NZ718251B2 - Piperazine derivatives and the use thereof as medicament - Google Patents

Abstract

The present inventions relate to substituted piperazine derivatives of general formula (I) and to the manufacture of said compounds, pharmaceutical compositions comprising a compound according to general formula (I), and the use of said compounds for the treatment of various medical conditions related to glycine transporter-1 (GlyT1). ed to glycine transporter-1 (GlyT1).

Description

Piperazine derivatives and the use thereof as medicament The present inventions relate to substituted piperazine derivatives of general formula (I) O R 03/S RN‘RZ and to the manufacture of said compounds, pharmaceutical compositions comprising a compound according to general formula (I), and the use of said compounds for the treatment of various medical conditions related to glycine orter-l.

OUND OF THE INVENTION A general overview of the role of glycine transporter-l (GlyTl) inhibitors for the treatment of diseases can be taken for example from W02010/086251. This role of e transporter-l (GlyTl) inhibitors is applicable for the present ion as well. In the following sectionexcerpts from pages 1 to 4 of /086251 will be cited in parts and/or modified and wherever considered appropriate further s, which are known in the art, are added, in order to provide state of the art background information for the present invention: Schizophrenia is a progressive and devastating psychiatric disease characterized by episodic positive ms such as delusions, inations, thought disorders and psychosis and tent negative symptoms such as flattened affect, impaired attention and social withdrawal, and cognitive impairments (Lewis DA and Lieberman JA, 2000, Neuron, 28: 325-33).

A hypothesis of schizophrenia was proposed in the mid-1960’ based upon the psychotomimetic action caused by the blockade of the glutamate system by compounds like phencyclidine (PCP) and related agents (e.g. ketamine) which are non-competitive antagonists of the glutamate yl-D-aspartate (NMDA) receptor. Interestingly in healthy eers, PCP-induced psychotomimetic action incorporates positive and negative symptoms as well as cognitive dysfunction, thus closely resembling schizophrenia in patients (Javitt DC et al., 1999, Biol. Psychiatry, 45:668-679); see also Jentsch and Roth, 1999, Neuropsychopharmacology 20:201-225). Therefore, increasing NMDA-receptor neurotransmission in the central nervous system offers an opportunity for the development of novel treatment approaches for schizophrenia and also other neurological and psychiatric diseases related to NMDA-receptor and/or glutamatergic dysfunction. The NMDA-receptor is a ligand-gated ion l composed of a ation oftwo NR1 and two NR2 subunits and requires the itant binding of glutamate at the NR2 subunit and glycine as a co-agonist at the NR1 subunit to be ted (Johnson and Ascher, 1987, Nature 9-531). One strategy to enhance NMDA receptor activity is to elevate the glycine concentration in the local microenvironment of synaptic NMDA receptors by tion of GlyTl (Bergeron R. et al., 1998, Proc. Natl. Acad. Sci. USA 95:15730- 15734). In fact, clinical studies with direct glycine site agonists D-serine and a prototype GlyTl-inhibitor, sarcosine, which increases glycine in the synaptic cleft, have demonstrated some efficacy for the ent of negative symptoms and to a lesser extent, positive and cognitive symptoms of schizophrenia (Tsai et al., 2004, Biol. Psychiatry 44:1081-1089; Lane et al., 2005, Biol. Psychiatry 63:9-12). ly, clinical cy regarding negative symptoms in schizophrenia patients was reported for the GlyTl- tor RG1678 tested in a clinical phase II trial as adjunctive treatment to marketed ychotics (Umbricht et al., 2011, Schizophr. Bull. 37(Suppl.1):324).

Efficacy in various animal models/tests for positive and negative symptoms of schizophrenia as well as in several memory tasks has been ed in the literature for different GlyTl-inhibitors. In detail, the selective GlyTl-inhibitors SSR504734 and SSR103800 were shown to be efficacious in two models for antipsychotic ty, i.e. reversal of NMDA-receptor antagonist d hyperlocomotion and pre-pulse-inhibition, well known models for positive symptoms of schizophrenia (Depoortere et al., 2005, Neuropsychopharmacology 30:1963-1985; Boulay et a1., 2008, Pharmacol. Biochem.

Behav. 91:47-58). Regarding negative symptoms, SSR504734 was demonstrated to se ne in the prefrontal cortex, a mechanistic in-vivo model for negative symptoms in phrenia rtere et a1., 2005, Neuropsychopharmacology 30:1963- 1985). Regarding memory enhancement, the selective GlyTl-inhibitors SSR504734 and SSR103800 were efficacious in the social recognition test (Depoortere et a1., 2005, Neuropsychopharmacology 30:1963-1985; Boulay et a1., 2008, Pharmacol. Biochem.

Behav. 91:47-58). Another GlyTl-inhibitor, NFPS, was shown to be active in the object recognition and social recognition test regarding reversal of MK—801-induced cognitive deficits (Karasawa et al., 2008, Behav. Brain Res. 186:78-83; Shimazaki et al., 2010, Psychopharmacology 209:263-270). In addition, an enhancing effect on long-term potentiation in hippocampal slices could be shown with NFPS demonstrating that inhibition of GlyTl leads to strengthening of synaptic plasticity which is crucial for memory formation on a cellular level (Kinney et a1., 2003, J. Neurosci. 23:75 86-7591). In fact, ate neurotransmission, in particular NMDA receptor activity, plays a critical role in synaptic plasticity, ng and memory, such as the NMDA receptors s to serve as a graded switch for gating the old of synaptic plasticity and memory formation (Bliss TV and gridge GL, 1993, , 361 :31-39).

In addition, GlyTl-inhibitors were shown to be efficacious in animal models of depression, anxiety and sleep, such as chronic mild stress, ultrasonic distress calls in rat pups and increased latency ofparadoxical sleep (Depoortere et a1., 2005, Neuropsychopharmacology : 1963-1985).

Two distinct glycine transporter genes have been cloned (GlyTl and GlyT2) from mammalian brain, which give rise to two transporters having 50 % amino acid sequence homology. GlyTl presents four isoforms arising from ative ng and alternative promoter usage (la, lb, 1c and 1d). Only two of these isoforms have been found in rodent brain (GlyTla and Glyle). GlyT2 also presents some degree of heterogeneity. Two GlyT2 iso forms (2a and 2b) have been identified in rodent brains. GlyTl is known to be located in CNS and in some peripheral tissues, whereas GlyT2 is specific to the CNS, primarily in the hindbrain and spinal cord (Zafra et a1., 1995, J. ci. 15:3952-3969). GlyTl is expressed in glia and neurons, and it is found to be located at glutamatergic synapses (Cubelos et al., 2005, Cereb. Cortex 15:448-459).

Glycine transporter inhibitors are suitable for the treatment of neurological and psychiatric disorders. The majority of es states implicated are psychoses, schizophrenia (Armer RE and Miller D], 2001, Exp. Opin. Ther. Patents 11: 2), psychotic mood disorders such as severe major sive disorder, mood disorders associated with psychotic disorders such as acute mania or depression, ated with bipolar disorders and mood ers, associated with phrenia, (Pralong ET et al., 2002, Prog. Neurobiol., 67:173-202), autistic disorders (Carlsson ML, 1998, J. Neural Trans. 105:525-535), cognitive disorders such as dementias, including age related dementia and senile dementia of the Alzheimer type, memory disorders in a mammal, including a human, attention deficit ers and pain (Armer RE and Miller D], 2001, Exp. Opin. Ther. Patents, 11:563-572).

Thus, increasing activation ofNMDA receptors via GlyTl tion may lead to agents that treat psychosis, schizophrenia ive, negative and cognitive symptoms), dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders, Alzheimer's disease, or other neurological and psychiatric disorders.

The before mentioned concepts related to the inhibition of GlyTl are of high interest, in particular with respect to cognitive impairment associated with Alzheimer’s disease or phrenia.

BRIEF SUMMARY OF THE INVENTION The present inventions relates to substituted piperazine derivatives of general formula (I) O R 06/8 w,R2 (I), wherein R1 and R2 are as herein described or salts thereof, preferably a pharmaceutically acceptable salt thereof.

The ion further relates to the manufacture of said active compounds, ceutical compositions comprising a nd according to general formula (I), and the use of said active compounds for the treatment of various medical conditions.

Aim ofthe invention The compounds of the invention according to general formula (I) show glycine transporter- l (GlyTl) inhibiting properties. Consequently, one aspect of the present invention relates to compounds according to formula I and salts thereof as modulators of GlyTl.

A further aspect of the invention relates to the physiologically able salts of the compounds of general formula (1) according to this invention with inorganic or organic acids.

In a further aspect the present invention relates to pharmaceutical compositions, containing at least one compound according to a (I) or a logically able salt thereof, optionally er with one or more inert carriers and/or diluents.

A further aspect of the t invention relates to compounds according to formula (I) or a physiologically able salt thereof or pharmaceutical compositions comprising compounds according to formula (I) or logically acceptable salts thereof for the use in the prevention and/or treatment of GlyTl-related pathologies.

A further aspect of the present invention relates to compounds according to formula I or a physiologically acceptable salt thereof or pharmaceutical compositions comprising compounds according to formula I or physiologically able salts thereof for the use in the prevention and/or treatment of diseases or conditions which can be influenced by inhibition of GlyTl such as conditions concerning positive and negative symptoms of schizophrenia as well as cognitive impairments ated with schizophrenia, Alzheimer’s Disease and other neurological and psychiatric disorders. The use comprises the cture of medicaments for the treatment of the corresponding diseases. 2014/072085 DETAILED DESCRIPTION OF THE ION In a first aspect the t invention relates to compounds of general formula (I) O R 06/8 orR2 (I), wherein is selected from the group R121 consisting yl and a 5 or 6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatonis independently selected from O, N or S, n the phenyl or the heteroaryl is optionally substituted with one or 3 . more R With one or two R3; , preferably is selected from the group R221 consisting of aryl, a 5 or 6 membered monocyclic heteroaryl and a 8 to 10 ed bicyclic heteroaryl, the mono- or bicyclic heteroaryl having 1, 2 or 3 heteroatoms ndently selected from O, N or S, wherein the aryl or the heteroaryl is optionally substituted with one or more R4, preferably with one or two R4; is selected from the group R321 consisting of halogen, a -C1_4-alkyl and a -C3_6- cycloalkyl, wherein the -C1_4-alkyl or the -C3_6-cycloalkyl is optionally substituted with one or more halogens; is selected from the group R421 consisting of halogen, -CN, -C1_4-alkyl, -C3_6- cycloalkyl, -C1_3-alkyl -C3_6-cycloalkyl and -O-C1_6-alkyl, wherein the C1_4-alkyl, -C3_ 6-cycloalkyl, -C1_3-alkyl -C3_6-cycloalkyl or the -O-C1_6-alkyl is optionally substituted with one or more halogens; or the tautomers thereof, the stereoisomers thereof, the mixtures thereof and the salts thereof Unless otherwise stated, the groups, residues, and substituents, particularly R1, R2, R3 and R4 are defined as above and hereinafter. If residues, substituents, or groups occur several times in a nd they may have the same or different meanings. Some preferred meanings of groups and substituents of the compounds according to the invention will be given after.

In a fiarther embodiment of the present invention 1 , R . . . 1s selected from the group R1’0 cons1st1ng of Haln (R3)n * * wherein Hal is a n, n is 0, l or 2, XisSorO, YisNorCH.

In a fiarther ment of the present invention R . . . is selected from the group Rlb cons1st1ng of Haln (R3)n Y/Z':\X * * wherein Hal is a halogen, nislor2, XisSorO, YisNorCH.

In a fithher ment of the t invention R1 is selected from the group R1c consisting of Haln R3 R3 \ x NYX wherein Hal is -F or -Cl, 11 is l or 2, XisSorO.

In a fithher embodiment of the present invention R1 is selected from the group R1d consisting of F F F F F F CI CF3 / 1\ is Z\ is 1\ is \ 8 NY8 \ s In a fithher embodiment of the present invention R1 is ed from the group Rle consisting of QQQQQ In a fithher embodiment of the present invention R1 is selected from the group R16, consisting of QQQQQ In a fithher embodiment of the present invention R1 is selected from the group R1f ting of F F Q/F F F QF * * * 'k * ’ ’ ’ - In a fithher embodiment of the present invention R1 is selected from the group ng consisting of F F ; ,F F ; F 1: * -k * ’ _ In a fithher embodiment of the present invention R3 is selected from the group R3’0 consisting of F, Cl, -CH3, -CH2CH3 or ropyl, wherein the -CH3, 3 and the cyclopropyl is optionally substituted with one or more halogens selected from F or In a fithher embodiment of the present invention R3 is selected from the group R3c consisting of F, Cl, -CH3, -CF3 and cyclopropyl.

In a further embodiment of the present invention -1]- is selected from the group R2’0 consisting of naphthyl, | H uY m» a»U* u Y * U * U—Y U—U *4]©W , , n U is independently from each other N or CH with the proviso that the ring system bears a maximum ofthree N-atoms , Y is O or S, W is O, S or NH and n the above mentioned ring systems are optionally substituted with one or more R4, preferably with one or two R4.

In a further embodiment of the present invention R2 is selected from the group R" consisting of 2014/072085 In a further embodiment of the present invention R2 is selected from the group R2d consisting of CF CF 3 3 "HERE /IN\NN\*3 /|N \ kaNTNNTNV kaNfi/NKKN* N \ \ \ I N| \ /N /N S O *\g—Z/CF3 * N \fl W/CF3 K \7/CF3* * N—N N— /:E> «oNS and .

In a further embodiment of the present invention R2 is selected from the group Rze consisting of In a fithher embodiment of the present invention R2 is selected from the group R2f ting of In a fithher embodiment of the present ion R4 is selected from the group R4b consisting of F, Cl, Br, -CN, -CH3, -CH2CH3 or cyclopropyl, wherein the -CH3, -CH2CH3 and the cyclopropyl is optionally substituted with one or more halogens selected from F or In a fithher embodiment of the present invention R4 is selected from the group R4c consisting of F, Cl, -CN, -CH3, -CF3 and cyclopropyl.

In a filrther aspect the present invention relates to compounds or salts thereof according to the structure of formula (II): In a fiarther aspect the t invention relates to compounds or salts thereof according to the structure of formula (III): oé/i"3 bN‘Rz (111).

Each RIX, RZX, R3X and R4X represents a characterized, individual ment for the corresponding substituent as described above. Thus given the above definitions, preferred individual embodiments of the first aspect of the invention are fully characterized by the term (RIX, RZX, R3X and R4X), wherein for each index x an individual figure is given that ranges from "a" to the highest letter given above. All individual embodiments described by the term in parentheses with filll ation of the indices X, referring to the definitions above, shall be comprised by the present invention.

The following Table 1 shows, exemplarily and in the order of increasing ence from the first line to the last line, such embodiments E-l to E-18 ofthe ion that are ered preferred. This means that embodiment E-18, represented by the entries in the last row of Table l, is the most preferred embodiment.

Table 1: Preferred embodiments E-l to E-18 ofthe invention WO 55698 R1 R2 R3 R4 E-1 R1a R2a R3a R4a E-2’ R1E‘ R2a R3a R4a E-2 R1b R2a R3a R4a E-3 R1a R2‘b R3a R4a E-4 R10 R2a R3a R4a E-5 R1b R2b R3a R4a E-6 R10 R2‘b R3a R4a E-7 R10 R2‘b Rsb R4b E-8 R10 R2‘b R30 R40 E-9 R10 R20 R30 _ E-10 R1d R2b - R4° E-11 R1d R2° — — E-12 R1d R2a - - E-13 R1" R2" — — E-14 R1" R2" — — E-14’ R16‘ R2" — — E-15 R1f R20 _ _ E-15’ R19 R2° - - E-16 R" R23 - - E-16’ R19 R2" - - E-17 R1f R2e _ _ E-17’ R19 R26 - - E-18 R" R2 - - E-18’ R19 R" - - and the tautomers thereof, the stereoisomers thereof, the mixtures thereof, and the salts thereof Accordingly, for e E-lO covers compounds of a I, wherein R . . . 1s selected from the group cons1st1ng of F F F F F F CI CF3 , \ 8 Z\ is 1\ i8 1\ :8 NY8 \ S 'k * R2 is selected from the group consisting of naphthyl, U \ U U Y Y w v w w* * U * U—Y U—U W wherein U is independently from each other N or CH with the proviso that the ring system bears a maximum ofthree N-atoms , Y is O or S, W is O, S or NH and wherein the above mentioned ring s are optionally substituted with one or more R4 and wherein R is ed from the group consisting of F, Cl, -CN, -CH3, -CF3 and cyclopropyl.

TERMS AND DEFINITIONS USED l definitions: Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the cation, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1_6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the first named subgroup is the radical attachment point, for example, the substituen "-C1_3- aryl" means an aryl group which is bound to a C1_3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.

An asterisk may be used in rmulas to indicate the bond which is connected to the core molecule as defined.

Stereochemistry/solvates/hydrates: Unless specifically ted (e. g. by stereochemical designators, perspective drawings, etc.), throughout the specification and the appended claims, a given chemical structure, formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc...) and racemates thereof as well as es in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any ofthe foregoing forms where such s and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and sovates thereof such as for instance hydrates ing solvates of the free compounds or es of a salt of the compound.

Alkyl: The term "C1_n-alkyl", wherein n is an integer from 2 to 11, either alone or in ation with another radical s an acyclic, saturated, branched or linear hydrocarbon radical with l to n C atoms. For example the term lkyl embraces the radicals H3C-, H3C- CH2-, H3C-CH2-CH2-, H3C-CH(CH3)—, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C- CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C- CH2-CH(CH3)-CH2-, (CH3)—CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-. fly]; The term "aryl" as used herein, either alone or in combination with another radical, s a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be r fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

Cycloalkyl: The term "C3_n-cycloalkyl", wherein n is an integer from 4 to 11, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example the term C3_7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Halogen: The term halogen generally denotes fluorine, chlorine, bromine and .

Heteroaryl: The term "heteroaryl" means a mono- or polycyclic-ring systems containing one or more heteroatoms selected from N, O or 8(0),, wherein r=0, l or 2, consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms is part of aromatic ring. The term oaryl" is intended to include all the possible ic forms.

Thus, the term "heteroaryl" includes the following exemplary structures which are not depicted as radicals as each form may be attached through a nt bond to any atom so long as appropriate valences are maintained: H O S g S OQSI’O H N‘N U U Q U m o m o H H 0 0‘ o\ ,o\ s\ N\ N £3 \/N EJN N\\_//N \xN \gN g} s o 0‘ s\ s\ N\ \(\D //\\O N N N \> \ \> \> N N N s N, O O, H H \ N\\ N N\ / /\ H N N N m m "D \ I\ \> '\ N / \> / N / N / N N N/ |\ \N f\ / / / / /N / ’ N / N\> / \ N N N \ N \ NJ H H 0% m / / N W"J NA?" \ N\// / \N/N \ N\N/ / NvN R/NJ/ / N \ N\> / | /N> /\N \\ N / \ N\N/ \ N\// Many ofthe terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.

Salts: The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, als, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and s without excessive toxicity, irritation, allergic response, or other problem or complication, and surate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.

Examples of ceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues 2014/072085 -2]- such as carboxylic acids; and the like. For example, such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2’-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2- aminoethanol, ethylenediamine, N—ethyl-glucamine, hydrabamine, lH-imidazole, lysine, magnesium hydroxide, 4-(2—hydroxyethyl)-morpholine, piperazine, potassium hydroxide, l-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2’,2"- nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2,2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphor- lO-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy- ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, filmaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, ic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid, ic acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL- lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (-)-L-malic acid, malonic acid, DL-mandelic acid, esulfonic acid, alene-l,5-disulfonic acid, naphthalene sulfonic acid, l-hydroxynaphthoic acid, nicotinic acid, nitric acid, ic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, c acid, c acid, succinic acid, sulfuric acid, tannic acid, tartaric acid, thiocyanic acid, p- esulfonic acid and undecylenic acid. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, m, magnesium, potassium, sodium, zinc and the like. (also see Pharmaceutical salts, Berge, S.M. et al., J.

Pharm. Sci, (1977), 66, 1—19).

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be ed by reacting the free acid or base forms of these compounds With a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or itrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention (e.g. trifluoro e salts,) also comprise a part of the invention.

The compounds according to the invention may be obtained using methods of synthesis known in principle. Preferably, the compounds are obtained by the following methods according to the invention which are described in more detail hereinafter.

PREPARATION The following s shall illustrate generally how to manufacture the compounds according to general formula (I) and the ponding intermediate compounds by way of example. The abbreviated substituents may be as defined above if not defined otherwise within the t of the schemes.

Scheme 1 Reaction with RZX: ologies A. Nucleophilic 2 Pd(PPh3)4 R 1 H R1 displacement R N N\ CI 3H CSzC03 N\ H2,Pd/C 10% E j + R1" ‘OH —> E I —> E j —> 1 j N H R N dioxane/ B.Buchwald H H20 AcOH C. Chan—Lam x : c1, Br, 1, B(OR)2 HOAt, F3 chiral HPLC F3 F3 EDC N N N TH F/ 1 J: j 1\\'[ j + 1): ] DMF R N R N R N Scheme 1: In a first step a Suzuki cross coupling reaction, starting from commercially ble 2-Chloro-pyrazine and the desired Boron tive, is performed (cfr. Saito R., Tokita M., Uda K., Tetrahedron, 2009, 3019-3026); the following hydrogenation step allows to obtain the zine derivative bearing a substituent at position 2 (R1) (cfr.

Blythin D., Chen X., Piwinski J.J., et al., Bioorg. Med. Chem. Lett., 2002, 3161-3165) .

The substituent R2 is then introduced via an arylation procedure (cfr. Huang X., Buchwald S.L. Et al., J. Am. Chem. 500., 2003, 6653-6655. Scanio M., Shi L. et al., J.Med.Chem, 2011, 7678-7692. Charles M., Schultz P., Buchwald S.L., Org. Lett., 2005, 3965-3968.

Chan D.M.T., Monaco K.L. et al., Tetr. Lett., 1998, 2933-2936. Chan D.M.T., Lam. P.Y.S. et al, Tetr. Lett., 2003, 3863-3866.) and the final amide coupling allows to obtain the final compounds as racemic mixtures. The single enantiomers can be obtained afier tion ofthe corresponding racemic mixtures by HPLC employing a chiral stationary phase.

Scheme 2 on with RZX: Methodologies 1.dioxane A. Nucleophilic displacement; 2. NaBH4, O H R1 B. Buchwald R2 /fl\v/ r—j NROHHLO c OmmLmn LG + N R1 NH2NH2 —> E :r H J: j R1 N X= Cl B , 1‘, I B R LG = Cl, Br, I a (O )2 o. O 0283—4 F32 R2 F32 N N N HOAt, 1): ] chiral HPLC E j + 11 ] EDC R N RM" R N _ 0‘0 "O DMF O b 0 Scheme 2: in the first step the 0t- haloketone is reacted with Ethane-1,2-diamine to provide afier treatment with a reducing agent such as sodiumboronhydride the zine derivative substituted at on 2 (R1) (cfr. Jirkovsky1., Santroch G. et al, J. Med. Chem., 1987, 388-394). The substituent R2 is introduced via an arylation procedure and the final amide coupling allows to obtain the final compounds as racemic mixtures.

The single enantiomers can be obtained after separation of the corresponding c mixtures by HPLC employing a chiral stationary phase.

Scheme 3 OH G1 OMe-HC1 BOCZO HdAt O OH 2;O NaHC03 OTS/Rl HCOOH EDC NH NJSVRl O#R1 O _> N —> O —> t—butanol/ 9’ H DCM R S’N b 1 H H N H20 0 O t- utano 2 O DMF \>’N Toluene k0 H Reaction with RZX: ologies A. philic displacement; 2 (12:33—40 B. Buchwald F5 0 OH R2 H C. Chan-Lam N N BH3-MeZS N l: j HOAt 1...]: j —» J: j —> R1""' N —>EDC R" N R i H THF N THF X : Cl B 9 r9 I B(OR) 0 9 2 DMF 8‘0 Scheme 3: in the first step the enantiomerically pure glycine derivative undergoes a protection step; then an amide formation takes place followed by the ring closure performed under acidic conditions. The di-ketopiperazine derivative is then reduced with borane to afford the enantiomerically pure piperazine derivative bearing the desired substituent at position 2 (R1). The substituent R2 is introduced via an arylation procedure and the amide ng allows to obtain the final compounds. This route allows to obtain the final compounds with known absolute configuration (cfr. M. Barfield, F.A.Al-Obeidi, V.J.Hruby and S.R.Walter, JAm.Chem.Soc.,l982,lO4, 3302-3306 and D.E.Nitecki,B.

Halpem, J.W. Westley, Journal nic Chemistry 1967, 864).

Scheme 4 Chiral DMAP UHNN/Q Br BHMezS DCC DIPEA HOm/kR1 + N /o N o U. U N ’R N R Reaction with RZX: Methodologies 008 //O A. Nucleophilic displacement; O N OH 0 CI B. ld H R2 A )\ N C. Chan-Lam . HOAt CI 0 /N . ., 1 HZ-Pd/C EDC —, N R —, V 1 R k j / R1 DCE ACOH H N N] DCM, (E H R N x : Cl, Br, 1, B(0R)2 Scheme 4: in the first step the enantiomerically pure (R)Hydr0xy-4,4-dimethyl—dihydr0- furan—2-0ne is acylated with a (it-halogenated acid derivative; the following step allows to obtain the piperazinone derivative which is then reduced with Borane; the benzyl group is removed in two consecutive steps, the substituent R2 is uced via an arylation procedure and the amide coupling allows to obtain the final compounds. This route allows to obtain the final compounds with known absolute configuration (cfr. Jung in Jang, Seock Yong Kang, Kyoung Hee Kang, Yong Sun Park, Tetrahedron, 2011, 6221-6226).

Scheme 5 0:334O on with RZX: Methodologies O- O A. Nucleophilic cement; B. Buchwald OYfi/O C. Chan—Lam 2 HOAt R [N"1—):rRBoczO EDC DCM R11:] THF oIofi/H DMF Rffigoocdioxane RJEJ R N X : Cl, Br, I, B(OR)2 Scheme 5: the piperazine derivatives obtained as described in Scheme 1-3 can undergo a protection step before the formation of the amide derivative; the ting group is then removed and the final step is characterized by the introduction of R2 substituent applying known literature procedures.

The single enantiomers can be obtained afier separation of the corresponding racemic mixtures by HPLC employing a chiral stationary phase.

Scheme 6 l. Chiral Acid; H O O diastereomeric N R Boc20 Y salt llization OYOfi/ [I N N DCM [j 1l j R1 \" N H R N 2. Free base recovery H after basic work up Reaction with RZX: 0‘ O Oreo—(OH Methodologles A. Nucleophilic Y displacement; N N Ofi/ B. Buchwald H0At HCl UH Oyofi/ RM-[N] C. Chan—Lam E j N EDC R1... N THF dioxane ——’ R1 WEN] O b X: Cl Br 1 B(OR)2 0 Scheme 6: the piperazine derivatives obtained as described in Schemes 1-3 can undergo, afier a protection step, a diastereomeric salt formation reaction afier treatment with an enantiomerically pure carboxylic acid; the diastereomeric salt can be crystallized and afier a basic work up the enantiomerically pure zine derivative is then converted into an amide tive. The protecting group is removed and the substituent R2 is introduced via an arylation procedure performed according to described literature procedures.

Scheme 7 HN O N 9H 0 o R\fi0 N 2% s\ HN%NH ll NON N N ( R4 0 R4 J: j NaOH/Hzo J: j NH20H N TEA Y 1 TMSNCO N R N , H , R1 R1 EtOH 11 j ACN THF N CHCI3 N 1 J: j Scheme 7: in the first step the piperazine-amide derivative, obtained as described in scheme 5, undergoes a reaction with trimethylsilyl isocyanate to form the ediate urea; afier ation by treatment with NaOH and CHClg, the cyano derivative can undergo a reaction with hydroxylamine and subsequent cyclization with a suitable anhydride to obtain the oxadiazole derivative.

The single omers can be obtained afier separation of the corresponding racemic mixtures by HPLC employing a chiral stationary phase.

Scheme 8 H2N o »=\ N Y N\ 0 1U "j I R N TMSNCO 1 R4)J\/Br 7 R N 0 THF tB OHU 1 R N fi/ 0 0 fi 0 0 fi Scheme 8: the ediate urea, obtained by reaction of the piperazine-amide derivative as described in Scheme 7, undergoes a cyclization reaction with a le bromomethyl- ketone to obtain the oxazole derivative.

The single enantiomers can be obtained after separation of the corresponding racemic mixtures by HPLC employing a chiral stationary phase.Scheme 9 Reaction With RZX: Methodologies A. Nucleophilic displacement; O" R2 H B. Buchwald I32 H 2 N 1): j C. Chan-Lam N R J: ] TFA N HATU J: j R1 N R j: R1 N _> J: j , DCM 1 DMF o o o A R H X O/OK A080 X : Cl, Br, I, B(OR)2 Scheme 9: in the first step the substituent R2 is introduced on the Boc protected piperazine derivative via an arylation procedure then the ting group is removed and the resulting amine can undergo a reaction with the carboxylic acid to obtain the final product.

The single enantiomers can be obtained after separation of the corresponding racemic mixtures by HPLC employing a chiral nary phase.

Scheme 10 U [U Q? Y .. ‘9 U / U LN] Cross coupling reaction Y R1 N —’ N] R1 N 0U).. GAO—OS.

RLi"; U U ‘7 H N Cross coupling reaction XOINJ U —(\ CISO Sb 8 GAG—‘0 "forO ] Trifluoromethyl group insertion \ N j I S \ o N Scheme 10: In case R1 and R2 contain a n atom, substitution at R1 and R2 can be achieved using described tic methodologies; the insertion of the cyclopropyl ring can be obtained applying the methodology described in: Hasnik Z., Pohl R., Hocek M., sis, 2009, 1309-1317; the insertion of the trifluoromethyl group can be ed applying the methodology bed in: Feng-Ling Qing, Junfa Fan, in Sun and Xiang-Jun Yue, J. Chem. 500., Perkin Trans. I, 1997, 3053-3057.

The compounds according to the invention are advantageously also obtainable using the methods described in the es that follow, which may also be combined for this purpose with s known to the skilled man from the literature.

METHOD OF TREATMENT The present invention refers to compounds, which are considered effective in the treatment of diseases ("active nds" according to general formula (I) and specifically the compound family classes and the members thereof). These active compounds according to the invention are effective and selective inhibitors of glycine transporter-l (GlyTl). Thus, the medicinal concepts discussed above, specifically in the section "Background of the Invention" at the introduction part of this description, are considered of high interest as field of application for the active compounds of the present invention. The active compounds of the present invention can be used for the development of medicaments.

Such medicaments shall preferably be used for the treatment of diseases in which the inhibition of GlyTl can evolve a therapeutic, lactic or disease modifying effect.

Preferably the medicaments shall be used to treat illnesses such as psychoses, dysfunction in memory and learning, schizophrenia (positive and negative symptoms of phrenia and cognitive impairment associated with schizophrenia), dementia like Alzheimer's disease and other diseases in which cognitive processes are impaired, such as attention deficit disorders, Parkinson’s disease, epilepsy and/or bipolar disorder.

The medicaments are for use in a method, preferably a eutic method, or a method for to improve perception, tration, cognition, learning or memory, like those occurring in particular in conditions, diseases and/or syndromes such as: mild cognitive impairment, amnestic mild cognitive impairment, age-associated ng and memory impairments, age-associated memory losses, ar dementia, craniocerebral , stroke, dementia occurring after strokes (post stroke dementia), post-traumatic dementia, general tration impairments, concentration impairments in children with learning and memory problems, Alzheimer's disease, mild Alzheimer’s disease, mild-to-moderate Alzheimer’s disease, moderate-to-severe Alzheimer’s disease, prodromal Alzheimer’s disease, Lewy body dementia, dementia with degeneration of the frontal lobes, including Pick's syndrome, Parkinson's disease, progressive nuclear palsy, ia with corticobasal degeneration, amyotropic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, epilepsy, temporal lobe sy, Korsakoffs psychosis or cognitive impairment associated with schizophrenia, prodromal phase of schizophrenia, major depressive disorder, depression, son’s disease, epilepsy, schizo-affective disorder or bipolar disorder.

Another aspect of the present invention concerns the treatment of a disease which is accessible by GlyTl-inhibition, in particular sleep disorders like insomnia or narcolepsy, bipolar disorder, depression, substance use disorders / abuse ers, hearing ers, attention deficit (hyperactive) disorder, inflammatory pain, athic pain, autism spectrum disorders or disorders of e control.

Thus the l aspect of the present invention can be summarized in that it is considered that a compound according to formula (I) as herein , in particular the cally defined species active compounds for use in or as a medicament.

Such a medicament preferably is for a therapeutic or prophylactic, preferably therapeutic method in the treatment of a CNS e.

In an alternative use, the medicament is for the treatment of a CNS disease, the treatment ofwhich is accessible by the inhibition of GlyTl.

In an alternative use, the ment is for the treatment of a e that is accessible by the tion of GlyTl.

In an alternative use, the medicament is for the use in a method for the treatment of Alzheimer’s e, schizophrenia (positive and negative symptoms) or cognitive impairment associated with Alzheimer’s disease or ated with schizophrenia.

In a further aspect of the invention, the present invention relates to the method of treatment or tion of a ion or disease selected from the above listed groups of conditions and diseases, wherein the method comprises the administration of a therapeutically effective amount of an active compound according to the invention in a human being in need thereof.

The dose range of an active compound ofthe present invention applicable per day is y from 0.1 to 5000 mg, ably from 0.1 to 1000 mg, preferably from 2 to 500 mg, more preferably from 5 to 250 mg, most preferably from 10 to 100 mg. A dosage unit (e.g. a tablet) preferably may contain between 2 and 250 mg, particularly preferably between 10 and 100 mg of the active compounds according to the invention.

Another aspect of the invention concerns the active compounds of the inventions for use in a therapeutic method or for use as a medicament. If indicated the therapeutic method or the medicament is preferably for the treatment of a condition or a disease selected from the group of conditions or a diseases as outlined above in this section, which is entitled "Method of Treatment".

PHARMACEUTICAL COMPOSITION Suitable preparations for administering the active compounds according to the invention will be apparent to those with ordinary skill in the art and include for example tablets, pills, es, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc. The t of the pharmaceutically active compound(s) should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as a whole.

Suitable tablets may be obtained, for example, by mixing one or more active compounds according to formula (I) with known excipients, for e inert diluents, carriers, disintegrants, adjuvants, surfactants, s and/or lubricants . The tablets may also consist of several layers.

Examples Examples which might rate possible pharmaceutical formulations, without being meant to be limiting: The term "active substance" s one or more active compounds according to the invention ing the salts thereof In the case of one of the aforementioned combinations with one or more other active substances the term "active substance" may also include the additional active substances. Standard procedures should be considered for the preparation of any the herein mentioned pharmaceutical ations.

HARD GELATINE SUPPOSITORY COMPOSITION active substance 150.0 mg active substance 150.0 mg lactose 87.0 mg polyethyleneglycol 1500 550.0 mg corn starch (dried) 80.0 mg polyethyleneglycol 6000 460.0 mg magnesium stearate 3.0 mg polyoxyethylene sorbitan 840.0 mg monostearate m M TABLETS active substance 100.0 mg 150.0 mg lactose 80.0 mg 89.0 mg corn starch 34.0 mg 40.0 mg polyvinylpyrrolidone 4.0 mg 10.0 mg magnesium te 2.0 mg 1.0 mg 220.0 mg 290.0 mg COMBINATION THERAPY / ATION WITH OTHER ACTIVE SUBSTANCES In r aspect the present invention relates to a combination therapy in which an active compound ing to the present invention is administered together with r active compound. Accordingly, the invention also refers to pharmaceutical formulations that provide such a combination of active ingredients, wherein one of which is an active compound of the present invention. Such ations may be fixed dose combinations (the active ingredients that are to be combined are subject of the same pharmaceutical formulation) or free dose combinations (active ingredients are in separate pharmaceutical formulations).

Consequently, a filrther aspect of the present invention refers to a combination of each of the active compounds of the present invention, preferably at least one active nd according to the present invention, with another active compound for example selected from the group of antipsychotics such as haloperidol, clozapine, idone, quetiapine, pazole, asenapine and olanzapine; antidepressants such as selective serotonin re- uptake tors and dual serotonin/noradrenaline re-uptake inhibitors; mood stabilizers such as lithium valproate and lamotrigine; beta-secretase inhibitors; gamma-secretase inhibitors; gamma-secretase tors; amyloid aggregation inhibitors such as e.g. scyllo-inositol; directly or indirectly acting neuroprotective and/or disease-modifying substances; anti-oxidants, such as e.g. vitamin E, ginko biloba or ginkolide; anti- inflammatory substances, such as e. g. Cox inhibitors, NSAIDs additionally or exclusively haVing AB (Abeta) lowering properties; HMG-CoA reductase inhibitors, such as statins; acetylcholine esterase inhibitors, such as donepezil, rivastigmine, tacrine, galantamine; NMDA or antagonists such as e.g. memantine; AMPA receptor agonists; AMPA receptor positive modulators, AMPkines, glycine transporter 1 inhibitors; monoamine receptor reuptake inhibitors; nces modulating the concentration or release of neurotransmitters; substances ng the secretion of growth hormone such as ibutamoren te and capromorelin; CB-l receptor antagonists or e agonists; otics such as minocyclin or rifampicin; PDEl, PDE2, PDE4, PDES, PDE9 or PDElO inhibitors, GABAA receptor inverse agonists; GABAA alpha5 or inverse agonists; GABAA receptor nists; nicotinic receptor agonists or partial agonists or positive modulators; alpha4beta2 nicotinic receptor agonists or partial agonists or ve modulators; alpha7 nicotinic receptor agonists or partial agonists or positive allosteric modulators;; histamine receptor H3 nists; 5-HT4 receptor agonists or partial agonists; 5-HT6 receptor antagonists; alpha2-adrenoreceptor antagonists, calcium nists; muscarinic receptor Ml agonists or partial agonists or positive modulators; muscarinic receptor M2 antagonists; muscarinic receptor M4 antagonists; muscarinic receptor M4 positive allosteric tors; metabotropic glutamate receptor 5 positive allosteric modulators; metabotropic glutamate receptor 2 antagonists; metabotropic glutamate receptor 2/3 agonists; metabotropic glutamate receptor 2 positive allosteric modulators and other substances that modulate receptors or enzymes in a manner such that the efficacy and/or safety of the active compounds according to the ion is increased and/or unwanted side effects are reduced.

The active compounds according to the invention may also be used in combination with immunotherapies such as e. g. active immunisation with Abeta or parts thereof or e sation with humanised anti-Abeta antibodies or antibody fragments for the treatment of the above mentioned diseases and conditions.

The active compounds according to the invention also may be combined with antipsychotics like haloperidol, flupentixol, fluspirilene, rothixene, prothipendyl, levomepromazine, clozapine, olanzapine, quetiapine, risperidone, paliperidone, amisulpride, ziprasidone, aripiprazol, ide, zotepine, sertindole, fluphenazine, perphenazine, perazine, promazine, chlorpromazine, levomepromazine, benperidol, bromperidol, pimozid, melperone, pipamperone, iloperidone, asenapine, perospirone, blonanserin, lurasidone.

WO 55698 The active compounds according to the invention also may be combined with antidepressants like amitriptyline imipramine hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine, amine (NORPRAMIN), doxepin (SINEQUAN, N), trimipramine (SURMONTIL).

Or the active compounds according to the invention also may be combined with serotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram A, CIPRAMIL) escitalopram (LEXAPRO, CIPRALEX), clomipramine (ANAFRANIL), duloxetine (CYMBALTA), femoxetine (MALEXIL), fenfluramine (PONDIMIN), norfenfluramine, fluoxetine (PROZAC), mine (LUVOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL, SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, MOLIPAXIN), venlafaxine (EFFEXOR), zimelidine (NORMUD, ZELMID), bicifadine, desvenlafaxine (PRISTIQ), brasofensme and tesofensine.

The combinations according to the present invention may be provided simultaneously in one and the same dosage form, i.e. in form of a combination preparation, for example the two ents may be orated in one , e. g. in ent layers of said tablet.

The combination may be also provided separately, in form of a free combination, i.e. the active compounds of the present ion are ed in one dosage form and one or more of the above mentioned combination partners is provided in another dosage form.

These two dosage forms may be equal dosage forms, for example a inistration of two tablets, one containing a therapeutically effective amount of the active compound of the present invention and one containing a therapeutically effective amount of the above ned combination partner. It is also possible to combine different administration forms, if desired. Any type of suitable administration forms may be ed.

The active compound according to the invention, or a physiologically acceptable salt thereof, in combination with another active substance may be used simultaneously or at staggered times, but particularly close together in time. If administered simultaneously, the two active substances are given to the patient together; if administered at staggered times the two active substances are given to the patient successively within a period of less than or equal to 12, particularly less than or equal to 6 hours. 2014/072085 The dosage or stration forms are not limited; in the frame of the present invention any suitable dosage form may be used. Exemplarily the dosage forms may be selected from solid preparations such as patches, tablets, capsules, pills, s, dragees, powders, troches, suppositories, liquid preparations such as solutions, suspensions, emulsions, drops, syrups, elixirs, or s preparations such as aerosols, sprays and the like.

The dosage forms are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of each active component being present. Depending from the administration route and dosage form the ingredients are selected accordingly.

The dosage for the mentioned combination partners may be expediently 1/5 of the normally recommended lowest dose up to l/ l of the normally ended dose.

The dosage forms are administered to the t for example 1, 2, 3, or 4 times daily depending on the nature of the formulation. In case of retarding or extended e formulations or other pharmaceutical formulations, the same may be applied differently (e.g. once weekly or monthly etc.). It is preferred that the active compounds of the invention be administered either three or fewer times, more preferably once or twice daily.

BIOLOGICAL ASSAY In-vitro effect: The in-vz’tro effect of the active compounds of the invention can be shown with the following biological assay.

GlyTl assay protocol: Cells expressing either endogenously the GlyTl transporter like JAR cells (human placental choriocarcinoma cells; e.g. WO 2008/002583) or SK—N—MC cells (human neuroblastoma cells; Depoortere et al., 2005, Neuropsychopharmacology 30: 1963-1985) or y neurons or cells which have been transfected with a plasmid encoding the cDNA of a fianctional GlyTl transporter and stably or transiently express GlyTl (e.g. WO 2006/08200) can be used to r glycine uptake in cells. Different protocols for determination of the glycine uptake into the cells described above can be applied in order to identify and rank nds which interfere with glycine uptake in the ed cell.

Compounds outlined in the examples below were characterized using human SK—N—MC cells (ATCC number HTB-lO) nously expressing the GlyTl transporter which is responsible for the uptake of glycine into these cells and the uptake of glycine into these cells is monitored using the Cytostar-T assay format (GE Healthcare, RPNQOl62) which is based on the radioactive glycine taken up by the cells and brought into proximity with the scintillant contained within the base of the plate. The radioactive decay is converted to a light signal based on the integration of the scintillation matrix into the assay plate. The uptake is recorded as kinetic and the slope of the measured counts over time is used to calculate IC50.

In detail, SK—N—MC cells are seeded into 96-well ar-T assay plates at a density of 200,000 cells/well and grown for 16-18 hours to confluence in growth medium as ended by ATCC. Before starting the assay, cells are washed once with HBSS (Hank’s buffered salt solution; Sigma, H8264) cont. 5 mM alanine (referred in here as HBSS/Ala) and afterwards the following reagents are added: 1. 80 ul/wellHBSS/Ala 2. 20 ul/well of HBSS/Ala containing 6x the concentration of compound in 6% DMSO 3. approx. 5-10 min incubation 4. 20 ul/well 3 uM glycine (3H-glycine (Perkin Elmer, 001MC, specific ty: 52 Ci/mmol; diluted 1:1 with unlabelled glycine) in HBSS/Ala.

In the final assay, e concentration is 500 nM (250 nM derived from the 3H-glycine Perkin Elmer, 250 nM unlabelled glycine), DMSO concentration is 1%.

The assay plate is immediately after addition of the 3H-glycine placed into a Micro-Beta Counter (Perkin Elmer) and the signal is recorded over 60 min.

WO 55698 To calculate uptake, the slope in the linear range of the kinetics is determined using GraphPadPrism and for the different slopes at the selected concentrations IC50 are calculated by curve fitting using the software GraphPadPrism.

Maximal e uptake in every experiment is determined by incubation of SK—N—MC cells with substrate but without inhibitor. Unspecific uptake of glycine by the cells is determined by incubating the cells with substrate and a reference GlyTl inhibitor e.g. lO uM RG-1678 (Pinard et al., 2010, J. Med. Chem. 53(12):4603-14).

Compounds are diluted from 10 mM stocks and in general, for IC50 determination 8 compound trations are used.

Table: ICSO data e number ICSO [nM] Example number ICSO [nM] 1 4 82 9 2 5 83 27 3 9620* 84 19 4 9 85 60 5 86 46 6 175 87 10 7 9 88 48 8 4 89 14 9 680 90 30 11 91 41 11 6 92 9 12 180 93 8 13 5 94 6 14 5 95 40 2972* 96 3 16 4o 97 4 WO 55698 -3 9- Example number ICSO [nM] Example number ICSO [nM] 17 35 98 7 18 4 99 3 19 84 100 7 133 101 6 21 5 102 3 22 57 103 87 23 56 104 18 24 98 105 24 23 106 8 26 11 107 12 27 14 108 37 28 103 109 18 29 20 110 40 60 111 7 31 4 112 242 32 4 113 9 33 31 114 10 34 30 115 153 9 116 125 36 93 117 7 37 69 118 32 38 16 119 180 39 11 120 38 40 142 121 1 41 62 122 3 42 2 123 6 43 69 124 10 44 101 125 15 45 11 126 15 WO 55698 Example number ICSO [nM] Example number ICSO [nM] 46 49 127 17 47 60 128 17 48 53 129 20 49 76 130 20 50 8 131 21 51 1 132 31 52 118 133 32 53 73 134 34 54 22 135 34 55 38 136 35 56 183 137 44 57 39 138 49 58 14 139 134 59 17 140 166 60 6 141 252 61 112 142 266 62 25 143 292 63 202 144 306 64 27 145 527 65 19 146 556 66 21 147 607 67 255 148 1 68 22 149 83 69 257 150 4 70 53 151 141 71 4 152 59 72 47 153 221 73 13 154 124 74 4 155 87 Example number IC50 [nM] e number IC50 [nM] 75 157 156 451 76 3 157 9 77 6 158 6 78 333 159 8 79 6 160 21 80 53 161 36 81 8 * The low solubility of the compound might have an impact on the determination of the IC50 values.

Compounds with an IC50 value of between 1 and 1000 nM are preferred, more preferred are active compounds with an IC50 value of n 1 and 100 nM, more red are compounds with an IC50 value of between 1 and 20 nM.

In-vivo effect: It is believed that the positive in-vz’tro efflcacy results of the active compounds of the present invention translate in positive in-vz’vo efficacy.

The in-vz’vo effect of the active compounds of this invention can be tested regarding e increase in CSF according to Perry et al. 2008 (Neuropharmacology 55:743-754), in the psychostimulant-induced hyperlocomotion test according to Boulay et al. 2008 acol. Biochem. Behav. 91 :47-5 8) or the social recognition test ing to Shimazaki et al. 2010 (Psychopharmacology 209: 263-270). For fiarther information concerning biological testing, it is also referred to these three citations.

Besides the inhibition property toward the target GlyTl transporter, active compounds ing to the present invention may provide fiarther advantageous pharmacokinetic properties.

E.g. active compounds according to the invention may show one or more advantages in the area of safety, low risk of causing drug - drug interaction and low clearance.

Active compounds according to the invention also might show one or more additional or ative advantages in the area of bioavailability, high fraction absorbed, blood brain transport properties, a able (e.g. high mean) mean residence time (mrt), favourable exposure in the effect compartment (Cerebrospinal fluid).

On the basis of the above mentioned features, active compounds according to the ion are believed to be suited for once daily administration for the treatment of diseases Where an adequate exposure in the cerobrospinal fluid is considered to be essential.

CHEMICAL MANUFACTURE Abbreviations: Ac Acetyl ACN itrile APCI Atmospheric re chemical ionization (in MS) amu atomic mass unit Boc ter-butyloxycarbonyl Burgess reagent: ycarbonylsulfamoyl-triethyl ammonium hydroxide inner salt CD1 1 l ’-carbonyldiimidazole d day dba dibenzylideneacetone DCM dichloromethane DIPEA diisopropylethylamine DME l ,2-dimethoxyethane DMF dimethylformamide ESI electrospray ionization (in MS) EtOAc ethylacetate EtOH ethanol EtzO diethylether Exp . example h hour(s) HATU zabenz0triaz0 lyl)-N,N,N’,N’-tetramethylur0nium— hexafluorophosphate HPLC high performance liquid chromatography HPLC-MS coupled high performance liquid tography-mass spectrometry IPA isopropyl alcohol M molar (mo l/L) MeOH methanol min minute(s) MS mass spectrometry 1 -methylpyrrolidin0ne reverse Phase room temperature retention time (in HPLC) TBTU O-(benzotriazo lyl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate TEA ylamine TFA trifluoroacetic acid THF tetrahydrofilran TLC ayer chromatography UPLC- MS ultra performance liquid chromatography - mass spectrometry Methods: UPLC-MS methods: Method 1 Instrument: LC/MS Waters Acquity UPLC System DAD, SQD single quadrupole; column: HSS C18 1,8 um 2,1 x 50 mm, Temp 35°C; mobile phase: A = H20 90% + 10% CH3CN + CF3COOH 0,1%, B = CH3CN 90% + H20 10%; gradient: 0.0 min 0% B —> 1.20 min WO 55698 100% B —> 1.45 min 100% B —> 1.55 min 0% B —> 1.75 min 0% B; flow rate: 0.70 mL/min; detection: UV 254 nm; detection: SQD, single quadrupole; ion source: ES+/ ES-; scan range: 90-900 amu Method 2 Instrument: LC/MS Waters Acquity UPLC System DAD, SQD single quadrupole; column: BEH C18 1,7um 2,1 x 50 mm, Temp 35°C; mobile phase: A = H20 90% + 10% CH3CN + NH4COOH 5 mmol, B = CH3CN 90% + H20 10%; gradient: 0.0 min 0% B —> 1.20 min 100% B —> 1.45 min 100% B —> 1.55 min 0% B —> 1.75 min 0% B; flow rate: 0.70 mL/min; detection: UV 254 nm; detection: SQD, single quadrupole; ion source: ES+/ ES-; scan range: 90-900 amu Method 23 Instrument: LC/MS Waters Acquity UPLC System DAD, SQD single quadrupole; column: BEH C18 1,7um 2,1 x 50 mm, Temp 35°C; mobile phase: A = H20 90% + 10% CH3CN + NH4COOH 5 mmol, B = CH3CN 90% + H20 10%; nt: 0.0 min 0% B —> 2.40 min 100% B —> 2.70 min 100% B —> 2.80 min 0% B —> 3.00 min 0% B; flow rate: 0.70 mL/min; detection: UV 254 nm; detection: SQD, single quadrupole; ion source: ES+/ ES-; scan range: 90-900 amu GC-MS methods: Method 3 Instrument: GC/MS Thermo Scientific TRACE GC ULTRA, DSQ II MS single quadrupole; column: Agilent DB-5MS, 25m x 0.2 5 mmol x 0.25 um; carrier gas: , 1 mL/min constant flow; oven program: 50°C, to 100°C in in, to 200°C in °C/min, to 320°C in 30°C/min (hold 10 min); detection: DSQ II MS single quadrupole; ion source: EI; scan range: 50- 450 amu HPLC-MS methods: WO 55698 Method 4 Instrument: LC/MS ThermoFinnigan. lec Surveyor DAD, MSQ Quadrupole; column: Synergi Hydro RP100A, 2.5 um, 3 X 50 mm; eluent A: 90% water + 10% ACN + ammonium formate 10 mM; eluent B = ACN 90%+10% H20 + NH4COOH 10 mM; nt: 0.0 min 0% B —> 1.50 min 0% B —> 8.00 min 100% B —> 10.00 min 100% B —> 11.00 min 0% B —> 12.00 min 0% B; flow rate: 0.7 mL/min; UV Detection: 254 nm; Ion source: APCI+/ APCI- Method 5 Instrument: LC/MS ThermoFinnigan HPLC Surveyor DAD, MSQ single pole; Column: i Hydro RP100A, 2,5 um, 3 x 50 mm; Eluent A : 90% water + 10% ACN + NH4COOH 5 Mm; eluent B = ACN 90% + 10% H20; gradient: 0.0 min 0% B —> 4 min 100% B —> 5.30 min 100% B —> 5.50 min 0% B —> 6.00 min 0% B; flow rate: 1.2 mL/min; UV Detection: 254 nm; Ion source: APCI+/ APCI-; scan range 100-900 amu Method 6 Instrument: LC/MS ThermoFinnigan HPLC Surveyor DAD, LCQFleet Ion Trap Column: Symmetry Shield RPS, 5 um, 4,6 x 150 mm; Eluent A: 90% water + 10% ACN + HCOOH 0.1%; eluent B: ACN 90% + H20 10% + HCOOH 0.1%; gradient: 0.0 min 5% B —> 1.5 min 5% B —> 11.05 min 95% B —> 13 min 95% B —> 13.03 min 5% B —> 15 min % B; flow rate: 1.0 mL/min; UV Detection: 254 nm, Finnigan Fleet, Ion Trap; Ion : ES+; scan range 100-900 amu Method 10 Instrument: LC/MS ThermoFinnigan HPLC Surveyor DAD, LCQFleet Ion Trap Column: Synergy Xselect CSH, 2.5 um, 4.6 x 50 mm; Eluent A: 90% water + 10% ACN + HCOOH 0.1%; eluent B: ACN 90% + H20 10% + HCOOH 0.1%; gradient: 0.0 min 0% B —> 4 min 100% B —> 5.30 min 100% B —> 5.50 min 0% B —> 6.00 min 0% B; flow rate: 1.4 mL/min; UV Detection: 254 nm, Finnigan Fleet, Ion Trap; Ion source: ES+; scan range 100-900 amu Method 7 Instrument: LC/MS Waters ce 2695 HPLC System DAD, Quattro Micro Triple quadrupole; Column: Xbridge Phenyl 3.5um 3X 30 mm, Temp 35°C; Eluent A: 90% 2014/072085 water + 10% ACN + NH4HC03 5mM; eluent B: ACN 90% + H20 10%; gradient: min 0% B—> 4.5 min 100% B—> 5.80 min 100% B—> 6.0 min 0% B; flow rate: 1.3 mL/min; UV Detection: 254 nm, Quattro Micro, triple quadrupole, Ion source: ES+/—; scan range 90- 1000 amu.

Method 8 ment: LC/MS Waters Alliance 2695 HPLC System DAD, Quattro Micro Triple quadrupole; Column: Gemini 3 um 4.6 X 50 mm, Temp 35°C; Eluent A: 90 % water + 10 % ACN + CF3COOH 0.1 %; eluent B: ACN gradient: 0.0 min 0% B—> 3.5 min 90% B—> 4.5 min 90% B—> 4.6 min 0% B; flow rate: 1.3 mL/min; UV Detection: 254 nm, Quattro Micro, triple quadrupole, Ion source: ES+/—; scan range 120-900 amu Method 11 Instrument: LC/MS Waters Alliance 2695 HPLC System DAD, Quattro Micro Triple quadrupole; Column: SunFire C18 3.5 um 4.6 X 50 mm, Temp 35°C; Eluent A: 90 % water + 10 % ACN + CF3COOH 0.05 %; eluent B: 90% ACN + 10% water gradient: 0.0min 0% B—> 4.5 min 100% B—> 5.8 min 100% B—> 6.0 min 0% B; flow rate: 1.3 mL/min; UV Detection: 254 nm, Quattro Micro, triple quadrupole, Ion source: ES+/—; scan range 90- 1000 amu.

Method 14 Instrument: LC/MS ThermoFinnigan HPLC or DAD, MSQ single pole; Column: Synergi Hydro RP100A, 2,5 um, 3 X 50 mm; Eluent A : 90% water + 10% ACN + NH4COOH 5 Mm; eluent B = ACN 90% + 10% H20; gradient: 0.0 min 0% B —> 1.50 min —> 0% B —> 9 min 100% B —> 10.50 min 100% B —> 11 min 0% B —> 12 min 0% B; flow rate: 1.2 mL/min; UV Detection: 254 nm; Ion source: APCI+/ APCI-; scan range 100- 900 amu.

Method 16 Instrument: LC/MS Waters Alliance 2695 HPLC System DAD, o Micro Triple quadrupole; Column: Atlantis dCl8 5 um 4.6 X 50 mm, Temp 35°C; Eluent A: 90 % water + 10 % ACN + CFgCOOH 0.05 %; eluent B: 90% ACN + 10% water gradient: 0.0 min 0% B —> 0.7 min 0% B —> 4.5 min 100% B—> 5.8 min 100% B—> 6.0 min 0% B; flow rate: 1.3 mL/min; UV ion: 254 nm, Quattro Micro, triple quadrupole, Ion source: ES+/—; scan range 90-1000 amu.

Method 17 Instrument: LC/MS Waters Alliance 2695 HPLC System DAD, Quattro Micro Triple pole; Column: zorbaX Eclipse XDB-C18 3.5 um 4.6 X 50 mm, Temp 35°C Eluent A: 90 % water + 10 % ACN + NH4COOH 5nM; eluent B: 90% ACN + 10% water gradient: 0.0 min 0% B —> 4.50 min 100% B —> 5.8 min 100% B—> 6.0 min 0% B; flow rate: 1.3 mL/min; UV Detection: 254 nm, Quattro Micro, triple quadrupole, Ion : ES+/—; scan range 90-1000 amu.

Method 18 Instrument: LC/MS Waters 1525 with DA- and MS-Detector, Column: Sunfire C18_4.6 X mm, 2.5 um, Temp 60°C, Eluent A: Water + CF3COOH 0.1 %; eluent B: MeOH; gradient: 0.0 min 5% B (4 mL/min) —>0.05 min 5% B (3 mL/min) —> 2.05 min 100% B (3 mL/min) —> 2.1 min 100% B (4.5 mL/min) —> 2.4 min 100% B (4.5 mL/min).

Method 19 Instrument: LC/MS Waters 1525 with DA- and MS-Detector, Column: Sunfire C18_4.6 X mm, 2.5 um, Temp 60°C, Eluent A: Water + CF3COOH 0.1 %; eluent B: Acetonitrile; gradient: 0.0 min 3% B (4 mL/min) —>0.15 min 3% B (3 mL/min) —> 2.15 min 100% B (3 mL/min) —> 2.2 min 100% B (4.5 mL/min) —> 2.4 min 100% B (4.5 mL/min).

Method 20 Instrument: Agilent 1200 with DA- and MS-Detector, Column: XBridge C18_3.0X30mm, 2.5um, Temp 60°C, Eluent A: Water + NH4OH 0.1 %; eluent B: itrile; gradient: 0.0 min 3% B (2.2 mL/min) —>0.2 min 3% B (2.2 ) —> 1.2 min 100% B (2.2 mL/min) —> 1.25 min 100% B (3 mL/min) —> 1.4 min 100% B (3 mL/min).

Method 21 Instrument: Agilent 1100 with DAD, Waters Autosampler and MS-Detector, Column: e C18_4.6 X 30 mm, 3.5 um, Temp 50°C, Eluent A: Water + H 0.1 %; eluent B: Acetonitrile; gradient: 0.0 min 5% B (4 mL/min) —>1.2 min 100% B —> 1.8 min 100% B; flow rate: 4 mL/min; Method 22 Instrument: Agilent 1100 with DAD, CTC Autosampler and Waters MS-Detector; Column: e C18_4.6 X 30 mm, 3.5 um, Temp 60°C; Eluent A: Water + NH4OH 0.1 %; eluent B: Acetonitrile; gradient: 0.0 min 2% B (4 mL/min) —>1.5 min 100% B —> 1.8 min 100% B; flow rate: 2.5 mL/min; Method 27 Instrument: LC/MS ThermoFinnigan HPLC or DAD, MSQ single quadrupole; : Synergi Hydro RP100A, 2,5 um, 3 x 50 mm Eluent A : 90% water + 10% ACN + NH4COOH 10 Mm; eluent B = ACN 90% + 10% H2O + NH4COOH 10 Mm; gradient: 0.0 min 0% B —> 6.50 min 100% B —> 7.50 min 100% B —> 8.0 min 0% B —> 9.00 min 0% B; flow rate: 1.2 mL/min; UV Detection: 254 nm; Ion source: APCI+/ APCI-; scan range 100-900 amu Chiral HPLC methods: Method 9 HPLC apparatus type: Agilent 1100; column: Daicel pack AD-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 70:30; flow rate: 1 mL/min, Temperature: 25°C; UV Detection: 254 nm Method 12 HPLC apparatus type: Agilent 1100; column: Daicel chiralpack IA, 5.0 um, 250 mm x 10 mm; method: eluent /IPA 60:40; flow rate: 1 mL/min, Temperature: 25°C; UV Detection: 254 nm Method 13 HPLC apparatus type: Agilent 1100; column: Daicel chiralpack IA, 5.0 um, 250 mm x 10 mm; method: eluent hexane/IPA 60:40; flow rate: 1 mL/min, Temperature: 25°C; UV Detection: 230 nm Method 15 HPLC tus type: Agilent 1100; column: Daicel chiralpack IA, 5.0 um, 250 mm x 10 mm; method: eluent hexane/IPA 70:30; flow rate: 1 mL/min, Temperature: 25°C; UV Detection: 230 nm Method 24 HPLC apparatus type: Agilent 1100; column: Daicel cel OD, 5.0 um, 250 mm X 10 mm; method: e1uent hexane/IPA 90: 10; flow rate: 0.5 mL/min, Temperature: 25°C; UV Detection: 230 nm Method 25 HPLC apparatus type: Agilent 1100; column: Daicel chiralcel O], 4.6 um, 250 mm X 10 mm; method: eluent hexane/ethanol 97:3; flow rate: 1 mL/min, Temperature: 25°C; UV Detection: 230 nm Method 26 HPLC apparatus type: Agilent 1100; column: Daicel pack AD-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 80:20; flow rate: 1 mL/min, Temperature: 25°C; UV Detection: 230 nm Microwave heating: Discover® CEM instruments, equipped with 10 and 35 mL vessels.

General comment concerning the presentation of the structures Compounds with stereogenic centre(s): If a chemical structure ses one stereogenic centre and if no stereochemical tions (e. g. by chemical designators, perspective drawings etc.) are given, then that structure refers to the racemic mixture.

According to the synthetic Schemes 3 and 4, starting from enantiopure starting materials is possible to obtain the final compounds with known te configuration; the before mentioned synthetic approaches have been used in the synthesis of examples 74 and 75 in order to establish the absolute configuration of the more active enantiomer. The absolute configuration of Example 74 is R and the absolute ration of Example 75 is S.

With the exception of examples 74 and 75 having known absolute ration, a perspective drawing is intended to indicate a single enantiomer but not the absolute configuration.

Example 1a / \ Br Pyridinium bromide perbromide (7.0 g, 21.9 mmol) is added to a solution of 1-(5-Fluorothiophenyl )-ethanone (3.0 g, 20.8 mmol) dissolved in 75 ml of trichloromethane and the resulting mixture is stirred 3 hours.

EtzO and H20 are added, phases are separated then the organic layer is washed with brine, dried and concentrated under reduced pressure. The residue is purified by Silica gel flash chromatography using cyclohexane/EtOAc 95:5 as eluent to obtain the title compound (3.3 g, 69% yield).

GC-MS (Method 3): R = 8.26 min MS (EI): m/z = 224 [M]+ Example lb / \ Br H3C S A solution of Bromoacetylbromide (1.6 ml, 18.8 mmol) dissolved in 10 ml of DCM is added dropwise to a d solution of triethylamine (5.2 ml, 37.6 mmol) dissolved in 50 ml ofDCM. Afier 20 minutes stirring, a on of 2-Methylthiophene (1.2 g, 12.5 mmol) is added and the reaction mixture is stirred overnight. 50 ml of icy water are added and afier 30 minutes stirring the mixture is extracted with DCM. The organic layer is separated, washed with brine, dried and concentrated under reduced pressure. The residue is d by silica gel flash chromatography, using cyclohexane/EtOAc 95:5 to 70:30 as eluent, to obtain 1.7 g of the title compound.

UPLC-MS (Method 1): R = 1.07 min MS (ES+): m/z = 1 [M+H]+ Example 2a (racemic mixture) win] A solution of -1,2-diamine (4.8 ml, 71.8 mmol) dissolved in 10 ml of dioxane is added dropwise, under nitrogen atmosphere, to a 0°C cooled solution of example 1a (3.3 g, 14.4 mmol) dissolved in 50 ml of e. The resulting mixture is stirred overnight at room temperature. The solvent is d under reduced pressure, the residue is dissolved in 60 ml of methanol and 3 ml of water; the solution is then cooled at 0°C, boronhydride (2.7 g, 71.8 mrnol) is added portionwise and the reaction mixture is stirred overnight at room temperature. 50 ml of 1N HCl solution are added; the reaction mixture is d during 15 minutes and methanol is removed under reduced pressure.

DCM followed by NaOH aqueous on (basic pH needs to be reached) is added; the phases are separated and the aqueous layer is extracted three times with DCM; the organic phase is dried and and the solvents removed under reducedpressure.

The residue is purified by Silica gel flash chromatography using as eluent DCM/MeOH/NH4OH (from 95:5:1 to 80:20:1) to obtain the title compound (2.7 g, 53% yield).

GC-MS (Method 3): Rt = 9.30 min MS (EI): m/z = 186 [M]+ Example 2b (racemic mixture) / \ ZI S I WO 55698 Bromoacetylbromide (3.1 ml, 35.7 mmol) dissolved in 10 ml of anhydrous DCM is added to a stirred suspension of aluminum chloride (7.0 g, 52.5 mmol) in 80 ml of anhydrous DCM and the mixture is stirred 20 s. 2-Iodothiophene (2.6 ml, 23.8 mmol) dissolved in 10 ml of anhydrous DCM is added dropwise and the resulting mixture is stirred overnight. The reaction is cooled with an ice/water bath, water is added and the mixture is extracted with DCM; the organic layer is separated, washed with brine, dried and concentrated under reduced pressure. The residue is purified by Silica gel flash chromatography using cyclohexane/EtOAc 95:5 as eluent to give 1.9 g of intermediate 2- Bromo(5-iodo-tiophenyl)-ethanone. The title compound is synthesized as described for example 2a using ethane-1,2-diamine (2.1 ml, 31.7 mmol) dissolved in 10 ml of e, 2-Bromo-l-(5-iodo-tiophenyl)-ethanone (1.9 g, 5.8 mmol)dissolved in 40 ml of dioxane, sodiumborohydride (655 mg, 17.3 mmol), 50 ml of methanol and 2 ml of water, to give 720 mg (40% yield) of pure product.

HPLC-MS (Method 5): R = 2.28 min MS (APCI+): m/z = 295 [M+H]+ General ure for examples 3b to 3h: Tetrakis(Triphenylphosphine)Palladium(0) (l-3% mol) is added to a mixture of 2- Chloropyrazine (1 eq), Aryl/Heteroaryl boronic acid (1 eq) and base (2 eq) suspended into the solvent. The reaction e is heated until the on is completed, the solvent is removed under reduced pressure and the residue is partitioned between water and EtOAc (or 1N aqueous NaOH and EtOAc); organic layer is separated, dried, concentrated under d pressure and the e is purified by Silica gel flash chromatography using a suitable eluent.

WO 55698 Product Rt [m1n],. (E81 + or Example Product Reactant, Base Solvent, temperature amount, method APCI+, y1eld. m/z) F QC Dioxane (40 ml), 3.1 g, 1.08 min, 3b N HO\B F E /\ F 193 OH (3g), Water (10 ml), 80°C 59% method 1 Cs2C03 (11.4 g) \F1 Anh drous 1,2-y OH F N (3.5 3.2 g, 1.02 min, E \ F Dimethoxyethane 193 g) 76% method 2 N/ (60 ml), 85°C Na2C03 (2N aq. solution, 21.8 ml) "Ox g Dioxane (40 ml) 2.5 1.04 min, , , 3d N\ E? g E / 193 OH F (3g), Water (10 ml), 70°C 72% method 1 Cs2C03 (11.4 g) "013$ Anhydrous 1,2- 1 4.0 g, 0.96 mm, 3e OH F E /\ (3.5 g) D1methoxyethane. 175 92% method 2 N NaZCO3 (2N aq. (120 ml), 80°C solution, 25 ml) N HO\B©\F Dioxane (60 ml), 3.7 g, 1.05 min, 3f E /\ F 1 175 OH (2.6 Water (15 ml), 80°C 80% method 1 g), Cs2CO3 (11.4 g) HO\BO Dioxane (60 ml), 3.0 g, 1.02 min, 3g E /\ 1 175 0H (3.9 Water (15 ml), 70°C 99% method 1 g), Cs2CO3 (11.4 g) HO\ F 1‘3 Dloxane (60 ml),. 2.8 g, 1.18 mm,- 3h N E / F \ OH F 225 o 0 F Water (12 ml), 70 C 84%) method 2 F (2.9 g), Cs2C03 (9.6 General procedure for es 31' to 3p (racemic mixture) sis: Example 3b to 3h are dissolved into the solvent, catalyst (10% W/W) is added and the resulting mixture is hydrogenated using a Parr equipment (starting sz 4 bar) until reaction is complete. The mixture is d over a celite pad, the filtrate is concentrated under reduced pressure and the residue is used Without further purification (for reactions performed in acetic acid the residue is then partitioned between DCM and aqueous NaOH and concentrated under reduced pressure).

Product Rt [min], (E81 + or Example Product Reactant, Catalyst Solvent, reaction time. . amount, method APCI+, m/z) 3b (3.0g), 10% Acetic acid (70 m1), 6 0.57 min, 33‘ N E F 2.6 g 199 Pd/C (300 m g) hours method 1 ( 1.9 g),10‘V0 Ethanol (50 m1, 3) 0.34 min, 3k N E F 1.8 g 199 Pd/C (200 m g) hours method 1 3d 2.5 10W0 Acetic acid 60 m1 3 0.44 min, 31 N ( g) , ( ) , 2.1 g 199 Pd/C (250 m g) hours method 1 36 , 10% 0.42 min, 3m E Acetic acid, 4 hours 4.0 g 181 Pd/C (400 m g) method 2 Ethanol (100 m1), N 3f(3.0 g), 10% 0.53 min, 3n E F water (20 ml), 72 2.9 g 181 Pd/C (300 m g) method 1 N hours Ethanol (100 ml), 3g (3.8 g), 10% 0.26 min, E water (10 ml), 24 3.8g 181 Pd/C (300 m g) method 1 N hours -5 5 _ Product Rt [min], (E81 + or Example Product Reactant, Catalyst Solvent, reaction time. . amount, method APCI+, m/z) 3h (2.8 g), 10% Ethanol (80 ml), 24 0.67 min, N F 3p E 2.8 g 231 F Pd/C (300 m g) hours method 2 e 3r (racemic mixture): S N] CI \IH Ethane-1,2-diamine (15.4 ml, 230 mmol) ved in 40 ml of anhydrous dioxane is added to at 5°C cooled solution of 2-Bromo(5-Chloro-Thiophenyl)—ethanone (10 g, 41.7 mmol) dissolved in 120 ml of anhydrous dioxane; the reaction mixture is stirred overnight at room temperature; 30 ml of MeOH and 2 ml of water are added, the reaction mixture is cooled to 0°C then boronhydride (4.4 g, 117 mmol) is added portionwise and the reaction mixture is stirred at room temperature 3 hours. The crude is poured in 160 ml of % aqueous HCl solution, washed with EtOAc then the aqueous layer is d by addition of 36% aqueous NaOH on and extracted with DCM. The organic layer is separated and concentrated under reduced pressure to obtain the title compound as crude (7.2 g).

UPLC-MS (Method 1): R = 0.53 min MS (ES+): m/z = 203 [M+H]+ Example 35 (racemic mixture) s N] H30 \ I H Example 3s is synthesized as described for e 3r starting from example lb (1.7 g, 6.4 mmol), instead of 2-Bromo(5-Chloro-Thiophenyl)-ethanone, ethane-1,2-diamine (2.4 ml, 35.4 mmol) and sodiumborohydride (731 mg, 38 mmol); after the work-up the crude is purified by silica gel flash chromatography, using DCM/MeOH/NH4OH (98202 to 80202) as eluent, to obtain the title compound (340 mg, 28% yield).

UPLC-MS (Method 1): R = 0.37 min MS (ES+): m/z = 183 [M+H]+ Example 14a W1N N N_ 3 Tetrakis(triphenylphosphine)palladium(0) (751 mg, 0.65 mmol) is added, under nitrogen here, to a solution of 2-(tributylstannyl)pyrazine (2.4 g, 6.5 mmol) and 2-bromo methylthiazole (2.3 g, 13.0 mmol), in 40 ml of dry toluene previously degassed bubbling nitrogen for 15 minutes and the reaction is refluxed 15 hours. Solvent is removed, the residue is suspended in EtzO and the precipitate is filtered off. Filtrate is trated under d pressure and the residue is purified by Silica gel flash cromatography using EtOAc/cyclohexane (from 10:90 to EtOAc 100%) as eluent to obtain the title nd (516 mg, 44% yield).

UPLC-MS (Method 2): R = 0.92 min MS (ES+): m/z =178[M+H]+ Example 15a ic Example 15b (racemic mixture mixture H309—CH3 H N>=O N N 94.1 O=< CH3 o H3 H3C—60H3 CH3 Palladium (70 mg, 10% on carbon) suspended in 5 ml of acetic acid is added to a solution of example 14a (516 mg, 2.85 mmol) in 20 ml of acetic acid, and the reaction is stirred under hydrogen atmosphere (4 bar) overnight. Platinum (IV) oxide hydrate (50 mg) is added and the mixture is further hydrogenated in the same ions for 24 hours. The catalyst is filtered off over a celite pad, the mixture is concentrated under reduced pressure and the residue is loaded over a SCX cartridge. The obtained product is dissolved in 8 ml ofDCM, cooled at 5°C and a on of di-tert-butyl-dicarbonate (561 mg, 2.57 mmol) in 2 ml of DCM is then added. After 1 hour stirring, aqueous NaHC03 is added, the organic layer is separated and concentrated under reduced pressure then the residue is purified by Silica gel flash cromatography using cyclohexane/EtOAc ( from 90: 10 to EtOAc 100%) as eluent to give example 15a (225 mg, 21% yield) and impure example 15b that is further d by RP flash chromatography to obtain 50 mg (6% yield) of the desired compound.

Example UPLC-MS (Method 2): Rt [min] MS (ES+): m/z 15a 1.34 384 15b 0.95 284 Example 16a (racemic mixture) N \ [NJ/LS CH3 HCl (4N dioxane solution, 2.9 ml, 11.7 mmol) is added to a solution of example 15a (225 mg, 0.59 mmol) dissolved in 6 ml of dioxane and the reaction mixture is stirred at room temperature overnight. Solvent is d under d pressure and the crude is purified over an SCX cartridge to give the title compound (90 mg, 84% yield).

UPLC-MS (Method 2): R = 0.44 min MS (ES+): m/z +H]+ Example 27a (racemic mixture) N /’ 81:1 e 30 (100 mg, 0.55 mmol), 2-ChloroFluoropyridine (67 ul, 0.67 mrnol), X-Phos (106 mg, 0.22 mmol), Tris(dibenzylideneacetone)dipalladium(0) (102 mg, 0.11 mmol) and sodium tert-butoxide (107 mg, 1.11 mmol) are ded under nitrogen atmosphere in 2 ml of previously degassed dioxane then the reaction mixture is heated in a microwave reactor, at 80°C, during 2 hours.

The crude reaction mixture is filtered and then purified by preparative HPLC-MS to obtain the title compound (102 mg, 67 % yield) UPLC-MS (Method 1): R = 0.78 min MS (ES+): m/z = 276 [M+H]+ Example 28a (racemic mixture) example 30 (100 mg, 0.55 mmol), 2-Chloropyrimidine (76.3 mg, 0.67 mmol) and N,N- diisopropylethylamine (192 ul, 1.11 mmol) are dissolved in 1 ml of DMSO and the reaction mixture is heated in a microwave reactor 30 minutes at 120°C. The crude t is partitioned between EtzO and water; the organic layer is then separated and concentrated under reduced pressure to obtain the title compound (158 mg).

UPLC-MS (Method 2): R = 0.76 min MS (ES+): m/z = 259 [M+H]+ Example 29a (racemic mixture) F/©):NjH Example 29a is synthesized as described for e 28a using example 30 (100 mg, 0.55 mmol), 2-ChloroFluoropyrimidine (82 ul, 0.67 mmol) instead of 2-Chloropyrimidine, N,N—diisopropylethylamine (192 ul, 1.11 mmol) and 1 ml ofDMSO. The crude t is partitioned between EtzO and water; the organic layer is then separated and concentrated under reduced pressure to obtain of the title compound (160 mg).

UPLC-MS (Method 2): R = 0.98 min MS (ES+): m/z = 277 [M+H]+ Example 30a ic mixture) Example 30a is synthesized as described for example 28a using e 30 (600 mg, 3.3 mmol), 2-Bromo(Trifluoromethyl)pyrazine (907 mg, 4.0 mmol) instead of 2- Chloropyrimidine, N,N—diisopropylethylamine (1.1 ml, 6.7 mmol) and 8 ml ofDMSO. The mixture is heated in a microwave reactor at 100°C during 2.5 hours. The crude product is partitioned n EtOAc and water then the organic layer is separated and concentrated under reduced pressure; the residue is purified by Silica gel flash chromatography, using EtOAc/Cyclohexane 1:1 to EtOAc 100% as eluent, to obtain the title compound (800 mg, 72 % yield).

HPLC-MS (Method 5): R = 3.21 min MS (APCI+): m/z = 327 [M+H]+ Example 31a (racemic mixture) @131 Example 31a is synthesized as described for example 27a using e 30 (300 mg, 1.67 mmol), 5-Bromo(Trifluoromethyl)pyrimidine (453 mg, 2.00 mmol) instead of 2-Chloro- -Fluoropyridine, X-Phos (317 mg, 0.67 mmol), Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (345 mg, 0.33 mmol), sodium tert-butoxide (320 mg, 3.33 mmol) and 4 ml ofpreViously ed dioxane. The mixture is heated in a microwave reactor during 2 hours at 100°C. The crude is partitioned between EtOAc and water, the organic phase is separated, dried and concentrated under reduced pressure; the residue is then purified by Silica gel flash chromatography using Cyclohexane/EtOAc 50:50 to 0:100 as eluent to obtain the title compound (175 mg, 32 % yield) HPLC-MS (Method 5): R = 3.10 min MS (APCI+): m/z = 327 [M+H]+ e 32a (racemic mixture) F \IH Example 32a is synthesized as described for example 27a using example 2a (70 mg, 0.38 mmol) instead of example 30, 5-Bromo(Trifluoromethyl)pyrimidine (102 mg, 0.45 mmol) instead of 2-ChloroFluoropyridine, X-Phos (72 mg, 0.15 mmol), Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (78 mg, 0.08 mmol) sodium tert-butoxide (72 mg, 0.75 mmol) and 1.5 ml ofpreViously degassed dioxane. The mixture is heated in a microwave reactor 2 hours at 100°C. The crude is partitioned between EtOAc and 1N aqueous HCl, the aqueous phase is separated, basified by addition of 32% aqueous NaOH then it is ted with EtOAc; the c layer is dried and concentrated under reduced pressure to obtain the title nd (175 mg) that is used as such without further purification.

UPLC-MS (Method l): R = 0.83 min MS (ES+): m/z = 333 [M+H]+ -62— Example 33a (racemic mixture) S j CI \/H e 33a is synthesized as bed for example 28a using example 3r (150 mg, 0.67 mmol) instead of example 30, 2-BromoMethylpyrazine (127 mg, 0.73 mmol) d of 2-Chloropyrimidine, N,N-diisopropylethylamine (289 ul, 1.66 mmol) and 1 ml of DMSO.

The mixture is heated in a microwave reactor 1 hour at 165 oC. The crude product is partitioned between DCM and water then the organic layer is separated and concentrated under reduced pressure; the residue is purified by Silica gel flash chromatography using as eluent DCM/MeOH 100:0 to 90: 10 to obtain the title compound (75 mg, 34 % yield).

UPLC-MS (Method 1): R = 0.71 min MS (ES+): m/z = 295 [M+H]+ Example 34a (racemic mixture) N /N Example 34a is synthesized as described for example 28a using example 3r (100 mg, 0.44 mmol) instead of e 30, 2-Chloromethylpyrimidine (74 mg, 0.58 mmol) instead of 2014/072085 2-Chloropyrimidine, N,N-diisopropylethylamine (307 ul, 1.78 mmol) and 1 ml of DMSO.

The mixture is heated in a microwave reactor during 30 minutes at 120°C. The crude product is purified by preparative HPLC-MS to obtain the title nd as trifluoroacetate salt (55 mg, 30 % yield) UPLC-MS (Method 1): R = 0.81 min MS (ES+): m/z = 295 [M+H]+ Example 35a (racemic mixture) 3 1 CI \IH Example 35a is synthesized as described for example 28a using example 3r (80 mg, 0.36 mmol) instead of e 30, 2-ChloroCyclopropylpyrimidine (73 mg, 0.46 mmol) instead of 2-Chloropyrimidine, N,N—diisopropylethylamine (122 ul, 0.71 mmol) and 1 ml of DMSO. The mixture is heated in a microwave reactor during 30 s at 140°C. The crude product is purified by preparative HPLC-MS to obtain the title compound as trifluoroacetate salt (72 mg, 47 % yield) UPLC-MS (Method 1): R = 0.89 min MS (ES+): m/z = 321 [M+H]+ Example 36a (racemic mixture) (51:1 Example 36a is sized as described for example 27a using example 3m (290 mg, 1.61 mmol) instead of example 30, 5-Bromo(Trifluoromethyl)pyrimidine (440 mg, 1.94 mmol) instead of 2-ChloroFluoropyridine, clohexylphosphino-2’-(N,N— dimethylamino)biphenyl (220 mg, 0.56 mmol) instead of X-Phos, Tris(dibenzylideneacetone)dipalladium(0) (140 mg, 0.15 mmol), potassium tert-butoxide (270 mg, 2.41 mmol) and 2 ml of DMSO. The mixture is heated in a microwave reactor during 40 minutes at 120°C. The crude is partitioned between EtOAc and water, the organic phase is ted, dried and concentrated under reduced pressure then the residue is purified by Silica gel flash chromatography using EtOAc/hexane/MeOH 80:20:1 as eluent to obtain the title compound (140 mg, 27 % yield) HPLC-MS (Method 11): R = 2.53 min MS (ES+): m/z = 327 [M+H]+ Example 37a (racemic mixture) CI \l" Example 37a is synthesized as bed for example 28a using example 3r (70 mg, 0.35 mmol) d of example 30, 2-Bromo(Trifluoromethyl)pyrazine (102 mg, 0.45 mmol) instead of 2-Chloropyrimidine, N,N—diisopropylethylamine (239 ul, 1.38 mmol) and 1 ml of DMSO. The mixture is heated in a microwave reactor during 30 minutes at 120°C. The crude product is ioned between EtZO and water then the organic layer is separated and concentrated under reduced pressure; the residue is purified by preparative HPLC-MS to obtain the title compound (70 mg, 44 % yield) as trifluoroacetate salt.

S (Method l): R = 0.90 min MS (ES+): m/z = 349 [M+H]+ Example 40b (racemic mixture) N,N—diisopropylethylamine (3.6 ml, 20.8 mmol) is added into a on of example 31 (2.1 g, 10.4 mmol) dissolved in 50 ml of acetonitrile. Di—tert-butyl-dicarbonate (2.0 g, 9.4 mmol) is added portionwise at 0°C and the reaction is stirred 2 hours. Water is added, acetonitrile is removed under reduced pressure and the residue is partitioned n DCM and water; the organic layer is separated, dried and concentrated under reduced pressure.

The crude product is purified by Silica gel flash chromatography using EtOAc/cylohexane 60:40 to 100:0 to obtain the title compound (2.5 g, 80% yield).

GC-MS (Method 3): R = 11.55 min MS (EI): m/z = 298 [M]+ The ing examples are synthesized in analogy to the preparation of example 40b : Reactant, amount, Product amount, Rt [min], (ESI p05 or Example Product solvent y1eld_ method APCI,or EI m/z) 0\ 0%CH. 400 Y CH3 N example 3k (1.8 g, F Rt = 0 75 min’ (racemic F I 8.0 mmol) DCM, 2.3 g 299 [M+H]+ N Method 1 mixture) n0 base used 40d 0% 0:?(33'43 example 3m (1.9 g, (racemic N( 9.5 mmol), DCM, 2.8 g CH3 Rt = 1.10 min, 281 [M+H]+ mixture) (i/EN] no base used Method 2 H C CH 3 Y 3 4.0 g, 80%0 (after 40e 0Y0 CH3 example 3n (2.9 g, N purification by Rt = 1.07 min, (racem1c. ] 16.2 mmol), DCM, 281 [M+H]+ N Silica gel flash Method 2 mixture) n0 base used chromatography) CH3 2.7 g 94W0 (after 40f , 0% o+cm example 30 (1.8 g,( _ purification by Rt = 2.95 min, 1c N + j 10.0 mmol), DCM, 281[M+H] Silica gel flash Method 5 mixture) N no base used F chromatography) 2-phenyl- 40g HSCQKEHs zine (5.0 g, 5.2 g, 64% (after 0Y0 30.8 mmol), purification by Rt = 0.9 min, ( . racem1c N 263[M+H]+ j ylamine(6.43 Silica gel flash Method 2 miXture) N H ml, 46.2 mmol), chromatography) Reactant, amount, Product amount, Rt [min], (ESI p05 or Example Product solvent y1eld_ method APCI,or EI m/z) H3C 6H3 2 Thlophen 2 yl'_ _ _ _ Y piperazine (540 mg, Rt = 3.06 min, (racem1c_ + N 805 mg 269[M+H] I 3.2 mmol), DCM, Method 5 mixture) 3 \ l H no base used CH3 example 3r (1.7 g, o /o 401. Y 7.6 mmol) N,N— N R. = 0.85 min, (racem1c_ j d11sopropylethylam__ 2.35 g 303[M+H]+ s cI N Meth d0 1 \ l H mixture) ine (4.0 m1, 22.9 mmol), THF H3C CH3 - o 750% 1.2 g, 78% (after 40] \Y example 3p (1.1 g, _ purification by Rt = 3.05 min, (racem1c I 4.6 mmol), DCM, H]+ fl Silica gel flash Method 7 e) no base used F chromatography) F F O\ 0 CH3 examp e1 3' (2 6 I t J . g, 2.39 g, 61% (after 40k 1 3 13.0 mmol), N,N— _ N purification by Rt = 1.11 min, (racemlc + H ropylethylam 299 [M+H] Slllca gel flash. .

F Method 2 mixture) ine (4.4 m1, 25.9 chromatography) mmol), acetonitrile H3C>rCH3 H C example 2a (1.3 g, 3 O O 1.0 g, 47% (after 41a \( 7.2 mmol), N,N— purlflcatlon by_ _ Rt = 3.09 mm,. N (racemlc_ diisopropylethylam 287 [M+H]+ Silica gel flash Method 5 mixture) S N 1ne (2.5 ml, 14.5 \ I H chromatography) mmol), acetonitrile Reactant, amount, Product amount, Rt [min], (ESI p05 or Example Product solvent y1eld_ method r EI m/z) H3C>(CH3 example 2b (720 H C mg, 2.5 mmol), 41b 3 O O _ N,N— Rt = 1.32 min, racem1c N 920 mg 395 [M+H]+ ] d11sopropylethylam.. Method 2 mixture 8 N _ | me ( 1 3 1 7 3 \ I H . m , . mmol), acetonitrile example 3s (340 H3C CH3 41C H3C o /0 mg, 1.8 mmol), Y N,N- R. = 0.82 min, . + racem1c N 410 mg 283 [M+H] j d11sopropylethylam.. Method 1 mixture 5 H36 \ / N ine (960 ul, 5.5 mmol), acetonitrile Example 42b (racemic e) o @o NTQF F H30)? 0 N—(3-dimethylaminopropyl)-N’-ethylcarbodiimide hloride (3.2 g, 16.6 mmol) is added to a mixture of example 40b (2.5 g, 8.3 mmol), tetrahydro-2H-thiopyran carboxilic acid l,l-dioxide (3.0 g, 16.6 mmol) and l-hydroxybenzotriazole (112 mg, 0.8 mmol) in 60 ml of DCM. The reaction mixture is stirred at room temperature overnight then water is added, the c layer is separated, washed with aqueous NaHC03 then dried and concentrated under reduced pressure. The residue is purified by Silica gel flash chromatography, using cyclohexane/EtOAc 40:60 to 0:100 as eluent, to obtain the title compound (3.8 g, 97% yield).

HPLC-MS (Method 5): R = 2.80 min MS (APCI+): m/z = 459 [M+H]+ The following examples are sized in analogy to the preparation of example 42b: Reactant, t amount, Rt [min],. e Product amount, or . (ESI p05 y1eld methOd solvent APCI, m/z) CHéHS Example 40d 0%(0 42c N CH3 90% F (2.7 g, N] R = 1 02 _ . mm, (racemic content, 8.7 3.5 g, 92% Ni 441 [M+H]+ eth d20 mixture) KKO 11111101), (‘3‘ DMF/THF 1:1 42d F 0% Example 40f ( N R, = 1.04 min, (racem1c. ] 1.7 + g, 5.8 2.3 g, 88% 441[M+H] N Meth d20 mixture) GAO mmol), DCM HSCXCHSCH3 0% 8 CH, 426 1 Example 40k F Rt = 2.89 min, N 403[M- (racemic. (2.4 g, 7.8 3.0 g, 81% F 0? Method 5 56+H]+ mixture) S\\//O mmol), DCM Reactant, MS Product amount, Rt .

Example Product , or . (ESI pos y1eld methOd solvent APCI, m/z) 42g N Example 41a (racem1c_ RI = 2,83 mm,. s 1 (1.0 g, 3.6 1.2 g, 75% 447[M+H] F / Meth0d5 mixture) 0/ mmol), DCM H30 CH3 H CW 3 O %O 42h Example 41b Rt = 3.05 min, . j (racem1c S (920 mg, 2.3 920 mg, 70% 555[M+H]+ I Method 5 . \ / m1xture) 0/ mmol), DCM Example 43a (racemic mixture) HATU (3.2 g, 8.4 mmol) and N,N—diisopropylethylamine (3.8 ml, 22.0 mmol) are added to a solution of tetrahydro-2H-thiopyrancarboxilic acid oxide (1.6 g, 8.8 mmol) in 15 ml of DMF. After 20 minutes stirring, example 40c (2.3 g, 7.3 mmol) is added, and the reaction is d at room temperature overnight. The mixture is concentrated under reduced pressure, then the residue is dissolved in EtOAc and washed with 5% NaHC03 solution, 5% HCl solution and water. The organic layer is separated, concentrated under reduced pressure and the e is purified by Silica gel flash cromatography using cyclohexane/EtOAc (from 50:50 to EtOAc 100%) as eluent, to obtain the title compound (2.1 g, 63% yield).

UPLC-MS (Method 1): R = 1.05 min MS (ES+): m/z = 459 [M+H]+ The following examples are synthesized in analogy to the ation of example 43a: Product Rt [min], Example Product Reactant, amount (ESI pos or amount, yield method APCI,m/z) Example 40e, (1.2 g, RI = 1.21 min, (racemic 3.9 mmol), in 1.2 g, 59% 441 [M+H]+ Method 1 mixture) acetonitrile Example 40g, (5.20 R = 3.16 min, (racemic 7.7 g, 92% 423 [M+H]+ g, 19.8 mmol) Method 8 Example 40h, (1.3 g, RI = 1.04 min, (racemic 2.0 g, 98% 429[M+H]+ 4.7 mmol) Method 1 mixture) 43e Example 40i, (1.7 g, Rt = 1.14 min, ic 5.3 mmol), in 2.4 g, 85% 463[M+H]+ Method 1 mixture) acetonitrile WO 55698 Product Rt [min], Example Product Reactant, amount (ESI p05 or t y1eld method APCI, m/Z) H3C CH3 43f I _ 1 Example 40j, (1.2 g, Rt = 1.18 min, (racem1c 1.2 g, 68% 491[M+H]+ N 3.6 mmol) Method 1 mixture) CF3 (VKOSfo H3C CH3 3 O O 43g N Example 41c (100 Rt 21'10 mm’‘ ( ' S j racem1c N mg 13 690 H30 l 1) e + + , . mmo m crud , g, 443[M H] / Method] mixture) 0 acetomtnle. .

Example 43h (racemic mixture) O O 3 FFflsji 1N \ l O@30 Copper(I) iodide (500 mg, 2.63 mmol) and hexamethylphosphoramide (1.8 ml, 10.1 mmol) are added to a stirred solution of example 42h (1.1 g, 2.02 mmol) ved in 6 ml of anhydrous DMF. After 5 minutes stirring, methyl-2,2-difluoro(fluorosulfonyl)-acetate (1.3 ml, 10.1 mmol) is added and the reaction mixture is heated at 100°C for 1 hour. The crude is poured into a ted aqueous NH4Cl solution and extracted with EtOAc; the organic layer is separated, dried and concentrated under reduced pressure. The residue is 2014/072085 d by silica gel flash chromatography, using cyclohexane/EtOAc 1:1 to 100% EtOAc as eluent, to obtain the title compound (770 mg, 69% yield).

HPLC-MS (Method 5): R = 3.12 min MS (APCI+): m/z = 495 [M—H]+ Example 44b_(racemic mixture) Example 43b (1.2 g, 2.3 mmol) is dissolved in 10 ml of dioxane; HCl (4N solution in dioxane, 3.7 ml, 14.8 mmol ) is added and the reaction mixture is stirred until complete conversion. The solid is filtered to obtain the desired product as hydrochloride salt (715 mg).

S (Method 1): R = 0.59 min MS (ES+): m/z = 341 [M+H]+ The following examples are synthesized in analogy to the preparation of example 44b, in case using aqueous NaOH on or NH4OH to obtain the free base: Reactant, Product Rt [min], Example Product (ESI pos or amount amount methOd APCI, m/z) 440 1 Example 436, 8 , . CI R, = 0.63 mm, (racem1c \/ 11.0 / (5.8 g, 2.8g 0/ Method 1 363[M+H]+ mixture) so mmol) Reactant, Product Rt [min], e Product (ESI pos or amount amount methOd APCI, m/z) 44d 1 Example 43f, N R = 0.70 min, ic_ (1.2 + g, 2.5 940 mg 391[M+H] O Method 1 mixture). o mmo )1 CF 3: 44f F 1 Example 42b, N Rt 2 0'57 min’ ( ' racem1c 0% (3 8. g 8 2 , . 2 5. g 359[M Hr+ F Method 2 mixture) Sf 11111101) 44g F 1 Example 42c, ( ' Rt 2 0'59 min’ racem1c (3 3 g 7 5 2 5 g 341 [M H?+ o¢ . , . .

Method 2 mixture) fiéo mol) 4411 1 Example 42d, N Rt 2 0'63 mm’. ( ' racem1c (2 3 g 51 1 7 g 341[M Hr+ . , . .

F o/ Method 2 mixture) 850 11111101) 441. Example 426, F 1 Rt 2 1'72 min’ ( ' N racem1c (3 0. g 64 21 + + 0% , . . g 359[M H] F Method 5 mixture) 0 sf 11111101) F 1 Example 43a, R = 0.59 mm,. N (racemic_ (2.1 + g, 4.6 1.6 g 359[M+H] 0 Method 1 mixture) :0 mmol) Reactant, Product Rt [min], Example Product (ESI pos or amount amount methOd APCI, m/z) 441 s 1 N Example 42g’ F R = 1.73 min, \ l ‘ (racemic O/ (1.2 g, 2.7 750 mg 347[M+H]+ Method 5 _ :0 mixture) S\\ mol) s 1 Example 43h, Rt: 3‘11mm’. (racemic FF \ l /N (820 mg, 1.7 575mg 397[M+H]+ 0 Method 16 mixture) s\:o mmol) 4411 Examp1e 43g, 470mg(as S R, = 0.60 mm,. (racernlc. H30 N / . + \ 1.4 / (690 mg, hydrochlorlde H] 0/ Method 1 mixture) S\:o mmol) salt) Example 45 a_(racemic mixture) Trifluoroacetic acid (14.1 ml, 183.4 mmol) is added to a 0°C cooled solution of example 43c (7.8 g, 18.3 mmol) in 75 ml of DCM. After 20 hours stirring at room temperature, t is removed under reduced pressure, and the residue is d over a SCX cartridge, to give the title nd (4.9 g, 83% yield).

UPLC-MS (Method l): R = 0.55 min MS (ES+): m/z = 323 [M+H]+ Example 46a (racemic mixture) @130SE)o 40 Example 46a is synthesized as described for example 45a starting from example 43d (2.0 g, 4.7 mmol) using trifluoroacetic acid (3.6 ml, 46.7 mmol) and 20 ml of DCM to obtain 1.5 g of product.

UPLC-MS d 4): R = 1.73 min MS (APCI+): m/z = 329 [M+H]+ Example 47a (racemic mixture) H30‘MSWIN] OA04 N,N-diisopropylethylamine (45 ul, 0.26 mmol) and 1,1-dioxothianecarbonyl de (52 mg, 0.26 mrnol previously prepared from the corresponding carboxilic acid and oxalyl chloride in anhydrous DCM) are added to a solution of e 15b (50 mg, 0.18 mrnol) in 2 ml of anhydrous DCM under nitrogen here. The reaction is stirred overnight.

The crude product is partitioned between DCM (5 ml) and 5% aqueous NaHC03 solution; the organic phase is separated, trifluoroacetic acid (400 ul) is added and the reaction is d overnight. The solvent is removed under reduced pressure and crude product is purified by SCX cartridge to obtain the title compound (46 mg, 85% content; the t is estimated at 254 nm,).

UPLC-MS (Method 1): R = 0.58 min MS (ES+): m/z = 344 [M+H]+ Example 48a (racemic mixture) HZN o s N] \ I A on of trimethylsilylisocyanate (137 ul, 1.03 mmol) dissolved in 4 ml of anhydrous THF is added dropwise to a suspension of example 44c (340 mg, 0.94 mrnol as free base) in 10 ml of anhydrous THF under nitrogen atmosphere and the reaction mixture is stirred hours. The solvent is removed under reduced pressure then a solution of HCl in methanol is added to the residue and the on is stirred 30 minutes. The solvent is removed to obtain the title nd (830 mg) used without further purification in the following step.

HPLC-MS (Method 11): R = 2.47 min MS (ES+): m/z = 406 [M+H]+ Example 48b (racemic mixture) O\ s 0%Give Example 48b is synthesized as described for e 48a starting from example 44m (300 mg, 0.72 mmol) instead of example 44c, hylsilylisocyanate (405 ul, 2.0 mmol) and ml of anhydrous THF to obtain the title compound (307 mg) used without filrther purification in the following step.

HPLC-MS d 10): R = 2.61 min MS (ES+): m/z = 440 [M+H]+ e 49a (racemic mixture) s N] CI \l GAO") Triethylamine (8 ul, 0.06 mmol) and 1.5 ml of 50% NaOH aqueous solution are added to a stirred solution of example 48a (255 mg, 0.57 mmol) dissolved in 20 ml of chloroform and the resulting mixture is vigorously stirred ght. Two ml of 50% NaOH aqueous solution are added and the reaction mixture is stirred during additional 8 hours. DCM and water are added to the mixture, the phases are separated; the organic layer is dried and concentrated under reduced pressure to obtain 280 mg of title compound used in the following step without fiarther purification.

HPLC-MS (Method 11): R = 3.03 min MS (ES+): m/z = 388 [M+H]+ Example 50a (racemic mixture) H2NYo e 50a is sized as bed for example 48a starting from example 44g (600 mg, 1.8 mmol) instead of example 44c and trimethylsilylisocyanate (270 ul, 2.0 mmol) to obtain the title compound (560 mg) used t fiarther purification in the following step.

UPLC-MS (Method 2): R = 0.60 min MS (ES+): m/z = 384 [M+H]+ Example 51a (racemic mixture) F 3 s/’0 (131 Triethylamine (20 ul, 0.17 mmol) and 6 ml of 50% aqueous NaOH solution are added to a stirred solution of example 50a (560 mg, 1.46 mmol) dissolved in 10 ml of chloroform and the resulting mixture is vigorously stirred 6 hours. DCM and water are added to the crudeand the phases are separated;the organic layer is dried and concentrated under reduced pressure; the residue is purified by Silica gel flash chromatography, using EtOAc/Hexane/MeOH 80:20:1 as eluent, to obtain the title nd (310 mg, 58% yield).

HPLC-MS (Method 17): R = 2.47 min MS (ES+): m/z = 366 [M+H]+ Example 52a (racemic mixture) HNYNH F j s//0 e 51a (300 mg, 0.82 mmol) and hydroxylamine (50% aqueous solution, 120 ul, 1.96 mmol) are dissolved in 3 ml of EtOH and the reaction is heated in a ave reactor during 30 minutes at 100°C. t is removed under reduced pressure, the residue is partitioned between water and DCM; the organic phase is separated and concentrated under reduced pressure to obtain the title compound (270 mg).

HPLC-MS (Method 17): R = 1.87 min MS (ES+): m/z = 399 [M+H]+ Example 53a (racemic mixture) CI 5, :3 Example 53a is synthesized as described for e 28a using example 44c (150 mg, 0.41 mmol) instead of example 30, 2,5-dibromopyrazine (108 mg, 0.45 mmol) instead of 2- Chloropyrimidine, N,N—diisopropylethylamine (179 ul, 1.03 mmol) and 1 ml of DMSO.

The mixture is heated in a microwave reactor during 2 hours at 130°C. After the work-up the crude is purified by Silica gel flash chromatography using Cyclohexane/EtOAc 60:40 to 20:80 as eluent to obtain the title compound (130 mg, 61% yield).

S (Method 1): R = 1.21 min MS (ES+): m/z = 519—521 [M+H]+ Example 54a (racemic mixture) Example 54a is synthesized as bed for example 53a using example 44g (370 mg, 1.1 mmol) instead of example 44c, 2,5-dibromopyrazine (260 mg, 1.1 mmol), N,N— diisopropylethylamine (210 ul, 1.2 mmol) and 2 ml of DMSO. The mixture is heated in a microwave reactor during 1 hour at 130°C. 460 mg of the title nd are obtained.

UPLC-MS (Method 1): R = 1.09 min MS (ES+): m/z = 497-499 [M+H]+ Example 55a (racemic mixture) WO 55698 -82— e 55a is synthesized as bed for example 48a starting from example 44h (350 mg, 1.0 mmol) instead of example 44c and trimethylsilylisocyanate (150 ul, 1.1 mmol) to obtain the title compound (390 mg) used Without further purification in the following step.

HPLC-MS (Method 5): R = 1.52 min MS (APCI+): m/z = 384 [M+H]+ Example 56a (racemic mixture) F o s//O Example 56a is synthesized as described for example 49a starting from example 55a (310 mg, 0.81 mmol) instead of example 48a, triethylamine (11 ul, 0.08 mmol) and 2.5 ml of 50% NaOH aqueous solution in 8 ml of chloroform; the reaction mixture was stirred overnight. After the work-up and the ation by Silica gel flash chromatography, using DCM/MeOH 95:5 as eluent, the title compound is obtained (149 mg, 45% yield).

HPLC-MS (Method 5): R = 1.96 min MS (APCI+): m/z = 366 [M+H]+ 2014/072085 Example 57a (racemic mixture) (IDH HNYNH F o s//O Example 57a is synthesized as described for e 52a starting from example 56a (149 mg, 0.41 mmol) instead of example 51a, hydroxylamine hydrochloride (57 mg, 0.82 mmol), N,N—diisopropylethylamine (140 ul, 0.82 mmol) to obtain the title compound (150 mg) used as such Without further purification.

HPLC-MS (Method 5): R = 1.46 min MS (APCI+): m/z = 399 [M+H]+ Example 58a A solution of 5-(Trifluoromethyl)—1,3,4-Oxadiazolamine (300 mg, 2.0 mmol) dissolved in 3 ml of diiodomethane is heated at 100°C and stirred 2 hours; isoamylnitrite (1.0 ml, 7.8 mmol) is slowly dropped and resulting reaction e is further stirred 20 minutes. The crude product is purified by Silica gel flash chromatography using cyclohexane/EtOAc 100:0 to 98:2 to obtain the title nd (95 mg).

GC-MS (Method 3): R = 3.04 min MS (EI): m/z = 263 [M]+ Example 59a (single enantiomer; R ration) OOWF H30 M NaHC03 (1.0 g, 11.9 mmol) is added to a stirred suspension of (R)Fluorophenylglicine (1.0 g, 5.9 mmol) in water. After 30 minutes, a solution of di-tert-butyldicarbonate (1.5 g, 7.1 mmol) ved in tert-butylalcohol is added dropwise and the resulting reaction mixture is stirred overnight at room temperature. The reaction is diluted with water then With 5% citric acid aqueous solution (until pH 4-5); then the mixture is then extracted with DCM; the organic layer is ted, dried over anhydrous NaZSO4 and concentrated under reduced pressure to obtain the title compound (1.6 g).

HPLC-MS d 17): R = 2.25 min MS (ES+): m/z = 292 [M+Na]+ Example 60a (single enantiomer; R configuration) H30\O/fl\V/H N o 4i\C)CH H30 CH3 NaHC03 (1.0 g, 11.9 mmol) is added to a stirred mixture of example 59a (1.5 g, 5.6 mmol) and glycine methyl ester hloride (700 mg, 5.6 mmol) dissolved in 40 ml of DCM and 10 ml of anhydrous DMF and the reaction is stirred 30 minutes. l-Hydroxy azabenzotriazole (830 mg, 6.1 mmol) and N—(3-Dimethylaminopropyl)-N'- Ethylcarbodiimidehydrochloride (1.2 g, 6.1 mmol) are added and the reaction mixture is stirred 16 hours at room temperature. Water and DCM are added, the organic layer is separated, washed with 5% citric acid aqueous solution, dried over anhydrous NaZSO4 and concentrated under reduced pressure. The residue is purified by Silica gel flash chromatography, using Hexane/EtOAc 6:4 as eluent, to obtain the title nd (19 g, 90% yield).

UPLC-MS (Method 2): R = 1.01 min MS (ES+): m/z = 341 [M+H]+ Example 6la (single enantiomer; R configuration) Formic acid (20 ml) is added to example 60a (19 g, 5.0 mmol) then, after 1 hour stirring, the acid is removed under reduced pressure, 10 ml of toluene and 25 ml of 2-butanol are added to the residue and the resulting mixture is refluxed 4 hour using a Dean-Stark tus. Solvent is removed under reduced re then the residue is suspended in EtOAc and filtered to obtain the title compound (550 mg).

UPLC-MS (Method 2): R = 0.53 min MS (ES+): m/z = 209 [M+H]+ Example 62a (single omer; R configuration) Borane-methyl sulfide complex (2.5 ml, 2M THF solution, 5 mmol) is added, at room temperature, to a stirred mixture of example 6la (200 mg, 1.0 mmol) in 5 ml of anhydrous THF under nitrogen here and the on is refluxed 20 hours. After cooling to room temperature, 3 ml of MeOH and 0.5 ml of HCl conc. are added and the mixture is heated 2 hour at 70°C. Solvents are removed under reduced pressure, the residue is partitioned between water and EtzO, the aqueous layer is separated, basified until pH 10 by addition of NH4OH and ted with DCM. The organic layer is separated, dried over a phase-separator dge and concentrated under reduced pressure to obtain the title compound (120 mg).

UPLC-MS (Method 23): R = 0.47 min MS (ES+): m/z = 181 [M+H]+ Example 63a (single enantiomer; R configuration) MEN] 23 H N,N—Diisopropylethylamine (30 uL, 0.2 mmol) is added to a stirred solution of example 62a (35 mg, 0.2 mmol) and 2-Chloro(Trifiuoromethyl)pyrimidine (36 mg, 0.2 mmol) dissolved in 1 ml of anhydrous DMSO; the reaction is heated in a ave reactor during 2 hours at 100°C. Water and EtOAc are added to the crude, the organic phase is separated, washed with water, dried and concentrated under reduced pressure. The residue is purified by Silica gel flash chromatography, using DCM/MeOH 100:2 as eluent, to obtain the title compound (30 mg, 47% yield).

UPLC-MS (Method 1): R = 0.90 min MS (ES+): m/z = 327 [M+H]+ Chiral HPLC d 15): R = 4.38 min Example 64a N,N‘-Dicyclohexylcarbodiimide (1.8 g, 8.6 mmol) is added to a d solution of alpha- BromoFluorophenylacetic acid (2.0 g, 8.6 mmol), D-(-)-Pantolactone (1.1 g, 8.6 mmol) and 4-Dimethylaminopyridine (100 mg, 0.8 mmol) in DCM and the reaction mixture is stirred 3 hours. The precipitate is filtered out and the filtrate is concentrated under reduced pressure; the residue is purified by Silica gel flash chromatography, using Hexane/EtOAc 8:2 as eluent, to obtain the title compound (2.6 g, 86% yield).

S (Method 1): R = 1.34 min MS (ES+): m/z = 345-347 [M+H]+ Example 65a (single enantiomer: S configuration) N,N’-dibenzylethylenediamine (2.1 g, 8.6 mmol) is added to a stirred solution of example 64a (2.5 g, 7.2 mmol), tetrabutylammonium iodide (2.7 g, 7.2 mmol) and N,N— Diisopropylethylamine (1.3 ml, 7.4 mmol) in 60 ml of DCM and the reaction mixture is stirred 16 hours. Water is added, the organic phase is separated, dried over anhydrous Na2S04 and concentrated under reduced pressure; the residue is purified by Silica gel flash chromatography, using Hexane/EtOAc/MeOH 70:30:1 as eluent, to obtain the title nd (2.2 g, 83% .

HPLC-MS (Method 17): R = 5.13 min MS (ES+): m/z = 375 [M+H]+ Chiral HPLC (Method 24): R = 29.7 min Example 66a (single enantiomer; S ration) (>1) Borane-Methylsulflde complex (2.0 M THF solution, 1.1 ml, 2.3 mmol) is added dropwise to a stirred solution of example 65a (160 mg, 0.4 mmol) in 6 ml of ous THF under nitrogen atmosphere and the reaction mixture is refluxed 8 hours; afler cooling to room temperature, 2 ml of MeOH and 0.5 ml of concentrated HCl solution are added and the reaction mixture is refluxed during 1 hour. t is concentrated under d pressure, the residue is partitioned between water and EtzO then the aqueous layer is separated and basifled by addition ofNH4OH until pH 10 and extracted with DCM. The organic layer is dried over anhydrous Na2S04 and concentrated under reduced re to obtain the title compound (1 10 mg). 2014/072085 UPLC-MS (Method 1): R = 1.13 min MS (ES+): m/z = 361 [M+H]+ Chiral HPLC (Method 24): R = 8.0 min Example 67a (single enantiomer; S configuration) £11"N] 1-chloroethylchloroformate (0.15 ml, 1.4 mmol) is added to a stirred solution of example 66a (100 mg, 0.3 mmol) ved in 2 ml of ous dichloroethane and the reaction mixture is stirred 10 hours. The solvent is concentrated under reduced pressure and 3 ml of MeOH are added to the e then the reaction mixture is heated at 80°C 2 hours.

Solvent is removed under reduced pressure, the residue is dissolved in water and basified by addition of NH4OH until pH 10 and the mixture is extracted with DCM; the c layer is separated, dried over a phase-separator cartridge and concentrated under reduced pressure to obtain the title compound (65 mg).

UPLC-MS (Method 1): R = 0.9 min MS (ES+): m/z = 271 [M+H]+ Example 68a (single enantiomer; S configuration) 02:1 Palladium hydroxide (40 mg) is added to a stirred solution of example 67a (50 mg, 0.2 mmol) dissolved in glacial acetic acid and the reaction mixture is hydrogenated into a Parr apparatus at 60 PSI for 3 hours. The catalyst is filtered out over a celite pad and the filtrate is concentrated under reduced pressure; the residue is treated with water, basified by addition ofNH4OH (pH 10) and the mixture is extracted with DCM. The organic phase is separated, dried and concentrated under d re to obtain the title compound (30 mg).

UPLC-MS d l): R = 0.26 min MS (ES+): m/z = 181 [M+H]+ Example 69a (single enantiomer; S configuration) N,N—Diisopropylethylamine (30 ul, 0.2 mmol) is added to a d solution of example 68a (30 mg, 0.2 mmol) and 2-Chloro(Trifiuoromethyl)pyrimidine (30 mg, 0.2 mmol) and the reaction mixture is heated in a microwave reactor 2 hours at 100°C. The crude is ioned between water and EtOAc then the organic layer is separated, washed with water, dried over anhydrous NazSO4 and concentrated under reduced pressure; the residue is purified by Silica gel fiash chromatography, using DCM/MeOH 100:2 as eluent, to obtain the title compound (35 mg, 64% yield).

UPLC-MS (method l): R = 0.89 min MS (ES+): m/z = 327 [M+H]+ WO 55698 e 70a (single enantiomer) D-(-)-Mandelic acid (19 g, 124.7 mmol) is added to a solution of racemic 3-(2,3-Difluoro- phenyl)-piperazinecarboxylic acid tert-butyl ester (37.2 g, 124.7 mmol, prepared in large scale as bed for the example 40c) dissolved in 300 ml of EtOAc; after 30 minutes stirring, the reaction mixture is cooled with an ice/water bath to about 0°C and stirred 1 hour. The White precipitate is filtered and then cristallized 5 times in refluxing EtOAc; 17.5 g of the mandelate salt are obtained; the chiral HPLC analysis performed on the free base gives enatiomeric excess > 98%,. Mother-liquors are collected, the solvent is removed under d re and the residue is cristallized, as described above, in EtOAc. 3.5 g of salt having enantiomeric excess > 98% are obtained. The diastereomeric salts are combined together (21 g) and treted with an aqueous NaOH solution. The aqueous layer is extracted with EtOAc to obtain the title compound as free base (13.3 g).

HPLC-MS (Method 27): R = 4.43 min MS (ES+): m/z = 299 [M+H]+ Chiral HPLC (Method 25): R = 6.88 min Example 71a (single enantiomer) 0 O+CH3 Y CH3 .....E I Tetrahydro-2H-thiopyrancarboxilic acid 1,1-dioxide (9.53 g, 53.5 mmol), l-Hydroxy azabenzotriazole (7.3 g, 53.5 mmol) and imethylaminopropyl)-N'- Ethylcarbodiimidehydrochloride (13.7 g, 71.3 mmol) are added to a solution of e 70a (13.3 g, 44.6 mmol) dissolved in 30 ml of anhydrous DMF and 140 ml of anhydrous THF under nitrogen atmosphere; the reaction mixture is stirred 72 hours then THF is evaporated under reduced pressure and the residue is partitioned between aqueous NaHC03 solution and EtOAc. The organic layer is separated, dried over anhydrous NaZSO4 and concentrated under reduced pressure. The crude is suspended in isopropyl ether, stirred, cooled with an ice-water bath and the solid is d to obtain the title compound (17.0 g).

S (Method 10): R = 4.43 min MS (ES+): m/z = 403[M-56+H]+ and 359 [M-100+H]+ Chiral HPLC (Method 25): R = 13.27 min Example 72a (single enantiomer) \\ N ")| The example 72a is synthesized as described for example 44b starting from example 71a (17.0 g, 37.1 mmol) using HCl (4N dioxane solution, 140 ml, 560 mmol) and 300 ml of 1,4-dioxane. The obtained hloride salt is dissoveld in water, washed with aqueous NaOH solution and ted with DCM to obtain the title compound (12.2 g).

HPLC-MS (Method 27): R = 2.50 min MS (APCI+): m/z = 359 [M+H]+ Chiral HPLC (Method 9): R = 11.66 min ary embodiments Example 1 (racemic mixture) Example 44k (300 mg, 0.8 mmol), 2-Chloro(trifluoromethyl)pyrimidine (199 mg, 1.09 mmol) and N,N—diisopropylethylamine (287 ul, 1.67 mmol) are dissolved in 4 ml of anhydrous DMSO and heated in a microwave reactor during 30 minutes at 150°C. The crude is partitioned between EtOAc and water, the organic layer is dried over anhydrous NaZSO4 then concentrated under reduced pressure to obtain 360 mg ofthe title product.

S (Method 10): R = 3.54 min MS (ES+): m/z = 505 [M+H]+ The enantiomers are obtained by HPLC using a chiral stationary phase.

Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack AD-H, 5.0 um, 250 mm x 20 mm; method: eluent / IPA 70:30; flow rate: 15 mL/min, Temperature: °C; UV Detection: 254 nm Example of tion by chiral HPLC: Submitted to separation: 665 mg of Example 1 prepared as described above; Obtained: 157 mg of enantiomer 1 (Exp. 2) and 40 mg of enantiomer 2 (Exp. 3) e 2: enantiomer 1 Example 3: enantiomer 2 F F F F F F \ \ I I NYN NYN N N ChiralHPLC HPLC-MS (Method 10): Rt Example MS (ES+): m/z Rt [mm]. [min] Exp. 2 10.88 3.57 505 (Method 9) Exp. 3 12.19 3.57 505 (Method 9) ative synthesis of e 2 (single enantiomer) A solution of example 72a (12.2 g, 33.9 mmol), isopropylethylamine (11.6 ml, 67.8 mmol) and 2-Chloro(Trifiuoromethyl)pyrimidine (6.8 g, 37.3 mmol) in 100 ml of anhydrous DMSO is heated at 100°C and stirred 30 minutes. After cooling to room temperature, water is added and the new formed precipitate is filtered and washed with water and with n-hexane. The solid is dissolved in EtOAc and washed with 10% aqueous citric acid solution; the organic layer is separated, dried over anhydrous Na2S04 and concentrated under reduced re. The residue is suspended in diethylether and filtered; then the resulting solid is purified by silica flash chromatography, using cyclohexane/EtOAc 1:1 to 20:80 as eluent, to obtain the title compound (15.0 g, 88% yield).

HPLC-MS (Method 10): R = 3.52 min MS (ES+): m/z = 505 [M+H]+ Chiral HPLC (Method 9): R = 10.88 min Example 4 (racemic mixture) Example 4 is synthesized as described for example 1 starting from example 44b (free base, 400 mg, 1.18 mmol) d of example 44k, 2-Chloro(trifluoromethyl)pyrimidine (279 mg, 1.53 mmol), N,N-diisopropylethylamine (402 ul, 2.35 mmol) and 5 ml of anhydrous DMSO. The mixture is heated in a ave reactor during 30 minutes at 150°C. The crude is purified by Silica gel flash chromatography, using Cyclohexane/EtOAc 70:30 to :80 as eluent, to obtain 559 mg (98 % yield) of product.

S d 10): R = 3.53 min MS (ES+): m/z = 487 [M+H]+ The enantiomers are obtained by HPLC separation using a chiral stationary phase.

Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack AD-H, 5.0 um, 250 mm x 20 mm; method: eluent / IPA 70:30; flow rate: 15 mL/min, Temperature: °C; UV Detection: 254 nm Example of separation by chiral HPLC: Submitted to separation: 500 mg of Example 4 prepared as described above; Obtained: 103 mg of enantiomer 1 (Exp. 5) and 122 mg of enantiomer 2 (Exp. 6) Example 5: enantiomer 1 Example 6: enantiomer 2 F F F F F F \ \ I I N N N N ChiralHPLC HPLC-MS (Method 10): Rt Example MS (ES+): m/z Rt [mm]. [min] Exp. 5 10.62 3.58 487 (Method 9) Exp. 6 11.99 3.57 487 (Method 9) Example 7 (racemic e) 0%03,\\/ O Example 7 is synthesized as described for example 1 starting from e 44g (560 mg, 1.65 mmol) instead of example 44k, 2-Chloro(trifluoromethyl)pyrimidine (400 mg, 2.19 mmol), N,N-diisopropylethylamine (570 ul, 3.33 mmol) ved in anhydrous DMSO.

The mixture is heated in a microwave reactor during 1 hour at 100°C to obtain, after purification by Silica gel flash chromatography using EtOAc/Hexane/MeOH 70:30:1 as eluent, 680 mg (85 % yield) of product.

HPLC-MS (Method 10): R = 3.48 min MS (ES+): m/z = 487 [M+H]+ The enantiomers are obtained by HPLC separation using a chiral stationary phase.

Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel pack AD-H, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 70:30; flow rate: 15 mL/min, Temperature: °C; UV Detection: 254 nm Example of separation by chiral HPLC: Submitted to separation: 680 mg of Example 7 prepared as described above; Obtained: 190 mg of enantiomer 1 (Exp. 8) and 90 mg of enantiomer 2 (Exp. 9) Example 8: enantiomer 1 Example 9: enantiomer 2 HPLC HPLC-MS (Method 10): Rt Example MS (ES+): m/z Rt [mm]. [min] Exp. 8 11.36 3.44 487 d 9) Exp. 9 14.82 3.43 487 (Method 9) Example 10 (racemic mixture) Example 10 is synthesized as bed for example 1 starting from example 44i (415 mg, 1.16 mmol) instead of example 44k, 2-Chloro(trifluoromethyl)pyrimidine (280 mg, 1.53 mmol), N,N—diisopropylethylamine (396 ul, 2.31 mmol) and 6 ml of anhydrous DMSO; the e is heated in a microwave reactor during 30 minutes at 140°C to obtain 514 mg ofthe desired product.

HPLC-MS (Method 10): R = 3.60 min MS (ES+): m/z = 505 [M+H]+ The enantiomers are obtained by HPLC separation using a chiral stationary phase.

Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 70:30; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 254 nm e of separation by chiral HPLC: Submitted to separation: 514 mg of Example 10 ed as described above; Obtained: 190 mg of enantiomer 1 (Exp. 11) and 100 mg of enantiomer 2 (Exp. 12) e 11: enantiomer 1 Example 12: enantiomer 2 ChiralHPLC HPLC-MS (Method 10): Rt Example MS (ES+): m/z Rt [mm]. [min] Exp. 11 15.55 3.57 505 (Method 15) Exp. 12 17.57 3.58 505 (Method 15) Example 13 (racemic mixture) Example 13 is synthesized as described for example 1 ng from example 44f (80 mg, 0.22 mmol) instead of example 44k, 2-Chloro(trifluoromethyl)pyrimidine (60 mg, 0.33 mmol), N,N—diisopropylethylamine (75 pl, 0.44 mmol) and 1 ml of anhydrous DMSO. The WO 55698 mixture is heated in a microwave reactor during 30 minutes 130°C. After purification by preparative HPLC-MS, 84 mg (75 % yield) of product are obtained.

HPLC-MS (Method 5): R = 3.08 min MS (APCI+): m/z = 505 [M+H]+ The enantiomers are obtained by HPLC separation using a chiral stationary phase.

Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack AD-H, 5.0 um, 250 mm x 20 mm; method: eluent / IPA 70:30; flow rate: 15 mL/min, Temperature: °C; UV Detection: 254 nm Example of separation by chiral HPLC: Submitted to separation: 70 mg of Example 13 prepared as bed above; Obtained: 26 mg of enantiomer 1 (Exp. 14) and 20 mg of enantiomer 2 (Exp. 15) Example 14: enantiomer 1 Example 15: enantiomer 2 ChiralHPLC HPLC-MS (Method 10): Rt Example MS (ES+): m/z Rt [mm]. [min] Exp. 14 11.76 3.58 505 d 9) Exp. 15 16.59 3.56 505 (Method 9) - l 0 l - Example 16 (racemic mixture) Example 44b (70 mg of free base, 0.21 mmol), 2-ChloroFluoropyridine (25 ul, 0.25 mmol), X-Phos (39 mg, 0.08 mmol), Tris(dibenzylideneacetone)dipalladium(0) (38 mg, 0.04 mmol) and sodium tert-butoxide (39 mg, 0.41 mmol) are suspended under nitrogen atmosphere in 2 ml of previously degassed dioxane ; the reaction e is heated in a microwave reactor, at 90°C, 2 hours.

The crude product is partitioned between water and EtOAc, the organic layer is separated, dried and concentrated under reduced pressure; the residue is purified by preparative S to obtain the title nd (30 mg, 34 % yield) HPLC-MS (Method 10): R = 3.25 min MS (ES+): m/z = 436 [M+H]+ Example 17 (racemic mixture) . 1 Example 17 is synthesized as described for example 1 starting from example 44b (70 mg of free base, 0.21 mmol) instead of e 44k, 2-ChloroFluoropyrimidine (41 ul, 0.33 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (71 ul, 0.41 mmol) and 2 ml of anhydrous DMSO The reaction mixture is heated in a microwave r during 2 hours at 120°C. The crude product is d by preparative HPLC-MS to obtain the title compound (62 mg, 69 % yield).

HPLC-MS (Method 10): R = 3.12 min MS (ES+): m/z = 437 [M+H]+ Example 18 (racemic mixture) WO 55698 N,N-diisopropylethylamine (72 ul, 0.42 mmol) followed, portionwise, by 1,1- dibromoformaldoxime (85 mg, 0.42 mmol) are added into a cooled solution (-20°C) of example 44k (150 mg, 0.42 mmol) dissolved in 5 ml of anhydrous THF, under nitrogen atmosphere; the reaction mixture is stirred 1.5 hours and the ature increased to 0°C. 2-Bromo-3,3,3-trifluoropropene (215 ul, 2.09 mrnol) is added dropwise followed by triethylamine (76 ul, 0.54 mmol) and the reaction is stirred 1 hour at 0°C and then 24 hours at room temperature. The crude is d with EtOAc and washed with water; the organic phase is concentrated under reduced pressure and the e is purified by preparative HPLC-MS to obtain the title compound (41 mg, 20 % yield).

HPLC-MS (Method 10): R = 3.44 min MS (ES+): m/z = 494 [M+H]+ Example 19 (racemic mixture) F D OA040 Example 19 is synthesized as bed for example 1 starting from example 44b (80 mg of free base, 0.23 mmol) instead of example 44k, 2-Chloro-Pyrimidine (40 mg, 0.35 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (80 ul, 0.46 mmol) and 1 ml of anhydrous DMSO. The reaction mixture is heated in a microwave reactor during 30 minutes at 130°C. After the work-up, the crude product is purified by ative HPLC-MS to obtain the title compound (43 mg, 45 % yield).

HPLC-MS (Method 5): R = 2.52 min —104— MS (APCI+): m/z = 419 [M+H]+ Example 20 (racemic mixture) Example 20 is synthesized as described for example 16 starting from example 44b (80 mg of free base, 0.24 mmol), 2-Bromopyridine (27 ul, 0.28 mmol) instead of 2-Chloro Fluoropyridine, X-Phos (45 mg, 0.09 mmol), Tris(dibenzylideneacetone)dipalladium(0) (43 mg, 0.05 mrnol), sodium tert-butoxide (45 mg, 0.47 mrnol) in degassed Dioxane. The reaction mixture is heated in a microwave reactor at 100°C during 2 hours. After the work- up, the crude product is d by preparative HPLC-MS to obtain, the title compound (32 mg, 33 % .

HPLC-MS (Method 5): R = 2.70 min MS ): m/z = 418 [M+H]+ Example 21 (racemic mixture) Example 21 is synthesized as described for example 1 starting from example 44k (100 mg, 0.28 mmol), 2-Fluoro(trifluoromethyl)Pyridine (51 ul, 0.42 mmol) instead of 2-Chloro- -(trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (96 ul, 0.56 mmol) in DMSO.

The on mixture is heated in a microwave reactor during 30 minutes at 130°C; the crude t is purified by preparative S to obtain the title compound (92 mg, 66 % yield).

S (Method 10): R = 3.67 min MS (ES+): m/z = 504 [M+H]+ Example 22 (racemic mixture) Example 22 is synthesized as described for example 1 starting from example 44k (70 mg, 0.21 mmol), 2-ChloroFluoropyrimidine (41 ul, 0.33 mmol) instead of 2-Chloro (trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (76 ul, 0.45 mmol) and 1 ml of anhydrous DMSO. The on mixture is heated in a microwave reactor during 30 minutes at 130°C. After the work-up, the crude product is purified by preparative HPLC- MS to obtain the title compound (67 mg, 66 % yield).

HPLC-MS (Method 10): R = 3.25 min MS (ES+): m/z = 455 [M+H]+ Example 23 (racemic mixture) e 23 is synthesized as described for example 1 starting from e 44k (80 mg, 0.23 mmol), 2-Chloro-Pyrimidine (38 mg, 0.33 mmol) instead of 2-Chloro (trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (77 ul, 0.45 mmol) and 1 ml of anhydrous DMSO. The reaction mixture is heated in a microwave reactor during 30 minutes at 130°C. After the p, the crude product is purified by preparative HPLC- MS to obtain the title compound (82 mg, 84 % .

HPLC-MS (Method 10): R = 2.90 min MS (ES+): m/z = 437 [M+H]+ Example 24 (racemic mixture) Example 24 is synthesized as described for example 16 starting from example 44k (100 mg, 0.28 mmol) instead of example 44b, 2-Bromopyridine (32 ul, 0.33 mmol) instead of 2- Chloro-S-Fluoropyridine, X-Phos (53 mg, 0.1 1 mmol), Tris(dibenzylideneacetone)dipalladium(0) (51 mg, 0.06 mmol), sodium tert-butoxide (54 2014/072085 mg, 0.56 mrnol) and degassed Dioxane. The reaction mixture is heated in a microwave reactor at 100°C during 2 hours. After the work-up, the crude product is purified by preparative HPLC-MS to obtain the title compound (55 mg, 45 % yield).

HPLC-MS (Method 5): R = 2.72 min MS (APCI+): m/z = 436 [M+H]+ Example 25 (racemic mixture) Example 25 is synthesized as described for example 16 starting from example 44k (120 mg, 0.33 mmol) d of example 44b, 2-ChloroFluoropyridine (40 ul, 0.39 mrnol), X-Phos (63 mg, 0.13 mmol), Tris(dibenzylideneacetone)dipalladium(0) (60 mg, 0.07 mrnol), sodium tert-butoxide (63 mg, 0.66 mrnol) and ed Dioxane. The reaction e is heated in a microwave reactor at 100°C during 2 hours. After the work-up, the crude t is purified by preparative HPLC-MS to obtain the title compound (64 mg, 43 % yield).

HPLC-MS (Method 5): R = 2.91 min MS (APCI+): m/z = 454 [M+H]+ Example 26 (racemic mixture) Example 26 is synthesized as described for example 1 starting from example 44k (70 mg, 0.18 mmol), o(trifluoromethyl)pyrazine (60 mg, 0.26 mmol) instead of 2- (trifluoromethyl)pyrimidine, N,N-diisopropylethylamine (60 ul, 0.35 mmol) and 1 ml of anhydrous DMSO. The reaction mixture is heated in a microwave reactor during minutes at 150 0C. After the work-up, the crude product is purified by preparative HPLC-MS to obtain the title compound (43 mg, 48 % .

HPLC-MS (Method 10): R = 3.52 min MS (ES+): m/z = 505 [M+H]+ Example 27 (racemic mixture) F j F o Example 27 is synthesized as described for example 16 starting from example 44f (80 mg, 0.22 mmol) d of example 44b, 2-ChloroFluoropyridine (35 mg, 0.26 mmol), X- Phos (42 mg, 0.09 mmol), Tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.04 mmol) sodium tert-butoxide (42 mg, 0.44 mmol) and degassed Dioxane. The on mixture is heated in a microwave reactor at 100°C during 2 hours. After the work-up, the crude product is purified by Silica gel flash chromatography using cyclohexane/EtOAc 30:70 to 0:100 as eluent to obtain the title compound (35 mg, 35 % yield).

HPLC-MS (Method 10): R = 3.29 min MS (ES+): m/z = 454 [M+H]+ Example 28 (racemic mixture) Example 28 is synthesized as described for example 16 starting from example 44f (80 mg, 0.22 mmol) instead of example 44b, opyridine (25 ul, 0.26 mmol) instead of 2- ChloroFluoropyridine, X-Phos (42 mg, 0.09 mmol), ibenzylideneacetone)dipalladium(0) (40 mg, 0.04 mmol), sodium tert-butoxide (42 mg, 0.44 mmol) and degassed e. The reaction e is heated in a microwave reactor at 100°C during 2 hours. After the work-up, the crude product is purified by Silica gel flash chromatography using cyclohexane/EtOAc 20:80 to 0:100 as eluent to obtain the title compound (57 mg, 59 % yield).

HPLC-MS (Method 5): R = 2.72 min MS (APCI+): m/z = 436 [M+H]+ -l 10- Example 29 (racemic mixture) F j F o Example 29 is synthesized as described for example 16 starting from example 44i (80 mg, 0.22 mmol) instead of example 44b, 2-ChloroFluoropyridine (35 mg, 0.26 mmol), X- Phos (42 mg, 0.09 mmol), Tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.04 mmol), sodium tert-butoxide (42 mg, 0.44 mmol) and degassed Dioxane. The reaction mixture is heated in a ave reactor at 100°C during 2 hours. After the p, the crude product is purified by Silica gel flash chromatography using cyclohexane/EtOAc 30:70 to 0: 100 as eluent to obtain the title compound (59 mg, 58 % yield).

HPLC-MS d 10): R = 3.38 min MS (ES+): m/z = 454 [M+H]+ Example 30 (racemic mixture) F j F o e 30 is synthesized as described for example 16 starting from example 44i (80 mg, 0.22 mmol) instead of example 44b, 2-Bromopyridine (32 ul, 0.26 mmol) instead of 2- Chloro-S-Fluoropyridine, X-Phos (42 mg, 0.09 mmol), -lll- Tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.04 mmol),sodium tert-butoxide (42 mg, 0.44 mmol) and degassed e.The reaction mixture is heated in a microwave reactor at 100°C during 2 hours. After the work-up, the crude product is purified by Silica gel flash chromatography using cyclohexane/EtOAc 20:80 to 0:100 as eluent to obtain the title compound (54 mg, 56 % yield).

HPLC-MS (Method 5): R = 2.76 min MS (APCI+): m/z = 436 [M+H]+ Example 31 ic mixture) Example 31 is synthesized as described for example 18 starting from example 44f (100 mg, 0.27 mmol) instead of example 44k, N,N-diisopropylethylamine (47 ul, 0.27 mmol), l,l-dibromoformaldoxime (56 mg, 0.27 mmol), 2-Bromo-3,3,3-trifluoropropene (140 pl, 137 mmol), ylamine (76 ul, 0.55 mmol) and 2 ml of ous THF. After the work- up, the crude product is purified by Silica gel flash chromatography using cyclohexane/EtOAc 40:60 to 20:80 as eluent to obtain the title compound (47 mg, 34 % yield).

HPLC-MS (Method 10): R = 3.54 min MS (ES+): m/z = 494 [M+H]+ -l 12- e 32 (racemic mixture) Example 32 is synthesized as described for example 18 starting from example 44i (100 mg, 0.27 mmol) instead of example 44k, N,N—diisopropylethylamine (47 pl, 0.27 mmol), l,l- dibromoformaldoxime (56 mg, 0.27 mmol), 2-Bromo-3,3,3-trifluoropropene (140 pl, 1.37 mmol), triethylamine (76 pl, 0.55 mmol) and 2 ml of anhydrous THF. After the work-up, the crude product is purified by Silica gel flash chromatography using cyclohexane/EtOAc :70 to 20:80 as eluent to obtain the title compound (45 mg, 33 % yield).

HPLC-MS d 10): R = 3.59 min MS (ES+): m/z = 494 [M+H]+ Example 33 (racemic mixture) F F /IN GAOSW10] 0 Example 33 is synthesized as described for e 1 starting from example 47a (46 mg, 85% content estimated at 254 nm, 0.11 mmol) instead of example 44k, 2-Fluoro (trifluoromethyl)pyridine (17 pl, 0. 14 mmol) instead of 2-Chloro -l 13 - (trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (39 ul, 0.23 mmol) and anhydrous DMSO. The reaction mixture is heated in a microwave reactor at 100°C during 1 hour. The crude product is purified by preparative S to obtain the title compound (ll mg, 19 % yield).

HPLC-MS (Method 5): R = 2.85 min MS (APCI+): m/z = 489 [M+H]+ Example 34 (racemic mixture) Example 34 is synthesized as described for example 1 starting from example 44f (80 mg, 0.22 mmol) instead of example 44k, 2-Bromo(trifluoromethyl)pyrazine (75 mg, 0.33 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (75 ul, 0.44 mmol) and 1 ml of anhydrous DMSO. The reaction e is heated in a microwave reactor at 130°C during 30 minutes. After the work-up, the crude product is purified by Silica gel flash chromatography using exane/EtOAc 20:80 to 0:100 as eluent to obtain the title compound (83 mg, 74 % .

HPLC-MS (Method 5): R = 2.96 min MS (APCI+): m/z = 505 [M+H]+ —1 14— e 35 (racemic mixture) F O Example 35 is synthesized as described for example 1 starting from example 44f (80 mg, 0.22 mmol) instead of example 44k, 2-Fluoro(trifluoromethyl)Pyridine (54 mg, 0.33 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (75 ul, 0.44 mmol and 1 ml of anhydrous DMSO. The reaction mixture is heated in a microwave reactor at 130°C during 30 minutes. After the work-up, the crude product is purified by Silica gel flash chromatography using cyclohexane/EtOAc 20:80 to 0:100 as eluent to obtain the title compound (37 mg, 33 % .

HPLC-MS (Method 5); Rt = 3.17 min MS (APCI+): m/z = 504 [M+H]+ Example 36 (racemic mixture) F O*0/0S/H Example 36 is synthesized as described for example 1 starting from example 44f (80 mg, 0.23 mmol) d of example 44k, 2-Chloro-Pyrimidine (38 mg, 0.33 mmol) d of 2-Chloro(trifluoromethyl)pyrimidine, N,N-diisopropylethylamine (75 ul, 0.44 mmol) and 1 ml of anhydrous DMSO. The reaction e is heated in a microwave reactor at -l 15 - 130°C during 30 s.The crude product is purified by preparative HPLC-MS to obtain the title compound (77 mg, 79 % yield).

S (Method 5): R = 2.37 min MS (APCI+): m/z = 437 [M+H]+ Example 37 (racemic mixture) F o Example 37 is synthesized as described for example 1 starting from example 44f (80 mg, 0.23 mmol) d of example 44k, 2-ChloroFluoro-Pyrimidine (44 mg, 0.33 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N-diisopropylethylamine (75 ul, 0.44 mmol) and 1 ml of anhydrous DMSO. The reaction mixture is heated in a microwave reactor at 130°C during 30 minutes. The crude product is d by preparative HPLC- MS to obtain the title compound (52 mg, 51 % yield).

HPLC-MS (Method 5): R = 2.67 min MS (APCI+): m/z = 455 [M+H]+ -ll6- Example 38 (racemic mixture) e 38 is synthesized as described for example 1 starting from example 44i (80 mg, 0.22 mmol) instead of example 44k, 2-Bromo(trifluoromethyl)pyrazine (75 mg, 0.23 mmol) instead of ro(trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (75 ul, 0.44 mmol) and 1 ml of anhydrous DMSO. The reaction mixture is heated in a microwave reactor at 130°C during 30 minutes. After the work-up, the crude product is purified by Silica gel flash chromatography using cyclohexane/EtOAc 20:80 to 0:100 as eluent to obtain the title compound (71 mg, 63 % yield).

S (Method 5): R = 3.00 min MS (APCI+): m/z = 505 [M+H]+ Example 39 (racemic mixture) F O Example 39 is sized as described for example 1 starting from example 44i (80 mg, 0.22 mmol) instead of example 44k, 2-Fluoro(trifluoromethyl)Pyridine (54 mg, 0.33 -ll7- mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N-diisopropylethylamine (75 ul, 0.44 mmol) and 1 ml of anhydrous DMSO. The reaction e is heated in a microwave reactor at 130°C during 30 s. After EtOAc/HZO work-up, the crude product is purified by Silica gel flash chromatography using cyclohexane/EtOAc 20:80 to 0:100 as eluent to obtain the title compound (77 mg, 68 % yield).

HPLC-MS (Method 5): R = 3.19 min MS (APCI+): m/z = 504 [M+H]+ Example 40 (racemic mixture) N /N F 1 F O Example 40 is sized as described for example 1 starting from example 44i (80 mg, 0.23 mmol) instead of example 44k, 2-Chloro-Pyrimidine (38 mg, 0.33 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N-diisopropylethylamine (75 ul, 0.44 mmol) and 1 ml of anhydrous DMSO. The on mixture is heated in a microwave reactor at 130°C during 30 minutes. After the work-up, the crude product is purified by Silica gel flash chromatography using cyclohexane/EtOAc 20:80 to 0:100 as eluent to obtain the title compound (74 mg, 76 % yield).

HPLC-MS d 5): R = 2.50 min MS (APCI+): m/z = 437 [M+H]+ WO 55698 Example 41 (racemic mixture) Example 41 is sized as described for example 1 starting from example 44i (80 mg, 0.23 mmol) instead of example 44k, 2-ChloroFluoro-Pyrimidine (44 mg, 0.33 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N-diisopropylethylamine (75 ul, 0.44 mmol) and 1 ml of anhydrous DMSO. The reaction mixture is heated in a microwave reactor at 130°C during 30 minutes. After the work-up, the crude product is purified by Silica gel flash chromatography using cyclohexane/EtOAc 20:80 to 0:100 as eluent to obtain the title compound (44 mg, 43 % yield).

HPLC-MS (Method 5): R = 2.78 min MS ): m/z = 455 [M+H]+ Example 42 (enantiomer 1) and example 43 (enantiomer 2) The racemic mixture of the title compounds is sized as described for example 1 starting from example 44h (205 mg, 0.60 mmol) instead of example 44k, ro (trifluoromethyl)Pyridine (106 ul, 0.88 mmol) d of 2-Chloro (trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (210 ul, 1.21 mmol) and anhydrous DMSO. The reaction mixture is heated in a microwave reactor at 100°C during 1 hour. H20 was added and the resulting solid was filtered to obtain the racemic compound (277 mg).

UPLC-MS (Method 1): R = 1.16 min MS (ES+): m/z = 486 [M+H]+ WO 55698 -ll9- The enantiomers are obtained by HPLC separation using a chiral stationary phase.

Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent / IPA 60:40; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 254 nm Example of separation by chiral HPLC: Submitted to separation: 266 mg of racemic mixture prepared as described above; Obtained: 94 mg of enantiomer 1 (Exp. 42) and 99 mg of enantiomer 2 (Exp. 43) Example 42: enantiomer 1 Example 43: omer 2 .010N] //O 0 O Chiral HPLC HPLC-MS (Method 5): Rt Example MS (APCI+): m/Z Rt [mm]. [min] Exp. 42 11-74 3.12 486 (Method 12) Exp. 43 13-89 3.15 486 (Method 12) Example 44 ic mixture) F o Example 44 is sized as described for example 16 starting from example 44h (60 mg, 0.18 mmol) instead of example 44b, 2-Bromopyridine (20 ul, 0.21 mmol) instead of 2- ChloroFluoropyridine, X-Phos (17 mg, 0.04 mmol), Tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.02 mmol),sodium utoxide (34 mg, 0.35 mrnol) and degassed Dioxane. The reaction mixture is heated in a microwave reactor at 80°C during 2 hour. The crude reaction mixture is filtered and the filtrate is concentrated under reduced pressure; the residue is purified by SCX cartridge and then by preparative HPLC-MS to obtain the title compound (43 mg, 59 % yield).

HPLC-MS (Method 5): R = 2.57 min MS (APCI+): m/z = 418 [M+H]+ e 45 (racemic e) Example 45 is synthesized as described for example 43a starting from example 27a (102 mg, 0.37 mmol) instead of example 40c, HATU (183 mg, 0.48 mmol), N,N— diisopropylethylamine (159 ul, 0.93 mmol), tetrahydro-2H-thiopyrancarboxilic acid 1,1- - l 2 l - dioxide (86 mg, 0.48 mmol) and 2 ml of DMF. The crude on mixture is purified by preparative S to obtain the title compound (132 mg, 82 % yield).

HPLC-MS (Method 5): R = 2.77 min MS (APCI+): m/z = 436 [M+H]+ Example 46 (racemic mixture) Example 46 is synthesized as described for example 16 ng from example 44g (100 mg, 0.29 mmol) instead of e 44b, 2-ChloroFluoropyridine (50 mg, 0.38 mmol), X-Phos (56 mg, 0.12 mmol), Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (61 mg, 0.06 mmol), sodium tert-butoxide (56 mg, 0.59 mrnol) and degassed Dioxane. The reaction mixture is heated in a microwave reactor at 100°C during 2 hours to obtain 80 mg (63 % yield) of title compound after purification by preparative HPLC-MS.

HPLC-MS (Method 5): R = 2.71 min MS (APCI+): m/z = 436 [M+H]+ Example 47 (racemic mixture) F I s//0 Example 47 is synthesized as described for example 16 ng from example 44g (100 mg, 0.29 mmol) instead of example 44b, opyridine, (32 ul, 0.35 mmol), X-Phos (15 mg, 0.03 mmol), Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (14 mg, 0.01 mmol) sodium tert-butoxide (56 mg, 0.59 mrnol) and degassed . The reaction mixture is heated in a microwave reactor at 100°C during 2 hours to obtain 90 mg (73 % yield) of title compound after purification by preparative HPLC-MS.

HPLC-MS (Method 5): R = 2.50 min MS (APCI+): m/z = 418 [M+H]+ Example 48 (racemic mixture) Example 48 is synthesized as described for example 1 starting from example 44g (100 mg, 0.29 mmol) instead of example 44k, 2-ChloroFluoropyrimidine (46 mg, 0.35 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (60 ul, 0.35 mmol) and 2 ml of anhydrous DMSO. The reaction e is heated in a microwave reactor at 100°C during 2 hours. Afier the work-up, crude t is purified by preparative HPLC-MS to obtain the title compound (85 mg, 66 % .

HPLC-MS (Method 5): R = 2.62 min MS (APCI+): m/z = 437 [M+H]+ Example 49 (racemic mixture) N /N F I Example 49 is synthesized as described for e 1 starting from example 44g (100 mg, 0.29 mmol) instead of example 44k, 2-Chloro-Pyrimidine (40 mg, 0.35 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N-diisopropylethylamine (60 ul, 0.35 mmol) and 2 ml of anhydrous DMSO. The reaction mixture is heated in a microwave reactor at 100°C during 2 hours. Afier the work-up, the crude product is purified by Silica gel flash chromatography using DCM/MeOH 100:2 as eluent to obtain the title compound (85 mg, 69 % yield).

S (Method 5): R = 2.25 min MS (APCI+): m/z = 419 [M+H]+ —124— Example 50 (racemic mixture) N,N—diisopropylethylamine (0,97 ml, 5.68 mrnol) is slowly added under nitrogen atmosphere to a cooled (-20 oC) suspension of 1,1-dibromoformaldoxime (1.1 g, 5.68 mmol) and example 44h (1.9 g, 5.68 mmol) in 20 ml of anhydrous THF. The temperature is increased at 0 oC and the reaction is d 20 minutes. o-3,3,3-trifluoropropene (3.0 ml, 28.5 mrnol) is added dropwise followed by triethylamine (1.2 ml, 8.53 mmol), the on is stirred 30 minutes at 0°C and then at room temperature overnight. The crude is diluted with EtOAc and washed with water, aqueous HCl solution and brine; the organic phase is dried and concentrated under reduced pressure; the residue is purified by Silica gel flash chromatography using EtOAc/cyclohexane 30:70 to 100:0 to obtain the title compound (1.2 g, 45 % yield).

S (Method 5): R = 2.97 min MS (APCI+): m/z = 476 [M+H]+ The enantiomers are obtained by HPLC separation using a chiral stationary phase.

Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; : eluent hexane/ IPA 60:40; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 1.2 g of Example 50 ed as described above; Obtained: 418 mg of enantiomer 1 (Exp. 51) and 484 mg of enantiomer 2 (Exp. 52) Example 51: enantiomer 1 e 52: enantiomer 2 Chiral HPLC HPLC-MS (Method 5): Rt e MS (APCI+): m/Z Rt [mm]. [min] Exp. 51 8-39 2.96 476 (Method 13) Exp. 52 10.61 2.95 476 (Method 13) e 53 (racemic mixture) Example 53 is synthesized as described for example 43a starting from example 28a (158 mg, 0.55 mmol) instead of example 40c, HATU (251 mg, 0.66 mrnol), N,N— diisopropylethylamine (236 ul, 1.38 mmol), tetrahydro-2H-thiopyrancarboxilic acid 1,1- dioxide (118 mg, 0.66 mmol) and 2 ml of DMF. The crude product is purified by preparative HPLC-MS to obtain the title compound (170 mg, 74 % yield).

HPLC-MS d 5): R = 2.35 min MS (APCI+): m/z = 419 [M+H]+ Example 54 (racemic mixture) N /N F O e 54 is synthesized as described for example 43a starting from example 29a (152 mg, 0.55 mmol) instead of example 40c, HATU (251 mg, 0.66 mrnol), N,N— diisopropylethylamine (236 ul, 1.38 mmol), tetrahydro-2H-thiopyrancarboxilic acid 1,1- dioxide (118 mg, 0.66 mmol) and 2 ml of DMF. The crude product is purified by preparative HPLC-MS to obtain the title compound (91 mg, 38 % yield).

HPLC-MS (Method 14): R = 5.56 min MS (APCI+): m/z = 437 [M+H]+ Example 55 (racemic mixture) F O Example 55 is synthesized as described for example 16 starting from example 44h (80 mg, 0.23 mmol) d of example 44b, oMethylpyridine (48 mg, 0.28 mmol) instead of 2-ChloroFluoropyridine, X-Phos (44 mg, 0.09 mmol), -l27- Tris(dibenzylideneacetone)dipalladium(0) (42 mg, 0.05 mmol), sodium tert-butoxide (44 mg, 0.46 mmol) and degassed Dioxane. The reaction mixture is heated in a microwave reactor at 100°C during 2 hours. After the work-up the e is purified by Silica gel flash chromatography using DCM/MeOH 97:3 as eluent to obtain 68 mg (67 % yield) of title compound HPLC-MS (Method 5): R = 2.76 min MS (APCI+): m/z = 432 [M+H]+ Example 56 (racemic mixture) F O%©/ Example 56 is sized as described for example 16 starting from example 44h (80 mg, 0.23 mmol) instead of e 44b, 2-MethylBromopyridine (48 mg, 0.28 mmol) instead of 2-ChloroFluoropyridine, X-Phos (44 mg, 0.09 mmol), Tris(dibenzylideneacetone)dipalladium(0) (42 mg, 0.05 mmol), sodium tert-butoxide (44 mg, 0.46 mmol) and degassed Dioxane. The reaction mixture is heated in a microwave reactor at 100°C during 2 hours. After the work-up the residue is purified by Silica gel flash chromatography using DCM/MeOH 97:3 as eluent to obtain the title nd (65 mg, 64 % yield) HPLC-MS (Method 5): R = 2.43 min MS (APCI+): m/z = 432 [M+H]+ -l28- Example 57 (racemic mixture) F OAOS/ Example 57 is synthesized as described for example 16 starting from e 44h (80 mg, 0.23 mmol) instead of example 44b, 3-Bromo(Cyclopropyl)pyridine (55 mg, 0.28 mmol) instead of 2-ChloroFluoropyridine, X-Phos (44 mg, 0.09 mmol), ibenzylideneacetone)dipalladium(0) (42 mg, 0.05 mmol), sodium tert-butoxide (44 mg, 0.46 mmol) and degassed Dioxane. The reaction mixture is heated in a microwave reactor at 100°C during 2 hours. After the work-up the residue is purified by Silica gel flash chromatography using DCM/MeOH 97:3 as eluent to obtain the title compound (22 mg, 21% yield) HPLC-MS d 5): R = 2.72 min MS (APCI+): m/z = 458 [M+H]+ Example 58 (racemic mixture) OAOS/ Example 58 is synthesized as described for example 16 starting from example 44b (100 mg of free base, 0.29 mmol), 3-Bromo(Cyclopropyl)pyridine (75 mg, 0.29 mmol) instead of 2-ChloroFluoropyridine, 9,9-Dimethyl—4,5-Bis(Di-tert-Butylphosphino)Xantene (l5 mg, 0.03 mrnol) instead of X-phos, Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (30 mg, 0.03 mrnol), sodium tert-butoxide (57 mg, 0.59 mrnol) and degassed Dioxane. The on mixture is heated in a microwave reactor at 100°C during 2 hours.

After the p the residue is purified by preparative HPLC-MS to obtain the title compound (41 mg, 31% yield) HPLC-MS (Method 16): R = 3.27 min MS (APCI+): m/z = 458 [M+H]+ Example 59 (racemic mixture) F O Example 59 is synthesized as described for example 42b starting from example 30a (800 mg, 2.40 mmol) instead of example 40b, N—(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (691 mg, 3.60 mmol), ydro-2H-thiopyrancarboxilic acid 1,1- dioxide (642 mg, 3.60 mmol), 1-hydroxybenzotriazole (32 mg, 0.24 mmol) and 2 ml of DCM. The crude product is partitioned n DCM and water, the c layer is separated and concentrated under reduced pressure. The residue is purified by Silica gel flash chromatography using cyclohexane/EtOAc 50:50 to 0:100 as eluent to obtain the title compound (820 mg, 63 % yield).

HPLC-MS (Method 10): R = 3.47 min MS (ES+): m/z = 487 [M+H]+ The enantiomers are obtained by HPLC separation using a chiral stationary phase.

Method for separation: -l30- HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 62:38; flow rate: 15 , Temperature: 25°C; UV Detection: 254 nm e of separation by chiral HPLC: Submitted to separation: 800 mg of Example 59 prepared as described above; Obtained: 330 mg of enantiomer 1 (Exp. 60) and 339 mg of enantiomer 2 (Exp. 61) Example 60: enantiomer 1 Example 61: enantiomer 2 F F F O*0/08/II Chiral HPLC HPLC-MS d 5): Rt Example MS (APCI+): m/Z Rt [mm]. [min] Exp. 60 14.35 2.90 487 (Method 12) Exp. 61 15-91 2.90 487 (Method 12) Example 62 (racemic mixture) Example 62 is synthesized as described for e 16 starting from example 44c (100 mg, 0.28 mmol) instead of example 44b, 5-BromoCyclopropylpyrimidine (66 mg, 0.33 mmol) instead of 2-ChloroFluoropyridine, X-Phos (53 mg, 0.11 mmol), ibenzylideneacetone)dipalladium(0) (51 mg, 0.06 mrnol), sodium tert-butoxide (53 mg, 0.55 mrnol) and degassed Dioxane. The reaction mixture is heated in a microwave reactor at 100°C during 1.5 hours. After addition of EtOAc the formed solid is filterd out and the filtrate is concentrated under reduced pressure; the e is first purified by preparative HPLC-MS then by SCX cartridge to obtain the title compound (25 mg, 19 % yield) HPLC-MS d 5): R = 2.69 min MS (APCI+): m/z = 481 [M+H]+ Example 63 (racemic mixture) F I O%©/ e 63 is synthesized as described for example 16 starting from example 44b (100 mg of free base, 0.29 mmol), 2-MethylBromopyridine (51 mg, 0.29 mmol) instead of 2- ChloroFluoropyridine, 9,9-Dimethyl—4,5-Bis(Di-tert-Butylphosphino)Xantene (15 mg, 0.03 mrnol) instead of X-phos, Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (30 mg, 0.03 mmol),sodium tert-butoxide (57 mg, 0.59 mrnol) and degassed e. The reaction mixture is heated in a microwave r at 100°C during 2 hours.

After the work-up the residue is purified by preparative HPLC-MS to obtain the title nd (64 mg, 51% yield) HPLC-MS (Method 5): R = 2.38 min MS (APCI+): m/z = 432 [M+H]+ Example 64 (racemic mixture) O%©/ Example 64 is synthesized as described for example 16 starting from example 44b (100 mg of free base, 0.29 mmol), 2-BromoMethylpyridine (51 mg, 0.29 mmol) instead of 2- ChloroFluoropyridine, 9,9-Dimethyl—4,5-Bis(Di-tert-Butylphosphino)Xantene (15 mg, 0.03 mrnol) instead of , Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (30 mg, 0.03 mrnol), sodium tert-butoxide (57 mg, 0.59 mrnol) and ed Dioxane. The reaction mixture is heated in a microwave reactor at 100°C during 2 hours.

After EtOAc/water work-up the residue is purified by preparative HPLC-MS to obtain the title compound (59 mg, 46% yield) HPLC-MS (Method 5): R = 2.76 min MS (APCI+): m/z = 432 [M+H]+ 2014/072085 - l 33- Example 65 (racemic mixture) F O%©/ Example 65 is synthesized as described for example 16 starting from example 44h (70 mg, 0.20 mmol) instead of example 44b, 5-BromoCyclopropylpyrimidine (48 mg, 0.24 mmol) instead of 2-ChloroFluoropyridine, X-Phos (38 mg, 0.08 mrnol), Tris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 sodium tert-butoxide (39 mg, 0.40 mmol) and degassed Dioxane. The reaction mixture is heated in a microwave reactor at 100°C during 2 hours. After addition of EtOAc the formed solid is filtered out over a celite pad and the filtrate is concentrated under reduced pressure; the residue is first purified by preparative HPLC-MS then by a work-up with DCM/citric acid to obtain the title compound (37 mg, 39 % yield) S (Method 5): R = 2.45 min MS (APCI+): m/z = 459 [M+H]+ Example 66 (racemic mixture) 0AOS/ Example 66 is synthesized as described for example 16 starting from example 44g (76 mg, 0.22 mmol) d of e 44b, 2-BromoMethylpyridine (46 mg, 0.27 mmol) —134— instead of 2-ChloroFluoropyridine, X-phos (43 mg, 0.09 mrnol), Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (46 mg, 0.04 mrnol), sodium tert-butoxide (43 mg, 0.45 mmol) and degassed Dioxane. The reaction e is heated in a ave reactor at 100°C during 2 hours. After the work-up the residue is purified by Silica gel flash chromatography using DCM/MeOH 100:2 as eluent to obtain the title compound (65 mg, 67% yield) HPLC-MS (Method 5): R = 2.68 min MS ): m/z = 432 [M+H]+ Example 67 (racemic mixture) OAOS/ e 67 is synthesized as described for example 16 starting from example 44g (76 mg, 0.22 mmol) instead of example 44b, 2-MethylBromopyridine (42 mg, 0.24 mmol) instead of 2-ChloroFluoropyridine, X-phos (43 mg, 0.09 mrnol), Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (46 mg, 0.04 mrnol), sodium tert-butoxide (43 mg, 0.45 mmol) and 2 ml of degassed Dioxane. The reaction mixture is heated in a microwave reactor at 100°C during 2 hours. After the work-up the e is purified by Silica gel flash chromatography using DCM/MeOH 100:4 as eluent to obtain the title compound (60 mg, 62% yield) HPLC-MS (Method 5): R = 2.33 min MS (APCI+): m/z = 432 [M+H]+ Example 68 ic mixture) OAOS/ Example 68 is synthesized as described for example 16 starting from example 44g (100 mg, 0.29 mmol) instead of example 44b, oCyclopropylpyrimidine (70 mg, 0.35 mmol) instead of 2-ChloroFluoropyridine, 2-dicyclohexylphosphino-2’-(N,N— dimethylamino)biphenyl (35 mg, 0.09 mmol) instead X-Phos, Tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mrnol), ium tert-butoxide (50 mg, 0.45 mmol) and degassed Dioxane. The reaction mixture is heated in a microwave reactor at 130°C during 1 hour. After the work-up the residue is purified by Silica gel flash chromatography using DCM/MeOH 100:4 as eluent to obtain the title compound (20 mg, % yield) HPLC-MS (Method 5): R = 3.32 min MS (APCI+): m/z = 459 [M+H]+ Example 69 (racemic mixture) Ffg: W"3,0*03.|| N,N-diisopropylethylamine (47 ul, 0.27 mmol) is added into a d solution of example 16a (25 mg, 0.14 mmol) and 2-ChloroTrifluoromethyl-(1,3,4)-Thiadiazole (19.7 ul, 0.18 mmol) dissolved in 1 ml of ous DMSO. The reaction mixture is heated in a microwave reactor at 100°C for 30 minutes. The crude is partitioned between EtzO and 5% aqueous NaHCOg, the aqueous layer is extracted with 1:1 EtZO/EtOAc e and then the collected organic phases are dried and concentrated under reduced pressure; the obtained crude intermediate is dissolved in 2 ml of ous DCM, N,N— diisopropylethylamine (35 ul, 0.20 mmol) and oxothianecarbonyl chloride (40 mg, 0.20 mrnol previously prepared from the corresponding carboxilic acid and oxalyl chloride in anhydrous DCM) are added and the reaction is stirred overnight. DCM is added and the reaction mixture is washed with 1N aqueous HCl; the organic layer is separated, dried and concentrated under reduced pressure; the residue is purified by ative HPLC-MS and then by Silica gel flash chromatography using Cyclohexane/EtOAc 40:60 to 0: 100 as eluent to obtain the title product (12 mg, 18 % yield).

HPLC-MS (Method 5): R = 2.56 min MS (APCI+): m/z = 496 [M+H]+ Example 70 (racemic mixture) O%©/ 0 Example 70 is sized as described for example 16 starting from example 44b (100 mg of free base, 0.29 mmol), 5-BromoCyclopropylpyrimidine (70 mg, 0.35 mmol) instead of 2-ChloroFluoropyridine, X-Phos (56 mg, 0.12 mmol), ibenzylideneacetone)dipalladium(0) (54 mg, 0.06 mmol), sodium tert-butoxide (56 mg, 0.59 mmol) and 2 ml of degassed Dioxane. The reaction mixture is heated in a -l37- ave reactor at 100°C during 2 hours. The crude reaction mixture is filtered and washed with EtOAc, the filtrate is trated under reduced re and the residue is purified by preparative HPLC-MS; collected fractions are concentrated under d pressure and the product is partitioned between EtOAc and aqueous HCl on. The organic layer is separated, washed with 5% aqueous NaHC03 solution; it is dried and concentrated under reduced pressure to obtain the title compound (61 mg).

HPLC-MS (Method 10): R = 2.93 min MS (ES+): m/z = 459 [M+H]+ Example 71 (racemic mixture) \ s CI fi/fi Example 49a (280 mg) and hydroxylamine (50% aqueous solution, 78 ul, 1.27 mmol) are dissolved in 2 ml of EtOH and the reaction is heated in a microwave reactor during 30 minutes at 100°C. The solvent is removed under reduced pressure to obtain 200 mg of crude 3 -(5 -Chloro-thiophenyl)(l l -dioxo-hexahydro- l lambda*6 * -thiopyran carbonyl)-N-hydroxy-piperazine-l-carboxamidine intermediate (HPLC-MS (Method =l.99 min, MS (ES+): m/z = 421 ) that is dissolved in 2 ml of acetonitrile; difluoroacetic anhydride (109 mg, 0.63 mmol) and N,N-diisopropylethylamine (160 ul, 0.94 mmol) are added and the reaction is heated in a microwave reactor during 30 minutes at 100°C. The t is removed and the crude is partitioned between EtOAc and water, the organic layer is separated and concentrated under reduced pressure; the residue is purified by Silica gel flash chromatography using DCM/MeOH 99:1 to 90:10 as eluent to obtain the title compound (35 mg, 10% yield over two steps). - l 3 8- HPLC-MS (Method 5): R = 3.00 min MS (APCI+): m/z = 481 [M+H]+ Example 72 (racemic e) W"$1.2054|| Example 72 is synthesized as described for example 69 starting from example 16a (25 mg, 0.14 mmol), N,N—diisopropylethylamine (47 ul, 0.27 mmol for the first step, 35 ul, 0.20 for the second), 2-BromoTrifluoromethylpyrazine (40 mg, 0.18 mmol) instead 2-Chloro Trifluoromethyl-(l,3,4)-Thiadiazole, oxothianecarbonyl chloride (40 mg, 0.20 mmol previously prepared from the corresponding carboxilic acid and oxalyl chloride in anhydrous DCM), to obtain, after the purification, the title compound (17 mg, 26 % yield).

S (Method 5): R = 2.83 min MS (APCI+): m/z = 490 [M+H]+ Example 73 (racemic mixture) Example 73 is synthesized as bed for example 1 starting from example 44h (60 mg, 0.18 mmol) instead of example 44k, ro(trifluoromethyl)pyrimidine (48 mg, 0.26 mmol), N,N—diisopropylethylamine (91 ul, 0.53 mmol) and 1 ml of anhydrous DMSO. The reaction mixture is heated in a microwave reactor at 100°C during 2 hours. The crude is d by preparative HPLC-MS to obtain the title compound (69 mg, 79% yield).

HPLC-MS (Method 10): R = 3.63 min MS (ES+): m/z = 487 [M+H]+ The enantiomers are obtained by HPLC tion using a chiral stationary phase.

Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 70:30; flow rate: 15 mL/min, Temperature: 26°C; UV Detection: 254 nm Example of separation by chiral HPLC: Submitted to separation: 620 mg of e 73; Obtained: 217 mg of enantiomer 1 (Exp. 74) and 223 mg of enantiomer 2 (Exp. 75) Example 74: enantiomer 1 Example 75: enantiomer 2 F F F F F F \ \ | | NYN N /N F O F O /O /O S/ S/ g H Chiral HPLC HPLC-MS (Method 10): Rt Example MS (138+): m/z Rt [min] [min] Exp. 74 14.85 3.61 487 —140— d 15) Exp. 75 19.42 3.60 487 (Method 15) Alternative synthesis of example 74 (single enantiomer; R- configuration) N—(3-Dimethylaminopropyl)-N'-Ethylcarbodiimidehydrochloride (15 mg, 0.1 mmol) is added to a stirred solution of example 63a (20 mg, 0.1 mmol), tetrahydro-2H-thiopyran carboxilic acid 1,1-dioxide (15 mg, 0.1 mmol) and 1-Hydroxyazabenzotriazole (10 mg, 0.1 mmol) dissolved in 0.5 ml of DMF and 1.5 ml of anhydrous THF under nitrogen atmosphere; the reaction is then stirred 16 hours. THF is removed under reduced pressure and the e is ioned between water and EtOAc. The organic layer is separated, dried over anhydrous NaZSO4 and concentrated under d pressure. Crude product is purified by Silica gel flash chromatography, using EtOAc/Hexane/MeOH 1 as eluent, to obtain the title nd (26 mg, 97% yield; enantiomeric excess 97.4%).

HPLC-MS (Method 10): R = 3.60 min MS (ES+): m/z = 487 [M+H]+ Chiral HPLC (Method 15): R = 14.9 min, 98.7% at 230 nm (R— Enantiomer) .0 min, 1.3% at 230 nm (S- enantiomer) ative synthesis of example 75 (single enantiomer; 8- configuration) N—(3-Dimethylaminopropyl)-N'-Ethylcarbodiimidehydrochloride (25 mg, 0.1 mmol) is added to a stirred solution of example 69a (30 mg, 0.1 mmol), tetrahydro-2H-thiopyran carboxilic acid oxide (20 mg, 0.1 mmol) and 1-Hydroxyazabenzotriazole (12 mg, 0.1 mmol) dissolved in 0.5 ml of DMF and 1.5 ml of anhydrous THF under nitrogen atmosphere then the reaction is stirred 16 hours. THF is removed under reduced pressure and the residue is partitioned between water and EtOAc. The organic layer is separated, washed with 5% NaHC03 aqueous solution, dried over anhydrous NaZSO4 and —141— concentrated under reduced re. The crude product is purified by Silica gel flash chromatography, using DCM/MeOH 100:2 as eluent, to obtain the title compound (30 mg, 74% yield; enantiomeric excess 89%).

UPLC-MS (Method 1): R = 1.18 min MS (ES+): m/z = 487 [M+H]+ Chiral HPLC d 15): R = 15.1 min, 5.5% (R— Enantiomer) R = 19.0 min, 94.5% (S- Enantiomer) Example 76 (racemic mixture) Example 76 is synthesized as described for e 50 using N,N-diisopropylethylamine (100 ul, 0.58 mmol), 1,1-dibromoformaldoxime (120 mg, 0.59 mmol), example 44g (200 mg, 0.59 mmol) instead of example 44h, o-3,3,3-trifluoropropene (0.31 ml, 2.94 mmol), triethylamine (100 ul, 1.22 mmol). After the work-up the residue is purified by Silica gel flash chromatography using DCM/MeOH 100:3 as eluent to obtain the title compound (70 mg, 25 % yield).

HPLC-MS (Method 5): R = 3.03min MS (APCI+): m/z = 476 [M+H]+ —142— Example 77 (racemic mixture) F \l *0 Example 77 is synthesized as described for example 50 using N,N—diisopropylethylamine (48 ul, 0.28 mmol), 1,1-dibromoformaldoxime (57 mg, 0.28 mmol), e 441 (100 mg, 0.28 mmol) instead of example 44h, o-3,3,3-trifluoropropene (247 mg, 1.41 mmol), triethylamine (79 ul, 0.57 mmol). After the work-up the residue is purified by Silica gel flash chromatography using EtOAc/cyclohexane 50:50 to 100:0 as eluent then by preparative HPLC-MS to obtain the title compound (42 mg, 30 % yield).

HPLC-MS (Method 5); Rt = 3.17 min MS (APCI+): m/z = 482 [M+H]+ Example 78 (racemic e) Example 53a (54 mg, 0.11 mmol), potassium cyclopropyltrifluoroborate (31 mg, 0.21 mmol), butyl-l-adamanthylphosphine (1.5 mg), palladium(II) acetate (0.5 mg) and cesium carbonate (102 mg, 0.31 mmol) are suspended in 0.9 ml of toluene and 0.1 ml of water and the reaction mixture is heated in a microwave reactor during 2 hours at 100°C. Potassium —143— cyclopropyltrifluoroborate (31 mg, 0.21 mmol) is added a second time and the reaction is heated in a ave reactor during 2 hours at 100°C.

The mixture is diluted with EtOAc and water, the organic layer is separated and concentrated under reduce pressure then the residue is ded in 0.9 ml of toluene and 0.1 ml of water, potassium cyclopropyltrifluoroborate (61 mg, 0.42 mmol), butyl-l- thy1phosphine (2 mg), palladium(II) acetate (1 mg) and cesium carbonate (102 mg, 0.31 mmol) are added and the reaction mixture is heated in a microwave reactor during 1 hour at 115°C.

EtOAc and water are added, the s layer is further extracted with DCM then the organic phases are collected, dried and concentrated under reduced pressure. The residue is purified by preparative HPLC-MS to obtain the title compound (11 mg, 22% yield).

HPLC-MS (Method 5): R = 3.21 min MS (APCI+): m/z = 487 [M+H]+ Example 79 (racemic mixture) Example 79 is synthesized as described for e 50 using N,N—diisopropylethylamine (71 ul, 0.41 mmol),1,1-dibromoformaldoxime (84 mg, 0.41 mmol), example 44c (150 mg, 0.41 mmol) d of example 44h, 2-Bromo-3,3,3-trifluoropropene (213 ul, 2.07 mmol), triethylamine (75 ul, 0.54 mmol). After the work-up the residue is purified by Silica gel flash chromatography using DCM/MeOH 100:0 to 90:10 as eluent then by preparative HPLC-MS to obtain the title compound (33 mg, 16 % yield). —144— HPLC-MS (Method 5): R = 3.40 min MS (APCI+): m/z = 498 [M+H]+ Example 80 (racemic mixture) F 0&0séo\\ e 80 is sized as described for e 42b starting from example 31a (175 mg, 0.54 mmol) instead of example 40b, N—(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (154 mg, 0.80 mmol), tetrahydro-2H-thiopyrancarboxilic acid 1,1- dioxide (143 mg, 0.80 mmol) and 1-hydroxybenzotriazole (7 mg, 0.05 mol), 5 ml of DCM. The crude is partitioned between DCM and water, the organic layer is washed with aqueous NaHCOg, dried and concentrated under reduced pressure and the residue is purified by Silica gel flash cromatography using EtOAc/cyclohexane 60:40 to 100:0 as , to obtain the title compound (111 mg, 42% yield).

HPLC-MS (Method 5): R = 2.80 min MS (APCI+): m/z = 487 [M+H]+ 2014/072085 —145— Example 81 (racemic e) Example 54a (280 mg, 0.51 mmol), potassium cyclopropyltrifluoroborate (210 mg, 1.42 mmol), butyl-l-adamanthylphosphine (60 mg, 0.17 mmol), palladium(II) acetate (13 mg, 0.06 mrnol) and K3PO4 (420 mg, 1.98 mmol) are suspended in 5 ml of degassed toluene and 0.25 ml of water and the reaction mixture is heated in a microwave reactor during 1 hour at 130°C. The crude is partitioned between EtOAc and water, the organic layer is separated, dried over Na2S04 and concentrated under reduced re. The residue is purified by Silica gel flash chromtography using DCM/MeOH 100:2 as eluent to obtain 45 mg (19 % yield) of the title compound.

HPLC-MS (Method 16): R = 3.94 min MS (ES+): m/z = 459 [M+H]+ Example 82 (racemic mixture) Example 82 is synthesized as described for example 1 starting from example 44b (100 mg of free base, 0.29 mmol) d of example 44k, 2-Chlorocyclopropylpyrimidine (68 mg, 0.43 mmol) d of 2-Chloro(trifiuoromethyl)pyrimidine, N,N— diisopropylethylamine (98 ul, 0.58 mmol) and 2 ml of anhydrous DMSO. The on mixture is heated 2 hours at 115°C in a microwave reactor; the crude is purified by preparativer HPLC-MS to obtain the title compound (41 mg, 31% yield) HPLC-MS (Method 5): R = 2.93 min MS (APCI+): m/z = 459 [M+H]+ Example 83 (racemic mixture) C' \' KO Example 83 is synthesized as bed for example 16 starting from example 44c (100 mg of the corresponding hydrochloride, 0.24 mmol) instead of example 44b, 5-Bromo (trifluoromethyl)pyrimidine (64 mg, 0.28 mmol) instead of 2-ChloroFluoropyridine, X- Phos (45 mg, 0.09 mmol), Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (49 mg, 0.05 mmol) and sodium tert-butoxide (57 mg, 0.59 mmol) in 2 ml of dioxane. The reaction mixture is heated 1.5 hours at 100°C in a microwave reactor. The on mixture is diluted with EtOAc, filtered over a celite pad and then it is concentrated under reduced pressure. The residue is purified by Silica gel flash chromatography using cyclohexane/EtOAc 98:2 to 70:30 as eluent to obtain 24 mg (20% yield) of the title product.

HPLC-MS (Method 14): R = 6.12 min MS (APCI+): m/z = 509 [M+H]+ —147— e 84 (racemic mixture) F \l \c\) Example 84 is sized as described for example 42b starting from example 32a (30 mg, 0.08 mmol) instead of example 40b, N—(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol), tetrahydro-2H-thiopyrancarboxilic acid l,l-dioxide (22 mg, 0.12 mmol) and l-hydroxybenzotriazole (1 mg, 0.01 mol), 3 ml of DCM. The crude is partitioned between DCM and water, the c layer is washed with aqueous NaHCOg, dried and concentrated under redcued pressure. The residue is purified by Silica gel flash cromatography using EtOAc/cyclohexane 50:50 to 100:0 as eluent, to obtain the title compound (ll mg, 26% yield).

HPLC-MS (Method 16): R = 4.05 min MS (ES+): m/z = 493 [M+H]+ Example 85 (racemic mixture) Example 85 is synthesized as described for example 16 starting from example 44b (100 mg of free base, 0.29 mrnol), 5-Bromo(trifiuoromethyl)pyrimidine (80 mg, 0.35 mmol) instead 2-ChloroFluoropyridine, X-Phos (56 mg, 0.12 mmol), Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (61 mg, 0.06 mrnol), sodium tert-butoxide (56 mg, 0.59 mrnol) and ed Dioxane; the reaction mixture is heated in a microwave reactor during 2 hours at 100°C. The crude reaction e is filtered and purified by ative HPLC-MS to obtain the title compound (86 mg, 60 % yield).

HPLC-MS (Method 5): R = 2.70 min MS (APCI+): m/z = 487 [M+H]+ Example 86 (racemic mixture) F fi’ Example 86 is synthesized as described for example 16 starting from example 44b (100 mg of free base, 0.29 mmol), 2-Bromomethylpyrazine (61 mg, 0.35 mmol) instead of 2- ChloroFluoropyridine, X-Phos (56 mg, 0.12 mmol), ibenzylideneacetone)dipalladium(0) chloroform adduct (61 mg, 0.06 mrnol), sodium tert-butoxide (56 mg, 0.59 mrnol) and degassed Dioxane; the reaction mixture is heated in a microwave reactor at 100°C during 2 hours. The crude on mixture is filtered and purified by preparative HPLC-MS to obtain the title compound (86 mg, 67 % yield).

S (Method 5): R = 2.37 min MS (APCI+): m/z = 433 [M+H]+ WO 55698 —149— Example 87 (racemic mixture) Fxii")\l GAO Example 87 is synthesized as described for example 16 starting from example 441 (60 mg, 0.17 mmol), omethylpyrazine (35 mg, 0.20 mmol) instead of 2-Chloro Fluoropyridine, 2-Dicyclohexylphosphino-2’,6’-Dimethoxybiphenyl (21 mg, 0.05 mmol) instead X-Phos, Tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.02 mmol), potassium utoxide (29 mg, 0.25 mmol) and Dioxane; the reaction mixture is heated in a microwave reactor at 130°C during 1 hour. After the work-up crude t was purified by preparative HPLC-MS to obtain the title compound (37 mg, 49 % yield).

HPLC-MS d 5): R = 2.48 min MS (APCI+): m/z = 439 [M+H]+ Example 88 (racemic mixture) F j s/’0 Example 88 is synthesized as described for example 16 starting from example 44g (100 mg, 0.29 mmol), 2-Bromomethylpyrazine (60 mg, 0.35 mmol) instead of 2-Chloro Fluoropyridine, 2-dicyclohexylphosphino-2’-(N,N—dimethylamino)biphenyl (40 mg, 0.10 WO 55698 - l 5 0- mmol) instead X-Phos, Tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol), potassium tert-butoxide (50 mg, 0.45 mmol) and Dioxane; the reaction mixture is heated at 130°C in a microwave reactor during 1 hour. After the work-up crude product was purified by preparative HPLC-MS to obtain the title compound (20 mg, 16 % yield).

HPLC-MS d 5): R = 2.33 min MS (APCI+): m/z = 433 [M+H]+ Example 89 (racemic e) s N] Example 89 is synthesized as described for e 43a starting from e 33a (75 mg, 0.23 mmol) instead of example 40c, HATU (105 mg, 0.27 mmol) and N,N— diisopropylethylamine (120 pl, 0.69 mmol), tetrahydro-2H-thiopyrancarboxilic acid l,l- dioxide (45 mg, 0.25 mol), 4 ml of acetonitrile instead of DMF. After the work-up the residue is purified by preparative HPLC-MS to obtain the title compound (23 mg, 20 % yield) as hydrochloride by addition of 37% HCl during the evaporation.

HPLC-MS (Method 5): R = 2.63 min MS (APCI+): m/z = 455 [M+H]+ -15 1- Example 90 ic mixture) o N Example 58a (56 mg, 0.21 mmol) is added into a solution of example 441 (50 mg, 0.14 mmol) and N,N—diisopropylethylamine (36 ul, 0.21 mmol) dissolved in 1 ml of DMSO.

After 6 hours stirring the reaction mixture is d by preparative HPLC-MS to obtain the title compound (41 mg, 59 % yield).

HPLC-MS (Method 5): R = 2.71 min MS (APCI+): m/z = 483 [M+H]+ Example 91 (racemic mixture) F o s/’O Example 91 is synthesized as described for example 16 starting from example 44h (60 mg, 0.17 mmol) instead of example 44b, 2-Bromomethylpyrazine (36 mg, 0.21 mmol) instead of 2-ChloroFluoropyridine, 2-Dicyclohexylphosphino-2’,6’-Dimethoxybiphenyl (21 mg, 0.05 mmol) instead of X-Phos, Tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.02 mmol), potassium tert-butoxide (29 mg, 0.25 mmol) and Dioxane; the reaction mixture is heated at 130°C in a microwave reactor during 1 hour. After the work-up, the crude product is purified by ative HPLC-MS to obtain the title compound (39 mg, 51 % yield).

HPLC-MS (Method 10): R = 2.84 min MS (ES+): m/z = 433 [M+H]+ e 92 (racemic mixture) s N] \ I Example 92 is synthesized as described for example 89 starting from example 34a (55 mg, 0.13 mmol) instead of example 33a, HATU (61 mg, 0.16 mmol) and N,N— diisopropylethylamine (70 ul, 0.40 mmol), tetrahydro-2H-thiopyrancarboxilic acid 1,1- dioxide (26 mg, 0.15 mol), 2 ml of itrile. After the work-up the residue is purified by preparative HPLC-MS to obtain the title compound (29 mg, 47 % yield).

HPLC-MS (Method 5): R = 2.88 min MS (APCI+): m/z = 455 [M+H]+ Example 93 (racemic mixture) s N] \ I e 93 is synthesized as described for example 89 starting from example 35a (70 mg, 0.16 mmol) instead of example 33a, HATU (73 mg, 0.19 mrnol) and N,N- diisopropylethylamine (84 ul, 0.48 mmol), tetrahydro-2H-thiopyrancarboxilic acid 1,1- dioxide (32 mg, 0.18 mol), 4 ml of itrile. After the work-up the residue is purified by preparative HPLC-MS to obtain the title compound (48 mg, 62 % yield).

HPLC-MS (Method 5); Rt = 3.17 min MS (APCI+): m/z = 481 [M+H]+ Example 94 (racemic mixture) Example 94 is synthesized as described for e 1 starting from example 44g (200 mg, 0.59 mmol) instead of example 44k, 2-Chlorocyclopropylpyrimidine (130 mg, 0.84 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (190 ul, 1.11 mmol) and 2 ml of ous DMSO; the reaction mixture is heated at 100°C during 30 minutes in a ave reactor; after work-up the crude is purified by —154— Silica gel flash chromatography using EtOAc/hexane/MeOH 80:20:l to obtain the title compound (110 mg, 41% yield) HPLC-MS d 10): R = 3.28 min MS (ES+): m/z = 459 [M+H]+ Example 95 (racemic mixture) . 1 e 95 is synthesized as described for example 42b starting from example 36a (130 mg, 0.36 mmol) instead of example 40b, N—(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (140 mg, 0.73 mmol), tetrahydro-2H-thiopyrancarboxilic acid l,l- dioxide (85 mg, 0.48 mmol) and l-hydroxybenzotriazole (6 mg, 0.04 mmol) in F 1:1 mixture instead of DCM. After the aqueous work-up the residue is purified by Silica gel flash chromatography, using hexane/EtOAc/MeOH 20:80:l as eluent, to obtain the title compound (110 mg, 63% yield) HPLC-MS (Method 10): R = 3.25 min MS (ES+): m/z = 487 [M+H]+ Example 96 (racemic mixture) \ I GAO/O Example 96 is sized as described for e 1 starting from example 441 (50 mg, 0.14 mmol) instead example 44k, 2-Bromo(trifluoromethyl)pyrazine (49 mg, 0.22 mmol) instead 2-Chloro(trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (49 ul, 0.29 mmol) and 1 ml of anhydrous DMSO; the on mixture is heated at 130°C during minutes in a microwave reactor; after the water/EtOAc work-up the crude is purified by Silica gel flash tography using EtOAc/cyclohexane 60:40 to 100:0 as eluent to obtain the title compound (37 mg, 51% yield) HPLC-MS (Method 5): R = 2.98 min MS (APCI+): m/z = 493 [M+H]+ Example 97 (racemic mixture) N /N 3,1,0N]o s//0 Example 97 is synthesized as described for example 1 starting from example 441 (50 mg, 0.14 mmol) instead of example 44k, 2-Chlorocyclopropylpyrimidine (34 mg, 0.22 -15 6- mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (49 ul, 0.29 mmol) and 1 ml of anhydrous DMSO; the reaction mixture is heated during 30 minutes at 130°C in a ave reactor; the crude is purified by preparative HPLC-MS to obtain the title compound (13 mg, 19% yield) HPLC-MS (Method 5): R = 2.96 min MS (APCI+): m/z = 465 [M+H]+ Example 98 (racemic e) Example 98 is synthesized as described for example 1 starting from example 441 (50 mg, 0.14 mmol) instead example 44k, 2-Chlorotrifluoromethyl-(1,3,4)-thiadiazole (40 mg, 0.21 mmol) instead 2-Chloro(trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (50 ul, 0.29 mmol) and 1 ml of anhydrous DMSO; the on mixture is heated during 30 minutes at 130°C in a microwave reactor; after the work-up the crude is purified by Silica gel flash chromatography using EtOAc/cyclohexane 60:40 to 100:0 as eluent to obtain the title nd (51 mg, 72% yield) HPLC-MS (Method 5): R = 3.44 min MS (APCI+): m/z = 499 [M+H]+ -15 7- Example 99 (racemic mixture) \ I GAO/O Example 99 is synthesized as bed for example 1 starting from example 441 (50 mg, 0.14 mmol) instead example 44k, 2-Chloro(trifluoromethyl)pyrimidine (39 mg, 0.21 mmol), N,N—diisopropylethylamine (49 ul, 0.28 mmol) and 1 m1 of anhydrous DMSO; the reaction mixture is heated during 30 minutes at 130°C in a microwave reactor; the crude is purified by preparative HPLC-MS to obtain the title compound (47 mg, 67% yield) S (Method 10): R = 3.15 min MS (ES+): m/z = 493 [M+H]+ Example 100 (racemic mixture) \ I GAO/O Example 100 is synthesized as described for example 1 starting from example 441 (70 mg, 0.20 mmol) instead example 44k, 2-ChloroMethylpyrimidine (39 mg, 0.30 mmol), N,N- diisopropylethylamine (69 ul, 0.40 mmol) and 1 m1 of anhydrous DMSO; the on mixture is heated during 30 minutes at 130°C in a ave reactor; the crude is d by preparative HPLC-MS to obtain the title compound (16 mg, 18% yield) - l 5 8- HPLC-MS (Method 5): R = 2.67 min MS ): m/z = 439 [M+H]+ Example 101 (racemic mixture) Example 101 is synthesized as described for example 1 starting from example 44h (50 mg, 0.15 mmol) instead example 44k, 2-Chlorocyclopropylpyrimidine (34 mg, 0.22 mmol) instead 2-Chloro(trifluoromethyl)pyrimidine, N,N-diisopropylethylamine (50 ul, 0.29 mmol) and 1 ml of anhydrous DMSO; the on mixture is heated during 30 minutes at 130°C in a microwave reactor; the crude is purified by preparative HPLC-MS to obtain the title nd (19 mg, 28% yield) HPLC-MS (Method 5): R = 2.87 min MS (APCI+): m/z = 459 [M+H]+ Example 102 (enantiomer 1) and example 103 (enantiomer 2) The racemic mixture of the title compounds is synthesized as described for example 1 starting from example 44c (90 mg of the corresponding hydrochloride, 0.2 mmol) d of example 44k, ro(trifluoromethyl)pyrimidine (52 mg, 0.3 mmol), N,N— diisopropylethylamine (133 pl, 0.8 mmol) and 1 ml of anhydrous DMSO; the reaction mixture is heated during 1 hour at 150°C in a microwave reactor; the crude is purified by ative HPLC-MS to obtain 73 mg (75% yield) ofracemic product.

HPLC-MS (Method 4): R = 7.07 min MS (APCI+): m/z = 509 [M+H]+ The enantiomers are ed by HPLC separation using a chiral stationary phase.

Method for tion: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 70:30; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 504 mg of racemic mixture; Obtained: 181 mg of enantiomer 1 (Exp. 102) and 183 mg of enantiomer 2 (Exp. 103) Example 102: enantiomer 1 Example 103: enantiomer 2 T NTN 3 IN] a" 030 xii") fi II 0 o Chiral HPLC HPLC-MS (Method 5): Rt Example MS ): m/Z Rt [mm]. [min] Exp. 102 14-09 3.32 509 (Method 15) Exp. 103 17-90 3.34 509 (Method 15) Example 104 (racemic mixture) Example 104 is synthesized as bed for example 1 starting from example 44b (60 mg of the corresponding hydrochloride, 0.19 mmol) instead of example 44k, 2-Chloro Methylpyrimidine (24 mg, 0.19 mmol) d of 2-Chloro(trifluoromethyl)pyrimidine, N,N-diisopropylethylamine (107 ul, 0.62 mmol) and 1 ml of anhydrous DMSO; the reaction mixture is heated during 30 minutes at 120°C in a microwave reactor; the crude is purified by preparative HPLC-MS to obtain the title compound (23 mg, 34% yield) HPLC-MS (Method 10): R = 3.08 min MS (ES+): m/z = 433 [M+H]+ Example 105 (racemic mixture) Example 105 is sized as described for example 1 starting from example 44g (130 mg, 0.38 mmol) instead of example 44k, roMethylpyrimidine (65 mg, 0.51 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, isopropylethylamine (120 pl, 0.70 mmol) and 1 ml of anhydrous DMSO; the reaction mixture is heated during - l 6 l - minutes at 100°C in a microwave reactor;; afier the work-up the crude is purified by Silica gel flash chromatography using EtOAc/hexane/MeOH 80:20:1 as eluent to obtain the title compound (60 mg, 36% yield) HPLC-MS (Method 10): R = 2.94 min MS (ES+): m/z = 433 [M+H]+ Example 106 (racemic mixture) Trifluoroacetic anhydride (180 ul, 1.29 mmol) is added into a stirred solution of example 52a (170 mg, 0.43 mmol) and triethylamine (230 ul, 1.65 mmol) dissolved in anhydrous acetonitrile; the reaction e is heated in a microwave reactor 35 minutes at 110°C.

The solvent is d under reduced pressure, the residue is partitioned n EtOAc and water then the organic layer is separated dried over NaZSO4 and concentrated under reduced pressure; the crude is purified by Silica gel flash chromatography using EtOAc/hexane/MeOH 1 as eluent to obtain the title nd (90 mg, 44% yield).

HPLC-MS (Method 10): R = 3.50 min MS (ES+): m/z = 477 [M+H]+ - l 62- e 107 (racemic mixture) Example 107 is synthesized as described for example 106 starting from difluoroacetic anhydride (100 pl, 0.80 mmol) instead of trifluoroacetic anhydride, example 52a (100 mg, 0.25 mmol) and ylamine (140 ul, 1.01 mmol) to obtain the title product (60 mg, 52% yield).

HPLC-MS (Method 10): R = 3.18 min MS (ES+): m/z = 459 [M+H]+ Example 108 (racemic mixture) N /N F o Example 108 is synthesized as described for e 1 starting from example 44h (50 mg, 0.15 mmol) instead of example 44k, 2-ChloroMethylpyrimidine (28 mg, 0.22 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N-diisopropylethylamine (50 ul, 0.29 mmol) and 1 ml of anhydrous DMSO; the reaction mixture is heated during 30 minutes at 120°C in a microwave reactor; the crude is purified by preparative S to obtain the title compound (19 mg, 29% yield).

HPLC-MS (Method 5): R = 2.59 min MS (APCI+): m/z = 433 [M+H]+ Example 109 (racemic mixture) Example 109 is synthesized as described for example 1 starting from e 44g (80 mg, 0.24 mmol) instead of example 44k, 2-Bromo(trifluoromethyl)pyrazine (70 mg, 0.31 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N—diisopropylethylamine (80 ul, 0.48 mmol) and 1 ml of anhydrous DMSO; the reaction mixture is heated during 30 minutes at 100°C in a microwave reactor. After the work-up the crude is purified by Silica gel flash tography using EtOAc/hexane/MeOH 80:20:1 as eluent to obtain the title compound (80 mg, 70% yield).

HPLC-MS (Method 5): R = 2.95 min MS (APCI+): m/z = 487 [M+H]+ Example 110 (racemic mixture) Example 110 is synthesized as described for example 1 starting from example 44b (60 mg of the corresponding hydrochloride, 0.15 mmol) instead of example 44k, 2-Bromo (trifluoromethyl)pyrazine (42 mg, 0.19 mmol) instead 2-Chloro (trifluoromethyl)pyrimidine, N,N-diisopropylethylamine (107 ul, 0.62 mmol) and 1 ml of anhydrous DMSO; the reaction mixture is heated during 30 minutes at 120°C in a microwave r. The crude is purified by preparative HPLC-MS to obtain the title compound (24 mg, 32% yield) HPLC-MS d 10): R = 3.48 min MS (ES+): m/z = 487 [M+H]+ Example 111 (racemic mixture) \ I GAO/O Example 111 is synthsized as described for example 89 starting from example 37a (70 mg of the corresponding trifluoroacetate, 0.15 mmol) instead example 33a, HATU (69 mg, 0.18 mmol) and isopropylethylamine (79 ul, 0.45 mmol), tetrahydro-2H-thiopyran- - l 65 - 4-carboxilic acid 1,1-dioxide (30 mg, 0.17 mol), 4 ml of acetonitrile. After the work-up the residue is purified by ative HPLC-MS to obtain the title nd (34 mg, 44 % HPLC-MS (Method 5): R = 3.37 min MS (APCI+): m/z = 509 [M+H]+ Example 112 (racemic mixture) A solution of 5-(Trifiuoromethyl)-1,3,4-Oxadiazol—2-amine (300 mg, 1.96 mmol) dissolved in 1.5 ml of diiodomethane is heated at 100°C; isoamylnitrite (1.04 ml, 7.81 mmol) is then slowly added dropwise and resulting reaction mixture is stirred 1 hour. The crude reaction is purified by Silica gel flash chromatography using hexane/EtzO 9:1 as eluent then the resulting 2-Iodotrifluoromethyl-[1,3,4]oxadiazole intermediate is added into a solution of example 44g (280 mg, 0.82 mmol) and N,N—diisopropylethylamine (430 ul, 2.51 mmol) dissolved in 3 ml of DMSO. After 2 hours stirring, water and EtOAc are added, the organic phase is separated and concentrated under reduced pressure. The residue is purified by Silica gel flash tography using EtOAc/hexane/MeOH 80:20:l as eluent to obtain the title nd (200 mg, 51 % yield).

HPLC-MS (Method 10): R = 3.10 min MS (ES+): m/z = 477 [M+H]+ Example 113 (racemic e) O"kFF F o S//O Example 113 is synthsized as described for example 106 starting from example 57a (75 mg,) instead of example 52a, trifluoroacetic anhydride (52 ul, 0.38 mmol), triethylamine (97 ul, 0.56 mmol) in 3 ml of anhydrous acetonitrile; the reaction e is heated at 100°C during 20 minutes. The crude is ioned between water and DCM, solvent is removed under reduced pressure and the residue is purified by Silica gel flash chromatography, using EtOAc/Cyclohexane 30:70 to EtOAc 100% as eluent, to obtain the title nd (23 mg, 25% yield).

HPLC-MS (Method 10): R = 3.56 min MS (ES+): m/z = 477 [M+H]+ Example 114 (racemic mixture) J:r\N F o S//O 0 Example 114 is synthsized as described for example 113 starting from example 57a (75 mg), difluoroacetic anhydride (47 ul, 0.38 mmol), triethylamine (97 ul, 0.56 mmol) in 3 ml of anhydrous acetonitrile; the reaction mixture is heated at 100°C during 20 minutes. The crude is partitioned between water and DCM, solvent is removed under d pressure - l 67- and the residue is purified by Silica gel flash chromatography, using EtOAc/Cyclohexane 50:50 to EtOAc 100% as eluent, to obtain the title compound (36 mg, 42% yield).

HPLC-MS (Method 10): R = 3.27 min MS (ES+): m/z = 459 [M+H]+ Example 115 ic mixture) F I Example 115 is synthesized as described for example 1 starting from e 44g (80 mg, 0.24 mmol) instead of example 44k, 2-BromoTrifluoromethyl-oxazole (76 mg, 0.35 mmol) d 2-Chloro(trifluoromethyl)pyrimidine, N,N-diisopropylethylamine (80 ul, 0.47 mmol) dissolved in DMSO. The crude product is purified by Silica gel flash chromatography, using EtOAc/Hexane/MeOH 70:30:l as eluent, to obtain the title compound (50 mg, 45% yield).

HPLC-MS (Method 10): R = 3.31 min MS (ES+): m/z = 476 [M+H]+ Example 116 (racemic mixture) Example 55a (80 mg, 0.20 mmol) and 3-Bromo-1,1,1-trifluoroacetone (115 ul, 1.02 mmol) are dissolved in 1 ml oftert-butylacohol and heated during 8 hours at 90°C. The solvent is removed under reduced pressure and the residue is purified by ative HPLC-MS to obtain the title compound (62 mg, 63% yield).

HPLC-MS (Method 10): R = 3.38 min MS (ES+): m/z = 476 [M+H]+ Example 117 (racemic mixture) O F N’\\ 2,2,6,6-Tetramethylpiperidine (68 ul, 0.39 mmol) ed by bromoformaldoxime (78 mg, 0.39 mmol) are added, under nitrogen atmosphere, into a cooled on (-20°C) of example 44b (128 mg of free base, 0.37 mmol) dissolved in 2 ml of anhydrous THF.

After 2 hours stirring (meanwhile the temperature increase to 0°C ) 2-Bromo-3,3,3- trifluoropropene (199 ul, 1.93 mrnol) is added followed by triethylamine (67 ul, 0.46 mmol, dissolved in 1 ml of anhydrous THF); after 3 hours, the temperature is increased to room temperature and the reaction mixture is fiarther stirred overnight; the crude is purified by preparative HPLC-MS to obtain the title compound (13 mg, 8% yield).

S (Method 5): R = 2.98 min MS (APCI+): m/z = 476 [M+H]+ Example 118 (racemic mixture) N_kF F I s/’O Example 118 is sythesized as described for example 1 starting from example 44g (80 mg, 0.24 mmol) instead of example 44k, 2-Chlorotrifluoromethyl-(1,3,4)-thiadiazole (70 mg, 0.37 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine, N,N— diisopropylethylamine (80 ul, 0.48 mmol) and dry DMSO; the reaction mixture is heated during 30 minutes at 150°C in a microwave reactor. The reaction mixture is poured into EtOAc/water mixture, the organic layer is separated, washed with water and dried over anhydrous Na2S04 and concentrated under d re. The residue is purified by Silica gel flash chromatography using Hexane/MeOH 70:30:l as eluent to obtain the title compound (85 mg, 73% yield).

HPLC-MS (Method 10): R = 3.26 min MS (ES+): m/z = 493 [M+H]+ Example 119 (racemic mixture) Example 119 is sythesized as described for example 1 starting from example 44d (78 mg, 0.20 mmol) instead of example 44k, 2-Chloro(trifluoromethyl)pyrimidine (48 mg, 0.26 mmol), N,N—diisopropylethylamine (68 ul, 0.40 mmol) and dry DMSO; the reaction mixture is heated during 30 minutes at 150°C in a microwave r. The reaction e is poured into Eth/Water mixture, the organic layer is separated, washed With 1N aqueous HCl then dried and concentrated under reduced pressure to obtain the title compound (98 mg, 92% yield).

HPLC-MS d 10): R = 3.78 min MS (ES+): m/z = 537 [M+H]+ Example 120 (racemic mixture) F o s/’O e 120 is sythesized as described for experiment 118 starting from example 44h (80 mg, 0.24 mmol) instead of example 44g, 2-Chlorotrifluoromethyl-(1,3,4)-thiadiazole (42 ul, 0.38 mmol), N,N—diisopropylethylamine (80 ul, 0.48 mmol) and dry DMSO; the - l 7 l - on mixture is heated during 30 minutes at 150°C in a microwave reactor;. The reaction mixture is purified by preparative HPLC-MS to obtain the title compound (87 mg, 74% .

HPLC-MS (Method 10): R = 3.35 min MS (ES+): m/z = 493 [M+H]+ Example 125 (racemic mixture) 2-Naphtaleneboronic acid (52 mg, 0.30 mmol) is added, followed by copper(II) acetate (50 mg, 0.28 mmol), to a solution of example 45a (22 mg of the corresponding trifluoroacetate salt, 0.05 mmol) and N,N—diisopropylethylamine (50 ul, 0.29 mmol) dissolved in 2 ml of dichloromethane; the reaction mixture is stirred 72 hours at room temperature. Water is added, the c phase is separated and trated under reduced pressure then the residue is d by prepartive HPLC-MS to obtain the title compound (8.7 mg, 39% yield).

HPLC-MS (Method 21): R = 0.96 min MS: m/z = 449 [M+H]+ The following examples are synthesized in analogy to the preparation of example 125: -l72- Boronic acid Rt [min], MS Example Product Reactant Product or ester method . m/z) amount, y1eld 121 l : Example 45a R = 0.95 F F OH 467 (racemlc. N (tr1fluoroacetate @3/, . + 2.6 mg, 11% N F \0H [M+H] mixture) salt) Method 21 122 l / Example 45a R = 0.93 N 433 (racemic (trifluoroacetate PH 8.3 mg, 38% min, . H@ [W] mixture) OH 0 salt) Method 21 123 / Example 46a Rt =O.93 N 439 (racemic o oace a er t t ,0H 5.7 mg 26%0 , min, \ Cl C N B\ [M+H]+ mixture) \ 0/ salt) Method 21 124 \éj e 453. "39 /OH Rt = 0.93 O B 497 (racemic N j (tr1fluoroacetate, by. 2.1 mg, 8.5% .

F Q mm, N F [M+H]+ mixture) *0 salt) F Method 21 126 Example 46a F F o R. = 0.95 N 473 . B racemIC trifluoroacetate H y \ 1.7 mg, 7% F O mm, [M+H]+ mixture) salt) Method 21 Boronic acid Rt [min], MS Example Product Reactant Product or ester method . m/z) amount, y1eld 1 Example 46a CI R = 0.92 N 439 . OH (racem1c j (trifluoroacetate / 6.3 mg, 29% min, C N B. [M+H]+ mixture) 5 0% salt) OH Method 21 130 E? Example 45a (3. B: R. =1.01 N OH 501 (racemlc, j (trifluoroacetate FF 1.0 mg, 4% min, N [M+H]+ F mixture) C 1 A0 salt) Method 21 131 K: Example 46a Hg R. = 0.93 pH O B 503 (racemic (trifluoroacetate >: N] \0H FF 2.5 mg, 10% min, [M HT+ \ N mixture) \ 5 *0 salt) F Method 21 132 Example 45a FF R = 0.95 F 467 (racemic (trifluoroacetate PH 3.7 mg, 16% min, N B\ [M+H]+ e) 0 salt) OH Method 21 134 i / e 45a R = 0.84 pH 429 (racemic (trifluoroacetate QBNOH 8.2 mg, 38% min, N H3070 [M+H]+ mixture) 0/ salt) Method 21 136 8 Example 45a CI R = 0.93 ic l j (trifluoroacetate @B/OH 7.4 mg, 34% min, \ [M+H]+ mixture) 0% OH salt) Method 21 -l74- c acid Rt [min], MS Example Product Reactant Product or ester method . m/z) amount, y1eld 137 ‘ / Example 46a OH R =0.95 l 455 (racemic N oroacetate B‘OH 7.7 mg, 34% min, \ [M+H] mixture) \ salt) Method 21 138 Example 46a F Rt = 0.95 N F F 473 (racem1c- (trifluoroacetate _ PH 3.7 mg, 16% mm, \\ N Ex [M+H]+ mixture) 8 0/ salt) OH Method 21 139 Q Example 46a Rt = 0.83 pH 435 (racemic j (trifluoroacetate @0th 9.0 mg, 41% min, \ N H3C*O [M+H] mixture) \ s 0% salt) Method 21 142 Example 46a R = 0.78 j 406 (racemic (trifluoroacetate @BxPH 3.7 mg, 18% min, \\ N [M+HY mixture) 3 0&0 salt) Ni OH Method 22 143 Y Example 45a Rt =0.59 ( - racemlc QINN] [hiNJ pfi Ntr1.fluoroacetate B 1 6. mg 8V 0 \0 , mm, [M+H]+ mixture) 0*0 salt) Method 21 -l75- Boronic acid Rt [min], MS Example Product Reactant Product or ester method . m/z) amount, y1eld Example 46a 129 © (33 mg, 0.1 Rt =1.81 M /OH 405 (racem1c_ Cg") 11111101, T10 N,N- @& 11.0 mg, 27% min, \ OH S °)\Os,o/ d11sopropyleth..

[M+H] mixture) Method 18 ylamine used) Example 46a 144 N (33 mg, 0.1 HO\B/OH Rt =1.98 . j (racem1c \ N 11111101, T10 N,N- 5.1 mg, 11% min, \ + 8 z .. [M+H] mixture) 0 s//o d11sopropyleth Method 18 O ylamine used) Example 127 (racemic mixture) 2-Chlorobenzothiazole (8.5 mg, 0.05 mmol), example 45a (22 mg of the corresponding trifluoroacetate salt, 0.05 mmol) and N,N—diisopropylethylamine (50 ul, 0.29 mmol) are dissolved in 2 ml of N—Methyl—2-Pyrrolidinone and heated overnight at 180°C. The on mixture is purified by tive S to obtain the title compound (8 mg, % .

HPLC-MS (Method 20): R = 0.84 min MS: m/z = 456 [M+H]+ The following examples are sized in analogy to the preparation of e 127: Rt [min], MS Example Product Reactants Product method . (m/Z) amount, yleld Q 45a (22 mg, 0.05 Y" Rt = 0.80 135 (racemic mmol of TFA salt), 14.0 mg, 64% min, 440 [M+H]+ mixture) 1 N 0 o IQ 45a (22 mg, 0.05 mmol ofTFA salt), R = N 0.81 _ N\ 145 (racemlc Y N C' 1 N 3.3 mg, 13% min, 507 [M+H] m1xture). N] \>~C| N Method 20 %K040 CI:3 Q 45a (22 mg, 0.05 0.80 N\ N R = 147 (racemlc. Y mmol of TFA salt), N 8.2 mg, 32% min, 507 [M+H]+ m1xture). Fsc N Method 20 0 K00 CK \%CIN Q 45a (22 mg, 0.05 Rt 2 081 140 (racemic NYN mmol OfTFA salt), gin."1 8.1 mg, 32% CI min, 507 [M+H] m1xture)_ N\ A0 %CI Method 20 go CI N 2014/072085 R, [min], MS Example Product Reactants Product method (m/z) amount, yield Q 45a (22 mg, 0.05 Rt 2 0'89 133 (130611110 NYS 1111110l OfTFA salt), .0 mg, 43% min, 470 [M+H]+ m1xture) QikoN] N N gV0 Method 20 $0 H30 8 mg 45a (22 mg, 0.05 Rt 2 0‘80 146 (130611110 "\YN 1111110l OfTFA salt), QLN"1 CI 1.9 mg, 8% min, 487 [M+H]+ mixture) N A0 fol Method 20 fico H30 N Example 141 ic mixture) FSCQ 0A03?) 2-Chloro(Trifluoromethyl)-1H-Benzimidazole (220 mg, 1.0 mmol), 2-Phenyl- piperazine-l-carboxylic acid tert-butyl ester (400 mg, 1.5 mmol), N,N— diisopropylethylamine (500 ul, 2.9 mmol) are dissolved in 3 ml of acetonitrile and heated in a microwave reactor 1.5 hours at 160°C and then 30 minutes at 170°C. The reaction mixture is stirred into an open flask at 90°C to evaporate the solvent then the residue is ved in 4 m1 of DCM; trifluoroacetic acid (2.0 m1, 26.0 mmol) is added and the reaction mixture is stirred until complete deprotection occurs; it is then concentrated at 50°C. The residue is dissolved in MeOH, d by on of Triethylamine and purified by preparative HPLC-MS to obtain 255 mg (74% yield) of the intermediate 2-(3- Phenyl-piperazin— 1 -yl)trifluoromethyl- 1 H-benzoimidazo le.

N,N-diisopropylethylamine (50 ul, 0.29 mmol) and HATU (40 mg, 0.11 mmol) are added into a solution of tetrahydro-2H-thiopyrancarboxylic acid 1,1-dioxide (18 mg, 0.10 mmol) dissolved in 2 ml of DMF. After 10 minutes stirring, 2-(3-Phenyl-piperazinyl) trifluoromethyl-lH-benzoimidazole (35 mg, 0.10 mrnol, prepared as described above) is added and the reaction mixture is d overnight, diluted with Methanol, water and trifluoroacetic acid and finally d by preparative HPLC-MS to obtain the title compund (41 mg, 81% yield on the last step).

HPLC-MS (Method 19): R = 1.19 min MS: m/z = 507 [M+H]+ Example 148 (enantiomer 1) and example 149 (enantiomer 2) The racemic mixture of the title compounds is synthesized as described for example 1 ng from example 44c (300 mg, 0.71 mmol of the corresponding hydrochloride) instead of example 44k, ro(Trifluoromethyl)-(1,3,4)-thiadiazole (200 mg, 1.06 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine and isopropylethylamine (489 ul, 2.82 mmol) in 4 ml of anhydrous DMSO. The reaction mixture is heated in a microwave reactor at 150°C during 30 minutes. The crude is partitioned between DCM and water; the organic layer is dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain 240 mg of the racemic mixture.

UPLC-MS (Method 1): R = 1.39 min MS (ES+): m/z = 515 [M+H]+ The enantiomers are obtained by HPLC separation using a chiral stationary phase.

Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 70:30; flow rate: 15 , Temperature: 25°C; UV ion: 254 nm Example of separation by chiral HPLC: WO 55698 Submitted to separation: 240 mg of racemic mixture prepared as described above; Obtained: 80 mg of enantiomer 1 (Exp. 148) and 90 mg of enantiomer 2 (Exp. 149) Example 148: enantiomer 1 Example 149: enantiomer 2 Chiral HPLC HP.LC_MS (Method 5)'. Rt Examp1e MS (APCI+):m/z Rt [min] [mm] Exp. 148 20.36 3.03 515 (Method 15) Exp. 149 24.80 3.00 515 d 15) Example 150 (racemic mixture) e 150 is synthesized as described for example 117 ng from example 45a (150 mg, 0.47 mmol) instead of example 44b, using 2,2,6,6-Tetramethylpiperidine (82 ul, 0.47 mmol), 1,1-dibromoforma1doxime (94 mg, 0.47 mmol), 2-Bromo-3,3,3-trifluoropropene (240 ul, 2.33 mmol) and triethylamine (97 ul, 0.70 mmol). The crude is partitioned between water and EtOAc; the organic layer is separated, concentrated under reduced pressure and the residue is purified by preparative HPLC-MS to obtain the title compound (33 mg, 15% yield).

S (Method 5): R = 2.91 min MS (APCI+): m/z = 458 [M+H]+ e 151 (racemic mixture) N /N s N] \’ *0 A solution of example 44c (100 mg of the corresponding hydrochloride, 0.25 mol), 2- chloro(trifluoromethyl)-pyrimidine (55 mg, 0.30 mmol) and N,N—diisopropylethylamine (129 ul, 0.75 mmol) dissolved in 1 ml of anhydrous DMSO is heated in a microwave reactor during 30 minutes at 150°C. The crude is purified by preparative HPLC-MS and the obtained impure intermediate is suspended in 0.9 m1 of anhydrous toluene; potassium cyclopropyltrifluoroborate (37 mg, 0.25 mmol), butyldiadamantylphosphine (3 mg, 0.01 mmol), palladium acetate (1 mg, 0.01 mmol), cesium carbonate (245 mg, 0.75 mmol) and 0.1 ml ofwater are added and the reaction mixture is heated in a microwave reactor during 2 hours at 100°C. The solvent is d under reduced pressure, the residue is suspended in DMF, filtered and purified by preparative HPLC-MS to obtain the title compound (18.7 mg, 14% yield).

HPLC-MS (Method 16): Rt = 4.63 min MS (ES+): m/z = 515 [M+H]+ e 152 (racemic mixture) / 3N Fgfis’jfi ]N \ / F / Example 152 is sized as described for example 117 starting from e 44m (90 mg, 0.23 mmol) instead of example 44b, using 2,2,6,6-Tetramethylpiperidine (40 ul, 0.23 mmol), 1,1-dibromoformaldoxime (46 mg, 0.23 mmol), 2-Bromo-3,3,3-trifluoropropene (117 ul, 1.14 mmol) and triethylamine (39 ul, 0.27 mmol). The crude is partitioned between water and EtOAc, the organic layer is separated and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography, using cyclohexane/EtOAc 1:1 to 100% EtOAc as , to obtain the impure title compound that is further purified by preparative HPLC-MS to obtain 5 mg (4% yield) of pure product.

HPLC-MS (Method 14): R = 6.82 min MS (APCI+): m/z = 532 [M+H]+ - l 82- Example 153 (racemic e) Ff§F=\O Example 153 is synthesized as described for example 116 ng from example 48b (80 mg, 0.72 mmol) instead of example 55a, 3-Bromo-1,1,1-trifluoroacetone (58 ul, 0.55 mol), 3 ml of tert-butylacohol, heating for 16 hours at 80°C. The solvent is removed under reduced pressure and the e is purified by silica gel flash chromatography, using cyclohexane/EtOAc 1:1 to 100% EtOAc as eluent, to obtain the title compound (36 mg, 35% yield).

HPLC-MS (Method 14): R = 6.58 min MS (APCI+): m/z = 532 [M+H]+ Example 154 (racemic mixture) Pf;_N\ FFflsji ]N \ I oAQ:O Example 154 is synthesized as described for example 1 starting from example 44m (as hydrochloride salt, 100 mg, 0.19 mmol) instead of example 44k, ro trifluoromethyl-(l,3,4)-thiadiazole (54 mg, 0.29 mmol) instead 2-Chloro (trifluoromethyl)pyrimidine, N,N-diisopropylethylamine (133 ul, 0.77 mmol) and 1 ml of ous DMSO; the reaction mixture is heated during 30 minutes at 150°C in a microwave reactor; the crude is d preparative HPLC-MS to obtain the title compound (98 mg, 93% yield) HPLC-MS (Method 10): R = 3.72 min MS (ES+): m/z = 549 [M+H]+ The enantiomers are obtained by HPLC using a chiral stationary phase.

Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 70:30; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 75 mg of Example 154 prepared as described above; ed: 30 mg of enantiomer 1 (Exp. 155) and 30 mg of enantiomer 2 (Exp. 156) Example 155: enantiomer 1 Example 156: enantiomer 2 F F F’g:_N\ Fri_N\ s , N s N s E 1 F N s 1 FW N F N \ I O o 850 = o ‘25 ChiralHPLC HPLC-MS d 10): Rt Example MS (ES+), rm' Rt [min] [min] Exp. 155 15.05 3 72' 549 (Method 15) Exp. 156 17.59 3 72' 549 (Method 15) Example 157 (racemic mixture) OAO/ Example 157 is synthesized as described for example 1 starting from example 44b (40 mg, 0.11 mmol) instead of example 44k, 2-Chloro(Trifluoromethyl)pyridine (20 ul, 0.16 mmol) instead of ro(trifluoromethyl)pyrimidine and N,N—diisopropylethylamine (73 ul, 0.42 mmol) in 1 ml of anhydrous DMSO. The crude product is purified by preparative S to obtain 27 mg (52% yield) of the title compound.

HPLC-MS (Method 5): R = 3.11 min MS (APCI+): m/z = 486 [M+H]+ Example 158 (racemic mixture) F F Mar]3 \l / Example 158 is synthesized as described for example 1 starting from example 44n (30 mg, 0.08 mmol) instead of example 44k, 2-Chloro(Trifluoromethyl)pyridine (20 ul, 0.12 mmol) instead of ro(trifluoromethyl)pyrimidine and N,N—diisopropylethylamine (55 ul, 0.32 mmol) in 1 ml of ous DMSO. The reaction mixture is heated in a WO 55698 - l 85 - microwave reactor during 1.5 hours at 150°C and the crude product is purified by preparative HPLC-MS to obtain 26 mg (60% yield) of the title compound.

HPLC-MS (Method 4): R = 6.97 min MS (APCI+): m/z = 488 [M+H]+ Example 159 (racemic mixture) F F N /N HpfljfiNs I Example 159 is synthesized as described for example 1 starting from example 44n (30 mg, 0.08 mmol) instead of e 44k, 2-Chloro(trifluoromethyl)pyrimidine (22 mg, 0.12 mmol) and N,N—diisopropylethylamine (55 ul, 0.32 mmol) in 1 ml of anhydrous DMSO.

The crude product is purified by preparative S to obtain 23 mg (55% yield) of the title compound.

HPLC-MS (Method 4): R = 6.94 min MS (APCI+): m/z = 489 [M+H]+ Example 160 (racemic mixture) N F N S s N: \ / Example 160 is synthesized as described for example 1 starting from example 44n (40 mg, 0. 11 mmol) instead of example 44k, 2-Chlorotrifluoromethyl-(l,3,4)-thiadiazole (30 mg, 0. 16 mmol) instead of 2-Chloro(trifluoromethyl)pyrimidine and N,N- diisopropylethylamine (73 ul, 0.42 mmol) in 1 ml of anhydrous DMSO. The crude t is d by preparative HPLC-MS to obtain 28 mg (50% yield) of the title compound.

S (Method 4): R = 6.43 min MS (APCI+): m/z = 495 [M+H]+ Example 161 (racemic e) F F | \"I s N] \ l Example 161 is synthesized as described for example 1 starting from example 44n (35 mg, 0.09 mmol) instead of example 44k, 3-Chlorotrifluoromethyl-pyridazine (25 mg, 0.14 mmol) instead of 2-Chloro(trifluoromethyl)-pyrimidine and N,N—diisopropylethylamine (64 ul, 0.37 mmol) in 1 ml of ous DMSO. The crude product is purified by preparative HPLC-MS to obtain 30 mg (62% yield) of the corresponding hydrochloride salt adding a solution of HCl in dioxane during the evaporation step.

HPLC-MS (Method 4): R = 6.20 min MS (APCI+): m/z = 489 [M+H]+

Claims (5)

1. A compound of general formula (I) or a salt thereof 0 R 03/S RN‘RZ (I), wherein 5 R1 represents phenyl or a 5 or 6 membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, N or S, wherein the phenyl or the heteroaryl is optionally substituted With one or more R. . . . 3 R2 represents aryl, a 5 or 6 membered monocyclic heteroaryl or a 8 to 10 membered 10 bicyclic aryl, the mono- or bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, N or S, wherein the aryl or the heteroaryl is ally substituted with one or more R4; R3 is a halogen, a lkyl or a C3_6-cycloalkyl, wherein the C1_4-alkyl or the C3_6- 15 cycloalkyl is ally substituted with one or more ns; R4 is a halogen, -CN, C1_4-alkyl, C3_6-cycloalkyl, -C1_3-alkyl -C3_6-cycloalkyl or -O-C1_6 alkyl, wherein the C1_4-alkyl, C3_6-cycloalkyl, -C1_3-alkyl cycloalkyl or the -O-C1_ 6-alkyl is optionally substituted with one or more halogens.

2. The compound of claim 1 or a salt thereof, wherein R1 is selected from the group consisting of WO 55698 - l 8 8- Haln (R3)n Y/:i:\X * * and wherein Hal is a halogen, n is 0, l or 2, R3 is a halogen, a C1_4-alkyl or a C3_6-cycloalkyl, wherein the C1_4-alkyl or the C3_6- cycloalkyl is optionally substituted with one or more halogens, YisNorCH.

3. The compound of claim 1 or a salt thereof, wherein R1 is selected from the group 10 consisting of F F F F F F CI CF3 / 1\ is Z\ is 1\ is \ 8 NY8 \ S

4. The nd of claim lor salt thereof, wherein R1 represents F F Q/F F F QF * * * 'k * ’ ’ ’ - 5

5. The compound of any one of claims 1 to 4 or salt thereof, wherein R2 is selected from the group consisting ofnaphthyl, I H uYU u Y * , U my my * U_Y U