WO 2006/116169 PCT/US2006/015215
1
METHODS FOR MODULATING BLADDER FUNCTION
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to United States Provisional Patent Application
serial number 60/674,487, filed April 24, 2005, the entirety of which is hereby incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds useful in modulation of bladder
activity, including in the treatment, prevention, inhibition, and/or amelioration of urinary
incontinence.
BACKGROUND OF THE INVENTION
[0003] According to the American Foundation for Urologic Disease, it is estimated that
over 12 million Americans suffer from urinary incontinence. At least 50% of nursing home
residents are affected. Both men and women suffer from urinary incontinence, although
women are disproportionately affected.
[0004] There are several different types of urinary incontinence with the major forms
being stress incontinence, urge incontinence, and mixed incontinence. Stress incontinence
refers to urinary leakage that occurs during physical activity, such as coughing, sneezing, or
laughing, that stresses the abdomen. Urge incontinence (also known as bladder instability,
neurogenic bladder, voiding dysfunction, hyperactive bladder or detrusor overactivity) results
from an overactive bladder contracting involuntarily, resulting in urine loss and an urgent
need to void. Urge incontinence is often caused by inappropriate action of the nerves that
normally control the bladder. Mixed incontinence is a combination of stress incontinence and
urge incontinence.
[0005] Available treatments for urinary incontinence are dismal, ranging from absorbent
pads, to mechanical devices that restrict urine flow, to devices that apply electric shocks to
various muscles. Efforts have been made to develop effective pharmacological interventions,
but thus far have met with limited success. One promising new area of investigation centers

WO 2006/116169 PCT/US2006/015215
2
upon recent findings that serotonin signaling pathways are involved in controlling muscles
involved in urine release. Specifically, it has been reported that agonists of the 5HT2c
serotonin receptor can be effective inhibitors of urinary incontinence. See United States
Patent Application 2004/0235856 by McMurray et al, the entire contents of which are
incorporated herein by reference. There remains a need for the identification of potent,
specific 5HT2c inhibitors that are effective inhibitors of urinary incontinence.
SUMMARY OF THE INVENTION
[0006] The present invention provides methods for modulating activity of bladder tissues
in a mammal, particularly including methods for maintaining urinary bladder control. In
particular, according to the present invention, compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
n is one or two;
each of R2 and R3 is independently hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl
or cyclopropyl;
each R is independently hydrogen, halogen, OH, lower alkyl, lower alkoxy, lower haloalkyl,
lower haloalkoxy, or CN;
Ar is thienyl, furyl, pyridyl, or phenyl, wherein Ar is optionally substituted with one or more
Rx substituents;
each Rx is independently selected from halogen, OH, lower alkyl, lower alkoxy, lower
haloalkyl, lower haloalkoxy, or CN; and
y is 0-3,
which are highly specific agonists of the 5HT2C receptor, are useful in the treatment of
urinary incontinence.
[0007J The present invention provides, among other things, methods of treating urinary
incontinence by administrating to an individual in need thereof a pharmaceutically effective
amount of a compound of formula I. The invention; also provides pharmaceutical

WO 2006/116169 PCT/US2006/015215
3
compositions of compounds of formula I formulated and dosed for treatment of urinary
incontinence, as well as combinations of compounds of formula I with one or more other
agents useful in the treatment of urinary incontinence and/or other disorders or diseases
suffered by individuals with urinary incontinence. Yet other aspects of the present invention
will be clear to those of ordinary skill in the art upon review of the present specification and
claims.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
1. Compounds
[0008] Compounds useful for modulating bladder function, and in particular treating
urinary incontinence according to the present invention include compounds of formula I

or a pharmaceutically acceptable salt thereof, wherein:
n is one or two;
each of R2 and R3 is independently hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl
or cyclopropyl;
each R1 is independently hydrogen, halogen, OH, lower alkyl, lower alkoxy, lower haloalkyl,
lower haloalkoxy, or CN;
Ar is thienyl, furyl, pyridyl, or phenyl, wherein Ar is optionally substituted with one or more
Rx substituents;
each Rx is independently selected from halogen, OH, lower alkyl, lower alkoxy, lower
haloalkyl, lower haloalkoxy, or CN; and
y is "0-3.
[0009] The term "lower alkyl," as used herein, refers to a hydrocarbon chain having up to
4 carbon atoms, preferably 1 to 3 carbon atoms, and more preferably 1 to 2 carbon atoms.
The term "alkyl" includes, but is not limited to, straight and branched chains such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl.

WO 2006/116169 PCT/US2006/015215
4
[0010] The term "alkoxy," as used herein, refers to the group -OR, wherein R is a lower
alkyl group.
[0011] The terms "halogen" or "halo," as used herein, refer to chlorine, bromine, fluorine
or iodine.
[0012] The term "haloalkyl," as used herein, or as part of a moiety such as "haloalkoxy"
refers to an alkyl group, as defined herein, that has one or more halogen substituents. In
certain embodiment, every hydrogen atom on said alkyl group is replaced by a halogen atom.
Such haloalkyl groups include -CF3. Such haloalkoxy groups include -OCF3.
[0013] It will be appreciated by those of ordinary skill in the art that reference to a
compound herein is intended to include reference to any and all related forms such as
stereoisomers, polymorphs, hydrates, etc. Also, compounds may be provided as pro-drugs or
other forms converted into the active agent during manufacture, processing, formulation,
delivery, or in the body.
[0014] The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable
salt" refers to salts derived from treating a compound of formula I with an organic or
inorganic acid such as, for example, acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric,
maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric,
nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic,
benzoic, or similarly known acceptable acids. In certain embodiments, the present invention
provides the hydrochloride salt of a compound of formula I.
[0015] As defined generally above, each of the R2 and R3 groups of formula I is
independently hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl or cyclopropyl. In
certain embodiments, one of the R2 and R3 groups of formula I is hydrogen and the other R~
or R3 group of formula I is hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl or
cyclopropyl. In other embodiments, neither of the R2 and R3 groups of formula I is
hydrogen. In still other embodiments, both of the R2 and R3 groups of formula I are
hydrogen.
[0016] As defined generally above, each R1 group of formula I is independently
hydrogen, halogen, OH, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, or CN.
In certain embodiments, each R1 group of formula I is hydrogen. In other embodiments, at
least one of R1 group of formula I is halogen. In still other embodiments, y is 1 and R1 is
halogen.

WO 2006/116169 PCT/US2006/015215
5
[0017] According to another embodiment, y is 1 and R1 is at the 5-position of the
dihydrobenzofuran ring of formula I, thus forming a compound of formula la:

or a pharmaceutically acceptable salt thereof, wherein each of R , R , R , Ar, and n are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein,
[0018] According to yet another embodiment, y is 1 and R1 is at the 6-position of the
dihydrobenzofuran ring of formula I, thus forming a compound of formula la':

or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, Ar, and n are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0019] As defined generally above, the Ar group of formula I is thienyl, furyl, pyridyl, or
phenyl, wherein Ar is optionally substituted with one or more substituents independently
selected from halogen, OH, lower alkyl, lower alkoxy, haloalkyl, haloalkoxy, or CN. In
certain embodiments, the Ar group of formula I is unsubstituted phenyl. In other
embodiments, the Ar group of formula I is phenyl with at least one substituent in the ortho
position. In other embodiments, the Ar group of formula I is phenyl with at least one
substituent in the ortho position selected from halogen, lower alkyl, lower alkoxy, or
trifiuoromethyl. According to another aspect the present invention provides a compound of
formula I wherein Ar is phenyl di-substituted in the ortho and meta positions with
independently selected halogen lower alkyl, or lower alkoxy. Yet another aspect of the
present invention provides a compound of formula I wherein Ar is phenyl di-substituted in
the ortho and para positions with independently selected halogen lower alkyl, or x lower

WO 2006/116169 PCT/US2006/015215
6
alkoxy. In other embodiment, the present invention provides a compound of formula I
wherein Ar is phenyl di-substituted. in the ortho positions with independently selected
halogen lower alkyl, or lower alkoxy. Exemplary substituents on the phenyl moiety of the Ar
group of formula I include OMe, fluoro, chloro, methyl, and trifluoromethyl.
[0020] In certain embodiments, the present invention provides a compound of formula
la' wherein Ar is phenyl with one substituent in the ortho position selected from halogen,
lower alkyl, lower alkoxy, or trifluoromethyl.
[0021] According to one embodiment, Ar is phenyl substituted with one Rx substituent in
the ortho-position, thus forming a compound of formula lb, or with an Rx substituent in both
ortho-positions, thus forming a compound of formula Ic:

or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, Rx, y and n are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0022] In certain embodiments, the Ar group of formula I is selected from the following:


WO 2006/116169 PCT/US2006/015215
7

[0023] According to yet another embodiment, the present invention provides a compound
of formula Id or Ie:

or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, Rx, y and n are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0024] According to another embodiment, the present invention provides a compound of
formula If or Ig:

or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, Rx, and n are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0001] In certain embodiments, the present invention provides a compound of formula Ih
orli:


WO 2006/116169 PCT/US2006/015215
8
or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, Rx, and n are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0025] Compounds of the present invention contain asymmetric carbon atoms and thus
give rise to stereoisomers, including enantiomers and diastereomers. Accordingly, it is
contemplated that the present invention relates to all of these stereoisomers, as well as to
mixtures of the stereoisomers. Throughout this application, the name of the product of this
invention, where the absolute configuration of an asymmetric center is not indicated, is
intended to embrace the individual stereoisomers as well as mixtures of stereoisomers. In
certain embodiments of the invention, compounds having an absolute (R) configuration are
preferred.
[0026] In certain embodiments, the present invention provides a compound of formula
VlaorVIb:

or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, Rx, y and n are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0027] According to another embodiment, the present invention provides a compound of
formula VIc or VId:


WO 2006/116169 PCT/US2006/015215
9
or a pharmaceutically acceptable salt thereof, wherein each R1, R2, R3, Rx, y and n are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0028] Where an enantiomer is preferred, it may, in some embodiments be provided
substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of
the corresponding enantiomer refers to a compound which is isolated or separated via
separation techniques or prepared free of the corresponding enantiomer. "Substantially free,"
as used herein, means that the compound is made up of a significantly greater proportion of
one enantiomer. In certain embodiments the compound is made up of at least about 90% by
weight of a preferred enantiomer. In other embodiments of the invention, the compound is
made up of at least about 99% by weight of a preferred enantiomer. Preferred enantiomers
may be isolated from racemic mixtures by any method known to those skilled in the art,
including chiral high pressure liquid chromatography (HPLC) and the formation and
crystallization of chiral salts or prepared by methods described herein. See, for example,
Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,
1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, EX. Stereochemistry of
Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and
Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN
1972).
[0029] It is further recognized that atropisomers of the present compounds may exit. The
present invention thus encompasses atropisomeric forms of compounds of formula I as
defined above, and in classes and sublcasses described above and herein.
[0030] Exemplary compounds useful for the methods of the present invention are set
forth in Table 1, below.

WO 2006/116169

10

PCT/US2006/015215

Table 1. Exemplary Compounds of Formula I
(±)-l-{7-[3,5-bis(trifluoromethyl)phe
(±)-1 -[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methanamine,
(±)-l-[7-(3)5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-1 -(7-phenyl-2,3 -dihydro-1 -benzofuran-2-yl)methanamine,
(+)-(l-(7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(-)-l-(7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(±)4-[7-(3-methylphenyl)-23-dihydro4-benzoruran-2-yl]methanamine,
(+)-1 - [7-(3-methylphenyl)-2,3 -dihydro-1 -benzofuran-2-yl] methanamine,
(-)-l-[7-(3-methylphenyl)-23-dihydro-l-benzofuran-2-yl]methanamine,
(±)-1 -(7-thien-3 -y 1-2,3 -dihydro-1 -benzoruran-2-yl)methanamine,
(+)-l -(7-thien-3-yl-2,3-dihydro-l -benzofuran-2-yl)methanamine,
(-)-1 -(7-thien-3 -yl-2,3 -dihydro-1 -benzofuran-2-yl)methanamine,
(±)-l-[7-(2-methylphenyl)-2,3-dihydro-l-benzofurari-2-yl]methanamine,
(+)-l-[7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-1 -[7-(2-methylphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methanamine,
(±)-l-[7-(2-fluorophenyl)-23-dihydro-l-benzofuran-2-yl]methanamine,
(+)-1 -[7-(2-fluorophenyl)-2,3-dihydro-1 -benzoruran-2-yl]methanamine,
(-)-l-[7-(2-fiuorophenyl)-23-dihydro-l-benzoruran-2-yl]methanamine,
(±)-l-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
(-)-l-{7-[2-(trifluoromethyl)phenyl]-23-dihydro-l-benzofuran-2-yl}methanamine,
(+)-l-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
(±)-l-[7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine5
(-)-l-[7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzoruran-2-yl]methanamine,
(+)-1 -[7-(2,6-dimethylphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methanamine,
(±)-1 -[7-(2-methoxyphenyl)-2>3 -dihydro-1 -benzoruran-2-yl]methanamine,
(±)-l-[7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(3-fluorophenyl)-2J3-dihydro-l-benzoruran-2-yl]methanamine,
(±)-l-[7-(3-chlorophenyl)-2,3-dihydro-l-benzoruran-2-yl]methanamine,
(+)-l-[7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-1 -[7-(3-chlorophenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methanamine,

WO 2006/116169 PCTAJS2006/015215
11
(±)-l-[7<3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-{743-(trifluoromethyl)phenyl]-23-dihydro4-benzoforan-2-yl}methanamine,
(±)-l-[7-(4-methylphenyl)-2,3-dihydro-l-benzofiiran-2-yl]methanamine3
(+)-147<4-methylphenyl)-23-dihydro4-benzofuran-2-yl]methanamineJ
(-)-147-(4-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l -[7-(4-fluorophenyl)-2,3-dihydro-l -benzor\iran-2-yl]methanamine,
(+)-l-[7-(4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[7-(4-fluorophenyl)-2-dihydro-l-beiizofuran-2-yl]methanamine,
(±)-l-[7-(4-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(4-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamines
(-)-l-[7-(4-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-1 -[7-(4-methoxyphenyl)-253-dihydro-1 -benzofuran-2-yl]methanamine,
(+)-l-[7-(4-methoxyphenyl)-2,3-dihydro-l-benzofliran-2-yl]methanamine,
(-)-1 - [7-(4-methoxyphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methanamine,
(±)-l-{7-[4-(trifluoromethyl)phenyl]-2s3-dihydro-l-benzoftiran-2-yl}methanamine,
(±)-l -[7-(2,4-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-l -(5-chloro-7-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(+)-1 -(5-chloro-7-phenyl-253-dihydro-1 -benzofuran-2-yl)methanamine,
(-)-1 -(5 -chloro-7-phenyl-2,3 -dihydro-1 -benzofuran-2-yl)methanamine,
(±)-l-[5-chloro-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[5-cUoro-7-(3-methylphenyl)-23-dihydro-l-benzofuran-2-yl]methanarnine,
(±)-l-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-(5-chloro-7-thien-3-yl-2,3-dihydro-l-benzoruran-2-yl)methylamine,
(-)-(5-chloro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylamine,
(+)-(5-chloro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylamine,
(+)-iV'-[(5-chloro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)rnethyl]-iVr-methylamine,
(-)-JV-[(5 -chloro-7-thien-3-y 1-2,3 -dihydro-1 -benzofiiran-2-yl)methyl] -TV-rnethylarnine,
(±)-1 -[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(+)-l-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-l-benzoruran-2-yl]methanamine,
(-)-l-[5-chloro-7-(2-methylphenyl)-23-dihydro-l-benzofuran-2-yl]methanarnine,
(±)-l-(4-fluoro-7-phenyl-2,3-dihydro-l-benzoftiran-2-yl)methanarnine,
(±)-l-[4-fluoro-7-(2-methylphenyl)-23-dihydro-l-benzofuran-2-yl]methanamine,

WO 2006/116169 PCT/US2006/015215
12
(±)-l-[7-(2-chlorophenyl)-5-fluoro-23-dihydro-l-benzof\u,an-2-yl]methanamine
(+)-l -[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(-)-l-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-(5-fluoro-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(±)-l-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofliran-2-yl]methanamine,
(+)-l-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[5-fluoro-7-(2-methylphenyl)-253-dihydro-l-benzofuran-2-yl]methanamine,
(±)-1 -[5-fluoro-7-(2-fluorophenyl)-2,3 -dihydro-1 -benzoforan-2-yl]methanamine,
(±)-l-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
(±)-(4,5-difluoro-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methylamine,
(±)-1 -[4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-1 -(5-chloro-2-methyl-7-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(±)-(5-chloro-2-methyl-74bien-3-yl-2,3-dihydro-l-benzofliran-2-yl)methylamine,
(±)-(5-cMoro-2-methyl-7-thien-2-yl-2,3-dihydro-l-benzofuran-2-yl)methylarnine,
(+)-l-[7-(2-methoxyphenyl)-23-dihydro-l-benzojFuran-2-yl]methanamine,
(-)-l-[7-(2-chlorophenyl)-23-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(2-cUorophenyl)-23-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(3-fluoropheriyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[7-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(3-methoxyphenyl)-23-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[7-(3-methoxyphenyl)-2y3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
(+)-l-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
(+)-1 - {7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1 -benzofuran-2-yl} methanamine,
(-)-1 - {7- [4-(trifluoromethyl)phenyl] -2,3 -dihydro-1 -benzofuran-2-yl} methanamine,
(±)-l-[7-(2,6-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(236-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzoluran-2-yl]methanamine,
(±)-l-[7-(254-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-1 -[7-(2,4-dimethoxyphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methanamine,
(+)-1 -[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,

WO 2006/116169 PCT/US2006/015215
13
(±)-1 -[7-(2,4-difluorophenyl)-2,3-dihydro-l -benzoforan-2-yl]methanamine,
(+)-l-[7-(2,4-difluorophenyl)-2,3-dihydro-l-benzofiiran-2-yl]methanamine3
(-)-l-[7-(2,4-difluorophenyl)-2,3-dihydro-l-benzofaran-2-yl]methanamine,
(-)-1 - [7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(+)-l-[7-(234-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-23-dihydro-l-benzoftiran-2-yl}methanamine,
(+)-l-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-23-dihydro-l-benzofuraQ-2-yl}methanamine,
(±)-l-[7-(23-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-{[7-(2,3-dimethoxyphenyl)-2,3-dihydro-l-benzof\iran-2-yl]methyl}amine,
(-)-{[(7-(2,3-dimethox>'phenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[(7-(2,3-dimethoxyphenyl)-2,3-dihydro-l-benzoftiran-2-yl]methyl}amine,
(+)- {[7-(4-chloro-2-methylphenyl)-2,3-dihydro-l -benzoftiran-2-yl]methyl} amine,
(-)-{[7-(4-cUoro-2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]metb.yl}amine,
(±)- {[7-(2,3-difluorophenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2,5-dimethylphenyl)-2,3-dihydro-l-benzoforan-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{ [7-(2,5-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(+)-{[7-(2,5-dich!orophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)- {[7-(2,5-dichlorophenyl)-2,3 -dihydro-1 -benzofuran~yl]methyl} amine,
(±)- {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(4-chloro-2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(5-chloro-2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(5-chloro-2-methoxyphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-[(7-pyridin-3-yl-2,3 -dihydro-1 -benzofuran-2-yl)m ethyl] amine,
(+)- {[7-pyridin-3 -yl-2,3 -dihydro-1 -benzofuran-2-yl] methyl} amine,
(-)- {[7-pyridin-3-yl-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)-{[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-fluoro-7-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-fluoro-7-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-fluoro-7-(3-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[5-fluoro-7-(4-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-fluoro-7-(4-chlorophenyl)-2,3-dihydro-l-benzoraran-2-yl]methyl}amine,

WO 2006/116169 PCT/US2006/015215
14
(±)-{[5-fluoro-7-(4-methylphenyl)-2,3-dihydro4-benzofuran-2-yl]methyl}amine,
(±)- {[5-fluoro-7-(4-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-[(5-fluoro-74bien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine,
(±)-{[5-fluoro-7-(3-fUryl)-2,3-dihydro-l-benzofiiran-2-yl]methyl}amine,
(±)- [(5 -fluoro-7-pyridin-2-yl-2,3 -dihydro-1 -benzofuran-2 -yl)m ethyl] amine,
(±)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-l-benzonaran-2-yl)methyl]amine,
(-)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine,
(+)- {[5-fluoro-7-pyridin-3-yl-2,3 -dihydro-1 -benzofuran-2-yl] methyl} amine,
(±)- [(5 -fluoro-7-pyridin-4-yl-2,3 -dihydro-1 -benzofuran-2-yl)methyl] amine,
(±)-[(5-fluoro-7-pyrimidin-5-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine,
(±)-{[7-(2,3-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzorliran-2-yl]methyl}amine,
(-)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-253-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2,4-difluorophenyl)-5 -fluoro-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[5-fluoro-7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)- {[5-fluoro-7-(2,4-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2,4-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzoturan-2-yl]methyl}amine,
(±)-{ [7-(2,5-difluorophenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofiiran-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-fluoro-7-(2-methoxy-5-methylphenyl)-2,3-dihydro-l-benzofuran-2-
yl] methyl} amine,
(±)-{[7-(2,6-difluorophenyl)-5-fluoro-2,3-dihydro-l-benzoruran-2-yl]methyl}amine,
(±)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)- {[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yljmethyl} amine,
(±)-{ [7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1 -benzoturan-2-yl]methyl} amine,

WO 2006/116169 PCT/US2006/015215
15
(±)-N- {[7-(2,6-dicMorophenyl)-5-fluoro-2,3-dihydro-1 -benzoforan-2-
yl]methyl} cyclopropanamine,
(±)-1 -cyclopropyl-N- {[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofttran-2-
yl]methyl}methanamine,
(±)-N- {[7-(236-dichlorophenyl)-5-fluoro-2,3-dihydro-l -benzofuran-2-yl]methyI}ethanamine,
(±)- {[7-(2,6-dicMorophenyl)-5-fluoro~2,3-dihydro-1 -benzofuran-2-ylJmethyl} dimethylamine,
(±)-{[5-cUoro-7-(2-fluorophenyl)-233-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[5-chIoro-7-(2-methoxyphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-cWoro-7-(3-furyl)-23-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[5-chloro-7-(2,3-difluorophenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methyl} amine,
(-)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)- {[5-chloro-7-(2,3 -difluorophenyI)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-chloro-7-(2,3-dicUorophenyl)-2,3-dihydro-l-benzoniran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(2,3-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(2,3-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[5-chloro-7-(2,4-dicWorophenyl)-2,3-dmydro-l-benzoruran-2-yl]methyl}amine,
(+)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-1 -benzof\iran-2-yl]methyl} amine,
(±)-{[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(2,5-dichlorophenyI)-2,3-dihydro-l-benzofiiran-2-yl]methyl}amine,
(±)- {[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2- yljmethyl} amine,
(±)-{[5-chloro-7-(3,4-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofiaran-2-yl]methyl}amine,
(-)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[5~chloro-7-(2,6-dichlorophenyI)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(+)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)- {[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1 -benzoniran-2-yl]methyl} amine,
(±)- {[(5-chloro-7-pyridin-3-yl-2,3-dihydro-1 -benzofuran-2-yl)methyl] amine,

WO 2006/116169 PCT/US2006/015215
16
(±)-N-{[5-chloro-7-(256-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}cyclopropanamine,
(±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}(cyclopropylmethyl)amine,
(±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro4-benzofuran-2-yl]methyl}ethanamine,
(±)-{[(5-methyl-7-phenyl-2)3-dihydro4-benzojEuran-2-yl)methyl]amine,
(±)-{[7-(2-methylphenyl)-5-methyl-2-dihydro4-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2-fluorophenyl)-5-methyl-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2-methoxyphenyl)-5-methyl-23-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2-chlorophenyl)-5-methyl-2s3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-({5-methyl-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzof\iran-2-yl}methyl)ainine,
(±)- {[7-(3 -chlorophenyl)-5 -methyl-2,3 -dihydro-1 -benzofuran-2-yl] methyl} amine,
(±)- {[7-(3 -methylphenyl)-5-methyl-2,3 -dihydro-1 -benzofuran-2-yl] methyl} amine,
(±)-{[7-(4-methylphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(4-fluorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(4-chlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(4-methoxyphenyl)-5 -methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1 -benzofiiran-2-yl] methyl} amine,
(-)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofbran-2-yl]methyl}amine,
(±)- {[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(-)"{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(+)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2,5 -dichlorophenyl)-5 -methyl-2,3 -dihydro-1 -benzofiiran-2-yl] methyl} amine,
(±)-{[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(-)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[5-ethyl-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[5-ethyl-7-(2-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[5-(trifluoromethyl)-7-(2-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-(trifluoromethyl)-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,

WO 2006/116169 PCT/US2006/015215
17
(±)- {[5-(trifluoromethyl)-7-(2-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-(trifluoromethyl)-7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl} amine,
(±)- {[5-(trifluoromethyl)-7-(2-(trifluoromethyl)phenyl)-2,3 -dihydro-1 -benzofuran-2-
yl]methyl} amine,
(±)-{[5-(trifluoromethyl)-7-(3-methylphenyl)-2,3-dihydro-l-benzofaran-2-yl]methyl}amine,
(±)-{[5-(trifluoromethyl)-7-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-(trifluoromethyl)-7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-(trifluoromethyl)-7-(3-methoxyphenyl)-2,3-dihydro-l-benzoftiran-2-
yljmethyl} amine,
(±)-{[5-(trijEluoromethyl)-7-(3-(trifluoromethyl)phenyl)-2,3-dihydro-l-benzoftiran-2-
yl]methyl} amine,
(±)- {[5-(trifluorometb.yl)-7-(4-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-(trifluoromethyl)-7-(4-fluorophenyl)-2,3-dihydro-l-benzofiiran-2-yl]methyl}amine,
(±)- {[5-(trifluoromethyl)-7-(4-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[5-(trifluoromethyl)-7-(4-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2-
yl]methyl}amine,
(±)- {[5 -(trifluoromethyl)-7-(4-(trifluoromethyl)phenyl)-2.3-dihydro-1 -benzofuran-2-
yl] methyl} amine,
(±)-{[7-(2,3-dimethylphenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl} amine,
(±)- {[7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1 -benzofuran-2-
yl]methyl}amine,
(±)-{[7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl} amine,
(±)-{[7-(2,3-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}amine,
(±)- {[7-(2,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1 -benzoniran-2-
yl]methyl} amine,
(±)- {[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1 -benzofuran-2-
yljmethyl} amine,

WO 2006/116169 PCT/US2006/015215
18
(±)-{[7-(3)4-difluorophenyl)-5-(trifliioromethyl)-2,3-dihydro4-benzofiiran-2-
yljmethyl} amine,
(±)-{ [7-(3-chloro-4-fluoroplienyl)-5-(trifluoromethyl)-2,3-dihydro-1 -benzofaran-2-
yl]methyl} amine,
(±)-{[7-(2,5-difluorophenyl)-5-(trifluoromethyl)-253-dihydro-l-benzoftiran-2-
yljmethyl} amine,
(±)-{ [7-(2,5-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1 -benzofurah~2-;
yl]methyl} amine,
(±)- {[7-(2,6-dimethylpheayl)-5-(trifluoromethyl)-2,3-dihydro-1 -benzofuran-2-
yljmethyl} amine,
(±)-4-[2-(aminomethyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-7-yl]benzonitrile
(±)-{[7-(3-foryl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-thien-3-yl-5-(trifluoromethyl)-2}3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-pyridin-3-yl-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2-fluorophenyl)-5-methoxy-2,3 -dihydro-1 -benzofiiran-2-yl]methyl} amine,
(±)-{[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2-methoxyphenyI)-5-methoxy-2,3-dihydro-l-benzofiiran-2-yl]methYl}amine,
(±)-{[5-methoxy-7-(3-thienyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,3-difluorophenyl)-5-methoxy-2(3-dihydro-l-benzofiiran-2-yl]methyl}amine,
(±)-{[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2,3-dimethylphenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,4-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-difluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(+)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)- {[7-(2,5 -dichlorophenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-yI]methyl} amine,
(±)-{[7-(2,5-dimethoxylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(5-cmoro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yljmethyl} amine,

WO 2006/116169 PCT/US2006/015215
19
(±)-{[7-(3-chIoro4-fluorophenyl)-5-methoxy-2,3-dihydro4-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2s6-dimethylphenyl)-5-methoxy-23-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-[(N-methyl-l-[7-(2-methoxyphenyl)-2,3-dihydro-l-benzofliran-2-yl]methanamine,
(±)- [(N-methyl-1 - [7-(3 -methylphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(3-fluorophenyl)-253-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)- [(N-methyl-1 - [7-(3 -methoxyphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methahamine,
(±)- [(N-methyl-1 - [7-(4-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamines
(±)- [(N-methyl-1 -[7-(4-fluorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(4-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(4-methoxyphenyl)-2,3-dihydro-l-benzoruran-2-yl]methanamine,
(±)-[(N-methyl-1 -[7-(2,3-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1 - [7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine5
(±)-[(N-methyl-l-[7-(2,4-difluorophenyl)-253-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1 -[7-(2,4-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1 -[7-(2,4-dirnethoxyphenyl)-2,3-dihydro-1 -benzoruran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,5-dimethylphenyl)-2J3-dihydro-l-benzoruran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,5-difluorophenyl)-2,3-dihydro-l-benzofiu,an-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofurari-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-l-benzoruran-2-
yl]methanamine,
(±)-[(N-methyl-1 -[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-
yl]methanamine,
(±)-[(N-methyl-l-[7-(2,6-dimethylphenyl)-23-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-N-methyl-l-(7-pyridin-3-yl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(±)-[(N-methyl-l-[7-(2,3-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-{[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl} methylamine,
(±)-{[5-fluoro-7-(2-chlorophenyl)-2,3-dihydro-l-benzoruran-2-yl]methyl}methylamine,
(±)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,

WO 2006/116169

20

PCT/US2006/015215

(-)-{[5-fluoro-7-(2-methylphenyl)-23-dihydro4-benzofuran-2-yl]methyl}methylamine,
(+)-{[5-fluoro-7-(2-methylphenyl)-2)3-dihydro-l-benzofaran-2-yl]methyl}methylamine,
(±)-{[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(253-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuraii-2-
yl]methyl}methylamine,
(±)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
r
(-)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro4-benzofuran-2-yl]methyl}methylamine,
(+)-[7-(2,4-dichlorophenyl)-5-fluoro-23-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,5-difluorophenyl)-5-fluoro-2)3-dihydro-l-benzoforan-2-yl]methyl}methylamine5
(±)-{[7-(2,5-dichloroplienyl)-5-fluoro-23-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)-{[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofb:an-2-yl]methyl}methylamine,
(-)-{[5-fluoro-7-(2,5-dichlorophenyl)-253-dihydro-l-benzofliran-2-yl]methyl}methylamine,
(±)-{[7-(2,5-dimethylphenyl)-5-fluoro-2J3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-fluoro-23-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-l-benzofuran-2-
yl] methyl} methyl amine,
(±)-{[5-fluoro-7-(2-methoxy-5-methylphenyl)-2.3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)- {[7-(5-chloro-2-methoxyphenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-
yl]methyl} methylamine,
(±)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]methylamine,
(±)-[(5-chloro-7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)- {[5-chloro-7-(2,6-dimemylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl}methylamine,
(±)-[(5-chloro-7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,3-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,3-dimethylphenyl)-2,3-dihydro-l-benzofliran-2-yl]methyl}methylamine,
(±)- {[5-chloro-7-(2,3-dimethoxyphenyl)-2,3-dihydro-1 -benzofuran-2-
yl] methyl} methylamine,
(±)-{[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-l-benzofliran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,

WO 2006/116169 PCT/US2006/015215
21
(±)- {[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-l -benzofuran-2-
yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,5-dichlorophenyl)-2-dihydro4-benzofuran-2-yl]methyl}methylamine}
(±)-{[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)-{[5-chloro-7-(3.4-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-[5-chloro-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-l-benzoftiran-2-
y 1] methyl} methylamine,
(±)-{[7-(2-fluorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-chlorophenyl)-5-methyl-2,3-dihydro4-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-methoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(3-methylphenyl)-5-methyl-23-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)- {[7-(3 -chlorophenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl }methylamine,
(±)-{[7-(4-methylphenyl)-5-methyl-2-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)- {[7-(4-chlorophenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(±)-{[7-(4-fluorophenyl)-5-methyl-2,3-dihydro4-benzofuran-2-yl]methyl}methylamine,
(±)- {[7-(4-methoxyphenyl)-5-methyl-2,3 -dihydro-1 -benzofiiran-2-yl]methyl} methylamine,
(±)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-
yljmethyl} methylamine,
(±)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)- {[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl}methyIamine,
(±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)- {[7-(2,3-difluorophenyl)-5-methoxy-2,3-dihydro-1 -benzofiiran-2-
yl]methyl}methylamine,

WO 2006/116169 PCT/US2006/015215
22
(±)- {[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-1 -benzofiuran-2-
yl]methyl}methylamine,
(±)-{[7<2,3-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofiiran-2-
yl]methyl}methylamine,
(±)- {[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-
yl]methyl} methylamine,
(±)- {[7-(2,5-difluorophenyl)~5-methoxy-2,3-dihydro-1 -benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(255-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofliran-2-
yl]methyl}methylamine,
(±)-{[7-(2,5-dimethylphenyl)-5-raethoxy-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(2,5-dimethoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl] methyl} methylamine,
(±)-{[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofliran-2-
yl]methyl}methylamine,
(±)-N-methyl-l-[7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methanamine,
(±)-N-methyl-1 - [7-(3,4-difluorophenyl)-5-(trifluoromethyl)-2,3 -dihydro-1 -benzofuran-2-
yl]methanamine,
(±)-N-methyl-l-[7-(2,5-difluorophenyl)-5-(tri'fluoromethyl)-2)3 -dihydro- l-benzofuran-2-
yl]methanamine,
(±)-N-methyl-l-[7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yljmethanamine,
(±)-{[7-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yljmethyl} methylamine,
(±)-N-methyl-l-[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methanamine,
(+){[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-) {[7-(2,6-dichlorophenyl)-5-fluoro-2,3 -dihydro-1 -benzofuran-2-yl]methyl} methylamine,

WO 2006/116169

23

PCT/US2006/015215

(R)4[7-(2-chloro-phenyl)5-Fluoro-2,3-dihydro-benzofuran-2-ylmethyl)methyl-amine,
(R)-[7-(2,6-dichloro-phenyl)-5-Fluoro-2s3-dihydro-benzofuran-2-ylmethyl]ethylamine,
(R)-[7-(2,6-dichloro-phenyl)-5-Fluoro-2,3-dihydro-benzofuran-2-ylmethyl]dimethylamine5
{[(2R)-7-(5-chloro-2-methylphenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
{[(2R)-7-(4-chloro-2-methylphenyl)-5-fluoro-23-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzoftu"an-2-yl]methyl} amine,
(+)-{[7-(2,6dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]ethyl}amine,
(±)- {2-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofiiran-2-yl] ethyl} amine,
(±)-{2-[7-(2-methoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]ethyl}amine,
(±)- {N-methyl-1 -[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(+)- {N-methyl-1 - [(7-(2,4,6-trichlorophenyl)-2,3 -dihydro-1 -benzofliran-2-yl]methanamine,
(-)-{N-methyl-l-[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(")-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)- {[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-
yl] methyl} methylamine,
(+)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-
yl] methyl} methylamine,
(+)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)- {[5-chloro-7-(2,6~dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl}methylamine,
(+)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(-)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-
yl] methyl} methylamine,
(-)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
or
(+)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine;
or a pharmaceutically acceptable salt thereof.

WO 2006/116169 PCT/US2006/015215
24
[0031] In certain embodiments, exemplary compounds of formula I are as set forth in
Table 1-a, below.
Table 1-a: Exemplary Compounds of formula I:
(±)-1 -(7-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(+)-(1-(7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine,
(-)-1 -(7-phenyl-2,3 -dihydro-1 -benzofuran-2-yl)methanamine,
(±)-1 - [7-(2-methylphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methanamine,
(+)-l-[7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
(-)-l-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
(+)-l - {7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l -benzofuran-2-yl}methanamine,
(±)-l-[7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-1 - [7-(2-methoxyphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methanamine,
(±)-l-[7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-1 -[7-(2,4-dichlorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methanamine,
(±)-l-[5-chloro-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-1 -[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-l-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-1 -[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamineJ
(-)-l-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,

WO 2006/116169 PCT/US2006/015215
25
(±)4-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro4-benzofuran-2-yl]methanamine,
(±)-1 - {5-fluoro-7-[2-(trifluoromethyl)phenyl] -2,3-dihydro-1 -benzofuran-2-yl} methanamine,
(±)-144,5-difluoro-7-(2-methylphenyl)-2,3-dihydro4-benzofuran-2-yl]methanamine,
(±)-1 -(5 -chloro-2-methyl-7-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(+)-l-[7-(2-methoxyphenyl)-2,3-dihydro-l-benzoftiran-2-yl]methanamine5
(-)-l-[7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-1 -[7-(2-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-1 -[7-(2,6-difluorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methanamine,
(±)-l-[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-l-[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-1 -[7-(2,6-dichlorophenyl)-2,3-dihydro-1 -benzofiiran-2-yl]methanamine,
(±)-l-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine}
(-)-l-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-l-benzofUran-2-yl]methanamine,
(±)-l-[7-(2,4-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-1 - [7-(2,4-difluorophenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methanamine,
(-)-1 - [7-(2,4-difluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(-)-l-[7-(2;4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine}
(+)-l-[7-(2s4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-1 - {5 -fluoro-7- [2-(trifluoromethyl)phenyl]-2,3-dihydro-1 -benzofuran-2-yl} methanamine,
(+)4-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro4-benzofuran-2-yl}methanamine,
(±)-l-[7-(23-dimethylphenyl)-2-dihydro-l-benzofiiran-2-yl]methanamine,
(±)- {[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(-)-{[(7-(2,3-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[(7-(2,3-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[7-(4-chloro-2-methylphenyl)-2)3-dihydro-l-benzoifuran-2-yl]methyl}amine,
(-)- {[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2,3-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(+)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,

WO 2006/116169 PCT/US2006/015215
26
(-)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran--yl]methyl}amine,
(±)-{[7-(2,456-trichlorophenyl)-253-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{ [7-(4-chloro-2-memylphenyl)-2,3-dihydro-l -berizofuran-2-yl]methyl} amine,
(±)-{[7-(5-chloro-2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(5-chloro-2-methoxyphenyl)-23-dihydro4-beiizofuran-2-yl]methyl}amine,
(±)-{[5-fluoro-7-(2-methoxyphenyl)-2)3-dihydro4-benzofliran-2-yl]methyl}amine5
(±)-{[7-(23-dichlorophenyl)-5-fluoro-2,3-dihydro4-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofLiran-2-yl]methyl}amine,
(+)-{[7-(253-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,4-difluorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2,4-dichlorophenyl)-5 -fluoro-2,3 -dihydro-1 -benzofuran-2-yl]methyl} amine,
(-)- {[5-fluoro-7-(2,4-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(+)- {[5-fluoro-7-(2,4-dichlorophenyl)-2,3-dihydro-1 -benzoniran-2-yl]methyl} amine,
(±)- {[7-(2,4-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1 -benzofaran-2-yl] methyl} amine,
(±)-{[7-(2,5-difluorophenyl)-5-fluoro-2,3-dihydro-l-benzofUran-2-yl]methyl}amine,
(±)-{[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2.5-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethoxyphenyl)-5-fluoro-2,3-dib.ydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-l-benzofliran-2-yl]methyl}amine,
(±)-{[5-fluoro-7-(2-methoxy-5-methylphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl} amine,
(±)- {[7-(2,6-difluorophenyl)-5-fluoro-2,3 -dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl] methyl} amine,
(+)-{[7-(2>6-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(")-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-
yl]methyl}cyclopropanamine,
(±)-l-cyclopropyl-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-
yl]methyl}methanamine,
(±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}ethanamine,

WO 2006/116169 PCT/US2006/015215
27
(±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro4-benzofuran-2-yl]methyl}dimethylamine,
(±)-{[5-chloro-7-(2-fluorophenyl)-2,3-dihydro-l-benzofiiran-2-yl]methyl}amine,
(±)- {[5-chloro-7-(2-methoxyphenyl)-2,3-dihydro- l-benzofuran-2-yl]methyl} amine,
(±)-{[5-chloro-7-(233-difluorophenyl)-2)3-dihydro-l-benzofliran-2-yl]methyl}amine,
(-)-{[5-chloro-7-(23-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(2,3-dichlorophenyl)-2)3-dihydro-l-benzojEuran-2-yl]methyl} amine,
(±)-{[5-cliIoro-7-(2,3-dimethylphenyl)-2,3-dihydro-l-benzofliran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(2,3-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-chIoro-7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine)
(-)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(+)- {[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{ [5-chIoro-7-(5-cliloro-2-methoxyphenyl)-2,3-dihydro-l -benzofuran-2- yl]methyl}amine,
(±)-{[5-chloro-7-(236-dimethylphenyl)-2,3-dihydro-l-benzoforan-2-yl]methyl}amine,
(-)-{[5-chloro-7-(256-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine>
(+)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)- {[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl}amine,
(±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-
yljmethyl} cyclopropanamine,
(±)-N- {[5-chloro-7~(2,6-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-
yl]methyl}(cyclopropyImethyl)amine,
(±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2s3-dihydro-l-benzofuran-2-yl]methyl}ethanamine,
(±)-{[7-(2-methylphenyl)-5-methyl-2,3-dihydro-l-benzoftiran-2-yl]methyl}amine,
(±)-{[7-(2-fluorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2-methoxyplienyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2-chlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,

WO 2006/116169

28

PCT/US2006/015215

(±)-({5-methyl-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)amine,
(±)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl}methyl)amine,
(-)- {[7-(2,3-dimethoxyphenyl)~5-methyl-2,3-dihydro-1 -benzofiiran-2-yl]methyl} amine,
(+)-{[7-(2,3-dimethoxyphenyl)-5-methyl-23-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofbran-2-yl]methyl}amine5
(+)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dichloroplienyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-1 ~benzofuran-2-yl]methyl}amine,
(±)- {[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1 ~benzofuran-2-yl]methyl} amine,
(-)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofijran-2-yl]methyl}amine,
(+)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-ethyl-7-(2-methylphenyl)-2,3-dihydro-l-benzofUran-2-yl]methyl}amine,
(±)-{[5-ethyl-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-(tri£luoromethyl)-7-(2-fluorophenyl)-2,3-dihydro-l-benzofliran-2-yl]methyl}amine,
(±)-{[5-(trifluoromethyl)-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-(trifluoromethyl)-7-(2-chlorophenyl)-2,3-dihydro-l-benzofliran-2-yl]methyl}amine,
(±)-{[5-(trifluoromethyl)-7-(2-methoxyphenyl)-2s3-dihydro-l-benzofuran-2-
yl]methyl} amine,
(±)- {[5-(trifluoromethyl)-7-(2-(trifluoromethyl)phenyl)-2,3-dihydro-1 -benzofuran-2-
yl]methyl} amine,
(±)- {[7-(2,3 -dimethylphenyl)-5-(trifluoromethyl)-2,3 -dihydro-1 -benzofuran-2-
yl]methyl} amine,
(±)-{[7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl} amine,
(±)- {[7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1 -benzofuran-2-
yl]methyl} amine,
(±)- {[7-(2,3 -dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1 -benzofuran-2-
yl]methyl} amine,
(±)- {[7-(2,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1 -benzofuran-2-
yl] methyl} amine,

WO 2006/116169 PCT/US2006/015215
29
(±)-{[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl] methyl} amine,
(±)-{[7-(2,5-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofliran-2-
yl]methyl}amine,
(±)-{[7-(2,5-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}amine,
(±)- {[7-(2,6-dimethylphenyl)-5 -(trifluoromethyl)-2,3-dihydro-1 -benzofuran-2-
yl]methyl} amine,
(±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-1 -benzofiiran-2-yl] methyl} amine,
(±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2-methoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2,3 -difluorophenyl)-5-methoxy-253 -dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,3-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-l-benzoforan-2-yl]methyl}amine,
(±)- {[7-(2,4-dichlorophenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2,5-difluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethoxylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-
yl]methyl} amine,
(±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofliran-2-yl]methyl}amine,
(±)-[(N-methyl-l-[7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,3-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(K-methyI-l-[7-(2,3-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,4-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)- [(N-methyl-1 - [7-(2,4-dichlorophenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,

WO 2006/116169 PCT7US2006/015215
30
(±)-[(N-methyl-l-[7-(2,5-dimethylphenyl)-2,3-dihydro4-benzofuran-2-yl]methanam
(±)-[(N-methyM7-(2,5-difluoropto
(±)-[(N-methyl-l-[7-(2,5-dichlorophenyl)-23-dihydro4-benzofuran-2-yl]metlianamine,
(±)-[(N-methyl-1 -[7-(2,6-dimethylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,6-dichIorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofiirari-2-yl]methyl}metliylamine,
(±)-[(-methyl-l-[7-(2,3-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-{[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyI}methylamine,
(±)-{[5-fluoro-7-(2-chlorophenyl)-2,3-dihydro-l-benzofliran-2-yl]methyl}methylamine,
(±)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)-{[5-fluoro-7-(2-methylphenyl)-2J3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzojEuran-2-yl]methyl}methylamine,
(±)-{[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-l-benzoftiran-2-yl]methyl}methylamine,
(±)-{[7-(253-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)-[7-(2,4-dichlorophenyl)-5-fIuoro-2!3-dihydro-l-benzofuran-2-yl]methyl}methylainine,
(+)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,5-difluorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}inethylamine,
(+)- {[5-fluoro-7-(2,5 -dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(-)-{[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamme,
(±)-{[7-(2,5-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(236-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)- {[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl] methyl }methylamine,
(±)-{[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)- {[5-fluoro-7-(2-methoxy-5-methylphenyl)-2,3-dihydro-1 -benzofuran-2-
yl]methyl}methylamine,
(±)- {[7-(5-chloro-2-methoxyphenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-
yl]methyl}methylamine,

WO 2006/116169 PCT/US2006/015215
31
(±)-[(5-chloro-7-(2-methoxyphenyl)-2,3-dmydro
(±)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro4-benzofuran-2-yl]methyl}methylamine,
(±)-[(5-chloro-7-(2-fluorophenyl)-23-dihydro4-benzoftiran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamineJ
(±)-{[5-chloro-7-(23-dichlorophenyl)-2,3-dihydro4-benzofean-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,3-dimethylphenyl)-23-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-
yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-l-benzofean-2-yl]methyl}methylamine,
(±)- {[5~chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1 -benzofui-an-2-yl]methyl}methylamine5
(±)-{[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-
yl] methyl} methylamine,
(±)-{[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-l-benzofiiran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro4-benzof\u,an-2-yl]methyl}methylamine,
(±)-{[5-chIoro-7-(5-chloro-2-methoxyphenyl)-2s3-dihydro-l-benzof\iran-2-
yljmethyl} methylamine,
(±)-{[7-(2-fluorophenyl)-5-methyl-2,3-dihydro-l-benzofliran-2-yl]methyl}methylamine,
(±)- {[7-(2-chlorophenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(±)-{[7-(2-methoxyphenyl)-5-methyl-2,3-dihydro-l-benzoforan-2-yl]methyl}methylamine,
(±)- {[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1 -benzofiiran-2-
yl]methyl}methylamine,
(±)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)- {[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl}methylamine,
(-)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±> {[7-(2,3-difluorophenyl)-5 -methoxy-2,3 -dihydro-1 -benzofuran-2-
yl]methyl} methylamine,

WO 2006/116169 PCT/US2006/015215
32
(±)-{[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)- {[7-(2,3 -dimethylphenyl)-5 -methoxy-2,3-dihydro-1 -benzofuran-2-
yl]methyl} methylamine,
(±)- {[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(2,5-difluorophenyl)-5-methoxy-253-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)- {[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-l -benzoforan-2-
yl] methyl} methylamine,
(±)-{[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl] methyl} methylamine,
(±)-{[7-(2,5-dimethoxyphenyl)-5-methoxy-2s3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofttran-2-
yl]methyl}methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofiiran-2-
yl]methyl}methylamine,
(±)-N-methyl-l-[7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methanamine,
(±)-N-methyl-l-[7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yljmethanamine,
(±)-N-methyl-l-[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methanamine,
(+) {[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l -benzofuran-2-yl]methyl}methylamine,
(-){[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(R)-[7-(2-chloro-phenyl)-(5-Fluoro-2,3-dihydro-benzofuran-2-ylmethyl)methyl-amine,
(R)-[7-(2,6-dichloro-phenyl)-5-Fluoro-2,3-dihydro-benzofuran-2-ylmethyl]ethylamine,
(R)-[7-(2,6-dichloro-phenyl)-5-Fluoro-2,3-dihydro-benzofuran-2-ylmethyl]dimethylamine,
{[(2R)-7-(5-chloro-2-methylphenyl)-5-fluoro-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
{[(2R)-7-(4-chloro-2-methylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,

WO 2006/116169

33

PCT/US2006/015215

(+)-{[7-(2,6 dichlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]methyl}amine,
(±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]ethyl}amine,
(±)-{2-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]ethyl}amine,
(±)-{2-[7<2-methoxyphenyl)-5-methoxy-233-dihydro-l-benzofiiran-2-yl]ethyl}amine,
(±)-{N-methyl4-[(7<2,4,64richlorophenyl)-2,3-dihydro4-benzofuran-2-yl]methanamine5
(+)-{N-methyl-l-[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-l-benzofuran-2-yi]methanamine,
(-)-{N-methyl-l-[(7-(2,4,64ricWorophenyl)-2,3-dihydro-l-benzoftu:an-2-yl]methanamine,
(+)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-d%
(-)-{[7-(2,6-dhnethylphenyl)-5-fluoro
(-)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(+)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(+)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)-{[5-chloro-7<2)5-dichlorophenyl)-23-dihydro4-benzoftiran-2-yl]methyl}methylamine,
(-)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)- {[7-(2,3 -dimethox>'phenyl)-5-methyl-2i3-dihydro-l -benzofuran-2-
yl] methyl} methylamine,
(-)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(-)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofliran-2-yl]methyl}methylamine,
or
(+)- {[7-(2,3 -dimethoxyphenyl)-5-fluoro-2,3 -dihydro-1 -benzofuran-2-
yl]methyl} methylamine;
or a pharmaceutical acceptable salt thereof.
[0032] Compounds of formula I for use in accordance with the present invention may be
obtained or produced according to any available means including methods described in detail
in United States patent application serial number 10/970,714, filed October 21, 2004, United
States provisional patent application serial numbers 60/621,023, filed October 21, 2004, and
60/621,024, filed October 21, 2004, and PCT publication number WO2005/044812, the
entirety of each of which is hereby incorporated herein by reference.

WO 2006/116169 PCT/US2006/015215
34
[0033] Without wishing to be bound by any particular theory, the present inventors note
that compounds of formula I are highly specific agonists of the 5HT2c receptor. The present
invention encompasses the recognition that this unique affinity and selectivity dispayed by
compounds of formula I renders them particularly useful for modulation of bladder control,
and particularly for treatment of urinary incontinence.
2. Pharmaceutical Compositions
[0034] Compounds of formula I may be administered neat in order to modulate bladder
activity in accordance with the present invention. More commonly, however, they are
administered in the context of a pharmaceutical composition, that contains a therapeutically
effective amount of one or more compound of formula I together with one or more other
ingredients known to those skilled in the art for formulating pharmaceutical compositions.
[0035] As used herein, the terms "pharmaceutically effective amount" or "therapeutically
effective amount" mean the total amount of each active component of the pharmaceutical
composition or method that is sufficient to show a meaningful patient benefit, i.e., treatment,
prevention or amelioration of urinary incontinence or the excessive or undesirable urge to
urinate, or a decrease in the frequency of incidence of urinary incontinence. When applied to
an individual active ingredient, administered alone, the term refers to that ingredient alone.
When applied to a combination, the term refers to combined amounts of the active
ingredients that result in the therapeutic effect, whether administered in combination, serially
or simultaneously.
[0036] In certain embodiments of the invention, compounds of formula I are
administered with a daily dose in the range of about 0.5 to about 500 mg, or about 1 mg to
about 500 mg. Doses may be administered as a single regimen, such as only prior to bedtime
or before travel, or as a continuous regimen divided by two or more doses over the course of
a day. The dosage levels and other dosage levels herein are for the average human subject
having a weight range of about 65 to 70 kg. The skilled person will readily be able to
determine the dosage levels required for a subject whose weight falls outside this range, such
as children and the elderly.
[0037] The dosage of the combination of the invention in such formulations will depend
on its potency, but can be expected to be in the range of from 1 to 500 mg of 5-HT2C receptor
agonist for administration up to three times a day. In some embodiments, the dose may be in

WO 2006/116169 PCT/US2006/015215
35
the range of about 10 to 100 mg (e.g. 10, 25, 50 and 100 mg) of 5-HT2c receptor agonist
which can be administered once, twice or three times a day (preferably once). However the
precise dose will be as determined by the prescribing physician and will depend on the age
and weight of the subject and severity of the symptoms.
[0038] Additional ingredients useful in preparing pharmaceutical compositions in
accordance with the present invention include, for example, carriers (e.g., in solid or liquid
form), flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants,
compression aids, binders, tablet-disintegrating agents, encapsulating materials, emulsifiers,
buffers, preservatives, sweeteners, thickening agents, coloring agents, viscosity regulators,
stabilizers or osmo-regulators, or combinations thereof.
[0039] Solid pharmaceutical compositions preferably contain one or more solid carriers,
and optionally one or more other additives such as flavoring agents, lubricants, solubilizers,
suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents
or an encapsulating material. Suitable solid carriers include, for example, calcium phosphate,
magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose,
sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes or ion exchange
resins, or combinations thereof. In powder pharmaceutical compositions, the carrier is
preferably a finely divided solid which is in admixture with the finely divided active
ingredient. In tablets, the active ingredient is generally mixed with a carrier having the
necessary compression properties in suitable proportions, and optionally, other additives, and
compacted into the desired shape and size. Solid pharmaceutical compositions, such as
powders and tablets, preferably contain up to 99% of the active ingredient.
[0040] Liquid pharmaceutical compositions preferably contain one or more compounds
of formula I and one or more liquid carriers to form solutions, suspensions, emulsions,
syrups, elixirs, or pressurized compositions. Pharmaceutically acceptable liquid carriers
include, for example water, organic solvents, pharmaceutically acceptable oils or fat, or
combinations thereof. The liquid carrier can contain other suitable pharmaceutical additives
such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents,
suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-
regulators, or combinations thereof. If the liquid formulation is intended for pediatric use, it
is generally desirable to avoid inclusion of alcohol.

WO 2006/116169 PCT/US2006/015215
36
[0041] Examples of liquid carriers suitable for oral or parenteral administration include
water (preferably containing additives such as cellulose derivatives such as sodium
carboxymethyl cellulose), alcohols or their derivatives (including monohydric alcohols or
polyhydric alcohols such as glycols) or oils (e.g., fractionated coconut oil and arachis oil).
For parenteral administration the carrier can also be an oily ester such as ethyl oleate and
isopropyl myristate. The liquid carrier for pressurized compositions can be halogenated
hydrocarbons or other pharmaceutically acceptable propellant.
[0042] Liquid pharmaceutical compositions which are sterile solutions or suspensions can
be administered parenterally, for example by, intramuscular, intraperitoneal, epidural,
intrathecal, intravenous or subcutaneous injection. Pharmaceutical compositions for oral or
transmucosal administration may be either in liquid or solid composition form.
[0043] In some embodiments of the invention, pharmaceutical compositions are provided
in unit dosage form, such as tablets or capsules. In such form, the composition is sub-divided
in unit dose containing appropriate quantities of the active ingredient(s). The unit dosage
forms can be packaged compositions, for example packeted powders, vials, ampoules, pre-
filled syringes or sachets containing liquids. The unit dosage form can be, for example, a
capsule or tablet itself, or it can be an appropriate number of any such compositions in
package form.
[0044] Thus, the present invention also provides a pharmaceutical composition in unit
dosage form for modulating bladder activity in a mammal, where the composition contains a
therapeutically effective unit dosage of at least one compound of formula I. As one skilled in
the art will recognize, the preferred therapeutically effective unit dosage will depend on for
example the method of administration. For example, a unit dosage for oral administration
often ranges from about 0.5 mg to about 500 mg and more typically from about 1 mg to about
500 mg of the compund of formula I.
[0045] The present invention also provides a therapeutic package for dispensing the
compounds of formula I to a mammal being treated for pain. In some embodiments, the
therapeutic package contains one or more unit dosages of the compound of formula I, a
container containing the one or more unit dosages, and labeling directing the use of the
package for treating pain in a mammal. In certain embodiments, the unit dose is in tablet or
capsule form. In some cases, each unit dosage is a therapeutically effective amount.

WO 2006/116169 PCT/US2006/015215
37
3. Other Pharmaceutical Agents
[0046] According to the present invention, compounds of formula I may be administered
alone to modulate bladder activity, or alternatively may be administered in combination with
(whether simultaneously or sequentially) one or more other pharmaceutical agents useful in
the modulation of bladder activity. Alternatively or additionally, the compounds of formula I
may be administered in combination with one or more other pharmaceutical agents useful in
the treatment or prevention of one or more other symptoms, disorders, or diseases suffered by
the individual in need of bladder activity modulation.
[0047] Other pharmaceutical agents useful in the modulation of bladder activity, and
particularly for treatment, prevention, inhibition, and/or amelioration of urinary incontinence,
include, for example, desmopressin acetate (available as DDAVP® Nasal Spray and
DDAVP® tablets from Aventis Pharmaceuticals), as well as a desmopressin acetate rhinal
tube (available from Ferring Pharmaceuticals Inc.). Other products include, for example,
tolterodine tartrate (available as DETROLTM tablets from Pharmacia & Upjohn), oxybutinin
chloride (available in the form of DITROPAN® tablets and syrup and DITROPAN XL®
extended release tablets from ALZA Pharmaceuticals), propanthaline bromide (available in
tablet form from Roxane Laboratories, Inc.), hyoscyamine and hyoscyamine sulfate
(available, respectively, as CYSTOPAZ® tablets and CYSTOPAZ-M® timed release
capsules from PolyMedica Pharmaceuticals (U.S.A.), Inc.), hyoscyamine hydrobromide,
flavoxate HC1 (available in URISPAS® 100 mg tablets from ALZA Pharmaceuticals),
imipramine HC1 (available in 10 mg, 25 mg and 50 mg tablets from Geneva Pharmaceuticals,
Inc.), phenylpropanolamine, midodrine HC1 (available in 2.5 mg and 5 mg PROAMATINE®
tablets from Shire US Inc.), phenoxybenzamine HC1 (available as DIBENZYLINE® capsules
from WellSpring Pharmaceuticals Corporation), and prazosin HC1 (available in
MINIPRESS® capsules from Pfizer Inc.). Each of these medicaments may be administered
in the pharmaceutically effective amounts and regimens known in the art, including those
listed in the Physicians' Desk Reference, 55 Edition, 2001, published by Medical Economics
Company, Inc. at Monvale, NJ 07645-1742, the relevant portions of which are incorporated
herein by reference.
[0048] Yet other pharmaceutical agents that can act to modulate bladder activity include,
for example, other regulators of the 5HT2C receptor. For example, United States Patent
Application 2004/0235856 (previously incorporated herein by reference in its entirety)

WO 2006/116169 PCT/US2006/015215
38
describes a variety of 5HT2C receptor modulators that are useful in accordance with the
practice of the present invention. Additional 5HT2C agonists are exemplified in Bishop et al.,
Expert Opin. Ther. Patent 13:1691-1705, 2003, the entire contents of which are incorporated
herein by reference.
[0049] Still other pharmaceutical agents that can act to modulate bladder activity include,
for example, modulators of one or more KCNQ potassium channels. In some embodiments
of the present invention, the compounds of formula I are administered in conjunction with
one or more agonists of KCNQ 2/3 or KCNQ3/5. Such KCNQ modulators include, for
example, compounds described in United States Patent Number 5,384,330 and those
described in United States Patent Number 5,565,483, as well as those described in United
States Patent Application Number 2002/0183395; and United States Patent Application
Number 2004/0029949. The entire contents of each of these patents and patent applications
is incorporated herein by reference. In some embodiments of the present invention, the
compounds of formula I are administered with retigabine.
[0050] In some embodiments of the present invention, compounds of formula I are
administered in conjunction with one or more compounds which act as vasopressin agonists
including, but not limited to those described in U.S. Patent No. 6,194,407 (Failli et al.), U.S.
Patent No. 6,090,803 (Failli et al), U.S. Patent No. 6,096,736 (Ogawa et al.), and U.S. Patent
No. 6,096,735 (Ogawa et al.).
[0051] In general, it will often be desirable in accordance with the present invention to
administer one or more compounds of formula I in conjunction with one or more alpha-
adrenergic receptor agonists and/or one or more other sympathomimetic drugs.
[0052] Other pharmaceutical agents that may be usefully administered in conjuction with
one or more compounds of formula I according to the present invention include agents useful
in the treatment of any other symptom, disorder, disease, or medical condition present in the
individual being treated, whether related or unrelated to the individual's bladder control
issues. Examples of such pharmaceutical agents include, for example, anti-angiogenic
agents, anti-neoplastic agents, anti-diabetic agents, anti-infective agents, or gastrointestinal
agents, pain management agents, or combinations thereof.
[0053] An exemplary listing of pharmaceutically active agents that may be administered
in conjunction with one or more compounds of formula I in accordance with the present
invention can be found in the Physicians' Desk Reference, 55 Edition, 2001, published by

WO 2006/116169 PCTYUS2006/015215
40
conditions of Frequency-Urgency Syndrome, and lazy bladder, also known as infrequent
voiding syndrome.
[0058] The methods of this invention may also be used to treat, prevent, inhibit, or limit
the urinary incontinence, urinary instability or urinary urgency associated with or resulting
from administrations of other medications, including diuretics, vasopressin antagonists,
anticholinergic agents, sedatives or hypnotic agents, narcotics, alpha-adrenergic agonists,
alpha-adrenergic antagonists, or calcium channel blockers.
[0059] The methods of this invention are useful for inducing or assisting in urinary
bladder control or preventing or treating the maladies described herein in humans in need of
such relief, including adult and pediatric uses. They may also be utilized for veterinary
applications, particularly including canine and feline bladder control methods. If desired, the
methods herein may also be used with farm animals, such as ovine, bovine, porcine and
equine breeds.
[0060] Inventive methods involve delivery of compounds of formula I via any
appropriate route of administration including, for example, oral, buccal, sublingual, rectal,
nasal, parenteral, intravenous, or other modes. In general, the compounds may be formulated
for immediate, delayed, modified, sustained, pulsed, or controlled-release delivery.
[0061] For inventive methods utilizing oral delivery, such delivery may be accomplished
using solid or liquid formulations, for example in the form of tablets, capsules, multi-
particulates, gels, films, ovules, elixirs, solutions or suspensions. In certain embodiments, the
compounds are administered as oral tablets or capsules or neat compound or powdered or
granular pharmaceutical formulations. Such preparations may be mixed chewable or liquid
formulations or food materials or liquids if desirable, for example to facilitate administration
to children, to individuals whose ability to swallow tablets is compromised, or to animals.
Examples of oral formulations contained in hard gelatin capsules can include those in which
the active compound comprises from about 45% to 50%, by weight, of the formulation.
Microcrystalline cellulose comprises from about 43% to about 47%, povidone comprises
from about 3% to about 4%, and silicon dioxide and magnesium stearate each comprise from
about 0.3% to about 0.7%, each by weight.
[0062] Modified release and pulsatile release oral dosage forms may contain excipients
such as those detailed for immediate release dosage forms together with additional excipients
that act as release rate modifiers, these being coated on and/or included in the body of the

WO 2006/116169 PCT/US2006/015215
41
device. Release rate modifiers include, but are not exclusively limited to,
hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, ethyl
cellulose, cellulose acetate, polyethylene oxide, Xanthan gum, Carbomer, ammonio
methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose
acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer and
mixtures thereof. Modified release and pulsatile release oral dosage forms may contain one
or a combination of release rate modifying excipients. Release rate modifying excipients
may be present both within the dosage form i.e., within the matrix, and/or on the dosage
form, i.e., upon the surface or coating.
[0063] Fast dispersing or dissolving dosage oral formulations (FDDFs) may contain the
following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium,
crospovidone, diascorbic acid, ethyl acrylate, ethyl cellulose, gelatin, hydroxypropylmethyl
cellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavouring, polyethylene
glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate,
sorbitol, xylitol. The terms dispersing or dissolving as used herein to describe FDDFs are
dependent upon the solubility of the drug substance used i.e. where the drug substance is
insoluble a fast dispersing dosage form can be prepared and where the drug substance is
soluble a fast dissolving dosage form can be prepared.
[0064] For inventive methods utilizing intravenous delivery, such administration may be,
for example, intracavernous, intravenous, intra-arterial, intraperitoneal, intrathecal,
intraventricular, intraurethral, intrasternal, intracranial, intramuscular or subcutaneous, or via
by infusion or needleless injection techniques. For such parenteral administration, the
compounds of formula I may be prepared and maintained in conventional lyophylized
formulations and reconstituted prior to administration with an intravenously acceptable saline
solution, such as a 0.9% saline solution. The pH of the intravenous formulation can be
adjusted, as is known in the art, with an intravenous and pharmaceutically acceptable acid,
such as methanesulfonic acid.
[0065] The compounds of formula I can also be administered intranasally or by
inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol
spray presentation from a pressurised container, pump, spray, atomiser or nebuliser, with or
without the use of a suitable propellant, e.g. dichlorodifluoromethane,
trichlorofluorornethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-

WO 2006/116169 PCT/US2006/015215
42
tetrafluoroethane (HFA 134A™) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA™),
carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may
be determined by providing a valve to deliver a metered amount. The pressurised container,
pump, spray, atomiser or nebuliser may contain a solution or suspension of the active
compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may
additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for
example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a
powder mix of the compounds of the invention and a suitable powder base such as lactose or
starch.
[0066] Aerosol or dry powder formulations are preferably arranged so that each metered
dose or "puff contains from 1 .mu.g to 50 mg of a compound of the invention for delivery to
the patient. The overall daily dose with an aerosol will be in the range of from 1 .mu.g to 50
mg which may be administered in a single dose or, more usually, in divided doses throughout
the day.
[0067] Alternatively, the compounds of formula I can be administered in the form of a
suppository or pessary, or they may be applied topically in the form of a gel, hydrogel, lotion,
solution, cream, ointment or dusting powder. The compounds of the invention may also be
dermally or transdermally administered, for example, by the use of a skin patch, depot or
subcutaneous injection. They may also be administered by the pulmonary or rectal routes.
[0068] For application topically to the skin, the compounds of formula I can be
formulated as a suitable ointment containing the active compound suspended or dissolved in,
for example, a mixture with one or more of the following: mineral oil, liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound,
emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or
cream, suspended or dissolved in, for example, a mixture of one or more of the following:
mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60,
cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
[0069] The compounds of formula I may also be used in combination with a
cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with
drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility,
dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-
cyclodextrin complexes are generally useful for most dosage forms and administration routes.

WO 2006/116169 PCT7US2006/015215
43
As an alternative to direct complexation with the drug the cyclodextrin may be used as an
auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-
cyclodextrins are most commonly used and suitable examples are described in published
international patent applications W091/11172, WO94/02518 and W098/55148.

WO 2006/116169 PCT/US2006/015215
44
CLAIMS
We claim:
1. A method of treating urinary incontinence in a mammal, comprising
administering to said mammal a therapeutically effective amount of a compound of formula
I:

or a pharmaceutical acceptable salt thereof, wherein:
n is one or two;
each of R2 and R3 is independently hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl
or cyclopropyl;
each R1 is independently hydrogen, halogen, OH, lower alkyl, lower alkoxy, lower haloalkyl,
lower haloalkoxy, or CN;
Ar is thienyl, furyi, pyridyl, or phenyl, wherein Ar is optionally substituted with one or more
Rx substituents;
each Rx is independently selected from halogen, OH, lower alkyl, lower alkoxy, lower
haloalkyl, lower haloalkoxy, or CN; and
y is 0-3.
2. The method according to claim 1, wherein one of R2 and R3 is hydrogen and
the other R2 and R3 group is hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl or
cyclopropyl.
3. The method according to claim 2, wherein both of R2 and R3 are hydrogen.
4. The method according to claim 1, wherein neither R2 and R3 is hydrogen.
5. The method according to claim 1, wherein y is zero.

WO 2006/116169 PCT/US2006/015215
45
6. The method according to claim 1, wherein y is other than zero and at least one
R1 group is halogen.
7. The method according to claim 1, wherein y is one and R1 is halogen, OH,
lower alkyl, lower alkoxy, trifluoromethyl, triiluoromethoxy, or CN.
8. The method according to claim 7, wherein y is one and R1 is fluoro or chloro.
9. The method according to claim 7, wherein said compound is of formula la or
la':

or a pharrnaceutically acceptable salt thereof.
10. The method according to claim 1, wherein Ar is unsubstituted phenyl.
11. The method according to claim 1, wherein Ar is phenyl with at least one
substituent in the ortho position.
12. The method according to claim 11, wherein Ar is phenyl with at least one
substituent in the ortho position selected from halogen, lower alkyl, lower alkoxy, or
trifluoromethyl.
13 The method according to claim 11, wherein said compound is of formula lb or
Ic:

WO 2006/116169 PCT/US2006/015215
46

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof.
14. The method according to claim 13, wherein said compound is of formula Id,
Ie, If, Ig, Ih, or Ii:

WO 2006/116169 PCT/US2006/015215
47
15. The method according to claim 1, wherein Ar is selected from:

16. The method according to claim 1, wherein said compound is selected from:
(±)4-{7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-l-benzoruran-2-yl}methanamine,
(±)-l-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(3,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-1 -(7-phenyl-2,3 -dihydro-1 -benzofuran-2-yl)methanamine,
(+)-(l-(7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(-)-1 -(7-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(±)-l-[7-(3-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-1 -[7-(3-methylphenyl)-2,3-dihydro-l -benzofuran-2-yl]methanamine,
(-)-1 - [7-(3-methylphenyl)-2,3-dihydro-1-benzoruran-2-yl]methanamine,
(±)-1 -(7-thien-3-yl-2,3 -dihydro-1 -benzofuran-2-yl)methanamine,
(+)-1 -(7 -thien-3-yl-2,3 -dihydro-1 -benzofuran-2-yl)rnethanamine,
(-)-1 -(7-thien-3 -yl-2,3 -dihydro-1 -benzofuran-2-yl)methanamine,
(±)-1 -[7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(+)-1 - [7-(2-methylphenyl)-2,3-dihydro-1 -benzoturan-2-yl]methanamine,
(-)-l-[7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,

WO 2006/116169

48

PCT/US2006/015215

(±)4-[7-(2-fluorophenyl)-2,3-dihydro4-benzofuran-2-yl]methanamine,
(+)-l - [7-(2-fluorophenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methanamine,
(-)-l-[7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)4-{72-(trifluoromethyl)phenyl]-2,3-dihydro4-benzofuran-2-yl}methanamine,
(-)-l-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
(+)-1 - { 7-[2-(trifluoromethyl)phenyl] -2,3-dihydro-1 -benzofuran-2-yl} methanamine,
(±)-l-[7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-1 -[7-(2,6-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(+)-l-[7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(2-chlorophenyl)-2,3-dihydro-l-benzofiiran-2-yl]methanamine,
(±)-l-[7-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-1 - [7-(3-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(+)-1 - [7-(3-chlorophenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methanamine,
(-)-l-[7-(3-chlorophenyl)-23-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[7-(3-methoxyphenyl)-23-dihydro-l-benzoturan-2-yl]methanamine,
(±)-l-{7-[3-(trifluoromethyl)phenyl]-2-dihydro-l-benzofuran-2-yl}methanamine,
(±)-l-[7-(4-methylphenyl)-23-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(4-methylphenyl)-2,3-dih.ydro-l-benzoruran-2-yl]methanamine,
(-)-l-[7-(4-methylphenyl)-2,3-dihydro-l-benzoruran-2-yl]rnethanamme,
(±)-1 - [7-(4-fluorophenyl)-2,3 -dihydro-1 -benzofuran-2-yl] methanamine,
(+)-1 - [7-(4-fluorophenyl)-2,3-dihydro-1 ~benzofuran-2-yl]methanamine,
(-)-l-[7-(4-fluorophenyl)-2,3-dihydro-l-benzoruran-2-yl]methanamine,
(±)-l-[7-(4-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(4-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-1 -[7-(4-chlorophenyl)-2,3-dihydro-1 -benzofaran-2-yl]methanamine,
(±)-l-[7-(4-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-1 -[7-(4-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(-)-l-[7-(4-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-{7-[4-(trifluoromethyl)phenyl]-2J3-dihydro-l-benzoruran-2-yl}methanamine)
(±)-l-[7-(2,4-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-(5-chloro-7-phenyl-2,3-dihydro-l-benzoruran-2-yl)methanamine,

WO 2006/116169 PCT/US2006/015215
49
(+)-l-(5-chloro-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(-)-l-(5-chloro-7-phenyl-2,3-dihydro-l-benzofiiran-2-yl)methanamine,
(±)-l-[5-chloro-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[5-chloro-7-(3-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)4-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-(5-chloro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylamine,
(-)-(5 -chloro-7-thien-3 -yl-2,3 -dihydro-1 -benzofuran-2~yl)methylamine,
(+)-(5-chloro-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylamine,
(+)-A[(5-chloro-74hien-3-yl-2,3-dihydro-benzofuran-2-yl)methyl]-A-methylamine,
(-)-Ar-[(5-chloro-74hien-3-yl-2J3-dihydro-l-benzoforan-2-yl)methyl]-A'r-methylamine,
(±)-l-[5-cliloro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-l-benzofliran-2-yl]methanamine)
(-)-l-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-(4-fluoro-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(±)-l-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofliran-2-yl]methanamine,
(±)-l-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-l-benzofiiran-2-yl]methanamine,
(+)-l-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-1 -[7-(2-chlorophenyl)-5-fluoro-2.3-dihydro-l -benzofuran-2-yl]methanamine,
(±)-1 -(5 -fluoro-7-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(±)-l-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofliran-2-yl]methanamine,
(-)-l-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-l-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)4-{5-fluoro-7-[2-(trifluoromethyl)plienyl]-2,3-dihydro-l-benzofuran-2-yl}methanamine,
(±)-(4,5-difluoro-7-plienyl-2,3-dihydro-l-benzofuran-2-yl)methylamine,
(±)-1 - [4,5-difluoro-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-l-(5-chloro-2-methyl-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methanamine,
(±)-(5-chloro-2-methyl-7-thien-3-yl-2,3-dihydro-l-benzofuran-2-yl)methylamine,
(±)-(5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-l-benzofuran-2-yl)methylamine,
(+)-1 -[7-(2-methoxyphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methanamine,
(-)-l-[7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(+)-l-[7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,

WO 2006/116169

50

PCT/US2006/01521S

(+)-l-[7-(3-fluorophenyl)-2,3-dihydro-l-benzoftiran-2-yl]methanamine,
(-)4-[7-(3-fluorophenyl)-23-dihydro4-benzofuran-2-yl]methanamine5
(+)-l-[7-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine;,
(-)-l-[7-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)-1 - {7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-l -benzofuran-2-yl}methanamine,
(+)4-{7-[3-(trifluoromethyl)phenyl]-23-dihydro4-benzofuran-2-yl}methanamine,
(+)4-{7444-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(2J4-dimethoxyphenyl)-2,3-dihydro4-benzofliran-2-yl]methyl}amine,
(±)-{[5-chloro-7<255-difluorophenyl)-23-dihydro4-benzofiu,an-2-yl]methyl}amine,
(±)-{ [5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)- {[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2- yljmethyl} amine,
(±)-{[5-chloro-7-(3,4-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-l-benzofiiran-2-yl]methyl}amine,
(±)~ {[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl] methyl} amine,
(-)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)- {[5 -chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(-)-{[5-chloro-7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[(5 -chloro-7-pyridin-3 -yl-2,3-dihydro-1 -benzofuran-2-yl)methyl] amine,
(±)-N- {[5-chloro-7-(2,6~dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-
yl]methyl}cyclopropanamine,
(±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}(cyclopropylmethyl)amine,
(±)-N-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}ethanamine,
(±)-{[(5-methyl-7-phenyl-2,3-dihydro-l-benzofuran-2-yl)methyl]amine5
(±)-{[7-(2-methylphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2-fluorophenyl)-5-methyl-2,3-dihydro-l-benzofliran-2-yl]methyl}amine,
(±)- {[7-(2-methoxyphenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl}amine,
(±)- {[7-(2-chlorophenyl)-5-methyl-2,3 -dihydro-1 -benzofuran-2-yl] methyl} amine,
(±)-({5-methyl-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-l-benzofuran-2-yl}methyl)amine,
(±)- {[7-(3-chlorophenyl)-5 -methyl-2,3 -dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(3-methylphenyl)-5-methyl-2,3-dihydro-l-benzoruran-2-yl]methyl}amine,
(±)- {[7-(4-memylphenyl)-5-methyl-2,3-dihydro-l -benzofuran-2-yl]methyl} amine,
(±)-{[7-(4-fluorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±). {[7-(4-chlorophenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[7-(4-methoxyphenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,

WO 2006/116169 PCT/US2006/015215
54
(-)-{[7-(2,3-dimethoxyphenyl)-5-me
(+)- {[7-(2,3 -dimethoxyphenyl)-5-methyl-2,3-dihydro-1 -benzofiiran-2-yl] methyl} amine,
(±)-{[7-(2,4-dichloroplienyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyi}amine,
(±)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl} amine,
(±)-{[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(-)- {[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(+)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofliran-2-yl]methyl}amine,
(±)- {[5-ethyl-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-ethyl-7-(2-chlorophenyl)-2,3-dihydro-l-benzoftiran-2-yl]methyl}amine,
(±)- {[5 -(trifluoromethyl)-7-(2-fluorophenyl)-2,3 -dihydro-1 -benzofuran-2-yl] methyl} amine,
(±)- {[5-(trifluoromethyl)-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl] methyl} amine,
(±)-{[5-(trifluoromethyl)-7-(2-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-(trifluoromethyl)-7-(2-methoxyphenyl)-2,3-dihydro-l-benzoforan-2-
yl] methyl} amine,
(±)-{[5-(trifluoromethyl)-7-(2-(trifluoromethyl)phenyl)-2,3-dihydro-l-benzofuran-2-
yl] methyl} amine,
(±)-{[5-(trifluoromethyl)-7-(3-methylphenyl)-2,3-dihydro-l-benzofliran-2-yl]methyl}amine,
(±)-{[5-(trifluoromethyl)-7-(3-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-(trifluoromethyl)-7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[5-(trifluoromethyl)-7-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-
yljmethyl} amine,
(±)- {[5-(trifluoromethyl)-7-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1 -benzofuran-2-
yl]methyl} amine,
(±)- {[5-(trifluoromethyl)-7-(4-methylphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[5-(trifluoromethyl)-7-(4-fluorophenyl)-2,3 -dihydro-1 -benzoruran-2-yl]methyl} amine,
(±)- {[5-(trifluoromethyl)-7-(4-chlorophenyl)-2,3-dihydro-1 -benzoruran-2-yl]methyl} amine,
(±)-{[5-(trifluoromethyl)-7-(4-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}amine,

WO 2006/116169 PCT/US2006/015215
55
(±)- {[5-(trifluoromethyl)-7-(4-(trifluoromethyl)phenyl)-2,3-dihydro-l -benzofuran-2-
yl]methyl} amine,
(±)- {[7-(2,3-dimethylphenyl)-5-(trifluoromethyl)-2,3-dihydro-l -benzofuran-2-
yl] methyl} amine,
(±)-{[7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yljmethyl} amine,
(±)-{[7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]metliyl} amine,
(±)- {[7-(2,3-dimethoxyphenyl)-5-(trifluoromethyl)-2s3-dihydro-1 -benzofiiran-2-
yl]methyl}amine,
(±)-{[7-(2,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl} amine,
(±)-{[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl} amine,
(±)-{[7-(3,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yljmethyl} amine,
(±)-{[7-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yljmethyl} amine,
(±)-{[7-(2,5-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}amine,
(±)- {[7-(2,5-dichlorophenyl)-5 -(trifluoromethyl)-2,3-dihydro-1 -benzofuran-2-
yl] methyl} amine,
(±)-{[7-(2,6-dimethylphenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzoforan-2-
yl]methyl}amine,
(±)-4-[2-(aminomethyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-7-yl]benzonitrile
(±)-{[7-(3-furyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-thien-3-yl-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-pyridin-3-yl-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2-methoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,

WO 2006/116169 PCT/US2006/015215
56
(±)-{[5-methoxy-7-(3,4liienyl)-23-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,3-difluorophenyl)-5-methoxy-2,3-dihydro4-benzoforan-2-yl]methyl}amine,
(±)-{[7-(23-dichlorophenyl)-5-methoxy-2,3-dihydro4-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2,3-dimethylphenyl)-5 -methoxy-2,3-dihydro-l -benzofuran-2-yl] methyl} amine,
(±)-{[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-l-benzofiiran-2-yl]methyl}amine,
(±)-{[7-(2,4-dichlorophenyl)-5-methoxy-2)3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-difluorophenyl)-5-metlioxy-2,3-dihydro-l-beiizofuran-2-yl]methyl}amine,
(±). {[7-(2,5 -dichlorophenyl)-5 -methoxy-2,3-dihydro-1 -benzofuran-2~yl]methyl} amine,
(+)-{[7<2,5-dichlorophenyl)-5-methoxy-2,3-dihydro4-benzofuran-2-yl]methyl}amine,
(-)-{[7-(2,5-dichlorophenyl)-5-methoxy-253-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(d=)-{[7-(2,5-dimethoxylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine5
(±)-{[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl]methyl} amine,
(±)-{[7-(3-chloro-4-fluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
(±)-[(N-methyl-l-[7-(2-methoxyphenyl)-2,3-dihydro-l-benzofliran-2-yl]methanamine,
(±)-[CN-methyl-l-[7-(3-metlrylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1 -[7-(3 -fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-[(N-metliyl-l-[7-(3-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(3-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(TSf-metliyl-l-[7-(4-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1 -[7-(4-fluorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(4-chlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine>
(±)-[(N-methyl-l-[7-(4-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,3-dimetliylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1 -[7-(2,3-dimethoxyphenyl)-2,3-dihydro-l -benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,4-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1 -[7-(2,4-dichlorophenyl)-2,3 -dihydro-1 -benzofiiran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-l-benzoforan-2-yl]methanamine,
(±)-[(N-methyl-1 -[7-(2,5-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)4(N-methyl-l-[7<2,5-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,

WO 2006/116169 PCT/US2006/015215
57
(±)-[(N-methyl-l-[7-(2,5-di
(±)-[(N-methyl-l-[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methanamine,
(±)-[(N-methyl-l-[7-(5-chloro-2-raethylphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methanamine,
(±)-[(N-methyl-1 -[7-(2,6-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-[(N-methyl-l-[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzoforan-2-yl]methanamine,
(-)-{[7-(2,6-dichlorophenyl)-23-dihydro4-benzofuran-2-yl]methyl}methylamine,
(+)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-N-methyl-1 -(7-pyridin-3~yl-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(±)-[(N-methyl-l-[7-(23-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(±)-{[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro4-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-fluoro-7-(2-chlorophenyl)-23-dihydro4-benzoforan-2-yl]methyl}methylamine,
(±)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)-{[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)-{[5-fluoro-7-(2-methylphenyl)-2-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)- {[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(±)-{[7-(233-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-
y 1] methyl} methylamine,
(±)-[7-(2,4-dichlorophenyl)-5-fluoro-2>3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-l-beiizofuran-2-yl]methyl}methylamine,
(+)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)- {[7-(2,5 -difluorophenyl)-5 -fluoro-2,3-dihydro-1 -benzbfuran-2-yl]methyl} methylamine,
(±)-{[7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)-{[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)-{[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzoftiran-2-yl]methyl}methylamine,
(±)-{[7-(2,5-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofiiran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,

WO 2006/116169 PCT/US2006/015215
58
(±)-{[5-fluoro-7-(2-methoxy-5-methylphenyl)-2,3-dihydro-l-benzofliran-2-
yl]methyl}methylamine,
(±)-{[7-(5-chloro-2-methoxyplienyl)-5-fluoro-2,3-dihydro-l-benzofiiran-2-
yl] methyl} methylamine,
(±)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-l-benzofuran-2-yl)methyl]methylamine,
(±)-[(5-chloro-7-(2-methoxyphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7K2,6-dimethylphenyl)-2)3-dihydro4-benzofuran-2-yl]methyl}methylamine,
(±)-[(5-chloro-7-(2-fluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,3-difluorophenyl)-23-dihydro4-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,3-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,3-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2J3-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-
yl] methyl} methylamine,
(±)-{[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)~ {[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)- {[5-chloro-7-(2,5-difluorophenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(±)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofliran-2-yl]methyl}methylamine,
(±)- {[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-l -benzofuran-2-
yl]methyl}methylamine,
(±)- {[5-chloro-7-(3.4-difluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl}methylamine,
(±)-[5-chloro-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-l-benzofuran-2-
yl] methyl} methylamine,
(±)-{[7-(2-fluorophenyl)-5-methyl-2,3-dihydro-l-benzofiaran-2-yl]methyl}methylamine,
(±)-{[7-(2-chlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl} methylamine,
(±)-{[7-(2-methoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(3-methylphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(3-chlorophenyl)-5-methyi-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)- {[7-(4-methylphenyl)-5-methyl-2,3-dihydro-l -benzofuran-2-yl]methyl} methylamine,
(±)- {[7-(4-chlorophenyl)-5-methyl-2,3-dihydro-l -benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(4-fluorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,

WO 2006/116169 PCT/US2006/015215
59
(±)-{[7-(4-methoxyphenyl)-5-m
(±)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofliran-2-yl]methyl}methylamine,
(±)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro4-benzofuran-2-yl]methyl}methylamine,
(+)-{[7-(2,5-dichlorophenyl)-5-methyl-23-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)-{[7-(255-dichlorophenyl)-5-methyl-253-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-yl]raethyl}methylamine,
(±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro4-benzofliran-2-yl]methyl}methylamine,
(±)-{[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro4-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,3-difluorophenyl)-5-methoxy-2,3-dihydro-l-benzoftjran-2-
yl]methyl} methylamine,
(±)- {[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(253-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzoftiran-2-
y 1] methyl} methylamine,
(±)-{[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(2,5-difluorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl]methyl} methylamine,
(±)-{[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofiiran-2-
yl]methyl}methylamine,
(±)-{[7-(2,5-dimethoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl] methyl} methylamine,
(±)-{[7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl] methyl} methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,

WO 2006/116169 PCT/US2006/015215
60
(±)-N-methyl447-(2,34ifluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzottiran-z-
yl]methanamine,
(±)-N-methyl-147-(3,4-difluorophenyl)-5-(trifluoromethyl)-23-dihydro4-benzofuran-2-
yl]methanamine,
(±)-N-methyl-l-[7<2,5-difluorophenyl)-5-(trifluoromethyl)-23-dihydro4-benzofuran-2-
yljmethanamine,
(±)-N-methyl-l-[7-(23-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methanamine,
(±)-{[7-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,
(±)-N-methyl-1 -[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-l -benzofuran-2-
yl]methanamine,
(+) {[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]methyl}methylamine,
(-){[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(R)-[7-(2-chloro-phenyl)-(5-Fluoro-2,3-dihydro-benzofuran-2-ylmethyl)methyl-amine,
(R)-[7-(2,6-dichloro-phenyl)-5-Fluoro-2,3-dihydro-benzofiiran-2-ylmethyl]ethylamine,
(U)-[7-(236-dichloro-phenyl)-5-Fluoro-2,3-dihydro-benzofuran-2-ylmethyl]dimethylamine,
{[(2R.)-7-(5-chloro-2-methylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}amine,
{[(2R)-7-(4-chloro-2-niethylphenyl)-5-fluoro-2!3-dihydro-l-benzofiiran-2-yl]methyl}amine,
(-)-{[7-(2,6-dichlorophenyl)-5-fluoro-23-dihydro-l-benzofuran-2-yl]methyl}amine,
(+)-{[7-(2,6 dichlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{2-[6-chloro-7-(2-chlorophenyl)-2,3-dihydro-l-benzofliran-2-yl]ethyl}amine,
(±)- {2-[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]ethyl} amine,
(±)-{2-[7-(2-methoxyphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-yl]ethyl}amine,
(±)- {N-methyl-1 - [(7-(2,4,6-trichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl] methanamine,
(+)-{N-methyl-l-[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methanamine,
(-)- {N-methyl-1 -[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methanamine,
(+)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)- {[?-(2,6-dimethylphenyl)-5-fluoro-2,3 -dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(-)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzofuran-2-
yl]methyl}methylamine,

WO 2006/116169 PCT/US2006/015215
61
(+)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-l-benzoftiran-2-
yl]methyl}methylamine,
(+)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(-)-{[5-cliloro-7-(2,5-dichlorophenyl)-2,3-dihydro4-benzofiiran-2-yl]methyl}methylamine,
(-)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)-{[5-chloro-7-(2,6-dimethylphenyl)-2}3-dihydro-l-benzofuran-2-yl]methyl}methylamine,
(+)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-
yl] methyl} methylamine,
(-)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-l-benzofuran-2-
yl] methyl} methylamine,
(-)-{[7-(233-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofliran-2-yl]methyl}methylamine,
or
(+)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-l-benzofiiran-2-
yl]methyl}methylamine;
or a pharmaceutically acceptable salt thereof.
17. The method of claim 1, wherein the urinary incontinence is urge incontinence.
18. The method of claim 17, wherein the urinary incontinence is secondary to
prostate hypertrophy.
19. The method of claim 1, wherein the urinary incontinence is mixed urge and
stress incontinence.
20. Use of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
n is one or two;

WO 2006/116169 PCT/US2006/015215
62
each of R2 and R3 is independently hydrogen, methyl, ethyl, 2-fluoroethyl, 2,2-difluoroethyl
or cyclopropyl;
each R1 is independently hydrogen, halogen, OH, lower alkyl, lower alkoxy, lower haloalkyl,
lower haloalkoxy, or CN;
Ar is thienyl, furyl, pyridyl, or phenyl, wherein Ar is optionally substituted with one or more
Rx subsituents;
each Rx is independently selected from halogen, OH, lower alkyl, lower alkoxy, lower
haloalkyl, lower haloalkoxy, or CN; and
y is 0-3, for preparing a medicament for treating urinary incontinence in a mammal.

This invention provides methods and pharmaceutical compositions for modulating bladder function, and in particular for maintaining bladder control or treating urinary incontinence.