WO2020012424A1 - Substituted (aza)indole derivatives - Google Patents

Substituted (aza)indole derivatives Download PDF

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WO2020012424A1
WO2020012424A1 PCT/IB2019/055950 IB2019055950W WO2020012424A1 WO 2020012424 A1 WO2020012424 A1 WO 2020012424A1 IB 2019055950 W IB2019055950 W IB 2019055950W WO 2020012424 A1 WO2020012424 A1 WO 2020012424A1
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disorder
disorders
methyl
formula
mmol
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PCT/IB2019/055950
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French (fr)
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István LEDNECZKI
János ÉLES
Pál TAPOLCSÁNYI
Anita HORVÁTH
Zsolt NÉMETHY
György István LÉVAY
János Galambos
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Richter Gedeon Nyrt.
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Publication of WO2020012424A1 publication Critical patent/WO2020012424A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to pharmacologically active substituted (aza)indole compounds, or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof, as well as to pharmaceutical compositions containing them and to their use as modulators of a7 nicotinic acetylcholine receptor activity in a mammalian subject.
  • Acetylcholine exerts its functions as a neurotransmitter in the mammalian central nervous system (CNS) by binding to cholinergic receptors.
  • the mammalian CNS contains two predominant types of ACh receptors: muscarinic (mAChR) and nicotinic (nAChR) receptors, based on the agonist activities of muscarine and nicotine, respectively.
  • Nicotinic acetylcholine receptors are ligand-gated ion channels made up of five subunits (Purves et al. Neuroscience 4th ed. (2008) 122-126).
  • the subunits of the nicotinic receptors belong to a multigene family and have been divided into two groups based on their amino acid sequences; one containing alpha, and another containing beta subunits. Pentameric assemblies of different subunit combinations result in large number of receptor subtypes with various pharmacological properties. Assembly of the most broadly expressed subtypes include muscle-type ⁇ (a1)2.bide), ganglion-type ((a3) 2 (b4)3) and CNS-type (a4) 2 (b2)3 or (a7)s) nAChR subtypes (Le Nov ere N et al. Journal of Molecular Evolution 40 (1995) 155- 172). al subunits have been shown to form functional receptors when expressed alone, and thus are presumed to form homooligomeric pentameric receptors.
  • Activation of the nAChR ion channel is primarily controlled by binding of ligands at conventional agonist binding sites, but is also regulated by either negative, or positive allosteric modulators (NAMs and PAMs).
  • the allosteric transition state model of the nAChR involves at least a resting state, an activated state and a "desensitized" closed channel state, a process by which receptors become insensitive to the agonist.
  • Different nAChR ligands can stabilize the conformational state of a receptor, to which they preferentially bind.
  • the agonists ACh and (-)-nicotine respectively stabilize the active and desensitized states.
  • nicotinic receptors Changes of the activity of nicotinic receptors have been implicated in a number of diseases. Reductions in nicotinic receptors have been hypothesized to mediate cognitive deficits seen in diseases, such as Alzheimer's disease and schizophrenia. The effects of nicotine from tobacco are also mediated by nicotinic receptors, and since the effect of nicotine is to stabilize receptors in a desensitized state, an increased activity of nicotinic receptors may reduce the desire to smoke.
  • nicotinic receptor agonists which act at the same site as ACh
  • ACh not only activates, but also blocks receptor activity through processes, which include desensitization and uncompetitive blockade.
  • prolonged activation appears to induce a long-lasting inactivation. Therefore, agonists of ACh can be expected to lose effectiveness upon chronic administration.
  • a7 nAChR is characterized by its fast activation kinetics and high permeability to Ca 2+ compared to other subtypes (Delbono et al. J. Pharmacol Exp. Ther. 280 (1997) 428-438), it also exhibits rapid desensitization following exposure to agonists at the orthosteric site (Castro et al. Neurosci. Let. 164 (1993) 137-140, Couturier et al. Neuron 5 (1990) 847-856).
  • the compounds of the present invention may be useful for the treatment of diseases and conditions mediated by, or associated to the positive allosteric modulation of the a7 nAChR, including, but not limited to psychotic disorders, for example schizophrenia (Deutsch SI et al. Schizophr Res 148 (2013) 138-144), schizophreniform disorder (Rowe AR et al. J Psychopharmacol 29 (2015) 197-211), schizoaffective disorder (Martin LF et al. Am J Med Genet B Neuropsychia.tr Genet 144B (2007) 611-614), delusional disorder (Carson R et ai.
  • Cognitive impairment including, for example the treatment of impairment of cognitive functions, as well as cognitive impairment as a result of stroke, Alzheimer's disease (Lewis AS et al. Prog Neuropsychopharmacol Bio l Psychiatry 75 (2017) 45-53), Huntington's disease (Foucault-Fruchard L et al. Neural Regen Res 13 (2016) 737-741), Pick disease (Feher A et al. Dement Geriatr Cogn Disord 28 (2009) 56-62), HIV associated dementia (Capo-Velez CM et al.
  • narcolepsy such as narcolepsy (Krahn et ai. ,/ Clin Sleep Med J (2009) 390), dyssornnias, primary' hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder, and dyssomnia not otherwise specified, parasomnias, sleep terror disorder, sleepwalking disorder, and parasomnia not otherwise specified; sleep disorders related to another mental disorder (including, insomnia related to another mental disorder and hypersomnia related to another mental disorder), sleep disorder due to a general medical condition, and substance-induced sleep disorder, metabolic and eating disorders (Somrn E Arch Immunol The r Exp 62 (2014) 62: 87-101), such as anorexia nervosa (Cuesto G et al.
  • Neurogas troenterol Mott l 21 (2009) 1239- 1249 autism spectrum disorders (Deutsch et al. Clin Neuropharmacol 33 (2010) 114-120), including autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified, attention deficit hyperactivity disorder (Wilens TE and Decker MW Biochem Pharmacol 74 (2007) 1212- 1223), disruptive behaviour disorders, oppositional defiant disorder and disruptive behaviour disorder not otherwise specified, and tic disorders such as Tourette's disorder (Gotti C and dementi F Prog Nenrobiol 74 (2004) 363-396), personality disorders (Kamens HM et al.
  • sexual dysfunctions such as sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorder, sexual dysfunction not otherwise specified, paraphilias, gender identity disorders, infertility (Bray C et al. Biol Reprod 73 (2005) 807-814), premenstrual syndrome (Gundisch D and Eibl C Expert Opin Ther Pat 21 (2011) 1867-1896), and sexual disorders not otherwise specified, disorders of the respiratory' system like cough (Canning BJ Am J Respir Grit Care Med 195 (2017) A4498), asthma (Santana FPR et al. Eur Respir J 48 (2016) PA5066), chronic obstructive pulmonary disease (Maouche K et al.
  • the compounds of the invention are also useful in treating 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.
  • sarcoidosis Nicotine Treatment for Pulmonary Sarcoidosis: A Clinical Trial Pilot Study Elliott Grouser MD, Principal Investigator, Ohio State University ClinicalTrials.gov Identifier: NCT02265874
  • psoriasis Westman M et al. Scand J Immunol 70 (2009) 136-140
  • ataxia Taslim N et al. Behav Brain Res 217 (201 1) 282-292
  • dystonia Zimmerman CN et al.
  • these compounds can also be combined with other therapeutic agents including, but not limited to acetylcholinesterase inhibitors (such as galantamine, rivastigmine, donepezil, tacrine, phenserine, ladostigil and ABT-089); NMDA receptor agonists or antagonists (such as memantine, neramexane, EVT101, and AZD4282); anti-amyloid antibodies including anti-amyloid humanized monoclonal antibodies (such as, bapineuzumab, ACCOOl, CAD 106, AZD3102, H12A11V1); beta- (such as verubecestat, and AZD3293) or gamma-secretase inhibitors (such as LY450139 and TAK 070) or modulators, tau phosphorylation inhibitors; ApoE4 conformation modulators; p25/CDK5 inhibitors; NK1/NK3 receptor antagonists; COX-2 inhibitors (such as celecoxib, r,
  • Known positive allosteric modulators of the al nicotinic acetylcholine receptor include 2-aniline-4-aryl thiazole derivatives (WO 2007/031440 A2, JANSSEN PHARMACEUTICA NY), amide derivatives (WO 2009/100294 A2, ABBOT LAB.), tri substituted 1,2,4-triazoles (WO 2009/1 15547 Al, JANSSEN PHARMACEUTICA NV), indole derivatives (WO 2009/127678 Al, GLAXO GROUP LTD.
  • the present invention is directed to a novel class of compounds that exhibit positive allosteric modulation of the cx7 nicotinic acetylcholine receptor.
  • Figure 1 illustrates the results of place recognition test of compound Example 3. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.) r 0.05; + p ⁇ 0.0l; + ⁇ p ⁇ 0.00l .
  • Figure 2 illustrates the results of place recognition test of compound Example 5. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). + p ⁇ 0 05; + p ⁇ 0.0l; 1 + p ⁇ 0.001.
  • Figure 3 illustrates the results of place recognition test of compound Example 23. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.) p 0.05; p ⁇ 0.01; + r ⁇ 0.001.
  • Figure 4 illustrates the results of place recognition test of compound Example 47. Exploration times spent in the novel [N] vs familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.) p 0.05; + ⁇ p ⁇ 0.01; i p ⁇ 0.00l .
  • Figure 5 illustrates the results of place recognition test of compound Example 51. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 nig/kg, ip ). + p ⁇ 0.05; p 0.01. p 0.001.
  • Figure 6 illustrates the results of place recognition test of compound Example 90. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.) p 0.05; + p ⁇ 0.01; + ⁇ p ⁇ 0.00l.
  • the present invention relates to compounds of formula (I),
  • R 1 is hydrogen or Ci-ealkyl
  • R 2 is hydrogen or Ci-ealkyl, 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 1 and R 5 are independently hydrogen, Ci-ealkyl, halogen, haloCi-ealkyl, Ci-ealkoxy, or CN; n and m are independently 0 or 1; with the proviso that, n and m cannot be 0 at the same time;
  • k and S are independently 1, 2 or 3;
  • Y is N or C(R 6 );
  • R 6 is hydrogen, Ci ⁇ alkyl, halogen, or haioCi-ealkyl
  • R 7 is hydrogen, Ci-ealkyl, or halogen
  • W is CH or N
  • Z is CH, C-Ciualkyl or N
  • L is an optionally substituted linker consisting of 1 , 2 or 3 atoms, represented by T-U-V, wherein T is CH?., C(O), NH, SO? or O; U is CH?, C(O), O or absent; and V is CH?, O or absent;
  • A is a saturated, unsaturated, or aromatic carbocyciyl, or a saturated, unsaturated, or aromatic heterocyclyl, wherein the heteroatoms are selected from the group of nitrogen, oxygen and sulphur; optionally substituted independently by one or more halogen atom or halogen atoms, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkyl, haloCi-ealkoxy, CN, or benzyl;
  • the present invention provides a compound of formula (I), as defined above for use in the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity.
  • the present invention provides the use of a compound of formula (I), as defined above, for the manufacture of a medicament for the treatment or prevention of a disease associated with a 7 nicotinic acetylcholine receptor activity.
  • the present invention provides a method for the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity comprising administering to a mammal in need of such treatment or prevention an effective amount of at least one compound of formula (I), as defined above.
  • the compounds of formula (I), as defined above can be administered in combination with other compounds used for the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity.
  • the present invention provides a process for the manufacture of the compounds of formula (I)
  • Phe present invention relates to compounds of formula i
  • R 1 is hydrogen or Ci-ealkyl
  • R 2 is hydrogen or Ci-ealkyl, 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, Ci-ealkyl, halogen, haloCi-ealkyl, Ci-ealkoxy, or CN; n and m are independently 0 or 1; with the proviso that, n and m cannot be 0 at the same time;
  • k and S are independently 1 , 2 or 3;
  • Y is N or C(R 6 );
  • R 6 is hydrogen, Ci-ealkyl, halogen, or haloCnealkyl
  • R 7 is hydrogen, Ci-ealkyl, or halogen
  • W is CI S or N
  • Z is CH, C-C i-alkvl or N;
  • L is an optionally substituted linker consisting of 1, 2 or 3 atoms, represented by T-U-V, wherein T is ( ! l ⁇ . C(0), NH, SO? or O; U is ( 1 l ⁇ . C(0), O or absent; and V is CH?, O or absent;
  • A is a saturated, unsaturated, or aromatic carbocyclyl, or a saturated, unsaturated, or aromatic heterocyclyl, wherein the heteroatoms are selected from the group of nitrogen, oxygen and sulphur, optionally substituted independently by one or more halogen atom or halogen atoms, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkyl, haloCi-ealkoxy, CN, or benzyl; or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
  • halo or“halogen”, as used herein as such or as part of another group, refers to fluoro, chloro, bromo or iodo.
  • Ci-ealkyl refers to a branched or straight chain saturated hydrocarbon group having one, two, three, four, five or six carbon atoms including, but not limited to, methyl, ethyl, «-propyl, /-propyl, «-butyl, sec- butyl, and fer/-hutyl.
  • haloCi-ealkyl refers to at least one halogen, as defined above, bonded to the parent molecular moiety through an“Ci-ealkyl” group, as defined above.
  • the halogens can be identical or different and the halogens can be attached to different carbon atoms or several halogens can be attached to the same carbon atom.
  • HaloCi-e.alkyl groups include, but are not limited to, difluoromethyl, trifluoromethyl and 2-chl oroethyl.
  • Ci-ealkoxy refers to an“Ci-ealkyl” group, as defined above, bonded to the parent molecular moiety through an oxygen atom including, but not limited to, m ethoxy, ethoxy, w-propoxy, /-propoxy and fer/-butoxy.
  • haloCi-ealkoxy refers to at least one halogen, as defined above, bonded to the parent molecular moiety through a“C -6alkoxy” group, as defined above.
  • the halogens can be identical or different and the halogens can be attached to different carbon atoms or several halogens can be attached to the same carbon atom.
  • HaloCi-ealkoxy groups include, but are not limited to, trifluoromethoxyl , difluoromethoxyl, trifluoroethoxyl .
  • saturated, unsaturated or aromatic carbocyclyl refers to monovalent saturated, un saturated or aromatic three to twelwe, preferably four to nine, more preferably six membered moiety, consisting of one to two rings.
  • the carbocyclyc ring may be optionally substituted as defined herein. Examples include, but are not limited to, optionally substituted cyclobutyl, cyclopentyl, cyclohexyl, eycloheptyl, phenyl, naphtyl, etc.
  • saturated, unsaturated or aromatic heterocyclyi refers to a monovalent saturated, unsaturated or aromatic three to twelwe membered moiety, consisting of one to two rings, incorporating one, two, or three heteroatoms (chosen from nitrogen, oxygen or sulphur, preferably nitrogen and oxygen).
  • the heterocyclyi ring may be optionally substituted as defined herein.
  • Examples include, but are not limited to, optionally substituted tetrahydrofuryl, 1-pyridyl, 2-pyridyl, 3-pyridyi, 4-pyrimidiny!, 5-pyrimidinyl, pyridazyl, indazolyl, indolyl, azaindolyl, isoquinolinyl, quinolinyl etc.
  • pharmaceutically acceptable describes an ingredient that is useful in preparing a pharmaceutical composition, is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes those acceptable for veterinary use as well as human pharmaceutical use.
  • hydrate means non-covalent combinations between water and solute.
  • solvent means non-covalent combinations between solvent and solute.
  • Solvents include, but are not limited to, ethanol, 2-propanol, acetonitrile and tetrahydrofuran.
  • Optionally substituted means unsubstituted or substituted with one or more of the substituents as described herein.
  • “one or more” means from one to the highest possible number of substitution, that is, from replacing one hydrogen to replacing ail hydrogens.
  • One, two or three substituents on a given atom are preferred.
  • Treating" or “treatment” of a disease state includes: a) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state, b) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or c) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
  • pharmaceutically acceptable salt refers to a conventional acid addition salt or a base addition salt, which preserves the biological efficacy and properties of the compounds of formula (I) and which can be formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • acid addition salts include salts derived from inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulphamic acid, phosphoric acid, nitric acid and perchloric acid and derived from various organic acids, such as, but not limited to, 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.
  • base addition salts are salts derived from ammonium-, potassium-, sodium- and quaternary ammonium hydroxides such as tetram eth,
  • pro-drag refers to derivatives of compounds of formula (I) according to the invention which themselves have no therapeutic effect but containing such groups which, after in vivo chemical or metabolic degradation (biotransformation) become“biologically active metabolite” which is responsible for the therapeutic effect.
  • decomposing groups associated with the compounds of formula (I) of the present invention in particular those suitable for prodrugs, are known in the art and may also be applied for the compounds of the present invention (Rautio et af, Nature Reviews - Drug Discovery 2008, 7:255-270).
  • the present invention relates to compounds of formula (I), wherein R 1 is hydrogen or Ci-salkyl;
  • R 2 is hydrogen or Ci-aalkyl, or R 2 is absent when n is 0;
  • R 3 is hydrogen or (), or R 3 is absent when m is 0,
  • R 4 and R 5 are independently hydrogen, Craalkyl, halogen, haloCraalkyl, Ciualkoxy, or CN; n and m are independently 0 or 1; with the proviso that, n and m cannot be 0 at the same time;
  • k imd 1 are independently 1 or 2, Y is N or C(R 6 );
  • R 6 is hydrogen, Cioaikyl, halogen, or haloCiualkyl
  • R 7 is hydrogen, Ci-3alkyl, or halogen
  • W is CH or N
  • Z is CH, C-Ci-3alkyl or N;
  • L is an optionally substituted linker consisting of 1, 2 or 3 atoms, represented by T-U-V, wherein T is CH2, C(O), NH, SO2 or O; U is CH2, C(O), O or absent; and V is O or absent;
  • A is a saturated, unsaturated, or aromatic 4-9 membered carbocycfyl, or a saturated, unsaturated, or aromatic 4-9 membered heterocyclyl, wherein the heteroatoms are selected from the group of nitrogen, oxygen and sulphur, optionally substituted independently by one or more halogen atom or halogen atoms, Ci-salkyl, Ci-salkoxy, haloCioalkyl, haloCioalkoxy, CN, or benzyl,
  • the present invention relates to compounds of formula (I), wherein R 1 is hydrogen or Ciualkyl;
  • R 2 is hydrogen or Ciua!kyl, 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, Ci-salkyl, halogen, haloCi-salkyl, Ci-salkoxy, or CN, n and m are independently 0 or 1; with the proviso 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, Ci-3aikyi, halogen, or haloCiualkyl
  • R 7 is hydrogen, Ciuaikyl, or halogen
  • W is CH or N
  • Z is CH or N
  • L is an optionally substituted linker consisting of 1 , 2 or 3 atoms, represented by T-U-V, wherein
  • T is CH2, C(O), NH, SO2 or O; U is CH2, C(O), O or absent, and V is O or absent;
  • A is a saturated, unsaturated, or aromatic 4-9 memhered carbocyclyl, or a saturated, unsaturated, or aromatic 4-9 membered heterocyclyi, wherein the heteroatom is nitrogen, optionally substituted independently by one or more halogen atom or halogen atoms, Ci- salkyl, Ci-3alkoxy, haloCi-salkyl, haloCi-salkoxy, CN, or benzyl;
  • the present invention relates to compounds of formula (I), wherein R 3 is hydrogen or (4 -alkyl;
  • R 2 is hydrogen or Ci- 3 alkyl, or R 2 is absent when n is 0;
  • R 3 is Q, or R 3 is absent when m is 0;
  • R 4 and I are independently hydrogen, Ciualkyl, halogen, haloCiualkyl, Ciualkoxy, or CN; n and m are independently 0 or 1; with the proviso that, n and m cannot be 0 at the same time;
  • k and 1 are independently 1 or 2;
  • Y is N or C(R 6 );
  • R 6 is hydrogen, Ciualkyl, halogen, or haloCi-salkyl
  • R 7 is hydrogen, Ciualkyl, or halogen
  • W is CH or N
  • Z is CH or N
  • L is linker selected from the group of -CH?.-, -0-, -NH-, -SO?-, -C(O)-, -CH2-O-,
  • A is a saturated, unsaturated, or aromatic 4-9 membered carbocyclyl, or a saturated, unsaturated, or aromatic 4-9 membered heterocyclyi, wherein the heteroatom is nitrogen, optionally substituted independently by one or more halogen atom or halogen atoms, C ualkyl, Ci-salkoxy, haloCiualkyl, haloCi-salkoxy, CN, or benzyl;
  • the present invention relates to compounds of formula (I), wherein R 3 is hydrogen or C i -alkyl;
  • R 2 is hydrogen or Ciualky!, 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, Ci-aalkyl, halogen, haloCt-aalkyl, Ciualkoxy, or CN; n and rn are independently 0 or 1 ; with the proviso that, n and m cannot be 0 at the same time;
  • k a d I are independently 1 or 2
  • Y is N or C(R 6 );
  • R 6 is hydrogen, Ci-salkyl, halogen, or haloCi-ia!ky!;
  • R 7 is hydrogen, Ci-3alkyl, or halogen
  • W is CH or N
  • L is linker selected from the group of: -CH2-, -0-, -NH-, -SO2-, -C(O)-, -CH2-O-,
  • A is an aromatic 6 membered carbocyclyl, or an aromatic 6 membered heterocyclyl, wherein the heteroatom is nitrogen, optionally substituted independently by one or more halogen atom or halogen atoms, Cnsalkyl, Ciualkoxy, haloCi-salkyl, haloCi-ealkoxy, CN, or benzyl;
  • the present invention relates to compounds of formula (I), wherein R 1 is hydrogen or Ci-talkyd;
  • R 2 is absent
  • R 3 is O
  • R 4 and R 5 are independently hydrogen, Ciualkyl, halogen, haloCiualkyl, or CN;
  • si is 0;
  • n 1;
  • k 2;
  • Y is N or C(R 6 );
  • R 6 is hydrogen, halogen, or haloCi-3alkyl
  • R 7 is hydrogen or halogen
  • W is CH or N;
  • Z is CH or N;
  • L is a linker selected from the group of: -CH?.-, -0-, -NH-, or -SO?-;
  • A is a phenyl, 2-pyridyl, or 3-pyridyl, optionally substituted independently by one or more halogen atom or halogen atoms, Ciualkyl, Csualkoxy, or haloCi-aalkyl;
  • the present invention relates to compounds of formula (I), wherein R 1 is hydrogen or Ci-3alkyl;
  • R 2 is absent
  • R 3 is O
  • R 4 and R 5 are independently hydrogen, Ci-3alkyl, halogen, haloCi-salkyl, or CN;
  • n 0;
  • n 1;
  • k 1;
  • Y is N or C(R 6 );
  • R 6 is hydrogen, halogen, or haloCiualkyl
  • R 7 is hydrogen or halogen
  • W is N
  • Z is CH or N
  • L is a linker selected from the group of: -CH ? -, -O-, -NH-, or -CH ? -Q ⁇ ;
  • A is a phenyl, 2-pyridyl, or 3-pyridyl, optionally substituted independently by one or more halogen atom or halogen atoms, Ciualkyl, Csualkoxy, or haloCi-aalkyl;
  • the present invention relates to compounds of formula (I), wherein R 1 is hydrogen or Ci-3alkyl;
  • R 2 is hydrogen or Ci-salkyl
  • R 3 is absent
  • R 4 and R 5 are independently hydrogen, Ci-3alkyl, halogen, haloCi-salkyl, or CN;
  • k 1;
  • Y is N or C(R 6 ):
  • R 6 is hydrogen, halogen, or haloCi-ialkyl
  • R 7 is hydrogen
  • W is N
  • Z is CH or C-Ci-3alkyi
  • L is a linker selected from the group of: -0-, -CH2-O-, -CH2-CH2-O-, -O-CH2-, -CH2-CH2-,M I ⁇ ( ' (( ) ) ⁇ , or -NH-CH2-;
  • A is a phenyl, 2-pyridyl, or 3-pyridyl, optionally substituted independently by one or more halogen atom or halogen atoms, Ci-ialkyl, Ciualkoxy, or haloCiualkyl;
  • the present invention relates to compounds of formula (I), wherein R 1 is hydrogen or Ci-3alkyl;
  • R 2 is hydrogen or Ci-salkyl
  • R 3 is absent
  • R 4 and R 5 are independently hydrogen, Ciualkyl, halogen, haloCiualkyl, or CN;
  • n 1 ;
  • n 0;
  • k 1;
  • Y is N or C(R 6 );
  • R 6 is hydrogen, halogen, or haloCiualkyl
  • R 7 is hydrogen
  • W is N
  • L is a linker selected from the group of: -0-, -CH2-, -CH2-O-, or -NH-;
  • A is a phenyl, 2-pyridyl, or 3-pyridyl, optionally substituted independently by one or more halogen atom or halogen atoms, Ci-salkyl, Ci-salkoxy, or haloCiualkyl; or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
  • the present invention relates to compounds of formula (I), wherein
  • R 1 is hydrogen or Ci-salkyl
  • R 2 is hydrogen or Ciualkyl
  • R 3 is absent
  • R 4 and R 5 are independently hydrogen, Ciualkyl, halogen, haloCiualkyl, or CN;
  • n 1 ;
  • n 0;
  • k 2;
  • Y is N or C(R 6 );
  • R 6 is hydrogen, halogen, or haloCiualkyl
  • R 7 is hydrogen
  • W is N
  • Z is ( ' l l or N;
  • L is a linker selected from the group of: -0-, -CH ⁇ -, -CH2-O-, or -C(O)-;
  • A is a phenyl, 2-pyridyl, or 3-pyridyl optionally substituted independently by one or more halogen atom or halogen atoms, Ci-3alkyl, Ciualkoxy, or haloCi-salkyl;
  • the present invention relates to compounds of formula (I), wherein R 1 is hydrogen or Ci-ralkyl;
  • R 2 is hydrogen or Ci- 3 alkyl
  • R 3 is absent
  • R 4 and R 5 are independently hydrogen, Ci-salkyl, halogen, haloCi-salkyl, or CN;
  • n 1;
  • Y is N or C(R 6 );
  • R 6 is hydrogen, halogen, or haloCiualkyl
  • R 7 is hydrogen
  • W is N
  • Z is CH or N
  • L is a linker selected from the group of: -0-, -CH2-O-, or -NH-;
  • A is a phenyl, 2-pyridyl, or 3-pyridyl, optionally substituted independently by one or more halogen atom or halogen atoms, Ci-salkyl, Ciualkoxy, or haloCi-ealkyl;
  • the present invention relates to compounds of formula (I) selected from the group of;
  • the present invention provides a compound of formula (I), as defined above for use in the treatment or prevention of a disease associated with cx7 nicotinic acetylcholine receptor activity.
  • the present invention provides the use of a compound of formula (I), as defined above, for the manufacture of a medicament for the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity.
  • the present invention provides a method for the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity comprising administering to a mammal in need of such treatment or prevention an effective amount of at least one compound of formula (I) or, as defined above.
  • the disease associated with a7 nicotinic acetylcholine receptor activity is selected from the group of psychotic disorders, including, but not limited to, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder or psychotic disorder not otherwise specified; cognitive impairment, including, but not limited to, cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, HIV associated dementia, frontotemporal dementia, Lewy body dementia, vascular dementia, cerebrovascular disease or other dementia states and dementia associated to other degenerative disorders, including, but not limited to, amyotrophic lateral sclerosis, other acute or sub-acute conditions that may cause cognitive decline, including, but not limited to, delirium, traumatic brain injury, senile dementia, mild cognitive impairment, Down’s syndrome, depression and cognitive deficit related to other diseases, and dyskinetic disorders including, but not limited to, Parkinson's disease,
  • the disease associated with a? nicotinic acetylcholine receptor activity is selected from the group of cognitive impairment, schizophrenia and autism.
  • the invention further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another therapeutic agent or agents, for the treatment of one or more of the conditions previously indicated.
  • therapeutic agents may be selected from: acetylcholinesterase inhibitors, NMDA receptor agonists or antagonists, anti-amyloid antibodies including anti-amyloid humanized monoclonal antibodies, beta- or gamma- secretase inhibitors or modulators, tau phosphorylation inhibitors, ApoE4 conformation modulators, p25/CDK5 inhibitors, NKI/NK3 receptor antagonists, COX-2 inhibitors, LRRK2 inhibitors, HMG-CoA reductase inhibitors, NSAIDs, vitamin E, glycine transport inhibitors, glycine site antagonists, LXR b agonists, androgen receptor modulators, blockers of Ab oligomer formation, NR2B antagonists, anti-inflammatory compounds, PPAR gamma
  • the therapeutic agents are selected from the goup of: acetylcholinesterase inhibitors, NMDA receptor antagonists, beta- secretase inhibitors, antipsychotics, GABAA receptor alpha5 subunit NAMs or PAMs, histamine Hz receptor antagonists, 5-HTe receptor antagonists, Ml or M4 mAChR agonists or PAMs, rnGluR2 antagonists or NAMs or PAMs, and levodopa.
  • the present invention provides a process for the manufacture of the compounds of formula (I) according to the following reaction route:
  • the compounds of formula (I) of the invention may be prepared in a variety of ways with synthetic methods known in the art of organic chemistry, or modifications that are familiar to those of ordinary skill in the art.
  • the starting materials used herein are commercially available or may be prepared either by routine methods known in the art or by the detailed synthetic routes.
  • R 1 to R', n, m, k, 1, Y, W, Z, L, and A are as defined in the first aspect.
  • Typical conditions comprise treatment of the reactants with a suitable coupling agent, such as HATU, HBTU, EDC, T3P in a suitable solvent, such as CH2CI2 or DMF.
  • a suitable coupling agent such as HATU, HBTU, EDC, T3P in a suitable solvent, such as CH2CI2 or DMF.
  • Alternative conditions comprise conversion of the carboxylic acid (formula (III) or formula (IV)) to the corresponding acid chloride, using oxaiyl chloride or Ghosez’s reagent in a suitable solvent, such as Cl 1 :0 or DMF, then reacting the formed acyl chloride with the corresponding amine in the presence of a suitable base, such as DIPEA or TEA to form an amide.
  • the reaction is carried out at a temperature in the range of 0 °C to room temperature. The necessary reaction time is 6-20 hours.
  • the progress of the reactions is followed by thin layer chromatography.
  • the work-up of the reaction mixture can be carried out by different methods, usually is quenched by the addition of water.
  • the product is isolated by extraction with a suitable organic solvent, and purified by crystallization or column chromatography.
  • the present disclosure includes within its scope all the possible isotopically labelled forms of the compounds.
  • the compounds of the present invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intraarticular, intrathecal, intraperitoneal, direct intraventricular, intracerebroventicular, intramedullary injection, intracisternal injection or infusion, subcutaneous injection or implant), ophtalmic, nasal, vaginal, rectal, sublingual and topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations comprising pharmaceutically acceptable excipients suitable for each route of administration.
  • compositions of the present invention usually contain 0.01 to 500 mg of the active ingredient in a single dosage unit. However, it is possible that the amount of the active ingredient in some compositions exceeds the upper or lower limits defined above.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • This dosage level and regimen can he adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and the host undergoing therapy.
  • compositions of the present invention may be formulated as different pharmaceutical dosage forms, including, but not limited to, solid oral dosage forms like tablets (e.g., buccal, sublingual, effervescents, chewable, orodispersible, freeze dried), capsules, lozenges, pastilles, pills, orodispersible films, granules, powders; liquid oral dosage forms, including, but not limited to, solutions, 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 eye preparations, nasal drops and sprays, transdermal dosage forms, suppositories, rectal capsules, rectal solutions, emulsions and suspensions, etc.
  • solid oral dosage forms like tablets (e.g., buccal, sublingual, effervescents, chewable, orodispersible, freeze dried), capsule
  • compositions of the present invention can be manufactured in any conventional manner, e.g., by mixing, dissolving, emulsifying, suspending, entrapping, freeze-drying, extruding, laminating, film-casting, granulating, grinding, encapsulating, dragee-making or tabletting processes.
  • compositions for use in accordance with the present invention thus can be formulated in any conventional manner using one or more physiologically acceptable excipients. Any of the well-known techniques and excipients may be used as suitable and as understood in the art.
  • Suitable excipients for the preparation of the dosage forms may be selected from the following categories, including, but not limited to, tablet and capsule fillers, tablet and capsule binders, release modifying agents, disintegrants, glidants, lubricants, sweetening agents, taste- masking agents, flavoring agents, coating agents, surfactants, antioxidants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, microencapsulating agents, ointment bases, penetration enhancers, solubilizing agents, solvents, suppository bases, and suspending agents.
  • the invention relates to the use of specific excipients which are capable of improving the solubility, dissolution, penetration, absorption and/or bioavailability of the active ingredient(s), including, but not limited to, hydrophilic polymers, hot melt extrusion excipients, surfactants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, superdisintegrants, microencapsulating agents, penetration enhancers, solubilizing agents, co-solvents, and suspending agents.
  • hydrophilic polymers hot melt extrusion excipients
  • surfactants e.g., surfactants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, superdisintegrants, microencapsulating agents, penetration enhancers, solubilizing agents, co-solvents, and suspending agents.
  • the compounds of formula (I) can be prepared in accordance with the general knowledge of one skilled in the art and/or using methods set forth in the Example and/or Intermediate sections that follow. Solvents, temperatures, pressures, and other reaction conditions can readily be selected by one of ordinary skill in the art. Starting materials are commercially available and/or readily prepared by one skilled in the art.
  • room temperature denotes a temperature in the range from 20 °C to 25 °C.
  • IPy 2 BF 4 bi s(py ri din e)i odo ium te trail uorob orate
  • ⁇ Y-Boc-hexahydro-lff-azepin-d-one was commercially available and it was easily reduced by sodium borohydride to obtain the corresponding hydroxyl derivative, which was further reacted in an analogous way as it is described for 3-[(4- methylphenoxy)methyl]azetidine. Racemic mixture was applied.
  • Trifluoroacetic acid 24 mL, 313 mmol was added to a solution of Z -hutyi 3-[(4- methylphenoxy)methyi]azetidine-l-carboxylate (2.3 g, 8.3 mmol) in CH2CI2 (50 mL) cooled to 0 °C in an ice water bath, and the solution was stirred for 1 hour at this temperature.
  • the solvent was removed under reduced pressure at 40 °C. Ice w3 ⁇ 4ter was added to the residue, and the pH of the mixture was adjusted to 9 by the addition of saturated NaHCCb solution.
  • the mixture was extracted with CH2CI2, the combined organic layer was washed with brine, dried over anhydrous NarSO-s and filtered. The solvent was removed under reduced pressure to obtain 3-[(4-methylphenoxy)methyl]azetidine (1.37 g, 7.7 mmol, 93 %).
  • the aqueous phase was extracted with CH2CI2 (3x20 mL), the combined organic phase was dried over anhydrous Na2S0 4 , filtered and concentrated in vacuo, to obtain 660 mg of the title compound, as a yellow oil.
  • the crude product was used in the next step without any purification.
  • the organic phase was stirred vigorously with 5 % hydrochloric acid solution at room temperature for 30 minutes.
  • the pH of the mixture was adjusted to 7-8 by the addition of 25 % aqueous ammonia solution, and extracted with EtOAc.
  • the organic phase was washed with water, dried over Na2S04, and evaporated to dryness.
  • the residue was purified by column chromatography on silica gel, using a mixture of EtOAc and cyclohexane (1 :5 to 1 :3) as eluent to give l-(l -methyl- l/f-indol-5-yl)ethanone. Yield: 1 17 g (28 %).
  • Step 1 l// ⁇ Pyrroloj2 3 ⁇ /
  • the intermediate is prepared as described in EP 178281 1 Al (EISAI R&D MAN CO LTD).
  • Step 2 1 -Methyl- l//-pyrrolor2.3-&lpyridine-5-carbonitrile
  • Step 3 ⁇ l-Methyl-l/7-pyrrolo[2J- ?lpyridin-5-vi ⁇ methanamine
  • i-(benzenesulfonyl)-5-bromo-i//-pyrrolo[2,3-6]pyridine 816 mg, 2 42 mmol
  • Zn(CN) 2 426 mg, 3.63 mmol
  • tetrakis(triphenylphosphine)palladium(0) 280 mg, 0.242 mmol
  • Step 2 1 -Methyl- pynOioi2 3- >lpyridine-5-carbonitrate
  • Step 4 (3-Chloro-l-methyl- pyrrolor2.3- >1pyridin-5-yl ⁇ methanamine
  • Step 3
  • Step 4 ⁇ 3-Bromo-t -methyl- l// ⁇ Dyrrolo[2 3-&1pyridin-5 ⁇ vHmethanamine
  • the intermediate is prepared as described in WO 2012/042915 Al (RAQUALIA PHARMA INC).
  • tert- Butyl lithium (1.7 M solution in pentane, 0.88 mL, 1.5 mmol) was added dropwise to a solution of tert- butyl 5-[(tetrahydro-2/7-pyran-2-yloxy)methyl]-l /7-indole-l-carboxylate (331 mg, 1 mmol) in tetrahydrofurane (20 mL) between -78 °C and -65 °C under argon atmosphere. The mixture was stirred at -70 °C for 20 minutes, then a solution of phenyl cyanate (20 % m/m, 0.75 mL, 1.6 mmol) in CH2CI2 w ? as added dropwise. It was stirred at
  • reaction mixture was adsorbed onto silica gel, and was purified by flash column chromatography (0 % to 10 % of MeOH in CH2CI2) to give rerf-butyl 5-(aminomethyl)-2-cyano-li/-indole-l- carboxylate (33 mg, 66 %), as white crystals.
  • Trifluoroacetic acid (0.4 mL, 5 mmol) was added to a solution of ter/-butyl 2-cyano- 5- ⁇ [(3 - ( [4-(trifluoromethyl)phenoxy]methyl ⁇ azetidine- 1 -carbonyl)amino]methyl ⁇ - 1 H- indole-l-carboxylate (135 mg, 0.25 mmol) in CH2CI2 (10 mL), cooled to 0 °C in an ice water bath, and the solution was stirred for 22 hours at room temperature.
  • Methylpyrrolidine derivatives are summarized in Table 12.
  • Active ingredient(s) 0.01 - 90 %
  • Active ingredient(s) 0.01 - 90 %
  • Active ingredient(s) 0 01 - 50 % Liquid vehicle 10 - 99.9 % Wetting agent 0 - 50 % Thickener 0 - 50 % Buffering agent quantum satis Osmotic agent 0 - 50 % Preservatives quantum satis
  • Active ingredient(s) 0.01 - 50 % Suppository base 1 - 99.9 % Surface-active agents 0 - 20 % Lubricants 0 - 20 % Preservatives quantum satis
  • Active ingredient(s) 0.01 - 50 %
  • Buffering agent quantum satis Preservatives quantum satis
  • Flp-In 293 cells stably expressing human a7 nAchR and human RIC-3 (oJ cells, generated in house.)
  • a7 cells stably expressing human a7 nAcliR were cultured in the medium detailed above, and were split twice a week.
  • fluorometric measurements of cytosolic Ca 2+ ion concentration [ ( a ' jo cells were seeded in 96-well microplates at a density of 60000 cells/well and maintained overnight in a tissue culture incubator at 37 °C under an atmosphere of 95 % air/5 % COi.
  • the plating medium was identical with the culture medium. 50 m ⁇ of the growth medium was aspirated with a cell washer (BioTek Elx405UCVWS).
  • the dye was excited at 485 nm, emission was sampled at 525 ntn at 1.4-s intervals. Baseline was recorded for 20 seconds followed by agonist stimulation. 50 m ⁇ 4x concentrated agonist solution was added to the cells using the pipetor of FlexStation II and fluorescence was monitored for an additional 40 seconds. Final DMSO concentration was 1 % for all treatments. To achieve this, a series of DMSO stock solutions were prepared from all test compounds. These stocks were stored under 0 °C and were further diluted in assay buffer to obtain the desired final concentration immediately before the measurement.
  • Table 16 shows the PAM ECso values in the [Ca 2+ ]i assay:
  • Scopolamine was dissolved in saline and administered at 1 mg/kg dose i.p.
  • Test compounds were administered 30 minutes before the acquisition trial (Tl) and scopolamine after the acquisition trial at a volume of 0.1 nil/10 g.
  • Tl acquisition trial
  • Procedure The task was carried out in a transparent plexiglass Y-maze (each arm has a length of 40 cm, an inner width of 11 cm and a height of 30 cm). Numerous visual cues were placed around the arms and were kept constant during the experiment. The test consisted of two trials (T1 and T2) separated by an intertrial interval of 30 minutes.
  • mice were placed in the starting arm of the maze at the beginning of each trial in Tl, one of the symmetric ar s of the maze was closed (it will be novel in T2) and the animals were allowed to explore the maze for 5 minutes (acquisition phase). In T2, mice had free access to all three arms for 2 minutes (retrieval phase). The time spent with exploration in the novel and familiar arms during T2 was measured. Differences between the exploration times spent in the familiar vs. novel arms of the maze for each group were evaluated by MANOVA, followed by Duncan post hoc test.
  • Table 17 shows the reversal of the scopolamine-induced amnesia in the place recognition assay in mice

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Abstract

The invention relates to substituted (aza)indole derivatives, or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof, as well as to pharmaceutical compositions containing them and to their use as modulators of α7 nicotinic acetylcholine receptor activity in a mammalian subject. (I)

Description

SUBSTITUTED (AZA)INDOLE DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to pharmacologically active substituted (aza)indole compounds, or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof, as well as to pharmaceutical compositions containing them and to their use as modulators of a7 nicotinic acetylcholine receptor activity in a mammalian subject.
BACKGROUND OF THE INVENTION
Acetylcholine (ACh) exerts its functions as a neurotransmitter in the mammalian central nervous system (CNS) by binding to cholinergic receptors. The mammalian CNS contains two predominant types of ACh receptors: muscarinic (mAChR) and nicotinic (nAChR) receptors, based on the agonist activities of muscarine and nicotine, respectively. Nicotinic acetylcholine receptors are ligand-gated ion channels made up of five subunits (Purves et al. Neuroscience 4th ed. (2008) 122-126). The subunits of the nicotinic receptors belong to a multigene family and have been divided into two groups based on their amino acid sequences; one containing alpha, and another containing beta subunits. Pentameric assemblies of different subunit combinations result in large number of receptor subtypes with various pharmacological properties. Assembly of the most broadly expressed subtypes include muscle-type ί(a1)2.bide), ganglion-type ((a3)2(b4)3) and CNS-type (a4)2(b2)3 or (a7)s) nAChR subtypes (Le Nov ere N et al. Journal of Molecular Evolution 40 (1995) 155- 172). al subunits have been shown to form functional receptors when expressed alone, and thus are presumed to form homooligomeric pentameric receptors.
Activation of the nAChR ion channel is primarily controlled by binding of ligands at conventional agonist binding sites, but is also regulated by either negative, or positive allosteric modulators (NAMs and PAMs). The allosteric transition state model of the nAChR involves at least a resting state, an activated state and a "desensitized" closed channel state, a process by which receptors become insensitive to the agonist. Different nAChR ligands can stabilize the conformational state of a receptor, to which they preferentially bind. For example, the agonists ACh and (-)-nicotine respectively stabilize the active and desensitized states. Changes of the activity of nicotinic receptors have been implicated in a number of diseases. Reductions in nicotinic receptors have been hypothesized to mediate cognitive deficits seen in diseases, such as Alzheimer's disease and schizophrenia. The effects of nicotine from tobacco are also mediated by nicotinic receptors, and since the effect of nicotine is to stabilize receptors in a desensitized state, an increased activity of nicotinic receptors may reduce the desire to smoke.
However, treatment with nicotinic receptor agonists, which act at the same site as ACh is problematic, because ACh not only activates, but also blocks receptor activity through processes, which include desensitization and uncompetitive blockade. Furthermore, prolonged activation appears to induce a long-lasting inactivation. Therefore, agonists of ACh can be expected to lose effectiveness upon chronic administration.
While the a7 nAChR is characterized by its fast activation kinetics and high permeability to Ca2+ compared to other subtypes (Delbono et al. J. Pharmacol Exp. Ther. 280 (1997) 428-438), it also exhibits rapid desensitization following exposure to agonists at the orthosteric site (Castro et al. Neurosci. Let. 164 (1993) 137-140, Couturier et al. Neuron 5 (1990) 847-856). In spite that development of a variety of a7-selective agonists and partial agonists has been carried out in the recent years, their clinical efficacy proved to be sub optimal, due to this receptor blockade (desensitisation) following the agonist activation. This problem may be overcomed by treatment with PAMs, enhancing a7 nAChR activation mediated by the endogenous agonist. The positive modulation of a7 nAChRs has been shown to have cognitive benefits in various preclinicai models (Thomsen et at. Giirr Pharm Des 16 (2010) 323-343; Lendvai et al. Brain Res Bull 93 (2013) 86-96).
The compounds of the present invention may be useful for the treatment of diseases and conditions mediated by, or associated to the positive allosteric modulation of the a7 nAChR, including, but not limited to psychotic disorders, for example schizophrenia (Deutsch SI et al. Schizophr Res 148 (2013) 138-144), schizophreniform disorder (Rowe AR et al. J Psychopharmacol 29 (2015) 197-211), schizoaffective disorder (Martin LF et al. Am J Med Genet B Neuropsychia.tr Genet 144B (2007) 611-614), delusional disorder (Carson R et ai. Neuromolecular Med 10 (2008) 377-384), brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder, or psychotic disorder not otherwise specified, cognitive impairment including, for example the treatment of impairment of cognitive functions, as well as cognitive impairment as a result of stroke, Alzheimer's disease (Lewis AS et al. Prog Neuropsychopharmacol Bio l Psychiatry 75 (2017) 45-53), Huntington's disease (Foucault-Fruchard L et al. Neural Regen Res 13 (2018) 737-741), Pick disease (Feher A et al. Dement Geriatr Cogn Disord 28 (2009) 56-62), HIV associated dementia (Capo-Velez CM et al. Sci Rep 8 (2018) 1829), frontotemporal dementia (Minami SS et al. Biochem Pharmacol 97 (2015) 454-462), Lewy body dementia (Perry EK et al. Neuroscience 64 (1995) 385-395), vascular dementia (Putignano S et al. Clin Interv Aging 7 (2012) 1 13-118), cerebrovascular disease (Si ML and Lee TJF ( 'ire Res 91 (2002) 62-69), or other dementia states, and dementia associated to other degenerative disorders (amyotrophic lateral sclerosis (Kawamata et al TherAdv Chronic Dis 2 (2011) 197-208), etc ), other acute or sub-acute conditions that may cause cognitive decline, such as delirium (Sfera A et al. Front: Med 2 (2015) 56), traumatic brain injur}' (Shin SS et al. Neural Regen Res 10 (2015) 1552-1554), senile dementia (Whitehouse PJ et et al. Science 215 (1982) 1237-1239), mild cognitive impairment (Ikonomovic MD et al. Arch Neurol 66 (2009) 646-651), Down’s syndrome (Deutsch SI et al. Clin Neuropharmacol 26 (2003) 277-283), depression and cognitive deficit related to other diseases and dyskinetic disorders (Parameswaran N et al. Soc Neurosci Abstr (2007)), such as Parkinson's disease (Quik M et al. Biochem Pharmacol 97 (2015) 399-407), as well as neuroleptic-induced parkinsonism, or tardive dyskinesias (Terry AV and Gearhart DA Eur J Pharmacol 571 (2007) 29-32), 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) 1 15- 122), cyclothymic disorder (Ancin I et al. J Affect Disord 133 (2011) 340-345), and bipolar disorder not otherwise specified, other mood disorders (Shytle RD et al. Depression and. Anxiety 16 (2002) 89-92), substance-induced mood disorder, and mood disorder not otherwise specified, anxiety disorders (Picciotto MR et al. Neuropharmacology 96 (2015) 235-243), panic disorder and panic attacks (ZvoJensky MJ et al. Clin Psychol Rev 25 (2005) 761-789), obsessive compulsive disorder (Tizabi Y et al. Biol Psychiatry 51 (2002) 164-171), posttraumatic stress disorder (Sun R et al. Neuroscience 344 (2017) 243-254), acute stress disorder (Mineur YS et ai. Neuropsychopharmacology 41 (2015) 1579-1587), generalized anxiety disorder (Cocores JA Prim Care Companion J Clin Psychiatry 10 (2008) 253-254), anxiety disorder due to a general medical condition, substance-induced anxiety disorder, phobias, and anxiety disorder not otherwise specified, substance related disorders for example substance use or substance-induced disorders, e.g. alcohol- (de Fiebre NC and de Fiebre CM Alcohol 31 (2003) 149-153; Diaper AM et ai. Br J Clin Pharmacol 77 (2014) 302-314) nicotine- (Leslie FM et al. Mol Pharmacol 83 (2013) 753-758), amphetamine- (Pubill D et al. Pharmaceuticals 4 (201 1) 822-847), phencyclidine- (Thomsen MS et al. Neuropharmacology 56 (2009) 1001-1009), opioid- (Zhang W, Ini j Clin Exp Med 8 (2015) 1871-1879), cannabis- (Solinas M et ai. J Neurosci 27 (2007) 5615-5620), cocaine- (Francis MM et al. Mol Pharmacol 60 (2001) 71-79), caffeine-, hallucinogen-, inhalant-, sedative-, hypnotic-, anxiolytic-, polysubstance- or other substance-related disorders, sleep disorders (McNamara JP et al. Psychol Health Med 19 (2014) 410-419), such as narcolepsy (Krahn et ai. ,/ Clin Sleep Med J (2009) 390), dyssornnias, primary' hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder, and dyssomnia not otherwise specified, parasomnias, sleep terror disorder, sleepwalking disorder, and parasomnia not otherwise specified; sleep disorders related to another mental disorder (including, insomnia related to another mental disorder and hypersomnia related to another mental disorder), sleep disorder due to a general medical condition, and substance-induced sleep disorder, metabolic and eating disorders (Somrn E Arch Immunol The r Exp 62 (2014) 62: 87-101), such as anorexia nervosa (Cuesto G et al. J Neurogenet 31 (2017) 266-287), bulimia nervosa, obesity (Lakhan SE and Kirchgessner A j Transl Med 9 (2011) 129-139), compulsive eating disorder, binge eating disorder, and eating disorder not otherwise specified, diabetes mellitus (Marrero MB et al. J Pharmacol Exp Ther 332 (2010) 173-180), ulcerative colitis (Salaga et al. JPET 356 (2016) 157-169), Crohn’s disease (Bencherif M et ai. Cell Mol Life Sci 68 (201 1 ) 931-949), irritable bowel syndrome (Keszthelyi D et al. Neurogas troenterol Mott l 21 (2009) 1239- 1249), autism spectrum disorders (Deutsch et al. Clin Neuropharmacol 33 (2010) 114-120), including autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified, attention deficit hyperactivity disorder (Wilens TE and Decker MW Biochem Pharmacol 74 (2007) 1212- 1223), disruptive behaviour disorders, oppositional defiant disorder and disruptive behaviour disorder not otherwise specified, and tic disorders such as Tourette's disorder (Gotti C and dementi F Prog Nenrobiol 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 disorder, sexual dysfunction not otherwise specified, paraphilias, gender identity disorders, infertility (Bray C et al. Biol Reprod 73 (2005) 807-814), premenstrual syndrome (Gundisch D and Eibl C Expert Opin Ther Pat 21 (2011) 1867-1896), and sexual disorders not otherwise specified, disorders of the respiratory' system like cough (Canning BJ Am J Respir Grit 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 Sc i USA 110 (2013) 4099-4104), lung inflammation (Enioutina EY et al. PLoS One 10 (2015) e0121 128), disorders of the cardiovascular system such as cardiac failure (Mai XK et al. j Immunol 200 (2018) 108.11), heart arrhythmia (Mazloom R et al PLoS One 8 (2013) e82251), and hypertension (Chen JK et al. BMC Cardiovasc Disord 12 (2012) 38).
The compounds of the invention are also useful in treating inflammation, inflammatory' and 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 Grouser MD, Principal Investigator, Ohio State University ClinicalTrials.gov Identifier: NCT02265874), psoriasis (Westman M et al. Scand J Immunol 70 (2009) 136-140), ataxia (Taslim N et al. Behav Brain Res 217 (201 1) 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) el3213), mania (Janowsky DS et al. Lancet 2 (1972) 632-635), restless legs syndrome (Buchfuhrer MJ Neurotherapeutics 9 (2012) 776- 790), progressive supranuclear palsy (Warren NM et al. Brain 128 (2005) 239-245), epilepsy (Bertrand D Epilepsy Curr 2 (2002) 191-193), myoclonus (Leppik IE Epilepsia 44 (2003) 2- 6), migraine (Liu Q et al. J Pain Res 11 (2018) 1129-1140), amnesia (Bali Zs K et al. Front Cell Neurosci 11 (2017) 271), chronic fatigue syndrome (Shan ZY et al. J Magn Resort Imaging 44 (2016) 1301-1311), cataplexy (Ebben MR and Krieger AC J Clin Sleep Med 8 (2012) 195-196), brain ischemia (Han Z et al. J Neurochern 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 (201 1): 110-119), jetlag (Shi M et al. el fe 3 (2014) e01473), cerebral amyloid angiopathy (Clifford PM et al. Brain Res 1234 (2008) 158- 171), sepsis (Ren C et al. Ini J Biol Sci 14 (2018) 748-759), and in general, in treating all types of diseases and disorders connected to the positive allosteric modulation of the a7 nAChR.
Furthermore, these compounds can also be combined with other therapeutic agents including, but not limited to acetylcholinesterase inhibitors (such as galantamine, rivastigmine, donepezil, tacrine, phenserine, ladostigil and ABT-089); NMDA receptor agonists or antagonists (such as memantine, neramexane, EVT101, and AZD4282); anti-amyloid antibodies including anti-amyloid humanized monoclonal antibodies (such as, bapineuzumab, ACCOOl, CAD 106, AZD3102, H12A11V1); beta- (such as verubecestat, and AZD3293) or gamma-secretase inhibitors (such as LY450139 and TAK 070) or modulators, tau phosphorylation inhibitors; ApoE4 conformation modulators; p25/CDK5 inhibitors; NK1/NK3 receptor antagonists; COX-2 inhibitors (such as celecoxib, rofecoxib, valdecoxib, 406381 and 644784); LRRK2 inhibitors; HMG-CoA reductase inhibitors; NSAIDs (such as ibuprofen); vitamin E; glycine transport inhibitors; glycine site antagonists (such as lacosamide); LXR b agonists; androgen receptor modulators, blockers of Ab oligomer formation; NR2B antagonists, anti-inflammatory compounds (such as (R)- flurbiprofen, nitroflurbiprofen, ND-1251, VP-025, HT-0712, and EHT-202); PPAR gamma agonists (such as pioglitazone and rosiglitazone); CB-1 receptor antagonists or inverse agonists (such as AVE1625); CB-2 agonists (such as 842166 and SAB378); VR-1 antagonists (such as AMG517, 705498, 782443, PAC2Q030, VI 14380, and A4256I 9); bradykinin B1 receptor antagonists (such as SSR240612 and NVPSAA164); sodium channel blockers and antagonists (such as VX409 and SPI860); NOS inhibitors (such as SD6010 and 274150); antibiotics; growth hormone secretagogues (such as ibutamoren, ibutamoren mesylate, and capromorelin); potassium channel openers, AMPA agonists or AMP A modulators (such as CX-717, LY 451395, LY404187 and S-18986); GSK3 inhibitors (such as AZD1080, SAR502250 and CEP 16805), neuronal nicotinic agonists, MARK ligands; Mi or Mr mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; mGluRS antagonists (such as AZD9272); alpha-adrenerg agonists; ADAM-10 ligands; sedatives, hypnotics, anxiolytics, antipsychotics, cyclopyrrolones, imidazopyri dines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents; orexin antagonists and agonists; prokineticin agonists and antagonists; T-type calcium channel antagonists; triazoiopyridines benzodiazepines, barbiturates; 5-HTIA antagonists (such as lecozotan); S-fflh antagonists; 5-HT4 agonists (such as PRX-03140); 5-HTe antagonists (such as GSK 742467, SGS-518, FK-962, SL-65.0155, SRA- 333 and xaliproden); histamine H3 receptor antagonists and inverse agonists (such as S38093, ABT-834, ABT 829, GSK 189254 and CEP16795); PDE4 inhibitors (such as HT0712); PDE9 inhibitors (such as BI40936); PDE10 inhibitors; HD AC inhibitors; KCNQ antagonists; GABAA inverse agonists; GABA signalling enhancers; GABA agonists, GABAA receptor alphaS subunit NAMs or PAMs, antipsychotics; MAO-B inhibitors; dopamine transport inhibitors; noradrenaline transport inhibitors; D2 agonists and partial agonists; anticholinergics (such as biperiden); COMT inhibitors (such as entacapone); A2a adenosine receptor antagonists; cholinergic agonists, compounds from the phenothiazine, thioxanthene (such as chlorprothixene and thiothixene), heterocyclic dibenzazepine (such as clozapine), butyrophenone (such as haloperidol), diphenyibutylpiperidine (such as pimozide) and indoione (such as moiindolone) classes of neuroleptic agents; loxapine, sulpiride and risperidone; levodopa; calcium channel blockers (such as ziconotide and NMED160); MMP inhibitors; thrombolytic agents; opioid analgesics (such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene); pramipexole; ropinirole; neutrophil inhibitory factor; SSRIs or SSNRIs, tricyclic antidepressant drugs; norepinephrine modulators; lithium; valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention.
Known positive allosteric modulators of the al nicotinic acetylcholine receptor include 2-aniline-4-aryl thiazole derivatives (WO 2007/031440 A2, JANSSEN PHARMACEUTICA NY), amide derivatives (WO 2009/100294 A2, ABBOT LAB.), tri substituted 1,2,4-triazoles (WO 2009/1 15547 Al, JANSSEN PHARMACEUTICA NV), indole derivatives (WO 2009/127678 Al, GLAXO GROUP LTD. and WO 2009/127679 Al, GLAXO GROUP LTD.), tetrazole-substituted aryl amide derivatives (WO 2009/043780 Al, HOFFMANN LA ROCHE), cyclopropyl aryl amide derivatives (WO 2009/043784 Al, HOFFMANN LA ROCHE), trisubstiuted pyrazoles (WO 2009/135944 Al, JANSSEN PHARMACEUTICA NV), pyrrole derivatives (WO 2014/141091 Al, LUPIN LTD), cy el opropy 1 b en zene derivatives (WO 2017/165256 Al , MERCK SHARP & DOHME CORP.), and substituted bicyclic heteroaryl derivatives (WO 2018/085171 Al, MERCK SHARP & DOHME CORP ).
The present invention is directed to a novel class of compounds that exhibit positive allosteric modulation of the cx7 nicotinic acetylcholine receptor.
BRIEF DESCRIPTION OF THE DRAWINGS
An exemplary embodiment of the present invention is illustrated by way of example in the accompanying drawings in which like reference numbers indicate the same or similar elements and in which:
Figure 1 illustrates the results of place recognition test of compound Example 3. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.) r 0.05; + p<0.0l; +÷ p<0.00l .
Figure 2 illustrates the results of place recognition test of compound Example 5. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.). +p<0 05; + p<0.0l; 1 + p<0.001.
Figure 3 illustrates the results of place recognition test of compound Example 23. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.) p 0.05; p<0.01; + r<0.001.
Figure 4 illustrates the results of place recognition test of compound Example 47. Exploration times spent in the novel [N] vs familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.) p 0.05; +÷p<0.01; i p<0.00l . Figure 5 illustrates the results of place recognition test of compound Example 51. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 nig/kg, ip ). +p<0.05; p 0.01. p 0.001.
Figure 6 illustrates the results of place recognition test of compound Example 90. Exploration times spent in the novel [N] vs. familiar [O] arms of the Y maze are depicted). Scop: scopolamine (1 mg/kg, ip.) p 0.05; + p<0.01; +÷ p<0.00l.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula (I),
Figure imgf000010_0001
wherein
R1 is hydrogen or Ci-ealkyl;
R2 is hydrogen or Ci-ealkyl, or R2 is absent when n is 0;
R3 is hydrogen or O, or R3 is absent when m is 0;
R1 and R5 are independently hydrogen, Ci-ealkyl, halogen, haloCi-ealkyl, Ci-ealkoxy, or CN; n and m are independently 0 or 1; with the proviso that, n and m cannot be 0 at the same time;
k and S are independently 1, 2 or 3;
Y is N or C(R6);
R6 is hydrogen, Ci^alkyl, halogen, or haioCi-ealkyl;
R7 is hydrogen, Ci-ealkyl, or halogen; lu
W is CH or N;
Z is CH, C-Ciualkyl or N;
L is an optionally substituted linker consisting of 1 , 2 or 3 atoms, represented by T-U-V, wherein T is CH?., C(O), NH, SO? or O; U is CH?, C(O), O or absent; and V is CH?, O or absent;
A is a saturated, unsaturated, or aromatic carbocyciyl, or a saturated, unsaturated, or aromatic heterocyclyl, wherein the heteroatoms are selected from the group of nitrogen, oxygen and sulphur; optionally substituted independently by one or more halogen atom or halogen atoms, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkyl, haloCi-ealkoxy, CN, or benzyl;
or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
In a further aspect, the present invention provides a compound of formula (I), as defined above for use in the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity.
In a further aspect, the present invention provides the use of a compound of formula (I), as defined above, for the manufacture of a medicament for the treatment or prevention of a disease associated with a 7 nicotinic acetylcholine receptor activity.
In a further aspect, the present invention provides a method for the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity comprising administering to a mammal in need of such treatment or prevention an effective amount of at least one compound of formula (I), as defined above.
In a further aspect, the compounds of formula (I), as defined above, can be administered in combination with other compounds used for the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity.
In a further aspect, the present invention provides a process for the manufacture of the compounds of formula (I)
Figure imgf000012_0001
Phe present invention relates to compounds of formula i
Figure imgf000012_0002
Figure imgf000012_0003
wherein
R1 is hydrogen or Ci-ealkyl;
R2 is hydrogen or Ci-ealkyl, or R2 is absent when n is 0;
R3 is hydrogen or O, or R3 is absent when m is 0;
R4 and R5 are independently hydrogen, Ci-ealkyl, halogen, haloCi-ealkyl, Ci-ealkoxy, or CN; n and m are independently 0 or 1; with the proviso that, n and m cannot be 0 at the same time;
k and S are independently 1 , 2 or 3;
Y is N or C(R6);
R6 is hydrogen, Ci-ealkyl, halogen, or haloCnealkyl,
R7 is hydrogen, Ci-ealkyl, or halogen;
W is CI S or N;
Z is CH, C-C i-alkvl or N;
L is an optionally substituted linker consisting of 1, 2 or 3 atoms, represented by T-U-V, wherein T is ( ! l·. C(0), NH, SO? or O; U is ( 1 l·. C(0), O or absent; and V is CH?, O or absent;
A is a saturated, unsaturated, or aromatic carbocyclyl, or a saturated, unsaturated, or aromatic heterocyclyl, wherein the heteroatoms are selected from the group of nitrogen, oxygen and sulphur, optionally substituted independently by one or more halogen atom or halogen atoms, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkyl, haloCi-ealkoxy, CN, or benzyl; or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
The term“halo” or“halogen”, as used herein as such or as part of another group, refers to fluoro, chloro, bromo or iodo.
The term“Ci-ealkyl”, as used herein as such or as part of another group, refers to a branched or straight chain saturated hydrocarbon group having one, two, three, four, five or six carbon atoms including, but not limited to, methyl, ethyl, «-propyl, /-propyl, «-butyl, sec- butyl, and fer/-hutyl.
The term“haloCi-ealkyl”, as used herein, refers to at least one halogen, as defined above, bonded to the parent molecular moiety through an“Ci-ealkyl” group, as defined above. When there are several halogens, the halogens can be identical or different and the halogens can be attached to different carbon atoms or several halogens can be attached to the same carbon atom. HaloCi-e.alkyl groups include, but are not limited to, difluoromethyl, trifluoromethyl and 2-chl oroethyl.
The term“Ci-ealkoxy”, as used herein refers to an“Ci-ealkyl” group, as defined above, bonded to the parent molecular moiety through an oxygen atom including, but not limited to, m ethoxy, ethoxy, w-propoxy, /-propoxy and fer/-butoxy.
The term“ haloCi-ealkoxy”, as used herein refers to at least one halogen, as defined above, bonded to the parent molecular moiety through a“C -6alkoxy” group, as defined above. When there are several halogens, the halogens can be identical or different and the halogens can be attached to different carbon atoms or several halogens can be attached to the same carbon atom. HaloCi-ealkoxy groups include, but are not limited to, trifluoromethoxyl , difluoromethoxyl, trifluoroethoxyl .
The term“saturated, unsaturated or aromatic carbocyclyl”, as used herein, refers to monovalent saturated, un saturated or aromatic three to twelwe, preferably four to nine, more preferably six membered moiety, consisting of one to two rings. The carbocyclyc ring may be optionally substituted as defined herein. Examples include, but are not limited to, optionally substituted cyclobutyl, cyclopentyl, cyclohexyl, eycloheptyl, phenyl, naphtyl, etc. The term“saturated, unsaturated or aromatic heterocyclyi”, as used herein, refers to a monovalent saturated, unsaturated or aromatic three to twelwe membered moiety, consisting of one to two rings, incorporating one, two, or three heteroatoms (chosen from nitrogen, oxygen or sulphur, preferably nitrogen and oxygen). The heterocyclyi ring may be optionally substituted as defined herein. Examples include, but are not limited to, optionally substituted tetrahydrofuryl, 1-pyridyl, 2-pyridyl, 3-pyridyi, 4-pyrimidiny!, 5-pyrimidinyl, pyridazyl, indazolyl, indolyl, azaindolyl, isoquinolinyl, quinolinyl etc.
The term“pharmaceutically acceptable” describes an ingredient that is useful in preparing a pharmaceutical composition, is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes those acceptable for veterinary use as well as human pharmaceutical use.
The term“hydrate” means non-covalent combinations between water and solute.
The term“solvate” means non-covalent combinations between solvent and solute. Solvents include, but are not limited to, ethanol, 2-propanol, acetonitrile and tetrahydrofuran.
"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
"Optionally substituted" means unsubstituted or substituted with one or more of the substituents as described herein. Here, "one or more” means from one to the highest possible number of substitution, that is, from replacing one hydrogen to replacing ail hydrogens. One, two or three substituents on a given atom are preferred.
"Treating" or "treatment" of a disease state includes: a) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state, b) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or c) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
The term“pharmaceutically acceptable salt” refers to a conventional acid addition salt or a base addition salt, which preserves the biological efficacy and properties of the compounds of formula (I) 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, hydroiodic acid, sulfuric acid, sulphamic acid, phosphoric acid, nitric acid and perchloric acid and derived from various organic acids, such as, but not limited to, 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 are salts derived from ammonium-, potassium-, sodium- and quaternary ammonium hydroxides such as tetram ethyl ammonium hydroxide.
The term“pro-drag” refers to derivatives of compounds of formula (I) according to the invention which themselves have no therapeutic effect but containing such groups which, after in vivo chemical or metabolic degradation (biotransformation) become“biologically active metabolite” which is responsible for the therapeutic effect. Such decomposing groups associated with the compounds of formula (I) of the present invention, in particular those suitable for prodrugs, are known in the art and may also be applied for the compounds of the present invention (Rautio et af, Nature Reviews - Drug Discovery 2008, 7:255-270).
In one embodiment, the present invention relates to compounds of formula (I), wherein R1 is hydrogen or Ci-salkyl;
R2 is hydrogen or Ci-aalkyl, or R2 is absent when n is 0;
R3 is hydrogen or (), or R3 is absent when m is 0,
R4 and R5 are independently hydrogen, Craalkyl, halogen, haloCraalkyl, Ciualkoxy, or CN; n and m are independently 0 or 1; with the proviso that, n and m cannot be 0 at the same time;
k imd 1 are independently 1 or 2, Y is N or C(R6);
R6 is hydrogen, Cioaikyl, halogen, or haloCiualkyl;
R7 is hydrogen, Ci-3alkyl, or halogen;
W is CH or N;
Z is CH, C-Ci-3alkyl or N;
L is an optionally substituted linker consisting of 1, 2 or 3 atoms, represented by T-U-V, wherein T is CH2, C(O), NH, SO2 or O; U is CH2, C(O), O or absent; and V is O or absent;
A is a saturated, unsaturated, or aromatic 4-9 membered carbocycfyl, or a saturated, unsaturated, or aromatic 4-9 membered heterocyclyl, wherein the heteroatoms are selected from the group of nitrogen, oxygen and sulphur, optionally substituted independently by one or more halogen atom or halogen atoms, Ci-salkyl, Ci-salkoxy, haloCioalkyl, haloCioalkoxy, CN, or benzyl,
or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
In one embodiment, the present invention relates to compounds of formula (I), wherein R1 is hydrogen or Ciualkyl;
R2 is hydrogen or Ciua!kyl, or R2 is absent when n is 0,
R3 is hydrogen or O, or R3 is absent when m is 0;
R4 and R5 are independently hydrogen, Ci-salkyl, halogen, haloCi-salkyl, Ci-salkoxy, or CN, n and m are independently 0 or 1; with the proviso that, n and m cannot be 0 at the same time;
k and I are independently 1 or 2,
Y is N or C(R6);
R6 is hydrogen, Ci-3aikyi, halogen, or haloCiualkyl;
R7 is hydrogen, Ciuaikyl, or halogen;
W is CH or N;
Z is CH or N;
L is an optionally substituted linker consisting of 1 , 2 or 3 atoms, represented by T-U-V, wherein
T is CH2, C(O), NH, SO2 or O; U is CH2, C(O), O or absent, and V is O or absent; A is a saturated, unsaturated, or aromatic 4-9 memhered carbocyclyl, or a saturated, unsaturated, or aromatic 4-9 membered heterocyclyi, wherein the heteroatom is nitrogen, optionally substituted independently by one or more halogen atom or halogen atoms, Ci- salkyl, Ci-3alkoxy, haloCi-salkyl, haloCi-salkoxy, CN, or benzyl;
or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
In one embodiment, the present invention relates to compounds of formula (I), wherein R3 is hydrogen or (4 -alkyl;
R2 is hydrogen or Ci-3alkyl, or R2 is absent when n is 0;
R3 is Q, or R3 is absent when m is 0;
R4 and I are independently hydrogen, Ciualkyl, halogen, haloCiualkyl, Ciualkoxy, or CN; n and m are independently 0 or 1; with the proviso that, n and m cannot be 0 at the same time;
k and 1 are independently 1 or 2;
Y is N or C(R6);
R6 is hydrogen, Ciualkyl, halogen, or haloCi-salkyl;
R7 is hydrogen, Ciualkyl, or halogen;
W is CH or N;
Z is CH or N;
L is linker selected from the group of -CH?.-, -0-, -NH-, -SO?-, -C(O)-, -CH2-O-,
-CH2-CH2-O-, -O-CH?-, -CH2-CH2-, -M I ·( '(())··. or -XI 1 ( 1 ! ··;
A is a saturated, unsaturated, or aromatic 4-9 membered carbocyclyl, or a saturated, unsaturated, or aromatic 4-9 membered heterocyclyi, wherein the heteroatom is nitrogen, optionally substituted independently by one or more halogen atom or halogen atoms, C ualkyl, Ci-salkoxy, haloCiualkyl, haloCi-salkoxy, CN, or benzyl;
or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof
In one embodiment, the present invention relates to compounds of formula (I), wherein R3 is hydrogen or C i -alkyl;
R2 is hydrogen or Ciualky!, or R2 is absent when n is 0, R3 is O, or R3 is absent when m is 0;
R4 and R5 are independently hydrogen, Ci-aalkyl, halogen, haloCt-aalkyl, Ciualkoxy, or CN; n and rn are independently 0 or 1 ; with the proviso that, n and m cannot be 0 at the same time;
k a d I are independently 1 or 2,
Y is N or C(R6);
R6 is hydrogen, Ci-salkyl, halogen, or haloCi-ia!ky!;
R7 is hydrogen, Ci-3alkyl, or halogen;
W is CH or N;
Z is CH or N;
L is linker selected from the group of: -CH2-, -0-, -NH-, -SO2-, -C(O)-, -CH2-O-,
-CH2-CH2-O-, -O-CH2-, -CH2-CH2-, -N ! !-('{( ) )-. or -NH-CH2-;
A is an aromatic 6 membered carbocyclyl, or an aromatic 6 membered heterocyclyl, wherein the heteroatom is nitrogen, optionally substituted independently by one or more halogen atom or halogen atoms, Cnsalkyl, Ciualkoxy, haloCi-salkyl, haloCi-ealkoxy, CN, or benzyl;
or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
In one embodiment, the present invention relates to compounds of formula (I), wherein R1 is hydrogen or Ci-talkyd;
R2 is absent;
R3 is O;
R4 and R5 are independently hydrogen, Ciualkyl, halogen, haloCiualkyl, or CN;
si is 0;
m is 1;
k is 2;
1 is 2;
Y is N or C(R6);
R6 is hydrogen, halogen, or haloCi-3alkyl;
R7 is hydrogen or halogen;
W is CH or N; Z is CH or N;
L is a linker selected from the group of: -CH?.-, -0-, -NH-, or -SO?-;
A is a phenyl, 2-pyridyl, or 3-pyridyl, optionally substituted independently by one or more halogen atom or halogen atoms, Ciualkyl, Csualkoxy, or haloCi-aalkyl;
or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
In one embodiment, the present invention relates to compounds of formula (I), wherein R1 is hydrogen or Ci-3alkyl;
R2 is absent;
R3 is O;
R4 and R5 are independently hydrogen, Ci-3alkyl, halogen, haloCi-salkyl, or CN;
n is 0;
m is 1;
k is 1;
l is 1;
Y is N or C(R6);
R6 is hydrogen, halogen, or haloCiualkyl,
R7 is hydrogen or halogen;
W is N;
Z is CH or N;
L is a linker selected from the group of: -CH?-, -O-, -NH-, or -CH?-Q~;
A is a phenyl, 2-pyridyl, or 3-pyridyl, optionally substituted independently by one or more halogen atom or halogen atoms, Ciualkyl, Csualkoxy, or haloCi-aalkyl;
or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
In one embodiment, the present invention relates to compounds of formula (I), wherein R1 is hydrogen or Ci-3alkyl;
R2 is hydrogen or Ci-salkyl;
R3 is absent;
R4 and R5 are independently hydrogen, Ci-3alkyl, halogen, haloCi-salkyl, or CN;
n is 1; m is 0;
k is 1;
1 is 1 ;
Y is N or C(R6):
R6 is hydrogen, halogen, or haloCi-ialkyl;
R7 is hydrogen;
W is N;
Z is CH or C-Ci-3alkyi;
L is a linker selected from the group of: -0-, -CH2-O-, -CH2-CH2-O-, -O-CH2-, -CH2-CH2-,M I ··( '(())·, or -NH-CH2-;
A is a phenyl, 2-pyridyl, or 3-pyridyl, optionally substituted independently by one or more halogen atom or halogen atoms, Ci-ialkyl, Ciualkoxy, or haloCiualkyl;
or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
In one embodiment, the present invention relates to compounds of formula (I), wherein R1 is hydrogen or Ci-3alkyl;
R2 is hydrogen or Ci-salkyl;
R3 is absent;
R4 and R5 are independently hydrogen, Ciualkyl, halogen, haloCiualkyl, or CN;
n is 1 ;
m is 0;
k is 1;
I is 2;
Y is N or C(R6);
R6 is hydrogen, halogen, or haloCiualkyl;
R7 is hydrogen;
W is N;
Z is CH;
L is a linker selected from the group of: -0-, -CH2-, -CH2-O-, or -NH-;
A is a phenyl, 2-pyridyl, or 3-pyridyl, optionally substituted independently by one or more halogen atom or halogen atoms, Ci-salkyl, Ci-salkoxy, or haloCiualkyl; or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
In one embodiment, the present invention relates to compounds of formula (I), wherein
R1 is hydrogen or Ci-salkyl;
R2 is hydrogen or Ciualkyl;
R3 is absent;
R4 and R5 are independently hydrogen, Ciualkyl, halogen, haloCiualkyl, or CN;
n is 1 ;
m is 0;
k is 2;
l is 2;
Y is N or C(R6);
R6 is hydrogen, halogen, or haloCiualkyl;
R7 is hydrogen;
W is N;
Z is ('l l or N;
L is a linker selected from the group of: -0-, -CH ·-, -CH2-O-, or -C(O)-;
A is a phenyl, 2-pyridyl, or 3-pyridyl optionally substituted independently by one or more halogen atom or halogen atoms, Ci-3alkyl, Ciualkoxy, or haloCi-salkyl;
or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof
In one embodiment, the present invention relates to compounds of formula (I), wherein R1 is hydrogen or Ci-ralkyl;
R2 is hydrogen or Ci-3alkyl;
R3 is absent;
R4 and R5 are independently hydrogen, Ci-salkyl, halogen, haloCi-salkyl, or CN;
n is 1;
m is 0,
k is 2; ! is 3;
Y is N or C(R6);
R6 is hydrogen, halogen, or haloCiualkyl,
R7 is hydrogen;
W is N;
Z is CH or N;
L is a linker selected from the group of: -0-, -CH2-O-, or -NH-;
A is a phenyl, 2-pyridyl, or 3-pyridyl, optionally substituted independently by one or more halogen atom or halogen atoms, Ci-salkyl, Ciualkoxy, or haloCi-ealkyl;
or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
In one embodiment, the present invention relates to compounds of formula (I) selected from the group of;
N-(l -methyl-lH-indol-5-yl)-2-{4-[(4-methylphenyl)methyl]piperazin-l-yl}-2- oxoacetamide;
N-{ 1 -methyl - 1 H-pyrrolo[2,3-b]pyridin-5-yl } -2-{4-[(4-methylphenyl)methyl]piperazin- 1 - y 1 } -2-oxoacetami de;
N-(3-fluoro- 1 -methyl- lH-indol-5-yl)-2-{4-[(4-methyiphenyi)methyl]piperazin- 1 -yl }-2- oxoacetamide,
N-(l -methyl-lH-indol-5-yl)-2-[4-(4-methylphenoxy)piperidin-l-yl]-2-oxoacetamide;
2-[4-(4-chlorophenoxy)piperidin-l-yl]-N-(l -methyl- lH-indol-5-yl)-2-oxoacetamide;
[( lH-indoi-5-yl)m ethyl] [(3 - { [4-(trifluoromethyl)phenoxy]methyl } azetidin- 1 - yl)methyl]amine;
N-({ l-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl}methyl)-3-{[4-
(tritluoromethyl)phenoxy]methyl}azetidine-l -carboxamide;
N-[(l -methyl-lH-indol-5-yl)methyl]-3-{[4-(trifluoromethoxy)phenoxy]methyl}azetidine-l - carboxamide; N-[(2-methyl-lH-indol-5-yl)methyl]-3-{[4-(trifluoromethyl)phenoxy]methyl }azetidine-l- carboxamide;
3-{[3-fluoro-4-(trifluoromethyl)phenoxy]methyl}-N-[(l -methyl- lH-indol-5- yl)methyl]azetidine- 1 -carboxamide;
3-{[3-fluoro-4-(trifluoromethyl)phenoxy]methyl}-N-[(lH-indol-5-yi)methyl]azetidine-l- carboxamide;
N- [(3 -fluoro- 1 -m ethyl - 1 H-i ndol - 5 -y l)methy 1 ] - 3 - { [4- (trifluoromethyl)phenoxy]methyi } azetidine- 1 -carboxamide;
3-methyl-N-({ l-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl}methyl)-3-{[4- (trifluoromethyl)phenoxy]methyl } azetidine- 1 -carboxamide;
N-[( 1 -methyl- lH-indol-5-yl)methyl]-3-[(4-methylphenoxy)methyl]pyrrolidine- 1 - carboxamide;
(3R)-3-(4-fluorophenoxy)-N-[(l -methyl-lH-indol-5-yl)methyl]pyrrolidine-l-carboxamide; (3 S)-3-(4-fluorophenoxy)-N-[(l-methyl-lH-indol-5-yl)methyl]pyrrolidine-l -carboxamide;
(3S)-N-[(l-methyl-lH-indol-5-yl)methyi]-3-[4-(trifluoromethyl)phenoxy]pyrrolidine-l- carboxamide,
(3 S)-3-(4-cyanophenoxy)-N-[(2-methyl-lH-indol-5-yl)methyl]pyrrolidine-l -carboxamide;
(3S)-N-[(l-methyl-lH-indol-5-yl)methyl]-3-{[4-
(trifl uoromethyl)pheny i ] amino } pyrrolidine- 1 -carboxami de;
N-[(l -methyl- lH-indol-5-yl)methyl]-4-{ [4-(trifluoromethyl)phenyl]methyl }piperazine-l- carboxamide;
4-(2,4-difluorophenoxy)-N-[(2-methyl-lH-indol -5-yl)methyl]piperi dine- 1 -carboxamide; or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
In a further aspect, the present invention provides a compound of formula (I), as defined above for use in the treatment or prevention of a disease associated with cx7 nicotinic acetylcholine receptor activity. In a further aspect, the present invention provides the use of a compound of formula (I), as defined above, for the manufacture of a medicament for the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity.
In a further aspect, the present invention provides a method for the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity comprising administering to a mammal in need of such treatment or prevention an effective amount of at least one compound of formula (I) or, as defined above.
In one embodiment, the disease associated with a7 nicotinic acetylcholine receptor activity is selected from the group of psychotic disorders, including, but not limited to, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder or psychotic disorder not otherwise specified; cognitive impairment, including, but not limited to, cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, HIV associated dementia, frontotemporal dementia, Lewy body dementia, vascular dementia, cerebrovascular disease or other dementia states and dementia associated to other degenerative disorders, including, but not limited to, amyotrophic lateral sclerosis, other acute or sub-acute conditions that may cause cognitive decline, including, but not limited to, delirium, traumatic brain injury, senile dementia, mild cognitive impairment, Down’s syndrome, depression and cognitive deficit related to other diseases, and dyskinetic disorders including, but not limited to, Parkinson's disease, neuroleptic-induced parkinsonism, or tardive dyskinesias, depression and mood disorders, including, but not limited to, depressive disorders and episodes, bipolar disorders, cyclothymic disorder, and bipolar disorder not otherwise specified, other mood disorders, substance-induced mood disorder and mood disorder not otherwise specified; anxiety- disorders, panic disorder and panic attacks, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder, phobias, and anxiety disorder not otherwise specified; substance related disorders, including, but not limited to, substance use or substance-induced disorders, including, but not limited to, alcohol-, nicotine-, amphetamine-, phencyclidine-, opioid-, cannabis-, cocaine-, caffeine-, hallucinogen-, inhalant-, sedative-, hypnotic-, anxiolytic-, polysubstance- or other substance-related disorders; sleep disorders, including, but not limited to, narcolepsy, dyssomnias, primary hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder and dyssomnia not otherwise specified, parasomnias, sleep terror disorder, sleepwalking disorder and parasomnia not otherwise specified; sleep disorders related to another mental disorder; sleep disorder due to a general medical condition and substance-induced sleep disorder; metabolic and eating disorders, including, but not limited to, anorexia nervosa, bulimia nervosa, obesity, compulsive eating disorder, binge eating disorder and eating disorder not otherwise specified; diabetes mellitus, ulcerative colitis, Crohn’s disease, irritable bowel syndrome, autism spectrum disorders, including, but not limited to, autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified; attention deficit hyperactivity disorder, disruptive behaviour disorders, oppositional defiant disorder and disruptive behaviour disorder not otherwise specified; and tic disorders, including, but not limited to, Tourette's disorder; personality disorders; sexual dysfunctions such as sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorder, sexual dysfunction not otherwise specified, paraphilias, gender identity disorders, infertility, premenstrual syndrome and sexual disorders not otherwise specified; disorders of the respiratory system like cough, asthma, chronic obstructive pulmonary disease, lung inflammation, disorders of the cardiovascular system such as cardiac failure, heart arrhythmia, 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, myoclonus, migraine, amnesia, chronic fatigue syndrome, cataplexy, brain ischemia, multiple sclerosis, encephalomyelitis, jetlag, cerebral amyloid angiopathy, and sepsis.
In one embodiment, the disease associated with a? nicotinic acetylcholine receptor activity is selected from the group of cognitive impairment, schizophrenia and autism.
The invention, further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another therapeutic agent or agents, for the treatment of one or more of the conditions previously indicated. Such therapeutic agents may be selected from: acetylcholinesterase inhibitors, NMDA receptor agonists or antagonists, anti-amyloid antibodies including anti-amyloid humanized monoclonal antibodies, beta- or gamma- secretase inhibitors or modulators, tau phosphorylation inhibitors, ApoE4 conformation modulators, p25/CDK5 inhibitors, NKI/NK3 receptor antagonists, COX-2 inhibitors, LRRK2 inhibitors, HMG-CoA reductase inhibitors, NSAIDs, vitamin E, glycine transport inhibitors, glycine site antagonists, LXR b agonists, androgen receptor modulators, blockers of Ab oligomer formation, NR2B antagonists, anti-inflammatory compounds, PPAR gamma agonists, CB-1 receptor antagonists or inverse agonists, CB-2 agonists, VR-1 antagonists, bradykinin B1 receptor antagonists, sodium channel blockers and antagonists, NOS inhibitors, antibiotics, growth hormone secretagogues, potassium channel openers, AMPA agonists or AMP A modulators, GSK3 inhibitors, neuronal nicotinic agonists, MARK ligands, IVli or M4 mAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, mGluR5 antagonists, alpha agonists, ADAM-10 ligands, sedatives, hypnotics, anxiolytics, antipsychotics, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, orexin antagonists and agonists, prokineticin agonists and antagonists, T-type calcium channel antagonists, triazoiopyridines benzodiazepines, barbiturates, 5-HTIA antagonists, 5-HT2 antagonists, 5-HT4 agonists, 5-HTό antagonists, histamine H3 receptor antagonists and inverse agonists, PDE4 inhibitors, PDEs inhibitors, PDEio inhibitors, HD AC inhibitors, KCNQ antagonists, GABAA inverse agonists, GABA signalling enhancers, GABA agonists, GABAA receptor alphaS subunit NAMs or PAMs, antipsychotics, MAO-B inhibitors, dopamine transport inhibitors, noradrenaline transport inhibitors, Dz agonists and partial agonists, anticholinergics, COMT inhibitors, A2a adenosine receptor antagonists, cholinergic agonists, neuroleptic agents, loxapine, sulpiride and risperidone, levodopa, calcium channel blockers, MMP inhibitors, thrombolytic agents, opioid analgesics, pramipexole, ropinirole, neutrophil inhibitory' factor, SSRIs or SSNRIs, tricyclic antidepressant drugs, norepinephrine modulators, lithium, valproate, gabapentin, pregabalin, rizatriptan, zolmitriptan, naratriptan, and sumatriptan.
In one embodiment, the therapeutic agents are selected from the goup of: acetylcholinesterase inhibitors, NMDA receptor antagonists, beta- secretase inhibitors, antipsychotics, GABAA receptor alpha5 subunit NAMs or PAMs, histamine Hz receptor antagonists, 5-HTe receptor antagonists, Ml or M4 mAChR agonists or PAMs, rnGluR2 antagonists or NAMs or PAMs, and levodopa. In a further aspect the present invention provides a process for the manufacture of the compounds of formula (I) according to the following reaction route:
The compounds of formula (I) of the invention may be prepared in a variety of ways with synthetic methods known in the art of organic chemistry, or modifications that are familiar to those of ordinary skill in the art. The starting materials used herein are commercially available or may be prepared either by routine methods known in the art or by the detailed synthetic routes.
In the following reaction schemes and hereinafter, unless otherwise stated R1 to R', n, m, k, 1, Y, W, Z, L, and A are as defined in the first aspect.
Throughout the specification, general formulae are designated by Roman numerals (I), (II), (III) etc.
Scheme 1
Compounds of formula (I) wherein the meaning of n is 0, R3 is O, and m is 1 , and the meaning of R1, R4, R3, R7, Y, k, 1, W, Z, L, A are described above for compound of formula (I) can be prepared according to Scheme 1 :
Figure imgf000027_0001
either by coupling compounds of formula (II)
Figure imgf000028_0001
- wherein the meaning of R1, R4, R3, R7, Y are described above for compound of formula (I)
- with compounds of formula (III)
Figure imgf000028_0002
- wherein the meaning of k, 1, W, Z, L, A are described above for compound of formula (I); or by coupling compounds of formula (IV)
Figure imgf000028_0003
- wherein the meaning of R1, R4, R5, R ', Y are described above for compound of formula (I)
- with compounds of formula (V)
Figure imgf000028_0004
V - wherein the meaning of W is N, and the meaning of k, 1, Z, L, A are described above for compound of formula (I).
Typical conditions comprise treatment of the reactants with a suitable coupling agent, such as HATU, HBTU, EDC, T3P in a suitable solvent, such as CH2CI2 or DMF. Alternative conditions comprise conversion of the carboxylic acid (formula (III) or formula (IV)) to the corresponding acid chloride, using oxaiyl chloride or Ghosez’s reagent in a suitable solvent, such as Cl 1 :0 or DMF, then reacting the formed acyl chloride with the corresponding amine in the presence of a suitable base, such as DIPEA or TEA to form an amide. The reaction is carried out at a temperature in the range of 0 °C to room temperature. The necessary reaction time is 6-20 hours. The progress of the reactions is followed by thin layer chromatography. The work-up of the reaction mixture can be carried out by different methods, usually is quenched by the addition of water. The product is isolated by extraction with a suitable organic solvent, and purified by crystallization or column chromatography.
Scheme 2
Compounds of formula (III) and formula (IV) can be prepared according to Scheme 2,
Figure imgf000029_0001
in which the treatment of either formula (II)
Figure imgf000030_0001
- wherein the meaning of R1, R4, R5, R7, Y are described above for compound of formula (I); or formula (V)
Figure imgf000030_0002
V
- wherein the meaning of W is N, and the meaning of k, 1, Z, L, A are described above for compound of formula (I) --- with ethyl/methyl 2-chl oro-2~oxoaceta:te in the presence of a base (such as DIPEA, TEA) in a suitable solvent, such as dichloromethane provides compounds of either formula (IV a)
Figure imgf000030_0003
wherein the meaning of R1, R4, R3, R7, Y are described above for compound of formula (I); or formula (Ilia)
Figure imgf000031_0001
- wherein the meaning of W is N, and the meaning of k, 1, Z, L, A are described above for compound of formula (I) - and the concomitant basic hydrolysis of these esters provides the appropriate carboxylic acids of either formula (IV)
Figure imgf000031_0002
- wherein the meaning of R1, R4, R3, R7, Y are described above for compound of formula
0); or formula (III)
Figure imgf000031_0003
- wherein the meaning of W is N, and the meaning of k, 1, Z, L, A are described above for compound of formula (I). Or the compounds of formula (III) can be prepared according to Scheme 3,
Figure imgf000032_0001
VI VII III in which treatment of formula (VI)
Figure imgf000032_0002
- wherein, the meaning of W is CH, and the meaning of k, 1, Z, L, A are described above for compound of formula (I) - with ethyl isocyanoacetate in the presence of a base, such as NaH, in a suitable solvent, such as THF provides compounds of formula (VII)
Figure imgf000032_0003
VII - wherein the meaning of W is CH, and the meaning of k, 1, Z, L, A are described above for compound of formula (I) - and the concomitant treatment of compounds of formula (VII) with aqueous HC1 solution is followed by the treatment with aqueous KOH solution resulted in compounds of formula (III)
Figure imgf000033_0001
in
- wherein the meaning of W is CH, and the meaning of k, 1, Z, L, A are described above for compound of formula (I).
Compounds of formula (I) can be prepared according to Scheme 4,
Figure imgf000033_0002
- wherein the meaning of R2 is Ci-6 alkyl or hydrogen, n is 1 , m is 0, W is N, and the meaning of Rl, R4, R3, R') Y, k, 1, Z, L, A are described above for compound of formula (I) - by the activation of the appropriate primary' amine compounds of formula (VIII)
Figure imgf000033_0003
- wherein n is 1 and the meaning of R1, R2, R4, R3, R7, Y are described above for compound of formula (I) - using standard procedures and reagents e.g., GDI, chloroformates or I, G-thiocarbonyldiimidazole in suitable solvents, e.g., CH2CI2 or DMF under argon atmosphere, followed by the reaction with compounds of formula (V)
Figure imgf000034_0001
- wherein the meaning of W is N, and the meaning of k, 1, L, Z, A are described above for compound of formula (I) - which is carried out at a temperature in the range of 0 °C to room temperature. The necessary reaction time is 15-20 hours. The progress of the reactions is followed by thin layer chromatography. The work-up of the reaction mixture can be carried out by different methods, usually is quenched by the addition of water. The product is isolated by extraction with a suitable organic solvent, and purified by crystallization or column chromatography.
The compounds of formula (II), formula (V) and formula (VIII) used herein are commercially available or can be prepared by methods known in the art, preferred methods include, but are not limited to those described below in the examples section.
The present disclosure includes within its scope all the possible isotopically labelled forms of the compounds.
The compounds of the present invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intraarticular, intrathecal, intraperitoneal, direct intraventricular, intracerebroventicular, intramedullary injection, intracisternal injection or infusion, subcutaneous injection or implant), ophtalmic, nasal, vaginal, rectal, sublingual and topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations comprising pharmaceutically acceptable excipients suitable for each route of administration.
Alternatively, one may administer the compounds in a local rather than systemic manner, for example, via injection of the compound directly in the renal or cardiac area, often in a modified release formulation. Furthermore, one may administer the drug in a targeted drag delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes are taken up selectively by the targeted organ. The pharmaceutical compositions of the present invention usually contain 0.01 to 500 mg of the active ingredient in a single dosage unit. However, it is possible that the amount of the active ingredient in some compositions exceeds the upper or lower limits defined above.
The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
This dosage level and regimen can he adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition and the host undergoing therapy.
As a further aspect of the invention, there is provided the pharmaceutical manufacture of medicaments containing the compounds of formula (I), or pharmaceutically acceptable acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
The pharmaceutical compositions of the present invention may be formulated as different pharmaceutical dosage forms, including, but not limited to, solid oral dosage forms like tablets (e.g., buccal, sublingual, effervescents, chewable, orodispersible, freeze dried), capsules, lozenges, pastilles, pills, orodispersible films, granules, powders; liquid oral dosage forms, including, but not limited to, solutions, 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 eye preparations, nasal drops and sprays, transdermal dosage forms, suppositories, rectal capsules, rectal solutions, emulsions and suspensions, etc.
The pharmaceutical compositions of the present invention can be manufactured in any conventional manner, e.g., by mixing, dissolving, emulsifying, suspending, entrapping, freeze-drying, extruding, laminating, film-casting, granulating, grinding, encapsulating, dragee-making or tabletting processes.
Pharmaceutical compositions for use in accordance with the present invention thus can be formulated in any conventional manner using one or more physiologically acceptable excipients. Any of the well-known techniques and excipients may be used as suitable and as understood in the art.
Suitable excipients for the preparation of the dosage forms may be selected from the following categories, including, but not limited to, tablet and capsule fillers, tablet and capsule binders, release modifying agents, disintegrants, glidants, lubricants, sweetening agents, taste- masking agents, flavoring agents, coating agents, surfactants, antioxidants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, microencapsulating agents, ointment bases, penetration enhancers, solubilizing agents, solvents, suppository bases, and suspending agents.
In one embodiment, the invention relates to the use of specific excipients which are capable of improving the solubility, dissolution, penetration, absorption and/or bioavailability of the active ingredient(s), including, but not limited to, hydrophilic polymers, hot melt extrusion excipients, surfactants, buffering agents, complexing agents, emulsifying agents, lyophilization aids, superdisintegrants, microencapsulating agents, penetration enhancers, solubilizing agents, co-solvents, and suspending agents. The above described ingredients and different routes of manufacture are merely representative. Other materials as well as processing techniques and the like well known in the art can also be used. EXAMPLES
The invention is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples set forth herein below, but rather defined by the claims appended hereto.
In general, the compounds of formula (I) can be prepared in accordance with the general knowledge of one skilled in the art and/or using methods set forth in the Example and/or Intermediate sections that follow. Solvents, temperatures, pressures, and other reaction conditions can readily be selected by one of ordinary skill in the art. Starting materials are commercially available and/or readily prepared by one skilled in the art.
The present invention will be now illustrated by the following not limiting examples.
In the following examples“room temperature” denotes a temperature in the range from 20 °C to 25 °C.
The abbreviations used in the specific examples have the following meanings:
AcOH acetic acid
atm atmosphere
cc. concentrated
Bl ! .Ti ll borane tetrahydrofuran complex solution
GDI 1 , 1 '-carbonyl diimidazol e
DCE 1 ,2-dichloroethane
DIPEA L/ AG-dii sopropylethy 1 amine
N,AP -dimethylformamide
DM SO dimethyl sulfoxide
EDC. HC1 A-(3-dimethylaminopropyl)-A'-ethylcarbodiimide hydrochloride
EDC Af-(3-dimethylaminopropyl)-Ar'-ethyicarbodiimide ESI electronspray ionisation
Et;0 diethyl ether
EtOAc ethyl acetate
EtOH ethanol
IPy2BF4 bi s(py ri din e)i odo ium te trail uorob orate
KO/Bu potassium fert-butoxide
LC-MS liquid chromatography coupled with mass spectroscopy
MeOH methanol
HATU l~[Bis(dimethylamino)methylene]-li/~i,2,3-triazolo[4,5~6]pyridinium 3-oxid hexafluorophosphate
HBTU N, AyA'' 'iV'-tetramethyl-O- 1 H -benzotriazol - 1 -y 1 jurani um hexafl uorophosphate
HEPES (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid)
HOBtHzO 1 -hydroxybenzotriazole hydrate
HPLC high-performance liquid chromatography
sodium fer/-butoxide
pyridinium chlorochromate
tris(dibenzylideneacetone)dipalladium(0)
palladium on activated charcoal
Pd(OH)2 / C palladium-hydroxide on activated charcoal
Pd(PPh3)2Cl2 bis(triphenylphosphine)palladium(II) dichloride
RP-HPLC reversed phase high-performance liquid chromatography
RuPhos 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl
Selectfluor 1 -Ch!oromethyl -4-fluoro- 1 ,4-diazoniabicycl o[2.2.2]octane
bi sitetrafluorob orate)
T3P propylphosphonic anhydride
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography Aromatic amine intermediates were purchased from commercially available sources or their synthesis was based on the chemical literature (Table 1).
Table 1
Figure imgf000039_0001
The synthesis is c etailed in the following chemical literature:
Mahal K. et al ChernMedChem 9 (2014) 847-854 Several aromatic amines were synthesized according to the following synthetic routes:
Figure imgf000040_0001
I S-Dimethyl-liZ-mdoI-S-amiiie
500 mg (3.08 mmol) of 5-nitroindole was solved in 10 mL of DMF and 0.135 g (5.625 mmol) of NaH was added. After stirring for 5 minutes, 0.21 1 mL (3.39 mmol) of methyl iodide was added, and the mixture was stirred overnight. Concentrated NELCl solution was added, and it was extracted twice with 10 mL of EtOAc. The combined organic phases were extracted twice with 10 mL of water, and twice with brine, dried over NaiSCL, and evaporated to dryness to obtain 536 mg of l-methyl-5-nitroindole.
To 2.5 mL of DMF at -20 °C, 0.312 mL (3.35 mmol) of phosphorus oxychloride was added. Afterwards, 536 mg (3.04 mmol) of 1 -methyl-5-nitroindole was added in portions. The mixture was stirred for 5 hours at room temperature. 5 mL of water was added, and the mixture was extracted with 20 mL of CH2CI2. The organic phase was extracted with 10 mL of water and 10 mL of brine twice. The organic layer was dried over Na?.S04, and evaporated to dryness to obtain 666 mg of l-methyl-5-nitro-lH-indole-3-carbaldehyde.
496 mg (2.43 mmol) of l-methyl-5-nitro-lH-indole-3-carbaldehyde was solved in 200 mL of methanol. The solution was hydrogenated with 207 mg of 10 % Pd/C at atmospheric pressure for 12 hours. The catalyst was filtered off, and the filtrate was evaporated. The crude product was purified with flash chromatography (hexane/EtOAc) to obtain 165 mg of 1,3- dimethyl-lH-indoi-5-amine.
Figure imgf000041_0001
O
benyzlamine
Figure imgf000041_0002
RuPlios
Figure imgf000041_0003
Pdydba), dry THF dry toluene
Figure imgf000041_0004
Figure imgf000041_0005
Figure imgf000041_0006
3-Flnoro-l-methyI-li?-pyrrolo[2,3-6]pyridiii-5-ami!ie
Under argon atmosphere, 1.86 g (9.4 mmol) of 5-bromo-7-azaindole was dissolved in 225 mL of dry acetonitrile and 45 mL of cc. acetic acid. The solution was heated to 40 °C, 5 g of Selectfluor (l -Chloroniethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafiuoroborate)) was added, and the resulting mixture was heated to 80 C'C, and stirred overnight. It was evaporated to dryness, and the crude product was dissolved in 200 mL of EtOAc, and washed twice with water. The organic layer was dried over NaiiSOr and was evaporated. After flash column chro atography (CHzCh/MeOH ::: 99/1) 362 mg of 5-bromo- 3-fluoro-7-azaindole was isolated.
A solution of 300 mg (1.4 mmol) of 5-bromo-3-fluoro-7-azaindole in 12 mL of city THF was cooled to 0 °C, and 140 mg of NaH (60 % m/m mineral oil suspension, 3.5 mmol, 2.5 mol equivalents) was added in portions. Afterwards, the solution was allowed to warm to room temperature (approx. 30 minutes) and 397 mg (2 mol equivalents) of iodom ethane was added dropwise, and the mixture was stirred overnight. The reaction was quenched by the addition of water. The mixture was extracted three times with EtOAc. The extract was dried over Na2S04, filtered and evaporated to dryness to obtain 380 mg of 5-bromo-3-fluoro-l- methyl-7-azaindole as a yellowish brown oil, which was used in the next step without further purification. 380 mg (1.4 mmol) of 5-bromo-3-fluoro-l-methyJ-7-azaindole was dissolved in 15 mL of dry toluene. Argon was streamed through the solution for 20 minutes. Afterwards, 0.305 mL (2.8 mmol) of benzylamine, 405 mg (4.2 mmol) of NaO/Bu, 66 mg (0.14 mmol) of RuPhos and 65 mg (0.07 mmol) of Pd:i(dba)3 was added. The reaction mixture was heated to 105 °C overnight. The mixture was allowed to cool to room temperature, water w'as added, and the mixture was extracted with EtOAc three times, dried over Na2.SQ4 and evaporated to dryness. The obtained 96 mg of 5-benzylamino-3-fluoro-l-methyl-7-azaindole was used without further purification.
96 mg (0.376 mmol) of 5-benzylamino-3-fluoro-l-methyl-7-azaindole w¾s hydrogenated in a mixture of 6 mL of methanol and 6 mL of EtOAc with 35 mg of 10 % Pd/C at atmospheric pressure for 48 hours. The catalyst was filtered off, and the solvent was evaporated. The crude product was purified with flash chromatography, using EtOAc as the eluent, to obtain 23 mg of 3-iluoro-l-methyl-l//-pyrrolo[2,3-/?]pyridin-5-amine.
Figure imgf000042_0001
200 mg (1.0 mmol) of 2-trifluoromethylindole w'as dissolved in 1 mL of acetic anhydride. The mixture w?as cooled to 0 °C and 131 mg (0.54 mmol) of Cu(N03)23H?.0 was added. The reaction mixture was stirred at room temperature for 2.5 hours. Water and diethyl ether was added, and the organic phase was extracted three times with 8 % NaHCCh solution and once with water. The organic phase was dried over NaiSCri, and evaporated to dryness. 63 mg of 2-trifluoromethyl-5-nitroindole was obtained. 63 mg (0.27 mmol) of 2-trifluoromethyl-5-nitroindole was hydrogenated at atmospheric pressure and room temperature with 6 mg of 10 % Pd/C catalyst in 5 mL of ethanol for 9 hours. Afterwards, another 6 mg of 10 % Pd/C was added, and the reaction was continued for two days. Having filtered the catalyst and evaporated the solvent, 55 mg of crude 2-trifluoromethyl-l/7-indol-5-amine was obtained, which was used in the next step without further purification.
Figure imgf000043_0001
3-Fluoro-lH-pyrrolo[2,3-6]pyridin-5-amine
1.0 g (6.13 mmol) of 5-Nitro-7-azaindole was dissolved in 145 mL of a mixture of dry acetonitrile and 30 mL of acetic acid. The mixture was heated to 40 °C and 3.5 g (9.2 mmol) of Selectfluor was added. The temperature was risen to 80 °C, and the mixture was kept at this temperature overnight. The solvent was evaporated, EtOAc was added, and the mixture was extracted with water three times. The organic phase was dried and evaporated, the residue was treated with diethyl ether, and the solid was filtered off. The resulted product was purified with 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 was hydrogenated in 156 mL of ethanol with 11 mg of 10 % Pd/C at atmospheric pressure for 24 hours. The catalyst was filtered off, and the filtrate was evaporated. The crude product was purified with flash chromatography, using 5 % methanol in CH2CI2 as eluent. 64 mg of 3-iluoro-!//-pyrrolo[2,3- Z>]pyridin-5-amine w?as obtained.
Figure imgf000044_0001
l-MethyS-7-(triileoromethyl)-ll/-mdol~5-am e
1 .72 g (8.36 mmol) of 4-nitro-2-(trifluoromethyl)aniline was solved in 20 mL of CH2CI2. While the temperature was held between 0 and 10 °C, 1.6 g (13.4 mmol) of IPV2BF4 was added in portions. Keeping the temperature between 0-5 °C, 2.37 mL (26.75 mmol) of trif!uoromethanesuifonie acid was added slowly. The obtained mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched by the addition of water (20 mL). After extraction with CH2CI2 (2x 20 mL), the combined organic layer was washed with saturated NaiSaCb solution (20 mL), dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue w?as purified by column chromatography on silica gel, eluting with cyclohexane - EtOAc (4: 1) to yield 1.52 g of 6-iodo-4-nitro-2-(trifluoromethyl)aniline.
To 560 mg (1.69 mmol) of 6-iodo-4-nitro-2-(trifluoromethyl)aniline, 5 mL of TEA was added under argon atmosphere. 101 mg of Pd(PPh3)2Ch, 30 mg of Cul and 0.30 mL of trimethyisiiylacetylene was added at room temperature, and the mixture was stirred overnight. Solvent and volatiles were removed at reduced pressure, and diethyl ether was added to the residue. After filtration over ceiite, the organic extract w¾s washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with cyclohexane - EtOAc (10: 1) to yield 300 mg of 4- nitro-2-(trifluoromethyl)-6-[2-(trimethylsilyl)ethynyl]aniline.
380 mg (1.256 mmol) of 4-nitro-2-(trifluoromethyl)-6-[2- (trimethylsilyl)ethynyl]aniline was dissolved in 4 mL of DMF and 240 mg of Cul was added. The reaction mixture was heated to 100 °C for 2 hours under argon atmosphere. After the completion of the reaction (monitored by TLC), the solvent was removed in vacuo and EtOAc was added to the residue. After filtration over celite, the organic extract was washed with brine, dried over anhydrous INfcSQr, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with cyclohexane - EtOAc (5: 1) to yield 220 mg of 5-nitro-7-(trifluoromethyl)-li7-indole.
Under argon atmosphere 127 mg (0.5 mmol) of 5-nitro-7-(trifluoromethyl)-l//-indole was 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 minutes, and 0.07 mL of methyl iodide in 2 mL of THF was added slowly. The mixture was stirred overnight at room temperature. Water and EtOAc was added, and the organic layer was separated, washed three times with water, dried over Na2.S04, and concentrated in vacuo to obtain 60 mg of 1 -methyl - 5-nitro-7-(trifluoromethyl)-l//~indole.
95 mg (0.41 mmol) of 5-nitro-7-(trifluoromethyl)-l-methyl-177-indole was solved in 20 mL of methanol. 10 mg of Pd(OH)2/'C was added, and hydrogenated at atmospheric pressure for 2 hours. Another 5 mg of Pd(QH)2/C was added and the hydrogenation was continued for 4 hours. The catalyst was filtered off, and the filtrate was concentrated in vacuum. The crude product was purified with column chromatography, using hexane - EtOAc 2: 1 as eluent to obtain 48 mg of l-methyJ-7-(trifluoromethyl)-li/-indol-5-amine.
Piperazine intermediates were either purchased from commercially available sources (Table 2) or synthesized (see below). Table 2
Figure imgf000046_0002
Non-purchasabie piperazine derivatives were synthesized according to the synthetic procedures detailed below:
Intermediate 22
Figure imgf000046_0001
4-{[6-(Trifluoromethyl)pyridin-3-yl]methyl}piperazine
0.53 g (3 mmol) of 2-Trifiuoromethyl~5~piridinecarhoxaIdehide and 0.55 g (3 mmol) of /erf-butyl piperazine- 1-carboxylate was solved in 40 mL of CH?.C1?., and 0.95 g (4.5 mmol) of sodium triacetoxy horohydride was added. The reaction was stirred at room temperature overnight. The reaction mixture was extracted with 15 mL of 20 % K2CO3, and with water, subsequently. The organic phase was dried with NazSCL, and evaporated in vacuo. The crude product was purified with column chromatography, using chloroform and ethanol as eluent, to yield 0.65 g (63 %) of tert- butyl 4- {[6-(trifluoromethyl)pyridin-3-yl]methyl (piperazine- 1- carboxyl ate.
0.65 g (1.88 mmol) of tert- Butyl 4-{[6-(trifluoromethyl)pyridin-3- yljmethyl) piperazine- l-carboxy!ate was treated with 10 mL of 30 % HC1 in EtOAc at 0 °C. After stirring the slurry for 3 hours, the precipitated product was filtered off, washed with diethyl ether and dried in vacuo , to yield 0.56 g of 4-{[6-(trifluoromethyl)pyridin-3- yijmethyl (piperazine hydrochloride.
Figure imgf000047_0001
4 {[5-(Trifluoromethyl)pyridin-2-yl]methyl}piperazine
Intermediate 23 was synthesized in an analogous way as described for Intermediate
24.
Figure imgf000047_0002
1.86 g (10 mmol) of fe/7-Butyl piperazine- 1-carboxylate, 2.23 g (10 mmol) of 4- chloro-3-fluorobenzylbromide and 2.78 g (20 mmol) of K2CO3 was solved in 30 mb of ethanol, and heated to reflux for 12 hours. The slurry was concentrated in vacuo , 20 mL of water was added, and it was extracted three times with 20 mL of CH2CI2. The combined organic layers were dried over Na2S04 and concentrated in vacuo to yield 3.28 g (99 %) of fer/-butyl 4-[(3-chloro-4-fluorophenyl) methyl] piperazine-l-carboxyJate.
3.28 g (10 mmol) of tert-butyl 4-[(3-chloro-4-fluorophenyl)methyl]piperazine-l- carboxylate was dissolved in 30 mL of CH2CI2. 7.7 mL of TFA was added, and stirred at room temperature overnight. The mixture was concentrated in vacuo. 50 ml of 10 % K2CO3 was added, and extracted with 60 mL of EtOAc twice. The combined extracts were dried over Na2S04 and concentrated in vacuo to obtain 2.1 g (92 %) of 4-[(3-chloro-4-fluorophenyl) methyijpiperazine as an off-white solid. Piperidine intermediates represented in Table 3 were purchased from commercially available sources.
Table 3
Figure imgf000048_0001
^Y-Boc-hexahydro-lff-azepin-d-one was commercially available and it was easily reduced by sodium borohydride to obtain the corresponding hydroxyl derivative, which was further reacted in an analogous way as it is described for 3-[(4- methylphenoxy)methyl]azetidine. Racemic mixture was applied.
Figure imgf000049_0001
Interm ediate 15 Intermed iate 38
Ethyl 2-{4-[(4-methylphenyl)methyl]piperazin-l-yl}-2-oxoacetate
To a solution of l-(4-methylbenzyl)piperazine (854 mg, 4.49 mmol) and TEA (0.94 mL, 6.7 mmol) in CH2CI2 (25 mL), ethyl chlorooxoacetate (0.6 mL, 5.37 mmol) was added at 0 °C under argon atmosphere, and the mixture was stirred at room temperature overnight. Dichloromethane (100 mL) was added, and the mixture was washed with water, dried over Na2SC>4, filtered and concentrated under reduced pressure to obtain the product (1 243 g, 95%) as light yellow oil. Intermediates in Table 4 were prepared according to the synthetic description of
Intermediate 38.
Table 4
Figure imgf000049_0002
Intermediate 48
Figure imgf000050_0001
Intermediate 38 Intermediate 48
2-{4~ {4-methyIphenyl}methyljpiperazin--!~yl}-2~o:soaeetk add
To a solution of ethyl 2-{4-[(4-methylphenyl)methyl]piperazin-l-yl}-2-oxoaceta†e (3.098 g, 10.67 mmol) in ethanol, a solution of NaOH (515 mg, 12.88 mmol, 1.2 mol equivalents) in water (5 ml) was added dropwise at 0 °C. The mixture was stirred at room temperature for 2.5 hours, and concentrated. The residue was dissolved in water (50 mL) extracted with diethyl ether, acidified with 12 9 mL of 1 M aqueous HC1 solution and extracted with CH2CI2. The aqueous layer was freeze dried to obtain the title compound (3.546 g) as a white solid containing 1.2 mol equival ents of Nad. This intermediate was used in the next step without further purification.
Intermediates in Table 5 were prepared according to the synthetic description of Intermediate 48.
Table 5
Figure imgf000050_0002
5u
Figure imgf000051_0001
2-Oxo-2-(l-{ 4-(trifluoroffiethyI)pheiiyI]methyI}piperidiii-4-yl)acetic add
To a solution of 4-piperidone monohydrate hydrochloride (3.0 g, 19.5 mmol) in DMF (60 mL), K2CO3 (5.4 g, 39 mmol) and l-(bromomethyl)-4-(trifluoromethyl)benzene (7.0 g 29.29 mmol, 1.5 mol equivalents) was added at room temperature under argon atmosphere. The mixture was stirred overnight under this condition. After the completion of the reaction (monitored by TLC- visualized by iodine - o-tolidine), the mixture was poured onto water (80 mL) and extracted with EtOAc (3x30 mL). The combined organic layer was washed with brine (3x30 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue w¾s chromatographed on silica gel, eluting with a mixture of cyclohexane - EtOAc (1 : 1) to yield 3.21 g of l-{[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 equivalents) in THF (100 mL), a solution of ethyl isocyanoacetate (1 .78 mL, 16 25 mmol) in THF (5 mL) was added over a period of 15 minutes at 0-5 °C under argon atmosphere. The mixture was stirred for 40 minutes under this condition, then a solution of !-{[4~ (trifluoromethyl)phenyi]methyl) piped din-4-one (3.21 g, 12.5 mmol) in THF (45 mL) w¾s added dropwise at 0-5 °C. The temperature was allowed to warm to room temperature, and the mixture w¾s stirred overnight. .After the completion of the reaction (monitored by TLC), the mixture w'as poured onto water (100 mL) and extracted with EtOAc (2x80 mL). The combined organic layer was washed with brine (2x30 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo to yield 1.27 g of ethyl 2-formamido-2-(l-{[4- (trifluoromethyl)phenyl]methyl}pipeiidin-4-ylidene)acetate. It was used in the next step without further purification.
To a stirred solution of ethyl 2-formamido-2-(l-{[4-(trifluoromethyl)phenyl]- methyl }piperidin-4-ylidene)acetate (1.27 g, 3.43 mmol) in EtOH (21 mL) 10 % aqueous solution of 1 !CI (21 mL) was added at 0-5 °C under argon atmosphere, then the mixture was stirred at room temperature overnight. After the completion of the reaction (monitored by TLC), a solution ofKOH (3.79 g, 67.7 mmol) dissolved in EtOH (28 ml) and water (10 mL); (pl f 12} was added to the obtained mixture. After the completion of the hydrolysis (monitored by TLC), the mixture’s pH was adjusted to 6 by the addition of 1 N HC1 solution. The precipitated solid was removed by filtration, and the mother liquor was concentrated in vacuo to yield 3.42 g (theor.1.08 g) of 2-oxo-2-(l-{[4- (trifluoromethyl)phenyi]methyl}piperidin-4~yl)acetic acid together with KC1. It was used in the next step without further purification. Intermediates in Table 6 were prepared according to the synthetic description of
Intermediate 58.
Table 6
Figure imgf000052_0001
In some amidation reaction (D, F, G methods) the aromatic amine was first acylated, and the corresponding ester was hydrolyzed to obtain the [(l-methyl-l/7-indol-5- yi)carbamoyi]formic acid.
Figure imgf000053_0001
1 -Methyl-l//-indol-5-amine (1.18 g, 8.07 mmol) and DIPEA (2.1 mL, 12.06 mmol) were dissolved in CH2CJ2 (50 mL), and ethyl oxalyl chloride (0.98 mL, 8.77 mmol) was added drop wise to the resulting reaction mixture at 0 °C. The mixture was stirred for 3 hours at room temperature. The reaction mixture was treated with saturated aqueous NaHCCb solution, and the organic phase was washed with water. The organic phase dried over NaiSOr and evaporated to dryness to result in ethyl [(l-methyl-li/-indol-5-yl)carbamoyl]formate. Yield:
1.2 g (61 %).
Ethyl [(l-methyl-li -indol-5-yl)carbamoyl]formate (1.2 g, 4.87 mmol) was hydrolysed with 2.1 mol equivalents of aqueous LiOHTfcO solution (426 mg, 10.15 mmol in 6 mL water) in methanol (30 ml). The reaction mixture was stirred for 4 hours. The pH of the mixture was adjusted to 3 by the addition of 1 M HC1 solution (ca. 10 mL) and extracted with EtOAc (2x40 mL). The organic phase was dried over NaiSOr and evaporated to dryness. Yield: 1 5 g of crude product of [(1 -methyl- !i/-indol-5-yl)carbamoyl]fomiic acid.
The amide coupling reactions resulted in the examples in Table 7 were carried out according to one of the following (A-H) methods. Method A:
N~(l -Methyl- lfiT-indol-5-yl)-2-{4-[(4-methyIphenyl)methyl]piperazin-l-yl}-2-
Figure imgf000054_0001
500 mg of 2-{4-[(4-methylphenyl)methyl]piperazin-l-yl}-2-oxoacetic acid (1.906 mmol) was dissolved in diy DMF under argon atmosphere. To this solution 350 mg (2.287 mmol, 1.2 mol equivalents) of 1-hydroxybenzotriazole hydrate (HOBt.HbO) and 438 mg (2.287 mmol, 1.2 mol equivalents) of JV-(3-dimethylaminopropyl)-/V’-ethylcarbodiimide hydrochloride (EDC.HC1) were added, and the mixture was stirred for 15 minutes under argon atmosphere. Afterwards, 278 mg (1 mol equivalent) of 1 -methyl- l/: -indol-5-amine and 386 mg (2 mol equivalents) of TEA were added. The resulted reaction mixture was stirred for 24 hours at room temperature under argon atmosphere. After the completion of the reaction (monitored by TLC), the mixture was diluted with water (20 mL), and extracted with EtOAc (3x20 mL). The combined organic layer was washed with water, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The crude product was purified by column chromatography to obtain 71 mg (10 %) of the title compound. LC-MS (ESI) m/z [M+H] 391 .2
Method B:
A7-{3~Fluoro~l-methyl-liT-pyrrolo|2,3-6]pyridm-5~yI}-2-{4~[(4-methylplienyI)methyI]
Figure imgf000054_0002
40 mg of 2-{4-[(4-methylphenyl)methyl]piperazin-l-yl ) -2-oxoacetic acid (0.152 mmol) was dissolved in dry DMF (1 mL) under argon atmosphere. To this solution 22.4 mg (23 pL, 0.168 mmol, 1.1 mol equivalents) of l-chloro-ALY, 2-trimethyl-l-propenylamine (Ghosez’s reagent) was added, and the mixture was stirred at room temperature for 30 minutes under argon atmosphere. Afterwards, a solution of 23 mg (0.91 mol equivalents) of 3-fluoro- 1 -methyl- l /-pyrrolo[2, 3 -6]pyridin-5-amine and TEA 22 pL (15.5 mg, 0.155 mmol) in DMF (0.5 mL) was added, and the reaction mixture was stirred for 4 hours at room temperature under argon atmosphere. After the completion of the reaction (monitored by TLC), the mixture was poured onto water (8 mL), and extracted with EtOAc (2x15 mL). The organic layer was dried over anhydrous NaiSCU, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with EtOAc to yield 16 mg (47 %) of the title compound. LC-MS (ESI) m/z | M 1 1 j + = 410.2
Method C:
Ar-[l-MethyI-7-(trifluoromethyI)-l//-indol-5-yl]-2-{4-[(4-methyIphenyl)methyl]-
Figure imgf000055_0001
To a solution of 20 mg (0.076 mmol) of 2-{4-[(4-methylphenyl)methyl]piperazin-l - yl} -2-oxoacetic acid in dry CH2CI2 (2 mL), oxalyl chloride (20 pL, 0.0236 mmol) and one drop of DMF w¾s added at 0 °C under nitrogen atmosphere. After addition, the mixture was stirred at 5-10 °C for 1 hour. After the completion of the reaction (monitored by TLC), the solvent was removed in vacuo , and dry CH2CI2 was evaporated from the residue several times. The solution of l-methyl-7-(trifluoromethyl)-li7-indoT5-amine (16 mg, 0.075 mmol ), TEA (20 pL) in CH2.CI2 (1 mL) was added dropwise. The obtained mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched by the addition of water (10 mL). The reaction mixture was extracted with CH2CI2 (2x), the combined organic layer was washed with water, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by preparative layer chromatography on silica gel, eluting with EtOAc - cyclohexane (1:1) to yield 8.0 mg (24 %) of the title compound. LC-MS (ESI) m/z | M I ! I -150.2
Method D:
/V-(l-Methyl-l/7-indol-5-yl)-2-oxo-2-(4-{[5-(trifIuoromethyl)pyridin-2-yl] methyl} piperazin-l-yl) acetamide
Figure imgf000056_0001
To a solution of 153 mg (0.7 mmol) of [(l-methyl-li7-indol-5-yl)carbamoyl]formic acid in dry CH2CI2 (30 mL), HBTU (265 mg, 0.7 mmol) and TEA (540 pL, 5.5 mol equivalents) was added at room temperature under argon atmosphere. The mixture was stirred for 20 minutes, then 1- {[5-(trifluoromethyl)pyridin-2-yl]methyl}piperazine (223 mg, 0.7 mmol) was added. The mixture was stirred at room temperature overnight. After the completion of the reaction (monitored by TEC), the reaction mixture was quenched by the addition of saturated NaHCCb solution (10 mL), the organic layer was washed with water (10 mL), then the organic phase was dried over anhydrous NaiSOr, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with CH2CI2 - MeOH (10:1) to yield 60 mg (20 %) of the title compound. LC-MS (ESI) m/z [M+H] ÷= 446.2
Method E:
2_{4-[(4-Methylphenyl)methyl]piperazin-l-yl}-lV-(naphthalen-2-yl)-2-oxoacetamide
Figure imgf000056_0002
To a suspension of 2-{4-[(4-methylphenyl)methyl]piperazin-l-yl}-2-oxoacetic acid (176 mg, 0.54 mmol) and naphthalen-2-amine (78 mg; 0.54 mmol) in dry DMF (2.5 mL), HATU (260 mg, 0.68 mmol, 1.26 mol equivalents) and DIPEA (190 pL, 2 mol equivalents) were added at room temperature. The mixture was shaken at room temperature overnight. After the completion of the reaction (monitored by TLC), the mixture was diluted with brine, and extracted with EtOAc (3x20 mL). The combined organic phase was washed with brine (3x20 mL), dried over anhydrous NaiSCri, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 40 % EtOAc in cyclohexane. The desired product was crystallized from EtiO as well, to yield 108.0 mg (51 %) of the title compound as a white solid. LC-MS (ESI) m/z [M+H] + = 398.2
Method F :
2-(4-BenzyIpiperazin-l-yl)-/V-(l-methyl-l//-indol-5-yl)-2-oxoacetamide
Figure imgf000057_0001
To a solution of 153 mg (0.7 mmol) of [(l-methyl-li7-indol-5-yl)carbamoyl]formic acid in dry CH2CI2 (15 mL), propylphosphonic anhydride solution, -50 % in DMF (T3P) (445 pL, 0.7 mmol) and DIPEA (250 pL, 2 mol equivalents) was added at room temperature under argon atmosphere. The mixture was stirred for 20 minutes, then l-benzylpiperazine (122 pL, 0.7 mmol) was added. The mixture was stirred at room temperature overnight. After the completion of the reaction (monitored by TLC), the reaction mixture was diluted with CH2CI2 (10 mL), quenched by the addition of saturated NaHCCb solution (10 mL). The organic layer was washed with water (2x10 mL), then the organic phase was dried over anhydrous NaiSOr, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with CH2CI2 - EtOH (98:2) to yield 43 mg (17 %) of the title compound. LC-MS (ESI) m/z [M+H] 377.2 Method G:
Figure imgf000058_0001
To a solution of 141 mg (0.8 mmol) of 3-[(4-methylphenoxy)methyl]azetidine, 174 nig (0.8 mmol) of [(1 -methyl- l//-indol-5-yl)carbamoyl]formic acid and 108 mg (0.8 mmol) of l-hydroxybenzotriazole hydrate (HOBt.HzO) and 154 mg (0.8 mmol) of JV-(3- dimethylaminopropyl)-Af'-ethylcarbodiimide hydrochloride (EDC.HC1) in dry DMF (3 mL), 224 mE (1.6 mmol) of TEA was added at room temperature under argon atmosphere. The mixture was stirred at room temperature for two days. After the completion of the reaction (monitored by TLC), the reaction mixture was diluted with CH2.CI2. and water. After the separation of the layers, the organic phase was washed again twice with CH2CI2, and the combined organic layer was washed with brine, and dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with cyclohexane - EtOAc (7:3) to yield 92 mg of the title compound. LC-MS (ESI) m/z [M+H] ÷ = 378.1.
Method H:
/V-{I-Methyl-l/y-pyrrolo[2,3-Z>]pyridin-5-yl}-2-oxo-2-(]-{[4-(trifluoroinethyl)phenyl] methyl}piperidin-4-yl)acetamide
Figure imgf000058_0002
To a solution of 200 mg (0.63 mmol) of 2-oxo-2-(l -{[4-(trifluoromethyl)phenyl]- methyl}piperidin-4-yl)acetic acid in dry DMF (5 mL), propylphosphonic anhydride solution, ~50 % in DMF (T3P) (370 pL, 0.63 mmol) and DIPEA (452 pL, 4 mol equivalents) was added at room temperature under argon atmosphere. The mixture was stirred for 20 minutes, then l-methyl-I/7-pyrrolo[2,3-Z>]pyridin-5-amine (93 mg, 0.63 mmol) was added. The mixture was stirred at room temperature overnight. Next day, additional 226 pL (0.38 mmol) of TOP solution (~50 % in DMF) was added to the mixture, and stirring was continued for 4 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel, eluting with cyclohexane - acetone (2: 1) to yield 40 mg of the title compound. LC-MS (ESI) m/z
Figure imgf000059_0001
445.2
Examples described in Table 7 were prepared using the corresponding amide coupling methods (method A-H).
Table 7
Figure imgf000059_0002
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Intermediate 62
Figure imgf000063_0001
Zert-Butyl 3-(hydroxymethyl)azetidine-l-carboxylate (2.88 g, 15.4 mmol) and TEA
(4,23 mL, 30.3 mmol) were dissolved in CH2CI2 (130 mL) at room temperature. To the solution, methanesulfonyl chloride (2.0 mL, 30 mmol) was added dropwise, followed by stirring at the same temperature for 2.5 hours, then the solvent was removed under reduced pressure. The residue was dissolved in EtOAc, and the solution was washed with a saturated aqueous solution of NaHCCb and with brine, dried over anhydrous Na2.S04, filtered, and concentrated under reduced pressure, to obtain tert-butyl 3- [(methanesulfonyloxy)methyl]azetidine-l-carboxylate (4.0 g) as a yellow liquid, which was used in the next step without further purification.
A mixture of fert-butyl 3-[(methanesulfonyioxy)methyi]azetidine~l~carboxylat6 (3.8 g, 14 mmol,), wcresol (1.95 g, 18 mmol), CS2CO3 (9.85 g, 30.2 mmol) and DMF (100 mL) was stirred at 1 10 °C overnight. The inorganic solid material was filtered off, the filtrate was concentrated under vacuum. The residue was dissolved in CH2CI2, washed in turn with water, 2 M aqueous NaOH solution and brine. The organic phase was dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: CH2CI2 - MeOH (98:2)) to obtain tert-butyl 3-[(4-methylphenoxy)methyl]azetidine- 1-carboxylate (2.3 g, 58 %) as light yel low oil.
Trifluoroacetic acid (24 mL, 313 mmol) was added to a solution of Z -hutyi 3-[(4- methylphenoxy)methyi]azetidine-l-carboxylate (2.3 g, 8.3 mmol) in CH2CI2 (50 mL) cooled to 0 °C in an ice water bath, and the solution was stirred for 1 hour at this temperature. The solvent was removed under reduced pressure at 40 °C. Ice w¾ter was added to the residue, and the pH of the mixture was adjusted to 9 by the addition of saturated NaHCCb solution. The mixture was extracted with CH2CI2, the combined organic layer was washed with brine, dried over anhydrous NarSO-s and filtered. The solvent was removed under reduced pressure to obtain 3-[(4-methylphenoxy)methyl]azetidine (1.37 g, 7.7 mmol, 93 %).
Intermediates in Table 8 were prepared according to the synthetic description of Intermediate 62.
Table 8
Figure imgf000064_0001
Figure imgf000065_0002
Figure imgf000065_0001
3-[(4-Methylphenyl)methoxy]azetidine
To a solution of fevt-butyl 3-hydroxyazetidine-l-carboxylate (commercially available) (1.0 g, 6 mmol) in DMF (10 mb), NaH (280 mg, 60 percent in oil, 12 mmol) was added with vigorous stirring at 0 °C under argon atmosphere. The solution was stirred for 30 minutes, then 4-methylbenzyl bromide (1.22 g, 6.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with MeOH (2 raL) at 0 °C, then by the addition of saturated NH4Q solution (40 mL). The mixture was extracted with Et?.0 (2x75 mL). The organic layers were combined, washed with water (20 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo , to obtain 1.38 g of terl· butyl 3-[(4- methylphenyl)methoxy]azetidine-T-earboxy!ate as an oil, used in the next step without any purification.
To the solution of fer/-butyl 3-[(4-methylphenyl)methoxy]azetidine-l-carboxylate (1012 nig, 4.03 mmol) in dry CH2CI2 (18 mL), TFA (18 mL, 3 mmol) was added at 0-2 °C under argon atmosphere. The reaction mixture was stirred under this condition for 30 minutes, then at room temperature for 1 hour. After the completion of the reaction (monitored by TLC), the mixture was concentrated in vacuo. The residue was dissolved in CH2CI2 (20 mL), the pH was adjusted to 10 by the addition of 1 N NaOH solution (under cooling). The aqueous phase was extracted with CH2CI2 (3x20 mL), the combined organic phase was dried over anhydrous Na2S04, filtered and concentrated in vacuo, to obtain 660 mg of the title compound, as a yellow oil. The crude product was used in the next step without any purification.
Figure imgf000066_0001
2-[(Azetidin-3-yloxy)methyI]-5-(trifluoromethyl)pyridine
2-[(Azetidin-3-yloxy)methyl]-5-(trifluoromethyl)pyridine was prepared according to to the synthetic description of Intermediate 89
Figure imgf000066_0002
To a solution of tert- butyl 3-aminoazetidine-l-carboxylate (commercially avai lable) (0.5 g, 2.9 mmol) and TEA (1.0 mL, 2.5 mol equivalents) in CH2CI2 (50 mL), y oluoyl chloride (539 mg, 3 48 mmol) was added dropwise with vigorous stirring at 0 °C under argon atmosphere. The reaction mixture was stirred at room temperature overnight. After the completion of the reaction (monitored by TLC), the mixture was washed with water (2x20 mL). The organic layer was dried over anhydrous Na?.S04, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: CH2CI2 - MeOH (98:2)), to obtain tert-hutyl 3-(4-methy]benzamido)az.etidine- ! -carboxylate (0.65 g, 77 %).
To the solution of te/7-butyl 3-(4-methylbenzamido)azetidine- l -carboxylate (650 mg, 2.24 mmol) in diy CH2CI2 (35 mL), TEA (3.4 mL, 44.4 mmol) was added at 0-2 °C under argon atmosphere. The reaction mixture was stirred under this condition for 30 minutes, then at room temperature overnight. After the completion of the reaction (monitored by TLC), the mixture was concentrated in vacuo. The residue was dissolved in CH2CI2 (50 mL), the pH was adjusted to 10 by the addition of 25 % aqueous solution of ammonia (under cooling). After phase separation the aqueous phase rvas extracted with CH2CI2 (3x20 mL), the combined organic phase was dried over anhydrous Na2S04, filtered and concentrated in vacuo to obtain 360 mg of the title compound. The crude product rvas used in the next step without any purification.
Intermediate 92
Figure imgf000067_0001
To a solution of /er/-butyl 3-aminoazetidine-l-carboxylate (0.5 g, 2 9 mmol) in methanol (30 mL), /2-tolualdehyde (0.35 mL, 2.9 mmol) was added with vigorous stirring at room temperature for two hours under argon atmosphere. Then NaBFLCN (360 mg, 5 73 mmol) was added, and the mixture was stirred for 24 hours. After the completion of the reaction (monitored by TLC), cold water was added to the mixture, and the pH was adjusted to 1 by the addition of cc. HC1 (under cooling). Methanol was removed in vacuo , and the aqueous mixture was extracted with EtOAc (20 mL) to remove impurities, then CH2CI2 (20 mL) was added, and the pH was adjusted to 9 by the addition of 25 % aqueous solution of ammonia (under cooling). After phase separation, the aqueous phase was extracted with CH2CI2 (3x20 mL), the combined organic phase was dried over anhydrous Na2.S04, filtered and concentrated in vacuo , to obtain 730 mg of rerr-butyl 3-{ [(4~ methylphenyl)methyl]amino}azetidine- l-carboxylate. It was used in the next step without any purification.
To the solution of tert- butyl 3-{[(4-methylphenyl)methyI]amino}azetidine~l~ carboxylate (0.73 mg, 1.5 mmol) in dry CH2CI2 (20 mL), TFA (2.4 mL, 31.4 mmol) was added at 0- 2 °C under argon atmosphere. The reaction mixture was stirred under this condition for 30 minutes, then at room temperature overnight. After the completion of the reaction (monitored by TLC), the mixture was concentrated in vacuo. The residue was dissolved in CH2CI2 (50 mL), the pH was adjusted to 10 by the addition of 25 % aqueous solution of ammonia (under cooling). After phase separation, the aqueous phase was extracted with CH2.CI2 (3x20 mL), the combined organic phase was dried over anhydrous Na2SCX filtered and concentrated in vacuo, to obtain 250 mg of the title compound. The crude productV-(Azetidin-3-yl)-4-methylbenzamide was used in the next step without any purification.
Intermediates with ethyl linker are presented in Table 9. Table 9
Figure imgf000069_0001
Intermediate 93 is commercially available.
Intermediates 94 and 95 can be synthesized based on the following literature: Palkowitz, M. D. Org. Lett. 19 (2017) pp 2270-2273.
The commercially available aminomethyl -indole derivatives are summarized in Table
10
Table 10
Figure imgf000069_0002
Commercially not available aminomethyl indole and azaindoie derivatives and their syntheses is described below.
Figure imgf000070_0002
A solution of 5 -bromo-l -methyl -1/7-indole (5.0 g, 23.80 mmol) in /V-methyl-2- pyrrolidone (90 rnL) was purged with nitrogen gas for 15 minutes. K3PO4 (10. 1 1 g, 47.60 mmol), tributyl(l -ethoxy vinyl)tin (8.05 mL, 23.82 mmol) and tetrakis(triphenylphosphine)paliadium(0) (1.38 g, 1.19 mmol) were added, and the mixture was stirred at 80-90 °C for 7.5 hours under nitrogen atmosphere. The reaction mixture was diluted with water, and extracted with EtOAc. The organic phase was stirred vigorously with 5 % hydrochloric acid solution at room temperature for 30 minutes. The pH of the mixture was adjusted to 7-8 by the addition of 25 % aqueous ammonia solution, and extracted with EtOAc. The organic phase was washed with water, dried over Na2S04, and evaporated to dryness. The residue was purified by column chromatography on silica gel, using a mixture of EtOAc and cyclohexane (1 :5 to 1 :3) as eluent to give l-(l -methyl- l/f-indol-5-yl)ethanone. Yield: 1 17 g (28 %).
Figure imgf000070_0001
DMF To a mixture of 1 -(l-methyl-1/7-indol-5-yl)ethanone (150 mg, 0.866 mmol) and f.Y)- 2-methyl-propane-2-suifmic acid amide (210 mg, 1.733 mmol) in DMF (2 mL), titanium(IV)isopropoxide (0.60 mL, 2.027 mmol) was added. The reaction mixture was heated at 100 °C / 60 W for 2 hours in a microwave reactor. This reaction was repeated 5 times, and the reaction mixtures were combined and diluted with EtOAc (140 mL), quenched with water (60 mL), and filtered through a plug of celite. The celite was washed with EtOAc, and the combined organic layer was washed with water and brine, and dried over Na2S04. After evaporation, the residue was purified by flash chromatography on silica gel (CH2CI2 - EtOAc 95:5 to 4: 1), obtaining 2-methyl-A-[(l£)-l-(l-methyl-l//-indol-5- yl)ethylidene]propane-2-sulfmamide. Yield: 371 mg (34 %).
Figure imgf000071_0001
To a solution of 2-methyl-iV-[(l£)-l-(l-methyl-l 7-indol-5-yl)ethylidene]propane-2- sulfmamide (38 mg, 0.1375 mmol) in THF (7 mL), Z-Selectride (1M in THE, 0.85 mL, 0.85 mmol) was added under inert atmosphere at room temperature. The reaction mixture was stirred for 1 hour, and then it was evaporated to dryness. The residue wns purified by column chromatography on silica gel, using EtOAc - cyclohexane (1 : 1) as eluent, resulting in 2- methyl-Ar-[(li?)-l-(l -methyl-l -indol-5-yl)ethyl]propane-2-sulfmamide. Yield: 53 mg (38 mg theoretical weight, 100 %) single diastereomer. The material was stored refrigerated until next step. The absolute configuration was not determined, analogous synthetic route was used as described in US 2012/0252853 A1 (SAMS ANETTΈ GRAVEN, LUNDBECK & CO AS
Figure imgf000071_0002
To a solution of 2-methyl-iV-[(1 R)-l-(l-methyl-li7-indol-5-yl)ethyl]propane-2- sulfmamide (38 mg, 0.1365 mmol) in diethyl ether (10 mL), HC1 (2 M in diethyl ether, 0.4 niL, 0.8 mmol) was added. The reaction mixture was stirred at this temperature for 3 hours, and then evaporated to dryness to give the title compound (29 mg theoretical weight) as HC1 salt. The material was used without further purification.
Intermediate 104
Figure imgf000072_0001
l-(2-Chloro-l£f-indol-5-yl)methanamine To a stirred solution of l/f-indoie-S-carbonitrile (7.10 g; 50 mmol, Combi-Blocks) in fe/7-butanol (250 mL), bromine (42.5 g; 13 5 mL, 275 mmol) was added dropwise (20 minutes) at 25 °C, and stirred for 1.5 hours. After completion, the reaction mixture was concentrated under vacuum. This residue rvas diluted with EtOAc (400 mL), and water (75 mL) was added. The organic layer was washed with water (2x100 mL), brine (100 mL), dried over anhydrous NaiSCfi, filtered and concentrated under reduced pressure. The crude residue was stirred with diisopropyl ether (100 mL) for 30 minutes. The precipitated crystals w^ere filtered off, washed with diisopropyl ether, and dried to yield 12.89 g (81 %) of 3,3-dibromo- 2-oxo-2,3-dihydro-li/-indole-5-carbonitrile as a reddish brown solid. To a suspension of 3, 3-dibromo-2-oxo-2, 3-dihydro- li7-indole-5-carbonitrile (12.89 g; 40.8 mmol) in AcOH (270 mL), Zn powder (16.3 g; 250 mmol) was added portionwise (ca. 2 g each ). The temperature of the mixture was not allowed to increase above 35 °C, and stirred for 2 hours at 30 °C. After completion, the reaction mixture was concentrated under vacuum. This residue was suspended in EtOAc (300 mL), filtered off, the solid was stirred with EtOAc (150 mL) again, then filtered off. The combined organic layer was concentrated in vacuo. The residue was stirred with 1 N HC1 solution (100 mL) for l hour, filtered off, washed with water (2x5 mL), and dried to yield 3.86 g (60 %) of 2-oxo-2,3 -dihydro- 177- indol e- 5 -carb onitril e .
To a stirred suspension of 2-oxo-2, 3-dihydro- l//-indole-5-carbonitrile (5.8 g; 36.9 mmol) in DCE (23 mL), POCI3 (11.5 g, 6.95 mL; 74.79 mmol) was added at 0 °C. The reaction mixture was refluxed for 30 minutes at 90 °C. After cooling the reaction, imidazole (2.75 g, 44.55 mmol) was added, and further heated at 90 °C for 2 hours. After completion, the reaction mixture was concentrated, and the residue was dissloved in EtOAc (110 mL), and washed with saturated NaHCQi solution (30 mL), brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The product was purified by column chromatography on silica gel, eluting with THF - w-hexane (9: 1) to yield 4 58 g (70 %) of 2- ehloro-l /7-indole-o-carbonitri!e, as a yellow solid.
To a stirred solution of 2-chioro-l//-indoie~5-carbonitrile (4.48 g, 25.3 mmol) in dry THF (23 mL), EίA1H4 (1 M in THF; 45 mL; 45 mol) was added at 0 °C under nitrogen atmosphere. The reaction mixture was refluxed at 65 °C for 2 hours. TLC showed formation of the product. The reaction mixture was quenched with EtOAc (20 mL) at 0 °C, and saturated aqueous Na2S04 solution (15 mL) was added dropwise. The reaction mixure was filtered through a pad of celite, and thoroughly washed with EtOAc (100 mL). The filtrate w?as washed with brine (50 mL), dried over anhydrous NaiSOr, filtered and concentrated in vacuo. The crude product was purified by crystallization from EtOAc (50 mL) to obtain 3.9 g (85 %) of the title compound as an off white solid. Intermediate 105
Figure imgf000074_0001
(2-ChIoro-l-methyl-l T-indol-5-yl)methanamine
(2-Chloro-l -m ethyl- li7-indol-5-yl)methanamine was prepared according to the synthetic description of its non-methylated derivative, Intermediate 104.
Intermediate 106
Figure imgf000074_0002
(3-ChIoro-l-methyl-l T-indol-5-yl)methanamine
To a stirred solution of (1 -methyl- li/-indol-5-yl)methanamine (640 mg; 3.995 mmol) and DIPEA (1 03 g; 1.39 raL, 7.98 mmol) in CH2CI2 (40 niL), a solution of di-/er/-butyl dicarbonate (B0C2O) (1.74 g; 7.97 mmol) in CH2CI2 (10 mL) was added at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2CI2 (20 mL), and washed with w¾ter (50 mL). The organic phase was washed with brine (50 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to give 786 mg (76 %) of ten- b uty 1 N-[( l -methy 1 - 1 H -in d o! - 5 -y 1 )m ethyl ] earb am ate .
To a stirred solution of tert- butyl r-[(!-methy!~i/:/-indol-5~y!)methyi]carbamate (160 mg; 0.615 mmol) in CH2.CI2. (4 mL), A-ehlorosuccinimide (82 mg; 0.61 mmol) was added at 0 °C under argon atmosphere. The reaction mixture was stirred at room temperature for 3.5 hours. The reaction mixture was diluted with CH2CI2 (20 mL), and washed with water (20 mL). The organic phase was washed with brine (15 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to give 145 mg (80 %) of tert- butyl 7V-[(3-chloro-l-methyl-l /7-indol-5-yl)methyl]carbamate.
To the solution of tert-hxiXy\ A/-[(3-chloro-l -methyl-l//-indol-5-yl)methyl]carbamate (72 mg, 0.244 mmol) in dry CH2CI2 (3 mL), TFA (300 mg; 0.2 mL, 3 mmol) was added at 0-2 °C under argon atmosphere. The reaction mixture was stirred at room temperature for 3 hours. After the completion of the reaction (monitored by TLC), the mixture was concentrated in vacuo. The residue was dissolved in CH2CI2 (20 mL), the pH was adjusted to 10 by the addition of 1 N NaOH solution (under cooling), the aqueous phase ¾s extracted with CH2CI2 (3x15 mL), the organic phase was dried over anhydrous NaiSCfi, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica, eluted by 10 % MeOH in CH2CI2, to obtain 49 mg of the title compound as a yellow' solid.
Figure imgf000075_0001
To a solution of lif-indole-S-carbonitrile (2.10 g, 14.8 mmol) in CH2G2 (60 mL), N- chlorosuccinimide (2 01 g, 15.05 mmol) was added portion-wise at 0 °C, and the mixture was stirred at room temperature overnight. The formed precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, with a 1 to 4 mixture of EtOAc and cyclohexane to obtain 3- chloro-!//-indol-5-carbonitrile (0.77 g, 30 %).
To a suspension of 3-chloro-i//~indol~5~carbonitrile (176 mg, 1 mmol) in diethyl ether (3 mL), 4 mL of 1 M BH3 solution in THF was added dropwise at 0 °C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by dropwise addition of methanol (5 mL) at 0 °C, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, with an eluent stepwise changed from CH2CI2 via a mixture of CH2CI2 --- methanol (9: 1) to a mixture of CH2CI2 - methanol - 25 % aqueous ammonia (89: 10: 1). Yield: 120 mg (67 %), yellowish oil. ίiM ΐ B ^ΐϋ
Figure imgf000076_0001
To a solution of l T-indole-5-carbonitrile (2.09 g, 14 7 mniol) in DMF (16 rnL), NaH (840 mg, 60 percent in oil, 21 mmol) was added with vigorous stirring at 0 °C under argon atmosphere. The solution was stirred for 30 minutes, then iodomethane (9 12 g, 4 rnL, 63 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched with water (50 rnL) and extracted with EtOAc (3x120 rnL). The organic layers were combined, washed with water (2x50 mL), dried over anhydrous NaiSCL, filtered and concentrated in vacuo , and dry toluene was evaporated from the residue to obtain 2.3 g of l-methyl-l -indole-5-carbonitrile as an off white solid used in the next step without any purification.
To the solution of 1 -methyl- li/-indole-5~carbonitrile (1.38 g, 8.83 mmol) in acetonitrile (40 mL), PCC (pyridinium chlorochromate, 7.6 g, 35.2 mmol) was added, and the mixture was refluxed for 7 hours. After the completion of the reaction (monitored by TLC), the reaction mixture was concentrated in vacuo , the residue was partitioned between H?0 and EtOAc. The insoluble part was filtered off, the organic layer was washed with brine, dried over anhydrous NaiSC , and the solvent was evaporated to dryness. The crude residue was purified by flash chromatography on silica, eluted by CH2CI2 to obtain 760 mg of 1 -methyl -
2.3-dioxo-2,3-dihydro-l f/-indole-5-carbonitrile, as an orange solid.
To the solution of bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor, 50 % in toluene, 5 mL, 10 mmol) 1 -methyl-2, 3-dioxo-2, 3 -dihydro- l/f-mdole-S-carbonitrile (502 mg, 2.7 mmol) was added under argon atmosphere, then 0.025 mL absolute EtOH was added, and the mixture was heated at 90 °C for 1 hour.
The reaction was quenched by MeOH (1 mL), and diluted with CH2CI2 (100 mL), then the mixture was poured onto cold saturated Na2SQ4 solution, and the product was extracted with CH2CI2. The extract was washed with brine, dried over anhydrous NaiSOr, and the solvent was evaporated to dryness. The crude residue was purified by flash chromatography- on silica, eluted by a gradient of 0-20 % EtO Ac/hexane to give 3,3-difluoro-l-methyl-2-oxo-
2.3-dihydro- li/-indole-5-carbonitrile as yellow solid (322 mg).
To the solution of 3, 3-difluoro-l -methyl -2-oxo-2, 3-dihydro- li7-indole-5-carbonitrile (510 mg, 2.45 mmol) in dry THF (10 mL), BH3.TFIF (1 M in THF) (7.5 mL, 7.5 mmol) was added at 0-2 °C under argon atmosphere. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (monitored by TLC), MeOH (10 mL) was added under cooling, and the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL), washed with saturated NaHCC solution (25 mL), then with brine (25 mL), dried over anhydrous NaiSOr, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica, eluted by 10 % MeOH in CH2CI2 to obtain 70 mg of the title compound as light yellow solid.
Intermediate 109
Figure imgf000077_0001
(3-Fluoro-l/ -indol-5-yl)methanamine was prepared according to the synthetic description of its JV-methylated derivative, Intermediate 108.
Figure imgf000078_0001
5 -(Aminomethyl)-I -methyl- l//-indole-3-carbonitrile was prepared according to synthetic scheme below:
Figure imgf000078_0002
To a solution of (1 -methyl- l /-indol-5-yl)methanamine (1.642 g, 10.2 mmol) and DIPEA (2.52 mL, 14.5 mmol) in CH2CI2 (100 niL), a solution of di-ter/-butyl dicarbonate (4 26 g, 19.5 mmol) in CH2CI2 (24 mL) was added dropwise at 0 °C under argon atmosphere. The mixture was stirred at room temperature overnight, quenched with water (100 mL), and extracted with CH2.CI2. The organic layer was washed with water, dried over Na2.SQ4, filtered and evaporated to dryness in vacuo. The residue was recrystallized from hexane to obtain tert- butyi [(l-methyl-l//-indol-5-yl)methyi]carbamate (1.58 g, 60 %), as white crystals.
Phosphoryi chloride (0.31 mL, 4 mmol) was added dropwise to DMF (1.5 mL, 19 mmol) at -5 °C (acetone - dry ice bath), and the mixture was stirred at 0 °C (ice - water bath) for 1.5 hours under argon atmosphere. The Vilsmeyer reagent, obtained in this way was added dropwise to a solution of tert- butyl [(1 -methyl- ii/-indol-5-yl)methyl]carbamate (780 mg, 3 mmol) in THF (5 mL) via a syringe at -7 °C under argon atmosphere, and the mixture was stirred at 0 °C for another hour. EtOAc (10 mL), then 3 M sodium acetate solution (4.5 mL) was added dropwise, and the mixture was stirred further at room temperature for 2 5 hours. Water (30mL) was added, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried and evaporated to dryness in vacuo. The residue was triturated with diethyl ether, filtered and dried to yield tert- butyl [(3 -formyl- 1 -methyl- li/- indol-5-yl)methyl]carbamate (568 mg, 66 %), as a pink solid.
A solution of tert- butyl [(3-formyl-l-methyl-l /-indol-5-yl)methyl]carbamate (288 mg 1 mmol), hydroxyJamine hydrochloride (83 mg, 1.2 mmol) and pyridine (0.1 mL, 1.25 mmol) in A.A-dimethylformamide (3 mL) was stirred at 60 °C for 45 minutes under argon atmosphere. The reaction mixture was cooled to room temperature, then cooled to 0 °C, and carbonyl diimidazole (811 mg, 5 mmol) was added portio vise. The mixture was stirred at 60 °C for 30 minutes under argon atmosphere, then TEA (0.28 mL, 2 mmol) was added, and the mixture was stirred further for 30 minutes. The reaction mixture was cooled to 0 °C, quenched by cautious addition of water, and extracted with EtOAc, dried over Na2S04, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel, with CH2CI2 as the eluent to yield le l- butyl [(3-cyano-l-methyl-l /-indol-5- yl)m ethyl] carbamate (141 mg, 50 %), as white crystals.
To a solution of tert-b\iXy\ [(3-cyano-l-methyl-lf/-indol-5-yl)methyl]carbamate (133 mg, 0.47 mmol) in CH2G2 (4 mL), TFA (0.46 mL, 6 mmol) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was evaporated to dryness under reduced pressure, water was added, and the pH of the mixture was adjusted to 10 by the addition of 2 M NaOH solution (0.6 mL) at 0 °C. The mixture was extracted with CH2CJ2, dried over NaiSCX filtered and evaporated in vacuo to yield the title compound (82 mg, 95 %), as white crystals. Intermediate 111
Figure imgf000080_0001
{l-metini-]Lfii-pyrro!o|2,3-6]pyridm-5-yI}met!iaeamme
Compound 5-bromo-li7-pyrrolo[2,3-/>]pyiidine is commercially available from Combi Blocks (catalog no : IN-0206), and the desired azaindole-amine is prepared in a sequence of steps illustrated above.
Step 1 : l//~Pyrroloj2 3~ /|pyridine~5~carbonitrile
The intermediate is prepared as described in EP 178281 1 Al (EISAI R&D MAN CO LTD).
Step 2: 1 -Methyl- l//-pyrrolor2.3-&lpyridine-5-carbonitrile
The intermediate is prepared as described in WO 2009/155017 A2 (MERCK & CO
Step 3 : { l-Methyl-l/7-pyrrolo[2J- ?lpyridin-5-vi}methanamine
The intermediate is prepared as described in WO 2012/042915 A1 (RAQUALIA PHARMA INC). Intermediate 112
Figure imgf000081_0001
{l,2-Dimethyl-li/-pyrrolo[2,3-7>]pyriclin-5-yl}methanainine
To a solution of 2-amino-5-cyanopyridine (500 mg, 4 2 mmol) in DMF (5 tnL), TFA (574 mg, 386 pL, 1.2 mol equivalents) was added. At room temperature A-iodosuccinimide (1.04 g, 4.62 mmol, 1.1 mol equivalents) was added, and the reaction mixture was heated at 50 °C for 3 hours. Complete conversion was indicated by TLC. After cooling the reaction mixture to room temperature, the product was precipitated by adding the reaction mixture to water. After neutralization with Na2S2C>3 and 1 N NaOH, 6-amino-5-iodopyridine-3- carbonitrile (660 mg) was collected by filtration as a brown solid. It was used in the next step without any purification.
To the degassed mixture of 6-amino-5-iodopyridine-3-carbonitrile (329 mg, 1 34 mmol), bis(triphenylphosphine)dichloropalladium(0) (95 mg, 0.134 mmol), Cul (128 mg, 0.671 mmol) and TEA (976 mg, 1.34 mL, 9.64 mmol) in absolute THF (18 mL), a propyne solution (3-4 % in THF; 13.2 mL) was added via septum at 0-5 °C. The mixture was stirred for 30 minutes at 0-5 °C, then for further 18 hours at room temperature. The reaction was quenched by the addition of NH4C1 solution. The solid was removed by filtration, and the cake was washed with CH2.CI2. The combined organic layer was dried over anhydrous Na2S()4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica, eluted by 40 % EtOAc in cyclohexane to obtain 150 mg of 6- amino-5-(prop-l-yn-l-yl)pyridine-3-carbonitrile as a yellow solid (71 %).
To a solution of 6-amino-5-(prop-l-yn-l-yl)pyridine-3-carbonitrile (300 mg, 1.91 mmol) in DMF (5 mL), KO/Bu (428 nig, 3 82 mmol, 2 mol equivalents) was added. The reaction mixture was heated at 90 °C for 5.5 hours. Complete conversion was indicated by TLC. After cooling to room temperature, the reaction mixture was poured onto water, and extracted with CH2CI2. The combined organic layer was dried over anhydrous Na?.S04, filtered and concentrated in vacuo to obtain 2-methyl-l -pyrrolo[2,3-0]pyridine-5- carbonitrile 279 mg (93 %), as a yellow solid. It was used in the next step without any purification.
To the solution of 2-methyl-I/ -pyrrolo[2,3-6]pyridine-5-carbonitrile (279 mg, 1.78 mmol) in DMF (7.5 mL), NaH (60 % in mineral oil) (92 mg, 2.31 mmol, 1 .3 mol equivalents) was added at 0 °C. The reaction mixture was stirred at this temperature for 30 minutes, then iodomethane (380 mg, 167 pL) in DMF (1.5 mL) was added dropwise. The mixture was stirred at room temperature overnight. Complete conversion was indicated by TLC. The mixture was poured onto water and extracted with CH2CI2 (3x20 mL). The combined organic layer was dried over anhydrous Na2S(>4, filtered and concentrated in vacuo to obtain l,2-dimethyl-li7-pyrrolo[2,3-Z>]pyridine-5-carbonitrile (298 mg, 98 %), as a yellow solid. It was used in the next step without any purification.
To a solution of l,2-dimethyl-l//-pyrrolo[2,3-Z>]pyridine-5-carbonitrile (297 mg, 1.73 mmol) in a mixture of MeOH (100 mL) and 25 % ammonia solution in water (25 mL) Raney -Ni (200 mg) was added, and the mixture was stirred at 1 atm of H2 at room temperature for 16 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure to obtain the title compound 226 mg (74 %), as a yellow solid. Intermediate 113
Figure imgf000083_0001
{2-methyl- lff-pyrrolo[2,3-2>]pyridin-5-yI}methanamine
To solution of 5-bromopyridin-2-amine (3.0 g, 17.34 mmol) in aqueous 2 M H2.SQ4 (30 mL), KIO3 (1 .85, 8.64 mmol) was added portionwise. 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 hours. After stirring the solution for an additional 30 minutes at this temperature, it was cooled, the pH of the mixture was adjusted to 8 by the addition of 6 M aqueous NaOH solution and extracted with EtOAc (3x). The organic phase was washed with 5 % Na2S203 solution, water and brine, dried over Na2.S04, and evaporated to dryness. The residue was chromatographed (silica gel, cyclohexane/ EtOAc, 67/33) to give 2.61 g (50.4 %) of 5-bromo-3~iodopyridin-2- amine as a yellow solid.
Under nitrogen atmosphere in a pressure flask 5-bromo-3-iodopyridin-2-amine (500 mg, 1.67 mmol) was dissolved in THF (27 mL). To the mixture Cul (159 mg, 0.836 mmol), bis(triphenylphosphine)palla.dium(II) dichloride (1 17 mg, 0.167 mmol), propyne (ca 3-4 % in heptane, 16.4 mL, 8.36 mmol) and TEA (1.67 mL, 12 mmol) was added. The flask was closed and the mixture was stirred overnight. The mixture was treated with saturated NH4CI, filtered through celite, extracted with CH2CI2 (2x). The combined organic layers were dried over Na2S04, and evaporated to dryness. The residue was chromatographed (silica gel, cyclohexane - EtOAc, (70:30)) to give 323 mg (92 %) of 5-bromo-3-(prop-l-yn-l-yl)pyridin- 2-amine as a yellow solid.
To a solution of 5-bromo-3-(prop-l-yn-l-yl)pyridin-2-amine (645 mg, 3.06 mmol) in DMF (27 mL), KO/Bu (686 mg, 6.11 mmol) was added, and the mixture was heated at 90 °C for 3 hours. After cooling, the reaction mixture was diluted with water and ice, the product was extracted with CH2CI2 (3x). The combined organic layers were dried over Xa.’SOi, and evaporated to dryness. The residue rvas chromatographed (silica gel, CH2CI2 - methanol - NH4OH (25 % aqueous), (99: 1 :0.1)) to give 504 mg (78 %) of 5-bromo-2-methyl-17/- pyrrolo[2,3-/>] pyridine. Under an inert atmosphere, 5-bromo-2-methyl-l//-pyrrolo[2,3-£]pyridine (450 mg,
2.13 mmol), Zn(CN)2 (376 mg, 3.2 mmol) and tetrakis(triphenyiphosphine)palladium(0) (246 mg, 0 213 mmol) were dissolved in l-methylpyrrolidin-2-one (18 mL), and heated at 150 °C overnight. After cooling, the reaction mixture was diluted with water, and the product was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over Xa’SOi and evaporated to dryness. The residue was chromatographed (silica gel, cyclohexane - EtOAc, (6:4)) to give 159 mg (47 %) of 2-methyl4/:/-pyrrolo[2,3~/>]pyridine~5~earbonitrile
To a solution of 2-methyl-l -pyrrolo[2,3-6]pyridine-5-carbonitrile (88 mg, 0.56 mmol) in a mixture of methanol (32 mL) and 25 % aqueous NILOH solution (8 mL), Raney -Ni (50 % slurry in water, 0.20 mL) was added, and hydrogenated using a hydrogen balloon at room temperature overnight. The reaction was filtered through a pad of celite, and concentrated. The crude product was dissolved in methanol and NELOH solution, filtered through silica gel (2 g) and evaporated to give 86 mg (96 %) of the title compound, as a yellow oil.
Figure imgf000084_0001
Figure imgf000085_0001
{l,3~dimethyI-lii pyrrolo[2,3~6]pyridiii~5-yI}metha!iamme
5-Bromo-li/-pyrrolo[2,3-6]pyridine (1 g, 5.075 mmol) was dissolved in DMF (8 mL) and cooled to 0 °C. Then NaH (300 mg, 7.51 mmol, 60 % dispersion in mineral oil) was added, and the mixture was stirred for 20 minutes at room temperature. After cooling the mixture to 0 °C, benzenesulfonyl chloride (0.78 mL, 6.09 mmol) was added dropwise, and allowed to warm to room temperature. After 2 hours reaction time, the mixture was treated with saturated NH4CI, extracted with CH2CI2 (2x). The combined organic layers were washed with water (2x) and brine, dried over NazSCL, and evaporated to dryness to give 1.71 g (100 %) of i-(benzenesulfonyl)-5-bromo-i//-pyrrolo[2,3-6]pyridine.
Under an inert atmosphere i-(benzenesulfonyl)-5-bromo-i//-pyrrolo[2,3-6]pyridine (816 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 1 10 °C for 9 hours. After cooling, the reaction mixture was diluted with water, the product was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na^SOr, and evaporated to dryness. The residue was chromatographed (silica gel, cyclohexane - EtOAc, (7:3)) to give 529 mg (77 %) of l-(benzenesuifonyl)-l//-pyrrolo[2,3-6]pyridine-5-carbonitrile.
To a cooled solution of 1 -(benzenesulfonyl)- l//-pyrrolo[2,3-Z>]pyridine-5-carbonitrile (528 mg, 1.86 mmol) in DMF (8 mL) bromine (191 pL, 3.73 mmol) was added slowly at 0 °C. Then the suspension was 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 NaOH solution, and extracted with CH2CI2. The organic phase was washed with saturated NaHCOr solution, 5 % NarSiCh solution and brine, dried over NaiSCX and evaporated to dryness to give 447 mg (66 %) of l-(benzenesulfonyl)-3-bromo-l//-pyrrolo[2,3-6]pyridine-5 Carbonitrile.
Under an inert atmosphere l-(benzenesulfonyl)-3-bromo-l/7-pyrrolo[2,3~ >]pyridine- 5-carhonitrile (447 mg, 1.23 mmol) was dissolved in THF (25 rnL), tetrakis(triphenylphosphine)palladium(0) (428 mg, 0.37 mmol) was added, followed by dropwise addition of trimethylalurninium solution (2.0 M in toluene, 2.47 rnL, 4.94 mmol), and then the mixture was heated to reflux for 7 hours. After repeated addition of tetrakis(triphenylphosphine)pailadium(0) (143 mg, 0.123 mmol) and trimethylalurninium solution (2.0 M in toluene, 1.23 mL, 2.47 mmol), the mixture was heated to reflux for another 4 hours. After cooling, the reaction was quenched with slow addition of saturated NaHCOs solution, the product was extracted with EtOAc (3x). The combined organic layers w'ere washed with brine, dried over NarSCri, and evaporated to dryness. The residue was chromatographed (silica gel, cyclohexane - EtOAc (8;2)) to give 158 mg (43 %) of 1- (benzenesuifonyl)-3-methyl-li7-pyrroio[2,3-5]pyridine-5-carbonitrile. To a solution of l-(benzenesulfonyl)-3-methyl-li7-pyrrolo[2,3-5]pyridine-5- earbonitrile (247 mg, 0.83 mmol) in methanol (17 mL), 6 M aqueous NaOH solution (1.73 mL, 10.4 mmol) was added, and the mixture was heated to reflux for 2 hours. The mixture was cooled and the solvent was evaporated. The pH of the residue was adjusted to 7 by addition oUwater and 10 % citric acid solution. After stirring for 30 minutes, the solid was filtered off and washed with water. The crude product was dried in a vacuum oven at 50 °C, and chromatographed (silica gel, cyclohexane --- EtOAc (8:2)) to give 94 mg (72 %) of 3- methyi-l//-pyrroio[2,3~6]pyridine-5-carbonitriie.
3-Methyl-li7-pyrrolo[2,3-5]pyridine-5-carbonitrile (93 mg, 0.59 mmol) was dissolved in DMF (2.5 mL) and cooled to 0 °C. Then NaH (31 mg, 0.77 mmol, 60 % dispersion in mineral oil) was added, and the mixture was stirred for 30 minutes at this temperature. Methyl iodide (56 pL, 0.9 mmol) in DMF (0.5 rnL) was added dropwise, then allowed to warm to room temperature and stirred overnight. Water was added slowly to the mixture, and extracted with CH Cb (3x). The combined organic layers were dried over Na2S04, and evaporated to dryness to give 100 mg (99 %) of l ,3-dimetby!~li7-pyrrolo[2,3~ 6]pyridine-5-carbonitriie. To a solution of l,3-dimethyl-l/i-pyrrolo[2,3-¾]pyridine-5-carbonitrile (100 mg, 0.584 mmol) in methanol (34 mL) and 25 % aqueous ammonium hydroxide solution (8.5 niL), Raney-Ni (0.21 mL, 50 % slurry in water) was added, and hydrogenated using a hydrogen balloon at room temperature for 4 hours. The reaction was filtered through a pad of celite and concentrated. 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.
Figure imgf000087_0001
{3~chloro~li/~pyrroIo [2,3-6] pyridin-5-yl}methanamine
Figure imgf000087_0002
{3-chloro-Lfir-pyrrolo[2,3-6]pyridin-5-yl}methanamine was prepared as described in WO 2016/083816 A1 (SMITH AL!JN JOHN).
Figure imgf000087_0003
{3-chloro-l-methyl-lfl-pyrroIo 2,3-6]pyridin-5-yl}methanamine Step 1 : lff-Pyrrolo[2.3-£]pyridine-5-carbonitrile
The intermediate was prepared as described in EP 1782811 Al (EISAI R&D MAN CO LTD)
Step 2: 1 -Methyl- pynOioi2 3- >lpyridine-5-carbonitiile
Figure imgf000088_0001
The intermediate was prepared as described in WO 2009/155017 A2 (MERCK & CO INC)
Step 3 : 3-Chloro-l-methvLl//-pyrrolo[2,3-¾lpYridine-5-carbomtrile
To a solution of l-methyl-lif-pyrrolo[2,3-5]pyridme-5-carbomtrile (600 mg, 3.69 mmol) in DMF (14 mL), A-chiorosuccininiide (502 mg, 3.76 mmol) was added with vigorous stirring at room temperature under argon atmosphere. The solution was stirred at room temperature overnight. After completion of the reaction (monitored by TLC), the mixture was concentrated in vacuo (dry toluene was evaporated from the residue several times). The residue was dissolved in a mixture of diethyl ether - EtOAc (1 : 1, 40 mL), and washed with water (3x15 mL). The organic layer was dried over anhydrous NaiSO·*, filtered and concentrated in vacuo , to obtain 670 mg of 3-chioro-l-methyi-li7-pyrroio[2,3-Z>]pyridine-5- carbonitrile, used in the next step without any purification.
Step 4: (3-Chloro-l-methyl- pyrrolor2.3- >1pyridin-5-yl }methanamine
Figure imgf000088_0002
The intermediate was prepared as described in WO 2012/042915 Al (RAQUALLA PHARMA INC).
Intermediate 117
Figure imgf000088_0003
{3-Bromo-l-methyl-l//-pyrrolo[2,3-^]pyridin-5-yl}methanamine
Steps 1-2:
The intermediates were prepared in a sequence of steps as illustrated for {3-chloro-l- methyl-l /7-pyrrolo[2,3-6]pyridin-5-yl }methanamine, by the same methods as described in EP1782811 A1 (EISAI R&D MAN CO LTD) and W02009/155017 A2 (MERCK & CO INC).
Step 3 :
To a solution of 1 -methyl-1 //-pyrrolo[2,3-/;>]pyridine-5~carbomtrile (358 mg, 2 28 mmol) in CH2CI2 (6.5 mL), iV-bromosuccinimide (446 mg, 2.51 mmol) was added with vigorous stirring at room temperature under argon atmosphere. The solution was stirred at room temperature overnight. After completion of the reaction (monitored by TEC), the mixture was diluted with CH2CI2 (25 mL) and washed with water (3x20 mL) The organic layer was dried over anhydrous Na2S04, filtered and concentrated in vacuo , to give 670 mg of 3-bromo-l-methyl-l//~pyrrolo[2,3-6]pyridine-5-carbonitrile used in the next step without any purification.
Step 4: {3-Bromo-t -methyl- l//~Dyrrolo[2 3-&1pyridin-5~vHmethanamine
The intermediate is prepared as described in WO 2012/042915 Al (RAQUALIA PHARMA INC).
Example 38
Figure imgf000089_0001
I nterm ed iate 96 Interm ediate 64 Exam ple 38
jV-{(l-methy!-liJ-indol-5-y!)methyi|-3-{[4-(trifluoromethy!)phenoxy]methy!}azetidine- l~earboxamkle
To a solution of (2-methyl-l//-indol-5-yl)methanamine (96 mg, 0.6 mmol) in CH2CI2 (6 mL), DIPEA (155 mg, 208 pL, 1.2 mmol) and 4-nitrophenyJ chloroformate (121 mg, 0.6 mmol) in CH2CI2 (3 mL) was added at 0 °C under argon atmosphere. The mixture was stirred for 1.5 hours under this condition. After the activation period 3-{[4- (trifluoromethyl)phenoxy]methyl}azetidine (138 mg, 0.6 mmol, Intermediate 66) in CH2CI2 (3 mL) was added dropwise, and the mixture was allowed to warm to room temperature, and stirred at this temperature overnight. After the completion of the reaction (monitored by TLC), the mixture was concentrated in vacuo. The crude product was chromatographed on silica gel, eluting with a mixture of cyclohexane and EtOAc, and the resulted product was further purified on preparative TLC to yield 64 mg (26 %) of the title compound. LC-MS (ESI) m/z I \ I 1 1 j = 418.3
Examples in Table 1 1 were prepared according to the method described above for Example 38.
Table 1 1
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0002
"The racemic mixture was separated on the chiral preparative chromatography and only- one enantiomer proved to be active (Example 63), however, its absolute configuration was not determined.
Examples synthesized via different synthetic routes:
Example 134
Figure imgf000099_0001
'fY-[(2-cya8io-li7- dof~5-yI)methyS]-3~{[4-(trifli8oromethyI)phe oxy]methyI}azet Iine-l~
A solution of hydroxymethyl- 1/7-indole (2.73 g, 18.55 mmol), 3,4-dihydro-2//-pyran (2.6 rnL, 28.5 mmol) and pyridinium / toluenesulfonate (470 mg, 1.87 mmol) in CH2CI2 was stirred at room temperature for 3 hours. Another portion of 3,4-dihydro-2i7-pyran (0.8 mL, 8.8 mmol) was added, and the mixture was stirred further for 2 hours. Water was added, and the pH of the mixture was adjusted to 8 by the addition of saturated NaHCCb solution. The mixture was extracted with CH2CI2, the combined organic layer was dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluent: CH2.CI2 - EtOAc (98:2)) to give 5-[(tetrahydro-2/7-pyran-2-yloxy)methyl]- l/7-indole
(2.47 g, 58 %), as light yellow oil.
To a solution of 5-[(tetrahydro-2/7-pyran-2-yloxy)methyl]-l /7-indole (1 00 g, 4.3 mmol), TEA (0.60 mL, 4.3 mmol) and 4-(dimethylamino)pyridine (51 mg, 0.4 mmol) in CH2CI2 (65 mL), di-fe/7-butyl dicarbonate (1.12 g, 51.3 mmol) was added under an inert atmosphere, and the mixture was stirred at room temperature for 3 hours. Dichloromethane was added, and the mixture was extracted with brine, dried over Na2S04, filtered and evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution: cyclohexane to cyclohexane - EtOAc = 95:5), to obtain tert- butyl 5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-l /7-indole-l-carboxylate (1.08 g, 75 %), as light yellow oil. tert- Butyl lithium (1.7 M solution in pentane, 0.88 mL, 1.5 mmol) was added dropwise to a solution of tert- butyl 5-[(tetrahydro-2/7-pyran-2-yloxy)methyl]-l /7-indole-l-carboxylate (331 mg, 1 mmol) in tetrahydrofurane (20 mL) between -78 °C and -65 °C under argon atmosphere. The mixture was stirred at -70 °C for 20 minutes, then a solution of phenyl cyanate (20 % m/m, 0.75 mL, 1.6 mmol) in CH2CI2 w?as added dropwise. It was stirred at
-70 °C for 30 minutes, allowed to reach room temperature and stirred further for 4 hours. The mixture was quenched by the addition of a saturated aqueous solution of NH4C1 (20 mL). The resulting mixture was extracted with EtOAc, the combined organic extracts were washed with brine, dried over Na2S()4, filtered and evaporated under reduced pressure to give a yellow' oil . This crude material was purified via flash column chromatography on silica gel (0 % to 3 % of EtOAc in CH2CI2), to give fert-butyf 2-cyano-5-[(tetrahydro-2//-pyran-2-yloxy)methyl]- lif-indole-l-carboxylate (133 mg, 47 %), as a white amorphous substance.
A solution of ter -butyl 2-cyano-5-[(tetrahydro-2 -pyran-2-yloxy)methyl]-li - indole-l-carboxylate (130 mg, 0 36 mmol) and pyridinium 7-toluenesulfonate (18 mg, 0 07 mmol) in ethanol (5 mL) was heated under reflux for 2 hours. After cooling to room temperature, the mixture was evaporated to dryness, brine was added, and it was extracted with EtOAc. The combined organic layer was dried over Na2S04, filtered and evaporated under reduced pressure to give /ert-butyl 2-cyano-5~(hydroxymethyl)-l//-indole~l- carboxyiate as a white solid (104 mg). The product was used in the next step without further purification.
To a solution of fe/7-buty! 2-cyano-5-(hydroxymethyl)-li/-indole-l-carboxylate (100 mg, 0.36) and diphenylphosphoryl azide (0 12 mL, 0.56 mmol) in tetrahydrofuran (5 mL), l,8-diazabicyclo(5.4.0)undec-7-ene (0.084 mL, 0.56 mmol) was added at 0 °C, then the mixture was heated under reflux for 3 hours. Another portion of diphenylphosphoryl azide (0.06 mL, 0.28 mmol) and !,8-diazabieyelo(5.4.0)undec-7-ene (0.042 mL, 0.28 mmol) were added at room temperature, and the mixture was stirred at reflux temperature for another hour. The solvent was evaporated in vacuo , and the residue was taken up in CH2CI2, extracted with a saturated solution of NaHCCh and brine, dried over NarSGy filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography (0 % to 50 % of CH2CI2 in cyclohexane) to give tert- butyl 5-(azidomethyl)-2~cyano-l/7-indole-l-carboxylate (57 mg, 51 %), as yellowish solid.
A solution of /er/-butyl 5-(azidomethyl)-2-cyano-l/7-indole-l-carboxylate (55 mg, 0.18 mmol) and triphenylphosphine (145 mg, 0.55 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature for 5.5 hours under argon atmosphere. Water (0.5 mL, 28 mmol) was added, and the mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was adsorbed onto silica gel, and was purified by flash column chromatography (0 % to 10 % of MeOH in CH2CI2) to give rerf-butyl 5-(aminomethyl)-2-cyano-li/-indole-l- carboxylate (33 mg, 66 %), as white crystals. To the mixture of of tert- butyl 5-(aminomethyl)-2-cyano-l/f-indole-l-carboxylate (122 mg, 0.45 mmol) and DIPEA (0.16 mL, 0.92 mmol) in DMF (4 mL), 4-nitrophenyl chloroformate (100 rng, 0.5 mmol) was added at 0 °C under argon atmosphere. The light yellow suspension was stirred for 2.5 hours under this condition, then another portion of 4- nitrophenyl chloroformate (25 mg, 0 125 mmol) 'as added, and the mixture was stirred for another hour, then another portion of 4-nitrophenyl chloroformate (25 mg, 0.125 mmol) was added, and the mixture was stirred for another hour A solution of 3-{[4~ (trifluoromethyl)phenoxy]methyl}azetidine (112 mg, 0.45 mmol) in CH2CI2 (2 mL) w¾s added at 0 °C, and the mixture w'as allowed to warm to room temperature, and stirred overnight. The mixture was concentrated in vacuo , and the residue was chromatographed on silica gel, using gradient elution with a mixture of 0 to 50 % EtOAc ~ ( P -Cl·, followed by a mixture of 0 to 3 % MeOl 1 - CH2CI2, to yield 136 mg (57 %) of tert- butyl 2-cyano-5-{[(3- { [4-(trifluoromethyl)phenoxy]methyl } azetidine- 1 -carbonyl)amino]methyl } - 1 //-indole- 1 - carboxyl ate.
Trifluoroacetic acid (0.4 mL, 5 mmol) was added to a solution of ter/-butyl 2-cyano- 5- { [(3 - ( [4-(trifluoromethyl)phenoxy]methyl } azetidine- 1 -carbonyl)amino]methyl } - 1 H- indole-l-carboxylate (135 mg, 0.25 mmol) in CH2CI2 (10 mL), cooled to 0 °C in an ice water bath, and the solution was stirred for 22 hours at room temperature. The solvent was removed under reduced pressure, and the residue w¾s chromatographed on silica gel, using gradient elution with a mixture of 0 to 3 % MeOH - C! I ('! ·. and further purified by preparative reversed-phase HPLC with a gradient of a mixture of acetonitrile and water, to obtain the title compound (24 mg, 0.056 mmol, 22 %). [M+H] + :=: 429.1
Example 135
i
Figure imgf000102_0001
ntermedier 97 intermedier 64 Example 135 V-[(l F7-indol-5-yl)methyl]-3-{[4-(triflnoroinethyl)phenoxy]inethyl}azetidine-l- carbothioamide
To a solution 3-{[4-(trifluoromethyl)phenoxy]methyl}azetidine (116 mg, 0.5 mmol) in DMF (2 rnL), 1,1’-thiocarbonyldiimidazole (98 mg, 0.55 mmol) was added at room temperature under argon atmosphere. The brownish-yellow solution was stirred for 1 hour under this condition. After the activation period, a solution of l~(i/:/-indol-5~yl)methanamine (72 mg, 0.49 mmol) in DMF (1 mL) w¾s added, and the mixture was stirred at this temperature overnight, then at 65 °C for 1 hour. After the completion of the reaction (monitored by TLC), the mixture was poured onto water (8 mL), and extracted with EtOAc (2x15 mL). The organic layer was dried over anhydrous Na?.S04, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with a mixture of CH2CI2 and MeOi I (95:5), to yield 23 mg of the title compound . LC-MS (ESI) m/z [M+H] += 420.2
Intermediate 118
Figure imgf000103_0001
3-[(4-methylphenoxy)methyl] pyrrolidine
Intermediate 118 was prepared according to the synthetic description of Intermediate 62.
Intermediate 119
Figure imgf000103_0002
3-{[4-(trifluoromethyl)phenoxy]methyl}pyrrolidine Intermediate 119 was prepared according to the synthetic description of Intermediate 62.
Methylpyrrolidine derivatives are summarized in Table 12.
Table 12
Figure imgf000104_0001
Other pyrrolidine intermediates in Table 13 w'ere prepared according to the synthetic description of Intermediate 62.
Table 13
Figure imgf000104_0002
Figure imgf000105_0001
*It can be synthesized starting from the corresponding aniline derivative
Examples in Table 14 were prepared according to the synthetic description of Example8. Table 14
Figure imgf000105_0002
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Piperidine, piperazine and azepane ring containing examples presented in Table 15 were prepared according to the synthetic description of Example 38.
Table 15
Figure imgf000109_0002
Figure imgf000110_0001
Figure imgf000111_0001
Preparation of pharmaceutical compositions
The following formulation examples illustrate representative pharmaceutical compositions of this invention. The present invention, however, is not limited to the following pharmaceutical compositions. A) Solid oral dosage forms
Active ingredient(s) 0.01 - 90 %
Filler 1 - 99 9 %
Binder 0 - 20 %
Disintegrant 0 - 20 %
Lubricant 0 - 10 %
Other specific excipient(s) 0 - 50 % II, Orodispersible films
Active ingredient(s) 0.01 - 90 %
Film forming agent 1 - 99 9 % Plasticizer 0 - 40 %
Other specific excipient(s) 0 - 50 %
B) Liquid oral dosage forms
Figure imgf000112_0001
Active ingredient(s) 0 01 - 50 % Liquid vehicle 10 - 99.9 % Wetting agent 0 - 50 % Thickener 0 - 50 % Buffering agent quantum satis Osmotic agent 0 - 50 % Preservatives quantum satis
IV, Syrups
Active ingredient(s) 0 01 - 50 % Solvent 10 - 99.9 %
Sugar component 1 - 20 % Flavouring agents 0 - 10 %
C) Parenteral dosage forms
Figure imgf000112_0002
Active ingredient(s) 0.01 - 50 % Solvent 10 - 99.9 %
Co-solvent 0 - 99.9 %
Osmotic agent 0 - 50 %
Buffering agent quantum satis I)) Other dosage forms
VI. , Suppositories
Active ingredient(s) 0.01 - 50 % Suppository base 1 - 99.9 % Surface-active agents 0 - 20 % Lubricants 0 - 20 % Preservatives quantum satis
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 agent 0 - 20 % Viscosity enhancer 0 - 20 %
Buffering agent quantum satis Preservatives quantum satis
y
Figure imgf000114_0001
Cells: Flp-In 293 cells stably expressing human a7 nAchR and human RIC-3 (oJ cells, generated in house.)
Materials: 96-well plates coated with PDL (Falcon), culture medium, assay buffer, DMSO, FLIPR Calcium 5 kit (Molecular Devices), probenecid, agonist and PAM test compounds.
Culture medium: Assay buffer:
- DMEM (Dulbecco's Modified Eagle Medium, Gibco) - 140 mM NaCl
- 10 % FBS (Fetal Bovine Serum, Gibco) - 5 mM KC1
- 1 % glutamine (Sigma G) - 10 mM HEPES
- 50 pg/ml Hygromycin B - 2 mM MgCb
- 800 pg/ml G418 - 2 mM CaCh
- 1 % penicillin-streptomycin-antimycotic sol. - 10 mM glucose
(PSA, Sigma) - 2 mM probenecid,
pH=7.4
Brief description of the method (Ca2+ fluorometry) a7 cells stably expressing human a7 nAcliR were cultured in the medium detailed above, and were split twice a week. For the fluorometric measurements of cytosolic Ca2+ ion concentration ([ ( a ' jo cells were seeded in 96-well microplates at a density of 60000 cells/well and maintained overnight in a tissue culture incubator at 37 °C under an atmosphere of 95 % air/5 % COi. The plating medium was identical with the culture medium. 50 mΐ of the growth medium was aspirated with a cell washer (BioTek Elx405UCVWS). Then 50 mΐ /well Calcium 5 kit diluted 2-fold in assay buffer was added manually using an 8-channel pipette. After an incubation period (20 minutes, 37 °C) 50 pl/well assay buffer containing vehicle (DMSO, 4 % added) or reference a7 PAMs (4x of the final concentration) were added manually and the ceils were incubated for an additional 10 minutes at 37 °C. Baseline and agonist-evoked [Ca2 ]i-changes were monitored with FlexStation II (Molecular Devices, Sunnyvale, CA), a plate reader fluorometer with integrated 8-channel fluid addition capability. Fluorescence measurements were carried out at 37 °C. The dye was excited at 485 nm, emission was sampled at 525 ntn at 1.4-s intervals. Baseline was recorded for 20 seconds followed by agonist stimulation. 50 mΐ 4x concentrated agonist solution was added to the cells using the pipetor of FlexStation II and fluorescence was monitored for an additional 40 seconds. Final DMSO concentration was 1 % for all treatments. To achieve this, a series of DMSO stock solutions were prepared from all test compounds. These stocks were stored under 0 °C and were further diluted in assay buffer to obtain the desired final concentration immediately before the measurement. Agonist and PAM concentration- response studies were conducted in the presence of saturating concentrations of PAMs (mostly PNU-120596, 5 mM) and agonists (mostly PNU-282987, 1 uM ). respectively. Results were expressed as AF/F values using SoftMax Pro software (Molecular Devices), where F was the resting fluorescence preceding agonist application and AF was the increase in fluorescence at a given time (AF = maximum fluorescence intensity values after stimulation minus average fluorescence intensity values before stimulation). In all experiments, all treatments were measured in multiple wells in parallel, and the mean AF/F values were used for analysis.
Table 16 shows the PAM ECso values in the [Ca2+]i assay:
Table 16
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0002
Figure imgf000117_0001
Animals: Male NMRI mice (Toxicoop, Hungary)
Substances: Scopolamine was dissolved in saline and administered at 1 mg/kg dose i.p. Test compounds were administered 30 minutes before the acquisition trial (Tl) and scopolamine after the acquisition trial at a volume of 0.1 nil/10 g. Procedure: The task was carried out in a transparent plexiglass Y-maze (each arm has a length of 40 cm, an inner width of 11 cm and a height of 30 cm). Numerous visual cues were placed around the arms and were kept constant during the experiment. The test consisted of two trials (T1 and T2) separated by an intertrial interval of 30 minutes. Mice were placed in the starting arm of the maze at the beginning of each trial in Tl, one of the symmetric ar s of the maze was closed (it will be novel in T2) and the animals were allowed to explore the maze for 5 minutes (acquisition phase). In T2, mice had free access to all three arms for 2 minutes (retrieval phase). The time spent with exploration in the novel and familiar arms during T2 was measured. Differences between the exploration times spent in the familiar vs. novel arms of the maze for each group were evaluated by MANOVA, followed by Duncan post hoc test.
Table 17 shows the reversal of the scopolamine-induced amnesia in the place recognition assay in mice;
Table 17
Figure imgf000118_0001
p 0 05; p 0.001
Significant differences (+p<0.05; ++p<0.01; + p<0 001) were observed between the exploration times spent in the novel vs. familiar arms of the maze.

Claims

Figure imgf000119_0001
wherein
R1 is hydrogen or Ci-ealkyl;
R2 is hydrogen or Ci-ealkyl, or R is absent when n is 0;
R3 is hydrogen or O; or R3 is absent when m is 0;
R4 and R5 are independently hydrogen, Ci-ealkyl, halogen, haloCi-ealkyl, Ci-ealkoxy, or CN;
si and m are independently 0 or 1, with the proviso that, n and m cannot be 0 at the same time;
k ami S are independently 1, 2 or 3;
Y is N or C(R6);
R6 is hydrogen, Ci-ealkyl, halogen, or haloCi-ealkyl;
R7 is hydrogen, Ci-ealkyl, or halogen;
W is CH or N;
Z is CH, C-Ci-salkyl or N;
L is an optionally substituted linker consisting of 1, 2 or 3 atoms, represented by T-U-V, wherein T is CH?, C(O), NH, SO2 or O; U is CH2, C(O), O or absent; and V is CH2, 0 or absent;
A is a saturated, unsaturated, or aromatic carbocyclyl, or a saturated, unsaturated, or aromatic heterocyclyl, wherein the heteroatoms are selected from the group of nitrogen, oxygen and sulphur; optionally substituted independently by one or more halogen atom or halogen atoms, Ci-ealkyl, Ci-ealkoxy, haloCi-ealkyl, haloCi-ealkoxy, CN, or benzyl; or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
2. A compound according to claim 1, wherein,
R3 is hydrogen or Ci-ealkyl;
R2 is hydrogen or Ci-aa!ky!, or R2 is absent when n is 0;
R3 is hydrogen or O, or RJ is absent when m is 0;
R1 and R5 are independently hydrogen, Ci-salkyl, halogen, haloCi-3aikyl, Ci-salkoxy, or CN;
n and m are independently 0 or 1; with the proviso that, n and m cannot be 0 at the same time;
k and S are independently 1 or 2;
Y is N or C(R6);
R6 is hydrogen, Ci-salkyl, halogen, or haloCi-sal yl;
R7 is hydrogen, Ci-salkyl, or halogen;
W is ( 1 ! or N;
Z is CH or N;
L is an optionally substituted linker consisting of 1, 2 or 3 atoms, represented by T-U-V, wherein T is C¾, C(0), NH, SO? or O; U is CH?„ C(O), O or absent; and V is O or absent;
A is a saturated, unsaturated, or aromatic 4-9 membered carbocyclyi, or a saturated, unsaturated, or aromatic 4-9 membered heterocyclyl, wherein the heteroatom is nitrogen, optionally substituted independently by one or more halogen atom or halogen atoms, Cioalkyl, Cusalkoxy, haloCi -3alkyl, haloCi oalkoxy, CN, or benzyl; or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hdrates thereof.
3. A compound according to claim 1, wherein
R3 is hydrogen or Ci-ralkyl;
R2 is hydrogen or Ci-salkyl, or R2 is absent when n is 0;
R3 is O, or R3 is absent when m is 0;
R4 and R5 are independently hydrogen, Ci-salkyl, halogen, haloCi-3aikyl, Ci-salkoxy, or CN; si and m are independently 0 or 1; with the proviso that, n and m cannot be 0 at the same time;
k a d I are independently 1 or 2,
Y is N or C(R6);
R6 is hydrogen, Ci-salkyl, halogen, or haloCi-ialkyl;
R7 is hydrogen, Ciualkyl, or halogen;
W is CH or N;
Z is CH or N;
L is linker selected from the group of: -CH2-, -0-, -NH-, -SO2-, -C(O)-, -CH2-O-, -CH2-CH2-O-, -O-CH2-, -CH2-CH2-, -NH-C(O)-, or -NH-CH2-;
A is an aromatic 6 membered carbocyclyl or an aromatic 6 membered heterocyclyl, wherein the heteroatoms are selected from the group of nitrogen, optionally substituted independently by one or more halogen atom or halogen atoms, Ciualkyl, Ci-3alkoxy, haloCi-saikyl, haloCi-salkoxy, CN, or benzyl;
or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof
4. A compound according to any one of claims 1 to 3, selected from the group of:
N-(1 -methyl-1 H-indol-5-yl)-2-{4-[(4-methylphenyl)methyl]piperazin-l-yl ) -2- oxoacetamide;
N-{ l-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl}-2-{4-[(4- methylphenyl)methyl Jpiperazin- 1 -yl } -2-oxoacetamide;
N-(3-fluoro- 1 -methyl- lH-indol-5-yl)-2- {4-[(4-methylphenyl)methyl]piperazin- 1 - yl } -2-oxoacetamide;
N-(1 -methyl-1 H-indol-5-yl)-2-[4-(4-methylphenoxy)piperi din- 1 -yl]-2- oxoacetamide;
2-[4-(4-ch!orophenoxy)piperi din- 1 -yl]-N-( 1 -methyl- IH-indol-5~yl)~2-oxoacetamide;
[(l H-indol-5-yl)methyl][(3-{[4-(trifluoromethyl)phenoxy]methyl}azetidin-l - yl)methyl] amine; N-({ l-methyl-lH-pyrrolo[2,3-b]pyridin-5-yl }methyl)-3-{ [4- (trifluoromethyl)phenoxy]methyl } azetidine- 1 -carboxamide;
N-[(l-methyl- 1 H-indol-5-yl)methyl]-3-{ [4- (trifluoromethoxy)phenoxy]methyl} azetidine- 1 -carboxamide;
N-[(2-methyl-IH-indol-5-yi)methyl]-3-{[4-
(trifiuoromethy!)phenoxyjjmethy! } azetidine- 1 -carboxamide;
3-{[3-fluoro-4-(trifluoromethyl)phenoxy]methyl}-N-[(l-me†hyl-l H-indol-5- yl)methyl]azetidine- 1 -carboxamide;
3 - { [3 -fl uoro~4-(trifluoromethy 1 jphenoxy ]methy 1 } -N - [( 1 H-indol-5 - yl)methyJ]azetidine-l-carboxamide;
N-[(3-fluoro- 1 -methyl- lH-indol-5-yl)methyl]-3- { [4-
(trifiuorornethyl)phenoxy jjrnethyl } azetidine- 1 -carboxamide;
3-methyl-N-({ l-methyl-l H-pyrrolo[2,3-b]pyridin-5-yl}methyl)-3-{[4-
(trifluoromethyl)phenoxy]methyl } azetidine- 1 -carboxamide;
N-[(l -methyl- lH-indol-5-yl)methyl]-3-[(4-methylphenoxy)methyl]pyrrolidine-l - carboxamide;
(3R)-3-(4-fluorophenoxy)-N-[(l-methyl-lH-indol-5-yl)methyl]pyrrolidine-l- carboxamide;
(3S)-3-(4-fluorophenoxy)-N-[(l-methyl-lH-indol-5-yl)methyl]pyrrolidine-l- carboxamide;
(3 S)-N - [( 1 -methyl- 1 H-i ndol-5 -yl)methyl] -3 - [4- (trifluoromethyl)phenoxy]pyrrolidine- 1 -carboxamide;
(3 S)-3-(4-cyanophenoxy)-N-[i 2-methyl- lH-indol-5-yl)methyI]pyrrolidine-l- carboxamide;
(3S)-N-[(l -methyl-l H-indol-5-yl)methyl]-3-{[4-
(trifluoromethyl)phenyl]amino}pyrrolidine-l -carboxamide;
N-[(l-methyl- 1 H-indol-5-yl)methyl]-4-{ [4-
(trifluoromethyl)phenyl]methyl}piperazine-l-carboxamide, 4-(2,4-difluorophenoxy)-N-[(2-methyl-lH-indol-5-yl)methyl]piperidine-l- carboxamide;
or pharmaceutically acceptable salts, biologically active metabolites, pro-drugs, racemates, enantiomers, diastereomers, solvates and hydrates thereof.
5. A compound according to any one of claims 1 to 4, for use in the treatment or prevention of a disease associated with o7 nicotinic acetylcholine receptor activity
6. A compound according to claim 5, wherein the disease is selected from the group of psychotic disorders, including, but not limited to, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder or psychotic disorder not otherwise specified, cognitive impairment, including, but not limited to, cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, HIV associated dementia, frontotemporal dementia, Lewy body dementia, vascular dementia, cerebrovascular disease or other dementia states and dementia associated to other degenerative disorders, including, but not limited to, amyotrophic lateral sclerosis, other acute or sub-acute conditions that may cause cognitive decline, including, but not limited to, delirium, traumatic brain injury', senile dementia, mild cognitive impairment, Down's syndrome, depression and cognitive deficit related to other diseases, and dyskinetie disorders including, but not limited to, Parkinson's disease, neuroleptic-induced parkinsonism, or tardive dyskinesias, depression and mood disorders, including, but not limited to, depressive disorders and episodes, bipolar disorders, cyclothymic disorder, and bipolar disorder not otherwise specified, other mood disorders, substance-induced mood disorder and mood disorder not otherwise specified, anxiety disorders, panic disorder and panic attacks, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder, phobias, and anxiety- disorder not otherwise specified, substance related disorders, including, but not limited to, substance use or substance-induced disorders, including, but not limited to, alcohol-, nicotine-, amphetamine-, phencyclidine-, opioid-, cannabis-, cocaine-, caffeine-, hallucinogen-, inhalant-, sedative-, hypnotic-, anxiolytic-, polysubstance- or other substance-related disorders, sleep disorders, including, but not limited to, narcolepsy, dyssomnias, primary' hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder and dyssomnia not otherwise specified, parasomnias, sleep terror disorder, sleepwalking disorder and parasomnia not otherwise specified, sleep disorders related to another mental disorder, sleep disorder due to a general medical condition and substance-induced sleep disorder, metabolic and eating disorders, including, but not limited to, anorexia nervosa, bulimia nervosa, obesity, compulsive eating disorder, binge eating disorder and eating disorder not otherwise specified, diabetes mellitus, ulcerative colitis, Crohn’s disease, irritable bowel syndrome, autism spectrum disorders, including, but not limited to, autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified, attention deficit hyperactivity disorder, disruptive behaviour disorders, oppositional defiant disorder and disruptive behaviour disorder not otherwise specified, and tic disorders, including, but not limited to, Tourette's disorder, personality disorders, sexual dysfunctions such as sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorder, sexual dysfunction not otherwise specified, paraphilias, gender identity disorders, infertility, premenstrual syndrome and sexual disorders not otherwise specified, disorders of the respiratory' system like cough, asthma, chronic obstructive pulmonary' disease, lung inflammation, disorders of the cardiovascular system such as cardiac failure, heart arrhythmia, 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, myoclonus, migraine, amnesia, chronic fatigue syndrome, cataplexy, brain ischemia, multiple sclerosis, encephalomyelitis, jetlag, cerebral amyloid angiopathy, and sepsis.
7. A compound according to claim 6, wherein the disease is selected from the group of cognitive impairment, schizophrenia, and autism.
8. Use of compound according to any one of claims 1 to 4, for the manufacture of a medicament for the treatment or prevention of a disease associated with a? nicotinic acetylcholine receptor activity.
9. Use according to claim 8, wherein the disease is selected from the group of psychotic disorders, including, but not limited to, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder or psychotic disorder not otherwise specified, cognitive impairment, including, but not limited to, cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, HIV associated dementia, frontotemporal dementia, Lewy body dementia, vascular dementia, cerebrovascular disease or other dementia states and dementia associated to other degenerative disorders, including, but not limited to, amyotrophic lateral sclerosis, other acute or sub-acute conditions that may cause cognitive decline, including, but not limited to, delirium, traumatic brain injury, senile dementia, mild cognitive impairment, Down’s syndrome, depression and cognitive deficit related to other diseases, and dyskinetic disorders including, but not limited to, Parkinson’s disease, neuroleptic-induced parkinsonism, or tardive dyskinesias, depression and mood disorders, including, but not limited to, depressive disorders and episodes, bipolar disorders, cyclothymic disorder, and bipolar disorder not otherwise specified, other mood disorders, substance-induced mood disorder and mood disorder not otherwise specified, anxiety disorders, panic disorder and panic attacks, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder, phobias, and anxiety- disorder not otherwise specified, substance related disorders, including, but not limited to, substance use or substance-induced disorders, including, but not limited to, alcohol-, nicotine-, amphetamine-, phencyclidine-, opioid-, cannabis-, cocaine-, caffeine-, hallucinogen-, inhalant-, sedative-, hypnotic-, anxiolytic-, polysubstance- or other substance-related disorders, sleep disorders, including, but not limited to, narcolepsy, dyssomnias, primary hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder and dyssomnia not otherwise specified, parasomnias, sleep terror disorder, sleepwalking disorder and parasomnia not otherwise specified, sleep disorders related to another mental disorder, sleep disorder due to a general medical condition and substance-induced sleep disorder, metabolic and eating disorders, including, but not limited to, anorexia nervosa, bulimia nervosa, obesity, compulsive eating disorder, binge eating disorder and eating disorder not otherwise specified, diabetes meilitus, ulcerative colitis, Crohn’s disease, irritable bowel syndrome, autism spectru disorders, including, but not limited to, autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified, attention deficit hyperactivity disorder, disruptive behaviour disorders, oppositional defiant disorder and disruptive behaviour disorder not otherwise specified, and tic disorders, including, but not limited to, Tourette's disorder, personality disorders, sexual dysfunctions such as sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorder, sexual dysfunction not otherwise specified, paraphilias, gender identity- disorders, infertility, premenstrual syndrome and sexual disorders not otherwise specified, disorders of the respiratory system like cough, asthma, chronic obstructive pulmonaiy disease, lung inflammation, disorders of the cardiovascular system such as cardiac failure, heart arrhythmia, 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, myoclonus, migraine, amnesia, chronic fatigue syndrome, cataplexy, brain ischemia, multiple sclerosis, encephalomyelitis, jetlag, cerebral amyloid angiopathy, and sepsis.
10. Use according to claim 9, wherein the disease is selected from the group of cognitive impairment, schizophrenia, and autism.
11. A method for the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity- comprising administering to a mammal in need of such treatment or prevention an effective amount of at least one compound compound according to any one of claims l to 4.
12. A method according to claim 11 , wherein the disease is selected from the group of psychotic disorders, including, but not limited to, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, psychotic disorder due to a general medical condition, substance-induced psychotic disorder or psychotic disorder not otherwise specified, cognitive impairment, including, but not limited to, cognitive impairment as a result of stroke, Alzheimer's disease, Huntington’s disease, Pick disease, HIV associated dementia, frontotemporal dementia, Lewy body dementia, vascular dementia, cerebrovascular disease or other dementia states and dementia associated to other degenerative disorders, including, but not limited to, amyotrophic lateral sclerosis, other acute or sub-acute conditions that may cause cognitive decline, including, but not limited to, delirium, traumatic brain injury, senile dementia, mild cognitive impairment, Down’s syndrome, depression and cognitive deficit related to other diseases, and dyskinetic disorders including, but not limited to, Parkinson's disease, neuroleptic-induced parkinsonism, or tardive dyskinesias, depression and mood disorders, including, but not limited to, depressive disorders and episodes, bipolar disorders, cyclothymic disorder, and bipolar disorder not otherwise specified, other mood disorders, substance-induced mood disorder and mood disorder not otherwise specified, anxiety disorders, panic disorder and panic attacks, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder, phobias, and anxiety disorder not otherwise specified, substance related disorders, including, but not limited to, substance use or substance-induced disorders, including, but not limited to, alcohol-, nicotine-, amphetamine-, phencyclidine-, opioid-, cannabis-, cocaine-, caffeine-, hallucinogen-, inhalant-, sedative-, hypnotic-, anxiolytic-, polysubstance- or other substance-related disorders, sleep disorders, including, but not limited to, narcolepsy, dyssomnias, primary hypersomnia, breathing-related sleep disorders, circadian rhythm sleep disorder and dyssomnia not otherwise specified, parasomnias, sleep terror disorder, sleepwalking disorder and parasomnia not otherwise specified, sleep disorders related to another mental disorder, sleep disorder due to a general medical condition and substance-induced sleep disorder, metabolic and eating disorders, including, but not limited to, anorexia nervosa, bulimia nervosa, obesity, compulsive eating disorder, binge eating disorder and eating disorder not otherwise specified, diabetes meilitus, ulcerative colitis, Crohn’s disease, irritable bowel syndrome, autism spectrum disorders, including, but not limited to, autistic disorder, Asperger's disorder, Rett's disorder, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified, attention deficit hyperactivity disorder, disruptive behaviour disorders, oppositional defiant disorder and disruptive behaviour disorder not otherwise specified, and tic disorders, including, but not limited to, Tourette's disorder, personality disorders, sexual dysfunctions such as sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorder, sexual dysfunction not otherwise specified, paraphilias, gender identity disorders, infertility, premenstrual syndrome and sexual disorders not otherwise specified, disorders of the respiratory system like cough, asthma, chronic obstructive pulmonary' disease, lung inflammation, disorders of the cardiovascular system such as cardiac failure, heart arrhythmia, 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, myoclonus, migraine, amnesia, chronic fatigue syndrome, cataplexy, brain ischemia, multiple sclerosis, encephalomyelitis, jetlag, cerebral amyloid angiopathy, and sepsis.
13. A method according to claim 12, wherein the disease is selected from the group of cognitive impairment, schizophrenia, and autism.
14. A pharmaceutical composition compri sing as active ingredient a compound according to any one of claims 1 to 4 and at least one pharmaceutically acceptable excipient.
15. A pharmaceutical composition according to claim 14, wherein the composition further comprises at least one other active ingredient.
16. A pharmaceutical composition according to claim 15, wherein the other active ingredient(s) are selected from the group of acetylcholinesterase inhibitors, NMDA receptor antagonists, beta- secretase inhibitors, antipsychotics, GABAA receptor alphaS subunit NAMs or PAMs, histamine Hr receptor antagonists, 5-HTV. receptor antagonists, Ml or M4 niAChR agonists or PAMs, mGluR2 antagonists or NAMs or PAMs, and levodopa.
17. Combination of a compound according to any one of claims 1 to 4 and at least one other active ingredient for use in the treatment or prevention of a disease associated with a7 nicotinic acetylcholine receptor activity.
18 Combination according to claim 17, wherein the other active ingredient(s) are selected from the group of acetylcholinesterase inhibitors, NMD A receptor antagonists, beta- secretase inhibitors, antipsychotics, GABAA receptor alphas subunit NAMs or PAMs, histamine H receptor antagonists, 5-HTe receptor antagonists. Ml or M4 mAChR agonists or PAMs, inGluRZ antagonists or NAMs or PAMs, and levodopa.
9. Process for the manufacture of compounds of formula (I) according to claim 1, characterized by
ROUTE A) step 1) treating either formula (II)
Figure imgf000129_0001
- wherein the meaning of R1, R4, R5, R7, Y are described above for compound of formula (I) - or formula (V)
Figure imgf000129_0002
V - wherein the meaning of W is N, and the meaning of k, 1, Z, L, A are described above for compound of formula (I) - with ethyl/methyl 2-chloro-2-oxoacetate in the presence of a base in a suitable solvent to obtain the compound of either formula (IVa)
Figure imgf000130_0001
- wherein the meaning of R1, R4, R\ R7, Y are described above for compound of formula (I) - or formula (Ilia)
Figure imgf000130_0002
- wherein the meaning of W is N, and the meaning of k, 1, Z, L, A are described above for compound of formula (I) - and then the concomitant basic hydrolysis of the obtained esters provides the appropriate carboxylic acids of either formula (IV)
Figure imgf000130_0003
- wherein the meaning of R1, R4, R5, R7, Y are described above for compound of formula (I) - or formula (III)
Figure imgf000131_0001
- wherein the meaning of W is N, and the meaning of k, 1, Z, L, A are described above for compound of formula (I); or treating formula (VI)
Figure imgf000131_0002
VI
- wherein the meaning of W is CH, and the meaning of k, 1, Z, L, A are described above for compound of formula (I) - with ethyl isocyanoacetate in the presence of a base, in a suitable solvent to provide compounds of formula (VII)
Figure imgf000131_0003
VII
- wherein the meaning of W is CH, and the meaning of k, 1, Z, L, A are described above for compound of formula (I) - and then treating compounds of formula (VII) with aqueous HC1 solution, and then with aqueous KOH solution to obtain compounds of formula (III),
Figure imgf000132_0001
III wherein the meaning of W is CH, and the meaning of k, 1, Z, L, A are described above for compound of formula (I); step 2) either coupling compounds of formula (II)
Figure imgf000132_0002
wherein the meaning of R1, R4, R3, R7, Y are described above for compound of formula (I) - with compounds of formula (III)
Figure imgf000132_0003
- wherein the meaning of k, 1, W, Z, L, A are described above for compound of formula (I);
or coupling compounds of formula (IV)
Figure imgf000132_0004
- wherein the meaning of R1, R4, R5, R7, Y are described above for compound of formula (I) - with compounds of formula (V)
V - wherein the meaning of W is N, and the meaning of k, 1, Z, L, A are described above for compound of formula (I) - to obtain compounds of formula (I) wherein the meaning of n is 0, Rf is O, m is 1, and the meaning of R1, R4, R5, R7, Y, k, 1, W, Z, L, A are described for compound of formula (I);
ROUTE B) reacting compounds of formula (VIII)
Figure imgf000133_0001
- wherein the meaning of n is l and the meaning of R1, R2, R4, R5, R ', Y are described above for compound of formula (I) - using standard procedures and reagents, such as CD I, chloroformates or I, G-thiocarbonyldi imidazole in suitable solvents, such as CH2CI2 or DMF, followed by the reaction with compounds of formula (V)
Figure imgf000133_0002
v
- wherein the meaning of W is N, and the meaning of k, 1, L, Z, A are described above for compound of formula (I) - to obtain compounds of formula (I) wherein the meaning of W is N, R2 is Ci-6aikyl or hydrogen, n is 1, m is 0, and the meaning of R1, R4, R5, R7, Y, k, 1, Z, L, A are described above for compound of formula (I).
20. A compound of 7-fluoro-li/-indol-5~amine.
21. A compound of 3-fluoro-l -methyl-l//-pynOlo[2,3-£]pyridin-5-amine.
22. A compound of 2-[(azetidin-3-yloxy)methyl]-5-(trifluoromethyl)pyridine.
23. A compound of { l ,2-dimethyl-l /7-pyrrolo[2,3-Z>]pyridin-5-yl}methanamine.
24. A compound of { l,3-dimethyl-l//-pyrrolo[2,3-6]pyridin-5-yl}methanamme.
25. A compound of {3-chloro-l-methyl-l /-pynOlo[2,3- ]pyridin-5-yl}methanamine.
26. A compound of {3-Bromo- I -methyMJY-pyrroio[2,3-5]pyridin-5-yl}methanamine.
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