Alpha-2-adrenergic receptor subtype C antagonists for the treatment of sleep apnea

Abstract

The present invention relates to alpha2-adrenergic receptor subtype C (alpha-2C) antagonists, in particular 3-substituted 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)azacycles of formula (I), for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

Description

[Technical field]

[0001] The present invention relates to alpha2-adrenergic receptor subtype C (alpha-2C) antagonists, in particular 3-substituted 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl) azacycles of formula (I), for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring. [Background technology]

[0002] 2. Background of the Invention Obstructive sleep apnea (OSA) is a sleep-related respiratory disorder characterized by repeated episodes of upper airway obstruction. When breathing, the patency of the upper airway is ensured by the interplay of two opposing forces. The dilator action of the upper airway musculature opposes the negative intraluminal pressure that constricts the lumen. The active contraction of the diaphragm and other accessory respiratory muscles generates a negative pressure in the airway and thus constitutes the driving force of breathing. The stability of the upper airway is substantially determined by the coordination and contraction properties of the dilator muscles of the upper airway.

[0003] Upper airway collapse in OSA is thought to occur at sleep onset due to a decrease in the activity of several upper airway dilator muscles, resulting in an inability to maintain the anatomically vulnerable airway open. However, several upper airway dilator muscles, including the genioglossus, the most important of the upper airway dilator muscles and innervated by the hypoglossal nerve, can increase their activity during sleep in response to respiratory stimuli, potentially countering some of these changes at sleep onset. OSA patients were observed to have apnea intervals with only 25-40% higher genioglossus activity compared to sleep periods with frequent obstructive apneas (Jordan AS, White DP, Lo YL, et al. Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea. Sleep 2009, 32(3):361-8). Noradrenaline is one of the most potent neuromodulators of hypoglossal motoneuron activity (Horner RL Neuromodulation of hypoglossal motoneurons during sleep. Respir Physiol Neurobiol 2008, 164(1-2):179-196). It is believed that a reduction in noradrenergic drive leads to a sleep-dependent reduction in hypoglossal motoneuron excitability, which in turn leads to a reduction in upper airway dilator muscle activity, particularly genioglossus muscle activity.

[0004] Alpha 2C-adrenergic receptors regulate the release of noradrenaline from central noradrenergic neurons, and they are autoreceptors involved in the presynaptic feedback inhibition of noradrenaline (Hein Let et al., Two functionally distinct alpha 2-adrenergic receptors regulate sympathetic neurotransmission Nature 1999, 402(6758):181-184). Increasing the activity of motor neurons of the hypoglossal nerve via alpha 2c-adrenergic receptor antagonism can stabilize the upper airways and protect them from collapse and obstruction. In addition, snoring can also be suppressed by mechanisms of stabilization of the upper airways.

[0005] In simple snoring, there is no obstruction of the upper airway. The narrowing of the upper airway increases the inhalation and exhalation flow rates. This, together with the relaxed muscles, causes the soft tissues of the mouth and throat to flap in the airflow. This slight vibration produces the typical snoring sound.

[0006] Obstructive snoring (upper airway resistance syndrome, severe snoring, hypopnea syndrome) is caused by recurrent partial obstruction of the upper airway during sleep. This leads to an increase in airway resistance and therefore an increase in the work of breathing with significant intrathoracic pressure fluctuations. The development of negative intrathoracic pressure during inspiration can thereby reach values ​​that result from complete airway obstruction in OSA. The pathophysiological effects on the heart, circulation and sleep quality are the same as in obstructive sleep apnea. The etiology is probably the same as in OSA. Obstructive snoring is often a precursor to OSA (Hollandt JH et al., Upper airway resistance syndrome (UARS)-obstructive snoring. HNO 2000, 48(8):628-634).

[0007] Central sleep apnea (CSA) occurs as a result of impaired brain function or respiratory control. CSA is characterized by a lack of drive to breathe during sleep, resulting in repeated periods of insufficient or absent ventilation and impaired gas exchange. CSA has several manifestations. These include highly induced periodic breathing, idiopathic CSA (ICSA), opiate-induced central apnea, obesity hypoventilation syndrome (OHS), and Cheyne-Stokes respiration (CSB). Although the exact triggering mechanisms involved in the various types of CSA can be quite different, an unstable ventilatory drive during sleep is the main underlying feature (Eckert DJ et al., Central sleep apnea:Pathophysiology and treatment. Chest 2007, 131(2):595-607).

[0008] US2018 / 0235934A1 describes a method for treating disorders such as obstructive sleep apnea using an agent for promoting hypoglossal motoneuron excitability. As an agent for promoting hypoglossal motoneuron excitability, a disinhibitor and / or stimulator of central noradrenergic neurons is described. In some embodiments, the disinhibitor of central noradrenergic neurons is an alpha2-adrenergic receptor antagonist such as yohimbine or an alpha2-adrenergic receptor subtype A (alpha-2A) antagonist or an alpha2-adrenergic receptor subtype C (alpha-2C) antagonist. The alpha2-adrenergic receptor antagonist is selected from the group consisting of atipamezole, MK-912, RS-79948, RX821002, [3H]2-methoxy-idazoxan and JP-1302.

[0009] Alpha 2C-adrenergic receptors belong to the family of G-protein-coupled receptors. Besides the different alpha 1-adrenergic receptors, there are three different alpha 2-adrenergic receptor subtypes (alpha 2A, alpha 2B and alpha 2C). They are involved in mediating several diverse physiological effects in various tissues upon stimulation by endogenous catecholamines (epinephrine, norepinephrine) derived either from the synapse or from the blood. Alpha 2-adrenergic receptors play an important physiological role mainly in the cardiovascular and central nervous systems. Alpha 2A- and alpha 2C-adrenergic receptors are the main autoreceptors involved in the presynaptic feedback inhibition of noradrenaline in the central nervous system. The potency and affinity of noradrenaline at alpha 2C-adrenergic receptors is higher than that for alpha 2A-adrenergic receptors. Alpha2C-adrenergic receptors inhibit noradrenaline release when endogenous concentrations of noradrenaline are low, whereas alpha2A-adrenergic receptors inhibit noradrenaline release when endogenous concentrations of noradrenaline are high. (Uys MM et al., Therapeutic Potential of Selectively Targeting α2C-Adrenoceptor in Cognition, Depression, and Schizophrenia-New Developments and Future Perspective. Frontiers in Psychiatry 2017 Aug 14;8:144. doi:10.3389 / fpsyt.2017.00144.eCollection 2017).

[0010] Arylpiperazines as α2-adrenergic receptor subtype C (alpha-2C) antagonists, and their preparation and use as medicines are known from WO03 / 082866A1, where it is disclosed that the compounds are useful for treating disorders such as stress-propagated disorders, Parkinson's disease, depression, schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, Tourette's syndrome, blepharospasm or other focal dystonia, temporal lobe epilepsy with psychosis, drug-induced psychosis, Huntington's disease, disorders caused by fluctuations in the level of sex hormones, panic disorder, Alzheimer's disease or mild cognitive impairment.Nothing is disclosed about the use of these compounds in the treatment of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] US Patent Application Publication No. 2018 / 0235934 [Patent Document 2] WO 03 / 082866 [Non-patent literature]

[0012] [Non-Patent Document 1] Jordan AS, White DP, Lo YL et al. Sleep 2009, 32(3):361-8 [Non-Patent Document 2] Horner RLRespir Physiol Neurobiol 2008, 164(1-2):179-196 [Non-Patent Document 3] Hein L. et al., Nature 1999, 402(6758):181-184 [Non-Patent Document 4] Hollandt JH et al., HNO 2000, 48(8):628-634 [Non-Patent Document 5] Eckert DJ et al., Chest 2007, 131(2):595-607 [Non-Patent Document 6] Uys MM et al., Frontiers in Psychiatry 2017 Aug 14;8:144.doi:10.3389 / fpsyt.2017.00144.eCollection 2017 Summary of the Invention [Problem to be solved by the invention]

[0013] The current gold standard treatment for OSA patients is continuous positive airway pressure (CPAP). The positive airflow pressure generated by the airflow turbine pump splint opens the upper airway and reverses all potential causes of pharyngeal collapse, thereby preventing hypopnea, apnea, and sleep fragmentation. Unfortunately, up to 50% of OSA patients cannot tolerate CPAP for long periods of time (M. Kohler, D. Smith, V. Tippett et al., Thorax 2010 65(9):829-32:Predictors of long-term compliance with continuous positive airway press). Thus, there remains a need to find effective therapeutic agents for the treatment and / or prevention of sleep-related breathing disorders, such as obstructive sleep apnea. Thus, the object of the present invention is to provide an effective therapeutic agent for the treatment and / or prevention of sleep-related breathing disorders, such as obstructive sleep apnea, central sleep apnea, and snoring.

[0014] Surprisingly, it has now been found that the 3-substituted 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)azacycles of formula (I) according to the present invention inhibit the collapsibility of the upper airway and are therefore suitable for the manufacture of medicaments for use in the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring. [Means for solving the problem]

[0015] The present invention relates to a compound of formula (I) for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring. [ka]

[0016] [During the ceremony, X is C(R5)(R6) or C(R7)(R8); Z is -[C(R4)2] n - or a single bond; R1 is, each independently, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, halo(C1-C6)alkyl, phenyl(C1-C6)alkoxy, (C1-C6)alkoxy-(C=O)-, CN, NO2, NH2, mono- or di(C1-C6)alkylamino or carboxy; R2 are, independently, H or (C1-C6)alkyl; Each R3 is independently H or (C1-C6)alkyl; R4 is, each independently, H, hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, hydroxy(C1-C6)alkyl, hydroxy(C2-C6)alkenyl, (C1-C6)alkoxy(C1-C6)alkyl, (C2-C6)alkenyloxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-, (C1-C6)alkoxy-(C=O)-, hydroxy(C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl; or both R and R attached to the same carbon ring atom together with the carbon ring atom to which they are attached form a -(C=O) group; R5 is H or hydroxy; or R4 and R5, which are attached to adjacent carbon ring atoms, form a bond between the carbon ring atoms to which they are attached; R6 is unsubstituted phenyl or phenyl substituted with 1 or 2 substituents R9; R7 is (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)alkoxy-(C=O)-; R8 is hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, halogen, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C2-C6)alkenyl, hydroxy(C1-C6)alkoxy, halo(C1-C6)alkoxy, phenyl(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C2-C6)alkenyloxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-, (C1,-C6)alkoxy-(C=O)-, (C1-C6)alkoxy-(C=O)-(C1-C6)alkyl, (C1-C6)alkyl-S-, (C1-C6)alkyl-(C=O)-O-, (C1-C6)alkyl-(C=O)-O-(C1-C6)alkyl, hydroxy-(C=O)-(C1-C6)alkoxy, hydroxy-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-S-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkyl- (C=O)-S-(C1-C6)alkyl (C1-C6)alkoxy-(C=-O)-(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkyl-S- (C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl-S-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-S- (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl- (O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-O-(O=S=O)-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-O-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-O-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-(O=S=O)-O-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-N(R, 10)-(C1-C6)alkyl, hydroxy(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, CN, NO2, (R 10 )2N-, (R 10 )2N-(C1-C6)alkyl, (R 10 )2N-(C=O)-, (R 10 )2N-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, (R 10 )2N-(C=O)-(C1-C6)alkyl-S-(C1-C6)alkyl, (R 10 )2N-(C=O)-(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, carboxy, R 11 -(O=S=O)-, R 11 -(O=S=O)-O- or (C1-C6)alkoxy-(C1-C6)alkoxy; or R4 and R8 bonded to adjacent carbon ring atoms, together with the carbon ring atoms to which they are bonded, form a fused phenyl ring, wherein said phenyl ring is unsubstituted or substituted with 1 or 2 substituents which are each independently hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)- or (C1-C6)alkoxy-(C=O)-; or R4 and R8, which are bonded to adjacent carbon ring atoms, together with the carbon ring atoms to which they are bonded, form a fused 5- or 6-membered saturated or unsaturated carbocyclic ring or a fused 5- or 6-membered saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein said carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents, each independently being hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, hydroxy(C1-C6) alkyl, halo(C,-C6) alkyl, (C1-C6) alkoxy(C1-C6) alkyl, (C1-C6) alkyl-(C=O)-, (C1-C6) alkoxy-(C=O)-, or oxo; or R7 and R8 together with the carbon ring atoms to which they are attached form a 5- or 6-membered saturated carbocyclic ring or a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein said carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents which are each independently hydroxy, (C1-C6) alkyl, or oxo; R9 is each independently selected from hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, halogen, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C2-C6)alkenyl, hydroxy(C1-C6)alkoxy, halo(C1-C6)alkoxy, phenyl(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C 6)Alkyl, (C2-C6)alkenyloxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-, (C1-C6)alkoxy-(C=O)-, (C1-C6)alkoxy-(C=O)-(C1-C6)alkyl, (C1-C6)alkyl-S-, (C1-C6)alkyl-(C=O)-O-, (C1-C6)alkyl-(C=O)-O-(C1-C6)alkyl, hydroxy-(C=O)-(C1-C6)alkoxy, hydroxy-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C =O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-S-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-S-(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkyl-S-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1 -C6)alkyl-S-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-S-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy hydroxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-O-(O=S=O)-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-O-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-O-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-(O=S=O)-O-(C1-C6)alkyl,(C1-C6) alkyl-(O=S=O)-N(R, 10 )-(C1-C6)alkyl, hydroxy(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, CN, NO2, (R 10 )2N-, (R 10 )2N-(C1-C6)alkyl, (R 10 )2N-(C=O)-, (R 10 )2N-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, (R 10 )2N-(C=O)-(C1-C6)alkyl-S-(C1-C6)alkyl, (R 10 )2N-(C=O)-(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, carboxy, R 11 -(O=S=O)- or R 11 -(O=S=O)-O-; or R and R bonded to adjacent carbon ring atoms together with the carbon ring atoms to which they are bonded form a fused phenyl ring, a fused 5- or 6-membered unsaturated carbocyclic ring, or a fused 5- or 6-membered unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from O and S, wherein said phenyl, carbocyclic ring, or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents each independently being hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy, hydroxy(C1-C6) alkyl, halo(C1-C6) alkyl, (C1-C6) alkoxy(C1-C6) alkyl, (C1-C6) alkyl-(C=O)-, or (C1-C6) alkoxy-(C=O)-; R 10 are each independently H, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)- or R 11 -(O=S=O)-; R 11are each independently hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino; m is 0, 1 or 2; and n is 1 or 2. or a pharma- ceutically acceptable salt or ester thereof, However, the compounds are 1-(7-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,3-dimethyl-piperidine, 1-(6-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,3-dimethyl-piperidine, 2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro- isoquinoline, 2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline, 2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline or 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl-3-(3-trifluoromethyl-phenyl)-pyrrolidine. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] In a possible subgroup of compounds of formula I, Z is -[C(R4)2]n-.

[0018] In a further possible subgroup of compounds of formula I, n is 1.

[0019] In another possible subgroup of compounds of formula I, n is 2.

[0020] In a further possible subgroup of compounds of formula I, Z is a single bond.

[0021] In a further possible subgroup of compounds of formula I, R2 is H.

[0022] In a further possible subgroup of compounds of formula I, R3 is H.

[0023] In a further possible subgroup of compounds of formula I, Each R4 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C1-C6)alkoxy(C1-C6)alkyl, (C2-C6)alkenyloxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-, (C1-C6)alkoxy-(C=O)-, hydroxy(C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl; for example, H.

[0024] In another possible subgroup of compounds of formula I, Each R4 is independently H, hydroxy, or (C1-C6)alkyl; for example, H.

[0025] In a further possible subgroup of compounds of formula I, m is 0.

[0026] In another possible subgroup of compounds of formula I, m is 1.

[0027] In a further possible subgroup of compounds of formula I, Each R1 is independently hydroxy, phenyl(C1-C6)alkoxy, (C1-C6)alkoxy-(C=O)-, CN, NO2, NH2, mono- or di(C1-C6)alkylamino or carboxy.

[0028] In a further possible subgroup of compounds of formula I, Each R1 is independently hydroxy, halogen, phenyl(C1-C6)alkoxy, or NO2.

[0029] In another possible subgroup of compounds of formula I, Each R1 is independently hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy or halogen; for example, hydroxy or halogen.

[0030] In a further possible subgroup of compounds of formula I, X is C(R5)(R6).

[0031] In a further possible subgroup of compounds of formula I, R5 is H.

[0032] In another possible subgroup of compounds of formula I, R5 is hydroxy.

[0033] In another possible subgroup of compounds of formula I, R4 and R5 which are attached to adjacent carbon ring atoms form a bond between the carbon ring atoms to which they are attached.

[0034] In a further possible subgroup of compounds of formula I, R6 is unsubstituted phenyl.

[0035] In another possible subgroup of compounds of formula I, R6 is phenyl substituted with 1 or 2 substituents R9; R9 is each independently hydroxy, (C2-C6)alkenyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C2-C6)alkenyl, hydroxy(C1-C6)alkoxy, halo(C1-C6)alkoxy, phenyl(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C2-C6)alkenyloxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-, (C1-C6)alkoxy-(C=O)-, (C1-C6)alkoxy-(C=O)-(C1-C6); Alkyl, (C1-C6)alkyl-S-, (C1-C6)alkyl-(C=O)-O-, (C1-C6)alkyl-(C=O)-O-(C1-C6)alkyl, hydroxy-(C=O)-(C1-C6)alkoxy, hydroxy-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-S-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkoxy( C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-S-(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkyl-S-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl-S-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-S-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-(O =S=O)-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-(O=S=O)(C1-C6)alkoxy(C1-C6)alkyl,(C1-C6)alkyl-O-(O=S=O)-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-O-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-O-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-(O=S=O)-O-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-N-(R, 10 )-(C1-C6)alkyl, hydroxy(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, CN, NO2, (R 10 )2N-, (R 10 )2N-(C1-C6)alkyl, (R 10 )2N-(C=O)-, (R 10 )2N-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, (R 10 )2N-(C=O)-(C1-C6)alkyl-S-(C1-C6)alkyl, (R 10 )2N-(C=O)-(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, carboxy, R 11 -(O=S=O)- or R 11 -(O=S=O)-O-; or R and R bonded to adjacent carbon ring atoms together with the carbon ring atoms to which they are bonded form a fused phenyl ring, a fused 5- or 6-membered unsaturated carbocyclic ring, or a fused 5- or 6-membered unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from O and S, wherein said phenyl, carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents which are each independently hydroxy, (C-C) alkyl, (C-C) alkoxy, hydroxy(C-C) alkyl, halo(C-C) alkyl, (C-C) alkoxy(C-C) alkyl, (C-C) alkyl-(C=O)- or (C-C) alkoxy-(C=O)-.

[0036] In another possible subgroup of compounds of formula I, R6 is phenyl substituted with 1 or 2 substituents R9; R9 is each independently selected from hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, halo(C1-C6)alkoxy, phenyl(C1-C6)alkoxy, (C1-C6)alkoxy-(C=O)-, (C1-C6)alkyl-(C=O)-O-, hydroxy-(C=O)-(C1-C6)alkoxy, CN, (R 10 )2N-, (R 10 )2N-(C=O)-, R 11 -(O=S=O)- or R 11 -(O=S=O)-O-; or R and R attached to adjacent carbon ring atoms together with the carbon ring atoms to which they are attached form a fused 5-membered unsaturated heterocyclic ring containing two heteroatoms selected from O, wherein said heterocyclic ring is unsubstituted; for example, R is phenyl substituted with one substituent R, R is hydroxy, (C-C) alkyl, (C-C) alkoxy, halogen, hydroxy(C-C) alkoxy or (R 10 )2N-.

[0037] In another possible subgroup of compounds of formula I, X is C(R7)(R8).

[0038] In a further possible subgroup of compounds of formula I, R7 is (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)alkoxy-(C=O)-; for example, (C1-C6)alkyl.

[0039] In a further possible subgroup of compounds of formula I, R8 is (C2-C6)alkenyl, halogen, halo(C1-C6)alkyl, hydroxy(C1-C6)alkenyl, hydroxy(C1-C6)alkoxy, halo(C1-C6)alkoxy, phenyl(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C2-C6)alkenyloxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-, (C1-C6)alkoxy-(C=O)-(C1-C6)alkyl, (C1-C6)alkyl-S-, hydroxy-(C=O)-(C1-C6)alkoxy, hydroxy hydroxy(C1-C6)alkyl-S-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-S-(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-(C)-C6)alkyl-S-(C1-C6)alkyl, (C 1-C6)alkyl-S-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl-S-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-S-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, (C1-C6) Alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-O-(O=S=O)-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-O-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-O-(C1-C6)alkyl,Hydroxy(C1-C6)alkyl-(O=S=O)-O-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-N(R, 10 )-(C1-C6)alkyl, hydroxy(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, CN, NO2, (R 10 )2N-, (R 10 )2N-(C1-C6)alkyl, (R 10 )2N-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, (R 10 )2N-(C=O)-(C1-C6)alkyl-S-(C1-C6)alkyl, (R 10 )2N-(C=O)-(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, R 11 -(O=S=O)- or R 11-(O=S=O)-O-; for example, (C2-C6)alkenyl, halogen, hydroxy(C2-C6)alkenyl, hydroxy(C1-C6)alkoxy, halo(C1-C6)alkoxy, (C2-C6)alkenyloxy(C1-C6)alkyl, hydroxy-(C=O)-(C1-C6)alkoxy, hydroxy-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl , hydroxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkyl-S-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl-S-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, )alkyl-S-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyi-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, alkoxy(C1-C6)alkyl-(O=S=O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-O-(O=S=O)-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-O-(OS=O)-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-O-(C1-C6)alkyl, hydroxy(C1-C6)alkyl-(O=S=O)-O-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-N(R 10 )-(C1-C6)alkyl, hydroxy(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl, CN, NO2, (R 10)2N-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, (R 10 )2N-(C=O)-(C1-C6)alkyl-S-(C1-C6)alkyl, (R 10 )2N-(C=O)-(C1-C6)alkyl-(O=S=O)-(C1-C6)alkyl or R 11 -(O=S=O)-O-.

[0040] In another possible subgroup of compounds of formula I, R8 is hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, halogen, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C2-C6)alkenyloxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-, (C1-C6)alkoxy-(C=O)-, (C1-C6)alkoxy-(C=O)-(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-O-(C1-C6)alkyl, hydroxy-(C=O)-(C1 -C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-S-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-O-(C1-C6)alkyl, hydroxy(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, CN, (R 10 )2N-(C1-C6)alkyl, (R 10)2N-(C=O)- or carboxy; for example, hydroxy, (C2-C6)alkenyl, halogen, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C2-C6)alkenyloxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-, (C1-C6)alkoxy-(C=O)-(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-O-(C1-C6)alkyl, hydroxy-(C=O)-(C1-C6)alkenyl koxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-S-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-O-(C1-C6)alkyl, hydroxy(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, CN, (R 10 )2N-(C1-C6)alkyl, (R 10 )2N-(C=O)- or carboxy; for example, hydroxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl or hydroxy(C1-C6)alkoxy(C1-C6)alkyl.

[0041] In another possible subgroup of compounds of formula I, R4 and R8 attached to adjacent carbon ring atoms together with the carbon ring atoms to which they are attached form a fused phenyl ring, wherein said phenyl ring is unsubstituted or substituted with one or two substituents which are each independently hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)- or (C1-C6)alkoxy-(C=O)-; for example, R4 and R8, which are bonded to adjacent carbon ring atoms, together with the carbon ring atoms to which they are bonded, form a fused phenyl ring, wherein said phenyl ring is substituted with one substituent which is hydroxy(C1-C6)alkyl or (C1-C6)alkoxy-(C=O)-.

[0042] In another possible subgroup of compounds of formula I, R4 and R8, which are bonded to adjacent carbon ring atoms, together with the carbon ring atoms to which they are bonded, form a fused 5- or 6-membered saturated or unsaturated carbocyclic ring or a fused 5- or 6-membered saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein said carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents which are each independently hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-, (C1-C6)alkoxy-(C=O)- or oxo.

[0043] In yet another possible subgroup of compounds of formula I, R4 and R8, which are attached to adjacent carbon ring atoms, together with the carbon ring atoms to which they are attached form a fused 6-membered saturated carbocyclic ring, which carbocyclic ring is unsubstituted.

[0044] In yet another possible subgroup of compounds of formula I, R4 and R8, which are bonded to adjacent carbon ring atoms, together with the carbon ring atoms to which they are bonded, form a fused 5- or 6-membered saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein said heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents which are each independently hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-, (C1-C6)alkoxy-(C=O)- or oxo.

[0045] In another possible subgroup of compounds of formula I, R7 and R8 together with the carbon ring atoms to which they are attached form a 5- or 6-membered saturated carbocyclic ring or a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein said carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents which are each independently hydroxy, (C1-C6) alkyl, or oxo; for example, R7 and R8 together with the carbon ring atoms to which they are attached form a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein said heterocyclic ring is unsubstituted or substituted with 1 or 2 substituents which are each independently hydroxy, (C1-C6) alkyl, or oxo.

[0046] In a further possible subgroup of compounds of formula I, X is C(R5)(R6) or C(R7)(R8); Z is -[C(R4)2]n- or a single bond; R1 is, independently at each occurrence, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, phenyl(C1-C6)alkoxy, or NO2; R2 is, independently at each occurrence, H; R3 is independently H; Each R4 is independently H, hydroxy, or (C1-C6)alkyl; or both R and R attached to the same carbon ring atom together with the carbon ring atom to which they are attached form a -(C=O) group; R5 is H; or R4 and R5, which are attached to adjacent carbon ring atoms, form a bond between the carbon ring atoms to which they are attached; R6 is unsubstituted phenyl or phenyl substituted with 1 or 2 substituents R9; R7 is (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl or (C1-C6)alkoxy-(C=O)-; R8 is hydroxy, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, halogen, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (C2-C6)alkenyloxy(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-, (C1-C6)alkoxy-(C=O)-, (C1-C6)alkoxy-(C=O)-(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-O-(C1-C6)alkyl, hydroxy-(C =O)-(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkyl-S-(C1-C6)alkyl, (C1-C6)alkyl-(C=O)-S-(C1-C6)alkyl, (C1-C6)alkyl-(O=S=O)-O-(C1-C6)alkyl, hydroxy(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, CN, (R 10 )2N-(C1-C6)alkyl, (R 10)2N—(C═O)—, carboxy, or (C1-C6)alkoxy-(C1-C6)alkoxy; or R4 and R8 bonded to adjacent carbon ring atoms, taken together with the carbon ring atoms to which they are bonded, form a fused phenyl ring, wherein said phenyl ring is unsubstituted or substituted with one or two substituents, each independently being hydroxy(C1-C6)alkyl or (C1-C6)alkoxy-(C=O)-; or R and R, which are bonded to adjacent carbon ring atoms, together with the carbon ring atoms to which they are bonded form a fused 6-membered saturated carbocyclic ring, wherein said carbocyclic ring is unsubstituted; R9 is each independently selected from hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, halo(C1-C6)alkoxy, phenyl(C1-C6)alkoxy, (C1-C6)alkoxy-(C=O)-, (C1-C6)alkyl-(C=O)-O-, hydroxy-(C=O)-(C1-C6)alkoxy, CN, (R 10 )2N-, (R 10 )2N-(C=O)-, R 11 -(O=S=O)- or R 11 -(O=S=O)-O-; or R and R attached to adjacent carbon ring atoms together with the carbon ring atoms to which they are attached form a fused 5- or 6-membered unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from O, wherein said phenyl, carbocyclic or heterocyclic ring is unsubstituted; R 10 are each independently H or (C1-C6)alkyl; R 11 are each independently (C1-C6)alkyl or halo(C1-C6)alkyl; m is 0, 1 or 2; and n is 1 or 2.

[0047] In another possible subgroup of compounds of formula I, X is C(R5)(R6) or C(R7)(R8); Z is -[C(R4)2]n-; Each R1 is independently hydroxy, (C1-C6) alkyl, or halogen; R2 is, independently at each occurrence, H; R3 is independently H; R4 is independently H; R5 is H; R6 is unsubstituted phenyl or phenyl substituted with 1 or 2 substituents R9; R7 is (C1-C6) alkyl; R8 is hydroxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl or hydroxy(C1-C6)alkoxy(C1-C6)alkyl; R9 is independently hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, hydroxy(C1-C6)alkoxy or (R 10 )2N-; R 10 are each independently H or (C1-C6)alkyl; m is 0 or 1; n is 1.

[0048] In yet another possible subgroup of compounds of formula I, X is C(R5)(R6) or C(R7)(R8); Z is a single bond; Each R1 is independently hydroxy, (C1-C6) alkyl, or halogen; R2 is, independently at each occurrence, H; R3 is independently H; R4 is independently H; R5 is H; R6 is unsubstituted phenyl or phenyl substituted with 1 or 2 substituents R9; R7 is (C1-C6) alkyl; R8 is hydroxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl or hydroxy(C1-C6)alkoxy(C1-C6)alkyl; R9 is independently hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, hydroxy(C1-C6)alkoxy or (R 10 )2N-; R 10 are each independently H or (C1-C6)alkyl; m is 0 or 1; n is 1.

[0049] In a further possible subgroup of compounds of formula I, the compounds are 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-5-phenyl-1,2,3,6-tetrahydropyridine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-phenylpiperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(2-methoxyphenyl)piperidine, 3-(4-chlorophenyl)-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine. Lysine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(3-methoxyphenyl)piperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-p-tolylpiperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(4-methoxyphenyl)piperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-o-tolylpiperidine, 4-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl]- (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-fluorophenyl)piperidine, 3-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol, 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-fluorophenyl)piperidine Piperidine, (S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-fluorophenyl)piperidine, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidine, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidine·HCl, (S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidine, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-fluorophenyl)piperidine, (S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-fluorophenyl)piperidine, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-trifluoromethyl-phenyl)piperidine, ( S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-trifluoromethyl-phenyl)piperidine, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-trifluoromethylphenyl)piperidine, (S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-trifluoromethylphenyl)piperidine, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4 ]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine HCl, (S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine, (R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol, (R*)- 3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol·HCl, (3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenyl)methanol, Acetic acid 3-{(S)-1-[(R*)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenyl ester·HCl, 2-(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)ethanol, 3-(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)propan-1-ol, trifluoromethanesulfonic acid 3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}phenyl ester, (3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}phenyl 3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}-benzonitrile, 3-benzo[1,3]dioxol-5-yl-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidine, 3-[(R*)-1-((S)-6-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol, (S)-2-[(R *)-3-(3-hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydrobenzo[1,4]dioxin-6-ol, 3-[(R*)-1-((S)-7-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol, (S)-3-[(R*)-3-(3-hydroxyphenyl)-piperidin-1-ylmethyl]-2,3-dihydrobenzo[1,4]dioxin-6-ol, 3-[(R*)-1-((S)-8-benzyloxy-2,3-dihydrobenzo[1,4] 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-yl]phenol, (S)-3-[(R*)-3-(3-hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydrobenzo[1,4]dioxin-5-ol, (R*)-3-[1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylic acid ethyl ester, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine-3-carboxylic acid ethyl ester, [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethoxymethyl-3-methylpiperidine, 3-chloromethyl-1-(2,3-dihydrobenzo[1 ,4]dioxin-2-ylmethyl)-3-methylpiperidine, 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]propan-2-ol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(1-methoxy-1-methylethyl)-3-methylpiperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-hydroxymethyl-3-methylpiperidin-4-ol, 1-(2,3-dihydrobenzo[ 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethyl ester, methanesulfonic acid 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethyl ester, [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]methanol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethyl-3-methoxymethylpiperidine, 1-(2,3-dihydrobenzo[1, 4]dioxin-2-ylmethyl)-3-methoxymethoxymethyl-3-methylpiperidine, 1-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]ethanone, 1-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]ethanol, 3-allyloxymethyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine, 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl-methoxy]ethanol, 3-allyloxymethyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidine, 3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidine-3-carboxylic acid ethyl ester, [3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]methanol, 3-allyl-1-(2,3-dihydrobenzo[ 1,4]dioxin-2-ylmethyl)-3-methoxymethylpiperidine, 3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethoxymethylpiperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-3-(2,2,2-trifluoroethoxymethyl)-piperidine, 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethoxy]ethanol, (S)-1-((R)-2,3-dihydrobenz[1,4]dioxin-2-ylmethyl)-3-methyl- 2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidine-3-carboxylate, {(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}methanol, 2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidine-3-carboxylate, 2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}-ethanol D-tartrate, (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxyethoxymethyl)-3-methylpiperidine, (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-3-(2,2,2-Trifluoroethoxymethyl)piperidine, methanesulfonic acid (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidin-3-ylmethyl ester, thioacetic acid S-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethyl} ester, 2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethyl-sulfanyl}ethanol, {(S)-1-[(S)-1, -(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}acetic acid tert-butyl ester, sodium {(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl-methoxy}acetate, 2-[(S)-1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl-methoxy]ethanol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl-3-methylpiperidin-3-ylmethoxy}acetic acid tert-butyl ester 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluoro-piperidine-3-carboxylic acid ethyl ester, [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluoro-piperidin-3-yl]methanol, (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidine-3-carboxylic acid ethyl ester, [(S)-1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl (S)-1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methyl-piperidine·HCl, (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methoxymethyl-3-methyl-piperidine, 3-methyl-((S)-1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl] ..., -{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}-phenylamine, (R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol oxalate, (S)-2-[(R*)-3-(3-hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydrobenzo[1,4]dioxin-5-ol, 1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxy-phenyl)-pyrrolidine, (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-fluoro-ethoxymethyl)-3-methyl-piperidine·HCl, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluoromethoxy-phenyl)-piperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidine-3-carboxylic acid methyl ester , [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpyrrolidin-3-yl]-methanol, 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidin-3-ylmethoxy]-ethanol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methyl-pyrrolidine or 3-[(R)-1-((S)-7-nitro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol.

[0050] It will be apparent to those skilled in the art that in compounds of formula I, the substituents R and R attached to adjacent carbon ring atoms together with the carbon ring atoms to which they are attached form a fused 5- or 6-membered unsaturated carbocyclic ring or a fused 5- or 6-membered unsaturated heterocyclic ring, wherein said carbocyclic or heterocyclic ring may have further unsaturated bonds in addition to the unsaturated bonds between the carbon ring atoms to which the substituents are attached.

[0051] The terms used herein have the meanings given below. The term "at least one" as used in the following sense refers to one or several, e.g., one. For example, the term "at least one halogen" refers to one or several halogens, e.g., one halogen.

[0052] The term "hydroxy" as used herein by itself or as part of another group refers to an --OH group.

[0053] The term "(C1-C6) alkyl" as used herein by itself or as part of another group refers to a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. Representative examples of (C1-C6) alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and n-hexyl.

[0054] The term "(C1-C6)alkoxy" as used herein by itself or as part of another group refers to a (C1-C6)alkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of (C1-C6)alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, 2,2-dimethylpropoxy, 3-methylbutoxy, and n-hexoxy.

[0055] The terms "halo" or "halogen" as used herein by themselves or as part of another group refer to fluorine, chlorine, bromine, or iodine.

[0056] The term "halo(C1-C6)alkyl" as used herein refers to at least one halogen, as defined herein, appended to the parent molecular moiety through a (C1-C6)alkyl group, as defined herein. When several halogens are present, the halogens may be the same or different. Representative examples of halo(C1-C6)alkyl include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2-chloroethyl, 3-bromopropyl, and 2-chloropropyl.

[0057] The term "phenyl(C1-C6)alkoxy," as used herein, refers to at least one phenyl group appended to the parent molecular moiety through a (C1-C6)alkoxy group, as defined herein. Representative examples of phenyl(C1-C6)alkoxy include, but are not limited to, phenylmethoxy, 2-phenylethoxy, and 3-phenylpropoxy.

[0058]

[0052] The term "amino" as used herein as part of another group refers to the group --NH2.

[0059] The term "mono(C1-C6)alkylamino," as used herein, refers to one (C1-C6)alkyl group, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein. Representative examples of mono(C1-C6)alkylamino include, but are not limited to, N-methylamino, N-ethylamino, and N-butylamino.

[0060] The term "dialkylamino," as used herein, refers to two (C1-C6) alkyl groups, as defined herein, appended to the parent molecular moiety through an amino group, as defined herein. The (C1-C6) alkyl groups can be the same or different. Representative examples of di(C1-C6) alkylamino include, but are not limited to, N,N-dimethylamino and N,N-diethylamino.

[0061] The term "carboxy" as used herein refers to a -COOH group.

[0062] The term "(C2-C6)alkenyl" as used herein by itself or as part of another group refers to a straight or branched chain hydrocarbon group having 2, 3, 4, 5 or 6 carbon atoms and containing at least one carbon-carbon double bond. Representative examples of (C2-C6)alkenyl include, but are not limited to, ethenyl and prop-2-enyl.

[0063] The term "hydroxy(C1-C6)alkyl" as used herein by itself or as part of another group refers to at least one hydroxy group, as defined herein, appended to the parent molecular moiety via a (C1-C6)alkyl group, as defined herein. Representative examples of hydroxy(C1-C6)alkyl include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2-dihydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-1-methylethyl, and 1-hydroxy-1-methylpropyl.

[0064] The term "hydroxy(C2-C6)alkenyl," as used herein, refers to at least one hydroxy group, as defined herein, appended to the parent molecular moiety through a (C2-C6)alkenyl group, as defined herein. Representative examples of hydroxy(C2-C6)alkenyl include, but are not limited to, 1-hydroxyethenyl, 2-hydroxyethenyl, and 1-hydroxyprop-2-enyl.

[0065] The term "(C1-C6)alkoxy(C1-C6)alkyl" as used herein by itself or as part of another group refers to at least one (C1-C6)alkoxy group, as defined herein, attached to the parent molecular moiety via a (C1-C6)alkyl group, as defined herein. When there are several (C1-C6)alkoxy groups, the (C1-C6)alkoxy groups may be the same or different. Representative examples of (C1-C6)alkoxy(C1-C6)alkyl include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl, 1-methyl-2-propoxyethyl, 1-methoxy-1-methylethyl and 4-methoxybutyl.

[0066] The term "(C2-C6) alkenyloxy" as used herein as part of another group refers to a (C2-C6) alkenyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of (C2-C6) alkenyloxy include, but are not limited to, ethenyloxy, prop-2-enyloxy, but-2-enyloxy, and hex-3-enyloxy.

[0067] The term "(C2-C6) alkenyloxy(C1-C6) alkyl" as used herein refers to at least one (C2-C6) alkenyloxy group, as defined herein, appended to the parent molecular moiety via a (C1-C6) alkyl group, as defined herein. When there are several (C2-C6) alkenyloxy groups, the (C2-C6) alkenyloxy groups may be the same or different. Representative examples of (C2-C6) alkenyloxy(C1-C6) alkyl include, but are not limited to, prop-2-enyloxymethyl and ethenyloxyethyl.

[0068] The term "hydroxy(C1-C6)alkoxy" as used herein by itself or as part of another group refers to at least one hydroxy group, as defined herein, appended to the parent molecular moiety through a (C1-C6)alkoxy group, as defined herein. Representative examples of hydroxy(C1-C6)alkoxy include, but are not limited to, hydroxymethoxy, dihydroxymethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 2-hydroxybutoxy, and 2-hydroxy-1-methylethoxy.

[0069] The term "(C1-C6)alkoxy(C1-C6)alkoxy" as used herein by itself or as part of another group refers to at least one (C1-C6)alkoxy group, as defined herein, attached to the parent molecular moiety through a (C1-C6)alkoxy group, as defined herein. The (C1-C6)alkoxy groups can be the same or different. Representative examples of (C1-C6)alkoxy(C1-C6)alkoxy include, but are not limited to, methoxymethoxy, propoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-butoxyethoxy, 2,2-dimethoxyethoxy, 1-methyl-2-propoxyethoxy, 2-methoxypropoxy and 4-methoxybutoxy.

[0070] The term "halo(C1-C6)alkoxy" as used herein by itself or as part of another group refers to at least one halogen, as defined herein, appended to the parent molecular moiety via a (C1-C6)alkoxy group, as defined herein. When several halogens are present, the halogens may be the same or different. Representative examples of halo(C1-C6)alkoxy include, but are not limited to, fluoromethoxy, chloromethoxy, difluoromethoxy, trifluoromethoxy, 2-bromoethoxy, 2,2,2-trichloroethoxy, 3-bromopropoxy, 2-chloropropoxy, and 4-chlorobutoxy.

[0071] The term "oxo" as used herein refers to the group ═O.

[0072] As used herein, the phrase "compounds of the invention" refers to compounds of Formula I.

[0073] The compounds of the present invention are compounds of formula (I) and the salts, solvates and solvates of the salts thereof, compounds of the formulae encompassed by formula (I) and described below and the salts, solvates and solvates of the salts thereof, if the compounds are not already salts, solvates and solvates of the salts thereof, compounds of the formulae encompassed by formula (I) and described below and the salts, solvates and solvates of the salts thereof, and compounds encompassed by formula (I) and listed below as examples and the salts, solvates and solvates of the salts thereof.

[0074] Compounds of the invention also include the N-oxides and S-oxides of compounds of formula (I) and their salts, solvates and solvates of the salts.

[0075] Preferred in the present invention salt are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not themselves suitable for pharmaceutical applications but which can be used, for example, for the isolation, purification or storage of the compounds of the invention.

[0076] Suitable pharma- ceutically acceptable salts of the compounds of the invention are, for example, acid addition salts of compounds of the invention having a sufficiently basic nitrogen atom in the chain or ring, for example, acid addition salts with inorganic acids or "mineral acids", such as, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, bisulfuric acid, phosphoric acid or nitric acid, for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid. , pectinic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid or thiocyanic acid.

[0077] Further suitable pharma- ceutically acceptable salts of the sufficiently acidic compounds of the present invention include alkali metal salts, e.g., sodium or potassium salts, alkaline earth metal salts, e.g., calcium, magnesium or strontium salts, or aluminum salts or zinc salts, or ammonium salts derived from ammonia or primary, secondary or tertiary amines having 1 to 20 carbon atoms, e.g., ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methyl ... and ammonium salts derived from ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium.

[0078] Those skilled in the art will further recognize that acid addition salts of the claimed compounds can be prepared via any of a number of known methods by reacting the compounds with a suitable inorganic or organic acid. Alternatively, alkali metal and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with a suitable base via a variety of known methods.

[0079] The present invention includes all possible salts of the compounds of the present invention, either as a single salt or as any mixture of said salts in any ratio.

[0080] Pharmaceutically acceptable esters, where applicable, are conventional in the pharmaceutical field and can be prepared by known methods using pharmaceutically acceptable acids that retain the pharmacological properties of the free form.Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols.Representative examples of pharmaceutically acceptable esters include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and benzyl esters.

[0081] The present invention includes within its scope all possible geometric isomers of the compounds, such as Z and E isomers (cis and trans isomers), as well as all possible optical isomers of the compounds, such as diastereomers and enantiomers. Moreover, the present invention includes within its scope both the individual isomers and any mixtures thereof, such as racemic mixtures. The individual isomers can be obtained using the corresponding isomeric forms of the starting materials or can be separated after preparation of the final compounds according to conventional separation methods.

[0082] To separate optical isomers, eg enantiomers, from their mixture, conventional resolution methods, eg fractional crystallization, can be used.

[0083] The compounds of formula (I) and (II), their production and their action as alpha2C antagonists for the treatment of diseases or conditions of the peripheral or central nervous system are generally disclosed in WO2009013390, in particular said compounds are an explicit part of the description of the present invention and are incorporated herein by reference.

[0084] The term effective amount as used herein refers to an amount of a compound of formula (I) effective for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

[0085] The present invention relates to (alpha-2C) antagonists, in particular 3-substituted 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)azacycles of formula (I), for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

[0086] The present invention further relates to the use of compounds of formula (I) for the preparation of a medicament for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

[0087] A further subject of the present invention is the use of a combination of one or more compounds of formula (I) with one or more other active compounds in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

[0088] A further subject of the present invention is a pharmaceutical composition comprising at least one compound of formula (I) in combination with one or more inert, non-toxic, pharma- ceutical suitable excipients for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

[0089] The present invention further relates to pharmaceutical compositions comprising the combination with one or more other active compounds in combination with one or more inert, non-toxic, pharma- ceutical suitable excipients for use in methods for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

[0090] The present invention also relates to a method for the treatment and / or prevention of sleep-related breathing disorders by systemically and / or locally administering a therapeutically effective amount of at least one compound of formula (I) or a medicament comprising at least one compound of formula (I) in combination with inert, non-toxic, pharma- ceutical acceptable excipients.

[0091] A further subject of the present invention is a combination of one or more compounds of formula (I) with one or more other active compounds for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

[0092] The 3-substituted 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)azacycles of formula (I) according to the invention can be used alone or, if necessary, in combination with one or more other pharmacologically active substances, provided that the combination does not result in undesirable and unacceptable side effects. Preferred examples of combinations suitable for the purpose of treating sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring, include: Respiratory stimulants, for example and preferably theophylline, doxapram, nikethamide or caffeine; psychostimulants, for example and preferably modafinil or armodafinil; Amphetamine and amphetamine derivatives, for example and preferably amphetamine, methamphetamine or methylphenidate; Serotonin reuptake inhibitors, for example and preferably fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine or trazodone; Serotonin precursors, for example and preferably L-tryptophan; Selective serotonin noradrenaline reuptake inhibitors, for example and preferably venlafaxine or duloxetine; noradrenergic and specific serotonergic antidepressants, for example and preferably mirtazapine; selective noradrenaline reuptake inhibitors, for example and preferably reboxetine or atomoxetine; Tricyclic antidepressants, for example and preferably amitriptyline, protriptyline, doxepin, trimipramine, imipramine, clomipramine or desipramine; Muscarinic receptor antagonists, for example and preferably oxybutynin; GABA agonists, such as, preferably, baclofen; Glucocorticoids, for example and preferably fluticasone, budesonide, beclomethasone, mometasone, tixocortol or triamcinolone; · Cannabinoid receptor agonists; TASK channel blockers, for example and preferably those generally and specifically disclosed in WO2017 / 097792A1, WO2017 / 097671A1, WO2018 / 015196A1, WO2018 / 228907A1 and WO2018 / 228909A1; Carboanhydrase inhibitors, for example and preferably acetazolamide, methazolamide or diclophenamide; Opioid and benzodiazepine receptor antagonists, for example and preferably flumazenil, naloxone or naltrexone; cholinesterase inhibitors, for example and preferably neostigmine, pyridostigmine, physostigmine, donepezil, galantamine or for example and preferably rivastigmine; an appetite suppressant, for example and preferably sibutramine, opiramate, phentermine, a lipase inhibitor or a cannabinoid receptor antagonist; Mineralocorticoid receptor antagonist.

[0093] A preferred subject of the present invention is the combination of one or more compounds of formula (I) or (II) with one or more other active compounds selected from the group consisting of muscarinic receptor antagonists, mineralocorticoid receptor antagonists, TASK channel blockers, diuretics, corticosteroids, for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

[0094] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a muscarinic receptor antagonist, by way of example and preferably oxybutynin.

[0095] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a TASK-channel blocker, for example and preferably a TASK channel blocker as generally and specifically disclosed in WO2017 / 097792A1, WO2017 / 097671A1, WO2018 / 015196A1, WO2018 / 228907A1 and WO2018 / 228909A1.

[0096] In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, by way of example and preferably spironolactone, eplerenone or finerenone.

[0097] In one preferred embodiment of the invention, the compounds of the invention are administered in combination with a diuretic, for example and preferably furosemide, bumetanide, torasemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

[0098] In one preferred embodiment of the invention, the compounds of the invention are administered in combination with a corticosteroid, by way of example and preferably prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, flunisolide, budesonide or fluticasone.

[0099] If necessary, the 3-substituted 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)azacycles of formula (I) according to the invention can also be used in conjunction with the use of one or more medical technical devices or auxiliaries, provided that this does not result in undesirable and unacceptable side effects. Medical devices and auxiliaries suitable for such combined use are, by way of example, preferably the following: Devices for positive airway pressure ventilation, such as, for example and preferably, CPAP (Continuous Positive Airway Pressure) devices, BiPAP (Bi-Level Positive Airway Pressure) devices and IPPV (Intermittent Positive Airway Pressure Ventilation) devices; · Hypoglossal nerve stimulator; · Intra-oral appliances, such as, preferably, protruding braces; · Disposable nasal valves; Nasal stents.

[0100] The 3-substituted 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)azacycles of formula (I) according to the invention can act systemically and / or locally. To this end, they can be administered in a suitable manner, for example by oral, parenteral, pulmonary, intrapulmonary (inhalation), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival or auricular route, or as an implant or stent.

[0101] A further subject of the present invention are pharmaceutical compositions comprising a compound of formula (I) according to the invention for systemic and / or local administration by oral, parenteral, pulmonary, intrapulmonary (inhalation), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival or auricular route or as an implant or stent. The preferred administration route is the oral route.

[0102] For these administration routes, the compounds according to the invention can be administered in suitable dosage forms.

[0103] For oral administration, dosage forms which release the compounds according to the invention rapidly and / or in a modified manner and which contain the compounds according to the invention in crystalline and / or amorphous and / or dissolved form are suitable in accordance with the state of the art, e.g. tablets (uncoated or coated tablets, e.g. having a gastric juice-resistant or slow-dissolving or insoluble coating which controls the release of the compounds according to the invention), tablets or films / wafers, films / lyophilisates which disintegrate rapidly in the oral cavity, capsules (e.g. hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

[0104] Parenteral administration can be performed by omitting the absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal or intralumbar administration) or by accompanying absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration).Dosage forms suitable for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

[0105] Other routes of administration are suitable, e.g. inhalation formulations (including powder inhalers and nebulizers), nasal drops, solutions or sprays, tablets for lingual, sublingual or buccal administration, tablets, films / wafers or capsules, suppositories, oral or ophthalmic formulations, vaginal capsules, aqueous suspensions (lotions, shakeable mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. plasters), milks, pastes, foams, dusting powders, implants or stents.

[0106] Oral or parenteral administration, particularly oral and intravenous administration, is preferred.

[0107] The compound according to the present invention can be converted into the dosage form described.This can be carried out by mixing with inert, non-toxic, pharma- ceutically suitable additives in a manner known per se.These additives include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants such as ascorbic acid), colorants (e.g., inorganic pigments such as iron oxide), and flavor or odor correctors.

[0108] In general, to achieve effective results in parenteral administration, it has been found to be advantageous to administer an amount of about 0.001 to 10 mg / kg, preferably about 0.01 to 1 mg / kg of body weight. In oral administration, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and very particularly preferably 0.1 to 15 mg / kg of body weight.

[0109] Nevertheless, sometimes it may be necessary to deviate from said amount, i.e. depending on body weight, route of administration, individual response to active substance, nature of preparation, and time or interval at which administration is carried out.Thus, in some cases it may be sufficient to manage below the above-mentioned minimum amount, while in other cases the upper limit stated must be exceeded.In case of administration of larger amounts, it may be advisable to divide them into several individual administrations throughout the day.

[0110] The following examples illustrate the present invention without, however, limiting the invention. EXAMPLES

[0111] A. Experimental Method The advantageous pharmacological properties of the compounds of this invention can be determined by the following methods.

[0112] The therapeutic potential of the compounds of the invention in sleep apnea can be evaluated preclinically in a porcine model of obstructive sleep apnea (OSA).

[0113] Using negative pressure it is possible to induce collapse and therefore obstruction of the upper airway in anesthetized spontaneously breathing pigs (Wirth KJ et al., Sleep 36(5)(2013) pp.699-708).

[0114] German Landrace pigs are used for this model. The pigs are anesthetized and a tracheotomy is performed. Two tracheotomies are inserted into the trachea, one in the rostral part of the trachea and the other in the caudal part. Using a connecting piece, the rostral cannula is connected to a tube to a negative pressure device and a distal tracheal cannula. The distal tracheal cannula serves for free tracheal breathing and is further connected to a tube with an open end via a connecting piece that bypasses the upper airway. By proper opening and clamping of these tubes, breathing can be switched from nasal breathing to bypassing the upper airway and breathing through the caudal tracheal cannula, connecting the (isolated) upper airway to a negative pressure device and generating airflow in the inspiratory direction.

[0115] At specific time points, the pigs are breathed through a caudal cannula and the collapsibility of the upper airway is tested by applying negative pressures of -50, -100 and -150 cm H2O to the upper airway. This collapses the upper airway, which is manifested as an obstruction of airflow and a drop in pressure in the tubing system. This test is performed before administration of the test substance and at regular intervals after administration of the test substance. A suitably effective test substance prevents this collapse of the airway during the inspiratory phase.

[0116] In this pig model of OSA, IC 50 Systemic administration of an α2-adrenergic receptor subtype C (alpha-2C) antagonist of formula (I) at an appropriate dose reaching 100 mg / kg / day is expected to inhibit upper airway collapsibility.

Claims

1. A compound of formula (I) for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring. 【Chemistry 1】 [During the ceremony, X is C(R ５ ) (R ６ ) or C(R ７ ) (R ８ ) and Z is -[C(R ４ ) ２ ] ｎ - or a single bond; R １ Each independently represents hydroxy, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, halogen, halo(C １ -C ６ ) alkyl, phenyl (C １ -C ６ ) alkoxy, (C １ -C ６ ) Alkoxy-(C=O)-, CN, NO ２ , N.H. ２ , mono- or di(C １ -C ６ ) alkylamino or carboxy; R ２ are each independently H or (C １ -C ６ ) alkyl; R ３ are each independently H or (C １ -C ６ ) alkyl; R ４ are each independently H, hydroxy, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, hydroxy (C １ -C ６ ) alkyl, hydroxy (C ２ -C ６ ) alkenyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyloxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(C=O)-, (C １ -C ６ ) alkoxy-(C=O)-, hydroxy(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl or (C １ -C ６ ) Alkoxy (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl; or R attached to the same carbon ring atom ４ and R ４ together with the carbon ring atom to which they are attached form a -(C=O) group; R ５ is H or hydroxy; or R bonded to adjacent carbon ring atoms ４ and R ５ form a bond between the carbon ring atoms to which they are attached; R ６ is unsubstituted phenyl or contains one or two substituents R ９ is phenyl substituted with; R ７ (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl or (C １ -C ６ ) alkoxy-(C═O)—; R ８ is hydroxy, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C １ -C ６ ) alkoxy, halogen, hydroxy (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, hydroxy (C ２ -C ６ ) alkenyl, hydroxy (C １ -C ６ ) alkoxy, halo (C １ -C ６ ) alkoxy, phenyl (C １ -C ６ ) alkoxy, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyloxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(C=O)-, (C １ -C ６ ) alkoxy-(C=O)-, (C １ -C ６ ) alkoxy-(C=O)-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-S-, (C １ -C ６ ) alkyl-(C=O)-O-, (C １ -C ６ ) alkyl-(C=O)-O-(C １ -C ６ ) alkyl, hydroxy-(C=O)-(C １ -C ６ ) alkoxy, hydroxy-(C=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-S-(C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl-S-(C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl-S-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(C=O)-S-(C １ -C ６ ) alkyl (C １ -C ６ ) alkoxy-(C=-O)-(C １ -C ６ ) alkyl-S-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-S- (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl-S-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl-S- (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-O-(O=S=O)-(C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl-O-(O=S=O)-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(O=S=O)-O-(C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl-(O=S=O)-O-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(O=S=O)-N(R １０ )-(C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, halo (C １ -C ６ ) Alkoxy (C １ -C ６ ) Alkyl, CN, NO ２ , (R １０ ) 2N-, (R １０ ) ２ N-(C １ -C ６ ) alkyl, (R １０ ) ２ N-(C=O)-, (R １０ ) ２ N-(C=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (R １０ ) ２ N-(C=O)-(C １ -C ６ ) alkyl-S-(C １ -C ６ ) alkyl, (R １０ ) ２ N-(C=O)-(C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) alkyl, carboxy, R １１ -(O=S=O)-, R １１ -(O=S=O)-O- or (C １ -C ６ ) alkoxy-(C １ -C ６ ) alkoxy; or R bonded to adjacent carbon ring atoms ４ and R ８ taken together with the carbon ring atoms to which they are attached form a fused phenyl ring, wherein said phenyl rings are unsubstituted or each independently selected from hydroxy, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, hydroxy (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(C=O)- or (C １ -C ６ ) substituted with 1 or 2 substituents which are alkoxy-(C=O)-; or R bonded to adjacent carbon ring atoms ４ and R ８ together with the carbon ring atoms to which they are attached form a fused 5- or 6-membered saturated or unsaturated carbocyclic ring or a fused 5- or 6-membered saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein said carbocyclic or heterocyclic ring is unsubstituted or each independently selected from hydroxy, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, hydroxy (C １ -C ６ ) alkyl, halo(C, -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(C=O)-, (C １ -C ６ ) substituted with 1 or 2 substituents which are alkoxy-(C=O)- or oxo; or R ７ and R ８ together with the carbon ring atoms to which they are attached form a 5- or 6-membered saturated carbocyclic ring or a 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein said carbocyclic or heterocyclic ring is unsubstituted or each independently selected from hydroxy, (C １ -C ６ ) substituted with 1 or 2 substituents which are alkyl or oxo; R ９ Each independently represents hydroxy, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C １ -C ６ ) alkoxy, halogen, hydroxy (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, hydroxy (C ２ -C ６ ) alkenyl, hydroxy (C １ -C ６ ) alkoxy, halo (C １ -C ６ ) alkoxy, phenyl (C １ -C ６ ) alkoxy, (C １ -C ６ ) Alkoxy (C １ -C ６） Alkyl, (C ２ -C ６ ) alkenyloxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(C=O)-, (C １ -C ６ ) alkoxy-(C=O)-, (C １ -C ６ ) alkoxy-(C=O)-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-S-, (C １ -C ６ ) alkyl-(C=O)-O-, (C １ -C ６ ) alkyl-(C=O)-O-(C １ -C ６ ) alkyl, hydroxy-(C=O)-(C １ -C ６ ) alkoxy, hydroxy-(C=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-S-(C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl-S-(C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl-S-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(C=O)-S-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C=O)-(C １ -C ６ ) alkyl-S-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-S-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl-S-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl-S-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-O-(O=S=O)-(C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl-O-(O=S=O)-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(O=S=O)-O-(C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl-(O=S=O)-O-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(O=S=O)-N(R １０ )-(C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, halo (C １ -C ６ ) Alkoxy (C １ -C ６ ) Alkyl, CN, NO ２ , (R １０ ) ２ N-, (R １０ ) ２ N-(C １ -C ６ ) alkyl, (R １０ ) ２ N-(C=O)-, (R １０ ) ２ N-(C=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (R １０ ) ２ N-(C=O)-(C １ -C ６ ) alkyl-S-(C １ -C ６ ) alkyl, (R １０ ) ２ N-(C=O)-(C １ -C ６ ) alkyl-(O=S=O)-(C １ -C ６ ) alkyl, carboxy, R １１ -(O=S=O)- or R １１ -(O=S=O)-O-; or R bonded to adjacent carbon ring atoms ９ and R ９ together with the carbocyclic atoms to which they are attached form a fused phenyl ring, a fused 5- or 6-membered unsaturated carbocyclic ring, or a fused 5- or 6-membered unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from O and S, wherein said phenyl, carbocyclic or heterocyclic ring is unsubstituted or each independently selected from hydroxy, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, hydroxy (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(C═O)- or (C １ -C ６ ) substituted by 1 or 2 substituents which are alkoxy-(C=O)-; R １０ are each independently H, (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(C=O)- or R １１ -(O=S=O)-; R １１ Each independently represents hydroxy, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, halo (C １ -C ６ ) alkyl or mono- or di(C １ -C ６ ) alkylamino; m is 0, 1 or 2; and n is 1 or 2. or a pharma- ceutically acceptable salt or ester thereof, wherein said compound is selected from the group consisting of 1-(7-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,3-dimethyl-piperidine, 1-(6-tert-butyl-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3,3-dimethyl-piperidine, 2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-6,7-dimethoxy-1-methyl- not 1,2,3,4-tetrahydro-isoquinoline, 2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline, 2-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline or 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl-3-(3-trifluoromethyl-phenyl)-pyrrolidine

2. Z is -[C(R ４ ) ２ ]n-, wherein n is 1, for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

3. R ２ is H, R ３ is H, R ４ are each independently H, hydroxy or (C １ -C ６ ) alkyl; 3. A compound according to any of claims 1 or 2 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

4. m is 0, R １ is hydroxy, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy or halogen; A compound according to any one of claims 1 to 3 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnoea and snoring.

5. X is C(R ５ ) (R ６ ) and / or R ５ is H, and / or R ６ is one substitution R ９ phenyl substituted with R ９ is hydroxy, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, halogen, hydroxy (C １ -C ６ ) alkoxy, or (R １０ ) ２ N-, A compound according to any one of claims 1 to 4 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnoea and snoring.

6. X is C(R ７ ) (R ８ ) and / or R ７ However, (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl or (C １ -C ６ ) alkoxy-(C═O)—; and / or R ８ But hydroxy (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkoxy, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl or hydroxy (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl; A compound according to any one of claims 1 to 4 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnoea and snoring.

7. X is C(R ５ ) (R ６ ) or C(R ７ ) (R ８ ) and Z is -[C(R ４ ) ２ ]n- or a single bond; R １ each independently represents hydroxy, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, halogen, phenyl (C １ -C ６ ) alkoxy or NO ２ and R ２ are each independently H; R ３ are each independently H; R ４ are each independently H, hydroxy or (C １ -C ６ ) alkyl; or R attached to the same carbon ring atom ４ and R ５ together with the carbon ring atom to which they are attached form a -(C=O) group; R ５ is H; or R bonded to adjacent carbon ring atoms ４ and R ５ form a bond between the carbon ring atoms to which they are attached; R ６ is unsubstituted phenyl or contains one or two substituents R ９ is phenyl substituted with; R ７ However, (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl or (C １ -C ６ ) alkoxy-(C═O)—; R ８ is hydroxy, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C １ -C ６ ) alkoxy, halogen, hydroxy (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkoxy, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyloxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(C=O)-, (C １ -C ６ ) alkoxy-(C=O)-, (C １ -C ６ ) alkoxy-(C=O)-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(C=O)-O-(C １ -C ６ ) alkyl, hydroxy-(C=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C=O)-(C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkyl-S-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(C=O)-S-(C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-(O=S=O)-O-(C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, halo (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, CN, (R １０ ) ２ N-(C １ -C ６ ) alkyl, (R １０ ) ２ N—(C═O)—, carboxy, or (C １ -C ６ ) alkoxy-(C １ -C ６ ) alkoxy; or R bonded to adjacent carbon ring atoms ４ and R ８ taken together with the carbon ring atoms to which they are attached form a fused phenyl ring, wherein said phenyl rings are unsubstituted or each independently selected from hydroxy (C １ -C ６ ) alkyl or (C １ -C ６ ) substituted with 1 or 2 substituents which are alkoxy-(C=O)-; or R bonded to adjacent carbon ring atoms ４ and R ８ together with the carbon ring atoms to which they are attached form a fused 6-membered saturated carbocyclic ring, wherein said carbocyclic ring is unsubstituted; R ９ each independently represents hydroxy, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, halogen, hydroxy (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkoxy, halo (C １ -C ６ ) alkoxy, phenyl (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkoxy-(C=O)-, (C １ -C ６ ) alkyl-(C=O)-O-, hydroxy-(C=O)-(C １ -C ６ ) alkoxy, CN, (R １０ ) ２ N-, (R １０ ) ２ N-(C=O)-, R １１ -(O=S=O)- or R １１ -(O=S=O)-O-; or R bonded to adjacent carbon ring atoms ９ and R ９ taken together with the carbocyclic atoms to which they are attached form a fused 5- or 6-membered unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from O, wherein said phenyl, carbocyclic or heterocyclic ring is unsubstituted; R １０ are each independently H or (C １ -C ６ ) alkyl; R １１ are each independently: (C １ -C ６ ) alkyl or halo(C １ -C ６ ) alkyl; m is 0, 1 or 2; and n is 1 or 2; 2. A compound according to claim 1 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

8. X is C(R ５ ) (R ６ ) or C(R ７ ) (R ８ ) and Z is -[C(R ４ ) ２ ]n-; R １ each independently represents hydroxy, (C １ -C ６ ) alkyl, or halogen; R ２ are each independently H; R ３ are each independently H; R ４ are each independently H; R ５ is H; R ６ is unsubstituted phenyl or contains one or two substituents R ９ is phenyl substituted with; R ７ However, (C １ -C ６ ) alkyl; R ８ But hydroxy (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkoxy, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl or hydroxy (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl; R ９ each independently represents hydroxy, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, halogen, hydroxy (C １ -C ６ ) alkoxy or (R １０ ) ２ N-; R １０ are each independently H or (C １ -C ６ ) alkyl; m is 0 or 1; n is 1; 8. A compound according to claim 7 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

9. X is C(R ５ ) (R ６ ) or C(R ７ ) (R ８ ) and Z is a single bond; R １ each independently represents hydroxy, (C １ -C ６ ) alkyl, or halogen; R ２ are each independently H; R ３ are each independently H; R ４ are each independently H; R ５ is H; R ６ is unsubstituted phenyl or contains one or two substituents R ９ is phenyl substituted with; R ７ However, (C １ -C ６ ) alkyl; R ８ But hydroxy (C １ -C ６ ) alkyl, hydroxy (C １ -C ６ ) alkoxy, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl or hydroxy (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl; R ９ each independently represents hydroxy, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, halogen, hydroxy (C １ -C ６ ) alkoxy or (R １０ ) ２ N-; R １０ are each independently H or (C １ -C ６ ) alkyl; m is 0 or 1; n is 1; 8. A compound according to claim 7 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

10. The compound is 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-5-phenyl-1,2,3,6-tetrahydropyridine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-phenylpiperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(2-methoxyphenyl)piperidine, 3-(4-chlorophenyl)-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3- (3-methoxyphenyl)piperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-p-tolylpiperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(4-methoxyphenyl)piperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-o-tolylpiperidine, 4-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl) (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-fluorophenyl)piperidine, 3-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol, 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-fluorophenyl)piperidine, (S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2- fluorophenyl)piperidine, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidine, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidine.HCl, (S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidine, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-fluorophenyl)piperidine, (S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-fluorophenyl)piperidine, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-trifluoromethyl-phenyl)piperidine, (S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-trifluoromethyl-phenyl)piperidine 1-(4-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl)-3-(4-trifluoromethylphenyl)piperidine, (S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(4-trifluoromethylphenyl)piperidine, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine, 1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine.HCl, (S*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine, (R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol, (R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol.HCl, (3-{(R*) -1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenyl)methanol, acetic acid 3-{(S)-1-[(R*)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenyl ester.HCl, 2-(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)ethanol, 3-(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)propan-1-ol, trifluoromethanesulfonic acid 3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}phenyl ester, (3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)acetic acid, 3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidin-3-yl}phenoxy)acetic acid, ethyl]-piperidin-3-yl}-benzonitrile, 3-benzo[1,3]dioxol-5-yl-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidine, 3-[(R*)-1-((S)-6-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol, (S)-2-[(R*)-3-(3-hydroxy-phenyl)-piperidin-1-ylmethyl]-2,3-dihydrobenzo[1,4]dioxin-6-ol, 3-[(R *)-1-((S)-7-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol, (S)-3-[(R*)-3-(3-hydroxyphenyl)-piperidin-1-ylmethyl]-2,3-dihydrobenzo[1,4]dioxin-6-ol, 3-[(R*)-1-((S)-8-benzyloxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol, (S)-3-[(R*)-3-(3-hydroxyphenyl)-piperidin-1-ylmethyl]-2,3-dihydrobenzo[1,4]dioxin-6-ol, (R*)-3-[1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylic acid ethyl ester, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine-3-carboxylic acid ethyl ester, [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethoxymethyl-3-methylpiperidine, 3-chloromethyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine, 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(1-methoxy-1-methylethyl)-3-methylpiperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-hydroxymethyl-3-methylpiperidin-4-ol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethyl ester of acetate, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-ylmethyl methanesulfonate ethyl piperidin-3-yl methyl ester, [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]methanol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethyl-3-methoxymethylpiperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethoxymethyl-3-methylpiperidine, 1-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]ethanone, 1-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl]ethanol, 3-allyloxymethyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidine, 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethylpiperidin-3-yl-methoxy]ethanol, 3-allyloxymethyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidine, 3-allyl-1-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidine-3-carboxylic acid ethyl ester, [3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]methanol, 3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethylpiperidine, 3-allyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-ethoxymethylpiperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)- (S)-1-((R)-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidine-3-carboxylate, {(S)-1-((S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl)-3-methyl-piperidine-3-carboxylate, {(S)-1-((R)- ... )-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}methanol, 2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}-ethanol, 2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}-ethanol D-tartrate, (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}-ethanol D-tartrate, 2-methoxyethoxymethyl)-3-methylpiperidine, (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-3-(2,2,2-trifluoroethoxymethyl)piperidine, methanesulfonic acid (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidin-3-ylmethyl ester, thioacetic acid S-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethyl} ester, 2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethyl-sulfanyl}ethanol, {(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl, tert-butyl {(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl-methoxy}acetate, 2-[(S)-1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl-methoxy]ethanol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluoro-piperidine-3-carboxylate carboxylic acid ethyl ester, [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-fluoro-piperidin-3-yl]methanol, (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methyl-piperidine-3-carboxylic acid ethyl ester, [(S)-1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidin-3-yl]-methanol, (S)-1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-piperidin-3-yl]methanol, 3-((R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methoxymethyl-3-methyl-piperidine, (S)-1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl)-3-methoxymethyl-3-methyl-piperidine.HCl, (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methoxymethyl-3-methyl-piperidine, 3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-piperidine-3-yl 1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxy-phenyl)-pyrrolidine, (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxy-phenyl)-pyrrolidine, (R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxy-phenyl)-pyrrolidine, (R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxy-phenyl)-pyrrolidine, (R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-fluoro-ethoxymethyl)-3-methyl-piperidine.HCl, (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluoromethoxy-phenyl)-piperidine, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidine-3-carboxylic acid methyl ester, [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl )-3-methylpyrrolidin-3-yl]-methanol, 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methyl-pyrrolidin-3-ylmethoxy]-ethanol, 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methyl-pyrrolidine or 3-[(R)-1-((S)-7-nitro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-piperidin-3-yl]-phenol, 2. A compound according to claim 1 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

11. The compound is (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-fluorophenyl)piperidine, or a pharma- ceutically acceptable salt or ester thereof.

2. A compound according to claim 1 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

12. The compound is (R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(3-methoxyphenyl)piperidine, or a pharma- ceutically acceptable salt or ester thereof.

2. A compound according to claim 1 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

13. The compound is (R*)-3-{1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenol, or a pharma- ceutically acceptable salt or ester thereof.

2. A compound according to claim 1 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

14. The compound is (3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenyl)methanol, or a pharma- ceutically acceptable salt or ester thereof.

2. A compound according to claim 1 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

15. The compound is 2-(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)ethanol, or a pharma- ceutically acceptable salt or ester thereof.

2. A compound according to claim 1 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

16. The compound is 3-(3-{(R*)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]piperidin-3-yl}phenoxy)propan-1-ol, or a pharma- ceutically acceptable salt or ester thereof.

2. A compound according to claim 1 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

17. The compound is (R*)-3-[1-((S)-7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-3-yl]phenol, or a pharma- ceutically acceptable salt or ester thereof.

2. A compound according to claim 1 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

18. The compound is {(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}methanol, or a pharma- ceutically acceptable salt or ester thereof.

2. A compound according to claim 1 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

19. The compound is 2-{(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-ylmethoxy}-ethanol, or a pharma- ceutically acceptable salt or ester thereof.

2. A compound according to claim 1 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

20. The compound is (S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-(2-methoxyethoxymethyl)-3-methylpiperidine, or a pharma- ceutically acceptable salt or ester thereof.

2. A compound according to claim 1 for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

21. The use of a compound according to any one of claims 1 to 20, wherein the sleep-related breathing disorders are obstructive and central sleep apnea and snoring.

22. A combination of one or more compounds of formula (I) with one or more other active compounds for use according to any of claims 1 to 20.

23. A pharmaceutical composition comprising at least one compound of formula (I) according to any of claims 1 to 20 in combination with one or more inert, non-toxic, pharma- ceutical suitable excipients for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

24. A pharmaceutical composition comprising the combination according to claim 22 in combination with one or more inert, non-toxic, pharma- ceutically suitable excipients for the use according to any one of claims 1 to 20.

25. A method for the treatment and / or prevention of sleep-related breathing disorders by systemically and / or locally administering a therapeutically effective amount of at least one compound according to any one of claims 1 to 20 or a medicament comprising at least one compound according to any one of claims 1 to 20 in combination with inert, non-toxic, pharma- ceutical acceptable excipients.

26. 26. The method of claim 25, wherein the medicament further comprises at least one additional active compound selected from the group consisting of muscarinic receptor antagonists, mineralocorticoid receptor antagonists, diuretics, and corticosteroids.

27. A medicament comprising a compound of formula (I) according to any one of claims 1 to 20 in combination with one or more further active ingredients selected from the group consisting of muscarinic receptor antagonists, mineralocorticoid receptor antagonists, diuretics, corticosteroids.

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