NZ612688B2 - (PYRIDIN-4-YL)BENZYLAMIDES AS ALLOSTERIC MODULATORS OF ALPHA 7 nAChR - Google Patents

Abstract

Disclosed are (pyridin-4-yl)benzylamides compounds and pharmaceutically acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy. The disclosure particularly relates to positive allosteric modulators of nicotinic acetylcholine receptors, such positive allosteric modulators having the capability to increase the efficacy of nicotinic receptor agonists. tors, such positive allosteric modulators having the capability to increase the efficacy of nicotinic receptor agonists.

Description

(PYRIDIN—4-YL)BENZYLAMIDES AS ALLOSTERIC MODULATORS OF ALPHA 7 nAChR Field of the invention The present invention relates to (pyridine-4—yl)benzylarnides and pharmaceutically acceptable salts thereof, processes for preparing them, pharmaceutical compositions ning them and their use in therapy. The invention particularly relates to allosteric modulators of nicotinic acetylcholine receptors, such allosteric modulators having the capability to increase the efficacy of nicotinic receptor agonists. ound Prior Art Allosteric tors of nicotinic acetylcholine alpha 7 receptors have been sed in WO-2007/031440, WO-ZOO7/118903, WO-2009/050186, WO-2009/050185, WO—2009/115547 and WO-2009/135944.

WO—ZOO6/O963 58 discloses azabicycloalkane derivates as nicotinic acetylcholine receptor agonists.

Background of the invention ergic receptors normally bind the endogenous ransmitter acetylcholine (ACh), thereby triggering the opening of ion channels. ACh receptors in the mammalian central nervous system can be d into muscarinic (mAChR) and nic (nAChR) subtypes based on the agonist activities of muscanne and nicotine, respectively. The nicotinic choline receptors are ligand-gated annels containing five subunits. Members of the nAChR subunit gene family have been divided into two groups based on their amino acid sequences; one group containing led alpha subunits, and a second group containing beta subunits. Three kinds of alpha subunits, alpha 7, alpha 8 and alpha 9, have been shown to form functional receptors when expressed alone and thus are presumed to form homooligomeric pentameric receptors.

An allosteric tion state model ofthe nAChR has been developed that involves least a resting state, an activated state and a "desensitized" closed channel state, a process by which receptors become insensitive to the agonist, Different nAChR ligands can ize the conformational state of a receptor to which they preferentially bind.

For example, the agonists ACh and (-)-nicotine respectively stabilize the active and desensitized states.

W0 2012/113850 Changes of the activity of nicotinic receptors have been ated in a number of es. Some of these, for example myasthenia gravis and autosomal dominant nocturnal front lobe epilepsy E) are associated with reductions in the activity ofnicotinic transmission either because ofa decrease in or number or increased desensitization.

Reductions in nic receptors have also been hypothesized to mediate cognitive deficits seen in diseases such as Alzheimer's disease and schizophrenia.

The effects of nicotine from o are also mediated by nicotinic receptors and since the effect of nicotine is to stabilize ors in a desensitized state, an increased activity of nicotinic receptors may reduce the desire to smoke. nds which bind nAChRs have been suggested for the treatment of a range of disorders ing reduced cholinergic function such as learning , cognition deficit, attention deficit and memory loss. Modulation of alpha 7 nicotinic or activity is expected to be beneficial in a number of diseases ing Alzheimer’s disease, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder, anxiety, schizophrenia, mania, bipolar disorder, Parkinson’s disease, Huntington’s disease, Tourette’s syndrome, brain trauma and other neurological, degenerative and psychiatric disorders in which there is loss of cholinergic synapses, including jetlag, nicotine addiction, and pain.

However, treatment with nicotinic receptor agonists which act at the same site as ACh is problematic because ACh not only activates, but also blocks receptor activity through processes which include desensitization and uncompetitive de. Furthermore, prolonged activation appears to induce a long—lasting inactivation. Therefore, agonists ofACh can be expected to lose iveness upon chronic administration.

At nicotinic ors in general, and of particular note at the alpha 7 nicotinic receptor, desensitization limits the duration of action of an applied agonist.

Description of the invention We have found that certain novel (pyridineyl)benzylamides can increase the efficacy of agonists at nicotinic acetylcholine ors (nAChR) Compounds having this type 3O of action (hereinafter referred to as "positive allosteric modulators") are likely to be useful for treatment of conditions associated with reductions in nicotinic ission.

In a therapeutic setting such nds could restore normal interneuronal communication without affecting the temporal profile of activation. In addition, positive allosteric modulators are not expected to produce long-term inactivation of receptors as may occur with prolonged application of agonists.

W0 2012/1 13850 Positive nAChR modulators of the t invention are useful for treatment and prophylaxis of psychotic disorders, intellectual impairment disorders and diseases, inflammatory diseases and conditions in which modulation of the alpha 7 nicotinic receptor is beneficial.

The present invention concerns (pyridineyl)benzylamides having positive allosteric modulator properties, in particular increasing the efficacy of agonists at the alpha 7 nicotinic receptor. The invention further relates to methods for their preparation and ceutical compositions sing them. The invention also relates to the use of these derivatives for the manufacture of a medicament for the treatment and prophylaxis of psychotic disorders, ectual impairment disorders and diseases, atory diseases and conditions in which modulation of the alpha 7 nicotinic receptor is beneficial The invention further relates to these derivatives for use in the treatment and prophylaxis of psychotic disorders, intellectual impairment disorders and es, inflammatory diseases and conditions in which modulation of the alpha 7 nicotinic receptor is beneficial.

In a first aspect, the present invention relates to a compound having the formula (1) Xn R3 {Had_ \ / 0 \_< R5 LN/Ux R1 R2 or a stereoisomer thereof, wherein n is 0, l or 2; X is fluoro or chloro; Y is N or CH; Z is O or CH2; R1 is C1_galkyl; C1.galkyl tuted with l, 2 or 3 halogen substituents; Cgacycloalkyl; (Cgécycloalkyl)Cmalkyl; (Cmalkyloxy)C16alkyl; (trihaloC14alkyloxy)C16alkyl; tetrahydrofuryl; ydropyranyl; ; phenyl substituted with l, 2 or 3 tuents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, Cmalkyl, and C14alkyloxy; or a monocyclic aromatic heterocyclic radical containing at least heteroatom selected from N, O and S, optionally tuted with l, 2 or where possible with 3 substituents selected from halogen, yl, Ciaalkyloxy, Cgigcycloalkyl, and trifluoromethyl; R2 and R3 are independently H, Claalkyl or trifluoromethyl; or R2 and R3 are taken together to form 1,2-ethanediyl or 1,3-propanediyl; R4 and R5 are independently H, CMalkyl, oromethyl, C3scycloalkyl C14alkyloxy; or an acid on salt thereof, or a solvate thereof.

In one embodiment, R1 is Cmalkyl; Cgigcycloalkyl; cyclopropyl substituted with l, 2, 3, or 4 methyl groups; cloalkylfll-galkyl; methoxymethyl; phenyl tuted with l, 2, or 3 substitents selected from fluoro, chloro, methyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, and aminosulfonyl; or furanyl, oxazolyl, olyl, oxadiazolyl, pyrrolyl, pyrazolyl, olyl, pyridinyl, minyl, pyrazinyl, pyridazinyl or benzisoxazolyl, each unsubstituted or substituted with 1, 2 or where possible 3 substituents selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropyl, methoxy, and trifluoromethyl.

In another embodiment, R1 is Cmalkyl; C14alkyl substituted with 3 fluoro substituents; Cmcycloalkyl; (Cgécycloalkyl)C1.zalkyl; methoxymethyl; methoxyethyl, — trifluoroethoxy)methyl; tetrahydropyranyl; phenyl; or phenyl substituted with l, 2 or 3 substituents selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, methyl, and methoxy; or furanyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, nyl, pyridiminyl, pyrazinyl, zinyl, thienyl, 1,2,3-thiadiazolyl, thiazolyl or benzisoxazolyl, each unsubstituted or substituted with l, 2 or where le 3 substituents selected from methyl, ethyl, propyl, isopropyl, n—butyl, isobutyl, sec—butyl, utyl, cyclopropyl, methoxy and trifluoromethyl.

In another embodiment, RI is furanyl, oxazolyl, isoxazolyl, pyrazolyl, nyl, pyrazinyl, thienyl, 1,2,3—thiadiazolyl, thiazolyl or benzisoxazolyl, each unsubstituted or substituted with 1, 2 or where possible 3 substituents selected from methyl, isopropyl, tert—butyl, cyclopropyl, methoxy and trifluoromethyl.

In another embodiment R2 is hydrogen, methyl or trifluoromethyl, In another embodiment R3 is hydrogen, methyl or trifluoromethyl.

In another embodiment R4L is hydrogen or methyl In another ment R5 is hydrogen or methyl.

In another embodiment, R1 is methyl, ethyl, n-propyl, pyl, n-butyl, isobutyl, sec- butyl, ten-butyl, cyclopropyl, cyclobutyl, cyclopentyl, (cyclopropyl)ethyl, (cyclopropyl)methyl, (cyclobutyl)methyl, (cyclohexyl)methyl, 3—methyl-isoxazol—5—yl, 3-methyl-isoxazolyl, 5-methyl-isoxazolyl, 2-methyltrifluoromethyl-oxazol yl, or 2-methyl-oxazolyl.

In r embodiment, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert—butyl, 2,2,2—trifluorethyl, 3,3,3—trifluoropropyl, 2-methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, lopropyl)ethyl, (cyclopropyl)methyl, (cyclobutyl)methyl, 4—fluoro—2-methylphenyl, 3—methyl-isoxazol-5—yl, 3—methyl— isoxazol-4—yl, S—methyl—isoxazol-3—yl, 2-methyl-5—trifluoromethyl—oxazol-4—y1, or 2-methyl—oxazol-4—yl.

In r embodiment, R1 is isopropyl, cyclopropyl (cyclopropyl)methyl, (cyclobutyl)methyl, 3-methylisoxazolyl or 5-methyl-isoxazolyl.

In another embodiment, R2 and R3 are methyl or trifluoromethyl and have the cis- configuration.

In another embodiment, R2 and R3 are methyl and have the trans-configuration.

In a red embodiment the compound is chosen from N-[[5-[(2R,6S)—2,6-dimethyl—4-morpholinyl]—2-(2,6-dimethyl nyl)phenyl]methy1]-cyclopropaneacetamide, N-[[5-[(2R,6S)-2,6-dimethylmorpholinyl](2,6-dimethyl pyridinyl)phenyl]methyl]—5-methylisoxazolecarboxamide, N—[[5—[(2R,6S)-2,6-dimethyl—4—morpholinyl](2,6-dimethyl~4- pyridinyl)phenyl]methyl]—3—methyl—4—isoxazolecarboxamide, N-[[5-[(2R,6S)—2,6~dimethyl—morpholinyl]—2-(2,6-dimethyl pyridinyl)phenyl]methyl]-4—fluoro~2-methyl—benzamide, N-[[5—[(2R,6S)—2,6—dimethyl-4—rnorpholinyl]~2-(2,6-dimethyl pyridinyl)phenyl]methyl]—2-methyl-propanamide, N~[[5—[(2R,6S)—2,6—dimethyl-4—morpholinyl]—2~(2,6-dimethyl—4— pyridinyl)pheny1]methyl]-cyclopropanecarboxamide, N-[[5-[(2R,6S)—2,6-dimethyl—4-morpholinyl]—2-(2,6-dimethyl pyridinyl)phenyl]methyl]-3,3,3—trifluoro—propanamide, [(2R,6S)-2,6-dimethylmorpholinyl](2,6-dimethyl—4—pyridinyl) fluorophenyl]methyl]—cyclopropaneacetamide, N—[[3~[(2R,6S)—2,6-dimethyl—4-morpholinyl]-6—(2,6—dimethylpyridinyl)-2— fluorophenyl]methyl]methyl-propanamide, N-[[3-[(2R,6S)-2,6-dimethylmorpholinyl](2,6-dimethylpyridinyl) fluorophenyl]methyl]methyl—3—isoxazolecarboxamide, I\—[[3-[(2R,6S)—2,6-dimethyl-4—morpholinyl](2,6-dimethyl-4—pyridinyl)—2- W0 2012/] 13850 henyl]methyl]methylisoxazolecarboxamide, N—[[3-[(2R,6S)—2,6-dimethylmorpholinyl](2,6-dimethy1pyridinyl) fluorophenyl]methyl]fluoro—2-methyl-benzamide, N—[[5—[(2R,6S)—2,6—dimethyl—4—morpholinyl]—2—(2,6-dimethy1-4—pyridiny1)—3— henyl]methyl]-cyclopropaneacetamide, N—[[5-[(2R,6S)-2,6-dimethylmorpholinyl]-2—(2,6-dimethyl~4-pyridinyI)-3~ fluorophenyl]methyl]-5—methy1-3 —isoxazolecarboxamide, N-[[5—[(2R,6S)—2,6-dimethyl~4-morpholiny1]—2—(2,6—dimethyl—4~pyridinyl)—3— fluorophenyl]methyl]-3—methy1isoxazolecarboxamide, [(2R,6S)~2,6—dimethyl—4—morpholiny1]-2—(2,6~dimethy1-4—pyridinyl)—3— fluorophenyl]methyl]-3,3,3 -trifluoro—propanamide, N—[[5-[(2R,6S)—2,6-dimethy1—4-morpholinyl]—2—(4—pyridiny1)phenyl]methyl]—2-methyl- propanamide N—[[5-[(2R,6S)~2,6—dimethyl—4-morpholinyl]—2-(2,6—dimethyl-4—pyridiny1)-3~ fluorophenyl]Inethyl]methy1—propanamide, N—[[5~[(2R,6S)—2,6—dimethyl—4—morpholinyl]—2—(4—pyridinyl)phenyl]methyl]— cyclopropaneacetamide, N-[[5-[(2R,6S)-2,6-di methylmorpholinyl](2-methyIpyri di ny1)phenyl]methy]]- 2-methyl-propanamide, N—[[5-[(2R,6S)-2,6-dimethyl—4—morpholinyl]—2-(2-methylpyridinyl)phenyl]methyl]— S-methyl-3~isoxazolecarboxamide, N—[[5-[(3R,5 S)—3,5-dimethyl- 1 'dinyl](2,6-dimethy1~4— pyridinyl)phenyl]methyl]—5-methyl-3—isoxazolecarboxamide, N—[[5-[(2R,6S)—2,6-dimethyl—4-rnorpholinyl]—2—(2-methy1~4-pyridiny])phenyl]methyl]- 4-fluoro—2—methyl—benzamide, N-[[5—[(2R,6S)-2,6—dimethyl—4-morpholiny1](4—pyridinyl)phenyl]methyl]—3-methy1- 4—isoxazolecarboxamide, N-[[2—(2,6-dimethyl—4-pyridinyl)—5-(4-morpholiny1)phenyl]methyl]- cyclopropaneacetamide, N—[[2-(2,6-dimethyl-4—pyridinyl)—5-(4~morpholinyl)phenyl]methyl]—5-methyl-3 - isoxazolecarboxamide, N-[[2-(2,6-dimethyl-4—pyridinyl)(4—morpholinyl)phenyl]methy1]methyl-4— isoxazolecarboxamide, N-[[2-(2,6-dimethylpyridinyl)(4-morpholiny1)phenyl]methyl]f1uoromethyl- benzami de, N—[[2-(2,6-dimethylpyridinyl)(4-morpholinyl)phenyl]methy1]-3,3 ,3-trifluoro- propanamide, W0 2012/1 13850 N-[[2-(2,6-dimethylpyridinyl)—S-(4-morpholinyl)phenyl]methyl]methy1- propanamide, N-[[2—(2,6-dimethylpyridinyl)—5-(4-morpholiny1)phenyl]methyl]- cyclopropanecarboxamide, N-[[5-[(2R,6S)-2,6-dimethylmorpholinyl](2-methyl-4~pyridinyl)pheny1]methyl]— cyclopropaneacetamide, 4—fluoromethyl-N—[[2-(2-methyl—4—pyridiny1)—5-(4-morpholinyl)phenyl]methy1]— benzamide, N—[[5—[(3R,5 S)-3,5-bis(trifluoromethyl)~1-piperidinyl](2,6-dimethyI pyridinyl)pheny1]methyl]—3 —methy1-4—isoxazolecarboxamide, N-[[5-[(3R,5S)-3,5—bis(trifluoromethy1)—1-piperidinyl]-2—(2,6-dimethyl nyl)pheny1]methyl]fluoromethy1—benzamide, N-[[5-[(3R,5S)-3,5-bis(trifluoromethyl)—1-piperidinyl](2,6—dimethyl pyridinyl)pheny1]methyl]methyl~3 —isoxazolecarb0xamide, [(3R,5 S)-3,5—bis(trifluoromethyl)—1 —piperidiny1]~2—(2,6—dimethyl-4~ pyridinyl)phenyl ]methy1]—cyclopropaneacetamide, N—[[5-[(3R,5 S)-3,5-bis(trifluoromethyl)—1-piperidinyl](2,6-dimethyl-4— pyridinyl)phenyl ]methyl]methyl-propanami de, N-[[5-[(2R,6S)-2,6-dimethyl—4-morpholinyl](2,6-dimethy1pyridiny1) fluorophenyl]methyl]—a1pha—methyl-cyclopropaneacetamide, N—[[5—[(2R,6S)—2,6—dimethyl—4—morpholinyl]~2—(2,6-dimethyl—4-pyridiny1)—3— henyl]methyl]-cyclopropanecarboxamide, (2,6-dimethyl—4—pyridiny1)—5-[3 -(trifluoromethy1)—1~piperidinyl]phenyl]methyl]- 3 —methyl-4—isoxazolecarboxamide, N—[[2-(2,6—dimethyl-4—pyridinyI)—5-[3 ~(trifluoromethyl)piperidinyl]phenyl]methyl]- 4-fluoro—2~methyl-benzamide, N—[[2—(2,6-dimethyl—4-pyridinyl)—5—[3—(trifluoromethyl)-1—piperidinyl]phenyl]methyl]- -methylisoxazolecarboxamide, N-[[2-(2,6-dimethy1pyridinyl)—5-[3—(trifluoromethyl)- 1-piperidinyl]phenyl]methyl]- cyclopropaneacetamide, N-[[2-(2,6~dimethyl-4—pyridinyl)—5-[3-(trifluoromethyl)piperidinyl]pheny1]methyl]- 2-methyl-propanamide, (2,6—dimethyl—4—pyridinyl)—3 —fluoro[3—(trifluoromethyl)- 1 — piperidinyl]pheny1]methyl]-a1pha-methyl-0yclopropaneacetamide, N—[[2-(2,6-dimethylpyridinyl)—3 —fluoro[3-(trifluoromethyl)-1 - piperidiny]]pheny1]methy1]—5-methyIisoxazolecarboxamide, N—[[2-(2,6-dimethyl—4—pyridinyl)-3—fluoro[3-(trifluoromethy1)— 1— W0 2012/] 13850 piperidinyl]phenyl]methyl]-cyclopropaneacetamide, N-[[2-(2,6-dimethyl—4-pyridinyl)—3-fluoro[3-(trifluoromethy1)- 1- piperidinyl]phenyl]methyl]-2—methyl-propanamide, N—[[2—(2,6—dimethyl—4—pyridinyl)-3—fluoro—5—[3-(trifluoromethyl)— 1- piperidinyl]pheny1]methy1]-cyclopropanecarboxamide, N—[[2—(2,6—dimethyl—4-pyridinyl)—3-fluor0—5-[3 -(trifluoromethy1)- 1 — piperidinyl]phenyl]methyl]-3 -methy1—4—isoxazolecarboxamide, [(2R,6S)—2,6-dimethylmorpholiny1]—2-(2,6-dimethyl-4~pyridinyl)—3— fluorophenyl]methyl]—cyclobutaneacetamide, N—[[5—[(2R,6S)—2,6—dimethyl~4—morpholinyl]—2~(2,6—dimethyl—4—pyridinyl)—3— fluorophenyl]methyl]-4,4,4-trifluoro~butanamide, N-[[5-[(2R,6S)—2,6—dimethylmorpholinyl]-2—(2,6-dimethylpyridiny]) fluorophenyl]methyl]-2—(2,2,2-trifluoroethoxy)~acetamide, N-[[5—[(2R,6S)-2,6-dimethyl~4-morpholinyl](2,6—di1nethy1—4-pyridinyl)-3— fluoropheny1]methyl]methyl-butanamide, N-[[5-[(2R,6S)—2,6—dimethyl—4-morpholinyl]—2-(2,6—dimethyl—4-pyridinyl)-3— fluorophenyl]methyl]—3,3-dimethyl-butanamide, N-[[5-[(2R,6S)-2,6-di methylmorpholinyl](2,6-dimethylpyridi nyl) fluorophenyl]methyl]-cyclobutanecarboxamide, N—[[3—[(2R,6S)~2,6-dimethyl—4—morpholinyl]—6-(2,6—dimethyl-4—pyridinyl)—2— fluoropheny1]methyl]—cyclopropanecarboxamide, N-[[3-[(2R,6S)—2,6—dimethylmorpholinyl](2,6-dimethylpyridiny1) phenyl]methyl]—3-methyl-butanamide, N-[[5-[(2R,6S)-2,6—dimethy1-4—morpholinyl]-3 —2-(2—methyl pyridinyl)phenyl]methy1]—cyclopropaneacetamide, N—[[5-[(2R,68)-2,6—dimethylmorpholinyl]—3 -fluoro(2—methyl-4— nyl)phenyl]methyl]—cyclopropanecarboxamide, N—[[5-[(2R,6S)—2,6—dimethyl-4—morpholinyl]fluoro(2-methyl-4— pyridinyl)phenyl]methyl]~2-methy1—propanamide, N—[[5-[(2R,6S)-2,6-dimethyl—4-morpholinyl]—3-fluoro—2-(2—methyl pyridinyl)phenyl]methyl]methy1—3-isoxazolecarboxamide, N-[[5-[(2R,6S)—2,6-dimethy1—4-morpholiny1]—3-fluoro(2—methyl-4— pyridiny1)phenyl]methyl]—3 —methy1-4—isoxazolecarboxamide, N-[[5-[(2R,6S)-2,6-dimethylmorpholinyl]—3 -fluoro(2-methyl pyridinyl)phenyl]methy1]methyl—butanamide, N—[[5—[(2R,6S)—2,6—dimethyl—4—morpholinyl](2,6-dimethyl-4—pyridinyl)—3- fluorophenyl]methyl]tetrahydro—2H—pyran-4—carboxamide, W0 2012/] 13850 N-[[5-[(2R,6S)-2,6-dimethylmorpholinyl](2-methylpyridinyl)phenyl]methyl]- cyclopropanecarboxamide, N-[[6-(2,6-dimethylpyridinyl)—2-fluoro—3-[(2R,6S)-tetrahydro-2,6-dimethy1—2H— pyran—4—yl]phenyl]methyl]—cyclopropaneacetamide, N-[[6-(2,6-dimethyl-4—pyridinyl)—2-fluor0-3—[(2R)(trifluoromethyl)—4- morpholiny1]phenyl]methyl]methy1-propanamide, N—[[6—(2,6-dimethyl—4-pyridinyl)—2-fluor0—3-[(2K)-2—(trifluoromethyl)-4— morpholinyl]phenyl]methyl]—5-methy1—3-isoxazolecarboxamide, N-[[6-(2,6—dimethyl-4—pyridinyl)—2—fluoro[(2R)—2-(trifluoromethyl)—4— morpholinyl]pheny1]methyl]—3~methy1—4—isoxazolecarboxamide, N-[[6-(2,6-dimethylpyridinyl)—2-fluoro—3-[(2R)—2—(trifluoromethyl)—4— morpholinyl]pheny1]methy1]-cyclopropaneacetamide, N—[[6-(2,6-dimethy1pyridinyl)-2—fluoro-3—(tetrahydro—2,6-dimethyl—2H-pyran—4- y1)phenyl]methyl]-cyclobutaneacetamide, (2,6-dimethyl-4—pyridinyl)fluoro—3~(tetrahydro-2,6-dimethy1—2H—pyran-4— y1)phenyl]methyl]-2—methyl—propanamide, N—[[6-(2,6-dimethylpyridinyl)fluoro(tetrahydro—2,6—dimethyl—2H-pyran—4- yl)phenyl]methyl]—5-methylisoxazolecarboxamide, N-[[6-(2,6-dimethyl—4-pyridinyl)fluoro(tetrahydro-2,6-dimethyl-2H—pyran y1)phenyl]methyl]-3 l—4-isoxazolecarboxamide, N-[[6—(2,6-dimethyl—4—pyridinyl)—2—fluoro—3-[(2R,6S)—tetrahydro—2,6—dimethy1—2H— 4-y1]phenyl]methyl]-cyclopropanecarboxamide, N—[[6-(2,6-dimethyl-4—pyridinyl)—2-fluoro[(2S)(trifluoromethyl)-4— morpholinyl]phenyl]methyl]-cyclopropaneacetamide, N—[[6-(2,6—dimethyl-4—pyridinyl)-2~fluoro—3-[(2R)—2-(trifluoromethyl) morpholinyl]phenyl]methy1]-cyclobutaneacetamide, N—[[6—(2,6-dimethyl~4-pyridinyl)—2-fluoro—3~[(2R)~2—(trifluoromethyI)-4— morpholinyl]phenyl]methy1]methy1-butanamide, N-[[2—(2,6-dimethylpyridinyl)fluoro—5—[(2R)—2—(trifluoromethyl) morpholinyl]phenyl]methyl]methy1-propanamide, N—[[2-(2,6-dimethylpyridinyl)—3 —fluoro[(ZR)—2-(trifluoromethyl) morpholiny]]pheny1]methyl]methy1-3~isoxazolecarboxamide, (2,6—dimethyl—4—pyridinyl)—3—fluoro—5—[(2R)—2—(trifluoromethyl)-4— morpholinyl]phenyl]methyl]methy1-butanamide, N—[[6-(2,6-dimethylpyridinyl)—2-fluoro[(2R,6S)-tetrahydro-2,6-dimethyl-2H- pyranyl]pheny1]methyl1-3—methyl-butanamide, N—[[6-(2,6-dimethyl-4—pyridinyl)—2—fluoro[(2S)(trifluoron1ethyl)-4— morpholinyl]pheny1]methyl]—2-methy1-propanamide, (2,6-dimethylpyridinyl)-3 -fluoro[(ZR)(trifluoromethyl) morpholinyl]pheny1]methy1]-cyclopropanecarboxamide, N—[[2—(2,6—dimethyl—4—pyridinyl)—3 —5—[(2R)—2—(trifluoromethyl)—4- morpholinyl]phenyl]methyl]methy1isoxazolecarboxamide, N-[[6~(2,6-dimethylpyridinyl)-2—fluoro[(2R)(trifluoromethyl)-4— morpholinyl]pheny1]methyl]~cyclopropanecarboxamide, N-[[5-[(2R,6S)-2,6-dimethy1—4—morpholinyl](2—methy1-4—pyridinyl)pheny1]methyl]— 3 -methyl—4-isoxazolecarboxamide . 1 .7HC1, N-[[2-(2,6—dimethyl—4—pyridinyl)—3 —fluoro—5- [(2R)~2—(trifluoromethyl)—4— morpholinyl]pheny1]methyl]—cyclopropaneacetamide, N-[[6~(2,6-dimethy1pyridinyl)—2—fluoro[(ZS)(trifluoromethyl)—4- morpholinyl]phenyl]methy1]—3~methy1—4-isoxazolecarboxamide, N-[[5-[(2R,6S)-2,6~di1nethy1—4-morpholinyl]-2—(2,6-di1nethy1pyridiny1)-4— fluorophenyl]methyl]-cyclopropanecarboxami de, N—[[5—[(2R,6S)—2,6—dimethyl-4—morpholinyl]—2—(2,6-dimethylpyridinyl)-4— fluorophenyl]methyl]-cyclopropaneacetamide, N—[[5-[(2R,6S)-2,6-di methyl-4—morpholinyl ](2,6-di methyl pyridi nyl)—4— heny1]methyl]methylisoxazolecarboxamide, N-[[5—[(2R,6S)-2,6-dimethyl—4-rnorpholinyl]—2-(2,6~dimethy1—4—pyridinyl)~4- fluorophenyl]methyl]—2~methyl—propanamide, N-[[2—(2,6-dimethylpyridinyl)—3 -fluoro[(2S)(trifluoromethy1)—4— morpholinyl]pheny1]methy1]-cyclobutaneacetamide, N—[[2-(2,6-dimethylpyridinyl)fluoro—5-(2-methylmorpholinyl)pheny1]methyl]- cyclobutaneacetamide, N—[[2-(2,6—dimethyl—4-pyridinyl)-3 -flu0ro—5-(2-methylmorpholinyl)phenyl]methyl]— 3 —methylisoxazolecarboxamide, N-[[2—(2,6-dimethyl—4-pyridinyl)—3 -fluoro[(2 S)(trifluoromethy1)-4— linyl]pheny1]methyl]methy1isoxazolecarboxarnide, N—[[2—(2,6—dimethyIpyridiny1)-3 -fluoro-5—{(2S)~2-(trifluoromethy1)~4— morpholinyl]phenyl]methy1]—5-methyl—3 -isoxazolecarboxamide, (2,6—dimethyl—4-pyridinyl)—3-fluoro—5-(2-methy1~4—morpholinyl)phenyl]methyl]— -methyl—3-isoxazolecarboxamide, N-[[2-(2,6-dimethylpyridinyl)f1uoro(2-methy1morpholinyl)pheny1]methyl]— 2-methyl-propanami de, N-[[2—(2,6-dimethylpyridinyl)—3 -flu0ro—5-[(2S)(trifluoromethyl) morpholinyl]phenyl]methyl]—2-methy1-propanamide, 2012/053047 (2,6-dimethy]pyridiny1)fluoro(2-methy1morpholinyl)phenyl]methy1]— cyclopropaneacetamide, N-[[2-(2,6-dimethylpyridinyl)—3 -fluoro[(ZS)(trifluoromethyl)~4- morpholinyl]phenyl]methyl]—cyclopropaneacetamide, N—[[2-(2,6-dimethyI—4—pyridinyl)—3 -fluoro—5—(2—methylmorpholinyl)phenyl]methyl]- cyclopropanecarboxamide, N~[[2-(2,6—dimethyl-4—pyridinyl)—3-fluoro—5—[(2S)(trifluoromethyl)—4- morpholinyl]phenyl]methyl]-cyclopropanecarb0xamide, N-[[2-(2,6-dimethyl—4-pyridinyl)—3—fluoro(2~methy1morpholinyl)pheny1]methyl]~ 3 -methyl—butanamide, N—[[2—(2,6-dimethyl—4-pyridinyl)—3-fluor0[(2S)-2—(trifluoromethyl)—4- morpholinyl]pheny1]methyl]methy1—butanamide, N-[[3-[(2R,6S)—2,6~dimethylmorpholinyl1—6-(2,6—dimethyl-4~pyridinyl)-2,5- difluorophenyl]methy1]-cyclopropanecarboxamide, N-[[3-[(2R,6S)—2,6—dimethyl-4—morpholinyl]—6—(2,6-dimethylpyridinyl)-2,5- difluorophenyl]methyl]-5—methyI—3-isoxazolecarboxamide, N-[[3-[(2R,6S)-2,6—dimethylmorpholinyl]—6-(2,6-dimethylpyridinyl)—2,5- difluorophenyl]methyl]-cyclopropaneacetami de, N-[[3-[(2R,6S)—2,6-dimethyl—4-morpholinyl](2,6-dimethylpyridinyl) fluorophenyl]methyl]—5,5,5—trifluoro—pentanamide, N—[[3—[(2R,6S)—2,6—dimethyl-4—rnorpholinyl]—6—(2,6-dimethyl—4-pyridinyl)—2- henyl]methy1]-cyclobutaneacetamide, [(2R,6$)—2,6-dimethyl—4-morpholinyl](2,6-dimethyl—4-pyridinyl)~2- fluorophenyl]methyl]-cyclohexanecarboxamide, N-[[3-[(2R,6S)—2,6-dimethyl—4—morpholinyl]—6-(2,6-dimethyl-4—py1‘idinyl)—2- fluorophenyl]methyl]methoxy-propanamide, N-[[3—[(2R,6S)~2,6-dimethyl—4—morpholinyl]—6-(2,6—dimethyl—4—pyridinyl)—2- fluorophenyl]methyl]—3,3-dimethy1-butanamide, N-[[3-[(2R,GS)—2,6-dimethyl—4—morpholinyl](2,6—dimethylpyridinyl)—2- fluorophenyl]methyl]-cyclobutanecarboxamide, N—[[3—[(2R,6S)-2,6-dimethyl—4-morpholinyl]~6-(2,6—dimethy1pyridinyl)—2- fluorophenyl]methyl]—alpha-methy1—cyclopropaneacetamide, 4,6-dichloro—N—[[3—[(2R,6S)—2,6-dimethyl-4—morpholinyl](2,6-dimethyl—4— pyridinyl)fluorophenyl]methy1]pyridinecarboxamide, 3-chloro-N—[[3-[(2R,6S)—2,6-dimethylmorpholinyl](2,6-dimethylpyridiny]) fluorophenyl]methyl]~2-fluoro—benzamide, N—[[6-(2,6-dimethyl-4—pyridinyl)—2-fluoro[(2S)—2~(trifluoromethyl)—4- W0 2012!]13850 linyl]pheny1]methyl]-5—methyl-3 -isoxazolecarboxamide, N-[[6-(2,6-dimethylpyridinyl)fluoro[(2S)(trifluoromethyl) morpholinyl]phenyl]methy1]—3-methyl—butanamide, I\—[[6-(2,6—dimethyl—4-pyridinyl)—2—fluoro—3-[(2S)—2—(trifluoromethyl)—4— morpholinyl]phenyl]methy1]-cyclopropanecarboxamide, I\-[[6—(2,6-dimethy1—4-pyridinyl)—2-fluoro—3—[(2S)-2—(trifluoromethyl)—4— morpholinyl]pheny1]methyl]~cyclobutaneacetamide, N—[[3-chlor0—5~[(2R,6S)—2,6~dimethyl-4—morpholinyl](2,6-dimethy1 pyridinyl)phenyl]methyl]—2-methy1-propanamide, chloro-5—[(2R,6S)—2,6—dimethy1—4—morpholiny1]—2-(2,6—dimethyl-4— pyridinyl)phenyl]methyl]—cyclopropaneacetamide, N—[[3—chloro~5—[(2R,6S)—2,6-dimethy1—4-morpholiny1]—2-(2,6-dimethyl-4~ pyridinyl)phenyl]methyl]methy1—3~isoxazolecarboxamide, N~[[2-[(2R,6S)—2,6-dimethyl-4—morpholinyl}-5—(2,6-dimethy1—4- pyridinyl)pheny1]methyl]-cyclopropaneacetamide, N—[[2~[(2R,6S)—2,6—dimethyl—4—morpholinyl]—5—(2,6—dimethy1—4~ pyridinyl)phenyl]methyl]—5-methyl-3 -isoxazolecarboxamide, N—[[2-[(2R,68)-2,6-di methylmorpholinyl ](2,6-dimethyl pyridinyl)phenyl]methyl]methyl-propanamide, N-[[2-[(2R,6S)-2,6—dimethyl—4-m0rpholinyl]~5-(2,6~dimethyl-4— pyridinyl)phenyl]methyl]—4-fluoromethyl-benzamide, [(2R,6S)-2,6—dimethylmorpholinyl]—5—(2,6-dimethyl pyridinyl)phenyl]methyl]methylisoxazolecarboxamide, N—[[2-(2,6-dimethyl-4—pyridinyl)—5-(8—0xa—3-azabicyclo[3 .2. 1]oct-3 - yl)phenyl]methy1]methy1—propanamide, N—[[2-(2,6-dimethylpyridinyl)(8-oxa—3 ~azabicyclo[3 .2. 1]oct—3 — y1)phenyl]methy1] —cyclopropaneacetamide, N—[[2-(2,6-dimethyl-4—pyridinyl)—5-(8—oxa—3-azabicyclo[3 .2. 1]oct-3 - y1)phenyl]methy1]~cyclopropanecarboxamide, y1-N-[[2-(2-methylpyridiny1)(4—morpholinyl)phenyl]methyl]- propanamide, N-[[2-(2—methy1pyridinyl)-5—(4-morpholinyl)pheny1]methy1]~ cyclopropaneacetamide, -methyl-N-[[2—(2-methyl-4—pyridinyl)(4-morpholinyl)phenyl]methyl] isoxazol ecarboxam i de, 3 -methyl-N—[[2-(2-methyl-4—pyridinyl)(4—morpholiny1)phenyl]rnethyl] isoxazolecarboxamide.

W0 2012/1 13850 A particular compound is N-[[5-[(2R,6S)-2,6-dimethylmorpholinyl](2,6- dimethylpyridinyl)phenyl]methyl]methyl-propanamide.

All possible combinations of the above-indicated interesting ments are considered to be ed within the scope of this invention.

When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates ise.

The term "halo" or en" as a group or part of a group is c for fluoro, chloro, bromo, iodo unless otherwise is ted or is clear from the context.

The term lkyl" as a group or part of a group refers to a hydrocarbyl radical of Formula CnH2n+1 wherein n is a number ranging from 1 to 8. C1.galkyl groups comprise from 1 to 8 carbon atoms, preferably from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms, still more preferably 1 to 2 carbon atoms.

Alkyl groups may be linear or branched and may be substituted as indicated herein.

When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain.

Thus, for example, C1.galkyl includes all linear, or branched alkyl groups with between 1 and 8 carbon atoms, and thus includes such as for example methyl, ethyl, n—propyl, pyl, butyl and its isomers (e.g. n—butyl, isobutyl and tert—butyl), pentyl, hexyl, heptyl, octyl and their isomers.

The term "C14a1k3'1" as a group or part of a group refers to a hydrocarbyl radical of Formula 1 wherein n is a number ranging from 1 to 4. C14alkyl groups comprise from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. C14alkyl includes all linear, or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes such as for example methyl, ethyl, n—propyl, isopropyl, butyl and its isomers e. g. n-butyl, isobutyl, sec~butyl and tert-butyl.

The term "Cmalkyloxy" as a group or part ofa group refers to a radical having the a -ORa wherein Ra is Cligalkyl. Non-limiting examples of suitable alkyloxy include methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tyloxy, tert-butyloxy, pentyloxy, and hexyloxy.

The term "CHalkyloxy" as a group or part of a group refers to a l having the Formula -ORb n Rb is C14alkyl. Non-limiting examples of suitable CMalkyloxy include methyloxy (also methoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy and tert-butyloxy.

W0 2012/] 13850 The term "haloC1_4alkyloxy" as a group or part of a group refers to a Claalkyloxy radical wherein said Cmalkyloxy radical is further substituted with l, 2 or 3 halo atoms. Non-limiting examples of suitable haloCHalkyloxy radicals include trifluoromethyloxy, trifluoroethyloxy, trifluoropropyloxy, and trifluorobutyloxy.

The term loalkyl" alone or in combination, refers to a cyclic saturated hydrocarbon radical having from 3 to 6 carbon atoms, Non—limiting examples of suitable cycloCMalkyl e cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Hereinbefore and hereinafter, the term "compound of formula (1)" is meant to e the addition salts, the solvates and the stereoisomers thereof.

The terms "stereoisomers" or "stereochemically isomeric forms" hereinbefore or hereinafter are used hangeably.

The invention includes all stereoisomers of the compound of Formula (I) either as a pure stereoisomer or as a mixture oftwo or more stereoisomers. omers are stereoisomers that are non—superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or c mixture.

Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. If a compound contains a disubstituted cycloalkyl group, the sub stituents may be in the cis or trans configuration.

Therefore, the invention includes omers, diastereomers, racemates, E s, Z isomers, cis isomers, trans isomers and mixtures thereof The absolute configuration is specified according to the Cahn-lngold-Prelog system.

The configuration at an asymmetric atom is specified by either R or S. ed compounds whose absolute configuration is not known can be ated by (+) or (—) depending on the direction in which they rotate plane polarized light.

When a specific stereoisomer is fied, this means that said stereoisomer is ntially free, i.e. associated with less than 50%, preferably less than 20%, more ably less than 10%, even more preferably less than 5%, in particular less than 2% and most ably less than 1%, of the other isomers. Thus, when a compound of formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is for instance specified as E, this means that the compound is substantially free ofthe Z isomer; when a compound of formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.

W0 2012/1 13850 For therapeutic use, salts of the compounds according to formula (I) are those wherein the countetion is pharmaceutically acceptable. However, salts of acids and bases which are non~pharmaceutically acceptable may also find use, for example, in the preparation or ation of a pharmaceutically acceptable compound. All salts, whether pharrnaceutically able or not are included within the ambit of the present invention.

The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove or after are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds according to formula (I) are able to form.

The ceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for e, inorganic acids such as hydrohalic acids, eg. hydrochloric or hydrobromic acid, sulfuric, nitric, oric and the like acids; or organic acids such as, for example, , propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

The term solvates refers to hydrates and alcoholates which the compounds according to formula (I) as well as the salts thereof, may form.

The chemical names of the nds of the present invention were generated according to the nomenclature rules agreed upon by the Chemical cts Service, using Advanced Chemical Development, Inc, nomenclature software (ACD/Name t version 10.01; Build 15494, 1 Dec 2006).

Some ofthe compounds according to formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

Preparation of the nds Depending on the position of acylaminomethylene group on the phenyl moiety and whether Y represents N or CH, three subgroups of Formula (1a), (Ib) and (1c) may be distinguished, each having its own synthetic methodology.

WC 2012/1 13850 -16— (1a) (1b) (10) (11) Where R2, R3, R4, R5, Z, and Xn are as defined in Formula (I), with a nd of Formula Rl-COZH (III) where R1 is as defined in Formula (I), in the presence of a suitable amide coupling reagent, such as HBTU, a suitable base, such as DIPEA, in le solvent, such as DCM and at a suitable temperature, such as room temperature.

Alternatively, the acylation reaction of (H) may be conducted with a symmetric or asymmetric anhydride, or an acyl halide of carboxylic acid (III).

Compounds of Formula (II), can be prepared by ng a compound ofFormula (IV), E{4 I{‘ W0 2012/1 13850 where R2, R3, R4, R5, Z, and Xn are as defined in Formula (I), with a suitable reducing agent, such as hydrogen, in the presence of a suitable catalyst, such as Raney Nickel, in a suitable solvent, such as 7M ammonia in methanol, at a suitable temperature, such as room temperature.

Compounds of Formula (IV) can be prepared by reacting a compound of Formula (V) Hal H, \ / N where, R2, R3, Z, and Xn are as defined in Formula (I), and Hal1 is a n atom such as iodine, bromine or chlorine with a compound of Formula (VI) _" 0 R5 (VI) where R4 and R5 are as defined in Formula (I), in the presence of a suitable catalyst, such as Pd(PPh3)4, with a suitable base, such as sodium carbonate, in a suitable solvent, such as oxane and ethanol/water (1:1) and at a suitable temperature, such as 120°C in a sealed tube, under a suitable inert atmosphere, such as a nitrogen atmosphere.

Compounds of a (V) can be prepared by ng a compound of Formula (VII) Hal1 \-\—/ r1312 (VII) where Hal1 and Xn are as defined as in Formula (V) and Hal2 is a halogen atom such fluorine, with a compound ofFormula (VIII) (VIII) W0 2012/1 13850 —18- where R2, R3, and Z are as defined in Formula (I), in the presence of a suitable base, such as potassium carbonate, in a suitable solvent, such as DMSO, at a suitable temperature, such as 100 °C.

Alternatively, compounds ofFormula (V) can be ed by reacting a compound of Formula (IX) xii-- Nflz \ / // L Compounds of Formula (IX) can be prepared by ng a compound ofFormula (X) \ / Hal where Xn is as defined in Formula (IX), and Hal3 is a halogen atom, such as bromine, with a nd of Formula (VIII), in the presence of a suitable catalyst, such Pd2(dba)3 or the Nolan catalyst [478980-01—7], a suitable , such as Xantphos, and a suitable base, such as sodium tert-butanolate, in a suitable solvent, such as toluene or monoglyme, at a suitable temperature, such as 120 °C, in a sealed tube, and under a suitable inert here, such as a nitrogen atmosphere.

Alternatively, compounds ofFormula (IV) can be prepared by reacting a compound of Formula (XI) XP\__ N/ \ \ Hal4 R5 // (XI) where, R4, R5, and XI] are as defined in Formula (I), and Hal4 is a halogen atom such as chlorine or bromine, with a compound of a , in the presence of a suitable W0 2012/] 13850 catalyst such as Pd2(dba)3 or the Nolan catalyst [478980-01—7], a le , such as Xantphos, and a suitable base, such as sodium tert—butanolate, in a suitable solvent, such as toluene or monoglyme, at a suitable temperature, such as 120 °C, in a sealed tube, and under a suitable inert atmosphere, such as a en atmosphere, U: Compounds of a (XI) can be prepared by reacting a compound of Formula (X11) (X11) where Hal4 and Xn are as defined in Formula (XI) and Hal5 is a halogen atom such bromine or iodine, with a compound of Formula (VI), in the presence of a le catalyst, such as Pd(PPh3)4, with a suitable base, such as sodium carbonate or potassium carbonate, in a suitable solvent, such as 1,4-dioxane or dimethoxyethane and water, and at a suitable temperature, such as 100°C, in a sealed tube, and under a suitable inert atmosphere, such as a nitrogen atmosphere.

Alternatively, compounds ofFormula (IV) can be prepared by reacting a compound of Formula (X111) R4 7 / '\— f‘< N \ __ \ / NL Compounds of Formula (XIII) can be prepared by reacting a compound of Formula (XIV) N/ \ Hal7 \ / R5 H316 (XIV) where R4, R5, Xn and Hal6 are as defined in Formula (XIII), and Hal7 is a halogen atom such as e, with a compound of Formula (VIII), in the presence of a suitable catalyst, such as Pd2(dba)3, a suitable ligand, such as os, and a suitable base, such as sodium tert—butanolate, in a suitable solvent, such as toluene, at a suitable temperature, such as 120 °C, in a sealed tube, and under a suitable inert atmosphere, such as a nitrogen atmosphere.

Compounds of a (XIV) can be ed by reacting a compound ofFormula (XV) Xl‘\_ Halgfl—Hafl Hal‘l" (XV) where X", Hal6 and Hal7 are as defined in Formula (XIV), and Hal8 is a halogen atom such as iodine, with a nd of Formula (VI), in the presence of a suitable catalyst, such as Pd(PPh3)4, in the presence of a le base, such as potassium carbonate, in suitable solvent, such as dimethoxyethane, and at a le temperature, such as 100 °C, in a sealed tube, and under a le inert atmosphere, such as a nitrogen atmosphere.

Compounds of Formula (Ib) can be ed by reacting a compound ofFormula (XVI), (XVI) where R2, R3, R4, R5, Z, and Xn are as defined in Formula (Ib), with a compound of Formula (III), in the presence of a suitable amide coupling reagent, such as HBTU, suitable base, such as DIPEA, in a suitable solvent, such as DCM and at a suitable temperature, such as room temperature. Alternatively, the acylation reaction of (XVI) may be conducted with a symmetric or asymmetric anhydride, or an acyl halide of carboxylic acid (1H).

Compounds of Formula (XVI), can be prepared by reacting a compound ofFormula (XVII), WC 2012/1 13850 (XVII) where R2, R3, R4, R5, Z, and Xn are as defined in a (1b), with a suitable reducing agent, such as hydrogen, in the ce of a suitable catalyst, such as Raney Nickel, in a suitable solvent, such as 7M ammonia in methanol, at a suitable ature, such as room temperature.

Compounds of Formula (XVII), can be prepared by ng a compound of Formula (XVIII), (XVIII) where R2, R3, Z, and Xn are as defined in Formula (Ib), and Hal9 is a halogen atom such as chlorine, with a compound of Formula (VI), in the presence of a suitable catalyst, such as Pd(PP113)4 or PdC12(dppf), with a suitable base, such as sodium carbonate, in a suitable solvent, such as a mixture of dioxane, ethanol and water, or acetonitrile, at a suitable temperature, such as 130°C, in a sealed tube, and under a suitable inert atmosphere, such as a nitrogen atmosphere.

Compounds of a ), can be prepared by reacting a compound ula (XIX), Hal9 \-\-/ Ha110 (XIX) where Hal9 and X1. are as defined in Formula (XVIII) and Hal10 is a halogen atom such as, bromine, with a compound of Formula (VIII), in the presence of a suitable catalyst, such as Pd2(dba)3, in the presence of a suitable ligand, such as Xantphos, with a suitable base, such as cesium carbonate, in a le solvent, such as dioxane, at a suitable temperature, such as 145 °C, in a sealed tube, and under a suitable inert atmosphere, such as a nitrogen atmosphere.

Compounds of Formula (10) can be prepared by reacting a compound ofFormula (XX), (XX) where R2, R3, R4, R5, Z, and X, are as defined in Formula (I), with a compound of Formula (III) (111) where R1 is as defined in Formula (I), in the presence of a suitable amide coupling reagent, such as HBTU, a suitable base, such as DIPEA, in a suitable solvent, such as DCM and at a suitable temperature, such as room temperature. Alternatively, the acylation reaction of (XX) may be conducted with a symmetric or asymmetric anhydride, or an acyl halide of carboxylic acid (111). nds of Formula (XX) can be prepared by reacting a compound of Formula (XXI), (XXI) where R2, R3, R4, R5, Z, and Xn are as defined in a (I), with a suitable reducing agent, such as hydrogen, in the presence of a suitable catalyst, such as platinum on charcoal, in a suitable solvent, such as THF, at a suitable temperature, such as 50 °C.

Compounds of Formula (XXl) can be prepared by reacting a compound ofFormula (XXII), (XXII) where R2, R3, R4, R5, Z, and X11 are as defined in Formula (I), with a suitable ng agent, such as hydrogen, in the ce of a suitable st, such as Raney Nickel, in a suitable solvent, such as 7M ammonia in methanol, at a suitable temperature, such as room temperature.

W0 2012/1 13850 Compounds ofFormula (XXII) can be prepared by reacting a compound of Formula RG—q B 2 115—0, \ (XXIII) where R2, R3, and z, are as defined in a (I), and R6 is Cw alkyl or both R6 together form C2.galkanediyl, with a compound of Formula (X1), in the presence of a suitable catalyst such as Pd(PPh3)4, with a suitable base, such as potassium carbonate, in a suitable solvent, such as dimethoxyethane, at a suitable temperature, such 100°C, under a suitable inert here, such as nitrogen atmosphere.

Compounds of Formula (XXIII) can be prepared by reacting a compound of Formula (XXIV), F3C—(\CF2)3 R2 I/Sf: O O \ Z (XXIV) where R2, R3, and Z, are as defined in Formula (I), with a le boron derivative, such as bis(pinacolato)diboron, in the presence of a suitable catalyst, such as PdC12(dppt), in the presence of a suitable ligand, such as dppf, with a suitable base, such as potassium acetate, in a suitable solvent, such as oxyethane, at a suitable temperature, such as 80 °C, under a suitable inert here, such as en atmosphere.

Compounds of Formula (XXIV) can be prepared by reacting a compound of a (XXV), (XXV) Where R2, R3, and Z, are as defined in Formula (I), with a suitable base, such as LDA, and with a suitable sulfonylating agent, such as perfluorobutanesulfonyl fluoride, in suitable solvent, such as THF, at a suitable temperature, such as -78 °C, under a suitable inert atmosphere, such as a nitrogen atmosphere.

W0 2012/1 13850 cology The compounds of the present invention were found to be positive allosteric modulators of the alpha 7 nicotinic receptor. The alpha 7 nicotinic receptor (alpha 7 nAChR) belongs to the superfamily of cys—loop, ionotropic ligand—gated ion channels which includes the 5—HT3, GABAA and glycine receptor families. It is activated by acetylcholine and its breakdown t choline and a major feature of the alpha 7 nAChR is its rapid desensitisation in the persistent presence of agonist. It is the second most nt nicotinic receptor e in the brain and is an important tor of release of many neurotransmitters. It has a discrete distribution in several brain structures with relevance to attentional and ive processes, such as the hippocampus and ontal cortex and has been implicated in a y of psychiatric and neurological disorders in humans. It is also implicated in the cholinergic inflammatory pathway.

Genetic evidence for its association with schizophrenia is seen in the form of strong linkage between a schizophrenia marker (sensory gating deficit) and the alpha 7 locus on 15ql3-14 and rphisms in the core promoter region of the alpha 7 gene.

Pathological evidence points to a loss of alpha 7 immunoreactivity and a-bungarotoxin (th)-binding in the hippocampus, frontal and cingulate cortex of schizophrenic brains, in Parkinson’s and Alzheimer’s disease, and in the paraventricular nucleus and nucleus 2O reuniens in autism, Pharmacological evidence such as the marked smoking habits of schizophrenics compared to normals has been interpreted as an attempt by the patients to self-medicate to make up for a deficit in alpha 7 nergic ission. Transient normalization of defects in sensory gating (pre-pulse inhibition, PPI) in both animal models and man upon nicotine administration and temporary restoration of normal sensory gating in phrenics when ain cholinergic activity is low (e.g. stage 2 sleep) have both been interpreted to be the result of transient activation of the alpha 7 nicotinic receptor followed by desensitization.

Thus there is good reason to suppose that activating the alpha 7 nAChR will have therapeutically beneficial effects for a number of CNS (psychiatric and neurological) disorders.

As already ned the alpha 7 nAChR rapidly desensitizes in the persistent presence of the natural transmitter acetylcholine as well as exogenous ligands such as nicotine.

In the desensitized state the receptor remains ligand-bound but functionally inactive, This is not so much a m for natural transmitters such as acetylcholine and choline W0 2012/1 13850 since these are substrates for very powerful own lcholinesterase) and clearance (choline orter) mechanisms. These transmitter breakdown/clearance mechanisms are likely to maintain the balance between activatible and desensitized alpha 7 nAChRs in a logically useful range. r, synthetic agonists, which are not substrates for the l own and clearance mechanisms are perceived to have a potential liability both for over-stimulation and also to push the alpha 7 nAChR population equilibrium towards a persistently desensitized state, which is undesirable in disorders in which deficiencies in alpha 7 nAChR expression or function play a role.

Agonists by their nature must target the ACh binding pocket which is highly conserved across the different nicotinic receptor subtypes leading to the potential for adverse reactions by non—specific activation of other nicotinic receptor subtypes. Therefore, to avoid these potential liabilities an alternative therapeutic strategy to alpha 7 agonism is to enhance receptor siveness to the natural agonists with a positive allosteric modulator (PAM). A PAM is defined as an agent which binds to a site distinct from the agonist binding site, and ore is not expected to have agonist or desensitization properties, but enhances the responsiveness of the alpha 7 nAChR to the natural transmitter. The value of this strategy is that for a given amount of transmitter the magnitude of the alpha 7 nAChR response is increased in the presence of the PAM ve to the level of transmission possible in its absence. Additionally, PAMs can also increase the y of the natural transmitter. So for disorders in which there is deficit in alpha 7 nAChR protein, the PAM—induced se in alpha 7 nicotinergic transmission can be ial. As a PAM relies on the ce ofthe natural transmitter the potential for over-stimulation is limited by the breakdown/clearance mechanisms for the natural transmitter.

The compounds of the present invention are classified as type 1-4, based on qualitative kinetic properties, as determined by whole—cell voltage—clamp recordings. This classification is based on the effect of an alpha 7 PAM compound, as bed hereinbefore, on the signal elicited by an agonist application. In particular, said agonist is choline at a concentration of 1 mM. In a preferred experimental setting, said alpha 7 PAM compound and choline are simultaneously applied to the cell, as described hereinafter. Desensitization is defined as the closure of the receptor upon activation during the application of the agonist in whole-cell voltage—clamp electrophysiology measurements seen as the reduction of the outward current after l activation by the agonist.

The definition of the PAM types 1-4 is described hereinafter: W0 2012/1 13850 —26- Type 0 compounds minimally change the effect size of the current elicited by 1 mM choline.

Type 1 nds e the effect size of the current elicited by 1 mM choline but minimally alter the kinetics ofthe receptor. In particular, the rate and the extent of desensitization and of deactivation of the receptor elicited by the agonist is not affected. The compound-modulated response to 1 mM e, therefore, is close to a linear scaling of the 1 mM choline response in absence ofthe alpha 7 PAM nd.

Type 2 compounds enhance the effect size of the current elicited by 1 mM choline while reducing the rate and/or the extent of desensitization. Deactivation of the receptor is generally unaffected Type 3 compounds enhance the effect size of the current elicited by 1 mM e.

When tested at higher concentrations up to 10 uM they completely t desensitization, in particular a 1 mM choline application of 250 milliseconds.

Deactivation of the receptor may be slowed down.

Type 4 nds allow for an initial desensitization of the or followed by a re-opening of the receptor during agoni st application. At low-potency concentrations of the alpha 7 PAM compound, the agonist-induced activation, which is followed by desensitization, can still be separated from the compound—induced re-opening as an initial inward current-maximum. At higher potency concentrations of the alpha 7 PAM compound, the re—opening occurs faster than the closure due to desensitization so that the initial current— maximum disappears.

A compound was considered to have interesting PAM-like activity when the potentiation of the peak current was at least 200% compared to the control choline response (= 100%). Such compounds are classified as belonging to a particular PAM type in the Experimental Part. Compounds not meeting the condition are not classified as belonging to a particular PAM-type.

A number of compounds according to the ion may prove active in the auditory evoked potential test. The DEA/2 inbred mouse strain used in this test shows sensory processing deficits similar to schizophrenia patients which are also correlated with reduced nic alpha 7 receptors in the hippocampus. The DEA/2 mouse has proven to be a useful model of schizophrenia-like y processing deficits. Human studies of nicotine effects on sensory sing ted the results in the DEA/2 mouse and studies with the selective alpha 7 agonist GTS—Zl in DEA/2 mice, predicted the effects W0 2012/1 13850 2012/053047 in . This model of sensory gating ability therefore has high translational nce.

It is accordingly an object ofthe present ion to provide methods of treatment that include administering either a positive allosten'c modulator as the only active U: substance, thus modulating the activity of endogenous nicotinic receptor ts such as acetylcholine or choline, or administering a ve allosteric modulator together with a nicotinic receptor agonist. In a particular form of this aspect of the invention, the method of treatment comprises treatment with a positive allosteric modulator of the alpha 7 nicotinic receptor as described herein and an alpha 7 nicotinic receptor agonist or partial agonist. Examples of suitable nds with alpha 7 nicotinic receptor agonistic activity include - 1,4-Diazabicyclo[3.2.2]nonane—4-carboxylic acid, 4-bromophenyl ester, monohydrochloride (SSR180711A) ; - (-)-spiro[l~azabicyclo[2.2.2.]octane~3,5’-oxazolidine]-2’-one; - 3—[(2,4-Dimethoxy)Benzylidene]—Anabaseine ochloride (GTS—Zl); - [N-[(3R)Azabicyclo[2.2.2]oct-3—yl]chlorobenzamide Hydrochloride] PNU-282987; - ne; - varenicline; - MEM3454; — AZD—0328; - MEM63908; - (+)—N—(l-azabicyclo[2.2.2]octyl)benzo[b]furan~2-carboxamide; ~ A—582941; — AR—R17779; - TC—l698; - PHA—709829; - tropisetron; - WAY—317538; - EVP-6124; and - TC-5619.

In particular, examples of suitable compounds with 0t7 nicotinic receptor agonistic activity include 1,4-Diazabicyclo[3.2.2]nonane—4-carboxylic acid, 4-bromophenyl ester, monohydrochlon'de (SSRl 8071 l A) ; (-)-spiro[1-azabicyclo[2.2.2.]octane-3,5’-oxazolidine]—2’-one; 3-[(2,4-Dimethoxy)Benzylidene]—Anabaseine Dihydrochloride (GTS-Zl); W0 2012/1 13850 R)Azabicyclo[2.2.2]octyl]—4-chlorobenzamide Hydrochloride] PNU-282987; ne; varenicline; MEM3454; AZD-0328; and MEM63908.

Positive nAChR modulators of the present invention are useful for treatment or prophylaxis of psychotic ers, intellectual impairment disorders or diseases or conditions in which modulation of alpha 7 nicotinic receptor activity is beneficial. A particular aspect of the method of the invention is a method of treatment for learning deficit, cognition deficit, attention deficit or memory loss, modulation of alpha 7 nicotinic receptor activity is expected to be beneficial in a number of diseases including Alzheimer’s disease, Lewy Body Dementia, Attention Deficit Hyperactivity er, anxiety, schizophrenia, mania, manic depression, son’s e, Huntington’s disease, Tourette’s syndrome, brain trauma or other neurological, degenerative or psychiatric ers in which there is loss of cholinergic synapses, including jetlag, nicotine addiction, pain.

The compounds may also find therapeutical use as anti—inflammatory medicines because the nic choline receptor alpha 7 subunit is essential for ting ne synthesis by the cholinergic inflammatory pathway. Examples of indications which may be treated by the compounds are endotoxaemia, endotoxic shock, sepsis, rheumatoid arthritis, asthma, multiple sclerosis, psoriasis, urticaria, inflammatory bowel disease, inflammatory bile disease, Crohn’s disease, ulcerative colitis, post- operative ileus, pancreatitis, heart e, acute lung injury and allograft rejection.

The compounds of the invention may find therapeutical use in the following indications as cognition in schizophrenia, cognition in Alzheimer’s disease, mild cognitive impairment, Parkinson’s disease, attention deficit hyperactivity disorder, ulcerative colitis, pancreatitis, arthritis, sepsis, postoperative ileus and acute lung injury.

In View of the above described pharmacological ties, the compounds according to formula (I) or any subgroup thereof, their pharmaceutically able addition salts, solvates and stereochemically isomeric forms, may be used as a ne. In particular, the present compounds can be used for the manufacture of a medicament for treatment or prophylaxis of psychotic disorders, intellectual impairment disorders or 3O diseases or conditions in which tion of the alpha 7 nicotinic receptor is beneficial.

In an embodiment the present invention relates to the compounds according to formula (I) for use in the treatment or prophylaxis, in particular treatment of psychotic disorders, ectual impairment disorders or es or conditions in which modulation of the 0:7 nicotinic receptor is beneficial, In an embodiment the present invention relates to the compounds ing to formula (I) for use in the treatment or prophylaxis, in particular treatment, of psychotic disorders, intellectual impairment disorders, or inflammatory diseases.

In an embodiment the present invention relates to the compounds according to formula (I) for treating or preventing, in particular treating, said diseases or conditions.

In View of the utility of the compounds according to formula (I), there is provided a method of treating or preventing warm~blooded animals, including humans, suffering from diseases in which modulation ofthe alpha 7 nicotinic receptor is beneficial, such as schizophrenia, mania, and manic sion, anxiety, Alzheimer’s disease, learning deficit, cognition deficit, ion deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder, Parkinson’ 3 disease, Huntington’s disease, te’s syndrome, brain , jetlag, nicotine addiction and pain. Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of a compound according to formula (I), a stereochemically isomeric form thereof, a pharmaceutically acceptable addition salt, or a solvate thereof, to warm-blooded animals, including humans.

One skilled in the art will ize that a therapeutically effective amount of the PAM’s of the present invention is the amount sufficient to modulate the activity of the alpha 7 nicotinic receptor and that this amount varies inter alia, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the condition of the t. Generally, an amount ofPAM to be administered as a therapeutic agent for treating diseases in which modulation of the alpha 7 nicotinic receptor is beneficial, such as schizophrenia, mania, and manic depression, anxiety, Alzheimer’s disease, learning deficit, ion deficit, attention deficit, memory loss, Lewy Body Dementia, ion Deficit Hyperactivity Disorder, Parkinson’s disease, Huntington’s e, Tourette’s me, brain trauma, , nicotine addiction and pain will be determined on a case by case by an attending physician.

Generally, a suitable dose is one that s in a tration of the PAM at the treatment site in the range of 0.5 nM to 200 uM, and more usually 5 nM to 50 M. To obtain these treatment concentrations, a patient in need of treatment likely will be administered between 0.01 mg/kg to 2.50 mg/kg body weight, in particular from 0.1 mg/kg to 0.50 mg/kg body weight. The amount of a compound according to the t ion, also ed to here as the active ingredient, which is required to achieve a therapeutically effect will be, of course vary on case-by-case basis, vary with the particular compound, the route of administration, the age and condition of the WC 2012/] 13850 recipient, and the particular disorder or disease being treated. A method of treatment may also include administering the active ingredient on a n of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably formulated prior to admission. As described herein below, suitable pharmaceutical formulations are prepared by known ures using well known and readily available ients.

Pharmaceutical compositions The present invention also es compositions for preventing or treating es in which modulation ofthe alpha 7 nicotinic receptor is beneficial, such as schizophrenia, mania, and manic depression, y, Alzheimer’s disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder, Parkinson’s e, Huntington’s disease, Tourette’s syndrome, brain trauma, jetlag, nicotine addiction and pain. Said compositions comprising a therapeutically effective amount of a compound ing to formula (I) and a ceutically acceptable carrier or diluent.

While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. ingly, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically able carrier or diluent. The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof The pharmaceutical compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et a1. Remington’s Pharmaceutical Sciences (18th ed, Mack hing Company, 1990, see especially Part 8 : Pharmaceutical preparations and their cture). A therapeutically ive amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in te admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid ations such as suspensions, syrups, elixirs and solutions: or solid rs such as starches, sugars, W0 2012/] 13850 kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ients, for e, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier ses saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a le wettable agent, ally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may tate the administration to the skin and/or may be helpful for ing the desired compositions. These compositions may be administered in various ways, e. g., as a transdermal patch, as a spot-on or as an ointment.

It is especially advantageous to ate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of .

Dosage unit form as used in the specification and claims herein refers to physically 2O discrete units suitable as unitary dosages, each unit containing a predetermined ty of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and l physical condition of the particular patient as well as other tion the individual may be taking, as is well known to those skilled in the art. rmore, it is evident that said effective daily amount may be lowered or increased ing on the response of the treated subject and/or depending on the tion of the physician prescribing the compounds ofthe instant ion.

Depending on the mode of administration, the pharmaceutical composition will comprise from 0.05 to 99 % by weight, preferably from 0.1 to 70 "/0 by weight, more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % W0 2012/1 13850 by weight, preferably from 30 to 99.9 % by weight, more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable r, all tages being based on the total weight of the composition.

The amount of a compound of Formula (I) that can be combined with a carrier material to produce a single dosage form will vary depending upon the e treated, the mammalian species, and the particular mode of administration. r, as a general guide, suitable unit doses for the compounds of the present invention can, for example, preferably n between 0.1 mg to about 1000 mg of the active nd. A preferred unit dose is between 1 mg to about 500 mg. A more preferred unit dose is between 1 mg to about 300mg. Even more preferred unit dose is between 1 mg to about 100 mg. Such unit doses can be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject administration, A preferred dosage is 0.01 to about 1.5 mg per kg weight of subject administration, and such therapy can extend for a number of weeks or months, and in some cases, years. It will be tood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been stered; and the ty of the particular disease undergoing therapy, as is well tood by those of skill in the area.

A typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or, multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient. The time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.

It can be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to start, interrupt, adjust, or terminate therapy in conjunction with dual patient se.

The present compounds can be used for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, o or the like. The compounds are preferably orally administered. The exact dosage and frequency of W0 2012/1 13850 administration depends on the particular nd according to formula (I) used, the ular condition being treated, the severity of the ion being treated, the age, weight, sex, extent of er and l physical ion of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the tion of the physician prescribing the compounds of the instant invention.

The compounds according to a (I) may also be used in combination with other conventional (77 nicotinic receptor agonists, such as for example 1,4—Diazabicyclo- [3.2.2]nonane—4—carboxylic acid, 4—bromophenyl ester, monohydrochloride (SSR180711A); (—)-spiro[l-azabicyclo[2.2.2.]octane-3,5’-oxazolidine]-2’—one; 3-[(2,4-Dimethoxy)Benzylidene]~Anabaseine Dihydrochloride (GTS-Zl); [N-[(3 R)—1-Azabicyclo[2.2.2]oct—3~yl]chlorobenzamide Hydrochloride] PNU-282987; nicotine; varenicline; 4; AZD—0328; MEM63908; (+)-N— (l—azabicyclo[2,2.2]oct-3—yl)benzo[b]furan—2—carboxamide; A—582941; AR-Rl7779; TC~1698; FHA-709829; tropisetron; WAY-317538; EVP-6124; and TC-S619.

Thus, the present invention also relates to the combination of a compound according to formula (I) and a alpha 7 nicotinic receptor agonist. Said combination may be used as a medicine. The present invention also relates to a product comprising (a) a compound according to formula (I), and (b) an alpha 7 nicotinic receptor agonist, as a combined preparation for aneous, separate or sequential use in the treatment of diseases wherein modulation of the alpha 7 nicotinic receptor is beneficial. The different drugs may be combined in a single preparation er with pharmaceutically acceptable carriers.

MENTAL PART Several methods for preparing the compounds of this invention are illustrated in the following Examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.

Hereinafter or hereinbefore, "min" means minutes; "MeOH" means methanol; "EtOH" means ethanol; "Eth" means diethyl ether; "TFA" means roacetic acid "NI-hOAc" means ammonium acetate, "HBTU" means O-(benzotriazol—l-yl)— N,N,N’,N’—tetramethyluronium hexafluorophosphate ; "DIPEA" means diisopropylethylamine; "LDA" means lithium diisopropylamine; "DCM" means dichloromethane; "VCD" means vibrational circular dichroism.

W0 2012/1 13850 Microwave assisted reactions were performed in a single-mode reactor: torTM Sixty EXP microwave reactor (Biotage AB), or in a multimode reactor: MicroSYNTH Labstation (Milestone, Inc).

The ing examples are intended to illustrate but not to limit the scope of the U: present invention.

A. Preparation of the Intermediates -chlor0—2-(2,6-dimethylpyridinyl)-benzonitrile (Intermediate 1) c1 cs (Intermediate 1) A mixture of 2-bromochlorobenzonitrile (10.03 g, 46.33 mmol), 2,6- dimethylpyridine—4-boronic acid, pinacol ester ([325142-95—8], 16.20 g, 69.50 mmol), tetrakis(triphenylphosphine)palladium (3.21 g, 2.78 mmol), 1,4-dioxane (50 mL), and sodium carbonate (14.73 g, 139.00 mmol) in water (50 mL) was stirred and heated under nitrogen atmosphere at 100 °C for 2 h. The reaction was diluted with CH2C12 and water and the layers were separated. The organic layer was dried with MgSO4, filtered and ated. The residue was purified by column chromatography on silica gel (eluent gradient from 100% DCM to 98/2 DCM/MeOH). The desired fractions were ted and evaporated, yielding 8.73 g (77 %) of Intermediate 1, after drying overnight under vacuum at 50 °C. 5-[(2R,6S)-2,6—dimethylmorpholinyl}-2—(2,6-dimethyl-4—pyridinyl)—benzonitrile (Intermediate 2) mediate 2) A mixture of Intermediate 1 (2.64 g, 10.88 mmol), cis-2,6-dimethylmorpholine (1.35 mL, 10.88 mmol), sodium tert-butoxide (1.57 g, 16.33 mmol) and dry toluene (15 mL) was uced in a pressure tube and was degassed with nitrogen for 5 min. Xantphos 58] (378 mg, 0.65 mmol) and Pd2(dba)3 (199 mg, 0.22 mmol) were added W0 20121113850 and the mixture was further degassed for 5 min. The tube was sealed and the reaction mixture was stirred at 120 °C for 1.5 h. The on mixture was diluted with CH2C12 and washed with water. The aqueous layer was extracted twice with CHzClz. The combined organic layers were washed with water, dried on MgSO4, filtered and evaporated. The residue was purified by column tography on silica gel (eluent nt from 100% DCM to 99/1 DCM/MeOH), yielding 2.69 g of Intermediate 2 (77 %) as a white solid after drying in a vacuum oven at 50°C ght. -[(2R,6$)-2,6—dimethylm0rpholinyl]~2~(2,6-dimethyl—4—pyridinyl)— benzenemethanamine (Intermediate 3) (Intermediate 3) Intermediate 2 (3.26 g, 10.14 mmol) was added to a suspension of Raney Nickel (1 g) in a 7 N ammonia solution in MeOH (200 mL). The reaction mixture was stirred at 14 °C under hydrogen atmosphere until 2 equivalents of hydrogen were absorbed. The catalyst was removed by filtration over diatomaceous earth. The solvent was evaporated, yielding ediate 3 quantitatively. Intermediate 3 was used without further purification. 3,5-bis(trifluoromethyl)piperidine (Intermediate 4) F C3 Q‘I (Intermediate 4) 3,5-bis(tn'fluoromethyl)pyridine —47~0] (10 g, 46.49 mmol) and 6 N HCl in isopropanol (7.75 mL, 46.49 mmol) were added to a suspension of Pt on charcoal 5 % (1 g) in EtOH (150 mL). ), The reaction mixture was stirred at 25 °C under hydrogen atmosphere until 3 equivalents of hydrogen were absorbed. The catalyst was removed by filtration over diatomaceous earth. The solvent was evaporated, yielding Intermediate 4 quantitatively as a 50:50 e of cis and trans isomers. Intermediate 4 was used without further purification.

W0 2012/1 13850 2012/053047 -3 6- Table I The following intermediates were prepared according to the procedures used for Intermediate 3 (starting from Intermediate 1, via Intermediate 2): Intermediate Structure Starti_ng from ‘0 ""2 Intermediate 1 and morpholine 6 ediate 1 and 8-Oxa—3— 0 NH2 N azabicyclo[3.2.1]octane hydrochloride [54745—74-3] 7 Intermediate 1 and cis-3,5- dimethylpiperidine Intermediate 1 and 4, with separation of the cis and trans isomers Intermediate 1 and 3—(trifluoromethyl)— piperidine Table 2 The following intermediates were prepared according to the procedures used for Intermediate 3 ing from 2-bromochlorobenzonitrile) : W0 2012/1 13850 Intermediate Structure Startin from JW 2-Bromochlorobenzonitn'1e and (OK/N NH: pyridine~4~boronic acid ([1692—15—5D instead of 2,6—dimethylpyridine—4—boronic I :N acid, l ester 11 2-Bromo—S-chlorobenzonitrile and 0/fi NH2 K/N% pyridine—4-boronic acid ([l6925D d of 2,6—dimethylpyridineboronic /N acid, pinacol ester, and with morpholine L_ instead of cis-2,6-dir&thylmorpholine 12 Z—Bromo-S~chlorobenzonitri1e and 2~ 0 "HZ (K/N methylpyridine—4—boronic acid, l ester ([6608671]) instead of 2,6— l \N ylpyridine-4—boronic acid, pinacol ester 2-bromo(4—m0rpholinyl)—benzonitrile (Intermediate 10) U3,CN (Intermediate 10) A mixture of 2-bromo—5-fluorobenzonitn'le (10 g, 50 mmol), morpholine (4.37 mL, 50 mmol), and potassium carbonate (6.91 g, 50 mmol), in DMSO (100 mL) was stirred at 100 °C for 48 h. The reaction mixture was poured into water (200 mL) and was stirred for 1 h. The precipitate was filtered off and purified by column tography on silica gel (eluent gradient from 50/50 to 100/0 DCM/heptane). The desired fractions were collected and evaporated, yielding 4.1 g (30 %) of ediate 10, after drying overnight under vacuum at 50 OC. 2-(2-methylpyridinyl)-5—(4-morpholinyl)-benzonitrile (Intermediate 11) ‘0N CN /I\‘ (Intermediate 11) A mixture of Intermediate 10 (4.1 g, 15.35 mmol), 2-methy1pyridine—4-bor0nic acid, pinacol ester ([6608671], 3.70 g, 16.88 mmol), tetrakis(triphenylphosphine) palladium (0.88 g, 0.77 mmol), 1,4-dioxane (50 mL), and sodium carbonate (3.58 g, 33.67 mmol) dissolved in water (20 mL) and EtOH (30 mL) was degassed and the vessel was closed. The reaction mixture was stirred and heated under a nitrogen atmosphere at 120 °C for 2 h. The solvent was ated. The residue was taken up in DCM and washed with water. The organic layer was dried with MgSO4 and evaporated. The e was purified by column tography on silica gel (eluent gradient from 100% DCM to 99/1 DCM/MeOH). The desired fractions were collected and evaporated, yielding 3.7 g (86 %) of Intermediate 11 after drying overnight under vacuum at 50 °C. 2-(2—methyl-4—pyridinyl)-5—(4—m0rpholinyl)—benzenemethanamine (Intermediate (Intermediate 12) ediate 12 was prepared according to the procedure used for Intermediate 3, starting from Intermediate 11 instead of Intermediate 2. 3—[(2R,6S)-2,6—dimethylm0rpholinyl]fluoro-benzonitrile (Intermediate 13) bN CN (Intermediate 13) A e of 3-bromo-5—fluorobenzonitrile (55.56 g, 277.80 mmol), cis—2,6- dimethylmorpholine (34.40 mL, 277.80 mmol), sodium tert-butoxide (40.05 g, 416.70 mmol) and dry toluene (300 mL) was introduced in a pressure tube and was degassed with nitrogen for 5 min. Xantphos [1612658] (9.64 g, 16.67 mmol) and Pd2(dba)3 (5.09 g, 5.55 mmol) were added and the mixture was further degassed for 5 min. The tube was sealed and the reaction mixture was stirred at 120 °C for 2 h. The reaction e was diluted with CH2C12 and washed with water. The aqueous layer was extracted with CH2C12. The combined organic layers were washed with water, dried on MgSO4, filtered and evaporated. The residue was purified by column tography on silica gel (eluent gradient from 100% DCM to 99/1 DCM/MeOH). The desired fractions were evaporated. The residue was ated in Eth and was filtered, yielding W0 2012/113850 -3 9- 33 g of Intermediate 13 (51 %) as a white solid after drying in a vacuum oven at 50°C overnight. -[(2R,6S)-2,6-dimethyl—4—morpholinyl]fluoroiod0-benzonitrile mediate 14) mediate 14) A solution of 6-tetramethylpiperidine (1882 mL, 110.58 mmol) in THF (1 L) was cooled to 0 °C. N—Butyllithium (2.5 M in hexanes, 44.23 mL, 110.58 mmol) was added dropwise while stirring at 0 °C. The reaction mixture was then stirred for 15 min at 0 °C. The resulting solution was cooled to ~78 °C and a solution of Intermediate 13 (29.44 g, 100.53 mmol) dissolved in THF (200 mL) was added dropwise over 20 min.

The dark yellow solution was stirred at -78 °C for 30 min before a solution of iodine (30.62 g, 120.64 mmol) dissolved in THF (250 ml) was added dropwise over 15 min.

The mixture was stirred for 30 min at -78 °C before being allowed to warm up to room temperature. Stirring was continued for 1 h. The reaction was quenched with aqueous NH4C1. The mixture was diluted with water and EtZO and the layers were separated.

The aqueous layer was extracted with Eth. The combined organic layer was washed again with aqueous Nazszog and was dried on MgSO4, filtered and evaporated. The residue was triturated in warm DCM and was d, yielding 31.28 g of Intermediate 14 (86 %) as a white solid after drying in a vacuum oven at 50°C overnight.

- S)—2,6-dimethylmorpholinyl](2,6-dimethylpyridinyl)—3-fluor0- benzonitrile (Intermediate 15) (Intermediate 15) A mixture of Intermediate 14 (12.09 g, 33.57 mmol), 2,6-dimethylpyridineboronic acid, pinacol ester ([3251428], 11.74 g, 50.35 mmol), tetrakis(triphenylphosphine)palladium (2.33 g, 2.01 mmol), 1,4-dioxane (100 mL), and W0 2012f113850 -40_ sodium carbonate 1 M (100 mL, 100 mmol) was degassed with nitrogen. The reaction e was stirred and heated under a nitrogen atmosphere at 140 °C for 12 h. The reaction mixture was diluted with DCM and water and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layer was dried with MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent gradient from 100% DCM to 99/1 DCM/MeOH). The d fractions were collected and ated, ng 8.37 g (73 %) of Intermediate 15, after drying overnight under vacuum at 50 OC. -[(2R,6$)—2,6-dimethyl-4—m0rpholinyl}(2,6-dimethyl—4-pyridinyl)fluor0— benzenemethanamine (Intermediate 13) (Intermediate 16) Intermediate 16 was prepared according to the procedure used for Intermediate 3, starting from Intermediate 15 instead of Intermediate 2. 5-[(2R,6S)—2,6-dimethyl-4—morpholinyl]fluoro—2-(2-methylpyridinyl)— benzenemethanamine (Intermediate l7) (Intermediate 17) Intermediate 17 was prepared according to the procedures used for Intermediate 13, starting from Intermediate 14, and using 2~methylpyridine—4—boronic acid, pinacol ester ([6608671] instead of 2,6-dimethylpyridineboronic acid, l ester. 2-bromo-N-(phenylmethyl)-N~(3,3,3-trifluoro-Z-hydr0xypropyl)—acetamide mediate 18) (Intermediate 18) 2012/053047 A solution of 1,1,1-Triflurobenzylaminopropanol ([178218-36—5], 11.64 53.12 mmol) and triethylamine (7.38 mL, 53.12 mmol) in DCM (150 mL) was cooled to 0 °C under nitrogen atmosphere. Bromoacetyl chloride (5.41 mL, 58.43 mmol) dissolved in DCM (50 mL) was added dropwise and the reaction mixture was stirred for 30 min. The reaction mixture was diluted with DCM, washed with HCl lN followed by aqueous sodium hydrogenocarbonate and brine. The organic layer was dried with MgSO4, ed and evaporated, yielding 18.07 g of ediate l8 (quantitative) that was used without further purification. 4—(phenylmethyl)-6—(trifluoromethyl)—3—morpholinone mediate 19) o/YO F3C (Intermediate 19) Intermediate 18 (123 g, 361.61 mmol) dissolved in dry THF (500 mL) was added dropwise to a suspension of sodium hydride (60 % dispersion in mineral oil, 17.35 g, 433.94 mmol) in dry THF (500 mL) cooled to —5 °C under nitrogen atmosphere. After addition, the reaction mixture was warmed to room temperature and stirred for 30 min.

The on was quenched by careful addition ofMeOH at 0 °C. The reaction e was then poured into HCl 1 N (100 mL) and the aqueous layer was extracted with EtOAc. The organic layer was washed with aqueous hydrogenocarbonate, and with brine before drying with MgSO4, filtration and evaporation, yielding 90 g of Intermediate 19 (96 %) as an oil that was used without further pun'fication. 4-(phenylmethyl)-2—(trifluoromethyl)-, (ZS)-morpholine (Intermediate 20) and 4- (phenylmethyl)—2-(trifluoromethyl)—, (2R)—morpholine (Intermediate 21) (Intermediate 20) (Intermediate 21) Borane/THF complex solution 1 M ([140446], 868 mL, 868.96 mmol) was added dropwise to a solution of Intermediate 19 (90 g, 347.18 mmol) dissolved in dry THF (850 mL) at room temperature under a nitrogen atmosphere. The e was stirred for 2.5 h at 70 °C (until no gas evolution occurred e). MeOH (70.32 mL, 1735.92 mmol) was then added dropwise, ed by HG] (3 M in water, 578 mL, 1735.92 mmol) and the mixture was stirred at 70 °C for another hour. The reaction mixture was then quenched with potassium carbonate (239.91 g, 1735.92 mmol) and dissolved in water (250 mL). The reaction mixture was extracted with diethyl ether.

The c layer was washed with brine, dried with MgSO4, d and evaporated.

The resulting oil was purified by column chromatography on silica gel (eluent: DCM), W0 2012/1 13850 yielding a clear oil that was then separated into its pure omers by column chromatography on Chiralcel OJ 1000A 20pm (Daicel) (eluent: heptane/iPrOH 99/1), yielding 27 g of Intermediate 21 (32 %) and 25 g of Intermediate 20 (29 9/0), both as clear oils. The absolute stereochemistry of these two enantiomers was determined by VCD. 2-(triflu0romethyl)—(2S)-morpholine hydrochloride (Intermediate 22) .HCl F3Ckm; (Intermediate 22) Intermediate 20 (25 g, 101.94 mmol) was added to a suspension of Pd on al 1O % (2 g) in MeOH (150 mL). The reaction mixture was stirred at 25 °C under a en atmosphere until 1 equivalent of hydrogen were absorbed. The catalyst was removed by filtration over diatomaceous earth. The filtrate was treated with aqueous HCl 5.5 M (18.5 mL, 101.94 mmol). The solvent was evaporated, yielding 18.46 g of ediate 22 (95 %) as a white solid. 2-(trifluoromethyl)—(2R)—morpholine hydrochloride (Intermediate 23) 1336‘"- NH ,HCl (Intermediate 203) Intermediate 21 (27 g, 110.09 mmol) was added to a suspension of Pd on charcoal % (2 g) in MeOH (150 mL). The reaction mixture was stirred at 25 0C under a hydrogen here until 1 equivalent ogen were absorbed. The catalyst was removed by filtration over diatomaceous earth. The filtrate was treated with aqueous HCl 5.5 M (20.0 mL, 110.09 mmol). The solvent was evaporated, yielding 16.4 g of Intermediate 23 (78 %) as a white solid. 3-fluoro—5-[(ZS)(trifluoromethyl)morpholinyl]-benzonitrile (Intermediate 24) mediate 24) A mixture of Intermediate 22 (4.94 g; 25 mmol) and sodium tert-butoxide (6 g, 62.5 mmol) in monoglyme (50 mL) was degassed for 15 min with nitrogen. The Nolan catalyst ([478980—01—7], 718 mg, 1.25 mmol) was added, followed by 3—bromo—5— fluorobenzonitn'le (5 g, 25 mmol). The reaction mixture was stirred at 50 °C for 48 h. 2012/053047 -43_ The reaction mixture was poured into ice/water. The mixture was neutralized with 1N HCl and was extracted twice with EtOAc. The ed organic layer was washed with brine, dried on MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent 50/50 ptane). The desired ons were evaporated and the residue was crystallized in iPrZO/heptane 1/10, yielding 3 g of Intermediate 24 (44 %) after drying in a vacuum oven at 50°C overnight. 2-i0do—3—fluor0-5—[(ZS)(trifluoron1ethyl)morpholinyl]—benz0nitrile (Intermediate 25) (Intermediate 25) Intermediate 25 was prepared according to the procedure used for Intermediate 14, starting from Intermediate 24 instead of Intermediate l3. 2—(2,6-dimethylpyridinyl)—3-fluoro[(ZS)(trifluoromethyl)morpholinyl]- benzonitrile (Intermediate 26) kid CN F N (Intermediate 26) A mixture of ediate 25 (4.03 g, 10.07 mmol), 2,6—dimethylpyridineboronic acid, pinacol ester ([3251428], 2.82 g, 12.09 mmol), tetrakis(triphenylphosphine)— palladium (582 mg, 0.50 mmol), dimethoxyethane (100 mL), and potassium carbonate 2 M (10.07 mL, 20.14 mmol) was degassed with nitrogen. The reaction mixture was stirred in a closed vessel and heated under en atmosphere at 145 °C for 3 h. After evaporation of the solvent, the reaction mixture was diluted with DCM and water and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layer was washed with brine, dried with MgSO4, filtered and evaporated. The e was purified by column chromatography on silica gel (eluent nt from /90 to 50/50 EtOAc/heptane). The desired fractions were collected and evaporated, yielding 2.05 g (54 %) of Intermediate 26, as a white solid after drying overnight under vacuum at 50 °C.

W0 20121113850 -dimethylpyridinyl)fluoro[(2S)—2-(triflu0r0methyl)—4—morpholinyl]- benzenemethanamine (Intermediate 27) and 2-(2,6-dimethyl-4—pyridinyl) fluoro—S—[2-(methyl)~4-morpholinyll—benzenemethanamine (Intermediate 28) o/\| 1tz o/fi NHz (Intermediate 27) (Intermediate 28) Intermediates 27 and 28 were prepared according to the procedure used for Intermediate 3, starting from Intermediate 26 instead of Intermediate 2, c intermediate 28 was formed as a side—product in this step (ratio 27:28 = 64:36). The two intermediates were used as a mixture for the synthesis of the final compounds 64 to 70 and 112 to 118, which were separated by chromatography. -dimethy1pyridiny1)—3-fluoro[(2R)—2-(trif1uoromethyl)-4~m0rph01inyl]- benzenemethanamine (Intermediate 29) o/fi N112 R K/ \' N F N (Intermediate 29) Intermediate 29 was prepared according to the procedures used for Intermediate 27, using Intermediate 23 instead of Intermediate 22.Racemic intermediate 28 was also ed as a side product in this step (ratio 29:28 = 88: 12). The two intermediates were used as a mixture for the synthesis of the final compounds 56 to 59 and 71 to 73 and 112 to 118, which were separated by chromatography. 3-flu0ro-5—[3—(trifluor0methyl)-l-piperidinyl]—benzonitrile (Intermediate 30) (Intermediate 30) A mixture of 3,5-difluorobenzonitrile (1.38 g, 9.9 mmol), 3-trifluoromethylpiperidine (1.82 g, 11.88 mmol) and diisopropylethylamine (2.56, 14.85 mmol) in acetonitrile (20 mL) was stirred in a re tube at 150°C for 72 h.The reaction mixture was evaporated, taken up in water/DCM, and basified with K2C03. The organic layer was ted and the water layer was ted once more with DCM. The combined organic layers were dried on MgSO4, filtered and evaporated. The e was purified by column chromatography on silica gel (eluent: gradient heptane/DCM 30/70 to 70/30) as eluent. The desired fractions were evaporated, ng 2.5 g of Intermediate (93 %) after drying in a vacuum oven at 50°C overnight. 2-(2,6-dimethyl-4—pyridinyl)-3—flu0r0{3-(trifluor0methyl)piperidinyl]— benzenemethanamine (Intermediate 31) N112 F N (Intermediate 31) Intermediate 31 was prepared according to the procedures used for ediate 27, starting from Intermediate 30 instead of Intermediate 24. 3-bromo-6—(2,6-dimethylpyridinyl)—2-fluoro—benzonitrile (Intermediate 32) Br CN (Intermediate 32) 3-Bromofluoro-6—iodobenzonitrile (10 g, 30.68 mmol), 2,6—dimethylpyridine—4- boronic acid, pinacol ester ([325142-95—8], 7.51 g, 32.22 mmol), and dimethoxyethane (400 mL) were charged in a pressure tube and the mixture was degassed with nitrogen.

Potassium carbonate 2 M (46 mL, 92.05 mmol) and tetrakis(triphenylphosphine)- palladium (1.77 g, l.53 mmol) were added while degassing with nitrogen. The reaction mixture was stirred and heated under nitrogen atmosphere at 100 °C for 17 h. The solvent was evaporated and the residue was diluted with DCM and water and the layers were separated. The aqueous layer was ted twice with DCM. The combined organic layer was dried with MgSO4, filtered and evaporated The residue was purified by column chromatography on silica gel (eluent: DCM). The desired fractions were ted and evaporated, yielding 5.96 g (63 %) of Intermediate 32 as an off-white solid afier drying overnight under vacuum at 50 °C.

W0 2012f] 13850 —46- 3-[(2R,6$)-2,6-dimethyl-4—morph0linyl](2,6-dimethylpyridinyl)—2—fluore- benzonitrile (Intermediate 33) b F N CN (Intermediate 33) U1 A mixture of Xantphos [161265—03—8] (265 mg, 0.46 mmol) and Pd2(dba)3 (191 0.21 mmol) in 1,4-dioxane (45 mL) was degassed for 5 min. Intermediate 110 (2.54 8.33 mmol), 6—dimethylmorpholine (l .24 mL, 999 mmol) and cesium carbonate (5.43 g, 16.66 mmol) were added and the mixture was further ed with nitrogen for 5 min. The tube was sealed and the reaction e was stirred at 140 °C for 1.5 h in a microwave oven. The reaction mixture was poured into water. The itate was filtered, rinsed with water and dried under vacuum. The resulting solid was purified by column chromatography on silica gel (eluent nt from 100% DCM to 98/2 DCM/MeOH). The desired fractions were evaporated, yielding 2.4 g of Intermediate 33 (85 %) as a yellow solid after drying in a vacuum oven at 50°C overnight. 3-[(2R,6S)—2,6-dimethyl-4—morpholinyl](2,6-dimethyl—4—pyridinyl)—2—fluor0- benzenemethanamine (Intermediate 34) (Intermediate 34) Intermediate 34 was prepared according to the procedure used for Intermediate 3, starting from Intermediate 33 instead of Intermediate 2. 6-(2,6—dimethylpyridinyl)—2—fluoro [(ZS)(triflu0romethyl)—4—m0rpholinyl]- benzonitrile (Intermediate 35) W0 2012/] 13850 o/\' F fik/N CN (Intermediate 35) A mixture ofXantphos [161265-03—8] (171 mg, 0.29 mmol) and Pd2(dba)3 (135 0.15 mmol) in dry toluene (30 mL) was ed for 5 min. Intermediate 22 (1.13 5.90 mmol), Intermediate 32 (1.5 g, 4.91 mmol) and sodium tert—butoxide (1.42 14.75 mmol) were added and the mixture was further degassed with nitrogen for 5 min.

The tube was sealed and the reaction mixture was stirred at 140 °C for 1 h. The solvent was evaporated and the residue was taken up in DCM and water. The layers were separated and the aqueous layer was extracted twice with DCM. The combined c layer was washed with brine, dried with MgSO4, filtered and evaporated. The residue was d by column chromatography on silica gel (eluent gradient from 100% DCM to 97/3 DCM/MeOH). The desired fractions were collected and evaporated, yielding 1.2 g (64 %) of Intermediate 35 as an orange solid after drying overnight under vacuum at 50 °C. 6-(2,6-dimethylpyridinyl)fluor0-3—[(ZS)(trifluor0methyl)morpholinyl]- benzenemethanamine (Intermediate 36) (Intermediate 36) Intermediate 36 was prepared according to the procedure used for Intermediate 3, starting from Intermediate 35 instead of ediate 2. 6-(2,6-dimethylpyridinyI)fluoro-3—[(2R)—2—(trifluoromethyI)morpholinyl]- emethanamine (Intermediate 37) o/fi F NH2 R K/ F3C\\\\' (Intermediate 37) W0 2012/1 13850 Intermediate 37 was prepared according to the procedure used for Intermediate 36, starting from Intermediate 23 instead of Intermediate 22.

Nonafluorobutane-l-sulfonic acid (2R,6S)—2,6-dimethyl—3,6-dihydro—2H-pyran yl ester (Intermediate 38) l Oslo/s/ F F 0 cis F F F r (Intermediate 38) LDA (2 M in THF/heptane/ethylbenzene, 93.62 mL, 187.25 mmol) was cooled to «78 °C under a nitrogen atmosphere. A solution of (2R,6S)-2,6-dimethyltetrahydro pyranone ([14505—80—7], 20 g, 156.04 mmol) in TI-IF (400 mL) was added dropwise while stirring at -78 °C. After addition, the reaction mixture was allowed to warm to 0 °C and was stirred for 1 h. The solution was cooled to —78 °C again and nonafluoro-I- butanesulfonylfluoride ([3754], 36.43 mL, 202.85 mmol) was then added dropwise.

The reaction mixture was d to warm to room temperature and was further d for 12 h. The on mixture was ed with saturated aqueous NaHCOs (300 mL) and the mixture was extracted twice with EtOAc (2 x 300 mL). The ed organic layer was washed with brine, dried with MgSO4, filtered, and evaporated. The crude e was purified by column chromatography on silica gel (eluent: nt EtOAc/heptane 0/100 to 5/95). The desired fractions were collected and evaporated, yielding 48.5 g (76 %) of Intermediate 38 as a clear oil. 3,6—dihydro-(ZR,6S)-2,6—dimethyl(4,4,5,5~tetramethyl-1,3,2—di0xaborolanyl)— 2H-pyran (Intermediate 39) (Intermediate 39) A pressure tube was charged with Intermediate 38 (48.5 g, 118.22 mmol), bis(pinacolato)diboron ([73183-34—3], 36.02 g, 141.86 mmol), 11'- bisdiphenylphosphino)ferrocene ([121508], 1.96 g, 3.55 mmol), potassium acetate (11.60 g, 118.22 mmol) and dimethoxyethane (944 mL). The e was degassed with nitrogen before the addition of [1,1'—bis(dipheny1phosphino)ferrocene]- dichloropalladium(II) ([72287—26-4], 1.90 g, 2.60 mmol). The reaction mixture was stirred at 80 °C for 3 h. After cooling, the reaction mixture was filtered on diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography on silica ge1(e1uent: gradient EtOAc/heptane 0/100 to 5/95). The desired fractions were collected and ated, yielding 22.2 g (79 %) of ediate 39 as a slightly yellow oil. 3-(3,6-dihydro—(ZR,6S)—2,6-dimethyl-2H-pyranyl)(2,6—dimethyl—4-pyridinyl)— Z-fluoro-benzonitrile (Intermediate 40) mediate 40) Intermediate 32 (1.70 g, 5.58 mmol), Intermediate 39 (1.46 g, 6.14 mmol), potassium IO carbonate 2 M (5.59 mL, 11.17 mmol) and tetrakis(triphenylphosphine)palladium (323 mg, 0.28 mmol) and dimethoxyethane (117 mL) were charged in a pressure tube and the mixture was degassed with nitrogen. The reaction mixture was stirred and heated under nitrogen atmosphere at 100 °C for 17 h. After cooling to room temperature, water was added to the reaction mixture until precipitation of the product.

The solid was recrystallised from this mixture by adding a small amount of acetonitrile to dissolve the t in the warm mixture. The crystallised solid was filtered, yielding 1.53 g (81 %) of Intermediate 40 as an off-white solid after drying overnight under vacuum at 50 °C. -dihydro-(ZR,6S)-2,6-dimethyl-2H—pyranyl)(2,6~dimethylpyridinyl)- 2-fluoro—benzenemethanamine (Intermediate 41) (Intermediate 41) Intermediate 41 was prepared according to the procedure used for Intermediate 3, starting from Intermediate 40 instead of Intermediate 2. 6-(2,6-dimethylpyridinyl)f.luoro—3—(tetrahydr0-(2R,6S)-2,6-dimethyl—ZH- 4-yl)—benzenemethanamine (Intermediate 42) W0 2012/1 13850 (Intermediate 42) Intermediate 41 (200 mg, 0.58 mmol) was added to a suspension of Pt on charcoal % (50 mg) in "[HF (40 mL) under nitrogen atmosphere. The reaction mixture was stirred at 50 °C under hydrogen atmosphere until 1 equivalent of en was absorbed. The catalyst was removed by filtration over diatomaceous earth. The solvent was ated, ng Intermediate 42 quantitatively as a clear oil, which was used t further purification. 4-(4—bromo-Z-chloro-S-fiuorophenyl)—2,6-dimethyl-pyridine (Intermediate 43) c1 N mediate 43) 1-bromo—5—ch1oro-2—fluoroiodo-benzene 572-73—5 ], 9.7 g, 28.93 mmol), 2,6- dimethylpyridineboronic acid, pinacol ester ([3251428], 8.09 g, 34.71 mmol), potassium carbonate 2 M (28.93 mL, 57.85 mmol) and tetrakis(triphenylphosphine)— palladium (2 g, 1.74 mmol) and dimethoxyethane (150 mL) were charged in a pressure tube and the mixture was degassed with nitrogen. The reaction mixture was stirred and heated under nitrogen atmosphere at 100 °C for 18 h. The solvent was evaporated. The residue was taken up in water and extracted with DCM. The organic layer was dried MgSO4, filtered and ated. The residue was purified by column chromatography on silica gel (eluent: gradient DCM/MeOH 100/0 to 97/3). The desired fractions were collected and evaporated, yielding 5.8 g (64 0/<3) of Intermediate 43. 4-[5-chloro(2,6-dimethylpyridinyl)flu0r0phenyl]-2,6-dimethyl—, (2R,6S)— morpholine (Intermediate 44) W0 2012/1 13850 A . A/N er /1\‘ (Intermediate 44) A pressure tube was d with a mixture of Intermediate 43 (5.6 g, 17.8 mmol), cis— 2,6~dimethylmorpholine (2.05 g, 17.8 mmol) and sodium tert-butoxide (2.56 g, 26.7 mmol) in toluene (150 mL). The mixture was ed for 5 min before Xantphos 58] (618 mg, 1.07 mmol) and Pd2(dba)3 (326 mg, 0.35 mmol) were added.

The mixture was further degassed for 15 min. The tube was sealed and the reaction mixture was d at 120 °C for 1 h. The solvent was evaporated. Water was added to the residue and it was extracted twice with DCM. The ed organic layer was dried on MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent gradient from 100% DCM to 98/2 DCM/MeOH).

The desired fractions were evaporated, yielding 2.4 g of Intermediate 44 (37 %) after drying in a vacuum oven at 50°C overnight. -[(2R,6S)-2,6—dimethylmorpholinyl]-2—(2,6-dimetliylpyridiny1)flu0r0- benzonitrile (Intermediate 45) (Intermediate 45) A pressure tube was charged with a mixture of Intermediate 44 (1 g, 2.86 mmol), zinc cyanide (202 mg, 1.72 mmol), triphenylphosphine (75 mg, 0.28 mmol) and tetrakis(triphenylphosphine)palladium (165 mg, 0.14 mmol) in acetonitrile (2 mL). The e was stirred at 170 °C in a microwave oven for 18 h. The solvent was evaporated and the residue was purified by preparative HPLC on RP Vydac® Denali® C18 - 10pm, 250g, 50m, mobile phase (0.5% NH4Ac solution in water + 10% CH3CN, CH3CN). The desired fractions were collected and concentrated. The precipitate was filtered off and washed with water, yielding 850 mg of Intermediate 45 (87 %).

W0 20121113850 _52_ —[(2R,6S)-2,6-dimethylmorpholinyl](2,6-dimethyl-4—pyridinyl)—4-fluoro- benzenemethanamine mediate 46) (Intermediate 46) Intermediate 46 was prepared according to the procedure used for ediate 3, starting from Intermediate 45 instead of Intermediate 2. 4-(2,4—dibr0m0-3,6-difluorophenyl)-2,6-dimethyl-pyridine (Intermediate 47) Br Br F ,N (Intermediate 47) 1,3-Dibromo—2,5-difluoro-4—iodo—benzene ([10005778], 3.6 g, 9.05 mmol), 2,6- dimethylpyridineboronic acid, pinacol ester ([3251428], 2.11 g, 9.05 mmol), potassium carbonate 2 M (9.05 mL, 18.1 mmol) and tetrakis(triphenylphosphine)— palladium (627 mg, 0.54 mmol) and dimethoxyethane (57 mL) were charged in a pressure tube and the mixture was degassed with nitrogen. The reaction e was d and heated under nitrogen atmosphere at 130 °C for 18 h. The solvent was evaporated. The residue was taken up in water and extracted with DCM. The organic layer was dried on MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel t: DCM). The desired fractions were collected and evaporated, yielding 1.6 g (47 %) of Intermediate 47. 4-[3—bromo~4—(2,6—dimethyi—4—pyridinyl)~2,5—difluor0phenyl]—2,6-dimethyl-, (2R,6S)—morpholine (Intermediate 48) WC 2012!] 13850 (Intermediate 48) A pressure tube was charged with a mixture of Intermediate 47 (800 mg, 2.12 mmol), 6-dimethylmorpholine (203 mg, 1.77 mmol) and sodium tert-butoxide (255 mg, 2.65 mmol) in toluene (150 mL). The mixture was ed for 5 min before Xantphos id="p-1612658" id="p-1612658" id="p-1612658"

[1612658] (61 mg, 0.10 mmol) and Pd2(dba)3 (32 mg, 0.03 mmol) were added. The e was further degassed for 15 min. The tube was sealed and the reaction mixture was stirred at 100 °C for 16 hr The solvent was evaporated. Water was added to the residue and it was extracted twice with DCM. The combined organic layer was dried on MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: DCM). The desired fractions were ated. The solid was recrystallised from heptane, yielding 229 mg of Intermediate 48 (31 %) after drying in a vacuum oven at 50°C overnight. 3-[(2R,6S)-2,6—dimethylm0rpholinyl](2,6-dimethyl-4—pyridinyl)—2,5-difluoro— benzonitrile (Intermediate 49) (Intermediate 49) A pressure tube was charged with a mixture of Intermediate 48 (280 mg, 0.68 mmol), zinc cyanide (48 mg, 0.41 mmol), triphenylphosphine (18 mg, 0.07 mmol) and tetrakis(triphenylphosphine)palladium (79 mg, 0.07 mmol) in acetonitrile (15 mL). The mixture was stirred at 150 °C in a ave oven for 18 h. The solvent was evaporated and the residue taken up in water and DCM. The organic layer was separated, dried with MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: DCM). The desired fractions were ted and concentrated, yielding Intermediate 49 tatively. 3-[(2R,6S)-2,6-dimethylm0rpholinyl]—6—(2,6-dimethyl—4-pyridinyl)—2,5—difluor0- benzenemethanamine (Intermediate 50) W0 2012/1 13850 (Intermediate 50) Intermediate 50 was prepared according to the procedure used for Intermediate 3, starting from ediate 49 instead of Intermediate 2. ochloro(2,6—dimethylpyridinyl)-benzonitrile (Intermediate 51) Br CN C1 /N (Intermediate 51) -bromo—3-chloro—2-iodobenzonitrile ([1000577-40—1], 6.9 g, 20.15 mmol), 2,6- dimethylpyridine—4—boronic acid, pinacol ester ([3251428], 5.64 g, 24.18 mmol), potassium carbonate 2 M (20.15 mL, 40.31 mmol), tetrakis(triphenylphosphine) ium (1.40 g, 1.21 mmol) and dimethoxyethane (150 mL) were charged in a re tube and the mixture was ed with nitrogen. The reaction mixture was stirred and heated under nitrogen atmosphere at 120 °C for 18 h. The solvent was evaporated. The residue was taken up in water and extracted with DCM. The organic layer was dried on MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: DCM). The desired fractions were collected and evaporated, yielding 2.3 g (35 %) of Intermediate 51. 3~chloro—5-[(2R,6S)-2,6—dimethylmorph01inyl]~2-(2,6-dimethyl—4—pyridinyl)— benzonitrile (Intermediate 52) JobN CN c1 N (Intermediate 52) A pressure tube was charged with a mixture of Intermediate 51 (2.2 g, 6.84 mmol), cis- 2,6-dimethylmorpholine (656 mg, 5.70 mmol) and sodium tert-butoxide (822 mg, 8.55 W0 2012/1 13850 mmol) in toluene (100 mL). The mixture was degassed for 5 min before Xantphos id="p-1612658" id="p-1612658" id="p-1612658"

[1612658] (198 mg, 0.34 mmol) and Pd2(dba)3 (104 mg, 0.11 mmol) were added.

The mixture was further degassed for 15 min. The tube was sealed and the reaction mixture was d at 100 °C for 5 h. The solvent was evaporated. Water was added to U: the residue and it was extracted with DCM. The combined organic layer was dried on MgSO4, filtered and ated. The residue was purified by column chromatography on silica gel t: DCM). The desired fractions were evaporated, ng 600 mg of Intermediate 52 (29 %) after drying in a vacuum oven at 50°C overnight. 3~ehloro—5—[(2R,6S)-2,6-dimethy1—4-morpholinyl]~2-(2,6-dimethylpyridinyl)- benzenemethanamine (Intermediate 53) c1 N mediate 53) Intermediate 53 was prepared according to the procedure used for Intermediate 3, starting from Intermediate 52 instead of Intermediate 2. 5~chloro—2-[(2R,6S)—2,6—dimethylmorpholinyl]—benzonitrile (Intermediate 54) mediate 54) A mixture of Xantphos [161265—03-8] (294 mg, 0.51 mmol) and Pd2(dba)3 (211 0.23 mmol) in dry 1,4-dioxane (75 mL) was degassed for 5 min. Cis—2,6— dimethylmorpholine (1.5 mL, 12.13 mmol), 2-bromo—5—chlorobenzonitrile (2.5 g, 11.55 mmol) and cesium carbonate (7.52 g, 23.10 mmol) were added and the mixture was further degassed with nitrogen for 5 min. The tube was sealed and the reaction mixture was stirred at 145 °C for 5 h. The solvent was evaporated and the residue was d by column chromatography on silica gel (eluent gradient DCM/heptanes 0/100 to 100/0). The desired fractions were collected and evaporated, yielding 1.39 g (39 %) of Intermediate 54 as a yellow oil. 2-[(2R,6S)—2,6-dimethylm0rph01inyl](2,6~dimethyl-4—pyridinyl)—benzonitrile (Intermediate 55) W0 2012f113850 (Intermediate 55) Intermediate 54 (550 mg, 2.19 mmol), 2,6-dimethylpyridineboronic acid, pinacol ester ([325142—95-8], 767 mg, 3.29 mmol), sodium carbonate (697 mg, 6.58 mmol) and tetrakis(triphenylphosphine)palladium (152 mg, 0.13 mmol), water (5 mL), EtOH (5 mL), and oxane (5 mL) were charged in a pressure tube and the mixture was degassed with en. The reaction mixture was stirred and heated under nitrogen atmosphere at 130 °C for 4 h. The solvent was evaporated. The e was taken up in water and extracted with DCM. The c layer was dried on MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent: gradient DCM/MeOH 100/0 to 99/I). The desired fractions were collected and evaporated. The solid was recrystallised from EtOAc, ng 485 mg (70 %) of Intermediate 55, after drying in a vacuum oven at 50°C overnight. 2—[(2R,6$)-2,6—dimethylmorpholinyl](2,6-dimethylpyridinyl)— benzencmethanamine (Intermediate 56) (Intermediate 56) Intermediate 56 was prepared according to the procedure used for Intermediate 3, starting from Intermediate 55 instead of Intermediate 2.

B. Pre aration of the Final com ounds Bl) Example 1 N-[lS—[(2R,6S)-2,6-dimethyl—4—morpholinyl](2,6—dimethyl pyridinyl)phcnyl]methyl]—cyclopropaneacetamide (Compound 1) (Compound 1) HBTU (1.00 g, 2.64 mmol) was added at room temperature to a mixture of Intermediate 3 (851 mg, 2.40 mmol), cyclopropylacetic acid (265 mg, 2.64 mmol), and DIPEA (0.91 mL, 5.29 mmol) in 20 ml dichloromethane. The mixture was stirred overnight at room temperature. The reaction mixture was washed with water and the organic layer was separated, dried with MgSO4 and concentrated under reduced pressure. The residue was purified on a silica column with an eluent gradient from 100% DCM to 98/2 DCM/MeOH. The desired pure fractions were collected and evaporated. The product was triturated in hot iPrQO/MeOH (70/30), cooled, filtered and dried in vacuum at 50 °C, yielding 485 mg (49 %) of Compound 1 as a yellow solid.

B2) Example 2 N-[[5—[(2R,6S)—2,6—dimethyl-4—morpholinyl]-2—(2,6—dimethyl-4— pyridinyl)phenyl]methyl]methyl-propanamide (Compound 2) (K/N (Compound 2) Isobutyryl de (1.09 g, 10.26 mmol) was added to a solution of Intermediate 3 (3.3 g, 9.33 mmol) and triethylamine (2.58 mL, 18.66 mmol) in DCM (200 mL). The on mixture was stirred for 1 h at room temperature. The on was washed with water and s sodium carbonate. The aqueous layer was extracted with DCM. The combined organic layer was dried with MgSO4, filtered and evaporated. The e was purified by column chromatography on silica gel with an eluent gradient from W0 2012/I 13850 —58- 100% DCM to 95/5 DCM/MeOH. The desired pure fractions were collected and evaporated. The resulting solid was recrystallised from acetonitrile, yielding 3.4 g (92 %) of Compound 2 as a white .

The compounds of Tables 3 to 5 were prepared according to either Example 1 or 2.

Table 3 R4 X3 X2 :Rs N\ / Y Z R5 X1 R2 CO. R1 R2 R3 R4 R5 X1 X2 X3 Y Z Stereo— CH3 H W0 2012/1 13850 C0. R1 R2 R3 R4 R5 X1 X2 X3 Y Z Stereo— No. try CH3 CH3 H H H H H N O cis H S CH~CH3HJ H HHH 16% Z O cis :9 CH3CH3H H HHH N 0 cis _'f ~1— 24"\ (1'13n CH CH3 C ' ' "I 3 H3 H H H :\ CH2 015 18 N, k / CF3 CF3 CH3 CH3 H H H N CH2 Ci 5 FQ’F CF3 CF3 CH3 CH3 H H H N CH2 CiS \ _‘|CF3 CF3 CHjCH3 H H H N [EH2 cis 21 € \N’0 l— l__ :; CF3 CF3 CH3 CH3 H H H N CH2 cis ‘l 22 W> 2_< CF3 CF3 CH3 CH3 H H H N CH2 CiS 23 _l :;x HTH CH3CH3HHHN o 2012/053047 CO. R1 R2 R3 R4 R5 X1 X2 X3 Y Z Stereo— No. chemistry 2 < CF3 H CH3 CH3 H H H N CH2 ; CH3 CH3 CH3 CH3 F H H N ‘To cis 37 W> < CH3 CH3 CH3 CH3 F H H N 0 cis 38 {"g k / CH3 CH3 CH3 CH3 F H H N 0 cis @F cm CH3 CH3 CHg F H H m o cis H cis cis —l CH3F H H CH O cis g_< CF; H CH3 CH3 F H H N I: R-enantiomer Co. R1 ‘szz R4 X1 X2 Y 2 Stereo— No. chemistry ( CF; CH3 [CH3 tiomer 57 * ‘Nzo _L < //i’1 CF; H CH3 CH3 H R—enantiomer H R—enantiomer 59 8% CH3 {CH3 CH3 cis S-enantiomer S-enantiomer S-enantiomer S-enantiomer S-enantiomer S—enantiomer J S—enantiomer R—enantiomer R—enantiomer R—enantiomer WO 13850 —62- Co. R1 R2 E R4 R5 X1 X2 X3 Y 2 Stereo— No. L chemistry 2_< CH3 CH3 CH3 CH3 H H F N O cis 78 i L_ _J 79;—<] IE3CH3CH3E13HHF N o cis <8) CH3 CH3 CH3 CH3 H H b F N O CiS F 46 cis O cis O cis O cis CF3 H CH3 CH3 H H F N_JO R-enantiomer —63- C0. R1 E2 R3 R4 R5 X1 X2 5(3—1—Y Z Stereo- No. chemistry \ CF3 H 3_ CH3 CH3 H H F N 10 R-enantiomer 100 ‘wo _1 1_ § CF: H CH3 CH3 H H F N O R-enantiomer 101 y _l_ 102 :—<[ CF; H CH3 CH3 H H F N O R—enantiomer é / 9 CFs H CH3 CH3 H H F N O R—enantiomer S H CH3 CH3 H H F N O R—enantiomer 104 W> 2 CF: H CH3 CH3 H H F N O S—enantiomer 105 vb / 9 CF3 3 H CH3 CH3 H H F N O tiomer ; ,N CFs H CH3 CH3 H H F N O S-enantiomer |_107 2% j_ _| 1; CF; H CH3 CH3 H H F N O S—enantiomer |_108 H> 4_ 109 Z—q CFs H CH3 CH3 H H F |_N O S-enantiomer ; CF3 H CH3 CH3 H H F N O S-enantiomer 110 —>_ L __| ‘L \ CF: H CH3 CH3 H H F |_N O S—enantiomer 111 g ‘N/0 J_ 3 CH3—1H CH3 CH3 H H FTN o 112 > ‘N’o CH3 H CH3 CH3 H H F N O 113 ZpW< L 1*\> CH3 H CH3 CH3 H H—1F N o 114 |_ 115 :4 TCHJH CH3 CH3 H H LF ’IN 0 2 CH3 H CH3 CH3 H H F N O 11—16 —>_ 1— —r 1— 3?? CH3 H CH3 CH3 H H F N o > /N g CH3 H CH3 'EH3 H H F N 0 118 E _| ; CH3 CH3 CH3 W3 H H C1 N ’10 cis 119 W> L 1 CH3 CH3 CH3 CH3 H H CT1N 0 cis 1 120 ‘Nzo >_< CH3 CH3 CH3 CH3 H. H Cl N +0 Cis L121 > _1 _l _J W0 2012/1 13850 chemistry W0 2012/] 13850 ~65— Table 5 >—NH Analytical Part LCMS (Liquid Chromatography/Mass spectrometry) LCMS Generalprocedure A The LC measurement was performed using an Acquity UPLC s) system comprising a binary pump, a sample organizer, a column heater (set at 55 °C), a diode- array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.18 seconds using a dwell time of 0.02 s. The capillary needle voltage was 3.5 kV and the source temperature was maintained at 140 °C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.

LCMS Generalprocedure B The HPLC measurement was med using an Alliance HT 2790 (Waters) system comprising a quaternary pump with degasser, an autosampler, a column oven (set at 40 °C, unless otherwise indicated), a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an ospray ionization source.

Mass a were acquired by scanning from 100 to 1000 in 1 second using a dwell time of 0.1 second. The capillary needle voltage was 3 kV and the source temperature ~66— was maintained at 140 °C. Nitrogen was used as the nebulizer gas. Data acquisition was med with a Waters-Micromass MassLynx-Openlynx data system.

LCMSMethod 1 In on to general procedure A: Reversed phase UPLC (Ultra mance Liquid U: Chromatography) was carried out on a bridged ethylsiloxane/silica hybrid (BEI-l) C18 column (1.7 pm, 2.1 x 50 mm; Waters Acquity) with a flow rate 01°08 mI/min. Two mobile phases (mobile phase A: 0.1 % formic acid in H20/methanol 95/5; mobile phase B: methanol) were used to run a gradient condition from 95 % A and 5 % B to 5 "/6 A and 95 % B in 1.3 minutes and hold for 0.2 minutes. An injection volume of 0.5 ul was used.

Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.

LCMSMethod 2 In addition to l procedure A: Reversed phase UPLC (Ultra Performance Liquid Chromatography) was carried out on a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 mm, 2.1 x 50 mm; Waters Acquity) with a flow rate of 0.8 ml/min Two mobile phases (25 mM ammonium e in HQO/acetonitrile 95/5; mobile phase B: acetonitrile) were used to run a gradient condition from 95 % A and 5 % B to 5 % A and 95 % B in 1.3 minutes and hold for 0.3 minutes. An injection volume of 0.5 111 was used.

Cone voltage was 30 V for ve ionization mode and 30 V for negative ionization mode.

LCMSMethod 3 In addition to general procedure B: ed phase HPLC was carried out on an Xterra MS C18 column (3.5 um, 46 x 100 mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 1 % A, 49 % B and 50 % C in 6.5 minutes, to 1 % A and 99 % B in 1 minute and hold these conditions for 1 minute and reequilibrate with 100 % A for 1.5 minutes. An injection volume of 10 ul was used. Cone voltage V for positive ionization mode and 20 V for negative ionization mode.

LCMSMethod 4 In addition to the general procedure B: Reversed phase HPLC was d out on Xterra MS C 18 column (3.5 pm, 4.6 x 100 mm) with a flow rate of 1.6 ml/min. Three mobile phases e phase A: 95% 25 mM ammoniumacetate + 5 % acetonitrile; W0 2012/1 13850 —67— mobile phase B: acetonitrile; mobile phase C: methanol) were employed to run a gradient condition from 100 % A to 1 % A, 49 % B and 50 % C in 6.5 minutes, to 1 % A, 99 % B in 0.5 minute and keep these conditions for 1 minute. An injection volume of 10 1.11 was used.

Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.

Melting Points For a number of compounds, melting points were determined with a DSC823e from Mettler—Toledo. Melting points were measured with a temperature gradient of °C/minute. Values are peak values.

The results of the ical measurements are shown in table 6.

Table 6: Analytical data — ion time (R in minutes), (MI-I)+ peak, LCMS method and melting oints ("mp7 is defined as g point; "—" means no value).

S2: R. (MHV 8811:. 2‘33; £3: R 7940* .. 2‘32; 1 0.93 408 1 - 23 _{ 120+ 502 2 170.61 2 0.93 396 2 196.03 24 0,81 380 2 _ 3 435 2 - 25 0‘86 407 2 _ - 26 2 - 462 2 - 27 2 _ 6 394 1 28 2 l— _ 7 436 1 29 2 _ 8 440 2 208.94 30 2 - 9 382 4 159.61 31 3 £157.07 421 3 174.99 32 2 _ 11 448 3 169.70 l—33 2 ] 163.71 12 421 3 - 34 2 132,42 13 394 3 172.14 35 2 142.23 14 380 3 166.21 36 2 _ 368 2 189.97 37 2 l_224,74 16 380 2 222.44 38 2 173.13 17 407 2 —l - 39 2 15938 18 433 2 171.14 40 _l 2 224.92 19 541 2 - . 41 2 247.07 568 2 - 42 5.34 412 3 280.34 21 1.23 541 2 218.48 43 5.66 428 3 2O6.87_J 22 1.19 514 2 162.13 44 1.07 482 2 199.64 LCMS mp.

Method W)" (°C) 53: 111311.51 2‘36" 192.86 82 484 1 _ 231.72 83 0.94 428 1 11 .. 195.20 84 1.00 442 1 _ 214.09 85 0.88 426 1 - 259.39 86 0.89 456 2 _ 211.48 87 0.94 412 2 - 233.47 88 0.91 398 2 - 89 0.94 400 2 _ r156.74 90 0.99 439 2 -7 225.57 91 0.93 439 2 1 185.08 92 0.991414 2 _ 217.88 93 1.19 478 2 161.17 172.11 94 1.19 491 2 71—19608 232.66 95 1.15 464 2 - 96 1.13 452 2 _ 167.75 97 1.10 450 2 1L 209.37 98 1.12 491 2 _ 165.24 m— 2 200.74 2 183.50 191.66 2 185.20 215.85 2 221.01 231.51 2 7219.09 170.67 2 184.64 L22295 2 _ 256.62 2 218.57 220.86 2 202.05 223 .44 2 3 225.23 2 222.86 L_253.73 2 184.77 2 l_180.90 2 _ 2 160.79 2 r165.89 2 231.96 2 _ 2 182.04 W0 2012/1 13850 WWWNNNNNNN—‘v—I WWDJMNNNNNNN Optical Rotation (OR) The optical rotation was measured using a Perkin Elmer 341 pol arimeter. [abzo indicates the optical rotation measured with light at the wavelength (7L) of 589 nm, at a temperature of 20 °C, in MeOH. The cell ngth is 1 dm. Behind the actual value the concentration which was used to measure the optical rotation is mentioned.

NMR (nuclear magnetic resonance) For a number of nds, 1H NMR a were recorded on a Bruker DPX-3 60, on a Bruker O or on a Bruker Avance 600 spectrometer with standard pulse sequences, operating at 360 MHz, 400 MHz and 600 MHZ respectively, using CHLOROFORM-d (deuterated chloroform, CDC13) or DMSO-dg, (deuterated DMSO, yl—d6 sulfoxide) as solvents. Chemical shifts (5) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as internal standard.

Compound 1 : 1H NMR (360 MHz, CHLOROFORM—d) 5 ppm 0.12 (m, J=4.8, 4.8, 4.8 Hz, 2 H) 0.48 - 0.58 (m, 2 H) 0.73 - 0.90 (m, 1 H) 1.28 (d, J=6.6 Hz, 6 H) 2.11 (d, J=7.3 Hz, 2 H) 2.41 - 2.51 (m, 2 H) 2.56 (s, 6 H) 3.51 (m, J=12.4 Hz, 2 H) 3.74 - 3.87 (m, 2 H) 4.46 (d, J=5.5 Hz, 2 H) 5.93 (t, J=5.3 Hz, 1 H) 6.88 (dd, J=8.4, 2.6 Hz, 1 H) 6.92 (s, 2 H) 6.95 (d, J=2.2 Hz, 1 H) 7.14 (d, J=8.8 Hz, 1 H) Compound 2 : 1H NMR (360 MHz, CHLOROFORM-d) 5 ppm 1.10 (d, J=7.0 Hz, 6 H) 1.28 (d, J=6.6 Hz, 6 H) 2.29 (spt, J=6.9 Hz, 1 H) 2.45 (dd, J=11.9, 10.8 Hz, 2 H) 2.55 (s, 6 H) 3.50 (dd, J=12.6, 2.0 Hz, 2 H) 3.71 — 3.89 (m, 2 H) 4.41 (d, J=5.5 Hz, 2 H) 5.45 (t, J=4.9 Hz, 1 H) 6.81 - 6.94 (m, 4 H) 7.14 (d, J=8.4 Hz, 1 H) W0 2012/113850 Compound 9 : 1H NMR (360 MHz, 6) 5 ppm 0.98 (d, J=6.6 Hz, 6 H) 1.16 (d, J=6.2 Hz, 6 H) 2.22 — 2.33 (m, 2 H) 2.39 (spt, J=7.0 Hz, 1 H) 2.48 (s, 3 H) 3.56 - 3.64 (m, 2 H) 3.64 - 3.76 (m, 2 H) 4.18 (d, J=5.5 Hz, 2 H) 6.87 - 6.99 (m, 2 H) 7.09 - 7.17 (m, 2 H) 7.20 (s, 1 H) 8.16 (t, J=5.5 Hz, 1 H) 8.42 (d, J=5.1 Hz, 1 H) Compound 37 : 1H NMR (360 MHz, CHLOROFORM—d) 5 ppm 0.13 (m, 1:49, 4.9, 4.9 Hz, 2 H) 0.50 - 0.61 (m, 2 H) 0.76 — 0.97 (m, 1 H) 1.25 (d, J=6.2 Hz, 6 H) 2.09 (d, J=7.0 Hz, 2 H) 2.50 (t, J=1 1.0 Hz, 2 H) 2.57 (s, 6 H) 3.31 (d, J=11.0 Hz, 2 H) 3.81 — 3.97 (m, 2 H) 4.48 (d, J=4.0 Hz, 2 H) 6.04 (t, J=4.0 Hz, 1 H) 6.88 - 7.03 (m, 4 H) Compound 59 : lHNMR (360 MHz, DMSO—dé) 5 ppm 0.02 — 0.14 (m, 2 H) 0.33 — 0.47 (m, 2 H) 0.83 - 1.03 (m, 1 H) 1.97 (d, J=7.0 Hz, 2 H) 2.44 (s, 6 H) 2.82 — 3.02 (m, 2 H) 3.29 (d, 1:121 Hz, 1 H) 3.47 (d, J=11.3 Hz, 1 H) 3.84 (td, 1:111, 2.0 Hz, 1 H) 4.02 - 4.20 (m, 3 H) 4.33 - 4.50 (m, 1 H) 7.01 (s, 2 H) 7.09 (d, J=8.4 Hz, 1 H) 7.17 (t, J=8.6 Hz, 1 H) 8.01 (t, #44 Hz, 1 H) Compound 74 : 1H NMR (360 MHz, CHLOROFORM-d) 5 ppm 0.08 - 0.18 (m, 2 H) 0.47 - 0.61 (m, 2 H) 0.72 - 0.91 (m, 1 H) 1.28 (d, J=6.2 Hz, 6 H) 2.10 (d, J=7.3 Hz, 2 H) 247(1, J=11.2 Hz, 2 H) 2.56 (s, 6 H) 3.41 — 3.54 (m, 2 H) 3.67 - 3.87 (m, 2 H) 4.32 (d, J=5.9 Hz, 2 H) 5.90 (t, J=5.7 Hz, 1 H) 6.58 (dd, J=12.8, 2.2 Hz, 1 H) 6.75 (d, J=2.6 Hz, 1 H) 6.90 (s, 2 H) Compound 75 : 1H NMR (360 MHz, FORM-d) 5 ppm 1.27 (d, J=6.2 Hz, 6 H) 2.46 (m, J=11.3, 11.3 Hz, 5 H) 2.54 (s, 6 H) 3.47 (dd, J=12.1, 1.8 Hz, 2 H) 3.70 — 3.85 (m, 2 H) 4.40 (d, J=5.9 Hz, 2 H) 6.36 - 6.43 (m, 1 H) 6.59 (dd, 1:126, 2.4 Hz, 1 H) 6.72 — 6.83 (m, 2 H) 6.89 (s, 2 H) Compound 78 : 1H NMR (360 MHz, CHLOROFORM—d) 5 ppm 1.10 (d, J=7.0 Hz, 6 H) 1.27 (d, J=6.2 Hz, 6 H) 2.28 (spt, J=7.1 Hz, 1 H) 2.39 - 2.51 (m, 2 H) 2.56 (s, 6 H) 3.47 (dd, J=12.1, 1.8 Hz, 2 H) 3.69 — 3.86 (m, 2 H) 4.27 (d, J=5.9 Hz, 2 H) 5.43 (‘1, J=4.6 Hz, 1 H) 6.57 (dd, 1:126, 2.4 Hz, 1 H) 6.70 (d, J=2.2 Hz, 1 H) 6.88 (s, 2 H) Compound 104 : 1H NMR (360 MHZ, DMSO-d6) 5 ppm 0.08 - 0.16 (m, 2 H) 0.35 - 0.47 (m, 2 H) 0.86 - 1.00 (m, 1 H) 1.98 (d, J=7.0 Hz, 2 H) 2.45 (s, 6 H) 2.73 — 2.91 (m, 2 H) 3.65 (d, J=12.4 Hz, 1 H) 3.71 - 3.85 (m, 2 H) 4.04 (d, J=5.9 Hz, 2 H) 4.07 - 4.15 (m, 1 H) 4.29 - 4.45 (m, 1 H) 6.84 (d, J=1.8 Hz, 1 H) 6.93 (dd, J=13.2, 2.2 Hz, 1 H) 6.97 (s, 2 H) 8.13 (t, J=5.7 Hz, 1 H) D. Pharmacological examples Example D.1 +flux : Ca; imaging (FDSS) (Qrolocolfij Materials W0 2012/1 13850 a) Assay buffer Hanks ed saline solution (HBSS, Invitrogen, Belgium), supplemented with mM HEPES (Invitrogen, Belgium), CaClz to a final concentration of 5 mM, 0.1 % Bovine serum albumin (Sigma—Aldrich NV, Belgium), b) Calcium-sensitive dye - Fluo-4AM Fluo-4AM ular , USA) was dissolved in DMSO containing 10% Pluronic acid (Molecular Probes, USA) to give a stock solution which was diluted in assay buffer supplemented with 5 mM probenicid (Sigma, Aldrich NV, Belgium) to give a final concentration of 2 uM. c) 384—well plates Black—sided, transparent bottomed 384 well plates coated with poly—D-lysine, PDL pre—coated (Corning, Incorporated, USA) (1) Calcium flux ement A Functional drug screening system (FDSS, tsu) was used to measure intracellular free-calcium flux signals.

Method Monolayers of human alpha 7-wt nAChR-expressing cells were grown in black-sided, transparent bottomed 384 well plates coated with PDL for 24 hours pn’or to loading with a fluorescent calcium indicator, fluo-4AM for up to 120 minutes.

PAM activity was ed in real time by applying the compounds to be tested to the loaded cells along with an alpha 7 nicotinic or agonist during constant monitoring of cellular fluorescence in a FDSS. Compounds giving peak fluorescent responses greater than the response due to agonist alone, were considered to be alpha 7 nAChR PAMs. The alpha 7 nicotinic receptor agonist was choline, applied at a sub—maximal concentration of 100 M. In a further setting of the present invention the compounds were applied prior to the alpha 7 nicotinic receptor agonist, in a particular 10 minutes prior to the t.

A control response to e was calculated on each plate from the difference in peak in fluorescence in wells receiving either choline or assay buffer alone. Compounds of the t invention were tested at a concentration range from 0401 uM to 30 uM.

Compounds were considered to have an interesting activity when they potentiated the choline signal at least with 200 % when tested at a concentration of 30 pM (the efficacy of 100 pM choline was defined as 100% in the absence of a PAM). An ECSO (or pECso) was determined as a concentration relating to half the maximal effect, when a clear sigmoidal curve with top plateau was obtained. The ECso (or pECso) was defined as W0 2012/1 13850 lower than maximal concentration in case the compound activity did not reach a top plateau at maximal concentration (indicated in table 7 as "< 5") The compounds also have a potentia’ting effect on the response to choline when measured by whole—cell patch clamp electrophysiology in GH4C1 cells stably xpressing the human wild-type alpha 7 receptor.

Example D.2 : Patch-clamp current recording Patch—clamp recording from ian cells has provided a powerful means of assessing the function of membrane—bound proteins thought to be subunits of ligand~gated ion channels. Activation of such proteins by endogenous or exogenous s cause opening ofa pore associated with the receptor through which ions flow down their electrochemical gradient. In the case of the human alpha 7—wt nAChR—expressing GH4Cl recombinant cell line the preferential permeability to calcium of this or means that calcium flows into the cell upon activation by ACh, choline and other nicotinic ligands giving rise to a calcium current. Since this receptor rapidly itizes in the presence of agonist it is important that an application system is used which is capable of very rapid switching of ons (< 100 ms) to prevent partial or full desensitisation of receptor responses coincident with the time of agonist application. Consequently, a second ient technique to assess the enhancement of nicotinic efficacy is a patch-clamp recording from human alpha 7—wt expressing GH4C1 cells coupled with a rapid-application system.

Materials a) Assay buffers The external recording solution consisted of 152 mM NaCl, 5 mM KC], 1 mM MgC12, 1 mM Calcium, 10 mM HEPES ; pH 7.3. The al recording solution consisted of 140 mM CsCl, 10 mM HEPES, 10 mM EGTA, 1 mM MgC12, pH 7.3. b) Patch—clamp recording was carried out using a Patch -clamp amplifier clamp 700A, Axon Instruments, CA, USA). Human alpha 7-wt nAChR-expressing GH4Cl cells were patch-clamped in the whole cell configuration (Hamill et a1, 1981) with borosilicate glass electrode of 1.5-3 MQ tip resistance when filled with the internal recording solution. Recordings were made on cells with membrane resistance >500 M9 and more preferably 1G9 and series resistance <15 MQ with at least 60% series resistance compensation. Membrane ial was clamped at —70 mV. 0) Agonists ACh, e,were purchased from Sigma-Aldri ch NV, Belgium. d) Compound application W0 2012/1 13850 A l6-channel Dynflow DF-16 microfluidics system (Cellectricon, Sweden) for rapid switching of ons (switching resolution time <100 ms) was used to apply control, t and PAM compounds to human alpha 7-wt nAChR—expressing GH4C1 cells.

Method Human alpha 7-wt expressing GH4Cl cells were plated in external recording solution in the Dynaflow perfiision chamber and were allowed to settle for up to minutes. Individual cells were whole-cell patched and gently lifted off the chamber bottom with the patch pipette into a continuously—flowing ion stream (12 til/min) of external recording solution. PAM activity was detected in real time by pre-applying the compounds to the loaded cells followed by an alpha 7 nicotinic receptor agonist during constant monitoring of cellular membrane current. Compounds giving current responses greater than the response due to agoni st alone, were considered to be alpha 7 nAChR PAM’s. The alpha 7 nicotinic receptor was activated by a non—selective nicotinic agonist, choline applied at a sub—maximal concentration of 1 mM. In a further setting of the present invention the compounds were applied prior to the alpha 7 nicotinic receptor agonist, 30 seconds prior to the agonist or 5 seconds prior to the agonist. A l response was ated from the area under the curve of the current elicited in each cell to the application of submaximal choline for 250 ms. Area under the curve is the integration of net t over time and is a common representation of the total ion flux h the channel. Increases in agonist y elicited by a positive allosteric modulator were calculated as percent potentiation of "area under curve" (AUC) of the agonist response. Potentiation greater than control AUC caused by compounds of the invention indicates that they are expected to have useful therapeutic ty. EC50 values (potency), maximal effect (% efficacy), and Hill slopes were estimated by fitting the data to the logistic on using GraphPad Prism (GraphPad Software, Inc, San Diego, CA).

Table 7 : Potency (pECso) and % efficacy for a number of compounds.

The pECso and % efficacy values are those from the Caz" assay as bed in D. It The PAM type is obtained from the patch clamp current recording as described hereinbefore ("-" means no value).

Claims (21)

Claims

1. A compound having the formula (I) or a stereoisomer f, wherein n is O, l or 2; X is fluoro or chloro; Y is N or CH; 10 Z is O or CH2; R1 is CHgalkyl; C1_ga1ky1 substituted with 1, 2 or 3 halogen substituents; C3_6cyclo— alkyl; (C3_6cycloalkyl)C1-6alkyl; (C1_6alkyloxy)C1_6alkyl; (trihaloC1_4alkyloxy)- C1_6alkyl; tetrahydrofuryl; tetrahydropyranyl; phenyl; or phenyl substituted with 1, 2 or 3 substituents selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, 15 C1-6alkyl, and kyloxy; or a monocyclic aromatic heterocyclic radical containing at least one heteroatom selected from N, O and S, optionally tuted with l, 2 or where possible with 3 substituents ed from halogen, C1_4alky1, C1_4alkyloxy, C3_6cycloalkyl, and trifluoromethyl; R2 and R3 are independently H, C1-4alkyl or trifluoromethyl; 20 or R2 and R3 are taken together to form l,2-ethanediyl or 1,3—propanediyl; R4 and R5 are independently H, C1_4a1kyl, trifluoromethyl, C3-6cycloalkyl or C1_4alkyloxy; or an acid addition salt thereof, or a solvate thereof.

2. The compound according to claim 1 wherein 25 R1 is C1-6alkyl; C1_4a1ky1 substituted with 3 fluoro tuents; C3-6cycloalky1; (C3_6cycloalkyl)C1-2alkyl; methoxymethyl; methoxyethyl; ydropyranyl; phenyl; phenyl substituted with 1, 2 or 3 tuents selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, methyl, and methoxy; or furanyl, oxazolyl, isoxazolyl, oxadiazolyl, yl, pyrazolyl, imidazolyl, 30 pyridinyl, pyridiminyl, nyl, pyridazinyl, thienyl, 1,2,3—thiadiazolyl, thiazolyl or benzisoxazolyl, each unsubstituted or substituted with l, 2 or where possible 3 tuents selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert— butyl, cyclopropyl, methoxy or trifluoromethyl.

3.The compound according to claim 1 or 2, wherein R2 is hydrogen, methyl or romethyl.

4.The compound according to any one of claims 1 to 3, wherein R3 is hydrogen, methyl or trifluoromethyl.

5.The compound according to any one of claims lto 4, wherein R4 is hydrogen or methyl.

6.The compound according to any one of claims 1 to 5, wherein R5 is hydrogen or 10 methyl.

7.The nd ing to any one of claims 1 to 6, wherein R1 is , ethyl, n—propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 2,2,2-trifluorethyl, 3,3,3-trifluoropropyl, 2-methoxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, l—(cyclopropyl)ethyl, (cyclopropy1)methyl, buty1)methy1, 4—fluoro-2— 15 methylphenyl, 3-methyl-isoxazol—5—yl, 3-methyl—isoxazolyl, 5-methyl-isoxazol- 3-yl, 2-methyltrifluoromethy1—oxazol—4-yl, 2-methy1-oxazolyl.

8.The compound ing to any one of claims 1 to 7, wherein R2 and R3 are methyl or trifluoromethyl and have the cis-configuration.

9.The compound according to any one of claims 1 to 8, wherein R4 and R5 are 20 methyl.

10. The compound according to claim 1 wherein the compound is N-[[5—[(2R,6S)—2,6— dimethyl-4—morpholinyl]—2-(2,6-dimethyl-4—pyridinyl)phenyl]methyl]methy1— propanamide.

11. A pharmaceutical composition comprising as active ingredient a compound as 25 defined in any one of claims 1 to 10.

12. A product comprising (a) a compound of formula (I) as defined in claim 1, and (b) a 0L7 nicotinic receptor agonist selected from 1,4—Diazabicyclo[3.2.2]nonanecarboxylic acid, 4-bromophenyl ester, 3O monohydrochloride; (-)—spiro[ 1 -azabicyclo [2.2.2] octane-3 ,5 ’ lidine] -2 ’ -one; (+)—N—(1-azabicyclo[2.2.2]octyl)benzo[b]furan—2—carboxamide; 3-[(2,4-Dimethoxy)Benzylidene]~Anabaseine Dihydrochloride; ~78- [N-[(3R)— l —Azabicyclo[2.2.2]oct-3 -yl]-4—chlorobenzamide Hydrochloride] PNU—282987; nicotine; varenicline; A-582941 ; AR-R17779; TC-l698 ; FHA-709829; tropisetron; WAY-317538; MEM3454; EVP-6124; TC-5619; MEM—63908; and AZD—0328, as a ed ation for simultaneous, separate or sequential use in preventing or treating of psychotic disorders, intellectual impairment disorders, or inflammatory diseases.

13. A compound as defined in any one of claims 1 to 10 for use as a medicine.

14. A compound as defined in any one of claims 1 to 10 for use in treating Alzheimer’s e, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder, anxiety, 10 phrenia, mania, manic depression, Parkinson’s disease, gton’s disease, te’s syndrome, brain trauma, jetlag, nicotine addiction, pain; endotoxaemia, endotoxic shock, sepsis, rheumatoid arthritis, asthma, multiple sis, psoriasis, urticaria, inflammatory bowel disease, inflammatory bile disease, Crohn’s disease, ulcerative colitis, perative ileus, pancreatitis, heart failure, acute lung injury 15 or allografi rejection; cognition in schizophrenia, cognition in Alzheimer’s disease, mild cognitive impairment, Parkinson’s disease, ion deficit hyperactivity er, ulcerative colitis, pancreatitis, arthritis, sepsis, erative ileus or acute lung injury.

15. A process ofpreparing a pharmaceutical composition as defined in claim 11 20 comprising the step of intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound as defined in any one of claims 1 to 10.

16. The use of a compound as defined in any one of claims 1 to 10 in the manufacture of a medicament for ng Alzheimer’s e, Lewy Body Dementia, Attention 25 Deficit ctivity er, anxiety, schizophrenia, mania, manic depression, Parkinson’s disease, Huntington’s e, Tourette’s syndrome, brain trauma, jetlag, nicotine addiction, pain; endotoxaemia, endotoxic shock, sepsis, rheumatoid arthritis, asthma, multiple sclerosis, psoriasis, urticaria, inflammatory bowel disease, inflammatory bile disease, Crohn’s disease, ulcerative s, post- 30 operative ileus, pancreatitis, heart failure, acute lung injury or allograft rejection; cognition in schizophrenia, cognition in Alzheimer’s disease, mild cognitive impairment, Parkinson’s disease, attention deficit hyperactivity disorder, ulcerative colitis, pancreatitis, arthritis, sepsis, postoperative ileus or acute lung injury.

17. A compound according to claim 1, substantially as herein described with reference 35 to any one of the examples.

18. A pharmaceutical composition according to claim 11, substantially as herein described with reference to any one of the examples.

19. A product according to claim 12, substantially as herein described with reference to any one of the examples.

20. A s according to claim 15, ntially as herein described with reference to any one ofthe examples.

21. A use according to claim 16, substantially as herein described with reference to any one of the examples.