OA17160A

OA17160A - 4-methyl-2,3,5,9,9b-pentaza-cyclopenta[a]-naphthalenes

Info

Publication number: OA17160A
Application number: OA1201500009
Authority: OA
Inventors: Riccardo Giovannini; Barbara Bertani; Sara Frattini; Antonio Giustino Di; Hans-Joachim Lankau; Hans Stange; Christian Grunwald; Norbert Höfgen; Barbara Langen; Ute Egerland
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2012-07-31
Filing date: 2013-07-29
Publication date: 2016-03-28

Abstract

The invention relates to 4-methyl-2,3,5,9,9bpentaaza-cyclopenta[a]naphthalenes derivatives of general formula (I)

Description

Boehriuger Ingelheim International GmbH

4-Methyl-2,3,5,9,9b-pentaaza-cyclopenta[a]naphthalenes

Field of the Invention

The invention relates to 4-methyl-2,3,5,9,9b-pentaaza-cyclopenta[a]naphthalene dérivatives of general formula (I) whlch are Inhibitors of phosphodiesterase 2 and/or 10, useful In treating central nervous System diseases and other diseases.

In addition, the invention relates to processes for preparing pharmaceutical compositions as well as processes for manufacture the compounds according to the invention.

R⁵

Background of the Invention

Cognitive dysfunction plays a rôle in a number of central nervous System disorders, Including neurological disorders, such as Alzheimer* s disease (AD), Parkinson disease and dementia, but also psychiatrie disorders, such as schizophrenia, dépréssion and bipolar disorders. As worid population grows older the number of patients with dementia and AD is growing. Therefore, most people are familiar with the cognitive déficits related to these neurological diseases (Massoud and Gauthier, 2010).

However, also In psychiatrie disorders cognitive Impairment adversely affect the progress and the treatment outcome of the disease. A most prominent example is schizophrenia. Schizophrenia has a heterogeneous symptomatic picture (American Psychiatrie Association, 1994) that may be divided Into three distinct disease domains: positive symptoms (psychotic épisodes of hallucinations, delusions and agitation), négative symptoms (social withdrawal, anhedonia, flattened affect) and cognitive déficits (déficits in executive fonction, verbal leaming and memory, verbal fluency) (Thompson and Meltzer, 1993).

Whereas positive symptoms are essentialiy alleviated by dopamine D2 receptor antagonlst and second génération antipsychotics négative symptoms and cognitive déficits are still hardly affected by current treatments. Therefore, research on cognitive déficits In schizophrenia has been intenslfied over the past years. A worldwide network initiative, called MATRICS, has been founded to characterise the cognitive déficits more deeply and to find novel thérapies (Young et al., 2009).

However, cognitive impalrment is also seen In patients with dépréssion, bipolar disorders (Sachs et al., 2007; Pavuluri et al., 2009) and in many patients with disorders usually first diagnosed In infancy, childhood and adolescence, such as attention deficit/hyperactivity disorder (ADHD) (Jucaite et al., 2005; Turner et al., 2003).

Dépréssion is a severe mental disorder whlch extremely impairs daily life. Its prevalence Is about 10 % of the worid population with an Incidence of 2 % according to WHO. Women are more affected than men and elder people more than younger people. The disorder mostly implies a life-long treatment due to the progression of the disease and permanent total disability.

The most prominent symptoms of the disease are anhedonla, feeling of hopelessness, decreased self esteem, loss of appetite and sleep disturbances. Suicide idéation is also a common symptom of dépréssion and about 10% of depressed patients (Holma et al., 2010) attempt suicide. Dépréssion is often combined with anxlety disorders. Interestingly, it Is less known that dépression is also regulariy assoclated with various cognitive impairments (Gualtieri et al., 2006;

Mandelli et al., 2006). Hère, déficits of attentional and executive fonctions are mostly reported (Paelecke-Habermann et al., 2005). Cognitive déficits are even discussed to be involved In the development of the disease (Beck dépression model, Beck, 2008). More recent studies indicate that the severity of the cognitive déficits may predict non-response to certain antidepressant treatment (Dunkin et al., 2000; Gorlyn et al.,

2008).

Up to now, current antidepressant therapy seems not to be sufficient regarding cognitive déficits. Elder antidepressants are reported to impair memory In animal models of leaming and memory probably due to their antichoiinergic component (Kumar and Kulkami, 1996). In contrast, SSRIs, In particular fluoxetine, are described to impair hippocampal-independent but not hippocampal dépendent leaming in different rodent models (Valluzi and Chan, 2007). At least, In clinic current therapy it Is not possible to fully reverse cognitive déficits. Thus, In dépressive patients who had been successfully treated cognitive performance could be improved but not normalised (Gualtieri et al., 2006). Therefore, an antidepressant with higher efficacy on cognitive impairment may improve disease outcome.

Bipolar disorders are characterized by complex symptomatology, including severe symptoms of mood disorders but also manie épisodes and cognitive déficits. The Diagnostic and Statistlcal Manual, 4th édition and International Classification of Mental Disorder recommend subgroups of bipolar disorder based on whether dépressive or manie [psychotic] symptoms and épisodes are dominating and on the frequency of the épisodes (Gaiwani, 2009). Pharmacological agents commonly used in the management of bipolar disorder include lithium; anticonvulsants, such as valproate, carbamazepine and lamotrigine; and recent years hâve witnessed increasing use of atypical antipsychotics (Altamura et al., 2011 ). As a problem of current therapy the development of tolérance against anticonvulsant treatment and 30% of treatment refractory cases are described (Post and Weiss, 2010; Gaiwani,

2009).

Attention déficit hyperactivity disorder (ADHD) is a central nervous system disorder that is mainly defined by its clinical signs. ADHD shows a heterogeneous symptom pattern in humans. The most important Indicators are attention déficits, impulsivity and a hyperactivity that is primarily seen in boys. The disease starts at an eariy âge and symptoms are most intense during childhood. After puberty the signs of the disease are more masked and focus on cognitive dysfunction (Jucalte et al. 2005; Turner et al. 2003). Although modem research broadened the understanding of the pathomechanism the exact etiology of the disease remains unclear.

Interestingly, the symptoms seen In ADHD are not due to a hyperactivity but a hypoactivity of the so called executive loop of the striatum (Winstanley et al., 2006; Plizska, 2005). The executive loop is responsible for the régulation of cognitive processes such as planning, working memory and attention (Benke et al., 2003; Easton et al., 2007). A dysfunction of the prefrontal cortex or other pathways within the loop Induces Impulsivity and a loss of the ability to filter stimuli that corne from the outslde. The latter causes the symptoms of sustained attention and hyperactivity (Roberts and Wallis, 2000; Gonzales et al., 2000). The dopaminergic neurotransmitter System plays a central role in regulating the activity of the executive loop (Jucaite et al., 2005). This conclusion is also supported by the current treatment for ADHD that aims for an activation of the dopaminergic neurotransmitter System (Jucaite et al., 2005).

Phosphodiesterases (PDE) are expressed in nearly ail mammalian cells. To date eleven famiiies of phosphodiesterases hâve been identified in mammals (Essayan, 2001). It is well established that PDEs are criticaliy involved in cell signalling. Specificaily, PDEs are known to inactivate the cyclic nucléotides cAMP and/or cGMP (Soderling and Beavo, 2000). The cyclic nucléotides cAMP and cGMP are syntheslsed by the adenylyl and guanylyl cyclases and are second messengers that control many key ceilular fonctions. The synthesis of cAMP and cGMP is regulated by different G-protein-coupled receptor types Including dopamine D1 and D2 receptors (Mutschler, 2001).

The phosphodiesterases of the different familles vary in their substrate selectivity. Thus, some famiiies only hydrolyse cAMP others only cGMP. Some phosphodiesterases, such as phosphodiesterase 2 and 10, inactivate both cAMP and cGMP (Menniti et al., 2006).

Furthermore, there Is a différence In the distribution of the different phosphodiesterases within the organism and additîonally, within any particular tissue or organ. For instance, the distribution pattern of the phosphodiesterases within the brain Is quite spécifie (Menniti et al., 2006).

τ

Finally, phosphodiesterase familles hâve different regulatory properties and intracellular location; some are bound to cell membranes and some are dissoclated in the cytoplasm, additionally, a division into various intracellular compartiments has been reported (Conti and Jin, 1999).

These différences in the fonction and location of the different PDE enzyme families suggest that the Indîvid ual phosphodiesterases are selectively involved in regulating many different physiological processes. Accordingly, sélective phosphodiesterase inhibitors may with fine specificity regulate different physiological and pathophysiologicai processes.

PDE2 and PDE10 hydrolyse both, cGMP and cAMP (Menniti et al., 2006; Soderling et al., 1999; Kotera et al., 1999).

They are both abundantiy expressed in the brain indicating their relevance in CNS fonction (Bolger et al., 1994; Menniti et al., 2001).

PDE2 mRNA Is mainiy distributed in olfactory bulb, olfactory tubercle, cortex, amygdala, striatum, and hippocampus (Lakics et al., 2005; van Staveren et al., 2003). PDE10 (PDE10A) is primarily expressed in the nucléus accumbens and the caudate putamen. Areas with moderate expression are the thalamus, hippocampus, frontal cortex and olfactory tubercle (Menniti et al., 2001).

Although there are certainly fine différences in the fonction and expression patterns of PDE2 and 10, the expression of PDE2 in the hippocampus, the cortex and in the striatum and the expression of PDE10 in striatum, hippocampus and frontal cortex indicate an involvement in the mechanism of leaming and memory/cognition. This Is further supported by the fact that increased levels of both cGMP and cAMP are involved in the process of short and long term potentiation (LTP) fomning (Blokland et al., 2006; Prickaerts et al., 2002). LTP is regarded as the electrophysiological basis of long term memory (Baddeley, 2003). Boess et al. (2004) showed that PDE2 inhibitors ampiify the génération of LTP. Additionaily, it is reported that the sélective PDE2 inhibitor BAY60-7550 enhances leaming and memory in rats and mice in different animal modeis (Boess et al., 2004; Rutten et al., 2006). Similar pro-cognitive effects are described for sélective PDE10 Inhibitors, such as papaverine and MP-10. Rodefer et al. (2005) hâve found that papaverine reverses attentional set-shifting déficits Induced by subchronlc administration of phencyclidine, an NMDA antagonlst, in rats. Grauer et al. (2009) could show a positive effect of papaverine and MP-10 on cognitive déficits in the novel object récognition and in propulse inhibition of acoustic startle response In rats. These data support the procognitive effect of PDE2 and/or 10 and a synergistic effect of PDE2 and 10 on cognltion.

Furthermore, the expression of PDE2 in the nucléus accumbens (part of the striatum), the olfactory bulb, the olfactory tubercle and the amygdala and the expression of PDE10 in the nucléus accumbens, the olfactory tubercle and the thalamus supports additional Involvement of PDE2 and 10 in the pathophysiology of anxiety and dépression (Modell et al., 1990). This Is supported by in vivo studies. The sélective PDE2 inhibitors BAY60-7550 and ND-7001 are described to be effective in animal models of anxiety and stress-induced behavior (Masood et al., 2008,2009).

In addition to the pro-cognitive and antidepressant potential of PDE10 inhibition there is evidence for an additional antipsychotic potential of PDE10 inhibitors. In the striatum PDE10 Is predominately found postsynaptic in the medium spiny neurons (Xie et al., 2006). By this location, PDE10 may hâve an important influence on the signal cascade induced by dopaminergic and glutamatergic Input on the striatum, two neurotransmitter Systems playing a predominate rôle In the pathomechanlsm of psychosis. Focuslng on the dopaminergic input on the medium spiny neurons, PDE10A Inhibitors by up-regulating cAMP and cGMP levels act as D1 agonists and D2 antagonists because the activation of Gs-protein coupled dopamine D1 receptor Increases intraceliular cAMP, whereas the activation of the Gi-protein coupled dopamine D2 receptor decreases Intraceliular cAMP levels through inhibition of adenylyl cyclase activity (Mutschler et al., 2001). Accordingly, PDE10 inhibitors are reported to be active in several animal models of schizophrenia (Schmidt et al., 2008; Sluciak et al., 2006; Grauer et al., 2009).

PDE10 Inhibitors hâve been disclosed recently in J. Med. Chem, 2011,54, 76217638.

For drugs with an intended action in the central nervous System (CNS), it Is assumed that unbound drug in interstitiel spaces in the brain is In direct contact or in equilibrium with the site of action (de Lange and Danhof, 2002).

It Is commonly accepted that unbound or free drug Is the species available for interaction with drug targets within the body, and this is referred to as the free drug hypothesis.

Because cerebrospinal fluid (CSF) is in direct contact with the brain tissue, it is assumed to readily equilibrate with brain interstitiel fluid concentration (Melneke et al., 2002; Shen et a!., 2004) so that CSF concentration is used as a common surrogate measure for drug unbound concentration in clinical pharmacology studies (Bonati et al., 1982; Chérubin et al., 1989; Garver, 1989; Reiter and Doron, 1996; Ostermann et a!., 2004). Accordingly, for compounds with an intended action in the central nervous System it is important that they reach a high CSF concentration and a high CSF to plasma ratio in order to hâve high pharmacological activity in the CNS.

Inhibition of the hERG channel by xenobiotics and subséquent delayed cardiac repolarization is associated with an increased risk for a spécifie polymorphie ventrlcular tachyarrhythmla, torsade de pointes, as established by Sanguinetti et al. (1995, Cell, Apr. 21, 81(2):299-307) and a large body of subséquent evidence. As such, low hERG channel Inhibition, such as that shown by the compounds of the présent invention, Is hlghly désirable for therapeutics.

Several familles of PDE2 inhibitors are known. Imidazotriazinones are clalmed In WO 2002/068423 for the treatment of e.g. memory deficiency, cognitive disorders, dementia and Alzheimer’s disease. Oxindoles are described in WO 2005/041957 for the treatment of dementia. Further Inhibitors of PDE2 are known from WO 2007/121319 for the treatment of anxiety and dépréssion, from WO 2013/034761, WO 2012/104293 and WO2013/000924 for the treatment of neurologlcal and psychiatrie disorders, from WO 2006/072615, WO 2006/072612, WO 2006/024640 and WO 2005/113517 for the treatment of arthritis, cancer, edema and septic shock, from WO 2005/063723 for the treatment of rénal and liver failure, liver dysfunction, restless leg syndrome, rheumatic disorders, arthritis, rhinitis, asthma and obesity, from WO 2005/041957 for the treatment of cancer and thrombotic disorders, from

WO 2006/102728 for the treatment of angina pectoris and hypertension from WO 2008/043461 for the treatment of cardiovascular disorders, erectile dysfunction, inflammation and rénal failure and from WO 2005/061497 for the treatment of e.g. dementia, memory disorders, cancer and osteoporosis.

Finally, benzodiazépines are described In WO 2005/063723 for the general treatment of CNS diseases including anxiety, dépréssion, ADHD, neurodegeneration, Alzheimer’s disease and psychosis.

Aim of the Invention

It has now been found that compounds of the présent invention according to general formula I are effective Inhibitors of phosphodiesterase 2 and/or 10.

Besldes the inhibition property toward phosphodiesterase 2 and/or 10 enzymes, the compounds of the présent invention provide further advantageous pharmacokinetic properties. For example the compounds of the présent invention show high concentration in cerebrospinal fluid (CSF) and hâve a high CSF to plasma ratio, which translates In lower efficacious doses of the compounds for disease treatment and as a conséquence in further potentlal advantages such as minimization of slde effects . Furthermore, compounds of the présent inventions show good metabolic stabllity and low potential of formation of biologicaliy active métabolite and low hERG potassium channel inhibition.

Accordingly, one aspect of the invention refers to compounds according to formula I, the tautomers thereof, the stereoisomers thereof, the mixtures thereof, the solvatés thereof, the hydrates thereof and salts thereof as Inhibitors of phosphodiesterase 2 and/or 10.

Another aspect of the invention refers to compounds according to formula I, the tautomers thereof, the stereoisomers thereof, the mixtures thereof, the solvatés thereof, the hydrates thereof and the physiologically acceptable salts thereof as inhibitors of phosphodiesterase 2 and/or 10 and reaching high concentrations in cerebrospinal fluid (CSF) and/or having high CSF to plasma ratio.

Another aspect of the Invention refers to compounds according to formula I, the tautomers thereof, the stereolsomers thereof, the mixtures thereof, the solvatés thereof, the hydrates thereof and the physiologically acceptable saits thereof as Inhibltors of phosphodiesterase 2 and/or 10 and showing good metabolic stability.

Another aspect of the Invention refers to compounds according to formula I, the tautomers thereof, the stereoisomers thereof, the mixtures thereof, the solvatés thereof, the hydrates thereof and the physiologically acceptable salis thereof as inhibltors of phosphodiesterase 2 and/or 10 with low hERG channei inhibition.

Another aspect of the invention refers to compounds according to formula I, the tautomers thereof, the stereolsomers thereof, the mixtures thereof, the solvatés thereof, the hydrates thereof and the physiologically acceptable salts thereof as inhibltors of phosphodiesterase 2 and/or 10 with low potential of forming biologically active métabolite.

In a further aspect this Invention relates to pharmaceutical compositions, containing at least one compound according to formula I, the tautomers thereof, the stereoisomers thereof, the mixtures thereof, the solvatés thereof, the hydrates thereof and the physiologically acceptable salts thereof optionally together with one or more inert carriers and/or diluents.

A further aspect of the présent Invention relates to compounds according to formula I, the tautomers thereof, the stereolsomers thereof, the mixtures thereof, the solvatés thereof, the hydrates thereof and the physiologically acceptable salts thereof or pharmaceutical compositions comprising compounds according to formula I, the tautomers thereof, the stereolsomers thereof, the mixtures thereof, the solvatés thereof, the hydrates thereof and the physiologically acceptable salts thereof for the use In the prévention and/or treatment of disorders associated with PDE2 and/or 10 hyperactivity and/or cAMP and/or cGMP hypofunction.

Another aspect of the Invention relates to processes of manufacture of the compounds of the présent invention.

A further aspect of the présent invention relates to compoiinds according to formula 1, the tautomers thereof, the stereolsomers thereof, the mixtures thereof, the solvatés thereof, the hydrates thereof and the physlologlcaily acceptable salts thereof or pharmaceutical compositions comprislng compounds according to formula I, the tautomers thereof, the stereolsomers thereof, the mixtures thereof, the solvatés thereof, the hydrates thereof and the physlologically acceptable salts thereof for the use in the prévention and/or treatment of diseases or conditions which can be influenced by inhibition of PDE2 and/or 10 hyperactivlty and/or cAMP and/or cGMP hypofunction, such as (1) disorders comprislng the symptom of cognitive deficlency;

(2) organic, including symptomatlc, mental disorders, dementia; (3) mental retardation; (4) mood affective disorders; (5) neurotic, stress-related and somatoform disorders including anxlety disorders; (6) behavloural and emotional disorders with onset usually occumng in childhood and adolescence, attention déficit hyperactivity syndrome (ADHD) Including Autism spectrum disorders; (7) disorders of psychoioglcal development, developmental disorders of scholastic skills; (8) schizophrénie and other psychotic disorders; (9) disorders of adult personality and behavlour; (10) mental and behavioural disorders due to psychoactive substance use; (11) extrapyramidal and movement disorders; (12) episodic and paroxysmal disorders, epilepsy; (13) Systemic atrophies primarily affecting the central nervous System, ataxia; (14) Behavioural syndromes associated with physiologlcal disturbances and physical factors; (15) sexual dysfunction comprising excessive sexuai drive; (16) factitious disorders.

In addition, the compounds of the présent invention can be used for the treatment, amelioration and / or prévention of cognitive impairment being related to perception, concentration, cognltlon, leaming or memory.

In addition, the compounds of the présent invention can be used for the treatment amelioration and / or prévention of cognitive impairment being related to ageassociated leaming and memory impairments, age-assoclated memory losses, vascular dementia, craniocerebral trauma, stroke, dementia occumng after strokes (post stroke dementia), post-traumatic dementia, general concentration impairments, concentration impairments in children with leaming and memory problems, Alzheimeris disease, Lewy body dementia, dementia with degeneration of the frontal lobes, induding Pick's syndrome, Parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyotropic latéral sclerosis (ALS), Huntington’s disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementîa or Korsakoffs psychosis. In addition, the compounds of the présent Invention can be used for the treatment of Alzheimer’s disease.

In addition compounds of the présent Invention can be used for the treatment of pain disorders, Including but not llmited to inflammatory, neuropatic and osteoarthritic pain.

In addition, the compounds of the présent invention can be used for the treatment of sleep disorders, bipolar disorder, metabolic syndrome, obesity, diabetis mellitus, hyperglycemia, dyslipidemia, impaired glucose tolérance, or a disease of the testes, brain, small intestine, skeletal muscle, heart, lung, thymus or spleen.

Other aims of the présent invention will become apparent to the sktlled man directly from the foregoing and following remarks.

Detailed description

In a first aspect the présent Invention relates to compounds of general formula I

I wherein

A is selected from the group A^a consisting of

rV	a	σ	σ
σ N	σ'	σ	σ

wherein above mentioned phenyl-, pyridinyl-, pyrimidinyl-, pyridazinyl and pyrazinyl groups are substituted with R¹ and R²;

R¹ Is selected from the group R^1a consisting of

H, halogen, NC-, Ci-e-alkyl-, Ci-e-alkyl-O-, C^-cycloalkyl and R⁸-(CH2)nO- with n = 0,1,2, 3 or 4, wherein above mentioned Ci^-alkyl-, Ci^-alkyl-O-, Cj^-cycloalkyl and R⁸-(CH₂)n-O- groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, HO- and optionally with 1 to 7 fluorine atoms substituted Ci-

3-alkyl-;

R² is selected from the group R^2a consisting of

H, HO-, halogen, Ci-e-alkyl-, Ci-e-alkyl-O-, C3*6-cycloalkyl, heterocyclyl, heterocyclyl-Ci-3-alkyl-, phenyl, heteroaryl, R⁸-(CH2)n-O- with n - 0.1,2, 3 or 4, and R⁸-ÎCH2)_m-(CH)(CH₃)-(CH2)o-O- with m = 0,1 or 2 and o = 0, 1 or 2, wherein above mentioned Ci^-alkyl-, Ci^-alkyl-O-, Cye-cycloalkyl, heterocyclyl, heterocyclyl-Ci.3-alkyl-, phenyl, heteroaryl, R⁸- (CH2)n-Oand R⁸-{CH2)m-(CH)(CH3)-(CH2)0-0-groups may optionally be substituted with 1 to 5 substituents Independently selected from the group consisting of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-O-, and optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-;

R³ is selected from the group R³³ consisting of

H, halogen, NC-, CM-alkyl- and Cj-e-cycloalkyl-, wherein the above mentioned CM-alkyl- and Cj^-cycloalkyl-groups may optionally be substituted with 1 to 9 substituants independently selected from the group consisting of halogen, NC-, HO-, Ci-3-alkyland Ci-3-alkyl-O-;

R⁴, R⁵ are selected independently of each other from the group R^4a/R^5a consisting of

H, halogen, NC-, HO-, Ci-e-alkyl-, C^-alkyl-O-, C3-e-cycloalkyl·, C^cycloalkyl-Ci-3-alkyl-, C3-8-cycloalkyl-O-, heterocyclyl-O-, heterocyclyl, heteroaryl, R⁷-CH2-O- and R⁷-(CH2)2-O-, wherein above mentioned C^alkyl-, C^alkyl-O-, C3-s-cycloalkyl-, C3-8-cycloalkyl-Ci.3-alkyl-, C3^-cycloalkyl-0-, heterocyclyl-O-, heterocyclyl, heteroaryl, R⁷-CH2-O- and R⁷-(CH2)2-O-groups, may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, optionally with 1 to 5 halogen atoms, substituted Ci-2-alkyl-, and optionally with 1 to 5 halogen atoms substituted Ci.2-alkyl-0-;

R^e Is selected from the group R⁶³ consisting of

H, NC-, Ci-e-alkyl-, C3-8-cycloalkyl-, C3-8-cycloalkyl-Ci.₃-alkyl- and C3-8cycloalkyl-Owherein above mentioned Ci^-alkyl- groups may optionally be substituted with 1-3 halogen atoms;

R⁷ is selected from the group R^7a consisting of

H, carbocyclyl, heterocyclyl and heteroaryl, wherein above mentioned carbocyclyl, heterocyclyl and heteroarylgroups may optionaliy be substituted with 1 to 4 substituents independently selected from the group consisting of HO-, optionally with 1 to 3 halogen atoms substituted Ci^-alkyl-, optionally with 1 to 3 halogen atoms substituted C_M-alkyl-O- and halogen;

R^e is seiected from the group R⁸³ consisting of

Cu-e-cycloalkyl, heterocyclyl, heterocyclyl-Ci^-alkyl-, phenyl and pyridyl, wherein above mentioned Cu-e-cycloalkyl, heterocyclyl, heterocyclylCi-3-alkyl-, phenyl and pyridyl groups may optionally be substituted with 1 to 5 substituents Independently selected from the group conslsting of HO-, fluorine and optionally with 1 to 7 halogen atoms substituted Ci-3-alkyl-;

the tautomers thereof, the stereoisomers thereof, the mixtures thereof, the solvatés thereof, the hydrates thereof and the salts thereof.

Unless otherwise stated, the groups, resldues, and substituents, particulariy R¹, R², R³, R⁴'⁵, R®, R⁷, R® and A are defined as above and hereinafter. If residues, substituents, or groups occur several times in a compound they may hâve the same or different meanings. Some preferred meanings of groups and substituents of the compounds according to the invention will be given hereinafter.

In a further embodiment of the présent invention A is selected from the group A^b consisting of wherein above mentioned phenyl- and pyridinyl- groups are substituted with R¹ and R².

In a further embodiment of the présent invention A Is selected from the group A^c consisting of wherein above mentioned phenyl- and pyridinyl- groups are substituted with R¹ and R².

In a further embodiment of the présent invention A is selected from the group A^d consisting of

In a further embodiment of the présent invention is selected from the group A® consisting of

In a further embodiment of the présent Invention A Is selected from the group A^f consisting of

whereln above mentioned phenyl-group Is substituted with R¹ and R².

In a further embodiment of the présent invention

A Is selected from the group A® consisting of

In a further embodiment of the présent Invention

R¹ is selected from the group R^1b consisting of

H, halogen, Ci-e-alkyl- and C^e-cycloaikyl whereln above mentioned Ci-e-aikyl- and Cs^-cycloalkyi-groups may optionally be substituted with 1 to 5 substituents Independently selected from the group consisting of halogen, HO- and optionally with 1 to 7 fluorine atoms substituted Cva-alkyl-.

In a further embodiment of the présent Invention

R¹ Is selected from the group R^1c consisting of

H, H3C-, F3C-, F2HC-, FH2C-, fluorine, chlorine and bromine.

In a further embodiment of the présent invention

R¹ is seiected from the group R^1c1 consisting of

H3O, fluorine and chlorine.

In a further embodiment of the présent invention

R¹ is seiected from the group R^1d consisting of

H, fluorine and chlorine.

In a further embodiment of the présent Invention

R² Is seiected from the group R^2a1 consisting of

HO-, Ci_6-alkyl-, Ci^-alkyi-O-, C^-cycloalkyl, C₃-e-cycloalkyi-Ci.3-alkyi-, heterocyclyl, heterocyclyl-Ci.3-alkyl-, phenyl, heteroaryl, R^e-(CH2)n-Owith n = 0,1,2,3 or 4, and R⁸-(CH2)m-(CH)(CH₃)-(CH2)₀-O- with m = 0,1 or 2 and o = 0,1 or 2 whereln above mentioned Ci-e-alkyl- and Ct-e-alkyl-O-groups are substituted with 1 to 5 substituents independently seiected from the group consisting of HO-, and optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-O-, and wherein above mentioned C-i-e-alkyi- and Ci^-alkyl-O-groups may optionally be substituted with 1 to 5 substituents Independently seiected from the group consisting of halogen, and optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-, and wherein above mentioned C^-cycloalkyl, C3-6-cycloalkyl-Ci-3-alkyl-, heterocyclyl, heterocyclyl-Ci.3-alkyl-, phenyl, heteroaryl, R⁸-(CH₂)_n-Oand R®-(CH2)m-(CHXCH3)-(CH2)o-0-groups may optionally be substituted with 1 to 5 substituents independently seiected from the group consisting of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted Ci.₃-aikyl-O-, and optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-.

In a further embodiment of the présent invention

R² Is selected from the group R^2b consisting of

H, HO-, Ci-i-alkyl-, CM-alkyl-0-, C3-e-cycloalkyl, heterocyclyl, heterocyclyl-Ci-3-alkyl-, phenyl, heteroaryl, R⁸-(CH2)n-O- with n = 0,1,2 or 3 and R⁸-(CH2)m-(CH)(CH3)-(CH2)0-O- with m = 0 or 1 and o = 0 or 1 wherein above mentloned Ci-4-alkyi-, Ci^-alkyl-O-, C3-6-cycloalkyl, heterocyclyl, heterocyclyi-Ci-3-aikyl-, R⁸-(CH2)n-O- and and R⁸(CH2)m-(^CH)(^CH3)-(CH2)o-O-groups may optionally be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted C1.3alkyl-O-, and optionally with 1 to 7 fluorine atoms substituted C1.3alkyl-.

In a further embodiment of the présent invention

R² is selected from the group R²*¹¹ consisting of

HO-, Ci_4-aikyl-, Ci-i-alkyl-O-, C3-e-cycloaikyl, C3^-cycioalkyl-Ci-3-alkyl-, heterocyclyl, heterocyclyl-Ci-3-alkyl-, phenyl, heteroaryl, R⁸-(CH2)n-Owith n = 0,1,2 or 3 and R⁸-(CH2)m-(CH)(CH3)-(CH2)o-O- with m = 0 or 1 and 0 = 0 or 1 wherein above mentioned Ci-ralkyl- and Ci-ralkyl-O- groups are substituted with 1 to 3 substituents independently selected from the group consisting of HO- and optionally with 1 to 7 fluorine atoms substituted Ci-3-aikyl-O-, and wherein above mentioned CM-alkyl- and Ci-4-alkyl-O-groups may optionally be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, and optionally with 1 to 7 fluorine atoms substituted Ci.3-aikyl-, and wherein above mentioned C3^-cycloalkyl-, C₃^-cycloaikyl-Ci-3-alkyl-, heterocyclyl, heterocyclyl-Ci.3-alkyl-, R⁸-(CH2)n-O- and and R⁸(CH2)_m-(CH)(CH₃)-(CH2)o-0-groups may optionally be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted C1.3alkyl-O-, and optionally with 1 to 7 fluorine atoms substituted C1.3alkyl-.

In a further embodiment of the présent invention

R² is selected from the group R^2c consisting of

H, HO-, CM-alkyl-, CM-alkyl-0-, Cî^-cycloalkyl, heterocyclyl, R⁸-(CH₂)_nO- with n = 0,1,2, or 3, and R^CHsMCHXCHaHC^Jo-O- with m = 0 or 1 and o = 0 or 1 wherein above mentioned Ci-4-alkyl-, Ci-4-alkyl-O-, Cj^-cycloalkyl, heterocyclyl, R⁸-(CH2)n-O- and and R⁸-(CH2)_m-(CH)(CH₃)-(CH₂)_o-Ogroups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-O-, and optionally with 1 to 7 fluorine atoms substituted Ci.3-alkyl-.

In a further embodiment of the présent invention

R² is selected from the group R^2c1 consisting of

HO-, Ci_4-alky1-, Ci-4-alkyl-O-, C₃-6-cycloalkyl, Cs-e-cycloalkyl-Ci-s-alkyl-, heterocyclyl, R⁸-(CH2)n-O- with n = 0,1,2, or 3, and R⁸-(CH2)m(CH)(CH₃)-(CH₂)o-0- with m = 0 or 1 and o = 0 or 1 wherein above mentioned CM-alkyl- and Ci^-alkyl-O-groups are substituted with 1 to 5, preferably 1 to 3, substituents independently selected from the group consisting of HO-, and optionally with 1 to 7 fluorine atoms substituted Cvs-alkyl-O-, and wherein above mentioned Ci-4-alkyl- and Ci^-alkyl-O-groups may optionally be substituted with 1 to 5, preferably 1 to 3, substituents independently selected from the group consisting of halogen, and optionally with 1 to 7 fluorine atoms substituted Ci.₃-alkyl-, and wherein above mentioned C₃-ecycloalkyl, C₃-e-cycloalkyl-Cb3-alkyl-, heterocyclyl, R⁸-(CH2)n-O- and and R⁸-(CH2)_m-(CH)(CH₃)-(CH₂)_o-O groups may optionally be substituted with 1 to 5, preferably 1 to 3, substituents independently selected from the group consisting of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted C1.3alkyt-O-, and optionally with 1 to 7 fluorine atoms substituted C1.3alkyl-.

In a further embodiment of the présent invention R² is selected from the group R^2d consisting of

H, HO-, CM-alkyl-, ÛM-alkyl-O-, a saturated 6 membered monocyclic heterocycle containing one heteroatom selected from N or O, R⁸-(CH2)nO- with n = 0,1 or 2, and R⁸-(CH2)m-(CH)(CH3)-(CH2)₀-O- with m = 0 or 1 and o = 0 or 1 wherein above mentioned C-M-alkyi-, Ci^-alkyi-O-, saturated 6 membered monocyclic heterocycle containing one heteroatom selected from N or O, R⁸-(CH2)n-O- and and R⁸-(CH2)m-(CH)(CH₃)(CH₂)_o-O- groups may optionally be substituted with 1 to 5 substituents Independently selected from the group consisting of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted C1.3alkyl-O-, and optionally with 1 to 7 fluorine atoms substituted C1.3alkyl-.

In a further embodiment of the présent invention

R² is selected from the group R^2d1 consisting of

HO-, Ci-4-alkyi-, C^-aikyl-O-, Cii-cycloalkyl, C3^-cycloaikyl-Ci.₃-aikyl-, a saturated 5 or 6 membered monocyclic heterocycle containing one heteroatom selected from N or O, R⁸-(CH2)n-O- with n = 0,1 or 2, and R⁸’(CH2)_m-(CH)(CH₃)-(CH2)o-O- with m = 0 or 1 and o = 0 or 1 wherein above mentioned C^-alkyl- and CM-alkyl-O-groups are substituted with 1 to 5, preferabiy 1 to 3, substituents independently selected from the group consisting of HO-, and optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyi-O-, and wherein above mentioned Ci^-alkyl- and CM-alkyl-O-groups may optionally be substituted with 1 to 5, preferably 1 to 3, substituents independently selected from the group consisting of halogen, and optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-, and wherein above mentioned Cj-e-cycloalkyl-, C3^-cycloalkyl-Ci.3-alkyl-, saturated 5 or 6 membered monocyclic heterocycle containing one heteroatom selected from N or O, R⁸-(CH2)n-O- and and R^a-(CH2)m(CH)(CH3XCH₂)o-O- groups may optionally be substituted with 1 to 5, preferably 1 to 3, substituents independently selected from the group consisting of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-O-, and optionally with 1 to 7 fluorine atoms substituted Ci_3-alkyl-.

In a further embodiment of the présent invention R² is selected from the group R²® consisting of

In a further embodiment of the présent Invention R² is selected from the group R²®¹ consisting of

In a further embodiment of the présent Invention R² is selected from the group R²* conslstlng of

In a further embodiment of the présent invention R² is selected from the group R²¹¹ consisting of

In a further embodiment of the présent invention

R³ is selected from the group R³³¹ consisting of

C3_e-cycloalkyl-, whereln the above mentioned C3-e-cycloalkyl-group may optionally be substituted with 1 to 9 substituents independently selected from the group consisting of halogen, NC-, HO-, Cvyalkyl- and Ci-3-alkyl-O-.

In a further embodiment of the présent invention

R³ Is selected from the group R^3b consisting of

H, Ci-3-alkyl-, cyclobutyl- and cyclopropyl-, wherein the above mentioned Ci-3-alkyl-, cyclobutyl- and cyclopropyl groups may optionally be substituted with 1 to 7 substituents independently selected from the group consisting of halogen, C1.3alkyl-O-, NC- and HO-.

In a further embodiment of the présent Invention

R³ is selected from the group R³⁰ consisting of

H, and H3C- and cyclopropyl-, wherein the above mentioned H3C- and cyclopropyl-groups may optionally be substituted with 1 to 3 fluorine atoms.

In a further embodiment of the présent invention R³ is selected from the group R^M consisting of

H and H₃C-, wherein the above mentioned H₃C-group may optionally be substituted with 1 to 3 fluorine atoms.

In a further embodiment of the présent invention

R³ Is selected from the group R³® consisting of

H.

In a further embodiment of the présent invention R³ is selected from the group R^3f consisting of

H₃C-, wherein the above mentioned HsC-group may optionally be substituted with 1 to 3 fluorine atoms.

In a further embodiment of the présent invention

R³ is selected from the group R³⁹ consisting of cyclopropyl-, wherein the above mentioned cyclopropyl-group may optionally be substituted with 1 to 7 substituents independently selected from the group consisting of halogen, Ci.₃-alkyl-O-, NC- and HO-.

In a further embodiment of the présent Invention

R⁴, R⁵ are selected independently of each other from the group R^4b/R^5b consisting of

H, halogen, HO-, H₃C-, F₃C-, H₃C-O-, F₂HC-O-FH₂C-O- F3C-O- C_Malkyl-O-, R⁷-CH2-O- and R⁷-(CH2)₂-O-, wherein above mentioned C^-alkyl-O-, R⁷-CH2-O- and R⁷-(CH2)₂-Ogroups, may optionally be substituted with 1 to 5 substituents Independently selected from the group consisting of halogen, optionally with 1 to 5 halogen atoms substituted Ci.₂-alkyl-, and optionally with 1 to 5 halogen atoms substituted Ci-₂-alkyl-O-.

In a further embodiment of the présent Invention

R⁴, R⁵ are selected Independently of each other from the group R^4c/R^5c consisting of

H, fluorine, chlorine, bromlne, HO-, H₃C-, F₃C-, H3C-O-, F3C-O- and R⁷CH₂-O-.

In a further embodiment of the présent Invention

R⁴, R⁵ are selected from the group R^4d/R^w consisting of

H-.

In a further embodiment of the présent invention

R⁶ is selected from the group R^6b consisting of

H, C^-alkyl- and cyclopropyi-, wherein above mentioned C^-alkyi-group may optionally be substituted with 1-9 fluorine and/or chlorine atoms.

In a further embodiment of the présent invention R® is selected from the group R⁶⁰ consisting of

H and Ci.₂-alkyi-, wherein above mentioned Ci-₂-alkyl- group may optionally be substituted with 1-5 fluorine and/or chlorine atoms.

In a further embodiment of the présent invention

R⁰ is selected from the group R^w conslsting of

H, H3C-, FH2C-, F2HC- and F3C-.

In a further embodiment of the présent invention

R⁰ is selected from the group R⁶® consisting of

Η₃0-, FH₂C-, F₂HC- and F3C-.

In a further embodiment of the présent Invention

R⁶ is selected from the group R⁰¹ consisting of H₃C-.

In a further embodiment of the présent invention

R⁷ is selected from the group R⁷” consisting of

H, phenyl, heteroaryl, cycloalkyl and heterocyclyl wherein above mentioned phenyl, heteroaryl, cycloalkyl and heterocyclyl-groups may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of halogen, and optionally with 1 to 3 halogen atoms substituted C1.3alkyl-O-.

In a further embodiment of the présent invention R⁷ Is selected from the group R^7c consisting of

H and phenyl, wherein above mentioned phenyi group may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of halogen and optionally with 1 to 3 halogen atoms substituted Ci-3-alkyl-O-.

In a further embodiment of the présent invention

R⁷ is selected from the group R^7d consisting of

H-.

In a further embodiment of the présent invention

R⁸ is selected from the group R^8b consisting of

C^-cycloalkyl, heterocyclyl and heterocydyl-Ci-3-alkyl-, whereln above mentioned C3-e-cycloalkyl, heterocyclyl and heterocyclyl-Ci-3-alkyl-groups may optionally be substituted with 1 to 5 substituents Independently selected from the group consisting of HO-, fluorine and optionally with 1 to 7 halogen atoms substituted Ci-3-a1kyl-.

In a further embodiment of the présent invention

R⁸ is selected from the group R⁸⁰ consisting of

Cj^-cycloalky! and heterocyclyl, wherein above mentioned C3-e-cycioalkyl and heterocydyl-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of HO-, fluorine and optionally with 1 to 7 halogen atoms substituted Ci-3-alkyl-.

In a further embodiment of the présent invention R⁸ is selected from the group R⁸⁰¹ consisting of

C3-6-cycloalkyl and a saturated 4 to 6 membered monocyclic heterocyde containing one or two heteroatoms selected from N or O, wherein above mentioned C3^-cydoalkyl and heterocyclyl-groups may optionally be substituted with 1 to 5 substituents Independently selected from the group consisting of HO-, fluorine and optionally with 1 to 7 halogen atoms substituted C^-alkyl-.

In a further embodiment of the présent invention R⁸ is selected from the group R⁸*¹ consisting of

Δ OO QÇOOd wherein above mentioned groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of HO-, fluorine and optionaily with 1 to 5 halogen atoms substituted Ci-₃aikyl-.

In a further embodiment of the présent Invention R⁸ Is selected from the group R^M1 consisting of

Δοαο QÇOOÔ * wherein above mentioned groups may optionaily be substituted with 1 to 5 substituents independently selected from the group consisting of HO-, fluorine and optionaily with 1 to 5 haiogen atoms substituted Ci.₃alkyi-.

In a further embodiment of the présent Invention R⁸ is selected from the group R⁸® consisting of

wherein above mentioned groups may optionaily be substituted with 1 to 3 substituents independently selected from the group consisting of HO-, fluorine and optionaily with 1 to 3 halogen atoms substituted Ciralkyl-.

In a further embodiment of the présent Invention R⁸ Is selected from the group R^8e1 consisting of

wherein above mentioned groups may optionaily be substituted with 1 to 3 substituents Independently selected from the group consisting of HO-, fluorine and optionally with 1 to 3 halogen atoms substîtuted C1.3alkyl-.

in a further embodîment of the présent Invention R® Is selected from the group R^ef consisting of

In a further embodîment of the présent Invention R is selected from the group R⁸¹¹ consisting of

Each R^1x, R^2x, R^3x, R^4x/5x,R^8x, R^7x, R^8x and A^K represents a characterized, individual embodîment for the corresponding substituent as described above. Thus given the above définitions, preferred individual embodiments of the first aspect of the invention are fully characterized by the term (R^1x, R^2x, R^3x, R^4x/5x,R^6x, R^7x, R^8x and A^x), 10 wherein for each index x an Individual figure Is given that ranges from “a to the highest ietter given above. Ail individual embodiments described by the term In parenthèses with full permutation of the indices x, referring to the définitions above, shall be comprised by the présent invention.

The following Table 1 shows, exemplarily and In the order of increasing preference 15 from the first line to the last line, such embodiments E-1 to E-37 of the invention that are considered preferred. This means that embodîment E-37, represented by the entries in the last row of Table 1, is the most preferred embodîment.

Table 1: Preferred embodiments E-1 to E-37 ofthe Invention

	A^K	_Rlx	_Rix	r5T	_R4x_/r5x	_Réx	R^ïx	r*⁵
E-1	A^b	-rTE-	r3F	_RJb	R^4b/R^5b	-rBF	-rTIT	-rET
E-2	A^c	R^1b	-r25-	-r35-	R^4b/R^&D	RtJb	“rTF	-rET
E-3	A^c	R^1c	-rZE	RJb	R^4d/R^so	RtJb	-rTc-	_R8b
E-4	A^c	-Rie-		-r3c	R^4c/R^ic	-rET	-rTîT	-rEB-
E-5	A^c	-Rie-	“r^25-	-r3c-	R^4c/R^5c	-rET	-r7T	“fF~
E-6	A^c	r1_C	-RTë-	-r3c-	R^/R⁵⁰	-rBc-	r/c	rBC
E-7	A^c	R^1c	R^Zd	r^3c	R^4C/R^5C	-rBc-	-rTc-	R⁸⁰
E-8	A^d	-Rie-	-rZS-	-r33“	R^4d/R^M	_RBe	-	RM
E-9	A®	-rT3-	-r23-	-r33-	R^4d/R^5d	-rST	-	R^Bf
E-10	A®	R^1d	R²®	~r33-	R^4d/R^M	-rW	-	-
E-11	A'	-rTO-	-r23-	-r33-	R^4d/R^M	-RBë-	-	-rET
E-12	a’	-rTÏ-	R²®	-r3T	R^/R⁵⁰	RtJJ	-	-
E-13	a’	-rTO-	R²’	-r33	R^4d/R^M	_RtJe	-	-
E-14	A¹	R^ld	R²'	-r3J-	R^4d/R^5d	-rET	-	-
E-15	A^a	-Rlâ-	-R2a	R³®¹	R^4a/R^5a	Rfe	-rTF	-Rter
E-16	A^b	-Rie-	-r2cT	R^3a1	R^4D/R^5b	-rEB-	-rTE-	-rBEF
E-17	A^d	-rTc-	R^2d	-R3à1	R^4c/R^5c	-rEE-	-	R^Bc
E-18	A®	-rTC-	-r2ïT	R³³¹	R^4d/R^M	-rEB-	-	-rE3-
E-19	A®	_R1_C	R^2d	-R3â1-	R^4d/R^M	-rBB-	-	-rBT
E-20	A^d	-rIc-	R^2d	“R³®^-	R^/R^M	-rEB-	-	-rBcI-
E-21	A®	R’C	-r3T-	“R³®	R^4d/R^M	_R6b	-	rM
E-22	A®	-Rie-	-r27-	R³®	R^4d/R^M	rEE-	-	Rbf
E-23	A®	_R1a	R^2a1	R³⁵	R^4a/R^5a	_RUa	rTF	R⁶³
E-24	A^b	Rlb	r2CT-	r^35-	R^4c/R^5c	rEE	r^/c	R«b
E-25	A^c	-rJc-	R²®¹	-R3â-	R^4d/R^M	_Rbe	•	_r8c1

E-26	F	R^1c	R*æ	“r⁵⁵	R^4d/R^M	r^	-	r“
E-27	A^d	R^lc	R^2d1	-r3c	R^4d/R^M	-rB3-	•	R⁸®¹
E-28	A^d	-RlcT-	R^2c1	-r3ô-	R*7R^M	-rKT	-	-rBÎT
E-29	A®	R^1c	R²³¹	R³⁰	R^/R⁵⁰	“rBc-	•	R⁰⁰¹
E-30	A®	R^1c	R^2d1	_RUb	r«_/rm	Hr⁸³	•	R^531-
E-31	A®	R^1cl	R²³¹	-rJc-	R^/R⁵³	-RtJë-	-	-
E-32	A'	R^lc	R^2di	R^3b	R^4d/R^M	-rBc-		R⁸®¹
E-33	a'	R^1cl	-RÎëT	“R³®^-	R^/R^	-rBÔ-	-	-
E-34	a’	R^lc1	R²’¹	R³⁰	R^w/R^m	-rBT	-	-
E-35	A®	R^lc	R^2c1	“R³³	R^/R⁵⁰			R⁸®¹
E-36	A®	R^lc	“R²³¹*	“r^35-	R*7R^m	r⁶³	-	R⁸'¹
E-37	A®	R^lc1	R^zn	-r3c	R^4d/R^M		•

Accordingly, for example E-15 covers compounds of formula I, wherein

A is selected from the group A^a consisting of

R¹

I wherein above mentioned phenyl-, pyridinyl-, pyrimidinyl-, pyridazinyland pyrazinyl- groups are substituted with R¹ and R²;

Is selected from the group R^ia consisting of

H, halogen, NC-, Ci^-alkyl-, C^-alkyl-O-, C^-cycloalkyl and R⁸-(CH2)_nO-with n = 0,1,2, 3 or 4, wherein above mentioned Ci^-alkyl-, Ci-e-alkyl-O-, C^e-cycloalkyl and R^e-(CH₂)n-O- groups may optionally be substituted with 1 to 5 substituents Independently selected from the group consisting of halogen, HO- and optionally with 1 to 7 fluorine atoms substituted Ci.

3-alkyl-;

R² Is selected from the group R^2a consisting of

H, HO-, halogen, Ci^-alkyl-, C^-alkyl-O-, Cys-cycloalkyl, heterocyclyl, heterocyclyl-Ci-3-alkyl-, phenyl, heteroaryl, R⁸-(CH2)n-O- with n = 0,1,2, 3 or 4, and R⁸-(CH₂)_m-(CH)(CH3)-(CH2)o-O- with m = 0,1 or 2 and o = 0, 1 or 2, wherein above mentioned C^-alkyl-, Ci-e-alkyl-O-, Cye-cycloalkyl, heterocyclyl, heterocyclyl-Ci-3-alkyl-, phenyl, heteroaryl, R⁸- (CHîïn-Oand R⁸-(CH₂)_m-(CH)(CH3)-(CH2)o-O-groups may optionally be substituted with 1 to 5 substituents Independently selected from the group consisting of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-O-, and optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-;

R³ is selected from the group R³³¹ consisting of

Cj^-cycloalkyl-, wherein the above mentioned C3^-cycloalkyl-group may optionally be substituted with 1 to 9 substituents Independently selected from the group consisting of halogen, NC-, HO-, Ci-3-alkyl- and Ci-3-alkyl-O-;

H, halogen, NC-, HO-, Ci^-alkyl-, Ci^-alkyl-O-, C₃-s-cycloalkyl-, C3-8cycloalkyl-Ci-3-alkyl-, C3^-cycloalkyl-O-, heterocyclyl-O-, heterocyclyl, heteroaryl, R⁷-CH2-O- and R⁷-(CH2)2-O-, wherein above mentioned Ci^-alkyl-, Ci-e-alkyl-O-, C3^-cycloalkyl-, C3_8-cycloalkyl-Ci.3-alkyl-, C3-8-cycloalkyl-O-, heterocyclyl-O-, heterocyclyl, heteroaryl, R⁷-CH2-O- and R^C^^-O-groups, may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, optionally with 1 to 5 halogen atoms, substituted Ci-2-alkyl-, and optionally with 1 to 5 halogen atoms substituted Ci.2-alkyl-O-;

R® is selected from the group R⁶³ consisting of

H, NC-, Ci-e-alkyl-, Ca-e-cycloalkyl-, CM-cycloalkyl-Ci-3-alkyl- and C3-8cycloalkyl-Owherein above mentioned Ci-e-alkyl- groups may optionally be substituted with 1-3 halogen atoms;

R⁷ is selected from the group R^7a consisting of

H, carbocyclyl, heterocyclyl and heteroaryl, wherein above mentioned carbocyclyl, heterocyclyl and heteroarylgroups may optionally be substituted with 1 to 4 substituents Independently selected from the group consisting of HO-, optionally with 1 to 3 halogen atoms substituted Ci^-alkyl-, optionally with 1 to 3 halogen atoms substituted Ci^-alkyl-O- and halogen;

R® Is selected from the group R®³ consisting of

Cj-e-cycloalkyl, heterocyclyl, heterocyclyl-Ci-3-alkyl-, phenyl and pyridyl, wherein above mentioned Cs-e-cycloalkyl, heterocyclyl, heterocyclylCvs-alkyl-, phenyl and pyridyi groups may optionally be substituted with 1 to 5 substituents Independently selected from the group consisting of HO-, fluorine and optionally with 1 to 7 halogen atoms substituted Ci-3-alkyl-;

Accordingly, for example E-23 covers compounds of formula I, wherein

A is selected from the group A^a consisting of

wherein above mentioned phenyl-, pyridinyl-, pyrimidinyl-, pyridazinyland pyrazinyl- groups are substituted with R¹ and R²;

R¹ is selected from the group R^1a consisting of

H, halogen, NC-, Ci-e-alkyl-, Ci-e-aikyl-O-, Cyc-cycloalkyl and R⁸-(CH2)_nO- withn = 0,1,2, 3 or 4, wherein above mentioned Ci^-alkyl-, Ci_e-aikyl-O-, Cj-e-cycloalkyl and R⁸-(CH2)_n-O- groups may optionally be substituted with 1 to 5 substituents independentiy seiected from the group consisting of haiogen, HO- and optionally with 1 to 7 fluorine atoms substituted Cv

3-alkyl-;

R² is selected from the group R^2a1 consisting of

HO-, Ci-6-aikyl-, Ci^-alkyl-O-, C3-e-cycloalkyl, C3-6-cycloalkyl-Ci.3-alkyl-, heterocyclyl, heterocyciyl-Ci-3-alkyl-, phenyl, heteroaryl, R®-{CH2)n-0with n = 0,1, 2, 3 or 4, and R⁸-(CH₂)_m-(CH)(CH3)-(CH2)_o-O- with m = 0,1 or 2 and o = 0,1 or 2 wherein above mentioned Ci-e-alkyl- and Ci-e-alkyl-O-groups are substituted with 1 to 5 substituents independentiy selected from the group consisting of HO-, and optionally with 1 to 7 fluorine atoms substituted Ci.3-alkyl-O-, and wherein above mentioned Ci-e-alkyl- and C^-alkyl-O-groups may optionally be substituted with 1 to 5 substituents independentiy selected from the group consisting of haiogen, and optionally with 1 to 7 fluorine atoms substituted C^-akyl-, and wherein above mentioned C^e-cycloalkyl, Ca-e-cycloalkyl-Cvs-alkyl-, heterocyclyl, heterocyclyl-Ci.3-alkyl-, phenyl, heteroaryl, R⁸-(CH2)n-Oand R⁸-(CH2)_m-(CHXCH3)-(CH2)o-O-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-O-, and optionally with 1 to 7 fluorine atoms substituted Ci_3-alkyl-;

R³ is selected from the group R³³ consisting of

H, halogen, NC-, CM-alkyl- and C^cycloalkyl-, wherein the above mentioned C^-alkyl- and C^cycloalkyl-groups may optionally be substituted with 1 to 9 substituents Independently selected from the group consisting of halogen, NC-, HO-, Ci-3-alkyland Ci-s-alkyl-O-;

H, halogen, NC-, HO-, Ci-e-alkyl-, Ci^-alkyl-O-, C3-8-cycloalkyl-, C₃-scycloalkyl-Ci-3-alkyl-, Cj-e-cycloalkyl-O-, heterocyclyl-O-, heterocyclyl, heteroaryl, R⁷-CH2-O- and R⁷-(CH2)2-Owherein above mentioned Ci^-alkyl-, C^-alkyl-O-, C3-8-cycloalkyl-, C3^-cycloalkyl-Ci-3-alkyl-, C^-cycloalkyl-O-, heterocyclyl-O-, heterocyclyl, heteroaryl, R⁷-CH2-O- and R⁷-(CH2)2-O-groups, may optionally be substituted with 1 to 5 substituents Independently selected from the group consisting of halogen, optionally with 1 to 5 halogen atoms, substituted Ci-2-alkyl-, and optionally with 1 to 5 halogen atoms substituted Ci.2-alkyl-0-;

R⁸ is selected from the group R⁶³ consisting of

H, NC-, Ci-e-alkyl-, C3^-cycloalkyl-, C3-a-cycloalkyl-Ci-3-alkyl- and Ca-ecycloalkyi-Owherein above mentioned C^-alkyl- groups may optionally be substituted with 1-3 halogen atoms;

R⁷ is selected from the group R^7a consisting of

H, carbocyclyl, heterocyclyl and heteroaryl, wherein above mentioned carbocyclyl, heterocyclyl and heteroarylgroups may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of HO-, optionally with 1 to 3 halogen atoms substituted Ci^-alkyl-, optionally with 1 to 3 halogen atoms substituted CM-alkyl-0- and halogen;

R⁸ Is selected from the group R⁸³ consisting of

C^-cycloalkyl, heterocyclyl, heterocyclyl-Ci.₃-alkyl-, phenyl and pyridyl, wherein above mentioned Cjj-e-cycloalkyl, heterocyclyl, heterocyclylCi-3-alkyl-, phenyl and pyridyl groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of HO-, fluorine and optionally with 1 to 7 halogen atoms substituted Ci_3-alkyl-;

Accordingly, for exampie E-29 covers compounds of formula I, wherein is selected from the group A® consisting of

R¹ Is selected from the group R^1c consisting of

H, H₃C-, F₃C-, F2HC-, FH₂C-, fluorine, chlorine and bromine:

R² is selected from the group R^2d1 consisting of HO-, Ci-4-alkyl-, C^-alkyl-O-, C^-cycloalkyl, C^-cycloalkyl-Ci-s-alkyl-, a saturated 5 or 6 membered monocyclic heterocycle containing one heteroatom selected from N or O, R⁸-(CH2)n-O- with n = 0,1 or 2, and

R⁸-(CH₂)m-(CH)(CH3XCH₂)o-0- with m = 0 or 1 and o = 0 or 1 wherein above mentioned C-M-alkyl- and Ci-4-alkyl-O-groups are substituted with 1 to 5, preferably 1 to 3, substituents Independently selected from the group consisting of HO-, and optionally with 1 to 7 fluorine atoms substituted Ci.₃-alkyl-O-, and wherein above mentioned ÜM-alkyl- and CM-alkyl-O-groups may optionally be substituted with 1 to 5, preferably 1 to 3, substituents Independently selected from the group consisting of halogen, and optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-, and wherein above mentioned C3^-cycloalkyl-, C3^-cycloalkyl-Ci.₃-alkyl-, saturated 5 or 6 membered monocyclic heterocycle containing one heteroatom selected from N or O, R®-(CH₂)_n-O- and and R®-(CH₂)_m(CH)(CH₃>(CH₂)_o-O- groups may optionally be substituted with 1 to 5, preferably 1 to 3, substituents Independently selected from the group consisting of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-O-, and optionally with 1 to 7 fluorine atoms substituted Ci.₃-alkyl-;

R³ is selected from the group R^3b consisting of

H, Ci-3-alkyl-, cyclobutyl- and cyclopropyl-, whereln the above mentioned Ci.3-alkyl-, cyclobutyl-, and cyclopropylgroups may optionally be substituted with 1 to 7 substituents Independently selected from the group consisting of halogen, Ci-₃alkyl-O-, NC- and H0-;

R⁴, R⁵ are selected from the group R^/R^ consisting of

H;

R® Is selected from the group R⁶⁰ consisting of

H and Ci-2-alkyl-, whereln above mentioned Ci_₂-alkyi- group may optionally be substituted with 1-5 fluorine and/or chlorine atoms;

R⁸ is seiected from the group R⁸⁰¹ consisting of

C^cycloalkyl and a saturated 4 to 6 membered monocyclic heterocycle containing one or two heteroatoms seiected from N or O, wherein above mentioned C^-cycloalkyl and heterocyclyl-groups may optionally be substituted with 1 to 5 substituents independently seiected from the group consisting of HO-, fluorine and optionally with 1 to 7 halogen atoms substituted Ci-₃-alkyl-;

Accordingly, for example E-37 covers compounds of formula I, wherein

A is seiected from the group A⁹ consisting of

R¹ Is seiected from the group R^1c1 consisting of H₃C-, fluorine and chlorine;

R² is seiected from the group R²¹¹ consisting of

R³ is seiected from the group R³⁰ consisting of

H, and H₃C- and cyclopropyl-, wherein the above mentioned H₃C- and cyclopropyl-groups may optionally be substituted with 1 to 3 fluorine atoms;

R⁴, R⁵ are selected from the group R^/R^ consisting of

H;

R® Is selected independently of each other from the group R^ef consisting of H₃C-;

the tautomers thereof, the stereolsomers thereof, the mixtures thereof, the solvatés thereof, the hydrates thereof and the salts thereof.

Further preferred are the following compounds listed In table 2:

No.	Structure	No.	Structure
I	αχ	Il	αχ N N
III	αχ	IV	αχ
V	αχ xxt	VI	αχ x>xc

VII	αχ	VIII	αχ Ν /4 ^s' oh V^z^ci
IX	αχ	X	χχ /=Ν ΗΟχΧν/θχ/Χ
XI	χχ	XII	XX °~χ£
XIII	χχ ci	XIV	χχ ”ά
XV	χχ .-0ΧΧ F	XVI	αχ ~*cc
XVII	χχ cxx	XVIII	χχ^Νχ >=Ν

XIX	αχ χ-ο OH	XX	αχ C0
XXI	XXX,	XXII	αχ N JM ^xC
XXIII		XXIV	αχ -0Χ:
XXV	αχ	XXVI	αχ <°Ί
XXVII	αχ 'VjA'ci	XXVIII	ΧΧζ ^f“7^^-0'C^CI F F
XXIX	-αχ F F	XXX	XXX ^,RX

XXXI	αχ	XXXII	1 Y
XXXIII	αγ ^Ν Λ rr°i>a HCT^	XXXIV	OCY oY~”
XXXV	αγ ^{Ν n} _l y	XXXVI	χχχ
XXXVII	αχ ό	XXXVIII	αχ Ύ
XXXIX		XL	αα ΛΧ
XLI	αχ >ί^ΟΌχι	XLII	αγ ₇°-c£ Tf
XLIII	αχ N h1^ ^Η0<ίΧι	XLIV	ΥΥΥ ^HO^CY\|

XLV		XLVI	JÛCX _F ^H9
XLVII	irr F^O'CÀcI	XLVIII	αχ oX::
XLIX	0¾	L	αχ xC
Ll	yx xX	LII	αχ
LUI	XXX cX	LIV	/XJ. ξζ χ^ζ ινΑ, 11
LV	χχχ /X OH	LVI	γίΖ'ν'' /==Ζ^=Ν

LVII	HO—/Λ ΧΛ-	LVIII	HO-	a Ό	IA / À
	ζγγ			ιΓΎ	N. /
	JL A 1			A	À
	—<^N N^ Z=N			N
LIX	LX	HO-	~C^

			V/	^Cl
	/N..		•S.	.N
	(Ύ Ί		A	Ύ	T
	VA		n.		1
			'N N
LXI		LXII		)
			HO-—,	C\
	VA-			νΛ	'Cl
	1 N			rv
			F
LXIII	ν' A	LXIV	^F F		A An
	Z ^N			/=A
	Al VA^CI		HO-	Ό	‘‘CI
	/YV			iPr
			A A	p
LXV	Ό O^èi	LXVI		N
		ho		<
			Z~^y	J \\ \__

LXVII	O^Z	LXVIII	aç /—' HO
LXIX	\z°^H Ν=γΛ w Cl	LXX	r^x^r^z'^N^Y^zX ^CI
LXXI	ΧΧζ /^λ~^Ν —^Cl	LXXII	MO ^N N^\. HO ^v 1 N
LXXIII		LXXIV	Sk, Cl
LXXV	K Qy.	LXXVI	O \__ T^v^² ,2 ^rXH

LXXVII		LXXVIII	< O G<
LXXIX	-Λ. Cl	LXXX	X> Cl
LXXXI	7« ^θΌ-ο, °χ/^ΟΗ	LXXXII	^-^bH ^<N
LXXXIII	OH CKJaJ- Cl	LXXXIV	xa ho ^^_Z~^N Cl
LXXXV	XXX z-r< HO \Λ^α	LXXXVI	XXX HO /==< ^N

LXXXVII	XIX,	LXXXVIII	îj?^·— Cl
LXXXIX	v w.·	xc	ÀzXXX
XCI	αχ	XCII	tfZ ^N O ^K-rf-·
XCIII		XCIV	SAA τχ/όι
xcv	.αχ	XCVI	id:

XCVII	αχ	XCVIII	a da	y v> /—N '—C!
			Loh N=f	—N
	\>ΟΗ ^N==\^_		V
XCIX		c	\ _ N
		f 74 Jn \==/ ^N

	Ί=


	Loh n^Z \γ_		Loh Ν=γ	v
Cl	\__	Cil	\ N
	Q-V		O^vⁿ
	Cl
	X,			v
		\ OH N==(	y
cm	Loh ⁿ=( 1	CIV	\/ 1
	ÇH'^N		Ya-x	N >T
			F
				hL /
			ΓΎ	Y

	\ OH N=/ \\
cv	< \ /~~~~ QV	CVI	“X~C	>N
		^Cl

CVII	>cc£°	CVIII	'^f
CIX	^N\	ex	αχ <xc£
CXI	(XX_F<ïa=	exil	%Q-'
CXIII	χΧζ <w^^N	CXIV	^<^oXC^^ci
cxv	^<XC$~'	CXVI	αχ,

CXVII	_Q/^	N )¾	/N. \ nT v> i:	CXVIII
hoVa^ F	O- ; Ti V
	F_x	if*			ΓΎ	,N. /
	e	-A N			1Λ V/ ^N	‘Λ
CXIX	r 0	\— / \ OH	CXX		)=4
		NL.	jA^CI		VV-a
						Λ
		N			\_z N=/ \\__
CXXI			CXXII	FV	4 Jn
	V	Γ V/~a			N
	l		Λ		ΓΥ	^Nv
	HO \	\ χ—Ν ^N λ		A_nA	An
CXXIII		Γν	N—/ V'^N	CXXIV	/ΧθΗ/^	\ ! /—N
		F		vz-
			Γ		ifA	^1—
		JU 7 N	S^N		Λ V/ ^N	Ά
cxxv		\0H ^N	CXXVI	oA^	Z
	0	/Λ
					OH

				isl ^1			îT^V	N.
		F if					F
	F_v			N			F^\ A	N'Y
						ψ N
CXXVII		F		ΥΓ	CXXVIII		F	w
							/=X	<
	HO	~7\~~	c				H0-7T^G '
		/\	F				^Cl
				zN^			bf 0H --(/	Λ
				VY			/ r \	7—N
			N			X N==Z \\
CXXIX	Z			W	cxxx	0^		b
	0	>	g*⁵⁵⁸	c			<y
	'—	Λ	Y
		OH					F
	OH							X
			\\			L ^N==< w
CXXXI		-0		N—/	CXXXII	0-	Z O S \___
		<y	V			Y	b
			F				\ F
							F J Æ~
		,οη[^		V..			0H	V..
			^N=< 1			\ N=/ ’Λ
CXXXIII				K	CXXXIV	o„	J~°x	N—/
						b-
			F				^λ—\ Cl
		II	-y					Λ ..
	F	II	N	N '''N			k. '^N=Y ’V
cxxxv	F^X	F	/=Z		CXXXVI	0-	n-	-a
		HO—	G					N
						F

Some terms used above and hereinafter to describe the compounds according to the Invention will now be dèfined more closeiy.

î

Terms not specifically defined herein shouid be given the meanings that would be given to them by one of skîll In the art In light of the disclosure and the context. As used in the spécification, however, unless speclfied to the contrary, the following terms hâve the meaning indicated and the foilowing conventions are adhered to. In the groups, radicals, or moieties defined below, the number of carbon atoms Is often specified preceding the group, for example Ci^-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for exampie, the substituent aryl-Ci.₃-aikyl- means an aryl group which is bound to a Ci-3-alkyl group, the latter of which is bound to the core molécule orto the group to which the substituent is attached.

Within the présent invention, the term “core molécule Is defined by the following structure:

In general, the attachment site of a given residue to another group shall be variable,

l.e. any capable atom, bearing hydrogens to be replaced, within this residue may be the linking spot to the group being attached, unless otherwise indicated.

In case a compound of the présent invention is deplcted In fomrt of a chemlcal name and as a formula In case of any discrepancy the formula shall prevail.

An asterisk may be used in sub-formulas to indicate the bond which is connected to the core molécule or to the substituent to which it is bound as defined.

Unless specifically indicated, throughout the spécification and the appended daims, a given chemlcal formula or name shall encompass tautomers and ail stéréo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc...) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including phamnaceutically acceptable salts thereof and solvatés thereof such as for instance hydrates Including solvatés of the free compounds or solvatés of a sait of the compound.

The phrase phamnaceutically acceptable or physlologlcally acceptable Is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human belngs and animais without excessive toxlcity, irritation, allergie response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.

As used herein, phamnaceutically acceptable salts or physlologicaliy acceptable salts refer to dérivatives of the disclosed compounds wherein the parent compound is modifiée! by making acid or base salts thereof. Examples of pharmaceutically acceptable salts or physiologically acceptable salts include, but are not limited to, minerai or organic acid salts of basic résidu es such as amines; alkali or organic salts of acidic résidu es such as carboxylic acids; and the like. For example, such salts Include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2’-iminobis(ethanol)), diethyiamine, 2(diethylaminoj-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-giucamine, hydrabamine, 1H-imidazole, lysine, magnésium hydroxide, 4-(2-hydroxyethyl)morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2’,2“-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2,2-dichioro-acetic acid, adipic acid, aiglnic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, clnnamic acid, citric acid, cyclamlc acid, decanoic acid, dodecylsulfuric acid, ethane-

1,2-disulfonic acid, ethanesuifonic acid, 2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, gaiactaric acid, gentislc acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (-)-L-malic acid, malonic acid, DL-mandeiic acid, methanesulfonic acid, gaiactaric acid, naphthalene-1,5-disuifonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid,

4-amino-salicylic acid, sebacic acid, stearic acid, succinlc acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Further pharmaceutically acceptable salts can be formed with cations from metais like aluminium, calcium, lithium, magnésium, potassium, sodium, zinc and the like (also see Pharmaceutical salts, Berge, S.M. et al., J. Pharm. Sci., (1977), 66,1-19).

The pharmaceutically acceptable salts of the présent invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generaily, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid In water or In an organlc diluent like ether, ethyl acetate, éthanol, Isopropanol, or acetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example are useful for purifying or Isoiating the compounds of the présent Invention (e.g. trifluoro acetate salts) aiso comprise a part of the invention.

The term substituted as used hereln means that any one or more hydrogens on the deslgnated atom Is repiaced with a sélection from the Indicated group, provided that the designated atom's viable valence number Is not exceeded, and that the substitution results in a stable compound.

The term partiaily unsaturated as used hereln means that in the deslgnated group or moiety 1,2, or more, preferably 1 or 2, double bonds are présent. Preferabiy, as used herein, the term partiaily unsaturated does not cover fully unsaturated groups or molettes.

Terms iike ...optionally with 1 to 7 fluorine atoms substituted Ci-₃-alkyl-O-..“ or “...optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-“ in a section iike ... groups may optionally be substituted with 1 to 5 substituents Independently selected from the group consisting of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted Ci-s-alkyl-O-. and optionally with 1 to 7 fluorine atoms substituted Ci.s-alkvl- means that the referenced group may be substituted with 1 to 5 substituents, wherein these substituents can be halogen, HO-, Ci-3-alkyl-O- which may be optionally fluorinated with 1 to 7 fluoro atoms, and Ci-3-alkyl-O- which may be optionally fluorinated with 1 to 7 fluoro atoms.

The term “halogen generaily dénotés fluorine, chlorine, bromine and iodine.

The term Ci-n-alkyT, wherein n is an integer from 2 to n, either alone or In combination with another radical dénotés an acyclic, saturated, branched or iinear hydrocarbon radical with 1 to n C atoms. For example the term Ci-s-aikyi embraces the radicals H₃C-, H3C-CH2-, H3C-CH2-CH2-, H₃C-CH(CH₃)-, H3C-CH2-CH2-CH2-, H₃C-CH2-CH(CH₃)-, H₃C-CH(CH₃)-CH2-, H3C-C(CH₃)2-, H3C-CH2-CH2-CH2-CH2-,

H₃C-CH2-CH2-CH(CH₃)-, H₃C-CH2-CH(CH₃)-CH2-, H₃C-CH(CH₃)-CH2-CH2-, h₃cCH₂-C(CH₃)₂-, H₃C-C(CH₃)2-CH2-, H₃C-CH(CH₃)-CH(CH₃)- and H₃C-CH2CH(CH₂CH₃)-.

The ternis carbocyclyl and carbocycle as used either alone or in combination with another radical, mean, if not mentioned otherwise, a mono- bi- or tricyclic ring structure consisting of 3 to 14 carbon atoms. The terms, if not mentioned otherwise, refers to fully saturated, partialiy saturated and aromatic ring Systems. The terms encompass fused, bridged and spirocyclic Systems.

Thus, the terms include the foliowing exemplary structures whlch are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:

^Δ □ ο ο ο o o O o o O O CD

CO CO COCO cP cP CX cP & ΟΘ θ 0 jg ΘΘ co

The term C^-cycloalkyl, wherein n is an integerfrom 4 to n, either alone or in combination with another radical dénotés a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example the term C^T-cycloalkyl Includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The terms heterocyclyl and heterocycle as used either alone or in combination with another radical, mean a saturated or unsaturated mono- or polycyclic ring

System containing one or more heteroatoms selected from N, O or S(O)r .wherein r=0,1 or 2, which may contain aromatic rings consisting of, if not mentioned otherwise, 3 to 14 ring atoms wherein none of the heteroatoms is part of an aromatic ring. The terms encompass fused, bridged and spirocyclic systems.The terms are

Intended to include ail the possible isomeric forms.

Thus, the terms include the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:

o

The term “aryl as used herein, either atone or In combination with another radical, dénotés a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. Aryi Inciudes, but Is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthy! and 10 dihydronaphthyl.

The term heteroary! means a mono- or polycyclic-ring Systems containing one or more heteroatoms selected from N, O or S(O)_r, wherein r=0,1 or 2, consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms Is part of an aromatic ring. The 15 term “heteroaryl Is intended to Inciude ail the possible Isomeric forms.

Thus, the term “heteroaryl inciudes the following exemplary structures which are not deplcted as radlcals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:

II

Many of the terms given above may be used repeatedly in the définition of a formula or group and in each case hâve one of the meanings given above, independently of one another.

The compounds accordlng to the invention may be obtained using methods of synthesls known in principle. Preferably, the compounds are obtained by the following methods according to the invention which are described in more detail hereinafter.

Préparation

The foilowing schemes illustrate generally how to manufacture the compounds of the présent invention by way of example. The abbreviated substituents may be as defined above if not defined otherwise withïn the context of the schemes :

Scheme 1:

	R5	R5
R4,	yS	/N. ,R6	^R4X	ίΎ T	i>°
	Λ <4
R3'	N		R3^	N N	''RS
	B	POCI3		C
		step 2

Scheme 1: In a first step, substituted 1,2-pyrido-diamines (A).commercially available or prepared following well known reported procedures, were reacted with the approprlate 1,2- keto ester or acid in EtOH or MeOH as solvents at room température, to form the corresponding pyrido[2,3-b] pyrazinone intermediates (B.C). Where required, regioisomers were separated by flash cromatography and treated with POChunder heatingto obtain the 2-chloro-pyridopyrazines(D). Nucleophilic substitution was performed using hydrazine hydrate in appropriate solvents (e.g. EtOH) at room température to form the corresponding pyrldo[2,3-b]pyrazin-3yl-idrazines dérivatives (F). Reaction with appropriate acyl chlorides or carboxylic acids in the presence of a coupling agent (e.g. HATU or TBTU) and a base (e.g. TEA or DIPEA), gave the corresponding hydrazides (E) which were submitted to in situ cyclization to triazoles core by heating in appropriate solvent (e.g. cyclohexanol).

Altematively, in step 5, preformed hydrazides dérivative were reacted with 2-chloropyridopyrazines (D) in appropriate solvents (such as DMF) to gave intermediates hydrazides (E) which were then converted to compounds G as described before or heating directly the 2-chloro-pyridopyrazines (D) with the appropriate hydrazides In approriate solvent such as cyclohexanol at high température.

Further examples of the présent invention were prepared following Scheme 2:

Scheme 2:

Further examples of the présent invention were prepared by alkylation of the appropriate phénol dérivative (obtained as described in Scheme 1) with alkylating agents (e.g. chloride, bromide or tosylates dérivatives) in the presence of a suitable base (e.g. tBuOK or CS2CO3) in a solvent like DMF under heating or by ring opening of the appropriate epoxides In the presence of a suitable base ( e.g. CS2CO3) In a solvent like DMF or DMA under conventional heating or microwave irradation. Rx and Ry : Examples 13,15,16,17,18,19,20,21,22, 23, 24,25, 26,27,28, 29, 30, 31, 32, 32a , 33, 34, 35, 35a, 36, 37, 38, 39, 40, 41,42, 43,44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58,106,107,108a, 108b, 108c, 108d, 109a, 109b, 109c, 109d, 110b,110d,111 were prepared following the above described procedures.

Scheme 3:

Further examples of the présent invention were prepared by aromatic nucleophilic substitution, reacting the appropriate aromatic fluoro dérivatives (prepared as described in Schemel ) with primary or secondary alcohols in the presence of a suitable base (e.g tBuOK or CS2CO3), in a solvent like DMF under heating. Exemples 58a, 58b, 58c were prepared foüowing the above described procedure.

Scheme 4:

Further examples of the présent invention were prepared by well-known cross coupling reaction (l.e Sonogashira, see for example Organic Le tiers, 2007 , vol. 9, p. 4057 - 4060) starting from appropriate aromatic halogen intermediates (X=Br,I). The resulting unsaturated triple bond intermediates were then converted to final compounds by appropriate réduction with Wilklnson's catalyst RhCI(TPP)3 under hydrogen atmosphère in toluene as solvent.

Examples 66, 67, 68, 69 were prepared foüowing the above described procedure. Altematively, the same synthetic approach was applied for the préparation of preformed hydrazydes which were then reacted with intermediate D as described in Scheme 1

Scheme 5

Examples 64 and 65 were prepared following the above described procedure.

Scheme 6:

a. IsopropylMgBr

b. ketone or aldéhyde THF

Further examples of the présent Invention were prepared as described in Scheme 6 : in a first step the appropriate aromatic alogen dérivatives (X=l) was treated with isopropyl magnésium bromide in a suitabie solvent (like THF) at low température 10 foliowed by addition of the appropriate ketone or aldéhyde dérivatives.

Examples 70, 71,72, 73, 74 were prepared following the above described procedure. Altematively, the same synthetic approach was applied for the préparation of preformed hydrazydes which were then reacted with intermediate D as described in Scheme 1.

Scheme 7

Examples 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 96a, 96b, 96c, 97 were prepared following the above described procedure.

Scheme 8:

a. n-BuLI. THF

b. DMF, THF

Further examples of the présent invention were prepared as described In Scheme 8: in a first step the appropriate aromatic aldéhyde is obtained by reaction of alogen dérivatives (X=l) with n-BuLi In a suitable solvent (like THF) at low température 10 followed by addition of dry DMF In THF. In a second step the suitable commercially available Grignard reagent Is added at low température.

Rz: Examples 59,61,62,63 were prepared following the above reported procedure.

Scheme 9

LiAJH,

Further examples of the présent Invention were prepared as described in Scheme 9: in a first step the appropriate ketone is obtained by reaction of alogen dérivatives (X=1,Br) with tributyl-(1-ethoxyvinyl-)tin in the presence of Pd(PPh3)4. The epoxide 5 obtained by reaction with appropriate trimethyl sulphonium ylide was then subjected to ring opening with hydride and subséquent oxidatlon with suitable agents such as manganèse dioxide in appropriate solvents (DCM).

Examples 76, 77,78,79 were prepared foliowing the above reported procedure.

In analogy, the omologated dérivatives Examples 80, 81 were obtained performing 10 the first step as described in Scheme 9a.

Scheme 9a

Scheme 10

Further examples of the présent Invention were prepared as described In Scheme 10: In a first step the appropriate double bond Is Installed by Suzuki coupling with suitable boronlc acids or esters (such as for example 2-lsopropenyl- dioxaboroiane, Scheme 10). In a second step, the hydratation of the double bond (HCI/dioxane) 10 allowed to introduce hydroxylic function.

Example 103,103b,103c were prepared following the above described procedure.

The compounds according to the invention are advantageously also obtainabie using the methods described In the examples that follow, whlch may also be combined for 15 this purpose with methods known to the skilled man from the literature.

As already mentioned, the compounds of general formula I according to the Invention and the physiologically acceptable salts thereof hâve valuable pharmacological properties, particulariy as inhlbitors of phosphodiesterase 2 and/or 10.

Blologlcal Examples

In-vitro effect:

The ln-vitro effect of the active compounds of the invention can be shown with the foiiowing biological assays.

a) radioactive PDE2 assav protocol:

For ail experiments the Phosphodiesterase [³H]cAMP SPA Enzyme Assay (TRKQ7090, GE Healthcare Europe GmbH) were used. The enzymatic activity of the PDE2 and the inhibitory potency of compounds was measured by the conversion of [³H]cAMP to [³H]AMP. [³H]AMP associate to the scintillator soaked yttrium-silicate beads resulting in an increase in scintillation events. Compounds that inhibit the respective enzymes decrease the génération of [³H]AMP and accordingly the number of counts detected.

SF9 lysate containing PDE2A Is incubated at room température for 1 h with [³H]cAMP and the reaction is terminated by addition of SPA beads in 18 mM zinc sulphate. The [³H]AMP bound to SPA beads is determined after at least 3 hours of sédimentation of the beads, the signal is recorded using the TopCount with a recording time of 3 min/well.

PDE 2A protein is expressed upon baculovirus infection In SF9 cells. The cells hâve been incubated upon Infection for ~3 days and protein production was confirmed by Western Blot. The cells were collected by centrifugation and the pellet frozen in liqutd nitrogen before it was resuspended In PBS containing 1% Triton X-100 and protease inhibitors. After 45 min incubation on ice, the cell débris was removed by centrifugation (13.000 rpm, 30 min).

The assay conditions were as follows :

total assay volume:	40 pl
protein amount:	5 ng
protein concentration:	500 pg/pl
substrate concentration:	20 nM;~1,08 mCt/l

Incubation time:

60 min

The buffer used for above described assay buffer was:

mM Tris/HCI, pH 7.4

8.3 mM MgCh

1.7 mM EGTA

0.1 % (w/v) BSA

0.05 % (v/v) Tween 20

In detail the protocol Is as follows:

Into a 384 well plate (OptiPlate, white), the following components are pipetted (either manually or using automated pipetting devlces):

pl test-compound solution (test compound diluted In assay buffer at twofold the desired concentration) +10 μΐ PDE 2A préparation (enzyme diluted in assay buffer to a concentration of 0,5 ng/μΙ protein) + 10 μΙ [³H]cAMP (diluted in assay buffer to a concentration of 80 nM cAMP)

Controls Included Into each experiment:

positive control: no Inhlbitor, DMSO at the concentration as used in the compound dilutions négative control: no PDE 2 (SF9 lysate instead of SF9/PDE 2A lysate)

Calculation of % Inhibition:

The activity of the positive control (minus the négative control = background) Is set to 100% and activity In the presence of compound Is expressed relative to these 100%.

Calculation of IC50:

IC50 are calculated with GraphPadPrism or other suited software setting the positive control as 100 and the négative control as 0. For calculation of IC50 usually 11 dilutions of the test compound are selected.

b) radioactive PDE10 assav protocol:

For assessing activity of compounds on PDE10 inhibition, the following modifications of the protocol described above are applied:

protein amount: 3 ng protein concentration: 75 pg/μΙ

In detail the protocol is as follows:

Into a 384 well plate (OptiPlate, white), the following components are pipetted (either manually or using automated pipetting devices):

pl test-compound solution (test compound diluted in assay buffer at twofold the desired concentration) + 10 μΙ PDE 10A préparation (enzyme diluted in assay buffer to a concentration of 0,3 ng/μΙ protein) + 10 μΙ cAMP tracer (diluted in assay buffer to a concentration of 80 nM cAMP, spécifie activity -4 mCi/l)

After addition of ail 3 components the plates are shortly spun and incubated at room température for 60 min. The reaction is stopped by the addition of 20 μΙ Yttrium SPA PDE Beads containing 18 mM zinc sulphate in water

After at least 3 hours sédimentation of the beads, the signal Is recorded using the TopCount with a recording time of 3 min/well.

PDE 10A protein is expressed upon baculovirus Infection In SF9 cells. The cells hâve been incubated upon Infection for -3 days and protein production was confirmed by Western Blot. The ceils were collected by centrifugation and the pellet frozen in liquid nitrogen before it was resuspended in PBS containing 1% Triton X-100 and protease inhibitors. After 45 min incubation on ice, the cell débris was removed by centrifugation (13.000 rpm, 30 min).

In the following table the resuis of the above described experiments are listed.

Table 3: Activity of the examples (Ex) compiled In the experimental part, based on above described assays (cAMPA SPA radioactive).

Ex.	PDE2 lC₅₀ [μΜ]	PDE10 IC,o [μΜ]	Ex.	PDE2 ICso [μΜ]	PDE10 IC₅₀ [μΜ]
1	0,016	0.421	25	0,055	3.26
2	0,004	0.040	26	0,116	1.38
3	0,155	0.411	27	0,004	0.97
4	0,138	0.441	28	0,009	>10
13	0,053	2.190	29	0,017	2.38
14	0,202	3.580	30	0,027	3.92
15	0,040	>10	31	0,007	1.90
16	0,058	1.876	32	0,003	1.76
17	0,098	5.72	33	0,004	2.50
18	0,071	3.01	34	0,009	1.89
19	0,146	3.01	35	0,009	1.30
20	0,028	2.76	36	0,219	0.85
21	0,070	2.82	37	0,171	3.08
22	0,115	>5	38	0,417	1.96
23	0,071	5.10	39	0,914	2.10
24	0,138	6.69	40	0,080	3.47

Another, non radioactive, in-vitro assay was performed as follows

c) Phosphodiesterase (PPE) 2A and 10 assay with fluorescent substrate

Assay princlple:

The PDE reaction cleaves cAMP to AMP. The IMAP System (Molecular Device) using fluorescence polarization (FP) as détection principle was used to measure enzyme activity. A fluorescent labeled cAMP was used as substrate for the reaction, generating a labeled AMP. The fluorescent AMP binds specifically to the large M(lll) based nano-particles which reduces the rotational speed of the substrate and thus increases its polarization.

Detaiied method:

The Inhibition of PDE 2A or 10 enzyme activity was assessed using IMAPPhosphodiesterase-cAMP fluorescence labeled substrate (Molecular Devices, Order No. R7506), IMAP TR-FRET screening express (Molecular Devices, Order No. R8160, the TR-FRET component will not be used) and PDE 2A or PDE10 protein expressed upon baculovirus infection In SF9 cells. The cells were incubated after infection for ~3 days and protein production was confirmed by Western Blot. The cells were collected by centrifugation and the pellet frozen in liquid nitrogen before it was resuspended in PBS containing 1% Triton X-100 and protease inhibitors. After 45 min incubation on ice, the cell débris was removed by centrifugation (13.000 rpm, 30 min). Since SF 9 cells do not express cAMP hydrolyzing enzymes to a high extent, no further purification of the protein was needed.

Ail reactions were performed in 384 weli plates, Perkin Elmer black optiplates and IMAP reaction buffer with 0.1% Tween20 (kit component)

Compounds were serial diluted In DMSO. With an intermediate dilution step with reaction buffer DMSO concentration was reduced to achieve 1% DMSO In the assay reaction. Setup of the assay started with 10pl enzyme (~10ng/well, depending on prep. batch), 5 pl compound, reaction was started by addition of 5 pl labeled cAMP (30 nM, final concentration), immedlately mixed for 15 seconds on a Eppendorf mixmate (2000 rpm) followed by an incubation at room température for 90 minutes In the dark. Reaction is stopped by adding of 60 pl blnding buffer for FP/cAMP (kit component). After at least 90 min of further Incubation (room température, dark) the assay was measured at 485 nm excitation/525 nm émission in an Envislon multilabel reader (PerkinElmer).

Each assay plate contained welis with vehicle contrais (1% DMSO) for the measurement of non-lnhiblted reaction (=100% contrai) and wells without enzyme as 0% contrais.

The analysis of the data was performed by calculation of the percentage of Inhibition in the presence of test compound compared to the vehicle control samples (100% control, no Inhibition) and a low control (0% control, no enzyme).

IC50 values are calculated with Assay Explorer or other suited software based on curve fitting of résulte of at least 8 different compound concentrations. The compound concentrations may vary according to the needed range, but typically cover the range between 10μΜ and 0.1 pM.

Table 3a: Activity of the examples (Ex) compiled in the experimental part, based on 10 above described assays (IMAP fluorescent).

Ex.	PDE2 IC₅₀[μΜ]	PDE10 ICso [μΜ]	Ex.	PDE2 IC50 [μΜ]	PDE10 IC₅₀ [μΜ]	Ex.	PDE2 ICso [μΜ]	PDE10 IC₅o [μΜ]
1	0,041	0,355	55	0,080	5,298	96	0,043	5,945
2	0,003	0,033	55a	0,033	2,435	96a	0,199	10,000
4	0,120	0,256	56	0,002	0,061	96b	0,087	10,000
5	0,003	0,005	56a	0,008	0,061	96c	0,591	7,460
6	0,003	0,010	56b	0,001	0,066	97	0,004	2,142
7	0,003	0,016	57	0,006	0,045	97a	0,004	5,945
8	0,002	0,008	57a	0,012	0,167	97b	0,004	0,891
9	0,001	0,015	57b	0,003	0,091	98	0,139	1,560
10	0,229	0,254	58	0,143	0,663	99	0,125	1,510
11	0,059	0,123	58a	0,054	0,713	100	0,017	3,856
12	0,009	0,044	58b	0,045	0,663	101	0,047	1,125
12a	0.036	0.170	58c	0,037	0,241	102	0,103	2,265
13	0,095	6,363	59	0,008	0,936	103	0,003	1,007
15	0,112	1,118	60	0,019	0,285	103b	0,100	10,000
16	0,098	8,700	61	0,004	0,534	103c	0,622	7980
17	0,162	10,200	62	0,011	1,300	104	0,036	7,715
18	0,090	8,418	63	0,060	1,710	104a	0,040	3,229
20	0,077	8,162	64	0,045	3,870	104b	0,030	9,765
21	0,022	7,047	65	0,214	3,545	105	0,023	1,540
22	0,207	9,317	66	0,003	0,674	105a	0,104	3,630

23	0,216	9,193	67	0,175	3,905	105b	0,038	3,410
25	0,038	7,333	68	0,002	1,007	106	0,160	1,940
27	0,018	0,958	69	0,001	0,891	106a	0,429	1,410
28	0,020	0,299	70	0,163	8,620	106b	0,050	2,500
29	0,037	5,097	71	0,109	2,080	107	0,007	0,022
30	0,020	2,573	72	0,032	2,865	111	0.022	3.980
31	0,008	2,897	73	0,189	10,000	108a	0,011	0,548
32	0,026	6,703	74	0,131	2,340	108b	0,059	0,594
32a	0,006	7,390	75	0,012	2,403	108c	0,024	0,262
33	0,005	3,417	76	0,021	1,105	108d	0,046	0,630
34	0,017	2,143	77	0,004	1,400	109a	0,014	1,670
35	0,017	1,477	78	0,010	2,845	109b	0,009	1,090
35a	0,003	0,822	79	0,144	0,305	109c	0,009	1,360
40	0,077	8,707	80	0,010	5,405	109d	0,004	1,830
41	0,050	2,770	81	0,007	5,384	110b	0,388	>10
42	0,035	2,520	82	0,199	5,615	110d	0,467	7,600
43	0,057	3,015	83	0,004	8,815	111a	0,065	1,830
43a	0,109	4,510	84	0,006	0,565	111b	0,011	2,130
44	0,156	6,037	85	0,006	4,325	112	0,018	7,000
45	0,005	1,488	86	0,434	5,750	112a	0,025	2,600
46	0,050	1,035	87	0,074	2,594	112b	0,068	2,500
47	0,008	0,852	88	0,001	0,302	113	0.0002	3,190
48	0,008	1,520	89	0,018	0,187	114	0,022	10,000
49	0,033	3,760	90	0,103	0,485	114a	0,009	10,000
50	0,194	7,120	91	0,001	0,077	114b	0,011	10,000
51	0,009	2,150	92	0,002	0,553	115	0,039	10,000
52	0,011	1,195	93	0,086	6,107	115a	0,082	10,000
53	0,140	2,830	94	0,001	2,719	115b	0,045	10,000
54	0,058	0,798	95	0,005	1,369

ln-vivo effect:

Animal Expérimente and sample analysis (CSF):

Test compounds were administered to animais (rat) different routes at doses of 10.0 or 5 pmol/kg, (both oral and intravenous). After compound administration, the animais were sacrificed in a CO₂ chamber and CSF samples were carefully collected by puncture of the cistema magna. Immediately after CSF sampiing, biood was taken by heart puncture and brains were dissected out. Biood was collected in EDTAcoated microvettes and plasma was prepared by centrifugation. Concentration of the test compounds in plasma, CSF or brain homogenate was determined uslng HPLCMS-MS.

Table 4 : Plasma, brain and CSF concentration

Ex.	Time(*) (h)	conc plasma (nmoi/L)	conc brain (nmol/L)	c(brain)/ c(plasma)	conc CSF (nmol/L)	c(csfx c(plasma)
44	0.5	2187	670	0.31	228	0.10
34	0.5	223	146	0.7	19	0.09
18	0.5	1225	351	0.3	163	0.13
20	0.5	338	272	0.82	37	0.11
45	2	801	183	0.20	25	0.03
64	2	783	254	0.5	37	0.06
76	2	463	218	0.5	18	0.04
75	2	1130	383	0.34	31	0.03
70	2	2377	695	0.29	276	0.12
47	2	622	441	0.7	22	0.04
49	2	239	47	0.2	13	0.06

(*) Time between administration and CSF sampiing

For the skilled In the art It Is évident from the experimental results shown above that the compounds of the présent invention are not only very potent phosphodiesterase 2 and/or 10 inhibitors but also reach high CSF concentrations and adéquate CSF to plasma ratios.

Metabollc stabllity

The metabolic stability of the compounds according to the invention has been Investigated as follows:

The metabolic dégradation of the test compound was assayed at 37 °C with pooled liver microsomes from various species. The final Incubation volume of 100 pi per time point contains TRIS buffer pH 7.6 at room température (0.1 M), magnésium chloride (5 mM), microsomal protein (1 mg/mL for human and dog, 0.5 mg/mL for other species) and the test compound at a final concentration of 1 pM. Following a short preincubation period at 37°C, the reactions were initiated by addition of betanlcotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM), and terminated by transferring an aliquot into solvent after different time points. After centrifugation (10000 g, 5 min), an aliquot of the supematant was assayed by LC10 MS/MS for the amount of parent compound. The half-iife was determined by the slope of the seml-logarithmic piot of the concentration-time profile.

Table 4: Stability of compounds of the présent invention in human liver microsomes.

Ex.	Half-life t1/2 [min]	Ex.	Half-life t1/2 [min]	Ex.	Half-life t1/2 [min]
1	130	54	130	76	130
5	43	55	130	77	90
6	66	55a	130	78	79
9	41	56	120	80	83
12	63	56a	110	81	26
13	130	56b	62	82	130
17	130	57	130	83	100
18	130	57a	130	84	39
20	130	57b	93	85	130
21	130	58	130	87	130
30	130	58a	130	88	53
32	130	58b	130	89	130
32a	36	58c	130	91	28
34	130	59	49	92	23

35	130	61	65	93	130
35a	130	62	130	94	38
42	130	63	130	96	110
43	130	64	130	97	51
44	130	66	57	99	130
45	130	67	130	100	12
46	130	68	39	101	22
47	130	69	53	102	130
48	130	70	130	104	130
49	130	71	130	104a	130
50	130	72	130	104b	130
51	130	73	130
52	130	75	130

hERG (human Ether-à-go-go-Related Gene) -Channel Assav hERG channel inhibition of compounds of the présent Invention has been investigated as follows:

HEK (human embryonic kidney) 293 cells were stably transfected with hERG cDNA. Cells were superfused with a bath solution containing (mM): NaCI (137), KCI (4.0), MgCI2 (1.0), CaCI2 (1.8), Glucose (10), HEPES (10), pH 7.4 with NaOH. Patch pipettes were made from borosilicate glass tubing using a horizontal puller and filled with pipette solution containing (mM): K-aspartate (130), MgCI2 (5.0), EGTA (5.0), K2ATP (4.0), HEPES (10.0), pH 7.2 with KOH. Résistance of the microelectrodes was in the range between 2 and 5 ΜΩ.

Stimulation and recordlng:

Membrane currents were recorded using an EPC-10 patch clamp amplifier and PatchMaster software. hERG-mediated membrane currents were recorded at 35’C, using the whole-cell configuration of the patch-clamp technique. Transfected HEK293 cells were clamped at a holding potential of -60 mV and hERG-mediated inactivating tail currents were elicited using a puise pattern with fixed amplitudes (activation/inactivation: 40 mV for 2000 ms; recovery: 120 mV for 2 ms; ramp to 40 mV in 2 ms; inactivating tail current: 40 mV for 50 ms) repeated at 15 s intervals. During each inter-pulse interval 4 puises scaled down by a factor of 0.2 were recorded for a P/n leak subtraction procedure. Rs compensation was employed up to a level that safely allowed recording devoid of ringing.

Compound préparation and application:

The different concentrations of the test compound were applied sequentially on each of the different cells Investigated. A steady state level of baseline current was measured for at least 6 sweeps prior to the application of the fïrst test compound concentration.

The test compound was dissolved In DMSO to yield a master stock solution which was diluted further in DMSO to stock solutions needed for the lower concentrations. Final dilutions in extracellular buffer were prepared freshly from these stocks by a 1:1000 dilution step each before starting the experiments.

Data analysis and IC50 détermination:

Peak current amplitudes were measured 3 ms afterthe ramp to +40 mV. For baseline and each concentration the peak currents of the three last sweeps before application of the next concentration were averaged. Residual currents (Ι/Ι0) were calculated for each cell as the fraction of actual average peak current and average baseline peak current.

The logistic concentration-response curve of the following form was fitted to the residual current data using a genetic algorithm:

1/10 = 1 -1/(1 +(C/IC50)**p)

C: actual concentration of compound (in pM)

IC50: half-inhibitory concentration (in pM) p: Hill slope

Table 4: hERG channei inhibition of compounds of the présent invention.

Ex.	hERG IC₅₀ [pM]	Ex.	hERG IC_S0 [pM]
13	>10	64	>10

18	>10	66	>10
20	>10	68	8.3
21	>10	75	>10
27	>10	76	>10
28	>10	80	>10
32	>10	82	>10
32a	>10	83	>10
34	>10	84	6.3
35a	>10	85	>10
45	>10	87	>10
47	>10	88	>10
48	>10	93	>10
49	>10
55	>10

In view of their ability to Inhibit the activity of phosphodiesterase 2 and/or 10 activity, their CSF values and their metaboiic stability and their low Inhibition of the hERG channel, the compounds of general formula I according to the Invention, Including the tautomers thereof, the stereoisomers thereof, the mixtures thereof, the hydrates thereof, the solvatés and the physlologlcally acceptable salts thereof, are suitable for the treatment and/or preventative treatment of ail those diseases or conditions whlch can be Influenced by Inhibition of PDE2 and/or 10 hyperactivity and/or cAMP and/or cGMP hypofunction. Therefore, compounds according to the invention, including the physlologically acceptable salts thereof, are particulariy suitable for the prévention or treatment of diseases, particulariy (1 ) disorders comprislng the symptom of cognitive deficlency; (2) organic, Including symptomatic, mental disorders, dementla; (3) mental retardation; (4) mood [affective] disorders; (5) neurotic, stress-reiated and somatoform disorders Including anxlety disorders; (6) behavioural and emotional disorders with onset usually occumng In childhood and adolescence, attention déficit hyperactivity syndrome (ADHD) and Autism spectrum disorders; (7) disorders of psychologlcal development, developmental disorders of scholastlc skills; (8) schizophrénie and other psychotic disorders; (9) disorders of adult personality and behaviour; (10) mental and behavioural disorders due to psychoactive substance use; (11) extrapyramidal and movement disorders; (12) episodic and paroxysmal disorders, epilepsy; (13) Systemlc atrophies primarily affecting the central nervous system, ataxia; (14) Behavioural syndromes associated with physiological disturbances and physical factors; (15) sexual dysfunction comprising excessive sexual drive; (16) factitious disorders.

In addition, the compounds according o the Invention can be used for the treatment, amelioration and / or prévention of cognitive Impairment belng related to perception, concentration, cognition, leaming or memory.

In addition, the compounds according to the invention can be used for the treatment amelioration and / or prévention of cognitive impairment being related to ageassociated leaming and memory impairments, age-associated memory losses, vascuiar dementia, craniocerebral trauma, stroke, dementia occurring after strokes (post stroke dementia), post-traumatic dementia, general concentration impairments, concentration impairments In children with leaming and memory problems, Alzhelmer*s disease, Lewy body dementia, dementia with degeneration of the frontal lobes, inciuding Pick's syndrome, Parklnson’s disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyotroplc latéral sclerosls (ALS), Huntington’s disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoffs psychosis. In addition, the compounds of the présent invention can be used for the treatment of Alzheimer*s disease.

In addition compounds according toe the Invention can be used for the treatment of pain disorders inciuding but not iimited to inflammatory, neuropatic and osteoarthritic 25 pain.

In addition, the compounds according to the invention can be used for the treatment of sleep disorders, bipolar disorder, metabolic syndrome, obeslty, diabetis meilitus, hyperglycémie, dyslipidemia, impaired glucose tolérance, or a disease of the testes, braln, small intestine, skeletal muscle, heart, lung, thymus or spleen.

Preferably the compounds according to the Invention are suitable for the treatment of Alzhelmer’s Disease and for the treatment schizophrenia.

More preferably the compounds according to the Inventionare suitable for symptomatic treatment of Alzhelmer’s Disease and for the treatment of cognitive Impalrment assoclated with schizophrenia.

In particular the compounds according to the invention are suitable for symptomatic treatment of prodromal and mild-to-moderate Alzhelmer’s Disease and for the treatment of cognitive impalrment associated with schizophrenia.

In a further aspect of the présent invention the présent Invention relates to methods for the treatment or prévention of above mentioned diseases and conditions, whlch method comprises the administration of an effective amount of a compound of general formula I, the tautomers thereof, the stereoisomers thereof, the mixtures thereof, the hydrates thereof, the solvatés and the physiologically acceptable salts thereof, to a human being.

The dose range of the compounds of general formula I applicable per day is usualiy from 0.1 to 1000 mg, preferably from 1 to 500 mg by oral route, in each case adminlstered 1 to 4 times a day.

Each dosage unit may convenientiy contain from 0.1 to 500 mg, preferably 1 to 100 mg.

The actual pharmaceutically effective amount or therapeutic dosage wïli of course dépend on factors known by those skilled In the art such as âge and weight of the patient, route of administration and severity of disease. In any case the combination will be adminlstered at dosages and In a manner which aliows a pharmaceutically effective amount to be delivered based upon patients unique condition.

Suitable préparations for administering the compounds of formula I, Including the physiologically acceptable salts thereof, will be apparent to those with ordinary sklll In the art and Include for example tablets, pills, capsules, supposltories, lozenges, troches, solutions, syrups, élixirs, sachets, injectables, inhalatives, powders, etc.. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 95 wt.-%, preferably 5.0 to 90 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants. The tablets may also consist of several layers.

For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, together with one or more inert conventional carriers and/or diluents, e.g. with com starch, lactose, glucose, microcrystalline cellulose, magnésium stéarate, citric acid, tartaric acid, water, polyvinylpyrrolidone, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof.

The compounds according to the Invention may also be used In conjunction with other active substances, particularly for the treatment and/or prévention of the diseases and conditions mentioned above. Other active substances which are suitable for such combinations include, for example, BACE Inhibltors; amyloid aggregation Inhibltors (e.g. ELND-005); directly or indirectly actlng neuroprotective and/or disease-modifying substances; anti-oxldants (e.g. vitamin E or ginkolide); antiinflammatory substances (e.g. Cox inhibltors, NSAIDs additionally or exclusively havîng Abeta lowering properties); HMG-CoA reductase Inhibltors (statins); acetylcholinesterase Inhibltors (e.g., donepezil, rivastigmine, tacrine, galantamine); NMDA receptor antagoniste (e.g. memantine); AMPA receptor agonists; AMPA receptor positive modulators, AMPAkines, monoamine receptor reuptake inhibltors, substances modulating the concentration or release of neurotransmitters; substances Inducing the sécrétion of growth hormone (e.g., ibutamoren mesylate and capromorelin); CB-1 receptor antagonists or Inverse agonists; antibiotics (e.g., minocyclin or rifampicin); PDE2, PDE4, PDE5, PDE9, PDE10 inhibltors, GABAA receptor inverse agonists, GABAA receptor antagonists, nicotinic receptor agonists or partial agonists or positive modulators, alpha4beta2 nicotinic receptor agonists or partial agonists or positive moduiators, alpha7 nicotinic receptor agonists or partial agonists or positive moduiators; histamine H3 antagonlsts, 5 HT-4 agonists or partial agonists, 5HT-6 antagonlsts, a!pha2-adrenoreceptor antagonlsts, calcium antagonlsts, muscarinlc receptor M1 agonists or partial agonists or positive moduiators, muscarinic receptor M2 antagonlsts, muscarinic receptor M4 antagonlsts, metabotropic glutamate-receptor 5 positive moduiators, glycine transporter 1 inhibltors, antidepressants, such as citalopram, fluoxetine, paroxetine, sertraline and trazodone; anxiolytics, such as lorazépam and oxazepam; antlphychotlcs, such as aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, rispéridone and ziprasidone, and other substances that modulate receptors or enzymes in a manner such that the efficacy and/or safety of the compounds accord in g to the invention is increased and/or unwanted slde effects are reduced. The compounds according to the invention may also be used in combination with immunothérapies (e.g., active immunisation with Abeta or parts thereof or passive immunisation with humanlsed antl-Abeta antibodies or nanobodies) for the treatment of the above-mentioned diseases and conditions.

The dosage for the combination partners mentioned above is usefully 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.

Therefore, In another aspect, thls invention relates to the use of a compound according to the invention or a physioiogically acceptable sait thereof combined with at least one of the active substances described above as a combination partner, for preparing a pharmaceutical composition which is suitable for the treatment or prévention of diseases or conditions which can be affected by Inhibitors of phosphodiesterase 2 and/or 10. These are preferably pathologies related to PDE2 and/or 10 hyperactivity and/or cAMP and/or cGMP hypofunction, particularly one of the diseases or conditions lîsted above, most particularly prodromal and mild-tomoderate Alzheimeris Dlsease and cognitive impairment associated with schizophrenia.

The use of the compound according to the invention, or a physioiogically acceptable sait thereof, in combination with another active substance may take place simultaneously or at staggered times, but particularly within a short space of time. if they are administered simultaneously, the two active substances are given to the patient together; while if they are used at staggered times the two active substances are given to the patient within a period of less than or equal to 12 hours, but particularly less than or equal to 6 hours.

Consequently, In another aspect, this invention relates to a pharmaceutical composition which comprises a compound according to the invention or a physïoiogically acceptable sait of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.

The compound according to the invention, or a physïoiogically acceptable sait thereof, and the additional active substance to be combined therewith may both be présent together in one formulation, for example a tabiet or capsule, or separately in two Identical or different formulations, for example as a so-called kit-of-parts.

Examples

The foilowlng examples are Intended to illustrate the Invention, without restricting its scope.

Chemical Manufacture

Abbrevlatlons:

ACN	acetonitrile
APCi	Atmospheric pressure chemical ionization
d	day
Cy	cyciohexane
DCM	dichioromethane
DIPEA	diisopropyiethylamine
DMF	dimethylformamide
DMA	dimethyiacetamlde
ESI	electrospray ionization (in MS)
EtOAc	ethylacetate
EtOH	éthanol
Ex.	example

h HATU	hour(s) 0-(7-azabenzotriazol-1-yl)-N_lN_lN',N-tetramethyluroniumhexafluoro phosphate
HPLC HPLC-MS	high performance liquid chromatography coupled high performance liquid chromatography-mass spectrometry
M MeOH	molar (mol/L) methanol
min	minute(s)
MS	mass spectrometry
NMP	1 -methyl-2-pyrrolidinone
rt	room température
Rt TBTU TEA TFA	rétention time (in HPLC) O-(benzotriazol-1 -y1)-N,N,N',N-tetramethyluronium tetrafluoroborate triethylamine trifluoroacetic acid
THF	tetrahydrofuran
TLC UPLC- MS	thin-layer chromatography ultra performance liquid chromatography - mass spectrometry

Methods:

UPLC-MS methods:

Method 1

Instrument: LC/MS Waters Acquity UPLC System DAD, SQD single quadrupole; column: HSS C18 1,8 pm 2,1 x 50 mm, Temp 35’C; mobile phase: A = H₂O 90% + 10% CH₃CN + CF3COOH 0,1%, B - CH₃CN 90% + H₂O 10%; gradient: 0.0 min 0% B -> 1.20 min 100% B -> 1.45 min 100% B -> 1.55 min 0% B -> 1.75 min 0% B; flow rate: 0.70 mL/min; détection: UV 254 nm; détection: SQD, single quadrupole; ion source: ES+/ ES-; scan range: 90-900 amu.

Method 2

Instrument: LC/MS Waters Acquity UPLC System DAD, SQD single quadrupole; column: BEH C18 1,7pm 2,1 x 50 mm, Temp 35’C; mobile phase: A = H₂O 90% + 10% CH₃CN + NH4COOH 5 mmol, B = CH₃CN 90% + H₂010%; gradient: 0.0 min

flow rate: 0.70 mUmin; détection: UV 254 nm; détection: SQD, single quadrupole; ion source: ES+/ ES-; scan range: 90-900 amu.

Method 3

Instrument: LC/MS Waters Acquity LIPLC System DAD, ELSD detector, SQD single quadrupole; column: HSS C18 1,8 pm 2,1 x 50 mm, Temp 35’C; mobile phase:

A = H₂O 90% + 10% CH₃CN + CF3COOH 0,1%, B = CH3CN 90% + H₂010%;

gradient: 0.0 min 0% B -> 2.40 min 100% B -> 2.70 min 100% B -> 2.80 min 0% B -> 3.00 min 0% B; flow rate: 0.70 mL/min; détection: UV 254 nm; détection: ELSD detector; détection: SQD, single quadrupole; ion source: ES+/ ES-; scan range: 90900 amu.

Method 4

Instrument: LC/MS Waters Acquity UPLC System DAD, ELSD detector, SQD single quadrupole; column: HSS C18 1,8 pm 2,1 x 50 mm, Temp 35^eC; mobile phase:

A = H₂O 90% + 10% CH3CN + NH4COOH 5 mmol, B = CH3CN 90% + H₂O 10%; gradient: 0.0 min 0% B -> 2.40 min 100% B -> 2.70 min 100% B -> 2.80 min 0% B -> 3.00 min 0% B; flow rate: 0.70 mL/mln; détection: UV 254 nm; détection: ELSD detector; détection: SQD, single quadrupole; Ion source: ES+/ ES-; scan range: 90900 amu.

HPLC-MS methods:

Method 5

Instrument: LC/MS ThermoFinnigan. Hplc Surveyor DAD, MSQ Quadrupole; column: Synergi Hydro-RP80A, 4 um, 4.60 x 100 mm; eluent A: 90% water + 10% ACN + ammonium formate 10 mM; eluent B = ACN 90%+10% H₂O + NH4COOH 10 mM; gradient: A (100) for 1.5 min, then to B (100) in 10 min for 1.5 min; flow rate: 1.2 mL/min; UV Détection: 254nm; Ion source: APCI.

Method 6

Instrument: LC/MS ThermoFinnigan HPLC Surveyor DAD, LCQ Fleet Ion Trap; column:

Simmetry Shield RP8, 5pm, 4,6 x 150 mm; eluent A: 90% water + 10% ACN + HCOOH 0.1%; eluent B = ACN 90%+10% H₂O + HCOOH 0.1%; gradient: 0.0 min 5% B -> 1.5 min 5% B -> 11.5 min 95% B -> 13.0 min 95% B -> 13.3 min 5% B ->

15.0 min 5% B; flow rate: 1.0 mL/min; UV Détection: 254 nm; Détection: Finnigan Fieet, Ion Trap; ion source: ES+; scan range: 100-900 amu.

Method 7

Instrument: LC/MS ThermoFinnigan. Hplc Surveyor DAD, MSQ Quadrupole; column: Synergi Hydro-RP8, 4 um, 4.60 x 100 mm; eluent A: 90% water + 10% ACN + ammonium formate 10 mM; eluent B = ACN 90%+10% H2O + NH4COOH 10 mM; gradient: 0.0 min 30% B -> 1.50 min 50% B -> 8.50 min 100% B -> 13.50 min 100% B -> 14.00 min 30% B -> 15.00 min 30% B; flow rate: 0.85 mL/min; UV Détection: 254 nm; Ion source: ES+.

Method 8

Instrument: LC/MS ThermoFinnigan. Hplc Surveyor DAD, MSQ Quadrupole; column: Synergi Hydro-RP100A, 2.5 um, 3 x 50 mm; eluent A: 90% water + 10% ACN + ammonium formate 10 mM; eluent B = ACN 90%+10% H2O + NH4COOH 10 mM; gradient: A (100) for 1.5 min, then to B (100) in 10 min for 1.5 min; flow rate: 0.7 mL/min; UV Détection: 254nm; Ion source: APCI.

Method 9

Instrument: LC/MS ThermoFinnigan. Hplc Surveyor DAD, MSQ Quadrupole; column: Synergi Hydro-RP100A, 2.5 um, 3 x 50 mm; eluent A: 90% water + 10% ACN + NH4COOH 5 mM; eiuent B = ACN 90%+10% H2O; gradient: A (100), then to B (100) in 4min for 1.3 min; flow rate: 1.2 mL/min; UV Détection: 254nm; Ion source: APCI.

Method 13

Instrument: LC/MS ThermoFinnigan HPLC Surveyor DAD, LCQ Fieet Ion Trap; column: Xselect CSH, 2.5 um, 4.6 x 50 mm; eluent A: 90% water + 10% ACN + HCOOH 0.1%; eluent B = ACN 90%+10% H₂O + HCOOH 0.1%; gradient: A (100), then to B (100) in 4min for 1.3 min; then to A(100) in 1.6min. flow rate: 1.4 mL/min; UV Détection: 254nm; Ion source: ESI.

Method 16

Instrument: LC/MS Waters Alliance 2695 HPLC System DAD, Quattro Micro Triple quadrupole; Column:Atlantis dC18 5pm 4,6 x 50 mm, Temp 35’C: Mobile phase:A = H₂O 90% + 10% CH₃CN + CF3COOH 0,05%; B = CH3CN 90% + 10% H₂O; flow rate: 1.3 mL/min; UV Détection: 254nm; Ion source: ESI.

Gradient:

Time in min %A %B

0.00	100	0
0.70	100	0
4.5	0	100
5.80	0	100
6.00	100	0

Method 17

Instrument: LC/MS ThermoFinnigan HPLC Surveyor DAD, LCQ Fleet Ion Trap; column: Xselect CSH, 2.5 um, 4.6 x 50 mm; eluent A: 90% water + 10% ACN + HCOOH 0.1%; eluent B = ACN 90%+10% H₂O + HCOOH 0.1%; flow rate: 1.4 mL/min; UV Détection: 254nm; Ion source: ESI Gradient:

Time in min: %A

0.00

1.00

8.50

10.0 %B

100

10.2 100 0

11.0 100 0

GC-MS methods:

Method 10 (3A.2)

Instrument: GC/MS Thermo Scientific TRACE GC ULTRA, DSQ II MS single quadrupole; column: Agitent DB-5MS, 25m x 0.2 5 mmol x 0.25 pm; carrier gas:Helium, 1 mL/min costantflow; oven program: 50’C, to 100^eC in 10^eC/min, to 200’C in 20°C/min, to 320°C in 30’C/min (hold 10 min); détection: DSQ II MS single quadrupole; Ion source: El; scan range: 50- 450 amu.

Préparative HPLC methods :

Method 11 :

Instrument: Waters Autopurification HPLC/MS System; column: Sunfire C18, ODB 5.0 pm, 19x100mm. MS Zq single quadropole; eluent A: 90% water + 0.05% TFA; eluent B = ACN gradient: 0.0 min 20% B -> 6.5 min 60% B -» 7.0 min 95% B -> 8.5 min 20% B flow rate: 40 mL/min; UV Détection: 254 nm; Ion source: ES+.

Method 12 :

Instrument: Waters Autopurification HPLC/MS System; column: Sunfire C18, ODB 5.0 pm, 19x100mm. MS Zq single quadropole; eluent A: 90% water + 0.05% TFA; eluent B = ACN gradient: 0.0 min 50% B -> 6.5 min 90% B -> 7.0 min 95% B -> 8.5 min 50% B flow rate: 40 mL/rrjin; UV Détection: 254 nm; Ion source: ES+.

Method 14:

Instrument: Waters Autopurification HPLC/MS System; column: Xbridge, C18 5 pm, 19x100mm. MS Zq single quadropole; eluent A: 90% water + NH4COOH 5mM, eluent B = ACN gradient: 0.0 min 40% B -> 6.5 min 80% B -> 7.0 min 95% B -> 8.0 min 95% B -> 8.5 min 40% B flow rate: 40 mL/min; UV Détection: 254 nm; Ion source: ES+.

Method 15

Instrument: Waters Autopurification HPLC/MS System; column: Xbridge, CI 8 5 pm, 19x100mm. MS Zq single quadropole; eluent A: 90% water + NH4COOH 5mM, eluent B = ACN gradient: 0.0 min 30% B -> 6.5 min 80% B -> 6.50 min 70% B -> 8.0 min 95% B -> 8.5 min 30% B flow rate: 40 mL/min; UV Détection: 254 nm; Ion source: ES+.

Chiral HPLC methods :

Instrument: HPLC Agitent 1100 (DAD equipped; UV Détection: 230 nm); flow rate: 15 mL/min; column température: 25^eC.

Method C1 column: Daicel Chiralpack AS-H; eluent: Hexane:EtOH=70:30

Method C1a column: Daicel Chiralpack AS-H; eluent: Hexane:EtOH=80:20

Method C2 column: Daicel Chiralpack AD-H; eluent: Hexane:lsopropanol=70:30

Method C2a column: Daicel Chiralpack AD-H; eluent: Hexane:lsopropanol=75:25

Method C2b column: Daicel Chiralpack AD-H; eluent: Hexane:lsopropanol=80:20

Method C2c column: Daicel Chiralpack AD-H; eluent: Hexane:lsopropanol=60:40

Method C3 column: Daicel Chiralcel OJ-H; eluent: Hexane:EtOH=80:20

The most suitable purification techniques applied for the purification of compounds of the présent invention are direct phase silica gel flash chromatography and reverse phase chromatography or préparative HPLC.

General comment concemlng the présentation of the structures

Compounds with stereogenic centre(s) : The structures depicted in the experimental section will not necessarily show ail the stereochemical possibilities of the compounds but only one.

The structural présentation of the compounds in the experimental section will show a stereochemical bond only in case where the absolute stereochemistry Is known.

The structurai présentation of the compounds in the experimental section with unknown absolute stereochemistry will show a pianar bond plus an additional comment that Indicates If the described compound is a racemic mixture, a single stereoisomer and where applicable the relative stereochemistry.

Two examples are given below.

Example 1 : the presented chemical structure is depicted as:

Racemic mixture

The added term racemic mixture points to the two stereochemical options and thus the manufactured compounds Is a mixture of:

and θ

When racemic mixtures of above deplcted structures are separated, the single stereoisomers are deplcted as :

Single stereotsomer a

Single stereotsomer b

The added term 'single stereolsomer' Indicates that the absolute configuration is unknown.

Single stereolsomer a Is assigned to the first eiuting Isomer In chiral HPLC, single stereolsomer b is assigned to the second eiuting isomer in chiral HPLC .

Example 2 : the presented chemical structure Is deplcted as:

O—'

TRANS-racemlc mixture

The added term TRANS- racemic mixture’ points to the two stereochemlcal options and thus the manufactured compounds Is a mixture of:

and θ

The same principles applies to ’CIS-racemlc mixture’.

When racemic mixtures of above deplcted structures are separated, the single stereoisomers are deplcted as:

&

O—f

TRANS- single stereolsomer a TRANS- single stereolsomer b

The added terni ’TRANS-single stereolsomer· indicates a relative configuration known (trans) and the planar bond indicates the unknown absolute configuration.

The same principies appiies to 'ClS-single stereoisomer¹.

Single stereoisomer a is assigned to the first eluting isomer in chiral HPLC, single stereoisomer b is assigned to the second eluting isomer in chiral HPLC .

Intermedlates

Intermediate 1 :

To a stirred solution of 2-oxo-propanoic acid (157 mL, 2.23 mmol) In dry MeOH (100 mL) at 0 *C, pyridine-2,3-diamine (20 g, 18 mmol) was added portionwise. The resultlng solution was stirred at room température ovemight, solvent was evaporated under reduced pressure and the suspension fiitered. The solid was washed with MeOH, dried to obtain 14 g of title compound.

HPLC-MS (Method 6): R_t = 5 min

MS:m/z=162 (M+H)*

Intermediate 2:

A mixture of Intermediate 1 (1 g) and phosphorus oxychloride (15 mL) was heated to 90 °C for 2.5 h. After cooling, the reaction mixture was carefully poured on ice, then neutraiized with a saturated solution of Na₂CO3 and diluted with DCM. Phases were separated, organlcs washed with a saturated solution of NaCI, dried over sodium sulphate and evaporated to obtain 0.95 g of the title compound.

HPLC-MS (Method 8): R_t = 4.54 min

MS: m/z = 180 (M+H)*

Intermedlate 3:

Cl

To a mixture of commercîally available 2-chloro-5-hydroxybenzoîc acid (4 g, 23.18mmol) In dry EtOH ( 90 mL), concentrated sulphuric acid (1 mL, 17.62mmol) was added. The mixture was stirred under reflux ovemight, then solvent evaporated under reduced pressure and the residue dissolved with DCM. A saturated solution of NaHCO₃ was added, phases were separated, organîcs dried over sodium sulphate, filtered and evaporated to obtain 5 g of the corresponding 2-chloro-5-hydroxybenzoic acid ethyl ester.

HPLC-MS (Method 2); R_t = 1.0 min

MS: m/z = 201.6 (M+H)*

Intermediate 4:

NH₂Hhk /O

Cl

Intermediate 3 (5 g, 23.62 mmol) was dissolved In EtOH (100 mL) and hydrazine hydrate (13.0 mL, 262.12 mmol) was added. Mixture was stirred under reflux for 24 h, solvent evaporated and the crude treated with 20 mL of water. The white solid formed was filtered and washed with water and dried for 3 h at 60°C over P2O5 to obtain 3.0 g of title compound.

HPLC-MS (Method 2): R₍ = 0.53 min

MS: m/z = 180 (M+H)*

Intermediate 5:

Intermediate 5 was prepared as described for Intermediate 3 starting from commercially available 2-fluoro-5-hydroxy-benzoic acid (1 g, 6.41 mmol) to obtain

1.17 g of the title compound.

HPLC-MS (Method 2): R₍ = 0.94 min

MS : m/z = 185.16 (M+H)*

The foilowing Ester Intermediates were prepared in analogy to Intermediate 3 starting from commercially availabie benzolc acids.

Starting benzoic acid	Ester Intermediate	MS m/z	Rt(min)	Method
ho^o Y	5a	ΟγΟ	180 [MJ*	9.73	10
ΗΟγΟ Y	5b	ΟγΟ Y	203 [M+H]*	1.2	2

HO^O A	5c	Ί «y» A	263 [MJ*	9.90	10
HO^O A	5d	Ί °y° A	310 [Mf	10.47	10
HO^O A	5e	Ί Oy° A	294 [MJ*	! î 9.52	10
ΗΟχ^Ο A	5f	Ί OyO A	242 [MJ*	9.42	10
HCkyO A	5g	OyO A	246 [MJ*	8.84	10
H°y° A	5h	Ί OyO A	290 [MJ*	10.15	10

Intermediate 51 ,ο

Step 1 ^Cl Step 2

Br

HO

HO .0

Step 1:

Step 1 was performed In analogy to what reported In iiterature référencé: Li, Yuanzhen et al. Organic Letters, 2007 , vol. 9, # 20 p. 4057 - 4060, starting from Ester Intermediate 5c.

Step 2:

Intermediate obtalned from Step 1 (0.5 g), was dissolved In toluene (10 mL). Wilkinson's cataiyst RhCi(TPP)3 (0.1g) was added and the réaction mixture stirred at 60°C under hydrogen atmosphère for 18h. The reaction mixture was fïltered on a celite pad and the solvent was removed under vacuum to obtain the deslred product (0.4 g).

GC-MS (Method 10) R_t =11,55 min

MS : m/z = 256 [M]+

Intermediate 5i

Under nitrogen atmosphère, starting Ester Intermediate 5e (5.0 g, 15.3 mmol) was dissolved in THF (40 mL), the reaction mixture was cooled to -50°C and stirred for 10 minutes. Isopropyl-magneslum-chloride (11 mL of a 2M solution In THF) was added dropwîse and the reaction mixture was stirred at -50°C for 2h. The reaction mixture was cooled to -78°C and a solution of cyclobutanone (2.15 g, 30.6 mmol) In THF (10 mL) was added dropwîse. The reaction mixture was stirred at -78°C for 1 h, then warmed to room température and stirred for 18h. The solvent was removed under vacuum, dichloromethane was added and the reaction mixture was washed with a saturated solution of NaHCOs, The organic phase was concentrated under vacuum and the crude product obtalned was purified by flash chromatography (eluent from 90:10 to 80:20 Cy/EtOAc) to obtain the desired product (3.0 g).

GC-MS (Method 10): R_t = 10.91 min

MS : m/z = 210 (M-28)⁺

The following Ester Intermediates were prepared in analogy to Intermediate 5j and purified applying the most suitable purification technique, starting from the corresponding Starting Esters Intermediates and commercially available ketones.

Starting Ester intermediate	Starting ketone	Ester intermediate Structure	MS m/z	Rt (min)	Method
5d	X	5k		255 [M+HJ*	4.23	16
5d	a.	51		284[M]⁺	12.58	10
5d	A	5m	AcX cr	243 [M+HJ*	1.04	2
5e	U	5n		268[M]⁺	11.97	10
5h	a.	5na	/—0 0 \_/	264[MJ*	12.18	10
5d		5q		253 [M+Hf	2.84	13

5e		5r	F	237 [M-17]*	2.68	13
5d	a	5s	cr	284[M]⁺	12.42	10

Intermedlate 5o

To a solution of Ester Intermediate 5m (0.37 g, 1.52 mmol) in dichloromethane (9 mL), pyridinium-para-toluenesulfonate (0.06 mg, 0.23 mmol) and 3,4-dihydro-2Hpyran (0.2 mL, 2,29 mmol) were added and the reaction mixture was stirred at room température for 4h. The reaction mixture was washed with water and the organic phase was concentrated under vacuum. Crude was purified by flash chromatography (eluent from 100:0 to 80:20 Cy/EtOAc) to obtain the desired product (0.4 g).

GC-MS (Method 10): R, = 12.52 min

MS : rn/z = 326 (M)⁺

Intermedlate 5d

Step 1:

Step 1 was performed in analogy to what reported in the literature référencé: Duong, Hung A.; et al. Angewandte Chemie, International Edition, 2011 , vol.50, p. 463 466, starting from commerclally available (3-bromo-4-chloro-phenyl)-acetic acid. Step 2:

Under nïtrogen atmosphère, a solution of Intermediate from Step 1 (0.24 g) in THF(10 mL) was stirred at -6O’C, méthylmagnésium bromide was added dropwise and the reaction mixture was stirred at -78 °C to r.t. for 2 h. The reaction mixture was quenched with saturated ammonium chloride water solution and extracted with ethyl acetate twice, dried over sodium sulfate and concentrated under vacuum to get the crude product as colour-less oil.

Step 3:

Step 3 was performed in analogy to Step 2 starting from Intermediate obtained in Step 2.

Step 4:

Step 4 was performed in analogy to préparation of Intermediate 5o, starting from Intermediate obtained in Step 3.

Step 5:

To a solution of the Intermediate obtained from Step 4 (15 g) in MeOH (150 mL), [1,1 ’-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)] (3.088g) and triethylamine (22 g, 21.4 mL) were added and the reaction mixture was stirred at 80’C under CO atmoshere for 36 h.

The solvent was removed under vacuum and the crude product obtained was purified by flash chromatography to get the desired product.

Intermediate 6:

NH, I ²

100

Intermediate 6 (4,4 g) was prepared as described for Intermediate 4 and purified applying the most suîtable purification technique, starting from Intermediate 5 (5.84 g, 0.03 mmol).

HPLC-MS (Method 2): R_t = 0.42 min

MS: m/z = 171.2 (M+H)⁺

The foüowing Hydrazide intermediates were prepared in analogy to intermediate 4 and purified applying the most suîtable purification technique, starting from the corresponding Ester Intermediates.

Starting Ester intermediate	Hydrazide Intermediate Structure	MSm/z	Rt(min)	Method
5a	6a	nh₂ HîL^O ...Λ	167 [M+H]⁺	0.47	17
5b	6b	NH, HN^O XX”	188 [Mf	9.47	10
5c	6c	nh₂HN^O jr	249 [M+HJ*	1.98	13
5d	6d	nh₂ HfL^O	296 [Mf	11.78	10
5e	6e	nh₂ Λ	281 [M+Hf	1.83	9

101

5f	6f	nh₂hn^o Λ	229[M+H]*	1.80	9
5g	6g	NH, HN^O Λ	233[M+H]*	1.55	9
5h	6h	ΗΝ^,Ο Λ	277 [M+H]*	1.94	9
5i	6i	NH₂ HNyO	256 [M+H]*	0.68	2
5j	6j	^η·^ν'ν^οτ&	225 [M+H]*	0.56	2
5k	6k	'·»5οΌ	241 [M+H]*	0.59	2
5I	6I		271 [M+H]*	0.57	2
5m	6m	cr	228 [M]*	11.79	10

102

5π	6n	F	255 [M+Hf	0.43	2
5na	6na		251 [M+H]*	0.57	2
5o	6o		313[M+Hf	0.85	2
5p	6p	NH_a O^NH C^¹o	327[M+Hf	0.90	2
5q	6q	CI^/^^/	257 [M+H]*	0.49	13
5r	6r	Ycx F	241 [M+Hf	0.44	2
5s	6s	ναθ° 00 ci	271 [M+Hf	0.58	2

Intermediate 7:

103

Commercially available 2-amlno-6-methyl-3-nitropyridine (12 g, 78.36 mmol) was dissolved in a mixture of dry THF/MeOH (1:1,60 mL) and hydrogenated In the presence of Pd/C (10%, 1.2 g) under 5 bar hydrogen atmosphère for 5 h. Catalyst was fïltered, solvent evaporated under reduced pressure to obtain 7 g of the title compound.

HPLC-MS (Method 2): R_t = 0.77 min

MS : m/z = 154(M+Hf

Intermediate 7a

Step 1 :

2-Amino-6-chloro-3-nitro-pyridine (20 g, 115 mmol), cyclopropylboronlc acid (12.8 g, 150 mmol), tricyclohexylphosphine (3.2 g, 11.5 mmol), 2,6-ditert-butyl-4methylphenol (5.08 g, 23 mmol), palladium acetate (1.3 g, 5.7 mmol) and tripotassium-phosphate (73 g, 346 mmol) were suspended In toluene (40 mL) and water (2 mL). The reaction mixture was stirred at reflux for 18h, diluted with ethyl acetate and washed with water. The organic phase was separated, concentrated under vacuum and dried over sodium sulfate. The crude product obtalned was purified by flash chromatography (eluent from 90:10 to 45:55 Cy/EtOAc) to obtain the deslred product (10.6 g).

GC-MS (Method 10): R_t = 10.54 min

MS : m/z = 179 (M)*

Step 2:

To a solution of Intermediate from Step 1 (6 g, 19 mmol) In absolute EtOH (120 mL), zinc (13.7 g, 209 mmol) and ammonium chloride (30.8 g, 573 mmol) were added and the reaction mixture was stirred at room température for 18 h. The reaction mixture was fïltered on a celite pad, the solvent was removed under vacuum and the crude

104 product obtained was purified by flash chromatography (eluent 90:10 dichloromethane/MeOH) to obtain the desired product (2.4 g). HPLC-MS (Method 9): R_t = 1.42 min

MS : m/z= 150 (M+H)*

Intermediate 7b

Step 1 :

Step 1 was performed In analogy to what described in Step 1 In the préparation of Intermediate 7a, starting from commercially available 2-lsopropenyl-4,4,5,5tetramethyl-[1,3,2]dioxaborolane.

Step 2:

Intermediate from Step 1 (5 g, 26.5 mmol) was dissolved In 20 mL of methanol, Pd/C (0.25 g) was added and the reaction mixture was stirred under hydrogen atmosphère (4 bar) for 2h at room température. The reaction mixture was filtered on a celite pad and the solvent was removed under vacuum to give the desired product (3 g). GC-MS (Method 10): R_t = 8.91 min

MS:m/z = 151 (M)⁺

Intermediate 7c:

Intermediate 7c (3.99 g) was prepared in analogy to Intermediate 7 and purified applying the most suitable purification technique, starting from commercially available

2-amino-3-nitro-5-picoline (5.0 g, 32.65 mmol).

Intermediate 7d

105

Intermediate 7d (4 g) was prepared In analogy to Intermediate 7b and purified applying the most suitable purification technique, starting from commerclally avaiiable

2-amino-5-chloro-3-nitro-pyridine (5 g, 26.5 mmol).

HPLC-MS (Method 2): R, = 0.6 min

MS: m/z = 152 (M+H)⁺

Intermediate 8:

To stirred solution of 2-oxo-propanoic acid (40.8 mL, 587 mmol) in dry MeOH (130 mL) at 0 *C, 6-methyl-pyridine-2,3-diamine (Intermediate 7,6.8 g, 55.2 mmol) dlssolved in dry MeOH (40mL) was added dropwise. The solution was stirred at room température ovemight then solvent was evaporated under reduced pressure and the resulting suspension filtered. The solid was washed with MeOH, dried to obtaln 1.35 g of title compound.

HPLC-MS (Method 9): R_t = 1.31 min

MS: m/z= 176 (M+H)*

Intermediate 8a

Step 1 :

Intermediate 7a (2.4 g, 15.2 mmol) was dissolved in absolute EtOH and stirred at 0^eC, Dimethylacetylenedicarboxylate (2.4 g, 16.8 mmol) was added dropwise and the

106 reaction mixture was allowed to react room température for 18h. The solid formed was filtered, washed with EtOH, Ethyl Ether and dried in vacuum to glve the desired product (3 g).

HPLC-MS (Method 13): Rt “ 3.16 min

MS : m/z = 260 (M+H)*

Step 2:

Intermediate obtained from Step 1 (3 g 0.01 mol) was dissolved in a sodium hydroxide water solution (1.36 g , 0.03 mol In 50 mL) and the reaction mixture was reflux for 2h. pH was adjusted to 2-3 and the reaction mixture was extracted with 10 ethyl acetate. The organic phase was dried over sodium sulfate, concentrated under vacuum. The crude product obtained was purified by flash chromatography (eluent from 80:20 to 20:80 Cy/EtOAc) to obtained the desired product (2.0 g).

HPLC-MS (Method 13): Rt = 2.46 min

MS: m/z = 202 (M+H)*

The following Amide Intermediates were prepared in analogy to Amide Intermediate 8a and purified applying the most suitable purification technique, sterling from the corrisponding Di-amine Intermediates.

Starting Di-amine Intermediate	Amide Intermediate Structure	MS m/z	Rt(min)	Method
7b	8b		204 [M+H]⁺	2.48	13
7c	8c		176 [M+H]⁺	1.88	13
7d	8d	Ατχ	204[M+H]*	0.78	2

107

6-(1-Methylcyclopropyl)pyridine-2,3diamlne (commercially available)	8e		216[M+Hf	4.96	17
6trifluoromethylpyridine-2,3-di amine (commercially available)	8f	^r F ^H	229 [M]⁺	9.42	10

Intermediate 9:

A mixture of Amlde intermediate 8 (1.35 g, 7.71 mmol)and phosphores oxychloride (16 mL) was heated to 90 °C for 3h. After cooling, solvent was reduced under reduced pressure, the reaction mixture was carefully poured on ice and neutralized with a saturated solution of Na₂CO3. DCM was added, phases were separated, organics washed with a saturated solution of NaCI, dried over sodium sulphate and evaporated to obtain 1.39 g of the title compound.

HPLC-MS (Method 8): R_t = 0.84min

MS :m/z= 194.6 (M+H)*

The following Chloride Intermediates were préparé in analogy to Chloride Intermediate 9 and purified applying the most suitable purification technique, starting from the corrisponding Amide Intermediates. Heating température reported in Table.

108

Starting Amide Intermediate	Chloride Intermediate Structure	Heating Température	MSm/z	Rt (min)	Method
8a	9a	3L <3^ V-r N N Cl	55°C	220 [M+Hf	1.01	2
8b	9b	\ N N Cl	80°C	222 [M+Hf	3.18	13
8c	9c		90°C	194 [M+Hf	2.52	13
8d	9d	N N Cl	55’C	222 [M+Hf	3.19	13
8e	9e		80°C	234 [M+H]*	1.15	2

Intermediate 9f

O

Intermediate 8f (1.35 g, 5.9 mmol) and N.N-diisopropylethylamine (2.28 g, 3 mmol) were dissolved In DMF (10 mL). The reaction mixture was cooled to O’C and methanesulfonylchloride (0.74 g, 6.48 mmol) was added dropwise. The reaction

109 mixture was allowed to reach room température and stirred for 4h. Ammonium chloride saturared water solution was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with citric acid (10% water solution), dried over sodium sulfate and concentrated under vacuum, to give the 5 deslred product (1.5 g).

HPLC-MS (Method 13): R_t = 3.09 min

MS : m/z = 308 (M+H)⁺

The following Intermediates were prepared based on well known reported 10 procedures starting from commerclally available starting materials.

Intermediate		Structure	Référencé
10	Toluene-4-sulfonlc acid 3-h vdroxv-3-m eth vlbutvi ester		Bioorganic & Médicinal Chemistry Letters (2007), 17(22), 61646168
11	Toiuene-4-sulfonlc acid 3-hvdroxv-butvi ester	0	Bioorganic & Médicinal Chemistry, 18(4), 1665-1675; 2010
12	Toluene-4-sulfonic acid 3.3.3-trifluoro-DroDvl ester	7^0 '0	US 2009-564132
13	Toluene-4-sulfonic acid tetrah vdroDvra n-4-vl ester		WO 2011-20767
14	Toluene-4-sulfonic acid 4.4-difIuoro-cvclohexvl ester		WO 2008-119663
15	Toluene-4-sulfonic acid tetrahvdro-furan-3-vl ester	°-Λθ' °	WO 2010-023594

110

16	Toluene-4-sulfonic acid (SHtetrahYdro-furan-3vl) ester	0	WO 2011-061590
17	Toluene-4-sulfonic acid fRHtetrahvdro-furan-3vl) ester	o ^c'^:) 0	WO 2010-102512
18	Toluene-4-sulfonic acid tetrahvdro-furan-3vtmethvl ester	cZn	WO 2011-084402
19	tert-Butvl-(R)-2-chloro1-methvi-ethoxvldiDhenvI-silane		Tetrahedron Letters (1982), 23(25), 25436.
20	tert-Butvl-(SV2-chloro- 1 -meth vl-et hoxv)diohenvl-s liane		Tetrahedron Letters (1982), 23(25), 25436.
21	24(S)-2-Chloro-lT methvl-ethoxv)-te trahvdro-pyran	a	Tetrahedron Letters (1982), 23(25), 25436.
26	Toluene-4-sulfonic acid 3-rnethyl-oxetan-3ylmethvl ester	°c^-\ f?_/=\ 0 ---^f	Synthetic Communications (2011), 41(17), 25392543
27	Toluene-4-sulfonic acid 1 -itetrahvdro-Dvran-4vî)-ethvl ester	O --'	Journal of □rganometallic Chemistry (1978), 150(2), 179-85

111

28	Toluene-4-sulfonic_acld 1.4-dioxaspiroM.Sldec-g-vl ester		WO 2010-006086
29	Toluene-4-sulfonlc acid 3-hvdroxv-cvclopentvl ester		US 2007-0049537

Intermediate 29a

Literature Reference: Journal of Organic Chemlstry USSR (English Translation), 5 1989 , vol. 25, #6.1 p. 1019-1025).

Epoxlde Intermediate 29a (4 g) was prepared In analogy to what described in W02010/47956 A1, startlng from methylene cyclobutane (5 g, 73 mmol). GC-MS (Method 10) R_t = 2.70 min [M]⁺= 83 , ;

Intermediate 29b

O

Epoxide Intermediate 29b (1 g) was prepared in analogy to what described In

WO2013/55577 A1 startlng from 3,6-Dihydro-2H-pyran (2 g, 23.78 mmol).

GC-MS (Method 10) R_t = 8.10 min [M]⁺= 99

ci

112

To a solution of Exampie 1 (0.2 g, 0.67 mmol) In dry DMF (3 mL), césium carbonate (0.63 g, 1.92 mmol) and Intermediate 28 (0.41 g, 1.28 mmol ) were added. Mixture was heated at 80°C for 1 h, then solvent evaporated under reduced pressure and the residue dissolved in DCM and washed with a saturated solution of NaCi. Phases were separated, organics dried over sodium sulphate and evaporated . The residue was purified by flash chromatography (eluent from 100:0 to 50:50 Cy/EtOAc) to obtain 0.21 g of the title compound.

HPLC-MS (Method 2): R_t =1.12 min

MS: m/z = 452 (M+H)*

Intermediate 30:

ci

To a solution of Intermediate 29c (0.21 g, 0.46 mmol) In acetone (10 mL), a 4M solution of HCl (1 mL) was added and mixture stirred at room température for 2 h. Soivent was evaporated under reduced pressure, the residue treated with DCM, washed with a saturated solution of NaHCO₃. Phases were separated, organics dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (eluent from 90:10 to 50:50 Cy/EtOAc) to obtain 0.18 g of the title compound.

HPLC-MS (Method 2): Rt =1.09 min

MS: m/z = 410 (M+H)*

The following intermediates were prepared In anaiogy to Example 1 and purified applying the most suitable purification technique, starting from the corresponding Chloride and Idrazlde Intermediates:

Chioride Inter- mediate

Hydrazide

Intermediate Structure

MS m/z

Ri (min)

Method

113

9	6c	30a	A	388 [Μ+Η]*	3.58	13
2	6d	30b	αχ A	,422 [Μ+Η]*	1.07	2
2	6h	30c	αχ N N Ά^Ν	402 [Μ+Η]*	3.00	9
2	6e	30d	αχ A	406 [Μ+Η]*	3.02	9
9a	6e	30e	Ά^Ν	446 [Μ+Η]*	3.78	13
2	6f	30f	αχ A	354 [Μ+Η]*	3.35	13

114

9a	6f	30g	Ÿ	394 [M+H]*	3.69	13
9a	6d	30h		462 [M+H]*	3.81	13
9a	69	30i		398 [M+H]*	3.72	13
9	6d	30j	XXJ 'O~«	436 [M+H]*	3.64	13
9b	6d	30k	~7 ^N V> Y	464 [M+H]*	3.99	13
9b	6f	30I	Y	396 [M+H]*	3.85	13
9e	6e	30m	Y”	460 [M+H]*	1.29	2

115

9d	6f	30n		397 [M+H]*	1.27	2
9a	6b	30o		354 [M+H]*	3.53	13
9f	6d	30r	_F /γγ Tⁿj=>	490 [M+H]*	1.25	2
9f	6g	30s	F	427 [M+H]*	1.15	2

Intermediate 30p

Intermediate 30p (0.26 g) was prepared In analogy to Example 1 and purified applying the most suitable purification technique, starting from Chloride Intermediate

9d (0.25 g, 1.01 mmol) and Hydrazide Intermediate 4 (0.19 g, 1.01 mmol). HPLC-MS (Method 2): R, =1.01 min

MS: m/z = 354 (M+H)*

116

Intemnediate 31

—N

To a solution of Example 1 (0.4 g, 1.3 mmol) in dry DMF (4 mL), césium carbonate (0.85 g, 2.62 mmol) and methylbromoacetate (0,152 mL, 1.56 mmol) were added. Mixture was stirred at room température ovemight, solvent evaporated and the residue treated with EtOAc. A saturated solution of NH4CI was added, phases were separated and evaporated. The crude was purified by flash chromatography (eluent from 50:50 to 0:100 Cy/EtOAc) to obtain 0.29 g of the title compound.

HPLC-MS (Method 13): R_t =3.06 min

MS: m/z = 384 (M+H)*

Intermedlate 32 (0.5 g) was prepared in analogy to Example 1 and purified applying the most suitable purification technique, starting from Intermedlate 9f (0.9 g, 2.52 mmol) and Hydrazide Intermedlate 6 (0.47 g, 2.77 mmol).

HPLC-MS (Method 13) R_t =3.11 min

MS : m/z = 380 (M+H)*

Exemplary embodlments:

Example 1:

117

N ^Η0Ό-_α

Intermediate 2 (0.60 g, 3.34 mmol) and Intermediate 4 (0.62 g, 3.34 mmol) were suspended in cyclohexanol (5 mL) and heated under reflux for 2 h. The resultlng solution was cooled and solvent evaporated under reduced pressure and the residue 5 purified by flash chromatography (eluent 95:5 DCM/EtOH) to obtain 0.95 g of the title compound.

HPLC-MS (Method 9): R₍ =2.17 min

MS: m/z = 312 (M+H)*

The following Examples were prepared in analogy to Exampie 1 and purified applying the most suitable purification technique, starting from the corresponding Chloride Intermediates and Hydrazide Intermediates:

Starting Chloride Intermediate	Starting Hydrazide Intermediate	Ex.	Structure	MS m/z [M+H]*	Rt (min)	Method
9	4	2	XXX A	326	0.93	2
9	3-hydroxy· benzhydrazide (commercially available)	3	χχχ A	292	2.62	13

118

2	6	4	αχ	296	0.79	13
9a	6	5		336	2.97	13
9a	6a	6	”~a	226	2.93	13
9b	6a	7		334	3,16	13
9b	6	8	-yOyÇ	338	3,14	13
9a	4	9	vz^ ^N\ 7 -a::	352	2,59	9
2	6a	10	ca ”-a	292	2.03	13

119

9c

4

11

T , O __/

326

2.96

13

Example 12

V/'CI

Example 12 (0.04 g) was prepared In analogy to Example 1 and purified applying the 5 most suitable purification technique, starting from Intermediate 9f (0.3 g, 0.68 mmol) and Hydrazide Intermediate 4 (0.27, 0.68 mmol).

HPLC-MS (Method 13) R_t =3.11 min

MS : m/z = 380 (M+H)⁺

Example 12a (0.15 g) was prepared in analogy to Example 12 and purified applying the most suitable purification technique, starting from the Hydrazide Intermediate 6a 15 (0.23 g, 1.45 mmol).

HPLC-MS (Method) R, =3.00 min

MS : m/z = 360 (M+H)⁺

Example 13:

120

To a solution of Example 1 (0.1 g, 0.24 mmol) in dry ACN (3 mL), césium carbonate (0.2 g) and commercially available 3-chloro-1-propanol (0.04 mL) were added. Mixture was heated at 80°C for 1 h, then solvent evaporated under reduced pressure and the residue dissolved in DCM and washed with a saturated solution of NaCI. Phases were separated, organics dried over sodium sulphate and evapoarated. The residue was purified by flash chromatography (eluent from 100:0 to 94:6 DCM/EtOH) to obtain 0.02 g of the title compound.

HPLC-MS (Method 8) R_t =5.23 min

MS:m/z = 370 (M+H)⁺

Example 14:

To a solution of Example 1 (0.05 g, 0.16 mmol) in dry DMF (3 mL), Intermediate 10 (0.05 g, 0.018 mmol) and césium carbonate (0.08 g, 0.24 mmol) were added and mixture heated at 100 *C for 2h. Solvent was evaporated, the residue was dissolved with DCM, washed with a saturated solution of NaCI. Phases were separated, organics dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (eluent from 70:30 to 20:80 Cy/EtOAc) to obtain 0.025 g of the title compound.

HPLC-MS (Method 9): R_t =2.57 min

MS : m/z = 398 (M+H)*

Example 15:

121

To a solution of Example 1 (0.08 g, 0.16 mmol) in dry ACN (3 mL), commercially available 2-bromo-ethanol (0.65g, 0.52mmol) and césium carbonate (0.5 g, 1.54 mmol) were added and mixture heated at 80 ’C for 48 h. Solvent was evaporated, the residue was dissolved with DCM, washed with 1N solution of NaOH and then with a saturated solution of NaCi. Phases were separated, organics dried over sodium sulphate and evaporated . The residue was purified by flash chromatography (eluent from 100:0 to 97:3 DCM/EtOH) to obtain 0.04 g of the title compound.

HPLC-MS (Method 6): R_t =8.75 min

MS: m/z = 356 (M+H)*

Example 16:

To a solution of Example 1 (0.05 g, 0.16 mmol) In dry DMF (3 mL), commercially available 1-bromo-2-propanol (0.09 g, 0.64 mmol) and potassium tert-butoxide (0.1 g, 0.96 mmol) were added and mixture heated at 130°C for 8h. Solvent was evaporated, the residue was dissolved with DCM, washed with 1N solution of NaOH and then with a saturated solution of NaCi. Phases were separated, organics dried over sodium sulphate and evapoarated. The residue was purified by flash chromatography (eluent from 100:0 to 97:3 DCM/EtOH) to obtain 0.05 g of the title compound.

HPLC-MS (Method 9): R, =2.23 min

MS: m/z = 370 (M+H)*

Example 17:

122

To a solution of Example 1 (0.085 g, 0.27 mmol) in dry DMF (3 mL), commercially available (R)-1-chloro-2-propanol (0.052 g, 0.55 mmol) and potassium tert-butoxide (0.093 g, 0.82 mmol) were added and mixture heated at 130 C for48h. Solvent was evaporated, the residue was dissolved with DCM, washed with 1N solution of NaOH and then with a saturated solution of NaCI. Phases were separated, organics dried over sodium sulphate and evaporated . The residue was purified by flash chromatography (eluent from 100:0 to 97:3 DCM/EtOH) to obtain 0.0085 g of the title compound.

HPLC-MS (Method 9): R, =2.22 min

MS : m/z = 370 (M+H)⁺

Exampie 18:

Example 18 was prepared as described for Exampie 17 starting from Example 1 (0.085 g, 0.27 mmol) and commercially available (S>1-chloro-2-propanol. The residue was purified by flash chromatography (eluent from 100:0 to 90:10 DCM/MeOH) to obtain 0.045 g of the title compound.

HPLC-MS (Method 9): R_t =2.19 min

MS: m/z = 370 (M+H)⁺

Exampie 19:

123

To a solution of Example 1 (0.115 g, 0.37 mmol) in dry DMF (3 mL), césium carbonate (0.36 g, 1.11 mmol) and Intermediate 11 (0.09 g, 0.37 mmol) were added and mixture heated at 100°C for 4h. Solvent was evaporated, the residue was dissolved with DCM, washed with a saturated solution of NaCI. Phases were separated, organics dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (eluent from 100:0 to 80:20 DCM/EtOH) to obtaln 0.025 g of the title compound.

HPLC-MS (Method 9): R_t =2.4 min

MS : m/z = 384 (M+H)⁺

Example 20:

Example 20 was prepared as described for Example 19 , starting from Example 1 (0.08 g, 0.26 mmol) and Intermediate 13 (0.2 g, 0.78 mmol). The residue was purified by flash chromatography (eluent from 100:0 to 50:50 Cy/EtOAc) to obtain 0.032 g of the title compound.

HPLC-MS (Method 9): R_t =2.65 min

MS : m/z = 396 (M+H)⁺

Example 21:

124

Example 21 was prepared as described for Example 20, starting from Example 1 (0.065g, 0.21 mmol) and Intermediate 14 (0.12 g, 0.42 mmol). The residue was purified by flash chromatography (eluent from 100:0 to 50:50 Cy/EtOAc) to obtain 5 0.035 g of the title compound.

HPLC-MS (Method 9): R_t =3.32 min

MS: m/z = 430 (M+H)*

Example 22 was prepared as described for Example 20, starting from Example 1 (0.1 g, 0.32 mmol) and Intermediate 15 (0.093 g, 0.38 mmol). The residue was purified by flash chromatography (eluent from 100:0 to 50:50 Cy/EtOAc) to obtain 0.032 g of the title compound.

HPLC-MS (Method 13): R_t =3.03 min

MS: m/z = 382 (M+H)*

O

125

Example 23 was prepared as described for Example 20, startlng from Example 1 (0.1 g, 0.32 mmol) and Intermedlate 17 (0.093 g, 0.38 mmol). The resldue was purified by flash chromatography (eluent from 100:0 to 50:50 Cy/EtOAc) to obtain 0.02 g of the title compound.

HPLC-MS (Method13): R, =3.07 min

MS : m/z = 382 (M+H)⁺

Example 24:

Example 24 was prepared as described for Example 20, starting from Example 1 (0.1 g, 0.32 mmol) and Intermedlate 16 (0.093 g, 0.38 mmol). The residue was purified by flash chromatography (eluent from 100:0 to 50:50 Cy/EtOAc) to obtain 0.03 g of the title compound.

HPLC-MS (Method 13): R, =3.05 min

MS ; m/z = 382 (M+H)*

Example 25:

N.

Example 25 was prepared as described for Example 20, starting from Example 1 (0.1 g, 0.32 mmol) and Intermediate 18 (0.097 g, 0.38 mmol). The residue was purified by flash chromatography (eluent from 100:0 to 50:50 Cy/EtOAc) to obtain 0.03 g of the title compound.

HPLC-MS (Method 13): R_t =3.18 min

MS : m/z = 396 (M+H)*

126

Example 26 was préparée! as described for Example 20, starting from Example 4 (0.08 g, 0.27 mmol) and commercially available 3-chloro-1-propanol (0.052 g, 0.54 mmol). The crude was purified by flash chromatography (eluent from 100:0 to 97:3 DCM/EtOH) to obtaln 0.052 g of the title compound.

HPLC-MS (Method 13): R, =2.71 min

MS: m/z = 354 (M+H)⁺

Example 27:

Example 27 was prepared as described for Example 20, starting from Example 2 (0.133 g, 80% content, 0.32 mmol) and commercially available 3-chloro-1-propanol (0.046 g, 0.49 mmol). The crude was purified by prep-HPLC (Method 11 ). Fractions contalning the pure compound were combined and evaporated to reduced volume, diluted with DCM and treated with a saturated solution of sodium carbonate . Phases were separated, dried over sodium sulphate and evaporated under reduced pressure to obtain 0.039 g of the title compound.

HPLC-MS (Method 9): R, =2.46 min

MS: m/z = 384(M+H)*

Example 28:

127

(0.133 g, 80% content, 0.32 mmol) and commerciaily available 2-bromo-ethanol (0.061 g, 0.49 mmol). The crude was purified by prep-HPLC (Method 12). Fractions containing the pure compound are combined and evaporated to reduced volume, diluted with DCM and treated with a saturated solution of sodium carbonate. Phases were separated, dried over sodium sulphate and evaporated under reduced pressure to obtaln 0.025 g of the title compound.

HPLC-MS (Method 9): R_t =2.35 min

MS : m/z = 370(M+H)⁺

Example 29:

To a solution of Example 2 (0.07 g, 0.20 mmol) and commerciaily available 2-bromomethylether (0.057 g, 0.41 mmol) in dry DMF (3 mL), césium carbonate (0.199 g, 0.61 mmol) was added and the mixture heated at 100°C for 1 h. Solvent was evaporated under reduced pressure, the residue dissolved with DCM and treated with water. Phases were separated, dried over sodium sulphate and the crude purified by flash cromatography (eluent from 80:20 to 40:60 hexane/EtOAc) to obtaln 0.023 g of the title compound.

HPLC-MS (Method 9): R_t =2.82 min

MS: m/z = 384 (M+H)*

128

Example 30:

F

To a solution of Example 2 (0.07 g, 0.20 mmol) and Intermediate 14 (0.12 g, 0.41 mmol) in dry DMF (3mL), césium carbonate (0.2 g, 0.61 mmol) was added and the mixture heated at 90°C for 2 h. Solvent was evaporated under reduced pressure, the residue dlssolved with DCM and treated with water. Phases were separated, dried over sodium sulphate and the crude purified by flash cromatography (eluent from 80:20 to 40:60 hexane/EtOAc) and then further purified by prep-HPLC (Method 14). Fractions containing the pure compound were combined and evaporated to reduced volume, diluted with DCM. Phases were separated, dried over sodium sulphate and evaporated under reduced pressure to obtain 0.047 g of the title compound. HPLC-MS (Method 9): R_t =3.56 min

MS: m/z = 444 (M+H)⁺

Example 31:

Example 31 was prepared as described for Example 30 starting from Example 2 (0.07 g, 0.20 mmol) and commercially available 1-bromo-3-methoxy-propane (0.063 g, 0.41 mmol). After heating for 3h at 100°C in dry DMF (3 mL), solvent was evaporated under reduced pressure, the residue dissolved with DCM and treated with water. Phases were separated, dried over sodium sulphate and the crude purified by flash cromatography (eluent from 88:12 to 0:100 Cy/EtOAc) to obtain 0.043 g of the title compound.

129

HPLC-MS (Method 13): R, =3.55 min

MS: m/z = 398 (M+H)*

Example 32:

C

Example 32 was prepared as described for Example 31 starting from Example 2 (0.09 g, 0.26 mmol) and Intermediate 13 (0.20 g, 0.78 mmol). Solvent was evaporated under reduced pressure, the residue dissolved with DCM and washed with 1N solution of NaOH. Phases were separated, dried over sodium sulphate and the crude purified by flash cromatography (eluent from 88:12 to 0:100 Cy/EtOAc) to obtain 0.037 g of the title compound.

HPLC-MS (Method 9): R_t =2.95 min ‘

MS: m/z = 410 (M+H)*

Example 32a

O,

Example 32a (0.06 g) was prepared In analogy to Example 32 and purified applying the most suitable purification technique, starting from Example 9 (0.08 g, 0.23 mmol). HPLC-MS (Method 16): R_t =4.51 min

MS: m/z = 436 (M+H)*

Example 33:

130

Example 33 was prepared as described for Example 31 startlng from Example 2 (0.07 g, 0.20 mmo!) and commercially available 1-bromo-3-trifluoro-methoxypropane (0.084 g, 0.41 mmol). Solvent was evaporated under reduced pressure, the residue dissolved with DCM and washed with water. Phases were separated, dried over sodium sulphate and the crude purified by flash cromatography (eluent from 88:12 to 0:100 Cy/EtOAc) and then further purified by prep-HPLC (Method 14). Fractions containing the pure compound were combined and evaporated to reduced volume, diluted with DCM. Phases were separated, dried over sodium sulphate and evaporated under reduced pressure to obtain 0.047 g of the title compound. cromatography (eluent from 88:12 to 0:100 Cy/EtOAc) to obtain 0.037 g of the title compound.

HPLC-MS (Method 13): R_t =1.06 min

MS: m/z = 452 (M+H)*

Example 34:

Cl

To a solution of Example 2 (0.082 g, 0.25 mmol) in dry DMF (3mL), potassium tertbutoxide (0.084 g, 0.65 mmol) and Intermediate 20 (0.176 g, 0.50 mmol) were added. The resulting solution was heated at 120°C for 5 h. The mixture was left at room température for 24 h. Solvent was evaporated under reduced pressure, the residue dissolved in DCM and treated with a 1N solution of NaOH. Phases were separated, dried over sodium sulphate and the crude purified by flash cromatography (eluent from 20:80 to 0:100 ACN/H2O) to obtain 0.033 g of the title compound.

131

HPLC-MS (Method 9): R_t =2.98 min

MS: m/z = 384 (M+H)⁺

To a solution of Example 2 (0.095 g, 0.29 mmol) in dry DMF (3 mL), potassium tertbutoxide (0.074 g, 0.22 mmol and Intermediate 19 (0.204 g, 0.58 mmol) were added. The resulting solution was heated at 120 *C for 5h. Soivent was evaporated under reduced pressure, the residue dissolved In DCM and treated with a 1N solution of NaOH. Phases were separated, dried over sodium suiphate and the crude purified by flash cromatography (eiuent from 80:20 to 0:100 Cy/EtOAc) to obtain 0.023 g of the title compound.

HPLC-MS (Method 13): R_t =2.98 min

MS: m/z = 384 (M+Hf

Example 35a

To a suspension of Intermediate 9a (0.08 g, 0.23 mmol) In dry DMF (4 mL), t-BuOK (0.076 g, 0.68 mmol) and Intermediate 21 (0.09 g, 0.45 mmoi) were added and the reaction mixture was heated at 90 °C for 5h. Dry DMF was then added and mixture heated at 110 °C ovemight. Soivent was evaporated under reduced pressure, the residue dissolved in DCM and treated with a 1N solution of NaOH. Phases were separated, dried over sodium suiphate and the crude purified by flash cromatography

132 (eluent from 80:20 to 0:100 Cy/EtOAc) to obtain 0.055 g of the protected intermed iate 1 -{2-chIo ro-5-[(S)-2-(tetra hyd ro-pyran-2-yloxy)-propoxy]-p henyl)-8cyclopropyl-4-methyl-2,3,5,9,9b-pentaaza-cyclopenta[a]naphthaiene.

The compound (0.055 g, 0.11 mmol) was then dissolved in dry MeOH (1 mL) and ptoluenesulfonic acid monohydrate (0.012 g, 0.06 mmol) was added. Mixture was stirred at room température for 1 h, solvent evaporated under reduced pressure and the residue purified by reverse phase flash cromatography (eluent ACN/H₂O from 10:100 to 100:0) and then by silica flash cromatography (eluent DCM/EtOH 90:10) to obtain 0.03 g of the title compound.

HPLC-MS (Method 9): R_t =2.69 min

MS: m/z = 384 (M+H)*

Example 36:

HO

To a solution of Example 3 (0.07 g, 0.24 mmol) in dry DMF (3 mL), césium carbonate (0.23g, 0.71 mmol) and commercially available 3-chloro-1-propanoI (0.024g,0.26 mmol) were added and the mixture heated at 100 ’C for 3 h. Solvent was evaporated under reduced pressure, the residue dissolved with DCM and washed with 1N solution of NaOH . Phases were separated, dried over sodium sulphate and the crude purified by prep-HPLC (Method 11). Fractions containing the pure compound were combined and evaporated to reduced volume, diluted with DCM and washed with a saturated solution of sodium carbonate. Phases were separated, dried over sodium sulphate and evaporated under reduced pressure to obtain 0.02 g of the title compound.

HPLC-MS (Method 13): R_t =2.71 min

MS: m/z = 350 (M+H)*

Example 37:

133

Cl

Example 37 was prepared as described for Example 32 starting from Example 1 (0.07 g, 0.22 mmol) and Intermediate 26 (0.22 g, 067 mmol). The residue was purified by flash cromatography (eluent from 100:0 to 50:50 Cy/EtOAc) to obtain 5 0.046 g of the title compound.

HPLC-MS (Method 13): R_t =3.15 min

MS: m/z = 396 (M+H)*

Example 38 was prepared as described for Example 32 starting from Example 1 (0.07 g, 0.22 mmol) and Intermediate 27 (0.127 g, 044 mmol). The residue was purified by flash cromatography (eluent from 100:0 to 50:50 Cy/EtOAc) to obtain 0.045 g of the title compound.

HPLC-MS (Method 13): R, =3.45 min

MS: m/z = 424 (M+H)*

Example 39

ci

To a solution of Intermediate 30 (0.18 g, 0.44 mmol) in absolute EtOH (10 mL) sodiumborohydride (0.008 g, 0.22 mmol) was added and the mixture stirred at room température for 30 min. Sovent was evaporated under reduced pressure, the residue

134 treated with DCM and washed with a saturated solution of sodiumcarbonate. Phases were separated, dried over sodium sulphate and evaporated under reduced pressure to obtain 0.047 g of the title compound.

HPLC-MS (Method 13): R₍ =2.96 min

MS: m/z = 410 (M+H)*

Example 40

ci

Example 40 was prepared as described Example 14, starting from Example 1 (0.075 g, 0.24 mmol) and Intermediate 31(0.12 g, 0.48 mmol). Crude was purified by flash chromatography (eluent from 100:0 to 95:5 DCM/EtOH) to obtain 0.046 g of the title compound.

HPLC-MS (Method 13): R» =2.87 min

MS: m/z = 396 (M+H)*

Example 41

Example 41 (0.05 g) was prepared as described for Example 22 and purified applying the most suitable purification technique, starting from Example 2 (0.1 g, 0.3 mmol).

HPLC-MS (Method 13): R₍ =3.21 min

MS: m/z = 396 (M+H)*

Example 42:

135

Example 42 (0.06 g) was prepared as described for Example 23 and purified applying the most suitable purification technique, starting from Example 2 (0.09 g, 0.28 mmol).

(HPLC-MS (Method 13): R_t =3.21 min

MS: m/z = 396 (M+H)*

Example 43:

Exampie 43 (0.03 g) was prepared as described for Example 24 and purified applying the most suitable purification technique, starting from Example 2 (0.09 g, 0.28 mmol).

HPLC-MS (Method 13): R_t =3.21 min

MS: m/z = 396 (M+H)⁺

Example 43a:

To a solution of ethylmagnesium bromide (0.7 mL of a 3M solution in diethyl ether) In dry DCM (2 mL) at -75°C, titanium(IV) Isopropoxide (0.2 mL, 0.7 mmol) was added.

Mixture was stirred for 10 min, then a solution of Intermediate 31 (0.28 g, 0.73 mmol)

136

In dry DCM (8 mL) was added dropwise. Mixture was allowed to reach room température and stirred at room température ovemight. Mixture was diluted with EtOAc, hydrochloric acid (1N solution) was added and phases separated. Organics were dried over sodium sulphate and evaporated under reduced pressure and the crude purified by silica flash cromatography (eluent AcOEt/EtOH 90:10) follwed by a reverse phase cromatography to obtain 0.006 g of the title compound.

HPLC-MS (Method 13): R_t =2.93 min

MS: m/z = 382 (M+H)*

Example 44:

Cl

Example 1 (0.07 mg, 0.2 mmol) was dissolved in DMF (3 mL), isobutylene oxide (0.03 mg, 0.43 mmol) and césium carbonate (208 mg, 0.64 mmol) were added and the reaction mixture was warmed to 100 °C for 2h. The solvent was removed, dichloromethane was added and the organic phase was washed with a 1M NaOH water solution, dried over sodium sulfate, concentrated under vacuum. The crude product obtained was purified by reverse phase chromatography to give the desired compound (29 mg).

HPLC-MS (Method 13): R_t =2.93 min

MS: m/z = 386 (M+H)*

The following Examples were prepared in analogy to Example 44 and purified applying the most suitable purification technique, starting from the corresponding Starting Example and the suitable epoxides.

137

Starting Example or Starting Intermediate	Starting Epoxide	Ex.#	Structure	MS m/z [M+Hf	Rt (min)	Method
9	>3	45		424	2,88	9
2	>5	46	XXX /~ⁿ	398	3,01	9
5	>3	47		408	3.19	13
6	>3	48		404	3.19	13
1	29a	49	HO ^N~\ >__ CHT a	396	3,04	13

138

10	29a	50	O	376	2.88	13
7	ys	51		406	3,32	13
8	>a	52		410	3,32	13
4	29a	53	Q ΓΥ-Ν ►k/v ⁿ=y v F	380	2,89	13
30p	Z	54	X_o ~ih^ Cl	426	3,56	13
1		55 TRANSracemic mixture	Λ Qy Cl	398	2,74	13

139

9		56 TRANSracemic mixture	θχ/^ΟΗ	438	3.10	13
6		57 TRANSracemic mixture		418	2.94	13

The following examples were obtained as single stereoisomers by chiral HPLC séparation of the corresponding racemic mixture.

Startlng Racemic Mixture	Ex.#	Structure	MS m/z [M+H]*	Rt (min) [LC*MS Method]	Rt(mln) [Chiral HPLC Method]
55 TRANSracemic mixture	55a TRANSsingle stereoisomer a	i-_r» c	398	2.63 [13]	8.23 [C1]

140

56 TRANSracemic mixture	56a TRANSsingle stereoisomer a	ΟχΟ'ΟΗ	438	3,03 [13]	12.13 [C2]
56 TRANSracemic mixture	56b TRANSsingle stereoisomer b	^Ox/^OH	438	3,03 [13]	16.56 [C2]
57 TRANSracemic mixture	57a TRANSsingle stereoisomer a		418	2.18 [13]	17.66 [C2]
57 TRANSracemic mixture	57b TRANS- single		418	2,81 [13]	19.81 [C2]

141

stereolsomer b

Example 58 (TRANS· single stereolsomer a):

Cl

Example 58 (0.01 g) was prepared in analogy to example 44 startlng from Example 1 (0.2 g, 0.61 mmol) and epoxide intermediate 29 (0.07 g, 0.73 mmol) after chiral HPLC séparation HPLC-MS (Method 13): R_t =2.63 min

MS: m/z = 412 (M+H)*

Chiral HPLC (Method C2): R_t = 16.84 min

Example 58a (CIS· racemlc mixture):

Οχ/Η)Η

To a solution of Intermediate 30o (0.13 g, 0.37 mmol) in dry DMF (3 mL), potassium tert.butoxide (0.083 g, 0.73 mmol) and commercially available 1,4-anhydroerythritol (0.06 mL, 0.73 mmol) were added and mixture heated at 90 C for 6 h. Solvent was evaporated, DCM and water added. Organics were separated, washed with a saturated solution of ammonium chloride, evaporated. The crude was purified by flash chromatography (eluent Cy/EtOAc 90:10 to 0:100) to give the desired compound (0.055 g).

HPLC-MS (Method 13): R, =2.94 min

MS: m/z = 438 (M+H)⁺

142

Example 58b was obtained by chiral HPLC séparation of Example 58. 5 HPLC-MS (Method 13): R_t =2.95 min

MS : m/z = 438 (M+H)⁺

Chiral HPLC (Method C1): R_t = 7.65 min

Example 58c (CIS- single stereolsomer b):

Further elution from the chiral column In the purification of Example 58 gave Example

58c

HPLC-MS (Method 13): R_t =2.95 min

MS : m/z = 438 (M+H)⁺

Chiral HPLC (Method C1 ): R_t = 9.54 min

Exampie 59 and Example 60:

143

Example 59

Example 60

Step 1 :

Scaffold Intermediate 30a (1.4 g, 3.5 mmol) was suspended in THF (40 mL) and stirred at -78^eC under nitrogen atmosphère. N-Butyllithium (3 mL of a 2,5M solution in hexane) was added dropwise and the reaction mixture was stirred at -78°C for 0.5h. A solution of N.N.dimethylformamide (1.43 mL, 17.6 mmol) in THF (15 mL) was added dropwise and the reaxtion mixture was stirred at -78’C for 30 minutes. Ammonium chloride saturated water solution (20 mL) was added and the reaction mixture was allowed to reach room température. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product obtained was purified by flash chromatography (eluent from 100:0 to 80:20 Cy/EtOAc) to obtain the title compound (0.3 g).

Step 2:

Intermediate obtained from Step 1 (0.07 g, 0.21 mmol) was suspended in THF (2 mL) and stirred at 0 °C. A 2M solution of isopropylmagnesium chloride in THF (0.1 mL) was added an the reaction mixture was allowed to reach room température in 2h. Ammonium chloride saturated water solution (20 mL) was added and the reaction mixture was allowed to reach room température. The reaction mixture was diluted with ethyi acetate and washed with water. The organic phase was washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product obtained was purified by flash chromatography (eluent 50:50 Cy/EtOAc) to obtain Example 60 (0.02 g).

HPLC-MS (Method 9): R_t =2.85 min

MS : m/z = 382 (M+H)*

Further elution from the column (eluent from 50:50 to 0:100 Cy/EtOAc) gave Example 60 (0.03 g)

HPLC-MS (Method 9): R_t =2.28 min

MS : m/z = 340 (M+H)*

144

The following examples were prepared In analogy to Example 59 and purified applying the most suîtable purification technique, starting from Scaffold Intermediate 30a and the corrsponding commerclally available Grignard reagents.

Grignard reagent	Ex.#	Structure	MS m/z (M+H)+	Rt (min)	Method
Cl——	61	xa HO ^N /-'	382	2,89	9
_Br—Mg*\	62	χχχ	368	3,12	13
—Mg’CI	63	ΧΧζ	354	2,93	13

Example 64 (0,03 g) was prepared in analogy to Example 1 and purified applying the most suitable purification technique,, starting from Intermediate 2 (0.1 g, 0.55 mmol) and Hydrazide intermediate 6i (0.15 g, 0,55 mmol).

HPLC-MS (Method 9): R_t =2.52 min

MS: m/z = 382 (M+H)⁺

145

Example 65:

Example 65 (0.03 mg) was prepared In analogy to the préparation of Intermediate 5i 5 and purified applying the most suitable purification technique, starting from Scaffold

Intermediate 30d (0.1 g, 0.25 mmol).

HPLC-MS (Method 9): R_t =2.45 min

MS : m/z = 366 (M+H)⁺

The following examples were prepared in analogy to Exampie 65 and purified applying the most suitable purification technique, starting from the corresponding Scaffold Intermediates.

Starting Intermediate	Ex.#	Structure	MS m/z (M+H)+	Rt (min)	Method
30e	66	pXXX W:	406	3.29	13
30f	67	αχ	362	3,83	16

146

30g	68	7' '	402	3,22	13
30h	69		422	3,33	13

Example 70:

Example 70 (0.03 g) was prepared in analogy to the préparation of Intermediate 5j and purified applying the most suitable purification technique, starting from Scaffold Intermediate 30b (0.16 g, 0.38 mmol) and acetone (0.07 mg, 1.13 mmol). HPLC-MS (Method 13): R_t = 2.67 min

MS: m/z = 354 (M+H)⁺ o

The following examples were prepared in analogy to Example 70 and purified appiying the most suitable purification technique, starting from the corresponding Scaffold Intermediates and commercially avaiiable ketons.

Starting Intermediate

Ketone

Ex.#

Structure

MS m/z (M+H)+

R. (mln)

Method

147

30j	Â	71	XXX, -fri /νΛ^α	368	2,95	13
30m	Â	72	XY	392	3,32	13
30c		73	αχ	346	2,77	13
30b	0 ô	74	αχ, OH cRy-ô.	382	2,61	13

Example 75:

148

Step 1:

Under N2 atmosphère, to a solution of Scaffold Intermediate 30g (1.0 g, 2.54 mmol) in toluene (35 mL), tributyl-(1-ethoxyviny1-)tin (1.3 mL, 3.04 mmol) and Pd tetrakis(triphenylphosphine) (580 mg, 0.51 mmol). The solution was stirred at 105°C for 18h. The reaction mixture was cooled at room température, concentrated In vacuo and the crude product obtained was dissolved In THF. A 2N water solution of HCl 2N (5ml) was added and the reaction mixture was stirred for 30 mins. After dilution with ethyl acetate, phases were separated and organic layer was dried over sodium sulfate and concentrated. The crude product obtained was purified by flash chromatography (eluent from 90:10 to 75:25 Cy/EtOAc) to obtain the desired compound (0.8 g).

HPLC-MS (Method 13): R_t = 3.09 min

MS : m/z = 358(M+H)*

Step 2:

To a solution of the intermediate from Step 1 (0.8 g, 2.2 mmol) In DCM (20 mL) 50% NaOH/H2O solution (0.8 mL) was added and the reaction mixture was stirred for 10 minutes. Trimethylsuifonium methyl sulfate (0.4 g, 2.8 mmol) was added and the reaction mixture was refluxed for 2h. The reaction mixture was diluted with DCM and washed with water. The organic layer was separated, dried over sodium sulfate and concentrated. The crude product obtained was purified by flash chromatography (eluent 85:15 Cy/EtOAc) to obtain the desired compound (0.5 g).

HPLC-MS (Method 13): R_t = 3.33 min

149

MS : m/z = 372(M+H)⁺

Step 3:

To a solution of lithiumaluminiumhydride (0.15 mL of a 2M solution in THF) In 15 mL of THF stirred at 0°C, the Intermediate from step 2 (0.4 g, 0.4 mmol) was added slowly. The reaction mixture was stirred for 1 h and allowe to reach room température. Water (2 mL) and NaOH (1 mL of a 2M water solution) were added and the reaction mixture was diluted with ethyl acetate. Organic phase was separated, dried over sodium sulfate and concentrated to give the desired product (0.28 g).

HPLOMS (Method 13): R_t = 3.0 min

MS : m/z = 376(M+H)⁺

Step 4:

Intermediate from step 3 (0.17 g, 0.38 mmol) was dissolved In DCM (10 mL), manganèse dioxide (0.38 g, 3.38 mmol) was added and the suspension was stirred for 1 h at room température. The reaction mixture was fil te red on a celite pad and the solvent was evaporated. The crude product obtained was purified by flash chromatography (eluent 90:10 DCM/MeOH) to obtaln the desired compound (0.14

9)·

HPLC-MS (Method 13): R_t = 3.04 min

MS : m/z = 374 (M+H)*

The following examples were prepared in analogy to Example 75 and purified applying the most suitable purification technique, starting from the corresponding Intermediates.

Starting Intermediate	Ex.	Structure	MS m/z (M+H)+	Rt (min)	Method
30e	76	fl F	378	3.12	13

150

30k	77	a .	396	3.37	13
30I	78	__Loh N=/ \\_	376	3.3	13
30n	79	JLoh ⁿ=( V	376	3,31	13
		Qv

Example 80 (0.02 g) was prepared In step 2, step 3 and step 4 step In analogy to Example 75 and purified applying the most suitable purification technique, starting from the Intermediate obtained In step 1.

Step 1 was performed as follow:

Scaffold Intermediate 30Î (1.35 g, 3.39 mmol) tri-n-butylmethoxytin (1.51 mL, 5.08 10 mmol), isopropenyl acetate (5.6 mL, 51 mmol), tri-o-tolylphosphine (0.07 g, 0.25 mmol) and palladium acetate (0.03 g) were suspended in toluene (30 mL) under

151 nitrogen atmosphère and stirred for 2h at room température, then at 110°C for 20 minutes. Water (10 mL) and a bicarbonate saturated water solution (3 mL) were added, toluene was removed under vacuum and DCM was added. The organic phase was separated, and concentrated. The crude product obtained was purified by flash chromatography (eluent from 30:70 to 0:100 cyclohexane/AcOEt) to obtain the desired compound (0.5 g).

Step 2, Step 3 and Step 4 were performed In analogy to Example 75.

HPLC-MS (Method 16): R_t = 3.13 min

MS: m/z = 392 (M+H)⁺

The following example was prepared in analogy to Example 80 and purified applying the most suitable purification technique, starting from the corresponding Scaffold Intermediates.

Intermediate	Ex.#	Structure	MS m/z (M+H)+	Rt (min)	Method
30g	81		388	5.75	17

Example 82:

Example 82 (0.09 g) was prepared In analogy to Example 1 starting from Chloride

Intermediate 2 (0.1 g, 0.61 mmol) and Hydrazide Intermediate 6p (0.2 g, 0.61 mmol). (HPLC-MS (Method 13): R_t2.80 =min

MS : m/z = 368 (M+H)⁺

152

The following examples were prepared in analogy to Example 62 and purified applying the most suitabie purification technique, starting from the corresponding Chloride and Hydrazide Intermediates.

Starting Chloride Intermediate	Starting Hydrazide Intermediate	Ex.#	Structure	MSm/z (M+H)+	Rt (min)	Method
9a	6p	83	/=<^Nχίλ»	408	3,24	13
9a	6j	84	/=N	390	3,18	13
9a	6o	85		394	3,22	13

153

2	6j	86	αχ xA	350	2,76	13
2	6k	87	αχ, %A	366	2.93	13
9a	6k	88		406	3,33	13
9	6k	89	Aï, A	380	3,05	13
9	6J	90	ÆCÇ «Ki'	364	2,91	13
9b	6k	91	^N _v 7	408	3.45	13

154

9b	6j	92		392	3.34	13
2	61	93	αχ ooX	396	2,96	13
9a	6I	94	71 ooX	436	3,08	13
9a	6n	95	F	420	2,9	13
9f	6I	96	ααχ w:	464	3,04	13
9f	6n	96a	F \ ? oot	448	2,98	13

155

9f	6na	96b	<W	444	2,94	13
9f	6r	96c	F rç'j'J ^F OH ^F	434	2,91	13
9a	6q	97	fVV Ψ^ν' N-y °Ji0	422	2.90	13
2	6s	112	αχ N N y Z^OH/^N 0—/ ^/-Cl	396	2.67	13
9a	6s	113	/—νθΠ/^^ °'-^//^Vj/^cl	436	3.10	13

156

9f	6s	114	^N	464	3.21	13
9f	6r	115		450	3.90	13

Startlng Racemic Mixture	Ex.#	Structure	MS m/z [M+H]*	Rt (min) [LC-MS Method]	Rt(mln) [Chiral HPLC Method]
97 Racemic mixture	97a Single stereoiso mer b	XT^n^n'^i ^N °\JvA^ci	422	2.,89 [13]	15.75 [C2a]
97 Racemic mixture	97b Single stereoiso mer a	S/'' \ ^N °JV-°	422	2.89 [13]	13.32 [C2a]

157

112 Racemic mixture	112a Single stereoiso mer a	o-c	αχ _vo_H	396	2.85 [13]	14.5 [C2a]
112	112b Single		αχ N N .OHl_/==J^==N	396	2.85 [13]	15.6
Racemic	stereoiso			[C2a]
mixture	mer b	0^	^ci
114	114a	F	πγ
		^F /	^ N N^n <ph >=»	464	3.21 [131	13.8[C2]
Racemic	Single
mixture	stereoiso	0—/
	mer a
114	114b	F	ΠΥ
		^F /	NN% \/^0H/⁼=<^^==N	464	3.21 [131	16.76[C2]
Racemic	Single
mixture	stereoiso	0—/
	mer b

158

115 Racemîc mixture	115a Single stereoiso mer a	F ^f“7 F	jQT N N \___ /	450	3.05 1131	28.0rC2bl

115	115b	F	Xxl
Racemîc	Single	^F / F	^X N N^_N \___ / ^N	450	3.05 1131	31.2IC2bl
mixture	stereoiso mer b	°\Z	οάΛ^α

Example 98 (Single stereolsomer a):

Example 98 (0.026 g) was prepared In analogy to Example 1 starting from Chloride Intermediate 2 (0.3 g, 1.45 mmol) and Hydrazide Intermediate 6q (0.4 g, 1.56 mmol) after semipreparative chiral purification.

HPLC-MS (Method 13): R_t =2.56 min

MS: m/z = 382 (M+H)*

Chiral HPLC (Method C1a): Rt = 9.55 min

Example 99 (Single stereolsomer b):

159

Example 99 (0.028 g) was obtalned via further elution from the column in the semipreparative chiral chromatographie purification of Example 98.

HPLC-MS (Method 13): R_t =2.52 min

MS: m/z = 382 (M+H)⁺

Chiral HPLC (Method C1a): R_t = 11.03 min

Example 100:

Step 1:

Scaffold Intermediate 30g (0.5 g, 1.27 mmol), 1-methoxy-2-methyl-1(trimethylsililoxy)propene (1.9 g, 11.4 mmol), bis(dibenzyiideneacetone)palladium(0) (0.14 g, 0.25 mmol) and zinc fluoride (0.19 g, 1.9 mmol) were suspended in DMF (25 mL) and stirred under nitrogen atmosphère for 10 minutes. Tri-tert-butyl-phosphine (0.06 mL, 0.25 mmol) was added and the reaction mixture was stirred at 115 °C for 18h. The reaction mixture was concentrated, an ammonium chloride water saturated solution was added and the reaction mixture was extracted with DCM. The organic phase was separated, dried over sodium sulfate and concentrated. The crude product obtained was purified by flash chromatography (eluent from 100:0 to 50:50 cyclohexane/AcOEt) to obtain the deslred compound (0.4 g).

Step 2:

The Intermediate obtained in Step 1 (0.4 g, 0.07 mmol) was dissolved in THF (6 mL) and stirred under nitrogen atmosphère at 0°C for 5 minutes. Lithiumaiuminium hydride (0.5 mL of a 2M solution in THF) was added. The reaction mixture was stirred

160 at 0 °C for 10 minutes then allowed to reach room température and stirred for 0.5h. The solvent was removed, the crude product was dissolved in DCM and the reaction mixture was washed with water (4 mL), bicarbonate saturated water solution (2 mL) and brine (2 mL). The organic phase was separated, dried over sodium sulfate and manganèse dioxide (0.15 g, 1.73 mmol) was added. The reaction mixture was stirred for 0.5 h, filtered on a celite pad and concentrated. The crude product obtained was purified by flash chromatography (eluent from 100:0 to 95:5 DCM/MeOH) to obtain the desired compound (0.1 g).

(HPLC-MS (Method 13): R_t =3.29 min

MS: m/z = 388 (M+H)*

Example 101:

HO

Example 101 (0.05 g) was prepared In analogy to Example 100 and purified applylng the most suitable purification technique, starting from Scaffold Intermediate 30i (0.36 g, 0.9 mmol).

HPLC-MS (Method): R_t = 3.3 min

MS: m/z = 392 (M+H)*

Example 102:

Step 1 :

161

Step 1 was performed in analogy to préparation of Example 1 starting from Chloride Intermediate 9 (0.3 g, 1.39 mmol) and Hydrazide Intermediate 6o (0.47 g, 1.39 mmol).

Step 2:

Intermediate from step 1 (0.09 g, 0.26 mmol) and hydrochloric acid (10 mL of a 37% water solution) were dlssolved In 10 mL of 1,4-dioxane. The reaction mixture was stirred at room température for 20 minutes. A bicarbonate saturated water solution was added, THF was removed in vacuum and the reaction mixture was extracted with DCM. The organic phase was separated, dried over sodium sulfate and concentrated. The crude product obtained was purified by flash chromatography (eluent from 100:0 to 90:10 DCM/MeOH) to obtain the title compound (0.03 g). HPLC-MS (Method 13): R_t = 2.95 min

MS: m/z = 360 (M+H)*

Example 103:

Br.

Step 1:

Under nitrogen atmosphère, Scaffold Intermediate 30g (0.3 g, 0.61 mmol), potassium carbonate (0.34 g, 2.4 mmol) and [1,TBis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.05 g) were suspended in toluene (150 mL) and stirred at room température for 10 minutes. 3,6-dihydro-2Hpyran-4-boronic acid pinacol ester (0.17 g, 0.79 mmol) was added and the reaction mixture was stlrres at 100°C for 4h. Water (30 mL) was added and the reaction mixture was extracted with AcOEt. The organic phase was separated and concentrated. The crude product obtained was purified by flash chromatography (eluent from 100:0 to 90:10 DCM/MeOH) to obtain the title compound (0.02 g).

Step 2:

162

Step 2 was performed in analogy to Step 2 in the préparation of Example 102. 0.02 g of the deslred product were obtained after purification by flash chromatography (eluent from 100:0 to 90:10 DCM/MeOH).

(HPLC-MS (Method 13): R_t = 2.88 min

MS : m/z = 416 (M+H)*

The following examples were prepared in analogy to Example 103 and purified applying the most suitable purification technique, starting from the corresponding Scaffold Intermediate and the boronic ester 2-lsopropenyl-4,4,5,5-tetramethyl10 [1,3,2]dioxaborolane.

Starting Intermediate	Ex.#	Structure	MS m/z (M+H)+	Rt (min)	Method
30r	103b	La-	422	3,25	13
30s	103c	La	406	3.17	13

OH

163

Intermediate obtained from Step 1 In préparation of Example 103 (50 mg, 0.13 mmol) was dissolved in DCM (5 mL). Osmium tetroxide (0.1 mL, 0.01 mmol) and 4-methylmorpho!ine-4-oxide (0.07g, 0.63 mmol) were added and the reaction mixture was stirred at room température for 5 h. The solvent was removed and the crude product obtained was was purified by flash chromatography (eluent from 100:0 to 80.20 DCM/MeOH) to obtain the title compound (0.03 g).

HPLC-MS (Method 13): R_t » 2.73 min

MS: m/z = 432(M+H)⁺

Example 104a (CIS-sIngle stereolsomer a):

OH

Example 104a was obtained via Chiral HPLC purification of Example 104. HPLC-MS (Method 13): R_t = 2.65 min

MS: m/z = 432 (M+H)⁺

Chiral HPLC (Method C2b): R_t = 18.70 min

Example 104b (CIS-sIngle stereolsomer b):

OH

Further elution from the chiral column gave Example 104b.

HPLC-MS (Method 13): R, = 2.65 min

MS: m/z = 432(M+H)⁺

Chiral HPLC (Method C2b): R_t = 21.04 min

164

Example 105 (CIS-racemlc mixture):

Example 105 (0.03 g) was prepared In analogy to Example 104, starting from 8Cyclopropyl-1-[5-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-phenyl]-4-methyl-2,3,5,9,9bpentaaza-cyclopenta[a]naphthalene (0.05g, 0.12 mmol) which was obtained as byproduct In the préparation of Example 95 and Isolated from the same flash chromatograpy purification.

HPLC-MS (Method 13): R_t = 2.68 min

MS: m/z = 436 (M+H)⁺

The following examples were obtained as single stereolsomers by chiral HPLC 15 séparation of the corresponding racemic mixture.

Starting Racemic Mixture	Ex.#	Structure	MS m/z [M+H]*	Rt(mln) [LC-MS Method]	Rt(mln) [Chiral HPLC Method]
105 CISRacemic mixture	105a CISSlngle stereolso mer a	OH	436	2,69 [13]	15.05 [C2b]

165

The following Examples were prepared In analogy to Example 44 and purified applying the most suitable purification technique, starting from the corresponding 5 Starting Example and the corresponding epoxldes.

Starting Example or Starting Intermediate	Starting Epoxlde	Ex.#	Structure	MS m/z (M+H)+	Rt (min)	Method
Intermediate 32	a	106 TRANSRacemlc mixture	F	450	2,97	13
5	oX°	107 TRANS- Racemic mixture	F	422	3,88	16
12	a	111 TRANSRacemic mixture	YY a	466	3.09	13

166

The following examples were obtalned as single stereoisomers by chiral HPLC séparation of the corresponding racemic mixture.

Starting Racemic Mixture	Ex.#	Structure	MS m/z [M+H]*	Rt(mln) [LC-MS Method]	Rt(mln) [Chiral HPLC Method]
106 TRANSRacemic mixture	106a TRANSsingle stereoiso mer a	F	450	2,95 [13]	7.77 [C2c]
106 TRANSRacemic mixture	106b TRANSsingle stereoiso mer b	F	450	2,98 [13]	11.58 [C2c]
111 TRANSRacemic mixture	111a TRANSslngle stereoiso mer a	a	466	3.10 [13]	13.65 [C2]
111 TRANSRacemic mixture	111b TRANSsingle stereoiso mer b	a	466	3.10 [13]	16.14 [C2]

The following examples were obtained as single stereoisomers by chiral HPLC séparation of the corresponding TRANS regioisomeric racemic mixtures. TRANS

167 regioisomerlc racemic mixtures were obtained in analogy to préparation of Example 44, starting from epoxide Intermediate 29 and the corresponding Starting Examples or Starting Intermediates.

Starting Example or Starting Intermediate	Ex.#	Structure	MS m/z [M+H]*	Rt(mln) [LC-MS Method]	Rt(mln) [Chlrai HPLC Method]
5	108a TRANSsingle stereoiso mer b	F	436	2,91 [13]	31.54 [C3]
5	108c TRANSsingle stereoiso mer b	F	436	2,91 [13]	44.59 [C2c]
5	108b TRANSsingle stereoiso mer a	F	436	2,92 [13]	27.61 [C3]
5	108d TRANSsingle stereoiso mer a	\ N—/ ’ F	436	2,91 [13]	22.06 [C2c]

168

9	109a TRANSsingle stereoiso mer a	Cl	452	3,03 [13]	23.62 (C2J
9	109c TRANSsingle stereoiso mer a	Cl	452	3,03 [13]	40.91 [C2]
9	109b TRANSsingle stereoiso mer b	Cl	452	3,03 [13]	89.29 [C2]
9	109d TRANSsingle stereoiso mer b	Cl	452	3,03 [13]	25.61 IC2]
Interm ediate 32	110b TRANSsingle stereoiso mer b	F	464	3.00 [13]	21.99 [C2]
Interm ediate 32	110d TRANSsingle stereoiso mer b	9^H F	464	3.02 [13]	62.95 [C2]

Claims

1. Compounds of formula I

R⁵

I wherein

A Is selected from the group A^a consisting of wherein above mentioned phenyl-, pyridinyl-, pyrimidinyl-, pyridazinyl and pyrazinyl groups are substituted with R¹ and R²;

R¹ is selected from the group R^1a consisting of

H, halogen, NC-, C^-alkyl-, C^-alkyl-O-, C^e-cycloalkyl and R⁸-(CH2)_nO-withn = 0,1,2,3 or 4, wherein above mentioned C₁__e-alkyl-, C^-alkyl-O-, C^-cycloalkyl and R⁸-(CH2)_n-O- groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, HO- and optionally with 1 to 7 fluorine atoms substituted C^

3-alkyl-;

R² is selected from the group R^2a consisting of

H, HO-, halogen, C^-alkyl-, C^alkyi-O-, C3-e-cycioalkyl, heterocyclyl,

170 heterocyclyl-Ci-3-alkyl’, phenyl, heteroaryl, R⁸-(CH2)n-O-with n = 0,1, 2, 3 or 4, and R⁸-(CH2)ni-(CH)(CH3)-(CH2)crO- with m = 0,1 or 2 and o - 0, 1 or 2, whereln above mentioned Ci^-alkyl-, Ci_6-alkyl-O-, C3^-cycloalkyl, heterocyclyl, heterocyclyt-Ci-3-alkyl-, phenyl, heteroaryl, R⁸- (CH2)n-Oand R⁸’(CH2)m-(CH)(CH₃)-(CH2)o-0-groups may optlonally be substituted with 1 to 5 substituents independently selected from the group consistlng of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-O-, and optionally with 1 to 7 fluorine atoms substituted Ci.₃-alkyi-;

R³ Is selected from the group R^3a consisting of

H, halogen, NC-, C<M-alkyl- and C^-cycloalkyl-, wherein the above mentioned CM-alkyl- and C^cycloalkyl-groups may optionally be substituted with 1 to 9 substituents Independently selected from the group consistlng of halogen, NC-, HO-, Ci_3-alkyland Ci<j-alkyl-O-;

R⁴, R⁵ are selected independently of each other from the group R^4a/R^5a consistlng of

H, halogen, NC-, HO-, C^alkyl-, Ci-e-alkyl-O-, C3-e-cycloalkyl-, Cmcycloalkyl-Ci-3-alkyl-, C3-8-cycloalkyl-0-, heterocyclyl-O-, heterocyclyl, heteroaryl, R⁷-CH2-O- and R⁷-(CH2)2-O-, wherein above mentioned Ci-e-alkyl-, C-i-6-alkyl-O-, C^e-cycloalkyl-, C3^-cycloalkyl-Ci-3-alkyl-, C₃.₈-cycloalkyl-0-, heterocyclyi-O-, heterocyclyl, heteroaryl, R⁷-CH2-O- and R⁷-(CH2)2-O-groups, may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, optionally with 1 to 5 halogen atoms, substituted Ci-2-alkyl-, and optionally with 1 to 5 halogen atoms substituted Ci-2-alkyl-O-;

R⁸ Is selected from the group R®³ consisting of

H, NC-, Ci-e-alkyi-, C^-cycloalkyl-, Cj^-cycloalkyl-Ci-a-alkyl- and C^e

171 cycloalkyl-0wherein above mentioned C-t^-alkyl- groups may optionally be substituted with 1-3 haiogen atoms;

R⁷ Is selected from the group R^7a consisting of

H, carbocydyl, heterocyclyl and heteroaryl, wherein above mentioned carbocydyl, heterocyclyl and heteroarylgroups may optionally be substituted with 1 to 4 substituents Independentiy selected from the group consisting of HO-, optionally with 1 to 3 haiogen atoms substituted C-M-alkyl-, optionally with 1 to 3 haiogen atoms substituted C-M-alkyl-O- and haiogen;

R⁸ is selected from the group R⁸³ consisting of

C^-cycloalkyl, heterocyclyl, heterocyclyl-Ci-3-alkyl-, phenyl and pyridyl, wherein above mentioned C^e-cycloalkyl, heterocydyi, heterocydylCi-3-alkyl-, phenyl and pyridyl groups may optionally be substituted with 1 to 5 substituents Independentiy selected from the group consisting of HO-, fluorine and optionally with 1 to 7 haiogen atoms substituted Ci_3-alkyl-;

the tautomers thereof, the stereolsomers thereof, the mixtures thereof, the solvatés 5 thereof, the hydrates thereof and the salts thereof.

2. A compound according to daim 1, wherein R² Is selected from the group R^2a1 consisting of

HO-, C^-alkyl-, C^-alkyl-O-, C3^-cycloalkyl, C3-e-cydoalkyl-Ci.3-alkyl-, heterocyclyl, heterocydyl-Ci-3-alkyl-, phenyl, heteroaryl, R⁸-(CH2)n-Owith n = 0,1,2, 3 or 4, and R⁸-(CH2)m-(CH)(CH₃)-(CH2)o-O- with m = 0.1 or 2 and o = 0,1 or 2 wherein above mentioned C^-alkyl- and Ci^-alkyl-O-groups are substituted with 1 to 5 substituents Independentiy selected from the group consisting of HO-, and optionally with 1 to 7 fluorine atoms substituted Ci.₃-alkyl-O-,

172 and wherein above mentioned Ci^-alkyl- and Ci^-alkyl-O-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, and optionally with 1 to 7 fluorine atoms substituted Ci_3-alkyl-, and wherein above mentioned C^-cycloalkyl, Ca^-cycloalkyl-Ci-s-alkyl-, heterocyclyl, heterocyclyi-Ci-3-alkyl-, phenyl, heteroaryl, R⁸-(CH2)n-Oand R⁸-(CH2)m-(CH)(CH3)-(CH2)0-O-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of haiogen, HO-, optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-O-, and optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-,

3. A compound according to claim 1, wherein

R³ Is selected from the group R³³¹ consisting of

C₃.6-cycioalkyl-, wherein the above mentioned C^cycloalkyl-group may optionally be substituted with 1 to 9 substituents independently selected from the group consisting of halogen, NC-, HO-, Ct-3-alkyl- and Ci-3-alkyl-O-.

4. A compound according to any one or more of daims 1 to 3, wherein

A is selected from the group A^b consisting of wherein above mentioned phenyl- and pyridinyl- groups are substituted with R¹ and R².

5. A compound according to any one or more of daims 1 to 3, wherein

A is selected from the group A* consisting of

173

6. A compound according to any one or more of daims 1 to 5, wherein

R¹ is selected from the group R^1b consisting of

H, halogen, Ci-e-alkyl- and Cü-e-cydoalkyl wherein above mentioned Ci-e-alkyl- and Cü-e-cycloalkyl-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, HO- and optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-.

7. A compound according to any one or more of daims 1 to 5, wherein R¹ is seleded from the group R^1c consisting of

H, H3C-, F3C-, F₂HC-, FH2C-, fluorine, chlorine and bramine.

8. A compound according to any one or more of daims 1 to 7, wherein R² is seleded from the group R^2b1 consisting of

HO-, CM-alkyl-, CM-alkyl-O-, C3-e-cycloalkyl, C3-6-cycloalkyl-Ci-3-alkyl·, heterocyclyl, heterocyclyl-Ci.3-alkyl-, phenyl, heteraaryl, R⁸-(CH2)n-Owith n = 0,1,2 or 3 and R⁸-ÎCH2)_m-(CH)(CH3)-(CH₂)o-O- with m = 0 or 1 and 0 - 0 or 1 wherein above mentioned CM-alkyl- and CM-alkyl-O- graups are substituted with 1 to 3 substituents independently seleded from the group consisting of HO- and optionally with 1 to 7 fluorine atoms substituted Ci.g-alkyl-O-, and wherein above mentioned ÛM-alkyl- and Ci-4-alkyl-O-groups may optionally be substituted with 1 to 3 substituents independently seleded from the group consisting of halogen, and optionally with 1 to 7 fluorine atoms substituted Ci-3-alkyl-, and wherein above mentioned C3-e-cycloalkyl-, C3-e-cycloalkyl-Ci.3-alkyl-, heterocyclyl, heterocydyl-Ci-3-alkyl-, R⁸-(CH2)n-O- and and R⁸(CH2)m-(CH)(CH3)-(CH₂)o-0-groups may optionally be substituted with 1 to 3 substituents independently selected from the group consisting

174 of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted C1-3alkyl-O-, and optionally with 1 to 7 fluorine atoms substituted C^alkyl-.

9. A compound according to any one or more of daims 1 to 7, wherein R² Is selected from the group R^2d1 consisting of

HO-, Ci-4-alkyl-, Cm-alkyl-0-, C₃-€-cycloalkyl, C3^-cycloalkyl-Ci.₃-alkyl-, a saturated 5 or 6 membered monocyclic heterocycle containing one heteroatom selected from N or O, R⁸-(CH2)n-O- with n = 0,1 or 2, and R⁸-(CH2)_m-(CH)(CH₃HCH₂)_o-O- with m = 0 or 1 and o = 0 or 1 wherein above mentioned Ci-4-alkyl- and C-M-alkyl-O-groups are substituted with 1 to 5 substituents Independently selected from the group consisting of HO-, and optionally with 1 to 7 fluorine atoms substituted Ci.₃-alkyl-O-, and wherein above mentioned Ci^-alkyl- and Ci-4-alkyl-O-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, and optionally with 1 to 7 fluorine atoms substituted Ci.₃-alkyl-, and wherein above mentioned C3^-cycloalkyl-, C₃^-cycloalkyl-Ci-3-alkyl-, saturated 5 or 6 membered monocyclic heterocycle containing one heteroatom selected from N or O, R⁸-(CH2)n-O- and and R⁸-(CH2)_m(CH)(CH3)-(CH₂)o-O- groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, HO-, optionally with 1 to 7 fluorine atoms substituted C1.3alkyl-O-, and optionally with 1 to 7 fluorine atoms substituted Cv₃alkyl-.

10. A compound according to any one or more of daims 1, 2 and 4 to 9, wherein R³ is selected from the group R^3b consisting of

H, Ci-3-alkyl-, cyclobutyl- and cyclopropyl-, wherein the above mentioned Ci-₃-alkyl-, cyclobutyl- and cyclopropyl

175 groups may optionaily be substituted with 1 to 7 substituents Independently selected from the group consisting of halogen, Ci-₃alkyl-O-, NC- and HO-.

11. A compound according to any one or more of daims 1,2 and 4 to 9, wherein R³ is selected from the group R³⁰ consisting of

H, and H₃C- and cyclopropyl-, wherein the above mentioned H₃C- and cyclopropyl-groups may optionaily be substituted with 1 to 3 fluorine atoms.

12. A compound according to any one or more of daims 1 to 11, wherein

R⁴, R⁵ are seleded independently of each other from the group R^4b/R^5b consisting of

H, halogen, HO-, H₃C-, F₃C-, H₃C-O-, F₂HC-O-, FH₂C-O-, F₃C-O-, C_Malkyl-O-, R⁷-CH_r0- and R^CH^-O-, wherein above mentioned Cm-alkyl-0-, R⁷-CH2-O- and R⁷-(CH₂)₂-Ogroups, may optionaily be substituted with 1 to 5 substituents independently seleded from the group consisting of halogen, optionaily with 1 to 5 halogen atoms substituted C^-alkyl-, and optionaily with 1 to 5 halogen atoms substituted C^ralkyl-O-.

13. A compound according to any one or more of daims 1 to 11, wherein

R⁴, R^s are seleded from the group R^/R⁵⁰ consisting of

H-.

14. A compound according to any one or more of daims 1 to 13, wherein

R® is selected from the group R^eb consisting of

H, Cm-alkyl- and cyclopropyl-, wherein above mentioned Cm-alkyl-group may optionaily be substituted with 1-9 fluorine and/or chlorine atoms.

10

15. A compound according to any one or more of daims 1 to 13, wherein

R® is seleded from the group R®° consisting of

176

H and Ci-2-alkyl-, wherein above mentioned Ci-2-alkyl- group may optionally be substituted with 1-5 fluorine and/or chlorine atoms.

16. A compound according to any one or more of daims 1 to 13, wherein R® is selected from the group R®⁰ consisting of

H₃C-, FH₂C-, F₂HC- and F₃C-.

17. A compound according to any one or more of daims 1 to 12 and 14 to 16, 5 wherein

R⁷ is seleded from the group R⁷¹¹ consisting of

H, phenyl, heteroaryi, cycloalkyl and heterocyclyl wherein above mentioned phenyl, heteroaryi, cycloalkyl and heterocyclyl-groups may optionally be substituted with 1 to 4 substituents independently seleded from the group consisting of halogen, and optionally with 1 to 3 halogen atoms substituted Ci.₃alkyl-O-.

18. A compound according to any one or more of daims 1 to 12 and 14 to 16, wherein

R⁷ is seleded from the group R^7c consisting of

H and phenyl, wherein above mentioned phenyl group may optionally be substituted with 1 to 4 substituents independently seleded from the group consisting of halogen and optionally with 1 to 3 halogen atoms substituted Ci-₃-alkyî-O-.

10

19. A compound according to any one or more of daims 1 to 18, wherein

R® is seleded from the group R^8b consisting of

C3-6-cycloalkyl, heterocyclyl and heterocyclyl-Ci.₃-alkyl-, wherein above mentioned C₃^-cycloalkyl, heterocyclyl and heterocyclyl-Ci.₃-alkyl-groups may optionally be substituted with 1 to 5 substituents independently seleded from the group consisting of HO-,

177 fluorine and optionally with 1 to 7 halogen atoms substituted Ci-3-alkyl-,

20. A compound according to any one or more of daims 1 to 18, wherein

R⁸ is selected from the group R^te1 consisting of

C^-cycloalkyl and a saturated 4 to 6 membered monocyclic heterocycle containing one or two heteroatoms selected from N or O, wherein above mentioned Cy€-cycloalkyl and heterocyclyl-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of HO-, fluorine and optionally with 1 to 7 halogen atoms substituted Ci-3-alkyl-.

21. A compound according to any one or more of daims 1 to 20, or a pharmaceutically acceptable tautomers thereof, stereoisomer thereof, mixtures thereof, solvaté thereof, hydrate thereof or sait thereof for use as a médicament.

22. Pharmaceutical compositions containing at least one compound according to one or more of the clalms 1 to 20 or a pharmaceutically acceptable tautomers thereof, stereoisomer thereof, mixtures thereof, solvaté thereof, hydrate thereof or sait thereof together with one or more pharmaceutically acceptable carrier.

23. A compound according to one or more of daims 1 to 20, or a pharmaceutically acceptable tautomer thereof, stereoisomer thereof, mixtures thereof, solvaté thereof, hydrate thereof or sait thereof or a pharmaceutical composition according to daim 22 for use in the prévention or treatment of (1 ) disorders comprislng the symptom of cognitive deficîency; (2) organic, including symptomatic, mental disorders, dementia;

(3) mental retardation; (4) mood [affective] disorders; (5) neurotic, stress-related and somatoform disorders Including anxiety disorders; (6) behavioural and emotional disorders with onset usually occurring In childhood and adolescence, attention déficit hyperactivity syndrome (ADHD) and Autism spectrum disorders; (7) disorders of psychological development, developmental disorders of scholastic skills; (8) schizophrénie and other psychotic disorders; (9) disorders of adult personality and behavlour; (10) mental and behavioural disorders due to psychoactive substance use; (11 ) extrapyramidal and movement disorders; (12) episodic and paroxysmal disorders, epilepsy; (13) Systemic atrophies primarily affecting the central nervous

178

System, ataxia; (14) Behavioural syndromes associated with physiological disturbances and physical factors; (15) sexual dysfunction comprising excessive sexual drive; (16) factitious disorders; (17) Treatment, amelioration and / or prévention of cognitive impairment being related to perception, concentration, cognition, leaming or memory; (18) Treatment amelioration and / or prévention of cognitive impairment being related to age-associated leaming and memory impairments; (19) Age-associated memory losses; (20) Vascular dementla; (21) Craniocerebral trauma; (22) Stroke; (23) Dementia occurring after strokes (post stroke dementia); (24) Post-traumatic dementia; (25) General concentration impairments; (26) Concentration impairments in children with leaming and memory problems; (27) Alzheimer’s disease; (28) Lewy body dementia; (29) Dementia with degeneration of the frontal lobes; including Pick's syndrome; (30) Parkînson’s disease; (31 ) Progressive nuclear palsy; (32) Dementia with corticobasal degeneration; (33) Amyotropic latéral sclerosis (ALS); (34) Huntington’s disease; (35) Multiple sclerosis; (36) Thalamlc degeneration; (37) Creutzfeld-Jacob dementia; (38) HIV dementia; (38) Schizophrenia with dementia or KorsakofTs psychosis; (39) Sleep disorders; (40) Bipolar disorder; (41) Metabolic syndrome; (42) Obesity; (43) Diabetis mellitus; (44) Hyperglycemia; (45) Dyslipidemia; (46) Impaired glucose tolérance; (47) Disease of the testes, brain, small Intestine, skeletal muscle, heart, lung, thymus or spleen and (48) pain disorders.