MXPA06005244A - Benzylether amine compounds useful as ccr-5 antagonists - Google Patents

Abstract

The present invention relates to compounds which are CCR-5 receptor antagonists of the general formula (I) wherein R1, R2, R3, R4, Ra, Rb, Rc, Rd, X, m and n are as defined herein. The invention further comprises pharmaceutical compositions comprising such compounds, as well as the use of such compounds to treat CCR-5 mediated disorders.

Description

AMINE BENCILETER COMPOUNDS USEFUL AS CCR-5 ANTAGONISTS This application claims the priority of the Provisional Application ÜS Series No. 60 / 519,002, filed on November 10, 2003, which is incorporated herein. totality as a reference.

Environment of the invention. Cytokines, chemoattractants or chemokines, are a family of proinflammatory mediators that promote the reestablishment and activation of leukocytes (e.g., • monocytes, lymphocytes and granulocytes). They can be released by many types of tissue cells after activation. The continuous release of chemokines at sites of inflammation mediates the progressive migration of effector cells in chronic inflammation The chemokines characterized so far are related • in the primary structure. They share - '-' four conserved cysteines, which form disulfide bonds. Based on this theme of conserved cysteine, the family is divided into two main branches, designated as the C-X-C chemokines (-quimiocins), and the C-C chemokines (β-chemokines), in which both first conserved cysteines are separated by an intervening residue, or adjacent, respectively (Baggiolini,., and Dahinden, CA, Immunology Today, 15: 127-133 (1994)).

C-C chemokines include RANTES (Regulated in Activation, Expressed Normal in T, and Secretada), to the macrophage inflammatory proteins la and lß (MlP-la and MlP-lβ), and to proteins 1-3 (MCP-1, MCP-2, MCP-3) chemotactic human monocyte, which have been characterized as chemoattractants and activators of monocytes or lymphocytes. Chemokines, such as R? NTES and MlP-la, have been implicated in a wide range of acute and chronic human inflammatory diseases, including rheumatoid arthritis, and respiratory diseases, such as asthma and allergic disorders. In particular, numerous laboratories have implicated chemokines in the pathophysiology of RA (rheumatoid arthritis). Several studies involving human arthritic patients have shown an increase in the expression levels of the CCR-5 ligands, the RANTES, the MlP-lß, and the MlP-lain in diseased synoviums and an increased selective accumulation of CCR lymphocytes. -5+ in diseased synovial fluid (Rathanas ami P. et al., Journal of Biological Chemistry 268: 5834-9 (1993) and Rot A. et al., Journal of Experimental Medicine 176: 1489-95 (1992)).

Chemokine receptors are members of a superfamily of G-protein coupled receptors (GPCRs) that are shared structural representations that reflect a common mechanism of action-of signal transduction (Gerard, C. and Gerard, NP, Annu Rev. Immunol., 12-775-808 (1994), Gerard, C and Gerard, NP, Curr Opin. Immunol., 6: 140-145 (1994)). The first receptor for C-C chemokines that was cloned and expressed, agglutinates the MlP-la and RANTES chemokines. Accordingly, this MIP-l / RANTES receiver was designated as - chemokine receptor C-C (also called CCR-1; Neote, K., et al., Cell, 72: 415-425 (1993); Horuk, R. et al., Patent WO 94/11504, May 26, 1994; Gao, J.-I et al., J. Exp. Med., 177: 1421-1427 (1993)). Three other receptors that agglutinate and / or signal in response to RANTES have been characterized: CCR-3 mediates agglutination and signaling of chemokines including eotaxin, RANTES and MCP-3 (Ponath et al., J. Exp. Med., 183: 2437 (1996)); CCR-4 agglutinates chemokines including RANTES, MlP-la and MCP-1 (Power, et al., J. Biol. Chem., 270: 19495 (1995)); and CCR-5 agglutinates chemokines including MlP-la, RANTES and MlP-lβ (Samson, et al., Biochem 35: 3362-3367 (1996)).

RANTES is a chemotactic chemokine for a variety of cell types, including monocytes, eosinophils, and a subset of T cells. The ability of RANTES to induce targeted migration of monocytes and a circulating T cell memory population (Schall , T. et al., Nature, 347: 669-71 '(1990)), suggests that this chemokine and its receptor (s) play an important role in chronic inflammatory diseases, since these diseases are characterized by destructive infiltrations of T cells and monocytes.

Description of the invention The present invention relates to compounds of the following formula I: to the enantiomers, diastereomers, solvate salts thereof, where: X is a bond or oxygen; is 07 1, 2, 3 or 4; n is O, 1 or 2; R1 is an optional substituent independently selected from each occurrence of halogen, alkyl, haloalkyl, nitro, or -NR5R6; - R2 is: a) hydrogen or b) alkyl, cycloalkyl, alkenyl, aryl or heteroaryl, any of which may be optionally substituted with a group Y; Y is: a) aryl or heteroaryl, any of which may be optionally substituted with one or more Z1, Z2, Z3; b) cycloalkyl or heterocycle, any of which may be optionally substituted with one or more Z1, ?3. c) -COOR7; d) -NR8R9; e) -CHR10 (OR1: L); f) -C (= 0) -NR8R9; g) -NR12- (C = 0) -NR8R9; h) -CN; i) -C (= N-OR13); j) alkoxy; R3 and R are independently selected from: a) hydrogen; b) alkyl, cycloalkyl, (cycloalkyl) alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl, or (heteroaryl) alkyl, any of which may be optionally substituted with one or more Z1, or c) - C (0) R *, -C (0) OR *, -C (0) NHR * O -S02R *; OR R3 and R4 together with the nitrogen atom to which they are linked can be combined to form an optionally substituted heterocycle or heteroaryl ring with one or more Z1, Z2, Z3; R5 and R6 are independently H, -C (0) R *, -S02R *, or -C (0) NR8aR9a; R7, R8, R8A, R9 and R9a are independently: a) hydrogen, or b) alkyl, cycloalkyl, cycloalkyl (alkyl), aryl, (aryl) alkyl, heterocycle, (heterocycle (alkyl), heteroaryl, or (heteroaryl) alkyl, any of which may be optionally substituted with one or more Z1, Z2, Z3; R10 is H, alkyl 'or -OR *; - R11 and R12 are independently H or alkyl; R 13 is alkyl; R * in each occurrence is independently alkyl, cycloalkyl, cycloalkyl (alkyl), aryl, (aryl (alkyl), _ heterocycle, heterocycle (alkyl, heteroaryl, or (heteroaryl (alkyl), any of which may be optionally substituted with one or more Z1, Z 'R and Rb are independently hydrogen, -OR103, alkyl , hydroxyalkyl, or haloalkyl, or Ra and Rb may be combined to form oxo, Rc and Rd in each occurrence are independently H, -OR10b, alkyl or haloalkyl; R10 and R10b are independently hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; Z1, Z2 and Z3 are optional substituents, selected independently from: (1) V, where V is: (i) alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl (alkyl, cycloalkenyl, cycloalkenyl (alkyl), aryl, aryl (alkyl), heterocycle, heterocycle (alkyl, heteroaryl, or heteroaryl (alkyl); (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) < 3ue is independently substituted by one or more (preferably from 1 to 3) of the following groups (2) to (13) of the definition of Z1 , (2) -OH or -0V, (3) -SH or -SV, (4) -C (0) H, -C (0) '0H, -C (0) V, -C (0) 0V or -0-C (0) V, (5) -S03H, -S (0) tV or SÍOJt fV ^ V where t is 1 or 2, (6) halo, (7) cyano, (8) nitro, (9) -i1-NV2V3, (10) -tk-N (V1) -U2-NV2V3, (11) -i1-N (V4) -2 -Vf (12) -U1-N (V) -Ü2-H, (13) oxo; U1 and U2 are each, independently: (1) in single bond, (2) -3-S (0) t-U4-, (3) -U3-C (0) -U4-, (4) -U3 -C (S) -Ü4-, (5) -U3-0-U4-, (6) -U3-S-U4-, (7) -U3-0-C (0) -U4-, (8) -U3-C (0) -O-U4-, (9) -U3-C (= NVla) ~ U4-, or (10) -uc (?) - c (?) -? R V1, Vla, V2, V3 and V4: • (1) are each independently hydrogen or a group provided in the definition of Z1; or (2) V2 and V3 together can be alkylene or alkenylene, completing a saturated or unsaturated ring of . 3- to 8-members together with the atoms to which they are attached, ring which is unsubstituted or substituted with one or more of the groups listed in the definition of Z1, or (3) V2 or V3 together with V1, may ' to be alkylene or alkylene which completes a saturated or unsaturated ring of 3- to 8-members together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more of the groups listed in the definition of Z1, and ü3 and ü4 are each, independently: (1) a single link; (2) alkylene, (3) alkenylene, or (4) alkynylene.

The formula above includes separate chiral species, p. ex. , diastereomers and enantiomers, as well as all mixtures thereof, e.g. ex. , racemates, etc.

The compounds of the present invention are useful in the prevention and treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases, allergic conditions, ac conditions, as well as autoimmune and immunodeficiency pathologies.

Also included in the invention are methods of using the compounds as agents for the treatment of disease states mediated by CCR-5, in particular for the treatment of inflammatory diseases or conditions, autoimmune disorders, and immunodeficiency disorders such as infection. for HIV.

In another aspect, the present invention can be used to evaluate specific antagonists of CCR-5 receptors. Accordingly, the present. invention is directed to the use of these compounds in the preparation and execution of screening tests for compounds that modulate the activity of CCR-5 receptors. For example, the compounds of this invention are useful for isolating receptor mutants, which are excellent tracking tools for more powerful compounds. Further, • the compounds of this invention are useful for establishing or determining the binding site of other compounds for CCR-5 receptors, e.g. ex. , by inhibition competitive.

The compounds of the invention can be used in • the treatment of mammals, preferably humans, which comprises administering to the mammal in need of an effective amount of a compound of the formula '- (I), or a pharmaceutically acceptable salt thereof, bptionally in the form of a separate diastereomer or enantiomer, e.g. ex. , less than 5%, 2%, or less of the other (s) 'chiral entity (s) (is). Preferred R2 groups include alkyl (especially methyl) substituted with Y, where Y is aryl (especially phenyl), cycloalkyl (especially cyclopropyl), -CHR10 (OR11), or heterocycle (especially 5-1,3 dioxolanyl), any of which may be optionally substituted with one or more Z1, Z2, Z. Preferred R2 groups include the following: - preferable -NR R groups include those in which R3 and R4 are independently H, alkyl, hydroxy (alkyl), (heteroaryl) alkyl (especially (pyridyl) alkyl), (heterocycle) alkyl (especially (morpholinyl) alkyl) or -C (0) NHR *, any of which may be optionally substituted with one or more Z1, Z2, Z3. Preferred -NR3R4 groups further include those groups in which R3 and R4 together with the nitrogen atom to which they are linked, combine to form a heterocycle or heteroaryl ring optionally substituted with one or more Z1, Z2, Z3, such as: The groups -NR > Preferred 3n R4 include the following: -lß- fifteen Preferred compounds of the formula I include the compounds of the following formula II: p enantiomers, diastereomers, salts and solvates thereof, where: m * is 0, 1, 2 or 3; Rla is halo (especially bromine); and X, R1, R2, R3, R4, Ra, Rb, Rc, Rd and n are defined as above in the formula I (including the preferable groups).

Preferred compounds of formula II include the compounds of the following formula III: m enantiomers, diastereomers, salts and solvates thereof, wherein: Z1 is halo (especially chloro), cyano, alkyl, haloalkyl, aryl, -C (0) OH, -C (0) V, -C (0) OV, o -ü ^ -NVk / 3 (especially where ü1 is -C '(O) -); Z2 and Z3 are optional substituents as defined above in formula I; and X, R1, Rla, R2, R3, R4, Ra, Rb, Rc, Rd and n and m * are defined above in formula II (including preferred groups).

Other preferred embodiments of the present invention include: a) a pharmaceutical composition comprising a compound of formula I in admixture with a pharmaceutically acceptable excipient, diluent or carrier; b) a method for modulating the activity of the chemokine receptor in a patient (eg, a mammal, eg, human) comprising administering an effective amount of a compound of the formula I; c) a method for the prevention or treatment of an inflammatory or unreasonable disorder or disorder, comprising administering to a patient an effective amount of a. composed of the formula I; d) a method for the prevention or treatment of asthma, allergic rhinitis, dermatitis, conjunctivitis or atherosclerosis, comprising administering to a patient an effective amount of a compound of the formula I; e) a method for prevention or treatment. of rheumatoid arthritis, comprising administering to a patient an effective amount of a compound of formula I; f) a method for preventing HIV infection, treating HIV infection, slowing the progression of AIDS, or treating AIDS, which comprises administering to a patient an effective amount of a compound of formula I; g) a method for the prevention or treatment of multiple sclerosis or psoriasis, which comprises • administering to a patient an effective amount of a compound of formula 1; h) a method for inhibiting the binding of MlP-la or MlP-lβ to a receptor, which comprises administering a therapeutically effective amount of a 'compound of formula I to a mammal in need thereof; i) a method for inhibiting the binding of RANTES to a receptor, comprising administering a therapeutically effective amount of a compound of formula I to a mammal in need thereof; Y j) a method for testing compounds that modulate the activity of a CCR-5 receptor, which comprises tracing it against a compound of the formula (I).

The preferable compounds of the formula (I) are: N - [[5-bromo-2- (4-chlorophenylmethoxy) phenyl] methyl] morpholinoethanamine dihydrochloride; -Bromo-2- (4-chlorophenylmethoxy) -N, N-diethylbenzonemethanamine hydrochloride; [[[[5-Bromo-2- (4-chlorophenylmethoxy) phenyl] methyl] amino] -2-propanol hydrochloride; L - [[5-bromo-2- (4-chloropheylmethoxy) phenyl] methyl] -4-ethylpiperazine dihydrochloride; N - [[5-bromo-2- (4-chlorophenylmethoxy) phenyl] methyl] -N ', N' -dimethylpropanediamine dihydrochloride; 3 - [[4-Bromo-2- '[(diethylamino) methyl] phenoxy] methyl] benzoic acid methyl ester hydrochloride; 4 - [[5-bromo-2- [(4-chlorophenyl) methoxy)] phenyl] methyl] thiomorpholine; -bromo-2 ~ [(4-chlorophenyl) methoxy)] - N-methyl-N- (phenylmethyl) benzenemethanamine; -bromo-2- [(4-chlorophenyl) methoxy)] - N-ethylbenzene ethanamine; 4 - [[5-bromo-2- [(4-chlorophenyl) methoxy)] phenylmethyl] morpholine; -bromo-2- [(4-chlorophenyl) methoxy)] - N- (phenylmethyl) benzenemethanamine; -bromo-2- [(4-chlorophenyl) methoxy)] - N, N-dimethyl-benzenemethanamine; 1, 1-dimethylethyl ester of. [l - [[5-Bromo-2 [(4-chlorophenyl) methoxy] phenyl] methyl] -3-pyrrolidinyl] carbamic acid; 3 - [[4-Bromo-2- [(diethylamino) methyl] phenoxy] methyl] benzoic acid methyl ester hydrochloride; l - [[5-Bromo-2 - [(4-iodophenyl) methoxy] phenyl] methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-iodo-enyl) -methoxy] -f-enyl] -methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-methyl-f-enyl) -methoxy] -phenyl] -methyl] -4-piperidinol; . l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinol; l - [[5-Bromo-2- [(6-methyl-3-pyridinyl) methoxy] phenyl] methyl] -4-piperidinol; l - [[4-br'omo-2- [(6-methyl-3-pyridinyl) methoxy] phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol; 4 - [[4-chloro-2- (4-morpholinylmethyl) phenoxy] methyl] benzonitrile; 4 - [[4-chloro-; 2- (1-pyrrolidinylmethyl) phenoxy] methyl] benzonitrile; l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -3-piperidinomethanol; - N - [[5-bromo-2- (4-chlorofenylmethoxy) phenyl] methyl] -N- (3-dimethylaminopropyl) -N'-phenylurea hydrochloride; 4 - [[4 ~ b] As ~ 2- [(dimethylamino) methyl] phenoxy] methyl] -N- (3, 4-dimethoxyphenylmethyl) benzamide hydrochloride; -Bromo-2 - [[4 - [(6,7-dimethoxy-3,4-dihydro-5,2 (1 H) -isoquinolinyl) carbonyl] phenyl] methoxy] -N, N-dimethylbenzenemethanamine hydrochloride; • 4-bromo-2- (bromomethyl) -l- [(4-chlorophenyl) methoxy] benzene; 0 '2 - [[[[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] amino] -l, 3-. propanediol; (2R) -l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -2-pyrrolidinemethanol trifluoroacetic acid salt; (2S) -l - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -2-pyrrolidinomethanesulfuryl acetic acid salt; (2R) -l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -3-pyrrolidinol trifluoroacetic acid salt; Na - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyljmethyl-N 1 - ^ - (diethylamino) ethyl] -N 2, N 2 -diethyl-1,2-ethanediamine; l - [[5-Bromo-2- [(4-chlorofenyl) et oxy] phenyl] met il] -4-. piperidinone; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] f-enyl] methyl] -4- (4- (bromophenyl) -4-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] f-enyl] methyl] -4-piperidinol;; 1, 1-dimethylethyl ester of [l - [[5-bromo-2- [(4- (chlorofenyl) methoxy] phenyl] methyl] -4-piperidinyl] -carbamic acid; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] f-enyl] methyl] -4-ethoxy-piperidine; 8 - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -1,4-dioxa-8- 'azaspiro [4.5] decane; [1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] methyl] carbamic acid 1, 1-dimethyl ester; -bromo-2- [(4-chlorofinyl) met oxy] benzenemethanamine; 1 - [[5-Bromo-2- [(4-chlorophenyl) methoxy] f-enyl] methyl] pyridinium bromide; Ethyl ester of l - [[5-bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -4-piperidinocarboxylic acid; 2 - [[[5-Bromo-2- [(4-chloro-enyl) -methoxy] -6-enyl] -methyl] -amino] -ethanol; 2 - [[[5-bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] (methyl) amino] -ethanol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -3-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -3-pyrrolinidol; (SS, 2S) -2 - [[[5-bromo-2- [(4-chloro-enyl) -methoxy] -fenyl] -methyl] -amino] -l- (4-nitrophenyl-1,3-propanediol; -Bromo-2- [(4-chlorofenyl) methoxy] -N, N, N-trimethyl-benzenemethanaminium iodide; (3R, 4S) -l - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -3,4-pyrr olidinodiol; L - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinocarboxylic acid; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4- 'piperidinamine; l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4- - - piperidinemethanamine; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -N-methyl-4-piperidinemethamine; [L - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] (ethyl) carbamic acid 1, 1-dimethylethyl ester; [L - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] (methyl) carbamic acid 1, 1-dimethylethyl ester l - [[5-Bromo-2- [(4-chlorophenyl) met oxy] phenyl] methyl] ^ N, N-diethyl-4- 'piperidinamine; N- [1 - [[5-bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -4-piperidinyl] -N '- (4-fluorophenyl) -urea; N- [l - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -3-pyrrolidinyl] -N '- (4-f luorofenyl) -urea; N - [[1 - [[5-bromo-2 - [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-piperidinyl] methyl] -N '- (4-f luorofenyl) -N-methyl -urea; N - [[1 - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] methyl] -N '^ [(4-f luorofenyl) methyl] -N- methyl-urea; N- [1 - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -3-pyrrolidinyl] -2-chloroacetamide; N- [[1 - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-piperidinyl] methyl] acetamide trifluoroacetic acid salt; Get ouf of . N- [l - [[5-bromo-2 - [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-piperidinyl] acetamide trifluoroacetic acid; N- [l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -3-pyrrolidinyl] -N-methyl-2-pyrazinecarboxamide; N - [[1 - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] methyl] -N, 4-dimethyl-3-piperidinecarboxamide; [L - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] carbamic acid methyl ester; 4 - [[4-Bromo-2- [(diethylamido) methyl] phenoxy] methyl] benzoic acid; . 5-bromo-N, N-diethyl-2 - [[4 - [[4- (phenylmethyl) -1- piperazinyl] carbonyl] phenyl] methoxy] benzenemethanaruine; N- (1,3-benzodioxo-5-ylmethyl) -4 - [[4-bromo-2- [(diethylamino) met yl] phenoxy] met il] benzamide; - 4 - [[4-bromo-2- [(diethylamino) methyl] phenoxy] methyl] -N- [(4-methoxy-phenyl) -methyl-benzamide; 4 - [[4-bromo-2- [(diethylamino) methyl] phenoxy] methyl] -N-methyl-N- (2-f-phenylethyl) benzamide; 4 - [[4-Bromo-2- [(diethylamino) methyl] phenoxy] methyl] -N- [2- (.4-bromo-phenyl) -ethyl] -benzamide; 4- [4 - [[4-bromo-2- [(diethylamino) methyl] f-enoxy] methyl] benzoyl] -N-octyl-1-piperazinecarboxamide; -bromo-N, N -diethyethyl-2 - [[4 - [[4 - [[3-nitrophenyl] sulfonyl] -l-piper acinyl] carbonyl] phenyl] methoxy] benzenemethamine; -bromo-N, N-diethyl-2 ~ [[4 - [[4- (2-furanylcarbonyl) -l-? Piperazinyl] carbonyl] phenyl] methoxy] benzenemethamine; -bromo-2 - [[4 - [[4- (2,6-dichlorobenzoyl) -l-piperazinyl] carbonyl] phenyl] methoxy] -N, N-diethylbenzenemethanamine; N - [[5 - [[4- [4 - [[4-bromo-2- [(diethylamino) methyl] phenoxy] methyl] -benzoyl] -l-piperazinyl] sulfonyl] -2-thienyl] methyl] benzamide; l- [(5-Bromo-2-propoxyphenyl) methyl] -4- (4-fluorophenyl) -4-piperidinol; [4-bromo-2 - [[4- (4-bromophenyl) -4-hydroxy-l- 'piperidinyl] methyl] f enoxy] -0-ethyloxymethanal; l- [(5-Bromo-2-propoxyphenyl) methyl] -4- (4-chlorofenyl) -4-piperidinol; l - [[5-Bromo-2- (pentyloxy) phenyl] mef il] -4- (4-bromo-phenyl) -4-piperidinol; l - [[5-Bromo-2- (hexyloxy) f-enyl] methyl] -4- (4-bromo-phenyl) -4-piperidinol; l- [(5-Bromo-2-methoxyphenyl) methyl] -4- (4-bromo-phenyl) -4-. piperidinol; • l - [[5-Bromo-2- (1,3-dioxolan-2-ylmethoxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol; l - [(5-Bromo-2-hydroxyphenyl) methyl] -4- (4-bromophenyl) -4-piperidinol; 'l - [[5-bromo-2- (2-methylpropoxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol; L - [[5-bromo-2- (heptyloxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol trifluoroacetic acid; L - [[5-bromo-2- (cyclopropylmethoxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol trifluoroacetic acid; L - [(5-bromo-2-butoxyphenyl] methyl] -4- (4-bromophenyl) -4-piperidinol trifluoroacetic acid; L - [[5-bromo-2- (2-methoxyethoxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol trifluoroacetic acid; 4- (4-Bromophenyl) -l- [(5-bromo-2-propoxyphenyl) methyl] -4-piperidinol trifluoroacetic acid; L- [(5-bromo-2-ethoxyphenyl) methyl] -4- (4-bromofenyl) -4-piperidinol trifluoroacetic acid; 4- (4-Bromophenyl) -l - [[5-bromo-2- (2-propenyloxy) phenyl] methyl] -4-piperidinol trifluoroacetic acid; Acid [(5-bromo-2 - [[4- (4-bromofenyl-4-hydroxy-l-piperidinyl] methyl] phenoxy] -acetonitrile trifluoroacetic acid; N- [2- [4-bromo [2 - [[4- (4-bromophenyl) -4-hydroxy-l-piperidinyl] methyl] phenox] ethyl] -N '-ethyl-urea; l - [[2- (2-aminoethoxy) -5-bromofenyl] methyl] -4- (4-bromofenyl) -4-piperidinol: 2-bromo-l- [5-bromo-2- [(4- chlorofenyl) methoxy] f enyl] -ethanone; 4 - [[4-Bromo-2- (bromoacetyl) phenoxy] methyl] benzoic acid methyl ester; l- [2 ~ ([1, V-bifenyl] -4-ylmethoxy) -5-bromophenyl] -2-bromoethanone 3 - [[4- [4 - [[4-bromo-2- (bromoacetyl) phenoxy] methyl] benzoyl] -l-piperazinyl] sulfonyl] -N-hydroxy-N-oxo-benzenamino; 2-bromo-l- [5-bromo-2- [(4-chlorofenyl) methoxy] phenyl] -l-propanone l- [5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] -2- (dimethylamino) - • ethanone; l- [2- ([l, 1'-biphenyl] -4-ylmethoxy) -5-bromophenyl] -2- (dimethylamino) -ethanone; l- [2- ([1,1'-bifenyl] -4-ylmethoxy) -5-bromofenyl] -2- • bromoet anona; -Bromo-2- [(4-chlorophenyl) xt? Ethoxy] -a - [[(2-hydroxyethyl) (methyl) amino] methyl] benzene-methanol trifluoroacetic acid salt; "Salt of acid to ~ [5-bromo-2 ~ [(4-chlorophenyl) methoxy] phenyl] -3-hydroxy-1-piperidinoethanol trifluoroacetic; Salt of a- [5-bromo-2- [(4-chlorofenyl) methoxy] phenyl] -3-hydroxy-1-pyrrolidinoethanol trifluoroacetic acid; (2S, 4R) -l- [2- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2-hydroxyethyl] -4-hydroxy-2-pyrrolidinecarboxylic acid trifluoroacetic acid salt; -Bromo-2- [(4-chlorophenyl) methoxy] - - [(dimethylamino) methyl] benzenemethanol trifluoroacetic acid salt; 2 ~ Amino-oí- [5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] -lH-imidazole-1-ethanol; - [5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] -4-hydroxy-1-piperidinoethanol; Trifluoroacetic acid salt of 4 - [[4-bromp-2- [l-hydroxy-2- (4-hydroxy-l-piperidinyl) ethyl] f enoxy] methyl] benzoic acid methyl ester; Trifluoroacetic acid salt of 4 - [[4-bromo-2- [l-hydroxy-2- (3-hydroxy-l-piperidinyl) ethyl] f-enoxy] methyl] benzoic acid methyl ester; 4 - [[4-Bromo-2- [2- [4 - [[(1,1-dimethylethoxy) carbonyl] amino] -l-piperidinyl] -l-hydroxyethyl] -hexano] methyl] benzoic acid methyl ester; 2- [[1, 1 '-bifinyl] -4-ylmethoxy) -5-bromo-a- [(dimethylamino) methyl] -benzenemethanol trifluoroacetic acid salt; 4 - [[4-Chloro-2- [l-hydroxy-2- (4-hydroxy-l-piperidinyl) ethyl] phenoxy] methyl] benzoic acid; . l- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2- (dimethylamino) -1-propanone; -Chloro-2- [(4-chlorophenyl) met oxy] -α- [- l- (dimethylamino) ethyl] benzenemethanol; • α- [5-Chloro-2- [(4-chloro-enyl) -methoxy] -phenyl] -β-methyl-1H-imidazole-1-ethanol; a- [5-chloro-2- [(4-chlorophenyl) methoxy] phenyl] -4- (4-chloro-enyl) -4-hydroxy-β-methyl-1-piperidinoethanol; • - [5-chloro-2- [(4-chlorofenyl) met oxy] phenyl] -4-hydroxy-β-methyl-4- (phenylmethyl) -1-piperidinoethanol; a- [5-chloro-2- [(4-chlorophenyl) methoxy] phenyl] -4- (4-f luorofenyl) -4-hydroxy-β-methyl-1-ylperidinoethanol; '5-chloro-2- [(4-chlorophenyl) methoxy] -a- [l- (diethylamino) ethylbenzenemethanol; a- [5-Bromo-2 - [[4 - [[4- [(3-nitrofenyl) sulf onyl] -l-piperazinyl] carbonyl] f-enyl] methoxy] phenyl] -3-hydroxy-1-piperidinoethanol; carbonyl] phenyl] methoxy] phenyl] -4-hydroxy-l-piperidinoethanol; a- [5-Bromo-2 - [[4 - [[4- [(3-nitrophenyl) sulfonyl] -l-piperazinyl] cafbonyl] phenyl] methoxy] phenyl] -3-hydroxy-l-pyrrolidinoethanol; -bromo-a- [(diethylamino) methyl] -2 - [[4 - [[4- [(3-nitrophenyl) sulfonyl] -l-piperazinyl] carbonyl] phenyl] methoxy] benzenemethanol; a- [5-Bromo-2- [(4-chlorofenyl) met oxy] phenyl] -l-piperazineethanol; - [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -4- (3-pyridinylcarbonyl) -1-piperazineethanol; - a- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -4- [(4-methyl-3-pyridinyl) carbonyl] -1-piperazineethanol; Methyl ester of 4 - [[4-bromo-2- [l-hydroxy-2- [4- [[(f-enylmethoxy) carbonyl] amino] -l-piperidinyl] ethyl] -f-enoxy] -methyl-benzoic acid; 4 - [[4-bromo-2- [l-hydroxy-2- (4-hydroxy-1-piperidinyl) ethyl] phenoxy] methyl] -N- (4-pyridinyl) benzamide; '4 - [[4-chloro-2- [l-hydroxy-2- (4-hydroxy-l- 4 - [[4-chloro-2- [l-hydroxy-2- (4-hydroxy-l-piperidinyl ) ethyl] phenoxy] methyl] -N- (3-hydroxypropyl) benzamide; 2- [5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] oxirane; 1- (2S) -a- [5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] -2- (hydroxymethyl) -1-pyrrolidinoethanol trifluoroacetic acid salt; (2R) -a- [5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] -2- (hydroxymethyl) -1-pyrrolidinoethanol trifluoroacetic acid salt; (3R) -a- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -3-hydroxy-l-pyrrolidinoethanol trifluoroacetic acid salt; -Bromo-2- [(4-chlorophenyl) methoxy] -a - [[2- (diethylamino) ethyl] ethylamino] methyl] -benzenemethanol trifluoroacetic acid salt; Salt of a- [5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] -1,4-piperidinodiethanol trifluoroacetic acid; a- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -4- (piperidyl) -1-piperidinoethanol; Salt of 5-bromo-2- [(4-chlorophenyl) methoxy] -a- salt of a- [5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] -4- (phenylmethyl) -1 acid -piperidinoethanol trifluoroacetic; -Bromo-2- [(4-chlorophenyl) methoxy] -a- [(dibutylamino) methyl] -benzenemethanol trifluoroacetic acid salt; -bromo-a [(butylethylamino) methyl] -2- [(4-chlorophenyl) methoxy] -benzenemethanol; . 5-Bromo-2- [(4-chlorophenyl) methoxy] -a - [[ethyl (2-hydroxyethyl) amino] methyl] -benzenemethanol trifluoroacetic acid salt; -Bromo-2- [(4-chlorophenyl) methoxy] -a - [[(2-hydroxyethyl) propylamino] methyl] -benzenemethanol trifluoroacetic acid salt; L- [2- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2-hydroxyethyl] -N, N-diethyl-3-piperidinocarboxamide trifluoroacetic acid salt; Salt of α- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -4- (4-bromophenyl) -4-hydroxy-1-piperidinoethanol trifluoroacetic acid; Salt of l- [l- [2- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2-hydroxyethyl] -4-piperidinyl] -l, 3-dihydro-H-benzimidazole-2 - trifluoroacetic ona; Exit of -l- [2- [5-bromo-2- [(4-chlorofenyl) methoxy] fyl] -2- acid. hydroxyethyl] -4-phenyl-4-piperidinocarbonitrile trifluoroacetic; Salt of a- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -1,4-dioxa-8-azaspiro [4.5] decane-8-ethanol trifluoroacetic acid; - Salt of 5-bromo-2- [(4-chlorophenyl) methoxy] -a - [[(2-hydroxyethyl) (phenylmethyl) amino] methyl] -benzenemethanol trifluoroacetic acid; -Bromo-2- [(4-chlorophenyl) methoxy] -a - [[[2- (dimethylamino)] ethyl] ethylamino] methyl] -benzenemethanol trifluoroacetic acid salt; Salt of a- [5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] -1,2,3,4,4-tetrahydro-l-quinolinoethanol trifluoroacetic acid; L- [2- [5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] -2-hydroxyethyl] -3,4-pyrrolidinodiol trifluoroacetic acid salt; • -Bromo-2- [(4-chlorophenyl) methoxy] -a- [(methylamino) methyl] -benzenemethanol trifluoroacetic acid salt; 2 - [[2- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2-hydroxyethyl] amino] -1,3-propanediol trifluoroacetic acid salt; -Bromo-2- [(4-chlorophenyl) methyxy] -a- [(diethylamino) methyl] -benzenemethanol-trifluoroacetic acid salt; 2 - [[2- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2-hydroxyethyl] amino] -2- (hydroxymethyl) -1,3-propanediol; - c- [5-bromo-2- [(4-chlorophenyl) methoxy] f-enyl] -l-pyrrolidinoethanol; a- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -l-piperidinoethanol; -bromo-2- [(4-chlorofenyl) methoxy] -a - [[(3-hydroxy-enyl) amino] methyl] benzenemethanol; -bromo-2- [(4-chlorophenyl) methoxy] -a- [[(cyclopropylmethyl) amino] methyl] benzenemethanol; -bromo-a - [[[2- (3-chlorophenyl) ethyl] amino] methyl] -2- [(4-chlorophenyl) methoxy] benzenemethanol; a- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -l-acetidinoethanol; . 5-bromo-2 - [(4-chlorophenyl) methoxy] -a - [(ethylmethylamino) methyl] benzenemethanol; ' -bromo-2- [(4-chlorophenyl) methoxy] -a- [(cyclopropylamino) methyl] benzenemethanol; • 5-Bromo-2 - [(4-chlorophenyl) methoxy] -a- [[(cyclopropylmethyl) m.ethylamino] methyl] benzenemethanol; - [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -4-thiomorpholinoethanol; • a ~ (Aminomethyl) -5-bromo-2 - [(4-chlorophenyl) methoxy] benzenemethanol; -bromo-2- [(4-chlorophenyl) methoxy] -a- [(cyclopropylmethylamino) methyl] benzenemethanol; (aS) -5-bromo-2- [(4-chlorophenyl) methoxy] -a- [(diethylamino) methyl] benzenemethanol; (aR) -5-bromo-2- [(4-chlorophenyl) methoxy] -a- [(diethylamino) methyl] benzenemethanol; a - [[bis (2-hydroxyethyl) amino] methyl] -5-bromo-2- [(4-chlorofenyl) methoxy] benzene-anol; a-5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] -4-methyl-1-piperazine-ethanol; -bromo-2- [(4-chlorofenyl) methoxy] -a - [[(1-methylethyl) amino] methyl] benzenemethanol; a- [5-Bromo-2- [(4-chlorophenyl) methoxy] -phenyl] -4-morpholinoethanol; -bromo-2- [(4-chlorophenyl) methoxy] -a - [[(2-hydroxyethyl) amino] methyl] -benzenemethanol; -bromo-2- [(4-chlorophenyl) methoxy] -a - [[(2-hydroxyethyl) amino] met yl] -benzenemethanol; -bromo-2- [(4-chlorofenyl) methoxy] -a-ethoxy-N, N-diethylbenzene-et anamine; -bromo-2- [(4-chlorophenyl) methoxy] -N, N-diethyl-a- (2-pyrynyloxy-benzeneethamine; -bromo-2- [(4-chlorofenyl) methoxy] -a- (methylamino) benzeneethanol l- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2-propen-l-one; (3R) - (X- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -3-hydroxy-1-pyrrolidinepropanol; -bromo-2 - [(4-chlorophenyl) methoxy] -a- [2- (dimethylamino) ethyl] -benzenemethanol; a- [5-bromo-2- [(-chlorophenyl) methoxkjphenyl] -4-hydroxy-l-piperidinopropanol; -bromo-2- [(4-chlorophenyl) methoxy] -a- [2- (dipropylamino) ethyl] -benzenemethanol; -bromo-2- [(4-chlorophenyl) methoxy] -a- [2- (diethylamino) ethyl] -benzenemethanol; -chloro-2- [(4-fluorophenyl) methoxy] benzeneethanamine; N - [[2- [5-chloro-2- [(4-fluorophenyl) methoxy] -phenyl] ethyl] -4-piperidinomethanamine; -chloro-2 - [(4-fluorophenyl) methoxy] -N, N-a-trimethylbenzeneethanamine; 4 - [[[2 [5-chloro-2- [(4-fluorofenyl) methoxy] f-enyl] ethyl] amino] methyl] benzonitrile; N- [2- [5-chloro-2 - [[(4-f luorofenyl) methoxy] phenyl] ethyl] -N - (lH-imidazol-5-ylmethyl) -lH-imidazole-4-methylamine; -Chloro-a-ethyl-2- [(4-fluorophenyl) methoxy] -N- [(4-fluorofenyl) methyl] benzeneethanamine; -chloro-a-ethyl-2- [(4-f luorofenyl) methoxy] -N- [(3-methyl-4-ethoxy-enyl) methyl] benzeneethanamine; Methyl ester of l - [[5-bromo-2- [(4-chlorophenyl) rato-oxy] -f-enyl] -methyl] -4-hydroxy-4-piperidine-carboxylic acid; L - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-hydroxy-4-piperidinecarboxylic acid; 4 - [[1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] carbonyl] -l-piperazineethanol; l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4- (1-piperazinylcarbonyl) -4-piperidinol; l - [[5-Bromo ~ 2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[(3R) -3-methylpiperazinyl] carbonyl] 4-piperidinol; 1, 4- [1 - [[5-bromo-2- [(4-chlorofennyl) -ethoxy] -f-enyl] -methyl] -4-piperidinyl] -l-piperazinecarboxylic acid i-dimethylethyl ester; l- [l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-piperidinyl] piperazine; l- [l - [[5-Bromo-2- [(4-chlorofenyl) methox-jf-enyl] methyl] -4-piperidinyl] -4- [(2, -dimethyl-3-pyridinyl) carbonyl] -piperazine; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -3-methyl-4-piperidinone; . l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -3-methyl-4-piperidinol; . _ 'l - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4,4'-difluoropiperidine; • 8 - [[5-bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -l, 3, 8-triazaspirol [4. 5] decane-2,4-dione; l - [[5-Bromo ~ 2- [(4-chlorofenyl) methoxyjf enyl] methyl] -4-phenyl-4-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-ethyl-4-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4- (trifluoromethyl) -4-piperidinol; l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -4-piperidinone oxime; l - [[5-Bromo-2 - [[(4- (trifluoromethyl) f-enyl] methoxy] f enikylmethyl] -4-fluoropiperidine; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4- (2-pyridinyloxy) piperidine; 2 - [[1 - [[5-bromo-2- [(4- (chlorophenyl)] methoxy] phenyl] methyl] -4-piperidinyl] oxy] pyrimidine; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -N-ethyl-4-piperidinamine; 6 - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -l-oxa-6- azaspiro [2.5] octane; 4- (aminomethyl) -l - [[5-bromo-2- [(4-chlorophenyl) methoxy] f-enyl] methyl] -4-piperidinol; l - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4 - [[[[1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] ] methyl] ~ 4-hydroxy-4-piperidinyl] methyl] amino] methyl] -4-piperidinol; 1, 1-dimethylethyl ester of 4 - [[1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -1-piperazinecarboxylic; 1, 1-dimethylethyl 4 - [[1 - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-hydroxy-4-piperidinyl] methyl] hexahydro-lH acid ester -l, 4-diazepine-l-carboxylic acid; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[4- (2-pyridinyl) -l-piperazinyl] methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[4- (2-pyridinyl) -l-piperazinyl] methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4- (1-piperazinylmethyl) -4-piperidinol; l - [[5-Bromo-2- [(4-chlorofenyl) methoxyjfenyl] methyl] -4 - [(hexahydro-lH-1,4-diazepin-1-yl) methyl] -4-piperidinol; l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[(4-methylphenyl) amino] methyl] -4-piperidinol; l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[(4-methoxyphenyl) amino] methyl] -4-piperidinol; l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[(3S) -3-methylpiperazinyl] methyl] -4-piperidinol; l - [[5-Bromo ~ 2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4- [(2,5-dimethyl-l-piperazinyl) methyl] -4-piperidinol; 4 - [[(3-aminopropyl) to ino]? T? Ethyl] -lr [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinol; l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[[(2- (l-piperidinyl) ethyl] amino] met il] -4-piperidinol; 1, 1-dimethylethyl ester of acid. 2 - [[[[1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] amino] methyl] -l-pyrrolidinecarboxylic acid; l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[(2-pyrrolidinylmethyl) amino] met il] -4-piperidinol; l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[4 - [(2,4-dimethyl-3-pyridinyl) carbonyl] -l-piperazinyl] methyl] -4- piperidinol; Ethyl 4 - [[1 - [[5-bromo-2- [(4-chloro-enyl) -methoxy] -fine] -methyl] -4-hydroxy-4-piperidinyl] -methyl] -1-piperazinecarboxylic acid ester; 4- [(4-acetyl-l-piperazinyl) methyl] -l - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-piperidinol; l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [(1-piperacylamino) methyl] -4-piperinidol; 4 - [[1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -1-piperazineethanol; 4 - [[1 - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -l-piperazinecarboxaldehyde; 4 - [[1 - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] phenylmethyl ester] -1-piperazinecarboxylic; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[4- (phenylmethyl) -l-piperazinyl] methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy] -fenyl] -methyl] -4 - [[(2-methylphenyl) amino] methyl] -4-piperidinol; l - [[1 - [[5-Bromo-2- [(4-chloro-enyl) -methoxy] -fenyl] -methyl] -4-hydroxy-4-piperidinyl] -methyl] -4-piperidinecarboxamide; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[(3 S) -3-methylpiperazinyl] methyl] -4-piperidinol; 4 - [[1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -2-piperazinone; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[(3 S) -3- et ilpiperazinyl] methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4- [(3,5-dimethyl-1-piperazinyl) methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy] -fenyl] -methyl] -4- (2, 5-diazabicyclic [2.2.1] hept-2-ylmethyl) -4- piperidinol; 1, 1-dimethylethyl ester of [l - [[1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -3-pyrrolidinyl ] carbamic; 4- [(3-amino-l-pyrrolidinyl) methyl] -l - [[5-bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4 - [[4- [2- (dimethylamino) ethyl] -l-piperazinyl] methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[4- [2- (4- 'morpholinyl) -2-oxoetyl] -l-piperazinyl] methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[4- [3- (4-morpholinyl) propyl] -l-piperazinyl] methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[4- [2- (4-morpholinyl) ethyl] -l-piperazinyl] methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy] -fenyl] -methyl] -4- [(dimethylamino) methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4- [(diethylamino) met il] -4-piperidinol; l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy.i] phenyl] methyl] -4 - [[(1-ethylethyl) amino] methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy] -fenyl] -methyl] -4- [(4-hydroxy-l-piperidinyl) methyl] -4-piperidinol; l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[(3R) -3-hydroxypyrrolidinyl] methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4 - [[[(4-f-lorofenyl) methyl] amino] -nethenyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chlorofenxl) methoxy] f-enyl] methyl] -4- (1H-imidazol-1-ylmethyl) -4-piperidinol; l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [(phenylamino) methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [(4-pyridinylamino) methyl] -4-piperidinol; l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[(2-hydroxyethyl) methylamino] methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4- [(4-methyl-1-piperazinyl) methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chloro-enyl) -ethoxy] -fenyl] -methyl] -4- [(dipropylamino) methyl] -4-piperidinol; - - - ' l ~ [[- 1 - [[5-Bromo ~ 2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N, N-diethyl-3-piperidinecarboxamide; - l - [[5-Bromo-2 ~ [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[(2, 2, 2-trifluoroethyl) amino) ethyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy] -fenyl] -methyl] -4 - [[(3-methylphenyl) amino) methyl] -4-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[[(IR) -1- phenylethyl] amino] methyl] -4-piperidinol; 4 - [[- 1 - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-. hydroxy-4-piperidinyl] methyl] -N-yl-1-piperazinecarboxamide; N - [[- l ~ [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N '- (2,6-difluorofenyl) ) urea; N - [[- 1 - [[5-bromo-2- [(4-chloro-enyl) -methoxy] -fenyl] -methyl] -4-hydroxy-4-piperidinyl] -methyl] -N '- (2,6-dimethoxyphenyl) ) urea; N - [[- l - [[5-Brorao-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N '- (2,6-diethylphenyl) urea; N - [[- 1 - [[5-bromo-2- [(4-chloro-enyl) -methoxy-fyl] -methyl] -4-hydroxy-4-piperidinyl] -methyl] -N '- (2,4,6-trichlorophenyl) ) urea; N - [[- l ~ [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N '- (2,6-dichlorophenyl) urea; N - [[- 1 - [[5-Brorao-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N '- (2,6-dimethylphenyl) urea; N - [[- 1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4- • hydroxy-4-piperidinyl] methyl] -N '- (2,6-dibromofenyl) ) urea; N - [[- 1 - [[5-bromo-2- [(-chlorofenyl) met.ox xjf-enyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N '- (4-bromo-2, 6-dimethylphenyl) urea; N- [2,6-Bis (1-methylethyl) phenyl] -N '- [[- 1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4 - piperidinyl] methyl] urea; N - [[- 1 - [[5-Bromo] 2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N '- (4-fluorophenyl) urea; 2-amino-N - [[- 1 - [[5-brort? O-2- [(4-chlorophenyl) methox-i] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] acetamide; N- [2 - [[[1 - l - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] amino] -2-oxoethyl] - 2,6-difluorobenzamide; N - [[- l ~ [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-hydroxy-4-piperidinyl] methyl] benzamide; N - [[- 1 - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-. hydroxy-4-? iperidinyl] methyl] -4-chlorobenzamide; 3 - [[[[1 - l - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] amino] carbonyl] -l-hydroxy-2 4- di-ethylpyridinium; • N - [[- l - [[5-bromo-2- [(4-chlorophenyl) methoxy] f-ethyl] methyl] -4-hydroxy-4-piperidinyl] methyl] acetamide; 2- (acetyl) -N - [[- 1 - [[5-bromo-2- [(4-chlorophenyl) ethoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] acetamide; [2 - [[[1 - [[5-Bromo-2- [(4-chlorophenyl) methoxy] f-enyl] methyl] -4-hydroxy-4-piperidinyl] methyl] amino] -2- phenyl ester. oxoethyl] carbamic; (aS) -a-amino-N - [[- 1 - [[5-bromo-2- [(4-chlorofenyl) met oxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] benzeneacet amide; N - [[- 1 - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -2-chloroacet amide; N - [[- 1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N-methylacet amide, or the pharmaceutically acceptable salts thereof, wherein these compounds may be in the form of individual optical isomers or mixtures thereof, such as diastereomeric mixtures or racemic mixtures.

The term "alkyl" is used herein in all occurrences (as a group per se or as a part of a group) with the meaning of straight or branched chain alkyl groups - of 1 to 6 carbon atoms, unless the Chain length is indicated otherwise, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like. they can be substituted one or more times by 'allogen, aryl, substituted aryl, hydroxy, methoxy, amino, substituted amino, nitro, carboxy or cyano.

The term "cycloalkyl", as used herein, by itself or as part of another group, refers to groups of • saturated and partially unsaturated cyclic hydrocarbons (containing 1 or 2 double bonds), containing 1 to 3 rings, including monocyclic alkyl, bicyclic alkyl and tricyclic alkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 7 carbons forming the rings. The rings of • Multiple ring cycloalkyls can be either fused, bridged and / or linked through one or more spiral bonds for 1 or 2 aromatic, cycloalkyl or heterocycle rings. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloocyl, Cyclodecyl, cyclododecyl, cyclohetenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, and similar.

Alkoxy means alkyl-O- groups in which the alkyl portion (substituted or unsubstituted) is in accordance with the above definition. Suitable alkoxy groups include methoxy, ethoxy, propoxy and butoxy.

The term "cyclic ether" means a cyclic ring of carbon atoms containing a. heteroatom O (eg, epoxide). The rings typically have 3-7 ring atoms and 1 or 2"O atoms.

Alkenyl represents C2-Ce carbon chains having one or two unsaturated bonds, provided that those two unsaturated bonds are not adjacent to each other.

The term "allyl" means a hydrocarbon radical of 3 to 8 or more carbon atoms, which contain a double bond between carbons 2 and 3, and includes, for example, propenyl, 2-butenyl, cinnamyl, and the like.

Here, suitable substituents of the amino groups can be the same or different, and include alkyl (optionally substituted), and cycloalkyl, e.g. ex. C3_7 cycloalkyl (optionally substituted, eg, as for alkyl alone). Typical substituents include OH and C6-6 alkoxy The terms "halo" or "halogen" are used here interchangeably in all occurrences, meaning radicals derived from the elements chlorine, fluorine, iodine or bromine. "Halogenated" is analogous, and refers to a degree of halogen substitutions from a single substitution to a complete one (per). Fluoride- (Ci-Cg) -alkyl represents a straight or branched alkyl chain substituted by 1 to 5 fluorine atoms, which may be attached to the same or different carbon atoms, e.g. ex. , -CH2F, -CHF2, -CF3, F3CCH2- and -CF2CF3.

The term "heteroaryl," as used herein, by itself or as a part of another group, refers to monocyclic and bicyclic aromatic rings containing from 5 to 10 atoms, including from 1 to 4 heteroatoms such as nitrogen, oxygen or sulfur, and the rings fused with an aryl, cycloalkyl, heteroaryl or heterocycle ring, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized Examples of heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl , imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolyl, isothiazolyl, furanyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triacyl, indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidasolyl, benzopyranyl, indolicinyl , benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinolinyl, qu inoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl, dihydroisoindolyl, tetrahydroquinolinyl, carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl. and similar.

The terms "heterocyclic" or "heterocycle" as used herein, by themselves or as part of another group, refer to fully saturated cyclic groups or • partially saturated, optionally substituted (for example, 3- to 13-membered monocyclic ring systems, 7 to 17 membered bicyclic, or 10 to 20 membered tricyclic, preferably containing a total of 3 to 10 ring atoms), have at least one heteroatom in at least one ring containing a carbon atom. Each ring The heterocyclic group containing a heteroatom can have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms can be optionally oxidized and the heteroatoms can be of nitrogen can optionally be quaternized. The heterocyclic group can be attached to any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of the multiple ring heterocycles can be either fused, bridged and / or joined through one or more spiral links to 1 or 2 aromatic, heteroaryl or cycloalkyl rings. Examples of heterocyclic groups include acetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, acepinyl, 4-piperidonyl. , tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, and similar.

The terms "ar" or "aryl" as used herein, by themselves or as part of another group, refer to the aromatic homocyclic aromatic groups (ie, hydrocarbon), oncyclic, bicyclic or tricyclic which (such as phenyl, biphenyl, naphthyl (including 1-naphthyl and 2-naphthyl) and anthracenyl) and may optionally include one to three additional rings (either cycloalkyl, heterocycle or heteroaryl) fused thereto. Examples include: and similar, The terms "arylalkyl", "aralkyl", "(aryl) alkyl" or (ar) alkyl "refer to a residue in which an aryl portion is attached to the parent structure via an alkyl residue, where the aryl and alkyl portions are in accordance with the In the similar way, terms such as "(heteroaryl) alkyl", "(heterocycle) alkyl" and "(cycloalkyl) alkyl" refer respectively to portions of heteroaryl, heterocycle and cycloalkyl which are attached to the parent structure via a -residue- of alkyl.

The term "acyl" or "Ac" refers for example to alkanoyl radicals having from 1 to 6 carbon atoms in which the portion of. alkyl can be substituted as defined above.

It will always be understood that the optional substituents are independently selected from each other.

Some of the compounds of the Formula and the related compounds are capable of forming both of the pharmaceutically acceptable acid and / or basic addition salts. All these forms are within the competence of the invention, since they are separate diastereomers and enantiomers.

The optical isomers can be obtained by resolution of the racemic mixtures according to the conventional processes, for example, by the formation of diastereomeric salts using an optically active acid or base, or by the formation of covalent diastereomers. Examples of suitable optically active acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoyluoyltartaric and camphorsulfonic. Mixtures of diastereomers can be separated into their individual diastereomers on the basis of their physical and / or chemical differences through methods known to those skilled in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids can therefore be released from separate diastereomeric salts. A different process for the separation of optical isomers involves the use of chiral chromatography (eg, chiral HPLC columns.), With or without conventional derivitization, optimally chosen to maximize the separation of the enantiomers. The chiral HPLC columns are manufactured by Diacel, p. ex. , the Chiracel OD and the Chiracel OJ, among many others, routinely selectable. Enzymatic separations, with or without derivitization, are also useful. The optically active compounds of the formula I can be obtained in a similar way using optically active starting materials.

The acid addition salts. Pharmaceutically acceptable compounds of formula I include salts derived from non-toxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrogen, hydroiodic, phosphorous, and the like, as well as salts derived from non-toxic organic acids , such as the aliphatic mono- and dicarboxylic acids, the alkanoic acids substituted with 2-phenyl-, the hydroxy alkanoic acids, the alkanedioic acids, the aromatic acids, the aliphatic and aromatic sulfonic acids, etc. these salts therefore include: sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrophosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chlorine, bromine, iodine,. acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are amino acid salts such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M. et al., "Pharmaceutical Salts", J. Pharma Sci., 1977; 66: 1).

The acid addition salts of the basic compounds of the formula I can be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms may differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents.

The pharmaceutically acceptable basic addition salts of the compounds of the formula I can be formed with metals or amines, such as the alkali metals and alkaline earths or the organic amines. Examples of the metals used as cations are sodium, potassium , magnesium, calcium, and the like. Examples of suitable amines are: N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see Berge, Supra, 1997).

The basic addition salts of the acidic compounds of the formula I can be prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms may differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents. Certain compounds of the present invention can exist in the insolvated forms as well as in solvated forms, including the hydrated forms. It is intended that solvated and insolvated forms be included within the competence of the present invention.

Certain compounds of the present invention possess one or more chiral centers and each center may exist in the R (D) or S (L) configuration. The present invention includes all diastereomeric, enantiomeric and epimeric forms as well as all mixtures thereof, such as racemic mixtures.

The activity of the compounds of the present invention can be evaluated using suitable assays, such as receptor agglutination assays and chemotaxis assays. For example, as written in the example section, antagonist compounds of the present invention have been identified using a MlPla binding assay .SPA Receptor CCR-5, and have been found to exhibit IC50 values in the range of from 0.01. μM up to 38 μM. These values are indicative of the intrinsic activity of the compounds in use, as modulators of chemokine receptor activity. There are many other similar screening assays, known to those skilled in the art, which can be used to determine the antagonistic activity of the CCR-5 receptor of the compounds of the present invention. One such screening technique is described in PCT Patent WO 92/01810. In another assay, for example, which can be used for the screening of a receptor antagonist, it is by contacting melanophore cells encoding the CCR-5 receptor with both RANTES and a compound to be scanned. The inhibition of the signal generated by the ligands indicates that a compound is an antagonist for the receptor, i.e., inhibits the activation of the receptor. .

Other screening techniques include the use of cells expressing the CCR-5 receptor (eg, transfected CHO cells, RBL-2 cells or other mammalian cells) in a system that measures changes in extracellular pH caused by activation of the receiver, for example, as described in Science, volume 246, pages 181-296 (October 1989), which is incorporated here as a reference. Potential antagonists can be contacted with a cell that expresses the CCR-5 receptor and - a second messenger response, p. ex. , signal transduction or pH changes, or making use of a reporter gene system, for example luciferase, that can be measured to determine if the potential antagonist is effective. " Another of these screening techniques involves introducing mRNA encoding the CCR-5 receptor into Xenopus oocytes, RBL-2 or other mammals to transiently express the receptor. The cells with the expressed receptor can therefore be contacted, in the case of antagonist screening, with RANTES and a compound to be screened, followed by detection of the inhibition of a calcium or cAMP signal.

Another screening technique involves expressing the CCR-5 receptor where the receptor is linked to a phospholipase C or D. As representative examples of those cells, the endothelial cells, the cells can be mentioned. of smooth muscles, embryonic kidney cells, etc. The screening of the antagonist can be carried out as described above, detecting the inhibition of the activation of the receptor from the second signal of the phospholipase.

Another method involves the tracing of the CCR-5 receptor inhibitors by determining the inhibition of agglutination of the labeled RANTES to the cells or membranes that have the receptor on the surface thereof. this method involves transfecting a cell . eukaryotic, such as the CHO cell or RBL-2, with DNA encoding the CCR-5 receptor, so that the cell expresses the receptor on its surface, and • contacts the cell with a potential antagonist in the presence in a way labeled RANTES. RANTES can be labeled, p. ex. , by radioactivity. The . number of agglutinated labeled ligands - to • the receptors, p. ex. , by measuring the radioactivity associated with the transfected cells or with the membrane of those cells. If the potential antagonist binds to the receptor, as determined by a reduction in the labeled ligand that binds to the receptors, the inhibitor is inhibited. • agglutinated ligand labeled with the receptor.

Another method involves the screening • of the inhibitors of CCR-5 determining the inhibition or stimulation of cAMP mediated by. CCR-5 and / or the accumulation or decrease of ademylate cyclase. This method involves transfecting a eukaryotic cell, such as a CHO cell or an RBL-2, with the CCR-5 receptor, to express the receptor on the surface of the cell. - Then the cell is exposed to potential antagonists in the presence of RANTES .. Then the amount of cAMP accumulation is measured. If the potential antagonist is. agglutinates with the receptor, and therefore inhibits the binding of CCR-5, the levels of cAMP mediated with CCR-5, or adenylate cyclase, the activity will be reduced or increased.

Another tracking technique is described in the Patent • US 5,928,881, which provides a method for determining whether an unknown ligand that is capable of agglutination with the CCR-5 receptor can bind to this receptor, which comprises contacting a mammalian cell expressing the CCR-5 receptor with RANTES, under conditions that allow the agglutination of the ligands to the CCR-5 receptor, detecting the presence of a ligand that binds to the receptor, and thereby determining whether the ligand binds to the CCR-5 receptor.

Kita, H., et al., J. Exp. Med. 183, 2421-2426 (1996), provides a review of the role of chemokines . in allergic inflammation, suggesting that agents that modulate chemokine receptors should be useful in disorders and allergic inflammatory diseases. The compounds that modulate the chemokine receptors are especially useful in the treatment and prevention of atopic conditions, including allergic rhinitis, dermatitis, conjunctivitis, and particularly bronchial asthma.

The migration of leukocytes from blood vessels to diseased tissues is important for the initiation of normal inflammatory responses that 'fight the disease. But this process, known as leukocyte recovery, is also involved in the onset and progression of diseases. Chronic inflammatory, allergic and autoimmune inflammatory and life threatening. Therefore, compounds that block the recovery of leukocytes to target tissues in inflammatory and autoimmune disease, would be a highly effective therapeutic intervention.

It has been recognized that, in order to efficiently enter the target cells, human immunodeficiency viruses require chemokine receptors, such as CCR-5 or CXCR4, as well as the primary CD4 receptor (Levy, N. Engl. Med., 335 (20), 1528-1530 (November 14, 199.6) The main cofactor for entry mediated "by envelope glycoproteins of certain strains of HIV-1 is CCR-5, a receptor for RANTES chemokines , MlP-la. And MIP-10 (Deng, et al., Nature, 381, 661666 (1996).) Accordingly, an agent that could block chemokine receptors in humans possessing normal chemokine receptors, it would prevent infection in healthy individuals and slow or stop viral progression in infected patients.Inhibition of chemokine receptors presents a viable method for the prevention or treatment of HIV infection and the prevention or treatment of AIDS.

Small molecule antagonists of the interaction between C-C chemokine receptors and their ligands, including RANTES and MlP-la, provide useful compounds to block chemokine receptors and inhibit harmful inflammatory processes "triggered" by the interaction of ligand receptor, as well as *, - - as valuable tools for the investigation of receptor-ligand interactions.

The selective inhibition of a CCR-5 receptor through treatment with the antagonists of the receptor of the invention, represents a therapeutic approach and / or • New preventive for the treatment of a broad spectrum of inflammatory or autoimmune diseases or conditions, in particular for the treatment of inflammatory diseases or conditions, atherosclerosis, restenosis, and autoimmune disorders such as arthritis and rejection of transplants.

In a preferred embodiment, the disease or condition is one that is associated with the infiltration of lymphocytes and / or monocytes into tissues (including recovery and / or accumulation in tissues), such as arthritis (e.g. rheumatoid arthritis), inflammatory bowel diseases (eg, Crohn's disease, ulcerative colitis), multiple sclerosis, idiopathic pulmonary fibrosis, and graft rejection (eg, in transplants), including allograft rejection or graft-versus-host disease. In addition, diseases characterized by basophil activation and / or eosinophil recovery can be treated according to the present invention, including allergic hypersensitivity disorders such as psoriasis, asthma and allergic rhinitis. Other diseases which can be treated with the compounds of formula I are: chronic contact dermatitis, sarcoidosis, dermatomyositis, fenfigoid skin and related diseases (eg, pemphigus vulgaris, P. foliaceus, P. erythematosus), glomerulonephritis, vasculitides (eg, necrotizing, cutaneous, and hypersensitivity vasculitis), hepatitis, diabetes, systemic lupus erythematosus, and myasthenia gravis. In addition to psoriasis, other inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, and reperfusion injury can also be treated.

Antagonists of the present invention bind with the CCR-5 receptor, making it inaccessible to ligands, so that normal biological activity is prevented. They can be administered to a mammal in need of treatment of the disease states mediated by the CCR-5. Therefore, the active ingredient can be administered to the mammal using the normal course of tests for treatment determination.

The term "disease status mediated by CCR-5" is used here in all occurrences and means any disease state that is affected or modulated by CCR-5.

The subject treated in the above methods is preferably a mammal, preferably a human being, male or female, in whom modulation of chemokine receptor activity is desired. As used herein, "modulation" is intended to encompass antagonism, agonism, partial antagonism, inverse agonism and / or partial agonism. In a preferred aspect of the present invention, modulation refers to antagonism of chemokine receptor activity, since the compounds of the invention are antagonists.

The combination therapy to modulate the activity of the chemokine receptor and therefore to prevent and treat the conditions noted above, is illustrated by the combination of the compounds of this invention and other compounds that are known for such purposes.

For example, in the treatment or prevention of inflammation, the present compounds can be used in conjunction with an anti-inflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as a 5-lipoxygenase inhibitor, an inhibitor of cyclooxygenase, such as the cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, a citric oxide inhibitor or an inhibitor of nitric oxide synthesis, an agent non-steroidal anti-inflammatory, or an anti-inflammatory agent cytokine suppressant, for example with a compound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen ,. indometacin, quetorolac, morphine, naproxen, phenacetin, piroxicam, a steroid analgesic, sulfetanil, sunlindac, tenidap, and the like. Similarly, current compounds can be administered with a pain reliever; a potentiator such as caffeine, an H2 antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-deoxy-ephedrine; an antitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or . dextromethorphan; a diuretic; and a sedative or non-sedating antihistamine. Similarly, the compounds of the present invention can be used in combination with other drugs that are used in the treatment / prevention / suppression or amelioration of diseases or conditions for which The compounds of the present invention are useful. Those other drugs can be administered through a route and in an amount commonly used for this, in a contemporary or sequential manner with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing these other drugs in addition to the compound of the present invention is preferable.

Accordingly, the pharmaceutical compositions of the present invention include those which contain one or more other active ingredients, in addition to a compound of the present invention. Examples of other active ingredients that can be combined with a compound of the present invention, whether administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists such as those described in U.S. Patent No. 5,510,332; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapa icin and other immunosuppressants of the FK-506 type; (d) antihistamines (histamine H1 antagonists), such as bromophenylamine, chlorophenylamine, dexchlorphenylamine, tripolidine, clemastine, diphenhydramine, diphenylpraline, tripelenamine, hydroxyzine, metdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, astemizola , terfenadine,. loratadine, cetricin, fexofenadine, descarboethoxy loratadine, and the like; (e) nonsteroidal anti-asthmatics such as beta-2 agonists (terbutaline, metaproteorol, fenoterol, isoetharine, albuterol, • bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide,. leukotriene antagonists' (zafirlucast, montelucast, pranlucast, iralucast, pobilucast, SKB-106, 203), inhibitors of leukotriene biosynthesis (cilueton, BAY-100-5) (f) nonsteroidal anti-inflammatory agents (NSAIDs), such as propionic acid derivatives (alminoprofen, benoxaprofen, bucilloxic acid, caiprofen, fenbufen, - fenoprofen, fluprofen, flubiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprocine, pirprofen, pranoprofen, - suprofen, triaprofenic acid, and thioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, phenolic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, thiopinac, tolemtin, cidometacin, and zomepirac), derivatives of fenamic acid (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflusinal and flufenal), oxicam (isoxicam, piroxicam, sudoxicam and tenoxicam), salicylates (acetylsalicylic acid, sulfasalazine) and pyrazolones (apazone, bezpiperilona, feprazona, mofebutazona, oxifenbutazona, fenilbutazona); (g) cyclooxygenase-2 (COX-2) inhibitors; (h). inhibitors of phosphodiesterase type IV (PDE-IV); (i) other antagonists of the chemokine receptors, especially CXCRA, CCR- ?, CCR-2, CCR-3 and CCR-5; (j) cholesterol-lowering agents, such as the HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), sequestrants. (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), and probucol; (k) antidiabetic agents such as insulin, sulfonylureas, biguanides (metformin), inhibitors of the. a-glucosidase (acarbose) and glitazones (troglitazone and pioglitazone); (1) preparations of interferon beta (interferon-beta-lac, interferon-beta-1.beta); (m) other compounds such as 5-aminosalicylic acid and prodrugs thereof, antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents.

The weight ratio of the compound of the present invention to the second active ingredient can be varied, and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID, the weight ratio of the compound of the present invention to the NSAID will generally be in the range of from about 1000: 1 to about 1: 1000, preferably from about 200: 1 to about 1: 200. Combinations of a compound of the present invention with other active ingredients will also generally be within the aforementioned range; but in each case, an effective dose of each active ingredient should be used.

The compounds of the present invention can be administered orally, parenterally (eg, intramuscular, intraperitoneal, intravenous, ICV, intracisternal infusion or injection, subcutaneous injection or implant), aerosol inhalation, nasal, vaginal, rectal, sublingual, or by topical routes of administration, and can be formulated, alone or together, in unit dose formulations containing pharmaceutically acceptable non-toxic carriers, adjuvants and vehicles appropriate for each route of administration. The compounds of the invention are effective for use in primates, "such as humans, as well as for the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, guinea pigs. , other species of bovine, ovine, equine, canine, feline, rodent or murid.However, the compounds of the invention are also effective for use in other species, such as avian species (eg, chickens).

Pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form, and may be prepared by any of the methods well known in the pharmacy art. All methods include the step of placing the active ingredient in association with the carrier which constitute one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by placing the active ingredient, uniformly and intimately, in association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active object compound is included in an amount sufficient to produce the desired effect during the process or condition of the diseases.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, pieces, lozenges, aqueous or oily suspensions, dispersible powders or granules, -emulsions, hard or soft capsules, or syrups. . or elixirs. Compositions designed for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and those compositions can contain one or more agents selected from the group consisting of: sweetening agents, flavoring agents, agents dyes and preservatives, to provide pharmaceutically elegant and palatable preparations.

The tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients for the manufacture of tablets, these excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncovered or covered by known techniques to retard disintegration and aging. absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time retardant material such as glyceryl monostearate or glyceryl distearate may be employed. They can also be covered by the techniques described in US Patent Nos. 4,256,108; , 166,452; and • 4,265,874, to form osmotic therapeutic tablets to control the release.

The formulations for oral use, hard gelatine capsules may also be present, in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules in which the active ingredient it is mixed with water or a medium of oil, for example, peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. These excipients are suspending agents, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl ethyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and acacia gum; the dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or products of the condensation of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or products of the condensation of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethylene oxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or products of the condensation of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan polyethylene monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example peanut oil (arachis), olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, solid paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents, may be added to provide a palatable oral preparation. These compositions can be preserved with the addition of an antioxidant, such as ascorbic acid.

Dispersible powders and granules suitable for the preparation of an aqueous suspension with the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, for example sweetening, flavoring and coloring agents.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase can be a vegetable agent, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be natural gums, for example acacia gum or tragacanth gum, naturally occurring phosphatides, for example soybeans, lecithin, and partial esters or esters derived from fatty acids and hexitol anhydrides, example sorbitan monooleate, and products of these partial esters with ethylene oxide, for example, sorbitan polyoxyethylene monooleate. The emulsions may also contain sweetening and flavoring agents. .

The syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The pharmaceutically acceptable compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known technique using the dispersing or wetting agents and suitable suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspensory medium. For this purpose, any • soft fixed oil including mono- or diglycerides can be used. In addition, fatty acids such as oleic acid find use. in the preparation of injectables.

The compounds of the present invention can also be administered in the form of suppositories, for 'rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature, and will therefore melt in the rectum to release the drug. These materials are cocoa butter and polyethylene glycols.

For tropical use, creams, ointments, gels, solutions or suspensions, etc., containing the compounds of the present invention are used. (For the purposes of this application, the topical application will include mouthwash and gargle). The pharmaceutical composition and the method of the present invention may further comprise other therapeutically active compounds as noted herein, which are usually applied in the treatment of the aforementioned pathological conditions.

The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending on a variety of factors, including the activity of the specific compound employed; the metabolic stability and the duration of the action of the compound; age, body weight, general health, sex and the patient's diet; the mode and time of administration; the range of excretion; the combination of the drug; the severity of the particular disease states; and the host receiving the therapy. Generally, a therapeutically effective daily dose is from 0.14 mg to about 14.3 mg / kg of body weight per day, of a compound of the invention, or of a pharmaceutically acceptable salt thereof; preferably, from about 0.7 mg to about 10 mg / kg of body weight per day; and most preferably, from about 1.4 mg to about 7.2 mg / kg of body weight per day. For example, for administration to a 70 kg person, the range of the dose will be from about 10 mg to about 1.0 grams per day of a compound of the invention, or a pharmaceutically acceptable salt thereof, preferably from from about 50 mg to about 700 mg per day, and most preferably, from about 100 mg to about 500 mg per day.

The compounds can be administered in a regimen of 1 to 4 times per day, preferably once or twice per day.

In the previous and following examples, all temperatures are set without correction at 10. degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.

The compounds of the invention can be made by methods known in the art, such as described in the Patents WO 00/66559; WO00 / 66558; . WO 02/079157, and WO 02/079194. With respect to the identified sub-genres and methods of making, the applicants incorporate as a reference the complete descriptions of the Patents WO 00/66559; WO00 / 66558; WO 02/079157, and WO 02/079194, as if they were established here completely.

In addition, here they are incorporated, as reference the - Complete descriptions of all the Applications, Patents and Publications, cited above or below.

The compounds of the invention can also be prepared as described in the following reaction schemes and through the methods described in the examples below.

Scheme 1 The 5-substituted 2-hydroxybenzaldehyde (1) is reacted with an arylmethyl bromide or substituted pyridylmethyl bromide (2) in the presence of the base, such as K2C03, in DMF at room temperature, to provide - (3) . The transformation from (3) to (5) can be achieved through two different paths: a) Reductive amination of (3) with amines (R 3rR> 4, NH) using a reducing reagent. such as NaBH (0Ac) 3 to provide (5); b) reduction of (3) with NaBH4, followed by bromination with CBr4 and PPh3, provided (4). Additional reaction of (4) with amines (R3R4NH), to provide (5). Additional reaction of (5) (R3 = H) with isocyanate (R9NC0), provides (6).

Scheme 2 The deprotonation of (7) (prepared according to Scheme 1) with NaH, followed by the alkylation with halides V2-X, provides (8). Deprotection of (7) u '(8) with TFA, followed by reaction with isocyanates (V3NC0), chloroformates (VOCOCI) and acids (VC02H) gives the corresponding product (10, 11 or 12), respectively.

Scheme 3 The hydrolysis of (13) (prepared according to Scheme I), followed by the linkage with amines (V2V3NH) provides (15). The amidation of (14) with Boc-piperazine, followed by deprotection and linking with isocyanates (V3NCO), acids (VC02H) or sulfonyl chlorides - (VS02C1) provides (18, 19 or 20), respectively.

Scheme 4 The compound (24) can be synthesized through the following two methods: a) alkylation of (1) with alkyl halides (R2-X), followed by reductive amination with (21), provides (24); ' b) the reductive amination of (1) with (21), followed by the alkylation with halides (R2-X), provides (24).

Scheme 5 The phenol (25) reacts with arylmethyl bromide or substituted pyridylmethyl halides (2) in the presence of a base, such as K2C03, in DMF at room temperature to provide (26). Bromination of (26), followed by reaction with amines (R3R4NH), provides (27). The reduction of (28) with a reducing agent such as NaBH4 provides (29).

Scheme 6 1) For it compound (29) with R3R4N = Boc-piperazine: deprotection of (29) with an acid such as TFA, followed by reaction with an activated acid (VC02H), provides (30); 2) for the compound (29) with Z1 = -C02Me: the reaction of (29) with an acid or base, followed by the reaction with V2V3NH, provides (31).

Scheme 7 The compound (3) (prepared according to Scheme 1) reacts with Me3S + I "using KOtBu as a base to provide the epoxide (32). The ring opening of the epoxide (32) with amines (R3RNH) provides (33) Alkylation of the alcohol of (33) with alkyl halides (R10a-X) using a base such as NaH, provides (34).

Scheme 8 The reaction of the aldehyde (3) with ethylene-magnesium chloride provides (35), which is converted to (36) by oxidation under conditions such as those described by S ern. The Michael addition of the amines (R3R4NH) to (36), followed by reduction with a reagent such as NaBH, provides (37).

Scheme 9 Condensation of (3) with R CH2N02, followed by reaction with a reducing agent such as LiAlH, provides (38). Reductive amination of (38) with aldehydes (R-CHO) provides (39).

Scheme 10 Treatment of (40) (prepared according to Scheme 1) with TMSCN and Znl2, followed by the reaction with MeOH / HCl affords the methyl ester (41). Hydrolysis of (41) to the acid, and amination with amines' (V2V3NH), provides (42).

Scheme 11 a) Reductive amination of (40) with N-Boc-piperazine provides (43). The removal of the Boc group under standard conditions and the binding with an activated acid (VC02H) provides (44). b) Deprotonation of (40), followed by treatment with halide (Z2-I) provides (45). The reduction of (45) provides (46). c) The treatment of (40) with DAST provides (47). d) The treatment of (40) with KCN and (NH4) 2C03 > provides (48).

Scheme 12 a) Treatment of (40) with a nucleophile such as an aryl or lithium alkyl reagent or TMSCF3 provides (49). b) Treatment of (40) with H2NOR 13 provides (50; c) The reduction of (40) with a reagent such as NaBH4, followed by treatment with DAST, provides (52). d) The reaction of (51) with alkyl halides (V-X) provides (53).

Scheme 13 The compound (40), prepared in accordance with Scheme 1, reacts with Me3S + I "to provide the epoxide (54) The opening of the epoxide ring (54) with amines (V2V3NH) provides (55).

Scheme 14 The linkage of (55) (V2 = V3 = H) with isocyanates (v4NCO) and acid chlorides (VCOCI) provides (56 and 57), respectively.

EXAMPLES Example 5-bromo-2- (4-chlorophenylmethoxy) benzaldehyde To a stirred solution of 5-bromo-2-hydroxybenzaldehyde (100 g, 0.5 mol) in DMF (600 mL) was added K2CO3 (206 g, 1.49 moi) at room temperature.

After 30 min, 4-chlorobenzylchloride (78 g, 0.48 mol) was added. The reaction mixture was maintained at 65 ° C overnight, "then cooled to room temperature, and poured into an ice-cooled mixture of EtOAc / water (1: 1, 2 L) .The solid was collected by filtration, washing with water and drying under vacuum for 20 h to give the desired product (160 g, 100%). XH NMR (400 MHz, CDCl 3): d 5.18 (s, 2 H), 6.92 (d, 1 H), 7.37 (m, 4H), 7.61 (d, 1H), 7.98 (s, ÍH), 10.4 (s, 1).

The following compounds were prepared in a similar manner: 4- [(4-Chloro-2-formylphenoxy) methyl] benzonitrile 5-bromo-2 - [[4- (trifluoromethyl) phenyl] methoxy] benzaldehyde 5-bromo-2- [(4-iodophenyl) methoxy] benzaldehyde 5- bromo-2- [(6-methyl-3-pyridinyl) methoxy] benzaldehyde 5-bromo-2 - [(4-methylphenyl) methoxybenzaldehyde Methyl ester of 4 - [[4-bromo-2- (bromomethyl) phenoxmethyl] ]-benzoic Example 2: N - [[5-bromo-2- (4-chlorophenylmethoxy) phenyl] methyl] morpholinoethenamine dihydrochloride To methylene chloride (50 mL) was added 4- (2-aminoethyl) morpholine (1 mL, 6.8 mmol), 5-bromo-2- (4-chlorophenylmethyl) benzaldehyde (1 g, 3.1 mmol) and sodium triacetoxyborohydride ( 1 g, 4.7 mmol) The reaction was stirred for 18 h and washed with 2N aqueous KOH.The organic layer was dried (MgSO.sub.4) and the solvent was removed in vacuo.The residue was crystallized from ether, petroleum. were dissolved in ethanol (100 L) and acidified with concentrated HCl.The solvent was removed in vacuo and the residue triturated with acetone, to give the title compound as a white solid, NMR (DMS.O-d6, 400 MHz): d 3.1 (br, 2H), 3.45 (br, 6H), 3.8 (br, 2H), 3.9 (br, 2H), 4.2 (s, 2H), 5.2 (s, 2H), 7.05 (d, ÍH), 7.45 (d, 2H), 7.55 (m, 3H), 7.8 (s, ÍH), 9.8 (br, 2H), 11.6 (br, ÍH).

The following compounds were prepared in a similar manner: -Bromo-2- (4-chlorophenylmethoxy) -N, N-diethylbenzenemethanamine hydrochloride. X H NMR (DMSO-d 6, 400 MHz): d 1. 15 (t, 6H), 3.0 (m, 4H), 4.2 (s, 2H), 5.15 (s, 2H), 7.15 (d, ÍH), 7.45 (d, 2H), 7.55 (m, 3H), 7.85 (s, 1H), 10.3 (br, ÍH). 1 - [[[[5-Bromo-2- (4-chlorofenylmethoxy) phenyl] methyl] amino] -2-propanol hydrochloride. 1 H NMR (DMSO-d 6, 400 MHz): d 1.05 (d, 3 H), 2.65 (m, H H), 2.85 (m, H H), 3.95 (m, H H), 4.1 (m, 2 H), 5.15 (s) , 2H), 5.4 (br, 1H), 7.15 (d, ÍH), 7.45 (d, 2H), 7.55 (m, 3H), 7.75 (s, 1H), 8.95 (br, 1H), 9.4 (br, 1 HOUR) .

L - [[5-bromo-2- (4-chlorofenylmethoxy) phenyl] methyl] -4-ethylpiperazine dihydrochloride. X H NMR (DMSO-d 6, 400 MHz): d 1.15 (m, 3 H), 3.0-3.8 (m, 12 H), 5.15 (s, 2 H), 7.1 (d, 1 H), 7.45 (d, 2 H), 7.55 (br, 1H).

N - [[5-bromo-2- (4-chlorofenylmethoxy) f-enyl] methyl] -N ', N' -dimethylpropanediamine dihydrochloride. 2H NMR (DMSO-d6, 400 MHz): d 2.15 (m, 2H), 2.7 (s, 6H), 3.0 (m, 2H), 2.7 (s, 6H), 3.0 (m, 2H), 3.1 (m , 2H, 4.1 (s, ÍH), 5.15 (s, 2H, 7.05 (d, ÍH), 7.45 (d, 2H, 7.55 (m, 3H), 7.75 (s, 1H, 9.6 br, 2H), 10.9 ( br, ÍH). 3 - [[4-Bromo-2 - [(diethylamino) methyl] f-eneo] methyl] benzoic acid methyl ester hydrochloride. H NMR (DMSO-d6, 400 MHz): d 1.15 (t, 3H), 3.0 (m, 4H), 3.8 (s, 3H), 4.2 (s, 2H), 5.25 (s, 2H), 7.15 (d, ÍH), 7.55 (, 2H), 7.8 (m, ÍH), 7.85 (m, 1H), 7.9 (m, 1H), 8.05 (s, 1H), 10.15 (br, 1 HOUR) . . 4 - [[5-bromo-2- [(4-chlorophenyl) methoxy)] phenyl] methyl] thiomorpholine. (DMSO-d6 / TFA): d 2.75-3.00 (m.4H), 3.20 (, 2H), 3.51 (m, 2H), 4.30 (br.s, ÍH), 5.20 (s, 2H), 7.18 (d. , ÍH), 7.44-7.54 (m, .4H), 7.62. (dd, ÍH), 7.73 (d, ÍH), 9.50 (br.s, ÍH). - -Bromo-2- [(4-chlorophenyl) methoxy)] - N -methyl-N- (phenylmethyl) benzenemethanamine. (DMS0-d6 / TFA): d 2.54 (s, 3H), 4.10-4.44 (m, 4H), 5.12 (q, 2H), 7.13 (d, ÍH), 7.36-7.50 (m, 9H), 7.56- 7.62 (m, 1H), 7.66 (d, 1H), 7.60 (br.s, ÍH). -bromo-2- [(4-chlorophenyl) methoxy)] - N-ethylbenzene-ethanamine. H NMR (CDC13): d 1.25 (t, 3H), 2.86 (q, 2H),. 3.95 (s, 2H), 5.15 (s, 2H), 6.82 (d, ÍH), 7.34-7.48 (, 5H), 7.67 (d, ÍH). 4 - [[5-Bromo-2 - [(4-chlorophenyl) methoxy)] phenyl] methyl] morpholine. XH NMR (CDC13-D20): d 3.92 (dd, 4H), 4.20 (s, 2H), 4.80 (s, 2H), 5.06 (s, 2H), 6.88 (d, ÍH), 7.30-7.42 • (m , 4H), 7.50 (m, ÍH), 7.58 (d, ÍH). -bromo-2- [(4-chlorophenyl) methoxy)] - N- (phenylmethyl) benzenemethanamine. H NMR (DMSO-d6 / TFA): d 4.10 (s, 2H), 4.17 (s, 2H), 5.12 (s, 2H), 7.09 (d, ÍH), 7.36-7.46 (m, 9H), 7.72 ( dd, 1H), 7.68 (d, 1H), 9.20 (br.s, 2H). 5-bromo-2- [(4-chlorofenyl) methoxy)] - N, N-dimethyl-benzenemethanamine. XH NMR (DMSO-d6 / TFA): d 2.70 (s, 6H), 4.25 (s, 2H), 5.17 (s, 2H), 7.12 (d, ÍH), 7.42-7.54 (m, 4H), 7.60 ( dd, 1H), 7.68 (d, ÍH), 9.20 (br.s, ÍH). [1 - [[5-Bromo-2 [(4-chlorofenyl) methoxy] f-enyl] methyl] -3-pyrrolidinyl] -carbamic acid 1, 1-dimethylethyl ester. XH-NMR (400 MHz, DMSO-d6): d 1.42 (s, 9H) -, 1.58 (m, - .IH), 2.3 (m, 2H), 2.6 (m, 2H), 2.8 (m, 1H) , 3.61 (dd, 2H), 4.2 (br.s, 1H), 4.9 (br.s, ÍH), 5.0 (s, 2H), 6.75 (d, ÍH, 7.29 (d, ÍH), 7.35 (dd, 4), 7.47 (d, 1H). 3 - [[4-Bromo-2- [(diethylamino) methyl] phenoxy] methyl] benzoic acid methyl ester hydrochloride. XH NMR (DMSO-de, 400 MHz): d 1.15 (t, 3H), 3.0 (m, 4H), 3.8 (s, 3H), 4.2 (s, 2H), 5.25 (s, 2H), 7.15 (d , HH), 7.55 (m, 2H, 7.8 (m, HH), 7.85 (m, HH), 7.9 (m, 1H9, 8.05 (s, 1H), 10.15 (br, HH). / L - [[5 -bromo-2- [(4-iododenyl) met oxy] fyl] methyl] -4-piperidinol Prepared in a manner similar to example 2, starting with 5-bromo-2 - [(4-iodophenyl) methoxy] benzaldehyde and 4-hydroxypiperidine. 1H NMR (400 MHz, DMSO-d6): d 1.38 (m, 2H), 1.62 (m, 2H, 2.1 (t, 2H) ', 2.6 (br., -d, 2H), 4.57 (br.s, ÍH), 5.04 s, 2H), 6.97 (d, 1H), 7.21 (d, 2H), 7.37 '(d, ÍH), 7.4 (s, 1H), 7.7 (d, 2H) . l - [[5-Bromo-2 - [(4-methylphenyl) methoxy] phenyl] methyl] -4-piperidinol. Prepared in a manner similar to Example 2, starting with 5-bromo-2- [(4-methylphenyl) methoxy] benzaldehyde and 4-hydroxypiperidine. X H NMR (400 MHz, DMSO-d 6): d 1.38 (m, 2 H), 1.67 (m, 2 H), 2.0 (t, 2 H), 2.24 (s, 3 H), 2.6 (m, 2 H, 3.4 (m, 4H), 4.5 (br.s, ÍH), 5.02 (s, 2H), 7.0 (d, ÍH), 7.16 (d, 2H), 7.3 (d, 2H), 7.34 (dd, ÍH), 7.4 (d, ÍH). l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] ethyl] -4-piperidinol. Prepared in a manner similar to Example 2, starting with 5-bromo-2 - [[(4-trifluoromethyl) phenyl] methoxy] -benzaldehyde and 4-hydroxypiperidine. XH NMR (400 MHz, DMSO-. D6): dl.38 (br.s, 2H), 1.7 (br.s, 2H), 1.7 (, 2H), 2.7 (br.s, 2H), 3.1 (, 1H), 3.5 (m, 4H), 5.21 (s, 2H), 7.0 . (dd, ÍH), 7.4 (d, ÍH), 7.43 (br.s, 1H), 7.62 (d, 2H), 7.74 ( , 2) . l - [[5-Bromo-2- [(6-methyl-3-pyridinyl) -Rethoxy] -phenyl] -methyl] -4-piperidinol.

Prepared in a manner similar to Example 2, starting with 5-bromo-2- [(6-methyl-3-pyridinyl) methoxy] -benzaldehyde and 4-hydroxypiperidine. XH NMR (CDC13): d 1.60 (, 2H), 1.88 (m, 2H), 2.19 (m, 2) 2.58 (s, 3H), 2.76 (m, 2H), 3.51 (s, 2H), 3.70 (m , 1H), 5.01 (s, 2H), '6.79 (d, .1H), 7..18 (d, 1H), 7.32' (dd, 1H), 7.51 (d, 1H), 7.64 (dd, 1H) ), 8.56 (d, 1H). - - l - [[4-bromo-2- [(6-methyl-3-pyridinyl) methoxy] phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol. Prepared in a manner similar to Example 2, starting with (6-methyl-3-pyridinyl) methoxy] benzaldehyde and 4- (4-bromophenyl) -4-hydroxypiperidine. XH NMR (DMSO-d6 / TFA): d 1.75 (br.d, 2H), 2.15 (m, 2H), 2.54 (s, 3H), 3.20-3.40 (, 4H), 4.45 (d, 2H), 5.45 (s, 2H), 7.22 (d, ÍH), 7.14 (m, 2H), 7.52 (m, 2H), 7.64 (dd, 1H), 7.78 (d, ÍH), 7.95 (br.d, • ÍH), 8.59 (br.d, ÍH), 8.96 (d, ÍH),.

The following compounds were prepared in a similar manner, starting with 4- [(4-chloro-2-formylphenoxy) methyl] benzonitrile. 4 - [[4-chloro-2- (4-morpholinylmethyl) phenoxy] methyl] benzonitrile. 2H NMR (CDC13, 400 MHz): d 2.50 (m, 4H), 3.55 (s, 2H), 3.75 (m, 4H), 5.10 (s, 2H), 6.80 (d, -1H), 7.18 (d, ÍH), 7.40 (s, 1H), 7.55 (d, 2H), 7.70 (d, 2H). 4 - [[4-chloro-2- (1-pyrrolidinylmethyl) phenoxy] methyl] benzonitrile. 'XH NMR (CDC13, 400 MHz): d 1.80 (m, 4H), 2.60 (m, 4H), 3.70 (s, 2H), 5.10 (s, 2H), 6.80 (d, lH), 7.15 (d, ÍH), 7.40 (s, ÍH), 7.55 (d, 2H), 7.70 (d, 2H). • ' l - [[5-Bromo-2- [(4-chlorophenyl) methoxyjphenyl] methyl] -3-piperidinomethanol. XH NMR (CD3OD, 400MHz): d 1.15 (m, 1H), 1.90 (m, 5H), 2.20 (, ÍH), 3.05 (, ÍH), 3.20 (m, 1H), 3.60 (m, 2H), 3.75 (s, 2H), 5.30 (s, 2H), 7.15 (d, 1H), 7.60 (, 6H).

Example 3: N - [[5-Bromo-2- (4-chlorophenylmethoxy) phenyl] methyl] -N- (3-dimethylaminopropyl) -N'-phenylurea hydrochloride.

To methylene chloride (50 mL) was added phenyl isocyanate (0.5 L, 3.8 mmol) and N - [[5-bromo-2- (4-chlorophenylmethoxy) phenyl] methylamino] -N ', N' -dimethylpropane-diamine. (0.8 'g, 1.9 mmol). After stirring for 24 h, the solvent was removed in vacuo. The residue was dissolved in ethanol (50 mL) and acidified with concentrated HCl. The solvent was removed in vacuo, and the residue triturated with ether, to give the title compound as a yellow foam. H NMR (DMSO-d6, 400 MHz): d 1.9 (m, 2H), 2.65 (s, 6H), 3.0 (m, 2H), 3.35 (m, 2H), 4.6 (s, 1H), 5.15 (s) , 2H), 6.9 (t, ÍH), 7.05 (d, ÍH), 7.2 (M, 3H), 7.45 (d, 4H), 7.55 (m, 3H), 8.5 (s, 2H), 10.2 (br, ÍH).

Example 4: 4 - [[4-Bromo-2-r [(dimethylamino) methyl] f-enoxy] methyl] -N- (3,4-dimethoxy-enyl-methyl) -benzamide hydrochloride.

To methylene chloride (600 mL) was added 4- (chloromethyl) benzoyl chloride (30 g, 159 mmol), veratrylamine (25 g, 150 mmol), and diisopropylethylamine (26 mL, 150 mmol), at -5 °. C. After warming to room temperature, the reaction was washed with 1N HCl and 10% dried K2C03.

(MgSO), and the solvent was removed in vacuo. Crystallization from ether gave 44 g of a brown solid. The solid was dissolved in DMSO (300 'mL) and 5-bromosalicylaldehyde (31 g, 150 mmol) and K2CO3 (24 g, 170 mmol) were added. After stirring at 35 ° C for 20 h, the reaction was drained in 10% K2CO3. The solid was collected by filtration and washed with acetonitrile and ether to give 56 g of a whitish solid. A portion of the solid (2 g, 4.1 mmol) was dissolved in methylene chloride (200 mL) and dimethylamine (10 mL of a 2M solution in THF, 20 mmol) and sodium triacetoxyborohydride (1.5 g, 7.0 mmol) were added. . The reaction was stirred for 18 h and washed with 10% aqueous KOH. The organic layer was dried (MgSO), and the solvent removed in vacuo. The solids were dissolved in acetone and acidified with HCl (g). The solid was filtered and washed with acetone and ether to give the title compound. XH NMR (DMSO-d6, 400 MHz): d 3.65 (s, 6H), 3.7 (s, 6H), 4.25 (s, 2H), 4.4 (s, 2H), 5.25 (s, 2H), 6.8 (n , 2H), 6.9 (s, ÍH), 7.1 (d, 1H), 7.55 (m, 3H), 7.8 (s, 1H), 7.9 (m, 2H), 9.0 (t, 1H), 10.6 (br, ÍH).

The following compound was prepared in a similar manner: -Bromo-2 - [[4- [(6,7-dimethoxy-3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] phenyl] methoxy] -N, N-dimethylbenzenemethanamine hydrochloride. 1 H NMR (DMSO-d 6, 400 MHz). : d 2.65 (s, 6H), 4.25 (s, 2H), 4.5 (, 2H), 5.2 (s, 2H), 6.7 (s, ÍH), 6.8 (br, ÍH), 7.15 (d, 1H), 7.45 (d, '2H), 7.55 (m, 3H), 7.85 (s, ÍH), 10.75 (br, 1H) ..

Example 5: 4-bromo-2- (bromomethyl) -l - [(4-chloro enyl) methoxy] benzene, To a stirred solution of 5-bromo-2- (4-chlorophenylmethyl) benzaldehyde (30 g, 81.5 mmol) in MeOH / CH 2 Cl 2 (300 mL / 300 mL) at 0 ° C, was added NaBH 4 (3.8 g, 97.8 mmol ) in three portions. After 30 min at 0 ° C and 1 h at room temperature, the solvents were removed in vacuo, and the resulting residue was diluted with water (200 L). The mixture was extracted with EtOAc (3x150 mL), washed with brine (2x100 mL), dried over Na2SO4, and concentrated, to give the crude product. This crude product was redissolved in CH2C12 (800 L), and PPh3 (23.6 g, 90 mmol) was added. After cooling to 0 ° C, CBr4 '(29.7 g, 90 mmol) was carefully added. The mixture was stirred at room temperature overnight, and concentrated to remove the solvents. The resulting mixture was purified . directly by flash chromatography to provide the title compound (29.3 g, 92% in two steps). XH NMR (400 MHz, CDC13): d 4.52 (s, 2H), '5.11 (s, 2H), 6.76 (d, 1H), 7.4 (m, 5H), 7.52 (s, 1).

Example 6: 2 - [[[[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] · amino] -1,3-propanediol.

To a stirred solution of 4-bromo-2- (bromomethyl) -1- [(4-chlorophenyl) methoxy] benzene (300 mg, 0.77 mmol) in DMF (3 mL), 2-amino-1,3-propanediol (300 mg, 3.3 mmol) was added at room temperature. After 2 h, the reaction mixture was purified directly by HPLC to give the title compound as a salt of trifluoroacetic acid. 2H NMR (400 MHz, -DMSO-d6): d 3.1 (br.s, ÍH), 3.4 (br., S, 2H), 3.62 (, 4H), 4.23 (s, 2H), 5.2 (s, 2H) ), 5.36 (br.s, ÍH), 7.1 (d, 1H), 7.43 (dd, 2H), 7.56 (m, 3H), 7.67 (s, ÍH), 8.63 (br. ÍH).

The following compounds were prepared in a similar manner: (2R) -l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -2-pyrrolidinemethanol trifluoroacetic acid salt. 1 H NMR (400 MHz, DMSO-d 6): d 1.78 (m, 2 H), 1.92 (m, 1 H), 2.0 (m, H H), 3.18 (m, 1 H), 3.31 (m, 1 H), 3.61 (m , 2H), 4.22 (m, 2H), 4.58 (, 2H), 5.2 (s, 2H), -7.19 (d, ÍH), 7.43 (d, 2H), 7.52 (d, 2H), 7.59 (dd, ÍH), 7.68 (d, 1), 9.21 (br.s, 1H.

Salt of (2S) -l - [[5-bromo-2 - [(4-chlorofenyl) methoxyjfenyl] methyl] -2-pyrrolidinomethane trifluoroacetic acid. H NMR (400 MHz, DMSO-d6): d 1.76 • (m, 2H), 1.95 (, HH), 2.0 (m, 1H), 3.18 (ra, HH), 3.31 (m, HH), 3.61 (m , 2H), 4.22 (m, 2H), 4.58 (m, 2H), 5.2 (s, 2H), 7.19 (d, ÍH), 7.43 (d, 2H), 7.52 (d, 2H), 7.57 (dd, ÍH), 7.68 (d, 1), 9.21 (br.s, 1H). (2R) -l - [[5-Bromo-2 - [(4-chlorofenyl) methoxy] f-enyl] methyl] -3-pyrrolidinol trifluoroacetic acid salt. XH NMR (400 MHz, DMSO-d6): d 1.92 (, 'HH), 3.18 (br.s, 1H), 3.5 (, 1H), 3.61 (m, 2H), 4.22 (m, 2H), 4.51 ( m, 2H), 5.2 (d, 2H), 7.19 (dd, 1H), 7.43 (dd, 2H), 7.52 (dd, 2H), 7.58 (dd, ÍH), 7.71 (d, 1), 10.01 (br d, 1H).

N1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -N1- [2- (diethylamino) ethyl] -N2, N2-diethyl-1,2-ethanediamine. XU NMR (DMSO-d6, 400 MHz): d 0.90 (t, 12H), 2.40 (m, 16H), 3.60 (s, 2H), 5.10 (s, 1H), 6.95 (d, 1H), 7.30 (d, ÍH) ), 7.45 (m, '4H), 7.60 (s, 1H). l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] f-enyl] methyl] -4-piperidinone. XH NMR (DMSO-d6): d 2.49-2.50 (m, 2H), 2.75 (m, 2 H), 3.35-3.51 (m, 4 H), 4.35 (br.s, 2 H), 5.15 (s, 2 H), 7.16 (br.d, 1 H), 7.42-7.54 (m, 4 H), 7.60 (br.d, 1 H), 7.86 (br.s, 1 H). l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy] -fenyl] -methyl] -4- (4-bromophenyl) -4-piperidinol. XH NMR (DMSO-d6 / TFA): d 1.75. (br.d, ÍH), 2.10 (m, 1H), 2.40-2.70 (m, 2H), 3.20-3.60 (m, -4H), 4.30-4.35 (m, 2H), 5.15 (m, 2H), 7.16 (m, ÍH), "7.32-7.54 (, 8H), 7..60 (, ÍH), 7.75 (m, 1H). l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinol. XH NMR (DMSO-d6 / TFA): d 1.54-1.72 (m, 2H), 1.80-1.92 (m, 2H), 2.94 (m, ÍH), 3.04-3.16 (m, 2H), 3.24-3.34 (, ÍH), 3.60 and 3.86 (each m, 1H), 4.18-4.24 (m, 2H), 5.14-5.17 (ra, 2H), 7.10-7.16 (m 17.40-7.50 (m, 47.56 (m, ÍH), .7.76 (m, 1H), 9.70 (br.s, ÍH).

[L - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] -carbamic acid 1, 1-dimethylethyl ester. XH NMR (CDC13): d 1.40-1.60 (m, 11H), 1.90 (br.d, 2H), 2.15"(br.d, 2H), 2.70 (br.d, 2H), 3.48 and 4.45 (each br .s, 1H), 3.50 (s, 2H), 5.00 (s, 2H), 6.74 (d, 1H), 7.29 (dd, ÍH), 7.32-7.38 (m, 4H), 7.49 (d, ÍH). l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-ethoxy-piperidine. XH NMR (DMSO-d6 / TFA): d 1.00-1.14 (m, '3H), 1.44-2.08 (m, 4H), 2.90-3.60 (m, 7H), 4.20 and 4.40 (each s, 2H), 5.12 (s, ÍH), 7.12 (m, 1H), 7.34-7.50 (m, 4H), 7.52-7.58 (m, ÍH), 7.66-7.70 (m, ÍH), 9.20 (br.s, ÍH). 8 - [[5-Bromo-2- [(4-chlorofenyl) met oxy] phenyl] methyl] -1,4-dioxa-8 ~ azaspiro [4.5] decane. 1 H NMR (DMSO-d 6 / TFA): d 1.92-2.08 (m, 4H), 3.20 (m, 2H), 3.48-3.56 (m, 2H), 4.03 (br.s, 4H), 4.44 (s, 2H ), 5.32 (s, 2H), 7.30 (dd, 1H), 7.54-7.66 (, 4H), 7.70-7.76 (, ÍH), 7.86- (d, 1H), 9.60 (br.s, 1H). [[1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] methyl] carbamic acid 1,1-dimethyl ester. XH NMR (DMSO-d6 / TFA): d 1.30-1.80 (m, 14H), 2.80-3.40 (m, 6H), 4.22 and 4-32 (each d, 2H), 5.18 (s, 2H), 6.92 (br.s, ÍH), 7.14-7.20 (m, ÍH), 7.44-7.54 (m, 4H), 7.60 (m, 1H), 7.68 and 7.74 (each d, 1H), 9.10-9.30 (m, ÍH). " -Bromo-2- [(4-chlorofenyl) methoxy] benzenemethanamine. 2H NMR (DMSO-d6): d 3.66 (s, 2H), 5.10 (s, 2H), 6.90-6.98 (m, ÍH), 7.30 (br.dd, 1H), 7.40-7.48 (m, 4H) , 7.50 (br.dd, 1H). 1 - [[5-Bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] pyridinium bromide. ? NMR. (DMSO-d6 / TFA): d '3.28 (s, 2H), 5.07 (s, 2H), 5.78 (s, 2H), 7.10 (d, 1H), 7.22-7.44 (m, 4H), 7.60 (dd) , 1H), 7.80 (d, ÍH), 8.03 (dd, 2H), 8.56 (m ", ÍH), 8.96 (dd, 2H).

Ethyl • l - [[5-bromo-2- [(4-chlorophenyl) methoxy] f-enyl] methyl] -4-piperidinocarboxylic acid ester. 1 HOUR NMR (DMSO-de / TFA) -: d 1.44 (t, 3H), 1.62-2.06 (, 4H), 2.54-2.80. (m, 1H), 2.92-3.06 (m, 2H), 3.18-3.42 (m, 2H), '4.00 (m, 2H), 4.18-4.28 (m, 2H), 5.16 (br.s, 2H), 7.16 (d, 'ÍH), 7.40-7.54 (m, 4H), 7.58-7.63 (m, ÍH), 7.68-7.74 (m, ÍH), 9.30-9.60 (m, ÍH). 2 - [[[[5-bromo-2- [(4-chlorofenyl) met oxy] f-enyl] methyl] amino] ethanol. U NMR (DMSO-d6 / TFA): d 2.95 (br.s, 2H), 3.65 (br.t, 2H), 4.10-4.20 (m, 2H), - 5.15 (s, 2H), 7.09 (d, ÍH), 7.40-7.58 (m, 5H), 7.64 (d, ÍH), 8.84 (br.s, 2H). 2 - [[[[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] (methyl) amino] -ethanol. XH NMR (DMSO-de / TFA): d 2.70 (s, 3H), 3.05-3.25 (m, 2H), 3.70 (t, 2H), 4.15-4.45 (m, 2H), 5.15 (s, 2H), 7.14 (d, 1H), 7.40-7.54 (m, 4H), 7.59 (dd, ÍH), 7.70 (d, ÍH), 9.40 (br.s, ÍH). l ~ [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] -ethyl] -3-piperidinol. XH NMR (DMSO-d6 / TFA): d 1.20-2.10 (m, 4H), 2.55-3.30 (, 4H), 3.65-4.00 (m, ÍH), 4.10-4.40 (m, 2H), 5.15 (dd, 2H), 7.12-7.18 (m, ÍH), 7.40-7.52 (m, 4) 7.56-7.61 (, 1H), 7.68-7.74 (m, 1H), 9.20 and 9.70 (each br.s, ÍH). l ~ [[5-Bromo-2 ~ [(4-chlorophenyl) met oxy] phenyl] methyl] -3-pyrrolinidol. XH NMR (DMSO-d6 / TFA): d 1.72-2.26 (m, 2H), 3.02-3.58 (m, 4H), 4.30 (m, 1H), 4.32-4.44 (m, 2H), • 5.14-5.22 ( m, 2H), 7.10-7.16 (m, HH), 7.40-7.52 (m, 4H), 7.54-7.60 (m, HH), 7.70-7.72 (m, 1H), 10.00-10.20. (my h) . '(1S, 2S) -2 ~ [[[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] amino] -l- (4-nitrophenyl-1,3-propanediol. XH NMR (DMSO - d6 / TFA): d 3.28 (m, '2H),. 3.58 (, 1H), 4.30 - (m, 2H), 4.96 (br.d, ÍH), 5.16 (, 2H), 7.08 (d, 1H), 7.40-7.44 (m, 2H), 7. 48-7.54 (, 3H), 7.58-7.64 (m, 3H), 8.18-8.22 (m, 2H), 8.50. (br.s, 1H), 9.00 (br.s, ÍH).

Example 6B: 5-Bromo-2 - [(4-chlorophenyl) methoxy] -N, N, N-trimethyl-benzenemethanaminium iodide.

To a stirred solution of 4-bromo-2- (bromomethyl) -1- [(4-chlorophenyl) methoxy] benzene (200 mg, 0.51 mmol) in DMF (5 mL), HMe2HCl (217 mg) was added, followed by by Cs2C03 (1.17 g, 0.51 mmol) at room temperature. After 4 h, the Cs2C03 was filtered and the DMF removed under vacuum. The residue was diluted with ethyl acetate, washed with water, brine, and dried (Na 2 SO 4). After filtering the solid, the resulting organic solution was concentrated in vacuo to give 5-bromo-2 - [(4-chlorophenyl) methoxy] -N, N-dimethylbenzene-methanamine (104 mg, 61%). To a stirred solution of 5- bromo-2- [(4-chlorophenyl) methoxy] -N, N-dimethylbenzene-methanamine (100 mg) in toluene (5 mL), Mel (0.19 mL, 5.1 mmol) was added to room temperature. The mixture was heated to • 50 ° C overnight. After cooling to room temperature, the solid was separated by filtration and washed with toluene to obtain the compound. 1H NMR. (DMSO-dd, 400 MHz): d 3.0 (s, 9H), 4.45 (s, 2H), 5.20 (s, 2H), 7.50 (m, 4H), 7.70 (m, 2H). - Example 7: (3R, 4S) -l - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -3,4-pyrrolidinediol.

A mixture of [[5-bromo-2 - [(4-chlorophenyl) 'rnetoxy] phenyl] methyl] -2,5-dihydro-lH-pyrrole (400 mg, 1.1 mmol), AD-mix-b (1.7 g) , 1.21 mmol), and MeS02NH2 (103 mg, 1.1 mmol) was stirred in t-BuOH-H20 (20 mL, 1: 1, v / v) at room temperature, for 2 days. The reaction was mitigated with the addition (in portion) of Na2S2? 5 (1 g). The mixture was partitioned with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by HPLC to give the title compound as a light yellow powder. XH NMR (DMSO-d6 / TFA): d '3.10-3.25 (m, 2H), 3.30-3.40 (m, 1H), 3.45-3.55 (m, ÍH), 4. 08 (m, ÍH), 4.22 (m, ÍH), 4.30 (m, ÍH), '4.44 (m, 1H), . 17 (d, 2H), 7.13 (dd, ÍH), 7.40-7.60 (, 5H), 7.72 (m, ÍH).

Example 8: l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinecarboxylic acid.

A mixture of l - [[5-bromo-2- [(4-cyclophenyl) methoxy] phenyl] methyl] -4-piperidinecarboxylic acid ethyl ester. (320 mg, 0.69 mmol), LiOH.H20 (200 mg) in THF-H20 (-5 mL, 4: 1, v / v), was stirred at room temperature under N2 for 2 days. The mixture was acidified with the addition of 1.0 HCl (aqueous). After removing THF and H20 under reduced vacuum, the residue was purified by HPLC to provide the product as a white powder. 1H NMR. (DMSO-de / TFA): d 1.60-2.10 (m, 4H), 2.40-3.40 (, 5H), 4.15-4.30 (, 2H), 5.16 (s, 2H), 7.15 (d, 1H), '7.40 -7.52 (m, 4H), 7.59 (dd, 1H), 7.69 (br.dd, 1H), 9.40-9.60 (m, ÍH).

Example 9: l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinamine.

To a solution of 1,1-dimethylethyl ester of acid [1 - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] -carbamic acid (12 mmol) in CH2C12 (20 mL) was added TFA (10 mL) at room temperature ambient. After stirring overnight, the solvent was removed in vacuo, and the mixture was diluted with EtOAc, washed with NaHCO3 (sat.) And brine, and dried over Na2SO4. After concentration, the residue was purified by recrystallization to provide the product as white crystals. 1 H NMR 5- (DMSO-d 6 / TFA): d 1.70 (m, 2H), 1.95-2.05 (m, 2H), 2.95- 3.45. (m, 5H), 4.18-4.25 (m, 2H), 5.15 (s, 2H), 7.14 (d, ÍH), 7.38-7.50 '(m, 4H), 7.57 (dd, 1H), 7.68 (d, 1H), 8.0 - (br.s, - 3H), 9.70 (br.s, ÍH). • The following compounds were prepared in a similar manner: l - [[5-Bromo-2- [(4-chlorophenyl) methoxyjphenyl] methyl] -4-piperidino ethanamine. X NMR (DMSO-d6 / TFA): d '1.26-1.96 (m, • 15 5H), 2.64-3.42 (m, 6H), 4.18-4.30. (m, 2H), 5.12-5.16 (m, 2H), 7.08-7.14 (m, 1H), 7.38-7.50 (m, 4H), 7.53-7.58 (m, ÍH), 7.68-7.70 (m, ÍH) , 7.76 (br.s, 3H), 9.20-9.40 (br.s, ÍH).

L - [[5-bromo-2- [(4-chlorophenyl) methoxyjphenyl] methyl] -N-methyl-4-piperidinemethanamine. XH NMR (DMSO-d6 / TFA): d 1.30-1.90 (m, 5H), 2.60-3.40 (m, 6H), 4.16-4.24 (each s, 2H), 5.06 (br.s, "2H), 7.00 (m, '1H), 7.28-7.40 (m, 4H), 7.47 (m, ÍH), 7.60-7.76 (m, ÍH), 8.36 (br.s, 1H), 9.20-9.30 (m, 1H).

Example 10: [l - [[5- bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] (ethyl) carbamic acid, 1-dimethylethyl ester.

To a suspension of NaH (220 mg, 95%, 12.7 mmol) in DMF (5 mL) was added a solution of 1,1-dimethylethyl ester of [l - [[5-bromo-2- [(4- chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] carbamic acid (4.2 g, 8.3 mol) in DMF (15 mL) at room temperature under N2. After 3'h to temp. amb., EtI (0.75 mL, 9.4 mmol) was added. Mix The resultant was stirred to t.a. under N2 for 24 h, and it was emptied in ice water while stirring vigorously.

The solid was collected by filtration, and was redissolved in CH2C12. The organic solution was washed with water and ice, dried over Na 2 SO 4, and concentrated. The residue was purified by flash chromatography to provide the title compound as a white powder. XH NMR (DMSO-d6 / TFA): d 0.92-1.04 (m, 3H), 1.38 (br.s, 9H), 1.70-1.80 (, 2H), 1.92-2.04 (, 2H), 2.96-3.22 (m , 4H), 3.40 (m, 2H), 3. 92 (m, ÍH), 4.24 and 4.37 (each m, 2H), 5.13 and 5.18 (each s, 2H), 7.16-7.21 (m, 1H), 7.42-7.56 (, 4H), 7. 59-7.65 (m, 1H), 7.72 and 7.81 (each d, 1H); 9.20 and 9. 50 (each br.s, 1H).

The following compound was prepared in a similar way: 1, 1-dimethylethyl ester [l - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] (methyl) carbamic H NMR (DMSO-de / TFA): d 1.24-1.70 (m, 12H) 7 2.02 (m, 2H), 2.85 (s, 3H), 2.90 (m, 2H), 3.10 (m, 2H), 3.55 (s, 2H), -5.00 (s, 2H), 6.75 (d, ÍH), 7.29 (dd, 1H), 7.35 (br.s, 4H), 7.50 (d, ÍH).

Example 11: 1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -, N-diethyl-4-piperidinamine.

To a stirred solution of l - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinamine (1.5 g, 3.66 mmol) in CH2C12 (30 mL) was added acetaldehyde ( 0.3 mL), . 3 mmol), followed by NaBH (OAc) 3. After 12 h, the solvent was removed and the resulting residue was diluted with EtOAc. The organic phase was washed with brine, and dried over Na2SO4. Concentration, followed by purification by flash chromatography, afforded the title compound as a white powder. XH NMR (CDC13): d 1.34 (t, 6H), 1. 82 (br.ddd, 2H), 1.98 (br.d, 2H), 2.12 (br.'dd, 2H), 3.00 (br.d, 2H), 3.08 (q, 4H), 3.17 (m, ÍH), 3.52 (s, 2H), 5.00 (s, 2H), 6.76 (d, ÍH), 7.28-7.38 (m, 5H) ), 7.45 (d, ÍH).

Example 12: N- [1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] -N '- (4-fluorophenyl) -urea.

To a stirred solution of l - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinamine (544 mg, 1.33 mol) in -CH2C12"(5 mL) was added 4-fluorophenyl isocianat'o (200 mg, 1.46 mmol). the reaction was stirred at room temperature for 3 h, then purified directly by column chromatography to provide the title compound. XH NMR (400 MHz, DMSO-d) : 1.4 (m, 2H), 1.76 (m, 2H), 2.1 (m, 2H), 2.7 (, 1H), 3.3 (d, 1H), 3.5 (br.s, 2H), 5.1 (s, 2H) , 6.1 (br.s, 1H), 7.0 (m, 3H), .7.4 (m, 3H), 7.46 (, 5H), '8.4 (s, 1H).

The following compounds were prepared in a similar manner: • N- [l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -3-pyrrolidinyl] -N '- (4-f luorofenyl) -urea. Starting with 1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -3-pyrrolidinamine and 4-f luorofenyl isocyanate. 1 H NMR (400 MHz, DMSO-dg): d 1.5 (m, HH), 2.16 (m, 1) 2.34 (m, HH), 2.4 (m, 1H), 2.6 (m, 1H), 2.7 (m, ÍH), 3.3 (br.s, ÍH), 3.6 (s, 2H), 4.1 (br.s, 1H), 5.1 (s, 2H), 7.0 (m, 3H), 7.46 (, 3H), 7.43 ( m, 5H), 8.36 (s, 1).

N - [[1 - [[5-bromo-2- [(4-chlorofenyl) methoxyl] fyl] methyl] -4-piperidinyl] methyl] -N '- (4-f luorofenyl) -N-methyl -urea Starting with: l - [[5-bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -N-methyl-4-piperidinomet anamine and 4-f luorofenyl isocyanate. XH NMR (DMSO-de / TFA): d 1.28-2.00 (m, 5H), 2.86-3.40 (m, 9H), 4.20 and 4.28 (each d, 2H), '5.12' (s, 2H), ' 6.22-6.99 (m, 2H), 7.08-7.12 (m, ÍH), 7.32-7.50 (m, 6H), 7.54 (dd, ÍH), 7.66 and 7.72 (each d, 1H), 8.20 (br.s , ÍH), 9.00-9.20 (m, ÍH).

N - [[1 - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] ~ 4-piperidinyl] methyl] -N '- [(4-f luorofenyl) methyl] - N-methyl-urea Starting with: l - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -N-methyl-4-piperidinometanami and 4-f luorof-enylmethyl isocyanate. aH NMR (DMSO-d6 / TFA): d 1.08-1.90 (m, 5H), 2.75 (s, 3H), 2.80-3.40 (m, 6H), 4.10-4.26 (m, 4H), 5.10 (s, 2H) ), 7.00 (br-.dd, ÍH), 7.10 (m, 1H), 7.19 (br.dd, 2H), 7.34-7.48 (m, 4H), 7.53 (br.dd, 1H), 7.62-7.72 (m, 1H), 9.00-9.20 (m, 1 HOUR) .

Example 14: N- [1 - [[5-bromo-2 - [(4-chlorophenyl) -methoxyphenyl] methyl] -3-pyrrolidinyl] -2-chloroacetamide.

To a stirred solution of l - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -3-pyrrolidinamide (238 mg, 0.6 mmol) in CH2C12 (5 L) at 0 ° C, added Et3N (0.4 mL) followed by 2-chloroacetylchloride (102 mg, 0.9 mmol). After the addition, the reaction mixture was stirred at room temperature for 3 h, then was quenched with NaHCO 3 (sat 10 mL) The reaction mixture was extracted with EtOAc (3x25 mL), washed with brine ( 1x15 mL), and dried over Na 2 SO.The concentration followed by purification by column chromatography afforded the title compound.XH NMR (400 MHz, DMSO-d 6): d 2.2 (m, 1H), - 2.5 (m, 1H). ), 3.0 (m, ÍH), 3.2 (m, 'ÍH), 3.8 (, ÍH), 4.0 (s, 2H), 4.25 (dd, 2H), 4.8 (m, ÍH), 5.1 (s, 2H) , 6.9 (d, ÍH), 7.37 (dd, 4H), 7.5 (dd, 1H), 7.63 (d, ÍH), 8.6 (br.s, ÍH).

The following compounds were prepared in a similar manner, starting with different amines and acetyl chlorides: Salt of N - [[l - [[5-bromo-2- [(4-chlorophenii) methoxy] phenyl] methyl] -4-piperidinyl] methyl] acetamide trifluoroacetic acid. Started with: l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] 4-piperidinomethanamine and acetic anhydride. 1 H NMR (DMSO-d6 / TFA): d 1.26-1.84 (m, 8H), 2.88-3.40 (m, 6H), 4.20-4.34 (m, 2H), 5.16-5.20 (m, 2H), 7.14-7.18 (m, ÍH), 7.44-7.54 • (, 4H), 7.60 (dd, 1H), 7.70-7.74 (m, ÍH), 7.95- (br.t, ÍH), 9.10-9.30 (m, ÍH).

De-acid. N- [l- [5-bromo-2 - [- (4-chlorofenyl) met oxy] phenyl] methyl] -4-piperidinyl] acetamide trifluoroacetic acid. Starting with l - [[5-bromo-2 ~ [(4'-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinamide and acetyl chloride. NMR (DMSO-d6 / TFA): d 1.46-1.92 (m, 7H), 3.00-3.40 (, 4H), 3.65-3.90 (m, ÍH), 4.15-4.25 (m, 2H), 5.10-5.20 (m, 2H), 7.12-7.18 (, ÍH), 7.40-7.54 (m, 4H), 7.60 (m, ÍH), 7.66-7.74 (m, ÍH), 7.94 (m, ÍH), 9.34 (br. Yes H) .

Example 14: N- [1 - [[5-Bromo-2 - [(4-chlorophenyl) -methoxyphenyl] methyl] -3-pyrrolidinyl] -N-methyl-2-pyrazinecarboxamide.

To a stirred solution of l - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -N-methyl-3-pyrrolidinamine '(234 mg, 0.59 mmol) in DMF (5 mL), Et3N' (237.4 mg, 2.35 mmol) was added, followed by 2-piperazinecarboxylic acid (88 mg, 0.71 mmol) and HATU (305 mg, 0.8 mmol). a ta After 12 h,. the reaction was quenched with NaHCO3 (sat 10 mL), and extracted with EtOAc (3x15 mL). The organic phase was washed with brine- (1x15 mL), and dried over Na2SO4. Concentration, followed by purification through column chromatography, afforded the title compound. H NMR (400 MHz, DMSO-d6): - d 1.9 (m, 1H), 2.38 (m, ÍH), 2.63 (m, ÍH), 2.8 (s, 2H), 3.1 (d, 3H), - 3-.4 (m, 1H), 3. 6 (dd, 2H), 5.0 (s, 2H), 6.8 (d, ÍH), 7.3 (dd, 1H), 7.35 (dd, 4H), 7.47 (dd, ÍH), 8.53 (br.s, ÍH), 8.62 (d, ÍH), 8.9 (dd, ÍH), 7.54 (m, 6H), 7.60 (m, ÍH), . 7.68-7.76, (m, ÍH), 8. 54-8.64 (m, ÍH), 9.24-9.40 (m, 1H).

The following compounds were prepared in a similar manner: N - [[1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] methyl] -N, -dimethyl-3-piperidinecarboxamide. Starting with: l - [[5-Bromo-2 - [(4-chlorophenyl) methoxyjphenyl] methyl] -N-methyl-4-piperidinomethanamine and 4-methyl-3-pyridinecarboxylic acid. 1 H NMR (DMSO-d 6 / TFA): d 1.00-2.26 (m, 5H), 2.44-2.52 (m, 3H), 2.80-3.54 (m, 9H), 4.20-4.44 (m, 2H), 5.14 (m , 2H), 7.14-7.20 (m, HH), 7.40-7.78 (, 6H), 7.96-8.04 (m, 1H), 8.80-8.96 (m, 2H), 9.20-9.30 (m, 1H).

Example 15: [l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] carbamic acid methyl ester.

To a stirred solution of l - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinamine "(246 mg, 0.6 mmol) in CH2C12 (5 mL) at 0 ° C, Et3N (0.4 mL) was added followed by methyl chloroformate (6-8- = - mg, - - 0.7-2 mmol) -_.-. After the addition, the reaction mixture was stirred at room temperature for 1 h, and was quenched with NaHCO 3 (sat 3 L) The reaction mixture was extracted with EtOAc (3x25 mL), washed with brine (1x15 mL) , and dried over Na 2 SO.The concentration followed by purification through column chromatography, gave the title compound Yi NMR (DMSO-d 6 / TFA): d 1.50-1.94 (m, 4H), 3.00- 3.70 (m, 8H), 4.16-4.22 (, 2H), 5.14-5.18 (m, 2H), 7.13-7.16 (m, 1H), 7.40-7.52 (m, 4H), 7.57-7.61 (m, 1H) , 7.66-7.71 (m, ÍH) Y Example 16: 4 - [[4-Bromo-2- [(diethylamino) -methyl] phenoxy] methyl] benzoic acid.

To a stirred solution of 5-bromo-2-hydroxybenzaldehyde (15 g, 75 mmol) in DMF (250 mL) was added K2CO3 (20.7 g, 150 mmol) at t.a. After 30 min, 4-bromomethylbenzoic acid methyl ester (17.2 g, 75 mmol) was added. The reaction mixture was maintained at t.a. overnight, then it was emptied - into a mixture of EtOAc / water cooled on ice (1: 1, 2L). The solid was collected by filtration, washed with water, and dried under vacuum for 20 h to give 4 - [[4-bromo-2 ~ (bromomethyl) -'-phenoxy] methyl] benzoic acid methyl ester (23 g, 88% ). To a stirred solution of methyl ester of - [[4-bromo-2- (bromomethyl) -phenoxy] methyl] benzoic acid methyl ester (10 g, 28.6 mmol) in EtOAc (200 mL) was added diethylamine (2.2 g, 76 mmol ) and HOAc (2 L), followed by NaBH (OAc) 3 (19 g, 90 mmol) at rt After 12 h, the mixture was diluted with EtOAc (250 mL), washed with brine (2x120 L), and dried over Na 2 SO 4. Concentration followed by purification by flash chromatography provided the ester (10.1 g, 87%). This ester '(10.1 g, 24.8 mmol) was hydrolysed with LiOH * H20 (1.32 g, 32 mmol) in THF (150 mL) and H20 (100 mL) at t.a. for 10 h, to provide the acid (9.4 g, 97%). XH NMR (400 MHz, DMSO): d 0.99 (t, 6H), 2.46 (q, 4H), 3.61 (s, 2H), 4.85 (s, 2H), 6.72 (d, ÍH), 7.0-7.2 (m , 4H), 8.1 (d, 2H).

Example 17: 5-bromo-N, N-diethyl-2 - [[4 - [[4- (phenylmethyl) -l-piperazinyl] carbonyl] phenyl] methoxy] benzene-methanamine.

To a stirred solution of 4 - [[4-bromo-2- [(diethylamino) methyl] phenoxy] methyl] benzoic acid (196 mg, 0.5 mmol) in THF (5 mL), EDC (115 mg) was successively added. , 0.6 mmol) and HOBT (81 mg, 0.6 mmol). After 15 min, 1-benzylpiperazine (0.091 mL), 0.53 mmol) was added. The reaction was stirred at t.a. overnight, and the solvent was concentrated in vacuo. The residue was diluted with ethyl acetate, washed with a 1M solution of Na2HS0, saturated NaHC03, and brine, and dried over Na2SO4. Concentration followed by purification by flash chromatography afforded the title compound. 1H NMR (CD3OD, 400 MHz) d (TMS) 1.05 (m, 6H), 2.55 (m, 8H), 3.45 (m, 2H), 3.55 (s, 2H), 3.70 (m, 4H), 5.15 (s) , 2H), 6.95 (d, ÍH), 7.30 (m, 6H), 7.40 (m, 2H), 7.50 (m, 1H), 7.54 '(m, 2H).' The following compounds were prepared in a similar way: N- (1,3-benzodioxo-5-ylmethyl) -4 - [[4-bromo-2- [(diethylamino) methyl] phenoxy] methyl] benzamide. XH NMR (CDC13, 400 MHz) d (TMS) 1.05 (t, 6H), 2.58 (q, 4H), 3.60 (s, 2H), 4.55 (d, 2H), 5.10 (s, 2H), 5.95 (s) , 2H), 6.35 (m, _1H), 6.80 (, 4H), 7.25 (, ÍH), 7.50 (d, 2H), 7.60 (s, ÍH), 7.80 (s, 2H). 4 - [[4-Bromo-2- [(diethylamino) methyl] phenoxy] methyl] -N- • [(4-methoxyphenyl) methyl] benzamide. 1H NMR (CDC13, 400 MHz) d (TMS) 1.05 (t, 6H), 2.58 (m, 4H), 3.60 (s, 2H), 3.80 (s, 3H), 4.60 (d, 2H), 5.10 (s, 2H), 6.30 (m, 1H), 6.70 (d, ÍH), '6.90 (d, 2H), 7.30 (m, 3H), 7.48 (d, 2H), 7.60 (s, ÍH), 7.80 (d, 2H). 4 - [[4-bromo-2- [(diethylamino) methyl] f-enoxy] methyl] -N-methyl-N- (2-f-eylethyl) -benzamide. XH NMR (CDC13, 400 MHz) d (TMS) 1.05 (t, 6H), 2.55 (m, 4H), 2.85 (s, .3H), 3.0 (m, ÍH), 3.16 (m, 1H), 3.50 ( , ÍH), 3.60 (s, 2H), 3.80 (m, 1H, 5.05 (s, 2H), 6.75 (d, HH), 6.95 (m, 1H), 7.10 (m, 1H), 7.30 (m, 7H) ), 7.60 (s, ÍH). 4 - [[4-Bromo-2- [(diethylamino) methyl] phenoxy] methyl] -N- [2- (4-bromo-phenyl) -ethyl] -benzamide. ^ NMR (CDC13, 400 MHz) d (TMS) 1.05 (t, 6H), 2.58 (q, 4H), 2.90 (t, 2H), 3.60 (s, ÍH), 3.70 (q, 2H), 5.10 (s) , 2H), 6.20 (m, ÍH), 6.70 (d, 1H), 7.10 (d, 2H), 7.25 (m, ÍH), 7.45 (m, 4H), 7.60 (s, '1H), 7.70 (d , 2H).

Example 18: 4- [4 - [[4-bromo-2- [(diethylamino) methyl] -phenoxy] methyl] benzoyl] -N-octyl-l-piperazinecarboxamide. -bromo-N, N, diethyl-2 - [[4- (1-piperazincarbonyl) -phenyl] methoxy] -benzenemethanamine (99 mg, 0.23 mmol) was dissolved in CH2Cl2 (5 mL), and octyl isocyanate (50 mg) was added. mg, 0 ..- 32 mmol). The reaction mixture was stirred at t.a. for 2 h. The solvent was concentrated in vacuo. Flash chromatography afforded the title compound. 1H NMR (CDC13, 400 MHz) ': d TMS) 0.90 (t, 3H), 1.05 (m, 6H), 1.30 (m, 10), 1.50 (, 2), 2.60 (m, 4H), 3.25 (m , 2H), 3.45 (m, 6H), 3.60 (s, 2H), 3.78 (m, 2H), 4.45 (m, 1H), 5.10 (s, 2H), 6.78 (d, ÍH), 7.30 (m, 1H), 7.45 (m, 4H), 7.65 (s, ÍH): Example 19: 5-bromo-N, N -diethyethyl-2 - [[4 - [[4 - [[3-nitrophenyl] sulfonyl] -l-piperazinyl] carbonyl] phenyl] methoxy] -benzenemethanamine.

-Bromo-N, N-diethyl-2 - [[4- (1-piperazinylcarbonyl] -phenyl] methoxy] benzenemethanamine (91. mg, 0.21 mmol) was dissolved in CH2C1 (5 mL), and -nitrobenzenesulfonyl (50 mg, 0.23 mmol) followed by triethylamine (0.043 mL, 0.34 mmol) and DMAP (2 mg), After 2 h, the solvent was removed in vacuo, flash column chromatography on silica gel. with a gradient of 1% to 3% MeOH in CH 2 Cl 2 yielded the title compound X H NMR (DMSO-d 6, 400 MHz): d (TMS) 0.95 (t, 6 H), 2.40 (m, 4 H), 3.0 ( m, 4H), 3.40-3.65 (m, 4H), 3.50 (s, 2H), 5.10 (s, 2H), 6.95 (d, ÍH), 7.35 (, 3H), 7.45 (m, 3H), 7.95 (t, ÍH), 8.15 (d, ÍH), 8.30 (s, 1H), 8.55 (d, ÍH).

The following compounds were prepared in a similar manner: -bromo-N, N-diethyl-2 - [[4 - [[4- (2-f uranylcarbonyl) -1-piperazinyl] carbonyl] phenyl] methoxy] benzenemethanamine. H NMR (CDC13, 400 MHz) d (TMS) 1.05 (t, 6H), 2.60 (q, 4H), 3.50- 3.90 (, 8H), 3.60 (s, 2H), 3.80. (s, 2H), 5.10 (s, 2H), 6.50 (s, 1H), 6.75 (d, 1H), 7.05 (d, ÍH), 7.30 (m, 1H), 7.50 (m, 5H), 7.60 ( s, 1H).

-Bromo ~ 2 ~ [[4 - [[4 ~ (2,6-dichlorobenzoyl) -1-piperazinyl] carbonyl] phenyl] methoxy] -N, N-diethylbenzene-methanamine: MS: 634 (M + 1). XH NMR (CDC13, 400 MHz): d (TMS) 1.05 (ra, 6H), 2.55 (m, 4H), 3.30 (m, 2H), 3.60 (s, 2H), 3.850 (m, 6H), 5.08 ( s, 2H), 6.70 (d, 1H), 7.25 to 7.50 (m, 8H), 7.60 (s, 1H).

N - [[5 - [[4- [4 - [[4-bromo-2- [(diethylamino) methyl] f-enoxy] methyl] benzoyl] -l-piperazinyl] sulfonyl] -2-thienyl] methyl] -benzamide . MS: 740 (M + 1). XH NMR (CDC13, 400 MHz): d (TMS) 1.05 (t, 6H), 2.55 (q, 4H), 3.10 (, 4H), 3.55-3.90 '(m, 4H), 3.60 (s, 2H), 4.80 (d, 2H), 5.06 (s, 2H), 6.70 (d, ÍH), 6.85 (m, ÍH), 7.05 (d, 1H), 7.25 (m, ÍH), 7.36 (m, 3H), 7.45 (m, 4H), 7.54 (m, 1H), 7.60 (s, ÍH), 7.80 (m 2H).

Example 20: l - [(5-Bromo-2-propoxyphenyl) methyl] -4- (4-fluorophenyl) -4-piperidinol.

A "A stirred mixture of 5-bromo-2-propoxy-benzaldehyde '(200 mg, 0.82 mmol) and 4- (4-fluorophenyl) -4-piperidinol (177 mg, 0.9 mmol) in EtOAc (10 mL) was added. add HOAc (70 mg, 1.2 mmol), followed by NaBH (OAc) 3 (262 mg, 1.2 mmol) at room temperature After 16 h, the reaction was developed in the usual way, and purified by column chromatography. to give the title compound as a white solid.1 NMR (DMSO-d6, 400 MHz): d 0.8-1.1 (t, 3H), 1.6-1.9 (m, 5H), 2.0-2.2 (m, 2H), 3.0-3.6 (m, 2H), 3.9-4.1 (m, 2H), 4.2-4.4 (m, 2H), 5.4-5.6 (m, 1H), 7.0-7.3 (m, 3H), 7.34-7.5 (m , 2H), 7.54-7.64 (m, 1H), 7.7-7.8 (m, ÍH). ' The following compounds were prepared in a similar way: [4-Bromo-2 - [[4- (4-bromophenyl) -4-hydroxy-l-piperidinyl] methyl] phenoxy] -0-ethyloxymethanal. aH NMR. (CDC13, 400 MHz): d 1.2-1.4 (m, 3H), 1.4-1.8 (m, 4H), 2.0-2.3 (m, 2H), 2.4-2.6 (m, 2H), 2.7-2.9 (, 2H) ), 3.5-3.68 (d, 2H), 4.1-4.3 (, 2H), 4.6 (d, ÍH), 4.8 (m, ÍH), 6.6-7.0 (m, 1H), 7.24-7.6 (m, 6H) . l- [(5-Bromo-2-propoxyphenyl) methyl] -4- (4-chlorophenyl) -4-piperidinol. 1H NMR (DMS0-d6, 400 MHz): d 0.8-1.1 (t, 3H), 1.4-1.6 (m, 2H), 1.6-1.8 (m, 4H), 1.8-2.0 (m, 2H), 2.3- 2.7 (m, 23.4-3.6 (m, 2H), 3.8-4.0 (m, 2H), '4.8-5.0. (S, 1H), 6.8-7.0 (m, 1H), 7.3-7.4 (m, 3H) , 7.4-7.6 (m, 3H). l - [[5-Bromo-2- (pentyloxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol. H NMR (DMSO-d6, 400 MHz): d 0.8- - 1.0 (t, 3H), 1.0-1.2 (m, 2H), 1.2-1.5 (m, 4H), 1.6-1.84 (m, 3H), 2.0 -2.3 (, 1H), 3.0-3.6 (m 4H), 3.9-4.1 (m, 2H), 4.2- - 4.4 (m, 2H), 5.5-5.7 (m, 1H), 7.0-7.2 (m, ÍH) ), 7.3-7.4 (, 2H), 7.5-7.7 (m 3H), 7.7-7.8 (m, ÍH). l - [[5-Bromo-2- (hexyloxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol. XH NMR (DMSO-d6, 400 MHz): d 0.7-1.0 (t, 3H), 1.0-1.5 (m, 6H), 1.6-1.9 (m, 4H), 2.0-2.2 (m, -H), 3.0 -3.6 (, 4H) ', 3.9-4.1 (m, 2H), 4.2-4.4 (m, 2H),' 5.5- 5.7 (m, ÍH), 7.0-7.2 (m, 1H), 7.3-7.4 (, 2H), 7.5-7.7 (m, 3H), 7.7-7.8 (m, 1H). l- [(5-Bromo-2-methoxyphenyl) methyl] -4- (4-bromofenyl) -4-piperidinol. XH NMR (DMS0-d6 / TFA): d 1.70-1.80 (m, 2H), 2.15 (m, 2H), 3.30 (m, 4H), 3.85 (s, 3H), 4.30 and 4.45 (each d, 2H) ), 7.06-7.10 (m, ÍH), 7.32-7.54 (m, 4H), 7.60 (dd, ÍH), 7.68-7.77 (m, ÍH), 9.30 (br.s, 1H). l - [[5-Bromo-2- (1,3-dioxolan-2-ylmethoxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol. XH NMR (CDC13): d 1.73 (m, 2H), 2.24 (ddd, 2H), 2.70 (ddd, 2H), 2.95 (m, 2H), 3.76 (s, 2H), 3.94-4.07 (m, 6H) , 5.29 (dd, 1H), 6.76 (d, 1H), 7.35 (dd, ÍH), 7.39 (, 2H), 7.47 (m, 2H), 7.55 (d, 1H).

Example 21: l - [(5-Bromo-2-hydroxyphenyl) methyl] -4- (4-bromophenyl) -4-piperidinol.

To a stirred mixture of 5-bromo-2-hydroxybenzaldehyde (7.06 g, 35 mmol), 4 (4-bromophenyl) -4-pipefinidol (10 g, 39 mmol), and HOAc (6 mL) in EtOAc (250 L) NaBH (OAc) 3 (7.4 g, 35 mmol) was added at The mixture was stirred at t.a. overnight, and diluted with EtOAc (300 mL), washed with brine (2x100 L), and dried over Na 2 SO 4. Concentration followed by purification through flash chromatography provided the title compound. 1 H NMR (400 MHz, DMS0-d 6): d 1.4-1.7 (m, 2H), 1.8-2.0 (m, 2H), 2.3-2.6 (m, 2H), 2.6-2.8 (m, 2H), 3.5- 3.8 (, 2H), 6.6-6.8 (, 1H), 7.2 (m, 2H), 7.2-5 (m, 4H).

Example 22: l - [[5-Bromo-2- (2-methylpropoxy) phenyl] -methyl] -4- (4-bromophenyl) -4-piperidinol.

A mixture of l- [5-bromo-2-hydroxyphenyl) methyl] -4- (4-bromophenyl) -4-piperidinol (150 mg, 0.34 mmol), Cs2C03 (200 mg, 0.61 mmol) in DMF (5 L) , in a sealed tube, was stirred at for 5 min, and isobutyl iodide (0.05 mL, 0.43 mmol) was added. The reaction was stirred at 50 ° C for 0.5 h, then s 75 ° C overnight (the reaction was monitored by HPLC). The reaction mixture was poured into ice water, and the crude product was obtained by filtration. The crude solid was redissolved in CH2C12, and dried over Ma2S04. Concentration, followed by HPLC, gave the title compound as a white powder, trifluoroacetic acid salt. hi NMR (DMSO-d6 / TFA): d 0.90 (d, 6H), 1.77 (br.d, 2H), 2.00-2.20 (m, 3H), 3.32 (m, 4H), 3.80 (d, 2H), 4.30 (d, 2H), 7.08 (d, ÍH), 7.34 (m, 2H), 7.52 (m, 2'H), 7.58, (dd, ÍH), 7.73 (d, ÍH).

The following compounds were prepared in a similar way: L - [[5-bromo-2- (heptyloxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol trifluoroacetic acid. 1H NMR (DMSO- 'd6 / TFA): d 0.83 (t, 3H), 1.11-1-44 (m, 8H) 1.68-1.80 (m 4H), 2.14 (m, 2H), 3.30 (m, 4H) , 4.02 (t, 2H), 4.28 (d, 2H), 7. 08 (d, ÍH), 7.34 (m, 2H), 7.52 '(m 2H), 7.59 (dd, ÍH), 7. 71 (d, 1H).

Acid l - [[5-bromo-2- (cyclopropylmethoxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol trifluoroacetic. 1 H NMR (DMSO-d 6 / TFA): - d 0.93 (m, HH), 1.48 (br.d, 2H), 1.84 (br.ddd, 2H), 3.06 (m, 4H), 3.60 (d, 2H) , 4.00 (d, 2H), 6.76 (d, 1H), 7.05 (m, 2H), 7.23 (m, 2H), 7.27 (dd, 1H), 7.42 (d, ÍH).

L - [(5-Bromo-2-butoxyphenyl] methyl] -4- (4-bromophenyl) -4-piperidinol trifluoroacetic acid. 1 H NMR (DMSO-d6 / TFA): d 0.93 (t, 3H), 1.42 (m , 2H), 1.64-1.82 (m, 4H), 2.14 (m, 2H), 3.30 (m, 4H), 4.02 (t, 2H), 4.28 (d, 2H),GIVE. 7. 09 (m, 1H), 7.36 (m, 2H), 7.53 (m, 2H), 7.58 (m, 1H), 7. 72 (d, 1H).

L - [[5-bromo-2- (2-methoxyethoxy) f-enyl] methyl] -4- (4-bromofenyl) -4-piperidinol trifluoroacetic acid. 1H NMR (DMSO-d6 / TFA): d 1.50 (br.d, 2H), 1.83 (br.ddd, 2H), 3.00 (s, 3H), 3.05 (m, 4H), 3.40 (m, 2H), 3.90 ( , 2H), 4.00 (d, 2H), 6.84 (m, ÍH), 7.07 (, 2H), 7.24 (m, 2H), 7.32 (m, ÍH), 7.45 (d, ÍH). 4- (4-Bromophenyl) -l- [(5-bromo-2-propoxyphenyl) methyl] -4-piperidinol trifluoroacetic acid. 1 H NMR (DMSO-ds / TFA): d 0.97 (t, 3 H), 1.68-1.84 (m, '4 H), 2.09-2.18 (m, 2 H), 3.30 (m, 4 H), 3.98 (m, 2 H) , 4.29 (d, 2H), 7.07 (, ÍH), 7.34 (m, 2H), 7.52 (m, 2H), 7.58 (m, 1H), 7.71 (d, 1H).

L- [(5-Bromo-2-ethoxyphenyl) methyl] -4- (4-bromophenyl) -4-piperidinol trifluoroacetic acid. 1 H NMR (DMSO-d 6 / TFA): d 1.34 (t, 3 H), 1.77 (m, 2 H), - 2.14 (m, 2 H), 3.30 (, 4H), '4.08 (q, 2H), 4.28 (m, 2H), 7.07 (m, ÍH),. 7.34 (, 2H), 7.52 (m, 2H), 7.58 (, 1H), 7.71 (d, ÍH). ' 4- (4-Bromophenyl) -l - [[5-bromo-2- (2-propenyloxy) phenyl] methyl] -4-piperidinol trifluoroacetic acid. aH NMR (DMSO-de / T'FA): d 1.75 (m, 2H), 2.15 (m, 2H), 3.30 (m, 4H), 4.30 (d, 2H), 4.53 (d, 2H), 5.25 ( d, 1H), 5.40 (d, 1H), 6.01 (, ÍH), 7.08 (m, ÍH), 7.34 (m, 2H), 7.52 (m, 2H), 7.59 (m, 1H), 7.72 (d, ÍH). • Acid [(5-bromo-2 - [[4- (4-bromophenyl-4-hydroxy-1-piperidinyl] methyl] phenoxy] -acetonitrile trifluoroacetic acid kH NMR (DMSO-d6 / TFA): d 1.85 (br.d , 2H), 2.20 (m, 2H), 3.40 (m, 4H), 4.40 (d, 2H), 5.35 (s, 2H), 7.32 (d, ÍH), 7.42 (m, 2H), 7.60 (m, 2H), 7.79 (m, 1H), 7.88 (d, 1H).

Pla y axis 23: N- [2- [4-bromo [2 - [[4- (4-bromophenyl) -4-hydroxy-l-piperidinyl] methyl] phenoxy] ethyl] -N '-ethyl-urea.

To a suspension of LiAlH4 (90 mg, 2.5 mmol) in Et20 (10 mL, anhydrous), was added dropwise a solution of [4-bromo [2 - [[4- (4-bromophenyl) -4-hydroxy-1-piperidinyl] methyl] phenoxy] acetonitrile (1.0 mmol) in Et20 (10 mL) at 0 ° C. After the addition, the mixture was stirred at r.t. 10 for 2 h, and then quenched with the addition of 15% NaOH (90 mL), and water (0.3 mL). MgSO 4 (8 g) was added to the resulting mixture, and vigorously stirred for 0.5 h. After removing the solvent, a crude product was obtained which was purified by HPLC to obtain l - [[2- (2-amino-a-methoxy) -5-bromophenyl] methyl] -4- (4-bromophenyl-4-piperinidol 1H NMR (DMSO-de / TFA): d 1.50 (d, 2H), 2.10 (, 2H), 3.15-3.30 (m, 6H), 4.12 (t, 2H), 4.35 (d, 2H), 7.02 (d, HH), 7.28 (m, 2H), 7.45 (m, 2H), 7.54 (m, HH), 7.69 (d, 1H). To a solution of l - [[2- (2 - 20. aminoethoxy-5-bromophenyl] methyl] -4- (4-bromophenyl-4-piperidinol ((100 mg, 0.21 mmol), and Et3N (0.15 L, 1.1 mmol) in CH2C12 (5 mL) was added EtNCO (0.03 mL, 0.4 mmol), at t.a. The mixture was stirred at t.a. under N2 during the night. After concentrating, the residue was purified by HPLC to give the title compound as an acid salt. trifluoroacetic (light yellow syrup). .1H NMR. (DMSO- 'd6 / TFA): d 0.95 (t, • 3H), 1.80 (br.d, 2H), 2.20 (m, 2H), 2.90 (q, 2H), 3.30 (m, 4H ), 3.4-0 (t, 2H), 4.00 (t, 2H), 4.30 (d, 2H), 7.06 (d, 1H), 7.35 (m, 2H), 7.53 (m 2H), 7.58 (, ÍH) 7.68 (d, 1H).

Example 24: 2-Bromo-l- [5-bromo-2 - [(4-allopurhenyl) -methoxyphenyl] -ethanone.

To a stirred solution of. 5-bromo-2-hydroxy-acetophenone (54 g, 0.25 mmol) in DMF (500 L) was added K2CO3 (100 g, 0.23 mol) at t.a. After 30 min, it was added • 4-chlorobenzyl chloride (36.6 g, 0.23 mmol) in one portion, and the fraction was kept at 70 ° C for 4 h. The mixture was cooled to t.a., and poured into an ice-cooled mixture of EtOAc / water (1: 1, 2L). The solid was collected by filtration, washed with water, and dried in vacuo for 20 h, to give 2- [5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] ethanone (65 g, 83%) . To a suspension of 2- [5-bramo-2 ~ [(4-chlorophenyl) methoxy] phenyl] -ethanone (20 g, 59 mmol) in CH2C12 (140 mL) -HOAc (5 mL) was added dropwise a Br 2 / CH 2 Cl 2 solution (14% 26 mL, 84 mmol) at rt under N2. After 3 h, the mixture was concentrated to the minimum volume, and the product precipitated. The solid was purified by recrystallization to give the product (11 g) as dark orange crystals. X H NMR (400 MHz, DMSO-d 6): d 3.3 (s, 2 H), 4.72 (s, 2 H), 5.14 (s, 2 H), 7.21 (d, Í H), 7.41 (d, 2 H), 7.5 (d , 2H), "7.72 (dd, ÍH), 7.76 (d, ÍH).

The following compounds were prepared in a similar way: Methyl ester of '4 - [[4-bromo-2- (bromoacetyl) phenoxy] methyl] benzoic acid. l-. { 2- ([l, l-bi-phenyl] -4-ylmethoxy) -5-bromophenyl] -2-bromoethanone 3 - [[4- [4 - [[4-bromo-2- (bromoacetyl) phenoxy] methyl] - • benzoyl] -l-piperazinyl] sulfonyl] -N-hydroxy-N-oxo-bencenaminium; 2-bromo-l- [5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] -1-propanone Example 25: l- [5-Bromo-2 - [(4-chlorophenyl) methoxy] -phenyl] -2- (dimethylamino) -ethanone.

To a solution of 2-bromo-l- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] ethanone (Ig, 2.6 mmol) in DMF (5 mL) was added Me2NH.HCl (420 mg, 5.2 mmol) and K2CO3 (1 g) while cooling in an ice-water bath. The mixture was stirred under the same conditions for 4 h. The mixture was emptied in ice water while stirring. vigorously. Filtered, the solid was dissolved in EtOAc; washing with brine; dried over Na2SO4, concentrated, and the residue was purified by flash chromatography to give the title compound as a white powder. kH NMR (DMSO-de): d 2.78 (s, 6H), 4.70 (s, 2H), 5.42 (s, 2H), 7.27 (d, 1H), 7.45-7.60 (, 4H), 7.83 (dd, 1H) ), 7.93 - (d, ÍH). • '.

The following compound was prepared in a similar manner: l- [2- ([1,1'-biphenyl] -4-ylmethoxy) ~ 5-bromophenyl] -2- (dimethylamino) -ethanone, initiated with l- [2- ([1,1'-biphenyl] - 4-ylmethoxy) -5-bromophenyl] -2-bromoethanone; 1 H NMR (400 MHz, DMSO-de): 2.8 (s, 6H), 4.78 (s, 2H), 5.4 (s, 2H), 7.32 (d, 1H), 7.36 (dt, 1H), 7.45 (t, 2H), 7.74 (m, 3H), 7.7 (dt, 2H), 7.85 (d, ÍH), 7.95 (d, 1H), 9.8 (Br.s, 1H).

Example 26: Salt of 5-bromo-2 - [(4-chlorophenyl) methoxy] -a - [[(2-hydroxyethyl) (methyl) amino] methyl] -benzenemethanol trifluoroacetic acid.

To a stirred solution of 2-bromo-l- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] ethanone (300 mg, 0.72 mmol) in DMF (5 L) was added MeNHCH2CH2OH (0.3 mL, 3.7 'mmol) at 0 ° C. After 10 min, the mixture was poured into ice water. The solid was collected by filtration, and then redissolved in MeOH (10 mL). The solution was added. NaBH 4 (-100 mg) and the reaction was stirred at r.t. during 1 'h. After removing the MeOH, the residue was diluted with EtOAc, dried over Na 2 SO 4, and concentrated. The residue was purified by HPLC to provide the product as a white powder. XH NMR (DMSO-d6 / TFA): d 2.75-2.90 (m, 3H), 3.05-3.35 (m, 4H), 3.65-3.75 (m, 2H), 5.15 (dd, 2H), 5.27 - (m, 1H), 7.02-7.07 (m, ÍH), 7.42-7.53 (m, 5H), 7.56 (br.s, 1H), '9.20-9.40 (, ÍH).

The following compounds were prepared in a similar way: Acid salt - [5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] -3-hydroxy-1-piperidinoethanol trifluoroacetic acid. l NMR (DMSO-d6 / TFA): d 1.20-2.10 (m, 4H), 2.50-4.00 (m, 7H), 5.10-5.18 (m, 2H), 5.26-5.34 (m, 1H), 7.02-7.07 (m, ÍH), 7.42-7.52 (m, 5H), 7.52- 7.56 (m, 1H), 9.00 and 9.60 (each m, ÍH).

Salt, of acid • a- [5-bromo-2 - [(4-chlorofenyl) methoxy] f-enyl] -3-hydroxy-l-pyrrolidinoethanol trifluoroacetic acid. XH NMR (DMSO-d6 / TFA): d 1.68-2.20 (m, 2H) 2.90-3.70 (m, 6H), 4.34-4.42 (, .1H), 5.10-5.24 (m, 3H), 7.04-7.08 ( m, 1H), 7.45-7.56 (, 6H), '9.80-10.00 (m, 1H). (2S, 4R) -1- [2- [5-Bromo ~ 2 - [(4-chlorophenyl) methoxy] phenyl] -2-hydroxyethyl] -4-hydroxy-2-pyrrolidinecarboxylic acid trifluoroacetic acid salt. H NMR (DMSO-d6 / TFA): d 2.02-2.28 (m, 2H), 3.06-3.54 (, 3H), 3.78-3.94 (m, 1H), 4.34-4.64 (m, ÍH), 4.50-4.66 ( m, HI), 5.10-5.28 (m, 3H), '7.01-7.05 (lH), 7.40-7.50 (m, 5H), 7.54-7.59 (m, 1H).

Salt of 5-bromo-2- [(4-chlorophenyl) methoxy] - - [(dimethylamino) methyl] benzene-methanol trifluoroacetic acid. XH NMR (DMSO-d6 / TFA): d 2.72-2.80 (m 6H), 3.12-3.18 (, 2H), 5.14 (dd, 2H), 5.22 (br.dd, ÍH), 7.05 (d, ÍH), 7.43-7.53 (m, '5H), 7.55 (d, ÍH), 9.50 (br.s, ÍH). 2-Amino-a- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -lH-imidazole-1-ethanol. XH NMR (DMSO-d6 / TFA): d 3.96 (d, 2H), 5.10-5.16 (m, 3H) ', 6.57 (d, 1H), 6.87 (d, 1H), 7.02 (d, ÍH), 7.40 -7.50 (, 7H), 7.54 (d, ÍH), 12.20 (s, ÍH). - [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -4-hydroxy-1-piperidinoethanol. XH NMR (DMSO-d6 / TFA): d 1.48-2.02 (m, 4H), 2.76-3.50 (m, 6H), 3.60-3.88- (each m, ÍH), 5.10-5.18 (, 2H), 5.22 -5.32 (m, ÍH), 7.04 (d, ÍH),. 7.40-7.52 (m, 5H), 7.54-7.58 (m, 1H), 9.40 (br.s, ÍH).

Salt of trifluoroacetic acid of 4 - [[4-bromo-2- [l-hydroxy-2- (4-hydroxy-l-piperidinyl) -ethyl] phenoxy] methyl] benzoic acid methyl ester. It was started with 4 - [[4-bromo-2- (bromoacetyl) phenoxy] methyl] benzoic acid methyl ester and 4-hydroxypiperidine. aH NMR (DMSO-d6 / TFA): d 1.50-2.00 (m, 4H), 2.80-3.70 (m, 7H), 3.82 (s, 3H), 5.24 (br.'s, 2H), 5.28-5.37 ( m, ÍH), 7.10 (d, 1H), 7.32-7.36 (m, 1H), 7.44 (dd, 1H), 7.58-7.63 (, 2H), 7.95-8.00 (m, 2H), 9.30 (br.s , 1 HOUR) . Salt of trifluoroacetic acid of 4 - [[4-bromo-2- [l-hydroxy-2- (3-hydroxy-l-piperidinyl) ethyl] phenoxy] methyl] benzoic acid methyl ester. Initiated with 4 - [[4-bromo-2- (bromoacetyl) phenoxy] methyl] -benzoic acid methyl ester and 3-hydroxypiperidine. 1H NMR (DMSO-d6 / TFA): d 1.20-2.10 (m, 4H), 2.50-4.00 (m, 10H), 5.20-5.30 (m, 2H), 5.30-5.40 (m, HI), 7.06-7.12 (m, 1H), 7.30-7.36 (m, 1H), 7.42-7.46 - (m, ÍH), 7.58-7.64 (m, 2H), 7.96-8.02 (m, 2H), 9.00-9.60 (m, 1H) ). 4 - [[4-Bromo-2- [2- [4 - [[(1, 1-dimethylethoxy) carbonyl] amino] -l-piperidinyl] -l-hydroxyethyl] phenoxy] methyl] benzoic acid methyl ester. It was started with 4 - [[4-bromo-2- (bromoacetyl) phenoxy] methyl] -benzoic acid methyl ester and 4 - [[(1, 1-dimethylethoxy) carbonyl] amino] -l-piperidinyl. 1 H NMR (400 MHz, DMSO): 1.4 (s, 9H), 1.9 (m, 2H), 2.1 (m, ÍH), 2.4 (m, 2H), 2.7 (m, 2H), 3.1 (m, 1H) , 3.5 (br.s, ÍH), 3.9 (s, 3H), 4.5 (br.s, 1H), 5.2 (m, 3H), 6.8 (d, 1H), 7.2 (d, 1H), 7.42 (d , 2H), 7.6 (s, 1H), 8.1 (d, 2H) .. 2- [[1, 1'-biphenyl] -4-ylmethoxy) -5-bromo-a- [(dimethylamino) methyl] -benzenemethanol trifluoroacetic acid salt. It was started with l- [2- ([1,1'-biphenyl] -4-ylmethoxy) -5-bromophenyl] -2-bromoethanone and dimethylamine. XH NMR (400 MHz, DMSO): 2.8 (m, 6H), 3.2 (m, 2H), 5.2 (s, 2H), . 23 (m, 1) 7.1 (d, ÍH), 7.36 (tt, ÍH), 7.46 (m, 3), 7.55 (m, 2H), 7.67"(m, 3H), 9.42 (br.s, ÍH).

Example 27: 4 - [[4-Chloro-2- [l-hydroxy-2- (4-hydroxy-1-piperidinyl) ethyl] f-yl] methyl] benzoic acid.

To a stirred solution of 4 - [[4-bromo-2- [2- [4 ~ [[(1, 1-dimethylethoxy) carbonyl] amino] -l-piperidinyl] -l-hydroxyethyl] phenoxymethyl ester. ] methyl] benzoic acid (3.2 g, 7.88 mmol). in THF (25 mL) and MeOH (25 mL), LiOH (495 mg, 11.83 mmol) in water (25 L) at t.a. After 10 h, the reaction was neutralized with 0.1 N HCl to pH 6, and extracted with EtOAc (3x60 mL). The organic phase was washed with brine (50 mL), and dried over a2S0. Concentration in vacuo followed by purification through a chromatography column gave the title product. 1 H NMR (400 MHz, DMSO-de): 1.75 (m, 4 H), 2 (m, 1 H), 3.08 (, 3 H), 3.24 (, 1 H), 3.4 (m, 1 H), 5.2 (s, 2 H) , 5.4 (dd, ÍH), 7.1 (d, 1H), 7.3 (dd, ÍH), 7.41 (dd, 1H), ..7.52 (d, 2H), 7.83 (d, 2H), 10.6 (br.s , ÍH).

Example 28: l- [5-Bromo-2 - [(4-chlorophenyl) methoxy] -phenyl] -2- (dimethylamino) -1-propanone.

To a stirred solution of 2-bromo-l- [5-bromo-2- [(4-fluorophenyl) methoxy] phenyl] -l-propanone (216 mg, 0.5 mmol) in DMF (3 ral) was added salt of dimethylamine.HCl (108 - mg), and CS2CO3 (494 mg). The reaction mixture was stirred for 2 h at t.a., and 2.5 eq. additional amine. After an additional hour, the DMF concentrated • to vacuum. The resulting residue was diluted with EtOAc, washed with water and brine, and dried over Na2SO4. Concentration in vacuo, followed by purification through flash column chromatography, provided the title compound. XH NMR (CDC13, 400 MHz): d 1.15 (d, 3H), 2.25 (s, 6H), 4.10 (q, ÍH), 5.05 (s, 2H), 6.80 (d, 1H), 7.38 (m, 4H ), 7.45 (d, ÍH), 7.60 (s, ÍH).

Example 29: 5-bromo-2 - [(4-chloro nyl) methoxy] -a - [- 1- (dimethylamino) tyl] benzenemethanol.

To the mixture of NaBH 4 (15.4 g) in ethanol (4 mL) "was added a solution of l- [5-bromo-2- [(4'-chlorophenyl) methoxy] -phenyl] -2- (dimethylamino) - 1-propanone (123 mg), 0.31 mmol) in ethanol (3 mL). The reaction mixture was stirred at t.a. overnight. The solvent was concentrated in vacuo, and the residue was diluted with ethyl acetate, washed with water, and extracted with ethyl acetate ((2X) .The combined organic phase was washed with brine, dried over Na 2 SO 4, concentration in vacuo, followed by purification with flash column chromatography, yielded the title compound.XH NMR (CDC13, 400 MHz): d 0.70 (d, 3H), 2.30 (s, 6H), 2.60 (m, ÍH), 4.80 (d , 1H), 5.00 (m, 2H), 6.75 (d, ÍH), 7.30 (m, 5H), 7.65 (s, ÍH).

The following compounds were prepared in a similar way: -Chloro-2- [(4-chlorophenyl) methoxy] -a - [- 1 - (dimethylamino) ethyl] benzenemethanol. XH NMR (CD30D, 400 MHz): d (TMS) 0.95 (d, 3H), 2.40 (s, 6H), 2.90 (m, 1H), 5.05 (m, 2H), 7.00 (d, ÍH), 7.20 (d, d, ÍH), 7.40 (m, 5H). a- [5-chloro-2 - [(4-chlorophenyl) methoxy] phenyl] -β-methyl-1H-imidazole-1-ethanol. XH NMR (CD3OD, 400 MHz): d (TMS) 1.3 (d, 3H), 4.50 (, HH), 5.10 (m, 3H), 6.80 (m, 1H), 7.00 (m, 2H), 7.20 (m , 2H), 7.45 (m, 5H). - [5-Chloro-2 - [(4-chlorophenyl) methoxy] phenyl] -4- (4-chlorophenyl) -4-hydroxy-β-methyl-1-piperidinoethanol, MS: 520 (M + 1). lH NMR (CD3OD, 400 MHz): d (TMS) 1.0 (d, 3H), 1.50 (m, 1H), 1.65 (, ÍH), 1.95 (m, 2H), 2.50 (m, ÍH), 2.90 (m , 4H), 5.05 (, 2H), 5.40 (m, 1H), 7.00 (d, ÍH), 7.20 (m, ÍH), 7.30 (d, 2H), 7.45 (m, 7H). a- [5-Chloro-2- [(4-chloro-enyl) -methyl-oxo-4-hydroxy-β-methyl-4- (phenylmethyl) -1-piperidinoethanol. ZH NMR (CD3OD, 400 MHz): d (TMS) 1.0 (d, 3H), 1.45 (m, ÍH), 1.70 - (m, 3H), "2.-70 (s, 2H), - 2.90 (m , .ÍH), 3.10 (m, ÍH), 3.30 (m, 3H), 5.0 (, 2H), 5.40 (s, ÍH), 6.90 (d, 1H), 7.20 (m, 6H), 7.40 (m , 5H). a- [5-chloro-2- [(4-chlorophenyl) methoxy] phenyl] -4- (4-fluorophenyl) -4-hydroxy-β-methyl-1-piperidinoethanol. "" "H NMR (CDC13, 400 MHz): d (TMS) 0.85 (d, 3H), 1.75 (m, 2H), 2.05 (m, 2H), 2.65 (m, 2H), 2.80 (m, 1H) , 2.90 (m, 1H), 3.0 (m, • ÍH), 5.05 (, 2H), 5.26 (m, 1H), 6.80 (d, ÍH), 7.05 (t, 2H), 7.20 (d, ÍH), 7.35 (, 4H), 7.45 (m, 2H) 7.50 (s, 1H). -chloro-2 ~ [(4-chlorophenyl) methoxy] -? ~ [1- (diethylamino) ethylbenzenemethanol. 1H NMR (CDC13, 400 MHz): • d (TMS) 0.85 (d, 3H), 0.95 (t, 6H), 2.50 (m, 4H), 3.05 (m, ÍH), 5.00 (m, 2H), 5.05 (, ÍH), 6.78 (d, ÍH), 7.15 (d, ÍH), 7.35 (m, 4H), 7.50 (s, ÍH).

Example 30: a- [5-bromo-2 - [[4 - [[4 - [(3-nitrophenyl) -sulfonyl] -l-piperazinyl] carbonyl] phenyl] methoxy] phenyl] -3- 'hydroxy-1- piperidinoethanol.

To a solution of 2-bromo-l- [5-bromo-2 - [[4 - [[4 - [(3-nitrophenyl) sulfonyl] -l-piperazinyl] carbonyl] phenyl] methoxy] -phenyl] ethanone (300 mg, 0.47 mmol) in DMF (5 mL) was added to t.-a. - 3-hydroxypiperidine HCl (330 mg, 2.4 mmol) and K2CO3 (300 mg). After 1 h, the mixture was poured into ice water. The solid was collected by filtration, and redissolved in MeOH (15 mL). To this solution was added NaBH4 (100 mg) and the mixture was kept at RT. overnight. After removal of the MeOH, the residue was diluted with EtOAc, washed with brine, dried over Na 2 SO 4 and concentrated. The residue was purified by HPLC to give the product as a white powder. XH NMR (DMSO-d6 / TFA): d 1.10-2.00 (m, 4H), 2.60-4.00 (m, 15H), 5.10-5.20 (m , 2H), 5.25-5.35 (m, 1H), 7.04-7.14 (m, ÍH), 7.26-7.56 (m, 6H), 7.86-7.98 (, 1H), 8.10-8.18 (m, ÍH), 8.32- 8.38 (m, ÍH), 8.48-8.60 (m, 1H).

The following compounds were prepared in a similar way: a- [5-Bromo-2 - [[4 - [[4 - [(3-nitrophenyl) sulfonyl] -l-piperazinyl] carbonyl] phenyl] methoxy] phenyl] -4-hydroxy-1-piperidinoethanol. XH NMR (DMSO-d6 / TFA): d 1.45-2.10 (m, 4H), - 2.70-3.90 (m, 15H), 5.08-5.32 (m 3H), 7.04-7.14 (m, ÍH), 7.20-7.56 (m, 6H), 7.88-7.98 (m, ÍH), 8.12-8.18 (m, ÍH), 8.34-8.38 (m, ÍH), 8.50-8.58 (m, ÍH). a- [5-Bromo-2 - [[4 - [[4 - [(. 3-nitrophenyl) sulfonyl] -! - piperazinyl] carbonyl] phenyl] methoxy] phenyl] -3-hydroxy-l-pyrrolidinoethanol. XH NMR (DMS0-d6 / TFA): d 1.70-2.20 (, 2H), 2.90-4.40"(m, 15H), 5.10-5.25 (m, 3H), 7.06-7.12 (m, ÍH), 7.28-7.52 (m, 6H), 7.92 (m, ÍH), 8.14 (br.d, 1H), 8.33 (br.s, ÍH), 8.54 (br.d, ÍH), 9.70 and 10.00 (each br.s, ÍH). -bromo-a- [(diethylamino) methyl] -2 - [[4 - [[4- [(3-nitrophenyl) sulfonyl] -l-piperazinyl] carbonyl] phenyl] methoxy] benzenemethanol. XH NMR (DMSO-de / TFA): 'd 0.90 (t, 3H), 1.10 (t, 3H), 3.00-3.80 (m, 15H), 5.05-5.20 (m, 3H), 7.08-7.14 (m, ÍH), 7.30-7.52 (, 6H), 7.88-7.96 (m, ÍH), 8.10-8.18 (, ÍH), 8.30-8.38 (m, 1H), 8.50-8.56 (m, ÍH), - 9.10 - ( br.s, ÍH).

Example 31: a- [5-bromo-2 - [(4-slorophenyl) methoxy] -phenyl] -l-piperazineethanol.

To a stirred solution of 2-bromo-l- [5-bromo-2 - [(4-chlorophenyl) methoxy] -phenyl] -ethanone (7.0 g, 17.5 mmol) in DMF (50 mL) was added N-Boc -piperazine (4.9 g, 26.3 mmol), followed by NaHCO 3 (10 g). After 14 h, the reaction mixture was poured into ice water (150 mL). The reaction mixture was extracted with EtOAc (3x80 mL), washed with brine (100 L), and dried over Na2SO4. Concentration in vacuo provided "- crude acetone-amine ..- (- .6 - .1 g) To a stirred solution of the acetone-amine MeOH (80 mL) at 0 ° C was added NaBH (796 mg, 21 mmol) After 30 min, the methanol was removed in vacuo, and the resulting reaction mixture was quenched with brine (80 L) and extracted with EtOAc (3x80 mL) .The organic phase was washed with brine. (100 mL) and dried over Na2SO4, concentration in vacuo followed by purification with column chromatography gave the product (7.21 g, 78%). To a stirred solution of the product (7 g, 13.3 mmol) in CH2C12 (60 mL). at room temperature, trifluoroacetic acid (30 mL) was added, after 2 h, the reaction mixture was concentrated in vacuo and redissolved in CH2C12 (200 mL), the solution was washed with 10% NaOH (3x25 mL). ) and brine (2x20 mL), dried (Na2SO4), and concentrated to give the title product.

Example 32: α- [5-Bromo-2 - [(4-slorophenyl) methoxy] -phenyl] -4- (3-pyridinylcarbonyl) -1-piperazineethanol.

To a stirred solution of a- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -l-piperazineethanol (371 mg, 0.87 mmol) in DMF (5 L) was added 3-pyridinecarboxylic acid (107 mg, 0.87 mmol), followed by HATU (306 mg, 0.8 mmol) and Et3N (271 mg, 2.68 mmol), at After 4 h, the reaction mixture was developed in the usual manner, and purified by column chromatography to provide the title compound. 1 H NMR (400 MHz, DMSO-de): 3.2 (br.s, 4H), 3.3 (dd, 2H), 3.56 (br.s, 4H), 5.0 (m, 1H), 5.06 (s, 2) 6.98 (d, 1H), 7.34 (dd, ÍH), 7.4 (d, 2H), 7.44 (d, 2H), 7.48 (dd, 2H), 7.76 - (m, ÍH), 8.55 (d, ÍH), 8.61 (dd, 1H).

The following compounds were prepared in a similar way: a- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -4- [(2-methyl-3-pyridinyl) carbonyl] -l-piperazineethanol. 1 H NMR (400 MHz, DMSO-de): 2.64 (s, 3 H), 3.0 (m, 2 H), 3.37 (m, 4 H), 3.6 (m, 4 H), 4.94 (m, H H), 5.04 (s, 2H), 6.98 (d, ÍH), 7.26 (dd, ÍH), 7.37 (dd, ÍH), 7.43 (d, 2H), 7.52 (dd, 2), 8.44 (d, ÍH). a- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -4 - [(4-methyl-3-pyridinyl) carbonyl] -l-piperazineethanol. 1 H NMR (400 MHz, DMSO-de): 2.57 (s, 3 H), 3.1 (m, 1 H), 3.2 (m, 2 H), 3.3 (m, 4 H), 3.6 (, 4 H), 5 (m, 1 H) ), 5.1 (s, 2H), 6.98 (d, 1H), 7.3 (dd, 1H), 7.35 (dd, ÍH), 7.4 (d, 2H), 7.52 (dd, 2), 7.64 (d, ÍH) 8.41 (d, 1H).

Example 33: 4 - [[4-Bromo-2- [l-hydroxy-2- [4 - [[(f-enylmethoxy) carbonyl] amino] -l-piperidinyl] -ethyl] f-eneo] methyl] methyl ester] benzoic To a stirred solution of 4 - [[4-bromo-2- [2- [4 - [[(1, 1-dimethylethoxy) carbonyl] amino] -l-piperidinyl] -l-hydroxyethyl] phenoxy] methyl ester] methyl] benzoic acid (450 mg, 0.8 mmol) in CH2C12 (5 L), TFA (2 mL) was added at room temperature. After 2 h, the reaction was concentrated in vacuo, and dried in vacuo for 2 h. This unprotected crude product was reacted with benzyloxycarbonyl chloride (178.2 mg, 1.05 mmol) at 0 ° C in the presence of EtN (440 mg) for 1 h. After normal development, the crude product was purified by column chromatography to provide the title product. XH NMR. (400 MHz, DMSO-de): 1.4 (m, 2H), 1.8 (m, 2H), 10 2.0 (m, ÍH), 2.3 - (m, 2H), 2.6 (, 2H), 2.96 (m, 1H) ), 3.5 (m, ÍH), 3.81 (s, 3H), 4.6 (s, 2H), 4.8-5.5 (m, 5H), 6.73 (d, ÍH), 7.3 (dd, 1), 7.18-7.35 ( m, 7H), 7.4 (d, 2H), 7.57 (d, ÍH), 8.1 (d, H).

Example 35: 4 - [[4-Bromo-2- [l-hydroxy-2- (4-hydroxy-1-piperidinyl) ethyl] phenoxy] methyl] -N- (4-pyridinyl) benzamide.

To a stirred solution of 4 - [[4-bromo-2- [l-hydroxy-2 ~ (4-hydroxy-1-piperidinyl) eti]] phenoxy] methyl] -20'-benzoic acid (300 mg-, 0.62 mmol ) in DMF (5 mL), 4-pyridinamine (87 mg, 0.92 mmol) was added, followed by HATU (351 mg, 0.92 mmol) and Et3N (187 mg, 1.85 mmol.), at room temperature. h, the reaction was purified by HPLC to provide the title product as a salt of trifluoroacetic acid. XH NMR (400 MHz, DMSO-d6): d 1.7. (m, 2H), 1.9 (m, 2H), 3.2 (m, 3H), 3.4 (m, 1H), 3.6 (m, 1H), 5.22 (s, 2H), 5.36 (, ÍH), 7.1 (d) , 1H), 7.34 (dd, 1H), 7.46 (d, 1H), 68 (d, 2H), 8.05 (d, 2H), 8.27 '(d, 2H), 8.75 (d, 2H), 9.5 (br .s, ÍH), 11.6 (d, 1H).

The following compound was prepared from a • Similarly: 4 - [[4-chloro-2- [l-hydroxy-2- (4-hydroxy-1-piperidinyl) ethyl] phenoxy] methyl] -N- (3-hydroxypropyl) benzamide. X H NMR (400 MHz, DMSO-d 6): 0.8 (t, 2 H), 1.22 (m, 2 H), 1.61 (m, H H), 1.82 (m, H H), 3.0-3.6 (m, 10 H), 5.2 ( s, 2H), 5.3 • (ra, ÍH), 7.1 (d, 1), 7.36 (dd, ÍH), 7.43 (t, ÍH), 7.58 (dd, 2H), 7.84 (dd, 2H), 9.23 (br.s, 1H) .

Example 36A: 2- [5-Bromo-2 - [(4-chlorophenyl) methoxy] -phenyl] oxirane.

To a homogeneous solution of (Me) 3SI (13.8 g, 67.6"mmol) in" DMSO (300"mL), -5-bromo-2- (4-chlorophenylmethyl) benzaldehyde (20.0 g, 61.4 mmol) was added, followed by KO-tBu (8.27 g, 73.7 mmol) at room temperature The reaction was maintained at room temperature overnight, and it was emptied into ice water (300 mL) The reaction mixture was extracted with EtOAc (3x200 mL). ), washed with brine (150 mL) and dried (Na 2 SO) The concentration, followed by purification by column chromatography, yielded the title compound X H NMR (400 MHz, DMSO): d 1.53 (m, 2 H), 1.84 (m, 2H), 2.6 (m, 6H), 3.6 (s, 2H), 5.02 (s, 2H), 6.78 (d, ÍH), 7.32 (d, 1H), 7.4 (s, 4H), 7.54 ( Yes H) .

Example 36B: 1- (2S) -a- [5-Bromo-2 - [(4-chloro-enyl) -methoxy] -phenyl] -2- (hydroxymethyl) -1-pyrrolidinoethanol trifluoroacetic acid salt.

To a stirred solution of 2- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] oxirane (340 mg, -1 mmol) in DMF (3mL), (2R) -pyrrolidinomethanol (152 mg, 1.5 mmol) was added at room temperature. The reaction mixture was maintained at 110 ° C for 8 h, and cooled to room temperature. The reaction was purified by HPLC to provide the title compound as a trifluoroacetic acid salt. XH NMR (400 MHz, DMSO-d6): 1.63 (m, HH), 1.7-2.1 (, 3H), 2.9 (m, HH), 3.24 (m, 2H), 3.3-3.7 '"(m, 9H) , 5.12 (s and 2H), 7.04 (t, ÍH), 7.46 (m, 6H).

The following compounds were prepared in a similar manner: (2R) - - [5-Bromo-2- [(4-chlorophenyl) -methoxy] phenyl] -2- (hydroxymethyl) -1-pyrrolidinoethanol trifluoroacetic acid salt. X H NMR (400 MHz, DMSO-d 6): 1.63 (, 1 H), 1.8-2.1 (m, 3 H), 2.9 (m, 1 H), 3.2 (m, 2 H), 3.3-3.7 (m, 10 H), 5.12 (s, 2H), 7.0 (t, ÍH), 7.4-7.6 (m, 6H). '(3R) -a- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -3-hydroxy-l-pyrrolidinoethanol trifluoroacetic acid salt. XH NMR (400 MHz, DMSO-d6): 1.6-1.9 (m, 2H), 3.0-3.7 (, 6H), 4.4 (m, HI), 5.1 (s, 2H), 5.2 (m, 1M), 7.0 (d, 1H), 7.3-7.6 (, 6H).

-Bromo-2- [(4-chlorophenyl) methoxy] -a- [[2- (diethylamino) ethyl] ethylamino] methyl] -benzenemethanol trifluoroacetic acid salt. aH NMR (DMSO-de / TFA): d H), 1.00-1.20 (m, 9H), 3.20-3.51 (m, 12H), 5.13 (s, 2H), 5.25 (br.s, 1H), 7.08 ( br.d, 1H), 7.40-7.53 (m, 5H), 7.62 (d, ÍH), 9.70 (br.s, 2H).

Salt of a- [5-bromo-2 - [(4-chlorophenyl) -me oxy] phenyl] -l, 4-piperidinodiethanol trifluoroacetic acid. 1 H NMR (DMSO-de / TFA): d 1.10-1.87 (m, 7H), 2.68-3.60 (m, 8H), 5.10-5.35 (m, 3H), 7.00-7.10 (m, ÍH), 7.40-7.55 (m, 5H), '7.57-7.61 (m, 1H), 9.20-9.40 (, ÍH). a- [5-Bromo-2- [(4-chloro-enyl) -methoxy] -fenyl] - - (piperidyl) -l-piperidinoethanol. XH NMR (DMSO-d6 / TFA): d 1.20-2.15 (m, 10H), 2.75-3.70 (m, 11H), 5.00 (br.s, 2H), • 5.20 (m, ÍH) r 6.90 (br. dd, ÍH), 7.30-7.40 (m, 5H), 7.47 (br.dd, 1H), 9.30-9.80 (m, 2H).

Salt of 5-bromo-2- [(4-chlorophenyl) methoxy] -a- [(dipropylamino) methyl] -benzenemethanol trifluoroacetic acid. 1H NMR (DMSO-dg / TFA): d 0.65 (t, 3H), 0.80 (t, 3H), 1.35-1.65 '(m, 4H), 2.90-3.15 (m, 6H), 5.05 (dd, 2H) , 5.10 (dd, 1H), 7.05 (d, 1H), 7.40-7.50 (m, 5H), 7.60 (d, ÍH), 9.18 (br.s, ÍH).

Salt of a- [5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] -4- (phenylmethyl) -1-piperidinoethanol trifluoroacetic acid. XH NMR (DMSO-d6 / TFA): d 1.20-1.85 - (m, 5H), 2.60-3.55 (m, 8H), - 5.00-5.30 (m, 3H), 7.00-7.30 (m, 6H), 7.35 -7.60 (m, 6-H) ', 9.20-9.40 (m, ÍH).

Salt of 5-bromo-2- [(4-chlorophenyl) methoxy] -a- [(dibutylamino) -trietyl] -benzenemethanol trifluoroacetic acid. 1 H NMR (DMSO-de / TFA): d 0.70 (t, 3H), 0.85 (t, 3H), 1.10 (m, 2H), 1.23 (m, 2H), 1.35-1.65 (, 4H), 2.90-3.20 . (m, 6H), 5.10 (m, 2H), 5.18 (m, 1H), 7.10 (d, 1H), 7.40-7.51 (m, 5H), 7.60 (d, ÍH), 9.30 (br.s, ÍH) ). -bromo-a [(butylethylamino) methyl] -2- [(4-chlorophenyl) methoxy] -benzenemethanol. 1H NMR (DMSO-d6 / TFA): d 0.70-1.60 (m, 10H), 2.90-3.20 (, 6H), 5.05-5.20 (, 3H), 7.10 (m, ÍH), 7.40-7.55 (m, 5H ), 7.62 (s, 1H), 9.10 (br.s, 1H).

-Bromo-2- [(4-chlorophenyl) methoxy] -a- • [[ethyl (2-hydroxyethyl) amino] methyl] -benzenemethanol trifluoroacetic acid salt. XH NMR (DMSO-d6 / TFA): d 0.90-1.15 (m, 3H), 3. 00-3.30 (m, 6H), 3.65 (m, 6H), 5.00 (br.s, .ÍH), 5.20 (m, ÍH), 6.92 (br.s, 1H), 7.30-7.45 (m, 5H), 7.58 (s, ÍH), 9.00 (br.s, ÍH).

• Salt of 5-brorao-2- [(4-chlorophenyl) methoxy] -a- [[(2-hydroxyethyl) propylamino] methyl] -benzenemethanol trifluoroacetic acid. XH NMR. (DMSO-d6 / TFA): d 0..64-0.76 (each t, 3H), 1.32-1.62 (m, 2H), 2.90-3.30 (m, 6H), 3.55-3.70 (m, - 2H) , 5.00-5.30 (m,, 3H), 7.02-7.10 (m, ÍH), 7.40-7.52 (iri, 5H) ", - 7.57 - (d, ÍH), 8.90-9.10 (m, ÍH).

L- [2- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2-hydroxyethyl] -N, N-diethyl-3-piperidinecarboxaramide trifluoroacetic acid salt. 1H NMR (DMSO-d6 / TFA): d 0.90-1.15 (m, 6H), 1.40-2.00 (m, 4H), 2.70-3.70 (m, 11H), 5.10 (m, 2H), 5.28-5.38 (m , ÍH), 7.00 (m, 1H), 7.36-7.50 (m, 5H), 7.60 (, 1H), 9.10-9.50 (m, HH).

Salt of α- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -4- (4-bromophenyl) -4-hydroxy-1-piperidinoethanol trifluoroacetic acid. XH NMR (DMSO-de / TFA): d 1.54-1.84 (m, 2H), 2.16-2.42, (m, 2H), 3.00-3.70 (m, 6H), 5.02-5.18 (m, 2H), 5.20- 5.28 (m, HH), 7.00-7.18 (m, 1H), 7.30-7.56 (m, 9H), 7.58-7.62 (m, HH), 9.30-9.50 (m, 1H).

Salt of l- [l ~ [2 ~ [5-bromo-2- [(4-chlorofenyl) methoxyphfinyl] -2-hydroxyethyl] -4-piperidinyl] -l, 3-dihydro-2H-benzimidazole-2 -trifluoroacetic ion. ki NMR (DMSO-de / TFA): d 1.82 (m, 2H), 2.60-2.86 (m, 2H), 3.00-3.40 (m, 4H), 3.54 (m, ÍH), 3.70 (m, 1H), 4.52 (m H H), 4.98-5.14 '(m, 2H), 5.18-5.36 (m, HH), 6.88-7.00 (, 4H), 7.34-7.46 (, 6H), 7.58-7.62 (m, HH), 9.60 (br.s, ÍH), 10.80 (m, ÍH).

Salt - from l- [2- [5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] -2-hydroxyethyl] -4-phenyl-4- piperidinocarbonitrile trifluoroacetic acid. XH NMR (DMSO- of / TFA): d 2.10-2.54 (m, 4H), 3.04 (m, ÍH), 3.24-3.48 (, 3H), 3.68 (m, 3H), 3.84 (m, 1H), 5.04 -5.18 (m, 2H), 5.36 (m, HH), 7.06 (d, HH), 7.36-7.56 (m, 10H), 7.59 (d, 1H), -9.70-9.90 (m, 1H).

Salt of a- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -1,4-dioxa-8-azaspiro [4.5] decane-8-ethanol trifluoroacetic acid. aH NMR (DMSO-d6 / TFA): d 1.72-2.10. '(m, 4H), 2.88 (m, ÍH), 3.08-3.30 (m, 3H), 3.40-3.58 (m, 2H), 3.92 (m, 4H), 5.14 (s, 2H), 5.28 (m, 1H), 7.06 (d, 1H), 7.42-7.54 (m, 5H), 7.58 (d, ÍH), 9.58 (br.s, 1H).

Salt of 5-bromo-2- [(4-chlorophenyl) methoxy] -a- [[(2-hydroxyethyl) (phenylmethyl) amino] methyl] -benzenemethanol "trifluoroacetic acid. XH NMR (DMSO-d6 / TFA): d 3.30-3.32 (m, 4H), 3.72 (br.s, 2H), 4.30-4.48 (m, 2H), 5.08 (br.s, 2H), 5.28 (m , 1H), 6.97 (br.s, 1H), 7.30-7.56 (, 11H), 9.30 (br.s, ÍH). ' -Bromo-2 ~ [(4-chlorophenyl) methoxy] -a- [[2- [(dimethylamino)] ethyl] ethylamino] methyl] -benzenemethanol trifluoroacetic acid salt. XH NMR (DMS0-d6 / TFA): d 1.00-1.25 (m, 3H), 2.75-2.90 (m, 6H), .3.10-3.60 (m, 8H), 5.15 (br.s, 2H), 5.25 ( br.s, ÍH) -, 7.10 (m, ÍH), 7.45-7.55 (m, 5H), 7.65 (d, ÍH).

• Salt of acid - [5-bromo-2 ~ [(4-chlorophenyl) etoxxjf enyl] -l, 2, 3, 4-tetrahydro-l-quinolinoethanol trifluoroacetic acid. XH NMR (DMSO-d6 / TFA): d 3.30-3.50. (m, 5H), 3.55-3.75 (m, ÍH), 4.10-4.40 (m, ÍH), 4.50 (m, 1H), 5.00-5.20 (, 2H), 5.28-5.45 (, ÍH), 7.00-7.26 (m, 5H), 7.36-7.53 (m, 5H), 7.59 (br.s, ÍH), 10.00-10.20 (m, 1H).

L- [2- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2-hydroxyethyl] -3,4-pyrrolidinodiol trifluoroacetic acid salt. XH NMR (DMSO-d6 / TFA): d 3.30-3.70 (m, 6H), 4.00-4.25 (m, 2H), 5.10-5.30 (m, 3H), 7.02-7.10 (m, ÍH), 7.44-7.54 (m, 5H), 7.54-7.58 (m, 1H), 9.70 (br.s, 1H).

-Bromo-2- [(4-chlorophenyl) methoxy] -a - [(methylamino) methyl] -benzenemethanol trifluoroacetic acid salt. XH NMR (DMSO-d6 / TFA): d 2.52 (, 3H), 2.90-3.10 (m, 2H), 5.10-5.18 (m, 3H), 7.02 (d, ÍH), 7.42-7.50 (m, 5H) , 7.17 (d, 1H), 8.50 (br.s, ÍH), 8.70 (br.s, 1H). 2 - [[2- [5-Bromo-2- [(4-chlorophenyl) methoxyjfenii] -2-hydroxyethyl] amino] -1,3-propanediol trifluoroacetic acid salt. l NMR (DMSO-d6 / TFA): d 2.90-3.00 (m, ÍH), 3'.16"(m, 1H)," 3.26 (m, ÍH), 3.54-3.66 (m, "4H), 5.13 (dd, 2H), 5.22 (dd, 1H), 7.04 (d, ÍH), 7.40-7.50 (m, 5H), 7.77 (d, ÍH), 8.20 (br.s, ÍH), 8.70 (br.s , lH).

-Bromo-2 - [(4-chlorophenyl) methoxy] -a- [(diethylamino) methyl] -benzenemethanol trifluoroacetic acid salt. 1 H NMR (DMSO-d 6 / TFA): d 0.96 (t, 3H), 1.12 (t, 3H), 2.98-3.16 (m, 6H), 5.11 (dd, 2H), 5.16 (dd, ÍH), 7.08 ( d, ÍH), 7.42-7.52 (m, 5H), 7.58 (d, 1H), 9.20 (br.s, 1H). 2 - [[2- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2-. hydroxyethyl] amino] -2- (hydroxymethyl) -1,3-propanediol. XH NMR (DMSO-de / TFA): d 2.97 (m, ÍH), 3.34 (m, ÍH), 3.56 (br.s, 6H), 5.14 (dd, 2H), 5.23 (dd, ÍH), 7.15 ( d, ÍH), 7.40-7.52 (m, 5H), 7.55 (d, 1H), 8.70 (br.s, 1H). 10 a- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -l-pyrrolidinoethanol. kH NMR (DMSO-d6 / TFA): d 1.8001.90 (, '4H), 2.85 (m, ÍH), 3.05 (m, ÍH), 3.20 (m, 2H), 3.50 (m, 2H), 5.10- 5-.20 (m, 3H), 7.25 (d, ÍH), 7.43-7.52 (m, 5H), 15. 7.55 (d, 1H), 9.70 (br.s, 1H). a- [5-Bromo-2 ~ [(4-chlorophenyl) methoxy] phenyl] -l-piperidinoethanol. XH NMR (DMSO-de / TFA): d 1.32 (m, ÍH), 1. 54-1.80 (m, 5H), 2.74 (m, 1H), 2.94 (, 1H), 3.02-3.18 0 '(m, 2H), 3.30-3.46 (m, "-2H), 5.13 (dd, 2H) , 5.26 (br.dd, . 1H), 7.05 (d, 1H), 7.43-7.53 (, 5H), 7.55 (d, 1H), 9.30 (br.s, ÍH).

-Bromo-2 - [(4-chlorophenyl) methoxy] -a - [[(3-5 hydroxyphenyl) amino] methyl] benzenemethanol. ki NMR (DMSO- of / TFA): d 3.22-3.38 (, 2H), 5.00-5.10 (m, 3H), 6.70. (br.dd, ÍH), 6.75 (br.dd, 1H), 6.80 (m, 1H), 7.02 (d, 1H), 7.14 (dd, ÍH), 7.28-7.44 (m, 5H), 7.60 (d , ÍH).

-Bromo-2- [(4-chlorofenyl) methoxy] -a- [[(cyclopropylmethyl) amino] methyl] benzenemethanol. XH NMR (DMSO- of / TFA): d 0.00 (m, 2H), 0.20 (m, 2H), 0.67 (m, 1H), • 2.40-2.70 (m, 3H), 2.88 (m, ÍH), 4.84-4.-96 (m, 3H), 6.76-6.84 (m, 1H), 7.12-7.24 (m, 5H), 7.28-7.34 (m, 1H), 8.30-8.46 (m, 2H).

-Bromo- - [[[2- (3-chlorofenyl) ethyl] amino] methyl] -2- [(4-chlorophenyl) methoxy] benzenemethanol. XH NMR (DMSO-d6 / TFA): d • 2.84-3.20 (m, 6H), 5.12 (s, 2H), 5.20 (dd, ÍH), 7.04 (m, ÍH), 7.15 (m, ÍH), 7.26-7.48 (, 8H), 7.57 (d, ÍH), 8.70 (br.s, ÍH), "8.90 (br.s, 1H). a- [5-Bromo ~ 2 - [(4-chlorophenyl) methoxy] phenyl] -l-acetidinoethanol. XH NMR (DMSO-d6 / TFA): d 2.18 (, 1H), 2.38 '(m, 1H), -3-.18 (m, HH), 3.30 (m, "ÍH), 3.83 (m, 1H) , 3.96-4.12 (m, 3H), 5.00 (dd, ÍH), 5.10-5.20 (m, 2H), 7.04 (dd, 1H), 7.40-7.54 (m, 6H), 9.90 (br.s, ÍH) .

-Bromo-2 - [(4-chlorophenyl) methoxy] -a- [(ethylmethylamino) methyl] benzenemethanol. 1H NMR (DMSO-d6 / TFA): 'd 1.00-1.20 (m, 3H), 2.68-2.76 (m, 3H), 3.00-3.22"(m, 4H), 5.08-5.24 (m, 3H), 7.02 -7.08 (m, 1H), 7.38-7.52 (m, 5H), 7.56-7.58 (, ÍH), 9.20 and 9.40 (each br.s, ÍH). -bromo-2- [(4-chlorophenyl) methoxy] -a- [(cyclopropylamino) methyl] benzenemethanol. XH NMR (DMSO- of / TFA): d 0.60-0.80 (m, 4H), 2.50-2.80 (, 2H), 3.00 (m, ÍH), 3.15 (m, 1H), 5.10 (dd, 2H), 5.18 (dd, ÍH), 7.02-7.08 (m, ÍH), 7.40-7.51 (m, 5H), 7.55-7.58 (m, ÍH), 8.00 (br.s, 1H), 8.80 (br.s, 1H ). -bromo-2- [(4-chlorophenyl) methoxy] -a- [[(cyclopropylmethyl) methylamino] methyl] benzenemethanol. - XH NMR (DMSO-de / TFA): d 0.00-0.30 (m, 4H), 0.50-0.80 (m, ÍH), 2.50-3..05 (m, 7H), 4.80-4.92 (m, 2H), 4.96- 5.02 (m, ÍH), 6. 78-6.84 (m, 1H), 7.14-7.28 (m, 5H), 7.32-7.35 (m, 1H), 9.00-9.20 (m, ÍH). a- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -4-thiomorpholinoethanol. XH NMR (DMSO-d6 / TFA): • - d 2.76 (m, 2H), 2.90-3.30 (, 6H), 3.56-3.64 (m, ÍH), 3.70-3.78 (m, ÍH), -5.12 ( br.s, 2H), 5.30 (br.dd, ÍH), 7.00-7.05 (m, ÍH), 7.40-7.52 (m, 5H), 7.56 (d, ÍH), 9.60 (br.s, 1H). a- (Aminomethyl) -5-bromo-2 - [(4-chlorophenyl) ethoxy] benzenemethanol. XH NMR (DMSO-d6 / TFA): d 2.75 (m, HH), 3.00 (m, HH), 5.05-5.15 (ra, 3H), 7.00-7.08 (m, HH), 7.38-7.50 (m, 5H ), 7.54 and 7.60 (each d, ÍH), 7.86 and 8.28 (each br. S, 3H).

-Bromo-2- [(4-chlorophenyl) methoxy] -a- [(cyclopropylmethylamino) methyl] benzenemethanol. XH NMR (DMSO-de / TFA): d 0.65-1.10 (m, 4H), 2.55-3.40 (m, 6H), 5.00-5.10 (m, 2H), 5.10-5.50 (m, ÍH), 7.00-7.10 (m, 1H), 7.40 -7.60 (m, 6H), 8.89-9.10 (m, ÍH). (aS) -5-bromo-2- [(4-chlorophenyl) methoxy] -a- [(diethylamino) methyl] benzenemethanol. XH NMR (DMSO- d6./TFA): d 1.10 (t, 3H), 1.13 (t, 3H), 3.15-3.30 (m, 6H), 5.25 (dd, 2H), 5.30 (dd, 1H), 7.21 -7.25 (m, ÍH), 7.56-7.67 (m, 5H), 7.72 (d, 1H), 9.20 (br.s, 1H). (aR) -5-bromo-2- [(4-chlorophenyl) methoxy] -a- [(diethylamino) methyl] benzenemethanol. XH NMR (DMSO-de / TFA): d 0.95 (t, 3H -) -, 1.10 (t, 3H), 3.00-3.15 (m, 6H), 5.10 (dd, 2H), 5.15 (dd, 1H), 7.04-7.08 (m, 1H), 7.40-7.50 (m, 5H), 7.58 (d, ÍH), 9.10 (br.s, 1H). ? - [[bis (2-hydroxyethyl) amino] methyl] -5-bromo-2 - [(4-chlorophenyl) methoxy] benzenemethanol. X.H NMR. (DMSO-d6 / TFA): d 3.20-3.38 (m, 6H), 3.62-3.76 (, 4H), 5.13 (dd, 2H), 5.26 (dd, ÍH), 7.03 (d, ÍH), 7.40-7.50 (m, 5H), 7.85 (d, ÍH), 8.65 (br.s, 1H). 'a-5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -4-methyl-' 1-piperazineethanol. XH NMR (DMSO-de / TFA): d 2.74 (s, 3H), 2.80-4.20 (m, '10H), 5.08-5.20 (m, 3H), 7.02 (d, 1H), 7.40-7.50 (m, 5H), 7.53 (d, ÍH).

-Bromo-2- [(4-chlorofenyl) methoxy] -a - [[(1-methylethyl) amino] methyl] -benzenemethanol. X H NMR (DMSO-d 6 / TFA): d 1.02 (d, 3 H), 1.03 (d, 3 H), 2.85 (m, 1 H), 3.05 (m, 1 H), 3.25 (, H), 5.10-5.16 (m , 3H), 7.06 (d, ÍH), 7.42-7.50 (m, 5H), 7.57 (d, 1H), 8.40-8.70 (m, 2H). a- [5-Bromo-2- [(4-chlorofenyl) methoxy] phenyl] -4- morpholinoethanol. XH NMR (DMSO-d6 / TFA): d 2.90-3.90 (m, 10H), 5.15 (dd, 2H), 5.30 (m, ÍH), 7.04 (d, ÍH), 7.43-7.53 (m, 5H), 7.55 (d, 1H), 10.00 (br.s, 1H).

-Bromo-2 - [(4-chlorophenyl) methoxy] -a - [[(2-hydroxyethyl) amino] methyl] -benzenemethanol. XH NMR (DMSO- of / TFA): d 2.88-3.02 (m, 3H), 3.12-3.20 (m, ÍH), 3.58-3.64 (, 2H), 5.10-5.24 (m, 3H), 7.04 (d, 1H), 7.42-7.50 (m, 5H), 7.54 (d, 1H), 8.50 (br.s, ÍH), 8.70 (br.s, ÍH). -bromo-2- [(4-chlorofenyl) methoxy] -a - [[(2-hydroxyethyl) amino] methyl] -benzenemethanol. XH NMR (DMSO- of / TFA): d 2.88-3.02 (m, 3H), 3.12-3.20 (m, ÍH), 3.58-3.64 '(m, 2H), 5.10-5.24 (m, 3H), 7.04 ( d, ÍH) ", 7.42-7.50 (m, 5H), 7.54 (d, ÍH), 8.50 - (br.s, 1H), 8.70 (br.s, ÍH).

Example 37: 5-bromo-2 - [(4-chlorophenyl) methoxy] -β-ethoxy-N, N-diethylbenzene-ethanamine.

To a suspension of NaH (95%, 20 mg, 0.83 mmol), 1.3 eg.) In DMF (3 mL), 5-bromo-2- [(4-chlorophenyl) methoxy] - - [(diethylaminomethyl) was added. ] benzenemethanol (270 mg, 0.65 mmol) at rt After stirring for one hour, Etl (0.07 mL), 0.95 mmol) was added, and the resulting mixture was stirred at rt. under N2 during the night. The mixture was poured into ice water, kept in the refrigerator overnight, and filtered. The solid was redissolved in EtOAc, and dried over Na2SO4. Concentration in vacuo, followed by purification- by HPLC, gave the title compound as a colorless syrup. XH NMR (DMSO-de / TFA): d 1. 00-1.22 (m, 9H), 3.00-3.90 (m, 8H), 4.80-5.00 (m, 1H), . 10-5.20 (, 2H), 7.08-7.20 (m, 1H), 7.40-7.60 (m, 6H), 9-. 10 (br.s, 1H).

The following compound was prepared in a similar way: -bromo-2- [(4-chlorophenyl) methoxy] -N, N-diethyl-β- (2-pyridinyloxy-benzeneethanamine. XH NMR (DMS0-d6 / TFA) .: d 1.02 (t, 3H), 1.18 (t, 3H), 2.80-3.20 (m, 4H), 3.35 (m, ÍH), 3.65 (, 1H), 4.70-5.25 (m, 3H), 6.58 y.6.80 (each, ÍH), 6.96- 7.18 (, 3H), 7.36-7.60 (m, 5H), 7.74 and 7.89 (each, ÍH), 8.04-8.14 (m, 1H), 9.32 (br.s, ÍH) 10 Example 38: 5-bromine -2 - [(4-slorophenyl) methoxy] -β- (methylamino) benzeneethanol.

A mixture of 2- [5-bromo-2 - [(4-chlorophenyl) methoxy] -15-phenyl] oxirane (500 mg, 1.47 mmol),. TMSCN (0.4 mL, 3.0 mmol), and Znl2 (cat.) In CH2C12 (5 mL), in a sealed tube, was shaken at 60 ° C for 4 h. After cooling to t.a., the reaction mixture was concentrated, and the resulting residue was diluted with EtOAc, washed with brine, and dried over Na2SO4. After removal of the solvent, the . He obtained the raw product. To a suspension of LiAlH4 (100 mg, 2.8 mmol) in Et20 (10 mL, anhydrous), a solution of the crude intermediate in Et20 (10 L) at t.a. After 4 h, the reaction was quenched with the addition of 15% NaOH (0.1 mL). After filtering the solid, the filtrate was concentrated. The residue was purified by HPLC to give the title compound as a white powder. XH NMR (DMSO-d6 / TFA): d 2.46 (, 3H), 3.71 (dd, ÍH), 3.82 (dd, ÍH), 4.54 (m, ÍH), 5.12-5.20 (m, 2H), 7.06-7.14 (m, 1H), 7.38-7.58 (m, 5H), 7.64-7.70 (m, ÍH), 8.85 (br.s, 1H), 8.95 (br.s, 1H).

Example 39: 1- [5-Bromo-2 - [(4-chlorophenyl) methoxy] -phenyl] -2-propen-1-one.

To a solution of vinylmagnesium bromide (1.0 M in THF, 80 L, 80 mmol), was added 5-bromo-2- (4-chlorophenylmethyl) benzaldehyde (21.5 g, 66 mmol) in THF (200 mL) at 0 ° C. After the addition, the mixture was stirred at t.a. for 2 h, and then poured into a cooled solution of 10% HCl (150 mL). The mixture was extracted with EtOAc (3x150 mL), washed with brine (2x60 mL), and dried over Na2S0. Concentration, followed by recrystallization from CH2Cl2 ~ hexane-EtOAc, gave the allyl alcohol product as a light yellow solid, To a stirred solution of the alcohol (3.8 g, 10.7 mmol) in CH2C12 (100 mL) was added. added Dess-Martin ioddannan (5 g, 12 mmol) at rt After 2 h, the reaction was quenched by adding Na 2 S 2 3 3 (10 g) and NaHCO 3 (sat, 20 mL) After removal of the solvent, the The residue was extracted with EtOAc, washed with brine, and dried over Na 2 SO 4 The concentration, followed by flash chromatography, gave the title compound as white needles X H NMR (400 MHz, DMSO-d 6): d 5.07 (s, 2H), 5.8 (d, HH), 6.22 (d, HH), 6.9 (m, 2H), 7.2-7.4 (m, 4H), 7.5 (d, HH), 7.7 (s, 1H).

Example 40: (3R) -a- [5-bromo-2- [(4-chlorophenyl) -methoxy] phenyl] -3-hydroxy-l-pyrrolidinopropanol.

To a solution of l- [5-bromo-2- [(4-chlorophenyl) -methoxy] -phenyl] -2-propen-l-one (300 mg, 0.85 mmol) in 10 L of MeOH-CH2Cl2 (1: 1, v / v), 3- (R) -hydroxypyrrolidine (0.1 mL, 1.25 mmol) was added at rt, under N2. After 30 min, the resulting mixture was added to a stirred solution of NaBH 4 in MeOH-CH 2 Cl 2 (10 mL, 1: 1, v / v), at t.a. The mixture was stirred at t.a. for 0.5 h. After removing the solvents, the residue was diluted with EtOAc, washed with brine, and dried over Na 2 SO 4. Concentration followed by purification by HPLC gave the title compound as a white powder. XH NMR (DMS0-d6 / TFA): d 1.70-2.22 (, 4H), 2.84-3.62 (m, 6H), 4.28-4.40 (m 1H), 5.06-5.14 (m, 2H), 6.94-7.00 (m , HH), 7.32-7.46 (m, 5H), 7.50-7.53 (m, 1H), 9.50-9.80 (m, 1H).

The following compounds were prepared in a similar way: -Bromo-2- [(4-chlorophenyl) methoxy] -a- [2- (dimethylamino) ethyl] -benzenemethanol. XH NMR (DMS0-d6 / TFA): d 5 1.78-1.88 (m, 1H), 1.96-2.06 (m, 1H), 2.70-2.78 (m, 6H), • 3.-14 (, 2H), 4.95 (br.dd, ÍH), 5.10-5.19 (m, 2H), 7.02 (d, 1H), 7.39 (dd, 1H), 7.43-7.49 (m, 4H) , 7.56 (d, 1H), 9.30 '(br.s, ÍH). a- [5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] -4-hydroxy-1-piperidinopropanol. XH NMR (DMSO-d6 / TFA): d • 1.42-2.10 (m, 6H), 2.88 (, ÍH), 3.04-3.28 (m, 4H),: 3.40 (br.t, 1H), 3.60 and 3.90 (each, 1H), 4.93 (br.dd , ÍH), 5.10-5.19 (m, 2H), 7.03 (d, 1H), 7.40 (dd, 1H), 7.44-7.49 (m, 4H), 7.55 (br.t, 1H), 9.06 (br.s, ÍH).

-Bromo-2- [(4-chlorophenyl) methoxy] -a- [2 - '(dipropylamino) ethyl] -benzenemethanol. XH NMR (DMSO-d6 / TFA): d 0. 83 (br.q, 6H), 1.54 (m, 4H), 1.80 (m, ÍH), 2.00 (m, 1H), 20 2.94 (m, 4H), 3.14 (m, 2H), 4.93 (m, ÍH) ), 5.08-5.18 (m, 2H), 6.98-7.04 (m, 1H), 7.36-7.50 (m, 5H), 7.57 (d, 1H), 9. 10 (br.s, 1H). : 5-bromo-2- [(4-chlorophenyl) methoxy] -a- [2- (diethylamino) ethyl] -benzenemethanol. XH. NMR (DMSO-d6 / TFA): d 1.07 (br.q, 6H), 1.76 (ÍH), 1.96 (m, 1H), 2.95-3.15 (, 6H), 4.90 (dd, ÍH), 5.10 (dd, 2H), 6.99 (br.dd, 1H), 7.34-7.48 (m, 5H), 7.54 (d, 1H), 9.05 (br.s, 1H).

Example 41: 5-chloro-2- [(4-fluorophenyl) methoxy] -. benzeneethenamine.

A mixture of 5-bromo-2- (4-chlorophenylmethyl) -benzaldehyde in HOAc (25 mL) was refluxed for 2 h. After cooling to t.a., the product was obtained by filtration (3.7 g). To a suspension of LiAlH4 (1.6 g, 40 • mmol) in THF (40 mL) at 0 ° C, a solution of the above product (3.5 g, 11.4 mmol) in THF (10 mL) was added dropwise. After the addition, the mixture was refluxed for 1.5 h, cooled to t.a., and quenched with concentrated NaOH (3 mL). The solid was filtered, and the solution was concentrated to provide the desired amine. XH. NMR • (400 MHz, DMSO-de): d 2.7 (t, 2H), 2.94 (t, 2H), 5.04 (s, 2H), 6.8 (d, ÍH), 7.0-7.24 (m, 4H), 7.4 ( m, 2H).

Example 42: N - [[2- [5-chloro-2 - [(4-fluorophenyl) -methoxy] phenyl] ethyl] -4-piperidinomethanamine.

To 5-chloro-2- [(4-fluorophenyl) ethoxy] -benzeneethanamine (280 mg, 1 mmol) in MeOH (5 mL) was added 4-pyridinecarboxaldehyde (93.5 μL) and BH3Py (0.19 mL, 8M). The reaction mixture was stirred at t.a. overnight. The solvent was removed under vacuum, and the resulting residue was diluted with methylene chloride, washed with water and brine, and dried over Na 2 SO 4. Concentration in vacuo, followed by purification by flash column chromatography, provided the title product. XH NMR (CDC13, 400 MHz): d 2.8 (m, 4H), 3.78 (s, 2H), 5.0 (s, 2H), 6.80 (d, 1H), 7.05 (t, 2H), 7.15 (m, 4H) ), 7.35 (m, 2H), 8.50 (s, 1H).

The following compounds were prepared in a similar way: -chloro-2- [(4-fluorophenyl) methoxy] -N, N-a-trimethylbenzeneethanamine. XH NMR (DMS0-d6, 400 MHz): d 0.80 '(d, 3H), 2.10 (s, 6H), 2.36 (m, 1H), 2.80 (, 2H), 5.05 (s, 2H), 6.80 (d , 1H), 7.0 (d, 1H), 7.20 (m, 4H), 7.50 (, 2H). 4 - [[[2- [5-chloro-2 - [(4'-fluorophenyl) methoxyjfenyl] ethyl] amino] methyl] benzonitrile. XH NMR (DMSO-de, 400 MHz): d (TMS) 2.95 (m, 2H), 3.10 (m, 2H), 4.25 (, 2H), 5.10 (s, 2H), 7.05 (d, 1H), 7.20 ( t, 2H), 7.25 (m, 2H), 7.45 (m, 2H), 7.65 (m, 2H), 7.90 (d, 2H).

N- [2- [5-chloro-2 - [[(4-f luorofenyl) methoxy] f-ethyl] -N- (lH-imidazol-5-ylmethyl) -lH-imidazole-4-methanamine. X H NMR (CDCl 3, 400 MHz): d (TMS) 2.65 (m, 2 H), 2.90 (m, 2 H), 3.60 (m, 4 H), 5.0 (s, 2 H), 6.80 (d, Í H), 6.90 (m s, 2H), 7.05 (t, 2H), 7.10 (, 2H), 7.35 (m, 2H), 7.60 (d, 2H).

-Chloro-a-ethyl-2- [(4-fluorofenyl) methoxy] -N- [(4-fluorophenyl) methyl] benzeneethanamine. XH NMR (DMS0-d6, 400 MHz) d (TMS) 0.75 (t, 3H), 2.65 (m, 1H), 2.78 (m, 2H), 3.70 (m, 2H), 5.0 (m, 2H), 7.05 (m, 3H), 7.20 (m, 6H), 7.40 (m, 2H).

-Chloro-a-ethyl-2- [(4-fluorophenyl) methoxy] -N - [(3-methyl-4-methoxyphenyl) methyl] benzeneethanamine. XH NMR (CDC13, 400 MHz): d (TMS) 0.85 (t, 3H), 1.65 (, 2H), 2.0 (s, 2H), 2.10 (s, 3H), '2.95 (m, 1H), 3.05 ( m, 2H), 3.75 (s, 3H), -3.80 (m, 2H), 4.90 (m, 2H), 6.70 (d, ÍH), 6.80 (d, ÍH), 6.95 (s, ÍH), 7.05 ( t, 2H) ', 7.20 (m, 5H).

Example 43: L - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinecarboxylic acid methyl ester.

To a stirred solution of lj [[5-bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -4-piperidinone (5 g, 12.2 mol) and Znl (500 mg, 1.6 mmol) in CH2C12 ( 10 mL), TMSCN (2 mL, 15 mmol) was added. The reaction mixture. was stirred at 70 ° C in a sealed tube for 5 h. After removing CH2C12, the residue was purified by flash chromatography to provide the intermediate cyanohydrin as a white solid. A solution of the intermediate above (1.8 g, 3.4 mmol) in MeOH (20 mL) was. saturated with HCl (g) at 0 ° C. The solution was tempered to t.a. and stirred during the night. The reaction mixture was drained - in cooled Et20 (400 mL), and the product precipitated. XH NMR (CDC13): d 1.58-1.68 (m, 2H), 2.13 (ddd, 2H), 2.46 (ddd, 2H), 2.70-2.78 (, 2H), 2.90 (br.s, 1H), 3.58 (s, 2H), 3.80 (s, 3H), 5.02 (s, 2H), 6.75 (d, 1H), 7.29 (dd, • ÍH), 7.36 (br.s, 4H), 7.53 (br.d, 1 HOUR) .

Example 44: l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -hydroxy-4-piperidinesarboxylic acid.

• A mixture of 1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinecarboxylic acid methyl ester (1 g) and LiOH (1.5 g) in 25 ml of THF-H20 (4: 1, v / v), was stirred at rt overnight. After removing the solvent, the resulting mixture was acidified with 1.0N HCl (aqu.) To pH 2-3. The mixture was extracted with CH2C12 and dried over Na2SO4. Concentration, followed by purification by flash chromatography, gave the title compound as a white solid. XH NMR (CDC13): d 1.64 (br.d, 2H), 2.50 (br.ddd, 2H), 3.02 (br.dd, 2H), 3.14-3.24 (m, 2H), 4.30 (br.s, 2H ), 5.07 (s, 2H), 6.81 (d, ÍH), 7.28-7.40 (m, 4H), '7.42 (dd-, ÍH), 7.81 (d, ÍH).

Example 45: 4 - [[1 - [[5-Bromo-2 - [(4-chlorophenyl) -methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] carbonyl] -l-piperazinesethanol.

To a stirred solution of l - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinocarboxylic acid (181 mg, 0.4 mmol) in DMF (5 mL) was he added 1- (2-hydroxyethyl) piperazine (65 mg, 0.5 mmol), followed by HATU (198 mg, 0.52 mmol) and DIEA (103 mg, 0.8 mmol), at After 4 h, the mixture was poured into ice water (10 mL) and extracted with EtOAc (3x15 mL). The organic phase was dried over Na 2 SO, and concentrated. The crude residue was purified by flash chromatography to give the title compound XH NMR (DMS0-d6 / TFA): -d 1.74-2.30 (, 4H), 2.88-3.76 (m, 14H), 4.24-4.90 (m, 4H), 5.16 (s, 2H), .7.12-7.18 (m, 1H), 7.40-7.52 (m, 4H), '7.57-7.62 (, 1H), 7.70 (d, ÍH), 9.40 (br.s, ÍH), 9.80 (br.s, ÍH).

The following compounds were prepared in a similar way: l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4- (l-piperazinylcarbonyl) -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.70-2.30 (m, 4H), 3.00-3.40 (m, 8H), 3.50-4.20 (, 4H), 4.28 (, 2H), 5.15 (m, 2H), 7.12-7.18 (m, 1H), 7.40-7.52 (m, 4H), 7.60 (dd, 1H), 7.68-7.73 (m, 1H), 8.80 (br.s, 2H), 9.35 (br.s, 1H ). 1 - . 1 - [[5-Bromo-2 - [(4-chlorofenyl) met oxy] phenyl] met il] -4 - [[(3R) -3-methylpiperazinyl] carbonyl] -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.18 (d, 3H), 1.70-2.30 (m, 4H), 2.70-3.50 (m, 9H), 4.10-4.76 (m, 4H), 5.14-5.20 (m , 2H), 7.12-7.18 (m, ÍH), 7.40-7.52 (m, 4H), 7.56-7.62 (m, ÍH), 7.68-7.72 (m, 1H), 8.80 (br.s, 1H), 9.10 (br.s, 1H), 9.40 (br.s, ÍH).

Example 46: 4- [1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] -1-piperazinecarboxylic acid 1, 1-dimethylethyl ester.

To one, stirred solution of l - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinone (600 mg, 1.49 mmol) in EtOAc (10 L), was added HOAc (98 mg, 1.63 mmol), followed by N-Boc-piperazine (304 mg, 1.63 mmol), and NaBH (OAc) 3 (474 mg, 2.24 mmol), in one portion, at room temperature. After 16 h, the reaction was quenched with brine (40 L), and extracted with EtOAc (3x35 mL). The organic phase was washed with brine (30 mL) and dried over Na2SO4. Concentration, followed by purification by column chromatography, afforded the title compound. X H NMR (400 MHz, DMSO): 1.42 (s, 9 H), 1.58 (m, 2 H), 1.76 (m, 3 H), 2.3 (m, H H), 2.95 (d, 2 H), 3.41 (m, 4 H) , 3.54 (s, 2H), 5 (s, 2H), 6.74 (d, ÍH), 7.28 (dd, ÍH), 7.36 (dd, 4H), 7.5 (d, 1).

Example 47: l- [l - [[5-Bromo-2 - [(4-chlorphenyl) -methoxyphenyl] methyl] -4-piperidinyl] piperazine.

To a stirred solution of l - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinone (640.5 mg, 1. 5 mmol) in THF (10 mL) at -78 ° C, LDA (0.9 mL, 1.8 mmol, 2.0 M in THF / hexane) was added. After 30 min it was added Mel (320 mg, 2.25 mmol), and the ration was allowed to warm to room temperature overnight. The reaction was mitigated with 0.1 N HCl (10 L) at 0 ° C, and Extracted with EtpAc (3x30 L). The organic phase was washed with brine (15 mL) and dried over Na2SO4. Concentration, followed by purification by column chromatography, afforded the title compound. XH NMR (400 MHz, DMSO-de): d 0.8 (d, 3H), 2.12 (m, 2H), 2.3-6 (m, 2H), 3.0 (, 2H), 3.6 (s, 2H), 5.1 ( s, 2H), 7.0 (d, ÍH), 7.45 (dd, 4H), 7.52 (d, 1H). 'Example 50: -. 1 - [[5-Bromo-2- [(4-chlorophenyl) methoxyphenyl] methyl] -3-methyl-4-piperidinol.

To a stirred solution of l - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -3-methyl-4-piperidinone (150 mg, 0.36 mmol) in MeOH (10 mL), at 0 ° C, NaBH4 was added (100 mg, 2.63 mmol) in one portion. After 30 min, the reaction mixture was diluted with brine (10 mL), and extracted with EtOAc (3x30 mL). The organic phase was layada with brina (10 mL) and dried over Na2SO4. Concentration, followed by purification by column chromatography, afforded the title compound. XH NMR (400 MHz, DMSO-d6): d 0.9 (d, 3H), 1.5 (, 2H), 1.7 (, 2H), 1.8 (m, ÍH), 2.0 (m, ÍH), '2.78 (m, 2H), 3.1 (m, 1H), 3.4. (s, 2H), 4.9 (s, 2H), 6.7 (d, ÍH), 7.2 (dd, ÍH), 7.32 (dd, 4H), 7.52 (d, 1H).

Example 51: l - [[5-broato-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -4,4-difluoropiperidine.

To a stirred solution of l - [[5-bromot2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinone (500 mg, 1.24 mmol) in CH2C12 (20 mL), at -78 ° C, he added DAST (978 mg, 6.19 mmol). The reaction mixture was allowed to warm to room temperature overnight, then cooled again to 0 ° C, and quenched with NaOH (10%, 15 mL). The reaction mixture was extracted with EtOAc (3x15 mL), washed with brine (10 mL), and dried over Na2SO4. Concentration, followed by purification by column chromatography, afforded the title compound. XH NMR (400 MHz, DMSO-d6): 1.9 (m, 4H), 3.55 (s, 2H), 5.1 (s, 2H), 7.0 (d, ÍH), 7.36 (dd, ÍH), 7.42 (m, 5H).

Example 52: 8 - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -1,3,8-triazaspiro [4.5] desano-2,4-dione.

A mixture of l - [[5-bromo-2- [(4-chlorophenyl) -'-methoxy] phenyl] methyl] -4-piperidinone (2 g, 4.9 mmol)., KCN (500 mg, 7.7 mmol) and ( NH4) 2C03 (2 -g, 19 mmol) in EtOH-H20 (40 mL, 1: 1) was stirred in a sealed tube at 120 ° C overnight. After diluting it with water, the cooled mixture was slowly acidified with concentrated hydrochloric acid.

The crude hydantoin product was recrystallized from CH2Cl2-MeOH to give the product as a white powder. H NMR (DMSO-d6 / TFA): d 1.82-2.20 (m, 4H), 3.10-3.50 (m, 4H), 4.25-4.35 (m, 2H), 5.20 (s, 2H), 7.19 (d, ÍH) ), 7.44-7.56 (m, 4H), 7.63 (m, ÍH), 7.81 (br.s, ÍH), 8.32 and 8.78 (each s, ÍH), 9.90-10.10 (m, ÍH), 10.80-10.90 (my h) . -. . .. ...

Example 53: l ~ [[5-Bromo-2 - [(4-chlorophenyl) methoxyphenyl] methyl] -4-phenyl-4-piperidinol.

To a solution of l ~ [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinone (300 mg, 0.73 mmol) in THF (5 mL), was added a solution of phenylmagnesium bromide (0.9 mL, 0.9 mmol, 1.0 M in THF), at 0 ° C. The mixture tempered until t.a. u was agitated for 1 h more. The reaction was mitigated with 1.0 N HCl (aqu.) At 0 ° C. After removing the THF in vacuo, the residue was diluted with EtOAc, washed with brine, and dried over Na 2 SO 4. The concentration, followed. by purification with HPLC, gives the title compound as a white powder. XH NMR (DMS0-d6 / TFA): d 1.62 and 1.78 (each br.d, 2H), 2.10-2.32 (m, 2H), 3.02-3.44 (, 4H), 4.32 and 4.44 (each br.d , 2H), 5.12 and 5.20 (each s, 2H), 7.16-7.26 (m, 2H), 7.30-7.54 (, 8H), 7.60-7.65 (m, ÍH), 7.75 and 7.81 (each d, 1H) ), 9.30-9.50 (m, ÍH).

The following compound was made in a similar way: l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-ethyl-4-piperidinol. XH NMR (DMS0-d6 / TFA): d 0.72 and 0.79 (each t, 3H), 1.30-1.74 (m, 6H), 2.80-3.25 (m, 4H), 4.20-4.30 (m, 2H), 5.13 and 5.17 (each s, 2H), 7.16 (d, 1H), 7.40-7.54 (, 4H), 7.57-7.63 (m, ÍH), 7.68-7.74 (m, ÍH).

Example 54: l - [[5-Bromo-2- [(4-chlorophenyl) methoxyjphenyl] methyl] -4- (trifluoromethyl) -4-piperidinol.

To a solution of l - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinone (380 mg, 0.93 mmol) in THF (5 L), TMSCF3 (0.3 mL, 2.03 mmol) and a catalytic amount of TMAF.H20, at rt After 1 h, 1 mL of HCl was added, and it was stirred for another 30 min. After removing the solvents, the residue was diluted with EtOAc; wash with NaHCO3 (sat.) and brine, and dry over Na2.S0. Concentration, followed by purification by HPLC, provided the title compound.

Example 55: l - [[5 ~ bromo ~ 2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinone oxime.

To a solution of l - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinone (300 mg, 0.73 mmol) and HONH2H. HCl (61 mg, 0.88 mmol) in CH2C12 (5 mL), pyridine (0.3 L, 3.7 mmol) was added at t.a. After 20 h, the solid was collected by filtration, and washed with hexane-EtOAc, to provide the product as a white solid. XH NMR (DMSO-d6 / TFA): d 2.30-3.50 (m, 8H), 4.26 '(br.s, 2H), 5.16 (s, 2H), 7.14 (d, ÍH), 7.40-7.54 (m, 4H), 7.58 (dd, ÍH), 7.86 (d, 1H), 10.80-10.90 ( my h) .

Example 56: 1 - [[5-bromo-2 - [[(4- (trifluoromethyl) enyl] methoxy] phenyl] methyl] -4-fluoropiperidine. To a solution of .l - [[5-bromo-2- [[(4- (trifluoromethyl) phenyl] methoxy] phenyl] methyl] -4-piperidinol (870 mg, 2.0 mmol) in CH2C12 (10 mL), DAST (0.85 mL, . 5 mmol), at -78 ° C. The mixture was warmed overnight. The mixture was again cooled to -78 ° C and mitigated with MeOH »After concentration, the residue was purified by recrystallization from hexane-EtOAc (collect the liquid) followed by flash chromatography to provide the product as a colorless syrup. XH NMR (DMSO-de / TFA): d 1.78-2.24 (m, 4H), 3.02-3.56 (, 4H), 4. 28-4.36 (m, 2H), 4.70-5.00 (m, 1H), 5.28 (s, 2H), 7.15 - (d, 1H), 7.59 (dd, lH), 7.66-7.75 (m 5H), 3.50 (br.s, ÍH). 57: 1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4- (2-pyridinyloxy) iperidine.

To a stirred solution of l - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinol (205 mg, 0.5 mmol) in DMF at 0 ° C was added NaH (16.1 mg, 0.7 mmol). After 30 min, 2-fluoropyridine (116 mg, 1.2 mmol) was added and the solution was maintained at 100 ° C for 5 h. After cooling to t.a., the reaction was developed in the usual manner, and purified by flash chromatography, to provide the title compound as a white powder. XH NMR (DMSO-d6 / TFA): d 1.82 (m, ÍH), 1.98-2.14 (, 2H), 2.26 (? T ?, ÍH), 3.18 (m, 2H), 3.30 (m, ÍH), 3.45 (m, HH), 4.30 (m, 2H), 5.06-5.30 (, 3H), 6.84 '(m, 1H), 7.00 (m, HH), 7.16 (m, HH), 7.36 (m, 1H), 7.40-7.54 (m 3H), 7.60 (m, ÍH), 7.70-7.80 (m, 2H), 8.14 (m, ÍH), 9.40 (br.s, ÍH).

The following compound was prepared in a similar manner: 2 - [[1 - [[5-bromo-2 - [(4- (chlorofenyl)] methoxy] phenyl] methyl] -4-piperidinyl] oxy] pyrimidine XH NMR (-DMSO-6 / TFA): d 1.84 (m, ÍH), 2.10 (m, 2H), 2".28 '(m, ÍH), 3.22 (br.s, 2H), 3.32 (m, ÍH), 3.46 (, 1H),' 4.30 (m, 2H), 5.12-5.30 (m, 3H), 7.16 (, 1H), 7.36-7.56 (m, 4H), 7.60 (m, 1H), 7.74 (m, 1H), 8.14-8.28 (m, 3H) -, 9.45 (br.s, ÍH).

E jelary 58: l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -N-ethyl-4-piperidinamine.

To a stirred solution of l - [[5-bromo ~ 2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinone (204 mg, 0.5 mmol) in CH2Cl2-MeOH (2 mL / 2 mL), ethylamine (0.2 mL) was added, followed by NaBH (0Ac) 3 (170 mg, 0.8 mmol) and HOAc (0.2 mL), at t.a. After 10 h, the reaction was developed in the usual manner, and purified by flash chromatography to give the title compound as a white powder. H NMR (DMS0-d6 / TFA): d 1.10-1.26 (m, 3H), 1.72 (m, 2H), 1.86-2.22 (m, 2H), 2.86-3.50 (m, 7H), 4.21 (br.s) , 2H), 5.16 (s, 2H), 7.15 (d, 1H), 7.40-7.52 (m, 4H), '7.59 (dd, ÍH), 7.67 (br.d, 1H), 8.90 (br.s, 2H), 10.00 (br. S, 1H).

Example 59: 6 - [[5-Bromo-2 ~ [(4-chlorophenyl) methoxy] phenyl] methyl] -l-oxa-6-azaspiro [2.5] octane.

To a homogeneous solution of (Me) 3SI (6.28 g, 30.7 mmol) in DMSO (150 mL), was added l - [[5-bromo-2 - [(4-chlorophenyl) methoxy] f-ethyl] -ethyl] 4 ~ piperidinone (8.0 g, 19.81 mmol), followed by KO-tBu (3.45 g, 30.71 mmol) at rt The reaction was maintained at t.a. overnight, and was poured into ice water (150 L). The reaction mixture was extracted with EtOAc (3x160 mL), washed with brine (150 mL), and dried over Ma2SO4. Concentration, followed by purification by column chromatography, afforded the title compound. XH NMR (400 MHz, DMS0-d6): 1.55 (m, 2H), 1.9 (, 2H), 2.6 (, 2H), 2.65 (s, 2H), 3.6 (s, 2H), 5.02 (s, 2H) , 6.78 (d, 1H), 7.3 (dd, ÍH), 7.36 (s, 4H), 7.53 (d, ÍH).

Example 60: 4- (aminomethyl) -l - [[5-bromo-2- [(4-chloro-e-enyl) -methoxy] -enyl] -methyl] -4-piperidinol, and l - [[5-bromo-2- [(4-Chloro-enyl) -methoxy] -phenyl] -methyl] -4 - [[[1 - [[5-bromo-2- [(4-chloro-enyl) -methoxy] -phenyl] -methyl] -4-hydroxy-4- • piperidinyl] methyl] amino] methyl] -4-piperidinol.

A mixture of 6 - [[5-bromo-2 - [(4-chlorophenyl) -methoxy] phenyl] methyl] -l-oxa-6-azaspiro [2.5] octane (4 g), NH40H (12 mL, 28-30% wt) in MeOH (50 mL), was stirred in a sealed tube at 75 ° C overnight. After concentration, the residue was purified directly by flash chromatography to provide 4- (aminomethyl) -1 - [[5-bromo-2 - [(4-chlorophenyl) methoxy] f-ethyl] -4] -piperidino? as a white solid. XH NMR (DMSO-d6 / TFA): d 1.70-1.96 (m, 4H), 2.80-3.80 (m, 6H), 4.26-4.38 (, 2H), 5.18-5.22 (m, 2H), 7.14-7.20 ( m, ÍH), 7.44-7.54 (m, 4H), 7.60-7.64 (m, 1H), 7.70-7.74 (m, 1H), 7.86 (br.s, 2H), 9.50 (m, 1H), and a by-product: l - [[5-bromo-'2 - [(4-chlorophenyl) methoxy] phenyl] methyl] - 4 - [[[l - [[5-bromo-2 - [(4-chlorophenyl) methoxy] ] phenyl] methyl] -4- hydr oxy-4-piperidinyl] met yl] amino] methyl] -4-piperidinol, as a light yellow solid. XH NMR (DMSO-d6 / TFA): d 1.68-2.06 (m.8H), 3.00-3.34 (m, 12H), 4.24-4.34 (, 4H), 5.14-5.20 '(m, 4H), 7.11-7.17 (, 2H), 7.40-7.51 (m, 8H), 7.56-7.61 (m, 2H), 7.68-7.71 (m 2H), 8.35 (br.s, 2H), 9.60 (m, 2H). The following compounds were prepared in a similar way: 1, 1-dimethylethyl ester of 4 - [[1 - [[5-bromo-2- [(4-chloro-enyl) -methoxy] -phenyl] -methyl] -4-hydroxy-4-piperidinyl] -methyl] -l-piperazinecarboxylic acid . XH NMR (DMSO- of / TFA): d 1.34-1.40 (, 9H), 1.68-2.10 (m, 4H), 3.00-4.00 (m, 14H), 4.25 (br.s, 2H), 5.15 (s, 2H), 7.12-7.17 (M, ÍH), 7.40-7.52 (m, 4H), 7.59 (dd, ÍH), 7.70 (d, 1H), 9.50 (br.s, 1H). 1, 1-dimethylethyl ester of 4 - [[1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] hexahydro-1H-1 , 4-diazepine-l-carboxylic acid. XH NMR (DMSO-dg / TFA): d 1.36-1.40 (, 9H), 1.68-2.16 (m, 6H), 3.10-3.80 (m, 14H), 4.30 (s, 2H), 5.15 (s, 2H) , 7.13-7.18 (, 1H), 7.41-7.52 (m, 4H), 7.59 (dd, ÍH), 7.70 (d, ÍH), 9.30-9.60 (m, 1H). l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4- [[4- (2-pyridinyl) -l-piperazinyl] methyl] -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.72-2.12 (m, 4H), 3.10-4.20 (, 14H), 4.30. (s, 2H), 5.18 (s, 2H), 6.97 (m, ÍH), 7.12-7.18 (m, 1H), 7.33 (m, 1H), 7.41-7.52 (m, 4H), 7.60 (m, ÍH) ), 7.70 (m, ÍH), 7.97 (m, 1H), 8.10-8.16 (m, lH), 9.60 (br.s, ÍH). l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4- [[4- (2-pyrimidinyl) -l-piperazinyl] methyl] -4-piperidinol. XH-NMR (DMSO ~ d6 / TFA): d 1.70-2.10 (m, 4H), 3.10-3.70 (m, 12H), 4.30 (s, 2H), 4.50 (br.s, 2H), 5.18 (s, 2H), 6.72 (m, ÍH), 7.13-7.18 - (m, 1H), 7.41-7.52 (m, 4H), 7.60 (m, 2H), 9.50 (, ÍH), 7.71 (d, ÍH), 8.40 (m, 2H), (br.s, ÍH). l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4- (l-piperazinylmethyl) -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.69-2.06 (m, .4H) and 3.10-3.Y1 (m, 14H), 4.-27 (br. S, - 2H), 5.14 (br.s , 2H), 7.07-7.13 (m, 1H), 7.36-7.48 (, 4H), 7.54 (m, ÍH), 7.69 (, 1H), 9.10 (br.s, 2H), 9.41 (br.s, ÍH) ). l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [(hexahydro-lH-1,4-diazepin-1-yl) methyl] -4-piperidinol .. ' 1 H NMR (DMSO-de / TFA): d 1.48-1.97 (m, 6H), 2.88-3.58 (m, 14H), 4.08 (br.s, 2H), 4.96 (br.s, 2H), 6.90 -6.95 (, ÍH), 7.18-7.30 (m, 4H), 7.37 (m, 1H), 7.50 (d, 1H), 8.70 (br.s, 2H), 9.22 (br.s, ÍH). l - [[5-br omo-2 - [(4-chlorofenyl) met oxy] fyl] methyl] -4 - [[(4-methylphenyl) amino] methyl] -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.70-2.06 (m, 4H), 2.22-2.24 (, 3H), 3.10-3.38 (m, 6H), 4.22-4.32 (m, 2H), 5.17 (s, 2H), 7.06-7.24 (m, 5H), 7.38-7.52 (m, 4H), 7.56-7.61. (m, 1H), 7.70 (d, 1H), 9.20-9.40 (m, ÍH). l - [[5-Bromo ~ 2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4- [[(4-methoxyphenyl) amino] methyl] -4-piperidinol. XH NMR (DMSO- de / TFA): d 1.72-2.08 (m, 4H), 3.10-3.42 (m, 6H), 3.72-3.76 (m, 3H), 4.26-4.32 (m, 2H), 5.18 (s) , 2H), 6.96-7.60 (m, 2H), 7.10-7.20 (, ÍH), 7.28-7.38 '(, 2H), 7.40-7.52 (, 4H), 7.58-7.62 (m, 1H), 7.70 (d , ÍH), 9.30-9.50 (m, ÍH). l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[(3 S) -3-methylpiperazinyl] methyl] -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.15-1.40 (m, 3H), 1.70-2.05 (, 4H), 2.95-3.70 (m, 13H), 4.28 (br.s, 2H), 5.18 (br. s, 2H), 7.12-7.18 (m, 1H), 7.40-7.52 (m, 4H), 7.58-7.62 (m, ÍH), 7.70 (d, ÍH), 9.10-9.60 (, 1H). l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4- [(2,5-dimethyl-l-piperazinyl) methyl] -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.16-1.30 (m, 6H), 1.70-2.08 (m, 4H), 3.00-3.74 (m, 12H), 4.26-4.34 (m, 2H), 5.18 (s, 2H) ), 7.13-7.17 (, 1H), 7.41-7.52 (m, 4H), 7.60 (dd, ÍH), 7.71 (d, ÍH), 9.50 (br.s, 1H). 4 - [[(3 -.aminopropyl) amino] methyl] -l - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinol. 1 H NMR (DMSO-de / TFA): d 1.66-2.00 (m, 6H), 2.80-3.36 (m, 10H), 4.26-4.34 (m, 2H), 5.18 (m, 2H), 7.11-7.18 (m , ÍH), 7.46 (AB, 4H), 7.60 (m, ÍH), 7.70 (m, 1H), 7.82 (br.s, 3H), 8.54 (br.s, 2H), 9.50 (br.s, ÍH) ). l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4 - [[[(2- (1-piperidinyl) ethyl] amino] methyl] -4-piperidinol. NMR (DMS0-d6 / TFA): d 1.30-2.02 (m, 10H), 2.86-3.48 (m, 14H), 4.26-4.32 (m, 2H), 5.16-5.19 (m, 2H), 7.11-7.17 ( m, ÍH), 7.50 (AB, 4H), 7.60 (m, ÍH), 7.70 (m-, ~ 1H), - 8.80 (br.s, ÍH), 9.60 (br.s, ÍH). 1, 1-dimethylethyl 2 - [[[[1 - [[5-bromo-2- [(4-chloro-enyl) -ethexy]] -phenyl] -methyl] -4-hydroxy-4-piperidinyl] -methyl] -amino] ethyl] -l-pyrrolidinocarboxylic acid. H NMR (DMSO-de / TFA): d 1.38 (m, 9H), 1.64-2.00 (m, 8H), 2.90-3.36 (m, 10H), 4.04 (m, ÍH), 4.24-4.30 (m, 2H) , 5.18 (br.s, 2H), 7.12-7.18 (, ÍH), 7.40-7.52 (m, 4H), 7.60 (m, 1H), 7.68-7.70 (, 1H), 8.40-8.60 (, 2H), 9.50 (br.s, ÍH). . l - [[5-Bromo-2- [(4-chlorofenyl) methoxyjfenyl] methyl] -4 - [[(2-pyrrolidinylmethyl) amino] -triethyl] -4-piperidinol. -XH NMR (DMSO-de / TFA): d 1.60-2.06 (m, 7H), 2.12 (m, 1H), 2.92-3.38 (m, 10H), 3.86 (br.s, 1H), 4.26-4.32 (, 2H), 5.18-5.20 (, 2H), 7.11-7.17 (m, 1H), 7.40-7.52 (m, 4H), 7.58-7.62 (m, 1H), 7.68-7.72 (m, ÍH), 8.60 (br.s, ÍH), 8.80 (br.s, 2H), 9. 05 (br.s, 1H), 9.60 (br.s, ÍH). l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4- [[4- [(2,4-dimethyl-3-pyridinyl) carbonyl] -l-piperazinyl] methyl] -4-piperidinol. aH NMR (DMS0-d6 / TFA): d 1.72-2.04 (, 4H), 2.42 (br.s, 3H), 2.56 (br.s, 3H), 2.86-3.58 (m, 14H), 4.28 (br. s, 2H), 5.18 (s, 2H), 7.12-7.18 (m, ÍH), 7.42-7.52 (, 4H), 7.60 (dd, ÍH), 7.70 (d, ÍH), 7.80-7.84 (m, lH ), 8.72 (br.d, ÍH), 9.60 (br.s, ÍH).

Ethyl 4 - [[1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] f-enyl] -methyl] -4-hydroxy-4-piperidinyl] methyl ester] -1-piperazinecarboyl. XH NMR (DMS0-d6 / TFA): d 1.14-1.20 (m, 3H), 1.70-2.06 (m, 4H), 3.10-3.90 (, 14H), 4.00-4.10 (m, 2H), 4.30 (br.s, 2H), 5.17 (s, 2H), 7.12-7.18 (, ÍH), 7. 42-7.52 (m, 4H), 7.60 (dd, ÍH), 7.70 (d, 1H), 9.50 (br.s, 1H). 4 ~ [(4 ~ acetyl-l-piperazinyl) methyl] -l - [[5-bromo-2 ~ [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinol. XH NMR (DMSO-d6 / TFA): d 1.70-2.08 (, 7H), 3.00-4.00 (, 14H), 4.30 (br.s, 2H), 5.18 (s, 2H), 7.12-7.18 (, 1H), 7.42 -7.52 (m, 4H), 7.60 (dd, ÍH), 7.70 (d, ÍH), 9.60 (br.s, ÍH). l - [[5-Bromo-2- [(4-chlorofenyl) methoxyjfenyl] methyl] -4 - [(l-piperazinylamino) methyl] -4-piperinidol. XH NMR- (DMSO-de / TFA): d 1.68-2.00 (m, 4H), 2.78-3.66 (m, 17H), 4.28 (br.s, 2H), 5.16-5.20 (m, 2H), 7.11- 7.18 (m, ÍH), 7.46 (AB, 4H), 7.60 (br.dd, ÍH), 7.70 (d, 1H) ', 9.55 (br.s, ÍH). 4 - [[1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -l-piperazineethanol. XH NMR (DMSO-d6 / TFA): d 1.70-2.04 (m, 4H), 3.06-3.76 (, 18H), 4.27 (br.s, 2H), 5.17 (s, 2H-), - 7.12-7.17 ( m, ÍH), 7.41-7.52 (m, 4H), 7.59 (dd, ÍH), 7.70 (d, ÍH), 9.70 (br.s, ÍH). 4 ~ [[l ~ [[5-Bromo-2 ~ [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -l-piperazinecarboxaldehyde. XH NMR (DMSO-de / TFA): d 1.70-2.08 (m, 4H), 3.08-3.76 (, 14H), 4.28 (br.s, 2H), 5.16 (s, 2H), 7.12-7.18 (m, ÍH), 7.40-7.52 (m, 4H), 7.56-7.62 (m, ÍH), 7.70 (d, ÍH), 8.01-8.04 (m, ÍH), 9.60 (br.s, ÍH). 4 - [[1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -1-piperazinecarboxylic acid phenylmethyl ester. XH NMR (DMSO-d6 / TFA): d 1.70-2.10 (m / 4H), 3.05-4.10 (, 14H), 4.30 (br.s, 2H), 5.08-5.10 (m, 2H), 5.17 (s, 2H), 7.12-7.18 (m, ÍH), 7.28-7.38 (m, 5H), 7.42-7.52 (m, 4H), 7.60 (dd, ÍH), 7.70 (d, ÍH), 9.55 (br.s, ÍH). l ~ [[5-Bromo-2 - [(4-chlorophenyl) methoxyjfenyl] methyl] -4- [[4- (phenylmethyl) -l-piperazinyl] methyl] -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.36-1.94 (m, 8H), .2.44-3.50 (m, 12H), 4.16 (br.s, 2H), 5.05 (s, 2H), 7.00-7.08 ( m, 4H), 7.12-7.18 (m, • 2H), 7.28-7.40 (m, 4H), 7.46-7.50 (m, 1H), 7.57-7.60 (m, ÍH), 8.60-9.40 (m, 2H) . l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 [[[(2-methylphenyl) amino] methyl] -4-piperidinol. XH NMR (DMSO- of / TFA): d 1.70-2.04 (, 4H), 2.12 and 2.18 (each s, 3H), '3.08-3.34 (m, 6H), 4.24-4.34 (, 2H), 5.16 ( m, 2H), 6.60-6.90 (m, 2H), 6.98-7.18 (, 3H), 7.38-7.52 (, 4H), 7. 59 (dd, ÍH), 7.69-7.72 (m, 1H), 9.20-9.40 (m, ÍH). l - [[1 - [[5-bromo-2- [(4-chloro-enyl) -methoxyphenyl] -methyl] -4-hydroxy-4-piperidinyl] methyl] -4-piperidinecarboxamide: da. XH 'NMR (DMSO-de / TFA): d 1.68-2.04 (m, 8H), 2.32 (m, 1H), 2. 90-3.65 (m, 10H), 4.30 (m, 2H), 5.18 (s, 2H), 6".88-6.98 (m, ÍH), 7.13-7.18 (ÍH), 7.36 (, ÍH), 7.42-7.52 (, 1H), 7. 60 (dd, .IH), 7.70 (d, ÍH), 8.90-9.60 (m, 2H). LC-MS (API150EX): calc: 550, found: 550. l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4- [[(3 S) -3-methylpiperazinyl] methyl] -4-piperidinol. XH NMR (DMSO- de / TFA): d 1.15-1.40 (m, 3H), "1.70-2.05 (m, 4H), 2.95-3.70 (m, 13H), 4.28 (br.s, 2H), 5.18 ( br.s, 2H), 7.12-7.18 (m, 1H), 7.40-7.52 (, 4H), 7.58-7.62 (m, 1H), 7.70 (d, ÍH), 9.10-9.60 (m, ÍH). 4 - [[l ~ [[5-Bromo ~ 2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -2-piperazinone. XH NMR (DMSO-de / TFA): d 1.68-2.06 (m, 4H), 3.10-3.70 (m, 10H), 3.75 (s, 2H), 4.28 (s, 2H), 5.18 (s, 2H), 7.12-7.18 (m, ÍH), 7.40-7.52 (m, 4H), 7.58-7.62 (m, 1H), 7.70 (d, ÍH), 8.38-8.42 (m, ÍH), 9.50 (br.s, 1H ). l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[(3 S) -3-methylpiperazinyl] methyl] -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.16-1.26 (m, 3H), 1.68-2.04 (, 4H), 2.95-3.65 (m, 13H), 4.28 (s, 2H), 5.18 (s, 2H) , 7.12-7.18 (m, ÍH), 7.40-7.52 (m, 4H), 7.59 (dd, ÍH), 7.70 (d, ÍH), 8.70-9.60 (m, 2H). l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [(3,5-dimethyl-l-piperazinyl) methyl] -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.16-1.24 (m, 6H), 1.68-2.08 (, 4H), 2.80-3.30 (m, 8H), 3.62 (m, 4H), 4.28 (s, 2H) , 5.18 (s, 2H), 7.12-7.18 (m, ÍH), 7.4Ü-7.52 (m, 4H), 7.60 (dd, 1H), 7.70 (d, 1H), 8.90-9.60 (, 2H). 1- [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4- (2,5-diazabicyclo [2.2.1] hept-2-ylmethyl) -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.66-2.40 (, 6H), 3.04-3.76 (m, 10H), 4.26 (s, 2H), 4.42 (br.s, ÍH), 4.58-4.64 (m, 1H ), 5.17 (m, 2H), 7.11-7.18 (m, ÍH), 7.40-7.52 (m, 4H), 7.56-7.62 (m, ÍH), 7.68-7.71 (m, ÍH), 9.20-9.60 (m , 2H). 1, 1-dimethylethyl ester of [l - [[1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -3-pyrrolidinyl ] carbamic. XH NMR (DMSO- of / TFA): d 1.66-2.32 (m, 6H), 2.85-4.20 (m, 11H), 4.25 (s, 2H), 5.15 (s, 2H), 7.12-7.18 (m, 1H ), 7.40-7.52 (m, 4H), 7.57-7.62 (m, ÍH), 7.70 (d, 1H), 9.50 (br.s, 1H). 4- [(3-amino-l-pyrrolidinyl) methyl] -l - [[5-bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.60-2.40 '(m, 6H), 3.00-4.10 (m, 11H), 4.30' (s, 2H), 5.16 (s, 2H), 7.10-7.18 (m, 1H) ), 7.40-7.52 (m, 4H), 7.56-7.62 (m, ÍH), 7.68-7.71 (m, ÍH), 8.20 (br.s, 3H), 9.60 (br.s, 1H). l - [[5-Bromo-2- [(-chlorofenyl) methoxyjfenyl] methyl] -4- [[4- [2- (dimethylamino) ethyl] -l-piperazinyl] methyl] -4-piperidinol.

XH NMR (DMSO-de / TFA): d 1.68-2.02 (, 4H), 2.74-2.80 (m, 6H), 2.80-3.40 (m, 18H), 4.27 (br.s, 2H), 5.16 (s, 2H), 7.12-7.18 (m, ÍH), 7.40-7.52 (m, 4H), 7.56-7.62 ( m, ÍH), 7.70 (d, ÍH), 9.50 (br.s, ÍH). l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -4- [[4- [2- (4-morpholinyl) -2-oxoethyl] -l-piperazinyl] methyl ] -4- piperidinol .. XH NMR (DMSO-d6 / TFA): d 1.68-2.02 (m, 4H), 3.02-3.64 (m, 22H), 4.26 (br.s, 2H), 4.36 (br.s , 2H), 5.17 (s, 2H), - 7.12-7.18 (m, .- 1H), 7.40-7-.52 (m, 4H) ,. 7.59 (dd, ÍH), 7.70 (d, ÍH), 9.55 (br.s, ÍH). l - [[5-Bromo-2- [(4-chlorofenyl) methoxyjfenyl] methyl] -4- [[4- [3- (4-morpholinyl) propyl] -l-piperazinyl] methyl] -4- piperidinol. XH NMR (DMSO-d6 / TFA): d 1.15-2.10 (m, 6H), 2.95-4.10 (m, 26H), 4.26 (s, 2H), 5.16 (s, 2H), 7.10-7.18 (m, 1H ), 7.40-7.50 (m, 4H), 7.56-7.62 (m, 1H), 7.69 (d, '1H), 9.50 (br.s, 1H). l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4- [[4- [2- (4-morpholinyl) ethyl] -l-piperazinyl] methyl] -4- piperidinol. XH NMR (DMSO-de / TFA): d 1.70-2.05 (m, 4H), 2.85-3.50 (m, 22H), 3.80 (br.s, 4H), 4.28 (br.s, 2H), 5.18 (s) , 2H), 7.12-7.18 (m, ÍH), 7.40-7.52 (m, 4H), 7.56-7.62 (m, ÍH), 7.70 (d, ÍH), 9.52 (br.s, ÍH). l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4- [(dimethylamino) methyl] -4-piperidinol. XH NMR (DMSO-d6 / TFA): d 1.68-2.20 (m, 4H), 2.83 (m, 6H), 3.06-3.34 (m, 6H), - 4.24-4.32 (m, 2H), 5.16 (s, 2H), 7.12-7.18 (, ÍH), 7.40-7.52 (, 4H), 7.56-7.60 (m, ÍH), 7.70 (d, 1H), 9.30 (br.s, ÍH), 9.60 (br.s, ÍH). l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -4- [(diethylamino) methyl] -4-piperidinol. XH NMR (DMSO-d6 / TFA): d - 1.16-1.24 (m, 6H), 1.72-2.08 (m, 4H), 3.06-3.36 (m, 10H), 4.28-4.38 (m, 2H), 5.19 (s, 2H), 7.15-7.20 (m, ÍH), 7.42-7.56 (m, 4H), 7.59-7.64 (m, ÍH), 7.72-7.76 (m, 1H), 8.80 (br.s, 1H), 9.40 (br.s, ÍH). l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4- '[[(1-methylethyl) amino] methyl] -4-piperidinol. XH NMR (DMSO- de / TFA): d 1.20-1.26 (m, 6H), 1.70-2.04 (m, 4H), 2.88-3.38 (m, 7H), 4.28-4.34 (m, 2H), 5.20 (s) , 2H), 7.14-7.20 (m, ÍH), 7.42-7.54 (, 4H), 7.58-7.64 (m, ÍH), 7.72-7.74 (, ÍH), 8.24 (br.s, 2H), 9.50 (br .Yes H) . 'l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -4- [(4-hydroxy-l-piperidinyl) methyl] -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.20-1.26 (m, 6H), 1.70-2.04 (m, 4H), 2.88-3.38 (m, 7H), 4.28-4.34 (m, 2H), 5.20 (s, 2H) ), 7.14-7.20 (, 1H), 7.42-7.54 (m, 4H), 7.58-7.64 (m, ÍH), 7.72-7.74 (m, 1H), 8.24 (br.s, 2H), 9.50 (br. Yes H) . l - [[5-Bromo ~ 2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 - [[(3R) -3-hydroxypyrrolidinyl] methyl] -4-piperidinol. XH NMR (DMS0-d6 / TFA): d 1.68-2.28 (m, 6H), 3.04-3.78 (m, 10H), 4.24-4.46 (m, 3H), 5.16 (s, 2H), 7.11-7.17. (m, 1H), 7.40-7.52 (, 4H), 7.56-7.60 (, ÍH), 7.70 (d, 1H), 9.60 (br. s, 1H). l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] ~ 4 - [[[(4-f luorofenyl) methyl] amino] methyl] -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.64-2.00 (m, 4H), 2.80-3.32 (m, 6H), 4.14 (br.s, 2H), 4.24-4.30 (m, 2H), 5.16 (m , 2H), 7.11-7.29 (m, 3H), 7.40-7.51 (, 4H), 7.53-7.61 (m, 3H), 7.67-7.70 (m, ÍH), 8.85 (br.s, 2H), 9.50 ( br.s, 1H). l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4- (lH-imidazol-l-ylmethyl) -4-piperidinol. XH NMR (DMSO-d6 / TFA): d 1.46-1.94 (m, 4H), 3.00-3.30 (m, 4H), 4.16-4.34 (m, 4H), . 15-5.20 (m, 2H), 7.13-7.17 (m, ÍH), 7.40-7.53 (m, 4H), 7.60 (dd, ÍH), 7-64-7.74 (m, 3H), 8.95 and 9.00 (each some, ÍH), 9.50 (br.s, ÍH). l - [[5-Bromo-2- [(4-chloro-enyl) -methoxyphenyl] -methyl] -4- [(phenylamino) methyl] -4-piperidinol. XH NMR (DMSO-d6 / TFA): d 1.66-2.04 (m, 4H), 3.08-3.30 (, 6H), 4.24-4.32 (, 2H), 5.16 (s, 2H), 6.70-7.02 (m, 3H) ), 7.12-7.28 (m, 3H), .7.38-7.50 (m, 4H), 7.58 (dd, ÍH), 7.68-7.72 (m, ÍH), 9.20-9.40 (m, ÍH). l ~ [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4- [(4-pyridinylamino) methyl] -4-piperidinol. XH NMR (DMSO-d6 / TFA): -d 1.44-1.96 (, 4H), 3.00-3.30 (m, 4H), 4.00-4.16 (ra, 2H), 4.24-4.34 (m, 2H), 5.14-5.18 (m, 2H), 6.76-6.82 (m, 2H), 7.14 (d, 1H), 7.38-7.54 (m 4H), 7.56-7.62. (m, ÍH), 7.68-7.74 (m, ÍH), 7.90-8.02 (m, 2H), 8.10-8.18 (, 2H), 9.50 (br.s, ÍH). l - [[5-Bromo-2 - [(4-chlorophenyl) ratoxy] phenyl] methyl] -4 - [[(2-hydroxyethyl) methylamino] methyl] -4-piperidinol, XH NMR (DMSO-de / TFA) : d 1.68-2.06 (, 4H), 2.86-2.94 (m, 3H), 3.04-3.40 (m, 8H), 3.70-3.80 (m, 2H), 4.26-4.32 (m, 2H), . 17 (s, 2H), 7.12-7.18 (, 1H), 7.40-7.52 (m, 4H), 7.58 (dd, ÍH), 8.99 (br.s, 2H), 9.50 (br.s, 1H). . l - [[5-Bromo ~ 2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4 ~ [(4-methyl-l-piperazinyl) methyl] -4-piperidinol. XH NMR (DMSO-dg / TFA): d 1.70-2.02 (m, 4H), 2.80-2.88 (m, 3H), 3.06-3.78 (m, 14H), 4.28 (br.s, 2H), 5.16 (s) , 2H), 7.11-7.16 (m, 1H), 7.40-7.52 (m, 4H), 7.56-7.60 (m, ÍH), 7.70 (d, 1H), 9.60 (br.s, 1H). l - [[5-b'romo-2- [(4-chlorophenii) methoxy] phenyl] methyl] -4- [(dipropylamino) methyl] -4-piperidinol. 'XH NMR (DMSO-d6 / TFA): d 0.82-0.90 (m, 6H), 1.58-2.08 (m, 8H), 3.00-3.30 (m, 10H), 4.25-4.35 (m, 2H), 5.18 ( s, 2H), 7.12-7.18 (m, ÍH), 7.40-7.52 (m, 4H), 7.60 - (dd, 1H), 7.69-7.73. (, ÍH), 8.99 (br.s, ÍH), 9.70 (br.s, ÍH). - -. l - [[1 - l - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N, N-diethyl-3-piperidinecarboxamide. XH NMR (DMSO-d6 / TFA): d 0.94-1.16 (m, 6H), 1.40-2.10 (m, 8H), 3.00-3.75 (m, 15H), 4.30 (br.s, 2H), 5.18 (s) , 2H), 7.12-7.18 (m, ÍH), 7.40-7.52 (m, 4H), 7.59 (dd, ÍH), 7.70 (, 1H), 9.10-9.30 (, ÍH), 9.50-9.70 (m, ÍH ). l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-. [[(2,2, 2-trifluoroethyl) amino) methyl] -4-piperidinol. XH NMR (DMSO-de / TFA): d 1.70-2.04 (m, 4H), 2.92-3.32 (m, 6H), 3.86 (m, 2H), 4.26-4.34 (m, 2H), 5.18 (s, 2H) ), 7.12-7.18 (m, 1H). l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy] -phenyl] -methyl] -4- [- [[(3-methyl-phenyl) -amino) -methyl] -4-piperidinol. XH NMR (DMSO- of / TFA): d 1.64-2.02 (m, 4H), 2.16 and 2.22 (each s, 3H), 3.02-3.30 (, 6I-I), 4.22-4.34 (m, 2H), 5.16 (br.s, 2H), 6.48-6.76 (m, 3H), 6.98-7.18 (m, 2H), 7.38-7.52 (m, 4H), 7.60 (dd, 1H), 7.68-7.72 (m, ÍH) ), 9.10-9.40 (m, 1H). l ~ [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4- [[[(1 R) -l-phenylethyl] amino] methyl] -4-piperidinol. XH NMR (DMSO- of / TFA): d 1.52-2.00 (m, 7H), 2.50-3.34 (m, 6H), 4.22-4.38 (m, 2H), 5.16 (br.s, 2H), 7.10-7.16 (m, ÍH), 7.35-7.54 (m, 9H), 7.58 (dd, ÍH), 7.65-7.70 (, ÍH), 8.70-9.60 (m, 3H). 4 - [[- l - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N-ethyl-l- piperazinecarboxy one way . XH NMR (DMSO-d6 / TFA): d 0.93-1.02 (m, 3H), 1.68-2.06 (m, 4H), 3.00-4.00 (m, 16H), 4.28 (br.s, 15. 2H), 5.18 (s, 2H), 7.12-7.17 (m, ÍH), 7.41-7.51 (m, 4H), 7.57-7.61 (ra, 1H), 7.70 (d, 1H), 9.55 (br.s, ÍH).

Example 61: N - [[- 1 - [[5-Bromo-2- [(4-chloro-enyl) -methoxyphenyl] -methyl] -4-hydroxy-4-piperidinyl] methyl] -N '- (2,6 -dif luorof enyl) urea.

To a stirred mixture of 4- (aminomethyl) -l - [[5- bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinol (150 mg, 0.34 mmol) and Et3N (69 mg, 0.68 mmol) in CH2C12 (5 mL), 5 was added dropwise to 2,6-difluorofenyl isocyanate (59 mg, 0.37 mmol) at 0 ° C. After the addition, the mixture was stirred overnight at t.a. The mixture was poured into ice water (10 mL), and extracted with CH2C12 (3x15 mL).

The organic phase was dried over Na 2 SO 4, and concentrated in vacuo. The crude product was purified by chromatography . column to provide the title product. XH NMR (DMSO-de, 400 MHz): d 1.1 (s, ÍH), 1.3-1.7 (m, 4H), 2.2-2.8 (m, 2H), 2.9-3.2 (m, 2H), 3.4-3.6 (s, 2H), 4.3-4.5 '. (s, 1H), . 0-5.2 (s, 2H), 6.2-6.4 (m, ÍH), 6.9-7.1 (m, 3H), 7.1-7.3 (m, 1H), 7.3-7.5 (m, 5H), 7.9-8.1 (m , 1 HOUR) .

The following compounds were prepared in a similar way: N - [[- l- [5-bromo-2- [(4-chlorophenyl) methoxy] fehyl] methyl] -4-hydroxy-4-piperidinyl] methyl] ~ N '- (2,6-dimethoxy-enyl) urea. 'XH NMR (CDC13, 400 MHz): d 1.1-1.8 (m, 5H), 2.3-3.0 (m, 4H), • 3.2-3.3 (m, 2H), 3.5-3.7 (m, 2H), 3.8- 3.9 (s, 6H), 5.0 (s, 2H), 5.2-5.4 (s, ÍH), 5.8-6.0 (s, 1H), 6.58-6.64 (d, 2H), 6.7-6.82 (d, 1H) ), 7.15-7.22 (m, 1H), 7.265-7.32 (m, 1H), 7.35 (s, 4.H), 7.50-7.57 (m, 1H).

N - [[- l - [[5-bromo-2- [(4-chlorofenyl) methoxyjf] methyl] '' -4-hydroxy-4-piperidinyl] methyl] -N '- (2,6-diethylf-enyl) urea. XH NMR (CDCl 3, 400 MHz): d 1.0-1.3 (t, 6H), 1.5-2.1 (, 3H), 2.4-2.8 (, 4H), 3.0-3.7 (m, 6H), 4.0-4.4 (m, 2H), 4.8-5.3 (m, 3H), 6.8-6.94 (, ÍH), 7.1-7.22 (, 3H), 7.26-7.33 (m, 2H), 7.33-7.45 (, 2H), 7.45-7.57 (m , 2H).

N - [[- 1 - [[5-bromo-2 - [(4-chlorophenyl) methoxyphfinyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N'- (2,4,6-trichlorophenyl) ) urea. XH NMR (CDC13, 400 MHz): d 1.6-1.8 (m, 4H), 2.3-2.5 (m, 3H), 2.5-2.7 (m, 2H), 3.2-3.4 (m, 2H), 3.5-3.7 (s, 2H), 4.9-5.1 (m, 3H), 6.7-6.8 (d, ÍH), 7.26-7.31 (m, ÍH), 7.32-7.36 (m, 4H), 7.37-7.41 (m, 2H), 7.47- 7.52 (, ÍH).

N - [[- l - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N '- (2,6-dichlorof) enyl) urea. XH NMR (DMSO, 400 MHz): d 1.4- 1.9 (m, 4H), 2.9-3.4 (m, 6H), 4.1-4.4 (m, 2H), 4.8-5.3 (m, 2H), 6.4-5.6 ( m, HH), 7.06-7.24 (m, 2H), 7.25-7.52 (m, 6H), "7.52-7.62 (m, HH), 7.63-7.74 (d, 1H).

N - [[- 1 - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] 4-hydroxy-4-piperidinyl] methyl] -N '- (2,6-dimethyl-enyl) urea. XH NMR (DMSO-d6 / TFA): d 1.56-1.84 (m, 4H), 2.08-2.14 (m, 6H), 3.04-3.28 (m, 6H), 4.22-4.28 (m, 2H), 5.14 (, 2H), 6.95-7.02 (m, 3H), 7.11-7.18 (m, ÍH), 7.34-7.52 (m, 4H), 7.56-7.64 (m, 2H), 7.70 (d, ÍH), 9.10-9.30 ( , ÍH).

N - [[- 1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N'- (2,6-dibromofenyl) urea. XH NMR (DMSO- 'd6): d 1.38-1.52 (m, 4H), 2.10 (s, 6H), 2.30-2.45 (m, 4H), 3.05 (d, 2H), 3.30 (s, 3H), 3.45 (s, 2H), 4.40 (s, 1H), 5.20 (s, 2H), .6.97 (d, ÍH), 7.21 (s, 2H), 7.33 (dd, '1H), 7.38-7.47 (, 5H) 7.61 (s, ÍH).

N - [[- 1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N '- (4-bromo-2,6) -methylmethyl) urea. XH NMR (DMSO-de / TFA): d 1.52-1.84 (m, 4H), 2.02-2.10 (m, 6H), 2.17 (s, 3H), 3.00-3.30 (m, 6H), 4.24 (m, 2H) ), 5.12-5.20 (m, 2H), 6.80 (s, 2H), 7.10-7.19 (m, 1H), 7.32-7.64 (m, 6H), 7.70 (d, 1H), 9.10-9.30 (, ÍH) .

N- [2,6-Bis (1-methylethyl) phenyl] -N '- [[- 1 - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-hydroxy -4- piperidinyl] methyl] urea. XH NMR (DMSO-d6 / TFA): d 1.10 (d, 12H), 1.55-1.85 (m, 4H), 3.00-3.30 (, 8H), 4.26 (br.s, 2H), 5.10-5.20 (m, 2H), 6.35 (br.s, 1H), 7.02-7.64 (m, 11H), 7.67-7.72 (m, 2H), 9.10-9.30 (m, ÍH).

N - [[- 1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N '- (4-fluorophenyl) urea. XH 'NMR (DMSO-de / TFA): d 1.60-1.95 (m, -4H), 3.10-3.40 (m, 6H), 4. 30-4.40 (m, 2H), 5.25 (s, 2H), 7.08 (, 2H), 7.20-7.24 (m, 1H), 7.39-7.46 (m, 2H), 7.48-7.60 (m, 4H), 7.67 (m, 1H), 7.76-7.80 (m, 1H), 8.70-8.80 (m, ÍH), 9.10 -9.30 (, ÍH).

Example 62: 2-amino-N - [[- 1 - [[5-bromo-2 - [(4-chlorophenyl) methoxphenyl] methyl] -4-hydroxy-4-piperidinyl] -ethyl] acetamide.

To a solution of 4- (aminomethyl) -l - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinol (150 mg, 0.35 mmol), N-Boc-glycine ( 86 mg, 0.49 mmol), and Et3N (0.3 L, 2.1 mmol) in DMF (4 mL), was added HATU (180 mg, 0.48 mmol) at After stirring at a.t. during the night, the mixture was emptied in ice water, and kept in the refrigerator overnight to precipitate the product. The crude product was collected by filtration, and the solid was redissolved in dichloromethane and dried over Na 2 SO 4. Concentration in vacuo provided the crude product, which was used directly in the next step. The residue was dissolved in TFA (5 mL) and CH2C12 (5 mL) and stirred at RT. under N2 for 1 h. After concentration, the residue was purified by HPLC to give the product as a white solid. XH NMR (DMS0-d6 / TFA): d 1.50-1.90 (m, 4H), 3.00-3.30 (m, 6H), 3.50 (m, 2H), 4.20-4.35 (m, 2H), 5.25 (, 2H) , 7.12-7.17 (m, ÍH), 7.40-7.52 (, 4H), 7.56-7.60 (m, 1H), 7.69 (d, 1H), 7.94 (, 3H), 8.28-8.38 (m, 1H) 9.20-9.30 (m, ÍH).

Example 63: N- [2 - [[[1 - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] amino] -2- oxoethyl] -2,6-difluorobenzamide.

To a solution of 4- (aminomethyl) -l - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinol (150 mg, 0. 30 mmol), 2,6-difluorobenzoic acid (57 mg, 0.36 mmol), 'and Et3N (0.15 mL, 1.1 mmol) in DMF (5 mL), HATU (150 mg, 0.4 mmol) was added at t.a. After stirring at a.t. during the night (the reaction was monitored by TLC), the reaction mixture was poured into ice water. The crude product was collected by filtration, and redissolved in CH2C1. The organic phase was dried over Na2SO4, and concentrated. The residue was purified by HPLC to give the title compound as a light yellow powder XH NMR (DMSO-d6 / TFA): d 1.50-1.90 (m, 4H), 3.00-3.28 (, 6H), 3.90 (m , 2H), 4.20 (m, 2H), 5.15 (s, 2H), 7.04-7.16 (m, 3H), 7.38-7.52 (m, 5H), 7.57 (m, 1H), 7.68 (d, 2H), 7.82-7.94 (m, 1H), 8.86-8.96 (m, ÍH), 9.02-9.20 (m, 1H).

The following compounds were prepared in a similar way: N - [[- 1 - [[5-Bromo-2- [(4-chloro-enyl) -methoxyf-enyl] -methyl]] -4-hydroxy-4-piperidinyl] methyl] benzamide. XH NMR (DMSO-. De / TFA): d 1.72-2.10 (m, 4H), 3.30-3.62 (, 6H) -, - 4.40-4.52 (m, 2H), 5.32-5.36 (m, 2H), 7.30-7.36 (m, ÍH), 7.58-7.70 (m, 7H), 77.74-7.78 (m, 1H), 7.84-7.92 (m, 1H), 8.00-8.06 (m, 2H), 8.54-8.68 (m, 1H), 9.20-9.40 (m, 1H) .

N - [[- 1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxyjfenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -4-chlorobenzamide. XH NMR (DMSO-d6 / TFA): d 1.52-1.90 (m, 4H), 3.00-3.40 (m, 6H), 4.20-4.32 (m, 2H), 5.12-5.16 (m, 2H), 7.09-7.14 (m, ÍH), 7.36-7.52 (m, 6H), 7.54-7.58 (m, 1H), 7.64-7.70 (m, ÍH), 7.82-7.90 (m, 2H), 8.44-8.56 (m, ÍH) , 9.00-9.20 (m, ÍH). 3 - [[[[1 - l - [[5-bromo-2 - [(4-chlorofenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] amino] carbonyl] -l-hydroxy- 2, 4- dimethylpyridinium. XH NMR (DMS0-d6 / TFA): d 1.56-1.98 (m, 4H), 3.20-3.46 (m, 6H), 4.22-4.38 (m, 2H), 5.16-5.22 (m, 2H), ' 7.14-7.20 (m, 1H), 7.42-7.56 (m, 5H), 7.58-7.64 (m, 2H), '7.68-7.76 (, 1H), 7.80-7.88 (m, ÍH), 7.94-7.96 (m , ÍH), 8.56-8.68 (m, 1H), 9.00-9.30 (m, ÍH). LC-MS (API150 EX): cale: 578, found: 578.

N - [[- 1 - [[5-Bromo ~ 2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] acetamide. XH 'NMR (DMSO-d6 / TFA): d 1.50-1.72 (m, 4H), 1.80 and 1.86 (each s, 3H), 3.00-3.26 (m, 6H), 4.20-4.30 (m, 2H), 5.16 (m, 2H), '7.12-7.18 (m, 1H), 7.40-7.50 (m, 4H), 7.56-7.62 (m,, ÍH), 7.68-7.72 (, ÍH), 7.84-7.96 (, 1H ), 9.15-9.30 (m, 1H).

EXAMPLE 64: 2- (Acetylamino) -N - [[- 1 - [[5-bromo-2 - [(4-chlorophenyl) methoxy.i] phenyl] methyl] -4-hydroxy-4-piperidinyl] met.il ] asetamid.

To a solution of 4- (aminomethyl) -l - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinol (100 mg, 0.2 mmol) and Et3N (1 mL, mmol) in CH2Cl2 (4 mL), Ac20 (0.5 L, 5 mmol) was added at The mixture was stirred at t.a. during the night, and then concentrated. The residue was purified by HPLC to give the title compound as a white powder. XH NMR (DMSO-d6 / TFA): d 1.50-1.68 (m, 4H), 1.80-1.83 (, 3H), 3.00-3.24 (m, 6H), 3.62-3.70 (m, 2H), 4.20-4.32 ( m, 2H), 5.14-5.18 (m, 2H), 7.10-7.16 (m, 1H), 7.40-7.52 (, 4H), 7.56-7.60 (m, ÍH), 7.66-7.72 (m, 1H), 7.78 -7.90 (m, ÍH), 8.03-8.15. (M, 1H), 9.00-9.20 (m, ÍH).

The following compounds were prepared in a similar way: Phenylmethyl ester of acid [2 - [[[1 - [[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] amino] -2-oxoethyl ] carbamic. XH NMR (DMSO-de / TFA): d 1.50-1.90 (m, 3.00-3.25 (m, 6H), 3.85-3.90 (m, 2H), 4.20-4.30 (, 2H), 5.15-5.20 (, 2H) , 7.10-7.16 (m, ÍH), 7.40-7.52 (m, 7H), 7.56-7.62 (m, 1H), 7.69 (d, ÍH), 7.82-7.86 (, 2H), 7.88-7.89 (m , ÍH), 8.66-8.80 (m, ÍH), 9.10-9.20 (, 1H). (a S) -a-amino-N - [[- 1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] benzeneacet amide. XH NMR (DMSO-d6 / TFA): d 1.24-1.84 (m, 4H), 2.86-3.28 (m, 8H), 4.20 (m, 2H), 4.22-4.32 (, 2H), 5.14-5.20 (m, 2H), 7.12-7.30 (m, 6H), 7.40-7.52 (, 4H), 7.59 (m, ÍH), 7.68-7-70 (m, 1H), 8.10 (br.s, 3H), 8.40-8.50 (, 1H), 9.20-9.30 (m, ÍH).

N - [[- 1 - [[5-Bromo-2 - [(4-chlorophenyl) methoxyjfenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -2-chloroacetamide. XH NMR (CDCI3): d 1.58-1.74 (, 4H), 2.44 (m, 2H), 2.64 (m, 2H), 3. 37 (d, 2H), 3.57 (s, 2H), 4.10 (s, 2H), 5.02 (s, 2H), 6. 75 (d, ÍH), 6.95 (m, ÍH), 7.29 (dd, ÍH), 7.35 (m, 4H), 7.50 (d, 1H).

N - [[- 1 - [[5-Bromo-2 - [(4-chloro-enyl) -methoxy] -fenyl] -methyl] -4-hydroxy-4-piperidinyl] -methyl] -N--acetylacet-amide. XH NMR (DMSO-d6 / TFA): d 1.92-2.40 (m, 4H), 2.36-2.42 (m, 3H),. 3.20-3.78 (m, 9H), 4.64-4.72 (m, 2H), 5.56 (m, 2H), 7.53-7.58 (m, HI), 7.82-7.94 (m, 4H), 7.97-8.20 (m, HI) ), 8.09-8.13 (m, ÍH), 9.40-9.60 (m, ÍH).

Example 65. This example illustrates the preparation of representative pharmaceutical compositions for oral administration containing a compound of the invention, or a pharmaceutically acceptable salt thereof: A. Ingredients% wt. / wt Compound of the invention 20.0% Lactose 79.5% Magnesium stearate 0.5% The ingredients above are mixed and dispensed into hard shell gelatin capsules containing 100 mg each, with one capsule approaching a total daily dosage.

B. Ingredients% wt. / wt. Compound of the invention 20.0% Magnesium stearate 0.9% Fungus 8.6% Lactose 69.6% PVP (polyvinylpyrrolidine) 0.9% The ingredients above, with the exception of magnesium stearate, are combined and granulated using water as a granulating liquid. Then the formulation is dried, mixed with the magnesium stearate, and formed into tablets with an appropriate tabletting machine.

C. Ingredients Compound of the invention 0.1 g Propylene glycol 20.0 g Polyethylene glycol 400 20.0 g Polysorbate 80 1.0 g Water q.s. 100 mL The compound of the invention is dissolved in the propylene glycol, the polyethylene glycol 400 and the sorbate 80. Then a sufficient amount of water is added, with stirring, to provide 100 mL of the solution, which is filtered and bottled.

D. Ingredients% wt. / wt. Compound of the invention 20.0% Peanut oil 78.0% Span 60 2.0% The ingredients above are melted, mixed and filled into soft elastic capsules.

E. Ingredients% wt. / wt. Compound of the invention 1.0% Methyl or carbo ethyl cellulose 2.0% 0.9% saline q.s. 100 mL The compound of the invention is dissolved in the saline / cellulose solution, filtered and bottled for its • use.

Example 66. This example illustrates the preparation of a representative pharmaceutical formulation for parenteral administration containing a compound of the invention, or a pharmaceutically acceptable salt thereof: Ingredients, - - Compound of the invention 0.02 g Glycol propylene "20.0 g- - Glycol polyethylene 400 20.0 g Polysorbate 80 - 1.0 g 0.9% saline solution q.s. 100 mL The compound of the invention is dissolved in the propylene glycol, the polyethylene glycol 400 and the polysorbate 80. A sufficient amount of 0.9% saline is then added, with stirring, to provide 100 mL of the. I.V. solution, which is filtered through a 0.2 m membrane filter and packed under sterile conditions.

Example 67. This example illustrates the preparation of a representative pharmaceutical composition in the form of a suppository containing a compound of the invention, or a pharmaceutically acceptable salt thereof: Ingredients% wt. / wt. Compound of the invention 1.0% Glycol polyethylene 1000 74.5% Glycol polyethylene 4000 24.5% The ingredients are melted together and mixed in a steam bath, and emptied into molds containing a total weight of 2.5 g.

Example 68. This example illustrates the preparation of a representative pharmaceutical formulation for insufflation containing a compound of the invention, or a pharmaceutically acceptable salt thereof: Ingredients% wt. / wt. Compound of the invention micronized 1.0% Lactose micronized 99.0% The ingredients are ground, mixed and packed in an insufflator with a dosing pump.

Example 69. This example illustrates the preparation, of a representative pharmaceutical formulation in nebulized form containing a compound of the invention, or a pharmaceutically acceptable salt thereof: Ingredients% wt. / wt. Compound of the invention 0.005% Water 89.995% Etahol '"- 10,000% The compound of the invention is dissolved in ethanol and mixed with water. The formulation is then packed in a nebulizer equipped with a dosing pump. * Example 70. This example illustrates the preparation of a representative pharmaceutical formulation in aerosol form containing a compound of the invention, or a pharmaceutically acceptable salt thereof: Ingredients t. / wt. Composed of. invention 0. 10% Propellant 11/12 9 £ 1. 90% 'Oleic acid 1. 00% • The compound of the invention is dispersed in oleic acid and propellants. Then the resulting mixture is emptied, into an aerosol container equipped with a metering valve.

Example 71. Proximity agglutination assay of the MlP-CCR-5 receptor scintillation.

A) assay regulator: 50 M Hepes, 5 mM MgCl 2, 30 μg / ml bacitracin, 0.1% BSA, pH 7.4.

B) Ligand: MIP ~ labeled with 1-125 at 20,000-25,000 cpm / platina. No-specific agglutination was defined (nsb, non-specific binding). since it agglutinated cpm in the presence of 100 nM unlabeled MlP-lb.

C) Cells: Human embryonic kidney, (HEK-293) expressing human CCR-5 and CD4, pretreated overnight with 5 mM sodium butyrate. Harvest the cells with saline regulated with calcium and magnesium-free phosphate. The number of cells is counted with the hemacytometer. The number of cells per test site was selected so that the total counts per minute (cpm) of agglutination were approximately 10% - of the total Ip-125-MIP-la-cpms per assay site.

D) Pearls: Use scintillation proximity test beads coated with wheat germ agglutinin (sold by Amersham Pharmacia Biotech Inc.) hydrated with the assay regulator for at least one hour before • of use. The final concentration of the beads was 0.2 mg of beads per platen.

E) Proximity Test of Cintilación: 100 ul of volume of the essay: 60 ul of mix of cell / pearls (premixed for at least 30 minutes), 20 ul of 1-125- 'MlP-la, 20 ul of the assay buffer for total binding value, or 2.0 ul of 0.5 uM MlP-lb for nsb, or 20 ul of the compound test. Shake the platen trays 96 for 30 minutes on an orbital shaker, then let them decant for 30 minutes before reading with a scintillation counter.

The above examples can be repeated with . similar success, substituting the generic or specifically described reactants and / or operating conditions of this invention, for those used in the previous examples.

From the above description, one skilled in the art can easily check the essential characteristics of this invention and, without departing from the spirit and competence thereof, can make various changes and modifications of the invention to adapt it to various uses. and conditions.

Claims (4)

E I V I N D I CA C I ON E S

1. Compound of formula I:

• enantiomers, diastereomers, salts and solvates thereof, where: X is a bond or oxygen; m is 0, 1, 2, 3 or 4; n is 0, 1 or 2; R1 is an optional substituent independently selected from each occurrence of halogen, alkyl, haloalkyl, nitro, or -NR5R6; R2 is: a) hydrogen or b) alkyl, cycloalkyl, alkenyl, aryl or heteroaryl, any of which may be optionally substituted with a group Y; Y is: a) aryl or heteroaryl, any of which may be optionally substituted with one or more Zx, Z2, Z3; b) cycloalkyl or heterocycle, any of which may be optionally substituted with one or more Z1, Z2, Z3; c) -COOR7; d) ~ NR8R9; -e) -CHRXO (OR1X); f) -C (= 0) -NR8R9; g) -NR12- (C = 0) -NR8R9; h) -CN; i) -C (= N-0R13); j) alkoxy; R3 and R4 are independently selected from: a) hydrogen; b) alkyl, cycloalkyl, (cycloalkyl) alkyl, aryl, (aryl) alkyl, heterocycle, (heterocycle) alkyl, heteroaryl, -o (heteroaryl) alkyl, any of which may be optionally substituted with one or more Z1, Z2, Z3; or c) -C (0) R *, -C (0) OR *, -C (0) NHR * or -S02R *; or R3 and. R4, together with the nitrogen atom to which they are linked, can be combined to form a heterocycle or heteroaryl ring optionally substituted with one or more Z1, Z2, Z3; R5 and R6 are independently H, -C (0) R *, -S02R *, or - C (0) NR8aR9a; R7, R8, R8a, R9 and R3a are independently: a) hydrogen, or b) alkyl, cycloalkyl, cycloalkyl (alkyl), aryl, (aryl) alkyl, heterocycle, (heterocycle (alkyl), heteroaryl, or (heteroaryl) alkyl, any of which can optionally be substituted with one or more Z1, Z2, Z3, R10 is H, alkyl or -OR *, R11 and Ri2 are independently H or alkyl, R13 is alkyl, or R * in each occurrence is independently alkyl, • cycloalkyl, cycloalkyl (alkyl), aryl, (aryl (alkyl), heterocycle, heterocycle (alkyl, heteroaryl, or (heteroaryl (alkyl), any of which may be optionally substituted with one or more Z1, Z2 , Z3, Ra and Rb are independently hydrogen, -OR10a, alkyl, hydroxyalkyl, or haloalkyl, or Ra and Rb may be combined to form oxo, Rc and Rd in each occurrence are independently H, - ORXOb, alkyl or haloalkyl; R10 are independently hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; Z1, Z2 and Z3 are optional substituents, selected independently from: (1) V, where V is: (i) alkyl, (hydroxy) alkyl, (alkoxy) alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) 'alkyl, cycloalkenyl, cycloalkenyl (alkyl), aryl, aryl (alkyl), heterocycle, heterocycle (alkyl, heteroaryl, or heteroaryl (alkyl; (ii) a group (i) that is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or - (ii) that is independently substituted by one or more (preferably 1 to 3) 'of the following groups (2) to (13) of the definition of Zx, (2) -OH or -OV, (3) -SH or -SV, (4) -C (0) H, -C (0) OH, -C (0) V, -C (0) OV or -0-C (0) V, (5) -S0H, -S (0) tV or S (0) tN (Vx) V where t is 1 or 2, (6) halo, (7) cyano, (8) nitro, ( 9) -UX-NV2V3, (10) ~ UX-N (VX) -U2 ~ NV2V3, (11) -UN (V4) -U2-V, (12) -ÜX-N (V4) -U2-H, (13) oxo; U1 and U2 are each, independently: (1) in single bond, (2) -U3-S (0) t-U4-, (3) -U3-C (0) -U4-, (3) -U3 -C (0) -U4-, (4) ~ U3-C (S) -U4-, (5) -U3-0-U4-, (6) ~ U3-S-U4-, (7) -U3 -0 ~ C (0) -U4-, (8) -U3-C (0) -0-U4-, (9) -U3-C (= NVXa) -U4-, or (10) -U3-C (0) -C (0) -U4-, V1, Vla, V2, V3 and V4: (1) are each independently hydrogen or a group provided in the definition of Z1; or (2) V2 and V3 together may be alkylene or alkenylene, by completing a saturated or unsaturated 3- to 8-membered ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more of the groups listed in the definition of Z1, or (3) V2 or V3 together with V1, may be alkylene or alkylene which completes a saturated or unsaturated ring of 3- to 8-members together with the nitrogen atoms to which they are attached, ring that is unsubstituted or substituted with one or more of the groups listed in the definition of Zx, and U3 and U4 are each, independently: (1) a single bond; (2) alkylene, (3) alkenylene, or (4) alkynylene.

2. The compound of claim 1, wherein R2 is alkyl substituted with Y; Y is aryl, cycloalkyl, heterocycle, -CHR, 110U (OR11), or -NR 1X2- (C = 0) -NR > 8BrR > 93, any of which may be optionally substituted with one or more Z1, Z2 and Z3.

3. The compound of claim 2, wherein R2 is methyl.

4. The compound of claim 2, wherein Y is phenyl, cyclopropyl or 1,3-dioxolanyl, any of which

10

fifteen

Y

8. Compound of claim 4, wherein: (a) R3 and R4 are independently H, .alkyl, (hydroxy) alkyl, (heteroaryl) alkyl, (heterocycle) alkyl or -C (0) NHR *, 'any of which may to be optionally substituted by one or more Z1, Z2, Z3; or (b) R3 and R4 together with the nitrogen atom to which they are linked, combine to form a heterocycle or heteroaryl ring, selected from:

9. Compound of claim 8, wherein -NR4 is a group selected from:

10. Compound of claim 9, wherein R2 is a group selected from:

11. Compound of claim 1, 2 6 4, having the following formula II:

II

enantiomers, diastereomers, salts and solvates thereof, wherein: m * is 0, 1, 2 or 3; and RXa is halo 12. Compound of claim 11, having the following formula III: enantiomers, diastereomers, salts and solvates thereof, wherein: Z1 is halo, cyano, alkyl, haloalkyl, aryl, -C (0) OH, -C (0) V, -C (0) OV, or -UX-NV2V3 13. Compound selected from: N - [[5-bromo-2- (4-chlorophenylmethoxy) phenyl] -ethyl] morpholinoethenamine;

5-Bromo-2- (4-chlorophenylmethoxy) -N, N-diethylbenzonemethanamine hydrochloride;

[[[[5-Bromo-2 ~ (4-chlorofenylmethoxy) phenyl] methyl] amino] -2-propanol hydrochloride;

L - [[5-bromo-2- (4-chlorophenylmethoxy) phenyl] methyl] -4-ethylpiperazine dihydrochloride;

N - [[5-bromo-2- (4-chlorophenylmethoxy) phenyl] methyl] -N ', N' -dimethylpropanediamine dihydrochloride;

3 - [[4-Bromo-2- [(diethylamino) ethyl] phenoxy] methyl] benzoic acid methyl ester hydrochloride;

4 - [[5-bromo-2- [(4-chlorophenyl) methoxy)] phenyl] methyl] thiomorpholine;

5-bromo-2- [(4-chlorophenyl) methoxy)] - N -methyl-N- (phenylmethyl) benzenemethanamine;

5-bromo-2- [(4-chlorophenyl) methoxy)] - N-ethylbenzenemethanamine;

4 - [[5-bromo-2- [(4-chlorophenyl) methoxy)] phenyl] methyl] morpholine;

5-bromo-2- [(4-chlorophenyl) methoxy)] - N- (phenylmethyl) benzenemethanamine;

5-bromo-2 ~ [(4-chlorophenyl) methoxy)] - N, N-dimethyl-benzenemethanamine;

1, 1-Dimethylethyl ester of [l - [[5-bromo-2 [(4-chlorophenyl) methoxy] phenyl] methyl] -3-pyrrolidinyl] carbamic acid;

3 - [[4-Bromo-2- [(diethylamino) met yl] phenoxy] methyl] benzoic acid methyl ester hydrochloride;

l - [[5-Bromo-2- [(4-Iodo-enyl) -methoxy] -phenyl] -methyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-methyl-f-enyl) -methoxy] -f-enyl] -methyl] -4-piperidinol;

. l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinol;

l - [[5-Bromo ~ 2- [(6-methyl-3-pyridinyl) methoxy] phenyl] methyl] -4-piperidinol;

• l - [[4-Bromo-2- [(6-methyl-3-pyridinyl) methoxy] phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol;

4 - [[4-chloro-2- (4-morpholinylmethyl) f enoxy] methyl] benzonitrile;

4 - [[4-chloro-2- (1-pyrrolidinylmethyl) f-enoxy] methyl] -benzonitrile;

l - [[5-Bromo-2- [(4-chlorophenyl) met oxy] f-enyl] methyl] -3-piperidinomet anol;

N - [[5-bromo-2- (4-chlorofenylmethoxy) phenyl] methyl] -N- (3-dimethylaminopropyl) -N'-phenylurea hydrochloride;

4 - [[4-Bromo-2- [(dimethylamino) methyl] f-enoxy] methyl] -N- (3,4-dimethoxy-enylmethyl) -benzamide hydrochloride;

• 5-Bromo ~ 2 - [[4- [(6,7-dimethoxy-3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] phenyl] methoxy] -N, N- 'dimethylbenzenemethanamine hydrochloride;

4-bromo-2- (bromomethyl) -l- [(4-chlorophenyl) methoxy] benzene;

• 2 - [[[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] amino] -l, 3-propanediol;

. (2R) -l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -2-pyrrolidinemethanol trifluoroacetic acid salt;

• (2S) -l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -2-pyrrolidinemethanol trifluoroacetic acid salt;

(2R) -l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -3-pyrrolidinol 'trifluoroacetic acid salt;

N1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -Nx- [2- (diethylamino) ethyl] -N2, N2-diethyl-l, 2-ethanediamine;

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy-f-enyl] -methyl] -4- • piperidinone;

l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol;

l - [[5-Bromo-2 ~ [(4-chlorofenyl) methoxyphfinyl] methyl] -4- "piperidinol;

[L - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] -carbamic acid 1, 1-dimethylethyl ester;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-ethoxy-piperidine;

8 - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -1,4-dioxa-8-azaspiro [4. 5] dean;

[1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] methyl] carbamic acid 1, 1-dimethyl ester;

5-bromo-2 - [(4-chlorophenyl) methoxy] benzenemethanamine;

1 - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] pyridinium bromide;

Ethyl ester of l - [[5-bromo-2 - [(4-chlorofenyl) methoxy] phenyl] methyl] -4-piperidinecarboxylic acid;

2 - [[[5-bromo-2 - [(4-chlorofenyl) met oxy] phenyl] methyl] amino] ethanol;

2 - [[[5-bromo-2- [(4-chloro-enyl) -methoxy] -f-enyl] -methyl] (methyl) amino] -ethanol;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -3-piperidinol;

. l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -3-pyrrolinidol;

(SS, 2S) -2 - [[[5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] amino] -l- (4-nitrophenyl-1,3-propanediol;

• 5-Bromo-2- [(4-chlorophenyl) methoxy] -N, N, N-trimethylbenzene-anaminium iodide;

(3R, 4S) -l - [[5-bromo ~ 2- [(4-chlorophenyl) methoxy] phenyl] methyl] -3,4-pyrrolidinediol;

L ~ [[5-bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -4- • piperidinocarboxylic acid;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinamine;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4- 'piperidinemethanamine;

l - [[5-Bromo-2- [(4-chlorofenyl) methoxyphfinyl] methyl] -N-methyl-4-piperidinemethanamine;

[L - [[5-Bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4-piperidinyl] (ethyl) carbamic acid 1, 1-dimethylethyl ester;

[L - [[5-Bromo-2- [(4-chlorophenyl) ethoxyf-foldyl] methyl] -4-piperidinyl] (methyl) carbamic acid 1, 1-dimethylethyl ester

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxyf-enyl] -methyl] -N, N-diethyl-4-piperidinamine;

N- [l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-piperidinyl] -N '- (4-f luorofenyl) -urea;

N- [1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -3-pyrrolidinyl] -N '- (4-f luorofenyl) -urea; 5 N - [[1 - [[5-Brorao-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4-piperidinyl] methyl] -N '- (4-f luorofenyl) -N-methyl-urea;

N - [[1 - [[5-bromo-2- [(4-chloro-enyl) -methoxy] -fyl] -methyl] -4-10-piperidinyl] -ethyl] -N '- [(4-f-luorofenyl) -methyl] ] -N-methyl-urea;

N- [1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -3-pyrrolidinyl] -2-chloroacetamide;

15 'Salt of N - [[l - [[5-bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl] -4-piperidinyl] methyl] acet-trifluoroacetic acid;

N- [l - [[5-Bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-piperidinyl] acetamide trifluoroacetic acid salt; 0 -. > • N- [1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -3-pyrrolidinyl] -N-methyl-2-pyrazinecarboxamide;

N - [[1 - [[5-brorao-2 - [(4-chlorophenyl) methoxy] phenyl] methyl] -4-5 piperidinyl] methyl] -N, 4-dimethyl-3-piperidinecarboxamide;

[L - [[5-Bromo-2- [(4-chlorofenyl) ethoxy] phenyl] methyl] -4-piperidinyl] carbamic acid methyl ester;

4 - [[4-bromo-2- [(diethylamino) methyl] f enoxy] methyl] benzoic acid;

5-bromo-N, N-diethyl 2 - [[4 - [[4- (phenylmethyl) -1- piperazinyl] carbonyl] f-enyl] methoxy] benzene-anamine;

N- (1,3-benzodioxo-5-ylmethyl) -4 - [[4-bromo-2- [(diethylamino) methyl] f enoxy] methyl] benzamide;

4 - [[4-Bromo-2- [(diethylamino) methyl] phenoxy] methyl] -N- [(4-methoxy-f-enyl) -methyl] -benzamide;

4 - [[4-bromo-2- [(diethylamino) methyl] phenoxy] methyl] -N-methyl-N- (2 '-f-phenylethyl) benzamide;

4 - [[4-bromo-2- [(diethylamino) ethyl] phenoxy] methyl] -N- [2- (4-bromo-phenyl) -ethyl] -benzamide;

4- [4 - [[4-bromo-2- [(diethylamino) met yl] phenoxy] met yl] benzoyl] -N-octyl-1-piperazinecarboxamide;

5-bromo-N, N -diethyethyl-2 - [[4 - [[4 - [[3-nitrofenyl] sulf onyl] -l-piperazinyl] carbonyl] f-enyl] methoxy] benzene-anamine;

5-bromo ~ N, N-diethyl-2 - [[4 - [[4- (2-furanylcarbonyl) -1-piperazinyl] carbonyl] f-ethyl] methoxy] benzenemethanamine; -

5-bromo-2 - [[4 - [[4- (2,6-dichlorobenzoyl) -l-piperazinyl] carbonyl] phenyl] methoxy] -N, N-diethylbenzenemethanamine;

N - [[5 - [[4- [4 - [[4-bromo-2- [(diethylamino) methyl] phenoxy] methyl] benzoyl] -l-piperazinyl] sulfonyl] -2-thienyl] methyl] benzamide;

l- [(5-Bromo-2-propoxyphenyl) methyl] -4- (4-fluorophenyl) -4-piperidinol;

[4-bromo-2 - [[4- (4-bromo-phenyl) -4-hydroxy-l-piperidinyl] methyl] f-enoxy] -0-ethyloxymethanal;

l- [(5-Bromo-2-propoxyphenyl) methyl] -4- (4-chlorophenyl) -4-piperidinol;

l - [[5-Bromo-2- (pentyloxy) phenyl] methyl] -4- (4-bromofenyl) -4-piperidinol;

l - [[5-Bromo-2- (hexyloxy) phenyl] methyl] -4- (4-bromo-phenyl) -4-piperidinol;

l- [(5-Bromo-2-methoxyphenyl) methyl] -4- (4-bromophenyl) -4-piperidinol;

l - [[5-Bromo-2- (1,3-dioxolan-2-ylmethoxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol;

l- [(5-Bromo-2-hydroxyphenyl) methyl] -4- (4-bromophenyl) -4-piperidinol; . l - [[5-Bromo-2- (2-methylpropoxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol;

L - [[5-bromo-2- (heptyloxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol trifluoroacetic acid;

Acid-1 - [[5-bromo-2- (cyclopropylmethoxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol trifluoroacetic acid;

L - [(5-bromo-2-butoxyphenyl] methyl] -4- (4-bromophenyl) -4-piperidinol trifiuoroacetic acid;

L - [[5-bromo-2- (2-methoxyethoxy) phenyl] methyl] -4- (4-bromophenyl) -4-piperidinol trifluoroacetic acid; • 4- (4-Bromophenyl) -l- [(5-bromo-2-propoxyphenyl) methyl] -4-piperidinol trifluoroacetic acid;

L - [(5-Bromo-2-ethoxyphenyl) methyl] -4- (4-bromophenyl) -4-piperidinol trifluoroacetic acid;

4- (4-Bromophenyl) -l - [[5-bromo-2- (2-propenyloxy) phenyl] methyl] -4-piperidinol trifluoroacetic acid;

[(5-Bromo-2 - [[4- (4-bromophenyl-4-hydroxy-1-piperidinyl] methyl] phenoxy] -acetonitrile trifluoroacetic acid;

N- [2- [4-bromo [2 - [[4- (-bromophenyl) -4-hydroxy-l-piperidinyl] methyl] f enoxy] ethyl] -N '-ethyl-urea;

l - [[2- (2-Aminoethoxy) -5-bromophenyl] methyl] -4- (4-bromophenyl) -4-piperidinol: 2-bromo-l- [5-bromo-2 - [(4-chlorofenyl ) methoxy] f-enyl] -ethanone;

Methyl ester of 4 - [[4-bromo-2- (bromoacetyl) phenoxmethyl] benzoic acid;

l- [2- ([1,1'-bifinyl] -4-ylmethoxy) -5-bromophenyl] -2-bromoethanone

3 - [[4- [4 - [[4-bromo-2 ~ (bromoacetyl) phenoxy] methyl] benzoyl] -l-piperazinyl] sulfonyl] -N-hydroxy-N-oxo-bencenaminium;

2-bromo-l- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -l-propanone

l- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2- (dimethylamino) -ethanone;

l- [2- ([1,1'-bifinyl] -4-ylmethoxy) -5-bromophenyl] -2- (dimethylamino) -ethanone;

l- [2- ([1,1'-biphenyl] -4-ylmethoxy) -5-bromophenyl] -2-bromoet anona;

Salt of 5-bromo-2- [(4-chlorofenyl) methoxy] -a - [[(2-hydroxyethyl) (methyl) amino] methyl] benzenemethanol. trifluoroacetic;

Salt of a- [5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] -3-hydroxy-1-piperidinoethanol trifluoroacetic acid;

A- [5-bromo-2 ~ [(4-chlorofenyl) methoxyjfenyl] -3-hydroxy-1-pyrrolidinoethanol trifluoroacetic acid salt;

Trifluoroacetic acid salt of (2S, 4R) -l- [2- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2-hydroxyethyl] -4-hydroxy-2-pyrrolidinecarboxylic acid;

Salt of 5-bromo-2 - [(4-chlorophenyl) methoxy] -a- acid. [(dimethylamino) ethyl] benzene-methanol trifluoroacetic;

2-Amino-a- [5-bromo-2- [(4-chlorophenyl) methoxy-phenyl] -lH-imidazole-1-ethanol;

a- [5-Brorao-2 - [(4-chlorophenyl) methoxy] phenyl] -4-hydroxy-1-- piperidinoethanol;

Salt of trifluoroacetic acid of 4 - [[4-bromo-2- [l-hydroxy-2- (4-hydroxy-l-pi? Eridinyl) ethyl] phenoxy] methyl] benzoic acid methyl ester;

• Trifluoroacetic acid salt of 4 - [[4-bromo-2- [l-hydroxy-2- (3-hydroxy-l-piperidinyl) ethyl] phenoxy] methyl] benzoic acid methyl ester;

4 - [[4-Bromo-2- [2- [4 - [[(1, 1-dimethylethoxy) carbonyl] amino] -l-piperidinyl] -l- 'hydroxyethyl] phenoxy] methyl] benzoic acid methyl ester;

Salt of 2- ([1,1'-biphenyl] -4-ylmethoxy) -5-bromo-a- [(dimethylamino) methyl] -benzenemethanol trifluoroacetic acid;

4 - [[4-Chloro-2- [l-hydroxy-2- (4-hydroxy-1-piperidinyl) -ethyl] phenoxy] methyl] benzoic acid;

l- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2- (dimethylamino) -1-propanone;

5-chloro-2 - [(4-chlorophenyl) methoxy] -a - [- l- (dimethylamino) ethyl] "benzenemethanol;

a- [5-chloro-2 - [(4-chlorophenyl) methoxy] phenyl] -β-methyl-lH-imidazole-1-ethanol;

a- [5-chloro-2- [(4-chlorophenyl) ethoxy-phenyl] -4- (4-chlorophenyl) -4- 'hydroxy-β-methyl-1-piperidinoethanol;

a- [5-chloro-2- [(4-chloro-phenyl) -methoxy-phenyl] -4-hydroxy-β-methyl-4- (phenylmethyl) -1-piperidinoethanol;

a- [5-chloro-2 - [(4-chlorophenyl) methoxy] phenyl] -4- (4-fluorophenyl) -4-hydroxy-β-methyl-1-piperidinoethanol;

5-chloro-2- [(4-chlorophenyl) methoxy] -a- [l- (diethylamino) ethylbenzenemethanol;

a- [5-bromo-2 - [[4 - [[4- [(3-nitrofenyl) sulf onyl] -l-piperazinyl] carbonyl] f-enyl] methoxy] f -yl] -3-hydroxy-1-piperidinoethanol;

a- [5-Bromo-2 - [[4 - [[4- [(3-nitrophenyl) sulf onyl] -l-piperazinyl] carbonyl] phenyl] methoxy] phenyl] -4-hydroxy-l-piperidinoethanol;

- [5-Bromo-2 - [[4 - [[4- [(3-nitrophenyl) sulf onyl] -l-piperazinyl] carbonyl] f-enyl] methoxy] f-enyl] -3-hydroxy-l-pyrrolidinoethanol;

5-bromo- - [(diethylamino) methyl] -2 - [[4 - [[4- [(3-nitrofenyl) sulf onyl] -l-piperazinyl] carbonyl] phenyl] met oxy] benzenemethanol;

a- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -l-piperazineethanol;

a- [5-Bromo-2- [(4-chlorofenyl) methoxy] phenyl] -4- (3-pyridinylcarbonyl) -1-piperazineethanol;

a- [5-Bromo-2- [(4-chloro-enyl) -methoxy] -fenyl] -4- [(4-methyl-3-pyridinyl) carbonyl] -l-piperazine-ethanol;

4 - [[4-Bromo-2- [l-hydroxy-2- [4 - [[(f-enylmethoxy) carbonyl] amino] -1-piperidinyl] ethyl] -6-enoxy] -ethyl-benzoic acid methyl ester;

4 - [[4-bromo-2- [l-hydroxy.i-2- (4-hydroxy-1-piperidinyl) ethylphenoxy] methyl] -N- (4-pyridinyl) benzamide;

4 - [[4-chloro-2- [l-hydroxy-2- (4-hydroxy-l-piperidinyl) ethyl] phenoxy] methyl] -N- (3-hydroxypropyl) benzamide;

2- [5-Bromo-2 - [(4-chlorophenyl) methoxy-phenyl] -oxirane;

Salt of 1- (2S) -a- [5-bromo-2- [(4-chlorophenyl) methoxy] fep.yl] -2- (hydroxymethyl) -1-pyrrolidinoethanol trifluoroacetic acid;

(2R) ~ a- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -2- (hydroxymethyl) -l-pyrrol.idinoet.anol trifluoroacetic acid salt;

(3R) -a- [5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] -3-hydroxy-l-pyrrolidinoethanol, t-fluoroacetic acid;

5-Bromo-2- [(4-chlorophenyl) methoxy] -a - [[2- (diethylamino) ethyl] ethylamino] methyl] -benzenemethanol trifluoroacetic acid salt;

Salt of a- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -l, 4-piperidine diethanol trifluoroacetic acid;

- [5-Bromo-2 - [(4-chlorophenyl) methoxykhphenyl] -4- (piperidyl) -1- piperidinoethanol;

5-Bromo-2- [(4-chlorophenyl) methoxy] - - [(dipropylamino) methyl] -benzenemethanol trifluoroacetic acid salt; 5 A- [5-Bromo ~ 2 - [(4-chlorophenyl) methoxy] phenyl] -4- (phenylmethyl) -1-piperidinoethanol trifluoroacetic acid salt;

5-Bromo-2- [(4-chlorophenyl) methoxy] -a-10 [(dibutylamino) methyl] -benzenemethanol trifluoroacetic acid salt;

5-bromo-a [(butylethylamino) ethyl] -2- [(4-chlorophenyl) methoxy] -benzenemethanol;

15. Salt of 5-bromo-2- [(4-chlorophenyl) methoxy] -a - [[ethyl (2-hydroxyethyl) amino] methyl] -benzenemethanol trifluoroacetic acid;

5-Bromo-2- [(4-chlorophenyl) methoxy] -a - [[(2-hydroxyethyl) propylamino] methyl] -benzenemethanol or trifluoroacetic acid salt;

Salt of acid. l- [2- [5-Bromo-2- [(4-chlorophenyl) methoxy-phenyl] -2-hydroxyethyl] -N, N-diethyl-3-piperidinocarboxamide trifluoroacetic; -5- [5-Bromo-2-acid salt - [(4-chlorophenyl) ratoxy] phenyl] -4- (4-bromophenyl) -4-hydroxy-1-piperidinoethanol trifluoroacetic;

Salt of l- [l- [2- [5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] -2-hydroxyethyl] -4-piperidinyl] -l, 3-dihydro-H-benzimidazole-2 - trifluoroacetic ona;

Salt of l- [2- [5-bromo-2- [(4-chlorophenyl) methoxy-phenyl] -2- • hydroxyethyl] -4-phenyl-4-piperidinocarbonitrile trifluoroacetic acid;

Salt of a- [5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] -1,4-dioxa-8-azaspiro [4.5] decane-8-ethanol trifluoroacetic acid;

• Salt of 5-bromo-2- [(4-chlorophenyl) methoxy] -a - [[(2-hydroxyethyl) (phenylmethyl) amino] methyl] -benzenemethanol trifluoroacetic acid;

5-Bromo-2 - [(4-chlorophenyl) methoxy] -a - [[[2- (dimethylamino)] ethyl] ethylamino] methyl] -benzenemethanol trifluoroacetic acid salt- [5-bromo-2] acid salt - [(4-chlorophenyl) methoxy-phenyl-1,2,3,4-tetrahydro-l-quinolinoethanol trifluoroacetic;

Salt of l- [2- [5-bromo-2- [(4-chlorophenyl) methoxy-phenyl] -2-hydroxyethyl] -3,4-pyrrolidinodiol trifluoroacetic acid;

5-Bromo-2- [(4-chlorophenyl) methoxy] -a- [(methylamino) methyl-benzenemethanol trifluoroacetic acid salt;

Salt of 2 - [[2- [5-bromo-2- [(4-chlorophenyl) methoxy-phenyl) -2-hydroxyethyl-amino-1, 3-propanediol trifluoroacetic acid;

Salt of 5-bromo-2- [(4-chlorophenyl) methoxy] -a-- [(diethylamino) methylj-benzenemethanol trifluoroacetic acid;

2 - [[2- [5-bromo-2 - [(4-chlorophenyl) methoxy] phenyl] -2-hydroxyethyl] amino] -2- (hydroxymethyl) -1,3-propanediol;

a- [5-Bromo-2 - [(4-chlorophenyl) methoxy-phenyl] -l- • pyrrolidinoethanol;

a- [5-bromo-2- [(4-chlorophenyl) methoxy-yl-phenyl] -l-piperidinoethanol;

5-Bromo ~ 2 - [(4-chlorophenyl) methoxy] -a - [[(3-hydroxyphenyl) aminojmethyl-benzenemethanol;

5-bromo-2 - [(4-chlorophenyl) methoxy] -a- [[(cyclopropylmethyl) aminojmethyl] benzenemethanol;

5-bromo-a - [[[2- (3-chlorophenyl) ethyl] aminojmethyl] -2- [(4-chlorophenyl) methoxybenzenemethanol;

- [5-bromo-2- [(4-chlorophenyl) methoxy-phenyl-1-acetidinoethanol;

5-Bromo ~ 2 - [(4-chlorophenyl) methoxy] - - [(ethylmethylamino) methyl] benzenemethanol;

5-bromo-2- [(4-chlorophenyl) methoxy-a ~ [(cyclopropylamino) methyl] benzenemethanol;

5-bromo-2- [(4-chlorophenyl) methoxy] -a- [[(cyclopropylmethyl) methylaminojmethylbenzenemethanol;

a- [5-bromo-2- [(4-chlorophenyl) methoxy-phenyl] -4-thiomorpholinoethanol;

a- (Aminomethyl) -5-bromo-2 - [(4-chlorophenyl) methoxybenzenemethanol;

5-bromo-2- [(4-chlorophenyl) methoxy] -a- [(cyclopropylmethylamino) methylbenzenemethanol;

(aS) -5-bromo-2- [(4-chlorophenyl) methoxy] -a- [(diethylamino) methyl] benzenemethanol;

(aR) -5-bromo-2- [(4-chlorophenyl) methoxy] -a- [(diethylamino) methyl] benzenemethanol;

a - [[bis (2-hydroxyethyl) amino] methylj-5-bromo-2- [(4-chlorofenyl) methoxybenzenemethanol;

a-5-bromo-2 ~ [(4-chlorofenyl) methoxyfine enylj-4-methyl-1-piperazineethanol;

5-bromo-2- [(4-chlorophenyl) methoxy] -a - [[(1-methylethyl) aminojmetilj bencenomet anol;

a- [5-bromo-2- [(4-chlorofenyl) methoxyfine] -4-morpholinoethanol;

5-bromo-2- [(4-chlorofenyl) methoxy] -a - [[(2-hydroxyethyl) aminojmethyl] -benzenemethanol;

5-bromo-2- [(4-chlorophenyl) methoxy] -a - [[(2-hydroxyethyl) aminoj ethylj-benzenemethanol;

5-bromo-2- [(4-chlorophenyl) methoxy] -a-ethoxy-N, N-diethylbenzene-t-anamine;

5-bromo-2- [(-chlorophenyl) methoxy] -N-N-diethyl-a- (2-pyridinyloxy-benzeneethanamine;

5-bromo-2 - [(4-chlorophenyl) methoxy] -a- (methylamino) benzeneethanol

l- [5-Bromo-2 - [(4-chlorophenyl) methoxy-phenyl-2-propen-l-one;

(3R) -a- [5-bromo-2- [(4-chlorophenyl) methoxy-phenyl] -3-hydroxy-l-pyrrolidinopropanol;

• 5-Bromo-2 - [(4-chlorophenyl) methoxy-a- [2- (diraethylamino) ethyl] -benzenemethanol;

a- [5-bromo-2- [(4-chlorophenyl) methoxyjphenyl] -4-hydroxy-1-piperidinopropanol;

5-bromo-2- [(4-chlorophenyl) methoxy] -a- [2- (dipropylamino) ethyl] -benzenemethanol;

5-bromo-2- [(4-chlorophenyl) methoxy] -a- [2- (diethylamino) ethyl-benzene-methane;

5-chloro-2- [(4-fluorophenyl) methoxy] benzeneethanamine; N - [[2- [5-chloro-2 - [(4-fluorophenyl) methoxy] -phenyl] ethyl] -4-piperidinomethanamine;

5-chloro-2- [(4-fluorophenyl) methoxy-N, N-a-. tri ethylbenzeneethanamine; 4 - [[[2 [5-chloro-2 ~ [(4-fluorophenyl) methoxy-f-enyl-ketoyl-benzyl] -benzonitrile, •

N- [2- [5-chloro-2 - [[(4-f luorofenyl) methoxyf-enyl] ethyl] -N- (1H- • imidazol-5-ylmethyl) -lH-imidazole-4-methanamine;

5-chloro-a-ethyl-2- [(4-f luorofenyl) methoxy] -N- [(4-fluorophil) methylbenzeneethanamine;

5-chloro-a-ethyl-2- [(4-f luorofenyl) met oxy] -N- [(3-methyl-4- (methoxyphenyl) methyl] benzeneethanamine;

Methyl ester of l - [[5-bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4-hydroxy-4-piperidinecarboxylic acid;

'L - [[5-Bromo-2- [(4-chlorofenyl) methoxyphfinyl] methyl] -4-hydroxy-4-piperidinecarboxylic acid;

4 - [[1 - [[5-bromo-2 - [. (4-chlorofenyl) methoxyphfinyl] methyl] -4-hydroxy-4-piperidinyl] carbonyl] -l-piperazineethanol;

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy-f-enyl] -methyl] -4- (1-piperazinylcarbonyl) -4-piperidinol; l - [[5-Bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4 - [[(3R) -3-methylpiperazinyljcarbonyl] 4-piperidinol;

4- [1 - [[5-Bromo-2- [(4-chlorofenyl) methoxyphfinyl] methyl-4-piperidinyl] -l-piperazinecarboxylic acid 1, 1-dimethylethyl ester;

l- [l - [[5-b'romo-2- [(4-chlorofenyl) methoxyphfinyl] methyl] -4-piperidinyljpiperazine;

l- [l - [[5-Bromo-2- [(4-chlorofenyl) methoxyphfinyl] methyl] -4-piperidinyl] -4- [(2,4-dimethyl-3-iridinyl) carbonylj-piperazine;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -3-methyl-4-piperidinone;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -3-methyl-4-piperidinoi;

l - [[5-Bromo-2- [(4-chlorofenyl) methoxyfine enylmethyl] -4,4-difluoropiperidine;

8 - [[5-bromo-2- [(4-chlorofenyl) methoxyfine] ethyl) -l, 3, 8-triazaspiro [4,5-decano-2,4-dione;

5"l - [[5-Bromo ~ 2- [(4-chlorofenyl) methoxyphfinyl] methyl] -4-phenyl-4-piperidinol;

l - [[5-Bromo ~ 2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4-ethyl-4-. piperidinol; 10 L - [[5-bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4- (trifluoromethyl) -4-piperidinol;

l - [[5-bromo-2 - [(4-chlorofenyl) methoxyf enyljmetilj-4-15. piperidinone oxime;

l - [[5-Bromo-2 - [[(4- (trifluoromethyl) phenyljmethoxy] phenyl] methylj- 4-fluoropiperidine;

0 l - [[5-bromo-2- [(4-chloro-enyl) -methoxyf-enyl] -methyl-4- (2- (pyridinyloxy) piper idine;

2 - [[l - [[5-bromo-2- [(4- (chlorophenyl) jmethoxyfineyl] methyl] -4- piperidinyl-5-pyxypyrimidin; 5 l - [[5-bromo-2- [(4-chlorofenyl) methoxyph enylmethyl-N-ethyl-4- piperidinamine;

6 - [[5-Bromo ~ 2 ~ [(4-chloro-enyl) -methoxyf-enyl] -methyl] -l-oxa-6- azaspiro [2. Sjoctane;

4- (aminomethyl) -l - [[5-bromo-2- [(4-chlorofenyl ') methoxyfine enylmethyl] -4-piperidinol;

l - [[5-bromo-2- [(4-chlorofenyl) methoxyphfenyl] methyl] -4 - [[[[l - [[5- bromo-2- [(4-chlorofenyl) methoxyf enyljmetilj-4 -hydroxy-4- piperidinyljmethyljaminojme til] - -piperidinol;

1, 1-dimethylethyl ester of 4 - [[1 - [[5-bromo-2- [(4-chlorophenyl) ethoxyphfinyl] methyl] -4-hydroxy-4-piperidinyl] methyl-1-piperazinecarboxylic acid;

1, 1-dimethylethyl ester of 4 - [[1 - [[5-bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4-hydroxy-4-piperidinyl] methyl] hexahydro-1H- 1, 4-diazepine-l-carboxylic acid;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4 - [[4- (2-pyridinyl) '-l-piperazinyl] methyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4 - [[4- (2-pyrimidinyl) -l-piperazinyl] methyl] -4-piperidinol;

l - [[5-Bromo-2- (4-chlorofenyl) methoxyphfinyl] methyl] -4- (1-piperazinylmethyl) -4-piperidinol;

l - [[5-Bromo-2- [(4-chloroform 1) methoxyfyl-enyl] methyl] -4- [(hexahydro-lH-1,4-diazepin-1-yl) methyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chlorofin-1) -methoxy-fyl-enyl] -methyl] -4 - [[(4-methyl-enyl) -amino-methyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxyf-enyl] -methyl] -4 - [[(4-methoxyphenyl) amino-methyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy-fyl-enyl] -methyl] -4 - [[(3 S) -3-methyl-piperazinyl-methyl-4-piperidinol;

l - [[5-Bromo-2- [(4-chloro-enyl) -ethoxy-fyl-enyl] -methyl] -4- [(2,5-dimethyl-1-piperazyl) -methyl] -4-piperidinol;

4 - [[(3-aminopropyl) amino] methyl] -l - [[5-bromo-2- [(4-chlorofenyl) methoxyphfinyl] methylj-4-piperidinol;

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy-f-enyl] -methyl] -4 - [[[(2- (1-piperidinyl) ethyl] amino] methyl-4-piperidinol;

1, 1-dimethylethyl ester of 2 - [[[[1 - [[5-bromo-2- [(4-chloro-enyl) -methoxyfine]] methyl] -4-hydroxy-4-piperidinyl] methyl] aminojmethyl] - l-pyrrolidinocarboxylic; • l - [[5-Bromo-2- [(4-chlorofenyl) methoxyphfinyl] methyl] -4 - [[(2-pyrrolidinylmethyl) aminojmethyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxyf-enyl] -methyl] -4 - [[4- [(2,4-dimethyl-3-pyridinyl) carbonyl] -l-piperazinylmethyl] -4 - • piperidinol;

Ethyl ester of 4 - [[1 - [[5-bromo-2- [(4-chlorophenyl) methoxyphfenylmethyl] -4-hydroxy-4-piperidinyl] methyl] -1- piperazinecarboxylic acid;

• 4- [(4-acetyl-l-piperazinyl) methyl] -l - [[5-bromo-2- [(4-chlorophenyl) methoxyf in enyljmethyl-4-piperidinol;

l - [[5-Brorao-2- [(4-chlorofenyl) methoxyfine enyljethyl] -4- [(1-piperacylamino) methyl] -4-piperinidol;

'4 - [[1 - [[5-bromo-2- [(4-chloro-enyl) -ethoxy-yf-enyl] -methyl] -4-hydroxy-4-piperidinyl] -methyl] -1-piperazine-ethanol;

4 - [[1 - [[5-Bromo-2- [(-chlorofenyl) methoxyfine-methyl-4-hydroxy-4-piperidinyl] methyl] -l-piperazinecarboxaldehyde;

4 - [[1 - [[5-Bromo-2- [(4-chlorophenyl) methoxyfinephenylmethyl] -4-hydroxy-4-piperidinyl] methyl] -1-piperazinecarboxylic acid phenylmethyl ester;

l - [[5-Bromo-2- [(4-chlorofenyl) methoxyphfinyl] methyl] -4 - [[4- (phenylmethyl) -l-piperazinyl] methyl] -4-piperidinol; 'l - [[5-Bromo-2- [(4-chloro-enyl) -methoxyf-enyl] -methyl] -4 - [[(2-methyl-phenyl) -amino] -methyl] -4-piperidinol;

l - [[1 - [[5-bromo-2- [(4-chloro-enyl) -methoxy-6-enylmethyl] -4-hydroxy-4-piperidinylmethyl] -4-piperidinecarboxamide;

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy-fyl-enyl] -methyl] -4 - [[(3 S) -3-methylpiperazinylmethyl] -4-piperidinol;

4 - [[1 - [[5-Bromo-2- [(4-chloro-enyl) -methoxy-6-enylmethyl] -4-hydroxy-4-piperidinyl-1-methyl-2-piper acinone;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxy-phenyl] -methyl] -4 - [[(3 S) -3-methyl-piperazinyl-j-methyl-4-piperidinol;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4- [(3,5-dimethyl-1-piperazinyl) methyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chlorofenyl) met oxy] phenyl] methyl] -4- (2,5-diazabicyclo [2.2.1] hept-2-ylmethyl) -4-piperidinol;

1, 1-dimethylethyl ester of [l - [[1 - [[5-bromo-2- [(4-chlorophenyl) methoxyfine-4-hydroxy-4-piperidinyl] methyl] -3-pyrrolidinylcarbamic acid;

4- [(3-amino-l-pyrrolidinyl) methyl] -l - [[5-bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4-piperidinol, •

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy-enylmethyl] -4 - [[4- [2- (dimethylamino) ethyl-1-piperazinylmethyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxyf-enyl] -methyl-4 - [[4- [2- (4-orf-olinyl) -2-oxoethyl] -l-piperazinyl] methyl-4 -piperidinol;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxyphfinyl] methylj-4 - [[4- [3- (4-morpholinyl) propyl] -l-piperazinyl] methyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyljmethylj-4 - [[4- [2- (4-morpholinyl) ethi] -l-piperazinyl] methylj-4-piperidinol;

• l - [[5-Bromo-2- [(4-chloro-enyl) -methoxyf-enyl] -methyl] -4- [(dimethylamino) methyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxyf-enyl] -methyl] -4-5 [(diethylamino) methyl] -4-piperidinol;

'' 1 - [[5-Bromo-2- [(4-chloro-enyl) -methoxy-phenyl] -ethyl] -4 - [[(1-methylethyl) amino] methyl] -4-piperidinol;

0 l - [[5-Bromo-2- [(4-chloro-enyl) -methoxyf-enyl] -methyl] -4- [(4-hydroxy-1-piperidinyl) met ilj-4-piperidinol;

l - [[5-brom.o ~ 2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4 - [[(3R) -3-hydroxypyrrolidinyljmethyl-4-piperidinol; 5 l - [[5-bromo-2- [(4-chlorofenyl) methoxyfine enylmethyl] -4 - [[[(4-fluorofenyl) methyl] aminojmethyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxyphfinyl] methylj-4- (1H-imidazol-1-ylmethyl) -4-piperidinol;

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxyf-enyl] -methyl] -4- [(f-enylamino) -methyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxyf-enylmethyl] -4- [(4-pyridinylamino) methyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxyf-enyljmet-4 - [[(2-hydroxyethyl) methylaminojmethyl-4-piperidinol;

• l - [[5-Bromo-2- [(4-chlorophenyl) methoxyf-enylmethyl] -4- [(4-methyl-l-piperazinyl) methyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4- [(dipropylamino) methylj-4-piperidinol;

• l - [[- l - [[5-bromo-2- [(4-chlorofenyl) methoxy] f-enyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N, N-diethyl-3- piperidinocarboxamide;

l - [[5-Bromo-2- [(4-chlorophenyl) methoxyphfinyl] methylj-4 - [[(2, 2, 2-trifluoroethyl) amino) methyl j-4-piperidinol;

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxyf-enyljmethyl-4 - [[(3-methyl-enyl) -amino) -methyl] -4-piperidinol;

l - [[5-Bromo-2- [(4-chloro-enyl) -methoxy-f-enyl] -methyl] -4 - [[[(IR) -1- phenylethyl] amino] methyl] -4-piperidinol;

4 - [[- 1 - [[5-Bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinylmethyl] -N-ethyl-1-piperazinecarboxamide;

N - [[- 1 - [[5-Bromo-2- [(4-chlorophenyl) methoxyf-foldyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N '- (2,6-difluorofenyl) urea;

A vN - [[- 1 - [[5-bromo-2- [(4-chloro-enyl) -methoxy-fyl] -methyl] -4-hydroxy-4-piperidinyl] methyl] -N '- (2, 6 dimethoxyphenyl) urea;

N - [[- 1 - [[5-Bromo-2- [(4-chloro-enyl) -methoxy-f-enyl] -methyl] -4-hydroxy-4-piperidinyl-methyl] -N '- (2,6-diethyl-f-enyl) -urea;

N - [[- 1 - [[5-bromo-2- [(4-chloro-enyl) -methoxy-4-methyl-4-hydroxy-4-piperidinyl] methyl] -N '- (2,4,6-trichlorophenyl) urea;

N - [[- 1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methyl] -4-hydroxy-4-piperidinyl] methyl] -N '- (2,6-dichlorofenyl) urea;

• N - [[- 1 - [[5-Bromo-2- [(4-chloro-enyl) -methoxy-viny] -methyl-4-hydroxy-4-piperidinyl-methyl] -N '- (2,6-dimethyl-phenyl) -urea;

N - [[- 1 - [[5-Bromo-2- [(4-chloro-enyl) -methoxyf-enyl] -methyl] -4-hydroxy-4-piperidinyl] -methyl] -N '- (2,6-dibromofenyl) urea;

• N - [[- 1 - [[5-Bromo-2- [(4-chloro-enyl) -methoxyfine-4-hydroxy-4-piperidinyl] methyl-N '- (4-bromo-2,6-dimethyl) enyl) urea;

N- [2,6-Bis (1-methylethyl) phenyl] -N '- [[- 1 - [[5-bromo-2- [(4-chlorofenyl) methoxyfine) enyljraethyl-4-hydroxy-4-. piperidinyljmetiljurea;

N - [[- 1 - [[5-bromo-2- [(4-chlorofenyl) methoxyfyl) -methyl-4-hydroxy-4-piperidinyl-methyl-N '- (4-fluorophenyl) urea;

2-amino-N - [[- 1 - [[5-bromo-2- [(4-chlorophenyl) methoxy] phenyl] methylj-. 4-hydroxy-4-piperidinyl] methyl] acetamide;

N- [2 - [[[1 - l - [[5-bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4-hydroxy-4-piperidinyl] methyl] amino] -2-oxoethyl] -2 6-difluorobenzamide;

• N - [[- 1 - [[5-bromo-2- [(4-chloro-enyl) -methoxy-f-enyl] -methyl] -4-hydroxy-4-piperidinyl-methyl-methylbenzamide;

N - [[- 1 - [[5-bromo-2- [(4-chloro-enyl) -methoxy-f-enyl] -methyl] -4-hydroxy-4-piperidinylmethyl] -4-chlorobenzamide;

• 3 - [[[[1 - l - [[5-bromo-2- [(4-chloro-enyl) -methoxyf-enyl] -methyl] -4-hydroxy-4-piperidinyl-methyl] -amino] -carbonyl] -l-hydroxy-2, 4- dimethylpyridinium;

N - [[- 1 - [[5-Bromo-2- [(4-chloro-enyl) -methoxy-4-enylmethyl] -4-hydroxy-4-piperidinyl-1-methyl] -acet-amide;

• 2- (acetylamino) -N - [[- 1 - [[5-bromo-2- [(4-chlorofenyl) methoxy] phenyl] methyl-J-4-hydroxy-4-piperidinylmethyl] acetamide;

[2 - [[[1 - l - [[5-Bromo-2- [(4-chlorofenyl) methoxyphfinyl] methyl] -4-hydroxy-4-phenylmethyl ester. piperidinyl] methyl] amino] -2-oxoethyl] carbamic;

(a S) -a-amino ~ N - [[- l - [[5-bromo-2- [(4-chlorophenyl) methoxyphfinyl] methyl] -4-hydroxy-4- piperidinyljmethylbenzeneaceta ida;

N - [[- 1 - [[5-bromo-2- [(4-chloro-enyl) -ethoxy-yf-enyl] -methyl] -4- '-hydroxy-4-piperidinylmethyl] -2-chloroacetamide;

N - [[- 1 - [[5-Bromo-2- [(4-chloro-enyl) -methoxy-viny] -methyl] -4-hydroxy-4-piperidinyl] -methyl] -N-methylacetamide; and enatomers, diastereomers, salts and solvates thereof. 14. A pharmaceutical composition comprising a compound of claim 1 and at least one carrier, carrier, diluent or pharmaceutically acceptable excipient thereof. 15. Method for treating an inflammatory or immunoregulatory disorder, comprising administering an effective amount of a compound of claim 1 to a patient in need thereof. 16. The method of claim 15, wherein the treated disorder is selected from asthma, allergic rhinitis, dermatitis, conjunctivitis and atherosclerosis. 17. The method of claim 15, wherein the treated disorder is rheumatoid arthritis. 18. The method of claim 15, wherein the treated disorder is multiple sclerosis. 19. The method of claim 15, wherein the disorder treated is psoriasis.