US20170158693A1

US20170158693A1 - Hexahydrodiazepinoquinolines carrying a cyclic radical

Info

Publication number: US20170158693A1
Application number: US15/435,553
Authority: US
Inventors: Gisela Backfisch; Margaretha Henrica Maria Bakker; Günter BLAICH; Wilfried Braje; Karla Drescher; Thomas Erhard; Andreas Haupt; Hannes Koolman; Viktor Lakics; Anna LINSENMEIER; Helmut Mack; Raimund PETER; Ana Lucia Relo; Xiaona Zhao; Jincheng Wang
Original assignee: AbbVie Deutschland GmbH and Co KG; AbbVie Inc
Current assignee: AbbVie Deutschland GmbH and Co KG; AbbVie Inc
Priority date: 2014-03-14
Filing date: 2017-02-17
Publication date: 2017-06-08
Also published as: WO2015136090A1; US9573950B2; EP3116873B1; US20150259343A1; EP3116873A1

Abstract

The present invention relates to tricyclic hexahydrodiazepinoquinolines carrying a cyclic substituent, to a method for producing them, to a pharmaceutical composition containing such compounds, to their use as modulators, especially agonists or partial agonists, of the 5-HT_2Creceptor, their use for preparing a medicament for the prevention or treatment of conditions and disorders which respond to the modulation of 5-HT_2Creceptor, to a method for preventing or treating conditions and disorders which respond to the modulation of 5-HT_2Creceptor, and processes for preparing such compounds and compositions.

Description

CROSS-REFERENCE TO RELATED APPLICATION(S)

This claims priority to U.S. Provisional Patent Application No. 61/953,424, filed on Mar. 14, 2014, the entire contents of which are fully incorporated herein by reference.

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Diseases, disorders and conditions where 5-HT_2Cmodulation is desired are for example depression, anxiety, schizophrenia, bipolar disorder, obsessive compulsive disorder, migraine, pain, epilepsy, substance abuse, eating disorders, obesity, diabetes, erectile dysfunction and others.
Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter and local hormone, is formed by the hydroxylation and decarboxylation of tryptophan. The greatest concentration is found in the enterochromaffin cells of the gastrointestinal tract, the remainder being predominantly present in platelets and in the Central Nervous System (CNS). 5-HT is implicated in a vast array of physiological and pathophysiological pathways. In the periphery, it contracts a number of smooth muscles and induces endothelium-dependent vasodilation. In the CNS, it is believed to be involved in a wide range of functions, including the control of appetite, mood, anxiety, hallucinations, sleep, vomiting and pain perception.
Neurons that secrete 5-HT are termed serotonergic. The function of 5-HT is exerted upon its interaction with specific (serotonergic) neurons. Seven types of 5-HT receptors have been identified: 5-HT₁(with subtypes 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1Eand 5-HT_1F), 5-HT₂(with subtypes 5-HT_2A, 5-HT_2Band 5-HT_2C), 5-HT₃, 5-HT₄, 5-HT₅(with subtypes 5-HT_5Aand 5-HT_5B), 5-HT₆and 5-HT₇. Most of these receptors are coupled to G-proteins that affect the activities of adenylate cyclase or phospholipase Cγ.
Alterations in the activity of multiple neurotransmitter receptor systems (dopamine, serotonin, glutamate, GABA, acetylcholine) have been implicated in the manifestation of the symptoms of schizophrenia. The most widely accepted “Dopamine Hypothesis of Schizophrenia” in its simplest form states that the positive symptoms of this pathology relate to a functional hyperactivity of the mesolimbic dopaminergic system, while the negative and cognitive aspects can be traced to a functional hypoactivity of the mesocortical dopaminergic projections. Atypical antipsychotics block the mesolimbic dopaminergic neurotransmission, thereby controlling positive symptoms, with little or no effect on the nigrostriatal system, leading to less induction of extrapyramidal side effects (EPS).
Primary negative and cognitive symptoms of schizophrenia reflect a dysfunction of the frontal cortex (“hypofrontality”), which is thought to be induced by a decreased tone in the mesocortical dopaminergic projection field [Davis K L, Kahn R S, Ko G and Davidson M (1991). Dopamine in schizophrenia: a review and re-conceptualization. Am J Psychiatry 148: 1474-86. Weinberger D R and Berman K F (1996). Prefrontal function in schizophrenia: confounds and controversies. Philos Trans R Soc Lond B Biol Sci 351: 1495-503]. Agents that selectively enhance dopamine levels in the cortex have the potential to address the negative symptoms of this disorder. Atypical antipsychotics lack robust efficacy against negative and cognitive components of the schizophrenic syndrome.
The schizophrenic symptomatology is further complicated by the occurrence of drug-induced so-called secondary negative symptoms and cognitive impairment, which are difficult to distinguish from primary negative and cognitive symptoms [Remington G and Kapur S (2000). Atypical antipsychotics: are some more atypical than others? Psychopharmacol 148: 3-15]. The occurrence of secondary negative symptoms not only limits therapeutic efficacy but also, together with these side effects, negatively affects patient compliance.
It may thus be hypothesized that a novel mechanistic approach that blocks dopaminergic neurotransmission in the limbic system but does not affect the striatal and pituitary projection fields, and stimulates frontocortical projection fields, would provide an efficacious treatment for all parts of the schizophrenic pathology, including its positive, negative and cognitive symptoms. Moreover, a selective compound that is substantially free of the ancillary pharmacology that characterizes current agents would be expected to avoid a variety of off-target side effects that plague current treatments such as extrapyramidal side effects (EPS) and weight gain.
The 5-HT_2Creceptor, previously named 5-HT1C, is a G-protein-coupled receptor, which couples to multiple cellular effector systems including the phospholipase C, A and D pathways. It is found primarily in the brain and its distribution is particularly high in the plexus choroideus, where it is assumed to control cerebrospinal fluid production [Kaufman M J, Hirata F (1996) Cyclic GMP inhibits phosphoinositide turnover in choroid plexus: evidence for interactions between second messengers concurrently triggered by 5-HT_2Creceptors. Neurosci Lett 206:153-156]. Very high levels were also found in the retrosplenial, piriform and entorhinal cortex, anterior olfactory nucleus, lateral septal nucleus, subthalamic nucleus, amygdala, subiculum and ventral part of CA3, lateral habenula, substantia nigra pars compacta, several brainstem nuclei and the whole grey matter of the spinal cord [Pompeiano M, Palacios J M, Mengod G (1994). Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT_2Aand 5-HT_2Creceptors. Brain Res Mol Brain Res 23:163-178]. A comparison of the distribution of 5-HT_2CmRNA with that of 5-HT_2Cprotein in monkey and human brains has revealed both pre- and postsynaptic localization [Lopez-Gimenez J F, Mengod G, Palacios J M, Vilaro M T (2001) Regional distribution and cellular localization of 5-HT_2Creceptor mRNA in monkey brain: comparison with [³H]mesulergine binding sites and choline acetyltransferase mRNA. Synapse 42:12-26].
It is anticipated that modulation of the 5-HT_2Creceptor will improve disorders such as depression, anxiety, schizophrenia, cognitive deficits of schizophrenia, obsessive compulsive disorder, bipolar disorder, neuropsychiatric symptoms in Parkinson′ disease, in Alzheimer's disease or Lewy Body dementia, migraine, epilepsy, substance abuse, eating disorders, obesity, diabetes, sexual dysfunction/erectile dysfunction, sleep disorders, psoriasis, Parkinson's disease, pain conditions and disorders, and spinal cord injury, smoking cessation, ocular hypertension and Alzheimer's disease. Modulators of the 5-HT_2Creceptor are also shown to be useful in the modulation of bladder function, including the prevention or treatment of urinary incontinence.
Compounds with a structure similar to the compounds of the present invention have been described in WO 2014/041131 and WO 03/091250.
There is an ongoing need for providing compounds having high affinity and in particular also high selectivity for the 5-HT_2Creceptor. In particular the compounds should have low affinity to adrenergic receptors, such as the α₁-adrenergic receptor, histamine receptors, such as the H₁-receptor, and dopaminergic receptors, such as the D₂-receptor, in order to avoid or reduce side effects associated with modulation of these receptors, such as postural hypotension, reflex tachycardia, potentiation of the antihypertensive effect of prazosin, terazosin, doxazosin and labetalol or dizziness associated with the blockade of the α₁-adrenergic receptor, weight gain, sedation, drowsiness or potentiation of central depressant drugs associated with the blockade of the H₁-receptor, or extrapyramidal movement disorder, such as dystonia, parkinsonism, akathisia, tardive dyskinesia or rabbit syndrome, or endocrine effects, such as prolactin elevation (galactorrhea, gynecomastia, mentstrual changes, sexual dysfunction in males), associated with the blockade of the D₂-receptor, and even more important no induction of weight gain in combination with severe metabolic dysfunction found for marketed antipsychotic drugs.
It is moreover desirable that the compounds have low affinity or alternatively an antagonistic effect to/on other serotonergic receptors, especially the 5-HT_2Aand/or 5-HT_2Breceptors, in order to avoid or reduce side effects associated with modulation of these receptors, such as changes (thickening) of the heart tissue associated with agonism at the 5-HT_2Breceptor, and psychotomimetic effect induced by agonism at the 5-HT_2Areceptor. Ideally they should show an agonistic action on the 5-HT_2Creceptor, an antagonistic action on the 5-HT_2Areceptor or alternatively no affinity to the 5-HT_2Areceptor and no affinity to the 5-HT_2Breceptor or alternatively an antagonistic action on the 5-HT_2Breceptor. Even more ideally the compounds should display an agonistic action on the 5-HT_2Creceptor in combination with an antagonistic action on the 5-HT_2Areceptor and no affinity to the 5-HT_2Breceptor.
Besides the affinity and selectivity for the 5-HT_2Creceptor, further properties may be advantageous for the treatment and/or prophylaxis of 5-HT_2C-related disorders, such as, for example:
1.) the metabolic stability, for example determined from the half-lives, measured in vitro, in liver microsomes from various species (e.g. rat or human);
2.) no or only low inhibition of cytochrome P450 (CYP) enzymes: cytochrome P450 (CYP) is the name for a superfamily of heme proteins having enzymatic activity (oxidase). They are also particularly important for the degradation (metabolism) of foreign substances such as drugs or xenobiotics in mammalian organisms. The principal representatives of the types and subtypes of CYP in the human body are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g. grapefruit juice, cimetidine, erythromycin) are used at the same time as medicinal substances which are degraded by this enzyme system and thus compete for the same binding site on the enzyme, the degradation thereof may be slowed down and thus effects and side effects of the administered medicinal substance may be undesirably enhanced;
3.) a suitable solubility in water (in mg/mL);
4.) suitable pharmacokinetics (time course of the concentration of the compound of the invention in plasma or in tissue, for example brain). The pharmacokinetics can be described by the following parameters: half-life (in h), volume of distribution (in l·kg-1), plasma clearance (in l·h-1·kg-1), AUC (area under the curve, area under the concentration-time curve, in ng·h·l-1), oral bioavailability (the dose-normalized ratio of AUC after oral administration and AUC after intravenous administration), the so-called brain-plasma ratio (the ratio of AUC in brain tissue and AUC in plasma);
5.) no or only low blockade of the hERG channel: compounds which block the hERG channel may cause a prolongation of the QT interval and thus lead to serious disturbances of cardiac rhythm (for example so-called “torsade de pointes”). The potential of compounds to block the hERG channel can be determined by means of the displacement assay with radiolabelled dofetilide which is described in the literature (G. J. Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187 199). A smaller IC50 in this dofetilide assay means a greater probability of potent hERG blockade. In addition, the blockade of the hERG channel can be measured by electrophysiological experiments on cells which have been transfected with the hERG channel, by so-called whole-cell patch clamping (G. J. Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187-199).
It was an object of the present invention to provide compounds for the treatment or prophylaxis of various 5-HT_2C-related diseases. The compounds were intended to have a high affinity to the 5-HT_2Creceptor and be potent and efficacious 5-HT_2Cagonists. In addition, the compounds of the invention were intended to have one or more of the aforementioned advantages, namely low affinity on other serotonergic receptors, and especially the lack of potent agonistic effect (antagonism preferred) on the 5-HT_2Aand/or 5-HT_2Breceptors, and additionally one or more of those advantages mentioned under 1.) to 5.).
The present invention provides compounds which have an affinity for the 5-HT_2C, thus allowing the treatment of disorders related to or affected by the 5-HT_2Creceptor.

SUMMARY OF THE INVENTION

The present invention relates to tricyclic hexahydrodiazepinoquinolines carrying a cyclic substituent, to a method for producing them, to compositions comprising such compounds, their use as modulators, especially agonists or partial agonists, of the 5-HT_2Creceptor, their use for preparing a medicament for the prevention or treatment of conditions and disorders which respond to the modulation of 5-HT_2Creceptor, to a method for preventing or treating conditions and disorders which respond to the modulation of 5-HT_2Creceptor, and processes for preparing such compounds and compositions.
In one aspect, the present invention relates to compounds of the formula (I):
wherein

R¹is selected from the group consisting of hydrogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO and SO₂and optionally also 1 or 2 C═O and/or C═S groups as ring members, where the cyclic moieties in the three last-mentioned radicals may be substituted with one or more substituents R¹⁰;
each R²is independently selected from the group consisting of cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, —CH₂NR^11aR^11b, —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹⁰; or
- two radicals R²bound to the same carbon atom, together with the carbon atom they are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring (i.e. a spiro-bound ring), where the ring may contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents R¹⁰;
R^3aand R^3b, independently of each other, are selected from the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, —CH₂NR^11aR^11b, —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹⁰;
R^4aand R^4b, independently of each other, are selected from the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, —CH₂NR^11aR^11b, —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹⁰; or
- R^4aand R^4bform together a group ═O or ═S; or
- R^4aand R^4b, together with the carbon atom they are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring (i.e. a spiro-bound ring), where the ring may contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents R¹⁰;
R^5aand R^5b, independently of each other, are selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —NR^11aR^11b, —CH₂NR^11aR^11b, —NR^11aC(O)R⁹, —C(═O)R⁹, SO₂NR^11aR^11b, C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl, phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹⁰; where
- R^5aand R^5bare not simultaneously hydroxyl; or
- R^5aand R^5b, together with the carbon atom they are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring (i.e. a spiro-bound ring), where the ring may contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents R¹⁰;
R⁶is a cyclic radical selected from the group consisting of C₃-C₆-cycloalkyl which may carry one or more radicals R⁸; and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO and SO₂, and optionally also 1 or 2 groups C═O and/or C═S, as ring members, where the heterocyclic ring may be substituted with one or more substituents R¹⁰;
each R⁷is independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, fluorinated C₃-C₈-cycloalkenyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy, C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —NR^11aR^11b, —CH₂NR^11aR^11b, —NR^11aC(O)R⁹, —C(═O)R⁹, SO₂NR^11aR^11b, C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl, phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹⁰; or
- two radicals R⁷bound on neighboring carbon atoms, together with the carbon atoms they are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered partially unsaturated or maximally unsaturated ring, where the ring may contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents R¹⁰;
each R⁸is independently selected from the group consisting of halogen, cyano, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, —NR^11aR^11b, —CH₂NR^11aR^11b, phenyl, phenyl-C₁-C₂-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the five last-mentioned radicals may be substituted with one or more substituents R¹⁰;
- or two radicals R⁸bound to the same carbon atom may form together a group ═O or ═S;
each R⁹is independently selected from the group consisting of hydrogen, cyano, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, —NR^11aR^11b, —CH₂NR^11aR^11b, phenyl, phenyl-C₁-C₂-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the five last-mentioned radicals may be substituted with one or more substituents R¹⁰;
each R¹⁰is independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —COOH, —NR^11aR^11b, —CH₂NR^11aR^11b, C₁-C₆-alkylcarbonyl, fluorinated C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, fluorinated C₁-C₆-alkoxycarbonyl, SO₂NR^11aR^11b, C₁-C₆-alkylcarbonyloxy and fluorinated C₁-C₆-alkylcarbonyloxy;
- or two radicals R¹⁰, together with the atom(s) they are bound to, form a saturated, partially unsaturated or maximally unsaturated 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring, where the heterocyclic ring contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members;
R^11aand R^11b, independently of each other and independently of each occurrence, are selected from the group consisting of hydrogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, fluorinated C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, fluorinated C₁-C₆-alkoxycarbonyl, phenyl and benzyl, where the phenyl moieties in the two last-mentioned radicals may carry 1, 2 or 3 substituents selected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy; or,
- if R^11aand R^11bare bound to the same nitrogen atom, together with this nitrogen atom may form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring, where the ring may further contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents selected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy;
a is 0, 1 or 2; and
b is 0, 1, 2 or 3;
or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier and/or auxiliary substance.
In yet another aspect, the invention relates to a compound of formula I or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for use as a medicament.
In yet another aspect, the invention relates to a compound of formula I or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for the treatment of disorders which responds to the modulation of the 5-HT_2Creceptor.
In yet another aspect, the invention relates to the use of a compound of formula I or of an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of disorders which respond to the modulation of the 5-HT_2Creceptor.
In yet another aspect, the invention relates to the use of a compound of formula I or of an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of disorders selected from the group consisting of damage of the central nervous system, disorders of the central nervous system, eating disorders, ocular hypertension, cardiovascular disorders, gastrointestinal disorders and diabetes, and especially from the group consisting of bipolar disorder, depression, atypical depression, mood episodes, adjustment disorders, anxiety, panic disorders, post-traumatic syndrome, psychoses, schizophrenia, cognitive deficits of schizophrenia, memory loss, dementia of aging, Alzheimer's disease, neuropsychiatric symptoms in Alzheimer's disease (e.g. aggression), behavioral disorders associated with dementia, social phobia, mental disorders in childhood, attention deficit hyperactivity disorder, organic mental disorders, autism, mutism, disruptive behavior disorder, impulse control disorder, borderline personality disorder, obsessive compulsive disorder, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, seizure disorders, epilepsy, substance use disorders, alcohol abuse, cocaine abuse, tobacco abuse, smoking cessation, sexual dysfunction/erectile dysfunction in males, sexual dysfunction in females, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea, chronic fatigue syndrome, psoriasis, Parkinson's disease, neuropsychiatric symptoms in Parkinson's disease (e.g. aggression), Lewy Body dementia, neuropsychiatric symptoms in Lewy Body dementia (e.g. aggression), spinal cord injury, trauma, stroke, pain, bladder dysfunction/urinary incontinence, encephalitis, meningitis, eating disorders, obesity, bulimia, weight loss, anorexia nervosa, ocular hypertension, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus, diabetes mellitus, type I diabetes, type II diabetes, type III diabetes, diabetes secondary to pancreatic diseases, diabetes related to steroid use, diabetes complications, hyperglycemia and insulin resistance.
In yet another aspect, the invention relates to a method for treating disorders which respond to the modulation of the 5-HT_2Creceptor, which method comprises administering to a subject in need thereof at least one compound of formula I or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof.
In yet another aspect, the invention relates to a method for treating disorders selected from the group consisting of damage of the central nervous system, disorders of the central nervous system, eating disorders, ocular hypertension, cardiovascular disorders, gastrointestinal disorders and diabetes, and especially from the group consisting of bipolar disorder, depression, atypical depression, mood episodes, adjustment disorders, anxiety, panic disorders, post-traumatic syndrome, psychoses, schizophrenia, cognitive deficits of schizophrenia, memory loss, dementia of aging, Alzheimer's disease, neuropsychiatric symptoms in Alzheimer's disease (e.g. aggression), behavioral disorders associated with dementia, social phobia, mental disorders in childhood, attention deficit hyperactivity disorder, organic mental disorders, autism, mutism, disruptive behavior disorder, impulse control disorder, borderline personality disorder, obsessive compulsive disorder, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, seizure disorders, epilepsy, substance use disorders, alcohol abuse, cocaine abuse, tobacco abuse, smoking cessation, sexual dysfunction/erectile dysfunction in males, sexual dysfunction in females, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea, chronic fatigue syndrome, psoriasis, Parkinson's disease, neuropsychiatric symptoms in Parkinson's disease (e.g. aggression), Lewy Body dementia, neuropsychiatric symptoms in Lewy Body dementia (e.g. aggression), spinal cord injury, trauma, stroke, pain, bladder dysfunction/urinary incontinence, encephalitis, meningitis, eating disorders, obesity, bulimia, weight loss, anorexia nervosa, ocular hypertension, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus, diabetes mellitus, type I diabetes, type II diabetes, type III diabetes, diabetes secondary to pancreatic diseases, diabetes related to steroid use, diabetes complications, hyperglycemia and insulin resistance, which method comprises administering to a subject in need thereof at least one compound of formula I or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

The compounds of the formula I may exist in different spatial arrangements. For example, if the compounds possess one or more centers of asymmetry, polysubstituted rings or double bonds, or as different tautomers, the present invention contemplates the possible use of enantiomeric mixtures, in particular racemates, diastereomeric mixtures and tautomeric mixtures, such as the respective essentially pure enantiomers, diastereomers and tautomers of the compounds of formula I and/or their salts.
It is likewise possible to use physiologically tolerated salts of the compounds of the formula I, especially acid addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid, C₁-C₄-alkylsulfonic acids, such as methanesulfonic acid, aromatic sulfonic acids, such as benzenesulfonic acid and toluenesulfonic acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid and benzoic acid. Other utilizable acids are described in Fortschritte der Arzneimittelforschung [Advances in drug research], Volume 10, pages 224 et seq., Birkhäauser Verlag, Basel and Stuttgart, 1966.
The compounds of formula I may also be present in the form of tautomers. In one aspect, tautomery may be present in compounds I wherein R^4aand R^4bform together a group ═O and R^5aor R^5bis H. For example, the compounds of formula I may have the following tautomeric formulae:
In another aspect, tautomery may be present in compounds I containing rings which have one or more C═O groups as ring members which are neighboured to a CH₂group.
The organic moieties mentioned in the above definitions of the variables are, like the term halogen, collective terms for individual listings of the individual group members. The prefix C_n-C_mindicates in each case the possible number of carbon atoms in the group.
The term “halogen” denotes in each case fluorine, bromine, chlorine or iodine. In one aspect, the halogen may be fluorine, chlorine or bromine.
The term “alkyl” as used herein and in the alkyl moieties of alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl and the like refers to saturated straight-chain or branched hydrocarbon radicals having 1 to 2 (“C₁-C₂-alkyl”), 1 to 3 (“C₁-C₃-alkyl”), 1 to 4 (“C₁-C₄-alkyl”) or 1 to 6 (“C₁-C₆-alkyl”) carbon atoms. C₁-C₂-Alkyl is methyl or ethyl. C₁-C₃-Alkyl is additionally propyl and isopropyl. C₁-C₄-Alkyl is additionally butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl) or 1,1-dimethylethyl (tert-butyl). C₁-C₆-Alkyl is additionally also, for example, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.
The term “fluorinated alkyl” as used herein refers to straight-chain or branched alkyl groups having 1 to 2 (“fluorinated C₁-C₂-alkyl”), 1 to 3 (“fluorinated C₁-C₃-alkyl”), 1 to 4 (“fluorinated C₁-C₄-alkyl”) or 1 to 6 (“fluorinated C₁-C₆-alkyl”) carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by fluorine atoms. Fluorinated C₁-C₂-alkyl is an alkyl group having 1 or 2 carbon atoms (as mentioned above), where at least one of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groups are replaced by fluorine atoms, such as difluoromethyl, trifluoromethyl, 1-fluoroethyl, (R)-1-fluoroethyl, (S)-1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl. Fluorinated C₁-C₄-alkyl is a straight-chain or branched alkyl group having 1 to 4 carbon atoms (as mentioned above), where at least one of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groups are replaced by fluorine atoms. Examples are, apart those listed above for C₁-C₂-fluoroalkyl, 1-fluoropropyl, (R)-1-fluoropropyl, (S)-1-fluoropropyl, 2-fluoropropyl, (R)-2-fluoropropyl, (S)-2-fluoropropyl, 3-fluoropropyl, 1,1-difluoropropyl, 2,2-difluoropropyl, 1,2-difluoropropyl, 2,3-difluoropropyl, 1,3-difluoropropyl, 3,3-difluoropropyl, 1,1,2-trifluoropropyl, 1,2,2-trifluoropropyl, 1,2,3-trifluoropropyl, 2,2,3-trifluoropropyl, 3,3,3-trifluoropropyl, 1,1,1-trifluoroprop-2-yl, 2-fluoro-1-methylethyl, (R)-2-fluoro-1-methylethyl, (S)-2-fluoro-1-methylethyl, 2,2-difluoro-1-methylethyl, (R)-2,2-difluoro-1-methylethyl, (S)-2,2-difluoro-1-methylethyl, 1,2-difluoro-1-methylethyl, (R)-1,2-difluoro-1-methylethyl, (S)-1,2-difluoro-1-methylethyl, 2,2,2-trifluoro-1-methylethyl, (R)-2,2,2-trifluoro-1-methylethyl, (S)-2,2,2-trifluoro-1-methylethyl, 2-fluoro-1-(fluoromethyl)ethyl, 1-(difluoromethyl)-2,2-difluoroethyl, 1-(trifluoromethyl)-2,2,2-trifluoroethyl, 1-(trifluoromethyl)-1,2,2,2-tetrafluoroethyl, 1-fluorobutyl, (R)-1-fluorobutyl, (S)-1-fluorobutyl, 2-fluorobutyl, (R)-2-fluorobutyl, (S)-2-fluorobutyl, 3-fluorobutyl, (R)-3-fluorobutyl, (S)-3-fluorobutyl, 4-fluorobutyl, 1,1-difluorobutyl, 2,2-difluorobutyl, 3,3-difluorobutyl, 4,4-difluorobutyl, 4,4,4-trifluorobutyl and the like. Fluorinated C₁-C₆-alkyl is a straight-chain or branched alkyl group having 1 to 6 carbon atoms (as mentioned above), where at least one of the hydrogen atoms, e.g. 1, 2, 3, 4 or 5 hydrogen atoms in these groups are replaced by fluorine atoms. Additionally examples include for C₁-C₄-fluoroalkyl, 1-fluoropentyl, (R)-1-fluoropentyl, (S)-1-fluoropentyl, 2-fluoropentyl, (R)-2-fluoropentyl, (S)-2-fluoropentyl, 3-fluoropentyl, (R)-3-fluoropentyl, (S)-3-fluoropentyl, 4-fluoropentyl, (R)-4-fluoropentyl, (S)-4-fluoropentyl, 5-fluoropentyl, (R)-5-fluoropentyl, (S)-5-fluoropentyl, 1-fluorohexyl, (R)-1-fluorohexyl, (S)-1-fluorohexyl, 2-fluorohexyl, (R)-2-fluorohexyl, (S)-2-fluorohexyl, 3-fluorohexyl, (R)-3-fluorohexyl, (S)-3-fluorohexyl, 4-fluorohexyl, (R)-4-fluorohexyl, (S)-4-fluorohexyl, 5-fluorohexyl, (R)-5-fluorohexyl, (S)-5-fluorohexyl, 6-fluorohexyl, (R)-6-fluorohexyl, (S)-6-fluorohexyl, and the like.
The term “alkenyl” as used herein refers to monounsaturated straight-chain or branched hydrocarbon radicals having 2 to 3 (“C₂-C₃-alkenyl”), 2 to 4 (“C₂-C₄-alkenyl”) or 2 to 6 (“C₂-C₆-alkenyl”) carbon atoms and a double bond in any position, such as C₂-C₃-alkenyl, such as ethenyl, 1-propenyl, 2-propenyl or 1-methylethenyl; C₂-C₄-alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl or 2-methyl-2-propenyl; and C₂-C₆-alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl and the like.
The term “fluorinated alkenyl” as used herein refers to unsaturated straight-chain or branched hydrocarbon radicals having 2 to 3 (“fluorinated C₂-C₃-alkenyl”), 2 to 4 (“fluorinated C₂-C₄-alkenyl”) or 2 to 6 (“fluorinated C₂-C₆-alkenyl”) carbon atoms and a double bond in any position (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by fluorine atoms, such as, fluorovinyl, fluoroallyl and the like.
The term “alkynyl” as used herein refers to straight-chain or branched hydrocarbon groups having 2 to 3 (“C₂-C₃-alkynyl”), 2 to 4 (“C₂-C₄-alkynyl”) or 2 to 6 (“C₂-C₆-alkynyl”) carbon atoms and one or two triple bonds in any position, such as C₂-C₃-alkynyl, such as ethynyl, 1-propynyl or 2-propynyl; C₂-C₄-alkynyl, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl and the like, and C₂-C₆-alkynyl, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and the like.
The term “fluorinated alkynyl” as used herein refers to unsaturated straight-chain or branched hydrocarbon radicals having 2 to 3 (“fluorinated C₂-C₃-alkynyl”), 3 to 4 (“fluorinated C₃-C₄-alkynyl”) or 2 to 6 (“fluorinated C₂-C₆-alkynyl”) carbon atoms and one or two triple bonds in any position (as mentioned above), where some or all of the hydrogen atoms in these groups are replaced by fluorine atoms.
The term “cycloalkyl” as used herein refers to monocyclic saturated hydrocarbon radicals having 3 to 8 (“C₃-C₈-cycloalkyl”), in particular 3 to 6 carbon atoms (“C₃-C₆-cycloalkyl”) or 3 to 5 carbon atoms (“C₃-C₅-cycloalkyl”) or 3 or 4 carbon atoms (“C₃-C₄-cycloalkyl”). Examples for C₃-C₄-cycloalkyl are cyclopropyl and cyclobutyl. Examples of C₃-C₅-cycloalkyl are cyclopropyl, cyclobutyl and cyclopentyl. Examples of C₃-C₆-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of C₃-C₈-cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The term “fluorinated cycloalkyl” as used herein refers to monocyclic saturated hydrocarbon groups having 3 to 8 (“C₃-C₈-halocycloalkyl”) or preferably 3 to 6 (“C₃-C₆-halocycloalkyl”) or 3 to 5 (“C₃-C₅-halocycloalkyl”) carbon ring members (as mentioned above) in which some or all of the hydrogen atoms are replaced by fluorine atoms. Examples include 1-fluorocyclopropyl, 2-fluorocyclopropyl, (S)- and (R)-2,2-difluorocyclopropyl, 1,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, pentafluorocyclopropyl, 1-fluorocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl, 1,2-difluorocyclobutyl, 1,3-difluorocyclobutyl, 2,3-difluorocyclobutyl, 2,4-difluorocyclobutyl, 1,2,2-trifluorocyclobutyl, 1-fluorocycloheptyl, 2-fluorocycloheptyl, 3-fluorocycloheptyl, 4-fluorocycloheptyl, 1,2-difluorocycloheptyl, 1,3-difluorocycloheptyl, 1,4-difluorocycloheptyl, 2,2-difluorocycloheptyl, 2,3-difluorocycloheptyl, 2,4-difluorocycloheptyl, 2,5-difluorocycloheptyl, 2,6-difluorocycloheptyl, 2,7-difluorocycloheptyl, 3,3-difluorocycloheptyl, 3,4-difluorocycloheptyl, 3,5-difluorocycloheptyl, 3,6-difluorocycloheptyl, 4,4-difluorocycloheptyl, 4,5-difluorocycloheptyl, and the like.
The term “cycloalkenyl” as used herein refers to monocyclic partially unsaturated, non-aromatic hydrocarbon radicals having 3 to 8 (“C₃-C₈-cycloalkenyl”), in particular 5 to 7 carbon atoms (“C₅-C₇-cycloalkenyl”) or 5 or 6 carbon atoms (“C₅-C₆-cycloalkenyl”) and one or more non-cumulative, preferably one, C—C double bonds in the ring. Examples for C₅-C₆-cycloalkenyl are cyclopent-1-en-1-yl, cyclopent-1-en-3-yl, cyclopent-1-en-4-yl, cyclopenta-1,3-dien-1-yl, cyclopenta-1,3-dien-2-yl, cyclopenta-1,3-dien-5-yl, cyclohex-1-en-1-yl, cyclohex-1-en-3-yl, cyclohex-1-en-4-yl, cyclohexa-1,3-dien-1-yl, cyclohexa-1,3-dien-2-yl, cyclohexa-1,3-dien-5-yl, cyclohexa-1,4-dien-1-yl and cyclohexa-1,4-dien-3-yl. Examples of C₅-C₇-cycloalkenyl are, apart those mentioned above, include for C₅-C₆-cycloalkenyl, cyclohept-1-en-1-yl, cyclohept-1-en-3-yl, cyclohept-1-en-4-yl, cyclohept-1-en-5-yl, cyclohepta-1,3-dien-1-yl, cyclohepta-1,3-dien-2-yl, cyclohepta-1,3-dien-5-yl, cyclohepta-1,3-dien-6-yl, cyclohepta-1,4-dien-1-yl, cyclohepta-1,4-dien-2-yl, cyclohepta-1,4-dien-3-yl and cyclohepta-1,4-dien-6-yl. Examples of C₃-C₈-cycloalkenyl are, apart those mentioned above for C₅-C₆-cycloalkenyl, cycloprop-1-en-1-yl, cycloprop-1-en-3-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclooct-1-en-1-yl, cyclooct-1-en-3-yl, cyclooct-1-en-4-yl, cyclooct-1-en-5-yl, cycloocta-1,3-dien-1-yl, cycloocta-1,3-dien-2-yl, cycloocta-1,3-dien-5-yl, cycloocta-1,3-dien-6-yl, cycloocta-1,4-dien-1-yl, cycloocta-1,4-dien-2-yl, cycloocta-1,4-dien-3-yl, cycloocta-1,4-dien-6-yl, cycloocta-1,4-dien-7-yl, cycloocta-1,5-dien-1-yl, and cycloocta-1,5-dien-3-yl.
The term “fluorinated cycloalkenyl” as used herein refers to monocyclic partially unsaturated, non-aromatic hydrocarbon radicals having 3 to 8 (“fluorinated C₃-C₈-cycloalkenyl”), in particular 5 to 7 carbon atoms (“fluorinated C₅-C₇-cycloalkenyl”) or 5 or 6 carbon atoms (“fluorinated C₅-C₆-cycloalkenyl”) and one or more non-cumulative, preferably one, C—C double bonds in the ring and in which some or all of the hydrogen atoms are replaced by fluorine atoms.
The term “cycloalkyl-C₁-C₄-alkyl” refers to a C₃-C₈-cycloalkyl group (“C₃-C₈-cycloalkyl-C₁-C₄-alkyl”), preferably a C₃-C₆-cycloalkyl group (“C₃-C₆-cycloalkyl-C₁-C₄-alkyl”) as defined above which is bound to the remainder of the molecule via a C₁-C₄-alkyl group, as defined above. The term “cycloalkyl-C₁-C₂-alkyl” refers to a C₃-C₈-cycloalkyl group (“C₃-C₈-cycloalkyl-C₁-C₂-alkyl”), preferably a C₃-C₆-cycloalkyl group (“C₃-C₆-cycloalkyl-C₁-C₂-alkyl”) as defined above which is bound to the remainder of the molecule via a C₁-C₂-alkyl group, as defined above. Examples for C₃-C₆-cycloalkyl-C₁-C₂-alkyl are cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl and cyclohexylethyl. Examples for C₃-C₆-cycloalkyl-C₁-C₄-alkyl, apart those mentioned for C₃-C₆-cycloalkyl-C₁-C₂-alkyl, are cyclopropylpropyl, cyclopropylbutyl, cyclobutylpropyl, cyclobutylbutyl, cyclopentylpropyl, cyclopentylbutyl, cyclohexylpropyl and cyclohexylbutyl. Examples for C₃-C₈-cycloalkyl-C₁-C₂-alkyl, apart those mentioned for C₃-C₆-cycloalkyl-C₁-C₂-alkyl, are cycloheptylmethyl, cycloheptylethyl, cyclooctylmethyl and cyclooctylethyl. Examples for C₃-C₈-cycloalkyl-C₁-C₄-alkyl, apart those mentioned for C₃-C₈-cycloalkyl-C₁-C₂-alkyl, are cycloheptylpropyl, cycloheptylbutyl, cyclooctylpropyland cyclooctylbutyl.
The term “fluorinated cycloalkyl-C₁-C₄-alkyl” refers to a fluorinated C₃-C₈-cycloalkyl group (“fluorinated C₃-C₈-cycloalkyl-C₁-C₄-alkyl”), preferably a fluorinated C₃-C₆-cycloalkyl group (“fluorinated C₃-C₆-cycloalkyl-C₁-C₄-alkyl”) as defined above which is bound to the remainder of the molecule via a C₁-C₄-alkyl group, as defined above. The term “fluorinated cycloalkyl-C₁-C₂-alkyl” refers to a fluorinated C₃-C₈-cycloalkyl group (“fluorinated C₃-C₈-cycloalkyl-C₁-C₂-alkyl”), preferably a fluorinated C₃-C₆-cycloalkyl group (“fluorinated C₃-C₆-cycloalkyl-C₁-C₂-alkyl”) as defined above which is bound to the remainder of the molecule via a C₁-C₂-alkyl group, as defined above.
The term “C₁-C₂-alkoxy” is a C₁-C₂-alkyl group, as defined above, attached via an oxygen atom. The term “C₁-C₃-alkoxy” is a C₁-C₃-alkyl group, as defined above, attached via an oxygen atom. The term “C₁-C₄-alkoxy” is a C₁-C₄-alkyl group, as defined above, attached via an oxygen atom. The term “C₁-C₆-alkoxy” is a C₁-C₆-alkyl group, as defined above, attached via an oxygen atom. C₁-C₂-Alkoxy is methoxy or ethoxy. C₁-C₃-Alkoxy is additionally, for example, n-propoxy and 1-methylethoxy (isopropoxy). C₁-C₄-Alkoxy is additionally, for example, butoxy, 1-methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) or 1,1-dimethylethoxy (tert-butoxy). C₁-C₆-Alkoxy is additionally, for example, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy. C₁-C₈-Alkoxy is additionally, for example, heptyloxy, octyloxy, 2-ethylhexyloxy and positional isomers thereof.
The term “fluorinated C₁-C₂-alkoxy” is a fluorinated C₁-C₂-alkyl group, as defined above, attached via an oxygen atom. The term “fluorinated C₁-C₃-alkoxy” is a fluorinated C₁-C₃-alkyl group, as defined above, attached via an oxygen atom. The term “fluorinated C₁-C₆-haloalkoxy” is a fluorinated C₁-C₆-alkyl group, as defined above, attached via an oxygen atom. Fluorinated C₁-C₂-alkoxy is, for example, OCH₂F, OCHF₂, OCF₃, 1-fluoroethoxy, (R)-1-fluoroethoxy, (S)-1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy, 1,2-difluoroethoxy, 2,2-difluoroethoxy, 1,1,2-trifluoroethoxy, 1,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy or OC₂F₅. Fluorinated C₁-C₃-alkoxy is additionally, for example, 1-fluoropropoxy, (R)-1-fluoropropoxy, (S)-1-fluoropropoxy, 2-fluoropropoxy, (R)-2-fluoropropoxy, (S)-2-fluoropropoxy, 3-fluoropropoxy, 1,1-difluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 3,3-difluoropropoxy, 3,3,3-trifluoropropoxy, (R)-2-fluoro-1-methylethoxy, (S)-2-fluoro-1-methylethoxy, (R)-2,2-difluoro-1-methylethoxy, (S)-2,2-difluoro-1-methylethoxy, (R)-1,2-difluoro-1-methylethoxy, (S)-1,2-difluoro-1-methylethoxy, (R)-2,2,2-trifluoro-1-methylethoxy, (S)-2,2,2-trifluoro-1-methylethoxy, 2-fluoro-1-(fluoromethyl)ethoxy, 1-(difluoromethyl)-2,2-difluoroethoxy, OCH₂—C₂F₅, OCF₂—C₂F₅or 1-(CH₂F)-2-fluoroethoxy. Fluorinated C₁-C₄-alkoxy is additionally, for example, 1-fluorobutoxy, (R)-1-fluorobutoxy, (S)-1-fluorobutoxy, 2-fluorobutoxy, 3-fluorobutoxy, 4-fluorobutoxy, 1,1-difluorobutoxy, 2,2-difluorobutoxy, 3,3-difluorobutoxy, 4,4-difluorobutoxy, 4,4,4-trifluorobutoxy or nonafluorobutoxy. Fluorinated C₁-C₆-alkoxy is additionally, for example, 5-fluoropentoxy, undecafluoropentoxy, 6-fluorohexoxy or tridecafluorohexoxy.
The term “C₁-C₄-alkoxy-C₁-C₄-alkyl” as used herein, refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms, as defined above, where one hydrogen atom is replaced by a C₁-C₄-alkoxy group, as defined above. The term “C₁-C₆-alkoxy-C₁-C₄-alkyl” as used herein, refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms, as defined above, where one hydrogen atom is replaced by a C₁-C₆-alkoxy group, as defined above. Examples are methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, n-butoxymethyl, sec-butoxymethyl, isobutoxymethyl, tert-butoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-propoxyethyl, 1-isopropoxyethyl, 1-n-butoxyethyl, 1-sec-butoxyethyl, 1-isobutoxyethyl, 1-tert-butoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 2-n-butoxyethyl, 2-sec-butoxyethyl, 2-isobutoxyethyl, 2-tert-butoxyethyl, 1-methoxypropyl, 1-ethoxypropyl, 1-propoxypropyl, 1-isopropoxypropyl, 1-n-butoxypropyl, 1-sec-butoxypropyl, 1-isobutoxypropyl, 1-tert-butoxypropyl, 2-methoxypropyl, 2-ethoxypropyl, 2-propoxypropyl, 2-isopropoxypropyl, 2-n-butoxypropyl, 2-sec-butoxypropyl, 2-isobutoxypropyl, 2-tert-butoxypropyl, 3-methoxypropyl, 3-ethoxypropyl, 3-propoxypropyl, 3-isopropoxypropyl, 3-n-butoxypropyl, 3-sec-butoxypropyl, 3-isobutoxypropyl, 3-tert-butoxypropyl and the like.
The term “fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl” as used herein, refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms, as defined above, where one hydrogen atom is replaced by a C₁-C₄-alkoxy group, as defined above, and wherein at least one, e.g. 1, 2, 3, 4 or all of the remaining hydrogen atoms (either in the alkoxy moiety or in the alkyl moiety or in both) are replaced by fluorine atoms. The term “fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl” as used herein, refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms, as defined above, where one hydrogen atom is replaced by a C₁-C₆-alkoxy group, as defined above, and wherein at least one, e.g. 1, 2, 3, 4 or all of the remaining hydrogen atoms (either in the alkoxy moiety or in the alkyl moiety or in both) are replaced by fluorine atoms. Examples are difluoromethoxymethyl (CHF₂OCH₂), trifluoromethoxymethyl, 1-difluoromethoxyethyl (CHF₂OCH(CH₃)), 1-trifluoromethoxyethyl (CF₃OCH(CH₃)), 2-difluoromethoxyethyl (CHF₂OCH₂CH₂), 2-trifluoromethoxyethyl (CF₃OCH₂CH₂), methoxy-difluoromethyl (CH₃OCF₂), 2-methoxy-1,1-difluoroethyl (CH₃OCH₂CF₂), 2-methoxy-2,2-difluoroethyl (CH₃OCF₂CH₂), and the like.
The term “hydroxy-C₁-C₄-alkyl” as used herein, refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms, as defined above, where one hydrogen atom is replaced by a hydroxyl group. The term “hydroxy-C₁-C₆-alkyl” as used herein, refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, as defined above, where one hydrogen atom is replaced by a hydroxyl group. Examples for hydroxy-C₁-C₄-alkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyprop-2-yl, 2-hydroxyprop-2-yl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 1-hydroxybut-2-yl, 2-hydroxybut-2-yl, 3-hydroxybut-2-yl, 4-hydroxybut-2-yl, hydroxy-tert-butyl and the like. Examples for hydroxy-C₁-C₆-alkyl are, apart those mentioned for hydroxy-C₁-C₄-alkyl, 1-hydroxypentyl, 2-hydroxypentyl, 3-hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl, 1-hydroxyhexyl, 2-hydroxyhexyl, 3-hydroxyhexyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 6-hydroxyhexyl and the like.
The term “hydroxy-C₁-C₄-alkoxy” as used herein, refers to a C₁-C₄-alkoxy group, as defined above, where one hydrogen atom is replaced by a hydroxy group. The term “hydroxy-C₁-C₆-alkoxy” as used herein, refers to a C₁-C₆-alkoxy group, as defined above, where one hydrogen atom is replaced by a hydroxy group. Examples for hydroxy-C₁-C₄-alkoxy include hydroxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxypropoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 1-hydroxy-2-propoxy, 2-hydroxy-2-propoxy, 1-hydroxybutoxy, 2-hydroxybutoxy, 3-hydroxybutoxy, 4-hydroxybutoxy, 1-hydroxy-2-butoxy, 2-hydroxy-2-butoxy, 3-hydroxy-2-butoxy, 4-hydroxy-2-butoxy, hydroxy-tert-butoxy and the like. Examples for hydroxy-C₁-C₆-alkoxy include, apart those mentioned for hydroxy-C₁-C₄-alkoxy, 1-hydroxypentoxy, 2-hydroxypentoxy, 3-hydroxypentoxy, 4-hydroxypentoxy, 5-hydroxypentoxy, 1-hydroxyhexoxy, 2-hydroxyhexoxy, 3-hydroxyhexoxy, 4-hydroxyhexoxy, 5-hydroxyhexoxy, 6-hydroxyhexoxy and the like.
The term “C₁-C₄-alkoxy-C₁-C₄-alkoxy” as used herein, refers to a C₁-C₄-alkoxy group, as defined above, where one hydrogen atom is replaced by a C₁-C₄-alkoxy group, as defined above. The term “C₁-C₆-alkoxy-C₁-C₄-alkoxy” as used herein, refers to a C₁-C₄-alkoxy group, as defined above, where one hydrogen atom is replaced by a C₁-C₆-alkoxy group, as defined above. Examples are methoxymethoxy, ethoxymethoxy, propoxymethoxy, isopropoxymethoxy, butoxymethoxy, sec-butoxymethoxy, isobutoxymethoxy, tert-butoxymethoxy, 1-methoxyethoxy, 1-ethoxyethoxy, 1-propoxyethoxy, 1-isopropoxyethoxy, 1-butoxyethoxy, 1-sec-butoxyethoxy, 1-isobutoxyethoxy, 1-tert-butoxyethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-propoxyethoxy, 2-isopropoxyethoxy, 2-butoxyethoxy, 2-sec-butoxyethoxy, 2-isobutoxyethoxy, 2-tert-butoxyethoxy, 1-methoxypropoxy, 1-ethoxypropoxy, 1-propoxypropoxy, 1-isopropoxypropoxy, 1-butoxypropoxy, 1-sec-butoxypropoxy, 1-isobutoxypropoxy, 1-tert-butoxypropoxy, 2-methoxypropoxy, 2-ethoxypropoxy, 2-propoxypropoxy, 2-isopropoxypropoxy, 2-butoxypropoxy, 2-sec-butoxypropoxy, 2-isobutoxypropoxy, 2-tert-butoxypropoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 3-propoxypropoxy, 3-isopropoxypropoxy, 3-butoxypropoxy, 3-sec-butoxypropoxy, 3-isobutoxypropoxy, 3-tert-butoxypropoxy and the like.
The term “C₁-C₂-alkylthio” is a C₁-C₂-alkyl group, as defined above, attached via a sulfur atom. The term “C₁-C₃-alkylthio” refers to a C₁-C₃-alkyl group, as defined above, attached via a sulfur atom. The term “C₁-C₄-alkylthio” is a C₁-C₄-alkyl group, as defined above, attached via a sulfur atom. The term “C₁-C₆-alkylthio” refers to a C₁-C₆-alkyl group, as defined above, attached via a sulfur atom. The term “C₁-C₁₀-alkylthio” refers to a C₁-C₁₀-alkyl group, as defined above, attached via a sulfur atom. C₁-C₂-Alkylthio is methylthio or ethylthio. C₁-C₃-Alkylthio is additionally, for example, n-propylthio or 1-methylethylthio (isopropylthio). C₁-C₄-Alkylthio is additionally, for example, butylthio, 1-methylpropylthio (sec-butylthio), 2-methylpropylthio (isobutylthio) or 1,1-dimethylethylthio (tert-butylthio). C₁-C₆-Alkylthio is additionally, for example, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio or 1-ethyl-2-methylpropylthio.
The term “fluorinated C₁-C₂-alkylthio” refers to a fluorinated C₁-C₂-alkyl group, as defined above, attached via a sulfur atom. The term “fluorinated C₁-C₃-alkylthio” refers to a fluorinated C₁-C₃-alkyl group, as defined above, attached via a sulfur atom. The term “fluorinated C₁-C₄-alkylthio” refers to a fluorinated C₁-C₄-alkyl group, as defined above, attached via a sulfur atom. The term “fluorinated C₁-C₆-alkylthio” refers to a fluorinated C₁-C₆-alkyl group, as defined above, attached via a sulfur atom. Fluorinated C₁-C₂-alkylthio refers to, for example, SCH₂F, SCHF₂, SCF₃, 2-fluoroethylthio, 2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, or SC₂F₅. Fluorinated C₁-C₃-alkylthio may additionally, for example, include 2-fluoropropylthio, 3-fluoropropylthio, 2,2-difluoropropylthio, 2,3-difluoropropylthio, 3,3,3-trifluoropropylthio, SCH₂—C₂F₅, SCF₂—C₂F₅or 1-(CH₂F)-2-fluoroethylthio. Fluorinated C₁-C₄-alkylthio may additionally, for example, include 4-fluorobutylthio or nonafluorobutylthio. Fluorinated C₁-C₆-alkylthio is additionally, for example, 5-fluoropentylthio, undecafluoropentylthio, 6-fluorohexylthio or dodecafluorohexylthio.
The term “C₁-C₂-alkylsulfinyl” refers to a C₁-C₂-alkyl group, as defined above, attached via a sulfinyl [S(O)] group. The term “C₁-C₄-alkylsulfinyl” is a C₁-C₄-alkyl group, as defined above, attached via a sulfinyl [S(O)] group. The term “C₁-C₆-alkylsulfinyl” is a C₁-C₆-alkyl group, as defined above, attached via a sulfinyl [S(O)] group. C₁-C₂-Alkylsulfinyl is methylsulfinyl or ethylsulfinyl. C₁-C₄-Alkylsulfinyl is additionally, for example, n-propylsulfinyl, 1-methylethylsulfinyl (isopropylsulfinyl), butylsulfinyl, 1-methylpropylsulfinyl (sec-butylsulfinyl), 2-methylpropylsulfinyl (isobutylsulfinyl) or 1,1-dimethylethylsulfinyl (tert-butylsulfinyl). C₁-C₆-Alkylsulfinyl is additionally, for example, pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl or 1-ethyl-2-methylpropylsulfinyl.
The term “fluorinated C₁-C₂-alkylsulfinyl” refers to a fluorinated C₁-C₂-alkyl group, as defined above, attached via a sulfinyl [S(O)] group. The term “fluorinated C₁-C₃-alkylsulfinyl” refers to a fluorinated C₁-C₃-alkyl group, as defined above, attached via a sulfinyl [S(O)] group. The term “fluorinated C₁-C₄-alkylsulfinyl” refers to a fluorinated C₁-C₄-alkyl group, as defined above, attached via a sulfinyl [S(O)] group. The term “fluorinated C₁-C₆-alkylsulfinyl” refers to a fluorinated C₁-C₆-alkyl group, as defined above, attached via a sulfinyl [S(O)] group. Fluorinated C₁-C₂-alkylsulfinyl is, for example, S(O)CH₂F, S(O)CHF₂, S(O)CF₃, 2-fluoroethylsulfinyl, 2,2-difluoroethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, or S(O)C₂F₅. Fluorinated C₁-C₃-alkylsulfinyl may additionally, for example, include 2-fluoropropylsulfinyl, 3-fluoropropylsulfinyl, 2,2-difluoropropylsulfinyl, 2,3-difluoropropylsulfinyl, 3,3,3-trifluoropropylsulfinyl, S(O)CH₂—C₂F₅, S(O)CF₂—C₂F₅or 1-(CH₂F)-2-fluoroethylsulfinyl. Fluorinated C₁-C₄-alkylsulfinyl may additionally, for example, include 4-fluorobutylsulfinyl or nonafluorobutylsulfinyl. Fluorinated C₁-C₆-alkylsulfinyl may additionally, for example, include 5-fluoropentylsulfinyl, undecafluoropentylsulfinyl, 6-fluorohexylsulfinyl or dodecafluorohexylsulfinyl.
The term “C₁-C₂-alkylsulfonyl” refers to a C₁-C₂-alkyl group, as defined above, attached via a sulfonyl [S(O)₂] group. The term “C₁-C₄-alkylsulfonyl” refers to a C₁-C₄-alkyl group, as defined above, attached via a sulfonyl [S(O)₂] group. The term “C₁-C₆-alkylsulfonyl” is a C₁-C₆-alkyl group, as defined above, attached via a sulfonyl [S(O)₂] group. C₁-C₂-Alkylsulfonyl refers to a methylsulfonyl or ethylsulfonyl. C₁-C₄-Alkylsulfonyl is additionally, for example, n-propylsulfonyl, 1-methylethylsulfonyl (isopropylsulfonyl), butylsulfonyl, 1-methylpropylsulfonyl (sec-butylsulfonyl), 2-methylpropylsulfonyl (isobutylsulfonyl) or 1,1-dimethylethylsulfonyl (tert-butylsulfonyl). C₁-C₆-Alkylsulfonyl is additionally, for example, pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropylsulfonyl or 1-ethyl-2-methylpropylsulfonyl.
The term “fluorinated C₁-C₂-alkylsulfonyl” refers to a fluorinated C₁-C₂-alkyl group, as defined above, attached via a sulfonyl [S(O)₂] group. The term “fluorinated C₁-C₃-alkylsulfonyl” refers to a fluorinated C₁-C₃-alkyl group, as defined above, attached via a sulfonyl [S(O)₂] group. The term “fluorinated C₁-C₄-alkylsulfonyl” refers to a fluorinated C₁-C₄-alkyl group, as defined above, attached via a sulfonyl [S(O)₂] group. The term “fluorinated C₁-C₆-alkylsulfonyl” refers to a fluorinated C₁-C₆-alkyl group, as defined above, attached via a sulfonyl [S(O)₂] group. Fluorinated C₁-C₂-alkylsulfonyl is, for example, S(O)₂CH₂F, S(O)₂CHF₂, S(O)₂CF₃, 2-fluoroethylsulfonyl, 2,2-difluoroethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, or S(O)₂C₂F₅. Fluorinated C₁-C₃-alkylsulfonyl is additionally, for example, 2-fluoropropylsulfonyl, 3-fluoropropylsulfonyl, 2,2-difluoropropylsulfonyl, 2,3-difluoropropylsulfonyl, 3,3,3-trifluoropropylsulfonyl, S(O)₂CH₂—C₂F₅, S(O)₂CF₂—C₂F₅or 1-(CH₂F)-2-fluoroethylsulfonyl. Fluorinated C₁-C₄-alkylsulfonyl is additionally, for example, 4-fluorobutylsulfonyl or nonafluorobutylsulfonyl. Fluorinated C₁-C₆-alkylsulfonyl is additionally, for example, 5-fluoropentylsulfonyl, undecafluoropentylsulfonyl, 6-fluorohexylsulfonyl or dodecafluorohexylsulfonyl.
C₁-C₄-Alkylcarbonyl refers to a straight-chain or branched alkyl group having from 1 to 4 carbon atoms), which is bound to the remainder of the molecule via a carbonyl group (CO), such as in acetyl, propionyl, isopropylcarbonyl, butylcarbonyl, sec-butylcarbonyl, isobutylcarbonyl, and tert-butylcarbonyl. C₁-C₆-Alkylcarbonyl is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms, which is bound to the remainder of the molecule via a carbonyl group (CO). Examples include, apart those listed above for C₁-C₄-alkylcarbonylpentylcarbonyl, hexylcarbonyl and the constitutional isomers thereof.
Fluorinated C₁-C₄-alkylcarbonyl refers to a straight-chain or branched fluorinated alkyl group having from 1 to 4 carbon atoms as defined above, which is bound to the remainder of the molecule via a carbonyl group (CO). Fluorinated C₁-C₆-alkylcarbonyl is a straight-chain or branched fluorinated alkyl group having from 1 to 6 carbon atoms as defined above, which is bound to the remainder of the molecule via a carbonyl group (CO). Examples include trifluoromethylcarbonyl, 2,2,2-trifluoroethylcarbonyl and the like.
C₃-C₆-cycloalkylcarbonyl relates to a C₃-C₆-cycloalkyl group as defined above which is bound to the remainder of the molecule via a carbonyl group (CO), such as in cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl.
C₁-C₆-Alkoxycarbonyl refers to a straight-chain or branched alkoxy group having from 1 to 6, especially 1 to 4 carbon atoms (═C₁-C₄-alkoxycarbonyl), in particular 1 to 3 carbon atoms (═C₁-C₃-alkoxycarbonyl), which is bound to the remainder of the molecule via a carbonyl group (CO), such as in methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, and isopropyloxycarbonyl.
Fluorinated C₁-C₆-alkoxycarbonyl refers to a straight-chain or branched fluorinated alkoxy group having from 1 to 6, especially 1 to 4 carbon atoms (=fluorinated C₁-C₄-alkoxycarbonyl), in particular 1 to 3 carbon atoms (=fluorinated C₁-C₃-alkoxycarbonyl) as defined above, which is bound to the remainder of the molecule via a carbonyl group (CO). Examples include trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl and the like.
C₁-C₄-Alkylcarbonyloxy refers to a straight-chain or branched alkyl group having from 1 to 4 carbon atoms, which is bound to the remainder of the molecule via a carbonyloxy group [C(O)—O—], such as in acet(yl)oxy, propionyloxy, isopropylcarbonyloxy, butylcarbonyloxy, sec-butylcarbonyloxy, isobutylcarbonyloxy, and tert-butylcarbonyloxy. C₁-C₆-Alkylcarbonyloxy is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms, which is bound to the remainder of the molecule via a carbonyloxy group [C(O—O—]. Examples include, apart those listed above for C₁-C₄-alkylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy and the constitutional isomers thereof.
Fluorinated C₁-C₄-alkylcarbonyloxy refers to a straight-chain or branched fluorinated alkyl group having from 1 to 4 carbon atoms as defined above, which is bound to the remainder of the molecule via a carbonyloxy group [C(O)—O—]. Fluorinated C₁-C₆-alkylcarbonyloxy is a straight-chain or branched fluorinated alkyl group having from 1 to 6 carbon atoms as defined above, which is bound to the remainder of the molecule via a carbonyloxy group [C(O)—O—]. Examples include trifluoromethylcarbonyloxy, 2,2,2-trifluoroethylcarbonyloxy and the like.
Phenyl-C₁-C₂-alkyl is a phenyl group bound to the remainder of the molecule via a C₁-C₂-alkyl group. Examples are benzyl, 1-phenylethyl and 2-phenylethyl (phenethyl).
The term “3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO and SO₂and optionally also 1 or 2 C═O and/or C═S groups as ring members” denotes a 3-, 4-, 5-, 6-, 7- or 8-membered, preferably a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximum unsaturated heteromonocyclic ring containing 1, 2, 3 or 4 (preferably 1, 2 or 3) heteroatoms or heteroatom groups selected from N, O, S, SO and SO₂and optionally also 1 or 2 C═O and/or C═S groups as ring members.
Unsaturated rings contain at least one C—C and/or C—N and/or N—N double bond(s). Maximally unsaturated rings contain as many conjugated C—C and/or C—N and/or N—N double bonds as allowed by the ring size. Maximally unsaturated 5- or 6-membered heterocyclic rings are aromatic. 7- and 8-membered rings cannot be aromatic. They are homoaromatic (7-membered ring, 3 double bonds) or have 4 double bonds (8-membered ring). Partially unsaturated rings contain less than the maximum number of C—C and/or C—N and/or N—N double bond(s) allowed by the ring size. The heterocyclic ring may be attached to the remainder of the molecule via a carbon ring member or via a nitrogen ring member. As a matter of course, the heterocyclic ring contains at least one carbon ring atom. If the ring contains more than one 0 ring atom, these are not adjacent.
In heterocyclic rings containing N as a ring member this nitrogen atom may either be present as tertiary N formally bound by a double and a single bond (like in pyridyl) or may be present as secondary NH (if N is not part of a ring double bond). In case that N is actually present as NH, and the ring is substituted, the substituent may either be bound to a carbon ring atom or to such a secondary nitrogen ring atom. In case that N is actually present as NH, the ring may either be bound to the remainder of the molecule via a carbon ring atom or such a secondary nitrogen ring atom.
Examples of a 3-, 4-, 5-, 6- or 7-membered saturated heterocyclic ring include: Oxiranyl, thiiranyl, aziridinyl, oxetanyl, thietanyl, azetidinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-2-on-3-yl, tetrahydrofuran-2-on-4-yl, tetrahydrofuran-2-on-5-yl, tetrahydrofuran-2-thion-3-yl, tetrahydrofuran-2-thion-4-yl, tetrahydrofuran-2-thion-5-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydrothien-2-on-3-yl, tetrahydrothien-2-on-4-yl, tetrahydrothien-2-on-5-yl, tetrahydrothien-2-thion-3-yl, tetrahydrothien-2-thion-4-yl, tetrahydrothien-2-thion-5-yl, pyrrolidin-1-yl, pyrrolidine-2-on-1-yl, pyrrolidine-2,5-dion-1-yl, pyrrolidine-2-thion-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidine-2-on-3-yl, pyrrolidine-2-on-4-yl, pyrrolidine-2-on-5-yl, pyrrolidine-2,5-dion-3-yl, pyrrolidine-2-thion-3-yl, pyrrolidine-2-thion-4-yl, pyrrolidine-2-thion-5-yl, pyrazolidin-1-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, imidazolidin-1-yl, imidazolidin-2-on-1-yl, imidazolidin-2-thion-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, imidazolidin-2-on-4-yl, imidazolidin-2-thion-4-yl, oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, oxazolidin-5-yl, isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, isoxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl, thiazolidin-5-yl, isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl, isothiazolidin-5-yl, 1,2,4-oxadiazolidin-3-yl, 1,2,4-oxadiazolidin-5-yl, 1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl, 1,3,4-oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl, 1,3,4-triazolidin-1-yl, 1,3,4-triazolidin-2-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-on-1-yl, piperidin-2,5-dion-1-yl, piperidine-2-thion-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-2-on-3-yl, piperidin-2,5-dion-3-yl, piperidin-2-thion-3-yl, piperidin-4-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, piperazin-1-yl, piperazin-2-yl, 1,3,5-hexahydrotriazin-1-yl, 1,3,5-hexahydrotriazin-2-yl and 1,2,4-hexahydrotriazin-3-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, 1-oxothiomorpholin-2-yl, 1-oxothiomorpholin-3-yl, 1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-2-yl, 1,1-dioxothiomorpholin-3-yl, 1,1-dioxothiomorpholin-4-yl, azepan-1-, -2-, -3- or -4-yl, oxepan-2-, -3-, -4- or -5-yl, hexahydro-1,3-diazepinyl, hexahydro-1,4-diazepinyl, hexahydro-1,3-oxazepinyl, hexahydro-1,4-oxazepinyl, hexahydro-1,3-dioxepinyl, hexahydro-1,4-dioxepinyl and the like.
Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered saturated heterocyclic ring further include oxocane, thiocane, azocane, [1,3]diazocane, [1,4]diazocane, [1,5]diazocane, [1,5]oxazocane and the like.
Examples of a 3-, 4-, 5-, 6- or 7-membered partially unsaturated heterocyclic ring include: 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3-dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl, 2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl, 3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl, 4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2-, 3-, 4-, 5- or 6-di- or tetrahydropyridinyl, 3-di- or tetrahydropyridazinyl, 4-di- or tetrahydropyridazinyl, 2-di- or tetrahydropyrimidinyl, 4-di- or tetrahydropyrimidinyl, 5-di- or tetrahydropyrimidinyl, di- or tetrahydropyrazinyl, 1,3,5-di- or tetrahydrotriazin-2-yl, 1,2,4-di- or tetrahydrotriazin-3-yl, 2,3,4,5-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 3,4,5,6-tetrahydro[2H]azepin-2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,6,7-tetrahydro[1H]azepin-1-, -2-, -3-, -4-, -5-, -6- or -7-yl, tetrahydrooxepinyl, such as 2,3,4,5-tetrahydro[1H]oxepin 2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,4,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, 2,3,6,7-tetrahydro[1H]oxepin-2-, -3-, -4-, -5-, -6- or -7-yl, tetrahydro-1,3-diazepinyl, tetrahydro-1,4-diazepinyl, tetrahydro-1,3-oxazepinyl, tetrahydro-1,4-oxazepinyl, tetrahydro-1,3-dioxepinyl and tetrahydro-1,4-dioxepinyl.
Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered partially unsaturated heterocyclic ring further include 1,2,3,4,5,6-hexahydroazocine, 2,3,4,5,6,7-hexahydroazocine, 1,2,3,4,5,8-hexahydroazocine, 1,2,3,4,7,8-hexahydroazocine, 1,2,3,4,5,6-hexahydro-[1,5]diazocine,1,2,3,4,7,8-hexahydro-[1,5]diazocine and the like.
Examples of a 3-, 4-, 5-, 6- or 7-membered maximally unsaturated (including aromatic) heterocyclic ring include 5- or 6-membered heteroaromatic rings, such as 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1,3,4-triazol-1-yl, 1,3,4-triazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 1-oxopyridin-2-yl, 1-oxopyridin-3-yl, 1-oxopyridin-4-yl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl, and also homoaromatic radicals, such as 1H-azepine, 1H-[1,3]-diazepine and 1H-[1,4]-diazepine.
Examples of a 3-, 4-, 5-, 6-, 7- or 8-membered maximally unsaturated heterocyclic ring further include [1,3]diazocine, [1,5]diazocine and [1,5]diazocine.
A 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members is either saturated, partially unsaturated and carbocyclic (if it contains only C═O and/or C═S as heteroatom group and no further heteroatoms or heteroatom groups) or saturated, partially unsaturated or maximally unsaturated heterocyclic. Examples are, in addition to the heterocyclic rings mentioned above, carbocyclic rings, such as cyclopropanonyl, cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, cyclohexandionyl, cycloheptanonyl, cyclooctanonyl, cyclopropanthionyl, cyclobutanthionyl, cyclopentanthionyl, cyclohexanthionyl, cyclohexandithionyl, cycloheptanthionyl, cyclooctanthionyl, cyclopropenonyl, cyclopentenonyl, cyclohexenonyl and the like.
Examples of a 4-membered saturated heterocyclic ring containing 1 heteroatom or heteroatom group selected from N, O, S, NO, SO and SO₂as ring member are oxetan-3-yl, oxetan-4-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, thietan-2-yl, thietan-3-yl, 1-oxothietan-2-yl, 1-oxothietan-3-yl, 1,1-dioxothietan-2-yl and 1,1-dioxothietan-3-yl.
Examples of a 3-, 4-, 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO and SO₂as ring members are, apart those listed above for the 4-membered saturated heterocyclic ring containing 1 heteroatom or heteroatom group selected from N, O, S, NO, SO and SO₂as ring member, oxiral-2-yl, aziridin-1-yl, aziridin-2-yl, thiiran-2-yl, 1-oxothiiran-2-yl, 1,1-dioxothiiran-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, pyrrolidin-1-yl, pyrroldin-2-yl, pyrrolidin-3-yl, pyrazolidin-1-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl, oxazolidin-5-yl, isoxazolidin-2-yl, isoxazolidin-3-yl, isoxazolidin-4-yl, isoxazolidin-5-yl, thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl, thiazolidin-5-yl, isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl, isothiazolidin-5-yl, tetrahydropyranyl, 4-tetrahydropyranyl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, hexahydropyridazin-3-yl, hexahydropyridazin-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl, hexahydropyrimidin-5-yl, piperazin-1-yl, piperazin-2-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, 1-oxothiomorpholin-2-yl, 1-oxothiomorpholin-3-yl, 1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-2-yl, 1,1-dioxothiomorpholin-3-yl and 1,1-dioxothiomorpholin-4-yl.
The remarks made above and in the following with respect to preferred aspects of the invention, e.g. to preferred meanings of the variables R¹, R², R^3a, R^3b, R^4a, R^4b, R^5a, R^5b, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^11a, R^11b, a and b of compounds I, to preferred compounds I and to preferred embodiments of the method or the use according to the invention, apply in each case on their own or in particular to combinations thereof.
In a preferred embodiment, R¹is selected from hydrogen and C₁-C₆-alkyl, in particular from hydrogen and methyl, and is specifically hydrogen.
In a preferred embodiment, R²is selected from cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, more preferably from C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl, even more preferably from C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl, in particular from methyl, ethyl, propyl, isopropyl and CF₃, more particularly from methyl, ethyl and CF₃, and is specifically methyl or CF₃. Among C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl radicals R², preference is given to CH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₃, CH₂OCF₃, CH₂CH₂OCF₃, CH₂OCHF₂and CH₂CH₂OCHF₂.
In a preferred embodiment, R^3aand R^3b, independently of each other, are selected from hydrogen, cyano, nitro, C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl. More preferably, R^3ais selected from hydrogen, cyano, nitro, C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl, and R^3bis hydrogen. Even more preferably, R^3ais selected from hydrogen and methyl and R^3bis hydrogen. In particular, both R^3aand R^3bare hydrogen.
In a preferred embodiment, R^4aand R^4b, independently of each other, are selected from hydrogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl, or form together a group ═O, or form together a group —(CH₂)_m—, where m is 2, 3 or 4, in particular 2 or 3, especially 2, thus forming together a spiro-bound ring. More preferably, R^4ais selected from hydrogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl and R^obis hydrogen, or R^4aand R^4bare methyl, or R^4aand R^4bform together a group —(CH₂)_m—, where m is 2, 3 or 4, in particular 2 or 3, especially 2, thus forming together a spiro-bound ring. In a particular embodiment, they are hydrogen.
In a preferred embodiment, R^5ais selected from hydrogen, halogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl and C₁-C₆-alkoxy-C₁-C₄-alkyl and R^5bis hydrogen. In particular, R^5ais hydrogen or methyl, specifically hydrogen, and R^5bis hydrogen.
Among C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl radicals R^4a, R^4band R^5bpreference is given to CH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₃, CH₂OCF₃, CH₂CH₂OCF₃, CH₂OCHF₂and CH₂CH₂OCHF₂.
In one embodiment, R⁶is C₃-C₆-cycloalkyl which may carry one or more, in particular one, radicals R⁸.
In another embodiment, R⁶is a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO and SO₂, and optionally also 1 or 2 groups C═O and/or C═S, as ring members, where the heterocyclic ring may be substituted with one or more substituents R¹⁰.
As a substituent on a cycloalkyl radical R⁶, preferably each R⁸is independently selected from the group consisting of halogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl. Among C₁-C₄-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl radicals R⁸, preference is given to CH₂OCH₃, CH₂CH₂OCH₃, CH₂OCH₂CH₃, CH₂CH₂OCH₂CH₃, CH₂OCF₃, CH₂CH₂OCF₃, CH₂OCHF₂and CH₂CH₂OCHF₂. In particular, R⁸is halogen, specifically F.
In a preferred embodiment, R⁶is unsubstituted C₃-C₆-cycloalkyl; i.e. is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In another preferred embodiment, R⁶is fluorinated C₃-C₆-cycloalkyl, such as 1-fluorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,2-difluorocyclobutyl, 3,3-difluorocyclobutyl and the like. More preferably, R⁶is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl or 3,3-difluorocyclobutyl. In particular, R⁶is selected from cyclopropyl and cyclobutyl, and is particularly preferably cyclopropyl. In another particular embodiment R⁶is 2,2-difluorocyclopropyl.
In an alternatively preferred embodiment, R⁶is a 3-, 4-, 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO and SO₂as ring members, where the heterocyclic ring may be substituted with one or more substituents R¹⁰, where R¹⁰has one of the above general or, in particular, one of the below preferred meanings.
In an alternative particular embodiment, R⁶is a 4-membered saturated heterocyclic ring containing 1 heteroatom or heteroatom group selected from N, O, S, NO, SO and SO₂, in particular from O, as ring member, where the heterocyclic ring may be substituted with one or more substituents R¹⁰, where R¹⁰has one of the above general or, in particular, one of the below preferred meanings. Specifically, R⁶is oxetan-3-yl which may be substituted with one or more, especially one, substituents R¹⁰, where R¹⁰has one of the above general or, in particular, one of the below preferred meanings.
In an alternative particular embodiment, R⁶is a 5- or 6-membered saturated heterocyclic ring containing 1 heteroatom or heteroatom group selected from N, O, S, NO, SO and SO₂, in particular from O, as ring member, where the heterocyclic ring may be substituted with one or more substituents R¹⁰, where R¹⁰has one of the above general or, in particular, one of the below preferred meanings. Specifically, R⁶is tetrahydrofuran-3-yl or tetrahydropyran-4-yl which may be substituted with one or more, especially one, substituents R¹⁰, where R¹⁰has one of the above general or, in particular, one of the below preferred meanings.
As a substituent on a heterocyclic ring R⁶, each R¹⁰is independently preferably selected from the group consisting of halogen, cyano, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy and fluorinated C₁-C₄-alkoxy, more preferably from F, Cl, cyano, CH₃, CF₃, OCH₃and OCF₃, and in particular from F, CH₃, CF₃, OCH₃and OCF₃. Specifically R¹⁰is CH₃.
In a preferred embodiment, each R²is independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy. More preferably, each R⁷is independently selected from halogen, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy and fluorinated C₁-C₄-alkoxy, and is in particular fluorine. In an alternative embodiment, each R²is independently selected from the group consisting of cyano and C₁-C₄-alkoxy-C₁-C₄-alkyl.
In a preferred embodiment, a is 0 or 1. If a is 1, R²is preferably bound in β-position to the nitrogen ring atom carrying R¹.
In particular, a is 0 if R⁶is carbocyclic, i.e. C₃-C₆-cycloalkyl which may carry one or more radicals R⁸; and a is 0 or 1 if R⁶is heterocyclic, i.e. a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO and SO₂, and optionally also 1 or 2 groups C═O and/or C═S, as ring members, where the heterocyclic ring may be substituted with one or more substituents R¹⁰.
In a preferred embodiment, b is 0 or 1 and specifically 0.
If not specified otherwise in a specific context, R⁹, R¹⁰, R^11aand R^11bhave following preferred meanings:
Preferably each R⁹is independently selected from the group consisting of hydrogen, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₃-C₆-cycloalkyl, fluorinated C₃-C₆-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, and —NR^11aR^11b, where R^11aand R^11bhave one of the above general or, in particular, one of the below preferred meanings. In particular, each R⁹is independently selected from the group consisting of hydrogen, C₁-C₄-alkyl, fluorinated C₁-C₂-alkyl, C₁-C₄-hydroxyalkyl, C₁-C₄-alkoxy, fluorinated C₁-C₂-alkoxy, and —NR^11aR^11b, where R^11aand R^11bhave one of the above general or, in particular, one of the below preferred meanings.
Preferably, each R¹⁰is independently selected from the group consisting of halogen, cyano, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy and fluorinated C₁-C₄-alkoxy, more preferably from F, Cl, cyano, CH₃, CF₃, OCH₃and OCF₃, and in particular from F, CH₃, CF₃, OCH₃and OCF₃.
Preferably, R^11aand R^11b, independently of each other and independently of each occurrence, are selected from the group consisting of hydrogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkylcarbonyl and fluorinated C₁-C₆-alkylcarbonyl.
In a particular embodiment, the compounds of the invention are compounds of formula I.1

- wherein R², R⁶, R⁷and b have one of the above general or, in particular, one of the above preferred meanings, and a is 0 or 1.

In a more particular embodiment, the compounds of the invention are compounds of formula I.1.1

- wherein
- R^7ais H, Cl, F or methyl, in particular H or F, specifically H;
- a is 0 or 1; and
- R², R⁶, R⁷and b have one of the above general or, in particular, one of the above preferred meanings.

In compounds I.1.1 (b-1) is preferably 0.
In compounds I.1 and I.1.1 R²is preferably methyl.
In compounds I.1 and I.1.1 a is preferably 0 if R⁶is a carbocyclic (i.e. cycloalkyl) radical, and is 0 or 1 if R⁶is heterocyclic.
Examples of preferred compounds are compounds of the following formulae Ia.1 to Ia.36, where the variables have one of the general or preferred meanings given above. Examples of preferred compounds are the individual compounds compiled in the tables 1 to 28080 below. Moreover, the meanings mentioned below for the individual variables in the tables are per se, independently of the combination in which they are mentioned, a particularly preferred embodiment of the substituents in question.

Table 1

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is cyclopropyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 2

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1-fluorocyclopropyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 3

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 2-fluorocyclopropyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 4

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 2,2-difluorocyclopropyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 5

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is cyclobutyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 6

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1-fluorocyclobutyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 7

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 2-fluorocyclobutyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 8

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 3-fluorocyclobutyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 9

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 2,2-difluorocyclobutyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 10

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 3,3-difluorocyclobutyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 11

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is cyclopentyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 12

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1-fluorocyclopentyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 13

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 2-fluorocyclopentyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 14

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 3-fluorocyclopentyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 15

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 2,2-difluorocyclopentyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 16

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 3,3-difluorocyclopentyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 17

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is cyclohexyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 18

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1-fluorocyclohexyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 19

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 2-fluorocyclohexyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 20

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 3-fluorocyclohexyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 21

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 4-fluorocyclohexyl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 22

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is aziridin-1-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 23

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1-(oxetan-3-yl)-aziridin-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 24

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1-(tetrahydrofuran-3-yl)-aziridin-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 25

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is oxiran-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 26

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is azetidin-1-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 27

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1-(oxetan-3-yl)-azetidin-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 28

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1-(tetrahydrofuran-3-yl)-azetidin-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 29

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1-(oxetan-3-yl)-azetidin-3-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 30

Table 31

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is oxetan-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 32

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is oxetan-3-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 33

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 3-methyloxetan-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 34

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 3-methyloxetan-3-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 35

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 2-methyloxetan-3-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 36

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is pyrrolidin-1-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 37

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1-(oxetan-3-yl)-pyrrolidin-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 38

Table 39

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1-(oxetan-3-yl)-pyrrolidin-3-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 40

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1-(tetrahydrofuran-3-yl)-pyrrolidin-3-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 41

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is tetrahydrofuran-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 42

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is tetrahydrofuran-3-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 43

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 3-(oxetan-3-yl)-oxazolidin-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 44

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is oxazolidin-3-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 45

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 3-(oxetan-3-yl)-oxazolidin-4-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 46

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 3-(oxetan-3-yl)-oxazolidin-5-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 47

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is isoxazolidin-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 48

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 2-(oxetan-3-yl)-isoxazolidin-3-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 49

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 2-(oxetan-3-yl)-isoxazolidin-4-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 50

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 2-(oxetan-3-yl)-isoxazolidin-5-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 51

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is piperidin-1-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 52

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 4-(oxetan-3-yl)-piperazine-1-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 53

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 4-(tetrahydrofuran-3-yl)-piperazine-1-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 54

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is morpholin-4-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 55

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is tetrahydropyran-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 56

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is tetrahydropyran-3-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 57

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is tetrahydropyran-4-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 58

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1,3-dioxan-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 59

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1,3-dioxan-4-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Table 60

Compounds of the formula Ia.1 in which R^4ais H, R^4bis H, R⁶is 1,4-dioxan-2-yl and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 61 to 120

Compounds of the formula Ia.1 in which R^4ais methyl, R^4bis H, R⁶is as defined in tables 1 to 60 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 121 to 180

Compounds of the formula Ia.1 in which R^4ais ethyl, R^4bis H, R⁶is as defined in tables 1 to 60 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 181 to 240

Compounds of the formula Ia.1 in which R^4ais CH₂OCH₃, R^4bis H, R⁶is as defined in tables 1 to 60 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 241 to 300

Compounds of the formula Ia.1 in which R^4ais CH₂OCH₂CH₃, R^4bis H, R⁶is as defined in tables 1 to 60 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 301 to 360

Compounds of the formula Ia.1 in which R^4ais CH₂CH₂OCH₃, R^4bis H, R⁶is as defined in tables 1 to 60 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 361 to 420

Compounds of the formula Ia.1 in which R^4ais CH₂CH₂OCH₂CH₃, R^4bis H, R⁶is as defined in tables 1 to 60 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 421 to 480

Compounds of the formula Ia.1 in which R^4ais CH₂OCHF₂, R^4bis H, R⁶is as defined in tables 1 to 60 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 481 to 540

Compounds of the formula Ia.1 in which R^4ais CH₂OCF₃, R^4bis H, R⁶is as defined in tables 1 to 60 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 541 to 600

Compounds of the formula Ia.1 in which R^4ais CH₂CH₂OCHF₂, R^4bis H, R⁶is as defined in tables 1 to 60 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 601 to 660

Compounds of the formula Ia.1 in which R^4ais CH₂CH₂OCF₃, R^4bis H, R⁶is as defined in tables 1 to 60 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 661 to 720

Compounds of the formula Ia.1 in which R^4ais methyl, R^4bis methyl, R⁶is as defined in tables 1 to 60 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 721 to 780

Compounds of the formula Ia.1 in which R^4aand R^4bform together —CH₂—CH₂—, R⁶is as defined in tables 1 to 60 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 781 to 1560

Compounds of the formula Ia.2 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 1561 to 2340

Compounds of the formula Ia.3 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 2341 to 3120

Compounds of the formula Ia.4 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 3121 to 3900

Compounds of the formula Ia.5 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 3901 to 4680

Compounds of the formula Ia.6 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 4681 to 5460

Compounds of the formula Ia.7 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 5461 to 6240

Compounds of the formula Ia.8 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 6241 to 7020

Compounds of the formula Ia.9 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 7021 to 7800

Compounds of the formula Ia.10 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 7801 to 8580

Compounds of the formula Ia.11 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 8581 to 9360

Compounds of the formula Ia.12 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 9361 to 10140

Compounds of the formula Ia.13 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 10141 to 10920

Compounds of the formula Ia.14 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 10921 to 11700

Compounds of the formula Ia.15 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 11701 to 12480

Compounds of the formula Ia.16 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 12481 to 13260

Compounds of the formula Ia.17 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 13261 to 14040

Compounds of the formula Ia.18 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 14041 to 14820

Compounds of the formula Ia.19 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 14821 to 15600

Compounds of the formula Ia.20 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 15601 to 16380

Compounds of the formula Ia.21 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 16381 to 17160

Compounds of the formula Ia.22 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 17161 to 17940

Compounds of the formula Ia.23 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 17941 to 18720

Compounds of the formula Ia.24 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 18721 to 19500

Compounds of the formula Ia.25 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 19501 to 20280

Compounds of the formula Ia.26 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 20281 to 21060

Compounds of the formula Ia.27 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 21061 to 21840

Compounds of the formula Ia.28 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 21841 to 22620

Compounds of the formula Ia.29 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 22621 to 23400

Compounds of the formula Ia.30 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 23401 to 24180

Compounds of the formula Ia.31 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 24181 to 24960

Compounds of the formula Ia.32 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 24961 to 25740

Compounds of the formula Ia.33 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 25741 to 26520

Compounds of the formula Ia.34 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 26521 to 27300

Compounds of the formula Ia.35 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

Tables 27301 to 28080

Compounds of the formula Ia.36 in which the combination of R^4a, R^4band R⁶is as defined in tables 1 to 780 and the combination of R^5a, R^5band R^7afor a compound corresponds in each case to one row of Table A.

TABLE A

No.	R^7a	R^5a	R^5b

A-1	H	H	H
A-2	F	H	H
A-3	Cl	H	H
A-4	CH₃	H	H
A-5	CHF₂	H	H
A-6	CF₃	H	H
A-7	OCH₃	H	H
A-8	OCHF₂	H	H
A-9	OCF₃	H	H
A-10	cyclopropyl	H	H
A-11	CN	H	H
A-12	CH₂OCH₃	H	H
A-13	CH₂CH₂OCH₃	H	H
A-14	H	CH₃	H
A-15	F	CH₃	H
A-16	Cl	CH₃	H
A-17	CH₃	CH₃	H
A-18	CHF₂	CH₃	H
A-19	CF₃	CH₃	H
A-20	OCH₃	CH₃	H
A-21	OCHF₂	CH₃	H
A-22	OCF₃	CH₃	H
A-23	cyclopropyl	CH₃	H
A-24	CN	CH₃	H
A-25	CH₂OCH₃	CH₃	H
A-26	CH₂CH₂OCH₃	CH₃	H
A-27	H	CH₂CH₃	H
A-28	F	CH₂CH₃	H
A-29	Cl	CH₂CH₃	H
A-30	CH₃	CH₂CH₃	H
A-31	CHF₂	CH₂CH₃	H
A-32	CF₃	CH₂CH₃	H
A-33	OCH₃	CH₂CH₃	H
A-34	OCHF₂	CH₂CH₃	H
A-35	OCF₃	CH₂CH₃	H
A-36	cyclopropyl	CH₂CH₃	H
A-37	CN	CH₂CH₃	H
A-38	CH₂OCH₃	CH₂CH₃	H
A-39	CH₂CH₂OCH₃	CH₂CH₃	H
A-40	H	CH₂OCH₃	H
A-41	F	CH₂OCH₃	H
A-42	Cl	CH₂OCH₃	H
A-43	CH₃	CH₂OCH₃	H
A-44	CHF₂	CH₂OCH₃	H
A-45	CF₃	CH₂OCH₃	H
A-46	OCH₃	CH₂OCH₃	H
A-47	OCHF₂	CH₂OCH₃	H
A-48	OCF₃	CH₂OCH₃	H
A-49	cyclopropyl	CH₂OCH₃	H
A-50	CN	CH₂OCH₃	H
A-51	CH₂OCH₃	CH₂OCH₃	H
A-52	CH₂CH₂OCH₃	CH₂OCH₃	H
A-53	H	CH₂OCH₂CH₃	H
A-54	F	CH₂OCH₂CH₃	H
A-55	Cl	CH₂OCH₂CH₃	H
A-56	CH₃	CH₂OCH₂CH₃	H
A-57	CHF₂	CH₂OCH₂CH₃	H
A-58	CF₃	CH₂OCH₂CH₃	H
A-59	OCH₃	CH₂OCH₂CH₃	H
A-60	OCHF₂	CH₂OCH₂CH₃	H
A-61	OCF₃	CH₂OCH₂CH₃	H
A-62	cyclopropyl	CH₂OCH₂CH₃	H
A-63	CN	CH₂OCH₂CH₃	H
A-64	CH₂OCH₃	CH₂OCH₂CH₃	H
A-65	CH₂CH₂OCH₃	CH₂OCH₂CH₃	H
A-66	H	CH₂CH₂OCH₃	H
A-67	F	CH₂CH₂OCH₃	H
A-68	Cl	CH₂CH₂OCH₃	H
A-69	CH₃	CH₂CH₂OCH₃	H
A-70	CHF₂	CH₂CH₂OCH₃	H
A-71	CF₃	CH₂CH₂OCH₃	H
A-72	OCH₃	CH₂CH₂OCH₃	H
A-73	OCHF₂	CH₂CH₂OCH₃	H
A-74	OCF₃	CH₂CH₂OCH₃	H
A-75	cyclopropyl	CH₂CH₂OCH₃	H
A-76	CN	CH₂CH₂OCH₃	H
A-77	CH₂OCH₃	CH₂CH₂OCH₃	H
A-78	CH₂CH₂OCH₃	CH₂CH₂OCH₃	H
A-79	H	CH₂CH₂OCH₂CH₃	H
A-80	F	CH₂CH₂OCH₂CH₃	H
A-81	Cl	CH₂CH₂OCH₂CH₃	H
A-82	CH₃	CH₂CH₂OCH₂CH₃	H
A-83	CHF₂	CH₂CH₂OCH₂CH₃	H
A-84	CF₃	CH₂CH₂OCH₂CH₃	H
A-85	OCH₃	CH₂CH₂OCH₂CH₃	H
A-86	OCHF₂	CH₂CH₂OCH₂CH₃	H
A-87	OCF₃	CH₂CH₂OCH₂CH₃	H
A-88	cyclopropyl	CH₂CH₂OCH₂CH₃	H
A-89	CN	CH₂CH₂OCH₂CH₃	H
A-90	CH₂OCH₃	CH₂CH₂OCH₂CH₃	H
A-91	CH₂CH₂OCH₃	CH₂CH₂OCH₂CH₃	H
A-92	H	CH₃	CH₃
A-93	F	CH₃	CH₃
A-94	Cl	CH₃	CH₃
A-95	CH₃	CH₃	CH₃
A-96	CHF₂	CH₃	CH₃
A-97	CF₃	CH₃	CH₃
A-98	OCH₃	CH₃	CH₃
A-99	OCHF₂	CH₃	CH₃
A-100	OCF₃	CH₃	CH₃
A-101	cyclopropyl	CH₃	CH₃
A-102	CN	CH₃	CH₃
A-103	CH₂OCH₃	CH₃	CH₃
A-104	CH₂CH₂OCH₃	CH₃	CH₃
A-105	H	CH₂CH₃	CH₃
A-106	F	CH₂CH₃	CH₃
A-107	Cl	CH₂CH₃	CH₃
A-108	CH₃	CH₂CH₃	CH₃
A-109	CHF₂	CH₂CH₃	CH₃
A-110	CF₃	CH₂CH₃	CH₃
A-111	OCH₃	CH₂CH₃	CH₃
A-112	OCHF₂	CH₂CH₃	CH₃
A-113	OCF₃	CH₂CH₃	CH₃
A-114	cyclopropyl	CH₂CH₃	CH₃
A-115	CN	CH₂CH₃	CH₃
A-116	CH₂OCH₃	CH₂CH₃	CH₃
A-117	CH₂CH₂OCH₃	CH₂CH₃	CH₃

Among the above compounds, preference is given to compounds Ia.1 and Ia.10; the latter especially if R⁶is a heterocyclic ring, for examples as defined in table 22 to 60.
In a specific embodiment, the invention relates to compounds I selected from the compounds of the examples, either in form of free bases or of any pharmaceutically acceptable salt thereof or a stereoisomer, the racemate or any mixture of stereoisomers thereof.
The compounds of the present invention can be prepared by using routine techniques familiar to a skilled person. In particular, the compounds of the formula I can be prepared according to the following schemes, wherein the variables, if not stated otherwise, are as defined above.
Compounds of formula I wherein R^4band R^5bare H (=compounds I′) can be synthesized as described in scheme 1 below. The readily available quinoline 1 in which X is a leaving group, such as Cl, Br I or triflate, is reacted with a suitable boron compound of R⁶, such as R⁶-boronic acid (R⁶—B(OH)₂) or the potassium (trifluoro)borate of R⁶(e.g. potassium cyclobutyl(trifluoro)borate or potassium cyclopropyl(trifluoro)borate) in a Suzuki coupling reaction to 2. The reaction is carried out in the presence of a Pd catalyst, such as Pd(OAc)₂, in general in the presence of a phosphine ligand (e.g. tricyclohexylphosphine; di(adamantan-1-yl)(butyl)-phosphine etc.), or tetrakis(triphenylphosphine)palladium(0) and the like. Quinoline 2 is then N-alkylated with a suitable protective group, such as benzyl, e.g. by reaction with benzyl bromide, to 3. Reduction of the quinolinium compound 3 with a suitable reduction agent, such as sodium borohydride and H₂/Raney nickel, yields the 1,2,3,4-tetrahydroquinoline 4, which is then deprotected to 5. Reaction with the 2-halogenoacetamide 6, wherein Y is Cl, Br or I, affords the acetamide 7, the keto group of which is reduced with common reduction agents, like borane, borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex or borohydrides such as sodium borohydride or LAH (lithium aluminium hydride) or DIBAL-H (diisobutyl aluminium hydride), to 8. Cyclization with formaldehyde/aldehyde/ketone 9 (C(O)R^3aR^3b=formaldehyde if R^3aand R^3bare hydrogen; another aldehyde if R^3ais hydrogen and R^3bis (fluorinated) alkyl, hydroxyalkyl, (fluorinated) alkenyl, (fluorinated) alkynyl, (fluorinated) cycloalkyl, phenyl, phenyl-alkyl or a heterocyclic ring; a ketone if R^3aand R^3bare (fluorinated) alkyl, hydroxyalkyl, (fluorinated) alkenyl, (fluorinated) alkynyl, (fluorinated) cycloalkyl, phenyl, phenyl-alkyl or a heterocyclic ring), generally in the presence of a strong acid, such as trifluoroacetic acid, yields I′. Alternatively, 2 can be reacted with the 2-halogenoacetamide 6 to 10, which is then reduced to 7.
Compounds of formula I wherein R^4a, R^4band R^5bare H (=compounds I″) can alternatively be synthesized as described in scheme 2 below. The boronic acid 11 and the α,β-unsaturated ester 12 are reacted in a 1,4-addition in the presence of a Rhodium catalyst, e.g. [RhOH(COD)]₂or Rh(acac)(CO)₂, if desired in the presence of a phosphine ligand, such as 1,4-bis(diphenylphosphino)butane (dppb), followed by lactam formation. The lactam 13 is then reduced with common reduction agents, like borane, borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex or borohydrides such as sodium borohydride, to the tetrahydroquinoline 14. Like in the reaction sequence of scheme 1, reaction with the 2-halogenoacetamide 6, wherein Y is Cl, Br or I, affords the acetamide 15, the keto group of which is reduced with common reduction agents, like borane, borane-tetrahydrofurane-complex, borane-dimethylsulfide-complex or borohydrides such as sodium borohydride or LAH (lithium aluminium hydride) or DIBAL-H (diisobutyl aluminium hydride), to 16. Cyclization with formaldehyde/aldehyde/ketone 9, generally in the presence of a strong acid, such as trifluoroacetic acid, yields I″.
For obtaining compounds I wherein R^4aand R^4bform together ═O, the lactam 13 is not reduced, but is directly reacted with the 2-halogenoacetamide 6 to 17, followed by reduction of the CO group in the amide to 18 and finally cyclisation, as shown in scheme 3 below. Alternatively, compounds I′″ can be obtained as described below scheme 4.
Compounds of formula I wherein R^4a, R^4band R^5bare H (=compounds I″) can alternatively be synthesized as described in scheme 4 below. The protected tetrahydrobenzodiazepine 19, wherein Z is a hydrogen or a halogen atom, such as Cl, Br or I and PG is a common protective group, such as a carbamate, especially boc, is acylated with the acrylic acid derivative 20, wherein LG is an appropriate leaving group, such as Cl or an anhydride or a chloroformate, in the presence of a base, such as triethylamine or Hünig's base, in an organic solvent, such as ether or methylene chloride. Reaction of 21 with a Lewis acid or a Brönstedt acid HA or irradiation with a suitable wavelength commonly derived from a mercury lamp in an adequate solvent, such as acetone or toluene, in a common photoreactor yields cyclization to 22. Reduction of the carbonyl group with common reduction agents like borohydrides such as sodium borohydride or borane-tetrahydrofurane-complex yields 23, which is deprotected using suitable reagents such as strong bases or acids to I″, wherein R^4aand R^4band R^5bare H. Compounds I″″ wherein R^4aand R^4bform together ═O can be obtained by skipping the reduction step to 23 and deprotecting 22.
Alternatively, compound 22 can be directly synthesized by reacting the tetrahydrobenzodiazepine 19, wherein Z is —B(OH)₂with the acrylic acid derivative 20 in a 1,4-addition in the presence of a Rhodium catalyst, e.g. [RhOH(COD)]₂or Rh(acac)(CO)₂, if desired in the presence of a phosphine ligand, such as 1,4-bis(diphenylphosphino)butane (dppb), followed by lactam formation to 22. This is then further reacted as described above.
If compound 22 is deprotected, this yields compound I′″ as well as other compounds I in which (R²)_ais not necessarily bound to the same position as in compounds I′″.
If desired, substituents R¹different from hydrogen can be introduced for example via alkylation under typical conditions such as stirring in an appropriate solvent in the presence of an alkylhalide and a base or via other common substitution reactions, or via reductive amination using a suitable aldehyde or ketone in the presence of reduction agent, such as borohydrides, e.g. triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride. —C(═O)R⁹as radical R¹can be introduced via amidation under typical amidation conditions, e.g. via reaction with a compound X—C(═O)R⁹, where X is OH or a halogen atom, under heating and removal of reaction water or using a coupling reagent, such as DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), HBTU ((0-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), HCTU (1H-benzotriazolium-1-[bis(dimethylamino)methylene]-5-chloro tetrafluoroborate), BOP ((benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium hexafluorophosphate), Py-BOP ((benzotriazol-1-yloxy)-tripyrrolidinphosphonium hexafluorophosphate) or Py-BrOP (bromotripyrrolidinphosphonium hexafluorophosphate).
Compounds I wherein R^5bis different from H can be prepared, for example, by reacting compound 22 with a compound LG-R^5bin the presence of a base, wherein LG is an appropriate leaving group, such as Cl or Br.
Alternatively to the method depicted in scheme 4, compounds I wherein R^4a, R^4band R^5bare H (=compounds I″) can be synthesized as described in scheme 5 below. Readily available anilines 24 are derivatized with carbonyl moieties 25 by acylation procedures employing appropriate leaving groups LG, such as chlorides or anhydrides, in the presence of a base such as triethylamine or Hünig's base, in an organic solvent, such as diethyl ether or methylene chloride to yield 26. Cyclization products 13 are received by irradiation with a suitable wavelength commonly derived from a mercury lamp in an adequate solvent such as acetone or toluene in a common photoreactor known to those skilled in the art. These are further reacted as depicted in schemes 2 and 3.
Compounds I wherein R^4aand R^4bare not H or do not form together a group ═O can be prepared by standard derivatization methods of compounds wherein R^4aand R^4bform together a group ═O. For instance, compounds wherein R^4aand R^4bform together a group ═S may be prepared by reaction with a sulfurization agent, such as Lawesson's reagent or P₂S₅. Alkyl and related groups as radicals R^4aand R^4bmay be introduced via Grignard reduction. Amino and related groups may be introduced via reductive amination. Hydroxyl group R^4aor R^4bmay be introduced by reducing the carbonyl group. This may be alkylated to yield alkoxy and related groups R^4aand R^4bor substituted by diverse groups.
If not otherwise indicated, the above-described reactions are generally carried out in a solvent at temperatures between room temperature and the boiling temperature of the solvent employed. Alternatively, the activation energy which is required for the reaction can be introduced into the reaction mixture using microwaves, something which has proved to be of value, in particular, in the case of the reactions catalyzed by transition metals (with regard to reactions using microwaves, see Tetrahedron 2001, 57, p. 9199 ff. p. 9225 ff. and also, in a general manner, “Microwaves in Organic Synthesis”, André Loupy (Ed.), Wiley-VCH 2002.
The acid addition salts of compounds I are prepared in a customary manner by mixing the free base with a corresponding acid, where appropriate in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether or diisopropyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.
Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that may not be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the preparation methods are within routine techniques.
Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protective Groups in Organic Synthesis (3^rded.), John Wiley & Sons, NY (1999), which is herein incorporated by reference in its entirety. Synthesis of the compounds of the invention may be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.
Starting materials, if not commercially available, may be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.
When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
Similarly, when a pure geometric isomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.
The present invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound I as defined above or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier and/or auxiliary substance.
The present invention further relates to a compound I as defined above or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for use as a medicament.
The present invention also relates to a compound I as defined above or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for the treatment of disorders which respond to the modulation of the 5-HT_2Creceptor.
The present invention also relates to the use of a compound I as defined above or of an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of disorders which respond to the modulation of the 5-HT_2Creceptor, and to a method for treating disorders which respond to the modulation of the 5-HT_2Creceptor, which method comprises administering to a subject in need thereof at least one compound I as defined above or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof.
The compounds of the present invention are modulators of the 5-HT_2Creceptor. Specifically, the compounds of formula I are agonists or partial agonists of the 5-HT_2Creceptor. Thus, in a specific embodiment, the invention relates to a compound I as defined above or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for the treatment of disorders which respond to 5-HT_2Creceptor agonists, further to the use of a compound I as defined above or of an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of disorders which respond to 5-HT_2Creceptor agonists, and to a method for treating disorders which respond to 5-HT_2Creceptor agonists, which method comprises administering to a subject in need thereof at least one compound I as defined above or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof.
Within the meaning of the invention, the term “disorder” denotes disturbances and/or anomalies which are as a rule regarded as being pathological conditions or functions and which can manifest themselves in the form of particular signs, symptoms and/or malfunctions. While the treatment according to the invention can be directed toward individual disorders, i.e. anomalies or pathological conditions, it is also possible for several anomalies, which may be causatively linked to each other, to be combined into patterns, i.e. syndromes, which can be treated in accordance with the invention.
In one aspect of the invention, the diseases to be treated are disorders are damage of the central nervous system, disorders of the central nervous system, eating disorders, ocular hypertension, cardiovascular disorders, gastrointestinal disorders and diabetes.
Disorders or diseases of the central nervous system are understood as meaning disorders which affect the spinal cord and, in particular, the brain. These are, for example, cognitive dysfunction, attention deficit disorder/hyperactivity syndrome and cognitive deficits related with schizophrenia, attention deficit/hyperactivity syndrome, personality disorders, affective disorders, motion or motor disorders, pain, migraine, sleep disorders (including disturbances of the Circadian rhythm), feeding disorders, diseases associated with neurodegeneration, addiction diseases, obesity or psoriasis.
Examples of cognitive dysfunction are deficits in memory, cognition, and learning, Alzheimer's disease, age-related cognitive decline, and mild cognitive impairment, or any combinations thereof. Examples of personality disorders are schizophrenia and cognitive deficits related to schizophrenia. Examples of affective disorders are depression, anxiety, bipolar disorder and obsessive compulsive disorders, or any combination thereof. Examples of motion or motor disorders are Parkinson's disease and epilepsy. Examples of feeding disorders are obesity, bulimia, weight loss and anorexia, especially anorexia nervosa. Examples of diseases associated with neurodegeneration are stroke, spinal or head trauma, and head injuries, such as hydrocephalus.
Pain condition includes nociceptive pain, neuropathic pain or a combination thereof. Such pain conditions or disorders can include, but are not limited to, post-operative pain, osteoarthritis pain, pain due to inflammation, rheumatoid arthritis pain, musculoskeletal pain, burn pain (including sunburn), ocular pain, the pain associated with dental conditions (such as dental caries and gingivitis), post-partum pain, bone fracture, herpes, HIV, traumatic nerve injury, stroke, post-ischemia, fibromyalgia, reflex sympathetic dystrophy, complex regional pain syndrome, spinal cord injury, sciatica, phantom limb pain, diabetic neuropathy, hyperalgesia and cancer.
In certain other embodiments, the disease condition is bladder dysfunction, including urinary incontinence.
Diabetes includes diabetes insipidus, diabetes mellitus, type I diabetes, type II diabetes, type III diabetes, diabetes secondary to pancreatic diseases, diabetes related to steroid use, diabetes complications, hyperglycemia and insulin resistance.
The addiction diseases include psychiatric disorders and behavioral disturbances which are caused by the abuse of psychotropic substances, such as pharmaceuticals or narcotics, and also other addiction diseases, such as addiction to gaming (impulse control disorders not elsewhere classified). Examples of addictive substances are: opioids (e.g. morphine, heroin and codeine), cocaine; nicotine; alcohol; substances which interact with the GABA chloride channel complex, sedatives, hypnotics and tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants, such as 3,4-methylenedioxy-N-methylamphetamine (ecstasy); amphetamine and amphetamine-like substances such as methylphenidate, other stimulants including caffeine and nicotine. Addictive substances which come particularly into consideration are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol. Especially, addiction disorders include alcohol abuse, cocaine abuse, tobacco abuse and smoking cessation.
With regard to the treatment of addiction diseases, particular preference is given to those compounds according to the invention of the formula (I) which themselves do not possess any psychotropic effect. This can also be observed in a test using rats, which, after having been administered compounds which can be used in accordance with the invention, reduce their self administration of psychotropic substances, for example cocaine.
Examples of gastrointestinal disorders are irritable bowel syndrome.
Preferably, the disorders are selected from the group consisting of bipolar disorder, depression, atypical depression, mood episodes, adjustment disorders, anxiety, panic disorders, post-traumatic syndrome, psychoses, schizophrenia, cognitive deficits of schizophrenia, memory loss, dementia of aging, Alzheimer's disease, neuropsychiatric symptoms in Alzheimer's disease (e.g. aggression), behavioral disorders associated with dementia, social phobia, mental disorders in childhood, attention deficit hyperactivity disorder, organic mental disorders, autism, mutism, disruptive behavior disorder, impulse control disorder, borderline personality disorder, obsessive compulsive disorder, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, seizure disorders, epilepsy, substance use disorders, alcohol abuse, cocaine abuse, tobacco abuse, smoking cessation, sexual dysfunction/erectile dysfunction in males, sexual dysfunction in females, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea, chronic fatigue syndrome, psoriasis, Parkinson's disease, psychosis in Parkinson's disease, neuropsychiatric symptoms in Parkinson's disease (e.g. aggression), Lewy Body dementia, neuropsychiatric symptoms in Lewy Body dementia (e.g. aggression), spinal cord injury, trauma, stroke, pain, bladder dysfunction/urinary incontinence, encephalitis, meningitis, eating disorders, obesity, bulimia, weight loss, anorexia nervosa, ocular hypertension, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus, diabetes mellitus, type I diabetes, type II diabetes, type III diabetes, diabetes secondary to pancreatic diseases, diabetes related to steroid use, diabetes complications, hyperglycemia and insulin resistance, and are specifically schizophrenia, depression, bipolar disorders, obesity, substance use disorders, neuropsychiatric symptoms in Alzheimer's disease (e.g. aggression) or neuropsychiatric symptoms in Parkinson's disease (e.g. aggression).
The compounds of the invention may be used for a preventive treatment (prophylaxis), in particular as relapse prophylaxis or phase prophylaxis, but are preferably used for a treatment in its proper sense (i.e. non-prophylactic), i.e. for the treatment of acute or chronic signs, symptoms and/or malfunctions. The treatment can be orientated symptomatically, for example as the suppression of symptoms. It can be effected over a short period, be orientated over the medium term or can be a long-term treatment, for example within the context of a maintenance therapy.
In another embodiment, the present invention relates to the use of a compound I as defined above or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing (the development of) a disease condition as described above and to a method for preventing (the development of) a disease condition as described above comprises administering to the subject in need of treatment thereof (e.g., a mammal, such as a human) a therapeutically effective amount of a compound I as defined above or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof. As used herein, the term “prevent” a disease condition by administration of any of the compounds described herein means that the detectable physical characteristics or symptoms of the disease or condition do not develop following the administration of the compound described herein. Alternatively, the method comprises administering to the subject a therapeutically effective amount of a compound I as defined above or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of at least one cognitive enhancing drug.
In yet another embodiment, the present invention relates to the use a compound I as defined above or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for preparing a medicament for preventing the progression (e.g., worsening) of a disease condition and to a method for preventing the progression (e.g., worsening) of a disease condition, which method comprises administering to the subject in need of treatment thereof (e.g., a mammal, such as a human) a therapeutically effective amount of a compound I as defined above or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof.
There are several lines of evidence suggesting that 5-HT_2Cagonists or partial agonists would have therapeutic use in a variety of diseases, disorders and conditions.
Knockout mice models lacking the 5-HT_2Creceptor exhibit hyperphagia, obesity and are more prone to seizures and sudden death [Tecott L H, Sun L M, Akana S F, Strack A M, Lowenstein D H, Dallman M F, Julius D (1995) Eating disorder and epilepsy in mice lacking 5-HT_2Cserotonin receptors. Nature 374:542-546]. They also exhibit compulsive-like behavior [Chou-Green J M, Holscher T D, Dallman M F, Akana S F (2003). Compulsive behavior in the 5-HT_2Creceptor knockout mouse. Phys. Behav. 78:641-649], hyperresponsiveness to repeated stress [Chou-Green J M, Holscher T D, Dallman M F, Akana S F (2003). Repeated stress in young and old 5-HT_2Creceptor knockout mouse. Phys. Behav. 79:217-226], wakefulness [Frank M G, Stryker M P, Tecott L H (2002). Sleep and sleep homeostasis in mice lacking the 5-HT_2Creceptor. Neuropsychopharmacology 27:869-873], hyperactivity and drug dependence [Rocha. B A, Goulding E H, O'Dell L E, Mead A N, Coufal N G, Parsons L H, Tecott L H (2002). Enhanced locomotor, reinforcing and neurochemical effects of cocaine in serotonin 5-hydroxytryptamine 2C receptor mutant mice. J. Neurosci. 22:10039-10045].
5-HT_2Cis unique among other G-protein-coupled receptors (GPCRs) in that its pre-mRNA is a substrate for base modification via hydrolytic deamination of adenosines to yield inosines. Five adenosines, located within a sequence encoding the putative second intracellular domain can be converted to inosines. This editing can alter the coding potential of the triplet codons and allows for the generation of multiple different receptor isoforms. The edited receptor isoforms were shown to have reduced ability to interact with G-proteins in the absence of agonist stimulation [Werry, T D, Loiacono R, Sexton P A, Christopoulos A (2008). RNA editing of the serotonin 5-HT_2Creceptor and its effects on cell signaling, pharmacology and brain function. Pharmac. Therap. 119:7-23].
Edited 5-HT_2Cisoforms with reduced function are significantly expressed in the brains of depressed suicide victims [Schmauss C (2003) Serotonin 2C receptors: suicide, serotonin, and runaway RNA editing. Neuroscientist 9:237-242. Iwamoto K, Kato T (2003). RNA editing of serotonin 2C receptor in human postmortem brains of major mental disorders. Neurosci. Lett. 346:169-172] and in the learned helplessness rats (a well established animal model of depression) [Iwamotoa K, Nakatanib N, Bundoa M, Yoshikawab T, Katoa T (2005). Altered RNA editing of serotonin 2C receptor in a rat model of depression. Neurosci. Res. 53: 69-76] suggesting a link between 5-HT_2Cfunction and depression. There are also implications of edited 5-HT_2Cisoforms and spatial memory [Du Y, Stasko M, Costa A C, Davissone M T, Gardiner K J (2007). Editing of the serotonin 2C receptor pre-mRNA Effects of the Morris Water Maze. Gene 391:186-197]. In addition, fully edited isoforms of the human 5-HT_2Creceptor display a striking reduction in sensitivity to lysergic acid diethylamide (LSD) and to atypical antipsychotic drugs clozapine and loxapine, suggesting a possible role of the receptor in the etiology and pharmacology of schizophrenia [Niswender C M, Herrick-Davis K., Dilley G E, Meltzer H Y, Overholser J C, Stockmeier C A, Emeson R B, Sanders-Bush E (2001). RNA Editing of the Human Serotonin 5-HT_2CReceptor: Alterations in Suicide and Implications for Serotonergic Pharmacotherapy. Neuropsychopharm. 24:478-491].
Recently, the availability of potent and selective 5-HT_2Creceptor agonists made it possible to directly investigate the effects of 5-HT_2Cagonists and their therapeutic potential. Thus recent studies demonstrated that selective 5-HT_2Cagonists resulted in decreased food intake and body weight gain in normal and obese rats [Smith B M, et al. (2008). Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT_2Creceptor agonist for the treatment of obesity. J Med Chem 51:305-313. Thomsen W J, Grottick A J, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D, Whelan K, Martin M, Morgan M, Chen W, Al-Shama H, Smith B, Chalmers D, Behan D (2008) Lorcaserin, A Novel Selective Human 5-HT_2CAgonist: In Vitro and In Vivo Pharmacological Characterization. J Pharmacol Exp Ther. 325:577-587. Rosenzweig-Lipson S, Zhang J, Mazandarani H, Harrison B L, Sabb A, Sabalski J, Stack G, Welmaker G, Barrett J E, Dunlop J (2006) Antiobesity-like effects of the 5-HT_2Creceptor agonist WAY-161503. Brain Res. 1073-1074:240-251. Dunlop J, Sabb A L, Mazandarani H, Zhang J, Kalgaonker S, Shukhina E, Sukoff S, Vogel R L, Stack G, Schechter L, Harrison B L, Rosenzweig-Lipson S (2005). WAY-163909 [97bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a novel 5-hydroxytryptamine 2C receptor-selective agonist with anorectic activity. J Pharmacol Exp Ther. 313:862-869.].
Furthermore, selective 5-HT_2Creceptor agonists produce antidepressant effects in animal models of depression comparable to those of SSRIs but with a much faster onset of action and a therapeutic window that avoids antidepressant-induced sexual dysfunction. These agonists were also effective in animal models of compulsive behavior such as scheduled induced polydipsia and they also exhibited decreased hyperactivity and aggression in rodents [Rosenzweig-Lipson S, Sabb A, Stack G, Mitchell P, Lucki I, Malberg J E, Grauer S, Brennan J, Cryan J F, Sukoff Rizzo S J, Dunlop J, Barrett J E, Marquis K L (2007) Antidepressant-like effects of the novel, selective, 5-HT_2Creceptor agonist WAY-163909 in rodents. Psychopharmacology (Berlin) 192:159-170. Rosenzweig-Lipson S, Dunlop J, Marquis K L (2007) 5-HT_2Creceptor agonists as an innovative approach for psychiatric disorders. Drug news Perspect, 20: 565-571. Cryan, J F, Lucki I (2000). Antidepressant-like behavioral effects mediated by 5-Hydroxytryptamine 2C receptors. J. Pharm. Exp. Ther. 295:1120-1126.].
Acute or chronic administration of 5-HT_2Cagonists decreases the firing rate of ventral tegmental area dopamine neurons but not that of substantia nigra. In addition 5-HT_2Cagonists reduce dopamine levels in the nucleus accumbens but not in the striatum (the region of the brain mostly associated with extrapyramidal side effects) [Di Matteo, V., Di Giovanni, G., Di Mascio, M., & Esposito, E. (1999). SB 242084, a selective serotonin 2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system. Neuropharmacology 38, 1195-1205. Di Giovanni, G., Di Matteo, V., Di Mascio, M., & Esposito, E. (2000). Preferential modulation of mesolimbic vs. nigrostriatal dopaminergic function by serotonin2C/2B receptor agonists: a combined in vivo electrophysiological and microdialysis study. Synapse 35, 53-61. Marquis K L, Sabb A L, Logue S F, Brennan J A, Piesla M J, Comery T A, Grauer S M, Ashby C R, Jr., Nguyen H Q, Dawson L A, Barrett J E, Stack G, Meltzer H Y, Harrison B L, Rosenzweig-Lipson S (2007) WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: A novel 5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity. J Pharmacol Exp Ther 320:486-496.]. Therefore it is expected that 5-HT_2Creceptor agonists will selectively decrease mesolimibic dopamine levels without affecting the nigrostriatal pathway thus avoiding the EPS side effects of typical antipsychotics. Several 5-HT_2Creceptor agonists have shown antipsychotic activity in animal models of schizophrenia without EPS based on the lack of effect in catalepsy [Marquis K L, Sabb A L, Logue S F, Brennan J A, Piesla M J, Comery T A, Grauer S M, Ashby C R, Jr., Nguyen H Q, Dawson L A, Barrett J E, Stack G, Meltzer H Y, Harrison B L, Rosenzweig-Lipson S (2007) WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: A novel 5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity. J Pharmacol Exp Ther 320:486-496. Siuciak J A, Chapin D S, McCarthy S A, Guanowsky V, Brown J, Chiang P, Marala R, Patterson T, Seymour P A, Swick A, Iredale P A (2007) CP-809,101, a selective 5-HT_2Cagonist, shows activity in animal models of antipsychotic activity. Neuropharmacology 52:279-290]. The antipsychotic activity of 5-HT_2Creceptor agonists without EPS coupled with their beneficial effects in mood disorders and cognition and their antiobesity like effects render 5-HT_2Creceptor agonists as unique agents to treat schizophrenia [Rosenzweig-Lipson S, Dunlop J, Marquis K L (2007) 5-HT_2Creceptor agonists as an innovative approach for psychiatric disorders. Drug news Perspect, 20: 565-571. Dunlop J, Marquis K L, Lim H K, Leung L, Kao J, Cheesman C, Rosenzweig-Lipson S (2006). Pharmacological profile of the 5-HT_2Creceptor agonist WAY-163909; therapeutic potential in multiple indications. CNS Dug Rev. 12:167-177.].
In addition 5-HT_2Cmodulation has been implicated in epilepsy [Isaac M (2005). Serotonergic 5-HT_2Creceptors as a potential therapeutic target for the antiepileptic drugs. Curr. Topics Med. Chem. 5:59:67], psoriasis [Thorslund K, Nordlind K (2007). Serotonergic drugs—a possible role in the treatment of psoriasis? Drug News Perspect 20:521-525], Parkinson's disease and related motor disorders [Esposito E, Di Matteo V, Pierucci M, Benigno A, Di Giavanni, G (2007). Role of central 5-HT_2Creceptor in the control of basal ganglia functions. The Basal Ganglia Pathophysiology: Recent Advances 97-127], behavioral deficits [Barr A M, Lahmann-Masten V, Paulus M, Gainetdinov R P, Caron M G, Geyer M A (2004). The selective serotonin-2A receptor antagonist M100907 reverses behavioral deficits in dopamine transporter knockout mice. Neuropsychopharmacology 29:221-228], anxiety [Dekeyne A, Mannoury la Cour C, Gobert A, Brocco M, Lejuene F, Serres F, Sharp T, Daszuta A, Soumier A, Papp M, Rivet J M, Flik G, Cremers T I, Muller O, Lavielle G, Millan M J (2208). 532006, a novel 5-HT_2Creceptor antagonists displaying broad-based antidepressant and anxiolytic properties in rodent models. Psychopharmacology 199:549-568. Nunes-de-Souza V, Nunes-de-Souza R L, Rodgers R J, Canto-de-Souza A (2008). 5-HT2 receptor activation in the midbrain periaqueductal grey (PAG) reduces anxiety-like behavior in mice. Behav. Brain Res. 187:72-79.], migraine [Leone M, Rigamonti A, D'Amico D, Grazzi L, Usai S, Bussone G (2001). The serotonergic system in migraine. Journal of Headache and Pain 2 (Suppl. 1):S43-S46], Alzheimer's disease [Atjona A A, Pooler A M, Lee R K, Wurtman R J (2002). Effect of a 5-HT_2Cserotonin agonist, dexnorfenfluramine, on amyloid precursor protein metabolism in guinea pigs. Brain Res. 951:135-140], pain and spinal cord injury [Nakae A, Nakai K, Tanaka T, Hagihira S, Shibata M, Ueda K, Masimo T (2008). The role of RNA editing of the serotonin 2C receptor in a rat model of oro-facial neuropathic pain. The European Journal of Neuroscience 27:2373-2379. Nakae A, Nakai. K, Tanaka T, Takashina M, Hagihira S, Shibata M, Ueda K, Mashimo T (2008). Serotonin 2C receptor mRNA editing in neuropathic pain model. Neurosci. Res. 60:228-231. Kao T, Shumsky J S, Jacob-Vadakot S, Timothy H B, Murray M, Moxon, K A (2006). Role of the 5-HT_2Creceptor in improving weight-supported stepping in adult rats spinalized as neonates. Brain Res. 1112:159-168.], sexual dysfunction [Motofei I G (2008). A dual physiological character for sexual function: the role of serotonergic receptors. BJU International 101:531-534. Shimada I, Maeno K, Kondoh Y, Kaku H, Sugasawa K Kimura Y, Hatanaka K.; Naitou Y, Wanibuchi F, Sakamoto S.; Tsukamoto S (2008). Synthesis and structure-activity relationships of a series of benzazepine derivatives as 5-HT_2Creceptor agonists. Bioorg. Med. Chem. 16:3309-3320.], smoking cessation [Fletcher P J, Le A D, Higgins G A (2008). Serotonin receptors as potential targets for modulation of nicotine use and dependence. Progress Brain Res. 172:361-83], substance dependence [Bubar M J, Cunningham K A (2008). Prospects for serotonin 5-HT2R pharmacotherapy in psychostimulant abuse. Progress Brain Res. 172:319-46], and ocular hypertension [Sharif N A, McLaughlin M A, Kelly C R (2006). AL-34662: a potent, selective, and efficacious ocular hypotensive serotonin-2 receptor agonist. J Ocul Pharmacol Ther. 23:1-13].
Further, 5HT modulation can be useful in the treatment of pain, both neuropathic and nociceptive pain, see for example U.S. Patent application publication US2007/0225277. Obata, Hideaki; Ito, Naomi; Sasaki, Masayuki; Saito, Shigeru; Goto, Fumio. Possible involvement of spinal noradrenergic mechanisms in the antiallodynic effect of intrathecally administered 5-HT2C receptor agonists in the rats with peripheral nerve injury. European Journal of Pharmacology (2007), 567(1-2), 89-94. Serotonin2C receptor mRNA editing in neuropathic pain model. Nakae, Aya;
Nakai, Kunihiro; Tanaka, Tatsuya; Takashina, Masaki; Hagihira, Satoshi; Shibata, Masahiko; Ueda, Koichi; Mashimo, Takashi. Department of Anesthesiology & Intensive Care Medicine, Graduate School of Medicine, Osaka University, Neuroscience Research (Amsterdam, Netherlands) (2008), 60(2), 228-231. Antiallodynic effects of intrathecally administered 5-HT2C receptor agonists in rats with nerve injury. Obata, Hideaki; Saito, Shigeru; Sakurazawa, Shinobu; Sasaki, Masayuki; Usui, Tadashi; Goto, Fumio. Department of Anesthesiology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan. Pain (2004), 108(1-2), 163-169. Influence of 5,7-dihydroxytryptamine (5,7-DHT) on the antinociceptive effect of serotonin (5-HT) 5-HT2C receptor agonist in male and female rats. Brus, Ryszard; Kasperska, Alicja; Oswiecimska, Joanna; Szkilnik, Ryszard. Department of Pharmacology, Silesian Medical University, Zabrze, Pol. Medical Science Monitor (1997), 3(5), 654-656.
Modulation of 5HT2 receptors may be beneficial in the treatment of conditions related to bladder function, in particular, urinary incontinence. [Discovery of a novel azepine series of potent and selective 5-HT2C agonists as potential treatments for urinary incontinence. Brennan, Paul E.; Whitlock, Gavin A.; Ho, Danny K. H.; Conlon, Kelly; McMurray, Gordon. Bioorganic & Medicinal Chemistry Letters (2009), 19(17), 4999-5003. Investigation of the role of 5-HT2 receptor subtypes in the control of the bladder and the urethra in the anesthetized female rat. Mbaki, Y.; Ramage, A. G. Department of Pharmacology, University College London, London, UK. British Journal of Pharmacology (2008), 155(3), 343-356.] In particular, compounds with agonist activity at 5-H_2Chave been shown to be useful in treating urinary incontinence, see for example U.S. Patent application publications US2008/0146583 and US 2007/0225274.
Further pre-clinical data suggest that 5-HT_2Cagonists could be useful for the treatment of a number of psychiatric diseases, including schizophrenia, bipolar disorders, depression/anxiety, substance use disorders and especially disorders like neuropsychiatric symptoms in Alzheimer's disease: Aggression, psychosis/agitation represent key unmet medical needs. Clinical (Shen J H Q et al., A 6-week randomized, double-blind, placebo-controlled, comparator referenced trial of vabicaserin in acute schizophrenia. Journal of Psychiatric Research 53 (2014) 14-22; Liu J et al., Prediction of Efficacy of Vabicaserin, a 5-HT_2CAgonist, for the Treatment of Schizophrenia Using a Quantitative Systems Pharmacology Model. CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e111) and preclinical data (Dunlop J et al., Characterization of Vabicaserin (SCA-136), a Selective 5-Hydroxytryptamine 2C Receptor Agonist. J Pharmacol Exp Ther (2011) 337, 673-80; Siuciak J et al., CP-809,101, a selective 5-HT_2Cagonist, shows activity in animal models of antipsychotic activity. Neuropharmacology 52 (2007) 279-290; Mosienko V et al., Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin. Transl Psychiatry (2012) 2, e122; Del Guidice T et al., Stimulation of 5-HT_2CReceptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase2 Loss of Function Mutation. Neuropsychopharmacology (2014) 39, 1125-1134; Rosenzweig-Lipson et al., Antidepressant-like effects of the novel, selective, 5-HT_2Creceptor agonist WAY-163909 in rodents. Psychopharmacology (2007) 192:159-170) suggest 5-HT_2Creceptor stimulation to result in therapeutic efficacy in aggression, psychosis agitation and moderate pro-cognitive effects (Del Guidice T et al., Stimulation of 5-HT_2CReceptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase2 Loss of Function Mutation. Neuropsychopharmacology (2014) 39, 1125-1134; Siuciak J et al., CP-809,101, a selective 5-HT_2Cagonist, shows activity in animal models of antipsychotic activity. Neuropharmacology 52 (2007) 279-290).
In the use and the method of the invention, an effective quantity of one or more compounds, as a rule formulated in accordance with pharmaceutical and veterinary practice, is administered to the individual to be treated, preferably a mammal, in particular a human being, productive animal or domestic animal. Whether such a treatment is indicated, and in which form it is to take place, depends on the individual case and is subject to medical assessment (diagnosis) which takes into consideration signs, symptoms and/or malfunctions which are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.
Actual dosage levels of active ingredients in the pharmaceutical compositions of the present invention can be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular subject (e.g., a mammal, preferably, a human (patient)), compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Compounds of the present invention can also be administered to a subject as a pharmaceutical composition comprising the compounds of interest in combination with at least one pharmaceutically acceptable carriers. The phrase “therapeutically effective amount” of the compound of the present invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well-known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The total daily dose of the compounds of this invention administered to a subject (namely, a mammal, such as a human) ranges from about 0.01 mg/kg body weight to about 100 mg/kg body weight. More preferable doses can be in the range of from about 0.01 mg/kg body weight to about 30 mg/kg body weight. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
In one aspect, the present invention provides pharmaceutical compositions. The pharmaceutical compositions of the present invention comprise the compounds of the present invention or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical compositions of the present invention comprise compounds of the present invention that can be formulated together with at least one non-toxic pharmaceutically acceptable carrier.
In yet another embodiment, the present invention provides a pharmaceutical composition comprising compounds of the present invention or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, alone or in combination with one or more compounds that are not the compounds of the present invention. Examples of one or more compounds that can be combined with the compounds of the present invention in pharmaceutical compositions, include, but are not limited to, one or more cognitive enhancing drugs.
The pharmaceutical compositions of this present invention can be administered to a subject (e.g., a mammal, such as a human) orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term “parenterally” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
The term “pharmaceutically acceptable carrier” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
Pharmaceutical compositions of the present invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned carriers.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
Dosage forms for topical administration of a compound of the present invention include powders, sprays, ointments and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase “pharmaceutically acceptable salt” means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq.). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, ethylammonium and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
The compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.
The following examples serve to explain the invention without limiting it.

EXAMPLES

The compounds were either characterized via proton-NMR in d₆-dimethylsulfoxide, d-chloroform or d₄-methanol on a 400 MHz, 500 MHz or 600 MHz NMR instrument (Bruker AVANCE), or by ¹³C-NMR at 125 MHz, or by mass spectrometry, generally recorded via HPLC-MS in a fast gradient on C18-material (electrospray-ionisation (ESI) mode).
The magnetic nuclear resonance spectral properties (NMR) refer to the chemical shifts (δ) expressed in parts per million (ppm). The relative area of the shifts in the ¹H-NMR spectrum corresponds to the number of hydrogen atoms for a particular functional type in the molecule. The nature of the shift, as regards multiplicity, is indicated as singlet (s), broad singlet (s. br.), doublet (d), broad doublet (d br.), triplet (t), broad triplet (t br.), quartet (q), quintet (quint.), multiplet (m), doublet of doublets (dd), doublet of doublets of doublets (ddd) etc.
Enantiomers were separated/purified by chiral supercritical fluid chromatography (SFC) (method A).

Method A:

Analytical Separation Method:

Instrument: Thar analytical SFC
Column: Chiralpak AD-3 3 μm, 0.46 cm id×10 cm L
Mobile phase: A for SFC CO₂and B for EtOH (0.05% IPAm)
Gradient: B in A from 10% to 40% in 5 minutes
Flow rate: 4.0 mL/min

Wavelength: 220 nm

System Back Pressure: 100 bar

Preparative Separation Method:

Instrument: Thar SFC Pre-80

Column: Chiralpak AD-H 5 μm, 3.0 cm id×25 cm L
Mobile phase: A for SFC CO₂and B EtOH (0.05% NH₄OH)

Gradient: A:B=78:22

Flow rate: 60 mL/min

Wavelength: 220 nm

System Back Pressure: 100 bar

Sample preparation: dissolved in Methanol, 14 mg/mL
Injection: 1.0 ml per injection.

IPAm: Isopropylamine

Preparative HPLC was carried out under following conditions:

Method A:

Instrument: Shimadzu LC-20AP preparative HPLC

Column: Luna(2) C18 250*50 mm i.d. 10 u

Mobile phase: A for H₂O (0.075% TFA) and B for MeCN
Gradient: B from 12% to 42% in 20 min
Flow rate: 80 ml/min

Wavelength: 220 &254 nm

Injection amount: 0.65 g per injection

Method B:

Instrument: Gilson 281 semi-preparative HPLC system
Mobile phase: A for H₂O (0.075% TFA) and B for MeCN

Column: Luna C18 100*30, 5 um, 100 A

Flow rate: 25 ml/min
Monitor wavelength: 220&254 nm

Gradient:


	Time	B %

	0.00	80
	12.0	100
	12.2	100
	14.2	100
	14.4	80
	16.0	80

Method C

C.1 Analytical SFC

Analytical samples were run on an Agilent 1260 Infinity Hybrid SFC System, controlled by Agilent OpenLab CDS ChemStation Edition. The system consists of an injector, a heated column compartment including a switch for 6 columns, a CO₂-booster pump, a binary pump module for CO₂and modifier flow and an UV-detector. The backpressure regulator was set to 160 bars and heated to 60° C. If not stated otherwise, the columns were 100 mm in length, 4.6 mm in diameter and packed with 5 μm material. They were kept at room temperature during analysis. As mobile phase, a mixture of liquefied CO₂and organic modifier with additive was used as indicated for each sample. The flow rate was kept at 3.5 mL/min.

C.2 Preparative SFC

Preparative separations were carried out on a Waters Prep 100q SFC System, controlled by Waters MassLynx Software. The system consists of an open bed injector/collector, a heated column compartment including a switch for 6 columns, a CO₂-booster pump, a pump module for modifier flow and an UV-detector. To enable quantitative collection, the gas liquid separator was driven with a make-up flow of 30 mL/min Methanol. The backpressure regulator was set to 120 bar and heated to 60° C. If not stated otherwise, the columns were 250 mm in length, 20 mm in diameter and packed with 5 μm material. They were kept at 30° C. during the separation. As mobile phase, a mixture of liquefied CO₂and organic modifier with additive was used as indicated for each sample. The flow rate was kept at 100 g/min.

LCMS Method:

LC/MS (The gradient was 1-90% B in 3.4 min, 90-100% B in 0.45 min, 100-1% B in 0.01 min, and then held at 1% B for 0.65 min (0.8 mL/min flow rate). Mobile phase A was 0.0375% TFA in water, mobile phase B was 0.018% TFA in MeCN. The column used for the chromatography was a 2.1×50 mm Venusil XBP-C18 column (5 μm particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive/negative electrospray ionization).

Abbreviations:

h hour(s)
min minute(s)
r.t. room temperature (20-25° C.)
PE petroleum ether
EtOH ethanol
MeOH methanol
DCM dichloromethane
DCE dichloroethane
THF tetrahydrofuran
DMF N,N-dimethylformamide
MeCN acetonitrile
EtOAc ethyl acetate
TFA trifluoroacetic acid
DIPEA diisopropylethyl amine
X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

I. Preparation Examples

Example 1

8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline (Compound Ia.1 wherein R⁶is cyclopropyl and R^4a, R^4b, R^5a, R^5band R^7aare hydrogen)

1.1 4-Cyclopropylquinoline

A mixture of 4-bromoquinoline (18 g, 87 mmol), cyclopropylboronic acid (29.7 g, 346 mmol), tricyclohexylphosphine (4.85 g, 17.3 mmol), K₃PO₄(73.5 g, 346 mmol) and PdOAc₂(1.942 g, 8.65 mmol) in toluene (200 mL) and water (20 mL) was stirred for 16 h at 100° C. under N₂. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (PE:EtOAc=10:1) to give the title compound (10 g, yield 61.2%).
¹H NMR (400 MHz; CDCl₃): δ 9.00 (d, J=4.4 Hz, 1H), 8.55 (d, J=8.4 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 7.93 (t, J=8.0 Hz, 1H), 7.80 (t, J=8.0 Hz, 1H), 7.24 (d, J=4.4 Hz, 1H), 2.68-2.61 (m, 1H), 1.42-1.36 (m, 2H), 1.09-1.05 (m, 2H).

1.2 1-(2-Amino-2-oxoethyl)-4-cyclopropylquinolin-1-ium bromide

A mixture of 4-cyclopropylquinoline from step 1.1 (9 g, 53.2 mmol) and 2-bromoacetamide (14.67 g, 106 mmol) in EtOH (100 mL) was stirred at 90° C. for 16 h. After cooling to 20° C., the mixture was filtered, and the residue was dried in high vacuum to give the title compound (9 g, yield 55.1%).
¹H NMR (400 MHz; d₆-DMSO): δ 9.24 (d, J=6.0 Hz, 1H), 8.88 (d, J=8.0 Hz, 1H), 8.24-8.13 (m, 3H), 8.03 (t, J=8.0 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=6.4 Hz, 1H), 5.71 (s, 2H), 3.11-3.05 (m, 1H), 1.55-1.52 (m, 2H), 1.34-1.31 (m, 2H).

1.3 2-(4-Cyclopropyl-2H-quinolin-1-yl)acetamide

To a solution of 1-(2-amino-2-oxoethyl)-4-cyclopropylquinolin-1-ium bromide from step 1.2 (9 g, 29.3 mmol) in MeOH (200 mL), NaBH₄(11.08 g, 293 mmol) was added in portions at 0° C., and then the mixture was stirred at 60° C. for 2 hours. After cooled to 20° C., water (50 mL) was added, and the reaction mixture was extracted with DCM (50 mL×2), and the organic phase was dried with Na₂SO₄, concentrated under reduced pressure to give crude title compound (5 g, 74.8% yield), which was used directly in the next step.
LCMS (ESI⁺): m/z 228.9 (M+H)⁺, RT: 1.03 min.

1.4 2-(4-Cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)acetamide

To a solution of 2-(4-cyclopropyl-2H-quinolin-1-yl)acetamide from step 1.3 (5 g, 21.9 mmol) in MeOH (100 mL), Raney Ni (1.286 g, 21.9 mmol) was added under Ar, and the reaction mixture was stirred for 12 h at 20° C. under H₂(15 psi of pressure). Then the mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (method A) to give the title compound (1.8 g, yield 35.7%)
¹H NMR (400 MHz; CDCl₃): δ 7.18 (d, J=7.2 Hz, 1H), 6.93 (t, J=7.2 Hz, 1H), 6.57 (t, J=7.6 Hz, 1H), 6.45 (s, 1H), 6.25 (d, J=8.4 Hz, 1H), 6.25 (s, 1H), 3.65 (s, 2H), 3.30-3.27 (m, 1H), 3.16-3.14 (m, 1H), 1.96-1.81 (m, 3H), 0.73-0.70 (m, 1H), 0.53-0.52 (m, 1H), 0.33-0.32 (m, 1H), 0.27-0.23 (m, 1H), 0.05-0.02 (m, 1H)

1.5 2-(4-Cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 2-(4-cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)acetamide from step 1.4 (1.8 g, 7.82 mmol) in THF (50 mL), a solution of BH₃-THF (15.6 mL, 15.63 mmol) was added at 0° C., and the reaction solution was stirred for 12 h at 70° C. After cooling to 20° C., MeOH (20 mL) was added dropwise at 0° C. The reaction solution was stirred for 30 minutes at 20° C. and then concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (method A) to give the title compound (900 mg, yield 53.2%)
¹H NMR (400 MHz; CDCl₃): δ 7.81 (s, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.93 (t, J=7.6 Hz, 1H), 6.57-6.49 (m, 2H), 3.41-3.38 (m, 3H), 3.33-3.19 (m, 1H), 3.08-3.07 (m, 1H), 2.99-2.96 (m, 2H), 1.89-1.86 (m, 1H), 1.80-1.73 (m, 2H), 0.71-0.68 (m, 1H), 0.53-0.52 (m, 1H), 0.35-0.32 (m, 1H), 0.25-0.22 (m, 1H), 0.05-0.02 (m, 1H)

1.6 8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

To a solution of 2-(4-cyclopropyl-3,4-dihydroquinolin-1(2H)-yl)ethanamine from step 1.5 (900 mg, 4.16 mmol) and 37% formaldehyde solution (0.93 mL, 12.48 mmol) in EtOH (15 mL), TFA (0.962 mL, 12.48 mmol) was added at 0° C., and the reaction mixture was stirred for 2 h at 80° C. Then the reaction solution was concentrated under reduced pressure and the residue was purified by preparative HPLC (method A) to give the title compound (500 mg, yield 52.6%).
LCMS (ESI⁺): m/z 229.1 (M+H)⁺, RT: 0.979 min.

1.7 Racemic Resolution of 8-cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline to (S)-8-cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline and (R)-8-cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline (500 mg, 2.19 mmol) was separated by chiral SFC (method A) to give enantiomer 1.A (107.7 mg, yield 21.5%), and enantiomer 1.B (125.6 mg, yield 25.1%).
Enantiomer 1.A was collected from 7.0 min to 9.6 min; and enantiomer 1.B was collected from 10.2 min to 12.8 min.
¹H NMR of enantiomer 1.A (400 MHz; CD₃OD): δ 7.33 (d, J=7.6 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 6.78 (t, J=7.6 Hz, 1H), 3.85 (s, 2H), 3.43-3.41 (m, 1H), 3.29-3.26 (m, 1H), 3.14-3.12 (m, 2H), 3.06-3.04 (m, 2H), 2.06-1.96 (m, 2H), 1.86-1.84 (m, 1H), 0.87-0.85 (m, 1H), 0.71-0.69 (m, 1H), 0.51-0.46 (m, 2H), 0.25-0.24 (m, 1H)
LCMS (ESI⁺) of enantiomer A: m/z 229.1 (M+H)⁺, RT: 2.455 min.
¹H NMR of enantiomer 1.B (400 MHz; CD₃OD): δ 7.45 (d, J=7.6 Hz, 1H), 7.12 (d, J=7.2 Hz, 1H), 6.87 (t, J=7.6 Hz, 1H), 4.16 (s, 2H), 3.48-3.43 (m, 1H), 3.32-3.30 (m, 5H), 2.07-1.98 (m, 2H), 1.87-1.86 (m, 1H), 0.87-0.85 (m, 1H), 0.71-0.69 (m, 1H), 0.51-0.46 (m, 2H), 0.26-0.25 (m, 1H)
LCMS (ESI⁺) of enantiomer B: m/z 229.1 (M+H)⁺, RT: 2.460 min.

Example 2

8-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline (Compound Ia.1 wherein R⁶is cyclobutyl and R^4a, R^4b, R^5a, R^5band R^7aare hydrogen)

2.1 4-Cyclobutylquinoline

A mixture of 4-bromoquinoline (600 mg, 2.88 mmol), di(adamantan-1-yl)(butyl)-phosphine (70 mg, 0.195 mmol), Pd(OAc)₂(26 mg, 0.116 mmol), potassium cyclobutyltrifluoroborate (600 mg, 3.70 mmol) and Cs₂CO₃(2819 mg, 8.65 mmol) in toluene (11 mL) and water (1.1 mL) was heated at 100° C. for 72 h under N₂. After cooling to 25° C., water (20 mL) was added, and the mixture was extracted with EtOAc (30 mL×2). The organic phase was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (method A) to give the title compound (300 mg, 56.8% yield) as yellow oil.
¹H NMR (400 MHz; CDCl₃): δ 8.85 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.93-7.91 (m, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.54-7.50 (m, 1H), 7.26 (d, J=4.9 Hz, 1H), 4.19-4.10 (m, 1H), 2.59-2.51 (m, 2H), 2.36-2.26 (m, 2H), 2.24-2.13 (m, 1H), 1.97-1.90 (m, 1H)

2.2 1-Benzyl-4-cyclobutyl-quinolin-1-ium bromide

A mixture of 4-cyclobutylquinoline from step 2.1 (100 mg, 0.546 mmol) and (bromomethyl)benzene (747 mg, 4.37 mmol) in toluene (15 mL) was stirred for 12 h at 80° C. After cooling, the resulting mixture was filtered and the residue was dried by high vacuum to give the title compound (50 mg, yield 13%), which was used in the next step without further purification.

2.3 1-Benzyl-4-cyclobutyl-1,2,3,4-tetrahydroquinoline

To a solution of 1-benzyl-4-cyclobutyl-quinolin-1-ium bromide from step 2.2 (200 mg, 0.565 mmol) in MeOH (20 mL) was added NaBH₄(320 mg, 8.47 mmol) in portions at 25° C. and the reaction mixture was stirred for 3 h at 25° C. Then Raney nickel (128 mg, 2.179 mmol) was added at 25° C. under Ar, and the reaction solution was stirred for 2 h at 15 psi pressure of H₂. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (method B) to give the title compound (100 mg, yield 49.6%).
¹H NMR (400 MHz; CDCl₃): δ 7.26-7.14 (m, 5H), 6.93-6.89 (m, 2H), 6.5-6.43 (m, 2H), 4.42 (t, J=4.9 Hz, 2H), 3.34-3.27 (m, 1H), 3.20-3.14 (m, 1H), 2.63-2.58 (m, 1H), 2.47-2.37 (m, 1H), 2.01-1.83 (m, 4H), 1.78-1.65 (m, 4H).

2.4 4-Cyclobutyl-1,2,3,4-tetrahydroquinoline

To a solution of 1-benzyl-4-cyclobutyl-1,2,3,4-tetrahydroquinoline from step 2.3 (195 mg, 0.703 mmol) in DCE (20 mL), 1-chloroethyl carbonochloridate (502 mg, 3.51 mmol) was added and the solution was heated to 80° C. for 12 h under N₂. After cooling to 20° C., MeOH (5 mL) was added and the resulting solution was heated to 80° C. for 3 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (method A, however gradient: B from 5% to 35% in 20 min and 0.25 g per injection) to give the title compound (126 mg, yield 96%).
¹H NMR (400 MHz; CDCl₃): δ 6.92-6.88 (m, 2H), 6.52-6.48 (m, 1H), 6.30 (d, J=8.0 Hz, 1H), 3.23-3.15 (m, 2H), 2.57-2.55 (m, 1H), 2.45-2.35 (m, 1H), 2.0-1.9 (m, 3H), 1.73-1.66 (m, 6H).

2.5 2-(4-Cyclobutyl-3,4-dihydroquinolin-1(2H)-yl)acetamide

To a solution of 4-cyclobutyl-1,2,3,4-tetrahydroquinoline from step 2.4 (100 mg, 0.534 mmol) in DMF (20 mL), 2-iodoacetamide (593 mg, 3.2 mmol) was added and the solution was heated to 120° C. for 12 h under N₂. Water (20 mL) was added; the mixture was extracted with EtOAc (50 mL×2), and the organic phase was washed with HCl (20 mL, 1N) and brine, dried and concentrated under reduced pressure to give the title compound (100 mg, yield 77%).
¹H NMR (400 MHz; CDCl₃): δ 7.04-6.96 (m, 2H), 6.64-6.60 (m, 1H), 6.438 (d, J=8.0 Hz, 1H), 6.35 (s, 1H), 5.35 (s, 1H), 3.82-3.69 (m, 2H), 3.29-3.25 (m, 1H), 3.17-3.14 (m, 1H), 2.62-2.59 (m, 1H), 2.39-2.35 (m, 1H), 1.98-1.85 (m, 4H), 1.75-1.69 (m, 4H).

2.6 2-(4-Cyclobutyl-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 2-(4-cyclobutyl-3,4-dihydroquinolin-1(2H)-yl)acetamide from step 2.5 (150 mg, 0.614 mmol) in THF (20 mL), BH₃.THF (5 mL, 5 mmol) was added, and the solution was heated to 80° C. for 12 h under N₂. After cooling to 25′C, MeOH (15 mL) was added dropwise, and the reaction solution mixture was stirred 30 minutes at 25° C. Then the resulting solution was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the title compound (100 mg, yield 77%) (method B, however with following gradient:
Time B %

0.00 15

12.0 55

12.1 55

12.2 100

13.5 100

13.6 15

15.0 15)

¹H NMR (400 MHz; CD₃OD): δ 7.04-6.96 (m, 2H), 6.54 (d, J=8.0, 1H), 6.58-6.54 (m, 1H), 3.59-3.51 (m, 2H), 3.21-3.11 (m, 3H), 3.82-3.69 (m, 2H), 3.29-3.25 (m, 1H), 3.17-3.14 (m, 1H), 2.62-2.59 (m, 1H), 2.65-2.55 (m, 1H), 2.5-2.4 (m, 1H), 2.06-1.76 (m, 9H).

2.7 8-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

To a solution of 2-(4-cyclobutyl-3,4-dihydroquinolin-1(2H)-yl)ethanamine from step 2.6 (150 mg, 0.651 mmol) in EtOH (20 mL), formaldehyde (0.448 mL, 6.51 mmol) and TFA (0.502 mL, 6.51 mmol) were added and the reaction mixture was heated at 80° C. for 2 h under N₂. The resulting solution was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the title compound (50 mg, yield 31.3%) (method B, however with following gradient:


	Time	B %

	0.00	10
	12.0	50
	12.1	50
	12.2	100
	13.5	100
	13.6	10
	15.0	10).

Example 3

8-(3-Methyloxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline (Compound Ia.1 wherein R⁶is 3-methyloxetan-3-yl and R^4a, R^4b, R^5a, R^5band R^7aare hydrogen)

3.1 4-(3-Methyloxetan-3-yl)-3,4-dihydroquinolin-2(1H)-one

In a 5 mL microwave vial containing 3-(3-methyloxetan-3-yl)-acrylic acid ethyl ester (500 mg, 0.588 mmol, 1.00 eq), 2-aminophenyl boronic ester (805 mg, 1.18 mmol, 2.00 eq), potassium carbonate (812 mg, 1.18 mmol, 2.00 eq) and [RhOH(COD)]₂(67 mg, 0.029 mmol, 0.05 eq) was added 2% wt. TPGS-750-M solution in water (3 mL) (TPGS-750-M: a surfactant composed of a lipophilic α-tocopherol moiety and a hydrophilic PEG-750-M chain, joined by a succinic acid linker; forms spontaneously micelles upon dissolution in water. From Sigma-Aldrich.). The mixture was stirred vigorously at ambient temperature for 24 h. Then the reaction mixture was extracted with ethyl acetate. The organic phase was dried over MgSO₄, filtrated and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the title compound (680 mg, 96% yield).
¹H NMR (500 MHz, CDCl₃) δ 9.15 (s, 1H), 7.22 (ddd, J=8.0, 6.5, 2.3 Hz, 1H), 7.06-6.97 (m, 2H), 6.89-6.83 (m, 1H), 4.83 (d, J=5.9 Hz, 1H), 4.63 (d, J=5.8 Hz, 1H), 4.41 (d, J=5.7 Hz, 1H), 4.29 (d, J=6.0 Hz, 1H), 3.57 (dd, J=7.3, 4.7 Hz, 1H), 2.70 (dd, J=16.6, 7.3 Hz, 1H), 2.40 (dd, J=16.7, 4.7 Hz, 1H), 1.32 (s, 3H) ppm.
¹³C NMR (125 MHz, CDCl₃) δ 171.45, 137.42, 128.34, 128.06, 123.40, 122.79, 116.16, 82.07, 81.95, 43.56, 42.78, 31.98, 19.10 ppm.
ESI-MS: m/z (%): 218.20 (100, [M+H]⁺).

3.2 4-(3-Methyloxetan-3-yl)-1,2,3,4-tetrahydroquinoline

640 mg of 4-(3-methyloxetan-3-yl)-3,4-dihydroquinolin-2(1H)-one from step 3.1 (2.95 mmol, 1.00 eq) was dissolved in 2 mL of THF (anhydrous) and 5.89 mL of borane tetrahydrofurane complex (5.89 mmol, 1 M in THF, 2.00 eq) was slowly added. The mixture was heated in a microwave at 60° C. for 20 min. Then the reaction mixture was quenched with HCl (1 M) and the aqueous phase was extracted with ethyl acetate. Subsequently the organic phase was extracted three times with HCl (1M) and NaOH (1M) was added to the aqueous phase until pH 10. This was then extracted with dichloromethane three times. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the title compound (345 mg, 52% yield).
ESI-MS: m/z (%): 204.10 (100, [M+H]⁺).

3.3 2-(4-(3-Methyloxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

A mixture of 170 mg of 4-(3-methyloxetan-3-yl)-1,2,3,4-tetrahydroquinoline from step 3.2 (0.836 mmol, 1.00 eq), 2-iodoacetamide (309 mg, 1.67 mmol, 2.00 eq) and DIPEA (0.57 ml, 3.35 mmol, 4.00 eq) in DMF (3 mL) was heated in a microwave at 130° C. for 2 h. Then NaOH (1M) was added and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the title compound (136 mg, 56% yield).
ESI-MS: m/z (%): 261.20 (100, [M+H]⁺).

3.4 2-(4-(3-Methyloxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 50 mg of 2-(4-(3-methyloxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide from step 3.3 (0,192 mmol, 1.00 eq) in THF (2 ml) 0.768 mL of lithium aluminium hydride (1 M in THF, 0.768 mmol, 4.00 eq) was slowly added at 0° C. The mixture was stirred at 0° C. for 10 min and was then warmed up to r.t. and stirred for further 6 h at r.t. Then water (0.02 mL) was added followed by 10% aqueous NaOH (0.02 mL) and water (0.069 mL) again. Subsequently MgSO₄was added, the mixture was filtrated and the solvent was evaporated. The crude product was purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the title compound (30 mg, 63% yield).
ESI-MS: m/z (%): 247.20 (100, [M+H]⁺).

3.5 8-(3-Methyloxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 30 mg of 2-(4-(3-methyloxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine from step 3.4 (0.122 mmol, 1.00 eq), formaldehyde (9.5 μL, 0.128 mmol, 1.10 eq) and TFA (10.3 μL, 0.128 mmol, 1.10 eq) in ethanol (1 mL) was stirred at ambient temperature for 2 h. Then NaOH (1M) was added and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the title compound (16 mg, 51% yield).
¹H NMR (600 MHz, CDCl₃) δ 6.98 (d, 1H), 6.74 (t, J=7.5 Hz, 1H), 6.44 (d, J=7.8, 1.3 Hz, 1H), 4.97 (d, J=5.4 Hz, 1H), 4.77 (d, J=5.5 Hz, 1H), 4.50 (dd, J=5.4, 0.8 Hz, 1H), 4.31 (dd, J=5.5, 0.8 Hz, 1H), 3.96 (d, J=14.3 Hz, 1H), 3.84 (d, J=14.3 Hz, 1H), 3.38 (dd, J=10.6, 5.5 Hz, 1H), 3.26-3.22 (m, 2H), 3.13-3.03 (m, 3H), 1.70-1.62 (m, 1H), 1.62-1.52 (m, 1H), 1.28 (s, 3H).
ESI-MS: m/z (%): 259.20 (100, [M+H]⁺).

Example 4

8-(2,2-Difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino [6,7,1-ij]quinoline (Compound Ia.1 wherein R⁶is 2,2-difluorocyclopropyl and R^4a, R^4b, R^5a, R^5band R^7aare hydrogen)

4.1 4-(2,2-Difluorocyclopropyl)-3,4-dihydroquinolin-2(1H)-one

A mixture of 1.26 g of (2,2-difluorocyclopropyl)-acrylic acid ethyl ester (7.16 mmol, 1.00 eq), 1.86 g of 2-aminophenyl boronic ester (13.6 mmol, 1.90 eq), 1.60 g of potassium tert-butoxide (14.3 mmol, 2.00 eq) and 163 mg of [RhOH(COD)]₂(0.358 mmol, 0.05 eq) in dioxane (10 mL) was heated in the microwave at 145° C. for 1 h. Then water and 1M HCl were added and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over MgSO₄, filtrated and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the title product (44%, 3.17 mmol). ESI-MS: m/z (%): 224.10 (100, [M+H]⁺).

4.2 4-(2,2-Difluorocyclopropyl)-1,2,3,4-tetrahydroquinoline

885 mg of 4-(2,2-difluorocyclopropyl)-3,4-dihydroquinolin-2(1H)-one (3.96 mmol, 1.00 eq) from step 4.1 was dissolved in 10 mL of THF (dry) and 5.95 mL of borane tetrahydrofurane complex (1 M in THF, 3.00 eq) were slowly added. The mixture was heated in a microwave at 90° C. for 2 h. Then the reaction mixture was quenched with HCl (1 M) and the aqueous phase was extracted with ethyl acetate. The organic phase was extracted three times with HCl (1M) and to the aqueous phase was added NaOH (1M) until pH 10 and was then extracted with dichloromethane three times. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the desired product (19%, 0.765 mmol).
ESI-MS: m/z (%): 210.15 (100, [M+H]⁺).

4.3 2-(4-(2,2-Difluorocyclopropyl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

A mixture of 180 mg of 4-(2,2-difluorocyclopropyl)-1,2,3,4-tetrahydroquinoline (0.860 mmol, 1.00 eq) from step 4.2, 318 mg 2-iodoacetamide (1.72 mmol, 2.00 eq) and 0.585 mL of DIPEA (3.35 mmol, 4.00 eq) in DMF (2 mL) was heated in a microwave at 100° C. for 8 h. Then NaOH (1M) was added and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the title product (93%, 0.803 mmol). ESI-MS: m/z (%): 267.15 (100, [M+H]⁺).

4.4 2-(4-(2,2-Difluorocyclopropyl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 225 mg of 2-(4-(2,2-difluorocyclopropyl)-3,4-dihydroquinolin-1(2H)-yl)acetamide (0.845 mmol, 1.00 eq) from step 4.3 in THF (10 ml) was added 1.27 mL of borane tetrahydrofurane complex (2 M in THF, 2.53 mmol, 3.00 eq). The mixture was heated in a microwave at 90° C. for 2 h. Then the reaction mixture was quenched with HCl (1 M) and the aqueous phase was extracted with ethyl acetate. The organic phase was extracted three times with HCl (1M) and to the aqueous phase was added NaOH (1M) until pH 10 and was then extracted with dichloromethane three times. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-30% methanol in dichloromethane) to yield the title product (64%, 0.543 mmol).
ESI-MS: m/z (%): 253.15 (100, [M+H]⁺).

4.5 8-(2,2-Difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 137 mg of 2-(4-(2,2-difluorocyclopropyl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine (0.543 mmol, 1.00 eq) from step 4.4, formaldehyde (0.570 mmol, 1.05 eq) and TFA (0.597 mmol, 1.10 eq) in ethanol (5 mL) was stirred at ambient temperature for 24 h. Then NaOH (1M) was added and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the title product (64%, 0.346 mmol).
ESI-MS: m/z (%): 265.20 (100, [M+H]⁺).
¹H NMR (500 MHz, CDCl₃) of mixture of diastereomers: δ 7.21-7.13 (m, 2H), 7.04-6.98 (m, 2H), 6.85 (t, J=7.5 Hz, 1H), 6.77 (t, J=7.5 Hz, 1H), 3.96-3.88 (m, 4H), 3.39-3.17 (m, 4H), 3.15-3.08 (m, 8H), 2.63-2.53 (m, 2H), 2.11-2.01 (m, 1H), 2.01-1.91 (m, 1H), 1.89-1.75 (m, 2H), 1.73-1.59 (m, 3H), 1.53-1.43 (m, 1H), 1.42-1.34 (m, 1H), 1.14-1.05 (m, 1H). (NH not detected)

4.6 Analytical Separation of the 4 Isomers of 8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline Obtained in Step 4.5

The separation was carried out in two steps via method C:
Two peaks were separated on a Phenomenex LUX Amylose-2 Column (250×4.6 mm, 5 μm) (t_R[min]=3.4, 4.1). The mobile phase consisted of 90% CO₂and 10% modifier. As modifier, MeOH with 0.2 Vol % of aqueous ammonia solution (25%) was used.
The first peak was then subjected to a second separation on a Daicel Chiralcel® OD-H column (100×4.6 mm, 5 μm) (t_R[min]=4.1, 4.6). The mobile phase consisted of 95% CO₂and 5% modifier. As modifier, MeOH with 0.2 Vol % of aqueous ammonia solution (25%) was used.
The second peak was separated on a Daicel Chiralpak® AD-H (100×4.6 mm, 5 μm) (t_R[min]=3.7, 4.5). The mobile phase consisted of 95% CO₂and 5% modifier. As modifier, MeOH with 0.2 Vol % of aqueous ammonia solution (25%) was used.

4.7 Preparative Separation of the 4 isomers of 8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline Obtained in Step 4.5

The separation of the 4 isomers was carried out in two steps by UV-detection at 214 nm:
Two peaks were separated on a Phenomenex LUX Amylose-2 Column (250×21.2 mm, 5 μm) (t_R[min]=3.1, 3.8). The mobile phase consisted of 90% CO₂and 10% modifier. As modifier, MeOH with 0.2 Vol % of aqueous ammonia solution (25%) was used.
The first peak was then subjected to a second separation on a Daicel Chiralcel® OD-H column (250×20 mm, 5 μm) (t_R[min]=9.2, 10.1). The mobile phase consisted of 95% CO₂and 5% modifier. As modifier, MeOH with 0.2 Vol % of aqueous ammonia solution (25%) was used.
The second peak was separated on a YMC CHIRAL Amylose-C column (250×20 mm, 5 μm) (t_R[min]=7.1, 8.2). The mobile phase consisted of 95% CO₂and 5% modifier. As modifier, MeOH with 0.1 Vol % diethylamine was used.

Isomer 4.A of 8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolone (Single Enantiomer of the Compound of Example 4.5)

ESI-MS: m/z (%): 265.20 (100, [M+H]⁺).
The retention time according to the analytical method described above is 4.1 min and according to the preparative method described above 9.2 min.

Isomer 4.B of 8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolone (Single Enantiomer of the Compound of Example 4.5)

ESI-MS: m/z (%): 265.20 (100, [M+H]⁺).
The retention time according to the analytical method described above is 4.6 min and according to the preparative method described above 10.1 min.

Isomer 4.0 of 8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolone (Single Enantiomer of the Compound of Example 4.5)

ESI-MS: m/z (%): 265.20 (100, [M+H]⁺).
The retention time according to the analytical method described above is 3.7 min and according to the preparative method described above method 7.1 min.

Isomer 4.D of 8-(2,2-difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinolone (Single Enantiomer of the Compound of Example 4.5)

ESI-MS: m/z (%): 265.20 (100, [M+H]⁺).
The retention time according to the analytical method described above is 4.5 min and according to the preparative method described above 8.2 min.

Example 5

8-(Oxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline (Compound Ia.1 Wherein R⁶is oxetan-3-yl and R^4a, R^4b, R^5a, R^5band R^7aare hydrogen)

5.1 4-(Oxetan-3-yl)-3,4-dihydroquinolin-2(1H)-one

A mixture of 750 mg of oxetan-3-yl-acrylic acid ethyl ester (2.40 mmol, 1.00 eq), 658 mg of 2-aminophenyl boronic ester (4.80 mmol, 2.00 eq), 664 mg of potassium carbonate (4.80 mmol, 2.00 eq) and 54.8 mg of [RhOH(COD)]₂(0.120 mmol, 0.05 eq) in 2% wt. TPGS-750-M solution in water (15 mL) was stirred vigorously at ambient temperature for the 48 h. Then the reaction mixture was extracted with ethyl acetate. The organic phase was dried over MgSO₄, filtrated and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the title product (90%, 2.17 mmol).
ESI-MS: m/z (%): 204.10 (100, [M+H]⁺).

5.2 4-(Oxetan-3-yl)-1,2,3,4-tetrahydroquinoline

To a solution of 882 mg of 4-(oxetan-3-yl)-3,4-dihydroquinolin-2(1H)-one (2.17 mmol, 1.00 eq) from step 5.1 in THF (20 ml) 6.51 mL of lithium aluminium hydride (1 M in THF, 6.51 mmol, 3.00 eq) was slowly added at 0° C. The mixture was stirred at 0° C. for 10 min and was then warmed up to room temperature and stirred for further 6 h at room temperature. Then the mixture was cooled to 0° C. and water (0.03 mL) was added followed by 10% aqueous NaOH (0.03 mL) and water (0.1 mL) again. The mixture was stirred at 0° C. for 1 h. Then MgSO₄was added and the mixture was filtrated and the solvent was evaporated. The crude product was purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the title product (13%, 0.301 mmol).
ESI-MS: m/z (%): 190.20 (100, [M+H]⁺).

5.3 2-(4-(Oxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

A mixture of 57 mg of 4-(oxetan-3-yl)-1,2,3,4-tetrahydroquinoline (0.301 mmol, 1.00 eq) from step 5.2, 111 mg of 2-iodoacetamide (0.602 mmol, 2.00 eq) and 0.205 mL of DIPEA (1.20 mmol, 4.00 eq) in DMF (1 mL) was heated in a microwave at 100° C. for 16 h. Then NaOH (1M) was added and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the title product (55%, 0.166 mmol).
ESI-MS: m/z (%): 247.20 (100, [M+H]⁺).

5.4 2-(4-(Oxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 41 mg of 2-(4-(oxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide (0.166 mmol, 1.00 eq) from step 5.3 in THF (4 ml) 0.499 mL of lithium aluminium hydride (1 M in THF, 0.499 mmol, 3.00 eq) was slowly added at 0° C. The mixture was stirred at 0° C. for 10 min and was then warmed up to room temperature and stirred for further 6 h at room temperature. Then the mixture was cooled to 0° C. and water (0.03 mL) was added followed by 10% aqueous NaOH (0.03 mL) and water (0.1 mL) again. The mixture was stirred at 0° C. for 1 h. Then MgSO₄was added and the mixture was filtrated and the solvent was evaporated. The crude product was purified by column chromatography on silica (eluent: 0-10% methanol in dichloromethane) to yield the title product (38%, 0.064 mmol).
ESI-MS: m/z (%): 233.20 (100, [M+H]⁺).

5.5 8-(Oxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 86 mg of 2-(4-(oxetan-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine (0.370 mmol, 1.00 eq) from step 5.4, formaldehyde (0.389 mmol, 1.05 eq) and TFA (0.407 mmol, 1.10 eq) in ethanol (3 mL) was stirred at ambient temperature for 2 h. Then NaOH (1M) was added and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by SFC to yield the title product (3.5%, 0.013 mmol).
ESI-MS: m/z (%): 245.30 (100, [M+H]⁺).
¹H NMR (500 MHz, Methanol-d₄): δ 6.97 (d, J=7.3, 1.4 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 6.70 (t, J=7.5 Hz, 1H), 4.90-4.80 (m, 1H), 4.79-4.70 (m, 2H), 4.68-4.60 (m, 1H), 3.79 (q, J=14.0 Hz, 2H), 3.36-3.27 (m, 2H), 3.27-3.17 (m, 2H), 3.20-3.06 (m, 3H), 3.05-2.92 (m, 2H), 1.94-1.84 (m, 1H), 1.67-1.57 (m, 1H).

Example 6

8-(Tetrahydro-2H-pyran-4-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline (Compound Ia.1 wherein R⁶is tetrahydro-2H-pyran-4-yl and R^4a, R^4b, R^5a, R^5band R^7aare hydrogen)

6.1 4-(Tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-2(1H)-one

A mixture of 100 mg of tetrahydropyran-4-yl-acrylic acid ethyl ester (0.588 mmol, 1.00 eq), 161 mg of 2-aminophenyl boronic ester (1.18 mmol, 2.00 eq), 162 mg of potassium carbonate (1.18 mmol, 2.00 eq) and 13.4 mg of [RhOH(COD)]₂(0.029 mmol, 0.05 eq) in 2% wt. TPGS-750-M solution in water (3 mL) was stirred vigorously at ambient temperature for 48 h and then at 70° C. for further 20 h. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over MgSO₄, filtrated and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-20% methanol in dichloromethane) to yield the title product (67%, 0.395 mmol).
ESI-MS: m/z (%): 232.20 (100, [M+H]⁺).

6.2 4-(Tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoline

To a solution of 91.4 mg of 4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-2(1H)-one (0.395 mmol, 1.00 eq) from step 6.1 in THF (2 ml) was added 0.790 mL of borane tetrahydrofurane complex (2 M in THF, 1.58 mmol, 4.00 eq). The mixture was stirred at room temperature for 16 h and then heated in a microwave at 90° C. for 2 h. Then the reaction mixture was quenched with HCl (1 M) and the aqueous phase was extracted with ethyl acetate. The organic phase was extracted three times with HCl (1M) and to the aqueous phase was added NaOH (1M) until pH 10 and was then extracted with dichloromethane three times. The organic phase was dried over MgSO₄and reduced under vacuum to yield the title product (44%, 0.173 mmol).
ESI-MS: m/z (%): 218.20 (100, [M+H]⁺).

6.3 2-(4-(Tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

A mixture of 37.6 mg of 4-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroquinoline (0.173 mmol, 1.00 eq) from step 6.2, 128 mg of 2-iodoacetamide (0.692 mmol, 4.00 eq) and 0.177 mL of DIPEA (1.04 mmol, 6.00 eq) in DMF (3 mL) was heated in a microwave at 120° C. for 8 h. Then NaOH (1M) was added and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-30% methanol in dichloromethane) to yield the title product.
ESI-MS: m/z (%): 275.20 (100, [M+H]⁺).

6.4 2-(4-(Tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 191 mg of 2-(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide (0.696 mmol, 1.00 eq) from step 6.3 in THF (5 ml) was added 1.74 mL of borane tetrahydrofurane complex (2 M in THF, 3.48 mmol, 5.00 eq). The mixture was stirred at room temperature for 16 h and then heated in a microwave at 90° C. for 1 h. Then the reaction mixture was quenched with HCl (1 M) and the aqueous phase was extracted with ethyl acetate. The organic phase was extracted three times with HCl (1M) and to the aqueous phase was added NaOH (1M) until pH 10 and was then extracted with dichloromethane three times. The organic phase was dried over MgSO₄and reduced under vacuum to yield the title product (76%, 0.529 mmol).
ESI-MS: m/z (%): 261.20 (100, [M+H]⁺).

6.5 8-(Tetrahydro-2H-pyran-4-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

A mixture of 33.8 mg of 2-(4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine (0.130 mmol, 1.00 eq) from step 6.4, formaldehyde (0.130 mmol, 1.00 eq) and TFA (0.143 mmol, 1.10 eq) in ethanol (2 mL) was stirred at ambient temperature for 48 h and then at 70° C. for further 4 h. The solvent was removed under vacuum. The residue was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over Na₂SO₄, filtrated and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-30% methanol in dichloromethane) to yield the title compound (15%, 0.019 mmol).
ESI-MS: m/z (%): 273.20 (100, [M+H]⁺).
¹H NMR (600 MHz, Methanol-d₄): δ 7.14 (td, J=7.4, 1.6 Hz, 2H), 6.85 (t, J=7.5 Hz, 1H), 4.29 (d, J=13.7 Hz, 1H), 4.17 (d, J=13.8 Hz, 1H), 4.01-3.91 (m, 2H), 3.63 (s, 1H), 3.50-3.45 (m, 1H), 3.43-3.30 (m, 4H), 3.26 (ddd, J=12.1, 10.4, 4.0 Hz, 1H), 2.66 (s, 1H), 2.63 (dt, J=7.9, 5.2 Hz, 1H), 2.09-2.01 (m, 1H), 1.89-1.82 (m, 1H), 1.82-1.74 (m, 1H), 1.61-1.55 (m, 1H), 1.55-1.49 (m, 2H), 1.39-1.27 (m, 1H). (NH not detected)

Example 7

8-(Tetrahydrofuran-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline (Compound Ia.1 wherein R⁶is tetrahydrofuran-3-yl and R^4a, R^4b, R^5a, R^5band R^7aare hydrogen)

7.1 4-(Tetrahydrofuran-3-yl)-3,4-dihydroquinolin-2(1H)-one

A mixture of 100 mg of tetrahydrofuran-3-yl-acrylic acid methyl ester (0.640 mmol, 1.00 eq), 175 mg of 2-aminophenyl boronic ester (1.28 mmol, 2.00 eq), 177 mg of potassium carbonate (1.28 mmol, 2.00 eq) and 14.6 mg of [RhOH(COD)]₂(0.032 mmol, 0.05 eq) in 2% wt. TPGS-750-M solution in water (3 mL) was stirred vigorously at ambient temperature for the 48 h and then at 70° C. for further 6 h. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over MgSO₄, filtrated and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-30% methanol in dichloromethane) to yield the title product (81%, 0.516 mmol).
ESI-MS: m/z (%): 218.20 (100, [M+H]⁺).

7.2 4-(Tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroquinoline

To a solution of 112 mg of 4-(tetrahydrofuran-3-yl)-3,4-dihydroquinolin-2(1H)-one (0.516 mmol, 1.00 eq) from step 7.1 in THF (2 ml) was added 1.03 mL of borane tetrahydrofurane complex (2 M in THF, 2.06 mmol, 4.00 eq). The mixture was stirred at room temperature for 16 h and then heated in a microwave at 90° C. for 2 h. Then the reaction mixture was quenched with HCl (1 M) and the aqueous phase was extracted with ethyl acetate. The organic phase was extracted three times with HCl (1M) and to the aqueous phase was added NaOH (1M) until pH 10 and was then extracted with dichloromethane three times. The organic phase was dried over MgSO₄and reduced under vacuum to yield the title product (69%, 0.358 mmol).
ESI-MS: m/z (%): 204.20 (100, [M+H]⁺).

7.3 2-(4-(Tetrahydrofuran-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide

A mixture of 72.7 mg of 4-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroquinoline (0.358 mmol, 1.00 eq) from step 7.2, 265 mg of 2-iodoacetamide (1.43 mmol, 4.00 eq) and 0.367 mL of DIPEA (1.43 mmol, 6.00 eq) in DMF (3 mL) was heated in a microwave at 120° C. for 8 h. Then NaOH (1M) was added and the mixture was extracted with dichloromethane. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-70% methanol in dichloromethane) to yield the title product.
ESI-MS: m/z (%): 261.20 (100, [M+H]⁺).

7.4 2-(4-(Tetrahydrofuran-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine

To a solution of 480 mg of 2-(4-(tetrahydrofuran-3-yl)-3,4-dihydroquinolin-1(2H)-yl)acetamide (1.84 mmol, 1.00 eq) from step 7.3 in THF (5 ml) was added 4.61 mL of borane tetrahydrofurane complex (2 M in THF, 9.22 mmol, 5.00 eq). The mixture was stirred at room temperature for 16 h and then heated in a microwave at 90° C. for 2 h. Then the reaction mixture was quenched with HCl (1 M) and the aqueous phase was extracted with ethyl acetate. The organic phase was extracted three times with HCl (1M) and to the aqueous phase was added NaOH (1M) until pH 10 and was then extracted with dichloromethane three times. The organic phase was dried over MgSO₄and reduced under vacuum. The crude product was purified by column chromatography on silica (eluent: 0-70% methanol in dichloromethane) to yield the title product (12%, 0.215 mmol).
ESI-MS: m/z (%): 247.20 (100, [M+H]⁺).
7.5 8-(Tetrahydrofuran-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline
A mixture of 53.0 mg of 2-(4-(tetrahydrofuran-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanamine (0.215 mmol, 1.00 eq) from step 7.4, formaldehyde (0.215 mmol, 1.00 eq) and TFA (0.237 mmol, 1.10 eq) in ethanol (2 mL) was stirred at ambient temperature for 84 h. Then the solvent was removed under vacuum. The residue was dissolved with DCM and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over Na₂SO₄, filtrated and reduced under vacuum. The crude product was purified by preparative HPLC to yield the title compound (38%, 0.082 mmol).
ESI-MS: m/z (%): 259.20 (100, [M+H]⁺).
¹H NMR of mixture of diastereomers (600 MHz, Methanol-d₄): δ 7.22-7.05 (m, 4H), 6.87-6.79 (m, 2H), 4.30 (d, J=13.9 Hz, 2H), 4.16 (dd, J=13.8, 4.4 Hz, 2H), 3.98-3.90 (m, 3H), 3.80-3.62 (m, 4H), 3.53-3.30 (m, 13H), 2.82-2.71 (m, 2H), 2.60-2.43 (m, 2H), 2.17-2.09 (m, 1H), 2.04-1.97 (m, 1H), 1.95-1.86 (m, 4H), 1.85-1.79 (m, 1H), 1.72-1.62 (m, 1H). (NH not detected)

Example 8

8-Cyclopropyl-10-(2-methoxyethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino [6,7,1-ij]quinoline (Compound Ia.1 wherein R⁶is cyclopropyl, R^4a, R^4b, R^5aand R^5bare hydrogen, and R^7ais 2-methoxyethyl)

8.1 tert-Butyl 8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

A solution of 980 mg of 8-cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline (4.29 mmol, 1.00 eq) from example 1.6, 1.20 mL of triethylamine (8.58 mmol, 2.00 eq) and 937 mg of di-tert-butyl dicarbonate (4.29 mmol, 1.00 eq) in DCM (20 mL) was stirred 30 min at room temperature. Then the organic phase was extracted with water, dried over MgSO₄and the solvent was evaporated to yield the title compound (100%, 4.29 mmol).
ESI-MS: m/z (%): 329.20 (100, [M+H]⁺).

8.2 tert-Butyl 10-bromo-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

A solution of 600 mg of tert-butyl 8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate (1.83 mmol, 1.00 eq) from step 8.1 in THF (20 mL) was cooled to 0° C. Then 325 mg N-bromosuccinimide (1.83 mmol, 1.00 eq) was added and the mixture was stirred for 30 min at 0° C. The solvent was evaporated to yield the title compound.
ESI-MS: m/z (%): 408.20 (100, [M+H]⁺).

8.3 tert-Butyl 8-cyclopropyl-10-(2-methoxyethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

Under an argon atmosphere a mixture of 100 mg of tert-butyl 10-bromo-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate (0.245 mmol, 1.00 eq) from step 8.2, 40.7 mg of potassium trifluoro (2-methoxyehtyl)borate (0.245 mmol, 1.00 eq), 240 mg of cesium carbonate (0.736 mmol, 3.00 eq), 2.04 mg of Pd(OAc)₂(0.009 mmol, 0.04 eq) and 8.19 mg of X-Phos (0.017 mmol, 0.07 eq) in degassed THF (4 mL) and water (0.5 mL) was heated in a microwave at 120° C. for 20 h. Then the solvent was evaporated to yield the title compound.
ESI-MS: m/z (%): 387.30 (100, [M+H]⁺).

8.4 8-Cyclopropyl-10-(2-methoxyethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

To a solution of 100 mg of tert-Butyl 8-cyclopropyl-10-(2-methoxyethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate (0.259 mmol, 1.00 eq) in DCM (3 mL) was added 0.199 mL TFA (2.59 mmol, 10.0 eq) and the mixture was stirred for 18 h at room temperature and then at 70° C. for further 8 h. The solvent was evaporated and the crude product was purified via preparative HPLC to yield the title compound (3.8%, 0.010 mmol).
ESI-MS: m/z (%): 287.30 (100, [M+H]⁺).
¹H NMR (500 MHz, Methanol-d₄): δ 7.36 (d, J=2.1 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 4.20 (d, J=1.8 Hz, 2H), 3.57 (t, J=6.7 Hz, 2H), 3.48-3.40 (m, 1H), 3.35-3.25 (m, 5H), 3.32 (s, 3H), 2.78 (t, J=6.7 Hz, 2H), 2.09-2.01 (m, 1H), 2.01-1.93 (m, 1H), 1.88-1.78 (m, 1H), 1.29 (s, 1H), 0.92-0.79 (m, 1H), 0.74-0.66 (m, 1H), 0.55-0.43 (m, 2H), 0.29-0.20 (m, 1H).

Example 9

8-Cyclopropyl-10-(methoxymethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline (Compound Ia.1 wherein R⁶is cyclopropyl, R^4a, R^4b, R^5aand R^5bare hydrogen, and R^7ais methoxymethyl)

9.1 tert-butyl 8-cyclopropyl-10-(methoxymethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

Under an argon atmosphere a mixture of 70 mg of tert-butyl 10-bromo-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino [6,7,1-ij]quinoline-2(6H)-carboxylate (0.172 mmol, 1.00 eq) from step 8.2, 52.2 mg of potassium trifluoro (2-methoxymehtyl)borate (0.344 mmol, 2.00 eq), 168 mg of cesium carbonate (0.516 mmol, 3.00 eq), 1.43 mg of Pd(OAc)₂(0.006 mmol, 0.04 eq) and 5.73 mg of X-Phos (0.012 mmol, 0.07 eq) in degassed dioxane (4 mL) and water (0.5 mL) was heated in a microwave at 130° C. for 40 h. Then the mixture was extracted with DCM and the organic phase was washed with water and dried over MgSO₄, filtrated and solvent was evaporated to yield the title compound.
ESI-MS: m/z (%): 373.30 (100, [M+H]⁺).

9.2 8-cyclopropyl-10-(methoxymethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline

To a solution of 51.6 mg of tert-butyl 8-cyclopropyl-10-(methoxymethyl)-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate (0.139 mmol, 1.00 eq) from step 9.2 in DCM (3 mL) was added 0.107 mL of TFA (1.39 mmol, 10.0 eq) and the mixture was stirred for 48 h at room temperature. Then the solvent was evaporated and the crude product was purified via preparative HPLC to yield the title compound (2.2%, 0.003 mmol).
ESI-MS: m/z (%): 273.20 (100, [M+H]⁺).

Example 10

8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-10-carbonitrile (compound Ia.1 wherein R⁶is cyclopropyl, R^4a, R^4b, R^5aand R^5bare hydrogen, and R^7ais cyano)

10.1 tert-Butyl 10-cyano-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate

Under an argon atmosphere a mixture of 30 mg of tert-butyl 10-bromo-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate (0.074 mmol, 1.00 eq) from step 8.2, 38.9 mg of potassium hexacyanoferrate(II) trihydrate (0.092 mmol, 1.25 eq), 25.4 mg of potassium carbonate (0.184 mmol, 2.50 eq), 3.31 mg of Pd(OAc)₂(0.015 mmol, 0.20 eq) and 14.04 mg of X-Phos (0.029 mmol, 0.40 eq) in degassed dioxane (2 mL) and water (2 mL) was heated in a microwave at 100° C. for 10 h. Then the mixture was extracted with DCM and the organic phase was washed with water and dried over MgSO₄, filtrated and the solvent was evaporated to yield the title compound.
ESI-MS: m/z (%): 354.30 (100, [M+H]⁺).

10.2 8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-10-carbonitrile

To a solution of 33.6 mg of tert-butyl 10-cyano-8-cyclopropyl-3,4,7,8-tetrahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-2(6H)-carboxylate (0.095 mmol, 1.00 eq) from step 10.1 in DCM (10 mL) was added 0.073 mL of TFA (0.951 mmol, 10.0 eq) and the mixture was stirred for 18 h at room temperature and heated in a microwave for further 4 h at 50° C. and then at 70° C. for further 3 h. The solvent was evaporated and the crude product was purified via preparative HPLC to yield the title compound (10%, 0.009 mmol).
ESI-MS: m/z (%): 254.20 (100, [M+H]⁺).
¹H NMR (600 MHz, Methanol-d₄): δ 7.66 (dd, J=2.1, 0.9 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 4.34 (s, 2H), 3.70-3.61 (m, 2H), 3.56-3.51 (m, 1H), 3.48 (t, J=5.1 Hz, 2H), 3.41-3.36 (m, 1H), 2.08-2.03 (m, 1H), 2.02-1.98 (m, 1H), 1.91-1.83 (m, 1H), 0.91-0.82 (m, 1H), 0.76-0.69 (m, 1H), 0.61-0.54 (m, 1H), 0.48-0.40 (m, 1H), 0.31-0.24 (m, 1H). (NH not detected)

II. Biological Tests

Functional Activity

1. Human 5-HT_2CFunctional Assay

The functional activity of compounds of formula I was assayed by incubation with U2OS_HTR_2C _{_}β-Arrestin cells (DiscoverX, 93-0289C3) to induce beta-arrestin2 recruitment to the 5-HT_2Creceptor. The agonist-induced recruitment and proximity of the receptor and beta-arrestin2 leads to complementation and formation of active β-galactosidase. The enzyme complementation results in enzyme activity, which is measured following the termination of the agonist incubation using DiscoveRx's detection reagent, which contains a chemiluminescent substrate which produces a high intensity signal. Cells were plated and a medium-change to a 1% serum containing medium was performed 24 h later. The next day, test compounds were added and incubated for 1.5 h before addition of detection reagent.
The response produced was measured and compared with the response produced by 10 [mu]M 5-HT or the maximal effect induced by 5-HT (defined as 100%) to which it was expressed as a percentage response (relative efficacy). Dose response curves were constructed using Graphpad Prism (Graph Software Inc.) or using in house adapted software using a 4 parameter dose response model with variable slope (fit=(Bottom+(Top−Bottom)/(1+10̂((Log EC50−x)*HillSlope))res=(y-fit)). Results are compiled in the table below.

2. Human 5-HT_2AFunctional Assay

Functional activity on the 5-HT_2Areceptor was determined by testing the effect of the compounds I on calcium mobilisation in CHO-K1 cells, stably transfected with human 5-HT_2Areceptor. Cells were seeded into sterile black 384-well plates with clear bottom at 25,000 cells/well in a volume of 25 μl and grown for 5-6 hours at 37° C., in 5% CO₂in tissue culture medium (“Ultra CHO” by LONZA), containing 1% dialysed FCS and 50 μg/ml gentamicin (Invitrogen). After this incubation, medium was replaced by a serum free version of the same tissue culture medium followed by incubation overnight at 37° C. and in 5% CO₂. Cells were then loaded with a fluorescent calcium-sensitive dye in the presence of 0.07% probenecid for an hour at 37° C., according to the manufacturer's protocol (Ca5-Assay Kit, Molecular Devices), followed by an additional 60 min incubation at room temperature. Serial compound dilutions (final concentrations of 10⁻¹⁰to 10⁻⁵M, prepared in HBSS+50 mM HEPES) were first added to the cells alone (“first addition” to assess agonism on the 5-HT_2Areceptor), then after 8 min, serotonin was added to the same wells at a final concentration of 3×10⁻⁸M (“second addition” to see potential antagonistic effect) and the maximal calcium response was determined using a FLIPR® Tetra instrument (Molecular Devices) in each of the two steps. The relative efficacy of the compounds was calculated as a percentage of the maximal effect induced by serotonin alone (defined as 100%). To determine EC₅₀/IC₅₀values, concentration-response curves were fitted using a four-parameter logistic equation (IDBS Biobook™). K_bvalues were calculated from IC₅₀values, according to Cheng & Prusoff.

3. Human 5-HT_2BFunctional Assay

Functional activity on the 5-HT_2Breceptor was determined by testing the effect of the compounds I on calcium mobilisation in CHO-FlpIn cells, stably transfected with human 5-HT_2Breceptor. Cells were seeded into sterile black 384-well plates with clear bottom at 30,000 cells/well in a volume of 25 μl and grown overnight at 37° C., in 5% CO₂in tissue culture medium (“CHO—S-SFM II” by Invitrogen), containing 1% dialysed FCS and 50 μg/ml gentamicin (Invitrogen). On the next morning, medium was replaced by a serum free version of the same tissue culture medium for a further incubation for 4 hours at 37° C. and in 5% CO₂. Cells were then loaded with a fluorescent calcium-sensitive dye in the presence of 0.07% probenecid for an hour at 37° C., according to the manufacturer's protocol (Ca5-Assay Kit, Molecular Devices), followed by an additional 60 min incubation at room temperature. Serial compound dilutions (final concentrations of 10⁻¹⁰to 10⁻⁵M, prepared in HBSS+50 mM HEPES) were first added to the cells alone (“first addition” to assess agonism on the 5-HT_2Breceptor), then after 8 min, serotonin was added to the same wells at a final concentration of 10⁻⁸M (“second addition” to see potential antagonistic effect) and the maximal calcium response was determined using a FLIPR® Tetra instrument (Molecular Devices) in each of the two steps. The relative efficacy of the compounds was calculated as a percentage of the maximal effect induced by serotonin alone (defined as 100%). To determine EC₅₀/IC₅₀values, concentration-response curves were fitted using a four-parameter logistic equation (IDBS Biobook™). K_bvalues were calculated from IC₅₀values, according to Cheng & Prusoff.

TABLE

					Selectivity⁴		Selectivity⁵
	EC50	%	EC50	%	(based on	EC50	(based on
#	5-HT_2C ¹	efficacy	5-HT_2A ²	efficacy	agonism)	5-HT_2B ³	agonism)

1	+++	105	+	25	122	*	antagonist
1.A	+++	89	*		antagonist⁶	*	antagonist
1.B	+++	121	++	50	23	*	antagonist
2	++	54	*		antagonist	*	antagonist
3	++	88	*		antagonist	*	full⁷
4	++	88	++	19	6	*	antagonist
4.A	++	85	*		antagonist	*	full
4.B	++	99	+	33	18	*	antagonist
4.C	++	80	*		antagonist	*	antagonist
4.D	++	111	**	24	45	*	antagonist
5	+	82	*		antagonist	*	full

¹Potency (EC50 5-HT_2C) in functional assay
²Potency (EC50 5-HT_2A) in functional assay
³Potency (EC50 5-HT_2B) in functional assay
⁴EC50 5-HT_2A/EC50 5-HT_2C
⁵EC50 5-HT_2B/EC50 5-HT_2C
⁶“antagonist” indicates functional antagonism with no measurable agonistic effect
⁷“full” indicates no measurable agonistic effect at 10 μM (highest concentration in assay)
Potency (EC50): * >10 μM ** 1 μM to 10 μM + from 200 nM to <1 μM ++ from 20 nM to <200 nM +++ <20 nM

Claims

We claim:

1. A compound of the formula I

wherein

R¹is selected from the group consisting of hydrogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO and SO₂and optionally also 1 or 2 C═O and/or C═S groups as ring members, where the cyclic moieties in the three last-mentioned radicals may be substituted with one or more substituents R¹⁰;

each R²is independently selected from the group consisting of cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, —CH₂NR^11aR^11b, —C(O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹⁰; or

two radicals R²bound to the same carbon atom, together with the carbon atom they are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring, where the ring may contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents R¹⁰;

R^3aand R^3b, independently of each other, are selected from the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, —CH₂NR^11aR^11b, —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹⁰;

R^4aand R^4b, independently of each other, are selected from the group consisting of hydrogen, cyano, nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, —CH₂NR^11aR^11b, —C(═O)R⁹, phenyl, phenyl-C₁-C₂-alkyl, and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹⁰; or

R^4aand R^4bform together a group ═O or ═S; or

R^4aand R^4b, together with the carbon atom they are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring, where the ring may contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents R¹⁰;

R^5aand R^5b, independently of each other, are selected from the group consisting of hydrogen, halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —NR^11aR^11b, —CH₂NR^11aR^11b, —NR^11aC(O)R⁹, —C(═O)R⁹, SO₂NR^11aR^11b, C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl, phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹⁰; where R^5aand R^5bare not simultaneously hydroxyl; or R^5aand R^5b, together with the carbon atom they are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring, where the ring may contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents R¹⁰;

R⁶is a cyclic radical selected from the group consisting of C₃-C₆-cycloalkyl which may carry one or more radicals R⁸; and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO and SO₂, and optionally also 1 or 2 groups C═O and/or C═S, as ring members, where the heterocyclic ring may be substituted with one or more substituents R¹⁰;

each R⁷is independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, fluorinated C₃-C₈-cycloalkenyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —NR^11aR^11b, —CH₂NR^11aR^11b, —NR^11aC(O)R⁹, —C(═O)R⁹, SO₂NR^11aR^11b, C₁-C₆-alkylcarbonyloxy, fluorinated C₁-C₆-alkylcarbonyloxy, phenyl, phenyl-C₁-C₂-alkyl, phenoxy, phenylsulfonyl, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the six last-mentioned radicals may be substituted with one or more substituents R¹⁰; or

two radicals R⁷bound on neighboring carbon atoms, together with the carbon atoms they are bound to, form a 3-, 4-, 5-, 6-, 7- or 8-membered partially unsaturated or maximally unsaturated ring, where the ring may contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents R¹⁰;

each R⁸is independently selected from the group consisting of halogen, cyano, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, —NR^11aR^11b, —CH₂NR^11aR^11b, phenyl, phenyl-C₁-C₂-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the five last-mentioned radicals may be substituted with one or more substituents R¹⁰;

or two radicals R⁸bound to the same carbon atom may form together a group ═O or ═S;

each R⁹is independently selected from the group consisting of hydrogen, cyano, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, —NR^11aR^11b, —CH₂NR^11aR^11b, phenyl, phenyl-C₁-C₂-alkyl, phenoxy, benzyloxy and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated ring containing 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members, where the cyclic moieties in the five last-mentioned radicals may be substituted with one or more substituents R¹⁰;

each R¹⁰is independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkoxy-C₁-C₄-alkyl, fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy, C₁-C₆-alkylthio, fluorinated C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, fluorinated C₁-C₆alkylsulfinyl C₁-C₆-alkylsulfonyl, fluorinated C₁-C₆-alkylsulfonyl, —COOH, —NR^11aR^11b, —CH₂NR^11aR^11b, C₁-C₆-alkylcarbonyl, fluorinated C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, fluorinated C₁-C₆-alkoxycarbonyl, SO₂NR^11aR^11b, C₁-C₆-alkylcarbonyloxy and fluorinated C₁-C₆-alkylcarbonyloxy;

or two radicals R¹⁰, together with the atom(s) they are bound to, form a saturated, partially unsaturated or maximally unsaturated 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclic ring, where the heterocyclic ring contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO, SO₂, C═O and C═S as ring members;

R^11aand R^11bindependently of each other and independently of each occurrence, are selected from the group consisting of hydrogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy, fluorinated C₁-C₆-alkoxy, C₁-C₆-alkylcarbonyl, fluorinated C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, fluorinated C₁-C₆-alkoxycarbonyl, phenyl and benzyl, where the phenyl moieties in the two last-mentioned radicals may carry 1, 2 or 3 substituents selected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy; or,

if R^11aand R^11bare bound to the same nitrogen atom, together with this nitrogen atom may form a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring, where the ring may further contain 1, 2, 3 or 4 heteroatoms or heteroatom-containing groups selected from O, S, N, SO, SO₂, C═O and C═S as ring members, and where the ring may be substituted with one or more substituents selected from halogen, cyano nitro, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy;

a is 0, 1 or 2; and

b is 0, 1, 2 or 3;

or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof.

2. The compound as claimed in claim 1, where R¹is selected from hydrogen and C₁-C₆-alkyl.

3. The compound as claimed in claim 2, where R¹is hydrogen.

4. The compound as claimed in any of the preceding claims, where R²is selected from C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₆-alkoxy-C₁-C₄-alkyl.

5. The compound as claimed in claim 4, where R²is selected from C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl.

6. The compound as claimed in claim 5, where R²is selected from methyl and CF₃.

7. The compound as claimed in any of the preceding claims, where R^3aand R^3b, independently of each other, are selected from hydrogen, cyano, nitro, C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl.

8. The compound as claimed in claim 7, where R^3ais selected from hydrogen, cyano, nitro, C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl; and R^3bis hydrogen.

9. The compound as claimed in claim 8, where R^3ais selected from hydrogen and methyl; and R^3bis hydrogen.

10. The compound as claimed in claim 9, where R^3aand R^3bare hydrogen.

11. The compound as claimed in any of the preceding claims, where R^4aand R^4b, independently of each other, are selected from hydrogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl, or form together a group ═O, or form together a group —(CH₂)_m—, where m is 2, 3 or 4.

12. The compound as claimed in claim 11, where R^4aand R^4bare hydrogen.

13. The compound as claimed in any of the preceding claims, where R^5ais selected from hydrogen, halogen, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl and C₁-C₆-alkoxy-C₁-C₄-alkyl and R^5bis hydrogen.

14. The compound as claimed in claim 13, where R^5ais hydrogen or methyl and R^5bis hydrogen.

15. The compound as claimed in any of the preceding claims, where R⁶is C₃-C₆-cycloalkyl which may carry one or more radicals R⁸; where R⁸is as defined in claim 1.

16. The compound as claimed in claim 15, where each R⁸is independently selected from the group consisting of halogen, cyano, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl and fluorinated C₁-C₄-alkoxy-C₁-C₄-alkyl.

17. The compound as claimed in any of claim 15 or 16, where R⁶is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl and 3,3-difluorocyclobutyl.

18. The compound as claimed in claim 17, where R⁶is selected from cyclopropyl and cyclobutyl.

19. The compound as claimed in claim 18, where R⁶is cyclopropyl.

20. The compound as claimed in claim 17, where R⁶is 2,2-difluorocyclopropyl.

21. The compound as claimed in any of claims 1 to 14, where R⁶is a 3-, 4-, 5-, 6- or 7-membered saturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO and SO₂, and optionally also 1 or 2 groups C═O and/or C═S, as ring members, where the heterocyclic ring may be substituted with one or more substituents R¹⁰;

where R¹⁰is as defined in claim 1.

22. The compound as claimed in claim 21, where R⁶is a 3-, 4-, 5- or 6-membered saturated heterocyclic ring containing 1 or 2 heteroatoms or heteroatom groups independently selected from N, O, S, NO, SO and SO₂as ring members, where the heterocyclic ring may be substituted with one or more substituents R¹⁰;

where R¹⁰is as defined in claim 1.

23. The compound as claimed in claim 22, where R⁶is a 4-membered saturated heterocyclic ring containing 1 heteroatom or heteroatom group selected from N, O, S, NO, SO and SO₂as ring member, where the heterocyclic ring may be substituted with one or more substituents R¹⁰;

where R¹⁰is as defined in claim 1.

24. The compound as claimed in claim 23, where R⁶is a 4-membered saturated heterocyclic ring containing an oxygen atom as ring member, where the heterocyclic ring may be substituted with one or more substituents R¹⁰; where R¹⁰is as defined in claim 1.

25. The compound as claimed in claim 24, where R⁶is oxetan-3-yl which may be substituted with one or more substituents R¹⁰; where R¹⁰is as defined in claim 1.

26. The compound as claimed in claim 22, where R⁶is a 5- or 6-membered saturated heterocyclic ring containing 1 heteroatom or heteroatom group selected from N, O, S, NO, SO and SO₂as ring member, where the heterocyclic ring may be substituted with one or more substituents R¹⁰;

where R¹⁰is as defined in claim 1.

27. The compound as claimed in claim 26, where R⁶is a 5- or 6-membered saturated heterocyclic ring containing an oxygen atom as ring member, where the heterocyclic ring may be substituted with one or more substituents R¹⁰; where R¹⁰is as defined in claim 1.

28. The compound as claimed in claim 27, where R⁶is tetrahydrofuran-3-yl or tetrahydropyran-4-yl which may be substituted with one or more substituents R¹⁰;

where R¹⁰is as defined in claim 1.

29. The compound as claimed in any of claims 21 to 28, where R¹⁰is selected from the group consisting of halogen, C₁-C₆-alkyl and fluorinated C₁-C₆-alkyl.

30. The compound as claimed in claim 29, where R¹⁰is methyl.

31. The compound as claimed in any of the preceding claims, where each R⁷is independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C₁-C₆-alkyl, fluorinated C₁-C₆-alkyl, C₂-C₆-alkenyl, fluorinated C₂-C₆-alkenyl, C₂-C₆-alkynyl, fluorinated C₂-C₆-alkynyl, C₃-C₈-cycloalkyl, fluorinated C₃-C₈-cycloalkyl, C₁-C₆-alkoxy and fluorinated C₁-C₆-alkoxy.

32. The compound as claimed in claim 31, where each R⁷is independently selected from halogen, C₁-C₄-alkyl, fluorinated C₁-C₄-alkyl, C₁-C₄-alkoxy and fluorinated C₁-C₄-alkoxy.

33. The compound as claimed in claim 32, where R⁷is fluorine.

34. The compound as claimed in any of claims 1 to 31, where each R⁷is independently selected from the group consisting of cyano and C₁-C₄-alkoxy-C₁-C₄-alkyl.

35. The compound as claimed in any of the preceding claims, where a is 0 or 1.

36. The compound as claimed in claim 35, where in case that a is 1, R²is bound in β-position to the nitrogen ring atom carrying R¹.

37. The compound as claimed in any of the preceding claims, where b is 0 or 1.

38. The compound as claimed in any of the preceding claims, of formula I.1

wherein R², R⁶, R⁷and b are as defined in any of claims 1, 4 to 6, 15 to 34 and 37 and a is 0 or 1.

39. The compound as claimed in claim 38, of formula I.1.1

wherein

R^7ais H, Cl, F or methyl;

a is 0 or 1; and

R², R⁶, R⁷and b are as defined in any of claims 1, 4 to 6, 15 to 34 and 37.

40. A compound selected from the group consisting of

8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;

(R)-8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;

(S)-8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;

8-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;

(R)-8-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;

(S)-8-Cyclobutyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;

8-(3-Methyloxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;

8-(2,2-Difluorocyclopropyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;

8-(Oxetan-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;

8-(Tetrahydro-2H-pyran-4-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;

8-(Tetrahydrofuran-3-yl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;

8-Cyclopropyl-10-(2-methoxyethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline;

8-Cyclopropyl-10-(methoxymethyl)-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline; and

8-Cyclopropyl-2,3,4,6,7,8-hexahydro-1H-[1,4]diazepino[6,7,1-ij]quinoline-10-carbonitrile;

and stereoisomers and pharmaceutically acceptable salts thereof.

41. A method for producing a compound of formula I according to claim 1 wherein R¹, R^4band R^5bare hydrogen and R², if present, is bound in β-position to the nitrogen ring atom carrying R¹(compound I′), comprising following steps:

reacting a quinoline compound 1 in which X is a leaving group with a boron compound of R⁶to the quinoline compound 2 in the presence of a Pd catalyst;

reacting the quinoline compound 2 with benzyl bromide to the N-protected quinolinium compound 3;

reducing the quinolinium compound 3 to the N-protected 1,2,3,4-tetrahydroquinoline compound 4;

deprotecting the N-protected 1,2,3,4-tetrahydroquinoline compound 4 to the 1,2,3,4-tetrahydroquinoline compound 5;

reacting the 1,2,3,4-tetrahydroquinoline compound 5 with the 2-halogenoacetamide 6, wherein Y is Cl, Br or I, to the 1-acetamide-substituted 1,2,3,4-tetrahydroquinoline compound 7;

reducing the carbonyl group of the 1-acetamide-substituted 1,2,3,4-tetrahydroquinoline compound 7 to the ethylamine-substituted tetrahydroquinoline compound 8;

reacting 8 with the aldehyde or ketone 9, wherein R^iaand R^abare as defined in claim 1, but for nitro or cyano, in the presence of a strong acid to I′; or

reacting 2 with the 2-halogenoacetamide 6 to 10, which is then reduced to 7, which is further reacted as described above:

42. A method for producing a compound of formula I according to claim 1 wherein R¹, R^4a, R^4band R^5bare hydrogen, and R², if present, is bound in β-position to the nitrogen ring atom carrying R¹(compound I″), comprising following steps:

reacting the boronic acid 11 and the α,β-unsaturated ester 12 in the presence of a Rhodium catalyst to the dihydroquinolone 13;

reducing the dihydroquinolone 13 to the 1,2,3,4-tetrahydroquinoline 14;

reacting the 1,2,3,4-tetrahydroquinoline 14 with the 2-halogenoacetamide 6, wherein Y is Cl, Br or I, to the 1-acetamide-substituted 1,2,3,4-tetrahydroquinoline compound 15;

reducing the carbonyl group of the 1-acetamide-substituted 1,2,3,4-tetrahydroquinoline compound 15 to the ethylamine-substituted tetrahydroquinoline compound 16; and

reacting 16 with the aldehyde or ketone 9, wherein R^3aand R^3bare as defined in claim 1, but for nitro or cyano, in the presence of a strong acid to I″:

43. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound as claimed in any of claims 1 to 40 or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier and/or auxiliary substance.

44. The compound as claimed in any of claims 1 to 40 or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for use as a medicament.

45. The compound as claimed in any of claims 1 to 40 or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for the treatment of disorders which respond to the modulation of the 5-HT_2creceptor.

46. The use of a compound as claimed in any of claims 1 to 40 or of an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of disorders which respond to the modulation of the 5-HT_2creceptor.

47. A method for treating disorders which respond to the modulation of the 5-HT_2creceptor, which method comprises administering to a subject in need thereof at least one compound as defined in any of claims 1 to 40 or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof.

48. The compound as claimed in claim 45 or the use as claimed in claim 46 or the method as claimed in claim 47, where the disorders are selected from the group consisting of damage of the central nervous system, disorders of the central nervous system, eating disorders, ocular hypertension, cardiovascular disorders, gastrointestinal disorders and diabetes.

49. The compound or the use or the method as claimed in claim 48, where the disorders are selected from the group consisting of bipolar disorder, depression, atypical depression, mood episodes, adjustment disorders, anxiety, panic disorders, post-traumatic syndrome, psychoses, schizophrenia, cognitive deficits of schizophrenia, memory loss, dementia of aging, Alzheimer's disease, neuropsychiatric symptoms in Alzheimer's disease, behavioral disorders associated with dementia, social phobia, mental disorders in childhood, attention deficit hyperactivity disorder, organic mental disorders, autism, mutism, disruptive behavior disorder, impulse control disorder, borderline personality disorder, obsessive compulsive disorder, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, seizure disorders, epilepsy, substance use disorders, alcohol abuse, cocaine abuse, tobacco abuse, smoking cessation, sexual dysfunction/erectile dysfunction in males, sexual dysfunction in females, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, sleep disorders, sleep apnoea, chronic fatigue syndrome, psoriasis, Parkinson's disease, psychosis in Parkinson's disease, neuropsychiatric symptoms in Parkinson's disease, Lewy Body dementia, neuropsychiatric symptoms in Lewy Body dementia, spinal cord injury, trauma, stroke, pain, bladder dysfunction/urinary incontinence, encephalitis, meningitis, eating disorders, obesity, bulimia, weight loss, anorexia nervosa, ocular hypertension, cardiovascular disorders, gastrointestinal disorders, diabetes insipidus, diabetes mellitus, type I diabetes, type II diabetes, type III diabetes, diabetes secondary to pancreatic diseases, diabetes related to steroid use, diabetes complications, hyperglycemia and insulin resistance.

50. The compound or the use or the method as claimed in claim 49, where the disorders are selected from schizophrenia, depression, bipolar disorders, obesity, substance use disorders, neuropsychiatric symptoms in Alzheimer's disease and neuropsychiatric symptoms in Parkinson's disease.