Active substance combination comprising a compound with npy receptor affinity and a compound with 5-ht6 receptor affinity

The present invention relates to an active substance combination comprising at least one compound with neuropeptide Y-receptor affinity, preferably neuropeptide Y5-receptor affinity, and at least one compound with 5-HT₆receptor affinity, a medicament comprising said active substance combination, and the use of said active substance combination for the manufacture of a medicament.

The superfamily of serotonin receptors (5-HT) includes 7 classes (5-HT₁-5-HT₇) encompassing 14 human subclasses [D. Hoyer, et al., Neuropharmacology, 1997, 36, 419]. The 5-HT₆receptor is the latest serotonin receptor identified by molecular cloning both in rats [F. J. Monsma, et al., Mol. Pharmacol., 1993, 43, 320; M. Ruat, et al., Biochem. Biophys. Res. Commun., 1993, 193, 268] and in humans [R. Kohen, et al., J. Neurochem., 1996, 66, 47]. Compounds with 5-HT₆receptor affinity are useful for the treatment of various disorders of the Central Nervous System and of the gastrointestinal tract, such as irritable intestine syndrome. Compounds with 5-HT₆receptor affinity are also useful in the treatment of anxiety, depression and cognitive memory disorders [M. Yoshioka, et al., Ann. NY Acad. Sci., 1998, 861, 244; A. Bourson, et al., Br. J. Pharmacol., 1998, 125, 1562; D. C. Rogers, et al., Br. J. Pharmacol. Suppl., 1999, 127, 22P; A. Bourson, et al., J. Pharmacol. Exp. Ther., 1995, 274, 173; A. J. Sleight, et al., Behav. Brain Res., 1996, 73, 245; T. A. Branchek, et al., Annu. Rev. Pharmacol. Toxicol., 2000, 40, 319; C. Routledge, et al., Br. J. Pharmacol., 2000, 130, 1606]. It has been shown that typical and atypical antipsychotic drugs for treating schizophrenia have a high affinity for 5-HT₆receptors [B. L. Roth, et al., J. Pharmacol. Exp. Ther., 1994, 268, 1403; C. E. Glatt, et al., Mol. Med., 1995, 1, 398; F. J. Mosma, et al., Mol. Pharmacol., 1993, 43, 320; T. Shinkai, et al., Am. J. Med. Genet., 1999, 88, 120]. Compounds with 5-HT₆receptor affinity are useful for treating infant hyperkinesia (ADHD, attention deficit/hyperactivity disorder) [W. D. Hirst, et al., Br. J. Pharmacol., 2000, 130, 1597; C. Gérard, et al., Brain Research, 1997, 746, 207; M. R. Pranzatelli, Drugs of Today, 1997, 33, 379]. Moreover, it has been shown that the 5-HT₆receptor also plays a role in food ingestion [Neuropharmacology, 41, 2001, 210-219].

Food ingestion disorders, particularly obesity, are a serious, fast growing threat to the health of humans of all age groups, since they increase the risk of developing other serious, even life-threatening diseases such as diabetes or coronary diseases.

Neuropeptide Y (NPY), first isolated in porcine brain extracts (Tatemoto et. al. Nature 1982, 296, 659), is a 36-aminoacid peptide belonging to the family of pancreatic polypeptides, and is one of the most abundant peptides in the brain and in the central nervous system. In addition, NPY is also distributed in several parts of the peripheral nervous system.

Several studies suggest a significant role of NPY in food ingestion regulation and particularly in food dysfunctions like obesity, anorexia and bulimia. Specifically, NPY is a powerful stimulant of food ingestion. Thus, appetite is significantly increased when NPY is injected directly into the CNS of satiated mice (Clark J. T. et. al. Endocrinology 1984, 115, 427; Levine A. S. et. al. Peptides 1984, 5, 1025; Stanley B. G. et. al. Life Sci. 1984, 35, 2635; Stanley B. G. et. al. Proc. Nat. Acad. Sci. USA 1985, 82, 3940). On the other hand, NPY may play a role in cognitive function regulation, e.g. memory (Flood J. F. et. al. Brain Res. 1987, 421, 280; Redrobe J. P. et. Al. Brain Res. 1999, 848, 153), and be active in anxiety (Heilig M. et. al. Reg. Peptides 1992, 41, 61) and depression (Heilig M. et. al. Eur. J. Pharmacol. 1988, 147, 465) processes.

NPY is also distributed in the peripheral system. Some studies suggest that it might be involved in hypertensive (Michel M. C: et. al. J. Hypertens. 1995, 13, 385), and analgesic (Gehlert D. R. Life Sci. 1994, 55, 551) processes, among others.

The endogenous proteins that constitute NPY-binding receptors have been widely studied. Several have been cloned and expressed. At present, six different receptor subtypes, named Y1 to Y6, are recognized (Hispkind P. A. et. al. Annu. Rep. Med. Chem. 1996, 31, 1; Grundemar L. et. al. TIPS Reviews., 15, 153, 1994). Each NPY receptor subtype is generally associated to a different biological activity. For example, Y2 receptor is involved in the induction of convulsions in rats (Dumont Y. et. al. Brit. J. Pharmacol. 2000, 129, 1075).

The most recently identified receptor is Y5 (Hu et. al. J. Biol. Chem. 1996, 271, 26315). There is evidence that Y5 receptor has a unique pharmacological profile related to food ingestion as compared to the other receptor subtypes. The fact that [D-Trp³²]NPY peptide, a selective Y5-receptor agonist with no affinity for Y1 receptor, stimulates food ingestion in rats (Gerald C. et. al. Nature, 1996, 382, 168), supports the hypothesis that Y5 receptor is related to exaggerated food consumption. Consequently, compounds having an affinity to the Y5 receptor should be effective to inhibit food ingestion and very useful to control diseases like obesity or other disorders of food ingestion (food intake), such as anorexia, bulimia, cachexia or type II diabetes. Moreover, it has been suggested that such compounds are useful to control diseases such as arthritis or epilepsy.

Whereas known compounds with NPY-receptor affinity and known compounds with 5-HT₆receptor affinity are generally effective for treating disorders related to NPY-receptors and to 5-HT₆receptors respectively, in some instances they show undesirable side effects.

It was therefore an object of the present invention to provide a medicament suitable for the prophylaxis and/or treatment of disorders related to NPY-receptors, preferably NPY5-receptors, and to 5-HT₆receptors, which preferably does not show the undesired side effects of the conventional compounds with NPY-receptor affinity or 5-HT₆receptor affinity, or at least less frequent and/or less pronounced.

Said object was achieved by providing an active substance combination comprising

(A) at least one compound with neuropeptide Y (NPY)-receptor affinity and

(B) at least one compound with 5-HT₆receptor affinity

It has surprisingly been found that the compounds with NPY-receptor affinity and the compounds with 5-HT₆receptor affinity show a synergic effect in their pharmacological activities. Consequently, the dose of the corresponding compounds may be reduced in comparison to the dose necessary for an individual administration of said compounds.

Preferably, the active substance combination of the present invention may comprise as a component (A) at least one compound with neuropeptide Y5 (NPY5)-receptor affinity.

Preferably, the active substance combination of the present invention may comprise as a component (A) at least one compound with neuropeptide Y (NPY)-receptor affinity, preferably with neuropeptide Y5 (NPY5)-receptor affinity, which is selected form the group consisting of the 1,4-disubstituted piperidine compounds of general formula (Ia),
embedded image

wherein

R^1a, R^2a, R^3a, R^4aare each independently selected from the group consisting of hydrogen, halogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro, cyano, —OR^12a, —OC(═O)R^13a, —SR^14a, —SOR^14a, —SO₂R^14a, —NH—SO₂R^14a, —SO₂NH₂and —NR^15aR^16amoiety,

R^5arepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical,

R^6a, R^7a, R^8a, R^9aare each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, a cyano and a —COOR^17amoiety,

A represents a bridge member —CHR^18a— or —CHR^18a—CH₂—,

R^10arepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^11arepresents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or

R^10aand R^11atogether with the bridging nitrogen atom form an optionally at least mono-substituted, saturated, unsaturated or aromatic heterocyclic ring that may contain at least one further heteroatom as a ring member and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem,

R^12arepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^13arepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^14arepresents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^15aand R^16aare each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

or R^15aand R^16atogether with the bridging nitrogen atom form a saturated, unsaturated or aromatic heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as ring member,

R^17arepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^18arepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

A mono- or polycyclic ring-system according to the present invention means a mono- or polycyclic hydrocarbon ring-system that may be saturated, unsaturated or aromatic. If the ring system is polycyclic, each of its different rings may show a different degree of saturation, i.e. it may be saturated, unsaturated or aromatic. Optionally each of the rings of the mono- or polycyclic ring system may contain one or more heteroatoms as ring members, which may be identical or different and which can preferably be selected from the group consisting of N, O, S and P, more preferably be selected from the group consisting of N, O and S. Preferably the polycyclic ring-system may comprise two rings that are condensed. The rings of the mono- or polycyclic ring-system are preferably 5- or 6-membered.

Those skilled in the art understand that the term “condensed” indicates that the condensed rings share more than one atom. The terms “annulated” or “fused” may also be used for this type of bonding.

If one or more of the residues R^1a-R^18arepresents an aliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkoxy, branched or unbranched C_1-4-perfluoroalkoxy, branched or unbranched C_1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO₂NH₂, —CO—C_1-4-alkyl, —SO—C_1-4-alkyl, —SO₂—C_1-4-alkyl, —NH—SO₂—C_1-4-alkyl, wherein the C_1-4-alkyl may in each case be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF₃and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.

If one or more of the residues R^1a-R^18arepresents or comprises a cycloaliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkyl, branched or unbranched C_1-4-alkoxy, branched or unbranched C_1-4-perfluoroalkoxy, phenoxy, benzoyl, cyclohexyl, branched or unbranched C_1-4-perfluoroalkyl, —NR^AaR^Bawherein R^Aa, R^Baare each independently selected from the group consisting of H, a branched or unbranched C_1-4-alkyl-radical, —CH₂—CH₂—OH and phenyl, carboxy, amido, cyano, nitro, —SO₂NH₂, —CO—C_1-4-alkyl, —CO—OC_1-4-alkyl, —SO—C_1-4-alkyl, —SO₂—C_1-4-alkyl, —NH—SO₂—C_1-14-alkyl, wherein C_1-4-alkyl may in each case be branched or unbranched, unsubstituted or at least mono-substituted phenyl or naphthyl and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, benzoyl, phenoxy, cyclohexyl, —CF₃, —CO—CH₃, —CO—OCH₃, —NR^AaR^Bawherein R^Aa, R^Baare each independently selected from the group consisting of H, a branched or unbranched C_1-4-alkyl-radical, —CH₂—CH₂—OH and phenyl, and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.

If one or more of the residues R^1a-R^4aand R^10a-R^18acomprises an alkylene group, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkoxy, branched or unbranched C_1-4-perfluoroalkoxy, branched or unbranched C_1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO₂NH₂, —CO—C_1-4-alkyl, —SO—C_1-4-alkyl, —SO₂—C_1-4-alkyl, —NH—SO₂—C_1-4-alkyl, wherein C_1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF₃and unsubstituted phenyl. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.

If one or more of the residues R^1a-R^4aand R^10a-R^18acomprises a mono- or polycyclic ringsystem, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkyl, branched or unbranched CIA-alkoxy, branched or unbranched C_1-4-perfluoroalkoxy, branched or unbranched C_1-4-perfluoroalkyl, amino, carboxy, amido, cyano, keto, nitro, —SO₂NH₂, —CO—C_1-4-alkyl, —SO—C_1-4-alkyl, —SO₂—C_1-4-alkyl, —NH—SO₂-C_1-4-alkyl, wherein C_1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl, more preferably from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, CF₃, keto, cyano and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.

If one or more of the residues R^1a-R^4aand R^10a-R^18arepresents or comprises an aryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkoxy, branched or unbranched C_1-4-alkyl, branched or unbranched C_1-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C_1-4-perfluoroalkyl, NR^AaR^Bawherein R^Aa, R^Baare each independently selected from the group consisting of H, a branched or unbranched C_1-4-alkyl-radical, —CH₂—CH₂—OH and phenyl, carboxy, amido, cyano, —CH(OH)(phenyl), nitro, —SO₂NH₂, —CO—C_1-4-alkyl, —CO—OC_1-4-alkyl, —SO—C_1-4-alkyl, —SO₂—C_1-4-alkyl, —NH—SO₂—C_1-4-alkyl, wherein C_1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, —CH(OH)(phenyl), methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF₃, —CO—CH₃, —CO—OCH₃, —NR^AR^Bwherein R^A, R^Bare each independently selected from the group consisting of H, a branched or unbranched C_1-4-alkyl-radical, —CH₂—CH₂—OH and phenyl, and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.

If one or more of the residues R^1a-R^4aand R^10a-R^18arepresents or comprises a heteroaryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkoxy, branched or unbranched C_1-4-alkyl, branched or unbranched C_1-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C_1-4-perfluoroalkyl, NR^AaR^Bawherein R^Aa, R^Baare each independently selected from the group consisting of H, a branched or unbranched C_1-4-alkyl-radical, —CH₂—CH₂—OH and phenyl, carboxy, amido, cyano, nitro, —CH(OH)(phenyl), —SO₂NH₂, —CO—C_1-4-alkyl, —CO—OC_1-4-alkyl, SO—C_1-4-alkyl, SO₂—C_1-4-alkyl, —NH—SO₂—C_1-4-alkyl, wherein C_1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF₃, —CH(OH)(phenyl), —CO—CH₃, —CO—OCH₃, —NR^AaR^Bawherein R^Aa, R^Baare each independently selected from the group consisting of H, a branched or unbranched C_1-4-alkyl-radical, —CH₂—CH₂—OH and phenyl, and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.

If R^10aand R^11aand/or R^15aand R^16aform a heterocyclic ring, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkoxy, branched or unbranched C_1-4-alkyl, branched or unbranched C_1-4-perfluoroalkoxy, branched or unbranched C_1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO₂NH₂, —CO—C_1-4-alkyl, —SO—C_1-4-alkyl, —SO₂—C_1-4-alkyl, —NH—SO₂—C_1-4-alkyl, wherein C_1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, methyl, CF₃and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.

If R^10aand R^11aand/or R^15aand R^16aform a heterocyclic ring, which contains one or more further heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O and S, more preferably from the group consisting of N and O.

If one or more of the residues R^1a-R^18arepresents or comprises a cycloaliphatic radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.

If one or more of the residues R^1a-R^4aand R^10a-R^18arepresents or comprises an heteroaryl radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.

Preferred compounds of general formula (Ia) are those, wherein R^1a, R^2a, R^3a, R^4aare each independently selected from the group consisting of H, F, Cl, Br, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro group, a cyano group, —OR^12a, —OC(═O)R^13a, —SR^14a, —SOR^14a, —SO₂R^14a, —NH—SO₂R^14a, —SO₂NH₂and —NR^15aR^16amoiety,

R^5arepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical,

R^6a, R^7a, R^8a, R^9aare each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical, a cyano and a COOR^17amoiety,

A^arepresents a bridge member —CHR^18a— or —CHR^18a—CH₂—,

R^10arepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^11arepresents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or an optionally at least mono substituted 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, or

R^10aand R^11atogether with the bridging nitrogen atom form an optionally at least mono-substituted, saturated, unsaturated or aromatic, 5- or 6-membered heterocyclic ring, which may contain at least one further heteroatom as a ring member and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem,

R^12arepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom containing as ring member C_3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^13arepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^14arepresents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^15aand R^16aeach are independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

or R^15aand R^16atogether with the bridging nitrogen atom form a saturated, unsaturated or aromatic, 5- or 6-membered heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as a ring member,

R^17arepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^18arepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

Particularly preferred are compounds of general formula (Ia), wherein R^1a, R^2a, R^3a, R^4aare each independently selected from the group consisting of H, F, Cl, Br, a saturated, branched or unbranched, optionally at least mono-substituted C_1-3-aliphatic radical, a saturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C₅- or C₆-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C₁- or C₂-alkylene group, a nitro group, a cyano group, —OR^12a, —OC(═O)R^13a—SR^14aand NR^15aR^16amoiety, preferably be selected from the group consisting of H, F, Cl, CH₃, CH₂CH₃, CF₃, CF₂CF₃, cyclopentyl, cyclohexyl, nitro, cyano and —OR^12aand the remaining residues R^5a-R^18aand A^ahave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

Also particularly preferred are compounds of general formula (Ia), wherein R^5arepresents H or a branched or unbranched C_1-3-alkyl radical, preferably H, CH₃or CH₂CH₃, and the remaining residues R^6a-R^18aand A^ahave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

Also particularly preferred are compounds of general formula (Ia), wherein R^6a, R^7a, R^8a, R^9aare each independently selected from the group consisting of H, a branched or unbranched C_1-3-alkyl radical, a cyano and a COOR^17amoiety, preferably selected from the group consisting of H, CH₃, CH₂CH₃and a cyano moiety, and the remaining residues R^10a-R^18aand A^ahave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

Also particularly preferred are compounds of general formula (Ia), wherein R^10arepresents hydrogen or a branched or unbranched C_1-4-alkyl radical, and the remaining residues R^11a-R^18aand A^ahave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

Also particularly preferred are compounds of general formula (Ia), wherein R^11ais selected from the group consisting of an unsubstituted phenyl radical, a phenyl radical optionally at least mono-substituted with a branched or unbranched C_1-4-alkyl-radical, a branched or unbranched C_1-4-alkoxy-radical, a branched or unbranched C_1-4-perfluoroalkyl-radical, a branched or unbranched C_1-4-perfluoroalkoxy-radical, F, Cl, Br, cyclohexyl, phenyl, phenoxy, phenylthio, benzoyl, cyano, —C(═O)C_1-2-alkyl, —C(═O)OC_1-2-alkyl, -carboxy, —CH(OH)(phenyl), —NR^AaR^Bawherein R^Aa, R^Baare each independently selected from the group consisting of H, a branched or unbranched C_1-4-alkyl-radical, —CH₂—CH₂—OH and an unsubstituted phenyl radical,

an unsubstituted thiazole radical,

a group of general formula (A)
embedded image

wherein

n is 1 or 2,

X represents CH or N,

Y represents CH₂, O, N—R^c, CH—OH or C(═O),

R^cis H or a branched or unbranched C_1-4-alkyl radical,

a group of formula (B),

a group of formula (C),

a group of general formula (D),

wherein R_Dis H or a branched or unbranched C_1-4-alkyl radical

and a group of general formula (E),
embedded image

wherein

R^Erepresents H, a branched or unbranched C_1-4-alkyl radical or a branched or unbranched C_1-4-alkoxy radical,

W represents a bond between the two aromatic rings, CH₂, CH—OH or C(═O),

Z represents CH₂, O, S, CH—OH, C(═O) or N—R^Fwhere R^Frepresents H or a branched or unbranched C_1-4-alkyl-radical, and the remaining residues R^12a-R^18aand A^ahave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

Also particularly preferred are compounds of general formula (Ia), wherein R^10aand R^11atogether with the bridging nitrogen atom form a saturated, 6-membered heterocyclic ring, which is at least mono-substituted with a methyl radical and/or condensed with an unsubstituted or at least mono-substituted phenyl- or cyclohexyl-radical, said phenyl- or cyclohexyl-radical preferably being at least mono-substituted with F and/or OCH₃, and the remaining residues R^12a-R^18aand A^ahave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

Also particularly preferred are compounds of general formula (Ia), wherein R^12arepresents H, a C_1-4-alkyl radical, a cyclohexyl radical or a phenyl radical, preferably H, CH₃, C₂H₅or a phenyl radical, and the remaining residues R^13a-R^18aand A^ahave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

Also particularly preferred are compounds of general formula (Ia), wherein R^13arepresents H, a C_1-4-alkyl radical, cyclohexyl or a phenyl radical, preferably H, CH₃, C₂H₅or phenyl, and the remaining residues R^14a-R^18aand A^ahave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

Also particularly preferred are compounds of general formula (Ia), wherein R^14arepresents H, a C_1-4-alkyl radical, cyclohexyl or a phenyl radical, preferably H, CH₃, C₂H₅or phenyl, and the remaining residues R^15a-R^18aand A^ahave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

Also particularly preferred are compounds of general formula (Ia), wherein R^15aand R^16aare each independently selected from the group consisting of H, a C_1-4-alkyl radical, cyclohexyl and a phenyl radical, preferably from the group consisting of H, CH₃, C₂H₅and phenyl, and the remaining residues R^17aand R^18aand A^ahave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

Also particularly preferred are compounds of general formula (Ia), wherein R^17arepresents H, a C_1-4-alkyl radical, cyclohexyl or a phenyl radical, preferably H, CH₃, C₂H₅or phenyl, and the remaining residues R^18aand A^ahave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

Also particularly preferred are compounds of general formula (Ia), wherein R^18arepresents H, a C_1-4-alkyl radical or a phenyl radical, preferably H, CH₃or phenyl, and the remaining residue A has the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

More particularly preferred are compounds of general formula (Ia), wherein at least two of the residues R^1a, R^2a, R^3a, R^4a, preferably R^2aand R^3a, do not represent hydrogen, and the residues from the group R^1a, R^2a, R^3aand R^4athat do not represent hydrogen as well as the remaining residues R^5a-R^18aand A^ahave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

More particularly preferred are compounds of general formula (Ia), wherein R^5ais CH₃or C₂H₅, and the remaining residues R^1a-R^4aand R^6a-R^18aand A^ahave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or physiologically acceptable salts thereof, or solvates, respectively.

Most preferred are the following benzoxazin-derived compounds of general formula (Ia):

[1] 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-2-yl)-acetamide,
[2] 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl-acetamide),
[3] 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide hydrochloride,
[4] N-(4-benzoyl-phenyl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[5] N-(4-benzoyl-phenyl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[6] 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-ylipiperidin-1-yl]-N-(5-oxo-5,6,7,8-tetrahidro-naphthalene-2-yl)-acetamide hydrochloride,
[7] 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-4-yl)-acetamide hydrochloride,
[8] N-(3-benzoyl-phenyl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[9] 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(1-oxo-indan-5-yl)-acetamide,
[10] 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(1-oxo-indan-5-yl)-acetamide hydrochloride,
[11] N-Indan-5-yl-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[12] N-(2-Methoxy-dibenzofuran-3-yl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride),
[13] N-(4-Cyclohexyl-phenyl)₂-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[14] 1-{1-[2-(3,4-Dihidro-2H-quinolin-1-yl)-2-oxo-ethyl]piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one hydrochloride,
[15] 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-2-phenyl-acetamide hydrochloride,
[16] 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-propionamide hydrochloride,
[17] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[18] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[19] 2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide,
[20] 2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide hydrochloride,
[21] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[22] N-(4-Cyclohexyl-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[23] N-(4-Cyclohexyl-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[24] N-(4-benzoyl-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[25] N-(9-Methyl-9H-carbazol-3-yl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl) piperidin-1-yl]-acetamide hydrochloride,
[26] N-(9,10-Dioxo-9,10-dihydro-anthracene-2-yl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[27] N-[4-(Ethyl-phenyl-amino)-phenyl]-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[28] 2-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-[4-methyl-phenyl-amino)-phenyl]-acetamide hydrochloride,
[29] 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-[4-phenoxy-phenyl)-acetamide hydrochloride,
[30] N-[4-(Isopropyl-phenyl-amino)-phenyl]-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[31] 3-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-propionamide hydrochloride,
[32] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide hydrochloride,
[33] N-(4-Chloro-phenyl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[34] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-chloro-phenyl)-acetamide hydrochloride,
[35] 2-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide hydrochloride,
[36] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide hydrochloride,
[37] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[38] N-(9-Hydroxy-9H-fluoren-2-yl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[39] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-hydroxy-9H-fluoren-3-yl)-acetamide hydrochloride,
[40] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[41] 2-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-trifluoromethyl-phenyl)acetamide hydrochloride,
[42] 2-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-phenyl-acetamide hydrochloride,
[43] 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)piperidin-1-yl]-N-(4-trifluoromethyl-phenyl)-acetamide hydrochloride,
[44] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-phenyl-acetamide hydrochloride,
[45] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-trifluoromethyl-phenyl)-acetamide hydrochloride,
[46] 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-phenyl-acetamide hydrochloride,
[47] N-(4-Chloro-phenyl)-2-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[48] N-(4-Cyano-phenyl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[49] N-(4-Cyano-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[50] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-cyano-phenyl)-acetamide hydrochloride,
[51] N-(4-Acethyl-phenyl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[52] 2-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide hydrochloride,
[53] N-(4-Acethyl-phenyl)-2-[4-(6-chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[54] N-(4-Acethyl-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[55] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide hydrochloride,
[56] N-(4-Benzoyl-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[57] N-(4-Benzoyl-phenyl)-2-[4-(6-chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[58] N-(2-Chloro-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[59] 2-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(2-trifluoromethyl-phenyl)-acetamide,
[60] 2-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-phenyl-acetamide,
[61] N-(4-Cyclohexyl-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[62] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-cyclohexyl-phenyl)-acetamide hydrochloride,
[63] N-(2-Benzoyl-phenyl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[64] N-(2-Benzoyl-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[65] N-(2-Benzoyl-phenyl)-2-[4-(6-chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[66] N-(2-Benzoyl-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[67] 2-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide hydrochloride,
[68] N-(4-Acethyl-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[69] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[70] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-2-yl)-acetamide hydrochloride,
[71] 2-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-2-yl)-acetamide hydrochloride,
[72] 2-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-2-yl)-acetamide hydrochloride,
[73] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-hydroxy-9H-fluoren-2-yl)-acetamide hydrochloride,
[74] N-(9-Hydroxy-9H-fluoren-2-yl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[75] N-(9-Hydroxy-9H-fluoren-2-yl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[76] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[77] N-(4-Cyclohexyl-phenyl)-2-[4-(7-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[78]. N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(5-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[79] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(6-metoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[80] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(7-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[81] 2-[4-(5-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)acetamide hydrochloride,
[82] 2-[4-(5-Fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide hydrochloride,
[83] 2-[4-(6-metoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide,
[84] N-Dibenzofuran-2-yl-2-[4-(8-metoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[85] 2-[4-(7-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-dibenzofuran-2-yl-acetamide,
[86] 2-[4-(6-Fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide,
[87] 2-[4-(7-Fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-hydroxy-9H-fluoren-3-yl)-acetamide,
[88] N-(9H-Carbazol-3-yl)-2-[4-(5-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[89] N-(9H-Carbazol-3-yl)-2-[4-(5-fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[90] N-(9H-carbazol-3-yl)-2-[4-(6-metoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[91] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(5-metoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[92] 2-[4-(5-Metoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide,
[93] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(7-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[94] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(8-metoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[95] N-Dibenzofuran-2-yl-2-[4-(5-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[96] N-[4-(Ethyl-phenyl-amino)-phenyl]-2-[4-(7-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[97] N-(9H-Carbazol-3-yl)-2-[4-(8-chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[98] N-[4-(Ethyl-phenyl-amino)-phenyl]-2-[4-(8-metoxi-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[99] N-(9-Hydroxy-9H-fluoren-4-yl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[100] N-[4-(Hydroxy-phenyl-methyl)-phenyl-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[101] N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[102] N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[103] N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[104] N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(6-chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[105] 2-[4-(7-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-thiazole-2-yl-acetamide,
[106] 2-[4-(6-Fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-thiazole-2-yl-acetamide,
[107] N-Dibenzothiophene-2-yl-2-[4-(5-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[108] 2-[4-(7-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-dibenzothiophene-2-yl-acetamide,
[109] 2-[4-(5-Hydroxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide,
[110] 1-{1-[2-(3,4-Dihydro-1H-isoquinoline-2-yl)-2-oxo-ethyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one hydrochloride,
[111] 2-[4-(6-Fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-quinoline-6-yl-acetamide,
[112] 2-[4-(6-Methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-quinoline-6-yl-acetamide,
[113] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-quinoline-6-yl-acetamide,
[114] 2-[4-(6-Fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(2-methyl-benzothiazole-5-yl)-acetamide,
[115] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(2-methyl-benzothiazole-5-yl)-acetamide,
[116] 2-[4-(6-Methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(2-methyl-benzothiazole-5-yl)-acetamide,
[117] N-(3-Dimethylamino-phenyl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[118] N-(4-Dimethylamino-phenyl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[119] N-(3-Dimethylamino-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[120] N-(4-Dimethylamino-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[121] N-(3-Dimethylamino-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[122] N-(4-Dimethylamino-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[123] N-(4-Diethylamino-phenyl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[124] 2-{2-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acethylamino}-benzoic acid methyl ester,
[125] 2-{2-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acethylamino}-benzoic acid methyl ester,
[126] N-(2-Methoxy-dibenzofuran-3-yl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide hydrochloride,
[127] N-2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(2-methoxy-dibenzofuran-3-yl-acetamide hydrochloride,
[128] 2-{2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acethylamino}-benzoic acid methyl ester,
[129] 2-{2-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acethylamino}-benzoic acid methyl ester,
[130] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-diethylamino-phenyl)-acetamide dihydrochloride,
[131] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-{4-[ethyl-(2-hydroxy-ethyl)-amino]-phenyl)acetamide dihydrochloride,
[132] N-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)piperidin-1-yl]-acetamide dihydrochloride,
[133] N-(4-Diethylamino-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide dihydrochloride,
[134] N-(4-Diethylamino-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide dihydrochloride,
[135] N-{4-[ethyl-(2-hydroxy-ethyl)-amino]-phenyl}-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide dihydrochloride,
[136] N-Benzo[1,3]dioxol-5-yl-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[137] N-Benzo[1,3]dioxol-5-yl-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[138] N-Benzo[1,3]dioxol-5-yl-2-[4-(6-chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[139] N-Benzo[1,3]dioxol-5-yl-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[140] N-{4-[ethyl-(2-hydroxy-ethyl)-amino]-phenyl}-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide dihydrochloride,
[141] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-dimethylamino-phenyl)-acetamide dihydrochloride,
[142] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(4-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[143] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(4-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[144] 2-[4-(4-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide,
[145] 2-{2-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamino}-benzoic acid,
[146] 1-{1-[2-(6-Fluoro-2-methyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
[147] 6-Chloro-1-{1-[2-(6-fluoro-2-methyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
[148] 1-{1-[2-(6-Fluoro-2-methyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
[149] 1-[1-[2-(6-Fluoro-2-methyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
[150] 1-{1-[2-(6-Methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one;
[151] 6-Chloro-1-(1-[2-(6-methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
[152] 1-{1-[2-(6-Methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
[153] 1-{1-[2-(6-Methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one,
[154] N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-oxo-7-trifluormethyl-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[155] N-(9H-carbazol-3-yl)-2-[4-(2-oxo-7-trifluormethyl-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[156] 2-[4-(2-Oxo-7-trifluormethyl-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide,
[157] N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(2-oxo-7-trifluormethyl-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[158] 2-4-(6,7-Difluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-hydroxy-9H-fluoren-3-yl)-acetamide,
[159] N-(9H-carbazol-3-yl)-2-[4-(6,7-difluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide,
[160] 2-4-(6,7-Difluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide,
[161] 2-4-(6,7-Difluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide,
[162] 2-[4-(4-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide,
[163] 2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(3-dimethylamino-phenyl)-acetamide.

The benzoxazinone-derived compounds of general formula (Ia), wherein R^1a-R^11aand A^ahave the meaning given above, may be prepared preferably by reaction of one compound of general formula (IIa),
embedded image

wherein

R^10aand R^11ahave the meaning given above, with at least one compound of general formula (IIIa),

wherein

A^ahas the meaning given above, F^arepresents halogen, hydroxy or an O-acyl group and G^arepresents halogen, preferably chlorine. The reaction occurs in inert solvents and in the presence of a base or/and auxiliary agents, resulting in compounds of general formula (IVa)
embedded image

wherein

A^a, G^a, R¹⁰and R¹¹have the above defined meaning.

These compounds are reacted with amines of general formula (Va) and/or a salt, preferably hydrochloride, thereof,
embedded image

wherein R^1ato R^9ahave the meaning as definded above, in a suitable reaction medium and in the presence of base and/or auxiliary agents when it is necessary.

The process may be illustrated as an example by the following reaction scheme:
embedded image

wherein R^1ato R^11aand A^ahave the meaning as given above.

Suitable reaction media are e.g. organic solvents, such as ethers, preferably diethyl ether, dioxane, tetrahydrofurane, dimethyl glycol ether, or alcohols, e.g. methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, or hydrocarbons, preferably benzene, toluene, xylene, hexane, cyclohexane, petroleum ether, or halogenated hydrocarbons, e.g. dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene, chlorobenzene or/and other solvents, preferably ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, diemthylformamide, hexamethylphosphoramide, acetonitril, acetone or nitromethane, are included. Mixtures based one or more of the afore mentioned solvents may also be used.

Bases that may be used in the processes according to the present invention are generally organic or inorganic bases, preferably alkali metal hydroxides, e.g. sodium hydroxyde or potassium hydroxyde, or obtained from other metals such as barium hydroxyde or different carbonates, preferably potassium carbonate, sodium carbonate, calcium carbonate, or alkoxides, e.g. sodium methoxide, potassium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide, or organic amines, preferably triethylamine, diisopropyethylamine or heterocycles, e.g. 1,4-diazabicyclo[2.2.2] octane, 1,8-diazabicyclo[5.4.0]undec-7-ene pyridine, diamino pyridine, dimethylaminopyridine, methylpiperidine or morpholine. Alkali metals such as sodium or ist hydrides, e.g. sodium hydride, may also be used. Mixtures based one or more of the afore mentioned bases may also be used.

The above mentioned bases may be used for the process as auxiliary agents, when appropriate. Other suitable auxiliary agents for the above mentioned reactions are, for example, dehydrating agents like carbodiimides, e.g. diisopropylcarbodiimide, cyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, or carbonylic compounds, e.g. carbonyldiimidazol or compounds like isobutylchloroformiate or methansulfonyl chloride, among others. These reagents are generally used in an amount comprised between 0.5 and 3 mol versus 1 mol of the corresponding carboxylic acids. These bases are generally used in an amount comprised between 0.05 and 10 mol versus 1 mol of the compounds of the invention.

During some of the synthetic reactions described or while preparing the compounds of general formulas (Ia), (IIa), (IIIa), (IVa) and (Va), the protection of sensitive groups or of reagents may be necessary and/or desirable. This can be performed by using conventional protective groups like those described in the literature [Protective groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & sons, 1991. The protective groups may be eliminated in the convenient later stage by means of methods well-known to those skilled in the art.

The compounds of general formulas (IIa), (IIIa), (IVa) and (Va) are either commercially available or can be produced according to methods known to those skilled in the art. The reaction of a compound of formula (IVa) with a compound of formula (Va) yield a benzoxazinone-derived compound of general formula (Ia) using conventional methods known to those skilled in the art.

The substituted benzoxazinone compounds of general formula (Va), wherein R^5arepresents H, are preferably synthesized from substituted anthranilic acid or esters thereof by reduction to the corresponding benzylalcohol (see scheme 2, method A). By reductive amination with 1-Boc-4-piperidone the Boc-piperidin-moiety is introduced. The benzoxazinone-ring is formed by cyclisation with triphosgene, a treatment in acidic media allows the elimination the protecting group of the piperidine according to the method described in Williams et al., J. Med. Chem. 1995 38, 4634 and later by Bell et al., J. Med. Chem., 1998, 41, 2146 which are hereby incorporated by reference and form part of the disclosure. By reacting such a substituted benzoxazinone compound of general formula (Va) with a halogenated amide of general formula (IVa) benzoxazinone derived compounds of general formula (Ia) are obtained.

By reduction of the corresponding ketones with NaBH₄in methanol or via other conventional methods (see scheme 2, method B, R5=Z) R^5asubstituted 2-amino-benzylalcohols are obtained, intermediates which allow, via the same previous synthetic process, to obtain compounds of general formula (Ia), wherein R^5amay be an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, optionally may contain at least an heteroatom as ring member of a cycloaliphatic ring or alkyl (denoted by Z in the method B)
embedded image

The compounds of general formula (IVa) are commercially available or may be produced according to scheme 1 by conventional methods known to those skilled in the art. Essentially the respective compound of general formula (IIa) is reacted with chloroacetyl chloride or the respective compound of general formula (IIIa) in the presence of an organic reaction medium, preferably dichloromethane and a base, preferably triethylamine and/or diisopropylethylamine.

The salts of benzoxazinone-derived compounds of general formula (Ia), wherein R^1a-R^11aand A^ahave the meaning as definded above, may be prepared in a way that at least one compound of general formula (Ia) having at least one basic group is reacted with an inorganic or organic acid, preferably in the presence of a suitable reaction medium. Suitable reaction media are the ones given above. Suitable inorganic acids are for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, suitable organic acids are e.g. citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, such as p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid.

The salts of benzoxazinone-derived compounds of general formula (Ia), wherein R^1a-R^11aand A^ahave the meaning as definded above, may be prepared in a way that at least one compound of general formula (Ia) having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium. Suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g. from alkaline metals, alkaline earth metals or organic cations, e.g. [NH_nR_4-n]⁺, wherein n is 0, 1, 2, 3 or 4 and R represents a branched or unbranched C_1-4-alkyl-radical.

Solvates, preferably hydrates, of the Benzoxazinone-derived compounds of general formula (Ia) may also be obtained by standard procedures known to those skilled in the art.

If the Benzoxazinone-derived compounds of general formula (Ia) are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or crystallization with chiral reagents.

The purification and isolation of the Benzoxazinone-derived compounds of general formula (Ia) or a corresponding stereoisomer, or salt, or solvate respectively, if required, may be carried out by conventional methods known to those skilled in the art, e.g. chromatographic methods or recrystallization.

Preferably, the active substance combination of the present invention may comprise as a component (B) at least one compound with 5-HT₆receptor affinity, which is selected form the group consisting of the benzoxazinone-derived sulfonamide compounds of general formula (Ib),
embedded image

wherein

R^1b, R^2b, R^3b, R^4bare each independently selected from the group consisting of hydrogen, halogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro group, a cyano group, —OR^10b, O(C═O)R^11b, (C═O)—O—R^11b, —SR^12b, —SOR^12b, —SO₂R^12b, —NH—SO₂R^12b, —SO₂NH₂and a —NR^13bR^14bmoiety,

R^5brepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical,

R^6b, R^7b, R^8b, R^9bare each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, a cyano group and a COOR^15bmoiety,

W^brepresents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical,

a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

an optionally at least mono-substituted aryl or heteroaryl radical, which may be bonded via an optionally mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

a NR^16bR^17b-moiety,

or a COR^18b-moiety

R^10brepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^11brepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^12brepresents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^13band R^14beach are independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

or R^13band R^14btogether with the bridging nitrogen atom form a saturated, unsaturated or aromatic heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as a ring member,

R^15brepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical or an optionally at least mono-substituted aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

R^16brepresents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical,

R^17brepresents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical, and

R^18brepresents an optionally at least mono-substituted aryl radical,

optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding salt thereof, preferably physiologically acceptable salts thereof, or a solvate, respectively,

and sulphonamide-derived compounds of general formula (Ic),
embedded image

wherein

R^1crepresents hydrogen, an optionally at least mono-substituted, linear or branched alkyl radical, an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted benzyl radical,

R^2crepresents a —NR^4cR^5cmoiety or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem,

R^3crepresents hydrogen or an optionally at least mono-substituted, linear or branched alkyl radical,

R^4cand R^5c, identical or different, represent hydrogen or an optionally at least mono-substituted, linear or branched alkyl radical, or

R^4cand R^5ctogether with the bridging nitrogen atom form an optionally at least mono-substituted, saturated or unsaturated heterocyclic ring, which may contain at least one further heteroatom as a ring member and/or may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem,

A^crepresents an optionally at least mono-substituted mono- or polycyclic aromatic ringsystem, which may be bonded via an optionally at least mono-substituted alkylene group, an optionally at least mono-substituted alkenylene group or an optionally at least mono-substituted alkynylene group and/or may contain at least one heteroatom as a ring member in one or more of its rings,

nc represents 0, 1, 2, 3 or 4;

optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a corresponding physiologically acceptable salt or a corresponding solvate,

and compounds of the general formula (Id)
embedded image

R^1drepresents a —NR^8dR^9dradical or a saturated or unsaturated, optionally at least mono-substituted cycloaliphatic radical, which may contain at least one heteroatom as a ring member and/or which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,

R^2d, R^3d, R^5d, R^6d, and R^7d, identical or different, each represent hydrogen, halogen, nitro, alkoxy, cyano, a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical, or an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted heteroaryl radical,

R^4dis hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,

R^8dand R^9d, identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,

or

R^8dand R^9dtogether with bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted heterocyclic ring, which may contain at least one additional heteroatom as a ring member and/or may be condensed with a saturated or unsaturated, optionally at least mono-substituted mono- or bicyclic cycloaliphatic ring system, which may optionally contain at least one heteroatom as a ring member,

A^drepresents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, which may be bonded via an optionally at least mono-substituted alkylene, alkenylene or alkynylene group and/or which may contain at least one heteroatom as a ring member in one or more of its rings,

and

nd is 0, 1, 2, 3 or 4;

optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a salt thereof, preferably a corresponding, physiologically acceptable salt thereof, or a corresponding solvate thereof, and

and sulphonamide-derived compounds of general formula (Ie),
embedded image

wherein

R^1erepresents a —NR^8eR^9eradical or a saturated or unsaturated, optionally at least mono-substituted cycloaliphatic radical, which may optionally contain at least one heteroatom as a ring member and/or which may be condensed with a saturated or unsaturated, optionally at least mono-substituted mono- or bicyclic cycloaliphatic ring system, which may optionally contain at least one heteroatom as a ring member,

R^2e, R^3e, R^4e, R^6eand R^7e, identical or different, each represent hydrogen, halogen, nitro, alkoxy, cyano, a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical or an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted heteroaryl radical,

R^5erepresents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,

R^8eand R^9e, identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,

or

R^8eand R^9etogether with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted heterocyclic ring, which may contain at least one additional heteroatom as a ring member and/or which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, mono- or bicyclic cycloaliphatic ring system which may optionally contain at least one heteroatom as a ring member,

A^erepresents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, which may be bonded via an optionally at least mono-substituted alkylene, alkenylene or alkynylene group and/or which may contain at least one heteroatom as a ring member in one or more of its rings

and

ne is 0, 1, 2, 3 or 4;

optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, at any mixture ratio, or a corresponding, physiologically acceptable salt, or a corresponding solvate

and sulphonamide-derived compounds of general formula (If),
embedded image

wherein

R^1frepresents a —NR^8fR^9fradical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,

R^2f, R^3f, R^4f, R^5fand R^7f, identical or different, each represent hydrogen, halogen, nitro, alkoxy, cyano, a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical, or an optionally at least mono-substituted phenyl radical or optionally at least mono-substituted heteroaryl radical,

R^6frepresents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,

R^8fand R^9f, identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,

or

R^8fand R^9f, together with the bridging nitrogen atom, form a saturated or unsaturated, optionally at least mono-substituted heterocyclic ring, which may contain at least one further heteroatom as a ring member and/or which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,

A^frepresents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, which may be bonded via an optionally at least mono-substituted alkylene, alkenylene or alkynylene group and/or which may contain at least one heteroatom as a ring member in one or more of its rings,

and

nf is 0, 1, 2, 3 or 4;

optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, at any mixture ratio, or a corresponding, physiologically acceptable salt, or a corresponding solvate

and sulphonamide-derived compounds of general formula (Ig).
embedded image

wherein

R^1gis a —NR^8gR^9gradical or a saturated or unsaturated, optionally at least mono-substituted cycloaliphatic radical, which may optionally contain at least one heteroatom as a ring member and which may be condensed with a saturated or unsaturated, optionally at least mono-substituted mono- or bicyclic cycloaliphatic ring system which may optionally contain at least one heteroatom as a ring member,

R^2g, R^3g, R^4g, R^5gand R^6g, identical or different, each represent hydrogen, halogen, nitro, alkoxy, cyano, a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical, or an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted heteroaryl radical,

R^7grepresents hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,

R^8gand R^9g, identical or different, represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,

or

R^8gand R^9gtogether with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted heterocyclic ring, which may contain at least one additional heteroatom as a ring member and/or which may be condensed with a saturated or unsaturated, optionally at least mono-substituted mono- or bicyclic cycloaliphatic ring system, which may optionally contain at least one heteroatom as a ring member,

A^grepresents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, which may be bonded via an optionally at least mono-substituted alkylene, alkenylene or alkynylene group and/or which may contain at least one heteroatom as a ring member in one or more of its rings,

ng is 0, 1, 2, 3 or 4;

optionally in the form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in the form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, at any mixture ratio, or a corresponding, physiologically acceptable salt, or a corresponding solvate,

and sulphonamide-derived compounds of general formula (Ih)
embedded image

wherein

R^1hrepresents a —NR^7hR^8hradical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,

R^2h, R^3h, R^4h, R^5hand R^6h, identical or different, each represent hydrogen, halogen, cyano, nitro, a saturated or unsaturated, linear or branched aliphatic radical, a linear or branched alkoxy radical, a linear or branched alkylthio radical, hydroxy, trifluoromethyl, a saturated or unsaturated cycloaliphatic radical, an alkylcarbonyl radical, a phenylcarbonyl or a —NR^9hR^10hgroup,

R^7hand R^8h, identical or different, each represent hydrogen or a saturated or unsaturated, optionally at least mono-substituted linear or branched aliphatic radical,

or

R^7hand R^8h, together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted, optionally at least one further heteroatom as a ring member containing heterocyclic ring which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,

R^9hand R^10h, identical or different, each represent hydrogen or a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical,

or

R^9hand R^10h, together with the bridging nitrogen atom form a saturated or unsaturated, optionally at least mono-substituted, optionally at least one further heteroatom as a ring member containing heterocyclic ring which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as a ring member containing mono- or bicyclic cycloaliphatic ring system,

A^hand B^h, identical or different, each represent a saturated or unsaturated, linear or branched, optionally at least mono-substituted aliphatic radical

or

A^hand B^h, together with the carbon atom to which they are bonded, form a saturated or unsaturated, but not aromatic, optionally at least mono-substituted cycloalkyl ring,

and

nh is 0, 1, 2, 3, or 4,

optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemate or in form of a mixture of at least two of their stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a salt thereof, preferably a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof.

The persons skilled in the state of the art understand that the active substance combination according to the present invention may comprise one or more compounds of one class of active substances with 5-HT₆receptor affinity or one or more compounds of one or more classes of active substances with 5-HT₆receptor affinity.

If one or more of the residues R^1b-R^17band W^brepresents an aliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkoxy, branched or unbranched C_1-4-perfluoroalkoxy, branched or unbranched C_1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO₂NH₂, —CO—C_1-4-alkyl, —SO—C_1-4-alkyl, —SO₂—C_1-4-alkyl, —NH—SO₂—C_1-4-alkyl, wherein the C_1-4-alkyl may in each case be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, CF₃and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.

If one or more of the residues R^1b-R^15brepresents or comprises a cycloaliphatic radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkyl, branched or unbranched C_1-1-alkoxy, branched or unbranched C_1-4-perfluoroalkoxy, phenoxy, benzoyl, cyclohexyl, branched or unbranched C_1-4-perfluoroalkyl, —NR^AbR^Bbwherein R^Ab, R^Bbare each independently selected from the group consisting of H, a branched or unbranched C_1-4-alkyl-radical, —CH₂—CH₂—OH and phenyl, carboxy, keto, amido, cyano, nitro, —SO₂NH₂, —CO—C_1-4-alkyl, —CO—OC_1-4-alkyl, —SO—C_1-4-alkyl, —SO₂—C_1-4-alkyl, —NH—SO₂—C_1-4-alkyl, wherein C_1-4-alkyl may in each case be branched or unbranched, unsubstituted or at least mono-substituted phenyl or naphthyl and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, keto, benzoyl, phenoxy, cyclohexyl, —CF₃, —CO—CH₃, —CO—OCH₃, —NR^AbR^Bbwherein R^Ab, R^Bbare each independently selected from the group consisting of H, a branched or unbranched C_1-4-alkyl-radical, —CH₂—CH₂—OH and phenyl, and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.

If one or more of the residues R^1b-R^4b, R^10b-R^15band W^bcomprises an alkylene group, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkoxy, branched or unbranched C_1-4-alkyl, branched or unbranched C_1-4-perfluoroalkoxy, branched or unbranched C_1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO₂NH₂, —CO—C_1-4-alkyl, —SO—C_1-4-alkyl, —SO₂—C_1-4-alkyl, —NH—SO₂—C_1-4-alkyl, wherein C_1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, methoxy, ethoxy, CF₃and unsubstituted phenyl. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.

If one or more of the residues R^1b-R^4band R^10b-R^15bcomprises a mono- or polycyclic ringsystem, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkyl, branched or unbranched C_1-4-alkoxy, branched or unbranched C_1-4-perfluoroalkoxy, branched or unbranched C_1-4-perfluorocarbonyl, branched or unbranched C_1-4-perfluoroalkyl, amino, carboxy, amido, cyano, keto, nitro, —SO₂NH₂, —CO—C_1-4-alkyl, —SO—C_1-4-alkyl, —SO₂—C_1-4-alkyl, —NH—SO₂—C_1-4-alkyl, wherein C_1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl, more preferably from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, CF₃, —(C═O)CF₃, keto, cyano and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.

If one or more of the residues R^1b-R^4b, R^10b-R^15band R^18brepresents or comprises an aryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkoxy, branched or unbranched C_1-4-alkyl, branched or unbranched C_1-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C_1-4-perfluoroalkyl, NR^AbR^Bbwherein R^Ab, R^Bbare each independently selected from the group consisting of H, a branched or unbranched C_1-4-alkyl-radical, —CH₂—CH₂—OH and phenyl, carboxy, amido, cyano, —CH(OH)(phenyl), nitro, —SO₂NH₂, —CO—C_1-4-alkyl, —CO—OC_1-4-alkyl, —SO—C_1-4-alkyl, —SO₂—C_1-4-alkyl, —NH—SO₂—C_1-4-alkyl, wherein C_1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, nitro, —CH(OH)(phenyl), methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF₃, OCF₃, —CO—CH₃, —CO—OCH₃, SO₂—CH₃, —NR^AbR^Bbwherein R^Ab, R^Bbare each independently selected from the group consisting of H, a branched or unbranched C_1-4-alkyl-radical, —CH₂—CH₂—OH and phenyl, and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, Br, CF₃, OCF₃, methyl and methoxy.

If one or more of the residues R^1b-R^4band R^10b-R^15brepresents or comprises a heteroaryl radical, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkoxy, branched or unbranched C_1-4-alkyl, branched or unbranched C_1-4-perfluoroalkoxy, unsubstituted or at least mono-substituted phenoxy, unsubstituted or at least mono-substituted benzoyl, cyclohexyl, branched or unbranched C_1-4-perfluoroalkyl, NR^AbR^Bbwherein R^Ab, R^Bbare each independently selected from the group consisting of H, a branched or unbranched C_1-4-alkyl-radical, —CH₂—CH₂—OH and phenyl, carboxy, amido, cyano, —CH(OH)(phenyl), nitro, —SO₂NH₂, —CO-C_1-4-alkyl, —CO—OC_1-4-alkyl, SO—C_1-4-alkyl, SO₂—C_1-4-alkyl, —NH—SO₂—C_1-4-alkyl, wherein C_1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methyl, ethyl, cyano, nitro, —CH(OH)(phenyl), methoxy, ethoxy, unsubstituted or at least mono-substituted benzoyl, unsubstituted or at least mono-substituted phenoxy, cyclohexyl, CF₃, OCF₃, —CO—CH₃, —CO—OCH₃, —SO₂CH₃, —NR^AbR^Bbwherein R^Ab, R^Bbare each independently selected from the group consisting of H, a branched or unbranched C_1-4alkyl-radical, —CH₂—CH₂—OH and phenyl, and an unsubstituted phenyl radical. If any one of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, Br, CF₃, OCF₃, methyl and methoxy.

If R^13band R^14bform a heterocyclic ring, which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C_1-4-alkoxy, branched or unbranched C_1-4-alkyl, branched or unbranched C_1-4-perfluoroalkoxy, branched or unbranched C_1-4-perfluoroalkyl, amino, carboxy, amido, cyano, nitro, —SO₂NH₂, —CO—C_1-4-alkyl, —SO—C_1-4-alkyl, —SO₂—C_1-4-alkyl, —NH—SO₂—C_1-4-alkyl, wherein C_1-4-alkyl may be branched or unbranched, an unsubstituted or at least mono-substituted phenyl or naphthyl radical and an unsubstituted or at least mono-substituted furanyl-, thienyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, pyridinyl-, pyrimidinyl-, quinolinyl- and isoquinolinyl radical, more preferably be selected from the group consisting of hydroxy, F, Cl, Br, methoxy, ethoxy, methyl, CF₃and an unsubstituted phenyl radical. If any of the above mentioned substitutents itself is at least mono-substituted, said substituents may preferably be selected from the group consisting of F, Cl, methyl and methoxy.

If R^13band R^14bform a heterocyclic ring, which contains one or more further heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O and S, more preferably from the group consisting of N and O.

If one or more of the residues R^1b-R^15band W^brepresents or comprises a cycloaliphatic radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.

If one or more of the residues R^1b-R^4b, R^10b-R^15band W^brepresents or comprises an heteroaryl radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of N, O, S and P, more preferably from the group consisting of N, O and S.

If W^brepresents or comprises a cycloaliphatic radical, a heteroaryl radical, an aryl radical and/or a mono- or polycyclic ring system which is substituted by one or more substituents, unless defined otherwise, each of these substituents may preferably be selected from the group consisting of hydroxy, nitro, carboxy, cyano, keto, halogen, C_1-20-alkyl, partially fluorinated C_1-4alkyl, partially chlorinated C_1-4alkyl, partially brominated C_1-4alkyl, C_1-5-alkoxy, partially fluorinated C_1-4alkoxy, partially chlorinated C_1-4alkoxy, partially brominated C_1-4alkoxy, C_2-6-alkenyl, SO₂—C_1-4-alkyl, (C═O)—C_1-5-alkyl, —(C═O)—O—C_1-5-alkyl, —(C═O)—Cl, —S—C_1-4-alkyl-, —(C═O)—H, —NH—(C═O)—NH—C_1-5-alkyl, —(C═O)—C_1-4-perfluoroalkyl, —NR^AbR^Bb, wherein R^Aband R^Bbare independently selected from the group consisting of H, C_1-4-alkyl and phenyl, NH—(C═O)—C_1-5-alkyl, —C_1-5-alkylen-(C═O)—C_1-5-alkyl, (1,3-Dihydro-1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, —SO₂-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, —SO₂-pyrrolidinyl, morpholinyl, SO2-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, O—CH₂-thiazolyl,-, NH-phenyl, and —C_1-4-Alkylen-NH—(C═O)-phenyl, more preferably from the group consisting of hydroxy, nitro, carboxy, cyano, keto, F, Cl, Br, I, C_1-12-alkyl, CH₂F, CHF₂, CF₃, CH2Cl, CH₂Cl₂, CCl₃, CH₂Br, CHBr₂, CBr₃, OCF₃, OCHF₂, OCH₂F, O—CH₂—CF₃, vinyl, SO2-CH₃, —(C═O)—CH₃, —(C═O)—C₂H₅, —(C═O)—O—CH₃, —(C═O)—O—C₂H₅, —(C═O)—Cl, —S—CH₃—, —(C═O)—H, —NH—(C═O)—NH—CH₃, —(C═O)—CF₃, dimethylamino, diethylamino, di-n-propylamino, di-iso-propylamino, di-n-butylamino, di-tert-butylamino, NH—(C═O)—CH₃, —CH₂—(C═O)—CH₃, —CH₂—(C═O)—C₂H₅, (1,3-Dihydro-1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, —SO₂-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, —SO₂-pyrrolidinyl, morpholinyl, SO₂-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, O—CH₂-thiazolyl,-, NH-phenyl, and —CH₂—NH—(C═O)-phenyl.

If any of the afore mentioned substituents itself is substituted by one or more substituents, said substituents may preferably be selected from the group consisting of halogen, nitro, cyano, hydroxy, —(C═O)—C_1-4-alkyl, C_1-4-alkyl, at least partially fluorinated C_1-4-alkyl, at least partially chlorinated C_1-4-alkyl, at least partially brominated C_1-4-alkyl, —S—C_1-4-alkyl, —C(═O)—O—C_1-5-alkyl, —(C═O)CH₂—F, —(C═O)—CH₂—Cl, —(C═O)—CH₂—Br, preferably from the group consisting of F, Cl, Br, CH₂F, CHF₂, CF₃, CH₂Cl, CHCl₂, CCl₃, CH₂Br, CHBr₂, CBr₃, nitro, cyano, hydroxy, —(C═O)—CH₃, CH₃, C₂H₅, —S—CH₃, —C(═O)—O—CH₃, —C(═O)—O—C₂H₅, —(C═O)—CH₂—F, —(C═O)—CH₂—Cl and —(C═O)—CH₂—Br.

The substituents for W^bmay preferably also be selected from the group consisting of hydroxy, nitro, carboxy, cyano, keto, halogen, C_1-20-alkyl, partially fluorinated C_1-4alkyl, partially chlorinated C_1-4alkyl, partially brominated C_1-4alkyl, C_1-5-alkoxy, partially fluorinated C_1-4alkoxy, partially chlorinated C_1-4alkoxy, partially brominated C_1-4alkoxy, C_2-6-alkenyl, SO₂—C_1-14-alkyl, —(C═O)—C_1-5-alkyl, —(C═O)—O—C_1-5-alkyl, —(C═O)—Cl, —S—C_1-4-alkyl-, —(C═O)—H, —NH—(C═O)—NH—C_1-5-alkyl, —(C═O)—C_1-4-perfluoroalkyl, —NR^AR^B, wherein R^Aand R^Bare independently selected from the group consisting of H, C_1-4-alkyl and phenyl, NH—(C═O)—C_1-5-alkyl, —C_1-5-alkylen-(C═O)—C_1-5-alkyl, (1,3-Dihydro-1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, —SO₂-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, —SO₂-pyrrolidinyl, morpholinyl, SO₂-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, O—CH₂-thiazolyl,-, NH-phenyl, and —C_1-4-Alkylen-NH—(C═O)-phenyl, more preferably from the group consisting of hydroxy, nitro, carboxy, cyano, keto, F, Cl, Br, I, C_1-12-alkyl, CH₂F, CHF₂, CF₃, CH₂Cl, CH₂Cl₂, CCl₃, CH₂Br, CHBr₂, CBr₃, OCF₃, OCHF₂, OCH₂F, O—CH₂—CF₃, vinyl, SO₂—CH₃, —(C═O)—CH₃, —(C═O)—C₂H₅, —(C═O)—O—CH₃, —(C═O)—O—C₂H₅, —(C═O)—Cl, —S—CH₃—, —(C═O)—H, —NH—(C═O)—NH—CH₃, —(C═O)—CF₃, dimethylamino, diethylamino, di-n-propylamino, di-iso-propylamino, di-n-butylamino, di-tert-butylamino, NH—(C═O)—CH₃, —CH₂—(C═O)—CH₃, —CH₂—(C═O)—C₂H₅, (1,3-Dihydro-1-oxo-2H-isoindol-2-yl), N-Phthalimidinyl-, (1,3-Dioxo-2-azaspiro[4,4]-non-2-yl, substituted or unsubstituted phenyl, —SO₂-phenyl, phenoxy, pyridinyl, pyridinyloxy, pyrazolyl, pyrimidinyl, pyrrolidinyl-, —SO₂-pyrrolidinyl, morpholinyl, SO₂-morpholinyl-, thiadiazolyl, oxadiazolyl, oxazolyl, thiazolyl, isoxazolyl, O—CH₂-thiazolyl,-, NH-phenyl, and —CH₂—NH—(C═O)-phenyl.

If any of the afore mentioned substituents itself is substituted by one or more substituents, said substituents may preferably be selected from the group consisting of halogen, nitro, cyano, hydroxy, —(C═O)—C_1-4-alkyl, C_1-4-alkyl, at least partially fluorinated C_1-4-alkyl, at least partially chlorinated C_1-4-alkyl, at least partially brominated C_1-4-alkyl, —S—C_1-4-alkyl, —C(═O)—O—C_1-5-alkyl, —(C═O)—CH₂—F, —(C═O)—CH₂—Cl, —(C═O)—CH₂—Br, preferably from the group consisting of F, Cl, Br, CH₂F, CHF₂, CF₃, CH₂Cl, CHCl₂, CCl₃, CH₂Br, CHBr₂, CBr₃, nitro, cyano, hydroxy, —(C═O)—CH₃, CH₃, C₂H₅, —S—CH₃, —C(═O)—O—CH₃, —C(═O)—O—C₂H₅, —(C═O)—CH₂—F, —(C═O)—CH₂—Cl and —(C═O)—CH₂—Br.

The use of compounds of general formula (Ib) is preferred, wherein R^1b, R^2b, R^3b, R^4bare each independently selected from the group consisting of H, F, Cl, Br, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a nitro, cyano, —OR^10b, —OC(═O)R^11b, —SR^12b, —SOR^12b, —SO₂R^12b, —NH—SO₂R^12b, —SO₂NH₂and a NR^13bR^14bmoiety,

preferably selected from the group consisting of H, F, Cl, Br, a saturated, branched or unbranched, optionally at least mono-substituted C_1-3-aliphatic radical, a saturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C₅- or C₆-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C₁- or C₂-alkylene group, a nitro, cyano, —OR^10b, —OC(═O)R^11b, —SR^12band —NR^13bR^14bmoiety,

more preferably selected from the group consisting of H, F, Cl, CH₃, CH₂CH₃, CF₃, CF₂CF₃, cyclopentyl, cyclohexyl, nitro, cyano and —OR^10b,

and R^5b-R^18band W^bhave the meaning as defined above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

Also preferred is the use of compounds of general formula (Ib), wherein R^5brepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical,

preferably represents H or a branched or unbranched C_1-3-alkyl radical,

more preferably H, CH₃or CH₂CH₃,

and R^1b-R^4b, R^6b-R^18band W^bhave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

Preferred is also the use of compounds of general formula (Ib), wherein R^6b, R^7b, R^8b, R^9bare each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical, a cyano and COOR^15bmoiety,

preferably selected from the group consisting of H, a branched or unbranched C_1-3-alkyl radical, a cyano and a COOR^15bgroup,

more preferably from the group consisting of H, CH₃, CH₂CH₃and a cyano moiety,

and R^1b-R^5b, R^10b-R^18band W^bhave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

Also preferred is the use of compounds of general formula (Ib), wherein W^brepresents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ringsystem, a NR^16bR^17b-moiety or a COR^18b-moiety,

preferably selected from the group consisting of 1-Naphthyl-, 5-Dimethylamino-napth-1-yl, 2-Naphthyl-, 2-Acetamido-4-methyl-5-thiazolyl-, 2-Thienyl-, 8-Quinolinyl-, Phenyl-, Pentafluorophenyl-, 2,4,5-Trichloro-phenyl-, 2,5-Dichloro-phenyl-, 2-Nitrophenyl-, 2,4-Dinitro-phenyl-, 3,5-Dichloro-2-hydroxy-phenyl-, 2,4,6-Trisisopropyl-phenyl-, 2-Mesityl-, 3-Nitro-phenyl-, 4-Bromo-phenyl-, 4-Fluoro-phenyl-, 4-Chlorophenyl-, 4-Chloro-3-nitro-phenyl-, 4-Iodo-phenyl-, N-Acetyl-sulfanilyl-, 4-Nitro-phenyl-, 4-Methoxy-phenyl-, Benzoic-acid-4-yl-, 4-tert-Butyl-phenyl-, p-Tolyl-, Trifluoromethyl-, Trichloromethyl-, Isopropyl-, Methyl-, Benzyl-, trans-styryl-, 2,2,2-Trifluoroethyl-, Ethyl-, Hexadecyl-, 2-Chloroethyl-, n-Propyl-, 3-Chloro-propyl-, n-Butyl-, Methyl-benzoate-2-yl-, 2-Nitro-4-(trifluoromethyl)-phenyl-, Pentamethyl-phenyl-, 2,3,5,6-Tetramethyl-phenyl-, 3-(Trifluoromethyl)-phenyl-, 3,5-Bis-(Trifluoromethyl)-phenyl-, Dichloromethyl-, Chloromethyl-, Dodecyl-, 1-Octyl-, 2,3,4-Trichloro-phenyl-, 2,5-Dimethoxy-phenyl-, o-Tolyl-, p-xylyl-2-yl-, Benzoic-acid-3-yl-, 4-Chloro-3-(trifluoromethyl)-phenyl-, 4-Chloro-5-nitro-benzoic acid-3-yl-, 6-(p-toluidino)-naphth-2-yl-, 4-Methoxy-2,3,6-trimethylphenyl-, 3,4-Dichlorophenyl-, 4,5-Dibromo-thiophene-2-yl-, 3-Chloro-4-fluoro-phenyl-, 4-Ethyl-phenyl-, 4-n-Propyl-phenyl-, 4-(1,1-Dimethylpropyl)-phenyl-, 4-Isopropyl-phenyl-, 4-Bromo-2,5-difluoro-phenyl-, 2-Fluoro-phenyl-, 3-Fluoro-phenyl-, 4-(Trifluoromethoxy)-phenyl-, 4-(Trifluoromethyl)-phenyl-, 2,4-Difluoro-phenyl-, 2,4-Dichloro-5-methyl-phenyl-, 4-Chloro-2,5-dimethyl-phenyl-, 5-Diethylamino-napth-2-yl-, Benzoyl chloride-3-yl-, 2-Chloro-phenyl-, 1-Octadecyl-, 4-Bromo-2,5-dichloro-thiophene-3-yl-, 2,5-Dichloro-thiophene-3-yl-, 5-Chloro-thiophene-2-yl-, 2-Methyl-5-nitro-phenyl-, 2-(Trifluoromethyl)-phenyl-, 3-Chloro-phenyl-, 3,5-Dichloro-phenyl-, 1-Decyl-, 3-Methyl-phenyl-, 2-Chloro-6-methyl-, 5-Bromo-2-methoxy-phenyl-, 3,4-Dimethoxy-phenyl-, 2-3-Dichloro-phenyl-, 2-Bromo-phenyl-, 3,5-Dichloro-4-(2-chloro-4-nitrophenoxy)-phenyl-, 2,3-Dichloro-thiophene-5-yl-, 3-Bromo-2-chloro-thiophene-5-yl-, 3-Bromo-5-chloro-thiophene-2-yl-, 2-(Benzoylaminomethyl)-thiophene-5-yl-, 4-(Phenyl-sulphonyl)-thiophene-2-yl-, 2-Phenyl-sulphonyl-thiophene-5-yl-, 3-Chloro-2-methyl-phenyl-, 2-[1-Methyl-5-(trifluoromethyl)pyrazol-3-yl]-thiophene-5-yl-, 5-Pyrid-2-yl-thiophene-2-yl-, 2-Chloro-5-(trifluoromethyl)-phenyl-, 2,6-Dichloro-phenyl-, 3-Bromo-phenyl-, 2-(Trifluoromethoxy)phenyl-, 4-Cyano-phenyl-, 2-Cyano-phenyl-, 4-n-Butoxy-phenyl-, 4-Acetamido-3-chloro-phenyl, 2,5-Dibromo-3,6-difluoro-phenyl-, 5-Chloro-1,3-dimethylpyrazole-4-yl-, 3,5-Dimethylisoxazole-4-yl-, 2-(2,4-Dichlorophenoxy)-phenyl-, 4-(2-Chloro-6-nitro-phenoxy)-phenyl-, 4-(3-Chloro-2-cyano-phenoxy)-phenyl-, 2,4-Dichloro-phenyl-, 2,4-Dimethyl-1,3-thiazole-5-yl-, Methyl-methane-sulfonyl-, 2,5-Bis-(2,2,2-Trifluoroethoxyyphenyl-, 2-Chloro-4-(trifluoromethyl)-phenyl-, 2-Chloro-4-fluoro-phenyl-, 5-Fluoro-2-methyl-phenyl-, 5-Chloro-2-methoxy-phenyl-, 2,4,6-Trichloro-phenyl-, 2-Hydroxy-benzoic acid-5-yl-, 5-(Di-n-propylamino)-naphth-1-yl-, 6-Methoxy-m-tolyl-, 2,5-Difluoro-phenyl-, 2,4-Dimethoxy-phenyl-, 2,5-Dibromo-phenyl-, 3,4-Dibromo-phenyl-, 2,2,5,7,8-Pentamethyl-chroman-6-yl-, 2-Methoxy-benzoic-acid-5-yl-, 5-Chloro-4-nitro-thiophene-2-yl-, 2,1,3-Benzothiadiazole-4-yl-, 1-Methyl-imidazole-4-yl-, Benzofurazan-4-yl-, 2-(Methoxycarbonyl)-thiophene-3-yl-, 5-(Isoxazol-3-yl)-thiophene-2-yl-, 2,4,5-Trifluoro-phenyl-, Biphenyl-4-yl-, Vinyl-phenyl-4-yl-, 2-Nitro-benzyl-, 5-Dichloro-methyl-furan-2-yl-, 5-Bromo-thiophene-2-yl-, 5-(4-Chlorobenzamidomethyl)-thiophene-2-yl-, 2,6-Difluoro-phenyl-, 2,5-Dimethoxy-4-nitro-phenyl-, Dibenzo[B,D]-furan-2-yl-, 2,3,4-Trifluoro-phenyl-, 3-Nitro-p-tolyl-, 4-Methoxy-2-nitro-phenyl-, 3,4-Difluoro-phenyl-, 4-(Bromoethyl)-phenyl-, 3,5-Dichloro-4-hydroxy-phenyl-, 4-n-Amyl-phenyl-, 5-Chloro-3-methylbenzo[B]-thiophene-2-yl-, 3-Methoxy-4-(methoxycarbonyl)-thiophene-2-yl-, 4-n-Butyl-phenyl-, 2-Chloro-4-cyano-phenyl-, 5-[2-(Methylthio)-pyrimidin-4-yl-]-thiophene-2-yl-, 3,5-Dinitro-4-methoxy-phenyl-, 4-Bromo-2-(trifluoromethoxy)-phenyl-, 4-Chloro-2,1,3-Benzoxadiazole-7-yl-, 2-(1-Naphthyl)-ethyl-, 3-Cyano-phenyl-, 5-Chloro-2,1,3-Benzoxadiazole-4-yl-, 3-Chloro-4-methyl-phenyl-, 4-Bromo-2-ethyl-phenyl-, 2,4-Dichloro-6-methyl-phenyl-, 6-Chloro-imidazo[2,1-B)-thiazole-5-yl-, 3-Methyl-benzo[B]-thiophene-2-yl-, 4-Methyl-sulphonyl-phenyl-, 2-Methyl-sulphonyl-phenyl-, 4-Bromo-2-methyl-phenyl-, 2,6-Dichloro-4-(trifluoromethyl)-phenyl-, 4-[[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]oxy]-phenyl-, 5-Chloro-naphth-1-yl-, 5-Chloro-naphth-2-yl-, 9,10-Dibromoanthracene-2-yl-, Isoquinoline-5-yl-, 4-Methoxy-2,3,6-trimethyl-phenyl-, 4′-Nitro-biphenyl-4-yl-, [(4-Phenoxy)-phenyl-, (1,3-Dihydro-1-oxo-2H-isoindol-2-yl-)-4-phenyl-, 4-Acetyl-phenyl-, 5-(2-Methyl-1,3-thiazole-4-yl)-thiophene-2-yl-, 5-(1-Methyl-3-(trifluoromethyl)pyrazol-5-yl-]-thiophene-2-yl-, 5-[5-Trifluoromethyl)-isoxazol-3-yl]-thiophene-2-yl-, 2-Iodo-phenyl-, p-Dodecyl-phenyl-, 4-[(3-Cyano-4-methoxy-2-pyridinyl)oxy]-phenyl-, 4-(N-phthalimidinyl)-phenyl-, 1,2,3,4-Tetrahydro-2-(trifluoroacetyl)isoquinoline-7-yl-, 4-Bromo-2-fluoro-phenyl-, 2-Fluoro-5-(trifluoromethyl)-phenyl-, 4-Fluoro-2-(trifluoromethyl)-phenyl-, 4-Fluoro-3-(trifluoromethyl)-phenyl-, 2,4,6-Trifluoro-phenyl-, 3-(Trifluoromethoxy)-phenyl-, 1,2-Dimethylimidazole-4-yl-, Ethyl-4-Carboxylate-3-yl-, 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-yl-, 3-Bromo-2-chloropyridine-5-yl-, 3-Methoxy-phenyl-, 2-Methoxy-4-methyl-phenyl-, 2-Chloro-4-fluorobenzoic-acid-5-yl-, 4-Chloro-naphth-1-yl-, 2,5-Dichloro-4-nitro-thiophene-3-yl-, 4-(4-Methoxy-phenoxy)-phenyl-, 4-(4-Chloro-phenoxy)-phenyl-, 4-(3,5-Dichloro-phenoxy)-phenyl-, 4-(3,4-Dichloro-phenoxy)-phenyl-, 4-(4-Fluoro-phenoxy)-phenyl-, 4-(4-Methyl-phenoxy)-phenyl-, 4-[4-(Trifluormethyl)-phenoxy-phenyl-, 4-[3,5-Bis-(trifluoromethyl)-phenoxy]-phenyl-, 3-(2-Methoxy-phenoxy)-phenyl-, [3-(2-Chloro-phenoxy)phenyl-, 3-(2-Methyl-phenoxy)-phenyl-, 4-[2-(Trifluoromethyl)-phenoxy]-phenyl-, 3-Phenyl-phenyl-, 3-(4-Methoxy-phenyl)-phenyl-, 3-(4-Chloro-phenyl)-phenyl-, 3-(3,5-Dichloro-phenyl)-phenyl-, 3-(3,4-Dichloro-phenyl)-phenyl-, 3-(4-Fluorophenyl)-phenyl-, 3-(4-Methylphenyl)-phenyl-, 3-[4-(Trifluoromethyl)phenyl]-phenyl-, 3-[3,5-Bis-(Trifluoromethyl)-phenyl]-phenyl-, 4-(4-Pyridyloxy)-phenyl)-, 4-(2-Methoxy-phenoxy)-phenyl-, 4-(2-Chloro-phenoxy)-phenyl-, 4-(2-Methyl-phenoxy)-phenyl-, 4-(4-Methoxy-phenoxy)-phenyl-, 4-(4-Chlorophenyl)-phenyl-, 4-(3,5-Dichlorophenyl)-phenyl-, 4-(3,4-Dichlorophenyl)-phenyl-, 4-(4-Fluorophenyl)-phenyl-, 4-(4-Methylphenyl)-phenyl-, 4-[4-(Trifluormethyl)-phenyl]-phenyl-, 4-[3,5-Bis-(Trifluoromethyl)-phenyl]-phenyl-, [3-(Trifluoromethyl)-phenyl]-methyl-, (4-Chlorophenyl)-methyl-, (3,5-Dichlorophenyl)-methyl-, (3,5-Dichlorophenyl)-methyl-, (4-Fluorophenyl)-methyl-, 4-Methylphenylmethyl-, [4-(Trifluoromethyl)-phenyl]-methyl-, Cyclopropyl-, 2-(2-Chlorophenyl)-2-Phenylethyl-, 2-(2-Trifluoromethylphenyl)-2-phenylethyl-, 5-[4-Cyano-1-methyl-5-(methylthioyl H-pyrazol-3-yl-thiophene-2-yl-, 3-Cyano-2,4-bis-(2,2,2-Trifluorothoxy)-phenyl-, 4-[(2-Chloro-1,3-Thiazol-5-yl)-methoxy]-phenyl-, 3-Nitro-phenylmethyl-, 4-Formylphenyl-, 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl-, [3,5-Bis-(Trifluoromethyl)-phenyl]-methyl-, (4-(2-Pyridyloxy)-phenyl)-, (4-(3-Pyridyloxy)-phenyl)-, 5-Iodo-naphth-1-yl-, Ethyl-2,5-dimethyl-1-phenylpyrrole-4-carboxylate-3-yl-, Ethyl-2-methyl-1,5-diphenyl-1H-pyrrole-3-carboxylate-4-yl-, Ethyl-5-(4-chlorophenyl)-2-methyl-3-furoate-4-yl, Ethyl-5-(4-chlorophenyl)-2-methyl-1-phenyl-3-carboxylate-4-yl-, Ethyl-2,5-dimethyl-3-furoate-4-yl-, 3-Chloro-4-(1,3-dioxo-2-Azaspiro[4,4]non-2-yl)-phenyl-, 5-Bromo-2,4-difluoro-phenyl-, 5-Chloro-2,4-difluorophenyl-, Coumarin-6-yl, 2-Methoxy-phenyl, (3-Phenoxy)-phenyl-, 3-(4-Methoxy-phenoxy)-phenyl-, 3-(4-Chlorophenoxy)-phenyl-, 3-(3,5-Dichlorophenoxy)-phenyl-, 3-(3,4-Dichlorophenoxy)-phenyl-, 3-(4-Fluorophenoxy)-phenyl-, 3-(4Methylphenoxy)-phenyl-, 3-[4-(Trifluoromethylyphenoxy]-phenyl-, 3-[3,5-(Trifluoromethyl)-phenoxy]-phenyl-, 3-[2-(Trifluoromethylyphenoxy]-phenyl-, 2,2-Diphenylethyl-, 4-Phenyl-5-(trifluoromethyl)-thiophene-3-yl-, Methyl-4-Phenyl-5-(Trifluoromethyl)-thiophene-2-carboxylate-3-yl-, Methyl-1,2,5-trimethylpyrrole-3-Carboxylate-4-yl-, 4-Fluoro-naphth-1-yl-, 3,5-Difluorophenyl-, 3-Fluoro-4-methoxy-phenyl-, 4-Chloro-2,5-difluorophenyl-, 2-Chloro-4,5-difluoro-phenyl-, 5-Fluoro-3-methylbenzo[B]-thiophene-2-yl-, Methyl-3-phenylpropionate-4-yl, Dihydrocinnamic Acid-4-yl-, Methyl-2,5-dimethyl-3-furoate-4-yl-, Methyl-2-furoate-5-yl-, Methyl-2-methyl-3-furoate-5-yl-, Methyl-1-methyl-1H-pyrrole-2-Carboxylate-5-yl-, 2-(5-Chloro-1,2,4-Thiadiazol-3-yl)-thiophene-5-yl-, 1,3,5-Trimethyl-1H-pyrazole-4-yl-, 3-Chloro-5-fluoro-2-methylphenyl-, Pentafluoroethoxytetrafluoroethyl-, 5-(5-Isoxazyl)-thiophene-2-yl-, 5-(5-Isoxazol-yl)-2-furyl-, 5-Methyl-2,1,3-benzothiadiazole-4-yl-, Biphenyl-2-yl-, 2,3-Dihydro-1,4-benzodioxine-6-yl-, 4-Methyl-Naphth-1-yl-, 5-Methyl-2-(Trifluormethyl)-3-Furyl-, 2,3-Dihydrobenzo[B]furan-5-yl-, 1-Benzothiophene-3-yl-, 4-Methyl-3,4-dihydro-2H-1,4-Benzoxazine-7-yl-, 5-Methyl-1-phenyl-1H-pyrazole-4-yl-, 6-Morpholino-3-Pyridinyl-, 4-(1H-Pyrazol-1-yl)-phenyl-, 6-Phenoxy-3-Pyridyl-, 3,4-Dihydro-2H-1,5-benzodioxepine-7-yl-, 5-(1,3-Oxazol-5-yl)-2-thienyl-, 4-(1,3-Oxazol-5-yl)-phenyl-, 5-Methyl-4-isoxazolyl, 2,1,3-Benzothiadiazole-5-yl-, 3-Thienyl-, 2-Methyl-benzyl-, 3-Chloro-benzyl-, 5-Acetamido-naphth-1-yl-, 3-Methyl-8-Quinolinyl-, 4-Chloro-2-nitrophenyl-, 6-Quinolinyl-, 1,3-Benzothiazole-6-yl-, 2-Morpholino-3-Pyridyl-, 2,5-Dimethyl-3-thienyl-, 5-[5-(Chloromethyl)-1,2,4-oxadiazol-3-yl]-2-thienyl-, Ethyl-3-[5-yl-2-thienyl-]1,2,4-oxadiazole-5-carboxylate-, 3-(5-Methyl-1,3,4-oxadiazol-2-yl)-phenyl-, 4-Isopropoxyphenyl-, 2,4-Dibromophenyl-, 3-Cyano-4-fluorophenyl-, 2,5-Bis-(Trifluoromethyl)-phenyl, 2-Bromo-4-fluorophenyl-, 4-Bromo-3-fluorophenyl-, 4-(Difluoromethoxy)-phenyl-, 3-(Difluoromethoxy)-phenyl-, 5-Chloro-2-fluoro-phenyl-, 3-Chloro-2-fluorophenyl-, 2-Fluoro-4-methylphenyl-, 4 Nitro-3-(trifluoromethyl)-phenyl-, 3-Fluoro-4-methylphenyl-, 4-Fluoro-2-methylphenyl-, 4-Bromo-3-(tifluoromethyl)-phenyl-, 4-Bromo-2-(trifluoromethyl)phenyl-, 3-Bromo-5-(trifluoromethyl)-phenyl-, 2-Bromo-4-(trifluoromethyl)-phenyl-, 2-Bromo-5-(trifluoromethyl)-phenyl-, 2,4-Dichloro-5-fluorophenyl-, 4,5-Dichloro-2-fluorophenyl-, 3,4,5-Trifluorophenyl-, 4-Chloro-2-fluorophenyl-, 2-Bromo-4,6-Difluorophenyl-, 2-Ethylphenyl-, 4-Bromo-2-chlorophenyl-, 4-Bromo-2,6-dichlorophenyl-, 2-Bromo-4,6-dichloro-phenyl-, 4-Bromo-2,6-dimethylphenyl-, 3,5-Dimethylphenyl-, 4-Bromo-3-methylphenyl-, 2-Methoxy-4-nitrophenyl-, 2,2-Dimethyl-6-Chromanyl-, Ethyl-3,5dimethyl-1H-pyrrole-2-carboxylate-4-yl-, Imidazo[1,2-A]pyridine-3-yl-, 3-(1,3-Oxazol-5-yl)-phenyl-, Ethyl-5-[4-yl)-phenyl]-2-methyl-3-furoate, Methyl-3-(yl)-4-methoxybenzoate, 1-Pyrrolidinylphenylsulfonyl-, Methyl-5-yl-4-methyl-2-thiophene-carboxylate, Methyl-3-yl-4-(isopropylsulfonyl)-2-thiophene, 2-Pyridyl-, 3-Fluoro-4-nitrophenyl-, 7-Chlorochromone-3-yl-, 4′-Bromobiphenyl-4-yl-, 4′-Acetyl-biphenyl-4-yl-, 4′-Bromo-2′-fluoro-biphenyl-4-yl-, 2-Chloro-4-(3-propyl-Ureido)-phenyl-, 3-(-Bromoacetyl)-phenyl-, 2-Bromo-3-(trifluoromethyl)-phenyl-, 1-Methyl-5-isatinyl-, 4-Isopropyl-benzoic-acid-3-yl-, 2-Chloro-3-thiophenecarboxylic-acid-5-yl-, 3-Pyridyl-, Cyclohexylmethyl-, 2-Methoxy-5-(N-phthalimidinyl)-phenyl-, 1-Benzothiophene-2-yl-, Morpholinophenylsulfonyl-, 3-(2-Methyl-4-pyrimidinyl)-phenyl-, and 2-Cyano-5-methylphenyl-,

and R¹-R^18bhave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

Also preferred is the use of compounds of general formula (Ib), wherein W b represents a linear or branched C_1-20-alkyl radical, preferably an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and 1,1-dimethyl-propyl; a linear or branched C_2-20-alkenyl radical; preferably a vinyl radical; —CF₃; —CHF₂; —CH₂F; —CCl₃; —CHCl₂; —CH₂Cl; —CH₂—CF₃; —CH₂CH₂—Cl; —CH₂—CH₂—CH₂Cl; —CH₂—S(═O)₂—CH₃; a cyclopropyl radical; a cyclobutyl radical; a cyclopentyl radical; a cyclohexyl radical; —CH₂-cyclopropyl; —CH₂-cyclobutyl; —CH₂-cyclopentyl; —CH₂-cyclohexyl; —N(CH₃)₂; —N(C₂H₅)₂; —N(n-CH₂—CH₂—CH₃)₂; phenyl; benzyl; naphthyl; —CH═CH-phenyl; —(CF₂)—(CF₂)—O-phenyl; —(CH₂)-naphtyl; —(CH₂)—(CH₂)-naphthyl; anthracenyl; —(C═O)-phenyl; thiophenyl; benzo[b]thiophenyl; furanyl; 2-oxo-2H-chromenyl; dibenzofuranyl; 2,3-dihydrobenzofuranyl; chromanyl; 2,3-dihydro-benzo[1,4]dioxinyl; 3,4-dihydro-2H-1,5-benzo-dioxepinyl; chromonyl; 1H-imidazolyl; pyridinyl; pyrrolidine-2,5-dionyl; pyrrolyl; 1H-pyrazolyl; 1H-pyrimidine-2,4-dionyl; quinolinyl; isoquinolinyl; 1H-Benzoimidazolyl; 1,4-dihydro-quinoxaline-2,3-dionyl; 1,2,3,4-tetrahydro-isoquinolinyl; 1,4-dihydro-benzo[b][1,4]diazepine-2,4-dionyl; 1,3-dihydro-1-oxo-2H-isoindolyl; phthalimidinyl; 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl; imidazo[1,2-a]pyridine; isatinyl; thiazolyl; 1,3-thiazolyl; 1,2,4-thiadiazolyl; imidazo[2,1-b]thiazolyl; 1,3-benzothiazolyl; benzo[1,2,5]thiadiazolyl; 2-oxo-2,3-dihydro-benzothiazolyl; 2,1,3-benzothiadiazolyl; imidazo[2,1-b]thiazolyl; isoxazolyl; benzo[1,2,5]oxadiazolyl; benzo[d]isoxazolyl; benzofurazanyl; 2-oxo-2,3-dihydro-benzooxazolyl; 3,4-dihydro-2H-benzo[1,4]oxazinyl; or 2,1,3-benzoxadiazolyl;

whereby each of these afore mentioned cyclic moieties may optionally be substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; n-butyl; iso-butyl; sec-butyl; tert-butyl; 1,1-dimethyl-propyl; n-pentyl; vinyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; morpholino; methoxy; ethoxy; n-propoxy; iso-propoxy; n-propoxy; F; Cl; Br; I; —CN; —OH; —CF₃; —CF₂H; —CH₂F; —CCl₃; —CClH₂; —CHCl₂; —CH₂—F; —CH₂—Cl; —CH₂—Br; —(C═O)—CH₂—Br; —OCF₃; —O—CH₂—CF₃; —O—CHF₂; —NO₂; —NH₂; —N(CH₃)₂; —N(C₂H₅)₂; —N(n-CH₂—CH₂—CH₃)₂; —N(n-CH₂—CH₂—CH₂—CH₃)₂; —NH—(C═O)—CH₃; —NH-phenyl; —(C═O)—CF₃; —(C═O)—OH; ═O (oxo); —(C═O)—H; —S(═O)₂—CH₃; —S(═O)₂-isopropyl; —S(═O)₂-phenyl; —S(═O)₂-pyrrolidinyl; —S(═O)₂-morpholino; —(CH₂)—(CH₂)—(C═O)—O—CH₃; —NH—C═O)—NH—CH₂—CH₂—CH₃; —(C═O)—CH₃; —(C═O)—O—CH₃; —(C═O)O—C₂H₅; —(CH₂)—NH—(C═O) phenyl; —CH₂—C(H)(phenyl)(phenyl); —O—CH₂-thiazolyl; 1,3-dioxo-2-azaspiro[4.4]non-2-yl; phenyl; phenoxy; isoxazolyl; 1,3-oxazolyl; 1,2,4-oxadiazolyl; 1,3,4-oxadiazolyl; pyridinyl; pyridinyloxy; pyrazolyl; pyrimidinyl and phthalimidinyl; and

whereby each of the cyclic moieties of these afore mentioned substituents may optionally be substituted with 1, 2, 3, 4 or 5 substituents that are independently selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; F; Cl; Br; I; CN; —CH₂—F; —CH₂—Cl; —CH₂—Br; —CF₃and —S—CH₃,

more preferably W^brepresents

an alkyl radical selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec.butyl; iso-butyl and tert-butyl; vinyl (CH₂═CH—); —N(CH₃)₂; 1-naphthyl; benzyl; 2-naphtyl; phenyl; 2-methyl-phenyl; 3-methyl-phenyl; 4-methyl-phenyl; 2-ethyl-phenyl; 3-ethyl-phenyl; 4-ethyl-phenyl; 2-n-propyl-phenyl; 3-n-propyl-phenyl; 4-n-propyl-phenyl; 2-isopropyl-phenyl; 3-isopropyl-phenyl; 4-isopropyl-phenyl; 2-n-butyl-phenyl; 3-n-butyl-phenyl; 4-n-butyl-phenyl; 2-iso-butyl-phenyl; 3-iso-butyl-phenyl; 4-iso-butyl-phenyl; 2-tert-butyl-phenyl; 3-tert-butyl-phenyl; 4-tert-butyl-phenyl; 1,1-dimethylpropyl-phenyl; 2-cyclopentyl-phenyl; 3-cyclopentyl-phenyl; 4-cyclopentyl-phenyl 2-cyclohexyl-phenyl; 3-cyclohexyl-phenyl; 4-cyclohexyl-phenyl; 2-methoxy-phenyl; 3-methoxy-phenyl; 4-methoxy-phenyl; 2-ethoxy-phenyl; 3-ethoxy-phenyl; 4-ethoxy-phenyl; 2-n-propoxy-phenyl; 3-n-propoxy-phenyl; 4-n-propoxy-phenyl; 2-iso-propoxy-phenyl; 3-iso-propoxy-phenyl; 4-isopropoxy-phenyl; 2-fluoro-phenyl; 3-fluoro-phenyl; 4-fluoro-phenyl; 2-chloro-phenyl; 3-chloro-phenyl; 4-chloro-phenyl; 2-bromo-phenyl; 3-bromo-phenyl; 4-bromo-phenyl; 2-trifluoromethyl-phenyl; 3-trifluoromethyl-phenyl; 4-trifluoromethyl-phenyl; 2-trifluoromethoxy-phenyl; 3-trifluoromethoxy-phenyl; 4-trifluoromethoxy-phenyl; 2-carboxy-phenyl; 3-carboxy-phenyl; 4-carboxy-phenyl; 2-acetyl-phenyl; 3-acetyl-phenyl; 4-acetyl-phenyl; 2-(C═O)—O—CH₃-phenyl; 3-(C═O)—O—CH₃-phenyl; 4-(C═O)—O—CH₃-phenyl; 2-(CH₂)—(CH₂)—(C═O)—O—CH₃; 3-(CH₂)—(CH₂)—(C═O)—O—CH₃; 4-(CH₂)(CH₂)—(C═O)—O—CH₃; 2-cyano-phenyl; 3-cyano-phenyl; 4-cyano-phenyl; 2-nitro-phenyl; 3-nitro-phenyl; 4-nitro-phenyl; 4-(4-bromophenoxy)-phenyl; 2-methylsulfonyl-phenyl; 3-methylsulfonyl-phenyl; 4-methylsulfonyl-phenyl; 2-phenyl-phenyl (biphenyl-2-yl); 3-phenyl-phenyl (biphenyl-3-yl); 4-phenyl-phenyl (biphenyl-4-yl); 2-phenoxy-phenyl; 3-phenoxy-phenyl; 4-phenoxy-phenyl; 2,4-dimethyl-phenyl; 3,4-dimethyl-phenyl; 2,4,6-trimethyl-phenyl; 2,3,5,6-tetramethyl-phenyl; pentamethyl-phenyl; 2,5-dimethoxy-phenyl; 3,4-dimethoxy-phenyl; 2,3-dichloro-phenyl; 2,4-dichloro-phenyl; 2,5-dichloro-phenyl; 3,4-dichloro-phenyl; 3,5-dichloro-phenyl; 2,6-dichloro-phenyl; 2,4-difluoro-phenyl; 3,4-difluoro-phenyl; 2,5-difluoro-phenyl; 2,6-difluoro-phenyl; 3-chloro-2-fluoro-phenyl; 3-chloro-4-fluoro-phenyl; 5-chloro-2-fluoro-phenyl; 2,3,4-trichloro-phenyl; 2,4,5-trichloro-phenyl; 2,4,6-trichloro-phenyl; 2,4,5-trifluoro-phenyl; 2,3,4-trifluoro-phenyl-; 2-chloro-4,5-difluoro-phenyl; 2-bromo-4-fluoro-phenyl; 2-bromo-4,6-difluoro-phenyl; 4-chloro-2,5-difluoro-phenyl; 5-chloro-2,4-difluoro-phenyl; 4-bromo-2,5-difluoro-phenyl; 5-bromo-2,4-difluoro-phenyl; pentafluoro-phenyl; 2,4-dinitro-phenyl; 4-chloro-3-nitro-phenyl; 2-methyl-5-nitro-phenyl; 5-bromo-2-methoxy-phenyl; 3-chloro-2-methyl-phenyl; 4-bromo-3-methyl-phenyl; 4-chloro-2,5-dimethyl-phenyl; 4-fluoro-3-methyl-phenyl; 5-fluoro-2-methyl-phenyl; 2-nitro-4-trifluoromethyl-phenyl; 2-methoxy-4-methyl-phenyl; 3,5-dichloro-2-hydroxy-phenyl; 3,5-dichloro-4-hydroxy-phenyl; 5-chloro-2,4-difluoro-phenyl; 3-chloro-4-(NH)—(C═O)—CH₃-phenyl; 2-chloro-6-methyl-phenyl; 2-chloro-5-trifluoromethyl-phenyl; 2-chloro-5-trifluoromethoxy-phenyl; 4-bromo-2trifluoromethoxy-phenyl; 4-bromo-2-trifluoromethyl-phenyl; 4-bromo-3-trifluoromethyl-phenyl; 3-carboxy-4-fluoro-phenyl; 3-carboxy-4-chloro-6-fluoro-phenyl; 4-methoxy-2,3,6-trimethyl-phenyl-; or one of the following groups:
embedded image

whereby in each case X denotes the position by which the respective substituent W^bis bonded to the —SO₂group of formula (Ib),

and R¹-R^18bhave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

Furthermore, the use of compounds of general formula (Ib) is preferred, wherein R¹⁰represents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

preferably H, a C_1-4-alkyl radical, cyclohexyl or a phenyl radical,

more preferably H, CH₃, C₂H₅or phenyl,

and R^1b-R^9b, R^11b-R^18band W^bhave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

Moreover, the use of compounds of general formula (Ib) is preferred, wherein R^11brepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

preferably H, a C_1-4-alkyl radical, cyclohexyl or a phenyl radical, more preferably H, CH₃, C₂H₅or phenyl,

and R^1b-R^10b, R^12b-R^18band W^bhave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

Preference is also given to the use of compounds of general formula (Ib), wherein R^12brepresents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

preferably represents H, a C_1-4-alkyl radical, cyclohexyl or a phenyl radical,

more preferably H, CH₃, C₂H₅or phenyl,

and R^1b-R^11b, R^13b-R^18band W^bhave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

Also preferred is the use of compounds of general formula (Ib), wherein R^13band R^14bare each independently selected from the group consisting of hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system, or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

preferably are each independently selected from the group consisting of H, a C_1-4-alkyl radical, cyclohexyl and a phenyl radical,

more preferably are each independently selected from the group consisting of H, CH₃, C₂H₅and phenyl,

and R^1b-R^12b, R^15b-R^8band W^bhave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

Furthermore, the use of compounds of general formula (Ib) is preferred, wherein R^13band R^14btogether with the bridging nitrogen atom form a saturated, unsaturated or aromatic, 5- or 6-membered heterocyclic ring, which may be at least mono-substituted and/or contain at least one further heteroatom as a ring member,

preferably form an unsubstituted piperidin or morpholine group,

and R^1b-R^12b, R^15b-R^18band W^bhave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

Also preferred are compounds of general formula (Ib), wherein R^15brepresents hydrogen, an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6-aliphatic radical, a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing C_3-8-cycloaliphatic radical or an optionally at least mono-substituted, 5- or 6-membered aryl- or heteroaryl radical, which may be bonded via an optionally at least mono-substituted C_1-6-alkylene group and/or may be condensed with an optionally at least mono-substituted mono- or polycyclic ring-system,

preferably represents H, a C_1-4-alkyl radical, cyclohexyl or a phenyl radical,

more preferably represents H, CH₃, C₂H₅or phenyl,

and R^1b-R^14b, R^16b-R^18band W^bhave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

Also preferred is the use of compounds of general formula (Ib), wherein R^16brepresents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6aliphatic radical,

preferably an unbranched or branched, saturated, unsubstituted C_1-3alkyl radical,

more preferably a methyl radical,

and R^1b-R^15b, R^17b, R^18band W^bhave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

Also preferred are compounds of general formula (Ib), wherein R^17brepresents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted C_1-6aliphatic radical,

preferably an unbranched or branched, saturated, unsubstituted C_1-3alkyl radical,

more preferably a methyl radical,

and R^1b-R^16b, R^18band W^bhave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

Also preferred are compounds of general formula (Ib) given above, wherein R^18brepresents a phenyl radical, which is optionally at least mono-substituted by a C_1-6aliphatic radical, more preferably a phenyl radical, which is optionally at least mono-substituted by a methyl group, and R^1b-R^17band W^bhave the meaning given above, optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemates or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or corresponding salts thereof, or corresponding solvates.

More preferred are compounds of general formula (Ib) given above, wherein

R^1b, R^2b, R^3b, R^4bare each independently selected from the group consisting of a hydrogen atom; a fluorine atom; a chlorine atom; a bromine atom; a methyl group and a methoxy group;

R^5brepresents a hydrogen atom;

R^6b, R^7b, R^8b, R^9beach represent a hydrogen atom;

W^brepresents

an alkyl radical selected from the group consisting of methyl; ethyl; n-propyl; iso-propyl; n-butyl; sec.butyl; iso-butyl and tert-butyl; vinyl (CH₂═CH—); —N(CH₃)₂; 1-naphthyl; benzyl; 2-naphtyl; phenyl; 2-methyl-phenyl; 3-methyl-phenyl; 4-methyl-phenyl; 2-ethyl-phenyl; 3-ethyl-phenyl; 4-ethyl-phenyl; 2-n-propyl-phenyl; 3-n-propyl-phenyl; 4-n-propyl-phenyl; 2-isopropyl-phenyl; 3-isopropyl-phenyl; 4-isopropyl-phenyl; 2-n-butyl-phenyl; 3-n-butyl-phenyl; 4-n-butyl-phenyl; 2-iso-butyl-phenyl; 3-iso-butyl-phenyl; 4-iso-butyl-phenyl; 2-tert-butyl-phenyl; 3-tert-butyl-phenyl; 4-tert-butyl-phenyl; 1,1-dimethylpropyl-phenyl; 2-cyclopentyl-phenyl; 3-cyclopentyl-phenyl; 4-cyclopentyl-phenyl 2-cyclohexyl-phenyl; 3-cyclohexyl-phenyl; 4-cyclohexyl-phenyl; 2-methoxy-phenyl; 3-methoxy-phenyl; 4-methoxy-phenyl; 2-ethoxy-phenyl; 3-ethoxy-phenyl; 4-ethoxy-phenyl; 2-n-propoxy-phenyl; 3-n-propoxy-phenyl; 4-n-propoxy-phenyl; 2-iso-propoxy-phenyl; 3-iso-propoxy-phenyl; 4-isopropoxy-phenyl; 2-fluoro-phenyl; 3-fluoro-phenyl; 4-fluoro-phenyl; 2-chloro-phenyl; 3-chloro-phenyl; 4-chloro-phenyl; 2-bromo-phenyl; 3-bromo-phenyl; 4-bromo-phenyl; 2-trifluoromethyl-phenyl; 3-trifluoromethyl-phenyl; 4-trifluoromethyl-phenyl; 2-trifluoromethoxy-phenyl; 3-trifluoromethoxy-phenyl; 4-trifluoromethoxy-phenyl; 2-carboxy-phenyl; 3-carboxy-phenyl; 4-carboxy-phenyl; 2-acetyl-phenyl; 3-acetyl-phenyl; 4-acetyl-phenyl; 2-(C═O)—O—CH₃-phenyl; 3-(C═O)—O—CH₃-phenyl; 4-(C═O)—O—CH₃-phenyl; 2-(CH₂)—(CH₂)—(C═O)—O—CH₃; 3-(CH₂)—(CH₂)—(C═O)—O—CH₃; 4-(CH₂)(CH₂)—(C═O)—O—CH₃; 2-cyano-phenyl; 3-cyano-phenyl; 4-cyano-phenyl; 2-nitro-phenyl; 3-nitro-phenyl; 4-nitro-phenyl; 4-(4-bromophenoxy)-phenyl; 2-methylsulfonyl-phenyl; 3-methylsulfonyl-phenyl; 4-methylsulfonyl-phenyl; 2-phenyl-phenyl (biphenyl-2-yl); 3-phenyl-phenyl (biphenyl-3-yl); 4-phenyl-phenyl (biphenyl-4-yl); 2-phenoxy-phenyl; 3-phenoxy-phenyl; 4-phenoxy-phenyl; 2,4-dimethyl-phenyl; 3,4-dimethyl-phenyl; 2,4,6-trimethyl-phenyl; 2,3,5,6-tetramethyl-phenyl; pentamethyl-phenyl; 2,5-dimethoxy-phenyl; 3,4-dimethoxy-phenyl; 2,3-dichloro-phenyl; 2,4-dichloro-phenyl; 2,5-dichloro-phenyl; 3,4-dichloro-phenyl; 3,5-dichloro-phenyl; 2,6-dichloro-phenyl; 2,4-difluoro-phenyl; 3,4-difluoro-phenyl; 2,5-difluoro-phenyl; 2,6-difluoro-phenyl; 3-chloro-2-fluoro-phenyl; 3-chloro-4-fluoro-phenyl; 5-chloro-2-fluoro-phenyl; 2,3,4-trichloro-phenyl; 2,4,5-trichloro-phenyl; 2,4,6-trichloro-phenyl; 2,4,5-trifluoro-phenyl; 2,3,4-trifluoro-phenyl-; 2-chloro-4,5-difluoro-phenyl; 2-bromo-4-fluoro-phenyl; 2-bromo-4,6-difluoro-phenyl; 4-chloro-2,5-difluoro-phenyl; 5-chloro-2,4-difluoro-phenyl; 4-bromo-2,5-difluoro-phenyl; 5-bromo-2,4-difluoro-phenyl; pentafluoro-phenyl; 2,4-dinitro-phenyl; 4-chloro-3-nitro-phenyl; 2-methyl-5-nitro-phenyl; 5-bromo-2-methoxy-phenyl; 3-chloro-2-methyl-phenyl; 4-bromo-3-methyl-phenyl; 4-chloro-2,5-dimethyl-phenyl; 4-fluoro-3-methyl-phenyl; 5-fluoro-2-methyl-phenyl; 2-nitro-4-trifluoromethyl-phenyl; 2-methoxy-4-methyl-phenyl; 3,5-dichloro-2-hydroxy-phenyl; 3,5-dichloro-4-hydroxy-phenyl; 5-chloro-2,4-difluoro-phenyl; 3-chloro-4-(NH)—(C═O)CH₃-phenyl; 2-chloro-6-methyl-phenyl; 2-chloro-5-trifluoromethyl-phenyl; 2-chloro-5-trifluoromethoxy-phenyl; 4-bromo-2-trifluoromethoxy-phenyl; 4-bromo-2-trifluoromethyl-phenyl; 4-bromo-3-trifluoromethyl-phenyl; 3-carboxy-4-fluoro-phenyl; 3-carboxy-4-chloro-6-fluoro-phenyl; 4-methoxy-2,3,6-trimethyl-phenyl-; or one of the following groups:
embedded image

whereby in each case X denotes the position by which the respective substituent W^bis bonded to the —SO₂group of formula (Ib).

optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a physiologically acceptable salt thereof, or a solvate, respectively.

Particularly preferred is the use of one or more benzoxazinone-derived sulfonamide compounds of general formula (Ib) selected from the group consisting of:
embedded image

Furthermore, particularly preferred is the use of one or more benzoxazinone-derived sulfonamide compounds of general formula (Ib) selected from the group consisting of:

N^oCompound11-[1-(Naphthalene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one21-[1-(Toluene-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one31-(1-Phenylmethanesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one41-(1-Benzenesulfonyl-piperidin-4-yl)-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one56-Chloro-1-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one66-Chloro-1-(1-phenylmethanesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one76-Chloro-1-[1-(naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one86-Chloro-1-[1-(naphthalene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one96-Chloro-1-[1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one101-[1-(Thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one111-[1-(4-Acetyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one122-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzonitrile131-[1-(2,4-Dimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one141-[1-(4-Methoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one151-[1-(2-Naphthalen-1-yl-ethanesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one168-Methyl-1-[1-(thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one171-[1-(4-Acetyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one182-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzonitrile191-[1-(2,4-Dimethyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one201-[1-(4-Methoxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one218-Methyl-1-[1-(2-naphthalen-1-yl-ethanesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one224-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonic aciddimethylamide232-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acidmethyl ester241-[1-(3-Trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one252-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid methyl ester268-Methyl-1-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one271-[1-(4-Acetyl-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one282-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzonitrile296-Chloro-1-[1-(4-methoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one302-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid methyl ester316-Chloro-1-[1-(2,4-dimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one326-Chloro-1-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one331-[1-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one341-{1-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-piperidin-4-yl}-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one351-[1-(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one368-Methyl-1-[1-(naphthalene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one378-Methyl-1-(1-phenylmethanesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one381-[1-(4-Bromo-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one396-Chloro-1-[1-(4-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one401-[1-(Butane-1-sulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one411-[1-(4-Bromo-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one421-[1-(4-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one431-[1-(Butane-1-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one446-Chloro-1-[1-(2-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one456-Chloro-1-[1-(3-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one461-[1-(Biphenyl-4-sulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one478-Methyl-1-[1-(2-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one488-Methyl-1-[1-(3-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one491-[1-(Biphenyl-4-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one508-Methyl-1-[1-(4-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one516-Chloro-1-[1-(4-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one521-(1-Ethanesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one531-[1-(Propane-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one541-[1-(Propane-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one556-Chloro-1-(1-ethanesulfonyl-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one566-Chloro-1-[1-(propane-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one576-Chloro-1-[1-(propane-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one586-Chloro-1-[1-(quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one591-[1-(4-Nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one606-Methyl-1-[1-(quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one616-Methyl-1-[1-(2-naphthalen-1-yl-ethanesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one626-Methyl-1-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one631-[1-(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one646-Methyl-1-[1-(naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one656-Methyl-1-[1-(naphthalene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one661-[1-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one676-Methyl-1-[1-(4-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one681-(1-Benzenesulfonyl-piperidin-4-yl)-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one691-[1-(4-Chloro-3-nitro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one701-[1-(5-Dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one711[1-(4-Chloro-3-nitro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one721[1-(4-Chloro-3-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one736-Chloro-1-[1-(4-chloro-3-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihdro-benzo[d][1,3]oxazin-2-one746-Chloro-1-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one751-[1-(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one761-[1-(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one776-Chloro-1-[1-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one781-[1-(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one791-[1-(2-Bromo-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one801-[1-(2-Bromo-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one811-[1-(2-Bromo-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydrobenzo[d][1,3]oxazin-2-one821-[1-(2-Bromo-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one836-Chloro-1-[1-(2,3-dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one841-[1-(2,3-Dichloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one851-[1-(2,4,5-Trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one868-Methyl-1-[1-(2,4,5-trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one876-Chloro-1-[1-(2,4,5-trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one886-Methyl-1-[1-(2,4,5-trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one891-[1-(5-Bromo-2-methoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one901-[1-(5-Bromo-2-methoxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one911-[1-(5-Bromo-2-methoxy-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one921-[1-(5-Bromo-2-methoxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one931-[1-(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one941-[1-(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one956-Chloro-1-[1-(2,5-dimethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one961-[1-(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one971-(1-Pentamethylbenzenesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one988-Methyl-1-(1-pentamethylbenzenesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one996-Chloro-1-(1-pentamethylbenzenesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one1006-Methyl-1-(1-pentamethylbenzenesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one1011-{1-[2-(2,2,2-Trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one1028-Methyl-1-{1-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one1036-Chloro-1-{1-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one1046-Methyl-1-{1-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one1051-[1-(2-Methyl-5-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1068-Methyl-1-[1-(2-methyl-5-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1076-Chloro-1-[1-(2-methyl-5-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1086-Methyl-1-[1-(2-methyl-5-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1091-[1-(4-Bromo-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1101-[1-(4-Bromo-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1111-[1-(4-Bromo-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one1121-[1-(4-Bromo-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1131-[1-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1141-[1-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1156-Chloro-1-[1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1161-[1-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1171-[1-(4-Methoxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1181-[1-(4-Isopropyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1191-[1-(4-Isopropyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1206-Chloro-1-[1-(4-isopropyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1211-[1-(4-Isopropyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1221-[1-(3-Chloro-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1231-[1-(3-Chloro-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1246-Chloro-1-[1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1251-[1-(3-Chloro-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1261-[1-(4-Bromo-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1276-Methyl-1-[1-(3-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1286-Methyl-1-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1291-[1-(4-Trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1301-[1-(2-Nitro-4-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1311-[1-(3-Fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1321-[1-(2,4-Dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1331-[1-(2,4,6-Trimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1341-[1-(2-Trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1358-Methyl-1-[1-(4-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1368-Methyl-1-[1-(2-nitro-4-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1371-[1-(3-Fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1381-[1-(2,4-Dichloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1398-Methyl-1-[1-(2,4,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1408-Methyl-1-[1-(2-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1411-[1-(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1421-[1-(4-Bromo-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1431-[1-(3-Nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1441-{1-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one1451-[1-(3-Methoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1461-[1-(2-Nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1478-Methyl-1-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1481-(1-Benzenesulfonyl-piperidin-4-yl)-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1491-[1-(3-Methoxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1501-[1-(2,4-Dimethyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1511-{1-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-piperidin-4-yl}-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1526-Methyl-1-[1-(thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1531-[1-(Toluene-3-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1541-[1-(5-Fluoro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1551-[1-(4-Isopropoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1561-[1-(3-Chloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1571-[1-(3,4-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1581-(1-Pentafluorobenzenesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one1598-Methyl-1-[1-(toluene-3-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1601-[1-(5-Fluoro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydrobenzo[d][1,3] oxazin-2-one1611-[1-(4-Isopropoxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3] oxazin-2-one1621-[1-(3-Chloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1631-[1-(3,4-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3] oxazin-2-one1648-Methyl-1-(1-pentafluorobenzenesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one1656-Methyl-1-[1-(toluene-3-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1661-[1-(5-Fluoro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1671-[1-(4-Isopropoxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1681-[1-(3-Chloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1691-[1-(3,4-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1706-Methyl-1-(1-pentafluorobenzenesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one1716-Methyl-1-[1-(4-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1726-Methyl-1-[1-(2-nitro-4-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1731-[1-(3-Fluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1741-[1-(2,4-Dichloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1756-Methyl-1-[1-(2,4,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1766-Methyl-1-[1-(2-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1771-[1-(3-Methoxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1786-Methyl-1-[1-(2-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1791-[1-(4-Acetyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1801-[1-(4-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one1816-Methyl-1-(1-phenylmethanesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one1822-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]benzoic acid methyl ester1836-Methyl-1-[1-(2-oxo-2H-chromene-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1846-Chloro-1-[1-(4-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1856-Chloro-1-[1-(3,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1861-{1-[4-(4-Bromo-phenoxy)-benzenesulfonyl]-piperidin-4-yl}-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one1876-Chloro-1-[1-(thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1886-Chloro-1-[1-(3-methoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1896-Chloro-1-[1-(2-oxo-2H-chromene-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1906-Chloro-1-[1-(toluene-3-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1916-Chloro-1-[1-(5-fluoro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1926-Chloro-1-[1-(4-isopropoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3] oxazin-2-one1936-Chloro-1-[1-(3-chloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1946-Chloro-1-[1-(3,4-dimethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1956-Chloro-1-(1-pentafluorobenzenesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one1966-Chloro-1-[1-(4-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1976-Chloro-1-[1-(2-nitro-4-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1986-Chloro-1-[1-(3-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one1996-Chloro-1-[1-(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2006-Chloro-1-[1-(2,4,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2016-Chloro-1-[1-(2-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2021-[1-(2-Oxo-2H-chromene-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2031-[1-(3,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2041-[1-(2,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2051-[1-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2061-[1-(4-Chloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2071-[1-(2,6-Dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2088-Methyl-1-[1-(2-oxo-2H-chromene-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2091-[1-(3,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2101-[1-(2,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2111-[1-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2121-[1-(4-Chloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2131-[1-(2-6-Dichloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2141-[1-(Biphenyl-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2156-Chloro-1-[1-(2,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2161-[1-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one2176-Chloro-1-[1-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2186-Chloro-1-[1-(2,6-dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2191-[1-(Biphenyl-4-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2202-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzonitrile2211-[1-(2,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]-6methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2221-[1-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2231-[1-(4-Chloro-benzenesulfonyl)-piperdin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2241-[1-(2,6-Dichloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2251-[1-(3,5-Dichloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2266-Methyl-1-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2271-[1-(5-Bromo-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2281-[1-(4-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2291-[1-(1-Methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2301-[1-(5-Bromo-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2311-[1-(6-Chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2321-[1-(4-Ethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2331-[1-(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2341-[1-(6-Chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2351-[1-(4-Ethyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2361-[1-(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2376-Chloro-1-[1-(6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2386-Chloro-1-[1-(4-ethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2391-[1-(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one2401-[1-(6-Chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2411-[1-(4-Ethyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2421-[1-(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2431-[1-(7-Chloro-benzo[1,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2441-[1-(2-Methoxy-4-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2453-{4-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-phenyl}-proionic acid methyl ester2461-[1-(2,4-Dinitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2471-[1-(7-Chloro-benzo[1,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2481-[1-(2-Methoxy-4-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2493-{4-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-phenyl}-propionic acid methyl ester2501-[1-(2,4-Dinitro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2511-[1-(7-Chloro-benzo[1,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2521-[1-(2-Methoxy-4-methyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2533-{4-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-phenyl}-propionic acid methyl ester2541-[1-(2,4-Dinitro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2556-Chloro-1-[1-(7-chloro-benzo[1,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2566-Chloro-1-[1-(2-methoxy-4-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2573-{4-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-phenyl}-propionic acid methyl ester2586-Chloro-1-[1-(2,4-dinitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2596-Chloro-1-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2601-[1-(5-Bromo-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one2618-Methyl-1-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2621-[1-(5-Bromo-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2631-[1-(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2641-[1-(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2651-[1-(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one2661-[1-(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2671-[1-(2,5-Difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2681-[1-(2,5-Difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2696-Chloro-1-[1-(2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2701-[1-(2,5-Difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2711-[1-(4-Chloro-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2721-[1-(4-Chloro-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2736-Chloro-1-[1-(4-chloro-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2741-[1-(4-Chloro-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2751-[1-(2,4,5-Trifluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2768-Methyl-1-[1-(2,4,5-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2776-Chloro-1-[1-(2,4,5-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2786-Methyl-1-[1-(2,4,5-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2791-[1-(3,5-Dichloro-2-hydroxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2801-[1-(2,6-Difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2811-[1-(2,6-Difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2826-Chloro-1-[1-(2,6-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2831-[1-(2,6-Difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2841-[1-(5-Chloro-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2851-[1-(5-Chloro-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2866-Chloro-1-[1-(5-chloro-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2871-[1-(5-Chloro-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2881-[1-(2-Chloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2891-[1-(2-Chloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2906-Chloro-1-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2911-[1-(2-Chloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one2926-Chloro-1-[1-(2-naphthalen-1-yl-ethanesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2936-Bromo-1-[1-(4-bromo-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2946-Bromo-1-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2956-Bromo-1-[1-(2,4-dimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2966-Bromo-1-[1-(2-naphthalen-1-yl-ethanesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2976-Bromo-1-[1-(quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2986-Bromo-1-[1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one2996-Bromo-1-[1-(3-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3006-Bromo-1-[1-(naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3016-Bromo-1-[1-(naphthalene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3021-(1-Benzenesulfonyl-piperidin-4-yl)-6-bromo-1,4-dihydro-benzo[d][1,3]oxazin-2-one3036-Bromo-1-{1-[4-(4-bromo-phenoxy)-benzenesulfonyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one3046-Bromo-1-[1-(thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3056-Bromo-1-[1-(2-methyl-5-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3066-Bromo-1-[1-(4-bromo-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3076-Bromo-1-[1-(toluene-3-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3086-Bromo-1-[1-(5-fluoro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3096-Bromo-1-[1-(4-isopropoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3106-Bromo-1-[1-(3-chloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3116-Bromo-1-[1-(3,4-dimethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3126-Bromo-1-(1-pentafluorobenzenesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one3136-Bromo-1-[1-(4-chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3146-Bromo-1-[1-(3-methoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3156-Bromo-1-[1-(4-isopropyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3166-Bromo-1-[1-(4-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3176-Bromo-1-[1-(3-chloro-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3186-Bromo-1-(1-pentamethylbenzenesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one3196-Bromo-1-[1-(2-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3206-Bromo-1-[1-(4-chloro-3-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3216-Bromo-1-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3226-Bromo-1-[1-(4-nitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3231-[1-(4-Acetyl-benzenesulfonyl)-piperidin-4-yl]-6-bromo-1,4-dihydro-benzo[d][1,3]oxazin-2-one3246-Bromo-1-[1-(4-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3251-[1-(Biphenyl-4-sulfonyl)-piperidin-4-yl]-6-bromo-1,4-dihydro-benzo[d][1,3]oxazin-2-one3266-Bromo-1-(1-phenylmethanesulfonyl-piperidin-4-yl)-1,4-dihydro-benzo[d][1,3]oxazin-2-one3276-Bromo-1-[1-(2,5-dimethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3286-Bromo-1-{1-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one3296-Bromo-1-[1-(2,3-dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3306-Bromo-1-[1-(2,4,5-trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3316-Bromo-1-[1-(5-bromo-2-methoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3326-Bromo-1-[1-(4-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3336-Bromo-1-[1-(2-nitro-4-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3346-Bromo-1-[1-(3-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3356-Bromo-1-[1-(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3366-Bromo-1-[1-(2,4,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3376-Bromo-1-[1-(2-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3386-Bromo-1-[1-(2-bromo-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3396-Bromo-1-[1-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3401-[1-(3,5-Dichloro-4-hydroxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3411-[1-(3,5-Dichloro-4-hydroxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one3426-Chloro-1-[1-(3,5-dichloro-4-hydroxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3431-[1-(3,5-Dichloro-4-hydroxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one3446-Bromo-1-[1-(3,5-dichloro-4-hydroxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3456-Chloro-1-[1-(3,5-dichloro-2-hydroxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3466-Bromo-1-[1-(3,5-dichloro-2-hydroxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3472-[4-(6-Bromo-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzonitrile3486-Bromo-1-[1-(4-methoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3492-[4-(6-Bromo-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid methyl ester3506-Bromo-1-[1-(3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3516-Bromo-1-[1-(2-oxo-2H-chromene-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3526-Bromo-1-[1-(3,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3536-Bromo-1-[1-(2,5-dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3546-Bromo-1-[1-(5-bromo-6-chloro-pyridine-3-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3556-Bromo-1-[1-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3566-Bromo-1-[1-(2,6-dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3576-Bromo-1-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3586-Bromo-1-[1-(5-bromo-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3596-Bromo-1-[1-(4-ethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3606-Bromo-1-[1-(6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3611-[1-(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-6-bromo-1,4-dihydro-benzo[d][1,3]oxazin-2-one3626-Bromo-1-[1-(7-chloro-benzo[1,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3636-Bromo-1-[1-(2-methoxy-4-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3643-{4-[4-(6-Bromo-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-phenyl}-propionic acid methyl ester3656-Bromo-1-[1-(2,4-dinitro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3661-[1-(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6-bromo-1,4-dihydro-benzo[d][1,3]oxazin-2-one3676-Bromo-1-[1-(2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3686-Bromo-1-[1-(4-chloro-2,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3696-Bromo-1-[1-(2,4,5-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3706-Bromo-1-[1-(2,6-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3716-Bromo-1-[1-(5-chloro-2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3726-Bromo-1-[1-(2-chloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3736-Bromo-1-[1-(2,3,4-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one374N-{4-[4-(6-Bromo-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-2-chloro-phenyl}-acetamide3751-[1-(2,3,4-Trifluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3768-Methyl-1-[1-(2,3,4-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3776-Chloro-1-[1-(2,3,4-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3786-Methyl-1-[1-(2,3,4-trifluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one379N-{2-Chloro-4-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-phenyl}-acetamide3801-[1-(3,4-Difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3811-[1-(3,4-Difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one3826-Chloro-1-[1-(3-4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3831-[1-(3,4-Difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one3846-Bromo-1-[1-(3,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one385N-{2-Chloro-4-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-phenyl}-acetamide3861-[1-(2-Chloro-4,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3871-[1-(2-Chloro-4,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one3886-Chloro-1-[1-(2-chloro-4,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3891-[1-(2-Chloro-4,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one3906-Bromo-1-[1-(2-chloro-4,5-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one391N-{2-Chloro-4-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-phenyl}-acetamide3921-[1-(Benzo[1,2,5]oxadiazole-4-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3931-[1-(Benzo[1,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one3941-[1-(Benzo[1,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one3951-[1-(Benzo[1,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one3961-[1-(Benzo[1,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-6-bromo-1,4-dihydro-benzo[d][1,3]oxazin-2-one397N-{2-Chloro-4-[4-(6-chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-phenyl}-acetamide3981-[1-(Benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one3991-[1-(Benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4001-[1-(Benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one4011-[1-(Benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4021-[1-(Benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-6-bromo-1,4-dihydro-benzo[d][1,3]oxazin-2-one4031-(1-Ethanesulfonyl-piperidin-4-yl)-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4041-[1-(2,4-Difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4051-[1-(2-4-Difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4066-Chloro-1-[1-(2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4071-[1-(2,4-Difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4086-Bromo-1-[1-(2,4-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4098-Methyl-1-[1-(propane-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4101-[1-(3,4-Dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4111-[1-(3,4-Dichloro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4126-Chloro-1-[1-(3,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4131-[1-(3,4-Dichloro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4146-Bromo-1-[1-(3,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4158-Methyl-1-[1-(propane-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4161-[1-(2-Chloro-6-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4171-[1-(2-Chloro-6-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4186-Chloro-1-[1-(2-chloro-6-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4191-[1-(2-Chloro-6-methyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4201-[1-(2-Chloro-6-methyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4218-Methyl-1-[1-(2,3,5,6-tetramethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4221-[1-(2,3,4-Trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4238-Methyl-1-[1-(2,3,4-trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4246-Chloro-1-[1-(2,3,4-trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4256-Methyl-1-[1-(2,3,4-trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4266-Bromo-1-[1-(2,3,4-trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4271-[1-(2,3,5,6-Tetramethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4281-[1-(Thiophene-3-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4298-Methyl-1-[1-(thiophene-3-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4306-Chloro-1-[1-(thiophene-3-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4316-Methyl-1-[1-(thiophene-3-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4326-Bromo-1-[1-(thiophene-3-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4336-Chloro-1-[1-(2,3,5,6-tetramethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4341-[1-(2,4,6-Trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4358-Methyl-1-[1-(2,4,6-trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4366-Chloro-1-[1-(2,4,6-trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4376-Methyl-1-[1-(2,4,6-trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4386-Bromo-1-[1-(2,4,6-trichloro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4396-Methyl-1-[1-(2,3,5,6-tetramethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4401-[1-(2-Bromo-4,6-difluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4411-[1-(2-Bromo-4,6-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one4421-[1-(2-Bromo-4,6-difluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4436-Bromo-1-[1-(2-bromo-4,6-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4446-Bromo-1-[1-(2,3,5,6-tetramethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4451-[1-(4-Bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4461-[1-(4-Bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4471-[1-(4-Bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one4481-[1-(4-Bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4496-Bromo-1-[1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4501-[1-(4-Phenoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4511-[1-(3-Bromo-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4521-[1-(3-Bromo-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4531-[1-(3-Bromo-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one4541-[1-(3-Bromo-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4556-Bromo-1-[1-(3-bromo-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4568-Methyl-1-[1-(4-phenoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4571-[1-(4-tert-Butyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4581-[1-(4-tert-Butyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4591-[1-(4-tert-Butyl-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one4601-[1-(4-tert-Butyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4616-Bromo-1-[1-(4-tert-butyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4626-Chloro-1-[1-(4-Phenoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4631-[1-(2-Bromo-4,6-difluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4641-[1-(2-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4656-Chloro-1-[1-(2-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4661-[1-(2-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4676-Bromo-1-[1-(2-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4688-Methyl-1-[1-(4-propyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4696-Chloro-1-[1-(4-propyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4706-Methyl-1-[1-(4-propyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4716-Bromo-1-[1-(4-propyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4721-[1-(3-Chloro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4736-Chloro-1-[1-(3-chloro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4741-[1-(3-Chloro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4756-Bromo-1-[1-(3-chloro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4761-[1-(4-Butyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4771-[1-(4-Butyl-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one4781-[1-(4-Butyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4796-Bromo-1-[1-(4-butyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4801-[1-(4-Bromo-3-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4811-[1-(4-Bromo-3-methyl-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one4821-[1-(4-Bromo-3-methyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4836-Bromo-1-[1-(4-bromo-3-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4841-{1-[4-(1,1-Dimethyl-propyl)-benzenesulfonyl]-piperidin-4-yl}-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4856-Chloro-1-{1-[4-(1,1-dimethyl-propyl)-benzenesulfonyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one4861-{1-[4-(1,1-Dimethyl-propyl)-benzenesulfonyl]-piperidin-4-yl}-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4876-Bromo-1-{1-[4-(1,1-dimethyl-propyl)-benzenesulfonyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one4881-(1-Ethenesulfonyl-piperidin-4-yl)-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4893-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid4903-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid4913-[4-(6-Bromo-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid4921-[1-(3-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4936-Chloro-1-[1-(3-chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one4941-[1-(3-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one4956-Bromo-1-[1-(3-chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one496N-{4-Methyl-5-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-thiazol-2-yl}-acetamide497N-{5-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-4-methyl-thiazol-2-yl}-acetamide498N-{4-Methyl-5-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-thiazol-2-yl}-acetamide499N-{5-[4-(6-Bromo-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-4-methyl-thiazol-2-yl}-acetamide5001-[1-(2-Bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one5011-[1-(2-Bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5021-[1-(2-Bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one5036-Bromo-1-[1-(2-bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5041-[1-(5-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one5056-Chloro-1-[1-(5-chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5061-[1-(5-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one5076-Bromo-1-[1-(5-chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5081-[1-(4-Bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one5091-[1-(4-Bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-6-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5101-[1-(4-Bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one5116-Bromo-1-[1-(4-bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5121-[1-(2-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5131-[1-(4-Propyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5141-[1-(3-Chloro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5151-[1-(4-Butyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5161-[1-(4-Bromo-3-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5171-{1-[4-(1,1-Dimethyl-propyl)-benzenesulfonyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one518N-{4-Methyl-5-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-thiazol-2-yl}-acetamide5191-[1-(3-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5201-[1-(2-Bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5211-[1-(4-Bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5221-[1-(5-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5231-[1-(Isoquinoline-5-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5246-Fluoro-1-[1-(2-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5256-Fluoro-1-[1-(4-propyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5261-[1-(3-Chloro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5271-[1-(4-Butyl-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5281-[1-(4-Bromo-3-methyl-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5291-{1-[4-(1,1-Dimethyl-propyl)-benzenesulfonyl]-piperidin-4-yl}-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one530N-{5-[4-(6-Fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-4-methyl-thiazol-2-yl}-acetamide5311-[1-(3-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5321-[1-(2-Bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5331-[1-(4-Bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5341-[1-(5-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5356-Fluoro-1-[1-(isoquinoline-5-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5366-Fluoro-1-[1-(quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5371-[1-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5386-Fluoro-1-[1-(napthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5396-Fluoro-1-[1-(napthalene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5401-[1-(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5411-[1-(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5428-Methoxy-1-[1-(quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5431-[1-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one5448-Methoxy-1-[1-(naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5458-Methoxy-1-[1-(naphthalene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5461-[1-(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one5471-[1-(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one5485-Chloro-1-[1-(2-methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5495-Chloro-1-[1-(4-propyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5505-Chloro-1-[1-(3-chloro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5511-[1-(4-Butyl-benzenesulfonyl)-piperidin-4-yl]-5-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5521-[1-(4-Bromo-3-methyl-benzenesulfonyl)-piperidin-4-yl]-5-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5535-Chloro-1-{1-[4-(1,1-dimethyl-propyl)-benzenesulfonyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one554N-{5-[4-(5-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-4-methyl-thiazol-2-yl}-acetamide5555-Chloro-1-[1-(3-chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5561-[1-(2-Bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-5-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5571-[1-(4-Bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-5-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5585-Chloro-1-[1-(5-chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5595-Chloro-1-[1-(isoquinoline-5-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5601-[1-(2-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one5611-[1-(2-Methanesulfonyl-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one5621-[1-(3-Chloro-2-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one5631-[1-(4-Butyl-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one5641-[1-(4-Bromo-3-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one5651-{1-[4-(1,1-Dimethyl-propyl)-benzenesulfonyl]-piperidin-4-yl}-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one566N-{5-[4-(8-Methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-4-methyl-thiazol-2-yl}-acetamide5671-[1-(3-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one5681-[1-(2-Bromo-4-fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one5691-[1-(4-Bromo-3-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one5701-[1-(5-Chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one5711-[1-(Isoquinoline-5-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one; hydrochloride5721-[1-(4-Methyl-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5736-Chloro-1-[1-(4-methyl-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5746-Methyl-1-[1-(4-methyl-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5758-Methyl-1-[1-(4-methyl-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5766-Fluoro-1-[1-(4-methyl-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5778-Methoxy-1-[1-(4-methyl-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5785-Chloro-1-[1-(4-methyl-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5795-Chloro-1-[1-(naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5805-Chloro-1-[1-(naphthalene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5815-Chloro-1-[1-(quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5825-Chloro-1-[1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5831-[1-(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-5-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5841-[1-(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-5-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one5856-Bromo-1-[1-(4-methyl-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one5862-Chloro-4-fluoro-5-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid5872-Chloro-5-[4-(6-chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-4-fluoro-benzoic acid5882-Chloro-4-fluoro-5-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid5892-Chloro-4-fluoro-5-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid5902-Chloro-4-fluoro-5-[4-(8-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid5912-Chloro-5-[4-(5-chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-4-fluoro-benzoic acid5923-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid5933-[4-(8-Methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid5943-[4-(5-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid5951-[1-(Isoquinoline-5-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; hydrochloride5966-Chloro-1-[1-(isoquinoline-5-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one; hydrochloride597-[1-(Isoquinoline-5-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one; hydrochloride5986,7-Difluoro-1-[1-(quinoline-8-sulfonyl)-piperidin-4-yl]1,4-dihydro-benzo[d][1,3]oxazin-2-one5991-[1-(5-Chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1,4-dihdro-benzo[d][1,3]oxazin-2-one6006,7-Difluoro-1-[1-(naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6016,7-Difluoro-1-[1-(naphthalene-2-sulfonyl)-piperidin-4-yl]1,4-dihydro-benzo[d][1,3]oxazin-2-one6021-[1-(Benzo[b]thiophene-2-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6031-[1-(Benzo[b]thiophene-3-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6041-[1-(5-Dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6051-[1-(Biphenyl-4-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6061-[1-(Benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6071-[1-(Benzo[1,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1,4-dihdro-benzo[d][1,3]oxazin-2-one6081-[1-(7-Chloro-benzo[1,2,5]oxadiazole-4-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6096,7-Difluoro-1-[1-(4-methyl-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6101-[1-(4-Chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6111-[1-(4-Fluoro-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6121-[1-(Dibenzofuran-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6131-[1-(2,3-Dihydro-benzofuran-5-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6141-[1-(Biphenyl-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6151-[1-(5-Isoxazol-5-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6161-[1-(4-Chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6171-[1-(4-Fluoro-naphthalene-1-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6181-[1-(Dibenzofuran-2-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6191-[1-(2,3-Dihydro-benzofuran-5-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6201-[1-(Biphenyl-2-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6211-[1-(5-Isoxazol-5-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6225-Chloro-1-[1-(4-chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6235-Chloro-1-[1-(4-fluoro-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6245-Chloro-1-[1-(dibenzofuran-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6255-Chloro-1-[1-(2,3-dihydro-benzofuran-5-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6261-[1-(Biphenyl-2-sulfonyl)-piperidin-4-yl]-5-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6275-Chloro-1-[1-(5-isoxazol-5-yl-thiophene-2-sulfony)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6281-[1-(4-Chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one6291-[1-(4-Fluoro-naphthalene-1-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one6301-[1-(Dibenzofuran-2-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one6311-[1-(2,3-Dihydro-benzofuran-5-sulfonyl)-piperidin-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one6321-[1-(Biphenyl-2-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one6331-[1-(5-Isoxazol-5-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one6346-Chloro-1-[1-(4-chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6356-Chloro-1-[1-(4-fluoro-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6366-Chloro-1-[1-(dibenzofuran-2-sulfonyl)-piperidin-4-yl]1,4-dihydro-benzo[d][1,3]oxazin-2-one6376-Chloro-1-[1-(2,3-dihydro-benzofuran-5-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6381-[1-(Biphenyl-2-sulfonyl)-piperidin-4-yl]-6-choro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6396-Chloro-1-[1-(5-isoxazol-5-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6401-[1-(4-Chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6411-[1-(4-Fluoro-naphthalene-1-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6421-[1-(Dibenzofuran-2-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6431-[1-(2,3-Dihydro-benzofuran-5-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6441-[1-(Biphenyl-2-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6451-[1-(5-Isoxazol-5-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihdro-benzo[d][1,3]oxazin-2-one6461-[1-(4-Chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1,4-dihdro-benzo[d][1,3]oxazin-2-one6476,7-Difluoro-1-[1-(4-fluoro-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6481-[1-(Dibenzofuran-2-sulfonyl)piperidin-4-yl]6,7-difluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6491-[1-(2,3-Dihydro-benzofuran-5-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6501-[1-(Biphenyl-2-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6516,7-Difluoro-1-[1-(5-isoxazol-5-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6521-[1-(1,2-Dimethyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6531-[1-(5-Methyl-benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6541-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6551-[1-(1,2-Dimethyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6568-Methyl-1-[1-(5-methyl-benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6571-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6586-Chloro-1-[1-(1,2-dimethyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6596-Chloro-1-[1-(5-methyl-benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6606-Chloro-1-[1-(3,5-dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6611-[1-(1,2-Dimethyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-8-methoxyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6628-Methoxy-1-[1-(5-methyl-benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6631-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one6645-Chloro-1-[1-(1,2-dimethyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6655-Chloro-1-[1-(5-methyl-benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6665-Chloro-1-[1-(3,5-dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6671-[1-(1,2-Dimethyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6686-Methyl-1-[1-(5-methyl-benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6691-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6701-[1-(1,2-Dimethyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6716-Fluoro-1-[1-(5-methyl-benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6721-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6731-[1-(1,2-Dimethyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6746,7-Difluoro-1-[1-(5-methyl-benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6751-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-6,7-difluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one6761-[1-(5-Chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6771-[1-(5-Chloro-naphthalene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one678N-{5-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-naphthalen-1-yl}-acetamide6791-[1-(5-Chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6801-[1-(5-Chloro-naphthalene-2-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one681N-{5-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-naphthalen-1-yl}-acetamide6825-Chloro-1-[1-(5-chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6835-Chloro-1-[1-(5-chloro-naphthalene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one684N-{5-[4-(5-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-naphthalen-1-yl}-acetamide6851-[1-(5-Chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one6861-[1-(5-Chloro-naphthalene-2-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one687N-{5-[4-(8-Methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-naphthalen-1-yl}-acetamide6882,5-Dimethyl-4-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-furan-3-carboxylic acid methyl ester6898-Methyl-1-[1-(2-oxo-2,3-dihydro-benzothiazole-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6901-[1-(4-Fluoro-3-methyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6918-Methyl-1-[1-(2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6921-[1-(4-Cyclohexyl-benzenesulfonyl)-pirperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one6932,5-Dimethyl-4-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-furan-3-carboxylic acid methyl ester6941-[1-(4-Fluoro-3-methyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6951-[1-(2-Oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6961-[1-(4-Cyclohexyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one6972-Fluoro-5-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid6982-Fluoro-5-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzoic acid6991-[1-(2-Oxo-2,3-dihydro-benzothiazole-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7001-[1-(5-Pyridin-2-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7013-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzonitrile7023-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-thiophene-2-carboxylic acid methyl ester7031-{5-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-naphthalen-1-yl}-pyrrolidine-2,5-dione7041-[1-(2-Chloro-5-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7051-[1-(3,4-Dimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7068-Methyl-1-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7073-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzonitrile7083-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-thiophene-2-carboxylic acid methyl ester7091-{5-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-naphthalen-1-yl}-pyrrolidine-2,5-dione7101-[1-(2-Chloro-5-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one7111-[1-(3,4-Dimethyl-benzenesulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one7125-Chloro-1-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7133-[4-(5-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzonitrile7143-[4-(5-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-thiophene-2-carboxylic acid methyl ester7151-{5-[4-(5-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-naphthalen-1-yl}-pyrrolidine-2,5-dione7165-Chloro-1-[1-(2-chloro-5-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7175-Chloro-1-[1-(3,4-dimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7186-Methyl-1-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7193-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzonitrile7203-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-thiophene-2-carboxylic acid methyl ester7211-{5-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-naphthalen-1-yl}-pyrrolidine-2,5-dione7221-[1-(2-Chloro-5-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one7231-[1-(3,4-Dimethyl-benzenesulfonyl)-piperidin-4yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one7246-Chloro-1-[1-(5-pyridin-2-yl-thiophene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7253-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-benzonitrile7263-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-thiophene-2-carboxylic acid methyl ester7271-{5-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-naphthalen-1-yl}-pyrrolidine-2,5-dione7286-Chloro-1-[1-(2-chloro-5-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7296-Chloro-1-[1-(3,4-dimethyl-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7301-[1-(5-Methyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7311-[1-(2,2-Dimethyl-chroman-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7321-[1-(4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7331-[1-(2,3-Dihydro-benzo[1,4]dioxine-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7341-[1-(1,3,5-Thrimethyl-1H-pyrazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7351-[1-(3-Methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7368-Methyl-1-[1-(5-methyl-isoxazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7371-[1-(2,2-Dimethyl-chroman-6-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one7388-Methyl-1-[1-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7391-[1-(2,3-Dihydro-benzo[1,4]dioxine-6-sulfonyl)-piperidin-4-yl]-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one7408-Methyl-1-[1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7418-Methyl-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7428-Methoxy-1-[1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-piperidin-4-yl]1,4-dihydro-benzo[d][1,3]oxazin-2-one7438-Methoxy-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-piperidin-4-yl]-1,4-dihdro-benzo[d][1,3]oxazin-2-one7441-[1-(Benzo[d]isoxazol-3-ylmethanesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7451-[1-(2,2,4,6,7-Pentamethyl-2,3-dihydro-benzofuran-5-sulfonyl)-piperidin-4-yl]-1,4-dihdro-benzo[d][1,3]oxazin-2-one7466-Methyl-5-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-1H-pyrimidine-2,4-dione7471-[1-(3-Methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7481-[1-(2,2,5,7,8-Pentamethyl-chroman-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7491,4-Dimethyl-6-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-1,4-dihydro-quinoxaline-2,3-dione7501-[1-(1H-Imidazole-4-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7511-[1-(2-Oxo-1,2,3,4-tetrahydro-quinoline-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7527-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione7538-Methyl-1-[1-(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7546-Chloro-1-[1-(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7555-Chloro-1-[1-(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7568-Methoxy-1-[1-(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7571-[1-(Pyridine-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7581-[1-(6,7-Dihydroxy-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one759Acetic acid 3-acetoxy-5-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidine-1-sulfonyl]-naphthalen-2-yl ester7601-[1-(1H-Benzoimidazole-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7611-[1-(1H-Benzoimidazole-2-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one7621-[1-(1H-Benzoimidazole-2-sulfonyl)-piperidin-4-yl]-5-chloro-1,4-dihydro-benzo[d][1,3]oxazin-2-one7631-[1-(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one7641-[1-(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one7651-[1-(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4-yl]-6,7-dihydro-1,4-dihydro-benzo[d][1,3]oxazin-2-one7665-Chloro-1-[1-(2,5-dimethoxy-benzenesulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7671-[1-(5-Dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-8-methoxy-1,4-dihydro-benzo[d][1,3]oxazin-2-one7685-Chloro-1-[1-(5-dimethylamino-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7696-Chloro-1-[1-(5-chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7701-[1-(5-Chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one7711-[1-(5-Chloro-naphthalene-1-sulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one7726-Chloro-1-[1-(5-chloro-naphthalene-2-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7731-[1-(5-Chloro-naphthalene-2-sulfonyl)-piperidin-4-yl]-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one7741-[1-(5-Chloro-naphthalene-2-sulfonyl)-piperidin-4-yl]-6-fluoro-1,4-dihydro-benzo[d][1,3]oxazin-2-one7756-Methyl-1-[1-(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7766-Fluoro-1-[1-(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7776,7-Difluoro-1-[1-(3-methyl-quinoline-8-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7786-Chloro-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7796-Methyl-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7806-Fluoro-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7816,7-Difluoro-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7825-Chloro-1-[1-(3-methyl-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7836-Chloro-1-[1-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7846-Methyl-1-[1-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7856-Fluoro-1-[1-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7868-Methoxy-1-[1-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one7875-Chloro-1-[1-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-piperidin-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one.

The benzoxazinone-derived sulphonamide compounds of general formula (Ib), wherein R^1b-R^9band W^bhave the meaning given above, may be prepared preferably by way of reaction of at least one piperidine compound of general formula (IIb) and/or a corresponding salt thereof, preferably a hydrochloride salt,
embedded image

wherein R^1bto R^9bhave the meaning given above, with at least one compound of general formula (IIIb),

wherein W^bhas the meaning given above, in a suitable reaction medium, optionally in the presence of at least one base and/or at least one auxiliary agent, to yield a compound of general formula (Ib).

Suitable reaction media include e.g. organic solvents, such as ethers, preferably diethyl ether, dioxane, tetrahydrofurane, dimethyl glycol ether, or alcohols, e.g. methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, or hydrocarbons, preferably benzene, toluene, xylene, hexane, cyclohexane, petroleum ether, or halogenated hydrocarbons, e.g. dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichloroethylene, chlorobenzene or/and other solvents, preferably ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, diemthylformamide, hexamethylphosphoramide, acetonitril, acetone or nitromethane, are included. Mixtures based one or more of the afore mentioned solvents may also be used.

During the synthetic reactions described above or while preparing the compounds of general formulas (IIb) or (IIIb) the protection of sensitive groups or of reagents may be necessary and/or desirable. This can be performed by using conventional protective groups like those described in the literature [Protective groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & sons, 1991. Said literature description is hereby incorporated by reference as part of the disclosure. The protective groups may also be eliminated as convenient by means well-known to those skilled in the art.

The compounds of general formulas (IIb) and (IIIb) are either commercially available or can be produced according to methods known to those skilled in the art. The reaction of compounds of general formulas (IIb) and (IIIb) to yield benzoxazinone-derived sulphonamide compounds of general formula (Ib) may also be facilitated by conventional methods known to those skilled in the art.

The substituted benzoxazinone compounds of general formula (IIb), wherein R^5brepresents H, are preferably synthesized from substituted anthranilic acid or a corresponding ester via the corresponding substituted benzylalcohol (see scheme 1, method A). By reductive amination with 1-Boc-(tert.-Butylcarbonyloxy)-4-piperidone the Boc-piperidin-moiety is introduced into the substituted benzylalcohol. The benzoxazinone-ring is formed by cyclisation with triphosgene. The elimination of the Boc-protecting group is carried out by treatment in acidic media according to the method described in Williams et al., J. Med. Chem. 1995 38, 4634 and later by Bell et al., J. Med. Chem., 1998, 41, 2146 which are hereby incorporated by reference and form part of the disclosure. By reacting such a substituted benzoxazinone compound of general formula (IIb) with a substituted sulfuryl chloride of general formula (IIIb) compounds of general formula (Ib) are obtained.

By reduction of the corresponding ketones via conventional methods known to those skilled in the art, e.g. by reduction with sodium borohydride (see scheme 1, method B, R^5b=Z) benzoxazinone derived sulphonamide compounds of general formula (Ib), wherein R^5brepresents an unbranched or branched, saturated or unsaturated, optionally at least mono-substituted aliphatic radical or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing cycloaliphatic radical (denoted by Z in method B) can be obtained.

The respective reagents used in said process for the preparation of benzoxazinone derived sulphonamide compounds of general formula (Ib) are either commercially available or can be obtained by methods well known to those skilled in the art.
embedded image

The salts of benzoxazinone-derived sulphonamide compounds of general formula (Ib), may be prepared in a way that at least one compound of general formula (Ib) having at least one basic group is reacted with at least one inorganic and/or organic acid, preferably in the presence of a suitable reaction medium. Suitable reaction media are, for example, the ones given above. Suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, suitable organic acids are e.g. citric acid, maleic acid, fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonic acid, methanesulfonic acid or camphersulfonic acid.

The salts of benzoxazinone-derived sulphonamide compounds of general formula (Ib), may be prepared in a way that at least one compound of general formula (Ib) having at least one acidic group is reacted with one or more suitable bases, preferably in the presence of a suitable reaction medium. Suitable bases are e.g. hydroxides, carbonates or alkoxides, which include suitable cations, derived e.g. from alkaline metals, alkaline earth metals or organic cations, e.g. [NH_nR_4-n]⁺, wherein n is 0, 1, 2, 3 or 4 and R represents a branched or unbranched C_1-4-alkyl-radical. Suitable reaction media are, for example, the ones given above.

Solvates, preferably hydrates, of the Benzoxazinone-derived sulphonamide compounds of general formula (Ib) or of the salts thereof may also be obtained by standard procedures known to those skilled in the art.

If the Benzoxazinone-derived compounds of general formula (Ib) are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or crystallization with chiral reagents.

The purification and isolation of the Benzoxazinone-derived sulphonamide compounds of general formula (Ib) or a corresponding stereoisomer, or salt, or solvate respectively, if required, may be carried out by conventional methods known to those skilled in the art, e.g. chromatographic methods or recrystallization.

If one or more of the residues R^1c, R^3c, R^4cand R^5crepresents an alkyl radical, which is substituted with one or more substituents, unless defined otherwise, each of the substituents may preferably be selected from the group consisting of hydroxy, fluorine, chlorine, bromine and trifluoromethyl.

If R^1crepresents a phenyl radical or a benzyl radical, which is substituted with one or more substituents, unless defined otherwise, each of the substituents may preferably be selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C₁-C₄-alkyl, branched or unbranched C₁-C₄-alkoxy, branched or unbranched C₁-C₄-perfluoroalkyl and branched or unbranched C₁-C₄-perfluoroalkoxy.

If R^2crepresents a saturated or unsaturated, optionally at least one heteroatom as ring member containing cycloaliphatic radical, which is substituted with one or more substituents and/or if it comprises a saturated or unsaturated, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem, which is substituted with one or more substituents, unless defined otherwise, each of the substituents may preferably be selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C₁-C₄-alkyl, branched or unbranched C₁-C₄-alkoxy, branched or unbranched C₁-C₄-perfluoroalkyl, branched or unbranched C₁-C₄-perfluoroalkoxy and benzyl, preferably from the group consisting of branched or unbranched C₁-C₄-alkyl and benzyl. The heteroatoms of the cycloaliphatic radical and/or of the mono- or bicyclic cycloaliphatic ringsystem may, independent from one another, preferably be selected from the group consisting of nitrogen, sulphur and oxygen, more preferably the heteroatom is nitrogen.

If R^4cand R^5ctogether with the bridging nitrogen atom form a saturated or unsaturated, optionally at least one further heteroatom as ring member containing heterocyclic ring, which is substituted with one or more substituents and/or which is condensed with a saturated or unsaturated, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem, which is substituted with one or more substituents, unless otherwise defined, each of the substituents, may preferably be selected from the group consisting of hydroxy, fluorine, chlorine, bromine, branched or unbranched C₁-C₄-alkyl, branched or unbranched C₁-C₄-alkoxy, branched or unbranched C₁-C₄-perfluoroalkyl, branched or unbranched C₁-C₄-perfluoroalkoxy and benzyl, preferably from the group consisting of branched or unbranched C₁-C₄-alkyl and benzyl. If the hetereocyclic ring contains one or more further heteroatoms and/or one or both of the mono- or bicyclic rings contain one or more heteroatoms, these heteroatoms may, independent from one another, preferably be selected from the group consisting of nitrogen, sulphur and oxygen, more preferably the heteroatom is nitrogen.

If A^crepresents a mono- or polycyclic aromatic ringsystem, which is substituted with one or more substituents, and which may be bonded via an optionally at least mono-substituted alkylene-, alkenylene- or alkynylene group and/or may contain at least one heteroatom as a ring member, unless otherwise defined, each of the substituents, may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C₁-C₄-alkyl, branched or unbranched C₁-C₄-alkoxy, branched or unbranched C₁-C₄-perfluoroalkyl, branched or unbranched C₁-C₄-perfluoroalkoxy, an optionally at least mono-substituted phenyl radical and 5- or 6 membered heteroaryl, preferably from the group consisting of halogen, branched or unbranched C₁-C₄-alkyl, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl, more preferably from the group consisting of fluorine, chlorine, branched or unbranched C₁-C₄-alkyl, an optionally at least mono-substituted phenyl radical, and 5- or 6-membered heteroaryl. If one or more of the rings of the mono- or polycyclic aromatic ringsystem contains one or more heteroatoms, these heteroatoms—like the heteroatoms of the afore mentioned 5- or 6 membered heteroaryl radical—may preferably be selected from the group consisting of oxygen, sulphur and nitrogen. If the afore mentioned phenyl radical is itself substituted with one or more substituents, each of the substituents may preferably be selected from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₄-alkyl, linear or branched C₁-C₄-alkoxy, linear or branched C₁-C₄-alkylthio, a trifluoromethyl moiety, a cyano moiety and a NR^8cR^9c-moiety, wherein R^8cand R^9c, identical or different, represent hydrogen or linear or branched C₁-C₄-alkyl.

If the afore mentioned alkylene-, alkenylene- or alkynylene group is substituted with one or more substituents, each of the substituents may preferably be selected from the group consisting of hydroxy, halogen, branched or unbranched C₁-C₄-alkyl, branched or unbranched C₁-C₄-alkoxy, branched or unbranched C₁-C₄-perfluoroalkyl, branched or unbranched C₁-C₄-perfluoroalkoxy or an optionally at least mono-substituted phenyl radical. If said phenyl radical is itself substituted by one or more substituents, each of the substituents may preferably be selected from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₄-alkyl, linear or branched C₁-C₄-alkoxy, linear or branched C₁-C₄-alkylthio, a trifluoromethyl moiety, a cyano moiety and a NR^8cR^9c-moiety, wherein R^8cand R^9c, identical or different, represent hydrogen or linear or branched C₁-C₄-alkyl.

Preferably used are sulphonamide derivatives of general formula (Ic), wherein R^1crepresents hydrogen, an optionally at least mono-substituted, linear or branched C_1-4-alkyl radical, an optionally at least mono-substituted phenyl radical or an optionally at least mono-substituted benzyl radical, preferably hydrogen, a linear or branched C_1-4-alkyl radical or a benzyl radical, more preferably hydrogen, and R^2cto R^5c, A^cand nc are as defined above.

Preference is also given to the use of sulphonamide derivatives of general formula (Ic), wherein R^2crepresents a —NR^4cR^5cmoiety or a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing 5- or 6-membered cycloaliphatic radical, which may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing mono- or bicyclic cycloaliphatic ringsystem, wherein the ring(s) is/are 5- or 6-membered, preferably a —NR^4cR^5cmoiety or a moiety selected from the group consisting of
embedded image

wherein, if present, the dotted line represents an optional chemical bond and R⁶represents hydrogen, a linear or branched C₁-C₄-alkyl radical or a benzyl radical, preferably hydrogen or a C₁-C₂alkyl radical, and R^1c, R^3c-R^5c, A^cand nc are as defined above.

Also preferred is the use of sulphonamide derivatives of general formula (Ic), wherein R^3crepresents hydrogen or an optionally at least mono-substituted, linear or branched C₁-C₄-alkyl radical, preferably hydrogen or a linear or branched C₁-C₄-alkyl radical, more preferably hydrogen or a C₁-C₂alkyl radical, and R^1c, R^2cR^4c, R^5c, A^cand nc are as defined above.

Furthermore, preference is also given to the use of sulphonamide derivatives of general formula (Ic), wherein R^4cand R^5c, identical or different, represent hydrogen or an optionally at least mono-substituted, linear or branched C₁-C₄-alkyl radical, or

R^4cand R^5ctogether with the bridging nitrogen atom form an optionally at least mono-substituted, saturated or unsaturated, 5- or 6-membered heterocyclic ring, which may contain at least one further heteroatom as a ring member and/or may be condensed with a saturated or unsaturated, optionally at least mono-substituted, optionally at least one heteroatom as ring member containing mono- or bicyclic aliphatic ringsystem, wherein the ring(s) is/are 5-, 6- or 7-membered, and R^1c, R^2c, R^3c, A^cand nc are as defined above.

Particularly preferred is the use of sulphonamide derivatives of general formula (Ic), wherein R^4cand R^5c, identical or different, represent hydrogen or a linear or branched C₁-C₄-alkyl radical, preferably a linear or branched C₁-C₄-alkyl radical, or

R^4cand R^5ctogether with the bridging nitrogen atom form a moiety selected from the group consisting of
embedded image

wherein R⁷represents hydrogen, a linear or branched C₁-C₄-alkyl radical or a benzyl radical, preferably hydrogen or a C₁-C₂alkyl radical, and R^1c-R^3c, A^cand nc are as defined above.

Moreover, the use of sulphonamide derivatives of general formula (Ic) is preferred, wherein A^crepresents an optionally at least mono-substituted mono- or bicyclic aromatic ringsystem, wherein the ring(s) is/are 5- or 6-membered, which may be bonded via a an optionally at least mono-substituted C₁-C₄-alkylene group, an optionally at least mono-substituted C₂-C₄-alkenylene or an optionally at least mono-substituted C₂-C₄-alkinylene group and/or may contain at least one heteroatom as a ring member, preferably an optionally at least mono-substituted mono- or bicyclic aromatic ringsystem, wherein the ring(s) is/are 5- or 6-membered and wherein one or both of the rings contain(s) at least one heteroatom, or a moiety selected from the group consisting of
embedded image

wherein X, Y, Z are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C₁-C₄-alkyl, linear or branched C₁-C₄-alkoxy, linear or branched C₁-C₄-alkylthio, a trifluoromethyl moiety, a cyano moiety and a NR⁸R⁹-moiety, wherein R⁸and R⁹, identical or different, represent hydrogen or linear or branched C₁-C₄-alkyl,

W represents a single chemical bond between the two rings, a CH₂-group, O, S or a NR¹⁰-moiety, wherein R¹⁰is hydrogen or linear or branched C₁-C₄-alkyl and

m is 0, 1, 2, 3 or 4.

and R^1c-R^5cand nc are as defined above.

Most preferred is the use of one or more sulphonamide derivatives selected from the group consisting of:

[1] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide,
[2] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide,
[3] Hydrochloride N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide,
[4] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-3,5-dichlorobenzenesulphonamide,
[5] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide,
[6] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-5-chlorothiophene-2-sulphonamide,
[7] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide,
[8] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide,
[9] N-[3-(2-dimethylamino-ethyl)-1H-indol-5-yl]-6-chloroimidazo[2,1-b]thiazol-5-sulphonamide,
[10] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide,
[11] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide hydrochloride,
[12] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide,
[13] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide hydrochloride,
[14] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-5-chlorothiophene-2-sulphonamide,
[15] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide,
[16] N-[3-(1-methylpiperidin-4-yl)-1H-indol-5-yl]quinoline-8-sulphonamide,
[17] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide,
[18] N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide,
[19] N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide,
[20] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-(2-pyridil)thiophene-2-sulphonamide,
[21] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-2,1,3-benzothiadiazol-4-sulphonamide,
[22] N-[3-(2-dimethylaminoethylyl H-indol-5-yl]quinoline-8-sulphonamide,
[23] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloronaphthalene-2-sulphonamide,
[24] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-4-phenoxybenzenesulphonamide,
[25] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-4-phenylbenzenesulphonamide,
[26] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-N-ethyl-naphthalene-2-sulphonamide,
[27] N-{3-[2-(morpholin-4-yl)ethyl]-1H-indol-5-yl}-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide,
[28] N-{3-[2-(morpholin-4-yl)ethyl]-1H-indol-5-yl}naphthalene-1-sulphonamide,
[29] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide,
[30] N-[3-dimethylaminomethyl-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide,
[31] N-[3-(2-dipropylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide,
[32] N-[3-(2-dipropylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide,
[33] N-[3-(2-dibutylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide,
[34] N-[3-(2-dibutylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide,
[35] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-5-chloronaphthalene-1-sulphonamide,
[36] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-trans-β-styrenesulphonamide,
[37] N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-trans-β-styrenesulphonamide,
[38] N-[3-(octahydroindolizin-7-yl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide,
[39] N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-6-chloroimidazo[2,1-b]thiazol-5-sulphonamide,
[40] N-{3-[2-(morpholin-4-yl)ethyl]-1H-indol-5-yl}naphthalene-2-sulphonamide,
[41] N-[3-(4-methylpiperazin-1-yl)methyl-1H-indol-5-yl]-α-toluenesulphonamide,
[42] N-[3-(3-diethylaminopropyl)-1H-indol-5-yl]naphthalene-2-sulphonamide,
[43] N-[3-(3-diethylaminopropyl)-1H-indol-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide,
[44] N-{3-[2-(pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}-5-chloro-3-methylbenzo[b]thiophene-2-sulphonamide,
[45] N-{3-[2-(pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}naphthalene-1-sulphonamide,
[46] N-{3-[2-(pyrrolidin-1-yl)ethyl]-1H-indol-5-yl}naphthalene-2-sulphonamide,
[47] N-[3-(2-dipropylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide,
[48] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloronaphthalene-1-sulphonamide,
[49] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide,
[50] N-{3-[2-(morpholin-4-yl)ethyl]-1H-indol-5-yl}quinoline-8-sulphonamide,
[51] N-{3-[2-(morpholin-4-yl)ethyl]-1H-indol-5-yl}-4-phenylbenzenesulphonamide,
[52] N-[3-(4-methylpiperazin-1-yl)ethyl-1H-indol-5-yl]naphthalene-2-sulphonamide and
[53] N-[3-(4-methylpiperazin-1-yl)ethyl-1H-indol-5-yl]-5-chloronaphthalene-1-sulphonamide.

The sulphonamide derivatives of general formula (Ic), wherein R^1c, R^2c, R^3c, nc and A^chave the above defined meaning, may preferably be prepared according to the following methods, wherein R¹, R², R³, n and A are R^1c, R^2c, R^3c, nc and A^c.

Method A:

At least one compound of general formula (IIc),
embedded image

wherein A has the meaning as defined above in the general formula (Ic) and X is a suitable leaving group, preferably a halogen atom, more preferably chlorine; is reacted with at least one substituted 5-aminoindol of general formula (IIIc)

wherein R₁, R₂, R₃and n have the meaning as defined above, or a suitably protected derivative thereof, and, if present, the protective groups are removed, in order to obtain the corresponding sulphonamide derivative of general formula (Ic), which may be purified and/or may be isolated by conventional methods known to those skilled in the art.

The reaction between the compounds of general formulas (IIc) and (IIIc) is usually carried out in the presence of an organic reaction medium, such as an dialkyl ether, particularly diethyl ether, or a cyclic ether, particularly tetrahydrofurane or dioxane, a halogenated organic hydrocarbon, particularly methylene chloride or chloroform, an alcohol, particularly methanol or ethanol, an aprotic dipolar solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable reaction medium. Mixtures of at least two of the above mentioned classes of compounds or of at least two compounds of one class may, of course, also be used.

The reaction is preferably carried out in the presence of a suitable base, e.g. an inorganic base such as hydroxides and/or carbonates of alkali metals, or an organic base, particularly triethylamine or pyridine.

The most suitable reaction temperatures range from 0° C. to ambient temperature, i.e. approximately 25° C., and the reaction time is preferably from 5 minutes to 24 hours.

The resulting sulphonamide derivative of general formula (Ic) may be purified and/or isolated according to conventional methods known to those skilled in the art.

Preferably the sulphonamide derivatives of general formula (Ic) can be isolated by evaporating the reaction medium, adding water and eventually adjusting the pH so that it is obtained as a solid that can be isolated by filtration; or it can be extracted by a solvent immiscible with water, such as chloroform, and purified by chromatography or recrystallisation from a suitable solvent.

The compounds of general formula (IIc) are commercially available or can be prepared according to standard methods known to those skilled in the art, e.g. by methods analogous to those described in the literature [E. E. Gilbert, Synthesis, 1969, 1, 3]. The compounds of general formula (IIIc) may also be prepared according to standard methods known to those skilled in the art, e.g. by methods analogous to those described in the literature [J. E. Macor, R. Post and K. Ryan, Synt Comm., 1993, 23, 1, 65-72.; J. Guillaume, C. Dumont, J. Laurent and N. Nédélec, Eur. J. Med. Chem., 1987, 22, 33-43; M. L. Saccarello, R. Stradi, Synthesis, 1979, 727]. The respective literature descriptions are incorporated by reference and form part of the disclosure.

Method B

The sulphonamide derivatives of general formula (Ic), wherein R¹, R², n and A are as defined above and R³represents an optionally at least mono-substituted, linear or branched C₁-C₄alkyl radical, may also be prepared by alkylation of a corresponding sulphonamide derivative of general formula (Ic), wherein R¹, R², n and A are as defined above and R³represents a hydrogen atom, with an alkyl halogenide or a dialkyl sulphate.

The alkylation reaction is preferably carried out in the presence of a suitable base, such as hydroxides and/or carbonates of alkali metals, metal hydrides, alkoxides such as sodium methoxide or potassium tert-butoxide, organometallic compounds such as butyl lithium or tert.-butyl lithium, in the presence of an organic reaction medium, such as dialkyl ether, particularly diethyl ether, or a cyclic ether, particularly tetrahydrofurane or dioxane, a hydrocarbon, particularly toluene, an alcohol, particularly methanol or ethanol, an aprotic dipolar solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable reaction medium. Mixtures of at least two of the above mentioned classes of compounds and/or of at least two compounds of one class may, of course, also be used.

The most suitable reaction temperatures range from 0° C. to the boiling point of the reaction medium, and reaction times preferably range from 1 to 24 hours.

The resulting sulphonamide derivative of general formula (Ic) can preferably be isolated by filtration, concentrating the filtrate at reduced pressure, adding water and eventually adjusting the pH so that it is obtained as a solid that can be isolated by filtration, or it can be extracted with a solvent immiscible in water such as chloroform and purified by chromatography or recrystallisation from a suitable solvent.

Method C

By condensation of a compound of general formula (Ic), wherein R₁, R₃, and A are as defined above, n is 0 and R₂represents a hydrogen atom, with a suitably substituted 4-piperidone the corresponding compound of general formula (Ic) is obtained, wherein R₁, R₃and A are as defined above, n is 0 and R₂represents a suitably substituted 1,2,3,6-tetrahydropyridine-4-yl radical.

The reaction can take place in both an acid and a basic reaction medium, preferably in a suitable solvent, preferably at temperatures ranging from 25 to 150° C.

Suitable basic conditions may be provided by the use of inorganic bases such as sodium or potassium hydroxide, or organic bases such as pyrrolidine or triethylamine in solvents such as methanol or ethanol. Preferably, solutions of sodium methoxide in methanol under reflux are used.

Reaction times range from 1 to 48 hours.

Suitable acidic conditions may be provided by the use of hydrochloric acid in ethanol or trifluoroacetic acid in acetic acid at temperatures ranging preferably from 50 to 100° C. and reaction times ranging from 1 to 48 hours.

The resulting sulphonamide derivative of general formula (Ic) can be isolated by dilution in water, eventually adjusting the pH, to obtain a solid that can be isolated by filtration; or it can be extracted with a solvent immiscible in water such as chloroform and purified by chromatography or by recrystallisation from a suitable solvent.

The compounds of general formula (Ic) wherein R₁, R₃and A are as defined above, n is 0 and R₂represents a hydrogen atom, can be prepared according to the method A from a corresponding 5-aminoindol.

Method D

The compound of general formula (Ic) wherein R₁, R₃and A are as defined above, n is 0 and R₂represents a suitably substituted 4-piperidinyl radical, can be prepared by reducing a compound of general formula (Ic) wherein R₁, R₃and A are as defined above, n is 0 and R₂represents a suitably substituted 1,2,3,6-tetrahydropyridin-4-yl radical prepared according to the method C.

Hydrogenation preferably takes place with the aid of a metallic catalyst such as palladium, platinum or rhodium on a suitable support such as carbon, aluminum oxide or barium sulphate, preferably palladium on carbon, with an initial hydrogen pressure of between 1 and 10 atmospheres, preferably between 2 and 5 atmospheres, in a solvent such as methanol or ethanol. The reaction time ranges from 1 hour to 3 days.

The resulting sulphonamide can be isolated by filtering the catalyst and concentrating the filtrate at reduced pressure. The product recovered can be used as is or it can be purified by chromatography or by recrystallisation from a suitable solvent.

Method E

The salts, preferably the pharmacologically acceptable salts of compounds with the general formula (Ic) can be prepared by conventional methods known to those skilled in the art, preferably by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulphuric, nitric acids or with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p-toluensulphonic acid, methansulphonic acid, etc., in a suitable solvent such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone and obtained with the usual techniques of precipitation or crystallisation of the corresponding salts.

Preferred physiologically acceptable salts of the sulphonamide derivatives of general formula (Ic) are the additions salts of mineral acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, and of organic acids, such as citric acid, maleic acid, tartaric acid or derivatives thereof, p-toluenesulphonic acid, methansulphonic acid, camphorsulphonic acid, etc.

The solvates, preferably the physiologically acceptable solvates, particularly hydrates, of the sulphonamide derivatives of general formula (Ic) or of the corresponding physiologically acceptable salts may be prepared by conventional methods known to those skilled in the art.

During one of the synthesis sequences described above, or in the preparation of suitable reactands used it may be necessary and/or desirable to protect sensitive or reactive groups in some of the molecules employed. This can be performed by means of conventional protective groups such as those described in the literature [Protective groups in Organic Chemistry, ed J. F. W. McOmie, Plenum Press, 1973; T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & sons, 1991]. The protective groups can be eliminated in a suitable latter stage by methods known to those skilled in the art. The respective literature descriptions are hereby incorporated by reference and form part of the disclosure.

If the sulphonamide derivatives of general formula (Ic) are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or crystallization with chiral reagents.

If one or more of the R^2d-R^9dmoieties are an alkyl radical which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine and trifluoromethyl.

If R^1dis a saturated or unsaturated cycloaliphatic radical, optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents and/or if it comprises a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C₁-C₆alkyl and benzyl. The heteroatoms of the cycloaliphatic radical and/or of the mono- or bi-cyclic cycloaliphatic ring can, independently from one another, be chosen preferably from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as an heteroatom.

If R^8dand R^9dtogether with the nitrogen atom bridge form a saturated or unsaturated heterocyclic ring, which can contain at least one additional heteroatom as a ring member, which is substituted by one or more substituents and/or condensed with a saturated or unsaturated mono- or bi-cyclic cycloaliphatic ring system, which can contain at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C₁-C₆alkyl and benzyl. If the heterocyclic ring contains one or more additional heteroatoms, and/or if one or both mono- or bi-cyclic rings contain one or more heteroatoms, these heteroatoms can, independently from one another, be preferably chosen from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as heteroatom.

If A^dis a mono or poly-cyclic aromatic ring system, which is substituted by one or more substituents, which can be bonded by means of an alkylene, alkenylene or alkynylene group, which is optionally at least monosubstituted, and/or can contain at least one heteroatom as a ring member, unless otherwise defined, each one of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy, a phenyl radical, optionally at least monosubstituted, and heteroaryl of 5 or 6 members, more preferably from the group consisting of halogen, linear or branched C₁-C₆alkyl, phenyl optionally at least monosubstituted and heteroaryl of 5 or 6 members, much more preferably from the group consisting of fluorine, chlorine, linear or branched C₁-C₆alkyl, phenyl radical, optionally at least monosubstituted and heteroaryl of 5 or 6 members. If one or more of the rings of a mono or poly-cyclic aromatic ring system contains one or more heteroatoms, these heteroatoms—like the heteroatoms of a previously mentioned heteroaryl radical of 5 or 6 members—can be preferably chosen from the group consisting of nitrogen, sulfur and oxygen. If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and an NR^12dR^13dradical, wherein R^12dand R^13d, identical or different, are hydrogen or linear or branched C₁-C₆alkyl.

The substituents for A^dmay preferably be selected from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, —O-phenyl, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl, more preferably from the group consisting of halogen, linear or branched C₁-C₆alkyl, —O-phenyl, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl, even more preferably from the group consisting of fluorine, chlorine, —O-phenyl, linear or branched C₁-C₆alkyl, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl. If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of these substituents may preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and a —NR^12dR^13dradical, wherein R^12dand R^13d, identical or different, represent hydrogen or a linear or branched C₁-C₆alkyl.

If the previously mentioned alkylene, alkenylene or alkynylene group is substituted by one or more substituents, each of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy or a phenyl radical, optionally at least monosubstituted. If said phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and an NR^12dR^13dradical, wherein R^12dand R^13d, identical or different, are hydrogen or linear or branched C₁-C₆alkyl.

Sulfonamide derivatives of general formula (Id) are preferred, wherein R^1dis an —NR^8dR^9dradical or a saturated or unsaturated, optionally at least monosubstituted cycloaliphatic radical of 5 or 6 members, which can optionally contain at least one heteroatom as a ring member, and which can be condensed with a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5 or 6 members, preferably an —NR^8dR^9dradical or a radical chosen from the group consisting of
embedded image

where, if present, the dotted line is an optional chemical bond, and R¹⁰is hydrogen, a linear or branched C₁-C₆alkyl radical or a benzyl radical, preferably hydrogen or a C₁-C₂alkyl radical, and R^2d-R^9d, A^dand nd are defined as above.

Sulfonamide derivatives of general formula (Id) are also preferred, wherein R^2d, R^3d, R^5d, R^6dand R^7dare hydrogen, a linear or branched C₁-C₆alkyl radical, a linear or branched C₂-C₆alkenyl radical, or a linear or branched C₂-C₆alkynyl radical, preferably hydrogen and R^1d, R^4d, R^8d, R^9d, A^dand nd are defined as above.

The use of sulfonamide derivatives of general formula (Id) is also preferred, wherein R^4d, is hydrogen, a linear or branched C₁-C₆alkyl radical, optionally at least monosubstituted, preferably hydrogen or a linear or branched C₁-C₆alkyl radical, more preferably hydrogen or C₁-C₂alkyl radical and R^1d-R^3d, R^5d-R^9d, A^dand nd are defined as above.

Furthermore, sulfonamide derivatives of general formula (Id) are also preferred, wherein R^8dand R^9d, identical or different, are hydrogen or a linear or branched optionally at least monosubstituted C₁-C₆alkyl radical, or

R^8dand R^9d, together with the nitrogen atom bridge, form a saturated or unsaturated heterocyclic ring of 5 or 6 members, which is optionally at least mono-substituted, which can contain at least one additional heteroatom as a ring member, and/or which can be condensed with a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5, 6 or 7 members, and R^1d-R^7d, A^dand nd are defined as above.

Particularly preferred is the use of sulfonamide derivatives of general formula (Id), wherein R^8dand R^9d, identical or different, are hydrogen or a linear or branched C₁-C₆alkyl radical, preferably a linear or branched C₁-C₆alkyl radical, or

R^8dand R^9dtogether with the nitrogen atom bridge form a radical chosen from the group consisting of
embedded image

wherein R¹¹is hydrogen, a linear or branched C₁-C₆alkyl radical or a benzyl radical, preferably hydrogen, or a C₁-C₂alkyl radical, and R^1d-R^9d, A^dand nd are defined as above.

Furthermore, sulfonamide derivatives of general formula (Id) are preferred, wherein A^dis a mono or poly-cyclic aromatic ring system, which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members and which can be bonded by means of an optionally at least monosubstituted C₁-C₆alkylene group, an optionally at least monosubstituted C₂-C₆alkenylene group or an optionally at least monosubstituted C₂-C₆alkynylene group, and/or which may can contain at least one heteroatom as a ring member, preferably a mono or poly-cyclic aromatic ring system which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members and in which one or more of the rings contain(s) at least one heteroatom or a radical chosen from the group consisting of
embedded image

in which X, Y and Z are each one independently chosen from a group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and an NR¹²R¹³radical, in which R¹²and R¹³, identical or different, are hydrogen or linear or branched C₁-C₆alkyl,

W is a single chemical bond between the two rings, a CH₂, O, S group or an NR¹⁴radical, wherein R¹⁴is hydrogen or linear or branched C₁-C₆alkyl, and

m is 0, 1, 2, 3 or 4;

and R^1d-R^11dand nd are defined as above.

Furthermore, sulfonamide derivatives of general formula (Id) are preferred, A^drepresents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered, which may be bonded via an optionally at least mono-substituted C₁-C₆alkylene group, an optionally at least mono-substituted C₂-C₆alkenylene group or an optionally at least mono-substituted C₂-C₆alkynylene group and/or wherein the ring(s) may contain at least one heteroatom as a ring member,

preferably A^drepresents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered and wherein one or more of the rings contain at least one heteroatom,

or a radical chosen from the group consisting of
embedded image

wherein X, Y, Z, independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, a trifluoromethyl radical, a cyano radical and a —NR¹²R¹³radical,

wherein R¹²and R¹³, identical or different, each represent hydrogen or linear or branched C₁-C₆alkyl,

W represents a single chemical bond between the two rings, a CH₂, O, S group or a NR¹⁴radical,

wherein R¹⁴is hydrogen or a linear or branched C₁-C₆alkyl,

m is 0, 1, 2, 3 or 4 and

m1 is 1 or 2, preferably 2, and R^1d-R^9dand nd are defined as above.

Also, particularly preferred are compounds of general formula (Id) given above,

wherein

R^1drepresents a —NR^8dR^9dradical,

R^2d, R^3d, R^5d, R^6dand R^7deach represent hydrogen,

R^4drepresents hydrogen,

R^8dand R^9d, identical or different, each represent methyl, ethyl, n-propyl, iso-propyl, more preferably methyl,

and

A^drepresents an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, benzo[b]thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1, 2 or 3 substituents selected from the group consisting of chlorine, methyl, phenyl and —O-phenyl and/or which may be bonded via a C_1-2alkylene group,

and

nd is 2;

optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, its racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a salt thereof, preferably a corresponding, physiologically acceptable salt thereof, or a corresponding solvate thereof.

The most preferred compounds of general formula (Id) may be selected from the group consisting of

[1] N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-naphtalene-2-sulfonamide,
[3] N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-naphtalene-1-sulfonamide,
[4] N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-4-phenylbenzenesulfonamide,
[5] N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-2-(naphtalene-1-yl)-ethanesulfonamide,
[6] N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-4-phenoxybenzenesulfonamide,
[7] N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-3,5-dichlorobenzenesulfonamide and

and their corresponding salts and solvates.

Furthermore, the most preferred compounds of general formula (Id) may be selected from the group consisting of

[1] N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-naphtalene-2-sulfonamide,
[3] N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-naphtalene-1-sulfonamide,
[4] N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-4-phenylbenzenesulfonamide,
[5] N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-2-(naphtalene-1-yl)-ethanesulfonamide,
[6] N-[1-(2-dimethylaminoethyl)-1H-indoleyl]-4-phenoxybenzenesulfonamide,
[7] N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-3,5-dichlorobenzenesulfonamide and
[8] 6-chloro-N-[1-(2-dimethylaminoethyl)-1H-indol-4-yl]-imidazo[2,1-b]thiazole-5-sulfonamide

and their corresponding salts and solvates.

The present invention likewise refers to the salts, preferably the physiologically acceptable salts of the compounds of general formula (Id), particularly the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.

Below, the residues R¹-R⁷, A and n in the general formulas (IId) and (IIId) are R^1d-R^7d, A^dand nd.

The derivatives of general formula (Id), wherein R^1d-R^9d, nd and A^dhave the previously indicated meaning, may be preferably prepared in a way that:

At least one compound of general Formula (IId),
embedded image

wherein A has the previously mentioned meaning in the general formula (Id), and X is an acceptable leaving group, preferably an halogen atom, more preferably chlorine; reacts with at least one substituted 4-aminoindole of general formula (IIId)

wherein R¹-R⁷and nd have the previously indicated meaning, or one of their suitable protected derivatives, and, if necessary, the protective groups are removed in order to obtain the corresponding sulfonamide derivative of formula (Id), which can be purified and/or isolated by means of conventional methods known in the state of the art.

The reaction between the compounds of general Formula (IId) and (IIId) is usually carried out in the presence of an organic reaction medium such as dialkyl ether, particularly diethyl ether or a cyclic ether, particularly tetrahydrofuran or dioxane, an halogenated organic hydrocarbon, particularly methylene chloride or chloroform, an alcohol, particularly methanol or ethanol, a dipolar aprotic solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable reaction medium. Naturally, mixtures of at least two of the classes of the mentioned compounds or at least two compounds of one class can also be used.

The reaction is preferably carried out in the presence of a suitable base, for example, an inorganic base such as alkaline metal hydroxides and carbonates, or in the presence of an organic base, particularly triethylamine or pyridine.

The most suitable reaction temperatures range between 0° C. and room temperature, that is, approximately 25° C., and the reaction time is preferably comprised between 5 minutes and 24 hours.

The resulting sulfonamide derivative of general Formula (Id) can be purified and/or isolated according to conventional methods known in the state of the art.

Preferably, the sulfonamide derivatives of general Formula (Id) can be isolated by evaporating the reaction medium, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.

The compounds of general formula (IId) are commercially available, or they can be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature [E. E. Gilbert, Synthesis, 1969, 1, 3]. The compounds of general formula (IIId) can also be prepared according to standard methods known in the state of the art, for example by methods similar to those described in: [Abou-Gharbia, Magid; Patel, Usha; Tokolics, Joseph; Freed, Meier. European Journal of Medicinal Chemistry (1988), 23(4), 373-7].

The sulfonamide derivatives of general Formula (Id), wherein R^1d-R^3d, R^5d-R^9d, nd and A^dhave the previously indicated meaning and R^4dis an alkyl radical, preferably a linear or branched C₁-C₆alkyl radical, optionally at least monosubstituted, they can also be prepared by alkylation of a sulfonamide derivative of general Formula (Id), wherein R^1d-R^3d, R^5d-R^9d, nd and A^dhave the previously indicated meaning, and R^4dis an hydrogen atom, with an alkyl halogenide or a dialkyl sulfate.

The alkylation reaction is carried out preferably in the presence of a suitable base, such as alkaline metal hydroxides and carbonates, metal hydrides, alkoxides such as sodium metoxide or potassium tert-butoxide, organometallic compounds such as butyllithium or tert-butyllithium, in the presence of an organic reaction medium such as dialkyl ether, particularly diethyl ether, or a cyclic ether, particularly tetrahydrofuran or dioxane, an hydrocarbon, particularly toluene, an alcohol, particularly methanol or ethanol, a dipolar aprotic solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable reaction medium. Naturally, mixtures of at least two of the classes of the mentioned compounds or at least two compounds of one class can also be used.

The most suitable reaction temperatures range between 0° C. and the boiling temperature of the reaction medium, and the reaction times are preferably comprised between 1 and 24 hours.

Preferably, the resulting sulfonamide derivative of general Formula (Id) can be isolated by filtration, concentrating the filtrate under reduced pressure, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.

The pharmaceutically acceptable salts of the compounds of general formula (Id), can be prepared by means of conventional methods known in the state of the art, preferably by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, or with organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc., in a suitable solvent, such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone, being obtained with the usual techniques for the precipitation or crystallization of the corresponding salts.

The preferred physiologically acceptable salts of the sulfonamide derivatives of general formula (Id) are the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and of organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.

The physiologically acceptable solvates, particularly hydrates, of the sulfonamide derivatives of general formula (Id) or of the corresponding, physiologically acceptable salts, can be prepared by methods known in the state of the art.

During some of the synthetic sequences described or in the preparation of the suitable reagents used, it may be necessary and/or desirable to protect sensitive or reactive groups in some of the molecules used. This can be carried out by means of the use of conventional protective groups such as those described in the literature [Protective groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1991]. The protective groups can be removed in the suitable subsequent stage by methods known in the state of the art. The respective literature descriptions are incorporated by reference and form part of the disclosure.

If the sulfonamide derivatives of general formula (Id) are obtained in the form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures can be separated by means of standard processes known in the state of the art, for example chromatographic methods or crystallization with chiral agents.

If one or more of the R^2e-R^9emoieties are an alkyl radical which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine and trifluoromethyl.

If R^1eis a saturated or unsaturated cycloaliphatic radical, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents and/or if it comprises a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C₁-C₆alkyl and benzyl. The heteroatoms of the cycloaliphatic radical and/or of the mono- or bi-cyclic cycloaliphatic ring can, independently from one another, be chosen preferably from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as an heteroatom.

If R^8eand R^9etogether with the nitrogen atom bridge form a saturated or unsaturated heterocyclic ring, which can contain at least one additional heteroatom as a ring member, which is substituted by one or more substituents and/or condensed with a saturated or unsaturated mono- or bi-cyclic cycloaliphatic ring system, which can contain at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy and benzyl, more preferably from the group consisting of linear or branched C₁-C₆alkyl and benzyl. If the heterocyclic ring contains one or more additional heteroatoms, and/or if one or both mono- or bi-cyclic rings contain one or more heteroatoms, these heteroatoms can, independently from one another, be preferably chosen from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as heteroatom.

If A^eis a mono or poly-cyclic aromatic ring system, which is substituted by one or more substituents, and which can be bonded by means of an optionally at least monosubstituted alkylene, alkenylene or alkynylene group, and/or can contain at least one heteroatom as a ring member, unless otherwise defined, each one of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy, a phenyl radical, optionally at least monosubstituted, and heteroaryl of 5 or 6 members, more preferably from the group consisting of halogen, linear or branched C₁-C₆alkyl, phenyl optionally at least monosubstituted and heteroaryl of 5 or 6 members, much more preferably from the group consisting of fluorine, chlorine, linear or branched C₁-C₆alkyl, phenyl radical, optionally at least monosubstituted and heteroaryl of 5 or 6 members. If one or more of the rings of a mono or poly-cyclic aromatic ring system contains one or more heteroatoms, these heteroatoms—like the heteroatoms of a previously mentioned heteroaryl radical of 5 or 6 members—can be preferably chosen from the group consisting of nitrogen, sulfur and oxygen. If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and an NR^12eR^13eradical, wherein R^12eand R^13e, identical or different, are hydrogen or linear or branched C₁-C₆alkyl.

Preferably the substituents for A^emay also be selected from the group consisting of nitro, —O-phenyl, —O—C_1-6alkyl, —C(═O)—C_1-6alkyl, hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl, more preferably from the group consisting of nitro, —O-phenyl, —C(═O)—C_1-6alkyl, linear or branched C₁-C₆alkoxy, halogen, linear or branched C₁-C₆alkyl, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl, even more preferably from the group consisting of nitro, —O-phenyl, —O—CH₃, —C(═O)—CH₃, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, an optionally at least mono-substituted phenyl radical and 5- or 6-membered heteroaryl. If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of these substituents may preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and a —NR^12eR^13eradical, wherein R^12eand R^13e, identical or different, represent hydrogen or a linear or branched C₁-C₆alkyl.

If the previously mentioned alkylene, alkenylene or alkynylene group is substituted by one or more substituents, each of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy or a phenyl radical, optionally at least monosubstituted. If said phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and an NR^12eR^13eradical, wherein R^12eand R^13e, identical or different, are hydrogen or linear or branched C₁-C₆alkyl.

Sulfonamide derivatives of general formula (Ie) are preferred, wherein R^1eis an —NR^8eR^9eradical or a saturated or unsaturated cycloaliphatic radical of 5 or 6 members, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, which can be condensed with a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member and wherein the ring/rings is/are of 5 or 6 members, preferably an —NR^8eR^9eradical or a radical chosen from the group consisting of
embedded image

where, if present, the dotted line is an optional chemical bond, and R¹⁰is hydrogen, a linear or branched C₁-C₆alkyl radical or a benzyl radical, preferably hydrogen or a C₁-C₂alkyl radical, and R^2e-R^9e, A^eand ne are defined as above.

Sulfonamide derivatives of general formula (Ie) are also preferred, wherein R^2e, R^3e, R^4e, R^6eand R^7e, are hydrogen, a linear or branched C₂-C₆alkyl radical, a linear or branched C₁-C₆alkenyl radical, or a linear or branched C₂-C₆alkynyl radical, preferably hydrogen and R^1e, R^5e, R^8e, R^9e, A^eand ne are defined as above.

The use of sulfonamide derivatives of general formula (Ie) is also preferred, wherein R^5e, is hydrogen or a linear or branched C₁-C₆alkyl radical, optionally at least monosubstituted, preferably hydrogen or a linear or branched C₁-C₆alkyl radical, more preferably hydrogen or an C₁-C₂alkyl radical and R^1e-R^4e, R^6e-R^9e, A^eand ne are defined as above.

Furthermore, the use of sulfonamide derivatives of general formula (Ie) is also preferred, wherein R^8eand R^9e, identical or different, are hydrogen or a linear or branched C₁-C₆alkyl radical, optionally at least monosubstituted, or

R^8eand R^9e, together with the nitrogen atom bridge, form a saturated or unsaturated heterocyclic ring of 5 or 6 members, which is optionally at least monosubstituted, which can contain at least one additional heteroatom as a ring member, and/or can be condensed with a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5, 6 or 7 members, and R^1e-R^7e, A^eand ne are defined as above.

Particularly preferred is the use of sulfonamide derivatives of general formula (Ie), wherein R^8eand R^9e, identical or different, are hydrogen or a linear or branched C₁-C₆alkyl radical, preferably a linear or branched C₁-C₆alkyl radical, or

R^8eand R^9etogether with the nitrogen atom bridge form a radical chosen from the group consisting of
embedded image

wherein R¹¹, if it is present, is hydrogen, a linear or branched C₁-C₆alkyl radical or a benzyl radical, preferably hydrogen, or a C₁-C₂alkyl radical, and R^1e-R^9e, A^eand ne are defined as above.

Furthermore, sulfonamide derivatives of general formula (Ie) are preferred, wherein A^eis a mono or poly-cyclic aromatic ring system, which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members, which can be bonded by means of an optionally at least mono-substituted C₁-C₆alkylene group, an optionally at least monosubstituted C₂-C₆alkenylene group, or an optionally at least monosubstituted C₂-C₆alkynylene group, and/or can contain at least one heteroatom as a ring member, preferably a mono or poly-cyclic aromatic ring system which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members and in which one or more of the rings contain(s) at least one heteroatom or a radical chosen from the group consisting of
embedded image

in which X, Y and Z are each one independently chosen from a group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and an NR¹²R¹³radical, in which R¹²and R¹³, identical or different, are hydrogen or linear or branched C₁-C₆alkyl,

W is a single chemical bond between the two rings, a CH₂, O, S group or an NR¹⁴radical, wherein R¹⁴is hydrogen or linear or branched C₁-C₆alkyl, and

m is 0, 1, 2, 3 or 4;

and R^1e-R^11eand ne are defined as above.

Furthermore, sulfonamide derivatives of general formula (Ie) are preferred, wherein A^erepresents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered, which may be bonded via an optionally at least mono-substituted C₁-C₆alkylene group, an optionally at least mono-substituted C₂-C₆alkenylene group or an optionally at least mono-substituted C₂-C₆alkynylene group and/or wherein the ring(s) may contain at least one heteroatom as a ring member,

preferably A^erepresents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered and wherein one or more of the rings contain at least one heteroatom,

or a radical chosen from the group consisting of
embedded image

wherein X, Y, Z, independently from one another, each represent a radical selected from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, acetyl, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, a trifluoromethyl radical, a cyano radical and a —NR¹²R¹³radical,

wherein R¹²and R¹³, identical or different, each represent hydrogen or linear or branched C₁-C₆alkyl,

W represents a single chemical bond between the two rings, a CH₂, O, S group or a NR¹⁴radical,

wherein R¹⁴is hydrogen or a linear or branched C₁-C₆alkyl,

m is 0, 1, 2, 3 or 4 and

m1 is 1 or 2, preferably 2, and R^1e-R^11eand ne are defined as above.

Also preferred are compounds of general formula (Ie),

wherein

R^1erepresents a —NR^8eR^9eradical,

R^2erepresents hydrogen or an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl and iso-propyl, more preferably hydrogen or methyl,

R^3e, R^4e, R^6eand R^7eeach represent hydrogen,

R^5erepresents hydrogen,

R^8eand R^9e, identical or different, each represent methyl, ethyl, n-propyl or iso-propyl, more preferably methyl or ethyl,

R^8eand R^9etogether with the bridging nitrogen form a 5- or 6-membered heterocyclic ring, more preferably form pyrrolidine or piperidine,

A^erepresents an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, quinolinyl, benzo[b]thiophenyl, benzo[1,2,5]thiadiazolyl, thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1, 2 or 3 substituents selected from the group consisting of fluorine, bromine, chlorine, methyl, phenyl, nitro, —C(═O)—CH₃, —O—CH₃and —O-phenyl and/or which may be bonded via a C_1-2alkylene group or a C₂alkenylene group,

and

ne is 2 or 3,

The most preferred compounds of general formula (Ie) may be selected from the group consisting of

[1] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide,
[3] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide,
[4] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chloronaphthalene-1-sulfonamide,
[5] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzenesulfonamide,
[6] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-quinoline-8-sulfonamide,
[7] N-[1-(2-dimethylaminoethylyl H-indole-5-yl]-4-phenoxybenzenesulfonamide,
[8] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-methylbenzenesulfonamide,
[9] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chlorothiophene-2-sulfonamide,
[10] N-[1-(2-dimethylaminoethylyl H-indole-5-yl]-benzo[1,2,5]thiadiazole-4-sulfonamide,
[11] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[12] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3,5-dichlorobenzenesulfonamide,
[13] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3-bromobenzenesulfonamide,
[14] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3-nitrobenzenesulfonamide,
[15] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-1-phenylmethanesulfonamide,
[16] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide,
[17] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide,
[18] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[19] trans-N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-2-phenylethenesulfonamide,
[20] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4,5-dichlorothiophene-2-sulfonamide,
[21] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-acetylbenzenesulfonamide,
[22] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-bromobenzenesulfonamide,
[23] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]4-methoxybenzenesulfonamide,
[24] N-[3-(2-diethylaminoethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[25] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-nitrobenzenesulfonamide,
[26] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-fluorobenzenesulfonamide,
[27] N-[1-(2-diethylaminoethyl)-1H-indole-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[28] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,

The most preferred compounds of general formula (Ie) may also be selected from the group consisting of

[1] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide,
[3] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide,
[4] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chloronaphthalene-1-sulfonamide,
[5] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzenesulfonamide,
[6] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-quinoline-8-sulfonamide,
[7] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-phenoxybenzenesulfonamide,
[8] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-methylbenzenesulfonamide,
[9] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-5-chlorothiophene-2-sulfonamide,
[10] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzo[1,2,5]thiadiazole-4-sulfonamide,
[11] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[12] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3,5-dichlorobenzenesulfonamide,
[13] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3-bromobenzenesulfonamide,
[14] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-3-nitrobenzenesulfonamide,
[15] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-1-phenylmethanesulfonamide,
[16] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide,
[17] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide,
[18] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[19] trans-N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-2-phenylethenesulfonamide,
[20] N-{1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4,5-dichlorothiophene-2-sulfonamide,
[21] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-acetylbenzenesulfonamide,
[22] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-bromobenzenesulfonamide,
[23] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-methoxybenzenesulfonamide,
[24] N-[3-(2-diethylaminoethyl)-1H-indole-5-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[25] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-nitrobenzenesulfonamide,
[26] N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-4-fluorobenzenesulfonamide,
[27] N-[1-(2-diethylaminoethyl)-1H-indole-5-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[28] N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[29] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-2-sulfonamide,
[30] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-1-sulfonamide,
[31] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-4-phenylbenzenesulfonamide,
[32] 5-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-3-methylbenzo[b]thiophene-2-sulfonamide,
[33] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-2-sulfonamide,
[34] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-1-sulfonamide,
[35] 6-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide,
[36] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenylbenzenesulfonamide,
[37] N-(1-(2-dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-2-(naphth-1-yl)-ethanesulfonamide,
[38] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenoxy-benzenesulfonamide,
[39] 3,5-dichloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-benzenesulfonamide,
[40] N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide,
[41] N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide and
[42] N-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide,
[43] 5-chloro-3-methyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzo[b]thiophene-2-sulfonamide,
[44] N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-2-sulfonamide,
[45] N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide,
[46] 6-chloro-N-(1-(3-piperidin-1-yl)propyl)-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide,
[47] 4-phenyl-N-(1-(3-(piperidin-1-yl)propyl)-H-indol-5-yl)benzenesulfonamide,
[48] 2-(naphth-1-yl)-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)ethanesulfonamide,
[49] 4-phenoxy-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide,
[50] 3,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonylamide,
[51] 4,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)thiophene-2-sulfonamide and
[52] 5-chloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide,

and their corresponding salts and solvates.

The present invention likewise refers to the physiologically acceptable salts of the compounds of general formula (Ie), particularly the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.

Below, the residues R¹-R⁷, A and n in the general formulas (IIe) to (Ve) are R^1e-R^7e, A^eand ne.

The derivatives of general formula (Ie), wherein R^1e-R^9e, ne and A^ehave the previously indicated meaning, may be preferably prepared in a way that:

At least one compound of general Formula (IIe),
embedded image

wherein A has the previously mentioned meaning in the general formula (Ie), and X is an acceptable leaving group, preferably an halogen atom, more preferably chlorine; reacts with at least one substituted 5-aminoindole of general formula (IIIe)

wherein R¹-R⁷and n have the previously indicated meaning, or one of their suitable protected derivatives, and, if necessary, the protective groups are removed in order to obtain the corresponding sulfonamide derivative of formula (Ie), which can be purified and/or isolated by means of conventional methods known in the state of the art.

The reaction between the compounds of general Formula (IIe) and (IIIe) is usually carried out in the presence of an organic reaction medium such as dialkyl ether, particularly diethyl ether or a cyclic ether, particularly tetrahydrofuran or dioxane, an halogenated organic hydrocarbon, particularly methylene chloride or chloroform, an alcohol, particularly methanol or ethanol, a dipolar aprotic solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable reaction medium. Naturally, mixtures of at least two of the classes of the mentioned compounds or at least two compounds of one class can also be used.

The most suitable reaction temperatures range between 0° C. and room temperature, that is, approximately 25° C., and the reaction time is preferably comprised between 5 minutes and 24 hours.

The resulting sulfonamide derivative of general Formula (Ie) can be purified and/or isolated according to conventional methods known in the state of the art.

Preferably, the sulfonamide derivatives of general Formula (Ie) can be isolated by evaporating the reaction medium, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.

The compounds of general formula (IIe) are commercially available, or they can be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature [E. E. Gilbert, Synthesis, 1969, 1, 3]. The compounds of general formula (IIIe) can also be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature: Pigerol, Charles; De Cointet de Fillain, Paul; Eymard, Pierre; Werbenec, Jean Pierre; Broll, Madeleine. (Labaz S. A., Fr.). Ger. Offen. (1977). DE 2727047 19771229. Schwink, Lothar; Stengelin, Siegfried; Gossel, Matthias. Preparation of indol-5-ylureas and relate compounds for the treatment of obesity and type II diabetes. WO 0315769 A1 20030227. One of them consists of nitro group reduction of derivatives of general formula (IVe) by methods known in the art, as for example: BRATTON, L. D.; ROTH, B. D.; TRIVEDI, B. K.; UNANGST, P. C.; J Heterocycl Chem, 2000, 37 (5), 1103-1108. FANGHAENEL, E.; CHTCHEGLOV, D.; J Prakt Chem/Chem-Ztg, 1996, 338 (8), 731-737. KUYPER, L. F.; BACCANARI, D. P.; JONES, M. L.; HUNTER, R. N.; TANSIK, R. L.; JOYNER, S. S.; BOYTOS, C. M.; RUDOLPH, S. K.; KNICK, V.; WILSON, H. R.; CADDELL, J. M.; FRIEDMAN, H. S.; ET AL.; J Med Chem, 1996, 39 (4), 892-903,
embedded image

wherein R¹-R⁷and n have the previously indicated meaning, or one of their suitably protected derivatives, and, if necessary, the protective groups are removed in order to obtain the corresponding amine of general formula (IIIe), which can be purified and/or isolated by means of conventional methods known in the state of the art.

The compounds of general formula (IVe) can also be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature: Journal of Heterocyclic Chemistry, 37(5), 1103-1108; 2000; Schwink, Lothar; Stengelin, Siegfried; Gossel, Matthias. Preparation of indol-5-ylureas and relate compounds for the treatment of obesity and type II diabetes WO 0315769 A1 20030227; Baxter, Andrew; Brough, Stephen; Mcinally, Thomas; Mortimore, Michael; Cladingboel, David. Preparation of N-aryl-1-adamantaneacetamides and analogs as purinergic P2Z receptor antagonists WO 9929660 A1 19990617; Pigerol, Charles; De Cointet de Fillain, Paul; Eymard, Pierre; Werbenec, Jean Pierre; Broil, Madeleine. Indole derivatives. Ger. Offen. (1977), DE 2727047 19771229

One of them consists in the alkylation of nitro derivatives of general formula (Ve) by methods known in the art, as for example: BHAGWAT, S. S.; GUDE, C.; Tetrahedron Lett, 1994, 35 (12), 1847-1850. BRATTON, L. D.; ROTH, B. D.; TRIVEDI, B. K.; UNANGST, P. C.; J Heterocycl Chem, 2000, 37 (5), 1103-1108
embedded image

wherein R²-R⁷and n have the previously mentioned meaning, or one of their suitably protected derivatives, and, if necessary, the protective groups are removed in order to obtain the corresponding amine of general formula (IIIe), which can be purified and/or isolated by means of conventional methods known in the state of the art.

The compounds of general formula (Ve) are commercially available or can also be prepared according to standard methods known in the state of the art, as for example YAMASHKIN, S. A.; YUROVSKAYA, M. A.; Chem Heterocycl Compd (N Y) 1999, 35 (12), 1426-1432. OTTONI, O.; CRUZ, R.; KRAMMER, N. H.; Tetrahedron Lett, 1999, 40 (6), 1117-1120. EZQUERRA, J.; PEDREGAL, C.; LAMAS, C.; BARLUENGA, J.; PEREZ, M.; GARCIA-MARTIN, M. A.; GONZALEZ, J. M.; J Org Chem, 1996, 61 (17), 5804-5812. FADDA, A. A.; Indian J Chem, Sect B: Org Chem Incl Med Chem, 1990, 29 (11), 1017-1019. KATRITZKY, A. R.; RACHWAL, S.; BAYYUK, S.; Org Prep Proced Int, 1991, 23 (3), 357-363. Inada, A.; Nakamura, Y.; Morita, Y.; Chem Lett, 1980,1287.

The respective literature descriptions are incorporated by reference and form part of the disclosure.

The sulfonamide derivatives of general Formula (Ie), wherein R^1e-R^4e, R^6e-R^7e, A^e, ne and A^ehave the previously indicated meaning and R^5eis an alkyl radical, preferably a linear or branched C₁-C₆alkyl radical, optionally at least monosubstituted, they can also be prepared by alkylation of a sulfonamide derivative of general Formula (Ie), wherein R^1e-R^4e, R^6e-R^7e, ne and A^ehave the previously indicated meaning, and R^5eis an hydrogen atom, with an alkyl halogenide or dialkyl sulfate.

The most suitable reaction temperatures range between 0° C. and the boiling temperature of the reaction medium, and the reaction times are preferably comprised between 1 and 24 hours.

Preferably, the resulting sulfonamide derivative of general Formula (Ie) can be isolated by filtration, concentrating the filtrate under reduced pressure, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.

The pharmaceutically acceptable salts of the compounds of general formula (Ie), can be prepared by means of conventional methods known in the state of the art, preferably by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, or with organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc., in a suitable solvent, such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone, being obtained with the usual techniques for the precipitation or crystallization of the corresponding salts.

The preferred physiologically acceptable salts of the sulfonamide derivatives of general formula (Ie) are the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and of organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.

The physiologically acceptable solvates, particularly hydrates, of the sulfonamide derivatives of general formula (Ie) or of the corresponding physiologically acceptable salts, can be prepared by methods known in the state of the art.

If the sulfonamide derivatives of general formula (Ie) are obtained in the form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures can be separated by means of standard processes known in the state of the art, for example chromatographic methods or crystallization with chiral agents.

If one or more of the residues R^2f-R^9frepresents an alkyl radical, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine and trifluoromethyl.

If R^1fis a saturated or unsaturated cycloaliphatic radical, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents and/or if it comprises a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C₁-C₆alkyl and benzyl. The heteroatoms of the cycloaliphatic radical and/or of the mono- or bi-cyclic cycloaliphatic ring can, independently from one another, be chosen preferably from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as an heteroatom.

If R^8fand R^9ftogether with the nitrogen atom bridge form a saturated or unsaturated heterocyclic ring, which can contain at least one additional heteroatom as a ring member, which is substituted by one or more substituents and/or condensed with a saturated or unsaturated mono- or bi-cyclic cycloaliphatic ring system, which can contain at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C₁-C₆alkyl and benzyl. If the heterocyclic ring contains one or more additional heteroatoms, and/or if one or both mono- or bi-cyclic rings contain one or more heteroatoms, these heteroatoms can, independently from one another, be preferably chosen from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as heteroatom.

If A^fis a mono or poly-cyclic aromatic ring system, substituted by one or more substituents, and which can be bonded by means of an optionally at least monosubstituted alkylene, alkenylene or alkynylene, and/or can contain at least one heteroatom as a ring member, unless otherwise defined, each one of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy, a phenyl radical, optionally at least monosubstituted, and heteroaryl of 5 or 6 members, preferably from the group consisting of halogen, linear or branched C₁-C₆alkyl, phenyl optionally at least monosubstituted and heteroaryl of 5 or 6 members, more preferably from the group consisting of fluorine, chlorine, linear or branched C₁-C₆alkyl, phenyl radical, optionally at least monosubstituted and heteroaryl of 5 or 6 members. If one or more of the rings of a mono or poly-cyclic aromatic ring system contains one or more heteroatoms, these heteroatoms—like the heteroatoms of a previously mentioned heteroaryl radical of 5 or 6 members—can be preferably chosen from the group consisting of nitrogen, sulfur and oxygen. If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and an NR^12fR^13fradical, wherein R^12fand R^13f, identical or different, are hydrogen or linear or branched C_1-6alkyl.

Preferably the substituents for A^fmay also be selected from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, —O-phenyl, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy, an optionally at least mono-substituted phenyl and 5- to 6-membered heteroaryl, more preferably from the group consisting of halogen, linear or branched C₁-C₆alkyl, —O-phenyl, optionally at least mono-substituted phenyl and 5- to 6-membered heteroaryl, even more preferably from the group consisting of fluorine, chlorine, —O-phenyl, linear or branched C₁-C₆alkyl, optionally at least mono-substituted phenyl and 5- to 6-membered heteroaryl. If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of these substituents may preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and a —NR^12fR^13fradical, wherein R^12fand R^13f, identical or different, each represent hydrogen or linear or branched C₁-C₆alkyl.

If the previously mentioned alkylene, alkenylene or alkynylene group is substituted by one or more substituents, each of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy or a phenyl radical, optionally at least monosubstituted. If said phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and an NR^12fR^13fradical, wherein R^12fand R^13f, identical or different, are hydrogen or linear or branched C₁-C₆alkyl.

Sulfonamide derivatives of general formula (If) are preferred, wherein R^1fis an —NR^8fR^9fradical or a saturated or unsaturated cycloaliphatic radical of 5 or 6 members, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and which can be condensed with a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5 or 6 members, preferably an —NR^8fR^9fradical or a radical chosen from the group consisting of
embedded image

where, if present, the dotted line is an optional chemical bond, and R¹⁰is hydrogen, a linear or branched C₁-C₆alkyl radical or a benzyl radical, preferably hydrogen or a C₁-C₂alkyl radical, and R^2f-R^9f, A^fand nf are defined as above.

Sulfonamide derivatives of general formula (If) are also preferred, wherein R^2f, R^3f, R^4f, R^5fand R^7fare hydrogen, a linear or branched C₁-C₆alkyl radical, a linear or branched C₂-C₆alkenyl radical, or a linear or branched C₂-C₆alkynyl radical, preferably hydrogen and R^1f, R^6f, R^8f, R^9f, A^fand nf are defined as above.

Sulfonamide derivatives of general formula (If) are also preferred, wherein R^6f, is hydrogen, a linear or branched C₁-C₆alkyl radical, which is optionally at least monosubstituted, preferably hydrogen or a linear or branched C₁-C₆alkyl radical, more preferably hydrogen or an C₁-C₂alkyl radical and R^1f-R^5f, R^7f-R^9f, A^fand nf are defined as above.

Furthermore, sulfonamide derivatives of general formula (If) are also preferred, wherein R^8fand R^9f, identical or different, are hydrogen, a linear or branched C₁-C₆alkyl radical, which is optionally at least monosubstituted, or

R^8fand R^9f, together with the nitrogen atom bridge, form a saturated or unsaturated heterocyclic ring of 5 or 6 members, which is optionally at least monosubstituted, which can contain at least one additional heteroatom as a ring member, and/or can be condensed with a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5, 6 or 7 members, and R^1f-R^7f, A^fand nf are defined as above.

Particularly preferred are sulfonamide derivatives of general formula (If), wherein R^8fand R^9f, identical or different, are hydrogen or a linear or branched C₁-C₆alkyl radical, preferably a linear or branched C₁-C₆alkyl radical, or

R^8fand R^9ftogether with the nitrogen atom bridge form a radical chosen from the group consisting of
embedded image

wherein R¹¹is hydrogen, a linear or branched C₁-C₆alkyl radical or a benzyl radical, preferably hydrogen, or a C₁-C₂alkyl radical, and R^1f-R^9f, A^fand nf are defined as above.

Furthermore, sulfonamide derivatives of general formula (If) are preferred, wherein A^fis a mono or poly-cyclic aromatic ring system, which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members and which can be bonded by means of an optionally at least mono-substituted C₁-C₆alkylen group, an optionally at least monosubstituted C₂-C₆alkenylen group or optionally at least monosubstituted, or a C₂-C₆alkynylen group and/or can contain at least one heteroatom as a ring member, preferably a mono or poly-cyclic aromatic ring system that is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members and in which one or more of the rings contain(s) at least one heteroatom or a radical chosen from the group consisting of
embedded image

in which X, Y and Z are each one independently chosen from a group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and an NR^12fR^13fradical, in which R^12fand R^13f, identical or different, are hydrogen or linear or branched C₁-C₆alkyl,

W is a single chemical bond between the two rings, a CH₂, O, S group or an NR¹⁴radical, wherein R¹⁴is hydrogen or linear or branched C₁-C₆alkyl,

m is 0, 1, 2, 3 or 4;

and R^1f-R^11fand nf are defined as above.

Furthermore, sulfonamide derivatives of general formula (If) are preferred, wherein A^frepresents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered, which may be bonded via an optionally at least mono-substituted C₁-C₆alkylene group, an optionally at least mono-substituted C₂-C₆alkenylene group or an optionally at least mono-substituted C₂-C₆alkynylene group and/or wherein the ring(s) may contain at least one heteroatom as a ring member,

preferably A^frepresents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered and wherein one or more of the rings contain at least one heteroatom,

Also preferred are compounds of general formula (If),

wherein

R^1frepresents a —NR^8fR^9fradical,

R^2f, R^3f, R^4f, R^5fand R^7feach represent hydrogen,

R^6frepresents hydrogen,

R^8fand R^9f, identical or different, each represent methyl, ethyl, n-propyl or n-propyl, more preferably methyl,

R^8fand R^9f, together with the bridging nitrogen atom form a 5- or 6-membered heterocyclic ring, more preferably form a pyrrolidine ring or a piperidine ring

and

Af represents an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, benzo[b]thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1, 2 or 3 substituents selected from the group consisting of chlorine, methyl, phenyl and —O-phenyl and/or which may be bonded via a C_1-2alkylene group,

and nf is 2,

optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a salt thereof, preferably a corresponding, physiologically acceptable salt thereof, or a corresponding solvate thereof.

Those most preferred sulfonamide derivatives of general formula (If) may be selected from the group consisting of

[1] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-naphthalene-2-sulfonamide,
[3] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-naphthalene-1-sulfonamide,
[4] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[5] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-4-phenylbenzenesulfonamide,
[6] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-2-(naphthalene-1-yl)-ethanesulfonamide,
[7] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-4-phenoxybenzenesulfonamide,
[8] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-3,5-dichlorobenzenesulfonamide,

and their corresponding salts and solvates.

Those most preferred sulfonamide derivatives of general formula (If) may also be selected from the group consisting of

[1] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[2] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-naphthalene-2-sulfonamide,
[3] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-naphthalene-1-sulfonamide,
[4] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide,
[5] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-4-phenylbenzenesulfonamide,
[6] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-2-(naphthalene-1-yl)-ethanesulfonamide,
[7] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-4-phenoxybenzenesulfonamide,
[8] N-[1-(2-Dimethylaminoethyl)-1H-indol-6-yl]-3,5-dichlorobenzenesulfonamide,
[9] 5-Chloro-3-methyl-N-[1-[2-(pyrrolidin-1-yl)ethyl-1H-indol-6-yl]-benzo[b]thiophene-2-sulfonamide,
[10] N-(1-[2-(Pyrrolidin-1-yl)ethyl]-1H-indol-6-yl]-napthyl-2-sulfonamide,
[11] N-[1-[2-Pyrrolidin-1-yl]ethyl]-1H-indol-6-yl]-naphthalene-1-sulfonamide,
[12] 6-Chloro-N-[1-[2-(pyrrolidin-1-yl)ethyl]-1H-indol-6-yl]-imidazo[2,1-b]thiazole-5-sulfonamide,
[13] 4-Phenyl-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-6-yl)-benzenesulfonamide
[14] 2-(Naphth-1-yl)-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-6-yl)-ethansulfonamide,
[15] 4-Phenoxy-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-6-yl)-benzenesulfonamide and
[16] 3,5-Dichloro-N-(1-(2-pyrrolidin-1-yl)-1H-indol-6-yl)-benzenesulfonamide,

and their corresponding salts and solvates.

The present invention likewise refers to the physiologically acceptable salts of the compounds of general formula (If), particularly the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.

Below, the residues R¹-R⁷, A and n in the general formulas (IIf) to (Vf) are R^1f-R^7f, A^fand nf.

The derivatives of general formula (If), wherein R^1f-R^9f, nf and A^fhave the previously indicated meaning, may be preferably prepared in a way that:

At least one compound of general Formula (IIf),
embedded image

wherein A has the previously mentioned meaning in the general formula (If), and X is an acceptable leaving group, preferably an halogen atom, more preferably chlorine; reacts with at least one substituted 6-aminoindole of general formula (IIIf)

wherein R¹-R⁷and n have the previously indicated meaning, or one of their suitable protected derivatives, and, if necessary, the protective groups are removed in order to obtain the corresponding sulfonamide derivative of formula (If), which can be purified and/or isolated by means of conventional methods known in the state of the art.

The reaction between the compounds of general Formula (IIf) and (IIIf) is usually carried out in the presence of an organic reaction medium such as dialkyl ether, particularly diethyl ether or a cyclic ether, particularly tetrahydrofuran or dioxane, an halogenated organic hydrocarbon, particularly methylene chloride or chloroform, an alcohol, particularly methanol or ethanol, a dipolar aprotic solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable reaction medium. Naturally, mixtures of at least two of the classes of the mentioned compounds or at least two compounds of one class can also be used.

The most suitable reaction temperatures range between 0° C. and room temperature, that is, approximately 25° C., and the reaction time is preferably comprised between 5 minutes and 24 hours.

The resulting sulfonamide derivative of general Formula (If) can be purified and/or isolated according to conventional methods known in the state of the art.

Preferably, the sulfonamide derivatives of general Formula (If) can be isolated by evaporating the reaction medium, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.

The compounds of general formula (IIf) are commercially available, or they can be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature [E. E. Gilbert, Synthesis, 1969, 1, 3]. The compounds of general formula (IIIf) can also be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature (Ham, Peter; Gaster, Laramie Mary; King, Francis David; Duckworth, David Malcolm. Preparation of N-heteroaryl-4′-oxadiazolylbiphenylcarboxamides as 5HT1D antagonists. WO 9532967 A1 19951207; Basanagoudar, L. D.; Siddappa, S. Cyanoethylation of nitroindoles. Journal of the Indian Chemical Society (1972), 49 (8), 811-13.; Chen, Guoqing; Adams, Jeffrey; Bemis, Jean; Booker, Shon; Cai, Guolin; Croghan, Michael; Dipietro, Lucian; Dominguez, Celia; Elbaum, Daniel; Germain, Julie; Geuns-Meyer, Stephanie; Handley, Michael; Huang, Qi; Kim, Joseph L.; Kim, Tae-seong; Kiselyov, Alexander; Ouyang, Xiaohu; Patel, Vinod F.; Smith, Leon M.; Stec, Markian; Tasker, Andrew; Xi, Ning; Xu, Shimin; Yuan, Chester Chenguang. Preparation of heterocyclylalkylamine derivatives as remedies for angiogenesis mediated diseases. WO 0266470 A1 20020829. European Journal of Medicinal Chemistry, 23 (4), 373-7; 1988]. One of them consists of nitro group reduction of derivatives of general formula (IVf) by methods known in the art, as for example YAMASHKIN, S. A.; YUROVSKAYA, M. A.; Chem Heterocycl Compd (N.Y.), 1999, 35 (12), 1426-1432. BOOTHROYD, S. R.; KERR, M. A.; Tetrahedron Lett, 1995,36 (14), 2411-2414. MACOR, J. E.; POST, R.; RYAN, K.; Synth Common, 1993, 23 (1), 65-72,
embedded image

wherein R¹-R⁷and n have the previously indicated meaning, or one of their suitably protected derivatives, and, if necessary, the protective groups are removed in order to obtain the corresponding amine of general formula (IIIf), which can be purified and/or isolated by means of conventional methods known in the state of the art.

The compounds of general formula (IVf) can also be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the European Journal of Medicinal Chemistry, 23 (4), 373-7; 1988; Farmaco, 51 (1), 75-8; 1996; Heterocycles, 55 (6), 1151-1159; 2001; Ham, Peter; Gaster, Laramie Mary; King, Francis David; Duckworth, David Malcolm. Preparation of N-heteroaryl-4′-oxadiazolylbiphenylcarboxamides as 5HT1 D antagonists, WO 9532967 A1 19951207.

One of them consists in the alkylation of nitro derivatives of general formula (IVf) by methods known in the art: MACCHIA, M.; MANERA, C.; NENCETTI, S.; ROSSELLO, A.; BROCCALI, G.; LIMONTA, D.; Farmaco, Ed Sci [FRPSAX] 1996, 51 (1), 75-78. BHAGWAT, S. S.; GUDE, C.; Tetrahedron Lett, 1994, 35 (12), 1847-1850. BRATTON, L. D.; ROTH, B. D.; TRIVEDI, B. K.; UNANGST, P. C.; J Heterocycl Chem, 2000, 37 (5), 1103-1108,
embedded image

wherein R²-R⁷and n have the previously mentioned meaning, or one of their suitably protected derivatives, and, if necessary, the protective groups are removed in order to obtain the corresponding amine of general formula (IIIf), which can be purified and/or isolated by means of conventional methods known in the state of the art.

The compounds of general formula (Vf) are commercially available or can also be prepared according to standard methods known in the state of the art, as for example OTTONI, O.; CRUZ, R.; KRAMMER, N. H.; Tetrahedron Lett [TELEAY] 1999,40 (6), 1117-1120. VOROB'EVA, S. L.; BUYANOV, V. N.; SUVOROV, N. N.; Khim Geterosikl Soedin [KGSSAQ] 1991, (5), 636-637. KATRITZKY, A. R.; RACHWAL, S.; BAYYUK, S.; Org Prep Proceed Int [OPPIAK] 1991, 23 (3), 357-363. MOSKALEV, N.; MAKOSZA, M.; Heterocycles [HTCYAM] 2000, 52 (2), 533-536.

The respective literature descriptions are incorporated by reference and form part of the disclosure.

The sulfonamide derivatives of general formula (If), wherein R^1f, nf and A^fhave the previously indicated meaning and R^6fis an alkyl radical, preferably a linear or branched C₁-C₆alkyl radical, optionally at least monosubstituted, they can also be prepared by alkylation of a sulfonamide derivative of general Formula (If), wherein R^1f-R^5f, R^7f, nf and A^fhave the previously indicated meaning, and R^6fis an hydrogen atom, with an alkyl halogenide or dialkyl sulfate.

The most suitable reaction temperatures range between 0° C. and the boiling temperature of the reaction medium, and the reaction times are preferably comprised between 1 and 24 hours.

Preferably, the resulting sulfonamide derivative of general formula (If) can be isolated by filtration, concentrating the filtrate under reduced pressure, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.

The pharmaceutically acceptable salts of the compounds of general formula (If), can be prepared by means of conventional methods known in the state of the art, preferably by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, or with organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc., in a suitable solvent, such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone, being obtained with the usual techniques for the precipitation or crystallization of the corresponding salts.

The preferred physiologically acceptable salts of the sulfonamide derivatives of general formula (If) are the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and of organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.

The physiologically acceptable solvates, particularly hydrates, of the sulfonamide derivatives of general formula (If) or of the corresponding physiologically acceptable salts, can be prepared by methods known in the state of the art.

If the sulfonamide derivatives of general formula (If) are obtained in the form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures can be separated by means of standard processes known in the state of the art, for example chromatographic methods or crystallization with chiral agents.

If one or more of the R^2g-R^9gmoieties represent an alkyl radical which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine and trifluoromethyl.

If R^1grepresents a saturated or unsaturated cycloaliphatic radical, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents and/or if it comprises a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C₁-C₆alkyl and benzyl. The heteroatoms of the cycloaliphatic radical and/or of the mono- or bi-cyclic cycloaliphatic ring can, independently from one another, be chosen preferably from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as an heteroatom.

If R^8gand R^9gtogether with the nitrogen atom bridge form a saturated or unsaturated heterocyclic ring, which can contain at least one additional heteroatom as a ring member, which is substituted by one or more substituents and/or condensed with a saturated or unsaturated mono- or bi-cyclic cycloaliphatic ring system, which can contain at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C₁-C₆alkyl and benzyl. If the heterocyclic ring contains one or more additional heteroatoms, and/or if one or both mono- or bi-cyclic rings contain one or more heteroatoms, these heteroatoms can, independently from one another, be preferably chosen from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as heteroatom.

If A^gis a mono or poly-cyclic aromatic ring system, which is substituted by one or more substituents, and which can be bonded by means of an optionally at least mono-substituted alkylene, alkenylene or alkynylene, and/or can contain at least one heteroatom as a ring member, unless otherwise defined, each one of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy, a phenyl radical, optionally at least monosubstituted, and heteroaryl of 5 or 6 members, more preferably from the group consisting of halogen, linear or branched C₁-C₆alkyl, phenyl optionally at least monosubstituted and heteroaryl of 5 or 6 members, much more preferably from the group consisting of fluorine, chlorine, linear or branched C₁-C₆alkyl, phenyl radical, optionally at least monosubstituted and heteroaryl of 5 or 6 members. If one or more of the rings of a mono or poly-cyclic aromatic ring system contains one or more heteroatoms, these heteroatoms—like the heteroatoms of a previously mentioned heteroaryl radical of 5 or 6 members—can be preferably chosen from the group consisting of nitrogen, sulfur and oxygen. If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and an NR^12gR^13gradical, wherein R^12gand R^13g, identical or different, are hydrogen or linear or branched C₁-C₆alkyl.

The substituents of A^gmay also preferably be selected from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy, an optionally at least mono-substituted phenyl, —O-phenyl and 5- to 6-membered heteroaryl, more preferably from the group consisting of halogen, linear or branched C₁-C₆alkyl, optionally at least mono-substituted phenyl, —O-phenyl and 5- to 6-membered heteroaryl, even more preferably from the group consisting of fluorine, chlorine, linear or branched C₁-C₆alkyl, optionally at least mono-substituted phenyl, —O-phenyl, and 5- to 6-membered heteroaryl. If the previously mentioned phenyl radical is itself substituted by one or more substituents, each one of the substituents may be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and an NR^12gR^13gradical, wherein R^12gand R^13g, identical or different, are hydrogen or linear or branched C₁-C₆alkyl.

If the previously mentioned alkylene, alkenylene or alkynylene group is substituted by one or more substituents, each of the substituents can be preferably chosen from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy or a phenyl radical, optionally at least monosubstituted. If said phenyl radical is itself substituted by one or more substituents, each one of the substituents can be preferably chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and an N^12gR^13gradical, wherein R^12gand R^13g, identical or different, are hydrogen or linear or branched C₁-C₆alkyl.

Sulfonamide derivatives of general formula (Ig) are preferred, wherein R^1gis an —NR^8gR^8gradical or a saturated or unsaturated cycloaliphatic radical of 5 or 6 members, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and which can be condensed with a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5 or 6 members, preferably an —NR^8gR^9gradical or a radical chosen from the group consisting of
embedded image

where, if present, the dotted line is an optional chemical bond, and R¹⁰is hydrogen, a linear or branched C₁-C₆alkyl radical or a benzyl radical, preferably hydrogen or a C₁-C₂alkyl radical, and R^2g-R^9g, A^gand ng are defined as above.

Sulfonamide derivatives of general formula (Ig) are also preferred, wherein R^2g, R^3g, R^4g, R^5gand R^6g, are hydrogen, a linear or branched C₁-C₆alkyl radical, a linear or branched C₂-C₆alkenyl radical, or a linear or branched C₂-C₆alkinyl radical, preferably hydrogen, and R^1g-R^7g, R^8g, R^9g, A^gand ng are defined as above.

The use of sulfonamide derivatives of general formula (Ig) is also preferred, wherein R^7g, is hydrogen or a linear or branched C₁-C₆alkyl radical, which is optionally at least monosubstituted, preferably hydrogen or a linear or branched C₁-C₆alkyl radical, more preferably hydrogen or an C₁-C₂alkyl radical and R^1g-R^6g, R^8g, R^9g, A^gand ng are defined as above.

Furthermore, sulfonamide derivatives of general formula (Ig) are also preferred, wherein R^8gand R^9g, identical or different, are hydrogen or a linear or branched C₁-C₆alkyl radical, which is optionally at least monosubstituted, or

R^8gand R^9g, together with the nitrogen atom bridge, form a saturated or unsaturated heterocyclic ring of 5 or 6 members, which is optionally at least monosubstituted, which can contain at least one additional heteroatom as a ring member, and/or which can be condensed with a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5, 6 or 7 members, and R^1g-R^7g, A^gand ng are defined as above.

Particularly preferred is the use of sulfonamide derivatives of general formula (Ig), wherein R^8gand R^9g, identical or different, are hydrogen or a linear or branched C₁-C₆alkyl radical, preferably a linear or branched C₁-C₆alkyl radical, or

R^8gand R^9gtogether with the nitrogen atom bridge form a radical chosen from the group consisting of
embedded image

wherein R¹¹, if it is present, is hydrogen, a linear or branched C₁-C₆alkyl radical or a benzyl radical, preferably hydrogen, or a C₁-C₂alkyl radical, and R^1g-R^9g, A^gand ng are defined as above.

Furthermore, sulfonamide derivatives of general formula (Ig) are preferred, wherein A^gis a mono or poly-cyclic aromatic ring system, which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members, and which can be bonded by means of an optionally at least mono-substituted C₁-C₆alkylene group, an optionally at least monosubstituted C₂-C₆alkenylene group, or an optionally at least monosubstituted C₂-C₆alkynyleen group, and/or can contain at least one heteroatom as a ring member, preferably a mono or poly-cyclic aromatic ring system, which is optionally at least monosubstituted, wherein the ring/rings is/are of 5 or 6 members and in which one or more of the rings contain(s) at least one heteroatom or a radical chosen from the group consisting of
embedded image

in which X, Y and Z are each one independently chosen from a group consisting of hydrogen, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, trifluoromethyl radical, cyano radical and an NR¹²R¹³radical, in which R¹²and R¹³, identical or different, are hydrogen or linear or branched C₁-C₆alkyl,

W is a single chemical bond between the two rings, a CH₂, O, S group or an NR¹⁴radical, wherein R¹⁴is hydrogen or linear or branched C₁-C₆alkyl, and

m is 0, 1, 2, 3 or 4;

and R^1g-R^11gand ng are defined as above.

Furthermore, sulfonamide derivatives of general formula (Ig) are preferred, wherein A^grepresents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered, which may be bonded via an optionally at least mono-substituted C₁-C₆alkylene group, an optionally at least mono-substituted C₂-C₆alkenylene group or an optionally at least mono-substituted C₂-C₆alkynylene group and/or wherein the ring(s) may contain at least one heteroatom as a ring member,

preferably A^grepresents an optionally at least mono-substituted mono- or polycyclic aromatic ring system, wherein the ring(s) is/are 5- or 6-membered and wherein one or more of the rings contain at least one heteroatom,

Also preferred are compounds of general formula (Ig),

wherein

R^1gis a —NR^8gR^9gradical,

R^2g, R^3g, R^4g, R^5gand R^6geach represent hydrogen,

R^7grepresents hydrogen,

R^8gand R^9g, identical or different, each represent methyl, ethyl, n-propyl or iso-propyl, more preferably methyl,

R^8gand R^9gtogether with the bridging nitrogen atom form a 5- or 6-membered heterocyclic ring, more preferably form a pyrrolidine or piperidine ring,

A^grepresents an aryl or heteroaryl radical selected from the group consisting of phenyl, naphthyl, benzo[b]thiophenyl and imidazo[2,1-b]thiazolyl which may be substituted by 1, 2 or 3 substituents selected from the group consisting of chlorine, methyl and phenyl and/or which may be bonded via a C_1-2alkylene group,

and

ng is 2;

The most preferred compounds general formula (Ig) may be selected from the group consisting of

[1] N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-naphtalene-1-sulfonamide,
[2] N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[3] N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-4-phenylbenzenesulfonamide and
[4] N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide

and their corresponding salts and solvates

The most preferred compounds general formula (Ig) may also be selected from the group consisting of

[1] N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-naphtalene-1-sulfonamide,
[2] N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,
[3] N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-4-phenylbenzenesulfonamide and
[4] N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide
[5] 5-chloro-3-methyl-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-7-yl)-benzo[b]thiophen-2-sulfonamide,
[6] N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-7-yl)naphthalene-1-sulfonamide,
[7] 6-chloro-N-(1-(2-(pyrroldin-1-yl)ethyl)-1H-indol-7-yl)imidazo[2,1-b]thiazole-5-sulfonamide and
[8] 2-(naphth-1-yl)-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-7-yl)ethansulfonamide

and their corresponding salts and solvates.

The present invention likewise refers to the physiologically acceptable salts of the compounds of general formula (Ig), particularly the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and with organic acids such as citric, maleic, fumaric, tartaric acids or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.

Below, the residues R¹-R⁷, A and n in the general formulas (IIg) and (IIIg) are R^1g-R^7g, A^gand ng.

The derivatives of general formula (Ig), wherein R^1g-R^9g, ng and A^ghave the previously indicated meaning, may be preferably prepared in a way that:

At least one compound of general Formula (IIg),
embedded image

wherein A has the previously mentioned meaning in the general formula (Ig), and X is an acceptable leaving group, preferably an halogen atom, more preferably chlorine; reacts with at least one substituted 7-aminoindole of general formula (IIIg)

wherein R¹-R⁷and n have the previously indicated meaning, or one of their suitable protected derivatives, and, if necessary, the protective groups are removed in order to obtain the corresponding sulfonamide derivative of general formula (Ig), which can be purified and/or isolated by means of conventional methods known in the state of the art.

The reaction between the compounds of general formula (IIg) and (IIIg) is usually carried out in the presence of an organic reaction medium such as dialkyl ether, particularly diethyl ether or a cyclic ether, particularly tetrahydrofuran or dioxane, an halogenated organic hydrocarbon, particularly methylene chloride or chloroform, an alcohol, particularly methanol or ethanol, a dipolar aprotic solvent, particularly acetonitrile, pyridine or dimethylformamide, or any other suitable reaction medium. Naturally, mixtures of at least two of the classes of the mentioned compounds or at least two compounds of one class can also be used.

The most suitable reaction temperatures range between 0° C. and room temperature, that is, approximately 25° C., and the reaction time is preferably comprised between 5 minutes and 24 hours.

The resulting sulfonamide derivative of general Formula (Ig) can be purified and/or isolated according to conventional methods known in the state of the art.

Preferably, the sulfonamide derivatives of general Formula (Ig) can be isolated by evaporating the reaction medium, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.

The compounds of general formula (IIg) are commercially available, or they can be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature [E. E. Gilbert, Synthesis, 1969, 1, 3]. The compounds of general formula (IIIg) can also be prepared according to standard methods known in the state of the art, for example by methods similar to those described in: [Abou-Gharbia, Magid; Patel, Usha; Tokolics, Joseph; Freed, Meier. European Journal of Medicinal Chemistry (1988), 23(4), 373-7].

The sulfonamide derivatives of general Formula (Ig), wherein R^1g, ng and A^ghave the previously indicated meaning and R^7gis an alkyl radical, preferably a linear or branched C₁-C₆alkyl radical, optionally at least monosubstituted, they can also be prepared by alkylation of a sulfonamide derivative of general formula (Ig), wherein R^1g-R^6g, ng and A^ghave the previously indicated meaning, and R^7gis an hydrogen atom, with an alkyl halogenide or dialkyl sulfate.

The most suitable reaction temperatures range between 0° C. and the boiling temperature of the reaction medium, and the reaction times are preferably comprised between 1 and 24 hours.

Preferably, the resulting sulfonamide derivative of general formula (Ig) can be isolated by filtration, concentrating the filtrate under reduced pressure, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.

The pharmaceutically acceptable salts of the compounds of general formula (Ig), can be prepared by means of conventional methods known in the state of the art, preferably by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, or with organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc., in a suitable solvent, such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone, being obtained with the usual techniques for the precipitation or crystallization of the corresponding salts.

The preferred physiologically acceptable salts of the sulfonamide derivatives of general formula (Ig) are the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and of organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.

The physiologically acceptable solvates, particularly hydrates, of the sulfonamide derivatives of general formula (Ig) or of the salts, preferably the corresponding, physiologically acceptable salts, can be prepared by methods known in the state of the art.

If the sulfonamide derivatives of general formula (Ig) are obtained in the form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures can be separated by means of standard processes known in the state of the art, for example chromatographic methods or crystallization with chiral agents.

If one or more of the substituents R^2h-R^8hrepresents an alkyl radical, an alkenyl radical, or an alkinyl radical, which is substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy, or a phenyl radical optionally at least monosubstituted. If said phenyl radical is the same one substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of fluorine, chlorine, bromine, a linear or branched C₁-C₆alkyl, a linear or branched C₁-C₆alkoxy, a linear or branched C₁-C₆alkylthio, a trifluoromethyl radical, a cyano radical and an NR^11hR^12hradical, where R^11hand R^12h, identical or different, are defined like R^7hand R^8h.

If R^1hrepresents a saturated or unsaturated cycloaliphatic radical, which is optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents and/or if it comprises a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, optionally containing at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy and benzyl, more preferably from the group consisting of linear or branched C₁-C₆alkyl and benzyl. The heteroatoms of the cycloaliphatic radical and/or of the mono- or bi-cyclic cycloaliphatic ring can, independently from one another, be chosen preferably from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as a heteroatom.

If R^7hand R^8htogether with the nitrogen atom to which they are bonded form a saturated or unsaturated heterocyclic ring, which can optionally contain at least one additional heteroatom as a ring member, which is substituted by one or more substituents and/or condensed with a saturated or unsaturated mono- or bi-cyclic cycloaliphatic ring system, which can contain at least one heteroatom as a ring member, which is substituted by one or more substituents, unless otherwise defined, each one of the substituents can preferably be chosen from the group consisting of hydroxy, fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy and benzyl, preferably from the group consisting of linear or branched C₁-C₆alkyl and benzyl. If the heterocyclic ring contains one or more additional heteroatoms, and/or if one or both mono- or bi-cyclic rings contains one or more heteroatoms, these heteroatoms can, independently from one another, be preferably chosen from the group consisting of nitrogen, sulfur and oxygen, more preferably nitrogen as a heteroatom.

If A^hrepresents an alkyl radical, an alkenyl radical, or an alkinyl radical, which is substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy or a phenyl radical, optionally at least monosubstituted. If said phenyl radical is the same one substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, a trifluoromethyl radical, a cyano radical and an NR^3hR^14hradical, where R^13hand R^14h, identical or different, are defined as R^7hand R^8h.

If B^hrepresents an alkyl radical, an alkenyl radical, or an alkinyl radical, which is substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy, or a phenyl radical optionally at least monosubstituted. If said phenyl radical is the same one substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, a trifluoromethyl radical, a cyano radical and an NR^15hR^16hradical, where R^15hand R^16h, identical or different, are defined as R^7hand R^8h.

If A^hand B^htogether with the carbon atom to which they are bonded form a saturated or unsaturated, but not aromatic, cycloalkyl ring, which is substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of hydroxy, halogen, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆perfluoroalkyl, linear or branched C₁-C₆perfluoroalkoxy or a phenyl radical, optionally at least monosubstituted. If said phenyl radical is the one substituted by one or more substituents, each one of the substituents can preferably be chosen from the group consisting of fluorine, chlorine, bromine, linear or branched C₁-C₆alkyl, linear or branched C₁-C₆alkoxy, linear or branched C₁-C₆alkylthio, a trifluoromethyl radical, a cyano radical and an NR^17hR^18hradical, where R^17hand R^18h, identical or different, are defined like R^7hand R^8h.

Sulfonamide derivatives of general formula (Ih) are preferred, where R^1hrepresents an NR^7hR^8hradical or a saturated or unsaturated cycloaliphatic radical of 5 or 6 members, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and which can be condensed with a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5 or 6 members, preferably an —NR^7hR^8hradical or a radical chosen from the group consisting of
embedded image

where, if present, the dotted line represents an optional chemical bond, and R¹⁹is hydrogen, a linear or branched C₁-C₆alkyl radical or a benzyl radical, preferably hydrogen or a C₁-C₂alkyl radical, and R^2h-R^6h, A^h, B^hand nh are defined as above.

Furthermore, sulfonamide derivatives of general formula (Ih) are also preferred, where R^7hand R^8h, identical or different, are hydrogen, a linear or branched C_1-6alkyl radical, which is optionally at least monosubstituted, a linear or branched C_2-6alkenyl radical, which is optionally at least monosubstituted, or a linear or branched C_2-6alkynyl radical, which is optionally at least monosubstituted, or

R^7hand R^8h, together with the nitrogen atom bridge, form a saturated or unsaturated heterocyclic ring of 5 or 6 members, which is optionally at least monosubstituted, which can contain at least one additional heteroatom as a ring member, and/or which can be condensed with a saturated or unsaturated, mono- or bi-cyclic cycloaliphatic ring system, which is optionally at least monosubstituted, which can optionally contain at least one heteroatom as a ring member, and wherein the ring/rings is/are of 5, 6 or 7 members, and R^1h-R^6h, A^h, B^hand nh are defined as above.

Particularly preferred are sulfonamide derivatives of general formula (Ih), where R^7hand R^8h, identical or different, are hydrogen or a linear or branched C₁-C₆alkyl radical, preferably a linear or branched C₁-C₆alkyl radical, or

R^7hand R^8htogether with the nitrogen atom bridge form a radical chosen from the group consisting of
embedded image

where R²⁰, if present, is hydrogen, a linear or branched C₁-C₆alkyl radical or a benzyl radical, preferably hydrogen, or a C₁-C₂alkyl radical, and R^1h-R^6h, A^h, B^hand nh are defined as above.

Furthermore, sulfonamide derivatives of general formula (Ih) are preferred, where A^hand B^h, identical or different, are a linear or branched C₁-C₆alkyl radical, a linear or branched C₁-C₆alkenyl radical, or a linear or branched C₁-C₆alkinyl radical, preferably a linear or branched C₁-C₆alkyl radical, or

A^hand B^h, together with the carbon atom to which they are bonded, form a saturated or unsaturated, but not aromatic, cycloalkyl ring, which is optionally substituted by one or more substituents, preferably a C₃-C₈cycloalkyl ring. Particularly preferred a cyclohexyl ring.

Sulfonamide derivatives of general Formula (Ih) are also preferred, wherein R^2h, R^3h, R^4h, R^5hand R^6h, identical or different, independently from one another, are, hydrogen, halogen, cyano, nitro, a linear or branched C₁-C₆alkyl radical, a linear or branched C₁-C₆alkenyl radical, a linear or branched C₁-C₆alkinyl adical, C_1-6-alkoxy, C_1-6-alkylthio, hydroxy, trifluoromethyl, C_3-8cycloalk(en)yl, C_1-6-alkylcarbonyl, phenylcarbonyl or a —NR^9hR^10hgroup, where R^9hand R^10h, are defined as R^7hand R^8h.

Also preferred are compounds of general formula (Ih),

wherein

R^1hrepresents an unsaturated, optionally at least one nitrogen atom as a ring member containing 5- or 6-membered cycloaliphatic radical, which may be substituted by a methyl group and/or which may be condensed with a 5-membered cycloaliphatic ring, more preferably R¹represents a moiety selected from the group consisting of
embedded image

R^2h, R^3h, R^4hand R^6heach represent hydrogen,

R^5hrepresents H, fluorine, chlorine, nitro or a —NR⁹R¹⁰group,

R^9hand R^10heach represent hydrogen,

A^hand B^htogether with the carbon atom to which they are bonded form a saturated or unsaturated, but not aromatic, C₃-C₈cycloalkyl ring, more preferably form a cyclohexyl ring,

and

nh is 0;

optionally in form of one of their stereoisomers, preferably enantiomers or diastereomers, their racemate or in form of a mixture of at least two of their stereoisomers, preferably enantiomers or diastereomers, in any mixing ratio, or a salt thereof, preferably a corresponding physiologically acceptable salt thereof or a corresponding solvate thereof.

Those most preferred compounds of general formula (Ih) are selected from the group consisting of

[1] 1-Cyclohexanesulfonyl-3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-5-nitro-1H-indole,
[2] 5-Chloro-1-cyclohexanesulfonyl-3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indole,
[3] 5-Amino-1-cyclohexanesulfonyl-3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indole and
[4] 1-Cyclohexanesulfonyl-5-fluoro-3-(1,2,3,5,8,8a-hexahydro-indolizine-7-yl)-1H-indole hydrochloride

and their corresponding salts and solvates.

The present invention likewise refers to the physiologically acceptable salts of the compounds of general formula (Ih), particularly the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and of organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.

Below, the residues R¹-R⁶, A, B and n in the general formulas (IIh) to (IVh) are R^1h-R^6h, A^h, B^hand nh.

The derivatives of general formula (Ih), wherein R^1h-R^6h, A^h, B^hand nh have the previously indicated meaning, may be preferably prepared in a way that:

At least one compound of general Formula (IIh),
embedded image

wherein A and B have the previously mentioned meaning in the general formula (Ih), and X is an acceptable leaving group, preferably an halogen atom, more preferably chlorine; reacts with at least one substituted indole of general formula (IIIh)

where R¹-R⁶and n have the previously indicated meaning, or one of their suitable protected derivatives, and, if necessary, the protective groups are removed in order to obtain the corresponding sulfonamide derivative of formula (Ih), which can be purified and/or isolated by means of conventional methods known in the state of the art.

The reaction is preferably carried out in the presence of a suitable strong base, for example, lithium diisopropylamide, butyllithium, sodium hydride, or sodium bis(trimethylsilyl)amide in an inert solvent, such as tetrahydrofurane, hexane or dimethylformamide.

The most suitable reaction temperatures range between −100° C. and room temperature, and the reaction time is preferably comprised between 5 minutes and 24 hours. The preferred conditions are sodium hydride in dimethylformamide at approximately 0° C.

The resulting sulfonamide derivative of general formula (Ih) can be purified and/or isolated according to conventional methods known in the state of the art.

Preferably, the sulfonamide derivatives of general formula (Ih) can be isolated by evaporating the reaction medium, adding water and, if necessary, adjusting the pH so that a solid which can be isolated by filtration is obtained; or it can be extracted with a water immiscible solvent, such as chloroform, and be purified by chromatography or recrystallization of a suitable solvent.

The compounds of general formula (IIh) are commercially available, or they can be prepared according to standard methods known in the state of the art, for example by methods similar to those described in the literature [KHANNA, V.; TAMILSELVAN, P.; KALRA, S. J. S.; IQBAL, J.; Tetrahedron 1994, 35 (32), 5935-5938; L. N. Aristarkhova et al., J. Org. Chem. USSR, 1970, 6, 2454-2458; E. E. Gilbert, Synthesis, 1969, 1, 3]. The compounds of general Formula (IIIh) can also be prepared according to standard methods known in the state of the art, for example, methods similar to those described in the literature. Substituted aromatic 5-HT1f agonist, WO9846570. Piperidine-indole compounds having 5-HT6 affinity, U.S. Pat. No. 6,133,287.

The respective descriptions in the literature are incorporated by reference and form part of the disclosure.

The sulfonamide derivatives of general formula (Ih), wherein R^2h, R^3h, R^4h, R^5hor R^6hare an amino group by reduction of the nitro group of derivatives of general formula (IVh) by methods known in the art, for example BRATTON, L. D.; ROTH, B. D.; TRIVEDI, B. K.; UNANGST, P. C.; J. Heterocycl Chem, 2000, 37 (5), 1103-1108. FANGHAENEL, E.; CHTCHEGLOV, D.; J Prakt Chem/Chem-Ztg, 1996, 338 (8), 731-737. KUYPER, L. F.; BACCANARI, D. P.; JONES, M. L.; HUNTER, R. N.; TANSIK, R. L.; JOYNER, S. S.; BOYTOS, C. M.; RUDOLPH, S. K.; KNICK, V.; WILSON, H. R.; CADDELL, J. M.; FRIEDMAN, H. S.; ET AL.; J Med Chem, 1996, 39 (4), 892-903,
embedded image

and the others R¹-R⁶, A, B and n have the previously mentioned meaning, or one of their derivatives suitably protected, and, if necessary, the protective groups are removed in order to obtain the corresponding amine of general Formula (Ih), which can be purified and/or isolated by means of conventional methods known in the state of the art.

The respective literature descriptions are incorporated by reference and form part of the disclosure.

The pharmaceutically acceptable salts of the compounds of general Formula (Ih), can be prepared by means of conventional methods known in the state of the art, preferably by reaction with a mineral acid, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, or with organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic acids, etc., in a suitable solvent, such as methanol, ethanol, diethyl ether, ethyl acetate, acetonitrile or acetone, being obtained with the usual techniques for the precipitation or crystallization of the corresponding salts.

The preferred physiologically acceptable salts of the sulfonamide derivatives of general formula (Ih) are the addition salts of mineral acids, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric acids, and of organic acids, such as citric, maleic, fumaric, tartaric acids, or their derivatives, p-toluenesulfonic, methanesulfonic, camphorsulfonic acids, etc.

The physiologically acceptable solvates, particularly hydrates, of the sulfonamide derivatives of general formula (Ih) or of the corresponding physiologically acceptable salts, can be prepared by methods known in the state of the art.

If the sulfonamide derivatives of general Formula (Ih) are obtained in the form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures can be separated by means of standard processes known in the state of the art, for example chromatographic methods or crystallization with chiral agents.

The active substance combination according to this invention comprises preferably 1-99% by weight of the component (A) and 99-1% by weight of the component (B), more preferably 10-80% by weight of the component (A) and 90-20% by weight of the component (B), these percentages being based on the total weight of both components (A) and (B).

Another aspect of the present invention is a medicament, which comprises an inventive active substance combination and optionally one or more pharmacologically acceptable adjuvants.

Said medicament is particularly suitable for simultaneous regulation of neuropeptide Y-receptors, preferably neuropeptide Y5-receptors, and 5-HT₆receptors, for the regulation of appetite, for maintenance, increase or reduction of body weight, for prophylaxis and/or treatment of disorders related to food ingestion, preferably for prophylaxis and/or treatment of obesity, anorexia, cachexia, bulimia, diabetes, preferably type II diabetes (non-insulin-dependent diabetes mellitus), or for prophylaxis and/or treatment of gastrointestinal tract disorders, preferably of the irritable bowel syndrome, for prophylaxis and/or treatment of Peripheral Nervous System Disorders, Central Nervous System Disorders, arthritis, epilepsy, anxiety, panic, depression, cognitive disorders, memory disorders, cardiovascular diseases, senile dementia processes, such as Alzheimer's, Parkinson's and/or Huntington's Disease, schizophrenia, psychosis, infantile hyperkinesia (ADHD, attention deficit/hyperactivity disorder), pain, hypertensive syndrome, inflammatoric diseases, immunologic diseases or for improvement of cognition.

Said medicament is more particularly suitable for simultaneous regulation of neuropeptide Y-receptors, preferably neuropeptide Y5-receptors, and 5-HT₆receptors, for the regulation of appetite, for maintenance, increase or reduction of body weight, for prophylaxis and/or treatment of disorders related to food ingestion, preferably for prophylaxis and/or treatment of obesity, anorexia, cachexia, bulimia, diabetes, preferably type II diabetes (non-insulin-dependent diabetes mellitus), or for prophylaxis and/or treatment of gastrointestinal tract disorders, preferably of the irritable bowel syndrome.

Another aspect of the present invention is the use of an inventive active substance combination for the manufacture of a medicament for simultaneous regulation of neuropeptide Y-receptors, preferably neuropeptide Y5-receptors, and 5-HT₆receptors, for the regulation of appetite, for maintenance, increase or reduction of body weight, for prophylaxis and/or treatment of disorders related to food ingestion, preferably for prophylaxis and/or treatment of obesity, anorexia, cachexia, bulimia, diabetes, preferably type II diabetes (non-insulin-dependent diabetes mellitus), or for prophylaxis and/or treatment of gastrointestinal tract disorders, preferably of the irritable bowel syndrome, for prophylaxis and/or treatment of Peripheral Nervous System Disorders, Central Nervous System Disorders, arthritis, epilepsy, anxiety, panic, depression, preferably biploar disorders, cognitive disorders, memory disorders, cardiovascular diseases, senile dementia processes, neurodegenerative disorders, preferably Alzheimer's disease, Parkinson's disease, Huntington's disease and/or multiple sclerosis, schizophrenia, psychosis, infantile hyperkinesia (ADHD, attention deficit/hyperactivity disorder), pain, hypertensive syndrome, inflammatoric diseases, immunologic diseases or for improvement of cognition.

Particularly preferred is the use of an inventive active substance combination for the manufacture of a medicament for simultaneous regulation of neuropeptide Y-receptors, preferably neuropeptide Y5-receptors, and 5-HT₆receptors, for the regulation of appetite, for maintenance, increase or reduction of body weight, for prophylaxis and/or treatment of disorders related to food ingestion, preferably for prophylaxis and/or treatment of obesity, anorexia, cachexia, bulimia, diabetes, preferably type II diabetes (non-insulin-dependent diabetes mellitus), or for prophylaxis and/or treatment of gastrointestinal tract disorders, preferably of the irritable bowel syndrome.

Those skilled in the art understand that the components (A) and (B) of the active substance combination according to the present invention may be administered simultaneously or sequentially to one another, whereby in each case components (A) and (B) may be administered via the same or different administration pathways, e.g. orally or parenterally, preferably both components (A) and (B) are administered simultaneously in one and the same administration form.

Yet another aspect of the present invention are pharmaceutical formulations in different pharmaceutical forms comprising an inventive active substance combination and optionally one or more pharmacologically acceptable adjuvants.

As well known to somebody skilled in the art the pharmaceutical formulations may—depending on their route of administration, also contain one or more auxiliary substances known to those skilled in the art.

The pharmaceutical formulations according to the present invention may be produced according to standard procedures known to those skilled in the art, e.g. from the tables of contents from “Pharmaceutics: the Science of Dosage Forms”, Second Edition, Aulton, M. E. (Ed.) Churchill Livingstone, Edinburgh (2002); “Encyclopedia of Pharmaceutical Technology”, Second Edition, Swarbrick, J. and Boylan J. C. (Eds.), Marcel Dekker, Inc. New York (2002); “Modern Pharmaceutics”, Fourth Edition, Banker G. S. and Rhodes C. T. (Eds.) Marcel Dekker, Inc. New York 2002 and “The Theory and Practice of Industrial Pharmacy”, Lachman L., Lieberman H. and Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986). The respective descriptions are incorporated by reference and are part of the disclosure.

Preferred pharmaceutical formulations are solid pharmaceutical forms, preferably tablets, chewing tablets, chewing gums, dragées, capsules, suppositories, powder preparations, transdermal therapeutic systems, transmucosal therapeutic systems, preferably tablets or capsules.

Preferred pharmaceutical formulations are also liquid and semi-liquid pharmaceutical forms such as drops or such as juice, sirup, solution, emulsion, suspension, preferably drops or solutions.

In an additional preferred embodiment, the pharmaceutical formulations are in the form of multiple particles, preferably microtablets, microcapsules, microspheroids, granules, crystals and pellets, optionally compacted in a tablet, filled in a capsule or suspended in a suitable liquid.

The pharmaceutical formulations according to the present invention are particularly suitable for oral, intravenous, intramuscular, subcutaneous, intrathecal, epidural, buccal, sublingual, pulmonal, rectal, transdermal, nasal or intracerebroventricular application, more particularly for oral, intravenous or intraperitoneal application.

In one embodiment of the present invention the pharmaceutical formulation comprises at least one of the components (A) and (B) of the active substance combination at least partially in a sustained-release form.

By incorporating one or both of these components (A) and (B) at least partially or completely in a sustained-release form it is possible to extend the duration of their effect, allowing for the beneficial effects of such a sustained-release form, e.g. the maintenance of even concentrations in the blood.

Suitable sustained-release forms as well as materials and methods for their preparation are known to those skilled in the art, e.g. from the tables of contents from “Modified-Release Drug Delivery Technology”, Rathbone, M. J. Hadgraft, J. and Roberts, M. S. (Eds.), Marcel Dekker, Inc., New York (2002); “Handbook of Pharmaceutical Controlled Release Technology”, Wise, D. L. (Ed.), Marcel Dekker, Inc. New York, (2000); “Controlled Drug Delivery”, Vol. I, Basic Concepts, Bruck, S. D. (Ed.), CRC Press Inc., Boca Raton (1983) and from Takada, K. and Yoshikawa, H., “Oral Drug delivery”, Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 728-742; Fix, J., “Oral drug delivery, small intestine and colon”, Encylopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-728. The respective descriptions are incorporated by reference and are part of the disclosure.

If the pharmaceutical formulation according to the present invention comprises at least one of the components (A) and (B) at least partially in a sustained-release form, said sustained release may preferably be achieved by the application of at least one coating or provision of a matrix comprising at least one sustained-release material.

The sustained-release material is preferably based on an optionally modified, water-insoluble, natural, semisynthetic or synthetic polymer, or a natural, semisynthetic or synthetic wax or fat or fatty alcohol or fatty acid, or on a mixture of at least two of these afore mentioned components.

The water-insoluble polymers used to produce a sustained-release material are preferably based on an acrylic resin, which is preferably selected from the group of poly(meth)acrylates, particularly preferably poly(C_1-4)alkyl (meth)acrylates, poly(C_1-4)dialkylamino(C_1-4)alkyl (meth)acrylates and/or copolymers or mixtures thereof, and very particularly preferably copolymers of ethyl acrylate and methyl methacrylate with a monomer molar ratio of 2:1 (Eudragit NE30D®), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate-chloride with a monomer molar ratio of 1:2:0.1 (Eudragit RS®), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate-chloride with a monomer molar ratio of 1:2:0.2 (Eudragit RL®), or a mixture of at least two of the above-mentioned copolymers. These coating materials are commercially available as 30 wt. % aqueous latex dispersions, i.e. as Eudragit RS30D®, Eudragit NE30D® or Eudragit RL30D®, and may also be used as such for coating purposes.

In another embodiment, the sustained-release material is based on water-insoluble cellulose derivatives, preferably alkyl celluloses, particularly preferably ethyl cellulose, or cellulose esters, e.g. cellulose acetate. Aqueous ethyl cellulose dispersions are commercially available, for example, under the trademarks Aquacoat® or Surelease®.

As natural, semisynthetic or synthetic waxes, fats or fatty alcohols, the sustained-release material may be based on carnauba wax, beeswax, glycerol monostearate, glycerol monobehenate, glycerol ditripalmitostearate, microcrystalline wax, cetyl alcohol, cetylstearyl alcohol or a mixture of at least two of these components.

The afore mentioned polymers of the sustained-release material may also comprise a conventional, physiologically acceptable plasticizer in amounts known to those skilled in the art.

Examples of suitable plasticizers are lipophilic diesters of a C₆-C₄₀aliphatic or aromatic dicarboxylic acid and a C₁-C₈aliphatic alcohol, e.g. dibutyl phthalate, diethyl phthalate, dibutyl sebacate or diethyl sebacate, hydrophilic or lipophilic citric acid esters, e.g. triethyl citrate, tributyl citrate, acetyltributyl citrate or acetyltriethyl citrate, polyethylene glycols, propylene glycol, glycerol esters, e.g. triacetin, Myvacet® (acetylated mono- and diglycerides, C₂₃H₄₄O₅to C₂₅H₄₇O₇), medium-chain triglycerides (Miglyol®), oleic acid or mixtures of at least two of said plasticizers.

Aqueous dispersions of Eudragit RS® and optionally Eudragit RL® preferably contain triethyl citrate. The sustained-release material may comprise one or more plasticisers in amounts of, for example, 5 to 50 wt. % based on the amount of polymer(s) used.

The sustained-release material may also contain other conventional auxiliary substances known to those skilled in the art, e.g. lubricants, coloured pigments or surfactants.

The pharmaceutical formulation of the present invention may also comprise at least one of the components (A) and (B) covered by an enteric coating form which dissolves as a function of pH. Because of this coating, part or all of the pharmaceutical formulation can pass through the stomach undissolved and the components (A) and/or (B) are only released in the intestinal tract. The enteric coating preferably dissolves at a pH of between 5 and 7.5.

The enteric coating may be based on any enteric material known to those skilled in the art, e.g. on methacrylic acid/methyl methacrylate copolymers with a monomer molar ratio of 1:1 (Eudragit L®), methacrylic acid/methyl methacrylate copolymers with a monomer molar ratio of 1:2 (Eudragit S®), methacrylic acid/ethyl acrylate copolymers with a monomer molar ratio of 1:1 (Eudragit L30D-55®), methacrylic acid/methyl acrylate/methyl methacrylate copolymers with a monomer molar ratio of 7:3:1 (Eudragit FS®), shellac, hydroxypropyl methyl cellulose acetate-succinates, cellulose acetate-phthalates or a mixture of at least two of these components, which can optionally also be used in combination with the above-mentioned water-insoluble poly(meth)acrylates, preferably in combination with Eudragit NE30D® and/or Eudragit RL® and/or Eudragit RS®.

The coatings of the pharmaceutical formulations of the present invention may be applied by the conventional processes known to those skilled in the art, e.g. from Johnson, J. L., “Pharmaceutical tablet coating”, Coatings Technology Handbook (Second Edition), Satas, D. and Tracton, A. A. (Eds), Marcel Dekker, Inc. New York, (2001), 863-866; Carstensen, T., “Coating Tablets in Advanced Pharmaceutical Solids”, Swarbrick, J. (Ed.), Marcel Dekker, Inc. New York (2001), 455-468; Leopold, C. S., “Coated dosage forms for colon-specific drug delivery”, Pharmaceutical Science & Technology Today, 2(5), 197-204 (1999), Rhodes, C. T. and Porter, S. C., Coatings, in Encyclopedia of Controlled Drug Delivery. Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 1, 299-311. The respective descriptions are incorporated by reference and are part of the disclosure.

In another embodiment, the pharmaceutical formulation of the present invention contains one or both of components (A) and (B) not only in sustained-release form, but also in non-sustained-release form. By combination with the immediately released form, a high initial dose can be achieved for the rapid onset of the beneficial effect. The slow release from the sustained-release form then prevents the beneficial effect from diminishing. Such a pharmaceutical formulation is particularly useful for the treatment of acute health problems.

This may be achieved, for example, by a pharmaceutical formulation having at least one immediate-release coating comprising at least one of the components (A) and (B) to provide for rapid onset of the beneficial effect after administration to the patient.

Pharmaceutical Methods:

Measurements of Food Ingestion (Behavioural Model)

Male W rats (200-270 g) from Harlan, S. A. are used. The animals are acclimatized to the housings during at least 5 days prior to being subjected to any treatment. During this period, the animals are housed (in groups of five) in translucent cages and have free access to water and food. The animals are housed in individual cages at least 24 hours prior to starting the treatment.

The effect of the active substance combination and of each one of the components (A) and (B) on food ingestion in rats in fasting conditions is then determined as follows:

The rats are kept in fasting conditions for 23 hours in their individual cages. After this period, the rats are distributed in four groups. To three of these groups doses of the component (A) (with vehicle), of the component (B) (with vehicle) and of the active substance combination (vehicle) have been administered respectively by the intraperitoneal route. To the fourth group just vehicle has been administered in the same way.

Immediately after this, the rat is left in the cage with pre-weighed food and the accumulated food intake is measured after 1, 2, 4 and 6 hours.

This food ingestion measuring method is also described in publications of Kask et al., European Journal of Pharmacology 414 (2001), 215-224, and Turnbull et al., Diabetes, Vol. 51, August, 2002. The respective bibliographic descriptions are incorporated as a reference and they form part of the disclosure.

Pharmacological Methods:

Neuropeptide Y5 Receptor Binding Studies:

Method (I)

The experimental protocol follows the method by M. Gobbi et al. as decribed in M. Gobbi, T. Mennini, A. Vezzani: Autoradiographic Reevaluation of the Binding Properties of [¹²⁵I][Leu³¹, Pro³⁴] Peptide YY and [¹²⁵I] Peptide YY_3-36to Neuropeptide Y Receptor Subtypes in Rat Forebrain, The Journal of Neurochemistry, 1999, 72, 1663-1670, which is hereby incorporated by reference and is part of the disclosure, with modifications. Male Wistar rats are sacrificed by decapitation, their brains are rapidly removed and the cortex is dissected. Homogenization is performed in cold conditions in the buffer: 120 mM NaCl, 4.7 mM KCl, 2.2 mM CaCl₂, 1.2 mM KH₂PO₄, 1.2 mM MgSO₄, 25 mM NaHCO₃, 5.5 mM glucose, pH 7.4, by means of a Ultra-Turrax homogenizer for 15 seconds at 13,500 rpm. The ratio between fresh tissue weight and buffer volume is of twenty times. The membrane is centrifuged for 10 min at 48,000 g. The supernatant is discarded and the pellet is washed, resuspended and recentrifuged three more times. The final membrane resuspension is performed in the buffer: 120 mM NaCl, 4.7 mM KCl, 2.2 mM CaCl₂, 1.2 mM KH₂PO₄, 1.2 mM MgSO₄, 25 mM NaHCO₃, 5.5 mM glucose, 0.1% BSA, 0.05% bacitracin, pH 7.4, at a 20 ml/g ratio of fresh tissue. The radioligand used is [¹²⁵I]-PYY_3-36at the concentration of 28 pM. Incubation volume: 500 μl. A 1 μM concentration of BIBP 3226 is added to the incubation medium in order to saturate receptor Y₁. Incubation is performed at 25° C. for 120 minutes and ended by rapid filtration in a Harvester Brandel Cell through fiber glass filters of the brand Schleicher & Schuell G F 3362 pretreated with a 0.5% polyethylenimine solution. The filters are cold-washed three times with two milliliters of the same buffer used in homogenization. The filters are transferred to vials and 5 ml of Ecoscint H liquid scintillation cocktail are added to each vial. The vials are allowed to reach steady state for a few hours before counting in a Wallac Winspectral 1414 scintillation counter. Non-specific binding is determined in the presence of 1 μM of pNPY (Neuropeptide Y of porcine origin). The assays are performed in triplicate.

Method (II)

The experimental protocol follows the method described by Y. Hu, B. T. Bloomquist et al. in Y. Hu, B. T. Bloomquist et al., The Journal of Biological Chemistry, 1996, 271, 26315-26319 with modifications. Cells C6 were transfected with the rat Y5 receptor. The cells were grown under standard culture conditions in 150 cm²dishes and they were harvested using a rubber scraper and 10 ml PBS. The cells from five dishes were collected and centrifuged 2.500 g for 5 min. The pellet was washed by resuspending in 3 ml buffer (Tris-HCl 10 mM, pH 7.4), homogenized using a Potter S homogenizer, 10 strokes at 600 rpm and centrifuged in cold conditions at 48.000 g for 20 min (4° C.). The resulting pellet was resuspended in cold 8 ml membrane buffer (Tris-HCl 25 mM, NaCl 120 mM, KCl 5 mM, KH₂PO₄1, 2 mM, CaCl₂2, 5 mM, MgSO₄1, 2 mM, BSA 0.15 mg/ml, Bacitracine 0.5 mg/ml, pH 7, 4) and rehomogenized using the Potter S, 10 strokes at 600 rpm. The protein concentration of the used membrane in the incubation was approximately 40 μg/ml. The radioligand is [¹²⁵I]-PYY in a concentration of 100 pM. The incubation volume is 200 μl. The incubation occurs at 25° C. for 2 h and is stopped by rapid filtration in a in a Harvester Brandell Cell through fiber glass filters of the brand Schleicher & Schuell G F 3362 pretreated for two hours with 0.5% polyethyleneimine solution. Filters are cold-washed two times with 5 ml cold filtration buffer: Tris-HCl 25 mM, NaCl 120 mM, KCl 5 mM, KH₂PO₄1.2 mM, CaCl₂2.5 mM, MgSO₄1.2 mM, pH 7.4. The filters were transferred into vials and 5 ml of Ecoscint H liquid scintillation cocktail are added to each vial. The vials are allowed to reach steady state for a few hours before counting with a Wallac Winspectral 1414 scintillation counter. Non-specific binding is determined in the presence of 1 μM of NPY. All binding assays were done in triplicate.

Method (III)

Binding to Neuropeptide Y₂

The experimental protocol follows the method by Y. Dumont et al. as described in Y. Dumont, A. Fournier, S. St-Pierre, R. Quirion: Characterization of Neuropeptide Y Binding Sites in Rat Brain Preparations Using [¹²⁵I][Leu³¹, Pro³⁴]Peptide YY and [¹²⁵I]Peptide YY_3-36as Selective Y1 and Y2 Radioligands, The Journal of Pharmacology and Experimental Therapeutics, 1995, 272, 673-680, with slight modifications. Male Wistar rats are sacrificed by decapitation, their brains are rapidly removed and the hypoccampus is dissected. Homogenization is performed in cold conditions in the buffer: 120 mM NaCl, 4.7 mM KCl, 2.2 mM CaCl₂, 1.2 mM KH₂PO₄, 1.2 mM MgSO₄, 25 mM NaHCO₃, 5.5 mM glucose, pH 7.4, by means of a Ultra-Turrax homogenizer for 15 seconds at 13,500 rpm. The ratio between fresh tissue weight and buffer volume is of ten times. The membrane is centrifuged for 10 min at 48,000 g. The supernatant is discarded and the pellet is washed, resuspended and recentrifuged two more times. The final membrane resuspension is performed in the buffer: 120 mM NaCl, 4.7 mM KCl, 2.2 mM CaCl₂, 1.2 mM KH₂PO₄, 1.2 mM MgSO₄, 25 mM NaHCO₃, 5.5 mM glucose, 0.1% BSA, 0.05% bacitracin, pH 7.4, at a 90 ml/g ratio of fresh issue. The radioligand used is [¹²⁵I]-PYY_3-36at the concentration of 28 pM. Incubation volume: 500 μl. Incubation is performed at 25° C. for 150 minutes and ended by rapid filtration in a Harvester Brandel Cell through fiber glass filters of the brand Schleicher & Schuell G F 3362 pretreated with a 0.5% polyethylenimine solution. The filters are cold-washed three times with three milliliters of the same buffer used in homogenization. The filters are transferred to vials and 5 ml of Ecoscint H liquid scintillation cocktail are added to each vial. The vials are allowed to reach steady state for a few hours before counting in a Wallac Winspectral 1414 scintillation counter. Non-specific binding is determined in the presence of 1 μM of pNPY (Neuropeptide Y of porcine origin). The assays are performed in triplicate.

Binding to the 5HT₆Serotonin Receptor

HEK-293 cell membranes expressing the recombinant human 5HT₆receptor were supplied by Receptor Biology. The receptor concentration in said membranes is 2.18 pmol/mg of protein and the protein concentration is 9.17 mg/ml. The experimental protocol follows the method of B. L. Roth et al. [B. L. Roth, S. C. Craigo, M. S. Choudhary, A. Uluer, F. J. Monsma, Y. Shen, H. Y. Meltzer, D. R. Sibley: Binding of Typical and Atypical Antipshychotic Agents to 5-Hydroxytryptamine-6 and Hydroxytryptamine-7 Receptors. The Journal of Pharmacology and Experimental Therapeutics, 1994, 268, 1403], with following slight modifications. The respective part of the literature descriptions is incorporated here by reference and form part of the disclosure. The commercial membrane is diluted (1:40 dilution) with the binding buffer: 50 mM Tris-HCl, 10 mM MgCl₂, 0.5 mM EDTA (pH 7.4). The radioligand used is [³H]-LSD at a concentration of 2.7 nM, the final volume being 200 μl. Incubation begins by adding 100 μl of the membrane suspension (≈22.9 μg of membrane protein), and is prolonged for 60 minutes at a temperature of 37° C. Incubation ends by quick filtration in a Harvester Brandel Cell through fiberglass filters of the Schleicher & Schuell G F 3362 trademark, pretreated with a 0.5% polyethyleneimine solution. The filters are washed three times with three milliliters of 50 mM Tris HCl buffer, pH 7.4. The filters are transferred to vials and 5 ml of Ecoscint H. liquid scintillation cocktail are added to each vial. The vials are left to equilibrate for several hours prior to their counting in a 1414 Wallac Winspectral scintillation counter. The non-specific binding is determined in the presence of 100 μM of serotonin. The assays are carried out in triplicate. The inhibition constants (K_i, nM) are calculated by non-linear regression analysis using the EBDA/LIGAND program [Munson and Rodbard, Analytical Biochemistry, 1980, 107, 220], which is incorporated here by reference and form part of the disclosure.

The present invention is illustrated below by the aid of examples. These illustrations are given solely by way of example and do not limit the general spirit of the present invention.

EXAMPLES

Preparation of the Compounds of General Formula (Ia):

The intermediates of general formulas (IVa) and (Va) were prepared by means of conventional methods known to those skilled in the art. The preparation of some of the intermediates of general formulas (IVa) and (Va) is shown below:

Example Aa

Synthesis of a Compound of General Formula (IVa)

2-chloro-N-(4-phenoxyphenyl)acetamide

embedded image

To a solution of 4-phenoxyaniline (1.85 g, 10 mmoles) and triethylamine (2.07 ml, 15 mmoles) in 25 ml dry dichloromethane, is added drop by drop to a solution of chloroacetyl chloride (1.18 g, 10.5 mmoles) in 10 ml dry dichloromethane. The resulting reaction mixture is stirred for 1 hour at room temperature. Afterwards said reaction mixture is washed with 2×30 ml HCl (2 N) 1×30 ml water, dried over sodium sulfate and evaporated. 2.48 g. (Yield 95%) of 2-chloro-N-(4-phenoxyphenyl)acetamide were obtained.

IR cm⁻¹(KBr):3270, 1660, 1506, 1490, 1236, 843, 752, 691.

Example Ba

Synthesis of a Compound of General Formula (Va)

Preparation of 6-Chloro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride

embedded image

a) 1-(tert-Butyloxycarbonyl)-4-[4-chloro-(2-hydroxymethylphenylamine)]piperidine

A solution of 1-(tert-butyloxycarbonyl)-4-piperidinone (20 g, 0.10 mol), 2-amino-5-chlorobenzylic alcohol (17.34 g, 0.11 mol) and acetic acid (14 mL, 0.22 mol) in dry toluene (500 mL) was heated at reflux temperature, with water elimination by means of azeotrope distillation with Dean-Stark, for 6 hours. The mixture was then cooled and vacuum concentrated up to half volume. NaBH₃CN (20 g, 0.32 mol) and dry THF (300 mL) were added to the resulting solution. Acetic acid (10 mL, 0.17 mol) was then dripped for one hour. The reaction was stirred at room temperature for 24 hours. The mixture was vacuum concentrated and the residue was dissolved in ethyl acetate (750 mL), washed with a NaHCO₃-saturated solution (4×250 mL) and a NaCl-saturated solution (250 mL), dried and evaporated to dryness. The residue was purified by means of flash chromatography eluting with a mixture of ethyl acetate: petroleum ether (1:3). The desired product was thus obtained as an oil (32.7 g, 96%). ¹H NMR (CDCl₃): 1.32 (d, J=11.2 Hz, 2H), 1.41 (s, 9H), 1.92 (d, J=11.2 Hz, 2H), 2.92 (t, J=12.0 Hz, 1H), 3.10 (s, 1H), 3.37 (m, 1H), 3.88 (d, J=13.7 Hz, 2H), 4.49 (s, 2H), 4.75 (s, 1H), 6.52 (d, J=8.6 Hz, 1H), 6.96 (s, 1H), 7.07 (d, J=8.6 Hz, 1H).

b.) 1-(1-tert-Butyloxycarbonyl-4-piperidinyl)-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one

N,N-diisopropylethylamine (DIEA) (43 mL, 0.25 mol) and triphosgene (8.65 g, 29.2 mmol) were added to a solution of 1-(tert-Butyloxycarbonyl)-4-[(4-chloro-(2-hydroxymethyl) phenyl-amino)]piperidine (27.0 g, 79 mmol) in dry THF (250 mL) cooled at 0° C. The reaction was stirred at 0° C. for 1 h and at room temperature for 72 h. Ethyl ether was added and the mixture was cooled at 0° C. for 3 h and the DIEA hydrochloride was then filtered. The filtered solution was evaporated to dryness and the residue was dissolved in ethyl acetate (750 mL), washed with 5% solution of critic acid (2×500 mL), water (250 mL) and NaHCO₃-saturated solution (2×500 mL). The ethyl acetate solution was dried (MgSO₄), filtered and evaporated under reduced pressure. The residue was brought to a boil with ethyl ether until the whole solid was dissolved and then cooled overnight to yield the desired compound in crystalline form (28.9 g, 67%).

Melting point: 177-179° C.

¹H NMR (CDCl₃): 1.46 (s, 9H), 1.79 (d, J=10.1 Hz, 1H), 2.54 (m, 2H), 2.78 (m, 2H), 3.96 (m, 1H), 4.28 (m, 2H), 5.02 (s, 2H), 6.98 (d, J=8.7 Hz, 1H) 7.13 (d, J=2.4 Hz, 1H), 7.28 (dd, J=8.7 Hz, J=2.4 Hz, 1H).

c.) 6-chloro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride

A solution of 1-[(1-tert-Butyloxycarbonyl)-4-piperidinyl]-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one (24 g, 65 mmol) in ethyl acetate (500 mL) was cooled at 0° C. Afterwards a 5 M solution of hydrogen chloride in ethyl ether (500 mL) was added and the resulting mixture was stirred at 0° C. for 4 h. The precipitate formed was collected by filtration, washed with ether and vacuum dried to yield the desired product as a solid (16.95 g, 97%).

Melting point: 254-257° C.

¹H NMR (CD₃OD): 2.13 (d, J=12.2 Hz, 2H), 2.88 (m, 2H), 3.20 (m, 2H), 3.53 (d, J=12.8 Hz, 2H), 4.24 (m, 1H), 5.16 (s, 2H), 7.31 (m, 2H), 7.41 (dd, J=8.8 Hz, J=2.6 Hz, 1H).

Several substituted 3,1-benzoxazin-2-one compounds were prepared via the respectively substituted benzyl alcohols obtained by reduction of the corresponding substituted anthranilic acids with lithium aluminium hydride and other reducing agents known and used in the state of the art (see scheme 2), e.g. por ejemplo 6-methyl-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 7-methyl-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 8-methyl-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 5-methoxy-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 6-fluoro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 8-methoxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 5-methyl-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 7-fluoro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 5-fluoro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 6-methoxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 5-chloro-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 7-chloro-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 8-chloro-1 piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one and others. The removal of the protecting group of the corresponding 8-methoxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one 6-methoxy-1-(piperidinylyl, 4-dihydro-2H-3,1-benzoxazin-2-one and 5-methoxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one compounds according to conventional methods, e.g. BBr₃in an inert organic solvent yields the respective 8-hydroxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 6-hydroxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one and 5-hydroxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one compounds. The unsubstituted benzoxazin-2-one 1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one is prepared according the method described in J. Med. Chem. 1995, 38, 4634 and J. Med. Chem. 1998, 41, 2146, which are hereby incorporated by reference and form part of the disclosure.

Reduction of the Substituted Anthranilics:

The reduction of the substituted anthranilic acids was performed by conventional methods known in the state of the art, e.g. by the use of LiAlH₄as reducing agent in anhydrous THF under an inert-gas atmosphere, e.g. argon or nitrogen. The process is very efficient and in most cases the corresponding 2-aminobenzylalcohols are obtained in very good yields.

General Method for the Reduction of Substituted Anthranilic Acids:

To a three neck flask, equipped with a mechanical stirrer and an inlet for gaseous nitrogen, 100 mL anhydrous THF and 116.6 mmoles of LiAlH₄were given and the resulting suspension cooled to 0° C. After the addition of 58.3 mmoles of the corresponding substituted anthranilic acid in 150 mL anhydrous THF, the resulting reaction mixture is warmed to room temperature and stirred or about an hour. Under cooling to 0° C. 4.7 mL water, 4.7 mL NaOH 15 wt.-%, and finally 14 mL water are carefully added to the mixture. The resulting suspension is filtered and washed with ethylacetate.

The organic phase is washed with water, dried and evaporated. In some cases the resulting product may be used without further purification.

Example 1a
Preparation of 1-{1-[N-(9-oxo-9H-fluoren-2-yl)aminocarbonylmethyl]-4-(piperidinyl)}-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride

A mixture of 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazinone hydrochloride (2.68 g, 10 mmol), N-(9-oxo-9H-fluoren-2-yl)-2-chloroacetamide (2.99 g, 11 mmol) and K₂CO₃(5.53 g, 40 mmol) in DMF (40 mL) was stirred overnight at room temperature. H₂O (100 mL) was then added and the precipitate formed was collected by filtration. The solid was dissolved in hot ethyl acetate, washed with water, decanted, dried and evaporated to dryness. The residue dissolved in EtOH was brought to pH=3 with a 1M solution of hydrogen chloride in EtOH and filtered to yield the desired hydrochloride in crystalline form (3.73 g, 74%).

Example 104a
Preparation of N-[4-chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(6-chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl]-piperidin-1-yl}-acetamide hydrochloride

embedded image

A mixture of 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazinone hydrochloride (161 mg, 0,60 mmol), 2-(2-chloroacetamide)-2′,5-dichlorobenzophenone (226 mg, 0,66 mmol) and K₂CO₃(330 mg, 2.40 mmol) in DMF (10 mL) is stirred at room temperature overnight. Afterwards H₂O (15 mL) is added and the formed precipitate harvested by filtration. The solid is dissolved in ethyl acetate, washed with water, decanted, dryed and evaporated. The residue dissolved in ethanol and upon addition of 0.22 ml of a 2.8 M solution of hydrochloric acid in ethanol abs. the hydrochloride salt is crystallized, which was filtered and dryed. 209 mg of a white solid were obtained.

Yield 61%.

IR (cm⁻¹) KBr: 3398, 2860, 1702, 1493, 1295, 1246, 1202, 1042, 946, 758.

¹H-NMR: 1.9 (d, J=12.9 Hz, 2H) 2.9 (m, 2H) 3.2 (m, 2H) 3.5 (d, J=11.2 Hz, 2H) 4.0 (s, 2H) 4.2 (m, 1H) 5.0 (s, 2H) 7.3 (m, 4H) 7.4 (m, 1H) 7.5 (m, 2H) 7.5 (m, 1H) 7.6 (dd, J=8.5, 2.4 Hz, 1H) 7.8 (d, J=8.5 Hz, 1H) 10.2 (s, 1H) 10.9 (s, 1H) (DMSO-d6).

Melting point: 201-204° C.

The melting point data of some of the benzoxazinone-derived compounds of general formula (Ia) prepared according to the analog method described in examples 1 and 104 are shown in the following table.

In the compounds according to examples 1-100 three of the substitutents R^1a, R^2a, R^3aand R^4aas well as the substituents R⁵to R⁹all represent H. Thus, the general formula (Ia) may be written in the simplified form (Ia) given below, wherein R^xindicates the respective substituents R^1a-R^4a.

(Ia)

MpExR^xAR¹⁰R¹¹Salt(° C.)IR cm⁻¹¹H-NMR (300 MHz), δ (solvent)1HCH₂H embedded image

HCl276-2803241, 1696, 1608, 1560, 1463, 1391, 1293, 1259, 1206, 739.2.00(d, J=12.6Hz, 2H), 2.90(m, J=12.6Hz, 2H), 3.43(m, 2H), 3.66(d, J=9.7Hz, 2H), 4.21(s, 2H), 4.28(m, 1H), 5.16(s, 2H), 7.13(m, 1H), 7.34(m, 4H), 7.59(d, J=7.0Hz, 2H), 7.76(m, 3H), 8.00(s, 1H), 10.26(s, 1H), 11.36(s, 1H). #(DMSO-d₆)2HCH₂H embedded image

—192-1941704, 1611, 1511, 1293, 1205, 768.1.74(d, J=10.8Hz, 2H), 2.38(m, 2H), 2.62(m, 2H), 2.99(d, J=11.1Hz, 2H), 3.24(s, 2H), 3.87(m, 1H), 5.12(s, 2H), 7.09(t, J=7.2Hz, 1H), 7.27(d, J=7.7Hz, 2H), 7.37(t, J=7.5Hz, 2H), 7.59(m, 4H), 7.68(d, J=7.5Hz, 1H), 8.07(s, 1H), #10.22(s, 1H). (DMSO-d₆)3HCH₂H embedded image

HCl>2753433, 1705, 1609, 1557, 1467, 1451, 1297, 1253, 1111, 7692.02(d, J=12.6Hz, 2H), 2.91(m, J=12.6Hz, 2H), 3.43(m, 2H), 3.67(d, J=9.9Hz, 2H), 4.26(m, 3H), 5.16(s, 2H), 7.13(m, 1H), 7.30(d, J=7.5Hz, 1H), 7.40(m, 3H), 7.64(m, 5H), 8.06(s, 1H), 10.29(s, 1H), 11.46(s, 1H). (DMSO-d₆)4HCH₂H embedded image

—133-1373630, 3449, 3249, 1682, 1600, 1516, 1498, 1316, 1282, 1045, 757, 6971.73(d, J=11.7Hz, 2H), 2.36(m, J=11.2Hz, 2H), 2.61(m, J=11.7Hz, 2H), 2.98(d, J=10.8Hz, 2H), 3.22(s, 2H), 3.87(m, J=11.7Hz, 1H), 5.11(s, 2H), 7.09(t, J=7.3Hz, 1H), 7.27(d, J=7.3Hz, #2H), 7.36(t, J=7.7Hz, 1H), 7.54(t, J=7.3Hz, 2H), 7.69(m, 5H), 7.83(s, 1H), 10.18(s, 1H). (DMSO-d₆)5HCH₂H embedded image

HCl238-2433457, 1685, 1599, 1542, 1401, 1280, 1034, 7002.00(d, J=11.9Hz, 2H), 2.91(m, J=12.6Hz, 2H), 3.41(m, 2H), 3.65(d, J=11.2Hz, 2H), 4.26(m, 3H), 5.16(s, 2H), 7.12(m, 1H), 7.30(d, J=7.5Hz, 1H), 7.39(d, J=3.8Hz, 2H), 7.54(m, 2H), 7.68(m, 3H), 7.81(m, 4H), 10.31(s, 1H), 11.51(s, #1H). (DMSO-d₆)6HCH₂H embedded image

HCl260-2643400, 1710, 1671, 1592, 1549, 1391, 1260, 1204, 1043, 7701.98(m, 4H), 2.52(m, 2H), 2.91(m, 4H), 3.41(m, 2H), 3.64(m, J=10.4Hz, 2H), 4.25(m, 3H), 5.16(s, 2H), 7.14(m, 1H), 7.30(d, J=7.3Hz, 1H), 7.40(m, 2H), 7.58(m, 2H), 7.86(d, J=8.6Hz, 1H), 10.22(s, 1H), 11.15(s, 1H). (DMSO-d₆)7HCH₂H embedded image

HCl270-2731710, 1698, 1608, 1541, 1466, 1390, 1292, 1263, 1201, 7372.03(d, J=12.1Hz, 2H), 2.90(m, J=11.2Hz, 2H), 3.49(m, 2H), 3.70(d, J=11.2Hz, 2H), 4.29(m, 1H), 4.40(s, 2H), 5.16(s, 2H), 7.14(m, 1H), 7.30(d, J=7.3Hz, 1H), 7.42(m, 4H), 7.61(m, 4H), 7.82(d, J=7.1Hz, 1H), 10.29(s, #1H), 10.96(s, 1H). (DMSO-d₆)8HCH₂H embedded image

HCl214-2183447, 1686, 1609, 1592, 1298, 1208, 1043, 7212.00(d, J=12.1Hz, 2H), 2.89(m, J=11.2Hz, 2H), 3.33(m, 2H), 3.64(d, J=10.6Hz, 2H), 4.17(s, 2H), 4.26(m, 1H), 5.16(s, 2H), 7.13(m, 1H), 7.34(m, 3H), 7.54(m, 4H), 7.71(m, 3H), 7.86(d, J=8.1Hz, 1H), 8.08(s, 1H), 10.17(s, 1H), 10.99(s, #1H). (DMSO-d₆)9HCH₂H embedded image

—206-2093327, 1720, 1696, 1592, 1514, 1285, 1206, 1045, 768, 7531.73(d, J=11.5Hz, 2H), 2.36(m, J=11.0Hz, 2H), 2.59(m, 4H), 2.97(d, J=10.8Hz, 2H), 3.05(m, 2H), 3.21(s, 2H), 3.86(m, 1H), 5.11(s, 2H), 7.09(t, J=7.2Hz, 1H), 7.27(d, J=7.5Hz, 2H), 7.36(m, 1H), 7.58(s, 2H), 7.95(s, 1H), 10.14(s, #1H). (DMSO-d₆)10HCH₂H embedded image

HCl272-2773463, 1709, 1595, 1555, 1390, 1284, 1256, 1204, 1042, 7712.00(d, J=12.4Hz, 2H), 2.60(m, 2H), 2.90(m, J=11.5Hz, 2H), 3.07(m, 2H), 3.41(m, 2H), 3.63(m, 2H), 4.25(m, 3H), 5.16(s, 2H), 7.12(m, 1H), 7.30(d, J=7.1Hz, 1H), 7.38(d, J=3.7Hz, 2H), 7.63(s, 2H), 7.94(s, 1H), 10.28(s, 1H), #11.48(s, 1H). (DMSO-d₆)11HCH₂H embedded image

HCl230-2312949, 1701, 1607, 1558, 1496, 1394, 1292, 1206, 1042, 7711.99(m, 4H), 2.83(m, 6H), 3.43(m, 2H), 3.63(d, J=10.1Hz, 2H), 4.17(s, 2H), 4.29(m, 1H), 5.15(s, 2H), 7.15(m, 2H), 7.30(d, J=7.5Hz, 1H), 7.37(m, 3H), 7.54(s, 1H), 10.24(s, 1H), 10.95(s, 1H). (DMSO-d₆)12HCH₂H embedded image

HCl182-1873448, 1592, 1560, 1432, 1400, 1299, 1209, 1043, 770, 7212.02(d, J=12.8Hz, 2H), 2.91(m, J=10.6Hz, 2H), 3.45(m, 2H), 3.68(d, J=12.1Hz, 2H), 3.99(s, 3H), 4.29(s, 2H), 4.42(m, 1H), 5.16(s, 2H), 7.10-8.40(10H), 10.18(s, 1H), 11.18(s, 1H). (DMSO-d₆)13HCH₂H embedded image

HCl256-2603422, 1701, 1609, 1550, 1393, 1292, 1260, 1205, 10431.29(m, 5H), 1.72(m, 5H), 2.00(d, J=13.2Hz, 2H), 2.45(m, 1H), 2.91(m, J=11.7Hz, 2H), 3.39(m, 2H), 3.64(m, 2H), 4.16(s, 2H), 4.30(m, 1H), 5.15(s, 2H), 7.13(m, 3H), 7.29(d, J=7.3Hz, 1H), 7.38(m, #2H), 7.54(d, J=8.2Hz, 2H), 10.28(s, 1H), 10.96(s, 1H). (DMSO-d₆)14HCH₂ embedded image

HCl198-2033427, 1677, 1497, 1390, 1297, 1205, 1039, 7531.91(m, 4H), 2.73(t, J=6.5Hz, 2H), 2.93(m, J=11.4Hz, 2H), 3.40(m, 2H), 3.66(m, 4H), 4.28(m, 1H), 4.52(m, 2H), 5.15(s, 2H), 7.25(m, 8H), 10.18(s, 1H). (DMSO-d₆)15HCHC₆H₅H embedded image

HCl247-2493435, 1709, 1691, 1608, 1561, 1298, 766, 7431.91(d, J=12.0Hz, 1H), 2.06(d, J=12.8Hz, 1H), 2.94(m, 3H), 3.23(m, 1H), 3.45(m, 1H), 3.78(m, 1H), 4.32(m, 1H), 5.14(s, 2H), 5.49(s, 1H), 7.12(m, 1H), 7.28(d, J=7.3Hz, 1H), 7.38(m, 3H), 7.59(m, 8H), 7.80(m, 2H), 8.07(s, 1H), #10.73(s, 1H), 12.16(s, 1H). (DMSO-d₆)16HCHCH₃H embedded image

HCl242-252—1.62(d, J=6.4Hz, 3H), 2.05(d, J=13.0Hz, 2H), 2.91(m, 2H), 3.57(m, 2H), 4.35(m, 2H), 5.16(s, 2H), 7.12(m, 1H), 7.38(m, 4H), 7.65(m, 5H), 8.14(s, 1H), 10.35(s, 1H), 11.77(s, 1H). (DMSO-d₆)17HCH₂H embedded image

—212-2143298, 2975, 1713, 1684, 1531, 1492, 1208, 1040, 768, 7471.29(t, J=7.0Hz, 3H), 1.77(d, J=10.6Hz, 2H), 2.39(m, 2H), 2.66(m, 2H), 3.04(d, J=11.6Hz, 2H), 3.20(s, 2H), 3.90(m, 1H), 3.04(d, J=11.0Hz, 2H), 3.20(s, 2H), 3.90(m, 1H), 4.41(q, J=7.0Hz, 2H), 5.13(s, 2H), 7.10(t, #J=7.5Hz, 1H), 7.17(t, J=7.5Hz, 1H), 7.29(m, 2H), 7.41(m, 2H), 7.58(m, 3H), 8.07(d, J=7.5Hz, 1H), 8.42(s, 1H), 9.76(s, 1H). (DMSO-d₆)18HCH₂H embedded image

HCl246-2503248, 2966, 1683, 1608, 1493, 1299, 1226, 1040, 771, 7451.28(t, J=6.8Hz, 3H), 2.00(d, J=11.9Hz, 3H), 2.93(m, J=11.5Hz, 2H), 3.43(m, 2H), 3.69(d, J=10.3Hz, 2H), 4.28(m, 3H), 4.41(q, J=6.8Hz, 2H), 5.16(s, 2H), 7.15(m, 2H), 7.30(d, J=7.3Hz, 1H), 7.41(m, 3H), 7.62(m, 3H), #8.05(d, J=7.9Hz, 1H), 8.47(s, 1H), 10.33(s, 1H), 11.15(s, 1H). (DMSO-d₆)196-CH₃CH₂H embedded image

—237-2391706, 1611, 1596, 1508, 1292, 12141.72(d, J=11.7Hz, 2H), 2.25(s, 3H), 2.38(m, 2H), 2.62(m, 2H), 2.99(d, J=11.0Hz, 2H), 3.23(s, 2H), 3.85(m, 1H), 5.06(s, 2H), 7.06(s, 1H), 7.15(s, 2H), 7.37(t, J=7.3Hz, 1H), 7.58(m, 4H), 7.67(d, J=7.3Hz, 1H), 8.06(s, 1H), 10.17(s, 1H). (DMSO-d₆)206-CH₃CH₂H embedded image

HCl250-2523411, 1707, 1683, 1608, 1551, 1296, 1252, 11111.99(d, J=13.4Hz, 2H), 2.27(s, 3H), 2.89(m, 2H), 3.42(m, 2H), 3.67(m, 2H), 4.28(m, 3H), 5.11(s, 2H), 7.09(m, 1H), 7.18(d, J=8.4Hz, 1H), 7.28(d, J=8.4Hz, 1H), 7.39(t, J=7.3Hz, 1H), 7.61(m, 5H), 8.07(s, #1H), 10.35(s, 1H), 11.65(s, 1H). #(DMSO-d₆)216-CH₃CH₂H embedded image

HCl247-2521683, 1492, 1460, 1299, 12251.29(t, J=7.0Hz, 3H), 2.00(t, J=11.9Hz, 3H), 2.27(s, 3H), 2.91(m, J=11.2Hz, 2H), 3.42(m, 2H), 3.68(d, J=10.4Hz, 2H), 4.22(m, 3H), 4.42(q, J=7.1Hz, 2H), 5.11(s, 2H), 7.10(m, 1H), 7.18(m, 2H), 7.30(d, J=8.4Hz, 1H), 7.45(m, 1H), 7.60(m, 3H), 8.05(d, J=7.9Hz, #1H), 8.46(s, 1H), 10.29(s, 1H), 11.09(s, 1H). (DMSO-d₆)226-CH₃CH₂H embedded image

—155-1572923, 2849, 1711, 1519, 1294, 1217, 10461.29(m, 5H), 1.72(m, 7H), 2.25(m, 3H), 2.36(m, 3H), 2.58(m, 2H), 2.95(d, J=10.8Hz, 2H), 3.12(s, 2H), 3.83(m, 1H), 5.06(s, 2H), 7.06(s, 1H), 7.13(m, 4H), 7.51(d, J=8.2Hz, 2H), 9.64(s, 1H). (DMSO-d₆)236-CH₃CH₂H embedded image

HCl242-2463428, 2925, 1711, 1691, 1507, 1293, 1218, 1039, 827, 7671.27(m, 5H), 1.71(m, 5H), 1.95(d, J=12.0Hz, 2H), 2.26(s, 3H), 2.43(m, 1H), 2.89(m, J=11.5Hz, 2H), 3.41(m, 2H), 3.57(m, 2H), 4.17(m, 2H), 4.26(m, 1H), 5.10(s, 2H), 7.09(s, 1H), 7.17(d, J=8.6Hz, 2H), #7.18(d, J=8.6Hz, 1H), 7.29(d, J=8.4Hz, 2H), 7.55(d, J=8.4Hz, 2H), 10.32(s, 1H), 11.11(s, 1H). (DMSO-d₆)246-CH₃CH₂H embedded image

HCl240-2443432, 2995, 1702, 1598, 1539, 1314, 1281, 1039, 7001.99(d, J=11.3Hz, 2H), 2.27(s, 3H), 2.90(m, 2H), 3.42(m, 2H), 3.65(m, 2H), 4.27(m, 3H), 5.11(s, 2H), 7.10(s, 1H), 7.18(d, J=8.2Hz, 1H), 7.29(d, J=8.2Hz, 2H), 7.55(t, J=7.3Hz, 2H), 7.66(m, 3H), 7.77(d, J=8.8Hz, 2H), #7.86(d, J=8.4Hz, 2H), 10.35(s, 1H), 11.61(s, 1H). (DMSO-d₆)25HCH₂H embedded image

HCl191-1933425, 3048, 1709, 1686, 1607, 1496, 1248, 1040, 771, 7502.03(d, J=12.4Hz, 2H), 2.93(m, J=11.2Hz, 2H), 3.42(m, 2H), 3.69(d, J=11.2Hz, 2H), 3.86(s, 3H), 4.22(s, 2H), 4.32(m, 1H), 5.17(s, 2H), 7.13(m, 1H), 7.20(d, J=7.3Hz, 1H), 7.30(d, J=7.3Hz, 1H), 7.43(m, 3H), 7.58(d, J=10.2Hz, #2H), 7.65(d, J=8.6Hz, 1H), 8.06(d, J=7.7Hz, 1H), 8.47(s, 1H), 10.29(s, 1H), 11.09(s, 1H). (DMSO-d₆)26HCH₂H embedded image

HCl280-2823466, 3078, 1679, 1591, 1551, 1332, 1293, 1201, 917, 7252.03(d, J=12.1Hz, 2H), 2.92(m, J=11.4Hz, 2H), 3.43(m, 2H), 3.69(d, J=9.7Hz, 2H), 4.29(m, 3H), 5.16(s, 2H), 7.14(m, 1H), 7.14(m, 1H), 7.30(d, J=7.3Hz, 1H), 7.39(d, J=7.3Hz, 1H), 7.39(d, J=3.8Hz, 2H), 7.92(m, 2H), 8.08(d, J=8.2Hz, #1H), 8.21(m, 3H), 8.57(s, 1H), 10.30(s, 1H), 11.65(s, 1H). (DMSO-d₆)27HCH₂H embedded image

HCl254-2573432, 2980, 1714, 1689, 1508, 1492, 1258, 1204, 770, 7531.09(t, J=7.0Hz, 3H), 2.00(d, J=12.1Hz, 2H), 2.90(m, J=11.3Hz, 2H), 3.37(m, 2H), 3.63(m, 2H), 3.71(q, J=7.0Hz, 2H), 4.15(s, 2H), 4.29(m, 1H), 5.16(s, 2H), 6.84(m, 3H), 7.01(d, J=9.0Hz, 2H), 7.12(m, 1H), 7.20(m, 2H), #7.30(d, J=7.3Hz, 1H), 7.39(d, J=3.8Hz, 2H), 7.56(d, J=8.8Hz, 2H), 10.23(s, 1H), 10.92(s, 1H). (DMSO-d₆)286-CH₃CH₂H embedded image

HCl226-2302976, 1708, 1690, 1509, 1378, 1291, 1256, 1216, 1040, 7661.09(t, J=7.0Hz, 3H), 1.98(d, J=13.0Hz, 2H), 2.27(s, 3H), 2.88(m, J=11.3Hz, 2H), 3.41(m, 2H), 3.63(d, J=11.2Hz, 2H), 3.70(q, J=7.0Hz, 2H), 4.15(s, 2H), 4.26(m, 1H), 5.10(s, 1H), 6.84(m, 3H), 7.00(d, J=9.0Hz, #2H), 7.10(m, 1H), 7.19(m, 2H), 7.25(m, 2H), 7.57(d, J=8.8Hz, 2H), 10.24(s, 1H), 10.97(s, 1H). (DMSO-d₆)29HCH₂H embedded image

HCl242-2483044, 1703, 1686, 1506, 1487, 1392, 1226, 1040, 751, 6942.01(d, J=12.8Hz, 2H), 2.90(m, J=12.1Hz, 2H), 3.41(m, 2H), 3.63(m, 2H), 4.18(s, 2H), 4.29(m, 1H), 5.16(s, 2H), 6.96(m, 2H), 7.03(m, 2H), 7.12(m, 2H), 7.35(m, 5H), 7.67(d, J=8.8Hz, 2H), 10.26(s, 2H), 11.13(s, 1H). #(DMSO-d₆)30HCH₂H embedded image

HCl171-1733399, 2976, 1707, 1655, 1498, 1321, 1254, 1117, 7531.02(d, J=6.6Hz, 6H), 1.92(d, J=12.4Hz, 2H), 2.86(m, J=10.6Hz, 2H), 3.18(m, J=11.5Hz, 2H), 3.50(m, J=11.5Hz, 2H), 3.65(s, 2H), 4.14(m, 1H), 4.78(hp, J=6.6Hz, 1H), 5.14(s, 2H), 6.90(t, #J=7.2Hz, 1H), 7.12(m, 6H), 7.30(m, 6H), 8.61(s, 1H), 9.85(s, 1H). (DMSO-d₆)31HCH₂CH₂H embedded image

HCl240-242—2.03(d, J=12.5Hz, 2H), 2.85(m, J=12.3Hz, 2H), 3.04(m, 2H), 3.24(m, J=12.1Hz, 2H), 3.44(m, 2H), 3.60(d, J=11.4Hz, 2H), 4.29(m, 1H), 5.16(s, 2H), 7.13(m, 1H), 7.30(d, J=6.8Hz, 1H), 7.38(m, 3H), 7.62(m, 4H), 8.07(s, 1H), 10.15(s, 1H), 10.97(s, 1H). (DMSO-d₆)326-ClCH₂H embedded image

HCl265-2682970, 1712, 1691, 1492, 1376, 1294, 1201, 10431.28(t, J=7.0Hz, 3H), 2.01(d, J=12.4Hz, 2H), 2.90(m, 2H), 3.43(m, 2H), 3.68(m, 2H), 4.27(m, 3H), 4.41(q, J=7.0Hz, 2H), 5.16(s, 2H), 7.17(t, J=7.4Hz, 1H), 7.44(m, 4H), 7.61(m, 3H), 8.05(d, J=7.9Hz, 1H), 8.47(s, 1H), #10.33(s, 1H), 11.16(s, 1H). (DMSO-d₆)33HCH₂H embedded image

HCl272-2763454, 3057, 1701, 1610, 1552, 1492, 1394, 1292, 1254, 10241.99(d, J=12.4Hz, 2H), 2.90(m, J=11.5Hz, 2H), 3.40(m, 2H), 3.63(d, J=11.0Hz, 2H), 4.20(s, 2H), 4.28(m, 1H), 5.15(s, 2H), 7.12(m, 1H), 7.29(d, J=7.3Hz, 1H), 7.40(m, 4H), 7.69(d, J=8.8Hz, #2H), 10.28(s, 1H), 11.35(s, 1H). (DMSO-d₆)346-ClCH₂H embedded image

HCl279-2823026, 1713, 1698, 1612, 1553, 1491, 1294, 1253, 1199, 1042,1.99(d, J=12.7Hz, 2H), 2.86(m, 2H), 3.41(m, 2H), 3.62(d, J=10.4Hz, 2H), 4.18(s, 2H), 4.27(m, 1H), 5.16(s, 2H), 7.40(m, 5H), 7.68(d, J=8.8Hz, 2H), 10.26(s, 1H), 11.24(s, 1H). (DMSO-d₆)358-CH₃CH₂H embedded image

HCl233-2363410, 3014, 1701, 1609, 1561, 1450, 1371, 1285, 1237, 1109, 916, 768, 7312.13(d, J=12.8Hz, 2H), 2.40(s, 3H), 2.91(m, 2H), 3.42(m, 2H), 3.63(d, J=10.2Hz, 2H), 3.84(m, 1H), 4.25(s, 2H), 5.09(s, 2H), 7.10(m, 2H), 7.25(d, J=6.8Hz, 1H), #7.38(t, J=7.4Hz, 1H), 7.62(m, 5H), 8.07(s, 1H), 10.27(s, 1H), 11.75(s, 1H). (DMSO-d₆)366-ClCH₂H embedded image

HCl245-2493421, 1701, 1609, 1560, 1371, 1298, 12012.01(d, J=11.8Hz, 2H), 2.88(m, 2H), 3.42(m, 2H), 3.66(d, J=11.8Hz, 2H), 4.30(m, 3H), 5.16(s, 2H), 7.39(m, 4H), 7.60(m, 5H), 8.08(s, 1H), 10.39(s, 1H), 11.75(s, 1H). (DMSO-d₆)378-CH₃CH₂H embedded image

HCl207-2123435, 1679, 1390, 1263, 7742.13(d, J=13.3Hz, 2H), 2.40(s, 3H), 2.91(m, J=12.0Hz, 2H), 3.36(m, 2H), 3.63(d, J=10.8Hz, 2H), 3.83(m, 1H), 4.18(s, 2H), 5.09(s, 2H), 5.45(s, 1H), 5.86(broad, 1H), 7.11(m, 2H), 7.33(m, 3H), 7.55(m, 3H), 7.64(d, J=7.3Hz, 1H), 8.05(s, #1H), 10.19(s, 1H), 11.22(s, 1H). (DMSO-d₆)38HCH₂H embedded image

HCl>225 (dec.)3406, 3059, 1702, 1604, 1461, 1395, 1205, 1042, 769, 7392.01(d, J=12.8Hz, 2H), 2.91(m, 2H), 3.42(m, 2H), 3.66(d, J=9.6Hz, 2H), 4.22(s, 2H), 4.29(m, 1H), 5.16(s, 2H), 5.45(s, 1H), 5.92(broad, 1H), 7.12(m, 1H), 7.32(m, 5H), 7.55(d, #J=7.2Hz, 1H), 7.62(d, J=8.1Hz, 1H), 7.72(m, 2H), 7.96(s, 1H), 10.27(s, 1H), 11.17(s, 1H). (DMSO-d₆)396-ClCH₂H embedded image

HCl219-2223422, 3045, 1701, 1559, 1491, 1295, 1200, 10422.01(d, J=11.9Hz, 2H), 2.88(m, 2H), 3.39(m, 2H), 3.66(d, J=9.8Hz, 2H), 4.27(m, 3H), 5.16(s, 2H), 5.45(s, 1H), 5.86(broad, 1H), 7.36(m, 5H), 7.54(m, 3H), 7.64(d, J=7.2Hz, 1H), 8.06(s, 1H), 10.28(s, 1H), 11.17(s, 1H). #(DMSO-d₆)408-CH₃CH₂H embedded image

HCl229-2323449, 2976, 1710, 1685, 1490, 1384, 1326, 1225, 953, 7451.28(t, J=7.0Hz, 3H), 2.13(d, J=12.8Hz, 2H), 2.40(s, 3H), 2.92(m, 2H), 3.40(m, 2H), 3.64(d, J=11.0Hz, 2H), 3.84(m, 1H), 4.17(s, 2H), 4.41(q, J=7.0Hz, 2H), 5.09(s, 2H), 7.13(m, 3H), 7.25(d, #J=7.3Hz, 1H), 7.44(m, 1H), 7.60(m, 3H), 8.05(d, J=7.7Hz, 1H), 8.43(s, 1H), 10.18(s, 1H), 11.09(s, 1H). (DMSO-d₆)418-CH₃CH₂H embedded image

HCl264-2743449, 2990, 1703, 1610, 1556, 1327, 1119, 1065, 952, 8442.1(d, J=12.7Hz, 2H), 2.4(s, 3H), 2.9(m, 2H) 3.4(m, 2H) 3.6(d, J=12.0Hz, 2H) 3.8(t, J=11.5Hz, 1H) 4.1(s, 2H) 5.1(s, 2H), 7.1(m, 2H) 7.2(d, J=7.1Hz, 1H) 7.7(d, J=8.5Hz, 2H) 7.8(s, #2H) 10.2(s, 1H) 11.1(s, 1H). (DMSO-d6)428-CH₃CH₂H embedded image

HCl232-2393190, 1696, 1599, 1556, 951, 773, 726, 6942.1(d, J=13.7Hz, 2H) 2.4(s, 3H) 3.0(m, 2H) 3.2(s, 2H) 3.6(m, 2H) 3.8(m, 1H) 4.1(s, 2H) 5.0(s, 2H) 7.1(m, 3H) 7.2(d, J=7.8Hz, 1H) 7.3(t, J=6.5Hz, 2H) 7.6(d, J=8.1Hz, 2H) 10.1(s, 1H) 10.6(s, 1H). (DMSO-d6)43HCH₂H embedded image

HCl276-2843407, 3055, 1708, 1610, 1555, 1324, 1112, 1065, 948, 8452.0(d, J=13.9Hz, 2H) 2.9(q, J=12.0Hz, 2H) 3.3(m, 2H) 3.6(d, J=12.2Hz, 2H) 4.2(s, 2H) 4.3(d, J=12.2Hz, 1H) 5.1(s, 2H) 7.1(m, 1H) 7.2(d, J=7.3Hz, 1H) 7.3(d, J=3.7Hz, 2H) 7.6(d, #J=8.8Hz, 2H) 7.8(m, 2H) 10.2(s, 1H) 10.9(s, 1H). (DMSO-d6)446-ClCH₂H embedded image

HCl265-2773001, 2494, 1712, 1696, 1602, 1559, 1259, 1041, 966, 7602.0(d, J=13.9Hz, 2H) 2.9(m, 2H) 3.3(m, 2H) 3.6(d, J=12.2Hz, 2H) 4.1(s, 2H) 4.3(m, 1H) 5.1(s, 2H) 7.1(t, J=7.3Hz, 1H) 7.3(m, 2H) 7.4(m, 3H) 7.6(d, J=7.6Hz, 2H) 10.1(s, 1H) 10.6(s, 1H). (DMSO-d6)456-ClCH₂H embedded image

HCl284-2852993, 2500, 1707, 1611, 1557, 1325, 1112, 1064, 949, 8452.0(d, J=12.9Hz, 2H) 2.9(q, J=13.2Hz, 2H) 3.3(m, 2H) 3.6(d, J=12.0Hz, 2H) 4.2(s, 2H) 4.3(m, 1H) 5.1(s, 2H) 7.4(m, 3H) 7.7(m, 2H) 7.8(m, 2H) 10.2(s, 1H) 11.0(s, 1H). (DMSO-d6)46HCH₂H embedded image

HCl262-2723405, 3068, 1707, 1609, 1557, 1259, 1043, 947, 7612.0(d, J=13.4Hz, 2H) 2.9(m, 2H) 3.3(m, 2H) 3.6(d, J=11.7Hz, 2H) 4.1(s, 2H) 4.3(m, 1H) 5.1(s, 2H) 7.1(dd, J=7.3, 5.9Hz, 2H) 7.3(m, 5H) 7.6(d, J=8.5Hz, 2H) 10.1(s, 1H) 10.6(s, 1H). (DMSO-d6)478-CH₃CH₂H embedded image

HCl245-2533277, 2991, 1726, 1681, 1597, 1541, 1492, 1280, 1255, 12012.1(d, J=13.2Hz, 2H) 2.4(s, 3H) 2.9(m, 2H) 3.3(m, 2H) 3.6(d, J=2.9Hz, 2H) 3.8(m, 1H) 4.1(s, 2H) 5.0(s, 2H) 7.1(m, 2H) 7.2(d, J=7.1Hz, 1H) 7.3(d, J=7.1Hz, 2H) 7.6(m, 2H) 10.2(s, 1H) 10.8(s, #1H). (DMSO-d6)48HCH₂H embedded image

HCl268-2823401, 2992, 2217, 1708, 1600, 1538, 1391, 1042, 950, 8422.0(d, J=12.7Hz, 2H) 2.9(m, 2H) 3.4(m, 2H) 3.7(d, J=11.5Hz, 2H) 4.3(m ,3H) 5.1(s, 2H) 7.1(m, 1H) 7.3(d, J=7.8Hz, 1H) 7.4(m, 2H) 7.8(m, 4H) 10.2(s, 1H) 11.1(s, 1H). (DMSO-d6)498-CH₃CH₂H embedded image

HCl229-2343448, 2978, 2223, 1707, 1600, 1541, 1035, 950, 8392.1(d, J=13.4Hz, 2H) 2.4(s, 3H) 2.9(m, 2H) 3.3(m, 2H) 3.6(d, J=11.4Hz, 2H) 3.8(t, J=11.0Hz, 1H) 4.1(s, 2H) 5.1(s, 2H) 7.1(m, 2H) 7.2(d, J=6.4Hz, 1H) 7.7(m, 4H) 10.2(s, 1H) 11.1(s, 1H). (DMSO-d6)506-ClCH₂H embedded image

HCl274-2783414, 2986, 2219, 1721, 1602, 1541, 1313, 1200, 1040, 8422.0(d, J=12.6Hz, 2H) 2.9(m, 2H) 3.3(m, 2H) 3.6(d, J=12.2Hz, 2H) 4.2(s, 2H) 4.3(m, 1H) 5.1(s, 2H) 7.4(m, 3H) 7.8(s, 4H) 10.2(s, 1H) 11.0(s, 1H). (DMSO-d6)51HCH₂H embedded image

HCl>2803448, 3044, 1708, 1600, 1395, 1261, 1043, 948, 842, 7712.0(d, J=13.5Hz, 2H) 2.5(s, 3H) 2.9(m, 2H) 3.3(m, 2H) 3.6(d, J=11.4Hz, 2H) 4.1(s, 2H) 4.3(m, 1H) 5.1(s, 2H) 7.1(m, 1H) 7.2(d, J=7.3Hz, 1H) 7.3(m, 2H) 7.7(d, J=8.8Hz, 2H) 7.9(d, J=8.8Hz, 2H) 10.2(s, 1H) 10.8(s, #1H). (DMSO-d6)528-CH₃CH₂H embedded image

HCl162-1673414, 3039 1710, 1691, 1506, 1487, 12282.1(d, J=13.0Hz, 2H) 2.3(s, 3H) 2.9(q, J=11.9Hz, 2H) 3.2(m, 2H) 3.6(d, J=11.1Hz, 2H) 3.8(t, J=11.3Hz, 1H) 4.0(s, 2H) 5.0(s, 2H) 6.9(m, 4H) 7.0(m, 3H) 7.2(d, J=7.0Hz, 1H) 7.3(t, J=8.4Hz, 2H) 7.6(d, J=8.9Hz, #2H) 10.1(s, 1H) 10.6(s, 1H). (DMSO-d6)536-ClCH₂H embedded image

HCl244-2863579, 3475, 2992, 1717, 1667, 1600, 1545, 1263, 1041, 9482.0(d, J=1.37Hz, 2H) 2.5(s, 3H) 2.9(m, 2H) 3.4(m, 2H) 3.7(d, J=11.9Hz, 2H) 4.2(s, 2H) 4.3(m, 1H) 5.1(s, 2H) 7.4(m, 3H) 7.7(d, J=8.6Hz, 2H) 8.0(d, J=8.6Hz, 2H) 10.2(s, 1H) 11.0(s, 1H). (DMSO-d6)548-CH₃CH₂H embedded image

HCl>2803422, 2967, 1701, 1676, 1590, 1407, 1256, 950, 835, 7732.1(d, J=14.5Hz, 2H) 2.4(s, 3H) 2.5(s, 3H) 2.9(m, 2H) 3.3(t, J=13.5Hz, 2H) 3.6(d, J=12.3Hz, 2H) 3.8(t, J=11.4Hz, 1H) 4.1(s, 2H) 5.1(s, 2H) 7.1(m, 2H) 7.2(d, J=7.3Hz, 1H) 7.7(d, J=8.8Hz, 2H) 7.9(d, J=8.8Hz, #2H) 10.2(s, 1H) 10.9(s, 1H). (DMSO-d6)556-ClCH₂H embedded image

HCl262-2672990, 1714, 1560, 1488, 1231, 1039, 950, 871, 7512.0(d, J=13.2Hz, 2H) 2.9(m, 2H) 3.3(m, 2H) 3.6(d, 2H) 4.1(s, 2H) 4.3(m, 1H) 5.1(s, 2H) 7.0(m, 4H) 7.1(t, J=7.4Hz, 1H) 7.3(m, 5H) 7.6(d, J=9.0Hz, 2H) 10.2(s, 1H) 10.6(s, 1H). (DMSO-d6)568-CH₃CH₂H embedded image

HCl2173432, 2894, 1701, 1649, 1597, 1541, 1281, 1033, 925, 8572.1(d, J=13.4Hz, 2H) 2.4(s, 3H) 2.9(m, 2H) 3.3(m, 2H) 3.6(d, J=11.4Hz, 2H) 3.8(m, 1H) 4.1(s, 2H) 5.0(s, 2H) 7.1(m, 2H) 7.2(d, J=7.5Hz, 1H) 7.5(m, 2H) 7.6(dd, J=6.9, 2.1Hz, 1H) 7.7(dd, J=8.2, 1.3Hz, 2H) 7.8(s, #4H) 10.2(s, 1H) 10.9(s, 1H). (DMSO-d6)576-ClCH₂H embedded image

HCl256-2593449, 3051, 1708, 1599, 1541, 1315, 1203, 1041, 949, 7022.0(d, J=13.2Hz, 2H) 2.9(m, 2H) 3.3(m, 2H) 3.6(d, J=9.9Hz, 2H) 4.2(s, 2H) 4.2(m, 1H) 5.1(s, 2H) 7.3(m, 3H) 7.5(t, J=7.3Hz, 2H) 7.6(t, J=7.9Hz, 1H) 7.7(m, 2H) 7.7(m, 4H) 10.2(s, #1H) 10.9(s, 1H). (DMSO-d6)586-CH₃CH₂H embedded image

—146-1483177, 3045, 1701, 1595, 1492, 1215, 1046, 966, 8081.9(d, J=13.7Hz, 2H) 2.3(s, 3H) 2.4(m, 2H) 2.9(m, J=12.4, 4.0Hz, 2H) 3.1(m, 2H) 3.2(s, 2H) 3.8(m, 1H) 5.1(s, 2H) 6.9(m, 2H) 7.1(d, J=8.4Hz, 1H) 7.3(d, 8.8Hz, 2H) 7.6(d, J=8.8Hz, 2H) 9.2(s, 1H). #(CDCl₃-d)596-CH₃CH₂H embedded image

—169-1733302, 3068, 1730, 1706, 1609, 1508, 1329, 1114, 1067, 8461.9(d, J=11.7Hz, 2H) 2.3(s, 3H) 2.4(m, 2H) 2.9(qd, J=12.6, 4.1Hz, 2H) 3.1(d, J=11.5Hz, 2H) 3.2(s, 2H) 3.8(t, J=12.0Hz, 1H) 5.1(s, 2H) 6.9(m, 2H) 7.1(d, J=9.0Hz, 1H) 7.6(d, #J=8.8Hz, 2H) 7.8(d, J=9.0Hz, 2H) 9.4(s, 1H). (CDCl₃-d)606-CH₃CH₂H embedded image

—154-1573550, 2799, 1697, 1601, 1522, 1443, 1213, 1047, 817, 7641.9(d, J=11.7Hz, 2H) 2.3(s, 3H) 2.4(t, J=11.2Hz, 2H) 2.9(qd, J=12.4, 3.6Hz, 2H) 3.1(d, J=11.7Hz, 2H) 3.2(s, 2H) 3.8(tt, J=12.0, 3.7Hz, 1H) 5.1(s, 2H) 6.9(d, J=8.4Hz, 1H) 7.0(s, #1H) 7.1(m, 2H) 7.4(m, 2H) 7.6(d, J=7.6Hz, 2H) 9.2(s, 1H). (CDCl₃-d)618-CH₃CH₂H embedded image

HCl249-2533449, 2922, 2849, 1695, 1611, 1550, 1257, 1037, 952, 8321.3(m, 4H) 1.7(m, 6H) 2.1(d, J=12.1Hz, 2H) 2.3(s, 3H) 2.4(s, 1H) 2.9(m, 2H) 3.2(t, J=11.6Hz, 2H) 3.6(d, J=10.8Hz, 2H) 3.8(t, J=10.6Hz, 1H) 4.0(s, 2H) 5.0(s, 2H) 7.0(m, 2H) 7.1(m, 3H) 7.4(d, #J=8.4Hz, 2H) 10.0(br, 1H) 10.4(s, 1H). (DMSO-d6)626-ClCH₂H embedded image

HCl249-2562929, 1692, 1607, 1547, 1293, 1201, 1043, 8301.3(m, 4H) 1.7(m, 6H) 2.0(d, J=15.7Hz, 2H) 2.4(m, 1H) 2.9(q, J=12.5Hz, 2H) 3.3(t, J=11.9Hz, 2H) 3.6(d, J=10.3Hz, 2H) 4.1(s, 2H) 4.2(t, J=12.1Hz, 1H) 5.1(s, 2H) 7.1(d, J=8.6Hz, 2H) 7.4(m, 3H) 7.5(d, J=8.6Hz, #2H) 10.1(br, 1H) 10.5(s, 1H). (DMSO-d6)63HCH₂H embedded image

HCl211-2163260, 3058, 1681, 1610, 1296, 1036, 954, 7721.9(d, J=13.7Hz, 2H) 2.8(m, 2H) 3.1(m, 2H) 3.3(d, J=10.6Hz, 2H) 3.9(s, 2H) 4.2(t, J=10.3Hz, 1H) 5.1(s, 2H) 7.1(t, J=7.1Hz, 1H), 7.4(m, 8H) 7.6(m, 2H) 7.7(d, J=7.1Hz, 2H) 10.1(br, 1H) 10.8(s, 1H). (DMSO-d6)648-CH₃CH₂H embedded image

HCl168-1763413, 2961, 1686, 1606, 1282, 1033, 951, 7752.0(d, J=13.4Hz, 2H) 2.3(s, 3H) 2.8(m, 2H) 3.0(m, 2H) 3.3(d, J=10.8Hz, 2H) 3.7(t, J=12.2Hz, 1H) 3.8(s, 2H) 5.0(s, 2H) 7.0(m, 2H) 7.2(d, J=7.7Hz, 1H) 7.3(t, J=7.5Hz, 1H) 7.4(m, 4H) 7.6(m, 2H) 7.7(d, #J=7.7Hz, 2H) 10.0(s, 1H) 10.7(s, 1H). (DMSO-d6)656-ClCH₂H embedded image

HCl167-1783259, 1686, 1491, 1299, 1205, 1041, 956, 7701.9(d, J=12.8Hz, 2H) 2.7(m, 2H) 3.1(m, 2H) 3.3(d, J=10.6Hz, 2H) 3.9(s, 2H), 4.2(m, 1H) 5.1(s, 2H) 7.4(m, 5H) 7.5(m, 3H) 7.6(m, 2H) 7.7(d, J=8.1Hz, 2H) 10.0(s, 1H), 10.8(s, 1H). (DMSO-d6)666-CH₃CH₂H embedded image

—167-1703448, 2938, 1702, 1634, 1509, 1445, 1156, 10451.8(d, J=9.3Hz, 2H) 2.3(s, 3H) 2.5(m, 2H) 2.9(qd, J=12.6, 3.5Hz, 2H) 3.0(d, J=11.2Hz, 2H) 3.2(s, 2H) 4.3(tt, J=12.8, 4.6Hz, 1H) 5.0(s, 2H) 7.0(m, 2H) 7.1(m, 1H) 7.5(m, 2H) 7.6(m, 4H) 7.8(m, 2H) 8.7(d, #J=8.1Hz, 1H) 11.9(s, 1H). (CDCl₃-d)676-CH₃CH₂H embedded image

HCl234-2373148, 2970, 2449, 1691, 1541, 1507, 1233, 10382.0(d, J=14.1Hz, 2H) 2.2(s, 3H) 2.9(m, 2H) 3.3(m, 2H) 3.6(d, J=12.1Hz, 2H), 4.1(s, 2H) 4.2(m, 1H) 5.1(s, 2H) 7.0(m, 6H) 7.2(m, 2H) 7.3(t, J=7.8Hz, 2H) 7.6(d, J=9.0Hz, 2H) 10.1(s, 1H) 10.6(s, 1H). (DMSO-d6)686-CH₃CH₂H embedded image

HCl273-2772927, 1705, 1666, 1594, 1595, 1508, 1267, 1117, 946, 8392.0(d, J=13.2Hz, 2H) 2.2(s, 3H) 2.5(s, 3H) 2.9(m, 2H) 3.4(m, 2H) 3.6(d, J=12.1Hz, 2H) 4.2(m, 3H) 5.1(s, 1H) 7.1(s, 1H) 7.2(m, 2H) 7.7(d, J=8.8Hz, 2H) 7.9(d, J=8.8Hz, 2H) #10.2(br, 1H) 10.9(s, 1H). (DMSO-d6)69HCH₂H embedded image

HCl270-2733328, 3071, 2547, 1715, 1691, 1606, 1259, 1045, 7752.0(d, J=11.5Hz, 2H) 2.9(m, 2H) 3.4(m, 2H) 3.7(d, J=12.3Hz, 2H) 4.2(s, 2H) 4.3(m, 1H) 5.1(s, 2H) 5.4(s, 1H), 7.1(m, 1H) 7.3(m, 2H) 7.3(m, 3H) 7.5(dd, J=8.2, 1.8Hz, 1H) 7.6(m, 2H) 7.6(d, J=7.1Hz, #1H) 8.0(d, J=1.6Hz, 1H) 10.1(s, 1H) 10.7(s, 1H). (DMSO-d6)706-ClCH₂H embedded image

HCl>300 (dec)2999, 1707, 1603, 1561, 1490, 1463, 1298, 12002.0(d, J=11.7Hz, 2H) 2.8(m, 2H) 3.1(m, 2H) 3.5(d, 2H) 4.3(m, 3H) 5.2(s, 2H) 7.3(m, 1H) 7.4(m, 3H) 7.6(m, 2H) 7.7(m, 3H) 8.0(s, 1H) 10.3(s, 1H) 11.4(s, 1H). (DMSO-d6)716-CH₃CH₂H embedded image

HCl281-2852985, 1701, 1604, 1561, 1466, 1300, 12622.0(d, J=11.7Hz, 2H) 2.3(s, 3H) 2.9(m, 2H) 3.2(m, 2H) 3.6(d, 2H) 4.2(m, 3H) 5.1(s, 2H) 7.1(s, 1H) 7.3(m, 3H) 7.6(m, 2H) 7.7(m, 3H) 8.0(s, 1H) 10.3(s, 1H) 11.4(s, 1H). (DMSO-d6)728-CH₃CH₂H embedded image

HCl>300 (dec)3448, 1686, 1603, 1561, 1463, 1304, 12762.0(d, J=11.9Hz, 2H) 2.4(s, 3H) 2.9(m, 2H) 3.3(m, 2H) 3.6(d, 2H) 3.8(m, 1H) 4.2(s, 2H) 5.1(s, 2H) 7.1(m, 2H) 7.3(m, 3H) 7.6(m, 2H) 7.7(m, 3H) 8.0(s, 1H) 10.3(s, 1H) 11.4(s, 1H). (DMSO-d6)736-ClCH₂H embedded image

HCl286-2893423, 3000, 1707, 1603, 1560, 1491, 1460, 1201, 10412.0(d, J=12.3Hz, 2H) 2.9(m, 2H) 3.3(m, 2H) 3.7(d, J=11.2Hz, 2H) 4.1(s, 2H) 4.3(m, 1H) 5.1(s, 2H) 5.4(s, 1H) 7.2(t, J=7.3Hz, 1H) 7.3(t, J=7.4Hz, 1H) 7.4(m, 3H) 7.5(m, 2H) 7.7(t, #J=8.8Hz, 2H) 7.9(s, 1H) 10.2(s, 1H) 10.7(s, 1H). (DMSO-d6)746-CH₃CH₂H embedded image

HCl196-1993392, 3045, 1695, 1560, 1458, 1295, 1217, 10402.0(d, J=12.1Hz, 2H) 2.3(s, 3H) 2.9(m, 2H) 3.4(m, 2H) 3.7(d, J=11.4Hz, 2H) 4.3(m, 3H) 5.1(s, 2H) 5.5(s, 1H) 5.9(br, 1H) 7.1(s, 1H) 7.2(d, J=8.4Hz, 1H) 7.3(m, 2H) 7.3(t, J=7.0Hz, 1H) 7.6(d, J=7.1Hz, 1H) 7.6(d, #J=7.9Hz, 1H) 7.7(m, 2H) 8.0(s, 1H) 10.3(s, 1H) 11.2(s, 1H). (DMSO-d6)758-CH₃CH₂H embedded image

HCl283-2853260, 1688, 1618, 1563, 1467, 1384, 1309, 12802.1(d, J=13.5Hz, 2H) 2.4(s, 3H) 2.9(m, 2H) 3.3(m, 2H) 3.6(d, J=11.0Hz, 2H) 3.8(t, J=11.7Hz, 1H) 4.1(s, 2H) 5.1(s, 2H) 5.4(s, 1H) 7.1(m, 2H) 7.2(td, J=7.4, 1.2Hz, 2H) 7.3(m, 1H) 7.5(d, J=6.8Hz, 2H) 7.7(m, 2H) #7.9(d, J=1.5Hz, 1H) 10.1(s, 1H) 10.7(s, 1H). (DMSO-d6)766-CH₃CH₂H embedded image

HCl238-2413399, 1693, 1618, 1559, 1295, 1217, 10412.0(d, J=13.2Hz, 2H) 2.2(s, 3H) 2.9(m, 2H) 3.3(m, 2H) 3.7(d, J=11.0Hz, 2H) 4.1(s, 2H) 4.2(m, 1H) 5.0(s, 2H) 5.4(s, 1H) 7.0(s, 1H) 7.1(d, J=8.4Hz, 1H) 7.3(m, 3H) 7.4(d, J=8.2Hz, 1H) 7.5(m, 2H) 7.6(d, J=7.3Hz, #1H) 8.0(s, 1H) 10.1(s, 1H) 10.7(s, 1H). (DMSO-d6)777-FCH₂H embedded image

HCl2732922, 1719, 1691, 1609, 1512, 1387, 1200, 1042, 8301.2(m, 1H) 1.4(m, 4H) 1.7(d, J=11.1Hz, 1H) 1.8(m, 4H) 2.0(d, J=11.6Hz, 2H) 2.5(m, 1H) 2.9(d, J=10.6Hz, 2H) 3.4(m, 2H) 3.6(m, 2H) 4.2(s, 2H) 4.3(m, 1H) 5.2(s, 2H) 7.0(t, J=8.3Hz, 1H) 7.2(d, J=8.1Hz, 2H) 7.4(m, 2H) 7.5(d, #J=8.1Hz, 2H) 10.2(s, 1H) 10.9(s, 1H). (DMSO-d6)785-FCH₂H embedded image

HCl2661717, 1693, 1625, 1479, 1306, 1242, 1207, 1067, 781, 7491.3(t, J=7.1Hz, 3H) 2.1(d, J=12.1Hz, 2H) 2.9(d, J=10.1Hz, 2H) 3.4(m, 2H) 3.7(m, 2H) 4.2(s, 2H) 4.4(m, 1H) 4.4(q, J=7.1Hz, 2H) 5.3(s, 2H) 7.1(t, J=8.6Hz, 1H) 7.2(t, J=7.3Hz, 1H) 7.3(d, J=8.1Hz, 1H) 7.5(m, #2H) 7.6(m, 3H) 8.1(d, J=7.6Hz, 1H) 8.5(s, 1H) 10.3(s, 1H) 11.0(s, 1H). (DMSO-d6)796-OCH₃CH₂H embedded image

HCl2582944, 1673, 1503, 1491, 1283, 1229, 1036, 809, 7391.3(t, J=7.1Hz, 3H) 2.0(d, J=11.6Hz, 2H) 2.9(d, J=10.6Hz, 2H) 3.4(m, 2H) 3.7(m, 2H) 3.8(s, 3H) 4.2(s, 2H) 4.3(m, 1H) 4.4(q, J=6.9Hz, 2H) 5.1(s, 2H) 6.9(m, 2H) 7.2(t, J=7.7Hz, 1H) 7.4(d, J=8.6Hz, 1H) 7.5(t, J=7.6Hz, 1H) #7.6(m, 3H) 8.1(d, J=7.6Hz, 1H) 8.5(s, 1H) 10.3(s, 1H) 11.0(s, 1H). (DMSO-d6)807-CH₃CH₂H embedded image

HCl2632973, 1712, 1491, 1385, 1299, 1227, 1037, 806, 7371.3(t, J=6.8Hz, 3H) 2.0(d, J=12.6Hz, 2H) 2.4(s, 3H) 3.0(d, J=14.1Hz, 2H) 3.5(m, 2H) 3.7(m, 2H) 4.2(s, 2H) 4.3(m, 1H) 4.4(q, J=6.9Hz, 2H) 5.1(s, 2H) 7.0(d, J=8.1Hz, 1H) 7.2(m, 3H) 7.5(t, J=7.6Hz, 1H) 7.6(m, 3H) 8.1(d, #J=8.1Hz, 1H) 8.5(s, 1H) 10.3(s, 1H) 11.0(s, 1H). (DMSO-d6)815-ClCH₂H embedded image

HCl2341692, 1589, 1462, 1301, 1229, 1047, 7831.3(t, J=6.8Hz, 3H) 2.1(d, J=11.1Hz, 2H) 2.9(m, 2H) 3.4(m, 2H) 3.7(d, J=11.6Hz, 2H) 4.2(s, 2H) 4.3(m, 1H) 4.4(q, J=6.6Hz, 2H) 5.3(s, 2H) 7.2(t, J=7.3Hz, 1H) 7.3(d, J=7.1Hz, 1H) 7.5(m, 3H) 7.6(m, 3H) 8.1(d, J=7.6Hz, 1H) 8.5(s, 1H) 10.2(s, #1H) 10.9(s, 1H). (DMSO-d6)825-FCH₂H embedded image

HCl2372989, 1719, 1624, 1507, 1488, 1229, 1071, 7792.0(d, J=12.6Hz, 2H) 2.9(d, J=11.1Hz, 2H) 3.4(m, 2H) 3.6(m, 2H) 4.2(s, 2H) 4.3(t, J=11.6Hz, 1H) 5.3(s, 2H) 7.0(d, J=8.1Hz, 2H) 7.0(m, 3H) 7.1(t, J=7.3Hz, 1H) 7.3(d, J=8.6Hz, 1H) 7.4(t, J=8.1Hz, 2H) 7.5(m, 1H) 7.7(d, J=9.1Hz, #2H) 10.3(s, 1H) 11.1(s, 1H). (DMSO-d6)836-OCH₃CH₂H embedded image

—2233293, 1701, 1507, 1465, 1294, 1218, 10401.9(d, J=12.1Hz, 2H) 2.5(t, J=11.6Hz, 2H) 2.9(m, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.8(m, 4H) 5.1(s, 2H) 6.7(d, J=2.0Hz, 1H) 6.9(m, 1H) 7.0(m, 1H) 7.3(t, J=7.6Hz, 1H) 7.4(d, J=8.1Hz, 1H) 7.5(t, J=7.6Hz, 1H) 7.6(m, 3H) #8.0(s, 1H) 9.5(s, 1H). (CDCl₃-d)848-OCH₃CH₂H embedded image

— 881718, 1483, 1286, 1223, 1191, 1079, 10372.0(d, J=11.6Hz, 2H) 2.4(t, J=10.9Hz, 2H) 2.9(qd, J=12.3, 4.0Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.8(m, 1H) 3.9(s, 3H) 5.0(s, 2H) 6.8(d, J=7.1Hz, 1H) 6.9(d, J=7.6Hz, 1H) 7.1(m, 1H) 7.3(t, J=7.6Hz, 1H) 7.5(t, J=7.8Hz, #1H) 7.6(m, 3H) 8.0(d, J=7.1Hz, 1H) 8.4(d, J=2.0Hz, 1H) 9.4(s, 1H). (CDCl₃-d)857-ClCH₂H embedded image

—2373270, 1719, 1676, 1604, 1508, 1483, 1195, 1048, 7491.9(d, J=12.1Hz, 2H) 2.5(t, J=11.1Hz, 2H) 2.9(qd, J=12.5, 4.0Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.8(m, 1H) 5.1(s, 2H) 7.1(s, 1H) 7.1(s, 2H) 7.3(t, J=7.1Hz, 1H) 7.5(t, J=7.8Hz, 1H) 7.6(m, 3H) 8.0(d, J=7.1Hz, 1H) #8.4(d, J=2.0Hz, 1H) 9.3(s, 1H). (CDCl₃-d)866-FCH₂H embedded image

—2373270, 1706, 1509, 1271, 1206, 1109, 1042, 7641.9(d, J=12.1Hz, 2H) 2.5(t, J=11.6Hz, 2H) 2.9(m, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.8(t, J=11.9Hz, 1H) 5.1(s, 2H) 6.9(d, J=6.6Hz, 1H) 7.0(m, 1H) 7.1(t, J=7.1Hz, 1H) 7.3(t, J=7.3Hz 1H) 7.4(d, J=7.6Hz, 1H) 7.5(t, #J=7.3Hz, 1H) 7.6(d, J=7.6Hz, 1H) 7.6(m, 2H) 8.0(s, 1H) 9.4(s, 1H). (CDCl₃-d)877-FCH₂H embedded image

—1363399, 1719, 1618, 1509, 1199, 1042, 7691.9(d, J=12.1Hz, 2H) 2.4(t, J=11.9Hz, 2H) 2.9(m, 2H) 3.1(m, 2H) 3.2(s, 2H) 3.8(qd, J=12.1, 3.8Hz, 1H) 5.1(s, 2H) 5.6(s, 1H) 6.8(m, 2H) 7.1(m, 1H) 7.3(t, J=6.8Hz, 1H) 7.4(m, 2H) 7.6(m, 3H) 8.0(d, J=2.0Hz, 1H) 9.2(s, 1H). (CDCl₃-d)885-CH₃CH₂H embedded image

—2133247, 1701, 1476, 1245, 1204, 1033, 7301.9(d, J=11.6Hz, 2H) 2.3(s, 3H) 2.4(t, J=11.4Hz, 2H) 2.9(qd, J=12.3, 4.0Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.8(ddd, J=11.9, 8.1, 3.8Hz, 1H) 5.1(s, 2H) 6.9(t, J=7.8Hz, 2H) 7.2(m, 2H) 7.4(m, 3H) 7.5(dd, J=8.6, 2.0Hz, #1H) 8.1(d, J=7.6Hz, 1H) 8.3(s, 1H) 8.4(s, 1H) 9.2(s, 1H). (CDCl₃-d)895-FCH₂H embedded image

—1953278, 1718, 1654, 1624, 1479, 1242, 1204, 1067, 7721.9(d, J=13.6Hz, 2H) 2.4(m, 2H) 2.9(qd, J=12.3, 3.5Hz, 2H) 3.2(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.9(m, 1H) 5.2(s, 2H) 6.9(d, J=9.1Hz, 2H) 7.2(ddd, J=8.0, 5.2, 3.0Hz, 1H) 7.3(m, 1H) 7.4(m, 3H) 7.5(dd, J=8.8, #2.3Hz, 1H) 8.1(d, J=7.6Hz, 1H) 8.1(s, 1H) 8.4(s, 1H) 9.2(s, 1H). (CDCl₃-d)906-OCH₃CH₂H embedded image

—1353293, 1701, 1502, 1289, 1215, 1042, 802, 746, 7261.9(d, J=10.6Hz, 2H) 2.4(t, J=11.1Hz, 2H) 2.9(qd, J=12.5, 3.5Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.8(s, 3H) 3.8(m, 1H) 5.1(s, 2H) 6.7(d, J=2.5Hz, 1H) 6.9(m, 1H) 7.0(d, J=9.1Hz, 1H) 7.2(ddd, #J=7.8, 5.6, 2.3Hz, 1H) 7.4(m, 3H) 7.5(dd, J=8.6, 2.0Hz, 1H) 8.1(d, J=8.1Hz, 1H) 8.3(s, 1H) 8.4(d, J=2.0Hz, 1H) 9.2(s, 1H). (CDCl₃-d)915-OCH₃CH₂H embedded image

—1002920, 1719, 1676, 1604, 1478, 1257, 1086, 772, 7491.4(t, J=7.1Hz, 3H) 1.9(d, J=12.1Hz, 2H) 2.4(t, J=11.4Hz, 2H) 2.9(m, 2H) 3.2(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.9(m, 4H) 4.4(q, J=7.1Hz, 2H) 5.2(s, 2H) 6.7(d, J=8.6Hz, 1H) 6.7(d, 8.1Hz, 1H) 7.2(t, #J=7.3Hz, 1H) 7.3(t, J=8.3Hz, 1H) 7.4(m, 2H) 7.5(m, 1H) 7.6(dd, J=8.6, 2.0Hz, 1H) 8.1(d, J=8.1Hz, 1H) 8.4(d, J=2.0Hz, 1H) 9.2(s, 1H). (CDCl₃-d)925-OCH₃CH₂H embedded image

— 732943, 1719, 1605, 1509, 1478, 1257, 1082, 7721.9(d, J=11.6Hz, 2H) 2.4(m, 2H) 2.9(m, 2H) 3.1(d, J=11.1Hz, 2H) 3.2(m, 2H) 3.8(m, 1H) 3.9(m, 3H) 5.2(m, 2H) 6.7(m, 2H) 7.0(m, 4H) 7.1(m, 1H) 7.3(m, 3H) 7.6(m, 2H) 9.1(s, 1H). (CDCl₃-d)937-CH₃CH₂H embedded image

—1363406, 2935, 1686, 1500, 1459, 1289, 1215, 10431.9(d, J=11.1Hz, 2H) 2.4(m, 2H) 2.9(qd, J=12.4, 3.8Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.8(m, 4H) 5.1(s, 2H) 5.3(s, 1H) 6.7(d, J=2.5Hz, 1H) 6.9(m, 1H) 7.0(d, J=8.6Hz, 1H) 7.2(m, 1H) 7.4(m, 3H) 7.5(dd, #J=8.6, 2.0Hz, 1H) 8.1(d, J=7.6Hz, 1H) 8.3(s, 1H) 8.4(d, J=2.0Hz, 1H) 9.2(s, 1H). (CDCl₃-d)948-OCH₃CH₂H embedded image

—1433422, 1701, 1522, 1491, 1286, 1225, 1036, 768, 7372.0(d, J=9.6Hz, 2H) 2.3(t, J=11.9Hz, 2H) 2.8(m, 2H) 3.1(d, J=11.1Hz, 2H) 3.1(s, 2H) 3.8(m, 1H) 3.9(s, 3H) 5.0(s, 2H) 5.6(s, 1H) 6.8(d, J=7.1Hz, 1H) 6.9(d, J=8.1Hz, 1H) 7.1(t, #J=7.8Hz, 1H) 7.4(m, 2H) 7.5(dd, J=8.1, 2.0Hz, 1H) 7.6(m, 2H) 7.7(d, J=7.7Hz, 1H) 8.0(s, 1H) 9.3(s, 1H). (CDCl₃-d)955-CH₃CH₂H embedded image

—2043330, 1719, 1685, 1526, 1482, 1193, 1041, 7731.9(d, J=12.1Hz, 2H) 2.3(s, 3H) 2.4(m, 2H) 3.0(qd, J=12.5, 3.5Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.8(qd, J=12.1, 3.8Hz, 1H) 5.1(s, 2H) 6.9(m, 2H) 7.3(m, 1H) 7.3(t, J=7.1Hz, 1H) 7.5(t, J=7.8Hz, 1H) 7.6(m, #3H) 8.0(d, J=7.6Hz, 1H) 8.4(d, J=2.0Hz, 1H) 9.3(s, 1H). (CDCl₃-d)967-CH₃CH₂H embedded image

—1991718, 1686, 1520, 1492, 1383, 1309, 1247, 1210, 10441.2(t, J=7.1Hz, 3H) 1.9(d, J=10.6Hz, 2H) 2.4(m, 5H) 2.9(qd, J=12.5, 4.0Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.8(q, J=7.1Hz, 2H) 3.8(m, 1H) 5.1(s, 2H) 6.9(m, 5H) 7.0(m, 3H) 7.2(m, 2H) 7.5(d, #J=8.6Hz, 2H) 9.1(s, 1H). (CDCl₃-d)978-ClCH₂H embedded image

—1803289, 1735, 1663, 1527, 1494, 1460, 1225, 1183, 10412.1(s, 2H) 2.4(t, J=10.9Hz, 2H) 2.9(qd, J=12.4, 3.8Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.9(tq, J=11.7, 3.8Hz, 1H) 5.0(s, 2H) 7.1(m, 2H) 7.2(m, 1H) 7.4(m, 4H) 7.6(dd, J=8.6, 2.0Hz, 1H) 8.1(s, #1H) 8.1(d, J=7.6Hz, 1H) 8.4(d, J=2.0Hz, 1H) 9.3(s, 1H). (CDCl₃-d)988-OCH₃CH₂H embedded image

—2163422, 2980, 1701, 1510, 1492, 1388, 1287, 1252, 1088, 10291.2(t, J=7.1Hz, 3H) 2.2(d, J=12.1Hz, 2H) 2.9(m, 2H) 3.3(m, 2H) 3.7(d, J=11.1Hz, 2H) 3.8(q, J=7.1Hz, 2H) 4.0(s, 3H) 4.1(m, 1H) 4.2(s, 2H) 5.2(s, 2H) 6.9(m, 4H) 7.1(d, J=8.6Hz, 2H) #7.2(m, 2H) 7.3(m, 2H) 7.6(d, J=8.6Hz, 2H) 10.2(s, 1H) 11.0(s, 1H). (CDCl₃-d)99HCH₂H embedded image

—209-2103356, 1715, 1686, 1608, 1498, 1467, 1389, 1291, 1204, 1043, 7382.0(d, J=9.7Hz, 2H) 2.5(t, J=12.3Hz, 2H) 3.0(m, 2H) 3.2(d, J=11.0Hz, 2H) 3.3(s, 2H) 3.9(m, 1H) 5.1(s, 2H) 5.6(d, J=9.7Hz, 1H) 7.1(m, 2H) 7.2(d, J=8.1Hz, 1H) 7.4(m, 4H) #7.7(d, J=7.3Hz, 1H) 7.8(t, J=7.8Hz, 1H) 8.0(d, J=7.3Hz, 1H) 8.3(d, J=8.4Hz, 1H) 9.7(s, 1H)100HCH₂H embedded image

—240-2493292, 3041, 2638, 1700, 1397, 1204, 1041, 7452.0(d, J=13.4Hz, 2H) 2.9(m, 2H) 3.4(m, 2H) 3.6(d, J=11.2Hz, 2H) 4.1(s, 2H) 4.3(m, 1H) 5.1(s, 2H) 5.7(s, 1H) 7.1(m, 1H) 7.2(m, 2H) 7.3(m, 4H) 7.3(m, 4H) 7.5(m, 1H) 7.6(m, 1H) 10.1(s, 1H) 10.6(s, 1H)N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-pipe-ridin-1-yl]-acetamide.Ex. 101 embedded image

1H-NMR 1.8(d, J=11.9Hz, 2H) 2.1(s, 3H) 2.5(t, J=11.8Hz, 2H) 2.8(m, 2H) 3.1(d, J=11.0Hz, 2H) 3.3(s, 2H) 4.4(t, J=12.6Hz, 1H) 5.0(s, 2H) 6.4(d, J=8.4Hz, 1H) 6.9(s, 1H) 7.5(m, 6H) 7.6(d, J=8.2Hz, 1H) 8.9(d, J=8.8Hz, 1H) 12.7(s, 1H)(CDCL₃-d) IR (KBr) 1705, 1648, 1561, 1500, 1284, 1220, #1093, 1041, 961, 821, 753 M.P.: 228-232° C.N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-pipe-ridin-1-yl]-acetamide hydrochloride.Ex. 102 embedded image

1H-NMR 2.0(d, J=13.7Hz, 2H) 2.9(m, 2H) 3.3(m, 2H) 3.5(m, 2H) 4.1(s, 2H) 4.2(m, 1H) 5.1(s, 1H) 7.1(s, 1H) 7.2(d, J=7.0Hz, 1H) 7.3(s, 3H) 7.5(m, 1H) 7.6(m, 3H) 7.7(d, J=8.2Hz, 1H) 7.8(m, 1H) 10.2(s, 1H) 11.0(s, 1H) (DMSO-d6) IR (KBr) 3386, 1702, 1686, 1523, 1288, 1238, 1041, 960, 761 M.P.: #175-184° C.N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-pipe-ridin-1-yl]-acetamide hydrochloride.Ex. 103 embedded image

1H-NMR 2.1(d, J=13.4Hz, 2H) 2.3(s, 3H) 2.9(m, 2H) 3.2(m, 2H) 3.5(m, 2H) 3.8(m, 1H) 4.0(s, 2H) 5.0(s, 2H) 7.0(m, 2H) 7.2(d, J=7.5Hz, 1H) 7.3(s, 1H) 7.4(m, 1H) 7.5(m, 3H) 7.6(d, J=8.8Hz, 1H) 7.8(d, J=8.4Hz, 1H) 10.1(s, 1H) 10.9(s, 1H)(DMSO-d6) IR (KBr) 3398, 2864, 1701, 1670, 1477, 1288, 1236, #852, 748 M.P.: 177-185° C.N-[4-Chloro-2-(2-chloro-benzoyl)-phenyl]-2-[4-(6-chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-pipe-ridin-1-yl]-acetamide hydrochloride.Ex. 104 embedded image

1H-NMR 1.9(d, J=12.9Hz, 2H) 2.9(m, 2H) 3.2(m, 2H) 3.5(d, J=11.2Hz, 2H) 4.0(s, 2H) 4.2(m, 1H) 5.0(s, 2H) 7.3(m, 4H) 7.4(m, 1H) 7.5(m, 2H) 7.5(m, 1H) 7.6(dd, J=8.5, 2.4Hz, 1H) 7.8(d, J=8.5Hz, 1H) 10.2(s, 1H) 10.9(s, 1H)(DMSO-d6) IR (KBr) 3398, 2860, 1702, 1675, 1493, 1295, 1246, 1202, #1042, 946, 758 M.P.: 201-204° C.2-[4-(7-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-thiazol-2-yl-acet-amide.Ex. 105 embedded image

1H-NMR 1.9(d, J=12.6Hz, 2H) 2.4(s, 3H) 2.5(m, 2H) 2.9(m, J=12.5, 4.0Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.3(s, 2H) 3.9(m, 1H) 5.0(s, 2H) 6.9(s, 1H) 6.9(d, J=7.6Hz, 1H) 7.0(d, J=3.5Hz, 1H) 7.0(d, J=7.6Hz, 1H) 7.5(d, J=3.5Hz, 1H) 10.4(s, 1H)(CDCl₃-d) IR (KBr) 2920,1718, 1618, #1528, 1458, 1383, 1294, 1208, 1143, 1045 M.P.: 193° C.2-[4-(6-Fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-thiazol-2-yl-acet-amide.Ex. 106 embedded image

1H-NMR 1.9(d, J=13.6Hz, 2H) 2.5(td, J=12.1, 2.0Hz, 2H) 2.8(qd, J=12.6, 3.8Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.3(s, 2H) 3.9(m, 1H) 5.1(s, 2H) 6.9(d, J=7.1Hz, 1H) 7.0(d, J=3.5Hz, 1H) 7.1(m, 2H) 7.5(d, J=3.5Hz, 1H) 10.3(s, 1H) (CDCl₃-d) IR (KBr) 2935, 1701, 1528, 1500, 1458, 1271, #1207, 1145, 1045, 730 M.P.: 67° C.N-Dibenzothiophen-2-yl-2-[4-(5-methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acet-amide.Ex. 107 embedded image

1H-NMR 1.9(d, J=12.1Hz, 2H) 2.4(m, 2H) 3.0(m, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.8(m, 4H) 5.2(s, 2H) 6.7(t, J=8.3Hz, 2H) 7.3(t, J=8.3Hz, 1H) 7.5(m, 2H) 7.6(dd, J=8.6, 2.0Hz, 1H) 7.8(m, 2H) 8.2(m, 1H) 8.6(d, J=2.0Hz, 1H) 9.3(s, 1H)(CDCl₃-d) IR (KBr) 2935, 1719, 1605, 1509, #1477, 1257, 1141, 1084, 766, 733 M.P.: 210° C.2-[4-(7-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-dibenzothiophen-2-yl-acet-amide.Ex. 108 embedded image

1H-NMR 1.9(d, J=11.1Hz, 2H) 2.5(t, J=11.1Hz, 2H) 2.9(qd, J=12.4, 3.8Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.8(ddd, J=12.1, 8.1, 4.0Hz, 1H) 5.1(s, 2H) 7.1(m, 3H) 7.5(dd, J=6.1, 3.0Hz, 2H) 7.6(d, J=8.6Hz, 1H) 7.8(m, 2H) 8.2(dd, J=5.8, 3.3Hz, 1H) 8.6(s, 1H) #9.3(s, 1H)(CDCl₃-d) IR (KBR) 3300, 1718, 1682, 1509, 1472, 1431, 1293, 1199, 1043, 806, 760, 726 M.P.: 236° C.2-[4-(5-Hydroxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide.Ex. 109 embedded image

1H-NMR 2.1(m, 2H) 3.0(d, J=12.1Hz, 2H) 3.5(m, 2H) 3.7(d, J=10.1Hz, 2H) 4.2(s, 2H) 4.3(m, 1H) 5.2(s, 2H) 6.7(d, J=8.1Hz, 1H) 6.9(m, 1H) 7.1(d, J=8.6Hz, 2H) 7.1(d, J=9.1Hz, 2H) 7.2(m, 2H) 7.5(t, J=8.1Hz, 2H) 7.7(d, J=8.6Hz, 2H) 10.2(s, 1H) 10.2(s, 1H) #10.9(s, 1H) (DMSO-d6) IR (KBr) 3192, 1701, 1609, 1560, 1508, 1476, 1229, 1071, 954, 779, 696 M.P.: 256° C.1-{1-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one hydrochloride.Ex. 110 embedded image

1H-NMR 2.0(d, J=12.7Hz, 2H) 2.8(t, J=6.0Hz, 1H) 2.9(m, 3H) 3.3(m, 2H) 3.6(m, 3H) 3.7(t, J=6.0Hz, 1H) 4.3(m, 1H) 4.4(s, 2H) 4.6(m, 2H) 5.2(s, 2H) 7.1(t, J=7.4Hz, 1H) 7.2(m, 4H) 7.3(d, J=7.1Hz, 1H) 7.4(m, 2H) 10.0(s, 1H) (DMSO-d6) IR (KBr) 3048, 2878, 1687, 1658, 1606, 1464, 1397, 1043, #771 M.P.: 226-230° C.2-[4-(6-Fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-quinolin-6-yl-acet-amide.Ex. 111 embedded image

1H-NMR 1.9(d, J=12.1Hz, 2H) 2.5(t, J=11.1Hz, 2H) 2.9(qd, J=12.5, 4.0Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.3(s, 2H) 3.8(m, 1H) 5.1(s, 2H) 6.9(dd, J=7.6, 2.5Hz, 1H) 7.0(m, 2H) 7.4(dd, J=8.1, 4.0Hz, 1H) 7.8(dd, J=8.8, 2.3Hz, 1H) 8.1(d, J=9.1Hz, 1H) 8.1(d, J=8.6Hz, 1H) #8.3(d, J=2.0Hz, 1H) 8.8(m, 1H) 9.4(s, 1H). (CDCl₃-d) IR (KBr) 1701, 1500, 1458, 1272, 1205, 1044, 768 M.P.: 84° C.2-[4-(6-Methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-quinolin-6-yl-acet-amide.Ex. 112 embedded image

1H-NMR 1.9(d, J=12.1Hz, 2H) 2.5(m, 2H) 2.9(qd, J=12.5, 4.0Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.8(m, 4H) 5.1(s, 2H) 6.7(d, J=2.5Hz, 1H) 6.9(m, 1H) 7.0(d, J=9.1Hz, 1H) 7.4(dd, J=8.3, 4.3Hz, 1H) 7.8(dd, J=9.1, 2.0Hz, 1H) 8.1(d, J=9.1Hz, 1H) 8.1(d, J=7.6Hz, 1H) 8.4(d, #J=2.5Hz, 1H) 8.8(m, 1H) 9.4(s, 1H). (CDCl₃-d) IR KBr) 3385, 1701, 1560, 1501, 1459, 1278, 1215, 1042 M.P.: 73° C.2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-quinolin-6-yl-acet-amideEx. 113 embedded image

1H-NMR 1.9(d, J=10.1Hz, 2H) 2.5(m, 2H) 2.9(qd, J=12.5, 4.0Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.3(s, 2H) 3.8(m, 1H) 5.1(s, 2H) 7.1(s, 1H) 7.1(m, 2H) 7.4(dd, J=8.6, 4.0Hz, 1H) 7.8(dd, J=9.1, 2.5Hz, 1H) 8.1(d, J=9.1Hz, 1H) 8.2(d, J=8.1Hz, 1H) 8.4(d, J=2.5Hz, 1H) 8.8(d, #J=2.5Hz, 1H) 9.4(s, 1H). (CDCl₃-d) IR (KBr) 3410, 1718, 1604, 1527, 1497, 1379, 1199, 1043 M.P.: 87° C.2-[4-(6-Fluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(2-methyl-benzothiazol-5-yl)-acetamideEx. 114 embedded image

1H-NMR 1.9(dd, J=12.4, 1.8Hz, 2H) 2.4(td, J=12.1, 2.0Hz, 2H) 2.8(s, 3H) 2.9(m, 2H) 3.1(d, J=12.1Hz, 2H) 3.2(s, 2H) 3.8(qd, J=12.1, 3.8Hz, 1H) 5.1(s, 2H) 6.9(dd, J=7.6, 2.5Hz, 1H) 7.0(m, 2H) 7.5(dd, J=8.6, 2.0Hz, 1H) 7.8(d, J=8.6Hz, 1H) 8.3(d, J=2.0Hz, 1H) 9.3(s, #1H). (CDCl₃-d) IR (KBr) 1701, 1501, 1459, 1271, 1206, 1045 M.P.: 99° C.2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(2-methyl-benzothiazol-5-yl)-actamide.Ex. 115 embedded image

1H-NMR 1.9(d, J=11.6Hz, 2H) 2.5(td, J=12.1, 2.5Hz, 2H) 2.8(s, 3H) 2.9(qd, J=12.5, 4.0Hz, 2H) 3.1(d, J=11.6Hz, 2H) 3.2(s, 2H) 3.8(m, 1H) 5.1(s, 2H) 7.0(s, 1H) 7.1(m, 2H) 7.5(dd, J=8.6, 2.0Hz, 1H) 7.8(d, J=8.6Hz, 1H) 8.4(s, 1H) 9.3(s, 1H). #(CDCl₃-d) IR (KBr) 1718, 1605, 1509, 1465, 1379, 1292, 1200, 1043 M.P.: 97° C.2-[4-(6-Methoxy-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(2-methyl-benzothiazol-5-yl)-acetamideEx 116 embedded image

1H-NMR 1.9(d, J=11.6Hz, 2H) 2.5(m, 2H) 2.8(s, 3H) 2.9(qd, J=12.5, 4.3Hz, 2H) 3.1(d, J=11.1Hz, 2H) 3.2(s, 2H) 3.8(s, 3H) 3.8(m, 1H) 5.1(s, 2H) 6.7(d, J=2.5Hz, 1H) 6.9(m, 1H) 7.0(d, J=9.1Hz, 1H) 7.6(dd, J=8.6, 2.0Hz, 1H) 7.8(d, J=8.6Hz, 1H) 8.3(d, J=2.0Hz, 1H) #9.3(s, 1H). (CDCl₃-d) IR (KBr) 1701, 1505, 1464, 1279, 1214, 1043 M.P.: 91° C.N-(3-Dimethylamino-phenyl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acet-amide.Ex. 117 embedded image

1H-NMR 1.9(d, J=11.9Hz, 2H) 2.4(t, J=11.8Hz, 2H) 2.9(tq, J=12.4, 3.9Hz, 2H) 3.0(s, 6H) 3.1(d, J=11.7Hz, 2H) 3.2(s, 2H) 3.8(m, 1H) 5.1(s, 1H) 6.5(dd, J=8.4, 2.4Hz, 1H) 6.9(d, J=7.9Hz, 1H) 7.1(m, 5H) 7.4(t, J=7.8Hz, 1H) 9.0(s, 1H) #(CDCl₃-d) IR (KBr) 3410, 2913, 1719, 1686, 1528, 1498, 1466, 1287, 1203, 1048, 764 M.P.: 148-153° C.N-(4-Dimethylamino-phenyl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acet-amide.Ex. 118 embedded image

1H-NMR 1.9(d, J=13.7Hz, 2H) 2.4(t, J=12.1Hz, 2H) 2.9(m, 2H) 2.9(s, 6H) 3.1(d, J=11.5Hz, 2H) 3.2(s, 2H) 3.8(m, 1H) 5.1(s, 2H) 6.7(m, 2H) 7.1(m, 3H) 7.4(m, 1H) 7.5(m, 2H) 8.9(s, 1H)(CDCl₃-d) IR (KBr) 3392, 1718, 1525, 1499, 1292, 1205, 1134, 1046, #813, 768, 753 M.P.: 128° C.N-(3-Dimethylamino-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-pipe-ridin-1-yl]-acetamide.Ex. 119 embedded image

1H-NMR 2.0(d, J=11.5Hz, 2H) 2.3(t, J=11.4Hz, 2H) 2.4(s, 3H) 2.9(m, 2H) 3.0(s, 6H) 3.1(m, 2H) 3.1(s, 2H) 3.4(m, 1H) 5.0(s, 2H) 6.5(m, 1H) 6.9(d, J=8.1Hz, 1H) 7.0(m, 2H) 7.2(m, 3H) 9.0(s, 1H)(CDCl₃-d) IR (KBr) 3346, 1719, 1677, 1611, 1500, 1474, #1283, 1217, 1036, 775 M.P.: 166° C.N-(4-Dimethylamino-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-pipe-ridin-1-yl]-acetamide.Ex. 120 embedded image

1H-NMR 2.0(d, J=11.9Hz, 2H) 2.3(t, J=11.6Hz, 2H) 2.4(s, 3H) 2.9(m, 2H) 2.9(s, 6H) 3.1(d, J=11.7Hz, 2H) 3.1(s, 2H) 3.4(tt, J=11.7, 3.7Hz, 1H) 5.0(s, 2H) 6.7(d, J=8.8Hz, 2H) 7.0(m, 2H) 7.2(d, J=6.0Hz, 1H) 7.5(d, J=9.0Hz, 2H) 8.9(s, #1H)(CDCl₃-d) IR (KBr) 3346, 1719, 1672, 1524, 1283, 1219, 1036, 813 M.P.: 152° C.N-(3-Dimethylamino-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-pipe-ridin-1-yl]-acetamideEx. 121 embedded image

1H-NMR 1.9(d, J=12.6Hz, 2H) 2.3(s, 3H) 2.4(m, 2H) 2.9(m, 2H) 3.0(s, 6H) 3.1(d, J=12.3Hz, 2H) 3.2(s, 2H) 3.8(m, 1H) 5.1(s, 2H) 6.5(s, 1H) 6.9(d, J=19.0Hz, 3H) 7.2(m, 3H) 9.0(s, 1H)(CDCl₃-d) IR (KBr) 3346, 1727, 1671, 1610, 1501, 1294, 1215, #1042, 806, 760 M.P.: 134-138° C.N-(4-Dimethylamino-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-pipe-ridin-1-yl]-acetamide.Ex. 122 embedded image

1H-NMR 1.9(d, J=11.9Hz, 2H) 2.3(s, 3H) 2.4(s, 2H) 2.8(s, 2H) 2.9(s, 6H) 3.1(d, 2H) 3.2(s, 2H) 3.8(s, 1H) 5.0(s, 2H) 6.7(d, J=8.9Hz, 2H) 7.0(m, 2H) 7.1(d, J=8.4Hz, 1H) 7.5(d, J=8.9Hz, 2H) 8.9(s, 1H)(CDCl₃-d) IR (KBr) 3278, 1719, 1523, 1509, #1214, 1045, 811, 763 M.P.: 120° C.N-(4-Diethylamino-phenyl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acet-amide.Ex. 123 embedded image

1H-NMR 1.1(t, J=7.0Hz, 6H) 1.9(d, J=12.3Hz, 2H) 2.4(td, J=11.9, 2.0Hz, 2H) 2.9(m, 2H) 3.1(d, J=11.7Hz, 2H) 3.2(s, 2H) 3.3(q, J=7.1Hz, 4H) 3.8(m, 1H) 5.1(s, 2H) 6.7(d, J=9.0Hz, 2H) 7.1(m, 3H) 7.4(d, J=9.0Hz, 1H) 7.4(d, J=9.0Hz, 2H) 8.9(s, #1H)(CDCl₃-d) IR (KBr) 3338, 1720, 1677, 1523, 1499, 1261, 1203, 1049, 817, 753 M.P.: 129° C.2-{2-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetylamino}-benzoic acidmethyl ester.Ex. 124 embedded image

1H-NMR 1.9(d, J=11.7Hz, 2H) 2.4(td, J=11.6, 1.8Hz, 2H) 3.0(qd, J=12.4, 3.9Hz, 2H) 3.1(d, J=11.3Hz, 2H) 3.2(s, 2H) 4.0(s, 3H) 4.2(qd, J=12.3, 3.8Hz, 1H) 5.1(s, 2H) 7.1(q, J=7.1Hz, 2H) 7.2(t, J=6.1Hz, 1H) 7.3(m, 1H) 7.5(d, J=8.2Hz, 1H) 7.5(m, 1H) #8.0(dd, J=8.0, 1.6Hz, 1H) 8.8(m, 1H) 12.1(s, 1H)(CDCl₃-d) IR (KBr) 3232, 1702, 1583, 1521, 1450, 1385, 1262, 1204, 1090, 1045, 772, 749 M.P.: 180° C.2-{2-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetylamino}-benzoicacid methyl ester.Ex. 125 embedded image

1H-NMR 1.9(d, J=12.3Hz, 2H) 2.3(t, J=12.7Hz, 2H) 2.4(s, 3H) 3.0(m, 4H) 3.2(s, 2H) 3.4(m, 1H) 4.1(s, 3H) 5.0(s, 2H) 7.1(m, 3H) 7.2(d, J=7.3Hz, 1H) 7.5(m, 1H) 8.0(dd, J=8.0, 1.7Hz, 1H) 8.8(d, J=8.4Hz, 1H) 12.2(s, 1H) (CDCl₃-d) IR #(KBr) 3202, 1727, 1705, 1508, 1449, 1270, 1215, 1089, 1033, 765 M.P.: 169° C.N-(2-Methoxy-dibenzofuran-3-yl)-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acet-amide hydrochlorideEx. 126 embedded image

1H-NMR 2.1(d, J=13.9Hz, 2H) 2.4(s, 3H) 2.9(m, 2H) 3.3(m, 2H) 3.6(d, J=11.2Hz, 2H) 3.8(m, 1H) 4.0(m, 3H) 4.2(s, 2H) 5.1(s, 2H) 7.1(m, 2H) 7.3(d, J=7.5Hz, 1H) 7.4(t, J=7.6Hz, 1H) 7.5(t, J=7.8Hz, 1H) 7.7(d, J=8.1Hz, 1H) 7.9(s, 1H) 8.1(d, J=6.8Hz, 1H) 8.4(s, 1H) #10.2(s, 1H) (DMSO-d6) IR (KBr) 3423, 1701, 1678, 1534, 1474, 1200, 1171, 1035, 760 M.P.: 272° C.N-2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]N-(2-methoxy-dibenzofuran-3-yl-acetamide hydrochlorideEx. 127 embedded image

1H-NMR 2.0(d, J=12.6Hz, 2H) 2.9(m, 2H) 3.3(m, 2H) 3.5(m, 1H) 3.7(d, J=10.1Hz, 2H) 4.0(s, 3H) 4.3(s, 2H) 5.2(s, 2H) 7.4(m, 5H) 7.7(d, J=8.1Hz, 1H) 7.9(s, 1H) 8.1(d, J=7.7Hz, 1H) 8.4(s, 1H) 10.2(s, 1H)(DMSO-d6) IR (KBr) 3422, 1701, 1541, 1459, #1299, 1196, 1166, 1036, 764 M.P.: 197° C.2-{2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetylamino}-benzoicacid methyl esterEx. 128 embedded image

1H-NMR 1.9(d, J=11.4Hz, 2H) 2.5(t, J=11.4Hz, 2H) 2.9(m, 2H) 3.1(d, J=11.5Hz, 2H) 3.2(s, 2H) 4.0(s, 3H) 4.2(qd, J=12.6, 3.9Hz, 1H) 5.1(s, 2H) 7.1(m, 2H) 7.3(m, 1H) 7.4(d, J=8.8Hz, 1H) 7.6(m, 1H) 8.1(dd, J=7.9, 1.6Hz, 1H) 8.8(d, J=8.4Hz, 1H) 12.1(s, #1H)(CDCl₃-d) IR (KBr) 1701, 1508, 1448, 1259, 1201. 1090, 756 M.P.: 153° C.2-{2-[4-(6-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetylamino}-benzoic acid methyl esterEx. 129 embedded image

1H-NMR 1.9(d, J=11.4Hz, 2H) 2.3(s, 3H) 2.4(m, 2H) 2.9(qd, J=12.4, 3.8Hz, 2H) 3.1(d, J=11.4Hz, 2H) 3.2(s, 2H) 4.0(s, 3H) 4.2(m, 1H) 5.0(s, 2H) 7.0(s, 1H) 7.1(m, 2H) 7.3(d, J=8.4Hz, 1H) 7.6(t, J=7.0Hz, 1H) 8.1(dd, J=8.1, 1.6Hz, 1H) 8.8(m, 1H) 12.1(s, #1H)(CDCl₃-d) IR (KBr) 1701, 1509, 1448, 1265, 1219, 1091, 756 M.P.: 153° C.2-[4-(6-Chloro2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-diethylamino-phenyl)-acetamide dihydrochlorideEx. 130 embedded image

1H-NMR 1.0(t, J=7.0Hz, 6H) 2.0(d, J=13.7Hz, 2H) 2.9(m, 2H) 3.4(m, 6H) 3.6(d, J=13.0Hz, 2H) 4.3(m, 3H) 5.2(s, 2H) 7.4(s, 3H) 7.8(s, 4H) 10.3(s, 1H) 11.5(s, 1H) 12.9(s, 1H)(DMSO-d6) IR (KBr) 3427. 2980, 2423, 1708, 1515, 1494, 1373, 1317, #1297, 1200 M.P.2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-{4-[ethyl-(2-hydroxy-ethyl)-amino]-phenyl}acetamide dihydrochlorideEx. 131 embedded image

1H-NMR 1.0(t, J=7.1Hz, 3H) 2.0(d, J=13.0Hz, 2H) 2.9(m, 2H) 3.4(m, 2H) 3.5(m, 6H) 3.6(d, J=11.9Hz, 2H) 4.2(s, 2H) 4.3(m, 1H) 5.2(s, 2H) 7.4(s, 3H) 7.6(m, 4H) 10.3(s, 1H) 11.4(s, 1H)(DMSO-d6) IR (KBr) 3392, 2958, 1701, 1515, 1493, 1376, 1316, #1201, 1039 M.P.N-{4-[ethyl-2(2-hydroxy-ethyl)-amino]-phenyl}-2-[4-(6-methyl-2-oxo-4H-ben-zo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide dihydrochlorideEx. 132 embedded image

1H-NMR 1.0(t, J=7.0Hz, 3H) 2.0(d, J=13.4Hz, 2H) 2.3(s, 3H) 2.9(m, 2H) 3.4(d, J=12.3Hz, 2H) 3.5(m, 6H) 3.6(d, J=10.8Hz, 2H) 4.3(m, 3H) 5.1(s, 2H) 7.1(s, 1H) 7.2(d, J=8.1Hz, 1H) 7.3(m, 1H) 7.7(m, 4H) 10.3(s, 1H) 11.4(s, #1H)(DMSO-d6) IR (KBr) 3366, 2983, 2508, 1701, 1619, 1563, 1509, 1318, 1294, 1261, 1217, 1039 M.P.:N-(4-Diethylamino-phenyl)-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-aceta-amide dihydrochlorideEx. 133 embedded image

1H-NMR 1.0(t, J=7.0Hz, 6H) 2.0(d, J=12.1Hz, 2H) 2.3(s, 3H) 2.9(m, 2H) 3.5(m, 6H) 3.6(d, J=11.0Hz, 2H) 4.3(m, 3H) 5.1(s, 2H) 7.1(s, 1H) 7.2(d, J=8.6Hz, 1H) 7.3(m, J=8.6Hz, 1H) 7.8(m, 4H) 10.3(s, 1H) 11.4(s, 1H) 12.9(s, 1H) #(DMSO-d6) IR (KBr) 3423, 2982, 1701, 1618, 1561, 1509, 1459, 1318, 1294, 1215, 1039 M.P.:N-(4-Diethylamino-phenyl)-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazi-1-yl)-piperidin-1-yl]-acet-amide dihydrochlorideEx. 134 embedded image

1H-NMR 1.0(t, J=7.0Hz, 6H) 2.1(d, J=13.5Hz, 2H) 2.4(s, 3H) 2.9(m, 2H) 3.3(m, 4H) 3.5(m, 4H) 3.8(t, J=11.6Hz, 1H) 4.2(s, 2H) 5.1(s, 2H) 7.1(m, 2H) 7.3(d, J=6.6Hz, 1H) 7.8(s, 4H) 10.2(s, 2H) 11.4(s, 1H) 12.8(s, #1H) (DMSO-d6) IR (KBr) 3412, 2804, 1693, 1622, 1577, 1519, 1473, 1382, 1289, 1261, 1224, 1021 M.P.N-{4-[ethyl-(2-hydroxy-ethyl)-amino]-phenyl}-2-[4-(8-methyl-2-oxo-4H-ben-zo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide dihydrochlorideEx. 135 embedded image

1H-NMR 1.0(t, J=7.0Hz, 3H) 2.1(d, J=12.5Hz, 2H) 2.4(s, 3H) 2.9(m, 2H) 3.3(m, 2H) 3.6(m, 9H) 4.1(s, 2H) 5.1(s, 2H) 7.1(m, 2H) 7.3(d, J=7.1Hz, 1H) 7.7(s, 4H) 10.2(s, 1H) 11.3(s, 1H)(DMSO-d6) IR (KBr) 3387, 2983, 2624, #1701, 1566, 1515, 1383, 1320, 1281, 1219 M.P.:N-Benzo[1,3]dioxol-5-yl-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acet-amideEx. 136 embedded image

1H-NMR 1.9(d, J=13.4Hz, 2H) 2.4(td, J=12.0, 2.0Hz, 2H) 2.9(m, 2H) 3.1(d, J=9.5Hz, 2H) 3.2(s, 2H) 3.8(tt, J=12.0, 4.0Hz, 1H) 5.1(s, 2H) 6.0(s, 2H) 6.8(d, J=8.2Hz, 1H) 6.9(m, 1H) 7.1(m, 3H) 7.4(m, 2H) 9.0(s, #1H)(CDCl₃-d) IR (KBr) 3417, 1719, 1686, 1542, 1491, 1241, 1204, 1034 M.P.: 183.8N-Benzo[1,3]dioxol-5-yl-2-[4-(6-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acet-amideEx. 137 embedded image

1H-NMR 1.9(d, J=10.4Hz, 2H) 2.3(s, 3H) 2.4(t, J=11.4Hz, 2H) 2.9(qd, J=12.3, 4.1Hz, 2H) 3.1(d, J=11.9Hz, 2H) 3.2(s, 2H) 3.8(tt, J=11.8, 3.7Hz, 1H) 5.1(s, 2H) 6.0(s, 2H) 6.8(d, J=8.2Hz, 1H) 6.9(m, 3H) 7.1(d, #J=9.9Hz, 1H) 7.3(d, J=2.0Hz, 1H) 9.1(s, 1H)(CDCl₃-d) IR (KBr) 3408, 1709, 1531, 1484, 1211, 1029, 809 M.P.: 123.0N-Benzo[1,3]dioxol-5-yl-2-[4-(6-chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acet-amideEx. 138 embedded image

1H-NMR 1.9(d, J=12.6Hz, 2H) 2.4(m, 2H) 2.9(qd, J=12.3, 3.7Hz, 2H) 3.1(d, J=11.5Hz, 2H) 3.2(s, 2H) 3.8(tt, J=11.9, 3.8Hz, 1H) 5.1(s, 2H) 6.0(s, 2H) 6.8(d, J=8.2Hz, 1H) 6.9(m, 1H) 7.0(d, J=8.6Hz, 1H) 7.2(d, #J=2.4Hz, 1H) 7.3(m, 2H) 9.0(s, 1H)(CDCl₃-d) IR (KBr) 3300, 1719, 1686, 1529, 1490, 1241, 1199, 1035 M.P.: 185.7-187.3N-Benzo[1,3]dioxol-5-yl-2-[4-(8-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acet-amideEx. 139 embedded image

1H-NMR 2.0(d, J=13.0Hz, 2H) 2.3(m, 2H) 2.4(s, 3H) 2.9(qd, J=12.2, 3.6Hz, 2H) 3.1(d, J=2.4Hz, 2H) 3.1(s, 2H) 3.4(tt, J=11.7, 3.7Hz, 1H) 5.0(s, 2H) 6.0(s, 2H) 6.8(d, J=8.2Hz, 1H) 6.9(m, 1H) 7.0(m, 2H) 7.2(d, #J=1.1Hz, 1H) 7.4(d, J=2.2Hz, 1H) 9.0(s, 1H)(CDCl₃-d) IR (KBr) 3316, 1711, 1686, 1534, 1490, 1242, 1212, 1033 M.P.: 173.5N-{4-[ethyl-(2-hydroxy-ethyl)-amino]-phenyl}-2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-pipe-ridin-1-yl]-acetamide dihydrochlorideEx. 140 embedded image

1H-NMR 1.0(t, J=7.0Hz, 3H) 2.0(d, J=13.4Hz, 2H) 2.9(m, 2H) 3.5(m, 9H) 4.2(s, 2H) 4.3(m, 1H) 5.2(s, 2H) 7.1(m, 1H) 7.3(d, J=7.3Hz, 1H) 7.4(s, 2H) 7.7(m, 4H) 10.3(s, 1H) 11.5(s, 1H)(DMSO-d6) IR #(KBr) 3342, 2943, 2501, 1702, 1515, 1467, 1316, 1260, 1204, 1043, 770 M.P.:2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-dimethylamino-phenyl)-acetamide dihydrochlorideEx. 141 embedded image

1H-NMR 2.0(d, J=12.6Hz, 2H) 2.9(m, 2H) 3.0(s, 6H) 3.4(d, J=11.9Hz, 2H) 3.6(m, 2H) 4.2(s, 2H) 4.3(m, 1H) 5.2(s, 2H) 7.4(m, 4H) 7.6(m, 3H) 10.2(s, 1H) 11.1(s, 1H) (DMSO-d6) IR (KBr) 3448, 2958, #2400, 1716, 1701, 1518, 1495, 1200 M.P.:

Example 142

N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(4-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide.

Example 143

N-(9-Ethyl-9H-carbazol-3-yl)-2-[4-(4-methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide.

Example 144

2-[4-(4-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide.

Example 145

2-{2-[4-(2-Oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamino}-benzoic acid.

Example 146

1-{1-[2-(6-Fluoro-2-methyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}1,4-dihydro-benzo[d][1,3]oxazin-2-one.

Example 147

6-Chloro-1-{1-[2-(6-fluoro-2-methyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one.

Example 148

1-{1-[2-(6-Fluoro-2-methyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one.

Example 149

1-(1-[2-(6-Fluoro-2-methyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one.

Example 150

1-{1-[2-(6-Methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one.

Example 151

6-Chloro-{1-[2-(6-methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-1,4-dihydro-benzo[d][1,3]oxazin-2-one.

Example 152

1-{1-[2-(6-Methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-8-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one.

Example 153

1-{1-[2-(6-Methoxy-2,2,4-trimethyl-3,4-dihydro-2H-quinoline-1-yl)-2-oxo-ethyl]-piperidin-4-yl}-6-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one.

Example 154

N-(9-Hydroxy-9H-fluoren-3-yl)-2-[4-(2-oxo-7-trifluormethyl-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide.

Example 155

N-(9H-carbazol-3-yl)-2-[4-(2-oxo-7-trifluormethyl-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide.

Example 156

2-[4-(2-Oxo-7-trifluormethyl-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-4-phenoxy-phenyl)-acetamide.

Example 157

N-(g-Ethyl-9H-carbazol-3-yl)-2-[4-(2-oxo-7-trifluormethyl-4H-benzo[d][1,3]oxazin-1-ylypiperidin-1-yl]-acetamide.

Example 158

2-4-(6,7-Difluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-hydroxy-9H-fluoren-3-yl)-acetamide.

Example 159

N-(9H-carbazol-3-yl)-2-[4-(6,7-difluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-acetamide.

Example 160

2-4-(6,7-Difluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(4-phenoxy-phenyl)-acetamide.

Example 161

2-4-(6,7-Difluoro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-ethyl-9H-carbazol-3-yl)-acetamide.

Example 162

2-[4-(4-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide.

Example 163

2-[4-(6-Chloro-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(3-dimethylamino-phenyl)-acetamide.

Preparation of the Compound of General Formula (Ib):

Example Ab

Synthesis of an Intermediate Compound of General Formula (IIb)

Preparation of 6-Chloro-1-(piperidine-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride

embedded image

b) 1-(tert-Butyloxycarbonyl)-4-[4-chloro-(2-hydroxymethylphenylamine)]piperidine

d.) 1-(1-tert-Butyloxycarbonyl-4-piperidinyl)-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one

N,N-diisopropylethylamine (DIEA) (43 mL, 0.25 mol) and triphosgene (8.65 g, 29.2 mmol) were added to a solution of 1-(tert-Butyloxycarbonyl)-4-[(4-chloro-(2-hydroxymethyl) phenyl-amino)]piperidine (27.0 g, 79 mmol) in dry THF (250 mL) cooled at 0° C. The reaction was stirred at 0° C. for 1 h and at room temperature for 72 h. Ethyl ether was added and the mixture was cooled at 0° C. for 3 h and the DIEA hydrochloride was then filtered. The filtered solution was evaporated to dryness and the residue was dissolved in ethyl acetate (750 mL), washed with 5% solution of critic acid (2×500 mL), water (250 mL) and NaHCO₃-saturated solution (2×500 mL). The ethyl acetate solution was dried (MgSO₄), filtered and evaporated under reduced pressure. The residue was brought to the boil with ethyl ether until the whole solid was dissolved and then cooled overnight to yield the desired compound in crystalline form (28.9 g, 67%).

Melting point: 177-179° C.

e.) 6-chloro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride

A solution of 1-[(1-tert-Butyloxycarbonyl)-4-piperidinyl]-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one (24 g, 65 mmol) in ethyl acetate (500 mL) was cooled at 0° C. A 5 M solution of hydrogen chloride in ethyl ether (500 mL) was then added and the resulting mixture was stirred at 0° C. for 4 h. The precipitate formed was collected by filtration, washed with ether and vacuum dried to yield the desired product as a solid (16.95 g, 97%).

Melting point: 254-257° C.

¹H NMR (CD₃OD): 2.13 (d, J=12.2 Hz, 2H), 2.88 (m, 2H), 3.20 (m, 2H), 3.53 (d, J=12.8 Hz, 2H), 4.24 (m, 1H), 5.16 (s, 2H), 7.31 (m, 2H), 7.41 (dd, J=8.8 Hz, J=2.6 Hz, 1H).

Several substituted 3,1-benzoxazin-2-one compounds were prepared via the respectively substituted benzyl alcohols by reducing the respectively substituted anthranilic acids with lithium aluminium hydride and other known reducing agents by methods well known to those skilled in the art (see scheme 1), e.g. por ejemplo 6-methyl-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 7-methyl-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 8-methyl-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 5-methoxy-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 6-fluoro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 8-methoxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 5-methyl-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 7-fluoro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 5-fluoro-1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 6-methoxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 5-chloro-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 7-chloro-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 8-chloro-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one and others. The reaction of the respective 5-methoxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 8-methoxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one and 6-methoxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one compounds according to conventional methods, e.g. BBr₃in an inert organic solvent yields the respective 5-hydroxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one, 8-hydroxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one and 6-hydroxy-1-(piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one compounds. The unsubstituted benzoxazin-2-one 1-(piperidin-4-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one is prepared according the method described in J. Med. Chem. 1995, 38, 4634 and J. Med. Chem. 1998, 41, 2146, which are hereby incorporated by reference and form part of the disclosure.

The substituted anthranilic acids were reduced by conventional methods known to those skilled in the art, e.g. by the use of LiAlH₄as reducing agent in anhydrous THF under an inert-gas atmosphere, e.g. argon or nitrogen. This process is very efficient and in most cases the respective 2-aminobenzylalcohols are obtained in very good yields.

General Instruction for the Reduction of Substituted Anthranilic Acids:

To a three neck flask, equipped with a mechanical stirrer and an inlet for gaseous nitrogen, 100 mL anhydrous THF and 116.6 mmoles of LiAlH₄were given and the resulting suspension cooled to 0° C. After the addition of 58.3 mmoles of the respective substituted anthranilic acid in 150 mL anhydrous THF, the resulting reaction mixture is warmed to room temperature and stirred or about an hour. Under cooling to 0° C. 4.7 mL water, 4.7 mL NaOH 15 wt.-%, and finally 14 mL water are carefully added to the mixture. The resulting suspension is filtered and washed with ethylacetate.

The organic phase is washed with water, dried and the solvent evaporated. In most cases the resulting product may be used without further purification.

Example 5b
Preparation of 1-[1-quinoline-8-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one

embedded image

150 mg (0.66 mmol) quinoline-8-sulfonyl chloride are added to a mixture of 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazinone hydrochloride (161 mg, 0.60 mmol) and diisopropylethylamin (230 mg, 1.80 mmol) in dichloromethane (10 ml) and the resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was then washed with water (3×15 mL) and the organic phase was separated, dryed and evaporated to dryness. A solid was obtained, which was recrystallized from ethanol. 182 mg of 1-[1-quinoline-8-sulfonyl)piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazin-2-one were obtained as a white solid (yield 69%).

IR (cm⁻¹) KBr: 1712, 1337, 1291, 1205, 1162, 1144, 1034, 717, 583

¹H-NMR (δ in ppm): 1.8 (d, J=9.5 Hz, 2H) 2.6 (qd, J=12.6, 4.4 Hz, 2H) 3.0 (td, J=12.8, 2.5 Hz, 2H) 4.1 (tt, J=12.5, 3.8 Hz, 1H) 4.3 (ddd, J=13.0, 2.3 Hz, 2H) 5.0 (s, 2H) 7.1 (m, 3H) 7.3 (m, 1H) 7.6 (dd, J=8.4, 4.2 Hz, 1H) 7.6 (m, 1H) 8.1 (dd, J=8.2, 1.3 Hz, 1H) 8.3 (dd, J=8.3, 1.7 Hz, 1H) 8.5 (dd, J=7.3, 1.5 Hz, 1H) 9.1 (dd, J=4.2, 1.8 Hz, 1H) (CDCl3-d).

Melting point: 170-172° C.

The compounds according to examples 1b-4b and 6b-10b given in the following table Ib were prepared analogously to the methods described above:

TABLE 1b1-[1-(Naphthyl-1-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazine-2-oneEx. 1b embedded image

1H-NMR: 1.8(d, J=10.5Hz, 2H) 2.4(m, 2H) 2.7(t, J=11.6Hz, 2H) 3.9(m, 3H) 5.1(s, 2H) 7.1(m, 2H) 7.2(m, 2H) 7.7(m, 3H) 8.1(d, J=8.1Hz, 1H) 8.2(d, J=7.8Hz, 1H) 8.3(d, J=8.1Hz, 1H) 8.7(d, J=8.3Hz, 1H)(DMSO-d6) IR (KBr) 1709, 1498, 1353, 1162, 1034, 770, 718, 579 Melting point: 147-149° C.1-(1-Phenylsulfonyl-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazine-2-oneEx. 2b embedded image

1H-NMR: 1.9(dd, J=12.1, 2.1Hz, 2H) 2.4(td, J=12.2, 2.4Hz, 2H) 2.7(qd, J=12.6, 4.3Hz, 2H) 3.9(tt, J=12.3, 3.9Hz, 1H) 4.0(dt, J=11.9, 2.1Hz, 2H) 5.0(s, 2H) 7.0(d, J=8.3Hz, 1H) 7.0(t, J=7.3Hz, 1H) 7.1(m, 1H) 7.3(m, 1H) 7.6(m, 3H) 7.8(m, 2H) (CDCl₃-d) IR (KBr) 1705, 1497, 1340, 1293, 1205, 1160, 736, #691, 576 Melting point: 172-174° C.1-[1-(5-chloro-3-methyl-benzo[b]tiophene-2-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazine-2-oneEx. 3b embedded image

1H-NMR: 1.8(d, J=10.8Hz, 2H) 2.5(m, 2H) 2.7(s, 3H) 2.8(t, J=11.4Hz, 2H) 3.8(d, J=11.4Hz, 2H) 3.9(m, 1H) 5.1(s, 2H) 7.0(t, J=7.2Hz, 1H) 7.2(d, J=8.1Hz, 1H) 7.2(m, 2H) 7.6(dd, J=8.6, 2.0Hz, 1H) 8.1(d, J=2.0Hz, 1H) 8.2(d, J=8.6Hz, 1H) (DMSO-d6) IR (KBr) 1717, 1358, 1248, 1201, 1160, 1035, 712, #554 Melting point: 204-206° C.8-Methyl-1-[1-(naphthyl-1-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazine-2-oneEx. 4b embedded image

1H-NMR: 1.9(d, J=12.5Hz, 2H) 2.3(s, 3H) 2.7(m, 4H) 3.3(m, 1H) 4.0(d, J=11.2Hz, 2H) 4.9(s, 2H) 7.0(m, 2H) 7.1(d, J=7.0Hz, 1H) 7.6(m, 3H) 7.9(m, 1H) 8.1(d, J=8.2Hz, 1H) 8.2(dd, J=7.3, 1.1Hz, 1H) 8.7(d, J=8.8Hz, 1H)(CDCl3-d) IR (KBr) 1712, 1316, 1279, 1222, 1160, 1135, 1025, 768, 607 Melting #point: 203-204° C.1-[1-(Quinolinyl-8-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazine-2-oneEx. 5b embedded image

1H-NMR: 1.8(d, J=9.5Hz, 2H) 2.6(qd, J=12.6, 4.4Hz, 2H) 3.0(td, J=12.8, 2.5Hz, 2H) 4.1(tt, J=12.5, 3.8Hz, 1H) 4.3(ddd, J=13.0, 2.3Hz, 2H) 5.0(s, 2H) 7.1(m, 3H) 7.3(m, 1H) 7.6(dd, J=8.4, 4.2Hz, 1H) 7.6(m, 1H) 8.1(dd, J=8.2, 1.3Hz, 1H) 8.3(dd, J=8.3, 1.7Hz, 1H) 8.5(dd, J=7.3, 1.5Hz, 1H) 9.1(dd, J=4.2, #1.8Hz, 1H)(CDCl3-d) IR (KBr) 1712, 1337, 1291, 1205, 1162, 1144, 1034, 717, 583 Melting point: 170-172° C.8-Methyl-1-[1-(quinolinyl-8-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazine-2-oneEx. 6b embedded image

1H-NMR: 1.9(d, J=12.6Hz, 2H) 2.3(s, 3H) 2.7(qd, J=12.2, 3.9Hz, 2H) 2.9(m, 2H) 3.3(tt, J=11.7, 3.4Hz, 1H) 4.3(d, J=12.8Hz, 2H) 4.9(s, 2H) 7.0(m, 2H) 7.1(d, J=7.3Hz, 1H) 7.5(dd, J=8.3, 4.1Hz, 1H) 7.6(m, 1H) 8.0(dd, J=8.2, 1.3Hz, 1H) 8.2(dd, J=8.3, 1.7Hz, 1H) 8.5(dd, J=7.3, 1.5Hz, 1H) 9.1(dd, J=4.2, #1.8Hz, 1H)(CDCl3-d) IR (KBr) 1702, 1329, 1284, 1218, 1024, 785, 701, 582 Melting point: 202-206° C.1-[1-(5-Dimethylamino-naphthyl-1-sulfonyl)-piperidine-4-yl]-8-Methyl-1,4-dihydro-benzo[d][1,3]oxazine-2-oneEx. 7b embedded image

1H-NMR: 1.9(d, J=11.9Hz, 2H) 2.3(s, 3H) 2.7(m, 4H) 2.9(s, 6H) 3.3(m, 1H) 4.0(d, J=9.9Hz, 2H) 4.9(s, 2H) 7.0(m, 2H) 7.2(m, J=7.3Hz, 2H) 7.5(m, 2H) 8.2(dd, J=7.3, 1.1Hz, 1H) 8.4(d, J=8.6Hz, 1H) 8.6(d, J=8.4Hz, 1H)(CDCl3-d) IR (KBr) 2981, 1711, 1336, 1221, 1149, 1025, 794, 709, 571 Melting #point: 202-203° C.1-[1-(5-Dimethylamino-naphthyl-1-sulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazine-2-oneEx. 8b embedded image

1H-NMR 1.8(dd, J=12.3, 3.5Hz, 2H) 2.7(m, 4H) 2.9(s, 6H) 4.0(m, 3H) 5.0(s, 2H) 6.9(d, J=8.2Hz, 1H) 7.1(m, 2H) 7.3(m, 2H) 7.6(td, J=8.9, 7.4Hz, 2H) 8.3(dd, J=7.3, 1.3Hz, 1H) 8.4(d, J=8.8Hz, 1H) 8.6(d, J=8.2Hz, 1H)(CDCl3-d) IR (KBr) 2935, 1720, 1319, 1242, 1144, 920, 791, 755, 642 Melting point: #182-186° C.1-[1-(2,3-Dichloro-phenylsulfonyl)-piperidine-4-yl]-1,4-dihydro-benzo[d][1,3]oxazine-2-oneEx. 9b embedded image

1H-NMR 1.9(d, J=10.1Hz, 2H) 2.7(qd, J=12.6, 4.2Hz, 2H) 3.0(td, J=12.7, 2.3Hz, 2H) 4.1(m, 3H) 5.1(s, 2H) 7.1(m, 3H) 7.3(m, 2H) 7.7(dd, J=8.0, 1.6Hz, 1H) 8.0(dd, J=8.0, 1.6Hz, 1H)(CDCl3-d) IR (KBr) 1697, 1395, 1244, 1165, 1045, 942, 710, 582 Melting point: 185-187° C.1-[1-(2,3-Dichloro-phenylsulfonyl)-piperidine-4-yl]-8-Methyl-1,4-dihydro-benzo[d][1,3]oxazine-2-oneEx. 10b embedded image

1H-NMR: 2.0(d, J=11.5Hz, 2H) 2.4(s, 3H) 2.8(m, 4H) 3.4(m, 1H) 4.0(d, J=9.9Hz, 2H) 5.0(s, 2H) 7.0(m, 2H) 7.2(d, J=7.7Hz, 1H) 7.3(t, J=8.0Hz, 1H) 7.7(dd, J=8.1, 1.5Hz, 1H) 8.0(dd, J=8.0, 1.6Hz, 1H)(CDCl3-d) IR (KBr) 1705, 1404, 1339, 1224, 1149, 939 Melting point: 184-185° C.

Preparation of the Compounds of General Formula (Ic):

Method Ac

Example 7c
Preparation of N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methyl-benzo[b]thiophene-2-sulphonamide

To a solution of 3.05 g (15 mMol) of 5-amino-3-(2-dimethylaminoethyl)-1H-indol in 100 ml of pyridine is added dropwise at ambient temperature a solution of 4.21 g (15 mMol) of 5-chloro-3-methyl-benzo[b]thiophene-2-sulphonyl chloride in 20 ml of pyridine. The reaction mixture is stirred at ambient temperature for 20 hours. It is then evaporated to dryness, slightly alkalinised with diluted ammonia and dissolved in ethyl acetate. The organic phase is washed with water and a saturated solution of sodium bicarbonate, it is separated and dried with anhydrous sodium sulphate. The organic solution is evaporated to dryness and the resulting solid is repeatedly washed with ethyl ether, to yield 5.5 g (82%) of N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methyl-benzo[b]thiophene-2-sulphonamide as a solid with m.p.=226-227° C.

Method Bc

Example 26c
Preparation of N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-N-ethyl-naphthalene-2-sulphonamide

To a mixture of 285 mg (0.7 mMol) of N-[3-(2-diethylaminoethyl)-1H-indol-5yl]naphthalene-2-sulphonamide (example 17) and 80 mg (0.7 mMol) of potassium t-butoxide in 3 ml of DMSO are stirred for 30 minutes at ambient temperature.

Then are added 105 mg (0.7 mMol) of ethyl iodide and left with stirring for 3 hours. Water is added and is extracted with ethyl acetate. The organic solution is evaporated to dryness and the resulting crude is purified by chromatography on silica gel, using as an eluent mixtures of methylene chloride/methanol/ammonia, yielding N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-N-ethyl-naphthalene-2-sulphonamide as a solid with m.p.=49-50° C.

Method Cc

Example 18c
Preparation of N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide

To a solution of 712 mg (13.2 mMol) of sodium methoxide in 100 ml of methanol are added 850 mg (2.64 mMol) of N-[1H-indol-5-yl]naphthalene-1-sulphonamide followed by 596 mg (5.28 mMol) of 1-methyl-4-piperidone and the resulting solution is heated to reflux for 48 hours. The reaction mixture is concentrated at reduced pressure and the residue obtained is purified by chromatography over silica gel, using as eluent mixtures of methylene chloride/methanol/ammonia, to yield 573 mg (52%) of N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide as a solid with m.p.=244-245° C.

Method Dc

Example 12c
Preparation of N-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide

To a solution of 417 mg (1 mMol) of N-[3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide in 50 ml of methanol are added 100 mg of 5% palladium on carbon. The mixture is hydrogenated at ambient temperature at an initial hydrogen pressure of 3 atmospheres for 20 hours. The reaction mixture is filtered and the filtrate is concentrated at reduced pressure to provide a crude that is suspended in ethyl ether, yielding 272 mg (65%) of N-[3-(1-methyl-piperidin-4-yl)-1H-indol-5-yl]naphthalene-1-sulphonamide as a solid with m.p.=254-256° C.

Method Ec

Example 3c
Preparation of N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide hydrochloride

1.05 g (2.5 mMol) of N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide (example 2) are dissolved in 10 ml of ethanol and 0.6 ml are added of a 4.2 N solution of hydrochloric acid in ethanol. It is allowed to crystallise at ambient temperature. N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-1-sulphonamide hydrochloride is obtained as a solid with m.p.=255-257° C.

The melting point and spectroscopic data for identifying some of the compounds used according to the present invention are shown in the following table:

ExR^1cR^2cncR^3cA^cSaltm.p.° C.IR cm⁻¹¹H-RMN (300 MHz), δ (solvent)1cH(CH₃CH₂)₂N—2H embedded image

—170-1733387, 2970, 2931, 1466, 1236, 1158, 1107, 1080, 993, 862, 805, 657, 565.0.88(t, 6H, J=7.1Hz); 2.28(s, 3H): 2.30-2.46(m, 6H); 2.58(m, 2H); 6.85(dd, 1H, J=8.6, 2.0Hz); 7.10(m, 2H); 7.20(d, 1H, J=8.6Hz); 7.50(dd, 1H, J=8.7, #2.0Hz); 7.90(d, 1H, J=2.0Hz); 7.98(d, 1H, J=8.7Hz); 10.10(bb, 1H); 10.80(s, 1H). (DMSO-d6)2cH(CH₃CH₂)₂N—2H embedded image

—1703451, 3337, 2972, 1466, 1319, 1237, 1157, 1132, 1091, 991, 770, 675, 583, 481.0.90(t, 6H, J=7.1Hz); 2.33-2.55(m, 8H); 6.69(dd, 1H, J=8.7, 1.8Hz); 6.95(s, 1H); 7.02(d, 1H, J=1.8Hz); 7.05(d, 1H, J=8.7Hz); 7.47(t, #1H, J=7.7Hz); 7.63(m, 1H); 7.70(m, 1H); 8.01(m, 2H); 8.12(d, 1H, J=7.5Hz); 8.77(d, 1H, J=8.1Hz); 10.10(bb, 1H); 10.66(s, 1H) (DMSO-d6)3cH(CH₃CH₂)₂N—2H embedded image

HCl255-2573378, 3065, 2558, 2489, 1460, 1317, 1162, 1143, 1131, 811, 687, 602, 588.1.22(t, 6H, J=7.2Hz); 2.91-3.18(m, 8H); 6.65(d, 1H, J=8.6Hz); 7.08(d, 1H, J=8.6Hz); 7.17(s, 1H); 7.20(d, 1H, J=1.8Hz); 7.54(t, 1H, #J=7.8Hz); 7.63(m, 1H); 7.70(m, 1H); 8.03(d, 1H, J=7.8Hz); 8.08(d, 1H, J=7.1Hz); 8.14(d, 1H, J=8.2Hz); 8.79(d, 1H, J=8.4Hz); 10.26(s, 1H); 10.90(bb, 1H); 11.01(s, 1H). (DMSO-d6)4cH(CH₃CH₂)₂N—2H embedded image

—168-1703309, 3047, 2974, 1566, 1467, 1235, 1167, 1143, 1116, 1001, 910, 799, 672, 587.0.95(t, 6H, J=7.1Hz); 2.44-2.58(m, 6H); 2.66(m, 2H); 6.79(dd, 1H, J=8.6, 1.7Hz); 7.08(d, 1H, J=0.9Hz); 7.13(d, 1H, #J=1.7Hz); 7.23(d, 1H, J=8.6Hz); 7.58(m, 2H); 7.87(m, 1H); 9.95(bb, 1H); 10.82(s, 1H). (DMSO-d6)5cH(CH₃CH₂)₂N—2H embedded image

—161-1633387, 2971, 1323, 1157, 1095, 765, 670, 5900.89(t, 6H, J=7.1Hz); 2.32-2.55(m, 6H); 2.62(m, 2H); 6.85(d, 1H, J=8.6Hz); 7.08(d, 1H, J=2.0Hz); 7.13(s, 1H); 7.18(d, 1H, J=8.6Hz); 7.33-7.50(m, 3H); 7.64(d, 2H, #J=7.5Hz); 7.72(sys AB, 2H, J=8.6Hz); 7.78(sys AB, 2H, J=8.6Hz); 9.80(bb, 1H); 10.75(s, 1H). (DMSO-d6)6cH(CH₃CH₂)₂N—2H embedded image

—180-1813375, 2978, 1467, 1417, 1236, 1212, 1115, 994, 624.0.96(t, 6H, J=7.1Hz); 2.52(m, 4H); 2.57(m, 2H); 2.66(m, 2H); 6.83(dd, 1H, J=8.6, 1.9Hz); 7.11(d, 1H, J=4.0Hz); 7.14(d, 1H, J=1.9Hz); 7.17(d, #1H, J=1.9Hz); 7.20-7.24(m, 2H); 10.01(bb, 1H); 10.81(s, 1H). (DMSO-d6)7cH(CH₃)₂N—2H embedded image

—226-2273422, 3238, 1332, 1155, 1114, 1079, 986, 861, 803, 655, 564.2.04(s, 6H); 2.23(m, 2H); 2.28(s, 3H), 2.59(m, 2H); 6.83(dd, 1H, J=8.4, 1.5Hz); 7.09(s, 2H); 7.19(d, 1H, J=8.4Hz); 7.49(dd, 1H, J=8.7, #1.6Hz); 7.91(d, 1H, J=1.6Hz); 7.99(d, 1H, J=8.7Hz); 10.13(bb, 1H), 10.79(s, 1H) (DMSO-d6)8cH(CH₃)₂N—2H embedded image

—203-2053357, 1475, 1282, 1157, 1127, 990, 957, 809, 773, 613, 587, 557, 498.2.09(s, 6H); 2.21(m, 2H); 2.54(m, 2H); 6.69(dd, 1H, J=8.6, 1.7Hz); 6.94(s, 1H); 7.03(s, 1H); 7.06(d, 1H, J=8.1Hz); 7.49(t, 1H, #J=7.8Hz); 7.64(m, 1H); 7.71(m, 1H); 8.02(m, 2H); 8.13(d, 1H, J=8.1Hz); 8.79(d, 1H, J=8.4Hz); 10.10(bb, 1H); 10.68(s, 1H) (DMSO-d6)9cH(CH₃)₂N—2H embedded image

—215 (desc)3247, 3094, 1467, 1272, 1261, 1230, 6252.17(s, 6H); 2.36(m, 2H); 2.65(m, 2H); 6.77(dd, J=8.6, 1.7Hz, 1H); 7.07(d, 1H); 7.09(s, 1H); 7.18(d, J=8.6Hz, 1H); 7.51(d, J=4.5Hz, 1H); 7.81(d, J=4.5Hz, 1H); 10.80(s, 1H). (DMSO-d6).10cH embedded image

—250 (desc)3407, 2390, 1466, 1334, 1156, 113, 1080, 651, 565.1.53-1.80(m, 4H); 2.26(s, 3H); 2.39-2.71(m, 6H); 3.02(d, 2H, J=8.8Hz); 6.76(d, 1H, J=8.8Hz); 7.05(s, 1H); 7.11(s, 1H); 7.19(d, 1H, J=8.8Hz); 7.51(d, 1H, J=8.7Hz); 7.91(s, 1H); 8.00(d, 1H, #J=8.7Hz); 10.10(bb, 1H); 10.90(s, 1H). (DMSO-d6)11cH embedded image

HCl220 (desc)3423, 3214, 3043, 2942, 2688, 1464, 1317, 1149, 1114, 1080, 748, 670, 6461.75-1.92(m, 4H); 2.31(s, 3H); 2.66(s, 3H); 2.80(m, 1H); 2.95(m, 2H); 3.24(d, 2H, J=11.4Hz); 6.76(d, 1H, J=8.7Hz); 7.07(s, 1H); #7.19(m, 2H); 7.50(d, 1H, J=8.6Hz); 7.93(s, 1Hz); 8.01(d, 1H, J=8.6Hz); 8.34(s, 1H); 10.90(bb, 1H); 11.01(s, 1H). (DMSO-d6)12cH embedded image

—254-2563343, 2938, 2929, 1470 1154, 1121, 1108, 988, 947, 805, 769, 589.1.49(m, 2H); 1.61(m, 2H); 2.14(m, 2H); 2.30(s, 3H); 2.40(m, 1H); 2.90(d, 2H, J=10.6Hz); 6.65(d, 1H, J=8.6Hz); 6.90(s, 1H); 6.96(s, 1H); 7.05(d, #1H, J=8.6Hz); 7.46(dt, 1H, J=7.51, 1.83Hz); 7.64(m, 1H); 7.71(m, 1H); 7.99(d, 1H, J=8.6Hz); 8.03(d, 1H, J=8.6Hz); 8.12(d, 1H, J=8.2Hz); 8.77(d, 1H, J=8.6Hz); 10.07(bb, 1H); 10.71(s, 1H). (DMSO-d6)13cH embedded image

HCl212 (desc)3423, 3269, 3114, 2955, 2733, 1469, 1321, 1155, 1133, 947, 769.1.80(m, 4H); 2.74(m, 4H); 3.04(m, 2H); 3.39(m, 2H); 6.63(d, 1H, J=8.6Hz); 7.00(s, 2H); 7.08(d, 1H, J=8.6Hz); 7.49(t, 1H, J=7.7Hz); 7.60-7.77(m, 2H); #8.04(d, 2H, J=7.5Hz); 8.13(d, 1H, J=8.2Hz); 8.79(d, 1H, J=8.2Hz); 10.16(s, 1H); 10.66(bb, 1H); 10.88(s, 1H). (DMSO-d6)14cH embedded image

—284 (desc)3371, 2943, 1468, 1410, 1324, 1148, 993, 604.1.62(m, 2H); 1.78(d, 2H, J=11.7Hz); 1.99(m, 2H); 2.18(s, 3H); 2.55(m, 1H); 2.84(d, 2H, J=10.6Hz); 6.81(d, 1H, J=8.6Hz); 7.07(s, 1H); 7.13(m, 1H); 7.16(s, 1H); 7.20-7.26(m, 1H); #9.90(bb, 1H); 10.83(s, 1H). (DMSO-d6)15cH embedded image

—247-2483361, 2936, 1318, 1155, 1095, 767, 670, 587.1.52(s, 2H); 1.67(m, 2H); 1.85(m, 2H) 2.08(s, 3H); 2.44(m, 1H); 2.67(d, 2H, 10.25Hz); 6.83(d, 1H, J=8.4Hz); 7.01(s, 1H); 7.03(s, 1H); 7.19(d, 1H, J=8.4Hz); 7.35-7.50(m, 3H); #7.63-7.73(m, 4H); 7.79(sys AB, 2H, J=7.6Hz); 9.71(bb, 1H); 10.76(s, 1H) (DMSO-d6).16cH embedded image

—280 (desc)3398, 3257, 2933, 1161, 1143, 789, 589.1.25-1.52(m, 4H); 1.85(m, 2H); 2.18(s, 3H); 2.27(m, 1H); 2.74(d, J=11.4Hz, 2H); 6.72(dd, J=8.6, 2.0Hz, 1H); 6.83(d, 1H, J=1.5Hz, 1H); 6.90(d, J=2.0Hz, 1H); 7.02(d, #J=8.6Hz, 1H); 7.57(m, 1H); 7.74(dd, J=8.4, 4.3Hz, 1H); 8.12(dd, J=7.3, 1.3Hz, 1H); 8.19(dd, J=8.2, 1.3Hz, 1H); 8.52(dd, J=8.4, 1.7Hz, 1H); 9.21(dd, J=4.3, 1.7Hz, 1H); 9.36(s, 1H); 10.64(s, 1H). (DMSO-d6).17cH(CH₃CH₂)₂N—2H embedded image

—172-1733199, 2970, 2930, 2870, 1327, 1153, 1130, 1110, 1075, 956, 676, 658, 551, 476.0.87(t, J=7.1Hz, 6H); 2.39(m, 6H); 2.55(m, 2H); ); 6.82(d, J=8.6Hz, 1H); 7.05(s, 1H); 7.09(s, 1H); 7.13(d, J=8.6Hz, 1H); 7.60(m, 2H); #7.73(d, J=8.6Hz, 1H); 7.95(d, J=7.9Hz, 1H) 8.01(m, 2H); 8.26(s, 1H); 9.86(bb, 1H); 10.71(s, 1H). (DMSO-d6).18cH embedded image

—244-245 (desc)3346, 2943, 1474, 1283, 1261, 1156, 1123, 801, 771, 589, 503.2.25(s, 3H); 2.31(m, 2H); 2.46(m, 2H); 2.90(m, 2H); 5.34(s, 1H); 6.78(dd, J=8.6, 2.0Hz, 1H); 7.09(d, J=1.5Hz, 1H); 7.14(d, J=8.6Hz, 1H); #7.25(d, J=2.0Hz, 1H); 7.49(t, J=7.8Hz, 1H); 7.66(m, 1H); 7.75(m, 1H); 8.04(m, 2H); 8.14(d, J=8.2Hz, 1H); 8.83(d, J=8.6Hz, 1H); 10.14(bb, 1H); 11.03(s, 1H). (DMSO-d6).19cH embedded image

—230 (desc)2796, 1452, 1316, 1149, 1114, 1080, 1001, 810, 646, 559.1.80-2.26(m, 8H); 2.04(s, 3H); 2.30(s, 3H); 3.41(s, 2H); 6.89(dd, J=8.6, 1.56Hz, 1H); 7.16(s, 1H); 7.22(d, J=8.6Hz, 1H); 7.29(s, 1H); 7.49(dd, #J=8.7, 1.7Hz, 1H); 7.90(d, J=1.7Hz, 1H); 7.98(d, J=8.7Hz, 1H); 10.13(bb, 1H); 10.93(s, 1H). (DMSO-d6).20cH(CH₃)₂N—2H embedded image

—209-2113377, 2951, 2798, 1469, 1429, 1321, 1158, 777, 594.2.05(s, 6H); 2.32(m, 2H); 2.65(m, 2H); 6.86(dd, J=8.6, 1.8Hz, 1H); 7.10(d, J=1.8Hz, 1H); 7.18(d, J=1.8Hz, 1H); 7.21(d, J=8.6Hz, 1H); 7.32(dd, J=7.5 4.6Hz, #1H); 7.36(d, J=3.9Hz, 1H); 7.71(d, J=3.9Hz, 1H); 7.83(m, 1H); 7.93(m, 1H); 8.49(d, J=4.6Hz, 1H); 9.97(bb, 1H); 10.79(s, 1H). (DMSO-d6).21cH(CH₃)₂N—2H embedded image

—1923321, 2949, 1474, 1327, 1152, 1138, 1104, 981, 614.2.10(s, 6H); 2.21(m, 2H); 2.56(m, 2H); 6.72(d, J=8.6Hz, 1H); 6.96(s, 1H); 7.03(s, 1H); 7.07(d, J=8.6Hz, 1H); 7.70(m, 1H); 8.07(d, J=7.0Hz, 1H); 8.29(d, #J=8.8Hz, 1H); 10.14(bb, 1H); 10.69(s, 1H). (DMSO-d6).22cH(CH₃)₂N—2H embedded image

—250 (desc)3252, 2857, 1459, 1426, 1333, 1161, 1144, 789, 680, 589.207(s, 6H); 2.16(m, 2H); 2.51(m, 2H); 6.73(dd, J=8.6, 1.8Hz, 1H); 6.94(s, 1H); 6.99(s, 1H); 7.02(d, J=8.6Hz, 1H); 7.59(t, J=7.8Hz, 1H); #7.73(dd, J=8.4, 4.1Hz, 1H); 8.18(m, 2H); 8.50(dd, J=8.4, 1.5Hz, 1H); 9.20(dd, J=4.1, 1.5Hz, 1H); 9.45(bb, 1H); 10.64(s, 1H). (DMSO-d6).23cH(CH₃)₂N—2H embedded image

—230-240 (desc)3404, 2944, 2918, 2855, 1465, 1332, 1157, 1140, 1080, 650, 639, 526.2.01(s, 6H); 2.18(m, 2H); 2.57(m, 2H); 6.81(dd, J=8.6, 1.7Hz, 1H); 7.02(s, 1H); 7.05(d, J=1.7Hz, 1H); #7.15(d, J=8.6Hz, 1H); 7.57(m, 1H); 7.82(d, J=7.5Hz, 1H); 7.91(d, J=8.9Hz, 1H); 8.06(d, J=8.2Hz, 1H); 8.29(d, J=8.9Hz, 1H); 8.35(s, 1H); 9.94(bb, 1H); 10.74(s, 1H). (DMSO-d6).24cH(CH₃)₂N—2H embedded image

—152-1543232, 2862, 2827, 2785, 1583, 1488, 1333, 1248, 1155, 1091, 755, 693, 571, 541.2.16(s, 6H); 2.37(m, 2H); 2.66(m, 2H); 6.80(d, J=8.6Hz, 1H); 6.96-7.12(m, 6H); 7.14-7.25(m, #2H); 7.41(m, 2H); 7.64(dd, J=8.5, 1.9Hz, 2H); 9.69(bb, 1H); 10.75(s, 1H). (DMSO-d6).25cH(CH₃)₂N—2H embedded image

—184-1863451, 3388, 2950, 2775, 1466, 1322, 1159, 1095, 763, 670, 591.2.08(s, 6H); 2.32(m, 2H); 2.64(m, 2H); 6.83(dd, J=8.6, 1.9Hz, 1H); 7.08(d, J=2.0Hz, 1H); 7.11(d, J=1.9Hz, 1H); 7.17(d, J=8.6Hz, #1H); 7.34-7.50(m, 3H); 7.66(d, J=7.5Hz, 2H); 7.72(AB sys, J=8.6Hz, 2H); 7.79(AB sys, J=8.6Hz, 2H); 9.79(s, 1H); 10.75(s, 1H). (DMSO-d6).26cH(CH₃CH₂)₂N—2Et embedded image

—49-503386, 2970, 2931, 1474, 1337, 1167, 1151, 1130, 1073, 661, 5500.82(t, J=7.0Hz, 6H); 0.98(t, J=7.0Hz, 3H); 2.37(q, J=7.0Hz, 4H); 2.49(m, 2H); 2.54(m, 2H); 3.66(q, #J=7.1Hz, 2H); 6.73(dd, J=8.61, 1.6Hz, 1H); 6.98(s, 1H); 7.17(d, J=1.6Hz, 1H); 7.26(d, J=8.61Hz, 1H); 7.56-7.72(m, 3H); 7.99-8.11(m, 3H); 8.26(s, 1H); 10.97(s, 1H). (DMSO-d6).27cH embedded image

—200-2013366, 2951, 2816, 1460, 1421, 1319, 1283, 1157, 1114, 1078, 865, 651, 5612.25(m, 6H); 2.27(s, 3H); 2.62(t, J=7.9H, 2H); 3.62(m, 4H); 6.84(d, J=8.2Hz, 1H); 7.06(s, 1H); 7.10(s, #1H); 7.20(d, J=8.6Hz, 1H); 7.50(d, J=8.6Hz, 1H); 7.92(s, 1H); 8.00(d, J=8.6Hz, 1H); 10.13(s, 1H); 10.80(s, 1H). (DMSO-d6)28cH embedded image

—218-2203389, 3152, 2916, 2819, 1466, 1313, 1157, 1129, 1108, 771, 5872.30(m, 6H); 2.56(m, 2H); 3.56(m, 4H); 6.69(d, J=8.4Hz, 1H); 6.93(s, 1H); 7.06(m, 2H); 7.48(t, J=7.3Hz, 1H); 7.67(m, #2H); 8.02(m, 2H); 8.13(d, J=8.1Hz, 1H); 8.78(d, J=8.1Hz, 1H); 10.10(s, 1H); 10.68(s, 1H). (DMSO-d6)29cH(CH₃CH₂)₂N—2CH₃ embedded image

—134-1362968, 2930, 1488, 1329, 1159, 1131, 1074, 660, 5500.98(t, J=7.1Hz, 6H); 2.55(m, 6H); 2.70(m, 2H); 3.67(s, 3H); 6.84(s, 1H); 6.93(dd, J=8.6, 2Hz, 1H); 7.10(d, #J=8.7Hz, 1H); 7.18(d, J=1.7Hz, 1H); 7.26(s, 1H); 7.57(m, 2H); 7.67(dd, J=8.7, 1.8Hz, 1H); 7.84(m, 3H); 8.27(d, J=1.7Hz, 1H). (DMSO-d6)30cH(CH₃)₂N—1H embedded image

—148-1523398, 2930, 1467, 1158, 1113, 1079, 861, 803, 651, 5611.89(m, 6H); 2.29(s, 3H); 2.48(s, 2H); 6.83(m, 1H); 7.18(m, 3H); 7.50(m, 1H); 7.91(m, 1H); 8.00(m, 1H); #10.13(b, 1H); 10.92(s, 1H). (DMSO-d6)31cH(CH₃CH₂CH₂)₂N—2H embedded image

—76-803399, 2959, 2931, 1466, 1159, 1132, 802, 770, 5880.82(t, J=6.7Hz, 6H); 1.34(q, J=6.71Hz, 4H); 2.31(m, 4H); 2.40(m, 2H); 2.52(m, 2H); 6.69(d, J=8.6Hz, #1H); 7.04(m, 3H); 7.47(m, 1H); 7.66(m, 2H); 8.02(m, 2H); 8.11(d, J=8.1Hz, 1H); 8.78(d, J=8.4Hz, 1H); 10.12(s, 1H); 10.67(s, 1H). (DMSO-d6)32cH(CH₃CH₂CH₂)₂N—2H embedded image

—90-953406, 2959, 2932, 2872, 1466, 1157, 1079, 861, 652, 5610.80(t, J=7.3Hz, 6H); 1.31(q, J=7.3Hz, 4H); 2.26(m, 7H); 2.38(m, 2H); #2.56(m, 2H); 6.83(dd, J=8.4, 1.8Hz, 1H); 7.08(s, 2H); 7.20(d, J=8.6Hz, 1H); 7.50(dd, J=8.6, 2.0Hz, 1H); 7.90(d, J=2.0Hz, 1H); 7.99(d, J=8.6Hz, 1H); 10.12(b, 1H); 10.79(s, 1H). (DMSO-d6)33cH(CH₃CH₂CH₂CH₂)₂N—2H embedded image

—79-803398, 2956, 2930, 2870, 1466, 1158, 1080, 862, 801, 653, 5620.84(t, J=6.8Hz, 6H); 1.24(m, 8H); 2.26(s, 3H); 2.28(m, 4H); 2.39(m, 2H); 2.57(m, 2H); #6.82(dd, J=8.6, 1.9Hz, 1H); 7.09(d, J=1.8Hz, 2H); 7.18(d, J=8.6Hz, 1H); 7.50(dd, J=8.6, 1.9Hz, 1H); 7.89(d, J=1.8Hz, 1H); 7.98(d, J=8.6Hz, 1H); 10.14(b, 1H); 10.78(s, 1H). (DMSO-d6)34cH(CH₃CH₂CH₂CH₂)₂N—2H embedded image

—111-1133291, 2955, 2926, 2870, 1327, 1158, 1136, 772, 676, 611, 5850.86(t, J=7.0Hz, 6H); 1.29(m, 8H); 2.35(m, 4H); 2.41(m, 2H); 2.53(m, #2H); 6.67(dd, J=8.5, 1.9Hz, 1H); 7.09(m, 3H); 7.48(t, J=7.9Hz, 1H); 7.68(m, 2H); 8.01(s, 1H); 8.04(s, 1H); 8.12(d, J=8.2Hz, 1H); 8.78(d, J=8.2Hz, 1H); 10.13(s, 1H); 10.67(s, 1H). (DMSO-d6)35cH(CH₃CH₂)₂N—2H embedded image

—154-1563402, 2978, 1471, 1285, 1162, 1135, 1018, 780, 629, 6060.88(t, J=6.7Hz, 6H); 2.41(m, 6H); 2.49(m, 2H); 6.71(d, J=8.1Hz, 1H); 6.88(s, 1H); 7.07(m, #2H); 7.66(m, 2H); 7.84(d, J=7.0Hz, 1H); 8.09(d, J=7.0Hz, 1H); 8.41(d, J=8.2Hz, 1H); 8.79(d, J=8.6Hz, 1H); 10.17(b, 1H); 10.71(s, 1H). (DMSO-d6)36cH(CH₃CH₂)₂N—2H embedded image

—125-1303404, 2972, 1473, 1319, 1142, 967, 745, 5410.94(t, J=7.1Hz, 6H); 2.50(q, J=7.1Hz, 4H); 2.59(m, 2H); 2.68(m, 2H); 6.94(dd, J=8.6, 1.8Hz, 1H); 7.26(m, #8H); 7.59(m, 2H); 9.54(b, 1H); 10.77(s, 1H). (DMSO-d6)37cH embedded image

—203 (desc)2809, 1340, 1150, 746, 5422.06(s, 3H); 2.22(m, 6H); 3.36(m, 2H); 3.49(s, 2H); 6.95(dd, J=8.6, 1.8Hz, 1H); 7.18(s, 2H); 7.24(m, 2H); 7.37(m, 3H); 7.45(d, J=1.8Hz, #1H); 7.61(m, 2H); 9.53(s, 1H); 10.90(s, 1H). (DMSO-d6)38cH embedded image

—142-1443413, 2929, 1157, 1113, 1080, 862, 651, 5641.12(m, 3H); 1.81(m, 9H); 2.22(s, 3H); 2.93(m, 2H); 6.84(dd, J=8.5, 1.7Hz, 1H); 6.99(s, 1H); 7.03(s, 1H); 7.20(d, #J=8.6Hz, 1H); 7.52(dd, J=8.6, 2.0Hz, 1H); 7.90(d, J=1.7Hz, 1H); 8.00(d, J=8.6Hz, 1H); 10.01(b, 1H); 10.61(s, 1H). (DMSO-d6)39cH(CH₃CH₂)₂N—2H embedded image

—197-1983338, 1466, 1270, 1237, 117, 986, 6260.96(t, J=7.1Hz, 6H); 2.53(m, 6H); 2.63(m, 2H); 6.78(dd, J=8.5, 1.6Hz, 1H); 7.10(s, 2H); 7.18(d, #J=8.6Hz, 1H); 7.51(d, J=4.6Hz, 1H); 7.80(d, J=4.6Hz, 1H); 10.78(s, 1H). (DMSO-d6)40cH embedded image

—85-903399, 3257, 2920, 2855, 2814, 1460, 1330, 1157, 1131, 1113, 1074, 659, 551, 4772.27(m, 6H); 2.61(t, J=7.9Hz, 2H); 3.52(t, J=4.6Hz, 4H); 6.82(dd, #J=8.6, 2.0Hz, 1H); 7.06(s, 1H); 7.07(s, 1H); 7.15(d, J=8.6Hz, 1H); 7.61(m, 2H); 7.74(dd, J=8.8, 1.8Hz, 1H); 7.96(d, J=8.1Hz, 1H); 8.03(m, 2H); 8.27(s, 1H); 9.87(s, 1H); 10.74(s, 1H). (DMSO-d6)41cH embedded image

—99-1023398, 2934, 2806, 1458, 1331, 1284, 1153, 1127, 700, 5422.11(s, 3H); 2.32(m, 6H); 3.35(m, 2H); 3.56(s, 2H); 4.29(s, 2H); 6.98(d, J=8.2Hz, 1H); 7.29(m, 7H); 7.53(s, 1H); 9.40(s, 1H); 10.94(s, 1H). (DMSO-d6)42cH(CH₃CH₂)₂N—3H embedded image

—128-1303259, 2973, 2939, 2827, 1468, 1332, 1159, 1131, 1075, 670, 5550.86(t, J=7.0Hz, 6H); 1.51(t, J=6.9Hz, 2H); 2.27(t, J=6.9Hz, 2H); 2.35(q, J=7.0Hz, 4H); 2.46(m, 2H); 6.77(d, #J=8.6Hz, 1H); 7.00(s, 1H); 7.10(m, 2H); 7.60(m, 2H); 7.72(d, J=8.8Hz, 1H); 7.95(d, J=7.9Hz, 1H); 8.02(m, 2H); 8.26(s, 1H); 9.86(b, 1H); 10.67(s, 1H). (DMSO-d6)43cH(CH₃CH₂)₂N—3H embedded image

—156-1583247, 2969, 2938, 1467, 1340, 1159, 1113, 1080, 862, 666, 5580.88(t, J=7.0Hz, 6H); 1.52(m, 2H); 2.29(m, 5H); 2.37(q, J=7.0Hz, 4H); 2.47(m, 2H); 6.81(dd, J=8.6, 1.5Hz, 1H); #7.06(d, J=1.6Hz, 1H); 7.12(d, J=1.5Hz, 1H); 7.18(d, J=8.6Hz, 1H); 7.51(dd, J=8.6, 2.0Hz, 1H); ); 7.91(d, J=2.0Hz, 1H); 7.99(d, J=8.6Hz, 1H); 10.06(b, 1H); 10.76(s, 1H). (DMSO-d6)44cH embedded image

—201-2033386, 2929, 1466, 1157, 1106, 1080, 992, 861, 650, 5641.62(m, 4H); 2.29(s, 3H); 2.30(m, 4H); 2.36(m, 2H); 2.63(m, 2H); 6.86(d, J=8.6Hz, 1H); 7.05(s, 1H); 7.09(s, 1H); 7.21(dd, J=8.6, 2.2Hz, #1H); 7.50(dd, J=8.7, 2.0Hz, 1H); 7.92(s, 1H); 7.99(dd, J=8.7, 2.2Hz, 1H); 10.10(b, 1H); 10.81(s, 1H). (DMSO-d6)45cH embedded image

—212-2143354, 2964, 2812, 1466, 1201, 1157, 1124, 808, 773, 5931.66(m, 4H); 2.36(m, 6H); 2.58(m, 2H); 6.71(d, J=8.6Hz, 1H); 6.93(s, 1H); 7.02(s, 1H); 7.07(d, J=8.6Hz, 1H); 7.48(m, 1H), 7.68(m, #2H); 8.02(dd, J=7.2, 1.2Hz, 2H); 8.12(d, J=8.2Hz, 1H); 8.79(d, J=8.6Hz, 1H); 10.10(b, 1H); 10.68(s, 1H). (DMSO-d6)46cH embedded image

—180-1823375, 2968, 2821, 1467, 1323, 1313, 1146, 1139, 1131, 1079, 972, 654, 5491.60(m, 4H); 2.26(m, 4H); 2.35(m, 2H); 2.61(m, 2H); 6.82(dd, J=8.6, 2.0Hz, 1H); 7.05(m, 2H); 7.14(d, J=8.6Hz, #1H); 7.61(m, 2H); 7.74(dd, J=8.6, 1.8Hz, 1H); 7.95(d, J=7.9Hz, 1H); 8.02(m, 2H); 8.27(s, 1H); 9.86(b, 1H); 10.72(s, 1H). (DMSO-d6)47cH(CH₃CH₂CH₂)₂N—2H embedded image

—58-64 (desc)3398, 3255, 2958, 2931, 2872, 1466, 1330, 1156, 1130, 1074, 659, 5510.79(t, J=7.3Hz, 6H); 1.31(q, J=7.3Hz, 4H); 2.28(t, J=7.3Hz, 4H); #2.42(m, 2H); 2.57(m, 2H); 6.80(dd, J=8.6, 1.7Hz, 1H); 7.04(d, J=1.7Hz, 1H); 7.12(m, 2H); 7.60(m, 2H); 7.72(dd, J=8.6, 1.7Hz, 1H); 7.98(m, 3H); 8.25(s, 1H); 9.87(b, 1H); 10.70(s, 1H). (DMSO-d6)48cH(CH₃)₂N—2H embedded image

—201-2033369, 1473, 1161, 1125, 1017, 789, 6192.06(s, 6H); 2.15(t, J=8.2Hz, 2H); 2.52(t, J=8.2Hz, 2H); 6.69(d, J=8.7Hz, 1H); 6.85(s, 1H); 7.02(s, 1H); 7.08(d, J=8.7Hz, 1H); #7.67(m, 2H); 7.84(d, J=7.3Hz, 1H); 8.10(d, J=7.3Hz, 1H); 8.41(d, J=8.4Hz, 1H); 8.79(d, J=8.7Hz, 1H); 10.15(b, 1H); 10.70(s, 1H). (DMDO-d6)49cH(CH₃)₂N—2H embedded image

—180-1903399, 3255, 2943, 1466, 1330, 1156, 1131, 1075, 659, 5502.03(s, 6H); 2.22(t, J=8.2Hz, 2H); 2.58(t, J=8.2Hz, 2H); 6.80(d, J=8.4Hz, 1H); 7.04(s, 1H); 7.07(s, 1H); 7.13(d, #J=8.6Hz, 1H); 7.60(m, 2H); 7.74(d, J=8.6Hz, 1H); 7.95(d, J=7.7Hz, 1H); 8.02(m, 2H); 8.26(s, 1H); 9.86(b, 1H); 10.71(s, 1H). (DMSO-d6)50cH embedded image

—234-2353400, 3279, 2913, 2852, 1464, 1420, 1315, 1163, 1118, 951, 5922.29(m, 6H); 2.54(m, 2H); 3.57(m, 4H); 6.72(d, J=8.1Hz, 1H); 7.01(m, 3H); 7.60(t, J=7.7Hz, 1H); 7.74(d, #J=8.4Hz, 1H); 8.19(m, 2H); 8.52(d, J=8.4Hz, 1H); 9.21(s, 1H); 9.44(s, 1H); 10.65(s, 1H). (DMSO-d6)51cH embedded image

—225-2283340, 2857, 1479, 1324, 1153, 1116, 1094, 768, 670, 5882.29(m, 6H); 2.66(m, 2H); 3.47(m, 4H); 6.84(d, J=8.6Hz, 1H); 7.07(s, 1H); 7.09(s, 1H); 7.18(d, J=8.4Hz, 1H); 7.45(m, #3H); 7.70(m, 4H); 7.79(m, 2H); 9.79(s, 1H); 10.77(s, 1H). (DMSO-d6)52cH embedded image

—129-1313367, 2924, 2852, 2799, 1465, 1311, 1154, 1130, 1077, 666, 5571.40-1.60(m, 4H), 1.83(m, 2H); 2.14(s, 3H); 2.36(m, 1H); 2.67(d, J=11.2Hz, 2H); 6.78(d, J=8.4Hz, 1H); 6.97(s, 1H); 7.00(s, 1H); #7.12(d, J=8.6Hz, 1H); 7.50-7.68(m, 2H); 7.73(d, J=9.0Hz, 1H); 8.00(m, 3H); 8.23(s, 1H); 9.78(b, 1H); 10.71(s, 1H). (DMSO-d6)53cH embedded image

—246-2493329, 2940, 2916, 1470, 1158, 1125, 1110, 1015, 791, 5981.35-1.47(m, 4H); 1.86(m, 2H); 2.17(s, 3H); 2.28(m, 1H); 2.76(d, J=10.6Hz, 2H); 6.68(d, J=8.8Hz, 1H); 6.75(s, 1H); 6.94(s, 1H); 7.08(d, J=9.0Hz, 1H); 7.60-7.73(m, 2H); #7.85(d, J=7.1Hz, 1H); 8.06(d, J=7.1Hz, 1H); 8.40(d, J=7.9Hz, 1H); 8.79(d, J=9.0Hz, 1H); 10.20(b, 1H); 10.68(s, 1H). (DMSO-d6)

Preparation of the Compounds of General Formula (Id):

Example 1d
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-5-chloro-3-methyl-benzo[b]thiophene-2-sulfonamide

185.5 mg (0.66 mMol) of 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride were added to a solution of 122 mg (0.6 mMol) of 4-amino-3-(2-dimethylaminoethyl)-1H-indole in 2 ml of dimethylformamide and 116 mg of N-ethyldiisopropylamine. The reaction mixture was stirred at the room temperature for 20 hours. Then it was evaporated to dryness, slightly alkalinized with sodium bicarbonate solution and extracted with chloroform. The organic phase was repeatedly washed with water and saturated solution of sodium bicarbonate, it was separated and dried with anhydrous sodium sulfate. The organic solution was evaporated to dryness and the resulting solid was purified by chromatography, obtaining 111 mg (42%) of N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-5-choloro-3-methyl-benzo[b]thiophene-2-sulfonamide as a creamy solid.

Example 2d
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-naphtalene-2-sulfonamide

121 mg (51%) of the mentioned compound were obtained from 122 mg (0.6 mMol) of 4-amino-1-(2-dimethylaminoethyl)-1H-indole and 149.5 mg (0.66 mMol) of naphtalene-2-sulfonyl chloride, by means of the process described in the Example 1d, as a creamy solid.

Example 3d
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-naphtalene-1-sulfonamide

130 mg (55%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 4-amino-1-(2-dimethylaminoethyl)-1H-indole and 149.5 mg (0.66 mMol) of naphtalene-1-sulfonyl chloride, by means of the process described in the Example 1d, as a creamy solid.

Example 4d
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-4 phenylbenzenesulfonamide

107 mg (42%) of the mentioned compound were obtained from 122 mg (0.6 mMol) of 4-amino-1-(2-dimethylaminoethyl)-1H-indole and 169 mg (0.66 mMol) of 4-phenylbenzenesulfonyl chloride, by means of the process described in the Example 1d, as a creamy solid.

Example 5d
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-2-(naphthalene-1-yl)-ethanesulfonamide

52 mg (21%) of the mentioned compound were obtained from 122 mg (0.6 mMol) of 4-amino-1-(2-dimethylaminoethyl)-1H-indole and 168 mg (0.66 mMol) of 2-(naphthalene-1-yl)-ethanesulfonyl chloride, by means of the process described in the Example 1d, as a yellowish solid.

Example 6d
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-4-phenoxybenzenesulfonamide

220 mg (84%) of the mentioned compound were obtained from 122 mg (0.6 mMol) of 4-amino-1-(2-dimethylaminoethyl)-1H-indole and 177 mg (0.66 mMol) of 4-phenoxybenzenesulfonyl chloride, by means of the process described in the Example 1d, as a oil.

Example 7d
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-4-yl]-3,5-dichlorobenzenesulfonamide

93 mg (38%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 7-amino-1-(2-dimethylaminoethyl)-1H-indole and 162 mg (0.66 mMol) of 3,5dichlorobenzenesulfonyl chloride, by means of the process described in Example 1d, as a creamy solid.

Example 8d
Preparation of 6-chloro-N-[1-(2-dimethylaminoethyl)-1H-indol-4-yl]-imidazo[2,1-b]thiazole-5-sulfonamide

100 mg (39%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 4-amino-1-(2-dimethylaminoethyl)-1H-indole and 170 mg (0.66 mMol) of 6-chloro-imidazo[2,1-b]-thiazole-5-sulfonyl chloride via the process described in Example 1 as a creamy solid.

The yields are indicative and no added effort was made to improve them. The melting point and spectroscopic data for identifying some of the compounds object of the present invention are indicated in the following table.

(Id)

m.p.ExR^1dR^2dR^3dR^4dR^5dR^6dR^7dndA^d° C.IR cm⁻¹¹H-NMR (300 MHz), δ (solvent)1d(CH₃)₂N—HHHHHH2 embedded image

78-803430, 2951, 1492, 1328, 1156, 1115, 1079, 859, 750, 649, 569.2.10(s, 6H); 2.28(s, 3H); 2.50(m, 2H); 4.14(t, 2H, J=6.3Hz); 6.43(d, 1H, J=2.0Hz); 6.92(d, 1H, J=7.5Hz); 7.00(t, 1H, J=7.7Hz); 7.17(d, 1H, J=2.2Hz); 7.25(d, 1H, #J=7.5Hz); 7.49(d, 1H, J=8.4Hz); 7.85(s, 1H); 7.99(d, 1H, J=8.5Hz). (DMSO-d6)2d(CH₃)₂N—HHHHHH2 embedded image

156-1583448, 2821, 1492, 1314, 1238, 1158, 1127, 1075, 1009, 752, 656, 645, 554, 543, 484.2.08(s, 6H); 2.48(m, 2H); 4.10(t, 2H, J=6.6Hz); 6.58(d, 1H, J=3.1Hz); 6.85-6.96(m, 2H); 7.15(d, 1H, #J=7.8Hz); 7.19(d, 1H, J=3.1Hz); 7.54-7.68(m, 2Hz); 7.83(dd, 1H, J=8.6Hz, J′=1.8Hz); 7.94(d, 1H, J=8.1Hz). (DMSO-d6)3d(CH₃)₂N—HHHHHH2 embedded image

169-1723279, 2943, 1403, 1318, 1162, 1132, 1003, 767, 745.2.08(s, 6H); 2.46(m, 2H); 4.07(t, 2H, J=6.7Hz); 6.45(d, 1H, J=3.2Hz); 6.81(d, 1H, J=6.8Hz); 6.88(t, 1H, J=7.7Hz); 7.09(d, 1H, J=8.2Hz); 7.12(d, 1H, J=3.2Hz); 7.52(m, 1H); #7.62(m, 1Hz); 7.70(m, 1H); 8.01(d, 1H, J=8.2Hz); 8.11(m, 2H), 8.87(d, 1H, J=8.4Hz). (DMSO-d6)4d(CH₃)₂N—HHHHHH2 embedded image

137-1403262, 2943, 1492, 1330, 1160, 1096, 750, 670, 590, 531.2.10(s, 6H); 2.51(m, 2H); 4.14(t, 2H, J=6.6Hz); 6.61(d, 1H, J=3.0Hz); 6.90(d, 1H, J=7.0Hz); 6.97(t, 1H, J=7.8Hz); 7.19(d, 1H, J=7.8Hz); 7.23(d, 1H, #J=3.2Hz); 7.36-7.69(m, 3H); 7.65(d, 2H, J=6.8Hz); 7.76(AB sys, 2H, J=8.6Hz); 7.82(AB sys, 2H, J=8.5Hz,). (DMSO-d6)5d(CH₃)₂N—HHHHHH2 embedded image

47-543430, 3255, 2941, 2760, 1492, 1322, 1150, 748.2.16(s, 6H); 2.59(m, 2H); 3.35(m, 4H); 4.24(t, 2H, J=6.3Hz); 6.89(m, 1H, J=3.1Hz); 7.05-7.11(m, 2H); 7.22(m, 1H); 7.28-7.38(m, 4H); 7.41(m, 2H); 7.74(d, 1H, J=7.18Hz), 7.86(d, 1H, #J=8.2Hz). (DMSO-d6)6d(CH₃)₂N—HHHHHH2 embedded image

oil2944, 2776, 1488, 1343, 1244, 1156, 1094, 751, 6952.12(s, 6H); 2.52(m, 2H); 4.15(t, 2H, J=6.5Hz); 6.51(d, 1H, J=3.0Hz); 6.85(d, 1H, J=7.6Hz); 6.97(m, 3H); 7.03(d, 2H, J=7.6Hz); 7.20(d, 2H, J=8.1Hz); 7.24(d, 1H, J=3.2Hz); 7.42(t, 2H, #J=7.9Hz); 7.70(d, 2H, J=8.9Hz). (DMSO-d6)7d(CH₃)₂N—HHHHHH2 embedded image

113-1183255, 3072, 2935, 1570, 1492, 1340, 1169, 1138, 803, 747, 670, 594.2.12(s, 6H); 2.54(t, 2H, J=6.6); 4.17(t, 2H, J=6.5Hz); 6.42(d, 1H, J=3.1Hz); 6.82(d, 1H, J=7.6Hz); 7.02(t, 1H, #J=8.0Hz); 7.26-7.30(m, 2H); 7.63(d, 2H, J=1.9Hz); 7.86(t, 1H, J=1.8Hz). (DMSO-d6)8d(CH₃)₂N—HHHHHH2 embedded image

95-1002.15(s, 6H); 2.56(t, 2H, J=6.2Hz); 4.17(t, 2H, J=6.6Hz); 6.31(d, 1H, J=2.8Hz); 6.89(d, 1H, J=7.3Hz); 7.01(m, 1H); 7.21(d, 1H, J=3.0Hz); 7.27(d, 1H, 8.0Hz); 7.49(d, 1H, J=4.4Hz); 7.72(d, 1H, J=4.4Hz). (DMSO-d6)

Preparation of the Compounds of General Formula (Ie):

Example 2e
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide

150 mg (0.66 mMol) of Naphthalene-2-sulfonyl chloride were added to a solution of 122 mg (0.6 mMol) of 5-amino-1-(2-dimethylaminoethyl)-1H-indole in 3 ml of dimethylformamide and 116 mg of N-ethyldiisopropylamine. The reaction mixture is stirred at the room temperature for 12 hours. Then it is evaporated to dryness, slightly alkalinized with sodium bicarbonate solution and extracted with chloroform. The organic phase is repeatedly washed with water and saturated solution of sodium bicarbonate, it is separated and dried with anhydrous sodium sulfate. The organic solution is evaporated to dryness and the resulting solid is purified by chromatography, obtaining 187 mg (80%) of N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-naphthalene-2-sulfonamide.

Example 10e
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzo-[1,2,5]thiadiazole-4-sulfonamide 4-sulfonamide

116 mg (0.66 mMol) of benzo-[1,2,5]thiadiazole-4-sulfonyl chloride were added to a solution of 168 mg (0.6 mMol) of 5-amino-1-(2-dimethylaminoethyl)-1H-indole in 5 ml of pyridine and 311 mg of N-ethyldiisopropylamine. The reaction mixture is stirred at the room temperature for 2 hours. Then it is evaporated to dryness, slightly alkalinized with sodium bicarbonate solution and extracted with chloroform. The organic phase is repeatedly washed with water and saturated solution of sodium bicarbonate, it is separated and dried with anhydrous sodium sulfate. The organic solution is evaporated to dryness and the resulting solid is treated with diethyl ether obtaining 183 mg (76%) of N-[1-(2-dimethylaminoethyl)-1H-indole-5-yl]-benzo-[1,2,5]thiadiazole-4-sulfonamide 4-sulfonamide.

Example 17e
Preparation of N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide

199 mg (0.88 mMol) of naphthalene-1-sulfonyl chloride were added to a solution of 335 mg (0.8 mMol) of 5-amino-1-(2-pyrrolidine-1-yl-ethyl)-1H-indole in 10 ml of methylene chloride and 0,44 mg of triethylamine. The reaction mixture is stirred at the room temperature for 12 hours. Then it is slightly alkalinized with sodium bicarbonate solution and extracted with methylene chloride. The organic phase is repeatedly washed with water and saturated solution of sodium bicarbonate, it is separated and dried with anhydrous sodium sulfate. The organic solution is evaporated to dryness and the resulting solid is treated with diethyl ether obtaining 264 mg (79%) of N-[1-(2-pyrrolidine-1-yl-ethyl)-1H-indole-5-yl]-naphthalene-1-sulfonamide as a solid.

Example 29e
Preparation of N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-2-sulfonamide

The reaction was carried out according to the procedure given in Example 1. 139 mg (0.6 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 150 mg (0.66 mMol) of 2-naphthyl-sulfonyl chloride were reacted to give 115 mg (45%) of the desired compound as a solid.

Example 30e
Preparation of N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-naphthalene-1-sulfonamide

Example 31e
Preparation of N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)-4-phenylbenzenesulfonamide

The reaction was carried out according to the procedure given in Example 1. 139 mg (0.6 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 167 mg (0.66 mMol) of 4-phenylbenzenesulfonyl chloride were reacted to give 181 mg (68%) of the desired compound as an oil.

Example 32e
Preparation of 5-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-3-methylbenzo[b]thiophene-2-sulfonamide

The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 186 mg (0.66 mMol) of 5-chloro-2-methylbenzo[b]thiophene-2-sulfonyl chloride were reacted to give 127 mg (46%) of the desired compound as a solid.

Example 33e
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-2-sulfonamide

The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 150 mg (0.66 mMol) of naphthyl-2-sulfonyl chloride were reacted to give 142 mg (58%) of the desired compound as a solid.

Example 34e
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-naphthalene-1-sulfonamide

The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 150 mg (0.66 mMol) of naphthyl-1-sulfonyl chloride were reacted to give 81 mg (33%) of the desired compound as a solid.

Example 35e
Preparation of 6-chloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide

The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 170 mg (0.66 mMol) of 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride were reacted to give 96 mg (37%) of the desired compound as a solid.

Example 36e
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenylbenzenesulfonamide

The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 167 mg (0.66 mMol) of 4-phenylbenzenesulfonyl chloride were reacted to give 160 mg (62%) of the desired compound as a solid.

Example 37e
Preparation of N-(1-(2-dimethylamino)ethyl-2-methyl-1H-indol-5-yl)-2-(naphth-1-yl)-ethanesulfonamide

The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 168 mg (0.66 mMol) of 2-(naphth-1-yl)-ethanesulfonyl chloride were reacted to give 108 mg (41%) of the desired compound as a solid.

Example 38e
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-4-phenoxy-benzenesulfonamide

The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 177 mg (0.66 mMol) of 4-phenoxy-benzenesulfonyl chloride were reacted to give 89 mg (33%) of the desired compound as a solid.

Example 39e
Preparation of 3,5-dichloro-N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)-benzenesulfonamide

The reaction was carried out according to the procedure given in Example 1. 130 mg (0.6 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 162 mg (0.66 mMol) of 3,5-dichloro-benzenesulfonyl chloride were reacted to give 81 mg (32%) of the desired compound as a solid.

Example 40e
Preparation of N-(1-(2-(dimethylamino)ethyl)-2-methyl-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide

The reaction was carried out according to the procedure given in Example 1. 108 mg (0.5 mMol) of 5-amino-1-(2-(dimethylamino)ethyl)-2-methyl-1H-indole and 128 mg (0.55 mMol) of benzo[b]thiophene-3-sulfonyl chloride were reacted to give 82 mg (39%) of the desired compound as a solid.

Example 41e
Preparation of N-(1-(2-(diethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide

The reaction was carried out according to the procedure given in Example 1. 115 mg (0.5 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 128 mg (0.55 mMol) of benzo[b]thiophene-3-sulfonyl chloride were reacted to give 91 mg (43%) of the desired compound as a solid.

Example 42e
Preparation of N-(1-(2-(dimethylamino)ethyl)-1H-indol-5-yl)benzo[b]thiophene-3-sulfonamide

The reaction was carried out according to the procedure given in Example 1. 102 mg (0.5 mMol) of 5-amino-1-(2-(diethylamino)ethyl)-1H-indole and 128 mg (0.55 mMol) of benzo[b]thiophene-3-sulfonyl chloride were reacted to give 91 mg (43%) of the desired compound as a solid.

Example 43e
Preparation of 5-chloro-3-methyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzo[b]thiophene-2-sulfonamide

The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 143 mg (0.51 mMol) of 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride were reacted to give 89 mg (38%) of the desired compound as a solid.

Example 44e
Preparation of N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-2-sulfonamide

The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 116 mg (0.51 mMol) of naphthyl-2-sulfonyl chloride were reacted to give 75 mg (37%) of the desired compound as a solid.

Example 45e
Preparation of N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide

Example 46e
Preparation of 6-chloro-N-(1-(3-piperidin-1-yl)propyl)-1H-indol-5-yl)imidazo[2,1-b]thiazole-5-sulfonamide

The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 131 mg (0.51 mMol) of 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride were reacted to give 91 mg (44%) of the desired compound as a solid.

Example 47e
Preparation of 4-phenyl-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide

The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 129 mg (0.51 mMol) of 4-phenylbenzenesulfonyl chloride were reacted to give 106 mg (49%) of the desired compound as a solid.

Example 48e
Preparation of 2-(naphth-1-yl)-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)ethanesulfonamide

The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 130 mg (0.51 mMol) of 2-(naphth-1-yl)ethanesulfonyl chloride were reacted to give 68 mg (31%) of the desired compound as a solid.

Example 49e
Preparation of 4-phenoxy-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonamide

The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 137 mg (0.51 mMol) of 4-phenoxybenzenesulfonyl chloride were reacted to give 86 mg (38%) of the desired compound as a solid.

Example 50e
Preparation of 3,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)benzenesulfonylamide

The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 125 mg (0.51 mMol) of 3,5-dichlorobenzenesulfonyl chloride were reacted to give 79 mg (37%) of the desired compound as a solid.

Example 51e
Preparation of 4,5-dichloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)thiophene-2-sulfonamide

The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 128 mg (0.51 mMol) of 4,5-dichlorothiophene-2-sulfonyl chloride were reacted to give 68 mg (31%) of the desired compound as a solid.

Example 52e
Preparation of 5-chloro-N-(1-(3-(piperidin-1-yl)propyl)-1H-indol-5-yl)naphthalene-1-sulfonamide

The reaction was carried out according to the procedure given in Example 1. 118 mg (0.46 mMol) of 5-amino-1-(3-(piperidin-1-yl)propyl))-1H-indole and 133 mg (0.51 mMol) of 5-chloro-napthyl-1-sulfonyl chloride were reacted to give 81 mg (37%) of the desired compound as a solid.

The yields are indicative and no added effort was made to improve them The melting point and spectroscopic data for identifying some of the compounds object of the present invention are indicated in the following table

m.p.ExR^1eR^2eR^3eR^4eR^5eR^6eR^7eneA^e° C.IR cm⁻¹¹H-NMR (300 MHz), δ (solvent) 1e(CH₃)₂N—HHHHHH2 embedded image

71-732950, 1334, 1160, 1080, 862, 652, 560.2.11(s, 6H); 2.36(s, 3H); 2.51(m, 2H); 4.14(t, 2H, J=6.6Hz,); 6.30(d, 1H, J=3Hz); 7.32(m, 2H); 7.50(dd, 1H, #J=8.7Hz, J′=2.0Hz); 7.93(d, 1H, J=2.0Hz); 7.99(d, 1H, J=8.7Hz). (DMSO-d6) 2e(CH₃)₂N—HHHHHH2 embedded image

54-573254, 3049, 2945, 1463, 1330, 1160, 1074, 658, 550.2.26(s, 6H); 2.63(t, 2H, J=7.1Hz); 4.14(t, 2H, J=7.1Hz); 6.35(d, 1H, J=3.1Hz); 6.88(dd, 1H, J=8.6Hz, #J′=2.0Hz); 7.10(d, 1H, 3.1Hz); 7.15(d, 1H, J=8.6Hz); 7.31(d, 1H, J=2.0Hz); 7.50-7.63(m, 2H); 7.69(dd, 1H, J=8.7Hz, J′=1.8Hz); 7.84(m, 3H); 8.29(s, 1H). (CDCl₃) 3e(CH₃)₂N—HHHHHH2 embedded image

179-1813106, 2783, 1491, 1318, 1159, 1130, 763, 586, 503.2.25(s, 6H); 2.63(t, 2H, J=7.0Hz); 4.11(t, 2H, J=7.0Hz); 6.28(d, 1H, J=3.1Hz); 6.68(dd, 1H, #J=8.6Hz, J′=2.0Hz); 7.03-7.11(m, 3H); 7.37(m, 1H); 7.58-7.70(m, 2H); 7.94(d, 1H, J=8.7Hz); 8.00(d, 1H, J=7.9Hz); 8.06(d, 1H, J=7.3Hz); 8.73(d, 1H, J=8.7Hz). (CDCl₃) 4e(CH₃)₂N—HHHHHH2 embedded image

172-1743257, 2935, 2768, 1488, 1334, 1167, 1138, 1013, 790, 606.2.26(s, 6H); 2.63(t, 2H, J=7.1Hz); 4.13(t, 2H, J=7.1Hz); 6.30(d, 1H, J=3.1Hz); 6.66(dd, 1H, J=8.6Hz, J′=2.0Hz); 7.05(d, #1H, J=8.7Hz); 7.08(d, 1H, J=3.1Hz); 7.11(d, 1H, J=2.0Hz); 7.46-7.58(m, 2H); 7.69(d, 1H, J=7.5Hz); 8.13(d, 1H, J=7.5Hz); 8.50(d, 1H, J=8.6Hz); 8.69(d, 1H, J=8.8Hz). (CDCl₃) 5e(CH₃)₂N—HHHHHH2 embedded image

139-1411463, 1334, 1306, 1164, 1090, 725, 589.2.28(s, 6H); 2.66(t, 2H, J=7.1Hz); 4.17(t, 2H, J=7.1Hz); 6.38(d, 1H, J=3.1Hz); 6.88(dd, 1H, J=8.6Hz, J′=2.0Hz); 7.13(d, 1H, J=3.1Hz); #7.18(d, 1H, J=8.6Hz); 7.27(m, 1H); 7.39(m, 2H); 7.48(m, 1H); 7.69(m, 2H). (CDCl₃) 6e(CH₃)₂N—HHHHHH2 embedded image

161-1643095, 02821, 2776, 1492, 1459, 1322, 1158, 1141, 782, 736, 596, 507.2.23(s, 6H); 2.58(t, 2H, J=7.1Hz); 4.08(t, 2H, J=7.1Hz); 6.24(d, 1H, J=3.1Hz); 6.88(dd, 1H, J=8.8, J′=2.0Hz); #7.03(d, 1H, J=3.1Hz); 7.07(d, 1H, J=8.8Hz); 7.10(d, 1H, J=2.0Hz); 7.51(t, 1H, J=7.8Hz); 7.64(dd, 1H, J=8.5, J′=4.3Hz); 8.00(d, 1H, J=8.2Hz); 8.26(m, 1H); 8.30(dd, 1H, J=8.2, J′=1.5Hz); 8.40(s, 1H); 9.20(dd, 1H, J=4.1, J′=1.4Hz). (CDCl₃) 7e(CH₃)₂N—HHHHHH2 embedded image

138-1403255, 2951, 1583, 1488, 1332, 1245, 1156, 1092, 866, 695, 569.2.28(s, 6H); 2.67(t, 2H, J=7.1Hz); 4.18(t, 2H, J=7.1Hz); 6.40(d, 1H, J=3.1Hz); 6.92(m, 3H); 7.02(d, #2H, J=7.7Hz); 7.14(d, 1H, J=3.1Hz); 7.20(d, 2H, J=8.5Hz); 7.28(d, 1H, J=1.9Hz); 7.37(m, 2H); 7.64(d, 2H, J=8.6Hz). (CDCl₃) 8e(CH₃)₂N—HHHHHH2 embedded image

126-1281474, 1287, 1156, 1088, 973, 730, 654, 554, 538.2.31(s, 6H); 2.36(s, 3H); 2.72(t, 2H, J=7.1Hz); 4.20(t, 2H, J=7.1Hz); 6.39(d, 1H, J=3.1Hz); 6.90(dd, 1H, J=8.6Hz, J′=1.6Hz); 7.13(d, 1H, #J=3.1Hz); 7.16-7.20(m, 3H); 7.26(m, 1H); 7.57(d, 2H, J=8.3Hz). (CDCl₃) 9e(CH₃)₂N—HHHHHH2 embedded image

145-1473095, 2951, 1416, 1319, 1148, 989, 730, 605, 537.2.33(s, 6H); 2.74(m, 2H); 4.24(t, 2H, J=7.1Hz); 6.44(d, 1H, J=3.1Hz); 6.79(d, 1H, J=4.0Hz); 6.95(dd, 1H, J=8.7Hz, J′=2.0Hz); 7.15(d, 1H, J=4.0Hz); 7.17(d, #1H, J=3.1Hz); 7.24(d, 1H, J=8.7Hz); 7.35(d, 1H, J=2.0Hz). (DMSO-d6)10e(CH₃)₂N—HHHHHH2 embedded image

166-1683103, 2783, 1526, 1488, 1331, 1154, 1140, 973, 734, 607.2.26(s, 6H); 2.63(t, 2H, J=7.1Hz); 4.12(t, 2H, J=7.1Hz); 6.29(d, 1H, J=3.1Hz); 6.80(dd, 1H, J=8.7Hz, J′=2.0Hz); 7.07(m, 2H); 7.15(d, 1H, #J=1.5Hz); 7.57(dd, 1H, J=8.8Hz, J′=7.1Hz); 8.10(d, 1H, J=7.1Hz); 8.16(d, 1H, J=8.8Hz). (CDCl₃)11e(CH₃)₂N—HHHHHH2 embedded image

50-523103, 2943, 1457, 1336, 1326, 1244, 1177, 1142, 727, 628, 528.2.26(s, 6H); 2.64(t, 2H, J=6.4Hz); 4.16(t, 2H, J=6.4Hz); 6.39(m, 1H); 6.78(d, 1H, J=4.0Hz); 6.94(d, 1H, J=8.4Hz); #7.15(m, 2H); 7.39(s, 1H); 7.55(d, 1H, J=4.0Hz). (CDCl₃)12e(CH₃)₂N—HHHHHH2 embedded image

124-1263064, 2935, 1333, 1166, 1136, 596, 587.2.28(s, 6H); 2.67(t, 2H, J=7.0Hz); 4.19(t, 2H, J=7.0Hz); 6.43(d, 1H, J=3.1Hz); 6.85(dd, 1H, J=8.6Hz, J′=2.0Hz); 7.17(d, 1H, J=3.1Hz); 7.22(d, 1H, J=8.6Hz); #7.31(d, 1H, J=2.0Hz); 7.48(t, 1H, J=1.8Hz); 7.56(d, 2H, J=1.8Hz). (CDCl₃)13e(CH₃)₂N—HHHHHH2 embedded image

114-1161464, 1335, 1286, 1161, 722, 584.2.28(s, 6H); 2.67(t, 2H, J=7.0Hz); 4.19(t, 2H, J=7.0Hz); 6.41(d, 1H, J=2.9Hz); 6.87(d, 1H, J=8.8Hz); 7.15(d, 1H, J=2.9Hz); 7.19-7.29(m, 3H); 7.56(d, 1H, #J=7.8Hz); 7.63(d, 1H, J=7.9Hz); 7.88(s, 1H). (CDCl₃)14d(CH₃)₂N—HHHHHH2 embedded image

138-1401541, 1481, 1365, 1330, 1235, 1150, 1124, 736, 580.2.28(s, 6H); 2.66(t, 2H, J=7.1Hz); 4.17(t, 2H, J=7.1Hz); 6.40(d, 1H, J=2.9Hz); 7.03(dd, 1H, J=8.7Hz, J′=1.8Hz); 7.15(d, #1H, J=2.9Hz); 7.21(d, 1H, J=8.7Hz); 7.39(d, 1H, J=1.8Hz); 7.48(m, 1H); 7.65(m, 1H); 7.71(d, 1H, J=8.8Hz); 7.86(d, 1H, J=7.8Hz). (CDCl₃)15e(CH₃)₂N—HHHHHH2 embedded image

163-1661329, 1288, 1153, 1126, 694, 545, 509.2.30(s, 6H); 2.70(t, 2H, J=7.1Hz); 4.22(t, 2H, J=7.1Hz); 4.29(s, 2H); 6.48(d, 1H, J=3.1Hz); 7.04(dd, 1H, J=8.8Hz, J′=2.2Hz); 7.19(d, 1H, J=3.1Hz); #7.31(d, 1H, J=8.8Hz); 7.33-7.40(m, 5H); 7.49(d, 1H, J=2.2Hz). (CDCl₃)16e embedded image

HHHHHH2

138-1402960, 1481, 1323, 1161, 1151, 1074, 659, 549, 480.1.57(m, 4H); 2.37(m, 4H); 2.66(t, 2H, J=6.8Hz); 4.12(t, 2H, J=6.8Hz); 6.25(d, 1H, J=3.1Hz); 6.82(dd, 1H, J=8.8Hz, J′=2.0Hz); 7.22(d, 1H, #2.0Hz); 7.25(d, 1H, J=8.6Hz); 7.29(d, 1H, J=3.1Hz); 7.54-7.66(m, 2H); 7.74(dd, 1H, J=8.7Hz, J′=1.8Hz); 7.94(m, 1H); 8.03(m, 2H); 8.28(s, 1H). (CDCl₃)17e embedded image

HHHHHH2

186-1892814, 1491, 1291, 1158, 1128, 763, 585.1.59(m, 4H); 2.39(m, 4H); 2.67(t, 2H, J=6.8Hz); 4.11(t, 2H, J=6.8Hz); 6.21(d, 1H, J=3.1Hz); 6.70(dd, 1H, J=8.8Hz, J′=1.8Hz); 7.10(d, 1H, 1.8Hz); 7.20(d, 1H, #J=8.8Hz); 7.27(d, 1H, J=3.1Hz); 7.50(m, 1H); 7.60-7.74(m, 2H); 8.03(m, 2H); 8.11(d, 1H, J=8.1Hz); 8.76(d, 1H, J=8.6Hz). (CDCl₃)18e embedded image

HHHHHH2

156-1582950, 2803, 1491, 1325, 1156, 1078, 650, 564.1.59(m, 4H); 2.36(m, 4H); 2.69(t, 2H, J=6.6Hz); 4.11(t, 2H, J=6.6Hz); 6.30(d, 1H, J=3.1Hz); 6.83(dd, 1H, J=8.7Hz, J′=1.9Hz); 7.25(d, 1H, 1.9Hz); 7.32(m, #2H); 7.50(dd, 1H, J=8.6Hz, J′=2.0Hz); 7.92(d, 1H, J=2.0Hz); 7.98(d, 1H, J=8.8Hz). (CDCl₃)19e(CH₃)₂N—HHHHHH2 embedded image

108-1112943, 2821, 1516, 1139, 752, 728, 542, 531.2.28(s, 6H); 2.68(t, 2H, J=7.1Hz); 4.19(t, 2H, J=7.1Hz); 6.43(d, 1H, J=3.1Hz); 6.82(d, 1H, J=16.6Hz); 7.09(dd, 1H, J=8.6, J′=2.0Hz); 7.15(d, 1H, J=3.3Hz); #7.25(m, 1H); 7.33-7.44(m, 6H); 7.49(d, 1H, J=2.0Hz). (CDCl₃)20e(CH₃)₂N—HHHHHH2 embedded image

120-1233095, 2943, 1421, 1325, 1148, 1020, 730, 609, 534.2.30(s, 6H); 2.69(t, 2H, J=7.1Hz); 4.21(t, 2H, J=7.1Hz); 6.46(d, 1H, J=3.1Hz); 6.93(dd, 1H, J=8.6, J′=2.0Hz); 7.17(s, #1H); 7.18(d, 1H, J=3.3Hz); 7.25(m, 1H); 7.39(d, 1H, J=2.0Hz). (CDCl₃)21e(CH₃)₂N—HHHHHH2 embedded image

175 (desc)1686, 1164, 1094, 637, 534, 475.2.12(s, 6H); 2.53(t, 2H, J=6.6Hz); 4.15(t, 2H, J=6.6Hz); 6.30(d, 1H, J=3.1Hz); 6.80(dd, 1H, J=8.6, J′=2.2Hz); 7.19(d, 1H, J=2.0Hz); 7.30-7.34(m, 2H); 7.57(AB sist., #2H, J=8.4Hz); 7.70(AB sist., 2H, J=8.4Hz). (DMSO-d6)22e(CH₃)₂N—HHHHHH2 embedded image

114-1172943, 1573, 1469, 1321, 1161, 1088, 737, 630, 538.2.13(s, 6H); 2.50-2.55(m, 5H); 4.14(t, 2H, J=6.3Hz); 6.29(d, 1H, J=3.0Hz); 6.82(d, 1H, J=8.2Hz); 7.20(s, 1H); #7.29-7.32(m, 2H); 7.79(AB sist., 2H, J=8.4Hz); 8.02(AB sist., 2H, J=8.4Hz). (DMSO-d6).23e(CH₃)₂N—HHHHHH2 embedded image

141-1442935, 1598, 1497, 1333, 1258, 1159, 1093, 1018, 836, 568, 560.2.28(s, 6H); 2.67(t, 2H, J=7.1Hz); 4.18(t, 2H, J=7.1Hz); 6.38(d, 1H, J=3.1Hz); 6.84(AB Sist., 2H, #J=9.0Hz); 6.90(dd, 1H, J=8.8, J′=2.0Hz); 7.13(d, 1H, J=3.3Hz); 7.19(d, 1H, J=8.8Hz); 7.27(d, 1H, J=2.0Hz); 7.62(AB sist., 2H, J=9Hz). (CDCl₃)24e(CH₃CH₂)₂N—HHHHHH2 embedded image

53-562969, 1486, 1334, 1161, 114, 1080, 862, 729, 652, 560.0.78(m, 6H); 2.32(s, 3H); 2.42(m, 4H); 2.65(m, 2H); 4.12(m, 2H); 6.30(d, 1H, J=3.0Hz); 6.82(d, 1H, J=8.6Hz); 7.26(d, 1H, #1.7Hz); 7.32(m, 2H); 7.50(dd, 1H, J=8.7Hz, J′=1.9Hz); 7.91(d, 1H, J=1.7Hz); 7.99(d, 1H, J=8.6Hz). (CDCl₃)25e(CH₃)₂N—HHHHHH2 embedded image

60-643095, 2768, 1529, 1349, 1165, 1090, 736.2.29(s, 6H); 2.67(t, 2H, J=7.0Hz); 4.18(t, 2H, J=7.0Hz); 6.40(d, 1H, J=3.1Hz); 6.85(dd, 1H, J=8.6Hz, J′=2.0Hz); 7.16(d, #1H, J=3.1Hz); 7.18(d, 1H, J=8.6Hz); 7.29(d, 1H, J=2.0Hz) 7.85(AB sys, J=8.8Hz, 2H); 8.21(AB sys, J=8.8Hz, 2H). (CDCl₃)26e(CH₃)₂N—HHHHHH2 embedded image

138-1403103, 2951, 1587, 1491, 1335, 1166, 1089, 557, 542.2.35(s, 6H); 2.83(m, 2H); 4.28(t, 2H, J=6.7Hz); 6.40(d, 1H, J=3.0Hz); 6.83(dd, 1H, J=8.6Hz, J′=2.0Hz); 7.20(d, 1H, #J=1.9Hz); 7.30-7.38(m, 4H); 7.70-7.75(m, 2H). (DMSO-d6).27e(CH₃CH₂)₂N—HHHHHH2 embedded image

68-703110, 2969, 1458, 1271, 1249, 1179, 1140, 727, 651.1.00(t, 6H, J=7.0Hz); 2.60(q, 4H, J=7.0Hz); 2.81(t, 2H, J=6.7Hz); 4.21(t, 2H, J=6.7Hz); 6.38(d, 1H J=3.0Hz); 6.79(d, 1H, #J=4.5Hz); 6.96(dd, 1H, J=8.6, J′=1.7Hz); 7.14(d, 1H, 3.0Hz); 7.19(d, 1H, J=8.8Hz); 7.40(d, 1H, J=1.5Hz); 7.59(d, 1H, J=4.4Hz). (CDCl₃)28e embedded image

HHHHHH2

81-843119, 2951, 2798, 1458, 1271, 1248, 1178, 1140, 727, 623.1.85(m, 6H); 2.68(m, 4H); 3.00(m, 2H); 4.38(m, 2H); 6.40(d, 1H, J=3.1Hz); 6.82(d, 1H, J=4.5Hz); 6.96(d, 1H, #J=8.6Hz); 7.19(d, 1H, 2.7Hz); 7.22(m, 1H); 7.41(m, 1H); 7.64(d, 1H, J=4.5Hz). (CDCl₃)29e(CH₂CH₂)₂N—HHHHHH2 embedded image

97-1040.95(t, 6H, J=7.1Hz); 2.54(q, 4H, J=7.0Hz); 2.76(t, 2H, J=6.7Hz); 4.07(t, 2H, J=6.7Hz); 6.66(dd, 1H, J=8.5, J′=1.7Hz); 6.91(s, 1H); 6.97(s, 1H); 7.01(d, 1H, J=8.8Hz); 7.22(dd, 1H, J=8.6, J′=1.6Hz); 7.26(s, 1H); #7.42-7.55(m, 3H); 7.63(d, 1H, J=8.1Hz); 7.70(d, 1H, J=8.2Hz); 8.03(s, 1H); 9.95(s, 1H). (CDCl3)30e(CH₃CH₂)₂N—HHHHHH2 embedded image

133-1350.87(m, 6H); 2.58(m, 4H); 2.76(m, 2H); 4.14(m, 2H); 6.24(s, 1H); 6.73(d, 1H, J=8.8Hz); 7.11(s, 1H); 7.21(d, 1H, J=8.0Hz); 7.29(s, 1H); 7.50(t, 1H, J=7.8Hz); 7.63-7.71(m, 2H); 8.04(d, 2H, J=7.5Hz); 8.13(d, 1H, #J=8.2Hz); 8.76(d, 1H, J=8.2Hz); 10.21(s, 1H). (DMSO-d6)31e(CH₃CH₂)₂N—HHHHHH2 embedded image

Oil0.83(m, 6H); 2.60(m, 4H); 2.70(m, 2H); 4.13(m, 2H); 6.30(d, 1H, J=2.6Hz); 6.87(d, 1H, J=8.6Hz); 7.24(s, 1H); 7.30(m, 2H); 7.44(m, 3H); 7.66(d, 2H, J=7.2Hz); 7.72(AB sys, 2H, J=8.5Hz); 7.78(AB sys, 2H, J=8.5Hz); 9.91(s, 1H). (DMSO-d6)32e(CH₃)₂N—CH₃HHHHH2 embedded image

203-2052.13(s, 6H); 2.33(s, 6H); 2.39(t, 2H, J=7.0Hz); 4.07(t, 2H, J=6.8Hz); 6.08(s, 1H); 6.76(dd, 1H, J=8.6, J′=2.0Hz); 7.13(d, 1H, J=2.0Hz); 7.20(d, 1H, J=8.6Hz); 7.51(dd, 1H, J=8.7, J′=2.0Hz); 7.93(d, 1H, J=2.0Hz); #8.00(d, 1H, J=8.8Hz); 10.20(s, 1H). (DMSO-d6)33e(CH₃)₂N—CH₃HHHHH2 embedded image

199-2002.11(s, 6H); 2.30(s, 3H); 2.35(t, 2H, J=7.0Hz); 4.03(t, 2H, J=7.0Hz); 6.03(s, 1H); 6.75(dd, 1H, J=8.6, J′=2.0Hz); 7.10(d, 1H, J=2.0Hz); 7.13(d, 1H, J=8.6Hz); 7.54-7.67(m, 2H); 7.73(dd, 1H, J=8.6, J′=1.8Hz); #7.95(d, 1H, J=7.9Hz); 8.02(d, 2H, J=8.6Hz); 8.27(d, 1H, J=1.5Hz); 9.89(s, 1H). (DMSO-d6)34e(CH₃)₂N—CH₃HHHHH2 embedded image

183-1842.12(s, 6H); 2.29(s, 3H); 2.35(t, 2H, J=7.0Hz); 4.01(t, 2H, J=7.0Hz); 5.98(s, 1H); 6.62(dd, 1H, J=8.7, J′=1.9Hz); 6.98(d, 1H, J=2.0Hz); 7.07(d, 1H, J=8.6Hz); 7.49(m, 1H); 7.63(m, 1H); 7.70(m, 1H); 8.02(d, 2H, J=7.5Hz); #8.12(d, 1H, J=8.0Hz); 8.75(d, 1H, J=8.4Hz); 10.15(s, 1H). (DMSO-d6)35e(CH₃)₂N—CH₃HHHHH2 embedded image

182-1832.14(s, 6H); 2.34(s, 3H); 2.39(m, 2H); 4.01(m, 2H); 6.09(s, 1H); 6.70(dd, 1H, J=8.5, J′1.8Hz); 7.08(d, 1H, J=1.8Hz); 7.21(d, 1H, J=8.5Hz); 7.51(d, 1H, J=4.5Hz); 7.80(d, 1H, J=4.5Hz). (DMSO-d6)36e(CH₃)₂N—CH₃HHHHH2 embedded image

176-1772.14(s, 6H); 2.33(s, 3H); 2.39(t, 2H, J=7.1Hz); 4.06(t, 2H, J=7.1Hz); 6.07(s, 1H); 6.79(dd, 1H, J=8.8, J′=2.0Hz); 7.11(d, 1H, J=1.8Hz); 7.19(d, 1H, J=8.8Hz); 7.36-7.48(m, 3H); 7.66(m, 2H); 7.72(AB sys, 2H, #J=8.8Hz); 7.79(AB sys, 2H, J=8.8Hz); 9.85(s, 1H). (DMSO-d6)37e(CH₃)₂N—CH₃HHHHH2 embedded image

135-1372.17(s, 6H); 2.38(s, 3H); 2.45(m, 2H); 3.30-3.45(m, 4H); 4.14(t, 2H, J=6.7Hz); 6.15(s, 1H); 7.04(d, 1H, J=8.5Hz); 7.26(m, 1H); 7.30-7.38(m, 4H); 7.44(m, 1H); 7.65(d, 1H, J=8.2Hz); 7.62(m, 1H); 7.87(d, 1H, #J=8.2Hz); 9.56(s, 1H). (DMSO-d6)38e(CH₃)₂N—CH₃HHHHH2 embedded image

147-1492.20(s, 6H); 2.34(s, 3H); 2.45(m, 2H); 4.10(t, 2H, J=7.1Hz); 6.08(s, 1H); 6.76(dd, 1H, J=8.6, J′=2.0Hz); 6.99(d, 2H, J=8.8Hz); 7.03-7.08(m, 3H); 7.17-7.24(m, 2H); 7.41(t, 2H, J=7.8Hz); 7.63(d, 2H, #J=8.8Hz); 9.73(s, 1H). (DMSO-d6)39e(CH₃)₂N—CH₃HHHHH2 embedded image

147-1492.15(s, 6H); 2.35(s, 3H); 2.41(t, 2H, J=6.7Hz); 4.10(t, 2H, J=7.1Hz); 6.12(s, 1H); 6.71(dd, 1H, J=8.6, J′=2.0Hz); 7.09(d, 1H, J=1.8Hz); 7.24(d, 1H, J=9.0Hz); 7.58(d, 2H, J=1.9Hz); 7.90(t, 1H, J=1.9Hz). (DMSO-d6)40e(CH₃)₂N—CH₃HHHHH2 embedded image

167-1692.14(s, 6H); 2.31(s, 3H); 2.38(m, 2H); 4.04(t, 2H, J=7.1Hz); 6.02(s, 1H); 6.66(dd, 1H, J=8.4, J′=1.8Hz); 7.04(d, 1H, J=1.6Hz); 7.12(d, 1H, J=8.2Hz); 7.40-7.51(m, 2H); 8.03(d, 1H, J=7.6Hz); 8.21(d, 1H, J=7.9Hz); #8.31(s, 1H); 10.08(s, 1H). (DMSO-d6)41e(CH₃)₂)₂N—HHHHHH2 embedded image

62-750.98(m, 6H); 2.54(m, 4H); 2.70(m, 2H); 4.18(m, 2H); 6.29(s, 1H); 6.77(d, 1H, J=8.5Hz); 7.18(s, 1H); 7.34(m, 2H); 7.39-7.52(m, 2H); 8.03(d, 1H, J=7.9Hz); 8.22(d, 1H, J=7.5Hz); 8.34(s, 1H); 10.18(s, 1H). (CDCl3)42e(CH₃)₂N—HHHHHH2 embedded image

61-722.12(s, 6H); 2.50(m, 2H); 4.12(t, 2H, J=6.7Hz); 6.25(d, 1H, J=3.1Hz); 6.75(dd, 1H, J=8.7, J′=2.1Hz); 7.17(d, 1H, J=1.9Hz); 7.25(d, 1H, J=8.9Hz); 7.30(d, 1H, J=3.2Hz); 7.48(m, 2H); 8.04(d, 1H, J=7.0Hz); 8.24(d, 1H, #J=7.4Hz); 8.34(s, 1H); 10.14(s, 1H). (CDCl3)43e embedded image

HHHHHH3

82-921.20-1.55(m, 6H); 1.88(m, 2H); 2.33(s, 3H); 2.16-2.60(m, 6H); 4.10(t, 2H, J=6.6Hz); 6.34(d, 1H, J=3.2Hz); 6.82(d, 1H, J=9.9Hz); 7.27-7.35(m, 3H); 7.50(dd, 1H, J=8.7, J′=2.0Hz); 7.91(d, 1H, J=2.2Hz); 7.99(d, 1H, #J=8.6Hz); 10.20(bs, 1H). (DMSO-d6)44e embedded image

HHHHHH3

92-1081.20-1.55(m, 6H); 1.87(m, 2H); 2.22-2.62(m, 6H); 4.06(t, 2H, J=6.6Hz); 6.28(d, 1H, J=2.9Hz); 6.83(dd, 1H, J=8.7, J′=2.0Hz); 7.24(d, 1H, J=2.0Hz); 7.27(m, 2H); 7.59(m, 1H); 7.64(m, 1H); 7.75(dd, 1H, J=8.8, J′=1.9Hz); #7.95(d, 1H), J=7.5Hz); 8.03(d, 2H, J=8.5Hz); 8.28(s, 1H); 9.97(s, 1H). (DMSO-d6)45e embedded image

HHHHHH3

105-1071.25-1.55(m, 6H); 1.81(m, 2H); 2.03-2.60(m, 6H); 4.03(t, 2H, J=6.4Hz); 6.23(d, 1H, J=3.1Hz); 6.70(d, 1H, J=8.9Hz); 7.11(d, 1H, J=1.8Hz); 7.20(d, 1H, J=8.9Hz); 7.24(d, 1H, J=3.1Hz); 7.49(dd, 1H, J=8.1, J′=7.4Hz); #7.59-7.66(m, 1H); 7.66-7.73(m, 1H); 8-8.05(m, 2H); 8.12(d, 1H, J=8.2Hz); 8.75(d, 1H, J=7.8Hz); 10.20(bs, 1H). (DMSO-d6)46e embedded image

HHHHHH3

85-861.36(m, 2H); 1.49(m, 4H); 1.86(m, 2H); 2.15-2.44(m, 6H); 4.10(t, 2H, J=6.7Hz); 6.33(d, 1H, J=3.1Hz); 6.79(dd, 1H, J=8.7, J′=2.0Hz); 7.21(d, 1H, J=2.0Hz); 7.30-7.36(m, 2H); 7.52(d, 1H, J=4.4Hz); 7.83(d, 1H, #J=4.4Hz); 10.25(bs, 1H). (DMSO-d6)47e embedded image

HHHHHH3

148-1501.34(m, 2H); 1.47(m, 4H); 1.86(m, 2H); 2.03-2.55(m, 6H); 4.09(t, 2H, J=6.6Hz); 6.32(d, 1H, J=2.8Hz); 6.87(dd, 1H, J=8.9, J′=1.8Hz); 7.26(d, 1H, J=1.9Hz); 7.28-7.34(m, 2H); 7.36-7.49(m, 3H); 7.66(m, 2H); 7.73(AB sys, 2H, #J=8.8Hz); 7.79(AB sys, 2H, J=8.8Hz); 9.91(s, 1H). (DMSO-d6)48e embedded image

HHHHHH3

59-611.20-1.56(m, 6H); 1.89(m, 2H); 2.12-2.50(m, 6H); 3.26-3.47(m, 4H); 4.16(t, 2H, J=6.2Hz); 6.40(d, 1H, J=2.3Hz); 7.13(d, 1H, J=8.6Hz); 7.24(t, 1H, J=7.5Hz); 7.34-7.50(m, 6H); 7.64(d, 1H, J=8.4Hz); 7.76(m, 1H); #7.87(d, 1H, J=8.2Hz); 9.65(s, 1H). (DMSO-d6)49e embedded image

HHHHHH3

64-661.20-1.58(m, 6H); 1.90(m, 2H); 2.20-2.55(m, 6H); 4.09(t, 2H, J=6.4Hz); 6.33(s, 1H); 6.84(dd, 1H, J=8.4Hz); 6.96-7.02(m, 2H); 7.04(d, 2H, J=7.9Hz); 7.17-7.24(m, 2H); 7.32(m, 2H); 7.41(m, 2H); 7.64(d, 2H, #J=8.6Hz); 9.79(s, 1H). (DMSO-d6)50e embedded image

HHHHHH3

56-581.35(m, 2H); 1.46(m, 4H); 1.83(m, 2H); 2.10(m, 2H); 2.24(m, 4H); 4.11(t, 2H, J=6.4Hz); 6.36(d, 1H, J=2.6Hz); 6.78(dd, 1H, J=8.8, J′=1.8Hz); 7.22(d, 1H, J=1.90Hz); 7.33(d, 1H, J=2.9Hz); 7.37(d, 1H, J=8.8Hz); 7.58(d, 2H, #J=8.6Hz); 7.89(t, 1H, J=1.9Hz); 9.99(s, 1H). (DMSO-d6)51e embedded image

HHHHHH3

70-721.38(m, 2H); 1.52(m, 2H); 1.91(m, 2H); 2.24(m, 2H); 2.37(m, 4H); 4.16(t, 2H, J=6.6Hz); 6.42(d, 1H, J=2.5Hz); 6.89(d, 1H, J=8.6Hz); 7.32(s, 1H); 7.37(d, 1H, J=2.8Hz); 7.43(d, 1H, J=8.6Hz); 7.48(s, 1H). (DMSO-d6)52e embedded image

HHHHHH3

92-961.13-1.70(m, 6H); 2.00(m, 2H); 2.68(m, 2H); 2.84(m, 2H); 3.26(m, 2H); 4.05(m, 2H); 6.22(d, 1H, J=3.1Hz); 6.71(m, 1H); 7.10-7.18(m, 3H); 7.52-7.53(m, 2H); 7.72(m, 1H); 8.15(d, 1H, J=7.3Hz); 8.37(d, 1H, J=8.5Hz); 8.77(d, 1H, #J=8.5Hz); 8.97(bs, 1H); 10.23(bs, 1H). (DMSO-d6 + TFA)

Preparation of the Compounds of General Formula (If)

Example 1f
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-6-yl]-5-chloro-3-methyl-benzo[b]thiophene-2-sulfonamide

185.6 mg (0.66 mMol) of 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride were added to a solution of 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1H-indole in 2 ml of dimethylformamide and 116 mg of N-ethyldiisopropylamine. The reaction mixture is stirred at the room temperature for 20 hours. Then it is evaporated to dryness, slightly alkalinized with sodium bicarbonate solution and extracted with chloroform. The organic phase is repeatedly washed with water and saturated solution of sodium bicarbonate, it is separated and dried with anhydrous sodium sulfate. The organic solution is evaporated to dryness and the resulting solid is purified by chromatography, obtaining 180 mg (67%) of N-[1-(2-dimethylaminoethyl)-1H-indole-6-yl]-5-choloro-3-methyl-benzo[b]thiophene-2-sulfonamide as an amorphous solid.

Example 2f
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-6-yl]-naphtalene-2-sulfonamide

187 mg (80%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1H-indole and 150 mg (0.66 mMol) of 2-naphtalenesulfonyl chloride, by means of the process described in the Example 1f, as a solid.

Example 3f
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-6-yl]-naphtalene-1-sulfonamide

157 mg (67%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1H-indole and 150 mg (0.66 mMol) of 1-naphtalenesulfonyl chloride, by means of the process described in the Example 1f, as a solid.

Example 4f
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-6-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide

170 mg (67%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1H-indole and 170 mg (0.66 mMol) of 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride, by means of the process described in the Example 1f, as a solid.

Example 5f
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-6-yl]-4 phenylbenzenesulfonamide

184 mg (73%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1H-indole and 167 mg (0.66 mMol) of 4-phenylbenzenesulfonyl chloride, by means of the process described in the Example 1f, as a solid.

Example 6f
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-6-yl]-2-(naphthalene-1-yl)-ethanesulfonamide

100 mg (40%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1H-indole and 168 mg (0.66 mMol) of 2-(naphthalene-1-yl)-ethanesulfonyl chloride, by means of the process described in the Example 1f, as a solid.

Example 7f
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-6-yl]-4-phenoxybenzenesulfonamide

190 mg (73%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1H-indole and 177 mg (0.66 mMol) of 4-phenoxybenzenesulfonyl chloride, by means of the process described in the Example 1f, as a solid.

Example 8f
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-6-yl]-3,5-dichlorobenzenesulfonamide

100 mg (41%) of the mentioned compound were obtained from 122 mg (0.6 mMol) of 6-amino-1-(2-dimethylaminoethyl)-1H-indole and 162 mg (0.66 mMol) of 3,5-dichlorobenzenesulfonyl chloride, by means of the process described in Example 1, as a solid.

Example 9f
Preparation of 5-Chloro-3-methyl-N-[1-[2-(pyrrolidin-1-yl)ethyl-1H-indol-6-yl]-benzo[b]thiophene-2-sulfonamide

165 mg (58%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol and 186 mg (0.66 mMol) of 5-chloro-3-methyl-benzo[b]-thiophene-2-sulfonyl chloride by means of the process described in Example 1 as a solid.

Example 10f
Preparation of N-(1-[2-(Pyrrolidin-1-yl)ethyl]-1H-indol-6-yl]-napthyl-2-sulfonamide

142 mg (57%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol and 150 mg (0.66 mMol) naphthalenesulfonyl chloride by means of the process described in Example 1 as a solid.

Example 11 f
Preparation of N-[1-[2-Pyrrolidin-1-yl]ethyl]-1H-indol-6-yl]-naphthalene-1-sulfonamide

166 (66%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol and 150 mg (0.66 mMol) naphthalenesulfonyl chloride by means of the process described in Example 1 as a solid.

Example 12f
Preparation of 6-Chloro-N-[1-[2-(pyrrolidin-1-yl)ethyl]-1H-indol-6-yl]-imidazo[2,1-b]thiazole-5-sulfonamide

170 mg (59%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol and 170 mg 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride by means of the process described in Example 1 as a solid.

Example 13f
Preparation of 4-Phenyl-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-6-yl)benzenesulfonamide

205 mg (77%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol and 169 mg (0.66 mmol) of 4-phenylbenzenesulfonyl chloride by means of the process described in Example 1 as an oil.

Example 14f
Preparation of 2-(Naphthyl-1-yl)-N-(1-(2-(pyrrolidin-1-yl)-ethansulfonamid

182 mg (68%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol and 182 mg (0.66 mmol) of 2-naphthalene-ethansulfonyl chloride by means of the process described in Example 1 as a solid.

Example 15f
Preparation of 4-Phenoxy-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-6-yl)-benzenesulfonamide

185 mg (67%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol and 177 mg (0.66 mmol) of 4-phenoxybenzenesulfonyl chloride by means of the process described in Example 1 as a solid.

Example 16f
Preparation of 3,5-Dichloro-N-(1-(2-(Pyrrolidin-1-yl)-1H-indol-6-yl)-benzenesulfonamide

122 mg (46%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 6-amino-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol and 162 mg (0.66 mmol) of 3,5-dichlorobenzenesulfonyl chloride by means of the process described in Example 1 as a solid.

ExR1^fR2^fR3^fR4^fR5^fR6^fR7^fnfA^fm.p. ° C.IR cm⁻¹¹H-NMR (300 MHz), δ (solvent) 1f(CH₃)₂N—HHHHHH2 embedded image

amor- phous3422, 3247, 2943, 1467, 1340, 1158, 1114, 1080, 862, 651, 557.2.19(,s 9H); 2.55(t, 2H, J=6.7Hz); 4.13(t, 2H, #J=6.7Hz); 6.42(d, 1H, 3.1Hz); 6.69(dd, 1H, J=8.3Hz, J′=1.9Hz); 7.13(d, 1H, 3.1Hz); 7.23(m, 1H); 7.45-7.37(m, 2H); 7.63(d, 1H, J=2.0Hz); 7.69(d, 1H, J=8.6Hz). (DMSO-d6) 2f(CH₃)₂N—HHHHHH2 embedded image

140-1433422, 3246, 2935, 2760, 1468, 1336, 1159, 1132, 1074, 753, 711, 678, 553.2.19(s, 6H); 2.55(t, #2H), J=7.0Hz); 4.11(t, 2H, J=7.0Hz); 6.39(d, 1H, J=3.1Hz); 6.67(dd, 1H, J=8.3Hz, J′=1.4Hz); 7.10(d, 1H, J=3.1Hz); 7.19(s, 1H); 7.39(d, 1H, J=8.4Hz); 7.49-7.65(m, 2H); 7.69(dd, 1H, J=8.9Hz, J′=1.6Hz); 7.81-7.88(m, 3H); 8.29(s, 1H). (DMSO-d6) 3f(CH₃)₂N—HHHHHH2 embedded image

139-1423437, 2943, 1507, 1461, 1330, 1192, 1162, 1135, 961, 813, 763, 580, 472.2.21(s, 6H); 2.50(t, 2H, J=7.0Hz); 4.03(t, 2H, J=7.0Hz), 6.35(d, 1H, J=3.1Hz); 6.48(dd, 1H), J=8.4Hz, #J′=1.7Hz); 7.00(s, 1H); 7.05(d, 1H, J=3.1Hz); 7.29(m, 1H); 7.37(t, 1H, J=7.8Hz); 7.60(m, 1H); 7.67(m, 1H); 7.92(d, 1H, J=8.1Hz); 7.98(d, 1H, J=8.1Hz); 8.10(d, 1H, J'27.3Hz); 8.73(d, 1H, J=8.8H). (DMSO-d6) 4f(CH₃)₂N—HHHHHH2 embedded image

amor- phous3448, 3110, 2814, 1459, 1325, 1250, 1178, 1141, 621.2.28(s, 6H); 2.61(t, 2H, J=7.0Hz); 4.14(t, 2H, J=7.0Hz); 6.41(d, 1H, J=3.1Hz); 6.81(m, 2H); 7.12(d, 1H, 3.1Hz); 7.19(m, 1H); 7.42(d, 1H, J=8.2Hz); 7.56(d, 1H, J=4.6Hz) (DMSO-d6) 5f(CH₃)₂N—HHHHHH2 embedded image

amor- phous3256, 2951, 2776, 1468, 1333, 1159, 1095, 763, 670, 591.2.24(s, 6H); 2.62(t, 2H, J=7.0Hz); 4.15(t, 2H, J=7.0Hz); 6.42(d, 1H, J=3.1Hz); 6.70(d, 1H, J=8.4Hz); 7.12(d, 1H, J=3.1Hz); 7.25(d, 1H, #J=3.3Hz); 7.34-7.48(m, 4H); 7.53(m, 2H); 7.59(AB sys, 2H, J=8.3Hz); 7.78(AB sys, 2H, J=8.3Hz). (DMSO-d6) 6f(CH₃)₂N—HHHHHH2 embedded image

amor- phous3254, 2944, 1509, 1468, 1326, 1147, 970, 782, 716, 540.2.15(s, 6H); 2.62(t, 2H, J=7.1Hz); 3.38(m, 2H); 3.49(m, 2H); 4.22(t, 2H, J=7.1Hz); 6.47(d, 1H, J=2.8Hz); 7.04(m, #2H); 7.23(d, 1H, J=3.1Hz); 7.26-7.45(m, 5H); 7.56(d, 1H, J=8.4Hz); 7.68(dd, 1H, J=7.5Hz, J′=7.5Hz); 7.77(d, 1H, J=8.3Hz). (DMSO-d6) 7f(CH₃)₂N—HHHHHH2 embedded image

amor- phous3255, 2935, 2768, 1583, 1488, 1334, 1245, 1154, 1093, 694, 570, 539.2.28(s, 6H); 2.65(t, 2H, J=7.0Hz); 4.16(t, 2H, J=7.0Hz); 6.42(d, 1H, J=3.0Hz); 6.65(dd, 1H, J=8.4Hz, #J′=1.7Hz); 6.90(AB sys, 2H, J=8.8Hz); 7.00(AB sys, 2H, J=7.9Hz); 7.13(d, 1H, J=3.1Hz); 7.19(m, 1H); 7.24(m, 1H); 7.37(m, 2H); 7.43(d, 1H, J=8.3Hz); 7.65(AB sys, 2H, J=8.9Hz). (DMSO-d6) 8f(CH₃)₂N—HHHHHH2 embedded image

150-1593437, 3072, 2920, 1568, 1471, 1346, 1303, 1171, 1140, 799, 670, 598.2.29(s, 6H), 2.66(t, 2H, J=6.8Hz); 4.18(t, 2H, J=6.8Hz); 6.45(d, 1H); 6.67(d, 1H, J=8.4Hz); 7.15(m, 1H); 7.19(m, 1H); 7.46(m, 2H); 7.59(m, 2H). (DMSO-d6) 9f embedded image

HHHHHH2

69-711.58(m, 4H); 2.31(m, 4H); 2.36(s, 3H); 2.59(m, 2H); 4.11(m, 2H); 6.31(s, 1H); 6.79(d, 1H, J=8.4Hz); 7.09(s, 1H); 7.29(d, 1H, J=2.3Hz); 7.38(d, 1H, J=8.5Hz); 7.51(d, 1H, J=8.6Hz); 7.94(d, 1H, J=1.0Hz); 8.00(d, 1H, J=8.35Hz); 10.39(b, 1H). (DMSO-d6)10f embedded image

HHHHHH2

54-601.54(m, 4H); 2.24(m, 4H); 2.50(m, 2H); 4.06(m, 2H); 6.25(s, 1H); 6.77(d, 1H, J=8.4Hz); 7.07(s, 1H); 7.23(m, 1H); 7.32(d, 1H, J=8.1Hz); 7.61(m, 2H); 7.75(d, 1H, J=8.8Hz); 7.95(d, 1H, J=7.6Hz); 8.03(m, 2H); 8.34(s, 1H); 10.11(b, 1H). (DMSO-d6)11f embedded image

HHHHHH2

160-1651.74(m, 4H); 2.71(m, 4H); 2.94(m, 2H); 4.24(m, 2H); 6.27(d, 1H, J=2.8Hz); 6.61(d, 1H, J=8.6Hz); 7.09(s, 1H); 7.24(d, 1H, J=8.5Hz); 7.28(d, 1H, J=2.8Hz); 7.54(t, 1H, J=7.9Hz); 7.63(m, 1H); 7.71(m 1H); 8.03(d, 1H, J=7.6Hz); 8.11-8.23(m, 2H); 8.77(d, 1H, J=8.2Hz); 10.46(b, 1H). (DMSO-d6)12f embedded image

HHHHHH2

53-571.64(m, 4H); 2.50(m, 4H); 2.70(m, 2H); 4.14(m, 2H); 6.31(d, 1H, J=2.8Hz); 6.71(d, 1H, J=8.8Hz); 7.11(s, 1H); 7.31(d, 1H, J=2.9Hz); 7.37(d, 1H, J=8.6Hz); 7.56(d, 1H, J=4.4Hz); 7.91(d, 1H, J=4.5Hz); 10.63(b, 1H). (DMSO-d6)13f embedded image

HHHHHH2

178-1811.55(m, 4H); 2.33(m, 4H); 2.61(m, 2H); 4.11(m, 2H); 6.30(d, 1H, J=2.8Hz); 6.79(dd, 1H, J=8.2, J′=1.6Hz); 7.09(s, 1H); 7.28(d, 1H, J=2.8Hz); 7.34-7.49(m, 4H); 7.67(d, 2H, J=7.0Hz); 7.76(AB sys, 2H, J=8.7Hz); 7.80(AB sys, 2H, J=8.7Hz); 10.05(bs, 1H). (DMSO-d6)14f embedded image

HHHHHH2

oil1.49(m, 4H); 2.31(m, 4H); 2.66(t, 2H, J=6.5Hz); 3.3(m, 4H); 4.16(t, 2H, J=6.5Hz); 6.40(dd, 1H, J=3.1 J′=0.7Hz); 7.04(dd, 1H, J=8.4, J′=1.8Hz); 7.13(m, 1H); 7.33-7.44(m, 5H); 7.48(d, 1H, J=8.6Hz); 7.52(d, 1H, J=8.4Hz); 7.75(t, 1H, J=4.8Hz); 7.85(d, 1H, J=8.1Hz); 9.84(s, 1H). (DMSO-d6)15f embedded image

HHHHHH2

59-621.61(m, 4H); 2.41(m, 4H); 2.66(t, 2H, J=6.5Hz); 4.12(t, 2H, J=6.5Hz); 6.30(d, 1H, J=2.8Hz); 6.75(dd, 1H, J=8.4, J′=1.4Hz); 6.99(d, 2H, J=8.8Hz); 7.04(d, 2H, J=7.9Hz); 7.10(s, 1H); 7.21(t, 1H, J=7.4Hz); 7.29(d, 1H, #J=3.1Hz); 7.36(d, 1H, J=8.5Hz); 7.41(t, 2H, J=7.9Hz); 7.69(d, 2H, J=8.8Hz); 9.98(bs, 1H). (DMSO-d6)16f embedded image

HHHHHH2

145-1571.62(m, 4H); 2.39(m, 4H); 2.64(t, 2H, J=6.7Hz), 4.15(t, 2H, J=6.7Hz); 6.32(d, 1H, J=3.1Hz); 6.73(dd, 1H, J=8.4, J′=1.8Hz); 7.10(s, 1H); 7.33(d, 1H, J=3.2Hz); 7.40(d, 1H, J=8.5Hz); 7.63(d, 2H, J=1.9Hz); 7.90(t, 1H, J=1.9Hz); 10.20(bs, 1H). (DMSO-d6)

Examples
Example 1g
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-naphtalene-1-sulfonamide

149.5 mg (0.66 mMol) of naphtalene-1-sulfonyl chloride were added to a solution of 122 mg (0.6 mMol) of 7-amino-3-(2-dimethylaminoethyl)-1H-indole in 2 ml of dimethylformamide and 116 mg of N-ethyldiisopropylamine. The reaction mixture was stirred at the room temperature for 20 hours. Then it was evaporated to dryness, slightly alkalinized with sodium bicarbonate solution and extracted with chloroform. The organic phase was repeatedly washed with water and saturated solution of sodium bicarbonate, it was separated and dried with anhydrous sodium sulfate. The organic solution was evaporated to dryness and the resulting solid was purified by chromatography, obtaining 120 mg (51%) of N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-naphtalene-1-sulfonamide as a solid cream.

Example 2g
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-5-chloro-3-methyl-benzo[b]thiophene-2-sulfonamide

80 mg (30%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 7-amino-1-(2-dimethylaminoethyl)-1H-indole and 166 mg (0.66 mMol) of 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride, by means of the process described in the Example 1g, as a yellowish solid.

Example 3g
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-4 phenylbenzenesulfonamide

27 mg (11%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 7-amino-1-(2-dimethylaminoethyl)-1H-indole and 167 mg (0.66 mMol) of 4-phenylbenzenesulfonyl chloride, by means of the process described in the Example 1g, as a solid cream.

Example 4g
Preparation of N-[1-(2-dimethylaminoethyl)-1H-indole-7-yl]-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide

69 mg (27%) of the mentioned compound are obtained from 122 mg (0.6 mMol) of 7-amino-1-(2-dimethylaminoethyl)-1H-indole and 170 mg (0.66 mMol) of 6-chloroimidazo[2,1-b]thiazole-5-sulfonyl chloride, by means of the process described in the Example 1g, as a solid cream.

Example 5g
Preparation of 5-chloro-3-methyl-N-(1-(2-(pyrrolidinyl)ethyl)-1H-indol-7-yl)-benzo[b]thiophen-2-sulfonamide

146 mg (51%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 7-amino-1-(2-pyrrolidin-1-yl)ethyl)-1H-indole and 186 mg (0.66 mMol) of 5-chloro-3-methyl-benzo[b]thiophen-2-sulfonyl chloride via the process described in Example 1, as a solid.

Example 6g
Preparation of N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-7-yl)naphthalene-1-sulfonamide

120 mg (48%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 7-amino-1-(2-pyrrolidin-1-yl)ethyl)-1H-indole and 150 mg (0.66 mMol) of naphthalene-1-sulfonyl chloride via the process described in Example 1, as a solid.

Example 7g
Preparation of 6-chloro-N-(1-(2-pyrroldin-1-yl)ethyl)-1H-indol-7-yl)imidazo[2,1-b]thiazole-5-sulfonamide

100 mg (37%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 7-amino-1-(2-pyrrolidin-1-yl)ethyl)-1H-indole and 170 mg (0.66 mMol) 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride via the process described in Example 1, as a solid.

Example 8g
Preparation of 2-(naphth-1-yl)-N-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-7-yl)ethansulfonamide

130 mg (49%) of the mentioned compound were obtained from 137 mg (0.6 mMol) of 7-amino-1-(2-pyrrolidin-1-yl)ethyl)-1H-indole and 168 mg (0.66 mMol) of 2-(naphth-1-yl)ethansulfonyl chloride via the process described in Example 1, as a solid. The yields are indicative and no added effort was made to improve them.

The melting point and spectroscopic data for identifying some of the compounds object of the present invention are indicated in the following table.

m.p.ExR^1gR^2gR^3gR^4gR^5gR^6gR^7gngA^g° C.IR cm⁻¹¹H-NMR (300 MHz), δ (solvent)1g(CH₃)₂N—HHHHHH2 embedded image

54-583422, 3057, 2943, 1489, 1315, 1158, 1132, 772, 5812.42(s, 6H); 2.89(t, 2H, J=6.4Hz); 4.88(t, 2H, J=6.4Hz); 6.17(d, 1H, J=7.6Hz); 6.44(d, 1H, J=3.1Hz); 6.60(t, 1H, J=7.8Hz); 7.16(d, 1H, J=3.3Hz); #7.32(dd, 1H, J=7.9Hz, J′=0.9Hz); 7.53(m, 1H); 7.63-7.67(m, 2H); 8.04-8.09(m, 2H); 8.17(d, 1H, J=8.4Hz); 8.75(m, 1H). (CD₃OD)2g(CH₃)₂N—HHHHHH2 embedded image

57-653448, 2951, 1488, 1315, 1278, 1150, 1113, 1079, 861, 728, 648, 559.2.40(s, 6H); 2.52(s, 3H); 3.08(t, 2H, J=5.7Hz); 4.66(t, 2H, J=5.7Hz), 6.36(d, 1H, 3.1Hz); 6.70(m, 2H); 7.15(dd, 1H, #J=7.0Hz, J′=1.7Hz); 7.24(d, 1H, J=3.1Hz); 7.49(dd, 1H, J=8.6Hz, J′=2.0Hz); 7.91(d, 1H, J=2.0Hz); 8.00(d, 1H, J=8.8Hz). (DMSO-d6)3g(CH₃)₂N—HHHHHH2 embedded image

137-1402943, 1481, 1332, 1316, 1158, 1096, 764, 729, 668, 581.2.33(s, 6H); 2.78(m, 2H); 4.24(m, 2H); 6.46(d, 1H, J=3.1Hz); 6.88(d, 1H, J=3.1Hz); 7.00(t, 1H, J=7.8Hz); 7.17(d, 1H, J=7.5Hz); 7.40-7.49(m, 4H); 7.58(m, #2H); 7.64(AB sys, 2H, J=8.4Hz); 7.86(AB sys, 2H, J=8.4Hz). (CDCl₃)4g(CH₃)₂N—HHHHHH2 embedded image

73-763448, 3110, 2928, 1485, 1459, 1316, 1270, 1238, 1182, 1124, 1091, 723, 622.2.66(s, 6H); 3.28(t, 2H, J=5.4Hz); 4.74(t, 2H); 6.30(d, 1H, J=3.1Hz); 6.64-6.70(m, 2H); 7.01(dd, 1H, #J=6.5Hz, J′=2.4Hz); 7.19(d, 1H, J=3.1Hz); 7.45(d, 1H, J=4.5Hz); 7.89(d, 1H, J=4.5Hz). (DMSO-d6)5g embedded image

HHHHHH2

82-851.87(m, 4H); 2.41(s, 3H); 3.02(m, 4H); 3.34(m, 2H); 4.70(m, 2H); 6.34(d, 1H, J=0.9Hz); 6.62-6.80(m, 2H); 7.09(d, 1H, J=7.47Hz); 7.21(s, 1H); 7.46(d, 1H, J=8.2Hz); 7.87(s, 1H); 7.97(d, 1H, J=8.6Hz). (DMSO-d6)6g embedded image

HHHHHH2

196-1991.79(m, 4H); 2.79(m, 4H); 3.18(m, 2H); 4.66(m, 2H); 6.30(d, 1H, J=8.3Hz); 6.35(d, 1H, J=1.6Hz); 6.60(m, 1H); 7.14(d, 1H, J=8.1Hz); 7.25(m, 1H); 7.56(m, 1H); 7.60-7.74(m, 2H); 8.05(m, 2H); 8.16(d, 1H, J=8.2Hz); 8.79(d, 1H, J=8.64Hz). (DMSO-d6)7g embedded image

HHHHHH2

92-951.84(m, 2H); 1.98(m, 2H); 3.04(m, 2H); 3.58(m, 4H); 4.87(t, 2H, J=6.7Hz); 6.15(d, 1H, J=7.8Hz); 6.49(d, 1H, J=2.6Hz); 6.73(t, 1H, J=7.6Hz); 7.33-7.43(m, 3H, J=5.3Hz); 7.46(d, 1H, J=7.9Hz); 9.83(bs, 1H); 10.32(s, 1H). (DMSO-d6 + TFA)8g embedded image

HHHHHH2

46-491.69(m, 4H); 2.59(m, 4H); 2.90(m, 2H); 3.53(m, 4H); 4.65(t, 2H, J=6.2Hz); 6.45(d, 1H, J=3.1Hz); 6.94(t, 1H, J=7.6Hz); 7.05(m, 1H); 7.35(d, 1H, J=3.1Hz); 7.39-7.56(m, 5H); 7.83(d, 1H, J=7.6Hz); 7.94(m, 2H). (DMSO-d6)

Examples
Example 1h
Preparation of 1-cyclohexanesulfonyl-3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-5-nitro-1H-indole

468 mg (9.8 mMol) of 50% sodium hydride in oil were added at 0° C. to a solution of 1.0 g (3.9 mMol) of 3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-5-nitro-1H-indole in 50 ml of anhydrous dimethylformamide, and the mixture was left to stir for 30 minutes. Then 2.14 g of cyclohexanesulfonyl chloride were added, and the stirring continued for 3 hours at room temperature. Water was added and evaporated to dryness. The resulting crude was treated with sodium bicarbonate and was extracted with chloroform. The organic phase was dried with anhydrous sodium sulfate and evaporated to dryness; the resulting solid was purified by chromatography, obtaining 900 mg (57%) of 1-cyclohexanesulfonyl-3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-5-nitro-1H-indole as a yellow solid.

Example 2h
5-chloro-1-cyclohexanesulfonyl-3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indole

900 mg (74%) of the mentioned compound were obtained from 770 mg (3.12 mMol) of 5-chloro-3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indole, and 1.7 g (9.36 mMol) of cyclohexanesulfonyl chloride by means of the process described in Example 1h, as a yellow solid.

Example 3h
5-amino-1-cyclohexanesulfonyl-3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl)-1H-indole

200 mg of 50% Pd/C with a humidity of 5% were added to a solution of 403 mg (1 mMol) of 1-cyclohexanesulfonyl-3-(1-methyl-1,2,3,6-tetrahydropyridine-4-yl) 5-nitro-1H-indole in 200 ml of ethanol. The resulting suspension was hydrogenized at 25 psi of overpressure for 20 hours. Then the catalyst was filtered and evaporated to drying. The resulting crude was purified by chromatography and 150 mg (40%) of the mentioned compound were obtained as a solid cream.

Example 4h
Preparation of 1-cyclohexanesulfonyl-5-fluoro-3-(1,2,3,5,8,8a-hexahydro-indolizine-7-yl)-1H-indole

1.95 g (78%) of 1-cyclohexanesulfonyl-5-fluoro-3-(1,2,3,5,8,8a-hexahydro-indolizine-7-yl)-1H-indole were obtained as an oil from 1.6 g (6.25 mMol) of 5-fluoro-3-(1,2,3,5,8,8a-hexahydro-indolizine-7-yl)-1H-indole and 3.42 g (18.76 mMol) of cyclohexanesulfonyl chloride by means of the process described in Example 1. Then 2 ml of a 6N ethanol/HCl solution were added to a solution of 1.95 g (4.85 mMol) of 1-cyclohexanesulfonyl-5-fluoro-3-(1,2,3,5,8,8a-hexahydro-indolizine-7-yl)-1H-indole in 20 ml of ethanol, precipitating a solid which was recrystallized from ethanol, obtaining 1.5 g (71%) of the mentioned compound as a white solid.

ExR^1hR^2hR^3hR^4hR^5hR^6hnh embedded image

Saltm.p. ° C.IR cm⁻¹¹H-NMR (300 MHz), δ(solvent)1h embedded image

HHHNO₂H0

—155-1603433, 2938, 2859, 1522, 1371, 1340, 1158, 1126, 988, 612.1.00-1.90 (m, 10H); 2.56 (s, 3H); 2.68 (m, 2H); 2.98 (m, 2H); 3.47 (m, 2H); 3.78 (m, 1H); 6.35 (s, 1H); 7.87 (s, 1H); 8.08 (d, 1H, J=9.2 Hz); 8.26 (dd, 1H, J=9.2 Hz, J′=1.9 Hz); 8.69 (d, 1H, J=1.8 Hz). (DMSO-d6)2h embedded image

HHHClH0

—88-903433, 2941, 2858, 2787, 1447, 1364, 1158, 1128, 1116, 614, 557.1.00-1.90 (m, 10H); 2.41 (s, 3H); 2.55 (m, 2H); 2.67 (m, 2H); 3.15 (m, 3H); 6.18 (m, 1H); 7.27 (dd, 1H, J=8.9 Hz, J′=2.0 Hz); 7.32 (s, 1H); 7.79 (d, 1H, J=2.0 Hz); 7.82 (d, 1H, J=1.8 Hz. (CDCl₃)3h embedded image

HHHNH₂H0

—75 (dec)3376, 2937, 2857, 2784, 1455, 1363, 1342, 1158, 1127, 987, 617, 565.1.00-1.90 (m, 10H); 2.40 (s, 3H); 2.54 (m, 2H); 2.66 (m, 2H); 3.13 (m, 3H); 6.16 (m, 1H); 6.71 (dd, 1H, J=8.8 Hz, J′=2.4 Hz); 7.09 (d, 1H, # J=2.2 Hz); 7.23 (s, 1H); 7.67 (d, 1H, J=8.8 Hz). (CDCl₃)4h embedded image

HHHFH0

HCl263 (dec)3424, 2941, 2499, 2451, 1466, 1445, 1371, 1348, 1188, 1157, 1127, 649, 619.1.18 (m, 3H); 1.38 (m, 2H); 1.54 (m, 1H); 1.73 (m, 5H); 2.01 (m 2H); 2.31 (m, 1H); 2.80 (m, 1H); 3.09 (m, 2H); 3.44 (m, 1H); 3.68 (m, 2H); # 1H); 7.28 (m, 1H); 7.78 (m, 2H); 7.90 (dd, 1H, J=9.0 Hz, J′=4.6 Hz); (DMSO-d6)

Pharmacological Data:

(Compounds According to the General Formula (Ia))

(a)

According to methods I and III Neuropeptide Y₅and Y₂Binding of the benzoxazine-derived compounds of general formula (Ia) has been determined. Some of the obtained values are given in the following table 1.

TABLE 1Neuropeptide Y₅Binding[¹²⁵I]-PYY_(3-36)Neuropeptide Y₂BindingCompoundBIBP 3226 sat.[¹²⁵I]-PYY_(3-36)according toRat cortexRat hypoccampusExampleK_i(nM)K_i(nM)3a6.4>10004a7.3>10005a8.3>10006a18.4>100018a3.4>100020a0.87>1000

(b)

According to method II Neuropeptide Y₅Binding of the benzoxazine-derived compounds of general formula (Ia) has been determined. Some of the values are given in the following table 2.

TABLE 2Neuropeptide Y₅Binding[¹²⁵I]-PYYY₅Rat RecombinantCompound according toReceptor Cell C6ExampleIC₅₀(nM)107a23.5111a7.7112a41.8114a40.7116a106.0

(Compounds of General Formula Ib)

The binding of the benzoxazinone derived sulphonamide compounds of general formula (Ib) was determined as described above.

The binding results of some these compounds are given in the following table 2b:

TABLE 2bCompoundaccording to% Inhibitionexample:10⁻⁶MK_i(nM)1b98.1 ± 4.051.73b107.44b2465b1526b165.97b888b68

(Compounds of General Formula Ic)

The binding of the inventively used sulphonamide derivatives of general formula (Ic) used inventively was determined as described above.

The binding results of some sulphonamide derivatives are given in the following table 1c:

TABLE 1cCompoundaccording to% Inhibitionexample:10⁻⁶MK_i(nM)1c98.1 ± 4.00.283c96.6 ± 5.23.54c96.2 ± 0.69.35c101.2 ± 0.1 1.06c97.6 ± 1.88.77c103.0 ± 7.9 0.138c94.5 ± 7.00.769c96.8 ± 3.72.211c101.30.9813c 98.34.714c95.7 ± 3.424.315c97.4 ± 0.86.816c94.4 ± 8.621.217c102.05.3

(Compounds of General Formula Id)

Binding of the new compounds of general Formula (Id) to the 5-HT₆receptor was determined as previously described.

The binding results for some of the compounds object of the present invention are indicated in the following table 1d:

TABLE 1d% InhibitionExample10⁻⁶M1d83.92d104.33d94.84d46.65d98.16d55.8772.3

(Compounds of General Formula Ie)

Binding of the new compounds of general formula (Ie) to the 5-HT₆receptor was determined as previously described.

The binding results for some of the compounds object of the present invention are indicated in the following table 1e:

TABLE 1eExampleK_i(nM) 3e94.2 4e112.411e1.8912e104.613e82.520e84.8

(Compounds of General Formula If)

Pharmacological Data:

Binding of the new compounds of general Formula (If) to the 5-HT₆receptor was determined as previously described.

The binding results for some of the compounds object of the present invention are indicated in the following table 1f:

TABLE 1f% InhibitionExample10⁻⁶MK_i(nM)1f98.690.22f97.741.23f95.319.84f90.855.25f93.4129.46f94.574.57f95.1118.68f86.9159.1

(Compounds of General Formula Ih)

Pharmacological Data:

Binding of the new compounds of general Formula (Ih) to the 5-HT₆receptor was determined as previously described.

The binding results for some of the compounds object of the present invention are indicated in the following table 1h:

TABLE 1h% InhibitionExample10⁻⁶MK_i(nM)1h59.8 ± 3.02h98.23h55.14h191

Two active substance combinations,

[23] N-[3-(2-dimethylaminoethylyl H-indol-5-yl]-5-chloronaphthalene-2-sulphonamide, 2-[4-(2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-2-yl)-acetamide, and

II)

[23] N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloronaphthalene-2-sulphonamide, 2-[4-(8-Methyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-piperidin-1-yl]-N-(9-oxo-9H-fluoren-3-yl)-acetamide hydrochloride

have been investigated according to the method of measurement of food ingestion described above.

Both combinations show a synergic effect in their pharmacological activities compared with the individual pharmacological activity for each compound.

Active substance combination comprising a compound with npy receptor affinity and a compound with 5-ht6 receptor affinity

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Priority Claims (1)

PCT Information