WO2008113559A2 - Indolizines and aza-analog derivatives thereof as cns active compounds - Google Patents

Indolizines and aza-analog derivatives thereof as cns active compounds Download PDF

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WO2008113559A2
WO2008113559A2 PCT/EP2008/002163 EP2008002163W WO2008113559A2 WO 2008113559 A2 WO2008113559 A2 WO 2008113559A2 EP 2008002163 W EP2008002163 W EP 2008002163W WO 2008113559 A2 WO2008113559 A2 WO 2008113559A2
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phenyl
butoxy
piperazin
alkyl
pyrazolo
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PCT/EP2008/002163
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French (fr)
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WO2008113559A3 (en
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Peter Gmeiner
Harald Huebner
Marika Skultety
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Schwarz Pharma Ag
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Priority to US12/532,371 priority Critical patent/US20100168125A1/en
Priority to JP2010500110A priority patent/JP2010521528A/en
Priority to EP08716614A priority patent/EP2137185A2/en
Publication of WO2008113559A2 publication Critical patent/WO2008113559A2/en
Publication of WO2008113559A3 publication Critical patent/WO2008113559A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Schizophrenia and other psychotic disorders including manic phases of bipolar disorder, acute idiopathic psychotic illnesses, and other conditions marked by severe agitation exhibit major disturbances in reasoning, often with delusions and hallucinations. Schizophrenia affects about 1 % of the population and about 5-10% of the affected patients commit suicide. The cost to the society is assessed to be several billions of dollars, and there is thus a significant need to provide effective pharmacological treatment options for the treatment of schizophrenia and other psychotic disorders.
  • pure D2 antagonists only have an impact on the so-called “positive symptoms” of psychotic disorders, like delusions and halluzinations, which are caused by the overexpression of dopamine receptors in some brain segments but are not effective on "negative symptoms” such as apathy or alogia which are thought to be caused by reduced dopaminergic activity in other areas of the CNS. Finally, about 30% of the patients do not respond well to typical D2 antagonists.
  • Atypical antipsychotics or “2 nd generation antipsychotics” have been developed. Examples include clozapine, risperidone, and ziprasidone. Atypical antipsychotics have a more complex receptor profile than first generation antipsychotics and besides showing high affinity binding to and inhibition of dopaminergic D2 receptors, also modulate other receptors, like serotonergic and/or adrenergic receptors.
  • clozapine also interacts with a couple of adrenergic, serotonergic, muscarinergic and histaminergic receptors and has proved effective in patients who respond poorly to standard neuroleptics (Goodman&Gilman's "The pharmacological Basis of therapeutics", Editor Laurence L. Brunton, 11 th edition, 2005).
  • risperidone and ziprasidone are combined D2/5-HT2a receptor antagonists and 5-HT1a agonists. It was thus suggested that atypicality may arise from interactions with the 5-hydroxytryptamine 5-HT2 receptor in addition to the dopaminergic D2 antagonism.
  • Compounds also acting as serotonin 5- HT1A agonists may additionally alleviate negative symptoms of schizophrenia and reduce the likelihood of extrapyramidal symptoms.
  • a full blockade of D2 receptors can lead to dopamine hypoactivity which is associated with side effects such as extrapyramidal motor dysfunction.
  • a novel strategy to overcome this shortcoming of existing antipsychotics is thus the development of partial dopamine receptor antagonist.
  • Such compounds like aripiprazole and bifeprunox, are sometimes called “3 rd generation antipsychotics", and do act as antagonist at D2 when there is an overstimulation of dopamine receptors while activating these D2 receptors when there is insufficient stimulation by endogenous dopamine. It is thus believed that partial D2 agonists act as "dopamine stabilisers", arid offer the advantage of full therapeutic efficacy with minimal side effect liability.
  • the modulation of the dopaminergic D3 and the D4 receptors is thought to be useful in the treatment of cognitive and affective symptoms associated with psychotic diseases.
  • the present patent application provides novel compounds that show high affinity to the dopaminergic D2 receptor, but which also interact with significant affinity with the 5-HT2 serotonergic receptor, the 5-HT1a serotonergic receptor and the dopaminergic D3 and D4 receptors.
  • a preferred embodiment of the present invention relates to new compounds which exert partial dopaminergic activity at the D2 receptor e.g. by having an intrinsic dopaminergic D2 activity that is up to about 50% of a full agonist.
  • the compounds as described in more detail further below and in the claims inter alia have a remarkable affinity at the D2 receptor, and do also show binding to the 5- HT2, the 5-HT1a, the D3 and D4 receptors in a range comparable to or even superior than other atypical antipsychotics like aripiprazole.
  • One embodiment of the present invention relates to compounds of the general formula I,
  • Q1 and Q2 are independently of each other N, CH or C-R1 ;
  • Q3 is CH or C-R 1 if at least one of Q1 and Q2 is different from nitrogen, and Q3 is selected from CH, C-R1 and N if Q1 and Q2 are both nitrogen;
  • n 0, 1 , 2 or 3;
  • any R1 is bonded to a C-atom of the heterocycle of formula I and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, alkyl, cycloalkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, phenylcarbonyl, phenylalkyl, phenylalkyloxy, phenylalkylcarbonyl, phenylalkyloxycarbonyl, alkyloxycarbonyl, alkylsulfonyl, phenylsulfonyl.sulfamoyl, alkylaminosulfonyl, dialkylaminosulfonyl,
  • X is a group having the formula
  • Y is chosen from among S and O;
  • R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, phenylcarbonyl, phenylalkyl, phenylalkyloxy, phenylalkylcarbonyl, phenylalkyloxycarbonyl, alkyloxycarbonyl, alkylsulfonyl, phenylsulfonyl, sulfamoyl, alkylaminosulfonyl, dialkylaminosulfonyl, pheny
  • R7 and R8 are independently selected from hydrogen, alkyl, cycloalkyl, phenyl, heteroaryl, phenylalkyl, alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, alkylcarbonyl, alkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7- membered cycle; and wherein each heterocycle is a monocyclic ring and wherein phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy, halogen, alkyl, carboxy
  • R9 and R10 are independently selected from among hydrogen and alkyl
  • R11 is hydroxyl, (C1-C3)alkyl, hydroxy-(C1-C3)alkyl, halogen-(C1-C3)alkyl or oxo;
  • heterocycle of formula I carries precisely one group X
  • any R1 is bonded to a C-atom of a heterocycle of formulas lla-lld and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C1-
  • each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherin each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, carboxy, NR
  • X is a group having the formula
  • R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3-C7)cycloalkyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1-
  • R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3-
  • each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected
  • R9 and R10 are independently selected from among hydrogen, and alkyl
  • R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo; provided that each heterocycle of formulas Ha-IId carries precisely one group X;
  • One preferred embodiment of the present invention is a compound of formula I or formula Ha 1 lib or He as described further above, wherein q is 1.
  • Another embodiment of the present invention is a compound of formula I or formula lla, lib or He as described further above, wherein k is 0.
  • Another embodiment of the present invention is a compound of formula I or formula Ma, lib or He as described further above, wherein R4 is fluoro or hydrogen, particularly hydrogen.
  • Another embodiment of the present invention is a compound of formula I or formula Ma, lib or Hc as described further above, wherein q is 1 , k is 0 and R4 is fluoro or hydrogen, particularly hydrogen.
  • Another embodiment of the present invention is a compound of formula I or formula Ma, lib or Hc as described further above, wherein k is 1 and R11 is preferably an C1- C6 alkyl, a hydroxyl, or an oxo group.
  • Another embodiment of the present invention is a compound of formula I or formula Ma, lib or He as described further above, wherein k is 2.
  • the two substituents R11 may be the same or different, and may be located at different or at the same C-Atom of the N-containing ring.
  • the two substituents are the same and are bound to the same ring C-atom such that they do not form a stereocenter.
  • Another embodiment of the present invention is a compound of formula I or formula Ma, lib or Hc as described further above, wherein m is 0, 1 or 2; p is 0 or 1 ; n is 2, 3 or 4; and each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1-
  • R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
  • R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, and particularly preferably hydrogen; and
  • R5 and R6 are independently selected from hydrogen, or fluoro; wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
  • a preferred embodiment of the present invention is a compound according to anyone of the preceding claims, having the formula Ma
  • Another embodiment of the present invention is a compound of formula Ma as described above, wherein the group X is bonded to the 2-, 4-, 5- or 6-position of the heteroaromatic ring system of formula Ha.
  • Another embodiment of the present invention is a compound of formula Ha as described above, wherein m is 1 , and R1 is in 3-position of the heteroaromatic ring system of the general formula Ma.
  • Another embodiment of the present invention is a compound of formula Ma as described further above, wherein X is
  • R2-R6 have the meaning as defined further above.
  • Another embodiment of the present invention is a compound of formula Ma as described above, wherein R4 is hydrogen or fluoro.
  • R1 , R2, R3, R4, R5, R6, R11 , k, m, n, p and q are as defined for compounds of formula I, further above.
  • any R1 is bonded to a C-atom of the heterocycle of formula III, and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1- C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-
  • R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1 -C10)alkyl, (C3-C6)cycloalkyl, (C1 -C10)alkyloxy, (C 1 -C 10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1- C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1- C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl,
  • each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R
  • R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3- C6)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (Ci-C ⁇ jalkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and where
  • R9 and R10 are independently selected from among hydrogen, and alkyl
  • R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo
  • heterocycle of formula III carries precisely one group X; in the form of the free base, their physiologically acceptable salts and possible enatiomers and diastereomers.
  • Another embodiment of the present invention is a compound of formula III as described above, wherein R4 is hydrogen or fluoro.
  • Another preferred embodiment of the present disclosure is a compound having the general formula III, wherein
  • each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1-
  • R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
  • R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, and particularly preferably hydrogen;
  • R5 and R6 are independently selected from hydrogen, or fluoro
  • R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
  • Another preferred embodiment of the present disclosure is a compound having the general formula III, wherein k is O; m is O or 1 ; n is 3; P is O; q is 1 ;
  • R1 is hydrogen, or formyl
  • R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
  • R4, R5 and R6 are all hydrogen.
  • R1 , R2, R3, R4, R5, R6, R11 , k, m, n, p and q are as defined for compounds of formula I, further above.
  • any R1 is bonded to a C-atom of the heterocycle of formula IV, and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-
  • R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1- C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1-C10)alkyl, phenyl(C1-C10)alkyl, phenyl(C1-C
  • R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3- C6)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein
  • R9 and R10 are independently selected from among hydrogen, and alkyl
  • R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo
  • heterocycle of formula IV carries precisely one group X
  • Another embodiment of the present invention is a compound of formula IV as described above, wherein R4 is hydrogen or fluoro.
  • each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1- C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxy methyl, nitro, NR7R8;
  • R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
  • R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, particularly preferably hydrogen;
  • R5 and R6 are independently selected from hydrogen, or fluoro
  • R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
  • R1 is hydrogen, or formyl, cyano, oxime, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxy methyl, nitro, NR7R8;
  • R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
  • R4 is selected from hydrogen, fluoro, and chloro, and is particularly preferably hydrogen;
  • R5 and R6 are both hydrogen.
  • R1 , R2, R3, R4, R5, R6, R11 , k, m, n, p and q are as defined for compounds of formula I, further above.
  • any R1 is bonded to a C-atom of the heterocycle of formulas V, and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-
  • R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1-
  • R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3-
  • each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected
  • R9 and R10 are independently selected from among hydrogen, and alkyl
  • R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo
  • heterocycle of formula V carries precisely one group X
  • Another embodiment of the present invention is a compound of formula V as described above, wherein R4 is hydrogen or fluoro.
  • Another preferred embodiment of the present disclosure is a compound of formula V as described above, wherein
  • each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1- C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxymethyl, nitro, NR7R8;
  • R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
  • R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, and particularly preferably hydrogen;
  • R5 and R6 are independently selected from hydrogen, or fluoro
  • R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
  • Another preferred embodiment of the present disclosure is a compound of formula IV as described above, wherein
  • R1 is hydrogen, or formyl
  • R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
  • R4, R5 and R6 are all hydrogen.
  • R1 , R2, R3, R4, R5, R6, R11 , k, m, n, p and q are as defined for compounds of formula I, further above.
  • any R1 is bonded to a C-atom of the heterocycle of formula Vl, and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1- C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1- C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1- C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl
  • R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino,
  • NR7R8 carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1- C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1- C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1-
  • each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C
  • R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3- C6)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein
  • R9 and R10 are independently selected from among hydrogen, and alkyl;
  • R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo;
  • heterocycle of formula Vl carries precisely one group X
  • Another preferred embodiment of the present disclosure is a compound of formula Vl as described above, wherein R4 is hydrogen or fluoro, and is preferably hydrogen.
  • Another preferred embodiment of the present disclosure is a compound of formula Vl as described above, wherein k is O or 1; m is O, 1 or 2; p is 0 or 1 ; n is 2, 3 or 4; q is 1 ;
  • each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1-
  • R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
  • R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, and particularly preferably hydrogen;
  • R5 and R6 are independently selected from hydrogen, or fluoro; wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
  • Another preferred embodiment of the present disclosure is a compound of formula Vl as described above, wherein
  • R1 is hydrogen, or formyl
  • R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
  • R4, R5 and R6 are all hydrogen.
  • R1 , R2, R3, R4, R5, R6, R11 , k, m, n, p and q are as defined for compounds of formula I, further above.
  • R1, , R2, R3, R4, R5, R6, R11 , k, m, n, p and q are as defined for compounds of formula I, further above.
  • any R1 is bonded to a C-atom of the heterocycle of formula VII, and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1- C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1- C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1- C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl,
  • each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherin each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)a!kyloxy,
  • R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1-
  • R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3-
  • each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected
  • R9 and R10 are independently selected from among hydrogen, and alkyl
  • R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo
  • heterocycle of formula VII carries precisely one group X
  • Another preferred embodiment of the present disclosure is a compound of formula VII as described above, wherein R4 is hydrogen or fluoro, and is preferably hydrogen.
  • Another preferred embodiment of the present disclosure is a compound of formula VII as described above, wherein k is 0 or 1 ; m is O 1 1 or 2; p is 0 or 1 ; n is 2, 3 or 4; q is 1 ;
  • each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1- C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxymethyl, nitro,
  • R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
  • R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, and particularly preferably hydrogen;
  • R5 and R6 are independently selected from hydrogen, or fluoro
  • R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
  • Another preferred embodiment of the present disclosure is a compound of formula VII as described above, wherein
  • R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
  • R4, R5 and R6 are all hydrogen.
  • R1 , R2, R3, R4, R5, R6, R11 , k, m, n, p and q are as defined for compounds of formula I, further above.
  • any R1 is bonded to a C-atom of the heterocycle of formula VIII 1 and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)aIkyl, (C3- C6)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2- C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1- C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1- C10)alkylcarbonyl
  • R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-C10)alkyloxy,
  • each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R
  • R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3- C6)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein
  • R9 and R10 are independently selected from among hydrogen, and alkyl
  • R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo
  • heterocycle of formula VIII carries precisely one group X;
  • R4 is hydrogen or fluoro, and is preferably hydrogen.
  • each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1-
  • R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1 -C3)alkyloxy, (C1 -C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
  • R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, and particularly preferably hydrogen;
  • R5 and R6 are independently selected from hydrogen, or fluoro
  • R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl,
  • R1 is hydrogen, or formyl
  • R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
  • R4, R5 and R6 are all hydrogen.
  • the compounds of the present invention can be prepared as follows:
  • a compound of formula Xl is reacted with an activated alkylene having the formula XII to give a compound of formula XIII formula Xl formula XII formula XIII
  • R1 , Q1 , Q2, Q3, X, Y, n, R11 , q, k, R2, R3, R4, R5, and R6 are as defined further above and in the claims for compounds of the formulas I 1 Ha, lib, Hc, Hd, III, IV 1 V, Vl, VII or VIII; and W and V are activating groups, which may be the same or different from each other;
  • the activating group is selected from among bromo, chloro, mesylate, triflate or tosylate.
  • R1 groups can be present in the starting material of the general formula Xl.
  • one or more R1 groups may be added to a compound of formula XVa in which one or more hydrogen atom(s) is/are then replaced by additional R1 group(s) to give a compound of I, Ua, lib, Mc, Md, III, IV, V, Vl, VII or VIII as described further above and in the claims.
  • This synthesis takes place by reaction of a compound of formula XVa with an activated precursor to get a compound of formula XVI as described as follows:
  • RV is selected from among bromo, chloro, iodine, formyl, hydroxymethyl, alkyl, oxime, cyano, aminomethyl, acylaminomethyl;
  • R1 , Q1 , Q3, X and m are as defined above.
  • a preferred embodiment relates to a method of producing a compound according to the present invention, comprising the synthesis of a compound of formula XVI as described above, wherein RV is selected from among bromo, chloro, iodine and formyl and wherein RV is introduced by the reaction of a compound of formula XVa with an activated precursor to get a compound of formula XVI.
  • activated precursors are ⁇ /-halogensuccinimide, hypohalogenic acids, sodium halogenites and phosphorousoxychloride in ⁇ /, ⁇ /-dimethylformamide or other well established formylation reactants and are preferably ⁇ /-chlorosuccinimide, ⁇ /-bromosuccinimide, ⁇ /-iodosuccinimide and phosphorousoxychloride in ⁇ /, ⁇ /-dimethylformamide.
  • the group R1 can be attached to the heterocyclic ring system by a two- step sequence starting with the introduction of a formyl group to give a compound of formula XVIa
  • the compound of formula XVII is comprised by formula I, Ma, MB, Mc, Hd, III, IV, V, Vl, VII and/or VIII, and wherein in formula XVII
  • RV is selected from among hydroxymethyl, alkyl, oxime, cyano, aminomethyl and acylaminomethyl,
  • the transfer of the formyl group to the group RV comprises condensation reactions, the reduction of the formyl group or a combination of both, condensation and reduction reactions.
  • all R2, R3, R4, R5 or R6 groups can be present in the starting material of the general formula XIV.
  • one or more R2, R3, R4, R5 or R6 groups may be introduced to a compound of formula XIX by transforming an appropriate precursor group R2', R3 1 , R4', R5' or R6' of a compound according to formula XVIII to give a compound of formula XIX comprised by formula I, Ma 1 lib, Hc, Hd, III, IV, V, Vl, VII or VIII as described further above and in the claims and as described as follows:
  • the compound of formula XIX is comprised by formula I, Ma, lib, Hc, Md, III, IV, V, Vl, VII and/or VIII, and wherein in formula XVIII
  • R2', R3', R4', R5' or R6' is selected from among nitro, formyl and alkyloxycarbonyl
  • R2, R3, R4, R5 or R6 is selected from among amino, hydroxymethyl, alkyl, oxime, cyano, aminomethyl, acylamino and acylaminomethyl,
  • a preferred embodiment relates to a method of producing a compound according to the present invention, comprising the synthesis of a compound of formula XIX as described above, wherein R3 is selected from among amino and acylamino and wherein R3 is introduced by the reaction of a compound of formula XVIII with an appropriate precursor R3 1 derived from nitro or amino to get a compound of formula
  • the compounds of the present invention are useful medicines, and may be used for the treatment of various diseases of the CNS system.
  • the present compounds in one mbodiment of the present invention may be of use for the production of a medicament for the treatment of a variety of diseases such as like a psychotic disease including manic phases of bipolar disorder, acute idiopathic psychotic illnesses, psychoses associated with other diseases, drug-induced psychoses, and particularly schizophrenia; attention deficit hyperactivity disorder
  • ADHD Alzheimer's disease
  • cognitive impairment idiopathic or drug-induced movement disorders such as akinesia and dyskinesia; Parkinson's disease; mood disorders including major depressive disorders, substance-induced mood disorders or other forms of depression; anxiety disorders including panic attack, social phobia, or generalized anxiety disorders; obsessive-compulsive disorders; stress-related disorders; addiction disorders; sleep disorders; sexual dysfunction; amnesic and/or cognitive disorders, especially dementia; eating disorders including anorexia and bulemia; pain; and neurodegenerative diseases including Chorea Huntington and multiple sclerosis.
  • Another embodiment of the present disclosure is a method of treating a subject having a disease selected from a psychotic disease including manic phases of bipolar disorder, acute idiopathic psychotic illnesses, psychoses associated with other diseases, drug-induced psychoses, and particularly schizophrenia; attention deficit disorder; autism; bipolar disorder; cognitive impairment; idiopathic or drug- induced movement disorders such as dyskinesia; Parkinson's disease; or depression by administering a compound as described herein, and specifically in the claims.
  • the subject to be treated with the presently disclosed compounds have been determined to be in need of a treatment of one or more of the above diseases based on a prior diagnosis of said disease or said diseases.
  • the presently disclosed compounds may be added to a pharmaceutically acceptable excipient or carrier.
  • a pharmaceutical composition comprising a compound as described in this specification and in the claims, and a pharmaceutical acceptable carrier.
  • the methods of administration which may easily be expected include oral, bukkal, sublingual, nasal, pulmonal, and rectal administration; intravenous, intramuscular, subcutaneous, and intracerebroventricular injections, wherein oral delivery is preferred.
  • the oral administration may be performed by providing the compounds of the present invention in the form of a tablet, a capsule, a drage 1 , a powder, a granulate, or in form of a liquid or a semi-solid.
  • a compound of formula (I), (Ha), (Mb), (lie), (lid), (III), (IV), (V), (Vl), (VII) or (VIII), an isomer thereof or a pharmaceutically acceptable salt thereof according to the present invention can be prepared as a pharmaceutical composition containing pharmaceutically acceptable carriers, adjuvants, diluents and the like.
  • the compounds of the present invention can be dissolved in oils, propylene glycol or other solvents which are commonly used to produce an injection.
  • suitable examples of the carriers include, but not limited to, physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc.
  • the compounds of the present invention may be formulated into injections by dissolving, suspending or emulsifying in water-soluble solvent such as saline and 5% dextrose, or in water-insoluble solvents such as vegetable oils, synthetic fatty acid glyceride, higher fatty acid esters and propylene glycol.
  • the formulations of the invention may include any of conventional additives such as dissolving agents, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.
  • Oral formulations may comprise e.g. sustained release agents, disintegrants, fillers, lubricants, stabilizers, antioxidants, stabilizers, flavours, dispersion agents, electrolytes, buffers or conservation agents.
  • sustained release agents e.g. sustained release agents, disintegrants, fillers, lubricants, stabilizers, antioxidants, stabilizers, flavours, dispersion agents, electrolytes, buffers or conservation agents.
  • Suitable excipients and formulations are known to those skilled in the art and are disclosed in standard monographs such as like Remington ("The science and practice of pharmacy", Lippincott, Williams & Wilkins, 2000).
  • sustained release agents are for example those that swell upon contact with water such as polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, other cellulose ethers, starch, pregelatinised starch, polymethacrylate, polyvinylacetate, microcrystalline cellulose, dextranes or mixtures thereof.
  • the pharmaceutical composition of the present invention can also contain disintegrants, such as pregelatinised starch, sodium starch glycolate, microcrystalline cellulose, carboxymethylcellulose sodium (CMC-Na), cross-linked
  • compositions according to the invention can further contain fillers and binders such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, starch (e.g. corn starch or potato starch), pregelatinised starch, fructose, sucrose, dextrose, dextranes, other sugars such as mannitol, maltitol, sorbitol, lactitol and saccharose, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, dicalciumphosphate dihydrate, tricalciumphophate, calcium lactate or mixtures thereof.
  • fillers and binders such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, starch (e.g. corn starch or potato starch), pregelatinised starch, fructose, sucrose, dextrose, dextranes, other sugars such as mannitol, maltito
  • the oral composition according to the invention can also comprise lubricants, antiadherents and/or glidants, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, glycerol dibehenate, talc, corn starch, silicone dioxide or mixtures thereof.
  • lubricants such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, glycerol dibehenate, talc, corn starch, silicone dioxide or mixtures thereof.
  • the preferable dose level of the compounds according to the present invention depends upon a variety of factors including the condition and body weight of the patient, severity of the particular disease, dosage form, and route and period of administration, but may appropriately be chosen by those skilled in the art.
  • the compounds of the present invention may be administered in an amount ranging from 0.001 to 10 mg/kg of body weight per day, and more preferably from 0.03 to 1 mg/kg of body weight per day.
  • Individual doses may range from about 0.1 to 500 mg of active ingredient per day, preferably from about 1 to 100 mg/day, and most preferably of between about 5 and 100 mg/day. Doses may be administered once a day, or several times a day with each divided portions.
  • Kit comprising a medicine or a pharmaceutical composition as described above, and instructions for its use.
  • the medicine according to the present invention may comprise one of the presently disclosed compounds as "stand alone" treatment of a psychological illness such as e.g. schizophrenia or bipolar disorder.
  • a presently disclosed compound may be administered together with other useful drugs in a combination therapy.
  • a compound according to the present invention may be combined with an antidepressant to treat a psychoses associated with depressions, e.g. bipolar disorder.
  • a compound of the present invention may be combined with a cognition enhancer.
  • the two or more active principles may be provided via the same formulation or as a "kit of parts", i.e. in separate galenic units.
  • the two or more active principles may be administered to the patient at the same time or subsequently, e.g. in an interval therapy.
  • Alkyl includes monovalent saturated aliphatic hydrocarbyl groups.
  • the hydrocarbon chain may be either straight-chained or branched.
  • Alkyl has preferably 1-15 carbon atoms ("C1-C15 alkyl”), more preferably 1-10 carbon atoms ("C1-C10 alkyl”), even more preferably 1-8 carbon atoms ("C1-C8 alkyl”) or 1-6 carbon atoms ("C1-C6 alkyl”), and in some instances even more preferably 1-5 carbon atoms (“C1-C5 alkyl”), 1-4 carbon atoms (“C1-C4 alkyl”), or only 1-3 carbon atoms ("C1-C3 alkyl”).
  • Alkylamino includes the group -NHR 1 , wherein R' is alkyl group as defined herein.
  • Alkylsulfonyl includes a radical-S(O) 2 R, wherein R is an alkyl group as defined herein. Representative examples include, but are not limited to, methanesulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.
  • Alkylthio includes a radical-S-R wherein R is an alkyl group as defined herein that may be optionally substituted as defined herein.
  • R is an alkyl group as defined herein that may be optionally substituted as defined herein.
  • ,alkylthio is a C1- C6-alkyl-S-group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.
  • Alkylaminosulfonyl includes the group -SO 2 -NH-Alkyl, wherein ,,alkyl” is preferably selected from the groups specified in the definition of “alkyl” further above. Most preferably n alkyl" in ..alkylaminosulfonyl” is a C1-C6-alkylgroup. Examples of ..alkylaminosulfonyl” are e.g. methylaminosulfonyl, ethylaminosulfonyl or butylaminosulfonyl.
  • ..Dialkylaminosulfonyl includes the group -SO 2 -N-dialkyl, wherein ,,alkyl” is preferably selected from the groups specified in the definition of "alkyl” further above. Most preferably ,,alkyl" in n dialkylaminosulfonyl” is a C1-C6-alkylgroup. Examples of ..alkylaminosulfonyl” are e.g. N,N-dimethylaminosulfonyl, N 1 N- methylethylaminosulfonyl or N.N-methylbutylaminosulfonyl.
  • ..Alkylsulfonylamino includes the group -NH-SO 2 -Alkyl, wherein alkyl is preferably selected from the groups specified in the definition of "alkyl” further above. Most preferably ..alkyl” in ..alkylsulfonylamino " is a C1-C6-alkylgroup, such as e.g. methanesulfonylamino.
  • Alkylcarbonyl includes the group -C(O)-alkyl, wherein alkyl is preferably selected from the groups specified in the definition of "alkyl” further above.
  • Alkylcarbonyl is particularly preferably -C(O)-CI -C6-Alkyl, and most preferably acetyl, propionyl oder butyryl.
  • Alkylaminocarbonyl includes the groups -C(O)-NH-alkyl wherein “alkyl” is preferably selected from the groups specified in the definition of “alkyl” further above.
  • Alkylaminocarbonyl is particularly preferably -C(O)-NH-(CI -C6)Alkyl
  • Dialkylaminocarbonyl includes the group -CO-N-dialkyl, wherein “alkyl” is preferably selected from the groups specified in the definition of “alkyl” further above. "Dialkylaminocarbonyl” is particularly preferably -C(O)-N-di(C1-C6)alkyl "Alkyloxy” or “alkoxy” includes the group -OR wherein R is "alkyl” as defined further above. Particular alkyloxy groups include, by way of example, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, 1 ,2- dimethylbutoxy, and the like.
  • Alkyloxyalkyloxy refers to the group -OROR', wherein R and R' are the same or different "alkyl” groups as defined further above.
  • Alkyloxyalkyloxyalkyl refers to the group -ROR 1 OR", wherein R, R' and R" are the same or different "alkyl” groups as defined further above.
  • Alkyloxyalkyamino refers to the group -NH(ROR'), wherein R and R' are the same or different "alkyl” groups as defined further above.
  • N-Alkyloxyalky-N-alkylamino refers to the group -NR(R 1 OR"), wherein R, R 1 and
  • R are the same or different "alkyl” groups as defined further above.
  • Alkenyl has preferably 2-15 carbon atoms ("C2-C15 alkenyl”), more preferably 2-10 carbon atoms (“C2-C10 alkenyl”), even more preferably 2-8 carbon atoms (“C2-C8 alkenyl”) or 2-6 carbon atoms (“C2-C6 alkenyl”), and in some instances even more preferably 2-5 carbon atoms (“C1-C5 alkenyl”), 2-4 carbon atoms (“C2-C4 alkenyl”), or only 2-3 carbon atoms (“C2-C3 alkenyl”).
  • a preferred "alkenyl” group is ethenyl (vinyl).
  • Alkynyl includes acetylenically unsaturated hydrocarbyl groups being straight- chained or branched and having at least 1 triple bond.
  • Alkynyl has preferably 2-15 carbon atoms ("C2-C15 alkynyl”), more preferably 2-10 carbon atoms (“C2-C10 alkynyl”), even more preferably 2-8 carbon atoms (“C2-C8 alkynyl”) or 2-6 carbon atoms (“C2-C6 alkynyl”), and in some instances even more preferably 2-5 carbon atoms (“C1-C5 alkynyl”), 2-4 carbon atoms ("C2-C4 alkynyl”), or only 2-3 carbon atoms ("C2-C3 alkynyl”).
  • a preferred alkynyl group is ethynyl (acetylenyl).
  • Dialkylamino includes the group -NR 1 R", wherein R 1 and R" are alkyl group as defined herein.
  • Amino refers to the radical-NH 2 .
  • Aryl refers to an aromatic hydrocarbyl radical.
  • aryl radicals are phenyl, naphthyl, indenyl, azulenyl, fluorine or anthracene, wherein phenyl is preferred.
  • Cycloalkyl refers to cyclic saturated aliphatic hydrocarbyl groups.
  • the numbers of C-atoms referenced in connection with a given cycloalkyl group corresponds to the number of ring forming carbon atoms, e.g. "C3-C6 cycloalkyl” refers to a cycloalkyl with between three and six ring-forming C atoms.
  • Examples of “cycloalkyl” are C3-C8 cycloalkyls, C3-C7 cycloalkyls, or more specifically C3-C6 cycloalkyls such as e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc. If indicated, a
  • cycloalkyl group may be unsubstituted or substituted with e.g. hydroxyl, alkyloxy, halogen, phenyl, amino, a group NR7R8 or with one or more alkyl groups, e.g. with
  • C1-C6 alkyl groups preferably with C1-C3 alkyl groups, particularly preferably with methyl groups. If a "cycloalkyl” carries more than one substituent, e.g. one or more alkyl substituent these substituents may be attached to the same or to different ring- forming carbon atoms.
  • Cycloalkyloxy refers to the group -OR, wherein R is "cycloalkyl” group as defined further above.
  • Cycloalkylamino refers to the group -NHR, wherein R is “cycloalkyl” group as defined further above.
  • N-Cycloalkylamino-N-alkylamino refers to the group -NRR', wherein R is the same or different “alkyl” group as defined further above and R' is "cycloalkyl” group as defined further above.
  • Cyano refers to the radical -C ⁇ N.
  • Halo or "halogen” refers to fluoro, chloro, bromo and iodo. Preferred halo groups are either fluoro or chloro.
  • Haloalkyl includes an “alkyl” group as defined further above which is substituted with one or more halogens which may be the same, e.g. in trifluoromethyl or pentafluoroethyl, or which may be different.
  • Heteroaryl refers to aromatic ring system containing at least one heteroatom such as O, S or N.
  • heteroaryl radicals are furanyl, thienyl, pyrollyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzthiazolyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, quinolizinyl, pteridinyl, carbazoly
  • Heteroarylcarbonyl refers to the group -CO-heteroaryl.
  • Hydrophosidyl refers to the radical -OH.
  • Haldroxyalkyl includes an “alkyl” group as defined further above which is substituted with one or more hydroxy groups.
  • Ni refers to the radical-NO 2 .
  • ..Phenyl is the aromatic radical -C6H5. Whether a phenyl group is substituted with one or more substituents, is specified throughout this specification and the claims.
  • ..Phenylalkyl comprises the group -alkyl-phenyl, wherein ..phenyl” and ..alkyl” have the meaning as defined further above. Examples of phenylalkyl groups are phenylethyl and benzyl, wherein benzyl is a particularly preferred phenylalkyl group.
  • ..Phenylalkyloxy comprises the group -O-alkyl-phenyl, wherein ..phenyl" and ..alkyl” have the meaning as defined further above.
  • Examples of phenylalkyloxy groups are phenylethyloxy and benzyloxy.
  • ..Phenoxy comprises the group-O-phenyl, wherein phenyl" has the meaning as defined further above
  • ..Phenylcarbonyl is -C(O)-phenyl, wherein phenyl" has the meaning as defined further above .
  • Phenylalkylcarbonyl is -C(O)-alkyl-phenyl, wherein ..phenyl" and ..alkyl” have the meaning as defined further above
  • ..Phenylalkyloxycarbonyl is the group -C(O)-O-alkyl-phenyl, wherein ..phenyl" and ..alkyl” have the meaning as defined further above
  • ..Sulfamoyl includes the group -SO 2 -NH 2 .
  • ..Sulfonylamino includes the group -NH-SO 2 H.
  • Trifluormethyl refers to the group -CF 3 .
  • heteroaryl is meant to be unsubstituted. If any “alkyl”, “alkenyl”, “alkynyl”, “phenyl”, or “heteroaryl”, is expressly stated to be substituted, this usually also refers to the respective “alkyl”, “alkenyl”, “alkynyl”, “phenyl”, or “heteroaryl” partial structures of more complex structures such as “alkyloxy”, “alkylsulfonyl”, “alkenyloxy", “phenoxy", “heteroaryloxy”, etc.
  • “Pharmaceutically acceptable” means being approved by a regulatory agency of the Federal or a state government or being listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic
  • ammonia arginine, benethamine, benzathine, calcium, choline, deanol, diethanolamine, diethylammonium, ethanolamine, ethylendiamine, meglumine, hydrabamine, imidazole, lysine, magnesium, hydroxyethylmorpholine, piperazine, potassium, epolamine, sodium, trolamine, tromethamine or zinc.
  • “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. "Preventing” or “prevention” refers to a reduction in risk of acquiring a disease or disorder (i. e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease). “Subject” includes humans. The terms “human,” “patient” and “subject” are used interchangeably herein.
  • “Therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i. e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.
  • treating refers to delaying or preventing the onset of the disease or disorder.
  • N-Amino-(4-methoxy)pyridinium-2, 4-dinitrophenolate (C2a) A suspension of 1 1.4 ml (0.112 mol) 4-methoxypyridine and 24.6 g (0.124 mol) O-(2,4- dinitrophenyl)hydroxylamine in 371 ml dichloromethane was stirred for 20 hrs at room temperature. After addition of diethylether the precipitate was filtered off and dried in under reduced pressure. Yield: 34 g (99 %) yellow solid.
  • Example E13 5-[3-[4-(2, 3-Dichlorophenyl)piperazin- 1 -yl]propoxymethyl]pyrazolo[1 , 5-a]py ⁇ dine
  • Example E27 i-fS-ft-ft-fcS-Dichlorophenyljpiperazin-i-ylfiutoxyJpyrazoloti. ⁇ -aJpyridine-S-yljethanone
  • Example E6 2-[4-[4-(2-Chlorophenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyridine-3-carbaldehyde
  • Example E10 4-[4-[4-(2, 3-Dichlorophenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyhdine-3-carbaldehyde
  • Example E12 4-[4-[4 ⁇ (2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine-3-carbaldehyde Synthesis worked according to the preparation of E21 when using 4-[4-[4-(2- chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E9). Yield: 149 mg (90 %) light yellow solid.
  • Example E54 e-p-ft-fcS-Dichlorophenyljpiperazin-i-ylJbutoxyJpyrazololtS-aJpyridine-S-carbaldehyde
  • Example E62 7-[4-[4-(2-Chlorophenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyridine-3-carbaldehyde
  • Example E43 3-Bromo-5-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine Synthesis worked according to the preparation of E42 when using 5-[4-[4-(2- methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E16). Yield: 11 mg (63 %) colourless oil.
  • Phenyl H4, Phenyl H5); 7.45 (d, J 2.6 Hz, 1H, H-4); 7.75 (s, 1 H, H-2); 8.56-8.59 (m, 2H,

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Abstract

The present application relates to indolizine-based compounds of the general formula (I) and aza-analogs thereof, which have medical utility, for example as antipsychotics.

Description

Indolizines and aza-analog derivatives thereof as CNS active compounds
Background:
Schizophrenia and other psychotic disorders including manic phases of bipolar disorder, acute idiopathic psychotic illnesses, and other conditions marked by severe agitation exhibit major disturbances in reasoning, often with delusions and hallucinations. Schizophrenia affects about 1 % of the population and about 5-10% of the affected patients commit suicide. The cost to the society is assessed to be several billions of dollars, and there is thus a significant need to provide effective pharmacological treatment options for the treatment of schizophrenia and other psychotic disorders.
It is currently believed that excessive dopamine activity is one of the major underlying causes of schizophrenia. Support for this hypothesis comes from the observation that most of the currently available antipsychotic agents are dopamine D2 receptor antagonists, so called neuroleptics. Examples of typical neuroleptics are haloperidol, loxapine, pimozide, phenothiazine derivatives such as chlorpromazine and fluphenazine, or thioxanthene derivatives such as thiothixene. However, due to their strong and selective D2 antagonism, these first generation antipsychotics have a substantial risk of adverse extrapyramidal neurological side effects as well as an increased release of prolactin. Also, pure D2 antagonists only have an impact on the so-called "positive symptoms" of psychotic disorders, like delusions and halluzinations, which are caused by the overexpression of dopamine receptors in some brain segments but are not effective on "negative symptoms" such as apathy or alogia which are thought to be caused by reduced dopaminergic activity in other areas of the CNS. Finally, about 30% of the patients do not respond well to typical D2 antagonists.
As a consequence, "atypical antipsychotics" or "2nd generation antipsychotics" have been developed. Examples include clozapine, risperidone, and ziprasidone. Atypical antipsychotics have a more complex receptor profile than first generation antipsychotics and besides showing high affinity binding to and inhibition of dopaminergic D2 receptors, also modulate other receptors, like serotonergic and/or adrenergic receptors. For example, clozapine also interacts with a couple of adrenergic, serotonergic, muscarinergic and histaminergic receptors and has proved effective in patients who respond poorly to standard neuroleptics (Goodman&Gilman's "The pharmacological Basis of therapeutics", Editor Laurence L. Brunton, 11th edition, 2005). Likewise, risperidone and ziprasidone are combined D2/5-HT2a receptor antagonists and 5-HT1a agonists. It was thus suggested that atypicality may arise from interactions with the 5-hydroxytryptamine 5-HT2 receptor in addition to the dopaminergic D2 antagonism. Compounds also acting as serotonin 5- HT1A agonists may additionally alleviate negative symptoms of schizophrenia and reduce the likelihood of extrapyramidal symptoms.
A full blockade of D2 receptors can lead to dopamine hypoactivity which is associated with side effects such as extrapyramidal motor dysfunction. A novel strategy to overcome this shortcoming of existing antipsychotics is thus the development of partial dopamine receptor antagonist. Such compounds, like aripiprazole and bifeprunox, are sometimes called "3rd generation antipsychotics", and do act as antagonist at D2 when there is an overstimulation of dopamine receptors while activating these D2 receptors when there is insufficient stimulation by endogenous dopamine. It is thus believed that partial D2 agonists act as "dopamine stabilisers", arid offer the advantage of full therapeutic efficacy with minimal side effect liability.
Moreover, the modulation of the dopaminergic D3 and the D4 receptors is thought to be useful in the treatment of cognitive and affective symptoms associated with psychotic diseases.
The chemical structures of clozapine, risperidone, ziprasidone and aripiprazole are depicted below:
Figure imgf000003_0001
In one embodiment, the present patent application provides novel compounds that show high affinity to the dopaminergic D2 receptor, but which also interact with significant affinity with the 5-HT2 serotonergic receptor, the 5-HT1a serotonergic receptor and the dopaminergic D3 and D4 receptors.
A preferred embodiment of the present invention relates to new compounds which exert partial dopaminergic activity at the D2 receptor e.g. by having an intrinsic dopaminergic D2 activity that is up to about 50% of a full agonist.
It has been now found, surprisingly, that in one embodiment indolizine derivatives having the general formula A
Figure imgf000004_0001
exhibit the target profile of a modern atypical antipsychotic.
In particular, the compounds as described in more detail further below and in the claims inter alia have a remarkable affinity at the D2 receptor, and do also show binding to the 5- HT2, the 5-HT1a, the D3 and D4 receptors in a range comparable to or even superior than other atypical antipsychotics like aripiprazole.
Detailed description of the invention
One embodiment of the present invention relates to compounds of the general formula I,
(R1),
Figure imgf000005_0001
formula I
wherein:
Q1 and Q2 are independently of each other N, CH or C-R1 ;
Q3 is CH or C-R 1 if at least one of Q1 and Q2 is different from nitrogen, and Q3 is selected from CH, C-R1 and N if Q1 and Q2 are both nitrogen;
m is 0, 1 , 2 or 3;
any R1 is bonded to a C-atom of the heterocycle of formula I and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, alkyl, cycloalkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, phenylcarbonyl, phenylalkyl, phenylalkyloxy, phenylalkylcarbonyl, phenylalkyloxycarbonyl, alkyloxycarbonyl, alkylsulfonyl, phenylsulfonyl.sulfamoyl, alkylaminosulfonyl, dialkylaminosulfonyl, phenylsulfonylamino and alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy , halogen, alkyl, cycloalkyl which is preferably unsubstituted, carboxy, NR7R8, cyano, trifluoromethyl and nitro; and wherein each cycloalkyl can be unsubstituted or substituted with hydroxyl, alkyloxy, halogen, alkyl, phenyl which is preferably unsubstituted, amino and NR7R8.
X is a group having the formula
Figure imgf000006_0001
wherein:
Y is chosen from among S and O;
k is 0, 1 or 2; n is 1-5; p is 0, 1 or 2; q is 1 or 2;
R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, phenylcarbonyl, phenylalkyl, phenylalkyloxy, phenylalkylcarbonyl, phenylalkyloxycarbonyl, alkyloxycarbonyl, alkylsulfonyl, phenylsulfonyl, sulfamoyl, alkylaminosulfonyl, dialkylaminosulfonyl, phenylsulfonylamino and alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy, halogen, alkyl, cycloalkyl which is preferably unsubstituted, carboxy, NR7R8, cyano, trifluormethyl and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen-containing 5-, 6- or 7-membered ring;
R7 and R8 are independently selected from hydrogen, alkyl, cycloalkyl, phenyl, heteroaryl, phenylalkyl, alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, alkylcarbonyl, alkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7- membered cycle; and wherein each heterocycle is a monocyclic ring and wherein phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy, halogen, alkyl, carboxy, NR9R10, cyano, trifluormethyl and nitro;
R9 and R10 are independently selected from among hydrogen and alkyl;
R11 is hydroxyl, (C1-C3)alkyl, hydroxy-(C1-C3)alkyl, halogen-(C1-C3)alkyl or oxo;
provided that the heterocycle of formula I carries precisely one group X;
in the form of the free base, their physiologically acceptable salts, possible conformational isomers, enatiomers, and diastereomers.
One embodiment of the present invention relates to compounds of formulas Ma-IId
Figure imgf000007_0001
formula Ma formula lib formula Hc formula Md wherein: m is 0, 1 , 2 or 3;
any R1 is bonded to a C-atom of a heterocycle of formulas lla-lld and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C1-
C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3- C7)cycloalkyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1- C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1- C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1-C10)alkyloxycarbonyl, (C1-
C10)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-C10)alkylaminosulfonyl, di(C1- C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherin each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro;
X is a group having the formula
Figure imgf000008_0001
wherein:
k is 0, 1 or 2; n is 1-5; p is 0, 1 or 2; q is 1 or 2; R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, (C3-C7)cycloalkyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1-
C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1- C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1- C10)alkyloxycarbonyl, (C1-C19)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1- C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen-containing 5-, 6- or 7-membered ring;
R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3-
C7)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, carboxy, NR9R10, cyano, trifluoromethyl, and nitro;
R9 and R10 are independently selected from among hydrogen, and alkyl;
R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo; provided that each heterocycle of formulas Ha-IId carries precisely one group X;
in the form of the free base, their physiologically acceptable salts and possible enatiomers and diastereomers.
One preferred embodiment of the present invention is a compound of formula I or formula Ha1 lib or He as described further above, wherein q is 1.
Another embodiment of the present invention is a compound of formula I or formula lla, lib or He as described further above, wherein k is 0.
Another embodiment of the present invention is a compound of formula I or formula Ma, lib or He as described further above, wherein R4 is fluoro or hydrogen, particularly hydrogen.
Another embodiment of the present invention is a compound of formula I or formula Ma, lib or Hc as described further above, wherein q is 1 , k is 0 and R4 is fluoro or hydrogen, particularly hydrogen.
Another embodiment of the present invention is a compound of formula I or formula
Ma, lib or Hc as described further above, wherein k is 1.
Another embodiment of the present invention is a compound of formula I or formula Ma, lib or Hc as described further above, wherein k is 1 and R11 is preferably an C1- C6 alkyl, a hydroxyl, or an oxo group.
Another embodiment of the present invention is a compound of formula I or formula Ma, lib or He as described further above, wherein k is 2. In this embodiment, the two substituents R11 may be the same or different, and may be located at different or at the same C-Atom of the N-containing ring. Preferably, the two substituents are the same and are bound to the same ring C-atom such that they do not form a stereocenter.
Another embodiment of the present invention is a compound of formula I or formula Ma, lib or Hc as described further above, wherein m is 0, 1 or 2; p is 0 or 1 ; n is 2, 3 or 4; and each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1-
C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxymethyl, nitro, NR7R8; wherein R7 and R8 are selected from among hydrogen, (C1-C3)alkyl, (C1- C3)alkylcarbonyl and phenyl(C1-C3)alkyl.
Another embodiment of the present invention is a compound of formula I or formula
Ha, lib, Mc or Hd as described further above, wherein
m is 0, 1 or 2; p is 0 or 1 ; n is 2, 3 or 4;
R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group; R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, and particularly preferably hydrogen; and
R5 and R6 are independently selected from hydrogen, or fluoro; wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
A preferred embodiment of the present invention is a compound according to anyone of the preceding claims, having the formula Ma
formula Ha
Figure imgf000011_0001
wherein X, R1 and m have the meaning as described further above.
Another embodiment of the present invention is a compound of formula Ma as described above, wherein the group X is bonded to the 2-, 4-, 5- or 6-position of the heteroaromatic ring system of formula Ha.
Another embodiment of the present invention is a compound of formula Ha as described above, wherein m is 1 , and R1 is in 3-position of the heteroaromatic ring system of the general formula Ma.
Another embodiment of the present invention is a compound of formula Ma as described further above, wherein X is
Figure imgf000012_0001
wherein p is 0 or 1 , and the sum of p and n is 3; and R2-R6 have the meaning as defined further above.
Another embodiment of the present invention is a compound of formula Ma as described above, wherein R4 is hydrogen or fluoro.
Another preferred embodiment of the present invention is a compound having the formula III
25
Figure imgf000012_0002
wherein:
R1 , R2, R3, R4, R5, R6, R11 , k, m, n, p and q are as defined for compounds of formula I, further above.
In a preferred embodiment,
k is O, 1 , or 2; m is 0, 1 , 2 or 3; n is 1-5; p is O, 1 or 2; q is 1 or 2, and is preferably 1 ;
any R1 is bonded to a C-atom of the heterocycle of formula III, and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1- C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-
C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1- C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1- C10)alkyloxycarbonyl, (C1-C10)alkyloxycarbonyl, (C1-C10)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherin each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy,
NR7R8, cyano, trifluoromethyl, and nitro;
R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1 -C10)alkyl, (C3-C6)cycloalkyl, (C1 -C10)alkyloxy, (C 1 -C 10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1- C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1- C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1- C10)alkyloxycarbonyl, (C1-C19)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-
C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen-containing 5-, 6- or 7-membered ring;
R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3- C6)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (Ci-Cβjalkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, carboxy, NR9R10, cyano, trifluoromethyl, and nitro;
R9 and R10 are independently selected from among hydrogen, and alkyl;
R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo;
provided that the heterocycle of formula III carries precisely one group X; in the form of the free base, their physiologically acceptable salts and possible enatiomers and diastereomers.
Another embodiment of the present invention is a compound of formula III as described above, wherein R4 is hydrogen or fluoro.
Another preferred embodiment of the present disclosure is a compound having the general formula III, wherein
k is O or i ; m is 0, 1 or 2; p is 0 or 1; n is 2, 3 or 4; q is 1 ;
each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1-
C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxymethyl, nitro,
NR7R8;
R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, and particularly preferably hydrogen;
R5 and R6 are independently selected from hydrogen, or fluoro;
wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
Another preferred embodiment of the present disclosure is a compound having the general formula III, wherein k is O; m is O or 1 ; n is 3; P is O; q is 1 ;
R1 is hydrogen, or formyl,
R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
R4, R5 and R6 are all hydrogen.
Another embodiment of the present disclosure is a compound having the formula IV
Figure imgf000016_0001
formula IV
wherein:
R1 , R2, R3, R4, R5, R6, R11 , k, m, n, p and q are as defined for compounds of formula I, further above.
In a preferred embodiment,
k is 0,1 or 2; m is 0, 1 , 2 or 3; n is 1-5; p is 0, 1 or 2; q is 1 or 2, and is preferably 1 ;
any R1 is bonded to a C-atom of the heterocycle of formula IV, and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-
C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1- C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1- C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1- CiO)alkyloxycarbonyl, (C1-C10)alkyloxycarbonyl, (C1-C10)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherin each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro;
R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1- C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1-
Ci0)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1- CiO)alkyloxycarbonyl, (C1-C19)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1- C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C 1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen-containing 5-, 6- or 7-membered ring;
R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3- C6)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, carboxy, NR9R10, cyano, trifluoromethyl, and nitro;
R9 and R10 are independently selected from among hydrogen, and alkyl;
R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo;
provided that the heterocycle of formula IV carries precisely one group X;
in the form of the free base, their physiologically acceptable salts and possible enatiomers and diastereomers.
Another embodiment of the present invention is a compound of formula IV as described above, wherein R4 is hydrogen or fluoro.
Another preferred embodiment of the present disclosure is a compound of formula
IV as described above, wherein
k is O or 1 ; m is 0, 1 or 2; p is 0 or 1 ; n is 2, 3 or 4; q is 1 ; each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1- C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxy methyl, nitro, NR7R8;
R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, particularly preferably hydrogen;
R5 and R6 are independently selected from hydrogen, or fluoro;
wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
Another preferred embodiment of the present disclosure is a compound of formula
IV as described above, wherein
k is 0; m is 0 or 1 ; n is 3; p is O; q is 1 ;
R1 is hydrogen, or formyl, cyano, oxime, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxy methyl, nitro, NR7R8;
R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino; R4 is selected from hydrogen, fluoro, and chloro, and is particularly preferably hydrogen;
R5 and R6 are both hydrogen.
Another preferred embodiment of the present invention are compounds having the formula V
Figure imgf000020_0001
formula V
wherein
R1 , R2, R3, R4, R5, R6, R11 , k, m, n, p and q are as defined for compounds of formula I, further above.
In a preferred embodiment,
k is 0, 1 or 2; m is 0, 1 , 2 or 3; n is 1-5; p is O, 1 or 2; q is 1 or 2, and is preferably 0;
any R1 is bonded to a C-atom of the heterocycle of formulas V, and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-
C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1- C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1- C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1- C10)alkyloxycarbonyl, (C1-C10)alkyloxycarbonyl, (C1-C10)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherin each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro;
R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1-
C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(Ci-C10)alkyl, phenyl(C1- C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1- CiO)alkyloxycarbonyl, (C1-C19)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1- CiO)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen-containing 5-, 6- or 7-membered ring;
R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3-
C6)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, carboxy, NR9R10, cyano, trifluoromethyl, and nitro;
R9 and R10 are independently selected from among hydrogen, and alkyl;
R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo;
provided that the heterocycle of formula V carries precisely one group X;
in the form of the free base, their physiologically acceptable salts and possible enatiomers and diastereomers.
Another embodiment of the present invention is a compound of formula V as described above, wherein R4 is hydrogen or fluoro.
Another preferred embodiment of the present disclosure is a compound of formula V as described above, wherein
k is 0 or 1 ; m is 0, 1 or 2; p is 0 or 1 ; n is 2, 3 or 4; q is 1 ;
each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1- C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxymethyl, nitro, NR7R8;
R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group; R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, and particularly preferably hydrogen;
R5 and R6 are independently selected from hydrogen, or fluoro;
wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
Another preferred embodiment of the present disclosure is a compound of formula IV as described above, wherein
K is O; m is O oM n is 3; p is O; q is 1 ;
R1 is hydrogen, or formyl,
R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
R4, R5 and R6 are all hydrogen.
Another preferred embodiment of the present invention are compounds having the general formula Vl
Figure imgf000024_0001
wherein:
R1 , R2, R3, R4, R5, R6, R11 , k, m, n, p and q are as defined for compounds of formula I, further above.
In a preferred embodiment,
k is 0,1 or 2; m is 0, 1 , 2 or 3; n is 1-5; p is O, 1 or 2; q is 1 or 2, and is preferably 1 ;
any R1 is bonded to a C-atom of the heterocycle of formula Vl, and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1- C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1- C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1- C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, pheny!(C1- C10)alkyloxycarbonyl, (C1 -C10)alkyloxycarbonyl, (C1 -C10)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherin each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro;
R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino,
NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1- C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1- C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1-
C10)alkyloxycarbonyl, (C1-C19)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1- C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen-containing 5-, 6- or 7-membered ring;
R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3- C6)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, carboxy, NR9R10, cyano, trifluoromethyl, and nitro;
R9 and R10 are independently selected from among hydrogen, and alkyl; R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo;
provided that the heterocycle of formula Vl carries precisely one group X;
in the form of the free base, their physiologically acceptable salts and possible enatiomers and diastereomers.
Another preferred embodiment of the present disclosure is a compound of formula Vl as described above, wherein R4 is hydrogen or fluoro, and is preferably hydrogen.
Another preferred embodiment of the present disclosure is a compound of formula Vl as described above, wherein k is O or 1; m is O, 1 or 2; p is 0 or 1 ; n is 2, 3 or 4; q is 1 ;
each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1-
C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxymethyl, nitro, NR7R8;
R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, and particularly preferably hydrogen;
R5 and R6 are independently selected from hydrogen, or fluoro; wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
Another preferred embodiment of the present disclosure is a compound of formula Vl as described above, wherein
k is O; m is 0 or 1 ; n is 3; p is O; q is 1 ;
R1 is hydrogen, or formyl,
R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
R4, R5 and R6 are all hydrogen.
Also presently disclosed are compounds having the general formula VII
Figure imgf000027_0001
wherein:
R1 , R2, R3, R4, R5, R6, R11 , k, m, n, p and q are as defined for compounds of formula I, further above. In a preferred embodiment,
k is 0,1 or 2; m is 0, 1, 2 or 3; n is 1-5; p is 0, 1 or 2; q is 1 or 2, and is preferably 1 ;
any R1 is bonded to a C-atom of the heterocycle of formula VII, and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1- C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1- C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1- C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-
C10)alkyloxycarbonyl, (C1 -C10)alkyloxycarbonyl, (C1 -C10)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherin each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)a!kyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro;
R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1-
C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1- C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1- C10)alkyloxycarbonyl, (C1-C19)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1- C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen-containing 5-, 6- or 7-membered ring;
R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3-
C6)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, carboxy, NR9R10, cyano, trifluoromethyl, and nitro;
R9 and R10 are independently selected from among hydrogen, and alkyl;
R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo;
provided that the heterocycle of formula VII carries precisely one group X;
in the form of the free base, their physiologically acceptable salts and possible enatiomers and diastereomers.
Another preferred embodiment of the present disclosure is a compound of formula VII as described above, wherein R4 is hydrogen or fluoro, and is preferably hydrogen. Another preferred embodiment of the present disclosure is a compound of formula VII as described above, wherein k is 0 or 1 ; m is O1 1 or 2; p is 0 or 1 ; n is 2, 3 or 4; q is 1 ;
each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1- C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxymethyl, nitro,
NR7R8;
R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, and particularly preferably hydrogen;
R5 and R6 are independently selected from hydrogen, or fluoro;
wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
Another preferred embodiment of the present disclosure is a compound of formula VII as described above, wherein
k is O; m is 0 or 1 ; n is 3; p is O; q is 1 ; R1 is hydrogen, or formyl,
R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
R4, R5 and R6 are all hydrogen.
Another embodiment of the present invention is a compound having formula VIII
Figure imgf000031_0001
wherein:
R1 , R2, R3, R4, R5, R6, R11 , k, m, n, p and q are as defined for compounds of formula I, further above.
In a preferred embodiment,
k is 0,1 or 2; m is 0, 1 , 2 or 3; n is 1-5; p is 0, 1 or 2; q is 1 or 2, and is preferably 1 ;
any R1 is bonded to a C-atom of the heterocycle of formula VIII1 and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)aIkyl, (C3- C6)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2- C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1- C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1- C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1-C10)alkyloxycarbonyl, (C1- C10)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-C10)alkylaminosulfonyl, di(C1- C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherin each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro;
R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-C10)alkyloxy,
(C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1- C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1- C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1- C10)alkyloxycarbonyl, (C1-C19)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-
C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen-containing 5-, 6- or 7-membered ring;
R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3- C6)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, carboxy, NR9R10, cyano, trifluoromethyl, and nitro;
R9 and R10 are independently selected from among hydrogen, and alkyl;
R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo;
provided that the heterocycle of formula VIII carries precisely one group X;
in the form of the free base, their physiologically acceptable salts and possible enatiomers and diastereomers.
Another preferred embodiment of the present disclosure is a compound of formula
VII as described above, wherein R4 is hydrogen or fluoro, and is preferably hydrogen.
Another preferred embodiment of the present disclosure is a compound of formula
VIII as described above, wherein k is 0 or 1 ; m is 0, 1 or 2; p is 0 or 1 ; n is 2, 3 or 4; q is 1 ;
each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1-
C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxymethyl, nitro, NR7R8;
R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1 -C3)alkyloxy, (C1 -C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8, and is preferably hydrogen or fluoro, and particularly preferably hydrogen;
R5 and R6 are independently selected from hydrogen, or fluoro;
wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl,
(C1-C3)alkyl, and phenyl(C1-C3)alkyl.
Another preferred embodiment of the present disclosure is a compound of formula
VIII as described above, wherein
k is O; m is 0 or 1 ; n is 3; p is O; q is 1 ;
R1 is hydrogen, or formyl,
R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
R4, R5 and R6 are all hydrogen.
Specific compounds in accordance with the present invention are
- 2-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 2-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine 2-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine 2-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 2-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde - 2-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 4-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 4-[4-[4-(2-Methoxyphenyl)piperazin-1 -yljbutoxy]pyrazolo[1 ,5-a]pyridine
- 4-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine - 4-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
. 4-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 4-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyιϊdin-3- carbaldehyde
5-[3-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]propoxymethyl]pyrazolo[1 ,5-a]pyridine
5-[3-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]propoxymethyl]pyrazolo[1 ,5-a]pyridin-
3-carbaldehyde
5-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine - 5-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine 5-[4-[4-(3-Nitrophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 5-[4-[4-(3-Aminophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine Λ/-[3-[4-[4-(Pyrazolo[1 ,5-a]pyridin-5-yloxy)butyl]piperazin-1 -yl]phenyl]acetamide - 5-[4-[4-(4-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 5-[4-[4-(4-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 5-[4-[4-(4-Hydroxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine 5-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]-3-methylpyrazolo[1 ,5-a]pyridine
- 3-Hydroxymethyl-5-[4-[4-(2-methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5- a]pyridine
- 5-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyιϊdin-3- carbaldeyhde
5-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldeyhde - 5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldeyhde
- 5-[4-[4-(3-Nitrophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde - Λ/-[3-[4-[4-(3-Formylpyrazolo[1 ,5-a]pyridin-5-yloxy)butyl]piperazin-1- yl]phenyl]acetamide
5-[4-[4-(4-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldeyhde
5-[4-[4-(4-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldeyhde
5-[4-[4-(4-Hydroxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldeyhde
- 1-[5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- yljethanone - 1-[5-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- yljethanone
- 1 -[5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- yljethanone 3-Aminomethyl-5-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5- a]pyridine
- Λ/-[5-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- ylmethyljacetamide
- ^ra/7S>5-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin- 3-carbaldehyde oxime - Cs-fransj-5-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde oxime
(rs-frans>)-5-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde oxime
- fs-c/sJ-5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde oxime fs-c/sJ-5-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde oxime
- (rs-c/s>)-5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde oxime 5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbonitrile
5-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbonitrile - 5-[4-[4-(2-ChIorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbonitrile
5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yi]butoxy]pyrazolo[1 ,5-a]pyridin-3- carboxylic acid ethyl ester
5-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carboxylic acid ethyl ester
- 5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3-carboxylic acid ethyl ester
- 3-Bromo-5-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 l5-a]pyridine 3-Bromo-5-[4-[4-(2-methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine - 3-Bromo-5-[4-[4-(2-chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 3-Chloro-5-[4-[4-(2,3-dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5- a]pyridine
- 3-Chloro-5-[4-[4-(2-methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine 3-Chloro-5-[4-[4-(2-chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine - 5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]-3-iodopyrazolo[1 ,5-a]pyridine
- 3-lodo-5-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine 5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]-3-iodopyrazolo[1 ,5-a]pyridine
- 6-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 6-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine - 6-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 6-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 6-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde - 6-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 7-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 7-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 7-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine - 7-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 7-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde - 7-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 7-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]tetrazolo[1 ,5-a]pyridine
- 7-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]tetrazolo[1 ,5-a]pyridine
- 7-[4-[4-(2-Chloroyphenyl)piperazin-1 -yl]butoxy]tetrazolo[1 ,5-a]pyridine
Other examples of compounds according to the present inventions are:
- 5-[4-[4-(3-Trifluoromethylphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine 5-[4-[4-(3-Trifluoromethylphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 5-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]-3-hydroxymethylpyrazolo[1 ,5- a]pyridine
5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]-3-hydroxymethylpyrazolo[1 ,5- a]pyridine - 5-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]-3-methylpyrazolo[1 ,5- a]pyridine
- 5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]-3-methylpyrazolo[1 ,5-a]pyridine
- 3-Aminomethyl-5-[4-[4-(2,3-dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5- a]pyridine - 3-Aminomethyl-5-[4-[4-(2-chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5- a]pyridine
Λ/-[5-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- ylmethyl]acetamide
- Λ/-[5-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- ylmethyl]acetamide
- 5-[4-(4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridine 5-[4-(4-(Chroman-8-yl)piperazin-1-yl)butoxy]pyrazolo[1 ,5-a]pyridine
- 5-[4-(4-(2,3-Dichlorophenyl)-1 ,4-diazepan-1-yl)butoxy]pyrazolo[1 ,5-a]pyridine
- 5-[4-(4-(2-Methoxyphenyl)-1 ,4-diazepan-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridine - 5-[4-(4-(2-Chlorophenyl)-1 ,4-diazepan-1-yl)butoxy]pyrazolo[1 ,5-a]pyridine - 5-[4-(4-(2,3-Dihydrobenzofuran-7-yl)-1 ,4-diazepan-1 -yl)butoxy]pyrazolo[1 ,5- a]pyridine
- 5-[4-(4-(Chroman-8-yl)-1 ,4-diazepan-1-yl)butoxy]pyrazolo[1 ,5-a]pyridine 5-[4-(4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridin- 3-carbaldehyde
- 5-[4-(4-(Chroman-8-yl)piperazin-1-yl)butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 5-[4-(4-(2,3-Dichlorophenyl)-1 ,4-diazepan-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde - 5-[4-(4-(2-Methoxyphenyl)-1 ,4-diazepan-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 5-[4-(4-(2-Chlorophenyl)-1 ,4-diazepan-1-yl)butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 5-[4-(4-(2,3-Dihydrobenzofuran-7-yl)-1 ,4-diazepan-1 -yl)butoxy]pyrazolo[1 ,5- a]pyridin-3-carbaldehyde
- 5-[4-(4-(Chroman-8-yl)-1 ,4-diazepan-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
. 7-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]indolizine
7-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]indolizine - 7-[4-[4-(2-Chloroyphenyl)piperazin-1-yl]butoxy]indolizine
- 6-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]imidazo[1 ,2-a]pyridine 6-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]imidazo[1 ,2-a]pyridine
- 6-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]imidazo[1,2-a]pyridine
- 8-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]imidazo[1 ,2-a]pyridine - 8-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]imidazo[1 ,2-a]pyridine
- 8-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]imidazo[1 ,2-a]pyridine
The compounds of the present invention can be prepared as follows:
A compound of formula Xl is reacted with an activated alkylene having the formula XII to give a compound of formula XIII
Figure imgf000040_0001
formula Xl formula XII formula XIII
which compound of formula XIII, optionally after (partial) purification, is then combined with a compound of {formula Xl Vj
Figure imgf000040_0002
formula XIV
to give a compound of formula XV
Figure imgf000040_0003
formula XV
wherein in anyone of formulas Xl, XII, XIII, XIV, and XV
R1 , Q1 , Q2, Q3, X, Y, n, R11 , q, k, R2, R3, R4, R5, and R6 are as defined further above and in the claims for compounds of the formulas I1 Ha, lib, Hc, Hd, III, IV1 V, Vl, VII or VIII; and W and V are activating groups, which may be the same or different from each other;
and optionally adding to the compound of formula XV, optionally after (partial) purification, one or more additional groups R1 to give a compound of anyone of formula I1 Ha, lib, Hc, Hd, III, IV, V, Vl, VII or VIII as described further above. In the general method described above, the activating group is selected from among bromo, chloro, mesylate, triflate or tosylate.
In the production method described above all R1 groups can be present in the starting material of the general formula Xl. Alternatively, one or more R1 groups may be added to a compound of formula XVa in which one or more hydrogen atom(s) is/are then replaced by additional R1 group(s) to give a compound of I, Ua, lib, Mc, Md, III, IV, V, Vl, VII or VIII as described further above and in the claims. This synthesis takes place by reaction of a compound of formula XVa with an activated precursor to get a compound of formula XVI as described as follows:
Figure imgf000041_0001
formula XVa formula XVI
wherein in formulas XVa and XVI
RV is selected from among bromo, chloro, iodine, formyl, hydroxymethyl, alkyl, oxime, cyano, aminomethyl, acylaminomethyl; and
R1 , Q1 , Q3, X and m are as defined above.
A preferred embodiment relates to a method of producing a compound according to the present invention, comprising the synthesis of a compound of formula XVI as described above, wherein RV is selected from among bromo, chloro, iodine and formyl and wherein RV is introduced by the reaction of a compound of formula XVa with an activated precursor to get a compound of formula XVI. Examples of activated precursors are Λ/-halogensuccinimide, hypohalogenic acids, sodium halogenites and phosphorousoxychloride in Λ/,Λ/-dimethylformamide or other well established formylation reactants and are preferably Λ/-chlorosuccinimide, Λ/-bromosuccinimide, Λ/-iodosuccinimide and phosphorousoxychloride in Λ/,Λ/-dimethylformamide. Alternatively, the group R1 can be attached to the heterocyclic ring system by a two- step sequence starting with the introduction of a formyl group to give a compound of formula XVIa
Figure imgf000042_0001
formula XVa formula XVIa
and subsequently transforming the formyl group of formula XVIa to give a compound of formula XVII as follows:
Figure imgf000042_0002
(R1)m (R1)m formula XVIa formula XVII
wherein
the compound of formula XVII is comprised by formula I, Ma, MB, Mc, Hd, III, IV, V, Vl, VII and/or VIII, and wherein in formula XVII
RV is selected from among hydroxymethyl, alkyl, oxime, cyano, aminomethyl and acylaminomethyl,
and Q1, Q3, X and m are as defined further above and in the claims.
The transfer of the formyl group to the group RV comprises condensation reactions, the reduction of the formyl group or a combination of both, condensation and reduction reactions. In the production method described above all R2, R3, R4, R5 or R6 groups can be present in the starting material of the general formula XIV. Alternatively, one or more R2, R3, R4, R5 or R6 groups may be introduced to a compound of formula XIX by transforming an appropriate precursor group R2', R31, R4', R5' or R6' of a compound according to formula XVIII to give a compound of formula XIX comprised by formula I, Ma1 lib, Hc, Hd, III, IV, V, Vl, VII or VIII as described further above and in the claims and as described as follows:
Figure imgf000043_0001
wherein
the compound of formula XIX is comprised by formula I, Ma, lib, Hc, Md, III, IV, V, Vl, VII and/or VIII, and wherein in formula XVIII
R2', R3', R4', R5' or R6' is selected from among nitro, formyl and alkyloxycarbonyl,
and wherein in formula XIX
R2, R3, R4, R5 or R6 is selected from among amino, hydroxymethyl, alkyl, oxime, cyano, aminomethyl, acylamino and acylaminomethyl,
and R1 , Q1 , Q2, Q3, X, Y, n, R11 , q and k are as defined further above and in the claims. A preferred embodiment relates to a method of producing a compound according to the present invention, comprising the synthesis of a compound of formula XIX as described above, wherein R3 is selected from among amino and acylamino and wherein R3 is introduced by the reaction of a compound of formula XVIII with an appropriate precursor R31 derived from nitro or amino to get a compound of formula
XIX.
The production of the individual compounds of the present invention is described in more detail in the experimental part of the present application.
The compounds of the present invention are useful medicines, and may be used for the treatment of various diseases of the CNS system.
Due to their remarkable affinity to the dopaminergic D2 receptor, as well as due to their modulating potency at the serotonergic 5-HT2 and 5-HT1a receptors, the present compounds in one mbodiment of the present invention may be of use for the production of a medicament for the treatment of a variety of diseases such as like a psychotic disease including manic phases of bipolar disorder, acute idiopathic psychotic illnesses, psychoses associated with other diseases, drug-induced psychoses, and particularly schizophrenia; attention deficit hyperactivity disorder
(ADHD); autism; bipolar disorder; cognitive impairment; idiopathic or drug-induced movement disorders such as akinesia and dyskinesia; Parkinson's disease; mood disorders including major depressive disorders, substance-induced mood disorders or other forms of depression; anxiety disorders including panic attack, social phobia, or generalized anxiety disorders; obsessive-compulsive disorders; stress-related disorders; addiction disorders; sleep disorders; sexual dysfunction; amnesic and/or cognitive disorders, especially dementia; eating disorders including anorexia and bulemia; pain; and neurodegenerative diseases including Chorea Huntington and multiple sclerosis.
Another embodiment of the present disclosure is a method of treating a subject having a disease selected from a psychotic disease including manic phases of bipolar disorder, acute idiopathic psychotic illnesses, psychoses associated with other diseases, drug-induced psychoses, and particularly schizophrenia; attention deficit disorder; autism; bipolar disorder; cognitive impairment; idiopathic or drug- induced movement disorders such as dyskinesia; Parkinson's disease; or depression by administering a compound as described herein, and specifically in the claims. According to one aspect of the invention, the subject to be treated with the presently disclosed compounds have been determined to be in need of a treatment of one or more of the above diseases based on a prior diagnosis of said disease or said diseases.
Prior to the administration to the patient, the presently disclosed compounds may be added to a pharmaceutically acceptable excipient or carrier. One aspect of the present invention is thus a pharmaceutical composition comprising a compound as described in this specification and in the claims, and a pharmaceutical acceptable carrier. Hereinafter, some formulating methods and kinds of excipients will be described, but the present invention is not limited to them. The pharmaceutical composition of the present invention can be administered to a mammalian subject such as domestic animals or human beings via various routes.
The methods of administration which may easily be expected include oral, bukkal, sublingual, nasal, pulmonal, and rectal administration; intravenous, intramuscular, subcutaneous, and intracerebroventricular injections, wherein oral delivery is preferred.
The oral administration may be performed by providing the compounds of the present invention in the form of a tablet, a capsule, a drage1, a powder, a granulate, or in form of a liquid or a semi-solid.
A compound of formula (I), (Ha), (Mb), (lie), (lid), (III), (IV), (V), (Vl), (VII) or (VIII), an isomer thereof or a pharmaceutically acceptable salt thereof according to the present invention can be prepared as a pharmaceutical composition containing pharmaceutically acceptable carriers, adjuvants, diluents and the like.
For instance, the compounds of the present invention can be dissolved in oils, propylene glycol or other solvents which are commonly used to produce an injection. Suitable examples of the carriers include, but not limited to, physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc. The compounds of the present invention may be formulated into injections by dissolving, suspending or emulsifying in water-soluble solvent such as saline and 5% dextrose, or in water-insoluble solvents such as vegetable oils, synthetic fatty acid glyceride, higher fatty acid esters and propylene glycol. The formulations of the invention may include any of conventional additives such as dissolving agents, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.
Oral formulations may comprise e.g. sustained release agents, disintegrants, fillers, lubricants, stabilizers, antioxidants, stabilizers, flavours, dispersion agents, electrolytes, buffers or conservation agents. Suitable excipients and formulations are known to those skilled in the art and are disclosed in standard monographs such as like Remington ("The science and practice of pharmacy", Lippincott, Williams & Wilkins, 2000). Typical sustained release agents are for example those that swell upon contact with water such as polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, other cellulose ethers, starch, pregelatinised starch, polymethacrylate, polyvinylacetate, microcrystalline cellulose, dextranes or mixtures thereof. The pharmaceutical composition of the present invention can also contain disintegrants, such as pregelatinised starch, sodium starch glycolate, microcrystalline cellulose, carboxymethylcellulose sodium (CMC-Na), cross-linked
CMC-Na, low-substituted hydroxypropylcellulose or mixtures thereof. The pharmaceutical compositions according to the invention can further contain fillers and binders such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, starch (e.g. corn starch or potato starch), pregelatinised starch, fructose, sucrose, dextrose, dextranes, other sugars such as mannitol, maltitol, sorbitol, lactitol and saccharose, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, dicalciumphosphate dihydrate, tricalciumphophate, calcium lactate or mixtures thereof. The oral composition according to the invention can also comprise lubricants, antiadherents and/or glidants, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, glycerol dibehenate, talc, corn starch, silicone dioxide or mixtures thereof.
The preferable dose level of the compounds according to the present invention depends upon a variety of factors including the condition and body weight of the patient, severity of the particular disease, dosage form, and route and period of administration, but may appropriately be chosen by those skilled in the art. The compounds of the present invention may be administered in an amount ranging from 0.001 to 10 mg/kg of body weight per day, and more preferably from 0.03 to 1 mg/kg of body weight per day. Individual doses may range from about 0.1 to 500 mg of active ingredient per day, preferably from about 1 to 100 mg/day, and most preferably of between about 5 and 100 mg/day. Doses may be administered once a day, or several times a day with each divided portions.
Another aspect of the present invention is a Kit comprising a medicine or a pharmaceutical composition as described above, and instructions for its use.
The medicine according to the present invention may comprise one of the presently disclosed compounds as "stand alone" treatment of a psychological illness such as e.g. schizophrenia or bipolar disorder.
In one embodiment, a presently disclosed compound may be administered together with other useful drugs in a combination therapy. For example, a compound according to the present invention may be combined with an antidepressant to treat a psychoses associated with depressions, e.g. bipolar disorder. Likewise a compound of the present invention may be combined with a cognition enhancer. In combination therapies the two or more active principles may be provided via the same formulation or as a "kit of parts", i.e. in separate galenic units. Also, the two or more active principles may be administered to the patient at the same time or subsequently, e.g. in an interval therapy.
Definitions: "Alkyl" includes monovalent saturated aliphatic hydrocarbyl groups. The hydrocarbon chain may be either straight-chained or branched. "Alkyl" has preferably 1-15 carbon atoms ("C1-C15 alkyl"), more preferably 1-10 carbon atoms ("C1-C10 alkyl"), even more preferably 1-8 carbon atoms ("C1-C8 alkyl") or 1-6 carbon atoms ("C1-C6 alkyl"), and in some instances even more preferably 1-5 carbon atoms ("C1-C5 alkyl"), 1-4 carbon atoms ("C1-C4 alkyl"), or only 1-3 carbon atoms ("C1-C3 alkyl"). This term is exemplified by groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, t-amyl, and the like. "Alkylamino" includes the group -NHR1, wherein R' is alkyl group as defined herein. "Alkylsulfonyl" includes a radical-S(O)2R, wherein R is an alkyl group as defined herein. Representative examples include, but are not limited to, methanesulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.
"Alkylthio" includes a radical-S-R wherein R is an alkyl group as defined herein that may be optionally substituted as defined herein. Preferably, ,,alkylthio" is a C1- C6-alkyl-S-group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.
"Alkylaminosulfonyl" includes the group -SO2-NH-Alkyl, wherein ,,alkyl" is preferably selected from the groups specified in the definition of "alkyl" further above. Most preferably nalkyl" in ..alkylaminosulfonyl" is a C1-C6-alkylgroup. Examples of ..alkylaminosulfonyl" are e.g. methylaminosulfonyl, ethylaminosulfonyl or butylaminosulfonyl.
..Dialkylaminosulfonyl" includes the group -SO2-N-dialkyl, wherein ,,alkyl" is preferably selected from the groups specified in the definition of "alkyl" further above. Most preferably ,,alkyl" in ndialkylaminosulfonyl" is a C1-C6-alkylgroup. Examples of ..alkylaminosulfonyl" are e.g. N,N-dimethylaminosulfonyl, N1N- methylethylaminosulfonyl or N.N-methylbutylaminosulfonyl.
..Alkylsulfonylamino" includes the group -NH-SO2-Alkyl, wherein alkyl is preferably selected from the groups specified in the definition of "alkyl" further above. Most preferably ..alkyl" in ..alkylsulfonylamino " is a C1-C6-alkylgroup, such as e.g. methanesulfonylamino. "Alkylcarbonyl" includes the group -C(O)-alkyl, wherein alkyl is preferably selected from the groups specified in the definition of "alkyl" further above. "Alkylcarbonyl" is particularly preferably -C(O)-CI -C6-Alkyl, and most preferably acetyl, propionyl oder butyryl. "Alkylaminocarbonyl" includes the groups -C(O)-NH-alkyl wherein "alkyl" is preferably selected from the groups specified in the definition of "alkyl" further above.
"Alkylaminocarbonyl" is particularly preferably -C(O)-NH-(CI -C6)Alkyl
"Dialkylaminocarbonyl" includes the group -CO-N-dialkyl, wherein "alkyl" is preferably selected from the groups specified in the definition of "alkyl" further above. "Dialkylaminocarbonyl" is particularly preferably -C(O)-N-di(C1-C6)alkyl "Alkyloxy" or "alkoxy" includes the group -OR wherein R is "alkyl" as defined further above. Particular alkyloxy groups include, by way of example, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, 1 ,2- dimethylbutoxy, and the like.
"Alkyloxyalkyloxy" refers to the group -OROR', wherein R and R' are the same or different "alkyl" groups as defined further above. "Alkyloxyalkyloxyalkyl" refers to the group -ROR1OR", wherein R, R' and R" are the same or different "alkyl" groups as defined further above.
"Alkyloxyalkyamino" refers to the group -NH(ROR'), wherein R and R' are the same or different "alkyl" groups as defined further above. "N-Alkyloxyalky-N-alkylamino" refers to the group -NR(R1OR"), wherein R, R1 and
R" are the same or different "alkyl" groups as defined further above.
"Alkyloxycarbonyl" refer to the radical -C(=0)-0-R, wherein R is an alkyl group as defined herein. Bevorzugt ist ..Alkyloxycarbonyl" eine (C1-C6- Alkyl)oxycarbonylgruppe. "Alkenyl" includes monovalent olefinically unsaturated hydrocarbyl groups being straight-chained or branched and having at least 1 double bond. "Alkenyl" has preferably 2-15 carbon atoms ("C2-C15 alkenyl"), more preferably 2-10 carbon atoms ("C2-C10 alkenyl"), even more preferably 2-8 carbon atoms ("C2-C8 alkenyl") or 2-6 carbon atoms ("C2-C6 alkenyl"), and in some instances even more preferably 2-5 carbon atoms ("C1-C5 alkenyl"), 2-4 carbon atoms ("C2-C4 alkenyl"), or only 2-3 carbon atoms ("C2-C3 alkenyl"). Particular alkenyl groups include ethenyl (- CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (C (CH3) =CH2), and the like. A preferred "alkenyl" group is ethenyl (vinyl).
"Alkynyl" includes acetylenically unsaturated hydrocarbyl groups being straight- chained or branched and having at least 1 triple bond. "Alkynyl" has preferably 2-15 carbon atoms ("C2-C15 alkynyl"), more preferably 2-10 carbon atoms ("C2-C10 alkynyl"), even more preferably 2-8 carbon atoms ("C2-C8 alkynyl") or 2-6 carbon atoms ("C2-C6 alkynyl"), and in some instances even more preferably 2-5 carbon atoms ("C1-C5 alkynyl"), 2-4 carbon atoms ("C2-C4 alkynyl"), or only 2-3 carbon atoms ("C2-C3 alkynyl"). A preferred alkynyl group is ethynyl (acetylenyl).
"Dialkylamino" includes the group -NR1R", wherein R1 and R" are alkyl group as defined herein.
"Amino" refers to the radical-NH2.
"Aryl" refers to an aromatic hydrocarbyl radical. Examples of "aryl" radicals are phenyl, naphthyl, indenyl, azulenyl, fluorine or anthracene, wherein phenyl is preferred.
"Carboxy" refers to the radical -C(=O)OH.
"Cycloalkyl" refers to cyclic saturated aliphatic hydrocarbyl groups. The numbers of C-atoms referenced in connection with a given cycloalkyl group corresponds to the number of ring forming carbon atoms, e.g. "C3-C6 cycloalkyl" refers to a cycloalkyl with between three and six ring-forming C atoms. Examples of "cycloalkyl" are C3-C8 cycloalkyls, C3-C7 cycloalkyls, or more specifically C3-C6 cycloalkyls such as e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc. If indicated, a
"cycloalkyl" group may be unsubstituted or substituted with e.g. hydroxyl, alkyloxy, halogen, phenyl, amino, a group NR7R8 or with one or more alkyl groups, e.g. with
C1-C6 alkyl groups, preferably with C1-C3 alkyl groups, particularly preferably with methyl groups. If a "cycloalkyl" carries more than one substituent, e.g. one or more alkyl substituent these substituents may be attached to the same or to different ring- forming carbon atoms. "Cycloalkyloxy" refers to the group -OR, wherein R is "cycloalkyl" group as defined further above.
"Cycloalkylamino" refers to the group -NHR, wherein R is "cycloalkyl" group as defined further above.
"N-Cycloalkylamino-N-alkylamino" refers to the group -NRR', wherein R is the same or different "alkyl" group as defined further above and R' is "cycloalkyl" group as defined further above.
"Cyano" refers to the radical -C≡N. "Formyl" refers to the group -C(=O)H "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo. Preferred halo groups are either fluoro or chloro.
"Haloalkyl" includes an "alkyl" group as defined further above which is substituted with one or more halogens which may be the same, e.g. in trifluoromethyl or pentafluoroethyl, or which may be different.
"Heteroaryl" refers to aromatic ring system containing at least one heteroatom such as O, S or N. Examples of heteroaryl radicals are furanyl, thienyl, pyrollyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzthiazolyl, purinyl, quinazolinyl, quinolinyl, isoquinolinyl, quinolizinyl, pteridinyl, carbazolyl, wherein one-ring sytems, and in particular pyridinyl, and imidazolyl are preferred.
"Heteroarylcarbonyl" refers to the group -CO-heteroaryl. "Hydroxy" refers to the radical -OH.
"Hydroxyalkyl" includes an "alkyl" group as defined further above which is substituted with one or more hydroxy groups. "Nitro" refers to the radical-NO2.
"Oxime" refers to the group -CH=N-OH.
..Phenyl" is the aromatic radical -C6H5. Whether a phenyl group is substituted with one or more substituents, is specified throughout this specification and the claims. ..Phenylalkyl" comprises the group -alkyl-phenyl, wherein ..phenyl" and ..alkyl" have the meaning as defined further above. Examples of phenylalkyl groups are phenylethyl and benzyl, wherein benzyl is a particularly preferred phenylalkyl group.
..Phenylalkyloxy" comprises the group -O-alkyl-phenyl, wherein ..phenyl" and ..alkyl" have the meaning as defined further above. Examples of phenylalkyloxy groups are phenylethyloxy and benzyloxy.
..Phenoxy" comprises the group-O-phenyl, wherein phenyl" has the meaning as defined further above
..Phenylcarbonyl" is -C(O)-phenyl, wherein phenyl" has the meaning as defined further above ..Phenylalkylcarbonyl" is -C(O)-alkyl-phenyl, wherein ..phenyl" and ..alkyl" have the meaning as defined further above
..Phenylalkyloxycarbonyl" is the group -C(O)-O-alkyl-phenyl, wherein ..phenyl" and ..alkyl" have the meaning as defined further above
..Phenylsulfonyl" is -SO2-phenyl, wherein phenyl" has the meaning as defined further above
..Sulfamoyl" includes the group -SO2-NH2.
..Sulfonylamino" includes the group -NH-SO2H.
"Trifluormethyl" refers to the group -CF3.
Unless expressly specified otherwise, any "alkyl", "alkenyl", "alkynyl", "phenyl", or
"heteroaryl" is meant to be unsubstituted. If any "alkyl", "alkenyl", "alkynyl", "phenyl", or "heteroaryl", is expressly stated to be substituted, this usually also refers to the respective "alkyl", "alkenyl", "alkynyl", "phenyl", or "heteroaryl" partial structures of more complex structures such as "alkyloxy", "alkylsulfonyl", "alkenyloxy", "phenoxy", "heteroaryloxy", etc.
"Pharmaceutically acceptable" means being approved by a regulatory agency of the Federal or a state government or being listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. "Pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4methylbicyclo [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, 2,2-dichloroacetate, adipate, alginate, ascorbate, aspartate, 2-acetamidobenzoate, caproate, caprate, camphorate, cyclamate, laurylsulfate, edisilate, esylate, isetionate, formate, galactarate, gentisate, gluceptate, glucuronate, oxoglutarate, hippurate, lactobionate, napadisilate, xinafoate, nicotinate, oleate, orotate, oxalate, palmitate, embonate, pidolate, p- aminosalicylate, sebacate, tannate, rhodanide, undecylenate, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced, such as e.g. ammonia, arginine, benethamine, benzathine, calcium, choline, deanol, diethanolamine, diethylammonium, ethanolamine, ethylendiamine, meglumine, hydrabamine, imidazole, lysine, magnesium, hydroxyethylmorpholine, piperazine, potassium, epolamine, sodium, trolamine, tromethamine or zinc.
"Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. "Preventing" or "prevention" refers to a reduction in risk of acquiring a disease or disorder (i. e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease). "Subject" includes humans. The terms "human," "patient" and "subject" are used interchangeably herein.
"Therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. "Treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i. e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e. g., stabilization of a discernible symptom), physiologically, (e. g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying or preventing the onset of the disease or disorder.
Modes for carrying out the invention:
1. Synthesis of heteroarene components according to formula Xl 1a) 5-Hydroxypyrazolo[1,5-a]pyridine (C4a), 4-hydroxypyrazolo[1,5-a]pyridine (C4b), 6- hydroxypyrazolo[1 ,5-a]pyridine (C4c), 7 '-hydroxy pyrazolo[1 ,5-a]pyridine (C4d), 5- hydroxymethylpyrazolo[1 , 5-a]pyridine (C4e)
Synthesis of the heteroarene components was accomplished when methoxypyridines (C1) were aminated with O-(2,4-dinitrophenyl)hydroxylamine to get the N-amino pyridinium salts (C2) which were cyclicyzed with methyl priolate to the methyl pyrazolopyridine carboxylates C3. Acidic hydrolysis and decarboxylation achieved the pyrazolopyridines C4.
Figure imgf000053_0001
C1a-d C2a-d C3a-d
Figure imgf000053_0002
N-Amino-(4-methoxy)pyridinium-2, 4-dinitrophenolate (C2a) A suspension of 1 1.4 ml (0.112 mol) 4-methoxypyridine and 24.6 g (0.124 mol) O-(2,4- dinitrophenyl)hydroxylamine in 371 ml dichloromethane was stirred for 20 hrs at room temperature. After addition of diethylether the precipitate was filtered off and dried in under reduced pressure. Yield: 34 g (99 %) yellow solid.
Mp.: 1400C. MS (El): m/z 184 (M+1)+ C6H3N2O5; 124 (M-I)+ C6H9N2O. IR (KBr) v (cnrV1): 3096; 1597; 1552; 1535; 1508; 1256; 739; 714. 1H NMR (DMSO-d6, 360 MHz) δ (ppm): 4.05 (s, 3H, OCH3); 6.36 (d, J = 9.8 Hz, 1 H, H-6 DNP); 7.52-7.54 (m, 2H, H-3/5 Pyr); 7.75 (br s, 2H, NH2); 7.81 (dd, J = 9.8 Hz, 3.2 Hz, 1H, H-5 DNP); 8.60 (d, J = 3.2 Hz, 1H, H-3 DNP); 8.65-8.67 (m, 2H, H-2/6 Pyr).
Methyl 5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (C3a)
To a mixture of 44.1 g (0.143 mol) aminopyridinium salt and 27.7 g (0.201 mol) K2CO3 in 310 ml dry DMF was added dropwise 12.6 ml (0.151 mol) methyl propiolate and stirred at room temperature for 16 hrs. The residue was filtered off and the filtrate was evaporated in vacuum. Then saturated NaHCO3 solution was added, extracted with dichloromethane and washed with 1 N HCI and H2O. Then, the organic layer was dried with MgSO4 and evaporated in vacuum. The crude product was purified by flash-chromatography (CH2CI2 and subsequently CH2CI2/Me0H 85:15). Yield: 13.8 g (51 %) yellow solid.
MS (El): m/z 206 (M)+. IR (NaCI) v (cm"1): 2952; 2840; 1699; 1649; 1538; 1280; 1217; 1052; 774. 1H NMR (CDCI3, 360 MHz) δ (ppm): 3.90 (s, 3H, COOCH3); 3.93 (s, 3H, OCH3); 6.62 (dd, J = 7.5 Hz, 2.8 Hz, 1 H, H-6); 7.42 (dd, J = 2.8 Hz, 0.7 Hz, 1H, H-4); 8.28 (s, 1 H, H-2); 8.32 (dd, J = 7.5 Hz, 0.7 Hz, 1H, H-7).
5-Hydroxypyrazolo[1 , 5-a]pyridine (C4a)
Methyl 5-methoxypyrazolo[1 ,5-a]pyridine-3-carboxylate (589 mg = 2.86 mmol) were treated with 9.5 ml hydrobromic acid (48%) and refluxed for 16 hrs. After cooling to room temperature the mixture was neutralized with 5N NaOH and extracted with diethylether. The organic layer was dried with MgSO4, evaporated and purified by flash- chromatography (hexane/EtOAc 1 :1).
Yield: 278 mg (73 %) light yellow solid.
Mp.: 216°C. MS (El): m/z 134 (M)+. IR (KBr) v (cm"1): 3139; 3094; 1649; 1521; 1188; 737;
715.1H NMR (DMSO-de, 360 MHz) δ (ppm): 6.23 (d, J = 1.8 Hz, 1H, H-3); 6.46 (dd, J = 7.4 Hz, 2.5 Hz, 1 H, H-6); 6.77 (d, J = 2.5 Hz, 1H, H-4); 7.79 (d, J = 1.8 Hz, 1H, H-2); 8.45 (d, J = 7.4 Hz, 1 H, H-7); 10.07 (s, 1 H, OH).
N-Amino-(3-methoxy)pyridinium-2, 4-dinitrophenolate (C2b) Synthesis worked according to the preparation of C2a when using 3-methoxypyridine. Yield: 9.2 g (85 %) yellow solid.
Mp.: 84°C. IR (KBr) v (cm 1): 3093; 1610; 1568; 1527; 1255; 748; 708. 1H NMR (DMSO-d6, 600 MHz) δ (ppm): 3.98 (s, 3H, OCH3); 6.60 (d, J = 9.6 Hz1 1H, H-6 DNP); 7.90-7.92 (m, 2H, H-2/4 Pyr); 7.94 (dd, J = 9.6 Hz, 3.2 Hz, 1H, H-5 DNP); 8.41 (td, J = 5.4 Hz1 1.5 Hz, 1 H, H-5 Pyr); 8.48 (br s, 2H1 NH2); 8.57-8.59 (m, 1 H, H-6 Pyr); 8.63 (d, J = 3.2 Hz1 1 H, H- 3 DNP).
Methyl 4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate, Methyl 6-methoxypyrazolo[1 ,5- a]pyridine-3-carboxylate (C3b) Synthesis worked according to the preparation of C3a when using N-amino-(3- methoxy)pyridinium-2,4-dinitrophenolate (C2b). Both isomers were separated by flash- chromatographie (CH2CI2 and subsequently CH2CI2/Me0H 85:15).
Methyl 4-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (C3b - isomere 1)
Yield: 5.96 g (51 %) orange solid. Mp.: 99°C. MS (El): m/z 206 (M)+. IR (NaCI) v (crτϊ1): 3113; 2950; 2844; 1717; 1556;
1520; 1285; 1211 ; 1057; 759. 1H NMR (CDCI3, 600 MHz) δ (ppm): 3.89 (s, 3H, COOCH3);
4.02 (S, 3H1 OCH3); 6.67 (d, J = 7.6 Hz, 1 H, H-5); 6.85 (dd. J = 7.6 Hz1 6.8 Hz, 1 H, H-6);
8.18 (d, J = 6.8 Hz1 1H1 H-7); 8.36 (s, 1H, H-2). 13C NMR (CDCI3, 360 MHz) δ (ppm): 51.5;
56.3; 104.3; 105.0 ; 113.5; 122.6; 134.1 ; 145.4; 152.0; 162.9.
Methyl 6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (C3b - isomere 2)
Yield: 1.57 g (13 %) orange solid.
Mp.: 154°C. MS(EI) m/z 206 (M+). IR (NaCI) v (cm"1): 3118; 2951 ; 2850; 1689; 1554;
1533; 1281 ; 1230; 1111 ; 744. 1H NMR (CDCI3, 600 MHz) δ (ppm): 3.87 (s, 3H, OCH3); 3.90 (S, 3H, COOCH3); 7.20 (dd, J = 9.6 Hz1 2.3 Hz1 1H1 H-5); 8.04 (d, J = 9.6 Hz, 1 H1 H-
4); 8.10 (d, J = 2.3 Hz, 1H, H-7); 8.31 (s, 1 H1 H-2). 13C NMR (CDCI3, 360 MHz) δ (ppm):
51.2; 56.2; 103.6; 111.8; 118.7; 122.2; 136.9; 144.1 ; 150.3; 163.8.
4-Hydroxypyrazolo[1 , 5-a]pyhdine (C4b) Synthesis worked according to the preparation of C4a when using methyl 4- methoxypyrazolo[1 ,5-a]pyridine-3-carboxylate (C3b - isomere 1). Yield: 2.6 g (72 %) yellow solid.
Mp.: 2000C. MS (APCI): m/z 135 (M+1)+. IR (KBr) v (crτϊ1): 3447; 3053; 1644; 1557; 1257; 1177; 740. 1H NMR (DMSOd6, 600 MHz) δ (ppm): 6.44 (d, J = 7.6 Hz, 1 H, H-5); 6.59- 6.60 (m, 1 H, H-3); 6.68 (dd, J = 7.6 Hz, 6.9 Hz1 1 H, H-6); 7.84 (d, J = 2.5 Hz, 1 H, H-2); 8.15 (d, J = 6.9 Hz, 1 H, H-7); 10.40 (s, 1H, OH).
6-Hydroxypyrazolo[1 , 5-a]pyhdine (C4c) Synthesis worked according to the preparation of C4a when using methyl 6- methoxypyrazolo[1 ,5-a]pyridine-3-carboxylate (C3b - isomere 2).
Yield: 760 mg (75 %) light violet solid.
Mp.: 117°C. MS (El): m/z 134 (M)+. IR (KBr) v (cm"1): 3278; 3028; 1645; 1520; 1254;
1138; 800. 1H NMR (DMSO-d6, 600 MHz) δ (ppm): 6.46 (d, J = 2.1 Hz, 1 H, H-3); 6.94 (dd, J = 9.5 Hz, 2.0 Hz, 1 H1 H-5); 7.53 (d, J = 9.5 Hz1 1H, H-4); 7.76 (d, J = 2.0 Hz, 1 H, H-7);
8.07-8.08 (m, 1 H1 H-2); 9.51 (s, 1 H, OH).
N-Amino-(2-methoxy)pyridinium-2, 4-dinitrophenolate (C2c)
Synthesis worked according to the preparation of C2a when using 2-methoxypyridine. Yield: 214 mg (13 %) yellow solid.
Mp.: 134°C. MS (El): m/z 184 (M+1)+ C6H3N2O5; 124 (M-I)+ C6H9N2O. IR (KBr) v (cm"1): 3284; 3099; 1603; 1558; 1522; 1132; 773. 1H NMR (DMSO-d6l 360 MHz) δ (ppm): 4.26 (s, 3H, OCH3); 6.32 (d, J = 9.8 Hz, 1H1 H-6 DNP); 7.50 (ddd, J = 7.8 Hz1 6.5 Hz, 1.3 Hz, 1H, H-5 Pyr); 7.69 (br s, 2H, NH2); 7.72 (dd, J = 8.8 Hz, 1.3 Hz, 1H1 H-3 Pyr); 7.78 (dd, J = 9.8 Hz1 3.2 Hz1 1 H1 H-5 DNP); 8.27 (ddd, J = 8.8 Hz1 7.8 Hz1 1.6 Hz1 1 H, H-4 Pyr); 8.55 (dd, J
= 6.5 Hz, 1.6 Hz1 1 H, H-6 Pyr); 8.59 (d, J = 3.2 Hz, 1 H1 H-3 DNP).
Methyl 7-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (C3c)
Synthesis worked according to the preparation of C3a when using N-amino-(2- methoxy)pyridinium-2,4-dinitrophenolate (C2c).
Yield: 640 mg (39 %) light yellow solid.
Mp.: 135°C. MS(EI) m/z 206 (M+). IR (NaCI) v (cm"1): 3099; 2953; 2850; 1701 ; 1637; 1533; 1246; 1043; 785. 1H NMR (CDCI3, 600 MHz) δ (ppm): 3.91 (s, 3H, COOCH3); 4.18 (S, 3H1 OCH3); 6.29 (dd, J = 7.8 Hz1 0.8 Hz1 1 H, H-6); 7.42 (dd, J = 8.7 Hz, 7.8 Hz1 1 H1 H- 5); 7.81 (dd, J = 8.7 Hz, 0.8 Hz, 1H, H-4); 8.44 (s, 1H1 H-2). 13C NMR (CDCI3, 600 MHz) δ (ppm): 51.2; 57.0; 91.0; 103.6; 110.7; 129.1 ; 142.6; 145.0; 151.5; 164.0.
7-Hydroxypyrazolo[1 , 5-a]pyridine (C4d) Synthesis worked according to the preparation of C4a when using methyl 7- methoxypyrazolo[1 ,5-a]pyridine-3-carboxylate (C3c). Yield: 499 mg (57 %) blue solid.
Mp.: 133°C. MS (APCI): m/z 135 (M+1)+. IR (KBr) v (cπT1): 3435; 3084; 1635; 1512; 1088; 770. 1H NMR (DMSO-d6, 600 MHz; 323K) δ (ppm): 5.99 (br d, J = 6.1 Hz, 1 H, H-6); 6.45- 6.46 (m, 1 H, H-3); 6.94 (br d, J = 8.1 Hz, 1 H, H-4); 7.09 (dd, J = 8.1 Hz, 6.1 Hz, 1 H, H-5); 7.91-7.92 (m, 1 H, H-2).
N-Amino-(4-hydroxymethyl)pyridinium-2,4-dinitrophenolate (C2d)
Synthesis worked according to the preparation of C2a when using A- hydroxymethylypyridine.
Yield: 3.3 g (86 %) yellow solid.
Mp.: 11O0C. MS (El): m/z 184 (M+1)+ C6H3N2O5; 124 (M-I)+ C6H9N2O. 1H NMR (DMSO-d6,
600 MHz) δ (ppm): 4.73 (s, 3H, CH2OH); 6.35 (d, J = 9.7 Hz, 1 H, H-6 DNP); 7.80 (dd, J = 9.7 Hz, 3.1 Hz, 1 H, H-5 DNP); 7.89-7.91 (m, 2H, H-3/5 Pyr); 8.28 (br s, 2H, NH2); 8.59 (d,
J = 3.1 Hz, 1 H, H-3 DNP); 8.70-8.71 (m, 2H, H-2/6 Pyr).
Methyl 5-hydroxymethylpyrazolo[1 , 5-a]pyridine-3-carboxylate (C3d) Synthesis worked according to the preparation of C3a when using N-amino-(4- hydroxymethyl)pyridinium-2,4-dinitrophenolate (C3c). Yield: 468 mg (32 %) beige solid.
Mp.: 1050C. MS (APCI): m/z 207 (M+1)+. 1H NMR (CDCI3, 600 MHz) δ (ppm): 3.90 (s, 3H, COOCH3); 4.79 (s, 2H, CH2OH); 6.96 (dd, J = 7.1 Hz, 1.7 Hz, 1 H, H-6); 8.06-8.07 (m, 1 H, H-4); 8.35 (s, 1 H, H-2); 8.44 (d, J = 7.1 Hz1 1 H, H-7).
5-Hydroxymethylpyrazolo[1 , 5-aJpyridine (C4e)
A mixture of 402 mg (1.95 mmol) methyl 5-hydroxymethylpyrazolo[1,5-a]pyridine-3- carboxylate (C3d) and 13.6 ml sulphuric acid (40%) was refluxed for 3 hrs and neutralized with 5N NaOH solution after cooling to room temperature. The solution was extracted with dichloromethane, the organic layers were dried with Na2SO4, evaporated and purified by flash-chromatography (EtOAc).
Yield: 289 mg (60 %) yellow solid.
Mp.: 470C. MS (El): m/z 148 (M)+. IR (NaCI) v (cnT1): 3335; 2849; 1648; 1439; 1339;
1054; 774. 1H NMR (CDCI3, 360 MHz) δ (ppm): 2.12 (br s, 1 H1 OH); 4.70 (s, 2H, CH2);
6.46 (dd, J = 2.2 Hz1 0.8 Hz1 1 H1 H-3); 6.71 (dd, J = 7.2 Hz1 1.7 Hz, 1 H, H-6); 7.48 (dd, J =
1.7 Hz1 0.8 Hz, 1 H1 H-4); 7.92 (d, J = 2.2 Hz1 1H1 H-2); 8.40 (d, J = 7.2 Hz, 1 H1 H-7).
1b) 2-Hydroxypyrazolo[1,5-a]pyridine (C4f)
The synthesis of 2-hydroxypyrazolo[1 ,5-a]pyridine was done according to literature (Ochi, M.; Miyasaka, T.; Kanada, K.; Arakawa, K. Bull. Chem. Soc. Japan, (1976), 49, 1980- 1984).
Figure imgf000058_0001
A solution of 4.14 g (36.6 mmol) hydroxylamine-O-sulfonic acid in 13.8 ml water was neutralized with KOH (2.6 N) at O0C and added dropwise to 26.2 ml (0.172 mol) ethyl 2- pyridylacetate. After stirring for 30 h at room temperature the mixture was extracted with dichloromethane, the aqueous layer was adjusted to pH 9 with Na2CO3 solution (10%) and extracted with dichloromethane. Then, the aqueous layer was adjusted to pH 5 with acetic acid, extracted with dichloromethane, the organic layer was dried with MgSO4 and evaporated. The crude product was purified by flash-chromatography (hexane/EtOAc 90:10).
Yield: 607 mg (39 %) white solid.
Mp.: 127-128°C. MS (APCI): m/z 135 (M+1)+. 1H NMR (DMSO-d6, 360 MHz) δ (ppm): 5.72 (d, J = 0.8 Hz, 1 H, H-3); 6.63 (ddd, J = 6.8 Hz, 6.8 Hz1 1.4 Hz1 1 H, H-6); 7.08 (ddd, J = 8.9 Hz, 6.8 Hz, 1.1 Hz, 1 H, H-5); 7.35 (ddd, J = 8.9 Hz, 1.4 Hz1 0.8 Hz1 1 H1 H-4); 8.32 (dd, J = 6.8 Hz, 1.1 Hz, 1 H, H-7); 10.40 (s, 1 H, OH).
1c) 1 -(5-Hydroxypyrazolo[1 ,5-a]pyridine-3-yl)ethanone (C4g), methyl 5- hydroxypyrazolo[1 , 5-a]pyridine-3-carboxylate (C4h) The synthesis of the 3-substituted 5-hydroxypyrazolo[1,5-a]pyridine derivatives C4g-h was achieved by cycloaddition reaction of O-protected 4-hydroxy-Λ/-aminopyridines with 3- butyn-2-one to get the acetyl substituted derivative C5a or with methyl propiolate to obtain the methyloxycarbonyl analogue C5b. Subsequent deprotection yielded the pyrazolo[1 ,5- a]pyridines C4g-h.
Figure imgf000059_0001
C1f C5a-b
Figure imgf000059_0002
C4g-h
1-(5-Benzyloxypyrazolo[1, 5-a]pyridine-3-yl)ethanone (C5a)
For the synthesis 1.5 g (1.92 mmol / 28 % content) hydroxylamine-O-mesitylene sulfonic acid in 3 ml dichloromethane were dried over Na2SO4. This solution was added dropwise to a solution of 355 mg (1.92 mmol) 4-benzyloxypyridine in 3 ml dichloromethane and the mixture was stirred for 1 h at O0C and for 1 h at room temperature. After addition of diethylether an oil was formed, which was washing with diethylether and dried at the rotavapor. To the residue was added 15 ml DMF, 250 mg (1.81 mmol) K2CO3 and 0.18 ml (2.24 mmol) 3-butyn-2-one, the mixture was stirred for 18 h at room temperature and filtered over celite, evaporated and extracted with dichloromethan after addition of saturated NaHCO3-solution. The organic layer was washed with 1 N HCI and water, dried with MgSO4, evaporated and purified by flash-chromatography (hexane/EtOAc 4:1). Yield: 225 mg (49 %) beige solid. Mp.:158°C. MS (El): m/z 266 (M)+. IR (NaCI) v (cπT1): 3099; 2922; 1655; 1525; 1275;
1217; 744. 1H NMR (CDCI3, 360 MHz) δ (ppm): 2.52 (s, 3H, COCH3); 5.18 (s, 2H, CH2); 6.73 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 7.36-7.49 (m, 5H, Phenyl); 7.82 (d, J = 2.6 Hz, 1 H1 H-4); 8.24 (s, 1 H, H-2); 8.35 (d, J = 7.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 27.8; 70.9; 98.5; 109.1 ; 112.5; 127.9; 128.6; 128.8; 129.9; 135.3; 142.0; 145.6; 159.7; 191.7. 1-(5-Hydroxypyrazolo[1 , 5-a]pyridine-3-yl)ethanone (C4g)
A suspension of 50 mg (0.11 mmol) 1-(5-benzyloxypyrazolo[1 ,5-a]pyridine-3-yl)ethanone (C5a) and 5 mg Pd/C (10%) in 3 ml ethanol were stirred for four days under H2- atmosphere at room temperature. Then the mixture was filtered over celite, evaporated and purified by flash-chromatography (CH2CI2/Me0H 95:5). Yield: 26 mg (79 %) beige solid.
Mp.:210°C. MS (El): m/z 176 (M)+. IR (NaCI) v (cm 1): 3456; 3089; 2885; 1649; 1599; 1525; 1269; 1225. 1H NMR (CDCI3, 360 MHz) δ (ppm): 2.59 (s, 3H, COCH3); 6.77 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 8.27 (s, 1 H, H-2); 8.38 (d, J = 2.6 Hz, 1H, H-4); 8.40 (d, J = 7.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 27.9; 100.1 ; 109.5; 1 10.9; 131.2; 142.3; 146.3; 161.2; 190.5.
Methyl 5-benzyloxypyrazolo[1,5-a]pyridine-3-carboxylate (C5b) Synthesis worked according to the preparation of C5a and as described in literature
(Eisner, J.; Boeckler, F.; Heinemann, F.W.; Hϋbner, H.; Gmeiner, P. J. Med. Chem.
(2005), 48, 5771-5779) when using methyl propiolate.
Yield: 2.5 g (23 %) yellow solid.
MS (APCI): m/z 283 (M+1)+. 1H NMR (CDCI3, 600 MHz) δ (ppm): 3.89 (s, 3H, COOCH3); 5.17 (s, 2H, CH2); 6.68 (dd, J = 7.6 Hz1 2.6 Hz, 1H, H-6); 7.36-7.48 (m, 5H, Phenyl); 7.53
(d, J = 2.6 Hz, 1 H, H-4); 8.28 (s, 1 H, H-2); 8.33 (d, J = 7.6 Hz1 1 H, H-7).
Methyl 5-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate (C4h)
A suspension of 30 mg (0.11 mmol) methyl 5-benzyloxypyrazolo[1 ,5-a]pyridine-3- carboxylate (C5b) and 8 mg Pd/C (10%) in 5 ml ethanol were stirred over night under H2- atmosphere at room temperature. Then, the mixture was filtered over celite, evaporated and purified by flash-chromatography (hexane/EtOAc 1 :1).
Yield: 16 mg (76 %) white solid.
Mp.: 264°C. MS (APCI): m/z 193 (M+1 )+. IR (KBr) v (cm 1): 3435; 3057; 2949; 1699; 1647; 1541 ; 1277; 1248; 1045. 1H NMR (DMSO-d6l 600 MHz) δ (ppm): 3.79 (s, 3H1 COOCH3);
6.70 (dd, J = 7.6 Hz, 2.6 Hz, 1 H1 H-6); 7.29 (d, J = 2.6 Hz1 1 H1 H-4); 8.27 (s, 1 H1 H-2);
8.67 (d, J = 7.6 Hz1 1 H1 H-7); 10.92 (s, 1 H1 OH). 13C NMR (DMSO-d6, 360 MHz) δ (ppm):
51.3; 99.2; 100.7; 108.7; 131.9; 143.0; 145.5; 158.8; 163.7.
1c) 7-Hydroxytetrazolo[1,5-a]pyridine (C4\) The synthesis of 7-hydroxytetrazolo[1 ,5-a]pyridine was achieved according to literature (Keith, J. M. J. Org. Chem. (2006), 71, 9540-9543) by reacting a protected hydroxypyridine and an activated azide derivative as follows:
Figure imgf000061_0001
C1f C5c
Figure imgf000061_0002
C4i
7-Benzyloxytetrazolo[1 , 5-a]pyridine (C5c)
A mixture consisting of 1.0 g (4.98 mol) 4-benzyloxypyridine-N-oxide (C1f), 2.15 ml (9.95 mol) diphenylphosphorylazide and 0.8 ml (9.95 mol) pyridine was refluxed for 24 hrs and passed through a silica gel column (CH2CI2). After recrystallization with ethyl acetate, the product was filtered off, washed with hexane and dried in vacuum.
Yield: 234 mg (21 %) crystalline white solid.
Mp.:173°C. MS (El) m/z 226 (M)+. IR (NaCI) v (cm"1): 3053; 2926; 1643; 1545; 1213; 804.
1H NMR (CDCI3, 600 MHz) δ (ppm): 5.21 (s, 2H, OCH3); 6.94 (dd, J = 7.5 Hz, 2.2 Hz, 1H, H-6); 7.24 (d, J = 2.2Hz, 1 H1 H-8); 7.36-7.46 (m, 5H, Phenyl); 8.63 (d, J = 7.5 Hz, 1 H1 H-5).
13C NMR (CDCI3, 600 MHz) δ (ppm): 71.4; 93.1 ; 112.2; 125.5; 127.8; 128.9; 129.0; 134.4;
150.3; 161.2.
7-Hydroxytetrazolo[1 , 5-a]pyridine (C4i) The solution of 50 mg (0.22 mmol) 7-benzyloxytetrazolo[1 ,5-a]pyridine (C5c) in 5 ml dichloromethane were treated with 0.44 ml (0.44 mmol) boron tribromide (1M solution in dichloromethane) and stirred for 4 hs at room temperature. After addition of 2 ml ethanol, stirring was continued for further 30 minutes at room temperature. Then the solvent was evaporated and the residue purified by flash-chromatography (EtOAc). Yield: 30 mg (99 %) beige solid. Mp.:67°C. MS (El) m/z 136 (M)+. IR (KBr) v (cm 1): 3433; 3047; 1647; 1207; 825. 1H NMR (DMSO-d6l 600 MHz) δ (ppm): 7.00 (dd, J = 7.3 Hz, 1.9 Hz, 1 H1 H-6); 7.15 (d, J = 1.9 Hz, 1 H, H-8); 9.10 (d, J = 7.3 Hz, 1H, H-5); 11.52 (br s, 1 H, OH). 13C NMR (CD3OD, 600 MHz) δ (ppm): 95.4; 114.1; 128.7; 152.6; 164.2.
2. Synthesis of the heteroarene components according to formula XiII
5-(4-Bromobutoxy)pyrazolo[1 , 5-a]pyridine (C6a), 2-(4-bromobutoxy)pyrazolo[1 , 5- ajpyridine (C6b), 4-(4-bromobutoxy)pyrazolo[1,5-a]pyridine (C6c), 6-(4- bromobutoxy)pyrazolo[1,5-a]pyridine (C6d), 7-(4-bromobutoxy)pyrazolo[1 ,5- ajpyridine (C6e), 5-(3-Bromopropoxymethyl)pyrazolo[1,5-a]pyridine (C6f), 1-[5-(4- brombutoxy)pyrazolo[1,5-a]pyridine-3-yl]ethanone (C6g), methyl 5-(4- bromobutoxy)pyrazolo[1,5-a]pyridine-3-carboxylate (C6h), 7-(4- bromobutoxy)tetrazolo[1 , 5-a]pyridine (C6i)
The synthesis of the components according to formula XIII were done by alkylation of the functional group in formula Xl with dibromoalkylidene derivatives of different length to get the compounds C6.
Figure imgf000062_0001
formula Xl
5-(4-Bromobutoxy)pyrazolo[1 , 5-a]pyridine (C6a)
To a mixture of 1.19 g (8.88 mmol) 5-hydroxypyrazolo[1 ,5-a]pyridine (C4a), 1.23 g (8.89 mmol) potassium carbonate and 44.1 ml of dry dimethylformamide was added dropwise 3.18 ml (26.67 mmol) 1 ,4-dibromobutane. The suspension was heated to 6O0C for 8 hrs. After adding water the solution was extracted with ethylacetate. The organic layer was dried with Na2SO4, evaporated and purified by flash-chromatography (hexane/EtOAc
20:30).
Yield: 1.7 g (71 %) orange oil.
MS (El): m/z 270 (M+1)+, 268 (M-I)+. IR (NaCI) v (cm"1): 3097; 2945; 2874; 1648; 1537; 1290; 1227; 1040; 746.1H NMR (CDCI3, 360 MHz) δ (ppm): 1.95-2.02 (m, 2H, OCH2CH2);
2.04-2.12 (m, 2H, CH2CH2Br); 3.50 (t, J = 6.5 Hz, 2H, CH2Br); 4.02 (t, J = 6.5 Hz, 2H, OCH2); 6.30-6.31 (m, 1 H, H-3); 6.43 (dd, J = 7.8 Hz, 2.6 Hz, 1 H, H-6); 6.72 (d, J = 2.6 Hz, 1H, H-4); 7.85 (d, J = 2.1 Hz1 1 H, H-2); 8.28 (d, J = 7.8 Hz1 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 27.6; 29.4; 33.2; 67.2; 95.4; 95.5; 106.6; 129.4; 141.0; 142.8; 155.5. C H N (%): C11H13N2OBr; calculated: C 49.09; H 4.87; N 10.41 ; found: C 48.94; H 4.78; N 10.23.
2-(4-Bromobutoxy)pyrazolo[1 , 5-a]pyridine (C6b)
Synthesis worked according to the preparation of C6a when using 2-hydroxypyrazolo[1 ,5- a]pyridine (C4f). Yield: 1.04 g (85 %) light yellow oil.
MS (El): m/z 270 (M+1)+, 268 (M-I)+. IR (NaCI) v (cnT1): 3089; 2949; 2858; 1635; 1531 ;
1257; 1149; 754. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.94-2.02 (m, 2H, OCH2CH2); 2.05-
2.13 (m, 2H, CH2CH2Br); 3.50 (t, J = 6.6 Hz, 2H, CH2Br); 4.29 (t, J = 6.1 Hz, 2H, OCH2);
5.82 (d, J = 0.8 Hz, 1 H, H-3); 6.59 (ddd, J = 7.0 Hz, 7.0 Hz, 1 ,3 Hz, 1 H, H-6); 7.04 (ddd, J = 8.9 Hz, 7.0 Hz, 1.1 Hz, 1 H, H-5); 7.29 (ddd, J = 8.9 Hz, 1.3 Hz, 0.8 Hz, 1H, H-4); 8.21
(dd, J = 7.0 Hz, 1.1 Hz, 1H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 28.0; 29.4; 33.5 ;
68.3; 79.8; 109.8; 116.4; 124.0; 128.3; 141.7; 165.6.
4-(4-Bromobutoxy)pyrazolo[1 , 5-a]pyridine (C6c) Synthesis worked according to the preparation of C6a when using 4-hydroxypyrazolo[1 ,5- ajpyridine (C4b).
Yield: 3.21 g (66 %) light green solid.
Mp.: 400C. MS (APCI): m/z 271 (M+2)\ 268 (M)+. IR (NaCI) v (cm1): 3109; 2952; 2873;
1548; 1279; 1241; 1094; 748.1H NMR (CDCI3, 360 MHz) δ (ppm): 2.01-2.16 (m, 4H, CH2CH2CH2CH2); 3.52 (t, J = 6.4 Hz, 2H, CH2Br); 4.13 (t, J = 5.7 Hz, 2H, OCH2); 6.34 (d,
J = 7.6 Hz, 1H, H-5); 6.61-6.65 (m, 2H, H-3, H-6); 7.87 (d, J = 2.4 Hz, 1H, H-2); 8.13 (d, J
= 6.9 Hz, 1H, H-7).13C NMR (CDCI3, 360 MHz) δ (ppm): 27.6; 29.5; 33.3; 67.4; 95.3; 99.8;
111.4; 121.9; 135.3; 140.8; 150.3.
C H N (0Zo^C11H13N2OBr; calculated: C 49.09; H 4.87; N 10.41 ; found: C 48.90; H 5.05; N 10.33.
6-(4-Bromobutoxy)pyrazolo[1 , 5-a]pyridine (C6d)
Synthesis worked according to the preparation of C6a when using 6-hydroxypyrazolo[1 ,5- a]pyridine (C4c). Yield: 153 mg (70 %) beige solid. Mp.: 55°C. MS (El): m/z 270 (M+1)\ 268 (M-I)+. IR (NaCI) v (cπT1): 3105; 2943; 2873;
1642; 1525; 1291; 1239; 1199; 1025; 756.1H NMR (CDCI3, 600 MHz) δ (ppm): 1.96-2.01
(m, 2H, OCH2CH2); 2.07-2.11 (m, 2H1 CH2CH2Br); 3.50 (t, J = 6.6 Hz, 2H1 CH2Br); 3.99 (t,
J = 5.9 Hz, 2H, OCH2); 6.45 (d, J = 2.1 Hz, 1H, H-3); 6.91 (dd, J = 9.5 Hz, 2.2 Hz, 1H, H- 5); 7.41 (d, J = 9.5 Hz, 1H, H-4); 7.84 (d, J = 2.2 Hz, 1H, H-7); 8.05-8.06 (m, 1H, H-2).13C
NMR (CDCI3, 600 MHz) δ (ppm): 27.8; 29.4; 33.3; 68.0; 96.8; 111.8; 117.9; 119.0; 136.5;
140.8; 148.2.
C H N (0Z0)IC11H13N2OBr; calculated: C 49.09; H 4.87; N 10.41; found: C 49.26; H 4.84; N
10.44.
7-(4-Bromobutoxy)pyrazolo[1 , 5-a]pyridine (C6e)
Synthesis worked according to the preparation of C6a when using 7-hydroxypyrazolo[1 ,5- a]pyridine (C4d).
Yield: 364 mg (31 %) white solid. Mp.: 66°C. MS (APCI): m/z 271 (M+2)+, 269 (M)+. IR (NaCI) v (cm"1): 3099; 2953; 1633;
1547; 1103; 773. 1H NMR (CDCI3, 360 MHz) δ (ppm): 2.13-2.17 (m, 4H,
OCH2CH2CH2CH2Br); 3.49-3.52 (m, 2H, CH2Br); 4.30-4.33 (m, 2H, OCH2); 6.05 (dd, J =
7.3 Hz, 1.1 Hz, 1 H, H-6); 6.50 (d, J = 2.3 Hz, 1 H, H-3); 7.07 (dd, J = 8.8 Hz, 7.3 Hz, 1 H,
H-5); 7.18 (dd, J = 8.8 Hz, 1.1 Hz, 1H, H-4); 7.99 (d, J = 2.3 Hz, 1H, H-2). 13C NMR (CDCI3, 360 MHz) δ (ppm): 27.5; 29.2; 33.2; 68.8; 89.2; 96.9; 110.1 ; 124.5; 142.1 ; 150.5.
5-(3-Bromopropoxymethyl)pyrazolo[1, 5-a]pyridine (C6f)
To a solution of 290 mg (7.25 mmol) NaOH in 0.60 ml water 173 mg (1.17 mmol) 5- hydroxymethylpyrazolo[1 ,5-a]pyridine (C4e), 0.75 ml (7.31 mmol) 1,3-dibromopropane and 23.8 mg (0.07 mmol) tetrabutylammonium hydrogensulfate was added. After stirring over night at room temperature, water was added and the mixture was extracted with hexane. The organic layer was washed with brine, dried with Na2SO4, evaporated and purified by preparative HPLC (RP-18; H2O with 0.1 % TFA 100% to MeCN 100%). Yield: 88 mg (28 %) light yellow oil. MS (El): m/z 270 (M+1)\ 268 (M-I)+. IR (NaCI) v (crτV1): 3088; 2962; 2858; 1645; 1516; 1257; 1101 ; 783. 1H NMR (CDCI3, 600 MHz) δ (ppm): 2.14-2.18 (m, 2H, CH2CH2Br); 3.56 (t, J = 5.8 Hz, 2H, CH2Br); 3.65 (t, J = 6.4 Hz, 2H, OCH2CH2); 4.53 (s, 2H, CH2O); 6.48 (d, J = 2.0 Hz, 1 H, H-3); 6.72 (dd, J = 7.2 Hz, 1.5 Hz, 1 H1 H-6); 7.47-7.48 (m, 1 H, H-4); 7.94 (d, J = 2.0 Hz, 1 H, H-2); 8.43 (d, J = 7.2 Hz, 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 30.4; 32.8; 68.0; 72.0; 96.8; 111.4; 115.7; 128.6; 134.2; 139.9; 142.3. 1 -[5-(4-Brombutoxy)pyrazolo[1 ,5-a]pyridine-3-yl]ethanone (C6g) Synthesis worked according to the preparation of C6a when using 1-(5- hydroxypyrazolo[1 ,5-a]pyridine-3-yl)ethanone (C4g). Yield: 58 mg (78 %) light yellow solid.
Mp.:62°C. MS (El): m/z 312 (M+1)\ 310 (M-I)+. IR (NaCI) v (cσT1): 3109; 2933; 2875; 1654; 1633; 1524; 1277; 1217; 795. 1H NMR (CDCI3, 600 MHz) δ (ppm): 2.00-2.04 (m, 2H, OCH2CH2); 2.07-2.11 (m, 2H, CH2CH2Br); 2.52 (s, 3H1 COCH3); 3.50 (t, J = 6.4 Hz, 2H, CH2Br); 4.14 (t, J = 6.0 Hz, 2H, OCH2); 6.66 (dd, J = 7.6 Hz, 2.6 Hz1 1 H1 H-6); 7.67 (d, J = 2.6 Hz, 1 H, H-4); 8.24 (s, 1 H1 H-2); 8.34 (d, J = 7.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 600
MHz) δ (ppm): 27.5; 27.8; 29.4; 33.1 ; 67.9; 98.0; 109.0; 112.4; 129.9; 142.0; 145.7; 159.9; 191.8.
Methyl 5-(4-bromobutoxy)pyrazolo[1 , 5-a]pyridine-3-carboxylate (C6h) Synthesis worked according to the preparation of C6a when using methyl 5- hydroxypyrazolo[1 ,5-a]pyridine-3-carboxylate (C4h). Yield: 200 mg (59 %) light yellow solid.
Mp.: 84°C. MS (El): m/z 328 (M+1)+, 326 (M-I)+. IR (NaCI) v (ctτT1): 3107; 2947; 1699; 1647; 1539; 1277; 1213; 1049; 773. 1H NMR (CDCI3, 600 MHz) δ (ppm): 2.00-2.05 (m, 2H, OCH2CH2); 2.07-2.11 (m, 2H, CH2CH2Br); 3.50 (t, J = 6.4 Hz, 2H, CH2Br); 3.89 (s, 3H,
COOCH3); 4.13 (t, J = 6.1 Hz, 2H, OCH2); 6.61 (dd, J = 7.5 Hz, 2.6 Hz, 1 H, H-6); 7.40 (d, J = 2.6 Hz, 1H1 H-4); 8.28 (s, 1H, H-2); 8.33 (d, J = 7.5 Hz, 1H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 27.5; 29.4; 33.1; 51.1 ; 67.8; 96.9; 102.4; 108.3; 130.1; 142.8; 145.3; 158.8; 164.1.
7-(4-Bromobutoxy)tetrazolo[1 , 5-a]pyridine (C6i)
Synthesis worked according to the preparation of C6a when using methyl 7- hydroxytetrazolo[1 ,2-a]pyridine (C4i).
Yield: 17 mg (36 %) beige solid. Mp.:77°C. MS (APCI) m/z 273 (M+2)\ 271 (M)+. IR (NaCI) v (cm"1): 3062; 2943; 1647;
1547; 1211 ; 1014; 818. 1H NMR (CDCI3, 600 MHz) δ (ppm): 2.04-2.13 (m, 4H, CH2CH2CH2Br); 3.51 (t, J = 6.5 Hz1 2H1 CH2Br); 4.16 (t, J = 5.9 Hz1 2H, OCH2); 6.87 (dd, J = 7.5 Hz, 2.3 Hz, 1 H, H-6); 7.15 (d, J = 2.3 Hz, 1 H, H-8); 8.62 (d, J = 7.5 Hz, 1 H, H-5). 13C NMR (CDCI3, 600 MHz) δ (ppm): 27.3; 29.2; 32.9; 68.5; 92.3; 112.1 ; 125.5; 150.5; 161.5. 3. Phenylpiperazine derivatives according to formula XIV
1-(2,3-Dichlorophenyl)piperazine (C7a), 1-(2-methoxyphenyl)piperazine (C7b), 1-(2- chlorophenyl)piperazine (C7c), 1-(4-methoxyphenyl)piperazine (C7Xd), 1-(4- chlorophenyl)piperazine (C7e), 1-(4-hydroxyphenyl)piperazine (C7f), 1-(3-
Nitrophenyl)piperazine (C7h),
Figure imgf000066_0001
C7a-f
Derivatives according to formula C7a-f were purchased: 1-(2, 3-Dichlorophenyl)piperazine (C7a) from Alfa Aesar, Karlsruhe (Germany) (R2, R3 = Cl, R4-R6 = H - [Order number: L18697]
1-(2-Methoxyphenyl)piperazine (C7b) from Acros Organics Janssen, Gee/ (Belgium) (R2 = OMe, R3-R6 = H - [Order number:
232872500] 1-(2-chlorophenyl)piperazine (C7c) from Sigma- Aldrich, Taufkirchen (Germany) (R2 = Cl, R3-R6 = H - [Order number:
C67605])
1-(4-Methoxyphenyl)piperazine (C7d) from Aesar, Karlsruhe (Germany) (R4=0Me, R2-R3 and R5-R6=H - [Order number: 2007])
1 -(4-chlorophenyl)piperazine (C7e) from Acros Organics Janssen, Gee/ (Belgium) (R4 = Cl, R2-R3 and R5-R6 = H - [Order number: 10992];
1-(4-hydroxyphenyl)piperazine (C7f) from Acros Organics Janssen, Gee/ (Belgium) (R4 = OH, R2-R3 and R5-R6 = H - [Order number: 1003300502])
1-(3-Nitrophenyl)piperazine (C7h) from ChemPur, Karlsruhe (Germany) (R3 = NO2; R2, R4-R6 = H - [Order number: fl19978]) 4. Synthesis of Example compounds according to formula XV
Example E15:
5-[4-[4-(2, 3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine
The synthesis of 5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine (E15) was started by reacting 455 mg (1.69 mmol) 5-(4-bromobutoxy)pyrazolo[1 ,5- ajpyridine (C6a) with 381 mg (2.54 mmol) in sodium iodide in 7.6 ml acetonitrile and refluxing for 30 minutes at 950C. Then, 430 mg (1.86 mmol) 1-(2,3-dichlorophenyl)- piperazine (C7a) in 0.26 ml (1.86 mmol) triethylamine was added and heated for futher 5 hrs at 850C. The mixture was cooled down, mixed with NaHCO3-solution and extracted with dichloromethane. The organic layer was dried with Na2SO4, evaporated and purified by flash-chromatography (CH2CI2/Me0H 98:2). Yield: 545 mg (77 %) beige solid. Mp.: 1050C. MS (APCI): m/z 421 (M+2)\ 419 (M)+. IR (NaCI) v (cnT1): 2944; 2817; 1647; 1578; 1290; 1227; 1190; 1044; 774. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.69-1.77 (m, 2H, CH2CH2N); 1.84-1.92 (m, 2H, OCH2CH2); 2.50 (t, J = 7.2 Hz, 2H, CH2N); 2.65-2.67 (m, 4H, Piperazine); 3.06-3.09 (m, 4H, Piperazine); 4.02 (t, J = 6.5 Hz, 2H, OCH2); 6.29-6.30 (m, 1 H, H-3); 6.44 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.73 (d, J = 2.6 Hz, 1 H, H-4); 6.95 (dd, J = 6.7 Hz, 2.9 Hz, 1 H, Phenyl H6); 7.13-7.15 (m, 2H, Phenyl H4, Phenyl H5); 7.85 (d, J = 2.1 Hz, 1 H, H-2); 8.28 (d, J = 7.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.4; 27.0; 51.4; 53.3; 58.2; 68.0; 95.3; 95.4; 106.8; 118.6; 124.6; 127.5; 127.6; 129.4; 134.1 ; 141.1; 142.8; 151.3; 155.7. C H N (%):C21H24N4OCI2; calculated.: C 60.15; H 5.77; N 13.36; found.: C 59.79; H 5.81 ; N 13.14.
Example E16:
5-[4-[4-(2- Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(2-methoxyphenyl)piperazine (C7b).
Yield: 246 mg (89 %) beige solid.
Mp.: 1210C. MS (El): m/z 380 (M)+. IR (NaCI) v (cm1): 3098; 2942; 2815; 1648; 1500;
1291; 1241; 1228; 1190; 748.1H NMR (CDCI3, 600 MHz) δ (ppm): 1.71-1.76 (m, 2H, CH2CH2N); 1.85-1.90 (m, 2H, OCH2CH2); 2.49 (t, J = 7.6 Hz, 2H, CH2N); 2.66-2.70 (m, 4H, Piperazine); 3.08-3.14 (m, 4H, Piperazine); 3.86 (s, 3H, OCH3); 4.02 (t, J = 6.3 Hz1 2H, OCH2); 6.29-6.30 (m, 1 H, H-3); 6.44 (dd, J = 7.6 Hz1 2.6 Hz1 1 H1 H-6); 6.73 (d, J = 2.6 Hz1 1 H1 H-4); 6.86 (dd, J = 7.8 Hz, 0.9 Hz1 1 H1 Phenyl H3); 6.92 (ddd, J = 7.5 Hz1 7.0 Hz1 0.9 Hz, 1 H1 Phenyl H5); 6.95 (dd, J = 7.5 Hz, 1.7 Hz, 1 H, Phenyl H6); 7.00 (ddd, J = 7.8 Hz, 7.0 Hz, 1.7 Hz, 1 H, Phenyl H4); 7.84 (d, J = 2.1 Hz, 1 H, H-2); 8.28 (d, J = 7.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.5; 27.1 ; 50.7; 53.5; 55.5; 58.3; 68.1 ; 95.4; 106.8; 111.3; 118.2; 121.0; 123.0; 129.4; 141.1 ; 141.4; 142.8; 152.4; 155.7. C H N (%):C22H28N4O2 x 0.3H2O; calculated.: C 68.48; H 7.47; N 14.52; found: C 68.51 ; H 7.71 ; N 14.38.
Example E17:
5-[4-[4-(2- Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(2-chlorophenyl)piperazine (C7c).
Yield: 619 mg (94 %) beige solid.
Mp.: 163°C. MS (El): m/z 386 (M+1)+, 384 (M-I)+. IR (NaCI) v (cm"1): 3097; 2945; 2816;
1648; 1480; 1290; 1228; 1192; 750.1H NMR (CDCI3, 600 MHz) δ (ppm): 1.71-1.76 (m, 2H,
CH2CH2N); 1.85-1.90 (m, 2H, OCH2CH2); 2.50 (t, J = 7.6 Hz1 2H, CH2N); 2.64-2.68 (m, 4H, Piperazine); 3.07-3.11 (m, 4H, Piperazine); 4.02 (t, J = 6.3 Hz1 2H1 OCH2); 6.29-6.30 (m,
1H1 H-3); 6.44 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.73 (d, J = 2.6 Hz, 1 H, H-4); 6.96 (ddd, J
= 7.8 Hz, 7.3 Hz, 1.3 Hz, 1H, Phenyl H4); 7.04 (dd, J = 8.0 Hz11.3 Hz, 1H, Phenyl H6);
7.21 (ddd, J = 8.0 Hz, 7.3 Hz, 1.2 Hz, 1H, Phenyl H5); 7.35 (dd, J = 7.8 Hz, 1.2 Hz, 1H,
Phenyl H3); 7.85 (d, J = 2.0 Hz, 1H, H-2); 8.28 (d, J = 7.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.5; 27.1; 51.3; 53.5; 58.2; 68.1 ; 95.4; 106.8; 120.5; 123.7; 127.7;
128.9 ; 129.4; 130.8; 141.1 ; 142.8; 149.4; 155.8.
C H N (%):C21H25N4OCI x 0.25H2O; calculated: C 64.77; H 6.60; N 14.39; found: C 65.02;
H 6.69; N 14.28.
Example E65:
5-[4-[4-(3-Nitrophenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyridine
Synthesis worked according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(3-nitrophenyl)piperazine (C7h). Yield: 385 mg (66 %) orange solid. Mp.: 73°C. MS (APCI) m/z 396 (M+1)+. IR (NaCI) v (cm 1): 3097; 2947; 2819; 1647; 1524; 1342; 1230; 1192; 737. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.72-1.77 (m, 2H, CH2CH2N); 1.87-1.91 (m, 2H, OCH2CH2); 2.49 (t, J = 7.5 Hz, 2H, CH2N); 2.63-2.64 (m, 4H, Piperazine); 3.29-3.31 (m, 4H, Piperazine); 4.02 (t, J = 6.2 Hz, 2H, OCH2); 6.30 (d, J = 1.7 Hz, 1 H, H-3); 6.44 (dd, J = 7.5 Hz, 2.4 Hz, 1 H, H-6); 6.74 (d, J = 2.4 Hz, 1H, H-4); 7.18 (dd, J = 8.1 Hz, 2.2 Hz, 1 H, Phenyl H6); 7.37 (dd, J = 8.1 Hz, 8.1 Hz, 1 H, Phenyl H5); 7.65 (dd, J = 8.1 Hz, 1.6 Hz, 1 H, Phenyl H4); 7.71-7.72 (m, 1 H, Phenyl H2); 7.85 (d, J = 1.7 Hz, 1 H, H-2); 8.29 (d, J = 7.5 Hz, 1 H, H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.5; 27.0; 48.4; 52.9; 58.0; 68.0; 95.3; 95.4; 106.7; 109.6; 113.7; 121.0; 129.4; 129.7; 141.1 ; 142.7; 149.3; 151.8; 155.6.
Example E18: 5-[{4-[4-(4-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(4-methoxyphenyl)piperazine (C7d). Yield: 210 mg (99 %) white solid.
Mp.: 1110C. MS (El): m/z 380 (M)+. IR (NaCI) v (cm 1): 3098; 2945; 2817; 1647; 1511 ; 1441 ; 1291 ; 1228; 1191 ; 822. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.70-1.75 (m, 2H, CH2CH2N); 1.85-1.89 (m, 2H, OCH2CH2); 2.48 (t, J = 7.6 Hz, 2H, CH2N); 2.62-2.64 (m, 4H, Piperazine); 3.10-3.12 (m, 4H, Piperazine); 3.76 (s, 3H, OCH3); 4.01 (t, J = 6.3 Hz, 2H, OCH2); 6.29-6.30 (m, 1 H, H-3); 6.43 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.73 (d, J = 2.6 Hz, 1 H, H-4); 6.83-6.84 (m, 2H, Phenyl H2, Phenyl H6); 6.89-6.91 (m, 2H, Phenyl H3, Phenyl H5); 7.84 (d, J = 2.1 Hz, 1 H, H-2); 8.28 (d, J = 7.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.5; 27.0; 50.7; 53.5; 55.7; 58.2; 68.1 ; 95.4; 106.8; 114.5; 118.2; 129.4; 141.1 ; 142.8; 145.8; 153.9; 155.7.
C H N (%):C22H28N4O2; calculated: C 69.45; H 7.42; N 14.72; found: C 69.28; H 7.51; N 14.78.
Example E19:
5-[4-[4-(4-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(4-chlorophenyl)piperazine (C7e). Yield: 191 mg (89 %) white solid. Mp.: 125°C. MS (El): m/z 386 (M+1)\ 384 (M-I)+. IR (NaCI) v (cm"1): 3067; 2946; 2815; 1647; 1485; 1289; 1227; 1191 ; 827; 775. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.70-1.75 (m, 2H, CH2CH2N); 1.85-1.90 (m, 2H, OCH2CH2); 2.47 (t, J = 7.6 Hz1 2H, CH2N); 2.60- 2.62 (m, 4H, Piperazine); 3.16-3.18 (m, 4H, Piperazine); 4.01 (t, J = 6.3 Hz, 2H1 OCH2); 6.29-6.30 (m, 1 H, H-3); 6.43 (dd, J = 7.6 Hz1 2.6 Hz, 1H, H-6); 6.73 (d, J = 2.6 Hz, 1 H, H- 4); 6.82-6.84 (m, 2H, Phenyl H2, Phenyl H6); 7.19-7.20 (m, 2H, Phenyl H3, Phenyl H5); 7.85 (d, J = 2.0 Hz, 1 H1 H-2); 8.28 (d, J = 7.6 Hz1 1 H1 H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.5; 27.0; 49.3; 53.2; 58.2; 68.0; 95.4; 106.7; 117.3; 124.5; 129.0; 129.4, 141.1 ; 142.8; 150.0; 155.7. C H N (%):C2iH25N4OCI x 0.2H2O; calculated: C 64.92; H 6.59; N 14.42; found: C 65.07; H 6.68; N 14.48.
Example E20: 5-[4-[4-(4-Hydroxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(4-hydroxyphenyl)piperazine (C7f). Yield: 140 mg (63 %) beige solid. Mp.: 124°C. MS (APCI): m/z 367 (M+1)+. IR (NaCI) v (cnT1): 3136; 2941; 2817; 1648; 1513; 1444; 1289; 1229; 1192; 823. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.72-1.77 (m, 2H1 CH2CH2N); 1.84-1.89 (m, 2H1 OCH2CH2); 2.50 (t, J = 7.6 Hz, 2H, CH2N); 2.65-2.66 (m, 4H1 Piperazine); 3.09-3.11 (m, 4H1 Piperazine); 4.00 (t, J = 6.3 Hz, 2H, OCH2); 6.30-6.31 (m, 1H1 H-3); 6.43 (dd, J = 7.6 Hz1 2.6 Hz1 1H, H-6); 6.73 (d, J = 2.6 Hz, 1H, H-4); 6.74-6.76 (m, 2H1 Phenyl H2, Phenyl H6); 6.83-6.84 (m, 2H1 Phenyl H3, Phenyl H5); 7.85 (d, J = 2.1 Hz1 1 H1 H-2); 8.28 (d, J = 7.6 Hz1 1 H1 H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.4;
27.1 ; 50.7; 53.4; 58.2; 68.0; 95.4; 95.5; 106.9; 116.0; 118.5; 129.3; 141.2; 142.6; 145.4; 150.2; 155.7.
Example E1 : 2-[4-[4-(2, 3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine
Synthesis worked according to the preparation of E15 when using 2-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6b) and 1-(2,3-dichlorophenyl)piperazine (C7a). Yield: 291 mg (62 %) beige solid. Mp.: 1610C. MS (El): m/z 420 (M+1 )+, 418 (M-I)+. IR (NaCI) v (cm"1): 3074; 2947; 2819; 1635; 1578; 1242; 1144; 1043; 781. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.85-1.92 (m, 4H1 OCH2CH2CH2CH2N); 2.69 (t, J = 6.8 Hz, 2H1 CH2N); 2.84-2.89 (m, 4H1 Piperazine); 3.20- 3.23 (m, 4H, Piperazine); 4.29 (t, J = 6.0 Hz, 2H, OCH2); 5.83 (d, J = 0.6 Hz, 1 H, H-3); 6.60 (ddd, J = 6.9 Hz, 6.9 Hz, 1.3 Hz1 1 H1 H-6); 6.97 (dd, J = 7.3 Hz1 2.3 Hz, 1 H, Phenyl H6); 7.05 (ddd, J = 8.9 Hz, 6.9 Hz, 1.1 Hz, 1H, H-5); 7.13-7.19 (m, 2H, Phenyl H4, Phenyl H5); 7.29 (ddd, J = 8.9 Hz, 1.3 Hz, 0.6 Hz, 1 H, H-4); 8.22 (dd, J = 6.9 Hz1 1.1 Hz1 1 H1 H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 22.7; 27.2; 50.4; 53.1 ; 58.1 ; 69.0; 79.8; 109.8; 116.5; 118.9; 124.0; 125.1 ; 127.6; 128.3; 134.2; 141.7; 150.6; 165.6.
Example E2:
2-[4-[4-(2- Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine
Synthesis worked according to the preparation of E15 when using 2-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6b) and 1-(2-methoxyphenyl)piperazine (C7b). Yield: 262 mg (62 %) orange oil.
MS (APCI): m/z 381 (M+1)+. IR (NaCI) v (cnrϊ1): 3068; 2941 ; 2818; 1635; 1502; 1240; 752. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.87-1.92 (m, 4H, OCH2CH2CH2CH2N); 2.69 (t, J = 7.5 Hz, 2H, CH2N); 2.86-2.91 (m, 4H, Piperazine); 3.23-3.26 (m, 4H1 Piperazine); 3.86 (s, 3H, OCH3); 4.29 (t, J = 5.7 Hz, 2H1 OCH2); 5.82 (d, J = 0.6 Hz, 1 H, H-3); 6.59 (ddd, J =
6.9 Hz1 6.9 Hz1 1.3 Hz1 1 H, H-6); 6.86 (dd, J = 7.9, 1.0 Hz, 1 H, Phenyl H3); 6.91-6.95 (m, 2H, Phenyl H5, Phenyl H6); 6.99-7.07 (m, 2H1 Phenyl H4, H-5); 7.29 (ddd, J = 8.9 Hz, 1.3 Hz, 0.6 Hz, 1H1 H-4); 8.22 (dd, J = 6.9 Hz1 1.1 Hz1 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 22.7; 27.2; 49.6; 53.1 ; 55.4; 58.0; 69.0; 79.8; 109.8; 111.4; 116.4; 118.5; 121.2; 123.4; 124.0; 128.4; 140.8; 141.7; 152.3; 165.7.
Example E3:
2-[4-[4-(2-Chlorophenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyridine
Synthesis worked according to the preparation of E15 when using 2-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6b) and 1-(2-chlorphenyl)piperazine (C7c). Yield: 237 mg (55 %) yellow oil.
MS (El): m/z 386 (M+1)+, 384 (M-I )+. IR (NaCI) v (cm"1): 3059; 2945; 2818; 1635; 1504; 1259; 1228; 770. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.86-1.93 (m, 4H, OCH2CH2CH2CH2N); 2.70 (t, J = 7.0 Hz, 2H, CH2N); 2.84-2.90 (m, 4H1 Piperazine); 3.22- 3.24 (m, 4H, Piperazine); 4.29 (t, J = 5.7 Hz1 2H, OCH2); 5.83 (d, J = 0.6 Hz, 1 H, H-3); 6.59 (ddd, J = 6.9 Hz, 6.9 Hz, 1.4 Hz, 1 H, H-6); 6.98 (ddd, J = 7.8 Hz, 7.3 Hz, 1.3 Hz, 1 H, Phenyl H4); 7.02-7.07 (m, 2H, Phenyl H6, H-5); 7.22 (ddd, J = 8.0 Hz1 7.3 Hz1 1.2 Hz1 1H1 Phenyl H5); 7.29 (ddd, J = 8.9 Hz, 1.4 Hz, 0.6 Hz, 1 H, H-4); 7.35 (dd, J = 7.8 Hz, 1.2 Hz, 1 H, Phenyl H3); 8.22 (dd, J = 6.9 Hz, 1.1 Hz1 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 22.7; 27.2; 50.2; 53.1 ; 58.0; 69.0; 79.8; 109.8; 116.4; 120.6; 123.9; 124.1 ; 127.7; 128.3; 128.8; 130.6; 141.6; 148.7; 165.7.
Example E7: 4-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 4-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6c) and 1-(2,3-dichlorophenyl)piperazine (C7a).
Yield: 741 mg (68 %) beige solid. Mp.: 910C. MS (APCI): m/z 421 (M+2)+, 419 (M)+. IR (NaCI) v (cm"1): 3062; 2946; 2817;
1578; 1548; 1277; 1241 ; 1093; 748. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.77-1.81 (m, 2H,
CH2CH2N); 1.92-1.97 (m, 2H, OCH2CH2); 2.55 (t, J = 7.6 Hz1 2H1 CH2N); 2.67-2.71 (m, 4H1
Piperazine); 3.07-3.11 (m, 4H, Piperazine); 4.14 (t, J = 6.3 Hz1 2H1 OCH2); 6.35 (d, J = 7.6
Hz1 1 H1 H-5); 6.63-6.65 (m, 2H, H-3, H-6); 6.95 (dd, J = 7.3 Hz, 2.4 Hz1 1 H1 Phenyl H6); 7.12-7.17 (m, 2H, Phenyl H4, Phenyl H5); 7.87 (d, J = 2.4 Hz1 1H1 H-2); 8.12 (d, J = 6.9
Hz1 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.4; 27.0; 51.2; 53.3; 58.1 ; 68.2; 95.3;
99.7; 111.4; 118.6; 121.7; 124.7; 127.4; 127.5; 134.1 ; 135.4; 140.7; 150.4; 151.2.
C H N (%):C21H24N4OCI2 x 0.5H2O; calculated: C 58.88; H 5.88; N 13.08; found: C 58.81;
H 5.61 ; N 12.96.
Example E8:
4-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 4-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6c) and 1 -(2-methoxyphenyl)piperazine (C7b).
Yield: 801 mg (81 %) beige solid.
Mp.: 740C. MS (APCI): m/z 381 (M+1)+. IR (NaCI) v (cnrϊ1): 3061 ; 2942; 2814; 1548; 1500;
1276; 1241; 747. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.73-1.81 (m, 2H1 CH2CH2N); 1.90-
1.97 (m, 2H1 OCH2CH2); 2.52 (t, J = 7.6 Hz1 2H1 CH2N); 2.65-2.70 (m, 4H, Piperazine); 3.09-3.13 (m, 4H, Piperazine); 3.86 (s, 3H1 OCH3); 4.13 (t, J = 6.3 Hz, 2H1 OCH2); 6.35 (d, J = 7.6 Hz, 1 H, H-5); 6.61-6.65 (m, 2H, H-3, H-6); 6.86 (dd, J = 7.9 Hz, 1.0 Hz, 1 H, Phenyl H3); 6.89-6.95 (m, 2H, Phenyl H5, Phenyl H6); 6.99 (ddd, J = 7.9 Hz, 7.0 Hz, 2.2 Hz, 1 H, Phenyl H4); 7.87 (d, J = 2.4 Hz, 1 H, H-2); 8.12 (d, J = 6.9 Hz, 1H, H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.5; 27.1 ; 50.7; 53.5; 55.4; 58.3; 68.3; 95.3; 99.7; 111.2; 111.4; 118.2; 121.0; 121.7; 122.9; 135.4; 140.7; 141.4; 150.4; 152.3.
C H N (0Zo)-C22H28N4O2 x 0.1H2O; calculated: C 69.12; H 7.44; N 14.66; found: C 68.95; H 7.29; N 14.60.
Example E9: 4-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 4-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6c) and 1-(2-chlorphenyl)piperazine (C7c). Yield: 785 mg (78 %) orange solid. Mp.: 88°C. MS (APCI): m/z 387 (M+2)\ 385 (M)+. IR (NaCI) v (cm"1): 3061 ; 2945; 2815;
1548; 1517; 1479; 1276; 1231 ; 748. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.76-1.81 (m, 2H, CH2CH2N); 1.92-1.97 (m, 2H1 OCH2CH2); 2.54 (t, J = 7.6 Hz, 2H, CH2N); 2.64-2.72 (m, 4H, Piperazine); 3.07-3.13 (m, 4H, Piperazine); 4.14 (t, J = 6.3 Hz, 2H, OCH2); 6.35 (d, J = 7.6 Hz, 1 H, H-5); 6.62-6.65 (m, 2H, H-3, H-6); 6.96 (ddd, J = 7.8 Hz, 7.3 Hz, 1.3 Hz, 1 H, Phenyl H4); 7.05 (dd, J = 8.0 Hz, 1.3 Hz, 1 H, Phenyl H6); 7.22 (ddd, J = 8.0 Hz, 7.3 Hz,
1.2 Hz, 1 H, Phenyl H5); 7.35 (dd, J = 7.8 Hz, 1.2 Hz, 1 H, Phenyl H3); 7.87 (d, J = 2.4 Hz, 1 H, H-2); 8.12 (d, J = 6.9 Hz, 1 H, H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.5; 27.1 ; 51.2; 53.4; 58.3; 68.3; 95.3; 99.8; 111.4; 120.4; 121.7; 123.7; 127.6; 128.8; 130.7; 135.4; 140.7; 149.3; 150.4. C H N (%):C21H25N4OCI x 0.6H2O; calculated: C 63.74; H 6.67; N 14.16; found: C 63.92; H 6.53; N 13.98.
Example E51 :
6-[4-[4-(2, 3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine
Synthesis worked according to the preparation of E15 when using 6-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6d) and 1-(2,3-dichlorophenyl)piperazine (C7a). Yield: 43 mg (69 %) beige solid. Mp.: 97°C. MS (APCI): m/z 421 (M+2)+, 419 (M)+. IR (NaCI) v (cm 1): 3106; 2944; 2811 ; 1647; 1578; 1291 ; 1240; 1199; 1043; 781. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.72-1.81 (m, 2H, CH2CH2N); 1.85-1.93 (m, 2H1 OCH2CH2); 2.54 (t, J = 7.6 Hz, 2H, CH2N); 2.68- 2.73 (m, 4H, Piperazine); 3.10-3.12 (m, 4H, Piperazine); 4.00 (t, J = 6.3 Hz, 2H, OCH2); 6.44-6.45 (m, 1 H, H-3); 6.92 (dd, J = 9.6 Hz, 2.2 Hz, 1 H, H-5); 6.96 (dd, J = 6.9 Hz, 2.6 Hz, 1H, Phenyl H6); 7.14-7.16 (m, 2H, Phenyl H4, Phenyl H5); 7.41 (d, J = 9.6 Hz, 1H, H-4); 7.84 (d, J = 2.2 Hz, 1 H, H-7); 8.07-8.08 (m, 1 H, H-2). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.2; 27.1; 51.1; 53.3; 58.1 ; 68.7; 96.7; 111.8; 117.9; 118.7; 119.1; 124.7; 127.5; 127.6; 134.1 ; 136.5; 140.8; 148.3; 151.2.
C H N (%):C2iH24N4OCl2 x 0.6H2O; calculated: C 58.64; H 5.91 ; N 13.03; found: C 58.86; H 5.81; N 12.78.
Example E52: 6-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 6-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6d) and 1-(2-methoxyphenyl)piperazine (C7b). Yield: 50 mg (89 %) beige oil.
MS (El): m/z 380 (M)+. IR (NaCI) v (cm'1): 3108; 2942; 2817; 1643; 1499; 1292; 1240; 1199; 748. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.80-1.85 (m, 2H, CH2CH2N); 1.87-1.91 (m, 2H1 OCH2CH2); 2.59 (t, J = 7.6 Hz, 2H1 CH2N); 2.77-2.82 (m, 4H, Piperazine); 3.17- 3.22 (m, 4H1 Piperazine); 3.86 (s, 3H, OCH3); 3.99 (t, J = 6.3 Hz, 2H, OCH2); 6.45 (d, J = 2.1 Hz1 1 H, H-3); 6.87 (dd, J = 7.9 Hz, 1.0 Hz, 1 H1 Phenyl H3); 6.91-6.93 (m, 2H, H-5, Phenyl H5); 6.95 (dd, J = 7.5 Hz, 2.0 Hz1 1 H1 Phenyl H6); 7.01 (ddd, J = 7.9 Hz, 7.0 Hz, 2.0 Hz, 1H1 Phenyl H4); 7.41 (d, J = 9.6 Hz1 1H1 H-4); 7.84 (d, J = 2.2 Hz1 1H1 H-7); 8.06- 8.07 (m, 1 H, H-2). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.1; 27.1; 50.2; 53.4; 55.4; 58.1; 68.7; 96.7; 111.2; 111.8; 117.9; 118.4; 119.0; 121.1 ; 123.2; 136.5; 140.8; 141.0; 148.3; 152.3.
Example E53:
6-[4-[4~(2-Chlorophenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a] pyridine
Synthesis worked according to the preparation of E15 when using 6-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6d) and 1-(2-chlorphenyl)piperazine (C7c).
Yield: 164 mg (81 %) beige solid.
Mp.: 860C. MS (APCI): m/z 387 (M+2)+, 385 (M)+. IR (NaCI) v (crτϊ1): 3088; 2943; 2818; 1643; 1525; 1479; 1291; 1233; 1199; 750.1H NMR (CDCI3, 600 MHz) δ (ppm): 1.78-1.83 (m, 2H, CH2CH2N); 1.86-1.91 (m, 2H1 OCH2CH2); 2.58 (t, J = 7.6 Hz, 2H, CH2N); 2.74- 2.78 (m, 4H1 Piperazine); 3.14-3.18 (m, 4H1 Piperazine); 3.99 (t, J = 6.3 Hz1 2H, OCH2); 6.44-6.45 (m. 1 H, H-3); 6.92 (dd, J = 9.6 Hz1 2.2 Hz, 1 H, H-5); 6.97 (ddd, J = 7.8 Hz1 7.3 Hz, 1.3 Hz, 1H, Phenyl H4); 7.05 (dd, J = 8.0 Hz1 1.3 Hz, 1 H, Phenyl H6); 7.22 (ddd, J = 8.0 Hz, 7.3 Hz1 1.2 Hz1 1H1 Phenyl H5); 7.35 (dd, J = 7.8 Hz1 1.2 Hz, 1H, Phenyl H3); 7.41 (d, J = 9.6 Hz1 1 H, H-4); 7.84 (d, J = 2.2 Hz, 1 H, H-7); 8.07-8.08 (m, 1 H1 H-2). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.1 ; 27.0; 50.8; 53.3; 58.1 ; 68.6; 96.7; 111.7; 117.9; 119.0; 120.5; 123.9; 127.7; 128.8; 130.7; 136.5; 140.8; 148.3; 149.1.
Example E57:
7-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 7-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6e) and 1-(2,3-dichlorophenyl)piperazine (C7a). Yield: 117 mg (75 %) light blue solid.
Mp.: 74°C. MS (APCI): m/z 421 (M+2)+, 419 (M)+. IR (NaCI) v (cm"1): 3058; 2951 ; 1633; 1547; 1103; 781. 1H NMR (CDCI3, 600 MHz) δ (ppm): 2.03-2.06 (m, 2H, CH2CH2N); 2.08- 2.11 (m, 2H1 OCH2CH2); 2.97 (t, J = 7.6 Hz1 2H, CH2N); 3.02-3.09 (m, 4H1 Piperazine); 3.28-3.30 (m, 4H1 Piperazine); 4.36 (t, J = 6.1 Hz1 2H, OCH2); 6.10 (dd, J = 7.3 Hz, 0.6 Hz, 1 H, H-6); 6.52 (d, J = 2.3 Hz1 1 H, H-3); 6.98 (dd, J = 7.8 Hz, 1.5 Hz, 1 H, Phenyl H6); 7.10 (dd, J = 8.4 Hz, 7.3 Hz, 1 H, H-5); 7.17 (dd, J = 8.4 Hz1 0.6 Hz1 1 H1 H-4); 7.19-7.21 (m, 2H, Phenyl H4, Phenyl H5); 7.98 (d, J = 2.3 Hz, 1H, H-2). 13C NMR (CDCI3, 600 MHz) δ (ppm): 22.4; 26.3; 46.9; 52.8; 57.6; 69.7; 89.4; 96.9; 110.2; 119.0; 124.6; 125.4; 127.6; 127.7; 134.1; 142.2; 150.3; 150.6.
Example E58: 7-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 7-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6e) and 1-(2-methoxyphenyl)piperazine (C7b).
Yield: 112 mg (79 %) light blue oil.
MS (APCI): m/z 381 (M+1)+. IR (NaCI) v (cm"1): 2937; 1632; 1547; 1500; 1244; 1022; 756.
1H NMR (CDCI3, 360 MHz) δ (ppm): 2.10-2.17 (m, 2H1 CH2CH2N); 2.34-2.42 (m, 2H,
OCH2CH2); 3.36-3.45 (m, 6H, CH2N, Piperazine); 3.56-3.61 (m, 4H, Piperazine); 3.87 (s, 3H1 OCH3); 4.39 (t, J = 5.7 Hz, 2H, OCH2); 6.12 (dd, J = 7.3 Hz, 1.1 Hz, 1 H, H-6); 6.53 (d, J = 2.2 Hz, 1 H1 H-3); 6.89 (dd, J = 7.9 Hz, 0.9 Hz, 1 H, Phenyl H3); 6.93-6.96 (m, 2H1 Phenyl H5, Phenyl H6); 7.07 (ddd, J = 7.9 Hz1 6.0 Hz1 2.7 Hz1 1H, Phenyl H4); 7.13 (dd, J = 8.5 Hz1 7.3 Hz1 1 H, H-5); 7.22 (dd, J = 8.5 Hz1 1.1 Hz, 1H1 H-4); 7.97 (d, J = 2.2 Hz1 1 H, H-2). 13C NMR (CDCI3, 360 MHz) δ (ppm): 21.3; 26.1 ; 47.1 ; 52.4; 55.5; 57.2; 69.3; 89.8; 97.1 ; 110.5; 111.5; 119.1; 121.3; 124.6; 138.8; 142.1 ; 150.3; 152.1.
Example E59: 7-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 7-(4- bromobutoxy)pyrazolo[1,5-a]pyridine (C6e) and 1-(2-chlorphenyl)piperazine (C7c). Yield: 90 mg (63 %) light blue oil.
MS (APCI): m/z 387 (M+2)+, 385 (M)+. IR (NaCI) v (crrT1): 3059; 2926; 1632; 1545; 1219; 1101 ; 771. 1H NMR (CDCI3, 360 MHz) δ (ppm): 2.10-2.17 (m, 2H, CH2CH2N); 2.29-2.38 (m, 2H, OCH2CH2); 3.37-3.48 (m, 6H, CH2N, Piperazine); 3.52-3.58 (m, 4H, Piperazine); 4.39 (t, J = 5.7 Hz, 2H, OCH2); 6.11 (dd, J = 7.3 Hz, 0.8 Hz, 1 H, H-6); 6.53 (d, J = 2.2 Hz, 1 H1 H-3); 7.06 (ddd, J = 7.8 Hz, 7.3 Hz, 1.3 Hz, 1 H, Phenyl H4); 7.10 (dd, J = 8.0 Hz1 1.3 Hz1 1 H1 Phenyl H6); 7.12 (dd, J = 8.9 Hz, 7.3 Hz, 1 H, H-5); 7.18 (ddd, J = 8.0 Hz, 7.3 Hz1 1.2 Hz1 1 H1 Phenyl H5); 7.22 (dd, J = 8.9 Hz1 0.8 Hz1 1 H1 H-4); 7.38 (dd, J = 7.8 Hz, 1.2 Hz, 1 H, Phenyl H3); 7.98 (d, J = 2.2 Hz, 1 H, H-2). 13C NMR (CDCI3, 360 MHz) δ (ppm): 21.6; 26.1 ; 48.1 ; 52.5; 57.4; 69.5; 89.7; 97.2; 110.5; 121.1 ; 124.6; 125.3; 128.1 ; 128.9; 130.7; 142.1 ; 147.1 ; 150.3.
Example E13: 5-[3-[4-(2, 3-Dichlorophenyl)piperazin- 1 -yl]propoxymethyl]pyrazolo[1 , 5-a]pyήdine
Synthesis worked according to the preparation of E15 when using 5-(3- bromopropoxymethyl)pyrazolo[1 ,5-a]pyridine (C6f) and 1-(2,3-dichlorophenyl)piperazine (C7a). Yield: 58 mg (99 %) yellow solid.
Mp.: 69°C. MS (El): m/z 420 (M+1 )+, 418 (M)+. IR (NaCI) v (cm'1): 2945; 2819; 1647; 1578; 1241; 1044; 780. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.84-1.92 (m, 2H, CH2CH2N); 2.55 (t, J = 6.7 Hz, 2H, CH2N); 2.63-2.68 (m, 4H, Piperazin); 3.05-3.08 (m, 4H, Piperazin); 3.59 (t, J = 6.4 Hz, 2H, OCH2CH2); 4.52-4.53 (m, 2H, CH2O); 6.47 (dd, J = 2.4 Hz1 0.9 Hz, 1 H, H-3); 6.73 (dd, J = 7.1 Hz, 1.8 Hz, 1 H, H-6); 6.95 (dd, J = 6.7 Hz, 3.0 Hz, 1H, Phenyl H6); 7.13-7.15 (m, 2H, Phenyl H4, Phenyl H5); 7.48 (dd, J = 1.8 Hz, 0.9 Hz, 1H, H-4); 7.93 (d, J = 2.4 Hz, 1H, H-2); 8.43 (d, J = 7.1 Hz, 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 27.2; 51.4; 53.4; 55.5; 69.0; 71.9; 96.8; 111.4; 115.6; 118.6; 124.7; 127.4; 127.6; 128.5; 134.1; 134.5; 139.9; 142.2; 151.3.
Example E27: i-fS-ft-ft-fcS-Dichlorophenyljpiperazin-i-ylfiutoxyJpyrazoloti.δ-aJpyridine-S-yljethanone
Synthesis worked according to the preparation of E17 when using 1-[5-(4- brombutoxy)pyrazolo[1 ,5-a]pyridine-3-yl]ethanone (C6g) and 1-(2,3- dichlorophenyl)piperazine (C7a).
Yield: 12 mg (53 %) orange oil.
MS (APCI): m/z 463 (M+2)+, 461 (M)+. IR (NaCI) v (cnrϊ1): 3097; 2947; 2819; 1655; 1524;
1277; 1217; 1043; 783. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.72-1.77 (m, 2H, CH2CH2N); 1.89-1.94 (m, 2H, OCH2CH2); 2.50-2.53 (m, 5H, CH2N, COCH3); 2.64-2.70 (m, 4H,
Piperazine); 3.06-3.11 (m, 4H, Piperazine); 4.15 (t, J = 6.4 Hz, 2H, OCH2); 6.66 (dd, J =
7.6 Hz, 2.6 Hz, 1 H, H-6); 6.97 (dd, J = 7.1 Hz, 2.2 Hz, 1H, Phenyl H6); 7.12-7.17 (m, 2H,
Phenyl H4, Phenyl H5); 7.68 (d, J = 2.6 Hz, 1 H, H-4); 8.24 (s, 1 H1 H-2); 8.33 (d, J = 7.6 Hz,
1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.3; 26.9; 27.8; 51.3; 53.4; 58.1; 68.8; 98.0; 109.1 ; 112.4; 118.7; 124.6; 127.5; 127.6; 129.8; 134.1 ; 142.1 ; 145.7; 151.3; 160.1 ;
191.7.
Example E28:
1-(5-[4~[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine-3-yl)ethanone
Synthesis worked according to the preparation of E17 when using 1-[5-(4- brombutoxy)pyrazolo[1,5-a]pyridine-3-yl]ethanone (C6g) and 1-(2- methoxyphenyl)piperazine (C7b).
Yield: 17 mg (78 %) orange oil. MS (APCI): m/z 423 (M+1)+. IR (NaCI) v (cm 1): 3064; 2943; 2812; 1653; 1524; 1275;
1240; 1217; 750. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.78-1.83 (m, 2H, CH2CH2N); 1.89-
1.94 (m, 2H, OCH2CH2); 2.52 (s, 3H, COCH3); 2.58 (t, J = 7.6 Hz, 2H, CH2N); 2.73-2.81
(m, 4H, Piperazine); 3.14-3.21 (m, 4H1 Piperazine); 3.87 (s, 3H, OCH3); 4.15 (t, J = 6.3 Hz,
2H, OCH2); 6.67 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.86 (dd, J = 7.9 Hz, 1.0 Hz, 1 H1 Phenyl H3); 6.92 (ddd, J = 7.5 Hz, 7.0 Hz, 1.0 Hz, 1 H, Phenyl H5); 6.95 (dd, J = 7.5 Hz, 2.0 Hz, 1 H, Phenyl H6); 7.01 (ddd, J = 7.9 Hz, 7.0 Hz, 2.0 Hz, 1 H, Phenyl H4); 7.68 (d, J = 2.6 Hz, 1 H, H-4); 8.24 (s, 1 H, H-2); 8.33 (d, J = 7.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.1 ; 26.8; 27.7; 50.3; 53.4; 55.4; 58.1 ; 68.6; 98.0; 109.0; 111.3; 112.4; 1 18.4; 121.1 ; 123.1 ; 129.8; 141.1 ; 142.1 ; 145.6; 152.3; 160.2; 191.7.
Example E29: 1-(5-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine-3-yl)ethanone
Synthesis worked according to the preparation of E17 when using 1-[5-(4- brombutoxy)pyrazolo[1 ,5-a]pyridine-3-yl]ethanone (C6g) and 1-(2-chlorophenyl)piperazine
(C7c).
Yield: 13 mg (51 %) orange oil.
MS (APCI): m/z 429 (M+2)+, 427 (M)+. IR (NaCI) v (cm"1): 3064; 2941 ; 2816; 1655; 1525;
1277; 1219; 1039; 760. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.74-1.79 (m, 2H, CH2CH2N); 1.89-1.94 (m, 2H, OCH2CH2); 2.52 (s, 3H, COCH3); 2.54 (t, J = 7.6 Hz, 2H, CH2N); 2.66-
2.74 (m, 4H, Piperazine); 3.10-3.15 (m, 4H1 Piperazine); 4.15 (t, J = 6.3 Hz, 2H, OCH2);
6.66 (dd, J = 7.6 Hz1 2.6 Hz, 1 H, H-6); 6.97 (ddd, J = 7.8 Hz, 7.3 Hz, 1.3 Hz, 1 H, Phenyl
H4); 7.06 (dd, J = 8.0 Hz, 1.3 Hz, 1 H1 Phenyl H6); 7.22 (ddd, J = 8.0 Hz1 7.3 Hz1 1.5 Hz,
1 H, Phenyl H5); 7.35 (dd, J = 7.8 Hz1 1.5 Hz1 1 H1 Phenyl H3); 7.68 (d, J = 2.6 Hz1 1 H, H- 4); 8.24 (s, 1 H, H-2); 8.33 (d, J = 7.6 Hz1 1 H1 H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm):
23.3; 26.9; 27.8; 51.1 ; 53.3; 58.1 ; 68.7; 98.0; 109.1 ; 112.4; 120.5; 123.7; 127.6; 128.8;
129.8; 130.6; 142.1 ; 145.7; 149.2; 160.0; 191.8.
Example E39: Methyl 5-[4-[4-(2, 3-dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine-3- carboxylate
Synthesis worked according to the preparation of E17 when using methyl 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine-3-carboxylate (C6h) and 1-(2,3- dichlorophenyl)piperazine (C7a).
Yield: 42 mg (58 %) beige solid.
Mp.: 73°C. MS (APCI): m/z 479 (M+2)+, 477 (M)+. IR (NaCI) v (cπV1): 3070; 2945; 2816; 1699; 1647; 1275; 1213; 1047; 777. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.72-1.77 (m, 2H, CH2CH2N); 1.89-1.94 (m, 2H, OCH2CH2); 2.52 (t, J = 7.5 Hz, 2H, CH2N); 2.64-2.70 (m, 4H, Piperazine); 3.06-3.11 (m, 4H, Piperazine); 3.89 (s, 3H, COOCH3); 4.13 (t, J = 6.5 Hz, 2H, OCH2); 6.61 (dd, J = 7.6 Hz, 2.6 Hz, 1H, H-6); 6.96 (dd, J = 7.3 Hz, 2.2 Hz, 1 H, Phenyl H6); 7.13-7.16 (m, 2H1 Phenyl H4, Phenyl H5); 7.41 (d, J = 2.6 Hz, 1H, H-4); 8.27 (s, 1 H, H-2); 8.32 (d, J = 7.6 Hz, 1H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.4; 26.9; 51.0; 51.4; 53.3; 58.1 ; 68.6; 96.8; 102.3; 108.4; 118.7; 124.6; 127.4; 127.5; 130.1; 134.1 ; 142.9; 145.3; 151.3; 159.0; 164.1.
Example E40:
Methyl 5-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine-3- carboxylate
Synthesis worked according to the preparation of E17 when using methyl 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine-3-carboxylate (C6h) and 1-(2- methoxyphenyl)piperazine (C7b).
Yield: 58 mg (87 %) beige solid. Mp.: 75°C. MS (APCI): m/z 439 (M+1)\ IR (NaCI) v (cm'1): 3064; 2945; 2816; 1699; 1647;
1539; 1275; 1242; 1213; 748. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.72-1.80 (m, 2H,
CH2CH2N); 1.87-1.95 (m, 2H, OCH2CH2); 2.53 (t, J = 7.6 Hz1 2H, CH2N); 2.68-2.74 (m, 4H,
Piperazine); 3.10-3.17 (m, 4H1 Piperazine); 3.86 (s, 3H, OCH3); 3.89 (s, 3H, COOCH3);
4.13 (t, J = 6.2 Hz1 2H1 OCH2); 6.60 (dd, J = 7.6 Hz, 2.6 Hz, 1 H1 H-6); 6.86 (dd, J = 8.0 Hz, 1.2 Hz, 1 H1 Phenyl H3); 6.89-6.96 (m, 2H, Phenyl H5, Phenyl H6); 7.00 (ddd, J = 8.0 Hz,
6.8 Hz, 2.4 Hz, 1 H, Phenyl H4); 7.40 (d, J = 2.6 Hz1 1 H, H-4); 8.27 (s, 1 H, H-2); 8.31 (d, J = 7.6 Hz, 1 H1 H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.3; 26.9; 50.5; 51.0; 53.5; 55.4; 58.2; 68.6; 96.8; 102.3; 108.4; 111.3; 118.3; 121.0; 123.0; 130.0; 141.3; 142.9; 145.3; 152.3; 159.0; 164.1.
Example E41:
Methyl δ-ft-ft-fi-chlorophenyljpiperazin-i-ylJbutoxyJpyrazololi.δ-aføyridine-S-carboxylate
Synthesis worked according to the preparation of E17 when using methyl 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine-3-carboxylate (C60h) and 1-(2- chlorophenyl)piperazine (C7c). Yield: 49 mg (72 %) orange oil.
MS (APCI): m/z 445 (M+2)+, 443 (M)+. IR (NaCI) v (crτϊ1): 3064; 2948; 2817; 1699; 1648; 1539; 1276; 1213; 1048; 751. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.79-1.84 (m, 2H, CH2CH2N); 1.90-1.94 (m, 2H1 OCH2CH2); 2.60 (t, J = 7.6 Hz1 2H, CH2N); 2.73-2.81 (m, 4H, Piperazine); 3.14-3.20 (m, 4H, Piperazine); 3.89 (s, 3H, COOCH3); 4.13 (t, J = 6.2 Hz, 2H, OCH2); 6.61 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.98 (ddd, J = 7.8 Hz, 7.3 Hz, 1.3 Hz, 1H, Phenyl H4); 7.06 (dd, J = 8.0 Hz, 1.3 Hz, 1H, Phenyl H6); 7.22 (ddd, J = 8.0 Hz, 7.3 Hz, 1.5 Hz, 1 H, Phenyl H5); 7.36 (dd, J = 7.8 Hz, 1.5 Hz, 1 H, Phenyl H3); 7.41 (d, J = 2.6 Hz, 1 H, H-4); 8.28 (s, 1 H, H-2); 8.32 (d, J = 7.6 Hz, 1H, H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.1; 26.8; 50.8; 51.0; 53.3; 58.0; 68.4; 96.8; 102.3; 108.4; 120.5; 123.9; 127.7; 128.8; 130.0; 130.7; 142.8; 145.3; 149.0; 159.0; 164.1.
Example E63: 7-[4-[4-(2, 3-Dichlorophenyl)piperazin-1-yl]butoxy]tetrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 7-(4- bromobutoxy)tetrazolo[1 ,5-a]pyridine (C6i) and 1-(2,3-dichlorophenyl)piperazine (C7a). Yield: 15 mg (62 %) beige solid. Mp.: 138°C. MS (APCI) m/z 423 (M+2)+, 421 (M)+. IR (NaCI) v (cm 1): 3066; 2947; 2819; 1643; 1578; 1242; 1203; 779. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.71-1.80 (m, 2H, CH2CH2N); 1.91-1.99 (m, 2H, OCH2CH2); 2.52 (t, J = 7.4 Hz, 2H, CH2N); 2.64-2.69 (m, 4H, Piperazine); 3.07-3.10 (m, 4H, Piperazine); 4.16 (t, J = 6.4 Hz, 2H, OCH2); 6.86 (dd, J = 7.5 Hz, 2.4 Hz, 1 H, H-6); 6.96 (dd, J = 6.4 Hz, 3.1 Hz, 1 H, Phenyl H6); 7.14-7.17 (m, 3H, H-8, Phenyl H4, Phenyl H5); 8.60 (dd, J = 7.5 Hz, 0.7 Hz, 1 H, H-5). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.2; 26.6; 51.4; 53.4; 58.0; 69.3; 92.3; 112.2; 118.7; 124.7; 125.4; 127.5; 127.6; 134.1 ; 150.5; 151.2; 161.7.
Example E97: 7-[4-[4-(2-Methoxyphenyl)piperazin- 1 -yl]butoxy]tetrazolo[1 , 5-a]pyridine
Synthesis worked according to the preparation of E15 when using 5-(4- bromobutoxy)tetrazolo[1 ,5-a]pyridine (C6i) and 1-(2-methoxyphenyl)piperazine (C7b). Yield: 19 mg (85 %) beige solid. Mp.: 124°C. MS (APCI) m/z 383 (M+1)+. IR (NaCI) v (cm 1): 3062; 2943; 2816; 1643;
1500; 1242; 1203; 742. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.77-1.85 (m, 2H, CH2CH2N); 1.91-1.99 (m, 2H, OCH2CH2); 2.57 (t, J = 7.6 Hz, 2H, CH2N); 2.72-2.78 (m, 4H, Piperazine); 3.13-3.19 (m, 4H, Piperazine); 3.86 (s, 3H, OCH3); 4.16 (t, J = 6.4 Hz, 2H, OCH2); 6.85-6.88 (m, 2H, Phenyl H3, H-6); 6.91-6.96 (m, 2H, Phenyl H5, Phenyl H6); 7.01 (ddd, J = 9.1 Hz, 6.6 Hz, 2.6 Hz1 1 H, Phenyl H4); 7.15 (dd, J = 2.4 Hz, 0.6 Hz, 1 H, H-8); 8.61 (dd, J = 7.5 Hz1 0.6 Hz, 1 H, H-5). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.1; 26.6; 50.4; 53.4; 55.4; 58.0; 69.2; 92.2; 111.2; 112.2; 118.3; 121.0; 123.1 ; 125.4; 141.1 ; 150.4; 152.3; 161.6.
Example E98:
7-[4-[4-(2-Chloroyphenyl)piperazin-1-yl]butoxy]tetrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E15 when using 5-(4- bromobutoxy)tetrazolo[1 ,5-a]pyridine (C6i) and 1-(2-chlorophenyl)piperazine (C7c). Yield: 12 mg (63 %) beige solid.
Mp.: 1010C. MS (APCI) m/z 389 (M+2)\ 387 (M)+. IR (NaCI) v (cm 1): 3070; 2943; 2816; 1647; 1477; 1203; 768. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.71-1.80 (m, 2H, CH2CH2N); 1.91-1.99 (m, 2H, OCH2CH2); 2.52 (t, J = 7.3 Hz, 2H, CH2N); 2.64-2.70 (m, 4H, Piperazine); 3.09-3.11 (m, 4H, Piperazine); 4.16 (t, J = 6.4 Hz, 2H, OCH2); 6.86 (dd, J = 7.5 Hz, 2.3 Hz, 1H, H-6); 6.97 (ddd, J = 7.8 Hz, 7.3 Hz, 1.5 Hz1 1H, Phenyl H4); 7.05 (dd, J = 8.1 Hz, 1.5 Hz, 1 H, Phenyl H6); 7.16 (dd, J = 2.3 Hz, 0.6 Hz, 1 H, H-7); 7.22 (ddd, J = 8.1 Hz, 7.3 Hz, 1.6 Hz, 1H, Phenyl H5); 7.35 (dd, J = 7.8 Hz1 1.6 Hz, 1 H, Phenyl H3); 8.60 (dd, J = 7.5 Hz, 0.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.3; 26.7; 51.3; 53.5; 58.1 ; 69.3; 92.3; 112.2; 120.5; 123.8; 125.4; 127.7 ; 128.8; 130.7; 149.3; 150.5; 161.7.
5. Synthesis of Example compounds according to formula XVI 5a) Compounds substituted with a formyl group in position 3
The synthesis of compounds according formula XVIa was achieved by formylation of the pyrazolo[1 ,5-a]pyridine scaffold in position 3.
Figure imgf000081_0001
formula XVa formula XVIa Example E21 :
5-[4-[4-(2, 3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine-3-carbaldehyde
For the synthesis 360 mg (0.86 mmol) 5-[4-[4-(2,3-dichlorophenyl)piperazin-1- yl]butoxy]pyrazolo[1,5-a]pyridine (E15), 2.75 ml dry dimethylformamide and 0.25 ml (2.66 mmol) phosphoroxychloride were stirred at room temperature for one hr. Then, water was added and the mixture was adjusted to basic conditions with 5N NaOH. After extraction with chloroform, the organic layer was dried with Na2SO4 and evaporated. The crude product was purified by flash-chromatography (CH2CI2/Me0H 98:2 and subsequently with 95:5).
Yield: 361 mg (94 %) beige solid.
Mp.: 1070C. MS (El): m/z 448 (M+1)+, 446 (M)+. IR (NaCI) v (crrϊ1): 2946; 2818; 1663; 1633; 1577; 1527; 1275; 1241 ; 1194; 1044; 774. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.70-1.78 (m, 2H, CH2CH2N); 1.88-1.96 (m, 2H, OCH2CH2); 2.51 (t, J = 7.6 Hz, 2H, CH2N); 2.64-2.68 (m, 4H1 Piperazine); 3.07-3.09 (m, 4H1 Piperazine); 4.16 (t, J = 6.5 Hz, 2H, OCH2); 6.71 (dd, J = 7.6 Hz, 2.6 Hz, 1H, H-6); 6.96 (dd, J = 6.5 Hz, 3.0 Hz, 1 H, Phenyl H6); 7.14-7.15 (m, 2H, Phenyl H4, Phenyl H5); 7.58 (d, J = 2.6 Hz, 1 H, H-4); 8.26 (s, 1 H, H-2); 8.37 (d, J = 7.6 Hz, 1 H1 H-7); 9.95 (s, 1 H1 CHO). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.3; 26.9; 51.4; 53.4; 58.0; 69.0; 97.8; 109.6; 113.3; 118.7; 124.6; 127.4; 127.5; 130.1 ; 134.1 ; 141.6; 147.6; 151.4; 160.7; 183.2.
C H N (0Zo^C22H24N4O2CI2 x 0.3H2O; calculated: C 58.36; H 5.48; N 12.37; found: C 58.34; H 5.43; N 12.27.
Example E22: 5-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 5-[4-[4-(2- methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine (E16). Yield: 846 mg (99 %) beige solid. Mp.: 900C. MS (El): m/z 408 (M)+. IR (NaCI) v (cm 1): 2941; 2816; 1663; 1633; 1527;
1275; 1241 ; 1194; 772. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.72-1.77 (m, 2H, CH2CH2N); 1.89-1.93 (m, 2H, OCH2CH2); 2.50 (t, J = 7.6 Hz1 2H1 CH2N); 2.67-2.70 (m, 4H1 Piperazine); 3.09-3.13 (m, 4H, Piperazine); 3.86 (s, 3H1 OCH3); 4.15 (t, J = 6.3 Hz1 2H, OCH2); 6.71 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.86 (dd, J = 7.9 Hz, 1.0 Hz, 1 H, Phenyl H3); 6.92 (ddd, J = 7.5 Hz, 7.0 Hz, 1.0 Hz1 1 H, Phenyl H5); 6.95 (dd, J = 7.5 Hz, 1.7 Hz1 1H, Phenyl H6); 6.99 (ddd, J = 7.9 Hz1 7.0 Hz1 1.7 Hz1 1H, Phenyl H4); 7.57 (d, J = 2.6 Hz1 1H1 H-4); 8.26 (s, 1H, H-2); 8.37 (d, J = 7.6 Hz1 1H1 H-7); 9.94 (s, 1H1 COH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.4; 26.9; 50.7; 53.5; 55.4; 58.2; 69.0; 97.9; 109.7; 111.3; 113.3; 118.3; 121.1 ; 123.0; 130.2; 141.4; 141.6; 147.5; 152.3; 160.7; 183.1. C H N (%):C23H28N4O3 x 0.3 H2O; calculated: C 66.74; H 6.97; N 13.54; found: C 66.62; H 6.79; N 13.52.
Example E23: δ-μ-μ-ft-ChlorophenyOpiperazin-i-yllbutoxyJpyrazololtS-aJpyridine-S-carbaldehyde
Synthesis worked according to the preparation of E21 when using 5-[4-[4-(2- chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E17).
Yield: 285 mg (80 %) white solid.
Mp.: 116°C. MS (El): m/z 414 (M+1 )+, 412 (M-I)+. IR (NaCI) v (cm"1): 2942; 2816; 1663; 1633; 1527; 1274; 1220; 1194; 772. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.72-1.77 (m, 2H1
CH2CH2N); 1.90-1.94 (m, 2H1 OCH2CH2); 2.51 (t, J = 7.6 Hz1 2H1 CH2N); 2.64-2.69 (m, 4H1
Piperazine); 3.07-3.12 (m, 4H1 Piperazine); 4.15 (t, J = 6.3 Hz1 2H1 OCH2); 6.71 (dd, J =
7.6 Hz1 2.6 Hz, 1 H1 H-6); 6.96 (ddd, J = 7.8 Hz1 7.3 Hz, 1.3 Hz1 1 H1 Phenyl H4); 7.05 (dd,
J = 8.0 Hz, 1.3 Hz1 1H1 Phenyl H6); 7.21 (ddd, J = 8.0 Hz, 7.3 Hz, 1.2 Hz, 1H, Phenyl H5); 7.35 (dd, J = 7.8 Hz, 1.2 Hz1 1 H1 Phenyl H3); 7.58 (d, J = 2.6 Hz, 1 H, H-4); 8.26 (s, 1 H, H-
2); 8.37 (d, J = 7.6 Hz, 1 H, H-7); 9.94 (s, 1 H1 COH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.4; 26.9; 51.3; 53.4; 58.1; 69.0; 97.7; 109.6; 113.2; 120.4; 123.7; 127.6; 128.8; 130.1 ; 130.7; 141.6; 147.5; 149.3; 160.7; 183.1.
C H N (%):C22H25N4O2CI x 0.1 H2O; calculated: C 63.72; H 6.13; N 13.51 ; found: C 63.84; H 6.42; N 13.69.
Example E69: 5-[4-[4-(3-Nitrophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 5-[4-[4-(3- nitrophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine (E65). Mp.: 178°C. MS (El) m/z 423 (M)+. IR (NaCI) v (cm"1): 3082; 2920; 2850; 1659; 1635; 1527; 1246; 1038. 1H NMR (DMSO-d6l 360 MHz) δ (ppm): 1.86-1.97 (m, 4H1 CH2CH2CH2N); 2.54-2.56 (m, 2H1 CH2N); 3.14-3.24 (m, 4H, Piperazine); 3.57-3.67 (m, 2H1 Piperazine); 3.98-4.08 (m, 2H1 Piperazine); 4.22 (t, J = 5.6 Hz, 2H1 OCH2); 6.92 (dd, J = 7.7 Hz1 2.7 Hz, 2H1 H-6); 7.49 (ddd, J = 8.4 Hz1 2.3 Hz, 1.0 Hz1 1 H1 Phenyl H6); 7.53 (dd, J = 8.4 Hz1 7.8 Hz1 1H1 Phenyl H5); 7.56 (dd, J = 2.7 Hz1 0.5 Hz1 1H1 H-4); 7.68 (ddd, J =
7.8 Hz, 2.3 Hz, 1.0 Hz, 1 H, Phenyl H4); 7.76 (dd, J = 2.3 Hz, 2.3 Hz1 1 H1 Phenyl H2); 8.53 (s, 1H1 H-2); 8.80 (dd, J = 7.7 Hz1 0.5 Hz, 1H, H-7); 9.94 (s, 1H, COH). 13C NMR (DMSO- d6, 360 MHz) δ (ppm): 21.3; 26.5; 45.8; 51.4; 56.0; 68.9; 97.9; 109.9; 110.2; 113.5; 114.8; 122.8; 131.3; 132.3; 141.9; 148.1 ; 149.8; 151.2; 160.9, 184.0.
Example E70: N-[3-[4-[4-(3-Formylpyrazolo[1,5-a]pyridin-5-yloxy)butyl]piperazin-1-yl]phenyl]acetamide
Synthesis worked according to the preparation of E21 when using N-[3-[4-[4- (pyrazolo[1 ,5-a]pyridin-5-yloxy)butyl]piperazin-1-yl]phenyl]acetamide (E67). Yield: 3.5 mg (22 %) beige oil. MS (APCI) m/z 436 (M+1)+. IR (NaCI) v (cm"1): 3027; 2934; 1662; 1628; 1527; 1273; 1134; 771. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.70-1.78 (m, 2H1 CH2CH2N); 1.88-1.95 (m, 2H1 OCH2CH2); 2.16 (s, 3H, COCH3); 2.47-2.52 (m, 2H, CH2N); 2.61-2.65 (m, 4H1 Piperazine); 3.21-3.24 (m, 4H, Piperazine); 4.13-4.18 (m, 2H, OCH2); 6.67 (dd, J = 8.2 Hz, 1.6 Hz, 1 H, Phenyl H6); 6.71 (dd, J = 7.4 Hz, 2.7 Hz, 2H, H-6); 6.80-6.84 (m, 1 H, Phenyl H4); 7.13 (br s, 1H, NH); 7.18 (dd, J = 8.2 Hz, 8.0 Hz, 1H1 Phenyl H5); 7.28-7.30 (m, 1H, Phenyl H2); 7.57 (d, J = 2.7 Hz, 1 H, H-4); 8.26 (s, 1H, H-2); 8.37 (d, J = 7.4 Hz, 1 H, H-7);
9.94 (S, 1 H, COH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 25.6; 26.9; 29.7; 48.9; 53.1; 58.0; 68.0; 97.8; 107.6; 109.6; 110.9; 111.9; 113.3; 129.5; 130.2; 138.8; 141.6; 147.5; 151.9; 160.7, 168.2; 183.1.
Example E24:
5-[4-[4~(4-Methoxyphenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyridine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 5-[4-[4-(4- methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E18). Yield: 44 mg (85 %) yellow solid.
Mp.: 114°C. MS (El): m/z 408 (M)+. IR (NaCI) v (cm 1): 3065; 2945; 2817; 1663; 1633; 1528; 1511; 1276; 1243; 1194; 751. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.71-1.76 (m, 2H1 CH2CH2N); 1.89-1.93 (m, 2H, OCH2CH2); 2.48 (t, J = 7.6 Hz, 2H, CH2N); 2.62-2.64 (m. 4H1 Piperazine); 3.10-3.12 (m, 4H, Piperazine); 3.76 (s, 3H, OCH3); 4.15 (t, J = 6.3 Hz, 2H, OCH2); 6.70 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.83-6.84 (m, 2H, Phenyl H2, Phenyl H6); 6.90-6.91 (m, 2H1 Phenyl H3, Phenyl H5); 7.57 (d, J = 2.6 Hz, 1 H, H-4); 8.26 (s, 1H, H-2); 8.37 (d, J = 7.6 Hz, 1 H, H-7); 9.94 (s, 1H, COH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.4; 26.9; 50.7; 53.5; 55.6; 58.1; 69.0; 97.8; 109.6; 113.3; 114.5; 118.2; 130.2; 141 ,6; 145.8; 147.5; 153.9; 160.7; 183.2. C H N (0Zo)IC23H28N4O3 x 0.7 H2O; calculated: C 65.60; H 7.04; N 13.31 ; found: C 65.39; H 6.68; N 13.18.
Example E25: δ-p-μ-μ-ChlorophenyQpiperazin-i-yllbutoxylpyrazolofi.S-aJpyridine-S-carbaldehyde
Synthesis worked according to the preparation of E21 when using 5-[4-[4-(4- chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine (E19).
Yield: 36 mg (68 %) light yellow solid.
Mp.: 113°C. MS (APCI): m/z415 (M+2)+, 413 (M)+. IR (NaCI) v (cm1): 2944; 2817; 1663; 1633; 1527; 1274; 1239; 1194; 772.1H NMR (CDCI3, 600 MHz) δ (ppm): 1.71-1.76 (m, 2H,
CH2CH2N); 1.89-1.94 (m, 2H, OCH2CH2); 2.48 (t, J = 7.6 Hz, 2H, CH2N); 2.61-2.62 (m, 4H,
Piperazine); 3.16-3.18 (m, 4H, Piperazine); 4.15 (t, J = 6.3 Hz, 2H, OCH2); 6.70 (dd, J =
7.6 Hz, 2.6 Hz, 1H, H-6); 6.83-6.84 (m, 2H, Phenyl H2, Phenyl H6); 7.19-7.20 (m, 2H,
Phenyl H3, Phenyl H5); 7.57 (d, J = 2.6 Hz, 1H, H-4); 8.26 (s, 1H, H-2); 8.37 (d, J = 7.6 Hz, 1H, H-7); 9.94 (s, 1H, COH).13C NMR (CDCI3, 360 MHz) δ (ppm): 23.4; 26.9; 49.2; 53.2;
58.0; 69.0; 97.8; 109.6; 113.2; 117.2; 124.6; 129.0; 130.2; 141.6; 147.6; 150.0; 160.7;
183.2.
C H N (%):C22H25N4O2CI x 0.3H2O; calculated: C 63.17; H 6.17; N 13.39; found: C 63.12;
H 6.13; N 13.18.
Example E26:
5-[4-[4-(4-Hydroxyphenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyridine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 5-[4-[4-(4- hydroxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E20).
Yield: 38 mg (89 %) beige solid.
Mp.: 164°C. MS (APCI): m/z 395 (M+1)+. IR (NaCI) v (crτV1): 3306; 2927; 2819; 1661;
1633; 1528; 1514; 1276; 1241; 1194; 771.1H NMR (CDCI3, 360 MHz) δ (ppm): 1.70-1.78
(m, 2H, CH2CH2N); 1.86-1.93 (m, 2H, OCH2CH2); 2.49 (t, J = 7.6 Hz, 2H, CH2N); 2.64- 2.66 (m, 4H, Piperazine); 3.08-3.11 (m, 4H, Piperazine); 4.13 (t, J = 6.3 Hz, 2H, OCH2); 6.69 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.74-6.76 (m, 2H1 Phenyl H2, Phenyl H6); 6.82- 6.85 (m, 2H, Phenyl H3, Phenyl H5); 7.57 (d, J = 2.6 Hz, 1 H1 H-4); 8.26 (s, 1 H, H-2); 8.36 (d, J = 7.6 Hz1 1 H, H-7); 9.93 (s, 1 H1 COH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.2; 26.9; 50.7; 53.4; 58.0; 68.9; 97.9; 109.7; 113.2; 116.0; 118.6; 130.2; 141.7; 145.6; 147.6; 150.3; 160.8; 183.3.
Example E4: 2-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 2-[4-[4-(2,3- dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E1 ).
Yield: 75 mg (70 %) yellow solid.
Mp.: 1000C. MS (APCI): m/z449 (M+2)+, 447 (M)+. IR (NaCI) v (cm"1): 3107; 2947; 2816;
1659; 1625; 1529; 1242; 1142; 1063; 756.1H NMR (CDCI3, 600 MHz) δ (ppm): 1.72-1.77 (m, 2H, CH2CH2N); 1.91-1.96 (m, 2H1 OCH2CH2); 2.52 (t, J = 7.8 Hz, 2H, CH2N); 2.63-
2.68 (m, 4H1 Piperazine); 3.05-3.10 (m, 4H, Piperazine); 4.47 (t, J = 6.5 Hz, 2H, OCH2);
6.93-6.96 (m, 2H, H-6, Phenyl H6); 7.12-7.16 (m, 2H, Phenyl H4, Phenyl H5); 7.46 (ddd, J
= 8.8 Hz, 7.0 Hz, 1.2 Hz, 2H, H-5); 8.14 (dd, J = 8.8 Hz, 1.4 Hz, 1 H1 H-4); 8.31 (dd, J = 6.7
Hz, 1.2 Hz, 1H, H-7); 9.93 (s, 1H, COH). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.4; 27.2; 51.4; 53.4; 58.2; 69.6; 98.8; 114.0; 118.3; 118.6; 124.5; 127.4; 127.5; 129.0; 129.6; 134.1 ;
141.2; 151.4; 167.4; 182.1.
C H N (%):C22H24N4O2CI2 x 0.2H2O; calculated: C 58.59; H 5.45; N 12.42; found: C 58.50;
H 5.48; N 12.19.
Example E5:
2-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 2-[4-[4-(2- methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine (E2). Yield: 72 mg (67 %) light yellow solid.
Mp.: 1010C. MS (APCI): m/z 409 (M+1 )+. IR (NaCI) v (cm'1): 2941 ; 3068; 2943; 2814; 1656; 1626; 1527; 1240; 1061; 754. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.71-1.79 (m, 2H, CH2CH2N); 1.89-1.97 (m, 2H1OCH2CH2); 2.51 (t, J = 7.5 Hz1 2H1 CH2N); 2.66-2.69 (m, 4H1 Piperazine); 3.09-3.12 (m, 4H1 Piperazine); 3.86 (s, 3H1 OCH3); 4.47 (t, J = 6.7 Hz, 2H1 OCH2); 6.86 (dd, J = 7.9, 1.0 Hz, 1 H, Phenyl H3); 6.91-6.95 (m, 3H, Phenyl H5, Phenyl H6, H-6); 6.99 (ddd, J = 7.9 Hz, 6.7 Hz, 2.6 Hz, 1H, Phenyl H4); 7.45 (ddd, J = 8.8 Hz, 6.9 Hz, 1.2 Hz, 1 H, H-5); 8.14 (dd, J = 8.8 Hz, 1.4 Hz, 1 H, H-4); 8.31 (dd, J = 6.7 Hz, 1.2 Hz, 1 H, H-7); 9.93 (s, 1H, COH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.4; 27.2; 50.7; 53.5; 55.4; 58.3; 69.7; 98.9; 111.3; 114.0; 118.2; 118.3; 121.0; 122.9; 129.0; 129.6; 141.2; 141.4; 152.3; 167.4; 182.2.
C H N (0Zo)-C23H28N4O3 x 0.6H2O; calculated: C 65.88; H 7.02; N 13.36; found: C 65.67; H 6.79; N 13.12.
Example E6: 2-[4-[4-(2-Chlorophenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyridine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 2-[4-[4-(2- chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine (E3). Yield: 69 mg (64 %) light yellow solid. Mp.: 1040C. MS (APCI): m/z 415 (M+2)+, 413 (M)+. IR (NaCI) v (cm"1): 3062; 2947; 2814; 1659; 1626; 1527; 1230; 1063; 756. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.72-1.78 (m, 2H, CH2CH2N); 1.91-1.96 (m, 2H, OCH2CH2); 2.52 (t, J = 7.8 Hz, 2H, CH2N); 2.63-2.69 (m, 4H, Piperazine); 3.07-3.12 (m, 4H, Piperazine); 4.47 (t, J = 6.4 Hz, 2H, OCH2); 6.94 (ddd, J = 7.0 Hz, 6.8 Hz, 1.4 Hz, 1H, H-6); 6.96 (ddd, J = 7.8 Hz, 7.3 Hz, 1.3 Hz, 1 H, Phenyl H4); 7.04 (dd, J = 8.0 Hz, 1.3 Hz, 1 H, Phenyl H6); 7.21 (ddd, J = 8.0 Hz, 7.3 Hz, 1.1 Hz, 1H,
Phenyl H5); 7.35 (dd, J = 7.8 Hz, 1.1 Hz, 1H, Phenyl H3); 7.46 (ddd, J = 8.9 Hz, 7.0 Hz1 1.2 Hz, 1 H, H-5); 8.14 (dd, J = 8.9 Hz, 1.4 Hz, 1H, H-4); 8.31 (dd, J = 6.8 Hz, 1.2 Hz, 1 H, H-7); 9.93 (s, 1H, COH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.7; 27.4; 51.2; 53.4; 58.2; 69.6; 98.8; 113.9; 118.3; 120.6; 123.6; 127.6; 128.8; 129.0; 129.6; 130.7; 141.2; 149.4; 167.4; 182.2.
C H N
Figure imgf000087_0001
x 0.2H2O; calculated: C 63.44; H 6.15; N 13.45; found: C 63.17; H 5.77; N 13.63.
Example E10: 4-[4-[4-(2, 3-Dichlorophenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyhdine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 4-[4-[4-(2,3- dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine (E7). Yield: 152 mg (85 %) beige solid. Mp.: 128°C. MS (APCI): m/z 449 (M+2)\ 447 (M)+. IR (NaCI) v (cπT1): 3065; 2947; 2818; 1661; 1518; 1278; 1072; 779. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.74-1.79 (m, 2H, CH2CH2N); 1.97-2.02 (m, 2H, OCH2CH2); 2.51 (t, J = 7.6 Hz, 2H, CH2N); 2.63-2.68 (m, 4H, Piperazine); 3.05-3.09 (m, 4H, Piperazine); 4.24 (t, J = 6.3 Hz, 2H, OCH2); 6.77 (d, J = 7.6 Hz, 1H, H-5); 6.88 (dd, J = 7.6 Hz1 6.9 Hz, 1H, H-6); 6.96 (dd, J = 7.3 Hz1 2.4 Hz, 1H1 Phenyl H6); 7.13-7.16 (m, 2H, Phenyl H4, Phenyl H5); 8.22 (d, J = 6.9 Hz, 1 H, H-7); 8.46 (S, 1 H, H-2); 10.40 (S1 1H, COH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.5; 27.0; 51.3; 53.4; 57.9; 69.0; 105.4; 113.6; 115.8; 118.6; 122.7; 124.6; 127.4; 127.5; 134.0; 135.2; 142.3; 151.3; 151.5; 184.7. C H N (%):C22H24N4O2CI2; calculated: C 59.07; H 5.41 ; N 12.52; found: C 59.13; H 5.27; N 12.46.
Example E11 :
4-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 4-[4-[4-(2- methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E8).
Yield: 135 mg (84 %) light yellow solid.
Mp.: 139°C. MS (APCI): m/z409 (M+1)+. IR (NaCI) v (cm"1): 3062; 2944; 2814; 1663; 1519; 1278; 1240; 749.1H NMR (CDCI3, 600 MHz) δ (ppm): 1.74-1.79 (m, 2H, CH2CH2N),
1.97-2.02 (m, 2H, OCH2CH2), 2.51 (t, J = 7.6 Hz, 2H, CH2N)1 2.65-2.68 (m, 4H, Piperazine), 3.08-3.12 (m, 4H, Piperazine), 3.86 (s, 3H, OCH3), 4.24 (t, J = 6.3 Hz, 2H, OCH2), 6.77 (d, J = 7.6 Hz, 1H, H-5), 6.85-6.88 (m, 2H, H-6, Phenyl H3), 6.92 (ddd, J = 7.5 Hz, 7.0 Hz, 1.0 Hz, 1 H, Phenyl H5), 6.94 (dd, J = 7.5 Hz, 2.2 Hz, 1 H, Phenyl H6), 6.99 (ddd, J = 7.9 Hz, 7.0 Hz, 2.2 Hz, 1H1 Phenyl H4), 8.22 (d, J = 6.9 Hz1 1H, H-7), 8.46 (s, 1H, H-2), 10.40 (S, 1 H, COH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.5; 27.1; 50.7; 53.5; 55.4; 58.1 ; 69.1 ; 105.5; 111.4; 113.6; 115.8; 118.3; 121.1 ; 122.7; 122.9; 135.3; 141.4; 142.3; 151.5; 152.4; 184.7. C H N (%):C23H28N4O3 x 0.3H2O; calculated: C 66.74; H 6.97; N 13.54; found: C 66.58; H 6.80; N 13.56.
Example E12: 4-[4-[4~(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine-3-carbaldehyde Synthesis worked according to the preparation of E21 when using 4-[4-[4-(2- chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E9). Yield: 149 mg (90 %) light yellow solid.
Mp.: 125°C. MS (APCI): m/z 415 (M+2)+, 413 (M)+. IR (NaCI) v (crrV1): 3069; 2945; 2817; 1662; 1518; 1278; 1226; 765. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.74-1.79 (m, 2H,
CH2CH2N); 1.97-2.02 (m, 2H, OCH2CH2); 2.51 (t, J = 7.6 Hz, 2H1 CH2N); 2.63-2.67 (m, 4H, Piperazine); 3.07-3.10 (m, 4H, Piperazine); 4.24 (t, J = 6.3 Hz, 2H, OCH2); 6.77 (d, J = 7.6 Hz, 1H, H-5); 6.88 (dd, J = 7.6 Hz, 6.9 Hz, 1H, H-6); 6.96 (ddd, J = 7.8 Hz, 7.3 Hz, 1.3 Hz, 1 H, Phenyl H4); 7.05 (dd, J = 8.0 Hz, 1.3 Hz, 1 H, Phenyl H6); 7.22 (ddd, J = 8.0 Hz, 7.3 Hz, 1.5 Hz, 1H, Phenyl H5); 7.35 (dd, J = 7.8 Hz, 1.5 Hz, 1H, Phenyl H3); 8.22 (d, J = 6.9 Hz, 1H, H-7); 8.46 (s, 1 H, H-2); 10.40 (s, 1H, COH). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.4; 27.0; 51.2; 53.4; 58.0; 69.0; 105.4; 113.5; 115.7; 120.3; 122.7; 123.6; 127.5; 128.8; 130.6; 135.2; 142.3; 149.3; 151.5; 184.7. C H N (0Zo)^22H25N4O2CI; calculated: C 63.99; H 6.10; N 13.57; found: C 63.97; H 6.1 1 ; N 13.56.
Example E54: e-p-ft-fcS-Dichlorophenyljpiperazin-i-ylJbutoxyJpyrazololtS-aJpyridine-S-carbaldehyde
Synthesis worked according to the preparation of E21 when using 6-[4-[4-(2,3- dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E51 ).
Yield: 40 mg (63 %) beige solid.
Mp.: 99°C. MS (APCI): m/z 449 (M+2)+, 447 (M)+. IR (NaCI) v (cnT1): 3096; 2946; 2818;
1663; 1578; 1519; 1278; 1242; 1185; 1044; 780. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.71-1.79 (m, 2H, CH2CH2N); 1.88-1.95 (m, 2H, OCH2CH2); 2.51 (t, J = 7.6 Hz, 2H,
CH2N); 2.64-2.70 (m, 4H, Piperazine); 3.06-3.11 (m, 4H, Piperazine); 4.05 (t, J = 6.4 Hz,
2H, OCH2); 6.96 (dd, J = 6.6 Hz, 3.0 Hz, 1H, Phenyl H6); 7.14-7.15 (m, 2H, Phenyl H4,
Phenyl H5); 7.30 (dd, J = 9.7 Hz, 2.2 Hz, 1 H, H-5); 8.16-8.18 (m, 2H, H-4, H-7); 8.29 (s,
1 H, H-2); 9.98 (s, 1 H, COH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.3; 27.0; 51.4; 53.4; 58.1 ; 69.1 ; 112.7; 113.8; 118.6; 119.1; 123.7; 124.6; 127.4; 127.6; 134.1 ; 135.5; 146.2;
150.6; 151.3; 183.1.
C H N (0Zo)O22H24N4O2CI2; calculated: C 59.07; H 5.41 ; N 12.52; found: C 58.68; H 5.43; N
12.16.
Example E55: 6-[4-[4-(2- Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 6-[4-[4-(2- methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E52). Yield: 135 mg (79 %) orange solid.
Mp.: 87°C. MS (APCI): m/z 409 (M+1)+. IR (NaCI) v (crτϊ1): 3099; 2943; 2816; 1663; 1519; 1278; 1241 ; 1185; 748. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.71-1.79 (m, 2H, CH2CH2N); 1.87-1.95 (m, 2H, OCH2CH2); 2.50 (t, J = 7.6 Hz, 2H, CH2N); 2.66-2.70 (m, 4H, Piperazine); 3.09-3.14 (m, 4H, Piperazine); 3.86 (s, 3H, OCH3); 4.05 (t, J = 6.4 Hz, 2H, OCH2); 6.86 (dd, J = 8.0 Hz, 1.3 Hz, 1 H, Phenyl H3); 6.89-6.96 (m, 2H, Phenyl H5, Phenyl H6); 7.00 (ddd, J = 8.0 Hz, 6.6 Hz, 2.5 Hz, 1 H1 Phenyl H4); 7.30 (dd, J = 9.7 Hz, 2.2 Hz, 1 H, H-5); 8.15-8.18 (m, 2H, H-4, H-7); 8.28 (s, 1 H, H-2); 9.98 (s, 1 H, COH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.3; 27.1 ; 50.7; 53.6; 55.4; 58.2; 69.1 ; 111.3; 112.7; 113.8; 118.2; 119.0; 121.0; 122.9; 123.7; 135.5; 141.4; 146.2; 150.6; 152.3; 183.1. C H N (%):C23H28N4O3 x 0.3H2O; calculated: C 66.74; H 6.97; N 13.54; found: C 66.39; H 6.76; N 13.89.
Example E56:
6-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 6-[4-[4-(2- chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E53).
Yield: 19 mg (32 %) light pink solid.
Mp.: 71°C. MS (APCI): m/z415 (M+2)+, 413 (M)+. IR (NaCI) v (cm"1): 3094; 2945; 2817; 1663; 1520; 1278; 1231; 1185; 765.1H NMR (CDCI3, 360 MHz) δ (ppm): 1.71-1.79 (m, 2H1
CH2CH2N); 1.88-1.95 (m, 2H, OCH2CH2); 2.51 (t, J = 7.6 Hz, 2H, CH2N); 2.65-2.70 (m, 4H,
Piperazine); 3.08-3.13 (m, 4H, Piperazine); 4.05 (t, J = 6.3 Hz, 2H1 OCH2); 6.97 (ddd, J =
7.8 Hz, 7.3 Hz, 1.3 Hz, 1 H, Phenyl H4); 7.05 (dd, J = 8.0 Hz, 1.3 Hz, 1 H1 Phenyl H6); 7.22
(ddd, J = 8.0 Hz, 7.3 Hz, 1.5 Hz, 1 H, Phenyl H5); 7.30 (dd, J = 9.7 Hz, 2.2 Hz, 1 H, H-5); 7.35 (dd, J = 7.8 Hz, 1.5 Hz, 1 H, Phenyl H3); 8.15-8.18 (m, 2H1 H-4, H-7); 8.29 (s, 1 H, H-
2); 9.98 (S, 1 H1 COH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.4; 27.0; 51.3; 53.5; 58.1 ;
69.1 ; 112.8; 113.9; 119.1 ; 120.5; 123.8; 127.6; 128.8; 130.7; 135.5; 146.2; 149.3; 150.6;
183.1.
C H N (%):C22H25N4O2CI; calculated: C 63.99; H 6.10; N 13.57; found: C 63.60; H 6.05; N 13.34. Example E60:
7-[4-[4-(2, 3-Dichlorophenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyridine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 7-[4-[4-(2,3- dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E57). Yield: 22 mg (40 %) light green oil.
MS (APCI): m/z 449 (M+2)+, 447 (M)+. IR (NaCI) v (cm"1): 3088; 2927; 2818; 1660; 1520; 1219; 1 138; 773. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.78-1.83 (m, 2H, CH2CH2N); 2.07- 2.11 (m, 2H, OCH2CHa); 2.54 (t, J = 7.2 Hz, 2H, CH2N); 2.63-2.69 (m, 4H, Piperazine);
3.03-3.07 (m, 4H, Piperazine); 4.41 (t, J = 6.6 Hz, 2H, OCH2); 6.43 (dd, J = 7.6 Hz, 0.8 Hz, 1 H, H-6); 6.94 (dd, J = 7.1 Hz1 2.4 Hz, 1 H, Phenyl H6); 7.12-7.15 (m, 2H, Phenyl H4, Phenyl H5); 7.52 (dd, J = 8.6 Hz, 7.6 Hz, 1H, H-5); 7.91 (dd, J = 8.6 Hz, 0.8 Hz, 1H, H-4); 8.42 (s, 1 H, H-2); 10.04 (s, 1 H, COH). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.1 ; 26.7; 51.3; 53.3; 57.8; 70.5; 93.8; 110.7; 113.7; 118.6; 124.6; 127.5; 127.6; 131.2; 134.0; 141.6; 146.7; 150.9; 151.2; 183.4.
Example E61:
7-[4-[4-(2-Methoxyphenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyridine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 7-[4-[4-(2- methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E58).
Yield: 14 mg (23 %) light yellow oil.
MS (APCI): m/z 409 (M+1)+. IR (NaCI) v (cm1): 3078; 2947; 2819; 1660; 1522; 1242; 1157; 783.1H NMR (CDCI3, 600 MHz) δ (ppm): 1.79-1.85 (m, 2H, CH2CH2N); 2.07-2.11
(m, 2H, OCH2CH2); 2.56 (t, J = 7.3 Hz, 2H, CH2N); 2.68-2.73 (m, 4H, Piperazine); 3.07- 3.12 (m, 4H, Piperazine); 3.86 (s, 3H, OCH3); 4.41 (t, J = 6.8 Hz, 2H, OCH2); 6.43 (dd, J = 7.7 Hz, 0.9 Hz, 1H, H-6); 6.89 (dd, J = 8.0 Hz, 1.1 Hz, 1H, Phenyl H3); 6.92-6.95 (m, 2H, Phenyl H5, Phenyl H6); 7.09 (ddd, J = 8.0 Hz, 7.2 Hz, 1.5 Hz, 1 H, Phenyl H4); 7.52 (dd, J = 8.6 Hz, 7.7 Hz, 1H, H-5); 7.91 (dd, J = 8.6 Hz, 0.9 Hz, 1H, H-4); 8.41 (s, 1 H, H-2); 10.04
(s, 1 H, COH). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.1; 26.8; 51.3; 53.5; 55.4; 57.9; 70.5; 93.8; 110.7; 111.3; 113.8; 118.2; 121.0; 123.0; 131.2; 141.2; 141.5; 146.7; 150.8; 152.3; 183.3.
Example E62: 7-[4-[4-(2-Chlorophenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyridine-3-carbaldehyde
Synthesis worked according to the preparation of E21 when using 7-[4-[4-(2- chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E59). Yield: 13 mg (26 %) light yellow oil.
MS (APCI): m/z 415 (M+2)\ 413 (M)+. IR (NaCI) v (cm"1): 3091 ; 2943; 2818; 1662; 1520; 1296; 1041; 785. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.78-1.83 (m, 2H1 CH2CH2N); 2.07- 2.12 (m, 2H, OCH2CH2); 2.54 (t, J = 7.6 Hz, 2H1 CH2N); 2.64-2.70 (m, 4H, Piperazine); 3.04-3.10 (m, 4H, Piperazine); 4.41 (t, J = 6.6 Hz1 2H, OCH2); 6.43 (dd, J = 7.9 Hz, 0.9 Hz, 1H, H-6); 6.97 (ddd, J = 7.8 Hz, 7.3 Hz, 1.3 Hz, 1H, Phenyl H4); 7.03 (dd, J = 8.0 Hz, 1.3 Hz, 1 H, Phenyl H6); 7.22 (ddd, J = 8.0 Hz, 7.3 Hz, 1.2 Hz, 1 H, Phenyl H5); 7.35 (dd, J = 7.8 Hz, 1.2 Hz, 1 H, Phenyl H3); 7.52 (dd, J = 8.6 Hz1 7.9 Hz, 1 H, H-5); 7.91 (dd, J = 8.6 Hz, 0.9 Hz, 1 H, H-4); 8.42 (s, 1 H, H-2); 10.04 (s, 1H, COH). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.1 ; 26.8; 51.2; 53.5; 57.8; 70.5; 93.8; 110.7; 113.8; 120.4; 123.8; 127.6; 128.8; 130.7; 131.1 ; 141.6; 146.7; 149.2; 150.9; 183.4.
Example E14:
5-[3-[4-(2, 3-Dichlorophenyl)piperazin-1-yl]propoxymethyl]pyrazolo[1, 5-a]pyridine-3- carbaldehyde
Synthesis worked according to the preparation of E21 when using 5-[3-[4-(2,3- dichlorophenyl)piperazin-1-yl]propoxymethyl]pyrazolo[1 ,5-a]pyridine (E13).
Yield: 58 mg (92 %) yellow solid.
Mp.: 900C. MS (El): m/z 448 (M+1)+, 446 (M-I)+. IR (NaCI) v (crrf1): 2922; 2819; 1666; 1638; 1522; 1241 ; 1199; 775. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.86-1.93 (m, 2H1
CH2CH2N); 2.56 (t, J = 6.7 Hz, 2H, CH2N); 2.64-2.67 (m, 4H, Piperazin); 3.05-3.08 (m, 4H,
Piperazin); 3.62 (t, J = 6.3 Hz, 2H, OCH2CH2); 4.63 (s, 2H1 CH2O); 6.95 (dd, J = 6.7 Hz1
3.0 Hz, 1H, Phenyl H6); 7.11 (dd, J = 7.1 Hz1 1.9 Hz1 1 H, H-6); 7.13-7.15 (m, 2H, Phenyl
H4, Phenyl H5); 8.23 (dd, J = 1.9 Hz, 0.8 Hz, 1H, H-4); 8.37 (s, 1 H, H-2); 8.54 (dd, J = 7.1 Hz, 0.8 Hz, 1 H, H-7); 10.03 (s, 1 H1 COH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 27.1 ; 51.3;
53.4; 55.3; 69.4; 71.4; 113.7; 114.7; 116.7; 118.6; 124.6; 127.4; 127.6; 129.1 ; 134.1 ;
139.7; 141.5; 147.0; 151.3; 183.3.
5b) Compounds substituted with a halogene group in position 3 The synthesis of compounds according to formula XVI bearing a halogene group at position 3 of the pyrazolo[1 ,5-a]scaffold was done as follows:
Figure imgf000093_0001
(R1)m (R1)m formula XVa formula XVI
Example E42:
3-Bromo-5-[4-[4-(2, 3-dichlorophenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyridine
For the synthesis 13.7 mg (0.033 mmol) 5-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy] pyrazolo[1 ,5-a]pyridine (E15), 1.16 ml dry chloroform and 7.0 mg (0.039 mmol) N- bromosuccinimide were stirred at room temperature for 3 days. Then the solvent was evaporated and the crude product was purified by flash-chromatography (CH2CI2/Me0H 98:2). Yield: 13 mg (80 %) white solid.
Mp.: 132°C. MS (APCI): m/z 501 (M+3)+, 499 (M+1)+, 497 (M-I)+. IR (NaCI) v (cnrϊ1): 3080; 2953; 2818; 1648; 1558; 1238; 1192; 1045. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.71-1.79 (m, 2H, CH2CH2N); 1.88-1.94 (m, 2H1 OCH2CHa); 2.52 (t, J = 7.6 Hz, 2H, CH2N); 2.66- 2.70 (m, 4H, Piperazine); 3.07-3.10 (m, 4H, Piperazine); 4.08 (t, J = 6.3 Hz, 2H1 OCH2); 6.48 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.65 (d, J = 2.6 Hz, 1H1 H-4); 6.96 (dd, J = 6.5 Hz, 3.0 Hz, 1 H, Phenyl H6); 7.13-7.16 (m, 2H1 Phenyl H4, Phenyl H5); 7.82 (s, 1 H, H-2); 8.25 (d, J = 7.6 Hz, 1 H1 H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.4; 27.0; 51.2; 53.3; 58.1 ; 68.4; 81.9; 93.8; 107.7; 118.6; 124.6; 127.4; 127.5; 129.8; 134.1 ; 139.2; 142.5; 151.3; 156.7.
Example E43: 3-Bromo-5-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine Synthesis worked according to the preparation of E42 when using 5-[4-[4-(2- methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E16). Yield: 11 mg (63 %) colourless oil.
MS (APCI): m/z 462 (M+2)\ 460 (M)+. IR (NaCI) v (cm 1): 2941 ; 2814; 1649; 1539; 1238; 1205; 1026; 748. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.71-1.79 (m, 2H, CH2CH2N); 1.86- 1.94 (m, 2H1 OCH2ChU); 2.51 (t, J = 7.6 Hz, 2H, CH2N); 2.67-2.70 (m, 4H, Piperazine); 3.10-3.13 (m, 4H, Piperazine); 3.87 (s, 3H, OCH3); 4.08 (t, J = 6.3 Hz1 2H, OCH2); 6.48 (dd, J = 7.6 Hz, 2.6 Hz, 1H, H-6); 6.65 (d, J = 2.6 Hz1 1 H, H-4); 6.86 (dd, J = 7.9 Hz1 1.0 Hz, 1 H, Phenyl H3); 6.91-6.96 (m, 2H, Phenyl H5, Phenyl H6); 7.00 (ddd, J = 7.9 Hz1 6.8 Hz1 2.2 Hz1 1 H, Phenyl H4); 7.81 (s, 1 H1 H-2); 8.23 (d, J = 7.6 Hz, 1 H1 H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.5; 27.0; 50.8; 53.6; 55.4; 58.3; 68.5; 81.8; 93.7; 107.6; 111.3; 118.3; 121.1 ; 123.0; 129.8; 139.2; 141.4; 142.5; 152.4; 156.7.
Example E44: 3-Bromo-5-[4-[4-(2-chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine
Synthesis worked according to the preparation of E42 when using 5-[4-[4-(2- chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E17).
Yield: 13 mg (91 %) white solid. Mp.: 84°C. MS (APCI): m/z 467 (M+3)+, 465 (M+1 )+, 463 (M-1 )+. IR (NaCI) v (crτf1): 2933;
2814; 1649; 1537; 1230; 1207; 1039; 754. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.71-1.81
(m, 2H, CH2CH2N); 1.87-1.95 (m, 2H, OCH2CH2); 2.54 (t, J = 7.6 Hz1 2H, CH2N); 2.68-
2.73 (m, 4H1 Piperazine); 3.11-3.13 (m, 4H, Piperazine); 4.08 (t, J = 6.3 Hz, 2H, OCH2);
6.48 (dd, J = 7.6 Hz, 2.6 Hz1 1 H1 H-6); 6.66 (d, J = 2.6 Hz1 1 H1 H-4); 6.98 (ddd, J = 7.8 Hz1 7.3 Hz1 1.3 Hz, 1 H1 Phenyl H4); 7.05 (dd, J = 8.0 Hz1 1.3 Hz1 1 H, Phenyl H6); 7.22 (ddd, J
= 8.0 Hz1 7.3 Hz1 1.5 Hz, 1 H1 Phenyl H5); 7.36 (dd, J = 7.8 Hz, 1.5 Hz1 1 H1 Phenyl H3);
7.82 (s, 1 H1 H-2); 8.23 (d, J = 7.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.3;
26.9; 51.1 ; 53.4; 58.1 ; 68.4; 81.9; 93.8; 107.7; 120.4; 123.8; 127.6; 128.8; 129.8; 130.7;
139.2; 142.5; 149.2; 156.6.
Example E45:
3-Chloro-5-[4-[4-(2, 3-dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine Synthesis worked according to the preparation of E42 when using 5-[4-[4-(2,3- dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine (E15) and N- chlorosuccinimide and the reaction took 27 hrs. Yield: 11 mg (78 %) white solid. Mp.: 133°C. MS (APCI): m/z 457 (M+3)\ 455 (M+1)\ 453 (M-I)+. IR (NaCI) v (cπV1): 2943; 2816; 1649; 1578; 1234; 1043; 773. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.72-1.78 (m, 2H1 CH2CH2N); 1.88-1.93 (m, 2H1 OCH2CH2); 2.52 (t, J = 7.6 Hz, 2H1 CH2N); 2.65-2.70 (m, 4H, Piperazine); 3.07-3.11 (m, 4H, Piperazine); 4.08 (t, J = 6.3 Hz, 2H1 OCH2); 6.47 (dd, J = 7.6 Hz, 2.6 Hz1 1H, H-6); 6.67 (d, J = 2.6 Hz, 1H, H-4); 6.96 (dd, J = 7.0 Hz1 2.4 Hz, 1H, Phenyl H6); 7.13-7.17 (m, 2H1 Phenyl H4, Phenyl H5); 7.79 (s, 1H1 H-2); 8.20 (d, J = 7.6 Hz, 1H1 H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.3; 26.8; 51.3; 53.3; 58.0; 68.3; 93.1 ; 98.0; 107.6; 118.6; 124.7; 127.4; 127.5; 129.8; 134.1 ; 137.7; 140.4; 151.3; 156.3.
Example E46: 3-Chloro-5-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine
Synthesis worked according to the preparation of E45 when using 5-[4-[4-(2- methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine (E16). Yield: 20 mg (96 %) white solid. Mp.: 68°C. MS (APCI): m/z 417 (M+2)\ 415 (M)+. IR (NaCI) v (crrf1): 3064; 2941 ; 2819; 1649; 1539; 1238; 1020; 750. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.72-1.78 (m, 2H1 CH2CH2N); 1.87-1.92 (m, 2H1 OCH2CH2); 2.52 (t, J = 7.6 Hz, 2H, CH2N); 2.69-2.72 (m, 4H, Piperazine); 3.10-3.14 (m, 4H, Piperazine); 3.86 (s, 3H1 OCH3); 4.07 (t, J = 6.3 Hz1 2H, OCH2); 6.47 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.67 (d, J = 2.6 Hz1 1 H1 H-4); 6.86 (dd, J = 7.9 Hz1 1.0 Hz, 1 H, Phenyl H3); 6.92 (ddd, J = 7.5 Hz, 7.0 Hz, 1.0 Hz, 1 H, Phenyl H5);
6.95 (dd, J = 7.5 Hz, 2.0 Hz, 1 H, Phenyl H6); 7.00 (ddd, J = 7.9 Hz, 7.0 Hz, 2.0 Hz, 1 H, Phenyl H4); 7.80 (s, 1 H, H-2); 8.21 (d, J = 7.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.3; 27.0; 50.6; 53.4; 55.4; 58.2; 68.4; 93.1; 98.1; 107.6; 111.2; 118.2; 121.0; 123.0; 129.8; 137.8; 140.5; 141.3; 152.3; 156.4. C H N (%):C22H27N4O2CI x 0.3H2O; calculated: C 62.86; H 6.62; N 13.33; found: C 63.06;
H 6.54; N 13.07.
Example E47:
S-Chloro-δ-ft-ft-ft-chlorophenytypiperazin-i-ylJbutoxyJpyrazoloti.δ-aJpyridine Synthesis worked according to the preparation of E45 when using 5-[4-[4-(2- chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E17).
Yield: 14 mg (68 %) beige solid.
Mp.: 63°C. MS (APCI): m/z 421 (M+2)+, 419 (M)+. IR (NaCI) v (cm 1): 3062; 2943; 2818; 1649; 1539; 1232; 1211 ; 1039; 770. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.74-1.79 (m, 2H,
CH2CH2N); 1.88-1.93 (m, 2H, OCH2CJi); 2.55 (t, J = 7.6 Hz1 2H1 CH2N); 2.68-2.73 (m, 4H1
Piperazine); 3.10-3.14 (m, 4H, Piperazine); 4.08 (t, J = 6.3 Hz. 2H, OCH2); 6.48 (dd, J =
7.6 Hz, 2.6 Hz, 1 H, H-6); 6.67 (d, J = 2.6 Hz, 1 H, H-4); 6.97 (ddd, J = 7.8 Hz, 7.3 Hz, 1.3
Hz, 1H, Phenyl H4); 7.05 (dd, J = 8.0 Hz1 1.3 Hz, 1H1 Phenyl H6); 7.22 (ddd, J = 8.0 Hz1 7.3 Hz1 1.5 Hz, 1 H, Phenyl H5); 7.36 (dd, J = 7.8 Hz1 1.5 Hz, 1 H, Phenyl H3); 7.80 (s, 1 H1
H-2); 8.21 (d, J = 7.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.3; 26.9; 51.1 ;
53.4; 58.1 ; 68.3; 93.1 ; 98.1 ; 107.6; 120.4; 123.8; 127.7; 128.8; 129.8; 130.7; 137.8; 140.5;
149.2; 156.4.
C H N (%):C2iH24N4OCI2 x 0.5H2O; calculated: C 58.88; H 5.88; N 13.08; found: C 58.90; H 5.76; N 12.91.
Example E48:
5-[4-[4-(2, 3-Dichlorophenyl)piperazin- 1 -yl]butoxy]3-iodo-pyrazolo[1 , 5-a]pyridine
Synthesis worked according to the preparation of E42 when using 5-[4-[4-(2,3- dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine (E15) and Λ/-iodosuccinimide and the reaction took 2 hrs.
Yield: 16 mg (98 %) beige solid.
Mp.: 1100C. MS (APCI): m/z 546 (M+1)+. IR (NaCI) v (cm"1): 3082; 2947; 2818; 1647; 1578; 1228; 1194; 1045; 775. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.74-1.79 (m, 2H,
CH2CH2N); 1.88-1.93 (m, 2H, OCH2CH2); 2.54 (t, J = 7.6 Hz, 2H, CH2N); 2.67-2.72 (m, 4H, Piperazine); 3.08-3.12 (m, 4H, Piperazine); 4.09 (t, J = 6.3 Hz, 2H, OCH2); 6.48 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.62 (d, J = 2.6 Hz1 1 H1 H-4); 6.96 (dd, J = 7.0 Hz1 2.4 Hz1 1H1 Phenyl H6); 7.12-7.17 (m, 2H, Phenyl H4, Phenyl H5); 7.85 (s, 1 H1 H-2); 8.27 (d, J = 7.6 Hz1 1 H, H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.3; 27.0; 45.5; 51.2; 53.2; 58.0; 68.3; 95.2; 107.7; 118.7; 124.7; 127.4; 127.5; 129.9; 134.0; 142.0; 146.8; 151.2; 157.2. C H N (%):C21H23N4OCI2I; calculated: C 46.26; H 4.25; N 10.28; found: C 46.19; H 4.44; N 10.38.
Example E49: 3-lodo-5-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E48 when using 5-[4-[4-(2- methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine (E16). Yield: 18 mg (91 %) light yellow solid.
Mp.: 610C. MS (El): m/z 506 (M)+. IR (NaCI) v (cm 1): 3064; 2941; 2819; 1647; 1537; 1240; 1026; 750. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.74-1.79 (m, 2H, CH2CH2N); 1.87- 1.93 (m, 2H, OCH2CH2); 2.53 (t, J = 7.6 Hz, 2H, CH2N); 2.69-2.73 (m, 4H1 Piperazine); 3.11-3.16 (m, 4H, Piperazine); 3.86 (s, 3H, OCH3); 4.09 (t, J = 6.3 Hz1 2H, OCH2); 6.47 (dd, J = 7.6 Hz1 2.6 Hz1 1 H, H-6); 6.61 (d, J = 2.6 Hz, 1 H1 H-4); 6.86 (dd, J = 7.9 Hz1 1.0 Hz1 1H, Phenyl H3); 6.92 (ddd, J = 7.5 Hz1 7.0 Hz1 1.0 Hz1 1 H1 Phenyl H5); 6.96 (dd, J =
7.5 Hz, 2.0 Hz, 1H1 Phenyl H6); 7.00 (ddd, J = 7.9 Hz1 7.0 Hz1 2.0 Hz, 1H, Phenyl H4); 7.85 (s, 1 H, H-2); 8.27 (d, J = 7.6 Hz, 1 H1 H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.4; 27.0; 45.4; 50.6; 53.4; 55.4; 58.2; 68.4; 95.2; 107.7; 111.2; 118.3; 121.1; 123.1 ; 129.9; 141.3; 142.1 ; 146.9; 152.4; 157.2.
Example E50: 5-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]-3-iodo-pyrazolo[1,5-a]pyridine
Synthesis worked according to the preparation of E48 when using 5-[4-[4-(2- chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E17). Yield: 10 mg (99 %) light yellow solid.
Mp.: 94°C. MS (APCI): m/z 512 (M+1)+. IR (NaCI) v (cm 1): 3062; 2941; 2818; 1647; 1537; 1228; 1200; 1039; 752. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.73-1.81 (m, 2H1 CH2CH2N); 1.87-1.95 (m, 2H, OCH2CH2); 2.55 (t, J = 7.6 Hz1 2H, CH2N); 2.69-2.73 (m, 4H,
Piperazine); 3.11-3.13 (m, 4H, Piperazine); 4.09 (t, J = 6.3 Hz, 2H, OCH2); 6.48 (dd, J =
7.6 Hz, 2.6 Hz, 1 H, H-6); 6.62 (d, J = 2.6 Hz, 1 H, H-4); 6.97 (ddd, J = 7.8 Hz, 7.3 Hz, 1.3 Hz, 1 H1 Phenyl H4); 7.05 (dd, J = 8.0 Hz1 1.3 Hz, 1 H, Phenyl H6); 7.22 (ddd, J = 8.0 Hz, 7.3 Hz1 1.5 Hz, 1 H1 Phenyl H5); 7.35 (dd, J = 7.8 Hz, 1.5 Hz, 1 H, Phenyl H3); 7.85 (s, 1 H, H-2); 8.26 (d, J = 7.6 Hz1 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.3; 27.1 ; 45.5;
51.1 ; 53.4; 58.1 ; 68.4; 95.2; 107.7; 120.4; 123.8; 127.6; 128.8; 129.9; 130.7; 142.0; 146.9; 149.2; 157.1.
6. Synthesis of exemplary compounds according to formula XVII and XIX The synthesis of compounds according to formula XVII started from formyl derivatives of formula XVIa, which were aminated with hydroxylamine to get the Example compounds E30 to E35 (formula XVII, R1" = HCNOH) and subsequently dehydratised to obtain the Example compounds E36 to E38 (formula XVII, R1" = CN):
Figure imgf000098_0001
(R1)m (R1)m (R1)m formula XVIa formula XVII formula XVII (R1" = HCNOH) (Rr = CN)
Example E30: (s-trans) 5-[4-[4-(2, 3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine-3~ carbaldehyde oxime
A solution of 18.0 mg (0.26 mmol) hydroxylamine hydrochloride in 0.74 ml water and 0.07 ml (0.13 mmol) 2N NaOH were cooled to O0C and adjusted to pH = 5 with 2N HCI. Then, 57.8 mg (0.13 mmol) 5-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5- a]pyridine-3-carbaldehyde (E21) solved in 6.45 ml ethanol were added dropwise and refluxed for 2 hrs. After cooling to room temperature, saturated NaHCO3-solution was added and the mixture was extracted with dichloromethane. The organic layer was dried with Na2SO4, evaporated and purified by flash-chromatography (CH2CI2/Me0H 98:2). Two isomeres were isolated with the first one representing the s-trans isomer. Yield: 25 mg (42 %) white solid.
Mp.: 189°C. MS (APCI): m/z 464 (M+2)\ 462 (M)+. IR (KBr) v (cm'1): 3446; 3078; 2956; 2831 ; 1647; 1578; 1535; 1267; 1244; 1038; 789. 1H NMR (DMSO-d6, 360 MHz) δ (ppm): 1.60-1.68 (m, 2H, CH2CH2N); 1.79-1.86 (m, 2H, OCH2CH2); 2.44 (br t, J = 7.6 Hz, 2H, CH2N); 2.52-2.60 (m, 4H, Piperazine); 2.97-3.00 (m, 4H, Piperazine); 4.09 (t, J = 6.4 Hz, 2H, OCH2); 6.68 (dd, J = 7.6 Hz1 2.6 Hz, 1H, H-6); 7.11 (dd, J = 6.5 Hz, 3.0 Hz, 1 H, Phenyl H6); 7.26-7.30 (m, 3H, Phenyl H4, Phenyl H5, H-4); 8.08 (s, 1 H, H-2); 8.29 (s, 1 H, CHNOH); 8.58 (d, J = 7.6 Hz, 1H, H-7); 10.63 (s, 1H, OH). 13C NMR (DMSO-d6, 360 MHz) δ (ppm): 23.2; 26.9; 51.4; 53.3; 57.8; 68.6; 97.0; 104.4; 108.0; 120.0; 124.9; 126.6; 129.0; 130.0; 133.2; 138.6; 142.5; 143.1 ; 151.6; 157.5.
C H N (%): C22H25N5O2CI2 x 0.4H2O; calculated: C 56.27; H 5.54; N 14.91 ; found: C 56.48; H 5.47; N 14.69.
Example E33:
(s-cis) 5-[4-[4-(2, 3-Dichlorophenyl)piperazin- 1-yl]butoxy]pyrazolo[1 , 5-a]pyridine-3- carbaldehyde oxime
Synthesis worked identical with the preparation of E30. Flash-chromatographie yielded two isomers with the second one representing the s-cis isomer.
Yield: 24 mg (39 %) white solid.
Mp.: 165°C. MS (El): m/z 463 (M+1)+, 461 (M)+. IR (NaCI) v (cm'1): 3425; 2846; 1684;
1649; 1542; 1204; 1051 ; 764. 1H NMR (DMSO-d6, 360 MHz) δ (ppm): 1.60-1.68 (m, 2H, CH2CH2N); 1.79-1.86 (m, 2H, OCH2CH2); 2.43 (t, J = 7.6 Hz, 2H1 CH2N); 2.52-2.58 (m, 4H,
Piperazine); 2.97-3.00 (m, 4H, Piperazine); 4.14 (t, J = 6.3 Hz, 2H, OCH2); 6.68 (dd, J =
7.6 Hz, 2.6 Hz, 1H, H-6); 7.11 (dd, J = 6.5 Hz, 3.0 Hz, 1H, Phenyl H6); 7.27-7.30 (m, 2H,
Phenyl H4, Phenyl H5); 7.45 (d, J = 2.6 Hz, 1H, H-4); 7.75 (s, 1 H, H-2); 8.56-8.59 (m, 2H,
CHNOH, H-7); 11.06 (s, 1 H, OH). 13C NMR (DMSO-d6, 360 MHz) δ (ppm): 23.2; 26.8; 51.5; 53.3; 57.7; 68.8; 95.6; 103.1 ; 108.0; 120.0; 124.8; 126.5; 128.9; 130.6; 133.1 ; 137.0;
140.5; 145.6; 151.7; 157.4.
C H N (%): C22H25N5O2CI2 x 0.5H2O; calculated: C 56.06; H 5.56; N 14.86; found: C 55.91 ;
H 5.40; N 14.73.
Example E31 :
(s-trans) 5-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine-3- carbaldehyde oxime
Synthesis worked according to the preparation of E30 when using 5-[4-[4-(2- methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine-3-carbaldehyde (E22).
Yield: 42 mg (46 %) white solid.
Mp.: 77°C. MS (El): m/z 423 (M)+. IR (NaCI) v (cm"1): 3257; 3064; 2945; 2823; 1647;
1541 ; 1269; 1242; 1026; 750. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.78-1.83 (m, 2H1
CH2CH2N); 1.86-1.90 (m, 2H, OCH2CH2); 2.55 (t, J = 7.6 Hz, 2H, CH2N); 2.71-2.77 (m, 4H, Piperazine); 3.14-3.20 (m, 4H, Piperazine); 3.87 (s, 3H1 OCH3); 4.05 (t, J = 6.3 Hz, 2H, OCH2); 6.45 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.86 (dd, J = 7.9 Hz, 1.0 Hz, 1H, Phenyl H3); 6.91 (ddd, J = 7.5 Hz, 7.0 Hz, 1.0 Hz, 1H, Phenyl H5); 6.96 (dd, J = 7.5 Hz, 2.0 Hz, 1 H, Phenyl H6); 7.00 (ddd, J = 7.9 Hz, 7.0 Hz, 2.0 Hz, 1H1 Phenyl H4); 7.20 (d, J = 2.6 Hz, 1 H, H-4); 7.93 (s, 1 H, H-2); 8.22 (d, J = 7.6 Hz, 1H, H-7); 8.27 (s, 1 H, CHNOH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.3; 27.1; 50.5; 53.5; 55.5; 58.3; 68.3; 97.2; 103.8; 107.9; 111.3; 118.4; 121.1 ; 123.1; 129.6; 138.6; 141.1; 143.3; 143.6; 152.3; 157.6. C H N (%): C23H29N5O3 x 0.5H2O; calculated: C 63.87; H 6.99; N 16.19; found: C 63.88; H 6.88; N 16.02.
Example E34:
(s-cis) 5-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine-3- carbaldehyde oxime
Synthesis worked identical with the preparation of E31. Flash-chromatographie yielded two isomers with the second one representing the s-cis isomer.
Yield: 39 mg (43 %) white solid.
Mp.: 138°C. MS (El): m/z 423 (M)+. IR (NaCI) v (cm'1): 3224; 2945; 2821; 1647; 1541;
1238; 1026; 750.1H NMR (CDCI3, 360 MHz) δ (ppm): 1.74-1.82 (m, 2H, CH2CH2N); 1.87-
1.94 (m, 2H, OCH2CH2); 2.54 (t, J = 7.6 Hz, 2H, CH2N); 2.70-2.75 (m, 4H, Piperazine); 3.12-3.18 (m, 4H, Piperazine); 3.87 (s, 3H, OCH3); 4.08 (t, J = 6.3 Hz, 2H, OCH2); 6.54
(dd, J = 7.6 Hz, 2.6 Hz, 1H, H-6); 6.86 (dd, J = 7.9 Hz, 1.0 Hz, 1H, Phenyl H3); 6.88-7.02
(m, 4H, Phenyl H4, Phenyl H5, Phenyl H6, H-4); 7.50 (s, 1H, H-2); 8.30 (d, J = 7.6 Hz, 1 H,
H-7); 8.67 (s, 1 H, CHNOH). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.3; 26.8; 50.5; 53.5;
55.4; 58.1; 68.3; 94.4; 102.4; 107.7; 111.2; 118.3; 121.1 ; 123.0; 129.9; 137.9; 140.5; 141.3; 146.2; 152.3; 157.6.
C H N (%): C23H29N5O3 x 0.7H2O; calculated: C 63.34; H 7.03; N 16.06; found: C 63.21 ; H
6.77; N 15.90.
Example E32: (s-trans) 5-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy[pyrazolo[1,5-a]pyridine-3- carbaldehyde oxime
Synthesis worked according to the preparation of E30 when using 5-[4-[4-(2- chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine-3-carbaldehyde (E23). Yield: 69 mg (44 %) white solid. Mp.: 174°C. MS (APCI): m/z 430 (M+2)\ 428 (M)+. IR (KBr) v (cm 1): 3440; 3066; 2943; 2825; 1645; 1539; 1273; 1238; 1036; 756. 1H NMR (DMSO-d6l 360 MHz) δ (ppm): 1.61- 1.66 (m, 2H, CH2CH2N); 1.80-1.84 (m, 2H, OCH2CH2); 2.43 (t, J = 7.6 Hz, 2H1 CH2N); 2.52-2.59 (m, 4H, Piperazine); 2.94-3.00 (m, 4H, Piperazine); 4.09 (t, J = 6.3 Hz, 2H, OCH2); 6.69 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 7.03 (ddd, J = 7.8 Hz, 7.3 Hz, 1.3 Hz, 1 H, Phenyl H4); 7.12 (dd, J = 8.0 Hz, 1.3 Hz, 1H1 Phenyl H6); 7.27 (ddd, J = 8.0 Hz, 7.3 Hz, 1.5 Hz, 1 H, Phenyl H5); 7.29 (d, J = 2.6 Hz, 1 H, H-4); 7.39 (dd, J = 7.8 Hz, 1.5 Hz, 1 H, Phenyl H3); 8.08 (s, 1 H, H-2); 8.29 (s, 1H1 CHNOH); 8.59 (d, J = 7.6 Hz1 1 H, H-7); 10.66 (s, 1 H1 OH). 13C NMR (DMSO-d6l 360 MHz) δ (ppm): 23.1 ; 26.8; 51.3; 53.3; 57.8; 68.6; 96.9; 104.3; 108.0; 121.3; 124.3; 128.1 ; 128.5; 130.9; 138.5; 142.5; 143.0; 149.5; 157.4. C H N (%):C22H26N5O2Cl x0.1 H2O; calculated: C 61.49; H 6.15; N 16.29; found: C 61.51 ; H 6.24; N 15.99.
Example E35: (s-cis) 5-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy[pyrazolo[1, 5-a]pyhdine-3- carbaldehyde oxime
Synthesis worked identical with the preparation of E32. Flash-chromatographie yielded two isomers with the second one representing the s-cis isomer. Yield: 82 mg (52 %) white solid.
Mp.: 16O0C. MS (APCI): m/z 430 (M+2)+, 428 (M)+. IR (KBr) v (cπϊ1): 3444; 3055; 2951 ; 2823; 1647; 1529; 1232; 1038; 752. 1H NMR (DMSO-d6l 600 MHz) δ (ppm): 1.62-1.67 (m, 2H1 CH2CH2N); 1.80-1.85 (m, 2H1 OCH2CH2); 2.43 (t, J = 7.6 Hz, 2H, CH2N); 2.53-2.58 (m, 4H, Piperazine); 2.95-2.99 (m, 4H, Piperazine); 4.14 (t, J = 6.3 Hz, 2H, OCH2); 6.69 (dd, J = 7.6 Hz, 2.6 Hz, 1H, H-6); 7.03 (ddd, J = 7.8 Hz, 7.3 Hz, 1.3 Hz, 1 H, Phenyl H4); 7.13 (dd, J = 8.0 Hz, 1.3 Hz, 1H, Phenyl H6); 7.28 (ddd, J = 8.0 Hz, 7.3 Hz1 1.5 Hz1 1H, Phenyl H5); 7.39 (dd, J = 7.8 Hz, 1.5 Hz1 1H, Phenyl H3); 7.46 (d, J = 2.6 Hz, 1H1 H-4); 7.76 (s, 1H, H- 2); 8.56-8.59 (m, 2H, CHNOH1 H-7); 11.08 (s, 1 H1 OH). 13C NMR (DMSO-d6l 360 MHz) δ (ppm): 23.2; 26.7; 51.4; 53.4; 57.8; 68.8; 95.7; 103.1; 108.1; 121.3; 124.3; 128.1 ; 128.5; 130.6; 130.8; 137.1 ; 140.5; 145.6; 149.6; 157.4.
C H N (%): C22H26N5O2CI xOJ H2O; calculated: C 59.98; H 6.27; N 15.90; found: C 60.23; H 6.11 ; N 15.63.
Example E36: δ-μ-μ-fcS-DichlorophenyOpiperazin-i-yqbutoxylpyrazoloti.δ-aJpyridine-S-carbonitrile For the synthesis 126 mg (0.272 mmol) 5-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy] pyrazolo[1 ,5-a]pyridine-3-carbaldehyde oxime (E30 or E33) and 1.35 ml acetic anhydride were refluxed for 8 hrs. After adding ice the mixture was extracted with chloroform and the organic layer was dried with Na2SO4, evaporated and purified by flash-chromatography (CH2CI2/Me0H 98:2). Yield: 86 mg (72 %) beige solid.
Mp.: 118°C. MS (APCI): m/z 446 (M+2)+, 444 (M)+. IR (NaCI) v (cnY1): 3065; 2948; 2817; 2219; 1648; 1578; 1542; 1243; 1064; 781. 1H NMR (CDCI3, 600 MHz) δ (ppm): 1.73-1.78 (m, 2H, CH2CH2N); 1.90-1.95 (m, 2H, OCH2CH2); 2.53 (t, J = 7.6 Hz, 2H1 CH2N); 2.67- 2.72 (m, 4H, Piperazine); 3.07-3.12 (m, 4H, Piperazine); 4.11 (t, J = 6.4 Hz1 2H, OCH2); 6.66 (dd, J = 7.6 Hz1 2.6 Hz, 1H1 H-6); 6.94 (d, J = 2.6 Hz, 1H1 H-4); 6.96 (dd, J = 7.2 Hz1 2.2 Hz1 1H1 Phenyl H6); 7.13-7.17 (m, 2H, Phenyl H4, Phenyl H5); 8.11 (s, 1 H, H-2); 8.35 (d, J = 7.6 Hz, 1 H1 H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.2; 26.8; 51.3; 53.3; 58.0; 68.9; 80.9; 95.0; 109.3; 114.5; 118.6; 124.7; 127.4; 127.5; 130.5; 134.0; 144.4; 145.6; 151.2; 159.2.
Example E37:
5-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine-3-carbonitrile
Synthesis worked according to the preparation of E36 when using 5-[4-[4-(2- methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine-3-carbaldehyde oxime (E31 or E34).
Yield: 30 mg (79 %) white solid. Mp.: 92°C. MS (El): m/z 405 (M)+. IR (NaCI) v (cm'1): 3070; 2937; 2816; 2219; 1648;
1542; 1240; 1028; 749. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.71-1.80 (m, 2H1 CH2CH2N);
1.88-1.96 (m, 2H, OCH2CH2); 2.52 (t, J = 8.0 Hz, 2H1 CH2N); 2.68-2.72 (m, 4H,
Piperazine); 3.10-3.14 (m, 4H, Piperazine); 3.86 (s, 3H, OCH3); 4.11 (t, J = 6.1 Hz, 2H,
OCH2); 6.66 (dd, J = 7.6 Hz1 2.6 Hz1 1 H, H-6); 6.86 (dd, J = 7.8 Hz, 1.4 Hz, 1 H1 Phenyl H3); 6.91-6.96 (m, 3H1 Phenyl H5, Phenyl H6, H-4); 7.02 (ddd, J = 7.8 Hz1 6.8 Hz, 2.5 Hz1
1 H1 Phenyl H4); 8.10 (s, 1 H, H-2); 8.34 (d, J = 7.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 360
MHz) δ (ppm): 23.3; 26.9; 50.7; 53.6; 55.5; 58.1 ; 69.0; 80.9; 95.0; 109.3; 111.3; 114.4;
118.2; 121.0; 122.9; 130.5; 141.4; 144.4; 145.6; 152.4; 159.3.
Example E38: S-μ-p-fi-Chlorophenyljpiperazin-i-ylJbutoxylpyrazololi.δ-aJpyridine-S-carbonitrile
Synthesis worked according to the preparation of E36 when using 5-[4-[4-(2- chlorophenylJpiperazin-i-yllbutoxyJpyrazoloIi .δ-alpyridine-S-carbaldehyde oxime (E32 or E35).
Yield: 44 mg (66 %) light yellow solid.
Mp.: 119°C. MS (El): m/z 411 (M+1 )+, 409 (M-1 )\ IR (NaCI) v (cm'1): 3061 ; 2944; 2815; 2220; 1648; 1543; 1244; 1038; 750. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.71-1.79 (m, 2H, CH1CH2N); 1.89-1.96 (m, 2H, OCH2CH2); 2.52 (t, J = 7.6 Hz, 2H, CH2N); 2.65-2.70 (m, 4H, Piperazine); 3.07-3.12 (m, 4H, Piperazine); 4.11 (t, J = 6.4 Hz, 2H, OCH2); 6.66 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.92-6.99 (m, 2H, H-4, Phenyl H4); 7.05 (dd, J = 8.1 Hz, 1.5 Hz, 1 H1 Phenyl H6); 7.22 (ddd, J = 8.1 Hz1 7.3 Hz, 1.2 Hz1 1H, Phenyl H5); 7.35 (dd, J = 7.8 Hz1 1.2 Hz1 1 H1 Phenyl H3); 8.11 (s, 1 H, H-2); 8.34 (d, J = 7.6 Hz1 1H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.4; 26.9; 51.3; 53.4; 58.1 ; 69.0; 80.9; 95.0; 109.2; 1 14.5; 120.4; 123.7; 127.6; 128.8; 130.5; 130.6; 144.4; 145.7; 149.4; 159.3.
The synthesis of compounds according to formula XVII started from formyl derivatives of formula XVIa1 which were subsequently hydrogenised to get the Example compounds E72 (formula XVII, R1" = CH2OH) and E75 (formula XVII, R111 = CH3):
H7ZPdZC
Figure imgf000103_0001
Figure imgf000103_0002
formula XVIa formula XVII formula XVII (R1" = CH2OH) (Rr = CH3)
Example E72: 3-Hydroxymethyl-[5-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
To a solution of 100 mg (0.245 mmol) 5-[4-[4-(2-methoxyphenyl)piperazin-1- yl]butoxy]pyrazolo[1 ,5-a]pyridine-3-carbaldehyde (E22) in 9.2 ml tetrahydrofuran was added 0.1 ml (0.245 mmol) LiAIH4 (2.4M solution in THF). After refluxing for one hour and stirring for another hour at room temperature, 2 ml saturated NaHCO3-solution were added. The mixture was filtered through Celite and MgSO4, evaporated and purified by flash-chromatography (CH2CI2/Me0H 95:5). Yield: 66 mg (66 %) colourless oil.
MS (El) m/z 410 (M)+. IR (NaCI) v (cm 1): 3361; 3059; 2941; 2818; 1647; 1500; 1242; 1014; 750. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.70-1.78 (m, 2H1 CH2CH2N); 1.84-1.92 (m, 2H, OCH2CH2); 2.50 (t, J = 7.7 Hz, 2H, CH2N); 2.66-2.70 (m, 4H, Piperazine); 3.08- 3.14 (m, 4H, Piperazine); 3.86 (s, 3H, OCH3); 4.04 (t, J = 6.1 Hz, 2H, OCH2); 4.79 (s, 2H, CH2OH); 6.46 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.80 (dd, J = 2.6 Hz, 0.6 Hz, 1H, H-4); 6.86 (dd, J = 7.9 Hz, 1.1 Hz, 1 H, Phenyl H3); 6.89-6.96 (m, 2H, Phenyl H5, Phenyl H6); 6.99 (ddd, J = 7.9 Hz, 7.0 Hz, 1.7 Hz, 1 H, Phenyl H4); 7.82 (s, 1 H, H-2); 8.25 (dd, J = 7.6 Hz, 0.6 Hz, 1H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.4; 27.1; 50.6; 53.5; 55.4; 55.7; 58.2; 68.2; 94.2; 107.2; 109.4; 111.3; 118.3; 121.1 ; 123.0; 129.5; 139.9; 141.4; 142.4; 152.3; 156.0.
Example E75:
5-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]-3-methylpyrazolo[1,5-a]pyridine
A suspension of 28 mg (0.068 mmol) 3-hydroxymethyl-5-[4-[4-(2- methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine (E72) and 2.8 mg Pd/C (10%) in 3.3 ml acetic acid were stirred for six hours under H2-atmosphere and 10 bar at room temperature. Then, the mixture was filtered over celite, evaporated and purified by preparative HPLC (MeCN/H2O/TFA). Yield: 6 mg (22 %) beige oil. MS (APCI) m/z 395 (M+1)+. IR (NaCI) v (cm 1): 3066; 2939; 2812; 1647; 1500; 1242; 1115; 748. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.72-1.81 (m, 2H, CH2CH2N); 1.84-1.92
(m, 2H, OCH2CH2); 2.24 (s, 3H, CH3); 2.55 (t, J = 7.2 Hz, 2H, CH2N); 2.69-2.77 (m, 4H, Piperazine); 3.09-3.16 (m, 4H, Piperazine); 3.87 (s, 3H, OCH3); 4.04 (t, J = 6.5 Hz, 2H, OCH2); 6.38 (dd, J = 7.6 Hz, 2.6 Hz, 1H, H-6); 6.57 (dd, J = 2.6 Hz, 0.6 Hz, 1H, H-4); 6.86 (dd, J = 7.9 Hz, 1.0 Hz, 1H, Phenyl H3); 6.89-6.96 (m, 2H, Phenyl H5, Phenyl H6); 7.00 (ddd, J = 7.9 Hz, 6.6 Hz, 2.6 Hz, 1 H, Phenyl H4); 7.67 (s, 1 H, H-2); 8.21 (dd, J = 7.6 Hz,
0.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 8.2; 25.7; 27.1; 50.4; 53.4; 55.4; 58.2; 68.0; 93.8; 100.0; 104.2; 106.2; 111.2; 118.3; 121.1; 123.1 ; 129.3; 139.1 ; 142.8; 152.4; 154.9. The synthesis of further compounds according to formula XVII started from cyano derivatives of formula XVII, which were hydrogenised to get the Example compounds E78 (formula XVII1 R1" = CH2NH2) and further acylated to get E81 (formula XVII, R1" = CH2NHCOCH3):
Figure imgf000105_0001
formula XVII formula XVII formula XVII (R111 = CN) (R1" = CH2NH2) (R1" = CH2NHCOCH3)
Example E78:
3-Aminomethyl-5-[4-[4-(2-methoxyphenyl)piperazin- 1 -yl]butoxy]pyrazolo[1 , 5-a]pyridine
To a solution of 42.2 mg (0.104 mmol) 5-[4-[4-(2-methoxyphenyl)piperazin-1- yl]butoxy]pyrazolo[1 ,5-a]pyridine-3-carbonitrile (E37) in 3.9 ml tetrahydrofuran was added 0.09 ml (0.208 mmol) LiAIH4 (2.4M solution in THF). After stirring for 16 hours at room temperature, 1 ml saturated NaHCO3-solution was added. The mixture was filtered through Celite and MgSO4, evaporated and purified by flash-chromatography (CH2CI2/Me0H 95:5).
Yield: 25 mg (59 %) yellow oil.
MS (El) m/z 409 (M)+. IR (NaCI) v (cm'1): 3367; 2943; 2816; 1647; 1500; 1238; 1022; 771. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.70-1.78 (m, 2H, CH2CH2N); 1.85-1.91 (m, 2H, OCH2CH2); 2.50 (t, J = 7.7 Hz, 2H, CH2N); 2.66-2.69 (m, 4H, Piperazine); 3.09-3.13 (m, 4H, Piperazine); 3.86 (s, 3H, OCH3); 3.97 (s, 2H, CH2NH2); 4.04 (t, J = 6.3 Hz, 2H, OCH2); 6.43 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.73 (dd, J = 2.5 Hz, 0.5 Hz, 1H, H-4); 6.86 (dd, J = 7.9 Hz, 1.0 Hz, 1 H, Phenyl H3); 6.91-6.95 (m, 2H, Phenyl H5, Phenyl H6); 6.99 (ddd, J = 7.9 Hz, 7.0 Hz, 1.7 Hz, 1H, Phenyl H4); 7.80 (s, 1H, H-2); 8.24 (dd, J = 7.6 Hz, 0.5 Hz, 1 H, H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.6; 27.1 ; 36.1 ; 50.8; 53.6; 55.4; 58.3; 68.2; 94.0; 106.8; 111.1; 111.2; 118.2; 121.0; 122.9; 129.4; 138.9; 141.4; 141.7; 152.3; 155.4.
Example E81 : N-[5-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridin-3- ylmethyljacetamide
A solution of 12.0 mg (0.029 mmol) 3-aminomethyl-5-[4-[4-(2-methoxyphenyI)piperazin-1- yl]butoxy]pyrazolo[1 ,5-a]pyridine (E78) in 0.01 ml (0.107 mmol) acetic anhydride and 0.2 ml pyridine was stirred for two hours at room temperature. Then, the mixture was evaporated and purified by flash-chromatography (CH2CI2/Me0H 95:5). Yield: 13 mg (97 %) yellow oil.
MS (APCI) m/z 452 (M+1)+. IR (NaCI) v (CITV1): 3278; 3062; 2939; 2819; 1651 ; 1500; 1242; 1111; 748. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.73-1.81 (m, 2H, CH2CH2N); 1.83- 1.89 (m, 2H1 OCH2CH2); 1.98 (s, 3H, COCH3); 2.55 (t, J = 7.3 Hz1 2H, CH2N); 2.72-2.77 (m, 4H1 Piperazine); 3.10-3.16 (m, 4H, Piperazine); 3.86 (s, 3H1 OCH3); 4.04 (t, J = 6.0 Hz, 2H1 OCH2); 4.51 (d, J = 5.4 Hz, 2H, CH2NH2); 5.66-5.71 (m, 1H1 NH); 6.45 (dd, J = 7.5 Hz, 2.6 Hz, 1 H, H-6); 6.82 (dd, J = 2.6 Hz, 0.5 Hz1 1 H, H-4); 6.86 (dd, J = 7.9 Hz, 1.0 Hz, 1H, Phenyl H3); 6.89-6.95 (m, 2H, Phenyl H5, Phenyl H6); 7.00 (ddd, J = 7.9 Hz1 6.3 Hz, 2.8 Hz, 1 H, Phenyl H4); 7.77 (s, 1 H1 H-2); 8.24 (dd, J = 7.5 Hz1 0.5 Hz, 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.1 ; 23.3; 26.9; 33.4; 50.3; 53.3; 55.4; 58.1 ; 68.2; 94.3; 106.3; 107.2; 111.3; 118.3; 121.1; 123.1; 129.5; 139.8; 141.2; 142.4; 152.3; 155.9; 169.9.
The synthesis of Example compounds according to formula XIX started from compounds described in formula XVIII. Hydrogenisation led to the Example compound E66 (formula XIX, R3 = NH2) which was subsequently acylated to obtain the Example compound E67 (formula XIX1 R3 = NHCOCH3):
Figure imgf000106_0001
Example E66: 5-[4-[4-(3-Aminophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
A suspension of 100 mg (0.25 mmol) 5-[4-[4-(3-nitrophenyl)piperazin-1- yl]butoxy]pyrazolo[1 ,5-a]pyridine (E65) and 10 mg Pd/C (10%) in 15 ml ethanol were stirred for five hours under H2-atmosphere at room temperature. Then, the mixture was filtered over celite, evaporated and purified by flash-chromatography (CH2CI2/Me0H 95:5). Yield: 57 mg (61 %) beige solid.
Mp.: 86°C. MS (APCI) m/z 366 (M+1)\ IR (NaCI) v (cnT1): 3350; 3097; 2943; 2816; 1647; 1601 ; 1192; 768. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.68-1.76 (m, 2H, CH2CH2N); 1.83- 1.91 (m, 2H, OCH2CH2); 2.46 (t, J = 7.5 Hz, 2H, CH2N); 2.58-2.61 (m, 4H, Piperazine); 3.16-3.19 (m, 4H, Piperazine); 3.60 (br s, 2H, NH2); 4.01 (t, J = 6.4 Hz, 2H, OCH2); 6.21 (ddd, J = 7.9 Hz, 2.1 Hz, 0.7 Hz, 1 H, Phenyl H4); 6.25 (dd, J = 2.3 Hz, 2.1 Hz, 1H, Phenyl H2); 6.29-6.30 (m, 1 H, H-3); 6.36 (ddd, J = 8.1 Hz, 2.3 Hz, 0.7 Hz, 1 H, Phenyl H6); 6.43 (dd, J = 7.6 Hz, 2.6 Hz, 1 H, H-6); 6.73 (d, J = 2.6 Hz, 1 H, H-4); 7.04 (dd, J = 8.1 Hz, 7.9 Hz, 1 H, Phenyl H5); 7.84 (d, J = 2.3 Hz, 1 H, H-2); 8.28 (d, J = 7.6 Hz, 1 H, H-7). 13C NMR (CDCI3, 360 MHz) δ (ppm): 23.5; 27.1 ; 49.2; 53.4; 58.2; 68.1 ; 95.4; 102.9; 106.7; 106.9; 107.0; 129.3; 129.9; 141.1 ; 142.8; 147.3; 152.6; 155.7.
Example E67: N-[3-[4-[4-(Pyrazolo[1,5-a]pyridin-5-yloxy)butyl]piperazin-1-yl]phenyl]acetamide
A solution of 22.0 mg (0.060 mmol) 5-[4-[4-(3-aminophenyl)piperazin-1- yl]butoxy]pyrazolo[1 ,5-a]pyridine (E66) and 1.5 mg (0.012 mmol) 4-dimethylaminopyridine in 0.45 ml acetic anhydride was stirred for four hours at room temperature. Then, the mixture was evaporated and purified by flash-chromatography (CH2CI2/MeOH 95:5). Yield: 23 mg (93 %) yellow oil.
MS (APCI) m/z 408 (M+1)+. IR (NaCI) v (cm"1): 3305; 3089; 2947; 2819; 1670; 1647; 1608; 1547; 1192; 752. 1H NMR (CDCI3, 360 MHz) δ (ppm): 1.69-1.77 (m, 2H, CH2CH2N); 1.83-1.90 (m, 2H, OCH2CH2); 2.14 (s, 3H, COCH3); 2.49 (t, J = 7.3 Hz, 2H, CH2N); 2.61- 2.64 (m, 4H, Piperazine); 3.20-3.23 (m, 4H, Piperazine); 4.01 (t, J = 6.3 Hz, 2H, OCH2);
6.30 (dd, J = 2.3 Hz, 0.9 Hz, 1H1 H-3); 6.44 (dd, J = 7.5 Hz, 2.6 Hz, 1H, H-6); 6.65 (dd, J = 8.3 Hz, 1.8 Hz, 1 H, Phenyl H6); 6.73 (dd, J = 2.6 Hz, 0.8 Hz, 1 H, H-4); 6.83 (dd, J = 8.0 Hz, 1.8 Hz, 1H, Phenyl H4); 7.16 (dd, J = 8.3 Hz, 8.0 Hz, 1H, Phenyl H5); 7.29-7.31 (m, 1 H, Phenyl H2); 7.43 (br s, 1 H, NH), 7.85 (d, J = 2.3 Hz, 1 H, H-2); 8.29 (d, J = 7.5 Hz, 1 H, H-7). 13C NMR (CDCI3, 600 MHz) δ (ppm): 23.1 ; 24.7; 26.9; 48.7; 53.0; 58.0; 67.9; 95.4; 95.5; 106.8; 107.6; 111.0; 111.8; 129.3; 129.4; 139.0; 141.1; 142.7; 151.9; 155.7; 168.4.
7. Synthesis of exemplary compounds
7a) Heteroarene components according to formula Xl
7-Hydroxyindolizine (C4j), 6-hydroxyimidazo[1 ,2-a]pyridine (C4k), 6- hydroxyimidazo[1 , 2-a]pyridine (C4I),
Heteroarene components according to formula Xl are available by suppliers of chemical substances:
Figure imgf000108_0001
formula Xl
For example, the following precursors can be purchased: 7-Hydroxyindolizine (C4j) from Chemstep, Carbon Blanc (France) (Q1 , Q2, Q3 = CH; Y = O; m, p = 0 - [Order number: 40238])
6-Hydroxyimidazo[1 , 2-a]pyridine (C4k) from Anichem LLC, Monmouth Junction (NJ) (Q 1, Q2 = CH; Q3 = N; Y = O; m, p = 0 - [Order number: A82110])
8-Hydroxyimidazo[1 , 2-aJpyridine (C4I) from ChemPur, Karlsruhe (Germany) (Q1, Q2 = CH; Q3 = N; Y = O; m, p = 0 - [Order number: 8X-0841]) or from Chemstep, Carbon Blanc (France) (Q1 , Q2 = CH; Q3 = N; Y = O; m, p = 0 - [Order number: 40412]).
7b) Synthesis of the heteroarene components according to formula XIII
7-(4-Bromobutoxy)indolizine (C6j), 6-(4-bromobutoxy)imidazo[1,2-a]pyridine (C6k), 8-(4-bromobutoxy)imidazo[1 , 2-a]pyridine (C6I), 7-(4-Bromobutoxy)indolizine (C6j)
Synthesis can be achieved according to the preparation of C6a when using 7- hydroxyindolizine (C4j).
6-(4-Bromobutoxy)imidazo[1,2-a]pyridine (C6k)
Synthesis can be achieved according to the preparation of C6a when using 6- hydroxyimidazo[1 ,2-a]pyridine (C4k).
8-(4-Bromobutoxy)imidazo[1,2-a]pyridine (C6I) Synthesis can be achieved according to the preparation of C6a when using 8- hydroxyimidazo[1 ,2-a]pyridine (C4I).
7c) Phenylpiperazine derivatives according to formula XIV 1-(3-Trifluoromethylphenyl)piperazine (C7g),
Figure imgf000109_0001
C7a-f
Derivatives according to formula C7g-h can be purchased: 1-(3-Trifluoromethylphenyl)piperazine (C7g) from Alfa Aesar, Karlsruhe (Germany) (R3 = CF3; R2, R4-R6 = H - [Order number: L05333])
7d) Synthesis of phenylpiperazine derivatives according to formula XIV 1~(2,3-Dihydrobenzofuran-7-yl)piperazine (C7i), 1-(8-chroman-8-yl)piperazine (C7j),
1-(2, 3-dichlorophenyl)- 1, 4-diazepane (C7k) , 1 -(2-methoxyphenyl)-1,4-diazepane (C7I), 1-(2-chlorophenyl)-1, 4-diazepane (C7m), 1-(2,3-dihydrobenzofuran-7-yl)-1,4- diazepane (C7n), 1-(8-chroman-8-yl)-1, 4-diazepane (C7o)
For the general synthesis of annulated phenylpiperazine derivatives according to formula C7 ring closure reaction of a halogene substituted phenole C8a with a bishalogenated alkylene gives the annulated compound C8b which can be substituted with piperazine to the products C7.
Figure imgf000110_0001
1-(2,3-Dihydrobenzofuran-7-yl)piperazine (C7i)
In detail, for the synthesis of compound C7i 2,6-dibromophenole (29 mmol) (C8a; R4-R6 =
H) is mixed with 1 ,2-dibromoethane (29 mmol) (r = 1) unter basic aqueous conditions (NaOH) and heated at reflux for 18 hrs. The resulting monoalkylation product can be solved in THF/hexane (4/1 ), cooled to -80 0C and then, a solution of 2,5 M butyllithium (18mmol) in hexane is added dropwise (17.1 mmol). The cyclisation product 7-bromo-2,3- dihydrobenzofurane (4 mmol) (C8b; r = 1) can be suspended together with NaOtBu (20 mmol), Pd2(dba)3 (2 mol%), BINAP (2 mol%) and piperazine (8 mmol) in 5 ml dry toluene and heated at 117 0C for 6 hrs to get the product.
1-(Chroman-8-yl)piperazine (C7j)
Synthesis can be achieved according to the preparation of C7i when using 1 ,3- dibromopropane (r = 2) to get the intermediate C8c (r = 2) which is reacted with piperazine to C7j.
For the general synthesis of phenyl substituted cyclic diamine derivatives according to formula XIV the bromo phenyl derivative C9a can be substituted with the cyclic diamine C8b to achive the compounds of formula XIV.
Figure imgf000110_0002
Figure imgf000110_0003
C9b formula XIV 1 -(2, 3-Dichlorophenyl)-1 , 4-diazepane (C7k)
Synthesis can be achieved according to the last step of the preparation of C7i when using 1-bromo-2,3-dichlorobenzene (C9a: R2, R3 = Cl; R4-R6 = H) and 1 ,4-diazeipane (C9b: q = 2; k = 0).
1-(2-Methoxyphenyl)-1, 4-diazepane (C7I)
Synthesis can be achieved according to the last step of the preparation of C7i when using 1-bromo-2-methoxybenzene (C9a: R2 = OMe; R3-R6 = H) and 1 , 4-diazepane (C9b: q = 2; k = 0).
1 -(2-Chlorophenyl)-1 , 4-diazepane (C7m)
Synthesis can be achieved according to the last step of the preparation of C7i when using
1-bromo-2-chlorobenzene (C9a: R2 = Cl; R3-R6 = H) and 1 ,4-diazepane (C9b: q = 2; k = 0).
1-(2, 3-Dihydrobenzofuran-7-yl)- 1,4-diazepane (C7n)
Synthesis can be achieved according to the last step of the preparation of C7i when using 7-bromo-2,3-dihydrobenzofuran (C8b: R4-R6 = H; r = 1) and 1 ,4-diazepane (C9b: q = 2; k = 0).
1-(Chroman-8-yl)-1 , 4-diazepane (C7o)
Synthesis can be achieved according to the last step of the preparation of C7i when using
8-bromochroman (C8c: R4-R6 = H; r = 2) and 1 ,4-diazepane (C9b: q = 2; k = 0).
7e) Synthesis of example compounds according to formula XV
Example E64: 5-[4-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridine
Synthesis works according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(3-trifluoromethylphenyl)piperazine (C7g). Example E83: 5-[4-(4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1-yl)butoxy]pyrazolo[1,5-a]pyridine
Synthesis works according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(2,3-dihydrobenzofuran-7-yl)piperazine (C7i).
Example E84:
5-[4-(4-(Chroman-8-yl)piperazin-1-yl)butoxy]pyrazolo[1,5-a]pyridine
Synthesis works according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(chroman-8-yl)piperazine (C7j).
Example E85: 5-[4-(4-(2,3-Dichlorophenyl)-1,4-diazepan-1-yl)butoxy]pyrazolo[1,5-a]pyhdine
Synthesis works according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(2,3-dichlorophenyl)-1 ,4-diazepane (C7k).
Example E86:
5-[4-(4-(2-Methoxyphenyl)-1 , 4-diazepan-1-yl)butoxy]pyrazolo[1, 5-a]pyridine
Synthesis works according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(2-methoxyphenyl)-1 ,4-diazepane (C7I).
Example E87: 5-[4-(4-(2-Chlorophenyl)-1,4-diazepan-1-yl)bυtoxy]pyrazolo[1,5-a]pyridine
Synthesis works according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(2-chlorophenyl)-1 ,4-diazepane (C7m).
Example E88:
5-[4-(4-(2,3-Dihydrobenzofuran-7-yl)-1,4-diazepan-1-yl)bυtoxy]pyrazolo[1,5-aJpyridine 5-[4-(4-(Chroman-8-yl)- 1, 4-diazepan- 1-yl)butoxy]pyrazolo[1, 5-a]pyridine Synthesis works according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(2,3-dihydrobenzofuran-7-yl)-1 ,4- diazepane (C7n).
Example E89:
5-[4-(4-(Chroman-8-yl)- 1, 4-diazepan-1-yl)butoxy]pyrazolo[1, 5-a]pyridine
Synthesis works according to the preparation of E15 when using 5-(4- bromobutoxy)pyrazolo[1 ,5-a]pyridine (C6a) and 1-(chroman-8-yl)-1 ,4-diazepane (C7o).
Example E99:
7-[4-[4-(2, 3-Dichlorophenyl)piperazin- 1 -yl]butoxy]indolizine
Synthesis works according to the preparation of E15 when using 7-(4- bromobutoxy)indolizine (C6j) and 1-(2,3-dichlorophenyl)piperazine (C7a).
Example E100:
7-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]indolizine
Synthesis works according to the preparation of E15 when using 7-(4- bromobutoxy)indolizine (C6j) and 1-(2-methoxyphenyl)piperazine (C7b).
Example E101 : 7-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]indolizine
Synthesis works according to the preparation of E15 when using 7-(4- bromobutoxy)indolizine (C6j) and 1-(2-chlorophenyl)piperazine (C7c).
Example E102:
6-[4-[4-(2, 3-Dichlorophenyl)piperazin-1-yl]butoxy]imidazo[1, 2-a]pyridine
Synthesis works according to the preparation of E15 when using 6-(4- bromobutoxy)imidazo[1 ,2-a]pyridine (C6k) and 1-(2,3-dichlorophenyl)piperazine (C7a). Example E103: 6-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]imidazo[1,2-a]pyridine
Synthesis works according to the preparation of E15 when using 6-(4- bromobutoxy)imidazo[1 ,2-a]pyridine (C6k) and 1-(2-methoxyphenyl)piperazine (C7b).
Example E104: 6-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]imidazo[1,2-a]pyridine
Synthesis works according to the preparation of E15 when using 6-(4- bromobutoxy)imidazo[1 ,2-a]pyridine (C6k) and 1-(2-chlorophenyl)piperazine (C7c).
Example E105:
8-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]imidazo[1,2-a]pyridine
Synthesis works according to the preparation of E15 when using 8-(4- bromobutoxy)imidazo[1 ,2-a]pyridine (C6I) and 1-(2,3-dichlorophenyl)piperazine (C7a).
Example E106: 8-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]imidazo[1, 2-a]pyridine
Synthesis works according to the preparation of E15 when using 8-(4- bromobutoxy)imidazo[1,2-a]pyridine (C6I) and 1-(2-methoxyphenyl)piperazine (C7b).
Example E107:
8-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]imidazo[1,2-a]pyridine
Synthesis works according to the preparation of E15 when using 8-(4- bromobutoxy)imidazo[1 ,2-a]pyridine (C6I) and 1-(2-chlorophenyl)piperazine (C7c).
7f) Synthesis of example compounds according to formula XVI
Example E68: 5-[4-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridin-3- carbaldehyde
Synthesis works according to the preparation of E21 when using 5-[4-[4-(3- trifluoromethylphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E64).
Example E90:
5-[4-(4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1-yl)butoxy]pyrazolo[1,5-a]pyridin-3- carbaldehyde
Synthesis works according to the preparation of E21 when using 5-[4-(4-(2,3- dihydrobenzofuran-7-yl)piperazin-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridine (E83).
Example E91 : S-ft-ft-tChromanS-ytypiperazin-i-yljbutoxylpyrazololi.S-aJpyridinS-carbaldehyde
Synthesis works according to the preparation of E21 when using 5-[4-(4-(chroman-8- yl)piperazin-1-yl)butoxy]pyrazolo[1 ,5-a]pyridine (E84).
Example E92:
5-[4-(4-(2, 3-Dichlorophenyl)-1 ,4-diazepan-1-yl)butoxy]pyrazolo[1 , 5-a]pyridin-3- carbaldehyde
Synthesis works according to the preparation of E21 when using 5-[4-(4-(2,3- dichlorophenyl)-1 ,4-diazepan-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridine (E85).
Example E93:
5-[4-(4-(2-Methoxyphenyl)-1,4-diazepan-1-yl)butoxy]pyrazolo[1, 5-a]pyridin-3- carbaldehyde
Synthesis works according to the preparation of E21 when using 5-[4-(4-(2- methoxyphenyl)-1 ,4-diazepan-1-yl)butoxy]pyrazolo[1 ,5-a]pyridine (E86).
Example E94: δ-μ-ft-fi-Chlorophenyiyi^-diazepan-i-yljbutoxylpyrazololi.δ-aJpyridin-S-carbaldehyde Synthesis works according to the preparation of E21 when using 5-[4-(4-(2-chlorophenyl)- 1 ,4-diazepan-1-yl)butoxy]pyrazolo[1 ,5-a]pyridine (E87).
Example E95:
5-[4-(4-(2, 3-Dihydrobenzofuran- 7-yl)- 1, 4-diazepan-1-yl)butoxy]pyrazolo[1, 5-a]pyridin-3- carbaldehyde
Synthesis works according to the preparation of E21 when using 5-[4-(4-(2,3- dihydrobenzofuran-7-yl)-1 ,4-diazepan-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridine (E88).
Example E96: S-P-μ-tChroman-δ-yty-i^-diazepan-i-ytybutoxyJpyrazolotf.δ-aJpyridinS-carbaldehyde
Synthesis works according to the preparation of E21 when using 5-[4-(4-(chroman-8-yl)- 1 ,4-diazepan-1-yl)butoxy]pyrazolo[1 ,5-a]pyridine (E89).
7g) Synthesis of example compounds according to formula XVII
Example E71 : 5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]-3-hydroxymethylpyrazolo[1,5-a]pyridine
Synthesis works according to the preparation of E72 when using 5-[4-[4-(2,3- dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine-3-carbaldehyde (E21.
Example E73: 5-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]-3-hydroxymethylpyrazolo[1,5-a]pyridine
Synthesis works according to the preparation of E72 when using 5-[4-[4-(2- chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine-3-carbaldehyde (E23).
Example E74: 5-[4-[4~(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]-3-methylpyrazolo[1,5-a]pyridine Synthesis works according to the preparation of E75 when using 5-[4-[4-(2,3- dichlorophenyl)piperazin-1 -yl]butoxy]-3-hydroxymethylpyrazolo[1 ,5-a]pyridine (E71 ).
Example E76: 5-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]-3-methylpyrazolo[1, 5-a]pyridine
Synthesis works according to the preparation of E75 when using 5-[4-[4-(2- chlorophenyl)piperazin-1 -yl]butoxy]-3-hydroxymethylpyrazolo[1 ,5-a]pyridine (E73).
Example E77:
3-Aminomethyl-5-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis works according to the preparation of E78 when using 5-[4-[4-(2,3- dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine-3-carbonitrile (E36)
Example E79: 3-Aminomethyl-5-[4-[4-(2-chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine
Synthesis works according to the preparation of E78 when using 5-[4-[4-(2- chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine-3-carbonitrile (E38).
Example E80:
N-[5-[4-[4-(2, 3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1, 5-a]pyridin-3- ylmethyljacetamide
Synthesis works according to the preparation of E81 when using 3-aminomethyl-5-[4-[4- (2,3-dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine (E77).
Example E82: N-β-ft-ft-fi-Chlorophenyljpiperazin-i-yljbutoxyJpyrazololi.δ-aJpyridinS- ylmethyljacetamide
Synthesis works according to the preparation of E81 when using 3-aminomethyl-5-[4-[4- (2-methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine (E78). (b) Biological Activity - In vitro tests: Receptor binding and functional experiments
Biological activity of the Example compounds has been determined in radioligand binding assys. These experiments have been done according to methods which are described in literature (Hϋbner, H.; Haubmann, C; Utz, W.; Gmeiner, P. et al. J. Med. Chem. (2000), 43, 756-762). For the determination of binding affinity to the receptors of the dopamine D2 family membranes were established carrying the human D2long, D2short, D3 or D4.4 receptor subtype expressed in Chinese hamster ovary cell lines. In principle, the binding experiments started when incubating an appropriate amount of memebrane with the radioligand [3H]spiperone and the particular test compounds diluted in a wide range of different concentrations from subnanomolar up to micromolar. In the same way binding affinities of the test compounds to the dopamine D1 receptor were determined when using native membrane preparations from porcine striatum and the D1 selective radioligand [3H]SCH 23390.
The investigation of receptor binding to the serotonin and adrenergic receptors was done according to a published procedure (Heindl, C; hϋbner, H.; Gmeiner, P. Tetrahedron: Asymmetry (2003), 14, 3141-3152). In detail, for the serotonin receptors membrane preparations from porcine cortical material was incubated with the 5-HT1A selective radioligands [3H]8-OH-DPAT and [3H]WAY 100635 and the 5-HT2 selective compound [3H]ketanserin. For the determination of alpha receptor binding cortical membranes and the radioligands [3H]prazosin (for α1) and [3H]RX821002 were established in identical manner.
The results of the binding experiments are summarized in Table 1 as mean values of 2 to 4 individual experiments each done in triplicate and expressed as Ki values in nM. Table 1 shows that with two exceptions all presently disclosed compounds have a Ki value at the D2s and D2I receptors of 300 nM or less. 32 of the 61 tested compounds even have a Ki value at the D2 receptors of 10 nm or less. Table 1 : Results of binding assays with dopaminergic and serotonergic receptors Ki-values given: A < 3OnM; B = 30-300 nM; C = 301-3000 nM; D > 3μM compound R1 R2 R3 R4 D2lo D2sh D3 D4.4 5-HT1a 5-HT2 aripiprazole - - - - A A A B B C
Figure imgf000119_0001
Figure imgf000120_0001
E57 H Cl Cl H B A A B B B
E58 H OMe H H B B B A A C
E59 H Cl H H B B A A B B
E50 CHO Cl Cl H B A A B B B
E61 CHO OMe H H C B C C B D
E62 CHO Cl H H B A B B A B
Figure imgf000121_0001
E63 H Cl Cl H A A A A B B
E97 H OMe H H A A A A A D
E98 H Cl H H A A A A A C
Moreover, most of the compounds of the present invention exhibit a remarkable affinity to at least one of the tested serotonin receptors. While aripiprazole shows a pronounced selectivity for the D2 receptors over the D4.4 receptor as well as over the 5-HT1 a (about 40 fold) and the 5-HT2A receptor (about 330 fold), many of the presently disclosed compounds are less selective compared to D4.4 and the serotonin receptors and tend to have a more "balanced" dopamine/serotonin and D2/D4.4 ratio, which may be associated with a reduced likelihood of extrapyramidal symptoms and an increased potency to alleviate negative symptoms of schizophrenia.
The investigation of functional activity was determined when measuring the binding of [35S]GTPyS to membranes after stimulation of the appropriate receptor as published in literature (Schlotter, K.; Boeckler, F.; Hϋbner, H.; Gmeiner, P. J. Med. Chem. (2005), 48, 3696-3699).
Table 2 shows the functional (intrinsic) activity of the compounds according to the present disclosure at the dopamine D2short receptor as a representative target molecule utilizing the GTPγS-incorporation assay when the intrinsic activity is given based on % activity of quinpirol: A=FuII antagonist (<15%); B=weak partial agonist (15-40%) C=strong partial agonist (40-75%) D=FuII agonist (>75%). Table 2: Intrinsic activities of the resently disclaimed compounds at the dopamine D2short receptor determined by mitogenesis assay and binding of [35S]GTPyS
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000123_0002
E57 H Cl Cl H B
E58 H OMe H H B
E59 H Cl H H B
E60 CHO Cl Cl H A
E61 CHO OMe H H A
Figure imgf000124_0001
E63 H Cl Cl H n.d
E97 H OMe H H n.d
E98 H Cl H H n.d n.d = values were not determined
(c) Biological Activity - In vivo tests: Auditory startle response and prepulse inhibition experiments
Pharmacological tests have been conducted using young adult, male mice which were housed under standard conditions until testing when they were in the age of 8 to 9 weeks.
Auditory startle response and prepulse (weak auditory stimulus) inhibition were used as a tool for assessment of deficiencies in sensor-motor gating, such as those seen in schizophrenia.
Mice were placed in a PPI chamber for acclimation and then treated with different trials including null (no stimuli), startle (120 dB), startle plus prepulse (4, 8 and 12 dB over background noise) or prepulse alone (82 dB).
Data was analyzed by repeated measures analysis of variance (ANOVA) followed by post-hoc analysis when appropriate. An effect was considered significant if p < 0.05.
The following test compounds have been investigated as representative examples: E16, E21, E22, E36 and E37 whose stimulating effects were compared to that induced by the reference compound aripiprazole.
Table 3 shows the results of the auditory startle response and the effects on prepulse inhibition induced by the test compounds at doses of 1 , 3 and 10 mg/kg when E16, E22 and E37 show a dose-dependent PPI and when E16 enhances PPI at doses with no startle effect similar to the effects of aripiprazole.
Table 3: In vivo effect of representative examples of the presently disclosed compounds on the auditory startle response (ASR) and prepulse inhibition (PPI) in mice at doses of 1 , 3 and 10 mg/kg
Figure imgf000125_0001
E16 H OMe H H O O T O ▲ O
E21 CHO Cl Cl CHO O ▲ O O O O
E22 CHO OMe H CHO ▼ ▼ T O ▲ ▲
E36 cyano Cl Cl H O O O O O O
E37 cyano OMe H H ▼ T ▼ ▲ ▲ ▲
▲ = enhanced effect; T = reduced or suppressed effect
(d) Biological Activity - Comparitive study with indolizine based example compounds bearing an ether bridged linker or a carboxamide linker
The indolizine based example compounds of the present patent application show a remarkable affinity at the D2 receptor, and also show binding to the 5-HT2, the 5-HT1a, the D3 and D4 receptors in a range comparable to or even superior than other atypical antipsychotics like aripiprazole.
These results are unexpected because structurally related indolizine derivatives are published as highly dopamine D3 receptor affine compounds with a remarkable selectivity over D2 receptors (see Table 4) (WO 2006/015737; Bettinetti, L., Schlotter, K., Huebner, H., Gmeiner, P. J. Med. Chem. (2002), 45, 4594-4597). These D3 selective compounds are always bearing a carboxamide moiety, especially a carboxamide butyl linker. Surprisingly, we found out in this application that combining the indolizine subunit and the phenylpiperazine substructure by an ether alkylene group, especially an oxybutylene linker, leads to example compounds with high D2 binding affinity and finally to the appropriate balance of binding to the dopamine D2, D3 , D4 and the serotonin 5-HT1A receptor subtypes, which is desired for antipsychotic compounds. Table 4: Comparison of binding profiles of selected indolizines bearing an ether alkylene linker and published derivatives with a carboxamide alkylene spacer. Ki values for the dopaminergic receptors D2long, D2short, D3 and D4 and the serotoninergic receptors 5- HT1A and 5-HT2 are given in [nM].
Figure imgf000126_0001
b data from Bettinetti, L., Schlotter, K., Huebner, H., Gmeiner, P. J. Med. Chem. (2002), 5, 4594-4597.

Claims

Claims
1. Compounds of the general formula I,
(R1 )m
Figure imgf000127_0001
formula I
wherein:
Q1 and Q2 are independently of each other N, CH or C-R1 ;
Q3 is CH or C-R1 if at least one of Q1 and Q2 is different from nitrogen, and Q3 is selected from CH, C-R1 and N if Q1 and Q2 are both nitrogen;
m is 0, 1 , 2 or 3;
any R1 is bonded to a C-atom of the heterocycle of formula I and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, alkyl, cycloalkyl, alkyloxy, alkylthio, alkenyl, alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, phenylcarbonyl, phenylalkyl, phenylalkyloxy, phenylalkylcarbonyl, phenylalkyloxycarbonyl, alkyloxycarbonyl, alkylsulfonyl, phenylsulfonyl.sulfamoyl, alkylaminosulfonyl, dialkylaminosulfonyl, phenylsulfonylamino and alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy, halogen, alkyl, cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl and nitro; and wherein each cycloalkyl can be unsubstituted or substituted with hydroxyl, alkyloxy, halogen, alkyl, phenyl, amino and NR7R8. X is a group having the formula
Figure imgf000128_0001
wherein:
Y is chosen from among S and O;
k is O, 1 or 2; n is 1-5; p is O1 1 or 2; q is 1 or 2;
R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, alkyl, alkyloxy, alkylthio, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, phenylcarbonyl, phenylalkyl, phenylalkyloxy, phenylalkylcarbonyl, phenylalkyloxycarbonyl, alkyloxycarbonyl, alkylsulfonyl, phenylsulfonyl, sulfamoyl, alkylaminosulfonyl, dialkylaminosulfonyl, phenylsulfonylamino and alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy, halogen, alkyl, cycloalkyl, carboxy, NR7R8, cyano, trifluormethyl and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen- containing 5-, 6- or 7-membered ring; R7 and R8 are independently selected from hydrogen, alkyl, cycloalkyl, phenyl, heteroaryl, phenylalkyl, alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7- membered cycle; and wherein each heterocycle is a monocyclic ring and wherein phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, alkyloxy, halogen, alkyl, carboxy, NR9R10, cyano, trifluormethyl and nitro;
R9 and R10 are independently selected from among hydrogen and alkyl;
R11 is hydroxyl, (C1-C3)alkyl, hydroxy-(C1-C3)alkyl, halogen-(C1-C3)alkyl or oxo;
provided that the heterocycle of formula I carries precisely one group X;
in the form of the free base, their physiologically acceptable salts, possible conformational isomers, enatiomers, and diastereomers.
2. A compound according to claim 1 , selected from the group of formulas Ma-IId
Figure imgf000129_0001
formula Ha formula lib formula Hc formula Hd
wherein:
m is 0, 1 , 2 or 3; any R1 is bonded to a C-atom of a heterocycle of formulas Ha-IId and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C7) cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-
C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1- C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1- C10)alkyloxycarbonyl, (C1-C10)alkyloxycarbonyl, (C1-C10)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherin each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C7) cycloalkyl, carboxy,
NR7R8, cyano, trifluoromethyl, and nitro;
X is a group having the formula
Figure imgf000130_0001
wherein:
k is 0, 1 or 2; n is 1-5; p is O, 1 or 2; q is 1 or 2;
R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino,
NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C7)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1- C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1- C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1- C10)alkyloxycarbonyl, (C1-C19)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-
C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen-containing 5-, 6- or 7-membered ring;
R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3- C7)cycloalkyl; phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (Ci-CΘJalkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, carboxy, NR9R10, cyano, trifluoromethyl, and nitro;
R9 and R10 are independently selected from among hydrogen, and alkyl;
R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo;
provided that each heterocycle of formulas Ma-IId carries precisely one group X; in the form of the free base, their physiologically acceptable salts and possible enatiomers and diastereomers.
3. A compound according to anyone of the preceding claims, wherein q is 1.
4. A compound according to anyone of the preceding claims, wherein k is 0.
5. A compound according to anyone of the preceding claims, wherein R4 is hydrogen.
6. A compound according to anyone of the preceding claims, wherein
m is 0, 1 or 2; p is 0 or 1; n is 2, 3 or 4;
each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1- C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxymethyl, nitro, NR7R8;
wherein R7 and R8 are selected from among hydrogen, (C1-C3)alkyl, (C1-
C3)alkylcarbonyl and phenyl(C1-C3)alkyl.
7. A compound according to anyone of the preceding claims, wherein
m is 0, 1 or 2; p is 0 or 1 ; n is 2, 3 or 4;
R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8; R5 and R6 are independently selected from hydrogen, or fluoro;
wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
8. A compound according to anyone of the preceding claims, having the formula Ha
2 formula Ma
Figure imgf000133_0001
wherein:
R1 , X, and m have the meaning as described in the previous claims.
9. A compound according to claim 7, wherein X is bonded to the 2-, A-, 5- or 6-position of the heteroaromatic ring system of formula Ma.
10. A compound according to anyone of claims 7-8, wherein m is 1 , and R1 is in 3- position of the heteroaromatic ring system of the general formula Ha.
11. A compound according to anyone of the preceding claims, wherein X is
R2 R3
R6 R5
and wherein p is O or 1 , and the sum of p and n is 3;
R2-R6 have the meaning as defined in any of the preceding claims.
12. A compound according to claim 1 , and having the formula
Figure imgf000134_0001
wherein:
k is O, 1 , or 2; m is 0, 1 , 2 or 3; n is 1-5; p is O, 1 or 2; q is 1 or 2, and is preferably 1 ;
any R1 is bonded to a C-atom of the heterocycle of formula III, and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1- C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1- C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1- C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1- C10)alkyloxycarbonyl, (C1 -C10)alkyloxycarbonyl, (C1 -C10)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1-
C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1- C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1- C10)alkyloxycarbonyl, (C1-C19)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1- C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen-containing 5-, 6- or 7-membered ring;
R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3-
C6)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, carboxy, NR9R10, cyano, trifluoromethyl, and nitro;
R9 and R10 are independently selected from among hydrogen, and alkyl;
R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo; provided that the heterocycle of formula III carries precisely one group X;
in the form of the free base, their physiologically acceptable salts and possible enatiomers and diastereomers.
13. A compound according to claim 12, wherein
k is O or 1 ; m is 0, 1 or 2; p is O oM ; n is 2, 3 or 4; q is 1;
each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1- C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxy methyl, nitro,
NR7R8;
R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8;
R5 and R6 are independently selected from hydrogen, or fluoro;
wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
14. A compound according to claims 12 or 13, wherein
k is O; m is 0 or 1; n is 3; p is O; q is 1 ;
R1 is hydrogen, or formyl,
R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
R4, R5 and R6 are all hydrogen.
15. A compound according to claim 1 , and having the formula IV
Figure imgf000137_0001
formula IV
wherein:
k is 0,1 or 2; m is 0, 1 , 2 or 3; n is 1-5; p is 0, 1 or 2; q is 1 or 2, and is preferably 1 ;
any R1 is bonded to a C-atom of the heterocycle of formula IV, and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1- C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1- C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1- C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1- C10)alkyloxycarbonyl, (C1 -C10)alkyloxycarbonyl, (C1 -C10)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherin each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro;
R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1-
C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1- C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1- C10)alkyloxycarbonyl, (C1-C19)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1- C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1 -C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen-containing 5-, 6- or 7-membered ring;
R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3-
C7)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, carboxy, NR9R10, cyano, trifluoromethyl, and nitro;
R9 and R10 are independently selected from among hydrogen, and alkyl;
R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo;
provided that the heterocycle of formula IV carries precisely one group X;
in the form of the free base, their physiologically acceptable salts and possible enatiomers and diastereomers.
16. A compound according to claim 15, wherein
k is 0 or 1 ; m is 0, 1 or 2; p is O or i ; n is 2, 3 or 4; q is 1 ;
each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1- C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxymethyl, nitro,
NR7R8;
R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8; R5 and R6 are independently selected from hydrogen, or fluoro;
wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
17. A compound according to claims 15 or 16, wherein
k is O; m is 0 or 1 ; n is 3; p is O; q is 1 ;
R1 is hydrogen, or formyl, cyano, oxime, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxymethyl, nitro, NR7R8;
R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
R4 is selected from hydrogen, fluoro and chloro
R5 and R6 are both hydrogen.
18. A compound according to claim 1 , and having the formula V
Figure imgf000140_0001
formula V
wherein k is O, 1 or 2; m is O, 1 , 2 or 3; n is 1-5; p is O1 1 or 2; q is 1 or 2, and is preferably 0;
any R1 is bonded to a C-atom of the heterocycle of formulas V, and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3-C6)cycloalkyl, (C1- C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1- C10)alkylaminocarbonyl, di(C1-C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1- C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1- C10)alkyloxycarbonyl, (C1-C10)alkyloxycarbonyl, (C1-C10)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherin each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro;
R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino,
NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, (C3-C6)cycloalkyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (C1-C10)alkylaminocarbonyl, di(C1- C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1- C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1-
C10)alkyloxycarbonyl, (C1-C19)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1- C10)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen-containing 5-, 6- or 7-membered ring;
R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3- C6)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, carboxy, NR9R10, cyano, trifluoromethyl, and nitro;
R9 and R10 are independently selected from among hydrogen, and alkyl;
R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo;
provided that the heterocycle of formula V carries precisely one group X;
in the form of the free base, their physiologically acceptable salts and possible enatiomers and diastereomers.
19. A compound according to claim 18, wherein
k is 0 or 1 ; m is 0, 1 or 2; p is 0 or 1; n is 2, 3 or 4; q is 1 ; each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1- C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxymethyl, nitro, NR7R8;
R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8;
R5 and R6 are independently selected from hydrogen, or fluoro;
wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (C1-C3)alkyl, and phenyl(C1-C3)alkyl.
20. A compound according to claims 18 or 19, wherein
K is O; m is 0 or 1 n is 3; p is O; q is 1;
R1 is hydrogen, or formyl,
R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
R4, R5 and R6 are all hydrogen.
21. A compound according to claim 1 , and having the formula Vl1 VII or VIII
Figure imgf000144_0001
Figure imgf000144_0002
k is 0,1 or 2; m is 0, 1 , 2 or 3; n is 1 -5; p is O, 1 or 2; q is 1 or 2, and is preferably 1 ;
any R1 is bonded to a C-atom of the heterocycle of formula Vl, VII or VIII1 and is independently of each other selected from the group comprising of hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C3- C6)cycloalkyl, (C1-C10)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2- C10)alkynyl, phenyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1- C10)alkylcarbonyl, (C1 -C10)alkylaminocarbonyl, di(C1 -C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1-C10)alkyloxy, phenyl(C1-
C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1-C10)alkyloxycarbonyl, (C1- C10)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1-C10)alkylaminosulfonyl, di(C1- C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and
NR7R8; and wherein each heteroaryl is a monocyclic ring and wherin each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro;
R2, R3, R4, R5 and R6 are in each case and independently of each other selected from the group comprising hydrogen, hydroxy, formyl, oxime, cyano, nitro, amino, NR7R8, carboxy, carbamoyl, (C1-C10)alkyl, (C1-Ci0)alkyloxy, (C1-C10)alkylthio, (C2-C10)alkenyl, (C2-C10)alkynyl, phenyl, (C3-C6)cycloalkyl, heteroaryl, phenoxy, halogen, trifluoromethyl, (C1-C10)alkylcarbonyl, (Ci-C10)alkylaminocarbonyl, di(C1-
C10)alkylaminocarbonyl, phenylcarbonyl, phenyl(C1-C10)alkyl, phenyl(C1- C10)alkyloxy, phenyl(C1-C10)alkylcarbonyl, phenyl(C1-C10)alkyloxycarbonyl, (C1- C10)alkyloxycarbonyl, (C1-C19)alkylsulfonyl, phenylsulfonyl, sulfamoyl, (C1- CiO)alkylaminosulfonyl, di(C1-C10)alkylaminosulfonyl, phenylsulfonylamino, and (C1-C10)alkylsulfonylamino; wherein each alkyl, alkenyl or alkynyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, and NR7R8; and wherein each heteroaryl is a monocyclic ring and wherein each phenyl or heteroaryl can be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1- C6)alkyloxy, halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, carboxy, NR7R8, cyano, trifluoromethyl, and nitro; and wherein two vicinal residues R2, R3, R4, R5 and R6 together with the C-atoms of the phenyl ring to which they are bonded, can form an oxygen and/or nitrogen-containing 5-, 6- or 7-membered ring; R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C3- C6)cycloalkyl, phenyl, heteroaryl, phenyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkyloxycarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, phenylcarbonyl, and heteroarylcarbonyl; wherein each alkyl may be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, phenyl, fluoro, carboxy, and NR9R10; and wherein R7 and R8 may form a 5- to 7-membered cycle; and wherein each heterocycle is a monocyclic ring and wherein each phenyl or heteroaryl be unsubstituted or substituted with one or more residues selected from among hydroxyl, (C1-C6)alkyloxy, halogen, (C1-C6)alkyl, carboxy, NR9R10, cyano, trifluoromethyl, and nitro;
R9 and R10 are independently selected from among hydrogen, and alkyl;
R11 is methyl, ethyl, hydroxyl, hydroxymethyl, or oxo;
provided that the heterocycle of any compound of formula Vl, VII or VIII carries precisely one group X;
in the form of the free base, their physiologically acceptable salts and possible enatiomers and diastereomers.
22. A compound according to claim 21, wherein
k is O or i ; m is 0, 1 or 2; p is 0 or 1 ; n is 2, 3 or 4; q is 1 ;
each R1 is independently selected from hydrogen, formyl, cyano, oxime, (C1-
C3)alkylcarbonyl, (C1-C3)alkyloxycarbonyl, chloro, bromo, iodo, hydroxymethyl, nitro,
NR7R8; R2 and R3 are independently selected from among hydrogen, fluoro, chloro, bromo, trifluoromethyl, (C1-C3)alkyloxy, (C1-C3)alkyl, -NR7R8, or R2 and R3 form together with the phenylring to which they are attached a dihydrobenzofurane, chromane, tetrahydrobenzoxepine or benzodioxole group;
R4 is selected from hydrogen, (C1-C3)alkyloxy, hydroxy, chloro, fluoro, trifluoromethyl, or NR7R8;
R5 and R6 are independently selected from hydrogen, or fluoro;
wherein R7 and R8 are independently selected from hydrogen, (C1-C3)alkylcarbonyl, (Ci-C3)alkyl, and phenyl(C1-C3)alkyl.
23. A compound according to claims 21 or 22, wherein
k is O; m is 0 or 1 ; n is 3; p is O; q is 1 ;
R1 is hydrogen, or formyl,
R2 and R3 are independently selected from hydrogen, methoxy, chloro, amino, and acetylamino;
R4, R5 and R6 are all hydrogen.
24. A compound selected from
2-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine
2-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine
2-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine - 2-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
2-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde - 2-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 4-[4-[4-(2,3-Dich!orophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 4-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 4-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine - 4-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 4-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 4-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
5-[3-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]propoxymethyl]pyrazolo[1 ,5-a]pyridine 5-[3-[4-(2,3-Dichlorophenyl)piperazin-1-yl]propoxymethyl]pyrazolo[1 ,5-a]pyridin- 3-carbaldehyde
5-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine - 5-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine 5-[4-[4-(4-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 5-[4-[4-(4-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridine 5-[4-[4-(4-Hydroxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine - 5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldeyhde
5-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldeyhde
5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyrϊdin-3- carbaldeyhde
5-[4-[4-(4-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldeyhde
- 5-[4-[4-(4-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldeyhde - 5-[4-[4-(4-Hydroxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldeyhde
- 1-[5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- yl]ethanone - 1-[5-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- yljethanone
- 1-[5-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- yl]ethanone
- (rs-frans;)-5-[4-[4-(2,3-DichIorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-aJpyridin- 3-carbaldehyde oxime
- fs-fransj-5-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde oxime
- ('s-frans>5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde oxime - fs-c/s^-5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde oxime
- fs-c/sJ-5-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde oxime fs-c/s>)-5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde oxime
- 5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbonitrile
- 5-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1,5-a]pyridin-3- carbonitrile - 5-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbonitrile
- 5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carboxylic acid ethyl ester
- 5-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carboxylic acid ethyl ester
- 5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3-carboxylic acid ethyl ester
- 3-Bromo-5-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 3-Bromo-5-[4-[4-(2-methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine - 3-Bromo-5-[4-[4-(2-chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine 3-Chloro-5-[4-[4-(2,3-dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5- a]pyridine
- 3-Chloro-5-[4-[4-(2-methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine 3-Chloro-5-[4-[4-(2-chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine - 5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]-3-iodopyrazolo[1 ,5-a]pyridine
3-lodo-5-[4-[4-(2-methoxyphenyI)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine 5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]-3-iodopyrazolo[1 ,5-a]pyridine
- 6-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 6-[4-[4-(2-MethoxyphenyI)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine - 6-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 6-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
6-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde - 6-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 7-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine 7-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridine 7-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine - 7-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
7-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 7-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 7-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]tetrazolo[1 ,5-a]pyridine 7-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]tetrazolo[1 ,5-a]pyridine 7-[4-[4-(2-Chloroyphenyl)piperazin-1-yl]butoxy]tetrazolo[1 ,5-a]pyridine
- 5-[4-[4-(3-Trifluoromethylphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine - 5-[4-[4-(3-Nitrophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine
- 5-[4-[4-(3-Aminophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridine
- Λ/-[3-[4-[4-(Pyrazolo[1 ,5-a]pyridin-5-yloxy)butyl]piperazin-1-yl]phenyl]acetamide 5-[4-[4-(3-TrifIuoromethylphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde 5-[4-[4-(3-Nitrophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- Λ/-[3-[4-[4-(3-Formylpyrazolo[1 ,5-a]pyridin-5-yloxy)butyl]piperazin-1 - yl]phenyl]acetamide - 5-[4-[4-(2,3-DichIorophenyl)piperazin-1 -yl]butoxy]-3-hydroxymethylpyrazolo[1 ,5- a]pyridine
3-Hydroxymethyl-5-[4-[4-(2-methoxyphenyl)piperazin-1 - yl]butoxy]methylpyrazolo[1 ,5-a]pyridine
5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]-3-hydroxymethylpyrazolo[1 ,5- a]pyridine
5-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]-3-methylpyrazolo[1 ,5- ajpyridine
5-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]-3-methylpyrazolo[1 ,5-a]pyridine
- 5-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]-3-methylpyrazolo[1 ,5-a]pyridine - 3-Aminomethyl-5-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5- a]pyridine
3-Aminomethyl-5-[4-[4-(2-methoxyphenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5- a]pyridine
3-Aminomethyl-5-[4-[4-(2-chlorophenyl)piperazin-1 -yl]butoxy]pyrazolo[1 ,5- a]pyridine
- Λ/-[5-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- ylmethyl]acetamide
- Λ/-[5-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butoxy]pyrazolo[1 ,5-a]pyridin-3- ylmethyl]acetamide - Λ/-[5-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]pyrazoIo[1 ,5-a]pyridin-3- ylmethyljacetamide
- 5-[4-(4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridine
- 5-[4-(4-(Chroman-8-yl)piperazin-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridine
- 5-[4-(4-(2,3-Dichlorophenyl)-1 ,4-diazepan-1-yl)butoxy]pyrazolo[1 ,5-a]pyridine - 5-[4-(4-(2-Methoxyphenyl)-1 ,4-diazepan-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridine
- 5-[4-(4-(2-Chlorophenyl)-1 ,4-diazepan-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridine
- 5-[4-(4-(2,3-Dihydrobenzofuran-7-yl)-1 ,4-diazepan-1 -yl)butoxy]pyrazolo[1 ,5- a]pyridine
- 5-[4-(4-(Chroman-8-yl)-1 ,4-diazepan-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridine 5-[4-(4-(2,3-Dihydrobenzofuran-7-yl)piperazin-1-yl)butoxy]pyrazolo[1 ,5-a]pyridin- 3-carbaldehyde
- 5-[4-(4-(Chroman-8-yl)piperazin-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde - 5-[4-(4-(2,3-Dichlorophenyl)-1 ,4-diazepan-1-yl)butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
5-[4-(4-(2-Methoxyphenyl)-1 ,4-diazepan-i -yl)butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 5-[4-(4-(2-Chlorophenyl)-1 ,4-diazepan-i -yl)butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde
- 5-[4-(4-(2,3-Dihydrobenzofuran-7-yl)-1 ,4-diazepan-1-yl)butoxy]pyrazolo[1 ,5- a]pyridin-3-carbaldehyde
- 5-[4-(4-(Chroman-8-yl)-1 ,4-diazepan-1 -yl)butoxy]pyrazolo[1 ,5-a]pyridin-3- carbaldehyde - 7-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]indolizine
- 7-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]indolizine 7-[4-[4-(2-Chloroyphenyl)piperazin-1 -yl]butoxy]indolizine
- 6-[4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]butoxy]imidazo[1 ,2-a]pyridine
- 6-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]imidazo[1 ,2-a]pyridine - 6-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butoxy]imidazo[1 ,2-a]pyridine
- 8-[4-[4-(2,3-Dichlorophenyl)piperazin-1 -yl]butoxy]imidazo[1 ,2-a]pyridine
- 8-[4-[4-(2-Methoxyphenyl)piperazin-1 -yl]butoxy]imidazo[1 ,2-a]pyridine 8-[4-[4-(2-Chlorophenyl)piperazin-1 -yl]butoxy]imidazo[1 ,2-a]pyridine
25. A medicine comprising a compound of anyone of claims 1-24.
26. Pharmaceutical composition comprising a compound of anyone of claims 1-24 and a pharmaceutical acceptable carrier.
27. Use of a compound according to anyone of claims 1-24 for preparing a medicament for the treatment of a disease selected from psychotic diseases including manic phases of bipolar disorder, acute idiopathic psychotic illnesses, psychoses associated with other diseases, drug-induced psychoses, and schizophrenia; attention deficit hyperactivity disorder (ADHD); autism; bipolar disorder; cognitive impairment; idiopathic or drug-induced movement disorders such as akinesia and diskinesia; Parkinson's disease; mood disorders including major depressive disorders, substance-induced mood disorders or other forms of depression; anxiety disorders including panic attack, social phobia, or generalized anxiety disorders; obsessive-compulsive disorders; stress-related disorders; addiction disorders; sleep disorders; sexual dysfunction; amnesic and/or cognitive disorders, especially dementia; eating disorders including anorexia and bulemia; pain; and neurodegenerative diseases including Chorea Huntington and multiple sclerosis.
28. Use ace to claim 27, wherein the disease is schizophrenia.
29. Method of treating a patient having a disease selected from psychotic diseases including manic phases of bipolar disorder, acute idiopathic psychotic illnesses, psychoses associated with other diseases, drug-induced psychoses, and schizophrenia; attention deficit hyperactivity disorder (ADHD); autism; bipolar disorder; cognitive impairment; idiopathic or drug-induced movement disorders such as akinesia and diskinesia; Parkinson's disease; mood disorders including major depressive disorders, substance-induced mood disorders or other forms of depression; anxiety disorders including panic attack, social phobia, or generalized anxiety disorders; obsessive-compulsive disorders; stress-related disorders; addiction disorders; sleep disorders; sexual dysfunction; amnesic and/or cognitive disorders, especially dementia; eating disorders including anorexia and bulemia; pain; and neurodegenerative diseases including Chorea Huntington and multiple sclerosis by administering a compound of anyone of claims 1-24.
30. Method according to claim 29, wherein the disease is schizophrenia.
31. Method according to claims 29-30, wherein the patient is selected for said treatment of said disease based on a prior diagnosis of said disease.
32. Kit comprising a medicine according to claim 25, and instructions for its use.
33. A method of producing a compound according to anyone of claims 1-24 comprising the steps of a. reacting a compound of formula Xl with an activated alkylene having the formula XII to give a compound of formula XIII
Figure imgf000154_0001
formula Xl formula XII formula XIII
which compound of formula XIII is then combined with a compound of formula XIV
Figure imgf000154_0002
formula XIV
to give a compound of formula XV
X
Figure imgf000154_0003
(R1)m formula XV
wherein in anyone of formulas Xl, XII, XIII, XIV, and XV
R1 , Q1 , Q2, X, Y1 n, R11 , q, k, R2, R3, R4, R5, and R6 are as defined in anyone of claims 1-20 for the compounds of formulas I, Ma, Mb, Nc, Nd, III, IV, V, Vl, VII or VIII; and
W and V are activating groups; and
(b) optionally adding to the compound of formula XV one or more additional groups R1 to give a compound of anyone of formula I, Ma, Hb1 Mc1 Md, III, IV1 V1 VI1 VII or VIII according to anyone of claims 1-24.
34. A method according to claim 33, wherein the activating groups W and V are independently selected from among bromo, chloro, iodine, mesylate, triflate or tosylate.
35. A method according to claim 33, wherein in step (b) to a compound of formula XVa an additional group R1' is added to give a compound of formula XVI, which compound of formula XVI is dentical to or can be further transformed into a compound of formula I, Ha, lib, Mc, Md, III, IV, V, Vl, VII or VIII according to anyone of claims 1 , 2, 12, 15, 18 or 21
Figure imgf000155_0001
formula XVa formula XVI
wherein in formulas XVa and XVI
R11 is selected from among bromo, chloro, iodine, formyl, hydroxymethyl, alkyl, oxime, cyano, aminomethyl, acylaminomethyl; and
R1 , Q1 , Q3, X and m are as defined in anyone of claims 1-23.
36. A method of producing a compound of formula XVI according to claim 35 wherein RT is selected from among bromo, chloro, iodine and formyl and RT is introduced by the reaction of a compound of formula XVa with an activated precursor to get a compound of formula XVI
37. A method according to claim 33, comprising the steps of
(b1) adding to a compound of formula XVa a formyl group to give a compound of formula XVIa
Figure imgf000156_0001
formula XVa formula XVIa
and
(b2) transforming the formyl group of formula XVIa to give a compound of formula XVII which compound of formula XVII is comprised by formula I, Ha1 lib, Hc, Hd, III, IV, V, Vl, VII or VIII according to anyone of claims 1 , 2, 12, 15, 18, or 21 ,
Figure imgf000156_0002
formula XVIa formula XVII
wherein R1" is selected from among hydroxymethyl, alkyl, oxime, cyano, aminomethyl and acylaminomethyl,
and Q1 , Q3, X and m as as defined in any of the claims 1-20.
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