HU231478B1 - Substituted (aza)indole derivatives - Google Patents

Description

SUBSTITUTED (AZA)INDOLE DERIVATIVES

SUBJECT OF THE INVENTION

The subject of the invention is pharmacologically active substituted (aza)indole 5 compounds, as well as their pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates, as well as pharmaceutical preparations containing them, and their use in nicotinic acetylcholine 7 as a receptor activity modulator in mammals.

DESCRIPTION OF THE STATE OF THE ART

Acetylcholine (ACh) acts as a neurotransmitter in the mammalian central nervous system (CNS) by binding to cholinergic receptors. The mammalian CNS contains two basic ACh receptor subtypes - muscarinic (mAChR) and nicotinic (nAChR) AChreceptors - which are distinguished based on the agonist activity of muscarine and nicotine 15 . Nicotinic ACh receptors are five-subunit ligand-gated ion channels (Purves et al., Neuroscience 4. (2008) 122126). The subunits of nicotinic receptors belong to a multigene family and are divided into two groups based on their amino acid sequence: one contains alpha and the other beta subunits. The pentamer 20 structures of different subunit combinations result in several receptor subtypes with different pharmacological properties. The most common subtypes include muscle-type ((α1)2βιδε), ganglion-type ((α3)2(β4)3) and CNS-type ((α4)2(β2)3 or (a7)s) nAChR subtypes (Le Nővére N et al., Journal of Molecular Evolution 40 (1995) 155-172). Αζα7 subunits have been shown to form 25 functional receptors when expressed by themselves, so it is assumed that they assemble into homooligomeric pentameric receptors.

The activity of nAChR ion channels is primarily regulated by ligands binding to conventional agonist binding sites, but also by negative or positive allosteric modulators (NAMs and PAMs). nAChR allosteric transient e

rs ffli

states model includes at least one resting, one activated, and one desensitized closed channel state, the latter process by which the receptors become desensitized to the agonist. Different nAChR ligands can stabilize a receptor conformational state to which they preferentially bind. For example, ACh and (5 )-nicotine stabilize active and desensitized states. Changes in the activity of nicotinic receptors are involved in many diseases. It is assumed that the development of cognitive deficits in diseases such as Alzheimer's disease and schizophrenia is due to the effect of a decrease in the number of nicotinic receptors. The effect of nicotine from tobacco is also mediated by nicotine receptors, and since the receptors are stabilized in a desensitized state under the influence of nicotine, the increased activity of nicotine receptors can reduce the desire to smoke.

However, treatment with nicotinic agonists acting at the same site as ACh raises problems because ACh not only activates but also blocks receptor activity through processes such as desensitization or non-competitive inhibition. Furthermore, prolonged activation induces prolonged inactivation. Consequently, ACh agonists are expected to lose their effectiveness with chronic use.

While α7 nAChR is characterized by fast activation kinetics and high Ca ²⁺ permeability compared to other subtypes (Delbono et al., J. Pharmacol. Exp. Ther.

280 (1997) 428-438), shows rapid desensitization following exposure to agonists acting on orthosteric binding sites (Castro et al., Neurosci Lett, 164 (1993) 137-140; Couturier et al., Neuron 5, (1990) 847-856). Although several α7-selective agonists and partial agonists have been developed in recent years, their clinical efficacy has been shown to be suboptimal due to receptor blockade (desensitization) following agonist activation. This problem can be overcome by treatment with PAMs that enhance endogenous agonist-mediated α7 nAChR activation. Positive modulation of α7 nAChRs in various preclinical models shows a cognitive enhancing effect (Thomsen et al., Curr Pharm Des 16 (2010) 323-343; Lendvai et al., Brain Res Bull 93 (2013)

86-96).

1837742

The compounds of the invention may be useful in the treatment of diseases and conditions mediated by or associated with positive allosteric modulation of α7 nAChR, including but not limited to the following psychotic disorders such as schizophrenia (Deutsch SI et al. Schizophr Rés 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, general health-related psychotic disorder 10, substance abuse-induced psychotic disorder or otherwise unspecified psychotic disorder, cognitive impairment, including for example treatment of cognitive impairment, and cognitive impairment due to stroke, Alzheimer's disease (Lewis AS et al Prog Neuropsychopharmacol Biol Psychiatry 75 (2017) 45-53), Huntington's disease (Foucault-Fruchard L et al 15 Neural Regen Rés 13 (2018) 737-741), Pick's disease (Fehér A et al Dement Geriatr Cogn Disord 28 (2009) 56-62), dementia associated with HIV infection (Capó-Vélez CM et al. Sci Rep 8 (2018) 1829), frontotemporal dementia (Minami SS et al. Biochem Pharmacol 97 (2015) 454-462), Lewy- somatic dementia (Perry EK et al Neuroscience 64 20 (1995) 385-395), vascular dementia (Putignano S et al Clin Interv

Aging 7 (2012) 113-118), cerebrovascular disease (Si ML and Lee TJF Circ Rés 91 (2002) 62-69), or other dementia conditions and dementia associated with other degenerative disorders (amyotrophic lateral sclerosis (Kawamata et al. Ther Adv Chronic Dis 2 (2011) 197-208), etc.), other acute or subacute conditions that can lead to cognitive decline, such as delirium (Sfera A et al Front Med 2 (2015) 56), traumatic brain injury (Shin SS and et al Neural Regen Res 10 (2015) 1552-1554), senile dementia (Whitehouse PJ et al Science 215 (1982) 1237-1239), mild cognitive impairment (Ikonomovic MD et al Arch Neurol 66 (2009) 646-651), Down 30 syndrome (Deutsch SI et al Clin Neuropharmacol 26 (2003) 277-283), depression and cognitive deficit associated with other diseases and dyskinetic disorders (Parameswaran N et al Soc Neurosci Abstr (2007)) as

1837742 eg Parkinson's disease (Quik M et al Biochem Pharmacol 97 (2015) 399407) and neuroleptic induced parkinsonism or tardive dyskinesias (Terry AV and Gearhart DA Eur J Pharmacol 571 (2007) 29-32), depression and mood disorders , including depressive disorders and episodes (Philip NS et al. Psychopharmacology 212 (2010) 1-12), bipolar disorders (Leonard S and Freedman R. Biol Psychiatry 60 (2006) 115-122), cyclothymia (Ancín I et al. J Affect Disord 133 (2011) 340-345), and bipolar disorders not otherwise specified, other mood disorders (Shytie RD et al. Depression and Anxiety 16 (2002) 89-92), substance use-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 (Tizabi Y et al Bioi Psychiatry 51 ( 2002) 164-171), post-traumatic 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 (Cocores JA Prim Care Companion J Clin Psychiatry 10 (2008) 253-254), general health state anxiety disorder, substance use-induced anxiety disorder, phobias and anxiety disorders not otherwise specified, substance use-related disorders such as substance use or substance use-induced disorders such as alcohol (de Fiebre NC and de Fiebre CM Alcohol 31 (2003) 149-153 ; Diaper AM et al BrJ Clin Pharmacol 77 (2014) 302-314), nicotine (Leslie FM et al Mol Pharmacol 83 (2013) 753-758), amphetamine (Pubill D et al Pharmaceuticals 4 (2011) 822-847), phencyclidine (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 J Neurosci 27 (2007) 5615-5620) , cocaine (Francis MM et al. Mol Pharmacol 60 (2001) 71-79), caffeine, hallucinogens, inhaled drugs, sedatives, hypnotics, anxiolytics, polytoxic or other substance use disorders, sleep disorders (McNamara JP et al. Psychol Health Med 19 (2014) 410419), such as narcolepsy (Krahn et al. J Clin Sleep Med 5 (2009) 390), dyssomnia, primary hypersomnia, breathing-related sleep disorders,

M

V

1%, S** m w H circadian rhythm sleep disorder and otherwise unspecified dyssomnia, parasomnia, pavor nocturnus, sleepwalking and otherwise unspecified parasomnia; other mental disorder-related sleep disorders (including other mental disorder-related insomnia and other mental disorder-related hypersomnia), general health-related sleep disorder and substance use-induced sleep disorder, metabolic and eating disorders (Somm E Arch Immunoi Ther Exp 62 (2014) 62: 87- 101), such as anorexia nervosa (Cuesto G et al J Neurogenet 31 (2017)266287), bulimia nervosa, obesity (Lakhan SE and Kirchgessner A J Transl Med 9 (2011)

129-139), compulsive eating disorder, binge eating disorder and other unspecified eating disorders, diabetes mellitus (Marrero MB et al. J Pharmacol Exp Ther 332 (2010) 173-180), ulcerative colitis (Salaga et al. JPET356 (2016) 157 -169), Crohn's disease (Bencherif M Cell Mol Life Sci 68 (2011) 931-949), irritable bowel syndrome (Keszthelyi D et al. Neurogastroenterol

Motil 21 (2009) 1239-1249), autism spectrum disorder (Deutsch et al. Clin Neuropharmacol 33 (2010) 114-120), including autistic disorder, Asperger syndrome, Rett syndrome, childhood disintegrative disorder, and otherwise not defined pervasive developmental disorder; attention deficit hyperactivity disorder (Wilens TE and Decker MW Biochem Pharmacol 74 (2007) 121220 1223), disruptive behavior disorders, oppositional defiant disorder and disruptive behavior disorder not otherwise specified, and tic disorders such as Tourette syndrome (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, orgasmic disorders, sexual pain disorders, sexual dysfunctions not otherwise specified , paraphilias, gender identity disorders, infertility (Bray C et al Bioi Repród 73 (2005) 807-814), premenstrual syndrome (Gündisch D and Eibl C Expert Opin Ther Pat 21 (2011) 1867-1896), and not otherwise specified sexual disorders, diseases of the respiratory system such as 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 Natl Acad Sci USA 770(2013) 4099fs m

We

H

4104), pneumonia (Enioutina EY et al. PLoS One 10 (2015) e0121128), cardiovascular disorders such as heart failure (Mai XK et al. J Immunoi 200 (2018) 108.11), cardiac arrhythmia (Mazloom R et al. PLoS One 8 (2013) e82251) and hypertension (Chen JK et al BMC Cardiovasc Disord 12 (2012) 38).

The compounds according to the invention may also be suitable for inflammation, inflammatory and neuropathic 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 University ClinicalTrials .gov ID: 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) e13213), mania (Janowsky DS et al Lancet 2 (1972)) 632-635), restless leg 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), catalepsy ( In this MR and Krieger ACJ Clin Sleep Med 8 (2012) 195-196), cerebral 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), cerebral amyloid angiopathy (PM et al Brain Res 1234 (2008) 158-171), for the treatment of sepsis (Ren C et al. Int J Biol Sci 14 (2018) 748-759) and in general all diseases

M ft ft w

r!

and for the treatment of a disorder associated with positive allosteric modulation of α7 nAChR.

In addition, these compounds may be combined with other therapeutic agents, including, but not limited to, acetylcholinesterase inhibitors (eg, galantamine, rivastigmine, donepezil, tacrine, phenserine, ladostigil, and ABT-089); NMDA receptor agonists or antagonists (eg, memantine, neramexane, EVT101, and AZD4282); anti-amyloid antibodies, including anti-amyloid humanized monoclonal antibodies (eg, bapineuzumab, ACCOOI, CAD 106, AZD3102, H12A11V1); beta- (eg, verubecestat and AZD3293) or gamma-secretase inhibitors (eg, LY450139 and TAK 070) or modulators; tau phosphorylation inhibitors; ApoE4 conformation modulators; p25/CDK5 inhibitors; NK1/NK3 receptor antagonists; COX-2 inhibitors (eg, celecoxib, rofecoxib, valdecoxib, 406381 and 644784); LRRK2 inhibitors; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory drugs (such as ibuprofen); vitamin E; glycine transport inhibitors; glycine binding site antagonists (eg, lacosamide); LXR β agonists; androgen receptor modulators; αβ oligomer formation blockers; 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 (eg, AVE1625); CB-2 agonists (such as 842166 and SAB378); VR-1 antagonists (eg AMG517, 705498, 782443, PAC20030, VI 14380 and A425619); bradykinin B1 receptor antagonists (eg, SSR240612 and NVPSAA164); sodium channel blockers and antagonists (such as VX409 and SPI860); NOS inhibitors (such as SD6010 and 274150); antibiotics;

growth hormone secretagogues (eg, ibutamoren, ibutamoren mesylate, and capromorelin); potassium channel openers; AMPA agonists or AMPA modulators (eg, CX-717, LY 451395, LY404187, and S-18986); GSK3 inhibitors (eg, AZD1080, SAR502250, and CEP16805); neuronal nicotinic agonists; MARK ligands; Mi or M4 mAChR agonists or PAMs;

mGluR2 antagonists or NAMs or PAMs; mGluR5 antagonists (eg, AZD9272); alpha-adrenergic agonists; ADAM-10 ligands; receipts, f ¹ ·. f»

M sedatives, 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, benzodiazepines, barbiturates; 5-HT1a antagonists (eg lecozotan); 5-HT2 antagonists; 5-HT4 agonists (eg, PRX-03140); 5-HT ₆ antagonists (eg GSK 742467, SGS-518, FK-962, SL65.0155, SRA-333 and xaliproden); histamine H3 receptor antagonists and inverse agonists (eg, S38093, ABT-834, ABT 829, GSK 189254, and CEP16795); PDE ₄ inhibitors (eg HT0712); PDE9 inhibitors (eg BI40936); PDE10 inhibitors; HDAC inhibitors; KCNQ antagonists; GABAa inverse agonists; GABA signaling enhancers; GABA agonists, GABAa receptor alpha5 subunit NAMs or PAMs, antipsychotics; MAO-B inhibitors; dopamine transport inhibitors; norepinephrine transport inhibitors, D2 agonists and partial agonists; anticholinergic agents (such as biperiden); COMT inhibitors (such as entacapone); A2a adenosine receptor antagonists; cholinergic agonists; compounds include phenothiazine, thioxanthene (such as chlorprothixene and thiothixene), heterocyclic dibenzazepine (such as clozapine), butyrophenone (such as haloperidol), diphenylbutylpiperidine (such as pimozide), and indoIon (such as molindolone) type neuroleptics; loxapine, sulpiride and risperidone; levodopa; calcium channel blockers (such as ziconotide and NMED160); MMP inhibitors; thrombolytics; opioid pain relievers (such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene); pramipexole; ropinirole; neutrophil inhibitory factor; SSRIs or SSNRIs - two; tricyclic antidepressants; norepinephrine modulators; lithium; valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan, or other active substances that affect receptors or enzymes, which either increase the efficacy, safety, convenience of treatment or reduce unwanted side effects or toxicity of the compounds of the invention.

Known positive allosteric modulators of the α7 nicotinic acetylcholine receptor include 2-aniline-4-arylthiazole derivatives (WO 2007/031440 A2, JANSSEN

P

V

R

N

We

H

PHARMACEUTICA NV), amide derivatives (WO 2009/100294 A2, ABBOT LAB.), trisubstituted 1,2,4-triazoles (WO 2009/115547 A1, JANSSEN PHARMACEUTICA NV), indole derivatives (WO 2009/127678 A1, GLAXO GROUP LTD and WO 2009/127679 A1, GLAXO GROUP LTD.), tetrazole substituted aryl amide derivatives (WO 2009/043784 A1, HOFFMANN LA ROCHE), cyclopropyl aryl amide derivatives (WO 2009/043784 A1, HOFFMANN LA ROCHE), trisubstituted pyrazoles (WO 2009/ 135944 A1, JANSSEN PHARMACEUTICA NV), pyrrole derivatives (WO 2014/141091 A1, LUPINE LTD), cyclopropylbenzene derivatives (WO 2017/165256 A1, MERCK SHARP & DOHME CORP) and substituted bicyclic heteroaryl derivatives (WO 2018/085171 A1, MERCK SHARP & DOHME CORP.).

The subject of the invention is a group of new compounds that are positive allosteric modulators of the α7 nicotinic acetylcholine receptor.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments of the invention are illustrated in the accompanying drawings, in which the same reference numerals denote the same or similar elements, and in which:

Figure 1 illustrates the results of the location recognition test for the compound according to Example 3. The exploration time spent in the new [N] and known [O] arms of the Y-ball is plotted. Scop: scopolamine (1 mg/kg, ip.). ⁺ p<0.05; ⁺⁺ p<0.01; ⁺⁺⁺ p<0.001.

Figure 2 illustrates the results of the location recognition test for the compound according to Example 5. The exploration time spent in the new [N] and known [O] arms of the Y-ball is plotted. Scop: scopolamine (1 mg/kg, ip.). ⁺ p<0.05; ⁺⁺ p<0.01; ⁺⁺⁺ p<0.001.

Figure 3 illustrates the results of the location recognition test for the compound according to Example 23. The exploration time spent in the new [N] and known [O] arms of the Y-ball is plotted. Scop: scopolamine (1 mg/kg, ip.). ⁺ p<0.05; ⁺⁺ p<0.01; ⁺⁺⁺ p<0.001.

b* is m w ft V r*. f*· w H

Figure 4 illustrates the results of the location recognition test for the compound according to Example 47. The exploration time spent in the new [N] and known [O] arms of the Y-ball is plotted. Scop: scopolamine (1 mg/kg, ip.). ⁺ p<0.05; ⁺⁺ p<0.01; ⁺⁺⁺ p<0.001.

Figure 5 illustrates the results of location recognition test 5 for the compound of Example 51. The exploration time spent in the new [N] and known [O] arms of the Y-ball is plotted. Scop: scopolamine (1 mg/kg, ip.). ⁺ p<0.05; ⁺⁺ p<0.01; ⁺⁺⁺ p<0.001.

Figure 6 illustrates the results of the location recognition test for the compound according to Example 90. The exploration time spent in the new [N] and known [O] arms of the Y-ball is plotted. Scop: scopolamine (1 mg/kg, ip.). ⁺ p<0.05; ⁺⁺ p<0.01; ⁺⁺⁺ p<0.001.

SUMMARY OF THE INVENTION

The present invention relates to compounds of general formula (I),

(I) where

R ¹ is hydrogen or C 1 -alkyl;

R ² is hydrogen or C 1-6 alkyl, or R ² is absent when n is 0;

R ³ is hydrogen or O, or R ³ is absent when m is 0;

R ⁴ and R ⁵ are independently hydrogen, C 1-6 alkyl, halogen, haloC 1-6 alkyl,

C 1-6 alkoxy, or CN;

n and m are independently 0 or 1; provided that n and m cannot be 0 at the same time;

k and I are independently 1, 2 or 3;

Y is N or C(R ⁶ );

R ⁶ is hydrogen, C 1-6 alkyl, halogen, or haloC 1-6 alkyl;

R ⁷ is hydrogen, C 1-6 alkyl, or halogen;

W is CH or N;

Z is CH, C 1 -C 1 alkyl or N;

L is an optionally substituted spacer consisting of 1, 2 or 3 atoms, denoted by T-U-V, where T is CH 2 , C(O), NH, SO 2 or O; U is CH 2 , C(O), O or absent; and V is CH 2 , O or absent;

A means a saturated, unsaturated or aromatic carbocycle, or a saturated, unsaturated or aromatic heterocycle, where the heteroatom is selected from the group consisting of nitrogen, oxygen and sulphur; which is optionally substituted independently of one another with one or more halogen atoms or halogen atoms, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkyl, CN, or benzyl groups;

or its pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.

According to a further aspect, the subject of the invention is a compound of the general formula (I) defined above for use in the treatment or prevention of a disease related to α7 nicotinic acetylcholine receptor activity.

According to a further aspect, the subject of the invention is the use of a compound of the general formula (I) defined above in the production of a medicine for the treatment or prevention of a disease related to the activity of the α7 nicotinic acetylcholine receptor 25.

According to a further aspect, the subject of the invention is a method for the treatment or prevention of a disease related to α7 nicotinic acetylcholine receptor activity, which includes the administration of at least one compound of formula (I) 30 as defined above to a mammal in need of such treatment or prevention.

n f·* F** m Μ' H

According to a further aspect, the compounds of general formula (I) defined above are administered together with other compounds used for the treatment or prevention of disease related to α7 nicotinic acetylcholine receptor activity.

According to a further aspect, the subject of the invention is a process for the preparation of compounds of general formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of general formula (I),

(I) where

R ¹ is hydrogen or C 1 -alkyl;

R ² is hydrogen or C 1-6 alkyl, or R ² is absent when n is 0;

R ³ is hydrogen or O, or R ³ is absent when m is 0;

R ⁴ and R ⁵ are independently hydrogen, C 1-6 alkyl, halogen, haloC 1-6 alkyl,

C 1-6 alkoxy, or CN;

n and m are independently 0 or 1; provided that n and m cannot be 0 at the same time;

k and I are independently 1, 2 or 3;

Y is N or C(R ⁶ );

R ⁶ is hydrogen, C 1-6 alkyl, halogen, or haloC 1-6 alkyl;

R ⁷ is hydrogen, C 1-6 alkyl, or halogen;

W is CH or N;

Z is CH, C1-3alkyl or N;

L is an optionally substituted spacer consisting of 1, 2 or 3 atoms, denoted by T-U-V, where T is CH 2 , C(O), NH, SO 2 or O; U is CH 2 , 5 C(O), O or absent; and V is CH 2 , O or absent;

A means a saturated, unsaturated or aromatic carbocycle, or a saturated, unsaturated or aromatic heterocycle, where the heteroatom is selected from the group consisting of nitrogen, oxygen and sulphur; which is optionally substituted independently of one another with one or more halogen atoms or halogen atoms, C 1-6 alkyl, C 6-6 alkoxy, haloC 1-6 alkyl, haloC 1-10 alkyl, CN, or benzyl groups;

or its pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.

The term halogen atom or halogen, as used alone or as part of another group, refers to a fluorine, chlorine, bromine or iodine atom.

The term C1-6alkyl, as used alone or as part of another group, refers to a branched or straight chain saturated hydrocarbon group containing one, two, three, four, five or six carbon atoms, including but not limited to methyl, ethyl -, n-propyl, /20 propyl, η-butyl, sec-butyl and tert-butyl groups.

The term haloCi-ealkyl, in the present description, refers to at least one halogen atom, as defined above, which is connected to the basic molecular framework through a Ci-ealkyl group, as defined above. If there are multiple halogen atoms, the halogen atoms can be the same or different, and the halogen atoms can be attached to different carbon atoms, or multiple halogen atoms can be attached to the same carbon atom. HaloCi-6alkyl includes, but is not limited to, difluoromethyl, trifluoromethyl, and 2-chloroethyl.

The term C1-6alkyl, as used herein, refers to the previously defined C1-6alkyl group, which is linked through an oxygen atom to the base

1837742 to the backbone, including, but not limited to, methoxy, ethoxy, n-propoxy, /propoxy, and tert-butoxy.

The term haloCi-C 1-6 alkoxy, in the present description, refers to at least one halogen atom, which is linked to the basic molecular skeleton through the previously defined C 1-C 1-C 6-6 alkoxy group. If there are multiple halogen atoms, the halogen atoms can be the same or different, and the halogen atoms can be attached to different carbon atoms, or multiple halogen atoms can be attached to the same carbon atom. HaloCi-C 1-6 alkoxy includes, but is not limited to, trifluoromethoxy, difluoromethoxy, trifluoroethoxy.

The term saturated, unsaturated or aromatic carbocycle, as used herein, means a monovalent saturated, unsaturated or aromatic three- to twelve-, preferably four- to nine-, more preferably six-membered group consisting of one or two rings. The carbocyclic ring may optionally be substituted as defined here. Examples include, but are not limited to, optionally substituted cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, etc. groups.

The term saturated, unsaturated, or aromatic heterocycle, as used herein, refers to a monovalent saturated, unsaturated, or aromatic three- to twelve-membered, one- or two-ring molecule containing one, two, or three heteroatoms (nitrogen, oxygen, or sulfur, preferably nitrogen and oxygen). The heterocyclic ring 20 can optionally be substituted as defined here. Examples include, but are not limited to, optionally substituted tetrahydrofuryl, 1-pyridyl, 2-pyridyl, 3-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazyl, indazolyl, indolyl, azaindolyl, isoquinolinyl, quinolinyl, etc. groups.

The term pharmaceutically acceptable means an ingredient suitable for the manufacture of a pharmaceutical composition, generally safe, non-toxic and biologically or otherwise unsuitable, and includes those acceptable for veterinary use and human use.

37742

The term hydrate refers to non-covalent interactions between water and solute.

The term solvate refers to non-covalent interactions between a solvent and a solute. Solvents include, but are not limited to, ethanol, 2-propanol, acetonitrile, and tetrahydrofuran.

The term "optional" or "in the event" means that the event or condition described below does not necessarily occur, and the description includes examples in which the event or condition occurs and includes examples in which it does not.

The term optionally substituted, as used herein, means unsubstituted or substituted with one or more substituents described herein. Here, the term one or more refers to the largest possible number of substitutions from one, i.e., from the substitution of one hydrogen to the substitution of all hydrogens. The presence of one, two or three substituents on the given atom is preferred.

To treat or treat a disease state includes:

a) the prevention of the disease state, i.e. the clinical symptoms of the disease do not develop in a patient who is exposed to the disease or is prone to it, but the symptoms of the disease state cannot yet be experienced or detected,

b) inhibiting the condition of the disease, i.e. stopping the condition or clinical symptoms of the disease, or

c) alleviation of the disease state, i.e. temporary or permanent regression of the disease state or clinical symptoms.

The term pharmaceutically acceptable salt means a conventional acid addition salt or base addition salt which preserves the compounds of formula (I)

Μ describes the biological effectiveness and properties of 1% fs, and which can be formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases. Examples of acid addition salts include salts derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, hydrogen iodide, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and perchloric acid, those derived from various organic acids, such as acetic acid, propionic acid, benzoic acid, glycolic 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 include salts derived from ammonium, potassium, sodium and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide.

The term prodrug refers to derivatives of compounds of the general formula (I) according to the invention, which do not have a therapeutic effect by themselves, but contain groups which, after chemical or metabolic degradation (biotransformation) in vivo, are transformed into a biologically active metabolite, which is responsible for the therapeutic effect. Degradable groups of this type related to the compounds of general formula (I) according to the invention - especially suitable for prodrugs - are known in the field and can also be used for the compounds according to the invention (Rautio et al., Nature Reviews - Drug Discovery 7 (2008) 255-270).

According to one embodiment, the present invention relates to compounds of general formula (I) where

R ¹ is hydrogen or C 1 -alkyl;

R ² is hydrogen or C 1 -alkyl, or R ² is absent when n is 0;

R ³ is hydrogen or O, or R ³ is absent when m is 0;

R ⁴ and R ⁵ are independently hydrogen, C 1-3 alkyl, halogen, haloC 1-3 alkyl, C 1-3 alkoxy, or CN;

n and m are independently 0 or 1; provided that n and m cannot be 0 at the same time;

k and I are independently 1 or 2;

Y is N or C(R ⁶ );

18377 42

R ⁶ is hydrogen, C 1-3 alkyl, halogen, or haloC 1-3 alkyl;

R ⁷ is hydrogen, C 1-6 alkyl, or halogen;

W is CH or N;

Z is CH, C1-3alkyl or N;

L is an optionally substituted spacer consisting of 1, 2 or 3 atoms, denoted by T-U-V, where T is CH 2 , C(O), NH, SO 2 or O; U is CH 2 , C(O), O or absent; and V is CH 2 , O or absent;

A means a saturated, unsaturated or aromatic 4-9 membered carbocycle, or a saturated, unsaturated or aromatic 4-9 membered heterocycle, where the heteroatom is selected from the group consisting of nitrogen, oxygen and 10 sulfur; which is optionally substituted independently with one or more halogen atoms or halogen atoms, C 1 -salkyl, C 1-3 alkoxy, haloC 1-3 alkyl, haloC 1-3 alkoxy, CN, or benzyl groups;

or its pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.

According to one embodiment, the present invention relates to compounds of formula (I) wherein

R ¹ is hydrogen or C 1-6 alkyl;

R ² is hydrogen or C 1 alkyl, or R ² is absent when n is 0;

R ³ is hydrogen or O, or R ³ is absent when m is 0;

R ⁴ and R ⁵ are independently hydrogen, C 1-3 alkyl, halogen, haloC 1-3 alkyl, C 1-3 alkoxy, or CN;

n and m are independently 0 or 1; provided that n and m cannot be 0 at the same time;

k and I are independently 1 or 2;

Y is N or C(R ⁶ );

R ⁶ is hydrogen, C 1-3 alkyl, halogen, or haloC 1-3 alkyl;

R ⁷ is hydrogen, C 1-6 alkyl, or halogen;

W is CH or N;

Z is CH or N;

1837742

L is an optionally substituted spacer consisting of 1, 2 or 3 atoms, denoted by T-U-V, where T is CH 2 , C(O), NH, SO 2 or O; U is CH 2 , C(O), O or absent; and V is CH 2 , O or absent;

A means a saturated, unsaturated or aromatic 4-9 membered carbocycle, or a saturated, unsaturated 5- or aromatic 4-9 membered heterocycle, where the heteroatom is nitrogen; which is optionally substituted independently of one another with one or more halogen atoms or halogen atoms, C 1-3 alkyl, C 1-3 alkoxy, haloC 1-salkyl, haloC 1-salkoxy, CN, or benzyl groups;

or its pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates.

According to one embodiment, the present invention relates to compounds of general formula (I), where R ¹ is hydrogen or C 1-3 alkyl;

R ² is hydrogen or C 1 alkyl, or R ² is absent when n is 0;

R ³ is O, or R ³ is absent when m is 0;

R ⁴ and R ⁵ are independently hydrogen, C 1-3 alkyl, halogen, haloC 1-3 alkyl, C 1-3 alkoxy, or CN;

n and m are independently 0 or 1; provided that n and m cannot be 0 at the same time;

k and I are independently 1 or 2;

Y is N or C(R ⁶ );

R ⁶ is hydrogen, C 1-3 alkyl, halogen, or haloC 1-3 alkyl;

R ⁷ is hydrogen, C 1-6 alkyl, or halogen;

W is CH or N;

Z is CH or N;

L is a spacer selected from the following group: -CH2-, -Ο-, -NH-, -SO2-, -C(O)-, -CH2O-,

-CH2-CH2-O-, -O-CH2-, -CH2-CH2-, -NH-C(O)-, or -NH-CH2-;

A means a saturated, unsaturated or aromatic 4-9 membered carbocycle, or a saturated, unsaturated 30 or aromatic 4-9 membered heterocycle, where the heteroatom is nitrogen; which is optionally substituted independently of one another with one or more halogen atoms or halogen

with 1,837,742 atoms, C 1-3 alkyl, C 1-3 alkoxy, haloC 1-4 alkyl, haloC 1-4 alkoxy, CN, or benzyl groups;

or its pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.

According to one embodiment, the present invention relates to compounds of formula (I) wherein

R ¹ is hydrogen or C 1 -alkyl;

R ² is hydrogen or C 1 -alkyl, or R ² is absent when n is 0;

R ³ is O, or R ³ is absent when m is 0;

R ⁴ and R ⁵ are independently hydrogen, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-3 alkoxy, or CN;

n and m are independently 0 or 1; provided that n and m cannot be 0 at the same time;

k and I are independently 1 or 2;

Y is N or C(R ⁶ );

R ⁶ is hydrogen, C 1-6 alkyl, halogen, or haloC 1-6 alkyl;

R ⁷ is hydrogen, C 1-6 alkyl, or halogen;

W is CH or N;

Z is CH or N;

L is a spacer selected from the following group: -CH2-, -Ο-, -NH-, -SO2-, -C(O)-, -CH20-,

-CH2-CH2-O-, -O-CH2-, -CH2-CH2-, -NH-C(O)-, or -NH-CH2-;

A means an aromatic six-membered carbocycle, or an aromatic six-membered heterocycle, wherein the heteroatom is nitrogen; which is optionally substituted independently of one another with one or more halogen atoms or halogen atoms, C 1 -alkyl, C 1 -alkoxy, haloC 1 -alkyl, haloC 1 -3 alkoxy, CN, or benzyl groups;

or its pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.

According to one embodiment, the present invention relates to compounds of formula (I) wherein

R ¹ is hydrogen or C 1 -alkyl;

1837742

R ² is not present;

R ³ is O;

R ⁴ and R ⁵ are independently hydrogen, C 1-6 alkyl, halogen, haloC 1-6 alkyl, or CN;

n means 0;

m is 1;

k means 2;

I means 2;

Y is N or C(R ⁶ );

R ⁶ is hydrogen, halogen, or haloC 1-6 alkyl;

R ⁷ is hydrogen or halogen;

W is CH or N;

Z is CH or N;

L is a spacer selected from the following group: -CH2-, -Ο-, -NH-, or -SO2-;

A is a phenyl, 2-pyridyl or 3-pyridyl group, optionally substituted independently of one another with one or more halogen atoms or halogen atoms, C 1-6 alkyl, C 1-3 alkoxy or haloC 1-6 alkyl groups;

or its pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.

According to one embodiment, the present invention relates to compounds of formula (I) wherein

R ¹ is hydrogen or C 1-3 alkyl;

R ² is not present;

R ³ is O;

R ⁴ and R ⁵ are independently hydrogen, C 1-6 alkyl, halogen, haloC 1-6 alkyl, or CN;

n means 0;

m is 1;

k means 1;

I means 1;

Y is N or C(R ⁶ );

M

V jS r*.

W

H

R ⁶ is hydrogen, halogen, or haloC 1-6 alkyl;

R ⁷ is hydrogen or halogen;

W is N;

Z is CH or N;

L is a spacer selected from the following group: -CH2-, -Ο-, -NH-, or -CH2-O-;

A is a phenyl, 2-pyridyl or 3-pyridyl group, optionally substituted independently of one another with one or more halogen atoms or halogen atoms, C 1-6 alkyl, C 1-3 alkoxy or haloC 1-6 alkyl groups;

or its pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates.

According to one embodiment, the present invention relates to compounds of general formula (I) where

R ¹ is hydrogen or C 1-6 alkyl;

R ² is hydrogen or Cisalkyl;

R ³ is not present;

R ⁴ and R ⁵ are independently hydrogen, C 1-3 alkyl, halogen, haloC 1-3 alkyl, or CN;

n means 1;

m means 0;

k means 1;

I means 1;

Y is N or C(R ⁶ );

R ⁶ is hydrogen, halogen, or haloC 1-6 alkyl;

R ⁷ is hydrogen;

W is N;

Z is CH or C-C1-3 alkyl;

L is a spacer selected from the group consisting of: 0-, -CH2-O-, -CH2-CH2-O-, -O-CH2-, CH2-CH2-, -NH-C(O)-, or -NH-CH2 -;

A is a phenyl, 2-pyridyl or 3-pyridyl group, optionally substituted independently with one or more halogen atoms or halogen atoms, C 1-3 alkyl, C 1-3 alkoxy or haloC 1-3 alkyl groups;

1837 7 42 or its pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates.

According to one embodiment, the present invention relates to compounds of formula (I) wherein

R ¹ is hydrogen or C 1 -alkyl;

R ² is hydrogen or C 1-3 alkyl;

R ³ is not present;

R ⁴ and R ⁵ are independently hydrogen, C 1-3 alkyl, halogen, haloC 1-3 alkyl, or CN;

meanings of n;

m means 0;

k means 1;

I means 2;

Y is N or C(R ⁶ );

R ⁶ is hydrogen, halogen, or haloC 1-6 alkyl;

R ⁷ is hydrogen;

W is N;

Z is CH;

L is a spacer selected from the following group: -O-, -CH2-, -CH2-O-, or -NH-;

A is a phenic, 2-pyridyl or 3-pyridyl group, optionally substituted independently of one another with one or more halogen atoms or halogen atoms, C 1-3 alkyl, C 1-3 alkoxy or haloC 1-3 alkyl groups;

or its pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.

According to one embodiment, the present invention relates to compounds of general formula (I) where

R ¹ is hydrogen or C 1 -alkyl;

R ² is hydrogen or C 1 alkyl;

R ³ is not present;

R ⁴ and R ⁵ are independently hydrogen, C 1-6 alkyl, halogen, haloC 1-6 alkyl, or CN;

Irish

I*·* m

0®

H n is 1;

m means 0;

k means 2;

I means 2;

Y is N or C(R ⁶ );

R ⁶ is hydrogen, halogen, or haloC 1-6 alkyl;

R ⁷ is hydrogen;

W is N;

Z is CH or N;

L is a spacer selected from the following group: -O-, -CH2-, -CH2-O-, or -C(O)-;

A is a phenyl, 2-pyridyl or 3-pyridyl group, optionally substituted independently of one another with one or more halogen atoms or halogen atoms, C 1-3 alkyl, C 1-3 alkoxy or haloC 1-3 alkyl groups;

or its pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates.

According to one embodiment, the present invention relates to compounds of general formula (I) where

R ¹ is hydrogen or C 1 -alkyl;

R ² is hydrogen or C 1 -alkyl;

R ³ is not present;

R ⁴ and R ⁵ are independently hydrogen, Cisalkyl, halogen, haloCi-salkyl, or CN;

n means 1;

m means 0;

k means 2;

I means 3;

Y is N or C(R ⁶ );

R ⁶ is hydrogen, halogen, or haloC 1-6 alkyl;

R ⁷ is hydrogen;

W is N;

Z is CH or N;

ft

V f**

Also m

w

H

L is a spacer selected from the following group: -O-, -CH2-O-, or -NH-;

A is a phenyl, 2-pyridyl or 3-pyridyl group, optionally substituted independently with one or more halogen atoms or halogen atoms, C 1-6 alkyl, C 1-3 alkoxy or haloC 1-6 alkyl groups;

or its pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.

According to one embodiment, the present invention relates to compounds of general formula (I) selected from the following group:

Λ/-(1-methyl-1/7-indol-5-yl)-2-{4-[(4-methylphenyl)methyl]piperazin-1-yl}-2-oxoacetamide

N-{ 1 -methyl-1H-pyrrol o[2,3-ö]pyridin-5-yl}-2-{4-[(4-methylphenyl)methyl]pyridin-1 -i 1}-2oxoacetamide;

N-(3-Fluoro-1-methyl-1H-indol-5-yl)-2-{4-[(4-methylphenyl)methyl]piperazin-1-yl}-2oxoacetamide ;

Λ-(1-methyl-1 H -indol-5-yl)-2-[4-(4-methylphenoxy)piperidin-1-yl]-2-oxoacetamide;

2-[4-(4-chlorophenoxy)piperidin-1-yl]- N -(1-methyl-1 H -indol-5-yl)-2-oxoacetamide;

[(1/7-indol-5-yl)methyl][(3-{[4-(trifluoromethyl)phenoxy]methyl}-azetidin-1-yl)methyl]amine;

Λ / -[( 1 -methyl-1 H -indol-5-yl)methyl]-3-{[4-(trifluoromethyl)phenoxy]methyl}azetidine-1-carboxamide;

N -[( 1 -Methyl-1 H -indol-5-yl)methyl]-3-{[4-(trifluoromethoxy)phenoxy]methyl}azetidine-1-carboxamide;

N -[(2-methyl-1 H -indol-5-yl)methyl]-3-{[4-(trifluoromethyl)phenoxy]methyl}azetidine-1-carboxamide;

3-{[3-Fluoro-4-(trifluoromethyl)phenoxy]methyl}- N -[(1-methyl-1 H -indol-5-yl)methyl]azetidine-1-carboxamide;

3-{[3-Fluoro-4-(trifluoromethyl)phenoxy]methyl}-[(1H-indol-5-yl)methyl]azetidine-1-carboxamide;

/N-[(3-fluoro-1-methyl-1/~/-i nd ol-5-yl)methyl]-3-{[4-(trifluoromethyl)phenoxy]methyl Iazetide n-1 25 carboxamide;

3-methyl-N-({1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-3-{[4(trifluoromethyl)phenoxy]methyl}azetidine-1-carboxamide ;

ft

V ft ft m

M

Η

Λ/-[(1-methyl-1H-indol-5-yl)methyl]-3-[(4-methylphenoxy)methyl]pyrrolidine-1-carboxamide;

(3R)-3-(4-fluorophenoxy)- N -[(1-methyl-1 H -indol-5-yl)methyl]pyrrolidine-1-carboxamide;

(3S)-3-(4-fluorophenoxy)- N -[(1-methyl-1 H -indol-5-yl)methyl]pyrrolidine-1-carboxamide;

(3S)- N -[(1-methyl-1H-indol-5-yl)methyl]-3-[4-(trifluoromethyl)phenoxy]pyrrolidine-1-carboxamide;

(3S)-3-(4-cyanophenoxy)- N -[(2-methyl-1H-indol-5-yl)methyl]pyrrolidine-1-carboxamide;

(3S)- N -[(1-methyl-1H-indol-5-yl)methyl]-3-{[4-(trifluoromethyl)phenyl]amino}pyrrolidine-1carboxamide;

Λ / -[(1-methyl-1H-indol-5-yl)methyl]-4-{[4-(trifluoromethyl)phenyl]methyl}piperazine-1-carboxamide;

4-(2,4-difluorophenoxy)- N -[(2-methyl-1/7-indol-5-yl)methyl]piperidine-1-carboxamide;

or its pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates.

According to a further aspect, the subject of the invention is a compound of the general formula (I) defined above for use in the treatment or prevention of a disease related to α7 nicotinic acetylcholine receptor activity.

According to a further aspect, the subject of the invention is the use of a compound of the general formula (I) defined above in the production of a medicine for the treatment or prevention of a disease related to α7 nicotinic acetylcholine receptor activity.

According to a further aspect, the subject of the invention is a method for the treatment or prevention of a disease related to α7 20 nicotinic acetylcholine receptor activity, which includes the administration of at least one compound of general formula (I) as defined above to a mammal in need of such treatment or prevention.

In one embodiment, the disease associated with α7 nicotinic acetylcholine receptor 25 activity is selected from the group consisting of psychotic disorders, including, but not limited to, schizophrenia, schizophrenic, schizoaffective disorder, delusional disorder, brief psychotic disorder, general cm V r* b* m

H health-related psychotic disorder, substance use-induced psychotic disorder or otherwise unspecified psychotic disorder, cognitive impairment, including, for example, treatment of cognitive impairment and cognitive impairment due to stroke, Alzheimer's disease, Huntington5 disease, Pick's disease, Dementia associated with HIV infection, frontotemporal dementia, Lewy body dementia, vascular dementia, cerebrovascular disease, or dementia associated with other dementia conditions and other degenerative disorders, including but not limited to amyotrophic lateral sclerosis, other acute or subacute conditions that may lead to cognitive decline, including but not limited to delirium, traumatic brain injury, senile dementia, mild cognitive impairment, Down syndrome, depression and cognitive deficits associated with other diseases and dyskinetic disorders, including but not limited to Parkinson's disease and neuroleptic-induced parkinsonism or tardive dyskinesias, depression and mood disorders, including but not limited to depressive disorders and episodes, bipolar disorders, cyclothymia, and bipolar disorders not otherwise specified, other mood disorders, substance use-induced mood disorder, and mood disorder not otherwise specified, anxiety disorders, panic disorder and panic attacks, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder associated with a general health condition, substance use-induced anxiety disorder, phobias and anxiety disorders not otherwise specified, substance use disorders, including but not limited to without limitation, substance use or substance use-induced disorders, including, but not limited to, alcohol, nicotine, amphetamine, phencyclidine, opioid, cannabis, cocaine, caffeine, hallucinogens, inhalants, sedatives, hypnotics, anxiolytics, polydrug addiction or other substance use disorders, sleep disorders including, but not limited to, narcolepsy, dyssomnia, primary hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder, dyssomnia not otherwise specified, parasomnia, pavor nocturnus, sleepwalking, parasomnia not otherwise specified; sleep disorders associated with other mental disorders, sleep disorders associated with general health and substance abuse-induced sleep disorders, metabolic and

N

V N

8Ö H eating disorders including, but not limited to, anorexia nervosa, bulimia nervosa, obesity, compulsive eating disorder, binge eating disorder, and eating disorders not otherwise specified, diabetes mellitus, ulcerative colitis, Crohn's disease, irritable bowel syndrome, autism spectrum disorder, including , but not limited to 5 autistic disorders, Asperger syndrome, Rett syndrome, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified; attention deficit hyperactivity disorder, disruptive behavior disorder, oppositional defiant disorder and otherwise unspecified disruptive behavior disorder, and tic disorders such as Tourette syndrome, personality disorders, 10 sexual dysfunctions such as sexual desire disorders, sexual arousal disorders, orgasm disorders, sexual pain disorders, sexual dysfunctions not otherwise specified, paraphilias, gender identity disorders, infertility premenstrual syndrome, sexual disorders not otherwise specified, diseases of the respiratory system such as cough, asthma, chronic obstructive pulmonary disease 15, pneumonia, cardiovascular disorders, including but not limited to, heart failure, cardiac arrhythmia and hypertension, inflammation, inflammatory and neuropathic pain, rheumatoid arthritis, osteoarthritis, allergy, sarcoidosis, psoriasis, ataxia, dystonia, systemic lupus erythematosus, mania, restless leg syndrome, progressive supranuclear palsy, epilepsy, migraine , 20 amnesia, chronic fatigue syndrome, catalepsy, cerebral ischemia, multiple sclerosis, encephalomyelitis, jet lag, cerebral amyloid angiopathy, and sepsis.

In one embodiment, the disease associated with α7 nicotinic acetylcholine receptor activity is selected from the group consisting of cognitive impairment, schizophrenia, and autism.

The invention further relates to combination therapies in which a compound of the invention or a pharmaceutical composition or preparation containing a compound of the invention is administered together with another therapeutic agent or agents for the treatment of one or more of the aforementioned conditions. Such therapeutic agents can be selected from the following: acetylcholinesterase inhibitors,

NMDA receptor agonists or antagonists, anti-amyloid antibodies, including anti-amyloid humanized monoclonal antibodies, beta- or gamma-secretase

T b* IS w

V f* h·. mw H 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; non-steroidal anti-inflammatory drugs, vitamin E, glycine transport inhibitors, glycine binding site antagonists, 5 LXR β agonists; androgen receptor modulators, αβ oligomer formation blockers, NR2B antagonists, anti-inflammatory compounds, PPAR gamma agonists, CB-1 receptor antagonists or inverse agonists, CB-2 agonists, VR-1 antagonists, bradykinin Bl receptor antagonists, sodium channel blockers and antagonists, NOS inhibitors, antibiotics , growth hormone secretagogues, potassium channel 10 openers, AMPA agonists or AMPA modulators, GSK3 inhibitors, neuronal nicotine agonists, MARK ligands; Mi or M ₄ mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs, mGluR5 antagonists, alpha-adrenergic agonists, ADAM-10 ligands, sedatives, hypnotics, anxiolytics, antipsychotics, cyclopyrrolones, imidazopyridines, 15 pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents; orexin antagonists and agonists; prokineticin agonists and antagonists; T-type calcium channel antagonists; triazolopyridines, benzodiazepines, barbiturates; 5-HT1a antagonists, 5-HT2 antagonists, 5-HT ₄ agonists, 5-ΗΤθ antagonists, histamine H3 receptor antagonists and inverse 20 agonists, PDE ₄ inhibitors, PDE9 inhibitors, PDE10 inhibitors, HDAC inhibitors, KCNQ antagonists, GABAa inverse agonists, GABA signal transduction enhancers, GABA agonists, GABAa receptor alpha5 subunit NAMs or PAMs, antipsychotics, MAO-B inhibitors, dopamine transport inhibitors, norepinephrine transport inhibitors, D2 agonists and partial agonists; anticholinergic 25 drugs, COMT inhibitors, A2a adenosine receptor antagonists, cholinergic agonists, neuroleptics, loxapine, sulpiride and risperidone, levodopa, calcium channel blockers, MMP inhibitors, thrombolytics, opioid analgesics, pramipexole, ropinirole, neutrophil inhibitory factor, SSRI or SSNRI, tricyclic antidepressants, norepinephrine modulators, lithium, valproate, gabapentin, pregabalin, rizatriptan, 30 zolmitriptan, naratriptan and sumatriptan.

According to one embodiment, the therapeutic agents are selected from the following: acetylcholinesterase inhibitors, NMDA receptor antagonists, beta-secretase inhibitors, antipsychotics, GABAa receptor alpha5 subunit NAMs or PAMs, histamine H3 receptor antagonists, 5-ΗΤθ receptor antagonists, M1 or M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs and levodopa.

According to a further aspect, the present invention provides a process for the preparation of compounds of formula (I) according to the following reaction pathway:

The compounds of the general formula (I) according to the invention can be prepared in various ways by synthetic methods known in organic chemistry or by modifications known to a specialist in the field. The starting materials used here can be obtained commercially or can be produced using the methods known in the field or the detailed synthetic routes.

In the following reaction schemes and hereafter, unless otherwise indicated, the meanings of R ¹ -R ⁷ , n, m, k, 1, Y, W, Z, L and A are the same as those defined in the first embodiment.

In the description, the general formulas are (I), (II), (III), etc. indicated by Roman numerals.

Reaction scheme 1

The compounds of general formula (I) in which n is 0, R ³ is an oxygen atom, and m is 1, and R ¹ , R ⁴ , R ⁵ , R ⁷ , Y, k, I, W, Z, L, A can be prepared according to reaction scheme 1 detailed above for the compounds of general formula (I):

Μ V ΙΓ* Γ*

V b. also, m tö

or the compounds of general formula (II).

- where the meanings of R ¹ , R ⁴ , R ⁵ , R ⁷ , Y are detailed above for the compounds of general formula (I) - and by connecting the compounds of general formula (III):

III

-where the meaning of k, I, W, Z, L, A is detailed above for the compounds of general formula (I);

or the compounds of general formula (IV).

- where the meanings of R ¹ , R ⁴ , R ⁵ , R ⁷ , Y are detailed above for the compounds of general formula (I) - and by connecting the compounds of general formula (V)

- where W means N, and the meanings of k, I, Z, L, A are detailed above for the compounds of general formula (I).

Typical conditions include treating the reagents with a suitable coupling agent such as HATU, HBTU, EDC, T3P using a suitable solvent such as CH 2 Cl 2 or DMF. Under alternative conditions, the carboxylic acids (acid) of general formula (III) or (IV) can be converted into the corresponding acid chloride with oxalyl chloride or Ghosez reagent in a suitable solvent, such as dichloromethane or dimethylformamide, and then the acyl chloride formed is reacted with the corresponding amine in a suitable in the presence of a base such as DIPEA or TEA to form an amide. The reaction is carried out at a temperature between 0°C and room temperature. The required reaction time is 6-20 hours. The progress of the reactions is followed by thin-layer chromatography. The processing of the reaction mixture can be carried out using different methods, it is usually stopped by adding water. The product is isolated by extraction with a suitable organic solvent and purified by crystallization or column chromatography.

Reaction scheme 2

The compounds of formulas (111) and (IV) can be prepared according to reaction scheme 2:

ft V ft ft rt ,Η

during which the compounds of formula (II)

- where the meaning of R ¹ , R ⁴ , R ⁵ , R ⁷ , Y is detailed above for the compounds of general formula (I);

or the compounds of general formula (V).

-where W is N, and k, I, Z, L, A are as detailed above for the compounds of general formula (I) - a base (for example DIPEA, TEA) is reacted with ethyl/methyl-2-chloro-2-oxoacetate in the presence of a suitable solvent, for example dichloromethane, thus the compounds of general formula (IVa).

1837742

- where the meaning of R ¹ , R ⁴ , R ⁵ , R ⁷ , Y is detailed above for the compounds of general formula (I);

or the compounds of general formula (Illa).

He

Illa

- where W means N, and the meanings of k, I, Z, L, A are detailed above for the compounds of general formula (I) - are obtained, and then by simultaneous basic hydrolysis of these esters, the corresponding carboxylic acids of general formula (IV) are obtained

- where the meaning of R ¹ , R ⁴ , R ⁵ , R ⁷ , Y is detailed above for the compounds of general formula (I);

or the compounds of formula (III).

1837742

- where W means N, and the meanings of k, I, Z, L, A are detailed above for the compounds of general formula (I).

Reaction scheme 3

Or the compounds of general formula (III) can also be prepared according to the 3rd reaction scheme,

during which the compounds of general formula (VI).

VI

- where W is CH, and k, I, Z, L, A are the previously detailed compounds of general formula (I) - react with ethyl isocyanoacetate in the presence of a base, for example NaH, in a suitable solvent, for example THF, thus the compounds of formula (VII) are obtained

1837742

VII

- where W is CH, and the meanings of k, I, Z, L, A are detailed above for compounds of general formula (I) - and compounds of general formula (VII) by reacting with aqueous hydrochloric acid solution and then with aqueous KOH solution to form (III ) compounds with the general formula are obtained

III

- where W is CH, and the meanings of k, I, Z, L, A are detailed above for the compounds of general formula (I).

Reaction scheme 4

The compounds of general formula (I) can also be prepared according to reaction scheme 4,

- where R ² is C1-6 alkyl or hydrogen, n is 1, m is 0, W is N, and R ¹ , R ⁴ , R ⁵ , R ⁷ , Y, k, I, Z, L, A are detailed above for the ih* f** MWH compounds of the general formula (I) - by activating the corresponding primary amine compounds of the general formula (Vili)

- where n means 1, and R ¹ , R ² , R ⁴ , R ⁵ , R ⁷ , Y means detailed above for the compounds of general formula (I) 5 - with usual procedures and reagents, e.g.

CDI, chloroformates or 1,1'-thiocarbonyldiimidazole in suitable solvents such as dichloromethane or DMF under an argon atmosphere and then reacted with compounds of formula (V)

-where W is N, and k, I, Z, L, A are as detailed above for the compounds of general formula (I) carried out at a temperature between -0 °C and room temperature. The required reaction time is 15-20 hours. The progress of the reactions is followed by thin-layer chromatography. The processing of the reaction mixture can be carried out using different methods, it is usually stopped by adding water. The product is isolated by extraction with a suitable organic solvent and purified by crystallization or column chromatography.

The compounds of general formulas (II), (V) and (Vili) can be obtained commercially or can be produced by methods known in the field, the preferred methods include, but are not limited to, those described in the following examples.

The content of the present description also covers all possible isotope-labeled forms of the compounds.

ft V r*. If ¹ ·* ο® H

The compounds of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intraarticular, intrathecal, intraperitoneal, intraventricular, intracerebroventicular, intramedullary injection, intracisternal injection or infusion, subcutaneous injection or implant), ophthalmic, nasal, vaginal, rectal, sublingual, and in topical routes of administration and may be formulated alone or together in suitable unit dosage forms containing pharmaceutically acceptable excipients suitable for each route of administration.

Alternatively, the compounds can be administered locally, i.e. non-systemically, for example by injecting the compound directly into the kidney or heart area, often in the form of a modified release formulation. In addition, the active ingredient can be administered in a targeted drug delivery system, for example in a liposome coated with a tissue-specific antibody. Liposomes are selectively taken up by the target organ.

The pharmaceutical preparations according to the invention usually contain 0.01 to 500 mg of active ingredient in one dosage unit. However, it is possible that the amount of the active ingredient in some preparations exceeds the upper or lower limits defined above.

The compounds can be administered 1-4 times a day, preferably once or twice a day.

This dosage level and schedule can be adjusted to ensure optimal therapeutic response. However, it is clear that the specific dose level and frequency of administration of a given dose may vary depending on a number of factors, including the activity of the specific compound, its metabolic stability, duration of action, age, body weight, general health, patient gender, nutrition, the method and time of administration, the speed of excretion, drug combinations, the severity of the given condition and the existing therapy.

Another subject of the invention is the production of medicines containing compounds of general formula (I) or their pharmaceutically acceptable salts, biologically active metabolites, prodrugs, racemates, enantiomers, diastereomers, solvates and hydrates.

The pharmaceutical compositions of the invention can be formulated into a variety of pharmaceutical dosage forms, including, but not limited to, solid oral dosage forms such as tablets (e.g., buccal, sublingual, effervescent, chewable, orodispersible, freeze-dried), capsules, lozenges, pastilles, pills, orodispersible films, granules, powders;

liquid oral dosage forms including, but not limited to, solutions, emulsions, suspensions, syrups, elixirs, oral drops; parenteral dosage forms, including but not limited to intravenous injections, intramuscular injections, subcutaneous injections; other dosage forms including, but not limited to, eye drops, semi-solid ophthalmic preparations, nasal drops and sprays, transdermal dosage forms, suppositories, rectal capsules, rectal solutions, emulsions and suspensions, etc.

The pharmaceutical compositions according to the invention can be prepared by any conventional method, for example mixing, dissolving, emulsifying, suspending, encapsulating, freeze drying, extruding, laminating, film forming, granulating, grinding, encapsulating, coating or tableting operations.

The pharmaceutical preparations according to the invention can thus be formulated in any usual way, with one or more physiologically acceptable excipients. Any known method and auxiliary material can be used in a manner known and appropriate in the field.

Excipients suitable for the production of dosage forms can be selected from the following categories, including, but not limited to, tablet and capsule fillers, tablet and capsule binders, release modifiers, disintegrants, lubricants, glidants, sweeteners, flavoring agents, flavoring agents, coating agents, surfactants, antioxidants , buffer materials,

1837742 complexing agents, emulsifiers, lyophilization aids, microencapsulating agents, ointment bases, penetration enhancers, solubilizers, solvents, cone bases and suspending agents.

According to one embodiment, the invention relates to the use of specific excipients capable of improving the solubility, dissolution, penetration, absorption and/or bioavailability of the active ingredient(s), including, but not limited to, hydrophilic polymers, melt extrusion aids, surfactants materials, buffer materials, complexing agents, emulsifiers, lyophilizing aids, superdisintegrants, microencapsulating agents, penetration enhancers, solubilizers, co-solvents and suspending agents.

The ingredients and different production methods described above are only representative. Other materials and production methods well known in the field can also be used.

EXAMPLES

The invention is further defined in the following examples. However, it should be noted that the examples are for illustrative purposes only. It is clear from the foregoing details and the examples that a person skilled in the art can learn the essential features of the invention and, without deviating from its essence and scope, can make various changes and modifications in order to adapt the invention to different applications and circumstances. As a result, the invention is not limited to the illustrative examples described below, but is defined in the claims.

In general, the compounds of general formula (I) can be prepared by the methods described in the following examples and/or intermediates with general knowledge for a specialist skilled in the field. Solvents,

1837742 temperatures, pressures and other reaction conditions would be readily chosen by one skilled in the art. The starting materials are commercially available and/or can be easily prepared by a specialist.

The present invention is illustrated by the following non-limiting examples.

In the examples below, room temperature means a temperature between 20 °C and 25 °C.

The meanings of the abbreviations used in the specific examples are as follows:

AcOH acetic acid atmosphere ATM 10 cc. concentrated BH3.THF borane-tetrahydrofuran complex solution CDI 1,Γ-carbonyldiimidazole DCE 1,2-dichloroethane DIPEA N, N-diisopropylethylamine 15 DMF N, N '-d i m etic If o rma m id DMSO dimethyl sulfoxide EDC.HCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride EDC (N-(3-dimethylaminopropyl)-A)-ethylcarbodiimide FALL electron sputter ionization 20 Et ₂ O diethyl ether EtOAc ethyl acetate EtOH ethanol IPy ₂ BF ₄ bis(pyridine)iodonium tetrafluoroborate KOtBu potassium tert-butylate 25 LC-MS mass spectrometer coupled liquid chromatography MeOH methanol SIX 7-azabenzotriazole-141-1,1,3,3-tetramethyluronium- hexafluorophosphate

1837742

HBTU O-(benztriazol-1-yl)-A/,A/,A/',/V'-tetramethyluronium hexafluoro- phosphate HAPPY 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid HOBt. H ₂ O 1-hydroxybenzotriazole hydrate 5 HPLC high performance liquid chromatography NaOtBu sodium tert-butylate PCC pyridinium chlorochromate Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd/C palladium on activated carbon 10 Pd(OH) ₂ /C palladium hydroxide on activated carbon Pd(PPh ₃ ) 2 Cl ₂ bis(triphenylphosphine)palladium(ll) dichloride RP-HPLC reversed-phase high-performance liquid chromatography RuPhos 2-Dicyclohexylphosphino-2',6-diisopropoxybiphenyl Selectfluor _J V-chloromelyl-/V'-fluorotriethyleneammonium bis(tetrafluoroborate) 15 T3P cyclic propylphosphonic anhydride trimer TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography 20

Some of the aromatic amine intermediates were commercially available, while others were synthesized based on the available chemical literature (Table 1).

f** tn w iN V IN IN

H

detailed in ohms:

Mahal K. et al ChemMedChem 9 (2014) 847-854

A number of aromatic amines were prepared by the following synthetic routes:

Intermediate 10

NaH Mel

DMF

1,3-Dimethyl-1H-indol-5-amine

Dissolve 500 mg (3.08 mmol) of 5-nitroindole in 10 mL of DMF and add 0.135 g (5.625 mmol) of NaH. After stirring for 5 minutes, 0.211 ml (3.39 mmol) of methyl iodide was added and the mixture was stirred overnight. Concentrated NFLCl solution was added and extracted twice with 10 mL of ethyl acetate. The combined organic phases are washed twice with 10 ml of water and twice with brine, then dried over Na2SO4 and evaporated to dryness. 536 mg of 1-methyl-5-nitroindole are obtained.

0.312 ml (3.35 mmol) of phosphorus oxychloride 10 is added to 2.5 ml of dimethylformamide at a temperature of -20 °C. 536 mg (3.04 mmol) of 1-methyl-5-nitroindole are then added in portions. The mixture is stirred for 5 hours at room temperature. 5 ml of water are added and the mixture is extracted with 20 ml of dichloromethane. The organic phase is extracted twice with 10 ml of water and 10 ml of brine. The organic phase is dried over Na2SÜ4 and evaporated to dryness. 666 mg of 1-methyl-5-nitro-1/-/-indole-3-carbaldehyde are obtained.

496 mg (2.43 mmol) of 1-methyl-5-nitro-1/-/-indole-3-carbaldehyde were dissolved in 200 ml of methanol. The solution is hydrogenated with 207 mg of 10% Pd/C at atmospheric pressure for 12 hours. The catalyst is filtered off and the filtrate is concentrated. The crude product is purified by flash column chromatography (hexane/EtOAc) to give 165 mg of 1,3-dimethyl-1/-/-indol-5-amine.

Intermediate 11

V IN N ¢4

NaOtBu benzylamine

3-Fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-amine

Under an argon atmosphere, 1.86 g (9.4 mmol) of 5-bromo-7-azaindole are dissolved in 225 ml of anhydrous acetonitrile and 45 ml of cc. in acetic acid. The solution was heated to 40 °C, 5 g of Selectfluor was added, and the resulting mixture was heated to 80 °C and stirred overnight. It is then evaporated to dryness and the crude product is dissolved in 200 ml of ethyl acetate and then washed twice with water. The organic phase is dried over NazSCL and then evaporated. 362 mg of 5-bromo-3-fluoro-7-azaindole is isolated by flash column chromatography (dichloromethane/methanol=99/1).

A solution of 300 mg (1.4 mmol) of 5-bromo-3-fluoro-7-azaindole in 12 ml of anhydrous tetrahydrofuran is cooled to 0 °C and 140 mg of NaH (60 m/m % mineral oil suspension, 3.5 mmol, 2.5 mol equivalent) are added in parts. The solution was then allowed to warm to room temperature (about 30 minutes), then 397 mg (2 mol equivalent) of iodomethane was added dropwise and the mixture was stirred overnight. The reaction is stopped by adding water. The mixture was extracted three times with ethyl acetate. The extract was dried over Na2SÜ4, filtered and evaporated to dryness, thus obtaining 380 mg of 5-bromo-3-fluoro-1-methyl-7-azaindole in the form of a yellowish-brown oil, which was used in the next step without further purification.

380 mg (1.4 mmol) of 5-bromo-3-fluoro-1-methyl-7-azaindole are dissolved in 15 ml of anhydrous toluene. Argon gas was flowed through the solution for 20 minutes. 0.405 mL (2.8 mmol) of benzylamine, 405 mg (4.2 mmol) of NaOfBu, 66 mg (0.14 mmol) of RuPhos and 65 mg (0.07 mmol) of Pd2(dba) are then added. s. The reaction mixture is a

V

N

W

W

It is heated to 105 °C overnight. The mixture is allowed to cool to room temperature, water is added, and the mixture is extracted three times with ethyl acetate, dried over Na2SO4 and evaporated to dryness. The obtained 96 mg of 5-benzylamino-3-fluoro-1-methyl-7-azaindole is used without further purification.

96 mg (0.376 mmol) of 5-benzylamino-3-fluoro-1-methyl-7-azaindole are hydrogenated in a mixture of 6 ml of methanol and ml of EtOAc in the presence of 35 mg of 10% Pd/C at atmospheric pressure for 48 hours. The catalyst is filtered off and the solvent is evaporated. The crude product is purified by flash column chromatography using EtOAc as eluent. 23 mg of 3-fluoro-1-methyl-1/-/-pyrrolo[2,3-ö]pyridine-10-5-amine are obtained.

Intermediate 12

2-(Trifluoromethyl)-! H-indol-5-amine

200 mg (1.0 mmol) of 2-(trifluoromethyl)-1H-indole are dissolved in 1 ml of acetic anhydride. The mixture is cooled to 0 °C and 131 mg (0.54 mmol) of Cu(NO3)2 3H2O is added. The reaction mixture was stirred at room temperature for 2.5 hours. Water and diethyl ether were added and the organic phase was extracted three times with 8% sodium bicarbonate solution and once with water. The organic phase is dried over Na2SO4 and evaporated to dryness. 63 mg of 5-nitro-2-(trifluoromethyl)-1/-/-indole are obtained.

mg (0.27 mmol) of 5-nitro-2-(trifluoromethyl)-1/-/-indole is hydrogenated at atmospheric pressure and room temperature in the presence of 6 mg of a 10% Pd/C catalyst in 5 ml of ethanol for 9 hours. After that, another 6 mg of 10% Pd/C was added,

N ft ft, Μ

Η and the reaction is continued for two days. The catalyst is filtered off and the solvent is evaporated, thus obtaining 55 mg of crude 2-(trifluoromethyl)-1/-/-indol-5-amine, which is used without further purification in the next step.

Intermediate 13

Selectfluor O ₂ n

h ₂ Pd/C

3-Fluoro-1H-pyrrolo[2,3-b]pyridin-5-amine

1.0 g (6.13 mmol) of 5-nitro-7-azaindole is dissolved in a mixture of 145 ml of anhydrous acetonitrile and 30 ml of acetic acid. The mixture is heated to 40 °C and 3.5 g (9.2 mmol) of Selectfluor is added. The temperature was raised to 80 °C and the mixture was kept at this temperature overnight. The solvent was evaporated, EtOAc was added, and the mixture was extracted three times with water. The organic phase is dried and evaporated, the residue is treated with diethyl ether, and the solid is filtered off. The product thus obtained is purified by column chromatography, using EtOAc as eluent to obtain 280 mg of 3-fluoro-5-nitro-7-azaindole.

110 mg (0.6 mmol) of 3-fluoro-5-nitro-7-azaindole in 156 ml of ethanol are hydrogenated using 11 mg of 10% Pd/C at atmospheric pressure for 24 hours. The catalyst is filtered off and the filtrate is concentrated. The crude product is purified by flash chromatography in dichloromethane containing 5% methanol as eluent. 64 mg of 3-fluoro-1/7-pyrrolo[2,3-b]pyridin-5-amine are obtained.

1837742

IPy ₂ BF ₄

Mel NaH

1-Methyl-7-(trifluoromethyl)-1H-indol-5-amine

1.72 g (8.36 mmol) of 4-nitro-2-(trifluoromethyl)aniline were dissolved in 20 ml of dichloromethane. While maintaining the temperature between 0 and 10 °C, 1.6 g (13.4 mmol) of IPy2BF4 is added portionwise. The temperature is maintained at 0-5°C and 2.37 mL (26.75 mmol) of trifluoromethanesulfonic acid is slowly added. The resulting mixture can be stirred at room temperature for 24 hours. The reaction mixture is stopped by adding 20 ml of water. After extraction with dichloromethane (2x20 ml), the combined organic phase is washed with saturated Na2S2Os solution (20 ml), dried over anhydrous Na2SO4, filtered and evaporated under vacuum. The residue is purified by column chromatography on silica gel, using a mixture of cyclohexane and ethyl acetate (4:1) as eluent. 1.52 g of 6-iodo-4-nitro-2-(trifluoromethyl)aniline are thus obtained.

5 ml of TEA was added to 560 mg (1.69 mmol) of 6-iodo-4-nitro-2-(trifluoromethyl)aniline under an argon atmosphere. At room temperature, 101 mg of Pd(PPh3)2Cl2, 30 mg of Cu, and 0.30 ml of trimethylsilylacetylene are added and the mixture is stirred overnight. The solvent and volatiles were removed under reduced pressure and diethyl ether was added to the residue. After filtration on a bed of Celite, the organic |N IN m w

Extract H is washed with saline, dried over anhydrous NazSO4, filtered and evaporated under vacuum. The residue is purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (10:1) as eluent. 300 mg of 4-nitro-2-(trifluoromethyl)-6-[2-(trimethylsilyl)ethynyl]aniline are thus obtained.

380 mg (1.256 mmol) of 4-nitro-2-(trifluoromethyl)-6-[2-(trimethylsilyl)ethynyl]aniline are dissolved in 4 ml of dimethylformamide and 240 mg of Cul are added. The reaction mixture is kept at 100 °C for 2 hours under an argon atmosphere. After the reaction was complete (monitored by thin layer chromatography), the solvent was removed in vacuo and EtOAc was added to the residue. After filtration on a bed of Celite, the organic extract 10 is washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under vacuum. The residue is purified by column chromatography on silica gel, using a mixture of cyclohexane and ethyl acetate (5:1) as the eluent to obtain 220 mg of 5-nitro-7(trifluoromethyl)-1H-indole.

In an argon atmosphere, 127 mg (0.5 mmol) of 5-nitro-7-(trifluoromethyl)-1H-indole 15 are dissolved in 5 ml of tetrahydrofuran. The mixture was cooled to 0 °C and 40 mg of NaH (60%, in mineral oil) was added. The suspension was stirred for 20 min and 0.07 mL of methyl iodide in 2 mL of THF was added slowly. The mixture is stirred overnight at room temperature. After adding water and EtOAc, the organic phase is separated, washed three times with water, dried over Na 2 SO 4 , and evaporated in vacuo. 60 mg of 1-methyl-5-nitro-7-(trifluoromethyl)-1/7-indole are obtained.

mg (0.41 mmol) of 5-nitro-7-(trifluoromethyl)-1-methyl-1/-/-indole was dissolved in 20 ml of methanol. 10 mg of Pd(OH)2/C are added and hydrogenated at atmospheric pressure for 2 hours. An additional 5 mg of Pd(OH)2/C is added and hydrogenation is continued for 4 hours. The catalyst is filtered off and the filtrate is evaporated under vacuum. The crude product is purified by column chromatography using a mixture of hexane and ethyl acetate (2:1) as eluent. 48 mg of 1-methyl-7(trifluoromethyl)-1/-/-indol-5-amine are obtained.

Piperazine intermediates were either purchased from a commercially available source (Table 2) or synthesized (see below).

tr fs W Mi nrf

Table 2

Intermediary Structure Intermediary Structure 15 Ό-υα 19 ^.CF, hn η r J 16 20 ^.OMe HN I \ lí 17 ox 21 LA „° ° ^? -α 18 Cu3

Non-commercial piperazine derivatives were synthesized according to the synthetic procedures described below:

Intermediate 22

4-{[6-(Trifluoromethyl)pyridin-3-yl]methyl}piperazine

0.53 g (3 mmol) of 2-trifluoromethyl-5-pyridinecarbaldehyde and 0.55 g (3 mmol) of tert-butyl (piperazine-1-carboxylate) were dissolved in 40 ml of dichloromethane and 0.95 g (4.5 mmol) sodium triacetoxyborohydride is added. The reaction mixture is stirred overnight at room temperature. The reaction mixture is then extracted with 15 ml of 20% potassium carbonate solution and water. The organic phase is dried over Na2SO4 and evaporated in vacuo. The crude product is purified by column chromatography, using chloroform and ethanol as eluents. 0.65 g (63%) of tert-butyl (4-{[615 (trifluoromethyl)pyridin-3-yl]methyl}piperazine-1-carboxylate) is obtained.

3 7 7 4 2

0.65 g (1.88 mmol) of tert-butyl (4-{[6-(trifluoromethyl)pyridin-3-yl] methyl}piperazine-1carboxylate) was treated with 10 ml of a 30% HCl solution in EtOAc- in at a temperature of 0 °C. The mixture is stirred for 3 hours, then the precipitated product is filtered off, washed with diethyl ether and dried under vacuum. 0.56 g of 4-{[6-(trifluoromethyl)pyridin-3-yl]methyl}piperazine hydrochloride is obtained.

Intermediate 23 w

4-{[5-(Trifluoromethyl)pyridin-2-yl]methyl}piperazine

Intermediate 23 was prepared analogously to intermediate 24.

Intermediate 24

4-[(3-Chloro-4-fluorophenyl)methyl]piperazine

1.86 g (10 mmol) of tert-butyl (piperazine-1-carboxylate), 2.23 g (10 mmol) of 3-fluoro-4-chlorobenzylbromide and 2.78 g (20 mmol) of HCCOs in 30 mL of ethanol dissolve and heat under reflux for 12 hours. The mixture is concentrated in vacuo, 20 ml of water are added and extracted three times with 20 ml of dichloromethane. The combined organic phases are dried over Na2SÜ4 and evaporated under vacuum. 3.28 g (99%) of tert-butyl {4-[(4-chloro-3-fluorophenyl)methyl]piperazine-1-carboxylate} are obtained.

3.28 g (10 mmol) of tert-butyl {4-[(4-chloro-3-fluorophenyl)methyl]piperazine-1-carboxylate} are dissolved in 30 ml of dichloromethane. Add 7.7 mL of TFA and stir overnight at room temperature. The mixture is evaporated under vacuum. 50 ml of 10% K2CO3 are added and extracted twice with 60 ml of ethyl acetate. The

I also m »

R f'· too

ΓΠ

The combined organic phases are dried over Na2SO4 and evaporated under vacuum. 2.1 g (92%) of 4-[(4-chloro-3-fluorophenyl)methyl]piperazine are obtained as an off-white solid.

The piperidine compounds shown in Table 3 were obtained from commercial sources 5 .

Table 3

Intermediary Structure Intermediary Structure 25 P P 32* i)—p Q 26 .OMe ^HN I \\C 33 ^Cl HN 27 34 T y--Z He 28 He 7 oh he T 35 29 ^HN I \\C 36 ^OMe HN > \\C 0 30 ^HN I arc 37 ^HN I i ll^ 0 31 He

*A/-Boc-hexahydro-1/7-azepin-4-one is commercially available and easily reduced with sodium borohydride to give the corresponding hydroxyl derivative, which was further reacted analogously as described in 3-[(4- in the case of methylphenoxy)methyl]azetidine. We used a racemic mixture.

Intermediate 38

Intermediate 15 p

Intermediate 38

Ethyl-(2-{4-[(4-methylphenyl)methyl]piperazin-1-yl}-2-oxoacetate)

To a solution of 854 mg (4.49 mmol) of 1-(4-methylbenzyl)piperazine and 0.94 ml (6.7 mmol) of TEA in 25 ml of dichloromethane at 0 °C was added 0.6 ml (5.37 mmol) of ethyl [chloro(oxo)acetate] is added and the mixture is stirred overnight at room temperature. Then 100 ml of dichloromethane is added and the mixture is washed with water, dried over _Na2SO4 , filtered and evaporated under reduced pressure. thus 1.43 g (95%) of the product is obtained in the form of a light yellow oil.

The intermediates described in Table 4 were prepared based on the synthetic description of intermediate 38.

Table 4

Intermediary Structure Starting intermediate Intermediary Structure Starting intermediate 38 0 Year 15 43 Ύα 27 39 Yoac: 24 44 0 Year 28 40 Aq _o a 21 45 0 Year 33

R

ALSO

Intermediary Structure Starting intermediate Intermediary Structure Starting intermediate 41 0 Yaxr 25 46 Voxr 34 42 26 47 Dare 35

Intermediate 48 ο

Intermediate 38 ο

Intermediate 48

2-{4-[(4-methylphenyl)methyl]piperazin-1-yl}-2-oxoacetic acid

To a solution of ethyl-(2-{4-[(4-methylphenyl)methyl]piperazin-1-yl}-2-oxoacetate) (3.098 g, 10.67 mmol) in ethanol was added NaOH (515 mg 12.88 mmol, mol equiv ) with water (5 ml) was added dropwise at 0 °C. The mixture is stirred at room temperature for 2.5 hours and then concentrated. The residue is dissolved in 50 ml of water, extracted with diethyl ether, acidified with 12.9 ml of 1 M aqueous HCl solution and extracted with CFhCl 10. The aqueous phase was freeze-dried to give 3.546 g of the title compound as a white solid containing 1.2 mol equivalents of sodium chloride. This intermediate was used in the next step without further purification.

The intermediates described in Table 5 were prepared based on the synthetic description 15 of intermediate 48.

Table 5

1837742

Intermediary Structure Starting intermediate Intermediary Structure Starting intermediate 48 0 Yoxr 38 53 0 YUA 43 49 0 VcuX 39 54 °τΧότ° 44 50 ° TX 40 55 v-axr 45 51 0 VXxr 41 56 "/q rr 46 52 0 42 57 0 Ya σ NH 47

Intermediate 58

K ₂ CO ₃

2-Oxo-2-(1-{[4-(trifluoromethyl)phenyl]methyl}piperidin-4-yl)acetic acid

To a solution of 4-piperidone monohydrate hydrochloride (3.0 g, 19.5 mmol) in 60 mL of dimethylformamide was added potassium carbonate (5.4 g, 39 mmol) and 4e 1% w Ή (trifluoromethyl)benzyl bromide (7 .0 g, 29.29 mmol, 1.5 mol equivalent) The mixture is stirred overnight at room temperature in an argon atmosphere. After completion of the reaction (monitoring with TLC, visualization with iodo-o-tolidine), the mixture was poured into water (80 ml) and extracted with EtOAc (3x30 ml). The combined organic phase is washed with brine (3x30 ml), dried over anhydrous Na ₂ SO 4 , filtered and evaporated under vacuum. The residue is chromatographed on silica gel, using a mixture of cyclohexane-EtOAc (1:1) as eluent to obtain 3.21 g of 1-{[4(trifluoromethyl)phenyl]methyl}piperidin-4-one.

To a stirred suspension of NaH (60%, in mineral oil) (751 mg 18.76 mmol, 1.5 mol equivalent) in 10 tetrahydrofuran (100 mL) was added a solution of ethyl isocyanoacetate (1.78 mL, 16.25 mmol) in 5 mL tetrahydrofuran over 15 min. at 0-5 °C in an argon atmosphere. The mixture is then stirred for 40 minutes, then a solution of 3.21 g (12.5 mmol) of 1-{[4-(trifluoromethyl)phenyl]methyl}piperidine-4-one prepared in 45 ml of tetrahydrofuran is added dropwise at 0-5 °C . The temperature was allowed to warm to room temperature and the mixture was stirred overnight. After the reaction was complete (monitored by thin layer chromatography), the mixture was poured into 100 mL of water and extracted with EtOAc (2x80 mL). The combined organic phase is washed with brine (2x30 ml), dried over anhydrous Na ₂ SC>4, filtered and evaporated under vacuum. 1.27 g of ethyl (2-(formylamino)-2-{1-[420 (trifluoromethyl)benzyl]piperidin-4-ylidene}acetate) is obtained, which is used in the next step without further purification.

To a solution of ethyl (2-(formylamino)-2-{1-[4-(trifluoromethyl)benzyl]piperidin-4-ylidene}acetate) (1.27 g, 3.43 mmol) in ethanol (21 mL) 10% HCl solution (21 ml) is added at 0-5 °C in an argon atmosphere, and then the mixture is stirred overnight at room temperature. After completion of the reaction (monitored by thin layer chromatography), a solution of KOH (3.79 g, 67.7 mmol) in 28 mL of EtOH and 10 mL of water (pH=12) was added to the resulting mixture. After the hydrolysis is complete (monitored by thin layer chromatography), the pH of the mixture is adjusted to 6 by adding 1 N HCl solution. The precipitated solid is removed by filtration and the mother liquor is evaporated under vacuum to give 3.42 g (1.08 g) of 2-oxo-2-(1-{[4V

IS m w (trifluoromethyl)phenylmethyl}piperidin-4-yl)acetic acid with KCl. In the next step, we use it without further cleaning.

The intermediates described in Table 6 were prepared based on the synthetic description of intermediate 58.

Table 6

Intermediary Structure 59 0 Υασ 60 0 ”/0Xr°

In certain amidation reactions (methods D, F, G), the aromatic amine is first acylated, and the corresponding ester is hydrolyzed to give [(1-methyl-1/-/-indol-5yl)carbamoyl]formic acid.

[(1-Methyl-1H-indol-5-yl)carbamoyl]formic acid

1-Methyl-1/-/-indol-5-amine (1.18 g, 8.07 mmol) and DIPEA (2.1 mL, 12.06 mmol) were dissolved in dichloromethane (50 mL) and ethyl -[chloro(oxo)acetate] (0.98 ml, 8.77 mmol) was added dropwise to the resulting reaction mixture at 0 °C. The mixture is stirred for 3 hours at room temperature. The reaction mixture is treated with saturated aqueous sodium bicarbonate solution and the organic phase is washed with water. The organic phase is r is also m w π

Dry over NazSCU and evaporate to dryness. Ethyl {[(1-methyl-1 H -indol-5yl)carbamoyl]formate} is obtained. Yield: 1.2 g (61%).

Ethyl {[(1-methyl-1/-/-indol-5-yl)carbamoyl]formate} (1.2 g, 4.87 mmol) was hydrolyzed with 2.1 mol equivalents of aqueous UOH.H2O solution (426 mg, 10.15 mmol 6 mL in 5 water) in methanol (30 mL). The reaction mixture was stirred for 4 hours. The mixture was adjusted to pH 3 by addition of 1 M HCl (ca. 10 mL) and extracted with EtOAc (2x40 mL). The organic phase is dried over Na2SO4 and evaporated to dryness. Yield: 1.5 g of crude product of [(1-methyl-1H-indol-5-yl)carbamoyl]formic acid.

As a result of the amide coupling reactions, the 10 examples in Table 7 were carried out according to one of the following procedures (A-H).

THE PROCEDURE:

N-(1-Methyl-1/7-indol-5-yl)-2-{4-[(4-methylphenyl)methyl]piperazin-1-yl}-2-oxoacetamide

DMF, Et _3N

EDC.HCI

HOBt. H ₂ O

500 mg of 2-{4-[(4-methylphenyl)methyl]piperazin-1-yl}-2-oxoacetic acid (1.906 mmol) was dissolved in anhydrous DMF under an argon atmosphere. To this solution was added 350 mg (2.287 mmol, 1.2 mol equiv) of 1-hydroxybenzotriazole hydrate (HOBLH2O) and 438 mg (2.287 mmol, 1.2 mol equiv) of A/-(3-dimethylaminopropyl)-/\/' ethyl carbodiimide hydrochloride (EDC.HCl) and the mixture was stirred under argon atmosphere for 15 min. 278 mg (1 mol equivalent) of 1-methyl-1/7-indol-5-amine and 386 mg (2 mol equivalent) of TEA are then added. The resulting reaction mixture was stirred for 24 hours at room temperature in an argon atmosphere. After completion of the reaction (monitored by thin layer chromatography), the mixture was diluted with water (20 mL) and extracted with EtOAc (3x20 mL). The combined organic phase is washed with water, dried over anhydrous Na2SÜ4, filtered and evaporated under vacuum. THE

N

N m

The crude product MH was purified by column chromatography to give 71 mg (10%) of the title compound. LC-MS (ESI) m/z [M+H] ⁺ = 391.2

PROCEDURE B:

M-{3-Fluoro-1-methyl-1H-pyrrolo[2,3-ö]pyridin-5-yl}-2-{4-[(45 methylphenyl)methyl]piperazin-1-yl}-2-oxoacetamide

mg of 2-(4-[(4-methylphenyl)methyl]piperazin-1-yl}-2-oxoacetic acid is dissolved in 1 mL of anhydrous DMF under an argon atmosphere. To this solution is added 22.4 mg (23 µl, 0.168 mmol, 1 .1 mol equivalent) of 1-chloro-/V,A/,-2-trimethylprop-1-en-1-amine (Ghosez reagent) and the mixture was stirred at room temperature for 30 minutes under an argon atmosphere. Then 23 mg (0. 91 mol equiv) of 3-fluoro-1-methyl-1Hpyrrolo[2,3-o]pyridin-5-amine and 22 μΙ TEA (15.5 mg, 0.155 mmol) in DMF (0.5 mL), and the reaction mixture is stirred in an argon atmosphere for 4 hours at room temperature

Pour into 8 ml of water and extract twice with 15 ml of ethyl acetate. The organic phase is dried over anhydrous NazSCh, filtered and evaporated in vacuo. The residue is chromatographed on silica gel, using ethyl acetate as eluent, to obtain 16 mg (47%) of the title compound. LC-MS (ESI) m/z [M+H] ⁺ = 410.2

PROCEDURE C:

N-[1-Methyl-7-(trifluoromethyl)-1H-indol-5-yl]-2-{4-[(4-methylphenyl)methyl]piperazin-1-yl}2-oxoacetamide

N V n IN

W

IN V IfN IN mw mg (0.076 mmol) to a solution of 2-{4-[(4-methylphenyl)methyl]piperazin-1-yl}-2-oxoacetic acid in 2 mL of anhydrous dichloromethane was added oxalyl chloride (20 µl, 0.0236 mmol ) and a drop of DMF is added at 0 °C under a nitrogen atmosphere. After dosing, the mixture can be stirred for 1 hour at a temperature of 5-10 °C. After completion of the reaction (monitored by thin layer chromatography), the solvent is removed in vacuo and the anhydrous ChhCh is evaporated several times from the residue. A solution of the residue in dichloromethane (2 mL) was added dropwise to a solution of 1-methyl-7-(trifluoromethyl)-1 H -indol-5-amine (16 mg, 0.075 mmol) and a solution of TEA (20 µl) in dichloromethane (1 mL). The resulting mixture can be stirred at room temperature for 12 hours. The reaction was quenched by the addition of water (10 mL). The reaction mixture is extracted twice with dichloromethane, the combined organic phase is washed with water, dried over anhydrous Na2SÜ4, filtered and evaporated under vacuum. The residue was purified by preparative layer chromatography on silica gel, using a mixture of EtOAc-cyclohexane (1:1) as the eluent, to obtain 8.0 mg (24%) of the title compound. LC-MS (ESI) m/z [M+H] ⁺ = 459.2

PROCEDURE D:

N-(1-Methyl-1H-indol-5-yl)-2-oxo-2-(4-{[5-(trifluoromethyl)pyridin-2-yl]methyl}piperazin-1-yl)acetamide

To a solution of 153 mg (0.7 mmol) [(1-methyl-1/-/-indol-5-yl)carbamoyl]formic acid (265 mg, 0.7 mmol) in 30 mL of anhydrous dichloromethane (265 mg, 0.7 mmol) was added HBTU (265 mg , 0.7 mmol) and TEA (540 pl, 5.5 mol equivalent) are added at room temperature under an argon atmosphere. The mixture can be stirred for 20 minutes, then 1-{[5(trifluoromethyl)pyridin-2-yl]methylpiperazine (223 mg, 0.7 mmol) is added. The mixture can be stirred overnight at room temperature. After the completion of the reaction (monitored by thin-layer chromatography25), the reaction is stopped by adding 10 ml of saturated NaHCOs solution, the organic phase is washed with water (10 ml), then the organic phase is dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under vacuum. The residue on silica gel ft C ft ft tn

Η is purified by column chromatography, using a mixture of dichloromethane and methanol (10:1) as eluant. 60 mg (20%) of the title compound are thus obtained. LC-MS (ESI) m/z [M+H] ⁺ = 446.2

THIS PROCEDURE:

2-{4-[(4-Methylphenyl)methyl]piperazin-1-yl}-N-(naphthalen-2-yl)-2-oxoacetamide o

He

2-{4-[(4-methylphenyl)methyl]piperazin-1-yl}-2-oxoacetic acid (176 mg, 0.54 mmol) and naphthalene-2-amine (78 mg, 0.54 mmol) in anhydrous DMF- (2.5 ml) HATU (260 mg, 0.68 mmol, 1.26 mol equivalent) and DIPEA (190 µl, 2 mol equivalent) are added to the suspension prepared in (2.5 ml) at room temperature. The mixture is shaken overnight at room temperature. After completion of the reaction (monitored by thin layer chromatography), the mixture was diluted with brine and extracted with EtOAc (3x20 mL). The combined organic phase is washed with brine (3x20 ml), dried over anhydrous Na2SO4, filtered and evaporated under vacuum. The residue is purified by flash chromatography on silica gel, using cyclohexane containing 40% ethyl acetate as eluent. The desired product was crystallized from Et 2 O to give 108.0 mg (51%) of the title compound as a white solid. LC-MS (ESI) m/z [M+H] ⁺ = 398.2

PROCEDURE F:

2-(4-Benzylpiperazin-1-yl)-N-(1-methyl-1H-indol-5-yl)-2-oxoacetamide o

To a solution of 153 mg (0.7 mmol) of [(1-methyl-1/-/-indol-5-yl)carbamoyl]formic acid in anhydrous methylene chloride (15 ml), a propylphosphonic anhydride solution (~50 % DMF- in, T3P) (445 μ!_, 0.7 mmol) and DIPEA (250 pL, 2 mol equiv) were added at room temperature under an argon atmosphere. The mixture was stirred for 20 min and then 1-benzylpiperazine (122 µL, 0.7 mmol) was added. The mixture is stirred overnight at room temperature. After completion of the reaction (monitored by thin layer chromatography5), the reaction mixture is diluted with dichloromethane (10 ml) and quenched by the addition of saturated sodium bicarbonate solution (10 ml). The organic phase is washed with water (2x10 ml), then the organic phase is dried over anhydrous _Na2SO4 , filtered and evaporated under vacuum. The residue is purified by column chromatography on silica gel, using ChhCb-EtOH (98:2) mixture 10 as eluent to obtain 43 mg (17%) of the title compound LC-MS (ESI) m/z [M+H] ⁺ = 377.2

G PROCEDURE:

N-(1-methyl-1H-indol-5-yl)-2-{3-[(4-methylphenoxy)methyl]azetidin-1-yl}-2-oxoacetamide

141 mg (0.8 mmol) 3-[(4-methylphenoxy)methyl]azetidine, 174 mg (0.8 mmol) [(1methyl-1/7-indol-5-yl)carbamoyl]formic acid, 108 g (0 .8 mmol) to a solution of 1-hydroxybenzotriazole hydrate (HOBt.H2O) and 154 mg (0.8 mmol) of A/-(3-dimethylaminopropyl)-A/'-ethylcarbodiimide hydrochloride (EDC.HCI) in anhydrous DMF (3 mL) add 224 µL (1.6 mmol) of TEA at room temperature under an argon atmosphere. The mixture is stirred at room temperature for two days. After the reaction is complete (monitored by thin layer chromatography), the reaction mixture is diluted with CFhCb and water. After separating the layers, the organic phase is washed twice with CFLCL, and the combined organic phase is washed with saturated saline, dried over anhydrous _Na2SO4 , filtered and evaporated under vacuum. The residue is purified by column chromatography on silica gel, using a mixture of cyclohexane and ethyl acetate (7:3) as eluent, to obtain 92 mg of the title compound. LC-MS (ESI) m/z [M+H] ⁺ = 378.1.

V f** ALSO ¢4

H PROCEDURE:

Λ/-{1-Methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-oxo-2-( 1 -{[4-(trifluoromethyl)pheni I] Methyl}piperidin-4-yl)acetamide

To a solution of 200 mg (0.63 mmol) of 2-oxo-2-(1-{[4-(trifluoromethyl)phenyl]methyl}piperidin-4-yl)acetic acid prepared in 5 ml of anhydrous dimethylformamide, add propylphosphonic anhydride solution (~50%) in DMF, T3P) (370 pL, 0.63 mmol) and 10 DIPEA (452 pL, 4 mol equiv) at room temperature under an argon atmosphere. The mixture was stirred for 20 minutes, then 1-methyl-1H-pyrrolo[2,3-ε]pyridin-5-amine (93 mg, 0.63 mmol) was added. The mixture is stirred overnight at room temperature. The following day, an additional 226 µl (0.38 mmol) of T3P solution (~50% in DMF) was added and stirring was continued for 4 h. The reaction mixture is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel using a mixture of cyclohexane and acetone (2:1) as eluent. 40 mg of the title compound are thus obtained. LC-MS (ESI) m/z [M+H] ⁺ = 445.2

The examples described in Table 7 were prepared using the appropriate amide coupling procedures (Procedure A-H).

M V ft r** M W H

M too

ALSO w w

H

Table 7

Example Structure Procedure Starting intermediate LC-MS (ESI) [M+H] ⁺ 1 Η THE 1 and 48 377.2 2 CCr/oaK Η THE 1 and 49 415.1 3 coVoxr / 2 and 48 391.2 4 ter/oxr / 10 and 48 405.2 5 E 3 and 48 392.2 6 <xr~/car / D 19 and 61 445.1 7 Cl θ tmVar H 0 OH It's 7 and 48 411.1 8 0 <Xrr\xa' / D 16 and 61 395.1 9 0 mVoar / D 17 and 61 411.1 10 ay/oar/ D 20 and 61 407.2

Μ V also I** m M HI

Example Structure Procedure Starting intermediate LC-MS (ESI) [M+H] ⁺ 11 δχΑοχτ / It's 6 and 48 409.2 12 ar/cuo / F 18 and 61 377.2 13 Cl θ tenAo-xr / D 9 and 48 425.2 14 caAoxr' D 23 and 61 446.2 15 caAoxr / D 22 and 61 446.2 16 coVoxr Η I 0 ^F OH E 4 and 48 395.2 17 χΛχσ / E 5 and 48 393.2 18 hyAoxr B 11 and 48 410.2 19 0 H B 12 and 48 445.2 20 ίχΑους H C 13 and 48 396.2

CM V also m M H

Example Structure Procedure Starting intermediate LC-MS (ESI) [M+H] ⁺ 21 I Ε 7 and 48 409.2 22 see ₃ C 14 and 48 459.2 23 0 οσΥαχτ THE 2 and 51 392.2 24 ccrVaxr Η THE 1 and 52 394.3 25 ceYaAL Η THE 1 and 53 378.2 26 ατΫλχτ E 2 and 54 412.2 27 <χΥα.σ° / E 2 and 55 410.2 28 coVaxr E 2 and 57 391.1 29 0 <χΥαχτ / THE* 2 and 59 390.2 30 αΧϊΥατ / E 2 and 58 444.2

W V b. b*

M ¢4

Example Structure Procedure Starting intermediate LC-MS (ESI) [M+H] ⁺ 31 He THE ,—z 0=/ \=o & H 3 and 58 445.2 32 8 & H 1 and 58 430.2 33 He M ,—z o=/ )=O HE. Mon 3 and 60 411.1 34 0 ΰτΓΎ πΓΊ fHT Η H 1 and 59 376.2 35 0 <fl ί π γ ι γΎ \Α^ 0 </Ν^Λ^ Η H 1 and 60 396.1 36 ccrűQ „ \-A<í8 ⁰ °ΧΧ THE 1 and 50 427.2 37 8 ζ ,χ ο=^ / ⁰ Ρ 0 ϋ G 61 and 62 378.2 *EDC and 4-(c using imethylamino)pyridine

Intermediate 62

3-[(4-Methylphenoxy)methyl]azetidine tert-butyl-[3-(hydroxymethyl)azetidine-1-carboxylate] (2.88 g, 15.4 mmol) and TEAt (4.23 mL, 30, 3 mmol) is dissolved in CH2Cl2 (130 mL) at room temperature. Methanesulfonyl chloride (2.0 ml, 30 mmol) was added dropwise to the solution, and then it was stirred at the same temperature for 2.5 hours, and then the solvent was removed under reduced pressure. The residue is dissolved in EtOAc and the solution is washed with saturated aqueous NaHCO 10 solution and brine, dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure to give tert-butyl 3-[(methanesulfonyloxy)-1-carboxylate as a yellow liquid , which is used without further purification in the next step.

tert-butyl {3-[(methanesulfonyloxy)methyl]azetidine-1-carboxylate} (3.8 g, 14 mmol), 15 p -cresol (1.95 g, 18 mmol), Cs2CC>3 (9.85 g, 30.2 mmol) and DMF (100 mL) was stirred overnight at 110 °C. The inorganic solid material is filtered off and the filtrate is evaporated under vacuum. The residue is dissolved in dichloromethane, washed with water, 2 M aqueous sodium hydroxide solution and brine. The organic phase is dried over anhydrous Na2SÜ4, filtered and evaporated. The residue is purified by column chromatography on silica gel, using a mixture of dichloromethane and methanol (98:2) as eluent. 2.3 g (58%) of tert-butyl {3-[(4-methylphenoxy)methyl]azetidine-1carboxylate} are thus obtained in the form of a light yellow oil.

Trifluoroacetic acid (24 g, 313 mmol) was added to a solution of tert -butyl {3-[(4-methylphenoxy)methyl]azetidine-1-carboxylate} (2.3 g, 8.3 mmol) in dichloromethane (50 mL) at 0 °C 25 in an ice water bath and the solution for 1 hour at this temperature

1837 7 42 stir. The solvent is removed under reduced pressure at 40 °C. Ice water is added to the residue and the pH of the mixture is adjusted to 9 by adding saturated NaHCOa solution. The mixture is extracted with dichloromethane, the combined organic phase is washed with saturated saline, dried over anhydrous Na2SÜ4 and filtered. The solvent was removed under reduced pressure to give 3-[(4-methylphenoxy)methyl]azetidine (1.37 g, 7.7 mmol, 93%).

The intermediates described in Table 8 were prepared based on the synthetic description of intermediate 62.

Table 8

Intermediary Structure Intermediary Structure 62 ΗΝ-Λ IX 76 63 HN-^\ XX Cl 77 ην-Λ N CF ₃ 64 ΗΝ-'Λ 78 HN-\ XI Y CFj F 65 ΗΝ'-Ά ΟΜβ 79 ην-Λ _F XX 66 HN-^\ V-X 80 ΗΝΛ NC F 67 I p 81 HN-\ T jl Cl 68 HN-X 82 ΗΝ-·-\ Xx F 69 HN-\ 83 HN-X F

WV

IF** ALSO

H ft ft ft ft m

H

To a solution of 3-[(4-Methylphenyl)methoxy]azetidine tert-butyl-(3-hydroxyazetidine-1-carboxylate) (1.0 g, 6 mmol) in DMF (10 mL) was added sodium hydride (280 mg, 12 mmol , 60% in oil) is added with vigorous stirring at 0 °C in an argon atmosphere. The solution was stirred for 30 min, then 4-(methylbenzyl)bromide (1.22 g, 6.6 mmol) was added. The reaction mixture is stirred overnight at room temperature. The reaction was quenched at 0 °C by addition of MeOH (2 mL) followed by saturated NHUCI (40 mL). The mixture was extracted with diethyl ether (2x75 mL). The organic phases are combined, washed with 20 ml of water, dried over anhydrous Na?SO4, filtered and evaporated under vacuum. 1.38 g of tert-butyl {3-[(4-methylphenyl)methoxy]azetidine-1-carboxylate} are obtained in the form of an oil, which is used in the next step without purification.

To a solution of tert-butyl {3-[(4-methylphenyl)methoxy]azetidine-1-carboxylate} (1012 mg, 4.03 mmol) in anhydrous dichloromethane (18 mL) was added TFA (18 mL, 3 mmol) 2 °C in an argon atmosphere. The reaction mixture is then stirred under these conditions for 30 minutes and then stirred for 1 hour at room temperature. After the reaction is complete (monitored by thin layer chromatography), the mixture is concentrated in vacuo. The residue is dissolved in dichloromethane (20 ml), the pH is adjusted to 10 by adding 1N sodium hydroxide solution (while cooling). The aqueous phase is extracted with dichloromethane (3x20 ml), the combined organic phase is dried over anhydrous Na2SO4, filtered and evaporated under vacuum. 660 mg of the title compound are obtained as a yellow oil. The raw product is used in the next step without purification.

Intermediate 90

2-[(Azetidin-3-yloxy)methyl]-5-(trifluoromethyl)pyridine

2-[(Azetidin-3-yloxy)methyl]-5-(trifluoromethyl)pyridine was prepared based on the synthetic description of intermediate 89.

M V

N m w H

Intermediate 91

/N-(Azetidin-3-yl)-4-methylbenzamide tert-butyl-(3-aminoazetidine-1-carboxylate) (0.5 g, 2.9 mmol) and TEA (1.0 mL, 2.5 mol equivalent) in dichloromethane (50 mL) was added dropwise p-toluoyl chloride (539 mg, 3.48 mmol) under an argon atmosphere at 0 °C with vigorous stirring. The reaction mixture is stirred overnight at room temperature. After completion of the reaction (monitored by thin layer chromatography), the mixture is washed with 10 ml of water (2x20 ml). The organic phase is dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue is purified by column chromatography on silica gel, using a mixture of dichloromethane and methanol (98:2) as eluent. 0.65 g (77%) of tert-butyl [3-(4-methylbenzamido)azetidine-1-carboxylate] is obtained.

To a solution of tert -butyl [3-(4-methylbenzamido)azetidine-1-carboxylate] (650 mg, 2.24 mmol) 15 in anhydrous dichloromethane (35 mL) was added TFA (3.4 mL, 44.4 mmol) is added at a temperature of 0-2 °C in an argon atmosphere. The reaction mixture is then stirred for 30 minutes under these conditions and then stirred overnight at room temperature. After the reaction is complete (monitored by thin layer chromatography), the mixture is concentrated in vacuo. The residue is dissolved in 20 dichloromethane (50 ml), the pH is adjusted to 10 by adding a 25% aqueous ammonia solution (during cooling). After phase separation, the aqueous phase is extracted with dichloromethane (3x20 ml), the combined organic phase is dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give 360 mg of the title compound. The raw product is used in the next step without purification.

Intermediate 92

To a solution of N-[(4-Methylphenyl)methyl]azetidin-3-amine tert-butyl-(3-aminoazetidin-1-carboxylate) (0.5 g, 2.9 mmol) in methanol (30 ml) was added p-toluenecarbaldehyde (0.35 mL, 2.9 mmol) is added at room temperature for two hours with vigorous stirring under an argon atmosphere. NaBHaCN (360 mg, 5.73 mmol) was then added and the mixture was stirred for 24 h. After the reaction is complete (monitored by thin-layer chromatography10), cold water is added to the mixture, and the pH is adjusted to cc. Adjust to 1 by adding HCl (during cooling). The methanol was removed in vacuo and the aqueous mixture was extracted with 20 mL of ethyl acetate to remove impurities, then dichloromethane (20 mL) was added and the pH was adjusted to 9 with 25% aqueous ammonia. cooling). After phase separation, the aqueous phase is extracted with 15 dichloromethane (3x20 ml), the combined organic phases are anhydrous

It is dried over _Na2SO4 , filtered and evaporated under vacuum. 730 mg of tert-butyl-(3-{[(4methylphenyl)]amino}azetidine-1-carboxylate) are obtained. In the next step, we use it without cleaning.

To a solution of tert-butyl-(3-{[(4-methylphenyl)methyl]amino}azetidine-1-carboxylate) (0.73 mg, 1.5 20 mmol) in anhydrous dichloromethane (20 mL) was added TFA (2, 4 ml, 31.4 mmol) at 0-2 °C in an argon atmosphere. The reaction mixture is then stirred for 30 minutes under these conditions and then stirred overnight at room temperature. After the reaction is complete (monitored by thin layer chromatography), the mixture is concentrated in vacuo. The residue is dissolved in 25 dichloromethane (50 ml), the pH is adjusted by adding a 25% aqueous ammonia solution

1837742 ft ft ft m w

Ή

to 10 (while cooling). After phase separation, the aqueous phase is extracted with dichloromethane (3x20 ml), the combined organic phase is dried over anhydrous Na2SC>4, filtered and evaporated under vacuum to obtain 250 mg of the title compound. The crude product, N-(Azetidin-3-yl)-4-methylbenzamide, is used in the next step without purification 5

The intermediates containing the ethyl linker are presented in Table 9.

Intermediate 93 is commercially available.

Intermediates 94 and 95 can be synthesized based on the following literature:

Palkowitz, M.D. Org. Became. 19(2017) 2270-2273.

The commercially available aminomethylindole derivatives are summarized in Table 10.

Table 10

Intermediary Structure Intermediary Structure 96 ohAA~ ^NH! / 100 nAA H 97 H 101 ^NH2H 98 H 102 / 99 /

Aminomethylindole and azaindole derivatives that are not commercially available and their synthesis are described below.

Intermediate 103

/ tri b úti l-(1-ethoxyvinyl)-one Pd(Ph ₃ ) ₄ , K ₃ PO ₄ , NMP

(1R)-1-(1-Methyl-1H-indol-5-yl)ethanamine

A solution of 5-bromo-1-methyl-1/7-indole (5.0 g, 23.80 mmol) in 90 ml of A/-methyl-2-pyrrolidone is purged with nitrogen gas for 15 minutes, then K3PO4 (10,11 g, 47.60 mmol), tributyl-(1-ethoxyvinyl)tin (8.05 mL, 23.82 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.38 g, 1.19 mmol) is added and 80-90 °C

1837742 on is stirred for 7.5 hours in a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase is vigorously stirred with 5% hydrochloric acid solution at room temperature for 30 minutes. The pH of the mixture was adjusted to 7-8 by adding a 25% aqueous ammonia solution, and then extracted with EtOAc. The organic phase is washed with water, dried over NazSO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel using a mixture of EtOAc and cyclohexane (1:51:3). 1-(1-methyl-1H-indol-5-yl)ethanone is thus obtained. Yield: 1.17 g (28%).

H ₂ N

Ti(IV) isopropylate

MW, 100°C DMF

to a solution of -(1-methyl-1 H -/-indol-5-yl)ethanone (150 mg, 0.866 mmol) and (S)-2-methylpropane-2sulfinamide (210 mg, 1.733 mmol) in dimethylformamide (2 mL) titanium(IV) isopropylate (0.60 mL, 2.027 mmol) was added. The reaction mixture is heated at 100 °C/60 W) for 2 hours in a microwave reactor. This reaction was repeated five times, and the reaction mixtures were combined, diluted with ethyl acetate (140 mL), quenched with water (60 mL), and filtered through Celite. Celite was washed with ethyl acetate, then the combined organic phase was washed with water and brine and dried over Na2SO4. After evaporation, the residue is purified by flash column chromatography on silica gel (CH2CI2 - EtOAc 95:5-4:1), thus 2-methyl-/V-[(1E)-1-(1-methyl-1/-/-indole-5 -yl)ethylidene]propane-2-sulfinamide 20 is obtained. Yield: 371 mg (34%).

ft r ft ft m 1»

2-Methyl-Λ/-[(1E)-1-(1-Methyl-1H-\ndol-5-yl)ethylidene]propane-2-su Ifinamid (38 mg, 0.1375 mmol) in 7 mL of THF was added L-selectide (1 M in THF, 0.85 mL, 0.85 mmol) under an inert atmosphere at room temperature. The reaction mixture is stirred for 1 hour and then evaporated to dryness. The residue is purified by column chromatography on silica gel using a mixture of EtOAc-cyclohexane (1:1). 2-methyl-Λ/-[( 1 F )-1-(1-methyl-1 H -indol-5-yl)ethyl]propane-2-sulfinamide is thus obtained. Yield: 53 mg (38 mg theoretical weight, 100%), one diastereomer. The material was stored refrigerated until the next step. The absolute configuration was not defined in US 2012/0252853 A1 (SAMSANETTE

GRAVEN, LUNDBECK & CO AS H) we used an analogous synthetic route.

2-Methyl-[(1R)-1-(1-methyl-1/7-indol-5-yl)ethyl]propane-2-sulfinamide (38 mg,

0.1365 mmol) in diethyl ether (10 ml), HCl solution (2 M in diethyl ether,

0.4 ml, 0.8 mmol) are added. The reaction mixture was stirred at this temperature for 3 hours and then evaporated to dryness, thus obtaining the title compound (29 mg theoretical weight) in the form of an HCl salt. The material is used without further purification.

18377 4

Intermediate 104

-(2-chloro r -1 H -indol-5-yl)methanamine

Bromine (42.5 g, 13.5 ml, 275 mmol) was added dropwise to a stirred solution of 1/-/-indole-5-carbonitrile (7.10 g, 50 mmol, Combi-blocks) and tert-butanol (250 ml) ( 20 minutes) at 25 °C and stirred for 1.5 hours. After completion of the reaction, the reaction mixture is evaporated under vacuum. This residue is diluted with 400 ml of ethyl acetate and 75 ml of water is added. The organic phase is washed with water (2x100 ml), brine (100 ml), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was stirred with 100 ml of diisopropyl ether for 30 minutes. The precipitated crystals are filtered off, washed with diisopropyl ether and dried. 12.89 g (81%) of 3,3-dibromo-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile are thus obtained in the form of a reddish-brown solid.

Zn powder (16.3 g , 250 mmol) are added in portions (approx. 2 g). The mixture is stirred for 2 hours at 30 °C, so that the temperature cannot rise above 35 °C. After completion of the reaction, the reaction mixture is evaporated under vacuum. This residue is suspended in ethyl acetate (300 ml), filtered, the solid is again mixed with ethyl acetate (150 ml),

CM

V is |*||, UN, m w H

IN C h* h* m

We will filter it. The combined organic phase is evaporated under vacuum. The residue is stirred with 1N hydrochloric acid solution (100 ml) for 1 hour, filtered, washed with water (2x5 ml) and dried, so that 3.86 g (60%) of 2-oxo-2,3-dihydro-1/-/-indole- 5-carbonitrile is obtained.

To a suspension of 2-oxo-2,3-dihydro-1/-/-indole-5-carbonitrile (5.8 g, 36.9 mmol) in DCE (23 mL) was added POCh (11.5 g, 6.95 ml, 74.79 mmol) are added at a temperature of 0 °C. The reaction mixture is refluxed for 30 minutes at 90 °C. After cooling the reaction, imidazole (2.75 g, 44.55 mmol) was added and the mixture was kept at 90 °C for another 2 h. After completion of the reaction, the reaction mixture is evaporated, the residue is dissolved in 110 ml of ethyl acetate, washed with saturated sodium bicarbonate solution (30 ml), brine (50 ml), dried over anhydrous Na2SO4, filtered and evaporated under vacuum.

The product is purified by column chromatography on silica gel, using a mixture of THF-nhexane (9:1) as eluent. 4.58 g (70%) of 2-chloro-1/7-indole-5-carbonitrile are obtained as a yellow solid.

LiAIH4 (1

M in THF; 45 ml; 45 mol) in a nitrogen atmosphere. The reaction mixture is refluxed at 65 °C for 2 hours. Thin layer chromatography shows the formation of the product. The reaction was quenched at 0°C with EtOAc (20 mL) and saturated aqueous sodium sulfate (15 mL) was added dropwise. The reaction mixture is filtered through Celite and then washed thoroughly with ethyl acetate (100 ml). The filtrate is washed with 50 ml of saturated aqueous salt solution, dried over anhydrous Na2SO4, filtered and evaporated under vacuum. The crude product was purified by crystallization from 50 ml of ethyl acetate to give 3.9 g (85%) of the title compound as an off-white solid.

Intermediate 105

(2-chloro-1-methyl-1H-indol-5-yl)methanamine

(2-Chloro-1-methyl-1H-indol-5-yl)methanamine is its non-methylated derivative, the

It was prepared based on the synthetic description of intermediate 104.

Intermediate 106

(3-Chloro-1-methyl-1H-indol-5-yl)methanamine (1-methyl-1/-/-indol-5-yl)methanamine (640 mg, 3.995 mmol) and DIPEA (1.03 g ,

1.39 mL, 7.98 mmol) in dichloromethane (40 mL) was added with stirring to a solution of tert-butyl dicarbonate (BOC2O) (1.74 g, 7.97 mmol) in dichloromethane (10 mL) at 0 °C under nitrogen in atmosphere. The reaction mixture is stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (20 mL) and washed with 50 mL of water. The organic phase is washed with brine (50 ml), dried over anhydrous Na2SO4, filtered and evaporated under vacuum. The crude product was purified by flash chromatography to give 786 mg (76%) of tert-butyl-{N-[(1-methyl-1H-indol-5yl)methyl]carbamate}.

To a solution of tert-butyl-{/\/-[( 1 -methyl-1H-indol-5-yl)methyl]carbamate} (160 mg, 0.615 mmol) in dichloromethane (4 mL) 20 with stirring was added /N-chlorosuccinimide ( 82 mg;

0.61 mmol) is added at 0 °C in an argon atmosphere. The reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was treated with dichloromethane (20 mL) ft V ft ft m

Dilute with H and wash with water (20 ml) and brine (15 ml), dry over anhydrous Na2SO4, filter and evaporate in vacuo. The crude product is purified by flash chromatography to give 145 mg (80%) of tert-butyl {N-[(3-chloro-1-methyl-1H-indol-5yl)methyl]carbamate}.

To a solution of tert-butyl {N-[(3-chloro-1-methyl-1/-/-indol-5-yl)methyl]carbamate} (72 mg, 0.244 mmol) in anhydrous dichloromethane (3 mL) TFA- t (300 mg, 0.2 ml, 3 mmol) is added at 0-2 °C under an argon atmosphere. The reaction mixture was stirred for 3 hours at room temperature. After the reaction is complete (monitored by thin layer chromatography), the mixture is concentrated in vacuo. The residue is dissolved in dichloromethane (20 ml), the pH is adjusted to 10 with 1N sodium hydroxide solution (while cooling), the aqueous phase is extracted with dichloromethane (3x15 ml), the organic phase is dried over anhydrous Na2SO4, filtered and evaporated under vacuum. . The crude product is purified by flash chromatography on silica gel, using dichloromethane containing 10% methanol as eluant, to obtain 49 mg of the title compound in the form of a yellow solid.

Intermediate 107

Cl

(3-Chloro-1H-indol-5-yl)methanamine

To a solution of 1/-/-indole-5-carbonitrile (2.10 g, 14.8 mmol) prepared in 60 ml of dichloromethane at 0 °C, /V-chlorosuccinimide (2.01 g, 15.05 mmol) is added in portions, then the mixture is stirred overnight at room temperature. The formed precipitate is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel using a 1:4 mixture of EtOAc and cyclohexane to give 0.77 g (30%) of 3-chloro-1H-indole-5-carbonitrile.

To a solution of 3-chloro-1/7-indole-5-carbonitrile (176 mg, 1 mmol) in 3 ml of diethyl ether at 0 °C, add 4 ml of 1M BH3 dropwise

ΓΜ

183774 in tetrahydrofuran, and can then be stirred at room temperature for 2 hours. The reaction mixture was quenched with methanol (5 ml) added dropwise at 0 °C and concentrated under vacuum. The residue is purified by column chromatography on silica gel, gradually changing the eluent first using CH2Cl2, then a mixture of ChhCb-methanol (9:1), and finally a mixture of ChhCb-methanol and 25% aqueous ammonia (89:10:1). Yield: 120 mg (67%), yellowish oil.

Intermediate 108

(3-Fluoro-1-methyl-1/7-indol-5-yl)methanamine

To a solution of 1/-/-indole-5-carbonitrile (2.09 g, 14.7 mmol) in 16 mL of dimethylformamide was added NaH (840 mg, 60% in oil, 21 mmol) with vigorous stirring under an argon atmosphere at 0 °C- you. The solution was stirred for 30 min, then iodomethane (9.12 g, 4 mL, 63 mmol) was added. The reaction mixture at room temperature

Stir for 4 hours. The reaction was quenched with water (50 mL) and extracted with EtOAc (3x120 mL). The organic phases are combined, washed with water (2x50 ml), dried over anhydrous Na2SO4, filtered and evaporated under vacuum, and the dry toluene is evaporated from the residue to give 2.3 g of white 1-methyl-1H-indole-5-carbonitrile , in the form of a solid, which is used in the next step without purification.

1837 7 4

PCC (pyridinium chlorochromate, 7.6 g, 35.2 mmol) was added to a solution of -methyl-1 / - / -indole-5-carbonitrile (1.38 g, 8.83 mmol) in 40 mL of acetonitrile. and the mixture is refluxed for 7 hours. After completion of the reaction (monitored by thin layer chromatography), the reaction mixture is concentrated in vacuo, and the residue 5 is partitioned between H2O and EtOAc. The insoluble part is filtered off, the organic phase is washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness. The crude residue is purified by flash chromatography on silica gel using dichloromethane as eluent to obtain 760 mg of 1-methyl-2,3-dioxo-2,3-dihydro-1H-indole-5-carbonitrile in the form of an orange solid.

1-Methyl-2,3-dioxo-2,3-dihydro-1/-/-indole-5-carbonitrile (502 mg, 2.7 mmol) was treated with bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor, 50% in toluene, 5 mL, 2.7 mmol) under argon atmosphere, then 0.025 mL of absolute EtOH was added and the mixture was heated at 90 °C for 1 h.

The reaction was quenched with methanol (1 mL) and diluted with dichloromethane (100 mL), then the mixture was poured into cold saturated Na2SO4 solution and the product was extracted with dichloromethane. The extract is washed with saline, dried over anhydrous Na2SO4 and evaporated to dryness. The crude residue is purified by flash chromatography on silica gel using a 0-20% ethyl acetate/hexane gradient to give 3,3-difluoro-1-methyl-2-oxo-2,3dihydro-1 /-/-indole-5-carbonitrile as a yellow solid (322 mg).

To a solution of 3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1/-/-indole-5-carbonitrile (510 mg, 2.45 mmol) in 10 mL of anhydrous tetrahydrofuran, BHa.THF (1 M in THF) is added at 0-2 °C under an argon atmosphere. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete (monitored by thin layer chromatography), 10 mL of MeOH was added and the mixture was concentrated in vacuo. The residue 25 is dissolved in 50 ml of ethyl acetate, washed with saturated aqueous NaHCCl solution (25 ml), then with saturated aqueous salt solution (25 ml), dried over anhydrous Na2SO4, filtered and evaporated under vacuum. The crude product is purified by flash chromatography on silica gel using dichloromethane containing 10% methanol as eluent to obtain 70 mg of the title compound as a pale yellow solid.

1837742

Intermediate 109

F

(3-Fluoro-1H-indol-5-yl)methanamine

(3-Fluoro-1/7-indol-5-yl)methanamine is its AZ-methylated derivative, the

108.

was prepared based on the synthetic description of the intermediate.

Intermediate 110

NC

5-(Aminomethyl)-1-methyl-1H-indole-3-carbonitrile

5-(Aminomethyl)-1-methyl-1Η-Ϊndole-3-carbonitrile was prepared by the following synthetic route:

nh ₂

Sorry ₂ O DIPEA

Ν' / ch ₂ ci.

HE

U POCI ₃ /DMF

NH 0 _____

J<f THF

1. nh ₂ oh.hci DMF pyridine

2. CDI TEA

TFA

CH ₂ Cl;

NC

nh To a solution of _2- (1-methyl-1/-/-indol-5-yl)methanamine (1.642 g, 10.2 mmol) and DIPEA (2.52 mL, 14.5 mmol) in dichloromethane (100 mL) was added di A solution of -tert-butyl dicarbonate (4.26 g, 19.5 mmol) in dichloromethane (24 ml) is added dropwise at 0 °C under an argon atmosphere. The mixture was stirred overnight at room temperature, quenched with water (100 mL) and extracted with dichloromethane. The organic phase is washed with water, dried over Na2SÜ4, filtered and evaporated to dryness under vacuum. ft is also m

recrystallization of the residue from hexane gave tert-butyl {[(1-methyl-1/7-indol-5yl)methyl]carbamate} (1.58 g, 60%) in the form of white crystals.

Phosphoryl chloride (0.3 mL, 4 mmol) was added dropwise to DMF (1.5 mL, 19 mmol) at 5 °C (acetone-dry ice bath), and the mixture at 0 °C (ice-water bath) 1 , we stir for 5 hours in an argon atmosphere. The Vilsmeyer reagent thus obtained was added dropwise using a syringe to a solution of tert-butyl-{[(1-methyl-1/-/-indole-54l)methyl]carbamate} (780 mg, 3 mmol) prepared in 5 ml of tetrahydrofuran under an argon atmosphere -7 °C and the mixture is stirred at 0 °C for one hour. EtOAc (10 mL) followed by 3M sodium acetate solution (4.5 mL) was added dropwise and the mixture was stirred at room temperature for an additional 2.5 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate. The combined organic phase is washed with brine, dried and evaporated to dryness under vacuum. The residue was triturated with diethyl ether, filtered and dried to give tert-butyl {[(3-formyl-1-methyl-1/-/-indol-5-yl)methyl]carbamate} (568 mg, 66% ) is obtained as a pink solid.

tert-butyl {[(3-formyl-1-methyl-1/-/-indol-5-yl)methyl]carbamate} (288 mg, 1 mmol), hydroxylamine hydrochloride (83 mg, 1.2 mmol), a solution of pyridine (0.1 mL, 1.25 mmol) and N,Ndimethylformamide (3 mL) was stirred at 60 °C for 45 min under an argon atmosphere. The reaction mixture is cooled to room temperature and then to 0 °C, and carbonyldiimidazole (811 mg, 5 mmol) is added in portions. The mixture is stirred in an argon atmosphere at 60 °C for 30 minutes, then TEA (0.28 ml, 2 mmol) is added and the mixture is stirred for another 30 minutes. The reaction mixture is cooled to 0 °C, then quenched by careful addition of water, extracted with EtOAc, dried over Na2SO4, filtered and evaporated under vacuum. The residue was purified by column chromatography on silica gel, eluting with CH2Cl2 to give tert-butyl {[(3-cyano-1-methyl-1/7-indol-5-yl)methylcarbamate} (141 25 mg, 50%) white crystals in the form of

To a solution of tert-butyl {[(3-cyano-1-methyl-1/-/-indol-5-yl)methylcarbamate} (133 mg, 0.47 mmol) in dichloromethane (4 mL) was added TFA (0, 46 ml, 6 mmol) are added at 0 °C and the mixture is stirred at room temperature for 2.5 hours. The reaction mixture is evaporated to dryness under reduced pressure, water is added, and the pH of the mixture is adjusted to 10 by adding 2M 30 NaOH solution (0.6 ml) at 0 °C. The mixture with dichloromethane

1837742 is extracted, dried over NazSCU, filtered and evaporated under vacuum. 82 mg (95%) of the title compound are obtained in the form of white crystals.

Intermediate 111

{1-Methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}methanamine

5-Bromo-1H-pyrrolo[2,3-b]pyridine is commercially available (Combi-blocks, catalog number: IN-0206) and the desired azaindolamine is prepared in the sequence of steps shown above.

Step 1: 1H-pyrrolo[2,3-b1pyridine-5-carbonitrile

The intermediate is produced according to patent description EP 1782811 A1 (EISAI R&D MAN CO LTD).

Step 2: 1-methyl-1 H -pyrrolo[2,3-ε1pyridine-5-carbonitrile

The intermediate is produced according to patent description WO 2009/155017 A2 (MERCK & CO INC) No. 15.

Step 3: (1-methyl-1 H -pyrrolo[2,3-ylpyridin-5-yl}methanamine

The intermediate is produced according to patent description WO 2012/042915 A1 (RAQUALIA PHARMA INC).

iN V IN IN

H

Intermediate 112

{1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl}methanamine

To a solution of 6-aminopyridine-3-carbonitrile (500 mg, 4.2 mmol) in 5 mL of dimethylformamide was added TFA (574 mg, 386 pl, 1.2 mol equivalent). N-iodosuccinimide (1.04 g, 4.62 mmol, 1.1 mol equiv) was added at room temperature and the reaction was heated at 50 °C for 3 h. Complete conversion is indicated by TLC. The reaction mixture was cooled to room temperature and the product was precipitated by adding the reaction mixture to water. Neutralize by adding N32S2O3 and 1N NaOH, then 6-amino-5-iodopyridine-3-carbonitrile (660 mg) is filtered as a brown solid. In the next step, we use it without cleaning.

6-Amino-5-iodopyridine-3-carbonitrile (329 mg, 1.34 mmol), bis(triphenylphosphine)dichloropalladium(O) (95 mg, 0.134 mmol), Cul (128 mg, 0.671 mmol) and TEA 15 (976 mg, 1.34 ml_, 9.64 mmol) in absolute THF (18 ml) to a degassed mixture was added propyne solution (3-4% in THF 13.2 ml) through the septum at 0-5 °C. The mixture is stirred for 30 minutes at 0-5 °C and then for another 18 hours at room temperature. The reaction is stopped by adding NH 4 Cl solution. The solid was filtered off and the residue was washed with CH 2 Cl 2 . The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude product is purified by flash chromatography on silica gel,

WV

N

R

W

Using cyclohexane containing 40% ethyl acetate as eluent, 150 mg of 6-amino-5(prop-1-yn-1-yl)pyridine-3-carbonitrile is obtained as a yellow solid (71%).

KO/Bu (428 mg, 3.82 mmol, 2 mol equivalent) The reaction mixture is heated at 90 °C for 5.5 hours. After cooling to room temperature, the reaction mixture is poured into water and the combined organic phase is filtered over anhydrous Na2SO4 279 mg (93%) of 2-methyl-1/7-pyrrolo[2,3-]pyridine-5-carbonitrile are obtained and used in the next step without purification.

To a solution of 2-methyl-1/-/-pyrrolo[2,3-b]pyridine-5-carbonitrile (279 mg, 1.78 mmol) in DMF (7.5 mL) was added NaH (60% in oil ) (92 mg, 2.31 mmol, 1.3 mol equiv) at 0 °C. The reaction mixture was stirred at this temperature for 30 min, then iodomethane (380 mg, 167 pl) in DMF (1.5 mL) was added dropwise. The mixture is stirred overnight at room temperature. Complete conversion is indicated by TLC. The mixture was poured into water and extracted with dichloromethane (3x20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give 298 mg (98%) of the title 1,2-dimethyl-1H-pyrrolo[2,3-ö]pyridine-5-carbonitrile as a yellow solid . In the next step, we use it without cleaning.

To a solution of 1,2-dimethyl-1H-pyrrolo[2,3-ö]pyridine-5-carbonitrile (297 mg, 1.73 mmol) in methanol (100 mL) and 25% aqueous ammonia (25 mL) was added Raney-Ni (200 mg) and the mixture was stirred under 1 atmosphere of H2 at room temperature for 16 h. The reaction mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure to give 226 mg (74%) of the title compound 25 as a yellow solid.

1837 7 4

V is also m w

{2-Methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}methanamine

To a solution of 5-bromopyridin-2-amine (3.0 g, 17.34 mmol) in aqueous 2M hhSCM (30 mL) was added KlOs (1.85 g, 8.64 mmol) in portions. The mixture was heated to 100 °C and a solution of KI (1.59 g, 9.57 mmol) in water (3 mL) was added dropwise over 1.5 h. The solution was stirred at this temperature for another 30 minutes, then cooled for 10 minutes, its pH was adjusted to 8 by adding 6M aqueous sodium hydroxide solution, and then extracted with EtOAc (3x). The organic phase is washed with a 5% Na2SO4 solution, water and brine, dried over Na2SO4 and evaporated to dryness. The residue was chromatographed on silica gel (cyclohexane/EtOAc, 67/33) to give 2.61 g (50.4%) of 5-bromo-3-iodopyridin-2-amine as a yellow solid.

Dissolve 5-bromo-3-iodopyridin-2-amine (500 mg, 1.67 mmol) in THF (27 mL) under a nitrogen atmosphere in a pressure-resistant flask. To the mixture was added Cul (159 mg, 0.836 mmol), bis(triphenylphosphine)palladium(II) dichloride (117 mg, 0.167 mmol), propyne (ca. 3-4% in heptane, 16.4 mL, 8.36 mmol ) and TEA (1.67 mL, 12 mmol). The flask is closed and the mixture is stirred overnight. The mixture is treated with saturated ammonium chloride solution, filtered through celite, and extracted with dichloromethane (2x). The combined organic phases are dried over Na2SÜ4 and evaporated to dryness. The residue was chromatographed on silica gel (cyclohexane-EtOAc, 70:30) to give 323 mg (92%) of 5-bromo-3-(prop-1-yn-1-yl)pyridin-2-amine as a yellow solid.

To a solution of 5-bromo-3-(prop-1-yn-1-yl)pyridin-2-amine (645 mg, 3.06 mmol) in DMF (27 mL) was added KOfBu (683 mg, 6 .11 mmol), and the mixture is heated at 90 °C for 3 hours. After cooling, the reaction mixture is diluted with water and ice, and the product is extracted with dichloromethane (3x). The combined organic phases are dried over Na2SÜ4 and evaporated to dryness. Chromatography of the residue on silica gel (CH2CI2 - methanol NH4OH (25% aqueous solution), (99:1:0.1)) gave 504 mg (78%) of 5-bromo-210 methyl-1/7-pyrrolo[2,3 -ö]pyridine is obtained.

5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (450 mg, 2.13 mmol), Zn(CN)2 (376 mg, 3.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (246 mg, 0.213 mmol) in 1-methylpyrrolidin-2-one (18 mL) and heated at 150 °C overnight. After cooling, the reaction mixture is diluted with water and the product is extracted with ethyl acetate (2x). The combined organic phases are dried over Na2SÜ4 and evaporated to dryness. Chromatography of the residue on silica gel (cyclohexane-ethyl acetate (6:4)) gives 159 mg (47%) of 2-methyl-1/-/-pyrrolo[2,3-b]pyridine-5-carbonitrile.

2-Methyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (88 mg, 0.56 mmol) was prepared with methanol (32 mL) and 25% aqueous ammonium hydroxide (8 mL) Raney-Ni (50% aqueous suspension, 0.20 ml) is added to its solution and hydrogenated with a hydrogen balloon overnight at room temperature. The reaction mixture is filtered through Celite and then evaporated. The crude product was dissolved in methanol and NFUOH solution, filtered through silica gel (2 g) and evaporated. 86 mg (96%) of the title compound were obtained as a yellow oil.

1837742

Intermediate 114

Zn(CN),

{1,3-dimethyl-1α7-pyrrolo[2,3-ö]pyridin-5-yl}methanamine

Dissolve 5-bromo-1/-/-pyrrolo[2,3-b]pyridine (5 g, 5.075 mmol) in 8 mL of DMF and cool to °C. NaH (300 mg, 7.51 mmol, 60% mineral oil dispersion) was then added and the mixture was stirred at room temperature for 20 min. The mixture was cooled to 0 °C, benzenesulfonyl chloride (0.78 mL, 6.09 mmol) was added dropwise and allowed to warm to room temperature. After a reaction time of 2 hours, the mixture is treated with saturated ammonium chloride solution and extracted with dichloromethane (2x). The combined organic phases are washed with water (2x) and brine, dried over Na2SO4 and evaporated to dryness, resulting in 1.71 g (100%)

-(benzenesulfonyl)-5-bromo-1H-pyrrolo[2,3-b]pyridine is obtained.

Under an inert atmosphere, 1-(benzenesulfonyl)-5-bromo-1/-/-pyrrolo[2,3-b]pyridine (816 15 mg, 2.42 mmol), Zn(CN)2 (426 mg, 3, 63 mmol) and tetrakis(triphenylphosphine)palladium(0) (280 mg, 0.242 mmol) were dissolved in 1-methylpyrrolidin-2-one (21 mL) and heated at 110 °C for 9 h. After cooling, the reaction mixture is diluted with water and the product is extracted with ethyl acetate (3x). The combined organic phases are washed with brine, dried over Na ₂ SO ₄ and evaporated to dryness. The residue was chromatographed on silica gel 20 (cyclohexane-ethyl acetate (7:3)) to give 529 mg (77%) of 1-(benzenesulfonyl)-1/-pyrrolo[2,3-b]pyridine-5-carbonitrile.

1837742

To a cooled solution of 1-(benzenesulfonyl)-1H-pyrrolo[2,3-ö]pyridine-5-carbonitrile (528 mg, 1.86 mmol) in 8 mL of DMF was slowly added bromine (191 pl, 3.73 mmol) 0 °C. The suspension was then allowed to warm to room temperature and stirred overnight. The pH of the mixture was adjusted to 9 by the addition of 2 M aqueous sodium hydroxide solution, and the organic phase was extracted with saturated NaHCO 3 solution 447 mg (66%) of 1-(benzenesulfonyl)-3-bromo-1/7-pyrrolo[2,3-o]pyridine-5-carbonitrile is obtained.

In an inert atmosphere, 1-(benzenesulfonyl)-3-bromo-1/-/-pyrrolo[2,3-ö]pyridine-510 carbonitrile (447 mg, 1.23 mmol) is dissolved in 25 ml of tetrahydrofuran, tetrakis(triphenylphosphine)palladium is added (0) (428 mg, 0.37 mmol), then trimethylaluminum solution (2.0 mol in toluene, 2.44 mL, 4.94 mmol) was added dropwise, and the mixture was refluxed for 7 hours. After repeated addition of tetrakis(triphenylphosphine)palladium(0) (143 mg, 0.123 mmol) and trimethylaluminum solution (2.0 mol in toluene, 1.23 mL, 2.47 mmol), the mixture was refluxed for another 4 hours. After cooling, the reaction was quenched by slow addition of saturated NaHCO 3 solution and the product was extracted with EtOAc (3x). The combined organic phases are washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was chromatographed on silica gel (cyclohexane/EtOAc (8:2)) to give 158 mg (43%) of 1-(benzenesulfonyl)-3-methyl-1H-pyrrolo[2,3-b]pyridine20 carbonitrile.

To a solution of 1-(benzenesulfonyl)-3-methyl-1/-/-pyrrolo[2,3-ö]pyridinecarbonitrile (247 mg, 0.83 mmol) prepared in 17 mL of methanol, 6M aqueous NaOH solution (1.73 mL , 10.4 mmol) is added and the mixture is refluxed for 2 hours. The mixture was cooled and the solvent was evaporated. The pH of the residue is adjusted to 7 by adding water and 10% citric acid. The reaction mixture is stirred for 30 minutes, then the solid material is filtered off and washed with water. The crude product is dried in a vacuum oven at 50 ⁰ Con and chromatographed on silica gel (cyclohexane - EtOAc (8:2)) to obtain 94 mg (72%) of 3-methyl-1H-pyrrolo[2,3-ö]pyridine-5-carbonitrile.

Dissolve 3-methyl-1/-/-pyrrolo[2,3-ö]pyridine-5-carbonitrile (93 mg, 0.59 mmol) in 2.5 mL of DMF and then cool to 0 °C. Then NaH (31 mg, 0.77 mmol, 60% wt

183774 mineral oil dispersion) is added and the mixture is stirred at this temperature for 30 minutes. Methyl iodide (56 µl, 0.9 mmol) in DMF (0.5 mL) was then added dropwise, then allowed to warm to room temperature and stirred overnight. Water is slowly added to the mixture and extracted with dichloromethane (3x). The combined organic phases are dried over Na2SO4 and evaporated to dryness. 100 mg (99%) of 1,3-dimethyl-1H-pyrrolo[2,3-o]pyridine-5-carbonitrile are obtained.

1,3-Dimethyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (100 mg, 0.584 mmol) with methanol (34 mL) and 25% aqueous ammonium hydroxide (8.5 mL) Raney-Ni (0.21 ml, 50% aqueous suspension) was added to the solution and hydrogenated with 10 hydrogen balloons at room temperature for 4 hours. The reaction mixture is filtered through Celite and then evaporated. The crude product was dissolved in methanol and ammonium hydroxide solution, filtered through silica gel (2 g) and evaporated to give 92 mg (90%) of the title compound as a yellow oil

Intermediate 115 {3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl}methanamine

{3-Chloro-1/-/-pyrrolo[2,3-ö]pyridin-5-yl}methanamine is prepared according to patent description WO 2016/083816 A1 (SMITH ALUN JOHN).

Intermediate 116

M V IN ALSO

AM m

W

{3-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}methanamine

Step 1: 1H-pyrrolo[2,3-ε1pyridine-5-carbonitrile

The intermediate is produced according to patent 5 description EP 1782811 A1 (EISAI R&D MAN CO LTD).

Step 2: 1-methyl-1/7-pyrrolo[2,3-ε1pyridine-5-carbonitrile

The intermediate is produced according to the patent description WO 2009/155017 A2 (MERCK & CO INC).

Step 3: 3-Chloro-1-methyl-1/-/-pyrrolo[2,3-blpyridine-5-carbonitrile

To a solution of 1-methyl-1H-pyrrolo[2,3-ö]pyridine-5-carbonitrile (600 mg, 3.69 mmol) in 14 mL of DMF was added N-chlorosuccinimide (502 mg, 3.76 mmol) with vigorous stirring meanwhile at room temperature in an argon atmosphere. The solution is stirred overnight at room temperature. After the completion of the reaction (monitored by thin layer chromatography), the mixture is evaporated in vacuo (anhydrous toluene is evaporated several times from the residue). The residue was dissolved in a mixture of diethyl ether and EtOAc (1:1.40 mL) and washed with water (3x15 mL). The organic phase is dried over anhydrous Na2SÜ4, filtered and evaporated under vacuum to give 670 mg of 3-chloro-1-methyl-1/-/-pyrrolo[2,3-ö]pyridine-5-carbonitrile, which is used in the next step without purification.

1837742 also fs m

Step 4: (3-chloro-1-methyl-1H-pyrrolo[2,3-ö1pyridin-5-yl}methanamine

The intermediate is produced according to patent description WO 2012/042915 A1 (RAQUALIA PHARMA INC).

Intermediate 117

Bro

{3-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}methanamine

1-2. step

The intermediates are prepared according to the steps described for {3-chloro-1-methyl-1H-pyrrolo[2,3-ö]pyridin-5-yl}methanamine, EP1782811 A1 (EISAI R&D MAN CO LTD) and W02009/155017 According to the procedures described in A2 (MERCK & CO INC) patent specifications.

Step 3:

A/-bromosuccinimide (446 mg, 2.51 mmol) was added to a solution of -methyl-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (358 mg, 2.28 mmol) in 6.5 mL of dichloromethane with stirring at room temperature in an argon atmosphere. The solution is stirred overnight at room temperature. After completion of the reaction (monitored by thin layer chromatography), dilute with dichloromethane (25 ml) and wash with water (3x20 ml). The organic phase is dried over anhydrous Na2SÜ4, filtered and evaporated under vacuum, so that 670 mg of 3-bromo-1-methyl-1/7-pyrrolo[2,3-o]pyridine-5carbonitrile is obtained, which is used in the next step without purification.

Step 4: {3-bromo-1-methyl-1H-pyrrolo[2,3-b1pyridin-5-yl}methanamine

The intermediate is produced according to patent description WO 2012/042915 A1 (RAQUALIA PHARMA INC).

38. Example

1.4-NO ₂ PhOCOCl

DIPEA CH ₂ CI ₂

2nd chair amin

Intermediate 96 Intermediate 64

Example 38

Λ/-[( 1 -methyl-1 H -indol-5-yl)methyl]-3-{[4-(trifluoromethyl)phenoxy]methyl}azetidine-1 carboxamide (2-methyl-1/7-indol-5 To a solution of -yl)methanamine (96 mg, 0.6 mmol) in 6 mL of dichloromethane 10 was added DIPEA (155 mg, 208 µl, 1.2 mmol) and 4-nitrophenyl(chloroformate) (121 mg, 0.6 mmol ) in dichloromethane (3 ml) in an argon atmosphere at a temperature of 0 °C. The mixture is stirred under unchanged conditions for another 1.5 hours. After the activation period, a solution of 3-{[4-(trifluoromethyl)phenoxy]methyl}azetidine (138 mg, 0.6 mmol, Intermedier 15 66) in CH2Cl2 (3 ml) is added dropwise, then the mixture is allowed to warm to room temperature, and stirred overnight at this temperature. After the reaction is complete (monitored by thin layer chromatography), the mixture is concentrated in vacuo. The crude product is chromatographed on silica gel, eluting with a mixture of cyclohexane and EtOAc, and then the resulting product is further purified by preparative thin layer chromatography to obtain 64 mg (26%) of the title compound.

LC-MS (ESI) m/z [M+H] ⁺ = 418.3

W V b* r*

The examples described in Table 11 are prepared according to the method described in Example 38.

Table 11

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 38 0 A ίΓ ^NH / ΪΧ 62 and 96 364.3 39 '3 >° Main 0 62 and 97 350.3 40 o Z^Ti ^{NH Ν} Λ \ II IV—V .c· ! U 63 and 96 384.2 41 δ 0 p F °< fe. 64 and 96 418.3 42 0 O< I 62 and 101 364.2 43 0 0 p F°=4 8 65 and 96 380.3 44 u. 0 0 F °< b 66 and 96 368.3 45 o A __ ^{NH Ν} Ά ~ \ JJ 0- ll Ί Η II 62 and 98 364.3

'« ft ft m w

CM fs IS ffll 0Ö H

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 46 J A 62 and 100 378.3 47 1 P0 He 64 and 97 404.2 48 '8' >° P 0 P 62 and 106 398.2 49 o /Ar Ar ^{nh n} \ \ II J AA _o^ /-. /-. —/ ΌυΟ 67 and 97 426.3 50 ci O 1.///- a. //Ύ[ ^NH Ν'! \ II J lA /O. /-. / XI cf. ₃ 64 and 106 452.2 51 δ 0 J °=4 64 and 111 419.3 52 o /An ^{nh n} A \ Il JA /O-..___. H |l ^^ocf ₃ 68 and 97 420.2 53 P J °< ft 69 and 97 336.2 54 z υ 0 J °Ρτ the 71 and 96 375.2 55 P0 p °< ft 69 and 96 350.2

CM V is IN m w H

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 56 Ο z^Ti ^{NH Ν} Λ \ II J V--Á. ,He. _ / XX ocf ₃ 68 and 96 434.2 57 o A] NH Ν-Λ X II J VV O. ^H U xoL ^^cf ₃ 64 and 98 418.2 58* : O K /^Ti NH ^N —\ \ II JV—V .cl ^H U ^JL 62 and 101 364.2 59 υ 0 J °< the 64 and 102 420.2 60 the >° He 0 p 72 and 96 419.2 61 0 Z0^l ^{NH Ν} Λ \ II J V--V ^,o. ^H ν' ^^cf ₃ 72 and 97 405.2 62 the >° F0 <07 \0 67 and 96 440.3 63 o 70^í| NH ν-Λ x II J VA. _o^ / ^NN ^ll ' Nís JL cf ₃ 72 and 111 420.2 64 8 0 o á 68 and 111 435.2 65 o ^{NH Ν} Λ I r ii ^H 79 and 97 372.2

NI

IN N M

M (H

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 66 1 /=° P 0 0-- η 79 and 96 386.2 67 O /9Xj Xf ^{nh n} —\ X JI J V--X /S. rn ^H JL X^^CI 63 and 97 370.1 68 1 P o 0^0, 81 and 96 404.1 69 0 Ζ^Ύι ίΓ ^{NH Ν} ”Λ \ JJ VV ^c* n^xx ri) hk JI X^f F 83 and 97 372.1 70 8 )=° 0 p pp n 83 and 96 386.2 71 9 0 P °< 8 70 and 97 337.2 72 o A /7 Τι ίΓ ^{NH ν} Λ X JI Vx ⁷ M 70 and 96 351.2 73 υ 0 0 P °=c the. 63 and 111 385.1 74 1 /Z ΪΙ ^{NH Ν} Λ X JI ✓J Vx z-Ο-. h L JI X^^CF ₃ 64 and 107 438.1

100

TENDON

IS m

M

H

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 75 0 Cl 81 and 96 418.2 76 1 >° he 69 and 111 351.1 77 X o °=4 ö. 82 and 96 436.1 78 X 0 J b 84 and 96 382.2 79 0 0 b b 85 and 96 378.2 80 X o j b. 84 and 97 368.2 81 o 0 0 °< b. 77 and 96 419.2 82 o NH Ν-Λ ^Cf_ \ JJ J U< O h LI] 69 and 104 370.1 83 o zT**Ti nh ^ν-Ά \ II J \-X\ ^H JX X f ^x ^^'cf ₃ 73 and 97 422.2

101

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 84 Ο z—< ^NH Ν'-'Ά \ JI J VA. .He. / Xl F CF ₃ 73 and 96 436.2 85 He /T>rf NH Ν-Λ \ JJ ,J V-Z. n--^^ rn h L J-L 71 and 97 361.2 86 0 /T>l NH ΝΛ \ JI J b-k /\ / XI CN 74 and 96 393.2 87 0 /Χπ ^{NH Ν} Λ ar CN 74 and 97 379.2 88 0 /^Ίι ^{NH Ν} Λ \ JJ X VK Λ x<\ N·^^ r π HL JJ CN 75 and 97 379.2 89 0 Z^Tj ^^7 NH Ν-Λ x JJ J V-X A / xy CN 75 and 96 393.2 90 0 XXi nh ν·Λ ^ _c . F 82 and 97 422.2 91 O 7/^Tl ^NH Ν-Λ X JJ ✓J \—-*·^ 7-°-> /X. h L Jl 77 and 97 405.3 92 F ° A /z^i ^T ^{NH Ν} Λ / <L ^-^ ZF ₃ 64 and 108 436.2

fM

V κ

ALSO ffl

H

102

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 93 Ο ο 0 Ο 64 and 104 438.1 94 8 0 Ο a υ 68 and 104 454.1 95 CI Ο A ζ/Τι 'ίΓ ^{νη ν} Λ \ II J V-—X .ο. --ν. 69 and 106 384.2 96 rf°=4 79 and 106 420.1 97 '8 ,ί' 0 π 80 and 96 393.2 98 Ο //^\ ΝΓ ^{ΝΗ Ν} Χ —\ II ,Ι VX .ο. / XX 64 and 99 432.2 99 Huh? Ο 0 0 °< Á 64 and 116 453.1 100 ρι Ο A //Ίι ^{ΝΗ Ν} Λ \ II I V--X ^- ^ο -^ / ^Ν XX ^^ocf ₃ 68 and 116 469.1 101 1 }=° Ρ 0 0 Ο - η 78 and 111 437.2 102 δ 0 0 °< .a 64 and 115 439.1

CM V c*. c»

H

103

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 103 ο 0 0 °s 1 63 and 116 419.1 104 υ ο 0 o °< h. 81 and 111 419.1 105 ο ^ΝΗ Ν-~Λ \ JI J 0--0. ,Ο. Α= / ^{Ν Ν} Ί0Τ 83 and 111 387.2 106 ξζ >° ο 0 Ο 64 and 117 497.0 107 F ° A __ /η ί ^Ν *Λ ι \ JI ,1 0--0 -ο. / Ul _F 79 and 108 404.2 108 huh? Ο 0 Ο 0 °< ,1. 64 and 110 443.2 109 < 0 0 0 Ο 63 and 117 463.0 110 ο // < ^{ΝΗ Ν} Λ \ II J 0-0. . ι ^ν ΎΊ ^^cf ₃ 64 and 112 433.2 111 ί Ν° / ⁵ ο 0 Ο 64 and 114 433.2 112 F ο 0^>. A ^{ΝΚ Ν} Ά 1 χ II J V-—0. ,ο. Js. r π ^Η 3L 79 and 109 390.2

Ν b> m

H

104

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 113 o Ar ^{NH Ν} Λ JJ Λ V-Ά r π h L JL ^^cf ₃ 64 and 113 419.1 114 or >° F0 *n 79 and 98 386.2 115 0 F o A' 79 and 103 400.2 116 o /X~~Yi χ ^{NH Ν} Λ \ JJ J va. h L JJ 69 and 98 350.2 117 1 A° F 0 0 o z 71 and 98 375.2 118 1 0 ,^1 a _ Z^H ίΓ ^{NH Ν} Ά X JJ A ^H Xx JL 64 and 101 418.1 119 o Ζ^Τι ίΓ ^{nh ν} Ά Γ if \ II J Α-Ά As.a / 86 and 96 432.2 120 O 0 0 k 87 and 96 433.2 121 o Oij ^{NH N} CX XJ 85 and 111 433.2 122 o A _Λ Ζ^Ύ| ^NH ΤΑ. _/Ν χχ °A(X 89 and 96 364.3

1837742

105

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 123 b P 0 d 8 90 and 96 419.2 124 o ^NH γζλ cf ₃ 94 and 96 416.2 125 <O LL υ °< a 94 and 111 417.2 126 o A \^Ίι ^{NH N} C3<N'-'XX' ¹ ua cf ₃ 95 and 96 417.2 127 O °< 8 95 and 97 402.2 128 o /YT| ^{NH N} X\ / XJ... 93 and 96 362.2 129 o ζΓΊι ΜΓ ^NH Π P^X-CF, X JJ J // ν^ _ν Ύ 76 and 111 433.2 130 8 >° f 0 88 and 96 350.3 131 0 A XYi ^{nh n} Y [IT \ II J ΝΎ<ί^ o Η 88 and 97 336.3 132 .Ρ ζ d b 91 and 96 377.2

Μ is Irish

106

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 133 P z d °=4 8. 92 and 96 363.3

* The racemic mixture was separated by chiral preparative chromatography and only one enantiomer was found to be active (Example 63), but its absolute configuration was not determined.

Examples produced by other synthetic routes:

Example 134

CH ₂ CI ₂

DHP PyOTs

PhOCN tBuLi

107

M-[(2-cyano-1H-indol-5-yl)methyl]-3-{[4-(trifluoromethyl)phenoxy]methyl}azetidine-1carboxamide

Hydroxymethyl-1H-indole (2.63 g, 18.55 mmol), 3,4-dihydro-2/-/-pyran (2.6 mL, 28.5 mmol) and pyridinium para-toluenesulfonate (470 mg, 187 mmol) with dichloromethane was stirred at room temperature for 3 hours. An additional 0.8 mL of 3,4-dihydro-2/7-pyran (8.8 mmol) was added and the mixture was stirred for an additional 2 h. Water is added and the pH of the mixture is adjusted to 8 by addition of saturated NaHCCl solution. The mixture is extracted with dichloromethane, the combined organic phase is dried over Na2SO4, filtered and evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2CI2 - EtOAc (98:2)), giving 5-[(tetrahydro2/-/-pyran-2-yl-oxy)methyl]-1/-/-indole (2.47 g, 58%) is obtained as a light yellow oil.

5-[(tetrahydro-2 H -pyran-2-yloxy)methyl]-1 H -indole (1.00 g, 4.3 mmol), TEA (0.60 mL, 4.3 mmol) and 4-(dimethylamino)pyridine (51 mg, 0.4 mmol) in dichloromethane (65 mL) was added di-tert-butyl dicarbonate (1.12 g, 51.3 mmol) under an inert atmosphere, and the mixture was stirred at room temperature Stir for 3 hours.

Dichloromethane was added and the mixture was extracted with brine, dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The residue is purified by column chromatography on silica gel (gradient elution: cyclohexane and cyclohexane-EtOAc = 95:5) to give 5-(tetrahydro-2H-pyran-2-yloxy)methyl]-1H-indole-1 20 carboxylate (1, 08 g, 75%) is obtained as a pale yellow oil.

To a solution of tert-butyl {5-[(tetrahydro-2/7-pyran-2-yloxy)methyl]-1H-'\ndol-1-carboxylate} (331 mg, 1 mmol) in 20 mL of tetrahydrofuran was added tert-butyllithium (1.7M solution in pentane, 0.88 mL, 1.5 mmol) dropwise at -78 °C to -65 °C under an argon atmosphere. The mixture was stirred at -70 °C for 20 minutes, then a solution of phenylcyanate (20 m/m%, 0.75 ml, 1.6 mmol) in dichloromethane was added dropwise. The mixture is stirred at -70 °C for 30 minutes, then allowed to warm to room temperature and stirred for another 4 hours. The reaction was quenched by the addition of saturated aqueous NH 4 Cl (20 mL). The resulting mixture is extracted with ethyl acetate, the combined organic extracts are washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give a yellow oil. THE

M

V b* b* w

H

The crude product 108 is purified by flash column chromatography on silica gel (0-3% EtOAc in CH2Cl2) to give tert-butyl {2-cyano-5-[(tetrahydro-2/-/-pyran-2-1H-indole-1-carboxylate } (133 mg, 47%) is obtained in the form of a white, amorphous substance.

tert-butyl {2-cyano-5-[(tetrahydro-2/7-pyran-2-1/-/-indole-1-carboxylate}) (130 mg, 0.36 mmol) and pyridinium p-toluenesulfonate ( 18 mg, 0.07 mmol) was refluxed for 2 h. The mixture was evaporated to dryness, brine was added, and the combined organic phase was dried over Na2SO4 and filtered under reduced pressure Evaporation gave tert-butyl-[2-cyano-5-(hydroxymethyl)-1 H -indole-1-carboxylate] (104 mg) as a white solid, which was used in the next step without further purification.

tert-butyl [2-cyano-5-(hydroxymethyl)-1/7-indole-1-carboxylate] (100 mg, 0.36) and diphenylphosphoryl azide (0.12 mL, 0.56 mmol) 5 mL 1,8-diazabicyclo[5.4.0]undec-7-ene (0.084 ml, 0.56 mmol) was added to its solution in tetrahydrofuran at 0 °C, and then the mixture was refluxed for 3 hours. An additional 0.06 mL (0.28 mmol) of diphenylphosphoryl azide and 0.042 mL (0.28 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added at room temperature and the mixture was stirred at reflux for an additional hour. The solvent is evaporated under vacuum, the residue is taken up in dichloromethane, extracted with saturated NaHCOa solution and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography (0-50% CH2Cl2 in cyclohexane) to give tert-butyl-[5(azidomethyl)-2-cyano-1/-/-indole-1-carboxylate] (57 mg, 51%) as a yellowish solid.

tert -Butyl-[5-(azidomethyl)-2-cyano-1 / -/-indole-1-carboxylate] (55 mg, 0.18 mmol) and triphenylphosphine (145 mg, 0.55 mmol) prepared with 2 mL of tetrahydrofuran solution is stirred at room temperature for 5.5 hours in an argon atmosphere. Water (0.5 mL, 28 mmol) was added and the mixture was stirred at the same temperature for 1.5 h. The reaction mixture was adsorbed onto silica gel and purified by flash column chromatography (0-10% MeOH in ChbCb) to give tert-butyl-[5f'·. Γ*< m

109

N V ft. ft

ÖU (aminomethyl)-2-cyano-1-(indole-1-carboxylate)] was obtained (33 mg, 66%) in the form of white crystals.

tert -Butyl-[5-(aminomethyl)-2-cyano-1/7-indole-1-carboxylate] (122 mg, 0.45 mmol) and DIPEA (0.16 mL, 0.92 mmol) in 4 mL DMF 45 nitrophenyl (chloroformate) (100 mg, 0.5 mmol) was added to a solution of The pale yellow suspension was further stirred under unchanged conditions for 2.5 hours, then an additional 25 mg of 4-nitrophenyl (chloroformate) (0.125 mmol) was added, and the mixture was stirred for an additional hour, then an additional 25 mg of 4-nitrophenyl was added. -(chloroformate) (0.125 mmol) and the mixture was stirred for an additional hour. A solution of 3-{[4-(trifluoromethyl)phenoxy]methyl}azetidine (112 mg, 0.45 mmol) in dichloromethane (2 mL) was added at 0 °C, and the mixture was allowed to warm to room temperature and stirred overnight. The mixture is concentrated in vacuo and the residue is chromatographed on silica gel with gradient elution with 0-10% EtOAc - CH2Cl2 mixture, then 0-3% MeOH - CH2CI2 mixture, giving

136 mg (57%) tert-butyl-(2-cyano-5-{[(3-{[4-(trifluoromethyl)phenoxy]methyl}azetidine-1carbonyl)amino]methyl}-1/7-indole-1- carboxylate) is obtained.

tert-Butyl-(2-cyano-5-{[(3-{[4-(trifluoromethyl)phenoxy]methyl}azetidine-1-carbonyl)amino]methyl}-1/-/-indole-1-carboxylate) ( 135 mg, 0.25 mmol) in 10 ml of dichloromethane, add trifluoroacetic acid (0.4 ml, 5 mmol) in an ice water bath

Cool to 0 °C and then stir the solution at room temperature for 22 hours. The solvent is removed under reduced pressure and the residue is chromatographed on silica gel, gradient elution with a mixture of 0-3% MeOH - CH2CI2, then purified by preparative reversed-phase HPLC, using a mixture of acetonitrile and water as a gradient, thus 24 mg (0.056 mmol, 22%) title we obtain a compound according to

[M+H] ⁺ = 429.1

110

Example 135

Η

Intermediate 97

N-[(1H-indol-5-yl)methyl]-3-{[4-(trifluoromethyl)phenoxy]methyl}azetidine-1-carbothioamide

To a solution of 3-{[4-(trifluoromethyl)phenoxy]methyl}azetidine (116 mg, 0.5 mmol) in 2 mL of DMF 5 was added 1,1'-thiocarbonylimidazole (98 mg, 0.55 mmol) at room temperature in an argon atmosphere. The brownish-yellow solution was stirred under these conditions for 1 hour. After the activation period, a solution of 1-(1/7-indol5-yl)methanamine (72 mg, 0.49 mmol) in DMF (1 mL) was added and the mixture was stirred at this temperature overnight, then at 65 °C for 1 hour. After completion of the reaction (monitored by thin layer chromatography), the mixture was poured into 8 mL of water and extracted with ethyl acetate (2x15 mL). The organic phase is dried over anhydrous Na2SO4, filtered and evaporated under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of CH2Cl2 and MeOH (95:5) to obtain 23 mg of the title compound. LC-MS (ESI) m/z [M+H] ⁺ = 420.2

Intermediate 118

3-[(4-methylphenoxy)methyl]pyrrolidine

Intermediate 118 is prepared according to the synthetic method described for intermediate 62.

n v r*. b*

W

H

111

Intermediate 119

3-{[4-(trifluoromethyl)phenoxy]methyl}pyrrolidine

Intermediate 119 is prepared according to the synthetic method described for intermediate 62.

The methylpyrrolidine derivatives are summarized in Table 12.

Table 12

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 136 He THE ° X,-—/ / 96 and 118 378.3 137 HE '—y °-\=/ H 97 and 118 364.3 138 0 H 97 and 119 418.2 139 o <flOC ^NH 0^o-/3- ^cf ' / 96 and 119 432.2

Other pyrrolidine intermediates listed in Table 13 are described in Table 62.

it is produced according to the synthetic method described under intermediate.

ft. ft

W

H

112 ft V is also m

H

Table 13

Intermediary Structure Intermediary Structure 120 0 126 F 121 0 F 127 HnF/*.....°\ ö cf ₃ 122 Κίθ..... ₀ OMe 128 HnC0.....0 Q CN 123 .....0 F 129* 0 see ₃ 124 Omg 130* - _o ..„ 0 cf ₃ 125 0 see ₃

*Can be synthesized starting from the appropriate aniline derivative

The examples described in Table 14 are prepared according to the method described in Example 38.

Table 14

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 140 0 X 96 and 120 364.3

113

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 141 0 /Oil Ύ NH N'A_ _p 97 and 120 350.3 142 0 K -X ZS| NH Λ..... ₀ F 96 and 123 368.2 143 O ΛΥΥ NH NX..... _o ' ° X OMe 96 and 122 380.2 144 O O~rf ^NH ? X—o F 96 and 121 368.2 145 O ZXjX-X NH N^\_ _o ' O^ OMe 96 and 124 380.2 146 0 Λγγ NH νΆ^ο cf ₃ 96 and 125 418.2 147 He /O| NH q ^0 F 97 and 121 354.2 148 0 /x Á -X /On 7r nh na^o CF ₃ 97 and 125 404.2 149 I -x or o^ F 106 and 126 420.2

What? £ z ε 8 τ

114

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 150 0 /YY NH ΝΛ o ca cf ₃ 96 and 127 419.2 151 0 _< Yrp^NH ^X N'A ₀ CF, 97 and 127 405.2 152 Eg O _____ A ΥΊιΥ ^NH , ^F F 107 and 126 406.1 153 0 /Ai yt ^{NH N} ^s—o ^F YY o-^ F 96 and 126 386.2 154 0 /An A^ ^{nh N} X—n F -zcr .>$ F 105 and 126 420.1 155 rí ° L/-/- P / Yl· ΊΓ ^NH । ° x-Ά ^L -a py i A CF, 106 and 127 453.1 156 o AP A CF ₃ 104 and 127 419.2 157 0 Z-, Y The Ά F 104 and 126 386.2 158 0 zYf nh ΥΎ-ο cf ₃ 104 and 125 418.2

1837742

115

Μ V Ν· Ν m w Η

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 159 χΤ|η ^NH f ;>-o ^H v# cf ₃ 107 and 127 439.1 160 0 A Ο,^ΥΥ^ΝΗ^Ν^ cf ₃ 105 and 127 439.1 161 0 CI-ΠΥ ^N ? >o °k cf ₃ 105 and 125 438.1 162 0 _ε! ΓηΡγ^ ^ΝΗ <ν° ; « Q F 105 and 126 406.1 163 ^c L/\/x I /~Π 'Τ NH n^\_ ₀ CF ₃ 106 and 125 452.1 164 Cl θ YrY'|^NH ^J 'N^\ _o cf ₃ 107 and 125 438.1 165 F ⁰ XPPNH 'N'''. ₀ F OJ F 108 and 126 404.2 166 F ⁰ N'Y-Ö f « F 109 and 126 390.1 167 O /Yii ⁵ ! NH Yy_ ₀ f CU F 111 and 126 387.2

116

Μ V r*. c·* Μ Μ Η

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 168 0 ΛΊΐ Ί ^ΝΗ ν >-ο - '-χ CF, 111 and 127 420.3 169 0 Z'Tf Xf ΝΗ w '-χ CF ₃ 111 and 125 419.3 170 F ⁰ 8χ^χ Α //-if Υ ^ΝΗ ^ΝΧ _ο < _N JU LV >=. Η ^Ν Χ cf. ₃ 109 and 127 423.1 171 F ⁰ Χ^Χ Α -X ' ίχ cf ₃ 109 and 125 422.1 172 0 _ΑΤ| Ί νη γ\-0 CN 104 and 128 375.2 173 0 <><ΧνΗ ^Ν^Χ _ο Η ' CN 97 and 128 361.1 174 0 ζ^^χ JL <fY%P ^N H Ν\ _ΝΗ cf ₃ 96 and 129 417.3 175 0 <ΓΧΡ ^ΝΗ Ο.....ΝΗ ' ° 0 cf ₃ 96 and 130 417.3

117

The example compounds containing piperidine, piperazine and azepane rings described in Table 15 are prepared according to the method described in Example 38.

Table 15

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 176 o ^χζχ 9 x\ XX/ XT ^NH [ 1 fi] 25 and 97 364.3 177 0 XX A χχ XXX /0Y| ^{NH N} | \\\ 25 and 96 378.3 178 0 29 and 96 382.3 179 O ____ z->x /χ X, /\ xx ,OMe /^Ί| ^{NH N} | \Nx 26 and 96 394.3 180 Xx^xx I XX xx^P Ζκϊ| ^{nh n} J í| N / _o xkJ F 31 and 106 434.1 181 Lx^ I x^ xx^P \B ^{NH N} l íi ίΓ^ Η 1 F 31 and 107 420.1 182 0 XW / 15 and 96 377.3 183 0 xXcvcr / 19 and 96 431.2

N

IN m

OH

H

118

Μ V b> F

W w H

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 184 Ο ~ Z\ OMe €Cr-oxr / 20 and 96 393.3 185 ox ^J oxr / 17 and 96 397.2 186 o O ^f fY ^NH L 1 ΆJ N^xO Cx^o^xO Η 1 F 31 and 98 400.2 187 HE 0 30 and 98 432.2 188 ter ^J CM/ F 31 and 109 404.2 189 O _ x\ -x\ IL xx xx „OMe ^NH l 1 if N-^x^ X/k/kk / Π O 26 and 96 406.2 190 O YlYj ^NH l 1 iT N kxk/xk O 29 and 96 394.2 191 0 ^{NH N} \ \ 11 xJ 1 λ~ο 32 and 96 392.3 192 ri ⁰ kx^ X /X, ^C, ter- oar / 17 and 106 431.1

119

Example Structure Starting intermediates LC-MS (ESI) [M+H] ⁺ 193 / 16 and 106 415.1 194 >° o b o 19 and 106 465.2

Production of medicinal products

The following formulation examples illustrate representative pharmaceutical compositions of the present invention. However, the present invention is not limited to the following pharmaceutical preparations.

A) Solid oral dosage forms

/., Tablets

Active ingredient(s)

Filler

Binder Disintegrant Lubricant

0.01-90 %

- 99.9 %

0-20%

0-20%

0-10%

Other specific auxiliary material(s) 0-50 %

II., Orodispersible films

Active ingredient(s)

Film forming material

Plasticizer

Other specific auxiliary material(s)

0.01 -90 %

- 99.9 %

0-40%

0-50%

R V

1% m

W

120 ft W ft ft m M H

5 10 15 B) Liquid oral dosage forms HI., Oral suspensions Active ingredient(s) 0.01 - 50 % Liquid carrier 10 - 99.9 % Wetting agent 0-50 % Thickener 0-50 % Buffer quantum satis Osmotic substance 0-50 % Preservatives quantum satis IV., Syrups Active ingredient(s) 0.01 - 50 % Solvent 10 - 99.9 % Sugar component 1 - 20 % Flavorings 0 - 10 % 20 C) Parenteral dosage forms V., Intravenous injections Active ingredient(s) Solvent Co-solvent Osmotic substance Buffer 0.01 -50 % 10-99.9% 0 - 99.9 % 0-50% quantum satis 25 30 D) Other dosage forms VI., Cones Active ingredient(s) Cone base material Surfactants Lubricants Preservatives 0.01 -50 % 1 - 99.9 % 0-20% 0-20% quantum satis

121

VII., 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 substance 0-20% Viscosity-increasing substance 0-20% Buffer quantum satis Preservatives quantum satis

BIOLOGICAL ACTIVITY

Human α7 nicotinic acetylcholine receptor fCa ²⁺ 1í study

Cells: Flp-ln 293 cells stably expressing human o7 nAchR and human RIC-3 (a7 cells generated in-house).

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

Cell culture medium - DMEM (Dulbecco's Modified Eagle Medium, Gibco) - 10 % FBS (Fetal Bovine Serum, Gibco) - 1 % glutamine (Sigma G) - 50 pg/ml Hygromycin B - 800 pg/ml G418 - 1 % penicillin-streptomycin -antimycotic solution (PSA, Sigma) Brief description of the Ca ²⁺ fluorometry method Test buffer: - 140 mM NaCl - 5 mM KCl - 10 mM HEPES - 2 mM MgCl - 2 mM CaCl - 10 mM glucose - 2 mM probenecid, pH=7.4

P V

TENDON

TENDON

122

α7 nAchR stably expressing α7 cells were cultured in the cell culture medium described above and passaged twice a week. For the fluorometric measurement of the cytosolic Ca ²⁺ concentration ([Ca ²⁺ ]i), the cells were divided into 96-well cell culture trays with a density of 60,000 cells/well and overnight in 5 incubators suitable for cell culture at 37°C, 95% atmospheric air/5% CO2 we kept it in atmosphere. The medium used for outplanting was the same as the medium used for cultivation. 50 μΙ of the medium was aspirated with a cell washer (BioTek Elx405UCVWS). Then, 50 µl/well of Calcium 5 kit, diluted twice in assay buffer, was added manually with an 8-channel pipette. After the incubation period (20 min, 10 37°C), 50 μΙ/well of assay buffer containing vehicle (4% added DMSO) or assay buffer containing reference compound α7 PAM at four times the final concentration was added manually, and the cells were incubated for an additional 10 minutes at 37 °C.

Baseline and agonist-induced [Ca ²⁺ ]i changes were monitored using a FlexStation 15 II ⁹⁶ (Molecular Devices, Sunnyvale, CA; an 8-channel plate reader fluorometer with integrated liquid dosing capability). Fluorescence measurements were performed at 37°C. The dye was excited at 485 nm, and the emission was measured at 525 nm in 1.4 second intervals. Baseline was recorded for 20 s, followed by agonist stimulation. Using the 20 FlexStation II pipettor, 50 μΙ of quadruple concentration agonist solution was added to the cells, and the fluorescence was monitored for another 40 seconds. The final concentration of DMSO was 1% for all treatments. To achieve this, we prepared a series of DMSO stock solutions of each tested compound. These stock solutions were stored at 0°C and further diluted in assay buffer immediately before the measurement to obtain the desired final concentration. Agonist and PAM concentration-effect studies were performed in the presence of saturating concentrations of PAMs (mostly PNU-120596, 5 μΜ) and agonists (mainly PNU-282987, 1 μΜ). Results were expressed as AF/F values using SoftMax Pro software (Molecular Devices), where F was the resting fluorescence before agonist application and AF was the increase in fluorescence over time (AF = maximum fluorescence intensity values after stimulation minus the average

1837742

123 fluorescence intensity values before stimulation). In each experiment, all treatments were measured in multiple parallel wells and the mean AF/F values were used for analysis.

Table 16 shows the PAM ECso values obtained in the [Ca ²⁺ ]i test:

Table 16

Example EC 50 (nM) Example EC 50 (nM) 1 500 86 590 2 760 88 2800 3 90 90 85 4 920 92 55 5 400 108 2200 6 100 109 900 7 2100 112 1300 8 980 113 1700 9 170 115 720 10 430 119 125 11 85 120 280 13 420 122 270 14 1200 123 1600 15 1900 124 580 16 110 126 1400 17 820 129 50 18 210 130 620 20 2600 132 1500 21 900 133 1500 22 940 134 780

ft. Sun h. ft w

H

124

23 120 135 200 Example EC 50 (nM) Example EC 50 (nM) 26 310 136 280 36 2800 139 570 38 40 140 170 40 55 141 450 41 80 142 320 42 650 143 730 43 60 144 120 44 220 145 510 46 490 146 130 47 160 149 130 48 50 150 110 49 410 152 420 51 200 154 2000 54 350 160 240 55 180 161 320 56 25 165 170 57 15 166 590 58 330 167 2200 59 670 172 500 60 40 174 380 65 730 175 330 68 160 176 950 69 380 179 410 71 3000 180 370

μ V also lb* w

Hl

125

74 500 182 490 Example EC 50 (nM) Example EC 50 (nM) 77 45 183 260 78 150 186 170 79 30 189 540 81 270 190 1400 82 470 191 600 83 250

In vivo pharmacology (location recognition test)

In vivo pharmacology (location recognition test)

Animals: Male NMRI mice (Toxicoop, Hungary)

Materials: Scopolamine was dissolved in physiological saline and administered i.p. at a dose of 1 mg/kg. we submitted. The test compounds were administered 30 minutes before the start of the acquisition trial (T1), and scopolamine was administered after the start of the acquisition trial in a volume of 0.1 ml/10 g.

Procedure: The task was performed using a transparent Plexiglas Y-ball (the length of each arm was 40 cm, the inner width was 11 cm, and the height was 30 cm). We placed a number of visual signals in the arms, which were kept at a constant location during the experiment. The study consisted of two trials (T1 and T2) separated by 15 30-min intertrial intervals. Mice were placed in the start arm of the maze at the beginning of each trial. In T1, one symmetrical arm of the maze was closed (in T2 this will be the new arm) and the animals were allowed to explore the platform for 5 minutes (acquisition phase). In T2, mice had free access to all three arms for 2 min (recovery phase). During T2, we measured the times spent in 20 explorations in the new and familiar arms. Spend time exploring the familiar or the new arm

1837 7 42

Differences between 126 times for each group were assessed with MANOVA, followed by Duncan's post hoc test.

Table 17 shows the reversal of scopolamine-induced amnesia in the place recognition test in mice:

Table 17

Dose (i.p.) 1 mg/kg 3 mg/kg 10 mg/kg Example 3 +++ ++ +++ Example 5 +++ ++ + Example 23 ++ +++ + Example 47 ++ + +++ Example 51 + ++ + + Example 90 ++ +++ +++

⁺ p<0.05; + ⁺ p<0.01; ⁺⁺⁺ p<0.001

A significant difference ( ⁺ p<0.05; ⁺⁺ p<0.01; ⁺⁺⁺ p<0.001) was observed in the exploration times between the new and familiar arms of the maze.

ft. ft. ft. ft

W

Η

Claims (11)

127 DEMAND POINTS 1. The compound of general formula (I), hi f* Í® ίΛ Hl ih (I) where R ¹ is hydrogen or C 1-6 alkyl; R ² is hydrogen or C 1-6 alkyl, or R ² is absent when n is 0; R ³ is hydrogen or O, or R ³ is absent when m is 0; R ⁴ and R ⁵ are independently hydrogen, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy, or CN; n and m are independently 0 or 1; provided that n and m cannot be 0 at the same time; k and I mean 1 Y is N or C(R ⁶ ); R ⁶ is hydrogen, C 1-6 alkyl, halogen, or haloC 1-6 alkyl; R ⁷ is hydrogen, C 1-6 alkyl, or halogen; W is N; Z is CH; L is an optionally substituted spacer consisting of 1, 2 or 3 atoms, denoted T-U-V, where T is CH 2 , C(O), NH, SO 2 or O; U is CH 2 , C(O), O or absent; and V is CH 2 , O or absent; A is a phenic, 2-pyridyl or 3-pyridyl group optionally substituted independently with one or more halogen atoms or halogen atoms, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, CN, or benzyl groups; ΙΙ··Ι· SZTNH-100386360 128 or its pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, solvates and hydrates. 2. A compound according to claim 1, wherein R ¹ is hydrogen or C 1-3 alkyl; R ² is hydrogen or C 1 -alkyl, or R ² is absent when n is 0; R ³ is hydrogen or O, or R ³ is absent when m is 0; R ⁴ and R ⁵ are independently hydrogen, C 1-3 alkyl, halogen, haloC 1-3 alkyl, C 1-3 alkoxy, or CN; n and m are independently 0 or 1; provided that n and m cannot be 0 at the same time; k and I mean 1; Y is N or C(R ⁶ ); R ⁶ is hydrogen, C 1-3 alkyl, halogen, or haloC 1-3 alkyl; R ⁷ is hydrogen, C 1-6 alkyl, or halogen; W is N; Z is CH; L is an optionally substituted spacer consisting of 1, 2 or 3 atoms, denoted T-U-V, where T is CH 2 , C(O), NH, SO 2 or O; U is CH 2 , C(O), O or absent; and V is CH 2 , O or absent; A is phenic, 2-pyridyl or 3-pyridyl; which is optionally substituted independently of one another with one or more halogen atoms or halogen atoms, C 1-3 alkyl, C 1-3 alkoxy, haloC 1-salkyl, haloC 1-salkoxy, CN, or benzyl groups; or pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, solvates and hydrates thereof. 3. The compound of claim 1, wherein R ¹ is hydrogen or C 1-3 alkyl; R ² is hydrogen or C 1 -alkyl, or R ² is absent when n is 0; R ³ is O, or R ³ is absent when m is 0; tfíi ft h 129 R ⁴ and R ⁵ are independently hydrogen, Ci- ₃ alkyl, halogen, haloCis alkyl, C 1-3 alkoxy, or CN; n and m are independently 0 or 1; provided that n and m cannot be 0 at the same time; k and I mean 1; Y is N or C(R ⁶ ); R ⁶ is hydrogen, C _1-3 alkyl, halogen, or haloC 1-3 alkyl; R ⁷ is hydrogen, C 1-3 alkyl, or halogen; W is N; Z is CH; L is a spacer selected from the following group: -CH2-, -Ο-, -NH-, -SO2-, -C(0)-, CH2-O-, -CH2-CH2-O-, -O-CH2-, -CH2-CH2-, -NH-C(O)-, or -NH-CH2-; Phenic, 2-pyridyl or 3-pyridyl; which is optionally substituted independently by one or more halogen atoms or halogen atoms, C1-3 alkyl, C1-3 alkoxy, haloC1-salkyl, haloC1-salkoxy, CN, or benzyl groups; or pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, solvates and hydrates thereof. 4. The 1-3. A compound according to any one of claims, selected from the following group: [(1H-indol-5-yl)methyl][(3-{[4-(trifluoromethyl)phenoxy]methyl}-azetidin-1-yl)methyl]amine; N-({1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-3-{[4(trifluoromethyl)phenoxy]methyl}azetidine-1-carboxamide; Λ / -[( 1 -methyl-1 H -indol-5-yl)methyl]-3-{[4-(trifluoromethoxy)phenoxy]methyl}azetidine-1-carboxamide; N -[(2-methyl-1/7-indol-5-yl)methyl]-3-{[4-(trifluoromethyl)phenoxy]methyl}azetidine-1-carboxamide; 3-{[3-Fluoro-4-(trifluoromethyl)phenoxy]methyl}- N -[(1-methyl-1 N -indol-5-yl)methyl]azetidine-1-carboxamide; air Iffll 130 3-{[3-Fluoro-4-(trifluoromethyl)phenoxy]methyl}- N -[(1H-indol-5-yl)methyl]azetidine-1-carboxamide; N -[(3-Fluoro-1-methyl-1H-indol-5-yl)methyl]-3-{[4-(trifluoromethyl)phenoxy]methyl}azetidine-1-carboxamide; 3-methyl-N-({1-methyl-1/7-pyrrolo[2,3-b]pyridin-5-yl}methyl)-3-{[4(trifluoromethyl)phenoxy]methyl}azetidine-1- carboxamide; or pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, solvates and hydrates thereof. 5. The 1-4. A compound according to any one of claims for use in the treatment or prevention of a disease associated with o7 nicotinic acetylcholine receptor activity, wherein the disease is selected from the group consisting of: psychotic disorders, including but not limited to schizophrenia, schizophrenic, schizoaffective disorder, delusional disorder, brief psychotic disorder, general health condition-related psychotic disorder, substance abuse-induced psychotic disorder or otherwise unspecified psychotic disorder, cognitive impairment, including for example treatment of cognitive impairment and cognitive impairment due to stroke, Alzheimer's disease, Huntington's disease, Pick's disease, HÍV dementia associated with infection, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, cerebrovascular disease, or dementia associated with other dementia conditions and other degenerative disorders, including but not limited to amyotrophic lateral sclerosis, other acute or subacute conditions that may lead to cognitive decline, including , but not limited to, delirium, traumatic brain injury, senile dementia, mild cognitive impairment, Down syndrome, depression and cognitive deficits associated with other diseases and dyskinetic disorders, including but not limited to Parkinson's disease and neuroleptic-induced parkinsonism or tardive dyskinesias, depression and mood disorders, including but not limited to depressive disorders and episodes, bipolar disorders, cyclothymia, and other unspecified bipolar disorders, other mood disorders, substance use-induced mood disorder, and otherwise unspecified mood disorder, anxiety do I disturb, Λ ft boy! 131 panic disorder and panic attacks, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, general health-related anxiety disorder, substance use-induced anxiety disorder, phobias and other unspecified anxiety disorders, substance use disorders, including but not limited to limited, substance use or substance use-induced disorders, including, but not limited to, alcohol, nicotine, amphetamine, phencyclidine, opioid, cannabis, cocaine, caffeine, hallucinogens, inhalants, sedatives, hypnotics, anxiolytics, polydrug addiction or other substance use disorders, sleep disorders including, but not limited to, narcolepsy, dyssomnia, primary hypersomnia, breathing-related sleep disorder, circadian rhythm sleep disorder, dyssomnia not otherwise specified, parasomnia, pavor nocturnus, sleepwalking, parasomnia not otherwise specified; sleep disorders associated with other mental disorders, general health-related sleep disorders and substance use-induced sleep disorders, metabolic and eating disorders including, but not limited to, anorexia nervosa, bulimia nervosa, obesity, compulsive eating disorder, binge eating disorder, and eating disorders not otherwise specified, diabetes mellitus, ulcerative colitis, Crohn's disease, irritable bowel syndrome, autism spectrum disorder, including but not limited to autistic disorder, Asperger's syndrome, Rett's syndrome, childhood disintegrative disorder, and not otherwise specified pervasive (pervasive) developmental disorder; attention deficit hyperactivity disorder, disruptive behavior disorder, oppositional defiant disorder and disruptive behavior disorder not otherwise specified, as well as tic disorders such as Tourette syndrome, personality disorders, sexual dysfunctions such as sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorders, other sexual dysfunctions not otherwise specified, paraphilias, gender identity disorders, infertility premenstrual syndrome, sexual disorders not otherwise specified, diseases of the respiratory system such as cough, asthma, chronic obstructive pulmonary disease, pneumonia, cardiovascular disorders, including but not limited to limited, heart failure, cardiac arrhythmia and hypertension, inflammation, inflammatory and neuropathic foot pain, rheumatoid arthritis, osteoarthritis, allergy, sarcoidosis, psoriasis, ϊΛ ft 132 ataxia, dystonia, systemic lupus erythematosus, mania, restless legs syndrome, progressive supranuclear palsy, epilepsy, migraine, amnesia, chronic fatigue syndrome, catalepsy, cerebral ischemia, multiple sclerosis, encephalomyelitis, jet lag, cerebral amyloid angiopathy, and sepsis. 6. The compound according to claim 5, wherein the disease is selected from the group of cognitive impairment, schizophrenia and autism. 7. The 1-4. The use of compounds according to any of claims 7 for the preparation of a drug suitable for the treatment or prevention of a disease related to nicotinic acetylcholine receptor activity, where the disease is selected from the following group: psychotic disorders, including, but not limited to, schizophrenia, schizophreniform, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorder related to a general health condition, substance abuse-induced psychotic disorder or otherwise unspecified psychotic disorder, cognitive impairment, including for example treatment of impairment of cognitive functions, as well as cognitive impairment due to stroke, Alzheimer's disease, Huntington's disease, Pick's disease, HÍV dementia associated with infection, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, cerebrovascular disease, or dementia associated with other dementia conditions and other degenerative disorders, including but not limited to amyotrophic lateral sclerosis, other acute or subacute conditions that may lead to cognitive decline, including , but not limited to, delirium, traumatic brain injury, senile dementia, mild cognitive impairment, Down syndrome, depression and cognitive deficits associated with other diseases and dyskinetic disorders, including but not limited to Parkinson's disease and neuroleptic-induced parkinsonism or tardive dyskinesias, depression and mood disorders, including but not limited to depressive disorders and episodes, bipolar disorders, cyclothymia, and bipolar disorders not otherwise specified, other mood disorders, substance use-induced mood disorder, and mood disorders not otherwise specified, anxiety disorders , panic disorder and panic attacks, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized B Ltd Λ R 133 anxiety, general health anxiety disorder, substance use-induced anxiety disorder, phobias and anxiety disorders not otherwise specified, substance use disorders, including but not limited to substance use or substance use-induced disorders, including but not limited to alcohol, nicotine, amphetamine, phencyclidine, opioid, cannabis, cocaine, caffeine, hallucinogens, inhalants, sedatives, hypnotics, anxiolytics, polydrug addiction or other substance use disorders, sleep disorders including, but not limited to, narcolepsy, dyssomnia, primary hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder, dyssomnia not otherwise specified, parasomnia, pavor nocturnus, sleepwalking, parasomnia not otherwise specified; sleep disorders associated with other mental disorders, general health-related sleep disorders and substance use-induced sleep disorders, metabolic and eating disorders including, but not limited to, anorexia nervosa, bulimia nervosa, obesity, compulsive eating disorder, binge eating disorder, and eating disorders not otherwise specified, diabetes mellitus, ulcerative colitis, Crohn's disease, irritable bowel syndrome, autism spectrum disorder, including but not limited to autistic disorder, Asperger syndrome, Rett syndrome, childhood disintegrative disorder, and pervasive ) developmental disorder; attention deficit hyperactivity disorder, disruptive behavior disorder, oppositional defiant disorder and disruptive behavior disorder not otherwise specified, as well as tic disorders such as Tourette syndrome, personality disorders, sexual dysfunctions such as sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorders, other sexual dysfunctions not otherwise specified, paraphilias, gender identity disorders, infertility premenstrual syndrome, sexual disorders not otherwise specified, diseases of the respiratory system such as cough, asthma, chronic obstructive pulmonary disease, pneumonia, cardiovascular disorders, including but not limited to limited, heart failure, cardiac arrhythmia and hypertension, inflammation, inflammatory and neuropathic pain, rheumatoid arthritis, osteoarthritis, allergy, sarcoidosis, psoriasis, ataxia, dystonia, systemic lupus erythematosus, ft mania, restless legs syndrome, progressive supranuclear palsy, ft ft 134 epilepsy, migraine, amnesia, chronic fatigue syndrome, catalepsy, cerebral ischemia, multiple sclerosis, encephalomyelitis, jet lag, cerebral amyloid angiopathy, and sepsis. 8. The application according to claim 7, where the disease is selected from the group of cognitive impairment, schizophrenia and autism. 9. Medicinal product, the active ingredient of which is 1-4. It contains a compound according to any one of the claims and at least one medically suitable excipient. 10. Pharmaceutical preparation according to claim 9, which contains at least one additional active ingredient. 11. Pharmaceutical preparation according to claim 10, where the additional active ingredient(s) are selected from the group below: acetylcholinesterase inhibitors, NMDA receptor antagonists, beta-secretase inhibitors, antipsychotics, GABAa receptor alpha5 subunit NAMs or PAMs, histamine H3 receptor antagonists, 5ΗΤθ receptor antagonists, M1 or M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs and levodopa. 12. The 1-4. A combination of a compound according to any one of claims and at least one additional active ingredient for use in the treatment or prevention of a disease related to nicotinic acetylcholine receptor activity 7 , wherein the disease is selected from the group consisting of psychotic disorders, including but not limited to schizophrenia, schizophrenic, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorder associated with a general medical condition, substance use-induced psychotic disorder or otherwise unspecified psychotic disorder, cognitive impairment, including for example treatment of cognitive impairment and cognitive impairment due to stroke, Alzheimer's disease, Huntington's disease , Pick's disease, dementia associated with HÍV infection, frontotemporal dementia, Lewy body dementia, vascular dementia, cerebrovascular disease, or dementia associated with other dementia conditions and other degenerative disorders, including but not limited to amyotrophic lateral sclerosis, other acute or subacute ΐΉΙ r * conditions that may lead to cognitive decline, including but not limited to ti yi ft 135 limited, delirium, traumatic brain injury, senile dementia, mild cognitive impairment, Down syndrome, depression and cognitive deficits associated with other diseases and dyskinetic disorders, including but not limited to Parkinson's disease and neuroleptic-induced parkinsonism or tardive dyskinesias , depression and mood disorders, including but not limited to depressive disorders and episodes, bipolar disorders, cyclothymia, and bipolar disorders not otherwise specified, other mood disorders, substance abuse-induced mood disorder, and mood disorders not otherwise specified, anxiety disorders, panic disorder and panic attacks, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, general health-related anxiety disorder, substance use-induced anxiety disorder, phobias and otherwise unspecified anxiety disorders, substance use disorders, including, but not limited to, substance use or substance use-induced disorders, including, but not limited to, alcohol, nicotine, amphetamine, phencyclidine, opioids, cannabis, cocaine, caffeine, hallucinogens, inhalants, sedatives, hypnotics, anxiolytics, polydrug addiction or other substance use disorders, sleep disorders including, but not limited to, narcolepsy, dyssomnia, primary hypersomnia, breathing-related sleep disorder, circadian rhythm sleep disorder, dyssomnia not otherwise specified, parasomnia, pavor nocturnus, sleepwalking, parasomnia not otherwise specified; sleep disorders associated with other mental disorders, general health-related sleep disorders and substance use-induced sleep disorders, metabolic and eating disorders including, but not limited to, anorexia nervosa, bulimia nervosa, obesity, compulsive eating disorder, binge eating disorder, and eating disorders not otherwise specified, diabetes mellitus, ulcerative colitis, Crohn's disease, irritable bowel syndrome, autism spectrum disorder, including but not limited to autistic disorder, Asperger syndrome, Rett syndrome, childhood disintegrative disorder, and pervasive ) developmental disorder; attention deficit hyperactivity disorder, disruptive behavior disorders, oppositional defiant disorder and other unspecified disruptive behavior disorders, as well as tic disorders, SS such as Tourette syndrome, personality disorders, sexual dysfunctions, 0® fi 136 ft ft te Mf*s ft ft ft eg sexual desire disorders, sexual arousal disorders, orgasm disorders, sexual pain disorders, sexual dysfunctions not otherwise specified, paraphilias, gender identity disorders, infertility premenstrual syndrome, sexual disorders not otherwise specified, diseases of the respiratory system such as cough, asthma, chronic obstructive pulmonary disease, pneumonia, cardiovascular disorders including but not limited to heart failure, cardiac arrhythmia and hypertension, inflammation, inflammatory and neuropathic pain, rheumatoid arthritis, osteoarthritis, allergy, sarcoidosis, psoriasis, ataxia, dystonia, systemic lupus erythematosus, mania, restless legs syndrome, progressive supranuclear palsy, epilepsy, migraine, amnesia, chronic fatigue syndrome, catalepsy, cerebral ischemia, multiple sclerosis, encephalomyelitis, jet lag, cerebral amyloid angiopathy, and sepsis . 13. The combination according to claim 12, where the additional active ingredient(s) are selected from the group below: acetylcholinesterase inhibitors, NMDA receptor antagonists, beta-secretase inhibitors, antipsychotics, GABAa receptor alpha5 subunit ΝΑΜ or PAMs, histamine H3 receptor antagonists, 5ΗΤδ receptor antagonists, M1 or M4 mAChR agonists or PAMs, mGluR2 antagonists or ΝΑΜs or PAMs and levodopa. 14. The production method of compounds of general formula (I) according to claim 1, characterized in that A. REACTION PATH) Step 1) the compounds of general formula (II). 137 - where the meanings of R ¹ , R ⁴ , R ⁵ , R ⁷ , Y are detailed above for compounds of general formula (I) - or compounds of general formula (V) - where W is N, and k, I, Z, L, A have the meanings detailed above for the compounds of general formula (I) - react with ethyl/methyl-2-chloro-2-oxoacetate in the presence of a base in a suitable solvent, so or the compounds of general formula (IVa) are obtained - where the meaning of R ¹ , R ⁴ , R ⁵ , R ⁷ , Y is detailed above for the compounds of formula (I) - or the compounds of formula (Illa) purple - where W means N, and the meanings of k, I, Z, L, A are detailed above for the compounds of general formula (I) - we obtain, then by simultaneous basic hydrolysis of these esters or corresponding carboxylic acids of general formula (IV) ih* Sift or ft 138 - where the meaning of R ¹ , R ⁴ , R ⁵ , R ⁷ , Y is as detailed above for compounds of general formula (I) or compounds of general formula (III) - where W means N, and the meanings of k, I, Z, L, A are detailed above for the compounds of general formula (I) - we get. or the compounds of formula (VI). VI - where W is CH, and k, I, Z, L, A have the meanings detailed above for the compounds of the general formula (I) - react with ethyl isocyanoacetate in a base, suitable solvent, thus obtaining the compounds of the general formula (VII) VII hs ft ft 139 Ml í ^üi HI ft ft - where W is CH, and the meanings of k, I, Z, L, A are detailed above for the compounds of general formula (I) - and the compounds of general formula (VII) reacting with aqueous hydrochloric acid solution and then with aqueous KOH solution to form (III ) compounds with the general formula are obtained III - where W is CH, and the meanings of k, I, Z, L, A are detailed above for the compounds of general formula (I). Step 2) compounds of general formula (II). - where the meanings of R ¹ , R ⁴ , R ⁵ , R ⁷ , Y are detailed above for the compounds of general formula (I) - and by connecting the compounds of general formula (III): HE III 140 - where the meaning of k, I, W, Z, L, A is detailed above for the compounds of general formula (I); or the compounds of general formula (IV). - where the meanings of R ¹ , R ⁴ , R ⁵ , R ⁷ , Y are detailed above for the compounds of general formula (I) - and by connecting the compounds of general formula (V) - where W is N, and the meanings of ak, I, Z, L, A are detailed above for the compounds of general formula (I) - we get the compounds of general formula (I), in which n is 0, R ³ is an oxygen atom, and m is 1, and the meanings of R ¹ , R ⁴ , R ⁵ , R ⁷ , Y, k, I, W, Z, L, and A are detailed above for the compounds of general formula (I). REACTION PATH B) the compounds of the general formula (Vili). - where n is 1, and R ¹ , R ² , R ⁴ , R ⁵ , R ⁷ , Y are as detailed above for the compounds of general formula (I) - with usual procedures and reagents, for example CDI, chloroformates or 1,1'- thiocarbonyldiimidazole, TENDON 0® ιΛ ft ft 141 in suitable solvents, for example dichloromethane or DMF, and then reacted with the compounds of general formula (V) - where W means N, and ak, I, Z, L, A have the meanings detailed above for the compounds of general formula (I) - the compounds of general formula (I) are obtained, where W means N, R ² means C1-6 alkyl or hydrogen, n means 1, m means 0, and the meaning of R ¹ , R ⁴ , R ⁵ , R ⁷ , Y, k, I, Z, L, A is detailed above for the compounds of general formula (I). ft. ltd. ft. ft. h