This application is divided out of the Indian Patent Application no.: 423/KOLNP/2005
Cross-Reference to Related Applications
[0001] This application is a continuation-in-part application of U.S. Application
Serial No. 60/410,072, filed September 12, 2002, the disclosure of which is
incorporated herein by reference in its entirety.
Field of the Invention
[0002] This invention relates to antidepressant cycloalkylamine derivatives of
heterocycle-fused benzodioxans, to processes for preparing them, methods of
using them and to pharmaceutical compositions containing them.
Background of the Invention
[0003] Major depression is a serious health problem affecting more than 5% of
the population, with a lifetime prevalence of 15-20%.
[0004] Selective serotonin reuptake inhibitors have produced success in
treating depression and related illnesses and have become among the most
prescribed drugs. They nonetheless have a slow onset of action, often taking
several weeks to produce their full therapeutic effect. Furthermore, they are
effective in less than two-thirds of patients.
[0005] Serotonin selective reuptake inhibitors (SSRIs) are well known for the
treatment of depression and other conditions. SSRIs work by blocking the
neuronal reuptake of serotonin, thereby increasing the concentration of serotonin
in the synaptic space, and thus increasing the activation of postsynaptic serotonin
receptors.
-1A-

[0006] However, although a single dose of an SSRI can inhibit the neuronal
serotonin transporter which would be expected to increase synaplic serotonin,
long-term treatment is required before clinical improvement is achieved.
[0007] It has been suggested that the SSRIs increase the serotonin levels in
the vicinity of the serotonergic cell bodies and that the excess serotonin activates
somatodendritic autoreceptors, 5HT1A receptors, causing a decrease in serotonin
release in major forebrain areas. This negative feedback limits the increment of
synaptic serotonin that can be induced by antidepressants.
[0008] A 5HT1A antagonist would limit the negative feedback and should
improve the efficacy of the serotonin reuptake mechanism (Perez, V., et al., The
Lancet, 349:1594-1597 (1997)). Such a combination therapy would be expected
to speed up the effect of the serotonin reuptake inhibitor.
[0009] Thus, it is highly desirable to provide improved compounds which both
inhibit serotonin reuptake and which are antagonists of the 5HTiA receptor.
Description of the Invention
[0010] In accordance with this invention, there is provided a group of novel
compounds of the formula:

wherein
R1 is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6
carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy
of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each
-2-

alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon
atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
R2 is hydrogen or alkyl of 1 to 6 carbons;
the group X—Y is -N=C(R3)-C(R4)=N-, -N=C(R3)-C(R5)=CH-, -N=C(R3)-
N=CH-, -N=C(R3)-O-, -NH-C(R6)=N- or -NH-C(R7)=CH-;
R3 and R4 are, independently, hydrogen, halo, amino, mono- or di-
alkylamino in which each alkyl group has 1 to 6 carbon atoms or alkyl of
1 to 6 carbon atoms;
R5 is hydrogen or alkyl of 1 to 6 carbon atoms;
R6 is hydrogen, halo, trifluoromethyl, pentafluoroethyl, amino, mono- or di-
alkylamino in which each alkyl group has 1 to 6 carbon atoms or alkyl of
1 to 6 carbon atoms;
R7 is hydrogen, halo, trifluoromethyl, pentafluoroethyl or allcyl of 1 to 6
carbon atoms;
m is 1 to 3;
n is 1 to 2;
p is 0 to 3;
Q is a heteroaryl moiety selected from the following:

wherein Z is NR12, S, or O;
R8, R9, R10, and R11 are, independently, hydrogen, hydroxy, halo, cyano,
carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl
of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino,
mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon
atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to
6 carbon atoms; and
R12 is hydrogen or alkyl of 1 to 6 carbon atoms;
-3-

or pharmaceutically acceptable salts thereof.
[0011] R1 is preferably hydrogen, halo, cyano, trifluoromethyl, alkyl of 1 to 6
carbon atoms or alkoxy of 1 to 6 carbon atoms. More preferably, R1 is hydrogen,
halo or alkoxy of 1 to 6 carbon atoms. In still more preferred embodiments of the
present invention, R1 is hydrogen.
[0012] R2 and R5 are preferably independently selected from hydrogen or alkyl
of 1 to 3 carbon atoms.
[0013] Preferably, the group X-Y is -N=C(R3)-C(R5)=CH- or -N=C(R3)-O-.
[0014] R3 and R4 are preferably independently selected from hydrogen, amino
or alkyl of 1 to 6 carbon atoms. More preferably, R3 and R4 are independently
hydrogen or alkyl of 1 to 3 carbon atoms.
[0015] R6 and R7 are preferably independently selected from hydrogen,
trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6 carbon atoms. More preferably,
R6 and R7 are independently hydrogen, trifluoromethyl or alkyl of 1 to 3 carbon
atoms.
[0016] R8, R9, R10, and R11 are preferably independently selected from
hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of 1 to 6 carbon atoms, or
alkoxy of 1 to 6 carbon atoms. In still more preferred embodiments of the present
R8, R9, R10, and R11 are preferably independently selected from hydrogen, cyano
or halogen.
[0017] Z is preferably NR12. When Z is NR12, R12 is preferably hydrogen or alkyl
of 1 to 3 carbon atoms.
[0018] The integers m and n are independently preferably 1 or 2. More
preferably, m is 1 and n is 2.
-4-

[0019] The integer p is preferably 0 or 1. More preferably, p is 0.
[0020] Preferably, Q is a heteroaryl moiety of the formula

wherein R1, R2, R3, R8, R9, R10, R11, and R12 are as described above.
-5-

[0023] This invention relates to both the R and S stereoisomers of the
benzodioxan methylamines as well as to mixtures of the R and S stereoisomers.
Throughout this application, the name of the product of this invention, where the
absolute configuration of the compounds of the invention is not indicated, Is
intended to embrace the individual R and S enantiomers as well as mixtures of
the two. In some embodiments of the present invention the S enantiomer is
preferred. For certain of the compounds of the invention (i.e., X—Y forms an
imidazole), tautomeric forms may exist. This application thus encompasses all
tautomeric forms of compounds of the present invention.
[0024] It will be recognized that the substituents on di-substituted cycloalkyl
rings may be arranged with cis or trans relative stereochemistry. It will be further
recognized that when n is 1, the cyclopentyl moiety of the present invention
contains two asymmetric carbon atoms. Thus, in addition to cis and trans
isomers, additional stereoisomers are possible for the cyclopentylamine moiety.
This application thus encompasses all stereoisomers, individually or as mixtures,
of the cycloalkylamine moiety. Furthermore, this application relates to all possible
diastereomers, individually or as mixtures, of the compounds of the present
invention.
[0025] Where a single stereoisomer is preferred, it may, in some embodiments
be provided substantially free of the corresponding enantiomer or diastereomers.
Thus, a single stereoisomer substantially free of the corresponding enantiomer or
diastereomers refers to a compound which is isolated or separated via separation
techniques or prepared free of the corresponding enantiomer or diastereomers.
"Substantially free," as used herein, means that the compound is made up of a
significantly greater proportion of one stereoisomer. In preferred embodiments
the compound is made up of at least about 90% by weight of a preferred
stereoisomer. In other embodiments of the invention, the compound is made up
of at least about 99% by weight of a preferred stereoisomer. Preferred
stereoisomers may be isolated from racemic mixtures or diastereomeric mixtures
by any method known to those skilled in the art, including high performance liquid
-6-

chromatography (HPLC) and the formation and crystallization of chiral salts or
prepared by methods described herein. See, for example, Jacques, ef a/.,
Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981);
Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L Stereochemistry of
Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving
Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame
Press, Notre Dame, IN 1972).
[0026] "Alkyl," as used herein, refers to an aliphatic hydrocarbon chain and
includes straight and branched chains such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and
isohexyl. "Lower alkyl" refers to alkyl having 1 to 3 carbon atoms.
[0027] "Alkanamido," as used herein, refers to the group R-C(=O)-NH- where R
is an alkyl group of 1 to 5 carbon atoms.
[0028] "Alkanoyloxy," as used herein, refers to the group R-C(=O)-O- where R
is an alkyl group of 1 to 5 carbon atoms.
[0029] "Alkanesulfonamido," as used herein, refers to the group R-S(O)z-NH-
where R is an alkyl group of 1 to 6 carbon atoms.
[0030] "Alkoxy," as used herein, refers to the group R-O- where R is an alkyl
group of 1 to 6 carbon atoms.
[0031] "Carboxamido," as used herein, refers to the group NH2-C(=O)- .
[0032] "Carboalkoxy," as used herein refers to the group R-O-C(=O)- where R
is an alkyl group of 1 to 5 carbon atoms.
[0033] "Halogen" (or "halo"), as used herein refers to chlorine, bromine, fluorine
and iodine.
-7-

[0034] Pharmaceutically acceptable salts are those derived from such organic
and inorganic acids as: acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric,
maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, '
phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic,
toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids.
[0035] Specific examples of compounds of Formula I are:
N-[(cis)-3-(1H-indol-3-yl)cyclopentyl]-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl]amine;
N-[(trans)-3-(1H-indol-3-yl)cyclopentyl]-N-{[(2S)-8-methyi-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine;
N-[(cis)-3-(5-fluoro-1H-indol-3-yl)cyclopentyl]-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine;
N-[(1R,3S)-3-(5-f!uoro-1H-indol-3-yl)cyclopentyl]-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine;
N-[(1S,3R)-3-(5-fluoro-1H-indo!-3-yl)cyclopentyl]-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine;
N-[(trans)-3-(5-fluoro-1H-indol-3-yl)cyclopentyl]-N-{t(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine;
N-[(1R,3R)-3-(5-fluoro-1H-indol-3-yl)cyclopentyl]-N-{[(2S)-8-methyI-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine;
N-[(1S,3S)-3-(5-fluoro-1H-indol-3-yl)cyclopentyl]-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine;
-8-

N-[(cis)-3-(5-f!uoro-1H-indoi-3-yl)cyclopentyl]-N-methyl-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine;
N-[(cis)-3-(5-fluoro-1-methyl-1H-indol-3-yl)cyc!opentyl]-N-{[(2S)-8-methyl-2I3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine;
N-[(1 R,3S)-3-(5-f!uoro-1 -methyl-1 H-indol-3-yl)cyclopentyn-N-{[(2S)-8-methy!-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine;
N-[(1 S,3R)-3-(5-fluoro-1 -methyl-1 H-indol-3-yl)cyclopentyl]-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quino!in-2-yl]methyl}amine;
N-[(trans)-3-(5-f!uoro-1-methyl-1H-indol-3-yl)cyc!opentyl]-N-{[(2S)-8-methyJ-2,3-
dihyro[1,4jdioxino[2,3-flquinolin-2-yl]methyl}amine;
N-[(cis)-4-(5-f!uoro-1HHndol-3-yl)cyclohexyl]-N-{[(2S)-8-methy!-2,3-
dihydro[1,4]dioxino[2,3-f]quino!in-2-y!]methyl}amine;
N-[(trans)-4-(5-fluoro-1H-indol-3-yl)cyclohexyl]-N-{[(2S)-8-methyl-2,3-
dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine;
N-[(trans)-3-(5-Fluoro-1H-indol-3-yi)cyclopenlyF]-N-{[(8S)-2-methyl-7,8-
dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-y]]methyl}amine;
N-[(cis)-3-(5-Fluoro-1H-indol-3-yl)cyclopentyl]-N-{[(8S)-2-methyl-7,8-
dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl}amine;
N-[(cis)-4-(5-fluoro-1H-indol-3-yl)cyclohexyl]-N-{[(8S)-2-methyl-7,8-
dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-yl]methyl}amine;
N-[(1R*,3S*)-3-(5-fluoro-1H-indol-3-y!)cyclopentyl]-N-methyl-N-{[(2S)-8-niethy!-
2,3-dihydro[1,4]-dioxino[2,3-f]quinolin-2-yl]methyl}amine;
-9-

and pharmaceutically acceptable salts thereof.
[0036] In another aspect, the invention relates to a method of treating a subject
suffering from a condition selected from depression, anxiety, panic disorder, post-
traumatic stress disorder, premenstrual dysphoric disorder, attention deficit
disorder, 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, and sexual
dysfunction which comprises providing to the subject suffering from said
condition, a therapeutically effective amount of a compound of the invention or a
pharmaceutically acceptable salt thereof.
[0037] In a further aspect, the invention relates to a pharmaceutical
composition comprising an effective amount of a compound of the invention or a
pharmaceutically acceptable salt thereof and a pharmaceutically acceptable
carrier or excipient.
[0038] In a further aspect, the invention relates to a compound of the invention
or a pharmaceutically acceptable salt thereof for use as a medicament.
[0039] In a still further aspect, the invention relates to the use of a compound of
the invention or a pharmaceutically acceptable salt thereof in the preparation of a
medicament for the treatment of depression, anxiety, panic disorder, post-
traumatic stress disorder, premenstrual dysphoric disorder, attention deficit
disorder, 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, and sexual
dysfunction.
[0040] Compounds of the present invention are suitably prepared in accordance
with the following general description and specific examples. Variables used are
as defined for Formula I, unless otherwise noted. Specifically (Scheme 1), the
appropriately substituted cycloalkylamine is combined with a suitably substituted
-10-

benzodioxan methyltosylate in a solvent such as dimethyl sulfoxide and heated to
a temperature of 70-100°C for several hours as illustrated below.

[0041] Alternatively compounds of the present invention may be prepared as
shown in Scheme 2 below. Specifically, a suitably substituted benzodioxan
methyltosylate or bromide is converted the corresponding azide by reaction with
sodium or potassium azide in an appropriate solvent such as dimethylformamide
or dimethylsulfoxide. The azide is then conveniently reduced to the primary
amine by methods known to those skilled in the art, such as hydrogenation over
palladium on carbon., The amine is then combined with an appropriately
substituted cycloalkanone in the presence of a reducing agent such as sodium
triacetoxyborohydride or sodium cyanoborohydride to give the compounds of the
invention wherein R2 is hydrogen:
-11 -


[0042] Compounds in which R2 is alkyl may be prepared as in Scheme 1 above,
or may be alternatively prepared from compounds of Formula I in which R2 is
hydrogen by reaction with a suitable aldehyde or ketone in the presence of a
reducing agent such as sodium triacetoxy borohydride or sodium
cyanoborohydride, as shown in Scheme 3.

[0043] The 2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethyltosylates (11) in
which R3 is H can be prepared as illustrated in Scheme 4 below. Specifically, the
appropriately substituted nitroguaiacol (5) is alkylated with allyl bromide in the
presence of a suitable base such as sodium hydride to produce (6) and then
-12-

demethylated by a reagent such as sodium hydroxide. The resulting 4-nitro-2-
allyloxyphenol (7) is then alkylated with glycidyl

tosylate or an epihalohydrin in the presence of a base such as sodium hydride to
produce (6) and heated in a high boiling solvent such as mesitylene or xylene to
effect both rearrangement of the allyl group and cyclization to the dioxan ring.
The resulting primary alcohol (9) is converted to the tosylate by reaction with p-
toluenesulfonyl chloride in the presence of a tertiary amine or alternatively to a
halide by reaction with carbon tetrabromide or carbon tetrachloride in combination
with triphenylphosphine. The ally! side chain is then isomerized by treatment with
catalytic bis-acetonitrile palladium (II) chloride in refluxing methylene chloride or
benzene to produce (10). Allylic oxidation with selenium dioxide in refluxing
-13-

dioxane/water gives the o-nitrocinnamaldehyde, which upon reduction with iron in
acetic acid cyclizes to the 2,3-dihydro-1,4-dioxino[2,3-f|quinoline-2-methyl-tosylate
orhalide(11).
[0044] The 2,3-dihydro-1,4-dioxino[2,3-f]quinolin-2-ylmethyltosylates (14) in
which R3 is alkyl may be prepared from the nitro olefin described above in the
manner described in Scheme 5. The rearranged olefin (10) is treated sequentially
with ozone and a tertiary amine or with osmium tetroxide and sodium periodate to
give the o-n'rtrobenzaldehyde (12). Condensation with the appropriate
triphenylphosphoranylidene ketone under Wittig conditions gives the o-nitrostyryl
ketone (13), which upon reduction by iron in acetic acid, cyclizes to the
corresponding 2,3-dihydro-1,4-dioxino[2,3-f]-quinoline-2-methyltosyIate
(14). Replacement of the tosylate with the appropriately substituted
cycloalkylamine as above gives the title compounds of the invention.

[0045] Substitution of trimethy! phosphonoacetate for the
triphenylphosphoranylidene ketone in the Wittig procedure above, followed by
reduction of the nitro group with tin (II) chloride and cyclization in acid gives the
compounds of the invention in which R3 is hydroxy. Alkylation of this hydroxy
-14-

derivative by a suitable alkyl halide or tosylate in the presence of base gives the
compounds of the invention in which R^ is alkoxy. Treatment of the hydroxy
derivative with an inorganic acid chloride such as phosphoryl chloride or bromide
gives the compounds of the invention in which R^ is halo. Substitution of diethyl
cyanomethylphosphonate for the triphenyl-phosphoranylidene ketone in the Wittig
procedure above, followed by reduction of the nitro group with tin (II) chloride and
cyclization in acid gives the compounds of the invention in which R3 is amino.
[0046] The o-nitrobenzaldehyde (12) used in the Wittig chemistry described in
Scheme 5 may be alternatively prepared as shown in Scheme 6. The appropriate
mono-allylated catechol (15) is elaborated with glycidyl tosylate as described
above to produce (16) and rearranged in refluxing mesitylene. Cyclization to the
benzodioxan methanol is

effected by treatment with sodium bicarbonate in ethano! and the alcohol (17) is
converted to the tosylate or halide. After rearrangement of the double bond by
-15-

treatment with catalytic bis-acetonitrile palladium chloride in refluxing methylene
chloride to produce 18 and cleavage with ozone or osmium tetroxide/sodium
periodate as described above, the resulting aldehyde (19) is regioselectively
nitrated with a combination of nitric acid and tin (IV) chloride to produce (12).
[0047] Compounds of the invention in which R^ is attached to position 6 of the
2,3-dihydro-1,4-dioxino[2,3-f]quinoline may be alternatively prepared by a
variation of the Skraup quinoline synthesis according to Scheme 7. The
appropriately substituted benzodioxan methyltosylate (20) is nitrated under
standard conditions with nitric acid in a solvent such as dichloroethane and the
resulting nitro compound (21) reduced by treatment with hydrogen in the
presence of a catalyst such as platinum on sulfide carbon. Treatment of the
resulting aniline (22) with acrolein in the presence of hydrogen chloride and an
oxidant such as p-chloranil or naphthoquinone gives the corresponding 2,3-
dihydro-1,4-dioxino[2,3-f]quinoline (23). Replacement of the tosylate with the
appropriately substituted cycloalkylamine as above gives the title compounds of
the invention.

[0048] The 2,3-dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethylarnines of the
invention are prepared as illustrated below (Scheme 8). The o-nitrobenzaldehyde
(12) described above is converted to the oxime (24) by treatment with
-16-

hydroxylamine hydrochloride in the presence of a suitable base such as sodium
acetate and the nitro group reduced to the amine by hydrogenation over
palladium on carbon. Cyclization to the quinazoline N-oxide is effected by
treatment at reflux with the appropriate ortho ester according to the method of
Ostrowski (Heterocycles, vol. 43, No. 2, p. 389, 1996). The quinazoline N-oxide
may be reduced to the quinazoline (25) by a suitable reducing agent such as
hydrogen over Raney-nickel. Alternatively, an extended period of reflux in the
ortho ester gives the reduced quinazoline directly via a disproportionation reaction
and the 2,3-dihydro-1,4-dioxino[2,3-f]quinazoline-2-methyltosylate or halide may
be isolated by column chromatography. Replacement of the tosylate or halide
with the appropriately substituted cycloalkylamine in some high boiling solvent
such as dimethyl sulfoxide gives the title compounds of the invention.

[0049] The 2,3-dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethylamines of the
invention may be alternatively prepared from the rearranged olefin described
above by the method outlined in Scheme 9 below. The nitro olefin (10) is first
reduced to the aniline by treatment with a suitable reducing agent such as
stannous chloride dihydrate in refuxing ethyl acetate and the resulting amine
acylated with the appropriate acyl halide or anhydride. The olefin (26) is then
converted to the aldehyde (27) by cleavage with catalytic osmium tetroxide in the
-17-

presence of excess sodium periodate. Cyclization directly to the 2,3-dihydro-1,4-
dioxino[2,3-f]quinazoline-2-methyltosylate (25) or halide is effected by treatment
of the amido aldehyde (27) with ammonia and replacement of the tosylate or
halide with the appropriately substituted cycloalkylamine in some high boiling
solvent such as dimethyl suifoxide as described above gives the title compounds
of the invention.

[0050] The 2,3-dihydro-1,4-dioxino[2,3-f]quinoxalin-2-ylmethylamines of the
invention are prepared as illustrated in Scheme 10 below. The o-
nitrobenzaldehyde (12) described above is oxidized to the o-nitrobenzoic acid (28)
by a suitable oxidant such as chromium trioxide (Jones' oxidation) or sodium
chlorite and the acid converted to the o-nitroaniline (29) with diphenylphosphoryl
azide (DPPA) in the presence of a tertiary base such as diisopropylethylamine.
Reduction of the resulting nitroaniline to the diamine (30) with hydrogen and
palladium on carbon and cyclization by treatment with the appropriate dicarbonyl
compound (for example, glyoxal, 2,3-butanedione, 3,4-hexanedione) gives the
2,3-dihydro-1,4-dioxino[2,3-f]quinoxaline-2-methyltosylate (31) or halide.
Replacement of the tosylate or halide with the appropriately substituted
cycloalkylamine in some high boiling solvent such as dimethyl suifoxide gives the
title compounds of the invention.
-18-


[0051] The 7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazol-8-ylmethylamines of
the invention are prepared as illustrated in Scheme 11 below. The o-
amidobenzaktehyde (27) described in Scheme 9 is converted to the phenol (32)
by treatment with meta-chloroperoxybenzoic acid in a Baeyer-Villager reaction
and cyclization to the 7,8-dihydro[1,4]dioxino[2,3-g][1,3]benzoxazole (33) is
effected by treatment at reflux with an appropriate dehydrating agent such as an
ortho ester or an acid catalyst such as p-toluenesulfonic acid. Replacement of
the tosylate or halide with the appropriately substituted cycloalkylamine in some
high boiling solvent such as dimethyl sulfoxide gives the title compounds of the
invention.
-19-


[0052] Alternatively (Scheme 12), the nitro olefin (10) may be reduced with tin
(II) chloride as described in Scheme 9 above and protected with a suitable
protecting group such as carbobenzoxy (Cbz) before the olefin is cleaved to the
aldehyde (35) by treatment with osmium tetroxide/sodium periodate and the
aldehyde converted to a phenol (36) by the Baeyer-Villager procedure.
Deprotection by treatment with hydrogen over palladium on carbon gives the o-
aminophenol, (37) which is cyclized to the 7,8-dihydro[1,4]dioxino[2,3-
g][1,3]benzoxazole (33) by treatment with the appropriate ortho ester, carboxylic
acid or anhydride. Treatment of the o-aminophenol with cyanogen bromide or
chloride or a suitably substituted carbamoyl chloride leads to compounds of the
invention in which R3 is amino. Treatment of the o-aminophenol with carbonyl
diimidazole gives the oxazolone which leads to compounds of the invention in
which R3 is halo via treatment with an inorganic anhydride such as phosphoryl
chloride or bromide. Replacement of the tosylate with the appropriately
substituted cycloalkylamine as above gives the title compounds of the invention.


[0053] Compounds of the invention in which R1 is hydrogen and R3 is alkyl are
most conveniently prepared according to Scheme 13 below. The appropriate
2',3',4'-trihydroxyacylphenone (38) is regioselectively alkylated with glycidyl
tosylate or an epihalohydrin in the presence of a base such as sodium carbonate
to give the corresponding 7-acyl-8-hydroxybenzodioxan-2-methanol (39).
Following conversion of the ketone to the oxime (40) by reaction with
hydroxylamine hydrochloride and sodium acetate, cyclization to the oxazole (41)
is effected by treatment with phosphoryl chloride in the appropriate
dimethylalkanoic acid amide. The resulting 7,8-dihydro-1,6,9-trioxa-3-aza-
cyclopenta[a]naphthalene-8-methanol is converted to the tosylate (42) by
treatment with p-toluenesulfonyl chloride in pyridine and combined with the
appropriate cycloalkylamine as described above to give the title compounds of the
invention.
-21 -


[0054] The 7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalenes of
the invention are prepared as illustrated in Scheme 14 below. The diamine (30)
described in Scheme 10 is cyclized by treatment at reflux with the appropriate
carboxylic acid to give the imidazole (43). Refluxing the diamine dihydrochloride
in higher boiling carboxylic acids occasionally causes replacement of a tosylate
group with a chloride. Replacement of the tosylate or halide with the
appropriately substituted piperidine in some high boiling solvent such as dimethyl
sulfoxide gives the 7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalenes
of the invention in which R6 is hydrogen, perfluoroalkyl or alkyl. Treatment of the
diamine described above with cyanogen bromide or chloride or a suitably
substituted carbamoy! chloride leads to compounds of the invention in which R6 is
amino. Treatment of the diamine with carbonyl diimidazole gives the imidazolone
which leads to compounds of the invention in which R6 is halo via treatment with
an inorganic anhydride such as phosphoryl chloride or bromide. Replacement of
the tosylate with the appropriately substituted cycloalkylamine as above gives the
title compounds of the invention.
-22-


[0055] The 2,3-dihydro-7H-[1,4]dioxino[2,3-e]indoles of the invention are
prepared as illustrated in Scheme 15 below. Specifically, the primary alcohol (9)
from the Claisen rearrangement described in Scheme 4 is converted to the
tosyiate (44) by reaction with p-toluenesulfonyl chloride in the presence of a
tertiary amine or pyridine, or alternatively to a halide by reaction with carbon
tetrabromide or carbon tetrachloride in combination with triphenylphosphine. The
allyl side chain is then cleaved to the aldehyde (45) by treatment with ozone at
low temperature, followed by work-up with a tertiary base such as
diisopropylethylamine or triethylamine, or by treatment with catalytic osmium
tetroxide and sodium periodate. Reduction of the nitro group with hydrogen over
platinum oxide leads directly to formation of the indole (46) in which R7 is
hydrogen. Alternatively, the aldehyde may be treated with an appropriate alkyl
Grignard reagent or with trifluoromethyl trimethylsilane in the presence of cesium
fluoride, then oxidized to a ketone with a suitable oxidant such as pyridinium
chlorochromate (PCC) or the Swern reagent and reduced with hydrogen over
platinum oxide to give the indoles in which R7 is alkyl or trifluoromethyl.
Replacement of the tosyiate or halide with the appropriately substituted
cycloalkylamine in some high boiling solvent such as dimethyl sulfoxide gives the
title compounds of the invention.
-23-


[0056] The 2,3-dihydro-7H-[1,4]dioxino[2,3-e]indoles of the invention may
alternatively be prepared following procedure (Scheme 16). The o-
nitrobenzaldehyde (12) is condensed with the appropriate nitroalkane in the
presence of a suitable base catalyst to yield the corresponding o,p"-dinitrostyrene
(47). Reduction of both nitro groups with hydrogen over palladium on carbon is
accompanied by cyclization to form the indole (48). Replacement of the tosylate
with the appropriately substituted cycloalkylamine as above gives the title
compounds of the invention.
-24-


[0057] In yet another method, compounds of the present invention may be
prepared in accordance with Scheme 17. The synthesis of compound I is
comprised of steps that begin with halogenation of 49 where R' is alkyl of 1-6
carbon atoms, with reagents such as N-halosuccinimide in acetonitrile to give 50
(where Hal is halogen such as Br, CI or I). Deprotection of 50 with Lewis acids
such as boron tribromide, boron trichloride, aluminum trichloride, ferric chloride,
or trimethylsilyl iodide in a suitable solvent such as methylene chloride, or with
strong protic acids such as HBr and HCI gives the salt 51. Free base 51 may be
obtained by neutralization with an Amberlyst A-21 resin slurry in polar solvents
such as ethanol or methanol. Alkylation of 51, either as the free base or as the
salt, with benzyl or substituted benzyl protected glycidyl ethers

R" is benzyl, substituted benzyl such as 4-bromobenzyl, 3,4-dimethoxybenzyl, 2-
or 4-nitrobenzyl, or 4-methoxybenzyl) in suitable polar solvents such as dimethyl
sulfoxide, dimethyl formamide, or dimethyl acetamide in the presence of bases
such as sodium carbonate, potassium carbonate, or triethylamine gives 52. The
compound 52 is then cyclized using palladium catalysts such as
tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, or
palladium acetate with ligands from the group consisting of (+) BINAP and
separate enantiomers thereof, (+) Tol-BINAP and separate enantiomers thereof;
-25-

1-1'-bis(diphenylphosphino) ferrocene, 1,3-bis(diphenylphosphino)propane, and
1,2 bis(diphenyl-phosphino)ethane in the presence of bases such as NaH, LiH,
KH, potassium carbonate, sodium carbonate, titanium carbonate, cesium
carbonate, potassium f-butoxide or potassium phosphate tribasic in a suitable
solvent such as toluene, or alternatively, with copper catalyst such as copper
iodide in the presence of bases such NaH, LiH, KH in a suitable solvent such as
toluene to afford 53. Deprotection of 53 with Lewis acids such as boron
tribromide, boron trichloride, aluminum trichloride, feme chloride, trimethylsilyl
iodide in a suitable solvent such as methylene chloride, or with strong protic acids
such as HBr and HCI or under reductive cleavage conditions using Pd catalyst
and hydrogen transfer reagents
-26-


such as hydrogen, cyclohexene, methyl cyclohexene, or ammonium formate
gives 54. The hydroxyl moiety of 54 can be activated with an aryl- or alkyl-
sulfonyl chloride such as p-toluenesulfonyl chloride, methanesulfonyl chloride, 2-,
3- or 4-nitrobenzenesulfonyl chloride, or 2- or 4-bromobenzenesulfonyl chloride in
the presence of bases such as triethylamine or pyridine in suitable solvents such
as methylene chloride, THF, or toluene to afford 55 where FT" is sulfonate such
as p-toluenesulfonate, methanesulfonate, 2-, 3-, or 4-nitrobenzenesulfonate, or 2-
or 4-bromobenzenesulfonate. The final coupling of 55 with cycloalkyamines
appropriate to the invention, in the presence of bases such as diisopropyl
ethylamine, potassium carbonate, or sodium carbonate in polar solvents such as
THF, dioxane, DMSO, DMF, or DMA affords compounds of Formula 1.
-27-

[0058] The substituted cydoalkylamines (2) relevant to the chemistry described
Scheme 1 are prepared as shown in Scheme 18. Specifically, a suitably
substituted cycloalkanone (56) is reacted with a secondary (FT is hydrogen) or
tertiary amine (FT is alkyl) in the presence of a suitable reducing agent such as
sodium triacetoxyborohydride or sodium cyanoborohydride to give the cyclopentyl
amine 57. In this method the amine may be a benzodioxan methanamine (4) as
described above (Scheme 2) to give the title compounds of the invention.
Alternatively, the reductive amination of Scheme 18 may produce intermediate
cydoalkylamines, which are then reacted with a suitably substituted benzodioxan
methyltosylate (1) or bromide as in Scheme 1 to give the title compounds of the
invention.

[0059] Intermediate cydoalkylamines in which R2 is hydrogen are best prepared
by using benzylamine (FT is benzyl) in the reductive amination of Scheme 18,
followed by debenzylation of the amine 58 by transfer hydrogenation using
ammonium formate and palladium on carbon in refluxing methanol (Scheme 19).

[00603 The cyclohexanones appropriate to the above chemistry are known
compounds or can be prepared by one schooled in the art. The intermediate 3-
-28-

indolylcyclopentanones (62) required for certain compounds of the invention may
be prepared as shown in Scheme 20. Specifically, a suitably substituted indole
(60) is reacted with cyclopentenone (61) in the presences of a Lewis acid to give
the corresponding 3-indol-3-yl-cyclopenanone (62)

[0081] A protocol similar to that used by Cheetham ef a/. {Neuropharmacol.
32:737, 1993) 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 rat frontal cortical membranes was determined using a Tom
Tech filtration device to separate bound from free 3H-paroxetine and a Wallac
1205 Beta Plate® counter to quantify bound radioactivity. Kj's thus determined for
standard clinical antidepressants are 1.96- nM for fluoxetine, 14.2 nM for
imipramine and 67.6 nM for zimelidine. A strong correlation has been found
between 3H-paroxetine binding in rat frontal cortex and 3H-serotonin uptake
inhibition.
[0062] High affinity for the serotonin 5HT1A receptor was established by testing
the claimed compound's ability to displace pH] 8-OH-DPAT (dipropylamino-
tetralin) from the 5HT1A serotonin receptor following a modification of the
procedure of Hall, ef al., J. Neurochem. 44,1685 (1985), which utilizes CHO cells
stably transfected with human 5HTIA receptors. The 5HTiA affinities for the
compounds of the invention are reported below as Kj's.
-29-

Antagonist activity at 5HT1A receptors was established by using a 35S-GTPyS
binding assay similar to that used by Lazareno and Birdsall (Br. J. Pharmacol.
109:1120,1993), in which the test compound's ability to affect the binding of ^S-
GTPyS to membranes containing cloned human 5HT1A receptors was determined.
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 inhibitory effect is represented as the J^, while its
potency is defined by the lC^,,.
[0063] The results of the three standard experimental test procedures
described in the preceding three paragraphs were as follows:
5-HT Transporter 5HT1A Receptor 5HTIA Function
Affinity Affinity
Compound Ki (nM) Kj(nM) IC50 (nM) (lmux.)
Example 1 1.25 2.56 EC50 = 33(Emax = 38%)
Example 2 1.69 12.81 nd
Example 3 0.93 4.73 83(100)
Example 3-lsomer A 0.38 8.73 69 (82)
Example 3-lsomer B 0.33 2.03 34(97)
Example 4 0.62 9.12 44(84)
Example 4-lsomer A 0.54 7.72 60 (56)
Example 4-!somer B 0.67 26.5 1440(100)
Example 5 3.69 5.35 142 (69)
Example 5-lsomer A 2.11 12.5 190(88)
Example 5-lsomer B 3.00 1.91 158(97)
Example 6 1.67 20.3 228 (55)
Example 7 19.0 51.7 nd
Example 8 4.16 14.6 EC5o = 66(Emax = 95%)
Example 9 0.84 5.01 242(100)
Example 10 1.38 28.55 172(85)
Example 11 1.46 16.36 274(100)
Example 12 11.0 84.37 nd
-30-

Example 13 5.45 18.8 494(100)
[0064] Like the antidepressants fluoxetine, paroxetine and sertraline, the
compounds of this invention have the ability to potently 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 disorder, childhood depression and dysthymia), anxiety, panic
disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also
known as pre-menstrual syndrome), attention deficit disorder (with and without
hyperactivity), obsessive compulsive disorder (including trichotillomania), social
anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as
anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol
addiction, sexual dysfunction (including premature ejaculation), and related
illnesses. Moreover, many of the compounds of this invention have potent affinity
for and antagonist activity at brain 5HT1A serotonin receptors. 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 5HT1A antagonism (Blier and Bergeron, 1995; F. Artigas era/., 1996;
M. B. Tome, era/., 1997). The compounds of the invention are thus exceedingly
interesting and useful for treating depressive illnesses. Thus the present
invention provides methods of treating, preventing, inhibiting or alleviating each of
the maladies listed above in a mammal, preferably in a human, the methods
comprising providing a pharmaceutically effective amount of a compound of this
invention to the mammal in need thereof.
[0065] Also encompassed by the present invention are pharmaceutical
compositions for treating or controlling disease states or conditions of the central
nervous system comprising at least one compound of Formula I, mixtures thereof,
and or pharmaceutical salts thereof, and a pharmaceutically acceptable carrier
therefore. Such compositions are prepared in accordance with acceptable
pharmaceutical procedures, such as described in Remington's Pharmaceutical
Sciences, 17th edition, ed. AKonoso R. Gennaro, Mack Publishing Company,
-31 -

Easton, PA (1985). Pharmaceutically acceptable carriers are those that are
compatible with the other ingredients in the formulation and biologically
acceptable.
[0066] The compounds of this invention may be administered orally or
parenterally, neat or in combination with conventional pharmaceutical carriers.
Applicable solid carriers can include one or more substances that may also act as
flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants,
compression aids, binders or tablet-disintegrating agents or an encapsulating
material. In powders, the carrier is a finely divided solid that is in admixture with
the finely divided active ingredient. In tablets, the active ingredient is mixed with a
earner having the necessary compression properties in suitable proportions and
compacted in the shape and size desired. The powders and tablets preferably
contain up to 99% of the active ingredient. Suitable solid carriers include, for
example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin,
starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,
polyvinylpyrrolidine, low melting waxes and ion exchange resins.
[0067] Liquid carriers may be used in preparing solutions, suspensions,
emulsions, syrups and elixirs. The active ingredient 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 such as
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 parenteral
administration include water (particularly containing additives as above, e.g.
cellulose derivatives, preferably 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.
-32-

[0068] Liquid pharmaceutical compositions that are sterile solutions or
suspensions can be administered by, for example, intramuscular, intraperitoneal
or subcutaneous injection. Sterile solutions can also be administered
intravenously. Oral administration may be either liquid or solid composition form.
[0069] Preferably the pharmaceutical composition is in unit dosage form, e.g.
as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or
suppositories. In such form, the composition is sub-divided in unit dose
containing appropriate quantities of the active ingredient; the unit dosage forms
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.
[0070] The amount provided to a patient will vary depending upon what is being
administered, the purpose of the administration, such as prophylaxis or therapy,
and the state of the patient, the manner of administration, and the like. In
therapeutic applications, 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. Generally, a starting dose is about 5 mg per day with gradual increase in
the daily dose to about 150 mg per day, to provide the desired dosage level in the
human.
Provide, as used herein, means either directly administering a compound or
composition of the present invention, or administering a prodrug, derivative or
analog which will form an equivalent amount of the active compound or substance
within the body.
-33-

[0071] The present invention includes prodrugs of compounds of Formula I, la
and Ib. 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. Various
forms of prodrugs are known in the art, for example, as discussed in Bundgaard,
(ed.)f Design of Prodnigs, Elsevier (1985); Widder, (ed.), Methods in
Enzymology, vol. 4, Academic Press (1985); Krogsgaard-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 Deliver Reviews,
8:1-38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 etseq. (1988);
and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems,
American Chemical Society (1975).
[0072] The following examples illustrate the production of representative
compounds of this invention.
INTERMEDIATE 1
3-Allyloxv-4-methoxvnitrobenzene
[0073] 97.5 g (0.51 mole) of the sodium salt of 5-nitroguaiacol was dissolved in
one liter of DMF and 1.5 equivalents of allyl bromide added. The reaction was
heated to 65°C for two hours, after which time much of the dark color had
discharged and tic (1:1 CH2Cl2/hexane) indicated loss of starting material. The
solvent was concentrated in vacuum and the residue washed with water. The
product was isolated by filtration and dried in a vacuum. This gave 112 g of pale
yellow solid. A sample recrystallized from methanol, gave m.p. 93-94°C.
INTERMEDIATE 2
2-Allyloxv-4-nitrophenol
[0074] To one liter of dimethyl sulfoxide was added 750 mL of 2 N aqueous
sodium hydroxide and the mixture was heated to 65°C. The pale yellow solid 3-
ailyloxy-4-methoxynitrobenzene prepared above was added in portions over a 30
minute period and then the temperature was raised to 95°C and maintained for 3
-34-

hours, after which time the starting material had been consumed. The mixture
was allowed to coo! and poured into a mixture of 1 L ice and 1 L 2 N HCI. 73
Grams of crude but homogeneous (by tic 1:1 CH2Cl2/hexane) desired product
was isolated as a light brown solid by filtration. This material was subsequently
dissolved in 1:1 hexane/methylene chloride and filtered through silica gel to give
68 g of pale yellow solid, which, when recrystallized from ethyl/acetate/hexane,
gave m.p. 61-62°C." The aqueous mother liquors from the initial crystallization
above were extracted with 2 L of ethyl acetate. This was dried over sodium
sulfate, filtered and evaporated to a dark oil. Column chromatography on silica
with 1:1 CH2Cl2/hexane gave an additional 12 g of the title compound as a yellow
solid. Elution with 2% MeOH in CHCI3 gave 12 g of a dark oil which slowly
crystallized in vacuum. This proved to be the Claisen product, 3-allyl-4-
nitrocatechol.
INTERMEDIATE 3
2-(2-Allvloxv-4-nitrophenoxyinethvn-oxirane
[0075] 20 g (0.50 mole) of 60% NaH/mineral oil was placed in a two liter flask
and washed with 500 ml_ of hexane. 1 L of DMF was added, followed by 77 g
(0.40 mole) of the 2-allyloxy-4-nitrophenol prepared in the previous step. Addition
of the phenol was performed in portions under argon. After stirring the mixture for
30 minutes at room temperature under argon, 108 g (0.48 moles) of (R)-glycidyl
tosylate was added and the mixture heated at 70-75°C under nitrogen overnight
Upon cooling, the DMF was removed in vacuum and replaced with one liter of
methylene chloride. This was washed with 500 ml_ portions of 2 N HCI, saturated
sodium bicarbonate and saturated brine and dried over sodium sulfate. The
mixture was filtered, concentrated to an oil in vacuum and column
chromatographed on silica gel using 1:1 hexane/methylene chloride as eluent
This gave 43 g of product contaminated with traces of the two starting materials,
followed by 21 g of pure product as a pale yellow solid. The impure material was
recrystallized from 1.2 L of 10% ethyl acetate/hexane to give 34 g of pure
(homogeneous on silica gel tic with 1:1 hexane/methylene chloride) (R)-2-(2-
a!Iyloxy-4-nitrophenoxymethyl)-oxirane: m.p. 64°C.
-35-

Elemental Analysis for: C12H13NO5
Calc'd: C, 57.37; H, 5.21; N, 5.58
Found: C, 57.50; H, 5.21; N, 5.43
INTERMEDIATE 4
(8-Allyll-7-nitro-2.3-dihvdro-benzo(1.4)dioxin-2-vlVmethanol
[0076] (R)-2-(2-AIIyloxy-4-nitrophenoxymethyl)-oxirane (20 g, 80 mmoles) pre-
pared as above was heated at 155°C in mesitylene for 24 hours under nitrogen.
Filtration of the black solid which formed gave 1.5 g of very polar material.
Evaporation of the solvent in vacuum followed by column chromatography on
silica gel with methylene chloride as eluent gave 10 g of recovered starting
material and 7.5 g of the desired rearranged (S)-(8-allyl-7-nitro-2,3-dihydro-
benzo(1,4)dioxin-2-yl)-methanol, which slowly crystallized on standing in vacuum
(m.p. 67°C). The yield based on recovered starting material is 75%.
Elemental Analysis for: C12H13NO5
Calc'd: C, 57.37; H, 5.21; N, 5.58
Found: C, 57.26; H, 5.20; N, 5.35
INTERMEDIATE 5
Toluene-4-sulfonic acid 8-allvl-7-nitro-2,3-dihvdro-benzo( 1,4)dioxin-2-vlmethvl
ester
[0077] 9.55 g (38.0 mmole) of (S)-(8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-
2-yl)-methanol was dissolved in 465 mL of pyridine, 29.0 g (152 mmole) of p-
toluenesulfonyl chloride was added and the mixture stirred at room temperature
under nitrogen overnight. Water was then added to quench the excess tosyl
chloride and the solvent was removed in vacuum and replaced with methylene
chloride. This solution was washed with 2 N HCI, with saturated sodium
bicarbonate, and with saturated brine, and dried over magnesium sulfate.
Filtration, evaporation in vacuum and column chromatography on silica gel with
1:1 hexane/methylene chloride as eluent gave 12.6 g (92%) of toluene-4-sulfonic
acid (R)-allyl-7-nitro-2,3-benzo(1,4)dioxin-2-ylmethyl ester, which slowly
crystallized to a tan solid (m.p. 60-62°C) upon standing.
-36-

Elemental Analysis for: C19H19NO7S
Calc'd: C, 56.29; H, 4.72; N, 3.45
Found: C, 56.13; H, 4.58; N, 3.44
INTERMEDIATE 6
{7-Nitro-8-f1 -propenvn-2.3-dihydro-1,4-benzodioxin-2-yl)methvl 4-
methvlbenzenesulfonate
[0078] To a solution of 10.0 g (24.0 mmole) of (R)-[8-allyl-7-nitro-2,3-dihydro-
1,4-benzodioxin-2-y!]methyl 4-methylbenzenesulfonate in 700 mL of benzene was
added 1.03 g of bis(acetonitrile)dichloropalladium (II) and the mixture was
refluxed under nitrogen for 48 hours. The catalyst was then removed by filtration
and the filtrate concentrated in vacuum to a brown oil. Column chromatography
on silica gel with methylene chloride as eluent gave 7.2 g of the title compound as
a mixture of E and Z isomers. A sample of {(2R)-7-nitro-8[(E)-1-propenyf]-2,3-
dihydro-1,4-benzodioxin-2-yi}methyl 4-methylbenzenesulfonate was obtained as a
yellow solid (m.p. 105-106°C) by evaporation of a pure E isomer-containing
fraction.
Elemental Analysis for. C19H19NO7S
Calc'd: C, 56.29; H, 4.72; N, 3.45
Found: C, 56.12; H, 4.64; N, 3.39
INTERMEDIATE 7
(8-Formvl-7- nitro-2,3-dihydro-1,4-benzodioxin -2-vPmethyl 4-
methylbenzenesulfonate
[0079] {(2R)-7-Nitro-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-
methyl-benzenesulfonate (10.5 g, 25.9 mmole) dissolved in 400 mL of methylene
chloride was treated with excess ozone at -78°C. Diisopropylethylamine (11.5
mL, 66.0 mmole) was then added dropwise over 30 minutes and the mixture
allowed to come to room temperature and stir overnight under a nitrogen
atmosphere. The mixture was then diluted to 600 mL with methylene chloride,
washed three times with 100 mL portions of 2N HCI (aq), twice with 200 mL
portions of saturated aqueous sodium bicarbonate and with 200 mL of saturated
-37-

brine. The solution was dried over magnesium sulfate, filtered and concentrated
in vacuum to a crude brown oil, which was column chromatographed on silica gel
with 10% hexane/methylene chloride to give 7.52 g of the (R)-enanfomer of the
title compound as a yellow solid. 1H-NMR (CDCI3): doublet 7.8 8 (2 H); doublet
7.62 5 (1 H); doublet 7.4 5 (2 H); doublet 7.0 8 (1 H); multiplet 4.4-4.6 8 (2 H);
multiplet 4.2 5 (3 H); singlet 2.4 8 (3 H).
INTERMEDIATE 8
{7-Nitro-8-r(E>3-oxo-1 -butenvn-2,3-dihvdro-1,4-benzodioxin-2-yl}methvl 4-
methvlbenzenesulfonate
[0080] To a solution of 3.00 g (7.37 mmole) of [(2R)-8-formyl-7-nitro-2,3-
dihydro-1,4-benzodioxin-2-y!]methyl 4-methylbenzenesulfonate in 250 mL of
toluene was added 2.90 g (9.10 mmole) of 1-triphenylphosphoranylidene-2-
propanone. The mixture was stirred at room temperature under nitrogen for 5
hours, during which time some product precipitated from solution. The solvent
was removed in vacuum and the crude residue was column chromatographed on
silica gel with methylene chloride as eluent to give 3.0 g of the (R)-enantiomer of
the title compound as a yellow solid. 1H-NMR (CDCI3): doublet 7.8 8 (2 H);
doublet 7.6 8 (1 H); doublet 7.5 8 (2 H); doublet 7.4 8 (2 H); doublet 6.95 8 (1 H);
doublet 6.6 8 (1 H); multiplet 4.5 8 (1 H); doublet of doublets 4.0 8 (1 H); multiplet
4.2 8 (3 H); singlet 2.45 8 (3 H); singlet 2.4 8 (3 H).
INTERMEDIATE 9
(8-Methv!-2,3-dihvdron ,41dioxinor2,3-f1quinolin-2-vl)methyl 4-
methylbenzenesulfonate
[0081] To a solution of {(2R)-7-nitro-8-[(E)-3-oxo-1 -butenyrj-2,3-dihydro-1,4-
benzo-dioxin-2-yl}methyl 4-methylbenzenesulfonate (3.40 g, 7.83 mmole) in 200
mL of acetic acid/ethanol (3:2) was added 2.25' g (40.2 mmole) of iron powder
and the mixture was heated at reflux under nitrogen for 8 hours. After the
reaction was complete, 150 mL of water was added and the mixture filtered
through a pad of celite. The filtrate was neutralized with saturated aqueous
sodium bicarbonate and extracted with ethyl acetate. The extract was dried over
-38-

magnesium sulfate, filtered and evaporated in vacuum. The residue was column
chromatographed on silica gel using a gradient elution commencing with 20%
ethyl acetate/hexane and ending with 70% ethyl acetate/hexane to give 2.5 g of
the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCI3): doublet
8.1 5 (1 H); doublet 7.6 5 (2 H); doublet 7.45 5 (1 H); multiplet 7.2 8 (4 H);
multiplet 4.6 5 (1 H); multiplet 4.3 8 (3 H); multiplet 4.1 8 (1 H); singlet 2.5 8 (3H);
singlet 2.4 8 (3 H).
INTERMEDIATE 10
1-r5-Hydroxv-3-(hvdroxvmethvlV-2.3-dihvdro-1,4-benzodioxin-6-vl1-1-ethanone
[0082] To a solution of 2',3',4'-trihydroxyacetophenone (10.6 g, 63.0 mmole) in
DMF.(75 mL) was added potassium carbonate (17.4 g, 126 mmole). After 5
minutes (R)-glycidyl tosylate (9.67 g, 42.3 mmole) was added, then the
heterogeneous mixture was heated to 70°C for 3 hours. After removal of the
solvent in vacuum, the residue was taken into water (800 mL) and was then
extracted with ethyl acetate (4 x 300 mL). The combined organic layers were
dried over magnesium sulfate, filtered and evaporate to dryness in vacuum. The
crude brown oil thus obtained was column chromatographed on silica gel with
40% hexane/ethyl acetate as eluent to give the (S)-enantiomer of the title
compound as a yellow oil which solidifies upon standing (7.5 g, 78%). MS (ESI)
m/z 223 (M-H)-.
Elemental Analysis for: C11H12O5 0.10H2O
Calc'd: C, 58.46; H, 5.44
Found: C, 58.02; H, 5.09
INTERMEDIATE 11
1-r5-Hvdroxv-3-(hvdroxvmethyl)-2.,3-dihvdro-1,4-benzodioxin-6-vn-1-ethanone
oxime
[0083] A solution of hydroxylamine hydrochloride (2.38 g, 34.2 mmole) in 1:1
ethanol/pyridine (100 mL) was added to a solution of 1-[(3S)-5-hydroxy-3-
(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-1-ethanone (1.92 g, 8.57
mmole) in ethanol (200 mL). It was then heated to reflux under nitrogen for 5
-39-

hours. Upon cooling, the solvent was removed and replaced with ethyl acetate.
The solution was then washed with water (200 ml_) and with aqueous 2N HCI
(100 ml_), dried over magnesium sulfate, filtered and evaporated in vacuum to
give 1.89 g (93%) of the (S)-enantiomer of the title compound as a gray solid,
m.p. 162 ° C. MS (ESI) m/z 240 (M+H)+.
Elemental Analysis for: C11H13NO5»0.35H2O
Calc'd: C, 53.81; H, 5.62; N, 5.71
Found: C, 53.51; H, 5.30; N, 5.58
INTERMEDIATE 12
r2-Methvl-7.8-dihvdrori,41dioxinor2,3-gin,31benzoxazol-8-vnmethanol
[0084] 3.03 g (12.6 mmole) of 1 -[(3S)-5-hydroxy-3-(hydroxymethyl)-2,3-dihydro-
1,4-benzodioxin-6-yl]-1-ethanone oxime was dissolved in a mixture of 1:3 N,N-
dimethylacetamide/acetonitrile (100 ml_). The solution was cooled in an ice/water
bath and a solution of phosphorus oxychloride (1.26 mL, 35 mmole) in 1:3 N,N-
dimethylacetamide/acetonitrile (30 mL) was added. The reaction mixture was
stirred under nitrogen over a period of 48 hours. It was then added to an ice cold,
saturated solution of sodium acetate, extracted with ethyl acetate, dried over
magnesium sulfate, filtered and evaporated in vacuum. The resulting crude oil
was column chromatographed on silica gel with 60% hexane/ethyl acetate to
remove impurities and the product eluted with 40% hexane/ethyl acetate. After
evaporation of the solvent in vacuum, 2.08 g (75%) of the (S)-enantiomer of the
title compound was obtained as a white solid, m.p. 120 °C. MS (ESI) m/z 222
(M+H)+.
Elemental Analysis for. C11H11NO4-0.20 H2O
Calc'd: C, 58.77; H, 5.11; N, 6.23
Found: C. 58.93; H, 4.91; N, 6.14
INTERMEDIATE 13
r2-Methvl-7, 8-dihvdro[1,41dioxinor2,3-qiri,31benzoxazol-8-vnmethvl 4-
methvlbenzenesulfonate
[0085] To a solution of [(8S)-2-methyl-7,8-dihydro[1,4]dioxino[2,3-
g][1,3]benzoxazol-8-yl]methanol (1.80 g, 8.14 mmole) in methylene chloride (100
-40-

mL) was added p-toluenesulfonyl chloride (3.90 g, 20.4 mmole). The mixture was
cooled in an ice bath and a solution of diisopropylethylamine (3.55 mL, 20.4
mmole) in methylene chloride (20 mL) was then added dropwise, followed by 4-
dimethylaminopyridine (0.65 g, 5.30 mmole). The solution was allowed to warm to
room temperature and was stirred under nitrogen overnight. The reaction was
diluted to 500 mL in volume with methylene chloride, then washed with aqueous 2
N HCI (200 mL), with saturated aqueous sodium bicarbonate (200 mL), and with
brine (150 mL), dried over magnesium sulfate, filtered and evaporated in vacuum
to a yellow oil. The crude oil was column chromatographed on silica gel using
methylene chloride to remove impurities and 3% methanol/methylene chloride to
elute the (R)-enantiomer of the title compound, which becomes a white solid
under vacuum (2.56 g, 84%), m.p. 123°C. MS (ESI) m/z 376 (M+H)+.
Elemental Analysis for: C18H17NO6S • 0.20 H2O
Calc'd: C, 57.04; H, 4.63; N, 3.70
Found: C, 56.75; H, 4.62; N, 3.51
INTERMEDIATE 14
3-(5-Fluorc-1H-indol-3-vl)-cvclopentanone
[0086] A mixture of 5-fluoroindole (6.0 g, 44.4 mmol) and 2-cyclopenten-1-one
(4.5 mL, 53.3 mmol) in nitromethane (22 mL) was cooled to —20°C in a carbon
tetrachloride-dry ice bath. A mixture of boron trifluoride etherate (1.6 mL, 11.1
mmol) and ethanol (2.2 mL, 43 mmol) was added dropwise from an addition
funnel. The reaction mixture was stirred at —20°C for 2 hours, then was
quenched with 5% aqueous sodium bicarbonate solution (100 mL), and extracted
with ethyl acetate (3 x 200 mL). The combined organic layers were washed with
water (100 mL) and brine (100 mL), then were dried over anhydrous sodium
sulfate, filtered and concentrated to give 9.5 g of the title compound. Trituration
with ethyl acetate afforded 5.6 g (58%) of the title compound as a yellow solid.
An analytical sample was recrystallized from ethyl acetate/methanol: mp 119-
120°C; MS (ESI) m/z 218 [M+H]+.
Elemental Analysis for: C13H12FNO
Calc'd: C, 71.81; H, 5.57; N, 6.45
-41 -

Found: C, 71.52; H, 5.41; N, 6.35
INTERMEDIATE 15
3-(1 H-indol-3-vD-cyclopentanone
[0087] This compound was prepared in similar manner as for Intermediate 14,
using indole (2.34 g, 20 mmol) and 2-cyclopenten-1-one (2.0 mL, 24.0 mmol) to
give 1.7 g (44%) of the desired product as a thick oil: MS (ESI) m/z 200 [M+H]+.
Elemental Analysis for: C13H13NO
Calc'd: C, 78.36; H, 6.58; N, 7.03
Found: C, 78.21; H, 6.49; N, 7.10
INTERMEDIATE 16
3-(5-Fluorc-1 -methyl-1 H-indol-3-yl)-cyclopentanone
[0088] A suspension of sodium hydride (60% dispersion in oil, 0.335 g, 8.2
mmol) in dimethylformamide (20 mL) was stirred at room temperature. A solution
of 3-(5-fIuoro-1H-indol-3-yl)-cyclopentanone (1.5 g, 6.9 mmol) in 10 mL of DMF
was added dropwise over 10 min. The reaction mixture was stirred at room
temperature for an additional 30 min, then iodomethane (3.1 g, 21.8 mmol) was
added- After stirring at room temperature for 24 hours, the reaction mixture was
poured into water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The
combined organic layers were washed with water (50 mL) and brine (50 mL), then
were dried over anhydrous sodium surfate, filtered, and concentrated to give 1.6 g
of crude product. Flash chromatography on silica gel (50% ethyl acetate /hexane)
afforded 1.2 g (81%) of the title compound as a thick oil which solidified on
standing. An analytical sample was recrystallized from ethyl acetate/hexane: mp
104-105°C; MS (ESI) m/z 232 [M+H]Elemental Analysis for: d4H14FNO
Calc'd: C, 72.71; H, 6.10; N, 6.06
Found: C, 72.48; H, 5.97; N, 5.96
-42-

INTERMEDIATE 17
N-Benzyl-3-(5-fluoro-IH-indol-3-yl)-cvclopentvlamine
[0089] A mixture 3-(5-fluoro-1H-indol-3-yl)-cyclopentanone (1.0 g, 4.61 mmol),
benzylamine (0.54 g, 5.05 mmol) and glacial acetic acid (0.7 mL, 1.08 mmol)
were stirred at room temperature for 30 minutes. Sodium triacetoxy borohydride
(1.5 g; 7.11 mmole) was added portionwise over a 10 minutes period. The
reaction was stirred at room temperature for 24 hours. The reaction mixture was
poured into 1 N aqueous NaOH (80 mL) and extracted with ethyl acetate (3 x 100
mL). The combined organic layers were washed with H2O (100 mL) and brine
(100 mL), then were dried over anhydrous sodium sulfate, filtered and
concentrated to give 1.5 g of a thick yellow oil. Flash chromatography on silica
gel (7% 2 M NH3 in methanol/ethyl acetate) afforded 0.5 g of the cis isomer (first
eluting) and 0.5 g of the trans isomer.
Cis isomer: MS (ESI) /n/z309 [M+H]+.
Elemental Analysis for: C20H21FN2 0.50 H2O
Calc'd: C, 75.68; H, 6.99; N, 8.83
Found: C, 75.91; H, 6.67; N, 8.70
Trans isomer: MS (ESI) mlz 309 [M+H]+.
Elemental Analysis for: C20H21FN2
Calc'd: C, 77.89; H, 6.86; N, 9.08
Found: C, 77.22; H, 6.91; N, 9.31
INTERMEDIATE 18
N-Benzyl-3-(1H-indole-3-vP-cvclopentylamine
[0090] This compound was prepared in similar manner as for Intermediate 17,
using 3-(1H-indol-3-yl)-cyclopentanone (3.0 g, 15 mmol) and benzylamine (1.95
g, 18 mmol) to give 4.7 g of the desired product as a mixture of cis and trans
isomers, which were separated by flash chromatography to afford 0.6 g of the cis
isomer (first eluting) and 1.0 g of the trans isomer.
Cis Isomer: MS (ESI) m/z 291 [M+H]+.
Elemental analysis for: C20H22N2 • 0.25 H2O(Cis A)
Calc'd: C, 72.49; H, 7.15; N, 8.45
Found: C, 72.75; H, 7.12; N, 8.46
-43-

Trans Isomer: MS (ESI) m/z 291 [M+Hf.
Elemental analysis for: C20H22N2 • 0.25 H2O(trans- B)
Calc'd: C, 72.49; H, 7.15; N, 8.45
Found: C, 72.46; H, 7.04; N, 8.47
INTERMEDIATE 19
N-Benzvi-3(5-fluoro-1-methvl-1H-indol-3vlVcyclopentvlarnine
[0091] This compound was prepared in the same manner as for Intermediate
17, using 3-(5-fluoro-1-methyl-1H-indol-3-yl)-cyclopentanone (1.25 g, 5.19 mmol)
and benzylamine (0.66 g, 6.2 mmol) to afford 1.7 g of the desired product as a
mixture of cis and trans isomers. Rash chromatography on silica gel (3% 2 M
NH3 in methanol/ethyl acetate) afforded 0.4 g (23%) of the cis isomer and 0.45 g
(27%) of the trans isomer.
Cis Isomer: MS (ESI) m/z 323 [M+H]+.
Elemental Analysis for: C21H23FN2 0.25 H2O
Calc'd: C, 77.15; H, 7.25; N, 8.57
Found: C, 77.38; H, 7.19; N, 8.53
Trans isomer: MS (ESI) m/z 323 [M+H]+.
Elemental Analysis for. C21H23FN2- 0.10 H2O
Calc'd: C, 77.79; H, 7.21; N, 8.64
Found: C, 77.68; H, 6.99; N, 8.69
INTERMEDIATE 20
cis-Benzvl-r4-(5-fluoro-1-H-indol-3-vl-)-cvclohexvn-amine
[0092] This compound was prepared in similar manner as for Intermediate 17,
using 4-(5-Fluoro-1-H-indol-3-y!)-cyclohexanone (0.6 g, 2.6 mmol) and
benzylamine (0.3 g, 2.8 mmol) to afford 1.0 of the desired product as a mixture of
cis and trans isomers. Flash chromatography on silica gel (3% 2M NH3 in
methanol/ethyl acetate) afforded 0.41 g (65%) of cis isomer and 0.22 g (33%) of
the trans isomer.
Cis isomer: MS (ESI) m/z 323 [M+H]+.
Elemental Analysis for: C21H23FN2»0.1 H2O
Calc'd: C, 77.79; H, 7.21; N, 8.64
-44-

Found: C, 77.44; H, 7.48; N, 8.87
Trans isomer: MS (ESI) m/z 323 [M+H]+.
Elemental Analysis for: C21H23FN2
Calc'd: C, 78.23; H, 7.19; N, 8.69
Found: C, 78.08; H, 7.49; N, 8.97
INTERMEDIATE 21
cis-3-(5-Fluoro-IH-indol-3-yl)-cyclopentvlamine
[0093] A mixture of cis-benzyl-3-(5-fluorcMH-indol-3-yl)-cyclopentylamine (0.45
g, 1.46 mmol), 0.2 g 10% Pd/C and ammonium formate (1.0 g, 15.9 mmol) in
methanol (30 ml_) were refluxed under nitrogen for 4 hours. The reaction mixture
was cooled, filtered through celite, and concentrated. The residue was diluted
with 1 N aqueous NaOH (50 mL) and extracted with ethyl acetate (3 x 50 ml_).
The combined organic layers were washed with water (50 mL) and brine (50 mL),
then were dried over anhydrous sodium sulfate, filtered and concentrated to give
0.28 g (100%) of the title compound as a thick oil: MS (ESI) m/z 219 [M+Hf.
Elemental Analysis for: C13H15FN2» 0.20 H2O
Calc'd: C, 70.37; H, 7.00; N, 12.63
Found: C, 70.65; H, 6.86; N, 12.67
INTERMEDIATE 22
trans-3-(5-Fluoro-1H-indol-3-vl)-cvclopentvlamine
[0094] A mixture of trans-benzyl-3-(5-fluoro-1H-indol-3-yl)-cyclopentylamine
(0.45 g, 1.46 mmol), 0.20 g 10% Pd/C, and ammonium formate (1.0 g, 15.9
mmol) in methanol (30 mL) were refluxed under nitrogen for 4 hours. The
reaction mixture was cooled, filtered through celite, and concentrated. The
residue was diluted with 1 N aqueous NaOH (50 mL) and extracted with ethyl
acetate (3 x 50 mL). The combined organic layers were washed with water (50
mL) and brine (50 mL), then were dried over anhydrous sodium sulfate, filtered,
and concentrated to give 0.28 g (100%) of the title compound as a thick oil: MS
(ESI)m/z219[M+H]+.
Elemental Analysis for: C13H15FN2« 0.10 H2O
-45-

Caic'd: C, 71.54; H, 6.93; N, 12.83
Found: C, 71.09; H, 6.67; N, 12.59
INTERMEDIATE 23
cis-3-(1 H-lndol-3-ylVcvclopentvlamine
[0095] This compound was prepared in the same manner as for Intermediate
20, using cis-benzyl-3-(1H-indol-3-yl)-cydopentylamine (1.3 g, 4.48 mmol) and
ammonium formate (1.6 g, 25.3 mmol) to afford 0.8 g (90%) of the desired
product as a thick oil which solidified upon standing: MS (ESI) m/z 201 [M+Hf.
Elemental analysis for: C13H16N20.1 H2O
Caic'd: C, 77.27; H, 8.08; N, 13.86
Found: C, 77.26; H, 8.17; N, 13.73
INTERMEDIATE 24
trans-3-(1H-lndol-3-vlVcvciopentylamine
[0096] This compound was prepared in the same manner as for Intermediate
20, using trans-benzyl-3-(1H-indol-3-yl)-cyclopentylamine (0.8 g, 2.8 mmol) and
ammonium formate (1.1 g,17.5 mmol) to afford 0.49 g (89%) of the desired
product as a thick oil, which solidified upon standing: MS (ESI) m/z 201 [M+H]Elemental analysis for: C13H16N2
Caic'd: C, 77.96; H, 8.05; N, 13.99
Found: C, 77.63; H, 8.06; N, 13.71
INTERMEDIATE 25
cis-3-(5-Huoro-1-methvHH-indol-3-vl)-cvclopentvlarnine
[0097] This compound was prepared in the same manner as for Intermediate
20, using cis-benzyl-3-(5-fluoro-1-methyl-1H-indol-3-yl)-cyclopentylamine (0.4 g,
1.2 mmol) to give 0.2 g (71 %) of the title compound as a thick oil, which was used
in the next reaction without purification: MS (ESI) m/z 233 [M+H]+.
-46-

INTERMEDIATE 26
trans-3-(5-FIuoro-1-methvl-1H-indol-3-yl)-cyclopenty!amine
[0098] This compound was prepared in the same manner as for Intermediate
20, using trans-benzyI-3-(5-fluoro-1-methyl-1H-indol-3-yl)-cycIopentylamine (0.42
g, 1.3 mmol) to give 0.3 g (79%) of the title compound as a thick oil, which was
used in the next reaction without purification: MS (ESI) m/z233 [M+H]+.
Elemental Analysis for C14H17FN2. 0.25 H2O
Calc'd: C. 71.01; H. 7.45; N, 11.83
Found: C, 71.14; H, 7.52; N, 11.67
i
INTERMEDIATE 27
cis-4-(5-Fluoro-1H-indol-3-v0-cvclohexylamine
[0099] This compound was prepared in the same manner as for Intermediate
20, using cis-benzyl-4-(5-fluoro-1-H-indol-3-yl)-cyclohexylamine (0.41 g, 1.3
mmol) to give 0.24 g (81%) of the desired amine as a white solid: mp 186-188°C;
MS (ESI) m/z233 [M+H]+.
Elemental Analysis for: C14H17FNz»0.1 H2O
Calc'd: C, 71.83; H, 7.41; N, 11.97
Found: C, 71.78; H, 7.62; N, 11.80
INTERMEDIATE 28
trans-4-(5-Fluoro-1H-indoI-3-vlVcvclohexvIamine
[0100] This compound was prepared in the same manner as for Intermediate
20, using trans-benzyl-4-(5-fluoro-1-H-indol-3-yl)-cyclohexylamine (0.21 g, 0.65
mmol) to give 0.135 g (89%) of the desired amine as a white solid: mp 205-
208°C; MS (ESI) m/z 233 [M+H]*
Elemental Analysis for C14H17FN2*0.25H2O
Calc'd: C, 71.01; H, 7.45; N, 11.83
Found: C, 70.99; H, 7.58; N, 11.80
-47-

EXAMPLE 1
N-r(cisV3-nH-indol-3-vncvclopentvn-N-(r(2SV8-methvl-2,3-
dihvdrori,41dioxinor2,3-flquinolin-2-vllmethvnamine
[0101] A mixture of toluene-4-sulfonic acid 8-methyl-2,3-dihydro-
[1,4]dioxino[2,3-f]quinolin-2-yl methyl ester (0.3 g, 0.77 mmol) and cis-3-(1H-
indoI-3-yl)-cyclopentylamine (0.26 g, 1.30 mmol) in DMSO (10 mL) were heated
at 80°C for 30 hours. The cooled reaction mixture was poured into 1 N aqueous
NaOH (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined
organic layers were washed with water (50 mL) and brine (50 mL), then were
dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.5 g of
crude product. Rash chromatography on silica gel afforded 0.06 g (18%) of the
desired product as its fumarate salt: MS (ESI) m/z 414 [M+H]*.
Elemental Analysis for C26H27N3O2 • C4H4O4
Calc'd: C, 68.04; H, 5.90; N, 7.93
Found: C, 67.80; H, 6.07; N, 7.93
EXAMPLE 2
N-[(trans)-3-(1H-indol-3-vl)cyclopentvn-N-fr(2S)-8-methvl-2,3-
dihvdrori,41dioxinof2.3-f|quinoli-2-vnmethyI}-amine
[0102] This compound was prepared in a manner similar to Example 1, using
toluene-4-sulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yl methyl
ester (0.3 g, 0.77 mmol) and trans-3-(1H-indol-3-yl)-cyclopentylamine (0.26 g,
1.30 mmol) to give 0.06 g (18%) of the desired product as its fumarate salt: MS
(ESI) m/z 414 [M+Hf.
Elemental Analysis for: C26H27N3O2 • C4H4O4
Calc'd: C, 68.04; H, 5.90; N, 7.93
Found: C, 67.76; H, 5.99; N, 8.23
-48-

EXAMPLE 3
N-r(cisV-3-(5-fluoro-1H-indol-3-vl)cvclopentvn-N-ff(2SV8-methv»-2,3-
dihvdron,4]dioxinor2,3-flquinolin-2-vnmethvUamine
[0103] Toluene-4-sulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-
2-yl methyl ester (0.48 g, 1.2 mmole) and cis-3-(5-fluoro-1 H-indol-3-yl)-
cyclopentylamine (0.35 g, 1.6 mmole) were combined in 5 mL of DMSO under
nitrogen. This solution was stirred and heated at 100°C under nitrogen for 5
hours. After the reaction was allowed to stand at room temperature overnight it
was stirred and heated at 100 "C for 3 hours more. The solvent was evaporated
at reduced pressure. The residue was partitioned between EtOAc and water.
The organic layer was washed with water twice, dried over magnesium sulfate
and concentrated in vacuum. The crude residue was column chromatographed
on silica gel with a gradient of EtOAC and hexane. Ther residue was dissolved in
EtOH and anrexcess of HCI/EtOH was added. Filtration of the precipitate
afforded 0.14 g of the title compound as a light yellow solid: mp > 230 °C (dec),
MS (APCI) m/z432 (M+H)+.
Elemental Analysis for. C26H26FN3O2»2HCI .0.5H2O
Calc'd: C, 60.82; H, 5.69; N, 8.18
Found: C, 60.50; H, 5.76; N, 7.75
[0104] The diastereomers of a 220 mg sample of the above compound were
separated by preparative chiral HPLC (Chiralcel OD 25 x 2 cm , 20% of 0.1%
diethylamine /ethanol in hexane)
Isomer A: N-r(1R*.3S*)-3-f5-fluoro-1H-indol-3-vncvclopentvn-N-ff(2SV8-methvl-
2.3-dihvdrori,41dioxinor2,3-f1quinolin-2-vllmethvl)amine: 0.08 g as a colorless oil.
This was dissolved in EtOH and added to fumaric acid (0.0236 g, 0.203 mmole).
Filtration gave 0.0846 g of the title compound as a white powder. m.p. 232-
233°C, MS (ESI) m/z432 (M+H)+.
Elemental Analysis for: C26H26FN3O2. C4H4O4 • 0.25 H2O
Calc'd: C, 65.27; H, 5.57; N, 7.61
Found: C, 65.20; H, 5.50; N, 7.56
Isomer B: N-rnS*.3R*)-3-f5-fluoro-1H-indol-3-vncvclopentvn-N-(r(2S)-8-methvl-
2.3-dihvdrori,41dioxinof2,3-f|quinolin-2-yrimethvl)amine: 0.0781 g as a colorless
-49-

oil. This was dissolved in EtOH and added to fumaric acid (0.0223 g, 0.192
mmole). Filtration gave 0.0763 g of the title compound as a white powder: m.p.
234-235°C, MS (ESI) m/z 432 (M+H)+.
Elemental Analysis for: C26H26FN3O2-C4H4O4
Calc'd: C, 65.80; H, 5.52; N, 7.67
Found: C, 65.50; H, 5.39; N, 7.57
EXAMPLE 4
N-raransV3-(5-fluoro-1H-indol-3-vncvclopentvn-N-(r(2SV8-niethvl-2,3-
dihydrori,41dioxinof2,3-f1quinoli-2-vnrnethv!}amine
[0105] Toluene-4-sulfonic acid (2R)-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-
f]quinolin-2-yImethyl ester (0.40 g, 1.0 mmole) and trans-3-(5-fluoro-1H-indol-3-
yl)-cyclopentylamine (0.30 g, 1.4 mmole) were combined in 3 ml_ of DMSO. This
solution was stirred at 100°C under nitrogen for 18 hours. The reaction was
cooled to room temperature. The DMSO was evaporated under reduced
pressure. The residue was partitioned between ethyl acetate and saturated
aqueous sodium carbonate. The organic phase was washed twice with water,
once with brine, dried over magnesium suifate and concentrated in vacuum to
give an oil. The crude residue was column chromatographed on silica gel using a
gradient of EtOAC and hexane to give 0.15 g of the title compound as a yellow
oil. To a solution of this in EtOH was added fumaric acid (0.0399 g, 0.344 mmole)
in EtOH. Filtration gave 0.1471 g of the title compound as a light yellow powder:
dec. > 245°C, MS (ESI) m/z 432 (M+H)+.
Elemental Analysis for. C26H26FN3O2 * 0.5 C4H4O4 0.75 H2O
Calc'd: C, 66.85; H, 5.91; N, 8.35
Found: C, 66.91; H, 5.58; N, 8.02
[0106] The diastereomers of an 88 mg sample of the above compound were
separated by preparative chiral HPLC (Chiralcel OD 25 x 2 cm, ethanol).
Isomer A: N-r(1S*.3S*)-3-(5-fluoro-1H-indol-3-vncvclopentvn-N-ir(2S)-8-methvl-
2,3-dihvdrof1.41dioxinor2,3-f1quinolin-2-vnmethvl)amine: 0.0211 g as an oil. This
was dissolved in EtOH and fumaric acid (0.0061 g, 0.053 mmole) was added.
-50-

Filtration gave 0.0173 g of the title compound (hemi-fumarate) as a white solid
fumarate: mp > 250 °C (dec).
Isomer B: N-[(1 R*,3R*)-3-(5-fluoro-1 H-indoI-3-yl)cyclopentyl]-N-{[(2S)-8-methyl-
2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine: 0.025 as oil. This was
dissolved in EtOH and fumaric acid (0.0071 g, 0.061 mmole) was added. Filtration
gave 0.0180 g of the title compound (hemi-fumarate) as a white powder. m.p.
207-210°C.
EXAMPLE 5
N-r(clsV3-(5-fluoro-1-methvl-1H-indol-3-vl)cvclopentvn-N-fr(2SV8-methvl-2.3-
dihvdrori.41dioxinor2,3-f1quinoH-2-vnmethvl}amine
[0107] This compound was prepared in a manner similar to Example 1, using
toluene-4-sulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yl methyl
ester (0.42 g, 1.09 mmol) and 3-cis-(5-fluoro-1-methyl-1H-indol-3-yl)-
cyclopentylamine (0.32 g, 1.4 mmol) to afford 0.16 g (33%) of the desired product
as a thick oil which was converted to the fumarate salt: MS (ESI) m/z446 [M+H]Elemental Analysis for C27H2BFN3O2 • C4H4O4 • H20
Calc'd: C, 64.24; H, 5.91; N, 7.25
Found: C, 64.10; H, 5.73; N, 6.98
[0108] The diastereomers of a 340 mg sample of the above compound were
separated by preparative chiral HPLC (Chiralcel OD 25 x 2 cm , 0.1%
diethylamine/ethanol).
Isomer A: RT = 9.78 min: N-f (1 R*.3S*V3-(5-fluoro-1 -methvl-1 H-indol-3-
vncvclopentvn-N-{f(2S)-8-methvl-2,3-dihydrof1.41dioxinof2.3-f1quinoli-2-
vnmethvllamine was characterized as its hemi-fumarate salt, hemi-hydrate (white
solid): mp 199-200°C; MS (ESI) m/z446 [M+H]+; [a]D -24.0° (c 1.0, DMSO)
Elemental Analysis for: C27H28FN3O2 • 0.50 C4H4O4 • 0.50 H20
Calc'd: C, 67.95; H, 6.10; N, 8.20
Found: C, 67.61; H, 5.77; N, 7.91
Isomer B: RT = 11.24 min: N-ff 1 S*.3R*)-3-(5-fluoro-1 -methvl-1 H-indol-3-
vncvclopentvll-N-{rf2S)-8-methvl-2,3-dihvdrof1,41dioxinor2.3-f1quinoli-2-
-51 -

ylimethvllamine was characterized as its fumarate salt (white solid): mp 200-
201 °C; MS (ESI) m/z446 [M+Hf; [a]D -32.4° (c0.54, DMSO)
Elemental Analysis fon C27H28FN3O2
Calc'd: C, 66.30; H, 5.74; N, 7.33
Found: C, 66.10; H, 5.70; N, 7.33
EXAMPLE 6
N-fftransV3-(5-fluoro-1-methvl-1H-indol-3-vncvclopentvn-N-ff(2S)-8-methv»-
2,3-dihvrori,41dioxinof2,3-f1quinolin-2-vnmethvl>amine
[0109] This compound was prepared in a manner similar to Example 1, using
toIuene-4-sulfonic acid 8-methyI-2,3-dihydro-[1,4]dioxino[2,3-f|quinolin-2-yl methyl
ester (0.49 g, 1.27 mmol) and trans-3-(5-fluoro-1-methyl-1H-indol-3-yl)-
cyclopentylamine (0.41 g, 1.8 mmol) to afford 0.26 g (56%) of the desired product
as a thick oil which was converted to the fumarate salt: MS (ESI) m/z 446 [M+H]1"
Elemental Analysis for C27H28FN3O2* C4H4O4
Calc'd: C, 66.30; H, 5.74; N, 7.48
Found: C, 65.93; H, 5.82; N, 7.35
EXAMPLE 7
fcisVN-r4-(5-fluoro-1H-indol-3-vncvclohexvn-N-fK2S)-8-methvl-2.3-
dihvdrori,41dioxinor2.3-f1quinolin-2-vnmethvl|amine
[0110] This compound was prepared in a manner similar to Example 1, using
toluene-4-sulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl
ester (0.5 g, 1.29 mmol) and cis-4-(5-f luoro-1 H-indol-3-yl)-cyclohexylamine (0.4 g,
1.72 mmol) to give 0.116 g (20%) product as an oxalate salt: MS (ESI) m/z 446
[M+H]+.
Elemental Analysis for: C27H28FN3O2 • C2H2O4 • 1.5 H2O
Calc'd: C, 61.91; H, 5.91; N, 7.47
Found: C, 62.03; H, 5.34; N, 7.10
-52-

EXAMPLE 8
(trans)-N-[4-(5-fiuoro-1H-indol-3-vncvclohexvn-N-{r(2SV8-methyl-2,3-
dihydrori,41dioxinor2,3-f1quinolin-2-vnmethvl|amine
[0111] This compound was prepared in a manner similar to Example 1, using
toluene-4-sulfonic acid 8-methyl-2T3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl
ester (0.5 g, 1.29 mmol) and trans-4-(5-fluoro-1H-indol-3-yl)-cyclohexylamine (0.4
g, 1.72 mmol) to give 0.09 g (18%) product as the fumarate salt MS (ESI) m/z
446 [M+H]+.
Elemental Analysis for. C27H28FN3O2 • C4H4O4
Calc'd: C, 66.30; H, 5.74; N, 7.48
Found: C, 66.54; H, 5.94; N, 7.91
EXAMPLE 9
N-r{cisV3-(5-fluoro-1H-indol-3-vl)cvclopentvn-N-methvl-N-ffl2S)-8-methv»-2,3-
dihvdrori,41dioxinof2.3-f1quinolin-2-vnmethvllamine
[0112] To a suspension of N-[(cis)-3-(5-fluoro-1H-indol-3-yl)cyc!opentyl]-N-
{[(2S)-8-methy!-2,3-dihydro[1,4]dioxino[2,3-f|quinolin-2-yl]methyl} fumarate
(Example 3-lsomer B, 190 mg, 0.347 mmol) and 100 μL (1.41 mmol) of
formaldehyde solution in 2 mL of THF was added sodium triacetoxyborohydride
(300 mg, 1.41 mmol). The resulting mixture was stirred at ambient temperature
for 24 hours. At that time, additional formaldehyde (100 μL, 1.41 mmol) and
sodium triacetoxyborohydride (275 mg, 1.30 mmol) were added. After stirring an
additional 3 hours, the reaction was diluted with saturated aqueous sodium
bicarbonate solution (40 mL) and extracted with dichloromethane (3 x 25 mL).
The combined organic layers were washed with brine (40 mL), then were dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography (2 x 20 cm SiO2, 3% MeOH/CH2CI2) afforded 126 mg (82%) of
the desired product, which was converted to its fumarate salt as a yellow solid:
[od]D -1.9° (c 1.0, MeOH); MS (ESI) m/z445 [M]+.
Elemental Analysis for: C27H28FN3O2 • C4H4O4 • 1.5 H2O • 0.10 C4H8O2
Calc'd: C, 63.13; H, 6.04; N, 7.03
Found: C, 63.41; H, 5.69; N, 6.64
-53-

EXAMPLE 10
N-r(trans)-3-(5-Fluoro-1H-indoI-3-vncvclopentvn-N-{rf8SV2-methvl-7,8-
dihydropl ,41dioxinor2,3-g1f 1 ,31benzoxazol-8-vllmethyl)amine
[0113] Toluene-4-sulfonic acid (8R)-2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-
cyclo-penta[a]naphthlen-8-ylmethyl ester (0.46 g, 1.2 mmole) and 3-(5-fluoro-1H-
indol-3-yl)-cyclopentylamine (0.27 g, 1.2 mmole) were combined in 8 mL of
DMSO under nitrogen. This solution was heated to 75-80°C under nitrogen for 5
hours. After cooling to room temperature, the reaction was partitioned between
ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase
was washed with brine, dried over magnesium sulfate and concentrated in vacuo.
Rash chromatography on silica gel (CH2CI2 then 1% MeOH/CH2CI2) afforded
0.175 g of the title compound as an off-white solid: m.p. 79-82 °C; MS (ESI) m/z
422 (M+H)+.
Elemental Analysis for: C24H24FN3O3»0.18CH2CI2
Calc'd: C, 66.50; H, 5.62; N, 9.62
Found: C, 66.87; H, 5.79; N, 9.25
EXAMPLE 11
N-rfcis)-3-(5-Fluoro-1H-indol-3-vl)-cvclopentvn-N-frf8Sy-2-methvl-7.8-
dihydroli ,41dioxinor2,3-g1f1,31benzoxazol-8-vllmethyl)amine
[0114] Toluene-4-sulfonic acid (8R)-2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-
cyclopenta-[a]naphthylen-8-ylmethyl ester (0.38 g, 1.0 mmole) and 3-(5-Fluoro-
1 H-indol-3-yI)-cyclopentyIamine (0.50 g, 2.3 mmole) were combined in 8 mL of
DMSO under nitrogen. This solution was heated to 80°C under nitrogen for 5
hours. After cooling to room temperature, the reaction was partitioned between
ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase
was washed with brine, dried over magnesium sulfate and concentrated in vacuo.
Flash chromatography on silica gel (CH2CI2then 1% MeOH/CH2CI2) afforded 0.23
g of the title compound as a white solid: m.p. 79-82 °C; MS (ESI) m/z 422
(M+H)+.
Elemental Analysis for. C24H24FN3O3
Calc'd: C, 68.39; H, 5.74; N, 9.97
-54-

Found: C, 68.52; H, 6.11; N, 9.58
EXAMPLE 12
N-[(cis)-4-(5-fluoro-1H-indol-3-vncvc!ohexvn-N-fr(8SV2-methvl-7.8-
dihydropl ,41dioxinor2,3-qin ,31benzoxazol-8-vnmethyl)anriine
[0115] Toluene-4-sutfonic acid (8R)-2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-
cyclopentata]naphthlen-8-ylmethyl ester (0.52 g, 1.39 mmole) and cis-4-(5-fluoro-
1 H-indol-3-yI)-cyclohexylamine (0.60 g, 2.6 mmole) were combined in 10 mL of
anhydrous DMSO under nitrogen. This solution was heated to 80°C under
nitrogen for 5 hours. After cooling to room temperature, the reaction was
partitioned between ethyl acetate and saturated aqueous sodium bicarbonate.
The organic phase was washed with brine, dried over magnesium sulfate and
concentrated in vacuo. Flash chromatography on silica gel (CH2CI2 then 1%
MeOH/CH2CI2) afforded 0.26 g of the title compound as a light yellow solid: m.p.
80-82°C; MS (ESI) /n/z436 (M+H)Elemental Analysis for: C25H26FN3O3. 0.16 C6H14 0.04 CH2CI2
Calc'd: C, 68.99; H, 6.31; N, 9.28
Found: C, 68.92; H, 6.71; N, 8.89
EXAMPLE 13
N-[(R*,3S*)-3-(5-fluoro-1H-indol-3-vncvc1opentv^N-methvl-N-ff(2S>-8-methvl-
2,3-dihvdrori,41dioxinor2.3-flquinolin-2-vnmethyl)amine
[0116] To a mixture of N-[(1R*,3S*)-3-(5-fluoro-1H-indol-3-yl)cyclopentyl]-N-
{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine fumarate
(200 mg, 0.365 mmol) and formaldehyde (37%, 50 μL, 0.67 mmol) in 2:1
tetrahydrofuran/methanol (3 mL) was added sodium triacetoxyborohydride (155
mg, 0.73 mmol). The reaction was allowed to stir at ambient temperature
overnight, then was quenched with saturated aqueous sodium bicarbonate (20
mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers
were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. Flash chromatography (2 x 20 cm silica gel, 3%
methanol/methylene chloride) afforded 115 mg (70%) of the title compound as a
-55-

semi-solid, which was converted to its fumarate salt as a white powder: mp 198-
199°C (dec); MS (ES) m/z 446 [M+H]+. [cc]D 5.3° (c 1.0, DMSO)
Elemental Analysis for: C27H28FN3O2 0.5 C4H404 - 0.5 H2O
Calc'd: C, 67.95; H, 6.10; N, 8.20
Found: C, 68.16; H, 5.88; N, 7.98
[0117] When ranges are used herein for physical properties, such as molecular
weight, or chemical properties, such as chemical formulae, all combinations and
subcombinations of ranges specific embodiments therein are intended to be
included.
[0118] The disclosures of each patent, patent application, and publication cited
or described in this document are hereby incorporated herein by reference, in
their entirety.
[0119] 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.
-56-

WE CLAIM:
1. A compound of formula I:

wherein:
R1 is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6
carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy
of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each
alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon
atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
R2 is hydrogen or alkyl of 1 to 6 carbons;
the group X—Y is -N=C(R3)-C(R4)=N-, -N=C(R3)-C(R5)=CH-,
-N=C(R3)-N=CH-, -N=C(R3)-O-, -NH-C(R6)=N- or -NH-C(R7)=CH-;
R3 and R4 are, independently, hydrogen, halo, amino, mono- or di-
alkylamino in which each alkyl group has 1 to 6 carbon atoms or alkyl of
1 to 6 carbon atoms;
R5 is hydrogen or alkyl of 1 to 6 carbon atoms;
R6 is hydrogen, halo, trifluoromethyl, pentafluoroethyl, amino, mono- or di-
alkylamino in which each alkyl group has 1 to 6 carbon atoms or alkyl of
1 to 6 carbon atoms;
R7 is hydrogen, halo, trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6
carbon atoms;
Q is a heteroaryl moiety selected from the following:
-57-


wherein Z is NR12, S, or O;
R8, R9, R10, arid-R11are, independently,- hydrogen, hydroxy,. halo, cyano,
carboxamido, carboaikoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl
of 1 to 6 carbon atoms, aikanoyloxy of 2 to 6 carbon atoms, amino,
mono- or di-alkylamino. in which each alkyl group has 1 to 6 carbon
atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to
6 carbon atoms;
R12 is hydrogen or alkyl of 1 to 6 carbon atoms;
m is 1 to 3;
n - is 1 to 2; and
p is 0 to 3;
or pharmaceuticaliy acceptable salts thereof.
2 A compound according to claim 1, wherein n is 2 and m is 1 or
pharmaceuticaHy acceptable salts thereof.
3. A compound according to claim 1 or 2, wherein p is 0 or pharmaceuticaliy
acceptable salts thereof.
4: . AxaampDund according to any one of claims 1 to 3, wherein the group X-Y
-is.-N=C(R3)-C(Rs)=CH- or -N=C(R3)-O- or pharmaceuticaHy acceptable salts
thereof.
5;—A compound according to any: one" of claims 1 to 4, wherein Q is a
- heteroaryl moiety of the formula
-58-


8. - The compound of claim 1 which-is N-[(cis)-3-(fH'indol-3-yl)cyc!opentyl]-N-
{[(2S}-8-methyl-2,3^dihydroE1,4]dioxino[2,3-flquinolin-2-yl3methy!}amine
or a pharmaceutically acceptable salt thereof.
- 59 -

,9. _.The.compound of.claim 1 which.is.-N-[(trans)-3-{1H-indol-3-yl)cyclopentyl]-
. N-{[(2S)-B-mithyl-2,3-dihydro[1,4]dioxino[2,3-flquinllin-2-yI]methyl]amtne or a
. -pharmaceuticaUy acceptable salt thereof.
10: The. compound of claim .1 which, is N-[(cis)-3=(5-fluoro-1H-indol-3-
yl)cyclopentyrj-N-{[(2S)-8-methy!-2,3-dihydro[1,4]dioxino[2,3-f]quinoiin-2-
- yl)methy}}arnine or a pharmaceuticaiiy acceptable sait thereof.
11.--The compound of claim 1 which is N-[(fR;3S)-3-t5-f!uoro-1H-indol-3-
yl)cyc!opentyi]-N-(I{2S}-&=rnethyl-2,3-dihydroI1,"4]dioxino[2,3-f]quinoiin-2-
yl]meihyljamine or a pharmaceutieally acceptable salt thereof.
12. The compound of claim 1" which is N-[(1S.3R)-3-(5-fluoro-1HHndoi-3-
yl)cydopentyl]-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyj}amine.orra pharmaceuticalJy. acceptable salt thereof.
13. . The. compound of claim 1 which is N-[(trans)-3-(5-fIuoro-1HH*ndol-3-
yl)cyclopentyl]-N"{[(2S)-8^rnethyl-2,3-dihydroI1,4]dioxino[2,3-i]quinolin-2-
yl]rnethyl}amine or a~pharmacentica]Iy acceptable sail thereof.
14. - The compound of claim 1 which is N-{(1 R,3R)-3-(5-fluoro-1 H-indol-3-
yi)cyclopentyl]-N-{t(2S)-8-methyl-2,3-dihydro[1>4]dioxino[2,3-f]quinolin-2-
yi]methyi}amine or a pharmaceuticaiiy acceptable sait thereof.
15. The compound of claim 1 which is N-[(1S,3S)-3-(5-fluoro-1H-indol-3-
yl)cyclopentyl]-N-{[(2S)-8-methyl-2,3-dihydro[1J4]dioxino[2,3-f]quinolin-2-
yl]methyl}amine or a pharmaceuticaiiy acceptable salt thereof.
16. The compound of claim 1 which is N-[(cis)-3-(5-fluoro-1H-indol-3-
yl)cyclopentyl]-N-methyl-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-
2-yl]methyl}amine or a pharmaceuticaiiy acceptable salt thereof.
-60-

17-. The compound of claim 1 which-is.N'{(cis)-3-(5-fluoro-1-methyl-1H-indol-3-
yl)-c1opentyl]N-{[{2S)-8-methyl-2,3--dhydro[1,4]-dioxino[2,3-f]quino!in-2-
yl]methyl}arnine or-a pharmaceatically acceptable salt thereof.
18. The compound of claim 1 which is N-[(1 R,3S)-3-(5-fluoro-1 -methyl-1 H-indol-
3-yl)cyc}QpetityJ]-N-{[{2S)-8-fnethyl-293-dihydro[1,4]diox5no{2J3-f]quinolir»-2-
yl]raefliyl}amine-Of a pharraaceutically acceptable salt thereof.
13. The compound of efairri 1 which is N-[(1 S,3R)-3-(5-fluoro-1 -methy]-1 H-indoI-
3^yl)cydDpentyl3-N-{l(2S)-8-methyl213-dihydro[1,4]dioxinol2,3-f3quinoliri-2-
yl]methyl]amineoraphammaceaticatiy acceptable salt thereof.
20. The compound of claim 1 which is N-[(trans)-3-(5'fluoro-1-Tnetliy]-1H-indol-
3-yl)cycbpentyf]-N-{{[2S)-8-methyl-'2-,3-dhydro[1,4]dio»not2f3-f]quinolin-2-
yi]methyi}araine or a pharmaceutically acceptable salt thereof.
21. The compound of claim 1 which is N-{{cis)-4-(5-fluoro-1 H-indol-3-
ylcyclohexyl]-N-{{(2S)-8-methyl-2,3-dihydro[2,3-f]quinolin-2-
yl]methyr}amine.or a pharmaceuticaily acceptable salt thereof.
22. The compound of claim 1 which is N-{(trans)-4-(5-f1uoro-1 H-indoi-3-
yl)cyolohexyl]-N-{[(2S)-8-methy!-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-
yl]methyl]amineor-a pharmaceutically acceptable salt thereof.
23. The compound of claim -1 which is N-{{irans)-3-(S-Huoro-1H-indol-3-
yl)cydopentyl]-N-{ft6S)-2-methyl-7,8-dJhydrot1,4-g]dioxino[2,3-g][1,3g]benzoxazol-8-
yl]methyl}amine orapharmaceutically acceptable salt there of.
24. The compound of claim .1 which is N-{(cis)-3-(5-Fluoro-1H-indol-3-
yl)cycJopentyl]-N-{[(8S)-2-methy^7,8-dihydro[1,4]dioxino[2,3-g3[1,3]benzoxazoI-8-
yi]methyl}amine or a pharmaceuticaily acceptable salt thereof.
-61-

25. The compound of claim 1 which is N-[(cis)-4-(5-fluoro-1H-indol-3-
yl)cycIohexyl]-N-{[(8S)-2-methyl-7)8-dihydro[1>4]dioxino[2,3-g][1,3]benzoxa2ol-8-
yl]methyl}amine; or a pharmaceutically acceptable salt thereof.
26. The compound of claim 1 which is N-[(1R*,3S*)-3-(5-fluoro-1H-indol-3-
yl)cyclopentyl]N-methyl-N-{{(2S)-8-methyl
2-yl]methyl}amine; or-a pharmaceutfcaliy acceptable salt thereof.
.27.- A-method .of-treating.a subject suffering" from a condition selected from
depression,, anxiety,-, panic disorder, post-traumatic stress disorder, premenstrual
dysphoric disorder,- attention -deficit -disorder, obsessive compulsive disorder,
social anxiety disorder,--generalized anjdety disorder-, obesity, eating disorders,
vasomotor flushing, cocaine and alcohol addiction, and sexual dysfunction,
comprising the'-step of'providing-to the subject suffering from said condition, a
therapeutically effective amount of a compound as-daimed in any one of claims
1 to 26.
28. The method of claim 27, wherein the condition is depression.
29. The method of claim 27, wherein the condition is selected from the group
consisting of obsessive compulsive disorder, panic attacks, generalized anxiety
disorder, and social anxiety disorder.
30 A .pharmaceutical composition, comprising an effective amount of
compound as claimed fn any one of claims 1 to 26 and a pharmaceuticaily
acceptable carrier or excipient.
3.1 A. compound as claimed in any-one of claims 1 to 26 for use as a
medicament.
32. Use of "a compound as claimed in any one of-claims 1 to 26 in the
preparation of. a medicament -for ihe -treatment of jdepression, anxiety, panic
-disarcterr post traumatic stress' disorder, premenstrual dysphoric disorder,
-62-

attention deficit disorder, obsessive compulsive disorder, social anxiety disorder,
generalized anxiety disorder, obesity, eating disorders, vasomotor flushing,
cocaine and alcohol addiction, and sexual dysfunction.
33. Use according to claim 32, wherein the condition is depression.
34. Use according to claim 32, wherein the condition is selected from the group
consisting of obsessive compulsive disorder, panic disorder, generalized anxiety
disorder, and social anxiety disorder.
35". A pharmaceutical composition substantially as herein described
particularly with reference to the examples .
Dated this 15th day of May 2007

Compounds of the formula: I are useful for the treatment of 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 pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive compulsive
disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders, vasomotor flushing, cocaine and alcohol
addiction, sexual dysfunction and related illnesses.