.99; N, 7.52.

F~nv-le 295 Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[3-[1-~t-butoxycarbonyl)piperidin-4-yl]propoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]~. vl~yl]-ben7imidazole W O 97~5041 PCTnJS97/00511 ~; ~~ CI

N

The title product is prepared from (RS) 2-(4-chloroph.3no~rymethyl)-4-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propoxy~-1-[3-[1-(t-buto~ycaLllonyl)piperidin-3-yl3~.o~yl]bçn7:imidazole using a st~nrlslrd trifluoroacetic acid deprotection protocol.
NMR and IR were consistent with the proposed title structure.
FDMS 511.4 ~M+) Analysis for C2sH3sclN4o2:
Theory: C, 53.62; H, 5.59; N, 7.58.
Found: C, 53.38; H, 5.64; N, 7.63.
m~le 296 Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[5-[1-(t-butu~ycalbonyl)piperidin-4-yl]pentoxy]-1-[3-[1-(t-butoxycarbonyl)piperidin-3-yl]~ yl]-benzimidazole W O 97/25041 PCT~US97/00511 ,BoC
~N

<

/~N

~N~ ~ Cl ~>
N~
BoC

A solution of (RS) 2-(4-chlorophenoxymethyl)-4-hy~l,o~y-l-~3 [1-(t-butoxycarhonyl)piperidin-3-yl]~ yl}ben~imidazole(75 mg, 0.15 m mol, 1.0 eq) in dry N,N-dimethylformamide (1.01) was treated with sodiu_ hydride (60% in oil, 7.5 mg, 0.18 m mol, 1.20 eq). The resulting ule was stirred at room tempe~a~ule for thirty minutes, after which time ~-[1-(t-butoxycarbonyl)piperidin-4-yl)]pentyl bromide (0.18 mmol, 1.2 eq) was added. The resulting mi~tllre was stirred for three hours at 70~C. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with diethyl ether (3 x 10 ml).
The org~nic fractions were comhine(l, washed with water (2 x 10 ml), then brine (1 x 10 ml), and then dried over sodium sulfate. The solvents were remnoved in vacuo to give a crude product. The title product was W O 97/25041 PCT~US97/00511 -further purified by fla~h chromatography to provide a crystalline product.
NMR and IR were consistent with the proposed title structure.
- FDMS 752 (M+) ~m.~le 297 Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[5-(piperidin-4-yl)pentoxy]-1-[3-(piperidin-3-yl)~l o~yl]-benzimidazole H

) N ~Cl ~N
E
The title product is prepared from (RS) 2-(4-chlorophenoxymethyl)-4-[5-[1-(t-butoxyca. bonyl)piperidin-4-yUpentoxy3-15 1-[3-[1-(t-but~xycalbonyl)piperidin-3-yl]propyl]ben~midazole using a standard trifluoroacetic acid deprotection protocol.

W O 97/2~041 PCT~US97/00~11 NMR and IR were consistent with the proposed title structure.
FDMS 555 (M+1) n~le 298 Preparation of (RS) 2-(4-chlorophenoxymethyl)-4-[5-[1-(t-buto~y~all~onyl)piperidin-3-yl]pentoxy]-1-[3-[1-(t-buto~ycall)onyl)piperidin-3-yl]~ yl]-ben~imidazole ~N--BoC

/D<~N
~~~Cl BoC

A solution of (RS) 2-(4-chloroph~noxymethyl)-4-hy~ o~y-1-[3-[l-(t-butoxycarbonyl)piperidin-3-yl]propyl]b~n7:imidazole (75 mg, 0.15 mmol, 1.0 eq) in dry N,N-dimethylform.qmir~e (1.0 ml) was treated with sodium hydride (60% in oil, 7.5 mg, 0.18 mmol, 1.20 eq). The resulting mixture was stirred at room tempe. a~ e for thirty minutes, af~cer which t.ime 5-[1-(t-buto~ycalbonyl)piperidin-3-yl)]pentyl bromide (0.18 W O 97/25041 PCT~US97/00511 m m ol, 1.2 eq) was added. The resulting mixture was stirred for three hours at 70~C. The reactlon was ~llçnrhed by the addition of water (10 ml). The aqueous fraction was extracted with diethyl ether (3 x 10 ml).
The organic fractions were cl)mhinefl, washed with water (2 x 10 ml), 5 then brine (1 x 10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to give a crude product. The title product was further purif;ed by flash chromatography to provide a cryst~lline product.
NMR and IR were consistent with the proposed title structure.
10 FDMS 7~3 (M~) ple 299 Preparation of (RS) 2-(4-chl oroph f~!n o~ymethyl)-4-[5-~piperidin-3-15 yl)pentoxy]-1-[3-(piperidin-3-yl)propyl]-b~n~imidazole ~ BoC

/~N
~N~~~Cl ~N
BoC

W O 97/25041 PCT~US97/OOSIl The title product is prepared from (RS) 2-(4-chlorophenoxymethyl)-4-[~-[1 -(t-butoxycarbonyl3piperidin-3-yl]pentoxy]-1-~3-[1-(t-butoxycarbonyl)piperidin-3-yl]~o~yl]ben~imi~Qle using a 5 standard trifluoroacetic acid deprotection protocol.
NMR and IR were consi~tent with the proposed title structure.
FDMS 556 (M+1) Preparation ~;9 Preparation of 2,3~ minophenol dihydrochloride salt OH
~2 ~2 HCl ~n~2 15 In a 2~0 ml single neck round bottom flask was added 2,3-~i~minophenol (10 g, 80.56 m m ol) to eth~nol (100 ml). This mixture was he~terl to 50~C to achieve dissolution. The resulting solution is cooled to -~ to 0~C and an excess of anhydrous hydrogen chloride gas was added to form a viscous slu~Ty. The resulting ~ re was stirred for two hours 20 at ~0~C, then filtered, and rinsed with chilled methanol (30 ml). The solvents were removed in vacuo and the residue was dried overnight.
Yield: 1~.29 g (96.3%).

Preparation 60 Preparation of 4-hyLoky-2-[(4-chloropheno2y)methyl]bçn~ ole CA 02242579 l998-07-08 W O 97/25041 PCT~US97/00~11 -OH

\>~~~

In a 50 ml single neck round bottom flask, under a nitrogen a~nosphere, 4-chlorophenoxyacetonitrile (0.46 g, 2.79 mmol~ was 5 admixed in methanol (11 ml). The contents were stirred to achieve dissolution. To this solution were added sodillm metho~ide (0.164 g, 3.0 mmol). The resulting mixture was stirred for about 40 rrlinl~tes. To this mixture was added 2,3~ minophenol dihydrochloride salt (0.~ g, 2.5 mmol) and the resulting mixture was stirred for two hours at room 10 tempe~tLL~e. The reaction mi~tllre was f;ltered and the filtrate was added to 60 ml of water. A light brown preçipit~te formed and this precipitate is removed by filtration, and washed with 20 ml of water.
The solid was dried in a vacuum oven overnight.
NMR was consistent with the proposed title structure.
Yield: 0.60 grams (86.1%).

Prep~ratiQn 61 Preparation of 4-llyd~ oxy-2-[(4-methylphenoxy)methyl]bçn~imidazole OH

~ ~CH8 In a ~0 ml single neck round bottom flask, under a nitrogen atmosphere, 4-methylphenoxyacetonitrile (2.79 mmol) was admixed in 25 methanol (11 ml). The cont~nts were stirred to achieve dissolution. To this solution were added sodium metho~ .164 g, 3.0 mmol). The W O 97/25041 PCTrUS97/00511 resulting ~ ,ule was stirred for about 40 minutes. To this mi~t~re was added Z,3~ m;nophenol dihydrochloride salt (0.5 g, 2.5 mmol) and the resulting ~ re was stirred for two hours at room temperature.
The reaction mixture was filtered and the filtrate was added to 60 ml of 5 water. A light brown precipitate formed and this precipitate is removed by filtration, and washed with 20 ml of water. The solid was dried in a vacuum oven overnight.
Pre~aration 62 Preparation of 4-benzyloxy-2-[(4-methylphenoxy)methyl]bçn7.imidazole In a 500 ml single neck round bottom flask, under a nitrogen atmosphere, 4-benzyloxy-2-[(4-methylphen--~y)methyl]b~n~imi~ ole (7.0 g, 27.5 mmol) and triphenylphosphine (9.31 g, 35.5 mmol~ were ~tlmi~d. To this was added anhydrous tetrahydrorulan (275 ml). The resulting mixture was 20 stirred for five minute to achieve a dark red solution, after which time benzyl alcohol ~3.79 ml, 36.6 mmol) and diethyl azodicarboxylate (5.9 ml, 37.5 mmol) were added. The resulting mixture was stirred at room temperature overnight. The re~ctinn ~i~ula was extracted with ethyl acetate (500 ml). The organic fraction was washed with water ~2 x 500 25 ml). The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The residue was then redissolved in methylene chloride (110 ml) and further purified by chromatography.
The desired fractions were collected and the title product was recrystallized from 80:20 he~nes:diethyl ether.
NMR was consistent with the proposed title structure.

F',~A~u?le 300 Preparation of 4-trifluoromethanesulfonyloxy-2-[(4-chlorophenoxy)methyl]-l-trifluoromethanesulfonylben~imidazole ~ ,CF3 O
o ~~, /\s~ o Cl F3~ O

In a 600 ml flasl~, under a nitrogen atmosphere, were added 4-hydroxy-2-[(4-chloropheno~ry)methyl]bçn7.imidazole (9.10 g, 33.1 mmol) 15 and pyridine (300 ml). The contents were then chilled to 0~C and trifluoromethaneslllfonic anhydride (23.36 g, 82.8 mrnol) was then added by syringe. The resulting ...ixl.-.e was st;rred at 0~C for two hours and then stirred at room temperature overnight. The progress of the reaction was monitored by thin layer chromatography. The solvents 2 ~ were then removed in vacuo. The residue was redissolved in ethyl ~cet,~te (5001) and washed with water (3 x 500 ml). The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. Yield: 14.64 g(82.0%).
IR was concistent with the proposed title structure.
25 FDMS 537.g~ (M+) Analysis for Cl6HgClF6N206S2:
Theory: C, 35.76; H, 1.68; N, 5.20.

W O 97/25041 PCT~US97/00511 Found: C, 34.83; H, 1.66; N, 5.15.
rn~;~le 301 5 Preparation of 4-(prop-2-enyl)-2-~(4-chloroph~no~y)methyl]-1-trifluoromethanesulfonylben7.imi~01e ~/ H2 ~ Cl In a 250 ml single neck round bottom flask, under a nitrogen atmosphere, were added 4-trifluoromethanesulfonyloxy-2-~(4-chloropheno~ry)methyl]-1-trifluoromethanesulfonylbçn7:imidazole (4.97 g, 9.22 mmol), lithium chloride (1.17 g, 27.65 lnmol), allyltributyltin (4.27 g, 12.90 mmol), and bis(triphenylphosphine)p~ ium(II) chloride (301.03 mg, 0.369 mmol) in anhydrous tetrahydrofuran (99 ml). The resulting mixture was stirred for five hours at reflux, followed by the addition of an additional 0.15 mg of the p~ ium catalyst. The contents were then stirred overnight. The progress of the re~ction was monitored by thin layer chromatography. The desired title product was further 20 purified by flash chromatography.
~rleld: 3.97 g (3~.8%) NMR was consistent with the proposed title structure.

~n~ 307 Preparation of 4-(ethenyl)-2-[(4-chlorophenoxy)methyl]-1-trifluoromethanesulfonylben7imi dazole W O 97/25041 PCT~US97/00511 ~2C~

~C '>~'~'13 /S~ ~ Cl In a 250 ml single neck round bottom flask, under a nitrogen atmosphere, were added 4-trifluoromethanesulfonyloxy-2-[(4-5 chlorophenoxy)methyl]-1-trifluoromethanesulfonylben~imidazole (5.00 g, 9.28 mmol), lithium chloride (1.18 g, 27.84 mmol), vinyltributyltin (4.12 g, 12.99 ~nol), and bis(triphenylphosphine)palladium(II) chloride (303 mg, 0.371 mmol) in anhyLous tetrahydrofuran (99 ml). The resulting ~ e was stirred for five hours at reflux, followed by the 10 addition of an additional 0.1~ mg of the palladil1m catalyst. The cont~nts were then stirred overnight. The progress of the reaction was monitored by thin layer chromatography. An additional 0.15 mg of the pAll~lium catalyst and 0.~ ml of vinyltributyltin were added to the reaction mixture and it was refluxed for five hours. The desired title product was further 15 purified by flash chromatography.
Yield: 3.87 g (33.6%) F,~flml~le 303 2 0 Preparation of 4-(ethenyl)-2-[(4-chlorophenoxy)methyl]-1-trifluoromethanesulfonylben7imidazole W O 97/25041 PCT~US97/00511 H ~
2~9 ~CI

To a 250 ml round bottom flask were added 4-trifluoromethanesulfonyloxy-2-[(4-chlorophenoxy)methyl]-1-trifluoromethanesulfonylbçn7irni~ ole (5.00 g, 9.28 mmol), palladium tetrakis(triphenylphosphine) (428 mg, 0.371 mmol), lithium chloride (2.95 g, 69.6 mmol) and vinyltributyltin (2.94 g, 9.28 mmol) to anhydrous tetrahydrofuran. The reaction mixture was heated to reflux and m:~int~ined at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography. An additional 428 mg of the p~ rlium catalyst was added and the resulting mixture was refluxed an additional three hours. To the reaction mixture was added cuprous iodide (36.3 mg, 0.02 eq) and the reAction ...i~ e was refluxed overnight. The solvents were removed in vacuo. The residue was redissolved in ethyl acetate (500 ml) and was washed wit~ 1:1 water:28%
aqueous ammonium hydroxide (3x). The organic fraction was dried over sodium sulfate. The desired title product was further purified by column chromatography.
~leld: 3.87 g (48.4%) 20 IR was consistent with the proposed title structure.
FDM~; 416.02 (M+) Analysis for Cl7H12ClF3N2O3S:
Theory: C, 48.99; H, 2.90; N, 6.72.
Found: C, 49.24; H, 3.18; N, 6.48.
Preparation 63 Preparation of 4-(ethenyl)-2-[(4-chlorophenoxy)methyl]ben~imidazole H2C~

In a 1001 round bottom flask, under a nitrogen 5 atmosphere, were added 4-(ethenyl)-2-[(4-chlorophenoxy)methyl]-1-trifluoromethanesulfonylb~n~imill~ole (1.42 g, 3.29 ~nol) and anhydrous methanol (20 ml). This solution was cooled to 0~C and potassium carbonate (911 mg, 6.59 mmolt was added. The resulting ~ix~...e was stirred for two hours at 0~C, permitted to warm to room 10 tempeialufe, and stirred at this temperature for about three days. The progress of t~e reaction was monitored by thin layer chromatography.
The desired title product was further purified by radial chromatography.
Yield: 0.74 g (75.1%) 15 IR and FDMS were consistent with the proposed title structure.
Analysis for Cl6Hl3clN2o:
Theory: C, 67.49; H, 4.60; N, 9.84.
Found: C, 67.47; H, 4.86; N, 9.73.

2 0 ~ m~ le 304 Preparation of 4-(ethenyl)-2-[(4-chloroph~no~y)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]beI-~imifl~ole W O 97/25041 PCT~US97/00511 ~C \~~~

~C

N-->
/

BoC

In a 100 ml round bottom flask, under a nitrogen atmosphere, were added 4-(ethenyl)-2-[(4-c~loroph~nQ~y)methyl]ben~imidazole (670 mg, 2.24 mmol) and anhydrous N,N-dimethylformamide (34 ml). To this solution was added ~odium hydride (60% in mineral oil, 98.67 mg, 2.46 mmol). The resulting mixture was stirred at room temperature for 45 minutes, and then 3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl bromide (755 mg, 2.47 mmol) was added. The resulting ~ e was heated to 100~C and stirred at this tempeldl u, e for about four hours. The progress of the re,qc~;on was monitored by thin layer chromatography. The reaction 11~; X 1 . . e was partitioned between ethyl acetate and brine. The a~ueous fiaction was extracted twice with brine. The organic fr~ction.q were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography .
Yield: 800 mg (68.1%) IR and FDMS were consistent with the proposed title structure.
Analysis for C2gH36ClN3O3:
Theory: C, 68.29; H, 7.11; N, 8.24.
Found: C, 68.01; H, 7.07; N, 8.30.

W O 97/25041 PCT~US97100511 - 28~;--PreDaration 64 Preparation of 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]bçn 7.imi dazole ~CH2 ~Cl In a 100 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(4-chloropheno~y)methyl]-1-trifluoromethanesulfonylb~n7.;midazole (1.00 g, 2.32 mTnol) and anhydrous methanol (18 ml). This solution was cooled to 0~C and potassium carbonate (641 mg, 4.64 mmol) was added. The resulting mi~t.lre was stirred for two hours at 0~C, permitted to warm to room temperature, and stirred at this temperature for about three days. The progress of the reaction was monitored by thin layer chromatography.
The desired title product was further purified by radial chromatography.
eld: 0.90 g (>99%) IR and FDMS were consistent with the proposed title structure.
Analysis for Cl7Hl~ClN20:
Theory: C, 68.34; H, 5.06; N, 9.38.
Found: C, 68.46; H, 6.24; N, 9.35.

mrle 305 Preparation of 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]~ yl]bçn~imitl~7:ole ~/CH2 1~ >'--N
BoC

In a 100 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(~
chlorophenoxy)methyl]ben7.imidazole (550 mg, 1.84 mmol) and anhydrous N,N-dimethylformAmi-le (59 ml). To this solution was added sodium hydride (60% in mineral oil, 81.04 mg, 2.03 mr~ol). The resulting mixture was stirred at room temperature for 60 minutes, and then 3-[1-(t-buto~ycall~onyl)piperidin-4-yl]~ol yl bromide (620 mg, 2.03 10 mmol) was added. The resulting ;xle was heated to 100~C and stirred at this tempe,alu~e for about three hours. The progress of the reaction was monitored by thin layer chromatography. The reslc~ion 111; X 1 l l l e was partitioned between ethyl acetate and brîne. The aqueous fi~action was extracted twice with brine. The organic fractions were combined and dried over sodillm sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
Yield: 622 mg (64.4%) IR and FDMS were consistent with the proposed title structure.
Analysis for C30H3gClN3O3:
Theory: C, 68.75; H, 7.31; N, 8.02.
Found: C, 68.47; H, 7.35; N, 8.22.

W O 97/25041 PCT~US97/00511 c F,~m~le 306 Preparation of 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-r3-5 (piperidin-4-yl)propyl]ben7imidazole trifluoroacetate CH

o,3~

~TFA

In a 1001 single neck round bottom flask, under a nitrogen atmosphere, 4-(prop-2-enyl)-2-[(4-chloroph~nl)~y)methyl~-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]l~lo~yl]ben7imidazole (300 mg, 0.572 mmol) was added to anhy~Lvus methylene chloride (201). To this was added trifluoroacetic acid (0.441, 652 mg, ~.72 Inol). The resulting mixture is stirred overnight at room temperature. The progress of the re~ on was monitored by thin layer chromatography. The solvents were removed in vacuo.
Yiel~: 222 mg (72.3%) NMR was consistent with the proposed title structure.

~ m~I~le 307 -Preparation of 4-(propyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]~l o~yl]b~n~imifl~7:ole W O 97/25041 PCT~US97/00511 C

N
BoC

In a 50 ml sinfle neck round bottom ila~k, under a nitrogen atmosphere, 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-buto~y~albonyl)piperidin-4-yl~.o~yl]b~n7.imidazole (100 mg, 0.19 mmol) was added to ethyl acetate (4 ml). To this solution was added 10%
p~ ;um on activated carbon (100 mg), followed by the addition of a hydrogen balloon. The reaction ~ ule was stirred for three hours at room temperature, then filtered through a bed of CELITETM. The desired title product was further purified by radial chromatography.
l~ield 86 mg (85.6%) IR ~nd NMR were consistent with the proposed title structure.
Analysis for C30H40ClN303:
Theory: C, 68.49; H, 7.66; N, 7.99.
Found: C, 68.76; H, 7.70; N, 8.03.

m1?le 308 Preparation of 4-(prop-2-enyl)-2-[(4-chloropheno~y)methyl]-1-[3-[~-[3-~piperidin- 1-yl)propyl]piperidin-4-ylJpropyl]ben ~i mi dazole W O 97/25041 PCTr~S97/00511 A

~/

N ~N

In a 25 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy3methyl]-1-~3-(piperidin-4-yl)~lopyl]bçn~imitl~ole (69.9 mg, 0.13 mmol3, potassium carbonate (161.9 mg, 1.17 mmol), potassium iodide (21.6 mg, 0.13 mmol), 3-(piperidin-1-yl)~lo~yl chloride (33.52 mg, 0.17 mmol) and N,N-dimethylform~mir~e (3 ml). The resulting ~ ,Ure was heated to 100~C
and m~int~ined at this temperature. The progress of the reaction was monitored by thin layer chromatography. The reaction was quenched by the addition of water. The aqueous fraction was extracted wtih ethyl acetate. The organic fractions were comhined, washed with water, and then dried over sodinm sulfate. The solvents were removed in vacuo.
The desired title product was further purified by radial chromatography.
Yield: 40 mg (55.9%) NMR was consistent with the proposed title structure.
FD~IS 548.22 (M+) ~.~m3~le 309 Preparation of 4-(prop-2-enyl)-2-[(4-chlorophP~nn~y3methyl]-1-[3-[1-[3-~phenyl3propyl]piperidin-4-yl]lJL~ rl]b.qn7imi~ ole W O 97/25041 PCT~US97/00511 ,sH2 In a 60 ml round bottom flask, under a nitrogen 5 atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl3yfopyl]b~n7irnidazole (898 mg, 2.12 mmol), potassium carbonate (1.46 g, 10.58 mmol), 3-(phenyl)~ yl chloride (0.2 ml, 506 mg, 2.{;4 mmol) and N,N-~imethylIormamide (7 ml). The resulting ~ e was heated to 60~C and mAint~ined at t_is temperature ovelnight. The 10 progress of the reaction was monitored by thin layer chromatography.
An additional 1 equivalent of potassium carbonate and 0.2 ml of 3-(phenyl)~lolJyl chloride were added and the resulting contents were stirred at 60~C for an additional two hours. The reaction was qllen~herl hy the addition o~ water. The aqueous fraction was extracted wtih ethyl 15 acetate. The organic fractions were coml~ined, washed with water, and then dried over sodium sulfate. The solvents were removed in vacuo.
The desired title product was further purified by radial chromatography.
Yield: 920 mg (80.2%) 20 NMR and IR was consi~tent with the proposed title structure.
Analysis for C34H40ClN30:
Theory: C, 7~;.32; H, 7.44; N, 7.7~;.
Found: C, 72.84; H, 7.22; N, 7.64.

WO 97/25041 PCT~US97/00511 -F~mple 310 Preparation of 4-(ethenyl)-2-[(4-chloropheno~y)methyl]-1-r3-[1-[3-5 (phenyl)propyl]piperidin-4-yl]~ yl]ben 7i mi(~ ole H2C~

In a 50 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]ben~imidazole (898 mg, 2.12 mmol), potassium carbonate (1.46 g, 10.~8 mmol~, 3-(phenyl)propyl chloride (0.2 ml, 606 mg, 2.54 m mol) and N,N-dimethylformamide (7 ml). The resulting mixture was heated to 60~C and rn~int~inef~ at this tempe.alule overnight. The 15 progress of the re~ction was monitored by thin layer chrnm~tography.
The reaction was quenched by the addition of water. The aqueous fraction was extracted wtih ethyl acetate. The organic fractions were combined, washed thrice with saturated sodium bicarbonate solution, and then dried over sodium sulfate. The solvents were removed in 20 vacuo. The desired title product was further purified by radial chromatography .
Yield: 810 mg (77.2%) NMR and IR was consistent with the proposed title structure.
Analysis for C33H3gClN3O:

W O 97~5041 PCTnJS97/00511 Theory: C, 7~.05; H, 7.2~; N, 7.96.
Found: C, 74.81; H, 7.05; N, 8.16.

F~rr~le 311 Preparation of 4-methoxy-2-[(4-chlorophenoxy~methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]ben~imidazole BoC
A solution of 4-~dl o~y-2-[(4-chloroph.qn-l~y)methyl]-1-~3-rl-(t-buto~ycalbonyl)piperidin-4-yl]~ yl]ben~imidazole (300 mg, 0.6 m~nol, 1 eq) in anhydrous N,N-dimethylformamide (3 m~ was treated w}th sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 1.1 eq). The 15 resulting mixture was stirred for thirty minutes at room temperature.
Methyl iodide (94 mg, 0.66 mmol, 1 eq) was added to the reaction and the re~ulting mixture was stirred for two hours at room temperature. The reaction was quenched with the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3 x 10 ml). The organic 20 fir~ctions were combined, washed with water (2 x 10 ml), then brine (1 x 10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by flash column chromatography to yield the title product as a crystalline product in 50%
yield.
25 NMR and IR were consistent with the proposed title structure.

W O 97/25041 PCT~US97/00511 ;

Analysis for C28H36ClN304:
Theory: C, 65.42; H, 7.06; N, 8.17.
Found: C, 6~.63; E, 7.14; N, 8.30.

~ le 312 Preparation of 4-methoxy-2-C(4-chloroph~no~y)methyl]-1-[3-(piperidin-4-yl)propyl]b~n7.imi~ ole trifluoroacetate \~0 / 0 \

N-- \ / 3 H
This product was prepared from 4-methoxy-2-[(4-chloropheno~y)methyl]-1-[3-(piperidin-4-yl)propyl]b~n ~imidazole tri~uoroacetate using standard trifluoroacetic acid deprotection protocols.
IR and NMR were consistent with the proposed title structure.
FDMS 413 (M+) Analysis for C23H28clN3o2 ~ 3 C2~l~3~2:
Theory: C, 46.07; H, 4.13; N, 5.~;6.
2 0 Found: C, 46.65; H, 4.38; N, 5.74.

~ le 313 Preparation of 4-methoxy-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(3-2 5 phenylpropyl)piperidin-4-yl~propyl]ben ~; mi dazole W O ~7/25041 PCT~US97/00511 ~ >~ ~

A solution of 4-methoxy-2-[(4-chlorophenoxy)methyl3-1-[3-5 (piperidin-4-yl)~.o~yl]b~n7.imidazole trifluoroacetate ~177 mg, 0.29 mmol, 1 eq) in anhydrous N,N-dimethylform~mitle (2 ml) was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting ..~ e was stirred at 80~C for six hours. The reaction was qliensh~d by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3 ~
10 ml). The organic fractions were combined, washed with water (3 x 10 ml), and brine (1 x 10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by coll~mn chromatography to yield the title product as a w~ite cryst~lline solid.
Yield: 72%
NMR and IR were consistent with the proposed title structure.
FDMS 631.2, 632 (M+) Analysis for C32H38ClN302:
Theory: C, 72.23; H, 7.20; N, 7.90.
Fnund: C, 72.14; H, 7.35; N, 7.82.

~ ,~le 314 W O ~7/25041 PCT~US97/00511 Preparation of 4-cyclopentoxy-2-[(4-chloroph çn o~y)methyl~- 1-[3-[ l-(t-butoxycarbonyl)piperidin-4-yl]propyl~ben~imidazole trifluoroacetate 0~

N
Bo~

A solution of 4-hy(llo~y-2-C(4-chlorophenoxy)methyl~ [3-[1-(t-butu~yca,l~onyl)piperidin-4-yl]lJlo~yl]b~n7imitlzl~0le trifluoroacetate (300 mg, 0.6 mmol, 1 eq) in anhydrous N,N-dimethylformamide (3 m) was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 10 1.1 eq3. The resulting ~ ue was stirred for thirty minutes at room tempe~ e. CYC1O~1O1JY1 bromide (0.66 mrrlol, 1 eq) was added to the reaction and the resulting ~ Lule was stirred for two hours at room tempel~ e. The reaction was qllen~h~d with the addition of water (~
ml). The aqueous fraction was extracted with ethyl acetate (3 x 10 ml).
15 The org~nic fractions were comhined, washed with water (2 x 10 ml), then brine (1 x 10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by flash coll~mn chromatography to yield the title product as a crystalline product in 50% yield.
20 NMR and IR were consistent with the proposed title structure.
FDMS 667 (M~) Analysis for C32H42ClN304:

CA 02242579 l998-07-08 W 097/25041 PCT~US97/00511 -29~-Theory: C, 67.65; H, 7.45; N, 7.40.
Found: C, 68.82; H,7.87; N, 7.55.

~nl~le 315 Preparation of 4-cyclopentoxy-2-~(4-chlorophenoxy)methyl]-1-[3-(pipe~din-4-yl) ~ov~l ~ n7imidazole trifluoroucetate ~C >\' ~
/ o \
<~> F3C OH

H-- \ / 3 This product was prepared from 4-cyclopentoxy-2-[(4-chlorophenoxy~methyl]-1-[3-~piperidin-4-yl)~3l o~yl]bcn ~im;dazole trifluoroacetate using standard trifluoroacetic acid deprotection protocols.
15 IR and NMR were consistent with the proposed title structure.
FDMS 468 (M+) Analysis for C2gH38ClN3O2 ~ 3 C2HF3O2:
Theory: C, 48.93; H, 4.60; N, 5.19.
Found: C, 47.33; H, 4.82; N, 5.37.
ml~le 316 W O 97/2S041 PCT~US97/00511 Preparation of 4-cyclopentoxy-2-[(4-chlorophel~o~ry)methyl]-1-~3-[1-~3-phenylpropyl)piperidin-4-yl]~ yl]ben ~imi dazole 0~

\~~~
~> Cl ~ '~

A solution of 4-cyclopentoxy-2-[(4-chlorophenoxy)methyl]-1-~3-(piperidin-4-yl)propyUb~n7imidazole trifluoroacetate (0.29 mmol, 1 eq) in anhydrous N,N-dilmethylform~mille ~2 ml~ was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.5 eq). The resulting ~ e was stirred at 80~C for six hours. The reaction was qn~n~hed by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3 x 10 ml). The organic fractions were comhined, washed with water (3 x 10 ml), and brine (1 x 10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by column chromatography to yield the title product as a white crystalline solid.
NMR and IR were consistent with the proposed title structure.
FDMS 586 (M+) Analysis for C36H44ClN302:
Theory. C, 73.76; H, 7.56; N, 7.17.
Found: C, 75.08; H, 7.85; N, 7.30.

W O 97/25041 PCT~US97/00511 - 2g8-F"~slTnrle 317 Preparation of 4-isopropoxy-2-[(4-chlorophenoxy)methyl:l- 1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl] l l o~yl]bqn 7:i mi dazole trifluoroacetate ~H3 OJ~CH3 BoC

A solution of 4-Lydlo~y-2-[(4-chloropheno~y)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yU~ yl~b~n~im~dazole trifluoroacetate (300 mg, 0.6 mrnol, 1 eq) in anhydrous N,N-dimethylformamide ~3 m) was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 1.1 eq). The resulting mi~ule was stirred for thirty minutes at room temperature. ISO1J1VL~Y1 bromide ~0.66 mmol, 1 eq) was added to the reaction and the resulting ~i2~ e was stirred for two hours at room temperature. The reaction was quenched with the addition of water (~;
ml~. The aqueous fraction was extracted with ethyl acetate (3 x 10 ml).
The organic fractions were comhin~d, washed with water (2 x 10 ml), the~ 1~rine (1 x 10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by flash col~mn chromatography to yield the title product as a crystalline r product.
NMR and IR were consistent with the proposed title structure.
FI~MS 541, 542 (M~) .

W O 97/25041 PCT~US97/00511 Analysis for C2gH36ClN3O4:
Theory: C, 66.47; H, 7.44; N, 7.75.
l~ound: C, 66.31; H, 7.54; N, 7.75.

F"r~nu?le 318 Preparation of 4-isopropoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)~ ~ o ~yl]ben ~i mi dazole tri~uoroacetate / o \
(~~ F3C OH
N-- \ / 3 H
This product was prepared from 4-isopropoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]ben7;mifi~ole trifluoroacetate using standard trifluoroacetic acid deprotection 15 protocols.
IR and NMR were consistent with the proposed title structure.
FDMS 413 (M~) Analysis for C2~H32clN3o2 ~ 3 C2HF3O2:
Theory: C, 47.49; H, 4.50; N, 5.36.
Found: C, 48.46; H, ~.03; N, 5.86.
le 319 W O 97/2~041 PCTnJS97/00511 Preparation of 4-isopropoxy-2-[(4-chloropheno~ry)methyl]-1-[3-[1-(3-phenyl~o~yl)piperidin-4-yl]~ro~yl3ber 7:imidazole olCH3 A solution of 4-isopropoxy-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl~bçn7imidazole trifluoroacetate (0.29 mmol, 1 eq) in anhydrous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenyl~u~yl bromide (87 mg, 0.43 m mol, ~.~ eq). The resulting mixture was stirred at 80~C for six hours. The reaction was qllenf~h~d by the addition of water (5 ml). The aqueous fraction was extracted with ethyl acetate (3 x 10 ml). The organic fractions were comhinetl, washed with water (3 x 10 ml), and bri~e (1 x 10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The re~idue was further purified by column chromatography to yield the title product as a white crystalline solid.
NMR and IR were consistent with the proposed title structure.
FDMS 559.1, ~60 (M+) Analysis for C34H42ClN302:
2 o Theory: C, 72.09; H, 7.56; N, 7.50.
Found: C, 73.09; H, 7.47; N, 7.l;2.

~:lrr~le 320 .

W O 97125041 PCT~US97/00511 Preparation of 4-(cyclohexylmethoxy)-2-~(4-chlorophenoxy)methyl]-1-~3-[l-(t-butoxycarbonyl)piperidin-4-yl]~-o~yl]ben~imidazole tri~uoroacetate N
BoC

A solution of 4-~ o~y-2-[(4-chloroph~oxy)methyl]-l-[3 (t-butoxycarbonyl)piperidin-4-yl]~lopyl]benzimidazole trifluoroacetate (300 mg, 0.6 ~ol, 1 eq) in anhydrous N,N-dimethylformamide (3 m) was treated with sodium hydride (60% in mineral oil, 26 mg, 0.66 mmol, 1.1 eq~. The resulting mixture was stirred for thirty minutes at room tempe~al~e. C~yclo~ ylmethyl bromide (0.66 mmol, 1 eq) was added to the reaction and the resulting lm~ e was stirred for two hours at room temperature. The reaction was qllenl.h~d with the addition of water (5 ml~. The aqueous fraction was extracted with ethyl acetate ~3 x 10 ml).
The organic fractions were comhined, washed with water (2 x 10 ml~, then brine (1 x 10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo. The residue was further purified by ~ash colllmn chromatography to yield the title product as a crystalline 2 o product.

CA 02242579 l998-07-08 NMR and IR were consistent with the proposed title structure.
FDMS ~96, {~96 (M+) Analysis for C34H46ClN304:
Theory: C, 68.~;0; H, 7.78; N, 7.05.
Found: C, 68.62; H, 7.83; N, 7.03.

m~le 321 Preparation of 4-(cyclohexylmethoxy~-2-[(4-chlorophenoxy)methyl]-1-[3-10 (piperidin-4-yl)propyl]ben~imidazole trifluoroacetate O \

H-- \ / 3 This product was prepared from 4-(cyclohexylmethoxy)-2-15 C(4-chlorophenoxy)methYl]- 1-C3-(piperidin-4-yl)propyl]b~n ~imi dazole trifluoroacetate using ~tandard trifluoroacetic acid deprotection protocols.
IR and NMR were consistent with the proposed title structure.
F:DMS 496 (M+) 20 Analysis for C3lH42ClN302 ~ 3 C2HF302:
Theory: C, 60.16; H, 4.93; N, 6.01.

W O 97/25041 PCTnUS97/00511 Found: C, 50.01; H, 5.04; N, 4.96.

m~le 322 5 Preparation of ~-(cyclohexylmethoxy)-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(3-phenylpropyl)piperidin-4-yl]~l o~yl]ben~imidazole A solution of 4-(cyclohexylmethoxy)-2-t(4-chlorophenoxy)methyl3-1-r3-(piperidin-4-yl)~ yl]bçn7imidazole trifluoroacetate (0.29 mmol, 1 eq) in anhydrous N,N-dimetll~lfo.,.~amide (2 ml) wae treated with potassium carbonate (120 mg, 0.87 mmol, 3 eq) and 3-phenylpropyl bromide (87 mg, 0.43 mmol, 1.6 eq). The resulting 15 mixture was stirred at 80~C for six hours. The reaction was qT1en(h~d - by the addition of water (~ ml). The aqueous fraction was extracted with ethyl acetate (3 x 10 ml). The organic fractions were comh;ned, washed with water (3 x 10 ml), and brine (1 x 10 ml), and then dried over sodium sulfaLte. The solvents were removed in vacuo. The residue was further W O 97/~5041 PCTAJS97tOO511 purified by column chromatography to yield the title product as a white crystalline solid.
NMR and IR were consistent with the proposed title structure.
FDMS 614 (M~) Analy~is for C38H48clN3o2:
Theory: C, 74.30; E, 7.88; N, 6.84.
Found: C, 74.26; H, 7.93; N, 6.91.

~ ple 323 Preparation of 4-(3-bromopropoxy)-2-[(4-chlorophenoxy)methyl]- 1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl] ~ yl]ben 7:i mi dazole Br ~:r~

BoC
A solution of 1,3-dibromopropane (41.3 mg, 0.3 mmol, 1.~ eq) in anhydrous N,N-dimethylforrn~mi-le (2 ml) was treated with a solution of 4-hyL o~y-2-[(4-chlorophenoxy)methyl]-1-[3-~1-(t-butoxycarbonyl)piperidin-4-yl]propyl]b~n~imidazole (100 mg, 0.2 rnrnol~ 1 20 eq3 in anhy~llous N,N-dimethylformamide (1 ml). The resulting e was stirred for twelve hours. The re~ction was q11~n~hed by the addition of water (10 ml). The aqueous fraction was extracted with diethyl ether (3 x 10 ml). The organic fr~cti--n~ were combined, washed with water (3 x 10 ml), and brine (1 x 10 ml), and then dried over sodium 5 sulfate. The solvents were removed in vacuo. The residue was subjected to column chromatography to yield the desired title product as a white crystalline product.
Yield: 80%
NMR and IR were consistent with the proposed title structure.
FDMS 620, 621 (M+) ~ J?le 324 Preparation of 4-[3-t2-(pyrroldin-1-ylmethyl)pyrrolidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-but~J~ycalbonyl)piperidin-4-yl]~.oL~yl3ben~imi(1~ole N

\>~0 N
BoC

W O 97/25041 PCT~US97/00511 . -306-A solution of 4-[3-bromopropoxy]-2-[(4-c:blorophenoxy)methyl]- 1-[3-[1-(t-buto~ycal 1,onyl)piperidin-4-yl]propyl]ben7imi~n~0le (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-5 dimethylformamide (2 ml) was treated with potassium carbonate (51.3mg, 0.37 mmol, 2 eq) and (S)-(+)-2-(pyrroldin-1-ylmethyl)pyrrolidine (28.7 mg, 0.19 mmol, 1.~i eq). The resulting mixture was stirred at 80~C for six hours. The reaction was ~ nr.hed by the addition of water (10 ml).
The aqueous fraction was extracted with ethyl acetate (3 x 10 ml). The 10 organic fractions were comhined, washed with water (3 x 10 ml), brine (1 x 10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to provide the title product.
Yield: 78%
15 NMR and IR were consistent with the proposed title structure.
FDM~3 694 (M+) le 3~

Preparation of (RS) 4-[3-[2-(pyrroldin-1-ylmethyl)pyrrolidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]- 1-[3-(piperidin-4-yl)propyl]ben7.irni-1~701e N~
o ' ~'-- '13 H

The title compound was prepared from (RS) 4-[3-~2-(pyrroldin- 1-ylmethyI)pyrrolidin- 1-yl]propoxy]-2-~(4-5 chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl~b~n~ ole using trifluoroacetic acid deprotection as described supra.
IR and NMR were consistent with the proposed title structure.
FDMS 594 (M+) 10 Analysis for C34Hs1Cll!~sOz:
Theory: C, 68.72; H, 8.14; N, 11.79.
Found: C, 68.91; H, 8.08; N, 11.70.

ml~le 326 Preparation of (RS) 4-[3-[2-[2-(piperidin-1-yl)ethyl]piperidin-1-yl]propoxy3-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl~ yl]benzimidazole W O 97/25041 PCT~US97/00511 N

\~0~3~

Cl <~

BoC

A solution of 4-[3-bromopropoxy]-2-[(4-chlorophenoxy)methyl}-1-[3-[1-(t-buto~yca. 13onyl)piperidin-4-yl]propyl]ben~imidazole (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-flimethylformamide (2 ml) was treated with potassium carbonate (~1.3 mg, 0.37 mmol, 2 eq) and 2-[2-(piperidin-1-yl)ethyl]piperidine (0.19 mmol, 1.5 eq). The resulting mixture was stirred at 80~C for six hours.
The reaction was quenched by the addition of water (10 ml). The 10 aqueous fraction was extracted with ethyl acetate (3 x 10 ml). The organic fractions were comhined, washed with water (3 x 10 ml), brine (1 x 10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to provide the title product.
15 NMR and IR were consistent with the proposed title structure.
FDMS 736.4 (M+) le 327 W O 97/25041 PCT~US97/00511 - 3~9-Pr~l~afd~ion of(RS) 4-~3-[2-[2-(pipe}idin-1-yl)ethyl:lpiperidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-1:3-(piperidin-4-yl)propyl]bçn~imidazole ~>
~N~ ~

The title compound was prepared from (RS) 4-[3-~2-[2-(piperidin-l-yl)ethyl]piperidin-l-yl]propoxy~-2-[14-chloropheno~y)methylJ- 1-[3-[1-(t-buto~y~al 1,onyl)piperidin-4-yl]propyl]ben~imidazole using trifluoroacetic acid deprotection as described supra.
NMR and IR were consistent with the proposed title structure.
FDMS 636 (M+)~~ Analysis for C37~Is4ClNsO2:
Theory: C, 69.84; H, 8.55; N, 11.01.
Found: C, 69.51; H, 8.76; N, 10.13.

~ple 328 CA 02242579 l998-07-08 W O 97/25041 PcTnusg7/OOSal Preparation of 4-[3-[4-(carboxamido)piperidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-buto~yc~l)onyl)piperidin-4-yl3~1 o~yl]ben 7 i mi dazole ~ ~ N H2 N

~\>~~~

BoC

A solution of 4-[3-bromopropoxy]-2-L(4-chloroph~no~y~methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]propyl]ben~im~dazole (77 mg, 0.124 rnrnol, 1 eq) in anhydrous N,N-dimethylform~mi~le (2 ml) was treated with potassium carbonate (61.3 mg, 0.37 mmol, 2 eq) and 4-(carb~ mi-lo)piperidine (0.19 mmol, 1.~ eq).
The resulting ~ . e was sti~red at 80~C~ for six hours. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was 15 extracted with ethyl acetate (3 x 10 ml). The organic fractions were combined, washed with water (3 x 10 ml), brine (1 x 10 ml), and then W O 97/25041 PCT~US97/OOSll -31~-dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was puri~ied by flash chromatography to provide the title product.
NMR and IR were consistent with the proposed title structure.
5 FDMS 668 (M+) ~ ?le 329 Preparation of 4-[3-[4-(carboxamido)piperidin-1-yl]propoxy]-2-[(4-10 chlorophenoxy)methyl]-1-[3-[1-(t-butogycarbonyl)piperidin-4-yl]l~l o~l]bçn~imifl~7:0le ~ ~ N H2 N

Y 15 The title compound was prepared from 4-[3-~4-(carboxamido)piperidin- l-yl]propoxy]-2-[~4-chlorophenoxy)methyl]-1-[3-W O 97/25041 PCT~US97/00511 [1-(t-buto~ycalbonyl)piperidin-4-yl]~ yl]be~7irnidazole using standard trifluoroacetic acid deprotection techniques, as described supra.
NMR and IR were consistent with the proposed title structure.
FDMS 568 (M+) 5 Analysis for C31H43ClNsO3:
Theory: C, 65.53; H, 7.45; N, 12.33.
Found: C, 65.26; H, 7.48; N, 12.11.
m;~?le 330 Preparation of 4-[3-[4-(methyl)piperidin- 1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]- 1-[3-[ l-(t-buto~y~,al IJonyl)piperidin-4-yl]propyl]bPn7.imidazole ~;

IN
BoC

W O 97/~5041 PCT~US97/00511 A solution of 4-[3-bromopropoxy}-2-t(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]~lo~yl]b~n7imidazole (77 mg, 0.124 mmol, 1 eq) in anhydrous N,N-dimethylforrn~mil1e (2 ml) was treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and 4-(methyl)piperidine (0.19 mmol, 1.5 eq). The resulting mixture was stirred at 80~C for six hours. The re~ctioI was ql~en~h~d by the addition of water (10 ml). The aqueous fraction was extracted with ethyl acetate (3 x 10 ml). The organic fractions were co~nhined, washed with water (3 x 10 ml), brine (1 x 10 ml), and then 10 dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to provide the title product.
NMR and IR were consistent with the proposed title structure.
FDMS 639 (M+) 15 Analysis for C36HslClN4O4:
Theory: C, 67.64; H, 8.04; N, 8.76.
Found: C, 67.89; H, 8.0~; N, 8.84.

rr~le 331 Preparation of 4-~3-[4-(methyl)piperidin- 1-yl]propoxy]-2-~(4-ch~orophenoxy3methyl] -1-[3-(piperidin-4-yl) ~ . o~yl]ben 7 i mi dazole W O 97/25041 PCT~US97/00511 N

The title compound was prepared from 4-[3-[4-(methyl)piperidin- 1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]- 1-[3-[1-(t-5 butoxycarbonyl)piperidin-4-yl]propyl]ben7imi dazole by standard trifluoroacetic acid deprotection as described supra.
NMR and IR were consistent with the proposed title structure.
FDMS 539 (M+) Analysis for C3lH43ClN402:
Theory: C, 69.06; H, 8.04;N, 10.39.
Found: C, 69.15; H, 8.02; N, 10.13.

F,~mu?le 332 Preparation of (RS) 4-[3-[3-(methyl)piperidin-1-yl]propoxy]-2-[(4-cblorophenoxy)methyl]-1-[3-[1-(t-butogycarbonyl)piperidin-4-yl]~.o~yl]ben7.imi-1~70le W O 97/25041 PCT~US97/00511 -31~-~CH3 BoC

A solution of 4-[3-bromopropoxy]-2-[(4-5 chloroph~no~y)methyl]-1-~3-[1-(t-but~ycallJonyl)piperidin-4-yl]~lo~yl]ben7.imirl~0le (77 mg, 0.124 mmol, 1 eq) in anhyd~ous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (51.3 mg, 0.37 mrllol, 2 eq) and (RS) 3-(methyl)piperidine ~O.lg mmol, 1.5 eq).
The resulting mixture was ~tirred at 80~C for six hours. The reaction 10 was qllçnl~hed by the addition of water (10 ml). The aqueous fraction was extracted with ethyl acetate (3 X 10 Illl). The organic fr~ction~ were comhin~d, washed with water (3 x 10 ml), brine (1 x 10 ml), and then dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to 15 provide the title product.
NMR and IR were consistent with the proposed title structure.
FDMS 639 ~M+) Analysis for C36Hs1ClN4O4:

W O 97/25041 PCTnJS97/00511 Theory: C, 67.64; H, 8.04; N, 8.76.
Found: C, 67.91; H, 7.9~; N, 8.82.
le 333 Preparation of (RS) 4-[3-~3-(methyl)piperidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]ben ~imidazole ~CH3 H

The title compound was prepared from (RS) 4-[3-[3-(methyl)piperidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-butoxyca~bonyl)piperidin-4-yl]propyl~ben~imidazole by standard trifluoroacetic acid deprotection as described supra.
15 NMR and IR were consistent with the proposed title structure.
FDMS 639 (M+) Analysis for C3lH43(~1N402:
Theory: C, 69.06; H, 8.04; N, 10.39.
Found: C, 69.29; H, 8.19; N, 10.24.

W O 97/25041 PCT~US97/00511 c ~ le 334 Preparation of (RS) 4-~3-[2-(methyl)piperidin-1-yl]propoxy]-2-[(4-5 chloroph en o~y)methyl]- 1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]~l opyl]ben 7:i mi dazole BoC

A solution of 4-[3-bromopropoxy]-2-[(4-chlorop~ en o~y)methyl]- 1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]~ yl]benzimidazole (77 mg, 0.124 mmol, 1 eq) in anhydlous N,N-dimethylformamide (2 ml) was treated with potassium carbonate (51.3 mg, 0.37 mmol, 2 eq) and (RS) 2-(methyl)piperidine (0.1~ mmol, 1.~ eq).
15 The resulting llli~l,Ulc~ was stirred at 80~C for six hours. The reaction was quenched by the addition of water (10 ml). The aqueous fraction was extracted with ethyl acetate (3 x 10 ml)~ The organic fractions were comhined, washed with water (3 x 10 ml), brine (1 x 10 ml), and then CA 02242579 l998-07-08 W O 97/25041 PCT~US97/00511 dried over sodium sulfate. The solvents were removed in vacuo to yield an oily crude product which was purified by flash chromatography to provide the title product.
NMR and IR were consistent with the proposed title structure.
5 FDMS 639 (M+) Analysis for C36Hs1ClN4O4:
Theory: C, 67.64; H, 8.04; N, 8.76.
Found: C, 67.89; H, 8.05; N, 8.84.

h~ m~le 33~;

Preparation of (~S) 4-[3-[2-(methyl)piperidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]ben7imitl~ole N C, N-H
The title compound was prepared from (RS) ~-[3-[2-(methyl)piperidin-1-yl]propoxy]-2-[(4-chlorophenoxy)methyl]-1-[3-[1-(t-but~y.,al~onyl)piperidin-4-yl~o~yl]b~n~imif~ ole by st~nrl~rd trifluoroacetic acid deprotection as described supra.
NMR and IR were consistent with the proposed title structure.
FDMS ~39 ~M+) Analysis for C3lH43ClN402:
Theory: C, 69.06; H, 8.04; N, 10.39.
Found: C, 70.89;H, 8.65;N, 9.05.
rnnle 336 Preparation of 2-~4-chlorophenQ~ymethyl)-4-methyl-1-[3-[1-[3-(1,1-diphenyl)propyl]piperidin-4-yl~propyl]ben~rnidazole trihydrochloride ~N

<~ ~\Cl ~ ~ ,n~ 3 HCl NMR was consistent with the desired title structure. FDMS ~91 (M+).
Analysis calculated for C3gH42ClN3O ~ 3 HCl ~ 0.26 H20.
Theory: C, 64.64; H, 6.50; N, 5.9~i.
Found: C, 64.61; H, 6.36; N, 5.99.
~ ~le 337 CA 02242579 l998-07-08 Prepartion of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-~1-(ben~imitl7.ol-2-ylmethyl)piperidin-4-yl}propyl]ben~imidazole ~> Cl HN ~> 3 ~CI

mp 218-20~.
NMR was consistent with the desired title structure. FDMS 528 (M+).
FAB exact mass calculated for C3lH3sclNso: ~
Theory: 528.2530 lo Found: 528.2541 ml?le 338 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[1-[3-(2,4-15 ~limethogybenzoyl)~ yl]piperidin-4-~l]propyl]b~n~imidazole ~~~

~~N

H3CO~OCH3 NM:E?~ was consistent with desired title structure. ESI MS 604 (M+1).
Single compound of high purity as evidenced by chromatographic 5 methods.

~ m~e 339 Preparation of 2-(4-chlorophenn~ymethyl3-4-methyl-1-[3-[1-[3-(4-10 me~hoxybenzoyl)~l o~yl]piperidin-4-yl]~. v~yl]bçn7:im;dazole ~' Cl O l l ,N~

W O 97/2~41 PCT~US97/OU511 NMR was consistent with desired title structure. ESI MS 574 (M~1).
Single compound of high purity as evidenced by chromatographic methods.

le 340 Preparation of 2-(4-chloropheno~ymethyl-4-methyl-1-[3-[1-[2-(~uinazolin-10 -yloxy)acetyl]piperidin-4-yl]~l o ~yl]be~ 7 i mi dazole /~N
~~~

~> ~\Cl ~0~ ~

NMR was consistent with desired title structure.
15 FAB exact mass calculated for C33H3~;ClNsO3:
Theory: 584.2420 Found: 584.2428 ;?le 341 Preparation of 2-(4-chlorophenoxymethyl)4-methyl-1-~3-[1-[2-~quinolin-2-yloxy)acetyl]piperidin-4-yl]~lolJyl]ben~imidazole W O 97/25041 PCT~US97/00511 ~,0~3~

<> Cl ~ ~o~N~/

FAB exact mass calculated for C34H36ClN403:
Theory: 583.2476 Found: ~83.2484 Single compound of high purity as evidenced by chromatograph~c methods.

~ nu?le 342 Preparation of 2-(4-chlorophenoxymethyl~-4-methyl- 1-[3-~1-[3-(indol-3-yl)propan-1-oyl]piperidin-4-yl]~l ollyl]ben7:i mi .1~ole ,~H3 ~ ~' ¢~ ~ Cl HN~,N

CA 02242579 l998-07-08 W O 97/25041 PCT~US97/00511 mp 153~C
NMR,Tl~. and W were consistent with the desired title structure.
FDMS 568 (M+).
Analysis calculated for C34H37ClN402:
Theory: C, 71.75; H, 6~55; N, 9.84.
Found: C, 71.56; H, 6.41; N, 9.89.

~le 343 Preparation of 2-(4-chlorophenoxymethyl )-4-methyl- 1-[3-[1-L4-~indol-3 -yl)butan-l-oyl]piperidin-4-yl]l~l o~yl]ben7:imi-1~7.01e ~,~
~> Cl ~\~
N~J

H

mp 151~C.
NMR, I:R and W were consistent with the desired title structure.
FDMS 582 ~M+~.
Analysis calculated for C3sH3sClN402:
Theory: C, 72.09; H, 6.74; N, 9.61.
Found: C, 72.22; H, 6.69; N, 9.67.
m~ple 344 Preparation of 2-(4-chlorophen-~ymethyl)-~methyl-1-[3-~1-[1-(2-phenylethyl~mino)butan-4-oyl]piperidin-4-yl~ yl]ben~imidazole ~Cl ~--N~
H
mp 112~C.
NMR, IR and UV were consistent with the desired title structure.
FDMS ~87 (M+).
Single compound of high purity as evidenced by chromatographic methods.
m~?le 34~
Preparation of 2-(4-chlorop~eno~ymethyl)-4-methyl-1-[3-[1-[1-(3-phenylpl o~yl ~min())butan-4-oyupiperidin-4-yl}propyl]benzimidazole W O g7/25041 PCTnUS97/OQ511 ¢ ~H' mp 113~C.
NMR, IR and W were consistent with the desired title structure.
5 FDMS 601 (M~).
Analysis calculated for C36H45ClN4O2:
Theory: C, 71.92; H, 7.54, N, 9.32.
Found: C, 71.72; H, 7.49; N, 9.24.

~~ le 346 Preparation of 2-(4-chlorophenoxymethyl-4-methyl-1-t3-[1-[4-(1-indol-3-yl)butyl]piperidin-4-yl]~ yl]ban~.imidazole W O 97/25041 PCT~US97/00511 ~0~ 3~

~> Cl ~\~

"N~J

N

NMR was consistent with the desired title structure. ESI MS l;69 (M~1).
Single compound of high purity as endenced by chromAto~raphic 5 methods.

F,XArn1?1e 347 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl- 1-[3-[1-r3-( 1-indol-3-10 yl~propyl]piperidin-4-yl]propyl]ben~imi~7.01e Cl W O 97/25041 PCT~US97/00511 NMR was consistent with the desired title structure. ESI MS ~55 (M~1).
Single compound of high purity as evidenced by chromatographic methods.

F,~ le 348 Preparation of 2-(4-chlorophel o~ymethyl-4-methyl-1-~3-~1-[3-(4-iodophenyl)~- o~yl]piperidin-4-yl]~ yl]ben7.imidazole ~> Cl I~~N~>

NMR was consistent with the desired title structure. ESI MS 642 (M+1~.
Single compound of high purity as evidenced by chromatographic methods .
?le 349 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[2-(4-iodophenyl)ethyl]piperidin-4-yl]propyl]b~n ~imidazole W O 97~5041 PCTnUS97/00511 .

~0~3~

<~ Cl ~

~N~

~J
I~

mp 121-122~C
NMR and IR were cons;stent with the de~ired title structure.
5 ESI MS 628 (M+1).
Analysis calculated for C31H3sClN3O:
Theory~ , 59.29; H, 5.62; N, 6.69.
Found: C, 59.22; H, ~;.62; N, 6.70.

~,~r~ml?le 3~0 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-(3-acetylpropyl)piperidin-4-yl]~ yl]ben7:imidazole W O 97/25041 PCT~US97/00511 ~' (~ Cl ~ .N~

NMR was consistent with the desired title structure. ESI MS 482 (M+1~.
Single compound of high purity as evidenced by chromatographic 5 methods.

~ rn~le 3~;1 Preparation of 2-(4-chloropheno~ymethyl)-4-methyl-1-[3-[1,1-10 dimethylpiperidin-4-ium]propyl]ben~imidazole iodide ~N

~\Cl H3C~ I ~J

I-mp 198-199~C.
15 NMR, IR and W were consistent with the desired title structure.

W O 97/25041 PCTnUS97/00511 FDMS 426 (M+ for C2sH33N30).
Analysis for C2sH33N3ClIN30 ~ 0.5 H20:
Theory: C, 53.34; H, 6.09; N, 7.49.
Found: C, ~3.19; H, 6.07; N, 7.46.

~ le 352 Preparation of 2-(4-chloroph~no~ymethyl)-4-methyl-1-[3-[1-methylpiperidin-4-yl].~l o~yl]bçn7imidazole ~N~0 3 H3C ~

The NMR was consistent with the desired title structure.
FAB exact mass calculated for C24H3lClN30:
Theory: 41~ ~1fi6 Found: 412.2146 Single compound of high purity as evidenced by chromatographic methods.

F~n~le 353 -Preparation of 2-(4-chloroph~nn~ymethyl)-4-meyhyl-1-[3-[1-[4-(phenyl)buty~]piperidin-4-yl]~rulJyl]b~n~i~nidazole W O 97/25041 PCTAJS97/OOSll ~~~

0~

The NMR was consistent with the desired title s~ructure. ESI MS 530 (M~1).
5 Single compound of high purity as evidenced hy chromatographic methods.

F,~mnle 354 Preparation of 2-(4-chlorophenoxymethyl)-4-methyl-1-[3-[1-[5-(phenyl)pentyl]piperidin-4-yl]propyl]bçn~imidazole ,~<CH3 ~N~-- '13, ~> Cl N~

W O 97125041 PCTnJS97/00511 The NMR was consistent with the desired title structure.
FDMS 643 (M+). ESI MS ~44 (M+1).
t Analysi~ calculated for C34H42clN3O:
Theory: C, 75.04; H, 7.78; N, 7.72.
Found: C, 74.84; H, 7.78; N, 7.89.

~.xAnn~le 354 Preparation of 2-(4-methylphenox9~nethyl)-4-benz~loxy-b~n~imidazole Yield: 53%
NMR was consistent with the proposed title structure.
mp 1~6-1~8~C
Analysis for C22H20N2O2:
Theory: C, 76.72; H, 6.8~; N, 8.13.
Found: C, 77.00; H, 5.84; N, 8.11.

~,~A~u?le 355 Preparation of 2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]~l o~yl]b~n~imidazole Yield: 9.0 grams NMR was consistent with the proposed title structure.
mp 116-118~C
Analysis for C3~H40N304Cl:
Theory: C, 69.20; H, 6.83; N, 7.12.
Found: C, 69.43; H, 6.69; N, 7.17.

h ~Arnple 356 Preparation of 2-(4-chloroph~ncl~ymethyl)-7-benzyloxy-1-[3-[1-(t-- butoxycarbonyl)piperidin-4-yl]~l o~yl]ben7imi(1A~ole Yield: ~.27 grams NMR was consistent with the proposed title structure.
Analysis for C34H40N3O4Cl:
Theory: C, 69.20; H, 6.83; N, 7.12.
~ound: C, 69.75; H, 7.23; N, 7.26.

W O 97/25041 PCT~US97/00~11 F',~m,~le 357 r. e~ ion of 2-(4-methylphenoxymethyl)-4-benzyloxy-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl]~l~,p~rl]ben~imidazole Yield: 7.60 grams NMR was consistent with the proposed title structure.
mp 116-118~C
Analysis for C35H43N304:
Theory: C, 73.78; H, 7.61; N, 7.37.
Found: C, 73.85; H, 7.72; N, 7.~0.

~r~m~le 358 15 Preparation of 2-(4-methylpheno~ymethyl)-7-benzylogy-1-[3-[1-(t-butoxycarbonyl)piperidin-4-yl],lJlo~yl]ben~imi~ole Yield: 4.50 grams NMR was consistent with the proposed title structure.
mp 153-1~4.5~C
20 Analysis for C36H43N304:
Theory: C, 73.78; H, 7.61; N, 7.37.
Found: C, 73.62; H, 7.66; N, 7.34.

~mnle 359 Preparation of 2-(4-chlorophenoxymethyl~-4-benzyloxy-1-[3-(piperidin-4-yl)propyl]ben ~im;dazole Yield: 55%
NMR was consi~tent with the proposed title structure.
30 mp 140-141~C
Analysis for C2"H3~N302Cl:
Theory: C, 71.08; H, 6.58; N, 8.58.
Found: C, 71.20; H, 6.64; N, 8.61.

F,~z~rr~?le 360 W O 97/25041 PCTrUS97/00511 Preparation of 2-(4-chloropheno~ymethyl)-7-benzyloxy-1-[3-(piperidin-4-yl)propyl]b~n7.imir~ole Yield: 98%
NMR was consistent with the proposed title structure.
5 Analysis for C~3~302Cl:
Theory: C, 71.08; H, 6.58; N, 8.58.
Found: C, 71.00;11, 6.80; N, 8.67.

F.~ ?le 361 Preparation of 2-(4-chloropheno~ymethyl)-4-benzyloxy~ 3-[1-(ethoxycarbonylpropyl)piperidin-4-yl31~l ol~yl]ben7imidazole The title compound was prepared from the compound of rnrle 360 by re~3ctin~ the compound with sodium bicarbonate and 3-(ethoxycarbonyl)~Lo~yl bromide in N,N-dimethylformamide, essentially as described supra.
Yield: 78%
NMR was consistent with the proposed title structure.
mp 63-65~C
AIlalysis for C35H42N3O2Cl:
Theory: C, 69.58; H, 7.01; N, 6.9~.
Found: C, 69.77; E~, 7.21; N, 6.70.

F'~nu?le 362 Preparation of 2-(4-chloropheno~ymethyl)-~benzylogy-~-[3-[1-[3-(piperidin- l-yl)propyl]piperidin-4-yl]~l olJ~l]ben 7.i mi ~ ole The title compound was prepared from the compound of rnple 360 by re~ctin~ the compound with sodium bicarbonate, sodium iodide, and 1-t3-chlo.o~o~yl)piperidine hydrochloride in N,N-- dimethylform~m;~e, essentially as described supra.
Yield: 64%
NMR was consistent with the proposed title structure.
mp 58-60~C~
Ana~ysis for C37H47N402Cl:
Theory: C, 72.23; H, 7.70; N, 9.11.

W O g7/25041 PCTAJS97/00511 Found: C, 72.08; H, 7.53; N, 8.86.

nu?le 363 Preparation of 2-(4-chlorophenl~ymethyl)-4-benzyloxy-1-[3-[1-[3-(carboxy)~ yl]piperidin-4-yl]propyl]ben 7i mi dazole Yield: 74%
NMR wa~ consistent with the proposed title structure.
mp 101-103~C
Analysis for C33H38N3O4Cl:
Theory: C, 68.80; H, 6.65; N, 7.29.
Found: C, 68.60; H, 6.89; N, 7.~2.

F,~mnle 364 Preparation of 2-(4-chlorophenoxymethyl)-4-benzyloxy- 1-[3-[1-[3-(piperidin- 1-ylcarbonyl)propyl]piperidin-4-yl]~l o~yl]ben 7.imi dazole Yield: 47%
NMR was consistent with the proposed title structure.
mp 145.5-147~C
Analysis for C38H47N4O3Cl:
Theory: C, 70.95; H, 7.37; N, 8,71.
Found: C, 70.86; H, 7.34; N,8.68.

~ le 365 Preparation of 2-(4-chlorophenoxymethyl)-4-benzyloxy-1-[3-[1-[4-(piperidin-1-yl)butyl]piperidin-4-yl]propyl]b~n~imidazole hernihydrate Yield: 34%
30 NMR was consistent with the proposed title structure.
mp 98-100~C
Analysis for C38H49N4O2Cl:
Theory: C, 71.49; H, 7.90; N, 8.78.
Found: C, 71.15; H, 7.73; N,8.71.~5 rnrle 366 W O 97/2S041 PCT~US97/00511 Preparation of 2-(4-chlorophenn~rymethyl)-4-benzyloxy-1-[3-[1-[3-(piperidin-l-yl~lo~yl]piperidin-4-yl]~-o~l]ben~imidazole hemihydrate Yield: 86%
NMR was consistent with the proposed title structure.
mp 108-110~C
Analysis for C37H47N4O2Cl:
Theory: C~, 72.23; H, 7.70; N, 9.11.
Found: C, 72.48; H, 7.8~; N, 9.05.
~m;~le 367 Preparation of 2-(4-chlorophenoxymethyl)-7-[3-[1-(t-buto~yc~ bonyl)piperidin-3-yupropoxy] -1-[3-[1-[3-(piperidin- 1-yl)~o~ piperidin-4-yl]lJ~o~yl~bçn7.imidazole hemihydrate Yield: 86%
NMR was consistent with the proposed title structure.
mp 108-110~C
Analysis for C37H47N4OaCl:
Theory: C, 72.23; H, 7.70; N, 9.11.
Found: C, 72.48; H, 7.85; N, 9.05.

By subst~nti~lly following the procedures desc~ibed above one skilled in the art can prepare the other compounds of Formula I.

The compounds of the present invention bind to receptors specific for neuropeptide Y as well as the closely related neuropeptides.
[For a review of neuropeptide Y receptors, see, D. Gehlert, T.ife Sciences, 3 0 65:5~ 62 (1994); P.A. Hipskind and D.R. Gehlert, Annual Re~orts in - Medicinal Ch~mi~try, 31:1 (1996)]. Receptors for neuropeptide Y and peptide YY have considerable overlap while pancreatic polypeptide - appears to have its own distinct set of receptors. Many, but not all, of the effects of neuropeptide Y can be replicated using peptide YY.
3 5 Two subtypes of receptors for neuropeptide Y were init.i~lly proposed on the basis of the afffnity of the 13-36 fr~FmPnt of neuropeptide CA 02242~79 l998-07-08 W O 97/2~041 PCTnJS97/OOSt Y using a preparation of the sympathetic nervous system. VVhile these are the best est~hli~h~d receptors for neuropeptide Y, a substantial body of evidence e~ists that there are additional receptor subtypes. The best est~hl;~herl is a Y-3 receptor that is responsive to neuropeptide Y, but not 5 to peptide YY. Another recently ~l~lin~ted receptor has been described that binds peptide YY with high ~fr~ y and neuropeptide Y with lower ~ ily. While the pharm~colQgy of the feeding response to neuropeptide Y appears to be Y-1 in nature, a separate "feeding receptor" has been proposed. Several of the receptors have been 10 successfully cloned to date. The following paragraphs s1lmm~rize the available information on the known neuropeptide Y receptor subtypes and their potqnti~l role in physiological function.

Y-l Receptor The Y-1 receptor is the best characterized receptor for neuropeptide Y. This receptor is generally con~itlered to be postsynaptic and mediates many of the known actions of neuropeptide Y in the periphery. Ori~in~lly, this receptor was described as having poor affinity for C-terminal fr~Tnents of neuropeptide Y, such as the 13-36 20 fr~grnent, but interacts with the full length neuropeptide Y and peptide YY with equal affinity. C. Wahlestedt, e~ al., Re~ulatory Pel~tides, 13:307-318 (1986); C. Wahlestedt, et al, NEURONAL M~ ~J~GERS IN
VASCUI,AR FUNCTION, 231-241 (Nobin, et al., eds. 1987). Substitution of the amino acid at position 34 with a proline (Pro34) results in a protein 25 which is speci~c for the Y-1 receptor. E.K. Potter, et al., h:1~ro~ean Jour~al of Ph~rm~rolo~y, 193:~5-19 (1991). This tool has been used to estP.hliRh a role for the Y-l receptor in a va~ety of functions. The receptor is thought to be coupled to adenylate cyclase in an inhibitory m~nner in cerebral cortex, vascular smooth muscle cells, and SK-N-MC
30 cells. [For a review, see, B.J. McDermott, et al., Cardiovascular Rese~rch. 27:893-90~ (1993~. This action is ~L~v~llted by applic~q1ion of pertussis to~in confirming the role of a G-protein coupled receptor. The Y-l receptor mediates the mohili~hon of intracellular calcium in a porcine vascular smooth muscle cells and human erythroleukemia cells.

CA 02242579 l998-07-08 WO 97/25041 PCTtUS97/OQ511 The cloned human Y-1 receptor can couple to either phosphotidylinositol hydrolysis or the inhibition of adenylate cyclase, dep~n~in~ on the type of cell in which the receptor is expressed. H.
Eerzog, ~, Procee~linFs of the National Academv of Sciences (U~
89:~i794-5798 (1992~. The Y-1 receptor has been reported to couple to either second messenger system when studied using tissue preparations or cell lines naturally expressing the receptor. D. Gehlert, supra. at 653. The Y-1 receptor cannot, thelefole, be distinguished solely on the basis of coupling to a single second messenger.
Modulation of a Y-1 receptor (either a typical or an atypical Y-l receptor) is believed to influence multiple physiological conditions, including, but not limited to, obesity or appetite disorder, adult onset diabetes, blllimiA nervosa, pheochromocytoma-induced hypertension, subarachnoid hemorrhage, neurogenic vascular hypertrophy, hyperte~ion, anxiety, and anorexia nervosa. PCT Patent Publication WO 96/16542, pllhli~h~ June 6, 1996, at page 135, and the ,er~- el.ces cited therein.

~-2 Receptor As with the Y-l receptor, this receptor subtype was first delineated using vascular preparations. Pharmacologically, the Y-2 receptor is distinguished from Y-l by exhibiting affinity for C-terminal fr~rnents of neuropeptide Y. The receptor is most often differentiated by the use of neuropeptide Y(13-36), though the 3-36 fr~ment of neuropeptide Y and peptide YY provides improved ~ll~i~y and selectivity. Y. Dumont, ~, ~society for Ne~7roscience Abstracts, 19:726 (1993). Like Y-l receptor, this receptor is coupled to the inhibition of adenylate cyclase, though in some preparations it may not be sensitive to pertussis toxin. The Y-2 receptor was found to reduce the intracellular 3 o levels of calcium in the synapse by selective inhibition of N-type calcillrn - cl~nne.l~. Like the Y-1 receptor, the Y-2 receptor may exhibit erential coupling to second me~sengers. The Y2 receptor is believed to be involved in morllllAting hypertension, epileptic seizure, and neurogenic vascular hypertrophy. PCT Patent Publication WO 96/16542, 3 5 published June 6, 1996, at page 135, and the references cited therein.

W O 97/2~041 PCT~US97/00511 The Y-2 receptors are found in a variety of brain regions, including the hippocampus, substantia nigra-lateralis, t~ mus, hypot.hAlSlmus, and brainstem. In the periphery, Y-2 is found in the peripheral nervous system, such as sympathetic, parasympathetic, and 5 sensory neurons. In all these tissues, Y-2 receptors mediate a decrease in the release of neul~Ldllsmitters. The Y-2 receptor has been cloned using expression cloning techniques. P.M. Rose, çt al., Jollrnal of Riolo~ical Chemistry. 270:22661 (1995); C. G~erald, et al., Journal of BioloFical Ch~mistry, 27():26758 (199~;); D.R. Gehlert, ~1., Molecular Ph~rmacolo~y 49:224(1996).

Y-3Receptor This receptor has high afflnity for neuropeptide Y while having lower affinity for peptide YY. While neuropeptide Y is a fully efficacious agonist at this receptor population, peptide YY is weakly efflcacious. This pharmacological property is used to define this receptor. A receptor that has ~imil~r pharmacology to the Y-3 receptor has been i~len~ified in the CA3 region of the hippocampus using electrophysiological techniques. This receptor may potentiate the excitatory response of these neurons to N-methyl-D-aspartate (NMDA).
F.P. Monnet, et al~ uropean Journal of Pharmacolo~y, 182:2û7-208 ~1990). This receptor is believed to mo~ te hypertension. PCT Patent pllhlic~tion WO 96/16542, pllhli~hed June 6, 1996, at page 136, and the references cited therein.
The presence of this receptor is best est~hli~he-l in the rat brainstem, specifically in the nucleus tractus solitarius. Application of neuropeptide Y to this region produces a dose-dep~n-l~nt reduction in blood pressure and heart rate. This area of the brain also may have significant contributions from the Y-1 and Y-2 receptor. Neuropeptide Y
also inhibits the acetylcholine-induced release of cate-hol~rnines from the adrenal medulla, presumably through a Y-3 receptor. C.
Wahlestedt, ~L, T.;fe ~:ciences, 50:PL7-PL14 (1992).

Pe};~ti~e ~Y Preferrin~ Rece~tor 3 5 A fourth receptor has been described that e~hibits a modest preference for peptide YY over neuropeptide Y. I~is receptor was first W O 97/2S041 PCTrUS97/00511 flesrrihed in the rat small intestine as having a 5-10 fold higher affinity for peptide YY over neuropeptide Y. M. Laburthe, et al., Endocrinolo~v.
118:1910-1917 (1986). Subsequently, this receptor was found in the adipocyte and a kidney ~loxi..~l tubule cell line. This receptor is 5 coupled in an inhibitory m~nner to adenylate cyclase and is sensitive to pertussis toxin.
In the intestine, this receptor produces a potent inhibition of ~uid and electrolyte secretion. The receptor is localized to the crypt cells where intestinal chloride secretion is believed to take place. The peptide 10 ~Y preferring receptor in adipocytes mediates a reduction in lipolysis by way of a cyclic adenosine monophosphate (cAMP)-dependent mechanism.

"FeeAin~ Receptorn One of the earliest discovered central effects of neuropeptide Y was a profound increase in food intake that was observed following the hypothalmic ~Amini.et~ation of the peptide to rats. The response was greatest when the peptide was infused into the perifornical region of the hypotllAl~mus. B.G. Stanley, et al., Br~in Research.604:30~317 (1993).
VVhile the pharmacology of this response resembled the Y-1 receptor, the 2-36 fr~grnent of neuropeptide Y was significantly more potent than neuropeptide Y. In addition, intracerebroventricular neuropeptide Y(2-36) fully stimulates feeding, but does not reduce body temperature as does full length neuropeptide Y. F.B. Jolicoeur, ~, P~r~in Research Rlllle~in, 26:309-311 (1991). Two recent patent public~tion~ describe the t~lor~in~ and expression of the Y5 receptor, believed to be the "feeding receptor". Patent Cooperation Treaty Pl]hlic~qtion WO 96/16542, published June 6, 1996; and Australian Patent Pl]hliç~tion AU 956467 A0, pl~hli~h~ Novem1~er 30, 1995.
- The biological activity of the compounds of the present in~ention was evaluated employing an initial screening assay which rapidly and accurately measured the hintlin~ of the tested compound to known neuropeptide Y receptor sites. Assays useful for evaluating neuropeptide Y receptor antagonists are well known in the art. See, e.~., United States Patents 5,284,839, issued February 8, 1994, which is herein incorporated by reference. See also. M.W. Walker, et al., Journal of Nel7rosciences, 8:2438-2446 (1988).

Nellro~e~tide Y Bintlin~ Assay The ability of the compounds of the instant invention were assessed as to their ability to bind to neuropeptide Y using a protocol essentially as described in M.W. Walker, et al.. supra. In this assay the cell line SK-N-MC was employed. This cell line was received from Sloane-Kettering Memorial Hospital, New York. These cells were cultured in T-150 flasks using Dulbecco's lVrinims~l Essential Media (DMEM) supplemented with 5% fetal calf serum. The cells were manually removed from the flasks by scraping, pelleted, and stored at -70~C.
The pellets were resuspended using a glass homogenizer in 2~ mM HEPES (pH 7.4) buffer COI-t~ining 2.5 mM calcium chloride, 1 mM magnesium chloride, and 2 g/L bacitracin. Incubations were performed in a final volume of 200 ~l cont~inin~ 0.1 nM 125I-peptide YY
(2200 Ci/mmol) and 0.2-0.4 mg protein for about two hours at room temperature.
Nonspecific hin-ling was defined as the amount of radioactivity rçm~ining bound to the tissue after incllh~ting in the presence of 1 ~LM neuropeptide Y. In some experiments various concentrations of compounds were included in the incubation mixture.
Incubations were terminated by rapid filtration through glass fiber filters which had been presoaked in 0.3% polyethylen~imine using a 96-well harvester. The filters were washed with 5 ml of 50 mM
Tris (pH 7.4) at 4~C and rapidly dried at 60~C. The filters were then treated with melt-on srintill~ on sheets and the radioactivity retained on the filters were counted. The results were analyzed using various software packages. Protein conc~nt.rations were measured using standard col~m~sie protein assay reagents using bovine serum al~umin as st~n~rds.

Many of the compounds prepared supra showed siFni~c~nt 3 5 activity as neuropeptide Y receptor antagonists (Ki = 10 ,u~ to 0.1 nM).
As the compounds of Formula I are effective neuropeptide Y receptor W O 97~5041 PCT~US97/00511 - 34'3 -,s antagonists, these compounds are of value in the tre~t.m~nt of a wide variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y. Thus, the invention provides methods for the treatment or 1~ evel~tion of a physiological disorder associated with an excess of neuropeptide Y, which method co~l~.ise6 ~mini~tering to a m~mmAl in need of said treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereo~ The term "physiological disorder associated with an excess of neuropeptide ~ encomr~ses those disorders associated with an inappropriate stimulation of neuropeptide Y receptors, regardless of the actual amount of neuropeptide Y present in the locale.
These physiological disorders include:
disorders or diseases pert~ining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock? cardiac hypertrophy, increased blood pressure, anginA, myocardial infarction, sudden cardiac death, congestive heart failure, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure;
conditions related to increased sympathetic nerve activity for ~mple, during or after coronary artery ~ y, and operations and s~ely in the gastrointestinal tract;
cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, dementia, seizure, and epilepsy;
conditions related to pain or nociception;
diseases related to abnormal gastrointestinal motility and secretion, such as different forms of ileus, urinary incontinence, and 3 0 ~rohn's disease;
abnormal drink and food intake disorders, such as obesity, anorexia, bl~limi~, and metabolic disorders;
- diseases related to sexual d~sfunction and reproductive disorders;
conditions or disorders associated with infl~mm~tion;

W O 97/25041 PCTnJS97/00~11 respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction; and diseases related to abnormal hormone release, such as leutini7:in~ hormone, growth hormone, insulin, and prolactin.

The compounds of Formula I are usually ~(lmini~tered in the form of pharmaceutical compositions. These compounds can be ~rnini.~tered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intr~n~l These 10 compounds are effective as both injectable and oral compositions. Such compositions are prepared in a m~nner well known in the pharmaceutical art and co~ ise at Ieast one act*e compound.
The present invention also includes methods e~ploying pharmaceutical compositions which contain, as the active ingredient, a 5 compound of Formula I associated with pharmaceutically acceptable carriers. In m~king the compositions of the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other cont~iner. VVhen the excipient serves as a 20 diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carTier or medil~n for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments co~t~ining for 25 ~ nple up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the h~lo~l;ate particle size prior to 3 0 coTnhining with the other ingredients. If the active compound is subs~n1;~l1y insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle ~ize is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 3 5 mesh.

W O 97/2~041 PCT~US97/00511 Some e~Amrles of suitable excipients include lactose, dextrose, sucrose, sorbitol, mAnnitol, starches, gum ~c~ci~q, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyll~yllolidone, cellulose, water, syrup, 5 and methyl cellulose. The formulations can additionally include:
lubricating agents such as talc, mA~nesium stearate, and mineral oil;
wetting agents; emulsifying and suspen~lin~ agents; preserving agents such as methyl- and propylhydio~{ylJ~n7:0Ates; sweetening agents; and flavoring agents. The compositions of the invention can be form~ ted 10 so as to provide quick, sustained or delayed release of the active ingredient after A~mini~tration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage c- ntAinin~ from about 6 to about 100 mg, more 5 usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages dosages for hllmAn subjects and other mAm~nAl.$~ each unit conf~ining a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association vwith a suitable 2 o pharmaceutical excipient.
The active compound is effective over a wide dosage range.
For ~lr~mrles, dosages per day normally fall within the range of about O.~i to about 3{~ mg/kg of body weight. In the tre~t.ment of adult hllmAnfi, the range of about 1 to about 15 mg/kg/day, in single or divided dose, is 2 5 especially preferred. Eowever, it will be understood that the amount of the compound actually ~mini~tered will be determined by a physician, in the light of the relevant Cil. u-~lstances~ including the condition to be treated, the chosen route of ~ m;ni~tration, the actual compound f3flmini~tered, the age, weight, and response of the individual patient, 3 o and the severity of the p~tient~s symptoms, and therefore the above dosage ranges are not in~en~1ed to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range mLay be more than adequate, while in other cases still larger doses may be employed without r~ll~in~ any harmful side effect, 35 provided that such larger doses are first divided into several smaller doses for ~mini~tration throughout the day.

W O 97/25041 PCT~US97/O~SII

For preparing solid compositions such as tablets the principal active ingredient is mixed with a phaImaceutical excipient to form a solid preform~ t;on composition cont,~inin~ a homogeneous mixture of a compound of the present invention. When referring to 5 these l~efo...~ tirn compositions as homogeneous, it is meant that the active ingredient is dipser~ed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformlll~tion is then subdivided into unit dosage forms of the type desc~ibed above Cont~ininF from 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For e~rnple, the tablet or pill can comprise an 15 inner dosage and an outer dosage component, the latter bein~ in the form of an envelope over the former. The two components can be separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duo~l~nllm or to be delayed in release. A variety of materials can be used 20 for such enteric layers or co~tin~ such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as .shPll:~c, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the pre~ent invention may be inco~porated for Arlministration orally or by 25 injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and ~irnil~r pharmaceutical vehicles.
Compositions for inh~l~tion or insufflation include 30 solutions and suspensions in pharmaceutically acceptable, aqueous or orgAnic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable e~ip;~nts as described supra. r~relably the compositions are ~lmin;.~tered by the oral or nasal respiratory route for local or systemic 35 effect. Compositions in ~lefe.ably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be W O 97/25041 PCT~US97/OOStl breathed directly from the nebl~ti~in~ device or the neb~ in~ device may be attached to a face mask, tent, or intermittent positive pressure breathing m~qrh;ne. Solution, suspension, or powder compsoitions may be ~11mini~tered, preferably orally or nasally, from devices which deliver 5 the forlm~ tion in an a~rol.l;ate m~nner The following ex~mrles illustrate the pharmaceutical compositions of the present invention.
-W O 97/25041 PCTnJS97/0051l Formulation Pre~aration 1 Hard gelatin capsules cont~ining the following ingredients are prepared:

Quantity In~redient ~m~/capsule) Active Ingredient 30 0 Starch 305.0 Magnesium stearate 5-0 The above ingredients are mixed and filled into hard gelatin 15 capsules in 340 mg quantities.

Formulation Pre~arati-.n 2 A tablet formula is prepared using ~e ingredients below:
Quantity ~n~redient (m~/tablet) Active Ingredient 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are blended and compressed to form tablets, each waighing 240 mg.

W O 97~5041 PCT~US97/00511 - 3~L9-Formulation Preparation 3 A dry powder inhaler formulation is prepared cont~ining the following components:

Tn~redient Wai~ht ~o Active Ingredient Lactose 96 The active ~ ule is mixed with the lactose and the mixture is added to a dry powder inh~l;ng appliance.

Formulation Prel~aration 4 Tablets, each cont~inin~ 30 mg of active ingredient, are prepared as follows:

Quantity Tn~redient ~m~/tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone ~as 10% solution in water) 4.0 mg Sodium carbogymethyl starch 4.5 mg M~gnesium stearate 0.5 mg Talc 1.0 m~
Total 120 mg The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinyl~yll~lidone is mixed with the resultant powders, which are 5 then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60~C and passed through a 16 mesh U.S. sieve. The sodium carbo~rmethyl starch, mAgneSium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mi~ing, are compressed on a tablet m~rhine 10 to yield tablets each w~ighing 120 mg.

Forrmll~tion Preparation 5 Capsules, each cont~inin~ 40 mg of medir~mer-t. are _ade as follows:

Quantity Tn~redient (m~/capsule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate l.O m~

Total 150.0 mg The active ingredient, cellulose, starch, and m~gnesium ~tearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.

W O97/2~041 PCT~US97/00511 -3~1-Formulation Preparation 6 Suppositories, each cont~ining 25 mg of active ingredient are made as follows:

Tn ~redient ~m 017 nt Active Ingredient 25 mg Saturated fatty acid glycerides to2,000 mg The active ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
Formulation Preparation 7 Suspensions, each cont~ining 50 mg of medi~ment per 5.0 ml dose are :made as follows:
Tn ~redient ~m ount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcryst~lline cellulose (89%) 50.0 mg Sucrose 1.76 g Sodium bçn7:o~te 10.0 mg Flavor and Color q.v.

3 5 Purified water to 6.0 ml W O 97/25041 PCTAJS97tOO511 The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed vwith a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium b~n~o~te, flavor, and 5 color are diluted with some of the water and added with stirriIlg.
Sufficient water is then added to produce the required volume.

Form~ tion Pre~aration 8 Capsules, each cont~q;ning 1~ mg of medicament, are made as follows:

Quantity Tn~re~lient (m~/capsule) Active Ingredient 1~.0 mg Starch 407.0 mg Magnesium stearate 3.0 m Total 425.0 mg The active ingredient, cellulose, starch, and magnesium steara~e are blended, passed through a No. 20 mesh U.S. sieve, and filled 25 into hard gelatin capsules in 425 mg quantities.

CA 02242579 l998-07-08 W O 97/25041 PCTAUS97tOO511 Form~ tion Preparation 9 An intravenous formulation may be prepared as follows:

Tn ~redient G~uantitv Active Ingredient 2~;0.0 mg Isotonic saline 1000 ml 1~
Formulation PreI?aration 10 A topical for~nulation may be prepared as follows:

TnPredient Quantitv Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20g White Soft Paraffin to 100 g The white soflG paraffin is heated until molten. The liquid praffin and25 emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.

W O 97~5041 PCTrUS97/00511 Formulation Pre~aration 11 Su~lingual or buccal tablets, each c--nt~ining 10 mg of active ingredient, may be prepared as follows:
Quantity ~n~redient Per Tablet Active Ingredient(s) 10.0 mg Glycerol Z10.6 mg Water 143.0 mg Sodium Citrate 4.5 mg Polyvinyl Alcohol 26.5 mg Polyvinyl~ oli-lnne 16.~ m~
Total 410.0 mg The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylE~yllolidone are ~l~lmi~ed together by continuous stirring and maint~ining the temperature at about 90~C. When the polymers have gone into solution, the solution is cooled to about ~0-56~C and the 25 medir~m~nt is slowly ~rlmi~d. The homogenous .. i~,~e is poured into forms made of an inert material to produce a drug-contS~inin~
diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the a~lo~.iate size.

Another preferred forrn~ ion employed in the methods of the present invention employs tr~n~tlermal delivery devices ("patches").
Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in cont~olled amounts. The construction and use of transdermal patches 3 5 for the delivery of pharmaceutical agents is well known in the art. See.
~.~., U.S. Patent ~,023,2~i2, issued June 11, 1991, herein incorporated by WO 97/2~041 PCTrUS97100511 efe. ellce. Such patches may be constructed for continuous, pulsatile, or on dem~n~ delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly.
5 Direct techni~ues usually involve pl~cempnt of a drug delivery catheter into the host's ventricular ~y~le~ to bypass the blood-brain bamer. One such impl~nt.~hle delivery system, used for the transport of biological factors to specif;c ~nz~tQrnical regions of the body, is described in U.S.
Patent ~,011,472, issued April 30, 1991, which is herein incorporated by 10 refernce.
Indirect techniques, which are generally preferred, usually involve form~ tin~ the compositions to provide for drug l~tPnti~tion by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
T.~tenti~tion is generally achieved through blocking of the hydlo~y, 15 carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be ~nh~n~ed by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.

Claims (3)

We Claim:
1. A method of treating or preventing a physiological disorder associated with an excess of neuropeptide Y, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of the formula wherein:

R1 is phenyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl(C1-C6 alkylenyl)-, phenyl(C1-C6 alkoxy), phenoxy(C1-C6 alkylenyl)-, phenyl(C1-C6 alkoxy)-(C1-C6 alkylenyl)-, naphtyl, naphthyl(C1-C6 alkylenyl)-, naphtyl(C1-C6 alkoxy), naphthyloxy(C1-C6 alkylenyl)-, or naphthyl(C1-C6 alkoxy)-(C1-C6 alkylenyl)-, any one of which phenyl, C3-C8 cycloalkyl, phenoxy, naphthyl, or naphthyloxy moieties may be substituted with one or groups selected from the group consisting of halo, trifluoromethyl, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, heterocyclic, unsaturated heterocyclic, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, phenoxy, phenyl(C1-C6 alkylenyl)-, phenyl(C1-C6 alkoxy)-, benzoyl, phenyl(C2-C7 alkanoyl)-, and phenyl(C2-C7 alkanoyloxy)-;

R2 is C1-C12 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkanoyl, C1-C6 alkoxy, heterocyclic(C1-C6 alkylenyl)-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, unsaturated heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, phenyl, phenyl(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6 alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, naphthyloxy(C1-C6 alkylenyl)-, benzoyl(C1-C6 alkylenyl)-, C2-C7 alkenyl, C2-C7 carbamoyl, C2-C7 amido, C1-C6 alkoxycarbonyl-, or C1-C6 haloalkyl, any one of which C1-C12 alkyl, phenyl, naphthyl, phenoxy, naphthyloxy, benzoyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, heterocyclic, or unsaturated heterocyclic moieties may be substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, phenyl, naphthyl, phenyl(C1-C6 alkylenyl)-, naphthyl(C1-C6 alkylenyl)-, halo, trifluoromethyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, heterocyclic, unsaturated heterocyclic, heterocyclic(C1-C6 alkylenyl)-, unsaturated heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy), unsaturated heterocyclic(C1-C6 alkoxy)-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C7 alkanoyl, C2-C7 alkanoyloxy, C1-C6 alkylamino, C1-C6 alkylthio, C1-C6 haloalkyl, amino, nitro, and hydroxy, or R2 may also be -(CH2)n-NR7R8, where, n is 0 to 10, and R7 and R8 are independently hydrogen, C1-C6 alkyl, C2-C7 alkanoyl, C1-C6 alkoxy, heterocyclic(C1-C6 alkylenyl)-, unsaturated heterocyclic(C1-C6 alkylenyl)-, phenyl, phenyl(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6 alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, nalphthyloxy(C1-C6 alkylenyl)-, benzoyl(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, C1-C6 haloalkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C8 cycloalkenyl, or C3-C8 cycloalkyl, any one of which phenyl, naphthyl, phenoxy, naphthyloxy, C3-C8 cycloalkyl, benzoyl, heterocyclic, unsaturated heterocyclic, heterocyclic(C1-C6 alkoxy)-, or unsaturated heterocyclic(C1-C6 alkoxy)- moieties may be substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, trifluoromethyl, alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic, unsaturated heterocyclic, heterocyclic(C1-C6 alkylenyl)-, unsaturated heterocyclic(Cl-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, C2-C7 alkanoyl, C2-C7 AlkAnoyloxy, C1-C6 alkylamino, C1-C6 alkylthio, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 haloalkyl, amino, nitro, and hydroxy;

and R3, R4, R6, and R6 are independently hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkanoyl, C2-C7 alkanoyloxy, C1-C6 alkylamino, C1-C6 alkylthio, benzoyl, phenoxy, phenyl(C1-C6 alkylenyl)-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl(C1-C6 alkoxy)-, phenyl(C1-C6 alkyleneamino)-, phenyl(C1-C6 alkyleneamino)-, phenyl(C2-C7 alkanoyl)-, phenyl(C2-C7 alkanoyloxy)-, heterocyclic, unsaturated heterocyclic, heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkylenyl)-, unsaturated heterocyclic(C1-C6 alkoxy)-, amino, nitro, hydroxy, trifluoromethyl, or-(CH2)n-NR7R8;
or a pharmaceutically acceptable salt or solvate thereof.
2. A compound of the formula wherein:

R1 is phenyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl(C1-C6 alkylenyl)-, phenyl(C1-C6 alkoxy), phenoxy(C1-C6 alkylenyl)-, phenyl(C1-C6 alkoxy)-(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6 alkylenyl)-, naphthyl(C1-C6 alkoxy), naphthyloxy(C1-C6 alkylenyl)-, or naphthyl(C1-C6 alkoxy)-(C1-C6 alkylenyl)-, any one of which phenyl, C3-C8 cycloalkyl, phenoxy, naphthyl, or naphthyloxy moieties may be substituted with one or groups selected from the group consisting of halo, trifluoromethyl, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, heterocyclic, unsaturated heterocyclic, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, phenoxy, phenyl(C1-C6 alkylenyl)-, phenyl(C1-C6 alkoxy)-, benzoyl, phenyl(C2-C7 Alk~noyl)-, and phenyl(C2-C7 alkanoyloxy)-;

R2 is C1-C12 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkanoyl, C1-C6 alkoxy, heterocyclic(C1-C6 alkylenyl)-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, unsaturated heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, phenyl, phenyl(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6 alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, naphthyloxy(C1-C6 alkylenyl)-, benzoyl(C1-C6 alkylenyl)-, C2-C7 alkenyl, C2-C7 carbamoyl, C2-C7 amido, C1-C6 alkoxycarbonyl-, or C1-C6 haloalkyl, any one of which C1-C12 alkyl, phenyl, naphtnyl, phenoxy, naphthyloxy, benzoyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, heterocyclic, or unsaturated heterocyclic moieties may be substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, phenyl, naphthyl, phenyl(C1-C6 alkylenyl)-, naphthyl(C1-C6 alkylenyl)-, halo, trifluoromethyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, heterocyclic, unsaturated heterocyclic, heterocyclic(C1-C6 alkylenyl)-, unsaturated heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C7 alkanoyl, C2-C7 alkanoyloxy, C1-C6 alkylamino, C1-C6 alkylthio, C1-C6 haloalkyl, amino, nitro, and hydroxy, or R2 may also be -(CH2)n-NR7R8, where, n is 0 to 10, and R7 and R8 are independent1y hydrogen, C1-C6 alkyl, C2-C7 alkanoyl, C1-C6 alkoxy, heterocyclic(C1-C6 alkylenyl)-, unsaturated heterocyclic(C1-C6 alkylenyl)-, phenyl, phenyl(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6 alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, naphthyloxy(C1-C6 alkylenyl)-, benzoyl(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, C1-C6 haloalkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C8 cycloalkenyl, or C3-C8 cycloalkyl, any one of which phenyl, naphthyl, phenoxy, naphthyloxy, C3-C8 cycloalkyl, benzoyl, heterocyclic, unsaturated heterocyclic, heterocyclic(C1-C6 alkoxy)-, or unsaturated heterocyclic(C1-C6 alkoxy)- moieties may be substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, trifluoromethyl, alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic, unsaturated heterocyclic, heterocyclic(C1-C6 alkylenyl)-, unsaturated heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, C2-C7 alkylenyl, C2-C7 alkanoyloxy, C1-C6 alkylamino, C1-C6 alkylthio, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 haloalkyl, amino, nitro, and hydroxy;

and R3, R4, R5, and R6 are independently hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkanoyl, C2-C7 alkanoyloxy, C1-C6 alkylamino, C1-C6 alkylthio, benzoyl, phenoxy, phenyl(C1-C6 alkylenyl)-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl(C1-C6 alkoxy)-, phenyl(C1-C6 alkylaneamino)-, phenyl(C1-C6 alkyleneamino)-, phenyl(C2-C7 alkanoyl)-, phenyl(C2-C7 alkanoyloxy)-, heterocyclic, unsaturated heterocyclic, heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkylenyl)-, unsaturated heterocyclic(C1-C6 alkoxy)-, amino, nitro, hydroxy, trifluoromethyl, or-(CH2)n-NR7R8;

or a salt or solvate thereof.
3. A pharmaceutical formulation comprising a compound of the formula wherein:

R1 is phenyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl(C1-C6 alkylenyl)-, phenyl(C1-C6 alkoxy), phenoxy(C1-C6 alkylenyl)-, phenyl(C1-C6 alkoxy)-(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6 alkylenyl)-, naphthyl(C1-C6 alkoxy), naphthyloxy(C1-C6 alkylenyl)-, or naphthyl(C1-C6 alkoxy)-(C1-C6 alkylenyl)-, any one of which phenyl, C3-C8 cycloalkyl, phenoxy, naphthyl, or naphthyloxy moieties may be substituted with one or groups selected from the group consisting of halo, trifluoromethyl, C1-C6 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, heterocyclic, unsaturated heterocyclic, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, phenoxy, phenyl(C1-C6 alkylenyl)-, phenyl(C1-C6 alkoxy)-, benzoyl, phenyl(C2-C7 alkanoyl)-, and phenyl(C2-C7 alkanoyloxy)-;

R2 is C1-C12 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkanoyl, C1-C6 alkoxy, heterocyclic(C1-C6 alkylenyl)-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, unsaturated heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, phenyl, phenyl(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6 alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, naphthyloxy(C1-C6 alkylenyl)-, benzoyl(C1-C6 alkylenyl)-, C2-C7 alkenyl, C2-C7 carbamoyl, C2-C7 amido, C2-C6 alkoxycarbonyl-, or C1-C6 haloalkyl, any one of which C1-C12 alkyl, phenyl, naphthyl, phenoxy, naphthyloxy, benzoyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, heterocyclic, or unsaturated heterocyclic moieties may be substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, phenyl, naphthyl, phenyl(C1-C6 alkylenyl)-, naphthyl(C1-C6 alkylenyl)-, halo, trifluoromethyl, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 alkoxy, heterocyclic, unsaturated heterocyclic, heterocyclic(C1-C6 alkylenyl)-, unsaturated heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, C3-c8 cycloalkyl, C3-C8 cycloalkenyl, C2-C7 alkanoyl, C2-C7 alkanoyloxy, C1-C6 alkylamino, C1-C6 alkylthio, C1-C6 haloalkyl, amino, nitro, and hydroxy, or R2 may also be -(CH2)n-NR7R8, where, n is 0 to 10, and R7 and R8 are independently hydrogen, C1-C6 alkyl, C2-C7 alkalnoyl, C1-C6 alkoxy, heterocyclic(C1-C6 alkylenyl)-, unsaturated heterocyclic(C1-C6 alkylenyl)-, phenyl, phenyl(C1-C6 alkylenyl)-, naphthyl, naphthyl(C1-C6 alkylenyl)-, phenoxy(C1-C6 alkylenyl)-, naphthyloxy(C1-C6 alkylenyl)-, benzoyl(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, C1-C6 haloalkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C8 cycloalkenyl, or C3-C8 cycloalkyl, any one of which phenyl, naphthyl, phenoxy, naphthyloxy, C3-C8 cycloalkyl, benzoyl, heterocyclic, unsaturated heterocyclic, heterocyclic(C1-C6 alkoxy)-, or unsaturated heterocyclic(C1-C6 alkoxy)- moieties may be substituted with one or more groups selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halo, trifluoromethyl, alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic, unsaturated heterocyclic, heterocyclic(C1-C6 alkylenyl)-, unsaturated heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkoxy)-, C2-C7 alkanoyl, C2-C7 alkanoyloxy, C1-C6 alkyliamino, C1-C6 alkylthio, C2-C7 alkenyl, C2-C7 alkynyl, C1-C6 haloalkyl, amino, nitro, and hydroxy;

and R3, R4, R5, and R6 are independently hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkenyl, C2-C7 alkynyl, C2-C7 alkanoyl, C2-C7 alkanoyloxy, C1-C6 alkylamino, C1-C6 alkylthio, benzoyl, phenoxy, phenyl(C1-C6 alkylenyl)-, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl(C1-C6 alkoxy)-, phenyl(C1-C6 alkyleneamino)-, phenyl(C1-C6 alkyleneamino)-, phenyl(C2-C7 alkanoyl)-, phenyl(C2-C7 alkalnoyloxy)-, heterocyclic, unsaturated heterocyclic, heterocyclic(C1-C6 alkylenyl)-, heterocyclic(C1-C6 alkoxy)-, unsaturated heterocyclic(C1-C6 alkylenyl)-, unsaturated heterocyclic(C1-C6 alkoxy)-, amino, nitro, hydroxy, trifluoromethyl, or-(CH2)n-NR7R8;

or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers, excipients, or diluents therefor.
CA002242579A 1996-01-09 1997-01-09 Benzimidzolyl neuropeptide y receptor antagonists Abandoned CA2242579A1 (en)

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