NOVEL (HETEROCYCLE/TETRAHYDROPYRIDINE)-(PIPERAZINYL)-1-
ALCANONE AND (HETEROCYCLE/DIHYDROPYRROLIDINE)-(PIPERAZINYL)-
1-ALCANONE DERIVATIVES, AND USE THEREOF AS p75 INHIBITORS
The present invention relates to (heterocycle-tetrahydropyridine)(piperazinyl)-1-
alkanone and (heterocycle-dihydropyrrolidine)(piperazinyl)-1-alkanone derivatives,
to their preparation and to their therapeutic use.
The compounds according to the present invention have affinity for the p75NTR
receptor of neurotrophins.
Neurotrophins belong to a family of proteins especially having cell survival and
differentiation as a biological effect.
The p75NTR receptor, a receptor of all neurotrophins, is a transmembrane
glycoprotein of the tumor necrosis factor (TNF) receptor family (W. J. Friedman
and L A. Greene, Exp. Cell. Res., 1999, 253, 131-142). The p75NTR receptor is
expressed in several cell types, and several biological functions are attributed
thereto: firstly, modulation of the affinity of neurotrophins for the tyrosine kinase
(trk) receptors; secondly, in the absence of trk, induction of a cell death signal by
apoptosis. Moreover, the neurotrophin precursors, proneurotrophins, are capable
of binding to p75NTR with high affinity, and are considered as powerful p75NTR-
dependent apoptosis inducers in neurons and certain cell lines.
In the central nervous system, numerous studies show that apoptosis occurs in
several pathologies, such as amyotrophic lateral sclerosis, multiple sclerosis,
Alzheimer's disease, Parkinson's disease, Huntington's disease and prion
diseases. p75NTR is also known to be overexpressed in various types of
neurodegenerative disease, for example Alzheimer's disease and amyotrophic
lateral sclerosis (ALS) (Longo F. M. et al., Curr. Alzheimer Res. 2007; 4: 503-506;
Lowry K.S. et al., Amyotroph. Lateral. Scler. Other. Motor. Neuron. Disord. 2001;
2:127-34).
Results suggest that p75NTR may play a predominant role in mechanisms leading
to neuronal death via post-ischemic apoptosis (P. P. Roux et al., J. Neurosci.,
1999, 19,6887-6896).
Results (V. Della-Bianca et al., J. Biol. Chem., 2001, 276: 38929-33) (S.
Rabizadeh et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 10703-10706) support the
hypothesis according to which p75NTR plays an important role in neuronal death
induced by the infectious prion protein (transmissible spongiform encephalopathy)
or by the ß-amyloid protein (Alzheimer's disease).
The p75NTR receptor is also associated with the Nogo receptor and involved in the
signaling of the inhibitory effects of these myelin proteins with respect to axonal
growth. As a result, the p75NTR receptor plays a major role in regulating neuronal
plasticity and in neuron-glia interactions and thus represents a therapeutic target
of choice for promoting nerve regeneration.
Beyond the nervous system and neurodegenerative diseases, it has been
suggested that p75NTR may play a role in cardiovascular diseases such as
atherosclerosis and myocardial ischemia (M. L. Bochaton-Pialat et al., Am. J.
Pathol., 1995,146, 1-6; H. Perlman, Circulation, 1997,95, 981-987). Recent
studies show an increase in the expression of p75NTR and of neurotrophins, and
massive apoptosis in atherosclerosis lesions.
Several studies also suggest that p75NTR is an inflammation mediator (Rihl M. et
al., Ann. Rheum. Dis. 2005; 64(11): 1542-9; Raychaudhuri S. P. et al., Prog. Brain.
Res. 2004;146: 433-7, Tokuoka S. et al., Br. J. Pharmacol. 2001, 134: 1580-
1586).
p75NTR is also described as playing an important role in inflammatory pain.
Specifically, lesion of the nerve is thought to selectively increase the expression
and axonal transport of p75NTR, involved in the induction of neuropathic pain.
Furthermore, the use of p75NTR-specific antibodies or of antisense
oligodeoxynucleotide capable of blocking the activity of the receptor in vivo is
thought to be capable of reversing neuropathic pain (heat- and cold-induced
hyperalgesia and mechanical allodynia) induced in rats after lesion of the L5
spinal nerve (Obata K. et al., J. Neurosci. 2006; 26: 11974-11986). An anti-p75NTR
neutralizing antibody considerably reduces the inflammatory pain induced by the
injection of adjuvant into the arch of the paw in mice, and also in a model of sciatic
nerve crush in mice (Watanabe T. et al., J. Neurosci. Res. 2008; 86: 3566-357;
Fukui Y. et al., J Orthop Res. 2010; 28(3): 279-83).
The expression of p75 is also described in chronic pancreatitis, with an
involvement in apoptosis of the exocrine and endocrine pancreas (Zhu Z. et al.,
Dig. Dis. Sci. 2003; 48 (4): 717-25).
Other reports have also described the importance of p75NTR in the development of
hepatic fibrosis (Kendall T. J. et al., Hepatology. 2009; 49 (3): 901-10).
p75NTR also plays a critical role in tumor biology.
Many compounds are known for interacting with the trkA/NGF/p75NTR system or
for having activity of NGF (nerve growth factor) type. Thus, patent application
WO 00/59893 describes substituted pyrimidine derivatives with activity of NGF
type and/or which increase the NGF activity on PC12 cells.
One subject of the present invention is compounds corresponding to formula (I):

in which;
- n represents 1 or 2;
- m represents 0 or 1;
- A represents a fused heterocyclic group of formula (Y)

and B represents a hydrogen atom;
or
A represents a hydrogen atom; and
B represents a fused heterocyclic group of formula (Y)

The fused heterocycle of formula Y may be attached to the rest of the molecule
via any of the available carbon atoms, and in which:
- U completes:
- either an aromatic or saturated 6-atom nucleus, containing one or two
nitrogen atoms, the nucleus possibly being substituted with one or two halogen
atoms, one or two (C1-C4)alkyl or (C1-C4)alkoxy groups, or one or two
perfluoroalkyl radicals;
- or an aromatic or saturated 5-atom nucleus, containing a nitrogen,
oxygen or sulfur atom, the nucleus possibly being substituted with one or two
groups (C1-C4)alkyl;
- X and X1 represent CH or N;
- R and R1 located on any of the available positions, independently represent a
hydrogen atom, a halogen atom, a group (C1-C4)alkyl, (C1-C4)alkoxy, a
perfluoroalkyl or trifluoromethoxy radical, a cyano or a group COOH, COOalkyl,
CONR3R4 or NHCOR3;
- -W- is a nitrogenous heterocycle chosen from:

-1-2 represents 1 or 2;
-1-3 represents 1, 2 or 3;
- R2 represents a group of formula:

- in which R5 and R6, located on any of the available positions, independently
represent a hydrogen atom, a halogen atom, a group (C1-C4)alkyl or (C1-
C4)alkoxy, a trifluoromethyl or trifluoromethoxy radical, a cyano or a group
COOH, COOalkyl, COOcycloalkyl, SOalkyl, SO2alkyl, CONR3R4, NR3R4 or
NHCOR3;
or one of the groups R5 and R6 may also represent a heterocycle chosen from:

- Z represents an oxygen or sulfur atom;
- R3 and R4 represent a hydrogen or a group C1-C6 alkyl.
The compounds of formula (I) may comprise one or more asymmetric carbon
atoms. They may thus exist in the form of enantiomers or diastereoisomers.
These enantiomers and diastereoisomers, and also mixtures thereof, including
racemic mixtures, form part of the invention.
The compounds of formula (I) may exist in the form of bases or of acid-addition
salts. Such addition salts form part of the invention.
These salts may be prepared with pharmaceutically acceptable acids, but the
salts of other acids that are useful, for example, for purifying or isolating the
compounds of formula (I) also form part of the invention.
In the context of the present invention, the following definitions apply:
- a halogen atom: a fluorine, a chlorine, a bromine or an iodine;
- an alkyl group: a saturated, linear, branched or cyclic aliphatic group. Examples
that may be mentioned include a group (C1-C4)alkyl which may represent a
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl or cyclobutyl;
- a fluoroalkyl group: an alkyl group in which one or more hydrogen atoms have
been replaced with a fluorine atom;
- a perfluoroalkyl group: an alkyl group in which all the hydrogen atoms have been
replaced with a fluorine atom, for example trifluoroalkyl;
- an alkoxy group: a radical -O-alkyl in which the alkyl group is as defined
previously;
- a perfluoroalkoxy group: an alkoxy group in which all the hydrogen atoms have
been replaced with a fluorine atom, for example trifluoroalkoxy;
- a cycloalkyl group: a cyclic alkyl group. Examples that may be mentioned include
cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., groups.
Among the compounds of formula (I) that are subjects of the invention, another
group of compounds is formed by the compounds of formula (I) in which:
- n represents 1 or 2; and/or
- m represents 0 or 1; and/or
- A represents a fused heterocyclic group of formula (Y)

and B represents a hydrogen atom;
or
A represents a hydrogen atom;
and B represents a fused heterocyclic group of formula (Y)

the fused heterocycle of formula Y possibly being attached to the rest of the
molecule via any of the available carbon atoms of the benzene nucleus;
- U completes:
- either an aromatic or saturated 6-atom nucleus, containing one or two
nitrogen atoms, the nucleus possibly being substituted with one or two halogen
atoms, one or two (C1-C4)alkyl or (C1-C4)alkoxy groups, or one or two
perfluoroalkyl radicals;
- or an aromatic or saturated 5-atom nucleus, containing a nitrogen,
oxygen or sulfur atom, the nucleus possibly being substituted with one or two
groups (C1-C4)alkyl; and/or
- X and X1 represent CH or N; and/or
- R and R1, located on any of the available positions, independently represent a
hydrogen atom, a halogen atom or a group (C1-C4)alkyl or COOalkyl; and/or
- -W- is a nitrogenous heterocycle chosen from:

or alternatively

- R2 represents a group of formula:

- R5 and R6, located on any of the available positions, independently represent a
halogen atom, a trifluoromethyl radical or a group COOH, COOalkyl or
COOcycloalkyl; or
one of the groups R5 and R6 may also represent a heterocycle chosen from:

- Z represents an oxygen or sulfur atom; and/or
- R3 and R4 represent a hydrogen or a methyl group.
Among the compounds of formula (I) that are subjects of the invention, mention
may be made especially of the following compounds:
- Compound 1: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(3,5-
dimethyl-2,3,5,6-tetrahydro[1,2']bipyrazinyl-4-yl)ethanone;
- Compound 2: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(8-
pyrimidin-2-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
- Compound 3: 1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(8-
pyrimidin-2-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
- Compound 4: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 5: 1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
((2S,5R)-2,5-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-yl)ethanone;
- Compound 6: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
((2S,5R)-2,5-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-yl)ethanone;
- Compound 7: 1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-
[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 8: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-[8-(5-
trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 9: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 10: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-[4-(2-methy!benzo[b]thiophen-7-yl)-3,6-dihydro-2H-pyridin-
1-yl]ethanone;
- Compound 11: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-[4-(2-propylbenzo[b]thiophen-7-yl)-3,6-dihydro-2H-pyridin-1-
yl]ethanone;
- Compound 12: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[5-(5-
trifluoromethylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-y[]ethanone;
- Compound 13: 1 -(4-benzo[b]thiophen-6-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-
[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 14: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2R,5S)-
2,5-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 15: 1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-
yl]-2-(8-pyrimidin-2-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
- Compound 16: 1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-
yl]-2-t4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 17: 4-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-
1-yI]-2-oxoethyl}-1-(5-trifiuoromethylpyridin-2-yl)piperazin-2-one;
- Compound 18: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-
1-yl]ethanone;
- Compound 19: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
((2S,6R)-2,6-dimethyl-4-quinolin-2-ylpiperazin-1-yl)ethanone;
- Compound 20: 1-(4-quinolin-8-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-
trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 21: 1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-
1-yl]-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 22: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[4-
(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 23: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-
fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 24: 1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-
1 -yl]-2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 25: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-
(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone;
- Compound 26: 1 -(4-benzofuran-3-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-[8-(5-
fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 27: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[4-
(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 28: 1-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[8-(5-
fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 29: 1 -(4-benzo[b]thiophen-3-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-
fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 30: 4-{2-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1 -yl]-2-oxoethyl}-
1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound 31: 4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-
oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound 32: 4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl]-
1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound 33: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-
trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 34: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-
2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 35: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,6R)-
2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)ethanone;
- Compound 36: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-
(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;
- Compound 37: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-
2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;
- Compound 38: 2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1 -yl]-
1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 39: 2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-
yl)piperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-
1-yl]ethanone;
- Compound 40: 2-((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)-1-[4-(2-
methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 41: 1 -(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)ethanone;
- Compound 42: 1-{4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)ethanone;
- Compound 43: 4-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-1 -(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound 44: 1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-
1-yl]-2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;
- Compound 45: 1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-
1-yl]-2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-
yl]ethanone;
- Compound 46: 1 -(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-[4-(5-
trifluoromethylpyridin-2-yl)piperazin-1-yl)ethanone;
- Compound 47: 1 -(4-ben2o[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl)ethanone;
- Compound 48: 5-{(3S,5R)-4-[2-(4-benzo[b]thiophen-4-yl-3,6-dihydro-2H-
pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}pyridine-2-carboxylic acid;
- Compound 49: 4-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-
pyridin-1-yl]-2-oxoethyl}-1-(6-trifluoromethylpyridin-3-yI)piperazin-2-one;
- Compound 50: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(6-
trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;
- Compound 51: Methyl 5-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-
pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}pyridine-2-carboxylate;
- Compound 52: Methyl 6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-
2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinate;
- Compound 53: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)ethanone;
- Compound 54: 1 -{4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-
[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl)ethanone;
- Compound 55: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-
((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)ethanone;
- Compound 56: 6-{(3S,5R)-4-[2-(4-benzo[b3thiophen-5-yl-3,6-dihydro-2H-
pyridin-1 -yl)-2-oxoethyl]-3,5-dimethylpiperazin-1 -yl}nicotinic acid;
- Compound 57: 6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-
2-oxoethyl]-3,5-dimethylpiperazin-1 -yl}nicotinic acid;
- Compound 58: Methyl 6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-7-yI-3,6-dihydro-
2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethyipiperazin-1-yl}nicotinate;
- Compound 59: 6-((3S,5R)-4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-
pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinic acid;
- Compound 60: 4-[2-(4-benzofuran-5-yl-3,6-dihydro-2H-pyridin-1-yi)-2-oxoethyl]-
1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound 61: Methyl 6-((3S,5R)-3,5-dimethyl-4-{2-[4-(2-
methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-
1-yl)nicotinate;
- Compound 62: 6-((3S,5R)-3,5-dimethyl-4-{2-[4-(2-methylbenzo[b]thiophen-5-
yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-1-yl)nicotinic acid;
- Compound 63: 1-(5-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-
2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 64: Ethyl 6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-
1 -yl)-2-oxoethyl]-3,5-dimethylpiperazin-1 -yl}nicotinate;
- Compound 65: Methyl 6-{3-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-
2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;
- Compound 66: Methyl 7-(1-{2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-
2-yl)piperazin-1-yl]acetyl}-1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene-2-
carboxylate;
- Compound 67: Methyl 5-(1-{2-[((2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-
2-yl)piperazin-1-yl]acetyl}-1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene-2-
carboxylate;
- Compound 68: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1 -yl]-1 -[4-(2-propylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-
yl]ethanone;
- Compound 69: Methyl 6-{3-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-
1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;
- Compound 70: Methyl 6-{3-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-
1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;
- Compound 71: 6-{3-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound 72: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-[4-(7-fluorobenzofuran-5-yl)-3,6-dihydro-2H-pyridin-1-
yl]ethanone;
- Compound 73: 1 -[4-(2,3-dimethylbenzofuran-6-yl)-3,6-dihydro-2H-pyridin-1 -yl]-
2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 74: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone;
- Compound 75: 1-(4-benzofuran-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(2,3,5,6-
tetrahydro-[1,2']bipyrazinyl-4-yl)ethanone;
- Compound 76: Methyl 6-{3-[2-oxo-2-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-
pyridin-1-yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;
- Compound 77: Methyl 6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-
2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinate;
- Compound 78: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(4-pyridin-3-
yl-[1,4]diazepan-1 -yl)ethanone;
- Compound 79: 6-{3-r2-oxo-2-(4-thieno[3,2-c]pyridin-4 -yl-3,6-dihydro-2H-pyridin-
1-yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound 80: 6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-
pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinic acid;
- Compound 81: Methyl 6-{3-[2-(3-benzofuran-7-yl-2,5-dihydropyrrol-1-yl)-2-
oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;
- Compound 82: Methyl 6-{3-[2-(3-benzo[b]thiophen-7-yl-2,5-dihydropyrrol-1 -yl)-
2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;
- Compound 83: 4-[2-(3-benzofuran-7-yl-2,5-dihydropyrrol-1 -yl)-2-oxoethyl]-1 -(5-
trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound 84: 6-{3-[2-(4-benzofuran-7-yl-2,3-dihydropyrrol-1 -yl)-2-oxoethyl]-
3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound 85: 6-{3-[2-(5-benzo[b]thiophen-7-yl-3,4-dihydro-2H-pyridin-1 -yl)-2-
oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound 86: 6-{3-[2-(4-benzo[b]thiophen-7-yl-2,3-dihydropyrrol-1 -yl)-2-
oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound 87: Methyl 6-(3-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-
2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicycloE3.2.1]oct-8-yl)nicotinate;
- Compound 88: 2-{(3S,5R)-4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-
pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}pyrimidine-5-carboxylic
acid;
- Compound 89: 3-(6-[3-t2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-
oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}pyridin-3-yl)-4H-[1,2,4]oxadiazol-5-
one;
- Compound 90: 3-(6-{3-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-
2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}pyridin-3-yl)-4H-[1,2,4]oxadiazol-5-
one;
- Compound 91: 6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-
pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinonitrile;
- Compound 92: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-
(3-chloro-5-trifluoromethylpyridin-2-yl)-3,6-dimethylpiperazin-1-yl]ethanone;
- Compound 93: 1 -(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-(8-pyridin-3-
yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
- Compound 94: 6-[3-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinonitrile;
- Compound 95: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[5-(5-
trifluoromethylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone;
- Compound 96: cyclobutyl 6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-
dihydro-2H-pyridin-1-yl]-2-oxoethyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinate;
- Compound 97: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yi)piperazin-1-yl]-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 98: 1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-(4-quinolin-2-
ylpiperazin-1-yl)ethanone;
- Compound 99: 1 -(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-[4-(7-
chloroquinolin-4-yl)piperazin-1-yl]ethanone;
- Compound 100: 2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-
yl]-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 101: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
[(2S,6R)-4-(5-chioropyridin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;
- Compound 102: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
((2R,5S)-2,5-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-yl]ethanone;
- Compound 103: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-[8-
(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 104: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-
(6-trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 105: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(4-
quinolin-2-ylpiperazin-1-yl)ethanone;
- Compound 106: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-
(7-chloroquinolin-4-yl)piperazin-1-yl]ethanone;
- Compound 107: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-[4-
(5-chloropyridin-2-yl)piperazin-1-yI]ethanone;
- Compound 108: 2-[4-(6-chloropyridin-2-yl)piperazin-1-yI]-1-[4-(1H-indol-3-yl)-
3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 109: 1-[4-(1 H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[4-(5-
trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 110: 2-((2S,6R)-2,6-dimethyl-4-quinolin-2-yl-piperazin-1-yl)-1-[4-
(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yI]ethanone;
- Compound 111: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(4-
pyridin-3-yl-[1,4]diazepan-1-yl)ethanone;
- Compound 112: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-
(5,6-dichloropyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 113: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-
(6-bromopyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 114: 1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-
yl]-2-(4-quinolin-2-ylpiperazin-1-yl)ethanone;
- Compound 115: 1-{4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[5-
(6-trifluoromethylpyridazin-3-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone;
- Compound 116: 1 -[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1 -
yl]-2-[4-(6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound______117: 2-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]-1-[4-{2-
methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 118: 4-[2-oxo-2-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-pyridin-
1-yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound 119: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-
2,6-dimethyl-4-(5-thiazol-2-ylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 120: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-{(2S,6R)-
2,6-dimethyl-4-[5-(2-methyI-2H-tetrazol-5-yl)pyridin-2-yl]piperazin-1-
yl}ethanone;
Compound 121: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone;
- Compound 122: 4-[2-oxo-2-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethyl]-1-
(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound 123: 1-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-
trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 124: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-{8-[5-(1-
methyl-1H-tetrazol-5-yl)pyridin-2-yl]-3,8-diazabicyclo[3.2.1]oct-3-yl}ethanone;
- Compound 125: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-
(5-methanesulfonylpyridin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;
in the form of a base or of an acid-addition salt.
In the text hereinbelow, the term "protecting group Pg" mean a group that makes it
possible, firstly, to protect a reactive function such as a hydroxyl or an amine
during a synthesis, and, secondly, to regenerate the intact reactive function at the
end of the synthesis. Examples of protecting groups and of protection and
deprotection methods are given in Protective Groups in Organic Synthesis, Green
et al., 2nd Edition (John Wiley & Sons, Inc., New York).
In accordance with the invention, the compounds of general formula (I) may be
prepared according to the process that follows.
Scheme 1
More specifically, the process for preparing the compounds of general formula (I)
in which A, B, m, n, W and R2 are as defined previously comprises the reaction of
a compound of formula (II):

in which A, B, m and n are defined as in the general formula (I) and Hal
represents a halogen atom, for example chlorine,
and of a compound of general formula (III):

in which W and R2 are defined as in the general formula (I), according to methods
known to those skilled in the art, for example in the presence of a base, in a
solvent as described in WO 03/104225. Thus, bases that may be mentioned
include organic bases such as triethylamine, N,N-diisopropylamine,
diisopropylethylamine (DPEA) or N-methylmorpholine or alkali metal carbonates
or bicarbonates such as potassium carbonate, sodium carbonate or sodium
bicarbonate and in the absence or presence of an alkali metal iodide such as
potassium iodide or sodium iodide. The reaction is performed in a solvent such as
acetonitrile, N,N-dimethylformamide (DMF), N-methylpyrrolidinone, toluene or 2-
propanol, and at a temperature between room temperature and the reflux
temperature of the solvent. The term "room temperature" means a temperature of
between 5 and 25°C. By way of example, the reaction may be performed in the
presence of sodium bicarbonate, sodium iodide in a solvent such as DMF. These
reactions may also be performed in a microwave reactor.
In the products of general formula (I) thus obtained, R, R1, R3, R4, R5 and R7
may be modified via treatments commonly used by those skilled in the art, for
instance hydrolysis of an ester group to give a carboxylic group or of a cyano to
obtain a tetrazole group.
Generally, the acid-addition salts of the compounds of general formula (I) may be
obtained by adding the appropriate acid, such as hydrochloric acid, hydrobromic
acid or oxalic acid.
The compounds of formula (111), optionally in the form of salts, may be prepared
from the corresponding compounds of formula (VIII):

in which W and R2 are as defined in formula (I) and Pg represents a protecting
group for a nitrogen atom of W. Preferably, Pg is a benzyl group and the
deprotection is performed according to standard methods that are well known to
those skilled in the art, for example via catalytic hydrogenation over Pd/C or by
treatment with chloroformates followed by hydrolysis in acidic medium.
The compounds of formula (VIII) may be prepared from the compounds of formula
(VI):

and (VII):

in which Pg, W and R2 are defined as previously and Hal represents a halogen
atom, preferably chlorine. This reaction is generally performed under the same
conditions as the reaction for the preparation of the compounds of formula (I) from
the compounds of formulae (II) and (III).
Alternatively, the compounds of formula (VIII) may be prepared via the Buchwald
coupling method in the presence of a suitably selected palladium catalyst and a
suitably selected phosphine, using as solvent inert solvents such as toluene or
xylene, at a temperature between room temperature and 110°C.
In the compounds of general formula (VIII) thus obtained, R7 and R8 may be
modified via treatments commonly used by those skilled in the art, for instance the
synthesis of an oxadiazole group starting with a cyano group or via the formation
of a boronic intermediate and via Suzuki coupling as described in the scheme
below.
Scheme 2

In Scheme 2 above, L represents a leaving group such as iodo, bromo or
trifluoromethanesulfonate, R7 represents heterocycles as described in the general
formula (I), R8 is as defined in the general formula (I) and B is a boron atom.
Examples of such reactions are described in the experimental section.
The compounds of formula (III), optionally in the form of salts, when W represents
an oxopiperazine, are commercially available or described in the literature, or may
be prepared from the corresponding compounds of formula (VIII) according to
methods that are described or known to those skilled in the art.
Examples of such preparations are described in the experimental section.
The compounds of formula (II) may be obtained by reacting a corresponding
compound of formula (IV):

in which A, B and m are defined as in the general formula (I), optionally in the form
of an acid-addition salt, with a compound of formula (V):

in which Hal and n are as defined in formula (II) and Hal' represents a halogen
atom, which may be identical to or different than Hal. Preferably, Hal' represents a
chlorine atom.
This reaction is generally performed in the presence of a base such as
triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in a solvent such
as dichloromethane, chloroform, tetrahydrofuran, dioxane or a mixture of these
solvents, and at a temperature of between 0°C and room temperature. The
compounds of formula (V) are generally commercially available.
Optionally, the process according to the invention comprises the subsequent step
that consists in isolating the desired product obtained.
The products of formulae (IV), (V), (VI) and (VII) and the reactants, when their
preparation method is not described, are commercially available or described in
the literature, or else may be prepared according to methods that are described or
known to those skilled in the art.
Alternatively, the compounds of formula (I) may be prepared according to the
following process:
Scheme 3

More specifically, the process for preparing the compounds of general formula (I)
in which A, B, R2, m and n are as defined previously comprises the reaction of a
compound of formula (XIV):

in which R2, W and n are defined as in the general formula (I)
and of a compound of general formula (IV)

in which A, B and m are defined as in the general formula (I), according to
methods known to those skilled in the art, for example in a solvent such as
dichloromethane, DMF or THF, in the presence of a base such as pyridine,
triethylamine, N,N-diisopropylamine or diisopropylethylamine (DPEA) and of a
coupling agent such as BOP, DBU or DCC. The reaction is performed at a
temperature between room temperature and the reflux temperature of the solvent.
The term "room temperature" means a temperature between 5 and 25°C. By way
of example, the reaction may be performed in the presence of sodium
bicarbonate, sodium iodide in a solvent such as DMF. These reactions may also
be performed in a microwave reactor.
In the compounds of general formula (I) thus obtained, R, R1, R3, R4, R5, R6, R7
and R8 may be modified with treatments commonly used by those skilled in the
art, for instance by hydrolysis of an ester group to give a carboxylic group or of a
cyano to obtain a tetrazole group.
Generally, the acid-addition salts of the compounds of general formula (I) may be
obtained by adding the appropriate acid, such as hydrochloric acid, hydrobromic
acid or oxalic acid.
The compounds of formula (XIV) may be obtained from compounds of formula
(XIII)

in which R2, W and n are defined as in the general formula (I) and Q represents a
residue that is capable of forming an ester, such as methyl, ethyl or benzyl, by
hydrolysis of the ester bond, according to methods that are well known to those
skilled in the art, for example via a treatment in an acidic or basic aqueous
medium, or alternatively via reduction in a polar solvent such as an alcohol or
THF, under a stream of hydrogen.
The compounds of formula (XIII) may be obtained from compounds of formula (III)

in which R2 and W are defined as in the general formula (I), optionally in the form
of an acid-addition salt, and from a compound of formula (XII):

in which Q represents a residue that is capable of forming an ester, such as
methyl, ethyl or benzyl, Hal represents a halogen atom, preferably a chlorine
atom, and n is as defined in the general formula (I).
This reaction is generally performed in the presence of a base, such as
triethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in a solvent such
as dichloromethane, chloroform, tetrahydrofuran, dioxane or a mixture of these
solvents, and at a temperature between 0°C and room temperature. The
compounds of formula (XII) are generally commercially available.
The compounds of formula (III), optionally in the form of salts, may be prepared
from the corresponding compounds of formula (VIII):

in which W and R2 are as defined in formula (I) and Pg represents a protecting
group for a nitrogen atom of W. Preferably, Pg is a benzyl group and the
deprotection is performed according to standard methods that are known to those
skilled in the art, for example via catalytic hydrogenation over Pd/C or by
treatment with chloroformates followed by hydrolysis in acidic medium.
The compounds of formula (VIII) may be prepared from the compounds of
formula (VI):

and (VII):

in which Pg, W and R2 are defined as previously and Hal represents a halogen
atom, preferably chlorine. This reaction is generally performed under the same
conditions as the reaction for preparing the compounds of formula (I) from the
compounds of formulae (II) and (III).
Alternatively, the compounds of formula (VIII) may be prepared via the
Buchwald coupling method in the presence of a suitably selected palladium
catalyst and a suitably selected phosphine, using as solvent inert solvents such as
toluene or xylene, at a temperature of between room temperature and 110°C.
In the compounds of general formula (VIII) thus obtained, R7 and R8 may be
modified via treatments generally used by those skilled in the art, for instance the
synthesis of an oxadiazole group starting with a cyano group, or alternatively via
Suzuki couplings as already described in Scheme 2 presented hereinabove.
The compounds of formula (III), optionally in the form of salts, where W
represents an oxopiperazine, are commercially available or described in the
literature, or else may be prepared, from the corresponding compounds of formula
(VII), according to methods that are described or known to those skilled in the art.
Examples of such preparations are described in the experimental section.
Optionally, the process according to the invention comprises the subsequent
step that consists in isolating the desired product obtained.
The products of formulae (IV), (VI), (VII) and (XII) and the reactants, when
their preparation method is not described, are commercially available or described
in the literature, or else may be prepared according to methods that are described
or known to those skilled in the art.
Examples of such preparations are described in the experimental section.
According to another of its aspects, a subject of the invention is also
compounds of formula (!l)
in which A, B, n and m are defined as in the general formula (I) and Hal
represents a halogen atom, preferably chlorine; optionally in the form of an acid-
addition salt. These compounds are useful as intermediates in the synthesis of the
compounds of formula (I).
The examples that follow describe the preparation of certain compounds in
accordance with the invention. These examples are not limiting, and serve merely
to illustrate the present invention. The numbers of the compounds presented as
examples refer to those given in the table hereinbelow, which illustrates the
chemical structures and physical properties of a number of compounds according
to the invention.
The physicochemical measurements were performed in the following manner:
The melting points were measured using a Buchi B540 machine.
The proton nuclear magnetic resonance (1H NMR) spectra were recorded under
the following conditions:
a) at 500 MHz on a Bruker machine equipped with an Avance III console;
b) at 400 MHz on a Bruker machine equipped with an Avance I console.
The chemical shifts are reported in ppm relative to the TMS frequency.
The spectra were recorded under the following temperature conditions:
Temp. A: 40°C
Temp. B: 30°C
The abbreviations used to characterize the signals are the following: s = singlet,
bs = broad singlet, m = multiplet, bm = broad multiplet, d = doublet, bd = broad
doublet, t = triplet, q = quadruplet.
* = not integratable because of the interference with a broad peak due to water.
** = not integratable because of the interference with a peak due to the NMR
solvent.
2Xs = two partially superposed singlets.
2Xbs = two partially superposed broad singlets.
2Xm = two partially superposed multiplets.
The compounds are analyzed by HPLC-UV-MS (liquid chromatography -UV
detection and mass detection) coupling.
The machine used is composed of a Thermo Surveyor chromatographic line
equipped with a Thermo diode array detector and a Thermo Deca XPMax ion-trap
mass spectrometer.
The analytical conditions are as follows:
HPLC conditions
Various HPLC conditions were used according to the compounds:
Method A
Eluent A: H2O + TFA 0.005% + CH3CN 5%
Eluent B: CH3CN
Gradient:

Column temperature: 30°C
Flow rate: 0.3ml/min
Detection: ? = 220 nm
Method B
Eluent A: H2O + TFA 0.005%
Eluent B: CH3CN
Gradient:

Column temperature: not controlled
Flow rate: 0.3 ml/min
Detection: ? = 220 nm
Method C
Eluent A: AcONH4 5 mM at pH 6.5
Eluent B: CH3CN
Gradient:

Column temperature: not controlled
Flow rate: 0.3 ml/min
Detection: ? = 220 nm
Method D
Eluent A: AcONH4 5 mM at pH 6.5
Eluent B: CH3CN
Gradient:

Column temperature: not controlled
Flow rate: 0.3 ml/min
Detection: ? = 220 nm
Method E
Eluent A:H2O + TFA 0.01%
Eluent B: CH3CN
Gradient:

Column temperature: 40°C
Flow rate: 0.5 ml/min
Detection: ? = 220 nm
Method F
Eluent A: H2O + TFA 0.005%
Eluent B: CH3CN
Gradient:

Column temperature: not controlled
Flow rate: 0.3 ml/min
Detection: ? = 220 nm
Method G
Eluent A: AcONH4 5 mM at pH 6.5
Eluent B: CH3CN
Gradient:

Column temperature: not controlled
Flow rate: 0.3 ml/min
Detection: ? = 220 nm
Method H
Eluent A: H2O + TFA 0.05%
Eluent B: CH3CN + TFA 0.035%
Gradient:

Column temperature: 40°C
Flow rate: 0.3 ml/min
Detection: ? = 220 nm
Method I
Eluent A:H2O + TFA 0.01%
Eluent B: CH3CN
Gradient:

Column temperature: 40°C
Flow rate: 0.5 ml/min
Detection: ? = 220 nm
The columns used are C18 columns with a particle size of between 2 and 5 µm,
preferably 3.5 µm.
Mass spectrometry conditions
The mass spectra are recorded in positive or negative electrospray (ESI) mode, in
order to observe the ions derived from the protonation of the analyzed compounds
(MH+ or MH-), or the formation of adducts with other cations such as Na+, K+, etc.
Thin-layer chromatography was performed on Merck Silica Gel 60 silica gel
TLC plates. The silica gel for the flash column chromatography is sold by Biotage
or Supelco.
All the solvents used are of "reagent grade" or "HPLC grade" purity.
Preparation 1
(3R,5S)-3,5-dimethyl-1-(5-trifluoromethylpyridin-2-yl)piperazine
0.8 g of 2-chloro-5-(trifluoromethyl)pyridine (compound of formula (VII)),
0.5 g of cis-2,6-dimethylpiperazine (compound of formula (VI)), 0.67 g of
potassium carbonate and 0.3 g of Nal are placed in 8 ml of DMF. The reaction is
performed in a CEMdiscover microwave initiator for 30 minutes at 160°C. The
mixture is then poured into saturated aqueous sodium chloride solution and
extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered and
evaporated under vacuum. 1.1 g of an oily material corresponding to the title
product are isolated.
Preparation 2
(3R,5S)-2,5-dimethyl-1-{5-trifIuoromethylpyridin-2-yl)piperazine
By performing the process as described in Preparation 1, but using 2,5-
trans-dimethylpiperazine instead of cis-2,6-dimethylpiperazine, the title compound
is obtained in the form of an oily material.
Preparation 3
2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane
hydrochloride
1.44 g of 2-chloro-5-fluoropyrimidine (compound of formula (VII)), 2.2 g of
1-benzyl-3,8-diazabicyclo[3.2.1]octane (compound of formula (VI)), 1.7 g of
potassium carbonate and 0.73 g of Nal are placed in 27 ml of N-
methylpyrrolidone. The mixture is heated at 110°C for 5 hours. It is then poured
into saturated aqueous sodium chloride solution and extracted with ethyl acetate.
The organic phase is dried over Na2SO4, filtered and evaporated under vacuum.
3.2 g of an oily material are isolated, and this material is purified by flash
chromatography on a Biotage® column, using 95/5 cyclohexane/ethyl acetate as
eiuent. 1.4 g of a white solid are isolated, and are dissolved in 35 ml of 1,2-
dichloroethane. 0.72 ml of 1-chloroethyl chloroformate is added at 0°C and the
mixture is stirred under a stream of nitrogen for 10 minutes at 0°C and then for
3 hours at 85°C. The solvent is evaporated off and 35 ml of methanol are added.
The mixture is heated for 30 minutes at the reflux temperature. The solvent is
evaporated off and the residue is treated with isopropanol. A white solid is
obtained, which is filtered off, and 900 mg of title product are isolated, m.p. = 236-
239°C
Preparation 4
(3R,5S)-3,5-dimethyl-1-(6-trifluoromethylpyridin-2-yl)piperazine
2.2 g of 2-trifluoromethy!-5-bromopyridine (compound of formula (VII)), 1.1 g
of cis-2,6-dimethylpiperazine (compound of formula (VI)), 0.22 g of palladium
acetate, 0.28 g of sodium t-butoxide and 1.3 g of tri-t-butylphosphine are placed in
16 ml of o-xylene. The mixture is heated at 120°C for 6 hours. The resulting
mixture is filtered through celite and the solvent is evaporated off. 1.8 g of an oily
material corresponding to the title product are isolated.
Preparation 5
Methyl 3,8-diazabicyclo[3.2.1]oct-8-ylnicotinate hydrochloride
0.42 g of methyl 6-chloronicotinate (compound of formula (VII)), 0.5 g of
1-benzyl-3,8-diazabicyclo[3.2.1]octane (compound of formula (VI)), 0.4 g of
potassium carbonate and 0.17 g of Nal are placed in 7 ml of N-methylpyrrolidone.
The mixture is heated for 7 hours at 110°C. It is then poured into saturated
aqueous sodium chloride solution and extracted with ethyl acetate. The organic
phase is dried over Na2SO4, filtered and evaporated under vacuum. 1.1 g of an
oily material are isolated, and this material is purified by flash chromatography on
a Biotage® column, using 8/2 cyclohexane/ethyl acetate as eluent. 520 mg of a
clear oil are isolated. The product obtained in the preceding step is hydrogenated
at 40°C under atmospheric pressure for 2 hours, in 20 ml of ethanol and 2 ml of
isopropanol/HCl, in the presence of 0.22 g of 10% Pd/C. The resulting mixture is
filtered and evaporated under vacuum, and 440 mg of the title product are isolated
in the form of a white solid corresponding to the title product.
Preparation 6
1 -(5-trifluoromethylpyridin-2-yl)piperazin-2-one hydrochloride
10 g of 2-chloro-5-(trifluoromethyl)pyridine and 40.5 ml of
N-benzylethylenediamine are heated at 135°C for 6 hours in a round-bottomed
flask. The resulting mixture is poured into water and extracted with ethyl acetate.
The extracts are dried and evaporated under vacuum; the crude product thus
obtained is purified by flash chromatography. The isolated product (compound of
formula (VIII)), 14 g, is dissolved in 200 ml of 2N HCI solution. 30 g of trimeric
glyoxal dihydrate are added and the mixture is stirred at room temperature for
72 hours. The resulting mixture is extracted with ethyl acetate. The extracts are
dried and evaporated under vacuum; the crude product thus obtained is purified
by flash chromatography. The isolated product, 10 g, is dissolved in 450 ml of
ethanol, followed by addition of 15 ml of a solution of isopropanol saturated with
HCI and 3 g of 10% Pd/C. This mixture is reacted under a stream of hydrogen for
4 hours at a temperature of 40°C. The resulting mixture is filtered and evaporated
under vacuum to give 3 g of the title compound, m.p. = 205-207°C.
Preparation 7
2-chloro-1-(2-phenyl-6,7-dihydro-4H-thiazolo[4,5-c]pyridin-5-
yl)ethanone
Step a) preparation of 1-(t~butoxycarboyl)-4-(7-benzo(b)thiophene)-4-
hydroxypiperidine:
45 g of 7-bromobenzothiophene are dissolved in 135 ml of THF and the
solution thus obtained is added dropwise to a suspension of 5.13 g of magnesium
in 10 ml of THF in a round-bottomed flask under nitrogen. A catalytic amount of
iodine is added and the mixture is heated at the reflux temperature for 3 hours.
The resulting mixture is cooled to room temperature and a solution of 36 g of 1-(t-
butoxycarbonyl)-4-piperidone in 80 ml of THF is added. This mixture is stirred for
3 hours at room temperature, and saturated ammonium chloride solution is added.
The resulting mixture is extracted with ethyl acetate. The extracts are dried
and evaporated under vacuum; the crude product thus obtained is purified by
flash chromatography using 95/5 hexane/ethyl acetate as eluent. 47.5 g of a white
solid with a melting point of 130-131 °C are isolated.
Step b) preparation of 4-(7-benzo(b)thiophene)-4-hydroxypiperidine
hydrochloride:
40 g of the product from step a) are dissolved in 650 ml of ethyl acetate.
88 ml of 37% HCI are added slowly and the mixture is stirred at room temperature
for 30 minutes. The solvents are evaporated off and the residue is treated with
acetone. The resulting mixture is filtered to give 34 g of a white solid with a
melting point of 232-233°C.
Step c) preparation of 4-(7-benzo(b)thiophene)-1,2,3,6-tetrahydropyridine
hydrochloride:
34 g of the product from step b) are dissolved in 437 ml of acetic acid.
20 ml of 96% sulfuric acid are added and the mixture is heated at a
temperature of 60°C for 2 hours. The resulting mixture is poured into a water/ice
mixture and the pH is made basic with 40% sodium hydroxide solution. The
resulting mixture is extracted with ethyl acetate. The extracts are dried and
evaporated under vacuum to give 30 g of product in the form of an oily material.
The formation of the hydrochloride is obtained in isopropanol using a solution of
isopropanol saturated with HCI. The product is filtered off to give 25.8 g of a white
solid with a melting point of 226-227°C.
Step d) preparation of 2-chloro-1-(2-phenyl-6,7-dihydro-4H-thiazolo[4,5-
c]pyridin-5-yl)ethanone:
2.8 g of the product from step c) are suspended in 50 ml of dichloromethane
in a round-bottomed flask equipped with a magnetic stirrer. 2.8 ml of triethylamine
are added and the mixture is cooled to 0°C. At 0°C, 1.5 ml of chloroacetyl
chloride, i.e. the compound of general formula (V) in which Hal=Hal'=CI and n=1,
are added dropwise. The mixture is reacted for 1 hour 30 minutes and is poured
into water. The resulting mixture is extracted with dichloromethane. The organic
phase is dried over Na2SO4, filtered and evaporated under vacuum. 4.1 g of an oil
material are isolated, and this material is purified by flash chromatography on a
Biotage® column, using 9/1 cyclohexane/ethyl acetate as eluent. 1.1 mg of the
title product are isolated in the form of a clear oil.
Preparation 8
1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-chloroethanone
By performing the process as described in Preparation 1, but using
7-bromobenzofuran instead of 7-bromobenzothiophene, the title compound is
obtained.
Preparation 9
1-(5-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-chloroethanone
By performing the process as described in Preparation 1, but using
7-bromobenzofuran instead of 7-bromobenzothiophene and 1-(t-butoxycarbonyl)-
3-piperidone instead of 1-(t-butoxycarbonyl)-4-piperidone, the title compound is
obtained.
Preparation 10
Methyl 5-[1-(2-chloroacetyl)-1,2,3,6-tetrahydropyridin-4-yl]-
benzo[b]thiophene-3-carboxylate
Step a) preparation of tert-Butyl 4-(2-methoxycarbonylbenzo[b]thiophen-5-
yl)-3,6-dihydro-2H-pyridine-1-carboxylate:
1.1 g of tert-butyl 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-
2H-pyridine-1-carboxylate (purity 70%), 0.7 g of methyl 5-
bromobenzo[b]thiophene-2-carboxylate, 0.15 g of PalladiumTetrakis (PdP(Ph3)4),
5.5 ml of 2M sodium carbonate solution and 0.42 g of lithium chloride are placed
in 30 ml of DME in a round-bottomed flask under a stream of nitrogen. The
mixture is heated at the reflux temperature for 3 hours. The solvent is evaporated
off and the residue is dissolved in 35 ml of ethyl acetate. This solution is washed
with 2M sodium carbonate solution. The organic phase is dried over Na2SO4,
filtered and evaporated under vacuum. 1.6 g of an oily material are isolated, and
this material is purified by flash chromatography on a Biotage® column, using
98/2 cyclohexane/ethyl acetate as eluent. 0.45 g of a yellowish solid is isolated.
Step b) preparation of methyl 5-(1,2,3,6-tetrahydropyridin-4-
yl)benzo[b]thiophene-2-carboxy!ate) hydrochloride:
0.45 g of the product from step a) is dissolved in 25 ml of ethyl acetate.
50 ml of a solution of ethyl acetate saturated with HCI are added slowly and the
mixture is stirred at room temperature for 3 hours. The solvents are evaporated off
and the residue is treated with acetone. This mixture is filtered to give 0.35 g of a
whitish solid.
Step c) preparation of methyl 5-[1-(2-chloroacetyl)-1,2,3,6-tetrahydropyridin-
4-yl]benzo[b]thiophene-3-carboxylate
By performing the process as described in step d) of Preparation 7, but
using the product of step b) instead of the product of step c) of Preparation 7,
0.4 g of the title product is obtained in the form of a clear oil.
Preparation 11
2-chloro-1 -(4-quinolin-8-yl-3,6-dihydro-2H-pyridin-1 -yl)ethanone
By performing the process as described in Preparation 10, but using
8-bromoquinoline instead of methyl 5-bromobenzo[b]thiophene-2-carboxylate, the
title compound is obtained.
Preparation 12
2-chloro-1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-
1-yl]ethanone
By performing the process as described in Preparation 1, but using
6-bromobenzodioxane instead of 7-bromobenzothiophene, the title compound is
obtained.
Preparation 13
1-(3-benzofuran-7-yl-2,5-dihydropyrrol-1-yl)-2-chloroethanone
By performing the process as described in Preparation 7, but using
1-(t-butoxycarbonyl)-3-pyrrolidone instead of 1-(t-butoxycarbonyl)-4-piperidone
and 7-bromobenzofuran instead of 7-bromobenzothiophene, the title compound is
obtained.
Preparation 14
Methyl 6-((3S,5R)-3,5-dimethylpiperazin-1-yl)nicotinate
By performing the process as described in Preparation 1, but using methyl
6-chloronicotinate instead of 2-trifluoromethyl-5-bromopyridine, the title compound
is obtained in the form of a clear oil.
Preparation 15
3-[6-(3,8-diazabicyclo[3.2.1]oct-8-yl)pyridin-3-yl]-4H-[1,2,4]oxadiazol-5-
one hydrochloride
Step a) 6-(3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinonitrile hydrochloride
By performing the process as described in Preparation 3, but using 6-
chloronicotinonitrile instead of 2-chloro-5-fIuoropyrimidine, the title compound is
obtained in the form of a white solid.
Step b) tert-Butyl 8-(5-cyanopyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-
carboxylate
7 g of the product from step a) are dissolved in 83 ml of DMF. 11.7 ml of
triethylamine are added. 6.7 g of (BOC)2O are added at 0°C, and the mixture is
stirred at room temperature for 1 hour. The resulting mixture is evaporated under
vacuum. The residue is washed with water and extracted with ethyl acetate. The
organic phase is dried over Na2SO4, filtered and evaporated under vacuum. 12 g
of an oily material are isolated, and this material is purified by flash
chromatography on an automatic Biotage® column, using 8/2 cyclohexane/ethyl
acetate in a gradient up to 100% ethyl acetate as eluent. 7.6 g of the title
compound are isolated in the form of a white solid.
Step c) tert-Butyl 8-[5-(N-hydroxycarbamimidoyl)pyridin-2-yl]-3,8-
diazabicyclo[3.2.1]octane-3-carboxylate
The product of step b) (7.6 g) is dissolved in 75 ml of ethanol, and a solution
of 3.36 g of hydroxylamine hydrochloride dissolved in 38 ml of water is added,
followed by addition of 5 g of sodium carbonate. The mixture is stirred at 90°C for
4 hours. The resulting mixture is cooled and filtered. 8 g of the title compound are
obtained in the form of a white solid.
Step d) tert-Butyl 8-[5-(5-oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl)pyridin-2-yl]-
3,8-diazabicyclo[3.2.1]octane-3-carboxylate
1 g of the compound from step c) is placed in a round-bottomed flask under
a stream of nitrogen, and 10 ml of DMF and 0.3 ml of pyridine are added. 0.23 ml
of methyl chloroformate is added at 0°C, and the mixture is stirred at room
temperature for 3 hours. The resulting mixture is washed with water and extracted
with ethyl acetate. The organic phase is dried over Na2SO4, filtered and
evaporated under vacuum. 30 ml of toluene are added and the resulting mixture is
stirred at reflux for 4 hours. The solvent is evaporated off to give 0.8 g of the title
compound.
Step e) 3-[6-(3,8-diazabicyclo[3.2.1]oct-8-yl)pyridin-3-yl]-4H-
[1,2,4]oxadiazol-5-one hydrochloride
The product is dissolved in 20 ml of ethyl acetate, a solution of ethyl acetate
saturated with HCI is added, and the mixture is stirred at room temperature for
2 hours. The solvent is evaporated off and the residue is treated with isopropanol.
This mixture is filtered to give 0.65 g of the title compound in the form of a yellow
solid.
Preparation 16
[(2R,6S)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-
yl]acetic acid
Step a) Ethyl [(2R,6S)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-
1-yl]acetate
3.6 g of the product of Preparation 1, 100 ml of THF, 1.9 ml of ethyl
bromoacetate and 4.7 ml of triethylamine are placed in a round-bottomed flask
equipped with a magnetic stirrer. The mixture is reacted for 7 hours at 80°C. The
solvent is evaporated off and the residue is washed with ethyl ether and filtered.
The filtration water is purified by flash chromatography on an automatic Biotage®
column using 8/2 cyclohexane/ethyl acetate at a gradient up to 7/3 ethyl
acetate/methanol as eluent. 2.5 g of the title product are isolated in the form of a
solid.
Step b) [(2R,6S)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)pipera2in-1-
yljacetic acid
2.5 g of the product from the preceding step are dissolved in 22 ml of
ethanol, followed by addition of 5 ml of aqueous 40% NaOH solution. The mixture
is reacted for 3 hours at 70°C. The pH is adjusted to 6 using 1N HCI solution. The
resulting mixture is extracted with ethyl acetate. The organic phase is dried over
Na2SO4, filtered and evaporated under vacuum. 1.6 g of the title product are
isolated in the form of a white solid.
Preparation 17
2-(1,2,3,6-tetrahydropyridin-4-yl)quinoIine hydrochloride
By performing the process as described in Preparation 10, but using
quinolin-2-yl trifluoromethanesulfonate instead of methyl 5-
bromobenzo[b]thiophene-2-carboxylate, the title compound is obtained in the form
of a white solid.
Preparation 18
(3S,5R)-3,5-dimethyl-1-(5-thiazol-2-ylpyridin-2-yl)piperazine
Step a) (3S,5R)-3,5-dimethyl-1 -(5-iodo-2-ylpyridin-2-yl)piperazine
By performing the process as described in Preparation 1, but using 2-fluoro-
5-iodopyridine instead of 2-chloro-5(trifluoromethyl)pyridine, the title compound is
obtained in the form of an oil.
Step b) tert-Butyl (2S,6R)-2,6-dimethyl-4-(5-iodo-2-ylpyridin-2-yl)piperazine-
1-carboxylate
0.35 g of the compound from step a), 0.26 g of (Boc)2O and 0.46 ml of
triethylamine are placed in 5 ml of DMF under a stream of nitrogen at 0°C. The
mixture is heated at a temperature of 140°C for 4 hours. The solvent is
evaporated off. 0.49 g of crude product is isolated. The residue is purified by flash
chromatography on a Biotage® column, using ethyl acetate as eluent. 0.43 g of
the title compound is isolated having the form of a pale yellow oil.
Step c) tert-Butyl (2S,6R)-2,6-dimethyl-4-[5-(4,4,5,5-tetramethyl-
[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate
0.43 g of the compound from step b), 0.29 g of bis(pinacol)diboron, 0.026 g
of palladiumCI2 (dppf)2-CH2CI2 and 0.31 g of potassium acetate are placed in
10 ml of DMSO in a round-bottomed flask under a stream of nitrogen. The mixture
is heated at 85°C for 2 hours. The resulting mixture is poured into saturated
aqueous NaCI solution and extracted with ethyl acetate. The organic phase is
dried over Na2SO4, filtered and evaporated under vacuum. 0.32 g of an oily
material is isolated, and this material is purified by flash chromatography on a
Biotage® column, using 9/1 cyclohexane/ethyl acetate as eluent. 0.28 g of a
yellowish solid is isolated.
Step d) tert-Butyl 2S,6R-2,6-dimethyl-4-(5-thiazol-2-ylpyridin-2-yl)piperazine-
1-carboxylate
0.28 g of the compound from step c), 0.092 g of 2-bromothiazole, 0.032 g of
palladiumTetrakis (PdP(Ph3)4) and 0.094 g of sodium bicarbonate are placed in
20 ml of DME and 3 ml of water in a round-bottomed flask under a stream of
nitrogen. The mixture is heated at the reflux temperature for 7 hours. The resulting
mixture is poured into saturated aqueous NaCI solution and extracted with ethyl
acetate. The organic phase is dried over Na2SO4, filtered and evaporated under
vacuum. 0.36 g of an oily material is isolated, and this material is purified by flash
chromatography on a Biotage® column, using 9/1 cyclohexane/ethyl acetate as
eluent. 0.2 g of a yellowish oil is isolated.
Step e) (3S,5R)-3,5-dimethyl-1-(5-thiazol-2-ylpyridin-2-yl)piperazine
trifluoroacetate
The compound from step d) (0.2 g) is dissolved slowly in 5 ml of
trifluoroacetic acid at 0°C. The mixture is then stirred for 2 hours at room
temperature. The trifluoroacetic acid is evaporated off under vacuum to give
0.15 g of the title compound in the form of a beige-colored solid.
Preparation 19
[3-oxo-4-(3-trifIuoromethylphenyl)piperazin-1-yl]acetic acid
Step a) Benzyl [3-oxo-4-(3-trifluoromethylphenyi)piperazin-1-yl]acetate
1.12 g of 1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one, 40 ml of THF and
0.87 ml of benzyl bromoacetate are placed in 1.5 ml of triethylamine in a round-
bottomed flask equipped with a magnetic stirrer. The mixture is reacted under a
stream of nitrogen overnight at room temperature. The solvent is evaporated off
and the residue is purified by flash chromatography on a Biotage® column, using
1/1 hexane/ethyl acetate as eluent. 2.9 g of title product are isolated in the form of
a white solid.
Step b) [3-oxo-4-(3-trifluoromethylphenyl)piperazin-1-yl]acetic acid
1 g of the product from the preceding step is dissolved in 150 ml of ethanol,
followed by addition of 0.15 g of 10% Pd/C. The mixture is reacted under a stream
of hydrogen for 4 hours at a temperature of 40°C. The resulting mixture is filtered
and evaporated under vacuum to give 0.74 g of the title compound in the form of a
white solid.
EXAMPLE 1
Compound 34:
1-(4-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-l-yl)-2-[(2S,6R)-2,6-
dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone
0.18 g of the compound obtained in Preparation 8 (compound of formula
(II)), 0.17 g of the compound obtained in Preparation 1 (compound of formula
(III)), 0.1 g of potassium carbonate and 0.04 g of Nal are reacted together in 3 ml
of DMF. The reaction is performed using a CEMdiscover microwave initiator for
30 minutes at 160°C. The mixture is poured into water and extracted with ethyl
acetate. The organic phase is dried over Na2SO4, filtered and evaporated under
vacuum. 0.36 g of an oily material is isolated. It is purified on a column by flash
chromatography using a Biotage® column eluted with a 6/4 cyclohexane/ethyl
acetate mixture. 0.180 g of a pale yellow solid is isolated, and is crystallized from
ethyl ether. The product is filtered off to give 0.08 g of title product in the form of a
white solid.
M.p.: 138-139°C
NMR Machine b). d (ppm, DMSO-d6): 1.06 (m, 6H); 2.56 - 2.79 (m, 4H); 3.19 (m,
*), 3.73 (m, 4H); 4.18 (m, 3H); 4.31 (m, 1H); 6.57 (m, 1H); 6.95 (d, J= 9.2Hz, 1H);
6.99 (d, J= 1.8Hz. 1H); 7.27 (m, 2H); 7.58 (d, J= 7.2Hz, 1H); 7.76 (dd, J= 9.2 and
2.2Hz, 1H); 8.01 (d, J= 1.7Hz, 1H); 8.39 (bs, 1H).
EXAMPLE 2
Compound 1:
H4-Benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-
dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone and the
oxalate thereof
By performing the process as described in Example 1, but using the
compound of Preparation 7 instead of the compound of Preparation 8, the title
compound is obtained.
It is dissolved in acetone and a solution of oxalic acid in acetone is added,
and the oxalate is obtained in the form of a white solid.
M.p.:60-61°C
NMR: (Machine b). d (ppm, DMSO-d6): 1.17 (m, 6H), 2.60 + 2.68 (2 x m,
2H); 2.97 (m, *); 3.36 (m, *); 3.76 (m, *); 4.00 (m, *); 4.14 - 4.43 (m, *); 6.30 (bs,
1H); 7.03 (d, J= 9.0Hz, 1H); 7.32 (d, J= 7.1Hz, 1H); 7.42 (t, J= 7.6Hz, 1H); 7.51 (d,
J= 5.3Hz, 1H); 7.77 (d, J= 5.5Hz, 1H); 7.83 (m, 2H); 8.43 (bs, 1H).
EXAMPLE 3
Compound 14:
1-(4-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2R,5S)-2,5-
dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone and the
oxalate thereof
By performing the process as described in Example 1, but using the
compound of Preparation 2 instead of the compound of Preparation 1, and the
compound of Preparation 8 instead of the compound of Preparation 7, the title
compound is obtained.
It is dissolved in acetone, a solution of oxalic acid in acetone is added and
the oxalate is obtained in the form of a white solid.
M.p.:130-131°C
NMR (Machine b). d (ppm, DMSO-d6): 1.02 (m, 3H); 1.15-1.32 (m, 3H); 2.64 (m,
2H); 2.78 (m, 1H); 2.92 (m, 1H); 2.90 (m, 1H); 3.26 (m, *); 3.34 - 3.67 (m, *); 3.66
-3.99 (m, *); 4.07-4.54 (m, *); 4.64 (m, *); 6.58 (m, 1H); 6.90 (m, 1H); 6.98 (d, J=
1.9Hz, 1H); 7.20 - 7.33 (m, 2H); 7.58 (d, J= 7.2Hz, 1H); 7.76 (m, 1H); 8.00 (d, J=
1.8Hz, 1H);8.39(m, 1H).
EXAMPLE 4
Compound 69:
Methyl 6-{3-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yI}nicotinate
0.47 g of the compound obtained in Preparation 7 (compound of formula
(II)), 0.45 g of the compound obtained in Preparation 5 (compound of formula
(III)), 0.57 ml of diisopropylethylamine and 18 ml of DMF are reacted together.
The mixture is heated at 100°C for 3 hours. It is poured into water and extracted
with ethyl acetate. The organic phase is dried over Na2SO4, filtered and
evaporated under vacuum. 0.58 g of a solid material is isolated. It is purified on a
column by flash chromatography, eluting with a 1/1 hexane/ethyl acetate mixture.
0.24 g of the title product is isolated. It is treated with diethyl ether and filtered to
give 0.21 g of a white solid.
M.p.: 153-154°C
NMR (Machine a). d (ppm, DMSO-d6): 1.87 (m, 2H), 1.98 (m, 2H); 2.40 (m, 2H);
2.56 (m, 1H); 2.71 (m, 3H); 3.17 + 3.20 (2 x s, 2H); 3.69 - 3.88 (m, 5H); 4.16 (s,
1H); 4.42 (s, 1H); 4.67 (bs, 2H); 6.29 + 6.32 (2 x m, 1H); 6.78 (m, 1H); 7.31 (d, J=
7.2Hz, 1H); 7.42 (t, J= 7.6Hz, 1H); 7.50 (d, J= 54Hz, 1H); 7.77 (d, J=5.3Hz, 1H);
7.82 (d, J= 7.5Hz, 1H); 7.93 (d, J= 8.7Hz, 1H); 8.64 (bs, 1H).
EXAMPLE 5
Compound 36:
1-(4-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-
fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone
By performing the process as described in Example 4, but using the
compound of Preparation 8 instead of the compound of Preparation 7, and the
compound of Preparation 4 instead of the compound of Preparation 5, the title
compound is obtained in the form of a white solid.
M.p.: 174-175°C
NMR (Machine a). d (ppm, DMSO-d6): 1.71 - 2.03 (m, 4H); 2.39 (m, 2H);
2.57 - 2.80 (m, 4H); 3.16 + 3.19 (2 x s, 2H); 3.73 + 3.82 (2 x m, 2H); 4.17 (bs,
1H); 4.42 (bs, 1H); 4.60 (m, 2H); 6.56 + 6.59 (2 x m, 1H); 6.98 (d, J= 2.3Hz, 1H);
7.27 (m, 2H); 7.58 (dd, J= 7.35 and 1.8Hz, 1H); 8.01 (d, J= 2.1Hz, 1H); 8.44 (m,
2H).
EXAMPLE 6
Compound 71:
6-{3-[2-(4-Benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid
0.147 g of the compound of Example 4 is dissolved in 2 ml of aqueous 3N
HCI solution. The mixture is heated at the reflux temperature for 2 hours. 2 ml of
aqueous 3N HCI are added. The mixture is heated at the reflux temperature for
1 hour. The resulting mixture is washed with ethyl ether. The pH is adjusted to 6
with NaHCO3 solution and the resulting mixture is extracted with ethyl acetate.
The organic phase is dried and evaporated to give 200 mg of an oily material. This
material is treated with diethyl ether and filtered to give 0.015 g of a pale yellow
solid corresponding to the title product.
M.p.: 121-122°C
NMR (Machine b). d (ppm, DMSO-d6): 1.75 - 2.06 (m, 4H); 2.41 (m, 2H);
2.56 (m, **); 2.70 (m, 3H); 3.12 - 3.33 (m, *); 3.68 - 3.90 (m, 2H); 4.16 (bs, 1H);
4.42 (bs, 1H); 4.66 (bs, 2H); 6.29 (m, 1H); 6.78 (m, 1H); 7.31 (d, J= 7Hz, 1H);
7.42 (dd ? t, J= ~8Hz, 1H); 7.50 (d, J= 5.6Hz, 1H); 7.77 (d, J= 5.4Hz, 1H); 7.82
(d, J= 8Hz, 1H); 7.91 (m, 1H); 8.63 (bs, 1H); 11.72-12.49 (bs, 1H).
EXAMPLE 7
Compound 32 :
4-[2-(4-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-oxoethyl]-1 -(5-
trifluoromethylpyridin-2-yl)piperazin-2-one
By performing the process as described in Example 4, but using the
compound of Preparation 8 instead of the compound of Preparation 7, and the
compound of Preparation 6 instead of the compound of Preparation 5, the title
compound is obtained in the form of a white solid.
M.p.: 151-152°C
NMR (Machine a). d (ppm, DMSO-d6): 2.64 (m, 0.9H); 2.73 (m, 1.1 H); 2.99
(m, 2H); 3.51 (s, 3H); 3.77 (m, 2H); 3.98 (m, 2H); 4.22 (s, 1.1H); 4.33 (s, 0.9H);
6.57 (bs, 1H); 6.98 (d, J=2.2Hz, 1H); 7.22 - 7.34 (m, 2H); 7.58 (bd, J= 7.5Hz, 1H);
7.99 (bs, 1H); 8.22 (m, 2H); 8.84 (m, 1H).
EXAMPLE 8
Compound 20:
1-(4-Quinolin-8-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-trifluoromethy)-
pyridin-2-yl)piperazin-1-yl]ethanone and the oxalate thereof
By performing the process as described in Example 4, but using the
compound of Preparation 11 instead of the compound of Preparation 7, and (5-
trifluoromethylpyridin-2-yl)piperazine instead of the compound of Preparation 5,
the title compound is obtained.
It is dissolved in acetone and a solution of oxalic acid in acetone is added, to
give the oxalate in the form of an amorphous beige-colored solid.
NMR (Machine b). d (ppm, DMSO-d6): 2.77 + 2.87 (2 x m, 2H); 3.02 (m,
4H); 3.53 - 3.98 (m, *); 4.22 (m, 2H); 5.96 (m, 1H); 7.03 (d, J= 9.1Hz, 1H); 7.50 -
7.65 (m, 3H); 7.86 (dd, J= 9.0 and 2.1Hz, 1H); 7.92 (m, 1H); 8.38 (dd, J= 8.2 and
1.8 Hz, 1H); 8.46 (bs, 1H); 8.90 (m, 1H).
EXAMPLE 9
Compound 45:
1-[4-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-
[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yI]ethanone
By performing the process as described in Example 1, but using the
compound of Preparation 12 instead of the compound of Preparation 7, the title
compound is obtained in the form of a white solid.
M.p.:200-201°C
NMR (Machine a). d (ppm, DMSO-d6): 1.05 (m, 6H); 2.39 + 2.50 (2 x m, **);
2.60 (m, 2H); 3.21 - 3.32 (m, *); 3.56 - 3.73 (m, 4H); 3.77 (m, 2H); 4.05 + 4.18 (2
x m, 2H); 4.24 (s, 4H); 6.05 (m, 1H); 6.82 (d, J= 8.4Hz, 1H); 6.89 - 6.96 (m, 2H);
7.39 (dd, J= 8.8 and 2.6Hz, 1H); 7.60 (d, J= 8.8Hz, 1H); 8.39 (d, J= 2.7Hz, 1H).
EXAMPLE 10
Compound 63:
1-(5-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-
dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone
By performing the process as described in Example 1, but using the
compound of Preparation 9 instead of the compound of Preparation 7, the title
compound is obtained in the form of a white solid.
M.p.: 129-130°C
NMR (Machine a). d (ppm, DMSO-d6): 1.06 (m, 6H); 2.33 + 2.44 (2 x m,
2H); 2.71 (m, 2H); 3.19 (m, *); 3.68 (m, 2H); 3.73 (s, 2H); 4.17 (m, 2H); 4.47 +
4.58 (2 x bs, 2H); 6.63 (bs, 1H); 6.94 (m, 1H); 6.70 (bs, 1H); 7.22 - 7.39 (m, 2H);
7.59 (d, J= 7.4Hz, 1H); 7.75 (bd, J= 9.0Hz, 1H); 8.02 (bs, 1H); 8.38 (bs, 1H).
EXAMPLE 11
Compound 67:
Methyl 5-(1-{2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)-
piperazin-1-yl]acetyl}-1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene-2-
carboxylate and the oxalate thereof
By performing the process as described in Example 1, but using the
compound of Preparation 10 instead of the compound of Preparation 7, the title
compound is obtained.
It is dissolved in acetone and a solution of oxalic acid in acetone is added, to
give the oxalate in the form of an amorphous beige-colored solid.
NMR (Machine b). d (ppm, DMSO-d6): 1.15 (m, 6H); 2.58 + 2.68 (2 x m, 2H); 2.95
(m, 2H); 3.35 (m, 2H); 3.74 (m, *); 3.82 - 4.08 (m, *); 4.12 - 4.40 (m, *); 6.31 (m,
1H); 7.03 (d, J= 9.0Hz, 1H); 7.70 (m, 1H); 7.83 (bd, J= 9.1Hz, 1H); 8.01 - 8.11
(m, 2H); 8.20 (bs, 1H); 8.43 (bs, 1H).
EXAMPLE 12
- Compound 83:
4-[2-(3-Benzofuran-7-yl-2,5-dihydropyrrol-1-yl)-2-oxoethyl]-1-(5-
trifluoromethylpyridin-2-yl)piperazin-2-one
By performing the process as described in Example 4, but using the
compound of Preparation 13 instead of the compound of Preparation 7, and the
compound of Preparation 6 instead of the compound of Preparation 5, the title
compound is obtained in the form of a white solid.
M.p. 184-186°C
NMR (Machine b). d (ppm, DMSO-d6): 2.89 - 3.12 (m, 4H); 3.45 - 3.59 (m, 4H);
3.80 - 4.02 (m, 4H); 4.74 + 4.83 (2 x s, 2H); 7.51 (m, 3H); 8.20 (m, 2H), 8.37 (m,
2H); 8.65-8.88 (m,2H).
EXAMPLE 13
- Compound 89:
3-(6-{3-[2-(4-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-oxoethyl3-
3,8-diazabicyclo[3.2.1]oct-8-yl}pyridin-3-yl)-4H-[1,2,4]oxadiazol-5-one
By performing the process as described in Example 4, but using the
compound of Preparation 8 instead of the compound of Preparation 7, and the
compound of Preparation 15 instead of the compound of Preparation 5, the title
compound is obtained in the form of a white solid.
M.p.: 230-232°C
NMR: (Temp. B). d (ppm, DMSO-d6): 1.76 - 2.04 (m, 4H), 2.41 (m, 2H), 2.56 -
2.81 (m, 4H), 3.17 + 3.21 (2Xs, 2H), 3.73 (m, 1H), 3.81 (m, 1H), 4.17 (m, 1H),
4.42 (m, 1H), 4.64 (m, 2H), 6.56 (m, 0.5H), 6.61 (m, 0.5H), 6.89 (m, 1H), 6.99 (d,
J= 2.2Hz, 1H), 7.24 - 7.32 (m, 2H), 7.58 (dd, J= 7.3 and 1.4Hz, 1H), 7.82 (m, 1H),
8.02 (m, 1H), 8.48 (m, 1H), 12.69 (bs, 1H).
EXAMPLE 14
Compound 51:
Methyl 6-{(3R,5S)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-
2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinate
By performing the process as described in Example 1, but using the
compound of Preparation 8 instead of the compound of Preparation 7, and the
compound of Preparation 14 instead of the compound of Preparation 1, the title
compound is obtained.
It is dissolved in acetone and a solution of oxalic acid in acetone is added, to give
the oxalate in the form of an amorphous white solid.
NMR: (Machine b, Temp. A). d (ppm, DMSO-d6): 1.19 (m, 6H), 2.67 + 2.76 (2Xm,
2H), 3.04 (m, **), 3.43 (m, **), 3.58- 4.58 (m, **), 6.58 (m, 1H), 6.88 - 7.12 (m,
2H), 7.28 (m, 2H), 7.59 (m, 1H), 7.90-8.12 (m, 2H), 8.68 (m, 1H).
EXAMPLE 15
- Compound 57
6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinic acid
By performing the process as described in Example 6, but using the
compound of Example 13 instead of the compound of Example 4, the title
compound is obtained in the form of an oily material. It is treated with diethyl ether
and filtered, to give a pale yellow solid corresponding to the title product.
M.p.:272-274°C
NMR: (Temp. B). d (ppm, DMSO-d6): 1.06 (m, 6H), 2.55 - 2.76 (m, 4H), 3.17 (m,
2H), 3.72 (m, 4H), 4.18 (m, 3H), 3.41 (s, 1H), 6.57 (m, 1H), 6.81 (d, J= 9.0Hz, 1H),
7.00 (d, J= 2.1Hz, 1H), 7.22 - 7.32 (m, 2H), 7.58 (d, J= 7.4Hz, 1H), 7.93 (d, J=
9.0Hz, 1H), 8.02 (s,1H), 8.62 (m, 1H).
EXAMPLE 16
Compound 118
4-[2-Oxo-2-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-pyridin-1-
yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one
0.11 g of the compound of Preparation 19 is suspended in a round-bottomed
flask equipped with a magnetic stirrer, in 13 ml of dichloromethane. 0.1 g of 4-
(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-c]pyridine, 0.19ml of triethylamine and
0.15 g of BOP are added. The mixture is reacted for 1 hour at room temperature.
It is then poured into water and extracted with dichloromethane. The organic
phase is dried over Na2SO4, filtered and evaporated under vacuum. 0.22 g of an
oily material is isolated. It is purified on a column by flash chromatography using a
Biotage® column eluted with ethyl acetate. 0.7 g of white solid is isolated.
M.p.: 145-148°C
NMR: (Machine a, Temp. B). d (ppm, DMSO-d6): 2.69 (m, 0.9H), 2.79 (m, 1.1H),
3.00 (m, 2H), 3.51 (m, 4H), 3.77 (m, 2H), 3.97 (m, 2H), 4.25 (m, 1.1H), 4.35 (m,
0.9H), 6.34 + 6.37 (2Xm, 1H), 7.75 (m, 1H), 7.84 + 7.88 (2Xm, 1H), 7.97 (m, 1H),
8.22 (m, 2H), 8.40 (m, 1H), 8.84 (m, 1H).
EXAMPLE 17
Compound 119
1-(4-Benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-2,6-
dimethyl -4-(5-thiazol-2-ylpyridin-2-yl)piperazin-1-yl]ethanone oxalate
By performing the process as described in Example 1, but using the compound of
Preparation 8 instead of the compound of Preparation 7, and the compound of
Preparation 18 instead of the compound of Preparation 1, the title compound is
obtained in free base form. It is dissolved in acetone and a solution of oxalic acid
in acetone is then added. The title product is obtained in the form of a white solid.
M.p.: 140-145°C
NMR: (Machine a, Temp. B). d (ppm, DMSO-d6): 1.21 (m, 6H), 2.67 (m, *),
2.77 (m, *), 2.91 - 3.95 (m, *), 4.04 - 4.47 (m, *), 6.59 (m, 1H), 7.00 (d, J= 2.1 Hz,
1H), 7.05 (m, 1H). 7.27 (m, 1H), 7.32 (m, 1H), 7.59 (d, J= 7.4Hz, 1H), 7.68 (bd, J=
3.2Hz, 1H), 7.86 (bd, J=3.2Hz, 1H), 8.03 (bd, 1H), 8.08 (m, 1H), 8.71 (bs, 1H)
EXAMPLE 18
Compound 121
2-[(2S,6R)-2,6-Dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-
1-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone
By performing the process as described in Example 16, but using the
compound of Preparation 16 instead of the compound of Preparation 19, and the
compound of Preparation 17 instead of 4-(1,2,3,6-tetrahydropyridin-4-
yl)thieno[3,2-c]pyridine, the title compound is obtained in the form of a white solid.
M.p.: 94-95°C
NMR: (Machine a, Temp.B). d (ppm, DMSO-d6): 1.06 (m, 6H), 2.66 - 2.78
(m, 3H), 2.85 (m, 1H), 3.20 (m, 2H), 3.66- 3.79 (m, 4H), 4.20 (m, 3H), 4.35 (m,
1H), 6.89 (m, 1H), 6.95 (d, J= 9.1Hz, 1H), 7.56 (m, 1H), 7.72 - 7.79 (m, 2H), 7.87
(d, J= 8.7Hz, 1H), 7.92 - 7.99 (m, 2H), 8.33 (m, 1H), 8.39 (m, 1H).
The following table describes the examples obtained by application and/or
adaptation of methods described using suitable reagents and starting materials:
The compounds according to the invention underwent biochemical studies.
Cell culture:
The SH-SY-5Y strain (human neuroblastoma) is conventionally cultured in a
DMEM culture medium (Dulbecco's Modified Eagle's Medium) (Gibco BRL,
France) containing FCS (5%) (fetal calf serum) (Boehringer Mannheim, Germany),
sodium pyruvate (1 mM) and glutamine (4 mM) in collagen-covered culture flasks
(Becton Dickinson, France).
The SK-N-BE parent strain (human neuroblastoma) and the clone Bep 75, stabiy
expressing the complete form of the human p75NTR receptor (SK-N-BE Bep 75)
are conventionally cultured in an RPMl culture medium containing FCS (5%),
sodium pyruvate (1 mM) and glutamine (4 mM). For the SK-N-BE Bep 75 cells,
hygromycin (200 ul/20 ml of medium) is added as selection agent.
Study of the dimerization of the p75NTR receptor independently of its ligand
The study of the dimerization of the p75NTR receptor is performed on a cell
suspension of the strain SK-N-BE Bep 75. The cells (2.5 x 104 cells/well) are
placed in wells (96-well plate) for 24 hours, and then preincubated for 1 hour at
37°C in the presence or absence of the compounds according to the invention.
Supernatent, obtained from a culture of human cells of HEK293 renal origin
expressing, after 48 hours of transfection, and secreting a soluble form of the
p75NTR receptor (extracellular part of the receptor) coupled to an alkaline
phosphatase, the latter at a final concentration of 10 nM, is then added. The
quantification of the specific binding of the soluble receptor to the receptor present
on SK-N-BE Bep 75 ceils is determined by measuring the enzyme activity of the
alkaline phosphatase after incubation of the cells for 1 hour at 37°C in the
presence of the supernatant. After filtering and transferring the filters into 24-well
plates, the alkaline phosphatase activity is determined by adding CDP-Star
chemoluminescent substrate (ready-to-use, Roche). The concentrations of the
compounds according to the invention that inhibit 50% (IC50) of the dimerization of
the p75NTR receptor are low, and range from 10-6 to 10-11M.
The compounds of formula (I) show activity in this test with IC50 values ranging
from 10-6 to 10-11M.
For example, compounds 1, 14, 34 and 36 showed, respectively, an IC50 value of
0.08 nM, 1.09 nM, 0.94 nM and 20 nM.
Measurement of the apoptosis
The cells (strains of human neuroblastomas SH-SY-5Y and SK-N-BE Bep 75) are
placed in Petri dishes 35 mm in diameter (Biocoat collagenl, (105 cells/well)) in a
suitable culture medium containing 5% FCS, for 24 hours. The culture medium is
then removed, the cells are rinsed with PBS (Dulbecco's Phosphate-buffered
saline), and then either fresh medium containing 5% FCS, or medium containing
NGF (at a concentration of 10 ng/ml), or beta-amyloid peptide (Aß1-40) (at a
concentration of 10 µM) is then added, in the presence or absence of the
compounds according to the invention. The apoptosis levels are measured
48 hours after the treatments in the case of the strain SH-SY-5Y, and 24 hours
later in the case of the strain SK-N-BE Bep 75, by quantifying the cytoplasmic
histones associated with the DNA fragments (cell death detection ELISA,
Boehringer Mannheim, Germany). The apoptosis levels are expressed as the
amount of oligonucleosomes/105 cells. Each value corresponds to the average of
9 experimental points distributed over 3 independent experiments.
The compounds of formula (I) show activity in this test, with IC50 values ranging
from 10-6 to 10-11M.
For example, compounds 19, 14 and 34 showed, respectively, an IC50 value of
1.07 nM, 1.33 nM and 3.39 nM.
Thus, the binding of the compounds according to the invention to p75NTR receptor
is reflected, firstly, at the biochemical level by inhibition of dimerization of the
receptor induced by the neurotrophins, or independently of the ligand, and,
secondly, at the cellular level, by inhibition of the proapoptotic effect mediated by
the p75NTR receptor.
Thus, according to one of the subjects of the present invention, the compounds of
formula (I) show very advantageous inhibitory activity on the dimerization of the
p75NTR receptor independently of its ligand.
The compounds according to the invention may thus be used for the preparation
of medicaments, in particular medicaments intended for preventing or treating any
pathology in which the p75NTR receptor is involved, more particularly those
indicated hereinbelow.
The compounds according to the invention may also be used for preventing or
treating any pathology in which the p75NTR receptor is involved, more particularly
those indicated hereinbelow.
Thus, according to another of its aspects, a subject of the invention is
medicaments comprising a compound of formula (I), or an addition salt thereof
with a pharmaceutically acceptable acid.
Thus, the compounds according to the invention may be used, in man or animals,
in the treatment or prevention of various p75NTR-dependent complaints such as
central and peripheral neurodegenerative diseases, for instance senile dementia,
epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's chorea, Down's
syndrome, prion diseases, amnesia, schizophrenia, depression, bipolar disorder;
amyotrophic lateral sclerosis, multiple sclerosis; cardiovascular complaints, for
instance post-ischemic heart damage, cardiomyopathies, myocardial infarction,
cardiac insufficiency, cardiac ischemia, cerebral infarction; peripheral
neuropathies (of diabetic, traumatic or iatrogenic origin); optic nerve and retinal
damage (retinal pigment degeneration, glaucoma); retinal ischemia; macular
degeneration, spinal cord trauma and cranial trauma; atherosclerosis; stenoses,
wound healing disorders; alopecia.
The compounds according to the invention may also be used in the treatment of
pancreatitis and hepatic fibrosis.
The compounds according to the invention may also be used in the treatment of
cancers, for instance lung cancer, thyroid cancer, pancreatic cancer, prostate
cancer, small intestine cancer, colorectal cancer and breast cancer, and in the
treatment of tumors, metastases and leukemias.
The compounds according to the invention may also be used in the treatment of
respiratory disorders, for instance pulmonary inflammation, allergy and asthma,
and chronic obstructive pulmonary disease.
The compounds according to the invention may also be used in the treatment of
cutaneous pain (of the skin, of the subcutaneous tissues and associated organs),
somatic pain, visceral pain (of the circulatory, respiratory, gastrointestinal or
urogenital system) and neurological pain.
The compounds according to the invention may be used in the treatment of
chronic neuropathic and inflammatory pain and in the treatment of autoimmune
diseases, such as rheumatoid arthritis.
The compounds according to the invention may also be used in the treatment of
diseases such as ankylosing spondylitis, psoriatic arthritis and plaque psoriasis.
The compounds according to the invention may also be used in the treatment of
bone fractures, and in the treatment or prevention of bone diseases such as
osteoporosis.
According to another of its aspects, the present invention relates to
pharmaceutical compositions comprising, as active principle, a compound
according to the invention. These pharmaceutical compositions contain an
effective dose of at least one compound according to the invention, or a
pharmaceutically acceptable salt of said compound, and also at least one
pharmaceutically acceptable excipient.
Said excipients are chosen, according to the pharmaceutical form and the
desired mode of administration, from the usual excipients known to those skilled in
the art.
In the pharmaceutical compositions of the present invention for oral, sublingual,
subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal,
transdermal or rectal administration, the active principle of formula (I) above, or
the salt thereof, may be administered in a unit administration form, as a mixture
with standard pharmaceutical excipients, to man and animals for the treatment or
prevention of the above disorders or diseases.
The appropriate unit forms of administration include oral forms such as tablets,
soft or hard gel capsules, powders, granules and oral solutions or suspensions,
sublingual, buccal, intratracheal, intraocular, intranasal and inhalation
administration forms, topical administration forms, parenteral administration forms
such as transdermal, subcutaneous, intramuscular or intravenous administration
forms, rectal administration forms and implants. For topical application, the
compounds according to the invention may be used in creams, gels, ointments or
lotions.
By way of example, a unit form of administration of a compound according
to the invention in tablet form may comprise the following components:

The dose of active principle administered per day may range from 0.01 to
100 mg/kg, in one or more dosage intakes, and preferentially 0.02 to 50 mg/kg. In
general, the daily dose of the compound of the invention will be the lowest
effective dose of the compound that is capable of producing a therapeutic effect.
There may be particular cases in which higher or lower dosages are appropriate;
such dosages do not depart from the scope of the invention. According to the
usual practice, the dosage that is appropriate to each patient is determined by the
doctor according to the mode of administration and the weight and response of
said patient.
According to another of its aspects, the present invention also relates to a
method for treating the pathologies indicated above, which comprises the
administration, to a patient, of an effective dose of a compound according to the
invention, or a pharmaceutically acceptable salt thereof.
CLAIMS
1. A compound corresponding to formula (I):
in which:
- n represents 1 or 2;
- m represents 0 or 1;
- A represents a fused heterocyclic group of formula (Y)

and B represents a hydrogen atom;
or
A represents a hydrogen atom; and
B represents a fused heterocyclic group of formula (Y)

The fused heterocycle of formula Y may be attached to the rest of the molecule
via any of the available carbon atoms, and in which:
- U completes:
- either an aromatic or saturated 6-atom nucleus, containing one or two
nitrogen atoms, the nucleus possibly being substituted with one or two halogen
atoms, one or two (C1-C4)alkyl or (C1-C4)alkoxy groups, or one or two
perfluoroalkyl radicals;
- or an aromatic or saturated 5-atom nucleus, containing a nitrogen,
oxygen or sulfur atom, the nucleus possibly being substituted with one or two
groups (C1-C4)alkyl;
- X and X1 represent CH or N;
- R and R1 located on any of the available positions, independently represent a
hydrogen atom, a halogen atom, a group (C1-C4)alkyl, (C1-C4)alkoxy, a
perfluoroalkyl or trifluoromethoxy radical, a cyano or a group COOH, COOalkyl,
CONR3R4 or NHCOR3;
--W- is a nitrogenous heterocycle chosen from:
-1-2 represents 1 or 2;
-1-3 represents 1, 2 or 3;
- R2 represents a group of formula:

- in which R5 and R6, located on any of the available positions, independently
represent a hydrogen atom, a halogen atom, a group (C1-C4)alkyl or (C1-
C4)alkoxy, a trifluoromethyl or trifluoromethoxy radical, a cyano or a group
COOH, COOalkyl, COOcycloalkyl, SOalkyl, SO2alkyl, CONR3R4, NR3R4 or
NHCOR3;
or one of the groups R5 and R6 may also represent a heterocycle chosen from:
- Z represents an oxygen or sulfur atom;
- R3 and R4 represent a hydrogen or a group C1-C6 alkyl;
in the form of the base or of an acid-addition salt.
2. The compound as claimed in claim 1, such that
- A represents a fused heterocyclic group of formula (Y)

and B represents a hydrogen atom;
or
A represents a hydrogen atom;
and B represents a fused heterocyclic group of formula (Y)

the fused heterocycle of formula Y possibly being attached to the rest of the
molecule via any of the available carbon atoms of the benzene nucleus;
in the form of the base or of an acid-addition salt.
3. The compound as claimed in either of claims 1 and 2, such that R and R1
located on any of the available positions, independently represent a hydrogen
atom, a halogen atom or a group (C1-C4)alkyl or COOalkyl; in the form of the base
or of an acid-addition salt.
4. The compound as claimed in one of claims 1 to 3, such that:
- -W- is a nitrogenous heterocycle chosen from:

- R3 and R4 represent a hydrogen atom or a methyl group;
in the form of the base or of an acid-addition salt.
5. The compound as claimed in one of claims 1 to 4, such that:
- R2 represents a group of formula:

- R5 and R6, located on any of the available positions, independently represent a
hydrogen atom, a trifluoromethyl radical or a group COOH, COOalkyl or
COOcycloalkyl; or
one of the groups R5 and R6 may also represent a heterocycle chosen from:

- 2 represents an oxygen or sulfur atom; and/or
- R3 and R4 represent a hydrogen or a methyl group;
in the form of the base or of an acid-addition salt.
6. The compound as claimed in any one of claims 1 to 5, chosen from:
- Compound 1: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(3,5-
dimethyl-2,3,5,6-tetrahydro[1,2']bipyrazinyl-4-yl)ethanone;
- Compound 2: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(8-
pyrimidin-2-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
- Compound 3: 1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(8-
pyrimidin-2-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
- Compound 4: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 5: 1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
((2S,5R)-2,5-dimethyl-2,3,5,6-tetrahydro[1,2']bipyrazinyl-4-yl)ethanone;
- Compound 6: 1-(4-benzofb]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
((2S,5R)-2,5-dimethyl-2,3,5,6-tetrahydro[1,2']bipyrazinyl-4-yl)ethanone;
- Compound 7: 1 -(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 8: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-
trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 9: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-
[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 10: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-7-yl)-3,6-dihydro-2H-pyridin-
1-yl]ethanone;
- Compound 11: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-[4-(2-propylbenzo[b]thiophen-7-yl)-3,6-dihydro-2H-pyridin-
1-yI]ethanone;
- Compound 12: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[5-(5-
trifluoromethylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone;
- Compound 13: 1 -(4-benzo[b]thiophen-6-yl-3,6-dihydro-2H-pyridin-1 -yl)-2-
[(2R,5S)-2,5-dimethyl-4-(5-trifIuoromethylpyridin-2-yl)piperazin-1-yI]ethanone;
- Compound 14: 1 -(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2R,5S)-
2,5-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 15: 1 -[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1 -
yl]-2-(8-pyrimidin-2-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
- Compound 16: 1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-
yl]-2-[4-(5-trifIuoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 17: 4-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-
1-yl]-2-oxoethyl}-1-(5-trifluoromethyIpyridin-2-yl)piperazin-2-one;
- Compound 18: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-
1-yl]ethanone;
- Compound 19: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
((2S,6R)-2,6-dimethyl-4-quinolin-2-ylpiperazin-1-yl)ethanone;
- Compound 20: 1-(4-quinoiin-8-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-
trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 21: 1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-
1-yl]-2-[4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 22: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-
[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 23: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-
fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 24: 1 -[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-
1-yl]-2-[8-(5-fIuoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 25: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-
(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone;
- Compound 26: 1-(4-benzofuran-3-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-
fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 27: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-
[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 28: 1-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[8-
(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 29: 1 -(4-benzo[b]thiophen-3-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-
fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 30: 4-{2-[4-(1 H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}-
1-(5-trifIuoromethylpyridin-2-yl)piperazin-2-one;
- Compound 31: 4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-1 -(5-trifIuoromethylpyridin-2-yl)piperazin-2-one;
- Compound 32: 4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound 33: 1 -(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-
trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 34: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-
2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 35: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-((2S,6R)-
2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)ethanone;
- Compound 36: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-
(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;
- Compound 37: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-
2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;
- Compound 38: 2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1 -
yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 39: 2-[(2S,6R)-2,6-dimethyl-4-(6-trifIuoromethylpyridin-3-
yl)piperazin-1-yl]-1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-
1-yl]ethanone;
- Compound 40: 2-((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)-1-[4-(2-
methyIbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 41: 1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)ethanone;
- Compound 42: 1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-dimethylpiperazin-1-yl)ethanone;
- Compound 43: 4-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound 44: 1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-
1-yl]-2-[(2S,6R)-4-(5-fluoropyrimidin-2-y[)-2,6-dimethylpiperazin-1-yl]ethanone;
- Compound 45: 1-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-dihydro-2H-pyridin-
1-yl]-2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-
yl]ethanone;
- Compound 46: 1-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(5-
trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 47: 1 -(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;
- Compound 48: 5-{(3S,5R)-4-[2-(4-benzo[b]thiophen-4-yl-3,6-dihydro-2H-
pyridin-1-yl)-2-oxoethyl3-3,5-dimethylpiperazin-1-yl}pyridine-2-carboxylic acid;
- Compound 49: 4-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yI)-3,6-dihydro-2H-
pyridin-1-yl]-2-oxoethyl}-1-(6-trifluoromethylpyridin-3-yl)piperazin-2-one;
- Compound 50: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(6-
trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;
- Compound 51: Methyl 5-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-
pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}pyridine-2-carboxylate;
- Compound 52: Methyl 6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-
2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinate;
- Compound 53: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;
- Compound 54: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-1-yl]ethanone;
- Compound 55: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
((2S,6R)-2,6-dimethyl-4-pyrimidin-5-ylpiperazin-1-yl)ethanone;
- Compound 56: 6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-
pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinic acid;
- Compound 57: 6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-
yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinic acid;
- Compound 58: Methyl 6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-
2H-pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinate;
- Compound 59: 6-{(3S,5R)-4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-
pyridin-1-yl)-2-oxoethyI]-3,5-dimethylpiperazin-1-yl}nicotinic acid;
- Compound 60: 4-[2-(4-benzofuran-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-1-(5-trifIuoromethylpyridin-2-yl)piperazin-2-one;
- Compound 61: Methyl 6-((3S,5R)-3,5-dimethyl-4-{2-[4-(2-
methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-
oxoethyl}piperazin-1-yl)nicotinate;
- Compound 62: 6-((3S,5R)-3,5-dimethyl-4-{2-[4-(2-methylbenzo[b]thiophen-5-
yl-)-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl}piperazin-1-yl)nicotinic acid;
- Compound 63: 1-(5-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-
2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 64: Ethyl 6-{(3S,5R)-4-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-
pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinate;
- Compound 65: Methyl 6-{3-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-
2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;
- Compound 66: Methyl 7-(1-{2-[2S,6R)-2,6-dimethyl-4-(5-
trifluoromethylpyridin-2-yl)piperazin-1-yl]acetyl}-1,2,3,6-tetrahydropyridin-4-
yl)benzo[b]thiophene-2-carboxylate;
- Compound 67: Methyl 5-(1-{2-[(2S,6R)-2,6-dimethyl-4-(5-
trif]uoromethylpyridin-2-yl)piperazin-1-yl]acetyl}-1,2,3,6-tetrahydropyridin-4-
yl)benzo[b]thiophene-2-carboxylate;
- Compound 68: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-[4-(2-propylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-
1-yl]ethanone;
- Compound 69: Methyl 6-{3-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-
1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;
- Compound 70: Methyl 6-{3-[2-(4-benzo[b]thiophen-5-yl-3,6-dihydro-2H-pyridin-
1-yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;
- Compound 71: 6-{3-[2-(4-benzofb]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound 72: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-[4-(7-fluorobenzofuran-5-yl)-3,6-dihydro-2H-pyridin-1-
yl]ethanone;
- Compound 73: 1-[4-(2,3-dimethylbenzofuran-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-
2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-
yl]ethanone;
- Compound 74: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-(4-quinolein-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone;
- Compound 75: 1-(4-benzofuran-5-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(2,3,5,6-
tetrahydro[1,2']bipyrazinyl-4-yl)ethanone;
- Compound 76: Methyl 6-{3-[2-oxo-2-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-
2H-pyridin-1-yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;
- Compound 77: Methyl 6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-
2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinate;
- Compound 78: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(4-pyridin-
3-yl-[1,4]diazepan-1-yl)ethanone;
- Compound 79: 6-{3-[2-oxo-2-(4-thieno[3,2-c]pyridin-4-yl-3,6-dihydro-2H-
pyridin-1-yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound 80: 6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-
pyridin-1-yl]-2-oxoethyl}-3,8-diazabicycloE3.2.1]oct-8-yl)nicotinic acid;
- Compound 81: Methyl 6-{3-[2-(3-benzofuran-7-yl-2,5-dihydropyrrol-1-yl)-2-
oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;
- Compound 82: Methyl 6-{3-[2-(3-benzo[b]thiophen-7-yl-2,5-dihydropyrrol-1-yl)-
2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinate;
- Compound 83: 4-[2-(3-benzofuran-7-yl-2,5-dihydropyrrol-1-yl)-2-oxoethyl]-1 -
(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound 84: 6-{3-[2-(4-benzofuran-7-yl-2,3-dihydropyrrol-1-yl)-2-oxoethyl]-
3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound 85: 6-{3-[2-(5-benzo[b]thiophen-7-yl-3,4-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound 86: 6-[3-[2-(4-benzo[b]thiophen-7-yl-2,3-dihydropyrrol-1-yl)-2-
oxoethyl3-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound 87: Methyl 6-(3-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3,6-
dihydro-2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinate;
- Compound 88: 2-{(3S,5R)-4-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-
pyridin-1-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}pyrimidine-5-carboxylic
acid;
- Compound 89: 3-(6-{3-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl)}pyridin-3-yl)-4H-[1,2,4]oxadiazol-5-
one;
- Compound 90: 3-(6-{3-[2-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1 -
yl)-2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}pyridin-3-yl)-4H-[1,2,4]oxadiazol-
5-one;
- Compound 91: 6-(3-{2-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-
pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.13oct-8-yl)nicotinonitrile;
- Compound 92: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-4-
(3-chloro-5-trifluoromethylpyridin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;
- Compound 93: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(8-pyridin-
3-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
- Compound 94: 6-{3-[2-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
oxoethyl]-3,8-diazabicycIo[3.2.1]oct-8-yl}nicotinonitrile;
- Compound 95: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[5-(5-
trifluoromethylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone;
- Compound 96: cyclobutyl 6-(3-[2-[4-(2-methylbenzotb]thiophen-5-yl)-3,6-
dihydro-2H-pyridin-1-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinate;
- Compound 97: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 98: 1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-(4-quinolin-2-
ylpiperazin-1-yl)ethanone;
- Compound 99: 1 -(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-(7-
chloroquinolin-4-yl)piperazin-1-yl]ethanone;
- Compound 100: 2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpipera2in-1-
yl]-1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 101: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
[(2S,6R)-4-(5-chloropyridin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;
- Compound 102: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-
((2R,5S)-2,5-dimethyl-2,3,5,6-tetrahydro-[1,2']bipyrazinyl-4-yl)ethanone;
- Compound 103: 1-(4-benzoEb]thiophen-7-y]-3,6-dihydro-2H-pyridin-1-yl)-2-[8-
(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl3ethanone;
- Compound 104: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-
(6-trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 105: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(4-
quinolin-2-ylpiperazin-1-yl)ethanone;
- Compound 106: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-
(7-chloro-quinolin-4-yl)piperazin-1-yl]ethanone;
- Compound 107: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-
(5-chloro-pyridin-2-y[)piperazin-1-yl]ethanone;
- Compound 108: 2-[4-(6-chloropyridin-2-yl)piperazin-1-yl]-1 -[4-(1 H-indol-3-yl)-
3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 109: 1-[4-(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-[4-(5-
trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 110: 2-((2S,6R)-2,6-dimethyl-4-quinolin-2-yl-piperazin-1-yl)-1-[4-
(1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 111: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-(4-
pyridin-3-yl[1,4]diazepan-1-yl)ethanone;
- Compound 112: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-
(5,6-dichloropyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 113: 1 -(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[4-
(6-bromopyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 114: 1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-
1-yl]-2-(4-quinolin-2-ylpiperazin-1-yl)ethanone;
- Compound 115: 1-(4-benzo[b]thiophen-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[5-
(6-trifIuoromethylpyridazin-3-yl)-2,5-diazabicyclo[2.2.13hept-2-yl]ethanone;
- Compound 116: 1-[4-(2-methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-
1-yl]-2-[4-{6-trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound______117: 2-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]-1-[4-(2-
methylbenzo[b]thiophen-5-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
- Compound 118: 4-[2-oxo-2-(4-thieno[3,2-c]pyridin-4-yl-3,6-clihydro-2H-pyridin-
1-yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound 119: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-
2,6-dimethyl-4-(5-thiazol-2-yIpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound 120: 1-(4-benzofuran-7-yl-3,6-dihydro~2H-pyridin-1-yl)-2-{(2S,6R)-
2,6-dimethyl-4-[5-(2-methyl-2H-tetrazol-5-yl)pyridin-2-yl]piperazin-1-
yl}ethanone;
- Compound 121: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-
yl)piperazin-1-yl]-1-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethanone;
- Compound 122: 4-[2-oxo-2-(4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)ethyl]-
1-(5-trifIuoromethylpyridin-2-yl)piperazin-2-one;
- Compound 123: 1-{4-quinolin-2-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[8-(5-
trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound 124: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-{8-[5-(1-
methyl-1H-tetrazol-5-yl)pyridin-2-yl]-3,8-diazabicyclo[3.2.1]oct-3-yl}ethanone;
- Compound 125: 1-(4-benzofuran-7-yl-3,6-dihydro-2H-pyridin-1-yl)-2-[(2S,6R)-
4-(5-methanesulfonyI-pyridin-2-yl)-2,6-dimethylpiperazin-1-yl]ethanone;
in the form of a base or of an acid-addition salt.
7. A process for preparing a compound of formula (I) as claimed in any one
of claims 1 to 6, characterized in that a compound of formula (II):
in which A, B, m and n are defined according to any one of claims 1 to 6 and Hal
represents a halogen atom,
and a compound of general formula (III):
H-W-R2
(III)
in which W and R2 are defined according to any one of claims 1 to 6, are reacted
together.
8. A compound of formula (II):
(II)
in which A, B, m and n are defined according to any one of claims 1 to 6 and Hal
represents a halogen atom;
except for 2-chloro-1-[4-(2-methoxyphenyl)-3,6-dihydro-2H-pyridin-1-yl]ethanone
and 2-chloro-1-[4-(4-bromophenyl)-3,6-dihydro-2H-pyridin-1-yl]ethanone;
in the form of the base or of an acid-addition salt.
9. A medicament, characterized in that it comprises a compound of formula (I) as
claimed in any one of claims 1 to 6, or an addition salt of this compound with a
pharmaceutically acceptable acid.
10. A pharmaceutical composition, characterized in that it comprises a compound
of formula (I) as claimed in any one of claims 1 to 6, or a pharmaceutically
acceptable salt, and also at least one pharmaceutically acceptable excipient.
11. The compound as claimed in any one of claims 1 to 6, as a medicament.
12. The compound as claimed in any one of claims 1 to 6, for the preparation of a
medicament for preventing or treating central and peripheral neurodegenerative
diseases, senile dementia, epilepsy, Alzheimer's disease, Parkinson's disease,
Huntington's chorea, Down's syndrome, prion diseases, amnesia, schizophrenia,
depression, bipolar disorder, amyotrophic lateral sclerosis, multiple sclerosis,
cardiovascular disorders, post-ischemic heart damage, cardiomyopathies,
myocardial infarction, cardiac insufficiency, cardiac ischemia, cerebral infarction;
peripheral neuropathies, optic nerve and retinal damage, retinal pigment
degeneration, glaucoma, retinal ischemia, macular degeneration, spinal cord
trauma, cranial trauma, atherosclerosis, stenosis, wound healing disorders,
alopecia, pancreatitis, hepatic fibrosis, cancers, tumors, metastases, leukemias,
respiratory disorders, pulmonary inflammation, allergy, asthma, chronic
obstructive pulmonary disease, cutaneous, somatic, visceral and neurological
pain, chronic neuropathic and inflammatory pain, autoimmune diseases,
rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis,
bone fractures, bone diseases and osteoporosis.
13. The compound as claimed in claim 12, having the capacity to inhibit
dimerization of the p75NTR receptor independently of its ligand.
14. The use of a compound as claimed in one of claims 1 to 6, for the preparation
of medicaments that are useful in the treatment and prevention of central and
peripheral neurodegenerative diseases, senile dementia, epilepsy, Alzheimer's
disease, Parkinson's disease, Huntington's chorea, Down's syndrome, prion
diseases, amnesia, schizophrenia, depression, bipolar disorder, amyotrophic
lateral sclerosis, multiple sclerosis, cardiovascular disorders, post-ischemic heart
damage, cardiomyopathies, myocardial infarction, cardiac insufficiency, cardiac
ischemia, cerebral infarction; peripheral neuropathies, optic nerve and retinal
damage, retinal pigment degeneration, glaucoma, retinal ischemia, macular
degeneration, spinal cord trauma, cranial trauma, atherosclerosis, stenosis,
wound healing disorders, alopecia, pancreatitis, hepatic fibrosis, cancers, tumors,
metastases, leukemias, respiratory disorders, pulmonary inflammation, allergy,
asthma, chronic obstructive pulmonary disease, cutaneous, somatic, visceral and
neurological pain, chronic neuropathic and inflammatory pain, autoimmune
diseases, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque
psoriasis, bone fractures, bone diseases and osteoporosis.

ABSTRACT

The invention relates to (heterocycle/tetrahydropyridine)-(piperazinyl)-1-alcanone and
(heterocycle/dihydropyrrolidine)-(piperazinyl)-1-alcanone derivatives of the general formula (I), where A, W, n, and R2 are as
defined in claim 1. The invention moreover relates to the method for preparing said derivatives and to the therapeutic use of said
derivatives.