MXPA06005226A - Morpholine derivatives as norepinephrine reuptake inhibitors - Google Patents

Abstract

Compounds of the general formula (I) are inhibitors of the reuptake of norepinephrine. As such, they may be useful for the treatment of disorders of the central and/or peripheral nervous system.

Description

MORPHOLINE DERIVATIVES AS INHIBITORS OF NOREPINEPHRINE REABSORPTION FIELD OF THE INVENTION This invention relates to new morpholine compounds, and to their use in the selective inhibition of norepinephrine reuptake.

BACKGROUND OF THE INVENTION The selective inhibition of norepinephrine reuptake is a relatively new mode of action for the treatment of affective disorders. Norepinephrine seems to play an important role in the alterations of vegetative function associated with affective, anxiety and cognitive disorders. Atomoxetine hydrochloride is a selective inhibitor of norepinephrine reuptake, and is marketed for the treatment of attention deficit hyperactivity disorder (ADHD). Reboxetine is also a selective inhibitor of norepinephrine reuptake, and is marketed for the treatment of depression. W099 / 15177 describes the use of reboxetine to treat ADHD and WO01 / 01973 describes the use of S, S-reboxetine to treat, among others, ADHD. WO2004 / 018441 discloses certain morpholine derivatives as selective inhibitors of the reuptake of norepinephrine.

In accordance with the present invention, a compound of formula (I) is provided wherein, X is OH, C1-C4 alkoxy, NH2 or NH (Cl-4 alkyl); R x is H or C 1 -C 4 alkyl; Ry is H or C1-C4 alkyl; each Rz group is independently H or C1-4 alkyl, with the proviso that no more than 3 Rz groups may be C1-C4 alkyl; R1 is C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 fluorine atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 fluorine atoms), C3-C6 cycloalkoxy, C1-C4 alkylsulfonyl, cyano, -CO-O (C1-C2 alkyl), -0-C0- (C1-C2 alkyl) and hydroxy); C2-C6 alkenyl (optionally substituted with 1, 2 or 3 halogen atoms); C3-C6 cycloalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkoxy and hydroxy), wherein a CC bond within the cycloalkyl portion is optionally substituted by a 0- bond C, SC or C = C; C4-C7 cycloalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkoxy and hydroxy), wherein a CC bond within the cycloalkyl portion is optionally substituted by a 0- bond C, SC or C = C; or CH2Ar2; and Ar and Ar2 are each independently a phenyl ring or a 5 or 6-membered heteroaryl ring each of which is optionally substituted with 1, 2 or 3 substituents (depending on the number of substitution positions available), each independently selected of C1-C4 alkyl (optionally substituted by 1, 2 or 3 halogen atoms), C1-C4 alkoxy (optionally substituted by 1, 2 or 3 halogen atoms), C1-C4 alkylthio (optionally substituted by 1, 2 or 3) halogen atoms), -CO-O (C 1 -C 4 alkyl), cyano, -NRR, -CONRR, halo and hydroxy and / or with 1 substituent selected from pyridyl, thiophenyl, phenyl, benzyl and phenoxy, each of which is a ring optionally substituted by 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted by 1, 2 or 3 halogen atoms), carboxy, nitro, hydroxy, cyano, -NRR, -CONRR, - S02NRR and S02R; and each R is independently H or C 1 -C 4 alkyl; or a pharmaceutically acceptable salt thereof.

In the present specification, the term "C 1 -C 4 alkyl" means a straight chain or branched chain, saturated, unsubstituted, monovalent radical having from 1 to 4 carbon atoms. Thus, the term "C 1 -C 4 alkyl" includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. In the present specification, the term "Cl-C4 alkoxy" means a straight chain or branched hydrocarbon radical., saturated, unsubstituted, monovalent, having from 1 to 4 carbon atoms, linked to the substitution point by a divalent O radical. Thus, the term "C 1 -C 4 alkoxy" includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. In the present specification, the term "C1-C4 alkylthio" means a straight chain or branched chain, saturated, unsubstituted, monovalent radical having from 1 to 4 carbon atoms, linked to the substitution point by a radical S divalent Thus, the term "C 1 -C 4 alkylthio" includes, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio and tert-butylthio. In the present specification, the term "C3-C6 cycloalkyl" means a cyclic, saturated, unsubstituted, monovalent hydrocarbon radical having from 3 to 6 carbon atoms. Thus, the term "C3-C6 cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In the present specification, the term "C4-C7 cycloalkylalkyl" means a cyclic, saturated, unsubstituted, monovalent hydrocarbon radical having from 3 to 6 carbon atoms attached to the substitution point by a straight chain or branched chain, saturated, unsubstituted, divalent radical, which has at least 1 carbon atom. Thus, the term "C4-C7 cycloalkyl" includes, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. In the present specification, the phrase "wherein a C-C bond within the cycloalkyl portion, is optionally substituted by a bond 0-C, S-C or C = C", means that either (i) either of the two adjacent carbon atoms within a cycloalkyl ring, can be linked by a double bond, preferably that a single bond (with the number of substituents on each carbon atom being reduced accordingly), or that ( ii) one of either of the two adjacent C atoms with a cycloalkyl ring (and any of these substituents), can be replaced by an oxygen or sulfur atom.

Examples of groups encompassed by this phrase when used in conjunction with the term C3-C6 cycloalkyl include, for example: Examples of groups encompassed by this phrase when used in conjunction with the term C4-C7 cycloalkylalkyl include, for example: In the present specification, the term "C2-C6 alkenyl" means a straight-chain or branched-chain, unsaturated, unsubstituted, monovalent hydrocarbon radical having from 2 to 6 carbon atoms and containing at least one carbon double bond -carbon. Thus, the term "C 1 -C 4 alkenyl" includes, for example, ethenyl, propenyl, 2-methyl-2-propenyl and butenyl. In the present specification, the term "C3-C6 cycloalkoxy" means a cyclic, saturated, insubstituted, monovalent hydrocarbon radical having from 3 to 6 carbon atoms in the ring, linked to the point of substitution by a divalent O-radical. Thus, the term "C3-C6 cycloalkyl" includes, for example, cyclopropoxy. In the present specification, the term "C1-C4 alkylsulfonyl" means a straight chain or branched chain, saturated, unsubstituted, monovalent radical having from 1 to 4 carbon atoms, linked to the substitution point by a radical S02 divalent Thus, the term "C 1 -C 4 alkylsulfonyl" includes, for example, methylsulfonyl. In the present specification, terms similar to the above definitions that specify different numbers of C atoms take on an analogous meaning. Specifically, "C 1 -C 6 alkyl" means a straight chain or branched chain, saturated, unsubstituted, monovalent radical having from 1 to 6 carbon atoms. Thus, the term "C 1 -C 6 alkyl" represents a larger series of compounds that encompass the "C 1 -C 4 alkyl" subset, but also include, for example, n-pentyl, 3-methyl-butyl, 2- methyl-butyl, 1-methyl-butyl, 2,2-dimethyl-propyl, n-hexyl, 4-methyl-pentyl and 3-methyl-pentyl. Specifically, "C1-C2 alkyl" means a saturated, unsubstituted, monovalent hydrocarbon radical having from 1 to 2 carbon atoms. Thus, the term "C 1 -C 2 alkyl" represents a subset of compounds within the term "C 1 -C 4 alkyl" and includes methyl and ethyl. In the present specification, the term "halo" or "halogen" means F, Cl, Br or I. In the present specification, the term "phenoxy" means an unsubstituted phenyl radical, monovalent, linked to the point of substitution by a divalent radical. In the present specification, the term "5-element heteroaryl ring" means an aromatic radical of elements including one or more heteroatoms each independently selected from N, 0 and S. Preferably, there are no more than three heteroatoms in total in the ring. More preferably, there are no more than two heteroatoms in total in the ring. More preferably, there is no more than one hetero atom in total in the ring. The term includes, for example, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, triazolyl, oxadiazolyl and thiadiazolyl groups. "Thiazolyl" as used herein includes 2-thiazolyl, 4-thiazolyl and 5-thiazolyl. "Isothiazolyl" as used herein includes 3-isothiazolyl, 4-isothiazolyl, and 5-isothiazolyl. "Oxazolyl" as used herein includes 2-oxazolyl, 4-oxazolyl and 5-oxazolyl. "Isoxazolyl" as used herein includes 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl. "Thiophenyl" as used herein includes 2-thiophenyl and 3-thiophenyl.

"Furanyl" as used herein includes 2-furanyl and 3-furanyl. "Pyrrolyl" as used herein includes 2-pyrrolyl and 3-pyrrolyl. "Imidazolyl" as used in this document includes 2-imidazolyl and 4-imidazolyl. "Triazolyl" as used herein includes 1-triazolyl, 4-triazolyl and 5-triazolyl. "Oxadiazolyl" as used herein includes 4- and 5- (1,2,3-oxadiazolyl), 3- and 5- (1,2,4-oxadiazolyl), 3- (1,2,5-oxadiazolyl) ), 2- (1, 3, 4-oxadiazolyl). "Thiadiazolyl" as used in this document includes 4- and 5- (1, 2, 3-thiadiazolyl), 3- and 5- (1, 2,4-thiadiazolyl), 3- (1,2,5-thiadiazolyl), 2- (1, 3, 4 -thiadiazolyl). In the present specification, the term "6-membered heteroaryl ring" means a 6-membered aromatic ring that includes one or more heteroatoms, each independently selected from N, O, and S. Preferably, there are no more than three heteroatoms in total in the ring. More preferably, there are no more than two heteroatoms in total in the ring. More preferably, there is no more than one hetero atom in total in the ring. The term includes, for example, the pyridyl, pyrimidyl, pyrazinyl, pyridazinyl and triazinyl groups. "Pyridyl" as used herein includes 2-pyridyl, 3-pyridyl and 4-pyridyl. "Pyrimidyl" as used herein includes 2-pyrimidyl, 4-pyrimidyl and 5-pyrimidyl. "Pyrazinyl" as used herein includes 2-pyrazinyl, and 3-pyrazinyl. "Pyridazinyl" as used herein includes 3-pyridazinyl, and 4-pyridazinyl. "Triazinyl" as used herein includes 2- (1, 3, 5-triazinyl), 3-, 5- and 6- (1, 2,4-triazinyl) and 4- and 5- (1, 2, 3-triazinyl). In the present specification, the term "ortho" refers to a position on the aromatic ring Arl, which is adjacent to the position from which Arl is linked to the remainder of the compound of formula (I). In the present specification, the term "N-protecting group" means a functional group which provides the atom to which it is unreacted attached under the reaction conditions to which the N-protected compound is subsequently exposed, except where said atom N-protected is also attached to an H atom and except where such conditions are specifically chosen to remove the N-protecting group. The choice of the N-protecting group will depend on the subsequent reaction conditions and the N-protecting groups suitable for given situations will be known to the person skilled in the art. Additional information on suitable N-protective groups, including methods for their addition and removal, is contained in the well-known text "Protective Groups in Organic Synthesis" (for its acronym in English, "Protective Groups in Organic Synthesis"), Theodora W Greene and Peter GM Wuts, John Wiley & Sons, Inc., New York, 1999, pp. 494-653. Examples of N-protecting groups include carbamates protecting groups -CO-ORA, where RA is, for example, methyl, ethyl, 9-fluorenylmethyl (Fmoc), 2,2,2-trichloroethyl (Troc), 2-trimethylsilylethyl ( Teoc), t-butyl (Boc), allyl (Alloc), benzyl (Cbz) or p-methoxybenzyl (Moz); amide protecting groups -C0-RB, wherein RB is, for example, H, methyl, benzyl or phenyl; protecting groups of alkylamine-Rc, wherein Rc is, for example, methyl, t-butyl, allyl, [2- (trimethylsilyl)) ethoxy] methyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, diphenylmethyl or triphenylmethyl (trityl ); and sulfonamide protecting groups -S02-RD, wherein RD is, for example, methyl, benzyl, phenyl or phenyl substituted with 1 to 5 substituents each independently selected from methyl, t-butyl, methoxy and nitro. In some cases, the reaction conditions employed mean that N-protecting groups which are stable under strongly basic conditions and / or in the presence of strong nucleophiles (such as organometallic reagents), are generally preferred. Examples of such preferred N-protecting groups include alkylamine-Rc protecting groups, wherein Rc is for example, methyl, butyl, allyl, [2- (trimethylsilyl)) ethoxy] methyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, diphenylmethyl or triphenylmethyl (trityl). Benzyl is an especially preferred N-protecting group. In a preferred embodiment of the present invention, X is OH, C1-C4 alkoxy, or NH2. More preferably, X is OH or NH2. More preferably X is OH. In a preferred embodiment of the present invention, Rx is H or methyl. More preferably Rx is H. In a preferred embodiment of the present invention, Ry is H or methyl. More preferably Ry is H. In a preferred embodiment of the present invention, each group Rz is independently H or methyl, with the proviso that no more than 3 Rz groups can be methyl. More preferably, each Rz is H. In a preferred embodiment of the present invention, R1 is C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C1-C4 alkylthio (optionally substituted with 1, 2 or 3 fluorine atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 fluorine atoms), C3-C6 cycloalkoxy, C1-C4 alkylsulfonyl, cyano, -C0-O (C1-C2 alkyl) ), -O-CO- (C1-C2 alkyl) and hydroxy). More preferably, R 1 is C 1 -C 6 alkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 fluorine atoms), cyano and hydroxy ). More preferably, R1 is C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogen atoms). More preferably, R 1 is C 1 -C 6 alkyl (optionally substituted with 1, 2 6 3 fluorine atoms). Examples of specific identities for Rl within this embodiment include methyl, ethyl, iso-propyl, iso-butyl, n-butyl, 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl. In a preferred embodiment of the present invention, R1 is C2-C6 alkenyl (optionally substituted with 1, 2 or 3 halogen atoms). In a preferred embodiment of the present invention, R1 is C3-C6 cycloalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C1-C4 alkoxy and hydroxy), wherein a CC link within the cycloalkyl portion is optionally substituted by a bond 0-C, SC or C = C. More preferably, R1 is C3-C6 cycloalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C1-C4 alkoxy and hydroxy), wherein a CC bond in the cycloalkyl portion is optionally substituted by a 0-C link. More preferably, R1 is C3-C6 cycloalkyl wherein a C-C bond within the cycloalkyl portion is optionally substituted by a 0-C bond. Examples of specific identities for Rl within this embodiment include cyclopropyl, cyclopentyl and tetrahydropyranyl (in particular, tetrahydro-2H-pyran-4-yl). In a preferred embodiment of the present invention, R 1 is C 3 -C 6 cycloalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkoxy and hydroxy). More preferably, R1 is C3-C6 cycloalkyl. Examples of specific identities for Rl within this embodiment include cyclopropyl and cyclopentyl. In a preferred embodiment of the present invention, R1 is C3-C6 cycloalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C1-C4 alkoxy and hydroxy), wherein a -CC link within of the cycloalkyl portion is substituted by a bond 0-C, SC or C = C. More preferably, R 1 is C 3 -C 6 cycloalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkoxy and hydroxy), wherein a CC bond within the cycloalkyl portion is substituted by a 0-C link. More preferably, R1 is C3-C6 cycloalkyl, wherein a C-C bond within the cycloalkyl portion is substituted by a 0-C bond. An example of a specific identity for Rl within this embodiment is tetrahydropyranyl (in particular, tetrahydro-2H-pyran-4-yl).

In a preferred embodiment of the present invention, R 1 is C 4 -C 7 cycloalkylalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkoxy and hydroxy), wherein a CC link within the cycloalkyl portion is optionally substituted by a bond 0-C, SC or C = C. In a preferred embodiment of the present invention, R1 is C4-C7 cycloalkylalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C1-C4 alkoxy and hydroxy). In a preferred embodiment of the present invention, R 1 is C 4 -C 7 cycloalkylalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkoxy and hydroxy), wherein a CC link within the cycloalkyl portion is substituted by a bond 0-C, SC or C = C. In a preferred embodiment of the present invention, R1 is CH2Ar2, wherein Ar2 is as defined above. More preferably, R1 is CH2Ar2 wherein Ar2 is a phenyl ring or a pyridyl ring (preferably 2-pyridyl) each of which may be substituted with 1, 2 or 3 substituents each independently selected from C1-C4 alkyl (optionally substituted with 1, 2 6 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), halo and hydroxy . More preferably, R1 is CH2Ar2 wherein Ar2 is a phenyl ring optionally substituted in the manner described in the preceding paragraph. More preferably, R1 is CH2Ar2 wherein Ar2 is a phenyl ring optionally substituted with 1 or 2 substituents each independently selected from C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), halo and hydroxy. Examples of specific identities for Rl within this embodiment include, phenylmethyl and (2-methoxy-phenyl) methyl. In a preferred embodiment of the present invention, Arl is a phenyl ring or a 5- or 6-membered heteroaryl ring; each of which is substituted in the ortho position with a substituent selected from C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), -CO-O (C 1 -C 4 alkyl), cyano, -NRR, -CONRR, halo, hydroxy, pyridyl, thiophenyl, phenyl, benzyl and phenoxy, each of the ortho substituents is optionally substituted ring (wherein one ring is present), with 1, 2 or 3 substituents each independently selected from halogen, C 1 -C 4 alkyl (optionally substituted with 1, 2 or 3 halogen atom, C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms) ), carboxy, nitro, hydroxy, cyano, -NRR, -CONRR, S02NRR and S02R, and each of which is (in addition to the ortho substitution), optionally further substituted with 1 or 2 substituents each independently selected from C1 alkyl -C4 (optionally substituted with 1, 2 or 3 halogen atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), -CO-O (C 1 -C 4 alkyl), cyano, -NRR, -CONRR, halo and hydroxy. More preferably, Arl is a phenyl ring or a pyridyl ring (preferably 2-pyridyl) each of which is substituted and optionally further substituted in the manner described in the preceding paragraph. More preferably, Arl is a group of the formula (a): wherein, A is N or CR6 (preferably CR6); R2 is C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C1-C4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), halo, hydroxy, pyridyl, thiophenyl, phenyl (optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), or C1-C4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms)) or phenoxy (optionally substituted with 1, 2 or 3 halogen atoms); R3 is H; R4 is H; R 5 is H, C 1 -C 4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), halo or hydroxy; and R6 (if present), is H or halo (preferably H). More preferably, Arl is a group of the formula (a), wherein A, is CR6; R2 is C1-C4 alkyl (optionally substituted with 1, 2 or 3 fluorine atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 fluorine atoms), halo or phenyl (optionally substituted with 1, 2 or 3 fluorine atoms); R3 is H; R4 is H; R5 is H or F; R6 is H or halo. More preferably, Arl is a group of the formula (a), wherein A is CR6; R2 is C1-C4 alkyl (optionally substituted with 1, 2 or 3 fluorine atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 fluorine atoms) or phenyl (optionally substituted with 1, 2 or 3 carbon atoms) fluorine); R3 is H; R4 is H; R5 is H or F; and R6 is H. Examples of specific identities for Arl include 2-methoxy-phenyl, 2-ethoxy-phenyl, 2-trifluoromethoxy-phenyl, 2-phenyl-phenyl, 2- (3-fluoro-phenyl) -phenyl, 2- chloro-phenyl, 2-methoxy-5-fluoro-phenyl, 2-chloro-6-fluoro-phenyl and 2-phenyl-5-fluoro-phenyl.

It will be appreciated that a compound of formula (I) above will possess at least two asymmetric carbon atoms. In the present specification, wherein a structure formula does not specify the stereochemistry in one or more chiral centers, all stereoisomers and all possible mixtures of stereoisomers (including, but not limited to, racemic mixtures) are contemplated, which can result from stereoisomerism in each or more chiral centers. Thus, the compounds defined by formula (I) above include each of the individual stereoisomers. and all possible mixtures thereof. While all stereoisomers and mixtures thereof are contemplated by the present invention, preferred embodiments include enantiomerically and diastereomerically pure compounds of Formula I. As used herein, the term "enantiomerically pure" refers to an enantiomeric excess which is greater than 90%, preferably greater than 95%, more preferably greater of 99%. As used herein, the term "diastereomerically pure" refers to a diastereomeric excess which is greater than 90%, preferably greater than 95%, more preferably greater than 99%. In a preferred embodiment of the invention, a compound of formula (II) is provided (H) wherein X, Rx, Ry, Rz, Rl and Arl are as defined for formula (I) above; or a pharmaceutically acceptable salt thereof. Preferably, said compound of formula (II) is both enantiomerically pure and diastereomerically pure. In a preferred embodiment of the present invention, there is provided a compound of formula (III) m wherein X, R1 and Ar1 are as defined for formula (I) above; or a pharmaceutically acceptable salt thereof. In a preferred embodiment of the present invention, there is provided a compound of formula (III) wherein X is OH or NH2; R1 is C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C1-C4 alkylthio (optionally substituted with 1, 2 or 3 fluorine atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 fluorine atoms), C3-C6 cycloalkoxy, C1-C4 alkylsulfonyl, cyano, -CO-O (C1-C2 alkyl), -O-CO- (C1-C2 alkyl) and hydroxy); C3-C6 cycloalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkoxy and hydroxy), wherein a CC bond within the cycloalkyl portion is optionally substituted by a 0- bond C, SC or C = C; or CH2Ar2, wherein Ar2 is a phenyl ring or a pyridyl ring (preferably 2-pyridyl) each of which can be substituted with 1, 2 or 3 substituents each independently selected from C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), halo and hydroxy; and Arl is a phenyl ring or a 5- or 6-membered heteroaryl ring; each of which is substituted in the ortho position with a substituent selected from C 1 -C 4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms) ), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), -CO-O (C 1 -C 4 alkoyl), cyano, -NRR, -CONRR, halo, hydroxy, pyridyl, thiophenyl, phenyl, benzyl and phenoxy, each of the ortho substituents is optionally substituted ring (wherein one ring is present), with 1, 2 or 3 substituents each independently selected from halogen, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atom, C1-C4 alkoxy (optionally substituted by 1, 2 or 3 halogen atoms), carboxy, nitro, hydroxy, cyano, -NRR, -CONRR, S02NRR and S02R, and each of which is (in addition to ortho replacement), optionally further substituted with 1 or 2 substituents each independently selected C 1 -C 4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), -C0-O (C 1 -C 4 alkyl), cyano, -NRR, -CONRR, halo and hydroxy; or a pharmaceutically acceptable salt thereof. In a preferred embodiment of the present invention, a compound of formula (IV) is provided (IV) wherein, X is OH or NH2; R 1 is C 1 -C 6 alkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 fluorine atoms), cyano and hydroxy); C3-C6 cycloalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C1-C4 alkoxy and hydroxy), wherein a CC bond within the cycloalkyl portion is optionally substituted by a 0- bond C, or CH2Ar2 wherein Ar2 is a phenyl ring optionally substituted with 1, 2 or 3 substituents, each independently selected from C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), halo and hydroxy; A is N or CR6 (preferably CR6); R2 is C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C1-C4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), halo, hydroxy, pyridyl, thiophenyl, phenyl (optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), or C1-C4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms)) or phenoxy (optionally substituted with 1, 2 or 3 halogen atoms); R3 is H; R4 is H; R 5 is H, C 1 -C 4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), halo or hydroxy; and R6 (if present), is H; or a pharmaceutically acceptable salt thereof. In a preferred embodiment of the present invention, there is provided a compound of formula (V) (V) wherein, X is OH or NH2; R1 is C1-C6 alkyl (optionally substituted with 1, 2 or 3 fluorine atoms), C3-C6 cycloalkyl wherein a CC bond within the cycloalkyl portion is optionally substituted by a bond 0-C or CH2Ar2, wherein Ar2 is a phenyl ring optionally substituted with 1 or 2 substituents each independently selected from C 1 -C 4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms) , halo and hydroxy; R2 is C1-C4 alkyl (optionally substituted with 1, 2 or 3 fluorine atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 fluorine atoms) or phenyl (optionally substituted with 1, 2 or 3 carbon atoms) fluorine); and R5 is H or F; or a pharmaceutically acceptable salt thereof. In a preferred embodiment of the present invention, a compound of formula (VI) (VD) is provided wherein, R1 is C1-C6 alkyl (optionally substituted with 1, 2 or 3 fluorine atoms) or C3-C6 cycloalkyl wherein a C-C bond within the cycloalkyl portion is optionally substituted by a 0-C bond; R2 is C1-C4 alkyl (optionally substituted with 1, 2 or 3 fluorine atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 fluorine atoms) or phenyl (optionally substituted with 1, 2 or 3 fluorine atoms); and R5 is H or F; or a pharmaceutically acceptable salt thereof. Specific embodiments of the present invention include the compounds 1- [1,1 '-biphenyl] -2-yl-2-morpholin-2-ylpropan-2-ol, 1- [5-fluoro-2- (methyloxy) phenyl] -2-morpholin-2-ylbutan-2-ol, 2-morpholin-2-yl-1-. { 2- [(trifluoromethyl) oxy] phenyl} butan-2-ol, 1- [1,1 '-biphenyl] -2-yl-2-morpholin-2-ylbutan-2-ol, 1- [5-fluoro-2- (methyloxy) phenyl] -3- methyl-2-morpholin-2-ylbutan-2-ol, 3-methyl-l- [(2-methyloxy) phenyl] -2-morpholin-2-ylbutan-2-ol, 1- [(2-ethyloxy) phenyl] ] -3-methyl-2-morpholin-2-ylbutan-2-ol, 3-methyl-2-morpholin-2-yl-1-. { 2- [(trifluoromethyl) oxy] butan-2-ol, 1- [1,1'-biphenyl] -2-yl-3-methyl-2-morpholin-2-ylbutan-2-ol, 1- (4- fluoro [1,1'-biphenyl] -2-yl) -3-methyl-2-morpholin-2-ylbutan-2-ol, 1- [5-fluoro-2- (methyloxy) phenyl] -4-methyl- 2-morpholin-2-yl-pentan-2-ol, 1- [2- (ethyloxy) phenyl] -4-methyl-2-morpholin-2-ylpentan-2-ol, 4-methyl-2-morpholin-2 -il-l-. { 2 [(trifluoromethyl) oxy] phenyl} pentan-2-ol, 1- [1, V-biphenyl] -2-yl-4-methyl-2-morpholin-2-ylpentan-2-ol, 1- (4-fluoro [1,1 '-biphenyl] -2-yl) -4-methyl-2-morpholin-2-ylpentan-2-ol, l-cyclopentyl-2- [5-fluoro-2- (methyloxy) phenyl] -1-morpholin-2-ylethanol, l -cyclopentyl-2- [2- (ethyloxy) phenyl] -l-morpholin-2-ylethanol, 1-cyclopentyl-l-morpholin-2-yl-2-. { 2- [(trifluoromethyl) oxy] phenyl} ethanol, 2- [1, V -biphenyl] -2-yl-l-cyclopentyl-l-morpholin-2-ylethanol, l-cyclopentyl-2- (4-fluoro [1,1'-biphenyl] -2-yl ) -1-morpholin-2-yl-ethanol, 2- [5-fluoro-2- (methyloxy) phenyl] -l-morpholin-2-yl-l-tetrahydro-2H-pyran-4-ylethanol, l-morpholin-2 -yl-l-tetrahydro-2H-pyran-4-yl-2-2- [(trifluoromethyl) oxy] phenyl} ethanol, 2- [1,1'-biphenyl] -2-yl-l-morpholin-2-yl-l-tetrahydro-2H-pyran-4-ylethanol, 2- (3'-fluoro-biphenyl-2-yl) ) -l-morpholin-2-yl-l- (tetrahydro-pyran-4-yl) -ethanol, 5, 5, 5-trifluoro-l- (5-fluoro-2-methoxy-phenyl) -2-morpholine- 2-yl-pentan-2-ol, 5,5,5-trifluoro-2-morpholin-2-yl-l- (2-trifluoromethoxy-phenyl) -pentan-2-ol, 1- [1, V -biphenyl] ] -2-H-5, 5, 5-trifluoro-2-morpholin-2-ylpentan-2-ol, 6,6,6-trifluoro-1- [5-fluoro-2- (methyloxy) phenyl] -2 - orfol-2-yl-hexan-2-ol, 1- [1, V -biphenyl] -2-H-6, 6,6-trifluoro-2-morpholin-2-yl] hexan-2-ol, l-cyclopropyl -2- [-2- (methyloxy) phenyl] -1-morpholin-2-ylethanol, l-cyclopropyl-2- [-2- (ethyloxy) phenyl] -l-morpholin-2-ylethanol, 2- [1, 1'-biphenyl] -2-yl-l-cyclopropyl-l-morpholin-2-yl-ethanol, 1,3-bis- (2-methoxy-phenyl) -2-morpholin-2-yl-propan-2-ol, 1- (2-methoxy-benzyl) -2- (2-methoxy-phenyl) -l-morpholin-2-yl-ethylamine, 2-morpholin-2-yl-l, 3-diphenyl-propan-2-ol, 1- (2-methoxy-phenyl) -2-morpholin-2-yl-hexan-2-ol, 2-morpholinyl-1-biphenyl-2-yl-hexan-2-ol, 1 - (2-chloro-6-fluoro-phenyl) -4-methyl-2-morpholin-2-yl-pentan-2-ol and 1- (2-chloro-phenyl) -4-methyl-2-morpholin-2 -yl-pentan-2-ol and pharmaceutically suitable salts thereof. The compounds of the present invention are inhibitors of norepinephrine reuptake. The biogenic amine transporters control the amount of biogenic amine neurotransmitters in the synaptic cleft. Inhibition of respective transporters leads to an elevation in the concentration of such neurotransmitters within the synaptic cleft. The compounds of formula (I) and their pharmaceutically acceptable salts preferably exhibit a value of. of less than 600 nM in the norepinephrine transporter as determined using the scintillation proximity assay described below. The most preferred compounds of formula (I) and their pharmaceutically acceptable salts exhibit a Ki value of less than 100 nM in the norepinephrine transporter. Even more preferred compounds of formula (I) and their pharmaceutically acceptable salts, exhibit a Ki value of less than 50 nM in the norepinephrine transporter. Especially preferred compounds of formula (I) and their pharmaceutically acceptable salts exhibit a Ki value of less than 20 nM in the norepinephrine transporter. Preferably, the compounds of the present invention selectively inhibit the norepinephrine transporter relative to the serotonin and dopamine transporters by a factor of at least five, more preferably by a factor of at least ten, using the scintillation proximity assays described below. In addition, the compounds of the present invention are preferably acid stable. Advantageously, they have a reduced interaction (both a substrate and an inhibitor), with the liver enzyme Cytochrome P450 (CYP2D6). That is, they preferably exhibit less than 75% metabolism via the CYP2D6 pathway in accordance with the CYP2D6 substrate assay described below, and preferably exhibit an IC50 of >6 μM in accordance with the CYP2D6 inhibitor assay described below. In view of their pharmacological activity, the compounds of the present invention are indicated for the treatment of disorders of the central and / or peripheral nervous system, in particular, disorders associated with norepinephrine dysfunction in mammals, especially humans, which include children, adolescents and Adults. The term "norepinephrine dysfunction" as used herein, refers to a reduction in the amount of norepinephrine neurotransmitter within the synaptic cleft, below what could be considered to be normal or desirable for a species, or an individual within such species. Thus, the phrase "disorders associated with norepinephrine dysfunction in mammals" refers to disorders which are associated with a reduction in the amount of norepinephrine neurotransmitter within the synaptic cleft, below what could be considered by be normal or desirable for mammalian species, or in an individual within the species in question. Disorders associated with norepinephrine dysfunction in mammals include, for example, nervous system conditions selected from the group consisting of an addictive disorder and withdrawal syndrome, an adjustment disorder (which includes depression, anxiety, anxiety and depression combined, impairment of conduct and alteration of behavior and mood combined), a mental and learning disorder associated with age (including Alzheimer's disease), alcohol addiction, allergies (particularly allergic rhinitis), anorexia nervosa, apathy, asthma, a deficit disorder of attention (ADD) due to general medical conditions, hyperactivity disorder and attention deficit disorder (ADHD) that includes the predominantly inattentive type of ADHD and the predominantly impulsive-hyperactive type of ADHD (and optionally by means of combination therapy with one or more stimulants such as methylphenidate, amphetamine and dextroamphetamine), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, acute or chronic stress, cognitive disorders (discussed in more detail below but including illusions, dementias, amnestic disorders, cognitive impairment medium (MCI), cognitive impairment associated with schizophrenia (CÍAS) and cognitive disorders not otherwise specified), communication disorders (including stuttering, expressive language disorder, combined receptive-expressive language disorder, phonological disorder and communication disorders not otherwise specified), behavioral disorders, cyclothymic disorder, dementia of the type Alzheimer's (DAT), depression (which includes adolescent depression and minor depression), dysthymic disorder, emotional dysregulation (which includes emotional dysregulation associated with ADHD, personality disorder, bipolar disorder, schizophrenia, schizoaffective disorder, and intermittent explosive disorder), fibromyalgia and other somato disorders forms (including somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated somatoform disorder and somatoform disorder NOS), generalized anxiety disorder, hot flushes or vasomotor symptoms, hypotensive states including orthostatic hypotension , impulse control disorders (including intermittent explosive disorder, kleptomania, pyromania, pathological games, trichotillomania, and impulse control disorders not otherwise specified), incontinence (ie, bedwetting, stress incontinence, genuine incontinence for stress and combined incontinence), an inhalation disorder, an intoxication disorder, learning disability (which includes language disorders and speech development (such as joint development disorder, expressive language development disorder, and language development disorder) receptive), learning disorders (such as reading disorder, math disorders, writing expression disorder and learning disorder not otherwise specified) and motor skills disorders (such as developmental coordination disorder), mania, headaches for migraine, neuropathic pain, nicotine addiction, obesity (that is, weight reduction of obese or overweight patients), obsessive compulsive disorders and related spectrum disorders, oppositional defiant disorder, pain that includes chronic pain, neuropathic pain and pain antinociceptive, pain disorder, Parkinson's disease (in particular, to improve dyskinesia, oscillations, balance, coordination, depression and motivation), peripheral neuropathy, personality changes due to a general medical condition (which includes labile type, uninhibited type, aggressive type, apathetic type, paranoid type, combined type and unspecified type), tr developmental penetrating asthma (including autistic disorder, Asperger's disorder, Rett's disorder, childhood dysregregative disorder and developmental penetrating disorder not otherwise specified), post-traumatic stress disorder, premenstrual dysphoric disorder (ie, syndrome) premenstrual and late luteal dysphoric disorder), psoriasis, psychoactive substance use disorders, a psychotic disorder (which includes schizophrenia, schizoaffective and schizophreniform disorders), seasonal affective disorder, a sleep disorder (such as narcolepsy and enuresis), phobia social (which includes social anxiety disorder), a specific developmental disorder, "drowning" syndrome of selective inhibition of serotonin reuptake (SSRI) (ie, where a patient fails to maintain a satisfactory response to therapy of SSRI after an initial period of satisfactory response), ICT disorders ( for example, Tourette's disease), tobacco addiction and vascular dementia. The compounds of the present invention are particularly suitable for the treatment of disorders of hyperactivity and attention deficit, ADHD. The compounds of the present invention are also particularly suitable for the treatment of schizophrenia. The term "cognitive disorders" (also variously referred to as a "cognitive failure", "cognitive impairment", "cognitive deficit", "cognitive impairment", "cognitive dysfunction" and the like), refers to dysfunction, decrease or loss of one or more cognitive functions, the processes by which knowledge is acquired, retained and used. Cognitive dysfunction includes cognitive changes associated with aging ("memory impairment associated with age"), as well as changes due to other causes. Cognitive impairment is most commonly due to delirium or dementia, but may also occur in association with a number of other medical or neuropsychiatric disorders. More localized cognitive deficits are diagnosed using the criteria described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Review (DSM-IV-TR, 2000), American Psychiatric Association, Washington, D. C, such as amnestic disorders (affecting memory) or cognitive disorders not otherwise specified (NOS), which include executive dysfunction, visuospatial / visuoconstructional impairment, attention deficits, disorientation, etc. These more localized cognitive disorders also have a wide variety of causes, some of which are of unknown etiology. A delirium is characterized by an alteration of consciousness with a reduced ability to focus, retain or change attention and a change in cognition that develops over a short period of time. Delirium is very common, and occurs on average, in approximately in general, in a fifth of hospitalized patients, and it is even more common in patients caring for nurses and those with terminal illnesses. The disorders included in the "Delirium" section of the DSM-IV-TR ™ are listed in accordance with the presumed etiology: Delirium due to a general medical condition, delirium induced by substance (ie, due to a drug abuse, a medication, or exposure to toxin), delirium due to multiple etiologies, or delirium not otherwise specified (if the etiology is undetermined). As described by Wise et al. ((2002) Delirium (Confusional States), In Wise and Rundell, Eds., The 7 American Psychiatric Publishing Textbook of Consultation-Liaison Psychiatry, Psychiatry in the Medically 111, (Text Book of Psychiatric Publication of Consultation-Linking Psychiatry, Psychiatry in the medically ill), Second Edition, American Psychiatric Publishing, Inc., Washington, D.C., Chapter 15, pp. 257-272, Table 15-4), the exemplary etiological bases of delirium include, but are not limited to , infection, abstinence from alcohol and drugs, acute metabolic conditions, trauma of various types, CNS pathologies, hypoxia, vitamin deficiencies, endocrinopathies, acute vascular conditions, toxins or drugs, and heavy metals. A dementia is a chronic condition, usually with a more gradual deterioration of memory and other intellectual functioning and other severe cognitive abilities, sufficient to interfere with the ability to perform activities of daily living. Although dementia can occur at any age, it mainly affects the elderly, occurring in more than 15% of people over 65 years of age and as much as 40% of people over 80 years of age. Dementia due to Alzheimer's disease is particularly common. Non-Alzheimer's cognitive impairments and / or dementias include, for example, those caused by or associated with: vascular diseases; Parkinson's disease, Lewy body disease (diffuse Lewy body disease); HIV AIDS; cognitive impairments means; medium neurocognitive disorders; memory impairments associated with age; neurological and / or psychiatric conditions that include epilepsy and epilepsy treatments; brain tumors, pea, lesions or other inflammatory brain diseases; multiple sclerosis; Down's Syndrome; Rett syndrome; progressive supranuclear palsia; dementia syndromes of the frontal lobe; schizophrenia and related psychiatric disorders; antipsychotic medications; traumatic brain injury (closed head injury), pugilistic dementia and other head traumas; hydrocephalus of normal pressure; surgery (which includes graft surgery by coronary artery bypass) and anesthesia, electroconvulsive shock therapy, and cancer and cancer therapies. Dementias are also listed in the "Dementia" section of the DSM-IV-TR ™ in accordance with the presumed etiology: dementia of the Alzheimer's type, vascular dementia, dementia due to other general medical conditions (eg, immunodeficiency virus disease). human [HIV], head trauma, Parkinson's disease, Huntington's disease), substance-induced persistent dementia (ie, due to drug abuse, medication or exposure to toxin), dementia due to multiple etiologies, or dementia not specified otherwise (if the etiology is indeterminate). As described by Gray and Cummings ((2002) Dementia, In Wise and Rundell, Eds., The American Psychiatric Publishing Textbook of Consultation-Liaison Psychiatry, Psychiatry in the Medically 111, Second Edition, American Psychiatric Publishing, Inc., Washington, D. C, Chapter 16, pp. 273-306, Table 16-1), exemplary etiologic bases of major dementia syndromes include, but are not limited to, degenerative disorders (cortical and subcortical), vascular disorders, myelinoclastic disorders, conditions traumatic, neoplastic disorders, hydrocephalic disorders, inflammatory conditions, infections, toxic conditions, metabolic disorders and psychiatric disorders. An amnestic disorder is characterized by a deterioration in memory in the absence of other significant accompanying cognitive impairments. Disorders in the "Amnestic Disorders" section of the DSM-IV-TR ™ are also listed in accordance with the presumed etiology: amnestic disorders due to a general medical condition, substance-induced persistent amnestic disorder, or amnesic disorder not otherwise specified. mode. Cognitive disorder not otherwise specified in DSM-IV-TR ™, covers presentations that are characterized by a cognitive dysfunction presumed to be due to a general medical condition or substance use that does not suggest the criteria for any of the disorders listed in the other part, in the DSM-IV-TR ™ section titled, "Delirium, Dementia and Amnesia and Other Cognitive Disorders". Dementia, amnestic disorders and cognitive disorders NOS, occur in patients with a wide variety of other disorders including, but not limited to Huntington's disease (chorea); Pick's disease; spinocerebellar ataxias (types 1-11); corticobasalgangliónica degeneration; neuroacanthocytosis; dentatorubropalidoluisiana atrophy (DRPLA); systemic lupus erythematosus; heavy metal poisoning; dementia for alcohol (Wernicke encephalopathy); fetal alcohol syndrome; single or multiple strokes, including small vessels (Binswager dementia: subcortical arteriosclerotic encephalopathy) and large vessels (dementia due to multiple infarcts); anoxic encephalopathy; tumors; anoxia of birth; premature birth; inborn errors of metabolism; neurofibromatosis (Type I); tuberous sclerosis; Hallervorden Spatz disease; Wilson's disease; post-infectious sequelae (eg, tuberculosis, viral encephalitis, bacterial meningitis); subdural hematoma; subcortical dementia; Creutzfeldt-Jakob disease; Gerstmann-Stráussler-Scheinker disease; general paresis; and syphilis. As discussed in detail above, cognitive failure can occur in patients who suffer from a number of disorders, including dementia or delirium, or due to a wide variety of other causes. The compounds of the present invention are useful for the treatment or prevention of cognitive impairment associated with, or due to, disorders or etiologies discussed above, including disorders formally classified in the DSM-IV-TR ™. For the convenience of the reader, the DSM-IV-TR ™ code numbers or descriptions are provided below. "ICD-9-CM codes" refer to codes for, for example, selected general medical conditions and medication-induced disorders contained in the International Classification of Disease, 9th Revision, Clinical Modification.

Delirium due to a general medical condition 293.0 Delirium induced by substance, including: Delirium from substance intoxication: Code of delirium from intoxication [specific substance]: (291.0 alcohol; 292.81 amphetamine [or similar substance to amphetamine]; 292.81 cannabis; 292.81 cocaine; 292.81 hallucinogen; 292.81 inhalant; 292.81 opioid; 292.81 phencyclidine [or substance similar to phencyclidine]; 292.81 sedative, hypnotic, or anxiolytic; 292.81 other substances [or unknown] [eg, cimetidine, digitalis, benztropine)].

Delirium for abstinence from substance: Code of delirium for abstinence [specific substance]: (291.0 alcohol, 292.81 sedative, hinóptico or anxiolytic; 292.81 other substance [or unknown]).

Delirium due to multiple etiologies: Multiple codes are used, reflecting specific delirium and specific etiologies, for example, 293.0 delirium due to viral encephalitis; 291.0 Delirium for abstinence from alcohol.

Delirium not otherwise specified 780.09 Dementia of Alzheimer's type 291.x * (code * ICD-9-CM) Subtypes: With early onset (the onset of dementia is at 65 years of age or less) With late onset (the onset of dementia is after 65 years of age) No alteration in behavior 294.10 With alteration in behavior 294.11 Vascular dementia 290.4x Subtypes: With delirium 290.41 With illusions 290.42 With depression 290.43 With alterations in behavior without uncomplicated code 290.40 Dementia due to HIV disease 294. lx * (code * ICD-9-CM) Dementia due to head trauma 294. Ix * (code * ICD-9-CM) Dementia due to Parkinson's disease 294. lx * (code * ICD-9-CM) Dementia due to Huntington's disease 294.1x * (code * ICD-9-CM) Dementia due to Pick 290 disease. Ix * (code * ICD-9-CM) Dementia due to Creutzfeldt-Jakob 290. lx * (code * ICD-9-CM) Dementia due to other general medical conditions 294. Ix * (code * ICD-9-CM) Code based on the presence or absence of an alteration in clinically significant behavior: No behavior alteration 294.10 With behavior alteration 294.11 Persistent substance-induced dementia Persistent dementia-induced code [specific substance]: (291.2 alcohol, 292.82 inhalant, 292.82 sedative, psycho-optic or anxiolytic; 292.83 other substance [or unknown]).

Dementia due to multiple etiologies Coding note: multiple codes are used based on specific dementias and specific etiologies, for example, 294.10 dementia of the Alzheimer type, with late onset, without alteration of the behavior; 290.40 vascular dementia, uncomplicated.

Dementia not otherwise specified 294.8 Amnesic alteration due to a general medical condition 294.0 Temporary or chronic Persistent amnesic alteration induced by substance Persistent amnestic alteration code induced [substance specific]: 291.1 alcohol; 292.83 sedative, hypnotic, or anxiolytic; 292.83 other substance [or unknown] Amnestic disorder not otherwise specified 294.8 Cognitive disorder not otherwise specified 294.9 Cognitive decline related to age 780.9 Examples of cognitive disorders due to various etiologies, or associated with several disorders of particular interest that can be prevented or treated using the compounds of the present invention include: improvement of cognitive functions and executive functioning (ability to plan, initiate, organize, carry perform, monitor and correct their own behavior), in normal subjects or in subjects who exhibit cognitive dysfunction; treatment of cognitive deficits and attention associated with prenatal exposure to substance abuse including, but not limited to, nicotine, alcohol, methamphetamine, cocaine, and heroin; treatment of cognitive impairment caused by chronic alcohol and drug abuse (persistent dementia induced by substance), side effects of medications, and treatment of appetite and drug withdrawal; treatment of cognitive deficiency in patients with Down syndrome; treatment of deficits in normal functioning of comorbid memory with major depressive and bipolar disorders; treatment of cognitive impairment associated with depression, mental retardation, bipolar disorder or schizophrenia; treatment of dementia syndromes associated with mania, conversion alteration and disease simulation; treatment of attention problems, prefrontal executive function, or memory due to trauma or headache; treatment of cognitive dysfunction in menopausal and post-menopausal women and in women who undergo hormone replacement therapy; treatment of cognitive deficits and fatigue due to, or associated with, cancer and cancer therapies (cognitive deficiencies are associated with a variety of cancer treatments, including cranial radiation, conventional chemotherapy (standard dose), high-dose chemotherapy and hematopoietic transplant (bone marrow), and biological agents). The compounds of the present invention are also useful in a method for treating a patient suffering from or susceptible to psychosis, comprising administering to said patient, an effective amount of a first component which is an antipsychotic, in combination with an amount effective of a second component which is a compound of formula (I). The invention also provides a pharmaceutical composition which comprises a first component that is antipsychotic, and a second component that is a compound of formula (I). In general expressions of this aspect of the present invention, the first component is a compound that acts as an antipsychotic. The antipsychotic can be either a typical antipsychotic or an atypical antipsychotic. Although both typical and atypical antipsychotics are useful for these methods and formulations of the present invention, it is preferred that the first component of the compound is an atypical antipsychotic. Typical antipsychotics include, but are not limited to: chlorpromazine, 2-chloro-10- (3-dimethylaminoprop-yl) phenothiazine, described in U.S. Patent 2,645,640. Its pharmacology has been reviewed (Crismon, Phychopharma-col. Bull., 4, 151 (October 1967); Doperidol, 1- (1- [3- (p-fluorobenzoyl) propyl] -1,2,3,6-tetrahydro -4-pyridyl) -2-benzimidazoline, is described in US Pat. No. 3,141,823; Haloperidol, 4- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] -1- (4-fluorophenyl) -1- butanone, is described in US Pat. No. 3,438,991, its therapeutic efficacy in psychosis has been reported (Beresford and Ward, Drugs, 33, 31-49 (1987); Thioridazine, l-hydroxy-10- [2- (1) hydrochloride. -methyl-2-pyridinyl) ethyl] -2- (methylthio) phenothiazine, is described by Bourquin, et al. (Helv. Chim. Acta, 41, 1072 (1958)). Its use as an antipsychotic has been reported (Axelsson , et al., Curr. Ther. Res., _ ^ 21 587 (1977)), and Trifluoperazine, 10- [3- (4-methyl-l-piperazinyl) -propyl] -2-trifluoromethylthiazine hydrochloride, is described in U.S. Patent 2,921,069.Apytic antipsychotics include, but are not limited to: Olanzapine, 2-methyl- 4- (4-methyl-1-piperazinyl) -10H-thieno [2, 3-b] [1,5] benzodiazepine is a known compound and is described in US Pat. No. 5,229,382, since it is useful for the treatment of schizophrenia, schizophreniform disorder, water mania, middle anxiety states and psychosis; Clozapine, 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [b, e] [1,4] diazepine, is described in US Pat. No. 3,539,573. Clinical efficacy in the treatment of schizophrenia is described (Hanes, et al., Psychopharmacol. Bull., 24, 62 (1988)); Risperidone, 3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) piperidino] ethyl] -2-methyl-6,7,8,8-tetrahydro-4H-pyrido [1, 2-a] pyrimidin-4-one, and its use in the treatment of psychotic diseases is described in U.S. Patent No. 4,804,663; Sertindole, 1- [2- [4- [5-chloro-1- (4-fluorophenyl) -lH-indol-3-yl] -1-piperidinyl] ethyl] imidazolidin-2-one, is described in the U.S. Patent No. 4,710,500. Its use in the treatment of schizophrenia is described in U.S. Patent Nos. 5,112,838 and 5,238,945; Quetiapine, 5- [2- (4-dibenzo [b, f] [1,4] thiazepin-11-yl-l-piperazinyl) ethoxy] ethanol, and its activity in trials which demonstrate utility in the treatment of schizophrenia , is described in U.S. Patent No. 4,879,288. Quetiapine is typically administered as its (E) -2-butanedioate salt (2: 1); Ziprasidone, 5- [2- [4- (1, 2-benzoisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-l, 3-dihydro-2H-indol-2-one, is typically administered as the hydrochloride monohydrate. The compound is described in U.S. Patent Nos. 4,831,031 and 5,312,925. Their activity in assays which demonstrate utility in the treatment of schizophrenia are described in U.S. Patent No. 4,831,031; and Aripiprazole (Abilify ™), 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl] butoxy] -3,4-dihydrocarbostyril (Patents) Americans 4,734,416 and 5,006,528), is a new antipsychotic indicated for the treatment of schizophrenia.

It will be understood that while the use of a single antipsychotic as a first compound component is preferred, combinations of two or more antipsychotics may be used as a first component if necessary or desired. Similarly, while the use of a single compound of formula (I) as a second compound component is preferred, combinations of two or more compounds of formula (I) can be used as a second component if necessary or desired. While all combinations of first and second components compounds are useful and valuable, certain combinations are particularly valued and are preferred, as follows: olanzapine / compound of formula (I) clozapine / compound of formula (I) risperidone / compound of formula ( I) sertindole / compound of formula (I) quetiapine / compound of formula (I) Ziprasidone / compound of formula (I) aripiprazole / compound of formula (I) in general, combinations and methods of treatment prefer using olanzapine as the first component. It is especially preferred that when the first component is olanzapine, it will be Form II olanzapine as described in U.S. Patent No. 5,736,541. Although Form II olanzapine is preferred, it is understood that as used herein, the term "olanzapine" encompasses all solvates and polymorphic forms unless specifically indicated. Conditions that can be treated by adjunctive therapy of the aspect of the present invention include, schizophrenia, schizophreniform diseases, bipolar disorder, acute mania and schizoaffective disorders. The titles given to these conditions represent multiple states of diseases. The following list illustrates the number of these disease states, many of which are classified in the DSM-IV-TR ™. The DSM-IV-TR ™ code numbers of these disease states are suppressed below, when available, for the convenience of the reader. Schizophrenia paranoid type 295.30 Schizophrenia Disorganized Type 295.10 schizophrenia catatonic type 295.20 schizophrenia type undifferentiated 295.90 Schizophrenia Residual Type 295.60 Schizophreniform Disorder 295.40 Schizoaffective 295.70 Disorder The present invention also encompasses the use of one or more compounds of formula (I) combination with one or more conventional Alzheimer's agents, for the prevention or treatment of cognitive dysfunction in patients suffering from Alzheimer's disease. The invention also provides a pharmaceutical composition which comprises a first component that is a conventional Alzheimer's agent and a second component that is a compound of formula (I). Conventional Alzheimer agents include inhibitors of acetylcholine degradation (i.e., cholinesterase or acetylcholinesterase inhibitors) within synapses, e.g., donepezil (Aricept), rivastigmine (Exelon), galantamine (Reminyl), and tacrine (Cognex®); the selective monoamine oxidase inhibitor selegiline (Eldepryl®); and memantine (Namenda ™), an NMDA receptor antagonist recently approved by the FDA for the treatment of moderate to severe Alzheimer's disease. Modafinil (Provigil®) is also used in the treatment of Alzheimer's disease. The present invention also encompasses the use of one or more compounds of formula (I) in combination with one or more conventional Parkinson's agents, for the treatment of cognitive dysfunction in Parkinson's disease. The invention also provides a pharmaceutical composition which comprises a first component that is a conventional Parkinson's agent and a second component that is a compound of formula (I). Conventional Parkinson's agents include levodopa; levodopa / carbidopa (Sinemet®); Stalevo (carbidopa / levodopa / entacapone); dopamine agonists, for example, bromocriptine; Mirapex® (Pramipexol), Permax® (pergolide), and Requip® (ropinirole); COMT inhibitors, for example, tolcapone and entacapone; Selegiline (Deprenyl®; Eldepryl®); propranolol; primidone; anticholinergics, for example, Cogentin®, Artane®, Akineton®, Disipal®, and Kemadrin®; and amantadine. In each of the combination treatments mentioned above, said first and second components can be administered simultaneously, separately or sequentially. Similarly, such compositions encompass combined preparations for simultaneous, separate or sequential use. The term "treatment" as used herein, refers to both prophylactic and curative treatment of disorders associated with norepinephrine dysfunction. In this way, the term "treatment" is proposed to refer to all processes where there may be a decrease, interruption, arrest, control or arrest of the progress of the disorders described in this document, but not necessarily indicate a total elimination of all the symptoms, and it is intended to include prophylactic and therapeutic treatment of such disorders. The compounds of the present invention are also indicated for the treatment of disorders, which are enhanced by an increase in the amount of the norepinephrine neurotransmitter within the synaptic cleft of a mammal above which it could be considered to be normal or desirable for the mammal species, or in individuals within the species in question. In another embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent, excipient or carrier. In another embodiment of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy. In another embodiment of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as an inhibitor in the reuptake of norepinephrine. Preferably, such inhibition occurs within mammalian cells (which include preparations of mammalian cell membranes), especially those found within the central and / or peripheral nervous system. More preferably, such inhibition occurs within the cells of the central nervous system of a mammal, especially a human, in need of it. In another embodiment of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, for treating disorders associated with norepinephrine dysfunction in mammals. In another embodiment of the present invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting the reuptake of norepinephrine. In another embodiment of the present invention, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of disorders associated with norepinephrine dysfunction in mammals. In another embodiment of the present invention, there is provided a method for inhibiting the reuptake of norepinephrine in mammals comprising, administering to a patient in need thereof, an effective amount of a compound of formula (I) or a pharmaceutically salt thereof. acceptable. In another embodiment of the present invention, there is provided a method for treating disorders associated with norepinephrine dysfunction in mammals comprising, administering to a patient in need thereof, an effective amount of a compound of formula (I) or a salt thereof. same pharmaceutically acceptable. The present invention includes the pharmaceutically acceptable salts of the compounds of formula (I). Suitable salts include acid addition salts, which include salts formed with inorganic acids, for example, hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acid, or with organic acids, such as organic sulfonic or organic carboxylic acids, for example, acetoxybenzoic, citric, glycolic, mandelic-1 acids , mandelic-dl, mandelic-d, maleic, mesotartaric, hydroxymelic, fumaric, lactobionic, malic, methanesulfonic, napsilic, naphthalenedisulfonic, naphthoic, oxalic, palmitic, phenylacetic, propionic, pyridylhydroxypyrubic, salicylic, stearic, succinic, sulfanilic, tartaric- 1, tartaric-dl, tartaric-d, 2-hydroxyethane sulfonic, toluene-p-sulphonic and xinafoic. The compounds of the present invention can be used as medicaments in human or veterinary medicine. The compounds can be administered by several routes, for example, by oral or rectal routes, topically or parenterally, for example, by injection and are usually employed in the form of pharmaceutical compositions. Such compositions can be prepared by methods well known in the pharmaceutical art and typically comprise at least one active compound in association with a pharmaceutically acceptable diluent, excipient or carrier. In making the compositions of the present invention, the active agent will usually be mixed with a carrier or diluent by a carrier, and / or attached with a carrier which can, for example, be in the form of a capsule, pouch, paper or other container. Where the carrier serves as a diluent, it can be solid, semi-solid or liquid material, which acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition can be in the form of tablets, lozenges, pouches, seals, elixirs, suspensions, solutions, syrups, aerosols (as a solid or liquid medium), ointments containing, for example, up to 10% in active compound weight, soft and hard gelatin capsules, suppositories, injection solutions and suspensions, and sterile packaged powders. Some examples of suitable carriers are lactose, dextrose, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as starch and petroleum jelly, saccharose sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, syrup, methylcellulose, methyl- and propyl-hydrobenzoate, talc, magnesium stearate and mineral oil. The compounds of formula (I) can also be lyophilized and the lyophilizates obtained used, for example, for the production of preparations for injection. The stated preparations can be sterilized and / or can contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts to affect the osmotic pressure, buffer substances, colorants, flavors and / or one or more additional active compounds, for example, one or more vitamins. The compositions of the invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient, employing procedures well known in the art. The compositions are preferably formulated in a unit dosage form, each dosage unit contains from about 5 to about 500 mg, more usually about 25 to about 300 mg of the active ingredient. The term "dosage unit form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a pharmaceutical carrier. suitable. The compounds of the present invention can be prepared by conventional organic chemistry techniques. General reaction schemes summarizing the synthetic routes for compounds of the present invention, are described below. For clarity, Rx, Ry and Rz are shown as H, however, it will be appreciated that analogous methods may be applied for other possible identities of Rx, Ry and Rz. The intermediates of formula (X), (XI), (XII), (XV) and (XVI), can be prepared as shown below (where P represents an N-protecting group and R7 and R8, which can be the same or different, each represents C1-C4 alkyl (optionally substituted with an OMe group), or, taken together with the N atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring).

(XV) (XVI) The N-protected ethanolamine is reacted with 2-chloroacrylonitrile to give a Michael adduct, which is then treated in situ with a base, such as potassium t-butoxide, to give a compound of formula (X). The compound of formula (X) can then be hydrolysed in H2SO4 / ethanol to give the ester of formula (XI). This, in turn, can be converted into the Weinreb amide of formula (XII) by adding a solution of (XI) to a premixed solution of N, N '-dimethylhydroxylamine and trimethylaluminium. Alternatively, the compound of formula (X) can be hydrolyzed in H20 / HC to give the acid of formula (XV). This, however, can be converted to the amide of formula (XVI) by reacting a solution of (XV) with oxalyl chloride or S0C12 to provide an acyl chloride which is then reacted with an amine of the formula R7R8NH such as dimethylamine or morpholine. The preferred enantiomers of the amides (XII) and (XVI) shown below, can be obtained by chiral chromatography.

(Xü) b (XVTjb The appropriate N-protecting groups will be known to a person skilled in the art.Additional information on suitable N-protecting groups is contained in the well-known text, "Protective Groups in Organic Synthesis", Theodora W Greene and Peter GM Wuts, John Wiley &Sons, Inc., New York, 1999, pp. 494- 653. Benzyl is an especially preferred N-protecting group The N-protected compounds of formula (I) wherein X is NH2, can be prepared from compounds of formula (X) as shown below: not isolated not isolated In route A, the intermediate (X) is treated with an excess of the Grignard reagent of ArlCH2MgBr, to provide an N-protected compound of formula (I), wherein X is NH2 and R1 is CH2Ar2 where Ar2 = Ar1. In route B, the intermediate (X) is treated with an equivalent of the Grignard reagent of RlMgBr, followed by an equivalent of the Grignard reagent of ArlCH2MgBr, to provide an N-protected compound of formula (I), wherein X is NH2. Alternatively, the Grignard reagent of ArlCH2MgBr, may be added first followed by RlMgBr. Preferably, a Lewis acid such as titanium isopropoxide is added to the reaction mixture between the addition of the Grignard reagents (see Charette, AB, Gagnon, A, Janes, M; Mellon, C; Tetrahedron Lett, 1998, 39 ( 29), 5147-5150 and Charette, AB, Gagnon, A; Tetrahedron: Asymmetry, 1999.10 (10), 1961-1968). The N-protected compounds of formula (I) wherein X is OH and R1 is CH2Ar2 wherein Ar2 = Ar1 can be prepared from compounds of formula (XI) as shown below: CXI) not isolated The intermediate (XI) is treated with an excess of Grignard reagent of ArlCH2MgBr to provide an N-protected compound of formula (I); where X is OH and Rl is CH2Ar2 where Ar2 = Arl. The N-protected compounds of formula (I) wherein X is OH, can be prepared from the Weinreb amide of formula (XII) or the amide of formula (XVI) as shown below: (xp) by (XVI) To a solution of (XII) or (XVI) a solution of the Grignard reagent requirement RlMgBr is added, to provide after the lifting, a compound of formula (XIII). When the reaction is conducted using the preferred enantiomers (XII) b or (XVI) b, it proceeds with retention of the stereochemistry to provide (XIII) b. (xpi) b To a solution of the ketone of formula (XIII), a solution of the Grignard reagent of ArlCH2MgBr is added, to provide an N-protected compound of formula (I), wherein X is OH. When the reaction is conducted using the preferred enantiomer (XIII) b, the reaction proceeds stereoselectively to provide an N-protected compound of formula (II) wherein X is OH.

Ketones of formula (XIII) can also be obtained via a different route as shown below: A solution of the N-protected morpholine is treated with a strong base such as lithium diisopropylamide. To this solution is added R1CHO aldehyde. The reduction of the carbonyl group of morpholine using, for example, borane-TH complex, followed by oxidation of the alcohol using, for example, Swern oxidation conditions, provides a compound of formula (XIII), which can be reacted forward as described in the reaction scheme previous, to provide an N-protected compound of formula (I) wherein X is OH. The N-protected compounds of the present invention, wherein X is C1-C4 alkoxy, can be synthesized by standard alkylation of the N-protected compounds of formula (I), wherein X = OH as shown below: Suitable strong bases will be known to the person skilled in the art, including, for example, sodium hydride. Similarly, suitable alkylating agents will be known to the person skilled in the art and include, for example, Cl-C4 alkyl halides, such as methyl iodide. The N-protected compounds of the present invention, wherein X is NH (C 1 -C 4 alkyl), can be synthesized by treatment of a compound of formula (I), wherein -X = NH 2 under reductive alkylation conditions, or using suitable alkylating agents known to a person skilled in the art including, for example, C1-C4 alkyl halides such as methyl iodide. The N-protected compounds of the present invention can be made after using standard organic chemistry to provide additional N-protected compounds of the present invention. For example, organometallic type couplings between an Arl-Br derivative and a phenylboronic acid as shown below, can provide Arl-phenyl derivatives.

The compounds of formula (I) can be obtained by deprotection of the N-protected intermediates as shown below: and Rz = H Additional information on suitable deprotection methods is contained in the well-known text "Protective Groups in Organic Synthesis", referenced above. Thus, in another embodiment of the present invention, there is provided a process for the preparation of compounds of formula (I), which comprises the step of deprotecting a compound of formula (XIV) (XIV) wherein P represents an N-protecting group and all other variables are as defined by formula (I) above, to provide a compound of formula (I), optionally followed by the step of forming a pharmaceutically acceptable salt. Examples of compounds of the present invention may be prepared by conventional organic chemistry techniques from N-benzyl-orfolin-2-carboxylic acid ethyl ester 1 or N-benzylmorpholine, as summarized in Schemes 1-4.

Scheme 1 o1 3 a1 &0, 77y82 Conversion of 1 to the Weinreb 2 amide, followed by treatment with a suitable Grignard reagent, leads to the ketones of formula (XIII) wherein P is benzyl as listed in Table 1. Table 1 The substituted cyclopropyl ketone 77 can alternatively be obtained from N-benzylmorpholine as summarized in Scheme 2.

Scheme 2 Treatment of N-benzylmorpholine with a strong base such as lithium diisopropylamide followed by addition of cyclopropylmethylaldehyde gives 75. Reduction of 75 with, for example, borane-THF complex gives 76. Addition of a solution of 76 to a solution Pre-mixed dimethyl sulfoxide and oxalyl chloride provides 77. The reaction of ketones listed in Table 1 with a suitably substituted Grignard reagent provides N-benzyl-substituted tertiary alcohols listed in Table 2 (wherein R2, R5 and R6 are H unless otherwise indicated), as summarized in Scheme 3.

Scheme 3 The debenzylation and salt formation as detailed in Scheme 4, leads to the tertiary alcohol salts listed in Table 2 (wherein R2, R5 and R6 are H unless otherwise indicated).

Scheme 4 Table 2 The compounds of Examples 1 to 32 and 35 to 38 can be obtained in enantiomerically pure form, via the route using chirally pure ester 1. The resolution of 1 in their enantiomers can be achieved through chiral HPLC. The conversion of the ester to the Weinreb amide does not alter the chiral center, thus providing the chirally pure amide 2. The conversion of the Weinreb amide to the ketone also does not alter the chiral center, thereby providing chirally pure ketones 3 to 10, 77 and 82. Alternatively, the chiral separation can be conducted in the amide 2 through chiral HPLC to provide its enantiomers. Alternatively, the chiral separation can be conducted in ketones 3 to 10, 77 and 82 via chiral HPLC to provide their enantiomers. The chiral separation of the ester, amide or ketones can also be achieved by other techniques known to those skilled in the art, such as fractional crystallization of diastereomeric salts formed with chiral acids. The addition of the benzyl Grignard reagent (Scheme 3) is a stereoselective process and predominantly provides a diastereomer with only small amounts of the second diastereomer. No epimerization is observed during the removal of the benzyl group. Alternatively, the enantiomerically pure products are obtained through conversion to an N-protected analog such as butyloxycarbonyl or carbobenzyloxy, followed by separation by chiral HPLC. Removal of the N-protecting group leads to enantiomerically highly enriched products. In the experimental procedures described below, the following abbreviations are used: CLAR = high performance liquid chromatography THF = tetrahydrofuran 2-MeTHF = 2-methyltetrahydrofuran DIBALH = diisobutylaluminum hydride DCM = dichloromethane FIA + (or FIA-EM) = mass spectrometry rapid ionization analysis EMCL = mass spectroscopy by liquid chromatography NMR = nuclear magnetic resonance PM = molecular weight MeOH = methanol EtOAc or AcOEt = ethyl acetate PS-DIEA = diisopropylethylamine supported by polymer DEA = diethylamine Rt = retention time cbz = carbobenzyloxy h, hr or hrs = hour or hours min or mins = minute or minutes ee = enantiomeric excess of = diastereomeric excess - eq. or equiv. = equivalent ACN = acetonitrile DMF = dimethylformamide DMEA = N, N-dimethylethanolamine NH3ac = 25% by weight aqueous ammonia Tmass = temperature of the reaction mixture The reported EMCL analytical data refer to either: (i) a run of 6 minutes, performed in a column (C18 50 x 3 mm 5 μm) using a gradient of [90% H20 (+ 0.04% formic acid) to 90% ACN (+ 0.04% formic acid)] for 4 minutes. minutes and then held for 2 minutes; or (ii) a 12 minute run, performed in a column (C18 100 x 3 mm 5 μm) using a gradient of [90% H20 (+ 0.04% formic acid) to 90% ACN (+ formic acid 0.04%)] for 9 minutes and then maintained for 3 minutes.

General Synthetic Procedures for the Preparation of Examples 1 to 32 and 35 to 38 General Procedure 1: Preparation of alkyl ketones of N-benzylmorpholine To a solution of carboxamide 2 in anhydrous THF at 0 ° C, a solution of the Grignard reagent requirement (1.2-3 equivalents, in one or two aliquots) was added. The reaction mixture was allowed to warm to room temperature and was allowed to stir for 45 minutes to 2 hours before quenching it with either 1M hydrochloric acid or saturated ammonium chloride solution and extracted either with DCM or ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the corresponding alkylketones 3-10, 77 and 82.

General Procedure 2: Preparation of tertiary alcohols of N-benzyl To a solution of ketones 3-10, 77 and 83 in anhydrous THF at 0 ° C, a solution of the benzyl Grignard reagent requirement (1.1-1.5 eq.) Was added. . The reaction mixture was allowed to warm to room temperature and was allowed to stir for 1-2 hours before quenching it by the addition of cold water. After extraction of the aqueous layer in DCM, the combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the tertiary N-benzyl alcohols of the title. The purification details are listed for individual compounds.

General Procedure 3: Debencylation of tertiary alcohols of N-benzyl To a solution of tertiary N-benzyl alcohol required in anhydrous DCM, solidified Hünig base (Argonaut, 3.56 mmol / g, 2-4 eqv.) And chloroformate were added. of a-chloroethyl (3 to 10 eq.) at room temperature under nitrogen. The reaction mixture was heated to 40 ° C and the reaction was monitored by analysis of FIA + and EMCL. After completion, the reaction mixture is filtered and the resin washed with DCM. The combined organic phases are concentrated in vacuo. Methanol is added and the solution is heated at 60 ° C for 1.5 to 8 hours. After complete consumption of the starting material, the methanol solution is evaporated to give a product, which is further purified as detailed for individual compounds.

General Procedure 4: Conversion of amines to hydrochloride salts To a solution of the requisite amine in dry diethyl ether (5-10 mL), hydrochloric acid (1.2 eq., 1M solution in diethyl ether) was added. The ether is blown with a stream of nitrogen or stirred in vacuo and the samples were either dried under high vacuum for several hours or freeze-dried (acetonitrile / water 1/1 [v / v]), to give the hydrochloride salts in quantitatively close returns.

General Procedure 5: Preparation of Grignard reagents and benzyl Grignard reagents Such reagents were prepared from the required benzyl halide or halide, using methods known to those skilled in the art (see for example, Fieser, LF and Fieser, M. Fk. 'Reagents for Organic Synthesis', (Reagents for organic synthesis), John Wiley and Sons Inc., Vol. 1, pp. 415-424 or March, J Advanced Organic Chemistry ", (Advanced organic chemistry), John Wiley and Sons Inc., 3rd Ed., Pp. 558-561). The halides or benzyl halides requirements, were either commercially available or prepared using previously published literature methods.

Preparation of Intermediaries for the Synthesis of Examples 1-32 4 - . 4-benzyl-morpholine-2-carbonyl trile A one liter reactor with mechanical stirring, cooled by an ice bath, is charged with N-benzylethanolamine (172.2 g, 1 eguiv available from Aldrich Chemical Company). 2-Chloroacrylonitrile (100 g, 1 equiv available from Aldrich Chemical Company) was added dropwise over 2 minutes. The temperature is maintained between 23 ° C and 29 ° C by means of the ice bath and subsequently a water bath at 15 ° C. After one night of stirring at room temperature (water bath), the mixture was dissolved in tetrahydrofuran and transferred to a 2 L reactor which is cooled to -5 ° C by an ice / NaCl bath. The total volume of tetrahydrofuran is 1.35 L. Potassium tert-butoxide (148 g) was added; 1.1 equiv.) In portions for 1 hour, maintaining the reaction temperature at 0 + 2 ° C. After 1 hour, after stirring at 0 ° C, the mixture is quenched with saturated NaHCO 3 (500 mL). The aqueous layer is extracted with diethyl ether (500 mL). The organic layers are dried over MgSO and evaporated to dryness. The title compound (149.8 g, 65%) is obtained after the percolation of 250 g of the dry residue in 1 kg of Si02, levigating with the following gradient: AcOEt at 5% - 95% n-heptane 2.5 L AcOEt at 10% - 90% n-heptane 2 L 15% AcOEt - 85% n-heptane 2 L 20% AcOEt - 80% n-heptane 5 L Alternatively, this intermediate can be prepared as follows: A coated reactor of glass of 1600 L under N2, is successively loaded with 2-chloroacrylonitrile (33.2 kg, 379 moles) and toluene (114 L) at 21 ° C. Then, N-benzylethanolamm (57 kg, 377 moles) is added and the reaction mixture is subsequently stirred at room temperature for about 17 hours. The mixture is then diluted with toluene (336 L), cooled down to about -12 ° C, and potassium t-butoxide (42.3 kg, 377 moles) is added in portions (10), maintaining approximately -13 ° C < T ass < about -2 ° C. The mixture is subsequently stirred at about 0 ° C for 2.5 h, then quenched by the addition of water (142.5 L), maintaining approximately 2 ° C < Tmass < about 8 ° C. The aqueous layer is separated after 35 minutes of subsequent stirring, allowing the mixture to reach 15 ° C and the toluene layer is washed with water (142.5 L) and the aqueous layer is separated. The organic layer is then concentrated under reduced pressure (150 mbar) maintaining the Tmass < 60 ° C to distill 162 kg of toluene. The filtrates are then diluted with toluene (114 L) and treated with Si02 (Merck silica gel 60, 0.063-0.1 mm, 74.1 kg), with stirring at room temperature for 1.25 hours. The Si02 is filtered and rinsed with toluene (2x114 L). Then, the filtrates are concentrated under reduced pressure (150 mbars), keeping the Tmass < 60 ° C to distill 351.8 kg of toluene. 4-Benzyl-morpholin-2-carboxylic acid hydrochloride (91) A 500 mL reactor under N2 is successively charged with toluene (36.72 mL) and 2-chloroacrylonitrile (10.7 g, 122. 23 mmol) at room temperature. Then, N-benzyl ethanolamine (18.36 g, 121.14 mmol) is added over 5 minutes and the reaction mixture is subsequently stirred at room temperature for 16 h. The mixture is then diluted with toluene (110.16 mL), cooled to -5 ° C and 2M potassium tert-butoxide solution in THF (121.14 mmol) is added slowly over 30 minutes, maintaining the temperature at -5 ° C at 0 ° C. The mixture is then stirred at about -5 ° C to 0 ° C for Ih, then quenched by adding water (45.9 mL). The aqueous layer is separated and the toluene layer is washed with water (45.9 mL) and then the mixture is allowed to warm to room temperature. The organic layer is then concentrated under reduced pressure at 40 ° C. The mixture is then diluted with toluene (100 mL) and extracted with aq. 6N (162 mL). This aqueous layer is heated to reflux for lh30, then the mixture is allowed to stir at room temperature overnight. After crystallization of 91, the solid is filtered, rinsed with aq. 6N (40 mL) and dried under reduced pressure at 40 ° C. (19 g, yield = 61%).

N-benzyl-2- (morpholine-4-carbonyl) -morpholine hydrochloride (92) A reactor of 250 mL under N2, is successively loaded with 91 (5 g, 19.41 mmol), dichloroethane (50 mL), DMF (0.014 mL, 1 mol%) and oxalyl chloride (1.86 mL, 21.35 mmol).

The mixture is heated to 60-65 ° C for 2h, before being cooled to 0 ° C. Then, morpholine (6.93 g, 79.60 mmol) in dichloromethane (20 mL) is added, during 15 minutes maintaining the temperature below 10 ° C. The heterogeneous solution is subsequently stirred for 1:30 min at room temperature and quenched with water (30 mL). The biphasic mixture is filtered on a Hyflo SuperCel® (10 g), after separation, the organic layer is concentrated under reduced pressure. The mixture is taken with isopropanol (80 mL) and aq. 12N (1.61 mL, 19.41 mmol), stirred for 10 minutes and concentrated under reduced pressure. The mixture is taken with isopropanol (13 L), heated to reflux until a homogeneous solution is formed, then cooled to room temperature. The precipitate is filtered, rinsed with isopropanol (10 mL) and dried under vacuum at 40 ° C overnight to obtain 92 as a whitish powder with 79% total yield. 4-Benzyl-morpholin-2-carboxylic acid ethyl ester (1) A stirred solution of 4-benzyl-morpholine-2-carbonitrile (113.0 g, 0.56 mol) in ethanol (1030 mL) was treated with concentrated sulfuric acid (165 mL) added in portions, (the exothermic, internal temperatures rise from ambient up to 65 ° C). The mixture is then heated under reflux for 66 hrs. The solution is cooled and then concentrated in vacuo at half volume, basified with aqueous potassium carbonate (care is taken to foam) and the product is extracted into diethyl ether. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to give an oil. This material is also evacuated under high vacuum. Yield = 121.3 g (87%). Alternatively, compound 1 can be synthesized as follows: A 100 L reactor attached to a scrubber filled with 1N NaOH (60 L) is charged under nitrogen with 4-benzyl-morpholin-2-carbonitrile (1867 g, 9.23 mol ) and ethanol (20 L). At Tmass = 15-20 ° C, concentrated sulfuric acid (2.76 L, 50 mol) is added to the solution for 20 minutes (highly exothermic). The solution is heated to reflux for 2.5 days. Then, 10 L of the solvent is distilled under vacuum and the reaction mixture is cooled to Tmass = 20-25 ° C. Water (40 L) is added for 25 minutes, followed by Na 2 CO 3 solution (1/2 saturated, 18 L) and NaHCO 3 (1/2 saturated, 7 L) to reach a pH ~ 7. Ethyl acetate is added (15 L ) and the phases are mixed for 15 minutes. The organic phase is separated and the aqueous phase is extracted with ethyl acetate (2 x 10 L). The combined organic layers are evaporated to dryness under vacuum to give 1 as a yellow to brown oil (1992 g, 87%). 4-Benzyl-morpholin-2-carboxylic acid ethyl ester (Ib) Compound 1 can be separated into its enantiomers by chiral HPLC under the following conditions: Chiralpak Daicel OJ 20 μm; 25 cm; 100% EtOH + 0.3% DMEA; 0.4 mL / min; detection at 260 nm. The desired enantiomer Ib is the peak eluting at Rt = 20.25 min.

I am using 4-benzyl-morpholin-2-carboxylic acid (2) To a stirred suspension of N, N-dimethylhydroxylamine (6.6 g, 67.6 mmol) in anhydrous DCM (200 ml) under nitrogen at 0 ° C was added dropwise a solution of trimethylammonium (2M solution in hexane, 34 ml, 67.6 mmol) for 30 minutes. The reaction mixture was allowed to warm to room temperature and was allowed to stir for 1 hour. Then a solution of ester 1 (6.74 g, 27 mmol) in anhydrous DCM (100 ml) was added and then added dropwise over 30 minutes and the reaction mixture was allowed to stir overnight before shutdown by cautious addition of buffer of phosphate solution (disodium hydrogen phosphate, pH 8). The precipitate was removed by filtration through a pad of celite and the residue was washed with chloroform. The organic phase was then concentrated in vacuo and washed with water. The aqueous layer was extracted again with chloroform and the organic phases were combined, washed with brine, dried over magnesium sulfate and the solvent evaporated in vacuo to give 2 as a yellow oil. Alternatively, the reaction should be worked up as follows: in addition to a solution of ester 1 (1 eq) the reaction mixture was allowed to stir for 1 hour before quenching by the addition of phosphate buffer solution (disodium hydrogen phosphate) , pH 8), followed by the addition of water. The aqueous layer was back extracted with DCM and the organic phases were combined, dried over magnesium sulfate and the DCM was evaporated in vacuo to give 2 as a yellow oil (3.36 g, 47%), MW 264.33; C 4 H 20 N 2 O 3; E NMR (CDC13): 7.47-7.22 (5H,), 4.55 (HH, d, 1.5 Hz), 4.00 (HH, dd, 11.5 Hz, 1.7 Hz), 3.75 (1H, dt, 11.5 Hz, 2.2 Hz), 3.65 (3H, s), 3.56 (2H, m), 3.17 (3H, s), 2.93 (1H, d, 11.3 Hz), 2.68 (1H, d, 11.3 Hz), 2.30 (2H, 11.3 Hz); EMCL: (6 min method) m / z 265 [M + H] +, R t 0.65 min.

Methoxy-methyl-4-benzyl-morpholin-2-carboxylic acid (2b) Ó & Compound 2 can be separated into its enantiomers by chiral HPLC under the following conditions: Daicel Chiralpak OJ 20 μm; 25 cm; n-heptane / isopropanol 80:20 v: v; 0.4 ml / min; detection at 220 nm. The desired 2b enantiomer is the peak levigating a (RT = ???? min). Alternatively, compound 2b can be substantially synthesized as described above by compound 2 using compound Ib in place of compound 1. 2-f nyl-5-fluorobenzyl bromide The title compound was prepared in 5 steps of commercially available 5-fluorosalicylic acid (Aldrich) following the procedures of the literature (JACS, 2000, 122, 4020-4028). PM 265.13; C? 3H? 0BrF; XH NMR (CDC13): 7.48-7.38 (5H, m), 7.26-7.19 (HH, m), 7.05 (HH, td, 8.3 Hz, 2.8 Hz), 4.39 (2H, s); 19 F NMR (CDC13): -114.72. (5-Flnoro-2-methoxy-phenyl) -methanol To a solution of 2-methoxy-5-fluorobenzaldehyde (11.093 g, 1 eq, available from Aldrich Chemical Company) in methanol at -10 ° C under nitrogen atmosphere was added NaBH4 (7.515 g, 2.7 equiv.) In portions. The solution was allowed to warm to room temperature and after 30 minutes the reaction solvent was removed under reduced pressure and replaced with dichloromethane. This solution was poured into ice water and further extracted with dichloromethane. The organic fractions were collected and dried (MgSO4) and the solvent was removed under reduced pressure to give the title compound as an oil (9.794 g, 87%). MW 156.16; C8H9F02; XR NMR (CDC13): 2.58 (m, HH), 3.81 (s, 3H), 4.63 (d, 2H, 6.3 Hz), 6.78 (dd, ÍH, 8.9 Hz and 4.3 Hz), 6.94 (td, ÍH , 8.5 Hz and 3.1 Hz), 7.04 (dd, ÍH, 8.7 Hz and 3.1 Hz).

-Fluoro-2-methoxybenzyl chloride Clean (5-fluoro-2-methoxy-phenyl) -methane (19.587 g, 1 equiv.) Was added to clean S0C12 (42.2 ml, 4.6 equiv.) At 78 ° C under a nitrogen atmosphere and the solution is then left Warm to room temperature and stir until gas evolution ceased. An equivalent volume of anhydrous toluene was added to the flask and the solution was heated to 60 ° C. Upon cooling, the reaction solution was poured into ice water. The toluene layer was separated and dried (MgSO 4) and the solvent was removed under reduced pressure. The crude material was sublimed (60-80 ° C / 0.05 mBar) to give the title compound as a white solid (13.40 g, 61%). PM 174.60; C8H8C1F0; X H NMR (CDC13): 3.87 (s, 3 H), 4.60 (s, 2 H), 6.79-7.20 (m, 3 H). 2-methoxy-5-fluorobenzylmagnesium bromide Magnesium chips (21.6 g, 0.888 mole, 2 eq) and diethyl ether (300 ml) were charged in a reactor under N2. A solution of 5-fluoro-2-methoxybenzyl chloride (116 g, 0.664 mol, 1.5 eq) in diethyl ether (200 ml) was charged in an addition funnel. Iodide crystals and a small amount of 5-fluoro-2-methoxybenzyl chloride solution were added and the reaction mixture was stirred to initiate the reaction. The remainder of the 5-fluoro-2-methoxybenzyl chloride solution is then added by dripping to keep the temperature of the reaction mixture below 28 ° C. The mixture was stirred for another 5 minutes at 19 ° C and after finishing the addition a white suspension formed. l- [4- (Phenylmethyl) morpholin-2-yl] ethan-l-one (3) Compound 3 is obtained from 2 (0.730 g, 2.8 mmol) and commercially available methylmagnesium bromide (Aldrich) (1M solution in THF, 3 ml, 3 mmol, 1.1 eq) in anhydrous THF (25 ml) following General Procedure 1 after of purification by automated column chromatography (levigating EtOAc / n-heptane 14/86 - 100/0 [v / v]) (0.3 g, 49%).

PM 235.33; CXH2? N02. EMCL (6 minutes method) m / z 220.1 [M + H] +, Rt 1.55 min. 1-14- (Phenylmethyl) morpholin-2-yl] propan-l-one (4) Compound 4 is obtained from 2 (0.70 g, 2.65 mmol) and ethylmagnesium bromide (Aldrich) commercially available (2.65 ml, 7.94 mmol, 3 eq) in anhydrous THF (25 ml) following the General Procedure 1 as a yellow oil (583 mg, 89%). PM 249.36; C? 5H23N02. EMCL (6 minute method) m / z 234.4 [M + H] +, Rt 1. 78 min. 2-Methyl-l- [4- (phenylmethyl) morpholin-3-yl] propan-l-one (5) ckY Compound 5 is obtained from 2 (3.018 g, 11.4 mmol) and commercially available isopropylmagnesium chloride (Aldrich) (2M solution in THF, 17.1 mL, 34.3 mmol, 3 eq) in THF (100 mL), following General Procedure 1 as a yellow oil (2.68 g, 89%). PM 263.38; Ci6H25N02; EMCL (6 minute method): m / z 248.2 [M + H] +, Rt 2.41 min. 3-Methyl-l- [4- (phenylmethyl) morpholin-2-yl] butan-l-one (6) Compound 6 is prepared from 2 (10 g, 37 mmol) in anhydrous tetrahydrofuran (50 ml) and commercially available isobutyl magnesium bromide (Aldrich) (2M solution in diethyl ether, 56 mmol, 28 ml, 1.5 eq) following the procedure General 1. After stirring for 1 hour, the reaction was quenched by the addition of aqueous hydrochloric acid (150 ml). THF was removed in vacuo and diethyl ether was added after adjusting the pH by addition of a saturated sodium bicarbonate solution. The organic phases were combined, dried over magnesium sulfate and the solvent was removed in vacuo. 6 was isolated in 80% purity (8.7 g, 67% with respect to the pure product). PM 261.37; C? 6H23N02, EMCL: (6 min method) m / z2622 [M + H] + RT 2.753 min.

Cyclopentyl [4- (phenylmethyl) mor folin-2-yl] methanone (7) Compound 7 was prepared from 2 (3.36 g, 12.7 mmol) in anhydrous tetrahydrofuran (120 ml) and commercially available cyclopentylmagnesium bromide (Aldrich) (2M solution in diethyl ether, 19.1 ml, 38.2 mmol, 3 eq) following the General Procedure 1 in quantitative yield as yellow oil. PM 273.38; C? 7H23N02; EMCL (6 min method) m / z 274 [M + H] +, Rt 2.24 min. [4- (Phenylmethyl) mo folin-2-yl] (tetrahydro-2H-pyran-4-yl) methanone (8) Compound 8 is obtained from 2 (2.84 g, 10.74 mmol) in anhydrous tetrahydrofuran (30 ml) and 4-tetrahydropyranyl magnesium chloride (Chem. Ber, 98, 1965, 3757) (2M solution in tetrahydrofuran, 6.5 ml, 13 mmol , 1.2 eq) following General Procedure 1. After 30 minutes additional 4-tetrahydropyranylmagnesium chloride (2M solution in diethyl ether, 6.5 ml, 13 mmol, 1 eq.) Was added. After stirring for 2 hours the reaction mixture was quenched by the addition of a solution of ammonium chloride (30 ml) and ethyl acetate (30 ml). The aqueous layer was extracted again with ethyl acetate (30 ml) and the organic phases were combined, dried over magnesium sulfate and the solvents were removed in vacuo. The resulting residue was purified by ion exchange chromatography to give 8 as a yellow oil (2.98 g, 96%). PM 289.38; Ca7H23N03; EMCL (6 min method) m / z 290 [M + H] +, Rt 2.20 min. Alternatively, compound 8 can be prepared as follows: a) Neutralization of 92 92 (97 g) was suspended in toluene (485 ml) under mechanical stirring and sodium carbonate (3.68 N, 97 ml, 1.2 equiv.) was added. The mixture was then diluted with water (194 ml) and stirred for 45 minutes at room temperature. Then, the biphasic mixture was filtered on Hyflo Super Cel® and transferred to a separate funnel. The aqueous layer was discarded and the organic layer (594.3 g) was concentrated under reduced pressure at 40 ° C to a mass of 348 g. Toluene (150 ml) was added and the organic layer was concentrated under the same conditions to a mass of 347 g. The free base of compound 92 as a toluene solution is then diluted with anhydrous THF (300 g) and the solution is easy to be added to the Grignard reagent. b) Grignard reagent formation A 3-necked inert 3 1 flask was charged with THF (50 ml) and magnesium swarf (9 g, 0.379 mol, 1.25 equiv.). The mixture was heated to Tmass = 60 ° C and iodide (0.150 g) and 4-chlorotetrahydropyran (1 ml) was added. The onset was observed within 5 minutes. The mixture was then heated to Tmass = 63-68 ° C and the addition of remaining 4-chlorotetrahydropyran (39.19 ml diluted with 188 ml) was carried out for 1 hour keeping the Tmass constant at about 68 ° C. After 40 minutes of post-stirring, the reaction mixture was allowed to cool to room temperature. c) Grignard Reaction The neutralized 92 toluene / THF solution was added to the Grignard reagent at 20-25 ° C for 45 minutes. The mixture is post-stirred at room temperature for 1 hour. Then, the reaction mixture was quenched by addition at 0-5 ° C to a mixture of acetic acid / H20 (44.3 ml of acetic acid and 245 ml of H20). The aqueous layer was separated and discarded and the organic layer was washed with H20 (60 ml). The aqueous layer was separated and discarded and the organic layer was washed with 2N NaOH (100 ml). The aqueous layer was separated and discarded and the organic layer was concentrated under reduced pressure at 40 ° C to 230 g. The residue was taken up with IPA (11) and concentrated as described above to yield 230 g of 8 as the free base. [4- (Phenylmethyl) morph 'olin-2-yl] (tetrahydro-2H-pyran-4-yl) methanone (8b) An inert 6 1 reactor was charged with THF (242.5 ml), magnesium (54.47 g, 2240 mmol) and 5% of the total amount of 4-chlorotetrahydropyran (12.28 ml, 112 mmol). Then, a small amount of methyl iodide (0.5 ml) and an iodide crystal were added. The reaction mixture was stirred and heated to 64-66 ° C. After the start, 4-chlorotetrahydropyran (233.22 ml, 2127 mmol) diluted in THF (890 ml) was slowly added over 135 minutes. The mixture was heated for an additional 30 minutes before being cooled to 0 ° C. Then, amine 2b Weinreb (370 g, 1400 mmol) diluted in THF was added (2777 ml) for 30 minutes between 0-4 ° C and the mixture was stirred for an additional 60 minutes. Then, acetic acid (48 ml, 0.83 mmol) was added to the mixture followed by a mixture of saturated NH4C1 / H20 55/45: v / v (2590 ml) keeping the temperature below 9 ° C. The organic layer was washed with a saturated NH4C1 / H20 mixture 60/40: v / v (500 ml) and, after separation, toluene (1800 ml) and water (1800 ml) were added to the organic solution. After the additional extraction, water (1100 ml) was added to the toluene mixture which was basified with 3.68 M Na2CO3ac (148 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to dryness to provide compound 8b as a free base (400.8 g, 98.6% yield). Alternatively compound 8b can be prepared as follows: R- (-) - mandelic acid (1.65 g, 10.8 mmol) was added to a solution of 8 (3.15 g, 10.8 mmol) in isopropanol (20 ml). After 2 min of post-stirring, a homogeneous solution was obtained at room temperature. The crystallization is after 5 minutes of post-agitation to form an easily stable suspension. This suspension is post-agitated for 21 hours at room temperature. The solids were filtered and washed with isopropanol (2 ml). The white crystals were dried under vacuum at 40 ° C for 5 hours to give 1.8 g of 8b R-mandelate with 37.5% yield and 99.2% ee. 0.5N K2C03 (2.4 mL, 1.2 mmol) was added dropwise to a stirred suspension of 8b R-mandelate (500 mg, 1.13 mmol) in toluene (5 mL). A biphasic solution was obtained. The free base 8b is completely present in the organic layer, which was separated and concentrated in a rotoevaporator and dried under vacuum at 40 ° C providing 8b as an oil in 98% yield. , 5f 5-Trifluoro-l- [4- (phenylmethyl) mo folin-2-yl] butan-l-one (9) Compound 9 is obtained from 2 (1.38 g, 5.23 mmol) and 3, 3, 3-trifluoropropylmagnesium bromide (20.9 mL, 10.50 mmol, 2 eq) in dry THF (45 mL) following General Procedure 1. Bromide was obtained of 3,3,3-trifluoropropylmagnesium from 3,3,3-trifluoropropyl bromide (Aldrich) commercially available following General Procedure 5. Purification by ion exchange chromatography gives 9 as an oil (1.24 g, 78.7%) . PM 301.31; C? 5H? 8F3N02; EMCL (6 minutes method): m / z 302.4 [M + H] +, Rt 2.66 min. , 5, 5-Trifluoro-l- (4- (phenylmethyl) mor folin-2-yl] pentan-l-one (10) Compound 10 was prepared from a solution of 2 (0.717 g, 2.71 mmol) in anhydrous tetrahydrofuran (20 ml) and 4,4,4-trifluorobutylmagnesium bromide (0.5 M solution in diethyl ether, 6.5 ml, 3.25 mmol, 1.2 eq. ). 4,4,4-Trifluorobutylmagnesium bromide was obtained from 4,4,4-trifluorobutyl bromide (Aldrich) commercially available following General Procedure 5. After 30 minutes, another 0.3 eq of bromide of 4.4 was added, 4-triluforobutylmagnesium (0.5 M solution in diethyl ether, 2.5 ml). After stirring for 2 hours the solvents were removed in vacuo and water (20 ml) and ethyl acetate (30 ml) were added to the residue. The organic phase was washed with brine, dried over magnesium sulfate and the solvent was removed in vacuo to give 10 as a clear oil (0.985 g). 10 was collected in the next step without further purification. PM 315.34; C? 6H20NO2F3; EMCL: (6 min method) m / z 316 [M + H] +, Rt 2.9 min. 4 - . 4-Benz Lmorfolin -3-one A solution of N-benzyl-N- (2-hydroxyethyl) chloroacetamide (627.7 g, 2.76 mmol) in tert-butanol (0.9 ml) was stirred under nitrogen while heating to 25-30 ° C. Potassium tert-butoxide (2.897 1 of a 1M solution of tert-butane, 2.90 mole, 1.05 eq) was added for 2 hours. The reaction mixture was then stirred at room temperature for 90 minutes. Ice-ice water (6 1) was added and the resulting dark solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated in vacuo to give a light brown oil (441 g, 84%), which was used in the next step without further purification; PM 191.23; CuH? 3N02; ^ NMR (CDC13): 7.29-7.40 (5H, m), 4.67 (2H, s), 4.28 (2H, s), 3.87 (2H, t, 5 Hz), 3.31 (2H, t, 5 Hz); EMCL: (12 min method) m / z 192 [M + H] + Rt 1.00 min 4-Benzyl-2- (cyclopropyl-hydroxy-methyl) -morpholin-3-one (75) To a solution of 4-benzyl-morpholin-3-one (9.5 g, 50 mmol) in THF (200 ml) was added dropwise lithium diisopropylamine (2M solution in THF, 27 ml, 54 mmol, 1.1 eq) for 20 minutes at -78 ° C followed by slow addition of cyclopropyl methylaldehyde (3.85 ml , 55 mmol, 1.1 eq). After stirring at -78 ° C for one hour, the reaction mixture was allowed to warm to room temperature and stirred for another 6 hours. The reaction was quenched by the addition of EtOAc and brine. The aqueous layer was extracted with EtOAc, the combined organic layers were dried over magnesium sulfate and reduced in vacuo. Purification using automated column chromatography (DCM / MeOH, 100/0 to 85/15 [v / v]) gives 75 in 75% purity with 4-benzyl-morpholin-3-one as the major impurity. This product is directly used in the next stage. PM 261.32; C15H? 9N03; EMCL (6 min method) m / z 261.32 [M + H] +, Rt 2.23 (4-Benzyl-morpholin-2-yl) -cyclopropyl-methanol (76) Borane-THF complex (1M solution in THF, 30 mmol, 4.1 eq) was slowly added to a solution of 75 (1.9 g, 7.3 mmol) in THF (100 mL). The reaction was heated to 60 ° C. After 24 hours, MeOH and hydrochloric acid (2M, excess) were added and the resulting mixture was heated for one hour at the same temperature. After careful addition of a solution of saturated NaHCO 3 and EtOAc, the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was removed in vacuo. Purification by ion exchange chromatography gives 76 (1.1 g, 61%). PM 247 .34; C? 5H2? N02; EMCL (6 min method) m / z 248 [M + H] +, Rt 2. 48 min.

Cyclopropyl [4- (phenylmethyl) morpholin-2-yl] methanone (77) A solution of dimethisulfoxide (0.69 ml, 9.7 mmol, 2.2 eq) in DCM (4.5 ml) was added slowly to a solution of oxalyl chloride (2.43 ml, 4.85 mmol, 1.1 eq) in DCM (2.5 ml) followed by a solution of 76 (1.09 g, 4.41 mmol) in DCM (0.7 ml) under nitrogen at -60 ° C. After stirring for 15 minutes, triethylamine (3.14 ml, 22.1 mmol) was added and stirring continued for 15 minutes. After the addition of water, the layers separated. The aqueous layer was washed with DCM.

The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was removed in vacuo. Purification using automated column chromatography (EtOAc / n-hexanes, 20/80 to 50/50 [v / v]) gives 77 as a yellow oil (0.69 g, 64%) PM 245.32; C? 5H19N02; EMCL (6 min method) m / z 246.3 [M + H] +, Rt 1095 min. 1- (4-Benzyl-morpholin-2-yl) -pentan-1-one (82) Compound 82 was prepared from 2 (0.87 g, 3. 28 mmol) in anhydrous tetrahydrofuran (30 ml) and n-butyl magnesium bromide (2M solution in THF, 5 mmol, 2.5 ml, 1.5 eq) commercially available (Aldrich) following General Procedure 1. After stirring for 1 hour Additional, n-butyl magnesium bromide (2M solution in THF, 1.6 mmol, 0.8 ml) was added and stirring continued for 30 minutes. The reaction was quenched by the addition of ammonium chloride solution (30 ml) followed by EtOAc. The organic phases were combined, dried over magnesium sulfate and the solvent was removed in vacuo to give 82 (0.82 g, 96%). PM 261.37; C? 6H23N02; EMCL (6 minute method): m / z 262.4 [M + H] +, Rt 2.34 min.

Example 1: Preparation of 1- [1,1'-biphenyl] -2-yl-2-morpholin-2-ylpropan-2-ol (12) 1-f1,1'-Biphenyl] -2-H- hydrochloride 2- [4- (Phenylmethyl) morpholin-2-ylpropan-2-ol (11) Compound 11 was prepared from 2-phenylbenzyl magnesium bromide (0.25 M solution in diethyl ether, 5.5 ml, 1.38 mmol) and 3 (275 mg, 1.25 mmol) in anhydrous THF (7 ml) following General Procedure 2. It was obtained 2-phenylbenzyl magnesium bromide of 2-phenylbenzyl bromide (Aldrich) commercially available following General Procedure 5. Additional equivalent of 2-phenylbenzyl magnesium bromide (10 ml, 2.5 mmol) was added before quenching the reaction with ice water (7 ml). 11 is obtained as an oil in 75% purity after ion exchange chromatography (column 5 g) and automated column chromatography (EtOAc / n-heptane 0/100 to 50/50 [v / v]) and was taken in the additional stage without further purification (0.23 g of isolated material). PM 387.53; C26H2gN02; EMCL (6 minutes method): m / z 388.2 [M + H] +, Rt 3.37 min.

L- [l, l r -Biphenyl] -2-yl-2-morpholin-2-ylpropan-2-ol hydrochloride (12) 12 is obtained from 11 (204 mg, 0.53 m ol), ot-chloroethyl chloroformate (0.23 ml, 2.11 mmol) and Hünig base supported by polymer (296 mg, 1.05 mmol) in DCM (5 ml) following General Procedure 3 Purification using ion exchange chromatography, followed by preparative EMCL and conversion to the hydrochloride salt following General Procedure 4 giving 12 as a foam (102 mg, 65%). PM 297.36; C? 9H23N02. HCl; XH NMR (CD3OD) d 7.15-7.39 (8H, m), 7.07-7.11 (HH, m), 3.97 (HH, dd, 3.0 Hz, 13.0 Hz), 3.56-3.65 (1H, m), 3.20-3.25 ( 1H, m), 3.08 (2H, t, 12.5 Hz), 2.82-2.99 (4H, m), 0.60 (3H, s); EMCL (12 minute method): m / z 298.2 [M-HC1 + H] +, Rt 4.38 min.

Example 12: Preparation of 1- [5-chloro-2- (methyloxy) enyl] -2-mor-olin-2-ylbutan-2-ol (14) 1- [5-Fluoro-2- (methyloxy) phenyl] hydrochloride ] -2- [4- (Phenylmethyl) mor folin-2-yl] butan-2-ol (13) Compound 13 is obtained from 4 (583 mg, 2.5 mmol) and 2-methoxy-5-fluorobenzylmagnesium bromide (5.5 ml, 2.75 mmol, 1. 1) in anhydrous THF (15 ml) following General Procedure 2. Additional equivalents of 2-methoxy-5-fluorobenzylmagnesium bromide (2M solution in diethyl ether, 10 ml, 5.0 mmol) were added after 30 minutes and the mixture was added. it was warmed to room temperature and allowed to stir overnight. After purification by ion exchange chromatography, 13 was obtained as a yellow oil in 67% purity (702 mg). The compound was taken in the next step without further purification. PM 373.47; C22H28FN03; EMCL (6 minutes method) m / z 374.2 [M + H] +, Rt 3.17 min. 1- [5-Fluoro-2- (methyloxy) phenyl] -2-morpholin-2-ylbutan-2-ol hydrochloride (14) 14 is obtained from 13 (717 mg, 1.92 mmol), a-chloroethyl chloroformate (0.83 ml, 3.84 mmol, 4 eq) and Hünig base supported by polymer (1.08 g, 3.84 mmol, 2 eq) in DCM (17 ml) following General Procedure 3. Purification by ion exchange chromatography followed by preparative EMCL and conversion to the hydrochloride salt following General Procedure 4 gives 14 as a solid (185 mg, 30%). PM 319.81; C15H22FN03.HC1; XH Rmn (CD3OD) d 6.94 (1 H, dt, 1.5 Hz, 9 Hz), 6.81-6.84 (2 H, m), 4.07 (H, d, 3.5, 13 Hz), 3.67-3.76 (4H, m), 3.56 (1H, dd, 2.5 Hz, 11 Hz), 3.33 (HH, m), 3.14-3.25 (HH, m), 3.00-3.08 (2H, m), 2.84 (2H, 14 Hz), 1.37-1.51 (1H, m), 1.05-1.19 (HH, m), 0.82 (3H, t, 7.5 Hz); EMCL (12 minute method): m / z 284. 1 [M-HC1 + H] +, Rt 3. 76 mm.

Example 3: Preparation of 2-morpholin-2-yl-1-hydrochloride. { 2- [(trifluoromethyl) oxy] enyl} butan-2-ol (16) 2- 14- (Phenylmethyl) morph olin-2-yl] -1-. { 2- [trifluoromethyl) oxy] phenyl} butan-2-ol (15) Compound 15 is obtained from 4 (1.1 g, 4.71 mmol) and commercially available 2-trifluoromethoxybenzylmagnesium bromide (Fluorochem) (10.4 ml 1, 5.19 mmol, 1.1 eq) in anhydrous THF (31 ml) following General Procedure 2. After After 30 minutes, additional equivalents of 2-trifluoromethoxybenzylmagnesium bromide (0.5 M solution in diethyl ether, 4.71 ml, 2.36 mmol) were added. Purification by ion exchange chromatography gives 15 as an oil (1.88 g, 98%). PM 409.45; C22H26F3N03; EMCL (6 minute method): m / z 410.4 [M + H] +, Rt 3.28 min. 2-Morpholin-2-yl-1-hydrochloride. { 2- [(trifluoromethyl) oxy] phenyl} butan-2-ol (16) 16 is obtained from 15 (1.88 g, 4.59 mmol), a-chloroethyl chloroformate (1.98 mL L, 18.4 mmol) and Hünig base supported by polymer (2.58 g, 9.18 mmol) in DCM (40 mL) following the General Procedure 3. Purification using ion exchange chromatography followed by automated column chromatography (levigant, MeOH / DCM 0/100 to 20/80 [v / v]) and conversion to the hydrochloride salt following General Procedure 4 gives 16 (258.5 mg, 17%) as a white solid. PM 319.33; C15H20F3NO3.HCl; 1 H NMR (CD3OD) - d 7.53 (ΔI, dd, 2 Hz, 7.5 Hz), 7.27-7.38 (3H, m), 4.20 (ΔI, dd, 3.5 Hz, 13 Hz), 3.85 (ΔI, td, 3 Hz , 13 Hz), 3.70 (HH, dd, 2 Hz, 11 Hz), 3.44 (1H, d, 13 Hz), 3.27-3.34 (HH, m), 3.12-3.22 (2H, m), 3.07 (1H, d, 14 Hz), 2.96 (1 H, d, 14 Hz), 1.55 (H, sextet, 7.5 Hz), 1.26 (H, sextet, 7.5 Hz), 0.93 (3 H, t, 7.5 Hz). EMCL (12 minute method): m / z 320.4 [M-HC1 + H] +, Rt 2.77 min.

Example 4: Preparation of 1- [1,1'-biphenyl] -2-yl-2-morpholin-2-butan-2-ol (18) 1-11,1 '-Biphenyl] -2-H- hydrochloride 2- [4- (phenylmethyl) morpholin-2-ylbutan-2-ol (17) Compound 17 is obtained from 3 (601 mg, 2.58 mmol) and 2-phenylbenzylmagnesium bromide (0.25 M solution in diethyl ether, 11.5 ml. , 2.84 mmol) in anhydrous THF (15 ml) following General Procedure 2. 2-Phenylbenzylmagnesium bromide of 2-phenylbenzyl bromide (Aldrich) was prepared commercially available following General Procedure 5. Additional equivalents of 2-phenylbenzyl bromide were added. phenylbenzylmagnesium (10.32 ml, 2.58 mmol). Purification by ion exchange chromatography followed by automated column chromatography (levigant, EtOAc / n-heptane 0/100 to 50/50 [v / v]) gives 17 (705 mg, 68%) as a 91% colorless oil of purity which is directly used in the next stage. PM 401.55; C27H3: LN02; EMCL (6 minute method): m / z 402.2 [M + H] +, Rt 3.56 min. 1- [1, 1 '-Biphenyl] -2-yl-2-morpholin-2-ylbutan-2-ol hydrochloride (18) 18 gives 17 (705 mg, 1.76 mmol) a-chloroethyl chloroformate (0.76 ml, 7.02 mmol) and Hünig base supported by polymer (988 g, 3.52 mmol) in DCM (15 ml) following General Procedure 3. Purification by ion exchange chromatography followed by automated column chromatography (levigant, MeOH / DCM 5/95 to 20/80 [v / v]) and conversion to hydrochloride salt following General Procedure 4 gives 18 (0.37 g, 62% ) as a yellow foam. PM 347.82; C20H25NO2.HCl; E NMR (CD3OD) d 7.43-7.46 (HH, m), 7.29-7.34 (3H,), 7.14-7.25 (5H, m), 7.06-7.11 (HH,), 3.94 (HH, dd, 3.5 Hz, 13 Hz), 3.55-3.64 (1H, m), 3.37 (ÍH, dd, 1.5 Hz, 11 Hz), 3.09 (2H, d, 12.5 Hz), 2.80-2.99 (4H, m), 1.11-1.23 (1H, m), 0.91 (1H, m), 0.38 (3H, t, 7.5 Hz). EMCL (12 minute method): m / z 312.1 [M-HC1 + H] +, Rt 4.67 min.

Example 5: Preparation of 1- [5-fluoro-2- (methyloxy) phenyl] -3-methyl-2-morpholin-2-ylbutan-2-ol (20) 1- [5-Fluoro-2- ( methyloxy) phenyl] -3-methyl-2- [4- (phenylmethyl) morpholin-2-yl] butan-2-ol (19) Compound 19 is obtained from 5 (0.7 g, 2.83 mmol) and 2-methoxy-5-fluoro-benzylmagnesium bromide (6.2 ml, 3.11 mmol, 1.1 eq) in anhydrous THF (15 ml 1) following General Procedure 2. Additional equivalents of 2-methoxy-5-fluoro-benzylmagnesium bromide (8.49 ml, 4.25 mmol) were added and the mixture was warmed to room temperature and allowed to stir overnight. Purification using automated column chromatography (levigant, n-heptane / EtOAc 100/0 to 75/25 [v / v]) gives 19 (0.53 g, 48%). MP 387.5; C23H3oFN03; EMCL (6 minutes method): m / z 388.2 [M + H] +, Rt 3.21 min. 1- [5- Fluoro-2- (methyloxy) phenyl] -3-methyl-2-morpholin-2-ylbutan-2- (20) hydrochloride is obtained from 19 (523 mg, 1.35 mmol), a-chloroethyl chloroformate (0.58 ml, 5.40 mmol, 4 eq) and PS-DIEA (0.76 g, 2.70 mmol, 2 eq) in DCM (10 ml) following the General Procedure 4. The purification by ion exchange chromatography and conversion to the hydrochloride salt following General Procedure 4 gives 20 as an off-white solid (0.26 g, 58%). PM 333.83; C? 6H2FN03.HCl; XH NMR (CD3OD) d 7.10 (1H, d, 9.5 Hz), 6.94 (2H, d, 6 Hz), 4.07 (ΔH, dd, 3.5 Hz, 13 Hz), 3.71-3.88 (5H, m), 3.21- 3.47 (2H, m), 2.99-3.11 (4H, m), 1.8 (1H, septet, 7 Hz), 1.04 (3H, d, 7 Hz), 0.94 (3H, d, 7.0 Hz); EMCL (12 minute method): m / z 298 [M-HC1 + H] +, Rt 4.29 min.

Example 6: Preparation of 3-methyl-l- [2-methyloxy) phenyl] -2-morpholin-2-ylbutan-2-ol (22) 2- (4-Benzyl-morpholin-2-yl) -1 hydrochloride - (2-methoxy-phenyl) -3-methyl-butan-2-ol (21) Compound 21 is obtained from 5 (1.5 g, 6.06 mmol) and 2-methoxybenzylmagnesium bromide (available from Rieke-Metals) (0.25 M solution in THF, 33.9 mL, 8.49 mmol) in anhydrous THF (30 mL) following the procedure General 1. Purification by column chromatography (levigant, EtOAc / n-heptane 0/100 to 40/60 [v / v]) gives 21 as a colorless oil (1.45 g, 48%). PM 369.51; C23H31N03.HC1; EMCL (6 minute method): m / z 370.2 [M-HC1 + H] +, Rt 2.77 min. 3-Methyl-1- (2-methyloxy) phenyl] -2-morpholin-2-ylbutan-2-ol hydrochloride (22) 22 is obtained from 21 (1.24 g, 3.37 mmol), a-chloroethyl chloroformate (3.63 ml, 33.7 mmol) and Hünig base supported by polymer (4.72 g, 16.8 mmol) in DCM (45 ml) following General Procedure 3 Purification using ion exchange chromatography followed by chiral preparative HPLC (gradient n-Heptane: EtOH: DEA 85: 15: 0.2, chiralcel-OD) gives two enantiomers, the first enantiomer levigando (Rt 9.5 min), and the second enantiomer levigating (Rt 11.41 min). The two enantiomers are converted to their respective hydrochloride salts 22a (146 mg) and 22b (138 mg) and obtained as white solids (total combined yield 28%). PM 315.84; C? 6H25N03.HCl; 1 H NMR (CD30D) d 7.22-7.34 (2H, m), 6.85-6.95 (2H, m), 4.08 (ΔH, dd, 3.6 Hz, 12.8 Hz), 3.86-3.9 (4H,), 3.77 (ΔI, td , 2.45 Hz, 12.4 Hz), 3.22-3.28 (1H,), 3.24 (1H, d, 12.8 Hz), 2.95-3.11 (4H, m), 1.83 (1H, septet, 6.8 Hz), 1.16 (3H , d, 7.0 Hz), 0.95 (3H, d, 7.0 Hz); EMCL (12 minute method): m / z 280.2 [M-HC1 + H] "1", Rt 4.05 min.

Example 7: Preparation of 1- [2-ethyloxy) phenyl] -3-methyl-2-morpholin-2-ylbutan-2-ol (24) 1- [2-Ethyloxy) phenyl] -3-methyl-2 hydrochloride - [4- phenylmethyl) morph olin-2-ylbutan-2-ol (23) BO 0H r Compound 23 is obtained from 5 (1.5 g, 6.06 mmol) and 2-ethoxybenzylmagnesium chloride (available from Rieke-Metals) ( 0.25 M solution in THF, 34 ml, 8.49 mmol) in anhydrous THF (30 ml) following General Procedure 2. After repeated repetition by automated column chromatography (1 levigating MeOH / DCM 0/100 to 10/90 [v / v]) followed by EtOAc / DCM 0/100 to 50/50 [v / v]) is obtained 23 as a colorless oil (0.8 g, 35%). MP 383.54, C24H33N03; EMCL (6 minute method): m / z 384.4 [M + H] +, Rt 3.04 min. 1- [2-Ethyloxy) phenyl] -3-methyl-2-morpholin-2-ylbutan-2-ol hydrochloride (24) Ork A-1 aH 24 is obtained from 23 (766 mg, 2.0 mmol) a-chloroethyl chloroformate (0.86 ml, 8.0 mmol) and Hünig base supported by polymer (1.12 g, 4.0 mmol) in DCM (30 ml) following General Procedure 3. Purification using ion exchange chromatography followed by automated column chromatography (levigant, MeOH / DCM 0/100 to 20/80 [v / v]) and chiral preparative chromatography (gradient n-Heptane: EtOH: DEA 95: 5: 0.2, quiracel AD) gives the first enantiomer levigando (Rt 13.40 min) and the second enantiomer levigando (Rt 15.63 min). After conversion to their respective hydrochloride salts, 24a (85 mg) and 24b (79 mg) are obtained as brown solids (combined yield 28%). PM 293.36; C17H27NO3.HCI; "XH NMR (CD3OD) d 7.06-7.09. (1H, m), 6.95-7.01 (HH, m), 6.66-6.75 (2H, m), 3.80-3.92 (3H, m), 3.46-3.63 (2H, m), 2.96-3.15 (2H, m), 2.66-2.86 (4H, m), 1.54-1.63 (ÍH, m), 1.22 (3H, t, 7.0 Hz), 0.82 (3H, d, 7.0 Hz), 0.71 (3H, d, 7.0 Hz); EMCL (12 minute method): m / z 294.2 [M-HC1 + H] +, Rt 4.60 min.

Example 8: 3-Methyl-2-morpholin-2-yl-1-hydrochloride. { 2- [(trifluoromethyl) oxylbutan-2-ol (26) 3-Methyl-2- 14- (phenylmethyl) morpholin-2-yl] -l-. { 2- [(trifluoromethyl) oxy] phenyl} butan-2-ol (25) Compound 25 is obtained from 5 (953 mg, 3.85 mmol) and commercially available 2-trifluoromethoxybenzylmagnesium bromide (Fluorochem) (8.48 ml, 4.24 mmol, 1.1 eq) in anhydrous THF (25 ml) following General Procedure 3 and addition of Additional 2-trifluoromethoxybenzylmagnesium bromide (3.85 ml, 1.93 mmol). Purification by ion exchange chromatography gives 25 as a yellow oil in 86% purity which is used in the next step without further purification (1.53 g of isolated material). PM 423.38; C23H28F3N03; EMCL (6 minute method) m / z 424.1 [M + H] +, Rt 3.53 min. 3-Methyl-2-morpholin-2-yl-1-hydrochloride. { 2- [(trifluoromethyl) oxy] butan-2-ol (26) 26 is obtained from 25 (1.53 g, 3.61 mmol), a-chloroethyl chloroformate (1.55 ml, 14.5 mmol, 4 eq) and Hünig base supported by polymer (2.03 g, 7.23 mmol, 2 eq) in DCM (30 ml ) following General Procedure 3. Purification by ion exchange chromatography, followed by automated column chromatography, levigating MeOH / DCM 0/100 to 20/80 [v / v]) and conversion to its hydrochloride salt following the General Procedure 4 gives 26 as a yellow solid (0.4 g, 29%). PM 379.82; C? 6H22F3N03.HCl; XE NMR (CD3OD) d 7.46 (1H, dd, 1.5 Hz, 7.5 Hz), 7.14-7.24 (3H, m), 3.94 (1H, dd, 3.5 Hz, 13 Hz), 3.80 (1H, dd, 2.5 Hz, 11.5 Hz) 3.69 (ÍH, td, 2.5 Hz, 13 Hz), 3.27 (ÍH, d, 13 Hz), 3.13 (1H, d, 12.5 Hz), 2.72-3.02 (4H, m), 1.70 (ÍH, septet, 7 Hz), 0.94 (3H, d, 7 Hz), 0.84 (3H, d, 7.0 Hz). EMCL (12 minute method): m / z 334. 4 [M-HC1 + H] +, Rt 2.94 min.

Example 9: Preparation of 1- [1,1'-biphenyl] -2-yl-3-methyl-2-morpholin-2-ylbutan-2-ol (28) 1-11, 1'-Biphenyl] - hydrochloride 2-yl-3-methyl-2- [4- (phenylmethyl) mo folin-2-ylbutan-2-ol (27) Compound 27 is obtained from 5 (0.7 g, 2.83 mmol) and 2-phenylbenzylmagnesium bromide (12.5 ml, 3.11 mmol) in anhydrous THF (15 ml) following General Procedure 2 and additional equivalents of the reactant 2-phenylbenzylmagnesium bromide ( 11.3 ml, 5.66 mmol). 2-Phenylbenzylmagnesium bromide of 2-phenylbenzylmagnesium bromide (Aldrich) commercially available following General Procedure 5 was prepared. Purification using ion exchange chromatography, followed by automated column chromatography. (levigant, EtOAc / n-heptane 0/100 to 20/80 [v / v]) gives 27 as an oil (0.46 g, 40%). PM 415.58; C28H33N02; EMCL (6 minute method): m / z 416.2 [M + H] +, Rt 3.45 min. 1- [1,1 '-Biphenyl] -2-yl-3-methyl-2-morpholin-2-ylbutan-2-ol hydrochloride (28) 28 is obtained from 27 (405 mg, 0.976 mmol), a-chloroethyl chloroformate (0.42 ml, 3.9 mmol) and base Hünig supported by polymer (0.55 mg, 1.95 mmol) in DCM (7 ml) following General Procedure 3. The crude product is purified using ion exchange chromatography, and then converted to its hydrochloride salt following the General Procedure 4 to give 28 as a white solid (0.23 g, 71%). PM 361.91; C21H27N02.HC1; XH NMR (CD30D) d 7.61-7.64 (1H, m), 7.19-7.47 (8H, m), 3.95 (1H, dd, 4 Hz, 13 Hz), 3.61-3.71 (2H, m), 3.04-3.19 ( 4H, m), 2.96 (ÍH, td, 4 Hz, 12.6 Hz), 2.70 (1H, dd, 13, 11.5 Hz), 1.67 (ÍH, septet, 7 Hz), 0. 75 (3H, d, 7 Hz), 0.63 (3H, d, 7 Hz); EMCL (12 minute method): m / z 326.2 [M-HC1 + H] +, Rt 5.02 min.

Example 10: Preparation of 1- (4-Fluoro [1, 1'-biphenyl] -2-yl) -3-methyl-2-morpholin-2-ylbutan-2-ol hydrochloride (30) 1- ( 4-Fluoro [1, 1 '-biphenyl] -2-yl) -3-methyl-2- [4- (phenylmethyl) morpholin-2-ylbutan-2-ol (29) Compound 29 is obtained from 5 (1.13 g, 4.57 mmol) and 2-phenyl-5-fluorobenzylmagnesium bromide (0.5 M in THF, 10.5 ml, 5.03 mmol) in anhydrous THF (30 ml) following General Procedure 2 ( After 30 minutes, add 2-phenyl-5-fluorobenzylmagnesium bromide (0.33 eq, 3 ml, 1.51 mmol)). 2-Phenyl-5-fluorobenzylmagnesium bromide is obtained from 2-phenyl-5-fluorobenzyl bromide following General Procedure 5. Purification by ion exchange chromatography followed by automated column chromatography (levigant, EtOAc / n-heptane 0/100 to 20/80 [v / v]) gives 29 as a yellow oil in 86% purity which is used directly in the next stage (1.58 g of recovered material). PM 415.58; C28H33N02; EMCL (6 minute method): m / z 434. 5 [M + H] +, Rt 3.71 min. 1- (4-Fluoro [1,1'-biphenyl] -2-yl) -3-methyl-2-morpholin-2-ylbutan-2-ol hydrochloride (30) is obtained from 29 (1.58 g, 3.63 mmol), a-chloroethyl chloroformate (1.57 ml, 3.63 mmol) and Hünig base supported by polymer (2.04 g, 7.26 mmol) in DCM (30 ml) following General Procedure 3 The crude product is purified using ion exchange chromatography, automated column chromatography (levigant, MeOH / DCM 0/100 to 20/80 [v / v]), and preparative EMCL. The conversion to the hydrochloride salt following General Procedure 4 gives 30 as a yellow solid (0.3 g, 22%). PM 379.91; C21H26FN02.HC1; aH NMR (CD3OD) d 7.20-7.35 (6H, m), 7.07-7.14 (ÍH, m), 6.90 (1H, td, 2.5 Hz, 8.5 Hz), 3.83 (1H, d, br, 10 Hz), 3.56 (2H, t, 10 Hz), 3.03-3.12 (2H, m), 2.79-2.98 (3H, m), 2.63 (H, t, 11.5 Hz), 1.55 (H, quintet, 7 Hz) , 0.64 (3H, d, 7 Hz), 0.51 (3H, d, 7 Hz); EMCL (12 minute method): m / z 344.1 [M-HC1 + H] "1", Rt 5.14 min.

Example 11: Preparation of 1- [5-chloro-2- (methyloxy) enyl] -4-methyl-2-morpholin-2-yl-pentan-2-ol (32) 1- [5-Fluoro- 2- (Methyloxy) phenyl] -4-methyl-2- [4- (phenylmethyl) morpholin-2-yl] pentan-2-ol (31) Compound 31 is obtained from 6 (465 mg, 1.78 mmol) and 2-methoxy-5-fluorobenzylmagnesium bromide (3.92 ml, 1.96 mmol, 1.1 equiv.) In dry THF (10 ml) following General Procedure 2. Purification by ion exchange chromatography followed by automated column chromatography (levigant, EtOAc / n-heptane 0/100 to 40/60 [v / v]) gives 31 as an oil (448 mg, 83% purity). PM 401.53; C24H32FN03; EMCL (6 minute method): m / z 402.2 [M + H] +, Rt 3.40 min. 1- (5-FTuoro-2- (methyloxy) phenyl] -4-methyl-2-morpholin-2-ylpentan-2-ol hydrochloride (32) OH 32 is obtained from 31 (448 mg, 1.12 mmol), a-chloroethyl chloroformate (0.48 ml, 447 mmol, 4 eq) and Hünig base supported by polymer (628 g, 2.23 mmol, 3 eq) in DCM (10 ml) following General Procedure 3. Purification by ion exchange chromatography followed by preparative EMCL and conversion to its hydrochloride salt following General Procedure 4 gives 32 as a white solid (0.11 g, 32%). PM 347.72; C? 7H26FN03.HCl; XH NMR (CD3OD) d 7. 05-7.08 (ÍH, m), 6.95-6.98 (2H, m), 4.16 (ÍH, dd, 3 Hz, 12.5 Hz), 3.75-3.86 (4H, m), 3.67 (ÍH, d, 10.5 Hz), 3.51 (ÍH, d, 12 Hz), 3.25-3.29 (HH, m), 3.07-3.20 (2H, m), 2.94 (2H, 14 Hz), 1.86-1.9 (HH, m), 1.53 (HH, dd, 5.5 Hz, 14.5 Hz) , 1.13 (ÍH, dd, 14.5 Hz, 5.5 Hz), 0.94 (3H, d, 2.5 Hz), 0.92 (3H, d, 2.5 Hz). EMCL (12 minute method): m / z 312.1 [M-HC1 + H] +, Rt 4.61 min.

Example 12: Preparation of 1- [2- (ethyloxy) phenyl] -4-methyl-2-morpholin-2-ylpentan-2-ol (34) l- [2- (Etyloxy) phenyl] -4-methyl-2 - [4- (Phenylmethyl) morph olin-2-ylpentan-2-ol (33) Compound 33 is obtained from 6 (3.0 g, 11.5 mmol) and 2-ethoxybenzylmagnesium chloride (available from Rieke Metals) (0.25 M in diethyl ether, 50.5 mL, 12.6 mmol) in anhydrous THF (55 mL) following the General Procedure 2. Two more equivalents of 2-ethoxybenzylmagnesium chloride (92 ml, 1.23 mmol) were added after 30 minutes. Purification by automated column chromatography (levigant, EtOAc / n-heptane 100 to 25/75 [v / v]) gives 33 (3.21 g) as a colorless oil in 86% purity as a mixture of diastereomers. PM 397.56; C25H35N03. EMCL (6 minute method): m / z 398.3 [M + H] +, Rt 3.42 & 3.60 min. l- [2- (Ethyloxy) phenyl] -4-methyl-2-morpholin-2-ylpentan-2-ol (34) 34 obtained from 33 (3.20 mg, 8.06 mmol) a-chloroethyl chloroformate (3.48 ml, 32.2 mmol) and Hünig base supported by polymer (4.53 g, 16.1 mmol) in DCM (100 ml) following General Procedure 3. Purification by ion exchange chromatography followed by automated column chromatography (levigant, MeOH / DCM 5/95 to 40/60 [v / v]), and preparative EMCL gives 34. Chiral preparative chromatography (gradient n-heptane: EtOH : DEA 60: 40: 0.2, quiracel-OD) produced the first enantiomer levigando 34a (13 mg) (Rt 8.25 min), and the second enantiomer levigando 34b (Rt 10.17 min) as colorless oils. PM 307.44; C18H29N03; XH NMR (CDC13) d 7.16-7.22 (2H, m), 6.84-6.93 (2H, m), 3.97-4.17 (2H, m), 3.90 (1H, dd, 3 Hz, 11 Hz), 3.53 (1H, td, 3 Hz, 11 Hz), 3.37 (ΔI, dd, 2 Hz, 10 Hz), 3.18 (ΔI, d, 12 Hz), 3.04 (1H, d, 14 Hz), 2.74-2.91 (4H, m) , 1.89 (1H, septet, 6 Hz), 1.52 (1H, dd, 5.5 Hz, 14 Hz), 1.44 (3H, t, 7 Hz), 1.11 (1H, dd, 6 Hz, 14 Hz), 0.93 (3H , d, 7 Hz), 0.90 (3H, d, 7 Hz); EMCL (12 minute method): m / z 308.2 [M-HC1 + H] +, Rt 4.92 min.

Example 13: Preparation of 4-methyl-2-morpholin-2-yl-1-hydrochloride. { 2 [trifluoromethyl) oxy] phenyl} pentan-2-ol (36) 4-Methyl-2- [4- (phenylmethyl) mo folin-2-yl] -1-2 [trifluoromethyl) oxy] phenyl} pentan-2-ol (35) Compound 35 was prepared from 6 (0.83 g, 3.19 mmol) and commercially available 2-trifluoromethoxybenzylmagnesium bromide (Fluorochem) (0.5M solution in THF, 7.02 ml, 3.51 mmol, 1.1 eq) in anhydrous THF (21 ml) following the General Procedure 2. Additional equivalents of 2-trifluoromethoxybenzylmagnesium bromide (3.19 ml, 1.60 mmol) were added after 30 minutes. Purification by ion exchange chromatography gives 35 as a yellow oil (1.39 g, 99.5%). PM 437.51; C24H30F3NO3; EMCL (6 minute method): m / z 438.1 [M + H] +, Rt 3.70 min. 4-Methyl-2-morpholin-2-yl-1-hydrochloride. { 2 [trifluoromethyl) oxy] phenyl} pentan-2-ol (36) 36 is obtained from 35 (1.39 g, 3.18 mmol), a-chloroethyl chloroformate (1.37 ml, 12.7 mmol, 4 eq) and Hünig base supported by polymer (1.79 g, 6.36 mmol, 2 eq) in DCM (25 ml ) following General Procedure 3. Purification by ion exchange chromatography followed by preparative EMCL and conversion to the hydrochloride salt following General Procedure 4 gives 36 (0.16 g, 14%) as foam. MP 383.82; C17H24F3N03.HC1; kH NMR (CD3OD) d 7.43 (H, d, 7 Hz), 7.16-7.27 (3H, m), 4.05 (1H, dd, 3 Hz, 13 Hz), 3.58- 3.74 (2H, m), 3.35-3.40 (1H, m), 3.23-3.14 (ÍH, m), 2.97-3.10 (3H, m), 2.76 (1H, d, 14 Hz), 1.75 (ÍH, septet, 6.5 Hz), 1.42 (1H, dd, 6 Hz, 14.5 Hz), 0.98-1.11 (1H, m) 0.83 (3H , d, 6 Hz), 0. 81 (3H, d, 6 Hz); EMCL (12 minute method): m / z 348.4 [M-HC1 + H] +, Rt 3.15 min.

Example 14: Preparation of 1- [1,1'-Biphenyl] -2-yl-4-methyl-2-morpholin-2-ylpentan-2-ol (38) 2- (4-Benzyl-morpholin-2-hydrochloride -il) -l-biphenyl-2-yl-4-methyl-pentan-2-ol (37) Compound 37 was prepared from 6 (2.5 g, 9.56 mmol) and 2-phenylbenzylmagnesium bromide (0.25M solution, 42.1 ml, 10.5 mmol, 1.1 eq) in anhydrous THF (21 ml) following General Procedure 2. Bromide was prepared of 2-phenylbenzylmagnesium from 2-phenylbenzyl bromide (Aldrich) commercially available following the Procedure General 5. Other equivalents of 2-phenylbenzylmagnesium bromide were added to drive the reaction to completion. Purification by automated levigating column chromatography, EtOAc / n-heptane 0/100 to 25/75 [v / v]) gives 37 (2.07 g, 50%), which is used in the next stage without further purification. PM 429.61; C29H35 02; FIA +: m / z [M + H] Y ! - [! '-Biphenyl] -2-yl-4-methyl-2-morpholin-2-yl-pentan-2-ol (38) Compound 38 is obtained from 37 (2.07 g, 4.81 mmol), a-chloroethyl chlormate (2.08 mL, 19.3 mmol) and Hünig base supported by polymer (2.7 g, 9.6 mmol) in DCM (60 ml) following General Procedure 3. Purification by ion exchange chromatography, crystallization of MEOH / diethyl ether gives 38 as a white solid (738 mg, 45%). PM 339.48; C22H29N02; XH NMR (CDC13) d 7.29-7.46 (8H, m), 7.23-7.28 (1H, m), 3.79-3.91 (2H, m), 3.66 (1H, dd, 10.9 Hz, 1.7 Hz), 3.18 (2H, dd, 12.8 Hz, 25.8 Hz), 2.84-3.04 (3H, m), 2.75 (1H, t, 11.5 Hz), 1.56-1.68 (ÍH, m), 1.22 (1H, dd, 5.65 Hz, 14.7 Hz), 0.98 (ÍH, dd, 5.65 Hz, 14.7 Hz), 0.81 (3H, d, 3.2 Hz), 0.78 (3H, d, 3.0 Hz). EMCL (12 minutes method): m / z 340.3 [M + H] +, Rt 5.62 min.

Phenylmyl -2- [1,1 '-bifinyl] -2-ylmethyl) -1-hydroxy-3-methylbutyljmorpholin-4-carboxylate (cbz-38) Benzyl chlormate (0.37 ml, 2.61 mmol) was added to a stirred mixture of 38 (738 mg, 2.17 mmol) with NaHCO3 (0.41 g) in a suspension of diethyl ether and water (24 ml) under N2 at room temperature. After 1 hour, the reaction was quenched with ice water (15 ml) and diluted with DCM. The two phases were separated, the aqueous phase was DCM extracted further, the combined organic fractions were dried over magnesium sulfate, filtered and evaporated in vacuo. The isolated oil was purified using automated column chromatography (levigant, EtOAc / n-heptane 0/100 to 30/70 [v / v]) followed by preparative chiral chromatography (gradient Heptane: EtOAc: DEA 35: 65: 0.2, quiracel AD-H) to give the first enantiomer levigando, cbz-38a (Rt 2.61 min), and the second enantiomer levigando, cbz-38b (Rt 2.99 min), both as a colorless oil. PM 473.62; C30H35NO4: EMCL (6 minute method): m / z 456.3 [M-H20 + H] + and 496. 2 [M + Na] +; Rt 5 .34 min. 1- [1,1 '-Biphenyl] -2-yl-4-methyl-2-morpholin-2-ylpentan-2-ol hydrochloride (38a) Palladium carbon (10% by weight) was added to a stirred solution of cbz-38a (0.39 g, 0.84 mmol) with ammonium formate (0.35 g, 8.4 mmol) in ethanol (10 mL) at room temperature under nitrogen. The hydrogenated mixture was heated to reflux for 30 minutes, allowed to cool to room temperature and then filtered through a pad of Celite. The filtrate was concentrated in vacuo, purified by ion exchange chromatography and then converted to the hydrochloride salt following General Procedure 4 to give 38a (0.25 g, 79%) as a yellow solid. P.M 375. 94; C22H29N02.HC1: XH NMR (CD3OD) d 7.48 (1H, bs), 7.11-7.33 (8H, m), 3.87 (1H, bs), 3.37-3.57 (2H, m), 3.25 (1H, s), 2. 77-3.10 (5H, m), 1.54 (HH, s, br), 1.07-1.19 (1H, m), 0.93- 1.00 (HH, m), 0.72 (3H, d, 6 Hz), 0.69 (3H, d, 6 Hz): EMCL (12 minutes method): m / z 340.2 [M-HC1 + H] +, Rt 5.30 min.

Example 15: Preparation of 1- (4-fluoro [1,1'-biphenyl] -2-yl) -4-methyl-2-morpholin-2-ylpentan-2-ol (40) 1- (4- Fluoro [1, 1 '-biphenyl] -2-yl-4-methyl-2- [4- (phenylmethyl) mor folin-2-yl] pentan-2-ol (39) Compound 39 was prepared from 6 (0.95 g, 3.65 mmol) and 2-phenyl-5-fluorobenzylmagnesium bromide (0.5 M solution in diethyl ether, 1.2 eq) following in General Procedure 2. 2-Phenyl-5-fluorobenzylmagnesium bromide is obtained from 2-phenyl-5-fluorobenzyl bromide following the procedure General 5. Subsequently, 2-phenyl-5-fluorobenzylmagnesium bromide was added in excess at room temperature and the reaction was allowed to stir for 1 hour. Purification by column chromatography (levigant, EtOAc / cyclohexane 50/50 [v / v]) gives 39 as a viscous oil (1.31 g, 80%). PM 447.60; C29H34FN02; EMCL: (6 minute method) m / z 448 [M + H] +, Rt 3.88 min. 1- (4-Fluoro [l, l 'biphenyl] -2-yl) -4-methyl-2-morpholin-2-ylpentan-2-ol hydrochloride (40) 40 is prepared from 39 (1.31 g, 2.92 mmol), a-chloroethyl chloroformate (0.9 ml) and Hünig base supported by a solid (1.64 g) in anhydrous DCM (30 ml) following General Procedure 3. The purification by ion exchange chromatography provides the free base of 40 as a viscous oil (0.71 g, 62%). After further purification using preparative UV-guided EMCL, the hydrochloride salt 40 (0.451 g, 39%) is obtained following General Procedure 4. MW 393.95; C22H28FN02.HC1; X H NMR (DMSO-de): d 9.16 (HH, s), 8.98 (HH, s), 7.44-7.32 (4H, m), 7.23-7.06 (4H, m), 3.83 (1H, dd, 12 Hz, 3 Hz), 3.59-3.50 (3H, m), 3.18 (H, d, 12.5 Hz), 3.08 (H, d, 12.5 Hz), 2.92-2.67 (4H, m), 1.54-1.40 (ÍH, m), 1.03 (1H, dd, 14.5 Hz, 5 Hz), 0.88 (ÍH, dd, 14.5 Hz, 6.5 Hz), 0.74 (3H, d, 6.5 Hz), 0.67 (3H, d, 6. 5 Hz); EMCL: (12 minute method) m / z 358 [M-HC1 + H] + Rt 5.47 min.

Example 6: Preparation hydrochloride of l-cyclopentyl-2- [5-fluoro-2- (methyloxy) phenyl] -l-morpholin-2-ylethanol (42) l-Cyclopentyl-2- [5-fluoro-2- (methyloxy ) phenyl] -l- [4- (phenylmethyl) mor folin-2-yl] ethanol (41) Compound 41 is obtained from 7 (0.7 g, 2.56 mmol) and 2-methoxy-5-fluorobenzylmagnesium bromide (5.63 ml, 2.82 mmol, 1.1 eq) in anhydrous THF (15 ml) following General Procedure 2. Equivalents were added of 2-methoxy-5-fluorobenzylmagnesium bromide (8.49 ml, 4.25 mmol). Purification by ion exchange chromatography gives 41 as a yellow oil (843 mg, 62% purity). PM 413.54; C25H32FN03; EMCL (6 minutes method): m / z 414.2 [M + H] + Rt 4.11 min.

L-Cyclopentyl-2- [5- fluoro-2- (methyloxy) phenyl] -1-morpholin-2-ylethanol hydrochloride (42) The free base of 42 is obtained from 41 (0.84 g, 2.04 mmol), a-chloroethyl chloroformate (0.88 ml, 8.16 mmol, 4 eq) and Hünig base supported by polymer (1.15 g, 4.08 mmol, 2 eq) in DCM (15 ml) following General Procedure 3. Purification by ion exchange chromatography, followed by automated chromatography (DCM / MeOH 95/5 to 80/20 [v / v]) and preparative EMCL and conversions in the hydrochloride salt following General Procedure 4 gives 42 as a colorless gum (0.18 g, 14.1%). PM 359.82; C? 8H26FN03.HCl; XE NMR (CD3OD) d 7.11-7.14 (HH, m), 6.95-6.97 (2H,), 4.07-4.15 (HH, m), 3.67-3.75 (2H, m), 3.43 (HH, d, 12 Hz) , 3.23 (3H, s), 3.22 (1H, d, 12 Hz), 2.92-3.10 (4H, m), 2.13-2.19 (ÍH,), 1.42-1.73 (8H, m); EMCL (12 minutes method): m / z 324.1 [M-HC1 + H] +, Rt 4.83 min.

Example 17: Preparation of l-cyclopentyl-2- [2- (ethyloxy) phenyl] -1-morpholin-2-ylethanol hydrochloride (44) l-Cyclopentyl-2- [2- (ethyloxy) phenyl] -1- [ 4- (phenylmethyl) mo folin-2-yl] ethanol (43) Compound 43 is obtained from 7 (2.09 g, 7.68 mmol) and 2-ethyloxybenzylmagnesium bromide (available from Reike Metals) (0.25 M solution in diethyl ester, 1.1 eq) following General Procedure 2. Purification by preparative EMCL gives 43 as a viscous oil (0.691 g, 22%). PM 409.57; C26H35N03; EMCL: (6 minute method) m / z 410 [M + H] +, Rt 3.8 min.

L-Cyclopentyl-2- [2- (ethyloxy) phenyl] -1-morpholin-2-ylethanol hydrochloride (44) The free base of 44 is obtained from 43 (0.691 g, 1.69 mmol), a-chloroethyl chloroformate (0.80 ml) and Hünig base supported by a solid (0.95 g) in anhydrous DCM following General Procedure 3. The purification by ion exchange and conversion to its hydrochloride salt following General Procedure 4 gives 44 (0.39 g, 65%). PM 355.91; C? 9H29N03.HCl; 2 H NMR (CD30D): d 7.12-7.22 (2H, m), 6.82-6.88 (2H, m), 4.09-4.16 (3H, m), 3.69-3.80 (2H,), 2.80-3.29 (6H, m) , 2.04-2.10 (1H,), 1.53-1.73 (11H, m); EMCL: (12 minute method) m / z 320 [M-HC1 + H] +, Rt 5.03 min.

Example 18: Preparation of 1-cyclopentyl-l-morpholin-2-yl-2- hydrochloride. { 2- (trifluoromethyl) oxy] phenyl} ethanol (46) l-Cyclopentyl-2- [5-fluoro-2- (methyloxy) phenyl] -1- [4- (phenylmethyl) morpholin-2-yl] ethanol (45) Compound 45 is obtained from 7 (0.6 g, 219 mmol) and 2-trifluoromethoxy-benzylmagnesium bromide (Fluorochem) available commercially (0.5 M solution in diethyl ether, 4.8 ml, 2.41 mmol, 1.1 eg) in anhydrous THF (15 ml. ) following General Procedure 2. After the addition of another 2 equivalents of 2-trifluoromethoxy-benzylmagnesium bromide and stirring for 2 hours at 0 ° C, purification by ion exchange chromatography gives 45 (0.89 g, 90%). PM 449.52, C25H3oF3N? 3. EMCL (6 minute method): m / z 450.2 [M + H] +, Rt 4.084 min.

L-Cyclopentyl-l-morpholin-2-yl-2- hydrochloride. { 2- [(trifluoromethyl) oxy] phenyl} Ethanol (46) The free base of 46 is obtained from 45 (886 mg, 1.97 mmol), a-chloroethyl chloroformate (0.85 ml, 7.9 mmol, 4 eq) and Hünig base supported by polymer (1.11 g, 3.94 mmol, 2 eg) in DCM (15 ml) following General Procedure 3. Purification by ion exchange chromatography followed by preparative EMCL and conversions to its hydrochloride salt following General Procedure 4 gives 46 as a gum (140 mg, 20%). PM 395.85; C? 8H24F3N03.HCl; H NMR (CD3OD) d 7.48-7.50 (HH, m), 7.14-7.25 (3H, m), 3.97 (HH, dd, 2.3 Hz, 12.5 Hz), 3.60-3.68 (2H, m), 3.27-3.31 (HH, m), 3.03 (2H, 12.5 Hz), 2.73-2.97 (3H,), 2.00-2.11 (ÍH, m), 1.30-1.63 (8H, m); EMCL (12 minutes method): m / z 360.14 [M-HC1 + H] +, Rt 5.14 min.

Example 19: Preparation of 2- [1,1'-biphenyl] -2-yl-l-cyclopentyl-l-morpholin-2-yl-ethanol (48) 2- [1,1 '-Biphenyl] -2-yl hydrochloride -l-cyclopentyl-1- [4- (phenylmethyl) mor folin-2-yl] ethanol (47) Compound 47 was prepared from 7 (1.27 g, 4.65 mmol) and 2-phenylbenzylmagnesium bromide (0.25 M solution in diethyl ether, 1.1 eq) following general procedure 2. 2-Phenylbenzylmagnesium bromide was prepared from bromide 2 phenylbenzyl (Aldrich) commercially available following General Procedure 5. Purification by flash column chromatography (levigant, cyclohexane / EtOAc 90/10 [v / v]) gives 47 as a viscous oil (1.75 g). 47 is taken in the next step without further purification. PM 441.62; C30H35NO2; EMCL: (6 minute method) m / z 442 [M + H] +, Rt 3.51 min. 2- [1,1 '-Biphenyl] -2-yl-l-cyclopentyl-l-morpholin-2-yl-ethanol hydrochloride (48) The free base of 48 is prepared from 47 (1.75 g, 3.95 mmol), Hünig base supported by a solid (2.22 g) and a-chloroethyl chloroformate (1.62 ml) in anhydrous DCM (30 ml) following General Procedure 3 Purification by ion exchange chromatography followed by flash column chromatography (levigant, MeOH / DCM 1/99 to 20/80 [v / v]) gives the free base as a viscous oil (805 mg, 58%) which is converted to 48 following General Procedure 4. PM 387.95; C23H29N02.HC1; aH NMR (CD3OD): d 7.66-7.40 (ΔH, m) 7.19-7.47 (8H, m), 3.92 (ΔH, dd, 13 Hz, 3.5 Hz), 3.59-3.67 (2H, m), 3.05-3.16 ( 4H, m), 2.93 (HH, td, 13 Hz, 3.5 Hz), 2.59 (1H, t, 12 Hz), 1.98-1.88 (HH, m), 1.55-1.19 (8H,); EMCL: (12 minute method) m / z 351 [M-HC1 + H] +, Rt 5.68 min.

Example 20: Preparation of l-cyclopentyl-2- (4-fluoro [1,1'-biphenyl] -2-yl) -l-morpholin-2-ylethanol hydrochloride (50) l-Cyclopentyl-2-hydrochloride 4-fluoro [1,1'-biphenyl] -2-yl) -1- [4- (phenylmethyl) orpholin-2-ylethanol (49) Compound 49 was obtained from 7 (0.9 g, 3.29 mmol) and 2-phenyl-5-fluorobenzylmagnesium bromide (0.5 M solution in THF, 7.24 mL, 3.62 mmol) in anhydrous THF (20 mL) following the General Procedure 2. 2-Phenyl-5-fluorobenzylmagnesium bromide was prepared from 2-phenyl-5-fluorobenzyl bromide following General Procedure 5. 2-Phenyl-5-fluorobenzylmagnesium bromide was added after 30 minutes (0.3 eq. , 2 ml, 0.99 mmol). Purification by ion exchange chromatography followed by automated column chromatography, levigating EtOAc / n-heptane 0/100 up /80 [v / v]) gives 49 (1.26 g, 83%) as-a colorless liquid. PM 459.61; C30H34FNO2; EMCL (6 minute method): m / z 460.5 [M + H] +, Rt 3. 98 min.

L-Cyclopentyl-2- (4-fluoro [1, 1 '-biphenyl] -2-yl) -1-morpholin-2-ylethanol hydrochloride (50) The free base 50 is obtained from 49 (1.26 mg, 2.73 mmol), a-chloroethyl chloroformate (1.18 ml, 10.9 mmol) and Hünig base supported by polymer (1.54 g, 5.47 mmol) in DCM (25 ml) following the General Procedure 3. Purification by ion exchange chromatography followed by automated column chromatography, levigating MeOH / DCM 100 to 20/80 [v / v]) and conversions to its hydrochloride salt gives 50 as a yellow solid (0.23 g, 2. 3%). PM 405.94; C23H28FN02.HC1; 2 H NMR (CD3OD) d 7.20-7.37 (6H, m), 7.08-7.13 (HH, m), 6.91 (1H, td, 3.5 Hz, 8.5 Hz), 3.80 (HH, dd, 3.5 Hz, 13.0 Hz), 3.42-3.54 (2H, m), 2.99-3.06 (2H, m), 2.93 (2H, s), 2.83 (ÍH, td, 4.0 Hz, 12.5 Hz), 2.53 (ÍH, t, 12.0 Hz), 1.73- 1.85 (1H, m), 1.12-1.44 (8H, m). EMCL (12 minutes method): m / z 370.2 [M-HC1 + H] +, Rt 5.46 min.

Example 21: Preparation of 2- [5-fluoro-2- (methyloxy) phenyl-1-morpholin-2-yl-1-tetrahydro-2H-pyran-4-ylethanol hydrochloride (52) 2- [5-Fluoro- 2- (methyloxy) phenyl] -1- [4- (phenylmethyl) mor folin-2-yl] -l-tetrahydro-2H-pyran-4-ylethanol (51) Compound 51 is obtained from 8 (0.6 g, 2.07 mmol) and 2-methoxy-5-fluorobenzylmagnesium bromide (4.6 mL, 2.28 mmol, 1.1 eq) in anhydrous THF (15 mL) following General Procedure 2. Equivalents were added Additional 2-methoxy-5-fluorobenzylmagnesium bromide (8.28 ml, 4.14 mmol) was added and the mixture was warmed to room temperature and allowed to stir overnight. Purification by ion exchange chromatography followed by automated chromatography (levigant, n-heptane / EtOAc 90/10 to 30/70 [v / v]) gives 51 as a colorless oil (375 mg, 42%). PM 429.54; C25H32FN0; EMCL (6 minutes method): m / z 430.2 [M + H] +, Rt 3.12 min. 2- [5-Fluoro-2-methyloxy) phenyl] -l-morpholin-2-yl-l-tetrahydro-2H-pyran-4-ylethanol hydrochloride (52) The free base of 52 is obtained from 51 (0.31 g, 0.73 mmol), a-chloroethyl chloroformate (0.31 ml, 2.9 mmol) and Hünig base supported by polymer (0.41 g, 1.45 mmol) in DCM (7 ml) following General Procedure 3. Purification by ion exchange chromatography and conversion to the hydrochloride salt following the procedure General 4 gives 52 as a white solid (0.19 g, 77%). P.M 375. 82; C? 8H26FN0, HCl; H NMR (CD30D): d 6.98-7.01 (1H, m), 6. 83-6.86 (2H, m), 3.99 (1H, dd, 3.5 Hz, 13 Hz), 3.82-3.87 (2H, m), 3.63-3.73 (5H, m), 3.12-3.33 (4H, m), 2.91-3.02 (2H, m), 2.81 (2H, 14 Hz), 1.31-1.73 (5H, m); EMCL (12 minute method): m / z 340.2 [M-HC1 + H] +, Rt 3.78 min.

Example 21a: Preparation of 2- [5-fluoro-2- (methyloxy) phenyl] -1-morpholin-2-yl-1-tetrahydro-2H-pyran-4-ylethanol hydrochloride (52b) 2- [5-Hydrochloride] -Fluoro-2- (methyloxy) phenyl] -1- [4- (phenylmethyl) morpholin-2-yl] -l-tetrahydro-2H-pyran-4-ylethanol (51b) 2-Methoxy-5-fluorobenzyl bromide was dissolved (455.6 g, 2.079 mol) in toluene (1592 ml). Dissolve 8b (400.8 g, 1386 mmol) in toluene (400 mL). An inert 20 1 vessel was charged with 2-MeTHF (1202 ml), magnesium (50.59 g, 2079 mol) and 1.5 M DIBALH (16 ml). The benzyl bromide solution was loaded into a funnel flask after the loading of 5% of the total amount of benzyl bromide was added to the magnesium mixture at 22 ° C. After 15 minutes, the rest of the benzyl bromide solution was added for 160 minutes at room temperature. After 1 hour of further stirring, solution 8b was slowly added to the mixture for 140 minutes at -15 ° C. After an additional 30 minutes, the quenching was carried out by addition of acetic acid (124 ml) maintaining the temperature below -5 ° C, then a mixture of water / acetic acid 10/1 v / v (2200 ml) was added maintaining the temperature below 10 ° C. The organic layer was extracted at room temperature, filtered to remove Mg conversions and left overnight. The organic layer was washed with water (500 ml), then basification was performed by the addition of water (1600 ml) and Nh3ac (311.8 ml). The organic layer was concentrated and i-propanol (2000 ml) was added. The azeotrope of toluene / i-propanol was removed under reduced pressure, then i-propanol was removed. The brown-orange oil was dissolved in i-propanol (2380 ml) then 12 N HClac (138.6 ml) and water (2380 ml) were added. The polar impurities were removed with a cyclohexane wash (4760 ml). Then the aqueous layer was basified with NH3ac and extracted with toluene (4 1). The organic layer was washed with water (500 ml), then the combined aqueous organic layers were extracted with toluene (4 1) and then this new toluene solution was washed with water (500 ml). The combined organic layers were concentrated under reduced pressure, then i-propanol (2 1) was added and the solution was again concentrated to give a crude oil of 51b (550 g, 91% yield).; 94% ee) and 100 g of i-propanol. This crude oil was diluted with THF (2000 ml) and 8.76 M HBrac (153.9 ml) was added. This mixture was allowed to stir overnight and a thin suspension was observed. The precipitate was washed with THF (150 ml) to give 34 g of the racemic 51 as the HBr salt. The mother liquors were concentrated then toluene (1500 ml), water (500 ml) and NH3ac (103.58 ml, 1386 mol) were added. The organic layer was extracted and washed with water (250 ml). The combined aqueous layers were extracted with toluene (500 ml). The combined organic layers were dried over MgSO 4 and concentrated under reduced pressure, then i-propanol (2 1) was added and again removed. Then, the oil was dissolved in i-propanol (11), 12 N HCl (121.3 ml) was added and the mixture allowed to stir for 15 minutes, then the solvents were partially removed to provide 51b as the desired diastereomer (1021). g; 98.4% ee). 2- [5-Fluoro-2-methyloxy) phenyl] -l-morpholin-2-yl-l-tetrahydro-2H-pyran-4-ylethanol hydrochloride (52b) A Parr bottle of 6 1 was charged with 51b (1021 g), i-propanol (3630 ml) and water (639 ml). After it was purged with N2, 5% PD-C with 52% humidity (105.6 g) was added and the mixture was then pressurized with hydrogen (50 psi (3.515 kg / cm2)). The reaction mixture was stirred for 9 hours 30 minutes, then the mixture was filtered on a Hyflo Super Cel® pad (100 g) pre-soaked with 80/20 i-propanol / water (500 ml). The catalyst was rinsed with an i-propanol: water mixture 80:20 (500 ml). The solvents were removed, then i-propanol (2000 ml) was added to be partially removed again. Then i-propanol (1400 ml) was added again and the heterogeneous mixture was concentrated to give an off white solid. To this crude alcohol 52b was added i-propanol (4474 ml) and the mixture was heated to reflux until a homogeneous solution formed. Afterwards, the mixture was cooled slowly and crystallization starting at 60 ° C. The powder was filtered at temperature, rinsed with i-propanol (2 x 350 ml) and dried under reduced pressure at 40 ° C to give the highly pure compound 52b with 80% recovery yield (98.4% of, 99.2% ee).

Example 22: Preparation of 1-morpholin-2-yl-1-tetrahydro-2H-pyran-4-yl-2-hydrochloride. { 2- [(trifluoromethyl) oxy] phenyl} ethanol (54) 1- [4- (Phenylmethyl) morpholin-2'yl] -l-1-tetrahydro-2H-pyran-4-yl-2-. { 2- [(trifluoromethyl) oxy] phenyl} Ethanol (53) Compound 53 is obtained from 8 (0.61 g, 2.11 mmol) and commercially available 2-trifluoromethoxybenzylmagnesium bromide (Fluorochem) (4.6 ml, 2.32 mmol, 1.1 eq) in anhydrous THF (15 ml) following General Procedure 2. Added additional 2-trifluoromethoxybenzylmagnesium bromide (4.22 ml, 2.11 mmol). Purification by ion exchange chromatography gives 53 as an oil of 88% purity (1.39 g of isolated material, 88% ca. purity) which is directly used in the next step. PM 465.52; C25H3oF3N0; EMCL (6 minute method): m / z 466.2 [M + H] +, RT 3.67 min.

L-Morpholin-2-yl-l-tetrahydro-2H-pyran-4-yl-2- hydrochloride. { 2- [(trifluoromethyl) oxy] phenyl} e tanol (54) The free base of 54 was obtained from 53 (0.27 g, 0.57 mmol), a-chloroethyl chloroformate (0.25 ml, 2.30 mmol, 4 eq) and Hünig base supported by polymer (0.32 g, 1.15 mmol), 2 eq) in DCM (5 ml) following General Procedure 3. The purification by ion exchange chromatography followed by EMCL (gradient) and conversion to the hydrochloride salt following General Procedure 4 gives 54 as a white solid (82 mg, 17%) . PM 411.85; C? 8H2F3N04.HCl. kH NMR (CD3OD) d 7.45-7.48 (1H, m), 7.16-7.27 (3H, m), 3.98 (1H, dd, 4. 0 Hz, 13 Hz), 3.65-3.88 (4H, m), 3.12-3.31 (4H, m), 2. 87- 3.01 (4H, m), 1.30-1.68 (5H, m); EMCL (12 minute method): m / z 376.1 [M-HC1 + H] +, Rt 4.28 min.

Example 23: Preparation of 2- [1,1'-biphenyl] -2-yl-l-morpholin-2-yl-l-tetrahydro-2H-pyran-4-ylethanol hydrochloride (56) 2- [1,1 '-Biphenyl] -2-yl-l- [4- (phenylmethyl) morpholin-2-yl] -1-tetrahydro-2H-pyran-4-ylethanol (55) Compound 55 was prepared from 8 (0.56 g, 1.94 mmol) and a solution of 2-phenylbenzylmagnesium bromide (0.25 M solution in diethyl ether, 9.31 ml, 2.33 mmol, 1.2 eq) following General Procedure 2. 2-Phenylbenzylmagnesium bromide was prepared from 2-phenylbenzyl bromide. (Aldrich) was commercially available following General Procedure 5. Additional 2-phenylbenzylmagnesium bromide (1 ml) was added and the reaction allowed to stir overnight. Purification by ion exchange chromatography gives 55 as a whitish foam-like solid (0.37 g, 68%). PM 457.62; C30H35NO3; EMCL (6 minutes method): m / z 458 [M + H] +, Rt 3.58 min. 2- [1,1 '-Biphenyl] -2-yl-l-morpholin-2-yl-l-tetrahydro-2H-pyran-4-ethanol hydrochloride (56) The free base of 56 is obtained from 55 (0.588 g, 1.28 mmol), Hünig base supported by a solid (0.72 g) and a-chloroethyl chloroformate (0.53 ml) in anhydrous DCM (20 ml) following General Procedure 3 Purification by ion exchange chromatography gives the free base of 56 as a viscous oil (0.483 g), contaminated with a small amount of the N-protected compound. The residue was treated with an excess of reagents (1 eq), Hünig base supported by a solid (0.36 g) and a-chloroethyl chloroformate (0.26 ml) in anhydrous DCM (20 ml) and methanol (20 ml) and purified by ion exchange chromatography to give the free base of 56 (0.432 g). Purification by preparative EMCL followed by conversion to its hydrochloride salt following General Procedure 4 gives 56 (0.280 g, 54%). PM 403.95; C23H29N03.HC1; ? E NMR (CD3OD): d 7.45-7.59 (HH,), 7.10-7.35 (8H, m), 3.85 (HH, dd, 13 Hz, 3.5 Hz), 3.75 (1H, dd, 11.5 Hz, 3.5 Hz) , 3.51-3.59 (3H, m), 2.83-3.12 (7H, m), 2.64 (1H, t, 12 Hz), 1.36-1.52 (2H, m), 1.02-1.21 (2H, m), 0.90-0.94 (ÍH, m); EMCL: (12 min method) m / z 368 [M-HC1 + H] 4", Rt 4.6 min.

Example 24 Preparation of 2- (3'-fluoro-biphenyl-2-yl) -1-morpholin-2-yl-1- (tetrahydro-pyran-4-yl) -ethanol (58) 2-Bromo-1- [ 4- (phenylmethyl) mo olin-2-yl] -l- (tetrahydro-pyran-4-yl) -ethanol Commercially available 2-brombenzylmagnesium bromide (Aldrich) (0.25 M solution in diethyl ether, 48.9 ml, 12.18 mmol, 2-6 eg) was added in three portions over 90 minutes to a solution of 8 (1.35 g, 4.7 mmol) in Dry THF (30 ml) at 0 ° C. After cooling with ice water, a solution of saturated ammonium chloride was added and the aqueous phase was washed with EtOAc. The combined organic phases were washed with brine and water, dried over magnesium sulfate and the solvents were removed in vacuo. Purification by ion exchange chromatography followed by purification using automated column chromatography (levigant, EtOAc / c-heptane 10/90 to 50/50 [v / v]) gives 57 (0.56 g, 26%). PM 460.42; C24H30BrNO3; EMCL (6 minutes method): m / z 462.4 [M + H] +, RT 3.11 min. 2- (3 '-Fluoro-biphenyl-2-yl) -1- [4- (phenylmethyl) mor folin-2-yl] -1- (tetrahydro-pyran-4-yl) -ethanol (57) To a suspension of Pd (0Ac) 2 (2.44 mg, 0.011 mmol, 0.02 eq) in acetonitrile (1.5 ml) was added triphenyl phosphine (11.4 mg, 0.043 mmol, 0.08 eq) under nitrogen at room temperature leading to the formation of a white precipitate. The addition of water (0.5 ml), 3-fluoro-phenylboronic acid (91.2 mg, 0.65 mmol, 1.2 eq) and 57 (0.25 mg, 0.54 mmol) gives a dark gray solution after 10-20 minutes which is heated to reflux and allowed to stir at reflux overnight. Additional 3-fluoro-phenylboronic acid (70 mg, 0.55 mmol, 1 eq) and Pd (0Ac) 2 (2-3 mg) were added and the mixture was allowed to stir at reflux for another 24 hours. Purification by ion exchange chromatography gives 57 (0.21 g, 83%). PM 475.61; C30H34FNO3; EMCL (6 minutes method): m / z 476.4 [M + H] +, Rt 3.41 min. 2- (3'-Fluoro-biphenyl-2-yl) -l-morpholin-2-yl-1- (tetrahydro-pyran-4-yl) -ethanol (58) Compound 58 is obtained from 57 (0.213 g, 0.45 mmol), Hünig base supported by a solid (0.25 g, 7.12 mmol, 4 eq) and a-chloroethyl chloroformate (0.19 ml, 1.79 mmol, 4 eq) in DCM anhydrous (7 ml) following General Procedure 3. The purification by ion exchange chromatography gives the free base of 58 as a white foam (125 mg) which is further purified by preparative EMCL. The conversion to its hydrochloride salt following General Procedure 4 gives 58 as a yellow gum (96.5 g, 56%). PM 421.94; C23H28H03.HC1; aH NMR (CD3OD): d 7.60-7.45 (HH, m), 6.90-7.45 (6H, m), 3.55-3.95 (5H, m), 2.85-3.30 (10H, m), 2.64 (1H, t, 12.0 Hz), 0.95-1.45 (5H, m); EMCL. (12 minutes method): m / z 386 [M-HC1 + H] +, Rt 4.64 min.

Example 25: Preparation of 5,5,5-trifluoro-1- (5-fluoro-2-methoxy-phenyl) -2-morpholin-2-yl-pentan-2-ol (60) 5, 5, 5-Tri f luoro- 1- [5-fluoro-2- (methyloxy) phenyl] -2- [4- (phenylmethyl) morpholin-2-yl] pentan-2-ol (59) Compound 59 is obtained from 9 (0.7 g, 2.32 mmol) and 2-methoxy-5-fluorobenzylmagnesium bromide (5.11 ml, 2.55 mmol, 1.1 eq) in dry THF (15 ml) following General Procedure 2. Purification by ion exchange chromatography gives 59 as an oil of 80% purity which is directly used in the next step (0.9 g of recovered material). PM 441.47; C23H27F4N04; EMCL (6 minutes method): m / z 442.4 [M + H] +, Rt 3.36 min. ,5,5-Trifluoro-l- [5-fluoro-2- (methyloxy) phenyl] • 2-morpholin-2-yl] pentan-2-ol hydrochloride (60) The free base of 60 is obtained from 59 (0.9 g, 2.04 mmol), a-chloroethyl chloroformate (0.88 ml, 8.15 mmol, 4 eq) and Hünig base supported by polymer (1.15 g, 4.08 mmol, 2 eq) in DCM (25 ml) following General Procedure 3. The purification by ion exchange chromatography followed by preparative EMCL and conversion to the hydrochloride salt following General Procedure 4 gives 60 as a yellow solid (0.133 g, 17% ). MP 387.80; C? 6H2? F4N03.HCl. XH NMR (CD3OD): d 6.93-6.96 (ÍH, m), 6.86-6.87 (2H, m), 4.09-4.13 (1H, m), 3.68-3.75 (4H, m), 3.42-3.47 (1H, m), 3.34-3.40 (ÍH, m), 3. 16-3.25 (ÍH, m), 3.03-3.11 (2H, m), 2.83 (2H, 14 Hz), 2.12-2.29 (2H, m), 1.58-1.68 (1H, m), 1.29-1.39 (ÍH, m). EMCL (12 minutes method): m / z 352.1 [M-HC1 + H] +, Rt 4.54 and 4. 66 min.

Example 26: Preparation of 5, 5, 5-trifluoro-2-morpholin-2-yl-l- (2-trifluoromethoxy-phenyl) -pentan-2-ol (62) 5.5, 5-trifluoro-2- [ 4- (phenylmethyl) mor folin-2-il] -1. { 2- trifluoromethyl) oxy] phenyl} pentan-2-ol (61) Compound 61 is obtained from 9 (0.7 g, 2.32 mmol) and commercially available 2-trifluoromethoxybenzylmagnesium bromide (Fluorochem) (5.12 ml, 2.56 mmol, 1.1 eq) in dry THF (15 ml) following General Procedure 2. Purification by ion exchange chromatography followed by automated column chromatography, levigating, n-heptane / EtOAc 100/0 to 50/50 [v / v]) gives 61 as an oil (0.27 g, 25%). PM 477.45; C23H25F6N03; EMCL (6 minutes method): m / z 478.4 [M + H] +, Rt 3.63 min. ,5,5-Trifluoro-2-morpholin-2-yl-1-hydrochloride. { 2-trifluoromethyl) oxy] phenyl} pentan-2-ol (62) The free base of 62 is obtained from 61 (0.25 g, 0.53 mmol), a-chloroethyl chloroformate (0.23 ml, 2.12 mmol, 4 eq) and Hünig base supported by polymer (0.30 g, 1.06 mmol, 2 eq) in DCM (5 ml) following General Procedure 3. Purification by ion exchange chromatography followed by preparative EMCL and conversion to its hydrochloride salt gives 62 as a yellow solid (0.051 g, 23%). PM 423.78; C? 6H? 9F6N03.HCl; XH NMR (CD30D): d 7.40-7.42 (ÍH, m), 7.19-7.30 (3H, m), 4.09-4.13 (1H,), 3.71-3.78 (HH, m), 3.50-3.53 (HH, m), 3.36-3.40 (1H, m), 3.08-3.22 (3H, m), 2.89 (2H, 14 Hz), 2.09-2.17 (2H, m), 1.65-1.75 (ÍH, m), 1.30-1.40 (1H, m); EMCL (12 minutes method): m / z 388.1 [M-HC1 + H] +, Rt 4.99 min.

Example 27: Preparation of 1- [1,1'-biphenyl] -2-yl-5,5,5-trifluoro-2-morpholin-2-ylpentan-2-ol hydrochloride (64) l- [1, 1] '-Biphenyl] -2-yl-5, 5,5-trifluoro-2- [4- (phenylmethyl) morph olin-2-ylpentan-2-ol (63) Compound 63 is obtained from 9 (0.7 g, 2.32 mmol) and 2-phenylbenzylmagnesium bromide (10.2 ml, 2.55 mmol, 1.1 eq) in dry THF (15 ml) following General Procedure 2. 2-Phenylbenzylmagnesium was prepared from of 2-phenylbenzyl bromide (Aldrich) commercially available following General Procedure 5. Purification by ion exchange chromatography followed by automated column chromatography (levigant, hexane / EtOAc 100/9 to 70/30 [v / v]) 63 as an oil (604 mg, 60% purity). PM 469.55; C28H3oF3N02; EMCL (6 minute method): m / z 470.4 [M + H] +, Rt 3.77 min. 1- [1,1 '-Biphenyl] -2-H-5,5,5-trifluoro-2-morpholin-2-ylpentan-2-ol hydrochloride (64) The free base of 64 is obtained from 63 (0.6 g, 1.29 mmol), a-chloroethyl chloroformate (0.56 ml, 5.15 mmol, 4 eq) and Hünig base supported by polymer (0.72 g, 2.58 mmol, 2 eq) in DCM (12 ml) following General Procedure 3. Purification by ion exchange followed by preparative EMCL and conversion to the hydrochloride salt following General Procedure 4 gives 64 as a yellow solid (0.16 g, 30%). PM 415.89; C21H24F3N02.HC1; XH NMR (CD3OD) d 7.43-7.46 (HH, m), 7.18-7.35 (7H, m), 7.10-7.13 (HH, m), 3.90-3.95 (1H, m), 3. 57-3.65 (ÍH, m), 3.34-3.38 (ÍH, m), 2.92 (2H, 14.5 Hz), 2. 88-3.13 (4H, m), 1.59-1.85 (2H, m), 1.15-1.39 (2H, m); EMCL (12 minutes method): m / z 380. 1 [M-HC1 + H] "1", Rt 5 .22 min.

Example 28: Preparation of 6,6,6-trifluoro-1- [5-fluoro-2- (methyloxy) phenyl] -2-morphol-2-ylhexan-2-ol (66) 6,6-6 hydrochloride Tri f luoro- 1- [5-fluoro-2- (methyloxy) phenyl] -2- [4-phenylmethyl) morpholin-2-yl] hexan-2-ol (65) Compound 65 is obtained from 10 (0.6 g, 1.90 mmol) and 2-methoxy-5-fluorobenzylmagnesium bromide (4.2 ml, 2.09 mmol, 1.1 eq) in anhydrous THF (15 ml) following General Procedure 2 (bromide was added of additional 2-methoxy-5-fluorobenzylmagnesium (3.8 ml, 1.90 mmol)). The purification by ion exchange chromatography gives 65 in 87% purity as an oil which is directly used in the next step (0.7 g of recovered material). PM 455.50; C24H32FN03; EMCL (6 minute method) m / z 456.2 [M + H] +, Rt 3.56 min. 6,6,6-Tri f luoro-1- [5-fluoro-2- (methyloxy) phenyl] -2-morphol-2-ylhexan-2-ol hydrochloride (66) The free base of 66 is obtained from 65 (0.7 g, 1.53 mmol), a-chloroethyl chloroformate (0.66 ml, 6.1 mmol, 4 eq) and Hünig base supported by polymer (0.86 g, 3.05 mmol, 2 eq) in DCM (13 ml) following General Procedure 3. Purification by ion exchange chromatography followed by automated column chromatography (eMeOH / DCM 0/100 to 20/80 [v / v]) and conversion to the hydrochloride salt gives 66 (0.19 g, 40%) as a white solid. PM 401.83; C? 7H23F4N03.HCl; XH NMR (CD3OD) d 7.04-7.08 (1H, m), 6.95-6.97 (2H, m), 4.21 (1H, dd, 3.0 Hz, 13.0 Hz), 3.78-3.87 (4H, m), 3.63 (H, d, 2.0 Hz, 11.0 Hz), 3.45-3.49 (H, m), 3.27-3.33 (H, m ), 3.12- 3.21 (2H, m), 2.97 (2H, 14.0 Hz), 1.97-2.13 (2H, m), 1.61-1.76 (2H, m), 1.48-1.58 (ÍH, m), 1.17-1.31 (ÍH, m); EMCL (12 minute method): m / z 366.1 [M-HC1 + H] +, Rt 4.72 min.

Example 29: Preparation of 1- [1,1'-biphenyl] -2-yl-6,6,6-trifluoro-2-morpholin-2-yl] hexan-2-ol (68) 1- [1 hydrochloride , 1 '-Biphenyl] -2-H-6, 6, 6-trifluoro-2- [4- (phenylmethyl) mor folin-2-yl] hexan-2-ol (67) Compound 6 was prepared from 10 (0.853 g, 2.71 mmol) and 2-phenylbenzylmagnesium bromide (0.25 M solution in diethyl ether, 1.2 eq) following General Procedure 2. 2-Phenylbenzylmagnesium bromide was prepared from bromide 2 phenylbenzyl (Aldrich) commercially available following General Procedure 5. Further 2-phenylbenzylmagnesium bromide (19.2 ml, 4.8 mmol) was then added. Purification by automated column chromatography (levigant, EtOAc / cyclohexane 20/80 to 40/60 [v / v]), followed by ion exchange chromatography gives 67 as a viscous oil (369 mg, 28%). PM 483.58; C29H32F3N02; EMCL: (6 min method) m / z 484 [M + H] +, Rt 4.26 min.

Chlorhydrate to! - [!,! '-Biphenyl] -2-yl-6, 6, 6-trifluoro-2-morpholin-2-yl] hexan-2-ol (68) The free base of 68 is obtained from 10 (0.369 g, 0.76 mmol), Hünig base supported by a solid (0.43 g) and a-chloroethyl chloroformate (0.32 ml) in anhydrous DCM (10 ml) following General Procedure 3 Purification by ion exchange chromatography gives the free base of 68 as a viscous oil (0.143 g, 48%) which is converted to the hydrochloride salt following General Procedure 4. PM 429.91; C22H26N02F3.HC1; XH NMR (CD3OD): 7.44-7.47 (1H, m), d 7.16-7.35 (7H, m), 7.08-7.11 (H, m), 3.94 (H, d, 12.5 Hz, 3.5 Hz), 3.57 (H) , t, 12.5 Hz), 3.34-3.38 (HH, m), 2.80-3.11 (6H, m), 1.65-3.90 (2H, m), 1.02-1.24 (4H, m). EMCL: (12 minute method) m / z 394 [M-HC1 + H] +, Rt 5.42 min.

Example 30: Preparation of l-Cyclopropyl-2- [-2- (methyloxy) phenyl] -l-morpholin-2-ylethanol hydrochloride (70) l-Cyclopropyl-2- [2- (methyloxy) phenyl] -l- [4- (phenylmethyl) mor folin-2-yl] ethanol (69) Compound 69 is obtained from 77 (0.5 g, 2.04 mmol) and 2-methoxybenzylmagnesium bromide (available from Rieke Metals) (0.25 M solution in THF, 9.0 mL, 2.24 mmol, 1.1 eq) in anhydrous THF (11 mL) following General Procedure 1. Additional 2-methoxybenzylmagnesium bromide (0.25 M solution in THF, 4.08 ml, 1.04 mmol, 0.5 eq) was added after 10 minutes. Purification by ion exchange chromatography gives 69 which is directly used in the next step (0.706 g, 94% purity> 90%). PM 367.49; C23H29N03; EMCL (6 minutes method): m / z 368 [M + H] +, Rt 2.52 min.

L-Cyclopropyl-2- [-2- (methyloxy) phenyl] -1-morpholin-2-ylethanol hydrochloride (70) The free base of 70 is obtained from 69 (0.706 g, 1.92 mmol), a-chloroethyl chloroformate (0.83 ml, 7.69 mmol, 4 eq) and Hünig base supported by polymer (1.08 g, 3.85 m ol, 2 eq) in DCM (25 ml) following General Procedure 3. Purification by ion exchange chromatography followed by automated column chromatography (levigant, DCM / MeOH, 90/10 to 50 / -50 [v / v]) gives the free base of 70 (0.29 g, 55%). A sample (0.06 g, 0.22 mmol) is converted into the hydrochloride salt 70 following General Procedure 4 (63 mg, 99%). MW 313.83, C? 6H23N03.Hc? -XH NMR (CD3OD): d 6.95-7.15 (2H, m), 6.60-6.85 (2H, m), 3.95 (1H, dd, 2 Hz, 10 Hz), 3.55- 3.7 (2H, m), 3.15-3.4 (2H, m), 3.05 (3H, s), 2.7-3.95 (5H, m), 0.4-0.55 (HH, m), 0.15-0.3 (HH, m), -0.1-0.1 (3H, m); EMCL (12 minute method): m / z 278.1 [M-HC1 + H] +, Rt 3.81 min.

Example 31: Preparation of l-Cyclopropyl-2- [-2- (ethyloxy) enyl] -l-morpholin-2-ylethanol hydrochloride (72) l-Cyclopropyl-2- [2- (methyloxy) phenyl] -1- [4- (phenylmethyl) -morf-olin-2-yl] tanol (71) Compound 71 is obtained from 77 (0.36 g, 1.47 mmol) and 2-ethoxybenzylmagnesium bromide (available from Reike Metals) (0.25 M solution in THF, 6.47 ml, 1.61 mmol, 1.1 eq) in Anhydrous THF (8 ml) following the General Procedure 1. Added 2-ethoxybenzyl magnesium bromide after 30 minutes (0.25 M solution in THF, 3.23 ml, 0.8 mmol, 0.5 eq) additional. Purification by ion exchange chromatography (levigante, EtOAc / n-heptane 0/100 to 40/60 [v / v]) gives 71. PM 381. 52; C24H3? N03; EMCL (6 minute method): m / z 382.4 [M + H] +, Rt 2. 83 min.

L-Cyclohydrochloride? Ropil-2- [-2- (ethyloxy) enyl] -1-morpholin-2-ylethanol (72) The free base of 72 is obtained from 71 (0.62 g, 1.62 mmol), a-chloroethyl chloroformate (0.93 g, 0.7 ml, 6.49 mmol) and Hünig base supported by polymer (0.91 g, 3.24 mmol, 2 eq) in DCM (20 ml) following General Procedure 3. Purification by ion exchange chromatography followed by automated column chromatography (levigant, DCM / MeOH 90/10 to 50 / -50 [v / v]) gives the free base of 72 as an oil (0.32 g, 68%) in 89% purity. Conversion to the hydrochloride salt following General Procedure 4 gives 72. MW 327.85; C? 7 H25N03.HCl; H NMR (CD3OD); d 6.9-7.05 (2H,), 6.60-6.8 (2H, m), 4.05 (1H, dd, 2 Hz, 10 Hz), 3.7-3.85 (2H, m), 3.6 (1H, dt, 2 Hz, 7 Hz), 3.15-3.45 (2H,), 2.8-2.95 (5H,), 1.15 (3H, t, 7 Hz), 0.4-0.55 (ÍH, m), 0.15-0.3 (1H, m), -0.1- 0.1 (3H, m). EMCL (12 minute method): m / z 292.1 [M-HC1 + H] +, Rt 4.44 min.

Example 32: Preparation of 2- [1,1'-biphenyl] -2-yl-l-cyclopropyl-l-morpholin-2-yl-ethanol hydrochloride (74) 2- [1,1 '-Biphenyl] -2-yl -l-cyclopropyl-1- [4- (phenylmethyl) -morpholin-2-yl] ethanol (73) Compound 73 is obtained from 77 (0.7 g, 2.86 mmol) and 2-phenylbenzylmagnesium bromide (0.25 M solution in THF, 12. 58 mL, 3.15 mmol, 1.1 eg) in anhydrous THF (15 mL) following General Procedure 1. 2-Phenylbenzylmagnesium bromide was prepared from 2-phenylbenzyl bromide.

(Aldrich) commercially available following the Procedure . After additional 2-phenylbenzylmagnesium bromide (0.25 M solution in THF, 6.3 ml, 1. 65 mmol, 0.5 eq). Purification by ion exchange chromatography gives 73 as a gum (1.07 g, 91%). P.M 413. 56, C28H3? N02, EMCL (6 minute method): m / z 414.4 [M + H] +, Rt 3. 11 min. 2- [1,1 '-biphenyl] -2-yl-l-cyclopropyl-l-morpholin-2-ylethanol (74) The free base of 74 is obtained from 73 (1.06 g, 2.57 mmol), a-chloroethyl chloroformate (1.11 ml, 10.3 mmol, 4 eq) and Hünig base supported by polymer (1.44 g, 5.13 mmol, 2 eq) in DCM (30 ml) following General Procedure 3. Purification by ion exchange chromatography followed by automated column chromatography gives the free base of 74 (0.54 g, 65%) which is converted to hydrochloride salt 74 following the General Procedure 4. PM 323.44; C2? H25N02. 1 H NMR (CDCl 3) dH 7.46-7.53 (HH, m), 7.30-7.44 (5H,), 7.18-7.30 (3H, m), 3.72-7.82 (1H, m), 3.33-3.51 (2H, m), 3.07-3.20 (3H,), 2.56-2.80 (4H,), 0.25-0.39 (2H,), 0.07- 0.19 (ÍH, m), - 0.09-0.03 (1H, m), -0.28-0.16 (ÍH,). EMCL (12 minute method): m / z 324.2 [M + H] +, Rt 4.96 min.

Example 33: Preparation of 1,3-Bis- (2-methoxy-phenyl) -2-mor-olin-2-yl-propan-2-ol (79) 2- (4-benzyl-morpholin-2-yl) hydrochloride ) -1, 3-bis- (2-methoxy-phenyl) -propan-2-ol (78) A solution of the 4-benzyl-morpholin-2-carboxylic acid ethyl ester (1.12 g, 4.49 mmol) in tetrahydrofuran (5 ml) was added to a stirred solution of 2-methoxybenzylmagnesium chloride (54 ml, 0.25 M solution in tetrahydrofuran). , commercially available from Rieke Metals) at -10 ° C under nitrogen atmosphere. After 1 hour, a saturated aqueous solution of sodium bicarbonate was added and extracted with diethyl ether. The organic layers were combined and extracted with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a residue to be taken without further purification. PM 447. 58; C28H33N0; EMCL (12 minute method): m / z) = 448. 2 [M + H] +) Rt 4. 8 min. 1,3-Bis- (2-methoxy phenyl) -2-morpholin-2-yl-propan-2-ol hydrochloride (79) HCl To a solution of 78 (2.2 g, 5 mmol) in EtOH (30 ml) under a nitrogen atmosphere was added ammonium formate (3.1 g, 50 mmol) followed by palladium or carbon (10%, 2.2 g). The resulting suspension was stirred and heated to reflux for one hour. The reaction mixture was allowed to cool to room temperature and then filtered through Celite®. The Celite® was washed with copious amounts of ethanol, the organic layers were combined and concentrated under reduced pressure to obtain a residue. The residue was purified and redissolved by chiral HPLC to give 79; PM 393.91; C2? H27N04.HCl; XH NMR (DMSO-D6): d 2.41-2.52 (m, HH), 2.61-2.78 (m, HH), 2.85-3.44 (m, 8H), 3.50-3.65 (m, 1H), 3.7 (s, 3H) ), 3.79 (s, 3H), 4.00-4.12 (m, ÍH), 6.79-7.01 (m, 4H), 7.07-7.25 (m, 3H), 7.26-7.35 (m, 1H); EMCL (12 minute method): m / z 358.1 [M-HC1 + H]) Rt 4.6 min, single major peak; Example 34: Preparation of l- (2-ethoxy-benzyl) -2- (2-methoxy-phenyl) -l-morpholin-2-yl-ethylamine di-hydrochloride 1- (4-Benzyl-morpholin-2-yl dihydrochloride ) -1- (2-methoxy-phenyl) -2- (2-methoxy-phenyl) -ethylamine (80) To a solution of 4-benzyl-morpholin-2-carbonitrile (10 g, 49.5 mmol) in dry diethyl ether (100 ml) at -10 ° C under a nitrogen atmosphere was added a solution of 2-methoxybenzylmagnesium chloride (0.25 M solution in tetrahydrofuran, 218 ml, 54.5 mmol) available from Aldrich Chemical Company or Rieke Metals) and the reaction mixture was further stirred at -10 ° C for 30 minutes. Then the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was then cooled to 0 ° C and quenched by the addition of hydrochloric acid (5N aqueous solution, 50 ml) and the resulting mixture was stirred for 10 minutes at 0 ° C. The solution was then basified with sodium hydroxide (2N aqueous solution), filtered through Celite® then extracted with diethyl ether, the organics were collected, dried (MgSO) and the solvent was removed under reduced pressure to give an residue which was taken up in methanol and purified by SCX-2 chromatography before chromatography on silica gel (levigant, ethyl acetate / n-hexanes, 0/100 to 40/60 [v / v]). Fractions containing the correct mass (FIA + [M + H] + = 447) are collected and purified via preparative HPLC to give 80 (72 mg), MW 566.69; C28H3N2? 3.C4H80; EMCL (12 minute method): m / z) = 447.2 [M-C4H804 + H] + Rt 4.60 min. 1- (2-Methoxy-benzyl) -2- (2-methoxy phenyl) -1-morpholin-2-yl-ethylamine dihydrochloride (81) To a methanolic solution of 80 (70 mg, 0.13 mmol) was added ammonium formate (100 mg, 1.6 mmol) and 10% Pd-C (150 mg). The reaction was stirred under nitrogen and heated to reflux for 30 minutes, then cooled and filtered through Celite®. The filtrate was concentrated in vacuo and the residue was taken up in methanol and purified by SCX-2® ion exchange resin and the resulting residue was redissolved in 2M hydrochloric acid in diethyl ether solution and then concentrated in vacuo to give 81 (1.7 mg, 0.3%). PM 429.39; C2? H28N203.2HCl, XH NMR (CD3OD): d 2.65-3.02 (m, 6H), 3.05-3.16 (m, ÍH), 3.24-3.41 (m, 2H), 3.52-3.65 (m, 1H), 3.70 (s, 3H), 3.80 (s, 3H), 3.91-4.05 (m, 1H), 6.84-7.08 (, 4H), 7.12-7.32 (m, 4H). EMCL (12 minute method) m / z 357.2 [M-2xHCl + H +] + Rt 2.07 min.

Example 35: Preparation of 1- (2-Methoxy-phenyl) -2-morpholin-2-yl-hexan-2-ol (84) 2- (4-Benzyl-morpholin-2-yl) -1- hydrochloride ( 2-methoxy-phenyl) -hexan-2-ol (83) Compound 83 is obtained from 82 (0.21 g, 0.81 mmol) and 2-phenyl-benzylmagnesium bromide (4.9 ml, 1.21 mmol, 1.5 eq) in anhydrous THF (10 ml) following General Procedure 2 and leaving it to stir for 50 minutes . Purification by ion exchange chromatography gives 83 (0.16 g crude) which was used directly in the next step. PM 383.54; C24H33N03; EMCL (6 minutes method): m / z 384.4 [M + H] +, Rt 3.05 min.

Salt of 1- (2-Methoxy-phenyl) -2-morpholin-2-yl-hexan-2-ol hydrochloride (84) HO NC | H The free base of 84 is obtained from 83 (0.23 g, 0.61 mmol), a-chloroethyl chloroformate (0.17 mg, 1.21 mmol) and Hünig base supported by polymer (0.47 g, 1.82 mmol, 3 eq) in DCM (10 ml) following General Procedure 3. Purification by ion exchange followed by preparative EMCL and conversion to the hydrochloride salt following General Procedure 4 gives 84 as a yellow solid (0.1 g, 6%). PM 329.87; C? 7H27N03.HCl; XH NMR (CD3OD): d 6.74-6.66 (, 2H), 6.46-6.33 (m, 2H), 3.69-3.61 (m, 1H), 3.32-3.24 (m, 2H), 3.14-3.07 (m, 1H) , 2.92-2.84 (m, ÍH), 2.83-2.69 (m, 3H), 2.67-2.56 (, 2H), 2.50-2.39 (m, 2H), 1.00-0.58 (m, 6H), 0.41-0.32 (m , 3H); EMCL (12 minute method): m / z 294.2 [M-HC1 + H] + and 316.2 [M-HCl + Na] +, Rt 4.158 min.

Example 36: Preparation of 2-Morpholinyl-1-biphenyl-2-yl-hexan-2-ol (86) 2- (4-Benzyl-morpholin-2-yl) -l-biphenyl-2-yl-hexan hydrochloride -2-ol (85) Compound 85 is obtained from 82 (0.21 g, 0.81 mmol) and 2-phenyl-benzylmagnesium bromide (4.9 ml, 1225 mmol, 1.5 eq) in anhydrous THF (10 ml) following General Procedure 2. Additional equivalents were added. 2-phenyl-benzyl magnesium bromide (20 ml, 5.0 mmol) and the mixture was allowed to stir for two hours. Purification by ion exchange chromatography gives 85 (0.16 g crude) which was used directly in the next step. PM 429.61; C25H3sN02; LCMS (6 minute method): m / z 430, [M + H] +, Rt 3.46 min. 2-Morpholinyl-1-biphenyl-2-yl-hexan-2-ol hydrochloride (86) The free base of 86 is obtained from 85 (0.16 g, crude), a-chloroethyl chloroformate (0.1 ml, 0.77 mmol, excess) and Hünig base supported by polymer (1.15 mmol, excess) in DCM (12 ml) following General Procedure 3. Purification by ion exchange followed by preparative EMCL and conversions to the hydrochloride salt following General Procedure 4 gives 86 as a yellow solid (16 mg, 5% in steps). PM 375.94; C22H29N02 HCl; XH NMR (CD3OD): d 7.90-7.35 (m, 9H), 4.30 (d, 1H, 10.5 Hz), 4.00-3.90 (t, 1H, 12 Hz), 3.72 (d, ÍH, 10.5 Hz), 3.55 ( bs, 2H), 3.44 (d, 2H, 11.5 Hz), 3.35-3.15 (m, 4H), 1.50-0.9 (m, 9H); EMCL (12 minute method): m / z 340.3 [M-HC1 + H] +, Rt 5.1 min.

Example 37: 1- (2-Chloro-6-fluoro-phenyl) -4-methyl-2-morpholin-2-yl-pentan-2-ol (88) 2- (4-Benzyl-morpholino-) hydrochloride salt 2-yl) -1- (2-chloro-6-f luoro-phenyl) -4-methyl-pentan-2-ol (87) Compound 87 is obtained from 6 (0.33 g, 1.28 mmol) and 2-chloro-6-fluoro-benzylmagnesium bromide (8 ml, 1.92 mmol, 1.5 eq) in anhydrous THF (15 ml) following General Procedure 2. added additional equivalent of additional 2-chloro-6-fluoro-benzylmagnesium bromide (20 ml, 3.75 eq) and the mixture was allowed to stir overnight. Purification by ion exchange chromatography gives 87 (0.52 g, 99%) as a mixture of two diastereomers (approximately 6: 1 ratio), MW 405.94; C23H29C1FN02; LCMS (6 minute method): m / z 406.2 [M + H] +, Rt 3.31 and 3.39 min.

Salt of 1- (2-Chloro-6-fluoro-phenyl) -4-methyl-2-morpholin-2-yl-pentan-2-ol hydrochloride (88) The free base of 88 is obtained from 87 (0.52 g, 1.27 mmol), a-chloroethyl chloroformate (0.28 ml, 2.54 mmol, 2 eq) and Hünig base supported by polymer (3.81 mmol, 0.98 g) in DCM (15 ml) following General Procedure 3. The purification by ion exchange and chiral and preparative chromatography guided by UV followed by conversion of the greater diastereomer to the hydrochloride salt following the General Procedure 4 gives 88 (0.145 g, 32%). PM 352.27; C? 6H23ClFN02.HCl,? E NMR (CD30D): d 7.27-7.18 (m, 2H), 7.09-6.99 (m, ÍH), 4.15-4.04 (m, ÍH), 3.89-3.73 (m, 2H), 3.60-3.50 (m, ÍH), 3.35-3.00 (m, 5H), 1.88-1.69 (m, 2H) , 1.32-1.15 (m, 1H), 0. 97-0.86 (m, 6H); EMCL (12 minute method): m / z 298.1 [M-HC1-H20 + H] + and 316.2 [M-HCl + H] "1", Rt 4.328 min.

Example 38: 1- (2-Chloro-phenyl) -4-methyl-2-morpholin-2-yl-pentan-2-ol hydrochloride salt (90) 2- (4-Benzyl-morpholin-2-yl) -1- (2-chloro-phenyl) -4-methyl-pentan-2-ol Compound 89 is obtained from 6 (0.33 g, 1.28 mmol) and 2-chloro-benzylmagnesium bromide (8 ml, 1.92 mmol, 1.5 eq) in Anhydrous THF (15 ml) following General Procedure 2. Additional equivalents of 2-chloro-benzylmagnesium bromide (20 ml, 3.75 eq) were added and the mixture was allowed to stir overnight. Purification by ion exchange chromatography gives 89 (0.598 g crude) which was directly used in the next step. PM 387.95; C 23 H 30 ClNO 2; LCMS (6 minute method): m / z 388.2 [M + H] +, Rt 3.13 min.

Salt of 1- (2-Chloro-phenyl) -4-methyl-2-morpholin-2-yl-pentan-2-ol hydrochloride (90) The free base of 90 is obtained from 89 (0.589 g, 1.27 mmol), a-chloroethyl chloroformate (0.31 ml, 2.82 mmol, 2.2 eq) and Hünig base supported by polymer (4.23 mmol, 1.1 g) in DCM (15 ml) following General Procedure 3. The purification by ion-exchange and chiral chromatography and preparative chromatography guided by UV followed by conversion of the greater diastereomer to the hydrochloride salt following General Procedure 4 gives 90 (0.083 g, 19% in two steps) . PM 334.29; C16H24C1N02.HC1; kH NMR (CD30D): d 7.51-7.44 (m, ÍH), 7.39-7.31 (m, ÍH), 7.26-7.14 (m, 2H) 4.13 (d, 1H, 9 Hz), 3.87-3.69 (m, 2H ), 3.47 (d, 1H, 9 Hz), 3.38-3.03 (m, 4H), 2.99-2.88 (m, 1H), 1.87-1.74 (m, ÍH), 1.67-1.57 (m, ÍH), 1.20- 1.09 (m, 1H), 0.95-0.83 (m, 6H); LCMS (12 minute method): m / z 280.2 [M-HC1-H20 + H] + and 298.2 [M-HC1 + H], Rt 4.314 min. The pharmacological profile of the present compounds can be demonstrated as follows. It has been found that all of the compounds exemplified above exhibit a K K value of less than 1 μm in the norepinephrine transporter as determined using the scintillation proximity assay. In addition, all the compounds exemplified above have been found to inhibit the norepinephrine transporter to a greater degree than the serotonin and dopamine transporters using scintillation proximity assays as described below.

Generation of stable cell lines expressing the human transporters of dopamine, norepinephrine and serotonin. Standard molecular cloning techniques were used to generate stable cell lines expressing the human transporters of dopamine, norepinephrine and serotonin. The polymerase chain reaction (PCR) was used to isolate and amplify each of the three full length cDNAs from an appropriate cDNA library. The PCR primers were designed using the following published sequence data: Human dopamine transporter: GenBank M95167. Reference: Vandenbergh DJ, Persian AM and Uhl GR. A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqlRFLPs (A human dopamine transporter cDNA predicts reduced glycosylation, exhibits a novel repeating element and provides racially-dimorphic TaqlRFLPs), Molecular Brain Research (1992) , volume 15, pages 161-166. Human norepinephrine transporter: GenBank M65105. Reference: Pacholczyk T, Blakely, RD and Amara SG. Express cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. (Cloning of expression of a human norepinephrine transporter sensitive to cocaine and antidepressant) Nature (1991) volume 350, pages 350-354. Human serotonin transporter: GenBank L05568. Reference: Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V and Blakely RD. Antidepressant-and cocaine-sensitive human serotonin transporter: Molecular cloning, expression, and chromosomal localization.

(Human serotonin transporter sensitive to antidepressant and cocaine: Molecular cloning, expression and chromosomal localization) Proceedings of the National Academy of Sciences of the USA (1993), volume 90, pages 2542-2546. The PCR products are cloned into a mammalian expression vector (e.g., cDNA3.1 (Invitrogen)) using standard ligation techniques. The constructs are then used to stably transfect HEK293 cells using commercially available lipofection reagents (Lipofectamine ™ - Invitrogen), following the manufacturer's protocol.

Scintillation proximity assays to determine the affinity of the test ligands in the norepinephrine transporter The compounds of the present invention are inhibitors of norepinephrine reuptake, and possess excellent activity in, for example, a scintillation proximity assay (eg, J. Gobel, DL Saussy and A. Goetz, J. Pharmacol. (1999), 42, 237-244). Thus, 3H-nisoxetine which binds to the norepinephrine reuptake sites in a cell line transfected with DNA encoding the norepinephrine-transporting human protein, is used to determine the affinity of ligands in the norepinephrine transporter.

Membrane Preparation: Cell pellets from large-scale production of HEK-293 cells expressing cloned human norepinephrine transporters, are homogenized in 4 volumes of 50 mM Tris-HCl containing 300 mM NaCl and 5 mM KCl, at pH 7.4. The homogenate was centrifuged twice (40,000 g, 10 min, 4 ° C), with pellets in re-suspension in 4 volumes of Tris-HCl buffer containing the above reagents, after the first centrifugation 7 8 volumes after the second centrifugation. The suspended homogenate is centrifuged (100 g, 10 min, 4 ° C) and the supernatant is maintained and centrifuged again (40,000 g, 20 min, 4 ° C). The pellet is suspended in Tris-HCl buffer containing the above reagents together with 10% sucrose w / v and 0.1 mM phenylmethylsulfonyl fluoride (PMSF). The membrane preparation is stored in aliquots (1 mL) at -80 ° C until required. The protein concentration of the membrane preparation is determined using a bicinchoninic acid protein assay (BCA) reagent kit (available from Pierce).

Linkage assay of [3 H] -nisoxetine: Each well of a 96-well microtiter plate is set to contain the following: 50 μl 2 nM of [N-methyl- ~ 3 H] -Nisoxetine hydrochloride (70.87 Ci / mmol, de NEN Life Science Products) 75 μl Assay buffer (50 mM Tris-HCl pH 7.4 containing 300 M NaCl and 5 mM KCl) 25 μl Test compound, assay buffer (total binding) or 10 μM HCl Desipramine (non-specific binding) 50 μl SPA poly (vinyl toluene) perlillas coated with wheat germ agglutinin (WGA PVT) (Amersham Biosciences RPNQ0001) (10 mg / mL). 50 μl Membrane (0.2 mg protein per mL). The microtiter plates are incubated at room temperature for 10 hours prior to reading in a Trilux scintillation counter. The results are analyzed using an automatic tape adjustment program (Multicalc, Packard, Milton Keynes, UK), to provide Ki values for each of the test compounds.

Serotonin Binding Assay The ability of a test compound to compete with [3 H] -citalopram for its binding sites on cloned human serotonin transporter-containing membranes is used as a measure of the ability of the test compound to block the absorption of serotonin via its specific transporter (Ramamoorthy, S., Giovanetti, E., Qian, Y., Blakely, R., (1998) J. Biol. Chem. 273, 2458).

Membrane Preparation: The preparation of the membrane is essentially similar to that for the norepinephrine transporter that contains membranes as described above. The membrane preparation is stored in aliquots (1 mL) at -70 ° C until required. The protein concentration of the membrane preparation is determined using a BCA protein assay reagent kit. [3H] -Citalopram Binding Assay: Each well of a 96-well microtiter plate is set to contain the following: 50 μl 2 nM [3H] -Citalopram (60-86 Ci / mmol, Amersham Biosciences) 75 μl assay (50 mM Tris-HCl pH 7.4 containing 300 mM NaCl and 5 mM KCl) 25 μl Compound diluted, assay buffer (total binding) or 100 μM Fluoxetine (non-specific binding) 50 μL SPA Perllets WGA PVT (40 mg / mL). 50 μl Preparation of membrane (0.4 mg of protein per mL). The microtiter plates are incubated at room temperature for 10 hours prior to reading in a Trilux scintillation counter. The results are analyzed using an automatic tape adjustment program (Multicalc, Packard, Milton Keynes, UK), to provide Ki values for each of the test compounds.

Dopamine Linkage Assay The ability of a test compound to compete with [3 H] -WIN35, 428, for its binding sites on human cell membranes containing cloned human dopamine transporter, has been used as a measure of capacity of such test compounds to block dopamine uptake via their specific transporter (Ramamoorthy et al., 1998 supra).

Membrane Preparation: It is essentially the same as for the membranes containing human cloned serotonin transporter, as described above.

Link assay of [3 H] -WIN35, 428 Each well of a 96-well microtitre plate is set to contain the following: 50 μl 4 nM of [3 H] -WIN35, 428 (84-87 Ci / mmol, from NEN Life Science Products) 75 μl Assay buffer (50 mM Tris-HCl pH 7.4 containing 150 mM NaCl and 5 mM KCl) 25 μl Diluted compound, assay buffer (total binding) or 100 μM Nomifensin (non-specific binding) ) 50 μl SPA WGA PVT Perlillas (10 mg / mL). 50 μl Preparation of membrane (0.2 mg of protein per mL). The microtiter plates are incubated at room temperature for 120 minutes prior to reading in a Trilux scintillation counter. The results are analyzed using an automatic tape adjustment program (Multicalc, Packard, Milton Keynes, UK), to provide Ki values for each of the test compounds.

Acid Stability The acid stability of a compound according to the invention can be determined as a solution in a buffer at 6 different pH values (0.1 N HCl, pH 2, pH 4, pH 6, pH 7 and pH 8) a 40 ° C during a course time of 72 hours. Samples can be taken at the beginning of the study and after 3, 6 and 24 hours and analyzed by capillary electrophoresis. The original sample used in the study may contain 0.8% of the undesired epimer as an internal standard. If the test compound is chemically and configurationally stable under acidic conditions, the samples taken at different time points during the study should not show any significant change in the percentage of the undesired epimer.

In vitro determination of the interaction of compounds with CYP2D6 in Human Liver Microsomes Cytochrome P450 2D6 (CYP2D6) is a mammalian enzyme which is commonly associated with the metabolism of approximately 30% of the pharmaceutical compounds. However, this enzyme exhibits genetic polymorphism, which results in the presence of both normal and scarce metabolizers in the population. A low involvement of CYP2D6 in the metabolism of the compounds (ie, the compound is a poor substrate of CYP2D6), is desirable to reduce any variability from subject to subject in the pharmacokinetics of the compound. Also, compounds with a low inhibitory potential for CYP2D6 are desirable to avoid drug-drug interactions with co-administered drugs that are substrates of CYP2D6. The compounds can be tested both as substrates and as inhibitors of this enzyme by means of the following tests.

Substrate assay CYP2D6 Principle: This assay determines the extent of the CYP2D6 enzyme involved in the total oxidative metabolism of a compound in microsomes. The preferred compounds of the present invention exhibit less than 75% of the total metabolism via the path of CY2PD6. For this ip-vitro assay, the extent of oxidative metabolism in human liver microsomes (HLM); is determined after 30 minutes of incubation in the absence and presence of Quinidine, a specific chemical inhibitor of CYP2D6. The difference in the extent of metabolism in the absence and presence of the inhibitor indicates the involvement of CYPD6 in the metabolism of the compound.

Materials and Methods: Human liver microsomes were acquired (mixture of 20 different donors, of mixed genres) from Human Biologics (Scottsdale, AZ, USA). Quinidine and β-NADPH (tetrasodium salt of ß-nicotinamide adenine dinucleotide phosphate, reduced form) were purchased from Sigma (St. Louis, MO, USA). All other reagents and solvents are analytical grade. A base solution of the new chemical entity (NCE) was prepared in a mixture of acetonitrile / water to reach a final concentration of acetonitrile in the incubation below 0.5%. The microsomal incubation mixture (total volume 0.1 ml) contains the NCE (4 μM), ß-NADPH (1 mM), microsomal proteins (0.5 mg / mL) and Quinidine (0 or 2 μM) in 100 mM buffer sodium phosphate at pH 7.4. The mixture is incubated for 30 minutes at 37 ° C in a shaking water bath. The reaction is terminated by the addition of acetonitrile (75 μL). The samples are vortexed and the denatured proteins are removed by centrifugation. The amount of NCE in the supernatant is analyzed by liquid chromatography / mass spectrometry (EM / LC), after the addition of an internal standard. A sample is taken at the beginning of the incubation (t = 0), and analyzed in a similar way. NCE analysis is performed by liquid chromatography / mass spectrometry. Then, ten μL of diluted samples (20 parts of dilution in the mobile phase) are injected onto a 5 μM and 2.1 m × 100 mm CN Spherisorb column.

(Waters Corp. Milford, MA, USA). The mobile phase consisting of a mixture of Solvent A / Solvent B, 30/70 (v / v), is pumped (Alliance 2795, Waters corp., Milford, MA, USA), through the column at a flow rate of 0.2 mL / minute. He Solvent A and Solvent B, are a mixture of ammonium formate . 10-3 M pH 4.5 / methanol in the proportions 95/5 (v / v) and 10/90 (v / v), for solvent A and solvent B, respectively. The NCE and the internal standard are quantified by monitoring their molecular ion using ZMD or ZQ mass spectrometer (Waters-Micromass corp., Manchester, UK), operated on a positive electro-ionization ionization. The extent of CYP2D6 involved (% of CYP2D6 involved), is calculated by comparing the extent of metabolism in the absence and presence of quinidine in the incubation. The extension of metabolism without inhibitor (%) is calculated as follows: (NCE response in samples without inhibition) time 0 - (NCE response in samples without inhibitor) time 30 x? or? (NCE response in samples without inhibitor) time 0 The extent of metabolism with inhibitor (%) is calculated as follows: (NCE response in samples without inhibition) time 0 - (NCE response in samples with inhibitor) time 30 x or? (NCE response in samples without inhibitor) time 0 where the NCE response is the area of the NCE divided by the area of the internal standard in the EM / LC analysis chromatogram, time 0 and time 30, correspond to 0 and 30 minutes of incubation time. The (%) of CYP2D6 involved is calculated as follows: (% extension of metabolism without inhibitor) - (% extension of metabolism with inhibitor) x] _ Q Q% extension of metabolism without inhibitor CYP2D6 inhibitor assay Principle: The CYP2D6 inhibitor assay evaluates the potential of a compound to inhibit CYP2D6. This is done by measuring the inhibition of bufuralol l-hydrolase activity by the compound compared to a control. The 1'-hydroxylation of bufuralol is a specific metabolic reaction for CYP2D6. Preferred compounds of the present invention exhibit an IC50 higher than 6 μM for CYP2D6 activity, IC50 is the concentration of the compound that gives 50% inhibition of CYP2D6 activity.

Materials and Methods Human liver microsomes (mixture of 20 different donors, combined genera) were purchased from Human Biologics (Scottsdale, AZ). Β-NADPH was purchased from Sigma (St. Louis, MO). Bufuralol is purchased from Ultrafine (Manchester, UK). All other reagents and solvents are analytical grade. The microsomal incubation mixture (total volume 0.1 mL), contains 10 μM bufuralol, ß-NADPH (2 mM) and microsomal proteins (0.5 mg / mL) and the new chemical entity (NCE) (0, 5 and 25 μM) in 10 mM sodium phosphate buffer at pH 7.4. The mixture is incubated in a water bath with shaking at 37 ° C for 5 minutes. The reaction is terminated by the addition of methanol (75 μL). The samples are vortexed and the denatured proteins are removed by centrifugation. The supernatant is analyzed by liquid chromatography connected to a fluorescence detector. The formation of 1'-hydroxybufuralol is monitored in control samples (0 μM NCE) and in samples incubated in the presence of NCE. The base solution of NCE is prepared in a mixture of acetonitrile / water to reach a final concentration of acetonitrile in the incubation below 1.0%. The determination of 1 '-hydroxybufuralol in the samples is carried out by liquid chromatography with fluorimetric detection as described below. Twenty-five μL of samples are injected onto a Chromolith Performance RP-18e column (100 mm x 4.6 mm) (Merck KGAa, Darmstadt, Germany). The mobile phase consisting of a mixture of solvent A and solvent B whose proportions change in accordance with the following linear gradient, are pumped through the column at a flow rate of 1 mL / min: Solvent A and solvent B consist of a mixture of 0.02 M potassium dihydrogen phosphate buffer pH 3 / methanol, in the proportion of 90/10 (v / v) for solvent A and 10/90 (v / v) for solvent B. Run time is 7.5 minutes. The formation of 1 '-hydroxybufuralol is monitored by fluorimetric detection with extinction a? 252 nm and emission to? 302 nm. The IC50 of the NCE for CYP2D6 is calculated by measuring the percentage inhibition of 1'-hydroxybufuralol formation in the presence of the NCE compared to the control samples (without NCE) at a known concentration of the NCE. The percentage of inhibition of 1'-hydroxybufuralol formation is calculated as follows: (1 '-hydroxybufuralol formed without inhibitor) - (1' -hydroxybufuralol with inhibitor) X 100 (1 '-hydroxybufuralol formed without inhibitor) IC 50 is calculated from the percentage of inhibition of 1'-hydroxybufuralol formation as follows (assuming competitive inhibition): NCE concentration x (100 - percentage of inhibition x? o? percentage of inhibition The IC50 estimation is assumed to be valid if the inhibition is between 20% and 80% (Moody GC, Griffin SJ, Mather AN, McGinnity DF, Riley RJ 1999. Fully automated analysis of activities catalyzed by the major human liver cytochrome P450 (CYP ) enzymes: assessment -of human CYP inhibition potential.

(Fully automated analysis of activities catalyzed by the main enzymes of human liver cytochrome P450 (CYP): assessment of inhibition potential of Human CYP) Xenobiotica, 29 (1): 53-75).

Claims (34)

1. A compound of formula (I) (0 characterized in that X is OH, C1-C4 alkoxy, NH2 or NH (Cl-4 alkyl); R x is H or C 1 -C 4 alkyl; Ry is H or C1-C4 alkyl; each Rz group is independently H or C1-4 alkyl, with the proviso that no more than 3 Rz groups may be C1-C4 alkyl; R1 is C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 fluorine atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 6 3 fluorine atoms), C3-C6 cycloalkoxy, C1-C4 alkylsulfonyl, cyano, -CO-O (C1-C2 alkyl), -O-CO- (C1-C2 alkyl) and hydroxy); C2-C6 alkenyl (optionally substituted with 1, 2 or 3 halogen atoms); C3-C6 cycloalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkoxy and hydroxy), wherein a CC bond within the cycloalkyl portion is optionally substituted by a 0- bond C, SC or C = C; C4-C7 cycloalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkoxy and hydroxy), wherein a CC bond within the cycloalkyl portion is optionally substituted by a 0- bond C, SC or C = C; or CH2Ar2; and Ar and Ar2 are each independently a phenyl ring or a 5 or 6-membered heteroaryl ring each of which is optionally substituted with 1, 2 or 3 substituents (depending on the number of substitution positions available), each independently selected of C1-C4 alkyl (optionally substituted by 1, 2 or 3 halogen atoms), C1-C4 alkoxy (optionally substituted by 1, 2 or 3 halogen atoms), C1-C4 alkylthio (optionally substituted by 1, 2 or 3) halogen atoms), -C0-O (C1-C4 alkyl), cyano, -NRR, -CONRR, halo and hydroxy and / or with 1 substituent selected from pyridyl, thiophenyl, phenyl, benzyl and phenoxy, each of which is a ring optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 6 3 halogen atoms), carboxy, nitro, hydroxy, cyano, -NRR, -CONRR, S02NRR and S02R; and each R is independently H or C 1 -C 4 alkyl; or a pharmaceutically acceptable salt thereof.

2 . A compound of formula (II)

(DD characterized in that X, Rx, Ry, Rz, Rl and Arl are as defined by formula (I) according to claim 1; or a pharmaceutically acceptable salt thereof. 3. A compound as claimed in accordance with any preceding claim or claim 30, characterized in that X ex OH.

4. A compound as claimed in accordance with any preceding claim or claim 30, characterized in that Rx is H.

5. A compound as claimed in accordance with any preceding claim or claim 30, characterized in that Ry is H.

6. A compound as claimed in any preceding claim or claim 30, characterized in that each Rz is H.

7. A compound as claimed in any of claims 1 to 6 or 30 to 32, characterized in that R1 is alkyl C1-C6 optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C1-C4 alkylthio (optionally substituted with 1, 2 or 3 fluorine atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 fluorine atoms), C3-C6 cycloalkoxy, C1-C4 alkylsulfonyl, cyanoC0-0 (C1-C2 alkyl), -0-C0- (C1-C2 alkyl) and hydroxy.

8. A compound as claimed in any of claims 1 to 6 or 30 to 32, characterized in that R1 is C2-C6 alkenyl, optionally substituted with 1, 2 or 3 halogen atoms.

9. A compound as claimed in any of claims 1 to 6 or 30 to 32, characterized in that R1 is C3-C6 cycloalkyl optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from alkoxy C1-C4 and hydroxy, wherein a C-C bond within the cycloalkyl portion is optionally substituted by a bond 0-C, S-C or C = C.

10. A compound as claimed in any of claims 1 to 6 or 30 to 32, characterized in that R1 is C4-C7 cycloalkyl optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from alkoxy C1-C4 and hydroxy, wherein a CC bond within the cycloalkyl portion, is optionally substituted by a bond 0-C, SC or C = C.

11. A compound as claimed in any one of claims 1 to 6 or 30 to 32, characterized in that R1 is CH2Ar2 wherein AR2 is a phenyl ring or a 5 or 6-membered heteroaryl ring each of which is optionally substituted with 1, 2 or 3 substituents (depending on the number of substitution positions available), each independently selected from C 1 -C 4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 6 3 halogen atoms), -CO-O (C 1 -C 4 alkyl), cyano, -NRR, -CONRR, halo and hydroxy and / or with 1 substituent selected from pyridyl, thiophenyl, phenyl, benzyl and phenoxy, each of which is a ring optionally substituted by 1, 2 or 3 halogen atoms), C 1 -C 4 alkyl (optionally substituted by 1, 2 or 3 halogen atoms), C1-C4 alkoxy (optionally substituted with 1, 2, 6, 3 halogen atoms), carboxy, nitro, hydroxy, cyano, -NRR, -CONRR, S02NRR and S02R.

12. A compound as claimed in accordance with any preceding claim or according to claim 30, characterized in that Arl is a phenyl ring or a 5- or 6-membered heteroaryl ring; each of which is substituted in the ortho position with a substituent selected from C 1 -C 4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 6 3 halogen atoms) ), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), -C 0-0 (C 1 -C 4 alkyl), cyano, -NRR, -CONRR, halo, hydroxy, pyridyl, thiophenyl, phenyl, benzyl and phenoxy, each of the ortho substituents is optionally substituted ring (wherein one ring is present), with 1, 2 or 3 substituents each independently selected from halogen, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atom, C1-C4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), carboxy, nitro, hydroxy, cyano, -NRR, -CONRR, S02NRR and S02R, and each of which is (in addition to the ortho) substitution, optionally further substituted with 1 or 2 substituents each independently selected of C 1 -C 4 alkoyl (optionally substituted with 1, 2, 6, 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3) halogen atoms), -CO-O (C 1 -C 4 alkyl), cyano, -NRR, -CONRR, halo and hydroxy.

13. A compound as claimed in accordance with any preceding claim, or in accordance with claim 30, characterized in that Arl is a group of the formula (a): wherein, A is N or CR6 (preferably CR6); R2 is C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C1-C4 alkylthio (optionally substituted with 1.2; 3 halogen atoms), halo, hydroxy, pyridyl, thiophenyl, phenyl (optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), or C1-C4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms)) or phenoxy (optionally substituted with 1, 2 or 3 halogen atoms); R3 is H; R4 is H; R 5 is H, C 1 -C 4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), halo or hydroxy; and R6 (if present) is H.

14. A compound of formula (III) m characterized in that X, R1 and Ar1 are as defined for formula (I) according to claim 1; or a pharmaceutically acceptable salt thereof.

15. A compound according to claim 14, characterized in that X is OH or NH2; R1 is C1-C6 alkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C1-C4 alkylthio (optionally substituted with 1, 2 or 3 fluorine atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 fluorine atoms), C3-C6 cycloalkoxy, C1-C4 alkylsulfonyl, cyano, -CO-O (C1-C2 alkyl), -O-CO- (C1-C2 alkyl) and hydroxy); C3-C6 cycloalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkoxy and hydroxy), wherein a CC bond within the cycloalkyl portion is optionally substituted by a 0- bond C, SC or C = C; or CH2Ar2, wherein Ar2 is a phenyl ring or a pyridyl ring (preferably 2-pyridyl) each of which can be substituted with 1, 2 or 3 substituents each independently selected from C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), halo and hydroxy; and Arl is a phenyl ring or a 5- or 6-membered heteroaryl ring; each of which is substituted in the ortho position with a substituent selected from C 1 -C 4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms) ), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), -CO-O (C 1 -C 4 alkoyl), cyano, -NRR, -CONRR, halo, hydroxy, pyridyl, thiophenyl, phenyl, benzyl and phenoxy, each of the ortho substituents is optionally substituted ring (wherein one ring is present), with 1, 2 or 3 substituents each independently selected from halogen, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atom, C1-C4 alkoxy (optionally substituted by 1, 2 or 3 halogen atoms), carboxy, nitro, hydroxy, cyano, -NRR, -CONRR, S02NRR and S02R, and each of which is (in addition to ortho replacement), optionally further substituted with 1 or 2 substituents each independently selected C 1 -C 4 alkyl (optionally substituted by 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted by 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted by 1, 2 or 3 halogen atoms), -CO-O (C 1 -C 4 alkyl), cyano, -NRR, -CONRR, halo and hydroxy; or a pharmaceutically acceptable salt thereof.

16. A compound of formula (IV) (IV) characterized in that, X is OH or NH2; R 1 is C 1 -C 6 alkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 fluorine atoms), cyano and hydroxy); C3-C6 cycloalkyl (optionally substituted with 1, 2 or 3 halogen atoms and / or with 1 substituent selected from C 1 -C 4 alkoxy and hydroxy), wherein a CC bond within the cycloalkyl portion is optionally substituted by a 0- bond C, or CH2Ar2 wherein Ar2 is a phenyl ring optionally substituted with 1, 2 or 3 substituents, each independently selected from C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), halo and hydroxy; A is N or CR6 (preferably CR6); R2 is C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C1-C4 alkylthio (optionally substituted with 1, 2 or 3 halogen atoms), halo, hydroxy, pyridyl, thiophenyl, phenyl (optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, C1-C4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), or C1-C4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms)) or phenoxy (optionally substituted with 1, 2 or 3 halogen atoms); R3 is H; R4 is H; R 5 is H, C 1 -C 4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkylthio (optionally substituted with 1, 2 0 3 halogen atoms), halo or hydroxy; and R6 (if present), is H; or a pharmaceutically acceptable salt thereof.

17. A compound of formula (V) (V) characterized in that X is OH or NH2; R1 is C1-C6 alkyl (optionally substituted with 1, 2 or 3 fluorine atoms), C3-C6 cycloalkyl wherein a CC bond within the cycloalkyl portion is optionally substituted by a bond 0-C or CH2Ar2, wherein Ar2 is a phenyl ring optionally substituted with 1 or 2 substituents each independently selected from C 1 -C 4 alkyl (optionally substituted with 1, 2 or 3 halogen atoms), C 1 -C 4 alkoxy (optionally substituted with 1, 2 or 3 halogen atoms) , halo and hydroxy; R2 is C1-C4 alkyl (optionally substituted with 1, 2 or 3 fluorine atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 fluorine atoms) or phenyl (optionally substituted with 1, 2 or 3 fluorine atoms); and R5 is H or F; or a pharmaceutically acceptable salt thereof.

18. A compound of formula (VI) (VD characterized in that, R1 is C1-C6 alkyl (optionally substituted with 1, 2 or 3 fluorine atoms) or C3-C6 cycloalkyl wherein a C-C bond within the cycloalkyl portion is optionally substituted by a 0-C bond; R2 is C1-C4 alkyl (optionally substituted with 1, 2 or 3 fluorine atoms), C1-C4 alkoxy (optionally substituted with 1, 2 or 3 fluorine atoms) or phenyl (optionally substituted with 1, 2 or 3 carbon atoms) fluorine); and R5 is H or F; or a pharmaceutically acceptable salt thereof.

19. A compound of formula or a pharmaceutically acceptable salt thereof,

20. A compound of the formula or a pharmaceutically acceptable salt thereof. 21. The hydrochloride salt of a compound, according to claim 20 or claim

21.

22. A pharmaceutical composition, characterized in that it comprises a compound as claimed in any of claims 1 to 21, except that it depends on any of claims 30 to 32, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent, excipient or carrier.

23. A compound as claimed in any one of claims 1 to 21, except when dependent on any of claims 30 to 32 for use in therapy.

24. A compound as claimed in any one of claims 1 to 21, except when dependent on any of claims 30 to 32, or a pharmaceutically acceptable salt thereof, for use as an inhibitor of norepinephrine reuptake.

25. A compound as claimed in any one of claims 1 to 21, except when dependent on any of claims 30 to 32, or a pharmaceutically acceptable salt thereof, characterized in that it is for the treatment of disorders associated with norepinephrine dysfunction in mammals

26. The use of a compound as claimed in any of claims 1 to 21, except when dependent on any of claims 30 to 32, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of disorders associated with norepinephrine dysfunction in mammals. A method for inhibiting norepinephrine reuptake in mammals, characterized in that it comprises administering to a patient in need thereof, an effective amount of a compound as claimed in any one of claims 1 to 21, except when dependent on any of claims 30 to 32, or a pharmaceutically acceptable salt thereof. A method for treating disorders associated with norepinephrine dysfunction in mammals, characterized in that it comprises administering to a patient in need thereof, an effective amount of a compound as claimed in any one of claims 1 to 21, except when it depends on any of claims 30 to 32, or a pharmaceutically acceptable salt thereof. 29. A process for the preparation of a compound of formula (I), characterized in that it comprises the step of deprotecting a compound of the formula (XIV) Rz R > Yz-, or? X R1 Rz l Rz P (XIV) wherein P represents an N-protecting group and all other variables are as defined by formula (I) according to claim 1, to provide a compound of formula (I), optionally followed by the step of forming a pharmaceutically acceptable salt. 30. A compound of the formula (XIV) (xrv) characterized in that P represents an N-protecting group and all other variables are as defined by formula (I) according to claim 1, or a salt thereof. 31. A compound of the formula (XII) or (xm characterized in that P represents an N-protecting group and all other variables are as defined by formula (I) according to claim 1, or a salt thereof. 32. A compound of the formula (XIII) b 5 (xm) b characterized in that P represents an N-protecting group and all other variables are as defined by formula (I) according to claim 1, or a salt thereof. 33. A compound according to any of claims 30 to 32, or a salt thereof, characterized in that R is a tetrahydro-2H-pyran-4-yl group. 34. A compound according to any of claims 30 to 33, or a salt thereof, characterized in that P is a benzyl group.