DE102004037445A1 - New indolizine and azaindolizine carboxamide derivatives, useful for treating e.g. schizophrenia and urinary incontinence, are ligands for serotinergic receptors - Google Patents

Abstract

(Aza)indolizine derivatives (I) as free bases, salts, enantiomers and diastereomers are new. (Aza)indolizine derivatives of formula (I) as free bases, salts, enantiomers and diastereomers are new. A : saturated or aromatic 6-membered ring; B' : aromatic 5-membered ring, and A plus B' contain at most 3 ring-forming N atoms; Q 1, Q 2 and Q 3N, CH or CR 1; Q 4NR, CHR' 1 or CHR 1R' 1; Q 5, Q 6 and Q 7CHR' 1 or CR 1R' 1; R 1hydroxy, alkyl, alkoxy, alkylthio, alkenyl, alkynyl, phenyl, phenoxy, halo, trifluoromethyl, alkylcarbonyl, phenylcarbonyl, alkoxycarbonyl, cyano, nitro, amino, carboxy, sulfo, sulfamoyl, (alkyl)aminosulfonyl or alkylsulfonylamino; R' 1hydrogen when A is aromatic but is absent when A is saturated; R : hydrogen, alkyl, phenyl, alkylcarbonyl, phenylcarbonyl, phenylalkyl or phenylsulfonyl when A is saturated but is absent if A is aromatic; X : group (X1), bound to a C atom of an aromatic A or B'; Y' : bridging group; R 2-R 6hydrogen or substituents; and R 7hydrogen, alkyl or phenylalkyl. The full definitions are given in the DEFINITIONS - Full Definitions field. Independent claims are also included for the following: (1) preparation of (I) by reacting a heterocyclic free acid, or its halide or ester, with the appropriate amine; and (2) method for preparing pyrazolo[1,5-a]pyrimidine derivatives (X) by reacting an Rx-pyridine with O-(2,4-dinitrophenyl)hydroxylamine of formula (a) to an N-aminopyridinium salt, then cycloaddition reaction of this with R''OOC-Ctriple boundC-R'. Rx : 0-4, same or different, halo, alkyl, alkylcarbonyl, phenylcarbonyl, hydroxyalkyl, cyano, trifluoromethyl or alkoxycarbonyl, but position * is not substituted; R' : hydrogen, alkyl, phenyl or alkoxycarbonyl; and R'' : alkyl. [Image] [Image] [Image] [Image] ACTIVITY : Uropathic; Neuroleptic; Tranquilizer; Nootropic; Antiparkinsonian; Antiemetic; Vasotropic; Ophthalmological; Cerebroprotective. MECHANISM OF ACTION : 5-HT1a or D3 serotonergic receptors. Test methods are described but no results for individual compounds are given.

Description

dopamine is considered an important neurotransmitter of the central nervous system. Its effect mediates dopamine by binding to five different Dopamine receptors. These can be due to their morphology and their type of signal transmission into classes D1-like (D1 and D5) and D2-like (D2, D3 and D4 receptors) (Neve, K. A. The Dopamine Receptors, Humana Press, 1997). Especially the subtypes of the D2 family play in the regulation central nervous system operations an important role. While the D2 receptors predominantly be expressed in the basal ganglia and there at the control and modulation of neuromotor circuits are involved D3 receptors especially in the mesolimbic system, in which emotional and cognitive operations to be controlled. disorders in the signal transduction of these receptors lead to numerous neuropathological changes, cause some serious illnesses. Thus presents In particular, the D3 receptor is a promising target for development of drugs for the treatment of psychiatric disorders such as schizophrenia or unipolar depression, from impaired consciousness as well for the treatment of neurodegenerative diseases such as Parkinsonism and the dyskinesias that occur during long-term therapy, but also for the treatment of drug addiction (Pulvirenti, L. et al. Trends Pharmacol. Sci. 2002, 23, 151-153, Joyce, J.N. Pharmacol. Ther. 2001, 90, 231-259) The goal is to be as possible D3 receptor-selective binding profile for such active substances. ever after intrinsic activity (full agonist, partial agonist, antagonist or inverse agonist) can such ligands stimulating, modulating or also inhibiting the pathological changed Dopamine signal transduction system influence and thus therapy these diseases are used.

Compounds with arylpiperazine structure have already been described as dopamine receptor-active ligands (Robarge, MJJ Med. Chem. 2001, 44, 3175-3186). Furthermore, benzamides and naphthamides with arylpiperazine partial structure are known as ligands of dopamine receptors (Perrone, RJ Med. Chem. 1998, 41, 4903-4909; EP 0 779 284 A1 ). Recently, heteroarenamides have also been described as D3 receptor-active compounds (Bettinetti, L. et al., J. Med. Chem., 2002, 45, 4594-4597, Leopoldo, M., et al., J. Med. Chem , 45, 5727-5735, WO 2004004729 A1). Recently, a phenylpiperazinylnaphthamide has also been reported to act as a selective D3 partial agonist, displaying hopeful activities in the animal model that could be used to treat cocaine addiction (Pilla, M. et al., Nature 1999, 400, 371-375). In addition, due to the characteristics of this compound, the severe movement abnormalities (dyskinesias) associated with long-term treatment of parkinsonism with the drug L-DOPA could be reversed (Bezard, E. et al., Nature Med., 2003, 9, 762-767). , Recent literature describes the neuroprotective effect of D3-selective partial agonists against MPTP-induced neuronal loss in mice as a murine model of parkinsonism (Boeckler, F. et al., Biochem. Pharmacol., 2003, 6, 1025-1032).

From the series of Arylpiperazinylheteroarencarboxamide especially structural examples with oxygen-, sulfur- or nitrogen-containing Heteroarencarbonsäurekomponenten are described (ES 2027898; EP 343 961 ; US 3646047 ; US 3734915 ; WO 2004/024878; Leopoldo, M. et al. J. Med. Chem. 2002, 45, 5727-5735, WO 2004004729 A1). Indolizine-substituted ligands are not disclosed in these references.

Bettinetti, L. et al. J. Med. Chem. 2002, 45, 4594-4597 described for the first time a few pyrazolo [1,5-a] pyridines with affinity to the D3 receptor. Other indolic-substituted ligands, however, are not yet known.

We have new as part of our structure-activity studies of dopamine receptor ligands Compounds of the formula (I) - (IV) discovered. These showed particularly high affinity and selective in in vitro investigations Binding properties at the D3 receptor. Some connections point also remarkable affinity for serotonergic receptors, in particular to the 5-HT1a receptor.

The compounds of the invention could thus be valuable therapeutics for the treatment of CNS disorders such as schizophrenia or various types of depression, neuroprotection in neurodegenerative diseases, addictions, glaucoma, cognitive disorders, restless leg syndrome, hyperactivity disorder (ADHD), hyperprolactinemia, hyperprolactinoma, Autism, in idiopathic or drug-induced extrapyramidal motor movement disorders, eg Akathisia, rigor, dystonia and dyskinesia as well as various diseases of the urinary tract represent.

in der bedeuten:
A ist ein gesättigter oder aromatischer 6-gliedriger Ring;
B ist ein aromatischer 5-gliedriger Ring;
das aus A+B gebildete Heteroaren weist insgesamt höchstens drei ringbildende N-Atome und genau eine Gruppe X als Substituenten auf;
Q1, Q2 und Q3 sind jeweils unabhängig voneinander N, CH oder C-R1;
Q4 ist N-R, CH-R1' oder C-R1R1';
Q5, Q6 und Q7 sind unabhängig voneinander CH-R1' oder C-R1R1';
R1 ist jeweils ausgewählt aus der Gruppe Hydroxy, Alkyl, Alkyloxy, Alkylthio, Alkenyl, Alkinyl, Phenyl, Phenoxy, Halogen, Trifluormethyl, Alkylcarbonyl, Phenylcarbonyl, Alkyloxycarbonyl, Cyano, Nitro, Amino, Carboxy, Sulfo, Sulfamoyl, Sulfonylamino, Alkylaminosulfonyl und Alkylsulfonylamino;
R1' fehlt, wenn Ring A aromatisch ist oder ist Wasserstoff, wenn Ring A gesättigt ist;
R fehlt, wenn Ring A aromatisch ist oder ist ausgewählt aus Wasserstoff, Alkyl, Phenyl, Alkylcarbonyl, Phenylcarbonyl, Phenylalkyl und Phenylsulfonyl, wenn Ring A gesättigt ist;
X ist eine an ein C-Atom eines aromatischen Rings A oder B gebundene Gruppe der allgemeinen Formel X1

wobei gilt:
Y ist eine unverzweigte, gesättigte oder ungesättigte Kohlenwasserstoffkette mit 2-5 Kohlenstoffatomen oder eine Kette -(CH2)_o-Z-(CH2)_p, worin Z ausgewählt ist aus den Resten Cyclopentyl, Cyclohexyl und Cycloheptyl, wobei o und p jeweils unabhängig voneinander den Wert 0, 1, 2 oder 3 haben und wobei die Summe aus o und p höchstens 3 ist;
R2, R3, R4, R5 und R6 sind jeweils unabhängig voneinander ausgewählt aus der Gruppe Wasserstoff, Hydroxy, Alkyl, Alkyloxy, Alkylthio, Alkenyl, Alkinyl, Phenyl; Phenoxy, Halogen, Trifluormethyl, Alkylcarbonyl, Phenylcarbonyl, Alkyloxycarbonyl, Cyano, Nitro, Amino, Carboxy, Sulfo, Sulfamoyl, Sulfonylamino, Alkylaminosulfonyl und Alkylsulfonylamino, wobei zwei benachbarte Reste R2, R3, R4, R5 und R6 auch gemeinsam mit den C-Atomen des Phenylrings an die sie gebunden sind, einen sauerstoffhaltigen 5-, 6- oder 7-gliedrigen Ring bilden können;
R7 ist Wasserstoff, Alkyl oder Phenylalkyl;
in Form der freien Base, deren physiologisch akzeptable Salze sowie möglicher Enantiomere und Diastereomere,
mit der Maßgabe, daß ausgenommen sind,

• (a) Verbindungen, in denen der Heterozyklus ein Pyrazolo[1,5-a]pyridin ist, insbesondere wenn dieses als einzigen Substituenten die Gruppe X, aber keinen Substituenten R1 trägt, wobei für X gilt: R2 = Methoxy; R3, R4, R5, R6 und R7 sind jeweils Wasserstoff und (i) Y = Ethyl, n-Propyl oder n-Butyl oder (ii) Y = n-Pentyl und X ist in 2- oder 3-Position mit dem Pyrazolo[1,5-a] pyridin-Kern verknüpft
• (b) Die Verbindung N-4-(4-(2-Chlorphenyl)piperazin-1-yl)butyl-7-methylpyrazolo[1,5-a]pyridin-3-ylcarbamid.

The invention relates to compounds of general formula I,

in which mean
A is a saturated or aromatic 6-membered ring;
B is an aromatic 5-membered ring;
the heteroarene formed from A + B has a total of at most three ring-forming N atoms and exactly one group X as substituents;
Q1, Q2 and Q3 are each independently N, CH or C-R1;
Q4 is NR, CH-R1 'or C-R1R1';
Q5, Q6 and Q7 are independently CH-R1 'or C-R1R1';
R 1 is in each case selected from the group hydroxy, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, phenylcarbonyl, alkyloxycarbonyl, cyano, nitro, amino, carboxy, sulfo, sulfamoyl, sulfonylamino, alkylaminosulfonyl and alkylsulfonylamino ;
R1 'is absent when ring A is aromatic or is hydrogen when ring A is saturated;
R is absent when ring A is aromatic or is selected from hydrogen, alkyl, phenyl, alkylcarbonyl, phenylcarbonyl, phenylalkyl and phenylsulfonyl when ring A is saturated;
X is a group of the general formula X1 bonded to a C atom of an aromatic ring A or B

where:
Y is an unbranched, saturated or unsaturated hydrocarbon chain of 2-5 carbon atoms or a chain - (CH 2) _o -Z- (CH 2) _p wherein Z is selected from the radicals cyclopentyl, cyclohexyl and cycloheptyl, where o and p are each independently have the value 0, 1, 2 or 3 and where the sum of o and p is at most 3;
R 2, R 3, R 4, R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl; Phenoxy, halogen, trifluoromethyl, alkylcarbonyl, phenylcarbonyl, alkyloxycarbonyl, cyano, nitro, amino, carboxy, sulfo, sulfamoyl, sulfonylamino, alkylaminosulfonyl and alkylsulfonylamino, wherein two adjacent radicals R2, R3, R4, R5 and R6 also together with the carbon atoms the phenyl ring to which they are attached can form an oxygenated 5-, 6- or 7-membered ring;
R7 is hydrogen, alkyl or phenylalkyl;
in the form of the free base, its physiologically acceptable salts and possible enantiomers and diastereomers,
with the proviso that they are exempt,

• (a) compounds in which the heterocycle is a pyrazolo [1,5-a] pyridine, especially when this carries as a single substituent the group X, but no substituent R1, wherein for X is: R2 = methoxy; R3, R4, R5, R6 and R7 are each hydrogen and (i) Y = ethyl, n-propyl or n-butyl or (ii) Y = n-pentyl and X is in the 2- or 3-position with the pyrazolo [ 1,5-a] pyridine nucleus linked
• (b) The compound N-4- (4- (2-chlorophenyl) piperazin-1-yl) butyl-7-methylpyrazolo [1,5-a] pyridin-3-ylcarbamide.

The Group X can react with any ring-forming carbon suitable for bonding be linked to an aromatic ring A or B. A is a saturated one Ring, X is bound to a carbon atom of the ring B. The meaning the groups Q1, Q2, Q3, Q4, Q5, Q6 and Q7 in formula I, as further described above, is therefore according to the invention so understand that one of the groups Q1, Q2, Q3, Q4, Q5, Q6 and Q7 included ring-forming carbons of an aromatic ring is substituted with the group X and the group forms C-X.

Of the Term "saturated Ring A "and grammatical equivalents This term in the present patent application means that the ring A maximally saturated is, that is, all ring-forming atoms of the ring A, which are not part at the same time of the aromatic ring B are completely saturated.

In an embodiment of the invention, the two rings A and B next to the group X at the most 4, 3, 2 or 1 substituents R1 or are apart from the Group X unsubstituted.

In a preferred embodiment of the invention are the substituents R 1 of the heteroarene in the compounds of the invention of the general formulas I, II, III and IV selected from the group hydroxy, Fluorine, chlorine, bromine, trifluoromethyl, cyano, amino, carboxy, sulfo, Sulfamoyl, unsubstituted or hydroxy-substituted C1-C6 Alkyl, unsubstituted or hydroxy-substituted C1-C6 alkyloxy, unsubstituted or hydroxy-substituted C1-C6 alkylthio, unsubstituted C 2 -C 6 alkynyl, unsubstituted or with fluorine, Chlorine or bromine and / or with one or more methoxy groups substituted phenyl, unsubstituted or with fluorine, chlorine or Bromine and / or substituted with one or more methoxy groups Phenoxy, -C (O) -C1-C6 alkyl, wherein the alkyl is unsubstituted or substituted with hydroxy, -C (O) -phenyl, wherein the phenyl is unsubstituted or with fluorine, chlorine or bromine and / or with one or more Methoxy is substituted, C1-C6 alkyloxycarbonyl, wherein the Alkyl is unsubstituted or substituted by hydroxy, C1-6 alkylaminosulfonyl, in particular methylaminosulfonyl and C1-6 alkylsulfonylamino, in particular methanesulfonylamino.

The substituent Q4 in ring A is, depending on the degree of saturation of the ring A, NR, CH-R1 'or C-R1R1'. In a saturated ring A, R1 'is hydrogen and Q4 is selected from NR, CH ₂ and CH-R1, wherein R is preferably selected from hydrogen, phenylalkyl and phenylsulfonyl, and wherein R1 has the meaning as defined above. In an aromatic ring A, the substituents R and R1 'are absent; Q4 is then selected from N, CH and C-R1. If Q4 comprises a nitrogen atom, it is preferably uncharged.

R2, R3, R4, R5 and R6 are in the compounds of the invention of the general Formulas I, II, III and IV are preferred and each independently selected from the group hydroxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, Amino, carboxy, sulfo, sulfamoyl, unsubstituted or with hydroxy substituted C1-C6 alkyl, unsubstituted or substituted with hydroxy C1-C6 alkyloxy, unsubstituted or substituted with hydroxy C1-C6 alkylthio, unsubstituted C2-C6 alkynyl, unsubstituted or with fluorine, chlorine or bromine and / or with one or more Methoxy substituted phenyl, unsubstituted or with Fluorine, chlorine or bromine and / or with one or more methoxy groups substituted phenoxy, -C (O) -C1-C6 alkyl, wherein the alkyl is unsubstituted or substituted with hydroxy, -C (O) -phenyl, wherein the phenyl unsubstituted or with fluorine, chlorine or bromine and / or with a or more methoxy groups, C1-C6 alkyloxycarbonyl, where the alkyl is unsubstituted or substituted by hydroxy, C 1-6 alkylaminosulfonyl, especially methylaminosulfonyl and C 1-6 Alkylsulfonylamino, especially methanesulfonylamino, or two adjacent Radicals R2, R3, R4, R5 and R6 together form the C atoms of the phenyl ring to which they are attached, an oxygen-containing 5-, 6- or 7-membered ring.

In a preferred embodiment of the invention, Y in the compounds according to the invention is a chain - (CH ₂ ) _p -Z- (CH ₂ ) _o -, where Z is selected from the radicals cyclopentyl, cyclohexyl and cycloheptyl, and where p and o independently of one another are selected from 0.1 and 2 and together give a value of at most 2 or 1 or both are 0.

dar, in der n den Wert 4 oder 5 hat und die Substituenten R2, R3, R4, R5, R6 und R7 die Bedeutung haben, wie weiter oben beschrieben.Y in the compounds of the general formula II is preferably a hydrocarbon chain of the formula - (CH 2) _q - with q = 2, 3, 4 or 5, very particularly preferably with n = 4 or 5. X thus particularly preferably represents a group of general formula X2

in which n has the value 4 or 5 and the substituents R 2, R 3, R 4, R 5, R 6 and R 7 have the meaning as described above.

In another embodiment of the invention is at least one of the substituents R2, R3, R4, R5 and R6 is a halogen atom, in particular fluorine or chlorine.

In another preferred embodiment at least one of the two radicals R2 and R3 stands for one non-hydrogen substituent, especially for halogen or C1-C6 alkyloxy while the radicals R4, R5 and R6 in the compounds of the invention or in formula X1 and Formula X2 respectively for Hydrogen stand.

In a preferred embodiment of the invention, especially when the heterocycle is a pyrazolo [1,5-a] pyridine is one of the two substituents R 2 or R 3 is a halogen, in particular Fluorine or chlorine, more preferably R2 and R3 are both halo, most preferably chlorine.

In a further preferred embodiment of the invention in the compounds of the general formula I two adjacent substituents selected from R2, R3, R4, R5 and R6, and in particular the substituents R2 and R3 together with the Phenyl to which they are attached, a chroman or Dihydrobenzofuran.

wobei gilt:
der Ring A ist jeweils gesättigt oder aromatisch;
die ringbildenden C-Atome der Ringe A und B können jeweils unabhängig voneinander mit R1 substituiert sein;
R, R1 und X haben die Bedeutung wie weiter vorstehend beschrieben.Examples of indolizine derivatives of the general formula I according to the invention are:

where:
the ring A is in each case saturated or aromatic;
the ring-forming carbon atoms of rings A and B may each be independently substituted with R1;
R, R1 and X are as previously described.

in der bedeuten:
der Indolizin-Kern kann in den Positionen 1-7, wie in Formel II dargestellt, außer der Gruppe X noch einen oder mehrere, z.B. 1, 2, 3 oder 4 weitere Substituenten R1 tragen, die jeweils unabhängig voneinander ausgewählt sind aus Hydroxy, Alkyl, Alkyloxy, Alkylthio, Alkenyl, Alkinyl, Phenyl, Phenoxy, Halogen, Trifluormethyl, Alkylcarbonyl, Phenylcarbonyl, Alkyloxycarbonyl, Cyano, Nitro, Amino, Carboxy, Sulfo, Sulfamoyl, Sulfonylamino, Alkylaminosulfonyl und Alkylsulfonylamino;
X ist mit einer beliebigen Position 1-7 des Indolizins verknüpft und stellt eine Gruppe der allgemeinen Formel X1 dar

worin gilt:
Y ist eine unverzweigte, gesättigte oder ungesättigte Kohlenwasserstoffkette mit 2-5 Kohlenstoffatomen oder eine Kette -(CH2)_o-Z-(CH2)_p, worin Z ausgewählt ist aus den Resten Cyclopentyl, Cyclohexyl und Cycloheptyl, wobei o und p jeweils unabhängig voneinander den Wert 0, 1, 2 oder 3 haben und wobei die Summe aus o und p höchstens 3 ist;
R2, R3, R4, R5 und R6 sind jeweils unabhängig voneinander ausgewählt aus der Gruppe Wasserstoff, Hydroxy, Alkyl, Alkyloxy, Alkylthio, Alkenyl, Alkinyl, Phenyl, Phenoxy, Halogen, Trifluormethyl, Alkylcarbonyl, Phenylcarbonyl, Alkyloxycarbonyl, Cyano, Nitro, Amino, Carboxy, Sulfo, Sulfamoyl, Sulfonylamino, Alkylaminosulfonyl und Alkylsulfonylamino, wobei zwei benachbarte Reste R2, R3, R4, R5 und R6 auch gemeinsam mit den C-Atomen des Phenylrings an die sie gebunden sind, einen sauerstoffhaltigen 5-, 6- oder 7-gliedrigen Ring bilden können;
R7 ist Wasserstoff, Alkyl oder Phenylalkyl.A preferred embodiment of the invention relates to compounds of the formula II

in which mean
the indolizine nucleus can carry in positions 1-7, as shown in formula II, in addition to the group X, one or more, for example 1, 2, 3 or 4 further substituents R 1, which are each independently selected from hydroxy, alkyl , Alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, phenylcarbonyl, alkyloxycarbonyl, cyano, nitro, amino, carboxy, sulfo, sulfamoyl, sulfonylamino, alkylaminosulfonyl and alkylsulfonylamino;
X is linked to any position 1-7 of indolizine and represents a group of general formula X1

where:
Y is an unbranched, saturated or unsaturated hydrocarbon chain of 2-5 carbon atoms or a chain - (CH 2) _o -Z- (CH 2) _p wherein Z is selected from the radicals cyclopentyl, cyclohexyl and cycloheptyl, where o and p are each independently have the value 0, 1, 2 or 3 and where the sum of o and p is at most 3;
R 2, R 3, R 4, R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, phenylcarbonyl, alkyloxycarbonyl, cyano, nitro, amino , Carboxy, sulfo, sulfamoyl, sulfonylamino, alkylaminosulfonyl and alkylsulfonylamino, wherein two adjacent radicals R 2, R 3, R 4, R 5 and R 6 together with the carbon atoms of the phenyl ring to which they are bonded, an oxygen-containing 5-, 6- or 7 -membered ring can form;
R7 is hydrogen, alkyl or phenylalkyl.

In an embodiment of the invention is the heteroarene in formula II except for the group X is unsubstituted.

Prefers is the substituent X with the 2-position of indolizine (formula II) linked.

In one embodiment of the invention, Y in the compounds of the general formula II is a chain - (CH 2) _o -Z- (CH 2) _p -, where Z is selected from the radicals cyclopentyl, cyclohexyl and cycloheptyl and where o and p are each independently have the value 0.1 or 2 and preferably both together have a value of at most 2 or 1 or both are 0.

dar, in der n den Wert 4 oder 5 hat und die Substituenten R2, R3, R4, R5, R6 und R7 die Bedeutung haben, wie weiter oben beschrieben.Y in the compounds of general formula II is preferably a hydrocarbon chain of the formula - (CH 2) _q - with q = 2, 3, 4 or 5, very particularly preferably with n = 4 or 5. X thus being particularly preferred in formula II a group of general formula X2

in which n has the value 4 or 5 and the substituents R 2, R 3, R 4, R 5, R 6 and R 7 have the meaning as described above.

R7 is preferably hydrogen.

In an embodiment the invention is at least one of the substituents R2, R3, R4, R5 and R6 in the compounds of general formula II a C1-6 Alkyloxy group, e.g. a methoxy or a halogen atom, in particular Fluorine or chlorine.

In another preferred embodiment at least one of the two radicals R2 and R3 is in the compounds of general formula II for a substituent other than hydrogen, in particular halogen or C1-6 alkyloxy while the radicals R4, R5 and R6 in formula II are each hydrogen.

In a preferred embodiment the invention is one of the two substituents R 2 or R 3 in the Compounds of general formula II a C1-6 alkyloxy group, in particular methoxy, or a halogen, in particular fluorine or Chlorine, more preferably R2 and R3 are both halogen, most preferably Chlorine.

In a further preferred embodiment of the invention in the compounds of the general formula II two adjacent substituents selected from R2, R3, R4, R5 and R6, and in particular the substituents R2 and R3 together with the Phenyl to which they are attached, a chroman or Dihydrobenzofuran.

in der bedeuten:
der Pyrazolo[1,5-a]pyridin-Kern kann in den Positionen 2-7, wie in Formel III dargestellt, außer der Gruppe X noch einen oder mehrere, z.B. 1, 2, 3 oder 4 weitere Substituenten R1 tragen, die jeweils unabhängig voneinander ausgewählt sind aus Hydroxy, Alkyl, Alkyloxy, Alkylthio, Alkenyl, Alkinyl, Phenyl, Phenoxy, Halogen, Trifluormethyl, Alkylcarbonyl, Phenylcarbonyl, Alkyloxycarbonyl, Cyano, Nitro, Amino, Carboxy, Sulfo, Sulfamoyl, Sulfonylamino, Alkylaminosulfonyl und Alkylsulfonylamino;
X ist mit einer beliebigen Position 2-7 des Pyrazolo[1,5-a]pyridins verknüpft und stellt eine Gruppe der allgemeinen Formel X1 dar

worin gilt:
Y ist eine unverzweigte, gesättigte oder ungesättigte Kohlenwasserstoffkette mit 2-5 Kohlenstoffatomen oder eine Kette -(CH2)_o-Z-(CH2)_p, worin Z ausgewählt ist aus den Resten Cyclopentyl, Cyclohexyl und Cycloheptyl, wobei o und p jeweils unabhängig voneinander den Wert 0, 1, 2 oder 3 haben und wobei die Summe aus o und p höchstens 3 ist;
R2, R3, R4, R5 und R6 sind jeweils unabhängig voneinander ausgewählt aus der Gruppe Wasserstoff, Hydroxy, Alkyl, Alkyloxy, Alkylthio, Alkenyl, Alkinyl, Phenyl, Phenoxy, Halogen, Trifluormethyl, Alkylcarbonyl, Phenylcarbonyl, Alkyloxycarbonyl, Cyano, Nitro, Amino, Carboxy, Sulfo, Sulfamoyl, Sulfonylamino, Alkylaminosulfonyl und Alkylsulfonylamino, wobei zwei benachbarte Reste R2, R3, R4, R5 und R6 auch gemeinsam mit den C-Atomen des Phenylrings an die sie gebunden sind, einen sauerstoffhaltigen 5-, 6- oder 7-gliedrigen Ring bilden können;
R7 ist Wasserstoff, Alkyl oder Phenylalkyl.Another preferred embodiment of the invention relates to compound of formula III

in which mean
the pyrazolo [1,5-a] pyridine nucleus can carry in positions 2-7, as shown in formula III, in addition to the group X, one or more, for example 1, 2, 3 or 4 further substituents R 1, in each case are independently selected from hydroxy, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, phenylcarbonyl, alkyloxycarbonyl, cyano, nitro, amino, carboxy, sulfo, sulfamoyl, sulfonylamino, alkylaminosulfonyl and alkylsulfonylamino;
X is linked to any position 2-7 of the pyrazolo [1,5-a] pyridine and represents a group of the general formula X1

where:
Y is an unbranched, saturated or unsaturated hydrocarbon chain of 2-5 carbon atoms or a chain - (CH 2) _o -Z- (CH 2) _p wherein Z is selected from the radicals cyclopentyl, cyclohexyl and cycloheptyl, where o and p are each independently have the value 0, 1, 2 or 3 and where the sum of o and p is at most 3;
R 2, R 3, R 4, R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, phenylcarbonyl, alkyloxycarbonyl, cyano, nitro, amino , Carboxy, sulfo, sulfamoyl, sulfonylamino, alkylaminosulfonyl and alkylsulfonylamino, wherein two adjacent radicals R 2, R 3, R 4, R 5 and R 6 together with the carbon atoms of the phenyl ring to which they are bonded, an oxygen-containing 5-, 6- or 7 -membered ring can form;
R7 is hydrogen, alkyl or phenylalkyl.

Prefers is the group X with positions 2, 5 or 6 of pyrazolo [1,5-a] pyridine connected to the formula III.

In an embodiment is the pyrazolo [1,5-a] pyridine nucleus in at least one of the positions 5 or 6 substituted. In a preferred embodiment of the invention, the pyrazolo carries [1,5-a] pyridine in position 5, a methoxy or CF3 radical and / or in position 6 is a halogen atom, especially when X is at position 2 of the heteroarene is bound.

In another preferred embodiment is the pyrazolo [1,5-a] pyridine nucleus in the compounds of general Formula III is unsubstituted except for the obligatory substituent X, especially when X is attached at positions 5 or 6 of the heteroarene is.

In one embodiment of the invention, Y in the compounds of general formula III is a chain - (CH 2) _o -Z- (CH 2) _p wherein Z is selected from the radicals cyclopentyl, cyclohexyl and cycloheptyl and where o and p are each independently of one another Have value 0.1 or 2 and preferably both together have a value of at most 2 or 1 or both are 0.

dar, in der n den Wert 4 oder 5 hat und die Substituenten R2, R3, R4, R5, R6 und R7 die Bedeutung haben, wie weiter oben beschrieben.Y in the compounds of the general formula III is preferably a hydrocarbon chain of the formula - (CH 2) _q - with q = 2, 3, 4 or 5, very particularly preferably with n = 4 or 5. The group X is therefore particularly important in formula III preferably a group of the general formula X2

in which n has the value 4 or 5 and the substituents R 2, R 3, R 4, R 5, R 6 and R 7 have the meaning as described above.

R7 is preferably hydrogen.

In an embodiment the invention is at least one of the substituents R2, R3, R4, R5 and R6 in the compounds of general formula III is a halogen atom, in particular fluorine or chlorine.

In another preferred embodiment at least one of the two radicals R2 and R3 is in the compounds of general formula III for a substituent other than hydrogen, especially for halogen, while the radicals R4, R5 and R6 are each hydrogen.

In a preferred embodiment the invention is one of the two substituents R 2 or R 3 in the Compounds of general formula III is a halogen, in particular Fluorine or chlorine, more preferably R2 and R3 are both halo, most preferably chlorine.

• (a) mindestens einer der Substituenten R3, R4, R5, R6 und R7 repäsentiert einen von Wasserstoff abweichenden Rest und/oder
• (b) der Pyrazolo[1,5-a]pyridin-Kern ist mit mindestens einem Substituenten R1 substituiert.

In one embodiment of the invention, R 2 in the compounds of the general formula III is a C 1-6 alkyloxy group, in particular methoxy

• (a) at least one of the substituents R3, R4, R5, R6 and R7 represents a radical other than hydrogen and / or
• (b) the pyrazolo [1,5-a] pyridine nucleus is substituted with at least one substituent R1.

In another embodiment R2 is not methoxy. In another embodiment of the invention is R2 in the compounds of the general formula III is not alkyloxy.

In a further embodiment of the invention form in the compounds of general formula III two adjacent substituents selected from R2, R3, R4, R5 and R6, and in particular the substituents R2 and R3 together with the Phenyl to which they are attached, a chroman or Dihydrobenzofuran.

in der bedeuten:
der Tetrahydropyrazolo[1,5-a]pyridin-Kern kann in den Positionen 2-7 wie in Formel IV dargestellt, außer der Gruppe X noch einen oder mehrere, z.B. 1, 2, 3 oder 4 weitere Substituenten R1 tragen, die jeweils unabhängig voneinander ausgewählt sind aus Hydroxy, Alkyl, Alkyloxy, Alkylthio, Alkenyl, Alkinyl, Phenyl, Phenoxy, Halogen, Trifluormethyl, Alkylcarbonyl, Phenylcarbonyl, Alkyloxycarbonyl, Cyano, Nitro, Amino, Carboxy, Sulfo, Sulfamoyl, Sulfonylamino, Alkylaminosulfonyl und Alkylsulfonylamino;
X ist mit Position 2 oder 3 des Tetrahydropyrazolo[1,5-a]pyridins verknüpft und stellt eine Gruppe der allgemeinen Formel X1 dar

worin gilt:
Y ist eine unverzweigte, gesättigte oder ungesättigte Kohlenwasserstoffkette mit 2-5 Kohlenstoffatomen oder eine Kette -(CH2)_o-Z-(CH2)_p, worin Z ausgewählt ist aus den Resten Cyclopentyl, Cyclohexyl und Cycloheptyl, wobei o und p jeweils unabhängig voneinander den Wert 0, 1, 2 oder 3 haben und wobei die Summe aus o und p höchstens 3 ist;
R2, R3, R4, R5 und R6 sind jeweils unabhängig voneinander ausgewählt aus der Gruppe Wasserstoff, Hydroxy, Alkyl, Alkyloxy, Alkylthio, Alkenyl, Alkinyl, Phenyl, Phenoxy, Halogen, Trifluormethyl, Alkylcarbonyl, Phenylcarbonyl, Alkyloxycarbonyl, Cyano, Nitro, Amino, Carboxy, Sulfo, Sulfamoyl, Sulfonylamino, Alkylaminosulfonyl auch Alkylsulfonylamino, wobei zwei benachbarte Reste R2, R3, R4, R5 und R6 auch gemeinsam mit den C-Atomen des Phenylrings an die sie gebunden sind, einen sauerstoffhaltigen 5-, 6- oder 7-gliedrigen Ring bilden können;
R7 ist Wasserstoff, Alkyl oder Phenylalkyl.Another preferred embodiment of the invention are compounds of general formula IV,

in which mean
the tetrahydropyrazolo [1,5-a] pyridine nucleus can be in positions 2-7 as shown in formula IV, except the group X nor one or more, for example 1, 2, 3 or 4 further substituents R1 carry, each independently are selected from among hydroxy, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, phenylcarbonyl, alkyloxycarbonyl, cyano, nitro, amino, carboxy, sulfo, sulfamoyl, sulfonylamino, alkylaminosulfonyl and alkylsulfonylamino;
X is linked to position 2 or 3 of the tetrahydropyrazolo [1,5-a] pyridine and represents a group of the general formula X1

where:
Y is an unbranched, saturated or unsaturated hydrocarbon chain of 2-5 carbon atoms or a chain - (CH 2) _o -Z- (CH 2) _p wherein Z is selected from the radicals cyclopentyl, cyclohexyl and cycloheptyl, where o and p are each independently have the value 0, 1, 2 or 3 and where the sum of o and p is at most 3;
R 2, R 3, R 4, R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, phenyl carbonyl, alkyloxycarbonyl, cyano, nitro, amino, carboxy, sulfo, sulfamoyl, sulfonylamino, alkylaminosulfonyl and alkylsulfonylamino, where two adjacent radicals R 2, R 3, R 4, R 5 and R 6 are also taken together with the C atoms of the phenyl ring to which they are attached, can form an oxygenated 5-, 6- or 7-membered ring;
R7 is hydrogen, alkyl or phenylalkyl.

In an embodiment of the invention is the heteroarene in formula IV except for the group X is unsubstituted.

In one embodiment of the invention, Y in the compounds of the general formula IV is a chain - (CH 2) _o -Z- (CH 2) _p , where Z is selected from the radicals cyclopentyl, cyclohexyl and cycloheptyl and where o and p are each independently of one another Have value 0.1 or 2 and preferably both together have a value of at most 2 or 1 or both are 0.

dar, in der n den Wert 4 oder 5 hat und die Substituenten R2, R3, R4, R5, R6 und R7 die Bedeutung haben, wie weiter oben beschrieben.In the compounds of the general formula IV, Y is preferably a hydrocarbon chain of the formula - (CH 2) _q - with q = 2, 3, 4 or 5, very particularly preferably with n = 4 or 5. X is thus particularly preferred in formula IV Group of the general formula X2

in which n has the value 4 or 5 and the substituents R 2, R 3, R 4, R 5, R 6 and R 7 have the meaning as described above.

Prefers R7 is hydrogen.

In an embodiment the invention is at least one of the substituents R2, R3, R4, R5 and R6 in the compounds of general formula IV a C1-6 Alkyloxy, in particular methoxy, or a halogen atom, in particular Fluorine or chlorine.

In another preferred embodiment at least one of the two radicals R2 and R3 is in the compounds the general formula IV for a substituent other than hydrogen, in particular halogen or C1-C6 alkyloxy while the radicals R4, R5 and R6 are each hydrogen.

In a preferred embodiment the invention is one of the two substituents R 2 or R 3 in the Compounds of general formula IV a C1-6 alkyloxy group, in particular methoxy or halogen, in particular fluorine or chlorine, more preferably R2 and R3 are both halo, especially preferably chlorine.

In a further embodiment of the invention form in the compounds of general formula IV two adjacent substituents selected from R2, R3, R4, R5 and R6, and in particular the substituents R2 and R3 together with the Phenyl to which they are attached, a chroman or Dihydrobenzofuran.

The The invention also relates to physiologically acceptable salts of the compounds of the invention. Examples for such Salts are described in the definitions below.

the It is also clear to a person skilled in the art that, depending on the choice of substituents, geometric Isomers and / or optically active compounds can arise. In In this case, both the isomers, racemates and the respective pure enantiomeric or optionally diastereomeric forms subject of the present invention.

The in the description and in the appended claims Substituents include in particular those explained below Groups.

"Alkyl" may be a branched or unbranched alkyl group which preferably has 1 to 10 C atoms, particularly preferably 1 to 6 C atoms ("C 1 -C 6 alkyl") and very particularly preferably 1, 2 or 3 C atoms has. "C 1 -C 6 alkyl" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl and n-hexyl. "Alkyl" can also be cyclic or contain a cyclic moiety, preference being given to cycles having 3-7 carbon atoms, for example cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Preferably, "alkyl" is not cyclic and does not contain a cyclic moiety.Alkyl groups may additionally be substituted with one or more substituents, especially hydroxy or amine. Preferably, "alkyl" is unsubstituted or substituted with hydroxy.

At least "alkenyl" and "alkynyl" indicate a double or triple bond. They can be branched or unbranched be and have preferably 2 to 6 carbon atoms. Alkenyle or Alkynyls are preferably so on the heteroarene or phenyl ring of the skeleton the compound bound that double or triple bond with is conjugated to the aromatic ring. Alkenyl and alkynyl can also be combined with a or more substituents, preferably with Phenyl, wherein the phenyl group is then particularly preferably on C atom 2 (when alkenyl or alkynyl is attached via the C atom 1 to the heteroaromatic or phenyl ring of the backbone is bound). Preferably, the alkenyls or alkynyls are unsubstituted.

"Alkyloxy" is the group -O-alkyl, wherein alkyl is preferably selected from the groups given above for "alkyl". Preferably, "alkyloxy" is a C 1 -C 6 alkyloxy group, especially preferably methoxy.

"Alkylthio" is the group -S-alkyl, wherein alkyl is preferably selected from the groups given above for "alkyl". Preferably, "alkylthio" is a C1-C6-alkyl-S group.

"Alkylaminosulfonyl" includes the groups -SO ₂ -NH-alkyl and -SO ₂ -N-dialkyl wherein alkyl is preferably selected from the groups identified above for "alkyl." Preferably, "alkyl" in "alkylaminosulfonyl" is a C 1 -C 6 Examples of "alkylaminosulfonyl" are, for example, methylaminosulfonyl, N, N-dimethylaminosulfonyl or butylaminosulfonyl.

"Alkylsulfonylamino" is the group -NH-SO ₂ -alkyl, wherein alkyl is preferably selected from the groups identified above for "alkyl." Preferably, "alkylsulfonylamino" is a C 1 -C 6 -alkylsulfonylamino group, eg, methanesulfonylamino.

"Phenyl" is preferably unsubstituted, but may optionally be substituted one or more times independently, e.g. with alkoxy, alkyl, trifluoromethyl or halogen.

"Phenylalkyl" is the group -alkyl-phenyl, wherein phenyl and alkyl have the meaning as defined above. Phenylalkyl includes, for example, phenylethyl and benzyl and is preferably benzyl.

"Phenoxy" is the group -O-phenyl, wherein phenyl has the meaning as further defined above.

"Alkylcarbonyl" includes the group -C (O) -alkyl, wherein alkyl is preferably selected from the groups indicated above for "alkyl" selected is, and particularly preferably -C (O) -C1-C6-alkyl. "Alkylcarbonyl" is preferred Acetyl, propionyl or butyryl.

"Phenylcarbonyl" is -C (O) -phenyl, wherein phenyl has the meaning as defined above

"Alkyloxycarbonyl" is the group -C (O) -O-alkyl, wherein alkyl is preferably selected from the groups given above for "alkyl". Preferably, "alkoxycarbonyl" is a (C 1 -C 6 -alkyl) oxycarbonyl group.

"Halogen" includes fluorine, chlorine, Bromine and iodine, and is preferably fluorine, chlorine or bromine.

"Sulfamoyl" includes the group -SO ₂ -NH ₂ .

"Sulfonylamino" includes the group -NH-SO ₂ H.

"Physiologically acceptable salts" include non-toxic addition salts of a base, especially a compound of formulas (I) to (IV) in the form of the free base, with organic or inorganic acids. Examples of inorganic acids include HCl, HBr, sulfuric acid and phosphoric acid. Organic acids include acetic acid, propionic acid, pyruvic acid, butyric acid, α-, β- or γ-hydroxybutyric acid, valeric acid, hydroxyvaleric acid, caproic acid, hydroxycaproic acid, caprylic acid, capric acid lauric, myristic, palmitic, stearic, glycolic, lactic, D-glucuronic, L-glucuronic, D-galacturonic, glycine, benzoic, hydroxybenzoic, gallic, salicylic, vanillic, coumaric, caffeic, hippuric, orotic, L-tartaric, D-tartaric acid, D, L-tartaric acid, meso-tartaric acid, fumaric acid, L-malic acid, D-malic acid, D, L-malic acid, oxalic acid, malonic acid, succinic acid, maleic acid, oxalacetic acid, glutaric acid, hydroxyglutaric acid, ketoglutaric acid, adipic acid, ketoadipic acid, Pimelic acid, glutamic acid, aspartic acid, phthalic acid, propane tricarboxylic acid, citric acid, isocitric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, embonic acid and trifluoromethanesulfonic acid.

• (B1): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butylindolizin-2-ylcarbamid
• (B2): N-4-(4-(3-Chlor-2-methoxyphenyl)piperazin-1-yl)butylindolizin-2-ylcarbamid
• (B3): N-4-(4-(2,3-Dichlorphenyl)piperazin-1-yl)butylindolizin-2-ylcarbamid
• (B4): N-4-(4-(2,3-Difluorphenyl)piperazin-1-yl)butylindolizin-2-ylcarbamid
• (B5): N-4-(4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1-yl)butylindolizin-2-ylcarbamid
• (B49): N-4-(4-(Chroman-8-yl)piperazin-1-yl)butylindolizin-2-ylcarbamid
• (B6): N-2-(4-(2,3-Dichlorphenyl)piperazin-1-yl)ethylpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B7): N-3-(4-(2,3-Dichlorphenyl)piperazin-1-yl)propylpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B8): N-4-(4-(2,3-Dichlorphenyl)piperazin-1-yl)butylpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B9): N-5-(4-(2,3-Dichlorphenyl)piperazin-1-yl)pentylpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B10): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl-3-brompyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B11): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl-3-chlorpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B50): N-4-(4-(2,3-Dichlorphenyl)piperazin-1-yl)butyl-5-methoxypyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B51): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl-5-methoxypyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B12): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl-5-methylpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B52): N-4-(4-(2,3-Dichlorphenyl)piperazin-1-yl)butyl-5-trifluormethylpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B53): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl-5-trifluormethylpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B54): N-4-(4-(2,3-Dichlorphenyl)piperazin-1-yl)butyl-6-brompyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B13): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl-6-brompyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B55): N-4-(4-(2,3-Dichlorphenyl)piperazin-1-yl)butyl-6-chlorpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B56): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl-6-chlorpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B57): N-4-(4-(2,3-Dichlorphenyl)piperazin-1-yl)butyl-6-fluorpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B58): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl-6-fluorpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B14): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl-3-methoxycarbonylpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B15): N-4-(4-(2,3-Dichlorphenyl)piperazin-1-yl)butyl-3-methoxycarbonylpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B59): N-5-(4-(2,3-Dichlorphenyl)piperazin-1-yl)pentyl-5-methoxypyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B60): N-5-(4-(2-Methoxyphenyl)piperazin-1-yl)pentyl-5-methoxypyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B61): N-5-(4-(2,3-Dichlorphenyl)piperazin-1-yl)pentyl-5-trifluormethylpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B62): N-5-(4-(2-Methoxyphenyl)piperazin-1-yl)pentyl-5-trifluormethylpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B63): N-5-(4-(2,3-Dichlorphenyl)piperazin-1-yl)pentyl-6-brompyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B64): N-5-(4-(2-Methoxyphenyl)piperazin-1-yl)pentyl-6-brompyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B65): N-5-(4-(2,3-Dichlorphenyl)piperazin-1-yl)pentyl-6-chlorpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B66): N-5-(4-(2-Methoxyphenyl)piperazin-1-yl)pentyl-6-chlorpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B67): N-5-(4-(2,3-Dichlorphenyl)piperazin-1-yl)pentyl-6-fluorpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B68): N-5-(4-(2-Methoxyphenyl)piperazin-1-yl)pentyl-6-fluorpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B16): trans-N-(4-((4-(2-Methoxyphenyl)piperazin-1-yl)methyl)cyclohex-1-yl)methylpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B17): trans-N-(4-((4-(2,3-Dichlorphenyl)piperazin-1-yl)methyl)cyclohex-1-yl)methylpyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B18): N-2-(4-(2,3-Dichlorphenyl)piperazin-1-yl)ethylpyrazolo[1,5-a]pyridin-3-ylcarbamid
• (B19): N-3-(4-(2,3-Dichlorphenyl)piperazin-1-yl)propylpyrazolo[1,5-a]pyridin-3-ylcarbamid
• (B20): N-4-(4-(2,3-Dichlorphenyl)piperazin-1-yl)butylpyrazolo[1,5-a]pyridin-3-ylcarbamid
• (B21): N-5-(4-(2,3-Dichlorphenyl)piperazin-1-yl)pentylpyrazolo[1,5-a]pyridin-3-ylcarbamid
• (B22): trans-N-(4-((4-(2-Methoxyphenyl)piperazin-1-yl)methyl)cyclohex-1-yl)methylpyrazolo[1,5-a]pyridin-3-ylcarbamid
• (B23): trans-N-(4-((4-(2,3-Dichlorphenyl)piperazin-1-yl)methyl)cyclohex-1-yl)methylpyrazolo[1,5-a]pyridin-3-ylcarbamid
• (B24): N-2-(4-(2,3-Dichlorphenyl)piperazin-1-yl)ethylpyrazolo[1,5-a]pyridin-5-ylcarbamid
• (B25): N-3-(4-(2,3-Dichlorphenyl)piperazin-1-yl)propylpyrazolo[1,5-a]pyridin-5-ylcarbamid
• (B26): N-4-(4-(2,3-Dichlorphenyl)piperazin-1-yl)butylpyrazolo[1,5-a]pyridin-5-ylcarbamid
• (B27): N-5-(4-(2,3-Dichlorphenyl)piperazin-1-yl)pentylpyrazolo[1,5-a]pyridin-5-ylcarbamid
• (B28): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl-3-brompyrazolo[1,5-a]pyridin-5-ylcarbamid
• (B29): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl-3-chlorpyrazolo[1,5-a]pyridin-5-ylcarbamid
• (B30): N-5-(4-(2-Methoxyphenyl)piperazin-1-yl)pentylpyrazolo[1,5-a]pyridin-5-ylcarbamid
• (B31): N-2-(4-(2,3-Dichlorphenyl)piperazin-1-yl)ethylpyrazolo[1,5-a]pyridin-6-ylcarbamid
• (B32): N-3-(4-(2,3-Dichlorphenyl)piperazin-1-yl)propylpyrazolo[1,5-a]pyridin-6-ylcarbamid
• (B33): N-4-(4-(2,3-Dichlorphenyl)piperazin-1-yl)butylpyrazolo[1,5-a]pyridin-6-ylcarbamid
• (B34): N-5-(4-(2,3-Dichlorphenyl)piperazin-1-yl)pentylpyrazolo[1,5-a]pyridin-6-ylcarbamid
• (B35): N-2-(4-(2,3-Dichlorphenyl)piperazin-1-yl)ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B36): N-3-(4-(2,3-Dichlorphenyl)piperazin-1-yl)propyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B37): N-4-(4-(2,3-Dichlorphenyl)piperazin-1-yl)butyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B38): N-5-(4-(2,3-Dichlorphenyl)piperazin-1-yl)pentyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B39): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B40): N-4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl-5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-ylcarbamid
• (B41): N-2-(4-(2,3-Dichlorphenyl)piperazin-1-yl)ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-ylcarbamid
• (B42): N-3-(4-(2,3-Dichlorphenyl)piperazin-1-yl)propyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-ylcarbamid
• (B43): N-4-(4-(2,3-Dichlorphenyl)piperazin-1-yl)butyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-ylcarbamid
• (B44): N-5-(4-(2,3-Dichlorphenyl)piperazin-1-yl)pentyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-ylcarbamid sowie pharmazeutisch akzeptable Salze dieser Verbindungen.

The following compounds represent specific embodiments of the compounds according to the invention:

• (B1): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butylindolizin-2-ylcarbamide
• (B2): N-4- (4- (3-chloro-2-methoxyphenyl) piperazin-1-yl) butylindolizin-2-ylcarbamide
• (B3): N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -butylindolizin-2-ylcarbamide
• (B4): N-4- (4- (2,3-Difluorophenyl) piperazin-1-yl) butylindolizin-2-ylcarbamide
• (B5): N-4- (4- (2,3-Dihydrobenzofuran-7-yl) piperazin-1-yl) butylindolizin-2-ylcarbamide
• (B49): N-4- (4- (chroman-8-yl) -piperazin-1-yl) -butylindolizin-2-ylcarbamide
• (B6): N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethylpyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B7): N-3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propylpyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B8): N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butylpyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B9): N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B10): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-3-bromopyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B11): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-3-chloropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B50): N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl-5-methoxypyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B51): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-5-methoxypyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B12): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-5-methylpyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B52): N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl-5-trifluoromethylpyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B53): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-5-trifluoromethylpyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B54): N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl-6-bromopyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B13): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-6-bromopyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B55): N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl-6-chloropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B56): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-6-chloropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B57): N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -butyl-6-fluoropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B58): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-6-fluoropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B14): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-3-methoxycarbonylpyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B15): N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -butyl-3-methoxycarbonyl-pyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B59): N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-5-methoxypyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B60): N-5- (4- (2-Methoxyphenyl) piperazin-1-yl) pentyl-5-methoxypyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B61): N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-5-trifluoromethylpyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B62): N-5- (4- (2-Methoxyphenyl) piperazin-1-yl) pentyl-5-trifluoromethylpyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B63): N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-6-bromopyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B64): N-5- (4- (2-Methoxyphenyl) piperazin-1-yl) pentyl-6-bromopyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B65): N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-6-chloropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B66): N-5- (4- (2-Methoxyphenyl) piperazin-1-yl) pentyl-6-chloropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B67): N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-6-fluoropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B68): N-5- (4- (2-Methoxyphenyl) piperazin-1-yl) pentyl-6-fluoropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B16): trans -N- (4 - ((4- (2-Methoxyphenyl) piperazin-1-yl) methyl) cyclohex-1-yl) methylpyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B17): trans -N- (4 - ((4- (2,3-dichlorophenyl) piperazin-1-yl) methyl) cyclohex-1-yl) methylpyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B18): N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethylpyrazolo [1,5-a] pyridin-3-ylcarbamide
• (B19): N-3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propylpyrazolo [1,5-a] pyridin-3-ylcarbamide
• (B20): N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butylpyrazolo [1,5-a] pyridin-3-ylcarbamide
• (B21): N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridin-3-ylcarbamide
• (B22): trans -N- (4 - ((4- (2-Methoxyphenyl) piperazin-1-yl) methyl) cyclohex-1-yl) methylpyrazolo [1,5-a] pyridin-3-ylcarbamide
• (B23): trans -N- (4 - ((4- (2,3-dichlorophenyl) piperazin-1-yl) methyl) cyclohex-1-yl) methylpyrazolo [1,5-a] pyridin-3-ylcarbamide
• (B24): N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethylpyrazolo [1,5-a] pyridin-5-ylcarbamide
• (B25): N-3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propylpyrazolo [1,5-a] pyridin-5-ylcarbamide
• (B26): N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butylpyrazolo [1,5-a] pyridin-5-ylcarbamide
• (B27): N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridin-5-ylcarbamide
• (B28): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-3-bromopyrazolo [1,5-a] pyridin-5-ylcarbamide
• (B29): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-3-chloropyrazolo [1,5-a] pyridin-5-ylcarbamide
• (B30): N-5- (4- (2-Methoxyphenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridin-5-ylcarbamide
• (B31): N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethylpyrazolo [1,5-a] pyridin-6-ylcarbamide
• (B32): N-3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propylpyrazolo [1,5-a] pyridin-6-ylcarbamide
• (B33): N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butylpyrazolo [1,5-a] pyridin-6-ylcarbamide
• (B34): N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridin-6-ylcarbamide
• (B35): N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B36): N-3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B37): N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -butyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B38): N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B39): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B40): N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-5-methyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamide
• (B41): N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-ylcarbamide
• (B42): N-3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-ylcarbamide
• (B43): N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -butyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-ylcarbamide
• (B44): N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-ylcarbamide and pharmaceutically acceptable Salts of these compounds.

links of formulas (I), (II), (III) and (IV) as defined are as drugs suitable. The compounds of the invention include affine or even high affinity ligands for D3 receptors.

Of the Term "affine D3 ligand " Compounds binding in a radioligand experiment (see Hübner, H., et al. et al. J. Med. Chem. 2000, 43, 756-762 and the section "Biological Activity") on human dopamine D3 receptors with a Ki value of not more than 500 nM show For "affine" ligands of other receptors the definition applies accordingly.

Of the Term "high affinity D3 ligands " Compounds used in a radioligand experiment (see Hübner, H. et al. J. Med. Chem. 2000, 43, 756-762 and the section "Biological activity") binding to human Dopamine D3 receptors with a Ki value of preferably no longer show as about 30 nM, more preferably not more than 3 nM. For "high affinity" ligands of others Receptors apply the definition accordingly.

One Aspect of the present invention relates to selective D3 ligands. The term "selective D3 ligands " Compounds described in the radioligand experiment for the D3 receptor as described in the following section "Biological activity" Have ki value, by a factor of at least 10 lower than for at least five of the seven of the following receptors is: dopamine D1, D2long, D2short and D4.4, serotonin receptors 5-HT1A and 5-HT2 and alpha 1 adrenoceptor.

One Another aspect of the invention relates to highly selective dopamine D3 ligands. The term "highly selective D3 ligands " Compounds used in the radioligand experiment for the D3 receptor, as in the following Section "Biological Activity ", a Ki value by a factor of at least 100 lower as for at least three, preferably for all of the dopamine receptors D1, D2long, D2short and D4.4 is.

D3 ligands can at the D3 receptor agonistic, antagonistic or partial agonist Have effect. The corresponding intrinsic activities of Compounds of the invention can be measured in mitogenesis assays as described in the literature (Hübner, H. et al. J. Med. Chem. 2000, 43, 4563-4569 and Löber, S. Bioorg. Med. Chem. Lett. 2002, 12.17, 2377-2380). Dependent on from the pathophysiology of the underlying disease therapeutically a stronger one agonistic, stronger be desired antagonistic or a partial agonist activity.

Finally, point some of the substances according to the invention also significant affinity for more pharmacological interesting receptors, e.g. the serotonin receptor, in particular the 5-HT1a receptor, or the dopamine D2 receptor.

Instead of A highly selective dopamine D3 receptor binding may vary by species the disease to be treated also binds to another Receptor desired be.

For example can be attractive for treating schizophrenia which is a high affinity D3 ligand and simultaneously an affine or even high affinity 5-HT1a receptor ligand is. In another embodiment The invention may be used to treat dyskinesias required be, in addition to D3-modulatory properties also D2-agonistic and having 5-HT1a modulatory properties. In other cases, e.g. in the treatment of urinary incontinence may even have a greater selectivity for the serotonin receptor desirable be.

The The present invention therefore excellently permits fine adjustment the desired affinity, activity and selectivity to various pharmacologically important receptors in particular the dopamine D3 receptors, but also, for example, with respect to the 5-HT1a receptor or the D2 receptor.

One Another object of the invention is therefore a pharmaceutical, the one or more of the compounds of the general formulas (I), (II), (III) and (IV) or one of the compounds specifically listed as defined above, optionally in the form of a pharmaceutical acceptable salt as well as a pharmaceutically acceptable adjuvant contains.

The The invention also relates to the use of one or more of the compounds of the general formulas (I), (II), (III) and (IV) or one of the specifically listed Compounds, optionally in the form of a pharmaceutically acceptable Salt, for the treatment, the indications mentioned here as well as for Production of a drug for the indications mentioned here.

Of the Term "treatment" of a disease in this patent application (a) already includes the therapy existing disease as well as (b) the prophylaxis of one yet or not completely pronounced Illness, if for the occurrence of such a disease is at risk.

Prefers For the preparation of medicaments, such compounds according to the invention are used selected, which are high affinity D3 ligands. Particularly preferred are selective or even highly selective D3 ligands used.

In another embodiment The invention selects compounds that are affine or even highly affine also or in particular for the 5-HT1a receptor.

The Compounds of the invention have potential in the therapy or prophylaxis of a number of Disorders, in particular, with a disorder of dopamine metabolism or the dopaminergic signal cascade, or optionally the serotonergic signal transmission accompanied.

One The invention therefore relates to the use of a compound according to the invention, as in this patent application including the claims and the examples described for the preparation of a medicament for the treatment of diseases associated with a disorder of the Dopamine metabolism and / or the dopaminergic signal cascade go along.

One Another object of the invention is the use of a compound of the invention, as in this patent application including the claims and the examples described for the preparation of a medicament for the treatment of diseases associated with a disorder of the Serotonin metabolism and / or serotonergic signal transmission accompanied.

diseases in whose pathogenesis dopaminergic and / or serotonergic processes are involved are, in particular, diseases of the central nervous system (CNS). An object of the invention is therefore the use of a compound of the invention, as in this patent application including the claims and the examples described for the preparation of a medicament for the treatment of CNS diseases.

The term "CNS disorders" in this patent application encompasses both disorders which originate in the CNS and whose symptoms are predominantly or exclusively noticeable in the CNS, such as, for example, psychosis, depression or cognitive disorders, as well as diseases which originate in the CNS whose symptoms are at least partly noticeable in other target organs, such as extrapyramidal motor movement disorders or hyperprolactinemia.

• (1) Psychosen und Angststörungen, inklusive Manien, idiopathischen Psychosen, Schizophrenie, Zwangsstörungen, Panikattacken, Phobien, Essstörungen, aggressive und autoagressive Störungen, Stereotypien und andere Persönlichkeitsstörungen
• (2) Drogenabhängigkeit, z.B. Kokain-, Alkohol-, Opiat- und Nikotinsucht;
• (3) Stimmungsstörungen, z.B. depressive Störungen insbesondere „major depression", manisch-depressive Störungen, organisch-bedingte Depressionen, z.B. im Zusammenhang mit neurodegenerativen Erkrankungen wie Morbus Parkinson oder Alzheimer
• (4) Bewegungsstörungen, inklusive Tremor, Rigor, Dyskinesien, Dystonien, wie bei Morbus Parkinson, Parkinsonismus (idiopathisch, z.B. bei Parkinson-Plus-Syndrom oder Medikamenten-induziert, z.B. nach L-Dopa oder Neuroleptika-Behandlung), Segawa-Syndrom, Tourette-Syndrom, Restless-Leg Syndrom
• (5) Schlafstörungen, inklusive durch Dopaminagonisten ausgelöste Narkolepsie oder Morbus Parkinson-assoziierte Schlafstörungen
• (6) Übelkeit: hier können Dopaminantagonisten entweder alleine oder in Kombination mit 5-HT3 Antagonisten eingesetzt werden
• (7) Kognitive Störungen und Demenzerkrankungen
• (8) Hyperprolaktinämie; Hyperprolaktinom sowie bei Medikamenten-unterstütztem Abstillen nach Schwangerschaften
• (9) Glaukoma
• (10) Hyperaktivitätssyndrom (ADHS);
• (11) Autismus, bzw. mit Autismus verbundene Störungen, insbesondere bei Verbindungen mit ausgeprägter serotonerger Wirkkomponente
• (12) Schlaganfall, insbesondere bei Verbindungen mit ausgeprägter serotonerger Wirkkomponente

Examples of CNS disorders that can be treated with the compounds of the invention are

• (1) psychosis and anxiety disorders, including mania, idiopathic psychosis, schizophrenia, obsessive-compulsive disorder, panic attacks, phobias, eating disorders, aggressive and autoagressive disorders, stereotypes and other personality disorders
• (2) drug addiction, eg cocaine, alcohol, opiate and nicotine addiction;
• (3) mood disorders, eg depressive disorders in particular "major depression", manic-depressive disorders, organic-induced depression, eg in connection with neurodegenerative diseases such as Parkinson's disease or Alzheimer's
• (4) movement disorders, including tremor, rigors, dyskinesias, dystonia, as in Parkinson's disease, Parkinsonism (idiopathic, eg Parkinson-Plus syndrome or drug-induced, eg, after L-dopa or neuroleptic treatment), Segawa syndrome, Tourette Syndrome, Restless Leg Syndrome
• (5) sleep disorders, including dopamine agonist-induced narcolepsy or Parkinson's-related sleep disorders
• (6) Nausea: Dopamine antagonists can be used either alone or in combination with 5-HT3 antagonists
• (7) cognitive disorders and dementia
• (8) hyperprolactinemia; Hyperprolactinoma and drug-assisted postpartum weaning
• (9) glaucoma
• (10) hyperactivity disorder (ADHD);
• (11) autism or autism-related disorders, especially in compounds with pronounced serotonergic activity component
• (12) Stroke, especially in compounds with a pronounced serotonergic active component

When Further therapeutic use may include treatment and prevention of neurodegenerative diseases are called, as the substances due to their neuroprotective effect destruction or the loss of neurons as the cause or consequence of a pathophysiological Delay event or to a halt. Such diseases are, for example, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, epilepsy, Morbus Parkinson's or synucleopathies, e.g. of the type of Parkinson's Plus syndrome.

Next the treatment of disease clearly involving the CNS arise and / or run, the substances of the invention can also be used to treat other disorders that not, not clearly or not exclusively CNS-associated. Such diseases are especially disorders of the urinary tract, such as e.g. sexual dysfunction, especially male erectile dysfunction and urinary incontinence. For the treatment of urinary incontinence in particular compounds with pronounced serotonergic active component suitable.

One The invention therefore relates to the use of a compound according to the invention for the manufacture of a medicament for the treatment of diseases of the urinary tract, especially of male erectile dysfunction and urinary incontinence.

diseases for the the compounds of the invention particularly suitable are schizophrenia, depressive disorders, L-dopa or neuroleptics-induced movement disorders, Parkinson's disease, Segawa syndrome, Restless leg syndrome, hyperprolactinemia, hyperprolactinoma, hyperactivity disorder (ADHD) and urinary incontinence.

• – Morbus Parkinson-assoziierte Bewegungsstörungen, z.B. Rigor, Tremor, Dystonie und Dyskinesie,
• – Segawa-Syndrom
• – Neuroleptika-induzierte (tardive) extrapyramidalmotorische Bewegungsstörungen, insbesondere Dyskinesie, Dystonie und Akathisie,
• – L-Dopa-induzierte extrapyramidalmotorische Bewegungsstörungen, insbesondere Dyskinesien und Dystonien
• – Restless Leg Syndrom

Movement disorders which are particularly amenable to therapy with the substances according to the invention are in particular

• - Parkinson's disease-related movement disorders, eg, rigor, tremor, dystonia and dyskinesia,
• - Segawa syndrome
• - neuroleptic-induced (tardive) extrapyramidal motor movement disorders, especially dyskinesia, dystonia and akathisia,
• - L-Dopa-induced extrapyramidal motor movement disorders, especially dyskinesia and dystonia
• - Restless Leg Syndrome

Finally, the medicaments of the invention dependent on from the disease to be treated as a combined preparation for be formed simultaneous or sequential gift.

For example may be a unit of sale containing one for the treatment of Parkinson's disease Contains L-dopa medication, Also include a pharmaceutical composition containing one or more the compounds of the invention with e.g. highly selective, partial agonist dopaminergic and / or contains serotonergic profile of action. It can L-Dopa and the compound of the invention in the same pharmaceutical formulation, e.g. a combination tablet, or in different application units, e.g. in the form of two separate tablets. Depending on your needs, both can Active ingredients are administered simultaneously or separately.

In a combination preparation For example, a sequential dose can be achieved by using a Dosage form, e.g. one oral tablet, two different ones Layers with differing release profile for the different having pharmaceutically active ingredients. The skilled person is clear that in the context of the present invention, various dosage forms and application schemes are conceivable, all the subject of the invention are.

A embodiment The invention therefore relates to a drug, the L-Dopa or a Neuroleptic and a compound of the invention for simultaneous or sequential administration to the patient contains.

In another embodiment invention, the sales unit may be a combination product or two application units containing two of the compounds of the invention with different receptor profile, e.g. a high affinity, highly selective D3 modulator and a high-affinity 5-HT1a modulator included.

One Another object of the invention is a method of treatment selected from a disease the above Diseases, by administration of one or more of the compounds of the invention, each alone or in combination with other medicines a mammal, which requires such treatment, the term "mammal" also and in particular Includes people.

Usually exist the medicaments according to invention from a pharmaceutical composition which, in addition to the compounds according to the invention, as described above, at least one pharmaceutically acceptable carrier or excipient.

the It is clear to a person skilled in the art that the pharmaceutical formulation depends on designed differently from the intended application path can be. For example, the pharmaceutical formulation for intravenous, intramuscular, intracutaneous, subcutaneous, oral, buccal, sublingual, nasal, transdermal; adapted by inhalation, rectal or intraperitoneal administration be.

Appropriate Formulations and this suitable pharmaceutical carriers or auxiliaries, such as fillers, Disintegrants, binders, lubricants, stabilizers, flavorings, Antioxidants, preservatives, dispersants or solvents, Buffers or electrolytes are those of skill in the pharmaceutical arts are known and are for example in standard works such as Sucker, Fuchs and Speiser ("Pharmaceutical Technology ", German Apotheker Verlag, 1991) and Remington ("Science and Practice of Pharmacy", Lippincott, Williams & Wilkins, 2000). described.

In a preferred embodiment The invention relates to the pharmaceutical compositions which the compounds of the invention contained, orally administered and can be used, for example, as a capsule, Tablet, powder, granules, dragee or in liquid form.

The formulation may be designed as a rapidly releasing dosage form, if a rapid onset of action is desired. Corresponding oral formulations are described, for example, in EP 0 548 356 or EP 1 126 821 ,

is whereas a protracted release is desirable, a formulation is available with delayed release of active ingredient. Corresponding oral formulations are also known in the art.

Alternative pharmaceutical preparations may, for example, be infusion or injection solutions gen, oils, suppositories, aerosols, sprays, patches, microcapsules or microparticles.

mit einer freien Base der allgemeinen Formel C

wobei gilt:
W ist ausgewählt aus OH, Cl, Br oder einer Gruppe

in der R8 für Alkyl steht;
Heteroaren steht jeweils für eine Gruppe, die ausgewählt ist aus

wobei
A, B, Q1, Q2, Q3, Q4, Q5, Q6 und Q7 jeweils die Bedeutung haben, wie weiter vorstehend definiert und wobei die durchkreuzte Bindung bei den Heteroarenen für eine Bindung der Gruppe -C(O)-W an ein C-Atom eines aromatischen Rings des Heteroarens steht;
die Heteroarene ein oder mehrfach substituiert sein können, wie vorstehend und in den Ansprüchen definiert;
Y, R2, R3, R4, R5 und R6 jeweils die Bedeutung haben, wie vorstehend und in den Ansprüchen definiert,
und wobei für den Fall, dass der Substituent W eine Hydroxygruppe ist, die entsprechende Säuregruppe vor der Umsetzung mit der freien Base der allgemeinen Formel C durch Zugabe von Aktivierungsreagenzien, wie z.B. Hydroxybenzotriazol, Hydroxyazabenzotriazol, HATU oder TBTU aktiviert wird.The compounds of the formulas (I) to (IV) were prepared by methods which have already been partially described in the literature (Bettinetti, L. et al., J. Med. Chem. 2002, 45, 4594-4597). For this purpose, the acid derivatives of type (A), which were either synthesized according to literature or their preparation methods were worked out in our laboratories, in the form of their carboxylic acid chlorides or alternatively by using special activating reagents such as hydroxybenzotriazole, hydroxyazabenzotriazole, HATU (Kienhöfer, A. Synlett 2001, 1811-1812) or TBTU (Knorr, R. Tetrahedron Lett. 1989, 30, 1927-1930) and reacted with the free base of type (C) to give the derivatives of the formulas (I) to (IV):
A compound according to formulas I to IV according to the invention can be prepared by reacting an acid derivative A.

with a free base of the general formula C

where:
W is selected from OH, Cl, Br or a group

wherein R 8 is alkyl;
Heteroaren stands for a group that is selected from

in which
A, B, Q1, Q2, Q3, Q4, Q5, Q6 and Q7 are each as defined above and where the crossed bond in the heteroarenes is for a bond of the group -C (O) -W to a C- Atom of an aromatic ring of the heteroarene;
the heteroarenes may be monosubstituted or polysubstituted as defined above and in the claims;
Y, R2, R3, R4, R5 and R6 are each as defined above and in the claims,
and in the event that the substituent W is a hydroxy group, the corresponding acid group is activated before the reaction with the free base of the general formula C by addition of activating reagents such as hydroxybenzotriazole, hydroxyazabenzotriazole, HATU or TBTU.

W is preferably chlorine, bromine or OH and more preferably chlorine or OH.

An important aspect in the synthesis of these target compounds is the efficient and cost-effective recovery of synthesis precursors. In the preparation of the pyrazolo [1,5-a] pyridines, an important structural class of this invention, the structure of the heterocyclic base is via a cycloaddition reaction of N-aminopyridine with substituted propiolic acid esters (Bettinetti, L. et al., J. Med. 2002, 45, 4594-4597). To date, the preparation of the pyridine precursors by N-amination with hydroxylamine derivatives as formulated below:

there the application of reaction (a) is severely restricted to the reaction of pyridine or picoline, whereas the amination of substituted pyridines after reaction (b) due to the high cost of use of the aminating reagent hydroxylamine-O-mesitylsulfonsäureester is limited.

We describe in this invention an efficient and inexpensive synthetic route for the preparation of differently substituted pyrazolo [1,5-a] pyridines starting from the synthesis of the necessary N-aminopyridines by reaction with O- (2,4-dinitrophenyl) hydroxylamine according to (c) ( Legault, C. et al., J. Org. Chem. 2003, 68, 7119-7122) and subsequent cycloaddition reaction with propiolic esters, as exemplified in the following equation (d):

Wherein
wherein Rx is 0, 1, 2, 3 or 4 identical or different substituents selected from halogen, alkyl, alkylcarbonyl, phenylcarbonyl, hydroxyalkyl, cyano, trifluoromethyl, and alkyloxycarbonyl, * denotes an unsubstituted CH group and wherein R 'is selected from Hydrogen, alkyl, phenyl and alkyloxycarbonyl and wherein R "is alkyl.

durch Umsetzung eines Pyridins der Formel

mit O-(2,4-Dinitrophenyl)hydroxylamin zu einem N-Aminopyridin der Formel

und anschließender Cycloadditionsreaktion mit einem Propiolsäureester der Formel

worin Rx für 0, 1, 2, 3 oder 4 gleiche oder verschiedene Substituenten ausgewählt aus Halogen, Alkyl, Alkylcarbonyl, Phenylcarbonyl, Hydroxyalkyl, Cyano, Trifluormethyl, und Alkyloxycarbonyl steht, * eine unsubstituierte CH-Gruppe kennzeichnet und worin R' ausgewählt ist aus Wasserstoff, Alkyl, Phenyl und Alkyloxycarbonyl und worin R'' für Alkyl steht.An object of the invention is therefore the preparation of a carboxylic acid derivative of a pyrazolo [1,5-a] pyridine having the general formula

by reaction of a pyridine of the formula

with O- (2,4-dinitrophenyl) hydroxylamine to an N-aminopyridine of the formula

and subsequent cycloaddition reaction with a propiolic acid ester of the formula

wherein Rx is 0, 1, 2, 3 or 4 identical or different substituents selected from halogen, alkyl, alkylcarbonyl, phenylcarbonyl, hydroxyalkyl, cyano, trifluoromethyl, and alkyloxycarbonyl, * denotes an unsubstituted CH group and wherein R 'is selected from Hydrogen, alkyl, phenyl and alkyloxycarbonyl and wherein R "is alkyl.

Synthesis of heteroarene carboxylic acid derivatives

Preparation of heteroarenecarboxylic acids of Type A1:

Indolizine-2-carboxylic acid

The Production of indolizine-2-carboxylic acid is carried out by synthesis of indole-2-carboxymethyl ester according to literature (Bode, M. L. Chem. Soc., Perkin, Trans., 1993, 1809-1813) and the following Hydrolysis.

To this is dissolved 0.05 g (2.86 mmol) of 2-indolizincarboxylic acid methyl ester in 5 ml of methanol and 5 ml of THF. Then treated with 2.5 ml of 2N NaOH and stirred for 10 hours at room temperature. The reaction solution is concentrated on a rotary evaporator and diluted with water, then washed with hexane, adjusted to pH 3-4 with HCl and taken up in diethyl ether. After drying with MgSO ₄ , the solvent is evaporated.
Yield: 0.04 g (85%).
Mp .: 222 ° C. MS: m / z 161 (M ⁺ ). IR (NaCl): 3429; 2924; 2852; 1741; 1664; 723. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 6:53 to 6:57 (m, 1H, H-6); 7.67-6.72 (m, 1H, H-7); 6.88 (s, 1H, H-1); 7.34 (d, J = 9.0 Hz, 1H, H-8); 7.87-7.88 (m, 2H, H-3, H-5).

Preparation of heteroarenecarboxylic acids of Type A2:

Pyrazolo [1,5-a] pyridine-2-carboxylic acid, pyrazolo [1,5-a] pyridine-3-carboxylic acid, pyrazolo [1,5-a] pyridine-5-carboxylic acid, pyrazolo [1,5-a] pyridine-6-carboxylic acid, 5-methoxypyrazolo [1,5-a] pyridine-2-carboxylic acid, 5-methylpyrazolo [1,5-a] pyridine-2-carboxylic acid, 5-trifluoromethyl-pyrazolo [1,5-a] pyridine-2-carboxylic acid, 6-Brompyrazo lo [1,5-a] pyridine-2-carboxylic acid, 6-chloropyrazolo [1,5-a] pyridine-2-carboxylic acid, 6-fluoropyrazolo [1,5-a] pyridine-2-carboxylic acid,

The Synthesis of these acid components takes place as described in the literature (Bettinetti, L. et al. J. Med. Chem. 2002, 45, 4594-4597).

The synthesis of 5-methoxypyrazolo [1,5-a] pyridine-2-carboxylic acid is carried out analogously to the general conditions for the synthesis of heteroaromatic carboxylic acids of type (A2). Yield: 0.28 g (72%).
Mp .: 220 ° C. MS: m / z 192 (M ⁺ ). IR (NaCl): 3050, 2939, 1704, 1652, 1411, 1230. ¹ H NMR (DMSO, 360 MHz) δ (ppm): 3.84 (s, 3H, CH ₃ O); 6.72 (dd, J = 7.5 Hz, 2.5 Hz, 1H, H-6); 6.82 (s, 1H, H-3); 7.09 (d, J = 2.5Hz, 1H, H-4), 8.58 (d, J = 7.5Hz, 1H, H-7), 12.96 (s, 1H, COOH).

The synthesis of 5-methylpyrazolo [1,5-a] pyridine-2-carboxylic acid is carried out analogously to the general conditions for the synthesis of heteroarenecarboxylic acids of type (A2). Yield: 0.43 g (93%).
Mp .: 203 ° C. MS: m / z 176 (M ⁺ ). IR (NaCl): 3133, 3050, 1697, 1405, 1270, 937. ¹ H NMR (DMSO, 360 MHz) δ (ppm): 6.87-6.90 (m, 1H, H-6); 6.91 (s, 1H, H-3); 7.52 (s, 1H, H-4); 8.62 (d, J = 7.4 Hz, 1H, H-7); 13.00 (br s, 1H, COOH). ¹³ C NMR (DMSO, 90 MHz) δ (ppm): 163.6, 145.3, 140.5, 134.6, 128.2, 117.1, 116.9, 98.5, 20.6.

The synthesis of 5-trifluoromethylpyrazolo [1,5-a] pyridine-2-carboxylic acid is carried out analogously to the general conditions for the synthesis of heteroarenecarboxylic acids of type (A2).
Yield: 0.54 g (84%).
Mp .: 230 ° C. MS: m / z 230 (M ⁺ ). IR (NaCl): 3445, 1698, 1495, 1460, 1331, 1241. ¹ H NMR (DMSO, 360 MHz) δ (ppm): 7.30 (dd, J = 7.4, 2.1 Hz, 1H, H-6); 7.32 (s, 1H, H-3); 8.36 (s, 1H, H-4); 8.97 (dd, J = 7.4 Hz, 0.7 Hz, 1H, H-7); 13.34 (brs, 1H, COOH). ¹³ C NMR (DMSO, 90 MHz) δ (ppm): 163.0 (CO ₂ H), 146.6 (C-7), 138.8 (C-2), 130.6 (C-3a), 124.4 (q, J = 34 Hz , C-5), 123.3 (q, J = 273 Hz, CF _3), 118.0 (q, J = 5 Hz, C-6), 109.6 (q, J = 3 Hz, C-4), 103.0 (C -3).

The synthesis of 6-bromopyrazolo [1,5-a] pyridine-2-carboxylic acid is carried out analogously to the general conditions for the synthesis of heteroarenecarboxylic acids of type (A2).
Yield: 0.27 g (70%).
Mp .: 226 ° C. MS: m / z 240 (M ⁺ ), 242 ((M + 2) ⁺ ). IR (NaCl): 3135, 3070, 1701, 1402, 1265, 920. ¹ H NMR (DMSO, 360 MHz) δ (ppm): 7.12 (d, J = 0.72 Hz, 1H, H-3); 7.44 (dd, J = 9.6 Hz, J = 1.8 Hz, 1H, H-5); 7.78 (dd, J = 9.6 Hz, J = 0.72 Hz, 1H, H-4); 9.16 (s, 1H, H-7); 13.19 (br s, 1H, COOH). ¹³ C NMR (DMSO, 90 MHz) δ (ppm): 163.2, 145.5, 139.1, 129.2, 127.5, 120.2, 108.4, 100.8.

The synthesis of 6-chloropyrazolo [1,5-a] pyridine-2-carboxylic acid is carried out analogously to the general conditions for the synthesis of heteroarenecarboxylic acids of type (A2).
Yield: 0.35 g (80%).
Mp .: 233 ° C. MS: m / z 196 (M ⁺ ), 198 ((M + 2) ⁺ ). IR (NaCl): 3444, 3080, 1699, 1506, 1495, 1269, 1063. ¹ H NMR (DMSO, 360 MHz) δ (ppm): 7.13 (d, J = 0.9 Hz, 1H, H-3); 7.36 (dd, J = 9.5 Hz, 1.8 Hz, 1H, H-5); 7.83 (dd, J = 9.5 Hz, 0.9 Hz, 1H, H-4); 8.97 (br s, 1H, H-7). ¹³ C NMR (DMSO, 90 MHz) δ (ppm): 163.1, 145.7, 139.0, 127.1, 125.7, 121.3, 120.0, 100.7.

The synthesis of 6-fluoropyrrazolo [1,5-a] pyridine-2-carboxylic acid is carried out analogously to the general conditions for the synthesis of heteroaromatic carboxylic acids of type (A2).
Yield: 0.17 g (71%).
Mp .: 245 ° C. MS: m / z 180 (M ⁺ ). IR (NaCl): 3135, 3080, 1698, 1510, 1494, 1269, 1064. ¹ H NMR (DMSO, 360 MHz) δ (ppm): 7.14 (d, J = 0.9 Hz, 1H, H-3); 7.43 (ddd, J = 9.8 Hz, 8.4 Hz, 2.3 Hz, 1H, H-6); 7.88 (ddd, J = 9.8 Hz, 5.9 Hz, 0.7 Hz, 1H, H-4); 9.05 (br d, J = 4.8 Hz, 1H, H-7). ¹³ C NMR (DMSO, 90 MHz) δ (ppm): 163.1 (CO ₂ H), 153.9 (d, J = 236 Hz, C-6), 145.6 (d, J = 3 Hz, C-3a), 138.3 (C-2), 120.0 (d, J = 9Hz, C-4), 116.8 (d, J = 26Hz, C-7), 116.3 (d, J = 41Hz, C-5), 100.7 ( C-3).

Preparation of heteroarenecarboxylic acids of Type A3:

3-bromopyrazolo [1,5-a] pyridine-2-carboxylic acid, 3-chloropyrazolo [1,5-a] pyridine-2-carboxylic acid, 3-bromopyrazolo [1,5-a] pyridine-5-carboxylic acid, 3- chloropyrazolo [1,5-a] pyridine-5-carboxylic acid

0.10 g (0.6 mmol) of pyrazolo [1,5-a] pyridine-2-carboxylic acid (A2) and 0.13 g (0.75 mmol) of N-bromosuccinimide are mixed with 7 ml of chloroform under a protective gas atmosphere, and 55 Stirred hours at room temperature. Subsequently, the solvent is evaporated in vacuo; Purification by flash chromatography phie (CH ₂ Cl ₂ -MeOH: 90-10) gives 3-bromopyrazolo [1,5-a] pyridine-2-carboxylic acid.
Yield 0.11 g (73%).
Mp .:> 300 ° C dec. MS: m / z 240 (M ⁺ ), 242 ((M + 2) ⁺ ). IR (NaCl): 3382, 1643, 15.77, 1523, 1467, 1396. ¹ H NMR (DMSO, 360 MHz) δ (ppm): 7.06-7.10 (m, 1H, H-6); 7.34-7.41 (m, 1H, H-5); 7.59 (d, J = 8.9 Hz, 1H, H-4); 9.24 (d, J = 6.7 Hz, 1H, H-7).

The synthesis of 3-chloropyrazolo [1,5-a] pyridine-2-carboxylic acid is carried out analogously to the general conditions for the synthesis of heteroarenecarboxylic acids of type (A3).
Yield: 60 mg (49%).
Mp .:> 300 ° C dec. MS: m / z 196 (M ⁺ ), 198 ((M + 2) ⁺ ). IR (NaCl): 3396, 3099, 1633, 1604, 1504, 1403, 1348. ¹ H NMR (DMSO, 360 MHz) δ (ppm): 7.04-7.08 (m, 1H, H-5); 7.34-7.38 (m, 1H, H-6); 7.61 (d, J = 9.2 Hz, 1H, H-4); 9.08 (br d, J = 5.7 Hz, 1H, H-7).

The synthesis of 3-bromopyrazolo [1,5-a] pyridine-5-carboxylic acid is carried out analogously to the general conditions for the synthesis of heteroarenecarboxylic acids of type (A3).
Yield: 0.13 g (87%).
Mp .:> 300 ° C dec. MS: m / z 240 (M ⁺ ), 242 ((M + 2) ⁺ ). IR (NaCl): 3382, 1643, 1577, 1523, 1467, 1396. ¹ H NMR (DMSO, 360 MHz) δ (ppm): 7.38 (d, J = 6.7 Hz, 1H, H-6); 8.07 (s, 1H, H-4); 8.25 (s, 1H, H-2); 8.75 (d, J = 7.1 Hz, 1H, H-7).

The synthesis of 3-chloropyrazolo [1,5-a] pyridine-5-carboxylic acid is carried out analogously to the general conditions for the synthesis of heteroarenecarboxylic acids of type (A3).
Yield: 75 mg (99%).
Smp.:180°C. MS: m / z 196 (M ⁺ ), 198 ((M + 2) ⁺ ). IR (NaCl): 3406, 3100, 1710, 1576, 1529, 1509, 1396. ¹ H NMR (DMSO, 360 MHz) δ (ppm): 7.42-7.45 (m, 1H, H-6); 8.10 (s, 1H, H-4); 8.16 (s, 1H Hz, H-2); 8.63 (br d, J = 7.1 Hz, 1H, H-7).

Preparation of heteroarenecarboxylic acids of Type A4:

4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-2-carboxylic acid, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-3-carboxylic acid, 4,5,6, 7-tetrahydro-5-methylpyrazolo [1,5-a] pyridine-2-carboxylic acid

0.20 g (1.2 mmol) of pyrazolo [1,5-a] pyridine-2-carboxylic acid (A2) are dissolved in 10 ml of ethanol and treated with 40 mg Pd / C 10% at 16 bar H ₂ pressure and 80 ° C hydrogenated in a 100 ml pressure tube for 4 hours. Filtration of Pd-Kohle and Einrotierten yields 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-2-carboxylic acid.
Yield: 0.20 g (98%).
Mp .: 118 ° C. MS: m / z 166 (M ⁺ ), IR (NaCl): 3135, 2951, 2867, 1717, 1215, 771. ¹ H NMR (DMSO, 360 MHz) δ (ppm): 1.74-1.81 (m, 2H, H-5); 1.94-2.00 (m, 2H, H-6); 2.75 (t, J = 6.4 Hz, 2H, H-4); 4.08-4.11 (m, 2H, H-7), 6.41 (s, 1H, H-3). ¹³ C NMR (DMSO, 90 MHz) δ (ppm): 163.4, 142.2, 140.2, 105.4, 48.0, 22.7, 22.0, 19.6.

The synthesis of 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-3-carboxylic acid is carried out analogously to the general conditions for the synthesis of heteroarenecarboxylic acids of the type (A4).
Yield: 0.30 g (37%).
Mp .: 210 ° C. MS: m / z 166 (M ⁺ ), IR (NaCl): 3399, 2957, 2921, 1705, 1551, 1230. ¹ H NMR (DMSO, 360 MHz) δ (ppm): 1.75-1.82 (m, 2H, H-5); 1.91-1.98 (m, 2H, H-6); 2.93 (t, J = 6.4 Hz, 2H, H-4); 4.17-4.20 (t, J = 6.0 Hz, 2H, H-7), 7.72 (s, 1H, H-2).

The synthesis of racemic 4,5,6,7-tetrahydro-5-methylpyrazolo [1,5-a] pyridine-3-carboxylic acid is analogous to the general conditions for the synthesis of heteroaromatic acids of type (A4).
Yield: 0.197 g (96%).
Mp .: 163 ° C. MS: m / z 180 (M ⁺ ), IR (NaCl): 3343, 2960, 2927, 2871, 1691, 1396, 1240, 780. ¹ H NMR (DMSO, 360 MHz) δ (ppm): 1.14 (d, J = 6.7 Hz, 3H, CH ₃ ); 1.70-1.82 (m, 1H, H-5); 1.97-2.11 (m, 2H, H-6); 2.39 (dd, J = 16.3 Hz, J = 10.3 Hz, 1H, H-4); 2.96 (dd, J = 16.3 Hz, J = 4.6 Hz, 1H, H-4); 4.09-4.17 (m, 1H, H-7); 4.37-4.43 (m, 1H, H-7); 6.56 (d, 1H, 0.72 Hz, H-3).

EFFICIENT SYNTHESIS OF SUBSTITUTED PYRAZOLO [1,5-a] PYRIDINES:

The We developed an efficient synthesis of substituted pyrazolo [1,5-a] pyridines is described using the example of the preparation of pyrazolo [1,5-a] pyridin-5-ylcarboxylic acid.

Preparation of N-aminopyridines:

N-amino-4-hxdroxymethylpyridinium 2,4-dinitrophenolate

To a solution of 1.50 g (7.54 mmol) of O- (2,4-dinitrophenyl) hydroxylamine in 10 ml of methylene chloride, 0.75 g (6.89 mmol) of 4-hydroxymethylpyridine are added dropwise under a protective gas atmosphere and 21 hours at room temperature touched. After addition of diethyl ether, the precipitated solid is filtered off and washed with ether. The product is used without purification for the next reaction.
Yield: 1.78 g (84%).
Mp .: 108 ° C.

Preparation of pyrazolo [1,5-a] pyridinecarboxylic acids:

5-Hydroxymethylpyrazolo [1,5-a] pyridin-3-ylcarboxylate

To a solution of 1.5 g (4.9 mmol) of N-amino-4-hydroxymethylpyridinium 2,4-dinitrophenolate in 8 ml of dry DMF is added 0.97 g (7 mmol) of potassium carbonate and 0.45 g (5, 3 mmol) Propylsäuremethyylester added dropwise. After stirring for 20 hours at room temperature, the mixture is filtered off, the solvent is evacuated, the residue is taken up in water, extracted with diethyl ether and the organic phase is dried with MgSO ₄ . Evaporation of the solvent and purification by flash chromatography on silica gel (EtOAc gasoline: 3-7) gives 5-hydroxymethylpyrazolo [1,5-a] pyridin-3-ylcarboxylic acid methyl ester.
Yield: 0.46 g (46%).

The analytical data and the further synthesis steps for the extraction of pyrazolo [1,5-a] pyridin-5-ylcarboxylic acid are described in the literature (Bettinetti, L., et al., J. Med. Chem., 2002, 45, 4594-4597).

SYNTHESIS OF AMINE COMPONENTS:

Preparation of amines Type C1:

4- (4- (2,3-dichlorophenyl) piperazin-1-yl) alkylamine, 4- (4- (2-methoxyphenyl) piperazin-1-yl) alkylamine

For the preparation of arylpiperazinylamines of type (C1), commercially available 2-methoxy- or 2,3-dichlorophenyl-piperazines can be alkylated with bromobutylphthalimide in xylene, for example. Subsequent hydrazinolysis of the phthalimide-substituted structures yields the primary amines of type (A1). This is exemplified by the following reaction scheme:

2.3 g (10 mmol) of 2,3-dichlorophenylpiperazine (base) are dissolved in 10 ml of xylene and heated to 70.degree. Then 1.4 g (5 mmol) of 4-bromobutylphthalimide (dissolved in 20 ml of xylene) are added dropwise and the reaction mixture is heated at 125 ° C. for 24 hours. After cooling the mixture to 0 ° C is filtered off and the filtrate evapurated. The resulting N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) butylphthalimide is purified by flash chromatography Matography on SiO ₂ with ethyl acetate.
Yield: 4.0 g (92%).

To a suspension of N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) butylphthalimide in 40 ml of ethanol is added a solution of 0.45 ml of 80% hydrazine hydrate (2.5 eq) in 5 ml Ethanol added dropwise. The mixture is refluxed for 3 hours, then cooled to room temperature, the precipitated solid is filtered off, and the ethanolic solution is evaporated in vacuo. Purification by flash chromatography (CH ₂ Cl ₂ -MeOH-Me ₂ EtN: 90-8-2) gives the free base 4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butylamine.
Yield: 0.900 g (60%).
MS: m / z 301 (M ⁺ ), 303 ((M + 4) ⁺ ), 305 (M + 4) ⁺ ); IR: (NaCl): 3397, 2939, 2817, 1641, 1572, 1500, 1482, 1376.1240, 1152, 1118, 1023, 917, 791, 749, 698, 661. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.48-1.64 (m, 4H, CH ₂ -CH ₂ ); 2.44 (t, J = 7.6 Hz, 2H, CH ₂ N); 2.64 (m, 4H, pip); 2.72-2.76 (m, 2H, H ₂ NC H ₂ ); 3.07 (m, 4H, pip); 6.93-6.99 (m, 1H, phenyl H-5); 7.11-7.17 (m, 2H, phenyl H-4, phenyl H-6).

Preparation of amines Type C2:

4- (4- (3-chloro-2-methoxyphenyl) piperazin-1-yl) butylamine, 4- (4- (2,3-difluorophenyl) piperazin-1-yl) butylamine

An alternative synthetic route for obtaining differently substituted phenylpiperazinylalkylamines of the type (C2) represents the reaction of the piperazine with a cyanoalkyl halide of corresponding chain length; as exemplified in the following reaction scheme:

The corresponding 2,3-disubstituted phenylpiperazines are accessible by palladium-catalyzed amination of 2,3-substituted haloaromatics with piperazine: Thus, for the synthesis of 4- (4- (3-chloro-2-methoxyphenyl) piperazin-1-yl) butylamine 1.7 g (10 mmol) piperazine (base) with 1.35 g NaOtBu (14 mmol), 0.024 g Pd (II) acetate (0.5 mol%), 0.12 g P (OtBu) ₃ (2 mol %) and dissolved with 1.3 ml of dichloroanisole (10 mmol) in 20 ml of toluene. After 21 hours heating to 70 ° C., the mixture is cooled to room temperature, filtered and the filtrate is subsequently evacuated to obtain 4- (3-chloro-2-methoxyphenyl) piperazine.
Yield: 0.8 g (37%).

0.8 g (3.7 mmol) of 4- (3-chloro-2-methoxyphenyl) piperazine and 0.8 g (7.5 mmol) of Na ₂ CO ₃ are dissolved in 20 ml of acetonitrile, heated to reflux for 15 hours, then cooled to room temperature and the solution evaporated in vacuo. The residue is taken up in water and the aqueous phase is extracted with methylene chloride, which is dried (with MgSO ₄ ) and the solvent is evaporated. Purification by flash chromatography (CHCl ₃ -EtOAc: 1-1) affords 4- (4- (3-chloro-2-methoxyphenyl) piperazin-1-yl) butyronitrile.
Yield: 0.4 g (35%).

1,0 ml LiAlH₄-Lösung (1 M in Diethylether) zugetropft und 1 Stunde bei Raumtemperatur gerührt. Nach erneutem Abkühlen auf 0°C wird mit gesättigter NaHCO₃-Lösung versetzt, durch eine Glasfritte mit Celite/MgSO₄/Celite filtriert und mit Methylenchlorid gewaschen. Evapurieren des Filtrats ergibt 4-(4-(3-Chlor-2-methoxyphenyl)piperazin-1-yl)butylamin.
Ausbeute: 0,1438 (96).
MS: m/z 297 (M⁺), 299 ((M+2)⁺), 301 ((M+4)⁺). IR: (NaCl): 3386, 2937, 2821, 1635, 1584, 1540, 1474, 1450, 1251, 1132, 1001, 964, 782, 744, 680, 668. ¹H NMR (CDCl₃, 360 MHz) δ (ppm): 1.60-1.67 (m, 4H, CH₂-CH₂); 2.41-2.45 (m, 2H, H₂N-CH₂); 2.61 (m, 4H, pip); 3.14 (m, 4H, pip); 3.22-3.26 (m, 2H, CH₂N); 3.86 (s, 1H, OCH₃); 6.79-6.82 (m, 1H, Phenyl); 6.95 (dd, J=8.0 Hz, J=8.0 Hz, 1H, Phenyl H-5); 7.00 (dd, J=1.8 Hz, J=8.0 Hz, 1H, Phenyl).Subsequently, 0.15 g of 4- (4- (3-chloro-2-methoxyphenyl) piperazin-1-yl) butyronitrile (0.5 mmol) are dissolved in 5 ml of dry diethyl ether and cooled to 0 ° C. Then get slow

1.0 ml of LiAlH ₄ solution (1 M in diethyl ether) was added dropwise and the mixture was stirred for 1 hour at room temperature. After renewed cooling to 0 ° C is treated with saturated NaHCO ₃ solution, filtered through a glass frit with Celite / MgSO ₄ / Celite and washed with methylene chloride. Evapurieren the filtrate yields 4- (4- (3-chloro-2-methoxyphenyl) piperazin-1-yl) butylamine.
Yield: 0.1438 (96).
MS: m / z 297 (M ⁺ ), 299 ((M + 2) ⁺ ), 301 ((M + 4) ⁺ ). IR: (NaCl): 3386, 2937, 2821, 1635, 1584, 1540, 1474, 1450, 1251, 1132, 1001, 964, 782, 744, 680, 668. ¹ H NMR (CDCl ₃ , 360 MHz) δ ( ppm): 1.60-1.67 (m, 4H, CH ₂ -CH ₂ ); 2.41-2.45 (m, 2H, H ₂ N -CH ₂ ); 2.61 (m, 4H, pip); 3.14 (m, 4H, pip); 3.22-3.26 (m, 2H, CH ₂ N); 3.86 (s, 1H, OCH ₃ ); 6.79-6.82 (m, 1H, phenyl); 6.95 (dd, J = 8.0 Hz, J = 8.0 Hz, 1H, phenyl H-5); 7.00 (dd, J = 1.8 Hz, J = 8.0 Hz, 1H, phenyl).

For the preparation of 4- (4- (2,3-difluorophenyl) piperazin-1-yl) butylamine, 0.56 g (5 mmol) of piperazine (base) with 0.675 g of NaOtBu (7 mmol), 0.046 g of Pd ₂ ( dba) ₃ (0.5 mol%), 0.093 g BINAP (2 mol%), 0.56 ml (5 mmol) of 1-bromo-2,3-difluorobenzene dissolved in 20 ml of toluene and for 18 hours at 115 ° C. heated. After cooling the reaction solution to room temperature, it is filtered off and the filtrate is evacuated to obtain 2,3-difluorophenylpiperazine.
Yield: 0.55 g (55%).

The subsequent reaction to 4- (4- (2,3-difluorophenyl) piperazin-1-yl) butylamine is analogous to the synthesis of amines of type (B2) described above.
Yield: 0.173 g (78% over 2 reaction steps).
MS: m / z 269 (M ⁺ ). IR: (NaCl): 3355, 2939, 2823, 1621, 1585, 1504, 1478, 1269, 1247, 1143, 1007, 774, 714. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.47-1.60 (m, 4H, CH ₂ -CH _2); 2.39-2.44 (m, 2H, H ₂ NC H ₂ ); 2.61-2.65 (m, 4H, pip); 2.71-2.75 (m, 2H, CH ₂ N); 3.12-3.15 (m, 4H, pip); 6.67-6.71 (m, 1H, phenyl); 6.73-6.80 (m, 1H, phenyl); 6.92-6.99 (m, 1H, phenyl).

Preparation of amines of type C3:

4- (4- (2,3-dihydrobenzofuran-7-yl) piperazin-1-yl) butylamine, 4- (4- (chroman-8-yl) piperazin-1-yl) butylamine

The synthesis is first carried out analogously to the literature (Kerrigan, F. Tetrahedron Lett. 1998, 2219-2222) until the recovery of 2,3-dihydrobenzofuran-7-ylpiperazine with a yield of 54% over 4 reaction steps. Subsequently, the free base is alkylated analogously to the general conditions for the synthesis of amines of type (C2) and the resulting nitrile is reduced to 4- (4- (2,3-dihydrobenzofuran-7-yl) piperazin-1yl) butylamine.
Yield: 0.27 g (86% over 2 reaction steps).
MS: m / z 275 (M ⁺ ). IR: (NaCl): 3359, 2939, 2820, 1609, 1487, 1456, 1254, 1190, 1132, 1012, 942, 870, 755, 661. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1:43 -1.63 (m, 4H, CH ₂ -CH ₂ ); 2:34 to 2:40 (m, 2H, H ₂ NC H _2; 2.62 (m, 4H, pip), 2.72-2.74 (m, 2H, O-CH ₂ -C H _2; 3:15 to 3:21 (m, 6H, pip, CH ₂ N); 4.56-4.61 (m, 2H, OC H ₂ -CH ₂ ); 6.69-6.71 (m, 1H, phenyl); 6.77-6.86 (m, 2H, phenyl).

The preparation of 4- (4- (chroman-8-yl) piperazin-1-yl) butylamine is carried out analogously to the general conditions for the synthesis of amines of the type (C3).
Yield: 0.058 g (57% over 2 reaction steps).
MS: m / z 289 (M ⁺ ). IR: (NaCl): 3354, 2933, 2870, 2814, 1664, 1479, 1461, 1247, 1196, 1024, 870, 737. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1:46 to 1:59 (m , 4H, CH ₂ -CH ₂ ); 1.96-2.03 (m, 2H, O-CH ₂ -C H ₂ -CH _2); 2.39-2.44 (m, 2H, C H ₂ -N); 2.65 (m, 4H, pip); 2.70-2.74 (m, 2H, O-CH ₂ -CH ₂ -CH ₂ ); 2.77-2.80 (m, 2H, C H ₂ -NH ₂ ); 3.08 (m, 4H, pip); 4.24-4.27 (m, 2H, OC H ₂ -CH ₂ -CH ₂ ); 6.71-6.79 (m, 3H, phenyl).

Preparation of amines of type C4:

trans-4- (4-Aminomethylcyclohex-1-ylmethyl) -1- (2-methoxyphenyl) piperazine, Trans-4- (4-aminomethylcyclohex-1-ylmethyl) -1- (2,3-dichlorophenyl) piperazine

The synthesis of the amine components with methylcyclohexylmethyl spacer between amine nitrogen and piperazine is carried out as follows:

outgoing of 1,4-Cyclohexylidendicarbonsäuredimethylester the reaction to 4-Azidomethylcyclohex-1-ylmethanol after Literature (Watanabe, T. Chem. Pharm. Bull. 1995, 43, 529-531). subsequent Oxidation to the aldehyde, reductive amination with the corresponding Phenylpiperazines and reduction of the azido group to the primary amine provides the amines of type (C4).

For the synthesis of trans-4-Azidomethylcyclohex-1-ylcarbaldehyd 0.10 g (0.6 mmol) of trans-4-Azidomethylcyclohex-1-ylmethanol are dissolved in 4 ml of dry DMSO and after addition of 0.21 g (0.77 mmol) IBX (1-hydroxy-1,2-benziodoxol-3 (1H) -one-1-oxide) for 5 hours at room temperature. Now diethyl ether and NaHCO ₃ solution are added and the organic phase is separated off. This is washed again with NaHCO ₃ solution and water and dried over MgSO ₄ . The solvent is evaporated in vacuo.
Yield: 75 mg (76%).
MS: m / z 167 (M ⁺ ); IR: (NaCl): 2927, 2856, 2097, 1723, 1452. ¹ H NMR (CDCl ₃ , 360 MHz) δ (ppm): 1.01-1.12 (m, 2H, C H ₂ -CH ₂ -CH-CHO) ; 1.24-1.35 (m, 2H, C H ₂ -CH ₂ -CH-CHO); 1.49-1.60 (m, 1H, CH); 1.90-1.95 (m, 2H, CH ₂ -C H ₂ -CH-CHO); 2:03 to 2:07 (m, 2H, CH ₂ -C H ₂ -CH-CHO); 2.15-2.24 (m, 1H, C H CHO); 3.18 (d, J = 6.8 Hz, 2H, CH ₂ N ₃ ); 9.63 (d, J = 1.4 Hz, 1H, CHO). ¹³ C NMR (CDCl ₃ , 90 MHz) δ (ppm): 204.0, 57.5, 50.0, 41.0, 37.3, 29.8, 29.2, 25.3.

The synthesis of trans-4- (4-azidomethylcyclohexylmethyl) -1- (2-methoxyphenyl) piperazine begins by dissolving 0.39 g (2.3 mmol) of trans-4-azidomethylcyclohex-1-ylcarbaldehyde and 0.56 g (2.9 mmol) of 2-methoxyphenylpiperazine in 15 ml of dichloromethane and the addition of 0.74 g (3.5 mmol) of sodium triacetoxyborohydride. After 23 hours of reaction at room temperature, the mixture is washed with NaHCO ₃ solution, the organic phase is concentrated and purified by flash chromatography (EtOAc gasoline: 1-1).
Yield: 0.78 g (97%).
IR: (NaCl): 2919, 2851, 2812, 2095, 1500, 1450, 1240. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 0.87-1.05 (m, 4H, CH ₂ -CH _2); 1.47-1.50 (m, 2H, CH); 1.80-1.91 (m, 4H, CH ₂ -CH ₂ ); 2.21 (d, J = 7.1 Hz, 2H, CH ₂ Npip); 2.59 (m, 4H, pip); 3.08 (m, 4H, pip); 3.14 (d, J = 6.4 Hz, 2H, CH ₂ N ₃ ); 3.86 (s, 3H, CH ₃ O); 6.84-7.01 (m, 4H, phenyl).

The synthesis of trans-4- (4-Azidomethylcyclohexylmethyl) -1- (2,3-dichlorophenyl) piperazine succeeds under the same conditions.
Yield: 0.80 g (85%).
IR: (NaCl): 2930, 2818, 2801, 2096, 1577, 1448. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 0.87-1.06 (m, 4H, CH ₂ -CH _2); 1.44-1.59 (m, 2H, CH); 1.81-1.90 (m, 4H, CH ₂ -CH ₂ ); 2.21 (d, J = 7.1 Hz, 2H, CH ₂ Npip); 2.57 (m, 4H, pip); 3.05 (m, 4H, pip); 3.14 (d, J = 6.4 Hz, 2H, CH ₂ N ₃ ); 6.92-6.97 (m, 1H, phenyl); 7.10-7.16 (m, 4H, phenyl). ¹³ C NMR (CDCl ₃ , 90 MHz) δ (ppm): 151.4, 134.0, 127.5, 127.4, 124.4, 117.5, 65.4, 58.0, 53.8, 51.4, 38.4, 35.0, 31.1, 30.3.

The amine component trans-4- (4-aminomethylcyclohex-1-ylmethyl) -1- (2-methoxyphenyl) piperazine is prepared by the preparation of a solution of 0.40 g (1.2 mmol) of trans-4- (4-azidomethylcyclohexylmethyl) -1- (2-methoxyphenyl) piperazine in 10 ml of methanol and addition of 0.10 g of Pd / C 10%. The suspension is stirred under H ₂ atmosphere for 23 hours at room temperature. The solvent is then evaporated in vacuo and purified by flash chromatography (CH ₂ Cl ₂ -CH ₃ OH-NEtMe ₂ : 90-8-2).
Yield: 0.14 g (39%) (slightly yellowish oil).
MS: 317 m / z (M ⁺ ); IR: (NaCl): 3382, 2912, 2842, 2811, 1500, 1240, 747. ¹ H NMR (CDCl ₃ , 360 MHz) δ (ppm): 0.87-1.05 (m, 4H, CH ₂ -CH ₂ ); 1.25-1.30 (m, 1H, CH); 1.45-1.56 (m, 1H, CH); 1.81-1.91 (m, 4H, CH ₂ -CH ₂ ); 2.21 (d, J = 7.1 Hz, 2H, H ₂ NC H ₂ ); 2.55 (d, J = 6.4 Hz, 2H, CH ₂ Npip); 2.59 (m, 4H, pip); 3.08 (m, 4H, pip); 3.86 (s, 3H, CH ₃ O); 6.84-7.01 (m, 4H, phenyl). ¹³ C NMR (CDCl ₃ , 90 MHz) δ (ppm): 152.3, 141.5, 122.7, 120.9, 118.1, 111.1, 65.7, 55.3, 53.9, 50.7, 48.7, 35.3, 31.4, 30.9, 30.4.

To produce trans-4- (4-aminomethylcyclohex-1-ylmethyl) -1- (2,3-dichlorophenyl) piperazine, to a solution of 0.20 g (0.52 mmol) of trans-4- (4-azidomethytcyclohexylmethyl ) -1- (2,3-dichlorophenyl) piperazine in 25 ml of dry THF add 1.05 ml of LiAlH ₄ solution (1 M in THF) and reflux for 8 hours. The solution is evaporated in vacuo and purified by flash chromatography (CH ₂ Cl ₂ -CH ₃ OH-NEtMe ₂ : 90-8-2).
Yield: 0.13 g (36%) (slightly yellowish oil).
MS: 355 m / z (M ⁺ ), 357 ((M + 2) ⁺ ), 359 ((M + 4) ⁺ ); IR: (NaCl): 3375, 2913, 2843, 2817, 1577, 1448, 778. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 0.85-0.98 (m, 4H, CH ₂ -CH _2); 1.19-1.31 (m, 1H, CH); 1.43-1.52 (m, 1H, CH); 1.80-1.88 (m, 4H, CH ₂ -CH ₂ ); 2.19 (d, J = 7.1 Hz, 2H, H ₂ NC H ₂ ); 2.53-2.56 (m, 6H, pip, CH ₂ Npip); 3.06-3.08 (m, 3H, pip); 3.17-3.20 (m, 1H, pip); 6.94-6.96 (m, 1H, phenyl), 7.10-7.15 (m, 2H, phenyl).

SYNTHESIS OF EXAMPLE CONNECTIONS

Example 1:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butylindolizin-2-ylcarbamid

0.019 g of indolizine-2-carboxylic acid (0.12 mmol) are dissolved in 4 ml of dry methylene chloride. Add 0.07 ml (0.42 mmol) of dry DIPEA. Subsequently, 0.042 g (0.13 mmol), dissolved in 0.5 ml of dry DMF, TBTU is slowly added dropwise at 0 ° C and stirred for 15 minutes at room temperature. The reaction solution is cooled again to 0 ° C and a solution of dissolved 0.034 g (0.13 mmol) of 4- (4- (2-methoxyphenyl) piperazin-1-yl) butylamine in 4 ml of dry methylene chloride at 0 ° C was added dropwise. After 1 hour, the reaction mixture is taken up in CH ₂ Cl ₂ and washed with saturated NaHCO ₃ solution and water. After drying the organic phase with MgSO ₄ , the solvent is evaporated and purified by flash chromatography (SiO ₂ ; CH ₂ Cl ₂ -CH ₃ OH: 98-2).
Yield: 39 mg (81%).
Mp .: 143⎕C; MS: m / z 406 (M ⁺ ); IR (NaCl): 2933; 2819; 1631; 1558; 1500; 1242; 1029; 750. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.67-1.69 (m, 4H, CH ₂ -CH _2); 2.50 (t, J = 6.9 Hz, 2H, CH ₂ N); 3.07 (m, 4H, pip); 3.11 (m, 4H, pip); 3.47-3.52 (m, 2H, C H ₂ NHCO); 3.86 (s, 3H, OCH ₃ ); 6.39 (br t, J = 5.1 Hz, 1H, NHCO); 6.49-6.53 (m, 1H, H-6); 6.59 (s, 1H, H-1); 6.68 (ddd, J = 9.1 Hz, J = 6.6 Hz, J = 1.1 Hz, 1H, H-7); 6.86 (d, J = 7.6 Hz, 1H, phenyl); 7.91-7.02 (m, 3H, phenyl); 7.33 (d, J = 9.1 Hz, 1H, H-8); 7.76 (d, J = 1.1 Hz, 1H, H-3); 7.87 (dd, J = 7.1 Hz, J = 0.9 Hz, 1H, H-5). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 164.9; 152.2; 141.1; 132.8; 125.4; 123.9; 122.9; 120.9; 119.8; 118.2; 113.9; 111.8; 111.2; 97.1; 89.3; 58.1; 55.3; 53.4; 50.4; 39.3; 27.6; 24.2.
CHN (%): C ₂₄ H ₃₀ N ₄ O ₂ × 0.5 H ₂ O
Re: C 69.37; H, 7.52; N 13.48 Gef .: C 69.07; H 7,30; N 13,46.

Example 2:

N-4- (4- (3-chloro-2-methoxyphenyl) piperazin-1-yl) butylindolizin-2-ylcarbamid

• Synthesis analogous to Example 1.
• Yield: 41 mg (75%).
• Mp .: 157 ° C. MS: m / z 440 (M ⁺ ), 442 ((M + 2) ⁺ ), 444 ((M + 4) ⁺ ). IR (NaCl): 3321; 2936; 2811; 1626; 1554; 1525; 1250; 1142; 739. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.66-1.68 (m, 4H, CH ₂ -CH _2); 2.48 (t, J = 6.9 Hz, 2H, CH ₂ Npip); 2.64 (m, 4H, pip); 3.14 (m, 4H, pip); 3.47-3.52 (m, 2H, C H ₂ NHCO); 3.86 (s, 3H, OCH ₃ ); 6.35 (br t, J = 5.0 Hz, 1H, NHCO); 6.49-6.53 (m, 1H, H-6); 6.58 (s, 1H, H-1); 6.69 (ddd, J = 9.1 Hz, J = 6.6 Hz, J = 1.1 Hz, 1H, H-7); 6.77 (dd, J = 8.0 Hz, J = 1.8 Hz, 1H, phenyl); 6.94 (t, J = 8.0 Hz, 1H, phenyl); 7.00 (dd, J = 8.0 Hz, J = 1.8 Hz, 1H, phenyl); 7.33 (d, J = 9.2 Hz, 1H, H-8); 7.74-7.75 (m, 1H, H-3); 7.85 (dd, J = 7.1 Hz, J = 0.9 Hz, 1H, H-5). ¹³ C NMR _(CDCl3, 90 Mhz) δ (ppm): 164.9; 148.6; 146.5; 132.8; 128.7; 125.4; 124.6; 123.9; 123.3; 119.8; 118.2; 117.0; 113.9; 111.8; 97.0; 58.9; 58.1; 53.7; 50.0; 39.4; 27.6; 24.2.
• CHN (%): C ₂₄ H ₂₉ ClN ₄ O ₂ .0.3 H ₂ O
• Re: C 64.49; H 6.69; N 12.53; Found: C, 64.57; H 6.72; N 12,46.

Example 3:

N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butylindolizin-2-ylcarbamid

• Synthesis analogous to Example 1.
• Yield: 30 mg (57%).
• M.p .: 179⎕C. MS: m / z 444 (M ⁺ ), 446 ((M + 2) ⁺ ), 448 ((M + 4) ⁺ ). IR (NaCl): 3427; 2925; 2852; 1631; 1529; 1244; 1043; 731. ¹ H NMR: (CDCl _3, 360 MHz) δ (ppm): 1.64-1.70 (m, 4H, CH ₂ -CH _2); 2.50 (t, J = 6.9 Hz, 2H, CH ₂ Npip); 2.66 (m, 4H, pip); 3.07 (m, 4H, pip); 3.47-3.52 (m, 2H, C H ₂ NHCO); 6.33 (br t, J = 5.1 Hz, 1H, NHCO); 6.49-6.53 (m, 1H, H-6); 6.58 (s, 1H, H-1); 6.69 (ddd, J = 9.1 Hz, J = 6.6 Hz, J = 1.1 Hz, 1H, H-7); 6.92 (dd, J = 7.3 Hz, J = 2.3 Hz, 1H, phenyl); 7.10-7.17 (m, 2H, phenyl); 7.33 (d, J = 9.2 Hz, 1H, H-8); 7.75-7.76 (m, 1H, H-3); 7.87 (dd, J = 7.1 Hz, J = 1.0 Hz, 1H, H-5). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 164.9; 151.2; 134.0; 132.9; 127.5; 127.4; 125.4; 124.6; 123.9; 119.8; 118.6; 118.3; 113.9; 111.8; 96.9; 58.0; 53.3; 51.1; 39.4; 27.7; 24.3.

Example 4:

N-4- (4- (2,3-difluorophenyl) piperazin-1-yl) butylindolizinyl-2-ylcarbamid

• Synthesis analogous to Example 1.
• Yield: 46 mg (93%).
• Mp .: 170 ° C. MS: m / z 412 (M ⁺ ). IR (NaCl): 3316; 2946; 2812; 1626; 1556; 1502; 1266; 1142; 767. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.62-1.70 (m, 4H, CH ₂ -CH _2); 2.46 (t, J = 6.9 Hz, 2H, CH ₂ Npip); 2.61-2.64 (m, 4H, pip); 3.11-3.13 (m, 4H, pip); 3.46-3.52 (m, 2H, C H ₂ NHCO); 6.29 (br t, J = 5.0 Hz, 1H, NHCO); 6.49-6.54 (m, 1H, H-6); 6.57 (s, 1H, H-1); 6.63-6.71 (m, 2H, phenyl, H-7); 6.74-6.80 (m, 1H, phenyl); 6.91-6.98 (m, 1H, phenyl); 7.33 (d, J = 9.0 Hz, 1H, H-8); 7.75 (d, J = 1.2 Hz, 1H, H-3); 7.85 (dd, J = 6.9 Hz, J = 1.1 Hz, 1H, H-5). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 164.9; 151.5 (dd, ¹ J _CC = 10.4 Hz, ¹ J _CF = 244.1 Hz, 1 C, phenylC-2); 143.9 (dd, ¹ J _CC = 13.9 Hz, ¹ J _CF = 246.9 Hz, 1 C, phenyl C-3); 141.9 (dd, ³ J = 5.5 Hz, ⁴ J = 2.1 Hz, 1 C, phenylC1); 132.9; 125.4; 123.5 (dd, ³ J = 8.3 Hz, ⁴ J = 4.9 Hz, 1 C, phenylC-4); 123.9; 119.8; 118.2; 117.0; 113.9; 111.8; 109.9; 96.9; 58.0; 53.2; 50.4; 39.4; 27.7; 24.3.

Example 5:

N-4- (4- (2,3-dihydrobenzofuran-7-yl) piperazin-1-yl) butylindolizin-2-ylcarbamid

• Synthesis analogous to Example 1.
• Yield: 47 mg (94%).
• Mp .: 159 ° C. MS: m / z 418 (M ⁺ ). IR (NaCl): 3323; 2941; 2817; 1634; 1557; 1267; 1146; 753. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.66-1.68 (m, 4H, CH ₂ -CH _2); 2.48 (t, J = 6.9 Hz, 2H, CH ₂ Npip); 2.67 (m, 4H, pip); 3:17 to 3:22 (m, 6H, O-CH ₂ -C H _2, pip); 3.46-3.51 (m, 2H, C H ₂ NHCO); 4.59 (t, J = 8.8 Hz, 2H, OC H ₂ -CH ₂ ); 6.38 (br t, J = 4.8 Hz, 1H, NHCO); 6.50 (ddd, J = 6.9 Hz, J = 6.6 Hz, J = 1.2 Hz, 1H, H-6); 6.59 (s, 1H, H-1); 6.66-6.70 (m, 2H, H-arom, H-7); 6.77-6.81 (m, 1H, H-arom); 6.86 (dd, J = 7.3 Hz, J = 1.1 Hz, 1H, H-arom); 7.33 (d, J = 9.0 Hz, 1H, H-8); 7.75 (dd, J = 2.1 Hz, J = 1.1 Hz, 1H, H-3); 7.86 (dd, J = 7.1 Hz, J = 1.1 Hz, 1H, H-5). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 164.9; 151.1; 136.2; 132.8; 127.5; 125.4; 123.9; 121.0; 119.8; 118.2; 118.1; 115.6; 113.9; 111.8; 97.1; 71.0; 58.1; 53.2; 49.3; 39.4; 30.1; 27.6; 24.2.

Example 10:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-3-brompyrazolo [1,5-a] pyridin-2-ylcarbamid

• Synthesis analogous to Example 38.
• Yield: 149 mg (74% over 2 reaction steps).
• Mp .: 108 ° C. IR (NaCl): 3413, 3326, 2938, 2817, 1668, 1542, 1500, 1240. ¹ H NMR (CDCl ₃ , 360 MHz) δ (ppm): 1.65-1.74 (m, 4H, CH ₂ -CH ₂ ) ; 2:45 to 2:49 (m, 2H, CH ₂ NPIP); 2.67 (m, 4H, pip); 3.10 (m, 4H, pip); 3.50-3.55 (m, 2H, C H ₂ NHCO); 3.86 (s, 3H, CH ₃ O); 6.84-7.01 (m, 5H, phenyl, H-6); 7.21-7.25 (m, 1H, H-5); 7.30 (br s, 1H, NHCO); 7.60 (br d, J = 8.9 Hz, 1H, H-4); 8.33 (d, J = 7.1 Hz, 1H, H-7). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 161.0, 152.3, 143.3, 141.4, 140.1, 128.6, 124.6, 122.8, 121.0, 118.2, 118.0, 114.5, 111.2, 85.0, 58.2, 55.3, 53.5, 50.6 , 39.2, 27.6, 24.4.
• CHN (%): C ₂₃ H ₂₈ BrN ₅ O ₂
• Re: C 56.79; H 5.80; N 14.40; Gef .: C 56.71; H 5.91; N 14.44.

Example 11:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-3-chloropyrazolo [1,5-a] pyridin-2-ylcarbamid

• Synthesis analogous to Example 38.
• Yield: 55 mg (61% over 2 reaction steps).
• Mp .: 121 ° C. MS: m / z 441 (M ⁺ ), 443 ((M + 2) ⁺ ); IR (NaCl): 3332, 2937, 2815, 1668, 1635, 1545, 1500, 1240. ¹ H NMR (CDCl ₃ , 360 MHz) δ (ppm): 1.65-1.74 (m, 4H, CH ₂ -CH ₂ ) ; 2:45 to 2:49 (m, 2H, CH ₂ NPIP); 2.67 (m, 4H, pip); 3.10 (m, 4H, pip); 3.50-3.56 (m, 2H, C H ₂ NHCO); 3.86 (s, 3H, CH ₃ O); 6.84-6.89 (m, 1H, H-6); 6.90-7.01 (m, 4H, phenyl); 7.20-7.27 (m, 2H, NHCO, H-5); 7.61 (br d, J = 8.9 Hz, 1H, H-4); 8.31 (d, J = 7.1 Hz, 1H, H-7). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 160.9, 152.3, 141.9, 141.3, 138.6, 128.5, 124.2, 122.8, 121.0, 118.2, 117.2, 114.4, 111.2, 101.0, 58.1, 55.3, 53.4, 50.5 , 39.1, 27.6, 24.4.

Example 12:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-5-methyl-pyrazolo [1,5-a] pyridin-2-ylcarbamid

• Synthesis analogous to Example 38.
• Yield: 60 mg (50% over 2 reaction steps).
• Mp .: 119 ° C. MS: m / z 421 (M ^+), IR (NaCl): 3411, 3336, 2937, 2871, 1662, 1500, 1240. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.65-1.72 (m , 4H, CH ₂ -CH ₂ ); 2:34 (s, 3H, CH _3); 2.44-2.48 (m, 2H, CH ₂ Npip); 2.66 (m, 4H, pip); 3.11 (m, 4H, pip); 3.49-3.54 (m, 2H, C H ₂ NHCO); 3.86 (s, 3H, CH ₃ O); 6.66 (d, J = 7.1 Hz, 1H, H-6); 6.85-7.01 (m, 5H, phenyl, H-3); 7.25 (br s, 1H, NHCO); 7.33 (s, 1H, H-4); 8.23 (d, J = 7.1 Hz, 1H, H-7).
• CHN (%): C ₂₄ H ₃₁ N ₅ O ₂
• Re: C 68.38; H 7.41; N 16.61; Found: C 67.99; H 7.51; N 16.69.

Example 13:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-6-brompyrazolo [1,5-a] pyridin-2-ylcarbamid

• Synthesis analogous to Example 38.
• Yield: 85 mg (84% over 2 reaction steps).
• Mp .: 104 ° C. MS: 485 m / z (M ⁺ ), 487 ((M + 2) ⁺ ); IR (NaCl): 3320, 2937, 2815, 1662, 1552, 1502, 1240. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.65-1.73 (m, 4H, CH ₂ -CH _2); 2:45 to 2:49 (m, 2H, CH ₂ NPIP); 2.67 (m, 4H, pip); 3.12 (m, 4H, pip); 3.49-3.55 (m, 2H, C H ₂ NNCO); 3.86 (s, 3H, CH ₃ O); 6.84-7.01 (m, 4H, phenyl); 7.07 (s, 1H, H-3); 7.20-7.23 (m, 1H, H-5); 7.28 (br s, 1H, NHCO); 7.49 (d, J = 9.6 Hz, 1H, H-4); 8.51 (br s, 1H, H-7). ¹³ C NMR (CDCl ₃ , 90 MHz) δ (ppm): 161.7, 152.3, 148.5, 141.3, 139.7, 128.6, 127.4, 122.9, 120.9, 119.6, 118.1, 111.2, 108.1, 98.8, 58.1, 55.3, 53.4, 50.5 , 39.2, 27.6, 24.3.
• CHN (%): C ₂₃ H ₂₈ BrN ₅ O ₂
• Re: C 56.79; H 5.80; N 14.40; Gef .: C 56.39; H 5.94; N 14.29.

Example 14:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-3-methoxycarbonylpyrazolo [1,5-a] pyridin-2-ylcarbamid

0.12 g (0.5 mmol) of pyrazolo [1,5-a] pyridine-2,3-dicarboxylic acid dimethyl ester, 0.24 g (1.0 mmol) of 1- (4-aminobutyl) -4- (2-methoxyphenyl ) piperazine and 4.0 mg (0.08 mmol) of sodium cyanide are mixed with 2 ml of methanol in a pressure tube and stirred at 50 ° C for 62 hours. Subsequently, the solvent is evaporated in vacuo to obtain the product.
Yield 0.21 g (89%).
Mp .: 149 ° C. IR (NaCl): 3286, 2940, 2815, 1683, 1660, 1502, 1444, 1240, 750. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.67-1.77 (m, 4H, CH ₂ -CH ₂ ); 2.47-2.51 (m, 2H, CH ₂ Npip); 2.67 (m, 4H, pip); 3.08 (m, 4H, pip); 3.56-3.61 (m, 2H, CH NHCO); 3.85 (s, 3H, CH ₃ O); 4.00 (s, 3H, CH ₃ O); 6.84-7.01 (m, 4H, phenyl) 7.03-7.07 (m, 1H, H-6), 7.45-7.50 (m, 1H, H-5), 8.15 (br d, J = 8.9 Hz, 1H, H- 4), 8.64 (br d, J = 6.7 Hz, 1H, H-7), 9.98 (br s, 1H, NHCO). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 165.4, 160.5, 152.3, 150.1, 142.3, 141.4, 129.7, 128.3, 122.8, 121.0, 120.5, 118.2, 115.1, 111.2, 100.6, 58.3, 55.3, 53.4 , 52.2, 50.5, 39.7, 27.3, 24.3.
C HN (%): C ₂₅ H ₃₁ N ₅ O ₄ .O.5 H ₂ O
Re: C 63.27; H 6.80; N 14.76; Gef .: C 62.94; H 6.73; N 14.74.

Example 15:

N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl-3-methoxycarbonylpyrazolo [1,5-a] pyridin-2-ylcarbamid

• Synthesis analogous to Example 14 and additional purification by flash chromatography (CH ₂ Cl ₂ -MeOH: 95-5).
• Yield: 0.20 g (78%).
• Mp .: 149 ° C. MS: m / z 503 (M ⁺ ), 505 ((M + 2) ⁺ ), 507 ((M + 4) ⁺ ). IR (NaCl): 3471, 3280, 3097, 2944, 2819, 1685, 1660, 1577, 1238. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.67-1.80 (m, 4H, CH ₂ -CH ₂ ); 2.49 (t, J = 7.1 Hz, 2H, CH ₂ Npip); 2.65 (m, 4H, pip); 3.05 (m, 4H, pip); 3.57- 3.62 (m, 2H, C H ₂ NHCO); 4:01 (s, 3H, CH ₃ O); 6.91-6.94 (m, 1H, phenyl), 7.04-7.08 (m, 1H, H-6), 7.10-7.16 (m, 2H, phenyl), 7.46-7.51 (m, 1H, H-5), 8.14- 8.17 (m, 1H, H-4), 8.63-8.66 (m, 1H, H-7), 10.03 (brs, 1H, NHCO). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 165.5, 160.5, 151.3, 150.0, 142.3, 133.9, 129.7, 128.3, 127.5, 127.4, 124.4, 120.5, 118.5, 115.1, 100.6, 58.2, 53.2, 52.2 , 51.3, 39.7, 27.3, 24.3.
• CHN (%): C ₂₄ H ₂₇ N ₅ O ₃
• Re: C 57.15; H 5.40; N 13.88; Found: C 57.00; H 5:34; N 13.86.

Example 16:

Trans-N- (4- (4- (2-methoxyphenyl) piperazin-1-yl) methylcyclohex-1-yl) methyl-pyrazolo [1,5-a] pyridin-2-ylcarbamid

0.025 g (0.15 mmol) of pyrazolo [1,5-a] pyridine-2-carboxylic acid, 0.026 g (0.17 mmol) of HOBt and 0.035 g (0.17 mmol) of N, N'-dicyclohexylcarbodiimide are mixed with 3 ml mixed dry methylene chloride and stirred for 0.5 hours at room temperature. Subsequently, a solution of 0.054 (0.16 mmol) of trans-4- (4-aminomethylcyclohex-1-yl) -1- (2-methoxyphenyl) piperazine in 2.5 ml of methylene chloride is added dropwise and stirred for 18 hours at room temperature. The precipitated solid is filtered off and the solution is evaporated in vacuo. Purification by flash chromatography (CH ₂ Cl ₂ -MeOH: 95-5).
Yield: 64 mg (90%).
Mp 149 ° C. MS: m / z 461 (M ⁺ ); IR (NaCl): 3419, 2917, 2845, 2813, 1667, 1635, 1551, 1500, 1240, 734. ¹ H NMR (CDCl ₃ , 360 MHz) δ (ppm): 0.90-1.10 (m, 4H, CH ₂ -cyclohex); 1.53-1.62 (m, 2H, CH-cyclohex); 1.88 (t, J = 10.7Hz, 4H, CH ₂ -cyclohex); 2.32 (d, J = 6.7 Hz, 2H, CH ₂ Npip); 2.72 (m, 4H, pip); 3.13 (m, 4H, pip); 3.32-3.36 (m, 2H, C H ₂ NHCO); 3.85 (s, 3H, CH ₃ O); 6.82-7.02 (m, 5H, phenyl, H-6), 7.05 (brs, 1H, H-3), 7.13-7.16 (m, 2H, H-5, NHCO), 7.58 (br d, J = 8.8 Hz, 1H, H-4), 8.38 (br d, J = 7.1 Hz, 1H, H-7). ¹³ C NMR (CDCl ₃ , 90 MHz) δ (ppm): 162.1, 152.2, 148.0, 141.3, 141.1, 128.4, 123.6, 123.0, 121.0, 119.2, 118.2, 113.5, 111.1, 97.9, 65.3, 55.3, 53.7, 50.1 , 45.3, 38.3, 34.7, 31.2, 30.4.

Example 17:

Trans-N- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) methylcyclohex-1-yl) methyl-pyrazolo [1,5-a] pyridin-2-ylcarbamid

• Synthesis analogous to Example 16.
• Yield: 13 mg (16%).
• Mp .: 138 ° C. MS: m / z 499 (M ⁺ ), 501 ((M + 2) ⁺ ), 503 ((M + 4) ⁺ ). IR (NaCl): 2920, 2844, 1669, 1635, 1557, 1448, 1239. ¹ H NMR (CDCl ₃ , 360 MHz) δ (ppm): 0.83-1.11 (m, 4H, CH ₂ -cyclohex); 1.50-1.61 (m, 2H, CH-cyclohex); 1.85-1.90 (m, 4H, CH ₂ -cyclohex); 2.17-2.22 (m, 2H, CH ₂ Npip); 2.50-2.58 (m, 4H, pip); 3.05-3.19 (m, 4H, pip); 3.36 (t, J = 6.4 Hz, 2H, C H ₂ NHCO); 6.82-6.87 (m, 1H, H-6); 6.92-6.98 (m, 1H, phenyl), 7.06 (br s, 1H, H-3); 7.10-7.18 (m, 4H, phenyl, H-5, NHCO); 7.59 (br d, J = 9.2 Hz, 1H, H-4); 8.38 (br d, J = 7.1 Hz, 1H, H-7). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 162.1, 151.5, 148.1, 141.4, 134.0, 128.4, 127.4, 124.4, 123.6, 119.3, 118.5, 113.5, 98.0, 91.6, 65.4, 53.7, 51.3, 45.4 , 38.5, 35.1, 31.2, 30.5.
• CHN (%): C ₂₆ H ₃₁ Cl ₂ N ₅ O ₂
• Re: C 62.40; H 6.24; N 13.99; Found: C 62.55; H 6.25; N 13:53.

Example 22:

Trans-N- (4- (4- (2-methoxyphenyl) piperazin-1-yl) methylcyclohex-1-yl) methylpyrazolo (1,5-a] pyridin-3-ylcarbamid

• Synthesis analogous to Example 16.
• Yield: 41 mg (66%).
• Smp.:76°C. MS: m / z 461 (M ⁺ ); IR (NaCl): 3313, 2916, 2844, 2813, 1637, 1627, 1556, 1531, 1499, 1240, 749. ¹ H NMR (CDCl ₃ , 360 MHz) δ (ppm): 0.89-1.09 (m, 4H, CH ₂ -cyclohex); 1.50-1.62 (m, 2H, CH-cyclohex); 1.88 (t, J = 10.8 Hz, 4H, CH ₂ -cyclohex); 2.25 (d, J = 7.1 Hz, 2H, CH ₂ Npip); 2.64 (m, 4H, pip); 3.10 (m, 4H, pip); 3.31-3.35 (m, 2H, C H ₂ NHCO); 3.85 (s, 3H, CH ₃ O); 5.94 (m, 1H, NHCO); 6.84-7.01 (m, 5H, phenyl, H-6), 7.32-7.37 (m, 1H, H-5), 8.14 (br s, 1H, H-2), 8.31 (br d, J = 8.8 Hz, 1H, H-4), 8.48 (br d, J = 7.1 Hz, 1H, H-7). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 163.3, 152.3, 141.4, 140.6, 140.1, 128.8, 126.3, 122.8, 121.0, 119.7, 118.2, 113.5, 111.1, 106.9, 65.4, 55.3, 53.9, 50.5 , 45.5, 38.5, 35.0, 31.2, 30.6.

Example 23:

Trans-N- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) methylcyclohex-1-yl) methyl-pyrazolo [1,5-a] pyridin-3-ylcarbamid

• Synthesis analogous to Example 16.
• Yield: 42 mg (51%).
• Mp .: 68 ° C. MS: m / z 499 (M ⁺ ), 501 ((M + 2) ⁺ ), 503 ((M + 4) ⁺ ). IR (NaCl): 3308, 2920, 2847, 1637, 1555, 1530, 1449, 1272, 1240, 745. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 0.88-1.10 (m, 4H, CH ₂ -cyclohex); 1.45-1.61 (m, 2H, CH-cyclohex); 1.87-1.91 (m, 4H, CH ₂ -cyclohex); 2.17-2.23 (m, 2H, CH ₂ Npip); 2.54-2.58 (m, 4H, pip); 3.06-3.19 (m, 4H, pip); 3.32-3.36 (m, 2H, C H ₂ NHCO); 5.90 (s, 1H, NHCO); 6.82-6.87 (m, 1H, H-6); 6.90-6.97 (m, 1H, phenyl), 7.11-7.18 (m, 2H, phenyl); 7.34-7.37 (m, 1H, H-5); 8.13 (s, 1H, H-2); 8.32 (br d, J = 8.9 Hz, 1H, H-4); 8.48 (br d, J = 7.1 Hz, 1H, H-7). ¹³ C NMR (CDCl ₃ , 90 MHz) δ (ppm): 163.3, 151.4, 140.6, 140.1, 133.6, 128.8, 127.4, 126.3, 124.4, 123.5, 119.0, 115.9, 113.6, 106.9, 65.4, 53.7, 51.3, 45.5 , 38.6, 35.1, 31.2, 30.6.

Example 28:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-3-brompyrazolo [1,5-a] pyridin-5-ylcarbamid

• Synthesis analogous to Example 38.
• Yield: 59 mg (59% over 2 reaction steps).
• Mp: 172 ° C. IR (NaCl): 3316, 2939, 2817, 1648, 1546, 1500, 1240. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.69-1.78 (m, 4H, CH ₂ -CH _2); 2.49-2.53 (m, 2H, CH ₂ Npip); 2.68 (m, 4H, pip); 3.04 (m, 4H, pip); 3.50-3.55 (m, 2H, C H ₂ NHCO); 3.84 (s, 3H, CH ₃ O); 6.76-7.01 (m, 4H, phenyl); 7.20-7.25 (m, 2H, NHCO, H-6); 7.88 (s, 1H, H-4); 7.98 (s, 1H, H-2); 8.42-8.44 (m, 1H, H-7). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 165.4, 152.2, 142.7, 140.9, 137.1, 131.2, 129.1, 123.0, 120.9, 118.1, 115.5, 111.1, 111.0, 86.4, 58.0, 55.3, 53.4, 50.4 , 40.2, 27.3, 24.4.
• CHN (%): C ₂₃ H ₂₈ BrN ₅ O ₂
• Re: C 56.79; H 5.80; N 14.40; Gef .: C 56.67; H 5.86; N 14.21.

Example 29:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-3-chloropyrazolo [1,5-a] pyridin-5-ylcarbamid

• Synthesis analogous to Example 38.
• Yield: 62 mg (54% over 2 reaction steps).
• Mp .: 155 ° C. MS: m / z 441 (M ⁺ ), 443 ((M + 2) ⁺ ); IR (NaCl): 3307, 2940, 2817, 1647, 1546, 1500, 1240. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.67-1.77 (m, 4H, CH ₂ -CH _2); 2.49-2.52 (m, 2H, CH ₂ Npip); 2.67 (m, 4H, pip); 3.04 (m, 4H, pip); 3.49-3.54 (m, 2H, C H ₂ NHCO); 3.84 (s, 3H, CH ₃ O); 6.77-7.01 (m, 4H, phenyl); 7.21 (d, J = 7.4 Hz, 1H, H-6); 7.18-7.22 (m, 1H, NHCO); 7.91 (s, 1H, H-4); 7.95 (s, 1H, H-2); 8.40 (d, J = 7.4 Hz, 1H, H-7). ¹³ C NMR (CDCl ₃ , 90 MHz) δ (ppm): 165.4, 152.2, 141.0, 140.6, 135.6, 130.7, 129.1, 123.0, 121.0, 118.1, 114.9, 111.2, 110.9, 102.5, 58.0, 55.3, 53.5, 50.4 , 40.2, 27.4, 24.5.
• CHN (%): C ₂₃ H ₂₈ ClN ₅ O ₂ · 0.2 N ₂ O
• Re: C 62.00; H 6.42; N 15.72; Gef .: C 61.66; H 6.41; N 15.72.

Example 30

N-5- (4- (2-methoxyphenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridin-5-ylcarbamid

• Synthesis analogous to Example 16.
• Yield: 63 mg (85%) (waxy).
• IR (NaCl): 3309, 2938, 2832, 1650, 1546, 1502, 1243. ¹ H NMR (CDCl ₃ , 360 MHz) δ (ppm): 1.42-1.50 (m, 2H, CH ₂ -C H ₂ -CH ₂ ); 1.58-1.73 (m, 4H, C H ₂ -CH ₂ -C H _2); 2.45 (t, J = 7.45 Hz, 2H, CH ₂ Npip); 2.68 (m, 4H, pip); 3.12 (m, 4H, pip); 3.47-3.52 (m, 2H, CH ₂ NHCO); 3.86 (s, 3H, CH ₃ O); 6.35 (br s, 1H, NHCO); 6.67 (br d, J = 2.1 Hz, 1H, H-3); 6.85-7.02 (m, 4H, phenyl); 7.12 (br d, J = 7.1 Hz, 1H, H-6), 8.01 (s, 1H, H-4), 8.01 (d, J = 2.1 Hz, 1H, H-2), 8.49 (br d, J = 7.1 Hz, 1H, H-7). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 165.6, 152.2, 142.8, 141.2, 139.0, 129.7, 128.6, 122.9, 121.0, 118.2, 117.4, 111.1, 109.6, 99.3, 58.4, 55.3, 53.4, 50.4 , 40.1, 29.4, 26.3, 24.8.

Example 39:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamid

0.050 g (0.3 mmol) of 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-2-carboxylic acid are dissolved in 2 ml of dry toluene. There are added 80 .mu.l (0.9 mmol) of oxalyl chloride and heated to 40 ° C until the onset of gas evolution. The mixture is then stirred first for 1 hour at room temperature, then at 60 ° C for 3.5 h. The solvent is evaporated in vacuo and the residue with 2 ml abs. Methylene chloride added. The acid chloride is added with stirring at 0 ° C. to a solution of 0.36 mmol 4- (4-aminobutyl) -1- (2-methoxyphenyl) piperazine (0.095 g) in 2 ml abs. Added methylene chloride. The solution is slowly warmed to room temperature and stirred for 1 hour. After addition of NaHCO ₃ solution is extracted with methylene chloride, the organic phase dried with MgSO ₄ and evaporated in vacuo. Purify by flash chromatography on silica gel (CH ₂ Cl ₂ -MeOH: 95-5).
Yield: 93 mg (75% over 2 reaction steps).
Smp.:62°C. MS: 411 m / z (M ⁺ ); IR (NaCl): 3355, 2929, 2852, 1662, 1531, 1240. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.61-1.65 (m, 4H, CH ₂ -CH _2); 1.83-1.90 (m, 2H, H-5); 2.01-2.08 (m, 2H, H-6); 2.44 (t, J = 6.7Hz, 2H, CH ₂ Npip); 2.65 (m, 4H, pip); 2.81 (t, J = 6.4 Hz, 2H, H-4); 3.10 (m, 4H, pip); 3.41-3.47 (m, 2H, CH ₂ NHCO); 3.86 (s, 3H, CH ₃ O); 4.09-4.12 (m, 2H, H-7); 6.49 (s, 1H, H-3), 6.84-7.00 (m, 4H, phenyl). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 162.4, 152.3, 145.9, 141.4, 140.7, 122.8, 121.0, 118.2, 111.2, 103.6, 58.2, 55.3, 53.4, 50.6, 48.2, 38.9, 27.7, 24.4 , 23.3, 22.6, 20.3.

Example 40:

(∀) -N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-5-methyl-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridin-2-ylcarbamid

• Synthesis analogous to Example 39.
• Yield: 107 mg (91% over 2 reaction steps).
• Mp .: 65 ° C. MS: 425 m / z (M ⁺ ); IR (NaCl): 3343, 2937, 2815, 1662, 1533, 1500, 1240. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.12 (d, 3H, J = 6.4 Hz, CH _3); 1.60-1.67 (m, 4H, CH ₂ -CH ₂ ); 1.68-1.78 (m, 1H, H-5); 1.96-2.08 (m, 2H, H-6); 2.36 (dd, J = 16.3 Hz, J = 10.3 Hz, 1H, H-4); 2.44 (t, J = 6.7 Hz, 2H, CH ₂ Npip); 2.65 (m, 4H, pip); 2.93 (dd, J = 16.3 Hz, J = 5.0 Hz, 1H, H-4); 3.10 (m, 4H, pip); 3.41-3.46 (m, 2H, C H ₂ NHCO); 3.86 (s, 3H, CH ₃ O); 3.98-4.06 (m, 1H, H-7); 4.19-4.25 (m, 1H, H-7); 6.47 (s, 1H, H-3), 6.84-7.01 (m, 4H, phenyl). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 162.4, 152.3, 146.2, 141.4, 140.7, 122.8, 120.9, 118.2, 111.2, 103.5, 58.2, 55.3, 53.4, 50.6, 47.5, 38.9, 31.2, 30.8 , 27.7, 27.1, 24.3, 20.8.

Example 49:

N-4- (chroman-8-yl) piperazin-1-yl) butylindolizin-2-ylcarbamid Synthesis analogous to Example 1.

• Yield: 30 mg (69%).
• Mp .: 75 ° C. MS: m / z 432 (M ⁺ ). IR (NaCl): 3321; 2935; 2873; 2817; 1636; 1558; 1266; 1143; 754. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.67-1.69 (m, 4H, CH ₂ -CH _2); 1.96-2.03 (m, 2H, O-CH ₂ -C H ₂ -CH _2); 2.51-2.55 (m, 2H, CH ₂ Npip); 2.72 (m, 4H, pip); 2.77-2.80 (m, 2H, O-CH ₂ -CH ₂ -C H _2); 3.10 (m, 4H, pip); 3.46-3.51 (m, 2H, C H ₂ NHCO); 4.23-4.26 (m, 2H, OC H ₂ -CH ₂ -CH ₂ ); 6.38 (br t, J = 4.1 Hz, 1H, NHCO); 6.51 (ddd, J = 6.9 Hz, J = 6.6 Hz, J = 1.2 Hz, 1H, H-6); 6.59 (s, 1H, H-1); 6.68 (ddd, 1H, J = 9.0 Hz, J = 6.6 Hz, J = 0.9 Hz, H-7); 6.71-6.80 (m, 3H, H-arom); 7.32 (d, J = 9.0 Hz, 1H, H-8); 7.76 (d, J = 1.1 Hz, 1H, H-3); 7.86 (dd, J = 7.1 Hz, J = 1.1 Hz, 1H, H-5). ¹³ C NMR (CDCl _3, 90 MHz) δ (ppm): 164.9; 147.6; 140.6; 132.8; 125.4; 124.0; 123.9; 122.7; 119.9; 119.8; 118.2; 115.9; 113.9; 111.8; 97.2; 66.5; 58.0; 53.4; 50.3; 39.2; 27.5; 25.1; 24.0; 22.7; 21.0

CREATING SUBSTANTS LIBRARIES BY FIXED PHASE SUPPORTED SYNTHESIS:

The preparation of a substance library of dopamine receptor-affinity ligands by solid-phase assisted synthesis is based on methods developed in our group and already described (Löber, S., et al., Org. Lett., 2003, 5, 1753-1755). The basis of this work is the development novel BAL linker, which led to the synthesis of the FIMT resin (formyl-indolyl-methyl-triazole). With the help of this functionalized polystyrene, two libraries (library 1 and library 2) of potent ligands could be synthesized:

following are the individual reaction steps of solid phase assisted synthesis of N- (ω- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -alkyl-heteroarylcarbamides (Library 1 with example 6-9, 18-21, 24-27, 31-38, 41-44).

Analogous This synthesis sequence was used in library 2 for the compounds example 13 and Example 50-68.

Preparation of the polymer-bound Compound D2 (Step 1):

Polymer bound ω- (4- (2,3-dichlorophenyl) piperazin-1-yl) alkylamine

0.100 g (1043 mmol / g) FIMT resin (D1), 4 eq NaBH (AcO) ₃ and a solution of 4 eq of the amine component in 5 ml dry methylene chloride are stirred for 24 hours at room temperature in a Teflon reaction vessel (PLS Organic Synthesiser; Rotation: 320 / min). Thereafter, the resin is filtered off and subjected to 3 × each of the following washing steps: methanol, methanol-0.1 N HCl (9-1), triethylamine (2% strength in methylene chloride) and methylene chloride. The resin is dried after the last wash in the course of filtration.

Preparation of the polymer-bound Compound D3 (Step 2):

Polymer bound N- (ω- (4- (2,3-dichlorophenyl) piperazin-1-y) -alky) heteroaromatic carbamide

The Resin obtained is suspended in 5 ml of methylene chloride-DMF: 9-1 and with 4 Eq acid, 4 eq HOAt and 4.5 eq N, N'-diisopropylcarbodiimide added. The reaction mixture is shaken for 48 hours at room temperature, then is filtered off and washed 3 times with DMF, methanol and dichloromethane and after the last washing step dried in the frit.

Cleavage of the polymer bound Target Compounds Example 6-9, 18-21, 24-27, 31-38, 41-44 (Step 3):

N- (ω- (4- (2,3-dichlorophenyl) piperazin-1-y) lalky) heteroarencarbamid

The obtained resin is washed with 5 ml of a solution of 2% trifluoroacetic acids in Methylene chloride and shaken for 2 hours at room temperature. The Resin is filtered, each 2 × with 3 ml of methanol and then Washed methylene chloride. Filtrate and washing liquids are combined, the solvents evapuriert and thereby receive the product.

Characterization of the solid-phase-synthesized substances:

The analytical review of by solid phase assisted Synthesis of products obtained by LC / MS analysis on a Chromatography system from Agilent (Binary Gradient System in combination with the ChemStation software) and the mass spectrometric Determination using a Bruker Esquire 2000 ion-trap mass spectrometer (Ionization in an APCI source).

The chromatographic separation was carried out on a Zorbax SB-C18 column (4.6 mm ID x 250 mm, 5 Dm) with a MeOH / 0.1 N aq.HCO ₂ H eluent system in the gradient from 50/50 to 90/10 at a flow rate of 0.5 ml / min. The detection was carried out by means of Agilent UVNIS detector at 254 nm.

CONNECTIONS OF THE SUBSTANCIAL LIBRARIES 1 and 2:

All Compounds of substance libraries 1 and 2 were discussed as above characterized analytically and in a biological screening method examined. The most promising test compounds then became one subjected to detailed spectroscopic examination and by characterized further receptor binding experiments.

LINKS OF LIBRARY 1:

Example 6:

N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl-pyrazolo [1,5-a] pyridin-2-ylcarbamid

• Molecular weight (MW) (calculated): 418.33; Mass (MS) (found): 418.7 (M + 1); Retention time (T _R in [min]): 11.2.

Example 7:

N-3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propylpyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 432.36; MS (gef): 432.4; T _R : 12.0 min.

Example 8:

N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butylpyrazolo [1,5-a] pyridin-2-ylcarbamid trifluoroacetic

• MW (over): 446.68; MS (gef): 446.5; T _R : 6.1 min.
• IR (NaCl): 3410, 3318, 2954, 2849, 1778, 1670, 1635, 1555, 1514, 1452, 1198. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.74-1.80 (m, 2H, C H ₂ -CH ₂ -Npip); 1.89-1.95 (m, 2H, CONH-CH ₂ C H ₂ ); 3.06-3.12 (m, 2H, CH ₂ Npip); 3.20-3.41 (m, 6H, pip); 3.52-3.58 (m, 2H, C H ₂ NHCO); 3.69-3.72 (m, 2H, pip); 5.30 (br s, 1H, HNpip); 6.86-6.89 (m, 1H, phenyl); 6-97-7.00 (m, 1H, H-6), 7.05 (s, 1H, H-3); 7.14-7.27 (m, 3H, phenyl, H-5), 7.42 (s, 1H, HNCO), 7.60 (d, J = 8.2 Hz, 1H, H-4), 8.49 (d, J = 6.7 Hz, 1H, H-7).

Example 9:

N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridin-2 ylcarbamide trifluoroacetic acid salt

• MW (calculated): 460.41; MS (gef): 460.0; T _R : 9.1 min.
• IR (NaCl): 3407, 3326, 2948, 1773, 1671, 1558, 1514, 1451, 1199. ¹ H NMR (CDCl ₃ , 360 MHz) δ (ppm): 1.46-1.54 (m, 2H, CH ₂ C H ₂ CH ₂ ); 1.67-1.75 (m, 2H, C H ₂ -CH ₂ -Npip); 1.84-1.93 (m, 2H, CH ₂ NPIP); 3.04-3.13 (m, 4H, CONH-CH ₂ C H ₂ , pip); 3.28-3.42 (m, 4H, pip); 3.49-3.54 (m, 2H, C H ₂ NHCO); 3.70-3.74 (m, 2H, pip); 6.24 (br s, 1H, HNpip); 6.86-6.89 (m, 1H, phenyl); 6-97-7.00 (m, 1H, H-6), 7.06 (s, 1H, H-3); 7.13-7.26 (m, 3H, phenyl, H-5), 7.30 (s, 1H, HNCO), 7.60 (d, J = 7.8Hz, 1H, H-4), 8.39 (d, J = 6.4Hz, 1H , H-7).

Example 18:

N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl-pyrazolo [1,5-a] pyridin-3-ylcarbamid

• MG (calculated): 418.33; MS (gef): 418.7; T _R : 11.0 min.

Example 19:

N-3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propylpyrazolo [1,5-a] pyridin-3-ylcarbamid

• MW (calculated): 432.36; MS (gef): 432.2; T _R : 8.4 min.

Example 20:

N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butylpyrazolo [1,5-a] pyridin-3-ylcarbamid

• MW (over): 446.68; MS (gef): 446.1; T _R : 6.5 min.

Example 21:

N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridin-3-ylcarbamid

• MW (calculated): 460.41; MS (gef): 460.1; T _R : 14.3 min.

Example 24:

N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl-pyrazolo [1,5-a] pyridin-5-ylcarbamid

• MG (calculated): 418.33; MS (gef): 418.5; T _R : 11.0 min.

Example 25:

N-3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propylpyrazolo [1,5-a] pyridin-5-ylcarbamid

• MW (calculated): 432.36; MS (gef): 431.9; T _R : 9.9 min.

Example 26:

N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butylpyrazolo [1,5-a] pyridin-5-ylcarbamid trifluoroacetic

• MW (over): 446.68; MS (gef): 446.0; T _R : 9.8 min.
• 1 R (NaCl): 3325, 2961, 2851, 1779, 1671, 1631, 1548, 1452, 1201. ¹ H NMR (CDCl ₃ , 360 MHz) δ (ppm): 1.74-1.85 (m, 2H, C H ₂ CH ₂ Npip); 1.95-2.06 (m, 2H, CONHCH ₂ C H ₂ ); 3:03 to 3:12 (m, 2H, CH ₂ NPIP); 3.14-3.23 (m, 2H, pip); 3.28-3.44 (m, 4H, pip); 3.51-3.70 (m, 4H, CH ₂ NHCO, pip); 6.70 (br s, 1H, HNpip); 6.97-6.99 (m, 1H, H-3); 6.99-7.01 (m, 1H, phenyl); 7.17-7.23 (m, 2H, phenyl); 7.24-7.26 (m, 1H, H-6), 7.65 (br s, 1H, HNCO); 8.01 (s, 1H, H-4), 8.14-8.27 (m, 1H, H-2), 8.45-8.57 (m, 1H, Hz, H-7).

Example 27:

N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridin-5ylcarbamid trifluoroacetic

• MW (calculated): 460.41; MS (gef): 460.0; T _R : 11.2 min.
• IR (NaCl): 3326, 2948, 2861, 1778, 1672, 1631, 1548, 1452, 1200. ¹ H NMR (CDCl ₃ , 360 MHz) δ (ppm): 1.48-1.59 (m, 2H, CH ₂ C H ₂ CH ₂ ); 1.66-1.77 (m, 2H, C H ₂ CH ₂ Npip); 1.85-1.97 (m, 2H, CONHCH ₂ C H ₂ ); 3:02 to 3:19 (m, 4H, CH ₂ NPIP, pip); 3.26-3.35 (m, 2H, pip); 3.36-3.46 (m, 3H, pip); 3.47-3.58 (m, 1H, pip); 3.64-3.75 (m, 2H, C H ₂ NNHCO); 6.73 (br s, 1H, HNpip); 6.96-6.98 (m, 1H, H-3); 6.98-7.00 (m, 1H, phenyl); 7.17-7.24 (m, 4H, phenyl, H-6, HNCO); 8.00-8.80 (m, 3H, H-4, H-2, H-7).

Example 31:

N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl-pyrazolo [1,5-a] pyridine-6-ylcarbamid

• MG (calculated): 418.33; MS (gef): 417.9; T _R : 7.3 min.

Example 32:

N-3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propylpyrazolo [1,5-a] pyridine-6-ylcarbamid

• MG (calculated): 436.39; MS (gef): 431.9; T _R : 8.6 min.

Example 33:

N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butylpyrazolo [1,5-a] pyridine-6-ylcarbamid

• MW (over): 446.68; MS (gef): 446.3; T _R : 7.4 min.

Example 34:

N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridine-6-ylcarbamid

• MW (calculated): 460.41; MS (gef): 460.0; T _R : 6.0 min.

Example 35:

N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 422.36; MS (gef): 422.4; T _R : 7.2 min.

Example 36:

N-3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamid

• MG (calculated): 436.39; MS (gef): 436.4; T _R : 6.3 min.

Example 37:

N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -butyl-4,5,6,7-tetrahydropyrazolo [7,5-a] pyridin-2-ylcarbamide trifluoroacetic acid salt

• MW (over): 450.42; MS (gef): 450.5; T _R : 6.2 min.
• IR (NaCl): 3407, 3328, 2956, 2867, 1776, 1669, 1631, 1578, 1534, 1451, 1197. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1.69-1.73 (m, 2H, C H ₂ CH ₂ NPIP); 1.84-1.89 (m, 4H, CONH-CH ₂ CH _2, H-5); 2.02-2.08 (m, 2H, H-6); 2.80-2.84 (m, 2H, H-4); 3.07-3.12 (m, 2H, CH ₂ Npip); 3.19-3.31 (m, 4H, pip); 3.38-3.48 (m, 4H, pip); 3.68-3.72 (m, 2H, C H ₂ NHCO); 4.11-4.15 (m, 2H, H-7); 6.50 (s, 1H, H-3); 6.96-6.98 (m, 1H, phenyl); 7.16-7.26 (m, 3H, phenyl, HNCO), 8.27 (br s, 1H, HNpip).

Example 38:

N-5- (4- (2,3-dichlorophenyl) -piperazin-1-yl) pentyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamide trifluoroacetic acid salt

• MW (calculated): 464.44; MS (gef): 464.1; T _R : 6.4 min.
• IR (NaCl): 3412, 3327, 2951, 2865, 1779, 1669, 1631, 1578, 1533, 1452, 1198. ¹ H NMR (CDCl _3, 360 MHz) δ (ppm): 1:43 to 1:49 (m, 2H, CH ₂ CH ₂ CH ₂ ); 1.63-1.67 (m, 2H, CH ₂ CH ₂ Npip); 1.81-1.90 (m, 4H, CONHCH ₂ C H ₂ , H-5); 2.03-2.05 (m, 2H, H-6); 2.80-2.83 (m, 2H, H-4); 3.03-3.12 (m, 4H, pip); 3.30 (t, J = 11.7 Hz, 2H, CH ₂ Npip); 3.38-3.45 (m, 4H, pip); 3.69-3.73 (m, 2H, C H ₂ NHCO); 4.11-4.14 (m, 2H, H-7); 6.50 (s, 1H, H-3); 6.98-7.00 (m, 1H, phenyl); 7.08 (br s, 1H, HNCO); 7.17-7.27 (m, 2H, phenyl), 7.83 (br s, 1H, HNpip).

Example 41:

N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethyl-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridin-3-ylcarbamid

• MW (calculated): 422.36; MS (gef): 421.9; T _R : 6.6 min.

Example 42:

N-3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-ylcarbamid

• MW (over): 450.42; MS (gef): 436.4; T _R : 5.9 min.

Example 43:

N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-ylcarbamid

• MW (over): 450.42; MS (gef): 450.5; T _R : 6.2 min.

Example 44:

N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyridin-3-ylcarbamid

• MW (calculated): 464.44; MS (gef): 464.1; T _R : 10.8 min.

LINKS OF LIBRARY 2:

Example 13:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-6-brompyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 486.42; MS (gef): 487.7; T _R : 19.3 min.

The Spectroscopic data of Example 13 are also described on page 28.

Example 50:

N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl-5-methoxy-pyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 476.41; MS (gef): 476.6; T _R : 17.2 min.

Example 51:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-5-methoxy-pyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (over): 437.55; MS (gef): 438.2; T _R : 18.5 min.

Example 52:

N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl-5-trifluoromethylpyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 514.38; MS (gef): 514.8; T _R : 18.2 min.

Example 53:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-5-trifluoromethylpyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 475.52; MS (gef): 476.2; T _R : 19.7 min.

Example 54:

N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl-6-brompyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (over): 525.28; MS (gef): 526.0; T _R : 17.9 min.

Example 55:

N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl-6-chloropyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 480.82; MS (gef): 481.8; T _R : 17.9 min.

Example 56:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-6-chloropyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (over): 441.96; MS (gef): 442.4; T _R : 19.1 min.

Example 57:

N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butyl-6-fluorpyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 464.37; MS (gef): 464.5; T _R : 17.4 min.

Example 58:

N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-6-fluorpyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 425.51; MS (gef): 426.2; T _R : 18.4 min.

Example 59:

N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-5-methoxy-pyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 490.43; MS (gef): 490.7; T _R : 17.5 min.

Example 60:

N-5- (4- (2-methoxyphenyl) piperazin-1-yl) pentyl-5-methoxy-pyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (over): 451.57; MS (gef): 452.4; T _R : 18.7 min.

Example 61:

N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-5-trifluoromethylpyrazolo [1,5-a] pyridin-2-ylcarbamid

• MG (calculated): 528.4; MS (gef): 529.5; T _R : 18.1 min.

Example 62:

N-5- (4- (2-methoxyphenyl) piperazin-1-yl) pentyl-5-trifluoromethylpyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 484.54; MS (gef): 490.2; T _R : 19.8 min.

Example 63:

N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-6-brompyrazolo [1,5-a] pyridin-2-ylcarbamid

• MG (calculated): 539.30; MS (gef): 540.0; T _R : 18.0 min.

Example 64:

N-5- (4- (2-methoxyphenyl) piperazin-1-yl) pentyl-6-brompyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (over): 500.44; MS (gef): 501.7; T _R : 19.4 min.

Example 65:

N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-6-chloropyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 494.84; MS (gef): 495.8; T _R : 17.9 min.

Example 66:

N-5- (4- (2-methoxyphenyl) piperazin-1-yl) pentyl-6-chloropyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (over): 455.98; MS (gef): 456.4; T _R : 19.2 min.

Example 67:

N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-6-fluorpyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 478.34; MS (gef): 478.7; T _R : 17.4 min.

Example 68:

N-5- (4- (2-methoxyphenyl) piperazin-1-yl) pentyl-6-fluorpyrazolo [1,5-a] pyridin-2-ylcarbamid

• MW (calculated): 439.53; MS (gef): 440.2; T _R : 18.6 min.

BIOLOGICAL ACTIVITY

The biological activities of the compounds of the invention were determined in Radioligandbindungsuntersuchungen. All radioligand experiments were carried out according to methods described by us (Hübner, H. et al., J. Med. Chem. 2000, 43, 756-762). For the measurement of the affinities to the receptors of the D2 family, membrane homogenates of Chinese hamster ovary cells (CHO cells) were used, each of which contained the human D2long, the human D2short (Hayes, G. et al., Mol. Endocrinol. 1992, 6, 920-926), the human D3 (Sokoloff, P. et al., Eur. J. Pharmacol., 1992, 225, 331-337), or the human D4.4 receptor subtype (Asghari, VJ Neurochem., 1995 , 65, 1157-1165) stably expressed. In principle, the binding assays were carried out by incubating the receptor homogenates with the radioligand [ ³ H] spiperone and the compound to be investigated in various concentrations. The affinities for the D1 receptor were determined using native membrane homogenates obtained from the striatum of the pig and the D1-selective radioligand [ ³ H] SCH 23390.

The biological testing of the substances obtained by solid-phase assisted synthesis was first carried out according to a screening approach. The ability of the test compounds to displace the radioligand from the binding site of the respective receptor subtype at three representative concentrations was investigated. For the most promising candidates were subsequently in comprehensive dose-We kung studies determined the binding properties to the various dopamine receptor subtypes and found, by way of example, the affinities for the 5-HT1A, 5-HT2 and α1 receptors.

The measurement of the binding strengths of the compounds to the serotonin receptor subtypes 5-HT1A and 5-HT2 were carried out according to methods described by us (Heindl, C. et al., Tetrahedron: Asymmetry 2003, 14, 3141-3152). For this purpose, we incubated porcine cortex membrane preparations with the radioligands [ ³ H] 8-OH-DPAT (for 5-HT1A) or [ ³ H] ketanserin (5-HT2) and the compounds in various concentrations. Similarly, the affinity of the test compounds for the porcine α1 receptor was examined using porcine cortex membrane preparations and the α1-selective radioligand [ ³ H] prazosin.

All showed compounds tested in the dopamine receptor binding assay good to very good affinities to the dopamine receptors with a clear binding preference too the subtypes of the D2 family. Independent of the partial structure is always a clear selectivity to recognize the D3 receptor, for all 40 tested connections with Ki values between 0.1 and about 60 nM was bound.

Highest D3 affinity and selectivity can be achieved are when substituted as heteroarene components indolizines or 2,3-dichloro Pyrazolo [1,5-a] pyridine with a chain length of 4-5 carbons between the Amide nitrogen and the nitrogen of piperazine can be used. Oriented on the ability to displace a radioligand at a defined test concentration also derivatives with 4,5,6,7-tetrahydropyrazolo [1,5-b] pyridine partial structure very high D3 affinity if they have a distance of 4-5 carbon atoms between the Amide nitrogen and the nitrogen of Piperazinteils carry (95-100% displacement at 10μM and> 70% displacement at 100nM).

Strong bond to the D2short receptor, for example, have the compounds 49, 9, 54, 55, 57, 19, 20, 21, 27, 34, 38 and 44.

Some Connections with shorter Distance between the amide nitrogen and the piperazine ring, e.g. links 18 or 41, show pronounced Binding to the D4 dopamine receptor.

at Many compounds also have strong binding to the α1 receptor to recognize. Particularly pronounced this property is when the amine component of the test compound in position 2 carries a methoxy substituent.

The binding strength Serotonin receptors are included in most compounds Affinities in the Range of 30 nM - 500 nM. Some compounds, e.g. Compounds 1, 5, 26 and 49 show also high affinity binding for the 5-HT1a receptor with affinities up to about 30 nM (+/- 10% Measurement accuracy).

Investigations to determine the intrinsic activity of the example compounds were carried out in a mitogenesis assay based on the literature (Hübner, H. et al., J. Med. Chem., 2000, 43, 4563-4569, Bettinetti, L. et al. Med. Chem. 2002, 45, 4594-4597). Various concentrations of the compound to be investigated were incubated with cells expressing D3 receptor, and then the receptor-mediated stimulation of the mitogenesis rate was measured by incorporation of the radioactive marker [ ³ H] thymidine. Agonist, partial agonist or antagonist effects were determined in comparison to the effect of the full agonist quinpirol.

In this test, the compounds tested show different intrinsic effects at the D3 receptor. Thus, some examples, eg, 5, 17, 22, and 23, have no [ ³ H] thymidine incorporation and are thus classifiable as antagonists. Other compounds, eg, 2, 4, and 16, show stimulation of the receptor in the range of 11% -35% and are more likely to be characterized as weakly partial agonistic, whereas a third group of substances, eg, Examples 1, 3, 8, 26, 27 and 49, with an intrinsic activity of 36-50% as partial agonists.

Claims (27)

Compounds of the general formula I,

in which: A is a saturated or aromatic 6-membered ring; B is an aromatic 5-membered ring; the heteroarene formed from A + B has a total of at most three ring-forming N atoms and exactly one group X as substituents; Q1, Q2 and Q3 are each independently N, CH or C-R1; Q4 is NR, CH-R1 'or C-R1 R1'; Q5, Q6 and Q7 are independently CH-R1 'or C-R1 R1'; R 1 is in each case selected from the group hydroxy, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, phenylcarbonyl, alkyloxycarbonyl, cyano, nitro, amino, carboxy, sulfo, sulfamoyl, sulfonylamino, alkylaminosulfonyl and alkylsulfonylamino ; R1 'is absent when ring A is aromatic or is hydrogen when ring A is saturated; R is absent when ring A is aromatic or is selected from hydrogen, alkyl, phenyl, alkylcarbonyl, phenylcarbonyl, phenylalkyl and phenylsulfonyl when ring A is saturated; X is a group of the general formula X1 bonded to a C atom of an aromatic ring A or B

where Y is a straight, saturated or unsaturated hydrocarbon chain of 2-5 carbon atoms or a chain - (CH 2) _o -Z- (CH 2) _p wherein Z is selected from the radicals cyclopentyl, cyclohexyl and cycloheptyl, where o and p each independently have the value 0, 1, 2 or 3 and wherein the sum of o and p is at most 3; R 2, R 3, R 4, R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, phenylcarbonyl, alkyloxycarbonyl, cyano, nitro, amino , Carboxy, sulfo, sulfamoyl, sulfonylamino, alkylaminosulfonyl and alkylsulfonylamino, wherein two adjacent radicals R 2, R 3, R 4, R 5 and R 6 together with the carbon atoms of the phenyl ring to which they are bonded, an oxygen-containing 5-, 6- or 7 -membered ring can form; R7 is hydrogen, alkyl or phenylalkyl; in the form of the free base, its physiologically acceptable salts and possible enantiomers and diastereomers, with the proviso that (a) compounds in which the heterocycle is a pyrazolo [1,5-a] pyridine have the sole substituent Group X, but bears no substituent R 1, where X is: R 2 = methoxy; R3, R4, R5, R6 and R7 are each hydrogen and (i) Y = ethyl, n-propyl or n-butyl or (ii) Y = n-pentyl and X is in the 2- or 3-position with the pyrazolo [ The compound N-4- (4- (2-chlorophenyl) piperazin-1-yl) butyl-7-methylpyrazolo [1,5-a] pyridin-3-ylcarbamide , Compounds according to any one of the preceding claims, selected from the group

where: ring A is in each case saturated or aromatic; the ring-forming carbon atoms of rings A and B may each be independently substituted with R1; R, R1 and X are as defined in claim 1. Compounds according to any one of the preceding claims, wherein Y represents a group - (CH ₂ ) _n - with n = 4 or 5. Compounds according to any one of the preceding claims, wherein R7 is hydrogen. Compounds according to one of the preceding claims having the general formula II

in which: the substituent X is linked to any position 1-7 of indolizine and represents a group of general formula X1 as described in the previous claims; the indolizine may carry in positions 1-7 except X nor one or more further substituents R1, which are selected from hydroxy, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, phenylcarbonyl, alkyloxycarbonyl, Cyano, nitro, amino, carboxy, sulfo, sulfamoyl, sulfonylamino, alkylaminosulfonyl and alkylsulfonylamino. Compounds according to claim 5, wherein X is in the 2-position linked to the indolizine is. Compounds according to any one of claims 5-6, wherein X is a group of general formula X2

where n is 4 or 5; R 2, R 3, R 4, R 5, R 6 and R 7 are radicals as described in claim 1. Compounds according to any one of claims 5-7, wherein at least one the two substituents R2 and R3 is a halogen atom or a methoxy group represents or wherein R2 and R3 together with the phenyl radical, to they are bound to form a chroman or dihydrobenzofuran. Compounds according to any one of claims 1-4, having the general formula III

in which: the substituent X is linked to any position 2-7 of the pyrazolo [1,5-a] pyridine and represents a group having the general formula X1 as described in any one of claims 1, 3 or 4; the pyrazolo [1,5-a] pyridine may carry in positions 2-7 except X nor one or more further substituents R1, which are selected from hydroxy, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, phenoxy, halogen, Trifluoromethyl, alkylcarbonyl, phenylcarbonyl, alkyloxycarbonyl, cyano, nitro, amino, carboxy, sulfo, sulfamoyl, sulfonylamino, alkylaminosulfonyl and alkylsulfonylamino. Compounds according to claim 9, wherein the group X associated with positions 2, 5 or 6 of the pyrazolo [1,5-a] pyridine is. Compounds according to any one of claims 9-10, wherein the pyrazolo [1,5-a] pyridine in position 5 is a methoxy or Trifluoromethyl radical and / or carries a halogen atom in position 6. Compounds according to any one of claims 9-11, wherein X is a group of general formula X2

where n is 4 or 5; R 2, R 3, R 4, R 5, R 6 and R 7 are radicals as described in claim 1. Compounds according to any one of claims 9-12, wherein the substituents R 2 and R 3 represent halogen atoms. Compounds according to any one of claims 1-4 having the general formula IV

in which: the substituent X is linked to the 2 or 3 position of the 4,5,6,7-tetrahydropyrazolo [1,5-a] -pyridine and represents a group having the general formula X1 as in one of the claims 1 , 3 or 4 described; the 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine may carry in positions 2-7, in addition to the group X, one or more further substituents R 1 selected from hydroxy, alkyl, alkyloxy, alkylthio , Alkenyl, alkynyl, phenyl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, phenylcarbonyl, alkyloxycarbonyl, cyano, nitro, amino, carboxy, sulfo, sulfamoyl, sulfonylamino, alkylaminosulfonyl and alkylsulfonylamino. Compounds according to any one of claims 13-14, wherein X is a group of general formula X2

where n is 4 or 5; R 2, R 3, R 4, R 5, R 6 and R 7 are radicals as described in claim 1. Compounds according to any one of claims 14-15, wherein at least one of the substituents R2 and R3 is a halogen atom or a methoxy group. Compound selected from N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butylindolizine-2-ylcarbamide N-4- (4- (3-chloro-2-methoxyphenyl) piperazin-1-yl) butylindolizine -2-ylcarbamide N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -butylindolizin-2-ylcarbamide N-4- (4- (2,3-difluorophenyl) -piperazin-1-yl) -butylindolizine -2-ylcarbamide N-4- (4- (2,3-Dihydrobenzofuran-7-yl) -piperazin-1-yl) -butylindolizin-2-ylcarbamide N-4- (4- (chroman-8-yl) -piperazine-1 -yl) butylindolizin-2-ylcarbamide N-2- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -ethyl-pyrazolo [1,5-a] pyridin-2-ylcarbamide N-3- (4- (2 , 3-dichlorophenyl) piperazin-1-yl) propylpyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butylpyrazolo [1,5- a] pyridin-2-ylcarbamide N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2- Methoxyphenyl) piperazin-1-yl) butyl-3-bromopyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-3-chloropyrazolo [1 , 5-a] pyridin-2-ylcarbamide N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) but yl-5-methoxypyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2-methoxyphenyl) -piperazin-1-yl) -butyl-5-methoxypyrazolo [1,5-a] pyridine-2 -ylcarbamide N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) -butyl-5-methylpyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2,3-dichlorophenyl ) piperazin-1-yl) butyl-5-trifluoromethylpyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-5-trifluoromethylpyrazolo [1, 5-a] pyridin-2-ylcarbamide N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -butyl-6-bromopyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) -butyl-6-bromopyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl ) butyl-6-chloropyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-6-chloropyrazolo [1,5-a] pyridine 2-ylcarbamide N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -butyl-6-fluoropyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2- Methoxyphenyl) piperazin-1-yl) butyl-6-fluoropyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl 3-methoxycarbonylpyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -butyl-3-methoxycarbonyl-pyrazolo [1,5-a] pyridine-2 -ylcarbamide N-5- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -pentyl-5-methoxypyrazolo [1,5-a] pyridin-2-ylcarbamide N-5- (4- (2-Methoxyphenyl ) piperazin-1-yl) pentyl-5-methoxypyrazolo [1,5-a] pyridin-2-ylcarbamide N-5- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -pentyl-5-trifluoromethyl-pyrazolo [ 1,5-a] pyridin-2-ylcarbamide N-5- (4- (2-methoxyphenyl) piperazin-1-yl) pentyl-5-trifluoromethylpyrazolo [1,5-a] pyridin-2-ylcarbamide N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentyl-6-bromopyrazolo [1,5-a] pyridin-2-ylcarbamide N-5- (4- (2-methoxyphenyl) -piperazin-1-yl ) pentyl-6-bromopyrazolo [1,5-a] pyridin-2-ylcarbamide N-5- (4- (2,3-dichlorophenyl) -piperazin-1-yl) pentyl-6-chloropyrazolo [1,5-a] pyridin-2-ylcarbamide N-5- (4- (2-methoxyphenyl) piperazin-1-yl) pentyl-6-chloropyrazolo [1,5-a] pyridin-2-ylcarbamide N-5- (4- (2, 3-dichlorophenyl) piperazin-1-yl) pentyl-6-fluoropyrazolo [1,5-a] pyridin-2-ylcarbamide N-5- (4- (2-Meth oxyphenyl) piperazin-1-yl) pentyl-6-fluoropyrazolo [1,5-a] pyridin-2-ylcarbamide trans -N- (4 - ((4- (2-methoxyphenyl) piperazin-1-yl) methyl) cyclohex 1-yl) methylpyrazolo [1,5-a] pyridin-2-ylcarbamide trans -N- (4 - ((4- (2,3-dichlorophenyl) piperazin-1-yl) methyl) cyclohex-1-yl) methylpyrazolo [1,5-a] pyridin-2-ylcarbamide N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethylpyrazolo [1,5-a] pyridin-3-ylcarbamide N-3 (4- (2,3-dichlorophenyl) -piperazin-1-yl) -propyl-pyrazolo [1,5-a] pyridin-3-ylcarbamide N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -butyl-pyrazolo [1,5-a] pyridin-3-ylcarbamide N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridin-3-ylcarbamide trans-N- ( 4 - ((4- (2-Methoxyphenyl) piperazin-1-yl) methyl) cyclohex-1-yl) methylpyrazolo [1,5-a] pyridin-3-ylcarbamide trans-N- (4 - ((4- (4-yl) 2,3-dichlorophenyl) piperazin-1-yl) methyl) cyclohex-1-yl) methylpyrazolo [1,5-a] pyridin-3-ylcarbamide N-2- (4- (2,3-dichlorophenyl) -piperazine-1 -yl) ethylpyrazolo [1,5-a] pyridin-5-ylcarbamide N-3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propylpyrazolo [1,5-a] pyrid in-5-ylcarbamide N-4- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -butylpyrazolo [1,5-a] pyridin-5-ylcarbamide N-5- (4- (2,3-) Dichlorophenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridin-5-ylcarbamide N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-3-bromopyrazolo [1,5-a ] pyridine-5-ylcarbamid N-4- (4- (2-Methoxyphenyl) piperazin-1-yl) butyl-3-chloropyrazolo [1,5-a] pyridin-5-ylcarbamide N-5- (4- (2-Methoxyphenyl) piperazine-1 -yl) pentylpyrazolo [1,5-a] pyridin-5-ylcarbamide N-2- (4- (2,3-dichlorophenyl) piperazin-1-yl) ethylpyrazolo [1,5-a] pyridin-6-ylcarbamide N -3- (4- (2,3-dichlorophenyl) piperazin-1-yl) propylpyrazolo [1,5-a] pyridin-6-ylcarbamide N-4- (4- (2,3-dichlorophenyl) -piperazine-1 yl) butylpyrazolo [1,5-a] pyridin-6-ylcarbamide N-5- (4- (2,3-dichlorophenyl) piperazin-1-yl) pentylpyrazolo [1,5-a] pyridin-6-ylcarbamide N- 2- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -ethyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamide N-3- (4- (2 , 3-dichlorophenyl) piperazin-1-yl) propyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2,3-dichlorophenyl) -piperazine 1-yl) butyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamide N-5- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -pentyl-4 , 5,6,7-Tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamide N-4- (4- (2-methoxyphenyl) -piperazin-1-yl) -butyl-4,5,6,7-tetrahydropyrazolo [ 1,5-a] pyridin-2-ylca rbamid N-4- (4- (2-methoxyphenyl) piperazin-1-yl) butyl-5-methyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-ylcarbamide N-2 (4- (2,3-dichlorophenyl) -piperazin-1-yl) -ethyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-ylcarbamide N-3- (4- (2,3 -Dichlorophenyl) piperazin-1-yl) propyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-ylcarbamide N-4- (4- (2,3-dichlorophenyl) -piperazine-1 yl) butyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-ylcarbamide N-5- (4- (2,3-dichlorophenyl) -piperazin-1-yl) -pentyl-4,5 , 6,7-tetrahydropyrazolo [1,5-a] pyridin-3-ylcarbamide Compounds according to a of the preceding claims as a medicine. Pharmaceutical composition comprising one or a plurality of the compounds according to any one of the preceding claims and a pharmaceutically acceptable adjuvant. Use of a compound according to one of the preceding claims for the manufacture of a medicament for the treatment of CNS disorders. Use of a compound according to one of the preceding claims for the manufacture of a medicament for the treatment of disorders of the Urinary tract. Use of a compound according to one of the preceding claims for the manufacture of a medicament for the treatment of diseases from the group psychosis, schizophrenia, anxiety disorders, obsessive-compulsive disorder, Drug addiction, depressive disorders, Drug-induced extrapyramidal motor disorders, Parkinson's disease, Segawa syndrome, Tourette syndrome, restless leg syndrome, sleep disorders, nausea, cognitive disorders, male erectile dysfunction, hyperprolactinemia, hyperprolactinoma, glaucoma, hyperactivity Disorder (ADHD), Autism, Stroke and Urinary Incontinence, Use according to one of the preceding claims, wherein the compound for the manufacture of a medicament for the treatment schizophrenia, depressive disorders, L-dopa or neuroleptics-induced movement disorders, Parkinson's disease, Segawa syndrome, restless leg syndrome, hyperprolactinemia, hyperprolactinoma, hyperactivity Disorder (ADHD) or urinary incontinence. Method for the treatment of CNS disease or a fault of the urinary tract in a mammal by administering one or more compounds after one the claims 1-17 to a mammal, which requires such treatment. The method of claim 24, wherein the disease or disorder selected is from the group of psychosis, schizophrenia, anxiety disorders, Obsessive-compulsive disorder, Drug addiction, depressive disorders, drug-induced extrapyramidal motor movement disorders, Parkinson's disease, Segawa syndrome, Tourette syndrome, restless leg syndrome, sleep disorders, nausea, cognitive disorders, male erectile Dysfunction, hyperprolactinemia, Hyperprolactinoma, glaucoma, hyperactivity disorder (ADHD), autism, Stroke and urinary incontinence. Preparation of compounds according to any one of claims 1-17 by reaction of an acid derivative A

with a free base of the general formula C

where W is selected from OH, Cl, Br or a group

wherein R 8 is alkyl; Heteroaren stands for a group that is selected from

wherein A, B, D1, Q2, Q3, Q4, Q5, Q6 and Q7 are each as defined in the preceding claims and wherein the crossed bond in the heteroarenes represents a bond of the group -C (O) -W a ring-forming C atom of an aromatic ring of the heteroarene; the heteroarenes may each bear one or more further substituents R 1 or R as defined in the preceding claims; Y, R2, R3, R4, R5 and R6 are each as defined in the preceding claims, and wherein in the event that the substituent W is a hydroxy group, the corresponding acid group before reacting with the free base of the general formula C is activated by adding one or more activating reagents. Preparation of a carboxylic acid derivative of a pyrazolo [1,5-a] pyridine having the general formula

by reaction of a pyridine of the formula

with O- (2,4-dinitrophenyl) hydroxylamine to an N-aminopyridine of the formula

and subsequent cycloaddition reaction with a propiolic acid ester of the formula

wherein Rx is 0, 1, 2, 3 or 4 identical or different substituents selected from halogen, alkyl, alkylcarbonyl, phenylcarbonyl, hydroxyalkyl, cyano, trifluoromethyl and alkyloxycarbonyl, * denotes an unsubstituted CH group and wherein R 'is selected from hydrogen , Alkyl, phenyl and alkyloxycarbonyl and wherein R "represents alkyl.