NOVEL (HETEROCYCLE/CONDENSED PIPERIDINE)-(PIPERAZINYL)-1-ALKANONE
OR (HETEROCYCLE/CONDENSED PYRROLIDINE)-(PIPERAZINYL)-1-ALKANONE
DERIVATIVES AND USE THEREOF AS p75 INHIBITORS
The subject of the present invention is (heterocycle-fused piperidine)-(piperazinyl)-
1 -alkanone derivatives and (heterocycle-fused pyrrolidine)-(piperazinyl)-1 -alkanone
derivatives, the preparation thereof and the therapeutic use thereof.
The compounds according to the present invention have an affinity for the p75NTR
neurotrophin receptor.
Neurotrophins belong to a family of proteins of which the biological effect is in
particular cell survival and differentiation.
The p75NTR receptor, which is the receptor for all neurotrophins, is a
transmembrane glycoprotein of the tumoral necrosis factor (TNF) receptor family
(W.J.Friedman and L.A.Greene, Exp. Ceil. Res., 1999,253, 131-142). The p75NTR
receptor is expressed in several cell types, and several biological functions have been
attributed to said receptor: firstly, modulation of the affinity of neurotrophins for receptor
tyrosine kinases (trk); secondly, in the absence of trk, induction of a signal for cell death
by apoptosis. Moreover, the neurotrophin precursors, proneurotrophins, are capable of
binding to p75NTR with a high affinity, and are considered to be powerful inducers of
p75NTR-dependent apoptosis in neurons and certain cell lines.
At the level of the centra! nervous system, many studies show that apoptosis is
involved in several pathological conditions, 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 diseases, such as 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 the mechanisms
resulting in post-ischaemic apoptotic neuron death (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 that p75NTR plays an important role in neuron death induced by the infectious
prion protein (transmissible spongiform encephalopathy) or by beta-amyloid protein
(Alzheimer's disease).
The p75NTR receptor is also associated with the Nogo receptor and involved in the
signalling of the inhibitory effects of these myelin proteins with respect to axon growth. As
a result, the p75NTR receptor plays a major rote in the regulation of 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 could play a role in cardiovascular diseases, such as
atherosclerosis and myocardial ischaemia (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, nerve damage appears to selectively increase the expression and the axonal
transport of p75NTR, implicated in the induction of neuropathic pain. Furthermore, the use
of a p75NTR-specific antibody or of oligodeoxynucleotide antisense capable of blocking the
activity of the receptor in vivo appears to be capable of reversing neuropathic pain (heat
and cold 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 inflammatory pain induced by the injection of
an adjuvant into the plantar arch in mice, and also in a model of sciatic nerve crush in
mice (Watanabe T. et a!., J. Neurosci. Res. 2008; 86: 3566-357; Fukui Y. et al. J Orthop
Res. 2010; 28(3): 279-83).
The expression of p75NTR is also described in chronic pancreatitis, with implication
in the apoptotic process 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 an essential role in tumour biology.
Many compounds are known to interact with the trkA/NGF/p75NTR system or to
have an NGF-type (nerve growth factor) activity. Thus, patent application WO 00/59893
describes substituted pyrimidine derivatives which have an NGF-type activity and/or which
increase the activity of NGF on PC12 cells.
The subject of the present invention is the compounds corresponding to formula {!):

in which:
- A represents a group:
- n represents 1 or 2;
- m represents 0 or 1;
- Y represents a carbon, nitrogen, sulphur or oxygen atom or a single or double bond;
- X, X1 and X2 represent a carbon, nitrogen, sulphur or oxygen atom, it being understood
that at least one of X, X1 and X2 is other than a carbon atom;
- R and R1, located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (C1-C4)alkyl group, a (C1-C4)alkoxy group, a
perfluoroalkyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COOalkyl,
CONR5R6 or NHCOR5 group;
or R1 represents a group chosen from:

the definition of R remaining unchanged;
- R3 and R4, located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (C1-C4)alkyl group, a (Cl-C4)aIkoxy group, a
perfluoroalkyl radical, a trifiuoromethoxy radical, a cyano, or a COOH, COOalkyi,
CONR5R6 or NHCOR5 group;
- -W- is a nitrogenous heterocycle chosen from:
-1-2 represents i ori;;
-1-3 represents 1, 2 or 3;
- R2 represents a group of formula:

- R7 and R8, located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (C1-C4)alkyl group, a (C1-C4)aikoxy group, a
trifluoromethyl radical, a trifiuoromethoxy radical, a cyano, or a COOH, COOalkyi,
COOcycloalkyl, SOaikyl, SO2alkyl, CONH2, CONR5R6 or NHCOR5 group;
or one of R7 and R8 represents a heterocycle chosen from:

Z represents an oxygen or sulphur atom;
- R5 and R6 represent a hydrogen or a C1-C6 alkyl group.
The compounds of formula (I) may comprise one or more asymmetrical carbon
atoms. They may therefore 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 addition salts with
acids. 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 term "a halogen atom" is intended to mean: a fluorine, a chlorine, a bromine
or an iodine;
- the term "an alkyl group" is intended to mean: a linear, branched or cyclic,
saturated aliphatic group. By way of examples, mention may be made of a C1-C4 alkyl
group which may represent a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,
cyclopropyl or cyclobutyl;
- the term "a fluoroaikyl group" is intended to mean: an alkyl group of which one
or more hydrogen atoms have been substituted with a fluorine atom;
- the term "a perfluoroaikyl group" is intended to mean: an alkyl group of which all
the hydrogen atoms have been substituted with a fluorine atom, for example a
trifluoroalkyl group such as trifiuoromethyl;
- the term "an alkoxy group" is intended to mean: an -O-alkyl radical where the
alkyl group is as defined above;
- the term "a perfluoroalkoxy group" is intended to mean: an alkoxy group of
which all the hydrogen atoms have been substituted with a fluorine atom, for
example a trifluoroalkoxy group such as trifluoromethoxy;
the term "a cycloalkyf group" is intended to mean: a cyclic alkyl group. By way
of examples, mention may be made of cyclopropyl, methylcyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyi, etc., groups.
Among the compounds of formula (I) which are subjects of the invention, another
group of compounds consists of the compounds of formula (I) in which:
- n represents 1; and/or
- m represents 0 or 1; and/or
- Y represents a nitrogen atom, or a single or double bond; and/or
- X, X1 and X2 represent a carbon, nitrogen or sulphur atom, it being understood that at
least one of X, X1 and X2 is other than a carbon atom; and/or
- R and R1, located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom or a (C1-C4) alkyl group;
or else
R1 represents a group:

and R is a hydrogen atom; and/or
- R3 and R4, located on any one of the available positions, represent a hydrogen atom, a
halogen atom, a (C1-C4) alkoxy group or a perfluoroalkyl radical; and/or
- -W- represents:

- R7 and R8, located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (C1-C4)alkyl group, a trifluoromethy! radical, or a
COOH, COOalkyl, SOalkyl or SO2alky! group;
or else
one of R7 and R8 represents a heterocycie chosen from:

- R5 and R6 represent a hydrogen atom or a methyl group;
in the form of a base or of an addition salt with an acid.
Among the compounds of formula (!) which are subjects of the invention, mention
may in particular be made of the following compounds:
- Compound No. 1: 1 -(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2-[8-(5-fiuoropyrimidin-
2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 2: 2-[8-(5-fluoropyrimidin-2-y!)-3,8-diazabicyclo[3.2.1 ]oct-3-yl]-1 -{2-
phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound No. 3: 1-(2-chloro-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-2-[8-(5-
fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl3ethanone;
- Compound No. 4: 2-[8-(5-fluoropyrimidin-2-yi)-3,8-diazabicyclo[3.2.1 ]oct-3-yl]-1 -(2-
phenyl-2,4,6,7-tetrahydropyrazoIo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 5: 6-{3-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid methyl ester;
- Compound No. 6: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-6,7-dihydro~4H-
thiazolo[5,4-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid;
- Compound No. 7: 6-{3-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yl)ethyi]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound No. 8: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-
thiazolo[5,4-c3pyridin-5-yi)ethyl3piperazin-1-yl}nicotinic acid;
- Compound No. 9: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifIuoromethylpyridin-2-yi)piperazin-1-
yl3-1-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound No. 10: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-
1-yl]-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 11: 4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazo!o[5,4-c]pyridin-5-
yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 12: 1-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-[4-(5-
trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound No. 13: 1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-[4-(5-
trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound No. 14: 4-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethyl]-1-(5-trifiuoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 15: 2-[(2S,6R)-4-(5-fiuoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]-1-
(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound No. 16: 2-((2S,6R)-2,6-dimethyl-4-pyrimidin-5-yl-piperazin-1 -yl)-1 -(2-
phenyf-2,4,6,7-tetrahydropyrazolo[4,3-c3pyridin-5-yl)ethanone;
- Compound No. 17: 2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1 -yl]-1 -
(2-phenyl-2,4,6,74etrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 18: 2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-
1-yl]-1-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound No. 19: 6-{3-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
y!)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid methyl ester;
- Compound No. 20: 2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yi)piperazin-
1-yl]-1-(2-phenyl-2,4,6,7-tetrahydropyrazo!o[4,3-c]pyridin-5-yl)ethanone;
- Compound______No. 21: 6-{(3S,5R)-315-dimethyl-4-[2-oxo-2-(2-pheny[-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinicacid;
- Compound No. 22: 2-((2S,6R)-2,6-dimethyl-4-pyrimidin-5-yl-piperazin-1 -yl)-1 -(2-
phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound No. 23: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yi)ethyl]piperazin-1-yl}nicotinic acid methyl ester;
- Compound No. 24: 6-{3-[2-oxo-2-(2-phenyI-2,4,6,7-tetrahydropyrazoio[4,3-c]pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1 ]oct-8-yl}nicotinic acid;
- Compound No. 25: 6-{2-oxo-4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-
c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid methyl ester;
- Compound No. 26: 2-[8-(5-fIuoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-(1-
phenyI-1,4,6,7-tetrahydropyrazo!o[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 27: 1-{2-phenyl-2,4,6,7,-tetrahydropyrazoio[4,3-c]pyridin-5-yl)-2-(4-
pyridin-3-yl[1,4]diazepan-1-yl)ethanone;
- Compound No. 28: 1-(2-phenyl-2,4,6,7-tetrahydropyrazo(o[4,3-c]pyridin-5-yl)-2-(8-
pyr!din-3-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
- Compound No. 29: 1-(2-pheny!-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-[8-(5-
trifluoromethylpyridin-2-yl)-3,8-diazabicycio[3.2.1]oct-3-yl]ethanone;
- Compound No. 30: 1 -{2-phenyl-6,7-dihydro-4H-thiazolot5,4-c]pyridin-5-yl)-2-(4-pyridin
-3-yl-[l ,4]diazepan-1 -yl)ethanone;
- Compound No. 31: 1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-(8-
pyrimidin-5-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
- Compound No. 32: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-{2-
methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 33: 6-{3-[2-oxo-2-(2-phenvl-4,6-dihvdropvrrolor3,4-d]thiazol-5-yl)ethyn-
3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid methyl ester;
- Compound No. 34: 4-{2-[2-(4-methoxyphenyl)-2,4,6,7-tetrahydropyrazolo[4,3-
c]pyridin-5-yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 35: 4-{2-[2-(4-fluorophenyl)-2,4,6,7-tetrahydropyrazolo[413-c]pyridin-5-
yl]-2-oxoethyl}-1-(5-trifluoromethy!pyridin-2-yl)piperazin-2-one;
- Compound No. 36: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-(2-
methyl-6,7-dihydro-4H-thiazolo[5,4-c3pyridin-5-yl)ethanone;
- Compound No. 37: 6-(3-{2-[2-(4-methoxyphenyl)-6,7-dihydro-4H-thiazolo[5,4-
c]pyridin-5-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.13oct-8-yl)nicotinic acid methyl ester;
- Compound No. 38: 6-(3-{2-[2-(4-fluorophenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yI]-2-oxoethyi}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotjnic acid methyl ester;
- Compound______No. 39: 6-(3-{2-oxo-2-[2-(5-trifluoromethylpyridin-2-yl)-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinic
acid methyl ester;
- Compound No. 40: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[2-
(5-trifluoromethylpyridin-2-yl)-2T4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone;
- Compound No. 41: 4-[2-oxo-2-(2-phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-
yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl}piperazin-2-one;
- Compound No. 42: 4-[2-oxo-2-(2-thiophen-3-yl-6,7-dihydro-4H-thiazoto[5,4-c]pyridin-
5-yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 43: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicycIo[3.2.1]oct-3-yl]-1-[2-
(4-methoxyphenyl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone;
- Compound No. 44: 6-{3-[2-oxo-2-(2-thiophen-3-yl-6,7-dihydro-4H-thiazolo[5,4-
c]pyridin-5-yl)ethyl]-3,8-diazabicyclo[3.2.1 ]oct-8-yl}nicotinic acid;
- Compound No. 45: 2-[8-(5-fiuoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.l3oct-3-yl3-1-E1-
(2,2,2-trif!uoroethyl)-4,5,6,7-tetrahydro-1H-indazol-5-yl3ethanone;
- Compound No. 46: 2-[8-{5-fIuoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[1-
(4-methoxyphenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c3pyridin-5-yl]ethanone;
- Compound No. 47: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicycfo[3.2.1 ]oct-3-yl]-1 -
(2,4,6,7-tetrahydropyrazoio[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 48: 6-{3-[2-oxo-2-(1-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid methyl ester;
- Compound No. 49: 6-{3-[2-oxo-2-(1-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yf}nicotinic acid;
- Compound No. 50: 1-(1-tert-buty!-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-[8-
(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 51: 1-[1-(4-fluorophenyl)-1,4,6,7-tetrahydropyrazoio[4,3-c]pyridin-5-yl]-
2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 52: 6-{(2R,5S)-2,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinonitrile;
- Compound______No. 53: 6-{(2R,5S)-2,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid;
- Compound No. 54: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicycloE3.2.1]oct-3-yl]-1-(2-
phenyl-4,7-dihydro-5H-fluoro[2,3-c]pyridin-6-yl)ethanone;
- Compound No. 55: 2-[8-(5-f!uoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1 ]oct-3-yl]-1-(2-
pheny!-1,4,5,7-tetrahydropyrrolo[2,3-c]pyridin-6-yl)ethanone;
- Compound No. 56: 6-{8-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}nicotinic acid methyl ester;
- Compound No. 57: 6-{8-E2-oxo-2-(2-phenyt-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethyl]-3,8-diazabicycioE3.2.1]oct-3-yl}nicotinic acid methyl ester;
- Compound No. 58: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.13oct-3-yl]-1-(2-
phenyl-6,7-dihydro-4H-oxazolo[4,5-c]pyridin-5-yl)ethanone;
- Compound No. 59: 6-{(2R,5S)-2,5-dimethyt-4-[2-oxo-2-(2-phenyl~6,7-dihydro-4H-
thiazolo[5,4-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinonitrile;
- Compound No. 60: 2-{8-[5-(5-methyl-[1,2,4]oxadiazoI-3-yl)pyridin-2-yl]-3,8-
diazabicyclo[3.2.1]oct-3-yl}-1-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yl)ethanone;
- Compound No. 61: 6-{8-[2-oxo-2-(2-phenyi-2,4,6,7-tetrahydropyrazolo[4,3-c] pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}nicotinic acid;
- Compound No. 62: 6-{8-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}nicotinic acid;
- Compound No. 63: 6-{(2R,5S)-2,5-dimethyl-4-E2-oxo-2-(2-phenyl-6,7-dihydro-4H-
thiazolo[5,4-c]pyridin-5-yl)ethyl]piperazin-l-yl}nicotinic acid;
- Compound No. 64: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1 ]oct-3-yl]-1 -(2-
pyridin-4-yl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound_______No. 65: 4-{2-oxo-2-[2-(5-trifluoromethylpyridin-2-yl)-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethyl}-1-{5-trifluoromethylpyridin-2-yl)piperazin-2-
one;
- Compound No. 66: 4-{2-oxo-2-[1-(2,2,2-trifluoroethyl)-1,4,6,7-tetrahydropyrazolo [4,3-
c]pyridin-5-yI]ethyf}-1-(5-trifIuoromethyipyridin-2-yl)piperazin-2-one;
- Compound No. 67: 2-[8-(5-fIuoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yI]-1-{2-
phenyl-7,8-dihydro-5H-pyrido[4I3-d]pyrimidin-6-yl)ethanone;
- Compound No. 68: 3-(6-{3-[2-oxo-2-(2-phenyl-2,416,7-tetrahydropyrazolo[4,3-c]
pyridin-5-yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}pyridin-3-yl)-4H-[1,2,4]oxadiazol-5-
one;
- Compound No. 69: 2-[8-(5-fluoropyrimidin-2-yI)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-{2-
phenyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)ethanone;
- Compound No. 70: 3-(6-{3-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yi)ethyl]-3,8-diazabicycloE3.2.1]oct-8-yl}pyridin-3-yl)-4H-[1,2,4]oxadiazol-5-one;
- Compound No. 71: 2-[8-(5-fluoropyrimidin-2-yl}-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-(2-
phenyl-6,7-dihydro-4H-thiazolo[4,5-c]pyridin-5-yl)ethanone;
- Compound No. 72: 2-{(3S,5R)-3,5-dimethy!-4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-
thiazolo[5,4-c]pyridin-5-yl)ethyl]piperazin-1-yl}pyrimidine-5-carboxylic acid;
- Compound No. 73: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-y!]-1-(2-
pyridin-3-y!-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound No. 74: 1 -(2-phenyl-6,7-dihydro-4H-thiazoio[5,4-c]pyridin-5-yl)-2-{8-[5-(1 H-
tetrazol-5-yl)pyridin-2-yl]-3,8-diazabicyclo[3.2.1]oct-3-yl}ethanone;
- Compound No. 75: 2-{(3S,5R)-3,5-dimethyi-4-[2-oxo-2-(2-phenyi-2,4I6,7-
tetrahydropyrazolo[4,3-c3pyridin-5-yl)ethyl3piperazin-1-yl}pyrimidine-5-carboxylic acid;
- Compound No. 76: 6-(3-{2-[2-(4-fluoropheny!)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yi3-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinonitrile;
- Compound No. 77: 6-{3-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethyl]-3,8-diazabtcyclo[3.2.1]oct-8-yl}nicotinonitrile;
- Compound No. 78: 4-[2-oxo-2-(2-phenyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-
yl)ethyl3-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 79: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid ethyl ester;
- Compound No. 80: 1 -[2-(4-fluorophenyl)-6,7-dihydro-4H-thiazolo[5,4-c3pyridin-5-yl]-2-
[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 81: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.13oct-3-yl]-1-[2-
{4-methoxyphenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]ethanone;
- Compound No. 82: 4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[4,5-c]pyridin-5-
yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 83: 4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-oxazolo[4,5-c3pyridin-5-
yt)ethyl]-1-{5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 84: 4-E2-oxo-2-(2-pyridin-3-yl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yl)ethyl3-1-(5-trifluoromethy!pyridin-2-yl)piperazin-2-one;
- Compound No. 85: 2-{8-[5-(2-methy!-2H-tetrazol-5-yl)pyridin-2-yl]-3,8-diazabicyclo
[3.2.1]oct-3-yl}-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yi)ethanone;
- Compound No. 86: 2-{(2S,6R)-2,6-dimethyl-4-[5-(1-methyl-1H-tetrazol-5-yl)pyridin-2-
yl]piperazin-1-yl}-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 87: 2-{(2S,6R)-2,6-dimethyl-4-[5-(2-methyl-2H-tetrazol-5-yl)pyridin-2-
yi]piperazin-1-yl}-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-y!)ethanone;
- Compound No. 88: 2-[8-(5-fIuoropyrimidin-2-yl)-3,8-diazabicycloE3.2.1]oct-3-yi]~1-[1-
(4-trifluoromethylpheny!)-1,4,6)7-tetrahydropyrazolo[4,3-c]pyridin-5-yf]ethanone;
- Compound No. 89: 2-{(2S,6R)-2,6-dimethyl-4-[5-(5-methyl[1,2,4]oxadiazol-3-yl)-
pyridin-2-yl]piperazin-1-yl}-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethanone;
- Compound No. 90: 2-[(2S,6R)-2,6-dimethyl-4-(5-[1,3l4]oxadiazol-2-ylpyridin-2-
yl)piperazin-1-yl]-1-{2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 91: 2-{(2S,6R)-2,6-dimethyl-4-[5-(3-methyl-[1,2,4]oxadiazoI-5-yl)-
pyridin-2-yl3piperazin-1-yl}-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethanone;
- Compound No. 92: 6-{(3S,5R)-4-[2-(1-tert-butyl-1,4,6,7-tetrahydropyrazolo[4,3-
c]pyridin-5-yl)-2-oxoethyl]-3,5-dimethyIpiperazin-1-yl}nicotinic acid methyl ester;
- Compound No. 93: 6-{(3S,5R)-4-[2-(1-tert-buty!-1,4,6,7-tetrahydropyrazoio[4,3-
c]pyridin-5-yl)-2-oxoethyl3-3,5-dimethylpiperazin-1-yl}nicotinic acid;
- Compound No. 94: 6-{3-[2-( 1 -tert-butyl-1 ^.ej-tetrahydropyrazolo[4,3-c]pyridin-S-yl)-
2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound No. 95: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-(2-
phenyl-6,7-dihydro-4H-oxazolot5,4-c]pyridin-5-yl)ethanone;
- Compound No. 96: 4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-
yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 97: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-
1-yl]-1-(2-phenyl-4,7-dihydro-5H-fluoro[2,3-c]pyridin-6-yl)ethanone;
- Compound No. 98: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-{2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid isopropyl ester;
- Compound No. 99: 1-(2-methyl-2,4,6I7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-[8-(5-
trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 100: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-
1-yl]-1-(2-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 101: 1-(2-phenyl-4,7-dihydro-5H-fIuoro[2,3-c]pyridin-6-yl)-2-[8-(5-
trifiuoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 102: 6-(3-{2-[2-(4-fluoropheny!)-6,7-dihydro-4H-thiazolo[5,4-c] pyridin-
5-yl3-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinic acid;
- Compound No. 103: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-
1-yl]-1-[-2-(5-trifluoromethyipyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[.4,3-c]pyridin-5-
yl]ethanone;
- Compound No. 104: 2-r8-f5-trifluoromethvlpvridin-2-yl)-3.8-diazabicvclo(3.2.1]oct-3-yl]-
1-yl]-1-[-2-(5-trifluoromethyipyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[.4,3-c]pyridin-5-
yl]ethanone;
- Compound No. 105: 6-{(3S,5R)-4-[2-{2-tert-butyl-2,4,6,7-tetrahydropyrazolo[4,3-
clpyridin-
5-yl3-2-oxoethyl}3,5-dimethylpiperazin-l-ylJnicotinicacid;
- Compound No. 106: 2-(8-pyridin-3-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)-1-[2-(5-
tnfluoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazoio[4,3-c]pyriclin-5-yl]ethanone;
- Compound No. 107: 2-[5-(6-trifluoromethylpyridazin-3-yl)-2,5-diazabicyclo[2.2.1] hept-
2-yl]-1-[2-(5-trifiuoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazoio[4,3-c] pyridin-5-
yl]ethanone;
- Compound No. 108: 2-(6,-chloro-2,3,5,6-tetrahydro[1,2']bipyrazinyl-4-yl)-1-[2-(5-
trifluoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone;
- Compound No. 109: 1-(2-phenyl-3,4l6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)-2-[8-(5-
trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 110: 2-[(2S,6R)-2,6-dimethy]-4-(5-trifluoromethy!pyridin-2-yl)piperazin-
l-yl]-1-phenyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)ethanone;
- Compound No. 111: 2-({3S,5R)-3,5-dimethyl-2,3,5,6-tetrahydro[1,2']bipyrazinyl-4-yI)-
1-[2-(5-trifluoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl]ethanone;
- Compound No. 112: 2-[(2S,6R)-4-(5-chloropyridin-2-yl)-2,6-dimethylpiperazin-1 -yl]-1 -
[2-(5-trifluoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl]ethanone;
- Compound No. 113: 2-[4-(7-chloroquinolin-4-yl)piperazin-1 -yl]-1 -(2-phenyi-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 114: 2-[4-(6-ch]loropyridin-2-yl)piperazin-1 -yl]-1 -(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 115: 1-(2-pyridin-4-yl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-[8-
(5-trifluoromethy!pyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 116: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-3,4,617-
tetrahydroimidazo[4,5-c]pyridin-5-yl)ethy!3piperazin-1-yi}nicotinic acid;
- Compound No. 117: 1-(2-pyridin-2-yl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-
[8-(5-trifluoromethyIpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yI]ethanone;
- Compound No. 118: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifIuoromethyipyridin-2-yl)piperazin-
1-yl]-1-(2-pyridin-2-yl-2,4,6I7-tetrahydropyrazolo[4,3-c]pyridin~5-yi)ethanone;
- Compound No. 119: 4-[2-oxo-2-(2-pyridin-2-y!-2,4,6,7-tetrahydropyrazoio[4,3-c3
pyridin-5-yl)ethyl]-1-(5-trifIuoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 120: 4-{2-[2-(4-fiuorophenyl)-3,4,6,7-tetrahydroimidazo[415-c]pyridin-5-
yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 121: 2-(8-pyridin-3-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)-1-(2-pyridin-2-yl-
2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 122: 1-[2-(2,2,2-trifluoroethyl)-2,4,6,7-tetrahydropyrazoloE4I3-c]pyridin-
5-yl]-2-[8-(5-trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 123: 1-[2-(4-fluorophenyl)-3,4,6,7-tetrahydroimidazo[4,5-c3pyridin-5-
yl]-2-[8-(5-trifluoromethylpyridin-2-yi)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 124: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-
1-yl]-1-[2-(4-fluoropheny!)-3,4,6,7-tetrahydroimidazo[4,5-c3pyridin-5-yl]ethanone;
- Compound No. 125: 4-{2-oxo-2-[2-(2,2,2-trifluoroethyl)-2,4,6,7-tetrahydropyrazolo
[4,3-c]pyridin-5-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 126: 2-[{2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-y!)piperazin-
1-yl]-1-[2-(2,2,2-trifluoroethyl)-2,4,6,7-tetrahydropyrazolo[4,3-c3pyridin-5-yl]ethanone;
- Compound No. 127: 1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-[5-(5-
trifluoromethylpyridin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethanone;
- Compound No. 128: 6-{3-[2-oxo-2-(2-phenyl-214,6,7-tetrahydropyrazolo[4,3-c]pyridin-
5-yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid cyclobutyl ester;
- Compound No. 129: 2-((2S,6R)-2,6-dimethyl-4-quinoIin-2-ylpiperazin-1 -yl)-1 -(2-
phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yi)ethanone;
- Compound No. 130: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4,617-
tetrahydropyrazoIo[4,3-c]pyridin-5-yi)ethyl]piperazin-1-yl}nicotinic acid ethyi ester;
- Compound_______No. 131: 2-[(2S,6R)-4-(5-methanesulphonylpyridin-2-yl)-2,6-
dimethyfpiperazin-1-yi]-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethanone;
- Compound No. 132: 2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1 -yl]-
1-[2-(4-methoxyphenyl)-6,7-dihydro-4H-thiazoIo[5,4-c]pyridin-5-yl]ethanone;
- Compound No. 133: 1-[2-(4-methoxyphenyl)-6,7-dihydro-4H~thiazolo[5,4-c]pyridin-5-
yl]-2-[5-(5-trifluoromethylpyridin-2-yl)-2,5-diazabicyclo[2.2.13hept-2-yl]ethanone;
- Compound No. 134: 1-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-{4-[5-
(2H-pyrazol-3-yl)pyridin-2-yl]piperazin-1-yl}ethanone;
- Compound No. 135: 2-[(2S,6R)-2,6-dimethyl-4-(5-thiazol-2-ylpyridin-2-yi)piperazin-1 -
yl]-1-(2-pheny[-2,4,6,7-tetrahydropyrazolo[4,3-c3pyridin-5-yl)ethanone;
- Compound No. 136: 1-(2-phenyi-6,7-dihydro-4H-thiazo[o[5,4-c3pyridin-5-yl)-2-t8-(5-
thiazol-2-ylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 137: 2-[8-(5-[1,2,4]oxadiazol-3-ylpyridin-2-yl)-3,8-diazabicyclo
t3.2.1]oct-3-yl]-1-(2-pheny!-2I4,6,7-tetrahydropyrazolo[4,3-c3pyridin-5-yl)ethanone;
- Compound No. 138: 1-(2-ethyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-[8-(5-
trifluoromethylpyridin-2-yl)-3,8-dia2abicycIo[3.2.1]oct-3-yl]ethanone;
- Compound No. 139: 2-[(2S,6R)-2,6-dimethy!-4-(5-[1I2,43oxadiazol-5-ylpyridin-2-
yl)piperazin-1-y(]-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 140: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-pyridin-2-yl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinicacid;
- Compound No. 141: 2-((2S,6R)-2,6-dimethyl-4-pyridin-3-ylpiperazin-1 -yl)-1 -(2-pyridin-
4-yl-2,4,6,7-tetrahydropyrazolo[413-c]pyridin-5-yl)ethanone;
- Compound No. 142: 2-((2S,6R)-2,6-dimethyl-4-pyridin-3-ylpiperazin-1-yl)-1-[2-(5-
fluoropyridin-2-yl)-2,4l6,7-tetrahydropyrazo!o[4,3-c]pyridin-5-y!3ethanone;
- Compound No. 143: 2-((2S,6R)-2,6-dimethyl-4-pyridin-3-ylpiperazin-1-yl)-1-[2-(5-
trifluoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone;
- Compound No. 144: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-pyridin-2-yi-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid methyl ester;
- Compound No. 145: 2-((2S,6R)-2,6-dimethyl-4-pyridin-3-ylpiperazin-1 -yl)-1 -(2-phenyl-
3,4,6,7-tetrahydroimidazo[4,5-c}pyridin-5-yl)ethanone;
- Compound No. 146: 2-[(2S,6R}-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-
1-yl]-1-(2-pyridazin-3-yl-2)4I6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 147: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-
1-yl]-1-(2-ethyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 148: 4-[2-(2-ethyl-2,4,6,7-tetrahydropyrazolo[4,3-c3pyridin-5-yl)-2-
oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 149: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyrtdin-5-yl)ethyl3piperazin-1-yl}nicotinic acid;
- Compound No. 150: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid;
in the form of a base or of an addition salt with an acid.
In the subsequent text, the term "protective group Pg" is intended to mean a group
which 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 synthesis. Examples of protective groups and also methods of protection and of
deprotection are given in Protective Groups in Organic Synthesis, Green et a!., 2nd
Edition (John Wiley & Sons, Inc., New York).
In accordance with the invention, the compounds of general formula (I) are
prepared according to the process which follows.
More specifically, the process for preparing the compounds of general formula (I) in
which R, R1, X, X1, X2, Y, W, R2, m and n are as defined above comprises the reaction
of a compound of formula (II):
(II)
in which R, R1, X, X1, X2, Y, m and n are defined as in general formula (I) and Hal
represents a halogen atom, for example chlorine;
and of a compound of general formula (III):
H-W-R2
(llI)
in which W and R2 are defined as in 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, by way of base, mention may be made of organic bases such as
triethylamine, N.N-dllsopropylamine, 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 in the
presence of an alkali metal iodide such as potassium iodide or sodium iodide. The
reaction is carried out in a solvent such as acetonitrile, N.N-dimethylformamide (DMF), N-
methylpyrrolidinone, toluene or propan-2-ol, and at a temperature between ambient
temperature and the reflux temperature of the solvent. The "ambient temperature" is
intended to mean a temperature between 5 and 25°C. By way of example, the reaction
can be carried out in the presence of sodium bicarbonate and of sodium iodide in a
solvent such as DMF. These reactions can also be carried out in a microwave reactor.
In the compounds of general formula (I) thus obtained, R, R1, R3, R4, R5, R6, R7 and R8
can be modified by treatments commonly used by those skilled in the art, for instance by
hydrolysis of an ester group so as to give a carboxylic group or of a cyano so as to obtain
a tetrazole group.
Generally, the acid addition salts of the compounds of general formula (I) can be
obtained by addition of the appropriate acid, such as hydrochloric acid, hydrobromic acid
or oxalic acid.
The compounds of formula (III), optionally in the form of salts, can be prepared from
the corresponding compounds of the formula (VIII):
in which W and R2 are as defined in formula (I) and Pg represents a protective group for
a nitrogen atom of W. Preferably, Pg is a benzyl group and the deprotection is carried out
according to conventional methods well known to those skilled in the art, for example by
catalytic hydrogenation on Pd/C or by treatment with chloroformates followed by
hydrolysis in an acid medium.
The compounds of formula (VIII) can be prepared from the compounds of formula
(VI):
Pg-W-H
(VI)
and (VII):
Hal-R2
(VII)
in which Pg, W and R2 are defined as above and Hal represents a halogen atom,
preferably chlorine. This reaction is generally carried out under the same conditions as
the reaction for preparing the compounds of formula (I) from the compounds of formulae
(II) and (ill).
Alternatively, the compounds of formula (VIll) can be prepared by the Buchwald
coupling method in the presence of a palladium catalyst and of an opportunely chosen
phosphine, using, as solvent, inert solvents such as toluene or xylene, at a temperature
between ambient temperature and 110°C.
In the compounds of general formula (VIII) thus obtained, R7 and R8 can be modified by
treatments commonly used by those skilled in the art, for instance the synthesis of an
oxadiazole group from a cyano group, or else by Suzuki couplings as described in the
scheme below.

In Scheme 2 above, L represents a leaving group such as iodo, bromo or
trifluoromethanesulphonate; R7 represents a heterocycle as described in general formula
(I), R8 is as defined in general formula (I) and B represents 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 else can be
prepared, from the corresponding compounds of formula (VII), according to methods
which 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) can be obtained by reaction of a corresponding
compound of formula (IV):
in which R, R1, X, X1, X2, Y and m are defined as in general formula (I), optionally in the
form of an acid addition salt, and of 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 from Hal. Preferably, Hal' represents a chlorine
atom.
This reaction is generally carried out 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 ambient temperature. The compounds of formula (V)
are generally commercially available.
Optionally, the process according to the invention comprises the subsequent step
consisting in isolating the desired product obtained.
The products of formulae (IV), (V), (VI) and (VII), and the reactants, when their
method of preparation is not described, are commercially available or described in the
literature, or else can be prepared according to methods which are described or known to
those skilled in the art.
Alternatively, the compounds of formula (I) can be prepared according to Scheme 3
which follows:

More specifically, the process for preparing the compounds of general formula (I) in which
R, R1, X, X1, X2, Y, W, R2, m and n are as defined above and Q represents a residue
capable of forming an ester, such as methyl, ethyl or benzyl, comprises the reaction of a
compound of formula (XIV):

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

in which R, R1, X, X1, X2, Y and m are defined as in 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 condensation agent such
as BOP, DBU or DCC. The reaction is carried out at a temperature between ambient
temperature and the reflux temperature of the solvent. The term "ambient temperature" is
intended to mean a temperature between 5 and 25°C. By way of example, the reaction
can be carried out in the presence of sodium bicarbonate, of sodium iodide, in a solvent
such as DMF. These reactions can also be carried out in a microwave reactor.
In the compounds of general formula (!) thus obtained, R, R1, R3, R4, R5, R6, R7 and R8
can be modified by treatments commonly used by those skilled in the art, for example by
hydrolysis of an ester group so as to give a carboxylic group or of a cyano so as to give a
tetrazole group.
Generally, the acid addition salts of the compounds of general formula (I) can be
obtained by addition of the appropriate acid, such as hydrochloric acid, hydrobromic acid
or oxalic acid.
The compounds of formula (XIV) can be obtained from compounds of formula (XIII)

in which R2, W and n are defined as in general formula (I) and Q represents a
residue capable of forming an ester, such as methyl, ethyl or benzyl, by hydrolysis of the
ester bond according to methods known to those skilled in the art, for example by a
treatment in an acidic or basic aqueous medium, or else by reduction in a polar solvent
such as an alcohol or THF, under a hydrogen stream.
The compounds of formula (XIII) can be obtained from compounds of formula (III)
H-W-R2
(III)
in which R2 and W are defined as in 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 capable of forming an ester such as methyl, ethyl or
benzyl. Hal represents a halogen atom, preferably a chlorine atom, n is as defined in
general formula (I).
This reaction is generally carried out 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 ambient temperature. The compounds of formula (XII)
are generally commercially available.
The compounds of formula (III), optionally in the form of salts, can be prepared from
the corresponding compounds of formula (VIII):

in which W and R2 are as defined in formula (I) and Pg represents a protective group for
a nitrogen atom of W. Preferably, Pg is a benzyl group and the deprotection is carried out
according to conventional methods known to those skilled in the art, for example by
catalytic hydrogenation on Pd/C or by treatment with chloroformates followed by
hydrolysis in an acid medium.
The compounds of formula (VIII) can be prepared from the compounds of formula
(VI):
and (VII):
in which Pg, W and R2 are defined as above and Hal represents a halogen atom,
preferably chlorine. This reaction is generally carried out under the same conditions as in
the reaction for preparing the compounds of formula (1) from the compounds of formulae
(IV) and (XIV).
Alternatively, the compounds of formula (VIII) can be prepared by the Buchwald
coupling method in the presence of a palladium catalyst and of an opportunely chosen
phosphine, using, as solvent, inert solvents such as toluene or xylene, at a temperature
between ambient temperature and 110°C.
In the compounds of general formula (VIII) thus obtained, R7 and R8 can be modified by
treatments commonly used by those skilled in the art, for instance the synthesis of an
oxadiazole group from a cyano group, or else by Suzuki couplings as already described in
Scheme 2 already set out above.
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 can be
prepared, from the corresponding compounds of formula (VII), according to methods
which 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
consisting in isolating the desired product obtained.
The products of formulae (IV), (VI) and (VII), and the reactants, when their method
of preparation is not described, are commercially available or described in the literature,
or else can be prepared according to methods which 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 (II)
in which R1, R, X, X1, X2, Y, m, n and Hal are defined as above; in the form of a base or
of an addition salt with an acid. These compounds are of use as synthesis intermediates
for the compounds of formula (I).
The following examples describe the preparation of certain compounds in
accordance with the invention. These examples are not limiting and merely illustrate the
present invention. The numbers of the compounds exemplified refer back to those as
were given in the table hereinafter, which illustrates the chemical structures and the
physical properties of some compounds according to the invention.
The physicochemical measurements were carried out in the following way:
The melting points were measured with a Buchi B540 instrument.
The proton nuclear magnetic resonance (1H NMR) spectra were recorded under
the following conditions:
a) at 500 MHz on a Bruker instrument equipped with an Avance III console;
b) at 400 MHz on a Bruker instrument 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 interference with a broad peak due to water.
** = not integratable because of interference with a peak due to the NMR solvent.
2Xs = two partially superimposed singlets.
2Xbs = two partially superimposed broad singlets.
2Xm = two partially superimposed multiplets.
The HPLC was carried out by means of a ThermoElectron LCQ Deca XP Max
stem equipped with an ion trap mass spectrometry detector and a diode array detector.
The conditions for analysis by liquid chromatography coupled to mass
lectrometry (LC/UV/MS) are the following:
- chromatographic system A
- Eluent A = H20 + 0.01 % TFA
- Eluent B = CH3CN
- Gradient of 98% of A to 95% of B in 10 minutes, then elution with 95% of B for
5 minutes.
Flow rate 0.5 ml/minute; temperature 40°C
- Injection of 2 pi of solution at 0.1 mg/ml in a mixture of CH3CN:H20 = 9:1
- chromatographic system B
- Eluent A = H20 + 0.05% TFA
- Eluent B = CH3CN + 0.035% TFA
- Gradient of 98% of A to 95% of B in 12 minutes, then elution with 95% of B for
3 minutes
- Flow rate 0.7 ml/minute; temperature 40°C
- Injection of 2 µI of solution at 0.1 mg/ml in a mixture of CH3CN:H20 = 9:1
- chromatographic system C
- Eluent A = 5 mM ammonium acetate buffer, pH 6.5
- Eluent B = CH3CN
- Gradient of 98% of A to 95% of B in 10 minutes, then elution with 95% of B for
5 minutes.
- Fiow rate 0.5 ml/minute; temperature 40°C
- Injection of 2 µl of solution at 0.1 mg/ml in a mixture of CH3CN:H20 = 9:1.
The products are detected by UV at 220 nm.
The columns used are C18 columns with a particle size between 2 and 5 urn,
preferably 3.5 urn.
For the mass spectrometry part:
Ionization mode: positive electrospray (ESI+)
Scanning from 100 to 1200 uma.
The thin-layer chromatography was carried out on Merck Silica gel 60 TLC plates.
The silica gel for 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-(thfluoromethy!)pyridine (compound of formula (VII)), 0.5 g of
cis-2,6-dimethylaminopiperazine (compound of formula (VI)), 0.67 g of potassium
carbonate and 0.3 g of Nal are charged to 8 ml of DMF. The reaction is carried out in a
CEM discover microwave initiator for 30 min at 160°C. The resulting product is then
poured into a saturated aqueous solution of sodium chloride and the resulting mixture is
extracted with ethyl acetate. The organic phase is dried over Na2S04, filtered and
evaporated under vacuum. 1.1 g of an oiiy material corresponding to the title product are
obtained.
Preparation 2
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 charged to 27 ml of N-methylpyrrolidone. The mixture is heated at
110°C for 5 hours. The resulting product is then poured into a saturated aqueous solution
of sodium chloride and the resulting mixture is extracted with ethyl acetate. The organic
phase is dried over Na2S04, filtered and evaporated under vacuum. 3.2 g of an oily
material are isolated, and purified by flash chromatography on a Biotage® column, elution
being carried out with 95 cyclohexane/5 ethyl acetate. 1.4 g of white solid are isolated,
and dissolved in 35 ml of 1,2-dichloroethane. 0.72 ml of 1-chloroethyl chloroformate is
added at 0°C and the mixture is left to stir under a nitrogen stream for 10 minutes at 0°C
and then 3 hours at 85°C. The solvent is evaporated off and 35 ml of methanol are
added. Heating is carried out 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, and 900 mg of title product are isolated. Mp 236-239°C.
Preparation 3
(3R,5S)-3,5-Dimethyl-1-(6-trifluoromethylpyridin-2-yl)piperazine
2.2 g of 2-trifluoromethyl-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-butyl phosphine are charged to 16 ml of o-xy!ene.
Heating is carried out at 120°C for 6 hours. The resulting product 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 4
3,8-Diazabicyclo[3.2.1]oct-8-ylnicotinic acid methyl ester hydrochloride
0.42 g of methyl 6-chioronicotinate (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 charged to 7 ml of N-methylpyrrolidone. Heating is carried out for
7 hours at 110°C. The resulting product is then poured into a saturated aqueous solution
of sodium chloride and the resulting mixture is extracted with ethyl acetate. The organic
phase is dried over Na2S04, filtered and evaporated under vacuum. 1.1 g of an oily
material are obtained, and purified by flash chromatography on a Biotage® column,
elution being carried out with 8 cyclohexane/2 ethyi acetate. 520 mg of a light 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.HCI, in the
presence of 0.22 g of Pd/C at 10%. Filtration is performed, evaporation is carried out
under vacuum, and 440 mg of the title product are isolated in the form of a white solid.
6-(2-Oxopiperazin-1-yl)nicotinic acid methyl ester hydrochloride
Step a) 6-(2-Benzyiaminoethylamino)nicotinic acid methyl ester:
4.6 g of methyl 6-chloronicotinate and 40.5 mi of N-benzylethy!enediamine are
heated at 135°C for 6 hours in a round-bottomed flask. The resulting product is poured
into water and extraction is carried out with ethyl acetate. The resulting product is dried
and evaporated under vacuum; the crude product thus obtained is purified by flash
chromatography.
Step b) 6-(4-Benzyl-2-oxopiperazin-1-yl)nicotinic acid methyl ester:
The product of step a), 2.2 g, is solubilized in 35 ml of a 2N solution of HCI. 5 g of trimeric
glyoxal dihydrate are added and the mixture is left to stir at ambient temperature for
120 hours. Extraction is carried out with ethyl acetate. The resulting product is dried and
evaporated under vacuum; the crude product thus obtained is purified by flash
chromatography.
Step c) (6-(2-Oxopiperazin-1-yl)nicotinic acid methy! ester hydrochloride):
The isolated product of 1.4 g is solubilized in 150 ml of ethanol and then 4 mi of a solution
of isopropanol saturated with HCi and 0.6 g of Pd/C at 10% are added. The mixture is left
to react under a hydrogen stream for 4 hours at a temperature of 40°C. Filtration is
performed, and evaporation under vacuum is carried out, and 0.52 g of the title
compound is obtained.
Preparation 6
2-Chloro-1-(2-phenyl-6,7-dihydro-4H-thiazolo[4,5-c]pyridin-5-yl)ethanone
Step a) (2-Bromo-4-piperidone):
10 g of 1-Boc~4-piperidone are dissolved in 280 mi of dichloromethane. 8g of
bromine are slowly added and the mixture is left to stir at ambient temperature for
2 hours. Evaporation is carried out under vacuum and a solid is obtained. It is treated with
isopropyl ether so as to obtain a white solid which is filtered.
Step b) (2-Phenyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine):
4.5 g of the product of step a) are charged to a round-bottomed flask with 34 ml of
DMF and 2.6 g of thiobenzamide. Heating is carried out at a temperature of 60°C for
6 hours. An aqueous ammonia solution is added until a basic pH is obtained and
evaporation is carried out under vacuum.
Purification is carried out on a column by flash chromatography by means of a
Biotage® column which is eluted with ethyl acetate and then with methanol. 4 g of a
brown solid are isolated, and crystallized with isopropanol. Filtration is carried out and
2.8 g of a beige solid are obtained.
Step c) (2-Chloro-1-(2-phenyI-6,7-dihydro-4H-thiazo(o[4,5-c]pyridin-5-yl)ethanone):
In a round-bottomed flask with a magnetic stirrer, 2.8 g of this product are
suspended in 50 ml of dichloromethane. 2.8 ml of triethyiamine are added and the mixture
is brought 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 run in dropwise. The mixture is left to react
for 1 and a half hours and poured into water. Extraction is carried out with
dichloromethane. The organic phase is dried over Na2S04, filtered and evaporated under
vacuum. 4.1 g of a dark oily fat are isolated, triturated, and then left to stand in the cold.
The resulting product is separated by settling out and the supernatant is evaporated off
under vacuum. 1.1 mg of the title product are isolated in the form of a light oil.
Preparations 7-I and 7-II
2-Chloro-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone (7-
I)
and 2-chIoro-1-(1-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethanone (7-II)
Step a) (3-[1 -Dimethylaminometh-(Z)-ylidene]-4-oxopiperidine-1 -carboxylic) acid
tert-butyl ester:
10 g of 1-Boc-4-piperidone and 7.2 g of N,N-dimethylformamide dimethylacetate
are refluxed in a round-bottomed flask. The crude product thus obtained is column-
purified by flash chromatography, and 2.4 g of an oily material are isolated.
Step b) 2-Phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c3pyridine-5-carboxyiic acid tert-
butyl ester (b-l) and 1-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid
tert-butyl ester (b-ll)):
The product of step a) (2.4 g) is dissolved in 27 ml of methanol. 1.24 g of
phenyihydrazine are added and the mixture is refluxed for 3 hours. Evaporation is carried
out under vacuum and column-purification is carried out by flash chromatography using a
Biotage® column, elution being carried out with a mixture of ethyl acetate and
cyclohexane. 1.8 g of an oily material are isolated.
Step c) (2-Phenyl-2,4,6,7-tetrahydropyrazoIo[4,3-c3pyridine- hydrochloride (c-l) and
1-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c3pyridine-5-hydrochloride (c-ll))
The mixture of the products of step b) (b-l and b-ll, 2.4 g) is slowly dissolved in
60 ml of trifluoroacetic acid at 0°C. The mixture is then left to stir for 2 hours at ambient
temperature. The trifluoroacetic acid is evaporated off, 37% hydrochloric acid is added
and the resulting mixture is evaporated to dryness under vacuum. Crystallization is
carried out with isopropanol. 1 g of beige solid is obtained.
Step d) 2-Chloro-1-(2-phenyl-2,4,6,7-tetrahydropyra2olo[4,3-c]pyridin-5-yl)ethanone
(7-I) and 2-chIoro-1-(1-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone (7-li)
The mixture of the products of step c) (c-l and c-ll, 1 g) is suspended in 26 ml of
dichloromethane, in a round-bottomed fiask with a magnetic stirrer. 1.23 ml of
triethylamine are added and the mixture is brought to 0°C. At 0°C, 0.5 ml of chioroacetyl
chloride, i.e. the compound of general formula (V) in which Hal=Har=CI and n=1, is run in
dropwise. The mixture is left to react for 1 and a half hours and is poured into water.
Extraction is carried out with dichloromethane. The organic phase is dried over Na2S04,
filtered and evaporated under vacuum. The residue is purified by flash chromatography
on a Biotage® column, elution being carried out with 9 cyclohexane/1 ethyl acetate.
0.15 g of the title product 7-I (more polar product) is isolated in the form of a light oil and
0.15 g of the title product 7-II (less poiar product) is isolated in the form of a light oil.
Preparation 8
2-Chloro-1-[1-(2,2,2-trif!uoroethyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl]ethanone
By carrying out the procedure as described in preparation 7, but using (2,2,2-
trifiuoroethyi)hydrazine instead of phenylhydrazine, the title compound is obtained in the
form of a light oil.
Preparation 9
2-Chloro-1-(2-pyridin-2-yl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yljethanone
Step a) 4-(Pyridin-2-ylhydrazono)piperidine-1-carboxylic acid tert-butyl ester:
The following are charged to a round-bottomed flask with a magnetic stirrer: 5 g of
N-Boc-piperidone, 2.45 g of pyridin-2-ylhydrazine, 100 ml of methanol and 95 ml of a
solution of methanol saturated with HCI. The mixture is left to react under a nitrogen
stream for 2 h at reflux temperature. The solvent is evaporated off under vacuum, the
resulting product is dissolved with dichloromethane and washing is carried out with a
saturated aqueous solution of NaHC03. The organic phase is dried over Na2S04 and the
solvent is evaporated off, and 4.0 g of the title product are isolated in the form of a red oil.
Step b) 2-Pyridin-2-yl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid
tert-butyl ester:
33 ml of DMF are charged to a round-bottomed flask and 3.7 ml of POCI3 are added
slowly at 0°C. The mixture is left to stir at OX for 30 min and then 33 ml of pyridine, 4.0 g
of the product of step a) and 5 ml of DMF are added. The mixture is then left to stir for
4 hours at a temperature of 80°C. 270 ml of water are added and extraction is carried out
with ethyl acetate. The organic phase is dried over Na2S04 and the solvent is evaporated
off. 4.0 g of the title product are isolated in the form of a black oil, which is purified by
flash chromatography on a Biotage® column, elution being carried out with 8 hexane/2
ethyl acetate. 0.78 g of the product is isolated in the form of a yellow solid.
Step c) 2-Pyridin-2-yl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine hydrochloride:
0.78 g of the product of step b) is dissolved at 0°C, in a round-bottomed flask, with
21 ml of trifluoroacetic acid. The solution is then left to stir for 2 hours at ambient
temperature.
The trifluoroacetic acid is evaporated off under vacuum, 37% hydrochloric acid is
added, and the resulting product is evaporated to dryness under vacuum. Crystallization
is carried out with isopropanol. 0.6 g of a beige solid is obtained.
Step d) 2-Chloro-1-[1-(2,2,2-trifluoroethy!)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-
5-yl]ethanone
0.3 g of the product of step c) is suspended in 4 mi of dichloromethane, in a round-
bottomed flask equipped with a magnetic stirrer. 0.36 ml of triethylamine is added and the
mixture is brought to 0°C. At 0°C, 0.12 ml of chioroacetyl chloride, i.e. the compound of
general formula (V) in which Hal=Hal'=CI and n=1, is run in dropwise. The mixture is left
to react for 1 and a half hours and poured into water. Extraction is carried out with
dichloromethane. The organic phase is dried over Na2S04, filtered and evaporated under
vacuum. The residue is purified by flash chromatography on a Biotage® column, elution
being carried out with 9 cyclohexane/1 ethyl acetate. 0.19 g of the title product is isolated
in the form of a light oil.
Preparation 10
2-(2,2,2-Trifluoroethyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine
hydrochloride:
By carrying out the procedure as described in Example 9 up to step c) but using
(2,2,2-trifluoroethyl)hydrazine instead of pyrid-2-ylhydrazine, the title compound is
obtained in the form of a pale yellow solid.
Preparation 11
6-((3R,5S)-4-Carboxymethyl-3,5-dimethyIpiperazin-1-yl)nicotinic acid ethyl
ester
Step a) 6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)nicotinic acid ethyl ester:
By carrying out the procedure as described in preparation 3, but using nicotinic acid
ethyl ester instead of 2-trifluoromethyl-5-bromopyridine, the title compound is obtained in
the form of a light oil.
Step b) 6-((3R,5S)-4-Benzyioxycarbonylmethyl-3,5-dimethylpiperazin-1-yl)nicotinic
acid ethyl ester
The following are charged to a round-bottomed flask equipped with a magnetic
stirrer: 3.6 g of the product of the preceding step, 132 ml of THF, 2.6 ml of
benzylbromoacetate and 4.4 ml of triethyiamine. The mixture is left to react under a
nitrogen stream overnight at ambient temperature. The solvent is evaporated off and
purification is carried out by flash chromatography on a Biotage® column, elution being
carried out with 7 hexane/3 ethyl acetate. 2.9 g of the title product are isolated in the form
of a clear oil.
Step c) 6-((3R,5S)-4-Carboxymethyl-3,5-dimethylpiperazin-1-yl)nicotinic acid ethyl
ester
2.9 g of the product of the preceding step are solubilized in 290 ml of ethanol, and then
1.74 g of Pd/C at 10% are added. The mixture is left to react under a hydrogen stream for
4 hours at a temperature of 40°C. The resulting product is filtered and evaporation is
carried out under vacuum, and 2.2 g of the title compound are obtained in the form of a
white solid.
Preparation 12
[(2R,6S)-2,6-Dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]acetic acid
Step a) [(2R,6S)-2I6-Dimethyi-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]acetic
acid ethyl ester
By carrying out the procedure as described in step b) of preparation 11, but using
the compound of preparation 3 instead of the compound of step a) of preparation 11 and
bromoacetic acid ethyl ester instead of bromoacetic acid benzyl ester, the title compound
is obtained in the form of solid.
Step b) [(2R,6S)-2,6-Dimethyi-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]acetic
acid:
2.5 g of the product of the preceding step are solubilized in 22 ml of ethanol, and
then 5 ml of a 40% aqueous NaOH solution are added. The mixture is left to react for
3 hours at a temperature of 70°C. The pH is regulated at 6 using a 1N solution of HCI.
Extraction is carried out with ethyl acetate. The organic phase is dried over Na2S04,
filtered and evaporated under vacuum. 1.6 g of the title product are isolated in the form of
a white solid.
Preparation 13
6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)nicotinic acid methyl ester
By carrying out the procedure as described in preparation 1, but using
6-chloronicotinic acid methyl ester instead of 2-chloro-5-(trifluoromethyl)pyridine, the title
compound is obtained in the form of an oil.
Preparation 14
2-Chloro-1-[2-(5-trifluoromethylpyridin-a-yl)-2,4,6,7-tetrahydropyrazolo[4,3-
c]pyridin-5-yl]ethanone
1 g of 2-(5-trifluoromethylpyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine
hydrochloride is suspended in 12 ml of dichloromethane, in a round-bottomed flask
equipped with a magnetic stirrer. 0.95 ml of triethylamine is added and the mixture is
brought to 0°C. At 0°C, 0.33 ml of chloroacetyl chloride, i.e. the compound of general
formula (V) in which Hal=Hal'=CI and n=1, is run in dropwise. The mixture is left to react
for 1 and a half hours and is poured into water. Extraction is carried out with
dichloromethane. The organic phase is dried over Na2S04, filtered and evaporated under
vacuum. The residue is purified by flash chromatography on a Biotage® column, elution
being carried out with 9 cyclohexane/1 ethyl acetate. 1.08 g of the title compound are
obtained in the form of a yellow solid.
8-Pyridin-3-yl-3,8-diazabicycIo[3.2.1]octane hydrochloride
Step a) 3-Benzyl-8-pyridin-3-yl-3,8-diazabicyclo[3.2.1]octane:
By carrying out the procedure as described in preparation 3, but using
3-bromopyridine instead of 2-trifluoromethyl-5-bromopyridine and 1-benzyI-3,8-
diazabicyclo[3.2.1]octane instead of cis-2,6-dimethylpiperazine, the title compound is
obtained in the form of an oil.
Step b) 8-Pyridin-3-yl-3,8-diazabicyclo[3.2.1]octane
The isolated product of 1.1 g is solubilized in 70 ml of ethanol, and then 4 ml of a
solution of isopropanol saturated with HCI and 0.6 g of Pd/C at 10% are added. The
mixture is left to react under a hydrogen stream for 4 hours at a temperature of 40°C. The
resulting product is filtered and evaporation is carried out under vacuum, and 0.84 g of
the title compound is obtained.
Preparation 16
(3R,5S)-3,5-Dimethyl-1-(5-[1,2,4]oxadiazol-3-ylpyridin-2-yl)piperazine
Step a) 6-((3R,5S)-3,5-Dimethylpiperazin-1-yl)nicotinonitrile
By carrying out the procedure as described in preparation 1, but using 2-chloro-5-
cyanopyridine instead of 2-chloro-5-(trifluoromethyl)pyridine, the title compound is
obtained in the form of an oil.
Step b) (3R,5S)-3,5-Dimethyl-1 -(5-[1,2,4]oxadiazol-3-ylpyridin-2-yl)piperazine
The following are charged to a round-bottomed flask equipped with a magnetic
stirrer: 1 g of the product of the preceding step, 15 ml of ethanol, an aqueous solution of
hydroxylamine hydrochioride (2 equivalents), and a solution of 0.98 g of Na2S04 in 7.2 ml
of water. The mixture is left to react under a nitrogen stream for 4 h at a temperature of
90°C. The precipitate which forms is filtered off and 0.5 g of the resulting crude product
(1.7g) is evaporated under vacuum. It is charged to a round-bottomed flask, to which
20 ml of acetic anhydride are added at 0°C.
The mixture is left to react under a nitrogen stream for 2.5 hours at the reflux
temperature. The resulting product is evaporated under vacuum and the residue is taken
up with ethyl acetate and a saturated aqueous solution of K2C03. The organic phase is
dried over Na2S04, filtered and evaporated under vacuum.
0.27 g of the resulting crude product is dissolved in 8 mi of 6N HCI. The solution is
left to react under a nitrogen stream for 2 h at the reflux temperature. The pH is regulated
at 9 with sodium hydroxide and extraction is carried out with ethyl acetate. The organic
phase is dried over Na2S04, filtered and evaporated under vacuum. The residue is
purified by flash chromatography on a Biotage® column, elution being carried out with 8
ethyl acetate/2 methanol. 0.1 g of the title product is obtained in the form of an oil which
has a tendency to solidify.
Preparation 17
1-[5-(2H-Pyrazol-3-yl)pyridin-2-yl]piperazine
Step a) 4-(5-lodopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester
By carrying out the procedure as described in preparation 1, but using 2-fluoro-5-
iodopyridine instead of 2-chloro-5-(trifluoromethyl)pyridine and N-Boc-piperazine instead
of cis-2,6-dimethyipiperazine, the title compound is obtained in the form of an oil.
Step b) 4-[5-(2H-Pyrazol-3-yl)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl
ester
0.2 g of compound of step a), 0.069 g of 1H-pyrazole-5-boronic acid, 0.03 g of
palladium tetrakis(triphenylphosphine), 0.087 g of sodium bicarbonate, 15 ml of DME and
2 ml of water are charged. The mixture is refluxed for 7 hours. The resulting product is
filtered through celite and the solvent is evaporated off. 0.23 g of crude product is
isolated. The residue is purified by flash chromatography on a Biotage® column, elution
being carried out with 7 hexane/3 ethyl acetate. 0.11 g of the title compound is isolated in
the form of a pale yellow solid.
Step c) 1-[5-(2H-Pyrazol-3-yl)pyridin-2-yl]piperazine trifluoroacetate
The compound of step b) (0.11 g) is dissolved slowly in 3.5 ml of trifluoroacetic acid
at 0°C. The resulting product is then left to stir for 2 hours at ambient temperature. The
trifluoroacetic acid is evaporated off under vacuum and 0.065 g of 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 carrying out the procedure 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) (2S,6R)-2,6-Dimethyl-4-(5-iodo-2-ylpyridin-2-yl)piperazine~1-carboxylic acid
tert-butyl ester
The following are charged under a nitrogen stream at 0°C: 0.35 g of compound of
step a), 0.26 g of (Boc)20, 0.46 ml of triethylamine and 5 ml of DMF. The mixture is
heated at 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, elution
being carried out with ethyl acetate. 0.43 g of the title compound is isolated in the form of
a pale yellow oil.
Step c) (2S,6R)-2,6-Dimethyl-4-[5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-
yi)pyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester
0.43 g of compound of step b), 0.29 g of bis(pinacol)diboron, 0.026 g of palladium
Cl2 (dppf)2CH2CI2, 0.31 g of potassium acetate and 10ml of DMSO are charged to a
round-bottomed flask under a nitrogen stream. The mixture is heated at 85°C for 2 hours.
It is poured into a saturated aqueous solution of NaCI and the mixture is extracted with
ethyl acetate. The organic phase is dried over Na2S04l filtered and evaporated under
vacuum. 0.32 g of an oily material is isolated, and is purified by flash chromatography on
a Biotage© column, elution being carried out with 9 cyclohexane/1 ethyl acetate. 0.28 g of
a yellowish solid is isolated.
Step d) (2S,6R)-2,6-Dimethyl-4-(5-thiazoI-2-ylpyridin-2-yl)piperazine-1-carboxyiic
acid tert-butyl ester
0.28 g of compound of step c), 0.092 g of 2-bromothiazole, 0.032 g of palladium
tetrakistriphenylphosphine (PdP(Ph3)4), 0.094 g of sodium bicarbonate, 20 ml of DME and
3 ml of water are charged to a round-bottomed flask under a nitrogen stream. The
mixture is refluxed for 7 hours. It is poured into a saturated aqueous solution of NaCI and
extraction is carried out with ethyl acetate. The organic phase is dried over Na2S04
filtered and evaporated under vacuum. 0.36 g of an oily material is isolated, and is
purified by flash chromatography on a Biotage® column, elution being carried out with 9
cyclohexane 9/1 ethyl acetate. 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 of step d) (0.2 g) is slowly dissolved in 5 ml of trifluoroacetic acid at
0°C. The resulting product is then left to stir for 2 hours at ambient temperature. The
trifluoroacetic acid is evaporated off under vacuum and 0.15 g of the title compound is
obtained in the form of a beige solid.
EXAMPLE 1
Compound No. 9:
2-[(2S,6R)-2,6-Dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-(2-
phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone
0.25 g of the compound obtained in preparation 6 (compound of formula (II)), 0.22 g
of the compound obtained in preparation 1 (compound of formula (111)), 0.13 g of
potassium carbonate and 0.06 g of Nal are reacted in 4 ml of DMF. The reaction is
carried out by means of a CEM discover microwave initiator for 30 min at 160°C. The
resulting product is poured into water and extraction is carried out with ethyl acetate. The
organic phase is dried over Na2S04, filtered and evaporated under vacuum. 500 mg of an
oily material are isolated. Column-purification is carried out by flash chromatography
using a Biotage® column, elution being carried out with an 8 cyclohexane/2 ethyl acetate
mixture. 400 mg of a pale yellow solid are isolated, and crystallized with ethyl ether.
Filtration is carried out and 0.25 g of the title product is obtained in the form of a white
solid.
Mp:(169-170)°C
NMR (apparatus b): 5 (ppm, dmso-d6): 1.04 (m, 6H); 2.65 - 2.76 (m, 2H); 2.82 +
2.94 (2 x m, 2H); 3.15 (m, 2H), 3.64 - 3.91 (m, 4H); 4.11 - 4.25 (m, 2H); 4.73 + 4.89 (2 x
s, 2H); 6.94 (d, 1H, J= 9 Hz); 7.44 - 7.54 (m, 3H); 7.76 (dd, 1H, J= 9 and 2 Hz); 7.89 (m,
2H);8.38(bs,1H).
EXAMPLE 2
Compound No. 18:
2-[(2S,6R)-2,6-Dimethyl-4-(6-trifluoromethyIpyridin-2-yl)piperazin-1-yl]-1-(2-
phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone
By carrying out the procedure as described in Example 1, but using the compound
of preparation 3 instead of the compound of preparation 1, the title compound is obtained
in the form of a white solid.
Mp:(168-169)°C
NMR: (apparatus a). 5 (ppm, dmso-d6): 1.06 (m, 6H); 2.57 - 2.65 (m, 2H); 2.76 -
3.05 (m, 2H); 3.25 (m, *); 3.65 - 3.92 (m, 6H); 4.75 + 4.90 (2 x bs, 2H); 7.40 (dd, J= 8.9
and 2.4 Hz, 1H); 7.45 - 7.53 (m, 3H); 7.60 (d, J= 8.8 Hz, 1H); 7.86 - 7.92 (m, 2H); 8.39
(d, J=2.7Hz, 1H).
Compound No. 19:
6-{3-[2-Oxo-2-(2-phenyl-2,4J6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]-3,8-
diazabicyclo[3.2.1]oct-8-yl}nicotinic acid methyl ester
0.45 g of the compound obtained in preparation 7-f {compound of formula (II)),
0.45 g of the compound obtained in preparation 4 (compound of formula (III)), 0.6 ml of
diisopropyiethyiamine and 44 ml of DMF are reacted together. The mixture is heated at
100°C for 2 hours. The resulting product is poured into water and extraction is carried out
with ethyl acetate. The organic phase is dried over Na2S04, filtered and evaporated under
vacuum. 700 g of a solid material are isolated. Column-purification is carried out by flash
chromatography using a column which is eluted with a 7 hexane/3 ethyl acetate mixture.
0.5 g of the title product is isolated. It is treated with diethyl ether, filtration is carried out,
and 0.45 g of a white solid is obtained.
Mp: (204-205)°C
NMR: (apparatus b). 5 (ppm, dmso-d6): 1.73 (m, 2H); 1,81 - 2.03 (m, 2H); 2.29 -
2.43 (m, 2H); 2.58-2.65 (m, 1H); 2.66-2.76 (m, 2H); 2.89 (m, 1H); 3.17 (s, 1H); 3.22
(s, *); 3.94 (m, 4H); 3.86 (m, 1H); 4.53 - 4.70 (m, 3H); 4.77 (bs, 1H); 6.77 (m, 1H); 7.27
(m, 1H); 7.44 - 7.52 (m, 2H); 7.73 - 7.79 (m, 2H); 7.92 (m, 1H); 8.28 + 8.33 (2 x s, 1H);
8.63 (m, 1H).
EXAMPLE 4
Compound No. 26:
2-[8-(5-Fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl3-1-(1-phenyl-
1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yJ)ethanone
By carrying out the procedure as described in Example 3, but using the compound
of preparation 7-II instead of the compound of preparation 7-I and the compound of
preparation 2 instead of the compound of preparation 4, the title compound is obtained in
the form of a white solid.
Mp: (148-150)°C
NMR: (apparatus b). 8 (ppm, dmso-d6): 1.74 (m, 2H); 1.79 - 1.99 (m, 2H); 2.31 -
2.45 (m, 2H); 2.61 - 2.75 (m, 2H); 2.84 (m, 1H); 2.98 (m, 1H); 3.18 + 3.22 (2 x s, 2H);
3.74 + 3.83 (2 x m, 2H); 4.47 - 4.65 (m, 3H); 4.71 (s, 1H); 7.33 - 7.42 (m, 1H), 7.45 -
7.66 (m,5H); 8.44 (m, 1H).
Compound No. 24:
6-{3-[2-Oxo-2-(2-phenyl-2,4J6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]-3,8-
diazabicyclo[3.2.1]oct-8-yl}nicotinic acid

0.4 g of the compound of Example 3 is dissolved in 8 ml of 20% aqueous NaOH
solution and 8 ml of methanol. The mixture is refluxed for 3 hours. The methanol is
evaporated off and the resulting product is washed with ethyl ether. The pH is adjusted to
6 with a 1N HCI solution and extraction is carried out with ethyl acetate. Drying is carried
out and the organic phase is evaporated, and 200 mg of an oily material are obtained.
The latter is treated with diethyl ether, filtration is carried out, and 0.45 g of a white solid
corresponding to the title product is obtained.
Mp: (202-206)°C
NMR: (apparatus a). 8 (ppm, dmso-d6): 1.73 (m, 2H); 1.83 - 2.01 (m, 2H); 2.28 -
2.44 (m, 2H); 2.57 - 2.64 (m, 1H); 2.66 - 2.77 (m, 2H); 2.89 (m, 1H); 3.16 (s, *); 3.79 +
3.87 (2 x m, 2H); 4.53 - 4.69 (m, 3H); 4.77 (s, 1H); 6.74 (m, 1H); 7.27 (m, 1H); 7.44 -
7.51 (m, 2H); 7.73 - 7.79 (m, 2H); 7.90 (m, 1H); 8.28 + 8.32 (2 x s, 1H); 8.62 (m, 1H);
11.92-12.54 (bs, 1H).
EXAMPLE 6
Compound No. 11:
4-[2-Oxo-2-(2-phenyl-6,7-dihydro-4H-thia2olo[5,4-c]pyridin-5-yl)ethyl]-1-(5-
trifluoromethylpyridin-2-yl)piperazin-2-one
By carrying out the procedure as described in Example 3, but using the compound
of preparation 6 instead of the compound of preparation 7-I and the compound of
preparation 5 instead of the compound of preparation 4, the title compound is obtained in
the form of a white solid.
Mp:(165-166)°C
NMR: (apparatus a). 5 (ppm, dmso-d6): 2.80 - 3.03 (m, 4H); 3.40 - 3.59 (m, 4H);
3.72 - 4.05 (m, 7H); 4.79 + 4.88 (2 x s, 2H); 7.39 - 7.55 (m, 3H); 7.74 - 7.94 (m, 2H);
8.05 - 8.35 (m, 2H); 8.82 (s, 0.4H); 8.95 (s, 0.6H).
EXAMPLE 7
Compound No. 23:
6-{(3S,5R)-3,5-Dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyra2olo[4,3-
c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid methyl ester hydrochloride
By carrying out the procedure as described in Example 1, but using the compound
of preparation 7-I instead of the compound of preparation 6 and the compound of
preparation 13 instead of the compound of preparation 1, the title compound (free base)
is obtained. It is dissolved in isopropanol and then a solution of hydrochloric acid in
isopropanol is added. The title product is obtained in the form of a white solid.
Mp: 210-212
NMR (apparatus a, temp. A). 5 (ppm, dmso-d6): 1.25 + 1.32 (2Xm, 6H), 2.75 - 3.00
(m, 2H), 3.10-3.63 (m, *), 3.66-4.01 (m, 6H), 4.32 - 4.81 (m, 6H), 7.07 (m, 1H), 7.29
(m, 1H), 7.49 (m, 2H), 7.78 (m, 2H), 8.06 (m, 1H), 8.27- 8.40 (m, 1H), 8.71 (m, 1H),9.19
(bs, 0.5H), 9.44 (bs, 0.5H).
EXAMPLE 8
Compound No. 21:
6-{(3S,5R)-3,5-Dimethyl-4-[2-oxo-2-(2-phenyl-2,4)6J7-tetrahydropyrazolo[4J3-
c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid hydrochloride
By carrying out the procedure as described in Example 5, but using the compound
of Example 7 instead of the compound of Example 3, the title compound (free base) is
obtained. It is dissolved in isopropanol and then a solution of hydrochloric acid in
isopropanol is added. The title product is obtained in the form of a white solid.
Mp: 209-211
NMR: (temp. B). 6 (ppm, dmso-d6): 1.24 (d, J= 6.5 Hz, 2.7H), 1.32 (d, J= 6.5 Hz,
3.3H), 2.80 (m, 0.8H), 2.94 (m, 1.2H), 3.14-3.30 (m, 1H), 3.44 (m, 1H), 3.49 - 4.26 (m,
*), 4.35-4.80 (m, 6H), 7.01 -7.11 (m, 1H), 7.29 (m, 1H), 7.49 (m, 2H), 7.73-7.84 (m,
2H), 8.05 (m, 1H), 8.33 (m, 0.8H), 8.39 (m, 0.2H), 8.66 - 8.72 (m, 1H), 9.28 + 9.44 (
2Xbs, 1H), 12.1-13.4 (bs, 1H).
EXAMPLE 9
Compound No. 106:
2-(8-Pyridin-3-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)-1-[2-(5-trifluoromethylpyridin-
2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone
By carrying out the procedure as described in Example 3, but using the compound
of preparation 14 instead of the compound of preparation 7-I and the compound of
preparation 15 instead of the compound of preparation 4, the title compound is obtained
in the form of a white solid.
Mp: (150-151 )°C
NMR: (temp. B). 5 (ppm, dmso-d6): 1.69 (m, 2H), 1.83-1.97 (m, 2H), 2.34 -2.66
(m, **), 2.75 (m, 1H),2.93(m, 1H), 3.11 (s, 1H),3.17(s, 1H), 3.80(m, 1H), 3.88 (m, 1H),
4.26 (m, 1H),4.33(m, 1H),4.59(s, 1H), 4.81 (s, 1H), 7.11 - 7.23 (m, 2H), 7.86 (m, 1H),
8.04 (m, 1H), 8.18 (m, 1H), 8.34 (m, 1H), 8.53 (s, 0.5H), 8.57 (s, 0.5H), 8.86 (m, 1H).
EXAMPLE 10
Compound No. 89:
2-({2S,6R)-2,6-Dimethyl-4-[5-(5-methyl-[1,2l4]oxadiazol-3-yl)pyridin-2-
yl]piperazin-1-yl)-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone
By carrying out the procedure as described in Example 1, but using the compound
of preparation 16 instead of the compound of preparation 1 and the compound of
preparation 7-I instead of the compound of preparation 6, the title compound is obtained
in the form of a white solid.
Mp:(163-164)°C
NMR: (temp. B). 8 (ppm, dmso-d6): 1.05 (m, 6H), 2.63 (s, 3H), 2.65 - 2.75 (m,
2.7H), 2.84 (m, 1.3H), 3.17 (m, 2H), 3.67 - 3.84 (m, 4H), 4.20 (m, 2H), 4.56 + 4.68 (2Xs,
2H), 6.96 (d, J= 9.0 Hz, 1H), 7.27 (m, 1H), 7.47 (m, 2H), 7.76 (m, 2H), 7.99 (dd, J= 9.0
and 2.3 Hz, 1H), 8.29 (s,1H), 8.67 (d, J= 2.3 Hz, 1H).
EXAMPLE 11
Compound No. 45:
2-[8-(5-Fluoropyrimidin-2-yl)-3,8-dia2abicyclo[3.2.1]oct-3-yl]-1-[1-(2,2,2-
trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]ethanone oxalate
By carrying out the procedure as described in Example 3, but using the compound
of preparation 8 instead of the compound of preparation 7-I and the compound of
preparation 2 instead of the compound of preparation 4, the title compound (free base) is
obtained. It is dissolved in acetone and then a solution of oxalic acid in acetone is added.
The title product is obtained in the form of a white solid.
Mp:(160-162)°C
NMR: (temp. A). 5 (ppm, dmso-d6): 1.61 - 1.78 (m, 2H), 1.81 - 1.98 (m, 2H), 2.34-
2.49 (m, 2H), 2.59 - 2.90 (m, 4H), 3.23 + 3.32 (2Xs, 2H), 3.78 (m, 2H), 4.40 - 4.67 (m,
4H), 5.02 (m, 2H), 7.44 + 7.46 (2Xs, 1H), 8.44 (m, 2H).
EXAMPLE 12
Compound No. 130:
6-{(3S,5R)-3,5-Dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-
c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid ethyl ester
1.88 g of 2-phenyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c3pyridine hydrochloride are
suspended in 123 ml of dichloromethane, in a round-bottomed flask equipped with a
magnetic stirrer. 2.5 g of the compound of preparation 11, 4.4 mi of triethylamine and
3.5 g of BOP are added. The mixture is reacted for 1 hour at a temperature of 20-25°C.
The resulting product is then poured into water and extraction is carried out with
dichloromethane. The organic phase is dried over Na2S04, filtered and evaporated under
vacuum. 6.07 g of an oily material are isolated. Said material is column-purified by flash
chromatography using an automatic Biotage® column, elution being carried out with ethyl
acetate. 1.8 g of a white solid are isolated.
NMR: (apparatus b, temp. B). 8 (ppm, dmso-d6): 1.04 (m, 6H), 1.29 (m, 3H), 2.70
(m, 2H), 2.83 + 2.94 (2Xm, 2H), 3.16 (m, 2H), 3.63 - 3.85 (m, 4H), 4.13 - 4.33 (m, 4H),
4.48-4.77 (m, 2H), 6.87 (m, 1H), 7.27 (m, 1H), 7.47 (m, 2H), 7.76 (m, 2H), 7.92 (m, 1H),
8.29 (bs, 1H), 8.63 (bs, 1H).
EXAMPLE 13
Compound No. 126:
2-[(2S,6R)-2,6-Dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1-[2-
(2,2,2-trifluoroethyI)-2,4,6,7-tetrahydropyrazolo[4,3-c3pyridin-5-yI]ethanone oxalate
By carrying out the procedure as described in Example 12, but using the compound
of preparation 12 instead of the compound of preparation 11 and the compound of
preparation 10 instead of 2-phenyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine
hydrochloride, the title compound (free base) is obtained. It is dissolved in acetone and
then a solution of oxalic acid in acetone is added. The title product is obtained in the form
of a white solid.
NMR: (apparatus b, temp. B). 5 (ppm, dmso-d6): 1.11 (m, 6H), 2.57 - 3.07 (m, 4H),
3.10-4.73 (m, *), 5.04 (m, 2H), 7.02 (m, 1H), 7.65 (m, 1H), 7.82 (m, 1H), 8.42 (m, 1H).
EXAMPLE 14
Compound No. 134
1-(2-Phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yI)-2-{4-[5-(2H-pyrazol-3-
yl)pyridin-2-yl]piperazin-1-yl}ethanone
By carrying out the procedure as described in Example 3, but using the compound
of preparation 17 instead of the compound of preparation 4 and the compound of
preparation 6 instead of the compound of preparation 7-I, the title compound is obtained
in the form of a white solid.
Mp:(231-237)°C
NMR: (apparatus a, temp. B). d (ppm, dmso-d6): 2.34 - 2.69 (m, *), 2.85 + 3.00
(2xm, 2H), 3.16 - 3.68 (m, **), 3.89 (m, 2H), 4.67 - 5.05 (m, 2H), 6.62 (m, 1H), 6.89 (m,
1H), 7.49 (m, 3H), 7.74 (m, 1H), 7.83 - 8.01 (m, 3H), 8.56 (m, 1H), 12.68 - 13.26 (m,
1H).
EXAMPLE 15
Compound No. 135
2-[(2S,6R)-2,6-Dimethyl-4-(5-thiazo-2-ylpyridin-2-yl)piperazin-1-yl]-1-(2-phenyl-
2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone
By carrying out the procedure as described in Example 1, but using the compound
of preparation 7-I instead of the compound of preparation 6 and the compound of
preparation 18 instead of the compound of preparation 1, the title compound is obtained
in the form of a free base.
Mp(173-174)°C
NMR: (apparatus a, temp. B). d (ppm, dmso-d6): 1.05 (m, 6H), 2.67 (m, 3H), 2.84
(m, 1H), 3.17 (m, 2H), 3.63 - 3.87 (m, 4H), 4.18 (m, 2H), 4.50 - 4.74 (m, 2H), 6.93 (d, J=
9.0 Hz, 1H), 7.27 (m, 1H), 7.47 (m, 2H), 7.64 (d, J= 3.3 Hz, 1H), 7.76 (m, 2H), 7.83 (d, J=
3.3 Hz, 1H), 8.00 (dd, J= 9.0 et2.4 Hz, 1H), 8.29 (s, 1H), 8.66 (d, J= 2.4 Hz, 1H).
The following table describes the examples obtained by application and/or
adaptation of the methods described, by means of the appropriate reactants and starting
products:
The SH-SY-5Y strain (human neuroblastoma) is cultured conventionally in a
DMEM culture medium (Dulbecco's Modified Eagle's Medium) (Gibco BRL, France)
containing FCS (5%) (foetal calf serum) (Boehringer Mannheim, Germany), sodium
pyruvate (1 mM) and glutamine (4 mM) in culture flasks coated with collagen (Becton
Dickinson, France).
The SK-N-BE parent strain (human neuroblastoma) and the Bep 75 clone, stably
expressing the whole form of the human p75NTR receptor (SK-N-BE Bep 75) are cultured
conventionally in an RPMI 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 p75NTR receptor dimerization study is carried out on a cell suspension of the
SK-N-BE Bep 75 strain. The cells (2.5 x 104 cells/well) are placed in wells (96-well plate)
for 24 h, and then preincubated for 1 h at 37°C in the presence or absence of the
compounds according to the invention. Supernatant is then added, this supernatant being
derived from the culture of HEK293 human cells of renal origin expressing, after 48 h of
transfection, and secreting a soluble form of the p75NTR receptor (extracellular part of the
receptor) coupled to an alkaline phosphatase, at the final concentration of 10 nM. The
quantification of the specific binding of the soluble p75NTR receptor to the receptor present
on SK-N-BE Bep 75 ceils is determined by measuring the alkaline phosphatase enzyme
activity after incubation of the cells for 1 hour at 37°C in the presence of the supernatant.
After filtration and transfer of the filters into 24-well plates, the alkaline phosphatase
activity is determined by adding CDP-Star chemiluminescent substrate (ready-to-use,
Roche). The concentrations inhibiting 50%(CI50) of the dimerization of the p75NTR
receptor, of the compounds according to the invention, are low and range from 10-6 to 10-
11M.
For example, compounds No. 9, 11, 19 and 24 showed an IC50 of 0.73 nM,
1.9 nM, 14 nM and 1.55 nM, respectively.
Measurement of apoptosis
The cells (human neuroblastoma strains SH-SY-5Y and SK-N-BE Bep 75) are
placed in 35 mm diameter Petri dishes (Biocoat collagen I, (105 ceils/well)) in an
appropriate culture medium containing 5% of FCS, for 24 h. The culture medium is then
removed, the cells are rinsed with PBS (Dulbecco's Phosphate buffered saline), and then
either fresh medium containing 5% of FCS or medium containing NGF (at the
concentration of 10 ng/ml), or beta-amyloid peptide (Aß1-40) (at the concentration of
10 uM) is added, this being in the presence or absence of the compounds according to
the invention. The degrees of apoptosis are measured 48 hours after the treatments in
the case of the SH-SY-5Y strain, and 24 hours after in the case of the SK-N-BE Bep 75
strain, by quantification of the DNA fragment-associated cytoplasmic histones (cell death
detection ELISA, Boehringer Mannheim, Germany). The degrees of apoptosis are
expressed as amount of oligonucleosomes/105 cells. Each value corresponds to the
mean of 9 experimental points distributed over 3 independent experiments.
The compounds of formula (I) exhibit an inhibitory activity on NGF-induced
apoptosis, with IC50 values which range from 10-6 to 10-11M.
For example, compounds No. 9 and 11 showed an IC5o of 0.72 nM and 4.46 nM,
respectively.
Thus, the binding of the compounds according to the invention to the p75NTR
receptor results, on the one hand, at the biochemical level, in the inhibition of the
dimerization of the receptor induced by neurotrophins, or independently of the ligand,
and, on the other hand, at the cellular level, in the 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) exhibit a very advantageous activity of inhibition of the dimerization of the
p75NTR receptor, independently of its ligand.
The compounds according to the invention can therefore be used for the
preparation of medicaments, in particular of medicaments for use in preventing or treating
any pathological condition where the p75NTR receptor is involved, more particularly those
indicated hereinafter.
The compounds according to the invention can also be used for preventing or
treating any pathological condition where the p75NTR receptor is involved, more
particularly those indicated hereinafter.
Thus, according to another of its aspects, a subject of the invention is
medicaments which comprise a compound of formula (i), or an addition salt of the latter
with a pharmaceutical^ acceptable acid.
Thus, the compounds according to the invention can be used, in humans or in
animals, in the treatment or prevention of various p75NTR-dependent conditions, 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 conditions, for instance
post-ischaemic cardiac damage, cardiomyopathies, myocardial infarction, heart failure,
cardiac ischaemia, cerebral infarction; peripheral neuropathies (of diabetic, traumatic or
iatrogenic origin); damage to the optic nerve and to the retina (retinal pigment
degeneration, glaucoma); retinal ischaemia; macular degeneration; spinal cord traumas
and cranial traumas; atherosclerosis; stenoses; cicatrization disorders; alopecia.
The compounds according to the invention may also be used in the treatment of
pancreatitis and of 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,
cancer of the small intestine and of the colon, or breast cancer, or in the treatment of
tumours, of metastases and of leukaemias.
The compounds according to the invention may also be used in the treatment of
respiratory disorders, for instance pulmonary inflammation, allergy, asthma and chronic
obstructive pulmonary disease.
The compounds according to the invention may also be used in the treatment of
cutaneous pain (in the skin, the subcutaneous tissues and the associated organs),
somatic pain, visceral pain (in 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 spondylarthritis, psoriatic arthritis, or plaque psoriasis.
The compounds according to the invention may also be used in the treatment of
bone fractures, or 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 ingredient, 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 method
of administration desired, from the customary excipients which are 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 ingredient of formula (I) above, or salt
thereof, may be administered in unit administration form, as a mixture with conventional
pharmaceutical excipients, to animals and to human beings for the prevention or
treatment of the disorders or of the diseases above.
The suitable unit administration forms comprise oral administration forms such as
tablets, hard or soft gel capsules, powders, granules and oral solutions or suspensions,
sublingual, buccal, intratracheal, intraocular, intra-auricular and intranasal administration
forms, forms for administration by inhalation, 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 administration form of a compound according to the
invention in tablet form may comprise the following components:
Compound according to the invention 50.0 mg
Mannitol 223.75 mg
Sodium croscaramellose 6.0 mg
Maize starch 15.0 mg
Hydroxypropylmethylceliulose 2.25 mg
Magnesium stearate 3.0 mg
The dose of active ingredient administered per day may reach 0.01 to 100 mg/kg,
as one or more intakes, preferably 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 capable of
producing a therapeutic effect.
There may be particular cases where higher or lower dosages are appropriate;
such dosages do not depart from the context of the invention. According to the customary
practice, the dosage suitable for each patient is determined by the physician according to
the method of administration and the weight and response of said patient.
According to another of its aspects, the present invention also relates to a method
of treating the pathological conditions 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. Compound corresponding to formula (I):
in which:
- A represents a group:
- n represents 1 or 2;
- m represents 0 or 1;
- Y represents a carbon, nitrogen, sulphur or oxygen atom or a single or double bond;
- X, X1 and X2 represent a carbon, nitrogen, sulphur or oxygen atom, it being understood
that at least one of X, X1 and X2 is other than a carbon atom;
- R and R1, located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (C1-C4)alkyl group, a (C1-C4)alkoxy group, a
perfluoroalkyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COOalkyl,
CONR5R6 or NHCOR5 group;
or R1 represents a group chosen from:

the definition of R remaining unchanged;
- R3 and R4, located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (C1-C4)alkyi group, a (C1-C4)alkoxy group, a
perfluoroalkyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COOalkyl,
CONR5R6 or NHCOR5 group;
- -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:

- R7 and R8, located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (C1-C4)a!kyl group, a (C1-C4)alkoxy group, a
trifluoromethyl radical, a trifluoromethoxy radical, a cyano, or a COOH, COOalkyl,
COOcycIoalkyl, SOalkyl, S02alkyl, CONH2, CONR5R6 or NHCOR5 group;
or one of R7 and R8 represents a heterocycle chosen from:

- Z represents an oxygen or sulphur atom;
- R5 and R6 represent a hydrogen or a C1-C6 alkyl group;
in the form of a base or of an addition salt with an acid.
2. Compound according to Claim 1, such that:
- W is a group of formula chosen from:

- R5 and R6 represent a hydrogen or a methyl group;
in the form of a base or of an addition salt with an acid.
3. Compound according to Claim 1 or 2, such that n represents 1;
in the form of a base or of an addition salt with an acid.
4. Compound according to any one of Claims 1 to 3, such that:
- R2 represents:

- R7 and R8, located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom, a (C1-C4) alkyl group, a trifluoromethyl radical, a COOH
group or a COOalkyl group;
or one of R7 and R8 represents a heterocycle chosen from:

in the form of a base or of an addition salt with an acid.
5. Compound according to any one of Claims 1 to 4, such that Y represents a nitrogen
atom or a single or double bond;
in the form of a base or of an addition salt with an acid.
6. Compound according to any one of Claims 1 to 5, such that X, X1 and X2 represent a
carbon, nitrogen or sulphur atom, it being understood that at least one of X, X1 and X2 is
other than a carbon atom;
in the form of a base or of an addition salt with an acid.
7. Compound according to any one of Claims 1 to 6, such that:
- R and R1, located on any one of the available positions, independently represent a
hydrogen atom, a halogen atom or a (C1-C4) alkyl group;
or else
R1 represents a group:

and R is a hydrogen atom;
- R3 and R4, located on any one of the available positions, represent a hydrogen atom, a
halogen atom, a (C1-C4) alkoxy group or a perfluoroalkyl radical;
in the form of a base or of an addition salt with an acid.
8. Compound according to any one of the preceding claims, chosen from:
- Compound No. 1: 1-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)-2-[8-(5-fluoropyrimidin-
2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 2: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-(2-
phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound No. 3: 1-(2-chloro-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-2-[8-(5-
fluoropyrirnidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 4: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-(2-
pheny!-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 5: 6-{3-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid methyl ester;
- Compound No. 6: 6-{(3S,5R)-3,5-dimethyl-4-[2~oxo-2-(2-phenyl-6,7-dihydro-4H-
thiazolo[5,4-c]pyridin-5-yl)ethyl3piperazin-1 -yl]nicotinic acid;
- Compound No. 7: 6-{3-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c3pyridin-5-
yl)ethyi]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound No. 8: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-
thiazolo[5,4-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid;
- Compound No. 9: 2-[(2S)6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-1 -
yl]-1-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound No. 10: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-
1-yl]-1-(2-phenyl-2,4,6l7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 11: 4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yl)ethyl]-1-(5-trifiuoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 12: 1-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-[4-(5-
trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound No. 13: 1-(2-phenyl-2,4,6,7-tetrahydropyrazoto[4l3-c]pyridin-5-yl)-2-[4-{5-
trifluoromethylpyridin-2-yl)piperazin-1-yl]ethanone;
- Compound No. 14: 4-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyrazo!o[4,3-c]pyridin-5-
yl)ethyl]-1-(5-trif!uoromethyipyridin-2-yl)piperazin-2-one;
- Compound No. 15: 2-[(2S,6R)-4-(5-fluoropyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl]-1-
(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound No. 16: 2-((2S,6R)-2,6-dimethyl-4-pyrimidin-5-yl-piperazin-1-yl)-1-(2-
phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 17: 2-[(2S,6R)-4-(5-fluoropyrimidin-2-yI)-2,6-dimethylpiperazin-1-yl]-1-
(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 18: 2-[(2S,6R)-2,6-dimethyl-4-(6-trifluoromethylpyridin-3-yl)piperazin-
1-yl]-1-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound No. 19: 6-{3-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid methyl ester;
- Compound No. 20: 2-[(2S,6R)-2,6-dimethy!-4-(6-trifluoromethylpyridin-3-yI)piperazin-
1-yl]-1-(2-phenyl-2)4)6,7-tetrahydropyrazoloE4l3-c]pyridin-5-yl)ethanone;
- Compound______No. 21: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-{2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid;
- Compound No. 22: 2-{(2S,6R)-2,6-dimethyl-4-pyrimidin-5-yl-piperazin-1 -yl)-1 -(2-
phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound______No. 23: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid methyl ester;
- Compound No. 24: 6-{3-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyrazoIo[4,3-c]pyridin-5-
yl)ethyl]-3,8-diazabicydo[3.2.1 ]oct-8-yl}nicotinic acid;
- Compound No. 25: 6-{2-oxo-4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-
c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid methyl ester;
- Compound No. 26: 2-[8-(5-fiuoropyrimidin-2-yl)-3,8-diazabicycloE3.2.1]oct-3-yl]-1-(1-
phenyl-1,4,6,7-tetrahydropyrazoloE4,3-c]pyridin-5-yl)ethanone;
- Compound No. 27: 1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-(4-
pyridin-3-yl[1,4]diazepan-1-yl)ethanone;
- Compound No. 28: 1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-(8-
pyridin-3-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
- Compound No. 29: 1 -(2-pheny!-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-[8-(5-
trifiuoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 30: 1-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-(4-pyridin
-3-yl~[1,4]diazepan-1 -yl)ethanone;
- Compound No. 31: 1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c3pyridin-5-yl)-2-(8-
pyrimidin-5-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)ethanone;
- Compound No. 32: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-{2-
methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 33: 6-(3-[2-oxo-2-(2-phenvl-4,6-dihvdropyrroio[3,4-d1thiazol-5-vl)ethyl1-
3,8-diazabicycio[3.2.1]oct-8-yl}nicotinic acid methyl ester;
- Compound No. 34: 4-{2-[2-(4-methoxyphenyl}-2,4,6,7-tetrahydropyrazolo[4,3-
c]pyridin-5-yi]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 35: 4-{2-[2-(4-fluorophenyl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 36: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1 ]oct-3-yl]-1 -(2-
methyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound No. 37: 6-(3-{2-[2-(4-methoxyphenyl)-6,7-dihydro-4H-thiazolo[5,4-
c]pyridin"5-yf]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinic acid methyl ester;
- Compound No. 38: 6-(3-{2-[2-(4-fluorophenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinic acid methyl ester;
- Compound No. 39: 6-(3-{2-oxo~2-[2-{5-trifluoromethylpyridin-2-yl)-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yi]ethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinic
acid methyl ester;
- Compound No. 40: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[2-
(5-trifluoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c3pyridin-5-yI]ethanone;
- Compound No. 41: 4-[2-oxo-2-(2-phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-
yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 42: 4-[2-oxo-2-(2-thiophen-3-yl-6,7-dihydro-4H-thiazolo[5,4-c3pyridin-
5-yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 43: 2-[8-(5-f!uoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[2-
(4-methoxyphenyl)-2,4,6,7-tetrahydropyrazoloE4,3-c]pyridin-5-yl]ethanone;
- Compound No. 44: 6-{3-[2-oxo-2-(2-thiophen-3-y!-6,7-dihydro-4H-thiazoIo[5,4-
c]pyridin-5-yl)ethyl]-3,8-diazabicycio[3.2.1]oct-8-yi}nicotinic acid;
- Compound No. 45: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[1-
(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-indazol-5-yl]ethanone;
- Compound No. 46: 2-[8-(5-fIuoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[1-
(4-methoxyphenyt)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone;
- Compound No. 47: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicycio[3.2.1]oct-3-yl]-1-
(2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 48: 6-{3-[2-oxo-2-(1 -phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethy!]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid methyl ester;
- Compound No. 49: 6-{3-[2-oxo-2-(1-phenyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound No. 50: 1-(l-tert-butyi-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-[8-
(5-fiuoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 51: 1-[1-(4-fluorophenyi)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]-
2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 52: 6-{(2R,5S)-2,5-dimethyl-4-[2-oxo-2-(2-pheny!-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethy!]piperazin-1-yl}nicotinonitrile;
- Compound No. 53: 6-{(2R,5S)-2,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c3pyridin-5-yl)ethy!]piperazin-1-yi}nicotinic acid;
- Compound No. 54: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-(2-
phenyl-4,7-dihydro-5H-fluoro[2,3-c]pyridin-6-yl)ethanone;
- Compound No. 55: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1 ]oct-3-yl]-1 -(2-
phenyl-1,4,5,7-tetrahydropyrrolo[2,3-c]pyridin-6-yl)ethanone;
- Compound No. 56: 6-{8-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}nicotinic acid methyl ester;
- Compound No. 57: 6-{8-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}nicotinic acid methyl ester;
- Compound No. 58: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicycIo[3.2.1]oct-3-yt]-1-(2-
phenyl-6,7-dihydro-4H-oxazolo[4,5-c3pyridin-5-yl)ethanone;
- Compound No. 59: 6-{(2R,5S)-2,5-dimethyl-4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-
thiazolo[5,4-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinonitrile;
- Compound No. 60: 2-{8-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)pyridin-2-y!]-3,8-
diazabicyclo[3.2.1]oct-3-yl}-1-(2-phenyl-6,7-dihydro-4H-thiazolot5,4-c]pyridin-5-
yl)ethanone;
- Compound No. 61: 6-{8-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyrazoio[4,3-c] pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-3-y[}nicotinic acid;
- Compound No. 62: 6-{8-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
y!)ethyl]-3,8-diazabicyclo[3.2.13oct-3-yl}nicotinic acid;
- Compound No. 63: 6-{(2R,5S)-2,5-dimethyl-4-[2-oxo-2-(2-phenyi-6,7-dihydro-4H-
thiazolo[5,4-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid;
- Compound No. 64: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl3-1-(2-
pyridin-4-yl-6,7-dihydro-4H-thtazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound_______No. 65: 4-{2-oxo-2-[2-(5-trif!uoromethylpyridin-2-yl)-2,4,6,7-
tetrahydropyrazoio[4,3-c]pyridin-5-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-
one;
- Compound No. 66: 4-{2-oxo-2-[1-(2,2,2-trifluoroethyl)-1,4,6,7-tetrahydropyrazolo [4,3-
c]pyridin-5-yl]ethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 67: 2-[8-(5-f!uoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-(2-
phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)ethanone;
- Compound No. 68: 3-(6-{3-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyrazo[o[4,3-c]
pyridin-5-yl)ethyl3-3,8-diazabicyclo[3.2.1]oct-8-yl}pyridin-3-yl)-4H-[1,2,4]oxadiazo!-5-
one;
- Compound No. 69: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1 ]oct-3-yl]-1 -(2-
phenyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)ethanone;
- Compound No. 70: 3-(6-{3-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yi}pyridin-3-yl)-4H-[1,2,4]oxadiazol-5-one;
- Compound No. 71: 2-E8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-(2-
phenyl-6,7-dihydro-4H-thiazolo[4,5-c]pyridin-5-yl)ethanone;
- Compound No. 72: 2-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-
thiazolo[5,4-c]pyridin-5-yl)ethyl]piperazin-1-yl}pyrimidine-5-carboxylic acid;
- Compound No. 73: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1 ]oct-3-yl]-1 -(2-
pyridin-3-yl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)ethanone;
- Compound No. 74: 1-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-{8-[5-(1 H-
tetrazol-5-yl)pyridin-2-yl]-3,8-diazabicyclo[3.2.1]oct-3-yl}ethanone;
- Compound No. 75: 2-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-214,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}pyrimidine-5-carboxylic acid;
- Compound No. 76: 6-(3-{2-[2-(4-fluorophenyl)-6,7-dihydro-4H-thiazo!o[5,4-c]pyridin-5-
yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.13oct-8-yl)nicotinonitrile;
- Compound No. 77: 6-{3-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyrazoio[4,3-c]pyridin-5-
yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8-yi}nicotinonitrile;
- Compound No. 78: 4-[2-oxo-2-(2-phenyl-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-
yl)ethyl]-1-(5-trifluoromethy!pyridin-2-yl)piperazin-2-one;
- Compound No. 79: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c3pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid ethyl ester;
- Compound No. 80: 1-t2-(4-fluorophenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-2-
[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 81: 2-[8-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.13oct-3-yl3-1-[2-
(4-methoxypheny)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yi]ethanone;
- Compound No. 82: 4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-thiazolo[4,5-c]pyridin-5-
y!)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 83: 4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-oxazolo[4,5-c]pyridin-5-
yl)ethyl3-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 84: 4-[2-oxo-2-(2-pyridin-3-yl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-
yl)ethyl]-1-(5-trifluoromethyipyridin-2-yl)piperazin-2-one;
- Compound No. 85: 2-{8-[5-(2-methyl-2H-tetrazol-5-yl)pyridin-2-yl]-3,8-diazabicyclo
[3.2.13oct-3-yl}-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 86: 2-{(2S,6R)-2,6-dimethyl-4-[5-(1-methyl-1 H-tetrazol-5-yl)-pyridin-2-
yl]piperazin-1-yl}-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c3pyridin-5-yl)ethanone;
- Compound No. 87: 2-{(2S,6R)-2,6-dimethy!-4-[5-(2-methyl-2H-tetrazol-5-yl)-pyridin-2-
y!]piperazin-1-yl}-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 88: 2-[8-{5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-[1-
(4-trifluoromethylphenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone;
- Compound No. 89: 2-{(2S,6R)-2,6-dimethyl-4-[5-(5-methyl[1,2,4]oxadiazoi-3-yi}-
pyridin-2-yl]piperazin-1-yl}-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4l3-c3pyridin-5-
yl)ethanone;
- Compound No. 90: 2-[{2S,6R)-2,6-dimethyl-4-(5-[1,3,4]oxadiazol-2-ylpyridin-2-
yl)piperazin-1-yl]-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 91: 2-{(2S,6R)-2,6-dimethyl-4-[5-(3-methyl-[1,2,4]oxadiazof-5-yI)-
pyridin-2-yl]piperazin-1-yl}-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
y!)ethanone;
- Compound No. 92: 6-{(3S,5R)-4-[2-(1-tert-butyl-1,4,6,7-tetrahydropyrazolo[4,3-
c]pyridin-5-yl)-2-oxoethyi]-3,5-dimethylpiperazin-1-yl}nicotinic acid methyl ester;
- Compound No. 93: 6-{(3S,5R)-4-[2-(1-tert-butyl-1,4,6,7-tetrahydropyrazolo[4,3-
c]pyridin-5-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinic acid;
- Compound No. 94: 6-{3-[2-(1-tert-butyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-
2-oxoethyl]-3,8-diazabicyclo[3.2.1]oct-8-yl}nicotinic acid;
- Compound No. 95: 2-[8-(5-f!uoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-1-{2-
phenyl-6,7-dihydro-4H-oxazolo[5,4-c3pyridin-5-yl)ethanone;
- Compound No. 96: 4-[2-oxo-2-(2-phenyl-6,7-dihydro-4H-oxazolo[5,4-c]pyridin-5-
yl)ethyl]-1-(5-trifluoromethyipyridin-2-yl)piperazin-2-one;
- Compound No. 97: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-
1-yl]-1-(2-phenyl-4,7-dihydro-5H-fluoro[2,3-c]pyridin-6-yl)ethanone;
- Compound No. 98: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid isopropyl ester;
- Compound No. 99: 1-(2-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-[8-{5-
trifiuoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 100: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethyipyridin-2-yl)piperazin-
1-yl]-1-(2-methyl-2,4I6,7-tetrahydropyrazolo[4l3-c]pyridin-5-yl)ethanone;
- Compound No. 101: 1-(2-phenyl-4,7-dihydro-5H-fIuoro[2,3-c]pyridin-6-yl)-2-[8-(5-
trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 102: 6-(3-{2-[2-(4-fiuorophenyi)-6,7-dihydro-4H-thiazo!o[5,4-c] pyridin-
5-yl]-2-oxoethyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)nicotinic acid;
- Compound No. 103: 2-[(2S,6R)-2,6-dimethyi-4-(5-trifiuoromethylpyridin-2-yl)piperazin-
1-yl]-1-[2-(5-trifluoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl]ethanone;
- Compound No. 104: 2-r8-(5-trifluoromethvlpvridin-2-yl)-3,8-diazabicvclo[3.2.]oct-3-yl]-
1-[2-(5-trifluoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl]ethanone;
- Compound No. 105: 6-{(3S,5R)-4-[2-(2-tert-butyl-2,4,6,7-tetrahydropyrazolo[4,3-
c]pyridin-5-yl)-2-oxoethyl]-3,5-dimethylpiperazin-1-yl}nicotinic acid;
- Compound No. 106: 2-(8-pyridin-3-yl-3,8-diazabicyclo[3.2.1]oct-3-yl)-1-[2-(5-
trifluoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone;
- Compound No. 107: 2-[5-(6-trifluoromethylpyridazin-3-yl)-2,5-diazabicyclo[2.2.1] hept-
2-yl]-1-[2-(5-trifiuoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c] pyridin-5-
yl]ethanone;
- Compound No. 108: 2-(6'-chloro-2,3,5,6-tetrahydro[1,2,]bipyrazinyl-4-yl)-1-[2-(5-
trifiuoromethylpyridin-2-yl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone;
- Compound No. 109: 1-{2-phenyl-3,4,6,7-tetrahydroimidazo[4,5-c3pyridin-5-yi)-2-E8-(5-
trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 110: 2-[(2SI6R)-2,6-dimethy!-4-(5-trifluoromethyipyridin-2-yl)piperazin-
1-yl]-1-(2-pheny!-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)ethanone;
- Compound No. 111: 2-((3S,5R)-3,5-dimethy!-2,3,5l6-tetrahydro[1,2']bipyraziny!-4-yl)-
1-[2-(5-trifluoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl]ethanone;
- Compound No. 112: 2-[(2S,6R)-4-(5-chloropyridin-2-yl)-2,6-dimethylpiperazin-1-yl]-1-
[2-(5-trifluoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl]ethanone;
- Compound No. 113: 2-[4-(7-chloroquinolin-4-yl)piperazin-1-yl]-1-(2-phenyl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 114: 2-[4-(6-chloropyridin-2-yl)piperazin-1-yl]-1-(2-phenyl-2,4,6,7-
tetrahydropyrazoIo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 115: 1-(2-pyridin-4-yl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-[8-
(5-trifluoromethylpyridin2-yl)-3,8-diazabicyclo[3,2.1]oct-3-yl]ethanone;
- Compound No. 116: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-3,4,6,7-
tetrahydroimidazo[4,5-c]pyridin-5-yl)ethy]piperazin-1-yl}nicotinic acid;
- Compound No. 117: 1-(2-pyridin-2-yl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yI)-2-
E8-(5-trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 118: 2-[(2S,6R)-2,6-dimethyi-4-(5-trifluoromethylpyridin-2-yl)piperazin-
1-yl]-1-(2-pyridin-2-yl-2,4,6,7-tetrahydropyrazo!o[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 119: 4-[2-oxo-2-(2-pyridin-2-yl-2,4,6,7-tetrahydropyrazolo[4,3-c]
pyridin-5-yl)ethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 120: 4-{2-[2-(4-fluorophenyl)-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-
yl]-2-oxoethyl}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 121: 2-(8-pyridin-3-yl-3,8-diazabicycloE3.2.1]oct-3-yl)-1-(2-pyridin-2-yl-
2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 122: 1-[2-(2,2,2-trifIuoroethyi)-2,4,6,7-tetrahydropyrazolo[4l3-c]pyridin-
5-yl]-2-[8-(5-trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-y!]ethanone;
- Compound No. 123: 1-[2-(4-fluorophenyl)-3,4,6,7-tetrahydroimidazo[4,5-c3pyridin-5-
yl]-2-[8-(5-trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 124: 2-[(2S,6R)-2,6-dimethyl-4-{5-trifiuoromethylpyridin-2-yi)piperazin-
1-yl]-1-t2-(4-fluorophenyl)-3,4,6,7-tetrahydroimidazoE4,5-c]pyridin-5-yl]ethanone;
- Compound No. 125: 4-{2-oxo-2-[2-(2,2,2-trifluoroethyl)-2,4,6,7-tetrahydropyrazoio
E4,3-c]pyridin-5-yl3ethy!}-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 126: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yI)piperazin-
1-yl]-1-[2-(2,2,2-trifluoroethy!)-2I4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone;
- Compound No. 127: 1-(2-phenyl-2,4l6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-[5-(5-
trifluoromethylpyridin-2-yf)-2,5-diazabicycIo[2.2.1]hept-2-y[]ethanone;
- Compound No. 128: 6-{3-[2-oxo-2-(2-phenyl-2,4,6,7-tetrahydropyrazoIo[4,3-c]pyridin-
5-yl)ethyl]-3,8-diazabicyclo[3.2.1]oct-8~yl}nicotinic acid cyclobutyl ester;
- Compound No. 129: 2-((2S,6R)-2,6-dimethyl-4-quinolin-2-ylpiperazin-1 -yl)-1 ~(2-
phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 130: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4I617-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid ethyl ester;
- Compound_______No. 131: 2-[(2S,6R)-4-(5-methanesuIphonylpyndin-2-yl)-2,6-
dimethylpiperazin-1-yl]-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-
yl)ethanone;
- Compound No. 132: 2-E(2S,6R)-4-(5-fiuoropyrimidin-2-yl)-2,6-dimethylpiperazin-1 -ylj-
1-[2-(4-methoxyphenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yi]ethanone;
- Compound No. 133: 1-[2-(4-methoxyphenyl)-6,7-dihydro-4H-thiazo!o[5,4-c3pyridin-5-
yl]-2-[5-(5-trifluoromethylpyridin-2-yl-6,7-diazabicyclo[2,2,1]hept-2-yl]ethanone;
- Compound No. 134: 1-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-{4-[5-
(2H-pyrazol-3-yi)pyridin-2-yl]piperazin-1-yl}ethanone;
- Compound No. 135: 2-[(2S,6R)-2,6-dimethyl-4-(5-thiazol-2-ylpyridin-2-yl)piperazin-1-
yl]-1-(2-phenyI-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 136: 1-(2-phenyl-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl)-2-[8-{5-
thiazol-2-ylpyridin-2-yl)-3,8-diazabicyclo[3.2.13oct-3-yl]ethanone;
- Compound No. 137: 2-[8-(5-[1,2,4]oxadiazol-3-ylpyridin-2-yl)-3,8-diazabicyclo
[3.2.13oct-3-yl]-1-(2-phenyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 138: 1-(2-ethyl-2,4,6,7-tetrahydropyrazolo[4,3-c3pyridin-5-yl)-2-[8-(5-
trifluoromethylpyridin-2-yl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethanone;
- Compound No. 139: 2-[(2S,6R)-2,6-dimethyl-4-(5-[1,2,4]oxadiazol-5-ylpyridin-2-
yl)piperazin-1-y!]-1-(2-phenyl-2,4,6,7-tetrahydropyrazoIo[4,3-c3pyridin-5-yl)ethanone;
- Compound No. 140: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-pyridin-2-yl-2J4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid;
- Compound No. 141: 2-((2S)6R)-2,6-dimethyi-4-pyridin-3-ylpiperazin-1-y!)-1-(2-pyridin-
4-yl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 142: 2-((2S,6R)-2,6-dimethyl-4-pyridin-3-yipiperazin-1-yi)-1-[2-(5-
fluoropyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone;
- Compound No. 143: 2-{(2S,6R)-2,6-dimethyl-4-pyridin-3-ylpiperazin-1 -yl)-1 -[2-(5-
trifluoromethylpyridin-2-yl)-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl]ethanone;
- Compound No. 144: 6-{(3S,5R)-3,5-dimethyi-4-E2-oxo-2-(2-pyridin-2-yl-2,4,6,7-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyi]piperazin-1-yl}nicotinic acid methyl ester;
- Compound No. 145: 2-((2S,6R)-2,6-dimethyl-4-pyridin-3-ylpiperazin-1-yl)-1-(2-phenyl-
3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)ethanone;
- Compound No. 146: 2-E(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-
1-yl]-1-(2-pyridazin-3-yi-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 147: 2-[(2S,6R)-2,6-dimethyl-4-(5-trifluoromethylpyridin-2-yl)piperazin-
1-y)]-1-(2-ethyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone;
- Compound No. 148: 4-[2-(2-ethy!-2,4,6)7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)-2-
oxoethyl]-1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one;
- Compound No. 149: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4,617-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyl]piperazin-1-yl}nicotinic acid;
- Compound No. 150: 6-{(3S,5R)-3,5-dimethyl-4-[2-oxo-2-(2-phenyl-2,4,617-
tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethyi]piperazin-1-yi}nicotinic acid;
in the form of a base or of an addition salt with an acid.
9. Process for preparing a compound of formula (i) according to any one of Claims
1 to 8, characterized in that a compound of formula (II):

in which Y, X, X1, X2, R1, R, n and m are defined according to any one of Claims 1 to 8
and Hal represents a halogen atom,
is reacted with a compound of general formula (III):
H-W-R2
(III)
in which W and R2 are as defined in any one of Claims 1 to 8.
10. Compound of formula (II):

in which Y, X, X1, X2, R1, R, n and m are defined according to any one of Claims 1 to 8
and Hal represents a halogen atom;
in the form of a base or of an addition salt with an acid.
11. Medicament, characterized in that it comprises a compound of formula (I)
according to any one of Claims 1 to 8, or an addition salt of this compound with a
pharmaceutical^ acceptable acid.
12. Pharmaceutical composition, characterized in that it comprises a compound of
formula (I) according to any one of Claims 1 to 8, or a pharmaceutically acceptable salt,
and also at least one pharmaceutically acceptable excipient.
13. Compound according to any one of Claims 1 to 8, as a medicament.
14. Compound according to any one of Claims 1 to 8, for the preparation of a
medicament for use in the prevention or treatment 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 conditions, post-ischaemic cardiac damage, cardiomyopathies, myocardial
infarction, heart failure, cardiac ischaemia, cerebral infarction; peripheral neuropathies,
damage to the optic nerve and to the retina, retinal pigment degeneration, glaucoma,
retinal ischaemia, macular degeneration, spinal cord traumas, cranial traumas,
atherosclerosis, stenoses, cicatrization disorders, alopecia, pancreatitis, hepatic fibrosis,
cancers, tumours, metastases, leukaemias, 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 spondylarthritis, psoriatic arthritis,
plaque psoriasis, bone fractures, bone diseases and osteoporosis.
15. Compound according to Claim 14, having the ability to inhibit the dimerization
of the p75NTR receptor independently of its ligand.
16. Use of a compound according to one of Claims 1 to 8, for the preparation of
medicaments of use in the treatment and prevention of centra! 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 conditions, post-ischaemic cardiac damage, cardiomyopathies, myocardial
infarction, heart failure, cardiac ischaemia, cerebral infarction; peripheral neuropathies,
damage to the optic nerve and to the retina, retinal pigment degeneration, glaucoma,
retinal ischaemia, macular -degeneration, spinal cord traumas, cranial traumas,
atherosclerosis, stenoses, cicatrization disorders, alopecia, pancreatitis, hepatic fibrosis,
cancers, tumours, metastases, leukaemias, 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 spondylarthritis, psoriatic arthritis,
plaque psoriasis, bone fractures, bone diseases and osteoporosis.

ABSTRACT

The invention relates to
(heterocycle/condensed piperidine)-
(piperazinyl)-1-alcanone or heterocycle/condensed pyrrolidine)-
(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.