Title of Invention

4-SUBSITUTED IMIDAZOLE-2-THIONES AND IMIDAZOL-2-ONES AS AGONISTS OF THE ALPHA-2B AND ALPHA-2C ADRENERGIC RECEPTORS

Abstract Compounds of Formula (I): where X is S and the variables have the meaning defined in the specification are specific or selective to alpha2B and/or alpha2C adrenergic receptors in preference over alpha2A adrenergic receptors, and as such have no or only minimal cardivascular and/or sedatory activity. These compounds of Formula (I) are useful as medicaments in mammals, including humans, for treatment of diseases and or alleviations of conditions which are responsive to treatment by agonists of alpha2B adrenergic receptors. Compounds of Formula (I) where X is O also have the advantageous property that they have no or only minimal cardivascular and/or sedatory activity and are useful for treating pain and other conditions with no or only minimal cardivascular and/or sedatory activity.
Full Text 4-(SUBSTITUTED CYCLOALKYLMETHYL) IMIDAZOLE-2-THIONES, 4-
(SUBSTITUTED CYCLOALKENYLMETHYL) IMIDAZOLE-2-THIONES, 4-
(SUBSTITUTED CYCLOALKYLMETHYL)IMIDAZOL-2-ONES AND 4-
(SUBSTITUTED CYCLOALKYLMETHYL) IMIDAZOL-2-ONES AND RELATED
COMPOUNDS
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to 4-(substituted cycloalkylmethyl) imidazole-2-
thiones, 4-(substituted cycloalkenylmethyl) imidazole-2-thiones and related
compounds and to their use as specific or selective agonists of alpha2B and/or alpha2c
adrenergic receptors. More specifically the present invention relates to the above-
noted compounds, pharmaceutical compositions containing these compounds as active
ingredient for modulating the alpha2B and/or alpha2C adrenergic receptors, and even
more specifically for utilizing these compounds and pharmaceutical compositions to
alleviate chronic pain, allodynia, muscle spasticity, diarrhea, neuropathic pain and
other diseases and conditions.
The present invention also relates to, 4-(substituted cycloalkylmethyl)
imidazol-2-ones and 4-(substituted cycloalkenylmethyl) imidazoI-2-ones and to
pharmaceutical compositions containing these compounds alleviate chronic pain,
allodynia, muscle spasticity, diarrhea, neuropathic pain and other diseases and
conditions.
Background Art
Human adrenergic receptors are integral membrane proteins which have been
classified into two broad classes, the alpha and the beta adrenergic receptors. Both

types mediate the action of the peripheral sympathetic nervous system upon binding of
catecholamines, norepinephrine and epinephrine.
Norepinephrine is produced by adrenergic nerve endings, while epinephrine is
produced by the adrenal medulla. The binding affinity of adrenergic receptors for
these compounds forms one basis of the classification: alpha receptors tend to bind
norepinephrine more strongly than epinephrine and much more strongly than the
synthetic compound isoproterenol. The preferred binding affinity of these hormones is
reversed for the beta receptors. In many tissues, the functional responses, such as
smooth muscle contraction, induced by alpha receptor activation are opposed to
responses induced by beta receptor binding.
Subsequently, the functional distinction between alpha and beta receptors was
further highlighted and refined by the pharmacological characterization of these
receptors from various animal and tissue sources. As a result, alpha and beta
adrenergic receptors were further subdivided into alphai, α2, β1, and β2 subtypes.
Functional differences between α1 and α2 receptors have been recognized, and
compounds which exhibit selective binding between these two subtypes have been
developed. Thus, in published international patent application WO 92/0073, the
selective ability of the R(+) enantiomer of terazosin to selectively bind to adrenergic
receptors of the α1 subtype was reported. The α1/α2 selectivity of this compound was
disclosed as being significant because agonist stimulation of the α2 receptors was said
to inhibit secretion of epinephrine and norepinephrine, while antagonism of the α2
receptor was said to increase secretion of these hormones. Thus, the use of non-
selective alpha-adrenergic blockers, such as phenoxybenzamine and phentolamine,
was said to be limited by their α2 adrenergic receptor mediated induction of increased
plasma catecholamine concentration and the attendant physiological sequelae
(increased heart rate and smooth muscle contraction).
For a further general background on the a-adrenergic receptors, the reader's attention
is directed to Robert R. Ruffolo, Jr., a-Adrenoreceptors: Molecular Biology,
Biochemistry and Pharmacology, (Progress in Basic and Clinical Pharmacology
series, Karger, 1991), wherein the basis of α1/α2 subclassification, the molecular

biology, signal transduction, agonist structure-activity relationships, receptor
functions, and therapeutic applications for compounds exhibiting a-adrenergic
receptor affinity is explored.
The cloning, sequencing and expression of alpha receptor subtypes from
animal tissues has led to the subclassification of the ai adrenoreceptors into aiA, OIIB,
and aiD. Similarly, the a2 adrenoreceptors have also been classified a2A, CLIB, and a2C
receptors. Each a2 receptor subtype appears to exhibit its own pharmacological and
tissue specificities. Compounds having a degree of specificity for one or more of
these subtypes may be more specific therapeutic agents for a given indication than an
a2 receptor pan-agonist (such as the drug clonidine) or a pan-antagonist
Among other indications, such as the treatment of glaucoma, hypertension,
sexual dysfunction, and depression, certain compounds having alpha 2 adrenergic
receptor agonist activity are known analgesics. However, many compounds having
such activity do not provide the activity and specificity desirable when treating
disorders modulated by alpha-2 adrenoreceptors. For example, many compounds
found to be effective agents in the treatment of pain are frequently found to have
undesirable side effects, such as causing hypotension and sedation at systemically
effective doses. There is a need for new drugs that provide relief from pain without
causing these undesirable side effects. Additionally, there is a need for agents which
display activity against pain, particularly chronic pain, such as chronic neuropathic
and visceral pain.
British Patent 1 499 485, published February 1,1978 describes certain
thiocarbamide derivatives; some of these are said to be useful in the treatment of
conditions such as hypertension, depression or pain.
PCT Publications WO01/00586 published on January 4,2002 and
WO99/28300 published on June 10,1999 describe certain imidazole derivatives
acting as agonists of alpha2B and/or alpha2C adrenergic receptors. United States Patent
No. 6,313,172 discloses phenylmethyl-thiourea derivatives used for freatment of pain.
United States patent No. 4,798,843 describes (phenyl)-imidazole-2-thiones and
substituted (phenyl)-inudazole-2-thiones. (

United States Patent Nos. 6,545,182 and 6,313,172 describe phenylmethyl-
(2hydroxy)ethylthiovireas which have no significant cardiovascular or sedative effects
and are useful for alleviating chronic pain and allodynia. United States Patent No.
6,534,542 describes cycloalkyl, cycloalkenyl, cycloalkylmethyl and
cycloalkenylmethyl (2-hydroxy)ethylthioureas and their use as specific or selective
agonists of alphas adrenergic receptors. In a different biological or pharmaceutical
context United States Published Application 20020094998, published on July 18 2002
and claiming priority of U.S. Provisional Application No. 6/0244,850 discloses a
compound without assigning the proper stereochemistry to it, which corresponds to
two compounds described in the present application with the proper stereochemistry.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of Formula 1

Formula 1
where the variable Y in the ring is optional and represents a heteroatom selected from
N, O and S with the proviso that the N atom is trivalent, and the O or S atoms are
divalent;
k is an integer having the values of 0 or 1;
n is an integer having the values 0, 1 or 2;
p is an integer having the values 0,1 or 2;
X is O or S;
the dashed lines represent a bond, or absence of bond with the proviso that only
one double bond is present in the ring and that two adjoining dashed lines do not both
represent a bond;

Rl, R2, R3, and R4 are independently H, phenyl, said phenyl group being
optionally substituted independently with one, two or three Q^alkyl, SO3H, N3,
halogen, CN, N02, NH2, C^alkoxy, C^thioalkoxy, Ci^alkylamino,
C^dialkylamino, C^alkynyl, C^alkehyl groups, 5 or 6 membered heteroaryl having
1 to 3 heteroatoms selected from 0, S, and N, said heteroaryl groups being optionally
substituted independently with one, two or three Ci^alkyl, SO3H, N3, halogen, CN,
NO2, NH2, Ci-6alkoxy, Ci^thioalkoxy, Ci.6alkylamino, C^dialkylamino, C2^alkynyl,
C2^alkenyl groups,
or said Ri, R2, R3, and R4 groups being independently alkyl of 1 to 4 carbons,
cycloalkyl of 3 to 5 carbons, CH2CN, CH2SR5, CI^NR^, COR5, CH2OR5, OR*,
SR$. NR^R^, alkenyl having 1 to 4 carbons, alkynyl having 1 to 4 carbons, cycloalkyl
having 3 to 6 carbons, F, CI, Br, I, CF3, or CN, an oxygen double bonded to the ring
carbon with the proviso that the adjacent dashed line within the ring represents
absence of a bond;
R5 is H, OR7, alkyl of 1 to 4 carbons, CF3, cycloalkyl of 3 to 6 carbons,
phenyl, phenyl substituted with one or two alkyl groups of 1 to 4 carbons, with F, CI,
Br, I, or with CF3, or R5 is a 5 or 6 membered heteroaryl having 1 to 3 heteroatoms
selected from O, S, and N, and 5 or 6 membered heteroaryl having 1 to 3 heteroatoms
selected from O, S, and N substituted with one or two alkyl groups of 1 to 4 carbons,
with F, CI, Br, I, or with CF3;
Rg is H, alkyl of 1 to 4 carbons, allyl, cycloalkyl of 3 to 6 carbons, phenyl,
phenyl substituted with one or two alkyl groups of 1 to 4 carbons, with F, CI, Br, I, or
with CF3, or R$ is 5 or 6 membered heteroaryl having 1 to 3 heteroatoms selected
from O, S, and N, or 5 or 6 membered heteroaryl having 1 to 3 heteroatoms selected
from O, S, and N substituted with one or two alkyl groups of 1 to 4 carbons, with F,
CI, Br, I, or with CF3;

R7 is H, alkyl of 1 to 4 carbons, allyl, cycloalkyl of 3 to 6 carbons, phenyl,
phenyl substituted with one or two alkyl groups of 1 to 4 carbons, with F, CI, Br, I, or
with CF3;
Rj and R2 or R2 and R3 or R3 and R4 together can form a ring together with
tiie respective carbons to which each of these is attached, the portion contributed by
Ri and R2 or by R2 and R3 or by R3 and R4 having the formulas (i), (ii), (iii), (iv) or
(v)
R« is independently H, alkyl of 1 to 6 carbons, alkenyl of 2 to 6 carbons,
alkynyl of 2 to 6 carbons, SO3H, N3, CN, N02, F, CI, Br, I, CF3, COR9, CH2OR9,
OR10; SR10, C|.6alkylaniino, or Ci.6dialkylamino,
R9 is H, alkyl of 1 to 6 carbons, or OR10, and

Rio independently is H or alkyl of 1 to 6 carbons.
In a second aspect the present invention is directed to pharmaceutical
compositions containing as the active ingredient one or more compounds of Formula
1, the compositions being utilized as medicaments in mammals, including humans, for
treatment of diseases and or alleviations of conditions which are responsive to
treatment by agonists of alpha2B adrenergic receptors. The compositions containing
the compounds of the invention are primarily, but not exclusively, used for alleviation
of chronic pain and/or allodynia. The compounds where the X group is S (thiones)
have the demonstrable advantageous property that they are specific or selective to
alpha2B and/or alpha2c adrenergic receptors in preference over alpha2A adrenergic
receptors, and as such have no or only minimal cardivascular and/or sedatory activity.
Compounds where the X group is O (oxo compounds) also have the advantageous
property that they have no or only minimal cardivascular and/or sedatory activity.
DETAILED DESCRIPTION OF THE INVENTION
A general description of the compounds of the invention is provided in the
Summary section of the present application for patent with reference to Formula 1. It
will be readily apparent to those skilled in the art that some of the compounds
depicted in these formulas may exist in trans (E) and cis (Z) isomeric forms.
Moreover, some of the compounds of the invention may contain one or more
asymmetric centers, such that the compounds may exist in enantiomeric as well as in
diastereomeric forms. Unless it is specifically noted otherwise, the scope of the
present invention includes all trans (E) and cis (Z) isomers, enantiomers,
diastereomers and racemic mixtures. Some of the compounds of the invention may
form salts with pharmaceutically acceptable acid or base, and such pharmaceutically
acceptable salts of the compounds of Formula 1 are also within the scope of the
invention.
Both the imidazole-2-thione and the imidazol-2-one derivative compounds of
the present invention can undergo tautomeric transformations and can be depicted by
the tautomeric formulas shown below. All tautomers of Formula 1 are within the
scope of the invention.


Generally speaking and referring to Formula 1 in the preferred compounds of
the invention the variable p represent the integer zero (0) or one (1) and the RJO
groups of the moiety [C(Rio)2]p are hydrogen. Thus, in the preferred compounds of
the invention a methylene (CH2) group connects the imidazole-2-thione or imidazol-2-
one nucleus with the cycloalkyl or cycloalkenyl ring shown in Formula 1, or there is
no such connecting group.
In the preferred compounds of the invention the variable n represents an integer
having the values zero (0) or one (1) so that the cycloalkyl or cycloalkenyl ring shown
in Formula 1 is preferably 5 or 6 membered.
The variables Rj, R2, R3, and R4 of the preferred compounds of the invention
represent hydrogen, alkyl of 1 to 4 carbons, an oxo group, and ethynyl. Alternatively
in many preferred compounds of the invention two adjacent ones of the Ri, R2, R3,
and R4 groups form a 5 or 6 membered ring which can be aromatic, or fully or partly
saturated but more preferably at least partly unsaturated. When the ring formed by
two adjacent ones of the Ri, R2, R3, and R4 groups is heteroaromatic then pyridyl,
thienyl, furyl, pyrollyl and imidazole rings are preferred with the thienyl, pyridyl and
piperidinyl being most preferred.

The variable Rg represents the substituent on the ring formed by two adjacent
ones of the Rj, R2, R3, and R4 groups and is preferably H, alkyl of 1 to 4 carbons,
OR9,Cl,Br,F,orCH2OH.
The presently most preferred 4-(substituted cycloalkylmethyl) imidazole-2-
thione and 4-(substituted cycloalkenylmethyl) imidazole-2-thione compounds of the
invention are disclosed by their structural formula in Table 1 together with their
activity in assays measuring their ability to act as agonists of alpha2A, alpha^ and
alpha2c adrenergic receptors. The presently most preferred 4-(substituted
cycloalkylmethyl) imidazol-2-one and 4-(substituted cycloalkenylmethyl) imidazol-2-
one compounds of the invention are disclosed by their structural formula in Table 2.
Table 1 (imidazole- 2-thione compounds)















































Reaction Scheme A illustrates a general method for obtaining the 4-
(substituted cycloalkylmethyl) imidazole-2-thione and 4-(substituted
cycloalkenylmethyl) imidazole-2-thione compounds of the invention. The starting
material in this scheme is a primary alcohol of Formula 2 where the variables have
the same definitions as in Formula 1. However the scheme is primarily applicable
when one of the Ri and R2 substituents is not H. Thus, the compound of Formula 2
has one C(Rio)2 unit less than the compound of Formula 1 in the corresponding
chain. However, for simplicity of illustration the scheme discloses the preparation of
the preferred class of 4-(substituted cycloalkylmethyl) imidazole-2-thione and 4-
(substituted cycloalkenyylmethyl) imidazole-2-thione compounds of the invention
where p is one (1) and Rio is hydrogen, and the starting material shown in the scheme
is designated with Formula 2 A. The compounds of Formula 2 and of Formula 2 A
can be obtained in accordance with known procedures in the chemical scientific and
patent literature or by such modifications of known procedures which are readily
apparent to the practicing synthetic organic chemist.


Referring still to Reaction Scheme A the primary cyclic alcohol of Formula
2 A is reacted with ethyl vinyl ether (EVE) in the presence of mercuric ions (mercuric
acetate Hg(OAc)2) to provide the vinyl ether of Formula 3 which is thereafter
oxidized and rearranged by treatment with lithium perchlorate (LiClO/O to provide the
4-(substituted cycloalkyl)-acetaldehydes or 4-(substituted cycloalkenyl)-acetaldehydes
of Formula 4. The aldehydes of Formula 4 are then reacted xviihpara-
toluenesulfonyl isocyanide (tosylmethylisocyanide, TosMIC), sodium cyanide
(NaCN) and thereafter heated with ammonia in an alcohol solvent to provide the 4-
(substituted cycloalkylmethyl) imidazole or 4-(substituted cycloalkenylmethyl)
imidazole compounds of Formula 5 which are preferably isolated as the fumarate
salt. The 4-(substituted cycloalkylmethyl) imidazole or 4-(substituted
cycloalkenylmethyl) imidazole compounds of Formula 5 are then reacted with
phenylchlorothionoformate (PhOC(S)Cl) to convert them to the corresponding
imidazole-2-thione compounds of Formula 6. The compounds of Formula 6 are
pharmaceutically active compounds of the invention and are within the scope of
Formula 1.


REACTION SCHEME A
Reaction Scheme B discloses another general synthetic routes to 4-(substituted
cycloalkylmethyl) imidazole-2-thiones and 4-(substituted cycloalkenylmethyl)
imidazole-2-thione compounds of the invention. This synthetic route is particularly
suitable for preparation of those compounds of the invention where the Ri substituent
of Formula 1 represents an oxo group, and where a suitably substituted cycloalkyl or
cycloalkenyl group of Formula 7 is readily available commercially or in accordance
with the chemical literature. In accordance with this scheme, the keto compound of
Formula 7 is heated with 4,5-imidazole carboxaldehyde of Formula 8 in the
presence of strong acid to yield (lH-imidazol-4-yl-methylene)-cycloalkyl or (1H-
imidazol-4-yl-methylene)-cycloalkenyl derivatives of Formula 9. 4,5-imidazole
carboxaldehyde is available from Aldrich. The methylene group of the imidazole
compound of Formula 9 is reduced by hydrogenation to provide (lH-imidazol-4-yI-
methyl)-cycloalkyl or (lH-imidazol-4-yl-methyl)-cycloalkenyl derivatives of
Formula 10. The (lH-irnidazol-4-yl-memyl)-cycloalkyl or (lH-imidazol-4-yl-
methyl)-cycloalkenyl derivatives of Formula 10 are reacted with
phenylchlorothionoformate (PhOC(S)Cl), as described above in connection with

Reaction Scheme A, to obtain the thione compounds of Formula 11. The
compounds of Formula 11 are pharmaceutically active compounds of the invention
and are within the scope of Formula 1.

REACTION SCHEME B
Reaction Scheme C discloses still another general synthetic route to the
preparation of the 4-(substituted cycloalkylmethyl) imidazole-2-thione and 4-
(substituted cycloalkenylmethyl) imidazole-2-thione compounds of the invention.
This synthetic route is particularly suitable for preparation of those compounds of the
invention where a corresponding, suitably substituted cycloalkyl or cycloalkenyl
methyl iodo (or chloro or bromo) compound of Formula 12 is available
commercially or in accordance with the chemical literature to serve as a starting
material. The iodo compound is reacted with l-N-(dimethylsulfamoyl)-2-tert-
butyldimethylsilyl imidazole of Formula 13 in the presence of /i-butyl lithium to give
4-(substituted cycloalkylmethyl or 4-(substituted cycloalkenylmethyl 1-N-
(dimethylsulfamoyl)-2-tert-butyldimethylsilyl imidazole of Formula 14. The
synthesis of l-N-(dimethylsulfamoyl)-2-^er/-butyldimethylsilyl imidazole is described
below in the experimental section of the present application for patent The tertiary
butyldimethylsilyl (TBS) group is removed from the compound of Formula 14 by
treatment with tetrabutylammonium fluoride (TBAF) to give 4-(substituted
cycloalkylmethyl or 4-(substituted cycloalkenylmethyl 1- N-(dimethylsulfamoyl)-

imidazole compounds of Formula 15. Treatment of the 4-(substituted
cycloalkylmethyl or 4-(substituted cycloalkenylmethyl 1- N-(dimethylsulfamoyl)-
imidazole compounds of Formula 15 with strong base, such as potassium hydroxide
removes the N-(dimethylsulfamoyl) group and the resulting 4-(substituted
cycloalkylmethyl or 4-(substituted cycloalkenylmethyl-imidazole compounds of
Formula 5 are isolated as the fumarate salt. The 4-(substituted cycloalkylmethyl or
4-(substituted cycloalkenylmethyl-imidazole compounds of Formula 5 are then
reacted with phenylchlorothionoformate (PhOC(S)Cl) to convert them to the
corresponding imidazole-2-thione compounds of Formula 6, as is described in
connection with Reaction Scheme A.

REACTION SCHEME C
Reaction Scheme D illustrates a general method for obtaining the 4-
(substituted cycloalkylmethyl) imidazol-2-one and 4-(substituted cycloalkenylmethyl)

imidazole-2-one compounds of the invention. The actual starting material in this
scheme can also be the primary alcohol of Formula 2 which is shown in Reaction
Scheme A, where the variables have the same definitions as in Formula 1. Thus, the
compound of Formula 2 has one C(Rio)2 unit less than the compound of Formula 1
in the corresponding chain. However, for simplicity of illustration the scheme
discloses the preparation of the preferred class of 4-(substituted cycloalkyhnethyl)
imidazol-2-one and 4-(substituted cycloalkenyylmethyl) imidazol-2-one compounds
of the invention where p is one (1) and Rjo is hydrogen. Because certain initial
reaction steps followed in this scheme are the same as in Reaction Scheme A, this
Scheme D illustrates the synthesis only from the compound of Formula 5, which is
obtained as described in Scheme A. Thus the compounds of Formula 5, preferably in
the form of the fumarate salt, are reacted with phenylchloroformate (PhOC(O)Cl) in
the presence of sodium bicarbonate, followed by reaction with sodium carbonate to
convert them to the corresponding imidazol-2-one compounds of Formula 16. The
compounds of Formula 16 are pharmaceutically active compounds of the invention
and are within the scope of Formula 1.

REACTION SCHEME D
Reaction Scheme E discloses another general synthetic routes to 4-(substituted
cycloalkylmethyl) imidazol-2-ones and 4-(substituted cycloalkenylmemyl) imidazol-
2-one compounds of the invention. Similarly to Reaction Scheme B this synthetic
route is particularly suitable for preparation of those compounds of the invention
where the R\ substituent of Formula 1 represents an oxo group, and where a suitably
substituted cycloalkyl or cycloalkenyl group of Formula 7 as shown in Reaction

Scheme B is readily available commercially or in accordance with the chemical
literature. In the reaction sequence disclosed in tins scheme the compounds of
Formula 10, obtained as shown in Reaction Scheme B, are reacted with
phenylchloroformate (PhOC(O)Cl) in Ihe presence of sodium bicarbonate, followed
by reaction with sodium carbonate to convert them to the corresponding imidazol-2-
one compounds of Formula 16.

REACTION SCHEME E
Another general presently preferred synthetic route shown in Reaction Scheme
F for the synthesis of the 4-(substituted cycloalkylmethyl) imidazol-2-one and 4-
(substituted cycloalkenylmethyl) imidazol-2-one compounds of the invention is
particularly suitable for preparation of those compounds of the invention where a
corresponding, suitably substituted cycloalkyl or cycloalkenyl methyl iodo (or chloro
or bromo) compound of Formula 12, shown in Reaction Scheme C, is available
commercially or in accordance with the chemical literature to serve as a starting
material. This synthetic route follows the route shown in Reaction Scheme C to
prepare the imidazole compounds of Formula 15, as shown in Scheme C. These are
thereafter converted to the corresponding cycloalkylmethyl) imidazol-2-one or 4-
(substituted cycloalkenylmethyl) imidazol-2-one compounds by reactions with
phenylchloroformate (PhOC(O)Cl) in the presence of sodium bicarbonate, followed
by reaction with sodium carbonate to yield the corresponding irnidazol-2-one
compounds of Formula 16.


REACTION SCHEME F
The reaction schemes incorporated in the experimental section of this application
illustrate the synthetic schemes which are employed for the synthesis of preferred
embodiments of compounds of the invention.
BIOLOGICAL ACTIVITY, MODES OF ADMINISTRATION
The imidazole-2-thione compounds of the invention are agonists of alpha2
adrenergic receptors, particularly they tend to be specific or selective agonists of
alpha2B and/or to a lesser extent alpha2c adrenergic receptors, in preference over
alpha2A adrenergic receptors. The specific or selective alpha2B and/or to a lesser
extent alpha2c agonist activity of the compounds of the invention is demonstrated in
an assay titled Receptor Selection and Amplification technology (RSAT) assay, which
is described in the publication by Messier et. Al, 1995, Pharmacol. Toxicol. 76, pp.
308 - 311 (incorporated herein by reference) and is also described below. Another
reference pertinent to this assay is Conklin et al. (1993) Nature 363:274-6, also
incorporated herein by reference.
Receptor Selection and Amplification Technology (RSAT) assay
The RSAT assay measures a receptor-mediated loss of contact inhibition mat
results in selective proliferation of receptor-containing cells in a mixed population of
confluent cells. The increase in cell number is assessed with an appropriate

transfected marker gene such as J}-galactosidase, the activity of which can be easily
measured in a 96-well format. Receptors that activate the G protein, Gq, elicit this
response. Alpha2 receptors, which normally couple to Gi, activate the RSAT
response when coexpressed with a hybrid Gq protein that has a Gi receptor
recognition domain, called Gq/i5.
NIH-3T3 cells are plated at a density of 2xl06 cells in 15 cm dishes and
maintained in Dulbecco's modified Eagle's medium supplemented with 10% calf
serum. One day later, cells are cotransfected by calcium phosphate precipitation with
mammalian expression plasmids encoding p-SV-p-galactosidase (5-10 fig), receptor
(1-2 ug) and G protein (1-2 ug). 40 ug salmon sperm DNA may also be included in
the transfection mixture. Fresh media is added on the following day and 1-2 days
later, cells are harvested and frozen in 50 assay aliquots. Cells are thawed and 100 ul
added to 100 ul aliquots of various concentrations of drugs in triplicate in 96-well
dishes. Incubations continue 72-96 hr at 37 °C. After washing with phosphate-
buffered saline, P-galactosidase enzyme activity is determined by adding 200 ul of the
chromogenic substrate (consisting of 3.5 mM o-nitrophenyl-p-D-galactopyranoside
and 0.5% nonidet P-40 in phosphate buffered saline), incubating overnight at 30 °C
and measuring optical density at 420 nm. The absorbance is a measure of enzyme
activity, which depends on cell number and reflects a receptor-mediated cell
proliferation. The EC50 and maximal effect of each drug at each alpha2 receptor is
determined. The efficacy or intrinsic activity is calculated as a ratio of the maximal
effect of the drug to the maximal effect of a standard full agonist for each receptor
subtype. Brimonidine, also called UK14304, the chemical structure of which is
shown below, is used as the standard agonist for the alpha^ alphas and alpha2c
receptors.


Diseases that may be treated with the compounds of this invention include, but are not
limited to:
MACULOPATHIES/ RETINAL DEGENERATION Non-Exudative Age Related
Macular Degeneration (ARMD), Exudative Age Related Macular Degeneration
(ARMD), Choroidal Neovascularization, Diabetic Retinopathy, Central Serous
Chorioretinopathy, Cystoid Macular Edema, Diabetic Macular Edema, Myopic Retinal
Degeneration,
UVEITIS/ RETINITIS/ CHOROIDiTIS/OTHER INFLAMMATORY DISEASES Acute
Multifocal Placoid Pigment Epitheliopathy, Behcet's Disease, Birdshot
Retinochoroidopathy, Infectious (Syphilis, Lyme, Tuberculosis, Toxoplasmosis),
Intermediate Uveitis (Pars Planitis), Multifocal Choroiditis, Multiple Evanescent White
Dot Syndrome (MEWDS), Ocular Sarcoidosis, Posterior Scleritis, Serpiginous
Choroiditis, Subretinal Fibrosis and Uveitis Syndrome, Vogt-Koyanagi-Harada
Syndrome, Punctate Inner Choroidopathy, Acute Posterior Multifocal Placoid Pigment
Epitheliopathy, Acute Retinal Pigement Epitheliitis, Acute Macular Neuroretinopathy
VASUCLAR DISEASES/ EXUDATIVE DISEASES Diabetic retinopathy, Retinal
Arterial Occlusive Disease, Central Retinal Vein Occlusion, Disseminated Intravascular
Coagulopathy, Branch Retinal Vein Occlusion, Hypertensive Fundus Changes, Ocular
Ischemic Syndrome, Retinal Arterial Microaneurysms, Coat's Disease, Parafoveal
Telangiectasis, Hemi-Retinal Vein Occlusion, Papillophlebitis, Central Retinal Artery
Occlusion, Branch Retinal Artery Occlusion, Carotid Artery Disease (CAD), Frosted
Branch Angiitis, Sickle Cell Retinopathy and other Hemoglobinopathies, Angioid
Streaks, Familial Exudative Vitreoretinopathy, Eales Disease
TRAUMATIC/ SURGICAL/ENVIRONMENTAL Sympathetic Ophthalmia, Uveitic
Retinal Disease, Retinal Detachment, Trauma, Laser, PDT, Photocoagulation,

Hypoperfusion During Surgery, Radiation Retinopathy, Bone Marrow Transplant
Retinopathy
PROLIFERATIVE DISORDERS Proliferative Vitreal Retinopathy and Epiretinal
Membranes
INFECTIOUS DISORDERS Ocular Histoplasmosis, Ocular Toxocariasis, Presumed
Ocular Histoplasmosis Syndrome (POHS), Endophthalmitis, Toxoplasmosis, Retinal
Diseases Associated with HIV Infection, Choroidal Disease Associate with HTV
Infection, Uveitic Disease Associate with HIV Infection, Viral Retinitis, Acute Retinal
Necrosis, Progressive Outer Retinal Necrosis, Fungal Retinal Diseases, Ocular Syphilis,
Ocular Tuberculosis, Diffuse Unilateral Subacute Neuroretinitis, Myiasis
GENETIC DISORDERS Retinitis Pigmentosa, Systemic Disorders with Accosiated
Retinal Dystrophies, Congenital Stationary Night Blindness, Cone Dystrophies,
Stargardt's Disease And Fundus Flavimaculatus, Best's Disease, Pattern Dystrophy of the
Retinal Pigmented Epithelium, X-Linked Retinoschisis, Sorsby's Fundus Dystrophy,
Benign Concentric Maculopathy, Bietti's Crystalline Dystrophy, pseudoxanthoma
elasticum
RETINAL TEARS/ HOLES Retinal Detachment, Macular Hole, Giant Retinal Tear
TUMORS Retinal Disease Associated With Tumors, Congenital Hypertrophy Of The
RPE, Posterior Uveal Melanoma, Choroidal Hemangioma, Choroidal Osteoma,
Choroidal Metastasis, Combined Hamartoma of the Retina and Retinal Pigmented
Epithelium, Retinoblastoma, Vasoproliferative Tumors of the Ocular Fundus, Retinal
Astrocytoma, Intraocular Lymphoid Tumors

The results of the RSAT assay with several exemplary compounds of the
invention are disclosed in Table 1 above together with the chemical formulas of these
examplary compounds. Each number in the table represents EC50 in nanomolar (nM)
concentration whereas the number in parenthesis in the table shows the fraction of
activity of the appropriate standard which is attained by the tested compound. NA
stands for "not active" at concentrations less than 10 micromolar. As is known EC50
is the concentration at which half of a given compound's maximal activity is
observed.
Generally speaking alpha2 agonists, can alleviate sympathetically-sensitized
conditions that are typically associated with periods of stress. These include 1) the
increased sensitivity to stimuli such as intracranial pressure, light and noise
characteristic of migraines and other headaches; 2) the increased sensitivity to colonic
stimuli characteristic of Irritable Bowel Syndrome and other GI disorders such as
functional dyspepsia; 3) the sensation of itch associated with psoriasis and other
dermatological conditions; 4) muscle tightness and spasticity; 5) sensitivity to
normally innocuous stimuli such as light touch and spontaneous pain characteristic of
conditions like fibromyalgia; 6) various cardiovascular disorders involving
hypertension, tachycardia, cardiac ischemia and peripheral vasoconstriction; 7)
metabolic disorders including obesity and insulin resistance; 8) behavioral disorders
such as drug and alcohol dependence, obsessive-compulsive disorder, Tourette's
syndrome, attention deficit disorder, anxiety and depression; 9) altered function of the
immune system such as autoimmune diseases including lupus erythematosis and dry
eye disorders; 10) chronic inflammatory disorders such as Crohn's disease and
gastritis; 11) sweating (hyperhydrosis) and shivering; and 12) sexual dysfunction.
Alpha2 agonists including alpha2B/2C agonists are also useful in the treatment
of glaucoma, elevated intraocular pressure, neurodegenerative diseases including
Alzheimer's, Parkinsons, ALS, schizophrenia, ischemic nerve injury such as stroke or
spinal injury, and retinal injury as occurs in glaucoma, macular degeneration, diabetic
retinopathy, retinal dystrophies, Lebers optic neuropathy, other optic neuropathies,
optic neuritis often associated with multiple sclerosis, retinal vein occlusions, and
1.

following procedures such as photodynamic therapy and LASIX. Also included are
chronic pain conditions such as cancer pain, post-operative pain, allodynic pain,
neuropathic pain, CRPS or causalgia, visceral pain.
A compound is considered selective agonist of alpha2B and/or alpha^
adrenergic receptors in preference over alpha2A receptors, if the compound is at least
ten (10) times more active towards either alpha^ or towards alpha2c receptors than
towards alpha2A receptors. It can be seen from these tables that the compounds of the
invention are specific or selective agonists of alpha2B and/or alpine adrenergic
receptors within the former definition, and in fact have no agonist like activity or only
insignificant agonist-like activity on alpha2A receptors.
Thus, the imidazole-2-thione compounds of the invention are useful for treating
conditions and diseases which are responsive to treatment by alpha2B and/or alpha2c
adrenergic receptor agonists. Such conditions and diseases include, but are not limited
to, pain including chronic pain (which may be, without limitation visceral,
inflammatory, referred or neuropathic in origin) neuropathic pain, corneal pain,
glaucoma, reducing elevated intraocular pressure, ischemic neuropathies and other
neurodegenerative diseases, diarrhea, and nasal congestion. Chronic pain may arise as
a result of, or be attendant to, conditions including without limitation: arthritis,
(including rheumatoid arthritis), spondylitis, gouty arthritis, osteoarthritis, juvenile
arthritis, and autoimmune diseases including without limitation, lupus erythematosus.
Visceral pain may include, without limitation, pain caused by cancer or attendant to
the treatment of cancer as, for example, by chemotherapy or radiation therapy. In
addition, the compounds of this invention are useful for treating muscle spasticity
including hyperactive micturition, diuresis, withdrawal syndromes, neurodegenerative
diseases including optic neuropathy, spinal ischemia and stroke, memory and
cognition deficits, attention deficit disorder, psychoses including manic disorders,
anxiety, depression, hypertension, congestive heart failure, cardiac ischemia and nasal
congestion, chronic gastrointestinal inflammations, Crohn's disease, gastritis, irritable
bowel disease (IBD), functional dyspepsia and ulcerative colitis. Surprisingly,
although the selective alpha2B or alpha2c adrenergic receptor agonist activity of the

imidazole-2-one compounds cannot be demonstrated in the RS AT assay, these
compounds also are useful for treating the same conditions.
The activity of the compounds of the invention is highly advantageous because
the administration of these compounds to mammals does not result in sedation or in
significant cardivascular effects (such as changes in blood pressure or heart rate).
The compounds of the invention act and can be used as a highly effective
analgesic, particularly in chronic pain models, with minimal undesirable side effects,
such as sedation and cardiovascular depression, commonly seen with other agonists of
the ct2 receptors.
The compounds of the invention may be administered at pharmaceutically
effective dosages. Such dosages are normally the minimum dose necessary to achieve
the desired therapeutic effect; in the treatment of chromic pain, this amount would be
roughly that necessary to reduce the discomfort caused by the pain to tolerable levels.
Generally, such doses will be in the range 1-1000 mg/day; more preferably in the
range 10 to 500 mg/day. However, the actual amount of the compound to be
administered in any given case will be determined by a physician taking into account
the relevant circumstances, such as the severity of the pain, the age and weight of the
patient, the patient's general physical condition, the cause of the pain, and the route of
administration.
The compounds are useful in the treatment of pain in a mammal; particularly a
human being. Preferably, the patient will be given the compound orally in any
acceptable form, such as a tablet, liquid, capsule, powder and the like. However, other
routes may be desirable or necessary, particularly if the patient suffers from nausea.
Such other routes may include, without exception, transdermal, parenteral,
subcutaneous, intranasal, intrathecal, intramuscular, intravenous, and intrarectal
modes of delivery. Additionally, the formulations may be designed to delay release of
the active compound over a given period of time, or to carefully control the amount of
drug released at a given time during the course of therapy.
Another aspect of the invention is drawn to therapeutic compositions
comprising the compounds of Formula 1 and pharmaceutically acceptable salts of

these compounds and a phannaceutically acceptable excipient. Such an excipient may
be a carrier or a diluent; this is usually mixed with the active compound, or permitted
to dilute or enclose the active compound. If a diluent, the carrier may be solid, semi-
solid, or liquid material that acts as a excipient or vehicle for the active compound.
The formulations may also include wetting agents, emulsifying agents, preserving
agents, sweetening agents, and/or flavoring agents. If used as in an ophthalmic or
infusion format, the formulation will usually contain one or more salt to influence the
osmotic pressure of the formulation.
In another aspect, the invention is directed to methods for the treatment of pain,
particularly chronic pain, through the administration of one or more compounds of
Formula 1 or phannaceutically acceptable salts thereof to a mammal in need
thereof. As indicated above, the compound will usually be formulated in a form
consistent with the desired mode of delivery.
It is known that chronic pain (such as pain from cancer, arthritis, and many
neuropathic injuries) and acute pain (such as that pain produced by an immediate
mechanical stimulus, such as tissue section, pinch, prick, or crush) are distinct
neurological phenomena mediated to a large degree either by different nerve fibers
and neuroreceptors or by a rearrangement or alteration of the function of these nerves
upon chronic stimulation. Sensation of acute pain is transmitted quite quickly,
primarily by afferent nerve fibers termed C fibers, which normally have a high
threshold for mechanical, thermal, and chemical stimulation. While the mechanisms
of chronic pain are not completely understood, acute tissue injury can give rise within
minutes or hours after the initial stimulation to secondary symptoms, including a
regional reduction in the magnitude of the stimulus necessary to elicit a pain response.
This phenomenon, which typically occurs in a region emanating from (but larger than)
the site of the original stimulus, is termed hyperalgesia. The secondary response can
give rise to profoundly enhanced sensitivity to mechanical or thermal stimulus.
The A afferent fibers (A(5 and A5 fibers) can be stimulated at a lower threshold
than C fibers, and appear to be involved in the sensation of chronic pain. For
example, under normal conditions, low threshold stimulation of these fibers (such as a

light brush or tickling) is not painful. However, under certain conditions such as those
following nerve injury or in the herpes virus-mediated condition known as shingles
the application of even such a light touch or the brush of clothing can be very painful.
This condition is termed allodynia and appears to be mediated at least in part by Ap
afferent nerves. C fibers may also be involved in the sensation of chronic pain, but if
so it appears clear that persistent firing of the neurons over time brings about some
sort of change which now results in the sensation of chronic pain.
By "acute pain" is meant immediate, usually high threshold, pain brought about
by injury such as a cut, crush, burn, or by chemical stimulation such as that
experienced upon exposure to capsaicin, the active ingredient in chili peppers.
By "chronic pain" is meant pain other than acute pain, such as, without
limitation, neuropathic pain, visceral pain (including that brought about by Crohn's
disease and irritable bowel syndrome (DBS)), and referred pain.
The following in vivo assays can be employed to demonstrate the biological activity
of the compounds of the invention.
Sedative Activity
To test sedation, six male Sprague-Dawley rats are given up to 3 mg/kg of the
test compound in a saline or DMSO vehicle by intraperitoneal injection (i.p.).
Sedation is graded 30 minutes following administration of the drug by monitoring
locomotor skills as follows.
The Sprague-Dawley rats are weighed and 1 ml/kg body weight of an
appropriate concentration (ie. 3 mg/ml for a final dose of 3 mg/kg) drug solution is
injected intraperitoneally. Typically the test compound is formulated in
approximately 10 to 50 % DMSO. The results are compared to controls that are
injected with 1 ml/kg saline or 10 to 50% DMSO. Rat activity is then determined 30
minutes after injection of the drug solution. Rats are placed in a dark covered chamber
and a digicom analyzer (Omnitech Electronic) quantitates their exploratory behavior
for a five-minute period. The machine records each time the rat interrupts an array of
32 photoelectric beams in the X and Y orientation.

Representative Compounds 18,23,49 and 61 of the invention were tested in
this assay intraperitoneally and up to a dose of 1 nag/kg, and were found to have no
sedative effect. The results in this test with other compounds of the invention are
also expected to show that the compounds of the invention have no significant
sedatory activity.
Effects on Cardiovascular System
To test the effect of the compounds on the cardiovascular system, typically six
cynomolgus monkeys are given 500 |xg/kg of the test compound by intravenous
injection (i.v.) Or 3 mg/kg by oral gavage. The effects of the compound on the
animals' blood pressure and heart rate is measured at time intervals from 30 minutes
to six hours following administration of the drug. The peak change from a baseline
measurement taken 30 minutes before drug administration is recorded using a blood
pressure cuff modified for use on monkeys.
Specifically and typically the monkeys are weighed (approximately 4 kg) and
an appropriate volume (0.1 ml/kg) of a 5 mg/ml solution of the test compound
formulated in 10 to 50 % DMSO is injected into the cephalic vein in the animals' arm.
Cardiovascular measurements are made with a BP 100S automated
sphygmomanometer (Nippon Colin, Japan) at 0.5,1,2,4 and 6 hours.
The results of this test show that the compounds of the invention have no or
only minimal detectable effect on the cardiovascular system.
Alleviation of Acute Pain
Models to measure sensitivity to acute pain have typically involved the acute
application of thermal stimuli; such a stimulus causes a programmed escape
mechanism to remove the affected area from the stimulus. The proper stimulus is
thought to involve the activation of high threshold thermoreceptors and C fiber dorsal
root ganglion neurons that transmit the pain signal to the spinal cord.
The escape response may be "wired" to occur solely through spinal neurons,
which receive the afferent input from the stimulated nerve receptors and cause the
"escape" neuromuscular response, or may be processed supraspinally - that is, at the
level of the brain. A commonly used method to measure nociceptive reflexes involves

quantification of the withdrawal or licking of the rodent paw following thermal
excitation. See Ding, D.M. et al., J. Neurosci. Methods 76:183-191 (1997) and
Hargreaves, K. et al., Pain 32:77-88 (1988), hereby incorporated by reference herein.
In a variation of this latter model, male Sprague-Dawley rats are tested by
being placed on a commercially available thermal stimulus device constructed as
described in Hargreaves et al. This device consists of a box containing a glass plate.
The nociceptive stimulus is provided by a focused projection bulb that is movable,
permitting the stimulus to be applied to the heel of one or both hindpaws of the test
animal. A timer is actuated with the light source, and the response latency (defined as
the time period between application of the stimulus and an abrupt withdrawal of the
hindpaw) is registered by use of a photodiode motion sensor array that turns off the
timer and light. Stimulus strength can be controlled by current regulation to the light
source. Heating is automatically terminated after 20 seconds to prevent tissue damage.
Typically four test animals per group are weighed (approximately 0.3 kg) and
injected intraperitonealy (i.p.) with 1 ml/kg of the test compound formulated in
approximately 10 to 50% dimethylsulfoxide (DMSO) vehicle. Animals typically
receive a 0.1 mg/kg and.a 1 mg/kg dose of the three compounds. Rats are acclimated
to the test chamber for about 15 minutes prior to testing. The paw withdrawal latency
is measured at 30,60 and 120 minutes after drug administration. The right and left
paws are tested 1 minute apart, and the response latencies for each paw are averaged.
Stimulus intensity is sufficient to provide a temperature of 45-50 degrees centigrade to
each rat hindpaw.
The results in this test are expected to show that the compounds of the
invention do not provide analgesic effects in this bioassay of acute pain.
Alleviation of Chronic Pain
A model in accordance with Kim and Chung 1992, Pain 150, pp 355-363
(Chung model), for chronic pain (in particular peripheral neuropathy) involves the
surgical ligation of the L5 (and optionally the L6) spinal nerves on one side in
experimental animals. Rats recovering from the surgery gain weight and display a
level of general activity similar to that of normal rats. However, these rats develop

abnormalities of the foot, wherein the hindpaw is moderately everted and the toes are
held together. More importantly, the hindpaw on the side affected by the surgery
appears to become sensitive to pain from low-threshold mechanical stimuli, such as
that producing a faint sensation of touch in a human, within about 1 week following
surgery. This sensitivity to normally non-painful touch is called "tactile allodynia"
and lasts for at least two months. The response includes lifting the affected hindpaw
to escape from the stimulus, licking the paw and holding it in the air for many
seconds. None of these responses is normally seen in the control group.
Rats are anesthetized before surgery. The surgical site is shaved and prepared
either with betadine or Novacaine. Incision is made from the thoracic vertebra Xlll
down toward the sacrum. Muscle tissue is separated from the spinal vertebra (left side)
at the L4 - S2 levels. The L6 vertebra is located and the transverse process is carefully
removed with a small rongeur to expose the L4 - L6 spinal nerves. The L5 and L6
spinal nerves are isolated and tightly ligated with 6-0 silk thread. The same procedure
is done on the right side as a control, except no ligation of the spinal nerves is
performed.
A complete hemostasis is confirmed, then the wounds are sutured. A small
amount of antibiotic ointment is applied to the incised area, and the rat is transferred
to the recovery plastic cage under a regulated heat-temperature lamp. On the day of
the experiment, at least seven days after the surgery, typically six rats per test group
are administered the test drugs by intraperitoneal (i.p.) injection or oral gavage. For
i.p. injection, the compounds are formulated in approximately 10 to 50% DMSO and
given in a volume of 1 ml/kg body weight.
Tactile allodynia is measured prior to and 30 minutes after drug administration
using von Frey hairs that are a series of fine hairs with incremental differences in
stiffness. Rats are placed in a plastic cage with a wire mesh bottom and allowed to
acclimate for approximately 30 minutes. The von Frey hairs are applied
perpendicularly through the mesh to the mid-plantar region of the rats' hindpaw with
sufficient force to cause slight buckling and held for 6-8 seconds. The applied force
has been calculated to range from 0.41 to 15.1 grams. If the paw is sharply

withdrawn, it is considered a positive response. A normal animal will not respond to
stimuli in this range, but a surgically ligated paw will be withdrawn in response to a 1-
2 gram hair. The 50% paw withdrawal threshold is determined using tine method of
Dixon, W.J., Ann. Rev. Pharmacol. Toxicol. 20:441-462 (1980). The post-drug
threshold is compared to the pre-drug threshold and the percent reversal of tactile
sensitivity is calculated based on a normal threshold of 15.1 grams. The results are
expressed in per cent (%) MPE, where the MPE value reflects the percentage reversal
of pain threshold to that of a normal animal (100 %). Table 3 below indicates results
of this test with Compounds 1,7 and 29 of the invention, administered i.p. and in oral
doses. The doses and the observed MPE values (± SEM) are shown in the table.


AH measurements 30 min following drug administration.
* p value The results shown in Table 3 illustrate that these compounds of the invention
significantly alleviate allodynic pain, and based on these test and/or on the compounds

ability to activate alpha2B and/or alpha2c adrenergic receptors in preference over
alpha2A adrenergic receptors, the compounds of the invention are expected to be useful
as analgesics to alleviate allodynia and chronic pain.
SPECIFIC EMBODIMENTS, EXPERIMENTAL

A solution of 3,4,5,6-tetrahydro-2H-pentalen-l-one (Intermediate Al)
(prepared in accordance with Cooke et al. J. Org Chem. 1980,45,1046, incorporated
herein by reference ) (1.5 g, 12.3 mmol) in MeOH (30 mL) and CeCl3-7H20 (3.6 g,
14.6 mmol) at 0 °C was treated with NaBH4 (494 mg, 14.6 mmol). The solution was
allowed to warm to rt and stirring was continued for 30 min. Water (100 mL) and
diethyl ether (150 mL) were added. The organic layer was dried over MgSC>4, filtered
and evaporated to dryness. The alcohol (Intermediate A2) was used in the next step
without further purification.
A solution of the alcohol (Intermediate A2) (0.85 g, 6.9 mmol) in efhyl vinyl
ether (50 mL) at rt was treated with Hg(OAc)2 (1.75 g, 5.5 mmol) at rt for 18h. The
mixture was quenched with 5-10% KOH solution (80 mL) and the product was

extracted with 50% ether:hexane (3 x 80 mL) and dried over MgSO4. The organic
layer was filtered and evaporated under vacuum. The crude vinyl ether (Intermediate
A3) was used directly in the next step.
A solution of 4M LiC104 in ether (15 mL) was treated with the crude vinyl
ether (Intermediate, A3) (-0.90 g). The mixture was allowed to stir for 20-30 min. at
rt. The reaction mixture was poured into water and extracted with ether (3 x 75 mL).
The organic layers were combined, dried over MgSO4 and evaporated to give the
crude aldehyde (Intermediate A4).
The following preparation followed the procedure by Home et al.
Heterocycles, 1994, 39,139, incorporated herein by reference. A solution of the
aldehyde (Intermediate A24) (0.85 g, 5.6 mmol) in EtOH (15 mL) was treated with
tosylmethyl isocyanide (TosMIC available from Aldrich, 1.1 g, 5.6 mmol) and NaCN
(-15 mg, cat). This mixture was allowed to stir at rt for 20 min. The solvent was
removed in vacuo and the residue was dissolved in ~ 7M NH3 in MeOH and
transferred to a resealable tube. This mixture was heated to at 100 °C for 15h. The
mixture was concentrated and purified by chromatography on SiOj with 5% MeOH
(sat. w/ NH3) '.CELjC^- The imidazole was purified further as the fumarate salt
(Intermediate A25).
A solution of 4-(l,2,3,4,5,6-hexahydro-pentalen-l-ylmethyl)-lH-imidazole;
fumarate salt (Intermediate A25) (160 mg, 0.5 mmol) in THF (3 mL) and water (3
mL) was treated with NaHC03 (420 mg, 5 mmol) at rt for 20 min. Phenylchloro
thionoformate (available from Aldrich, 180 uL, 1.3 mmol) was added and stirring was
continued for 4h. The mixture was diluted with water (15 mL) and extracted with
ether (3 x 25 mL). The organic portions were combined, dried over MgSO4, filtered
and freed of solvent. The residue was dissolved in MeOH (4 mL) and treated with
NEt3 (0.35 mL) for 18h. The solvent was removed under vacuum and the product was
washed on a glass frit with 50% CH^CLjhexanes to give a white solid (-50%) 4-
(l,2,3,4,5,6-hexahydro-pentalen-l-ylmemyl)-l,3-dmydro-iniidazole-2-1iiione
(Compound 1)

JH NMR (500 MHz, CDC13 w/ TMS): 810.6 (s, 1H), 6.41 (s, 1H), 2.80 (brs, 1H),
2.67-2.63 (m, 2H), 2.43-2.36 (m, 2H), 2.21-2.10 (m, 6H), 1.86-1.83 (m, 1H).
Example A-l (Compound 2)
Use of 3-methyl-cyclopent-2-enone (commercially available from Aldrich) in
Method A produced 4-(3-memyl-cyclopent-2-enylmemyl)-l,3-dihydro-iinidazole-2-
thione (Compound 2).
*H NMR (500 MHz, CDC13 w/ TMS): 8 11.5 (brs, 1H), 11.3 (brs, 1H), 6.43 (s, 1H),
5.23 (s, 1H), 2.95 (s, 1H), 2.55-2.45 (m, 2H), 2.20 (brs, 2H), 2.08-2.06 (m, 1H), 1.69
(s, 3H), 1.49-1.47 (m, 1H).
Example A-2 (Compound 3)
Use of 3-ethyl-cyclopent-2-enone (available in accordance with the publication
of Woods et. at, J. Amer. Chem. Soc. 1949, 71,2020, incorporated herein by
reference) in Method A produced 4-(3-ethyl-cyclopent-2-enylmethyl)-l,3-dihydro-
imidazole-2-thione. *H NMR (500 MHz, CD3OD-d4): 8 6.53 (s, 1H), 5.26 (s, 1H),
2.91 (brs, 1H), 2.51-2.37 (m, 2H), 2.26-2.22 (m, 2H), 2.08-2.02 (m, 3H) 1.52-1.48 (m,
1H), 1.03 (t,/= 8.0 Hx,3H).
Example A-3 (Compound 4)
Use of 2,3,4,5,6,7-hexahydro-indenone (available in accordance with the
publication of Cooke et. al., J. Org. Chem., supra incorporated herein by reference) in
Method A produced 4-(2,3,4,5,6,7-hexahydro-lH-inden-l-ylmethyl)-l,3-dihydro-
imidazole-2-thione (Compound 4).
JH NMR (500 MHz, DMSO-d6 w/ TMS): 8 11.82 (s, 1H), 11.61 (s, 1H), 6.51 (s, 1H),
2.71 (brs, 1H), 2.62-2.51 (m, 1H), 2.12-2.03 (m, 3H), 1.90-1.82 (m, 1H), 1.56-1.36
(m,5H).
Example A-4 (Compound 5)
Use of 2-methyl-cyclohex-2-enone (available in accordance with the
publication of Hua et. al. J. Org. Chem. 1997, 62,6888, incorporated herein by
reference) in Method A produced 4-(2-methyl-cyclohex-2-enylmethyl)-l,3-dihydro-
imidazole-2-thione (Compound 5).

JH NMR (300 MHz, DMSO-d6): 8 11.89 (s, tH), 11.65 (s, 1H), 6.55 (s, 1H), 5.39 (s,
1H), 2.66-2.61 (m, 1H), 2.16-2.13 (m, 1H), 1.90 (brs, 2H), 1.65 (s, 3H), 1.47-1.36 (m,
4H).
Example A-5 (Compound 6)
Use of 2-ethyl-cyclohex-2-enone (available in accordance with the publication
of Htta et. al J. Org. Chem. supra) in the method of A produced 4-(2-ethyl-cyclohex-
2-enylmethyl)-13-dihydro-imidazole-2-tbione (Compound 6).
!H NMR (300 MHz, DMSO-d6): 8 11.90 (s, 1H), 11.60 (s, 1H), 6.56 (s, 1H), 5.40 (s,
1H), 2.65-2.50 (m, 1H), 2.30-2.10 (m, 2H), 2.00-1.92 (m, 4H), 1.60-1.36 (m, 4H),
0.98 (t, 7=7.5 Hz, 3H).
Example A-6 (Compound 7)
Use of indanone (commercially available from Aldrich) in Method A produced
4-mdan-l-ylmethyl-l,3-dihydro-imidazole-2-thione (Compound 7).
'H NMR (500 MHz, DMSO-d6 w/ TMS): 8 11.92 (brs, 1H), 11.68 (brs, 1H), 7.19 (s,
1H), 7.12 (s, 3H), 6.52 (s, 1H), 3.37-3.33 (m, 1H), 2.87-2.71 (m, 3H), 2.40 (dd, J=
9.3, 5.4 Hz, 1H), 2.13-2.05 (m, 1H), 1.66-1.59 (m, 1H).
Example A-7 (Compound 8)
Use of 2-methyl-indanone (commercially available from Aldrich) in the
method of A produced 4-(2-memyl-mdan-l-ylmethyl)-l,3-dmydro-irnidazole-2-thione
(Compound 8).
JH NMR (500 MHz, DMSO-d6 w/TMS): 8 11.97 (s, 1H), 11:67 (s, 1H), 7.18-6.91
(series of m, 4 H), 6.52 and 6.47 (s, 1H), 3.39-3.23 (m, 2H), 3.0-2.87 (m, 2H), 2.48 (s,
3H), 2.61-2.45 (m,2H).
Example A-8 (Compound 9)
Use of 3-methyl-indanone (commercially available from Aldrich) in Method A
produced 4-(3-methyl-mdan-l-ylmethyl)-l,3-dmydro-imidazole-2-thione as a mixture
of diastereomers (Compound 9)
'H NMR (500 MHz, DMSO-d6 w/ TMS): 8 11.96 (s, 1H), 11.67 (s, 1H), 7.19-7.08
(m, 4H), 6.58 (6.51) (s, 1H), 3.43-3.00 (series of m, 2H), 2.69-2.31 (series of m, 2H),
1.99-1.94 (m, 1H), 1.71-1.67 (m, 1H), 1.20 (1.18) (s, 3H).

Example A-9 (Compound 10)
Use of 3,4-dihydro-2H-naphthalen-l-one (commercially available from
Aldrich) in Method A produced 4-(l,2,3,4-tefrahydro-naphmalen-l-ymiethyl)-l>3-
dihydro-imidazple-2-thione (Compound 10).
'H NMR (500 MHz, DMSO-d6 w/ TMS): 8 12.01 (s, 1H), 11.67 (s, 1H), 7.24-7.04
(m, 4H), 6.54 (s, 1H), 3.20-3.01 (m, 2H), 2.69 (brs, 3H), 1.80-1.40 (m, 4H).
Example A-10 (Compound 11)
Use of 5-chloro-indanone (commercially available from Aldrich) in Method A
produced 4-(5-chloro-indan-1 -ylmethyl)-1,3-dfliy dro-imida2»le-2-tbione (Compound
11).
JH NMR (500 MHz, DMSO-d6 w/TMS): 8 11.95 (s, 1H), 11.68(s, 1H), 7.27-7.12
(m, 3H), 6.53 (s, 1H), 3.35-3.30 (m, 1H), 2.87-2.76 (m, 3H), 2.45-2.40 (m, 1H), 2.16-
2.12 (m, 1H), 1.70-1.67 (m, 1H).
Example A-ll (Compound 12)
Use of 4-methykindanone (commercially available from Aldrich) in Method A
produced 4-(4-methyl-indan-1 -ylmethyl)-1,3-dihydro-irnidazole-2-thione (Compound
12).
'H NMR (500 MHz, DMSO-d6 w/ TMS): 8 11.95 (s, 1H), 11.67 (s, 1H), 7.06-6.95
(m, 3H), 6.52 (s, 1H), 3.38 (brs, 1H), 2.81-2.76 (m, 2H), 2.68 (m, 1H), 2.42-2.37 (m,
1H), 2.20 (s, 3H), 2.14-2.10 (m, 1H), 1.67-1.64 (m, 1H).
Example A-12 (Compound 13)
Use of 5-fluoro-indanone (commercially available from Aldrich) in Method A
produced 4-(5-fluoro-mdan-l-ylmemyl)-l,3-dihydro-irmdazole-2-tliione (Compound
13). JH NMR (500 MHz, DMSO-d6 w/ TMS): 8 11.96 (s, 1H), 11.68 (s, 1H), 7.14-
6.93 (m, 3H), 6.53 (s, 1H), 3.36 (brs, 1H), 2.88-2.77 (series of m, 3H), 2.44-2.39 (m,
1H), 2.16-2.14 (m, 1H), 1.71-1.69 (m, 1H).
Example A-13 (Compound 14)
Use of 5-methoxy-indan-l-one(commercially available from Aldrich) in Method A
produced 4-(5-methoxy-indan-1 -ylmethyl)-1,3-dihydro-imidazole-2-thione
(Compound 14).

*H NMR (300 MHz, DMSO-d6 w/TMS): 8 11.93 (s, 1H), 11.65 (s, 1H), 7.01 (d,J=
8.1 Hz, 1H), 6.78 (s, 1H) 6.71-6.68 (m ,1H), 6.51 (s, 1H), 3.70 (s, 3H), 2.83-2.72 (m,
4H), 2.42-2.34 (m, 1H), 2.13-2.09 (m, 1H), 1.68-1.64 (m, 1H).
Example A-14 (Compound 15)
Use of 5-bromo-indanone (commercially available from Aldrich) in Method A
produced 4-(5-bromo-md^-l-ylmethyl)-l,3-dihydro-miidazole-2-triiorie (Compound
15).
XH NMR (500 MHz, DMSO-d6 w/ TMS): 8 (11.95 (s, 1H), 11.68 (s, 1H), 7.41 (s,
1H), 7.32 (d, J = 8.1 Hz, 1H), 7.08 (d, J= 8.1 Hz, 1H), 6.53 (s, 1H), 2.89-2.74 (m,
3H), 2.46-2.39 (m, 2H), 2.15-2.10 (m, 1H), 1.72-1.64 (m, 1H).
Example A-15 (Compound 16)
Use of 6-methyl-indanone (commercially available from Aldrich) in Method A
produced 4-(6^memyl-mdan-l-ylmethyl)-l,3-duiydro-irmdazole-2-thione (Compound
16).
'H NMR (300 MHz, DMSO-d6 w/TMS): 8 11.93 (s, 1H), 11.65 (s, 1H), 7.10-6.94
(m, 3H), 6.53 (s, 1H), 2.85-2.65 (m, 3H), 2.37 (dd, J= 9.6, 5.1 Hz, 1H), 2.16-2.04 (m,
1H), 1.69-1.57 (m,lH).
Example A-16 (Compound 17)
Use of 6-methoxy-indan-l-one (commercially available from Aldrich) in
Method A produced 4-(6-methoxy-mdan-l-ylmemyl)-l,3-dihydro-miidazole-2-thione
(Compound 17).
JH NMR (300 MHz, DMSO-d6 w/ TMS): 8 11.93 (s, 1H), 11.66 (s, 1H), 7.11-7.07
(m, 1H), 6.72-6.69 (m, 2H), 6.53 (s, 1H), 3.70 (s, 3H), 3.36-3.33 (m, 1H), 2.83-2.50
(m, 3H), 4.10 (dd, 7= 9.5, 5.4 Hz, 1H), 2.18-2.06 (m, 1H), 1.69-1.64 (m, 1H).
Example A-17 (Compound 100)
Chiral HPLC of Compound 7 under the following conditions: ChiralCel OJ®
column, 10% IPA:hexane, rt, uv 220nm, lmL/m, produced the following enantiomer:
first eluting (+)-(i?)-4-mdan-l-ylmethyl-l,3-dihydro-imidazole-2-thione (Compound
100), 99% ee.
opt rotation [a]D20 +33° (c 1.02 in MeOH)

JH NMR same as Example A-6, Compound 7
Example A-18 (Compound 101)
Chiral HPLC of Compound 7 under the following conditions: ChiralCel OJ®
column, 10% IPA:hexane, rt, uv 220nm, lmL/m, produced the following enantiomer:
second eluting (-)-(iS)^-indan-l-ylmemyl-l,3-dihydro-iniidazole-2-thione
(Compound 101), 98% ee.
opt. rotation [a]D20 -38° (c 1.84 in MeOH)
!H NMR same as Example A-6, Compound 7.
Example A-19 (Compound 102)
Use of 6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carbaldehyde (obtained as
described in Jennesken, et. al. J. Org. Chem. 1986, 51,2162, incorporated herein by
reference) in Method A produced 4-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-
l,3-dihydro-imidazole-2-thione (Compound 102).
lU NMR (300 MHz, DMSO-d6) 8 11.8 (s, 1H), 11.6 (s, 1H), 7.14-7.07 (m, 4H),
6.48(s, 1H), 2.89-2.74 (m, 5H), 2.14-2.04 (m, 2H), 1.42-1.31 (m, 2H).
Example A-20 (Compound 103)
Use of thiochroman-4-one (commercially available from Aldrich) used in
Method A produced 4-thioclu,oman-4-ylmemyl-l,3-dmydro-imidazole-2-thione
(Compound 103).
*H NMR (300 MHz, CDC13) 8 12.0 (s, 1H), 11.7 (s, 1H), 7.13-6.97 (m, 4H), 6.60 (s,
1H), 3.16-3.12 (m, 2H), 2.87-2.84 (m, 1H), 2.59-2.56 (m, 2H), 1.93-1.90 (m, 1H),
1.75(t,J=9.0Hz, 1H).
Example A-21 (Compound 104)
Use of 2-chloro-cyclopent-2-enone (obtained as described in Kim, et. al.
Synthesis 1993,283, incorporated herein by reference) in Method A produced (4-(2-
chloro-cyclopent^-enylmemyl^l^-dihydro-imidazole^-thione (Compound 104).
aH NMR (300 MHz, MeOH-d4) 8 6.58 (s, 1H), 5.75 (s, 1H), 3.00-2.80 (m, 2H), 2.40
(dd, J= 9.0, 6.0 Hz, 1H), 2.32-2.21 (m, 3H), 1.75-1.65 (m, 1H).
Example A-22 (Compound 105)

Use 01 (2-bromo-i-methyl-cyclopent-2-enyl)-acetaldehyde (Intermediate
TWELVE-2) in Method A produced 4-(2-bromo-3-methyl-cyclopent-2-enylmethyl)-
l,3-dmydro-imidazole-2-thione (Compound 105).
!H NMR (300 MHz, MeOH-d4) 6 6.55 (s, 1H), 3.00 (brs, 1H), 2.90 (dd, 7= 11.1,3.9
Hz, 1H), 2.41-2.32 (dd, J= 9.6, 5.4 Hz, 1H), 2.27-2.23 (m, 2H), 2.13-2.01 (m, 1H),
1.73 (s,3H), 1.72-1.60 (m, iff).

A solution of 3-cyclopentene-l-carboxylic acid (Intermediate Bl, available
from Aldrich, 2 g, 17.8 mmol) in ether (100 mL) was treated with LiAlH* (19 mL, 1M
in ether) at 0 °C for 30 min. The reaction mixture was quenched by addition of
Rochelle's salt solution. The mixture was extracted with 50% Et20:hexanes (3 x 50
mL). The extracts were dried over MgSO4, filtered and evaporated to dryness. The
material (Intermediate B2) was used directly in the next step.
A solution of triphenylphosphine (10.3 g, 39 mmol) in THF (50 mL) at 0 °C
was treated with diethyl azodicarboxylate (DEAD) (6 mL) and the mixture was

allowed to stir for about 5 min. A solution of cyclopent-3-enyl-methanol
(Intermediate B2, 1.8 g, 18.3 mmol) and acetone cynaohydrin (3.4 mL, 38 mmol) in
THF (50 mL) was added via syringe over 5 min. The mixture was allowed to stir at 0
°C for 40 min. The ice bath was removed and stirring was continued for 17h. The
mixture was quenched with water and extracted with ether. The ether layer was dried
over MgSO4 and the mixture was carefully freed of solvent. The residue was purified
by chromatography with 10 % etherrpentane to give cyclopent-3-enyl-acetonitrile
(Intermediate B3) 1.16 g (60%) over two steps.
A solution of (diisobutyl aluminum hydride (DIBAL) (7 mL, 1M in
cyclohexane) was added to cyclopent-3-enyl-acetonitrile (Intermediate B3,520 mg,
4.9 mmol) at -70 °C. After 30 min, the mixture was quenched with Rochelle's salt
solution. The aqueous phase was extracted with ether (3 x 20 mL) and the combined
organic layers were dried over MgSO4, filtered and evaporated to dryness. The crude
aldehyde (Intermediate B4) (~0.5 g) was employed in the next step.
Formation of 4-cyclopent-3-enylmemyl-l,3-dmydro-irnidazole-2-thione
(Compound 18) was completed by employing the same procedure, without formation
of the fumarate, as described in Example A, and indicated above in the reaction
scheme.
JH NMR (500 MHz, DMSO-d6 w/ IMS) 5 11.8 (s, 1H) 11.6 (s, 1H) 6.56 (s, 1H) 5.65
(s, 2H) 2.50-2.35 (m, 5H), 1.98-1.94 (m, 2H).


A solution of cyclohexenol (Intermediate CI, available from Aldrich, 2.0 g,
20.4 mmol) in triethyl orthoacetate (30 mL) and propionic acid (~0.025.mL, cat) was
heated to remove ethanoL After the ethanol was removed heating was continued at
145 °C for Ih. The triethyl orthoacetate was removed by simple distillation. After
the residue cooled to it the product was purified by chromatography on Si02 with 5%
ether:hexane to give the ester (Intermediate C2) as a clear colorless oil 1.08 g
(-31%).
A solution of the above ethyl ester (Intermediate C2, 1.0 g, 5.9 mmol) was dissolved
in hexanes (50 mL) and cooled to -78 °C. A solution of DB3AL (5.8 mL 1.0 M in
cyclohexane) was added dropwise. After 15 min, diethyl ether (50 mL) was added
and the mixture was stirred with Rochelle's salt solution (25 mL) for 10 m. The
organic layer was separated, dried and filtered. Chromatography on Si02 wim 7%
Et20:hexane delivered the aldehyde (Intermediate C3) as a clear colorless oil, 0.52g
(74%). The aldehyde (Intermediate C3) was subjected to the Biichi protocol (Home
et al), as described above in Method A. The fumarate salt of the imidazole
(Intermediate C4) was obtained (25% overall). Formation of 4-cyclohex-2-

enylmethyl-l,3-dihydro-imidazole-2-thione (Compound 19) was completed by
employing the same procedure as described in Example A.
'H NMR (500 MHz, DMSO-d6 w/ TMS) 8 11.9 (s, 1H), 11.7 (s, 1H), 6.56 (s,
1H), 5.7-5.4 (m, 2H) 2.37-2.20 (m, 3H), 1.93-1.16 (series of m, 6H).

A solution of 2-cyclopentene-l-one (Intermediate Dl, commercially available
from Aldrich) (1.5 mL, 17.5 mmol) in CH2C12 (40 mL) at 0 °C was treated with
bromine (0.86 mL, 16.6 mmol) in CH2C12 (30 mL) over 10 min. (see: J. Org Chem.
1982 47, 5088 incorporated herein by reference). The mixture was allowed to stir at 0
°C for one hour. Triemylamine (3.8 mL) was added and the mixture was allowed to
stir at rt for 1.5h. The mixture was diluted with CH2C12 .washed with 10% HC1. The
combined layers were washed with sat. NaHC03, brine and dried over Na2SO4. The
mixture was filtered and evaporated to give 2-bromo-cyclopent-2-enone
(Intermediate D2, 2.85 g).
The bromoenone (Intermediate D2, -17.5 mmol) was dissolved in 0.4M
CeCl3 »7H20 in MeOH (66 mL) at 0 °C. Sodium borohydride was added portion-

wise and stirring was continued for 10 min. after addition was complete. The mixture
was quenched with saturated NH4CI and extracted with ether. The combined organic
layers were washed with sat. NH4CI, H2O, brine, and dried over Na2SO4, filtered and
evaporated to dryness. The material was purified by column chromatography 15%
EtOAc:Hx to give 2-bromo-cyclopent-2-enol (Intermediate D3, ~2g, 70% over 2
steps).
The alcohol (Intermediate D3,16 mmol) in THF (30 mL) at 0 °C was treated
with isobutyl magnesium bromide (40 mmol). The catalyst, 1,3-
bis(diphenylphosphino)propane nickel (II) chloride (0.75 mmol) (NiCl2dppp) was
added in one portion and the mixture was heated to reflux for 3h. (see: Organ et al. J.
Org. Chem. 1997, 62,1523, incorporated herein by reference). The reaction mixture
was cooled to rt and quenched with sat. NH4CI solution. The mixture was filtered and
partitioned between brine and diethyl ether. The organic layer was removed and dried
over Na2SO4, filtered and concentrated under vacuum. The oil was purified by
chromatography on Si02 with 20% EtOAc:Hx to yield 2-isobutyl-cyclopent-2-enol
(Intermediate D4). Use of 2-isobutyl-cyclopent-2-enol (Intermediate D4) in
Method A produced 4-(2-isobutyl-cyclopent-2-enylmemyl)-l,3-dmydro-imidazole-2-
thione (Compound 20).
*H NMR (300 MHz, CD3OD-d4): 5 6.55 (s, 1H), 5.38 (s, 1H), 2.80-2.68 (m, 2H),
2.26-2.18 (m, 3H), 2.03-1.73 (series of m, 4H), 1.58-1.51 (m, 1H), 0.93 (d, J= 6.3 Hz,
3H),0.83(d,./=6.3Hz,3H).
Example D-l (Compound 21)
Use of vinyl magnesium bromide (commercially available from Aldrich) in Method
D produced 2-vinyl-cyclopent-2-enol. The employment of this alcohol in Method A
produced 4-(2-vmyl-cyclopent-2-enylmemyl)-l,3-dmydro-imidazole-2-thione
(Compound 21).
'H NMR (300 MHz, CD3OD-d4): 5 6.55-6.43 (m, 2H), 5.74 (s, 1H), 5.27-5.06 (m,
2H), 3.11 (s, 1H), 2.79 (dd, J= 3.3,11.7 Hz, 1H), 2.34-2.26 (m, 3H), 2.01-1.94 (m,
1H), 1.79-1.75 (m, 1H).
Example D-2 (Compound 22)

Use of 1-propenylmagnesium bromide (commercially available from Aldrich)
in Method D produced 2-propenyI-cycIopent-2-enol. Employment of this alcohol in
Method A produced the cis/trans isomers: 4-(2-propenyl-cyclopent-2-enylmethyl)-
1,3-dfliydro-imidazole-2-mione (Compound 22).
*H NMR (300 MHz, CD3OD-d4): 5 6.56-6.52 (m, 1H), 6.18 (6.13) (s, 1H), 5.82-5.49
(m, 2H), 5.56 (s, 1H), 3.05 (m, 1H), 2.78-2.66 (m, 1H), 2.33-2.15 (m, 3H), 2.04-1.87
(m, !H), 1.77 (d, J= 6.3 Hz, 3H), 1.73-1.55 (m, 1H).


1-Tetralone (commercially available from Aldrich) (Intermediate El, 1.24 g,
8.5 mmol) and 4,5-imidazole carboxaldehyde (Formula 8, (0.82 g, 8.5 rnmol) were
added to 8.5 mL of a 40% solution of H2SO4. The solution was heated for 24 h at 90
°C. After cooling to rt, the reaction was made basic with excess concentrated
NH4OH. The mixture was extracted twice with THF. The organic layers were
combined and washed with brine. The organic layer was separated and dried over
Na2SC>4. The mixture was filtered and the filtrate concentrated under reduced pressure
to afford ~2.2 g of a yellow solid 2-(lH-imidazol-4-ylmethylene)-3,4-dihydro-2H-
naphthalen-1-one (Intermediate E3). The crude product (Intermediate E3) was
suspended in ethanol (100 mL) and a palladium on carbon catalyst (10%, 0.27 g)
added. The mixture was shaken in a Parr hydrogenator apparatus while under 40 psi
of hydrogen. After 19h the reaction mixture was filtered through Celite and the
filtrate concentrated under reduced pressure. Column chromatography with 5-7%
MeOH:CHCl3 afforded -0.9 g (45%) of a solid comprising 2-(lH-imidazol-4-
ylmethylene)-3,4-dihydro-2H-naphthalen-l-one (Intermediate E4). The synthesis of
2-(2-&ioxo-2,3-dmydro-lH-imidazol-4-ylmethyl)-3,4-dmydro-2H-naphthalen-l-one
(Intermediate E5) was completed by subjecting the imidazole (Intermediate E4) to
the conditions described in Method A for Example A for the conversion to the thione
(Intermediate E5 ).
'H NMR (500 MHz, DMSO-d6 w/ TMS) 5 11.9 (s, 1H), 11.7 (s, 1H), 7.88 (d, J= 7.5
Hz, 1H), 7.57-7.54 (m, 1H), 7.37-7.34 (m, 2H), 6.58 (s, 1H), 3.08-2.97 (m, 2H), 2.86-
2.85 (m, 1H), 2.43 (dd, J = 9.0,6.0 Hz, 1H), 2.08 (dd, /= 4.0,4.5 Hz, 1H), 1.1 (brs,
1H).
The racemic 2-(2-thioxo-2,3-dihydro-lH-imidazol-4-ylmethyl)-3,4-dihydro-
2H-naphthalen-l-one (Intermediate E5) was separated by chiral HPLC using a
ChiralPak AD 4.6x220 mm (Daicel Chem. Ind. Ltd.) with isocratic flow 1.2 mL/m,
10% isopropyl alcohol in acetonitrile mobile phase at 20 °C andUV210nm. The
first peak with 6.5 min. retention time gave Compound 23 (-) S with [a]D20 -66.4 (c =
0.57 in 9% DMSOrMeOH). The second fraction at 14.0 min. gave Compound 24 (+)
R with [a]D20 +61.9 (c = 0.63 in 10% DMSO:MeOH). The absolute stereochemistry

of Compounds 23 and 24, as shown in the scheme, was assigned by derivatization
followed by X-ray crystallography.
Following the procedure of Example E, fused ring compounds are reacted to yield the
thione derivatives listed below.
Example £-1 (Compound 25)
5-(2-Thioxo-2,3-a!ihydro-lH-imidazol-4-ylmethyl)-6,7-dihydro-5H-
benzo[b]thiophen-4-one is prepared by using 6,7-dihydro-5H-benzo[b]thiophen-4-
one as a starting material in Method E.
JH NMR (500 MHz, DMSO-d6 w/ TMS): 8 11.87 (s, 1H), 11.69 (s, 1H), 7.40 (d, J=
5.5 Hz, 1H), 7.27 (d, J=* 5.5 Hz, 1H), 6.57 (s, 1H), 3.13-2.98 (m, 3H), 2.80-2.79 (m,
1H),2.41 (dd,J=9.5,6.0 Hz, 1H), 2.15-2.11 (m, 1H), 1.81-1.78 (m, 1H).
Example E-2 (Compound 26)
4-Memyl-2-(2-tmoxo-2,3-dihydro-lH-miidazol-4-ylmettiyl)-3,4Himydro-2H-
naphthalen-1-one (Compound 26 is prepared by using 4-methyl-3,4-dihydro-2H-
naphthalen-1-one (commercially available from Aldrich) as a starting material in
Method E.
*H NMR (300 MHz, CD3OD-d4): 5 diastereomers: 7.99-7.90 (m, 1H), 7.60-7.48 (m,
2H), 7.36-7.31 (t, J= 9 Hz, 1H), 6.62 (6.60) (s, 1H), 3.19-3.12 (m, 2H), 2.90-2.82 (m,
1H), 2.63 (dd, J= 7.5, 9.0 Hz, 1H), 2.17-1.98 (m, 1H), 1.57-1.44 (m, 1H), 1.40 (t, J=
7.0 Hz, 3H).
Example E-3 (Compound 27)
2-(2-Thioxo-2,3-dihydro- lH-imidazol-4-ylmethyl)-indan-l-one (Compound
27) is prepared by using indanone (commercially available from Aldrich) as starting
material in Method E.
JH NMR (300 MHz, 300 MHz, CD3OD-d4): 8 7.72-7.38 (m, 4H), 6.61 (s, 1H), 3.38-
3.33 (m, 1H), 3.08-2.99 (m, 2H), 2.87 (dd, 7= 13.2,4.1 Hz, 1H), 2.67-2.60 (m, 1H).
Example E-4 (Compound 28)
6-Hydroxy-2-(2-thioxo-2,3-dihydro-1 H-imidazol-4-ylmethyl>3,4-dihydro-2H-
naphthalen-1-one is prepared by substituting 6-hydroxy-3,4-dihydro-2H-naphthalen-l-
one (commercially available from Aldrich) in Method E.

'H NMR (300 MHz, CD3OD-d4): 8 7.85 (d, J = 8.8 Hz, 1H), 6.81 (s, 1H), 6.70 (dd, J
= 6.1,2.4 Hz, 1H), 6.61 (d, 7= 2.3 Hz, 1H), 3.22 (dd, J = 3.8,10.6 Hz, 1H), 2.92-2.88
(m, 2H), 2.78-2.62 (m, 2H), 2.14-2.09 (m, 1H), 1.78-1.70 (m, 1H).
Example £-5 (Compound 106)
Use of 7,8-dihydro-6H-quinolin-5-one (obtained as described in Huang, et al,
Synthetic Communications, 1998,28,1197, incorporated herein by reference) in
Method E produced 6-(lH-imidazoI-4-ylmethyI)-2,3,4,6,7,8-hexahydro-lH-quinolin-
5-one as a side product of the reduction step. This reduced material was used in
Method E to produce 6-(2-1hioxo-2,3-dihydro-lH-iinidazol-4-ylmethyl)-2,3,4,6,7,8-
hexahydro-lH-quinolin-5-one (Compound 106).
*H NMR(300 MHz, MeOH-d4) 8 6.58 (s, 1H), 3.25-3.21 (m, 2H), 2.95 (dd, 7= 6.6,
2.2 Hz, 1H), 2.57 (dd, 7= 5.4,3.9 Hz, 1H), 2.47-2.30 (m, 5H), 1.96-1.92 (m, 1H),
1.80-1.76 (m, 2H), 1.63-1.56 (m, 1H).
Example E-6 (Compound 107)
Use of 7,8-dihydro-6H-quinolin-5-one (obtained as described in Huang, et. al.
Synthetic Communications, 1998,28, 1197, incorporated herein by reference) in
Method E produced 6-(2-thioxo-2,3-dmydro-lH-mndazol-4-ylmethyl)-7,8-dihydro-
6H-quinolin-5-one (Compound 107).
'H NMR (300 MHz, MeOH-d4) 8 8.46 (dd, /= 4.8,1.8 Hz, 1H), 8.33 (dd, J= 7.8,1.5
Hz, 1H), 7.42 (dd, /= 8.1,4.8 Hz, 1H), 6.63 (s, 1H), 3.22-3.12 (m, 3H), 2.95-2.85 (m,
1H), 2.71-2.63 (dd, 7=4.8,3.3 Hz, 1H), 2.30-2.21 (m, 1H), 1.94-1.81 (m, 1H).


5-(lH-Imida2ol-4-ylmethyl)-6,7-dihydro-5H-benzo[b]thiophen-4-one
(Intermediate Fl, an intermediate already prepared by Method E in the synthesis of
Example E-l, Compound 25,0.44 g, 1.90 mmol) was added to methanol (20 mL).
Sodium borohydride (74 mg, 1.95 mmol) was added to the solution. After stirring for
2.5h at rt the reaction mixture was quenched with water. The mixture was extracted
twice with ethyl acetate. The organic layers were combined and washed with brine.
The organic layer was separated and dried over Na2SO4. The mixture was filtered and
the filtrate concentrated under reduced pressure to afford 0.4 g of a white solid 5-(lH-
irmdazol-4-ylmemyl)^,5,6,7-tetrahydrobenzo[b]thiophen-4-ol (Intermediate F2).
The crude product (Intermediate F2) was dissolved in CH2C12 (25 mL).
Triethylsilane (2.5 mL, 15.6 mmol) and triflouroacetic acid (4.8 mL, 62 mmol) were
added and the mixture was stirred at rt for 22h. The solution was made basic with 2N
NaOH and the organic layer separated and washed with brine. The solution was dried
over Na2SO4. The mixture was filtered and the filtrate concentrated under reduced
pressure. Column chromatography with 7% methanol in chloroform afforded 0.39 g

(80%) of Intermediate F3. The product was dissolved in methanol and an excess of
hydrogen chloride (HC1) in ether was added. The solution was concentrated under
reduced pressure to yield 0.3 g of a solid. Column chromatography with 7% methanol
in chloroform afforded 0.21 g (~45%) of the hydrochloride salt of 4-(4,5,6,7-
tetrahydro-benzo[>]miophen-5-ylme&yl)-l,3-dihydro-inudUizole-2-thione
(Intermediate F3), as white crystals after recrystallization from a mixture of acetone
and methanol. The synthesis of 4-(4,5,6,7-tetrahydro-benzo[b]thiophen-5-ylmethyl)-
l,3-dihydro-imidazole-2-thione (Compound 29) was completed by subjecting the
hydrochloride salt of the imidazole (Intermediate F3) to the conditions described in
Method A for the synthesis of Compound 1 (Example A) 4-(4,5,6,7-tetrahydro-
berizo[b]miophen-5-ylmemyl)-l,3-dihydro-irnidazole-2-thione (Compound 29):
'H NMR (500 MHz, DMSO-d6 w/ TMS) 8 11.9 (s,lH), 11.7 (s, 1H), 7.22 (d, J= 5
Hz, 1H), 6.75 (d, /= 5 Hz, 1H), 6.60 (s, 1H), 2.80-2.59 (series of m, 4H), 2.42-1.87
(series of m, 4 H), 1.43-1.35 (m, 1H).
Example F-l (Compound 30)
4-(l,2,3,4-Tetrahydro-naphmalen-2-ylmemyl)-l,3-dmydro-irmdazole-2-thione
(Compound 30) is prepared by using 2-(lH-imidazol-4-ylmethylene)-3,4-dihydro-
2H-naphthalen-l-one as a starting material (see: method E above in Method F.
JH NMR (300 MHz, CD3OD-d4): 6 7.03-7.01 (m, 4H), 6.60 (s, 1H), 2.82-2.76 (m,
3H), 2.52 (d, J= 6.7 Hz, 1H), 2.45 (dd, J= 10.3,6.4 Hz, 1H), 2.01-1.92 (m, 3H),
1.43-1.39 (m, 1H).
Example F-2 (Compound 108)
4-(l,2,3,4-TerrahyoVo-naphmalen-2-ylmemyl)-lH-irnidazole (prepared by the
process in Method F) was separated by chiral HPLC under the following conditions:
ChiralPakAD® column, with 10% EtOH:hexane. The first fraction eluted was (-)-(5>
4-(l,2,3,4-te1xahydro-naphmalen-2-ylmemyl)-lH-imidazole and it was converted to (-
H^-4 (Compound 108) by the applicable process steps described in Method A.
opt rotation [a]D2Q -85° (c 0.75 in MeOH:DMSO 1:1)
!H NMR same as Compound 30.

Example F-3 (Compound 109)
(+)-(i?)-4-( 1,2,3,4-Tetrahydro-naphthalen-2-ylmethyl)-1,3 -dmydro-imidazole-
2-thione was isolated as the second fraction in accordance with the method reported
for Example F-2 (Compound 109).
opt. rotation [a]D20 +78° (c 1.25 in DMSO)
]H NMR same as Compound 30.

1-Decalone (Intermediate Gl, commercially available from Aldrich) (10.0 g,
66 mmol) and 4(5)-imidazole carboxaldehyde (Formula 8, 6.3 g, 66 mmol) were
added to EtOH (100 mL). NaOH (5.2 g, 130 mmol) in HzO (20 mL) was added and
the mixture was heated at reflux for 5 days. The mixture was cooled to rt and
acidified with aqueous HCL The solution was extracted with THF/ethyl acetate and
the organic layers were combined and washed with brine. The organic phase was

dried over MgSC»4, filtered and freed of solvent The crude product was heated at
reflux in 40% H2SO4 for 24h. The reaction was cooled to rt and made basic with
saturated K2C03. The solution was extracted with THF/ethyl acetate and the organic
layers were combined and washed with brine. The organic phase was dried over
MgSO4 and the solvent removed under reduced pressure. Purification by flash
chromatography (15:1 CH3Cl/MeOH) afforded Intermediate G2 (4.9 g, 32% yield).
The synthesis of compound 2-(2-mioxo-2,3-dihydro-lH-irnida2X)l-4-ylmethyl)-
3,4,5,6,7,8-hexahydro-2H-naphthalen-l-one (Compound 31) was completed by
subjecting the imidazole (Intermediate G2) to the applicable process steps described
in Method A in connection with Example A. Compound 31:
*H NMR (500 MHz, DMSO-d6 w/ TMS) 8 11.8 (s, 1H), 11.7 (s, 1H), 6.52 (s, 1H),
2.89 (dd, J= 4,4.5 Hz, 1H), 2.29-1.47 (series of m, 14H).
The free base of the hydrochloride salt of Intermediate G2 (3.0 g, 11 mmol)
was generated with NaOH and then added to diethylene glycol (100 mL). To the
solution was added hydrazine hydrate (3.2 mL, 100 mmol) and the mixture was stirred
overnight at rt. NaOH (3.1 g, 77 mmol) was added and the solution heated at reflux
for 5 days. The solution was cooled to rt and diluted with water. The aqueous layer
was extracted with THF/ethyl acetate. The organic layers were combined, washed
with brine, dried MgSO4 and the solvent removed under reduced pressure.
Purification by flash chromatography (8:1 CHjCLMeOH) afforded Intermediate G3
(0.64 g, 27% yield).
4-(2,3,4,4a,5,6,7,8-Octahydro-naphmalen-2-ylmemyl)-lH-imidazole
(Intermediate G3) (1.0 g, 4.6 mmol) was added to 10 mL of concentrated HC1. The
solution was stirred at rt for 30 m and neutralized with K2CO3. The solution was
extracted with THF/ethyl acetate. The organic layers were combined and washed with
brine, and dried over MgSO4. The solvent was removed under reduced pressure.
Purification by flash chromatography (15:1 CH3Cl/MeOH) gave Intermediate G4.
The synthesis of compound 4-(l,2,3,4,5,6,7,8-octahydro-naphthalenylmethyl)-
1,3-dihydro-imidazole-2-thione (Compound 32) was completed by subjecting the

imidazole Intermediate G4 to the applicable process steps described in Method A
in connection with Example A. Compound 32:
'H NMR (500 MHz, DMSO-d6 w/ IMS) 8 11.8 (s, 1H), 11.6 (s, 1H), 6.54 (s, 1H),
2.28 (d, J= 6.5 Hz, 2H), 1.88-1.45 (m, 14H), 1.11 (brs, 1H).
Example G-2 (Compound 110)
Intermediate G4 was separated by chiral HPLC: ChiralPakAD® column, with
10% EtOH:hexane. Use of (J?)-4-( 1^,3,4,5,6,7,8-octahydro-naphthalen-2-ylmethyl>-
lH-imidazole) in the applicable process steps described in Method A produced
(1,2,3,4,5,6,7,8-octahydro-naphthalen-2-ylmethyl)-1,3^mydro-imidazole-2-thione
(Corapoud 110)
JH NMR same as Compound 32.

1,2,3,4-Tetrahydro-naphthalen-l-ol (Intermediate HI commercially available
from Aldrich, 13 mL, 93 mmol) was dissolved in dry hexane (300 mL) and heated to

70 °C. A solution of nBuLi (75 mL, 2.5M in hexane) and N,N,N',N'-
tetramethylethylenediamine (TMEDA) 28 mL) in dry hexane (30 mL) was added
dropwise via an addition funnel to the solution. The addition was completed and
heating was continued for 2h. The mixture was cooled to 0 °C and CO2 gas was
bubbled through the mixture for 8-12L The solution was stored at it for 24h before
dilution with H20 and acidification wilh 3N HC1 and cone. HC1 until pH ~2. The
aqueous layer was extracted with ethyl acetate. The organic layer was extracted with
sat NaHCOj (3x) and the combined basic aqueous extracts were cooled to 0 °C and
acidified with 3N HC1 to HCI until a pale yellow solid precipitated. The resulting
carboxylic acid (Intermediate H2) (28%) was collected by filtration and dried under
vacuum.
Intermediate H2 was used in the next step without further purification. It was
dissolved in THF (70 mL) and added dropwise to a solution of LiAHL; (28 mL, 1M in
THF). The reaction was stirred at rt for lh and heated to reflux (90 °C) for 2h. The
mixture was cooled to rt, quenched with Rochelle's salt solution and stirred for lh.
The aqueous layer was separated and extracted with ethyl acetate. The organic layers
were combined, dried over MgSO4, filtered and freed of solvent to give 8-
hydroxymethyl-l,2,3,4-tetrahydro-naphthalen-l-ol (Intermediate H3) (57%) as a
white solid that was sufficiently pure for the subsequent process steps.
The diol (Intermediate H3) (2.42 g, 13.5 mmol) was dissolved in CH2C12 (75
mL) and reacted with dihydropyran (1.3 mL, 13.8 mmol) and pyridiniumpara-toluene
sulfonate (PPTS) (350 mg, 1.36 mmol) at rt for 18h. The mixture was concentrated
onto S1O2 and purified by chromatography with 10% EtOAcHx. The
tetrahydropyranyl (THP) protected alcohol (2.02 g, 7.70 mmol) was dissolved in
CH2CI2 (10 mL) and added to a mixture of pyridinium chlorochromate (PCC) (4.9 g,
22.2 mmol), sodium acetate (310 mg, 3.56 mmol) and celite (~10 g) in CH2CI2 (100
mL). The mixture was reacted at rt for 18h and filtered through celite. The residue
was purified by chromatography on Si02 with 20 to 30% EtOAc:Hx to yield 8-
(tetrahydro-pyran-2-yloxymethyl)-3,4-dihydro-2H-naphthalen-l-one (Intermediate
H4) (-55%).

The THP-protected ketone (Intermediate H4) was dissolved in EtOH (15 mL)
and reacted with imidazole carboxaldehyde (Formula 8,0.50 g, 5.1 mmol) and 2N
NaOH (2 mL) at reflux for 36h. The mixture was cooled to rt and subjected to a
standard aqueous work-up. The crude residue was hydrogenated in a mixture of EtOH
(150 mL) and Pd (160 mg, 10% on C) under 40 psi of H2. After 18h at rt the THP
protected compound was isolated (12%). The THP group was removed in a mixture
of acetic acid (4 mL), THF (2 mL) and H20 (lmL) at 80 °C over 4h. The mixture
was made slightly basic and extracted with EtOAc. The organic layer was dried over
MgSO/j, filtered and concentrated. The synthesis of the 8-hydroxymethyl-2-(2-thioxo-
2,3-dihydro- lH-mudazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-l-one (Compound
33) was completed by subjecting the imidazole compound Intermediate H4 to the
applicable process steps described in Method A in connection with Example A.
Compound 33:
'H NMR (300 MHz, CD3OD-d4) 5 7.59-7.47 (m, 2H), 7.23 (d, /= 7.5 Hz, 1H), 6.61
(s, 1H), 4.98-4.88 (m, 2H), 3.13-3.04 (m, 2H), 2.87-2.79 (m, 1H), 2.64 (dd, J= 4.5,
7.2 Hz, 1H), 2.20-2.11 (m, 1H), 1.85-1.71 (m, 1H).

8-(Tetrahydro-pyran-2-yloxymethyl)-3,4-dihydro-2H-naphthalen-l-one
(Intermediate H4) (obtained in Method H, 550 mg, 2.11 mmol) was hydrogenated
with H2 (balloon) and 10% Pd/C (190 mg) at rt for 18h. The mixture was filtered
through celite and the crude product was isolated by evaporation of the solvent under

reduced pressure. 8-Methyl-3,4-dihydro-2H-naphthalen-l-one (Intermediate 12) was
subjected to the applicable process steps of Method E to produce (Compound 34).
JH NMR (300 MHz, CD3OD-d4) 5 7.32 (t, J= 7.7 Hz, 1H), 7.13-7.08 (m, 2H), 6.60
(s, 1H), 3.05-3.00 (m, 3H), 3.82-2.58 (m, 2H), 2.57 (s, 3H), 2.16-2.09 (m, 1H), 1.82-
1.73 (m,lH).

5,6,7,8-Tetrahydro-naphthalen-l-ylamine (Intermediate Jl, commercially
available from Aldrich) (5 mL, 35.3 mmol) was dissolved in CH2C12 (40 mL) and
treated with NEt3 (10 mL) and acetyl chloride (3.8 mL, 53 mmol) at rt for Ih. The
mixture was diluted in CHCI3 and acidified with sat NH4CI. The aqueous layer was
extracted with CHQ3. The organic fractions were combined, dried and evaporated
and the amide was used without further purification. The resulting amide ( 35.3
mmol) in acetone (450 mL) and aqueous MgSO4 (5 g in 28 mL) at 0 °C was treated
with KMn04 (16.8 g, 105 mmol). The mixture was allowed to stir at 0 °C for 2h. The
mixture was diluted with H20 and extracted several times with CHC13. The pooled
fractions were washed with brine and dried over MgSO4, filtered and evaporated to
dryness. The residue was purified by chromatography on Si02 to give N-(8-oxo-

5,6,7,8-tetrahydro-naphthalen-l-yl)-acetamide (Intermediate J2) as a yellow oil.
(57%, in two 2 steps)
The amide (Intermediate J2,4.12 g, 20.3 mmol) was heated at 90 °C in 6N
HC1 (140 mL) for 3h. The mixture was cooled to rt and Na2GC>3 was added in small
portions followed by addition of 2N NaOH until the mixture was at pH 8. The
aqueous layer was extracted with EtOAc and the organic fractions were combined,
washed with brine, dried, filtered and concentrated to give 8-amino-3,4-dihydro-2H-
naphthalen-1-one (Intermediated) as a dark red solid 1.82 g (56%).
The amine (Intermediate J3,1.83 g, 11.3 mmol) in CH2C12 (17 mL) was
added to BF3«OEt2 (2.80 mL, 22.1 mmol) at -15 °C. More CH2C12 (20 mL) was
added to the precipitate. Next, t-butyl nitrite (1.8 mL, 12.9 mmol) in CH2C12 (20 mL)
was added at -15 °C and stirred for 10 min. and at 0 °C for 20 m. The mixture was
diluted with pentane (40 mL), filtered and the solids were collected, washed with
ether, and dried under vacuum. The solids were placed in a flask and heated to 115
°C for 10-15 min. followed by addition of 2N NaOH and CHC13. The suspension was
filtered and the aqueous phase was extracted with CHCI3. The organic layers were
combined, dried over MgSO^ filtered and purified by chromatography on Si02 with
15 % EtOAc:Hx. The product, 8-fluoro-3,4-dihydro-2H-naphthalen-l-one
(Intermediate J4) was isolated; 750 mg (40%).
8-Fluoro-3,4-dihydro-2H-naphthalen-l-one (Intermediate J4) was subjected
to the applicable process steps of method E to produce (Compound 35).
rH NMR (300 MHz, CD3OD-d4) 5 7.53-7.46 (m, 1H), 7.12 (d, /= 7.4 Hz, 1H), 7.02
(dd, 7= 8.2,3.5 Hz, 1H), 6.61 (s, 1H), 3.12-3.04 (m, 3H), 2.88-2.78 (m, 1H), 2.62 (dd,
/= 8.2, 7.1 Hz, 1H), 2.20-2.11 (m, 1H), 1.86-1.75 (m, 1H).
Example J-l (Compound 111)
Use of 6-amino-3,4-dihydro-2H-naphthalen-l-one (commercially available
from Aldrich) in the applicable process steps in Method J produced 6-fluoro-2-(2-
mioxo-2,3-d&ydro-lH-irmdazol-4-ylmemyl)-3,4-dmydro-2H-naphthalen-l-one
(Compound 111).

JH NMR (300 MHz, MeOH-d4) 8 8.05-8.00 (m, 1H), 7.08-7.00 (m, 2H), 6.61 (s, 1H),
3.16-3.10 (m, 1H), 3.07-2.98 (m, 2H), 2.86-2.76 (m, 1H), 2.64 (dd, /- 8.1, 7.8 Hz,
1H), 2.20-2.13 (m, 1H), 1.87-1.73 (m, 1H).

8-(2-Benzyloxy-emyl)-l,4-dioxa-spiro[4.5]decane (Intermediate Kl, 1.02 g,
3.70 mmol) (prepared in accordance with the publication Ciufolini et. al. J. Amer.
Chem. Soc 1991,113,8016, incorporated herein by reference) was dissolved in
acetone (100 mL) : H20 (5 mL) and reacted with TsOH (140 mg, 0.74 mmol) at 45 °C
for 5h. After a standard aqueous work-up the material was purified by
chromatography on S1O2 to give 4-(2-beri2yloxy-etb.yl)-cyclohexanone as a colorless
oil (97%).
A solution of LDA (33 ml, 1.5 M in Et20) in THF (50 mL) at -78 °C was
treated with 4-(2-benzyloxy-ethyl)-cyclohexanone (9.5 g, 40.2 mmol). The mixture
was warmed to 0 °C over 30 min. before re-cooling to -78 °C and adding HMPA (7
mL). Methyl cyanoformate (CNC02Me, 4.1 mL, 85 mmol) was added and the
mixture was stirred for 15 m before aqueous quench and work-up. The product was

purified by chromatography on Si02 with 10 % EtOAc:Hx. 5-(2-Benzyloxy-ethyl)-2-
oxo-) cyclohexanecarboxylic acid methyl ester was isolated, 5,8 g (49%).
A mixture of 5-(2-ben2yloxy-ethyl)-2-oxo-cyclohexanecarboxylic acid methyl
ester in anhydrous MeOH (10 mL) was reacted with NaOMe solution (16.6 mL, 8.28
mmol) at rt for 15 min. Iodoethane (2.76 mL, 34.5 mmol) was added via syringe and
the mixture was stored at rt for 48 h. Another portion of NaOMe (8.3 mmol) and EtI
(35 mmol) was added and the mixture was allowed to react until the starting material
was not present (by TLC). The solution was quenched with an aqueous work-up and
the resultant residue was purified by chromatography to yield 5-(2-benzyloxy-ethyl)-
l-ethyl-2-dxo-cyclohexanecarboxylic acid methyl ester (Intermediate K2,1.87 g
(86%). The keto-ester (Intermediate K2) was heated at 90 °C in 10% KOH (100
mL) for lOh, then 6h at rt. The mixture was cooled to 0 °C and acidified with HC1.
The solution was wanned to 40 °C for 15 min. and then stored at rt for 2h. The
mixture was neutralized to pH 7 with NaOH and the organic material was recovered
by extraction with chloroform. The resulting 4-(2-ben:zyloxy-ethyl)-2-ethyl-
cyclohexanone (Intermediate K3) was isolated by standard work-up and used
without further purification (88%). Intermediate K3 (1.36 g, 5.24 mmol) was
dissolved in THF (75 mL) and treated with MeMgBr (2.62 mL, 7.9 mmol) at 0 °C and
reacted at rt for lh. The organic material was isolated from an aqueous, acidic work-
up and purified by chromatography to give 4-(2-benzyloxy-ethyl)-2-ethyl-l-methyl-
cyclohexanol 1.36 g (94%). 4-(2-ben2yloxy-emyl)-2-ethyl-l-methyl-cyclohexanol
(1.39 g, 5.04 mmol) and TsOH-H20 (0.48 g, 2.52 mmol) were heated to reflux in
benzene (~100 mL) for 18h in the presence of MgSC>4 (~250 mg). After an aqueous
work-up and chromatographic purification, the product [2-(3-etibyl-4-methyl-
cyclohex-3-enyl)-emoxymethyl]-benzene (Intermediate K4) was isolated as a pale
yellow oil 0.912 g (71%).
The benzyl protected alcohol (Intermediate K4,5 mmol) in THF (20 mL) was
cooled to -70 °C and NH3 was condensed in the same flask (-20 mL). Na chunks
were added and the mixture was allowed to stir at -70 "C for 15 min. The mixture
was warmed to -30 CC for 20 min. The mixture was quenched with NH4CI and

isolated by extraction. The residue was purified by chromatography on Si02 with 25
%EtOAc:Hx(99%).
The deprotected alcohol was oxidized by the standard "Swern" procedure
(Maricuso, Synthesis 1981 pl65, incorporated herein by reference) as follows: The
alcohol (5 mmol) was added to a solution of oxalyl chloride (3.5 mL, 7.0 mmol) in
CH2C12 (30 mL) with DMSO (0.64 mL, 9.0 mmol) at -78 °C. After 40 rnin., NEt3
(2.50 mL) was added and the mixture was warmed to it After standard aqueous
work-up and purification, (3-ethyl-4-memyl-cyclohex-3-enyl)-acetaldehyde
(Intermediate K5) was isolated (-90%).
The (Intermediate K5) was converted to 4-(3-erayl-4-methyl-cyclohex-3-
enylmethyl)-1,3-dihydro-irnidazole-2-thione (Compound 36) by applying the
applicable process steps of Method A.
JH NMR (300 MHz, CD3OD) 5 6.54 (s, 1H), 2.40 (d, J= 7.0 Hz, 2H), 2.02-1.95 (m,
4H), 1.83-1.67 (m, 4H), 1.59 (s, 3H), 1.25-1.15 (m, 1H).

Imidazole (Intermediate LI, available from Aldrich, 20.0 g, 0.29 moi),
triethylamine (41.0 mL, 0.29 mol) andiV.JV-dimethylsulfamoyl chloride (31.6 mL,
0.29 mol) were added to benzene (320 mL). The reaction was stirred for 48h at rt and
then filtered. The filtrate was collected and concentrated under reduced pressure.
Vacuum distillation of the crude produc (-0.5 rnmHg, 115-118 °C) afforded
dimethylsulfamoyl) imidazole (Intermediate L2) 38.7 g (76%) as a clear and
colorless oil. Upon cooling the product solidifies to give white crystals . 1-
(Dimethylsulfamoyl) imidazole (Intermediate L2) (18.8 g, 0.11 mol) was added to

THF (430 mL). The solution was cooled to -78 °C. A solution of n-BuLi (70.9 mL,
1.6 M in hexane) was added dropwise to the reaction mixture. Upon completion, the
solution was stirred for lh at -78 °C. f-Butyldimethylsilylchloride (TBSC1) (17.8 g,
0.12 mol) in THF (50 mL) was added via cannula to the mixture. After the addition
was completed the reaction mixture was wanned slowly to it and stirred for 24h. The
mixture was diluted with water and the organic layer separated The organic phase
was washed with brine and then dried over NajSCU. The mixture was filtered and the
filtrate concentrated under reduced pressure. Column chromatography on SiC>2 with
20% ethyl acetate/ hexane afforded l-dimethylsulfamoyl-2-f-butyldimethylsilyl
imidazole (Formula 13) as a light yellow solid. Recrystallization from pentane gave
30 g (94%) of white crystals.


2,3-Dimethyl-l,3-butadiene (available from Aldrich, 10.2 g, 123.7 mmol),
ethyl aciylate (11.1 g, 110.5 mmol) and hydroquinone (0.12 g, 1.11 mmol) were
heated with stirring at 165 °C in a sealed tube for 16h and men at 205 °C for an
additional 4h. Kugelrohr distillation of the resulting residue at 150 °C and 0.5 torr
gave 14.1 g (70%) of cyclohexene ester (Intermediate Ml) as an oil. To a solution of
the ester (Intermediate Ml, 13.6 g, 72.3 mmol) in THF (200 mL) at -78 °C was
added a LiAlH4 (54.3 mL, 1M in diethyl ether). This mixture was stirred for In at 20
°C and then quenched at 0 °C by careful, addition of H20 (2 mL), NaOH (2 mL of a
15% aqueous solution), and an additional portion of H2O (6 mL). The solids were
filtered off and the filtrate was concentrated under reduced pressure. Kugelrohr
distillation of the resulting residue at 150-180 °C and 0.5 torr gave 10.0 g (98%) of
the alcohol (Intermediate M2) as a colorless volatile oil in the 0 °C bulb. To a
solution of triphenyl phosphine (27.1 g, 103.5 mmol), and imidazole (7.04 g, 103.5
mmol) in anhydrous benzene (450 ml) under argon was added I2 (22.8 g, 89.6 mmol)
in benzene (170 ml) over a period of 10 minutes with rapid mechanical stirring. After
an additional 10 rnin. the alcohol (Intermediate M2, 9.23 g, 65.9 mmol) in benzene
(100 ml) was added to this rapidly stirring mixture over a period of 5 rnin. After 2h
the reaction was diluted with hexanes (800 ml) and the solids were filtered off. The
organics were washed with 3 portions of H20 (800 ml), dried (MgSO^, filtered and
concentrated under reduced pressure. The residual solids were filtered off and the
resulting oil was purified by kugelrohr distillation at 200 °C and 0.5 torr to give 12.0 g
(73%) of the iodide (Intermediate M3) as a pale oil in the 0 °C bulb. To a solution
of 1- N-(dimethylsulfamoyl)-2-tert-butyldimethylsilyl imidazole (Formula 13,4.34 g,
15.0 mmol) in anhydrous THF (50 ml) at -78 °C under argon was added n-BuLi (5.76
mL 2.5 M in hexanes). This mixture was stirred for 10 rnin. at -10 °C and then cooled
to -20 "C before adding the iodide (Intermediate M3, 3.00 g, 12:00 mmol) in THF
(25 ml) dropwise via cannula. The resulting solution was stirred for 16 h at 20 °C,
then quenched with saturated aqueous NaHC03 and concentrated under reduced
pressure. The residues were taken up in diethyl ether and washed consecutively with
H20 and brine, dried (MgSO4) and concentrated. Subsequent purification by

chromatography on Si02 with 5-10% EtOAc:hexanes gave 0.89 g (15%) of the
imidazole derivative (Intermediate M4) as a pale oil. To a solution of Intermediate
M4 (0.89 g, 2.17 mmol) in anhydrous THF (25 ml) under argon was added
tetrabutylammonium fluoride (2.38 ml, 1 M in THF) and the resultant solution was
stirred for lh at 20 °C. The mixture was concentrated under reduced pressure and the
residues were diluted with diethyl ether and washed consecutively with saturated
aqueous NaHCC>3 and brine, dried (MgSO4) and concentrated. The residues were
purified by chromatography on Si02 wim 50% EtOAc.Hx to give 0.56 g (87%) of the
imidazole derivative Intermediate M5 as a pale oil. To a solution of Intermediate
M5 (0.53 g, 1.77 mmol) in MeOH (5 ml) was added aqueous KOH (15 ml of a 5M
solution) and the mixture was heated at reflux for 32h. The mixture was concentrated
under reduced pressure, diluted with H20 (5 ml) and extracted exhaustively with
CHCI3. The combined organic fractions were washed consecutively with H2O and
brine, dried (MgSO4) and concentrated under reduced pressure. The product was
recrystallized by stirring in MeOH with an equimolar amount of fumaric acid until all
solids had disappeared followed by the addition of a small amount of diethyl ether. 4-
(3,4-Dimemyl-cyclohex-3-enylmemyl>lH-imidazole-fumarate 0.27 g (57%) was
recovered as pale yellow crystals. 4-(3,4-Dimethyl-cyclohex-3-enylmethyl)-lH-
imidazole-fumarate was converted to 4-(3,4-dimethyl-cyclohex-3-enylmethyl)-l,3-
dihydro-imidazole-2-thione (Compound 37) by using the applicable process steps of
Method A.
!H NMR (300 MHz, CD3OD-d4): 8 6.54 (s, 1H), 2.40 (d, J= 6 Hz, 2H), 1.95-1.66
(m, 5H), 1.59 (s, 6H), 1.29-1.18 (m, 2H).
Example N (Compound 38)
Method N: Procedure for the preparation of 4-(4-methvl-cvclohex-3-envlmethvlVL3-
dihvdro-imidazole-2-thione (Compound 38)



To a sluny of NaH (60% in oil) (6.92 g, 288 mmol) in anhydrous THF (1500
mL) at 0 °C under argon with vigorous mechanical stirring added the trimethyl
phosphonoacetate (available from Aldrich, 52.5 g, 288 mrnoL) dropwise. Stirred this
mixture an additional 30 min. before adding the 1,4-cyclohexanedione mono-ethylene
ketal (available from Aldrich, 41 g, 260 mmol) in THF (170 mL) dropwise. The
mixture was stirred an additional 18h at 20 °C and then concentrated under reduced.
pressure. This residue was taken up in diethyl ether (1 L) and washed with H2O and
brine, dried (MgSO^, filtered and concentrated to give 60 g (98%) of the unsaturated
ester (Intermediate Nl) which was used in the next reacrion step without further
purification. To a solution of the unsaturated ester (Intermediate Nl) in EtOAc (500
mL) was added Pd (10 wt % on activated carbon) (2.13g). This slurry was saturated
with H2 by repeated evacuations and H2 backfills and then stirred for 16h under a
balloon atmosphere of H2. Celite (5 g) was added to the reaction, me Pd was filtered
off and the filtrate was concentrated under reduced pressure to give 60 g (98%) of the
saturated ester (Intermediate N2) which was used in the next step without further
purification.
To a solution of LiAlH4 (200 mL, 1 M in diethyl ether) at -78 °C under argon
was added the unsaturated ester (Intermediate N2) in anhydrous THF (400 ml) in a
slow stream with vigorous mechanical stirring. The mixture was warmed to rt and
additional THF (600 mL) was added. The reaction mixture was stirred for an
additional lh. The mixture was cooled to 0 °C and quenched by the careful,
consecutive addition of H20 (7.60 ml), NaOH (7.60 ml of a 15% aqueous solution),
and an additional portion of H20 (22.80 ml). The solids were filtered off and the
filtrate was concentrated under reduced pressure. Subsequent purification by
chromatography on Si02 with 20-50% EtOAc:hexanes gave 51 g (98%) of the alcohol
(Intermediate N3) as a pale oil. To a solution of oxalyl chloride (20.65 ml, 41.29
mmol) in anhydrous CH2C12 (100 ml) at -78 °C under argon was added dropwise a
solution of DMSO (6.72 g, 86.0 mmol) in CH2C12 (25 ml). After mechanical stirring
for 15 min. a solution of the alcohol (Intermediate N3, 6.40 g, 34.4 mmol) in CH2C12
(80 ml) was added dropwise and the mixture was stirred an additional 15 min. at -78

°C before adding triethylamine (27.9 g, 275 mmol). The reaction was stirred 2h at 20
°C and then quenched with saturated aqueous NaHC03. This mixture was extracted
CH2CI2 and the combined organic fractions were washed consecutively with H20 and
brine, dried (MgSO4) and concentrated under reduced pressure. The resulting solids
were purified by chromatography on Si02 with 20-30% EtOAc:hexanes to give 5.08
g, (79%) of the aldehyde (Intermediate N4) as a white solid. A solution of the
aldehyde (Intermediate N4,5.08 g, 27.59 mmol) in EtOH (40 ml) was treated with
tosylmethyl isocyanide (TosMIC) (5.15 g, 26.3 mmol) and NaCN (0.13 g, 2.68 mmol)
at 20 °C for 3h and then refrigerated. After 2h of refrigeration the solids were filtered
off, dissolved in anhydrous MeOH, saturated with NH3 (30 ml) and heated in a sealed
tube at 100 °C for 3.5h. The reaction was then concentrated under reduced pressure
and the residues were taken up in CHC13, washed consecutively with saturated
aqueous NaHC03 and brine, dried (MgSO4) and concentrated to a red oil. This residue
was further purified by chromatography on Si02 with 5-10% MeOH (saturated with
NH3): CH2C12 to give 1.87 g (31%) of the imidazole derivative (Intermediate N5) as
a pink oil. A solution of Intermediate N5 (0.55 g, 2.48 mmol) in acetone (20 ml)
containing HC1 (5 N, 0.5 ml) was stirred for 5h. The reaction was concentrated under
reduced pressure, the residues were taken up in H2O, neutralized to pH 7 with
saturated aqueous NaHC03 and extracted exhaustively with CHClj/isopropyl alcohol
(3:1). The combined organic portions were washed consecutively wim H20 and brine,
dried (MgSO4) and concentrated. Chromatography on Si02 with 5-10% MeOH
(saturated with NH3): CH2C12 gave 0.43 g (97%) of the desired ketone (Intermediate
N6).
A solution of Intermediate N6 (0.20 g, 1.11 mmol) in anhydrous DMF (4 ml)
under argon was treated with trietiiylamine (0.14 g, 1.33 mmol) and
dimethylsulfamoyl chloride (0.19 g, 1.33 mmol) under argon and stirred 16h. The
solids were filtered off and the filtrate was concentrated at via kugelrohr at 100 °C
and 0.5 torr. The residues were taken up in CHCI3 and washed consecutively with
H20 and brine, dried (MgSO4) and concentrated. Chromatography on Si02 with 1-5%
MeOH:CH2Cl2 gave 0.22 g (69%) of the desired imidazole derivative (Intermediate

NT) as a mixture of regioisomers which were used in the next step without separation.
A solution of Intermediate N7 (0.18 g, 0.62 mmol) in anhydrous THF (10 ml) under
argon was treated with methylmagnesium chloride (0.32 ml, 3.0 M in THF) and the
resulting mixture was stirred 16h. The reaction was quenched with a small amount of
MeOH, concentrated under reduced pressure and the residues were taken up in H2O.
The mixture was acidified hy the dropwise addition of 1 N HCI until the solution was
homogenous and men the pH was adjusted to 7 with saturated aqueous NaHC03. The
organic materials were extracted into CHC13 and the combined organic portions were
washed consecutively with H2O and brine, dried (MgSO4) and concentrated.
Chromatography on Si02 with 5% MeOH:CH2Cl2 gave 0.18 g (95%) of the
cyclohexyl alcohol derivative (Intermediate N8) as a mixture of regioisomers which
were carried on without separation. A solution of Intermediate N8 (0.14 g, 0.46
mmol) in anhydrous benzene (3 ml) at 0 °C under argon was treated with
(methoxycarbonylsulfamoyl) triethylammonium hydroxide, inner salt (Burgess
reagent) (0.12 g, 0.51 mmol) and stirred lh at 20 °C. The reaction was concentrated
under reduced pressure and subsequent purification by chromatography on SiC>2 with
5% MeOH:CH2Cl2 gave 0.12 g (92%) of the alkenes Intermediates N9 and N10 as a
mixture of isomers which were used in the next step without separation. The mixture
of isomers Intermediate N9 and N10 (0.12 g, 0.42 mmol) were refluxed in a solution
composed of MeOH (2 ml) and KOH (2 ml of a 5 N solution) for 30h. The reaction
was concentrated under reduced pressure and the residues were taken up in H20 and
extracted exhaustively with CHC13. The combined organic portions were washed
consecutively with H20 and brine, dried (MgSO4) and concentrated. Chromatography
on Si02 with 5-10% MeOH (saturated with NH3): CH2C12 gave 0.05 g (67%) of
alkenes Intermediates Nil and N12 as a mixture of isomers which were used in the
next step without separation.
The mixture of alkenes Intermediates Nil and N12 (45 mg, 0.26 mmol) and
/7-toluenesulfonic acid hydrate (63 g, 0.32 mmol) were heated at reflux in 1,2-
dichloroethane (2 ml) under argon for 20h. The reaction was concentrated under
reduced pressure and the residues were purified by chromatography on Si02 with 10%

MeOH (saturated with NHj): CH2CI2 to give the free base of imidazole derivative
(Intermediate N13 as one isomer. The imidazole (Intermediate N13) was
recrystallized by stirring in MeOH or THF with an equimolar amount of fumaric acid
until all solids had disappeared followed by the addition of a small amount of diethyl
ether and cold storage. The irnidazole-fumaric acid salt was recovered as white
crystals 40 mg (54%). This material was subjected to the applicable process steps of
Method A to obtain 4-(4-memyl-cyclohex-3-enylmethyl)-l^^mydro-imidazole-2-
thione (Compound 38):
'H NMR (300 MHz, CD3OD-d4): 5 6.54 (s, 1H), 5.34 (s, 1H), 2.39 (d, J= 6.4 Hz,
2H), 2.10-1.90 (m, 3H), 1.80-1.72 (m, 2H), 1.62 (s, 3H), 1.30-1.20 (m, 1H).
Example N-l (Compound 39)
4-(4-Efliyl-cyclohex-3-enyhnemyl)-l,3-dmydro-imidazole-2-uiione
(Compound 39) was prepared by using ethyl magnesium chloride instead of methyl
magnesium chloride in the applicable step of Method N.
*H NMR (300 MHz, CD3OD-d4): 5 6.54 (s, 1H), 5.34 (brs,lH), 2.41 (d, J= 6.4 Hz,
2H), 2.02-1.92 (m, 5H), 1.78-1.72 (m, 3H), 1.31-1.20 (m, 1H), 0.98 (t, /= 7.5 Hz,
3H).
Example O (Compound 40)
Procedure for the preparation of 4-(4-emvnvl-cyclohex-3-envlmethvlV1.3-dihvdto-
imidazole-2-thione (Compound 40)


The alcohol (Intermediate Ol, obtainable in accordance with the publication
Ciufolini et. al J. Amer. Chem. Soc. 1991,113,8016 ) (1.83 g, 12.88 mmol),
chlorotriethylsilane (TESC1,2.14 g, 14.17 mmol), and Et3N (1.43 g, 14.17 mmol)
were stirred in THF (anhydrous, 50 ml) for 16h at 20 °C. The resultant solution was
taken up in Et20 and washed consecutively with 5% aqueous NH4CI, saturated
aqueous NaHCC>3, H2O, brine, dried (MgSO^, filtered and concentrated under
reduced pressure. Subsequent purification by chromatography on SiC>2 with 5-10%
EtOAc:hexanes gave 3.26 g (99%) of the triethylsilyl protected keto alcohol
(Intermediate 02) as a pale oil.
To a solution of the keto alcohol (Intermediate 02,3.38 g, 13.22 mmol) in
THF (anhydrous, 50 ml) at 0°C under argon was added ethynyl magnesiun chloride
(44.1 ml of a 0.5 M solution in THF). This mixture was allowed to stir at 20 °C for 6h
and was then recooled to 0 °C and quenched with H20. The resultant solution was
taken up in EtOAc and washed consecutively with saturated aqueous NH4CI, saturated
aqueous NaHC03, H20, brine, dried (MgSO4), filtered and concentrated under

reduced pressure. Subsequent purification by chromatography on Si02 with 10-15%
BtOAc:hexanes gave 2.99 g (80%) of the alcohol (Intermediate 03) as a pale oil.
To a solution of Intermediate 03 (2.94 g, 10.44 mmol) in THF (anhydrous,
50 ml) at 0°C under argon was added l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (7:63
gj 50.12 mmol) and MeSO2Cl (3.71 g, 32.36 mmol). This mixture was allowed to stir
at 20°C for 20h and was then recooled to 0°C and quenched with MeOH. The mixture
Was concentrated under reduced pressure and the residues were taken up in Et20 and
washed consecutively with saturated aqueous NH4CI, saturated aqueous NaHC03 and
bjine, dried (MgSO,*) and concentrated under reduced pressure. The residues were
purified by chromatography on Si02 with 2% EtOAc:hexanes to give 0.88 g of the
eidyne (Intermediate 04) which was used in the next step without further
purification.
The enyne (Intermediate 04,0.88 g, 3.34 mmol) was stirred in a solution of
THF/AcOH/H20 (4 ml in a ratio of 8:8:1) at 20 °C for 3h. The mixture was
concentrated under reduced pressure and the residues were taken up in Et20 and
washed consecutively with saturated aqueous K2C03, H20 and brine, dried (MgSGt)
and concentrated under reduced pressure. The residues were purified by
chromatography on Si02 with 30% EtOAc:hexanes to give 0.50 g of the alcohol
(Intermediate 05) which was used in the next step without further purification.
To a solution of oxalyl chloride (2 ml of a 2.0 M solution in CH2C12) in CH2C12
(auhydrous, 10 ml) at -78 °C under argon added DMSO (0.65 g, 8.33 mmol) in
CH2C12 (anhydrous, 5 ml) dropwise via cannula The reaction was stirred for 15 rnin.
after addition was complete and then the alcohol (Intermediate 05, 0.50 g, 3.33
mmol) was added in CH2C12 (anhydrous, 10 ml) dropwise via cannula and stirred for
an additional 15 minutes before adding neat Et3N (2.70 g, 26.66 mmol). The reaction
was allowed to warm to 20 °C and stirred 2h and then quenched with saturated
aqueous NaHC03. This mixture was extracted with CH2C12. and the combined organic
frjactions were washed with H20 and brine, dried (MgSO4) and concentrated under
reduced pressure. The residues were purified by chromatography on Si02 with 15%
EtOAcitexanes to give 0.32 g (65%) of the aldehyde (Intermediate O6).

A solution of the aldehyde Intermediate 06 (0.38 g, 2.54 mmol) in EtOH
(^hydrous, 1.5 ml) was treated with tosylmethyl isocyanide (TosMIQ (0.52 g, 2.67
n|mol) and NaCN (0.013 g, 0.25 mmol) at 20°C for 2h. This mixture was concentrated
u^ider reduced pressure and the resulting residue was taken up in MeOH saturated
With NH3 (anhydrous, 10 ml) and heated in a sealed tube at 100°C for 3.5h. The
reaction was then concentrated under reduced pressure and purified by
chromatography on Si02 with 10% MeOH:CH2Cl2 to give 0.16 g (35%) of the
iihidazole derivative (Intermediate 07) as an amber oil.
4-(4-Ethynyl-cyclohex-3-enylmethyl)-1,3-dmydro-imidazole-2-thione
(Compound 40) was prepared by subjecting the imidazole derivative Intermediate
7!to the applicable process steps of Method A.
*& NMR (300 MHz, CD3OD-d4): 5 6.57 (s, 1H), 6.08 (brs, 1H), 3.10 (s, 1H), 2.43 (d,
J^= 6.4 Hz, 2H), 2.18-2.14 (m, 3H), 1.85-1.75 (m, 3H), 1.30-1.25 (m, 1H).

A solution of 2-bromo-cyclopent-2-enol (Intermediate D3) (21.7 g, 133.1
mjmol) in ethyl vinyl ether (300 mL) was treated with Hg(OAc)2 (31.8 g, 99 mmol) at
rt jfor 60 h. The mixture was quenched with 5% NaOH (150 mL) and filtered through
cejlite. The residue was concentrated to yield l-bromo-5-vinyloxy-cyclopentene as a
pale yellow oil, 14.2 g (46%). l-Bromo-5-vinyloxy-cyclopentene (14.1 g, 74.4 mmol)

in1 toluene was heated in a re-sealable tube at 130 °C for 24 h. (2-Bromo-cyclopent-2-
e^yfj-acetaldehyde (Intermediate ONE1) was isolated after flash chromatography on
silica gel with hexanes to 5% ethyl acetate:hexanes, 10.4 g (74%).
(2-Bromo-cyclbpent-2-enyl)-acetaldehyde (Intermediate ONE1) (1.85 g, 9.32
mrnol) in benzene (70 mL) was treated with Na2C03 (14.0 mL, 2M in H2O.) and
pjienylboronic acid (2.27 g, 18.6 mmol) in EtOH (40 mL).
T)5trakis(triphenylphosphine) palladium(0), Pd(PPh3)4 catalyst (1.61 g, 1.40 mmol)
1
wtas added and the mixture was heated to 80 °C for 3.5 h. until no starting material
regained. The benzene was replaced with diethyl ether and the mixture was filtered
titjrough celite. The filtrate was washed with sat. K2CO3, brine and dried over MgSO^
Pure (2-phenyl-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE2) 1.07 g (62%)
was isolated by chromatography on silica gel. Use of (2-phenyl-cyclopent-2-enyl)-
a^etaldehyde (Intermediate ONE2) in Method A (without formation of the fumarate)
produced 4-[(2-phenylcyclopent-2-en-1 -yl)methyl]-l ,3-dmydro-2^-imidazole-2-
titjione (Compound 112).
JH NMR (300 MHz, CDC13) 8 11.5 (s, 1H), 11.3 (s, 1H), 7.39 -7.16 (m, 5H),
6|32 (s, 1H), 6.07 (s, 1H), 3.46 (brs, 1H), 2.78 (dd, J= 15.1, 3.4 Hz, 1H), 2.43-2.28
(1^ 3H), 2.10 (dd, /= 13.2,8.2 Hz, 1H) 1.82-1.67 (m, 1H).
Example ONE-1 (Compound 113)
Use of 4-methylphenylboronic acid (commercially available from Aldrich) in
Method ONE produced 4-[2-(4-methylphenyl)cyclopent-2-en-l-yl]methyl-l,3-
djhydro-2#-imidazole-2-thione (Compound 113).
1H NMR (300 MHz, CDC13) 8 11.6 (s, 1H), 11.5 (s, 1H), 7.33-7.12 (m, 4H), 6.32 (s,
JH), 6.02 (s, 1H), 3.50-3.40 (m, 1H), 2.80-2.74 (m, 1H), 2.38 (brs, 3H), 2.29 (s, 3H),
2.11-2.00 (m, 1H), 1.74-1.70 (m, 1H).
Example ONE-2 (Compound 114)
Use of 4-methoxyphenylboronic acid (commercially available from Aldrich) in
tyethod ONE produced 4-[2-(4-methoxyphenyl)cyclopent-2-en-l-yl]methyl-l,3-
djhydro-2#-irmdazole-2-thione (Compound 114).

% NMR (300 MHz, CDC13) 5 11.8 (s, H), 11.6 (s, 1H), 7.36 (d, J= 9 Hz, 2H), 6.85
(4 J= 9 Hz, 2H), 6.33 (s, 1H), 5.95 (s, 1H), 3.75 (s, 3H), 3.41 (brs, 1H), 2.82-2.78 (m,
Itf), 2.36 (s, 1H), 2.35-2.30 (m, 2H), 2.11-2.00 (m, 1H), 1.78-1.70 (m, 1H).
Example ONE-3 (Compound 115)
Use of 4-cyanophenylboronic acid (commercially available from Aldrich) in
Mjethod ONE produced 4-[5-(2-mioxo-2y3-dihydro-lH-imidazol-4-ylmethyl>
cjjclopent-l-enyl]-benzonitrile (Compound 115).
'ti NMR (300 MHz, DMSO-d6) 8 12.0 (s, 1H), 11.7 (s, 1H), 7.81-7.75 (m, 4H), 6.55
(sj 1H), 6.50 (s, 1H), 3.41 (brs, 2H), 2.51-2.42 (m, 2H), 2.16-1.95 (m, 2H), 1.76-1.74
(nMH).
Example ONE-4 (Compound 116)
Use of 3-nitrophenylboronic acid (commercially available from Aldrich) in
Mjethod ONE produced 4-[2-(3-nitrophenyl)cyclopent-2-en-l-yl]methyl-l,3-dihydro-
2#-imidazole-2-thione (Compound 116).
% NMR (300 MHz, CDC13) 5 12.1 (s, 1H), 11.5 (s, 1H), 820 (s, 1H), 7.96 (d,/= 12
Hi, 1H), 7.73 (d, J= 9 Hz, 1H), 7.47 (t, J= 6 Hz, 1H), 6.41 (s, 1H), 6.22 (s, 1H), 3.50
(bjrs, 1H), 2.76-2.70 (m, 1H), 2.45-2.30 (m, 3H), 2.13-2.00 (m, 1H), 1.82-1.76 (m,
1H).
Example TWO
Mjethod TWO: procedure for the preparation of (+~)-4-r(S*V2-(3-fluorophenvlV 2-
cvclopent-2-envlmemvl-13-dmvdro-imidazole-2-thione (Compound 117)


Use of (/?)-2-methyl-oxazaborolidine catalyst (20 mol%) (commercially
available from Aldrich) with BH3«SMe2 in the reduction of Intermediate D2 (see:
Cbrey, E. J.; Chen C.-P.; Reichard, G. A. Tetrahedron Lett. 1989,30, 6275 and
X^vier, L. C. et al; Organic Syntheses 1996, 74, 50 incorporated herein by reference)
pijoduced (-)-(iS)-2-bromo-cyclopent-2-enol (Intermediate TWOl). Use of optically
enriched (-)-(5)-2-bromo-cyclopent-2-enol (Intermediate TWOl) and substituting 3-
flfcorophenylboronic acid (commercially available from Aldrich) in Method TWO
piloduced(+)^-[(S*)-2-(3-fluorophenyl)-cyclopent-2-enylmethyl]-l,3-dihydro-
in|iidazole-2-tbione (Compound 117).
o^t rotation [a]D20 + 116.3° (c 2.45 in CHC13)
lU NMR same as Compound 129 (see below)
Example TWO-1 (Compound 118)
Use of (i?)-2-methyl-oxazaborolidine catalyst with BH3»SMe2 for the reduction
st^p and substituting 4-fluorophenylboronic acid (commercially available from
Aldrich) in Method TWO produced (+)-4-[(S*)-2-(4-fluorophenyl)-cyclopent-2-
e^ylmemyl]-l,3-dmydro-imidazole-2-fliione (Compound 118).
opt rotation [a]D20 + 90.0° (c 4.07 in MeOH)
Chiral HPLC isolation of Compound 118: From racemic Compound 123 (see
Example THREE) isolation of the 2nd eluting enantiomer from the following
conditions: Chiral HPLC; 10% isopropyl alcohol/hexane at 1 mL/m on aChiralcel OJ
4.6x250 mm column; detector uv at 220 nm; rt; isocratic; collect 14.7 m (peak two).
9^% ee; opt. rotation [a]D20 + 75° (c 1.03 in MeOH)

^ NMR same as Compound 123 (see below)
Example TWO-2 (Compound 119)
Use of (7?)-2-methyl-oxazaborolidine catalyst with BH3»SMe2 for the reduction
stfcp and substituting 3,5-difluorophenyIboronic acid (commercially available from
Aldrich) in Method TWO produced (+)-4-[(S*)-2-(3,5-difluorophenyl)-cyclopent-2-
e4ylmemyl]-13-dmydro-imidazole-2-thione (Compound 119).
opt. rotation [a]D20 + 87.8° (c 0.90 in MeOH)
'ij NMR same as compound 126.
Example TWO-3 (Compound 120)
Use of (S)-2-methyl-oxazaborolidine catalyst (20 mol%) with BH3«SMe2 in the
reduction of Intermediate D2 produced (+)-(i?)-2-bromo-cyclopent-2-enol. Use of
optically enriched (+)-(i?)-2-bromo-cyclopent-2-enol and substituting 3-
ftyiorophenylboronic acid (commercially available from Aldrich) in Method TWO
produced (-)^-[(R*)-2-(3-fiuorophenyl)^yclopent-2-enylmethyl]-l,3-dihydro-
iitoidazole-2-thione (Compound 120).
ojrt. rotation [afo20 -108.9 (c - 1.24 in CHC13)
Chiral HPLC isolation of Compound 120: same as for Compound 18 (see
above) collect 12.6 m (peak one). 99% ee; opt rotation [a]D20 - 86° (c 1.10 in
MeOH).
!{[ NMR same as Compound 129 (see below).
Example TWO-4 (Compound 121)
Use of (iS)-2-memyI-oxazaborolidine catalyst with BH^SMej for the reduction
step and substituting 4-fluorophenylboronic acid (commercially available from
Aldrich) in Method TWO produced (-)-4-[(R*)-2-(4-fluorophenyl)-cyclopent-2-
efiylmethyl]-l,3-dihydro-imida2»le-2-uiione (Compound 121).
opt. rotation [ct]D20 -85.6° (c 1.24 in MeOH)
2JI NMR same as Compound 123.
Example TWO-5 (Compound 122)
Use of (iS)-2-methyl-oxazaborolidine catalyst with BH3#SMe2 for the reduction
sjtep and substituting 3,5-difluorophenyIboronic acid (commercially available from

Aldrich) in Method TWO produced (-)-4-[(R*)-2-(3,5-difluorophenyl)-cyclopent-2-
ei^ylmethyl]-l,3-dihydro-iniidazole-2-thione (Compound 122).
otft rotation [a]D20 -96.1° (c 1.32 in MeOH)
*!£ NMR same as Compound 126.

2-Bromo-cyclopemt-2-enol (Intermediate D3) (1.1 g, 6.7 mmol) and me 4-
fltioroboronic acid (commercially available from Aldrich) (1.09 g, 7.8 mmol) in
d|oxane (20 mL) was treated with 2M Na2C03 (14 mL) and degassed. Pd(PPh3)4 (0.4
g„ ~5 mol %) was added to the mixture and degassed with N2 gas for 15 m. The
reaction mixture was heated to reflux for one hour, cooled to rt and diluted with ether
aifrd water. The aqueous layer was extracted with ether. The combined layers were
wiashed with brine and dried over Na2SO4. The suspension was filtered and freed of
solvent. The residue was purified by chromatography on S1O2 to give 2-(4-
flburophenyl)-cyclopent-2-enol (Intermediate THREE1).
Use of 2-(4-flourophenyl)-cycIopent-2-enol (Intermediate THREE1) in
Method A produced 4-[2-(4-fluoro-phenyl)-cyclopent-2-enylmethyl]-l,3-dihydro-
intidazole-2-thione (Compound 123).
'$ NMR (500 MHz, CDC13) 8 11.3 (s, 1H), 11.1 (s, 1H), 7.42-7.38 (m, 2H), 7.06-
7.00 (m, 2H), 6.37 (s, 1H), 6.025 (s, 1H), 3.43 (s, 1H), 2.79-2.72 (m, 1H), 2.42-2.29
(nX 3H), 2.16-2.08 (m, 1H), 1.78-1.76 (m, 1H).

Example THREE-1 (Compound 124)
Use of 3,4-difluorophenylboronic acid (commercially available from Aldrich)
inj Method THREE produced 4-[2-(3,4-difluorophenyl)-cyclopent-2-enylmethyl]-l,3-
dijhydro-imidazole-2-thione (Compound 124).
*i NMR (300 MHz, MeOD-d4) 8 7.41-7.34 (m, 1H), 7.24-7.15 (m, 2H), 6.49 (s, 1H),
6i5 (s, 1H), 3.40 (brs, 1H), 2.73-2.68 (m, 1H), 2.48-2.42 (m, 2H), 2.35-2.27 (m, 1H),
2.20-2.05 (m, 1H), 1.90-1.78 (m, 1H).
Example THREE-2 (Compound 125)
Use of 5-cUoromiophene-2-boronic acid (commercially available from
Ajdrich) in Method THREE produced 4-[2-(5-chloro-thiophen-2-yl)-cyclopent-2-
e4ylmethyl]-l,3-dihydro-imidazole-2-tbione (Compound 125).
'$ NMR (300 MHz, MeOD-d4) 8 6.84 (s, 2H), 6.52 (s, 1H), 5.96 (s, 1H), 3.29 (brs,
1|I), 2.82-2.76 (m, 1H), 2.44-2.36 (m, 3H), 2.14-2.00 (m, 1H), 1.86-1.77 (m, 1H).

2-Bromo-cyclopent-2-enol (Intermediate D3) (2.18 g, 13.4 mmol) and NJtf-
djmethylacetamide dimethyl acetal (3.5 mL, 21.5 mmol) in m-xylene (~20 mL) were
heated to 140 °C for 14 h. The mixture was freed of solvent and the residue was
purified on a column of silica gel with 30% to 50% EtOAc:hexanes to give 2-(2-

br (6^%) as a brown oil.
2-(2-Bromo-cyclopent-2-enyl)-iV^-dimethyl-acetainide (Intermediate
F0UR1) (1.16 g, 5 mmol) in benzene (36 mL), and Na2G03 (5 mL, 2M) was treated
l
i
wijth a solution of 3,5-difluoroboronic acid (1.1 g, 6.96 mmol) in EtOH (25 mL).
Te(trakis(triphenylphosphine) palladium(0) [Pd(PPh3)4] (0.3 g, 5 mol%) was added and
th^ degassed mixture was heated to 80 °C for 1.5 h. The mixture was diluted with
wetter and extracted with diethyl ether (2x). The combined organic layers were dried
ov(er MgSC>4, filtered and evaporated to dryness. The oil was purified by column
chromatography on silica gel with 40% EtOAc:hexane to give 2-[2-(3,5-difluoro-
pyenyl)Kjyclopent-2-enyl]-/^-dimethyl-acetamide 0.93 g (70%) as a light yellow
solid. This amide was reduced with DD3AL (14.2 mL, 1M in hexane) in Et20:THF
(5il) (60 mL) at -78 °C over 1.5 h. The mixture was subjected to an aqueous work-up
wjth Rochelle's salt solution. The aldehyde, 2-(3,5-difluoro-phenyl)-cyclopent-2-
erjyl]-acetaldehyde (Intermediate FOUR2) was isolated in an approximate yield of
76%.
Use of Intermediate FOUR2 and 3,5-difluorophenylboronic acid
(commercially available from Aldrich) in Method A produced 4-[2-(3,5-
dijfluorophenyI)-cyclopent-2-enylmethyl J-1,3-dmydro-imidazole-2-thione
(Compound 126).
% NMR (300 MHz, MeOD-d4) 8 7.11-7.08 (m, 2H), 6.82-6.77 (m, 1H), 6.26 (s, 1H),
3.40 (brs, 1H), 2.72-2.69 (m, 1H), 2.49-2.41 (m, 2H), 2.34-2.29 (m, 1H), 2.16-2.08
(rh,lH), 1.84-1.79 (m,.lH).
Example FIVE
Method FIVE: Procedure for the preparation of 4-[2-C2-fluorophenvfl-cvclopent-
2-jenylmethvll-1.3-dmydro-imidazole-2-thione fCompound 127)


2-(2-Bromo-cyclopent-2-emyl)-i\y^-dimethyl-acetamide (Intermediate
FlOURl) (1.93 g, 8.3 mmol) in THF (50 mL) was reacted with lithium
tiiiethylborohydride (19 mL, 1 M in THF) at 0 CC for lh. The mixture was treated
With an aqueous work-up and the resultant alcohol was purified by column
cjiromatography to give 0.92 g of 2-(2-bromo-cyclopent-2-enyl)-ethanol
Intermediate FTVE1.
2-(2-Bromo-cyclopent-2-enyl)-ethanol Intermediate FIVE1 (1.21 g, 6.33
njunol) in benzene (40 mL), and Na2C03 (7 mL, 2M) was treated with a solution of 2-
fjuorophenylboronic acid (1.08 g, 7.72 mmol) in EtOH (28 mL).
Tfetrakis(triphenylphosphine) palladium(0), Pd(PPh3)4 (0.38 g, 5 mol%) was added
aftd the mixture was heated to 80 °C for 1.5 h. The mixture was diluted with water
ahd extracted with diethyl ether (2x). The combined organic layers were dried over
]NJlgSO4, filtered and evaporated to dryness. The oil was purified by column
cjiromatography on silica gel with 30% EtOAc:hexane to give 2-[2-(2-fluoro-phenyl)-
cjyclopent-2-enylj-ethanol Intermediate FTVE2 (1.21 g).
The alcohol Intermediate FTVE2 (1.2 g, 5.87 mmol) in acetonitrile (20 mL)
was mixed with 4A molecular sieves (1.21 g), 4-methyl morpholine-/V-oxide (1.38 g,
111.8 mmol) and TPAP: tetrapropylammonium perruthenate (0.22 g, 10 mol% catalyst)
a|t rt for 1 h. The aldehyde, [2-(2-fluoro-phenyl)-cyclopent-2-enyl]-acetaldehyde
((Intermediate FIVE3) was purified on a column of silica gel eluted with 10 %
$tOAc:Hexane (-25%).

Use of [2-(2-fluoro-phenyl)-cyclopent-2-enyl]-acetaldehyde (Intermediate
F1JVE3) in Method A produced 4-[2-(2-fluorophenyl)-cyclopent-2-enylmemyl]-l,3-
du^ydro-irnidazole-2-thione (Compound 127).
*E[ NMR (300 MHz, MeOD-d4) 8 7.41-7.36 (in, 1H), 7.27-7.20 (m, 1H), 7.16-7.63
(n), 2H), 6.42 (s, 1H), 6.15 (s, 1H), 3.52 (m, 1H), 2.67-2.60 (m, 1H), 2.52-2.37 (m,
2ljr), 2.34-2.26 (m, 1H), 2.21-2.08 (m, 1H), 1.80-1.69 (m, 1H).

A jmixture of two compounds: 4-[2-(2,4-difluoro-phenyl)-cyclopent-2-enylmethyl]-
li^-imidazole and 4-(2-bromo-cyclopent-2-enylmemyl)-lff-iirridazole (Intermediate
S^Xl) (produced with procedures as in Method FIVE, but without complete coupling
oif the boronic acid) were subjected to the reaction found in Method P. The mixture,
Intermediate SEX2 was subjected to the coupling reaction as follows. Intermediate
S^X2 (0.25g, -1.1 mmol) in benzene (8 mL), and Na2C03 (1 mL, 2M) was treated
wfth a solution of 2,4-difluoroboronic acid (commercially available from Aldrich)
(0J.31 g) in EtOH (6 mL). Tetrakis(triphenylphosphine) palladium(0) Pd(PPh3)4 (~ 5
mbl%) was added and the mixture was heated to 80 °C for 3 h. The mixture was
diluted with water and extracted with diethyl ether (2x). The combined organic layers
wja-e dried over MgSO4, filtered and evaporated to dryness. The oil was purified by

cojumn chromatography on silica gel with 30% EtOAahexane to give Intermediate
Slfc (0.14 g).
Finally, Intermediate SK3 was converted to the thione compound by use of
LaWesson's reagent in the standard fashion as follows. Intermediate SIX3 (0.14 g,
O.fj mmol) and Lawesson's reagent [2,4-bis(4-memoxyphenyl)-l,3-dithia-2,4-
dip|hosphetane-2,4-disulfide] (commercially available from Aldrich) (0.45 g, ~1.1
mifiol) in dioxane were heated at reflux for several hours. The mixture was poured
on^o silica gel and the solvent was removed under vacuum. The crude material was
placed onto a column of silica and the product was eluted with 4% NH3-MeOH:
Cl|[2Cl2. This method produced 4-[2-(2,4-diiluorophenyl)-cyclopent-2-enylmethyl]-
l4-dmydro-irnidazole-2-thione (Compound 128).
'B( NMR (300 MHz, MeOD-d4) 8 7.44-7.36 (m, 1H), 6.95-6.88 (m, 2H), 6.42 (s, 1H),
6.J2 (s, 1H), 3.47 (brs, 1H), 2.64-2.58 (m, 1H), 2.51-2.44 (m, 2H), 2.35-2.26 (m, 1H),
240-2.08 (m, 1H), 1.79-1.69 (m, 1H).

(2-Bromo-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE1) was
transformed via reactions as described in Method P to 4-(2-bromo-cyclopent-2-
enj/lmethyl)-l,3-dmydro-irnidazol-2-one (IntermediateSEVENl). Intermediate
SIfVENI was processed according to Method SIX into 4-[2-(3-fluorophenyl)-
cyblopent-2-enymiemyl]-l,3-dihydro-iniidazole-2-thione (Compound 129).
^ NMR (500 MHz, MeOD-d4) 5 7.35-7.30 (m, 1H), 7.27 (d, J= 8.5 Hz, 1H), 7.21
(dj J= 10.5 Hz, 1H), 6.97-6.93 (m, 1H), 6.49 (s, 1H), 6.19 (s, 1H), 3.43 (brs, 1H),

2.13-2.70 (m, 1H), 2.50-2.40 (m, 2H), 2.33-2.28 (m, 1H), 2.17-2.09 (m, 1H), 1.84-
l.js (m, 1H).

Use of 2,5-difluorophenylboronic acid (commercially available from Aldrich)
in JMeihod THREE produced 2-(2,5-difluoro-phenyl)-cyclopent-2-enol (Intermediate
EllGHTl). Use of procedures in Method ONE and Method A produced 4-[2-(2,5-
dii luorofluorophenyl)-cyclopent-2-enylmethyl]-1,3-dihydro-imidazole-2-thione
(Compound 130).
•fij NMR (300 MHz, MeOD-d4) 5 7.17-7.10 (m, 1H), 7.09-7.02 (m, 1H), 6.98-6.91
(nj, 1H), 6.44 (s, 1H), 6.26 (s, 1H), 3.47 (brs, 1H), 2.66-2.60 (m, 1H), 2.51-2.42 (m,
2H), 2.34-2.26 (m, 1H), 2.18-2.05 (m, 1H), 1.78-1.69 (m, 1H).
Example EIGHT-1 (Compound 131)
Use of thiophene-2-boronic acid (commercially available from Aldrich) in
Method EIGHT produced 4-[2-thiophen-2-yl-cyclopent-2-enylmethyl]-l,3-dihydro-
iir^dazole-2-thione (Compound 131).
^ NMR (300 MHz, MeOD-d4) 5 7.22 (d, J = 5.1 Hz, 1H), 7.05 (d, J= 3.6 Hz, 1H),
6.9|9-6.96 (m, 1H), 6.49 (s, 1H), 5.98 (s, 1H), 3.30 (brs, 1H), 2.85-2.80 (m, 1H), 2.44-
2.37 (m, 3H), 2.14-2.01 (m, 1H), 1.85-1.77 (m, 1H).
Example NINE


3-Ethoxy-cyclopent-2-enone (Intermediate NINE1) (commercially available
fijom Aldrich) (10.0 g, 77.6 mmol) in carbon tetrachloride (15 mL) at 0 °C was treated
v^ith NBS (15.3 g, -85 mmol) added portion-wise over 30 m. After lh at 0 °C the
nkixture was partitioned between CH2CI2 and saturated NaHCOs. The aqueous layer
vf as extracted with CH2C12. The pooled organic layers were washed with H20 (2x)
ahd dried over MgSO4. The mixture was filtered and evaporated to dryness. The
splid was recrystallized from pentane.ether to give 13.3 g of 2-bromo-3-ethoxy-
cjyclopent-2-enone (Intermediate NINE2).
2-Bromo-3-ethoxy-cyclopent-2-enone (Intermediate NINE2) (10.5 g, 51.2
nimol) and K2C03 (14.2 g, 102 mmol) in toluene (100 mL), benzene (100 mL) and
ty20 (50 mL) was treated with a solution of 4-fluorophenyIboronic acid (9.31 g, 66.5)
rji EtOH (100 mL). Tetrakis(triphenyIphosphine) palladium(0) Pd(PPh3)4 (3g, 2.6
rjimol), bis(dibenzylideneacetone)palladium(0)s Pd2(dba)3 (0.47 g, 0.5 mmol) and
tjiphenylphosphine (0.27 g, 1.0 mmol) were added and the mixture was purged with
Tff2for 15 m. The mixture was heated to 100 °C for 15 h. The mixture was diluted
Mth. water and EtOAc:hexane. After extracting with EtOAc:hexane, the combined
Organic layers were dried over MgSO4, filtered and evaporated to dryness. The crude
o-il was purified by column chromatography on silica gel with 2.5% EtOAc:CH2Cl2 to

gvfe 3-ethoxy-2-(4-fluoro-phenyl)-cyclopent-2-enone (Intermediate NINE3) 7.85 g
(7()%).
Cerium chloride* 7H20 was dried under vacuum (~ 1 Torr) with gradual heating
to |l40 °C. The cerium chloride«nH20 (3.6 g, 13.6 mmol) was dried further under
vacuum with heating to 170 °C over 3 h. The material was cooled to rt and suspended
in [THF (20 mL). Stirring was continued for 2h. 3-Emoxy-2-(4-fiuoro-phenyl)-
cyj;lopent-2-enone (Intermediate NINE3) (2.0 g, 9.1 mmol) in THF (-20 mL) was
adjied to this mixture. The reaction mixture was cooled to 0 °C and ethyl magnesium
bromide (commercially available from Aldrich) (13 mL, 39 mmol, 3M in ether) was
adjied dropwise. The mixture was warmed to rt and allowed to stir for 15 h. The
wl^ole was cooled to 0 °C and quenched by the addition of 2% HC1 (100 mL) and
stijred for 15 m. The mixture was extracted with EtOAc and the combined organic
laiers were evaporated to give the crude oil that was used in the next step without
fuither purification. The reduction with NaBIL; was performed as in Method A to
yield Intermediate NINE4.
Use of 3-ethyl-2-(4-fluoro-phenyl)-cyclopent-2-enol of (Intermediate NINE4)
in Method A produced 4-[3-ethyl-2-(4-fluoro-phenyl)-3-methyl-cyclopent-2-
enjylmethyl]-l,3-dihydro-imidazole-2-thione (Compound 132).
'KJ NMR (300 MHz, CDC13) 8 11.4 (s, 1H), 11.2 (s, 1H), 7.16-7.10 (m, 2H), 7.02-
6.$6 (m, 2H), 6.03 (s, 1H), 3.37 (brs, 1H), 2.61-2.01 (series of m, 7H), 1.58-1.49 (m,
lfJ0,O.97(t,./=8.4Hz,3H).
Example NENE-1 (Compound 133)
Use of /j-propyl magnesium chloride (commercially available from Aldrich) in
Method NINE produced 4-[2-(4-fluoro-phenyl)- 3-propyl-cyclopent-2-enylmethyl]-
l,|-dihydro-imidazole-2-thione (Compound 133).
!H NMR (300 MHz, CDC13) 6 11.5 (s, 1H), 11.3 (s, 1H), 7.12 (dd, J= 5.7, 8.7 Hz,
2H), 6.99 (t, J = 8.4 Hz, 2H), 6.30 (s, 1H), 3.37 (brs, 1H), 2.61-2.54 (m, 1H), 2.47-
2.01 (m, 6H), 1.59-1.47 (m, 1H), 1.45-1.32 (m, 2H), 0.81 (t, J= 7.5 Hz, 3H).
Example NTNE-2 (Compound 134)

Use of isopropyl magnesium chloride (commercially available from Aldrich) in
Msthod NINE produced 4-[2-(4-fluoro-phenyl)- 3-isopropyl-cyclopent-2-enylmethyl]-
l,J-dihydro-imidazole-2-thione (Compound 134).
J4 NMR (300 MHz, CDC13) 5 11.6 (s, 1H), 11.4 (s, 1H), 7.11 (dd, J= 5.7, 8.7 Hz,
2H), 6.98 (t, /= 8.7 Hz, 2H), 6.30 (s, 1H), 3.33 (brs, 1H), 2.71-2.50 (m, 2H), 2.38-
2.p0 (m, 2H), 2.20-1.99 (m, 2H), 1.55-1.44 (m, 1H), 1.05 (d, J= 6.6 Hz, 3H), 0.85 (d,
7=}= 6.9 Hz, 3H).
Example NINE-3 (Compound 135)
Use of cyclopropyl magnesium bromide (made from cyclopropyl bromide
(commercially available from Aldrich) and Mg(0)) in Method NINE produced 4-[3-
cj|clopropyl-2-(4-fluorc-phenyl)-cyclopeot-2-enylmethyl]-l,3-dmydro-imidazole-2-
thjkme (Compound 135).
lff. NMR (300 MHz, MeOD-d4) 8 7.32 (dd, J= 6.0,9.0 Hz, 2H), 7.07 (t, /= 8.7 Hz,
2fc, 6.38 (s, 1H), 3.39 (brs, 1H), 2.58-2.52 (m, 1H), 2.23-2.01 (m, 4H), 1.68-1.49
(series of m, 2H), 0.73-0.66 (m, 1H), 0.60-0.51 (m, 3H).
Example NINE-4 (Compound 136)
Use of 3-ethoxy-cyclohex-2-enone as the starting material and methyl
mjagnesium bromide (both commercially available from Aldrich) in Method NINE
pi(oduced4-[2-(4-iluoro-phenyl)-3-methyl-cyclohex-2-enylmemyl]-l,3-dihydro-
inkidazole-2-thione (Compound 136).
'^ NMR (300 MHz, CDC13) 8 7.10-6.90 (m, 4H), 6.30 (s, 1H), 2.66 (brs, 1H), 2.42-
2.(21 (m, 2H), 2.14-2.04 (m, 2H), 1.71-1.57 (m, 4H), 1.49 (s, 3H).
Example TEN
Method TEN: Procedure for the preparation of produced 4-[2-methvl-5-(2-
th|ioxo-2,3 -dihvdro-1 H-imidazol-4-yl-methyl)cyclopent-1 -envllbenzonitrile
(Compound 137)


2-Bromo-3-methyl-cyclopent-2-enone (Intermediate TEN1) (commercially
available from Aldrich) (2.04 g, 11.4 mmol) andK2C03 (3.16 g in 11 mL HzO) in
tojuene (45 mL) was treated with a solution 4-cyanophenylboronic acid (commercially
avjailable from Aldrich) (2.2 g, 15 mmol) in EtOH (27 mL).
Te^akis(friphenylphosphine) palladium(0) Pd(PPh3)4 (0.4 g),
bi^(dibenzylideneacetone) palladium(O), Pd2(dba)3 (0.055 g, ~5 mol%) and
tribhenylphosphine (0.4 g) were added and the mixture was purged with N2 for 15 m.
Tr^e mixture was heated to 80 °C for 15 h. The mixture was diluted with water and
EtJ0Ac:hexane. After extracting with EtOAchexane, me combined organic layers
w^re dried over MgSO4, filtered and evaporated to dryness. The crude oil was
pujrified by column chromatography on silica gel with CH2C12 to give 4-(2-methyl-5-
oxjo-cyclopent-l-enyl)-benzonitrile (Intermediate TEN2) 1.74 g.
Use of 4-(2-methyl-5-oxo-cyclopent-l-enyl)-benzonitrile (Intermediate
TJfN2) in Method A produced 4-[2-methyl-5-(2-thioxo-2,3-dihydro-lH-imidazol-4-
yl-jmethyl)cyclopent-l-enyl]benzonitrile (Compound 137).
^ NMR (500 MHz, MeOD-d4) 8 7.70 (d, J= 8.5 Hz, 2H), 7.40 (d, J= 8.5 Hz, 2H),
6.3^8 (s, 1H), 3.50 (brs, 1H), 2.61-2.52 (m, 2H), 2.45-2.13 (series of m, 3H), 1.78 (s,
3IJT), 1.68-1.61 (m, 1H).
Example TEN-1 (Compound 138)
Use of 4-nitrophenylboronic acid (commercially available from Aldrich) in
Method TEN produced 4-[3-methyl-2-(nitro-phenyl)-cyclopent-2-enylmethyl]-l,3-
dil^ydro-imidazole-2-thione (Compound 138).

^ NMR (300 MHz, CDC13) 6 11.6 (s, 1H), 10.8 (s, 1H), 8.17 (d, J= 8.7 Hz, 2H),
7.^9 (d, J= 9.0 Hz, 2H), 6.35 (s, 1H), 3.54 (brs, 1H), 2.64-2.09 (m, 5H), 1.78 (s, 3H),
1.J64-1.53 (m, 1H).
Example TEN-2 (139)
Use of 3,5-difluorophenylboronic acid (commercially available from Aldrich)
in) Method TEN produced 4-[2-(3,5-difluorophenyl)-3-methyl-cyclopent-2-
ei|ylinethyl]-l,3-dihydro-imidazole-2-thione (Compound 139).
l1f NMR (300 MHz, CDC13) 8 11.0 (s, 1H), 10.6 (s, 1H), 6.77-6.63 (m, 3H), 6.32 (s,
lfe, 3.40 (brs, 1H), 2.65-2.05 (series of m, 5H), 1.76 (s, 3H), 1.61-1.50 (s, 1H).

2-Bromo-3-methyl-cyclopent-2-enone (Intermediate TWELVE1)
( pjroduce(2-bromo-3-methyl-cyclopent-2-enyl)-acetaldehyde (Intermediate
lf\VELVE2).
(2-Bromo-3-methyl-cyclopent-2-enyl)-acetaldehyde (Intermediate
^WELVE2) (7.28 mmol) in benzene (50 mL) was treated with Na2C03 (7.3 mL, 2M
spin.) and 4-fluorophenylboronic acid (1.4 g, 10.0 mmol) in EtOH (35 mL).
ijetrakis(triphenylphosphine) palladium(0), Pd(PPh3)4 catalyst (0.54 g, -5 mo!%) was
1

adjled and the mixture was heated to 80 °C for 15 h. until no starting material
regained. The mixture was filtered through celite. The filtrate was partitioned
between EtOAc and water. The aqueous layer was extracted with EtOAc and the
orjjanic layers were combined and dried over MgSC>4. Chromatography on silica gel
wih 20% EtOAc.hexane delivered [2-(4-fluoro-phenyl)-3-methyl-cyclopent-2-enyl]-
acjrtaldehyde (Intermediate TWELVE3) 0.8 g.
[2-(4-fluoro-phenyl)-3-methyl-cyclopent-2-enyl]-acetaldehyde (Intermediate
TljvELVE3) in Method A produced 4-[2-(4-fluoro-phenyl)-3-methyl-cyclopent-2-
en^lmethyl]-l,3-dihydro-imidazole-2-thione (Compound 140).
'fit NMR (500 MHz, MeOD-d4) 5 7.22 (dd, J = 5.5, 9.0 Hz, 2H), 7.06 (t, J = 9.0 Hz,
2lj), 6.04 (s, 1H), 3.39 (brs, 1H), 2.56-2.46 (m, 2H), 2.38-2.32 (m, 1H), 2.22-2.17 (m,
llj), 2.13-2.06 (m, 1H), 1.75 (s, 3H), 1.62-1.56 (m, 1H).

A mixture of CuCl2 (2.0,14.8 mmol) and /-butyl nitrite (2.3 mL, 17.4 mmoi) in
acjetonitrile (30 mL) at 65 °C was treated with 8-amino-3,4-dihydro-2H-naphthalen-l-
orje (Intermediate J3) in acetonitrile (15 mL) over 10 m. The mixture was
cojncentrated onto silica gel and purified by column chromatography with 10 %
EtjOAc:hexane to give 8-chloro-3,4-dihydro-2H-naphthalen-l-one (Intermediate
S^XTEENalpha-1). Use of 8-chloro-3,4-dihydro-2H-naphthalen-l-one
(Intermediate SIXTEENalpha-1) in Method E (note: Pt02 was used as a substitute
fo)r Pd/C as described in Method E) produced 8-chloro-2-(2-thioxo-2,3-dihydro-lH-
injiidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-l-one (Compound 141).

*H NMR (300 MHz, MeOH-d4) 8 7.42-7.32 (m, 2H), 7.24 (d, /= 6.3 Hx, 1H),
6.^1 (s, 1H), 3.10-3.03 (m, 3H), 2.92-2.82 (m, 1H), 2.63 (dd, J= 7.8, 7.2 Hz, 1H),
24o-2.12 (m, 1H), 1.85-1.71 (m, 1H).

Use of indan-4-ylamine (Intermediate SIXTEEN-beta-1) (commercially
avjailable from Aldrich) in Method J produced 7-amino-indan-l-one (Intermediate
SJXTEENbeta-2). A mixture of 7-amino-indan-l-one (Intermediate
S^XTEENbeta-2 ) (1.44 g, 9.8 mmol) in water (11 mL)s acetic acid (11 mL), and HC1
(2[7 mL) was treated with a solution of NaN02 (0.75 g in 2.8 mL) at 0 °C. A solution
oij KI in water (1.76 g 10.4 mmol in 2.8 mL) was added and the mixture was heated to
60| °C for 1 h. The mixture was cooled and quenched with solid NaHSO3 followed by
wkter. The product was extracted with CH2C12 (3x) and washed with sat. NaHC03
aijd brine. The compound was purified by column chromatography on silica gel with
60| to 70% CH2Cl2:hexane. 7-Iodo-indan-l-one (Intermediate SEXTEENbeta3) was
isolated as a light yellow solid (31%).
Example SEVENTEEN (Compound 142)

Use of indan-2-yl-acetic acid (commercially available from Lancaster)
(Intermediate SEVENTEEN-1) (1.58 g, 8.88 mmol) in THF (15 mL) was added

drjopwise to a solution of LiAlH4 (9 mL, 1M in Et20) in THF (10 mL) at 0 °C. The
mixture was reacted for 2 h at rt and quenched with Rochelle's salt solution and
extracted with Et20 (3x). The organic layer was dried over MgSO4, filtered and
concentrated under vacuum. The alcohol (1.35 g, 94 %) was used in the next step
without further purification. A solution of 2-indan-2-yl-ethanol (1.35 g, 8.32 mmol)
inj 18 mL of CH2Ch and CH3CN (2mL) was treated with 4 A molecular sieves (4.2 g)
Ni-methylmorpholine-N-oxide(1.5 g, 13.5 mmol) and TPAP: tetra-n-
pitapylammonium perruthenate(VII) (commercially available from Aldrich) (0.3 g,
0J85 mmol). The mixture was stirred for 16 h at rt. The mixture was poured directly
o^ito a column of silica gel and eluted with 10 % EtOAc:hexane. To give indan-2-yl-
a a ylmethyl-l,3-dihydro-irnidazole-2-thione (Compound 142).
^ NMR (300 MHz, MeOH-d4) 8 7.16-7.12 (m, 2H), 7.10-7.06 (m, 2H), 6.59
(i 1H), 3.02 (dd, 7= 7.8, 7.2 Hz, 1H), 2.76-2.57 (m, 5H).
Example SEVENTEEN-1 (Compound 143)
Use of indan-2-carboxylic acid (commercially available from TCI America) in
Method SEVENTEEN produced 4-indan-2-yl-l,3-dihydro-imidazole-2-thione
(Compound 144).
't NMR (300 MHz, MeOH-d4) 5 7.21 (m, 2H), 7.14-7.11 (m, 2H), 6.58 (s, 1H),
3i55-3.44 (m, 1H), 3.29-3.20 (m, 2H), 3.03-2.92 (m, 2H)
Example SEVENTEEN-2 (Compound 144)
Use of l,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (commercially
available from Aldrich) in Method SEVENTEEN produced 4-(l,2,3,4-tetrahydro-
n(aphthalen-2-yl)-l,3-dihydro-imidazoIe-2-thione (Compound 144).
^ NMR (300 MHz, MeOH-d4) 6 7.06 (brs, 4H), 6.54 (s, 1H), 3.09-3.03 (m, 1H),
2196-2.78 (m, 4H), 2.19-2.13 (m, 1H), 1.86-1.73 (m, 1H).
Example EIGHTEEN (Compound 145)
Procedure for the preparation of 4-(5-fluoro-indan-2-vl)-l,3-dihvdro-unidazole-2-
thione (Compound 145).


To a mixture of NaH (2.64 g, 66 mmol) in dimethylcarbonate (4.2 mL, 50
njmol) in THF (30 mL) was added a solution of 5-fluoroindanone (commercially
available from Aldrich) (5 g, 33 mmol). After 30 m at 65 °C the mixture was cooled
to| rt, acidified with HC1 (aq) and extracted with Et20 or EtOAc. The organic layers
Were washed with water, dried over MgSO4 and evaporated to dryness. The residue
Wjas used in the next step without further purification. The keto-ester was dissolved in
AjcOH (100 mL) and 70 % perchloric acid (2 mL). 10 % Pd/C (2 g) was added and
trje mixture was hydrogenated at 50 psi for 18 h. The mixture was diluted with Et20
o\ CHC13 and water and filtered through a pad of celite. The organic layer was
separated and the aqueous layer was extracted with Et20. The organic fractions were
pooled, washed with water, dried over MgSO4, filtered and evaporated to leave a
residue. The residue was purified by chromatography on silica gel with 15 % EtOAc:
h^xane to give 5-fluoro-indan-2-carboxylic acid methyl ester (Intermediate
EJLGHTEEN-3), 2.25 g. Use of 5-fluoro-indan-2-carboxylic acid methyl ester
(Intermediate EIGHTEEN-3) in Method SEVENTEEN produced 4-(5-fluoro-
ir^an-2-yl)-l,3-dmydro-imidazole-2-thione (Compound 145).
^ NMR (300 MHz, DMSO-d6) 5 12.0 (s, 1H), 11.7 (s, 1H), 7.20 (dd, J= 5.7, 8.4 Hz,
1 jl), 7.04 (d, J= 9.3 Hz, 1H), 6.92 (t, 7= 8.8 Hz, 1H), 6.59 (s, 1H), 3.42 (t, J= 8.7
Hk, 1H), 3.18-3.07 (m, 2H), 2.94-2.81 (m, 2H).
Example EIGHTEEN-1 (Compound 146)
Use of 7-methyl-indan-l-one (commercially available from Aldrich) in Method
EIGHTEEN produced 4-(4-methyl-mdan-2-yl)-l,3-dmydro-imidazole-2-thione
(Compound 146).
'i NMR (300 MHz, DMSO-d6) 5 12.0 (s, 1H), 11.6 (s, 1H), 7.02-7.00 (m, 2H), 6.94-
6.^2 (m, 1H), 6.60 (s, 1H), 3.43-3.32 (m, 1H), 3.18-3.07 (m, 2H), 2.93-2.76 (m, 2H),
2.^9 (s,3H).

Example EIGHTEEN-2 (Compound 147)
Use of 6-methyl-indan-l-one (commercially available from Aldrich) in Method
EIGHTEEN produced 4 (Compound 147).
^ NMR (300 MHz, DMSO-d6) 8 12.0 (s, 1H), 11.6 (s, 1H), 7.07 (d, J= 12 Hz, 1H)>
7.pi (s, 1H), 6.92 (d, J= 7.5 Hz, 1H), 6.58 (s, 1H), 3.38-3.29 (m, 1H), 3.12-3.04 (m,
2^), 2.89-2.80 (m, 2H), 2.24 (s, 3H).

Use of 5-bromo-indan-l-one (Intermediate NINETEEN-1) in a reaction with
NJaH and dimethylcarbonate (refer to procedures in Method EIGHTEEN) produced
5Jbromo-l-oxo-indan-2-carboxylic acid methyl ester (Intermediate NINETEEN-2).
A| solution of 5-bromo-l-oxo-indan-2-carboxylic acid methyl ester (4.75 g, 17.7
njmol) in TFA (80 mL) at 0 °C was treated with triethylsilane (TES) (17.0 mL, 6.0
ei) and stirred for 18 h. After evaporation of the solvent, the residue was diluted with
E^O and washed with H20 (5 x 100 mL), sat. NaHC03 (3x 50 mL), brine (1 x 75 mL)
a£d dried over MgSC>4 to give crude 5-bromo-indan-2-carboxylic acid methyl ester
(intermediate NTNETEEN-3). A solution of 5-bromo-indan-2-carboxylic acid
irjethyl ester (Intermediate NINETEEN-3) in AcOH containing 20% HC1 was stirred
oyernight. After evaporation of the solvent, the residue was dissolved in IN NaOH.
T|ie resulting mixture was washed with Et20 (3 x 75 mL) after which it was acidified
wjith HC1 (aq). The solution was extracted with CH2C12 (3 x 150 mL) and the
combined organic extracts was washed with H20 (3 x 100 mL), brine (1 x 75 mL),
d|ied over MgSC>4 and concentrated to give crude 5-bromo-indan-2-carboxylic acid.
Lfse of 5-bromo-indan-2-carboxylic acid in Method EIGHTEEN produced 4-(5-
bj,omo-indan-2-yI)-l,3-dihydro-imidazole-2-thione (Compound 148).

% NMR (300 MHz, DMSO-d6) 8 12.0 (s, 1H), 11.7 (s, 1H), 7.41 (s, 1H), 7.30 (d, J=
i
8.| Hz, 1H), 7.16 (d, /= 7.8 Hz, 1H), 6.60 (s, 1H), 3.46-3.35 (m, 1H), 3.19-3.06 (m,
2rfe, 2.95-2.81 (m, 2H).
Example NINETEEN-1 (Compound 149)
4-Bromo-indan-l-one was obtained by the following procedure: A solution of
3-j(2-bromo-phenyl)-propionic acid (commercially available from Oakwood Products)
(lp\0 g, 65.5 mmol) in CH2C12 at 0 °C was reacted with oxalyl chloride (7.2 mL, 1.5
ed) followed by 2-3 drops of DMF. The mixture was stirred until no more gas
evolution was observed. As the mixture was concentrated and the residue was
dissolved in CH2C12, cooled to 0 °C, and treated with A1C13 (9.6 g, 1.1 eq). After 1 h
thfe mixture was quenched with water and the layers were separated. The aqueous
layer was extracted with Et20 (3 x 150 mL) and the combined organic extracts were
washed with H20 (3 x 100 mL), saturated NaHC03 (3 x 100 mL), brine (1 x 100 mL),
dijied over MgSO4 and concentrated. 4-Bromoindan-l-one, 10.5 g (76%) was
obtained by chromatography using 10 % EtOAc:hexane as eluant. Use of 4-bromo-
in|dan-1 -one in Method NINETEEN produced 4-(4-bromo-indan-2-yl)-1,3-dihydro-
injudazole-2-thione (Compound 149).
% NMR (300 MHz, DMSO-d6) 5 12.0 (s, 1H), 11.7 (s, 1H), 7.34 (d, ./= 7.8 Hz, 1H),
7.(22 (d, /= 7.5 Hz, 1H), 7.09 (t, 7= 7.5 Hz, 1H), 6.63 (s, 1H), 3.50-3.40 (m, 1H),
3^0-3.12 (m, 2H), 3.06-2.85 (m, 2H).
Example NINETEEN-2 (Compound 150)
Use of 2,5-dimethylcinnamic acid in Method TWENTY (refer to Example
TtWENTY-4) produced 4,7-dimethyl-l-indanone. Use of 4,7-dimethyl-l-indanone in
Method NINETEEN produced 4-(4,7-dimethyl-indan-2-yl)-l,3-dihydro-imidazole-2-
tbjione (Compound 150)
ty NMR (300 MHz, MeOH-d4) 8 6.85 (s, 2H), 6.59 (s, 1H), 3.55-3.45 (m, 1H), 3.30-
3J19 (m, 2H), 2.90-2.80 (m, 2H), 2.19 (s, 6H).
Example NTNETEEN-3 (Compound 151)

Use of 5-chloro-indan-1 -one (commercially available from Aldrich) in Method
NINETEEN produced 4-(5-chloro-indan-2-yl)-1,3-dihydro-imidazole-2-thione
(Compound 151).
% NMR (300 MHz, MeOH-d4) 8 7.22-7.12 (m, 3H), 6.59 (s, 1H), 3.60-3.49 (m, 1H),
3J27-3.19 (m, 2H), 3.02-2.91 (m, 2H).
Example NENETEEN-4 (Compound 152)
Thionyl chloride (10.0 mL, 1.5 eq) and 3-chloro-2-methyl-benzoic acid
(Commercially available from Aldrich) (15.6 g, 91.4 mmol) in benzene was refluxed
uhtil no more gas evolution was observed. After cooling to rt the mixture was
concentrated. The concentrate was diluted with dichloroethane and added to a
solution of of A1C13 (12.2 g, 1.0 eq) in dichloroethane at 10-20 °C. Ethylene was
bubbled through the mixture for 4 h. and the mixture was stirred overnight. The
njixture was quenched with 4 N HC1. The resulting layers were separated and the
aqueous layer was extracted with Et20 (3 x 250 mL). The combined organic extract
yjas washed with H20 (3 x 150 mL), saturated NaHC03 (3 x 150 mL), brine (1 x 150
nJL), dried over MgSO4 and concentrated. Concentrated sulfuric acid was added and
tfye mixture was stirred at 85 °C for 1 h. After cooling to rt, the reaction mixture was
qjienched with ice-water. The mixture was extracted with Et20 (3 x 250 mL) and the
combined organic extracts were washed with H20 (3 x 200 mL), saturated NaHC03 (3
x|200 mL), brine (1 x 100 mL), dried over MgSO4 and concentrated. Pure 6-chloro-7-
m1 ethyl-1-indanone (11.9 g, 72%) was obtained after column chromatography using 20
% EtOAc:hexane as eluant. Use of 6-chloro-7-methyl-1-indanone in Method
NINETEEN produced 4-(5-chloro-4-methyl-indan-2-yl)-1,3-dihydro-imidazole-2-
thione (Compound 152).
'£ NMR (300 MHz, MeOH-d4) 6 7.16 (d, 7= 8.5 Hz, 1H), 7.02 (d, J= 8.5 Hz, 1H),
6J62 (s, 1H), 3.59-3.52 (m, 1H), 3.31-3.24 (m, 2H), 3.00-2.92 (m, 2H), 2.30 (s, 3H).
Example NINETEEN-5 (Compound 153)
Thionyl chloride (5.73 mL, ~79 mmol) and 2,3-dichloro-benzoic acid
(commercially available from Aldrich) (10.0 g, 52.4 mmol) in benzene was heated to
reflux until no more gas evolution was observed. After cooling to rt the mixture was

c0ncentrated. The concentrate was diluted with dichloroethane and added to AICI3
(7.0 g, ~53 nimol) in dichloroethane at 10-20 °C. Ethylene was bubbled through the
mixture for 4 h. The mixture was stirred overnight and quenched with 4 N HC1. The
resulting layers were separated and the aqueous layer was extracted with Et20 (3 x
2^0 mL). The combined organic extracts were washed with H20 (3 x 150 mL),
saturated NaHCOs (3 x 150 mL), brine (1 x 150 mL), dried over MgSO4 and
concentrated. The concentrate was added to a slurry of A1C13 (9.0 g) and NaCl (2.4 g)
at 130 °C. The resulting mixture was stirred at 180 °C for 2 hours after which it was
cooled to room temperature and quenched with ice followed by concentrated HC1.
The mixture was extracted with CH2CI2 (3 x 500 mL) and the combined organic
extracts were concentrated and purified by column chromatography using 20%
HtOAc:hexane eluant to give 6.8 g (80%) of 6,7-dichloro-l-indanone. Use of 6,7-
dichloro-indan-1-one in Method NINETEEN produced 4-(4,5-dichloro-indan-2-yl)-
l>3-dihydro-imidazole-2-thione (Compound 153).
'ftNMR (300 MHz, MeOH-d4) 5 7.31 (d,7= 7.8 Hz, 1H), 7.14 (d, J= 8.1 Hz, 1H),
6162 (s, 1H), 3.67-3.56 (m, 1H), 3.42-3.31 (m, 2H), 3.09-2.99 (m, 2H).
Example NINETEEN-6 (Compound 154)
Use of 3-methyl-indan-l-one (commercially available from Aldrich) in Method
NINETEEN produced 4-(l-methyl-indan-2-yl)-l,3-dihydro-imidazole-2-thione
(Compound 154).
'ft NMR (300 MHz, DMSO-d6) 5 12.0 (s, 1H), 11.7 (s, 1H), 7.20-7.10 (m, 4H), 6.69
($, 1H), 3.17-3.04 (m, 2H), 2.96-2.78 (m, 2H), 1.22 (d, J= 6.6 Hz, 3H).
Example NEVETEEN-7 (Compound 155)
Use of 7-iodo-indan-l-one (Intermediate SIXTEENbeta3) in Method
ISTNETEEN produced 4-(4-iodo-mdan-2-yl)-l,3-dihydro-imidazole-2-thione
(Compound 155).
lH NMR (300 MHz, DMSO-d6) 6 12.0 (s, 1H), 11.7 (s, 1H), 7.55 (d, J= 8.1 Hz, 1H),
7.24 (d, J= 7.5 Hz, 1H), 6.93 (t, /= 7.8 Hz, 1H), 6.63 (s, 1H), 3.48-3.39 (m, 2H),
3.18-3.03 (m, 2H), 2.92-2.83 (m, 1H).


A solution of 2,3-difluorocinnamic acid (2.8 g, 15.2 mol) (commercially
available from Lancaster) (Intermediate TWENTY-1) in ethanol (100 mL) was
h^drogenated with H2 (balloon) and 10 % Pd/C (0.3 g) at rt for 16 h. The mixture was
filtered through Celite® and the solvent was evaporated to give 3-(2,3-difluoro-
phenyl)-propionic acid as a solid, 2.68 g (98 %). A mixture of 3-(2,3-difluoro-
pfyenyl)-propionic acid (2.7 g, 14.4 mmol) in CH2C12 at 0 °C was treated with oxalyl
chloride (8.7 mL, 2 M in CH2C12) and a few drops of DMF. The reaction mixture was
stirred for 2 h at rt. The solution was decanted from the dark colored residues and the
solvent was removed under vacuum. The residue was dissolved in CH2C12 (20 mL)
and added to a mixture of A1C13 (1.92 g, 14.4 mmol) in CH2C12 (25 mL). The mixture
w^s heated at 50 °C for 16 h. The entire mixture was poured into ice water. The
acjueous phase was removed and extracted with CH2C12. The organic layers were
combined, washed with sat. NaHC03 solution, brine, and dried over Na2SO4, filtered,
an|d evaporated to dryness. The residue was purified by chromatography on silica gel
with 20 % EtOAc-.hexane to give 4,5-difluoro-indan-l-one (Intermediate TWENTY-
2)i1.65g(68%).

A solution of give 4,5-difluoro-indan-l-one (Intermediate TWENTY-2) (1.36
gj 8.10 mmol) in benzene (20 mL) and ether (20 mL) was treated with a few iodine
crystals followed by ethyl bromoacetate (1.4 mL, 12.3 mmol) and zinc dust (1.60 g,
2j*.4mmol). The mixture was heated to 70 °C for 16 h at rt. The mixture was cooled
tcj rt and filtered through a pad of Celite. The filtrate was evaporated and the residue
((|4,5-difluoro-l-hydroxy-indan-l-yl)-acetic acid ethyl ester) was dissolved in benzene
ahd treated with a catalytic amount of /?TsOH. The mixture was heated at reflux in a
EJean-Stark trap for 16 h. The mixture was cooled to rt and diluted with aqueous acid
ahd ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic
layers were pooled and dried over MgSO4. The solution was filtered, evaporated and
purified by chromatography on silica gel with 10 to 15 % etherrhexane to give a
njixture of E- and Z-(4,5-difluoro-indan-l-ylidene)-acetic acid ethyl ester
(intermediate TWENTY-3) as a solid, 1.1 g.
A mixture of E- and Z-(4,5-difluoro-indan-l-ylidene)-acetic acid ethyl ester
intermediate TWENTY-3) (1.1 g) in EtOAc (25 mL) was hydrogenated with 10%
P|d/C (0.16 g) under H2 (balloon) at rt for 16 h. The mixture was filtered through a
bjsd of Celite® and the filtrate was evaporated under vacuum. The ester, (4,5-
dtfluoro-indan-l-yl)-acetic acid ethyl ester (1.1 g, 4.58 mmol) in THF (60 mL) and
tyeOH (1 mL) was treated with LiBH4 (0.21 g, 8.5 mmol) at 65 °C for 5 h. The
niixture was cooled and THF was removed under vacuum. The solution was diluted
with EtOAc and sat. NH4CI. The layers were separated and the organic layer was
djied over MgSO4 and filtered. After evaporation, the alcohol, 2-(4,5-difluoro-indan-
li-yl)-ethanol (Intermediate TWENTY-4) was isolated as a clear, colorless oil, 1.7 g,
($8%). Use, 2-(4,5-difluoro-indan-l-yl>ethanol (Intermediate TWENTY-4) in
Method SEVENTEEN produced 4-(4,5-difluoro-indan-l-ylmethyl)-l,3-dihydro-
iifridazole-2-thione (Compoundl56).
% NMR (300 MHz, MeOH-d4) 6 7.05-6.96 (m, 1H), 6.89-6.85 (m, 1H), 6.52 (s, 1H),
3146-3.38 (m, 1H), 3.00-2.83 (m, 3H), 2.61-2.54 (dd, /= 9.0, 6.0 Hz, 1H), 2.36-2.24
OMH), 1.90-1.79 (m, 1H).
Example TWENTY-1 (Compound 157)

Use of 6-fluoro-indan-l-one (commercially available from Lancaster) in
itethod TWENTY produced 4-(6-fluoro-indan-l-ylmethyl)-l,3-dihydro-imidazole-2-
^lione (Compound 157).
*JH NMR(300 MHz, MeOH-d4) 8 7.18-7.13 (m, 1H), 6.87-6.82 (m, 2H), 6.52 (m,
}H), 3.45-3.34 (m, 1H), 2.92-2.74 (m, 3H), 2.60-2.52 (dd, /= 9.0,6.0 Hz, 1H), 2.31-
il9 (m, 1H), 1.84-1.73 (m, 1H).
Example TWENTY-2 (Compound 158)
Use of 3-(3,4-difluoro-phenyl)-acrylic acid (commercially available from
Aldrich) in Method TWENTY produced 4-(5,6-difluoro-indan-l-ylmethyl)-l,3-
4ihydro-irnidazole-2-thione (Compound 158).
'JH NMR (300 MHz, MeOH-d4) 8 7.10-7.00 (m, 2H), 6.53 (s, 1H), 3.41-3.36 9m, 1H),
^.90-2.79 (m, 3H), 2.60-2.52 (dd, J= 9.6,5.7 Hz, 1H), 2.32-2.20 (m, 1H), 1.86-1.74
(fcffl).
Example TWENTY-3 (Compound 159)
Use of 2-fluorocinnamic acid (commercially available from Aldrich) in Method
"tWENTY produced 4-(4-fluoro-indan-l-ylmethyl)-l,3-dmydro-imidazole-2-thione
((Compound 159).
*|H NMR (300 MHz, MeOH-d4) 8 7.18-7.11 (m, 1H), 6.94 (d, J= 7.3 Hz, 1H), 6.85 (t,
i= 8.4 Hz, 1H), 6.50 (s, 1H), 3.50-3.42 (m, 1H), 2.93-2.80 (m, 3H), 2.62-2.54 (m,
JH), 2.30-2.24 (m, 1H), 1.86-1.80 (m, 1H).
Example TWENTY-4 (Compound 160)
Use of 2,5-dimethylcinnamic acid (commercially available from Lancaster) in
Method TWENTY produced 4,7-dimethylindan-l-one. Use of 4,7-dimethylindan-l-
dne in Method A produced 4^4,7-dimethyl-mdan-l-ylmemyl)-l,3-dihydro-imidazole-
2-thione (Compound 160).
'|H NMR (300 MHz, DMSO-d6) 8 12.0 (s, 1H), 11.6 (s, 1H), 6.86-6.80 (m, 2H), s,
JH), 3.43-3.36 (m, 1H), 2.83-2.47 (m, 3H), 2.23-2.18 (m, 3H), 2.12 (s, 3H), 1.95-1.76
(MH).
Example TWENTY-5 (Compound 161)

Use of 8-chloro-3,4-dihydro-2H-naphthalen-1 -one (Intermediate SIXTEEN-1) in
Method TWENTY (note.: for both of the hydrogenation procedures: substitute 5% Rh
lletrahydro-naphthalen- 1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 161).
|H NMR (300 MHz, DMSO-d6) 8 12.0 (s, 1H), 11.7 (m, 1H), 7.22 (d, /= 7.2 Hz,
}H), 7.12 (t, J= 7.5 Hz, 1H), 6.63 (s, 1H), 2.81-2.60 (m, 3H), 2.49-2.35 (m, 2H),
1.80-1.50 (m,4H).

Use of 7,8-dihydro-6H-quinolin-5-one (Intermediate TWENTYTWO-1)
(jobtained as described in Molina, et. al. Tetrahedron 1995, 51,1265, incorporated
herein by reference) in Method E produced 6-(lH-imidazol-4-ylmethyl)-7,8-dihydro-
6H-quinolin-5-one (Intermediate TWENTYTWO-2). To a solution of 6-(lH-
ijmidazol-4-ylmethyl)-7,8-dihydro-6H-quinolin-5-one (Intermediate
^WENTYTWO-2) (1.31 g, 227 mmol) in diethylene glycol (10 mL) was added
hydrazine (6.3 mL, 200 mmol) followed by KOH (4.85 g, 56.2 mmol). The mixture
^vas heated to 170 °C for 5 h. The mixture was diluted with water (200 mL) and sat.
ifjaHCCV The aqueous solution was extracted with CHCI3 (3 x 50 mL). The
Combined organic portions were washed with water and brine. The organic layer was
4ried over MgSC»4, filtered and evaporated to give 6-(lH-imidazol-4-ylmethyl)-
5,6,7,8-tetrahydro-quinoIine as a foamy solid, 1.15 g (92%). By the applicable
process steps described in Method A, the imidazole compound was used to produce 4-
(J5,6,7,8-tetrahyd^o-qumolm-6-ylmethyl)-l,3-dmydro-irnidazole-2-thione (Compound
}62).

'k NMR (300 MHz, DMSO-d6) 511.9 (s, 1H), 11.7 (s, 1H), 8.29 (d, J= 3.3 Hz, 1H),
7.45 (d, J= 12 Hz, 1H), 7.10 (dd, J= 7.5,4.5 Hz, 1H), 6.62 (s, 1H), 2.93-2.71 (m,
3^1), 2.51-2.37 (m, 3H), 2.04-1.90 (m, 2H), 1.50-1.37 (m, 1H).

Use of 2-chlorocinnamic acid (Intermediate TWENT YTHREE-1)
(commercially available from Aldrich) in the applicable process steps described in
I^ethod TWENTY and Method NINETEEN produced 4-chloro-indan-2-carboxylic
a csjrboxylic acid methyl ester (Intermediate TWENTYTHREE-2) in the applicable
process steps described in Method SEVENTEEN and Method A produced 4-(4-
clfloro-indan-2-yl)-l,3-dihydro-imidazole-2-thione (Compound 163).
'ijl NMR (300 MHz, MeOH-d4) 8 7.13 (brs, 3H), 6.60 (s, 1H), 3.61-3.50 (m, 1H),
3J38-3.28 (m, 2H), 3.09-2.93 (m, 2H).
Example TWENTYTHREE-1 (Compound 164)
Use of 3,5-difluorocinnamic acid (commercially available from Aldrich) in
Iv|ethod TWENTY produced 5,7-difluoro indan-1-one. Use of 5,7-difluoro indan-1-
ojie in Method TWENTYTHREE produced 4-(4,6-difluoro-indan-2-yl)-l,3-dihydro-
irjudazole-2-thione (Compound 164).
^ NMR (300 MHz, DMSO-d6) 8 12.1 (s, 1H), 11.7 (s, 1H), 7.01-6.96 (m, 2H), 6.66
(sj, 1H), 3.57-3.46 (m, 1H), 3.26-3.16 (m, 2H), 3.01-2.83 (m, 2H).
Example TWENTYTHREE-2 (Compound 165)
Use of 3-fluoro-5-methoxycinnamic acid (commercially available from
Ajldrich) in the applicable process steps described in Method TWENTY and Method

NINETEEN produced 4-fluoro-6-methoxy-indan-2-carboxylic acid methyl ester as an
intermediate. This material was subjected to the applicable process steps described in
to ethod SEVENTEEN and Method A in order to produce 4-(4-fluoro-6-methoxy-
irdan-2-yl)-l,3-dihydro-imidazole-2-thione (Compound 165).
*]I NMR (500 MHz, DMSO-d6) 8 12.0 (s, 1H), 11.7 (s, 1H), 6.68-6.65 (m, 2H), 6.62
(s, 1H), 3.45-3.38 (m, 1H), 3.17-3.12 (m, 1H), 3.10-3.04 (m, 1H), 2.91-2.86 (m, 1H),
2J73-2.69 (m, 1H).
Use of 2-chlorocinnamic acid (Intermediate TWENTYTHREE-1)
(c ommercially available from Aldrich) in the applicable process steps described in
Method TWENTY produced 4-chloro-indan-l-one (Intermediate TWENTYFOUR-
1\ Triethylphosphonoacetate (3.5 mL, 17.2 mmol) was added to a mixture of NaH
((.69 g, 12.2 mmol) in THF (25 mL). After 30 m, a solution of 4-chloro-indan-l-one
(Intermediate TWENTYFOUR-1) (1.46 g, 8.8 mmol) in THF (20 mL) was added to
the mixture. The reaction mixture was allowed to stir for 16 h at rt. The solution was
quenched with water and diluted with EtOAc. The layers were separated and the
organic phase was dried over MgSO4, filtered and evaporated under reduced pressure.
TJie residue was subjected to chromatography on silica gel with 3% EtOAc:hexane.
Tne fractions that contained the unsaturated esters were collected and evaporated to

give the product, 1.67g. The mixture of esters (1.67g, 7.06 mmol) in EtOAc was
h] xlrogenated in the presence of 5% Rh on Alumina (0.14 g) at 40-50 psi H2 at rt for 2
d. The mixture was filtered through a plug of Celite® and concentrated in vacuo to
pioduce (4-chloro-indan-l-yl)-acetic acid ethyl ester (Intermediate
TWENTYFOUR-2). Use of (4-chloro-indan-l-yl)-acetic acid ethyl ester
(Intermediate TWENTYFOUR-2) in the applicable process steps described in
V. ethod SEVENTEEN and Method A produced 4-(4-chloro-indan-l-ylmethyl)-l,3-
dihydro-imidazole-2-thione (Compound 166).
JH NMR (300 MHz, MeOH-d4) 5 7.16-7.04 (m, 3H), 6.51 (s, 1H), 3.53-3.44 (m, 1H),
3.01-2.80 (m, 3H), 2.60 (dd, J= 8.7,6 Hz, 1H), 2.31-2.19 (m, 1H), 1.85-1.74 (m, 1H).
Example TWENTYFOUR-1 (Compound 167)
Use of 4-bromoindanone (obtained by the procedures in Example
NINETEEN-1 (Compound 149) in Method TWENTYFOUR produced 4-(4-bromo-
irdan-l-ylmethyl)-l,3-dmydro-imidazole-2-thione (Compound 167).
'11 NMR (300 MHz, MeOH-d4) 8 7.31 (dd, J= 7.5,0.6 Hz, 1H), 7.11-7.02 (m, 2H),
6.51 (s, 1H), 3.56-3.47 (m, 1H), 2.99-2.78 (m, 3H), 2.63-2.55 (m, 1H), 2.30-2.19 (m,
111), 1.84-1.73 (m, 1H).
Example TWENTYFOUR-2 (Compound 168)
Use of 6,7-dihydro-5H-quinolin-8-one (obtained as described in Lemke, et. al.
J. Med. Chem., 1977,20,1351, incorporated herein by reference) in the applicable
process steps described in Method TWENTYFOUR produced E- and Z-(6,7-dihydro-
5H-quinolin-8-ylidene)-acetic acid ethyl ester. Note: The reduction procedure for the
fixture of esters was as follows. E- and Z-(6,7-dihydro-5H-quinolin-8-ylidene)-acetic
acid ethyl ester (2.3 g, 10.6 mmol) was hydrogenated in a mixture of TFA (20 mL),
at id Pt02 (150 mg) under 50 psi H2 for 50 m at rt. The mixture was filtered through a
b( :d of Celite® and using EtOAc. The filtrate was added to crushed ice and made
biisic (pH 8) with NaOH solution. The aqueous layer was extracted with EtOAc and
the pooled organic layers were dried over MgSO4, filtered, added to silica gel and
e^ raporated to dryness. The material was eluted through a column of silica gel with 20
°/
1.77g (77%). Use of (5,6,7,8-tetrahydro-quinolin-8-yl)-acetic acid ethyl ester in the
applicable process steps described in Method SEVENTEEN and Method A produced
4-(5,6,7,8-tetrahydro-quinolin-8-ylmethyl)-l,3-dihydro-iniidazole-2-thione
(Compound 168).
1B NMR (300 MHz, MeOH-d4) 8 8.36 (d, J= 5.1 Hz, 1H), 7.53 (d, J= 7.5 Hz, 1H),
j.18 (dd, J = 4.5, 7.5 Hz, 1H), 6.54 (s, 1H), 3.10-3.00 (m, 2H), 2.78 (brs, 2H), 2.73-
i64 9m, 1H), 1.90-1,82 (m, 2H), 1.75-1.68 (m, 2H).

A solution of 2-(lH-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-l-one
(intermediate E4) (2.11 g, 9.3 mmol) in DMF (25 mL) was treated with triethyl
^mine (1.9 mL, 13.6 mmol) and triphenylmethylchloride (tritylchloride) (2.74 g, 9.6
jnmol, added dropwise in DMF (25 mL)). After 16 h at rt the mixture was partitioned
between water and dichloromethane. The aqueous layer was extracted with
tHchloromethane and the organic layers were collected and dried over MgSO4, filtered
knd concentrated onto silica gel. The material was placed on a column of silica gel

and eluted with 50% EtOAc:hexane. The appropriate fractions were collected and 2-
(l-trityl-lH-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-l-one (Intermediate
^WENTYFTVE-1) was isolated as a white solid, 3.58 g (82%). Sodium hydride (1.2
eqv) in DMF (25 mL) was reacted with diethyl(cyanomethyl) phosphonate (available
f om Aldrich) (1.3 eqv) (added dropwise). After 30 m at rt a solution of 2-(l-trityl-
1 H-imidazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1 -one (Intermediate
^WENTYTTVE-1) in DMF (20 mL) was added in a dropwise fashion to the mixture.
The mixture was stirred for 16 h at rt. Another aliquot (1.2 eqv) of prepared NaH and
c iethyl(cyanomethyl) phosphonate in DMF was added to the mixture and the solution
was heated to 40 °C for 18 h. The mixture was quenched with sat. NH4CI, diluted
with water, and extracted with EtOAc. The organic layers were dried over MgSC>4,
filtered and concentrated onto silica gel. The material was eluted from a column of
silica gel with 40 % EtOAc:hexane. Two isomers E and Z (trans and cis) were
Collected from the column and carried onto the next step. A solution of the mixed
tjrans and cis isomers of [2-(l-trityl-lH-imidazol-4-ylmethyl)-3,4-dihydro-2H-
n'aphthalen-l-ylidenej-acetonitrile (0.33 g) was stirred in 95 % TFA (trifluoroacetic
i
ajcid, 9.5 mL) and water (0.5 mL) for 2 h at rt to remove the trityl protective group.
'the pH of the mixture was adjusted with 2M NaOH and extracted with EtOAc. The
rjiixture was subjected to an aqueous work-up and concentrated onto silica gel. The
rjiaterial was eluted from a column of silica gel with 5% NH3*MeOH in CH2CI2 to
dive [2-( 1 H-imidazol-4-ylrnethyl)-3,4-dihydro-2H-naphthalen-1 -ylidene]-acetonitrile
(\rans isomer) (Intermediate TWENTYFTVE-2) as a clear colorless oil (-0.1 g). The
(().27 g). Use of [2-(lH-inndazol-4-ylmethyl)-3,4-dihydro-2H-naphthalen-l-ylidene]-
abetonitrile (Intermediate TWENTYFTVE-2) in the applicable process steps
described in Method A produced [2-(2-mioxo-2,3-dihydro-lH-imidazol-4-ylmethyl)-
3J,4-dihydro-2H-naphthalen-l-ylidene]-acetonitrile (Compound 169 trans isomer)
H NMR (300 MHz, MeOH-d4) 8 8.04 (d, J = 8.0 Hz, 1H), 7.40 (t, / = 7.5 Hz,
l|H), 7.30-7.26 (m, 2H), 6.53 (s, 1H), 5.46 (s, 1H), 3.03-2.96 (m, 2H), 2.89-2.83 (m,
lJH), 2.61 (d, J= 7.0 Hz, 2H), 2.12-2.06 (m, 1H), 1.86-1.80 (m, 1H).

Example TWENTYFIVE-1 (Compound 170)
Use of Intermediate TWENTYFIVE-3 (see above preparation) in the
applicable process steps described in Method A produced [2-(2-thioxo-2,3-dihydro-
1 H-imida2M)l-4-ylmethyl)-3,4-dihydro-2H-naphthalen-1 -ylidene]-acetonitrile
[Compound 170 cis isomer).
'H NMR (300 MHz, DMSO-d6) 6 12.0 (s, 1H), 11.7 (s, 1H), 7.71 (d, J= 8.1 Hz, 1H),
7.36 (t, J= 7.5 Hz, 1H), 7.25-7.20 (m, 2H), 6.52 (s, 1H), 6.17 (s, 1H), 3.44-3.36 (m,
|lH), 3.02-2.91 (m, 1H), 2.76-2.70 (m, 1H), 2.58-2.38 (m, 2H), 1.87-1.84 (m, 2H).
|
t
A solution of 3-(/-butyl-dimethyl-silanyloxy)-propionaldehyde (Intermediate
TWENTYSIX-1) (1.5 g, 7.96 mmol) (obtained as described inBerque, etalJ. Org.
Chem. 1999, 373, incorporated herein by reference) in diethyl ether (60 ml), at-30
|°C, was treated with a solution of allylMgBr (9.6 mL, 1.0 M in ether). The mixture
(was allowed to warm to 0 °C and remained at this temperature for 1 h. The solution
was diluted with water (30 mL) and die layers were separated. The aqueous layer was
jextracted with ether (2x15 mL). The organic phases were combined and dried over
iMgSCU. The solution was filtered and evaporated under reduced pressure. The crude
jmaterial was purified by chromatography on Si02 with 10% EtOAc:hexane to give 1-

(?-butyl-dimethyl-silanyloxy)-hex-5-en-3-ol (Intermediate TWENTYSK-2) 1.7 g
(93 %). l-(/-Butyl-dimethyl-silanyloxy)-hex-5-en-3-ol (Intermediate
TWENTYSIX-2) (0.94 g, 4.1 mmol) in THF (10 mL) was treated with KHMDS
(14.8 mL, 0.5 M in toluene) at 0 °C to 20 °C for 1 h. 2-Bromo-2-methyl propene (1.1
g mL, 8.2 mmol) was added via syringe at 0 °C. The mixture was allowed to warm to
rt. Stirring was continued for 16 h. The mixture was quenched with water. The
organic layer was dried over MgSC«4, filtered and evaporated in vacuo. The residue
| was purified by chromatography on SiC«2 with 5% ethenhexane to give ^-butyl-
jdimethyl-[3-(2-methyl-allyloxy)-hex-5-enyloxy]-silane (Intermediate
! TWENTYSIX-3) 1.16 g, (86 %). A solution of f-butyl-dimethyl-[3-(2-methyl-
allyloxy)-hex-5-enyloxy]-silane (Intermediate TWENTYSIX-3) (1.0 g, 3.73 mmol)
in CH2CI2 was treated with Grubbs catalyst (260 mg, 0.32 mmol) (commercially
I available from Strem). The progress of the reaction was followed by TLC and was
I complete after 3 d at rt. The solvent was removed under vacuum and the material was
J purified by chromatography on silica gel with 2 % ether hexane to give t-bvtyl-
!dimethyl-[2-(5-methyl-3,6-dihydro-2H-pyran-2-yl)-ethoxy]-silane (Intermediate
! TWENTYSIX-4), -450 mg. A solution of/-butyl-dimethyl-[2-(5-methyl-3,6-
| dihydro-2H-pyran-2-yl>ethoxy]-silane (Intermediate TWENTYSIX-4) (-450 mg)
i in ether (7 mL) was treated with TBAF (5 mL, 1 M in THF) at rt for 3 h. The mixture
: was diluted with ether (20 mL) and washed with water (1x10 mL). The organic layer
i was isolated and dried over MgSO4, filtered and evaporated under vacuum.
! Chromatography on Si02 with 30 to 60 % EtOAc:hexane gave 2-(5-methyl-3,6-
i dihydro-2H-pyran-2-yl)-ethanol, 100 mg. A solution of oxalyl chloride (0.5 mL, 1
I mmol) in CH2C12 (1 mL) was treated with DMSO (0.080 mL, 1.1 mmol) at-78 °C for
130 m. A solution of 2-(5-methyl-3,6-dihydro-2H-pyran-2-yl)-ethanol (100 mg) was
I added and the mixture was allowed to stir for 30 m. Triethylamine (0.5 mL, -3
; mmol) was added and the mixture was allowed to stir for 45 m. The solution was
; quenched with water and CH2CI2 (10 mL). The organic layer was isolated, dried and
! evaporated. The residue was purified on silica gel with 30 % EtOAc:hexane to give
! (5-methyl-3,6-dihydro-2H-pyran-2-yl)-acetaldehyde (Intermediate TWENTYSK-

5), 90 mg. Use of (5-methyl-3,6-dihydro-2H-pyran-2-yl)-acetaldehyde (Intermediate
TWENTYSLX-5) in the applicable process steps described in Method A produced 4-
!(5-me1hyl-3,6-dihydro-2H-pyran-2-ylmethyl)-l,3-dihydro-imidazole-2-thione
((Compound 171).
I'H NMR (300 MHz, CDC13) 8 10.8 (s, 1H), 9.95 (s, 1H), 6.47 (s, 1H), 5.46 (s, 1H),
J4.05'(s, 2H), 3.73-3.62 (m, 1H), 2.76-2.63 (m, 1H), 2.58 (dd, J= 8.4, 7.5 Hz, 1H),
12.03-1.88 (m, 2H), 1.61 (s, 3H).

A solution of 4-(l,2,3,4,5,6-hexahydro-pentalen-l-ylmethyl)-lH-imidazole;
| fumarate salt (Intermediate A5 as described in Example A, 340 mg, 1.81 mmol) in
ITHF (15 mL) and water (15 mL) was treated with NaHC03 (1.52 g, 18 mmol) at rt for
i 30 m. Phenyl chloroformate (600 mL, 4.7 mmol) was added and stirring was
i continued for 1 h at 65 °C. The mixture was diluted with water (30 mL) and extracted
I with EtOAc (3 x 30 mL). The organic portions were combined and freed of solvent.
! The residue was dissolved in EtOH (15 mL) : water (15 mL) and treated with Na2C03
i (500 mg) for 1.5 h at 95 °C. The mixture was cooled to rt and the product was
collected on a glass frit to give a white solid (~50%) 4-( 1,2,3,4,5,6-Hexahydro-
I pentalen-l-ylmethyl)-l,3-dihydro-imidazol-2-one (Compound 41).
! 'H NMR (300 MHz, DMSO -d6): 6 9.69 (s, 1H), 9.38 (s, 1H), 5.92 (s, 1H), 2.70 (brs,
! 1H), 2.40-2.30 (m, 3H), 2.12-1.99 (m, 9H), 1.85-1.78 (m, 1H).
Example P2 (Compound 42)
Use of 3-methyl-cyclopent-2-enone (commercially available from Aldrich) in
I the applicable steps combined from Method A and Method P produced 4-(3-methyl-
j cyclopent-2-enylmemyl)-l,3-dihydro-imidazol-2-one (Compound 42).

1H NMR (300 MHz, DMSO-d6 w/ IMS): 8 9.67 (s, 1H), 9.38 (s, 1H), 5.93 (s, 1H),
^.25 (s, 1H), 3.16 (d, /= 5.4 Hz, 1H), 2.82-2.11 (m, 3H), 2.0-1.96 (m, 1H), 1.67 (s,
^H), 1.50-1.46 (m,lH).
Example P3 (Compound 43)
Use of 2-ethyl-cyclopent-2-enone (commercially available from Aldrich) in the
applicable steps combined from Method A and Method P produced 4-(2-ethyl-
cyclopent-2-enylmethyl)-l,3-dihydro-imidazol-2-one (Compound 43).
'HNMR (300 MHz, CD3OD-d4): 5 6.05 (s, 1H), 5.38 (brs, 1H), 3.31-3.29 (m, 1H),
i.75 (brs, 1H), 2.67-2.60 (m, 1H), 2.25-1.98 (series of m, 7H), 1.62-1.55 (m, 1H), 1.07
()t,y=10Hz,3H).
Example P4 (Compound 44)
Use of 2,3-dimethyl-cyclopent-2-enone (commercially available from Aldrich)
ijn the applicable steps combined from Method A and Method P produced 4-(2,3-
• j'H NMR (300 MHz, CD3OD-d4): 8 6.04 (s, 1H), 2.73 (brs, 1H), 2.68-2.61 (m, 1H),
£.27-2.19 (m, 2H), 2.13-2.05 (m, 1H), 1.99-1.87 (m, 1H), 1.63 (s, 6H), 1.55-1.46 (m,
tH).
Example P5 (Compound 45)
Use of 3,4-dihydro-2H-naphthalen-1 -one (commercially available from
jMdrich) in the applicable steps combined from Method A and Method P produced 4-
(l,2,3,4-tefrahydrcHnaphthalen-l-ylmethyl)-l,3-dihydro-irnidazol-2-one (Compound
JI5).
JH NMR (300 MHz, DMSO-d6 w/ TMS): 8 9.86 (s, 1H), 9.40 (s, 1H), 7.16-7.04 (m,
jtH), 5.96 (s, 1H), 2.97 (brs, 1H), 2.69-2.29 (series of m, 5H), 1.66-1.60 (m, 3H).
Example P6 (Compound 46)
Use of indan-1-one (commercially available from Aldrich) in the applicable
iteps combined from Method A and Method P produced 4-indan-1-ylmethy 1-1,3-
jiihydro-imidazol-2-one (Compound 46).

^ NMR (300 MHz, DMSO-d6 w/ TMS): 8 9.83 (s, 1H), 9.43 (s, 1H), 7.21-7.13 (m,
4lj), 5.95 (s, 1H), 3.40-3.28 (m, 1H), 2.95-2.63 (m, 3H), 2.30-2.12 (m, 2H), 1.70-1.59
(41H)-
Example F7 (Compound 47 )
; Use of 3 -methyl-indan-1 -one (commercially available from Aldrich) in the
applicable steps combined from Method A and Method P produced 4-(3-methyl-
indan-l-ylmethyl)-l,3-dihydro-imidazol-2-one (Compound 47).
JH NMR (500 MHz, DMSO-d6 w/ TMS): 8 (diastereomers) 9.85 (s, 1H), 9.45 (s, 1H),
7. J7-7.08 (m, 4H), 6.00 (5.92) (s, 1H), 3.34-2.86 (series of m, 2H), 2.37-2.22 (series
ofjm,2H), 1.99-1.95 (m, 1H), 1.71-1.67 (m, 1H), 1.18 (1.25)(d,/=6.5Hz,3H), 1.50-
l.J4(m,2H).
Example P8 (Compound 48)
Use of 4-methyl-indan-l-one (commercially available from Aldrich) in the
applicable steps combined from Method A and Method P produced 4-(4-methyl-
inaan-1 -ylmethyl)-1,3-dihydro-imidazol-2-one.
^ NMR (500 MHz, DMSO-d6 w/TMS): 8 9.83 (s, 1H), 9.44 (s, 1H), 7.02-6.91 (m,
3^), 5.92 (s, 1H), 3.28 (brs, 1H), 2.79-2.74 (m, 1H), 2.66-2.63 (m, 2H), 2.25-2.10 (m,
2KJ), 2.17 (s, 3H), 1.65-1.61 (m, 1H).
Example P9 (Compound 49)
Use of 5-fluoro-indan-l-one (commercially available from Aldrich) in the
applicable steps combined from Method A and Method P produced 4-(5-fluoro-indan-
l-)[lmethyl)-l,3-dihydro-imidazol-2-one (Compound 49).
'HJNMR (300 MHz, DMSO-d6 w/TMS): 5 9.83 (s, 1H), 9.44 (s, 1H), 7.14-6.91 (m,
3H(), 5.95 (s, 1H), 3.31-3.28 (m, 1H), 2.88-2.60 (m, 3H), 2.31-2.14 (m, 2H), 1.75-1.70
(mjlH). -
Example P10 (Compound 50)
Use of 5-methoxy-indan-l-one (commercially available from Aldrich) in the
applicable steps combined from Method A and Method P produced 4-(5-methoxy-
indjan-1-ylmethyl)-l,3-dihydro-imidazol-2-one (Compound 50).

Jfl| NMR (500 MHz, DMSO-d6 w/ TMS): 8 9.81 (s, 1H), 9.43 (s, 1H), 7.02-6.67 (m,
3lj), 5.94 (s, 1H), 3.26-3.23 (m, 1H), 3.70 (s, 3H), 2.83-2.59 (series of m, 3H), 2.26-
2. jo (m, 2H), 1.67-1.63 (m, 1H).
Example Pll (Compound 51)
Use of 5-bromo-indan-1 -one (commercially available from Aldrich) in the
apj )licable steps combined from Method A and Method P produced 4-(5-bromo-indan-
l-ylmethyl)-l,3-dihydrp-imidazol-2-one (Compound 51).
*H NMR (500 MHz, DMSO-d6 w/ TMS): 8 9.83 (s, 1H), 9.45 (s, 1H), 7.39 (d, /= 5
Hz, 1H), 7.30 (d, /= 8.5 Hz, 1H), 7.07 (d, J= 8.5 Hz, 1H), 5.95 (s, 1H), 3.29 (brs,
1H), 2.87-2.61 (series of m, 3H), 2.31-2.14 (m, 2H), 1.70-1.68 (m, 1H).
Example P12 (Compound 52)
Use of 6-methyl-indan-l-one (commercially available from Aldrich) in the
applicable steps combined from Method A and Method P produced 4-(6-methyl-
inaan-l-ylmethyl)-l,3-dihydro-imidazol-2-one (Compound 52).
'HJNMR (500 MHz, DMSO-d6 w/ TMS): 8 9.87 (s, 1H), 9.48 (s, 1H), 7.07 (d, J= 7.5
Hz 1H), 6.97-6.93 (m, 2H), 5.96 (s, 1H), 3.29-3.26 (m, 1H), 3.80-2.66 (m, 3H), 2.25
(s, pH), 2.36-2.11 (m, 2H), 1.66-1.62 (m, 1H).
Example P13 (Compound 53)
Use of 6-methoxy-indan-l-one (commercially available from Aldrich) in the
applicable steps combined from Method A and Method P produced 4-(6-methoxy-
mdW-l-ylmethyl)-l,3-dihydro-imidazol-2-one (Compound 53).
JH|NMR (500 MHz, DMSO-d6 w/ TMS): 8 9.86 (s, 1H), 9.48 (s, 1H), 7.08 (d, J= 7.5
Hzj 1H), 6.69 (brs, 2H), 3.69 (s, 3H), 3.30-3.27 (m, 1H), 2.78-2.65 (series of m, 3H),
2.2^-2.10 (m,2H), 1.68-1.64 (m, 1H).
Example Q (Compound 54)
Procedure for preparation of 4-n-oxo-1.2.3.4-tetrahvdro-naphthalen-2-vlmethvl)-1.3-
dihydro-imidazol-2-one (Compound 54) and 4-(4,5,6.7-tetrahydro-
benko|l)]miophen-5-vlmemvl)-1.3-dmvd^o-imidazol-2-one (Compound 55)


2f(lH-imidazol-4-ylmemylene)-3,4-dihydro-2H-naphmalen-l-one (Intermediate E4,
a^ described in Example E, 1.4g) was subjected to the applicable steps of Method P to
provide 4-(l-oxo-l,2,3,4-tetrahyd^o-naph1halen-2-ylmethyl)-l,3-dihyd^-imida2»l-2-
one (Compound 54) isolated as a white solid (~50%).
^ NMR (300 MHz, DMSO-d* w/ TMS) 5 9.70 (s, 1H), 9.45 (s, 1H), 7.88-7.86 (m,
1 jl), 7.57-7.51 (m, 1H), 7.37-7.32 (m, 2H), 2.95-2.90 (m, 3H), 2.82-2.70 (m, 1H),
2.f30-2.20 (m, 1H), 2.15-2.05 (m, 1H), 1.75-1.68 (m, 1H).
Synthesis of 4-(4,5,6,7-tetrahydro-benzo[b]thiophen-5-ylmethyl)-l,3-dihydro-
in^idazol-2-one (Compound 55) from 6,7-dihydro-5H-benzo[b]miophen-4-one was
accomplished from 4-(4,5,6,7-tetrahydro-benzo[b]thiophen-5-ylmethyl)-lH-
injidazole (Intermediate F3 as described in Example A) in the applicable reaction
sequence of Method P, and shown below.

4-(4,5,6,7-tetrahydro-benzo|b]thiophen-5-ylmemyl)-l,3-dmydro-irnidazol-2-one
(Compound 55):
JH| NMR (300 MHz, DMSO-d6) 8 9.72 (s, 1H), 9.42 (s, 1H), 7.21 (d, J= 6.0 Hz, 1H),
6.J5 (d, J= 6.0 Hz, 1H), 5.99 (s, 1H), 2.83-2.60 (m, 3H), 2.28-2.15 (m, 3H), 2.02-1.85
(m[2H), 1.43-1.35 (m,lH).
Example R (Compound 56)
Method R: Synthesis of4-(3-hydroxymethyl-cyclohex-3-enylmethyl)-l,3-dihydro-
imjdazol-2-one (Compound 56)


8-(2-Benzyloxy-ethyl)-1,4-dioxa-spiro[4.5]decane (Intermediate Rl, 1.02 g,
3.^0 mmol) (obtainable as desribed in the publication by Ciufolini et. al. J. Amer.
Cliem. Soc. 1991,113, 8016, incorporated herein by reference) was dissolved in
acetone (100 mL) : H20 (5 mL) and reacted with TsOH (140 mg, 0.74 mmol) at 45.
°(| for 5 h. After a standard aqueous work-up the material was purified by
chromatography on Si02 to give 4-(2-benzyloxy-ethyl)-cyclohexanone as a colorless
oi^ (97%).
A solution of LDA (33 ml, 1.5 M in Et20) in THF (50 mL) at -78 °C was
trekted with 4-(2-benzyloxy-ethyl)-cyclohexanone (9.5 g, 40.2 mmol). The mixture
wais warmed to 0 °C over 30 m before re-cooling to -78 °C and adding HMPA (7
ml,). Methyl cyanoformate (4.1 mL, 85 mmol) was added and the mixture was stirred
forj 15 m before aqueous quench and work-up. The product was purified by
chiomatography on S1O2 with 10 % EtOAc:Hx. 5-(2-Benzyloxy-ethyl)-2-oxo-
cy an bquivalent of NaBRt in MeOH at-10 °C to provide the alcohol (Intermediate
R2). Intermediate R2 was purified by chromatography on Si02 with 30 to 50 %
Et(j)AC:Hx. (-90% yield).
A solution of 5-(2-benzyloxy-ethyl)-2-hydroxy-cyclohexanecarboxylic acid
methyl ester (Intermediate R2, 0.72 g, 2.48 mmol) in pyridine (10 mL) was treated

with SOC12 (0.73 mL, 12.4 mmol) at-20 °C. The mixture was allowed to react for 15
m| and was then warmed to 55 °C for 16 h. The solvents were removed under
vecuum and the residue was diluted in ether at 0°C. The solution was quenched with
w iter, washed with 1M HC1, 5% NaOH and brine. The organic material was dried
o\ er MgSC>4 filtered and freed of solvent The mixture was diluted with benzene and
w; iter was removed by azeotropic distillation under vacuum. The residue was
di isolved in benzene (15 mL) and DBU (0.76 mL, 5 mmol) was added. The mixture
Wi is reacted for 30 m at it After work-up and chromatography on Si02 with 20 %
ElJ0Ac:Hx 5-(2-benzyloxy-ethyl)-cyclohex-l-enecarboxylic acid methyl ester
(Intermediate R3) was isolated 0.56 g (82%).
Intermediate R3 was dissolved in THF (100 mL) and added to a solution of
D^BAL (70 mL, 1M in hexanes) in THF (160 mL) at -35 °C for 35 m. The mixture
was quenched with Rochelle's salt solution, and extracted with ether. The dried
residue was purified by chromatography on SiC>2 with 30% EtOAcrHx to yield [5-(2-
beazyloxy-ethyl)-cyclohex-l-enyl]-methanol 4.6 g (80%). A solution of the alcohol
(4 0 g, 18.7 mmol) in DMF (60 mL) was treated with triemylamine (3 mL) followed
by) TBSC1 (3.0 g, 22.4 mol) for 20 m at rt. The residue was isolated from an aqueous
1
work-up and purified by chromatography to give [5-(2-benzyloxy-ethyl)-cyclohex-l-
en>lmethoxy]-tert-butyl-dimethyl-silane (Intermediate R4,3.6 g (63%). The benzyl
ani tert-butyl-dimethyl-silyl protected alcohol (Intermediate R4,2.0 g, 5.55 mmol)
in THF (20 mL) was cooled to -70 °C and NH3 was condensed in this flask (~20 mL).
N^ chunks were added and the mixture was allowed to stir at -70 °C for 15 m. The
mixture was warmed to -30 °C for 20 m. The mixture was quenched with NH4CI and
th ex raction. The residue was purified by chromatography on SiC>2 with 25 %
EtOAc:Hx (99%).
The alcohol was oxidized by the standard "Swern" protocol (see Mancuso
Syathesis supra) as follows. The alcohol 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-
cy chloride (3.55 mL, 7.1 mmol) in CH2C12 (30 mL) with DMSO (0.63 mL, 8.9 mmol) at

-' 8 °C. After 40 m, NEt3 (2.51 mL) was added and the mixture was warmed to it
A iter standard aqueous work-up and purification, [3-(tert-butyl-dimethyl-
sii anyloxymethyl)-cyclohex-3-enyl]-acetaldehyde (Intermediate R5) was isolated
(-95%). The aldehyde (Intermediate R5) was subjected to the applicable steps of
Method P to form 4-(3-hydroxymethyl-cyclohex-3-enylmemyl)-l^-dmydro-imidazol-
2- one (Compound 56).
J4 NMR (300 MHz, CD3OD-d4) 8 6.04 (s, 1H), 5.66 (s, 1H), 3.90 (s, 2H), 2.34 (d, J=
7.|t Hz, 2H), 2.15-2.06 (m, 3H), 1.85-1.65 (m, 3H), 1.29-1.15 (m, 1H).

5-(2-Benzyloxy-ethyl)-cyclohex-l-enecarboxylic acid methyl ester
(Intermediate R3 obtained above in Example Rl in accordance with Method R) was
reduced with DIBAL. The resulting alcohol (Intermediate R7, 1.18 g, 4.81 mmol)
in THF (20 mL) at 0 °C was treated with sulfur trioxide-pyridine. (1.15 g, 7.21 mmol)
foj- 3 h. LiAlHt (15 mL, 15 mmol) was injected into the mixture at 0 °C. The
>
solution was allowed to warm to rt for 18 h. The mixture was subjected to an aqueous
wi>rk-up and purified by chromatography to give [2-(3-methyl-cyclohex-3-enyl)-
etioxymethylj-benzene (Intermediate R8, 0.90 g, 82%). Deprotection with Na/NH3
and subsequent "Swern" oxidation produced (3-methyl-cyclohex-3-enyl)-
ac staldehyde (Intermediate R9). (3-methyl-cyclohex-3-enyl)-acetaldehyde

(Intermediate R9) was subjected to the applicable steps combined from Method A
aijd Method P to yield 4-(3-methyl-cyclohex-3-enylmemyl)-l,3Klihydio-imidazol-2-
one (Compound 57).
'H NMR (300 MHz, DMSO-d6) d 9.64 (s, 1H), 9.35 (s, 1H), 5.92 (s, 1H), 2.14 (d, /=
6.J9 Hz, 2H), 1.94-1.74 (m, 4H), 1.62-1.50 (m, 2H), 1.57 (s, 3H), 1.09-0.96 (m, 1H).

(3-Ethyl-4-methyl-cyclohex-3-enyl)-acetaldehyde (Intermediate Kl as
piepared in Example K) was subjected to the applicable steps combined from Method
A and Method P to yield 4-(3-ethyl-4-methyl-cyclohex-3-enylmethyl)-l,3-dihydro-
iniidazol-2-one (Compound 58).
^t NMR (300 MHz, CD3OD) 8 6.05 (s, 1H), 2.29 (d, 7= 6.9 Hz, 2 H), 2.00-1.97 (m,
411), 1.75-1.59 (m, 6H), 1.26-1.12 (m, 1H), 1.0-0.88 (m, 4H).
Example R4 (Compound 59)
Piocedure for the preparation of 4-(3-ethvl-cvclohex-3-envlmethvlV1.3-dihvdro-
iniidazol-2-one (Compound 59)


A solution of 4-(2-hydroxy-ethyl)-cyclohexanone (Intermediate RIO, 6.8 g,
52.6 mmol, (obtainable as described in the publication by Ciufolini et. al. J. Amer.

am. Soc. 1991,113, 8016) was dissolved in CH2C12 (75 mL) and treated with
opropylethylamine (9.2 mL, 52.6 mmol) followed by tri-isopropylsilyl
uoromethane sulfonate (TIPSTf) (15.3 g, 50.2 mmol) at -30 °C. The reaction
m xture was warmed to 0 °C for 1 h. The mixture was subjected to an aqueous work-
up and purified by chromatography on Si02 to give 4-(2-triisopropylsilanyloxy-ethyl)-
cy slohexanone (Intermediate Rl 1, 11.8 g (82%). Intermediate Rll was
converted via Intermediate R12 to the unsaturated aldehyde, 5-(2-
tri sopropylsilanyloxy-ethyl)-cyclohex-l-enecarbaldehyde (Intermediate R13)
A solution of TMS-diazomethane (4.61 mL, 9.22 mmol) in THF (60 mL) was
reicted with n-BuLi (5.0 mL, 7.99 mmol) at -78 °C for 0.5 h. 5-(2-
tri|sopropylsilanyloxy-ethyl)-cyclohex-l-enecarbaldehyde (Intermediate R13) was
added via cannula. The mixture was reacted at —78 °C for 1 h and at 0 °C for 1 h.
After work-up and chromatographic purification, [2-(3-ethynyl-cyclohex-3-enyl)-
etlioxy]-triisopropyl-silane (Intermediate R14) was isolated, 1.44 g (77%). To
Intermediate R14 in THF (70 mL) at 0 °C was injected tetrabutyl ammonium
i

fli oride (TBAF). After 2 h at rt the mixture was subjected to an aqueous work-up.
Tt e material was purified by chromatography to give the alcohol, 2-(3-ethynyl-
cy ;lohex-3-enyl)-ethanol 0.68 g, (98%). The alcohol was oxidized by a Swern
re; tction to the aldehyde stage and aldehyde was subjected to the applicable step of
M ;thod A to yield 4-(3-ethynyl-cyclohex-3-enylmethyl)-lH-imidazole
(Ii itermediate R15).
A mixture of NiCl2 (0.364 g, 2.81 mmol) in EtOH (20 mL) was reacted with
(0.053 mg, 1.40 mmol) atrt for 15 m after saturation of the solution with
hy drogen gas. Ethylene diamine (0.17 g, 2.81 mmol) was added followed by the
all :ynyl imidazol (Intermediate R15, 0.26 g, 1.40 mmol) at rt for 45 m under an
ati nosphere of hydrogen gas. The mixture was filtered, diluted with chloroform and
su ?jected to an aqueous work-up. The residue was purified by chromatography on
Si 32 to give 4-(3-vinyl-cyclohex-3-enylmethyl)-lH-imidazole (72%). To 4-(3-vinyl-
cy|clohex-3-enylmemyl)-lH-irnidazole (0.09 g, 0.47 mmol) in ethanol (3 mL) at 0 °C
wjs added H2NNH2-H20 (0.93 mL, 19.1 mmol) followed by H2C>2 (30%) (0.488 g,
14.4 mmol) and the mixture was stirred for 45 m at 0 °C and an additional 6 h at rt.
Tt e reaction was quenched and the material was purified by an aqueous work-up.
The imidazole compound was purified further by isolation of the fumaric acid salt.
The fumarate was converted to the compound 4-(3-ethyl-cyclohex-3-enylmethyl)-l,3-
dihydro-imidazol-2-one (Compound 59) by the applicable step of Method P.
1 'H NMR (300 MHz, CD3OD) 8 6.05 (s, 1H), 5.37 (s, 1H), 2.31 (d, J= 6.6 Hz, 2H),
2.^)3-1.10 (m, 9H), 0.97 (t,/= 7.5 Hz, 3H).


To Intermediate M5 (obtained in accordance with Example M (0.53 g, 1.77
m nol) in MeOH (5 ml) was added aqueous KOH (15 ml of a 5M solution) and the
m xture was heated at reflux for 32 h. The mixture was concentrated under reduced
pressure, diluted with H20 (5 ml) and extracted exhaustively with CHC13. The
co tnbined organic fractions were washed consecutively with H2O and brine, dried
(h [gSO,}) and concentrated under reduced pressure. The resulting imidazole was
re rrystallized by stirring in MeOH with an equimolar amount of furnaric acid until all
so ids had disappeared followed by the addition of a small amount of diethyl ether. 4-
(3 4-Dimemyl-cyclohex-3-enylmethyl)-lH-imidazole-fumarate 0.27 g (57%) was
recovered as pale yellow crystals. 4-(3,4-dimethyl-cyclohex-3-enylmethyl)-lH-
irr idazole-fumarate was subjected to the applicable steps of Method P to yield 4-(3,4-
du nethyl-cyclohex-3-enylmemyl)-l,3-dihydro-irnidazol-2-one (Compound 60).
JB NMR (300 MHz, CD3OD-d4): d 6.04 (s, 1H), 2.29 (d, /= 9 Hz, 2H), 2.00-1.96
.(no, 3H), 1.79-1.69 (m, 3H), 1.59 (s, 6H), 1.21-1.17 (m, 1H).
Example T (Compound 61 and Compound 62)
Procedure for the preparation of R-(+>4-(5-fluoro-indan-l-vlmethylVl,3-
dil ;vdro-imidazol-2-one (Compound 61) and of S-(-)-4-(5-fluoro-indan-l-vlmethvl)-
1.; -dihvdro-imidazol-2-one (Compound 62)


To 1,3-dithiane (available from Aldrich, 34.1 g, 283.4 mmol) in THF
(ai [hydrous, 373 ml) at -30 "°C under argon was added M-BuLi (136.0 ml of a 2 M
so ution in cyclohexane) at a rate by which the internal temperature of the reaction
WJ s maintained below -25 °C. After addition was complete the reaction was allowed

td warm to -15 °C and stirred for 2 hours. The reaction was then allowed to warm to
0 °C and 5-fluoro-indan-l-one (Intermediate Tl, commercially available from
A Idrich) (34.0 g, 226.7 mmol) in THF (anhydrous, 1 L) was added dropwise over 2
b >urs. After stirring for 20 hours at 0 °C the reaction was concentrated at reduced
pi essure and the residues were taken up in Et20 (600 ml) and washed consecutively
with IN HC1, H20 and brine and men concentrated at reduced pressure. This residue
was taken up in benzene (1 L) and/7-toluenesulfonic acid-H20 (8.6 g, 45.3 mmol) was
ac ded. This solution was refluxed in a flask equipped with a Dean Stark trap until no
m ore H20 was collected. The reaction was cooled to 20 °C and washed consecutively
with H20, saturated aqueous NaHC03, brine, dried (MgSO4), filtered and
ct ncentrated at reduced pressure. This residue was taken up in a solution of glacial
A ;OH (1 L) and concentrated HC1 (400 ml) and heated at reflux for 3 hours. The
re action was concentrated at reduced pressure and subjected to azeotropic removal of
ac ueous liquid by distillation on a rotary evaporator (3 times) with toluene (100 ml).
Tl ie residues were taken up in Et20 (200 ml) and washed with H20 until the washings
w ;re neutral. This solution was extracted 3 times with NaOH (75 ml portions of a 5%
ac ueous solution) and the combined aqueous portions were washed 3 times with Et20
(50 ml portions), then treated with decolorizing charcoal and filtered through celite.
Tl ie resulting aqueous solution was cooled to 0 °C, carefully acidified to pH 3 with
COQC HC1 and extracted 3 times with CH2C12. The combined organic portions were
witshed with H20 and brine, dried (MgSO4), filtered and concentrated at reduced
pr ;ssure. The resulting solids were recrystallized from hexanes to give 26.2 g (64%)
of racemic carboxylic acid (Intermediate T2).
To the racemic carboxylic acid (Intermediate T2,107.1 g, 595.0 mmol) in
re: luxing acetone (500 ml) was added in portions (-)-cinchonidine (175.2 g, 595.0 '
mi nol). Additional acetone was gradually added to the refluxing mixture until most
so ids had gone into solution (final volume was 3.5 L). The solution was filtered
wl ile hot and then reduced in volume to 800 ml and H20 (900 ml) was added with
sti Ting. The resulting solution was allowed to stand for 16 hours at room temperature.
The resulting solid salt was removed by filtration and recrystallized four more times in

s milar manner from acetone and H20 to give a white solid which was taken up in 0
°C 5N HC1 (200 ml). This solution was extracted 3 times with Et20 (200 ml portions)
a id the combined Et20 portions were washed successively with IN HC1, H2O and
brine, dried (MgSO^), filtered and concentrated under reduced pressure to give 18.9 g
(15% of theoretical) of (S)-5-fluoro-indan-l-carboxylic acid (Intermediate T3) as a
pale solid with [a] D -33.5 (c = 3.66, benzene).
(S)-5-Fluoro-indan-l-carboxylic acid (Intermediate T3) was used in the
s ^thesis of R-(+)^-(5-fluoro-md^-l-ylmemyl)-l,3-dmydro-imidazol-2-one
(Compound 61) in analogy to the procedure shown in the scheme above for the
synthesis of Compound 62 which is described below. Compound 61: [a]20D+12.5
(,:=0.6,DMSO).
l]l NMR (500 MHz, DMSO-d6) 8 9.80 (s, 1H), 9.42 (s, 1H), 7.11-7.08 (m, 1H), 7.01-
6.99 (m, 1H), 6.91-6.87 (m, 1H), 5.93 (s, 1H), 3.30-3.25 (m, 1H), 2.88-2.70 (m, 2H),
2 65-2.58 (m, 1H), 2.32-2.10 (m, 2H), 1.71-1.66 (m, 1H).
The combined mother liquors from the resolution of Intermediate T3 were
c mcentrated under reduced pressure until no acetone remained and acidified to pH 3
with 0 °C 5N HC1. This solution was extracted 3 times with Et20 (200 ml portions)
aid the combined Et20 portions were washed successively with IN HCl, H20 and
b ine, dried (MgSO4), filtered and concentrated under reduced pressure to give a
y ;llow solid (71 g). This residue was recrystallized from hexane to give pure 5-fluoro-
ii dan-1-carboxylic acid (Intermediate 2a, 58.6 g, 325.5 mmol) which was enriched
ii the R enantiomer. To Intermediate 2a in refluxing acetone (1 L) was added
p llverized brucine (128.4 g, 325.5 mmol). After most solids had dissolved the
solution was hot filtered and reheated to reflux as H20 (1 L) was added gradually.
Excess acetone was boiled off until the solution became hazy. The solution was
al lowed to stand in a recrystallization dish for 1 month before solids appeared. The
resultant solids were broken up, filtered off and recrystallized four more times in
si lular manner from acetone and H20 to give a buff colored solid which was taken up
ir 0 °C IN HCl (150 ml). This solution was extracted 3 times with Et20 (75 ml
portions) and the combined Et20 portions were washed successively with IN HCl,

H2 3 and brine, dried (MgSC^), filtered and concentrated under reduced pressure to
gi-s e 6.13 g of (R)-5-fluoro-indan-l-carboxylic acid (Intermediate T4) as a pale solid
wr ich rotates sodium light at 20 °C with [a]20D +31.8 (c = 4.49, benzene).
To a solution of LAH (33.8 ml of a 1M solution in THF) in THF (anhydrous,
30 ml) at 0 °C under argon was added the carboxylic acid (Intermediate T4,3.04 g,
16 90 mmol) in THF (anhydrous, 30 ml) dropwise via syringe. This mixture was
sti Ted 30 minutes at 0 °C and then allowed to stir at 20 °C for 1 hour. The reaction
WJ s then recooled to 0 °C and quenched with the successive addition of H2O (1.3 ml),
15 Vo aqueous NaOH (1.3 ml) and H20 (2.6 ml). This mixture was stirred 30 minutes
at >0 °C and then filtered. The filtrate was concentrated under reduced pressure and
th gr 'e 2.69 g of the alcohol (Intermediate T5,96%) with [a]20D +17.1 (c = 6.04,
beizene).
Triphenylphosphine (10.62 g, 40.48 mmol) in a solution of THF (anhydrous,
125 ml) at 0 °C under argon was treated with DEAD (6.77 g, 38.86 mmol). After
sti xing 5 minutes the alcohol (Intermediate T5,2.69 g, 16.93 mmol) and acetone
cy mohydrin (3.31 g, 38.86 mmol) in THF (anhydrous, 50 ml) were added
co icurrently via cannula. This mixture was allowed to stir at 20 °C for 20 hours. The
m xture was concentrated under reduced pressure, the residues were taken up in Et20,
wj ished consecutively with saturated aqueous K2C03, H20 and brine, dried (MgSO^
and concentrated under reduced pressure. The residues were purified by
chromatography on Si02 with 20% EtOAc:hexanes to give 2.69 g of the nitrile
(I) itermediate T6). This mixture was carried on without further purification.
To the nitrile (Intermediate T6, 2.00 g, 11.43 mmol) in Et20 (anhydrous, 50
ni) at -78 °C under argon was added DIBAL (22.9 rm of a 1 M solution in THF) and
thi; reaction was allowed to warm gradually to -40 °C. Additional DIBAL (21.0 ml of
a M solution in THF) was added to the reaction mixture at -40 °C over a period of
}
hours until no starting material was visible by thin layer chromatography. The
ction was quenched with a saturated aqueous solution of sodium potassium tartrate,
er stirring a 20 °C for 1 hour the solids were filtered off and the filtrate was taken

i p in Et20 and washed consecutively with H20 and brine, dried (MgSO4) and
c oncentrated under reduced pressure. The residues were purified by chromatography
c n Si02 with 10% EtOAc:hexanes to give 0.94 g of pure aldehyde (Intermediate T7,
47%) with [a]20D -2.5 (c = 5.58, benzene).
A solution of the aldehyde (Intermediate T7, 0.90 g, 5.06 mmol) in EtOH
(mhydrous, 15 ml) was treated with tosylmethyl isocyanide (TosMIC) (0.94 g, 4.81
nimol) and NaCN (0.013 g, 0.25 mmol) at 20 °C for 20 minutes. This mixture was
c Micentrated under reduced pressure and the resulting residue was taken up in MeOH
s iturated with NH3 (anhydrous, 10 ml) and heated in a sealed tube at 100 °C for 16
haurs. The reaction mixture was concentrated under reduced pressure and purified by
c xromatography on Si02 with 10% MeOH:CH2Cl2 to give 0.59 g (54%) of the
b aidazole (Intermediate T8) which rotates sodium light at 20 °C with [a]20D -14.7 (c
= 3.72, MeOH).
To the imidazole (Intermediate T8,0.55 g, 2.56 mmol) in a solution of THF
(: 5 ml) and H20 (15 ml) was added NaHC03 (2.15 g, 25.60 mmol) followed by
p lenyl chloroformate (1.00 g, 6.40 mmol). After heating at 65 °C for 2 hours the
n ixture was cooled and washed consecutively with H20 and brine, dried (MgSO4)
and concentrated under reduced pressure. The residues were taken up in EtOH (10 ml)
and H20 (15 ml), treated with Na2C03 (0.77 ml, 7.29 mmol) and heated at reflux for 1
hour. After cooling the solids were filtered off, washed with H20, Et20 and dried for
20 hours under high vacuum to give (Compound 62, 0.39 g (66%) with [a]20D -10.0
(c = 1.08, in DMSO). *H NMR (300 MHz, DMSO-d6) 5 9.80 (s, 1H), 9.42 (s, 1H),
7.15-7.06 (m, 1H), 7.04-6.97 (m, 1H), 6.96-6.87 (m, 1H), 5.93 (s, 1H), 3.35-3.21 (m,
HI), 2.92-2.68 (m, 2H), 2.67-2.56 (m, 1H), 2.32-2.09 (m, 2H), 1.76-1.62 (m, 1H).
I
i


A solution of 5-hydroxyindanone (available from Aldrich, 1.48 g, 10 mmol) in
C H2C12 (10 mL) and dihydropyran (5mL) was treated with camphor sulphonic acid
(• -50 mg catalytic amount) at 0 °C. The mixture was allowed to warm to room
temperature and stirring was continued for 2h. The mixture was subjected to an
aqueous work-up, extracted with ether, dried over MgSC>4, filtered and evaporated to
dryness. The protected indanone, 5-(tetrahydro-pyran-2-yloxy)-indan-l-one was used
in the next step without further purification.
Use of 5-(tetrahydro-pyran-2-yloxy)-indan-l-one in the applicable steps of
]\ lethod A and Method P produced Compound 63. Note: a separation of the THP
protected compound, 4-[5-(tetrahydro-pyran-2-yloxy)-indan-l-ylmethyl]-lH-
imidazole from the hydroxy compound l-(lH-imidazol-4-ylmethyl)-hidan-5-ol
(intermediate U4, shown in the scheme above) was accomplished by
c iromatography on S1O2 with 3 to 5% NH3-MeOH in CH2C12.
4-(5-hyd^oxy-mdan-l-ylmemyl)-l,3-dmydro-imidazol-2-one (Compound 63):
!
i
1

'H NMR (300 MHz, CD3OD-d4): 8 6.93 (d, J= 13 Hz, 1H), 6.62-6.53 (m, 2H), 6.01
(s, 1H), 2.83-2.68 (m, 4H), 2.43-2.35 (m, 1H), 2.24-2.17 (m, 1H), 1.16-1.69 (m, 1H).

2-Bromo-3-methyl-cyclopent-2-enone (Intermediate VI, commercially
i vailable from Aldrich) (18 mmol) was dissolved in 0.4M CeCl3 7H20 in MeOH (66
r iL) at 0 °C. Sodium borohydride (20 mmol) was added portion-wise and stirring
\ ras continued for 10 m after addition was complete. The mixture was quenched with
s aturated NH4CI and extracted with ether. The combined organic layers were washed
A nth sat. NH4CI, H20, brine, and dried over Na2SO4, filtered and evaporated to
cryness. The material was purified by column chromatography 15% EtOAc:Hx to
jive 2-bromo-3-methyl-cyclopent-2-enol (Intermediate V2, ~80%).
The alcohol (Intermediate V2, 16 mmol) in THE (30 mL) at 0 °C was treated
\ ath ethyl magnesium bromide (40 mmol). The catalyst, 1,3-
bis(diphenylphosphino)propane nickel (II) chloride (0.75 mmol) (NiCl2dppp) was
added in one portion and the mixture was heated to reflux for 3 hours following the
procedure of Organ et al. J. Org. Chem. 1997, 62,1523, incorporated herein by
r jference.) The reaction mixture was cooled to rt and quenched with sat NH4CI
s Dlution. The mixture was filtered and partitioned between brine and diethyl ether.

The organic layer was removed and dried over Na2SO4, filtered and concentrated
under vacuum. The oil was purified by chromatography on SiO2 with 20% EtOAc:Hx
to yield 2-ethyl-3-methyl-cyclopent-2-enol (Intermediate V3). Use of the alcohol
( ntermediate V3) in the applicable steps of Method A and Method P produced 4-(2-
ethyl-3-memyl-cyclopent-2-enylmethyl)-l,3-dihydro-imidazol-2-one (Compound
64). 1H NMR (300 MHz, CD3OD-d4): δ 6.03 (s, 1H), 2.88 (brs, 1H), 2.65-2.59 (m,
1H), 2.27-1.83 (series of m, 6H), 1.62 (s, 3H), 1.54-1.45 (m, 1H), 0.97 (t, J= 6 Hz,
3H).

WE CLAIM;
1. Compounds of the formula

where the variable Y in the ring is optional and represents a heteroatom selected
from N, O and S with the proviso that the N atom is trivalent, and the O or S
atoms are divalent;
k is an integer having the values of 0 or 1;
n is an integer having the values 0, 1 or 2;
p is an integer having the values 0, 1 or 2;
X is O or S;
the dashed lines represent a bond, or absence of bond with the proviso that
only one double bond is present in the ring and that two adjoining dashed lines do
not both represent a bond;
R1, R2, R3, and R4 are independently H, phenyl, said phenyl group being
optionally substituted independently with one, two or three C1-6alkyl, SO3H, N3,
halogen, CN, NO2, NH2, C1-6alkoxy, C1-6thioalkoxy, C1-6alkylamino,
C1-6dialkylamino, C2-6alkynyl or C2-6alkenyl groups, 5 or 6 membered heteroaryl
having 1 to 3 heteroatoms selected from O, S, and N, said heteroaryl groups being
optionally substituted independently with one, two or three C1-6alkyl, SO3H, N3,
halogen, CN, NO2, NH2, C1-6alkoxy, C1-6thioalkoxy, C1-6alkylamino, C1-
6dialkylamino, C2-6alkynyl or C2-6alkenyl groups,

or said R1, R2, R3, and R4 groups are independently alkyl of 1 to 4 carbons,
cycloalkyl of 3 to 5 carbons, CH2CN, CH2SR5, CH2NR6R6, COR5, CH2OR5, OR6,
SR6. NR6R6, alkenyl having 1 to 4 carbons, alkynyl having 1 to 4 carbons,
cycloalkyl having 3 to 6 carbons, F, Cl, Br, I, CF3, or CN, an oxygen double
bonded to the ring carbon with the proviso that the adjacent dashed line within the
ring represents absence of a bond;
R5 is H, OR7, alkyl of 1 to 4 carbons, CF3, cycloalkyl of 3 to 6 carbons,
phenyl, phenyl substituted with one or two alkyl groups of 1 to 4 carbons, with F,
Cl, Br, I, or with CF3, or R5 is a 5 or 6 membered heteroaryl having 1 to 3
heteroatoms selected from O, S, and N, and 5 or 6 membered heteroaryl having 1
to 3 heteroatoms selected from O, S, and N substituted with one or two alkyl
groups of 1 to 4 carbons, with F, Cl, Br, I, or with CF3;
R6 is H, alkyl of 1 to 4 carbons, allyl, cycloalkyl of 3 to 6 carbons, phenyl,
phenyl substituted with one or two alkyl groups of 1 to 4 carbons, with F, Cl, Br, I,
or with CF3, or R6 is 5 or 6 membered heteroaryl having 1 to 3 heteroatoms
selected from O, S, and N, or 5 or 6 membered heteroaryl having 1 to 3
heteroatoms selected from O, S, and N substituted with one or two alkyl groups of
1 to 4 carbons, with F, Cl, Br, I, or with CF3;
R7 is H, alkyl of 1 to 4 carbons, allyl, cycloalkyl of 3 to 6 carbons, phenyl,
phenyl substituted with one or two alkyl groups of 1 to 4 carbons, with F, Cl, Br, I,
or with CF3;
R1 and R2 or R2 and R3 or R3 and R4 together can form a ring together
with the respective carbons to which each of these is attached, the portion
contributed by R1 and R2 or by R2 and R3 or by R3 and R4 having the formulas
(i), (ii), (iii) or (iv)


m is an integer having the values 0 to 3;
R8 is independently H, alkyl of 1 to 6 carbons, alkenyl of 2 to 6 carbons,
alkynyl of 2 to 6 carbons, SO3H, N3, CN, NO2, F, Cl, Br, I, CF3, COR9, CH2OR9,
OR10; SR10, C1-6alkylamino, or C1-6dialkylamino;
R9 is H, alkyl of 1 to 6 carbons, or OR10, and
R10 independently is H or alkyl of 1 to 6 carbons.
2. A compound as claimed in Claim 1 where p is one (1).
3. A compound as claimed in Claim 1 where p is zero (0).
4. A compound as claimed in Claim 1 where [C (R10)]p represents CH2.
5. A compound as claimed in Claim 1 where n is zero (0).
6. A compound as claimed in Claim 1 where n is one (1).
7. A compound as claimed in Claim 1 where n is two (2).

8. A compound as claimed in Claim 1 where Rl, R2, R3, and R4
independently are hydrogen, alkyl of 1 to 4 carbons, an oxo group, ethynyl,
CH2CN, Cl, Br, or cyclopropyl.
9. A compound as claimed in Claim 1 where R1 and R2 or R2 and R3 or
R3 and R4 groups form a 5 or 6 membered carbocylic ring which is
saturated or partly unsaturated.

10. A compound as claimed in Claim 9 where R8 independently is H,
alkyl of 1 to 4 carbons, OR9, Cl, Br, I, F, or CH2OH.
11. A compound as claimed in Claim 1 where R1 and R2 or R2 and R3 or
R3 and R4 groups form a heteroaromatic ring selected from the group
consisting of pyridyl, thienyl, furyl, pyrollyl and imidazolyl.

12. A compound as claimed in Claim 11 where the heteroaromatic ring
contains one N atom as the heteroatom.
13. A compound as claimed in Claim 1 where Y is S or O.
14. A compound as claimed in Claim 1 where one of the R1, R2, R3, and
R4 groups is phenyl or phenyl substituted independently with one, two or
three C1-6alkyl, SO3H, N3, halogen, CN, NO2, NH2, C1-6alkoxy, C1-
6thioalkoxy, C1-6alkylamino, C1-6dialkylamino, C2-6alkynyl or C2.
6alkenyl groups.
15. A compound as claimed in Claim 14 where the phenyl group is
substituted with one or two alkyl, CN, NO2, F or alkoxy groups.
16. A compound as claimed in Claim 1 where one of the R1, R2, R3, and
R4 groups is heteroaryl or heteroaryl substituted independently with one,
two or three C1-6alkyl, SO3H, N3, halogen, CN, NO2, NH2, C1-6alkoxy, C1-
6thioalkoxy, C1-6alkylamino, C1-6dialkylamino, C2-6alkynyl, C2-6alkenyl
groups.
17. A compound as claimed in Claim 16 where the heteroaryl group is

thienyl or chloro-substituted thienyl.
18. A compound as claimed in Claim 1 where X is S.
19. A compound as claimed in Claim 1 where X is SO.
20. A compound of the formula

where X is O or S;
the dashed lines represent a bond, or absence of bond with the proviso that
only one double bond is present in the ring and that two adjoining dashed lines do
not both represent a bond;
R1, R2, R3, and R4 are independently H, phenyl, said phenyl group being
optionally substituted independently with one, two or three C1-6alkyl, SO3H, N3,
halogen, CN, NO2, NH2, C1-6alkoxy, C1-6thioalkoxy, C1-6alkylamino,
C1-6dialkylamino, C2-6alkynyl or C2-6alkenyl groups,
or said R1, R2, R3, and R4 groups are independently alkyl of 1 to 4 carbons,
cycloalkyl of 3 to 5 carbons, CH2CN, CH2SR5, CH2NR6R6, COR5, CH2OR5, OR6,
SR6. NR6R6, alkenyl having 1 to 4 carbons, alkynyl having 1 to 4 carbons,
cycloalkyl having 3 to 6 carbons, F, Cl, Br, I, CF3, or CN, an oxygen double
bonded to the ring carbon with the proviso that the adjacent dashed line within the
ring represents absence of a bond;
R5 is H, OR7, alkyl of 1 to 4 carbons, CF3, cycloalkyl of 3 to 6 carbons,
phenyl, phenyl substituted with one or two alkyl groups of 1 to 4 carbons, with F,
Cl, Br, I, or with CF3;

R6 is H, alkyl of 1 to 4 carbons, allyl, cycloalkyl of 3 to 6 carbons, phenyl,
phenyl substituted with one or two alkyl groups of 1 to 4 carbons, with F, Cl, Br, I,
or with CF3, and
R7 is H, alkyl of 1 to 4 carbons, allyl, cycloalkyl of 3 to 6 carbons, phenyl,
phenyl substituted with one or two alkyl groups of 1 to 4 carbons, with F, Cl, Br, I,
or with CF3.
21. A compound as claimed in Claim 20 where X is S.
22. A compound of the formula

where X is O or S;
the dashed lines represent a bond, or absence of bond with the proviso that
only one double bond is present in the ring and that two adjoining dashed lines do
not both represent a bond;
R1, R2, R3, and R4 are independently H, phenyl, said phenyl group being
optionally substituted independently with one, two or three C1-6alkyl, SO3H, N3,
halogen, CN, NO2, NH2, C1-6alkoxy, C1-6thioalkoxy, C1-6alkylamino,
C1-6dialkylamino, C2-6alkynyl or C2-6alkenyl groups,
or said R1, R2, R3, and R4 groups are independently alkyl of 1 to 4 carbons,
cycloalkyl of 3 to 5 carbons, CH2CN, CH2SR5, CH2NR6R6, COR5, CH2OR5, OR6,
SR6. NR6R6, alkenyl having 1 to 4 carbons, alkynyl having 1 to 4 carbons,
cycloalkyl having 3 to 6 carbons, F, Cl, Br, I, CF3, or CN, an oxygen double
bonded to the ring carbon with the proviso that the adjacent dashed line within the

ring represents absence of a bond;
R5 is H, OR7, alkyl of 1 to 4 carbons, CF3, cycloalkyl of 3 to 6 carbons,
phenyl, phenyl substituted with one or two alkyl groups of 1 to 4 carbons, with F,
Cl, Br, I, or with CF3;
R6 is H, alkyl of 1 to 4 carbons, allyl, cycloalkyl of 3 to 6 carbons, phenyl,
phenyl substituted with one or two alkyl groups of 1 to 4 carbons, with F, Cl, Br, I,
or with CF3, and
R7 is H, alkyl of 1 to 4 carbons, allyl, cycloalkyl of 3 to 6 carbons, phenyl,
phenyl substituted with one or two alkyl groups of 1 to 4 carbons, with F, Cl, Br, I,
or with CF3.
23. A compound as claimed in Claim 22 where X is S.
24. A compound as claimed in Claim 23 that has the formula


Compounds of Formula (I): where X is S and the variables have the meaning defined in the specification are specific
or selective to alpha2B and/or alpha2C adrenergic receptors in preference over alpha2A adrenergic receptors, and as such have no
or only minimal cardivascular and/or sedatory activity. These compounds of Formula (I) are useful as medicaments in mammals,
including humans, for treatment of diseases and or alleviations of conditions which are responsive to treatment by agonists of alpha2B
adrenergic receptors. Compounds of Formula (I) where X is O also have the advantageous property that they have no or only minimal
cardivascular and/or sedatory activity and are useful for treating pain and other conditions with no or only minimal cardivascular
and/or sedatory activity.

Documents:

1817-kolnp-2004-assignment.pdf

1817-kolnp-2004-correspondence.pdf

1817-kolnp-2004-examination report.pdf

1817-kolnp-2004-form 13.pdf

1817-kolnp-2004-form 18.pdf

1817-kolnp-2004-form 3.pdf

1817-kolnp-2004-form 5.pdf

1817-kolnp-2004-gpa.pdf

1817-kolnp-2004-granted-abstract.pdf

1817-kolnp-2004-granted-claims.pdf

1817-kolnp-2004-granted-description (complete).pdf

1817-kolnp-2004-granted-form 1.pdf

1817-kolnp-2004-granted-specification.pdf

1817-kolnp-2004-others.pdf

1817-kolnp-2004-reply to examination report.pdf


Patent Number 250655
Indian Patent Application Number 1817/KOLNP/2004
PG Journal Number 03/2012
Publication Date 20-Jan-2012
Grant Date 16-Jan-2012
Date of Filing 30-Nov-2004
Name of Patentee ALLERGAN INC.
Applicant Address 2525 DUPONT DRIVE, T2-7H IRVINE, CA
Inventors:
# Inventor's Name Inventor's Address
1 CHOW KEN 20 TIDAL SURF, NEWPORT COAST, CA 92657
2 HEIDELBAUGH TODD 18886 MOUNT CASTILE, FOUNTAIN VALLEY, CA 92708
3 GIL DANIEL W 2541 POINT DEL MAR, CORONA DEL MAR, CA 92625
4 GARST MICHAEL E 2627 RAQUETA DRIVE NEWPORT BEACH, CA 92660
5 WHEELER LARRY A 18 VALLEY VIEW, IRVINE, CA 92612
6 NGUYEN PHONG X 1048 WINGFOOT STREET, PLACENTIA, CA 92870
7 GOMEZ DARIO G 218 AMHERST AISLE, IRVINE, CA 92612
PCT International Classification Number C07D233/84
PCT International Application Number PCT/US2003/15441
PCT International Filing date 2003-05-16
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10/153,328 2002-05-21 U.S.A.