METHODS FOR TREATING COGNITIVE AND OTHER DISORDERS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to United States provisional patent application
serial number 60/785,778, filed March 24, 2006, the entirety of which is hereby incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds useful in treating disorders associated
with 5HT2C modulation.
BACKGROUND OF THE INVENTION
[0003] Cognition is the ability of one's brain to think:, to process and store information,
and to solve problems. Cognitive abilities include memory, language, attention, perception,
and reasoning. Cognition is a high level of behavior unique to humans. Many cognitive
disorders affect the elderly, such as Alzheimer's disease and memory deficit. However, there
are also many cognitive disorders that affect children, adolescents, and young adults.
[0004] There are a variety of brain abnormalities which prevent infants and children from
developing normal social and/or cognitive skills. Disorders of the basic psychological
processes can affect the way a child/adolescent learns. Many children/adolescents with
learning disabilities have average or above average intelligence. However, learning
disabilities may cause difficulties in listening, thinking, talking, reading, writing, spelling, or
arithmetic. Such learning disabilities include perceptual handicaps, dyslexia, dyscalculia,
dysgraphia and developmental aphasia.
[0005] Attention deficit disorders (ADD), also known as attention deficit hyperactivity
disorder (ADHD), is a well-known cognitive disorder that affects children and adults alike. It
is estimated that between 3% and 8% of all children have ADD. ADD is characterized by
symptoms such as hyperactivity, impulsiveness, distractibility and difficulty sustaining
attention for periods of time. Symptoms may be different in each person with ADD. Some
may have more of a problem with inability to focus, while others may have the most difficult
time with impulsiveness. Medications are available to treat ADD, often in the form of

stimulants such as Ritalin, Adderal, and Strattera, to name a few. However, there are certain
side effects associated with such treatments, including decreased appetite and problems
sleeping.
[0006] Accordingly, there remains a need to develop treatments for the variety of
cognitive disorders affecting patients of all ages.
SUMMARY OF THE INVENTION
[0007] The present invention provides methods for treating a cognitive disorder in a
mammal, including methods for treating a learning disorder, an attention deficit disorder, an
impulsivity disorder, or a behavioral addiction, among others. 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 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,
which are highly selective agonists, or partial agonists, of the 5HT2C receptor, are useful in
the treatment of cognitive and other disorders as described herein.
[0008] The present invention provides, among other things, methods of a cognitive
disorder by administrating to an individual in need thereof a pharmaceutically effective
amount of a compound of formula I. The invention also provides pharmaceutical

compositions of compounds of formula I formulated and dosed for treatment of a cognitive
disorder, as well as combinations of compounds of formula I with one or more other agents
useful in the treatment of cognitive and/or other disorders or diseases suffered by individuals
with cognitive disorders. 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.
BRIEF DESCRIPTIONOF THE DRAWING
[0009] Figure 1 shows the effects of Compound 1 on adjunctive and normal drinking
behavior in Sprague-Dawley rats.
[0010] Figure 2 shows the effects of Compound 1 on acetylcholine in medial prefrontal
cortex.
[0011] Figure 3 shows the effects of Compound 1 on glutamate in medial prefrontal
cortex.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
1. Compounds
[0012] Compounds useful for treating cognitive, and other disorders, 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 subsituents;

each Rx is independently selected from halogen, OH, lower alkyl, lower alkoxy, lower ,
haloalkyl, lower haloalkoxy, or CN; and
y is 0-3,
[0013] The term "lower" as used herein in connection with a group, e.g., alkyl, 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.
[0014] The term "alkoxy," as used herein, refers to the group -OR, wherein R is a lower
alkyl group.
[0015] The terms "halogen" or "halo," as used herein, refer to chlorine, bromine, fluorine
or iodine.
[0016] 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.
[0017] 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.
[0018] 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.
[0019] As defmed 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 R2
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.
[0020] 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.
[0021] 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 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.
[0022] 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 Ia':

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.
[0023] 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 subsituents 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
trifluoromethyl. According to another aspect the present invention provides a compound of
formula 1 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-subsituted in the
ortho and para positions with independently selected halogen lower alkyl, or lower alkoxy.
In other embodiment, the present invention provides a compound of formula I wherein Ar is
phenyl di-subsituted 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.
[0024] In certain embodiments, the present invention provides a compound of formula
Ia' wherein Ar is phenyl with one substituent in the ortho position selected from halogen,
lower alkyl, lower alkoxy, or trifluoromethyl.
[0025] According to one embodiment, Ar is phenyl substituted with one Rx substituent in
the ortho-position, thus forming a compound of formula Ib, 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.
[0026] In certain embodiments, the Ar group of formula I is selected from the following:


[0027] 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, and n are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0028] 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.
[0029] In certain embodiments, the present invention provides a compound of formula Ih
or Ii:

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.
[0030] 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.
[0031] In certain embodiments, the present invention provides a compound of formula
IIa or IIb:


or a pharmaceutically acceptable salt thereof, wherein each Rl, R2, R3, AR, y and n are as
defined above for compounds of formula I and in classes and subclasses as described above
and herein.
[0032] According to another embodiment, the present invention provides a compound of
formula IIe or IId:

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.
[0033] In certain embodiments, the present invention provides a compound of formula
IlIa or IIIb:

or a pharmaceutically acceptable salt thereof, wherein each R1 and Rx are as defined above
for compounds of formula I and in classes and subclasses as described above and herein.

[0034] In other embodiments, the present invention provides a compound of formula IIIc
or IIId
or a phannaceutically acceptable salt thereof, wherein R1 is as defined above for compounds
of formula I and in classes and subclasses as described above and herein.
[0035] According to another aspect, methods of the present invention are carried out with
the following compound:

or a pharmaceutically acceptable salt thereof.
[0036] 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, E.L. 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).
[0037] 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.
[0038] Exemplary compounds useful for methods of the present invention are set forth in
Table 1, below.
Table 1. Exemplary Compounds of Formula I
(±)-1 - { 7-[3,5-bis(trifluoromethyl)phenyl] -2,3-dihydro-1 -benzofuran-2-yl} methanamine,
(±)-1 -[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl] methanamine,
(±)-1 -[7-(3>5-dichlorophenyl)-2,3-dihydro-1 -benzofuran -2-yl]methanamine,
(±)-1-(7-phenyl-2,3^ihydro-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-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yi]methanamine,
(+)-1 -[7-(3-methylphenyl)-2,3-dihydro-1 -benzofuran-2-y 1] methanamine,
(-)-1-[7-(3-memylphenyl)-2,3-dihydro-1-benzofuran-,2-yl]methanamine,
(±)-1-(7-thien-3-yl-2J3-dihydro-1-benzofuran-2-yl)methanamine,
(+)-l -(7-thien-3-yl-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(-)-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 -benzofuran-2-yl]methanamine,
(-)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-l -[7-(2-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(+)-1 -[7-(2-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-y l]methanamine,
(-)-l -[7-(2-fluorophenyl)-2,3-dihydro-l -benzofuran-2-yl]methanamine,
(±)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-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,
(±)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,

(-)-1-{7-[4-(trifluoromethyl)phenyl]-23-dihydro-1-benzofuran-2-yl}methanamine,
(±)-1-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-1-[7-{2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)1-[7-(2,6-dichIorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(+)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-1-[7^2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanainine,
(r)-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,
(±)-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,
(-)-1-[7-(2,4-difluoropheny])-2,3-dihydro-1-ben2ofuran-2-yl]methanamine,
(-)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1 -b€nzofuran-2-yl]methanamine,
(+)-1-[7-(2,4-dichlorophenyl)-2J3-dihydro-1-benzofuran-2-yl]methanamine,
(-)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofliran-2-yl}methanamine,
(+)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine,
(±)-1 -[7-(2,3-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-{[7-(23-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}arnine,
(-)-{[('7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-beii2ofuran-2-yl]methyl}amine,
(+)-{[(7-(2,3-dimethoxyphenyl)-2J3-dihydro-1-benzofuran-2-yl]methyl}amine>
(+)_ {[7-(4-chloro-2-methylphenyl)-2,3 -dihydro-1 -benzo:furan-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-1-benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,5-dimethylphenyl)-2,3-dihydro-1-ben2ofuran-2-yl]methyl}amine,
(±)-{ [7-(2,5-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(±)-{ [7-(2,5-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(+)-{ [7-(2,5-dimethoxyphenyl)-2,3-dihydro-1-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-methylpheny)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(±)-{[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(±)-{[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(±)-[(7-pyridin-3-yl-2,3-dihydro-1 -benzofuran-2-y])methyl]amine,

[0040] 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 WO 2005/044812 and United States patent application serial number 10/970,714, filed
October 21, 2004; WO2006/047288 and United States provisional patent application serial
number 60/621,023, filed October 21, 2004, and in WO 2006/47228 and United States
provisional patent application serial number 60/621,024, filed October 21, 2004, the entirety
of each of which is hereby incorporated herein by reference.
[0041] Without wishing to be bound by any particular theory, the present inventors note
that compounds of formula I are highly specific agonists, or partial agonists, of the 5HT2C
receptor. The present invention encompasses the recognition that this unique affinity and
selectivity displayed by compounds of formula I renders them particularly useful for treating
cognitive, and other disorders. The present invention also contemplates that compounds of
formula I are associated with a rapid onset of action. In addition, compounds of formula I
lack the side-effect of sexual dysfunction.
2. Pharmaceutical Compositions
[0042] Compounds of formula I may be administered neat in order to treat a cognitive, or
other disorder, 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.
[0043] 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 a cognitive, or other disorder,,. 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.
[0044] 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.
[0045] 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
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.
[0046] 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.
[0047] 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.
[0048] In certain embodiments, a compound of formula I is provided in a disintegrating
tablet formulation suitable for pediatric administration.

[0049] 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.
[0050] 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
[0051] In certain embodiments, a liquid pharmaceutical composition is provided wherein
said composition is suitable for pediatric administration. In other embodiments, the liquid
composition is a syrup or suspension.
[0052] 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.
[0053] 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.
[0054] Thus, the present invention also provides a pharmaceutical composition in unit
dosage form for a cognitive, or other disorder, in a patient, 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 compound of formula I.
[0055] The present invention also provides a therapeutic package for dispensing the
compounds of formula I to a patient being treated for a cognitive, or other disorder as
described herein. 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 a cognitive, or other disorder, in a
patient. In certain embodiments, the unit dose is in tablet or capsule form. In some cases,
each unit dosage is a therapeutically effective amount.
3. Other Pharmaceutical Agents
[0056] According to the present invention, compounds of formula I may be administered
alone to treat one or more cognitive, or other disorders, or alternatively may be administered
in combination with (whether simultaneously or sequentially) one or more other
pharmaceutical agents useful to treat one or more cognitive, or other disorders, as described
herein. 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 treatment of one or more cognitive, or other disorders, as described herein.
[0057] 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
Medical Economics Co., Inc., Montvale, NJ. For many of these listed agents,
pharmaceutically effective dosages and regimens are known in the art; many are presented in
the Physicians' Desk Reference itself.
4. Uses

[0058] Methods of this invention are useful for treating one or more cognitive, or other
disorders, as described herein, in a patient.
[0059] In certain embodiments, the present invention provides a method of treating one
or more intellectual deficit disorders comprising administering a compound of the present
invention. In other embodiments, such intellectual deficit disorders include dementia, such as
dementia of aging, vascular dementia, mild cognitive impairment, age-related cognitive
. decline, and mild neurocognitive disorder; Alzheimer's disease, and memory deficit,
attention deficit disorders (ADD, also known as Attention Deficit Hyperactivity Disorder or
ADHD) in both children and adults. In certain embodiments, the present invention provides a
method of treating ADD and/or ADHD in a pediatric patient comprising administering to said
patient a compound of formula I or pharmaceutical composition thereof.
[0060] In other embodiments, the present invention provides a method of treating one or
more cognition disorders. According to another aspect, the cognition disorder is a learning
disorder. Such learning disorders are known in the art and include autism, dyslexia,
Asperger's syndrome, a neurobiological disorder similar to autism and characterized by
serious deficits in social and communication skills; specific learning disability, a disorder in
one or more of the basic psychological processes involved in understanding or in using
spoken or written language, which may manifest itself in an imperfect ability to listen, think,
speak, read, write, spell or to do mathematical calculations; dysgraphia, a disorder that causes
difficulty with forming letters or writing within a defined space; dyscalculia, a disorder that
causes people to have problems doing arithmetic and grasping mathematical concepts;
dyspraxia, a problem with the body's system of motion that interferes with a person's ability
to make a controlled or coordinated physical response in a given situation; visual perceptual
deficit, difficulty receiving and/or processing accurate information from the sense of sight,
although there is nothing wrong with vision; and auditory perceptual deficit, difficulty
receiving accurate information through auditory means, even though there is no problem with
hearing.
[0061] In certain embodiments, the present invention provides a method for treating one
or more impulsivity disorders (e.g. borderline personality disorder), disruptive behavior
disorders, or impulse control disorders. In certain embodiments, the present invention
provides a method for treating Tourette's Syndrome (TS), an inherited, neurological disorder
characterized by repeated and involuntary body movements (tics) and/or uncontrollable vocal

sounds. In other embodiments, the present invention provides a method for treating
trichotillomania.
[0062] According to another aspect, the present invention provides a method for treating
one or more behavioral addictions and addictive disorders. Behavioral addictions and
addictive disorders result from the intoxication one senses from the release of brain
chemicals (e.g., serotonin, adrenaline, epinepherine, etc.) during certain activities. Such
disorders are known in the art and include gambling, sex addiction, eating disorders,
spending addiction, rage/anger, workaholism, exercise addiction, risk taking addictions
(e.g. kleptomania and pyromania), and perfectionism, to name a few.
[0063] In certain embodiments, a compound of the present invention is administered in
combination with one or more cognitive improvement agents. Such agents are well known in
the art and include donepezil hydrochloride (Aricept™) and other acetylcholinesterase
inhibitors; galantamine, neuroprotective agents (e.g., memantine); ADD/ADHD agents (e.g.,
Ritalin™, Strattera™, Concerta™ and Adderall™), and methylphenidate.
[0064] As 5-HT2C modulators, compounds of the present invention are useful for treating
a variety of disorders. Such disorders include premenstrual: syndrome (PMS), premenstrual
dysphoric disorder (PMDD), or late luteal phase syndrome, motion or motor disorders such
as Parkinson's disease; chronic fatigue syndrome, anorexia nervosa, disorders of sleep (e.g.,
sleep apnea), and mutism.
[0065] Premenstrual dysphoric disorder, or PMDD, is a severe form of PMS. Like PMS,
PMDD typically occurs the week before the onset of menstruation and disappears a few days
after. PMDD is characterized by severe monthly mood swings and physical symptoms that
interfere with everyday life, especially a woman's relationships with her family and friends.
PMDD symptoms go far beyond what are considered manageable or normal premenstrual
symptoms.
[0066] PMDD is a combination of symptoms that may include irritability, depressed
mood, anxiety, sleep disturbance, difficulty concentrating, angry outbursts, breast tenderness
and bloating. The diagnostic criteria emphasize symptoms of depressed mood, anxiety, mood
swings or irritability. The condition affects up to one in 20 American women who have
regular menstrual periods. According to another embodiment, the present invention provides
a method for treating one or more symptoms associated with PMDD.
[0067] Selective serotonin reuptake inhibitors (SSRIs) are the current preferred method

for treating symptoms associated with PMDD. According to another aspect, the present
invention provides a method for treating PMDD, or one or more symptoms associated with
PMDD, by administering a compound of formula I in combination with an SSRI. In certain
embodiments, the SSRI is fluoxetine, venlafaxine, paroxetine, duloxetine, or sertraline.
[0068] 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.
[0069] 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.
[0070] 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
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.

[0071] 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.
[0072] 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.
[00731 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 pressurized container, pump, spray, atomizer or nebuliser, with or
without the use of a suitable propellant, e.g. dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-
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 pressurized aerosol, the dosage unit may
be determined by providing a valve to deliver a metered amount. The pressurized container,
pump, spray, atomizer 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.

[0074] 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.
[0075] 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.
[0076] 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.
[0077] 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.
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.

EXEMPLIFICATION
Example i
[0078] Compound 1, (7-(2,6-dichIorophenyl)-5fluoro-2,3-dihydrobenzofuran-2-
yl)methan-amine, was used to exemplify the effect of compounds of the present invention on
on compulsive behavior.
Introduction
[0079] Compound 1 is a potent full agonist at the 5-HT2C receptor (Ki = 0.37 nM; EC50 =
0.4 nM). Several lines of evidence suggest that 5-HT2C agonists may be effective treatments
for obsessive-compulsive disorder (OCD). For example, 5-HT2C agonists have been shown
to be effective in animal models of compulsive behavior stfch as schedule-induced polydipsia
(SIP), 8-OH-DPAT-induced scratching in squirrel monkeys, marble burying, and excessive
eating of palatable foods. Furthermore, 5-HT2C receptor knockout mice exhibit compulsive-
like behaviors.
[0080] The present studies were conducted to evaluate the effects of Compound 1 in a
schedule-induced polydipsia model of obsessive-compulsive disorder in rats. In this model, a
food pellet is delivered once per minute for a two-hour period. A water bottle is available in
the test chamber. Under this schedule, water intake is tremendously increased relative to
animals that receive 120 food pellets at the start of a session and are given two hours to eat
and drink. This excessive manifestation of a normal behavior (drinking) provides face
validity to the model. Moreover, since the rats are not water deprived, the adjunctive
drinking does not serve a physiological function. Most importantly, clinically effective drugs
for the treatment of obsessive-compulsive disorder decrease adjunctive drinking.



[0082] Male Sprague-Dawley rats weighing 300 - 400 grams were individually housed
in an AALAC-accredited facility that was maintained on a 12-h light dark cycle (lights on at
0600 h) with freely available water. All in vivo studies were performed in accordance to the
Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the
National Institutes of Health (Pub. 85-23, 1985). Rats were maintained at approximately
85% of their free-feeding body weights by food presented during the session and by post-
session feeding.
[0083] Procedure Experimental sessions were conducted in a standard operant
conditioning chamber placed inside a ventilated sound-attenuating shell that was equipped
with white noise to mask extraneous sounds (Med Associates, Georgia, VT). A food trough
was on the front panel of the chamber and a water bottle was mounted to the side panel.
Experimental sessions were 120 minutes in duration and were conducted five days per week
(Monday through Friday). Test sessions occurred generally on Tuesdays and Fridays, with
the remaining days serving as control days. For each session, one food pellet (Bioserv, 45
mg precision dustless pellet) was dispensed into the food trough each minute for the duration
of the session, for a total of 120 pellets being delivered. This schedule of food presentation
elicits an abnormal adjunctive drinking behavior in rats such that they consume and
exaggerated volume of water, approximately 5-10 fold larger than under normal conditions.
Compound 1 or vehicle was administered immediately prior to the start of the experimental
session. Each dose of Compound 1 was tested on a separate day, with the appropriate control
sessions being conducted prior to each test. At the end of the test session, the volume of
water and the number of food pellets that each rat consumed were measured.
[0084] In order to determine if Compound 1 would affect normal eating and drinking
behavior, Compound 1 or vehicle was tested under modified conditions. Under these
modified conditions, 120 food pellets were placed into the food trough at the beginning of the
session and no further food pellets were dispensed. At the end of the test session, the volume

of water and the number of food pellets consumed by each rat were measured as described
earlier.
[0085] Water consumption was calculated and expressed as percent (%) of vehicle
control intake. Results were analyzed using a one-way ANOVA with least significant
difference (LSD) post-hoc test. Statistically significant decreases in adjunctive drinking were
defined as p < 0.05 relative to mean vehicle control values. Where appropriate, ED50 values
(dose that decreases adjunctive water intake to. 50% of vehicle values) were calculated using
a logistic dose response analysis.
RESULTS AND DISCUSSION
[0086] The effect of Compound 1 (0.1 - 1 mg/kg, i.p.) on schedule-induced polydipsia
Was evaluated. Compound 1 produced a dose-dependent decrease in adjunctive drinking
behavior (F(3,20) — 16.91, p < 0.0001). Post hoc tests revealed that doses of 0.3 and 1 mg/kg
of Compound 1 produced statistically significant reductions in adjunctive drinking behavior
of 45% (p = 0.003) and 81% (p < 0.0001) respectively. The ED50 value was 0.36 mg/kg
(95% CI: 0.22 - 0.57 mg/kg). At the highest dose of 1 mg/kg, one of the six rats did not eat
all of the food pellets presented. When tested under the modified procedure to assess effects
on normal feeding and drinking behavior, 1 mg/kg of Compound 1 decreased water
consumption by 26% relative to vehicle controls and two of the six rats tested failed to eat all
of the food pellets presented (Figure 1).
[0087] The present studies demonstrate that Compound 1 produced dose-dependent
decreases in adjunctive drinking following i.p. administration. The anti-OCD-like effects of
Compound 1 on SIP occurred following an acute administration. In contrast, the effects of
serotonin reuptake inhibitors generally require chronic administration in this model. Taken
together with previous studies demonstrating that 5-HT2C agonists are effective in animal
models of compulsive behaviors, these results suggest that Compound 1 may be an effective
treatment for obsessive-compulsive disorder and may have more rapid onset than current
pharmacotherapies.

Example 2
Assessment of Effect on Acetylcholine and Glutamate Levels
[0088] Compound 1 was used to exemplify the effect of compounds of the present
invention on rat brain acetylcholine and glutamate using in vivo microdialysis.
MATERIALS AND METHODS
[0089] Animals: Adult male Sprague-Dawley rats (Charles River, Wilmington, MA)
weighing 280-350 g at the time of surgery were used for all microdialysis experiments. Adult
male Long-Evans rats (Charles River, Wilmington, MA) weighing 180-220 g were used for
NOR studies. Rats were housed individually for recognition memory studies. AU animals
had free access to food and water and were group housed in the AAALAC-accredited facility
that was maintained on a 12 h light dark cycle (lights on at 0600 h) for at least 1 week prior to
surgery or behavioral testing. All in vivo studies were performed in accordance to the 'Guide
for the Care and Use of Laboratory Animals' as adopted and promulgated by the National
Institutes of Health (Pub. 85-23, 1985). The animals used in microdialysis are listed in Table
2.1.

[0090] Stereotaxic Surgery Following induction of anesthesia with 3% halothane
(Fluothane; Zeneca, Cheshire, UK), animals were secured in a stereotaxic frame with ear and
incisor bars (David Kopf, Tujunga, CA). Anesthesia was maintained by continuous
administration of halothane (1 - 2 %) while a microdialysis guide cannula (CMA/12, CMA
Microdialysis, Stockholm, Sweden) was implanted above the dorsal hippocampus (AP: -
4.3mm ML: -2.6mm DV: -2.1mm) or the medial prefrontal cortex (AP: 3.2mm ML: -0.6mm
DV: -3.8mm). The guide cannula was secured to the skull using dental acrylic (Plastics one,

Roanoke, VA, USA) and two small stainless-steel screws (Plastics one, Roanoke, VA, USA).
Following surgery, animals were individually housed in Plexiglas cages (45 cm sq.), with free
access to food and water. The following day rats were used in microdialysis experiments.
[0091] Microdialysis Microdialysis probes (CMA 12/02; CMA Microdialysis,
Stockholm, Sweden) were equilibrated according to manufacturer's specifications.
Microdialysis probes were perfused with artificial cerebrospinal fluid (aCSF: 125 mM NaCl,
3 mM KC1, 0.8 mM MgCl2, 185 mM CaCl2, 1.54 mM Na2HPO4 and 0.225 mM NaH2PO4;
pH 7.4) prior to insertion in the guide cannula. The microdialysis probe was then inserted via
the guide cannula into the dorsal hippocampus or medial prefrontal cortex and perfused with
aCSF at a flow rate of 0.5 µl/min. A 3 h stabilization period was allowed following probe
insertion before dialysate sampling was initiated. Samples were collected every 40 min for
acetylcholine analysis and immediately frozen on dry ice after collection. After baseline
samples were collected (2 h), rats were dosed with Compound 1 or vehicle (t=0). Following
dosing, dialysis samples were collected for 200 min. At the end of the experiment, animals
were euthanized and probe placement was verified histologically. Data from animals with
incorrect probe placement were discarded.
[0093] Acetylcholine data were quantified using peak area against an internal standard
and acquired using Masslynx software (Micromass, Beverly, MA, USA). The mean of the
concentration of baseline samples was calculated and denoted as 0%. All sample values were
expressed as a percent change from this pre-injection mean baseline value (% change from
baseline). Neurochemical data, excluding pre-injection values, were analyzed by a two-way
analysis of variance (ANOVA) with repeated measures (time). All statistical analyses were
performed using SAS (v 1.03) within Excel® (Microsoft).

High Performance Liquid Chromatography (HPLC) Analysis
[0094] Dialysate (10 µL) was collected and analyzed for extracellular glutamate
concentrations. HPLC methods were conducted using the following methods:
10 µL dialysate containing glutamate was separated by HPLC. These units consisted of two
Jasco PU-980 pumps (Jasco Ltd, Essex, U.K) as the gradient, a BAS sentinel autosampler
(BAS) and a Jasco PF-920 fluorometer with excitation wavelength of 448 nm. The emission
wavelength was 485 nm. Mobile phase A was 0.05 M acetate buffer (pH 6.5) with
20%methanol (V: V) and mobile phase B was a 0.05 M acetate buffer (pH 6.5) with 80%
methanol (V:V). The gradient consisted of a linear transition from 80% mobile phase A to
0% in 18 minutes. The column was allowed to re-equilibrate for 10 min prior to each
injection. Each sample was diluted 1:1 with normal Krebs solution containing 2.5 µM alpha-
aminoadipic acid (3-dihydro-1-benzofuran-2-yl)methanamine,
(±)-1 -[7-(3-methylphenyl)-2,3-dihydro-1-bebzofuran-2-yl]methanamine,
(+)-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(-)-1 -[7-(3-methylphenyl)-2,3-dihydro-1 -benzofuran-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)methanamine,
(-)-1 -(7-thien-3-yl-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(±)-1 - [7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanarnine,
(+)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(-)-1 -[7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanarnine,
(±)-1-[7-(2-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(+)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(-)-1-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine,
(-)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine,
(+)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine,
(±)-1 -[7-(2,6-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamme,
(-)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(+)-1 -[7-(2,6-dimethylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-1 -[7-(2-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(±)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,

(±)-1 -[7-(3-fluorophenyl)-2,3-dihydro-1 -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,
(-)-1 -[7-(3-chlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-1 -[7-(3-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl] methanamine,
(±)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine,
(±)-1 -[7-(4-methylphenyl-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(+)-1 -[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(-)-1 -[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-1 -[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(+)-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(-)-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(+)-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(-)-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-1-[7-(4-methoxyphenyl)-2,3-dihydro-1n-benzofuran-2-yllmethanamine,
(+)-1-[7-(4-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
*
(-)"' -[7-(4-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2-y l)rnethanamine,
Qty 1 -{ 7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1 -benzofuran-2-yl}methanamine,
(±)-1-[7-(2,4-dichJorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine,
(+)-1 -(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine,
(-)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine,
(±)-1-[5-chloro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl}methanamine,
(±)-1-[5-chloro-7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-1-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-(5-chloro-7-thien-3-yl-2,3-dihydro-1-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-1-benzofuran-2-yl)methylamine,
(+)-N-[(5-chloro-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]-N-methylaxnine,
(-)-N-[(5-chloro-7-thien-3-yl-2,3-dihydro-1 -benzofuran-2 -yl)methyl]-N-methylamine,
(±)-1-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,

(+)-1-[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(-)-1 -[5-chloro-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(±)-1-(4-fluoro-7-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(±)-1-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-1 -[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(+)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(-)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methananiine,
(±)-1 -(5-fluoro-7-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methanamine,
(±)-1 -[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-y]]methanamine,
(+)-1 -[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(-)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanaminc,
(±)-1-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-hydro-1-benzofuran-2-yl}methanamine,
(±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methylamine,
(±)-1-[4,5-difluoro-7-(2-methylpheny])-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-7-thien-3-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine,
(±)(5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine,
(+)-1 -[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(-)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(+)-1-[7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(+)-1-I7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(-)-1-[7-(3-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(+)-1 -[7-(3-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(-)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-y]]methanamine,
(-)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine,
(+)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine,
(+)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine,
(-)-1-{7-[4-(trifluoromethyl)phcnyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine,
(±)-1-[7-(2,6-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-y]]methanamine,
(-)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,

(+)- 1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-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,
(+)-1-[7-(2,4-dimethoxyphenyl)-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-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl)methanamine,
(-)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(-)-1-[7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(+)-1 -[7-(2,4-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methanamine,
(-)-1 - { 5-fluoro-7- [2-(trifluoromethyl)phenyl]-2,3-dihydro-1 -benzofuran-2-yl} methanamine,
(+)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine,
(±)-1-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-{[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl}methyl}amine,
(-)-{[(7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(+)-{[(7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(+)-{[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl} amine,
(-)-{[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,3-difluorophenyl)-2,3-dihydror 1 -benzofuran-2-yl]methyl } amine,
(±)-{[7-(2,5-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(±) {[7-(2,5-dimethoxyphenyl)-2,3-dihydro-1 -benzofuran-2-yl)methyl}amine,
(±)-{[7-(2,5-dichlorophenyI)-2,3-dihydro-1-benzofuran-2-y]]methyl}amine,
(+)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-y]]methyl}amine,
(-)-{[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-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-1-benzofuran-2-yl]methyl}amine,
(±)- {[7-(5 -chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methy]} 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)methyl]amine,
(+)- { [7-pyridin-3 -yl-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(-)- {[7-pyridin-3-y 1-2,3-dihydro-1 -benzofuran-2-yl] methyl} amine,
(±)-{[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(±)- {[5-fluoro-7-(3-fluorophenyl)-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-1-benzofuran-2-yl]methy]} amine,
(±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofiuran-2-yl]methyl}amine,
(±)-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-
yl)methyl}cyclopropanamine,
(±)-1-cyclopropyl-N-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-
yl]methyl}methanamine,
(±)-N-{[7-2,6-dichorophenyl)-5-fluoro-23-dihydro-1-benzofuran-2-yl]methyl}ethanamine,
(±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]methyl} dimethylamine,
(±)-{[5-chloro-7-(2-fiuorophenyl)-2,3 -dihydro-1 -benzofuran-2-yI]methyl} amine,
(±)-{ [5-chloro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl} amine,
(±)- {[5-chloro-7-(3-furyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofiuran-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-1-benzofuran-2-yl]methyl}amine,
(±)-{[5-chloro-7-(2,3-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-chloro-7-(2,3-dimethylphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-chloro-7-(2,3-dimethoxyphenyl)-2,3-dihydro -1 -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-1 -benzofuran-2-ylJmethyl}amine,
(-)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-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-1-benzofuran-2-yl]methyl}amine,
(±)- {[5-chloro- 7 -(2,5 -dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl} amine,
(±)-{[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2- yl]methyl}amine,
(±)- {[5-chloro-7-(3,4-difluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-chloro-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-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-dimethylphenyl)-2,3-dihydro-1-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-1-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-1-benzofuran-2-y]]methyl}amine,
(±)-{[(5-chloro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methy]]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-1-benzofuran-2-
yl]methyl} (cyclopropylmethyl)amine,
(±)-N-{[5-chloro-7-(2,6-dimethylpheny])-2,3-dihydro-1-benzofuran-2-yl]methyl}ethanamine,
(±)- {[(5-methyl-7-phenyl-2,3-dihydro-1 -benzofuran-2-yl)methyl]amine,
(±)- {[7-(2-methylphenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-(2-fluorophenyl)-5-methy]-2,3-dihydro-1-benzofuran-2-yl)methyl}amine,
(±)-{[7-(2-methoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}arnine,
(±)- {[7-(2-chlorophcnyl)-5 -methyl-2,3-dihydro-1 -benzofuran-2-yl]mcthyl} amine,
(±)-({5-methyl-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)amine,
(±)-{[7-(3-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-ylJmethyl}amine,
(±)-{[7-(3-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(±)-{[7-(4-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(±)- {[7-(4-fluorophenyl)-5-methyl -2,3 -dihydro-1 -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-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-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-1-benzofuran-2-yl]methyl}amine,
(+)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl}methyl}amine,
(±)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-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-1-benzofuran-2 -yl]methyl}amine,
(+)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-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-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-(trifluoromethyl)-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(±)-{[5-(trifloromethy])-7-(2-methoxyphenyl)-2,3-dihydro-1-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-1-benzofuran-2-yl]methyl}amine,
(±)- {[5-(trifluoromethyl)-7-(3-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[5-(trifluoromemyl)-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(±)- { [5-(trifluoromethyl)-7-(3-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2 -
yl]methyl} 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-fluoropheny l)-2,3-dihydro-1-benzofuran-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-1-benzofuran-2-
yl]methyl} amine,
(±)-{[7-(2,3-difluorophenyl)-5-(trifIuoromethyl)-2,3-dihydro-1-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-dihydxo-1 -benzofuran-2-
yl]methyl}amine,

(±)-{[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-
yl]methyl}amine,
(±)-{[7-(3,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-
yl]methyl}amine,
(±)-{[7-(3-chloro-4-fluorophcnyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-
yl]methyl} amine,
(±).{[7-(2,5-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-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-1-benzofuran-2-
yl)methyl} amine,
(±)-4-[2-(aminomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-7-yI]benzonitrile
(±)- {[7-(3-furyl)-5-(trifluoromethyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)-{[7-thien-3-yl-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(±)-{[7-pyridin-3-yl-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2-fluorophenyl)-5 -methoxy-2,3-dihydro-1 -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-1-benzofuran-2-yl]methyl}amine,
(±)- {[7-(2-methoxyphenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-yl]methyl} amine,
(±)- {[5-methoxy-7-(3-thienyl)-2,3-dihydro-1-benzofuran-2-yl] methyl} amine,
(±)-{[7-(2,3-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl} amine,
(±)-{i7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-1-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-benozfuran-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-1-benzofuran-2-y]]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-1-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-yl]methyl}amine,
(±)-{[7-(2,5-dimethoxylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,

(±)-{ [7-(5-chloro-2-methoxyphenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-
yl]methyl}amine,
(±)-{[7-(3-chloro-4-fluorophenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-yl]methyl}amine,
(±)-{[7-(2,6-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(±)-[(N-methyl-1-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1-[7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1-[7-(4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1-[7-(4-chlorophenyl)-2,3-dihydro-1-benzofuran-2-y]}methanamine,
(±)-[(N-methyl-1-[7-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-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]methanamine,
(±)-[(N-methyl-1 -(7-(2,4-difluorophenyl)-2,3-dihydro-1 -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-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1-[7-(2,5-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methy]-1-[7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1-[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1-[7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1 -benzofuran-2-
yl] methanamine,
(±)-[(N-methyl-1-[7-(5-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-
yl] methanamine,
(±)-[(N-methyI-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-[(N-methyl-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(-)- { [7-(2,6-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl}methylamine,
(+)-{[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-N-methyl-1-(7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2 -yl)methanamine,
(±)-[(N-memyl-1-[7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(±)-{[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,

(±)-{[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl)methyl}methylamine,
(±)-{[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl)methyl}methylamine,
(±)-{[5-chloro-7-(2,4-dimethoxyphenyl)-2,3-dihydro-1 -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-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(5-chloro-2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-
yl]methyl}methylamine,
(±)-{[5-chloro-7-(3,4-difluorophenyl)-2,3-dihydro-1-benzof uran-2-yl]methyl} methylamine,
(±)-[5-chloro-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1 -benzofuran-2-
yl]methyl }methylamine,
(±)-{(7-(2-fluorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-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-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(3-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{{7-(3-chlorophenyl)-5-methy]-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±) {[7-(4-methylphenyl)-5-methyl-2,3-dihydro-1 -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-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±y {[7-(4-methoxyphenyl)-5-methyl-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(±)-{ [7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-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-1-benzofuran-2-yJ]methyl}methylamine,
(-)- {[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl }methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl)methyl}methylamine,
(±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,

(±)- {[5-fluoro-7-(2-chlorophenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(±)- {[5-fluoro-7-(2-methylphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(-)- {[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(+)- {[5-fluoro-7-(2-methylphenyl)-2,3 -dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(±)-{[5-fluoro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)- {[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-
yl]methyl} methylamine,
(±)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(-)-[7-(2,4-dichloropheny])-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(+)-[7-(2,4-dichlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(±)-{[7-(2,5-difluorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{ [7-(2,5-dichlorophenyl)-5-fluoro-2,3-dihydro-1 -benzofuran-2-yl]methyl}methylamine,
(+)-{[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(-)- {[5-fluoro-7-(2,5-dichlorophenyl)-2,3-dihydro-1 -benzofuran-2-yl]methyl} methylamine,
(±)- {[7-(2,5-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl }methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-ylJmethyl}methylamine,
(±)-{[5-fluoro-7-(5-methoxy-2-methylphenyl)-2,3-dihydro-1-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,
(±)-[(5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine,
(±)-[(5-chloro-7-(2-methoxypheny])-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl)methyl}methylamine,
(±)-[(5-chloro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)- {[5-chloro-7-(2,3-difluorophenyl)-2,3-dihydro-1-benzofuran-2 -yl]methyl} methylamine,
(±)-{[5-chloro-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,3-dimethylphenyl)-2,3-dihydro-1-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-1-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-1-benzofuran-2-
yl]methyl}methy]amine,
(±)-{[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[5-chloro-7-(2,4-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl methylamine,
(±)- {[5-chloro-7-(5-chloro-2-methoxyphenyl}-2,3-dihydro-1 -benzofuran-2-
yl]methyl}rnethylamine,
(±)-{[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-]-benzofuran-2-
yl]methyl}methylamine,
(±)-{(7-(2-fluorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-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-1-benzofuran-2-yl]methyl}methylamine,
(±)-{(7-(3-methylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(3-chlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(4-methylphenyl)-5-methyl-2,3-dihydro-1-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-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(4-methoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,3-dimethoxypheny])-5-methyl-2,3-dihydro-1-benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(2,4-dichlorophenyl)-5-methyl-2,3-dihydro-1-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-1-benzofuran-2-yl]methyl}methylamine,
(-)-{[7-(2,5-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2,6-dimethylphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{(7-(2,6-dichlorophenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-fluorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-chlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
(±)-{[7-(2-methylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,

(±)-{[7-(2,3-difluorophenyl)-5 -methoxy-2,3-dihydro-1 -benzofuran-2-
yl]methyl }methylamine,
(±)-{[7-(2,3-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(2,3-dimethylpheny])-5-methoxy-2,3-dihydro-1-benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(2,4-difluorophenyl)-5-methoxy-2,3-dihydro-1-benzoluran-2-
yl]methyl} methylamine,
(±)- {[7-(2,5-difluorophenyl)-5-methoxy-2,3-dihydro-1 -benzofuran-2-
yl]methyl }methylamine,
(±)-{[7-(2,5-dichlorophenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-
yl]methyl}methylamine,
(±)-{[7-(2,5-dimethylphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-
yl]methyl} methylamine,
(±)-{[7-(2,5-dimethoxyphenyl)-5-methoxy-2,3-dihydro-1-benzofuran-2-
y 1] methyl} methylamine,
(±)- {[7-(5-chloro-2-methoxyphenyl)-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,
(±)-N-methyl-1-[7-(2,3-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-
yl]methanamine,
(±)-N-methyl-1-[7-(3,4-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1 -benzofuran-2-
yl]methanamine,
(±)-N-methyl-1-[7-(2,5-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-
yl]methanamine,
(±)-N-methyl-1-[7-(2,3-dichlorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-
yl]methanamine,
(±)-{[7-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-
yl]methyl} methylamine,
(±)-N-methyl-1-[7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-
yl]methanamine,

(+){[7-{2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-ben2ofiiran-2-y]]methyl}methylamine,
(-){[7-(2,6-dichlorophcnyl)-5-fluoro-2,3-dihydro-]-benzofuran-2-yl]methyl}methylamine,
(R)-[7-(2-chloro-phenyl)-(5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl)methy]-amine,
(R)-[7-(2,6-dichloro-phenyl)-5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl]methylamine,
(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-1-benzofuran-2-yl]methyl}amine,
{[(2R)-7-(4-chloro-2-methylphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine,
(-)- {[7-(2,6-dichlorophenyl)-5 -fluoro-2,3 -dihydro-1-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-1-benzofuran-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-metboxy-2,3-dihydro-1-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-benzofuran-2-yl]methanamine,
(-)-{N-methyl-1-[(7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine,
(+)-{[7-(2,6-dimethylphenyl)-5-fluoro-2,3:dihydro-1-benzofuran-2-yl]methyl}methylamine,
(-)-{[7-(2,6-dimethylpheny])-5-fluoro-2,3-dihydro-1-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-1-benzofuran-2-yl]methyl}methylamine,
(-)-{[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-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-1-benzofuran-2-yl]methyl}methylamine,
(+)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-
yl]methyl}methylamine,
(-)-{[7-(2,3-dimethoxyphenyl)-5-methyl-2,3-dihydro-1-benzofuran-2-
yl]methyl}methylamine,
(-)- {[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}methylamine,
or

(+)-{[7-(2,3-dimethoxyphenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-
yl]methyl} methylamine;
or a pharmaceutically acceptable salt thereof.
17. The method of any one of claims 1 to 16, wherein the cognitive disorder is
ADD or ADHD. .
18. The method of any one of claims 1 to 16, wherein the cognitive disorder is a
learning disorder.
19. The method of claim 18, wherein the learning disorder is autism, dyslexia,
Asperger's syndrome, a specific learning disability, dysgraphia, dyscalculia, dyspraxia, visual
perceptual deficit, or auditory perceptual deficit.
20. The method of any one of claims 1 to 16, wherein the cognitive disorder is an
impulsivity disorder.
21. The method of claim 20, wherein the impulsivity disorder is borderline
personality disorder, a disruptive behavior disorder, an impulse control disorders, or
Tourette's Syndrome.
22. The method of any one of claims 1 to 16, wherein the cognitive disorder is a
behavioral addiction or addictive disorder.
23. The method of claim 22, wherein the behavioral addiction or addictive
disorder is gambling, sex addiction, eating disorders, spending addiction, rage/anger,
workaholism, exercise addiction, a risk taking addiction, or perfectionism.
24. The method of any one of claims 1 to 23, further comprising administering an
additional therapeutic agent selected from an acetylcholinesterase inhibitor, galantamine, a
neuroprotective agent, a therapeutic agent for treating ADD/ADHD.

25. The method of claim 24, wherein the additional agent is selected from
donepezil hydrochloride, galantamine, memantine, methylphenidate, atomoxetine, or
amphetamine/dextroamphetamine.
26. The method of any one of claims 1 to 25, wherein the patient is a pediatric
patient.
27. A method for treating PMS or PMDD, or one or more symptoms associated
with PMS or PMDD, in a patient, comprising administering to said patient a therapeutically
effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof as
defined in any one of claims 1 to 16.
28. The method of claim 27, wherein said symptom is one or more of irritability,
depressed mood, anxiety, sleep disturbance, difficulty concentrating, angry outbursts, breast
tenderness and bloating.
29. The method of claim 27 or claim 28, further comprising administering to said
patient a selective serotonin reuptake inhibitor.
30. The method of claim 29, wherein said selective serotonin reuptake inhibitor is
fluoxetine, venlafaxine, paroxetine, duloxetine, or sertraline.

This invention provides methods and pharmaceutical compositions for treating cognitive disorders such as learning disorders, ADD/ADHD, and other disorders.