WO2014049133A1

WO2014049133A1 - New positive allosteric modulators of nicotinic acetylcholine receptor

Info

Publication number: WO2014049133A1
Application number: PCT/EP2013/070231
Authority: WO
Inventors: Jørgen ESKILDSEN
Original assignee: H. Lundbeck A/S
Priority date: 2012-09-28
Filing date: 2013-09-27
Publication date: 2014-04-03

Abstract

The present invention relates to indole derivatives useful in therapy, to compositions comprising said compounds, and to methods of treating diseases comprising administration of said com- pounds. The compounds referred to are positive allosteric modulators (PAMs) of the nicotinic acetylcholine α7 receptor.

Description

TITLE

New positive allosteric modulators of nicotinic acetylcholine receptor

FIELD OF THE INVENTION

The present invention relates to compounds useful in therapy, to compositions comprising said compounds, and to methods of treating diseases comprising administration of said compounds. The compounds referred to are positive allosteric modulators (PAMs) of the nicotinic acetylcholine ol receptor.

BACKGROUND OF THE INVENTION

Nicotinic acetylcholine receptors (nAChRs) belong to the super family of ligand gated ionic channels, and gate the flow of cations including calcium. The nAChRs are endogenously activated by acetylcholine (ACh) and can be divided into nicotinic receptors of the neuromuscular junction and neuronal nicotinic receptors (NNRs). The NNRs are widely expressed throughout the central nervous system (CNS) and the peripheral nervous system (PNS). The NNRs have been suggested to play an important role in CNS function by modulating the release of many neurotransmitters, for example, ACh, norepinephrine, dopamine, serotonin, and GABA, among others, resulting in a wide range of physiological effects.

Seventeen subunits of nAChRs have been reported to date, which are identified as α2-α10, β1 -β4, γ, δ and ε. From these subunits, nine subunits, o2 through a 7 and β2 through β4, prominently exist in the mammalian brain. Many functionally distinct nAChR complexes exist, for example five ol subunits can form a receptor as a homomeric functional pentamer or combinations of different subunits can form heteromeric receptors such as α4β2 and α3β4 receptors (Gotti, C. et al., Prog. Neurobiol. ,2004, 74: 363-396;

Gotti, C. et al., Biochemical Pharmacology, 2009, 78: 703-71 1 )

The homomeric a7 receptor is one of the most abundant NNRs, along with α4β2 receptors, in the brain, wherein it is heavily expressed in the hippocampus, cortex, thalamic nu- clei, ventral tegmental area and substantia nigra (Broad, L. M. et al., Drugs of the Future, 2007, 32(2): 161 -170, Poorthuis, R.B., Biochem Pharmacol. 2009 1 ;78(7):668-76).

The role of o7 NNR in neuronal signalling has been actively investigated. The a7 NNRs have been demonstrated to regulate interneuron excitability and modulate the release of excitatory as well as inhibitory neurotransmitters. In addition, a7 NNRs have been reported to be involved in neuroprotective effects in experimental models of cellular damage (Shimo- hama, S., Biol Pharm Bull. 2009, 32(3):332-6). Studies have shown that a7 subunits, when expressed recombinant in-vitro, activate and desensitize rapidly, and exhibit relatively higher calcium permeability compared to other NNR combinations (Papke R.L. et al., J Pharmacol Exp Ther. 2009, 329(2)791 -807).

The NNRs, in general, are involved in various cognitive functions, such as learning, memory and attention, and therefore in CNS disorders, i.e. Alzheimer's disease (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD), Tourette's syndrome, schizophrenia, bipolar disorder, pain and tobacco dependence (Keller, J. J. et al., Be- hav. Brain Res. 2005, 162: 143-52; Haydar, S.N. et al., Curr Top Med Chem. 2010;10(2):144- 52).

The a7 NNRs in particular, have also been linked to cognitive disorders including, for example, ADHD, autism spectrum disorders, AD, mild cognitive impairment (MCI), age associated memory impairment (AAMI) senile dementia, frontotemporal lobar degeneration, HIV associated dementia (HAD), HIV associated cognitive impairment (HIV-CI), Pick's disease, dementia associated with Lewy bodies, cognitive impairment associated with Multiple Sclero- sis, Vascular Dementia, cognitive impairment in Epilepsy, cognitive impairment associated with fragile X, cognitive impairment associated with Friedreich's Ataxia, and dementia associated with Down's syndrome, as well as cognitive impairment associated with schizophrenia. In addition, a7-NNRs have been shown to be involved in the neuroprotective effects of nicotine both in vitro (Jonnala, R. B. et al., J. Neurosci. Res., 2001 , 66: 565- 572) and in vivo (Shimohama, S., Brain Res., 1998, 779: 359-363) as well as in pain signalling. More particularly, neurodegeneration underlies several progressive CNS disorders, including, but not limited to, AD, PD, amyotrophic lateral sclerosis, Huntington's disease, dementia with Lewy bodies, as well as diminished CNS function resulting from traumatic brain injury. For example, the impaired function of a7 NNRs by beta-amyloid peptides linked to AD has been implicated as a key factor in development of the cognitive deficits associated with the disease (Liu, Q.-S. et al., PNAS, 2001 ,98: 4734-4739). Thus, modulating the activity of a7 NNRs demonstrates promising potential to prevent or treat a variety of diseases indicated above, such as AD, other dementias, other neurodegenerative diseases, schizophrenia and neurodegeneration, with an underlying pathology that involves cognitive function including, for example, aspects of learning, memory, and attention (Thomsen, M.S. et al., Curr. Pharm. Des. 2010

Jan;16(3):323-43; Olincy, A. et al., Arch Gen Psychiatry. 2006, 63(6):630-8; Deutsch, S.I., Clin Neuropharmacol. 2010, 33(3):1 14-20; Feuerbach, D., Neuropharmacology. 2009, 56(1 ): 254-63)

The NNR ligands, including a7 ligands, have also been implicated in weight control, diabetis inflammation, obsessive-compulsive disorder (OCD), angiogenesis and as potential analgesics (Marrero, M.B. et al., J. Pharmacol. Exp. Ther. 2010, 332(1 ):173-80; Vincler, M., Exp. Opin. Invest. Drugs, 2005, 14 (10): 1 191 -1 198; Rosas-Ballina, M., J. Intern Med. 2009 265(6):663-79; Arias, H.R., Int. J. Biochem. Cell Biol. 2009, 41 (7):1441 -51 ; Tizabi Y, Biol Psychiatry. 2002 Jan 15;51 (2): 164-71 ).

Nicotine is known to enhance attention and cognitive performance, reduced anxiety, enhanced sensory gating, and analgesia and neuroprotective effects when administered. Such effects are mediated by the non-selective effect of nicotine at multiple nicotinic receptor subtypes. However, nicotine also exerts adverse events, such as cardiovascular and gastrointestinal problems (Karaconji, I.B. et al., Arh Hig Rada Toksikol. 2005 56(4):363-71 ). Consequently, there is a need to identify subtype-selective compounds that retain the beneficial ef- fects of nicotine, or an NNR ligand, while eliminating or decreasing adverse effects.

Examples of reported NNR ligands are a7 NNR agonists, such as DMXB-A,

SSR18071 1 and ABT-107, which have shown some beneficial effects on cognitive processing both in rodents and humans (H312: 1213-22; Olincy, A. et al., Arch Gen Psychiatry. 2006 63(6):630-8; Pichat, P. et al., Neuropsychopharmacology. 2007 32(1 ):17-34; Bitner R.S., J Pharmacol Exp Then 2010 1 ;334(3):875-86). In addition, modulation of a7 NNRs have been reported to improve negative symptoms in patients with schizophrenia (Freedman, R. et al., Am J Psychiatry. 2008 165(8):1040-7).

Despite the beneficial effects of NNR ligands, it remains uncertain whether chronic treatment with agonists affecting NNRs may provide suboptimal benefit due to sustained acti- vation and desensitization of the NNRs, in particular the a7 NNR subtype. In contrast to agonists, administering a positive allosteric modulator (PAM) can reinforce endogenous cholinergic transmission without directly stimulating the target receptor. Nicotinic PAMs can selectively modulate the activity of ACh at NNRs, preserving the activation and deactivation kinetics of the receptor. Accordingly, a7 NNR-selective PAMs have emerged (Faghih, R., Recent Pat CNS Drug Discov. 2007, 2(2):99-106).

Consequently, it would be beneficial to increase a7 NNR function by enhancing the effect of the endogenous neurotransmitter acetylcholine via PAMs. This could reinforce the endogenous cholinergic neurotransmission without directly activating a7 NNRs, like agonists. Indeed, PAMs for enhancing channel activity have been proven clinically successful for GABAa receptors where benzodiazepines and barbiturates, behave as PAMs acting at distinct sites (Hevers, W. et al., Mol. Neurobiol., 1998, 18: 35-86).

To date, only a few NNR PAMs are known, such as 5-hydroxyindole (5-HI), ivermectin, galantamine, and SLURP-1 , a peptide derived from acetylcholinesterase (AChE).

Genistein, a kinase inhibitor was also reported to increase a7 responses. PNU-120596, a urea derivative, was reported to increase the potency ACh as well as improve auditory gating deficits induced by amphetamine in rats. Also, NS1738, JNJ-1930942 and compound 6 have been reported to potentiate the response of ACh and exert beneficial effect in experimental models of sensory and cognitive processing in rodents. Other NNR PAMs include derivatives of quinuclidine, indole, benzopyrazole, thiazole, and benzoisothiazoles (Hurst, R. S. et al., J. Neurosci., 2005, 25: 4396-4405; Faghih, R., Recent Pat CNS Drug Discov. 2007, 2(2):99- 106; Timmermann, D.B., J Pharmacol Exp Ther. 2007, 323(1 ):294-307; Ng, H.J. et al., Proc. Natl. Acad. Sci. U S A. 2007, 104(19):8059-64; Dinklo T, J Pharmacol Exp Ther. 201 1 336(2):560-74.).

Of particular examples WO 01/32619 discloses that compounds of the following core structure possess PAM activity

tructure

with PAM activity

WO 2009/127678 and WO 2010/1 19078 discloses compounds with the core structures

with PAM activity based on an in vitro assay. Likewise WO 2009/127679 discloses 25 com- pounds of similar structures with PAM activity.

The a7 NNR PAMs presently known generally demonstrate weak activity, have a range of non-specific effects, or can only achieve limited access to the central nervous system where a7 NNRs are abundantly expressed. Accordingly, it would be beneficial to identify and provide new PAM compounds of a7 NNRs and compositions for treating diseases and disorders wherein a7 NNRs are involved. It would further be particularly beneficial if such compounds can provide improved efficacy of treatment while reducing adverse effects associated with compounds targeting neuronal nicotinic receptors by selectively modulating a7 NNRs. SUMMARY OF THE INVENTION

The objective of the present invention is to provide compounds that are positive allo- steric modulators (PAMs) of the nicotinic acetylcholine receptor subtype ol.

The compounds of the present invention are defined by formula [I] below:

[I]

wherein R1 , R2, R4 and R5 are selected independently from H, Ci_-4alkyl, C₂-₄alkenyl, C_2- ₄alkynyl, fluorine and cyano, wherein said Ci_-4alkyl, C_2-4alkenyl or C_2-4alkynyl is optionally substituted with one or more fluorine;

R3 is selected from H, Ci_-4alkyl, C_2-4alkenyl, C_2-4alkynyl and cyano, wherein said Ci_-4alkyl, C_2- ₄alkenyl or C_2-4alkynyl is optionally substituted with one or more fluorine;

R6 represents H or methyl;

Q is selected from (i)-(iii), the arrow indicating the attachment point:

(i) (ii) (iii) n is 0, 1 or 2;

R7 represents a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the rest is C; and wherein said monocyclic saturated ring moiety is optionally substituted with one or more methyl;

R8 and R9 are selected independently from H and methyl;

and pharmaceutically acceptable salts thereof.

In one embodiment, the invention relates to a compound according to formula [I], and pharmaceutically acceptable salts thereof, for use as a medicament.

In one embodiment, the invention relates to a compound according to formula [I], and pharmaceutically acceptable salts thereof, for use in therapy. In one embodiment, the invention relates to a compound according to formula [I], and pharmaceutically acceptable salts thereof, for use in the treatment of a disease or disorder selected from Psychosis; Schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; Attention Deficit Hyperactivity Disorder (ADHD); autism spectrum disor- ders, Alzheimer's disease (AD); mild cognitive impairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's Disease; Parkinson's disease (PD); obsessive-compulsive disorder (OCD); traumatic brain injury; epilepsy; posttraumatic stress; Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain.

In one embodiment, the invention relates to a pharmaceutical composition comprising a compound according to formula [I] and pharmaceuetically acceptable salts thereof, and one or more pharmaceutically acceptable carrier or excipient.

In one embodiment, the invention relates to a kit comprising a compound according to formula [I], and pharmaceutically acceptable salts thereof, together with a compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithi- urn; sodium channel blockers and GABA signaling enhancers.

In one embodiment, the invention relates to a method for the treatment of a disease or disorder selected from Psychosis; Schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; Attention Deficit Hyperactivity Disorder (ADHD); autism spectrum disorders, Alzheimer's disease (AD); mild cognitive impairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's Disease; Parkinson's disease (PD); obsessive-compulsive disorder (OCD); traumatic brain injury; epilepsy; post-traumatic stress; Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disor- ders, reduced angiogenesis; amyotrophic lateral sclerosis and pain, which method comprises the administration of a therapeutically effective amount of a compound according to formula [I], and pharmaceutically acceptable salts thereof.

In one embodiment, the invention relates to the use of a compound according to formula [I], and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of a disease or disorder selected from Psychosis; Schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; Attention Deficit Hyperactivity Disorder (ADHD); autism spectrum disorders, Alzheimer's disease (AD); mild cognitive impairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's Disease; Parkinson's disease (PD); obsessive-compulsive disorder (OCD); traumatic brain injury; epilepsy; post-traumatic stress; Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain. Definitions

In the present context, "optionally substituted" means that the indicated moiety may or may not be substituted, and when substituted is mono-, di-, or tri-substituted, such as with 1 , 2 or 3 substituents. In some instances, the substituent is fluorine.

In the present context, "alkyl" is intended to indicate a straight, branched and/or cyclic saturated hydrocarbon. In particular "Ci_-4alkyl" is intended to indicate such hydrocarbon having 1 , 2, 3 or 4 carbon atoms. Examples of Ci_-4alkyl include methyl, ethyl, propyl, butyl, cyclo- propyl, cyclobutyl, methylcyclopropyl, 2-methyl-propyl and tert-butyl.

In the present context, "alkenyl" is intended to indicate a non-aromatic, straight, branched and/or cyclic hydrocarbon comprising at least one carbon-carbon double bond. In particular "C₂-₄alkenyl" is intended to indicate such hydrocarbon having 2, 3 or 4 carbon atoms. Examples of C_2-4alkenyl include ethenyl, 1 -propenyl, 2-propenyl, 1 -butenyl, 2-butenyl and 3-butenyl.

In the present context, "alkynyl" is intended to indicate a non-aromatic, straight, branched and/or cyclic hydrocarbon comprising at least one carbon-carbon triple bond and optionally also one or more carbon-carbon double bonds. In particular "C₂-₄alkynyl" is intended to indicate such hydrocarbon having 2, 3 or 4 carbon atoms. Examples of C_2-4alkynyl include ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl and 5-but-1 -en-3-ynyl.

In the present context, the term "cyano" indicates the group -C≡N, which consists of a carbon atom triple-bonded to a nitrogen atom.

In the present context, "monocyclic moiety" is intended to indicate a cyclic moiety comprising only one ring, said cyclic moiety can be saturated or unsaturated. Monocyclic saturated ring moieties of the present invention includes oxetanyl, tetrahydrofuranyl and tetrahy- dropyranyl.

In the present context, "ring atom" is intended to indicate the atoms constituting a ring, and ring atoms are selected from C, N, O and S. In the present context, pharmaceutically acceptable salts include pharmaceutical acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids.

Examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.

Examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroace- tic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, ma- leic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesul- fonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline and the like. Further examples of pharmaceutical acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Berge, S.M. et al., J. Pharm. Sci. 1977,66,2, which is incorporated herein by reference.

Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like.

Examples of ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyl-, sec-butyl-, tert-butyl-, tetrame- thylammonium salts and the like.

In the present context, pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyeth- ylene and water. Similarly, the carrier may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

In the present context, the term "therapeutically effective amount" of a compound means an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. An amount adequate to accomplish this is defined as "therapeutically effective amount". Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by con- structing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician. In the present context, the terms "treatment" and "treating" mean the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The terms are intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatments are two separate aspects of the present invention. The patient to be treated is preferably a mammal, in particular a human being.

In the present context, the term "cognitive disorders" is intended to indicate disorders characterized by abnormalities in aspects of perception, problem solving, language, learning, working memory, memory, social recognition, attention and pre-attentional processing, such as but not limited to Attention Deficit Hyperactivity Disorder (ADHD), autism spectrum disorders, Alzheimer's disease (AD), mild cognitive impairment (MCI), age associated memory impairment (AAMI), senile dementia, vascular dementia, frontotemporal lobe dementia, Pick's disease, dementia associated with Lewy bodies, and dementia associated with Down's syn- drome, cognitive impairment associated with Multiple Sclerosis, cognitive impairment in epilepsy, cognitive impairment associated with fragile X, cognitive impairment associated with neurofibromatosis, cognitive impairment associated with Friedreich's Ataxia, progressive supranuclear palsy (PSP), HIV associated dementia (HAD), HIV associated cognitive impairment (HIV-CI), Huntington's Disease, Parkinson's disease (PD), traumatic brain injury, epi- lepsy, post-traumatic stress, Wernicke-Korsakoff syndrome (WKS), post-traumatic amnesia, cognitive deficits associated with depression as well as cognitive impairment associated with schizophrenia.

The cognitive enhancing properties of a compound can be assessed e.g. by the atten- tional set-shifting paradigm which is an animal model allowing assessment of executive func- tioning via intra-dimensional (ID) versus extra-dimensional (ED) shift discrimination learning. The study can be performed by testing whether the compound is attenuating "attentional performance impairment" induced by subchronic PCP administration in rats as described by Rodefer; J.S. et al., Eur. J. Neurosci. 21 :1070-1076 (2005).

In the present context, the term "autism spectrum disorders" is intended to indicate disorders characterized by widespread abnormalities of social interactions and verbal and non-verbal communication, as well as restricted interests, repetitive behavior and attention, such as by not limited to autism, Asperger syndrome, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), Rett syndrome, Angelmann syndrome, fragile X, DiGeorge syndrome and Childhood Disintegrative Disorder.

In the present context, the term "inflammatory disorders" is intended to indicate disor- ders characterized by abnormalities in the immune system such as by not limited to, allergic reactions and myopathies resulting in abnormal inflammation as well as non-immune diseases with etiological origins in inflammatory processes are thought to include by not be limited to cancer, atherosclerosis, osteoarthritis, rheumatoid arthritis and ischaemic heart disease.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have found that certain new compounds are positive allosteric modulators (PAMs) of NNRs, and as such may be used in the treatment of various diseases and disorders.

PAMs of NNRs may be dosed in combination with other drugs in order to achieve more efficacious treatment in certain patient populations. An ol NNR PAM may act synergis- tically with another drug, this has been described in animals for the combination of compounds affecting nicotinic receptors, including a7 NNRs and D2 antagonism (Wiker, C, Int. J. Neuropsychopharmacol. 2008 Sep;1 1 (6):845-50).

Thus, compounds of the present invention may be useful treatment in the combination with another drug e.g. selected from acetylcholinesterase inhibitors, glutamate receptor antagonists, dopamine transport inhibitors, noradrenalin transport inhibitors, D2 antagonists, D2 partial agonists, PDE10 antagonists, 5-HT2A antagonists, 5-HT6 antagonists and KCNQ antagonists, lithium, sodium channel blockers, GABA signalling enhancers.

In one embodiment, compounds of the present invention are used for treatment of patients who are already in treatment with another drug selected from the list above. In one embodiment, compounds of the present invention are adapted for administration simultaneous with said other drug. In one embodiment compounds of the present invention are adapted for administration sequentially with said other drug. In one embodiment, compounds of the pre- sent invention are used as the sole medicament in treatment of a patient. In one embodiment, compounds of the present invention are used for treatment of patients who are not already in treatment with another drug selected from the list above. Embodiments according to the invention

In the following, embodiments of the invention are disclosed. The first embodiment is denoted E1 , the second embodiment is denoted E2 and so forth.

A compound according to formula [I]

[I]

R6 represents H or methyl;

Q is selected from (i)-(iii), the arrow indicating the attachment point:

(i) (ii) (iii) n is 0, 1 or 2;

R8 and R9 are selected independently from H and methyl;

and pharmaceutically acceptable salts thereof. E2. The compound according to embodiment 1 , wherein R1 , R2, R4 and R5 are selected independently from H, methyl, trifluoromethyl and fluorine. E3. The compound according to any of embodiments 1 -2, wherein R3 is H.

E4. The compound according to any of embodiments 1 -3, wherein all of R1 -R5 are H. E5. The compound according to any of embodiments 1 -3, wherein R1 is selected from methyl and trifluoromethyl, and all of R2-R5 are H.

E6. The compound according to any of embodiments 1 -3, wherein R1 is selected from methyl and trifluoromethyl, and one or two of R1 , R2, R4 and R5 are fluorine and the remain- ing of R2-R5 are H.

El. The compound according to any of embodiments 1 -6, wherein n is 0 or 1.

E8. The compound according to any of embodiments 1 -7, wherein R6 represents methyl, and wherein said compound is essentially the R-enantiomer as depicted in formula [Γ]

[II E9. The compound according to any of embodiments 1 -7, wherein R6 represents H.

E10. The compound according to any of embodiments 1 -9, wherein Q is selected from (i) and (ii). E1 1. The compound according to any of embodiments 1 -9, wherein Q is (iii).

E12. The compound according to any of embodiments 1 -6 and 8-9, wherein Q is selected from (i)-(iii) with the proviso that if Q is (iii) then n is 1 or 2. E13. The compound according to any of embodiments 1 -12, wherein R7 is selected from (iv)-(vi), the arrow indicating the attachment point:

(iv) (v) (vi) wherein R10 is selected from H and methyl. E14. The compound according to embodiment 13, wherein R10 is H.

E15. The compound according to any of embodiments 1 -14, wherein both of R8 and R9 are H. E16. The compound according to embodiment 1 , with the proviso that the compound of formula [1 ] is not N-[(2-methyl-1 H-indol-5-yl)methyl]-1 -(oxetan-3-yl)pyrazole-4-carboxamide, racemic N-[(2-methyl-1 H-indol-5-yl)methyl]-1 -tetrahydrofuran-3-yl-pyrazole-4-carboxamide or N-[(1 R)-1 -(2-methyl-1 H-indol-5-yl)ethyl]-1 -(oxetan-3-yl)pyrazole-4-carboxamide. E17. The compound according to embodiment 1 selected from

1 : 1 -Oxetan-3-yl- 1 H-pyrazole-4-carboxylic acid [(R)- 1 -( 6-fluoro- 1 H-indol-5-yl)-ethyl]-amide; 2: 3-Methyl-1 -(R)-tetrahydro-furan-3-yl-1 H-pyrazole-4-carboxylic acid (2-methyl-1H-indol-5- ylmethyl)-amide;

3: 3-Oxetan-3-yl-isoxazole-5-carboxylic acid [(R)-1-(2-methyl-1 H-indol-5-yl)-ethyl]-amide; 4: 3-(3-Methyl-oxetan-3-yl)-isoxazole-5-carboxylic acid [(R)-1-(2-methyl-1H-indol-5-yl)-ethyl]- amide;

5: (S)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid [(R)-1 -(2-methyl-1H-indol-5-yl)- ethyl]-amide;

6 : (R)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid [(R)- 1 -(2-methyl- 1 H-indol-5-yl)- ethyl]-amide;

7: (S)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid (2-methyl-1H-indol-5-ylmethyl)- amide;

8: (R)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid (2-methyl-1H-indol-5-ylmethyl)- amide;

9: (S)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid (1H-indol-5-ylmethyl)-amide; 10 : (R)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid ( 1 H-indol-5-ylmethyl)-amide; 11 : 3-(Tetrahydro-pyran-4-yl)-isoxazole-5-carboxylic acid (2-methyl-1H-indol-5-ylmethyl)- amide; 12: 3-(Tetrahydro-pyran-4-yl)-isoxazole-5-carboxylic acid (1H-indol-5-ylmethyl)-amide;

13: 3-(Tetrahydro-pyran-4-yl)-isoxazole-5-carboxylic acid [(R)-1 -(2-methyl-1H-indol-5-yl)- ethyl]-amide;

14 : 3-Oxetan-3-ylmethyl-isoxazole-5-carboxylic acid ( 2-methyl- 1 H-indol-5-ylmethyl)-amide; 15: 3-Oxetan-3-ylmethyl-isoxazole-5-carboxylic acid (1H-indol-5-ylmethyl)-amide;

16 : 3-Oxetan-3-ylmethyl-isoxazole-5-carboxylic acid [(R)-1 -(2-methyl- 1 H-indol-5-yl)-ethyl]- amide;

17: 1 -Oxetan-3-yl- 1 H-pyrazole-4-carboxylic acid ( 6, 7-difluoro- 1 H-indol-5-ylmethyl)-amide; 18: 1 -Oxetan-3-yl-1 'H-pyrazole-4-carboxylic acid (6-fluoro-1H-indol-5-ylmethyl)-amide;

19: 7 -Oxetan-3-yl- 1 H-pyrazole-4-carboxylic acid (7-fluoro- 1 H-indol-5-ylmethyl)-amide;

20 : 1 -Oxetan-3-yl- 1 H-pyrazole-4-carboxylic acid ( 6, 7-difluoro-2-methyl- 1 H-indol-5-ylmethyl)- amide;

21 : 3-(3-Methyl-oxetan-3-yl)-isoxazole-5-carboxylic acid (2-methyl-1H-indol-5-ylmethyl)- amide;

22 : 1 -Oxetan-3-yl- 1 H-pyrazole-4-carboxylic acid [(R)- 1 -(7-fluoro- 1 H-indol-5-yl)-ethyl]-amide; 23 : 5-Methyl- 1 -(S)-tetrahydro-furan-3-yl- 1 H-pyrazole-4-carboxylic acid ( 2-methyl- 1 H-indol-5- ylmethyl)-amide;

24 : 3-Methyl- 1 -(S)-tetrahydro-furan-3-yl- 1 H-pyrazole-4-carboxylic acid ( 2-methyl- 1 H-indol-5- ylmethyl)-amide;

25: 1 -(Tetrahydro-furan-3-yl)-1H-pyrazole-4-carboxylic acid (2-trifluoromethyl-1H-indol-5- ylmethyl)-amide;

26: 1-Oxetan-3-yl-1H-pyrazole-4-carboxylic acid (2-trifluoromethyl-1H-indol-5-ylmethyl)- amide;

27: 3,5-Dimethyl-1-(S)-tetrahydro-furan-3-yl-1H-pyrazole-4-carboxylic acid (2-methyl-1H- indol-5-ylmethyl)-amide;

28: 5-Methyl-1 -(R)-tetrahydro-furan-3-yl-1H-pyrazole-4-carboxylic acid (2-methyl-1H-indol-5- ylmethyl)-amide;

29: 3,5-Dimethyl-1-(R)-tetrahydro-furan-3-yl-1H-pyrazole-4-carboxylic acid (2-methyl-1H- indol-5-ylmethyl)-amide;

30: (S)-1 -(Tetrahydro-furan-3-yl)-1H-pyrazole-4-carboxylic acid (2-methyl-1H-indol-5- ylmethyl)-amide;

31 : 1 -(Tetrahydro-pyran-4-yl)-1H-pyrazole-4-carboxylic acid (2-methyl-1H-indol-5-ylmethyl)- amide;

32: (R)-1 -(Tetrahydro-furan-3-yl)-1H-pyrazole-4-carboxylic acid (2-methyl-1H-indol-5- ylmethyl)-amide;

33: 1-Oxetan-3-yl-1H-pyrazole-4-carboxylic acid (7-fluoro-2-methyl-1H-indol-5-ylmethyl)- amide;

34: 3-Oxetan-3-yl-isoxazole-5-carboxylic acid (7-fluoro-2-methyl-1H-indol-5-ylmethyl)-amide.

E18. A compound according to any of embodiments 1 -17 for use as a medicament.

E19. A compound according to any of embodiments 1 -17, for use in therapy.

E20. A compound according to any of embodiments 1 -17, for use in the treatment of a disease or disorder selected from Psychosis; Schizophrenia; cognitive disorders; cognitive im- pairment associated with schizophrenia; Attention Deficit Hyperactivity Disorder (ADHD); autism spectrum disorders, Alzheimer's disease (AD); mild cognitive impairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's Disease; Parkinson's disease (PD); obsessive-compulsive disorder (OCD); traumatic brain injury; epilepsy; post-traumatic stress; Wernicke-Korsakoff syndrome (WKS); posttraumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain.

E21. The compound according to embodiment 20, wherein said a disease or disorder is selected from schizophrenia; AD; ADHD; autism spectrum disorders; PD; amyotrophic lateral sclerosis; Huntington's disease; dementia associated with Lewy bodies and pain.

E22. The compound according to embodiment 21 , wherein said disease or disorder is selected from schizophrenia; AD; ADHD and autism spectrum disorders.

E23. The compound according to embodiment 22, wherein said disease or disorder is selected from negative and/or cognitive symptoms of schizophrenia.

E24. The compound according to any of embodiments 1 -17, for use concomitantly or se- quentially with a therapeutically effective amount of a compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers in the treatment of a disease or disorder accord- ing to any of embodiments 20-23. E25. A pharmaceutical composition comprising a compound according to any of embodiments 1 -17, and one or more pharmaceutically acceptable carrier or excipient.

E26. The composition according to embodiment 25, which composition additionally com- prises a second compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.

E27. The composition according to embodiment 26, wherein said second compound is an acetylcholinesterase inhibitor.

E28. A kit comprising a compound according to any of embodiments 1 -17, together with a second compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers. E29. The kit according to embodiment 28, wherein said second compound is an acetylcholinesterase inhibitor.

E30. A method for the treatment of a disease or disorder selected from Psychosis; Schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; Attention Deficit Hyperactivity Disorder (ADHD); autism spectrum disorders, Alzheimer's disease (AD); mild cognitive impairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's Disease; Parkinson's disease (PD); obsessive- compulsive disorder (OCD); traumatic brain injury; epilepsy; post-traumatic stress; Wernicke- Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain, which method comprises the administration of a therapeutically effective amount of a compound according to any of embodiments 1 -17 to a patient in need thereof. E31. The method according to embodiment 30, wherein said disease or disorder is selected from schizophrenia; AD; ADHD; autism spectrum disorders; PD; amyotrophic lateral sclerosis; Huntington's disease; dementia associated with Lewy bodies and pain. E32. The method according to embodiment 31 , wherein said disease or disorder is selected from schizophrenia; AD; ADHD and autism spectrum disorders.

E33. The method according to embodiment 32, wherein said treatment comprises the treatment of negative and/or cognitive symptoms of schizophrenia.

E34. The method according to any of embodiments 30-33, wherein said treatment further comprises the administration of a therapeutically effective amount of a second compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.

E35. The method according to embodiment 34, wherein said second compound is an acetylcholinesterase inhibitor.

E36. Use of a compound according to any of embodiments 1 -17, for the manufacture of a medicament for the treatment of a disease or disorder selected from Psychosis; Schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; Attention Deficit Hyperactivity Disorder (ADHD); autism spectrum disorders, Alzheimer's disease (AD); mild cognitive impairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's Disease; Parkinson's disease (PD); obsessive- compulsive disorder (OCD); traumatic brain injury; epilepsy; post-traumatic stress; Wernicke- Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with de- pression; diabetes, weight control, inflammatory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain.

E37. The use according to embodiment 36, wherein said disease or disorder is selected from schizophrenia; AD; ADHD; autism spectrum disorders; PD; amyotrophic lateral sclerosis; Huntington's disease; dementia associated with Lewy bodies and pain. E38. The use according to embodiment 37, wherein said disease or disorder is selected from schizophrenia; AD; ADHD and autism spectrum disorders.

E39. The use according to embodiment 38, wherein said disease or disorder is selected from the positive, negative and/or cognitive symptoms of schizophrenia.

E40. The use according to any of embodiments 36-39, wherein said medicament further comprises a second compound selected from the list consisting of acetylcholinesterase inhibitors; glutamate receptor antagonists; dopamine transport inhibitors; noradrenalin transport inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5- HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABA signaling enhancers.

E41. The use according to embodiment 41 , wherein said second compound is an acetyl- cholinesterase inhibitor.

The compounds of the invention may exist in unsolvated as well as in solvated forms in which the solvent molecules are selected from pharmaceutically acceptable solvents such as water, ethanol and the like. In general, such solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.

Included also in this invention are isotopically labeled compounds, which are identical to those claimed in formula [I], wherein one or more atoms are represented by an atom of the same element having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (e.g., ²H, ³H, ¹¹C, ¹³C, ¹⁵N, ¹⁸F and the like).

The compounds of the present invention may have one or more asymmetric centres and it is intended that any optical isomers (i.e. enantiomers or diastereomers), in the form of separated, pure or partially purified optical isomers and any mixtures thereof including race- mic mixtures, i.e. a mixture of stereoisomers, are included within the scope of the invention.

When R6 is other than H, the compounds of the present invention may have an asymmetric centre at C-R6 indicated with an arrow below. In a preferred embodiment, the compounds of the invention wherein R6 is other than H are manufactured from a chiral intermediate e.g. (R)-1 -(2-Methyl-1 H-indol-5-yl)-ethylamine (IM3) with the stereochemistry around R6 as indicated by the arrow below.

In this context is understood that when specifying the enantiomeric form, then the compound is in enantiomeric excess, e.g. essentially in a pure, mono-enantiomeric form. Accordingly, one embodiment of the invention relates to a compound of the invention having an enantiomeric excess of at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98%.

Racemic forms can be resolved into the optical antipodes by known methods, for example by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolv- ing racemates into the optical antipodes is based upon chromatography of an optically active matrix. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives. Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981 ). Optically active compounds can also be prepared from optically active starting materials.

Furthermore, when a double bond or a fully or partially saturated ring system is present in the molecule geometric isomers may be formed. It is intended that any geometric isomers, as separated, pure or partially purified geometric isomers or mixtures thereof are in- eluded within the scope of the invention. Likewise, molecules having a bond with restricted rotation may form geometric isomers. These are also intended to be included within the scope of the present invention.

Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms that the compounds are able to form are included within the scope of the present invention.

The compounds of the present invention may be administered alone as a pure compound or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.

Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants, etc.

In one embodiment, the compound of the present invention is administered in an amount from about 0.001 mg/kg body weight to about 100 mg/kg body weight per day. In particular, daily dosages may be in the range of 0.01 mg/kg body weight to about 50 mg/kg body weight per day. The exact dosages will depend upon the frequency and mode of administration, the sex, the age the weight, and the general condition of the subject to be treated, the nature and the severity of the condition to be treated, any concomitant diseases to be treated, the desired effect of the treatment and other factors known to those skilled in the art.

A typical oral dosage for adults will be in the range of 0.1 -1000 mg/day of a compound of the present invention, such as 1 -500 mg/day, such as 1 -100 mg/day or 1 -50 mg/day.

Conveniently, the compounds of the invention are administered in a unit dosage form contain- ing said compounds in an amount of about 0.1 to 500 mg, such as 10 mg, 50 mg 100 mg, 150 mg, 200 mg or 250 mg of a compound of the present invention.

For parenteral administration, solutions of the compound of the invention in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administra- tion. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, su- crose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospho lipids, fatty acids, fatty acid amines, polyoxyethylene and water. The pharmaceutical compositions formed by combining the compound of the invention and the pharmaceutical acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation may be tablet, e.g. placed in a hard gelatine capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier may vary but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gela- tine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents followed by the compression of the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, mag- nesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law), regardless of any separately provided incorporation of particular documents made elsewhere herein.

The use of the terms "a" and "an" and "the" and similar referents in the context of de- scribing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. For example, the phrase "the compound" is to be understood as referring to various "compounds" of the invention or particular described aspect, unless otherwise indicated.

The description herein of any aspect or aspect of the invention using terms such as "comprising", "having," "including," or "containing" with reference to an element or elements is intended to provide support for a similar aspect or aspect of the invention that "consists of, "consists essentially of, or "substantially comprises" that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

It should be understood that the various aspects, embodiments, implementations and features of the invention mentioned herein may be claimed separately, or in any combination.

General Synthetic Schemes

The compounds of formula [I] may be prepared by methods described below, together 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 available commercially or may be prepared by routine methods known in the art, such as those method described in standard reference books such as "Compendium of Organic Synthetic Methods, Vol. Ι-ΧΙΓ (published with Wiley-lnterscience). Preferred methods include, but are not limited to, those described below.

The schemes are representative of methods useful in synthesizing the compounds of the present invention. They are not to constrain the scope of the invention in any way.

It is understood that when typical or preferred reagents and experimental conditions are used (e.g. equivalents, solvents, temperatures, reaction times etc.) alternative experimental condi- tions can also be used - unless otherwise stated. The optimum reaction conditions may vary with specific reactants and experimental conditions, but can be optimized by a person skilled in the art by using routine optimization approaches.

Experimental Procedures and Working Examples

Synthesis of various compounds of the present invention are described in the following. Additional compounds within the scope of this invention may be prepared using the methods illustrated in these examples, either alone or in combination with techniques generally known in the art. The synthesis of substituted indoles is well described in the art, for example by Taber, D.F. and Tirunahari, P.K., Tetrahedron, 201 1 , 67: 7195-7210 and references cited herein.

1.8

Scheme 1

Scheme 1 illustrates methods for preparing chiral indole amine compounds depicted by formula 1 .8. PG = suitable protecting group.

Cyano compounds depicted by formula 1.2 can be prepared by cyanation of compounds depicted by formula 1 .1 by treatment under conditions such as CuCN in quinoline. Addition of organometallic reagents to cyano compounds depicted by formula 1.2 followed by hydrolysis of the resulting addition product can provide ketone compounds depicted by formula 1.3. Alternatively, for R6 = methyl bromides depicted by formula 1.1 can be reacted with (1 - ethoxy-vinyl)-trialkyl-stannanes under palladium catalysis to give acetyl compounds depicted by formula 1 .3 (R6 = methyl).

Cyano compounds depicted by formula 1 .2 can be reduced to formyl compounds depicted by formula 1.4 by reagents such as DIBAL-H in solvents such as methylene chloride. These formyl compounds can reacted with chiral ie f-butane sulfinamide to give chiral tert- butylsulfinylmides depicted by formula 1 .5. Addition of organometallic reagents to sulfi- nylimides depicted by formula 1.5 will give compounds depicted by formula 1.7 with of high diastereomeric purity. Deprotection of compounds depicted by formula 1 .7 by for example HCI in methanol can give chiral indole amine compounds depicted by formula 1.8.

Compounds depicted by formula 1.3 can react with ie f-butane sulfinamide to give imines depicted by formula 1.6 under Lewis acid mediated conditions. One such Lewis acid could be Ti(OEt)₄. Imines depicted by formula 1.6 can be transformed to compounds depicted by for- mula 1 .7 under reducing conditions such as DIBAL-H or L-selectride in solvents such as THF. Formation of sulfinylimides and their use for the stereoselective synthesis of amines is well- described in the literature, for example in recent review Ellman, J. A.; Owens, T. D.; Tang, T. P., Acc. Chem. Res. 2002, 35, 984.

Alternatively, racemic indole amine compounds could be envisaged separated into pure enantiomers by using e.g. chiral SFC or preparative HPLC methods.

2.5

Scheme 2

Scheme 2 illustrates methods for preparing isoxazole compounds depicted by formula 2.4.

Aldehyde compounds depicted by formula 2.1 can react with hydroxylamine to form oximes depicted by formula 2.2. These oximes can react with pronynoic acid alkyl esters under treatment with compounds like sodium hypochlorite to give isoxazole compound depicted by formula 2.3. These esters can be hydrolyzed to isoxazole carboxylic acids depicted by formula 2.4 under treatment with, for example, NaOH in water. Alternatively, isoxazole com- pounds depicted by formula 2.3 can be prepared by treating nitro compounds depicted by formula 2.5 under conditions like boc-anhydride in solvents such as acetonitrile in the presence DMAP. Additional methods for the synthesis of isoxazoles are well described in the art, for example in Teresa M.V.D., Pinho e Melo, Current Organic Chemistry, 2005, 9: 925-958 and references cited herein.

3.1

Scheme 3

Scheme 3 illustrates methods for preparing pyrazoles depicted by formula 3.4.

Pyrazoles depicted by formula 3.1 can be reacted with halides in solvents such as DMF in the presence base e.g. Cs₂C0₃ to give pyrazoles of formulas 3.2 and 3.3. Alternatively, alcohols depicted by formula 3.5, which may or may not be chiral, can be transformed to electrophilic tosylates by treatment with TsCI in the presence of a base such as NaH. Tosylates depicted by formula 3.6 can then be reacted with pyrazoles depicted by formula 3.1 in solvents such as DMF in the presence of bases such as Cs₂C0₃ to give compounds such as those depicted by formulas 3.2 and 3.3. For unsymmetrical pyrazoles depicted by formula 3.1 the alkylated pyrazoles can be separated into isomers 3.2 and 3.3 by standard methods. When chiral tosylates depicted by formula 3.6 are enantiomerically pure, enantiomerically enriched pyrazoles depicted by formulas 3.2 and 3.3 based on inversion of the stereocenter are obtained. Hy- drolysis of the ester functionality provides pyrazoles depicted by formula 3.4.

Scheme 4

Scheme 4 illustrates methods for preparing compounds of the invention.

If X is a hydroxyl, the carboxylic acid II and the amine III can be condensed to form the amide I using standard peptide coupling chemistry, e.g. as described in the textbook Synthetic Peptides A user's Guide (Edited by Gregory A. Grant, W. H. Freeman and company (1992) ISBN 0-7167-7009-1) or as described in the textbook Houben-Weyl Volume E22a Synthesis of peptides (George Thiemes Verlag Stuttgart (2003) 4th ed.). If X is a chloride (e.g. prepared from the carboxylic acid depicted by formula 4.1 , X = OH, using thionyl chloride) 4.1 can be reacted with 1 .8 to form I in the presence of a tertiary amine in a suitable solvent.

EXAMPLES

The invention will be illustrated by the following non-limiting examples. Abbreviations

brine = saturated aqueous solution of sodium chloride, cone = concentrated. DIPEA = N,N- Diisopropylethylamine. DMAC = Ν,Ν-Dimethylacetamide. DMAP = 4-(dimethylamino) pyri- dine. DMF = dimethyl formamide. DMSO = dimethyl sulfoxide. EtOAc = ethyl acetate, h = hours. HATU = 0-(7-Azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophos- phate. HOBt = 1 -Hydroxybenzotriazole. HPLC = High Performance Liquid Chromatography. LC = Liquid Chromatography, min = minutes. mL = milliliters. Mukaiyama reagent = 2-chloro- 1 -methyl-pyridinium iodide. TBME = tert-butyl methyl ether. THF = tetrahydrofuran. t_R = reten- tion time

Spectroscopic methods

Analytical LCMS

Method A:

Analytical LCMS was performed using a Waters Acquity UPLC-MS consisting of Waters Aq- uity including column manager, binary solvent manager, sample organizer, PDA detector (op- erating at 254 nm), ELS detector and SQ-MS equipped with APPI-source operating in positive ion mode (ESI-source, APCI-source positive ion mode, negative ion mode).

LC-conditions: The column was a Acquity UPLC BEH C18 1 .7μη"ΐ; 2.1 x50 mm operating at 60°C with 1 .2 mL/min of a binary gradient consisting of water + 0.05% TFA (A) and acetoni- trile + 5% water + 0.035% TFA (B).

Gradient: Time, min. %B

0.00 10.0

1 .00 99.9

1 .01 10.0

1 .15 10.0

Method B:

LC-MS were run on Waters Aquity UPLC-MS consisting of Waters Aquity including column manager, binary solvent manager, sample organizer, PDA detector (operating at 254 nM), ELS detector, and TQ-MS equipped with APPI-source operating in positive ion mode.

LC-conditions: The column was Acquity UPLC BEH C18 1 .7μηι ; 2.1x50 mm operating at 60°C with 1.2 mL/min of a binary gradient consisting of water + 0.05% trifluoroacetic acid (A) and acetonitrile + 5% water + 0.05% trifluoroacetic acid.

Gradient: Time, min. %B

0.00 10

1 .00 100

1 .01 10

1 .15 10

¹H NMR spectra

¹H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX-500 instrument at T=303.3 K or at 600 MHz on a Bruker Avance AV-lll-600 instrument or at 400 MHz on a Vari- an 400MR instrument at T=298.15 K or at 400 MHz on a Varian vnmrs instrument. Chemical shift values are expressed in ppm-values relative to tetramethylsilane unless noted otherwise. The following abbreviations or their combinations are used for multiplicity of NMR signals: s = singlet, d = doublet, m = multiplet, t = triplet and br = broad. Preparation of intermediates

Synthesis of indoleamines

Step 1 :

To a mixture of NaH (4.7 g, 1 18.3 mmol) in anhydrous THF (200 mL) was added reagent 1 (21 g, 98.6 mmol) at 0 °C. The mixture was kept at 0 °C for 30 min and then a solution of benzenesulfonyl chloride (20.9 g, 1 18.3 mmol) in anhydrous THF (200 mL) was added slowly at 0 °C. After addition, the resulting mixture was stirred at 0 °C for 4 hours and subsequently at 25 °C for 2 hours. The reaction was quenched with H₂0 (100 mL). The mixture was extracted with EtOAc (400 mL). The organic layer was washed with brine, dried over Na₂S0₄ and concentrated in vacuo. Flash chromatography (silica, petroleum ether : EtOAc from 40:1 to 2:1 ) gave reagent 2 as a colorless solid (32 g, 92%). ¹H NMR (DMSO) δ 8.05-8.07 (m, 2

H), 7.92-7.99 (m, 1 H), 7.89-7.90 (m, 2 H), 7.70-7.75(m, 1 H), 7.60-7.63(m, 2 H), 6.82-6.83(m, 1 H). Step 2:

To a mixture of reagent 2 (35.0 g, 98.8 mmol), LiCI (12.6 g, 296.4 mmol) and Pd(PPh₃)₄ in di- oxane (300 mL) was added tributyl-(1 -ethoxy-vinyl)-stannane (40.1 mL, 1 18.6 mmol). The mixture was heated to reflux under N₂ overnight. The mixture was evaporated to dryness and the residue was then dissolved in water. The pH was adjusted to approx. 4 by addition of a 10% aqueous HCI solution. The solution was extracted with EtOAc (500 mL). The combined organic layers were washed with brine, dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether : EtOAc from 40:1 to 2:1 ) gave reagent 3 as a yellow solid (26.6 g, 85%). ¹H NMR (DMSO) δ 8.07-8.12 (m, 3 H), 7.94 (d, J = 3.6 Hz, 1 H), 7.72- 7.83 (m, 2 H), 7.61 -7.65 (m, 2 H), 6.97 (d, J = 3.6 Hz, 1 H), 2.59 (d, J = 4.4 Hz, 3 H).

Step 3:

A mixture of reagent 3 (26.6 g, 82.9 mmol), (S)-2-methyl-propane-2-sulfinic acid amide (25.1 g, 207.3 mmol) and Ti(OiPr)₄ (47.1 g, 165.8 mmol) in anhydrous toluene (250 mL) was heated to reflux overnight. The mixture was diluted with toluene (200 mL), quenched with water (50 mL), filtered through a plug of celite. The plug of celite was washed with toluene. The combined filtrates were concentrated in vacuo. Flash chromatography (silica, petroleum ether: EtOAc 10:1 to 5:1 ) gave reagent 4 as a yellow oil (21 .0 g, 60%) which was used without further purification.

Step 4:

To a solution of reagent 4 (21.0 g, 50.0 mmol) in anhydrous THF (200 mL) was added L- selectride (100 mL, 1 M, 100 mmol) drop wise at -78°C under N₂. The mixture was kept at - 78°C for 4 h and then allowed to reach room temperature overnight. The mixture was quenched with brine and extracted with EtOAc (200 mL). The combined organic layers were dried over Na₂S0₄ and then evaporated to dryness. Flash chromatography (silica, petroleum ether : EtOAc from 10:1 to 2:1 ) gave reagent 5 as a yellow wax (14.2 g, 67%). ¹H NMR (DMSO) δ 8.03-8.05(m, 2 H), 7.82 (d, J = 3.6 Hz, 1 H), 7.59-7.73 (m, 5 H), 6.86 (m, 1 H), 5.41 (d, J = 6.0 Hz, 1 H), 4.67-4.67 (m, 1 H), 1 .46 (d, J = 7.2 Hz, 3 H), 1 .05 (d, 9 H).

Step 5:

To a solution of reagent 5 (14.2 g, 33.6 mmol) in anhydrous dioxane (200 mL) was added NaOH (3 M in H₂0, 180 mL) at room temperature. The mixture was heated to reflux overnight. The volatiles were removed under reduced pressure and the remaining mixture was extracted with EtOAc (200 mL). The combined organic layers were dried over Na₂S0₄, filtered and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 10:1 to 2:1 ) gave reagent 6 as a yellow wax (6.5 g, 68%). ¹H NMR (DMSO) δ 7.57 (d, J = 7.6 Hz, 1 H), 7.30-7.31 (m, 1 H), 7.1 1 (d, J = 1 1.2 Hz, 1 H), 6.40-6.41 (m, 1 H), 5.31 (d, J = 6.0 Hz, 1 H), 4.67-4.70 (m, 1 H), 1.52 (d, J = 7.2 Hz, 3 H), 1.09 (s, 9 H).

Step 6:

To a solution of reagent 6 (400 mg, 1.42 mmol) in anhydrous dioxane (4 mL) was added HCI (2 M in dioxane, 1 mL) at room temperature and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness to give the title compound IM1 as the HCI salt. The material was used in the next step without further purification.

I M2 : C-(2-Methyl- 1 H-indol-5-yl)-methylamine

Step 1 :

5-bromo-2-methylindole (6.00 g, 28.6 mmol) was dissolved in quinoline (50 mL). Copper cyanide (7.46 g, 83.3 mmol) was added. The mixture was refluxed for 1 hour.

The mixture was cooled to room temperature, diluted with EtOAc (500 mL) and washed with ice-cold hydrochloric acid (1 N). The organic layer was washed with brine, dried over MgS0₄, filtered and evaporated to dryness. Flash chromatography (silica, heptanes: EtOAc 1 :1 ) gave 2-methyl-1 H-indole-5-carbonitrile as a brown solid (4.1 1 g, 83%). Step 2:

LiAIH₄ (9.70 g, 255 mmol) was suspended in THF (400 mL) and the resulting suspension was cooled in a ice/water bath. A solution of 2-methyl-1 H-indole-5-carbonitrile (1 1 .4 g, 73 mmol) in THF (100 mL) was added drop wise over 30 minutes while keeping the internal temperature at 5-7 °C. The mixture was then heated to reflux for 1 h. The mixture was cooled in an ice- water bath. To this mixture was sequentially added 20 mL water, 10 mL sodium hydroxide- solution (5 M) and 50 mL water and the mixture was stirred for 10 minutes. A generous amount of MgS04 was added. The mixture was stirred for additional 10 minutes and then filtered. The residue was thoroughly extracted with THF. To the combined filtrates was added EtOAc (1 L) and this solution was dried with MgS04. The mixture was filtered and evaporated to dryness to give the title compound IM2 as a light-yellow powder (1 1 .9 g, 97%).

1 H NMR (500 MHz, DMSO) δ 10.76 (s, 1 H), 7.31 (s, 1 H), 7.18 (d, J = 8.2 Hz, 1 H), 6.95 (d, J = 8.2 Hz, 1 H), 6.05 (s, 1 H), 3.73 (s, 2H), 2.36 (s, 3H).

IM3: (R)- 1-(2-Methyl- 1 H-indol-5-yl)-ethylamine

Step 1 :

To a solution of NaH (2.45 g, 61 .2 mmol) in THF (150 mL) was added reagent 1 (10.0 g, 51 .0 mmol) in THF (50 mL) drop wise at 0°C and the mixture was stirred at room temperature for 30 min. A solution of benzenesulfonyl chloride (9.9 g, 56.1 mmol) in THF (50 mL) was added drop wise at 0°C. The resulting mixture was stirred at 50°C overnight. The mixture was quenched with saturated aqueous NH₄CI solution (100 mL) and the aqueous layer was extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na₂S0₄ and concentrated in vacuo. Flash chromatography (silica, petroleum ether: EtOAc from 20:1 to 5:1 ) gave reagent 2 as a yellow solid (16.9 g, 99%). ¹H NMR (CDCI₃) δ 7.80-7.76 (m, 3H), 7.67-7.59 (d, J = 2.0 Hz, 1 H), 7.49-7.45 (m, 2H), 7.38-7.31 (m, 3H), 6.52-6.51 (m, 1 H).

Step 2:

To a solution of n-BuLi (48.4 mL, 121.1 mmol) in THF (200 mL) was added a solution of diiso- propyl-amine (12.3 g, 121 .1 mmol) in THF (50 mL) drop wise at 0°C. The mixture was stirred at 0°C for 30 min. The mixture was cooled to -78°C and a solution of reagent 2 (34.0 g, 101 .2 mmol) in THF (200 mL) was added drop wise. The resulting mixture was stirred at -78°C for 2 hours. CH₃I (17.2 g, 121.1 mmol) in THF (50 mL) was added drop wise, the cooling bath was removed and the mixture was allowed to reach room temperature overnight. The mixture was quenched with saturated aqueous NH₄CI solution (200 mL). The aqueous layer was extracted with EtOAc (500 mL x 3), dried over anhydrous Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc from 20:1 to 5:1 ) gave reagent 3 as a white solid (32.2 g, 93%). ¹H-NMR (CDCI₃) δ 8.04 (d, J = 8.8 Hz, 1 H), 7.76-7.74 (m, 2H), 7.57-7.53 (m, 2H), 7.46-7.36 (m, 2H), 7.34 (s, 1 H), 6.29 (s, 1 H) , 2.58 (s, 3H).

Step 3:

To a solution of reagent 3 (10.0 g, 28.5 mmol) and LiCI (3.8 g, 85.5 mmol) in anhydrous 1 ,4- dioxane (100 mL) was added tributyl-(1 -ethoxy-vinyl)-stannane (15.5 g, 42.7 mmol) and Pd(PPh₃)₄ (3.3 g, 2.8 mmol). The resulting mixture was heated to reflux for 24 hours under N₂. The mixture was cooled to room temperature and quenched with water (100 mL). The mixture was acidified with 10% aqueous HCI and stirred for 0.5 hour at room temperature. The mixture was extracted with methylene chloride (200 mL x 3), dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc from 100:1 to 10:1 ) to gave reagent 4 as a yellow solid (3.2 g, 36%) as a yellow solid. ¹H NMR (DMSO) δ 8.1 1 -8.09 (m, 2 H), 7.88-7.84 (m, 3 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.59-7.54 (m, 2 H), 6.57-6.55 (m, 1 H), 2.59 (d, J = 1.2 Hz, 3 H), 2.56 (s, 3 H).

Step 4:

A mixture of reagent 4 (3.10 g, 9.89 mmol), (S)-2-methyl-propane-2-sulfinic acid amide (1.44 g, 19.79 mmol) and Ti(OiPr)₄ (5.62 g, 19.79 mmol) in anhydrous THF (50 mL) was heated to reflux overnight. The mixture was diluted with THF (500 mL), quenched with water (20 mL) and filtered through a plug celite. The celite was washed with THF. The combined filtrates were concentrated in vacuo. Flash chromatography (silica, petroleum ether: EtOAc from 10:1 to 2:1 ) gave reagent 5 as a yellow wax (2.65 g, 65%). ¹H NMR (DMSO) δ 8.09-8.03 (m, 2 H), 7.88-7.86 (m, 3 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.59-7.55 (m, 2 H), 6.67 (s, 1 H), 2.71 (s, 3 H), 2.59 (s, 3 H), 1.19 (s, 9 H).

Step 5:

To a solution of reagent 5 (600 mg, 1 .44 mmol) in anhydrous THF (10 mL) was added L- selectride (3.02 mL, 1 M, 3.02 mmol) at -78°C. The resulting mixture was kept under N₂ at - 78°C for 4 hours. The mixture was quenched with saturated aqueous NH₄CI solution (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na₂S0₄, filtered and evaporated to dryness. Flash chromatography (silica, petroleum ether : EtOAc from 10:1 to 1 :1 ) gave reagent 6 as a yellow wax (520 mg, 87%). ¹H NMR (DMSO) δ 8.01 - 7.93 (m, 1 H), 7.93-7.91 (m, 2 H), 7.77-7.73 (m, 1 H), 7.66-7.62 (m, 2 H), 7.48-7.32 (m, 1 H), 7.32-7.30 (m, 1 H), 6.61 (t, J = 1 .2 Hz, 1 H), 5.39 (d, J = 5.2 Hz, 1 H), 4.49 (t, J = 1 .2 Hz, 1 H), 2.65 (d, J = 1 .2 Hz, 3 H), 1 .51 (d, J = 6.8 Hz, 3 H), 1 .13 (s, 9 H).

Step 6:

To a solution of reagent 6 (520 mg, 1.24 mmol) in anhydrous MeOH (20 mL) was added HCI (6 M in MeOH, 2 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The mixture was evaporated to dryness to give reagent 7 (410 mg) as the HCI salt. The material was used without further purification. Step 7:

To a solution of reagent 7 (410 mg, 1.3 mmol) in MeOH (5 mL) was added KOH (aq., 3.0 M, 3 mL) drop wise at room temperature. The resulting mixture was stirred at 80°C overnight. The mixture was concentrated and the residue was extracted with EtOAc (20 mL x 3). The combined the organic layers were dried over anhydrous Na₂S0₄ and concentrated in vacuo to give the title compound IM3 as a yellow solid (210 mg, 93%) sufficiently pure for the next step.

IM4: C-(1 H-lndol-5-yl)-methylamine

The compound was commercially available from Sigma Aldrich (catalog no 655864).

IM5: C-(6, 7-Difluoro-1H-indol-5-yl)-methylamine

7

Step 1 :

A mixture of reagent 1 (20.00 g, 96.2 mmol) in AcOH (200 mL) was added N-iodosuccinimide (22.72 g, 101.0 mmol) in portions. The mixture was kept at 25°C for 3 hours. The solvent was removed in vacuo to afford reagent 2 as a brown solid (30.0 g, 93%) sufficiently pure for the next step. ¹H NMR (CDCI₃) δ 7.56-7.58 (m, 1 H), 4.28 (s, 2 H).

Step 2:

To a mixture of reagent 2 (16.00 g, 47.9 mmol), Pd(PPh₃)₂CI₂ (1 .60 g, 2.28 mmol) and Cul (0.45 g, 2.37 mmol) in Et₃N (200 mL) was added ethynyl-trimethyl-silane (8.00 mL, 57.4 mmol) drop wise with stirring at 0°C. The reaction was warmed to 25°C and stirred for 14 h. The volume was reduced in vacuo and the residue was extracted with MTBE (500 mL). The combined organic layers were dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 50:1 ) gave reagent 3 as a yellow solid (13.20 g, 91 %). ¹H NMR (DMSO) δ 7.29-7.32 (m, 1 H), 3.33 (s, 2 H), 0.27 (s, 9 H).

Step 3:

To a mixture of reagent 3 (12.20 g, 40.1 mmol) in DMF (200 mL) was added Cul (15.20 g, 80.2 mmol). The reaction was heated to 100°C and stirred for 5 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was extracted with EtOAc (200 mL). The organic layer was dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 30:1 to 3:1 ) gave reagent 4 as a yellow solid (9.20 g, 91 %). ¹H NMR (CDCIs) δ 8.73 (d, J = 6.0 Hz, 1 H), 7.55-7.54 (m, 1 H), 7.25 (d, J = 2.4 Hz, 1 H), 6.50-6.48 (m, 1 H). Step 4:

To a suspension of NaH (60% w/w in oil) (2.20 g, 91 .7 mmol) in THF (30 mL) was added reagent 4 (9.20 g, 39.6 mmol) in THF (100 mL) drop wise at 0°C. The mixture was stirred at room temperature for 30 min. A solution of benzenesulfonyl chloride (8.40 g, 47.6 mmol) in THF (100 mL) was then added drop wise at 0°C. The mixture was stirred at 60°C overnight. The residue was quenched with saturated aqueous NH₄CI solution (100 mL) and the aqueous layer was extracted by EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous Na₂S0₄ and evaporated to dryness to give reagent 5 as a yellow solid sufficiently pure for the next step (14.40 g, 97%). ¹H NMR (CDCI₃) δ 7.95-7.93 (m, 2 H), 7.77 (d, J = 3.6 Hz, 1 H), 7.65-7.60 (m, 1 H), 7.54-7.47 (m, 3 H), 6.60-6.59(m, 1 H).

Step 5:

A mixture of reagent 5 (10.00 g, 26.9 mmol) and CuCN (4.20 g, 46.9 mmol) in NMP (50 mL) was stirred at reflux for 4 hours. The reaction was cooled to room temperature and then poured into ice water. The precipitate was collected by filtration and washed with water. The remanens was suspended in THF (500 mL) and filtered. The filtrate was concentrated in vacuo and purified flash chromatography (silica, petroleum ether: EtOAc 20:1 to 5:1 ) to give reagent 6 as a yellow solid (7.30 g, 85%).

Step 6:

A mixture of reagent 6 (7.0 g, 22.0 mmol), Raney-Ni (0.3 g) and NH_3.H₂0 (aq., 14.0 mL) in THF (70 mL) was hydrogenated under an atmosphere of H₂ (50 psi) at room temperature overnight. The mixture was filtered through a plug of celite. The filtrate was concentrated to give reagent 7 as a white solid (7.0 g, 99%) sufficiently pure for the next step.

Step 7:

To a solution of reagent 7 (7.00 g, 21 .7 mmol) in MeOH\THF (50 mL\50 mL) was added NaOH (aq., 1.0 M, 50 mL) drop wise at room temperature. The mixture was stirred at 15°C overnight. The mixture was evaporated to dryness, and the residue was extracted with MTBE (100 mL). The organic layer was evaporated to dryness to give the title compound IM5 as a colorless solid (2.50 g, 64%) sufficiently pure for the next step. ¹H NMR (DMSO) 5 1 1.63 (s, 1 H), 7.37-7.35 (m, 2H), 6.47-6.45 (m, 1 H), 3.81 (s, 2H), 1 .79-1 .76 (m, 2H).

The compound was prepared in a sequence of steps analogously to the preparation of IM5 illustrated above. Flash chromatography (silica, CH₂CI₂: MeOH = 10:1 ) gave the title compound IM6 as a colorless solid (0.94 g, 46%). ¹H NMR (DMSO) δ 1 1.03 (s, 1 H), 7.52 (m, 1 H), 7.28 (m, 1 H), 7.09 (m, 1 H), 6.38-6.37 (m, 1 H), 3.77 (s, 2 H).

4 5

The compound was prepared in a sequence of steps analogously to the preparation of IM5 as illustrated above to give the title compound IM7 as a colorless solid (0.44 g, 47%). ¹H NMR (CDCIs) δ 8.74 (s, 1 H), 7.33 (s, 1 H), 7.21 -7.26 (m, 1 H), 9.88-6.91 (m, 1 H), 6.53-6.55 (m, 1 H), 3.94 (s, 2 H).

IM8: C- 6, 7-Difluoro-2-methyl-1H-indol-5-yl)-methylamine

4

The compound was prepared in a sequence of steps as illustrated above. Reagent 1 was prepared as described in the preparation of reagent 5 in the reaction scheme of IM5. Step 1 was performed analogously to the preparation of compound IM3 and steps 3 and 4 analogously to the preparation of compound IM5 to give the title compound IM8 as colorless crystals (1.42 g, 49%). ¹H NMR (DMSO) δ 1 1.41 (s, 1 H), 7.26 (m, 1 H), 6.20 (s, 1 H), 3.83 (s, 2 H), 2.41 (s, 3 H), 1.80 (s, 2 H).

IM9: (R)- 1-(7-Fluoro- 1 H-indol-5-yl)-ethylamine

Step 1 :

A mixture of reagent 1 (30 g, 140.8 mmol), Zn(CN)₂ (9.8 g, 84.5 mmol), Zn (2.3 g, 35.2 mmol), Pd₂(dba)₃ (6.45 g, 7.04 mmol)_, dppf (7.80 g, 14.1 mmol) in DMA (200 mL) was refluxed for 12 hours under N₂. The mixture was cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was extracted with EtOAc (300 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 40:1 to 2:1 ) gave reagent 2 as a yellow solid (15.4 g, 68%). ¹H NMR (CDCI₃) δ 8.71 (s, 1 H), 7.81 (s, 1 H), 7.38 (m, 1 H), 7.15 (m, 1 H), 6.68-6.70 (m, 1 H).

Step 2:

To a mixture of reagent 2 (7.0 g, 43.7 mmol) in anhydrous THF (70 mL) was added MeLi (68.3 mL, 109.3 mmol) drop wise at -78°C under N₂. The mixture was stirred at -78°C for 4 h and then at 0°C for 1 h. The mixture was quenched with HCI (2N aq., 80 mL) and the mixture was vigorously stirred at room temperature for 2 hours. The mixture was extracted with EtOAc (300 mL). The combined organic layers were washed with brine, dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 20:1 to 5:1 ) gave reagent 3 as a yellow solid (5.5 g, 70%). ¹H NMR (CDCI₃) δ 8.70 (s, 1 H), 8.1 1 (s, 1 H), 7.59 (m, 1 H), 7.32-7.33 (m, 1 H), 6.71 -6.72 (m, 1 H), 2.66 (s, 3 H).

Step 3:

A mixture of reagent 3 (5.5 g, 30.8 mmol), (S)-2-methyl-propane-2-sulfinic acid amide (5.6 g, 46.2 mmol) and Ti(OiPr)₄ (17.5 g, 61 .6 mmol) in anhydrous THF (60 mL) was heated to reflux overnight. After cooling to room temperature, the mixture was diluted with THF (500 mL). The mixture was quenched with water (20 mL) and the resulting mixture was filtered through a plug of celite. The celite plug was extracted with THF (200 mL). The combined filtrates were evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 10:1 to 5:1 ) gave reagent 4 as a yellow oil (3.3 g, 33%). ¹H NMR (CDCI₃) δ 12.12 (s, 1 H), 8.23 (s, 1 H), 7.66-7.70 (m, 2 H), 6.83-6.85 (m, 1 H), 2.92 (s, 3 H), 1.39 (s, 9 H).

Step 4:

To a solution of reagent 4 (3.3 g, 1 1.9 mmol) in anhydrous THF (30 mL) was added L- selectride (23.8 mL, 1 M, 23.8 mmol) drop wise at -78 °C under N₂. The mixture was kept at - 78°C for 4 hours and warmed to room temperature overnight. The reaction was quenched with brine and the resulting mixture was extracted with EtOAc (200 mL). The combined organic layers were dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (si I i— ca, petroleum ether: EtOAc 10:1 to 2:1 ) gave reagent 5 as a yellow semi-solid (2.85 g, 85%). ¹H NMR (CDCIs) δ 8.68 (s, 1 H), 7.36 (s, 1 H), 7.22-7.24 (m, 1 H), 6.88 (m, 1 H), 6.53-6.55 (m, 1 H), 4.63-4.66 (m, 1 H), 1.57(d, 3 H), 1.20 (s, 9 H).

Step 5:

To a solution of reagent 5 (1 .0 g, 3.5 mmol) in anhydrous dioxane (20 mL) was added HCI (2 M in dioxane, 10 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness to give crude compound IM9 as the HCI salt, sufficiently pure for the next step.

I M 10 : C-(2- Trifluoromethyl- 1 H-indol-5-yl)-methylamine

The compound was prepared as described in WO2009/127678A1 .

IM11 : C-(7-Fluoro-2-methyl-1H-indol-5-yl)-methylamine

Step 1 :

To a solution of reagent 1 (13 g, 0.096 mol) in 200 mL of CH₂CI₂ was added ICI (20 g, 0.12 mol) at room temperature. The mixture was stirred at room temperature overnight. The mix- ture was evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 50:1 ) gave reagent 2 (13.6 g, 54%). ¹H NMR (CDCI₃) δ 7.72 (t, 1 H), 7.24-7.27 (m, 1 H), 4.70 (br s, 2 H).

Step 2:

To a solution of reagent 2 (12.3 g, 0.047 mol) in 250 mL of Et₃N was added Pd(PPh₃)₂CI₂ (4 g, 5.7 mmol), Cul (1.5 g, 7.9 mmol) and LiCI (3 g, 0.071 mol). The mixture was flushed with N₂ three times. Prop-1 -yne gas was bubbled through the solution for 2 h. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc (600 mL). The organic layer was washed with brine (2 x 300 mL), dried over anhy- drous Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether : EtOAc 50:1 ) gave reagent 3 (7.7 g, 94%). ¹H NMR (DMSO) δ 7.51 -7.54 (m, 1 H), 7.41 (m, 1 H), 6.37 (br s, 2 H), 2.10 (s 3 H).

Step 3:

To a solution of reagent 3 (7.7 g, 0.044 mol) in 100 mL of DMF was added Cul (16.8 g, 0.088 mol). The mixture was flushed with N₂ three times and heated to 100°C for 5 h. After cooling to room temperature, the mixture was filtered. The filtrate was extracted with EtOAc (200 mL). The combined organic layers were washed with brine (100 mL 2), dried over anhydrous Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 60:1 ) gave reagent 4 (2.6 g, 34%). ¹H NMR (DMSO) δ 12.03 (br s, 1 H), 7.81 (s, 1 H), 7.31 - 7.34 (m, 1 H), 6.38 (s, 1 H), 2.43 (s, 3 H). Step 4:

A mixture of reagent 4 (2.6 g, 0.015 mol), Raney-Ni (0.2 g) and aqueous NH₃ (2 mL) in EtOH (25 mL) was hydrogenated under H₂ (45 psi) overnight at room temperature. The mixture was filtered through a plug of celite. The filtrate evaporated to dryness to give the title compound IM11 (2.4 g, 91 %) sufficiently pure for the next step.

Synthesis of carboxylic acids

To a solution of 1 H-pyrazole-4-carboxylic acid ethyl ester (1 .0 g, 7.13 mmol) in DMF (10 mL) was added Cs₂C0₃ (6.97 g, 21.40 mmol) and 3-bromo-oxetane (1 .07 g, 7.84 mmol) and the mixture was stirred for 16 h at 100 °C. The mixture was then quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na₂S0₄ and evaporated to dryness to give 1 -oxetan-3-yl-1 H-pyrazole-4-carboxylic acid ethyl ester as a colorless oil (1 .0 g, 64%) which was used without further purification.

Step 2:

To a solution of 1 -oxetan-3-yl-1 H-pyrazole-4-carboxylic acid ethyl ester (1 .7 g, 8.66 mmol) in THF:CH₃OH:Water (10:30:10 mL) was added LiOH (0.72 g, 17.32 mmol) at room temperature. The mixture was stirred for 4 h and then concentrated in vacuo. The pH was adjusted to 2-3 using 1 N HCI. The mixture was extracted with EtOAc (3 x 30 mL), the combined organic layers were dried over Na₂S0₄ and evaporated to dryness. The remanens was washed with CH₃CN (10 mL) and filtered to give the title compound IM12 as a colorless solid (800 mg, 55%) which was used without further purification. 1 H NMR (DMSO) δ 12.39 (1 H, br s), 8.37 (1 H, s), 7.93 (1 H, s), 5.65-5.58 (1 H, m), 4.92-4.89 -4.86 (2H, m).

IM13: 3-Methyl-1 -(R)-tetrahydro-furan-3-yl-1 H-pyrazole-4-carboxylic acid

and

-Methyl- 1 -(R)-tetrahydro-furan-3-yl- 1 H-pyrazole-4-carboxylic acid

Step 1 :

To a suspension of NaH (673 mg, 28.0 mmol) in THF (20 mL) was added a solution of (S)- tetrahydro-furan-3-ol (2.06 g, 23.4 mmol) in THF (40 mL) drop wise over 30 min with stirring at 0°C. Then a solution of 4-methyl-benzenesulfonyl chloride (5.33 g, 28.1 mmol) in THF (30 mL) was added drop wise. The resulting mixture was kept at 25°C for 15 h. The mixture was quenched with water and extracted with EtOAc (100 mL). The combined organic layers were dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 10:1 ) gave reagent 2 as a colorless solid (4.50 g, 80%). ¹H NMR (CDCI₃) 5 7.79 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 5.10-5.13 (m, 1 H), 3.78-3.84 (m, 4 H), 2.45 (s, 3 H), 2.08-2.12 (m, 2 H).

Step 2:

To a mixture of reagent 2 (2.77 g, 1 1.4 mmol) and Cs₂C0₃ (3.1 1 g, 9.5 mmol) in DMF (30 mL) was added 3-methyl-1 H-pyrazole-4-carboxylic acid ethyl ester (1 .47 mL, 9.5 mol). The mix- ture was kept at 80°C for 14 h. The mixture was concentrated and the residue was extracted with EtOAc (50 mL). The combined organic layers were washed with water. The organic layer was dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether : EtOAc 3:1 ) gave a mixture of reagents 3 and 4 as a solid (1 .58 g, 62%).

Step 3:

To a mixture of reagents 3 and 4 (1 .58 g, 7.1 mmol) in EtOH (20 mL) was added NaOH (564 mg, 14.1 mmol) and water (1 mL). The mixture was heated to 50°C for 5 h. The volatiles were removed in vacuo and the pH adjusted to approximately pH = 3 using 1 N HCI. The mix- ture was extracted with EtOAc (50 mL). The organic layer was dried over Na₂S0₄ and evaporated to dryness. Separation by SFC gave compound IM13 as a colorless crystals (830 mg, 60%) ¹ H NMR (CDCIs) δ 7.98 (s, 1 H), 4.89-4.94 (m, 1 H), 2.42-2.50 (m, 1 H), 2.43 (s, 3 H), 2.26-2.34 (m, 1 H) and compound IM14 as colorless crystals (360 mg, 26%) as white solid ¹ H NMR (CDCI3) δ 7.93 (s, 1 H), 4.84-7.90 (m, 1 H), 3.95-4.21 (m, 4 H), 2.59 (s, 3 H), 2.36-2.45 (m, 2 H)

SFC separation was carried out on a Berger Multigram I I instrument. Column: Chiralcel OJ 250 x 30 mm I.D., 5 [Ji m . Mobile phase: Supercritical C0₂/ MEOH =80/20 at 70 mL/min. Column Temp: 38°C. Nozzle Pressure: 100 Bar. Nozzle Temp: 60°C. Evaporator Temp: 20°C. Trimmer Temp: 25°C. Wavelength: 220 nm.

IM15: 3-Methyl-1 -(S)-tetrahydro-furan-3-yl-1 H-pyrazole-4-carboxylic acid

and

IM16: 5-Methyl-1 -(S)-tetrahydro-furan-3-yl-1 H-pyrazole-4-carboxylic acid

The title compounds were prepared as described for IM13 and IM14 starting with (R)- tetrahydro-furan-3-ol. The SFC was carried out on the ethyl ester step. Hydrolysis of the pure ethyl esters gave IM15 as colorless crystals (681 mg, 77%) ¹ H NMR (DMSO) δ 12.20 (s, 1 H), 8.20 (s, 1 H), 4.98-5.03 (m, 1 H), 3.96-4.03 (m, 2 H), 3.91 -3.96 (m, 1 H), 3.81 -3.87 (m, 1 H), 2.37-2.42 (m, 4 H), 2.29-2.37 (m, 1 H) and IM16 as colorless crystals ¹ H NMR (DMSO) δ

12.23 (s, 1 H), 7.81 (s, 1 H), 5.09-5.14 (m, 1 H), 4.00-4.10 (m, 2 H), 3.83-3.88 (m, 2 H), 2.55- 2.58 (m, 3 H), 2.36-2.41 (m, 1 H), 2.27-2.34 (m, 1 H). The SFC separation on the ester stage was carried out on a Thar SFC-200 machine. Column: Chiralpak AD 300 50 mm I.D., 5 μηι. Mobile phase: Supercritical C0₂/ MeOH(0.1 %

NH₃H₂0) =80/20 at 160 mL/min. Column Temp: 38°C. Nozzle Pressure: 100 Bar. Nozzle Temp: 60°C. Evaporator Temp: 20°C. Trimmer Temp: 25°C. Wavelength: 220 nm.

I -Dimethyl-1-(R)-tetrahydro-furan-3-yl-1H-pyrazole-4-carboxylic acid

Step 1 :

To a solution of reagent 1 (4.6 mg, 26.7 mmol) in EtOH (50 mL) was added hydrazine hydrochloride (1.8 g, 26.7 mmol). The mixture was heated to reflux for 2 hours. The solvent was removed under reduced pressure and the residue was washed with EtOAc to give reagent 2 as a colorless solid (3.1 g, 69%) sufficiently pure for the next step.

Step 2:

To a mixture of NaH (475.9 mg, 1 1 .9 mmol) in DMF (5 mL) was added reagent 2 (0.8 g, 4.8 mmol). The mixture was kept at 0°C for 30 min. To this mixture was added toluene-4-sulfonic acid (S)-(tetrahydro-furan-3-yl) ester (1 .38 g, 5.7 mmol). The resulting mixture was kept at 25°C for 16 h. The solution was quenched with water and the volatiles removed in vacuo. The mixture was extracted with EtOAc (50 mL). The combined organic layers were dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 3:1 ) gave reagent 3 as a solid (0.7 g, 63%) sufficiently pure for the next step.

Step 3:

To a solution of reagent 3 (0.7 g, 2.9 mmol) in EtOH (10 mL) was added NaOH (235 mg, 5.8 mmol) and water (1 mL). The mixture was stirred at 25°C for 24 h. The mixture was evapo- rated to dryness to give the title compound IM17 (0.6 g, quant.) sufficiently pure for the next step.

IM18: 3,5-Dimethyl-1-(S)-tetrahydro-furan-3-yl-1H-pyrazole-4-carboxylic acid

IM18 was prepared as described for IM17 starting from toluene-4-sulfonic acid (R)- (tetrahydro-furan-3-yl) ester. Flash chromatography in the last step (silica, petroleum ether : EtOAc 100:1 to 1 :2) gave the title compound IM18 as a colorless solid (603 mg, 68%). ¹H NMR (DMSO) δ 12.19 (s, 1 H), 5.02-5.08 (m, 1 H), 4.00-4.07 (m, 2 H), 3.81 -3.89 (m, 2 H), 2.26-2.56 (m, 8 H).

-Oxetan-3-yl-isoxazole-5-carboxylic acid

The compound was prepared as described in J. Med. Chem. 2010, 53, 3327-3246.

Step 1 :

To a solution of reagent 1 (20 g, 0.278 mol) in MeN0₂ (50 mL) was slowly added Et₃N (1 .0 mL) at room temperature. The resulting solution was stirred overnight. The mixture was evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 5:1 to 3:1 ) gave reagent 2 as a colorless oil (34 g, 92%). ¹H NMR (CDCI₃) δ 4.76 (s, 2 H), 4.65 (d, J = 8.0 Hz, 2 H), 4.90 (01, 2 1-1), 3.39 (s, 1 H).

Step 2:

To a solution of reagent 2 (5.8 g, 44 mol) and Et₃N (17.6 g, 174 mmol) in anhydrous meth- ylene chloride (60 mL) at -78°C was added MsCI (13.68 g, 120 mmol) drop wise over 30 min. The mixture was stirred at this temperature for 1 hour. The reaction was poured into ice water, extracted with methylene chloride (30 mL x 2). The combined organic layers were washed with brine, dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 20:1 to 5:1 ) gave reagent 3 as a colorless oil (2.5 g, 50%). ¹H NMR (CDCIs) δ 6.85-6.88 (m, 1 H), 5.58-5.62 (m, 2 H), 5.31 -5.34 (m, 2 H).

Step 3:

To a solution of reagent 3 (2.5 g, 21 .7 mmol) in anhydrous EtOH (50 mL) at 0°C was slowly added NaBH₄ (1 .24 g, 32.6 mmol). The mixture was stirred at 0°C for 2 hours. The reaction was quenched by addition of aqueous NH₄CI solution and subsequently the mixture was evaporated to dryness. The residue was extracted with EtOAc: petroleum ether (2:1 , 100 mL). The organic layer was evaporated to dryness to give crude reagent 4 as a pale yellow oil (2.0 g, 79%) sufficiently pure for the next step. ¹H NMR (CDCI₃) δ 4.90 (t, J = 7.2 Hz, 2 H), 4.72 (d, J = 8.0 Hz, 2 H), 4.47 (t, J = 6.4 Hz, 2 H), 3.63-3.73 (m, 1 H).

Step 4:

To a stirred solution of Boc₂0 (8.89 g, 41 mmol), propynoic acid ethyl ester (5.03 g, 51 mmol) and DMAP (0.21 g, 1.7 mmol) in MeCN (75 mL) at room temperature was slowly added a solution of reagent 4 (2.0 g, 17.09 mmol) in MeCN (20 mL). The resulting mixture was stirred at room temperature overnight. The mixture was evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 20:1 to 2:1 ) gave reagent 5 as a yellow oil (400 mg, 12%). ¹H NMR (CDCI₃) δ 7.04 (s, 1 H), 4.98-5.03 (m, 2 H), 4.72 (t, J = 6.4 Hz, 2 H), 4.38 (m, 2 H), 4.34- 4.36 (m, 1 H), 1 .35 (t, J = 7.2 Hz, 3 H).

Step 5:

A mixture of reagent 5 (400 mg, 2.0 mmol) and NaOH (120 mg, 3.0 mmol) in THF (2.5 mL), EtOH (2.5 mL) and water (5 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo and the aqueous layer was acidified by addition of 2N HCI to pH ap- proximately 2.0. The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na₂S0₄ and evaporated to dryness to give the title compound IM19 as a yellow solid (240 mg, 71 %). ¹H NMR (DMSO) δ 7.32 (s, 1 H), 4.91 -4.85 (t, J = 6.4 Hz, 2 H), 4.67 (t, J = 6.4 Hz, 2 H), 4.34-4.43(m, 1 H).

IM20: 3-(3-Methyl-oxetan-3-yl)-isoxazole-5-carboxylic acid

Step 1 :

A mixture of reagent 1 (0.5 g, 5.0 mmol), NH₂OH.HCI (0.35 g, 5.0 mmol) and NaOH (0.2 g, 5.0 mmol) in THF (10 mL) was stirred at 40-50°C overnight. The reaction was cooled in ice bath, then added propynoic acid ethyl ester (1.0 g, 10 mmol), followed by adding NaOCI

(5-6% aqueous solution, 5 mL). After addition, the mixture was stirred at room temperature for 4 hours. The mixture was extracted with TBME (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 100 to 10:1 ) gave reagent 3 as a colorless oil (0.5 g, 47%). ¹H NMR (CDCI₃) δ 7.00 (s, 1 H), 4.90 (d, J = 6.0 Hz, 2 H), 4.64 (d, J = 6.0 Hz, 2 H), 4.42 (m, 2 H), 1 .76 (s, 3 H), 1 .40 (t, J = 7.2 Hz, 3 H).

Step 2:

A mixture of reagent 3 (0.5 g, 2.37 mmol) and NaOH (189 mg, 4.74 mmol) in THF (5 mL), EtOH (5 mL) and water (10 mL) was stirred at 50°C for 4 hours. The volatiles were removed in vacuo and the aqueous layer was acidified by addition of 2N HCI until pH was approximately 2. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na₂S0₄ and evaporated to dryness to give the title compound IM20 as a colorless solid (0.3 g, 69%). ¹H NMR (DMSO) δ 7.35 (s, 1 H), 4.80 (d, J = 6.0 Hz, 2 H), 4.51 (d, J = 6.0 Hz, 2 H), 1 .66 (s, 3 H).

IM21 : (+)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid

and

-)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid

+22.5 (C=0.21 , MeOH) -12.5 (C=0.19, MeOH)

Step 1 :

A mixture of reagent 1 (10 g, 0.1 mol), NH₂OH.HCI (7 g, 0.1 mol) and NaOH (4.4 g, 0.1 1 mol) in THF (50 mL) was stirred at 40~50°C overnight. The mixture was then cooled in an ice bath. To this mixture was simultaneously added propynoic acid ethyl ester (20 g, 0.2 mol) and

NaOCI (5-6% aqueous solution, 100 mL) over 0.5 h. The mixture was stirred at 0°C for 4 h. The mixture was extracted with TBME (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 50:1 to 10:1 ) gave reagent 3 as a colorless oil (6.0 g, 28%). ¹H NMR (CDCI₃) δ 6.79 (s, 1 H), 4.34 (m, 2 H), 4.04-3.99 (m, 1 H), 3.98-3.92 (m, 1 H), 3.87-3.80 (m, 1 H), 3.78-3.73 (m, 1 H), 3.60-3.52 (m, 1 H), 2.38-2.28 (m, 1 H), 2.05-1.96 (m, 1 H), 1 .33 (t, J = 7.2 Hz, 3 H).

Step 2:

A mixture of reagent 3 (3.0 g, 14.2 mmol) and NaOH (1.0 g, 25 mmol) in THF (5 mL), EtOH (5 mL) and water (10 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo and then the aqueous layer was acidified by addition of 2N HCI to pH < 2. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na₂S0₄ and evaporated to dryness to give a racemic mixture of acids as a colorless solid (2.5 g, 96%). The isomers were separated by SFC (detail was shown below) to give title compound IM21 as the first peak as a yellow solid (0.9 g) ¹H NMR (DMSO) δ 7.15 (s, 1 H), 3.99-3.94 (m, 1 H), 3.87-3.81 (m, 1 H), 3.78-3.72 (m, 1 H), 3.69-3.64 (m, 1 H), 3.57-3.49 (m, 1 H), 2.32-2.22 (m, 1 H), 2.06-1.96 (m, 1 H) [a]_D ²⁰ = 22.5 (c = 0.21 g/100 mL, MeOH) and title compound IM22 as the second peak as a yellow solid (0.85 g) ¹H NMR (DMSO) δ 7.15 (s, 1 H), 3.99-3.94 (m, 1 H), 3.87-3.81 (m, 1 H), 3.78-3.72 (m, 1 H), 3.69-3.64 (m, 1 H), 3.57-3.49 (m, 1 H), 2.32-2.22 (m, 1 H), 2.06-1.96 (m, 1 H). [a]_D ²⁰ = - 12.5 (c = 0.19 g/100 mL, MeOH). The SFC separation on the ester stage was carried out on a Thar SFC-200 machine. Column: Chiralpak AD 250 30 mm I.D., 5 μηι. Mobile phase: Supercritical C0₂/MeOH+NH₄OH = 85/15 at 150 mL/min. Column Temp: 38°C. Nozzle Pressure: 100 Bar. Nozzle Temp: 60°C. Evaporator Temp: 20°C. Trimmer Temp: 25°C. Wavelength: 220 nm.

IM23: 3-(Tetrahydro-pyran-4-yl)-isoxazole-5-carboxylic acid

2 3

Step 1 :

Reagent 1 (12.66 g, 0.08 mol) was dissolved in toluene (160 mL). The solution was cooled to -78°C and DIBAL-H (80 mL, 1.0 M) was slowly added under N₂. The reaction mixture was stirred at -78 °C for 2 h. Then the reaction was then quenched by careful addition of brine. The cooling bath was removed and the mixture was stirred at room temperature for 2 h. The mixture was filtered through a plug of celite with was subsequently extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂S0₄ and evaporated to dry- ness to give reagent 2 sufficiently pure for the next step.

Step 2:

The solution of reagent 2 (9.13 g, 0.08 mol), NH₂OH.HCI (6.12 g, 88 mmol) and NaOH (3.5 g, 88 mmol) in anhydrous THF (80 mL) was stirred at room temperature for 68 hours. To this mixture was simultaneously added propynoic acid ethyl ester (9.05 g, 0.08 mol) and NaOCI (80 mL, 5-7% aqueous solution) drop wise at 0°C. The reaction mixture was stirred at 0°C for 4 h. The aqueous layer was extracted with MTBE (50 mL x 3). The combined organic layers were dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 10:0 to 3:1 ) gave reagent 4 as a yellow oil (6.86 g, 38%). ¹H NMR (CDCI₃) 5 6.82 (s, 1 H), 4.41 (m, 2 H), 4.02-4.13 (m, 2 H), 3.49-3.57 (m, 2 H), 3.04-3.10 (m, 1 H), 1 .42-1 .93 (m, 4 H), 1 .40 (t, J = 7.2 Hz, 3 H).

Step 3:

A mixture of reagent 4 (6.86 g, 30.52 mmol) and NaOH (0.4 g, 10 mmol) in H₂0 /THF/EtOH (40 mL/20 mL/20 mL) was stirred at room temperature for 2 h. The volatiles were removed in vacuo. The aqueous layer was cooled to 0°C and washed with with MTBE (50 mL x 2). The aqueous layer was acidified with 2 N HCI pH was approximately 1. The precipitate was collected by filtration and dried in vacuo to give title compound IM23 as a colorless solid (4.96 g, 83%). ¹H NMR (CDCIs) δ 7.20 (s, 1 H), 3.91 (d, J = 1.6 Hz, 2 H), 3.40-3.88 (m, 2 H), 2.99-3.08 (m, 1 H), 1 .73-1.85 (m, 2 H), 1 .63-1 .74 (m, 2 H).

IM24: 3-Oxetan-3-ylmethyl-isoxazole-5-carboxylic acid

Step 1 :

To a suspension of NaH (13.0 g, 0.32 mol) in THF (70 mL) was added malonic acid diethyl ester (51.9 g, 0.32 mol) drop wise at 0°C. When no more gas was formed reagent 1 (57.2 g, 0.27 mol) was added. The mixture was stirred at 75°C for 5 h. The mixture was allowed to reach room temperature and then quenched with water (300 mL). The mixture was extracted with MTBE (250 mL x 3). The combined organic layers were dried over MgS0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 20:1 to 10:1 ) gave reagent 2 as a colorless oil (69.6 g, 74%). ¹H NMR (CDCI₃) δ 7.24-7.34 (m, 5 H), 4.42 (s, 2 H), 4.10-4.22 (m, 4 H), 3.57 (t, J = 7.2 Hz, 1 H), 3.51 (t, J = 6.4 Hz, 1 H), 3.33 (s, 1 H), 2.17- 2.22 (m, 2 H), 1 .20-1.28 (m, 6 H).

Step 2:

To a suspension of LiAIH₄ (30.91 g, 0.81 mol) in THF (300 mL) was added a solution of rea- gent 2 (108.90 g, 0.37 mol) in THF (100 mL) drop wise at 0°C. The mixture was stirred at room temperature for 14 h. The mixture was quenched by the sequential addition of H₂0 (94 mL), 15%NaOH (94 mL) and H₂0 (188 mL). The mixture was diluted with EtOAc (500 mL) and then filtered. The filtrate was evaporated to dryness to give reagent 3 as a colorless oil (42.6 g, 55%) sufficiently pure for the next step. ¹H NMR (CDCI₃) δ 7.21 -7.33 (m, 5 H), 4.80 (s, 2 H), 3.49-3.71 (m, 8 H), 1 .77-1 .81 (m, 1 H), 1 .56-1 .62 (m, 2 H).

Step 3:

To a solution of reagent 3 (41.8 g, 0.20 mol) in THF (600 mL) was added n-BuLi (88 mL, 0.22 mol) drop wise at 0 °C. The reaction mixture was stirred for 30 minutes at 0 °C. A solution of TsCI (42.0 g, 0.22 mol) in the THF (200 mL) was added and the reaction mixture was stirred for 1 h. A solution of n-BuLi in heptanes (88 mL, 0.22 mol) was added drop wise. The reaction mixture was heated to 60°C for 14 hours. The mixture was diluted with MTBE (300 mL) and then quenched by careful addition of H₂0 (300 mL). The mixture was extracted with MTBE (400 mL x 2). The combined organic layers were dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 9:1 to 1 :9) gave reagent 4 as a colorless oil (29.72 g, yield: 77%). ¹H NMR (CDCI₃) δ 7.17-7.28 (m, 5 H), 4.69 (m, 2 H), 4.36 (m, 4 H), 3.37 (t, J = 6.4 Hz, 2 H), 3.02-3.10 (m, 1 H), 1 .88-1 .96 (m, 2 H).

Step 4:

A solution of reagent 4 (23.6 g, 0.12 mol) and Pd(OH)₂/C (3.0 g) in MeOH (150 mL) was purged with hydrogen and then stirred at 50 psi for 48 h at room temperature. The reaction mixture was filtered and evaporated to dryness to give reagent 5 as a colorless oil (12.15 g) sufficiently pure for the next step. ¹H NMR (CDCIs) 5 3.74-3.81 (m, 2 H), 3.63-3.70 (m, 1 H), 3.54-3.58 (m, 2 H), 3.46-3.53 (m, 1 H), 2.34-2.44 (m, 1 H), 2.20 (s, 1 H), 1 .90-1 .99 (m, 1 H), 1 .56-1 .61 (m, 1 H)..

Step 5:

To a solution of reagent 5 (8.0 g, 78.33 mmol) in methylene chloride (80 mL) was added Dess-Martin Periodinane (34.88 g, 82.25 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduce pressure. The residue was treated with petroleum ether: EtOAc (5:1 ) and the mixture was filtered. The filtrate was evaporated to dryness to give reagent 6 as a colorless oil sufficiently pure for the next step.

Step 6 to 8 was carried out as described above to give the title compound IM24 as a colorless solid (0.78 g). ¹H NMR (DMSO) δ 7.05 (s, 1 H), 4.66 (m, 2 H), 4.32 (t, J = 6.0 Hz, 2 H), 3.06- 3.38 (m, 1 H), 3.10 (d, J = 8.0 Hz, 2 H).

IM25: 1 -(Tetrahydro-pyran-4-yl)-1H-pyrazole-4-carboxylic acid

Step 1 :

To a mixture of NaH (1.8 g, 40 mmol) in anhydrous THF (10 mL) was added reagent 1 (2.0 g, 20 mmol). The mixture was stirred at room temperature for 1 h before addition of a solution of 4-methylbenzene-1 -sulfonyl chloride (4.6 g, 24 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature for 15 h. The solution was quenched with saturated, aqueous NH₄CI solution (30 mL). The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether : EtOAc 100:1 to 1 :1 ) gave reagent 2 (4.7 g, 92%). ¹H NMR (CDCIs) δ 7.79 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 4.0 Hz, 2 H), 4.64-4.70 (m, 1 H), 3.82-3.87 (m, 2 H), 3.42-3.48 (m, 2 H), 2.43 (s, 3 H) , 1 .75-1.87 (m, 2 H), 1 .68-1.74 (m, 2 H).

Step 2:

To a mixture of reagent 2 (2.7 g, 10.5 mmol) and Cs₂C0₃ (3.1 g, 9.5 mmol) in DMF (30 mL) was added ethyl 1 H-pyrazole-4-carboxylate (1 .3 g, 9.5 mol). The mixture was kept at 80 °C for 14 h. The mixture was then concentrated in vacuo and the residue was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with H₂0, dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether : EtOAc 3:1 ) gave reagent 3 (0.8 g, 38%). ¹H NMR (CDCI₃) δ 7.92 (s, 1 H), 7.88 (s, 1 H), 4.25 (m, 2 H), 4.03- 4.05 (m, 3 H), 3.47-3.53 (m, 2 H), 2.00-2.10 (m, 4 H), 1 .31 (t, J = 7.2 Hz, 3 H).

Step 3:

To a mixture of reagent 3 (0.9 g, 4.0 mmol) in EtOH (10 mL) was added NaOH (320 mg, 8 mmol) and water (2 mL). The mixture was heated to 50°C for 12 h. The volatiles were re- moved in vacuo. The pH of the aqueous layer adjusted to approximately 3 using 1 N HCI and the mixture was then extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na₂S0₄ and evaporated to dryness to give the title compound IM25 as a colorless solid (562 mg, 72%). ¹H NMR (CDCI₃) δ 8.01 (s, 1 H), 8.00 (s, 1 H), 4.36-4.44 (m, 1 H), 4.1 1 - 4.15 (m, 2 H), 3.52-3.59 (m, 2 H), 2.02-2.17 (m, 1 H).

IM26: 1 - Tetrahydro-furan-3-yl)-1H-pyrazole-4-carboxylic acid

Step 1 :

To a solution of tetrahydro-furan-3-ol (9.0 g, 79 mmol) and triethyl amine (20 mL, 176 mmol) in THF (200 mL) was added methanesulfonyl chloride (12.9 g, 1 13 mmol) at 0°C. The mixture was stirred overnight and then evaporated to dryness. The residue was extracted with EtOAc (3 x 300 mL) and washed with saturated, aqueous NaHC0₃. The organic layer was dried over Na₂S0₄ and evaporated to dryness to give methanesulfonic acid tetrahydro-furan-3-yl ester as a yellow viscous liquid (12.4 g, 94%) which was used without further purification.

Step 2:

To a solution of 4-iodo-1 H-pyrazole (1 1.0 g, 56.7 mmol) in DMF (100 mL) was added NaH (2.50 g, 62.38 mmol, 60% in oil). The mixture was stirred at 25°C for 30 min. A solution of me- thanesulfonic acid tetrahydro-furan-3-yl ester (10.4 g, 62.38 mmol) in DMF (20 mL) was added drop wise. The mixture was then stirred at 1 10 °C for 48 hours. This mixture was evaporated to dryness and purified by preparative HPLC (Method H) to give 4-iodo-1 -(tetrahydro- furan-3-yl)-1 H-pyrazole as a colorless oil (8.03 g, 53%). Step 3:

To a solution of 4-iodo-1 -(tetrahydro-furan-3-yl)-1 H-pyrazole (7.00 g, 26.8 mmol) in THF (100 mL) was added i-PrMgCI (2 M in THF, 106.0 mL) drop wise at 0 °C. The mixture was then stirred at 25°C for 30 min. DMF (9.69 g, 132.5 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with saturated, aqueous NH₄CI (200 mL) and then evaporated to dryness. Flash chromatography (silica, EtOAc : petroleum ether 1 :2) gave 1 -(tetrahydro-furan-3-yl)-1 H-pyrazole-4-carbaldehyde as a colorless solid (3.04 g, 60%).

Step 4: To a solution of 1 -(tetrahydro-furan-3-yl)-1 H-pyrazole-4-carbaldehyde (3.00 g, 18.05 mmol) in dioxane (150 mL) and H₂0 (30 mL) was added KMn0₄ (3.0 g, 20 mmol) at 25 °C. The mixture was stirred at room temperature for 5 hours and then evaporated to dryness. The remanens was washed with CH₃CN and EtOAc to give the title compound IM26 as colorless crystals (2.20 g, 67% yield) which was used in the next step without further purification.

1 H NMR (DMSO) δ 7.69 (s, 1 H), 7.44 (s, 1 H), 4.95-4.89 (m, 1 H), 3.96-3.90 (m, 2H), 3.84-3.77 (m, 2H), 2.37-2.28 (m, 1 H), 2.25-2.17 (m, 1 H).

IM27: (S)-1 -(Tetrahydro-furan-3-yl)-1H-pyrazole-4-carboxylic acid

Step 1 :

To a solution of toluene-4-sulfonic acid (R)-(tetrahydro-furan-3-yl) ester (1.5 g, 6.2 mmol) and Cs₂C0₃ (1 .83 g, 5.6 mmol) in DMF (20 mL) was added 1 H-pyrazole-4-carboxylic acid ethyl ester (789 mg, 5.6 mol). The mixture was kept at 80°C for 14 h. The volatiles were removed in vacuo and the residue was extracted with EtOAc (50 mL). The combined organic layers were washed with H₂0, dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 3:1 ) gave reagent 2 as a solid (1.07 g, 91 %). ¹H NMR (CDCI₃) δ 7.97 (s, 1 H), 7.90 (s, 1 H), 4.95-5.00 (m, 1 H), 4.27 (q, J = 6.4 Hz, 2 H), 4.01 -4.15 (m, 3 H), 3.90-3.96 (m, 1 H), 2.43-2.52 (m, 1 H), 2.27-2.34 (m, 1 H), 1.33 (t, J = 6.4 Hz, 3 H).

Step 2:

To a solution of reagent 2 (1 .07 g, 5.1 mmol) in EtOH (15 mL) was added NaOH (1.22 g, 30.5 mmol) and water (15 mL). The mixture was heated to 55°C for 6 h. The volatiles were removed in vacuo and the pH adjusted to approximately 3 using 1 N HCI. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na₂S0₄ and then evaporated to dryness to give the title compound IM27 as colorless crystals (802 mg, 86%). ¹H NMR (DMSO) δ 12.40 (s, 1 H), 8.33 (s, 1 H), 7.89 (s, 1 H), 5.09-5.15 (m, 1 H), 4.00-4.05 (m, 2 H), 3.84-3.89 (m, 1 H), 3.92-3.96 (m, 1 H), 2.41 -2.48 (m, 1 H), 2.34-2.40 (m, 1 H).

IM28 : (R)- 1 -(Tetrahydro-furan-3-yl)- 1 H-pyrazole-4-carboxylic acid

The compound was prepared analogously to IM27 starting with toluene-4-sulfonic acid (S)- (tetrahydro-furan-3-yl) ester to give the title compound IM28 as colorless crystals (1.48 g, 92%) sufficiently pure for the next step. mpounds of the invention:

Compound 1 : 1 -Oxetan-3-yl-1H-pyrazole-4-carboxylic acid [(R)-1 -(6-fluoro-1 H-indol-5-yl)- ethyl]-amide

To the mixture of IM1 (204.5 mg, 1 .2 mmol), IM12 (212.5 mg, 1 .27 mmol) and Et₃N (348.5 mg, 3.5 mmol) in anhydrous DMF (2 mL) was added HATU (524.4 mg, 1 .4 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was separated by preparative HPLC give the title compound as a colorless solid (150 mg, 46%). ¹H NMR (DMSO) δ 1 1 .06 (s, 1 H), 8.40-8.43 (m, 2 H), 8.06 (s, 1 H), 7.55 (d, 1 H), 7.30 (m ,1 H), 7.14 (d, 1 H), 6.39-6.41 (m, 1 H), 5.55-5.56 (m, 1 H), 5.37-5.41 (m, 1 H), 4.92 (m, 2 H) 4.86 (m, 2 H), 1.47 (m, 3 H). LCMS Method B (m/z) 329.1 (MH⁺); t_R = 0.46. [a]_D ²⁰ = 47.0 ° (c = 0.1 g/100 mL, MeOH).

Preparative HPLC was conducted on a Gilson 215 instrument. Column: Phenomenex Gemini C18 150^*30 mm^*5 μηη. Mobile phase A: water with 0.05% ammonia solution. Mobile phase B: acetonitrile. Column temperature: 30 °C. Gradient : 23-53% B 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min. Flow rate: 100 mL/min.

Compound 2: 3-Methyl-1 -(R)-tetrahydro-furan-3-yl-1 H-pyrazole-4-carboxylic acid (2-methyl- 1 H-indol-5-ylmethyl)-amide

To a solution of IM2 (830 mg, 4.2 mmol) and IM13 (681 .9 mg, 4.26 mmol) in DMF (10 mL) was added Mukaiyama's reagent (1 .12 g, 4.7 mmol) and DIPEA (1 mL). The resulting mixture stirred at 25°C for 14 hours. The mixture was evaporated to dryness and the resulting residue was extracted with EtOAc (100 mL). The organic layer was dried over Na₂S0₄ and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 1 : 1 ) gave the title compound as a yellow solid (252.6 mg, 17.6%). ¹H NMR (CDCI₃) δ 7.94 (s, 1 H), 7.76 (s, 1 H), 7.47 (s, 1 H), 7.25-7.26 (m, 1 H), 7.08 (m, 1 H), 6.19-6.20 (m, 1 H), 5.85 (br s, 1 H), 4.85- 4.88 (m, 1 H), 4.63 (d, J = 5.2 Hz, 1 H), 3.86-4.15 (m, 4 H), 2.38-2.47 (m, 7 H), 2.21 -2.29 (m, 1 H). [a]_D ²⁰ = 12.5 ° (c = 0.16 g/100 mL, MeOH). LCMS Method B (m/z) 339.1 (MH⁺); t_R = 0.50.

Compound 3: 3-Oxetan-3-yl-isoxazole-5-carboxylic acid [(R)-1 -(2-methyl-1H-indol-5-yl)- ethyl]-amide

To a mixture of IM3 (62 mg, 0.36 mmol), IM19 (66 mg, 0.39 mmol) and Et₃N (138 mg, 0.54 mmol) in anhydrous THF (5 mL) was added Mukaiyama's reagent (138 mg, 0.54 mmol). The reaction was stirred at room temperature for 4 h. The mixture was evaporated to dryness purified by preparative HPLC to give the title compound as a colorless solid (43.7 mg, 37.3%). ¹H NMR (CDCIs) δ 7.83 (s, 1 H), 7.45 (d, 1 H), 7.21 (s, 1 H), 7.06 (m, 1 H), 6.96 (s, 1 H), 6.71 (d, 1 H), 6.14 (m, 1 H), 5.31 -5.28 (m, 1 H), 5.00-4.96 (m, 2 H), 4.73-4.69 (m, 2 H), 4.35-4.28 (m, 1 H), 2.38 (d, 3 H), 1.61 (d, J = 6.8 Hz, 3 H). LCMS Method B (m/z) 326.1 (MH+); t_R = 0.55. [a]_D ²⁰ = 126.0 ⁰ (c = 0.1 g/100 mL, MeOH).

Preparative HPLC was performed on a Gilson GX281 instrument. Column: Phenomenex Gemini C18 250^*21.2 mm^*5 μηη. Mobile phase A: water with 0.05% ammonia solution. Mobile phase B: acetonitrile. Column temperature: 30 °C. Gradient: 40-72% B 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min. Flow rate: 100 mL/min. he following compounds were prepared analogously:

Compound 4: 3-(3-Methyl-oxetan-3-yl)-isoxazole-5-carboxylic acid [(R)-1-(2-methyl-1H-indol- 5-yl)-ethyl]-amide

Prepared using IM3 and IM20.

[a]₂₀ ^D = 86 ° (c = 0.1 g/100 ml_, MeOH). LCMS Method B (m/z) 340.1 (MH⁺); t_R = 0.60.

Compound 5: (S)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid [(R)-1 -(2-methyl-1 H- indol-5-yl)-ethyl]-amide

Prepared using IM3 and IM21.

[a]₂₀ ^D = 97 ° (c = 0.1 g/100 ml_, MeOH). LCMS Method B (m/z) 340.1 (MH⁺); t_R = 0.59.

Compound 6: (R)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid [(R)-1-(2-methyl-1H- indol-5-yl)-ethyl]-amide

Prepared using IM3 and IM22.

[a]₂₀ ^D = 132 ° (c = 0.1 g/100 mL, MeOH). LCMS Method B (m/z) 340.1 (MH⁺); t_R = 0.59.

Compound 7: (S)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid (2-methyl-1 H-indol-5- ylmethyl)-amide

Prepared using IM2 and IM21.

[a]₂₀ ^D = 16.0 ° (c = 0.294 g/100 mL, MeOH). LCMS Method B (m/z) 326.1 (MH⁺); t_R = 0.55.

Compound 8: (R)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid (2-methyl-1 H-indol-5- ylmethyl)-amide

Prepared using IM2 and IM22.

[a]₂₀ ^D = -13.9 ° (c = 0.317 g/100 mL, MeOH). LCMS Method B (m/z) 326.1 (MH⁺); t_R = 0.55.

Compound 9: (S)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid (1H-indol-5- ylmethyl)-amide

Prepared using IM4 and IM21.

[a]₂₀ ^D = 22 ° (c = 0.1 g/100 mL, MeOH). LCMS Method B (m/z) 312.1 (MH⁺); t_R = 0.49.

Compound 10: (R)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid (1 H-indol-5- ylmethyl)-amide

Prepared using IM4 and IM22.

[a]₂₀ ^D = -12 ° (c = 0.1 g/100 mL, MeOH). LCMS Method B (m/z) 312.1 (MH⁺); t_R = 0.49.

Compound 11 : 3-(Tetrahydro-pyran-4-yl)-isoxazole-5-carboxylic acid (2-methyl-1H-indol-5- ylmethyl)-amide

Prepared using IM2 and IM23.

LCMS Method B (m/z) 340.2 (MH⁺); t_R = 0.57.

Compound 12: 3-(Tetrahydro-pyran-4-yl)-isoxazole-5-carboxylic acid (1 H-indol-5-ylmethyl)- amide

Prepared using IM4 and IM23.

LCMS Method B (m/z) 326.2 (MH⁺); t_R = 0.52.

Compound 13: 3-(Tetrahydro-pyran-4-yl)-isoxazole-5-carboxylic acid [(R)-1-(2-methyl-1H- indol-5-yl)-ethyl]-amide

Prepared using IM3 and IM23.

[a]₂₀ ^D = 29.6 ° (c = 0.1 g/100 mL, MeOH). LCMS Method B (m/z) 354.1 (MH⁺); t_R = 0.61 .

Compound 14: 3-Oxetan-3-ylmethyl-isoxazole-5-carboxylic acid (2-methyl-1H-indol-5- ylmethyl)-amide

Prepared using IM2 and IM24.

LCMS Method B (m/z) 326.2 (MH⁺); t_R = 0.52.

Compound 15: 3-Oxetan-3-ylmethyl-isoxazole-5-carboxylic acid (1 H-indol-5-ylmethyl)-amide Prepared using IM4 and IM24.

LCMS Method B (m/z) 312.2 (MH⁺); t_R = 0.47.

Compound 16: 3-Oxetan-3-ylmethyl-isoxazole-5-carboxylic acid [(R)-1-(2-methyl-1H-indol-5- yl)-ethyl]-amide

Prepared using IM3 and IM24.

[a]₂₀ ^D = 41 ° (c = 0.1 g/100 ml_, MeOH). LCMS Method B (m/z) 340.2 (MH⁺); t_R = 0.57.

Compound 17: 1 -Oxetan-3-yl-1 H-pyrazole-4-carboxylic acid (6, 7-difluoro-1H-indol-5- ylmethyl)-amide

To a mixture of IM12 (185 mg, 1.1 mmol) and HATU (501 mg, 1.3 mmol) in anhydrous DMF (2 mL) was added Et₃N (218 mg, 2.2 mmol). After stirring at room temperature for 10 min IM5 (200 mg, 1.1 mmol) in anhydrous DMF (2 mL) was added. The reaction mixture was stirred at room temperature overnight. The mixture was evaporated to dryness. Preparative HPLC gave the title compound as a colorless solid (280 mg, 77%). ¹H NMR (DMSO) δ 1 1 .70 (s, 1 H), 8.63-8.60 (m, 1 H), 8.36 (s, 1 H), 8.03 (s, 1 H), 7.40-7.39 (m, 1 H), 7.29 (m, 1 H), 6.49-6.48 (m, 1 H), 5.62-5.55 (m, 1 H), 4.93-4.89 (m, 2 H), 4.87-4.83 (m, 2 H), 4.52(m, 2 H ). LCMS Method A (m/z) 333.1 (MH⁺); t_R = 0.45.

Preparative HPLC was performed on a Gilson GX281 instrument. Column: Phenomenex Gemini C18 150^*30 mm^*5 μηη. Mobile phase A: water with 0.05% ammonia solution. Mobile phase B: acetonitrile. Column temperature: 30°C. Gradient: 33-53% B 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min. Flow rate: 100 mL/min.

The following compounds were prepared analogously:

Compound 18: 1-Oxetan-3-yl-1H-pyrazole-4-carboxylic acid (6-fluoro-1 H-indol-5-ylmethyl)- amide

Prepared using IM6 and IM12.

LCMS Method A (m/z) 315.0 (MH⁺); t_R = 0.42.

Compound 19: 1-Oxetan-3-yl-1H-pyrazole-4-carboxylic acid (7-fluoro-1H-indol-5-ylmethyl)- amide

Prepared using IM7 and IM12.

LCMS Method A (m/z) 315.3 (MH⁺); t_R = 0.43.

Compound 20: 1-Oxetan-3-yl-1H-pyrazole-4-carboxylic acid (6, 7-difluoro-2-methyl-1H-indol-

5-ylmethyl)-amide

Prepared using IM8 and IM12.

LCMS Method A (m/z) 347.2 (MH⁺); t_R = 0.50.

Compound 21 : 3-(3-Methyl-oxetan-3-yl)-isoxazole-5-carboxylic acid (2-methyl-1 H-indol-5- ylmethyl)-amide

Prepared using IM2 and IM20.

LCMS Method B (m/z) 326.1 (MH⁺); t_R = 0.58.

Compound 22: 1-Oxetan-3-yl-1H-pyrazole-4-carboxylic acid [(R)-1-(7-fluoro-1 H-indol-5-yl)- ethyl]-amide

Prepared using IM9 and IM12.

[a]₂₀ ^D = 77.6 ° (c = 0.05 g/100 ml_, MeOH). LCMS Method B (m/z) 329.0 (MH⁺); t_R = 0.46.

Compound 23: 5-Methyl-1 -(S)-tetrahydro-furan-3-yl-1 H-pyrazole-4-carboxylic acid (2-methyl- 1 H-indol-5-ylmethyl)-amide

Prepared using IM2 and IM16.

[a]₂₀ ^D = -5.6 ° (c = 0.1 g/100 mL, MeOH). LCMS Method B (m/z) 339.1 (MH⁺); t_R = 0.51.

Compound 24: 3-Methyl-1 -(S)-tetrahydro-furan-3-yl-1 H-pyrazole-4-carboxylic acid (2-methyl- 1 H-indol-5-ylmethyl)-amide

Prepared using IM2 and IM15.

[a]₂₀ ^D = -42 ° (c = 0.1 g/100 ml_, MeOH). LCMS Method B (m/z) 339.1 (MH⁺); t_R = 0.50.

Compound 25: 1 -(Tetrahydro-furan-3-yl)-1 H-pyrazole-4-carboxylic acid (2-trifluoromethyl-1H- indol-5-ylmethyl)-amide

Prepared using IM10 and IM26.

LCMS Method B (m/z) 379.0 (MH⁺); t_R = 0.56.

Compound 26: 1 -Oxetan-3-yl-1 H-pyrazole-4-carboxylic acid (2-trifluoromethyl-1 H-indol-5- ylmethyl)-amide

Prepared using IM10 and IM12.

LCMS Method B (m/z) 365.0 (MH⁺); t_R = 0.54.

Compound 27: 3,5-Dimethyl-1-(S)-tetrahydro-furan-3-yl-1H-pyrazole-4-carboxylic acid (2- methyl- 1 H-indol-5-ylmethyl)-amide

Prepared using IM2 and IM18.

[a]₂₀ ^D = -2.25 ° (c = 0.4 g/100 mL, MeOH). LCMS Method B (m/z) 353.1 (MH⁺); t_R = 0.52.

Compound 28: 5-Methyl-1 -(R)-tetrahydro-furan-3-yl-1 H-pyrazole-4-carboxylic acid (2-methyl- 1 H-indol-5-ylmethyl)-amide

Prepared using IM2 and IM14.

[a]₂₀ ^D = 10 ° (c = 0.17 g/100 mL, MeOH). LCMS Method B (m/z) 339.2 (MH⁺); t_R = 0.51.

Compound 29: 3,5-Dimethyl-1-(R)-tetrahydro-furan-3-yl-1H-pyrazole-4-carboxylic acid (2- methyl- 1 H-indol-5-ylmethyl)-amide

Prepared using IM2 and IM17.

[a]₂₀ ^D = 4.5 ° (c = 0.178 g /100 mL, MeOH). LCMS Method B (m/z) 353.1 (MH⁺); t_R = 0.52.

Compound 30: (S)-1 -(Tetrahydro-furan-3-yl)-1H-pyrazole-4-carboxylic acid (2-methyl-1H- indol-5-ylmethyl)-amide

Prepared using IM2 and IM27.

[a]₂₀ ^D = -15.9 ° (c = 0.7 g/100 mL,MeOH). LCMS Method B (m/z) 325.2 (MH⁺); t_R = 0.48.

Compound 31 ; 1 ' -(Tetrahydro-pyran-4-yl)-1 H-pyrazole-4-carboxylic acid (2-methyl-1 H-indol- 5-ylmet yl)-amide

Prepared using IM2 and IM25.

LCMS Method B (m/z) 339.2 (MH⁺); t_R

Compound 32: (R)-1 -(Tetrahydro-furan-3-yl)-1H-pyrazole-4-carboxylic acid (2-methyl-1H- indol-5-ylmethyl)-amide

Prepared using IM2 and IM28.

[a]₂₀ ^D = 13.2 ° (c = 0.205 g/100 mL,MeOH). LCMS Method B (m/z) 325.2 (MH⁺); t_R = 0.48.

Compound 33: 1-Oxetan-3-yl-1H-pyrazole-4-carboxylic acid (7-fluoro-2-methyl-1 H-indol-5- ylmethyl)-amide

To a solution of IM12 (0.25 g, 1 .49 mmol) in 10 mL of methylene chloride was added HATU (0.608 g, 1 .6 mmol) and Et₃N (0.29 g, 2.9 mmol). The mixture was stirred for 30 min. Compound IM11 (0.32 g, 1 .79 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was extracted with methylene chloride (200 mL). The organic layer was washed with brine (100 mL ^χ 2), dried over anhydrous Na₂S0₄ and evaporated to dryness. Purification by preparative HPLC have the title compound (0.228 g, 47%). ¹H NMR (CDCI₃) <5 8.16 (br s, 1 H), 8.03 (s, 1 H), 7.79 (s, 1 H), 7.21 (s, 1 H), 6.10-6.20 (m, 2 H), 5.37-5.42 (m, 1 H), 4.99-5.04 (m, 4 H), 4.61 (m, 2 H), 2.44 (s, 3 H). LCMS Method B (m/z) 329.1 (MH⁺); t_R = 0.50.

Preparative HPLC was performed on a Gilson GX281 instrument. Column: Phenomenex Gemini C18 250^*21.2 mm^*5 μηι. Mobile phase A: water with 0.05% ammonia solution. Mobile phase B: acetonitrile. Column temperature: 30°C. Gradient: 20-40% B.

The following compound was prepared analogously:

Compound 34: 3-Oxetan-3-yl-isoxazole-5-carboxylic acid (7-fluoro-2-methyl-1H-indol-5- ylmethyl)-amide

Prepared using IM11 and IM19.

LCMS Method B (m/z) 330.1 (MKT); t_R = 0.56.

In vitro assays

The nicotinic acetylcholine receptor a7 is a calcium-permeable ion channel, whose activity can be measured by over expression in mammalian cells or oocytes. These two individual assays are described in Examples 2 and 3, respectively.

Example 2: a7 NNR flux assay

The nicotinic acetylcholine receptor a7 is a calcium-permeable ion channel, whose activity can be measured by over expression in mammalian cells or oocytes. In this version of the assay, the human a7 receptor is stably expressed in the rat GH4C1 cell line. The assay was used to identify positive allosteric modulators (PAMs) of the a7 receptor. Activation of the channel was measured by loading cells with the calcium-sensitive fluorescent dye Calcium-4 (Assay kit from Molecular Devices), and then measuring real-time changes in fluorescence upon treatment with test compounds.

The cell line ChanClone GH4C1 -nAChRalpha7 from Genionics was seeded from frozen stock in 384-well plates in culture media 2-3 days before experiment to form an approximately 80% confluent layer on the day of experiment.

Cell plating and dye loading

The cell culture were split into "22.5cm x 22.5cm"-plates with approximately 100x10³ cells/cm². After four days incubation in a humidified incubator at 37°C and 5% C0₂, it had grown to an 80-90% confluent layer, and the cells were harvested.

Culture media:

500 mL DMEM/F12 (Gibco 31331 )

50 mL FBS (Gibco 10091 -155, lot 453269FD)

5 mL Sodium Pyruvate (Gibco 1 1360)

5 mL Pen/Strep (Gibco 15140) 0.1 mg/mL G-418 (Gibco 1 181 1 -064)

Two or three days before the experiment the cells were seeded in 384 well plates from Greiner bio-one (781946, CELLCOAT, Poly-D-Lysine, black, \iC\ear).

The media was poured off and the plate washed with PBS and left to drain. 5 mL Trypsin was added, cells were washed and incubated (at room temperature) for about 10 seconds. Trypsin was poured of quickly and the cells were incubated for 2 minutes at 37°C (if the cells were not already detached). Cells were resuspended in 10 mL culture media and transfered to 50 mL tubes.

The cell suspension was counted (NucleoCounter, total cell count) from the first plates to estimate the total cell number of the whole batch.

The cells were seeded in 384 well plates with 30 [\Uwe\\ (30000 cells/well) while stirring the cell suspension or otherwise preventing the cells from precipitating.

The plates were incubated at room temperature for 30-45 minutes.

The plates were placed in incubator for two days (37°C and 5% C0₂).

Loading the Cells

The loading buffer was 5% v/v Calcium-4 Kit and 2.5 mM Probenecid in assay buffer.

190 mL assay buffer

10 mL Kit-solution

2 mL 250 mM Probenecid

This volume was enough for 3 x 8 cell plates.

Culture media was removed from the cell plates and 20 μί loading buffer was added in each well. The cell plates were placed in trays and incubated 90 minutes in the incubator (37°C). Thereafter the plates were incubated 30 minutes at toom temperature, still protected from light. Now the cell plates were ready to run in the Functional Drug Screening System (FDSS).The assay buffer was HBSS with 20 mM HEPES, pH 7.4 and 3 mM CaCI₂.

FDSS Ca assay

200 nL 10 mM compound solution in DMSO was diluted in 50 μί assay buffer. The fi- nal test concentrations in the cell plates were 20-10-5-2.5-1 .25-0.625-0.312-0.156-0.078-

0.039 μΜ. Assay buffer and 3 μΜ PNU-120596 were used for control.

The agonist acetylcholine was added to a final concentration of 20 μΜ (-EC100).

In the FDSS7000 the Ex480-Em540 was measured with 1 second intervals. The baseline was made of 5 frames before addition of test compounds, and 95 frames more were made before addition of acetylcholine. The measurement stopped 30 frames after the 2^nd addition. Raw data for each well were collected as "the maximum fluorescence count" in the interval 100-131 seconds and as "the average fluorescence count" in the interval 96-100 seconds. The positive allosteric modulation in the 2^nd addition was the enhancement of agonist response with test compound compared to agonist alone.

Results were calculated as % modulation of test compound compared to the reference

PNU-120596 set to 100%. From these data EC₅₀ curves were generated giving EC₅₀, hill and maximum stimulation.

The compounds of the invention were shown to be PAMs of the ol receptor. The compounds of the present invention characterized in the flux assay generally possess EC₅₀ values below 10.000 nM or less. Many compounds, in fact have EC₅₀ values below 5.000 nM. Table 1 shows EC₅₀ values for exemplified compounds of the invention.

Table 1

Example 3: ol NNR oocyte assay

Expression of a7 nACh receptors in Xenopus oocytes.

Oocytes were surgically removed from mature female Xenepus laevis anaesthetized in 0.4% MS-222 for 10-15 min. The oocytes were then digested at room temperature for 2-3 hours with 0.5 mg/mL collagenase (type IA Sigma-Aldrich) in OR2 buffer (82.5 mM NaCI, 2.0 mM KCI, 1 .0 mM MgCI₂ and 5.0 mM HEPES, pH 7.6). Oocytes avoid of the follicle layer were selected and incubated for 24 hours in Modified Barth's Saline buffer (88 mM NaCI, 1 mM KCI, 15 mM HEPES, 2.4 mM NaHC0₃, 0.41 mM CaCI₂, 0.82 mM MgS0₄, 0.3 mM Ca(N0₃)₂) supplemented with 2 mM sodium pyruvate, 0.1 U/l penicillin and 0.1 μg/l streptomycin. Stage IV oocytes were identified and injected with 4.2-48 nl of nuclease free water containing 0.1 - 1 .2 ng of cRNA coding for human a7 nACh receptors or 3.0 - 32 ng of cRNA coding for rat a7 nACh receptors and incubated at 18°C for 1-10 days when they were used for electrophysiological recordings.

Electrophysiological recordings of a7 nACh receptors expressed in oocytes.

Oocytes were used for electrophysiological recordings 1-10 days after injection. Oocytes were placed in a 1 mL bath and perfused with Ringer buffer (1 15 mM NaCI, 2.5 mM KCI, 10 mM HEPES, 1.8 mM CaCI₂, 0.1 mM MgCI₂, pH 7.5). Cells were impaled with agar plugged 0.2 - 1 ΜΩ electrodes containing 3 M KCI and voltage clamped at -90 mV by a GeneClamp 500B amplifier. The experiments were performed at room temperature. Oocytes were continuously perfused with Ringer buffer and the drugs were applied in the perfusate. ACh (30 μΜ) applied for 30 sec were used as the standard agonist for activation of the a7 nACh receptors. In the standard screening set-up the new test compound (10 μΜ or 30 μΜ) were applied for 1 min of pre-application allowing for evaluation of agonistic activity followed by 30 sec of co-application with ACh (30 μΜ) allowing for evaluation of PAM activity. The response of co-application was compared to the agonistic response obtained with ACh alone. The drug induced effects on both the peak response and the total charge (AUC) response were calculated thus giving the effect of drug induced PAM activity as fold modulation of the control response.

For more elaborate studies doses-response curves can be performed for evaluation of max-fold modulation and EC₅₀ values for both peak and AUC responses.

Claims

1 . A compound according to formula [I]

[I]

R6 represents H or methyl;

Q is selected from (i)-(iii), the arrow indicating the attachment point:

(i) (ii) (iii) n is 0, 1 or 2;

R8 and R9 are selected independently from H and methyl;

and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 , wherein R1 , R2, R4 and R5 are selected independently from H, methyl, trifluoromethyl and fluorine.

3. The compound according to any of claims 1 -2, wherein R3 is H.

4. The compound according to any of claims 1 -3, wherein all of R1 -R5 are H.

5. The compound according to any of claims 1 -3, wherein R1 is selected from methyl and trifluoromethyl, and all of R2-R5 are H.

6. The compound according to any of claims 1 -3, wherein R1 is selected from methyl and trifluoromethyl, and one or two of R1 , R2, R4 and R5 are fluorine and the remaining of R2-R5 are H.

7. The compound according to any of claims 1 -6, wherein n is 0 or 1.

8. The compound according to any of claims 1 -7, wherein R6 represents methyl, and wherein said compound is essentially the R-enantiomer as depicted in formula [Γ]

10. The compound according to any of claims 1 -9, wherein R7 is selected from (iv)-(vi), the arrow indicating the attachment point:

(iv) (v) (vi) wherein R10 is selected from H and methyl.

1 1 . The compound according to any of claims 1 -10, wherein both of R8 and R9 are H.

12. The compound according to claim 1 selected from

3: 3-Oxetan-3-yl-isoxazole-5-carboxylic acid [(R)-1-(2-methyl-1 H-indol-5-yl)-ethyl]-amide; 4 : 3-(3-Methyl-oxetan-3-yl)-isoxazole-5-carboxylic acid [(R)-1 -(2-methyl- 1 H-indol-5-yl)-ethyl]- amide;

5: (S)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid [(R)-1-(2-methyl-1H-indol-5-yl)- ethyl]-amide;

6 : (R)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid [(R)- 1 -(2-methyl- 1 H-indol-5-yl)- ethylj-amide;

9 : (S)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid ( 1 H-indol-5-ylmethyl)-amide; 10 : (R)-3-(Tetrahydro-furan-3-yl)-isoxazole-5-carboxylic acid ( 1 H-indol-5-ylmethyl)-amide; 11 : 3-(Tetrahydro-pyran-4-yl)-isoxazole-5-carboxylic acid (2-methyl-1H-indol-5-ylmethyl)- amide;

12: 3-(Tetrahydro-pyran-4-yl)-isoxazole-5-carboxylic acid (1H-indol-5-ylmethyl)-amide;

13: 3-(Tetrahydro-pyran-4-yl)-isoxazole-5-carboxylic acid [(R)-1 -(2-methyl-1H-indol-5-yl)- ethylj-amide;

14: 3-Oxetan-3-ylmethyl-isoxazole-5-carboxylic acid (2-methyl-1H-indol-5-ylmethyl)-amide; 15: 3-Oxetan-3-ylmethyl-isoxazole-5-carboxylic acid (1H-indol-5-ylmethyl)-amide;

16 : 3-Oxetan-3-ylmethyl-isoxazole-5-carboxylic acid [(R)-1 -(2-methyl- 1 H-indol-5-yl)-ethyl]- amide; 17: 7 -Oxetan-3-yl- 1 H-pyrazole-4-carboxylic acid ( 6, 7-difluoro- 1 H-indol-5-ylmethyl)-amide; 18: 1-Oxetan-3-yl-1H-pyrazole-4-carboxylic acid (6-fluoro-1H-indol-5-ylmethyl)-amide;

19: 1-Oxetan-3-yl-1H-pyrazole-4-carboxylic acid (7-fluoro-1H-indol-5-ylmethyl)-amide;

13. A compound according to any of claims 1 -12 for use as a medicament.

14. A compound according to any of claims 1 -12, for use in the treatment of a disease or disorder selected from Psychosis; Schizophrenia; cognitive disorders; cognitive impairment associated with schizophrenia; Attention Deficit Hyperactivity Disorder (ADHD); autism spectrum disorders, Alzheimer's disease (AD); mild cognitive impairment (MCI); age associated memory impairment (AAMI); senile dementia; AIDS dementia; Pick's disease; dementia associated with Lewy bodies; dementia associated with Down's syndrome; Huntington's Disease; Parkinson's disease (PD); obsessive-compulsive disorder (OCD); traumatic brain injury; epilepsy; post-traumatic stress; Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive deficits associated with depression; diabetes, weight control, inflammatory disorders, reduced angiogenesis; amyotrophic lateral sclerosis and pain.

15. A pharmaceutical composition comprising a compound according to any of claims 1 - 12, and one or more pharmaceutically acceptable carrier or excipient.