OA20784A - Spirochromane derivatives - Google Patents

Abstract

The invention relates to spirochromane derivatives, or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof, as well as to pharmaceutical compositions containing them and to their use as modulators of a7 nicotinic acetylcholine receptor activity in a mammalian subject

Description

SPIROCHROMANE DERIVATIVES

FIELD OF THE INVENTION

The présent invention relates to pharmacologically active spirochromane compounds, or pharmaceutically acceptable salis, bîologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof, as well as to pharmaceuticai compositions containing them and to their use as modulators of a7 nicotinic acétylcholine receptor activîty in a mammalian subject.

BACKGROUND OF THE INVENTION

Acétylcholine (ACh) exerts its functions as a neurotransmitter in the mammalian central nervous System (CNS) by binding to cholinergic receptors. The mammalian CNS contains two prédominant types of ACh receptors: muscarinic (mAChR) and nicotinic (nAChR) receptors, based on the agonist activities of muscarine and nicotine, respectively. Nicotinic acétylcholine receptors are ligand-gated ion channels made up of five subunits (Purves et al. Neuroscience 4th ed. (2008) 122-126). The subunits of the nicotinic receptors belong to a multigene family and hâve been divided into two groups based on their amino acid sequences; one containing alpha, and another containing beta subunits. Pentameric assemblies of different subunit combinations resuit in large number of receptor subtypes with varions pharmacological properties. Assembly of the most broadly expressed subtypes include muscle-type ((al)₂β|δε), ganglion-type ((α3)₂(β4)ΐ) and CNS-type (α4)₂(β2)3 or (a7)s) nAChR subtypes (Le Novère N et al. Journal of Molecular Evolution 40 (1995) 155-172). a7 subunits hâve been shown to form functional receptors when expressed alone, and thus are presumed to form homooligomeric pentameric receptors.

Activation of the nAChR ion channel is primarily controlled by binding of ligands at conventional agonist binding sites, but is also régulâted by either négative, or positive allosteric modulators (NAMs and PAMs). The allosteric transition State model of the nAChR involves at least a resting State, an activated State and a desensitized closed channel State, a process b y which receptors become insensitive to the agonist. Different nAChR ligands can stabilize the confonnational State of a receptor, to which they preferentialïy bind. For example, the agonists ACh and (-)-nîcotine respectively stabilize the active and desensitized States. Changes of the activity of nicotinic receptors hâve been implicated in a number of diseases. Réductions in nicotinic receptors hâve been hypothesized to médiate cognitive déficits seen in diseases, such as Alzheimer's disease and schizophrenia. The effects of nicotine from tobacco are also mediated by nicotinic receptors, and since the effect of nicotine is to stabilize receptors in a desensitized state, an increased activity of nicotinic receptors may reduce the desire to smoke.

However, treatment with nicotinic receptor agonists, which act at the same site as ACh is problematic, because ACh not only activâtes, but also blocks receptor activity through processes, which înclude desensitization and uncompetitive blockade. Furthermore, prolonged activation appears to induce a long-lastîng inactivation. Therefore, agonists of ACh can be expectcd to lose effectiveness upon chronic administration.

While the a7 nAChR is characterized by its fast activation kinetics and high permeability to Ca²⁺ compared to other subtypes (Delbono et al. J. Pharmacol. Exp. Ther. 280 (1997) 428438), it also exhibits rapid desensitization following exposure to agonists at the orthosteric site (Castro et al. Neurosci. Lett. 164 (1993) 137-140; Couturier et al. Neuron 5 (1990) 847-856). In spite that development of a variety of «7-selective agonists and partial agonists has been carried out in the recent years, their clînical efficacy proved to be suboptimal, due to this receptor blockade (desensitisation) following the agonist activation. This problem may be overcomed by treatment with PAMs, enhancing a 7 nAChR activation mediated by the endogenous agonist. The positive modulation of al nAChRs has been shown to hâve cognitive benefits in various preclinical models (Thomsen et al. Curr Pharm Des 16 (2010) 323-343; Lendvai et al. Brain Res Bull 93 (2013) 86-96).

The compounds of the présent invention may be useful for the treatment of diseases and conditions mediated by, or associated to the positive allosteric modulation of the al nAChR, including, but not limited to psychotic disorders, for example schizophrenia (Deutsch SI et al. Schizophr Res 148 (2013) 138-144), schizophreniform disorder (Rowe AR et al. J Psychopharmacol 29 (2015) 197-211), schizoaffective disorder (Martin LF et al. Am J Med Genet B Neuropsychiatr Genet 144B (2007) 611-614), delusional disorder (Carson R et al. Neuromolecular Med 10 (2008) 377-384), brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, or psychotic disorder not otherwise specified, cognitive impairment including, for example the treatment of impairment of cognitive functions, as well as cognitive impairment as a resuit of stroke, Alzheimer's disease (Lewis AS et al, Prog Neuropsychopharmacol Biol Psychiatry 75 (2017) 45-53), Huntington's disease (Foucault-Fruchard L et al. Neural Regen Res 13 (2018) 737-741), Pick disease (Fehér A et al. Dement Geriatr Cogn Disord 28 (2009) 56-62), HIV associated dementia (Capô-Vélez CM et al. Sci Rep 8 (2018) 1829), frontotemporal dementia (Minami SS et al. Biochem Pharmacol 97 (2015) 454-462), Lewy body dementia (Perry EK et al. Neuroscience 64 (1995) 385-395), vascular dementia (Putîgnano S et al. Clin Interv Aging 7 (2012) 113-118), cerebrovascular disease (Si ML and Lee TJF Cire Res 91 (2002) 62-69), or other dementia States, and dementia associated to other degenerative disorders (amyotrophie latéral sclerosis (Kawamata et al. Ther Adv Chronic Dis 2 (2011) 197-208), etc.), other acute or sub-acute conditions that may cause cognitive décliné, such as delirium (Sfera A et al. Front Med 2 (2015) 56), traumatic brain injury (Shin SS et al. Neural Regen Res 10 (2015) 1552-1554), senîle dementia (Whitehouse PJ et et al. Science 215 (1982) 1237-1239), mild cognitive impairment (Ikonomovic MD et al. Arch Neurol 66 (2009) 646-651), Down’s syndrome (Deutsch SI et al. Clin Neuropharmacol 26 (2003) 277-283), dépréssion and cognitive déficit related to other diseases and dyskinetic disorders (Parameswaran N et al. Soc Neurosci Abstr (2007)), such as Parkinson’s disease (Quik M et al. Biochem Pharmacol 97 (2015) 399-407), as well as neuroleptic-induced parkinsonism, or tardive dyskinesias (Terry AV and Gearhart DA Eur J Pharmacol 571 (2007) 29-32), dépréssion and mood disorders, including dépressive disorders and épisodes (Philip NS et al. Psychopharmacology 212 (2010) 1-12), bipolar disorders (Leonard S and Freedman R. Biol Psychiatry 60 (2006) 115-122), cyclothymie disorder (Ancin I et al. J Affect Disord 133 (2011) 340-345), and bipolar disorder not otherwise specified, other mood disorders (Shytle RD et al. Dépréssion and Anxiety 16 (2002) 89-92), substance-induced mood disorder and mood disorder not otherwise specified, anxiety disorders (Picciotto MR et al. Neuropharmacology 96 (2015) 235-243), panic disorder and panic attacks (Zvolensky MJ et al. Clin Psychol Rev 25 (2005) 761-789), obsessive compulsive disorder (Tîzabi Y et al. Biol Psychiatry 51 (2002) 164-171), posttraumatic stress disorder (Sun R et al. Neuroscience 344 (2017) 243-254), acute stress disorder (Mineur YS et al. Neuropsychopharmacology 41 (2015) 1579-1587), generalized anxiety disorder (Cocores JA Prim Care Companion J Clin Psychiatry 10 (2008) 253-254), anxiety disorder due to a general medical condition, substance-induced anxiety disorder, phobias, and anxiety disorder not otherwise specified, substance related disorders for ex ample substance use or substance-induced disorders, e.g., alcohol- (de Fiebre NC and de Fiebre CM Alcohol 31 (2003) 149-153; Diaper AM et al. Br J Clin Pharmacol 77(2014) 302-314) nicotine- (Leslie FM et al. Mol Pharmacol 83 (2013) 753-758), amphétamine- (Pubill

D et al, Pharmaceuticals 4 (2011) 822-847), phencyclidîne- (Thomsen MS et al, Neuropharmacology 56 (2009) 1001-1009), opioid- (Zhang W, Int J Clin Exp Med 8 (2015) 1871-1879), cannabis- (Solinas M et al. JNeurosci 27 (2007) 5615-5620), cocaine- (Francis MM et al. Mol Pharmacol 60 (2001) 71-79), caffeine-, hallucinogen-, inhalant-, sédative-, hypnotic-, anxiolytîc-, polysubstance- or other substance-related disorders; sleep disorders (McNamara JP et al. Psychol Health Med 19 (2014) 410-419) such as narcolepsy (Krahn et al J Clin Sleep Med 5 (2009) 390), dyssomnias, primary hypersomnia, breathîng-related sleep disorders, circadian rhythm sleep dîsorder, and dyssomnîa not otherwise specified; parasomnias, sleep terror disorder, sleepwalking disorder, and parasomnia not otherwise specified; sleep disorders related to another mental disorder (including insomnia related to another mental disorder and hypersomnia related to another mental disorder), sleep disorder due to a general medical condition and substance-induced sleep disorder; metabolic and eatîng disorders (Somm E Arch Immunol Ther Exp 62 (2014) 62: 87-101), such as anorexia nervosa (Cuesto G et al. J Neurogenet 31 (2017) 266-287), bulîmia nervosa, obesity (Lakhan SE and Kirchgessner A J Transi Med 9 (2011) 129-139), compulsive eating disorder, binge eating disorder and eating disorder not otherwise specified; diabètes mellitus (Marrero MB et al. J Pharmacol Exp Ther 332 (2010) 173-180), ulcerative colitis (Salaga et al. JPET 356 (2016) 157-169), Crohn’s disease (Bencherif M et al. Cell Mol Life Sci 68 (2011) 931-949), irritable bowel syndrome (Keszthelyi D et al. Neurogastroenterol Motil 21 (2009) 1239-1249), autism spectrum disorders (Deutsch et al. Clin Neuropharmacol 33 (2010) 114-120), including autistic disorder, Asperger's disorder, Retfs disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified; attention déficit hyperactivity disorder (Wilens TE and Decker MW Biochem Pharmacol 74 (2007) 1212-1223), disruptive behaviour disorders, oppositional défiant disorder and disruptive behaviour disorder not otherwise specified; and tic disorders such as Tourette's disorder (Gotti C and Clementi F Prog Neurobiol 74 (2004) 363-396), personality disorders (Kamens HM et al. Behav Genet 46 (2016) 693-704); sexual dysfunctions such as sexual desire disorders, sexual arousal disorders, orgasmîc disorders, sexual pain disorder, sexual dysfunction not otherwise specified, paraphilias, gender identity disorders, infertility (Bray C et al. Biol Reprod 73 (2005) 807-814), premenstrual syndrome (Gündisch D and Eibl C Expert Opin Ther Pat 21 (2011) 1867-1896), and sexual disorders not otherwise specified, disorders of the respiratory System like cough (Canning BJ Am J Respir Crit Care Med 195 (2017) A4498), asthma (Santana FPR et al. Eur Respir J 48 (2016) PA5066), chronic obstructive pulmonary disease (Maouche K et al. Proc Hall Acad Sci USA 110 (2013) 4099-4104), lung inflammation (Enioutina EY et al. PLoS One 10 (2015) e0121128), disorders of the cardiovascular System such as cardiac failure (Mai XK et al. J Immunol 200 (2018) 108.11), heart arrhythmia (Mazloom R et al. PLoS One 8 (2013) e82251), and hypertension (Chen JK et al. BMC Cardiovasc Disord 12 (2012)38).

The compounds of the invention are also useful in treating inflammation, inflammatory and neuropathie pain (Alsharari SD et al. Biochem Pharmacol 86 (2013) 1201-1207), rheumatoid arthritis (van Maanen MA et al. Arthritis & Rheumatism 60 (2009) 1272-1281), osteoarthritis (Lee SE Neurosci Lett 548 (2013) 291-295), allergy (Yamamoto T et al. PLoS One 9 (2014) e85888), sarcoidosis (Nicotine Treatment for Pulmonary Sarcoidosis: A Clinical Trial Pilot Study Elliott Crouser MD, Principal Investigator, Ohio State Universîty ClinicalTrials.gov Identifier: NCT02265874), psoriasis (Westman M et al. Scand J Immunol 70 (2009) 136-140), ataxia (Taslim N et al. Behav Brain Res 217 (2011) 282-292), dystonia (Zimmerman CN et al. Front Syst Neurosci 11 (2017) 43), systemic lupus erythematosus (Fairley AS and Mathis KW Physiol Rep 5 (2017) el 3213), mania (Janowsky DS et ai. Lancet 2 (1972) 632-635), restless legs syndrome (Buchfuhrer MJ Neurotherapeutics 9 (2012) 776-790), progressive supranuclear palsy (Warren NM et al. Brain 128 (2005) 239-245), epilepsy (Bertrand D Epilepsy Curr 2 (2002) 191-193), myoclonus (Leppik IE Epilepsia 44 (2003) 2-6), migraine (Liu Q et al. J Pain Res 11 (2018) 1129-1140), amnesia (Bali Zs K et al. Front Cell Neurosci 11 (2017) 271), chronic fatigue syndrome (Shan ZY et al. J Magn Reson Imaging 44 (2016) 1301-1311), cataplexy (Ebben MR and Krieger AC J Clin Sleep Med 8 (2012) 195-196), brain ischemia (Han Z et al. J Neurochem 131 (2014) 498-508), multiple sclerosis (Di Bari M et al. Cent Nerv Syst Agents Med Chem 17 (2017) 109-115), encephalomyelitis (Hao J et al. Exp Neurol 227 (2011): 110-119), jetlag (Shi M et al. eLife 3 (2014) e01473), cérébral amyloid angiopathy (Clifford PM et al. Brain Res 1234 (2008) 158-171), sepsis (Ren C étal. IntJBiolSci 14 (2018) 748-759), and in general, in treating ail types of diseases and disorders connected to the positive allosteric modulation of the a7 nAChR.

Furthermore, these compounds can also be combined with other therapeutic agents including, but not limited to acetylcholinesterase inhibitors (such as galantamine, rivastigmine, donepezil, tacrine, phenserine, ladostigii and ABT-089); NMDA receptor agonists or antagonists (such as memantine, neramexane, EVT101 and AZD4282); anti-amyloid antibodies including antî-amyloid humanized monoclonal antibodies (such as bapineuzumab, ACCOO1, CAD 106, AZD3102, H12A11V1); beta- (such as verubecestat, and

AZD3293) or gamma-secretase înhîbitors (such as LY450139 and TAK 070) or modulators; tau phosphorylation inhîbitors; ApoE4 conformation modulators; p25/CDK5 inhibitors; NKI/NK3 receptor antagonists; COX-2 inhibitors (such as celecoxib, rofecoxib, valdecoxib, 406381 and 644784); LRRK2 inhibitors; HMG-CoA reductase inhibitors; NSAIDs (such as ibuprofen); vitamin E; glycine transport inhibitors; glycine site antagonists (such as lacosamide); LXR β agonists; androgen receptor modulators; blockers of Αβ oligomer formation; NR2B antagonists, anti-inflammatory compounds (such as (R)-flurbiprofen, nitroflurbiprofen, ND-1251, VP-025, HT-0712, and EHT-202); PPAR gamma agonists (such as pioglitazone and rosiglitazone); CB-1 receptor antagonists or inverse agonists (such as AVE1625); CB-2 agonists (such as 842166 and SAB378); VR-1 antagonists (such as AMG517, 705498, 782443, PAC20030, VI 14380 and A425619); bradykinin B1 receptor antagonists (such as SSR240612 and NVPSAA164); sodium channel blockers and antagonists (such as VX409 and SPI860); NOS inhibitors (such as SD6010 and 274150); antibiotics; growth honnone secretagogues (such as ibutamoren, ibutamoren mesylate, and capromorelin); potassium channel openers; AMP A agonists or AMP A modulators (such as CX-717, LY 451395, LY404187 and S-18986); GSK3 inhibitors (such as AZDI080, SAR502250 and CEP 16805); neuronal nicotinic agonists; MARK ligands; Mj or M₄ mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; mGluR5 antagonists (such as AZD9272); alphaadrenerg agonists; ADAM-I0 ligands; sédatives, hypnotics, anxiolytics, antipsychotics, cyclopyrrolones, imidazopyridînes, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents; orexin antagonists and agonists; prokineticin agonists and antagonists; T-type calcium channel antagonists; triazolopyridines benzodiazépines, barbiturates; 5-HTia antagonists (such as lecozotan); 5-HT2 antagonists; 5-HT₄ agonists (such as PRX03140);

5-HT₆ antagonists (such as GSK 742467, SGS-518, FK-962, SL-65.0I55, SRA- 333 and xaliproden); histamine H? receptor antagonists and inverse agonists (such as S38093, ABT-834, ABT 829, GSK 189254 and CEP 16795); PDE₄ inhibitors (such as HT0712); PDE9 inhibitors (such as BI40936); PDE10 inhibitors; HDAC inhibitors; KCNQ antagonists; GABAa inverse agonists; GABA sîgnalling enhancers; G AB A agonists, G AB A a receptor alpha5 subunit NAMs or PAMs, antipsychotics; MAO-B inhibitors; dopamine transport inhibitors; noradrenalîne transport inhibitors; D2 agonists and partial agonists; anticholinergîcs (such as biperiden); COMT inhibitors (such as entacapone); A2a adenosine receptor antagonists; cholinergic agonists; compounds from the phenothiazine, thioxanthene (such as chlorprothixene and thiothixene), heterocyclic dibenzazepine (such as clozapine), butyrophenone (such as haloperidol), diphenylbutylpiperidine (such as pimozide) and indolone (such as molindolone) classes of neuroleptic agents; loxapine, sulpiride and rispéridone; levodopa; calcium channel blockers (such as ziconotide and NMED160);

MMP inhîbitors; thrombolytic agents; opioid analgésies (such as codeîne, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene); pramipexole; ropinirole; neutrophil inhibitory factor; SSRIs or SSNRIs; tricyclic antidepressant drugs; norepinephrine modulators; lithium; valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan or other drugs that affect receptors or enzymes that either increase the effîcacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the présent invention.

Known positive allosteric modulators of the a7 nicotinic acétylcholine receptor include 2-aniline-4-aryl thiazole dérivatives (WO 2007/031440 A2, JANSSEN PHARMACEUTICA NV), amide dérivatives (WO 2009/100294 A2, ABBOT LAB.), trisubstituted 1,2,4-triazoles (WO 2009/115547 Al, JANSSEN PHARMACEUTICA NV), indole dérivatives (WO 2009/127678 Al, GLAXO GROUP LTD. and WO 2009/127679 Al, GLAXO GROUP LTD.), tetrazole-substîtuted aryl amide dérivatives (WO 2009/043780 Al, HOFFMANN LA ROCHE), cyclopropyl aryl amide dérivatives (WO 2009/043784 Al, HOFFMANN LA ROCHE), trisubstiuted pyrazoles (WO 2009/135944 Al, JANSSEN PHARMACEUTICA NV), pyrrole dérivatives (WO 2014/141091 Al, LUPIN LTD), cyclopropylbenzene dérivatives (WO 2017/165256 Al, MERCK SHARP & DOHME CORP.), and substituted bicyclic heteroaryl dérivatives (WO 2018/085171 Al, MERCK SHARP & DOHME CORP.).

The présent invention is directed to a novel class of compounds that exhibit positive allosteric modulation of the al nicotinic acétylcholine receptor.

BRIEF DESCRIPTION OF THE DRAWINGS

An exemplary embodiment of the présent invention is illustrated by way of example in the accompanying drawings in which like reference numbers indicate the same or sîmilar éléments and in which:

Figure 1 illustrâtes the results of place récognition test of compound Example l. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). ⁺p<0.05; ⁺⁺p<0.01; ^+πρ<0.001.

Figure 2 illustrâtes the results of place récognition test of compound Example 6. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.).⁺p<0.05; ^h+p<0.01; ^<0.001.

Figure 3 illustrâtes the results of place récognition test of compound Example 7. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). ⁺p<0.05; ⁺⁺p<0.01; ⁺⁺⁺p<0.001.

Figure 4 illustrâtes the results of place récognition test of compound Example 26. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). ⁺p<0.05; ⁺⁺p<0.0I; ⁺⁺⁺p<0.001.

Figure 5 illustrâtes the results of place récognition test of compound Exampie 41. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). ^<0.05; ⁺'^rp<0.01 ; ⁺⁺⁺p<0.001.

Figure 6 illustrâtes the results of place récognition test of compound Example 43. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (l mg/kg, ip.). ⁺p<0.05; ⁺⁺p<0.01; ⁺ ^<0.001.

Figure 7 illustrâtes the results of place récognition test of compound Example 52. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). p<0.05; ^<0.01; ⁺⁺⁺p<0.001.

Figure 8 illustrâtes the results of place récognition test of compound Example 61. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). ⁺p<0.05; ⁺⁺p<0.01; ⁺⁺⁺p<0.001.

SUMMARY OF THE INVENTION

The présent invention relates to compounds of formula (1),

(I) wherein

A is a five or six membered heterocycle;

B is a six membered carbocycle or heterocycle;

X is C or N;

Yis C or N;

Z is C or N;

W is O or S;

R¹ is H, Ci.^alkyl, halogen or haloCYéalkyl;

R² is H or O;

R³ is H, Ci_₆alkyl, halogen, haloCi^alkyl or Cbéalkoxy;

R⁴ isHorCi.₆alkyl;

R⁵ is H or Ci^alkyl;

n and m are independently 1 or 2;

is a single - or double-bond;

or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In a further aspect, the présent invention relates to compounds of formula (II),

(il) wherein

Vis Cor S;

Z is C or N;

W is O or S;

R^,a is H, Ci.₆alkyl, or haloC^alkyl;

R^lb is H, Ci-6alkyl, halogen, or haloCi.&alkyl;

R^le is H, Ci^alkyl, halogen, or haloCi^alkyl when V is C; or R^lc is absent when V is S;

R² is H or O;

R³ is H, C].₆alkyl, halogen, haloC[.r,alkyl, or Ci_₆alkoxy;

n and m: independently 1 or 2;

is a single - or double-bond;

or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantîomers, diastereomers, solvatés and hydrates thereof.

In a further aspect, the présent invention provides a compound of formula (I) or formula (II), as defined above for use in the treatment or prévention of a disease associated with a7 nicotinic acétylcholine receptor activity.

In a further aspect, the présent invention provides the use of a compound of formula (I) or formula (II), as defined above, for the manufacture of a médicament for the treatment or prévention of a disease associated with a7 nicotinic acétylcholine receptor activity.

In a further aspect, the présent invention provides a method for the treatment or prévention of a disease associated with u7 nicotinic acétylcholine receptor activity comprising administering to a mammal in need of such treatment or prévention an effective amount of at least one compound of formula (I) or formula (II), as defined above.

In a further aspect, the compounds of formula (I) or formula (II), as defined above, can be administered in combination with other compounds used for the treatment or prévention of a disease associated with «7 nicotinic acétylcholine receptor activity.

In a further aspect, the présent invention provides a process for the manufacture of the compounds of formula (II).

DETAILED DESCRIPTION OF THE INVENTION

The présent invention relates to compounds of formula (I),

R⁴ R⁵ W wherein:

A is a five or six membered heterocycle;

B is a six membered carbocycle or heterocycle;

Xis CorN;

Y is C or N;

Z is C or N;

W is O or S;

R¹ is H, Ci.₆alkyl, halogen or haloCi^alkyl;

R² is H or O;

R³ is H, Ci_₆alkyl, halogen, haloC^alkyl or Ci^alkoxy;

R⁴ is H or Ci^alkyl;

R⁵ is H or Ci_(,alkyl;

n and m are independently 1 or 2;

is a single - or double-bond;

or phannaceutical ly acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

The term “five membered heterocycle”, as used herein, refers to to an optionally substituted saturated, unsaturated or aromatic ring System having five atoms and incorporating one, two, three or four heteroatoms (chosen from nitrogen, oxygen or sulfiir). Ex amples of five membered heterocyclyc moieties include, but are not limited to, pyrrolydinyl, pyrrolyl, tetrahydrofuryl, dihydrofiiryl, furyl, tetrahydrothiophenyl, thiophenyl, imidazolidinyl, imidazolyl, pyrazolidinyl, pyrazolyl, oxazolidinyl, isoxazolidinyl, oxazolyl, isoxazolyl, thiazolidinyl, isothiazolidinyl, thiazoiyl, isothiazolyl, dioxolanyl, dithiolanyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl.

The tenu “six membered heterocycle”, as used herein, refers to an optionally substituted saturated, unsaturated or aromatic ring System having six atoms and incorporating one, two, three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). Examples of six membered heterocycles include, but are not limited to, piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, dihydropyranyl, tetrahdydropyranyl, pyranyl, thîopyranyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl.

The tenu “six membered carbocycle” as used herein, refers to an optionally substituted saturated, unsaturated or aromatic ring System having six carbon atoms including, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.

The term “halo” or “halogen”, as used herein as such or as part of another group, refers to fluoro, chloro, bromo or iodo.

The term “Ci-ealkyl”, as used herein as such or as part of another group, refers to a branched or straight chain saturated hydrocarbon group having one, two, three, four, five or six carbon atoms including, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, and fôrt-butyl.

The term “haloCi-salkyl”, as used herein, refers to at least one halogen, as defïned above, bonded to the parent molecular moiety through an “Ci^alkyl” group, as defïned above. When there are several halogens, the halogens can be identical or different and the halogens can be attached to different carbon atoms or several halogens can be attached to the same carbon atom.

HaloC[.₆alkyl groups include, but are not limited to, difluoromethyl, trifluoromethyl and 2chloroethyl.

The terni “Ci-6alkoxy”, as used herein refers to an “C|-6alkyl” group, as defined above, bonded to the parent molecular moiety through an oxygen atom including, but not limited to, methoxy, ethoxy, n-propoxy, j-propoxy and terr-butoxy.

The term “pharmaceutically acceptable” describes an ingrédient that is useful in preparing a pharmaceutical composition, is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes those acceptable for veterinary use as well as human pharmaceutical use.

The term pharmaceutically acceptable sait refers a conventional acid addition sait or a base addition sait, which préserves the biological efficacy and properties of the compounds of formula (I) or formula (II) and which can be formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases. Ex amples of acid addition salts include salts derived from inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfurie acid, sulphamic acid, phosphoric acid, nitric acid and perchloric acid and derived from various organic acids, such as, but not limited to, acetic acid, propionîc acid, benzoic acid, glycolîc acid, phenylacetic acid, salicylic acid, malonic acid, maleic acid, oleic acid, pamoic acid, palmitic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, succinic acid, citric acid, malic acid, lactic acid, glutamic acid, fumaric acid and the like. Examples of base addition salts are salts derived from ammonium-, potassium-, sodium- and quatemary ammonium hydroxides such as tétraméthylammonium hydroxide.

The term “pro-drug” refers to dérivatives of compounds of formula (I) or formula (II) according to the invention which themselves hâve no therapeutic effect but containing such groups which, after in vivo Chemical or metabolic dégradation (biotransformation) become a “biologically active métabolite” which is responsible for the therapeutic effect. Such decomposing groups associated with the compounds of formula (I) or formula (II) of the présent invention, în particular those suitable for prodrugs, are known in the art and may also be applied for the compounds of the présent invention (Rautio et al., Nature Reviews - Drug Discovery 2008, 7:255-270).

The term “hydrate” means non-covalent combinations between water and soluté.

The tenn “solvaté” means non-covalent combinations between solvent and soluté. Solvents include, but are not limited to, éthanol, 2-propanol, acetonîtrile and tetrahydrofuran.

Optional or optionally means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

Optionally substituted means unsubstituted or substituted with one or more of the substituents as described herein. Here, one or more means from one to the highest possible number of substitution, that is, from replacîng one hydrogen to replacing ail hydrogens. One, two or three substituents on a given atom are preferred.

Treating or treatment of a disease State includes:

a) preventing the disease State, i.e. causing the clinical symptoms of the disease State not to develop in a subject that may be exposed to or predisposed to the disease State, but does not yet expérience or display symptoms of the disease State,

b) inhibiting the disease State, i.e., arresting the development of the disease State or its clinical symptoms, or

c) relieving the disease State, i.e., causing temporary or permanent régression of the disease State or its clinical symptoms.

In one embodiment, the présent invention relates to compounds of formula (I), wherein A îs five membered heterocycle, wherein the members of the ring are selected from the group consisting of carbon, nitrogen, oxygen, and sulphur;

B is a six membered carbocycle or a heterocycle, wherein the members of the ring are selected from the group consisting of carbon, nitrogen, oxygen, and sulphur;

Xis C;

Yis C;

ZisCorN;

W is O or S;

R¹ îs H, Ci.₆alkyl, halogen or haloCi-éalkyl;

R² is H or O;

R³ is H, Ci-ealkyl, halogen, haloCbéalkyl or Ci-éalkoxy;

R⁴ is H;

R⁵ is H;

n and m are independently 1 or 2;

is a single - or double-bond;

or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relates to compounds of formula (II),

(II) wherein

Vis C or S;

Z is C or N;

W is O or S;

R^la is H, Ci.₆alkyl, or haloCi^alkyl;

R^lfl is H, Cj^alkyl, halogen, or haloC]_₆alkyl;

R^le îs H, Ci^alkyl, halogen, or haloCi^alkyl when V is C; or R^lc is absent when V is S;

R² is H or O;

R³ is H, Ci^alkyl, halogen, haloC].6 alkyl, or Cnsalkoxy;

n and m are independently 1 or 2;

is a single - or double-bond;

or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relates to compounds of fonnula (II), wherein

V is C or S;

ZisCorN;

W is O or S;

R^,a is H, Ci.4alkyl, orhaloCj_4alkyl;

R^lb is H, CMalkyl, halogen, or haloCi^alkyl;

R^le is H, Ci-4alkyl, halogen, or haloC].4alkyl when V is C; or R^,c is absent when V is S;

R² is H;

R³ is H, Ci^alkyl, halogen, haloCj^alkyl, or Ci.₄alkoxy;

n and m are independently 1 or 2;

is a single bond when it is attached to R², and a single - or double bond within the ring; or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relates to compounds of formula (II), wherein V is C or S;

Z is C or N;

W is O or S;

R^,a is H, C_Malkyl, or haloCi^alkyl;

R^lhis H, Ci-4alkyl, halogen, or haloCi^alkyl;

R^lc is H, Ci-4alkyl, halogen, or haloCj^alkyl when V is C; or R^lc is absent when V is S;

R² is H;

R³ is H, CMalkyl, halogen, haloC^alkyl, or Ci^alkoxy;

n and ni are 1 ;

is a single bond when it is attached to R , and a single - or double bond within the ring; or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relates to compounds of formula (II), wherein V is C or S;

Z is C or N;

W is O or S;

R^la is H, CMalkyl, or haloC|.4alkyl;

R^,b îs H, Ci.₄alkyl, halogen, or haloCi.₄alkyl;

R^le is H, Ci.₄alkyl, halogen, or haloCi-₄alkyl when V is C; or R^lc is absent when V is S;

R² is H;

R³ is H, Ci^alkyl, halogen, haloCi.₄alkyl, or Ci.₄alkoxy;

n and m are 2;

is a single bond when it îs attached to R², and a single - or double bond wîthin the ring; or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relates to compounds of formula (II), wherein V is C or S;

Z is C or N;

W is O or S;

R^Ia îs H, Ci^alkyl, or haloC|.₄alkyl;

R^,b is H, C^alkyl, halogen, or haloCi.₄alkyl;

R^lc is H, C^alkyl, halogen, or haloCi.₄alkyl when V is C; or R^lcis absent when V is S;

R² is H;

R³ îs H, C|.₄alkyl, halogen, haloCj.₄alkyI, or Cj.₄alkoxy;

n is 1 ;

m is 2;

is a single bond when it is attached to R², and a single - or double bond wîthin the ring; or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relates to compounds of formula (II), wherein V is C or S;

Z is C or N;

W is O or S;

R^,a is H, C,.4alkyl, or haloC_l.₄alkyl;

R^lb is H, C^alkyl, halogen, or haloC|.₄alkyl;

R^u is H, C^alkyl, halogen, or haloCi-₄alkyl when V is C; or R^lc is absent when V is S;

R² is O;

R³ is H, CMalkyl, halogen, haloCi^alkyl, or Ci^alkoxy;

ii and m are independently 1 or 2;

is a double bond when it is attached to R², and a single bond within the ring;

or phannaceutically acceptable salts, biologîcally active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relates to compounds of formula (II), wherein Vis Cor S;

Z is C or N;

W îs O or S;

R^Iil is H, Ci^alkyl, or haloCi^alkyl;

R^lb is H, Cj^alkyl, halogen, orhaloC₁.₄alkyI;

R^lc is H, Ci„4alkyl, halogen, or haloCi^alkyl when V is C; or R^lc is absent when V is S;

R² is O;

R³ is H, Ci^alkyl, halogen, haloCi^alkyl, or C[_4alkoxy;

n and m are 1 ;

is a double bond when it is attached to R², and a single bond wîthin the ring;

or phannaceutically acceptable salts, biologîcally active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof

In one embodiment, the présent invention relates to compounds of formula (II), wherein V is C or S;

ZisC or N;

WisOorS;

R^la is H, Cj^alkyl, or haloCi^alkyl;

R^,b is H, C]-4aIkyl, halogen, or haloCi^alkyl;

R^k is H, C|.₄alkyl, halogen, or haloCi^alkyl when V is C; or R^k is absent when V is S;

R² is O;

R³ is H, C|.4alkyl, halogen, haloCi^alkyl, or Ci^alkoxy;

n and m are 2;

’ is a double bond when it is attached to R², and a single bond within the ring;

or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relates to compounds of formula (II), wherein

V is C or S;

ZisCorN;

W is O or S;

R^Ia is H, Ci^alkyl, or haloCualkyl;

R^lb is H, Ci^alkyl, halogen, or haloC].4alkyl;

R^lc is H, Ci^alkyl, halogen, or haloCi^alkyl when V is C; or R^lc is absent when V is S;

R² is O;

R³ is H, Cj^alkyl, halogen, haloCj.4alkyl, or Ci^alkoxy;

n is 1;

ni is 2;

is a double bond when it is attached to R , and a single bond within the ring;

or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relates to compounds of formula (II), wherein VisC;

Z is C or N;

Wis O;

R^ia is H, Cj.₆alkyl, or haIoCi.₆alkyl;

R^lb is H, Cj.6alkyl, halogen, or haloCi-ealkyl;

R^k is H, Ci^alkyl, halogen, or haloCi^alkyl;

R² is H or O;

R³ is H, Ci.₆alkyl, halogen, or haloCi^alkyl;

n and m are independently 1 or 2;

is a single - or double-bond;

or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relates to compounds of fonnula (II), wherein V is C;

ZisC or N;

Wis O;

R^la is H, C1.4alk.yl, or haloCj.4alkyl;

R^,b is H, Cualkyl, halogen, or haloCMalkyl;

R^lc is H, C;_4alkyl, halogen, or haloCi^alkyl;

R² is H or O;

R³ is H, CMalkyl, halogen, or haloCMalkyl;

n and m are independently 1 or 2;

is a single - or double-bond;

or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relates to compounds of formula (II), wherein VisC;

Z is C or N;

W is O or S;

R^la is H, CMalkyl, or haloC|.4alkyl;

R^,b is H, CMalkyl, halogen, or haloCMalkyl;

R^lc is H, CMalkyl, halogen, or haloCMalkyl;

R² is O;

R³ is H, CMalkyl, halogen, haloCj.₄alkyl, or CMalkoxy;

n and m are 1 ;

is a double bond when it is attached to R², and a single bond within the ring;

or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relates to compounds of formula (II), wherein Vis C;

Z is C or N;

W is O or S;

R^,a is H, CMalkyl, or haloCi.₄alkyl;

R^lb is H, Cj^alkyl, halogen, or haloCMalkyl;

R^lc is H, Ci.₄alkyi, halogen, or haloCMalkyl;

R² is O;

R³ is H, CMalkyl, halogen, haloC|.₄alkyl, or CMalkoxy;

n and m are 2;

is a double bond when it is attached to R², and a single bond within the ring;

or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relaies to compounds of formula (II), wherein

Vis C;

Z is C or N;

W is O or S;

R^1£l îs H, C].4alkyl, or haloCMalkyl;

R^lb is H, CMalkyl, halogen, or haloCMalkyl;

R^,€ is H, C].₄alkyl, halogen, or haloCi.₄alkyl

R² is O;

R³ is H, C|.₄alkyl, halogen, haloCi.₄alkyl, or Ci-₄alkoxy;

n is 1;

m is 2;

is a double bond when it is attached to R , and a single bond within the ring;

or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In one embodiment, the présent invention relates to compounds of formula (I) or formula (II) selected from the group of:

6'-Fluoro-N-[(2-methyl-177-indol-5-yl)methyl]-4'-oxo-3',4'-dihydrospiro[azetidine-3,2'[l]benzopyran]-l-carboxamide;

6-chloro-N-[(l -methyl-1 Z7-indol-5-yl)methyl]-4-oxo-3,4-dihydrospiro[ 1 -benzopyran-2,4'piperidine]-! ’-carboxamide;

6’-chloro-A^L[(l-methyl-lH-mdol-5-yl)methyl]-4’-oxo-3',4'-dihydiOspiro[azetidine-3,2'[ 1 ] benzopyran]-1 -carboxamide;

7'-fluoro-Λ^Γ-[(l-methyl-177-indol-5-yl)methyl]-4'-oxo-3’,4'-dihydrospiro[azetidine-3,2^,[ 1 Jbenzopyran]-1 -carboxamide;

Λ7-[( 1 -methyl-1 /f-indol-5-yl)methylJ-4'-oxo-3',4'-dihydrospiro[azetidine-3,2'-[ 1 ]benzopyran]-1 carboxamide;

6-chloro-AH(l-methyl-lf/-indol-5-yl)methyl]-3,4-dÎhydrospiro[l-benzopyran-2,4'-piperidÎne]1 '-carboxamide;

À^S-chloro-l-methyl-lH-indol-S-yllmethylj-ô'-fluoroM'-oxo-S'A'-dihydrospiiOfazetidine-j^'[ 1 Jbenzopyran] -1 -carboxamide;

6'-chloro-A-[( l/f-indol-5-yl)methyl]-4'-oxo-3',4'-dihydrospiro[azetidine-3,2'-[ 1 jbenzopyran] -1 carboxamide;

6'-fluoro-A^r-[(l-methyl-lF/-indol-5-yl)methyl]-3',4'-dihydiOSpiro[azetidine-3,2^,-[l]benzopyran]1-carboxamide;

6'-fiuoro-7V-[(l-methyl-l/7-mdol-5-yl)methyl]spiro[azetidine-3,2’-chromene]-l-carboxamide;

A4(l-methyl-l//-mdol-5-yl)methyi]-3',4'-dihydrospiro[azetidine-3,2’-[l]benzopyran]-lcarboxamide;

6'-chloro-Aⁱ'-[(2-methyl-17/-mdol-5-yl)methyl]-4'-oxo-3',4'-dihydrospiro[azetidine-3_J2’[ 1 ]benzopyran]-1 -carboxamide;

6',8'-difluoro-A^r-[(2-methyl-l//-indoI-5-yl)methyl]-4'-oxo-3',4'-dihydrospiro[azetidine-3,2'[ 1 jbenzopyran]-1 -carboxamide;

7'-chloro-Λ^/-[(2-chloro-lZ7-indol-5-yl)methyl]-4^,-oxo-3',4'-dihydrospiro[azetidine-3,2^,[ 1 Jbenzopyran] -1 -carboxamide;

7'-chloro-A^r-[(2-methyl-l//-indol-5-yl)methyl]-4'-oxo-3’₎4'-dihydrospiro[azetidine-3,2'[ 1 ]benzopyran] -1 -carboxamide;

7^,-fluoro-V-[(2-methyl-17/-indol-5-yl)inethyl]-4'-oxo-3',4'-dihydrospiro[azetidine-3,2’[ 1 ] benzopyran] -1-carboxami de;

A^r-[(2-methyl-177-indol-5-yl)methyl]-4'-oxo-6'-(trifluoromethyl)-3^,,4'-dihydrospiro[azetidine3,2'- [ 1 Jbenzopyran]-1 -carboxamide;

7V-[(l-methyl-l/-7-indol-5-yl)methyl]-4'-oxo-7'-(trifluoromethyl)-3',4'-dihydrospiro[azetidine-

3,2 '-[ 1 ]benzopyran]-l -carboxamide;

V-[(2-methyl-l/7-indoI-5-yl)methyl]-4'-oxo-7'-(trifluoromethyl)-3',4'-dihydrospiro[azetidine-

3,2 '-[l ]benzopyran]-l-carboxamide;

6^,,8'-dichloro-A^z-[(2-methyl-lZ7-indol-5-yl)methyl]-4'-oxo-3',4'-dîhydrospiro[azetidine-3,2’[ 1 ]benzopyran]-1 -carboxamide;

7'-fluoro-4'-oxo-M{[2-(Îrifluoromethyl)-177-indol-5-yl]methyl}-3',4'-dihydrospiro[azetidine-3,2'[ 1 ]benzopyran] -1 -carboxamide;

7V-{[2-(difluoromethyl)-l/7-indol-5-yl]methyl}-7'-fluoro-4'-oxo-3’,4'-dihydrospiro[azetidine-3,2’[I]benzopyran]-1 -carboxamide;

or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

In a further aspect, the présent invention provides a compound of formula (I) or formula (II), as defined above for use in the treatment or prévention of a disease associated with a7 nicotinic acétylcholine receptor activity.

In a further aspect, the présent invention provides the use of a compound of formula (I) or formula (II), as defined above, for the manufacture of a médicament for the treatment or prévention of a disease associated with a7 nicotinic acétylcholine receptor activity.

In a further aspect, the présent invention provides a method for the treatment or prévention of a disease associated with «7 nicotinic acétylcholine receptor activity comprising administering to a mammal in need of such treatment or prévention an effective amount of at least one compound of formula (I) or formula (II), as defined above.

In one embodiment, the disease associated with «7 nicotinic acétylcholine receptor activity is selected from the group of psychotic disorders, including, but not limited to, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder or psychotic disorder not otherwise specified; cognitive impainnent, including, but not limited to, cognitive impainnent as a resuit of stroke, Alzheimer's disease, Huntington's disease, Pick disease, HIV associated dementia, frontotemporal dementia, Lewy body dementia, vascular dementia, cerebrovascular disease or other dementia States and dementia associated to other degenerative disorders, including. but not limited to, amyotrophie latéral sclerosis, other acute or sub-acute conditions that may cause cognitive décliné, including, but not limited to, delirium, traumatic brain injury, senile dementia, mild cognitive impairment, Down’s syndrome, dépréssion and cognitive déficit related to other diseases, and dyskinetic disorders including, but not limited to, Parkinson's disease, neuroleptic-induced parkinsonism, or tardive dyskinesias, dépréssion and mood disorders, including, but not limited to, dépressive disorders and épisodes, bipolar disorders, cyclothymie disorder, and bipolar disorder not otherwise specifîed, other mood disorders, substance-induced mood disorder and mood disorder not otherwise specifîed; anxiety disorders, panic disorder and panic attacks, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder, phobias, and anxiety disorder not otherwise specifîed; substance related disorders, including, but not limited to, substance use or substance-induced disorders, including, but not limited to, alcohol-, nicotine-, amphétamine-, phencyclidîne-, opioid-, cannabis-, cocaïne-, caffeine-, hallucinogen-, inhalant-, sédative-, hypnotic-, anxiolytic-, polysubstance- or other substance-related disorders; sleep disorders, including, but not limited to, narcolepsy, dyssomnias, primary hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder and dyssomnia not otherwise specifîed; parasomnias, sleep terror disorder, sleepwalking disorder and parasomnia not otherwise specifîed; sleep disorders related to another mental disorder; sleep disorder due to a general medical condition and substance-induced sleep disorder; metabolic and eating disorders, including, but not limited to, anorexia nervosa, bulimia nervosa, obesity, compulsive eating disorder, binge eating disorder and eating disorder not otherwise specifîed; diabètes mellitus, ulcerative colitîs, Crohn’s disease, irritable bowel syndrome; autism spectrum disorders, including, but not limited to, autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specifîed; attention déficit hyperactivity disorder, disruptive behaviour disorders, oppositional défiant disorder and disruptive behaviour disorder not otherwise specifîed; and tic disorders, including, but not limited to, Tourette's disorder; personality disorders; sexual dysfunctions such as sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorder, sexual dysfunction not otherwise specifîed, paraphilias, gender identity disorders, infertiüty, premenstrual syndrome and sexual disorders not otherwise specifîed; disorders of the respiratory System like cough, asthma, chronic obstructive pulmonary disease, lung inflammation, disorders of the cardîovascular System such as cardiac failure, heart arrhythmia, hypertension;

inflammation, inflammatory and neuropathie pain, rheumatoid arthritîs, osteoarthritis, allergy, sarcoidosis, psoriasis, ataxia, dystonia, systemic lupus erythematosus, mania, restless legs syndrome, progressive supranuclear palsy, epilepsy, myoclonus, migraine, amnesia, chronic fatigue syndrome, cataplexy, brain ischemîa, multiple sclerosis, encephalomyelîtis, jetlag, cérébral amyloid angiopathy, and sepsis.

In one embodiment, the disease associated with a7 nicotinic acétylcholine receptor activity is selected from the group of cognitive impairment, schizophrenia, and autism.

The invention, further relates to combination thérapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another therapeutic agent or agents, for the treatment of one or more of the conditions previously indicated. Such therapeutic agents may be selected from: acetylcholinesterase inhibitors, NMDA receptor agonists or antagonists, antî-amyloîd antibodies including anti-amyloid humanized monoclonal antibodies, beta- or gamma-secretase inhibitors or modulators, tau phosphorylation inhibitors, ApoE4 conformation modulators, p25/CDK5 inhibitors, NK1/NK3 receptor antagonists, COX-2 inhibitors, LRRK2 inhibitors, HMG-CoA reductase inhibitors, NSAIDs, vitamin E, glycine transport inhibitors, glycine site antagonists, LXR β agonists, androgen receptor modulators, blockers of Αβ oligomer formation, NR2B antagonists, anti-inflainmatory compounds, PPAR gamma agonists, CB-1 receptor antagonists or inverse agonists, CB-2 agonists, VR-1 antagonists, bradykinin B1 receptor antagonists, sodium channel blockers and antagonists, NOS inhibitors, antibiotics, growth hormone secretagogues, potassium channel openers, AMP A agonists or AMP A modulators, GSK3 inhibitors, neuronal nicotinic agonists, MARK ligands, M| or M₄ mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, mGiuR5 antagonists, alpha-adrenerg agonists, ADAM-10 ligands, sédatives, hypnotics, anxiolytics, antipsychotics, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, orexin antagonists and agonists, prokineticin agonists and antagonists, T-type calcium channel antagonists, triazolopyridines benzodiazépines, barbiturates, 5-HTi_A antagonists, 5-HT2 antagonists, 5-HT₄ agonists, 5-HT₆ antagonists, histamine H3 receptor antagonists and inverse agonists, PDE₄ inhibitors, PDE9 inhibitors, PDEw inhibitors. HDAC inhibitors, KCNQ antagonists, GABA_a inverse agonists, GABA signallîng enhancers, GABA agonists, GABA_a receptor alpha5 subunit NAMs or PAMs, antipsychotics, MAO-B inhibitors, dopamine transport inhibitors, noradrenalîne transport inhibitors, D2 agonists and partial agonists, anticholinergics, COMT inhibîtors, A2a adenosine receptor antagonists, cholinergic agonists, neuroleptic agents, loxapine, sulpiride and rispéridone, levodopa, calcium channel blockers, MMP inhibîtors, thrombolytîc agents, opioid analgésies, pramipexole, ropinîrole, neutrophil inhibitory factor, SSRIs or SSNRIs, tricyclic antidepressant drugs, norepinephrine modulators, lithium, valproate, 5 gabapentin, pregabalin, rizatriptan, zolmitriptan, naratriptan, and sumatrîptan.

In one embodiment, the therapeutic agents are selected from the goup of acetylcholinesterase inhibîtors, NMDA receptor antagonists, beta- secretase inhibîtors, antipsychotics, GABAa receptor alpha5 subunit NAMs or PAMs, histamine H3 receptor antagonists, 5ΉΤΰ receptor antagonists, Ml or M4 mAChR agonists or PAMs, mGluR2 10 antagonists or NAMs or PAMs, and levodopa.

In a further aspect the présent invention provides a process for the manufacture of the compounds of formula (II) according to the following reaction route:

Compounds in accordance with the présent invention were synthesized in line with the synthetic routes and schemes described below.

Throughout the spécification, general formulae are designated by Roman mimerais (I), (II), (III) etc.

Scheme 1

(IX) (Vlîl)

Scheme 2

(X)

Scheme 1

Reactîng an acetophenone dérivative of formula (III)

(III)

- wherein the meaning of R³ is described above for compound of formula (II) — with a nitrogencontaining cyclic alîphatic ketone dérivative of formula (IV)

(IV)

- wherein the meaning of n and m is described above for compound of formula (II) - either in two separated steps via formula (VII)

(VII)

- wherein the meaning of n and m is described above for compound of formula (II) - or directly in one step to provide the spirochromanone compound of formula (V)

- wherein the meaning of R³, n and m is as described above for formula (II) - which is then reacted with

a.) hydrogen chioride to provide the spirochromanone sait derîvative of formula (VI) o

h ^NCe o-À J ' 'm

HCl (VI)

- wherein the meaning of R³, n and m is as described above for fonnula (II) - or

b.) complex hydrides to provide the appropriate spiiOchromanol derîvative of fonnula (VIII)

(VIII)

- wherein the meaning of R³, n and m is as described above for formula (II) - then compound of fonnula (VIII) is reduced with triethylphosphine to provide the 3,4-dihydrospirochromene/spirochromene derîvative of formula (IX)

(IX)

- wherein the meaning of R³, n and m is as described above for fonnula (II).

Scheme 2

Then, the so obtained dérivative of formula (IX) or formula (VI) is reacted with the heterocyclic amine dérivatives of formula (X)

(X)

- wherein the meaning of R^la, R^lb, R^lc, V and Z is as described above for formula (II) providing the carbamide/thiocarbamide dérivative of formula (II)

- wherein the meaning of R^la, R^lb, R^lc, R², R³, V, Z, n, m and W are as described above for fonnula (II).

The synthesis of protected spirochroinan-4-one of formula (V) can be carried out by different routes:

a) The condensation of acetophenone dérivatives of formula (III) with nitrogencontaining cyclic aliphatic ketone dérivatives of fonnula (IV) is preferably carried out in a suitable solvent, e.g., methanol, preferably in the presence of pyrrolidine. The reaction is preferably carried out at the boiling point of the solvent. The necessary reaction time îs 15-20 hours. The reactions are followed by thin layer chromatography. The reaction mixture is quenched b y évaporation of the solvent. The product of formula (V) îs isolated by extraction with a suitable organic solvent, or by filtration, after removing the organic solvent, or by column chromatography.

b) The réaction of an acetophenone dérivative of formula (III) with nitrogen-containing cyclîc alîphatic ketone dérivatives of formula (IV) is preferably carried oui in a suitable solvent, e.g., tetrahydrofuran, preferably in the presence of a strong base, e.g., lithium diisopropyl amide. The reaction is carried out at a température in the range of -20 °C to room température. The necessary reaction time is 3-4 hours. The progress of the reaction is followed by thin layer chromatography. The reaction mixture is quenched by addition of saturated ammonium chloride solution. The product of formula (VII) is îsolated by extraction with a suitable organic solvent and by filtration, after removîng the organic solvent.

The dehydrocyclization of the dérivatives of formula (VII) is preferably carried out in suitable solvents, in the presence of, e.g., trifluoroacetic anhydride and DBU ( 1 ,S-diazabicyclo[5.4.0]undec-7-ene).

Unless otherwise specified, solvents, température and other reaction conditions may be readily selected by one of ordinary skîll in the art. Spécifie procedures are provided in the Examples section. Réactions may be further processed in a conventional manner, e.g., by eliminating the solvent from the residue and further purifying according to méthodologies generally known in the art, including, but not limited to, crystallization, extraction, trituration and chromatography.

The desired deprotected spirochroman-4-on salts of formula (VI) can be obtained by using different méthodologies from the prior art. It is preferably carried out in EtOAc with hydrochloric acid in the range of 0 °C to room température. The necessary reaction time is 2-3 hours. The progress of the réaction is followed by thin layer chromatography, and the product is isolated by filtration.

Réduction of the dérivatives of formula (V) (carbonyl group of spiroketone) is preferably carried out in suitable solvents e.g., éthanol with NaBFU. The progress of the reaction is followed by TLC. The crude spirochroman-4-ol is isolated by eliminating the solvent, then the residue is partitioned between DCM and water, and evaporating the organic phase to obtain the title compound, which is used without purification in the fortheoming step.

The reductive deoxygenation of spîrochroman-4-ol dérivatives of formula (VIII) is accomplished by the well-known reducing method called “ionic hydrogénation”: by the treatment of the hydroxy dérivatives with the Et₃SiH/CF₃COOH System at 90 °C for

6-18 hours. The progress of the réaction is followed by thin layer chromatography. The reaction mixture is evaporated, the residue is treated with saturated NaHCOa solution, and the product of formula (IX) is isolated by extraction with a suitable organic solvent.

Most of the primary amine dérivatives of formula (X) are either commercially available, or can be synthesized from commercially available startîng materials and reagents by one skilled in the art using different methods described in the prior art. The synthesis of some new amine dérivatives of formula (X) are described in the Examples section.

The compounds of formula (II) above can be prepared by the activation of the appropriate primary amine compounds of formula (X) using standard procedures and reagents, e.g., CDI (Ι,Γ-carbonyldiimidazole), chloroformâtes or Ι,Γ-thiocarbonyldiimidazole in suitable solvents, e.g., DCM under argon athmosphere followed by the addition of the reactant (formula (VI) or formula (IX)). The reaction is carried out at a température in the range of 0 °C to room température. The necessary reaction time is

15-20 hours. The progress of the reactions is followed by thin layer chromatography. The workup of the reaction mixture can be carried out by different methods, usually it is quenched by the addition of water. The product is isolated by extraction with a suitable organic solvent, and purified by crystallîzation or column chromatography.

The présent disclosure includes within its scope ail the possible isotopically labelled foims of the compounds.

The compounds of the présent invention can be administered by oral, parentéral (e.g., intramuscular, intraperitoneal, intravenous, intraarticular, intrathecal, intraperitoneal, direct intraventricular, intracerebroventicular, intramedullary injection, intracistemal injection or infusion, subcutaneous injection or implant), ophtalmie, nasal, vaginal, rectal, sublingual and topical routes of administration and may be formulated, alone or together, in suitable dosage unît formulations comprising pharmaceutically acceptable excipients suitable for each route of administration.

Alternative! y, one may administer the compounds in a local rather than systemic manner, for ex ample, via injection of the compound directly in the rénal or cardîac area, often in a modified release formulation. Furthermore, one may administer the drug in a targeted drug delivery System, for example, in a liposome coated with a tissue-specific antibody. The liposomes are taken up selectively by the targeted organ.

The pharmaceutical compositions of the présent invention usually contain 0.01 to 500 mg of the active ingrédient in a single dosage unit. However, it is possible that the amount of the active ingrédient in some compositions exceeds the upper or lower limits defined above.

The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

This dosage level and regimen can be adjusted to provide the optimal therapeutic response. It will be understood, however, that the spécifie dose level and frequency of dosage for any particular patient may be varied and will dépend upon a variety of factors including the activity of the spécifie compound employed, the metaboiic stability and length of action of that compound, the âge, body weight, general health, sex, diet, mode and time of administration, rate of excrétion, drug combination, the severity of the particular condition and the host undergoing therapy.

As a further aspect of the invention, there is provided the pharmaceutical manufacture of médicaments containing the compounds of formula (1) or formula (II) or pharmaceutically acceptable salts, biologically active métabolites, pro-drugs, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

The pharmaceutical compositions of the présent invention may be formulated as different pharmaceutical dosage fonns, including, but not limited to, solid oral dosage forms like tablets (e.g., buccal, sublingual, effervescents, chewable, orodispersible, freeze dried), capsules, lozenges, pastilles, pills, orodispersible films, granules, powders; liquid oral dosage forms, including, but not limited to, solutions, émulsions, suspensions, syrups, élixirs, oral drops; parentéral dosage forms, including, but not limited to, intravenous injections, intramuscular injections, subeutaneous injections; other dosage forms, including, but not limited to, eye drops, semi-solid eye préparations, nasal drops or sprays, transdermal dosage forms, suppositories, rectal capsules, rectal solutions, émulsions and suspensions, etc.

The pharmaceutical compositions of the présent invention can be manufactured in any conventional manner, e.g., by mixing, dissolving, emulsifying, suspending, entrapping, freeze drying, extruding, laminating, film-casting, granulating, grinding, encapsulating, dragee-making or tabletting processes.

Pharmaceuticai compositions for use in accordance with the présent invention thus can be formulated in any conventional manner using one or more physiologically acceptable excipients. Any of the well-known techniques and excipients may be used as suîtable and as understood in the art.

Suitable excipients for the préparation of the dosage forms may be selected from the following categories, including, but not limited to, tablet and capsule fillers, tablet and capsule binders, release modifying agents, disintegrants, glidants, lubricants, sweetening agents, tastemaskîng agents, flavorîng agents, coating agents, surfactants, antioxidants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, microencapsulating agents, ointment bases, pénétration enhancers, solubilizing agents, solvents, suppository bases, and suspending agents.

In one embodiment, the invention relates to the use of spécifie excipients which are capable of improving the solubility, dissolution, pénétration, absorption and/or bioavailability of the active ingredient(s), including, but not limited to, hydrophilic polymers, bot melt extrusion excipients, surfactants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, superdisintegrants, microencapsulating agents, pénétration enhancers, solubilizing agents, co-solvents, and suspending agents.

The above described ingrédients and different routes of manufacture are merely représentative. Other materials as well as processing techniques and the like well known in the art can also be used.

EXAMPLES

The invention is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Ex amples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make varions changes and modifications to adapt the invention to varions uses and conditions. As a resuit, the invention is not limited by the illustrative examples set forth herein below, but rather defmed by the claims appended hereto.

In general, the compounds of formula (I) and formula (II) can be prepared in accordance with the general knowledge of one skilled in the art and/or using methods set forth in the Example and/or Intermediate sections that follow. Solvents, températures, pressures, and other reaction conditions can readily be selected by one of ordinary skill in the art. Starting materials are commercially available and/or readily prepared by one skilled in the art.

The présent invention will be now illustrated by the followîng not limiting examples.

In the followîng examples “room température” dénotés a température in the range from 20 °C to 25 °C.

The abbrevîations used in the spécifie examples hâve the followîng meanings:

AcOH	acetic acid
abs.	absolute
aq.	aqueous
atm	atmosphère
BOC2O	di-tert-butyl dicarbonate
BH3.THF	borane tetrahydrofuran complex solution
CDI	1,1 ’-carbonyldiimidazole
DBU	l,8-diazabicyclo[5.4.0]undec-7-ene
DCE	1,2-dichloroethane
DCM	dichloromethane
DIPEA	N,N-diisopropylethylamine
DMF	N,N’-dimethylformamide
DMSO	dimethyl sulfoxide
EtOAc	ethylacetate
Et3SiH	triethylsilane
ESI	electronspray ionizatîon
HEPES	(4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid)
HPLC	high-performance liquid chromatography

LC-MS	liquid chromatography coupled with mass spectroscopy
MeOH	methanol
w-BuLi	n-butyllithium solution
NMP	N -methyl -2 -pyrrolidone
PCC	pyridinium chlorochromate
sat.	saturated
TEA	triethyl amine
TFA	trifluoroacetic acid
THF	tetrahydrofuran
TLC	thin layer chromatography

ïntermediate 1 ο

HCl

6’-Chloro-3^,,4^,-dihydrospiro[azetidine-3,2’-[l]benzopyran]-4’-one hydrochioride

Cl

Ha

Step I: rert-Butyl ô'-chlorçM-ûxo-S’d'-dihydrospirorazetidine-SJ'-ITlbenzopvranl-lcarboxylate

A solution of 3,42 g (20 mmol) toï-butyl 3-oxoazetidine-l-carboxylate, 3.41g (20 mmol) of l-(5-chloro-2-hydroxyphenyl)ethan-l-one and 1.42 g (1.67 mL, 20 mmol) of pyrrolîdine in methanol (20 mL) was refluxed for 20 hours. The reaction mixture was evaporated in vacuo, the brown residue was dissolved in dichloromethane (120 mL), and partitioned with 1 N HCl, then the organic layer was washed with water (2x50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude produet was chromatographed on sîlica gel eluting with DCM: MeOH to yield 3.02 g (46 %) of the title 5 compound.

Step 2: ô'-Chloro-S'A-dihydrospirolazetidine-S^'-lllbenzopyranl^’-one hydrochloride

To the solution of 3.0 g (8.9 mmol) of ieri-butyl 6'-οΗ1ογο-4'-οχο-3',4’dihydrospiro[azetidine-3,2'-[l]benzopyran]-l-carboxylate (from the previous step) in EtOAc (30 mL), 20 % hydrochloric acid in EtOAc (30 mL) was added at 0 °C in 10 minutes. After the 10 addition, the mixture was allowed to warm to room température and stîrred at this température for 2 hours. Then the reaction mixture was concentrated to approximately 15 mL in vacuo, and was diluted with diethyl ether (20 mL). The precipitated light brown crystal was filtered off, washed with diethyl ether and dried to yield 2.0 g (90 %) of the title compound.

Compounds of Table 1 were prepared from the appropriate acetophenone and 15 nîtrogen-containing cyclic aliphatic ketone in the presence of pyrrolidine according to the method described for Intermediate 1.

6	Ο
HCl		Ï?\^-F J
7		0
	ΗΝ. . HCl·^	J	J
		0
8	ηΌ		y	0 \
	HCl
		O
9	I1			?
		0
10	H-NC		y	^F
	HCl	F
		0
11	HN HCl·^	J	J
		0
12	h-nQ		Fs J	F XF
	HCl
		O
13	h-*C/ HCJ		F	F Λ-f
		0
14			y
	HCl
		0
15	hn^.	/ □'''Ss	y	-Cl
	HCl	Cl
		0
16	HN. HÇR'	JoA		T
		0
17				?
	HCl			Cl

Intermediate 18 ο

HCI

3’,4'-Dihydrospiro[azetidine-3,2’-pyrano[3,2-b]pyridm]-4'-one hydrochloride

Step I : Zbrf-butyl 4'-oxo-3’,4’-dihvdrospiro[azetidine-3,2^,-pvrano[3,2-b1pyridine]-l-carboxvlate

A solution of l-(3-hydroxypyridin-2-yl) ethanone (160 mg; 1.17 mmol), N-ter/butoxycarbonyl-3-azetidinon (205 mg, 1.2 mmol) and pyrrolidinc (0.1 mL, 1.2 mmol) in toluene (4 mL) was stirred at reflux for 28 hours. Upon completion of the reaction (monitored by TLC), the mixture was concentrated under vacuum, and the obtained dark brown residue was partitioned between EtOAc (30 mL) and 1 N hydrochloric acid (10 mL). The layers were separated. The aqueous layer was extracted with EtOAc (2x 20 mL). The combined organic ex tracts were successively washed with water (2x 20 mL), saturated NaHCOj solution (20 mL) and brine (20 mL). The residue, obtained after évaporation of the solvent was purified by flash silica gel column chromatography using 30 % n-hexane in EtOAc as eluent, to yield 100 mg (29 %) of the title compound.

Step 2

To the solution of 113 mg (0.389 mmol) of tert-butyl 4^,-oxo-3',4^,-dihydrospiro[azetidine3,2'-pyrano[3,2-b]pyridine]-l-carboxylate (from the previous step) in EtOAc (2 mL), 20 % hydrochloric acid in EtOAc (2 mL) was added at 0 °C in 10 minutes. After addition, the mixture was allowed to wann to room température, and stirred at this température for 2 hours. Then the reaction mixture was concentrated to approximately 15 mL in vacuo, and was diluted with diethyl ether (3 mL). The precipitated light brown crystal was filtered off, washed with diethyl ether, and dried to yield 80 mg (91 %) of the title compound.

Intermediate 19

T'-Fluoro-SM’-dihydrospiroIazetidine-S^'-mbenzopyranJ-d'-one hydrochloride

Step 1 : teH-Butyl 3-f2-(4-fluoro-2-hydroxvphenvl)-2-oxoethyl1-3-hydroxvazetidme-lcarboxylate

To a solution of diisopropylamine (17.7 mL, 125 mmol) in THF (50 mL) cooled to -15 °C, 2.5 M π-BuLi in hexane (50 mL) was added dropwise under nitrogen atmosphère, and the mixture was stirred at -15 °C for 30 minutes. Th en a solution of 8.96 g (58.14 mmol) of 4’fluoro- 2’-hydroxyacetophenone in THF (50 mL) was added dropwise, and the mixture was stirred at - 15 °C for 1 hour, and then treated with a solution of teri-butyl 3-oxoazetidine-lcarboxylate (12.9 g, 75.6 mmol) in THF (50 mL) dropwise for 20 minutes, allowed to warm to room température and stirred at this température for 1 hour. The reaction mixture was quenched by addition of saturated NH₄C1 solution (100 mL). The reaction mixture was extracted with ethyl acetate (2x90 mL), the combined organic layer was washed with brine (120 mL), dried over anhydrous NaiSCU, filtered and concentrated in vacuo. The residue was triturated with diisopropyl ether (50 mL), the precipitated white crystals were filtered off, washed with diisopropyl ether, and dried to yield 16.79 g (89 %) of the title compound.

Step 2: Zm-Butyl 7'-fluoro-4'-oxo-3^t,4’-dihvdrospiroiazetidine-3.2^l-[l1benzopyran1-l-carboxylate

To a solution of 14.2 g (43.6 mmol) of ieri-butyl 3-(2-(4-11 uoro-2-hydroxyphenyl)-2oxoethyl]-3-hydroxyazetidine-l-carboxylate in dry pyridine (35 mL), 14.48 g (9.58 mL, 68.12 mmol) of trifuoroacetic anhydride was added dropwise under nitrogen atmosphère at - 10 °C. After addition, the mixture was allowed to warm to room température and stirred at this température for 1 to 2 hours. Then the reaction mixture was diluted with éthanol (80 mL), and treated with 49 g (48 mL) of l,8-diazabicyclo[5.4.0]undec-7-ene. During the addition, the mixture’s température was raised to 50 °C and kept at this température for 1 hour. The mixture was concentrated in vacuo, and the residue was dissolved in EtOAc (160 mL), and washed with water (2x80 mL), 1 N HCl (80 mL), 1 M NaHCCh solution (80 mL) and brine (40 mL). The organic layer was dried over anhydrous Na2SO₄, filtered and concentrated in vacuo. The residue was trîturated with a mixture of diethyl ether and n-hexane (1:1, 40 mL), the precipitated white crystals were filtered off, washed with diethyl ether and dried to yield 4.9 g (36 %) of the title compound.

The evaporated mother liquor was chromatographed on silica gel eluting with CH2CI2 to yield an additional 2.05 g (15 %) ofthe title compound.

Step 3: 7'-Fluoro-3',4'-dihydrosniro[azetidine-3,2'-[l1benzopvran1-4'-one hydrochloride

To the solution of 6.05 g (19.7 mmol) of reri-butyl 7'-fluoro-4’-oxo-3',4'dihydrospiro[azetidine-3,2’-[l]benzopyran]-l-carboxylate (from the previous step) in EtOAc (60 mL), 20 % HCl in EtOAc (60 mL) was added at 0 °C for 10 minutes. After addition, the mixture was allowed to warm to room température, and stirred at this température for 2 hours. Then the reaction mixture’s volume was reduced to 15-20 mL in vacuo, and was diluted with diethyl ether (30 mL). The precipitated white crystals were filtered off, washed with diethyl ether, and dried to yield 4.53 g (94 %) of the title compound.

Intermediate 20

S'^-Dihydrospirolazetidine-Sjl'-Illbenzopyran

Step 1. fôrt-Butyl 4'-oxo-3’,4'-dilÎydrospiro[azetidÎne-3,2'-[llbenzopyran1-l-carboxylate

This intermediate was prepared from the appropriate 2-hydroxy-acetophenone and tertbutyl 3-oxoazetidine-I-carboxylate with pyrrolîdine according to the method described for Intermediate 1.

Step 2. teri-But vl 4’-hydroxy-3'.4'-dihvdrospiro[azetidine-3,2-11 Ibenzop yran]-1 -carboxylate

To the solution of 400 mg (1.38 mmol) of iert-butyl 4'-oxo-3’,4’-dihydrospiro[azetidiue3,2'-[l]benzopyran]-l -carboxylate in MeOH (5 mL), NaBH₄ (52.3 mg, 1.38 mmol) was added portionwise under ice-water cooling. After addition, the mixture was allowed to warm to room température, and stirred at this température for 4 hours. Then the reaction mixture was concentrated in vacuo, and the residue was dîssolved in EtOAc (15 mL), washed with water and brine. The organic layer was dried over anhydrous Na2SO₄, filtered and concentrated in vacuo, to yield 320 mg (79 %) of the title compound. The obtained crude spirochroman-4-ol is used in the next step without any purification.

Step 3. 3',4'-Dihvdrospiro[azetidine-3,2'-[ 1 Ibenzopyran

To the solution of tert-butyl 4'-hydroxy-3^,,4'-dihydrospiro[azetidine-3,2'-[l]benzopyran]I-carboxylate (292 mg, 1 mmol) in trifluoroacetic acid (4 mL), EtjSiH (450 mg, 4 mmol) was added and the mixture was stirred at 90 °C for 16 hours. Then the reaction mixture was 5 concentrated in vacuo, and the residue was dissolved in water, and the pH was adjusted to 9 by the addition of 1.5 N NaOH solution. The mixture was extracted with CH2CI2 (3x), the combined extracts were dried over anhydrous Na₂SC>4, filtered and concentrated in vacuo, to yield 80 mg (50 %) of the title compound. The obtained crude 3,4-dihydrospirochromene dérivative was used in the next step without any purification.

Compounds of Table 2 were prepared from the appropriate spirochroman-4-on, spirochroman-4-ol, 3,4-dihydrospirochromene reaction sequence by the methods described for Intermediate 20.

Table 2

Intermediate	Structure
21		Γ ο	^.^ci
22	HN^
23	HN		w
24	X		JT
25		OoX	v/

Intennediate 24 and 25 originated from the reductive deoxygenation reaction of tert-butyl 15 6'-fluoro-4'-hydroxy-3',4'-dihydrospiro[azetidine-3,2'-[l]benzopyran]-l-carboxylate were used in the next step without séparation.

Intermediate 26

(lJ7-indol-5-yI)methanamine

The compound is commercîally avaîlable from Sigma Aldrich (catalog no.: 655864).

Intermediate 27

/ ( 1 -Methyl-1 Æ-indol-5-yl) meth ana min e

The compound is commercîally avaîlable from Maybridge (catalog no.: CC41413DA).

Intermediate 28

(2-MethyI-I/Z-indol·5~yI)methan amine

The compound is commercîally avaîlable from Enamine (catalog no.: EN300-209649).

Intermediate 29

(2-Chloro-lEf-indoI-5-yl)methanamine

Step 1: 3,3-Dibromo-2-oxo-2.3-dihydro-lZ7-indoIe-5-carbonitrile

To a stirred solution of lf/-indole-5-carbonitrile (7.10 g; 50 mmol, Combi-Blocks) in tert-butanol (250 mL), bromine (42.5 g; 13.5 mL, 275 mmol) was added dropwise (20 min) at 25 °C and stirred for 1.5 hours. Aller completion, the reaction mixture was concentrated under vacuum. This residue was diluted with EtOAc (400 mL), and water (75 mL) was added. The organic layer was washed with water (2x100 mL), brine (100 mL), drîed over anhydrous NazSOi, filtered and concentrated under reduced pressure. The crude residue was stirred with diisopropyl ether (100 mL) for 30 minutes. The precipitated crystals were filtered off, washed with diisopropyl ether, and dried to yield 12.89 g (81 %) of the title compound as a reddish brown solid.

Step 2: 2-Oxo-2.3-dihydro-l/7-indole-5-carbonitrile

To a suspension of 3,3-dibromo-2-oxo-2,3-dihydro-lZf- indole-5-carbonitrile (12.89 g; 40.8 mmol) in AcOH (270 mL), Zn powder (16.3 g; 250 mmol) was added portionwise (ca. 2 g each). The température of the mixture was not allowed to increase above 35 °C and stirred for 2 hours at 30 °C. Aller completion, the reaction mixture was concentrated under vacuum. This residue was suspended in EtOAc (300 mL), filtered off, the solid was stirred with EtOAc (150 mL) again, then filtered off. The combined organic layer was concentrated in vacuo. The residue was stirred with 1 N HCl solution (100 mL) for 1 hour, filtered off, washed with water (2x5 mL), and dried to yield 3.86 g (60 %) of the title compound.

Step 3: 2-Chloro-l/7-indole-5-carbonitnle

To a stirred suspension of 2-oxoindoline-5-carbonitrile (5.8 g; 36.9 mmol) in DCE (23 ml), POClj (11.5 g, 6.95 mL; 74.79 mmol) was added at 0 °C. The reaction mixture was refluxed for 30 minutes at 90 °C. After cooling the reaction, imidazole (2.75 g, 44.55 mmol) was added and further heated at 90 °C for 2 hours. After completion, the reaction mixture was concentrated and the residue was dissloved in EtOAc (110 mL) and washed with saturated NaHCO₃ solution (30 mL), brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel eluting with THF: n-Hexane 9:1 to yield 4.58 g (70 %) of the title compound as a yellow solid.

Step 4: (2-Chloro-17/-indol-5-vÎ)methanamine

To a stirred solution of 2-chloiO-l//-indole-5-carbonitrile (4.48 g; 25.3 mmol) in dry TFIF (23 mL), LiAlH₄ (1 M in THF; 45 mL; 45 mol) was added at 0 °C under nitrogen atmosphère. The reaction mixture was refluxed at 65 °C for 2 hours. TLC showed formation of the product. The reaction mixture was quenched with EtOAc (20 mL) at 0 °C and sat. aq. Na₂SO₄ solution (15 mL) was added dropwise. The reaction mixure was filtered through celite pad and thoroughly washed with ethyl acetate (100 mL). The filtrate was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by crystallization from EtOAc (50 mL) to give 3.9 g (85 %) of the title compound as an off white solid.

Intermediate 30

(3-Chloro-l-methyl-lÆ-indol-5-yl)methanamine

Step 1 : tërt-Butyl TV-Kl -methyl- lZf-indol-5-yl)methyl1carbamate

To a stirred solution of (i-methyl-I/7-indol-5-yl)methanamine (640 mg; 3.995 inmol) and DIPEA (1.03g; 1.39 mL, 7.98 mmoi) in CH2CI2 (40 mL), a solution of di-fôrf-butyl dicarbonate (BocjO) (1.74 g; 7.97 mmol) in CH2CI2 (10 mL) was added at 0 °C under nitrogen atmosphère. 5 The reaction mixture was stirred at room température overnight. TLC showed formation of the product. The reaction mixture was diluted with CH2CI2 (20 mL) and washed with water (50 mL). The organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to give 786 mg (76 %) of the title compound as a white solid.

Step 2: tert-Butyl V-r(3-chloro-l-methyl-l/7-indol-5-yl)methyl]carbamate

To a stirred solution of toV-butyl A-[(l-methyl-l/7-indol-5-yl)methyl]carbamate (160 mg; 0.615 mmol) in CH2CI2 (4 mL), A-chlorosuccinimide (82 mg; 0.61 mmol) was added ai 0 °C under argon atmosphère. The reaction mixture was stirred at room température for 3.5 hours. TLC showed formation of the product. The reaction mixture was diluted with CH2CI2 (20 15 mL), and washed with water (20 mL). The organic phase was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to give 145 mg (80 %) of the title compound as an oil.

Step 3: (3-Chloro-l-methvl-177-indol-5-yl)methanamine

To the solution of im-butyl A^L[(3-chioro-l-methyl-lH-indol-5-yl)methyl]carbamate (72 20 mg, 0.244 mmol) in dry CH₂Cl₂ (3 mL), CF3COOH (300 mg; 0.2 mL, 3 mmol) was added at 0-2 °C under argon atmosphère. The reaction mixture was stirred at room température for 3 hours. After the completion of the reaction (monîtored by TLC) the mixture was concentrated in vacuo. The residue was dissolved in CH₂C1₂ (20 mL), the pFI was adjusted to 10 by the addition of 1 N NaOH solution (under cooling), the aqueous phase was extracted with CH2CI2 (3x15 mL), the 25 organic phase was dried over anhydrous Na₂SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica, eluted by 10 % MeOH in CH2CI2, to give 49 mg of the tille compound as a yellow solid.

Intermediate 31

(3-FIuoro-l-methyl-l/Z-indol-5-yl)methanamine

Step 1: 1 -Methvl-1 #-indole-5-carbonitrile

To a solution of l/f-indole-5-carbonitrile (2.09 g, 14.7 mmol) in DMF (16 mL), NaH (840 mg, 60 percent in oil, 21 mmol) was added with vigorous stirring at 0 °C under argon atmosphère. The solution was stirred for 30 minutes, then iodomethane (9.12 g, 4 mL, 63 mmol) was added. The reaction mixture was stirred at room température for 4 hours. The reaction was quenched with water (50 mL), and extracted with EtOAc (3x120 mL). The organic layers were combined, washed with water (2x50 mL), dried over anhydrous Na2SO4, fîltered and concentrated in vacuo, and dry toiuene was evaporated from the residue to give 2.3 g of the title compound as an off white solid, used in the next step without any purification.

Step 2: l-Methyl-2.3-dioxo-2.3-dihvdro-lZ/-indole-5-carbonitrile

To the solution of l-methyl-l/f-indole-5-carbonitrile (1.38 g, 8.83 mmol) in acetonitrile (40 mL), PCC (7.6 g, 35.2 mmol) was added and the mixture was refluxed for 7 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was concentrated in vacuo, and the residue was partitioned between H2O and EtOAc. The insoluble part was fîltered off, the organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was evaporated to dryness. The crude residue was purifïed by flash chromatography on silica eluted by CH2CI2 to give 760 mg of the title compound as an orange solid.

Step 3: 3,3-Difluoro-l-methvl-2-oxo-2,3-dihvdro-lÆ-indole-5-carbonitrilc

To the solution of bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor, 50 % in toluène, 5 mL, 10 mmol) l-methyl-2,3-dioxo-2,3-dihydro-177-indole-5-carbonitrile (502 mg, 2.7 mmol) was added under argon atmosphère, then 25 pL abs. EtOH was added, and the mixture was heated at 90 °C for 1 hour.

The reaction was quenched by MeOH (1 mL) and diluted with CH2CI2 (100 mL), then the mixture was poured onto cold saturated Na2SO4 solution, and the product was extracted with dichloromethane. The extract was washed with brîne, dried over anhydrous Na2SO₄, and the solvent was evaporated to dryness. The crude residue was purifïed by flash chromatography on silica, eluted by a gradient of 0-20 % EtOAc/hexane to give 322 mg of the title compound as a yellow solid.

Step 4; QrFluoro^T^nethyLl^mdçT^yTlmethanamine

To the solution of 3,3-Difluoro-1 -methyI-2-oxo-2,3-dihydro- 13/-indole-5-carbomtrile (510 mg, 2.45 mmol) in dry THF (10 mL), BH3.THF (i M in THF) (7.5 mL , 7.5 mmol) was added at 0-2 °C under argon atmosphère. The reaction mixture was stirred at room température for 3 hours. After completîon of the reaction (monitored by TLC), MeOH (10 mL) was added under cooling, and the mixture was concentrated in vacuo, The residue was dissolved in EtOAc (50 mL), washed with saturated NaHCOj solution (25 mL), then with brine (25 mL), dried over anhydrous Na₂SO4, filtered and concentrated in vacuo. The crude product was purifïed by by flash chromatography on silica, eluted by 10 % MeOH in CH2CI2 to give 70 mg of the title compound as light yellow solid.

ïntermediate 32

step 3

N H,

Compound 5’broino-l//-pyrrolo[2,3-ô]pyridine is commercially available from Combi Blocks (catalog no.: IN-0206) and the desired azaindole-amine is prepared in a sequence of steps illustrated above.

Step 1: 177-P yrrolo [2,3 -6]pyridLne-5 - carbonitrile

The intermediate is prepared as described in EP 1782811 Al (EISAI R&D MAN CO LTD).

Step 2: l-Methyl-l/7-pvrroIo[2,3-&lpyridine-5-carbonitrile

The intermediate is prepared as described in WO 2009/155017 A2 (MERCK & CO INC).

Step 3 : {l-Methyl-l/7-pyrrolo[2,3-&]pyridin-5-yl}methanamine

The intermediate îs prepared as described in WO 2012/042915 Al (RAQUALIA PHARMA INC).

Intermediate 33

{3-Chloro-l-methyl-lf7-pyrrolo[2,3-6]pyndin-5-yl}methanamine

Compound 5-bromo-l/7-pyrrolo[2,3-6]pyridine is commercially available from Combi Blocks (catalog no.: IN-0206), and the desired 3-chloroazaindole dérivative is prepared in a sequenee of steps illustrated above.

Step 1 : l/7-PvrroloF2,3-blDvridine-5-carbonitrile

The intermediate is prepared as described in EP 1782811 Al (EISAI R&D MAN CO LTD)

Step 2: 1-Methyl-l//-pyrrolol2.3-ô1pyridine-5-carbonitrile

The intermediate is prepared as described in WO 2009/155017 A2 (MERCK & CO INC)

Step 3: 3-Chloro-1 -methyl- i7-Z-pyrroIor2.3-ô1pvridine-5-carbonitrite

To a solution of 1 -methyl- lH-pyrrolo[2,3-b]pyridine-5-carbonitrile (600 mg, 3.69 mmol) in DMF (14 mL), TV-chlorosuccinimide (502 mg, 3.76 mmol) was added with vigorous stirring at room température under argon atmosphère. The solution was stirred at room température ovemîght. After completion of the reaction (monitored by TLC), the mixture was concentrated in vacuo (dry toluene was evaporated from the residue several times). The residue was dissolved in a mixture of dîethyl ether - EtOAc (1:1, 40 mL), and washed with water (3x15 mL). The organic layer was dried over anhydrous NaiSO4, filtered and concentrated in vacuo to give 670 mg of the title compound, used in the next step without any purification.

Step 4: (3-Chloro-l-inethyl-lZZ-pvrrolo[2.3-à1pyridin-5-vBmethanamine

The intermediate is prepared as described in WO 2012/042915 Al (RAQUALIA PHARMA INC).

Intermediate 34

{3-Bromo-l-methyl-l£r-pyrrolo[2,3-b]pyridiii-5-yI}methanamine

Step 1-2:

The intermediates were prepared in a sequence of steps described for Intermediate 33, by the saine methods as described in EP 1782811 Al (EISAI R&D MAN CO LTD) and WO 2009/155017 A2 (MERCK & CO INC).

Step 3: 3-Bromo-l-methyl-l/f-pyrrolo[2.3-b1pyridine-5-carboiiitrile

To a solution of l-methyl-177-pyrrolo[2,3-6]pyridine-5-carbonitrile (358 mg, 2.28 mmol) in CH2CI2 (6.5 mL), Wbromosuccinimide (446 mg, 2.51 mmol) was added with vigorous stirring at room température under argon atmosphère. The solution was stirred ai room température ovemight. After completion of the reaction (monitored by TLC) the mixture was diluted with CH2CI2 (25 mL) and washed with water (3x20 mL). The organic layer was dried over anhydrous Na2$O4, filtered and concentrated in vacuo to give 670 mg of the title compound, used in the next step without any purification.

Step 4: [3-Bromo-l-methvl-177-pyrrolor2,3-Î>1pyridin-5-ynmethanarnine

The intermediate is prepared as described in WO 2012/042915 Al (RAQUALIA PHARMA INC).

Intermediate 35

{l,2-Dimethyl-17f-pyrrolo[2,3-ô]pyridîn-5-yl}methanamine

Step 1: 6-Amino-5-iodopyridine-3-carbonitrile

To a solution of 2-amino-5-cyanopyridine (500 mg, 4.2 mmol) in DMF (5 mL), 10 trifluoroacetic acid (574 mg, 386 uL, 1.2 mol équivalents) was added. At room température Niodosuccinimide (1.04 g, 4.62 mmol, 1.1 mol équivalents) was added and the reaction mixture was heated at 50 °C for 3 hours. Complété conversion was mdicated by TLC. After cooling the reaction mixture to room températures the product was precipitated by adding the reaction mixture to water. After neutralization with NajS^O^ and 1 N NaOH the title compound (660 mg) 15 was collected by filtration as a brown solid. It was used in the next step without any purification.

Step 2: 6-Amino-5-(prop-l-vn-l-yl)pvridine-3-carbonitrile

To the degassed mixture of 6-amino-5-(prop-l-yn-i-yl)pyridine-3-carbonitriIe (329 mg, 1.34 mmol), bis'(triphenylphosphine)dichloropalladîum(0) (95 mg, 0.134 mmol), copper (I) iodide (128 mg, 0.671 mmol) and triethylamîne (976 mg, 1.34 mL, 9.64 mmol) in abs. THF (18 mL) a propyn solution (3-4 % in THF; 13.2 mL) was added via septum at 0-5 °C. The mixture was stirred for 30 minutes at 0-5 °C, then for a further 18 hours at room température. The reaction was quenched by the addition of NH4CI solution. The solid was removed by filtration and the cake was washed with CH2CI2. The combined organic layer was dried with anhydrous Na2SO₄, filtered and concentrated in vacuo. The crude product was purified b y flash chromatography on silica, eluted by 40 % EtOAc in cyclohexane to give 150 mg of the title compound as a yeliow soiid (71 %).

Step 3: 2-Methvi-l//-pyrToIor2.3-&lpyridine-5-carbonitrile

To a solution of 6-amino-5-(prop-l-yn-l-yl)pyridine-3-carbonitrile (300 mg, 1.91 mmol) in DMF (5 mL), potassium ZerZ-butoxide (428 mg, 3.82 mmol, 2 mol équivalents) was added. The reaction mixture was heated at 90 °C for 5.5 hours. Complété conversion was indicated by TLC. After cooling the reaction mixture to room température the mixture was poured onto water and extracted with CH2CI2. The combined organic layer was dried with anhydrous Na2SO₄, filtered and concentrated in vacuo to give 279 mg (93 %) of the title compound as a yeliow solid. It was used in the next step without any purification.

Step 4: L2-Dimethvl-l/7-pvrroÎo[2.3-Î>1pvridine-5-carbonitrile

To the solution of 2-methyl-1/7-pyrrolo[2,3-7']pyridine-5-carbonitnle (279 mg, 1.78 mmol) in DMF (7.5 mL), sodium hydrîde (60 % in minerai oil) (92 mg, 2.31 mmol, 1.3 mol équivalents) was added at 0 °C. The reaction mixture was stîrred at thîs température for 30 minutes, then iodomethane (380 mg, 167 uL) in DMF (1.5 mL) was added dropwise. The mixture was stirred at room température ovemight. Complété conversion was indicated by TLC. The mixtute was poured onto water and extracted with CFLCE (3x20 mL). The combined organic layer was dried over anhydrous Na2SO₄, filtered and concentrated in vacuo, to give 298 mg (98 %) of the title compound as a yeliow solid. It was used in the next step without any purification.

Step 5: 1 -( 1.2-Dimethyl- lÆ-pynolo[2,3-à1pvridin-5-vl)methanarnine

To a solution of l,2-dimethyl-177-pyrrolo[2,3-ô]pyridine-5-carbonitrile (297 mg, 1.73 mmol) in a mixture of MeOH (100 mL) and 25 % ammonia solution in water (25 mL), Raney-Ni (200 mg) was added and the mixture was stirred ai 1 atm of H₃ at room température for 16 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure to give 226 mg (74 %) of the title compound as a yeliow solid.

Intermediate 36

[2-(TrifluoromethyI)-l/f-indol-5-yl]methanamme

The intermediate is prepared as described in WO 2009/127678 Al (GLAXO GROUP LTD).

Intermediate 37

[2-(difluoromethyl)-1 H-indol-5-yI] me t ha namin e

The compound ethyl 5-bromo-lH-indole-2-carboxylate is commercially available from Aldrich (catalog no.: 724718) and the desîred 2-difluoromethylindole-amine is prepared in a sequence of steps illustrated below.

Step 1 : (5-Bromo-1 H-indol^-yliméthanol

To the solution 5-bromo-lÆ-indole-2-carboxylate (2.08 g, 7.77 mmol) in dry THF (30 mL), L1AIH4 solution (1 M in THF) (7.0 mL , 7.0 mmol) was added at 0-2 °C under argon atmosphère, then the reaction mixture was stirred at room température for 4 hours. After the completion of the reaction (monitored by TLC), NH4CI solution (20 mL) was added under cooling, and the mixture was extracted with EtOAc (2x50 mL). The combined organic layer was washed with brine, dried over anhydrous Na₂SO4, filtered and concentrated in vacuo, to give 1.73 g of the crude compound as a light brown solid. It was used in the next step without any purification.

Step 2: 5-Bromo-1 /Z-indole-2-carbaldehyde

To the solution (5-bromo-l//-indol-2-yl)methanol (1.0 g, 4,42 mmol) in dry acetonitrile (20 mL), MnO₂ (1.92 g , 22.1 mmol) was added, and the reaction mixture was stirred at room température ovemight. After the completion of the reaction (monitored by TLC), the suspension was filtered off, and washed with EtOAc (5x15 mL). The combined organic layer was washed with brine, dried over anhydrous Na₂SÛ4, filtered and concentrated in vacuo. The crude brown solid was crystallized from acetone to give 656 mg (66 % of the title compound.

Step 3: /m-Buty! 5-bromo-2-formyl-1//-indole-1 -carboxylate

To a stirred solution of 5-bromo-l/Z-indole-2-carbaldehyde (518 mg; 2.2 mmol) and 4(dimethylamino)pyridine (27 mg; 0.22 mmol) in acetonitrile (20 mL), Boc₂0 (965 mg; 4.4 mmol) was added at 0 °C under nitrogen atmosphère. The reaction mixture was stirred ai room température ovemight. TLC showed formation of the product. The reaction mixture was evaporated to dryness, and the crude product was purified by flash chromatography to give 664 mg (93 %) of the title compound as a yellow solid.

Step 4: ten-Butyl 5-bromo-2-(difluoromethvl)-lff-indole-I-carboxylate

To the solution of rert-butyl 5-bromo-2-formyl-l/7-indole-l-carboxylate (657 mg, 2.027 mmol) in dry dichloromethane (20 mL), Deoxo-Fluor® (bis(2methoxyethyl)(trifluorosulphanyl) amine) solution 50 % in THF (6.28 g, 14.2 mmol) was added, and the reaction mixture was stirred at room température ovemight. After the completion of the reaction (monitored by TLC), the mixture was diluted with CH₂C1₂₎ washed with saturated NaHCO₃ solution and brine. The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to give 642 mg (91 %) of the title compound as a yellow oil.

Step 5: 2-(Difluoromethyi)-177-indole-5-carbonitrile

To the solution of teri-butyl 5-bromo-2-(difluoromethyl)-l/f-indole-l-carboxylate (639 mg, 1.848 mmol) in NMP (15 mL), zinc cyanide (326 mg, 2.77 mmol) and tetrakis(triphenylphosphine)palladium(0) (214 mg, 0.184 mmol) was added, and the reaction mixture was stirred at 70 °C for 3 hours, then at 90 °C for 3 hours under argon atmosphère. The progress of the reaction was followed by TLC. The mixture was poured onto water (100 mL), and extracted with EtOAc (3x30 mL). The combined organic phase was washed with water (4x50 mL) and brine. The organic phase was dried over anhydrous Na2SO₄, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to give 241 mg (68 %) of the title compound as a white soiid.

Step 6: r2-(Difluoromethyl)-lZ7-indol-5-yl]methanamine

To a solution of 2-(difluoromethyl)-17/-indole-5-carbonitrile (211 mg, 1.08 mmol) in a mixture of MeOH (24 mL) and 25 % ammonia solution in water (6 mL), Raney-Ni (100 mg) was added and the mixture was stirred at 1 atm of H2 at room température for 3 hours. The reaction mixture was filtered through a celite pad, then washed with MeOH (3x10 mL), and then the filtrate was concentrated under reduced pressure to give 218 mg (approximately 100 %) of the title compound as a light brown solid.

Intermediate 38 A -^x ^x Ν-ΧΖ l-(l,3-benzothiazol-6-yl)methanamine

The intermediate is prepared as described in WO 2011/079804 Al (HUTCHISON MEDIPHARMA LTD) or US 20100298314 Al (SCHERING CORP).

Intermediate 39

I l-(l-Methyl-l,2,3,4-tetrahydroquinolin-6-yl)methanamine

The compound is commercially availabié from Enamine (catalog no.: EN3 00-57206).

Example 1

6'-Fluoro-7V-[(2-methyl-l//-indol-5-yl)methyl]-4'-oxo-3',4'-dihydrospiro[azetidine-3,2'[ 1] benzopyran]-l -carboxamide

To the mixture of 800 mg (5.0 mmol) of 2(methyl-lH-indol-5-yl)methanamine (Intermediate 26) and 1.295 g (1.75 mL, 10 mmol) of DIPEA in 120 mL of dichloromethane (CH2CI2), 4-nitrophenyl chlorofonnate (1020 mg, 5.06 mmol) was added at 0 °C under argon atmosphère. The lîght yellow suspension was stirred for 1 hour under this condition. After the activation period, the mixture of 6'-fluoro-3',4'dihydrospiro[azetidine-3,2'-[l]benzopyran]-4'-one hydrochloride (1.22 g, 5 mmol, Intermediate 6) and 1.75 mL DIPEA (7.75 mmol) in 30 mL CH2CI2 was added. After addition, the mixture was allowed to warm to room température and was stirred at this température for 22 hours. After the complet!on of the réaction (monitored by TLC), the mixture was washed with water (2x40 mL), then with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo, to give 1.8 g of the crude compound. The residue was chromatographed on silica gel, eluting with a mixture of CH2CI2 and MeOH (10:1) to yield 1.02 g (50%) of the title compound. LC-MS (ESI) m/z [M+H] ⁺ = 394.1

The following examples in Table 3 were synthesized according to the procedure described for Example 1.

Table 3

Example	Structure	Intermediates	LC-MS (ESI) [M+H]+
2	0	Int. 28 and Int. 2	438.2
N-Xz X/' !
0
3	O o >o o=( b	Int. 28 and Int. 1	410.1
4	0 Λ^ΧΖΧ 1 Z^ I] nh n ir X/ /	'xJO 0	Int. 27 and Int. 5	404.2
5	θ Z T /=O t—Z □η 0[ ° O	Int. 27 and Int. 3	424.1
5-Aa	O Z—' o=/ T Z O ,Z^	Int. 27 and Int. 3	424.1
5-B3	\ T X νη νά ,χ N'XX L A /A / θ4 ci	Int. 27 and Int. 3	424.1
6	0 /r il NH \ V°x^x^F XJj 0	Int. 27 and Int. 19	394.1

7	0 // f |f NH \V°Xx-'ta ' Χθ 0	Int. 27 and Int. 4	376.2
8	0 NH N N-^ta/ \ta /	ο	Int. 27 and Int. 16	422.2
9	0 tay γ nh n ' H	CCJ 0	Int. 26 and Int. 16	408.2
10	O /tata |-p NH ^N N \ta / L	XI	Int. 27 and Int. 21	424.2
11	O Λ 1 Λ ιΡ^ΝΗ^Ν^ /	'XQ	Int. 27 and Int. 23	390.2
12	0 || ΝΗ Ν Η	Ρ ο	Int. 26 and Int. 21	410.2
13	0 _ π Λ ÇU c	ta	Int. 26 and Int. 23	376.2
14	0 Ζ^ρ il nh ν /	XI 0	Int. 27 and Int. 7	422.2

15	Cl C Ζ/ρ Ij NH N Ν-χζ ^χ/ !	χθχί'^χ. Xïï/XXXF 0	Int. 30 and Int.7	456.2
16	σ O Z Z O X	^Ο^ζχ XI Χ^Χχ/Χρ	Int. 27 and Int. 22	408.2
17	0 z/^r il NH ΝΆ o /nAJ ^çcx 0	Int. 27 and Int. 6	394.1
18	Cl θ Cl· Il NH : 'z°x/\ / XQf 0	Int. 30 and Int. 6	428.1
19	0 |P NH N X νΆ>/ \/ H	^θ^^χ XI 0	Int. 26 and Int. 2	424.1
20	Cl θ X^zx 1 x /X]Z Tp NH N N-^XX XX /	xJkJ 0	Int. 30 and Int. 7	456.2
21	^z'^Z Z n	1 ςσ° 0	Int. 27 and Int. 9	434.2
22	pi 0 Lxx Kx NH N Ν-·χ/ X/ !	χθχ^Χχθ xXJ 0	Int. 30 and Int. 9	468.2

23	Ci θ ΌΧ	Int. 30 and Int. 24	414.1
24	\ ο ο °=ζ ζ ¥ύ X	Int. 27 and Int. 8	406.2
25	Cl 0 πτχχ ! γ^ο- 0	Int. 30 and Int. 8	440.1
26	I ζ X \7 ζ τν \=ο ο=/ ο □	Int. 26 and Int. 1	396.1
27	ο AAÂ	Int. 27 and Int. 24	380.2
28	0 ΧΧ [ ΝΗ WVs /nJU XXf	Int. 27 and Int. 25	378,2
29	ο CiXf|XNH χνχ^\ T il Η 11^'^F 0	Int. 29 and Int. 6	414.1
30	ο I Z XS \7 ^Ζ. Ο=Ζ Ο Ο\	Int. 29 and Int. 8	426.1

31	ο //γ γ ΝΗ ΝΆ ο ν-ΧΧ Xf Xj] Η 'ν 0	Int. 28 and Int. 4	376.2
32	0 αχΧΥΝΗ χχν>%> χ τ y Τ ο	Int. 29 and Int. 4	396.1
33	ο I □ χχΧΧΝΗ ΝΧ-%^ νΧΧ χ^ χ χ	Int. 29 and Int. 24	400.1
34	0 ΧΧΧ ΝΗ ' Υ°Ύ\ \ΧΧ X X χ 'Τ':''τ 0	Int. 32 and Int. 6	395.2
35	0 z nAJ ΌΟ	Int. 27 and Int. 20	362.2
36	I .<ΥμιΤ ΝΗ ΝΆ ο νΑΧ Xf χχ Η Χ^α 0	Int. 28 and Int. 1	410.1
37	Cl θ tO-YÇQ 0	Int. 30 and Int. 4	410.1
38	χ î ΧΧΧΗ Ν.'Λ,Ο^ν /^ χχχ 0	Int. 31 and Int. 6	412.2

39	Cl θ z/f Y NH Vv°\YX X1 0	Int. 33 and Int. 6	429.1
40	O Zr Y NH ιΥγθγγ^ n-XX χΐ 0	Int. 32 and Int. 1	411.1
41	0 Υ^ΎΥ 0	Int. 28 and Int. 10	412.2
42	^z 7 \7 Z >° O=Z O Q	Int. 27 and Int. 17	410.1
43	Q O O >=o Z O X Z Z ü	Int. 29 and Int. 17	430.1
44	O \=Q Z X) X Z Z Ô	Int. 29 and Int. 10	432.2
45	0 ^3 o-Xfir^ ν-ΎΥ X L Γ H Y^' 0	Int. 29 and Int. 19	414.1
46	0 NH N^Vo^^CI MT X J H T< 0	Int. 28 and Int. 17	410.2

47	0 JL î Λτ iT NH xx 0	Int. 32 and Int. 10	413.2
48	O \=o °< Z o X	Int.27 and Int. 10	421.1
49	0 NH ...F N 'V ΧΓ X Y 0	Int. 28 and Int. 19	394.2
50	0 il NH Z Y^^CF, 0	Int. 27 and Int. 12	444.1
51	IZ Y \7 Z T. 2=0 _-Z O=Z O O	Int. 28 and Int. 12	444.2
52	0 ifYli NH vX0^^^3 /^ ^çu 0	Int. 27 and Int. 13	444.1
53	Z T. _z o=Ç o O	Int. 34 and Int. 6	473.1
54	O O O /—O o=/ T Z yX ώΥ.Χ--	Int. 34 and Int. 1	489.1

55	l ω ο 2=ο ζ X/ X χ	Int. 28 and Int. 13	444.1
56	0 c /χχχ™ Ν\Χ°^> ν^υυ X X X Η Χ^^' 0	Int. 29 and Int. 1	430.1
57	0 Η Cl XjXJ X ΤΊ Η Y^ci 0	Int. 28 and Int. 15	444.1
58	0 Ρ^νύ, 0	Int. 32 and Int. 15	445.1
59	Λ δ ο δ=ο °χ ζ	Int. 32 and Int. 13	445.2
60	0 Λ π f'N'f 'Ν Η^Ν Λ ο γχν ο	Int. 27 and Int. 14	404.2
61	0 F cYt Υ^ΥΥ0-^^/ 3 \-χγ χ γ j Η χχ^χ^ ο	Int. 36 and Int. 19	448.2
62	σι Q Ο Ο 2=0 °χ ζ 1 ο	Int. 29 and Int. 13	464.1

63	T y, Z T, X° o=/ O	Int. 26 and Int. 19	380.1
64	O NH N H	F Y 1 O	Int. 28 and Int. 11	440.2
65	rt Q O )=o Z^ °< Z Çy (x z^	Int. 35 and Int. 13	459.1
66h	Z Z \7 V» ^-Z o=ç O Q	Int. 28 and Int. 1	426.2
67	O >° O=Z O	Int. 32 and Int. 19	395.1
68	0 . X CI-YnpH H	F χΟ^^Λχ Y 1 'rT^^F O	Int. 29 and Int. 11	460.2
69	0 I HF2C^yYY^H Τ>0^^ Y 1 ï H ΐ'·'*^ 0	Int. 37 and Int. 19	430.3
70	0 ^XT^q-vy 0	Int. 38 and Int. 19	398.2

71e	0 ' °u F	Int. 39 and Int. 19	410.2
72d	Cf θ O	Example 31	410.1
73	0 iï nh n > /N n O	Int. 32 and Int. 16	423.2
74e	0 O	Int. 27 and Int. 18	377.2

^aThe racemic form of the title compound Example 5 was prepared from Intermediate 26 and Intermediate 3 according to the methods described for Example 1. The two (A and B) enantiomers were separated using chiral préparative HP LC. Their absolute configuration is not determîned.

^b,c,d,eSyntheses see below, respectively.

Example 66^b s

O

6'-Chloro-N-[(2-InethyI-lH-indol·5-yl)methyl]-4’-oxo-3’,4’-dihydrospiro[azetidine-3,2’[l]benzopyran]-l'Carbothioamide

To a solution of 80.1 mg (0.5 mmol) of 2-(methyl-lH-indol-5-yl)methanamine (Intermediate 28) in 2 mL of DMF, 1,1 ’-thiocarbonyl-diimidazole (98 mg, 0.55 mmol) was added at room température under argon atmosphère. The brownish-yellow solution was stirred for 1 hour under this condition. After the activation period, the mixture of 6'-chloro-3',4'dihydrospiro[azetidine~3,2’-[l]benzopyran]-4'-one hydrochloride (130 mg, 0.5 mmol, Intermediate 1) and 0.131 mL of DIPEA (0.75 mmol) in 2 mL DMF was added, and the mixture was stirred at this température for 20 hours. After the completion of the reaction (monitored by TLC), the mixture was poured onto water (8 mL) and extracted with EtOAc (2x15 mL). The organic layer was dried over anhydrous Na2SÛ4, filtered and concentrâted in vacuo. The residue was chromatographed on süica gel, eluting with a mixture of CH2O2 and MeOH (10:1) to yield 100 mg (47 %) of the title compound. LC-MS (ESI) m/z [M+H] ⁺= 426.2

7'-Fluoro-N-[(l-methyl-l,2,3,4-tetrahydroquinolin-6-yl)methyl]-4'-oxo-3^,,4'dihydrospiro[azetidine-3,2'-[l]bcnzopyran]-l-carboxamide

To the mixture of 88 mg (0.5 mmol) of l-(l-methyl-l,2,3,4-tetrahydroquinolin-6yl)methanamine (Intermediate 39) and 175 pL (1.0 mmol) of DIPEA in 20 mL of dichloromethane (CH2CI2), 4-nitrophenyl chloroformate (111 mg, 0.55 mmol) was added at 0 °C under argon atmosphère. The light yellow suspension was stirred for 1.5 hours under this condition. After the activation period, the mixture of 7'-fluoro-3',4’-dihydrospîro[azetidine-3,2'[l]benzopyran]-4'-one hydrochloride (122 mg, 0.5 mmol, Intermediate 19) and 131 pL DIPEA (0.75 mmol) in 5 mL CH2CI2 was added. After addition, the mixture was allowed to warm to room température, and stirred at this température for 24 hours. After the completion of the reaction (monitored by TLC), the mixture was washed with water (2x20 mL), then with brine. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give 300 mg of the crude compound. The residue was chromatographed on silica gel, eluting with a mixture of CH₂C1₂ and MeOH (99:1), to yield 30 mg (15%) of the title compound. LC-MS (ESI) m/z [M+H] ⁺ = 410.2

Example 72^d

N- [ (3-Chlor o-2-methyl-1 H-indol-5-yl) methyl] -4 ' -oxo-3 ' ,4 ’-dîhydrospir o[ azetidin e-3,2 [ 1 ] benzopyran ]-l-carboxamide

To a solution ofN-[(2-methyl-lH-indol-5-yl)methyl]-4'-oxo-3',4'-dihydrospiro[azetidine3,2'-[l]benzopyran]-l-carboxamide (Example 31) (100 mg, 0.266 mmol) in DCM (2 mL), Nchlorosuccinimîde (36 mg, 0.266 mmol) was added with vigorous stirring at room température under argon atmosphère. The solution was stirred at room température ovemight. After the complet!on of the reaction (monitored by TLC), the mixture was diluted with DCM (20 mL), and washed with water (3x15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography to give 35 mg of the title compound. LC-MS (ESI) m/z [M+HJ ⁺= 410.1

Example 74^e

N-[(l-methyl-lH-indoI-5-yl)methyl]-4'-oxo-3’,4'-dihydrospiro[azetidme-3,2'pyrano[3,2- b]pyridine]-l-carboxamide

To the mixture of 56 mg (0.35 mmol) of (1 -methyl-lH-indol-5-yl)methanamme (Intermediate 27) and 122 pL (0.7 mmol) of N,N- diisopropylethylamine (DIPEA) în 10 mL of dichloromethane (CH2CI2), 4-nitrophenyl chloroformate (71 mg, 0.35 mmol) was added at 0 °C under argon atmosphère. The light yeliow suspension was stirred for 1 hour under this condition. After the activation period, the mixture of 3',4'-dihydrospiro[azetidine-3,2'-pyrano[3,2b]pyridin]-4'-one hydrochloride (80 mg, 0.35 mmol, Intermediate 18) and 92 pL DIPEA (0.53 mmol) in 2 mL CH2CI2 was added. After addition, the mixture was allowcd to warm to room température, and stirred at this température for 24 hours. After the completion of the reaction (monitored by TLC), the mixture was washed with water (2x10 mL), then with brine. The organic layer was dried over anhydrous Na2SO₄, filtered and concentrated in vacuo, to give 60 mg of the crude compound. The residue was chromatographed on silica gel, eluting with a mixture of CH2CI2 and MeOH (99:1) to yield 7 mg (5 %) of the title compound. LC-MS (ESI) m/z [M+H] ⁺= 377.2

Préparation of pharmaceutical compositions

The following formulation examples illustrais représentative pharmaceutical compositions of this invention. The présent invention, however, is not limited to the following pharmaceutical compositions.

A) Solid oral dosage forms

L, Tablets

Active ingredient(s)	0.01-90%
Filler	1 - 99.9 %
Binder	0-20 %
Disintegrant	0-20 %
Lubricant	0-10%
Other spécifie excipient(s)	0-50 %

IL, Orodispersible films Active ingredient(s)	0.01-90%
Film forming agent	1 - 99.9 %
Plasticizer	0-40 %
Other spécifie excipient(s)	0-50 %

B) Liquid oral dosage forms

IIL, Oral suspensions

Active ingredient(s)	0.01 - 50 %
Liquid vehicle	10 — 99.9%
Wetting agent	0-50 %
Thickener	0-50 %
Buffering agent	quantum satîs
Osmotic agent	0 - 50 %
Preservatives	quantum satis
IV., Syrups
Active ingredient(s)	0.01 - 50 %
Solvent	10-99.9 %
Sugar component	1 - 20 %
Flavouring agents	0-10%
C) Parentéral dosage forms
V., Intravenous injections
Active îngredient(s)	0.01 - 50 %
Solvent	10-99.9%
Co-solvent	0 - 99.9 %
Osmotic agent	0-50 %
Buffering agent	quantum satis
D) Other dosage forms
VL, Suppositories
Active ingredient(s)	0.01-50%
Suppository base	1 - 99.9 %
Surface-active agents	0-20 %
Lubricants	0-20 %
Preservatives	quantum satis

VIL, Nasal drops or nasal sprays

Active ingredient(s)	0.01 -50%
Water	0 - 99.9 %
Solvent	0 - 99.9 %
Co-solvent	0 - 99.9 %
Osmotic agent	0-20 %
Viscosity enhancer	0-20 %
Buffering agent	quantum satis
Preservatives	quantum satis

BIOLOGICAL ACTIVITY

Human ct7 nicotinic acétylcholine receptor [Ca2+]i assay

Cells: Flp-In 293 cells stably expressing human «7 nAchR and human RIC-3 (et 7 cells, 15 generated in house, )

Materials: 96-well plates coated with PDL (Falcon), culture medium, assay bu fier, DMSO, FLIPR Calcium 5 kit (Molecular Devices), probenecid, agonist and PAM test compounds.

Culture medium: 20 - DMEM (Dulbecco’s Modified Eagle Medium, Gibco) - 10 % FBS (Fêtai Bovine Sérum, Gibco) - 1 % glutamine (Sigma G) — 50 pg/ml Hygromycin B - 800 pg/ml G418 25 - 1 % penicillin-streptomycin-antimycotic sol. (PSA, Sigma) L

Assay buffer: - 140 mM NaCl - 5 mM KC1 - 10 mM HEPES - 2 mM MgCl2 - 2 mM CaCh - 10 mM glucose - 2 mM probenecid, pH=7.4

2+

Brief description of the method (Ca fluorometiy) «7 cells cells stably expressing human al nAchR were cultured in the medium detailed above, and were split twice a week. For the fluorometric measurements of cytosolic Ca ion concentration ([Ca²'^h]i) cells were seeded in 96-well microplates at a density of 60000 cells/well and maintained ovemight in a tissue culture incubator at 37 °C under an atmosphère of 95 % air/5 % CO₂. The plating medium was identical with the culture medium. 50 μΐ of the growth medium was aspirated with a cell washer (BioTek EIx405UCVWS). Then 50 μΐ/well Calcium 5 kit diluted 2-foId in assay buffer was added manuaily using an 8-channeI pipette. After an incubation period (20 minutes, 37 °C) 50 μΙ/well assay buffer containing vehicle (DMSO, 4 % added) or reference «7 P AM s (4x of the final concentration) were added manuaily and the cells were incubated for an additional 10 minutes at 37 °C. Baseline and agonist-evoked [Ca²⁺],changes were monitored with FlexStation II (Molecular Devices, Sunnyvale, CA), a plate reader fluorometer with integrated 8-channel fluid addition capability. Fluorescence measurements were carried out at 37 °C. The dye was excited at

485 nm, émission was sampled at 525 nm at 1.4-s intervals. Baseline was recorded for 20 seconds followed by agonist stimulation. 50 μΐ 4x concentrated agonist solution was added to the cells using the pipettor of FlexStation II and fluorescence was monitored for an additional 40 seconds. Final DMSO concentration was 1 % for ail treatments. To achieve this, a sériés of DMSO stock solutions were prepared from ail test compounds. These stocks were stored under 0 °C and were further diluted in assay buffer to obtain the desired final concentration immediately before the measurement. Agonist and PAM concentration-response studies were conducted in the presence of saturating concentrations of PAMs (mostly PNU-120596, 5 μΜ) and agonists (mostly PNU-282987, 1 μΜ), respectively. Results were expressed as AF/F values using SoftMax Pro software (Molecular Devices), where F was the resting fluorescence preceding agonist application and AF was the increase in fluorescence at a given tîme (AF = maximum fluorescence intensity values after stimulation minus average fluorescence intensity values before stimulation). In ail experiments, ail treatments were measured in multiple wells in parallel, and the mean AF/F values were used for analysis.

Table 4 shows the P AM EC50 values in the [Ca²]j assay:

Table 4

Example	EC$o (nM)
1	120
3	120
5	210
5a	430
5b	400
6	190
7	230
10	100
21	280
25	230
26	390
37	130
38	220
39	730
41	60
43	360
50	150
52	130
53	850
58	470
59	500
65	750
69	120
71	2300

In vivo pharmacology (place récognition test)

Animais: Male NMRI mice (Toxicoop, Hungary)

Substances: Scopolamine was dissolved in saline and administered at 1 mg/kg dose î.p.

Test compounds were administered 30 minutes before the acquisition trial (Tl) and scopolamine after the acquisition trial at a volume of 0.1 ml/10 g.

Procedure; The task was carried out in a transparent plexiglass Y-maze (each arm has a length of 40 cm, an inner width of 11 cm and a height of 30 cm). Numerous visual eues were placed around the anns and were kept constant during the experiment. The test consisted of two trials (Tl and T2) separated b y an intertrial interval of 30 minutes. Mice were placed in the starting arm of the maze at the beginning of each trial. In Tl, one of the symmetric arms of the maze was closed (it will be novel in T2) and the animais were allowed to explore the maze for 5 minutes (acquisition phase). In T2, mice had free access to ail three arms for 2 minutes (retrieval phase). The time spent with exploration in the novel and familiar anns during T2 was measured.

Différences between the exploration times spent in the familiar vs. novel arms of the maze for each group were evaluated by MANOVA, followed by Duncan post hoc test.

Table 5 shows the reversai of the scopolamine-induced amnesia in the place récognition assay in mice:

Table 5

	Dose (î.p.)
1 mg/hg	3 mg/kg	10 mg/kg
Example 1	++	-	-
Example 6	+	++	+++
Example 7	I |· {'	+++	+++
Example 26	-	+	-
Example 41	H-	H-
Example 43	+	+++	+++
Example 52	-	-	+

Example 61

-

++

+++

⁺p<0.05; ⁺⁺p<0.01; ^pO.OOl

Significant différences (⁺p<0.05; ^<0.01; ^pO.OOl) were observed between the exploration times spent in the novel vs. familiar arms of the maze.

Claims (16)

1. [ 1 Jbenzopyran]-! -carboxamide;

   [ 1 ]benzopyran]-1 -carboxamide;

   [ 1 [benzopyran]-1 -carboxamide;

   [ 1 ]benzopyran]-l -carboxamide;

   [ 1 ]benzopyran]-1 -carboxamide;

   N-[( 1 -methyl -1 H-indol-5 -yl)m ethyl] -4'-oxo-3 ',4'-dihydrospiro [azeti di ne-3,2’-

   [ 1 ]benzopyran]-1 -carboxamide;

   1. A compound of formula (II),

   (II) wherein

   V is C or S;

   Z is C or N;

   W is O or S;

   R^lH is H, Ci-ealkyl, or haloCi^alkyl;

   R^Ib is H, Cpealkyl, halogen, or haloCj-ealkyl;

   R^lc is H, Ci-ealkyl. halogen, or haloCj-eaikyl when V is carbon; or R^lc is absent when V is sulphur;

   R² is H or O;

   R³ is H, Ci-ealkyl, halogen, haloCi-ealkyl, or Ci-ealkoxy;

   n and m are independently 1 or 2;

   is a single - or double-bond;

   or pharmaceutical ly acceptable salts, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.
2. 2. A compound according to claim 1, wherein

   Vis C;

   Z is C or N;

   WisO;

   R^la is H, Ci^alkyl, or haloCi.ôalkyl;

   R^)b is H, Ci^alkyl, halogen, or haloCi.₆alkyl;

   R^lc is H, Ci.₆alkyl_f halogen, or haloCj^alkyl;

   R² is H or O;

   R³ is H, Ci-6alkyl, halogen, or haloC]._âalkyl;

   n and ni are independently 1 or 2;

   is a single - or double-bond.
3. 3. A compound according to any one of daims 1 or 2, selected from the group of:
4. 4. A compound according to any one of daims 1 to 3 or of formula (I),

   (D wherein:

   A is a five or six membered heterocycle:

   B is a six membered carbocycle or heterocycle;

   X is C or N;

   Y is C or N;

   Z is C or N;

   W is 0 or S;

   R¹ îs H, Ci^alkyl, halogen or haloCi^alkyl;

   R² is II or O;

   R³ is H. Ci-galkyl, halogen, haloCi-6alkyl or Ci-6alkoxy;

   R⁴ is H or Ci^alkyl;

   R⁵ is H or Ci.₆alkyl;

   n and in are independently 1 or 2;

   is a single - or double-bond;

   or pharmaçéutically acceptable salts, racemates, enautiomers, diastereomers, solvatés and hydrates thereof for use in the treatment or prévention of a disease associated with a7 nicotinic acétylcholine receptor activity.
5. 5 - wherein the meaning of R^!a, R^lb _s R^1C,V, and Z is as described above for formula (II) - providing formula (II)

   - wherein the meaning of R^ia, R^Ib: R^lc, R², R³,V, Z, n} m, and W are as described above

   5. A compound for use according to daim 4, wherein

   A is five membered heterocycle, wherein the members ofthe ring aie selected from the group consisting of carbon, nitrogen, oxygen, and sulphur;

   B îs a six membered carbocycle or a heterocycle, wherein the members of the ring are selected from the group consisting of carbon, nitrogen, oxygen, and sulphur;

   Xis C;

   Vis C;

   Z/s C or N;

   W is O or S;

   R¹ is H, Ci^alkyl, halogen or halo Ci.₆alkyl;

   R² îs H or O;

   R³ is H, Ci.₆alkyl, halogen, haloC].6alkyl or Ci-ealkoxy;

   R⁴ is H;

   R⁵ is H;

   n and m are independently 1 or 2;

   is a single - or double-bond.
6. 6. A compound for use according to claim 5, wherein the disease is selected from the group of psychotic dîsorders, including, but not limited to, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder or psychotic disorder not otherwise specified, cognitive impairment, including, but not limited to, cognitive impairment as a result of stroke. Alzheimer's disease, Huntington's disease, Pick disease, HIV associated dementîa, frontotemporal dementia, Lewy body dementia, vascular dementia, cerebrovascular disease or other dementia States and dementia associated to other degenerative disorders, including, but not limited to, amyotrophie latéral sclerosis, other acute or sub-acute conditions that may cause cognitive décliné, including, but not limited to, delirium, traumatic braîn injury, senile dementia, mild cognitive impairment, Down’s syndrome, dépréssion and cognitive déficit related to other diseases, and dyskinetic disorders including, but not limited to, Parkinson's disease, neuroleptic-induced parkinsonism, or tardive dyskinesîas, dépréssion Z i and mood disorders, including, but not limited to, dépressive disorders and épisodes, bipolar disorders, cyclothymie disorder, and bipolar disorder not otherwise specified, other mood disorders, substance-induced mood disorder and mood disorder not otherwise specified, anxiety disorders, panic disorder and panic attacks, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder, phobîas, and anxiety disorder not otherwise specified, substance related disorders, including, but not limited to, substance use or substance-induced disorders, including, but not limited to, alcohol-, nicotine-, amphétamine-, phencyclidine-, opioid-, cannabis-, cocaïne-, caffeine-, hallucinogen-, inhalant-, sédative-, hypnotic-, anxiolytic-, polysubstance- or other substance-related disorders, sleep disorders, including. but not limited to, narcolepsy, dyssomnias, primary hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder and dyssomnia not otherwise specified, parasonmias. sleep terror disorder, sleepwalking disorder and parasomnia not otherwise specified, sleep disorders related to another mental disorder, sleep disorder due to a general medical condition and substance-induced sleep disorder, metabolic and eating disorders, including, but not limited to, anorexia nervosa, bulimia nervosa, obesity, compulsive eating disorder, binge eating disorder and eating disorder not otherwise specified, diabètes mellitus, ulcerative colitis, Crohn’s disease, irritable bowel syndrome, autism spectrum disorders, including, but not limited to, autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified, attention déficit hyperactivity disorder, disruptive behaviour disorders, oppositional défiant disorder and disruptive behaviour disorder not otherwise specified, and tic disorders, including, but not limited to, Tourette’s disorder, personality disorders, sexual dysfunctions such as sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorder, sexual dysfunction not otherwise specified, paraphilias, gender identity disorders, infertility, premenstrua! syndrome and sexual disorders not otherwise specified, disorders of the respiratory System lîke cough, asthma, chronic obstructive pulmonary disease, lung inflammation, disorders of the cardiovascular System snch as cardiac failure, heart arrhytlimia, hypertension, inflammation, inflammatory and neuropathie pain, rheumatoid arthritis, osteoarthritis, allergy, sarcoidosis, psoriasis, ataxia, dystonia, systemic lupus erythematosus, mania, restless legs syndrome, progressive supranuclear palsy, epilepsy, myoclonus, migraine, amnesia, chronic fatigue syndrome, cataplexy, brain ischemia, multiple sclerosis, encephalomyelitis, jetlag, cérébral amyloid angiopathy, and sepsis.

   6'_I8'-difluoro-N-[(2-methyl-lH-indol-5-yl)methyl]-4'-oxo-3'_J4^,-dihydrospnO[azetidme3,2'-[ 1 ] benzopyran] -1-carboxamide;

   6’-chloro-N-[(2-methyl-lH-indol-5-yl)nieÎhyl]-47oxo-3\4'-dihydj^

   6'-fluoiO-N-[(l-methy1-lH-indol-5-yl)methyl]spiro[azetidine-3,2'-chiOniene]-lcarboxamide;

   N-[(1-methyl-1H-indol-5-yl)methyl]-3',4’-dihydrospiro[azetidine-3,2'-[l]benzopyran]-lcarboxamide;

   6'-fluoro-N-[( 1 -methyl-1 H-indol-S-yLmethylJ-S’^'-dihydrospirofazetidine-S ,2’-

   6'-chioro-N-[(lH-indol-5-yl)methyl]-4'-oxo-3',4'-dihydrospiiO[azetidine“3,2'-

   6-chloiO-R-[(l-methyl-lH-indol-5-yI)methyl]-3,4-dihydrospiro[l]-benzopyran-2,4'piperidine]-1 '-carboxamide;

   N-[(3-diloro-l-methyl-lH-indol-5-yl)methyl]-6'-fluoro-4'-oxo-3',4'~ dihydrospiiO[azeÎidine-3,2'-[l]benzopyran]-l-carboxamide;

   6'-chloro-N-[(l-methyRlH-indol-5-yl)methyl]-4'-oxo-3^, _s4^,-dihydiOspiro[azetidine-3,2'-

   6-chloiO-N-[(l-methyl-lH-indol-5-yl)methyl]-4-oxo-3,4-dihydrospiro[l-benzopyran2,4'-piperidine]-r-carboxamide;

   6'-F1uoiO-N-[(2-methyl-lH-indol-5-yl)methyl]-4'-oxo-3',4'-dihydrospiro[azetÎdine-3,2'[ 1]benzopyran]-1 -carboxamide;
7. 7. A compound for use according to daim 6, wherein the disease îs selected from the group of cognitive impairment, schizophrenia, and autism.

   7'-fluoro-4^l-oxo-N-{[2-(trifluoromethyl)-lH-indol-5-yl]methyl}-3'₅4'dihydrospiro[azetidine-3,2'-[l Jbenzopyran]-!-carboxamide;

   N“{[2-(difluoromethyl)-nÎ-Îndol-5-yl]methyl}-7'-f!uoiO-4'-oxo-3',4'dihydrospiro [azetidine-3,2'-[1 jbenzopyran]-1 -carboxamide;

   or pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, solvatés and hydrates thereof.

   §0

   7'-fluoro -N - [(2-methyl -1 H-indo 1-5-yl)methy 1] -4'-oxo-3 \4 '-dîhydro spiro [azeti dine-3,2'[ 1 Jbenzopyran]-1 -carboxamide;

   N-[(2-methyl-lH-indol-5-yl)methyl]-4^,-oxo-6'-(trifluoromethyl)-3’,4'dihydrospirofazetidine-S^'-fl Jbenzopyran]-!-carboxamide;

   N-[(l-methyl-lH-indol-5-yl)methyl]-4'-oxo-7'-(ü-ifluoiOmethyl)-3^,,4^ldihydiOspiro[azetidine-3₅2'-[ 1 Jbenzopyran] -1 -carboxamide;

   N-[(2-methyl-1 H-indo 1-5-y l)methyl]-4'-oxo-7'-(trifiuoromethyi)-3',4’dihydrospiro [azetidine-3,2'-[ 1 Jbenzopyran] -1 -carboxamide;

   7'-chloiO-N-[(2-methyl-lH-indol-5-yl)methyI]-4^,-oxo-3’,4^,-dihydiOspiro[azetidine-3,2'[ 1 Jbenzopyran] -1 -carboxamide;

   7'-chloro-N-[(2-chloro-lH-mdol-5-yl)methyl]-4'-oxo-3',4'-dihydroΞpilΌ[azetidine-3,2^,[1 Jbenzopyran]-!-carboxamide;

   7'-fluoiO-N-[(l-melhyl-lH-indol-5-yl)methy]]-4'-oxo-3',4'-dihydrospiiO[azetidine-3,2'-
8. 8. A pharmaceuticai composition comprising as active ingrédient a compound according to any one of daims 1 to 3 and at least one pharmaceutically acceptable excipient.

   &, 8 ’-dichforo-N-[(2-methyl-1 H-i ndo 1-5-yl)methyl] -4'-oxo-3 ’,4’-dihy drospiro [azetidine3,2'-[!]benzopyran]-l-carboxamide;
9. 9. A pharmaceuticai composition according to daim 8, wherein the composition further comprises at least one other active ingrédient.
10. 10 for formula (II).

    10, A pharmaceutical composition accordîng to claîm 9, wherein the other active ingredîent(s) are selected from the group of acetylcholinesterase inhibitors, NMDA receptor antagonists, beta- secretase inhibitors, antipsychotics, GABA_a receptor alpha5 subunit NAMs or PAMs, histamine H3 receptor antagonists, 5-ΗΤή receptor antagonists, Ml or M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, and levodopa.
11. 11. Combination of a compound accordîng to any one of daims 1 to 3 and at least one other active ingrédient for use in the treatment or prévention of a disease associated with a 7 nîcotinic acétylcholine receptor activity.
12. 12. Combination for use accordîng to daim 11, wherein the other active ingredient(s) are selected from the group of acetylcholinesterase inhibitors, NMDA receptor antagonists, beta- secretase inhibitors, antipsychotics, GABAa receptor alpha5 subunit NAMs or PAMs, histamine H3 receptor antagonists, 5-1-11'6 receptor antagonists, Ml or M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, and levodopa.
13. 13. Process for the manufacture of compounds of formula (II) accordîng to daim 1, characterized by reacting a compound of formula (III)

    (III) ' O

    - whereip the meaning of R is described above for compound of formula (II) — with a compound of formula (IV)

    (IV)

    - wherein the meaning of n and m is described above for compound of formula (II) either in two separated steps via formula (VII)

    (VII)

    - wherein the meaning of n and m is described above for compound of formula (H), or directly in one step to provide a compound of formula (V)

    - wherein the meaning of R³, n and m is as described above for formula (II) - which is then reacted with

    a.) hydrogen chloride to provide formula (VI)

    - wherein the meaning of R³, n and m is as described above for formula (II),

    b.) complex hydrides to provide formula (VIII) _O^^H

    (VIII)
14. 14. A compound of {l,2-dimethyi-lH-pyriOlo[2,3-b]pyridm-5-yl}methanamine.
15. 15. A compound of {3-BiOmo-l-methyI-lH-pyrroIo[2,3-b]pyridin-5-yl }methanamine.

    15 - wherein the meaning of R³, n and m is as described above for formula (II) - then compound of formula (VIII) is reduced with triethylphosphine to provide formula (IX)

    (IX)

    - wherein the meaning of R³, n and m is as described above for formula (II) - then the obtained dérivative of formula (IX) or formula (VI) -is reacted with formula (X)

    (X)
16. 16. A compound of 3',4'-Dihydrospiro[azetidine-3_î2^,-pyrano[3.2-b]pyiidin]-4'~one hydrochloride.