Method and apparatus for manure treatment
FIELD OF THE INVENTION
The present invention relates to pharmacologically active aryl piperazines, or
pharmaceutically acceptable salts and esters thereof, as well as to pharmaceutical
compositions comprising them and to their use as alpha2C antagonists. The compounds of
the invention can be used in their labeled or unlabeled form.
BACKGROUND OF THE INVENTION
It is generally known and accepted in the art that compounds exhibiting alpha adrenergic
activity may be used for the treatment of a wide variety of diseases and conditions of the
peripheric system and the central nervous system (CNS).
The alpha adrenergic receptors can be divided on a pharmacological basis into alphal and
alpha2 adrenoceptors, which can both be further divided into subtypes. Three genetically
encoded subtypes, namely alpha2A, alpha2B, and alpha2C adrenoceptors, have been
discovered in human. A fourth pharmacologically defined subtype, namely alpha2D
adrenoceptor, is known in some other mammals and in rodents. It corresponds to the
genetically defined alpha2A adrenoceptor.
The alpha2 adrenoceptor subtypes have distinct tissue distributions and functional roles. For
instance, while alpha2A adrenoceptors are widely expressed in various tissues, alpha2C
adrenoceptors are concentrated in the CNS and appear to play a role in the modulation of
specific CNS mediated behavioral and physiological responses.
Some compounds that are non-specific for any of the above-mentioned alpha2 subtypes and
some compounds that are specific for certain alpha2 subtypes are known in the art. For
example, atipamezole disclosed in EP 183 492 Al (compound XV at page 13) is a non-
specific alpha2 antagonist. Compounds that are selective antagonists for the alpha2C
subtype and are useful for the treatment of mental illness, e.g. mental disturbance induced
by stress, are described in US 5,902,807. Such compounds are, for example, MK-912 and
BAM-13 03. Imidazole derivatives having agonist-like activity for alpha2B or 2B/2C
adrenoceptors are disclosed in iso 99/28300. Quinoline derivatives useful as alpha2

antagonists are disclosed in iso 01/64645 and iso 2004/067513. Arylquinolizine
derivatives useful as alpha2 antagonists are disclosed in iso 03/082866.
In order to be able to reduce the risk of adverse events during treatment, an enhanced
selectivity of the alpha2 antagonists, isould be desirable. For example, the use of non-
selective alpha2 antagonists is attributed with side effects, such as increases in blood
pressure, heart rate, salivary secretion, gastrointestinal secretion, and anxiety. Also an
enhanced potency of the alpha2C antagonists isould be desirable, in order to be able to
reduce the dose needed.
As to known aryl piperazines, l-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine has been disclosed in US 3,362,956. l-(Chroman-2-ylmethyl)-4-
O-tolylpiperazine has been disclosed in Indian J. Chem. 20B (1981) 1063. A fluorophenyl
piperazine has been disclosed for example, in Eur. J. Med. Chem. 35 (2000) 663..
SUMMARY OF THE INVENTION
An object of the present invention is to provide further alpha2C antagonists that can be used
for the treatment of diseases or conditions of the peripheric or central nervous system
wherein alpha2C antagonists are indicated to be useful. Accordingly, an object of the
present invention is to provide further compounds to be used as alpha2C antagonists in the
treatment of mammals. Furthermore, pharmaceutical compositions comprising the present
compounds are provided.
The alpha2 antagonists of the present invention have an improved selectivity for the
alpha2C adrenoceptor subtype and/or an enhanced potency.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel alpha2C antagonists having the general formula I,


wherein
X is O,S or CH2;
Z is-[CH2]n-;
A, B, D and E are independently C or N provided that at least three of A, B, D and E are C;
R1 is H, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)
alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyl5 hydroxy(C1-C6)
alkoxy(C1-C6)alkyl,(C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl,(C1-C6)alkoxy-(C1-C6)-,
CN, (R5)2N-, (R5)2N-(C1-C6)alkyl, (R5)2N-(CO)-, Sn-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-
S(C1-C6)allcyl,(C1-C6)alkoxy(C1-C6)alkyI-S-(C1-C6)alkyl,hydroxy(C1-C6)alkyl-S(Op)-(C1-C6)
alkyl, (C1-C6)alkoxy(C1-C6)alkyl-S(Op)-(C1-C6)alkyl or furyl;
R2 is H, halogen, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy(C1-C6)alkyl;
R3 is H, halogen, (C1-C6)alkyl or phenyl;
R4 is halogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, CN or (R5)2N-;
R5 is, independently at each occurence, H, (C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl;
m is 0, 1 or 2;
n is 1 or 2; and
p is 1 or 2,
in labeled or unlabeled form, or a pharmaceutically acceptable salt or ester thereof,
with the provisos, that
a) R1, R2 and R3 are not simultaneously H;
b) when A is C and tiso of R1, R2 and R3 is H, then the third of R1, R2 and R3 is not halogen;
c) the compound is not l-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(2-
methoxyphenyl)piperazine, l-(chroman-2-ylmethyl)-4-o-tolylpiperazine or l-((2,3-
dihydrobenzo [b] [ 1,4]dioxin-2-yl)methyl)-4-(6-methylpyridin-2-yl)piperazine.
In a possible subgroup of the compounds of formula I, X is O.
In a further possible subgroup of the compounds of formula I, A, B, D and E are C.
In another possible subgroup of the compounds of formula I, A is N; and B, D and E are C.
In a further possible subgroup of the compounds of formula I, n is 1.
In a further possible subgroup of the compounds of formula I, n is 2.

In another possible subgroup of the compounds of formula I,
X is 0, S or CH2;
Z is-[CH2]n-;
A is C or N;
B, D and E are C;
R1 is H, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)
alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-, CN,
(R5)2N-(C1-C6)alkyl, (R5)2N-(C=O)- or furyl;
R2 is H, halogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;
R3 is H, (C1-C6)alkyl or phenyl;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
. m is 0; and
n is 1 or 2; for example
X is O ;
Z is-[CH2]n-;
A is C or N;
B, D and E are C;
R1 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)
alkyl, halo(C1-C6)alkoxy,halo(C1-C6)alkoxy(C1-C6)alkyl5 (C1-C6)alkoxy-(C=O)-, CN,
(R5)2N-(C1-C6)alkyl, (R5)2N-(C=O)- or furyl;
R2 is H, halogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;
R3 is H, (C1-C6)alkyl or phenyl;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is 1 or 2; such as
X is O;
Z is-[CH2]n-;
A, B, D and E are C;
R1 is (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy,
halo(C1-C6)aIkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-, CN, (R5)2N-(C1-C6)alkyl, (R5)2N-
(C=O)-or furyl;

R2 is H or halogen;
R3 is H;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is 1 or 2; or
X is O ;
Z is-[CH2]n-;
A is N;
B, D and E are C;
R1 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)
alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-, CN,
(R5)2N-(C1-C6)alkyl, (R5)2N-(C=O)- or furyl;
R2 is H or halogen;
R3 is H;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is 1 or 2; or
X is O;
Z is-[CH2]n-;
AisN;
B, D and E are C;
R1 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)
alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-, CN,
(R5)2N-(C1-C6)alkyl, (R5)2N-(C=O)- or furyl;
R2 is H, halogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;
R3 is H, (C1-C6)alkyl or phenyl;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is l;or
X is O;
Zis-[CH2]n-;

A is N;
B, D and E are C;
R1 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)
alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-, CN,
(R5)2N-(C1-C6)alkyl, (R5)2N-(C=O)- or foryl;
R2 is H, halogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyI;
R3 is H, (C1-C6)alkyl or phenyl;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is 2; or
X is O;
Zis-[CH2]n-;
A, B, D and E are C;
R1 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)
alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-, CN,
(R5)2N-(C1-C6)alkyl, (R5)2N-(C=O)- or foryl;
R2 is H, halogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;
R3 is H, (C1-C6)alkyl or phenyl;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is 1; or
X is O;
Zis-[CH2]„-;
A, B, D and E are C,
R1 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)
alkyl, halo(Cl-C6)alkoxy, halo(CrC6)alkoxy(Cl-C6)alkyl, (C1-C6)alkoxy-(C=0)-, CN,
(R5)2N-(C1-C6)alkyl, (R5)2N-(C=O)- or foryl;
R2 is H, halogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;
R3 is H, (C1-C6)alkyl or phenyl;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and

n is 2.
In yet another possible subgroup of the compounds of formula I, the compound is methyl 2-
(4-((2,3-dihydrobenzo[b] [1,4]dioxin-2-yl)methyl)piperazin-l-yl)benzoate, (2-(4-((2,3-
dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)phenyl)methanol, l-((2,3-
dihydrobenzo[Z] [1,4]dioxin-2-yl)methyl)-4-(2-(methoxymethyl)phenyl)piperazine5 2-(4-
((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)benzonitrile, (2-(4-((2,3-
dihydrobenzo [b] [ 1,4]dioxin-2-yl)methyl)piperazin-1 -yl)phenyl)methanamine, 1 -(2-(4-((2,3 -
dihydrobenzo[b][l,4]dooxin-2-yl)methyl)piperazin-l-yl)phenyl)-iV'-methylmethanamine, 1-
((2,3-dihydrobenzo[b][l,4]dioxm-2-yl)memyl)-4-(2-(emoxymethyl)phenyl)piperazine, 2-(2-
(4-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)phenyl)propan-2-ol, 1-
((2,3 -dihydrobenzo [b] [ 1,4] dioxin-2-yl)methyl)-4-(3 -(methoxymethyl)pyridin-2-
yl)piperazine, (S)-(2-(4-((7-fiuoro-2,3 -dihydrobenzo [b] [ 1,4] dioxin-2-yl)methyl)-piperazin-
l-yI)pyridin-3-yl)methanol, (5)-(2-(4-((7-fluoro-2,3-dihydrobenzo[Z][l,4]dioxin-2-
yl)methyl)-piperazin-1-yl)pyridin-3-yl)methanol-HCl, (S)-1-((7-fiuoro-2,3 -
dihydrobenzo[6] [14]dioxin-2-yl)methyl)-4-(3-(methoxymethyl)pyridin-2-yl)piperazine
•HCl,(5)-l-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(3-((2-
fluoroethoxy)methyl)pyridin-2-yl)piperazine, 1 -(2,3-dichlorophenyl)-4-((2,3 -
dihydrobenzo [6] [1,4] dioxin-2-yl)methyl)piperazine, (2-(4-((2,3-
dihydrobenzo[b] [ 1,4] dioxin-2-yl)methyl)piperazin-1-yl)pyridin-3 -yl)methanol, (S)-(2-(4-
((2,3 -dihydrobenzo [b] [ 1,4] dioxin-2-yl)methyl)piperazin-l -yl)pyridin-3 -yl)methanol, (S)-1 -
((2,3 -dihydrobenzo [b] [ 1,4] dioxin-2-yl)methyl)-4-(2-(methoxymethyl)phenyl)piperazine,
(R)1-((2,3-dihydrobenzo[b][l ,4]dioxin-2-yl)methyl)-4-(2-
(methoxymethyl)phenyl)piperazine, (S)-(2-(4-((2,3-dihydrobenzo [6] [1,4]dioxin-2-
yl)methyl)piperazin-1 -yl)phenyl)methanol, (5)-1 -((2,3-dihydrobenzo [b] [ 1,4] dioxin-2-
yl)memyl)-4-(3-(methoxymethyl)pyridin-2-yl)piperazine, (l-((2,3-
dihydrobenzo[b] [ 1,4]oxathiin-2-yl)methyl)-4-(2-(methoxymethyI)phenyl)piperazine, 1 -
(chroman-2-ylmethyl)-4-(2-(methoxymethyl)phenyl)piperazine, (2-(4-((2,3-
dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)-6-fluorophenyl)methanol, (2-(4-
((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyi)piperazin-'l-yl)-3-fluorophenyl)methanol, (2-
(4-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)-5-fluorophenyl)methanol,
(5)-l-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(2-propylphenyl)piperazine, (S)-l-
((2,3-dmydrobenzo[b][l,4]dioxin-2-yl)memyl)-4-(2-(1rifluoromethoxy)phenyi)piperazine,

(S)-1-(biphenyl-3-yl)-4-((2,3-dihydrobenzo[b][ 1,4]dioxin-2-yl)methyl)piperazine, (S)-1 -
((2,3-dihydrobenzo[6] [1,4]dioxin-2-yl)methyl)-4-(2-(furan-2-yl)phenyl)piperazines (5)-ethyl
2-(4-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)benzoate5 (5)-l-((2,3-
dihydrobenzo [b] [ 1,4]dioxin-2-yl)memyl)-4-o-tolyipiperazine, (S)-1 -((2,3 -
dihydrobenzo [b] [1 ,4]dioxin-2-yl)methyl)-4-m-tolylpiperazine, (S)-(3-(4-((2,3-
dihydrobenzo[b]][l,4]dioxin-2-yl)methyl)piperazin-l-yl)4-methylphenyl)methanol(5)-(3-
(4-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yI)phenyl)methanol, (S)-2-(2-
(4-((2,3 -dihydrobenzo [b] [ 1,4]dioxin-2-yl)methyl)piperazin-1 -yl)phenyl)ethanol, methyl 2-
(4-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-l,4-diazepan-l-yl)benzoate,(2-(4-((2,3-
dihydrobenzo [b] [ 1,4]dioxin-2-yl)methyl)-1,4-diazepan-1 -yl)phenyl)methanol, 2-(4-((2,3 -
dihydrobenzo[b][l,4]dioxin-2-yl)me11iyl)-l,4-diazepan-l-yl)nic)tinonitrile,2-(4-((233-
dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-1,4-diazepan-1 -yl)nicotinamide, (2-(4-((2,3-
dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-l,4-diazepan-l-yl)pyridin-3-yl)methanol or (S)-(2-
(4-((2,3 -dihydrobenzo [b] [1,4] dioxin-2-yl)methyl)-1,4-diazepan-1-yl)pyridin-3-yl)methanol.
The terms employed herein have the meanings indicated below. The term "at least one"
employed in the meanings below refers to one or several, such as one.
The term "hydroxy", as employed herein as such or as part of another group, refers to a -OH
group.
The term "(C1-C6)alkyl", as employed herein as such or as part of another group, refers to a
straight or branched chain saturated hydrocarbon group having 1,2, 3, 4, δ or 6 carbon
atom(s). Representative examples of (C1-C6)alkyl include, but are not limited to, methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tot-butyl, n-pentyl, iso-pentyl, and
n-hexyl.
The term "(C1-C6)alkoxy", as employed herein as such or as part of another group, refers to
an (C1-C6)alkyl group, as defined herein, appended to the parent molecular moiety through
an oxygen atom. Representative examples of (C1-C6)alkoxy include, but are not limited to,
methoxy, ethoxy, n-propoxy, n-butoxy, iso-butoxy, sec-butoxy, teri-butoxy,
2,2-dimethylpropoxy, 3-methylbutoxy, and n-hexoxy.
The term "halo" or "halogen", as employed herein as such or as part of another group, refers

to fluorine, chlorine, bromine or iodine.
The term "hydroxy(C1-C6)alkyl", as employed herein as such or as part of another group,
refers to at least one hydroxy group, as defined herein, appended to the parent molecular
moiety through an (C1-C6)alkyl group, as defined herein. Representative examples of
hydroxy(C1-C6)alkyl include, but are not limited to, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 2,2-dihydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-
1-methylethyl, and 1 -hydroxy-1 -methylpropyl.
The term "(C1-C6)alkoxy(C1-C6)alkyl", as employed herein as such or as part of another
group, refers to at least one (C1-C6)alkoxy group, as defined herein, appended to the parent
molecular moiety through an (C1-C6)alkyl group, as defined herein. When there are several
(C1-C6)alkoxy groups, the (C1-C6)alkoxy groups can be identical or different.
Representative examples of (C1-C6)alkoxy(C1-C6)alkyl include, but are not limited to,
methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl,
2,2-dimethoxyethyl, l-methyl-2-propoxyethyl, 1-methoxy-l-methylethyl, and
4-methoxybutyl.
The term "hydroxy(C1-C6)alkoxy", as employed herein as such or as part of another group,
refers to at least one hydroxy group, as defined herein, appended to the parent molecular
moiety through an (C1-C6)alkoxy group, as defined herein. Representative examples of
hydroxy(C1-C6)alkoxy include, but are not limited to, hydroxymethoxy, dihydroxymethoxy,
2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 2-hydroxybutoxy, and 2-hydroxy-
1-methylethoxy.
The term "(C1-C6)alkoxy(C1-C6)alkoxy", as employed herein as such or as part of another ■
group, refers to at least one (C1-C6)alkoxy group, as defined herein, appended to the parent
molecular moiety through an (C1-C6)alkoxy group, as defined herein. The (C1-C6)aIkoxy
groups can be identical or different. Representative examples of
(C1-C6)alkoxy(C1-C6)aIkoxy include, but are not limited to, methoxymethoxy,
propoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-butoxyethoxy,
2,2-dimethoxyethoxy, l-methyl-2-propoxyethoxy, 2-methoxypropoxy and
4-methoxybutoxy.

The term "halo(C1-C6)alkoxy", as employed herein as such or as part of another group,
refers to at least one halogen, as defined herein, appended to the parent molecular moiety
through an (C1-C6)alkoxy group, as defined herein. When there are several halogens, the
halogens can be identical or different. Representative examples of halo(C1-C6)alkoxy
include, but are not limited to, fluoromethoxy, chloromethoxy, diffuoromethoxy,
trifluoromethoxy, 2-bromoethoxy, 2,2,2-trichloroethoxy, 3-bromopropoxy,
2-chloropropoxy, and 4-chlorobutoxy.
The expression "compounds of the invention" as employed herein refers to the compounds
of formula I.
Pharmaceutically acceptable salts, e.g. acid addition salts, with both organic and inorganic
acids, are known in the field of pharmaceuticals. Representative examples of
pharmaceutically acceptable acid addition salts include, but are not limited to, chlorides,
bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates,
maleates, citrates, benzoates, salicylates, ascorbates, acetates and oxalates.
Pharmaceutically acceptable esters, when applicable, may be prepared by known methods
using pharmaceutically acceptable acids that are conventional in the field of
pharmaceuticals and that retain the pharmacological properties of the free form. Non-
limiting examples of these esters include esters of aliphatic or aromatic alcohols.
Representative examples of pharmaceutically acceptable esters include, but are not limited
to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and benzyl
esters.
The invention includes within its scope all the possible geometric isomers, e.g. Z and E
isomers (cis and trans isomers), of the compounds as well as all the possible optical
isomers, e.g. diastereomers and enantiomers, of the compounds. Furthermore, the invention
includes in its scope both the individual isomers and any mixtures thereof, e.g. racemic
mixtures. The individual isomers may be obtained using the corresponding isomeric forms
of the starting material or they may be separated after the preparation of the end compound
according to conventional separation methods. For the separation of optical isomers, e.g.
enantiomers, from the mixture thereof, conventional resolution methods, e.g. fractional
crystallization, may be used.

The invention further includes isotopically-labeled compounds of formula I; for example a
carbon-isotope labeled compound of formula I; such as (5)-l-((2,3-
dmydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(3-([nC]-methoxymethyl)pyridin-2-
yl)piperazine.
An isotopically or radio-labeled compound is a compound of formula I, wherein one or
more atoms are replaced or substituted by an atom having an atomic mass or mass number
different from the atomic mass or mass number typically found in nature. Examples of
isotopes that can be incorporated into compounds of the invention include, but are not
limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine,
iodine and chlorine, such as 2H, 3H,11C, I3C, 14C, 13N, 15N, 150,170,180,35P, 32P, 35S, 18F,
123I,125Iand36Cl, or any subset thereof. The radionuclide that is incorporated in the instant
radio-labeled compounds will depend on the specific application of that radio-labeled
compound. Positron emitting isotopes such as 11C, 13N, I50, and 18F are useful for positron
emissing tomography (PET) studies. (Textbook of drug desigtt and discovery. 3rd edition,
Chapter 8: Radiotracers: synthesis and use in imaging by C. Halldin and T. Hogberg.)
PET is so far the only method that can offer quantitative information on molecular
recognition (e.g. receptor binding) in vivo in man. However, there have not been tracers
available for studying alpha2C adrenoceptor occupancy. The labeled compounds of formula
I can be used as novel alpha2C-receptor selective PET tracers in humans and animals; for
example, carbon-11 labeled compounds of formula I be used as novel alpha2C-receptor
selective PET tracers.
Isotopically labeled compounds of the invention can generally be prepared by following
procedures analogous to those disclosed in the schemes and / or in the examples herein
below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
For example, carbon-isotope labeled compounds of formula I can be prepared by
methylation of a suitable precursor, using several different nC-labeled methylating agents.
Representative examples of nC-labeled methylating agents include, but are not limited to,
uC-iodomethane, nC-bromomethane and HC-methyl triflate. A person skilled in the art
also understands that said suitable precursor must contain a suitable reactive functional
group, such as hydroxy, thiol, carboxyl or amino.

Compounds of the invention can be prepared by a variety of synthetic routes analogously or
according to the methods known in the literature using suitable starting materials. The
starting materials used in the processes herein are either commercially available or can be
prepared via synthetic routes known in the literature.
Compounds of formula I are generally made up of a suitable acid and an aryl piperazine
fragment. For example, the benzodioxane ring system containing starting materials are
compounds of formulae A and B:

One starting compound is 2,3-dihydrobenzo[b][l,4]dioxine-2-carboxylic acid (formula A,
R4 = H), which is commercially available and also easily resolved into its enantiomers as
described in Tetrahedron: Asymmetry 16 (2005) 1639.
Compounds of formula B, possessing a leaving group L (most suitably a halogen, mesylate
or tosylate) and group(s) R4 (as defined above) can be prepared according to known
methods. When R4 = H, enantiomers of formula B are easily derived from the corresponding
enantiomer of formula A via reduction and insertion of a desired leaving group.
The other half in formula I, i.e. aryl piperazines and homopiperazines of formula C, when
not commercially available, can be synthesized by alkylation of piperazine, in most cases N-
protected, with an electron deficient aryl halide.

In formula C, Z is as defined above and Ar is:


wherein A, B, D, E and R1-R3 are as defined above.
In general, compounds of formula I can be prepared analogously or according to the
following scheme 1:

wherein X, Z, Ar, R4 and m are as defined above. This method is especially suitable for
preparing the enantiomers of formula I, as the enantiomers of formula A are easily available.
Another route for preparing compounds of formula I is the direct alkylation of aryl
piperazines C with benzodioxanes B as shown in scheme 2:


wherein L, R4, m, Z and Ar are as defined above.
Furthermore, the common method to construct aryl piperazines via ring closure of
bis(cMoroemyl)amines with anilines (e.g. Tetrahedron Lett. 46 (2005) 7921 and references
cited therein) is applied to benzodioxane derivatives. Reacting compound D with substituted
anilines E gives rise to compounds of formula I (scheme 3):

wherein Ri - R3 are as defined above.
In some cases, as compared to scheme 2, a slightly modified order of events is employed.
Commercial (2,3-dihydrobenzo[b3[lJ4]dioxin-2-yl)(piperazin-l-yl)methanone F is alkylated
with electron deficient aryl halides G to afford intermediates H, which are further
transformable to certain compounds of formula I (scheme 4):

Scheme 4
wherein X is halogen, EWG is an electron withdrawing group (e.g. COOR, CHO etc.) and
R2 and R3 defined as above.
In the synthesis of homopiperazines, mainly the routes described in schemes 1 and 2 are
utilized.
A person skilled in the art realizes that any starting material or intermediate in the reactions
described above can be protected, if necessary, in a manner known in the art. Any protected

functionality can subsequently be deprotected in a manner known in the art.
The synthetic routes described above are meant to illustrate the preparation of the
compounds of formula I and the preparation is by no means limited thereto, i.e. there are
also other possible synthetic methods which are within the general knowledge of a person
skilled in the art.
The compounds of formula I may be converted, if desired, into their pharmaceutically
acceptable salt or ester form using methods known in the art.
The present invention will be explained in more detail by the following examples. The
examples are meant for illustrating purposes only and do not limit the scope of the invention
defined in the claims.
Abbreviations: ACN = acetonitrile, DCM = dichloromethane, DIPEA = N,N-
diisopropylethylamine, DMF = N,N-dimethylformamide, EtOAc = ethyl acetate, IPA =
isopropanol, LAH = lithium aluminum hydride, LC-MS = liquid chromatography — mass
spectrometry, RT = room temperature, THF = tetrahydrofuran, TLC = thin layer
chromatography.
Column chromatography was performed on Silica gel 60 obtained from Merck, or using a
CombiFlash instrument together with Redisep columns, both provided by Teledyne ISCO.
Microwave heating was performed using an Emrys Optimiser microwave reactor from
Personal Chemistry or an Initiator 2.0 microwave reactor from Biotage. The structures of
the products were confirmed by 1H NMR. The spectra were measured with a Bruker Avance
400 instrument. LC-MS analyses were performed using Waters 2690 Alliance HPLC and
Waters Micromass ZQ4000 single quadrupole mass spectrometer using ESI.
Preparation of starting materials
Methyl 2-(piperazin-l-yl)benzoate was prepared in tiso steps from 1-benzylpiperazine and
methyl 2-fiuorobenzoate following the lines in iso 03/009850.
Methyl 2-(l,4-diazepan-l-yl)nicotinate was prepared using the method described in US
6,562,827.

(R)-2,3-Dihydrobenzo[b][l,4]dioxine-2-carboxylic acid was resolved from the
commercially available racemate as described in Tetrahedron: Asymmetry 16 (2005) 1639.
(R)-(2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyl methanesulfonate was prepared from
(R)-2,3-dihydrobenzo[b][l,4]dioxine-2-carboxylic acid according to Tetrahedron:
Asymmetry 14 (2003) 3779.
(R)-2,3-Dihydrobenzo[b][l,4]dioxine-2-carbonyl chloride was prepared in the standard
manner by refluxing (R)-2,3-dmydrobenzo[l,4]dioxine-2-carboxylic acid with excess
thionyl chloride in toluene for 3 h. Evaporation to dryness gave the acid chloride in high
yield.
2,3-Dihydrobenzo[b][l,4]oxathiine-2-carboxylic acid was prepared from ethyl 2,3-
dihydrpbenzo[b][l,4]oxathiine-2-carboxylate according to J.MedChem. 27 (1984) 1535.
Preparation of intermediates
Intermediate Al: Ethyl 2-(4-benzylpiperazin-l-yI)nicotinate
A mixture of ethyl 2-chloronicotinate (43.5 g, 234 mmol), 1-benzylpiperazine (39.8 ml, 234
mmol) and K2C03 (35.5 g, 257 mmol) in DMF (200 ml) was refluxed for 4 h. After cooling
to RT the mixture was poured into ice water (800 ml). The water phase was extracted 3 x
with EtOAc and the combined organic layers were washed with water and brine. Drying and
evaporation gave 75.5 g of the title compound.
1HNMR (CDC13): δ 1.36 (t, 3H), 2.54-2.57 (m, 4H), 3.43-3,46 (m, 4H), 3.55 (s, 2H), 4.32
(q, 2H), 6.69-6.72 (dd, 1H), 7.34-7.36 (m, 5H), 7.92-7.96 (dd51H), 8.24-8.27 (dd, 1H).
Intermediate A2: (2-(4-Benzylpiperazin-l-yl)pyridin-3-yI)methanol
LAH pellets (9.3 g, 246 .mmol) were dissolved in dry THF (240 ml) at 45 °C under nitrogen
atmosphere. After cooling to RT ethyl 2-(4-benzylpiperazin-l-yl)nicotinate (40 g, 123
mmol) in dry THF (300 ml) was added. The mixture was refluxed for 2 h 15 min. 4 M KOH
(61.5 ml) was slowly added to the hot reaction mixture and stirring was continued for
additional 20 min at 60 °C. The precipitate was filtered and washed with EtOAc and the
filtrate was evaporated to dryness to give 33.6 g of the title alcohol.
1H NMR(CDCl3): δ 2.62-2.65 (m, 4H), 3.16-3.19 (m, 4H), 3.59 (s, 2H), 4.20-4.35 (br s,

1H), 4.73 (s, 2H), 6.97-7.00 (dd, 1H), 7.24-7.37 (m, 5H), 7.53-7.55 (dd51H), 8.26-8.28 (dd,
1H).
Intermediate A3: l-Benzyl-4-(3-(methoxymethyl)pyridin-2-yl)piperazine
A dispersion of NaH (60 % in oil, 14 g, 349 mmol) in dry THF (170 ml) was heated to 60
°C under nitrogen atmosphere. (2-(4-Benzylpiperazin-l-yl)pyridin-3-yl)methanol (33 g, 116
mmol) in dry THF (170 ml) was added dropwise to the mixture. After stirring for 3 h at 60
°C, the mixture was cooled to 0 °C and methyl iodide (9.4 ml, 151 mmol) in dry THF (70
ml) was added. The mixture was further stirred for 1 h at RT and again cooled to 0 °C.
Water was added until foaming stopped and after that more water (300 ml) was added. The
crude product was extracted with EtOAc and the combined organic layers were evaporated.
Water (300 ml) was added to the residue and the pH was adjusted to 1-2 with concentrated
HC1. The mixture was stirred at 40-50 °C for 1 h, after which EtOAc Was added and the
phases were separated. The organic phase was washed once with 1 M HC1 (30 ml). The
acidic water phases were combined, the pH adjusted to 10 with δ M NaOH followed by
extraction with EtOAc (3x). The combined organic phases were washed with water, dried
and evaporated to give 26.6 g of the title compound.
1HNMR (CDC13): δ 2.59-2.62 (m, 4H), 3.19-3.22 (m, 4H), 3.40 (s, 3H), 3.59 (s, 2H), 4.40
(s, 2H), 6.90-6.93 (dd, 1H), 7.26-7.37 (m, 5H), 7.65-7.68 (dd, 1H), 8.22-8.24 (dd, 1H).
Intermediate A4: l-(3-(Methoxymethyl)pyridin-2-yl)piperazine
Under nitrogen flow, a 1 liter reaction flask was charged with 10 % Pd/C (5.26 g, 20 w-%)
and MeOH (400 ml). l-BenzylT4-(3-(methoxymethyl)pyridin-2-yl)piperazine (26.3 g, 88
mmol) in MeOH (100 ml) and ammonium formate (16.7 g, 265 mmol) were added to the
mixture, which was then refluxed for 2 h 15 min. During this period paraformaldehyde
accumulated inside the condenser. The Pd catalyst was filtered off through a celite pad,
which was washed with DCM. The combined filtrates were evaporated and brine and DCM
were added to the residue. Organic phase was separated, washed with saturated NaHCO3,
dried and evaporated to dryness to afford 16.5 g of the title piperazine.
1H NMR (CDCI3): 8 3.03-3.05 (m, 4H), 3.14-3.17 (m, 4H), 3.42 (s, 3H), 4.43 (s, 2H), 6.92-
6.95 (dd, 1H), 7.68-7.70 (dd, 1H), 8.23-8.25 (dd, 1H).

Intermediate A5: Ethyl 2-(piperazin-l-yl)nicotinate
As above, a mixture of ethyl 2-(4-benzylpiperazin-l-yl)nicotinate (14.97 g, 46.0 mmol),
ammonium formate (6.38 g, 101 mmol) and 10 % Pd/C (3 g, 46.0 mmol) in methanol (150
ml) was refluxed for 2 h. After cooling, the mixture was filtered through Celite. The filtrate
was concentrated in vacuo to afford 10.25 g of the title compound.
1H NMR (CDC13): δ 1.39 (t, 3H), 2.95-2.99 (m, 4H), 3.35-3.40 (m, 4H), 4.36 (q, 2H), 6.72-
6.74 (m, 1H), 7.94-7.99 (m, 1H), 8.26-8.30 (m, 1H).
Intermediate A6: l-Benzyl-4-(2-(methoxymethyl)phenyI)piperazine
As in the preparation of intermediate A3, (2-(4-benzyIpiperazin-l-yl)phenyl)methanol (30 g,
0.106 mol) was treated with NaH (60 % in oil, 13 g, 0.325 mol) in dry.THF (365 ml) at 60
°C for 4 h. The mixture was then cooled to 10 °C and Mel (8.6 ml, 1.3 eq) in THF (96 ml)
was added. After stirring at 20-22 °C for 1 h, the mixture was cooled to 10 °C and water
was added dropwise until the effervescence ceased. More water (600 ml) was then added,
followed by extraction with EtOAc (3x500 ml). After removing the mineral oil originating
from NaH, 29 g of the title compound was obtained.
*H NMR (CDCI3): δ 2.61 (br s, 4H), 2.96 (t, 4H), 3.41 (s, 3H), 3.58 (s, 2H), 4.52 (s, 2H),
7.05-7.11 (m, 2H), 7.22-7.39 (m, 6H), 7.42 (dd, 1H).
Intermediate A7: l-(2-(MethoxymethyI)phenyI)piperazine
As in the preparation of intermediate A4, a mixture of l-benzyl-4-(2-
(methoxymethyl)phenyl)-piperazine (14.0 g, 47.2 mmol), ammonium formate (9.38 g, 0.149
mol) and 10 % Pd/C (2.3 g) in MeOH (260 ml) was refluxed for 1 h. The catalyst was
filtered, MeOH was evaporated and water (300 ml) was added to the residue. The aqueous
phase was extracted with EtOAc (3x100 ml) and the combined organic layers were washed
with water and 1 M NaHC03. After drying" and evaporation 7.1 g of the title compound was
obtained.
1HNMR (CDCI3): 8 1.57 (br s, 1H), 2.85-2.93 (m, 4H), 2.99-3.06 (m, 4H), 3.43 (s, 3H),
4.54 (s, 2H), 7.05-7.13 (m, 2H), 7.27 (ddd, 1H), 7.44 (dd, 1H).
Intermediate A8: t-Butyl 4-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyI)-l,4-
diazepane-1-carboxylate

A mixture of 2-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine (150 mg, 0.65 mmol), t-
butyl 1,4-diazepane-l-carboxylate (130 mg, 0.65 mmol) and DIPEA (0.4 ml, 2.32 mmol) in
DMF (1.5 ml) was heated in a microwave reactor at 160 °C for 10 min and then poured into
water. The mixture was extracted with EtOAc (3x20 ml). The organic layer was dried and
evaporated to dryness. The crude product was purified by flash chromatography (gradient of
heptane and EtOAc) to give 93.4 mg of the title compound.
1H NMR (DMSO-d6): δ 1.39 (s, 9H), 1.71 (m, 2H), 2.72 (m, 6H), 3.35 (m, 4H), 3.96 (m,
1H), 4.27 (m, 2H), 6.82 (m, 4H).
Intermediate A9: l-((2,3-Dihydrobenzo[b] [l,4]dioxin-2-yI)methyl)-l,4-diazepane
Amixture of ^-butyl 4-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-l,4-diazepane-l-
carboxylate (1.68 g, 4.82 mmol) and cone. HC1 (2 ml) was stirred at room temperature for 3
h. The mixture was poured into ice water, basified to pH 9 and extracted with DCM (3x20
ml). The organic layer was dried and evaporated to give 0.96 g of the title compound.
1H NMR (CDC13): δ 1.80 (m, 2H), 2.52 (s, 1H), 2.60-3.10 (m, 10H), 3.98 (m, 1H), 4.27 (m,
2H), 6.82 (m, 4H).
Intermediate A10: (R)-N;N-Bis(2-chloroethyl)-2,3-dihydrobenzo[b][l,4]dioxine-2-
carboxamide
(R)-2,3-Dihydrobenzp[b][l,4]dioxine-2-carbonyl chloride (11.1 mmol) was reacted with
bis(2-chloroethyl)amine-HCl (1.89 g, 10.6 mmol) in the presence of triethylamine (3.43 ml,
24.4 mmol) in DCM (20 ml). Aqueous isork-up, including washes with 1 M NaOH and 1 M
HC1, gave 5.72 g of the title compound.
1H NMR (CDCI3): 8 3.64-3.82 (m, 6H), 3.99-4.01 (m, 2H), 4.26-4.36 (m, 1H), 4.48-4.55
(m, 1H), 4.91-4.96 (m, 1H), 6.83-6.95 (m, 4H).,
Intermediate All: (5)-2-Chloro-A^-(2-chloroethyl)-iV-((2,3-dihydrobenzo[b][l,4]dioxin-
2-yl)methyI)ethanamine-HCl
(i?)-N,N-Bis(2-chloroethyl)-2,3-dihydrobenzo[b][l,4]dioxine-2-carboxamide (3.04 g, 9.99
mmol) was dissolved in THF (50 ml). 1 M BHb-THF-complex (50 ml, 50 mmol) was added
and the mixture refluxed for 2 h under an inert atmosphere. After cooling, 6 M HC1 (20 ml)
was added and the mixture was stirred at 65 C for 20 min. The mixture was cooled and it

was made alkaline by adding solid KOH. Water (50 ml) was added. The mixture was
extracted with EtOAc (3x50 ml), the organic layers were pooled, dried and evaporated to
dryness. The crude product was purified by flash chromatography to give 1.98 g of the title
compound..
'HNMR (CDC13): 8 2.81-2.88 (m, 1H), 2.91-3.10 (m, 4H), 3.50-3.59 (m, 5H), 4.00-4.25
(m, 1H), 4.19-4.27 (m, 1H), 4.28-4.34 (m, 1H), 6.81-6.91 (m, 4H).
Preparation of compounds of the invention
Via alleviation of aryl piperazines with 2-(bromomethvD-2,3-
dihvdrobenzof61 ri,4|dioxine
EXAMPLE 1: Methyl 2-(4-((2,3-dmydrobenzo[*][l,4]dioxin-2-yl)methyI)piperazin-l-
yI)benzoate
A mixture of 2-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine (0.53 g, 2.406 mmol),
methyl 2-(piperazin-l-yl)benzoate (0.55 g, 2.406 mmol) and K2C03 (0.366 g, 2.647 mmol)
in DMF (20 ml) was heated in a microwave reactor at 150 °C for 2 h. Water was added to
the cooled mixture, which was then extracted three times with EtOAc. The combined
extracts were washed well with water and brine, dried and evaporated to give the crude
product, which was purified by flash chromatography (gradient of heptane and EtOAc) to
give 0.397 g of the title compound.
*HNMR (CDCI3): 8 2.62-2.82 (m, 6H), 3.05-3.13 (m, 4H), 3.89 (s, 3H), 4.02 (dd, 1H),
4.29-4.40 (m, 2H), 6.80-6.92 (m, 4H), 7.02 (dd, 1H), 7.04 (d, 1H), 7.41 (dd, 1H), 7.73 (d,
1H).
EXAMPLE 2r(2-(4-((2,3-Dihydrobenzo[6] [l,4]dioxin-2-yl)methyl)piperazin-l-
yl)phenyI)methanol
Methyl 2-(4-((2,3-dihydrobenzo[b][l,4]dioxin-2-yi)methyl)piperazin-l-yl)benzoate (0.60 g,
1.629 mmol) was reduced with LAH (0.31 g, 8.145 mmol) in THF (50 ml). After 1 h at RT,
the mixture was isorked up .with 2 M NaOH to give the crude product, which was purified
by flash chromatography (gradient of heptane and EtOAc) to afford 0.476 g of the title
compound.
lHNMR (CDCI3): 8 2.62-2.90 (m, 6H)5 3.00-3.06 (m, 4H), 4.04 (dd, 1H), 4.30-4.38 (m,

2H), 4.80 (s, 2H), 5.26 (br s, 1H), 6.81-6.93 (m, 4H), 7.08-7.32 (m, 4H).
EXAMPLE 3: l-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(2-
(methoxymethyI)phenyl)piperazine
(2-(4-((23-Dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)phenyl)methanol(356
mg, 1.05 mmol) was treated first with NaH (60 %, 126 mg, 3.14 mmol) in dry THF (2 ml) at
60 °C for 2 h. Then, methyl iodide (0.08 ml, 1.26 mmol) in dry THF (1 ml) was added to the
cooled (ca. 10 °C) mixture and stirring was continued for 1 h at RT. The mixture was
poured into ice water and extracted with EtOAc. The crude product obtained after drying
and evaporation was purified by flash chromatography (gradient of heptane and EtOAc) to
give 155 mg of the title compound.
*HNMR (CDC13): δ 2.62-2.82 (m, 6H), 2.82-3.02 (m, 4H), 3.42 (s, 3H), 4.03 (dd, 1H),
4.31-4.39 (m, 2H), 4.53 (s, 2H), 6.81-6.93 (m, 4H), 7.06-7.12 (m, 2H), 7.27 (dd, 1H), 7.43
(d,lH).
The compound obtained above (155 mg, 0.44 mmol) was dissolved in EtOAc (3 ml) and 1
M HCl/Et20 (0.6 ml) was added. The precipitate was filtered, washed with a small amount
of cold EtOAc and dried in vacuo at 30 °C to afford 153 mg of the HC1 salt of the title
compound.
'HNMR (DMSO-de): δ 3.17-3.28 (m, 4H), 3.29-3.64 (m, 5H), 3.34 (s, 3H), 3.77 (br d, 1H),
4.09 (dd, 1H), 4.36 (dd, 1H), 4.47 (s, 2H), 5.00 (m, 1H), 6.86-7.00 (m, 4H), 7.10-7.17 (m,
2H), 7.32 (dd, 1H), 7.39 (d, 1H), 11.27 (br s, 1H).
EXAMPLE 4:2-(4-((2,3-Dihydrobenzo[£] [l,4]dioxin-2-yI)methyl)piperazin-l-
yl)benzonitrile
A mixture of 2-(bromomethyl)-2,3-dihydrobenzo[&][l,4]dioxine (0.624 g, 2.72 mmol), 1-
(2-cyanophenyl)piperazine (0.510 g, 2.72 mmol) and K2C03 (0.414 g, 3.00 mmol) in DMF '
(20 ml) was heated in a microwave reactor at 200 °C for 7 min. Water was added to the
cooled mixture, which was extracted three times with EtOAc. The combined extracts were
washed well with water and brine, dried and evaporated to give the crude product, which
was purified by flash chromatography (gradient of heptane and EtOAc) to yield 0.42 g of the
title compound.

reaction with ethyl iodide (184 mg, 1.181 mmol). The crude product was purified twice by
flash chromatography (gradient of heptane and EtOAc) to furnish 31 mg of the title
compound.
1H NMR (CDC13): δ 1.25 (t, 3H), 2.61-2.83 (m, 6H), 2.90-3.05 (m, 4H), 3.58 (q5 2H), 4.03
(dd, 1H), 4.30-4.40 (m, 2H), 4.57 (s, 2H), 6.80-6.93 (m, 4H), 7.07 (d, 1H), 7.09 (dd, 1H),
7.25 (dd, 1H), 7.45 (d, 1H).
EXAMPLE 8: 2~(2-(4-((2,3-Dihydrobenzo[6] [l,4]dioxin-2-yl)methyl)piperazin-l-
yl)phenyl)propan-2-ol
Methyl 2-(4-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)benzoate (370
mg, 1.0 mmol) was refluxed with 3 M MeMgCl/THF (1.5 ml) in dry THF (7 ml) for 3 h.
The excess Grignard reagent was destroyed by careful addition of 1 M HC1, after which the
mixture was made alkaline with 1 M NaOH. More water was added and the aqueous phase
was extracted with EtOAc. Washing the combined extracts with water, drying and
evaporation gave 380 mg of the crude alcohol product. The pure title compound was
obtained by purification by flash chromatography (gradient of heptane and EtOAc).
'HNMR (CDCI3): 8 1.58 (s, 6H), 2.45-2.60 (m, 2H), 2.66 (dd, 1H), 2.77 (dd, 1H), 2.94-
3.16 (m, 6H), 4.04 (dd, 1H), 4.30-4.38 (m, 2H), 6.81-6.92 (m, 4H), 7.19 (dd, 1H), 7.26 (dd,
1H), 7.30 (d, 1H), 7.36 (d, 1H), 9.12 (br s, 1H).
EXAMPLE 9: l-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyI)-4-(3-
(methoxymethyI)pyridin-2-yI)piperazine
A mixture of 2-(bromomethyl)-2,3-dihydrobenzo[b][l,4]dioxine (1.6 g, 6.98 mmol), l-(3-
(methoxymethyl)pyridin-2-yl)piperazine (1.3 g, 6.27 mmol), K2C03 (0.87 g, 6.30 mmol)
and KI (52 mg, 0.31 mmol) in DMF (35 ml) was heated at 120 °C for 4.5 h. Water was
added to the cooled mixture, which was then extracted with EtOAc. The combined organic
layers were extracted with 1 N HC1, the acid phase was made alkaline arid extracted with
EtOAc. Drying and evaporation gave 1.99 g of the crude product, which was recrystallised
from IP A to afford 1.23 g of the title compound.
1H NMR (CDCI3): δ 2.63-2.82 (m, 6 H), 3.21 (br t, 4H), 3.42 (s, 3H), 4.03 (dd, 1H), 4.32-
4.39 (m, 2H), 4.42 (s, 2H), 6.80-6.92 (m, 4H), 6.93 (dd, 1H), 7.68 (dd, 1H), 8.24 (dd, 1H).

EXAMPLE 10: (5)-(2-(4-((7-Fluoro-2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-
piperazin-l-yl)pyridin-3-yl)methanoI
Step A: (S)-Ethyl 2-(4-((7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-
piperazin-l-yl)nicotinate
A mixture of (i?)-(7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl 4-methylbenzene-
sulfonate (1.23 g, 3.6 mmol), ethyl 2-(piperazin-l-yl)nicotinate (0.85 g, 3.6 mmol) and
K2CO3 (0.55 g, 4.0 mmol) in acetonitrile (10 ml) was heated in a microwave reactor at 150
°C for 40 min. The solvent was evaporated and water (50 ml) was added. Extraction with
EtOAc (3 x 30 ml) afforded after drying and evaporation a crude product mixture which was
purified with flash chromatography (gradient of DCM and MeOH) to give 1.12 g of the title
compound.
1H NMR (DMSO-d6): 8 1.30 (t, 3H), 2.52-2.62 (m, 6H), 3.32-3.34 (m, 4H), 3.97 (dd, 1H),
4.27 (q, 2H), 4.31 (m, 1H), 4.42 (m51H), 6.66 (m, 1H), 6.78 (dd, 1H), 6.82 (dd, 1H), 6,88
(dd, 1H), 7.90 (dd, 1H), 8.37 (dd, 1H).
Step B: (S)-(2-(4-((7-Fluoro-2^-dihydrobenzol£] [l,4]dioxin-2-yl)methyl)-piperazin-l-
yl)pyridin-3-yI)methanol
(5)-E%12-(4-((7-fluoro-2J3-dmydrobenzo[b][l,4]dioxin-2-yl)methyl)-piperazin-l-
yl)nicotinate (1.12 g, 2.80 mmol)'was dissolved in THF (10 ml) and added dropwise to the
cooled (0-5 °C ) solution of LAH (0.53 g, 14.0 mmol) in THF (10 ml). The mixture was
then allowed to warm up to ambient temperature and after 2 h stirring, water (10 ml) was
cautiously added to the mixture. Celite was added and the solids filtered and washed with
EtOAc. The combined filtrates were evaporated to dryness and coevaporated once with
toluene. Toluene (20 ml) and 1 M HC1 (40 ml) were added, the layers were separated and
water extracted with toluene (20 ml). The water phase was made alkaline with NaOH and
extracted with EtOAc (2 x 40 ml). The organic phase was dried and evaporated to give 0.85
g of the title compound.
JHNlvlR (CDC13): 8 2.64-2.79 (m, 6H), 3.18-3.20 (m, 4H), 3.97-4.02 (m, 1H), 4.09 (m,
1H), 4.29-4.37 (m, 2H), 4.74 (m, 2H), 6.52-6.57 (m, 1H), 6.61-6.64 (m, 1H), 6.78-6.82 (m,
1H), 7.00-7.03 (m, 1H), 7.56-7.58 (m, 1H), 8.28-8.29 (m, 1H).

'HNMR (CDCI3): δ 2.67 (dd, 1H), 2.71-2.88 (m, 5H), 3.20-3.30 (m, 4H), 4.03 (dd, 1H),
4.29-4.39 (m, 2H), 6.81-6.93 (m, 4H), 6.97-7.05 (m, 2H), 7.48 (dd, 1H), 7.56 (d, 1H).
EXAMPLE 5: (2-(4-((2,3-Dihydrobenzo[A][l,4]dioxin-2-yl)methyl)piperazin-l-
yl)phenyl)methanamine
2-(4-((2,3-Dihydrobenzo[i][l,4]dioxin-2-yl)methyl)piperazin-l-yl)benzonitrile(0.55g,
1.640 mmol) was reduced with LAH (124 mg, 3.28 mmol) in refluxing THF (20 ml) (2 h).
isork-up with 2 N NaOH gave the crude product, which was purified by "flash
chromatography (gradient of heptane and EtOAc) to give 0.285 g of the title compound.
1H NMR (CDClj): 8 1.62 (br s, 2H), 2.61-2.85 (m, 6H), 2.91-3.02 (m, 4H), 3.89 (s, 2H),
4.03 (dd, 1H), 4.30-4.39 (m, 2H), 6.79-6.93 (m, 4H), 7.09 (dd, 1H), 7.13 (d, 1H), 7.24 (dd,
lH),7.31(d,lH).
EXAMPLE 6: l-(2-(4-((2,3-Dihydrobenzo[£] [l,4]dioxin-2-yl)methyI)piperazin-l-
yI)phenyI)-Ar-methyImethanamine
(2-(4-((2,3-Dihydrobenzo[&][l,4]dioxin-2-yl)memyl)piperazin-l-yl)phenyl)memanarnine
(240 mg, 0.71 mmol) was stirred in DCM (5 ml) and triethylamine (0.15 ml, 1.06 mmol).
The mixture was cooled to 0 °C followed by addition of ethyl chloroformate (0.10 ml) in
dry DCM (1 ml). The cooling bath was removed and stirring was continued for 30 min.
Water was then added, the DCM phase was separated and the aqueous layer extracted once
with DCM. After drying procedures, 231 mg of the carbamate intermediate was obtained.
This was immediately reduced with LAH (85 mg, 2.24 mmol) in refluxing THF (5 ml).
isork-up with 2 N NaOH gave the crude product, which was purified by flash
chromatography (gradient of heptane and EtOAc) to afford 91 mg of the title compound.
'HNMR (CDCI3): δ 2.30 (br s, 1H), 2.44 (s, 3H), 2.60-2.73 (m, 6H), 2.91-3.04 (m, 4H),
3.80 (s, 2H), 4.03 (dd, 1H), 4.30-4.39 (m, 2H), 6.80-6.93 (m, 4H), 7.07 (dd, 1H), 7.12 (d,
1H), 7.24 (dd,lH), 7.3 l(d, 1H).
EXAMPLE 7: l-((2,3-Dihydrobenzo[6I[l,4]dioxin-2-yI)methyl)-4-(2-
(ethoxymethyl)phenyl)piperazine
Analogously to example 3, (2-(4-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-
yl)phenyl)methanol (335 mg, 0.984 mmol) was treated with NaH (3 eq) followed by

EXAMPLE 11: (5)-(2-(4-((7-Fluoro-2,3-dihydrobenzo[6] [l,4]dioxin-2-yl)methyl)-
piperazin-l-yl)pyridin-3-yI)methanol'HCl
(5)-(2-(4-((7-Fluoro-2,3-dihydrobenzo[6] [1,4]dioxin-2-yl)methyl)-piperazin-l -yl)pyridin-3-
yl)methanol (0.76 g, 2.1 mmol) was dissolved in IPA (4 ml) with warming and 8 %
HCl/EtOAc (4 ml) was added. The precipitate was filtered to give 0.56 g of the title product.
*H NMR (CDC13): 8 3,38-3.46 (m, 4H), 3.57-3.67 (m, 3H), 4.07-4.15 (m, 5H), 4.28-4.32
(m, 1H), 4.68 (m, 2H), 5.08 (m, 1H), 6.52-6.57 (m, 1H), 6.60-6.65 (m, 1H), 6.71-6.74 (m,
1H), 6.83-6.87 (m, 1H), 8.16-8.18 (m, 1H), 8.28-8.30 (m, 1H).
EXAMPLE 12: (£)-l-((7-Fluoro-2,3-dihydrobenzo[6] [l,4]dioxin-2-yI)methyl)-4-(3-
(methoxymethyl)pyridin-2-yl)piperazine *HC1
(i?)-(7-Fluoro-2,3-dihydrobenzo[6] [1,4]dioxin-2-yl)methyl 4-methylbenzenesulfonate
(1.353 g, 4 mmol), l-(3-(methoxymethyl)pyridin-2-yl)piperazine (0.829 g, 4 mmol),
potassium carbonate (0.608 g, 4.40 mmol) and acetonitrile (10 ml) were mixed and heated
in a microwave reactor at 120 °C for 60 minutes. The mixture was evaporated, water (50 ml)
was added. The aqueous mixture was extracted with EtOAc (3 x 20 ml). The organics were
dried and evaporated to dryness. Flash chromatography (gradient of heptane/EtOAc) gave a
pure product which was dissolved in 10 % HCl/EtOH and evaporated to dryness. This
procedure was repeated. 1.64 g of the title compound was obtained.
*H NMR (DMSO-d6): δ 2.49-2.51 (m, 6H)5 3.08-3.28 (m, 4H), 3.33 (s, 3H), 3.96-4.00 (m,
1H), 4.29-4.33 (m, 1H), 4.37 (s, 2H), 4.40-4.47 (m, 2H), 6.64-6.68 (m, 1H), 6.78-6.81 (m,
1H), 6.87-6.90 (m, 1H), 6.98-7.00 (m, 1H), 7.67-7-69 (m, 1H), 8.18-8.20 (m, 1H).
EXAMPLE 13: (5)-l-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(3-((2-
fluoroethoxy)methyl)pyridin-2-yl)piperazine
Step A: (5)-2-((2-(4-((2,3-Dihydrobenzo[6] [l,4]dioxin-2-yl)methyl)piperazin-l-
yl)pyridin-3-yI)methoxy)ethanoI
To a mixture of (5)-l-((2,3-dihydrobenzo[b][l>4]dioxin-2-yl)methyl)-4-(2-
(methoxymethyl)phenyl)piperazine (300 mg, 0.88 mmol) and 50% NaOH (75 mL) was
added tetra-n-butyl ammonium bromide (28 mg, 0.088 mmol, 10 mol%) and the mixture
was stirred for 15 min. 2-(3-Bromoethoxy)tetrahydro-2n-pyran (0.42 ml, 2.64 mmol, 300

mol%) was added slowly and the reaction mixture was warmed to 60 °C. After 2 h brine
(100 mL) was added and the mixture was extracted with toluene (2 x 50 mL + 75 mL). The
combined organic layers were washed with brine (50 mL), dried with Na2S04, filtered and
concentrated to dryness. The residue was dissolved in acetone (10 mL) and 1 M HC1 was
added until the pH was ~3 (pH paper). After overnight stirring pH was adjusted to 1-2 and
the mixture was stirred overnight. The mixture was neutralised with 50% NaOH (pH paper)
and acetone was evaporated. DCM (20 mL) was added and the mixture was washed with
water (10 mL), saturated NaHC03 (5 mL) and brine (10 mL). The organic layer was dried
withNa2S04, filtered and concentrated in vacuo. Purification by column chromatography
(EtOAcrheptane, 3:2-4:1-0:1, v/v) afforded 253 mg of the title compound.
Step B: (S)-l-((2,3-Dihydrobenzo[£][l,4]dioxin-2-yl)methyl)-4-(3-((2-
fluoroethoxy)methyl)pyridin-2-yl)piperazine
(S)-2-((2^(4-((2,3-Dihydroberizo[63[l34]dioxin-2-yl)methyl)piperazin-l-yl)pyridin-3-
yl)methoxy)ethario.l (250 mg, 0.65 mmol) and dry DCM (8.8 mL) were charged under
nitrogen into a dry 50 mL round-bottomed flask fitted with a magnetical stirrer and
thermometer. The solution was cooled to ~0 °C and DAST (127 uL, 0.97 mmol, 150 mol%)
was added. The reaction mixture was allowed to warm to room temperature and after 2 h
more DAST (42 uL, 0.32 mmol, 50 mol%) was added. The reaction mixture was stirred for
7.5 h in total. Saturated Na2C03 solution (3.9 mL) was added at 0 °C. The mixture was
allowed to warm to room temperature and water (1.5 mL) was added. The layers were
separated and the aqueous layer was extracted with DCM (2x4 mL). The combined organic
layers were dried with Na2S04, filtered and concentrated in vacuo. Purification by column
chromatography (EtOAc:heptane, 1:1-1:0, v/v) afforded 155 mg of the title compound.
1H NMR (MeOn-d4): 8 2.70-2.81 (m, 6H), 3.19-3.22 (m, 4H), 3.66-3.70 (m, 1H), 3.85-98
(m, 1H), 3.98-4.01.(m, 1H), 4.28-4.46 (m, 3H), 4.56 (s, 2H), 4.66-4.70 (m, 1H), 6.76-7.84
(m, 4H), 7.04-7.06 (m, 1H), 7.78-7.82 (m, 1H), 8.15-8.18 (m, 1H)
Via reduction of amide intermediates
EXAMPLE 14: l-(2,3-Dich!orophenyl)-4-((2,3-dihydrobenzo[b][l,4]dioxin-2-
yl)methyl)piperazine
Step A: (4-(2,3-Dichlorophenyl)piperazin-l-yl)(2,3-dihydrobenzo[A][l,4]dioxin-2-
yl)methanone
2,3-Dihydrobenzo[£][l,4]dioxine-2-carbonyl chloride (220 mg, 1.11 mmol) was reacted

with l-(2,3-dichlorophenyl)piperazine (257 mg, 1.11 mmol) and triethylamine (0.23 ml,
1.66 mmol) in DCM (3 ml) at 0 °C. The stiired mixture was then allowed to reach RT.
Water was added, the DCM layer separated and the aqueous phase extracted once with
DCM. The combined organic layers were washed with water, dried and evaporated to give
330 mg of the crude amide, which was used without purification in the next step.
lHNMR (CDC13): 8 2.98-3.18 (m, 4H), 3.67-3.83 (m, 2H), 3.91-4.04 (m, 2H), 4.36 (dd,
1H), 4.53 (dd, 1H), 4.88 (dd, 1H), 6.80-7.25 (m, 7H).
Step B: l-(2,3-Dichlorophenyl)-4-((2,3-dihydrobenzo[b][l,4]dioxin-2-
yl)methyl)piperazine
(4-(2,3-Dichlorophenyl)piperazin-1 -yl)(2,3 -dihydrobenzo[&] [1,4 jdioxin-2-yl)methanone
(328 mg, 0.834 mmol) was reduced with LAH (158 mg, 4.17 mmol) in refluxing THF (20
ml) (-3 h). isork-up with 2 N NaOH gave the crude product, which was purified by flash..
chromatography (heptane/EtOAc/triethylamine, 7:3:0.5) to give 134 mg of the title
compound.
'HNMR (CDCI3): δ 2.63-2.85 (m, 6H), 3.05-3.15 (m, 4H), 4.03 (dd, 1H), 4.30-4.40 (m,
2H), 6.80-7.02 (m, 5H), 7.12-7.18 (m, 2H).
EXAMPLE IS: (2-(4-((2,3-Dihydrobenzo[6] [l,4]dioxin-2-yl)methyl)piperazin-l-
yl)pyridin-3-yl)methanol
Step A: Ethyl 2-(4-(2,3-dihydrobenzo[£]{l,4]dioxine-2-carbohyI)piperazin-l-
yl)nicotinate
2,3-Dihydrobenzo[b][l,4]dioxine-2-carbonyl chloride (1.032 mmol) was stirred in 7:3
THF/water (10 ml). Ethyl 2-(piperazin-l-yl)nicotinate (220 mg, 0.935 mmol) was added at 0
°C. The mixture was then stirred at RT for 4 h. THF was removed by evaporation and the
remaining aqueous phase was extracted with DCM (20 ml). The organic phase was washed
(water, 1 M HC1 and 1 M Na2C03), dried and evaporated to dryness to afford 255 mg of the
title compound.
'HNMR(CDCI3): δ 1.39 (t, 3H), 3.44-3.78 (m, 4H), 3.86-3.40 (m, 4H), 4.31-4.39 (m, 3H), .
4.48-4.53 (m, 1H), 4.84.4.90 (m, 1H), 6.79-6.97 (m, 5H), 7.95-7.99 (m, 1H), 8.29-8.31(m,
1H).

Step B: (2-(4-((2,3TDihydrobenzo[6] [l,41dioxin-2-yl)methyl)piperazin-l-yI)pyridin-3-
yI)methanol
Ethyl 2-(4-(23-dih^y^obenzo[b][l54]dioxine-2-carbonyl)piperazin-l-yl)nicotinate (255 mg,
0.642 mmol) was dissolved in THF (3 ml) and cooled on an ice-bath. LAH (77 mg, 2.03
mmol) was added and the mixture was stirred for 1 h while the temperature was allowed to
reach r.t. The reaction was quenched with water. The mixture was filtered through Celite
and evaporated to dryness. Flash chromatography afforded 43 mg of the title compound.
'HNMR (CDCI3): see example 16.
EXAMPLE 16: (5)-(2-(4-((2,3-Dihydrobenzo[A] [l,4]dioxin-2-yl)methyl)piperazin-l-
yI)pyridin-3-yI)methanoI
Step A: (J?)-Ethyl 2-(4-(2,3-dihydrobenzo[&l[l,4]dioxine-2-carbonyl)piperazin-l-
yl)nicotinate
(J?)-2,3-Dihydrobenzo[b][l54]dioxine-2-carbonyl chloride (10.3 g, 52.0 mmol) in THF (30
ml) was added dropwise to an ice-cold mixture of THF (100 ml), water (40 ml), ethyl 2-
(piperazin-l-yl)nicotinate (10.2 g, 43.4 mmol) and K2C03 (5.99 g, 43.4 mmol). The
temperature was allowed to reach RT. The mixture was stirred for 17 h and concentrated in
vacuo. Water (100 ml) was added. This mixture was extracted with EtOAc (2x250 ml). The
organic layers were pooled, dried and evaporated to dryness to afford 14.7 g of the crude
product. Part of this (13.7 g) was purified by flash chromatography to afford 10.7 g of the
title compound.
1H NMR (CDCb): δ 1.39 (t, 3H), 3.44-3.78 (m, 4H), 3.86-3.40 (m, 4H), 4.31-4.39 (m, 3H),
•4.48-4.53 (m, 1H), 4.84.4.90.(m, 1H), 6.79-6.97 (m, 5H), 7.95-7.99 (m, 1H), 8.29-8.33 (m,
1H).
Step B: (5)-(2-(4-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyI)piperazin-l-yl)pyridin-
3-yI)methanol
To an ice-cold suspension of LAH (1.232 g, 30.8 mmol) and THF (120 ml) was added
dropwise a solution of (i?)-ethyl 2-(4-(253-dihydrobenzo[b][l,4]dioxine-2-
carbonyl)piperazin-l-yl)nicotinate (3.065 g, 7.71 mmol) in THF (30 ml). The temperature
was allowed to reach RT and the mixture was stirred for 3 h. Water (20 ml) was added. The

mixture was filtered through Celite and evaporated to dryness. Flash chromatography gave
560 mg of the title compound.
1H NMR (CDCI3): δ 2.6-2.9 (m, 6H), 3.19 (br t, 4H), 4.03 (dd, 1H), 4.14 (br s, 1H), 4.30-
4.39 (m, 2H), 4.73 (s, 2H), 6.80-6.92 (m, 4H)5 7.00 (dd,1H), 7.57 (dd, 1H), 8.27 (dd, 1H).
EXAMPLE 17: (5)-l-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(2-
(methoxymethyl)phenyl)piperazine
Step A: (JR)-(2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)(4-(2-
(methoxymethyI)phenyl)piperazin-l-yl)methanone
As in example 14, Step A, (i2)-2,3-dihydrobenzo[b][l,4]dioxine-2-carbonyl chloride (220
mg, 1.11 mmol) was reacted with l-(2-(meth6xymethyl)phenyl)piperazine (229 mg, 1.11
mmol) and triethylamine (0.23 ml, 1.66 mmol) in DCM (3.3 ml) at 0 °C to give 300 mg of
the crude desired amide.
'HNMR (CDCI3): 6 2.88-3.12 (m, 4H), 3.44 (s, 3H), 3.66-3.81 (m, 2H), 3.83-3.98 (m, 2H),
4.36 (dd, 1H), 4.52 (dd, 1H), 4.56 (s, 2H), 4.88 (dd, 1H), 6.82-6.95 (m, 4H), 7.08 (ds 1H),
7.14 (dd, 1H), 7.30 (dd, 1H), 7.45 (d, 1H).
Step B: (.S)-l-((2,3-Dihydrobenzo[b][l,4}dioxiii-2-yl)methyl)-4-(2-
(methoxymethyl)phenyl)piperazine
(if)-(2,3-Dihydrobenzo[&][l,4]dioxin-2-yl)(4-(2-(methoxymethyl)phenyl)-piperazin-l-
yl)methanone (366 mg, 0.99 mmol) was reduced with LAH (188 mg, 4.97 mmol) in dry
THF (22 ml, reflux 2 h). isork-up with 2 N NaOH gave the crude product, which was
purified by flash chromatography (gradient of heptane and EtOAc) to give 90 mg of the title
compound.
*H NMR (CDCI3): see example 3.
EXAMPLE 18: (^-l-P^-DihydrobenzoIft][l,41dioxin-2-yl)methyl)-4-(2-
(methoxymethyl)phenyI)piperazine
The corresponding (iJ)-isomer was prepared analogously to the above example 17 by first
reacting (.S)-2,3-dihydrobenzo[b][l,4]dioxine-2-carbonyl chloride (220 mg, 1.11 mmol) and
l-(2-(methoxymethyl)phenyl)piperazine (229 mg, 1.11 mmol) in the presence of

triethylamine (0.23 mL, 1.66 mmol) in DCM (3.3 raL). Reduction of the crude amide (345
mg, 0.94 mmol) with δ eq of LAH (178 mg, 4.68 mmol) in refluxing THF gave, after
purification by flash chromatography (gradient of heptane and EtOAc), 87 mg'of the title
compound.
JH NMR (CDC13): see example 3.
EXAMPLE 19: (S)-(2-(4-((2,3-Dihydrobeiizo[£][l,4]dioxin-2-yl)methyl)piperazin-l-
yl)phenyl)methanol
Step A: (K)-Methyl 2-(4-(2,3-dihydrobenzo[b][l,4]dioxine-2-carbonyl)piperazin-l-
yl)benzoate
As in example 17, (i?)-2,3-dihydrobenzo[b][l,4]dioxine-2-carbonyl chloride (0.50 g, 2.54
mmol) was reacted with methyl 2-(piperazin-l-yl)benzoate (0.56 g, 2.54 mmol) and
triethylamine (0.54 ml, 3.81 mmol) in DCM (8 ml) at 0 °C to give 0.87 g of the crude
amide.
'HNMR (CDCI3): 8 3.00-3.23 (m, 4H), 3.68-3.83 (m, 2H), 3.88-4.00 (m, 2H), 3.90 (s, 3H),
4.35 (dd, 1H), 4.52 (dd, 1H), 4.87 (dd, 1H), 6.82-6.95 (m, 4H), 7.04-7.11 (m, 2H), 7.46 (dd,
1H), 7.81 (d, 1H).
Step B: (S)-(2-(4-((23-Dihydrobenzo[b][l,4]dioxin-2-yI)methyl)piperazin-l-
yl)phenyl)methanoI
The above amide (0.87 g, 2.27 mmol) was reduced with LAH (0.52 g, 13.65 mmol) in dry
THF (55 ml, reflux 2 h). isork-up with 2.5 M NaOH gave the crude product, which was
purified by flash chromatography (gradient of heptane and EtOAc) to give 188 mg of the
title compound.
*H NMR (CDCI3): see example 2.
EXAMPLE 20: (5)-l-((23-Dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(3-
(methoxymethyI)pyridin-2-yl)piperazine
Step A: (/?)-(2,3-Dihydrobenzo[61[l,41dioxin-2-yl)(4-(3-(methoxymethyl)pyridiii-2-
yl)piperazin-l-yl)methanone
l-(3-(Methoxymethyl)pyridin-2-yl)piperazine (25 g, 121 mmol) and K2C03 (25 g, 181

mmol) were dissolved in a mixture of water (200 ml) and THF (300 ml). Crude (i?)-2,3-
dihydrobenzo[b][l,4]dioxine-2-carbonyl chloride, previously prepared from (J?)-2,3-
dihydrobenzo[b][l,4]dioxine-2-carboxylic acid (28.3 g, 157 mmol), was dissolved in dry
THF (100 ml) and added in 10 min to the mixture at 20±5°C with efficient stirring. Stirring
was continued for additional 30 min at RT, after which the phases were separated. The
organic phase was washed with brine, dried and evaporated to afford 42.4 g of the title
product.
'HNMR (CDC13): δ 3.17-3.37 (m, 4H), 3.45(s, 3H), 3.70-3.78 (m, 3H), 3.85-3.96 (m, 2H),
4.33-4.38 (m, 1H), 4.45 (s, 2H), 4.51-4.54 (m, 1H), 4.87-4.89 (dd, 1H), 6.85-7.02 (m, 5H),
7.71-7.73 (dd, 1H), 8.26-8.27 (dd, 1H).
Step B: (S)-l-((2,34)ihydrobenzo[A][l,4]dioxin-2-yl)methyi)-4-(3-
(methoxymethyI)pyridin-2-yI)piperazine
(i?)-(23-Dihydroben2o[b][l,4]dioxin-2-yl)(4-(3-(memoxymethyl)pyridin-2-yl)piperazin-l-
yl)-methanone (42 g, 108 mmol) was dissolved in THF (420 ml). 1 M BH3-THF solution
(397 ml, 397 mmol) was added slowly to the stirred solution while the temperature was kept
under 40 °C. Stirring was continued for 2.5 h at 40 °C. After cooling to RT MeOH (120 ml)
and water (65 ml) were added and the solvents were evaporated. To the residue were added
EtOH (65 ml), water (65 ml) and cone. HC1 (63 ml) and the mixture was heated for 1.5 h at
60 °C. Under cooling the pH of the mixture was adjusted to 10 with 50 % NaOH solution.
DCM was added and the formed precipitate was filtered off. Phases were separated and the
water phase was washed with DCM. Combined organic layers were dried and evaporated.
The crude product was recrystallised from IP A to give 29 g of the pure title compound.
'HNMR (CDCI3): δ 2.65-2.79 (m, 6H), 3.20-3.22 (m, 4H), 3.42 (s, 3 H), 4.01-4.06 (dd,
1H), 4.33-4.37 (ms 2H), 4.42 (s, 2H), 6.83-6.96 (m, 5H), 7.68-7.70 (dd, 1H), 8.23-8.25 (dd,
1H).
EXAMPLE 21: (l-((2,3-Dihydrobenzo[A] [l,4]oxathiin-2-yl)methyI)-4-(2-
(methoxymethyl)phenyl)piperazine
Step A: (2,3-Dihydrobenzo[b][l,4]oxathiin-2-yl)(4-(2-
(methoxymethyl)phenyl)piperazin-l-yl)methanone

2,3-Dihydrobenzo[b][l,4]oxathiine-2-carboxylic acid (112 mg, 0.48 mmol) was treated with
thionyl chloride (0.21 ml, 2.85 mmol) in refluxing toluene for 1 h. After cooling, the
mixture was evaporated to dryness and redissolved in DCM (2 ml). This solution was added
to a stirred mixture of l-(3-(methoxymemyl)pyridin-2-yl)piperazine (100 mg, 0.48 mmol),
triethylamine (0.080 ml, 0.57 mmol) and DCM (1 ml). After 30 min at RT, the mixture was
washed with 1 M Na2CC>3 and evaporated to dryness to give 119 mg of the crude amide.
'HNMR(CDC13): 8 2.89-3.11 (m, 4H), 3.18-3.23 (m, 1H), 3.41-3.55 (m, 4H)5 3.64-3.99
(m, 4H), 4.56 (s, 2H), 4.89-4.92 (m, 1H), 6.85-6.92 (m, 2H), 6.97-7.05 (m, 1H), 7.06-7.18
(m, 3H), 7.26-7.33 (m, 1H), 7.42-7.49 (m, 1H).
Step B: (l-((2,3-Dihydrobenzo[b][l,4]oxathiin-2-yl)methyl)-4-(2-
(methoxymethyl)phenyl)piperazine
The amide from step A (119 mg, 0.309 mmol) was reduced with LAH (65 mg, 1.70 mmol)
in dry THF (4 ml), first at RT for 2 h and then at refluxing temperature for 30 min. isork-up
with 1 M NaOH and water, gave the crude product after filtration and evaporation. This was
purified by flash chromatography (gradient of heptane and EtOAc) to give 30 mg of the title
compound.
1H NMR (CDCI3): 8 2.63-2.8S (m, 6H), 2.94-3.00 (m, 4H), 3.02-3.10 (m. 1H), 3.15-3.22
(m, 1H), 3.42 (s, 3H), 4.35-4.45 (m, 1H), 4.53 (s, 2H), 6.82-6.88 (m, 2H), 6.97-7.02 (m,
1H), 7.04-7.12 (m, 3H), 7.24-7.30 (m, 1H), 7.42-7.45 (m, 1H).
EXAMPLE 22: l-(Chroman-2-ylmethyI)-4-(2-(methoxymethyl)phenyI)piperazine
Step A: Chroman-2-yl(4-(2-(methoxymethyl)phenyI)piperazin-l-yI)methanone
As in the above example, crude chroman-2-carbonyl chloride, prepared from chroman-2-
carboxylic acid (198 mg, 1.11 mmol), was reacted with l-(2-
(methoxymethyl)phenyl)piperazine (229 mg, 1.11 mmol) in the presence of triethylamine
(0.23 ml, 1.67 mmol) in DCM (3.3 ml) to 343 mg of the crude amide, which was used as
such in the next step.
1H NMR (CDC13): 8 2.20-2.29 (m, 2H), 2.82-3.08 (m, 6H), 3.43 (s, 3H), 3.68-3.95 (m, 4H),
4.56 (s, 2H), 4.82 (dd, 1H), 6.83-6.91 (m, 2H), 7.05-7.17 (m, 2H), 7.29 (ddd, 1H), 7.45 (dd,
1H).

StepB: l-(Chroman-2-ylmethyl)-4-(2-(methoxymethyI)phenyl)piperazine
The above amide (339 mg, 0.925 mmol) was reduced with LAH (176 mg, 4.63 mmol) in
refluxing THF (20 ml) (3 h). isork-up with 2 N NaOH gave the crude product, which was
purified by flash chromatography (gradient of heptane and EtOAc) to give 139 mg of the
title compound.
*H NMR (CDC13): δ 1.75-1.88 (m, 1H), 2.04-2.14 (m, 1H), 2.61-2.93 (m, 8H), 2.98 (br t,
4H), 3.42 (s, 3H), 4.20-4.28 (m, 1H), 4.54 (s, 2H), 6.80-6.87 (m, 2H), 7.02-7.12 (m, 4H),
7.26 (ddd, 1 H), 7.43 (dd, 1H).
The compound was treated with 1 M HCWE^O in EtOAc to form a HC1 salt in the usual
manner.
lH NMR (DMSO-d6): 8 1.68-1.82 (m, 1H), 2.01-2.11 (m, 1H), 2.72-2.93 (m, 2H), 3.16-3.28
(m, 4H), 3.30-3.65 (m, 8H), 3.72-3.81 (m, 1H), 4.48 (m, 2H), 4.65-4.75 (m, 1H), 6:83-6.92
(m, 2H), 7.08-7.18 (m, 4H), 7.32 (dd, 1H), 7.40 (d, 1H), 10.75 (br s, 1H).
Via alleviation of piperazine derivatives with electron-deficient haloarenes
EXAMPLE 23: (2-(4-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)-6-
fluorophenyl)methanol
Step A: 2-(4-(23-Dihydrobenzo[b][l,4]dioxine-2-carbonyl)piperazin-l-yl)-6-
fluorobenzaldehyde
A mixture of (2,3-dihydrobenzo[i][l,4]dioxin-2-yl)(piperazin-l-yl)methanone (0.20 g, 0.81
mmol), 2,6-difluorobenzaldehyde (0.36 g, 2.56 mmol) and K2C03 (0.59 g, 4.26 mmol) in
DMF (7 ml) was heated in a microwave reactor at 160 °C for 20 min. The mixture was
poured into water and extracted with EtOAc (3x5 ml). The organic layer was dried and
evaporated to give 0.35 g of the title aldehyde.
lHNMR (DMSO-cU): 8 3.11 (m, 4H), 3.71 (m, 4H), 4.21 (m, 1H), 4.41 (m, 1H), 5.27 (m,
1H), 6.83 (m, 3H), 6.94 (m, 2H), 7.05 (m, 1H), 7.61 (m, 1H), 10.21 (s, 1H).
Step B: (2-(4-((2,3-Dihydrobenzo[6] [l,4]dioxin-2-yl)methyl)piperazin-l-yI)-6-
fluorophenyl)methanol
The crude product from the above step (0.32 g, 0.90 mmol) in THF (5 ml) was added to a

suspension of LAH (0.17 g, 4.46 rnmol) in dry THF (2 ml). The reaction mixture was heated
in a microwave reactor at .80 °C for 10 min, after which it was poured into ice water and
extracted with EtOAc (3><10 ml). The combined organic layers were dried and evaporated.
The crude product was purified by flash chromatography (gradient of heptane and EtOAc)
to give 36 mg of the title compound.
1H NMR (DMSO-d6): δ 2.61 (m5 6H), 3.01 (m, 4H), 4.02 (m, 1H), 4.30 (m, 2H), 4.51 (s,
2H), 5.01 (s, 1H), 6.86 (m, 6H), 7.31 (m', 1H).
EXAMPLE 24: (2-(4-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)-3-
fluorophenyI)methanoI
Step A: 2-(4-(2,3-Dihydrobenzo[A][l,4]dioxine-2-carbonyl)piperazin-l-yI)-3-
fluorobehzaldehyde
(2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)(piperazin-l-yl)methanone (0.20 g, 0.81 mmol), 2,3-
difluo'robenzaldehyde (0.18 g, 1.28 mmol) and K2C03 (0.29 g, 2.13 mmol) in DMF (3 ml)
were heated in a microwave reactor at 160 °C for 20 min. The mixture was poured into
water and extracted with EtOAc (3 x5 ml). After drying and evaporation, 0.14 g of the crude
aldehyde was obtained.
1H NMR (DMSO-d6): δ 3.19 (m, 4H), 3.60 (m, 4H), 4.12 (m, 1H), 4.39 (m, 1H), 5.22 (m,
1H), 6.83 (m, 4H), 7.56 (m, 1H), 7.70 (m, 1H), 7.80 (m, 1H), 10.21 (s, 1H).
Step B: (2-(4-((2,3-Dihydrobenzo[6] [l,4]dioxin-2-yI)methyl)piperazin-l-yl)-3-
fluorophenyl)methanol
The product obtained in the above manner (0.32 g, 0.90 mmol) in dry THF (4 ml) was
added to a suspension of LAH (0.17 g, 4.46 mmol) in dry THF (2 ml). The reaction mixture
was heated under microwaves at 80 °C for 10 min, after which it was isorked up as in
example 23, Step B. The crude product was purified by column chromatography (gradient
of heptane and EtOAc) to give 18.0 mg of the title compound.
1H NMR (DMSO-d6): δ 2.61 (m, 6H), 3.01 (m, 4H), 4.02 (m, 1H), 4.30 (m, 2H), 4.53 (s,
2H), 5.01 (s, 1H), 6.85 (m, 6H), 7.30 (m, 1H).
EXAMPLE 25: (2-(4-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)-5-
fluorophenyl)methanoI

Step A: 2-(4-(2,3-Dihydrobenzo[6] [l,4]dioxine-2-carbonyI)piperazin-l-yl)-5-
fluorobenzaldehyde
As in the tiso previous examples, (2,3-dihydrobenzo[b3[l,4]dioxin-2-yl)(piperazin-l-
yl)methanone (0.20 g, 0.81 mmol), 2,5-difluorobenzaldehyde (0.38 g, 2.70 mmol) and
K2CO3 (0.62 g, 4.50 mmol) in DMF (7 ml) were reacted under microwaves at 160 °C for 15
min. isork-up as above gave 0.27 g of the aldehyde intermediate.
'HNMR(DMSO-de): δ 3.10 (m, 4H), 3.70 (m, 4H), 4.21 (m, 1H), 4.40 (m, 1H), 5.28 (m,
1H), 6.83 (m, 3H), 6.90 (m, 2H), 7.40 (m, 1H), 7.60 (m, 1H)310.18 (s, 1H).
Step B: (2-(4-((2,3-Dihydrobenzo[6] [l,4]dioxin-2-yl)methyl)piperazin-l-yl)-5-
fluorophenyl)methanol
The product obtained in Step A (0.27 g, 0.70 mmol) was.reduced with LAH(0.13 g, 3.50
mmol) in dry THF (5 ml) as above. The crude product was purified by flash
chromatography (gradient of heptane and EtOAc) to give 13.1 mg of the title compound.
'HNMR(DMSO-d6): 8 2.61 (m, 6H), 3.01 (m, 4H), 4.03 (m, 1H), 4.51 (m, 2H), 4.51 (d,
2H), 5.45 (t, 1H), 6.86 (m, 6H), 7.21 (m,1H).
Arvl piperazines via ring closure

General Procedure: A suitable aniline derivative (0.2 mmol), (S)-2-chloro-AT-(2-
chloroethyl)-iV-((2,3-dihydrobenzo[&]-[l,4]dioxin-2-yl)methyl)ethanamine (0.25 mmol),
triethylamine (0.105 ml, 0.75 mmol) and ACN (1 ml) were mixed and heated in a sealed
vial at 180 °C for 1-2 h using a microwave reactor. After cooling, the mixture was absorbed
on a plug of silica gel. Flash chromatography using a gradient of heptane/EtOAc gave the
desired compound.
EXAMPLE 26: (5)-l-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(2-
propylphenyI)piperazine
Using the general procedure, 2-propylaniline was reacted with (5)-2-chloro-Ar-(2-

cUoroethyl)-iV-((2,3-dihydrobenzo[i][l,4]-dioxin-2-yl)raethyl)ethanamine to give 10.4 mg
of the title compound.
'HNMRCCDCls): 8 0.97 (t, 3H), 1.59-1.71 (m, 2H), 2.58-2.83 (m, 12H), 3.98-4.08 (m5
1H), 4.33-4.38 (m, 2H), 6.82-6.92 (m, 4H), 7.00-7.23 (m, 4H).
EXAMPLE 27: (5)-l-((2,3-Dihydrobenzo[6] [l,4]dioxin-2-yl)methyl)-4-(2-
(trifluoromethoxy)phenyl)piperazine
Using the general procedure, 2-(trifluoromethoxy)aniline was reacted with (^^-chloro-A''-
(2-chloroethyl)-iV-((2,3-dihydrobeiizo[&][l54]dioxin-2-yl)methyl)ethanamine to give 2.3 mg
of the title compound.
'HNMR (CDC13): 8 2.60-2.84 (m, 4H), 3.05-3.16 (m, 4H), 4.00-4.06 (m, 1H), 4.08-4.16
(m, 2H), 4.30-4.37 (m, 2H), 6.82-6.92 (m, 4H), 6.97-7.05 (m, 2H), 7.16-7.25 (m, 2H).
EXAMPLE 28: (5)-l-(Biphenyl-3-yI)-4-((2^-dihydrobenzo[b][l,4]dioxin-2-
yl)methyl)piperazine
Using the general procedure, biphenyl-3-amine was reacted with ()S}-2-chloro-iV-(2-
chIoroethyl)-A^-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)ethanamine to give 12.9 mg
of the title compound.
*H NMR (CDCI3): 8 2.62-2.88 (m, 6H), 3.23-3.35 (m, 4H), 3.99-4.04 (m, 1H), 4.32-4.40
(m, 2H), 6.78-6.99 (m, 5H), 7.04-7.18 (m, 2H), 7.31-7.50 (m, 4H), 7.56-7.21 (m, 2H).
EXAMPLE 29: (S)-l-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyI)-4-(2-(furan-2-
yl)phenyl)piperazine
Using the general procedure, 2-(furan-2-yl)aniline was reacted with (.S)-2-chloro-iV-(2-
chloroethyl)-JV-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)ethanamine to give 6.4 mg of
the title compound.
1H NMR (CDCI3): 8 2.59-2.89 (m, 6H), 2.90-3.08 (m, 4H), 3.99-4.07 (m, 1H)3 4.29-4.40
(m, 2H), 6.47-6.52 (m, 1H), 6.80-6.93 (m, 4H), 7.08-7.30 (m, 4H), 7.44-7.49 (m, 1H), 7.77-
7.82 (m, 1H).
EXAMPLE 30: (S>EthyI 2-(4-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-
l-yl)benzoate

Using the General Procedure,, ethyl 2-aminobenzoate was reacted with (5)-2-chloro-iV-(2-
cMoroethyl)W-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)ethanarnine to give 5.0 mg of
the title compound.
'HNMR (CDCI3): 8 1.39 (t, 3H), 2.61-2.83 (m, 6H), 3.01-3.17 (m, 4H), 3.91-4.06 (m, 1H),
4.30-4.40 (m, 4H), 6.81-6.92 (m, 4H), 6.97-7.07 (m, 2H), 7.37-7.44 (m, 1H), 7.69-7.74 (m,
1H). "
EXAMPLE 31: (£)-l-((2,3-Dihydrobenzo[A] {l,4]dioxin-2-yl)methyl)-4-o-
tolylpiperazine
Using the general procedure, o-toluidine was reacted with (5)-2-chloro-7|/-(2-chloroethyl)-Ar-
((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)ethanamine to givd 27.6 mg of the title
compound.
'HNMR (CDCI3): δ 2.30 (s, 3H), 2.59-2.85 (m, 6H), 2.85-3.01 (m, 4H), 3.96-4.10 (m, 1H),
4.28-4.42 (m5 2H), 6.79-6.95 (m, 4H), 6.95-7.09 (m, 2H), 7.15-7.22 (m, 2H).
EXAMPLE 32: (S)-l-((2,3-Dihydrobenzo[6] [l,4]dioxin-2-yl)methyl)-4-m-
tolylpiperazine
Using the general procedure, m-toluidine was reacted with (5)-2-chloro-A/-(2-chloroethyl)-
iV-((2,3-dihydrobenzo[&][l,4]dioxin-2-yl)methyl)ethanamineto give 17.5 mg of the title
compound.
'HNMR(CDC13): 8 2.31 (s, 3H), 2.66-2.85 (m, 6H), 3.15-3.28 (m, 4H), 3.97-4.09 (m, 1H),
4.26-4.42 (m, 2H), 6.65-6.80 (m, 3H), 6.80-6.94 (m, 4H), 7.09-7.23 (m, 1H).
EXAMPLE 33: (5)-(3-(4-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yI)methyl)piperazin-l-yl)-
4-methylphenyl)methanol
Using the general procedure, (3-amino-4-methylphenyl)methanol was reacted with (5)-2-
cUoro-iy-(2-ch1oroemyl)-A^-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)ethanarnineto
give 5.2 mg of the title compound.
*HNMR (CDC13): 8 2.29 (s, 3H), 2.62-2.85 (m, 6H), 2.92-2.98 (m, 4H), 4.00-4.07 (m51H)5
4.30-4.39 (m, 2H), 4.64 (s, 2H), 6.80-6.94 (m, 4H), 6.97-7.01 (m, 1H), 7.03-7.06 (m, 1H),
7.14-7.20 (m, 1H).

EXAMPLE 34: (»S)-(3-(4-((2,3-Dihydrobenzo[6] [l,4]dioxm-2-yl)methyl)piperazin-l-
yl)phenyI)methanol
Using the general procedure, (3-aminophenyl)methanol was reacted with (S)-2-chloro-JV-(2-
chloroethyl)-iV-((2,3-dihydrobenzo[Z>][l,4]dioxin-2-yl)methyl)ethanamine to give 18.9 mg
of the title compound.
1H NMR (CDC13): δ 2.57-2.87 (m, 6H), 3.20-3.26 (m, 4H), 3.94-4.00 (m, 1H), 4.24-4.40
(m, 2H), 4.66 (s, 2H), 6.80-6.97 (m, 5H), 6.93-6.97 (m, 1H), 7.18-7.27 (m, 2H).
EXAMPLE 35: (S)-2-(2-(4-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yI)methyl)piperazin-l-
yI)phenyl)ethanol
3-(2-Aminophenyl)ethan-l-ol (24 mg, 0.172 mmol), (S)-2-chloro-iV-(2-chloroethyl)-#-((2,3-
dihydrobenzo[b][l,4]dioxin-2-yl)methyl)ethanamine (50 mg, 0.172 mmol), triethylamine
(0.060 ml, 0.43 mmol) and acetonitrile (0.5 ml) were mixed and heated in a sealed vial at
180 °C for 2 h using a microwave reactor. After cooling, the mixture was absorbed on a
plug of silica gel. Flash chromatography using a gradient of heptane/EtOAc gave 15.0 mg of
the title compound.
JH NMR (CDCI3): δ 2.50-3.19 (m, 14H), 3.74-3.19 (m, 2H), 3.98-4.08 (m, 1H), 4.26-4.38
(m, 2H), 4.89 (br s, 1H), 6.75-6.96 (m, 4H), 7.07-7.28 (m, 4H).
Homopiperazines
EXAMPLE 36: Methyl 2-(4-((2,3-dihydrobenzo[A][l,4Jdioxin-2-yl)methyl)-l,4-
diazepan-l-yl)benzoate
A mixture of l-((2,3-dihydrobenzo[&][l,4]dioxin-2-yl)methyl)-l,4-diazepane (0.21 g, 0.86
mmol), methyl 2-fiuorobenzoate (0.20 g, 1.28 mmol) and K2CO3 (0.18 g, 1.30 mmol) in
DMF (8 ml) was heated in a microwave reactor at 220 °C for 30 min. The mixture was
poured into water and extracted with EtOAc (3x20 ml). The organic layer was dried and
evaporated. The crude product was purified by flash chromatography (gradient of DCM and
MeOH) to give 0.20 g of the title compound.
'HNMR (CDCI3): 8 1.91 (m, 2H), 2.73 (m, 1H), 2.86 (m3 4H), 3.43 (m, 4H), 3.88 (s, 3H),
3.97 (dd, 1H), 4.33 (m, 2H), 6.85 (m, 1H);6.81 (m, 5H), 6.97 (d, 1H), 7.31 (t, 1H), 7.59 (dd,
1H).

EXAMPLE 37: (2-(4-((2,3-Dihydrobenzo[Al[l,4]dioxin-2-yl)methyl)-l,4-diazepan-l-
yl)phenyl)methanol
To a suspension of LAH (100 mg, 2.63 mmol) in dry THF (2 ml) was added methyl 2-(4-
((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-l,4-diazepan-l-yl)benzoate (200 mg, 0.52
mmol) in dry THF (5 ml). The reaction mixture was heated in a microwave reactor at 80 °C
for 10 min. The reaction mixture was poured into ice water and extracted with EtOAc (3x20
ml). The combined organic phases were dried and evaporated. Flash chromatography
(heptane/EtOAc, 40:60) of the crude product gave 41 mg of the title compound.
1H NMR (CDC13): 8 1.92 (m, 2H), 2.75 (m, 1H), 2.95 (m, 6H), 3.19 (m, 4H), 4.04 (m, 1H),
4.35 (m, 1H), 4.38 (dd, 1H), 4.78 (s, 2H), 6.89 (m, 4H), 7.07 (t, 1H, 7.18 (m, 3H).
EXAMPLE 38: 2-(4-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)mcthyl)-l,4-diazepan-l-
yl)nicotinonitrile
A mixture of 2-(bromomethyl)-2,3-dihydrobenzo[6J[l,4]dioxine (150 mg, 0.65 mmol), 2-
(l,4-diazepan-l-yl)nicotinonitrile (131 mg, 0.65 mmol) and DIPEA (0.4 ml, 2.32 mmol) in
DMF (1.5 ml) was heated in a microwave reactor at 160 °C for 20 min. The mixture was
poured into water and extracted with EtOAc (3><20 ml). The combined organic layers were
dried and evaporated to dryness. The crude product was purified by flash chromatography
(gradient of DCM and MeOH) to give 97 mg of the title compound.
1H NMR (DMSO-de): δ 1.91 (m, 2H), 2.49-2.51 (m, 4H), 2.73 (m, 2H), 3.08-3.92 (m, 5H),
4.23 (m, 2H), 6.72 (dd, 1H), 6.81 (m, 4H), 7.93 (dd, 1H), 8.33 (dd, 1H).
EXAMPLE 39: 2-(4-((23-Dihydrobenzo[6] [l,4]dioxin-2-yl)methyl)-l,4-diazepani-l-
yl)nicotinamide
A mixture of 2-(4-((2,3-dihydrobenzo[b][154]dioxin-2-yl)methy])-1,4-diazepan-1 -
yl)nicotinonitrile (1.36 g, 3.88 mmol), NaOH (70 %, 25 ml) in EtOH (25 ml) was heated at
140 °C for 10 h. The mixture was poured into water and extracted with EtOAc (3^10 ml).
The combined organic layers were dried and evaporated to give 0.64 g of the title
compound.
'HNMR (DMSO-de): δ 1.84 (m, 2H), 2.63 (m, 5H), 2.87 (m, 2H), 3.51 (t, 2H), 3.59 (t, 2H),
3.92 (dd, 1H), 4.23 (m, 2H), 6.62 (dd, 1H), 6.82 (m, 4H), 7.29 (s, III), 7.52 (d, 1H), 7.54 (s,

lH),8.10(d, 1H).
EXAMPLE 40: (2-(4-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyI)-l,4-diazepan-l-
yI)pyridin-3-yI)methanol
Step A: 2-(4-((2,3-Dihydrobenzo[A] [l,4]dioxin-2-yl)methyl)-l,4-diazepan-l-yl)nicotinic
acid
The aqueous phase from the above experiment was acidified to pH δ and extracted with
EtOAc (3x10 ml). The combined extracts were dried and evaporated to give 0.27 g of the
title product.
1H NMR (DMSO-d6): δ 1.91 (m, 2H), 2.62 (m3 5H)5_2.80 (m, 2H), 3.49 (t, 2H), 3.55 (t, 2H),
3.92 (dd, 1H), 4:25 (m, 2H), 6.73 (dd, 1H), 6.84 (m, 4H), 7.80 (d, 1H), 8.10 (d, 1H).
StepB:(2-(4-((2,3-Dihydrobenzo[A][l,4]dioxin-2-yl)methyl)-lj4-diazepan-l-yl)pyridin-
3-yl)methanol
To a suspension of LAH(0.10 g, 2.63 mmol) in dry THF (3 ml) was added the above
obtained nicotinic acid derivative (0.19 g, 0.51 mmol) in dry THF (10 ml). The reaction
mixture was heated in a microwave reactor at 80 °C for 10 min. The reaction mixture was
poured into ice water and extracted with EtOAc (3x10 ml). The combined organic phases
were dried and evaporated. The crude product was purified by flash chromatography
(gradient of DCM and MeOH) to give 0.11 g of the title compound.
1H NMR (CDC13): δ 1.96 (m, 2H), 2.78 (m, 2H), 2.93 (m, 6H), 3.45 (m, 5H); 4.04 (m, 1H),
4.33 (m, 1H), 4.36 (m, 1H), 4.68 (s, 1H), 6.83 (m, 4H), 7.55 (d, 1H), 8.20 (d, 1H).
EXAMPLE 41: 0SM2-(4-((2,3-Dihydrobenzo[6] [l,41dioxin-2-yI)methyl)-l,4-diazepan-
l-yl)pyridin-3-yl)methanol
Step A: (5)-MethyI 2-(4-((i2^-dihydrobenzo{b][l,4]dioxin-2-yI)methyl)-l,4-diazepan-l-
yl)nicotinate
(i?)-(2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyl methanesulfonate (311 mg, 1.27 mmol),
methyl 2-(l ,4-diazepan-l-yl)nicotinate (300 mg, 1.27 mmol), K2CO3 (194 mg, 1.40 mmol)
and KI (12 mg) were heated in DMF (9 ml) at 120 °C for 2 h. The cooled mixture was
poured into water, which was extracted with EtOAc. The combined extracts were washed

several times with water, dried and evaporated. Purification of the crude product by flash
chromatography (heptane/EtOAc, 1:1) afforded 71 mg of the title compound.
'HNMR (CDCI3): δ 1.92-2.02 (m, 2H), 2.60-2.82 (m, 4H), 2.85-3.01 (m, 2H), 3.48 (t, 2H)5
3.65 (t, 2H), 3.86 (s, 3H), 3.95 (dd, 1H), 4.18-4.29 (m, 2H), 6.61 (dd, 1H), 6.78-6.88 (m,
4H), 7.86 (dd, 1H), 8.21 (dd, 1H).
Step B: (£)-(2-(4-((2,3-Dihydrobenzo [b] [1,4] dioxin-2-yl)methyl)-l,4-diazepan-l-
yl)pyridin-3-yl)methanol
The ester obtained in the above step (71 mg, 0.19 mmol) was reduced with LAH (28 mg,
0.74 mmol) in dry THF (5 ml, reflux 2 h) to give, after standard isork-up with 2.5 M NaOH,
67 mg of the title alcohol. .
'HNMR (CDCI3): δ 1.87-2.02 (m, 2H), 2.75 (dd, 1H), 2.82-3.01 (m, 5H), 3.43 (dd, 2H),
3.48 (m, 2H), 4.01 (dd, 1H), 4.23-4.31 (m, 1H), 4.33 (dd, 1H), 4.67 (s, 2H), 6.80-6.90 (m,
5H), 7.55 (dd, 1H), 8.18 (dd, 1H).
Preparation of a labeled PET tracer
EXAMPLE 42: (5)-l-((2^-Dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(3-([nC]-
methoxymethyl)pyridin-2-yl)piperazine
(5)-(2-(4-((2,3-Dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)pyridin-3-
yl)methanol (1 mg) was methylated with [nC]methyl triflate in ACN (0.2 ml), in the
presencel M tetrabutylammonium hydroxide (0.003 ml), for 3 minutes at 80 °C.
Purification with HPLC gave the title compound, suitable for formulation and use as a ' 'C-
labeled PET-tracer.
[uC]methyl triflate was prepared starting from [nC]iodomethane according to the
procedure described in Appl. Radial hot. 43 (1992) 1383.
[nC]iodomethane was prepared starting from cyclotrone produced ["C]methane according
to the procedure described in Appl. Radiat. hot. 48 (1997) 153.
As already mentioned hereinbefore, the compounds of formula I show interesting
pharmacological properties, namely they exhibit an improved selectivity for the alpha2C
adrenoceptor subtype and/or an enhanced potency. Said properties are demonstrated with

the pharmacological test presented below.
EXPERIMENT 1: Determination of alpha2A and alpha2C antagonistic activity in
vitro
Chinese hamster ovary (CHO) cells stably transfected with human alpha2A or alpha2C
receptors (University of Turku, Finland) were cotransfected with the expression vector
pCEP-Gotl6 (Molecular Devices, CA, USA) were used in this experiment. The cells were
maintained at 37 °C in a δ % CO2 / 95 % air atmosphere. The cells were cultured in HAM
F-12 medium supplemented with 10 % FCS, 25 mM HEPES, 100 IU/ml penicillin, 100
ug/ml streptomycin, 500 (j,g/ml geneticin and 240 ug/ml hygromycin B. The cells were
subcultured twice weekly with 0.25 % trypsin and 1 mM EDTA. The subculture ratio was
1:5-l :20. The growth medium was changed every 2 or 3 days. AH cell culture reagents were
from Gibco. The day before the experiment the cells were plated into black-walled, clear
bottom 96-well plates at a density of 30,000-45,000 cells/well.
The growth medium was removed and the cells were incubated with the test compounds and
the FLIPR Calcium 3 Assay reagent (Molecular Devices, CA, USA) for 1 h at 37 °C in dark.
The test compounds (concentrations in cells 100 pM -10 uM) were dissolved in
Probenecid-Ringer consisting of 150 mM NaCl, 3 mM KC1,1.2 mM MgCl2, 1 mM CaCl2, δ mM glucose, 20 mM HEPES and 2.5 mM probenecid (pH 7.4 adjusted with 1.0 M NaOH).
The osmolarity was adjusted to 322 milliosmoles with Osmostat® OM-6020 osmometer
(DIC Kyoto Daiichi Kagagu Co. Ltd, Japan). The changes in intracellular calcium were
1
monitored using FLEXstation benchtop scanning fluorometer with integrated fluid transfer
isorkstation (Molecular Devices, CA, USA) and displayed using SOFTmax PRO version
3.2 software. All experiments were performed at 37 °C. The test compounds dissolved in
Probenecid-Ringer were applied by FLEX station at 17 s time point. The IC50 value for a
given test compound was determined from dose-response curves, which ranged from 0.01
nM to 10 pM. In order to determine antagonism, the cells were stimulated either with 100
nM adrenaline or 200 nM noradrenaline and the test compounds were added to the cells at
least δ min before the experiment. Typically, there were four replicates at each
concentration and seven different dose levels. For example, if the number of plates from
which results were obtained was three, 84 (4 * 7 * 3) wells were thus measured to construct
dose-response relationship. The samples were excited at 485 nm and emission was detected

at 525 nm with a 515 nm cut-off filter. Reading time was 60 s per well and the
photomultiplier sensitivity value was set to 15. The minimum fluorescence value subtracted
from the maximum value for each well was used in the calculations. SOFTmax PRO
version 3.2 software was used for analyzing the results. Fitting of the antagonist dose-
response results was performed with the free Hill equation and the IC50 values were fitted
with Michaelis-Menten equation in Sigma Plot 8.0.
The results are shown in Table 1.

In vivo effects of the compounds of formula I can be demonstrated with the pharmacological
tests as described in iso 03/082866.
The compounds of formula I exhibit alpha2C antagonistic activity. The present invention
thus provides compounds for use as a medicament. Compounds for use in the treatment of
diseases or conditions where an alpha2C antagonist is indicated to be useful are also
provided. Furthermore, a method for the treatment of diseases or conditions where an
alpha2C antagonist is indicated to be useful is provided. In said method an effective amount
of at least one compound of formula I is administered to a mammal, e.g. human, in need of
such treatment. The use of the compounds of formula I for the manufacture of a medicament
for the treatment of diseases or conditions where an alpha2C antagonist is indicated to be
useful is also provided.
In one embodiment of the invention the aforementioned disease or condition where an
alpha2C antagonist is indicated to be useful is a mental disorder propagated by stress,
Parkinson's disease, depression, schizophrenia, attention deficit hyperactivity disorder, post-
traumatic stress disorder, obsessive compulsive disorder, Tourette's syndrome,

blepharospasm or other focal dystonias, temporal lobe epilepsy with psychosis, a drug-
induced psychosis, Huntington's disease, a disorder caused by fluctuation of the levels of
sex hormones, panic disorder, Alzheimer's disease or mild cognitive impairment; for
example, a mental disorder propagated by stress, Parkinson's disease, depression,
schizophrenia, attention deficit hyperactivity disorder, obsessive compulsive disorder or
Alzheimer's disease; such as a mental disorder propagated by stress, depression or
schizophrenia.
Representative examples of drug-induced psychoses include, but are not limited to,
psychosis caused by chronic use of dopaminergic agents.
Representative examples of disorders caused by fluctuation of the levels of sex hormones
include, but are not limited to, premenstrual syndrome and hot flashes.
The compounds of the invention can be administered, for example, enterally, topically or
parenterally by means of any pharmaceutical formulation useful for said administration and
comprising at least one active compound of formula I in pharmaceutically acceptable and
effective amounts together with pharmaceutically acceptable diluents, carriers and/or
excipients known in the art. The manufacture of such pharmaceutical formulations is known
in the art.
The therapeutic dose to be given to a subject in need of the treatment will vary depending on
the compound being administered, the species, the age and the sex of the subject being
treated, the particular condition being treated, as well as the route and method of
administration, and is easily determined by a person skilled in the art. Accordingly, the
typical dosage for oral administration is from 10 ng/kg to 100 mg/kg per day and for
parenteral administration from 1 ng/kg to 10 mg/kg for an adult mammal.
The compounds of the invention are given to the subject as such or in combination with one
or more other active ingredients, each in its own composition or some or all of the active
ingredients combined in a single composition, and/or suitable pharmaceutical excipients.
Suitable pharmaceutical excipients include conventionally used excipients and formulation
aids, such as fillers, binders, disintegrating agents, lubricants, solvents, gel forming agents,
emulsifiers, stabilizers, colorants and/or preservatives.

The compounds of the invention are formulated into dosage forms using commonly known
pharmaceutical manufacturing methods. The dosage forms can be, for example, tablets,
capsules, granules,-suppositories, emulsions, suspensions or solutions. Depending on the
route of administration and the galenic form, the amount of the active ingredient in a
formulation can typically vary between 0.01 % and 100 % by weight.
A person skilled in the art will appreciate that the embodiments described in this application
can be modified without departing from the inventive concept. A person skilled in the art
also understands that the invention is not limited to the particular embodiments disclosed
but is intended to also cover modifications of the embodiments that are within the scope of
the invention.

CLAIMS
1. A compound of formula I,

wherein
X is O, S or CH2;
Z is-[CH2]n-;
A, B, D and E are independently C or N provided that at least three of A, B, D and E are C;
R1 is H, halogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)
alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)
alkoxy(C1-C6)alkyl3(C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-,
CN, (R5)2N-, (R5)2N-(C1-C6)aikyl, (R5)2N-(C=O)-, Sn-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-
S-(C1-C6)alkyl,(C1-C6)alkoxy(C1-C6)alkyl-S-(C1-C6)aIkyl3hydroxy(C1-C6)alkyl-S(Op)-(C1-
C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-S(Op)-(C1-C6)aIkyl or furyl;
R2 is H, halogen, (C1-C6)alkyl, (C1-C6)alkoxy or hydroxy(C1-C6)alkyl;
R3 is H, halogen, (C1-C6)alkyl or phenyl;
R4 is halogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, CN or (C1-C6);
Rs is, independently at each occurence, H, (C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl;
m is 0,1 or 2;
n is 1 or 2; and
p is 1 or 2,
in labeled or unlabeled form, or a pharmaceutically acceptable salt or ester thereof, with the
provisos, that
a) R1, R2 and R3 are not simultaneously H;
b) when A is C and tiso of R1, R2 and R3 is H, then the third of R1, R2 and R3 is not halogen;
c) the compound is not l-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(2-
methoxyphenyl)piperazines l-(chroman-2-ylmethyl)-4-o-tolylpiperazine or l-((2,3-
dihyd^oberizo[R][l,4]dioxm-2-yl)memyl)4-(6-methylpyridin-2-yl)piperazine.

2. A compound according to claim 1, wherein X is O.
3. A compound according to any one of claims 1 or 2, wherein A, B, D and E are C.
4. A compound according to any one of claims 1 or 2, wherein A is N; and B, D and E are
C.
5. A compound according to any one of claims 1 to 4, wherein n is 1.
6. A compound according to any one of claims 1 to 4, wherein n is 2.
7. A compound according to claim 1, wherein
X is O, S or CH2;
Zis-[CH2]n-;
A is C or N;
B, D and E are C;
Ri is H, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)
alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=0), CN,
(R5)2N-(C1-C6)alkyl, (R5)2N-(C=O)- or furyl;
R2 is H, halogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;
R3 is H, (C1-C6)alkyl or phenyl;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is 1 or 2.
8. A compound according to claim 7, wherein
X is O;
Z is-[CH2]n-;
A is C or N;
B, D and E are C;
Ri is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C,-C6)alkyl, (C1-C6)alkoxy(C1-C6)
alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=0)-, CN,
(R5)2N-(C1-C6)alkyl, (R5)2N-(C=O)- or furyl;
R2 is H, halogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;
R3 is H, (C1-C6)alkyl or phenyl;

R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is 1 or 2.
9. A compound according to claim 8, wherein
X is O;
Z is-[CH2]n-;
A, B, D and E are C;
R1 is (C1-C6)alkyl, hydroxy(C1-C6)alkyl,.(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy,
halo(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O), CN, (Rs)2N-(C1-C6)alkyl, (R5)2N-
(C=O)-or furyl;
R2 is H or halogen;
R3 is H;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is 1 or 2.
10. A compound according to claim 8, wherein
X is O;
Z is-[CH2]n-;
A is N;
B, D and E are C;
R1 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)
alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-, CN,
(R5)2N-(C1-C6)alkyl3 (R5)2N-(C=O) or furyl;
R2 is H or halogen;
R3 is H;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is 1 or 2.
11. A compound according to claim 8, wherein
X is O;
Z is-[CH2]n-;

A is N;
B, D and E are C;
R1 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)
alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-, CN,
(R5)2N-(C1-C6)alkyl, (R5)2N-(C=O)- or furyl;
R2 is H, halogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;
R3 is H, (C1-C6)alkyl or phenyl;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is 1.
12. A compound according to claim 8, wherein
X is O;
Z is-[CH2]n-;
A is N;
B, D and E are C; .
R1 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (d-C6)alkoxy(C1-
C6)alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=0)-, CN,
(R5)2N-(C1-C6)alkyl, (R5)2N-(C=O)- or furyl;
R2 is H, halogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;
R3 is H, (C1-C6)alkyl or phenyl;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is 2.
13. A compound according to claim 8, wherein
X is O;
Zis-[CH2]n-;
A, B, D and E are C;
R1 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-
C6)alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=0)-, CN,
(R5)2N-(C1-C6)alkyl, (R5)2N-(C=O)- or furyl;
R2 is H, halogen, ((C1-C6)alkyl or hydroxy(C1-C6)alkyl;

R3 is H, (C1-C6)alkyl or phenyl;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is 1.
14. A compound according to claim 8, wherein
X is O;
Z is-[CH2]n-;
A, B, D and E are C;
R1 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-
C6)alkyl, halo(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkyls (C1-C6)alkoxy-(C=O)-, CN,
(R5)2N-(C1-C6)alkyl5 (R5)2N-(C=0)-or furyl;
R2 is H, halogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;
R3 is H, (C1-C6)alkyl or phenyl;
R5 is, independently at each occurence, H or (C1-C6)alkyl;
m is 0; and
n is 2.
15. A compound according to claim 1, wherein the compound is methyl 2-(4-((2,3-
dihydrobenzo [b] [ 1,4] dioxin-2-yl)methyl)piperazin-1 -yl)benzoate, (2-(4-((2,3 -
dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazdn-l-yl)phenyl)methanol, l-((2,3-
dihydrobenzo[b] [1,4]dioxin-2-yl)methyl)-4-(2-(methoxymethyl)phenyl)piperazine, 2-(4-
((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)benzonitrile, (2-(4-((2,3-
dihydrobenzo[b] [ 1,4] dioxin-2-yl)methyl)piperazin-1 -yl)phenyl)methanamine, 1 -(2-(4-((2,3 -
dihydrobenzo[b][l,4]dioxin-2-yl)memyl)piperazin-l-yl)phenyl)-iV-methylmemanamine, 1-
((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(2-(ethoxymethyl)phenyl)piperazine, 2-(2-
(4-((2,3 -dihydrobenzo [b] [1,4]dioxin-2-yl)methyl)piperazin-1-yl)phenyl)propan-2-ol, 1-
((2,3-dihydrobenzo[b][l,4]dioxin-2-yI)memyl)-4-(3-(methoxymethyl)pyridin-2-
yl)piperazine, (S)-(2-(4-((7-fluoro-2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-piperazin-
1 -yl)pyridin-3-yl)methanol, (s)-(2-(4-((7-fluoro-2,3-dihydrobenzo[6] [ 1,4]dioxin-2-
yl)methyl)-piperazin-l-yl)pyridin-3-yl)methanol-HCl, (S)-l-((7-fluoro-2,3-
dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(3-(methoxymethyl)pyridin-2-yl)piperazine
HC1, (5)-l-((2,3-dihydrobenzo[6] [1,4]dioxin-2-yl)methyl)-4-(3-((2-

fluoroethoxy)methyl)pyridin-2-yl)piperazine, 1 -(2,3-dichlorophenyl)-4-((2,3 -
dihydrobenzo[6] [1,4]dioxin-2-yl)methyl)piperazine, (2-(4-((2,3-
dihydrobenzo[6] [1,4]dioxin-2-yl)methyl)pipera2in-l-yl)pyridin-3-yl)niethanol3 (5)-(2-(4-
((2,3-dihydrobenzo[&][l,4]dioxiri-2-yl)methyl)piperazin-l-yl)pyridin-3-yl)methanol, (5)-l-
((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(2-(methoxymethyl)phenyl)piperazine,
(i?)-l-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(2-
(methoxymethyl)phenyl)piperazine, (5)-(2-(4-((2,3-dihydrobenzo[b][l,4]dioxin-2-
yl)methyl)piperazin-l-yl)phenyl)methanol, (S)-l-((2,3-dihydrobenzo[&][l,4]dioxin-2-
yl)methyl)-4-(3-(methoxymethyl)pyridin-2-yl)piperazine, (l-((2,3-
ciihydrobenzo[b]] [1,4]oxathiin-2-yl)methyl)-4-(2-(metb.oxymethyl)phenyl)piperazine, 1 -
(chrQman-2-ylmethyl)-4-(2-(methoxymethyl)phenyl)piperaziiie, (2-(4-((2,3-
dihydrobenz6[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)-6-fluorophenyl)methanol, (2-(4-
((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-l -yl)-3-fluorophenyl)methanol, (2-
(4-((2,3 -dihydrobenzo[b] [ 1,4]dioxin-2-yl)methyl)piperazin-1 -yl)-5-fluorophenyl)methanol,
(S)-1 -((2,3-dihydrobenzo[b] [ 1,4]dioxin-2-yl)methyl)-4-(2-propylphenyl)piperazine, (S)-1 -
((2,3-dihydrobenzo[b][l34]dioxin-2-yl)methyl)-4-(2-(trifluoromethoxy)phenyl)piperazine5
(,S)-l-(biphenyl-3-yl)-4-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazine, (S)-l-
((2,3-dihydrobenzo[&][1,4]dioxin-2-yl)methyl)-4-(2-(furan-2-yl)phenyl)piperazine, (S)-ethyl
2-(4-((2,3-dihydrobenzo[&][l,4]dioxin-2-yl)methyl)piperazin-l-yl)benzoate, (5)-l-((2,3-
dihydrobenzo[i][l,4]dioxin-2-yl)methyl)-4-o-tolylpiperazine, (S)-l-((2,3-
dihydrobenzo[6] [1,4]dioxin-2-yl)methyl)-4-w-tolylpiperazine5 (5)-(3-(4-((2,3-
dihydrobenzo[6] [1,4]dioxin-2-yl)methyl)piperazin-l-yl)-4-methylphenyl)methanol, (5)-(3-
(4-((2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)piperazin-l-yl)phenyl)methanol, (S)-2-(2-
(4-((2,3-dihydrobenzo[b][l ,4]dioxin-2-yl)methyl)piperazin-l-yl)phenyl)ethanol, methyl 2-
(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl): 1,4-diazepan-1 -yl)benzoate, (2-(4-((2,3-
dihydrobenzo[i][l,4]dioxin-2-yl)methyl)-l,4-diazepan-l-yl)phenyl)methanol,2-(4-((2,3-
dihydrobenzo[b] [ 134]dioxin-2-yl)methyl)-1,4-diazepan-1 -yl)nicotinonitrile, 2-(4-((2,3-
dihydrobenzo[b][l54]dioxin-2-yl)methyl)-l54-diazepan-l-yl)nicotinamide, (2-(4-((2,3-
dihydrobenzo[£][l ,4]dioxin-2-yl)methyl)-l ,4-diazepan-l-yl)pyridin-3-yl)methanol or (5)-(2-
(4-((23-dihydrobenzo[b][l,4]dioxin-2-yl)methyl)-l54-diazepan-l-yl)pyridin-3-yl)methanol.
16. A carbon-isotope labeled compound of formula I according to claim 1.

17. A compound according to claim 16, wherein the compound is (S)-l-((2,3-
dihydrobenzo [b] [ 1,4]dioxin-2-yl)methyl)-4-(3 -([n C]-methoxymethyl)pyridin-2-
yl)piperazine.
18. A compound according to any one of claims 1 to 15 for use as a medicament.
19. A compound according to any one of claims 1 to 15 for use in the treatment of a disease
or a condition where an aIpha2C antagonist is indicated to be useful.
20. A compound according to claim 19, wherein the disease or the condition is a mental
disorder propagated by stress, Parkinson's disease, depression, schizophrenia, attention
deficit hyperactivity disorder, post-traumatic stress disorder, obsessive compulsive disorder,
Tourette's syndrome, blepharospasm or other focal dystonias, temporal lobe epilepsy with
psychosis, a drug-induced psychosis, Huntington's disease, a disorder caused by fluctuation
of the levels of sex hormones, panic disorder, Alzheimer's disease or mild cognitive
impairment.
21. A method for the treatment of a disease or a condition where an alpha2C antagonist is
indicated to be useful, which method comprises administering to a mammal in need of such
treatment an effective amount of at least one compound according to claim 1.
22. A method according to claim 21, wherein the disease or the condition is a mental
disorder propagated by stress, Parkinson's disease, depression, schizophrenia, attention
deficit hyperactivity disorder, post-traumatic stress disorder, obsessive compulsive disorder,
Tourette's syndrome, blepharospasm or other focal dystonias, temporal lobe epilepsy with
psychosis, a drug-induced psychosis, Huntington's disease, a disorder caused by fluctuation
of the levels of sex hormones, panic disorder, Alzheimer's disease or mild cognitive
impairment.
23. A pharmaceutical composition comprising at least one compound according to any one
of claims 1 to 15 and a pharmaceutically acceptable carrier, diluent and/or excipient.
24. A pharmaceutical composition according to claim 23 wherein the composition
comprises further at least one other active ingredient.
25. A labeled compound according to any one of claims 1 to 15 for use as an alpha2C-

receptor selective PET tracer compound in animal and human PET studies.
26. A 11C labeled compound according to any one of claims 1 to 15 for use as an alpha2C-
receptor selective PET tracer compound in animal and human PET studies.
27. A compound according to claim 26, wherein the compound is (S)-l-((2,3-
dmydrobenzo[b][l,4]dioxin-2-yl)methyl)-4-(3-[11C]-methoxymethyl)pyridin-2-
yl)piperazine.

Compounds of formula (I), wherein X, Z, A, B, D, E,R1-R4 and m are as defined in the claims, exhibit alpha2C an-
tagonistic activity and are thus useful as alpha2C antagonists.