WO 2006/138549 PCT/US2006/023467
COMPOUNDS USEFUL AS SEROTONIN INHIBITORS AND 5-HT1A AGONISTS
AND ANTAGONISTS
FIELD OF THE INVENTION
[0001] The present invention relates to novel 3-amino chroman and 2-amino
tetralin derivatives, and in particular, to their use as both serotonin reuptake inhibitors and
as 5-HTIA receptor agonists or antagonists, and to their related use for, inter alia, the
treatment and/or prevention of depression and other conditions related to or affected by
the reuptake of serotonin and the 5-HT1A receptor.
BACKGROUND OF THE INVENTION
[0002] Major depressive disorder affects an estimated 340 million people
worldwide. Depression is the most frequently diagnosed psychiatric disorder and,
according to the World Health Organization, is the fourth greatest public health problem.
If left untreated, the effects of depression can be devastating, robbing people of the
energy or motivation to perform everyday activities and, in some cases, leading to
suicide. Symptoms of the disorder include feelings of sadness or emptiness, lack of
interest or pleasure in nearly all activities, and feelings of worthlessness or inappropriate
guilt. In addition to the personal costs of depression, the disorder also has been estimated
to result in more than $40 billion in annual costs in the United States alone, due to
premature death, lost productivity, and absenteeism.
[0003] Selective serotonin reuptake inhibitors (SSRIs) have had significant
success in treating depression and related illnesses and have become among the most
prescribed drugs since the 1980s. Some of the most widely known SSRIs are fluoxetine,
sertraline, paroxetine, fluvoxamine and citalopram. Although they have a favorable side
effect profile compared to tricyclic antidepressants (TCAs), they have their own particular
set of side effects due to the non-selective stimulation of serotonergic sites. They
typically have a slow onset of action, often taking several weeks to produce their full
therapeutic effect. Furthermore, they have generally been found to be effective in less
than two-thirds of patients.
[0004] SSRIs are believed to work by blocking the neuronal reuptake of
serotonin, increasing the concentration of serotonin in the synaptic space, and thus
increasing the activation of postsynaptic serotonin receptors. Although a single dose of a

WO 2006/138549 PCT/US2006/023467
SSRI can inhibit the neuronal serotonin transporter, and thus would be expected to
increase synaptic serotonin, clinical improvement has generally been observed only after
long-term treatment. It has been suggested that the delay in onset of antidepressant action
of the SSRIs is the result of an increase in serotonin levels in the vicinity of the
serotonergic cell bodies. This excess serotonin is believed to activate somatodendritic
autoreceptors, i.e., 5-HT1A receptors, reduce cell firing activity and, in turn, decrease
serotonin release in major forebrain areas. This negative feedback limits the increment of
synaptic serotonin that can be induced by antidepressants acutely. Over time, the
somatodendritic autoreceptors become desensitized, allowing the full effect of the SSRIs
to be expressed in the forebrain. This time period has been found to correspond to the
latency for the onset of antidepressant activity [Perez, V., et ah, The Lancet, 1997, 349:
1594-1597].
[0005] In contrast to the SSRIs, a 5-HT1A agonist or partial agonist acts directly
on postsynaptic serotonin receptors to increase serotonergic neurotransmission during the
latency period for the SSRI effect. Accordingly, the 5-HT1A partial agonists, buspirone
and gepirone [Feiger, A., Psychophannacol. Bull., 1996, 32(4): 659-665; Wilcox, C,
Psychopharmacol. Bull., 1996, 32(93): 335-342], and the 5-HT1A agonist, flesinoxan
[Grof, P., International Clinical Psychopharmacology, 1993, 8(3): 167-172], have shown
efficacy in clinical trials for the treatment of depression. Furthermore, such agents are
believed to stimulate the somatodendritic autoreceptors, thus hastening their
desensitization and decreasing the SSRI latency period. An agent with a dual mechanism
of antidepressant action would be expected to have greater efficacy and thus reduce the
number of patients refractory to treatment. Indeed, buspirone augmentation to standard
SSRI therapy has been shown to produce marked clinical improvement in patients
initially unresponsive to standard antidepressant therapy [Dimitriou, E., J. Clinical
Psychophannacol., 1998,18(6): 465-469].
[0006] There is still an unfilled need for a single agent with a dual mechanism of
antidepressant action, i.e., one that not only inhibits or blocks serotonin reuptake (to
increase levels of serotonin in the synapse) but also antagonizes the 5-HT1A receptors (to
reduce the latency period). The present invention is directed to these, as well as other
important ends.
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SUMMARY OF THE INVENTION
[0007] This invention relates to 3-amino chroman and 2-amino tetralin
derivatives, and in particular, to methods of their use in the treatment and/or prevention of
serotonin-related disorders, such as depression (including, but not limited to major
depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-
traumatic stress disorder, premenstrual dysphoric disorder (also known as premenstrual
syndrome), attention deficit disorder (with or without hyperactivity), obsessive-
compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating
disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and
alcohol addiction, sexual dysfunction, cognitive deficits resulting from neurodegenerative
disorders like Alzheimer's disease, and related illnesses. Preferred compounds have the
ability to bind 5-HT1A receptors, act as agonists, partial agonists or antagonists at the 5-
HT1A receptors, and act as serotonin reuptake inhibitors.
[0008] In one aspect, the present invention provides 3-amino chroman and 2-
amino tetralin derivatives of Formula (I):

stereoisomer or pharmaceutically-acceptable salt thereof;
[0009] R3 is a hydrogen, hydroxyl, halogen, -(C1-C3)-alkyl, -O-(C1-C3)-alkyl, -
(C3-C6)-cycloalkyl, -SO2R20, or -COR20, wherein -(C1-C3)-alkyl, -O-(C1-C3)-alkyl, or
-(C3-C6)-cycloalkyl are optionally branched;
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[0010] R4 and R5 are each independently hydrogen, hydroxyl, linear or branched -
(C1-C6)-alkyl, linear or branched -(C2-C6)-alkenyl, halogen, -COR14, -OR14, -SR14,
-SO2NR14R15,
-NO2, -CONR14R15 or -(C3-C6)-cycloalkyl, wherein one or two carbon atoms of the alkyl,
alkenyl or cycloalkyl is optionally replaced by a nitrogen, oxygen or sulfur atom;
[0011] R6 is hydrogen, a linear or branched -(C1-C6)-alkyl or a linear or branched
-(CH2)m-B, wherein 1-3 carbon atoms of the -(C1-C6)-alkyl or -(CH2)m- chain may
optionally be replaced by a nitrogen or oxygen atom, provided that R6 has at least two
carbon atoms in sequence (-(C1-C2)-) directly attached to the nitrogen of Formula (I),
wherein B is a (C3-C5)-cycloalkyl, a saturated, partially saturated or aromatic (C5-C7)-
carbocyclie ring or a phenyl fused to a saturated, partially saturated or aromatic (C5-C7)-
carbocyclic ring, wherein the cycloalkyl, phenyl or carbocyclic ring is optionally
substituted by one to two substituents per ring, wherein said substituents are
independently selected from the group consisting of halogen, cyano, -(C1-C6)-alkyl, -(C2-
C6)-alkenyl, -(C2-C6)-alkynyl,- (C3-C7)-carbocycle, -(C1-C6)-alkoxy, —OCF3, -(C6-C10)-
aryl and -(C2-C9)-heterocycle; further wherein one or two ring atoms in the cycloalkyl,
phenyl or carbocyclic ring may optionally be replaced by a nitrogen, oxygen or sulfur
atom, and m is a number from 0 to 7;
[0012] R7 is selected from a linear or branched -(C1-C6)-alkylene-, linear or
branched -(C2-C6)-alkenylene- or -(CH2)p-(C3-C6)-cycloalkyl-(CH2)q-, each of which is
optionally substituted with a halogen or hydroxyl, wherein at least one ring atom of the -
(C3-C6)-cycloalkyl is optionally replaced by a nitrogen, sulfur or oxygen, and at least two
ring atoms of the alkylene, alkenylene or cycloalkyl are carbon atoms, and p and q are
each independently 0, 1 or 2;
[0013] Q is selected from -(C1-C3)-alkylene-, -O-(C1-C2)-alkylene- -(C2-C3)-
alkenylene-, or -O-(C2)-alkenylene—, wherein the alkylene or alkenylene is optionally
substituted with a -(C1-C3)-alkyl or a halogen, and wherein for -O-(C1-C2)-alkylene- or -
O-(C2-C3)-alkenylene-, the O is directly attached to the phenyl ring;
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[0014]
[0015] R8, R9, R10, and R11 are each independently hydrogen, cyano, carboxamido,
carboalkoxy, trifluoromethyl, hydroxyl, linear or branched -(C1-C6)-alkyl, linear or
branched -(C2-C6)-alkenyl, halogen, -OCF3, alkanoyloxy, alkanamido, alkanesulfonyl,
alkanesulfonamido, phenyl, -NR16R17, -, -COR16, -OR16, -SR16, -OR16, or -NO2, W, X
and Y are each independently -CR18R19-, -O-, -NR18- or -S-;
[0016] X and Y are each independently -CR18R19-, -O-, -NR18- or -S-;
[0017] Z1 is carbon or nitrogen, Z2 is carbon and Z3 is carbon, nitrogen, oxygen or
sulfur; wherein at least one of Z1 and Z3 is not carbon, wherein a double bond is
optionally present between Z1 and Z2, wherein A1 is attached to R7 through Z1, Z2 or Z3
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except when Z3 is oxygen, and further wherein when R7 is linked to Z3, then Z3 is
nitrogen;
[0018] R12 and R13 are each independently hydrogen or a linear or branched -(C1-
C6)-alkyl, wherein R12 and R13 may be attached at any of Z1, Z2 or Z3, and further wherein
R13 is optionally present at Z1 or Z2 when Z3 is oxygen;
[0019] R14, R15, R16, R17, R18 and R19 are each independently hydrogen, hydroxyl,
halogen, a linear or branched (C1-C6-alkyl or a linear or branched (C2-C6)-alkenyl; R20 is
a hydrogen, a linear or branched (C1-C6)-alkyl or a (C3-C7)-cycloalkyl; and the dotted
lines represent optional double bonds.
[0020] In preferred embodiments, in the compound of Formula (I), where A is A2,
Y is -NH- or -O-. Alternatively, in preferred embodiments in the compound of Formula
(I), where A is A1, R7 is linked at Zl, Z3 is -N-, R13 is hydrogen or -CH3, and a double
bond is present between Z1 and Z2. In additional preferred embodiments, where A is A1,
Z1 is carbon, Z3 is -O-, R13 is not present, and a double bond is present between Z1 and
Z2.
[0021] In addition, preferred are compounds according to claim 1 of Formula (I),
wherein X is -O-.
[0022] Further preferred are compounds of Formula (I) wherein R6 is selected
from:
[0023] -(CH2)m-B, m is 0 or 1, and B is a C3-C6-cycloalkyl, a linear C2 -C4-alkyl,
or a branched C3-C5-alkyl,
[0024] -(CH2)m-B, m is 0 or 1, and B is an aromatic (C5-C7)-carbocyclic ring,
wherein one to two ring atoms may optionally be replaced by an oxygen, and
[0025] -(CH2)m-B, m is 2, 3 or 4, and B is a phenyl fused to a saturated, partially
saturated or aromatic (C5-C7)-carbocyclic ring, wherein the phenyl or carbocyclic ring is
optionally substituted by one to two halogen atoms, further wherein one to two ring atoms
of the (C5-C7)-carbocyclic ring may optionally be replaced by a nitrogen or oxygen atom.
6

7
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WO 2006/138549 PCT/US2006/023467

wherein R12 is a linear -(C1-C6)-alkyl, preferably methyl or ethyl.
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[0029] Also preferred are compounds of Formula (I), wherein A is

[0030] In preferred embodiments of compounds of Formula (I), at least one of R5,
R8, R9, R10 and R11 is fluorine. In particular embodiments, R8, R9, and R11 are hydrogen
and R10 is fluorine.
[0031] Further, R3 is preferably -CH3 or hydrogen, and more preferably -CH3 in
particular embodiments.
[0032] Q is preferably -CH2- -(CH2)2-,-O-(CH2)2-, -O-(CH2)2- -CH2=CH2-
or-O-CH2=CH2-.
[0033] Preferably, in the compound of Formula (I), R4 or R5 is -O-CH2 or -NO2.
In additional embodiments, R4 is preferably hydrogen. Further embodiments include R5
preferably being -OR14, halogen or hydrogen and in particular, R5 being -OCH3.
[0034] R7 is preferably a linear -(C1-C4)-alkylene- or -(CH2)P-(C3-C6)-
cycloalkyl-(CH2)q-. In further preferred embodiments, R7 is

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[0035] Further preferred, are compounds of Formula (I), wherein R10 is a nitrile
group.
[0036] In some preferred embodiments, the present invention provides
compounds of Formula (Ia):

wherein R3, R4, R5, R6, R7, R8, R9, R10 and R11 are as previously defined, or a prodrug,
stereoisomer or pharmaceutically-acceptable salt thereof.
[0037] In other preferred embodiments, the present invention is directed to
compounds of Formula (Ib)

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(Ib)
wherein R3, R4, R5, R6, R7, R8, R9, R10 and R11, are as previously defined, or a prodrug,
stereoisomer or pharmaceutically-acceptable salt thereof.
[0038] In additional embodiments, the compounds are of Formula (Ic)

wherein R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are as previously defined, or a prodrug,
stereoisomer or pharmaceutically-acceptable salt thereof. Particular embodiments include
at least one of the following: R3, R4, R5, R9 and R11 are hydrogen; R5 is -OCH3 or fluorine;
R6 is — (CH2)m-B, with -B being a — (C3-C5)-cycloalkyl (in particular where m is 1 and B is
a C4-cycloalkyl ring, i.e., cyclobutyl ring); R7 is -(CH2)p-(C3-C6)-cycloalkyl-(CH2)q-
(particularly where p is 0 and q is 1 or p is 1 and q is 0, and the cycloalkyl is a -C4-
cycloalkyl-, i.e., -cyclobutyl-); R10 is a halogen, preferably fluorine; and R12 is a -(C1-
C6)-alkyl, preferably a methyl or ethyl group.
[0039] In another embodiment, the present invention is directed to the compounds
or a prodrug, stereoisomer or pharmaceutically-acceptable salt thereof of the compound
of Formula (I) or Formula (Ia) or Formula (Ib) or Formula (Ic) and one or more
pharmaceutically acceptable carriers.
[0040] In one embodiment, the compounds or pharmaceutically acceptable salts
of the compounds of the Formula (I) or Formula (Ia) or Formula (Ib) or Formula (Ic) are
useful as serotonin reuptake inhibitors.
[0041] In a further embodiment, the compounds or pharmaceutically acceptable
salts of the compounds of the Formula (I) or Formula (Ia) or Formula (Ib) or Formula (Ic)
are useful as agonists and/or antagonists of 5-HT1A receptors.
[0042] The present invention also provides methods of treating and/or preventing
a serotonin-related disorder in a patient suspected of suffering from a serotonin-related
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disorder, comprising the step of administering to the patient a therapeutically effective
amount of a compound of Formula (I) or Formula (Ia) or Formula (Ib). In a further
embodiment, the present invention provides methods for treating and/or preventing
depression (including, but not limited to major depressive disorder, childhood depression
and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual
dysphoric disorder (also known as premenstrual syndrome), attention deficit disorder
(with or without hyperactivity), obsessive compulsive disorder, social anxiety disorder,
generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa and
bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction,
cognitive deficits resulting from neurodegenerative disorders like Alzheimer's disease,
and related illnesses.
[0043] In another embodiment, the present invention is directed to methods of
inhibiting the reuptake of serotonin in a patient in need thereof, comprising the step of
administering to the patient a therapeutically effective amount of a compound of Formula
(I) or Formula (Ia) or Formula (Ib).
[0044] The present invention is also directed to a method of agonizing and/or
antagonizing 5-HT1A receptors in a patient in need thereof, comprising the step of
administering to the patient a therapeutically effective amount of a compound of Formula
(I) or Formula (Ia) or Formula (Ib).
[0045] The present invention further relates to a method of making a compound of
the invention of Formula (I), wherein said method comprises
[0046] (a) nitrating a compound of formula (II)

[0047] (b) reducing the compound to provide a compound of formula (III)
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[0048] (c) subjecting the compound of formula (HI) to reductive amination
with an aldehyde of formula (IV)

[0049] wherein R2 is the corresponding aldehyde of R7 under conditions sufficient
to produce a compound of formula

[0050] wherein said compound of formula (V) is optionally subjected to an
alkylation in the presence of a base under conditions effective to produce a compound of
formula (VI)
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[0051] or is optionally subjected to a reductive animation by reacting with a
compound of formula R6CHO to produce a compound of forumula (VII)

[0052] Further encompassed is a method of making a compound of the invention
of Formula (I), wherein said method comprises
[0053] (a) combining a compound of formula (III)
with a compound of formula (VIII)
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wherein R2 is the corresponding amine of R7, under conditions sufficient for reductive
amination;
[0054] (b) combining the product of (a) with a compound of formula R6CHO
under conditions for reductive amination, to obtain a compound of formula (EX)

[0055] Preferably, the method further comprises the step of alkylating the
compound of formula (II) with an alkyl halide under conditions sufficient to produce a
compound of formula (IIa)

prior to step (b), wherein R3 is a -(C1-C3)-alkyl.
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[0056] The instant invention further provides a method of making a compound of
formula (XII)
wherein said method comprises
[0057] (a) subjecting a compound of formula (X)

to a rearrangement reaction under conditions sufficient to produce a compound of formula
(XI)
[0058] (b) isolating the compound of formula (XI),
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[0059] (c) deprotecting the compound of formula (XI) to produce a compound
of formula (XII)
[0060] The present invention further includes a method whereby the compound of
formula (XII) is subject to a propargylating reaction under conditions sufficient to
produce a compound of formula (XIIa)

[0061] subjecting the compound of formula (XIIa) to a cyclization reaction under
conditions sufficient to produce a compound of formula (XIII)

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[0062] Preferably, R3 is hydrogen or a -(C1-C3) alkyl. For R3 to be an alkyl, for
example, the compound is alkylated by reaction with an alkyl halide under conditions
sufficient to substitute R3 for H. Other methods known in the art may be used to
substitute additional R3 groups.
[0063] Additionally, the invention provides a method of making a compound of
Formula (I), wherein said method comprises
[0064] (a) nitrating a compound of formula (XIII)

[0065] (b) reducing the compound to produce a compound of formula (XIV)

[0066] (c) subjecting the compound of formula (XIV) to reductive animation with
an aldehyde of forumula (IV)
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[0067] wherein R2 is the corresponding aldehyde of R7 under conditions sufficient
to produce a compound of formula (XV)

[0068] wherein said compound of formula (XV) is optionally subjected to an
alkylation in the presence of a base under conditions effective to produce a compound of
formula (XVI)

[0069] wherein R6 is a -(C1-C3)-alkyl, or is optionally subjected to a reductive
amination by reacting with a compound of formula R6CHO to produce a compound of
formula (XVII)
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wherein R6 is as defined in claim 1.
[0070] The invention further provides a method of making a compound of
Formula (I), wherein the method comprises
[0071] (a) combining a compound of formula (XIV)

with a compound of formula (VIII)

under conditions for reductive amination;
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[0072] (b) combining the product of (a) with a compound of formula R6CHO
under conditions for reductive amination, to obtain a compound of formula (XVI)

[0073] The present invention further provides a method of making a compound of
formula (IIb)
comprising
[0074] (a) protecting a carboxylic acid of formula (XVII)

wherein R1 is -Br, -Cl or -OSO2CF3, by alkylation under conditions sufficient to produce
a compound of formula (XVIII)
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[0075] (b) replacing R1 with a methyl group to produce a compound of
formula (XIX)

[0076] (c) halogenating the compound of formula (XIX) and heating under
conditions sufficient to produce a compound of formula (XX)

[0077] (d) deprotecting the compound of formula (XX) under conditions
sufficient to produce a compound of formula (XXI)

[0078] (e) propargylating under conditions sufficient to produce a compound
of formula (XXII)
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[0079] (f) subjecting the compound of formula (XXII) to a cyclization
reaction under conditions sufficient to produce a compound of formula (IIb)

[0080] Preferably, R3 is hydrogen or a -(C1-C3) alkyl. For R3 to be an alkyl, for
example, the compound may be alkylated by reaction with an alkyl halide under
conditions sufficient to substitute R3 for H. Other methods known in the art may be used
to substitute additional R3 groups.
[0081] A method for making a compound of formula (XXIII)

comprising
[0082] (a) reacting a compound of formula (XXIV)
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with a compound of formula (XXV)

under conditions sufficient to produce a compound of formula (XXVI)

[0083] (b) reducing the compound of formula (XXVI) to produce a saturated
methyl ester of formula (XXVII)

[0084] (c) hydrolyzing the ester under conditions sufficient to provide a
carboxylic acid of formula (XXVIII)
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[0085] (d) cyclyzing the carboxylic acid by heating in the presence of a Lewis
acid under conditions sufficient to provide a compound of formula (XXIX)

[0086] The invention further provides a method, which method is further
comprising
[0087] (e) subjecting the compound of formula (XXIX) to a rearrangement
reaction under reaction conditions sufficient to produce a compound of formula (XXX)

[0088] (b) isolating the compound of formula (XXX),
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[0089] (c) deprotecting the compound of formula (XXX) to produce a
compound of formula (XXXI)

[0090] A compound of formula XXXI may optionally be substituted with R3 as
defined in Formula I by methods known by those skilled in the art.
[0091] It should be understood that these preferred processes may be modified in
accordance with ordinary skill in the art.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
(a) Definitions
[0092] The term "(C1-C6)-alkyl" as used herein refers to a linear or branched,
saturated hydrocarbon having from 1 to 6 carbon atoms. Representative (C1-C6)-alkyl
groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,
tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. In one
embodiment, the (C1-C6)-alkyl group is substituted with one or more of the following
groups: halogen, -N3, -NO2, -CN, -OR', -SR',
-SO2R', -SO2N(R')2, -N(R')2, -COR', -CO2R', -NR'CO2R', -NR'COR', -NR'CONR', or
-CON(R')2, wherein each R' is independently hydrogen or unsubstituted (C1-C6)-alkyl.
[0093] The term "(C2-C6)-alkenyl" as used herein refers to a linear or branched
hydrocarbon having from 2 to 6 carbon atoms and having at least one carbon-carbon
double bond. In one embodiment, the (C2-C6)-alkenyl has one or two double bonds. The
(C2-C6)-alkenyl moiety may exist in the E or Z conformation and the compounds of the
present invention include both conformations. In one embodiment, the (C2-C6)-alkenyl
group is substituted with one or more of the following groups: halogen, -N3, -NO2, -CN, -
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OR', -SR', -SO2R' -SO2N(R')2, -N(R')2, -COR', -CO2R', -NR'CO2R', -NR'COR', -
NR'CONR', or -CON(R')2, wherein each R' is independently hydrogen or unsubstituted
(C1-C6)-alkyl.
[0094] The term "(C2-C6)-alkynyl" as used herein refers to a linear or branched
hydrocarbon having from 2 to 6 carbon atoms and having at least one carbon-carbon
triple bond. In one embodiment, the (C2-C6)-alkynyl group is substituted with one or
more of the following groups: halogen, -N3, -NO2, -CN, -OR', -SR', -SO2R', -SO2N(R')2,
-N(R')2)-COR',-CO2R',
-NR'CO2R', -NR'COR', -NR'CONR', or -CON(R')2, wherein each R' is independently
hydrogen or unsubstituted (C1-C6)-alkyl.
[0095] The term "administer", "administering", or "administration", as used
herein refers to either directly administering a compound or phannaceutically acceptable
salt of the compound or a composition to an animal, or administering a prodrug derivative
or analog of the compound or pharmaceutically acceptable salt of the compound or
composition to the animal, which can form an equivalent amount of active compound
within the animal's body.
[0096] The term "animal" as used herein includes, without limitation, a human,
mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon, or rhesus.
In one embodiment, the animal is a mammal. In another embodiment, the animal is a
human.
[0097] The term "aryl" as used herein refers to an aromatic species containing 1
to 3 aromatic rings, either fused or linked. In one embodiment, the aryl group is
substituted with one or more of the following groups: VH, -V-halogen, -V-N3, -V-NO2, -
V-CN, -V-OR', -V-SR',
-V-SO2R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-CO2R', -V-NR'CO2R', -V-
NR'COR',
-V-NR'CONR', or -V-CON(R')2, wherein each R' is independently hydrogen or
unsubstituted (C1-C6)-alkyl; and wherein each V is independently a bond or (C1-C6)-alkyl.
[0098] The term "conditions effective to" as used herein refers to synthetic
reaction conditions which will be apparent to those skilled in the art of synthetic organic
chemistry.
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[0099] The term "cyclic group" as used herein includes a cycloalkyl group and a
heterocyclic group. Any suitable ring position of the cyclic group may be covalently
linked to the defined chemical structure. In one embodiment, the cyclic group is
substituted with one or more of the following groups: VH, -V-halogen, -V-N3, -V-NO2, -
V-CN, -V-OR', -V-SR', -V-SO2R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-CO2R', -V-
NR'CO2R', -V-NR'COR', -V-NR'CONR', or-V-CON(R')2, wherein each R' is
independently hydrogen or unsubstituted (C1-C6)-alkyl; and wherein each V is
independently a bond or (C1-C6)-alkyl.
[0100] The term "cycloalkyl group" as used herein refers to a three- to seven-
membered saturated or partially unsaturated carbon ring. Any suitable ring position of
the cycloalkyl group may be covalently linked to the defined chemical structure.
Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
and cycloheptyl. In one embodiment, the cycloalkyl group is substituted with one or
more of the following groups: VH,
-V-halogen, -V-N3, -V-NO2, -V-CN, -V-OR', -V-SR', -V-SO2R', -V-SO2N(R')2, -V-
N(R')2,
-V-COR', -V-CO2R', -V-NR'CO2R', -V-NR'COR', -V-NR'CONR', or-V-CON(R')2,
wherein each R' is independently hydrogen or unsubstituted (C1-C6)-alkyl; and wherein
each V is independently a bond or (C1-C6)-alkyl.
[0101] The term "effective amount" as used herein refers to an amount of a
compound or pharmaceutically acceptable salt of a compound that, when administered to
an animal, is effective to prevent, to at least partially ameliorate, or to cure, a condition
from which the animal suffers or is suspected to suffer.
[0102] The term "carrier", as used herein, shall encompass carriers, excipients,
and diluents.
[0103] The term "prodrug", as used herein means a compound which is
convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula
(I),(Ia)or(Ib).
[0104] The term "halogen" as used herein refers to fluorine, chlorine, bromine,
and iodine.
[0105] The term "heterocyclic group" as used herein refers to a three- to seven-
membered saturated, partially saturated, or unsaturated cycloalkyl group in which one to
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WO 2006/138549 PCT/US2006/023467
four of the ring carbon atoms have been independently replaced with a N, O, or S atom.
Any suitable ring position of the heterocyclic group may be covalently linked to the
defined chemical structure. Exemplary heterocyclic groups include, but are not limited
to, azepanyl, azetidinyl, aziridinyl, furanyl, furazanyl, homopiperazinyl, imidazolidinyl,
imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl,
oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, piperazinyl, piperidinyl,
pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl,
pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,
quinuclidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thienyl, thienothiazolyl,
thienooxazolyl, thienoimidazolyl, thiomorpholinyl, thiophenyl, triazinyl, and triazolyl. In
one embodiment, the heterocyclic group is substituted with one or more of the following
groups: VH, -V-halogen, -V-N3, -V-NO2, -V-CN, -V-OR', -V-SR', -V-SO2R',
-V-SG2N(R')2, -V-N(R')2, -V-COR', -V-CO2R', -V-NR'CO2R', -V-NR'COR', -V-
NR'CONR', or -V-CON(R')2, wherein each R' is independently hydrogen or
unsubstituted (Cl-C6)-alkyl; and wherein each V is independently a bond or (C1-C6)-
alkyl.
[0106] The term "isolated and purified" as used herein refers to a component
separated from other components of a reaction mixture or a natural source. In certain
embodiments, the isolate contains at least about 50%, at least about 55%, at least about
60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at
least about 85%, at least about 90%, at least about 95%, or at least about 98% of the
compound or pharmaceuticalry acceptable salt of the compound by weight of the isolate.
[0107] The term "pharmaceutically acceptable salt" as used herein refers to a salt
of an acid and a basic nitrogen atom of a compound of the present invention. Exemplary
salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride,
hydrochloride, bromide, hydrobromide, iodide, nitrate, bisulfate, phosphate, acid
phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,
glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, camphorsulfonate, napthalenesulfonate, propionate,
succinate, fumarate, maleate, malonate, mandelate, malate, phthalate, and pamoate. The
term "pharmaceutically acceptable salt" as used herein also refers to a salt of a compound
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WO 2006/138549 PCT/US2006/023467
of the present invention having an acidic functional group, such as a carboxylic acid
functional group, and a base. Exemplary bases include, but are not limited to, hydroxide
of alkali metals including sodium, potassium, and lithium; hydroxides of alkaline earth
metals such as calcium and magnesium; hydroxides of other metals, such as aluminum
and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-,
di-, or tri-alkylamines, dicyclob.exylamine; tributyl amine; pyridine; N-methyl, N-
ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C1-C6)-alkylamine),
such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-
D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such
as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also
includes a hydrate of a compound of the present invention.
[0108] The term "phenyl" as used herein refers to a substituted or unsubstituted
phenyl group. In one embodiment, the phenyl group is substituted with one or more of
the following groups: VH, -V-halogen, -V-N3, -V-NO2, -V-CN, -V-OR', -V-SR', -V-
SO2R', -V-SO2N(R')2,
-V-N(R')2, -V-COR', -V-CO2R', -V-NR'CO2R', -V-NR'COR', -V-NR'CONR', or
—V-CON(R')2, wherein each R' is independently hydrogen or unsubstituted (C1-C6)-alkyl;
and wherein each V is independently a bond or (C1-C6)-alkyl.
[0109] The term "substantially free of its corresponding opposite enantiomer" as
used herein means that the compound contains no more than about 10% by weight of its
corresponding opposite enantiomer. In other embodiments, the compound that is
substantially free of its corresponding opposite entantiomer contains no more than about
5%, no more than about 1%, no more than about 0.5%, or no more than about 0.1% by
weight of its corresponding opposite enantiomer. An enantiomer that is substantially free
of its corresponding opposite enantiomer includes a compound that has been isolated and
purified or has been prepared substantially free of its corresponding opposite enantiomer.
[0110] The term "tautomer" as used herein refers to compounds produced by the
phenomenon wherein a proton of one atom of a molecule shifts to another atom. See,
Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures,
Fourth Edition, John Wiley & Sons, pages 69-74 (1992).
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(b) Compounds and Pharmaceutically Acceptable Salts of Compounds of the
Invention
[0111] In one embodiment, the present invention is directed to compounds of the
Formula (I):

or a prodrug, stereoisomer or pharmaceutically-acceptable salt thereof, wherein
[0112] R3 is a hydrogen, hydroxyl, halogen, -(C1-C3)-alkyl, -O-(C1-C3)-alkyl, -
(C3-C6)-cycloalkyl, -SO2R20, or-COR20, wherein -(C1-C3)-alkyl, -O-(C1-C3)-alkyl, or
-(C3-C6)-cycloalkyl are optionally branched.
[0113] R4 and R5 are each independently hydrogen, hydroxyl, linear or branched -
(C1-C6)-alkyl, linear or branched -(C2-C6)-alkenyl, halogen, -COR14, -OR14, -SR14,
-SO2NR14R15, -NO2, -CONR14R15 or -(C3-C6)-cycloalkyl, which optionally contains a
nitrogen, oxygen or sulfur atom;
[0114] R6 is hydrogen, a linear or branched -(C1-C6)-alkyl or a linear or branched
-(CH2)m-B, the -(C1-C6)-alkyl or -(CH2)m-B which may optionally be substituted with at
least one nitrogen or oxygen atom provided that R6 has at least two carbon atoms in
sequence directly attached to the nitrogen of Formula (I), wherein B is a (C3-C5)-
cycloalkyl, a saturated, partially saturated or aromatic (C5-C7)-carbocyclic ring or a
phenyl fused to a saturated, partially saturated or aromatic (C5-C7)-carbocyclic ring,
wherein the cycloalkyl, phenyl or carbocyclic ring is optionally substituted by one to two
substituents per ring, wherein said substituents are independently selected from the group
consisting of halogen, cyano, -(C1-C6)-alkyl, -(C2-C6)-alkenyl, -(C2-C6)-alkynyl,- (C3-C7)-
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carbocycle, -(C1-C6)-alkoxy, —OCF3, -(C6-C10)-aryl and -(C2-C9)-heterocycle; further
wherein one or two ring atoms of the cycloalkyl, phenyl or carbocyclic ring may
optionally be replaced by a nitrogen, oxygen or sulfur atom, and m is a number from 0 to
7;
[0115] R7 is selected from a linear or branched -(C1-C6-alkylene-, linear or
branched -(C2-C6)-alkeny1ene- or -(CH2)P-(C3-C6)-cycloalkyl-(CH2)q-, each of which is
optionally substituted with a halogen or hydroxyl, wherein one or two ring atoms of the
cycloalkyl may optionally replaced by a nitrogen, sulfur or oxygen atom, and p and q are
each independently 0, 1 or 2;
[0116] Q is selected from -(C1-C3)-alkylene-, -O-(C1-C2)-alkylene-, -(C2-C3)-
alkenylene—, or -O-(C2)—alkenylene-, wherein the alkylene or alkenylene is optionally
substituted with a -(C1-C3)-alkyl or a halogen, and wherein for -O-(C1-C2)-alkylene- or -
O-(C2-C3)-alkenylene-, the O is directly attached to the phenyl ring;
[0117] A is
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(A2)
[0118] R8, R9, R10, and R11 are each independently hydrogen, cyano, carboxamido,
carboalkoxy, trifluoromethyl, hydroxyl, linear or branched -(C1-C6)-alkyl, linear or
branched -(C2-C6)-alkenyl, halogen, -OCF3, alkanoyloxy, alkanamido, alkanesulfonyl,
alkanesulfonamido, phenyl, -NR16R17, -, -COR16, -OR16, -SR16, -OR16, or -NO2, W, X,
Y and Z are each independently -CR18R19-, -O-, -NR18- or -S-;
[0119] X and Y are each independently -CR18R19-, -O-, -NR18- or -S-;
[0120] z1 is carbon or nitrogen, Z2 is carbon and Z3 is carbon, nitrogen, oxygen or
sulfur; wherein at least one of Z1 and Z3 is not carbon, wherein a double bond is
optionally present between Z1 and Z2, wherein A1 is attached to R7 through Z1, Z2 or Z3,
except when Z3 is oxygen, and further wherein when R7 is linked to Z3, then Z3 is
nitrogen;
[0121] R12 and R13 are each independently hydrogen or a linear or branched -(C1-
C6)-alkyl, wherein R12 and R13 may be attached at any of Z1, Z2 or Z3, and further wherein
R13 is optionally present at Z1 or Z2 when Z3 is oxygen;
[0122] R14, R15, R16, R17, R18 and R19 are each independently hydrogen, hydroxyl,
halogen, a linear or branched (C1-C6)-alkyl or a linear or branched (C2-C6)-alkenyl; R20 is
a hydrogen, a linear or branched (C1-C6)-alkyl or a (C3-C7)-cycloalkyl; and the dotted
lines represent optional double bonds.
[0123] This invention relates to both the R and S stereoisomers of the 3-amino-
chroman or 2-amino-tetralin derivatives, as well as to racemic mixtures of the R and S
stereoisomers. Throughout this application, the name of the product of this invention,
where the absolute configuration of the 3-amino-chromans or 2-amino tetralins is not
indicated, is intended to embrace the individual R and S enantiomers, as well as racemic
mixtures.
[0124] This invention also relates to both the R and S stereoisomers at the carbon
alpha or beta from the basic nitrogen. Throughout this application, the name of the
product of this invention, where the absolute configuration at the above two positions is
not indicated, is intended to embrace the individual R and S enantiomers.
[0125] Where a stereoisomer is preferred, it may in some embodiments be
rovided substantially free of the corresponding enantiomer. Thus, an enantiomer
substantially free of the corresponding enantiomer refers to a compound that is isolated or
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WO 2006/138549 PCT/US2006/023467
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 stereoisomer, preferably less than about 50%, more
preferably less than about 75%, and even more preferably less than about 90%. The
preferred stereoisomer was isolated from racemic mixtures by high performance liquid
chromatography (HPLC) using a chiral column.
[0126] The following compounds of Formula (I) are particularly preferred:
8-{[3-(5-fluoro-lH-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-1(7H)-one;
(8S)-8-{[3-5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-l(7H)-one;
(8R)-8-{[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-1(7H)-one;
8-{(cyclopropylmethyl)[3-(5-fluro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
(8S)-8-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
(8R)-8-{(cyclopropylmemyl)[3-5-fluoro-1H-indol-3-yl)propyl]arnino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{cyclobutyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{(cyclobutylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{(cyclobutylmemyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-[[3-(5-fluoro-1H-indol-3-yl)propyl](methyl)arnino]-2,3,8,9-
tetrahydropyrano [3,2-e] isoindol-1(7H)-one;
8-{ethyl[3-(5-fluoro-1H-indol-3-yl)propyl]arrrino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-l(7H)-one;
8-[[3-(5-fluoro-1H-indol-3-yl)propyl](isobutyl)amino]-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{(cyclohexylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]axnino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
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WO 2006/138549 PCT/US2006/023467
8-{benzyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-1(7H)-one;
8-[[3-(5-fluoro-1H-indol-3-yl)propyl](3-furylmethyl)amino]-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{[3-(5,7-difluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-1 (7H)-one;
8-{cyclobutyl[3-(5,7-difluoro-1H-indol-3-yl)propyl]araino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
3-{3-[(1-oxo-1, 2, 3, 7, 8, 9-hexahydropyrano[3, 2-e]isoindol-8-yl)amino]propyl}-1H-
indole-5-carbonitrile;
3-{3-[(cyclopropylmethyl)(1-oxo-1,2,3,7,8,9-hexahydropyrano[3,2-e]isoindol-8-
yl)amino]propyl}-1H-indole-5-carbonitrile;
3-(3-{(cyclopropylmethyl)[(8S)-1-oxo-l,2,3,7,8,9-hexahydropyrano[3,2-
e]isoindol-8-yl]amino}propyl)-1H-indole-5-carbonitrile;
3-(3-{ (cyclopropylmethyl)[(8R)-1-oxo-1 ,2,3,7,8,9-hexahydropyrano[3,2-
e]isoindol-8-yl]amino}propyl)-1H-indole-5-carbonitrile;
8-{[4-(5-fluoro-1H-indol-3-yl)butyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-1 (7H)-one;
8-{(cyclopropylmethyl)[4-(5-fluoro-1H-indol-3-yl)butyl]amino}-2,3,8,9-
tetrahydropyrano [3,2-e]isoindol-1 (7H)-one;
8-{[(6-fluoro-2,3,4,9-tetrab.ydro-1H-carbazol-3-yl)methyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2-meihyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]a}-2-methyl-
2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
(8S)-8-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2-methyl-
2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
(8R)-8-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2-methyl-
2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-[[3-(5-fluoro-1H-indol-3-yl)propyl](methyl)amino]-2-methyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
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8-{ethyl[3-(5-fluoro-1H-mdol-3-yl)propyl]amino}-2-methyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one;
8-[[3-(5-fluoro-1H-indol-3-yl)propyl](isobutyl)amino]-2-methyl-2,3,8,9-
tetrahydropyrano [3,2-e]isoindol-1(7H)-one;
8-{cyclobutyl[3-(5-fluoro-1H-indoI-3-yl)propyl]amino}-2-methyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{(cyclobutylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2-methyl-
2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
3-{3-[(2-methyl-1-oxo-1,2,3,7,8,9-hexahydropyrano[3,2-e]isoindol-8-
yl)amiao]propyl}-1H-indole-5-carbonitrile;
3-{3-[(cyclopropylmethyl)(2-methyl-1-oxo-1,2,3,7,8,9-hexahydropyrano[3,2-
e]isoindol-8-yl)amino]propyl}-1H-indole-5-carbonitrile;
8-{[3-(5,7-difluoro-1H-indol-3-yl)propyl]amino}-2-methyl-2,3,8,9-
tetrahydropyrano [3,2-e]isoindol-1(7H)-one;
8-{(cyclopropylmethyl)[3-(5,7-difluoro-1H-indol-3-yl)propyl]amino}-2-methyl-
2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{[(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methyl]amino}-2-methyl-
2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{(cyclopropylmethyl)[(6-fluoro-2,3,4,9-tetrahydro- 1H-carbazol-3-
yl)methyl]amino}-2-methyl-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{cyclobutyl[(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methyl]amino} -2-
methyl-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
9-{[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-tetrahydro-2H-pyrano[2,3-
h]isoquinolin-1(8H)-one;
9-[[3-(5-fluoro-1H-indol-3-yl)propyl](methyl)amino]-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one;
9-{ethyl[3-(5-fluoro-m-indol-3-yl)propyl]amino}-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one;
9-[[3-(5-fluoro-1H-indol-3-yl)propyl](propyl)amino]-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1 (8H)-one;
9-[[3-(5-fluoro-1H-indol-3-yl)propyl](isobutyl)amino]-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-l(8H)-one;
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WO 2006/138549 PCT/US2006/023467
9-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-
tetrahydro-2H-pyrauo[2,3-h]isoquinolin-1(8H)-one;
9-{cyclobutyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one;
94[3-(5-fluoro-1H-indol-3-yl)propyl](isopropyl)amino]-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one;
9-{benzyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one;
94[3-(5-fluoro-1H-indol-3-yl)propyl](pyridin-4-ylmethyl)amino]-3,4,9,10-
tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one;
9-[[3-(5-fluoro-1H-indol-3-yl)propyl](3,3,3-trifluoropropyl)amino]-3,4,9,10-
tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one;
6-fluoro-9-{[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one;
9-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-6-fluoro-
3,4,9,10-tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one;
9-{ethyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-6-fluoro-3,4,9,10-tetxahydro-
2H-pyrano [2,3-h]isoquinolin-1(8H)-one;
8-{Cyclopropylmethyl-[3-(5-fluoro-3-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-
cyclobutyl]-amino}-5-methoxy-2,3,8,9-tetrahydro-7H-pyrano[3,2-e]isoindol-1-
one;
8-{Cyclopropylinsthyl-[3-(5-fluoro-3-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-
cyclobutyl]-amino}-5-fluoro--2,3,8,9-tetrabiydro-7H-pyrano[3,2-e]isoindol-1-one;
8-{Cyclopbutylmethyl-[3-(5-fluoro-3-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-
cyclobutyl]-amino}-5-methoxy-2,3,8,9-tetrahydro-7H-pyrano[3,2-e]isoindol-1-
one; or
8-{Cyclobutylmethyl-[3-(5-fluoro-3-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-
cyclobutyl]-amino}-5-fluoro-2,3,8,9-tetrahydro-7H-pyrano[3,2-e]isoindol-1-one.
[0127] The compound of general Formula (I) and compounds of structures (Ia)
and (Ib) may be prepared by conventional synthetic techniques. In the following synthetic
techniques, suitable aprotic polar solvents include, but are not limited to, dimethyl
sulfoxide, dimethylformamide, tetrahydrofuran, acetone and ethanol. Suitable acid
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WO 2006/138549 PCT/US2006/023467
binding agents include, but are not limited to, organic tertiary bases, such as, for example,
triethylamine, triethanolamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and
diisopropylethylamine (D1PEA); and alkaline metal carbonates, such as, for example,
potassium carbonate and sodium carbonates. Suitable reducing agents include, but are not
limited to, sodium cyanoborohydride and sodium triacetoxyborohydride.
[0128] Methods for making cycloalkylfused indole, benzothiphene, benzofuran
and indene derivatives are described in Provisional Application No. 60/653,666
(AM101783), filed February _, 2005. Methods for making 3-amino chroman and 2-
amino tetralin derivatives are described in Application No. 10/898,866, filed July 26,
2004. The disclosures of methods for making these compounds are hereby incorporated
by reference in their entirety.
General Synthetic Scheme(s) for Preparation of Compounds
[0129] Compounds of Formula (I) may be prepared by conventional methods as
illustrated in the following synthetic schemes.
[0130] According to Scheme I, a suitably substituted ortho-bromobenzoic acid is
protected as the methyl ester by alkylation with methyl iodide in the presence of a base
such as DBU in a polar solvent like DMF. The bromo functionality is replaced by a
methyl on treatment with dimethylzinc in the presence of a nickel catalyst. Benzylic
bromination under standard conditions followed by heating with ammonia yields the
lactam. Deprotection of the methyl ether under standard conditions with a Lewis acid
such as BBr3 yields the phenol. The phenol is propargylated under standard conditions
with propargyl bromide and a base such as potassium carbonate. The propargyl ether is
then subject to heating in N,N-diethylaniline to yield the dihydropyran.
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[0131] As shown in Scheme 2, the dihydropyran is subject to nitration with
sodium nitrite and iodine. Reduction of the nitroolefm with sodium borohydride and silica
yields the saturated nitro compound, which is reduced to the amine by treatment with
Raney nickel and hydrazine.
[0132] This amine is then subject to reductive amination under standard
conditions with a appropriately substituted aldehyde in the presence of
sodiumcyanoborohydride and acetic acid in a polar solvent such as methanol. The groups
R8 and R10 are as defined.
[0133] This secondary amine is then subject to one of two reaction conditions
depending on the choice of R6 that is required. When R6 is a methyl, the secondary amine
is alkylated with trimethyloxonium tetrafluoroborate in the presence of a base such as
Hunig's base (diisopropylethylamine). For the rest, a second reductive amination gives
additional compounds of this invention where R6 is as defined in the generic structure.
The preparation of the bicyclic aldehyde employed in this synthesis was previously
disclosed in U.S. Application No. 10/898,866, filed July 26,2004, which is hereby
incorporated by reference in its entirety.
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[0134] Compounds of this invention can also be prepared as in Scheme 3 by two
successive reductive animations. The preparation of the tricyclic aldehyde has been
previously disclosed in Provisional Application No. 60/653,666 (AM101783), filed
February _, 2005, which is hereby incorporated by reference in its entirety.
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WO 2006/138549 PCT/US2006/023467

[0135] Scheme 4 describes the preparation of compounds in this invention
wherein the nitrogen on the lactam moiety is alkylated. At the stage of the dihydropyran,
which is prepared as described in Scheme 1, alkylation with an alkyl halide such as
methyl iodide (Mel) after treatment with a base such as sodium hydride (NaH), yields the
alkylated lactam. The rest of the synthesis follows the sequence described in Scheme 2.

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[0136] Scheme 5 describes the synthesis of compounds in this invention that
contain a six-membered lactam ring. An appropriately substituted indanone is subject to a
modified Schmidt rearrangement with sodium azide and methanesulfonic acid. This
reaction yields a mixture of regioisomeric lactams from which the desired lactam is
separated by standard column chromatography. This lactam is then subject to the same
sequence of steps described in schemes 1 and 2 to yield the desired targets.

[0137] Scheme 6 describes the preparation of intermediates that contain a fluorine
substituent para to the carbonyl group of the lactam. An appropriately substituted
bromobenzene is subject to a Heck reaction with methyl acrylate in the presence of a
catalytic amount of palladium acetate (Pd(OAc)2) and tri-o-tolylphosphine (P(o-tol)3).
The unsaturated methyl ester is reduced to the saturated methyl ester under standard
hydrogenation conditions using catalytic palladium on carbon under an atmosphere of
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hydrogen. The methyl ester is then hydrolysed under standard conditions to give the
carboxylic acid. This carboxylic acid is then cyclized by heating in the presence of a
Lewis acid such as aluminum trichloride (AlCl3) to give the indanone. The indanone is
then subject to a modified Schmidt rearrangement as described in scheme 5 to yield a
mixture of regioisomeric lactams. The desired lactam (as shown) is then isolated by
column chromatography.
[0138] This hydroxyl-lactam is then subject to the same sequence of steps shown
in scheme 5 to yield compounds of this invention.

[0139] One of skill in the art will recognize that Schemes 1-6 can be adapted to
produce the other compounds and pharmaceutialy acceptable salts of compounds
according to the present invention.
Therapeutic Administration
[0140] The terms "effective amount", "therapeutically effective amount" and
"effective dosage" as used herein, refer to the amount of a compound of Formula (I), (Ia)
and (Ib) that, when administered to a patient, is effective to at least partially ameliorate a
condition form which the patient is suspected to suffer. Such conditions include, but are
not limited to, depression (including, but not limited to major depressive disorder,
childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress
disorder, premenstrual dysphoric disorder (also known as premenstrual syndrome),
attention deficit disorder (with or without hyperactivity), obsessive compulsive disorder,
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social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as
anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction,
sexual dysfunction, cognitive deficits resulting from neurodegenerative disorders like
Alzheimer's disease, and related illnesses.
[0141] Compounds of Formula (I) have been found to act as serotonin reuptake
inhibitors and to have an affinity for the 5-HT1A reuptake transporter. They are therefore
useful in the treatment of diseases affected by disorders of the serotonin affected
neurological systems, including, but not limited to, depression (including, but not limited
to major depressive disorder, childhood depression and dysthymia), anxiety, panic
disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as
premenstrual syndrome), attention deficit disorder (with or without hyperactivity),
obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder,
obesity, eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor
flushing, cocaine and alcohol addiction, sexual dysfunction, cognitive deficits resulting
from neurodegenerative disorders like Alzheimer's disease, and related illnesses. The
present invention thus provides pharmaceutical compositions comprising at least one
compound of Formula (I); and optionally one or more pharmaceuticalry acceptable
carrier, excipient, or diluents.
[0142] When administered to an animal, the compounds or pharmaceutically
acceptable salts of the compounds can be administered neat or as a component of a
composition that comprises a physiologically acceptable carrier or vehicle. A
composition of the invention can be prepared using a method comprising admixing the
compound or a pharmaceutically acceptable salt of the compound and a physiologically
acceptable carrier, excipient, or diluent. Admixing can be accomplished using methods
well known for admixing a compound or a pharmaceutically acceptable salt of the
compound and a physiologically acceptable carrier, exipient, or diluent.
[0143] The present compositions comprising compounds or pharmaceutically
acceptable salts of the compounds of the invention can be administered orally. The
compounds or pharmaceutically acceptable salts of compounds of the invention can also
be administered by any other convenient route, for example, by infusion or bolus
injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal,
vaginal, and intestinal mucosa, etc.) and can be administered together with another
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therapeutic agent. Administration can be systemic or local. Various known delivery
systems, including encapsulation in liposomes, microparticles, microcapsules, and
capsules, can be used.
[0144] Methods of administration include, but are not limited to, intradermal,
intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral,
sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical,
particularly to the ears, nose, eyes, or skin. In some instances, administration will result
of release of the compound or a pharmaceutically acceptable salt of the compound into
the bloodstream. The mode of administration is left to the discretion of the practitioner.
[0145] In one embodiment, the compound or a pharmaceutically acceptable salt of
the compound is administered orally.
[0146] In another embodiment, the compound or a pharmaceutically acceptable
salt of the compound is administered intravenously.
[0147] In another embodiment, it may be desirable to administer the compound or
a pharmaceutically acceptable salt of the compound locally. This can be achieved, for
example, by local infusion during surgery, topical application, e.g., in conjunction with a
wound dressing after surgery, by injection, by means of a catheter, by means of a
suppository or edema, or by means of an implant, said implant being of a porous, non-
porous, or gelatinous material, including membranes, such as sialastic membranes, or
fibers.
[0148] In certain embodiments, it can be desirable to introduce the compound or a
pharmaceutically acceptable salt of the compound into the central nervous system,
circulatory system or gastrointestinal tract by any suitable route, including
intraventricular, intrathecal injection, paraspinal injection, epidural injection, enema, and
by injection adjacent to the peripheral nerve. Intraventricular injection can be facilitated
by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya
reservoir.
[0149] Pulmonary administration can also be employed, e.g., by use of an inhaler
or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a
fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, the compound
or a pharmaceutically acceptable salt of the compound can be formulated as a
suppository, with traditional binders and excipients such as triglycerides.
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[0150] In another embodiment, the compound or a pharmaceutically acceptable
salt of the compound can be delivered in a vesicle, in particular a liposome (see Langer,
Science 249:1527-1533 (1990) and Treat et al, Liposomes in the Therapy of Infectious
Disease and Cancer 317-327 and 353-365 (1989)).
[0151] In yet another embodiment, the compound or a pharmaceutically
acceptable salt of the compound can be delivered in a controlled-release system or
sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled
Release, vol. 2, pp. 115-138 (1984)). Other controlled or sustained-release systems
discussed in the review by Langer, Science 249:1527-1533 (1990) can be used. In one
embodiment, a pump can be used (Langer, Science 249:1527-1533 (1990); Sefton, CRC
Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al, Surgery 8&507 (1980); and
Saudek et al., N. Engl. JMed. 321:574 (1989)). In another embodiment, polymeric
materials can be used (see Medical Applications of Controlled Release (Langer and Wise
eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance
(Smolen and Ball eds., 1984); Ranger and Peppas, /. Macromol. Set Rev. Macromol.
Chan. 2:61 (1983); Levy et al, Science 228:190 (1935); During et al, Ann. Neural.
25:351 (1989); and Howard et al., J. Neurosurg. 71:105 (1989)).
[0152] In yet another embodiment, a controlled- or sustained-release system can
be placed in proximity of a target of the compound or a pharmaceutically acceptable salt
of the compound, e.g., the reproductive organs, thus requiring only a fraction of the
systemic dose.
[0153] The present compositions can optionally comprise a suitable amount of a
physiologically acceptable excipient.
[0154] Such physiologically acceptable excipients can be liquids, such as water
and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as
peanut oil, soybean oil, mineral oil, sesame oil and the like. The physiologically
acceptable excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin,
colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening,
lubricating, and coloring agents can be used. In one embodiment the physiologically
acceptable excipients are sterile when administered to an animal. The physiologically
acceptable excipient should be stable under the conditions of manufacture and storage and
should be preserved against the contaminating action of microorganisms. Water is a
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particularly useful excipient when the compound or a pharmaceutically acceptable salt of
the compound is administered intravenously. Saline solutions and aqueous dextrose and
glycerol solutions can also be employed as liquid excipients, particularly for injectable
solutions. Suitable physiologically acceptable excipients also include starch, glucose,
lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol
monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water,
ethanol and the like. The present compositions, if desired, can also contain minor
amounts of wetting or emulsifying agents, or pH buffering agents.
[0155] Liquid carriers may be used in preparing solutions, suspensions,
emulsions, syrups, and elixirs. The compound or pharmaceutically acceptable salt of the
compound of this invention can be dissolved or suspended in a pharmaceutically
acceptable liquid carrier such as water, an organic solvent, a mixture of both, or
pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable
pharmaceutical additives including solubilizers, emulsifiers, buffers, preservatives,
sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity
regulators, stabilizers, or osmo-regulators. Suitable examples of liquid carriers for oral
and prenteral administration include water (particular containing additives as above, e.g.,
cellulose derivatives, including sodium carboxymethyl cellulose solution), alcohols
(including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their
derivatives, and 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. Sterile liquid carriers are used in sterile liquid form compositions for
parenteral administration. The liquid carrier for pressurized compositions can be
halogenated hydrocarbon or other pharmaceutically acceptable propellant.
[0156] The present compositions can take the form of solutions, suspensions,
emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-
release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other
form suitable for use. In one embodiment, the composition is in the form of a capsule.
Other examples of suitable physiologically acceptable excipients are described in
Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro, ed., 19th ed.
1995).
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[0157] In one embodiment, the compound or a pharmaceutically acceptable salt of
the compound is formulated in accordance with routine procedures as a composition
adapted for oral administration to humans. Compositions for oral delivery can be in the
form of tablets, lozenges, buccal forms, troches, aqueous or oily suspensions or solutions,
granules, powders, emulsions, capsules, syrups, or elixirs for example. Orally
administered compositions can contain one or more agents, for example, sweetening
agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil
of wintergreen, or cherry; coloring agents; and preserving agents, to provide a
pharmaceutically palatable preparation. In powders, the carrier can be a finely divided
solid, which is an admixture with the finely divided compound or pharmaceutically
acceptable salt of the compound. In tablets, the compound or pharmaceutically
acceptable salt of the compound is mixed with a carrier having the necessary compression
properties in suitable proportions and compacted in the shape and size desired. The
powders and tablets can contain up to about 99% of the compound or pharmaceutically
acceptable salt of the compound.
[0158] Capsules may contain mixtures of the compounds or pharmaceutically
acceptable salts of the compounds with inert fillers and/or diluents such as
pharmaceutically acceptable starches (e.g., corn, potato, or tapioca starch), sugars,
artificial sweetening agents, powdered celluloses (such as crystalline and microcrystalline
celluloses), flours, gelatins, gums, etc.
[0159] Tablet formulations can be made by conventional compression, wet
granulation, or dry granulation methods and utilize pharmaceutically acceptable diluents,
binding agents, lubricants, disintegrants, surface modifying agents (including surfactants),
suspending or stabilizing agents (including, but not limited to, magnesium stearate, stearic
acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl
cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose,
carboxymethylcellulose calcium, polyvinylpyrroldine, alginic acid, acacia gum, xanthan
gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol,
dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low
melting waxes, and ion exchange resins. Surface modifying agents include nonionic and
anionic surface modifying agents. Representative examples of surface modifying agents
include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate,
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cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon
dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and
triethanolamine.
[0160] Moreover, when in a tablet or pill form, the compositions can be coated to
delay disintegration and absorption in the gastrointestinal tract, thereby providing a
sustained action over an extended period of time. Selectively permeable membranes
surrounding an osmotically active driving compound or a pharmaceutically acceptable
salt of the compound are also suitable for orally administered compositions. In these
latter platforms, fluid from the environment surrounding the capsule can be imbibed by
the driving compound, which swells to displace the agent or agent composition through
an aperture. These delivery platforms can provide an essentially zero order delivery
profile as opposed to the spiked profiles of immediate release formulations. A time-delay
material such as glycerol monostearate or glycerol stearate can also be used. Oral
compositions can include standard excipients such as mannitol, lactose, starch,
magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one
embodiment the excipients are of pharmaceutical grade.
[0161] In another embodiment, the compound or a pharmaceutically acceptable
salt of the compound can be formulated for intravenous administration. Typically,
compositions for intravenous administration comprise sterile isotonic aqueous buffer.
Where necessary, the compositions can also include a solubilizing agent. Compositions
for intravenous administration can optionally include a local anesthetic such as lignocaine
to lessen pain at the site of the injection. Generally, the ingredients are supplied either
separately or mixed together in unit dosage form, for example, as a dry lyophilized
powder or water-free concentrate in a hermetically sealed container such as an ampule or
sachette indicating the quantity of active agent. Where the compound or a
pharmaceutically acceptable salt of the compound is to be administered by infusion, it can
be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade
water or saline. Where the compound or a pharmaceutically acceptable salt of the
compound is administered by injection, an ampule of sterile water for injection or saline
can be provided so that the ingredients can be mixed prior to administration.
[0162] In another embodiment, the compound or pharmaceutically acceptable salt
of the compound can be administered transdermally thorugh the use of a transdermal
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patch. Transdermal administrations include administrations across the surface of the
body and the inner linings of the bodily passages including epithelial and mucosal tissues.
Such administrations can be carried out using the present compounds or pharmaceutically
acceptable salts of the compounds, in lotions, creams, foams, patches, suspensions,
solutions, and suppositories (e.g., rectal or vaginal).
[0163] Transdermal administration can be accomplished through the use of a
transdermal patch containing the compound or pharmaceutically acceptable salt of the
compound and a carrier that is inert to the compound or pharmaceutically acceptable salt
of the compound, is non-toxic to the skin, and allows delivery of the agent for systemic
absorption into the blood stream via the skin. The carrier may take any number of forms
such as creams or ointments, pastes, gels, or occlusive devices. The creams or ointments
may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil
type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic
petroleum containing the active ingredient may also be suitable. A variety of occlusive
devices may be used to release the compound or pharmaceutically acceptable salt of the
compund into the blood stream, such as a semi-permeable membrane covering a reservoir
containing the compound or pharmaceutically acceptable salt of the compound with or
without a carrier, or a matrix containing the active ingredient.
[0164] The compounds or pharmaceutically acceptable salts of the compounds of
the invention may be administered rectally or vaginally in the form of a conventional
suppository. Suppository formulations may be made from traditional materials, including
cocoa butter, with or without the addition of waxes to alter the suppository's melting
point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of
various molecular weights, may also be used.
[0165] The compound or a pharmaceutically acceptable salt of the compound can
be administered by controlled-release or sustained-release means or by delivery devices
that are known to those of ordinary skill in the art. Such dosage forms can be used to
provide controlled- or sustained-release of one or more active ingredients using, for
example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable
membranes, osmotic systems, multilayer coatings, microparticles, liposomes,
microspheres, or a combination thereof to provide the desired release profile in varying
proportions. Suitable controlled- or sustained-release formulations known to those skilled
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in the art, including those described herein, can be readily selected for use with the active
ingredients of the invention. The invention thus encompasses single unit dosage forms
suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and
caplets that are adapted for controlled- or sustained-release.
[0166] In one embodiment a controlled- or sustained-release composition
comprises a minimal amount of the compound or a pharmaceutically acceptable salt of
the compound to treat or prevent a condition related to or affected by the reuptake of
serotonin and the 5-HT1A receptor in a minimal amount of time. Advantages of
controlled- or sustained-release compositions include extended activity of the drug,
reduced dosage frequency, and increased compliance by the animal being treated. In
addition, controlled- or sustained-release compositions can favorably affect the tune of
onset of action or other characteristics, such as blood levels of the compound or a
pharmaceutically acceptable salt of the compound, and can thus reduce the occurrence of
adverse side effects.
[0167] Controlled- or sustained-release compositions can initially release an
amount of the compound or a pharmaceutically acceptable salt of the compound that
promptly produces the desired therapeutic or prophylactic effect, and gradually and
continually release other amounts of the compound or a pharmaceutically acceptable salt
of the compound to maintain this level of therapeutic or prophylactic effect over an
extended period of time. To maintain a constant level of the compound or a
pharmaceutically acceptable salt of the compound in the body, the compound or a
pharmaceutically acceptable salt of the compound can be released from the dosage form
at a rate that will replace the amount of the compound or a pharmaceutically acceptable
salt of the compound being metabolized and excreted from the body. Controlled- or
sustained-release of an active ingredient can be stimulated by various conditions,
including but not limited to, changes in pH, changes in temperature, concentration or
availability of enzymes, concentration or availability of water, or other physiological
conditions or compounds.
[0168] In certain embodiments, the present invention is directed to prodrugs of the
compounds or pharmaceutically acceptable salts of compounds of the present invention.
Various forms of prodrugs are known in the art, for example as discussed in Bundgaard
(ed.), Design of Prodrugs, Elsevier (1985); Widder et al. (ed.), Methods in Enzymology,
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vol. 4, Academic Press (1985); Kgrogsgaard-Larsen et al (ed.); "Design and Application
of Prodrugs", Textbook of Drug Design and Development, Chapter 5,113-191 (1991);
Bundgaard et al, Journal of Drug Delivery Reviews, 8:1-38 (1992); Bundgaard et al., J.
Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.), Prodrugs
as Novel Drug Delivery Systems, American Chemical Society (1975).
[0169] The amount of the compound or a phanpaceutically acceptable salt of the
compound that is effective for treating or preventing a condition related to or affected by
the reuptake of serotonin and the 5-HT1A receptor will vary. In vitro or in vivo assays can
optionally be employed to help identify optimal dosage ranges. The precise dose to be
employed can also depend on the route of administration, the condition, the seriousness of
the condition being treated, as well as various physical factors related to the individual
being treated, and can be decided according to the judgment of a health-care practitioner.
Equivalent dosages may be administered over various time periods including, but not
limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12
hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72
hours, about every week, about every two weeks, about every three weeks, about every
month, and about every two months. The number and frequency of dosages
corresponding to a completed course of therapy will be determined according to the
judgment of a health-care practitioner. The effective dosage amounts described herein
refer to total amounts administered; that is, if more than one compound or a
pharmaceutically acceptable salt of the compound is administered, the effective dosage
amounts correspond to the total amount administered.
[0170] The amount of the compound or a pharmaceutically acceptable salt of the
compound that is effective for treating or preventing a condition related to or affected by
the reuptake of serotonin and the 5-HT1A receptor will typically range from about 0.001
mg/kg to about 250 mg/kg of body weight per day, in one embodiment, from about 1
mg/kg to about 250 mg/kg body weight per day, in another embodiment, from about 1
mg/kg to about 50 mg/kg body weight per day, and in another embodiment, from about 5
mg/kg to about 25 mg/kg of body weight per day. The compounds may be given in a
single dose or in two or more divided doses.
[0171] In one embodiment, the pharmaceutical composition is in unit dosage
form, e.g., as a tablet, capsule, powder, solution, suspension, emulsion, granule, or
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suppository. In such form, the composition is sub-divided in unit dose containing
appropriate quantities of the active ingredient; the unit dosage form can be packaged
compositions, for example, packeted powders, vials, ampoules, prefilled syringes or
sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet
itself, or it can be the appropriate number of any such compositions in package form.
Such unit dosage form may contain from 0.1 to 100 mg of a compound of the invention
and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25
mg of a compound of the present invention. Such compositions may be administered
from 1 to 6 times a day, more usually from 1 to 4 times a day.
[0172] When administered for the treatment or inhibition of a particular disease
state or disorder, it is understood that the effective dosage may vary depending upon the
particular compound utilized, the mode of administration, the condition, and severity
thereof, of the condition being treated, as well as the various physical factors related to
the individual being treated. In therapeutic application, compounds of the present
invention are provided to a patient already suffering from a disease in an amount
sufficient to cure or at least partially ameliorate the symptoms of the disease and its
complications. An amount adequate to accomplish this is defined as a "therapeutically
effective amount". The dosage to be used in the treatment of a specific case must be
subjectively determined by the attending physician. The variables involved include the
specific condition and the size, age and response pattern of the patient. Effective
administration of the compounds of this invention may be given at an oral dose of from
about 0.1 mg/day to about 1000 mg/day. Preferably, administration will be from about 10
mg/day to about 600 mg/day, more preferably, a starting dose is about 5 mg/day with
gradual increase in the daily dose to about 150 mg/day, to provide the desired dosage
level in the human. Doses may be administered in a single dose or in two or more
divided doses. The projected daily dosages are expected to vary with route of
administration.
[0173] The compound or a pharmaceutically acceptable salt of the compound can
be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to
use in humans. Animal model systems can be used to demonstrate safety and efficacy.
[0174] The present methods for treating or preventing a condition related to or
affected by the reuptake of serotonin and the 5-HT1A receptor can further comprise
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administering another therapeutic agent to the animal being administered the compound
or a pharmaceutically acceptable salt of the compound. In one embodiment, the other
therapeutic agent is administered in an effective amount.
[0175] Effective amounts of the other therapeutic agents are well known to those
skilled in the art. However, it is well within the skilled artisan's purview to determine the
other therapeutic agent's optimal effective amount range. The compound or a
pharmaceutically acceptable salt of the compound and the other therapeutic agent can act
additively or synergistically.
[0176] In one embodiment, the compound or a pharmaceutically acceptable salt of
the compound is administered concurrently with another therapeutic agent.
[0177] In one embodiment, a composition comprising an effective amount of the
compound or a pharmaceutically acceptable salt of the compound and an effective
amount of another therapeutic agent within the same composition can be administered.
[0178] In another embodiment, a composition comprising an effective amount of
the compound or a pharmaceutically acceptable salt of the compound and a separate
composition comprising an effective amount of another therapeutic agent can be
concurrently administered. In another embodiment, an effective amount of the compound
or a pharmaceutically acceptable salt of the compound is administered prior to or
subsequent to administration of an effective amount of another therapeutic agent. In this
embodiment, the compound or a pharmaceutically acceptable salt of the compound is
administered while the other therapeutic agent exerts its therapeutic effect, or the other
therapeutic agent is administered while the compound or a pharmaceutically acceptable
salt of the compound exerts its preventative or therapeutic effect for treating or preventing
a condition related to or affected by the reuptake of serotonin and the 5-HT1A receptor.
[0179] Thus, in one embodiment, the invention provides a composition
comprising an effective amount of the compound or a pharmaceutically acceptable salt of
the compound of the present invention and a pharmaceutically acceptable carrier. In
another embodiment, the pharmaceutically acceptable carrier is suitable for oral
administration and the composition comprises an oral dosage form.
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(c) Therapeutic or Prophylactic Uses
[0180] In one embodiment, the compounds or pharmaceutically acceptable salts
of the compounds of the present invention are useful as serotonin reuptake inhibitors and
as 5-HT1A receptor agonists or antagonists. Accordingly, the compounds and
pharmaceutically acceptable salts of the compounds of the present invention are useful for
treating a mammal with a condition related to or affected by the reuptake of serotonin and
the 5-HT1A receptor.
[0181] In one embodiment, the invention provides a method for treating a
condition related to or affected by the reuptake of serotonin and the 5-HT1A receptor,
comprising administering to a mammal in need thereof a compound or a pharmaceutically
acceptable salt of the compound of Formula (I), Formula (Ia) or Formula (Ib) or Formula
(Ic) in an amount effective to treat a condition related to or affected by the reuptake of
serotonin and the 5-HT1A receptor.
[0182] In one embodiment, the condition is depression (including, but not limited
to major depressive disorder, childhood depression and dysthymia). In additional
embodiments, the condition is anxiety, panic disorder or post-traumatic stress disorder.
[0183] In a further embodiment, the condition is premenstrual dysphoric disorder
(also known as premenstrual syndrome).
[0184] Additionally, the condition to be treated or prevented can be attention
deficit disorder (with or without hyperactivity).
[0185] A further embodiment is the treatment or prevention of obsessive
compulsive disorder. Additionally, the condition to be treated or prevented is social
anxiety disorder or generalized anxiety disorder.
[0186] In one embodiment, the condition to be treated or prevented is obesity,
eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing,
cocaine and alcohol addiction or sexual dysfunction.
[0187] Further conditions to be treated or prevented are cognitive deficits
resulting from neurodegenerative disorders like Alzheimer's disease, and related illnesses
in mammals including man.
[0188] In one embodiment, the present invention is directed to a method for
modulating the reuptake of serotonin or the activity of a 5-HT1A receptor, comprising
contacting the receptor with an effective amount of a compound or pharmaceutically
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acceptable salt of the compound of Formula (I) or Formula (1a). In one embodiment, the
method further comprises determining the activity of the receptor. In one embodiment,
the step of determining the activity of the receptor is performed before the step of
contacting the receptor with the compound or a pharmaceutically acceptable salt of the
compound. In another embodiment, the step of determining the activity of the receptor is
performed after the step of contacting the receptor with the compound or a
pharmaceutically acceptable salt of the compound.
[0189] The compounds and pharmaceutically acceptable salts of the compounds
of Formula (I) or Formula (1a) or Formula (Ib) or Formula (Ic) are also useful in the
manufacture of medicaments for treating a condition related to or affected by the reuptake
of serotonin and the 5-HT1A receptor in a mammal.
[0190] Accordingly, in one embodiment, the invention provides the use of a
compound or pharmaceutically acceptable salt of the compound of Formula (I) or
Formula (1a) or Formula (Ib) or Formula (Ic) for the manufacture of a medicament for
treating a condition related to or affected by the reuptake of serotonin and the 5-HTIA
receptor.
[0191] In one embodiment, the present invention is directed to the use of a
compound or pharmaceutically acceptable salt of the compound of Formula (I) or
Formula (Ia) or Formula (Ib) or Formula (Ic) for the manufacture of a medicament for
modulating the activity of reuptake of serotonin and of the 5-HT1A receptor. In one
embodiment, the medicament is also for determining the activity of the receptor.
[0192] The present invention further provides a compound of the invention for
use as an active therapeutic substance. Compounds of the invention are of particular use
in the treatment of diseases affected by disorders of serotonin.
[0193] The present invention further provides a method for treating depression
(including, but not limited to major depressive disorder, childhood depression and
dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual
dysphoric disorder (also known as premenstrual syndrome), attention deficit disorder
(with or without hyperactivity), obsessive compulsive disorder, social anxiety disorder,
generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa and
bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction,
cognitive deficits resulting from neurodegenerative disorders like Alzheimer's disease,
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and related illnesses in mammals including man, which comprises administering to the
afflicted mammal an effective amount of a compound or a pharmaceutical composition of
the invention.
EXAMPLES
Example 1
8-{[3-(5-fluoro-1H-indoI-3-yI)propyI]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindoI-1(7H)-one (3)
[0194] To a solution of 8-armno-2,3,8,9-tetrahydropyrano [3,2-e] isoindol -1
(7H)-one (1) (200 nag, 0.98 mmol) in anhydrous MeOH (20 ml) was added 3-(5-fmoro-
1H-indol-3-yl) propanal (2) (191 mg, 1 mmol), AcOH (0.14 ml), and NaBH3CN (123 mg,
1.96 mmol). Resulting reaction mixture was stirred at room temperature for 2 hr. The
solvent was removed in vacuo and the residue was re-dissolved in CH2Cl2 (150 ml). The
solution was washed with 1 N NaOH (20 ml) and H2O, Sat. NaCl. The organic solution
was separated, dried over Na2SO4, then concentrated in vacuo. The crude compound was
purified on silica gel eluting with EtOAc/Hexane (4:1) to yield (3) (304 mg, 82 %) as a
white solid. MS (APPI) m/z 380.
Example 2
(8S)-8-{[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-l(7H)-one (4)
[0195] The title compound (4) was chirally separated from (3) from Example 1. It
was dissolved methylene chloride and treated with 1 equivalent of etherate HC1 to give
HC1 salt. [a]D25 = -11.0° (c = 1% SOLUTION, DMSO); MS (ES) m/z 380.1.
Example 3
(8R)-8-{[3-(5-fluoro-1H-indoI-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-l(7H)-one (5)
[0196] The title compound (5) was chirally separated from (3) from Example 1. It
was dissolved in methylene chloride and treated with 1 equivalent of etherate HC1 to give
HC1 salt. [a]D25 = +12.6° (c = 1% SOLUTION, DMSO); MS (ES) m/z 380.1.
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Example 4
8-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one(6)
[0197] To a solution of (7) WAY-255377 (45 mg, 0.12 mmol) in anhydrous
methanol (3 ml) was added cyclopropanecarboxaldehyde (21 mg, 0.30 mmol), acetic
acid (0.017 ml), and NaBH3CN (15 mg, 0.24 mmol). Resulting reaction mixture was
stirred at room temperature for 4 hr. The solvent was removed in vacuo and the residue
was re-dissolved in CH2Cl2 (150 ml). The solution was washed with 1 N NaOH and H2O,
Sat. NaCl. The organic solution was separated, dried over Na2SO4, then concentrated in
vacuo. The crude compound was purified on silica gel eluting with EtOAc/Hexane (2:1)
to yield free tertiary amine, which was treated with 1 equivalent of etherate HC1 to give
HC1 salt (41 mg, 73 %). MS (ES) m/z 432.2.
Example 5
(8S)-8-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one(8)
[0198] The title compound (8) was chirally separated from (6) in Example 4. It
was dissolved in methylene chloride and treated with 1 equivalent of etherate HC1 to give
HC1 salt. [a]D25 = +18.0° (c = 4.93MG/.7ML, DMSO); MS (ES) m/z 434.2.
Example 6
(8R)-8-{(cyclopropyImethyl)[3-(5-fluoro-1H-indoI-3-yI)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one(9)
[0199] The title compound (9) was chirally separated from (6) in Example 4. It
was dissolved in methylene chloride and treated with 1 equivalent of etherate HC1 to give
HC1 salt. [a]D25 = -22.70° (c = 5.86/.7ML, DMSO); MS (ES) m/z 434.2.
Example 7
8-{cyclobutyl[3-(5-fluoro-lH-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano
[3,2-e]isoindol-l(7H)-one (10)
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[0200] The title compound (10) was prepared as in Example 4. MS (ES) m/z
434.2.
Example 8
8-{(cycIobutylmethyl)[3-(5-fluoro-1H-indoI-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one(11)
[0201] The title compound (11) was prepared as in Example 4. MS (ES) m/z
446.2
Example 9
8-r[3-(5-fluoro-lH4ndol-3-yl)propyl](methyl)amino]-2,3,8,9-tetrahydropyrano[3,2-e]
isoindol-l(7H)-one (12)
[0202] To a mixture of (3) (52 mg, 0.137 mmol) and Me3OBF4 (40 mg, 0.274
mmol) in methylene chloride (5 ml) was added Hunig's base (40 µl, 0.274 mmol). The
reaction mixture was stirred at 50 °C for 2 hr, then diluted with 100 ml of methylene
chloride. It was washed with H2O, saturated NaCl. The organic solution was dried over
Na2SO4 and concentrated in vacuo. The residue was purified on silica gel eluting with
(80 % EtOAc/Hexane) to give the title compound, which was treated with 1 equivalent of
etherate HCl to give HCl salt. MS (ES) m/z 394.1.
Example 10
8-{ethyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-l(7H)-one (13)
[0203] The title compound (13) was prepared as in Example 4. MS (ES) m/z
408.2.
Example 11
84[3-(5-fluoro-lH-indol-3-yI)propyl](isobutyl)amino]-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-l(7H)-one (14)
[0204] The title compound (14) was prepared as in Example 4. MS (ES) m/z
436.3.
Example 12
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8-{(cyclohexylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyI]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one(15)
[0205] The title compound (15) was prepared as Example 4. MS (ES) m/z 476.3.
Example 13
8-{benzyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindoI-l(7H)-one (16)
[0206] The title compound (16) was prepared as inExample 4. MS (ES) m/z
470.2.
Example 14
84[3-(5-fluoro-1H-indol-3-yl)propyl](3-furybnethyl)amino]-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one(17)
[0207] The title compound (17) was prepared as in Example 4. MS (ES) m/z
460.2.
Example 15
8-{[3-(5,7-difluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-l(7H)-one (18)
[0208] The title compound (18) was prepared as in Example 1. MS (ES) m/z
398.1.
Example 16
8-{cyclobutyI[3-(5,7-difluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindoI-l(7H)-one(19)
[0209] The title compound (19) was prepared as in Example 4. MS (ES) m/z
450.2.
Example 17
3-{3-[(l-oxo-1,2,3,7,8,9-hexahydropyrano[3,2-e]isomdol-8-yI)amino]propyl}-1H-
indole-5-carbonitrile (20)
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[0210] To a mixture of (1) (60 mg, 0.294 mmol), 4-(5-fluoro- 1H-indol-3-
yl)butanal (21), 64 mg, 0.309 mmol) in acetic acid (37 µl, 0.62 mmol)and methanol (2
ml) was added NaBH3CN (37 mg, 0.59 mmol) in portions. Resulting mixture was stirred
for 1.5 hr. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2
and washed with 1N NaOH and saturated NaCl. The organic solution was dried over
Na2SO4 and concentrated in vacuo. The compound was purified on silica gel eluting with
60 % EtOAc/ Hexane to give (20) as a solid (78 mg, 69 %). The title compound was
dissolved in methylene chloride and treated with 1 equivalent of etherate HC1 to give HC1
salt. MS (ES) m/z 385.2.
Example 18
3-{3-[(cyclopropylmethyl)(l-oxo-l,2,3,7,8,9-hexahydropyrano[3,2-e]isoindoI-8-
yl)amino]propyl}-1H-indok-5-carbonitrile (22)
[0211] The title compound (22) was prepared as in Example 4. MS (ES) m/z
441.2.
Example 19
3-(3-{(cyclopropylmethyl)[(8S)-1-oxo-l,2,3,7,8,9-hexahydropyrano[3,2-e]isoindol-8-
yl]amino}propyl)-1H-indole-5-carbonitrile(23)
[0212] The title compound (23) was chirally separated from Example 18. It was
dissolved in methylene chloride and treated with 1 equivalent of etherate HCl to give HCl
salt. [a]D25 = +23.06° (c = 5.04MG/.7ML, DMSO); MS (ES) m/z 441.2.
Example 20
3-(3-{(cydopropylmethyI)[(8R)-1-oxo-l,2,3,7,8,9-hexahydropyrano[3,2-e]isoindol-8-
yl]amino}propyl)-1H-indole-5-carbonitrile(24)
[0213] The title compound (24) was chirally separated from Example 18. It was
dissolved in methylene chloride and treated with 1 equivalent of etherate HCl to give HCl
salt. [a]D25 = -24.30° (c = 5.24MG A7ML, DMSO); MS m/z 441.2.
Example 21
8-{[4-(5-fluoro-1H-indol-3-yl)butyl]amino}-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-
l(7H)-one (25)
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[0214] To a mixture of (1) (60 mg, 0.294 mmol), 4-(5-fluoro-1H-indol-3-
yl)butanal (21), 63 mg, 0.294 mmol) in acetic acid (37 µl, 0.62 mmol)and methanol (4
ml) was added NaBH3CN (37 mg, 0.588 mmol) in portions. Resulting mixture was
stirred for 1.5 hr. The solvent was removed in vacuo and the residue was dissolved in
CH2Cl2 and washed with 1 N NaOH and saturated NaCl. The organic solution was dried
over Na2SO4 and concentrated in vacuo. The compound was purified on silica gel eluting
with 60 % EtOAc/ Hexane to give (25) as a solid (90 mg, 78 %). MS (ES) m/z 394.2;
Example 22
8-{(cyclopropylmethyI)[4-(5-fluoro-1H-indol-3-yl)butyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one(26)
[0215] The title compound (26) was prepared as in Example 4. MS (ES) m/z
448.2
Example 23
8-{[(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one(27)
[0216] To a mixture of (1) (60 mg, 0.294 mmol), 6-fluoro-2,3,4,9-tetrahydro-1H-
carbazole-3-carbaldehyde ((28), 64 mg, 0.294 mmol) in acetic acid (38 mg, 0.588 mmol)
and methanol (3 ml) was added NaBH3CN (37 mg, 0.588 mmol) in portions. The
resulting mixture was stirred for 40 min. The solvent was removed in vacuo and the
residue was dissolved in methylene chloride. The organic solution was washed with 1N
NaOH and saturated NaCl befor being dried over with Na2SO4. The concentration of
organic solution in vacuo gave crude (27), which was purified on silica gel eluting with
80 % EtOAc/Hexane to give a white solid (71 mg, 60 %). MS (ES) m/z 406.2
Example 24
8-{[3-(5-fluoro-1H-indol-3-yl)propyI]amino}-2-methyl-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-l(7H)-one (29)
[0217] To a mixture of (30) (90 mg, 0.41 mmol), 3-(5-fluoro-1H-indol-3-
yl)propanal ((2), 93 mg, 0.580 mmol) in acetic acid (49 µl, 0.588 mmol) and methanol (8
ml) was added NaBH3CN (52 mg, 0.82 mmol) in portions. The resulting mixture was
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stirred for 45 min. The solvent was removed in vacuo and the residue was dissolved in
methylene chloride. The organic solution was washed with 1N NaOH and saturated NaCl
before being dried over with Na2SO4. Concentration of organic solution gave the crude
compound, which was purified on silica gel (80 % EtOAc/Hexane) to give (29) as a free
base. It was treated with 1 equivalent etherate HC1 to give the title compound as a HCl
salt. MS (ES) m/z 394.2.
Example 25
8-{(cyclopropyImethyl)[3-5-fluoro4H4ndoI-3-yl)propyI]amino}-2-methyI-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one(30)
[0218] The title compound (30) was prepared as in Example 4. MS (ES) m/z
448.3.
Example 26
(8S)-8-{(cyclopropylmethyl)[3-(5-fluoro-1H-indoI-3-yl)propyl]amino}-2-methyl-
2,3,8,9-tetrahydropyrano[3,2-e]isoindol-l(7H)-one(31)
[0219] The title compound (31) was chirally separated from (30). It was
dissolved methylene chloride and treated with 1 equivalent of etherate HC1 to give HC1
salt. [a]D25 = +16.69° (c = 4.53/.7ML, DMSO); MS (ES) m/z 448.2.
Example 27
(8R)-8-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2-methyl-
2,3,8,9-tetrahydropyrano[3,2-e]isoindol-l(7H)-one(32)
[0220] The title compound (32) was chirally separated from (30). It was
dissolved methylene chloride and treated with 1 equivalent of etherate HC1 to give HC1
salt. [a]D25 = -14.66° (c = 4.01MG/.7ML, DMSO); MS (ES) m/z 448.2.
Example 28
8-[[3-(5-fluoro-1H-indol-3-yl)propyl](methyl)amino]-2-methyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one(33)
[0221] The title compound (33) was prepared as in Example 9. MS (ES) m/z
408.2.
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Example 29
8-{ethyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2-methyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one(34)
[0222] The title compound (34) was prepared as in Example 4. MS (ES) m/z
422.2.
Example 30
8-[[3-(5-fluoro-1H-indol-3-yI)propyl](isobutyl)amino]-2-methyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one(35)
[0223] The title compound (35) was prepared as in Example 4. MS (ES) m/z
448.2.
Example 31
8-{cyclobutyI[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2-methyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l(7H)-one(36)
[0224] The title compound (36) was prepared as in Example 4. MS (ES) m/z
446.2.
Example 32
8-{(cyclobutylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2-methyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-l (7H)-one (37)
[0225] The title compound (37) was prepared as in Example 4. MS (ES) m/z
460.2.
Example 33
3-{3-[(2-methyl-1-oxo-l,2,3,7,8,9-hexahydropyrano[3,2-e]isoindol-8-
yl)amino]propyl}-1H-indole-5-carbonitriIe(38)
[0226] The title compound (38) was prepared as in Example 17. MS (ES) m/z
399.2;
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Example 34
3-{3-[(cycIopropyImethyI)(2-methyI-1-oxo-1,2,3,7,8,9-hexahydropyrano[3,2-
e]isoindol-8-yl)amino]propyI}-1H-indoIe-5-carbonitrile(39)
[0227] The title compound (39) was prepared as in Example 4. MS (ES) m/z
455.3.
Example 35
8-{[3-(5,7-difluoro-1H-indol-3-yI)propyI]amino}-2-methyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one(40)
[0228] To a mixture of (1) (202 mg, 0.99 mmol), 3-(5,7-difluoro-1H-indol-3-
yl)propanal ((41), 247 mg, 1.09 mmol) in acetic acid (145 µl, 2.36 mmol)and methanol
(10 ml) was added NaBH3CN (126 mg, 2.00 mmol) in portions. Resulting mixture was
stirred for 2.0 hr. The solvent was removed in vacuo and the residue was dissolved in
CH2C12 and washed with 1 N NaOH and saturated NaCl. The organic solution was dried
over Na2SO4 and concentrated in vacuo. The compound was purified on silica gel eluting
with 70 % EtOAc/ Hexane to give (18), which was treated with 1 equivalent of etherate
HCl to form HCl salt. MS (ES) m/z 412.2.
Example 36
8-{(cyclopropylmethyl)[3-(5,7-difluoro-1H-indol-3-yl)propyI]amino}-2-methyl-
2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one(41)
[0229] The title compound (41) was prepared as in Example 4. MS (ES) m/z
466.2.
Example 37
8-{[(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methyl]amino}-2-methyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one (42)
[0230] The title compound (42) was prepared as in Example 4. MS (ES) m/z
420.2.
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Example 38
8-{(cyclopropylmethyl)[(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)methyl]amino}-2-methyl-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one(43)
[0231] To a solution of (42) (52 mg, 0.124 mmol) in anhydrous methanol (5 ml)
was added cyclopropanecarboxaldehyde (10 mg, 0.149 mmol), acetic acid (0.015 ml), and
NaBH3CN (15 mg, 0.24 mmol). Resulting reaction mixture was stirred at room
temperature for 4 hr. The solvent was removed in vacuo and the residue was re-dissolved
in CH2Cl2 (150 ml). The solution was washed with 1 N NaOH, H2O and saturated NaCl.
The organic solution was separated, dried over Na2SO4, then concentrated in vacuo. The
crude compound was purified on silica gel eluting with EtOAc/Hexane (2:1) to yield free
tertiary amine, which was treated with 1 equivalent of etherate HCl to give HCl salt. MS
(ES) m/z 473.3.
Example 39
8-{cydobutyl[(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methyl]amino}-2-
methyl-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-l(7H)-one(44)
[0232] The title compound (44) was prepared as in Example 4. MS (ES) m/z
472.3.
Example 40
9-{[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-tetrahydro-2H-pyrano[2,3-
fa]isoquinolin-l(8H)-one (45)
[0233] To a mixture of 9-amino-3,4,9,10-tetrahydro-2H-pyrano [2,3-h]
isoquinolin-1(8H)-one (46) (130 mg, 0.596 mmol), 3-(5-fluoro-1H-indol-3-yl)propanal
((2), 113 mg, 0.596 mmol) in acetic acid (70 µl) and methanol (20 ml) was added
NaBH3CN (75 mg, 1.19 mmol) in portions. The resulting mixture was stirred for 2hr.
The solvent was removed in vacuo and the residue was dissolved in methylene chloride.
The organic solution was washed with 1N NaOH and saturated NaCl before being dried
over with Na2SO4. Concentration of organic solution gave the crude compound, which
was purified on silica gel (100 % EtOAc) to give the desired compound, which was
treated with 1 equivalent of etherate HCL to form HC1 salt for title compound. MS
(APPI) m/z 394.4.
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Example 41
9-[[3-(5-fluoro-1H-indol-3-yl)propyl](methyl)amino]-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-l(8H)-one(47)
[0234] The title compound (47) was prepared as in Example 9. MS (ES) m/z
406.0.
Example 42
9-{ethyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-l(8H)-one(48)
[0235] To a solution of 9-amino-6-fluro-3,4,9,10-tetrahydro-2H-pyrano [2,3-
h]isoquinolin-1(8H)-one (49) (55 mg, 0.14 mmol) in anhydrous methanol (3 ml) was
added acetoaldehyde (12 mg, 0.21 mmol), acetic acid (0.018 ml), and NaBH3CN (18 mg,
0.29 mmol). Resulting reaction mixture was stirred at room temperature for 3 hr. The
solvent was removed in vacuo and the residue was re-dissolved in CH2Cl2 (150 ml). The
solution was washed with 1 N NaOH and H2O, Sat. NaCl. The organic solution was
separated, dried over Na2SO4, and then concentrated in vacuo. The crude compound was
purified on silica gel eluting with EtOAc/Hexane (2:1) to yield free tertiary amine, which
was treated with 1 equivalent of etherate HCl to give HCl salt (35 mg, 60 %). S (APPI)
m/z 422.
Example 43
9-[[3-5-fluoro-1H-indol-3-yl)propyl](propyl)amino]-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-l(8H)-one(50)
[0236] The title compound (50) was prepared as in Example 42. MS (ES) m/z
436.2.
Example 44
94[3-(5-fluoro-lH-indol-3-yl)propyl](isobutyl)amino]-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one(51)
[0237] The title compound (51) was prepared as in Example 42. MS (ES) m/z
450.2.
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Example 45
9-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-
tetrahydro-2H-pyrano[2,3-h]isoquinolin-l(8H)-one (52)
[0238] The title compound (52) was prepared as in Example 42. MS (ES) m/z
448.2.
Example 46
9-{cyclobutyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino]-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one(53)
[0239] The title compound (53) was prepared as in Example 42. MS (ES) m/z
448.2.
Example 47
9-[[3-(5-fluoro-1H-indol-3-yl)propyl](isopropyl)amino]-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one(54)
[0240] The title compound (54) was prepared as in Example 42. MS (ES) m/z
434.2.
Example 48
9-{benzyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one (55)
[0241] The title compound (55) was prepared as in Example 42. MS (ES) m/z
482.2;
Example 49
9-[[3-(5-fluoro-1H-indol-3-yl)propyl](pyridin-4-ylmethyl)amino]-3,4,9,10-
tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one(56)
[0242] The title compound (56) was prepared as Example 42. MS (ES) m/z 483.2.
Example 50
9-[[3-(5-fluoro-1H-indol-3-yl)propyl3(3,3,3-trifluoropropyl)amino]-3,4,9,10-
tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one(57)
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WO 2006/138549 PCT/US2006/023467
[0243] The title compound (57) was prepared as in Example 42. MS (ES) m/z
490.2;
Example 51
6-fluoro-9-{[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinoIin-l(8H)-one (58)
[0244] To a solution of 9-amino-6-fluor-3,4,9,10-tetraliydro-2H-pyrano [2,3-h]
isoquinolin-1(8H)-one (49) (110 mg, 0.47 mmol) in anhydrous methanol (7 ml) was
added 3-(5-fluoro-1H-indol-3-yl) propanal (2) (89 mg, 0.47 mmol), acetic acid (0.060
ml), and NaBH3CN (59 mg, 0.930 mmol). Resulting reaction mixture was stirred at room
temperature for 3 hr. The solvent was removed in vacuo and the residue was re-dissolved
in CH2Cl2 (120 ml). The solution was washed with 1 N NaOH and H2O, saturated, NaCl.
The organic solution was separated, dried over Na2SO4, then concentrated in vacuo. The
crude compound was purified on silica gel eluting with 80 % EtOAc/Hexane to yield the
title compound. MS (ES) m/z 410.2.
Example 52
9-{(cyclopropylmethyl)[3-(5-fluoro-1H-indoI-3-yl)propyl]amino}-6-fluoro-3,4,9,10-
tetrahydro-2H-pyrano[2,3-h]isoquinolin-l(8H)-one(59)
[0245] To a solution of (58) (55 mg, 0.134 mmol) in anhydrous methanol (4 ml)
was added cyclopropanecarboxaldehyde (12 mg, 0.161 mmol), acetic acid (20 µl), and
NaBH3CN (17 mg, 0.268 mmol). Resulting reaction mixture was stirred at room
temperature for 2 hr. The solvent was removed in vacuo and the residue was re-dissolved
in CH2Cl2 (120 ml). The solution was washed with 1 N NaOH and H2O, saturated NaCl.
The organic solution was separated, dried over Na2SO4, then concentrated in vacuo. The
crude compound was purified on silica gel eluting with 80 %EtOAc/Hexane to yield free
tertiary amine, which was treated with 1 equivalent of etherate HCl to give HCl salt (41
mg, 60 %). MS (APPI) m/z 466.
Example 53
9-{ethyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-6-fluoro-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-l(8H)-one (60)
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[0246] The title compound (60) was prepared as in Example 52. MS (APPI) m/z
440.
Example 54
3-{3-[(6-fluoro-1-oxo-1,3,4,8,9,10-hexahydro-2H-pyrano[2,3-h]isoquinolin-9-
yl)amino]propyl}-1H-indole-5-carbonitrile(61)
[0247] The title compound (61) was prepared as in Example 17. MS (ES) m/z
419.1.
Example 55
3-{3-[ethyl(6-fluoro-1-oxo-l,3,4,8,9,10-hexahydro-2H-pyrano[2,3-h]isoquinolin-9-
yl)amino]propyl}-1H-indole-5-carbonitrile(62)
[0248] The title compound (62) was prepared as in Example 4. MS (ES) m/z
445.2.
Example 56
3-{3-[(cyclopropylmethyl)(6-fluoro-1-oxo-l,3,4,8,9,10-hexahydro-2H-pyrano[2,3-
h]isoquinolin-9-yl)amino]propyl}-1H-indole-5-carbonitrile (63)
[0249] The title compound (63) was prepared as in Example 4. MS (ES) m/z
471.2.
Example 57
3-{3-[cyclobutyl(6-fluoro-1-oxo-1,3,4,8,9,10-hexahydro-2H-pyrano[2,3-h]isoquinolin-
9-yl)amino]propyl}-1H-indole-5-carbonitrile(64)
[0250] The title compound (64) was prepared as in Example 4. MS (ES) m/z
471.2.
Example 58
3-{3-[(6-fluoro-1-oxo-1,3,4,8,9,10-hexahydro-2H-pyrano[2,3-h]isoquinolin-9-
yl)(propyl)amino]propyl}-1H-indole-5-carbonitrile(65)
[0251] The title compound (65) was prepared as in Example 4. MS (ES) m/z
459.2.
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WO 2006/138549 PCT/US2006/023467
Example 59
3-{3-[(6-fluoro-1-oxo-l,3,4,8,9,10-hexahydro-2H-pyrano[2,3-h]isoquinolin-9-
yl)(isobutyl)amino]propyl}-1H-indole-5-carbonitrile(66)
[0252] The title compound (66)was prepared as in Example 4. MS (ES) m/z
473.1.
Example 60
3-{3-[(6-fluoro-1-oxo-l,3,4,8,9,10-hexahydro-2H-pyrano[2,3-h]isoquinolin-9-
yl)(isopropyl)amino]propyl}-1H-indole-5-carbonitrile(67)
[0253] The title compound (67) was prepared as in Example 4. MS (APPI) m/z
461.
Example 61
3-{3-[benzyl(6-fluoro-1-oxo-l,3,4,8,9,10-hexahydro-2H-pyrano[2,3-h]isoquinolin-9-
yl)amino]propyl}-1H-indole-5-carbonitrile(68)
[0254] The title compound (68) was prepared as in Example 4. MS (APPI) m/z
509.
Example 62
8-amino-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one(1)
[0255] To a solution of 8-nitro-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one
((69), 700 mg, 2.99 mmol) in EtOH (35 ml)/THF (5 ml) was added hydrazine
monohydrate (1.65 ml, 34 mmol), followed by addition of Raney-Nickel (50 mg). The
reaction mixture was stirred for 4 hr. The catalyst residue was filtered under vacuum and
organic solution was concentrated in vacuo to give the title compound as a solid (420 mg,
69%). MS (ES) m/z 205.1
Example 63
8-nitro-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one(69)
[0256] To 8-nitro-2,3-dihydropyrano[3,2-e]isoindol-1(7H)-one ((70), 1.1 g, 4.74
mmol) in solvent A (CHCl3,100 ml) and solvent B (i-PrOH 4 ml) was added silica gel
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WO 2006/138549 PCT/US2006/023467
(3.3 g), followed by addition of sodium boronhydride (400 mg, 11.5 mmol) in portions.
Resulting mixture was stirred for 2 hr. The silica gel was filtered and washed well with
CHCl3. The filtrate was washed with H2O, and sat NaCl. The organic solution was
separated and dried over Na2SO4 and concentrated in vacuo to give the title compound
(790 mg, 71 %) as a solid.
MS (APPI) m/z 235.2.
Example 64
8-nitro-2,3-dihydropyrano[3,2-e]isoindol-1(7H)-one(70)
[0257] To a mixture of 2,3-dihydropyrano[3,2-e]isoindol-1(7H)-one ((71) 2.3 g,
12.3 mmol) in N-methylpyrrolidine(150 ml) and H2O (3 ml) was added NaNO2 (3.4 g,
49.2 mmol) in portions. To the mixture cooled at 0 °C was added iodine (9.4 g, 36.9
mmol). The reaction mixture was stirred fur 3 hr, then quenched with 58 % NaHSO3 (12
ml), H2O (12 ml), followed by addition of another 30 ml of 58 % NaHSO3 solution. The
solid was participated, filtered, and washed with H2O. The desired compound was air-
dried under vacuum to give the title compound (2.41 g, 84 %) as a yellow solid. MS (ES)
m/z 233.2.
Example 65
2,3-dihydropyrano[3,2-e]isoindol-1(7H)-one(71)
[0258] The mixture of 6-(prop-2-ynyloxy)isoindolin-1-one ((72),4.4 g, 23.5
mmol) and N, N-Diethylaniline 70 ml) was stirred at 210 °C for overnight. Reaction
solution was directly loaded on silica gel eluting with Hexane/EtOAc/CH2Cl2 (3:3:1 ratio)
to give the title compound (2.8 g, 64 %) as a brown solid. MS (ES) m/z 188.1.
Example 66
6-(prop-2-ynyloxy)isoindolin-1-one(72)
[0259] The mixture of 6-hydroxyisoindolin-1-one ((73), 5.1 g, 34.2 mmol),
propargyl bromide (80 % solution in toluene, 5.70 ml, 51.3 mmol) K2CO3 (9.44 g, 68.4
mmol), KI (1.14 g, 6.8 mmol) in acetone was refluxed for overnight. The reaction
mixture was filtered under vacuum and concentrated in vacuo to give the title compound
(4.4 g, 68 %) as a solid. MS (ES) m/z 188.1.
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Example 67
6-hydroxyisoindolin-1-one (73)
[0260] To a suspension of (74) (7.07 g, 43.4 mmol) in CH2Cl2 (600 ml) was
added BBr3
(1M in CH2Cl2, 86.7 ml). The reaction mixture was stirred at room temperature for 4 hr.
The solvent and boron residue was removed in vacuo and the remaining solid was
dissolved in CH2Cl2, the solution was neutralized with 1N NaOH (PH = 6.5). Desired
compound was precipitated out and filtered. The organic solution was separated and
washed with sat. NaCl, dried over Na2SO4 to give the title compound (combined weight
5.1 g, 78 %). MS (ES) m/z 150.1.
Example 68
6-methoxyisoindolin-1-one (74)
[0261] A solution of methyl 2-(bromomethyl)-5-methoxybenzoate ((75), 5.0 g,
19.3 mmol) in MeOH was placed in pressure flask and to it ammonia/methanol (2M, 30
ml) was added. Resulting mixture was stirred at 125 °C for 2 hr. The solvent and excess
NH3 was removed in vacuo and the residue was triturated with Hexane/EtOAc (1:2 ratio).
The compound was filtrated under vacuum and air-dried for 2 hr to give the title
compound (2.51 g, 65 % ) as a pale yellow solid. The filtrated was concentrated and
purified on silica gel (Hexane/EtOAc/MeOH 3:1:0.5 ratio) to yield another 270 mg of
desired compound. Combined yield was 86 %. MS (ES) m/z 164.1.
Example 69
Methyl 2-(bromomethyl)-5-methoxybenzoate (75)
[0262] A mixture of ( 5.68 g, 31.1 mmol), NBS(6.74 g, 37.9 mmol), AIBN (259
mg,
1.58 mmol) in carbon tetrachloride was refluxed for 2 hr. The reaction mixture was
cooled at
room temperature and the solid was filtrated under vacuum. The filtrate was
concentrated in
vacuo to obtain (75) (8.01 g, >98 % ) as an oil without purification.
Example 70
8-amino-2-methyl-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one(31)
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WO 2006/138549 PCT/US2006/023467
[0263] The title compound (31) was prepared as in Example 62. MS (ES) m/z
219.2.
Example 71
2-methyl-8-nitro-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one(76)
[0264] The title compound (76) was prepared as in Example 63. MS (ES) m/z
249.1.
Example 72
2-methyl-8-nitro-2,3-dihydropyrano[3,2-e]isoindol-1(7H)-one(77)
[0265] The title compound (77) was prepared as in Example 64. MS (ES) m/z
247.0.
Example 73
2-methyl-2,3-dihydropyrano[3,2-e]isomdol-1(7H)-one(78)
[0266] To a suspension of 2,3-dihydropyrano[3,2-e]isoindol-1(7H)-one ((71), 100
mg, 0.54 mmol) in THF (5 ml) was added sodium hydride (95 %, 21 mg, 0.80 mmol) in
portions. Resulting mixture was stirred for 45 min, then added iodomethane (0.37 ml) via
syringe. Reaction was continued for 2.5 hr before removing THF in vacuo. The residue
was dissolved in CH2Cl2, washed with H2O, sat. NaCl. The organic solution was dried
over anhydrous Na2SO4 and concentrated in vacuo to give WAY 257034 as a solid
(88mg, 74 %). MS (ES) m/z 202.1.
Example 74
9-amino-3,4,9,10-tetrahydro-2H-pyrano[2,3-h]isoqumolin-1(8H)-one(46)
[0267] The title compound (46) was prepared as in Example 62. MS (ES) m/z
219.1.
Example 75
9-nitro-3,4,9,10-tetrahydro-2H-pyrano[2,3-h]isoquinolin-l(8H)-one(79)
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WO 2006/138549 PCT/US2006/023467
[0268] The title compound (79) was prepared as in Example 63. MS (ES) m/z
249.1.
Example 76
9-nitro-3,4-dihydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one(80)
[0269] The title compound (80) was prepared as in Example 64. MS (ES) m/z
247.1.
Example 77
3,4-dihydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one(81)
[0270] The title compound (81) was prepared as in Example 65. MS (ES) m/z
202.1.
Example 78
7-(prop-2-yn-1-yloxy)-3,4-dihydroisoquinolin-l(2H)-one (82)
[0271] The title compound (82) was prepared as in Example 66. MS (ES) m/z
202.1.
Example 79
7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one(83)
[0272] The title compound (83) was prepared as in Example 67. MS (ES) m/z
162.1.
Example 80
7-methoxy-3,4-dihydroisoquinolin-1(2H)-one(84)
[0273] To a mixture of 6-Methoxy-1-indanone (15 g, 92.6 mmol), sodium azide (
26.7 g, 277.8 mmol), in CHCl3 was added methane sulfonic acid (60 g, 926 mmol) via
addition funnel at 0 °C. Reaction mixture was warm to room temperature. Stirring was
continued for 3 hr, then poured into cold water. The organics were extracted with
methylene chloride and washed with water, sat. NaCl and dried over Na2SO4. Organic
solution was concentrated in vacuo and the residue was purified with silica gel eluting
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WO 2006/138549 PCT/US2006/023467
with 20 % EtOAc/Hexane to give the title compound as a yellow solid (10.5 g, 63 %). MS
(ES)m/z 178.1.
Example 81
9-amino-6-fluoro-3,4,9,10-tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one(49)
[0274] The title compound (49) was prepared as in Example 62. MS (ES) m/z
237.1.
Example 82
6-fluoro-9-nitro-3,4,9,10-tetrahydro-2H-pyrano[2,3-h]isoquinolin-l(8H)-one(85)
[0275] The title compound (85) was prepared as in Example 63. MS (ES) m/z
267.1.
Example 83
6-fluoro-9-nitro-3,4-dihydro-2H-pyrano[2,3-h1isoquinolin-l(8H)-one(86)
[0276] The title compound (86) was prepared as in Example 64. MS (ES) m/z
265.1.
Example 84
6-fluoro-3,4-dihydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one(87)
[0277] The title compound (87) was prepared as in Example 65. MS (ES) m/z
220.1.
Example 85
6-fluoro -7-(prop-2-yn-1-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (88)
[0278] The title compound (88) was prepared as in Example 66. MS (ES) m/z
220.1.
Example 86
6-fluoro-7-hydroxy-3,4-dihydroisoquinolin-l(2H)-one(89)
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[0279] To a solution of 5-fluoro-6-hydroxyindan-1-one ((90),10.5 g, 63.3 mmol)
in chloroform (600 ml) was added NaN3 (12.3 g, 190 mmol), followed by dropwise
addition of methanasulfonic acid (33 ml, 506 mmol). Resulting mixture was stirred for 3
hr. The reaction mixture was poured into cold water and extracted with chloroform (3X).
Organic extracts were combined and washed with H2O and sat. NaCl, then dried over
Na2SO4. Concentration in vacuo gave a mixture of required product and reversed lactam.
Purification of crude product on silica eluting with 30-60 % EtOAc/Hexane offered the
title compound as a off-white solid (5.3 g, 46 %). MS (ES) m/z 180.0.
Example 87
Methyl (2E)-3-(3-Fluoro-4-hydroxyphenyl)acrylate (91)
[0280] To a mixture of 4-Bromo-2-fluorophenol (25 g, 0.13 mol) and methyl
acrylate (23.41 ml, 0.26 mol) in DMF (500 ml) was added triethylamine (36 ml, 0.26
mol) and tri-o-tolylphosphine (1.95 g, 6.5 mmol) and Pd(OAc)2 (2.91 g, 13 mmol).
Reaction mixture was stirred under nitrogen at 100 °C for 3 hr. About 200 ml of DMF
was removed by rotavapor and remaining reaction solution was diluted with EtOAc (300
ml). Palladium residue was filtered under vacuum and the filtrate was washed H2O and
sat. NaCl. Organic solution was dried over Na2SO4 and concentrated in vacuo. The
compound was purified with chromatograghy eluting with EtOAc/Hex (20-40 %) to give
WAY-263609 as a solid (18.2 g, 72 %). 1H NMR/CDCl3, δ, 7.60 (d, 1H), 7.19-7.30 (m,
2H), 6.97-7.04 (t, 1H), 6.30 (d, 1H), 5.90 (s, 1H), 3.80 (s, 3H).
Example 88
Methyl (2E)-3-(3-Fluoro-4-hydroxyphenyl)propanoaie (92)
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WO 2006/138549 PCT/US2006/023467
[0281] A mixture of (91) (18.2 g, 93.3 mmol) Pd/C (1.9 g) in MeOH (150 ml) was
hydrogenated at 50 psi for 18 hr. The reaction mixture was filtered and the filtrate was
concentrated in vacuo to give WAY 263610 as a solid (15.4 g, 84 %). 1H NMR/CDCl3,
δ, 6.85(m, 2H), 6.80 (d, 1H), 4.20-4.50 (broad s, 1H), 3.67 (s, 3H), 2.81-2.88 (t, 3H),
2.55-2.60 (t, 2H).
Example 89
3-(3-fluoro-4-hydroxyphenyl)propanoic acid (93)
[0282] To a solution of (92) (15 g, 75.8 mmol) in MeOH (150 ml)/THF (150 ml)
H2O (50 ml) was added LiOH (6.36 g, 103 mmol). The reaction mixture was stirred for 3
hr. The solvents were removed in vacuo and to the residue was added CH2Cl2 (500 ml).
It was acedified with 2N HCl until PH = 2. Organic solution was separated, washed with
sat. NaCl and dried over Na2SO4. Concentration in vacuo gave WAY-263667 (11.6 g, 83
%). 1H NMR/CDCl3, δ, 6.80-6.95 (m, 3H), 2.84-2.90 (t, 2H), 2.60-2.66 (t, 2H). MS (ES)
m/z 183.0.
Example 90
5-fluoro-6-hydroxymdan-1-one (90)
[0283] A mixture of (93) (11.6 g, 63.0 mmol) and AlCl3 (57 g, 87.6 mmol), NaCl
(25g, 483 mmol) was melted and stirred at 185 °C for 15 min, then poured into cold
water. The suspended solid was stirred for 10 min before being filtered. The solid was
air-dried for 4 hr under vacuum to give 263709 as an off-white solid (9.2 g, 88 %). 1H
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WO 2006/138549 PCT/US2006/023467
NMR/CD3OD, δ,7.21 (d, 1H), 7.18 (d, 1H), 3.02-3.08 (t, 2H), 2.61-2.68 (t, 3H). MS (ES)
m/z 165.1.
Example 91
6-fluoro-7-hydroxy-3,4-dihydroisoquinoIin-l(2H)-one (89)
[0284] To a solution of (90) (10.5 g, 63.3 mmol) in chloroform (600 ml) was
added NaN3 (12.3 g, 190 mmol), followed by dropwise addition of methanasulfonic acid
(33 ml, 506 mmol). Resulting mixture was stirred for 3 hr. The reaction mixture was
poured into cold water and extracted with chloroform (3X). Organic extracts were
combined and washed with H2O and sat. NaCl, then dried over Na2SO4. Concentration in
vacuo gave a mixture of required product and reversed lactam. Purification of crude
product on silica eluting with 30-60 % EtOAc/Hex offered WAY-263746 as a off-white
solid (5.3 g, 46 %). 1H NMR/CD3OD, δ,7.48 (d, 1H), 7.00 (d, 1H), 3.43-3.49 (t, 2H),
2.83-2.89 (t, 2H). MS (ES) m/z 180.0.
Example 92

8-{[3-(5-fluoro-lH-indol-3-yl)propyl]amino)-2-(methylsulfonyl)-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one(94)
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[0285] To a solution of methylsulfonyl substituted lactam amino chroman (118
mg, 0.418 mol) and 3-(5-fluoro-1H-indol-3-yl)propanal (88 mg, 0.460 mmol) in methanol
(15 ml) was added acetic acid (0.05 ml), followed by addition of NaBH3CN (53 mg,
0.836 mmol). Reaction mixture was stirred at room temperature for 2 hr. The solvent
was removed in vacuo and the residue was partitioned in methylene chloride and H2O.
The organic solution was washed with sat. NaCl, dride over Na2SO4 and concentrated in
vacuo. The residue was purified on silica gel eluting with 80 % EtOAc/ Hexane to give
the title compound (94) (25 mg). MS (ES) m/z 458.2.
Example 93
2-(methylsulfonyl)-2,3-dihydropyrano[3,2-e]isoindol-l(7H)-one(95)

[0286] To a solution of 2,3-dihydropyrano[3,2-e]isoindol-1(7H)-one (71) (500
mg, 2.67 mmol) in THF (35 ml) was added NaH (95 %, 87 mg, 3.47 mmol) in portions.
Resulting mixture was stirred for 40 min before adding MeSO2Cl by syringe. Stirring
was continued for 1 hour. The solvent was removed in vacuo and the residue was
portioned with CH2Cl2. The organic solution was washed with H2O, sat. NaCl and dried
over Na2SO4. Concentration in vacuo gave the title compound (95) as a solid (490 mg,
69 %). MS (ES) m/z 266.0.
Example 94
Testing Affinity of Compounds for the 5-HT Transporter
[0287] A protocol similar to that used by Cheetham et al. (NeurophaRMacol.,
1993, 32: 737) was used to determine the affinity of the compounds of the invention for
the serotonin transporter. The compound's ability to displace 3H-paroxetine from male
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rat cortical membranes was determined using a Tom Tech filtration device to separate
bound from free 3H-paroxetine and Wallac 1205 Beta Plate® counter to quantitate bound
radioactivity. Kis thus determined for standard clinical antidepressants are 1.96 nM for
fiuoxetine, 14.2 nM for imipramime and 67.6 nM for zimelidine. A strong correlation has
been found between H-paroxetine binding in rat frontal cortex and 3H-serotonin uptake
inhibition.
[0288] High affinity for the serotonin 5-HTIA receptor was established by testing
the claimed compound's ability to displace [3H] 8-OH-DPAT (dipropylaminotetralin)
from the 5-HT1A serotonin receptor following a modification of the procedure of Hall et
al., (J. Neurochem., 1985,44: 1685) which utilizes CHO cells stably transfected with
human 5-HT1A receptors. The 5-HT1A affinities for the compounds of the invention are
reported below as Kis.
[0289] The agonist or antagonist activity at 5-HT1A receptors was established by
using two different assays. The 35S-GTPγS binding assay similar to that used by
Lazareno and Birdsall (Br. J. Pharmacol, 1993,109: 1120) was used to determine the
test compound's ability to affect the binding of 35S-GTPγS to membranes containing
cloned human 5-HT1A receptors. Agonists produce an increase in binding whereas
antagonists produce no increase but rather reverse the effects of the standard agonist 8-
OH-DPAT. The test compound's maximum stimulatory effect is represented as the Emax,
while its potency is defined by the EC50. The test compound's maximum inhibitory effect
is represented as the Imax, while its potency is defined by the IC50. The second assay
measured cAMP accumulation upon binding of the ligand to the 5-HT1A receptor.
Antagonists block the effect of the standard agonist 8-OH-DPAT resulting in an increase
in cAMP accumulation while agonists have the reverse effect. The test compound's
maximum stimulatory or inhibitory effect is represented as the Emax while its potency is
defined by either IC50 for an antagonist or EC50 for an agonist. [3H]-8-OH-DPAT was
used to determine maximum agonist or antagonist response in both functional assays.
[0290] The results of the three standard experimental test procedures described
above were as follows:
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Example 95
8-OH-DPAT Binding in CHO Cells Stabily Transfected with Human 5HT1a
Receptor.
[0291] MATERIALS AND METHODS: Stabily transfected CHO cells are grown
in DMEM containing 10% heat inactivated FBS and non-essential amino acids. Cells are
scraped off the plate, transfered to centrifuge tubes, and washed twice by centrifugation
(2000 rpm for 10 min., 4 C) in buffer (50 mM Tris pH 7.5). The resulting pellets are
aliquoted and placed at -80 C. On day of assay, the cells are thawed on ice, and
resuspended in buffer. The binding assay is performed in a 96 well microtiter plate in a
total volume of 250 mL.
[0292] Non-specific binding is determined in the presence of 10 mM 5HT, final
ligand concentration is 1.5 nM. Following a 30 minute incubation at room temperature,
the reaction is terminated by the addition of ice cold buffer and rapid filtration through a
GF/B filter presoaked for 30 minutes in 0.5% PEL Compounds are initially tested in a
single point assay to determine percent inhibition at 1, 0.1, and 0.01 mM. Subsequently,
Ki values are determined for compounds defined to be active.
[0293] MEASUREMENTS: Percent Inhibition
Ki - as determined by RFComp (Lundon Software)
REFERENCE COMPOUNDS: Serotonin
8-OH-DPAT
Example 96
cAMP RIA in CHO Cell Stabily Transfected with the h5HT1a Receptor.
[0294] MATERIALS AND METHODS: Stabily transfected CHO cells are grown
in DMEM containing 10% heat inactivated FBS and non-essential amino acids. The cells
are plated at a density of x 10(6) cells per well in a 24 well plate and incubated for 2 days
in a CO2 incubator. On the second day, the media is replaced with 0.5 ml treatment buffer
(DMEM + 25 mM HEPES, 5 mM theophylline, 10 µM pargyline) and incubated 10
minutes at 37 C.
Wells are treated with forskolin (1 uM final cone) followed immediately by test
compound (0.1 and 1 uM for initial screen) and incubated for an additional 10 min at 37
C. Reaction is terminated by removal of the media and addition of 0.5 ml ice cold assay
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buffer (supplied in RIA kit). Plates are stored at -20 C prior to assessment of cAMP
formation by RIA.
Compounds shown to have no agonist activities are further analyzed for ability to reverse
agonist activity. In separate experiments, 6 concentrations of antagonist are preincubated
for 20 min prior to the addition of agonist and forskolin. Cells are harvested as described.
The cAMP kit is supplied by Amersham and the RIA is performed as per kit instructions.
[0295] MEASUREMENTS: Initial Screen - Percent inhibition of forskolin
stimulated cAMP
Secondary screen - IC50 of reversal of agonist activity.
CALCULATIONS: Calculations of IC50 performed by GraphPad Prism
REFERENCE COMPOUNDS: Serotonin
Buspirone
Example 97
3H-Paroxetine binding to assess affinity of drugs for the serotonin transporter:
[0296] A protocol similar to that used by Cheetham et al. (Neuropharmacol.
32:737,1993) was used to determine the affinity of compounds for the serotonin
transporter. Briefly, frontal cortical membranes prepared from male S.D. rats were
incubated with 3H-paroxetine (0.1 nM) for 60 min at 25°C. All tubes also contained
either vehicle, test compound (one to eight concentrations), or a saturating concentration
of fluoxetine (10 µM) to define specific binding. All reactions are terminated by the
addition of ice cold Tris buffer followed by rapid filtration using a Tom Tech filtration
device to separate bound from free 3H-paroxetine. Bound radioactivity was quantitated
using a Wallac 1205 Beta Plate® counter. Nonlinear regression analysis was used to
determine IC50 values which were converted to Ki values using the method of Cheng and
Prusoff (Biochem. Pharmacol. 22: 3099,1973); Ki = IC50/((Radioligand conc.)/(1 +
KD)).
[0297] Like the antidepressants fluoxetine, paroxetine and sertraline, the
compounds of this invention have the ability to block the reuptake of the brain
neurotransmitter serotonin. They are thus useful for the treatment of diseases commonly
treated by the administration of serotonin selective reuptake inhibitor (SSRI)
antidepressants, such as depression, (including but not limited to major depressive
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disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic
stress disorder, premenstrual dysphoric disorder (also known as premenstrual syndrome),
attention deficit disorder (with and without hyperactivity), obsessive compulsive disorder,
social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as
anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction,
sexual dysfunction, cognitive deficits resulting from neurodegenerative disorders like
Alzheimer's disease, and related illnesses. Moreover, some of the compounds of this
invention have potent affinity for and antagonist activity at brain 5-HT1A serotonin
receptors. Fairly recent clinical trials employing drug mixtures (e.g. fluoxetine and
pindolol) have demonstrated a more rapid onset of antidepressant efficacy for a treatment
combining SSRI activity and 5-HTIA antagonism (Blier and Bergeron, J. Clin.
Psychopharmacol., 1995,15(3): 217-22; F. Artigas et al, Trends Neurosci, 1996, 19(9):
378-83; Tome et al, J. Affect Disord, 1997,44(2-3): 101-9). The compounds of this
invention are thus interesting and useful for treating depressive illnesses.
[0298] When ranges are used herein for physical properties, such as molecular
weight, or chemical properties, such as chemical formulae, all combination and
subcombinations of ranges of specific embodiments therein are intended to be included.
[0299] The disclosure of each patent, patent application, and publication cited or
described in this document are hereby incorporated herein by reference, in their entirety.
[0300] Those skilled in the art will appreciate that numerous changes and
modifications can be made to the preferred embodiments of the invention and that such
changes and modifications can be made without departing from the spirit of the invention.
It is, therefore, intended that the appended claims cover all such equivalent variations as
fall within the true spirit and scope of the invention.
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CLAIMS
What is claimed is:
1. A compound of the Formula (I):

or a pharmaceutically acceptable salt thereof or stereoisomer thereof,
wherein
R3 is a hydrogen, hydroxyl, halogen, -(C1-C3)-alkyl, -O-(C1-C3)-alkyl, -(C3-C6)-
cycloalkyl,
-SO2R20 , or -COR20, wherein -(C1-C3)-alkyl, -O-(C1-C3)-alkyl, or -(C3-C6)-
cycloalkyl are optionally branched.
R4 and R5 are each independently hydrogen, hydroxyl, linear or branched -(C1-C6)-lkyl,
linear or branched -(C2-C6)-alkenyl, halogen, -COR14, -OR14, -SR14,
-SO2NR14R15, -NO2, -CONR14R15 or -(C3-C6)-cycloalkyl, which optionally
contains a nitrogen, oxygen or sulfur atom,
R6 is hydrogen, a linear or branched -(C1-C6)-alkyl or a linear or branched -(CH2)m-B,
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the -(C1-C6)-alkyl or -(CH2)m-B which may optionally be substituted with at least
one nitrogen or oxygen atom provided that R6 has at least two carbon atoms in
sequence directly attached to the nitrogen of Formula (I),
wherein B is a (C3-C5)-cycloalkyl, a saturated, partially saturated or aromatic (C5-
C7)-carbocyclic ring 01 a phenyl fused to a saturated, partially saturated or
aromatic (C5-C7)-carbocyclic ring, wherein the cycloalkyl, phenyl or carbocyclic
ring is optionally substituted by one to two substituents per ring, wherein said
substituents are independently selected from the group consisting of halogen,
cyano, -(C1-C6)-alkyl, -(C2-C6)-alkenyl, -(C2-C6)-alkynyl,- (C3-C7)-carbocycle, -
(C1-C6)-alkoxy, —OCF3, -(C6-C10)-aryl and -(C2-C9)-heterocycle; further wherein
one or two ring atoms in the cycloalkyl, phenyl or carbocyclic ring may optionally
be replaced by nitrogen, oxygen or sulfur, and
m is a number from 0 to 7;
R7 is selected from linear or branched -(C1-C6)-alkylene-, linear or branched -(C2-C6)-
alkenylene- or-(CH2)p-(C3-C6)-cycloalkyl-(CH2)q-, each of which is optionally
substituted with a halogen or hydroxyl,
wherein at least one ring atom of the -(C3-C6)-cycloalkyl is optionally replaced
with a nitrogen, sulfur or oxygen, and at least two ring atoms of the alkylene,
alkenylene or cycloalkyl are carbon atoms, and
p and q are each independently 0,1 or 2;
Q is selected from -(C1-C3)-alkylene-, -O-(C1-C2)-alkylene-, -(C2-C3)-alkenylene-, or
-O-(C2)-alkenylene-,
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wherein the alkylene or alkenylene is optionally substituted with a -(C1-C3)-alkyl
or a halogen, and wherein for -O-(C1-C2)-alkylene- or -O-(C2-C3)-alkenylene-,
the O is directly attached to the phenyl ring;
A is

R6, R8,R9, R10, and R11 are each independently hydrogen, cyano, carboxamido,
carboalkoxy, trifluoromethyl, hydroxyl, linear or branched -(C1-C6)-alkyl, linear
or branched
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-(C2-C6)-alkenyl, halogen, -OCF3, aikanoyloxy, alkanamido, alkanesulfonyl,
alkanesulfonamido, phenyl,-NR16R17,-, -COR16, -OR16, -SR16, -OR16, or
-NO2,
X and Y are each independently -CR18R19-, -O-, -NR18- or -S-;
Z1 is carbon or nitrogen, Z2 is carbon and Z3 is carbon, nitrogen, oxygen or sulfur;
wherein at least one of Z1 and Z3 is not carbon, wherein a double bond is
optionally present between Z1 and Z2, wherein A1 is attached to R7 through Z1, Z2
or Z3 except when Z3 is oxygen, and further wherein when R7 is linked to Z3, then
Z3 is nitrogen;
R12 and R13 are each independently hydrogen or a linear or branched -(C1-C6)-alkyl,
wherein R12 and R13 may be attached at any of Z1, Z2 or Z3, and further wherein
R13 is optionally present at Z1 or Z2 when Z3 is oxygen;
R14, R15, R16, R17, R18 and R19 are each independently hydrogen, hydroxyl, halogen, a
linear or branched (C1-C6)-alkyl or a linear or branched (C2-C6)-alkenyl;
R20 is a hydrogen, a linear or branched (C1-C6)-alkyl or a (C3-C7)-cycloalkyl;
and the dotted lines represent optional double bonds.
2. The compound according to claim 1 of Formula (I), wherein Y is -NH-.
3. The compound according to claim 1 of Formula (I), wherein Y is -O-.
4. The compound according to any one of claims 1 to 3 of Formula (I), wherein X is
-O-.
5. The compound according to any one of claims 1 to 4 of Formula (I), wherein R6 is
-(CH2)m-B, m is 0 or 1, and B is a C3-C6-cycloalkyl.
6. The compound according to any one of claims 1 to 4 of Formula (I), wherein R6 is
a linear C2-C4-alkyl.
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7. The compound according to any one of claims 1 to 4 of Formula (I), wherein R6 is
a branched C3-C5-alkyl.
8. The compound according to any one of claims 1 to 4 of Formula (I), wherein R6 is
-(CH2)m-B, m is 0 or 1, and B is an aromatic (C5-C7)-carbocyclic ring or a phenyl fused to
a saturated, partially saturated or aromatic (C5-C7)-carbocyclic ring.
9. The compound according to claim 8 of Formula (I), wherein the (C5-C7)-
carbocyclic ring comprises a —O—.
10. The compound according to claim 8 or claim 9 of Formula (I), wherein R6 is -
(CH2)m-B, m is 2,3 or 4, and B is a phenyl fused to a saturated, partially saturated or
aromatic (C5-C7)-carbocyclic ring.
11. The compound according to claim 10 of Formula (I), wherein the (C5-C7)-
carbocyclic ring comprises a —NH—.
12. The compound according to claim 11 of Formula (I), wherein the (C5-C7)-
carbocyclic ring is substituted with at least one fluorine atom.
13. The compound according to any one of claims 1 to 12 of Formula (I), wherein A
is
14. The compound according to claim 13 of Formula (I), wherein Z3 is -NH.
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15. The compound according to any one of claims 1 to 12 of Formula (I), wherein A
is

16. The compound according to claim 15 of Formula (I), wherein Z3 is -NH-.
17. The compound according to any one of claims 1 to 12 of Formula (I), wherein A
is
18. The compound according to claim 17 of Formula (I), wherein Y is -NH-.
19. The compound according to any one of claims 1 to 18 of Formula (I), wherein R7
is a linear C1-C4 alkyl.
20. The compound according to any one of claims 1 to 19 of Formula (I), wherein at
least one of R5, R8, R9, R10 and R11 is fluorine.
21. The compound according to any one of claims 1 to 20 of Formula (I), wherein R3
is -CH3.
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22. The compound according to any one of claims 1 to 21 of Formula (I), wherein Q
is-CH2-or-(CH2)2-.
23. The compound according to any one of claims 1 to 21 of Formula (I), wherein Q
is -O-(CH2)- or -O-(CH2)2-.
24. The compound according to any one of claims 1 to 21 of Formula (I), wherein Q
is -CH2=CH2- or -O-CH2=CH2-.
25. The compound according to any one of claims 1 to 24 of Formula (I), wherein R4
or R5 is -O-CH2 or -NO2.
26. The compound according to any one of claims 1 to 18 of Formula (I), wherein R7
is
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27. The compound according to any one of claims 1 to 18 of Formula (I), wherein R7
is
-(CH3)p-(C3-C6)-cycloalkyl-(CH3)q-, and p and q are not both 0.
28. The compound according to any one of claims 1 to 27 of Formula (I), wherein R10
is a nitrile group.
29. The compound according to claim 13 of Formula (I), wherein A is

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30. The compound according to claim 13 of Formula (I), wherein A is

31. A compound according to claim 1, of Formula (1a):

wherein R3, R4, R5, R6, R7, R8,R9, R10 and R11, are as previously defined.
32. A compound according to claim 1, of Formula (Ib):
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wherein R3, R4, R5, R6, R7, R8, R9, R10 and R11, are as previously defined.
33. A compound according to claim 1, wherein the compound is:
8-{[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-1 (7H)-one;
(8S)-8-{[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-1 (7H)-one;
(8R)-8-{[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-1 (7H)-one;
8-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
(8S)-8-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
(8R)-8- {(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino} -2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{cyclobutyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano
[3,2-e]isoindol-1(7H)-one;
8-{(cyclobutylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
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8-{(cyclobutylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-[[3-(5-fluoro-1H-indol-3-yl)propyl](methyl)amino]-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one
8-{ethyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-1(7H)-one;
8-[[3-(5-fluoro-1H-indol-3-yl)propyl](isobutyl)amino]-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{(cyclohexylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{benzyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-1(7H)-one;
8-[[3-(5-fluoro-1H-indol-3-yl)propyl](3-furylmethyl)amino]-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1 (7H)-one;
8-{[3-(5,7-difluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-1(7H)-one;
8-{cyclobutyl[3-(5,7-difluoro-1H-indol-3-yl)propyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
3-{3-[(1-oxo-1,2,3,7,8,9-hexahydropyrano[3,2-e]isoindol-8-yl)amino]propyl}-1H-
indole-5-carbonitrile;
3-{3-[(cyclopropylmethyl)(1-oxo-1,2,3,7,8,9-hexahydropyrano[3,2-e]isoindol-8-
yl)amino]propyl}-1H-indole-5-carbonitrile;
3-(3-{(cyclopropylmethyl)[(8S)-1-oxo-l,2,3,7,8,9-hexahydropyrano[3,2-
e]isoindol-8-yl]amino}propyl)-1H-indole-5-carbonitrile;
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3-(3-{(cyclopropylmethyl)[(8R)-1-oxo-l,2,3,7,8,9-hexahydropyrano[3,2-
e]isoindol-8-yl]amino}propyl)-1H-indole-5-carbonitrile;
8-{[4-(5-fluoro-1H-indol-3-yl)butyl] amino}-2,3,8,9-tetrahydropyrano[3,2-
e]isoindol-1(7H)-one;
8-{(cyclopropylmethyl)[4-(5-fluoro-1H-indol-3-yl)butyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{[(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methyl]amino}-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2-methyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]arnino}-2-methyl-
2,3,8,9-tetrahydropyrano [3,2-e]isoindol-1 (7H)-one;
(8S)-8-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2-methyl-
2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
(8R)-8-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2-methyl-
2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-[[3-(5-fluoro-1H-indol-3-yl)propyl](methyl)amino]-2-methyl-2,3,8,9-
tetrahydropyrano [3,2-e] isoindol-1 (7H)-one;
8-{ethyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2-methyl-2,3,8,9-
tetrahydropyrano [3,2-e]isoindol-1 (7H)-one;
8-[[3-(5-fluoro-1H-indol-3-yl)propyl](isobutyl)amino]-2-methyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{cyclobutyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-2-methyl-2,3,8,9-
tetrahydropyrano [3,2-e] isoindol-1 (7H)-one;
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8- {(cyclobutylmethyl) [3-(5-fluoro-1H-indol-3-yl)propyl] amino} -2-methyl-
2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
3-{3-[(2-methyl-1-oxo-l,2,3,7,8,9-hexahydropyrano[3,2-e]isoindol-8-
yl)amino]propyl}-1H-indole-5-carbonitrile;
3-{3-[(cycIopropylmethyl)(2-methyl- 1-oxo-1,2,3,7,8,9-hexahydropyrano[3,2-
e]isoindol-8-yl)amino]propyl}-1H-indole-5-carbonitrile;
8-{[3-(5,7-difluoro-1H-indol-3-yl)propyl]amino}-2-methyl-2,3,8,9-
tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8-{(cyclopropylmethyl)[3-(5,7-difluoro-1H-indol-3-yl)propyl]amtno}-2-methyl-
2,3,8,9-tetrahydropyrano [3,2-e]isoindol-1(7H)-one;
8-{[(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methyI]amino}-2-methyl-
2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one;
8- {(cyclopropylmethyl)[(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-
yl)methyl] amino}-2-methyl-2,3,8,9-tetrahydropyrano [3,2-e]isoindol-1 (7H)-one;
8-[cyclobutyl[(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methyl]amino}-2-
methyl-2,3,8,9-tetrahydropyrano [3,2-e] isoindol-1 (7H)-one;
9-{[3-(5-fluoro-1H-indol-3-yl)propyl3amino}-3,4,9,10-tetrahydro-2H-pyrano[2,3-
h]isoquinolin-1 (8H)-one;
9-[[3-(5-fluoro-1H-indol-3-yl)propyl](methyl)amino]-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one;
9-{ethyl[3-(5-fluoro-1H-indol-3-yl)propyl] amino }-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one;
9-[[3-(5-fluoro-1H-indol-3-yl)propyl](propyl)amino]-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one;
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9-[[3-(5-fluoro-1H-indol-3-yl)propyl](isobutyl)amino]-3,4,9,l0-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one;
9-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-
tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one;
9-{cyclobutyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one;
9- [[3-(5-fluoro-1H-indol-3-yl)propyl] (isopropyl)amino] -3,4,9,10-tetrahydro-2H-
pyrano [2,3 -h]isoquinolin-1(8H)-one;
9-{benzyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one;
9-[[3-(5-fluoro-1H-indol-3-yl)propyl](pyridin-4-ylmethyl)amino]-3,4,9,10-
tetrahydro-2H-pyrano[2,3-h]isoquinolin-l(8H)-one;
9-[[3-(5-fluoro-1H-indol-3-yl)propyl](3,3,3-trifluoropropyl)amino]-3,4,9,10-
tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one;
6-fluoro-9-{[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-3,4,9,10-tetrahydro-2H-
pyrano[2,3-h]isoquinolin-1(8H)-one;
9-{(cyclopropylmethyl)[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-6-fluoro-
3,4,9,10-tetrahydro-2H-pyrano[2,3-h]isoquinolin-1(8H)-one; or
9-{ethyl[3-(5-fluoro-1H-indol-3-yl)propyl]amino}-6-fluoro-3,4,9,10-tetrahydro-
2H-pyrano [2,3 -h]isoquinolin-1(8H)-one;
8-{Cyclopropylmethyl-[3-(5-fluoro-3-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-
cyclobutyl]-amino}-5-methoxy-2,3,8,9-tetrahydro-7H-pyrano[3,2-e]isoindol-1-
one; or
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8{Cyclopropylmethyl-[3-(5-fluoro-3-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-
cyclobutyl]amino}-5-fluoro-2,3,8,9-tetrahydro-7H-pyrano[3,2-e]isoindol-1-one;
8-{Cyclopbutylmethyl-[3-(5-fluoro-3-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-
cyclobutyl]-amino}-5-methoxy-2,3,8,9-tetrahydro-7H-pyrano[3,2-e]isoindol-1-
one; or
8-{Cyclobutylmethyl-[3-(5-fluoro-3-methyl-2,3-dihydro-1H-indol-3-ylmethyl)-
cyclobutyl]-amino}-5-fluoro-2,3,8,9-tetrahydro-7H-pyrano[3,2-e]isoindol-1-one,
or pharmaceutically acceptable salt thereof.
34. A composition of matter comprising at least one compound according to any one
of claims 1 to 33 or 53 to 58 of Formula (I) and a pharmaceutically acceptable
carrier therefore.
35. A method of treating a central nervous system disorder in a patient comprising
administering to a patient in need of such treatment a compound according to any
one of claims 1 to 33 or 53 to 58 in an amount effective for treating said disorder.
36. A method of inhibiting a serotonin receptor in a patient comprising administering
to a patient in need of such treatment a compound according to any one of claims
1 to 33 or 53 to 58 in an amount effective for inhibiting said receptor.
37. A method of modulating activity of a 5-HT1A receptor in a patient comprising
administering to a patient in need of such treatment a compound according to any
one of claim 1 to 33 or 53 to 58 in an amount effective for modulating said
activity.
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38. A method of antagonizing a 5-HT1A receptor in a patient comprising administering
to a patient in need of such treatment a compound according to any one of claims
1 to 33 or 53 to 58 in an amount effective for antagonizing said receptor.
39. A method of binding a 5-HT1A receptor in a patient comprising administering to a
patient in need of such treatment a compound according to any one of claims 1 to
33 or 53 to 58 in an amount effective for binding said receptor.
40. A method of modulating serotonin reuptake in a patient comprising administering
to a patient in need of such treatment a compound according to any one of claims
1 to 33 or 53 to 58 in an amount effective for modulating said activity.
41. A method of making a compound according to any one of claims 1 to 33 or 53 to
58 of Formula (I), wherein said method comprises
(a) nitrating a compound of formula (II)

(b) reducing the compound to provide a compound of formula (III)

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(c) subjecting the compound of formula (III) to reductive amination with an
aldehyde of formula (IV)

wherein R2 is the corresponding aldehyde of R7 under conditions sufficient to produce a
compound of formula

wherein said compound of formula (V) is optionally subjected to an alkylation in the
presence of a base under conditions effective to produce a compound of formula (VI)

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or is optionally subjected to a reductive amination by reacting with a compound of
formula R6CHO to produce a compound of forumula (VII)

42. A method of making a compound according to claim 1 of Formula (I), wherein
said method comprises
(a) combining a compound of formula (III)

with a compound of formula (VIII)

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wherein R2 is the corresponding amine of R7, under conditions sufficient for reductive
amination;
(b) combining the product of (a) with a compound of formula R6CHO under
conditions for reductive amination,
to obtain a compound of formula (IX)

43. A method according to claim 41, wherein said method further comprises the step
of alkylating the compound of formula (IT) with an alkyl halide under conditions
sufficient to produce a compound of formula (IIa)

prior to step (b), wherein R3 is a -(C1-C3)-alkyl.
44. A method of making a compound of formula (XII)
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wherein said method comprises
(a) subjecting a compound of formula (X)

to a rearrangement reaction under conditions sufficient to produce a compound of formula
(XI)
(b) isolating the compound of formula (XI),
(c) deprotecting the compound of formula (XI) to produce a compound of
formula (XII)
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wherein R4 and R5 are each independently hydrogen, hydroxyl, linear or branched -(C1-
C6)-alkyl, linear or branched -(C2-C6)-alkenyl, halogen, -COR14, -OR14, -SR14,
-SO2NR14R15, -NO2, -CONR14R15 or -(C3-C6)-cycloalkyl, which optionally
contains a nitrogen, oxygen or sulfur atom, and
R14 and R15 are each independently hydrogen, hydroxyl, halogen, a linear or branched
(C1-C6)-alkyl or a linear or branched (C2-C6)-alkenyl.
45. The method according to claim 44, further comprising
subjecting the compound of formula (XII) to a propargylating reaction under
conditions sufficient to produce a compound of formula (XIIa)

subjecting the compound of formula (XIIa) to a cyclization reaction under
conditions sufficient to produce a compound of formula (XIII)
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46. A method of making a compound according to claim 1 of Formula (I), wherein
said method comprises
(a) nitrating a compound of formula (XIII)

(b) reducing the compound to produce a compound of formula (XIV)

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and
(c) subjecting the compound of formula (XIV) to reductive amination with an
aldehyde of forumula (IV)

wherein R2 is the corresponding aldehyde of R7 under conditions sufficient to produce a
compound of formula (XV)

wherein said compound of formula (XV) is optionally subjected to an alkylation in the
presence of a base under conditions effective to produce a compound of formula (XVI)

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(XVI)
wherein R6 is a -(C1-C3)-alkyl,
or is optionally subjected to a reductive amination by reacting with a compound of
formula R6CHO to produce a compound of formula (XVH)

wherein R6 is as defined in claim 1.
47. A method of making a compound according to claim 1 of Formula (I), wherein
said method comprises
(a) combining a compound of formula (XIV)

with a compound of formula (VET)
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under conditions for reductive amination;
(b) combining the product of (a) with a compound of formula R6CHO under
conditions for reductive amination,
to obtain a compound of formula (XVI)

48. A method of making a compound of formula (IIb)
comprising
(a) protecting a carboxylic acid of formula (XVII)
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wherein R1 is -Br, -Cl or -OSO2CF3,
R4 and R5 are each independently hydrogen, hydroxyl, linear or branched -(C1-C6)-aIkyl,
linear or branched -(C2-C6)-alkenyl, halogen, -COR14, -OR14, -SR14,
-SO2NR14R15, -NO2, -CONR14R15 or -(C3-C6)-cycloalkyl, which optionally
contains a nitrogen, oxygen or sulfur atom, wherein R14 and R15 are each
independently hydrogen, hydroxyl, halogen, a linear or branched (C1-C6)-alkyl or
a linear or branched (C2-C6)-alkenyl,
and R3 is a hydrogen, hydroxyl, halogen, -(C1-C3)-alkyl, -O-(C1-C3)-alkyl, -(C3-C6)-
cycloalkyl, -SO2R20 , or -COR20, wherein -(C1-C3)-alkyl, -O-(C1-C3)-alkyl, or
—(C3-C6)-cycloalkyl are optionally branched;
by alkylation under conditions sufficient to produce a compound of formula (XVII)

(b) replacing R1 with a methyl group to produce a compound of formula
(XIX)

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(XIX)
(c) halogenating the compound of formula (XIX) and heating under
conditions sufficient to produce a compound of formula (XX)

(d) deprotecting the compound of formula (XX) under conditions sufficient to
produce a compound of formula (XXI)

(e) propargylating under conditions sufficient to produce a compound of
formula (XXII)

(f) subjecting the compound of formula (XXII) to a cyclization reaction under
conditions sufficient to produce a compound of formula (IIb)
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49. A method for making a compound of formula (XXIH)

comprising
(a) reacting a compound of formula (XXIV)

with a compound of formula (XXV)

under conditions sufficient to produce a compound of formula (XXVI)
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(b) reducing the compound of formula (XXVI) to produce a saturatured
methyl ester of formula (XXVII)

(c) hydrolyzing the ester under conditions sufficient to provide a carboxylic
acid of formula (XXVIII)
(d) cyclyzing the carboxylic acid by heating in the presence of a Lewis acid
under conditions sufficient to provide a compound of formula (XXIX)
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wherein R4 and R5 are each independently hydrogen, hydroxyl, linear or branched -(C1-
C6)-alkyl, linear or branched -(C2-C6)-alkenyl, halogen, -COR14, -OR14, -SR14,
-SO2NR14R15, -NO2, -CONR14R15 or -(C3-C6)-cycloalkyl, which optionally
contains a nitrogen, oxygen or sulfur atom, wherein R14 and R15 are each
independently hydrogen, hydroxyl, halogen, a linear or branched (C1-C6)-alkyl or
a linear or branched (C2-C6)-alkenyl.
50. A method for making a compound of formula (XXXI)

said method comprising the steps of
(a) subjecting the compound of formula (XXIX) to a rearrangement reaction
under reaction conditions sufficient to produce a compound of formula (XXX)
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(b) isolating the compound of formula (XXX),
(c) deprotecting the compound of formula (XXX) to produce a compound of
formula (XXXI)
wherein R4 and R5 are each independently hydrogen, hydroxyl, linear or branched -(C1-
C6)-alkyl, linear or branched -(C2-C6)-alkenyl, halogen, -COR14, -OR14, -SR14,
-SO2NR14R15, -NO2, -CONR14R15 or -(C3-C6)-cycloalkyl, which optionally
contains a nitrogen, oxygen or sulfur atom, wherein R14 and R15 are each
independently hydrogen, hydroxyl, halogen, a linear or branched (C1-C6)-alkyl or
a linear or branched (C2-C6)-alkenyl.
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51. A compound as claimed in any one of claims 1 to 33 or 53 to 58 for use as a
medicament.
52. Use of a compound as claimed in any one of claims 1 to 33 or 53 to 58 in the
preparation of a medicament for the treatment of a central nervous system disorder
in a patient, the inhibition of a serotonin receptor in a patient, the modulation of
the activity of a 5-HT1A receptor in a patient, the antagonizion of a 5-HT1A
receptor in a patient, binding a 5-HT1A receptor in a patient, or the modulation of
serotonin reuptake in a patient.
53. A compound according to claim 1, of Formula (Ic):

wherein R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are as previously defined.
54. The compound of claim 53, wherein at least one R3, R4, R5, R6, R7, R8, R9, R10 and
R11 are defined as follows: R3, R4,R8,R9 and R11 are hydrogen; Rsis -OCH3 or fluorine;
R6 is -(CH2)n-B, with -B being a -(C3-C5)-cycloalkyl; R7 is -(CH2)p-(C3-C6)-cycloalkyl-
(CH2)q-; R10 is a halogen; and R12 is a -(C1-C6)-alkyl.
55. The compound of claim 54, wherein for B, p is 0 and q is 1 or p is 1 and q is 0,
and the cycloalkyl is cyclobutyl.
56. The compound of claim 54, wherein R5 is -OCH3.
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57. The compound of claim 54, wherein R10 is fluorine.
58. The compound of claim 54, wherein R12 is a methyl or ethyl group.
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3-Amino chroman and 2-amino tetralin derivatives and compositions containing such compounds are disclosed. Such compounds are useful for modulating activity of a 5-HT1A receptor (agonizing or antagonizing) in a patient. These compounds are further useful for inhibiting binding to a serotonin receptor. Methods of using the 3-amino chroman and 2-amino tetralin compounds and compositions containing such compounds in the treatment of serotonin disorders, such as depression and anxiety, are
also disclosed.