BACKGROUND OF THE INVENTION Migration of leukocytes from blood vessels into diseased tissues is important to the initiation of normal disease-fighting inflammatory responses. This process is known as leukocyte recruitment. This process, however, also is involved in the onset and progression of inflammatory and autoimmune disease states. The pathology of these diseases results from the attack of the body's immune defenses on normal, healthy tissues. Thus, blocking leukocyte recruitment to target tissues in inflammatory and autoimmune diseases is a desirable therapeutic intervention.

Leukocyte recruitment is mediated at a molecular level by chemoattractant receptors.

These receptors are on the surface of leukocytes and bind chemoattractant cytokines that are secreted by cells at the site of the damage or infection. Receptor binding activates leukocytes, increases adhesiveness of the adhesion molecules that mediate transendothelial migration, and promotes directed migration of the cells towards the source of the chemoattractant cytokine.

It has been determined that there is a large family (>20 members) of structurally related chemoattractant cytokines. These molecules share the ability to stimulate cell migration and have been termed chemokines. Each chemokine contains four cystein residues and two internal disulfide bonds. Chemokines can be grouped into two subfamilies, based on whether the two amino terminal cysteine residues (C) are adjacent to each other (C- C) or are separated by an amino acid (C-X-C).

All of the identified chemokine receptors belong to the seven transmembrane G protein-coupled receptor family (Murdoch and Finn, Blood, 2000,95 : 3032). These receptors mediate the binding and signaling of more than one chemokine. To date 18 human chemokine receptors have been identified. Of these receptors, 5 bind C-X-C chemokines (CXC1-CXC5) and 9 purportedly bind C-C chemokines (CCRl-CCR9) (Murdoch and Finn, Blood, 2000,95 : 3032). Chemokine receptors also serve as coreceptors for Human Immunodeficiency Virus (HIV) entry into cells. This came from the observation that RANTES, MIP-1 a, and MIP-1p suppressed infection of susceptible cells in vitro by macrophage-tropic primary HIV-1 isolates. The chemokine receptor CXCR-4 was found to support infection and cell fusion to CD4+ cells by laboratory-adapted, T-tropic HIV-1 strains.

The human CCR8 receptor has been shown to interact with the human chemokine I- 309. This chemokine is a potent monocyte chemoattractant and inhibits apoptosis in thymic cells. The CCR8 receptor is constitutively expressed in monocytes in the spleen and thymus, but not in other peripheral blood leukocytes (Tiffany et al., J. Exp. Med. , 1997,186 : 165).

This data appears to be in agreement with the role of I-309 in monocyte activation and thymic cell survival. Additionally, CCR8 is preferentially expressed in Th2-polarized cells and is transiently increased after T-cell receptor and C28 engagement, suggesting that CCR8 plays a role in the control of Th2 responses and that up-regulation of CCR8 after antigen encounter may contribute to the proper positioning of activated T-cells within sites of antigenic challenge or specialized areas of lymphoid tissues (Zingoni et al., J. Immunol., 1998, 161: 547; D'Ambrosio et al., J. Immunol., 1998,161 : 5111). CCR8 also has been shown to serve as a co-receptor for HIV-1.

With the significant role that CCR8 plays in Th2 mediated response, there is a continuing need to develop compounds and pharmaceutical compositions that may be used in the treatment of Th2 inflammatory conditions.

SUMMARY OF THE INVENTION The invention relates to compounds that have C-C chemokine receptor antagonizing activity and to a method for treating a subject having an inflammatory or viral disorder (e. g., a chemokine associated disorder, immunological disorder, neurological disorder, viral disorder, asthma) using such compounds. The compounds have the general formula : In one aspect, the compound has the formula :

In another aspect, the compound has the formula : In another aspect, the compound is of Formula I wherein Q4 is selected from the group consisting of :

R6 is selected from the group consisting of halogen, optionally substituted C1-Clo alkyl, optionally substituted C2-Clo alkenyl, optionally substituted C2-Clo alkynyl, optionally substituted C3-Clo cycloalkyl, optionally substituted C3-C1o cycloalkenyl, optionally substituted C3-C1o cycloalkynyl, optionally substituted Cs-Cio cycloalkoxy, cyano, Cl-calo alkoxy, C2-C10 alkenyloxy, C2-CIo alkynyloxy, benzyloxy, optionally substituted amino, optionally substituted amido, -O (CF3), -C (=O) O (Rl),-C (=O) (R1),-SO2C (=O) Rl, SO2, SO2NR1R2, trifluoromethyl, aryl, aralkyl, heteroaryl and heteroaralkyl.

The invention further relates to a method for treating an inflammatory disorder or viral disorder. The method comprises administering to a subject in need thereof an effective amound of a compound described herein.

The invention further relates to pharamaceutical or physiological compositions comprising a compound as described herein.

The invention further relates to the use of the compounds described herein in therapy (including palliative, curative and prophylactic therapy) or diagnosis, and to the use of such compounds for the manufacture of a medicament for the treatment of a particular disease or condition as described herein (e. g. , a chemokine associated disorder, immunological disorder, neurological disorder, viral disorder, asthma).

DETAILED DESCRIPTION OF THE INVENTION The invention is directed to novel compounds described herein as compounds of Groups 1 to 11, and to therapeutic methods that employ the compounds described herein.

Group 1 Compounds of Group 1 are defined in Formula (I):

wherein L is selected from the group consisting of a O, S, NRa, bond, SO2,-C (=O), and (CR'R")m; m is from 1 to 8; R'and R"independently are selected from the group consisting of hydrogen, optionally substituted alkyl, cyano, and optionally substituted alkenyl ; R6, R, R8, R9 and R10 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, optionally substituted Cl-Clo alkyl, optionally substituted C2-Clo alkenyl, optionally substituted C2-Clo alkynyl, optionally substituted C3-Clo cycloalkyl, optionally substituted Cs-Cio cycloalkenyl, optionally substituted C3-Clo cycloalkynyl, optionally substituted C3-Clo cycloalkoxy, cyano, Cl-Clo alkoxy, C2-Clo alkenyloxy, C2-Clo alkynyloxy, benzyloxy, optionally substituted amino, optionally substituted amido,-O (CF3), -C (=O) O (R1),-C (=O) (R1), -SO2C (=O) Rl, SO2, SO2NRIR2, trifluoromethyl, aryl, aralkyl, heteroaryl and heteroaralkyl ; Ri and R2 are independently hydrogen or optionally substituted alkyl ; Q3 is selected from the group consisting of a bond, optionally substituted alkyl, optionally substituted alkenyl, alkynyl,-C (=O)-(CH2)c, (CH2)c -C(=O), NRa-C(=O)-(CH2)c, -C (=O)-NRa- (CH2) c, NRa, O, S, and SO2 ; c is 0, 1 or 2 ; Ra is selected from hydrogen, optionally substituted alkyl, optionally substituted alkylaryl, or optionally substituted cycloalkyl ; and Q4 is selected from the group consisting of hydrogen, optionally substituted aromatic, optionally substituted heteroaromatic, optionally substituted non-aromatic heterocyclic, and optionally substituted amino.

Group 2 The invention is also directed to compounds of Group 1 wherein L is selected from the group consisting of O, NRa, CR'R"and S. Preferably, L is O.

Group 3 The invention is also directed to compounds of any of Groups 1 or 2, wherein R6 is selected from the group consisting of halogen and Cl-calo alkoxy; and R7-Rlo are hydrogen.

Preferably, the Ci-Cio alkoxy is a methoxy and the halogen is a chloro. Thus, in some compounds of Group 3, L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O), and (a) R6 is alkoxy (preferably methoxy) and R7-R10 are hydrogen; or (b) R6 is halogen (preferably chloro) and R7-R10 are hydrogen.

Group 4 Compounds of Group 4 are compounds of Groups 1 to 3, wherein Q3 is selected from the group consisting of a bond or optionally substituted alkyl. Thus, in some compounds of Group 4, Q3 is selected from the group consisting of a bond or optionally substituted alkyl and L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O). In other compounds of Group 4, Q3 is selected from the group consisting of a bond or optionally substituted alkyl, L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O), and (a) R6 is alkoxy (preferably methoxy) and R7-R10 are hydrogen; or (b) R6 is halogen (preferably chloro) and R7-R10 are hydrogen.

Group 5 The invention is also directed to compounds of Group 5, which are compounds of Groups 1 to 4, wherein Q3 is-CH2-or CR'R". Thus, in preferred compounds of Group 4, Q3 is-CH2-or CR'R"and L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O). In more preferred compounds of the invention, Q3 is-CH2-or CR'R", L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O), and (a) R6 is alkoxy (preferably methoxy) and R7-R10 are hydrogen; or (b) R6 is halogen (preferably chloro) and R7-R10 are hydrogen.

In more preferred compounds of Group 5, R'is cyano or methyl and R"is hydrogen.

Thus, in preferred compounds of Group 4, Q3 is-CH2-or CR'R" (wherein R'is cyano or methyl and R"is hydrogen), and L is selected from the group consisting of O, NRa, CR'R"

or S (preferably L is O), In more preferred compounds of Group 5, Q3 is-CH2-or CR'R" (wherein R'is cyano or methyl and R"is hydrogen), L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is (O), and (a) R6 is alkoxy (preferably methoxy) and R7-R10 are hydrogen ; or (b) R6 is halogen (preferably chloro) and R7-R10 are hydrogen.

Group 6 The invention is also directed to compounds of any of Groups 1 to 5, wherein Q4 is selected from

wherein a is 0 to 3 ; b is 0 to 3 ; R", R12, R13, R14, R15, R16, R17, R18, and R19 are each independently chosen from the group consisting of hydrogen, hydroxyl, halogen, optionally substituted alkyl, optionally

substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, cyano, alkoxy, alkenyloxy, alkynyloxy, benzyloxy, optionally substituted amino, optionally substituted amido,-O (CF3), -C(=O)O(R41), -C(=O)(R41), -SO2C(=O)R41, SO2, SO2NR41R42, trifluoromethyl, aryl, aralkyl, heteroaryl and heteroaralkyl ; any two of R12, R13, R14 and R15 may be taken together to form an optionally substituted carbocyclic group optionally interrupted by one or more heteroatoms; any two of R16, R17, R18, R19 may be taken together to form an optionally substituted carbocycle optionally interrupted by one or more heteroatoms; or R'8 or R19 together with Q5Q6 and the atoms to which they are bonded form an optionally substituted non-aromatic carbocyclic group, optionally substituted non-aromatic heterocyclic group, optionally substituted aryl ring or optionally substituted heteroaryl ring; R20 is selected from the group consisting of hydrogen, hydroxyl, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, cyano, alkoxy, alkenyloxy, alkynyloxy, benzyloxy, optionally substituted <BR> <BR> <BR> amino, optionally substituted amido,-O (CF3), -C (=O) O (R41),-C (=O) (R41),-S02C (=O) R4l, SO2, SO2NR41R42, trifluoromethyl, aryl, aralkyl, heteroaryl and heteroaralkyl ; Xl is independently selected from the group consisting of CR26R27, NR28,-(C=O), O and a bond; X2 is independently selected from the group consisting of CR29R30, NR31, -(C=O) and O ; X3 is independently selected from the group consisting of CR32R33,-C (R32) =, NR34,- N=,- (C=O) and O ; X4 is independently selected from the group consisting of CR35R36, NR37, =N-, - (C=O) and O ; X5 is independently selected from the group consisting of CR38R39, NR40,-(C=O) and O ; with the proviso that R35 and R38 or R32 and R35 may be joined together via an optionally substituted C1-6 alkyl bridge that may be optionally interrupted by one or more heteroatoms to form a non-aromatic carbocyclic or heterocyclic group, or R35 and R38 or R32 and R35 may be joined together via an optionally substituted C1-6 alkenyl bridge that may be optionally interrupted by one or more heteroatoms to form an aromatic ring;

R26, R27, R29, R30, R32, R33, R35, R36, R38 and R39 are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, cyano, alkoxy, alkenyloxy, alkynyloxy, benzyloxy, optionally substituted amino, optionally substituted amido, -O(CF3), -C(=O)O(R41), -C(=O)(R41), -SO2C(=O)R41, SO2, SO2NR41R42, trifluoromethyl, aryl, aralkyl, heteroaryl and heteroaralkyl; with the proviso that when X4is CR35R36 and X3is CR32R33 or X5 is CR38R39, R3s and R38 or R32 and R35 optionally form a non-aromatic carbocyclic group, a non-aromatic heterocyclic group, aryl ring or heteroaryl ring; and Wo are each independently selected from the group consisting of hydrogen, alkyl, S02R43, aryl, and benzyl; hydrogen, hydroxyl, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally cycloalkenyl, optionally substituted cycloalkynyl, optionally substituted amino, optionally substituted amido-C (=O) O (R41),-C (=O) (R41), -So2NR41R42, trifluoromethyl, aryl, aralkyl, heteroaryl or heteroaralkyl Q5 is selected from the group consisting of a bond,-C (R41R42)d-C(=O)-NR43-, -(NR43)z-C(=O)-C(R41R42)d-C(=O)-C(R41R42)d-, -(CR41R42)d-C(=O)-, -(NR43)z-C(=O)-NR44, -(NR43)z-C(=S)-NR44-, -(NR43)z-C(=O)-CH=CH-, -(NR43)z-C(R41R42)d-, -C(=O)-CH=CH-CH2-, -C(=O)-CH=CH-, -(NR43)z-C(R41R42)d-, -C(R41R42)d-NR43-, -SO2(CR41R42)d-, -(CR41R42)d-, -(NR43)z-C(=O)-(CR41R42)d-, -C(=O)-(CR41R42)d-, -C(=O)-(CR41R42)d-O-, or is absent; d is 0, 1,2, 3,4, 5,6, 7 or 8 ; zis0or2 ; R41, R42, R43 and R44 are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, cyano, alkoxy, alkenyloxy, alkynyloxy, benzyloxy, optionally substituted amino, optionally substituted amido,-O (CF3), -C(=O)O(R45), -C(=O)(R45), -SO2C(=O)R45, SO2, SO2R45, SO2NR54R55, trifluoromethyl, aryl, aralkyl, heteroaryl and heteroaralkyl ; or R41 and R42 may be linked via a C2-C8 optionally substituted alkyl or alkenyl bridge where one or more carbons may be replaced by O, S, NR54 or NR46 ;

R54 and R55 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkylaryl, optionally substituted cycloalkyl, -SO2-, (C1-10 optionally substituted alkyl),-S02- (C2-10 optionally substituted alkenyl,-S02- (C2-10 optionally substituted alkynyl),-SO2-aryl, optionally substituted aryl, and-S02-heteroaryl ; R45is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, cyano, alkoxy, alkenyloxy, alkynyloxy, benzyloxy, optionally substituted aryloxy, optionally substituted amino, optionally substituted amido, -O (CF3), -C (=O) O (R41), -C(=O)(R41), - S02C (=O) R41,-SO2,-So2NR41R42, trifluoromethyl, aryl, benzyl, aralkyl, heteroaryl and heteroaralkyl ; Q6 is an optionally substituted aromatic ring, optionally substituted non-aromatic heterocycle, optionally substituted alkyl, or an optionally substituted heteraromatic ring.

In preferred compounds of Group 6, Q4 is as defined above, and Q3 is-CH2-or CR'R". In more preferred compounds of Group 6, Q4 is as defined above, Q3 is -CH2- or CR'R", and L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O). In more preferred compounds of the invention, Q4 is as defined above, Q3 is -CH2- or CR'R", L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O), and (a) R6 is alkoxy and R7-R10 are hydrogen ; or (b) R6 is alkoxy and R7-R10 are hydrogen.

In more preferred compounds of Group 6, Q4 is as defined above and Q3 is-CH2-or CR'R" (wherein R'is cyano or methyl and R"is hydrogen). In additional preferred compounds, Q4 is as defined above, Q3 is-CH2-or CR'R" (wherein R'is cyano or methyl and R"is hydrogen), and L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O). In more preferred compounds of Group 6, Q4 is as defined above, Q3 is -CH2- or CR'R" (wherein R'is cyano or methyl and R"is hydrogen), L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O), and (a) R6 is alkoxy and R7- Rio are hydrogen ; or (b) R6 is alkoxy and R7-R10 are hydrogen.

Group 7 Compounds of Group 7 are compounds of any of Groups 1 to 6, wherein Q4 is

In preferred compounds of Group 7, Q4 is as defined above, and Q3 is-CH2-or CR'R". In more preferred compounds of Group 7, Q4 is as defined above, Q3 is-CH2-or CR'R", and L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O). In more preferred compounds of Group 7, Q4 is as defined above, Q3 is-CH2-or CR'R", L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O), and (a) R6 is alkoxy (preferably methoxy) and R7-R10 are hydrogen; or (b) R6 is halogen (preferably chloro) and R7-R10 are hydrogen.

In more preferred compounds of Group 7, Q4 is as defined above and Q3 is-CH2-or CR'R" (wherein R'is cyano or methyl and R"is hydrogen). In additional preferred compounds, Q4 is as defined above, Q3 is-CH2-or CR'R" (wherein R'is cyano or methyl and R"is hydrogen), and L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O). In more preferred compounds of Group 7, Q4 is as defined above, Q3 is -CH2- or CR'R" (wherein R'is cyano or methyl and R"is hydrogen), L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O), and (a) R6 is alkoxy (preferably methoxy) and R7-R10 are hydrogen; or (b) R6 is halogen (preferably chloro) and R7-R10 are hydrogen.

In more preferred embodiments of Group 7 as described above, Q4 is Group 8 The compounds of Group 8 are compounds of any of Groups 1 to 6, in which Q4 is selected from the group consisting of :

In preferred compounds of Group 8, Q4 is as defined above, and Q3 iS-CH2-or CR'R". In more preferred compounds of Group 8, Q4 is as defined above, Q3 is-CH2-or CR'R", and L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O). In more preferred compounds of Group 8, Q4 is as defined above, Q3 is-CH2-or CR'R", L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O), and (a) R6 is alkoxy (preferably methoxy) and R7-R10 are hydrogen; or (b) R6 is halogen (preferably chloro) and R7-R10 are hydrogen.

In more preferred compounds of Group 8, Q4 is as defined above and Q3 is-CH2-or CR'R" (wherein R'is cyano or methyl and R"is hydrogen). In additional preferred compounds, Q4 is as defined above, Q3 is-CH2-or CR'R" (wherein R'is cyano or methyl and R"is hydrogen), and L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O). In more preferred compounds of Group 8, Q4 is as defined above, Q3 is -CH2- or CR'R" (wherein R'is cyano or methyl and R"is hydrogen), L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O), and (a) R6 is alkoxy (preferably methoxy) and R7-R10 are hydrogen; or (b) R6 is halogen (preferably chloro) and R7-R10 are hydrogen.

In preferred embodiments of Group 8, R34 is SO2R44. More preferably, R34 is SO2R44 and R44 is alkyl.

Group 9 The compounds of Group 9 are compounds of any of Groups 1 to 8, wherein Q5 is selected from the group consisting of : 0 0 0 - N -N , I zo f I zo (g) n e N N 0 1 6 1 N R4s-CHZ, and a bond ; 120 N R wherein eislto3 ; f is 1 to 7 ; g is 0 to 3 ; h is 0 to 3 ; i is 0 or 1 ; R20 and R46 are independently hydrogen, hydroxyl, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally cycloalkenyl, optionally substituted cycloalkynyl, cyano, alkoxy, alkenyloxy, alkynyloxy, benzyloxy, optionally substituted amino, optionally substituted amido, -O(CF3), -C(=O)O(R41), -C(=O)(R41), -SO2C(=O)R41, SO2, SO2NR41R42, trifluoromethyl, aryl, aralkyl, heteroaryl or heteroaralkyl.

In preferred embodiments of Group 9, Q5 is as defined above, Q4 is as defined in Group 7, and Q3 is-CH2-and CR'R". In more preferred compounds of Group 9, Q5 is as defined above, Q4 is as defined in Group 7, Q3 is-CH2-or CR'R", and L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O). In more preferred compounds of Group 9, Q5 is as defined above, Q4 is as defined in Group 7, Q3 is-CH2-or CR'R", L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O), and (a) R6 is

alkoxy (preferably methoxy) and R7-R10 are hydrogen; or (b) R6 is halogen (preferably chloro) and R7-R10 are hydrogen.

In more preferred compounds of Group 9, Q5 is as defined above, Q4 is as defined in Group 7 and Q3 is-CH2-or CR'R" (wherein R'is cyano or methyl and R"is hydrogen). In additional preferred compounds, Q5 is as defined above, Q4 is as defined in Group 7, Q3 is -CH2-or CR'R"(whereinR'is cyano or methyl and R"is hydrogen), and L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O). In more preferred compounds of Group 9, Q5 is as defined above, Q4 is as defined in Group 7, Q3 is-CH2-or CR'R" (wherein R'is cyano or methyl and R"is hydrogen), L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O), and (a) R6 is alkoxy (preferably methoxy) and R7-R10 are hydrogen; or (b) R6 is halogen (preferably chloro) and R7-R10 are hydrogen.

In additional preferred embodiments of Group 9, Q5 is as defined above, Q4 is as defined in Group 8, and Q3 is-CH2-or CR'R". In more preferred compounds of Group 9, Q5 is as defined above, Q4 is as defined in Group 8, Q3 is -CH2- or CR'R", and L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O). In more preferred compounds of Group 9, Q5 is as defined above, Q4 is as defined in Group 8, Q3 is -CH2- or CR'R", L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O), and (a) R6 is alkoxy (preferably methoxy) and R7-R10 are hydrogen; or (b) R6 is halogen (preferably chloro) and R7-R10 are hydrogen.

In more preferred compounds of Group 9, Q 5is as defined above, R4 is as defined in Group 8 and Q3 is-CH2-or CR'R" (wherein R'is cyano or methyl and R"is hydrogen). In additional preferred compounds, Q5 is as defined above, Q4 is as defined in Group 8, Q3 is -CH2- or CR'R" (wherein R'is cyano or methyl and R"is hydrogen), and L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O). In more preferred compounds of Group 9, Q5 is as defined above, Q4 is as defined in Group 8, Q3 is-CH2-or CR'R" (wherein R'is cyano or methyl and R"is hydrogen), L is selected from the group consisting of O, NRa, CR'R"and S (preferably L is O), and (a) R6 is alkoxy (preferably methoxy) and R7-R10 are hydrogen; or (b) R6 is halogen (preferably chloro) and R7-R10 are hydrogen.

In one embodiment of Group 9, Q5 is In an alternative embodiment of Group 9, Q5 is

Group 10 The Group 10 compounds of the invention are compounds of Groups 6 to9, wherein Q6 is selected from the group consisting of:

wherein the selected group can be substituted with one or more substitutents, R47, which are chosen independently for each position capable of substitution from the group consisting of hydrogen, hydroxyl, halogen, optionally substituted alkyl, optionally substituted alkenyl,

optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, cyano, alkoxy, alkenyloxy, alkynyloxy, benzyloxy, optionally substituted amino, optionally substituted amido,-O (CF3), - C (=O) O (R41),-C (=O) (R4i),-S02C (=O) R41, S02, S02NR41R42 rifluoromethyl, aryl, aralkyl, heteroaryl and heteroaralkyl ; R48 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, -C(=O)O(R41), -C(=O)(R41), trifluoromethyl, aryl, aralkyl, heteroaryl and heteroaralkyl ; and R49 is selected from the group consisting of hydrogen, hydroxyl, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally cycloalkenyl, optionally substituted cycloalkynyl, cyano, alkoxy, alkenyloxy, alkynyloxy, benzyloxy, optionally substituted amino, optionally substituted amido, -O(CF3), -C (=O)O(R41), -C(=O)(R41), -SO2C(=O)R41, SO2, SO2NR41R42, trifluoromethyl, aryl, aralkyl, heteroaryl and heteroaralkyl.

In one embodiment of Group 10 compounds, Q6 is

Group 11 The compounds of Group 11 are compounds of Group 10, wherein R47 is chosen independently for each position capable of substitution from the group consisting of hydrogen, chloro, bromo, fluoro, iodo, CF3, phenyl, -S (0) 2-N-alkyl, alkyl, and

Certain compounds of the invention contain stereocenters and may be obtained as different stereoisomers (e. g. , diastereomers and enantiomers). For example, as described above, in certain embodiments Q5 is and when g is 1 and h is zero, Q5 can have a formula selected from

It is pointed out that the invention includes all isomeric forms and racemic mixtures of the disclosed compounds, and a method of treating a subject with both pure isomers and mixtures thereof, including racemic mixtures. Stereoisomers can be separated and isolated using any suitable method, such as chromatography. One stereoisomer may be more active than another. The desired isomer can be determined, for example, by screening.

In a particular aspect, the invention is a compound of Formula I wherein Q4 is

The compounds of this aspect have the formula wherein Q3 is optionally substituted alkyl ; and Q5 is selected from the group consisting of

R6-R10, R11-R19, R41, R42, R46, L, a, b, f, g, h and Q6 are as defined above for Formula I. In certain embodiments, R46 is a substituted alkyl, such as-CH (CH2) (CH2) -COOH. In other embodiments, a is 1, b is 1, R12 and R13 are methyl, and R14, R15, R16, R17, Ris and R19 are hydrogen. In another embodiment, the compound is defined by Formula Ia with the proviso that the compound is not In another aspect, the invention is a compound of formula I wherein Q4 is

The compounds of this aspect have the formula wherein Q3 is optionally substituted alkyl ; and R6-R10, R12-R19, a, b, Xl, X2, X3, X4 and X5 are as defined above for Formula I.

In another aspect, the invention is a compound of Formula I wherein Q4 is selected from the group consisting of

is selected from the group consisting of halogen, optionally substituted Cl-calo alkyl, optionally substituted C2-Clo alkenyl, optionally substituted C2-C1o alkynyl, optionally substituted C3-C1o cycloalkyl, optionally substituted Cs-Cio cycloalkenyl, optionally substituted C3-C1o cycloalkynyl, optionally substituted Cs-Cio cycloalkoxy, cyano, Cl-calo alkoxy, C2-C1o alkenyloxy, C2-C1o alkynyloxy, benzyloxy, optionally substituted amino, optionally substituted amido,-O (CF3), -C (=O) O (R1),-C (=O) (R1),-SO2C (=O) R1, S02, S02NR1R2, trifluoromethyl, aryl, aralkyl, heteroaryl and heteroaralkyl.

Particularly preferred compounds are selected from the group consisting of The present invention further contemplates a method for treating a chemokine associated disorder in a subject comprising administration to said subject an effective amount of any of the compounds of the invention as defined above. Preferably the chemokine associated disorder is treated through modulation of a P-chemokine receptor.

The present invention also contemplates methods where the chemokine associated disorder is a neurological disorder, immunological disorder, chemokine associated disorder is characterized by unwanted cellular proliferation, unwanted cellular migration, abnormal cellular signal transduction, abnormal amounts of chemokine stimulated chemotaxis, or a viral disorder.

In one embodiment the disorders are selected from the group consisting of Alzheimer's disease, dementias related to Alzheimer's disease, Parkison's disease, Lewy diffuse body disease, multiple sclerosis, amytrophic lateral sclerosis, progressive supranuclear palsy, epilepsy, Jakob-Creuztfeldt disease, stroke, traumatic injury to the brain, traumatic injury to the spinal cord, spinal crush, central nervous system trauma, peripheral nervous system trauma, immune thyroiditis, hypertliyriodism, type I diabetes mellitus, insulin related diabetes, Addison's disease, autoimmune oophoritis, autoimmune orchiitis, autoimmune hemolytic anemia, paroxysmal cold hemoglobinuria, autoimmune thrombocytopenia, autimmune neutropenia, pernicious anemia, autoimmune coagulopathies, myasthenia gravis, allerigic encephalomyelitis, pemphigus, bullous diseases, rheumatic carditis, Goodpasture's syndrome, T-cell leukemia, postcardiotomy syndrome, arthritis, rheimatoid arthritis, osteoarthritis, keratitis, parotitis, polymositis, dermatomyositis, scleroderma, acquired immune deficiency syndrome, lupus, multiple sclerosis, restinosis, idiopathic pulmonary fibrosis, allergic hypersensitivity disorders, allergic rhinitis, psoriasis, chronic contact dermatitis, sarcoidosis, dermatomyositis, skin pemphigoid, pemphigus vulgaris, p. foliacius, p. erthematosus, glomerulonephritides, vasculitides, cutaneous vasculitis, hypersensitivity vasculitis, hepatitis, systemic lupus erthematosus, myasthenia gravis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, uricaria, reperfusion injury, transplant rejection, graft rejection, allograft rejection, artherosclerosis, asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, arthritis, osteoarthritis, and rheumatoid arthritis.

The present invention also contemplates a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically or physiologically acceptable carrier, where the effective amount is effective to treat a chemokine associated disorder. The"effective amount"of a compound is an amount sufficient to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in the prevention of or a decrease in the symptoms associated with an inflammatory or viral disorder. For example, the effective amount can result in the inhibition of one or more processes mediated by the binding of a chemokine to a receptor in a subject with an inflammatory or viral disorder. Examples of such processes include leukocyte migration, integrin activation, transient increases in the concentration of intracellular free calcium [Ca2+] i and granule release of proinflammatory mediators.

The invention contemplates a method for treating an inflammatory disease in a subject comprising administration to said subject an effective amount of a compound as defined above. Preferably, the inflammatory disease is a neurological disorder, an immunological disorder, or a viral disorder.

The disorders may be selected from the group consisting of Alzheimer's disease, dementias related to Alzheimer's disease, Parkison's disease, Lewy diffuse body disease, multiple sclerosis, amytrophic lateral sclerosis, progressive supranuclear palsy, epilepsy, Jakob-Creuztfeldt disease, stroke, traumatic injury to the brain, traumatic injury to the spinal cord, spinal crush, central nervous system trauma, peripheral nervous system trauma, immune thyroiditis, hyperthyriodism, type I diabetes mellitus, insulin related diabetes, Addison's disease, autoimmune oophoritis, autoimmune orchiitis, autoimmune hemolytic anemia, paroxysmal cold hemoglobinuria, autoimmune thrombocytopenia, autimmune neutropenia, pernicious anemia, autoimmune coagulopathies, myasthenia gravis, allerigic encephalomyelitis, pemphigus, bullous diseases, rheumatic carditis, Goodpasture's syndrome, postcardiotomy syndrome, arthritis, rheimatoid arthritis, osteoarthritis, keratitis, parotitis, polymositis, dennatomyositis, scleroderma, acquired immune deficiency syndrome, lupus, multiple sclerosis, restinosis, idiopathic pulmonary fibrosis, allergic hypersensitivity disorders, allergic rhinitis, psoriasis, chronic contact dermatitis, sarcoidosis, dermatomyositis, skin pemphigoid, pemphigus vulgaris, p. foliacius, p. erthematosus, glomerulonephritides, vasculitides, cutaneous vasculitis, hypersensitivity vasculitis, hepatitis, systemic lupus erthematosus, myasthenia gravis, dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, uricaria, reperfusion injury, transplant rejection, graft rejection, allograft rejection, artherosclerosis, asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, arthritis, osteoarthritis, and rheumatoid arthritis.

The invention also contemplates a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention as defined above and a pharmaceutically or physiologically acceptable carrier, where the effective amount is effective to treat an inflammatory disease or a viral disorder.

The present invention further contemplates pharmaceutical compositions comprising at least one compound encompassed by the formula of the present invention. Alternatively, the pharmaceutical composition may comprise a salt or prodrug of at least one compound encompassed by the formula of the present invention. The pharmaceutical composition comprises an inflammatory treating effective amount of at least one compound of the present

invention. In a specific embodiment, the present invention contemplates a pharmaceutical composition comprising a CCR8 antagonist or anti-viral effective amount of at least one compound of the present invention. Dosage unit forms containing the pharmaceutical composition of the present invention also are provided.

Another embodiment of the present invention is a method of inhibiting CCR8 in a patient in need thereof by administering a CCR8 antagonist effective amount of the pharmaceutical composition of the present invention. In a specific embodiment, the compounds of the present invention are contemplated for the use of treating an inflammatory or anti-viral condition, which encompasses those conditions that are described below.

Definitions As used herein, "optionally substituted"means that the chemical group that immediately follows the phrase is unsubstituted or"substited"as described herein. For example, an optionally substituted C1-Clo alkyl is a Cl-calo alkyl or a substituted Cl-calo alkyl.

As used herein, the term"substituted"means that the radical is substituted with one or more substituents selected from the group consisting of carboxy, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, cycloalkynyloxy, nitro, halogen, cyano, amino, (di) alkyl amino, (di) alkenyl amino, (di) aryl amino, aryl, substituted aryl, non-aromatic heterocyclic, substituted non-aromatic heterocyclic, heteroaryl, substituted heteroaryl, aralkyl, heteroaralkyl, acyl, acyloxy, sulfonamide, sulfonyl, oxo,-S03H,-CHO-,-(CH2) n-NH2, - n-NH-alkyl,-(CH2) n-N (alkyl) 2, wherein n is an integer from 1 to 8.

As used herein, the term"alkyl"refers to a straight or branched hydrocarbon group having from one to twelve carbon atoms and a single radical. Suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl and the like. In some embodiments, preferred alkyl groups are those having from one to eight carbon atoms, and more preferred alkyl groups are those having from one to four carbon atoms. Any alkyl group (or alkyl moiety) may be substituted with one or more substituents independently selected for each position.

As used herein, the term"alkenyl"refers to a straight or branched hydrocarbon group that contains from one to twelve carbon atoms and a single radical, and has one or more double bonds between carbon atoms. Suitable alkenyl groups include, e. g., n-butenyl, cyclooctenyl and the like. In some embodiments, preferred alkenyl groups are those having

from one to eight carbon atoms, and more preferred alkenyl groups are those having from one to four carbon atoms. Any alkenyl group (or alkenyl moiety) may be substituted.

As used herein, the term"alkynyl"refers to a straight or branched hydrocarbon group that contains from one to twelve carbon atoms and a single radical, and has one or more triple bonds between carbon atoms. Suitable alkynyl groups include, e. g., n-butynyl. In some embodiments, preferred alkynyl groups are those having from one to eight carbon atoms, and more preferred alkynyl groups are those having from one to four carbon atoms. Any alkynyl group (or alkynyl moiety) may be substituted.

As used herein, the term"cycloalkyl"means a non-aromatic mono or multicyclic hydrocarbon ring system of from 3 to 12 carbon atoms having a single radical. Preferred monocyclic cycloalkyl groups are those having, from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group (or cycloalkyl moiety) as defined herein may optionally be substituted.

As used herein, the term"cycloalkenyl"means a non-aromatic mono or multicyclic hydrocarbon ring system of from 3 to 12 carbon atoms having a single radical and at least one C_C. Preferred cycloalkynyl groups are those having from 3 to 6 carbon atoms. The cycloalkenyl group (or cycloalkenyl moiety) as defined herein may optionally be substituted.

As used herein, the term"cycloalkynyl"means a non-aromatic mono or multicyclic hydrocarbon ring system of from 3 to 12 carbon atoms having a single radical and at least one C=-C. Preferred cycloalkynyl groups are those having from 3 to 6 carbon atoms. The cycloalkynyl group (or cycloalkynyl moiety) as defined herein may optionally be substituted.

As used herein, the term"alkoxy"refers to the group-O-alkyl, wherein the alkyl moiety is as defined above. In some embodiments, preferred alkoxy groups are those having 1 to 8 carbon atoms. Suitable alkoxy groups include methoxy, ethoxy, propoxy, butoxy, and the like.

As used herein, the term"alkenyloxy"is a group-O-alkenyl, wherein the alkenyl moiety is as defined above. In some embodiments, preferred alkenyloxy groups are those having 1 to 8 carbon atoms in the alkenyl moiety.

As used herein, the term"alkynyloxy"is a group-O-alkynyl, wherein the alkynyl moiety is as defined above. In some embodiments, preferred alkynyloxy groups are those having 1 to 8 carbon atoms in the alkynyl moiety.

As used herein, the term"acyl"is a group-RC (=O)-, wherein R may be an alkyl, alkenyl, alkynyl, aryl, amino, amino alkyl, amino alkenyl, amino alkynyl or amino aryl

moiety, as those terms are defined herein. In some embodiments, preferred alkyl, alkenyl and alkynyl R groups are those having from one to eight carbon atoms, more preferably from one to five carbon atoms. Exemplary aryl R groups are phenyl and naphthyl.

As used herein, the term"acyloxy"is a group 0-acyl, wherein the acyl moiety is as described above.

As used herein, the term"sulfonamide"refers to the group SO2NH-.

As used herein, the term"sulfonyl"refers to the group S02-.

As used herein, the term"halo"or"halogen"encompasses fluorine, chlorine, bromine and iodine.

As used herein, the term"ring system"refers to an aromatic or non-aromatic carbocyclic compound, in which one or more of the ring carbon atoms may be replaced by a heteroatom, such as nitrogen, oxygen or sulfur.

As used herein, the term"fused ring system"refers to ring systems wherein at least two adjacent carbon centers join one or more cyclic structures. A fused ring system as used herein may be aromatic or non-aromatic, or may be composed of separate aromatic and non- aromatic moieties.

As used herein, the term"spirocyclic"refers to a ring system in which a ring has one carbon atom in common with a second cyclic group.

As used herein, the term"polycyclic ring system"refers to ring systems having two or more cyclic compounds bonded in tandem. A polycyclic ring system as used herein may be aromatic or non-aromatic, or may be composed of separate aromatic and non-aromatic moieties.

As used herein, the tenn"non-aromatic heterocyclic"means a closed ring structure having from about five to about fifteen atoms in the ring, in which one or more of the atoms in the ring is an atom other than carbon, such as oxygen, nitrogen or sulfur. A heterocyclic group may be a fused or polycyclic ring system. Examples of suitable non-aromatic heterocyclic groups and substituted heterocyclic groups include, but are not limited to, piperidine, piperazine, pyrrolidine, imidazoline, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino, tetrahydroquinoline and tetrahydroisoquinoline.

As used herein, the term"aryl"means an aromatic carbocyclic ring structure having from about five to about fifteen carbon atoms. An aryl group may be a fused or polycyclic ring system. Examples of suitable aryl groups include, phenyl, naphthyl and anthracyl.

As used herein, the term"heteroaryl"means a closed aromatic ring structure having from about five to about fifteen atoms in the ring, in which one or more of the atoms in the ring is an atom other than carbon, such as oxygen, nitrogen or sulfur. Examples of suitable heteroaryl groups and substituted heteroaryl groups include, but are not limited to, indole, quinoline, thiophene, pyridine, imidazole, quinoline, isoquinoline, benzothiophene, oxazole, benzimidazole, imidazole, tetrazole and azepine.

As used herein, the terms"arylalkyl"and"aralkyl"are used interchangeably, and refer to-alkyl-aryl, wherein the"alkyl"and"aryl"moieties are as defined herein.

As used herein, the term"heteroarylalkyl"and"heteroaralkyl"are used interchangeably, and refer to-alkyl-heteroaryl, wherein the"alkyl"and"heteroaryl"moieties are as defined herein.

The term"protected hydroxy"or"protected carboxy"refers to the use of a"hydroxy protecting group, "a substituent of a hydroxy group that is commonly employed to block or protect the hydroxy functionality (including the hydroxy functionality of a carboxyl group) while reactions are carried out on other functional groups on the compound. Examples of such hydroxy protecting groups include tetrahydropyranyl, 2-methoxyprop-2-yl, 1-ethoxyeth-1-yl, methoxymethyl, p-methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, benzyl, trimethylsilyl, and the like.

The term"protected amino"refers to the use of an"amino protecting group,"a substituent of an amino group that is commonly employed to block or protect the amino functionality or reactions that are carried out on the compounds.

As used herein, the term"amino"refers to the group-NH2.

As used herein, the term"N-substituted amino"refers to an amino group in which the N atom of the amino group is once substituted. A non-limiting example of a suitable N- substituted amino groups includes alkylamino.

As used herein, the tenn"N, N-substituted amino"refers to an amino group in which the N atom of the amino group is twice substituted. Suitable N, N-substituted amino groups include dialkylamino.

As used herein, the symbol"-"represents a chemical bond. The symbol"---" represents an optional chemical bond, such that the symbol indicates that the linked atoms can be joined by either a single or a double bond.

As used herein, the term"patient"refers to any animal (e. g. , mammals, birds, fish) in need of therapy, such as humans, cows, dogs, cats, sheep, horses, chickens, pigs and the like.

In an embodiment of this invention, the patient is in need of treatment of an inflammatory condition.

The compounds described herein can be prepared and administered as neutral compounds, salts, esters, amides and/or prodrugs. As used herein, the phrase "pharmaceutically or physiologically acceptable salts, esters, amides, and prodrugs"refers to those salts (e. g., carboxylate salts, amino acid addition salts), esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.

The compounds described herein can form pharmaceutically or physiologically acceptable acid addition and/or base salts. All of these forms are within the scope of the present invention.

Pharmaceutically or physiologically acceptable salts of the compounds described herein include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, 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 salts of amino acids such as arginate, gluconate, galacturonate and the like (see, for example, Berge S. M. et al.,"Pharmaceutical Salts, "J. of Pharma. Sci. , 1977; 66: 1).

Acid addition salts of compounds which contain a basic group (e. g., amine) can be prepared using suitable methods. For example, acid addition salts can be prepared by contacting the free base form of a compound with a sufficient amount of a 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 form of a compound can differ from a salt forms somewhat in certain physical properties such as solubility in polar solvents.

Pharmaceutically or physiologically acceptable base addition salts can be formed with suitable metals or amines, such as alkali and alkaline earth metals or organic amines.

Examples of metals which are suitable for use as cations in base addition salts include sodium, potassium, magnesium, calcium and the like. Amines suitable for use as cations in base addition salts include N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, supra, 1977).

Base addition salts of compounds which contain an acidic group (e. g., carboxylic acid) can be prepared using suitable methods. For example, the free acid form of a compound can be contacted with a sufficient amount of the desired base to produce a salt in the conventional manner. The free acid form can be regenerated by contacting the salt form with a suitable acid and isolating the free acid in the conventional manner. The free acid form of a compound can differ from the base addition salt form somewhat in certain physical properties such as solubility in polar solvents.

Examples of pharmaceutically or physiologically acceptable, nontoxic esters of the compounds of this invention include Cl-C6 alkyl esters. In certain embodiments, the alkyl group of the alkyl ester is a straight or branched chain C1-C6 alkyl group. Acceptable alkyl esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 esters are preferred. Esters of the compounds of the present invention can be prepared using any suitable method.

Examples of pharmaceutically acceptable, nontoxic amides of the compounds of this invention include amides derived from ammonia, primary Cl-C6 alkyl amines and secondary C1-C6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines, the amine may also be in the form of a 5-or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines, and Ci-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared using any suitable method.

The term"prodrug"refers to compounds that can be transformed in vivo (e. g., following administration to an animal), by metabolic processes or other processes, to yield a compound of the above formulae, for example, by hydrolysis in blood. A thorough

discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed.

Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

The terms"viral condition","viral disease", or"viral disorder"refer to either an acute or chronic viral condition, which results from infectious causes. In particular embodiments, the viral condition, viral disease or viral disorder is associated with infection by simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV-1, HIV-2, including M-trophic and/or T-trophic strains), papilloma virus (e. g. , human papilloma virus 16); flaviviruses such as Hepatitis B and Hepatitis C; Herpes virus (e. g., Herpes simplex virus (HSV-1, HSV-2), cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, human herpes virus (e. g. , HHV6, HHV7, HHV8,) herpes viruses which infect livestock, such as horses, cattle, pigs, chickens, turkeys and fish (e. g. , pseudorabies virus, porcine cytomegalovirus) ) ; parvovirus (e. g. , parvo virus B19), human influenza virus A, human influenza virus B, rhinovirus, coronaviruses, enterovirus, human parainfluenza virus, respiratory syncytial virus (RSV), adenovirus (e. g. , adenovirus-8), togavirus (e. g. , rubella virus), paramyxovirus (e. g., Measles virus, Mumps virus), rhabdoviruses (e. g. , rabies virus, molola virus, vesicular stomatitis virus), rotavirus, enteric calicivirus (e. g. , Norwalk virus), enterovirus (e. g., coxsackievirus, echovirus, poliovirus), reovirus, lymphocyte choriomeningitis virus, bunyamwera virus, group C virus, tahyna virus, toscana virus, punta toro virus, dengue virus, orbivirus (e. g., Orungo virus, Tribec virus, Kemerova virus, Lipovnik virus), encephalitis viruses (e. g. , California encephalitis virus, La Crosse encephalitis virus, St. Loius encephalitis virus, West Nile virus, eastern equine encephalitis virus, Japanese encephalitis virus), for example.

The terms"inflammatory condition", "inflammatory disease", or"inflammatory disorder"refer to either an acute or chronic inflammatory condition, which can result from infections or non-infectious causes. Various infectious conditions include meningitis, encephalitis, uveitis, colitis, dermatitis, and adult respiratory distress syndrome.

Non-infectious causes include trauma (burns, cuts, contusions, crush injuries), autoimmune diseases, and organ rejection episodes. Thus, in specific embodiments, an inflammatory condition results from a condition selected from the group that includes: atherosclerosis (arteriosclerosis); autoimmune conditions, such as multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), rheumatoid arthritis and other forms of

inflammatory arthritis, Sjogren's Syndrome, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, Type I diabetes mellitus, myasthenia gravis, Hashimoto's thyroditis, Graves'disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease including Crohn's Disease (regional enteritis) and ulcerative colitis, pernicious anemia, inflammatory dennatoses ; usual interstitial pneumonitis (UIP), asbestosis, silicosis, berylliosis, talcosis, the various forms all forms of pneumoconiosis, sarcoidosis (in the lung and in any other organ), desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa); inflammatory dermatoses not presumed to be autoimmune; chronic active hepatitis; delayed-type hypersensitivity reactions (e. g., poison ivy dennatitis) ; pneumonia or other respiratory tract inflammation due to any cause; Adult Respiratory Distress Syndrome (ARDS) from any etiology; encephalitis, with inflammatory edema; immediate hypersensitivity reactions including, but not limited to, asthma, hayfever, cutaneous allergies, acute anaphylaxis; diseases involving acute deposition of immune complexes, including, but not limited to, rheumatic fever, acute and/or chronic glomerulonephritis due to any etiology, including specifically post-infectious (e. g., post-Streptococcal) glomerulonephritis, acute exacerbations of Systemic Lupus Erythematosus; pyelonephritis; cellulitis; cystitis; acute cholecystitis; and conditions producing transient ischemia anywhere along the gastrointestinal tract, bladder, heart, or other organ, especially those prone to rupture; sequelae of organ transplantation or tissue allograft, including allograft rejection in the acute time period following allogeneic organ or tissue transplantation and chronic host-versus-graft rejection.

As used herein, the term"treat"refers to reducing or completely removing an undesired condition. Therefore, as used in the context of the present invention the term means to reduce an inflammatory condition or to completely remove the condition.

Assessment of the efficacy of the treatment may be determined by anyone of ordinary skill in the art using methods that are well known and identified.

Therapeutic Methods The invention also provides methods for treating or preventing inflammatory conditions, by administration of at least one therapeutic of the invention. Such therapeutics include the aforementioned molecules, oligopeptides, proteins, and combinations thereof.

While not wishing to be bound by any particular theory or mechanism, it is believed that compounds of the invention are antagonists of a chemokine receptor. Preferably, the compounds antagonize the CCR8, and that therapeutic benefits derived from the method of the invention are the result of antagonism of CCR8 function. Thus, the compounds of the invention can be used to treat a patient having a condition involving cells which express CCR8 on their surface and which respond to signals transduced through CCR8, as well as the specific conditions recited herein.

To enhance the efficacy of the therapeutics contained in the invention, these treatments may be administered in conjunction with other therapies which block the function of other molecules involved in the inflammatory or viral pathway.

The subjects to which the present invention is applicable may be any mammalian or vertebrate species, which include, but are not limited to, cows, horses, sheep, pigs, fowl (e. g., chickens), goats, cats, dogs, hamsters, mice, rats, monkeys, rabbits, chimpanzees, and humans. In a preferred embodiment, the subject is a human.

Pharmaceutical Compositions The invention also relates to pharmaceutical and/or physiological compositions which contain the compounds described herein. Such compositions can contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be controlled by various antibacterial and antifungal agents, for example, parabens,, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound can be admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate; or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alignates, gelatin,

polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate ; (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Such solid compositions or solid compositions that are similar to those described-can be employed as fillers in soft-and hard-filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings or other suitable coatings or shells.

Several such coating and/or shells are well known in the art, and can contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be used in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically or physiologically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like. If desired, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and/or perfuming agents.

The formulation may include a carrier. The carrier is a macromolecule which is soluble in the circulatory system and which is physiologically acceptable where physiological

acceptance means that those of skill in the art would accept injection of said carrier into a patient as part of a therapeutic regime. The carrier preferably is relatively stable in the circulatory system with an acceptable plasma half life for clearance. Such macromolecules include but are not limited to Soya lecithin, oleic acid and sorbitan trioleate, with sorbitan trioleate preferred.

Suspensions, in addition to the active compounds, can contain suspending agents, such as, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and the like. Mixtures of suspending agents can be employed if desired. Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.

Compositions suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays and inhalants. The active component can be admixed under suitable conditions (e. g., sterile conditions) with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

The present invention further provides aerosol formulations and dosage forms. In general such dosage forms contain the compounds of the present invention in a pharmaceutically or physiologically acceptable diluent. Pharmaceutically or physiologically acceptable diluents include but are not limited to sterile water, saline, buffered saline,

dextrose solution, and the like. In a specific embodiment, a diluent that may be used in the present invention or the pharmaceutical formulation of the present invention is phosphate buffered saline, or a buffered saline solution generally between the pH 7.0-8. 0 range or water.

The present invention further contemplates liquid aerosol formulations comprising the compound of the present invention and another therapeutically effective drug. It is also contemplated that the present aerosol formulation can be prepared as a dry powder formulation comprising a finely divided powder form of the compound and a dispersant.

The liquid aerosol formulation of the present invention may include, as optional ingredients, pharmaceutically or physiologically acceptable carriers, diluents, solubilizing or emulsifying agents, surfactants and excipients.

The formulations of the present embodiment may also include other agents useful for pH maintenance, solution stabilization, or for the regulation of osmotic pressure. Examples of the agents include but are not limited to salts, such as sodium chloride, or potassium chloride; and carbohydrates, such as glucose, galactose or mannose, and the like.

The present invention further contemplates dry powder formulations comprising the compound of the present invention and another therapeutically effective drug. Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing the compound of the present invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e. g., 50 to 90% by weight of the formulation.

The quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to about 1000 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.

Administration The pharmaceutical compositions of the present invention may be administered by a variety of routes such as intravenous, intratracheal, subcutaneous, oral, parenteral, buccal, sublingual, opthalmic, pulmonary, transmucosal, transdermal, and intramuscular. Unit

dosage forms also can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches known to those of ordinary skill in the art. The pharmaceutical composition or unit dosage forms of the present invention may be administered to an animal, preferably a human being, in need of treatment of an inflammatory condition.

The pharmaceutical composition or unit dosage form of the present invention may be administered according to a dosage and administration regimen defined by routine testing in light of the guidelines given above in order to obtain optimal anti-inflammatory or anti-viral activity while minimizing toxicity or side-effects for a particular patient. However, such fine turning of the therapeutic regimen is routine in light of the guidelines given herein. The dosage of the active agents of the present invention may vary according to a variety of factors such as underlying disease state, the individual's condition, weight, sex and age and the mode of administration.

For combination therapy according to the invention, the active agents may initially be provided as separate dosage forms until an optimum dosage combination and administration regimen is achieved. The exact dosage and administration regimen utilizing the combination therapy of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity and etiology of the inflammatory condition to be treated ; the route of administration ; the renal and hepatic function of the patient; the treatment history of the patient; and the responsiveness of the patient. Optimal precision in achieving concentrations of active agents within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the absorption, distribution, metabolism, excretion of a drug, and responsiveness of the patient to the dosage regimen.

However, such fine tuning of the therapeutic regimen is routine in light of the guidelines given herein. The pharmaceutical composition or unit dosage form may be administered in a single daily dose, or the total daily dosage may be administered in divided doses. In addition, co-administration or sequential administration of other active agents may be desirable.

In a specific embodiment, pulmonary delivery of the present compounds (or derivatives thereof) is contemplated. The compounds (or derivative) are delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of this include Adjei et al. (Pharmaceutical Research, 7: 565-569 (1990); Adjei et al., International Journal of Pharmaceutics, 63: 135-144 (1990) (leuprolide

acetate); Braquet et al. , Journal of Cardiovascular Pharmacology, 13 (suppl. 5): 143-146 (1989) (endothelin-1) ; Hubbard et al. , Annals of Internal Medicine, Vol. III, pp. 206-212 (1989) (al-antitrypsin) ; Smith et al. , J. Clin. Invest. 84: 1145-1146 (1989) (a-l-proteinase) ; Oswein et al. ,"Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (1990) (recombinant human growth hormone); Debs et al. , J. Immunol. 140: 3482-3488 (1988) (interferon-y and tumor necrosis factor alpha); Platz et al., U. S. Patent No. 5,284, 656 (granulocyte colony stimulating factor) ). A method and composition for pulmonary delivery of drugs for systemic effect is described in U. S.

Patent No. 5,451, 569.

Contemplated for use in the practice of this invention are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art. With regard to construction of the delivery device, any form of aerosolization known in the art, including but not limited to spray bottles, nebulization, atomization or pump aerosolization of a liquid formulation, and aerosolization of a dry powder formulation, can be used in the practice of the invention.

All such devices require the use of formulations suitable for the dispensing of compounds of the present invention. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated. Chemically modified compounds may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.

Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise the compound of the present invention (or derivative) dissolved in water. The formulation may also include a buffer and a simple sugar (e. g., for stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compounds caused by atomization of the solution in forming the aerosol.

Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the compounds (or derivative) suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon,

or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1, 1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.

The liquid aerosol formulations contain the compounds of the present invention and a dispersing agent in a physiologically acceptable diluent. The dry powder aerosol formulations of the present invention consist of a finely divided solid form of the compounds of the present invention and a dispersing agent. With either the liquid or dry powder aerosol formulation, the formulation must be aerosolized. That is, it must be broken down into liquid or solid particles in order to ensure that the aerosolized dose actually reaches the mucous membranes of the nasal passages or the lung. The term"aerosol particle"is used herein to describe the liquid or solid particle suitable for nasal or pulmonary administration, i. e. , that will reach the mucous membranes. Other considerations, such as construction of the delivery device, additional components in the formulation, and particle characteristics are important.

These aspects of nasal or pulmonary administration of a drug are well known in the art, and manipulation of formulations, aerosolization means and construction of a delivery device require at most routine experimentation by one of ordinary skill in the art.

Often, the aerosolization of a liquid or a dry powder formulation for inhalation into the lung will require a propellant. The propellant may be any propellant generally used in the art. Specific nonlimiting examples of such useful propellants are a chlorofluorocarbon, a hydrofluorocarbon, a hydochlorofluorocarbon, or a hydrocarbon, including trifluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1, 1,1, 2-tetrafluoroethane, or combinations thereof.

In a specific embodiment, the dosage is administered as needed. One of ordinary skill in the art can readily determine a volume or weight of aerosol corresponding to this dosage based on the concentration of compound in an aerosol formulation of the invention.

The compounds and compositions of the present invention may be combined with other compounds and compositions, known to one of ordinary skill in the art, to treat any of the above described disease states. For example, compounds of the present invention may be administered prior, concurrently, or after administration of another compound. For example, the compounds of the present invention may be used in combination with compounds used in the treatment of AIDS and HIV. A non-comprehensive list of AIDS and HIV drugs are shown in WO 00/42045.

A pharmaceutical composition for parenteral administration contains from about 0. 01 % to about 100% by weight of the active agents of the present invention, based upon 100% weight of total pharmaceutical composition.

Generally, transdermal dosage forms contain from about 0. 01% to about 100% by weight of the active agents, based upon 100% total weight of the dosage.

Synthetic Method Compounds of the present invention may be prepared according to the methods described herein by various synthetic schemes (as shown in the Experimental Section of the application). Alternatively, the compounds may be prepared by any method known to one of ordinary skill in the art.

Examples General. All reactions involving air-sensitive reagents were performed under a nitrogen atmosphere. Reagents were used as received from commercial suppliers unless otherwise noted. 1H NMR data were recorded using the Bruker UltraShield 300 MHz/54mm instrument equipped with Bruker B-ACS60 Auto Sampler or the Varian 300 MHz instrument. Intermediates and final compounds were purified by flash chromatography using one of the following instruments : 1. Biotage 4-channel Quad UV Flash Collector equipped with a Quad 1 Pump Module and the Quad 12/25 Cartridge module. 2. Biotage 12-channel Quad UV Flash Collector equipped with a Quad 3 Pump Module and a Quad 3 Cartridge module. 3. ISCO combi-flash chromatography instrument. LC/MS spectra were obtained using aMicroMass Platform LC (Phenomenx C18 column, 5 micron, 50x4. 6 mm) equipped with a Gilson 215 Liquid Handler. Standard LC/MS conditions is as follows: Formic acid-Standard conditions: % C (Water) 95.0 HP1100 LC Pump Gradient Timetable % D (Acetonitrile) 5.0 % Formic Acid 0.1 The gradient Timetable contains 5 entries which are: Flow (ml/min) 3.500 Stop Time (mins) 4.4 Time A% B% C% D% Flow Pressure Min Pressure (bar) 0 0.00 0.0 0.0 95.0 5.0 3.500 400 Max Pressure (bar) 400 3.50 0.0 0.0 0.0 100.0 3.500 400 Oven Temperature Left (°C) 25.0 4. 30 0.0 0.0 0.0 100.0 3.500 400 Oven Temperature Right (°C) 25.0 4.40 0.0 0.0 95.0 5.0 4.000 400 5.00 0.0 0.0 95.0 5.0 4.000 400

LC-MS data were acquired using the"Formic acid-Standard"method unless otherwise noted.

Preparation of 3-aryloxybenzaldehyde Scheme 1 H-, aB OH H I B. OH 0 OH Cu (OAc) 2, Pyrdine, 4A Mol. sieves 0 CICH2CH2CI, rt, 16-18h. 0 je"' HA HO 3-Formyl phenyl boronic acid (1.5 equiv) and the appropriate phenol (1.0 equiv) was mixed with copper acetate (1.0 equiv), 4A molecular sieves and pyridine (5.0 equiv) in dichloroethane (0.1 M solution) and the resulting mixture was stirred vigorously for 18 h at ambient atmosphere and room temperature. The reaction mixture was filtered and concentrated. Column chromatography of the residue using hexane/ethyl acetate provided the corresponding 3-aryloxybenzaldehyde 1.

Table 1 No R I 1-1 3- (2-Methoxy-phenoxy)-benzaldehyde os 1-2 3-(2-Isopropyl-phenoxy)-benzaldehyde tJ ? 1-3 3- (2-Isopropoxy-phenoxy)-benzaldehyde I 1-4 2- (3-Fonryl-phenoxy)-benzoic acid methyl ester 0 01 kan, 1-5 3-(2-Methoxy-4-propenyl-phenoxy)-benzaldehyde ? RS ou 1-6 3- (2-Chloro-phenoxy)-benzaldehyde ci 1-7 3- sifanyl-phenoxy)-ben7aldehyde tJp s 1-8 3-(2-Trifluoromethyl-phenoxy)-belv7aldehyde Ji3 F F F 1-9 3-(2, 6-Dimethyl-phenoxy)-benzaldehyde 2z43 / 1-10 3- (2, 6-Dimethoxy-phenoxy)-benzaldehyde o 1-11 3- (2-tert-Butyl-phenoxy)-benzaldehyde 1-12 3-(2-Trifluoromethoxy-phenoxy)-benzaldehyde dJ ; 3 OF F 1-13 3- (2-Benzyloxy-phenoxy)-benzaldehyde, XI No R zu 1-14 3- (2-Cyclopentyloxy-phenoxy)-benzaldehyde xi 1-15 3- (2-Bromo-phenoxy)-benzaldehyde Br 1-16 3- (2-Ethyl-phenoxy)-benzaldehyde fT' 1-17 3-(4-Fluoro-2-methoxy-phenoxy)-benzaldehyde xJv os 1. 18 2- (3-Formyl-phenoxy)-benzonitrile CN 1-19 3- (2-Isoxazol-5-yl-phenoxy)-benzaldehyde N- I 1-20 3- (2-Allyloxy-phenoxy)-benzaldehyde 1-21 3-(2-Methoxy-5-methyl-phenoxy)-3 benzaldehyde CN 1-22 4- (3-Formyl-phenoxy)-3-methoxy-benzonitrile ou Preparation of 3-aryloxy-benzyl amines Scheme 2

3-aryloxy benzaldehyde 1 was mixed with an approriate amine (1.2 eq. ) and sodium triacetoxy borohydride (1.2 eq. ) in dichloroethane containing acetic acid (1%) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2C12 and washed with saturated aqueous sodium bicarbonate solution and brine and dried over sodium sulfate. Column chromatography provided the corresponding 3- aryloxy-benzyl amine 2.

2-1: 8- [3- (2-Methoxy-phenoxy)-benzyl]-l-phenyl-1, 3,8-triaza-spiro [4.5] decan-4-one 2-2: 8- [3- (2-Isopropyl-phenoxy)-benzyl]-l-phenyl-1, 3, 8-triaza-spiro [4.5] decan-4-one 2-3: 1-11- [3- (2-Isopropyl-phenoxy)-benzyl]-piperidin-4-yll-1, 3-dihydro-benzoimidazo1-2- one 2-4: 1- {1- [3- (2-Isopropoxy-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro-benzoimidazol-2- one 2-5: 8- [3- (2-Isopropoxy-phenoxy)-benzyl]-l-phenyl-1, 3,8-triaza-spiro [4.5] decan-4-one 2-6: 2- {3- [4- (2-Oxo-2, 3-dihydro-benzoimidazol-1-yl)-piperidin-1-ylmethyl]-phenoxy} - benzoic acid methyl ester 2-7: 2- [3- (4-Oxo-l-phenyl-1, 3,8-triaza-spiro [4.5] dec-8-ylmethyl)-phenoxy]-benzoic acid methyl ester 2-8: 1- {1- [3- (2-Methoxy-4-propenyl-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro- benzoimidazol-2-one 2-9: 8- [3- (2-Methoxy-4-propenyl-phenoxy)-benzyl]-l-phenyl-1, 3,8-triaza-spiro [4.5] decan-4- one 2-10: 1- {1- [3- (2-Chloro-phenoxy)-benzyl]-piperidm-4-yl}-1, 3-dihydro-benzoimidazol-2-one 2-11: 8- [3- (2-Chloro-phenoxy)-benzyl]-l-phenyl-1, 3, 8-triaza-spiro [4.5] decan-4-one 2-12: 8- [3- (2-Methylsulfanyl-phenoxy)-benzyl]-1-phenyl-1, 3,8-triaza-spiro [4.5] decan-4-one 2-13: 1- {1- [3- (2-Methylsulfanyl-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro- benzoimidazol-2-one 2-14: 1-Phenyl-8- [3- (2-trifluoromethyl-phenoxy)-benzyl]-1, 3,8-triaza-spiro [4.5] decan-4-one

2-15: 1- 1- [3- (2-Trifluorometliyl-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro- benzoimidazol-2-one 2-16: 1- 1- [3- (2, 6-Dimethyl-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro-benzoimidazol-2- one 2-17: 1- {1-[3-(2,6-Dimethoxy-phenoxy)-benzyl]-piperidin-4-yl}-1,3-di hydro-benzoimidazol- 2-one 2-18: 8- [3- (2, 6-Dimethoxy-phenoxy)-benzyl]-l-phenyl-1, 3,8-triaza-spiro [4.5] decan-4-one 2-19: 1-11- [3- (2-tert-Butyl-phenoxy)-benzyl]-piperidin-4-ylf-1, 3-dihydro-benzoimidazol-2- one 2-20: 1-Phenyl-8- [3- (2-trifluoromethoxy-phenoxy)-benzyl]-1, 3,8-triaza-spiro [4.5] decan-4- one 2-21: 1- {1- [3- (2-Trifluoromethoxy-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro- benzoimidazol-2-one 2-22: 8-[3-(2-Benzyloxy-phenoxy)-benzyl]-1-phenyl-1, 3,8-triaza-spiro [4.5] decan-4-one 2-23: 1- {1- [3- (2-Benzyloxy-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro-benzoimidazol-2- one 2-24: 8- [3- (2-Cyclopentyloxy-phenoxy)-benzyl]-1-phenyl-1, 3,8-triaza-spiro [4.5] decan-4-one 2-25: 1- {1- [3- (2-Cyclopentyloxy-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro- benzoimidazol-2-one 2-26: 8- [3- (2-Bromo-phenoxy)-benzyl]-1-phenyl-1, 3,8-triaza-spiro [4.5] decan-4-one 2-27: 1- {1- [3- (2-Bromo-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro-benzoimidazol-2-one 2-28 : 8- [3- (2-Ethyl-phenoxy)-benzyl]-1-phenyl-1, 3,8-triaza-spiro [4.5] decan-4-one 2-29: 1- {1- [3- (2-Ethyl-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro-benzoimidazol-2-one 2-30 : 8- [3- (4-Fluoro-2-methoxy-phenoxy)-benzyl]-1-phenyl-1, 3,8-triaza-spiro [4.5] decan-4- one 2-31: 1- {l- [3- (4-Fluoro-2-methoxy-phenoxy)-benzyl]-piperidin-4-yll-1, 3-dihydro- benzoimidazol-2-one 2-32 : 2- [3- (4-Oxo-l-phenyl-1, 3,8-triaza-spiro [4.5] dec-8-ylmethyl)-phenoxy]-benzonitrile 2-33 : 2- {3- [4- (2-Oxo-2, 3-dihydro-benzoimidazol-1-yl)-piperidin-1-ylmethyl]-phenoxy} - benzonitrile 2-34: 8-[3-(2-Isoxazol-5-yl-phenoxy)-benzyl]-1-phenyl-1, 3,8-triaza-spiro [4.5] decan-4-one 2-35: 1-11- [3- (2-Isoxazol-5-yl-phenoxy)-benzyl]-piperidin-4-yll-1, 3-dihydro-benzoimidazol- 2-one 2-36: 8- [3- (2-Allyloxy-phenoxy)-benzyl]-l-phenyl-1, 3,8-triaza-spiro [4.5] decan-4-one 2-37: 1- {1- [3- (2-Allyloxy-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro-benzoimidazol-2- one 2-38: 3-Methoxy-4- [3- (4-oxo-l-phenyl-1, 3,8-triaza-spiro [4.5] dec-8-ylmethyl)-phenoxy]- benzonitrile 2-39: 3-Methoxy-4-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-pip eridin-1-ylmethyl]- phenoxy}-benzonitrile 2-40: 8- (3-Phenoxy-benzyl)-1-phenyl-1, 3,8-triaza-spiro [4.5] decan-4-one 2-41: 1- [1- (3-Phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro-benzoimidazol-2-one 2-42: 1-11- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yll-1, 3-dihydro-benzoimidazol-2- one Table 2 R1 Retentioll time (min) z 0 \ I H'VN_ 2t HM$ 1. 74 444 6 HN--/- 2-2-Z-L 2. 01 456. 17 T 6 0 2-3 Y -C-1. 97 442. 18 0 JJ HN\- 2-4 1. 81 458. 12 Y 0 O-C d 0 2-5-p N 1. 85 472. 17 Y 6 0ici 2-6'I I HNk N-cN-1. 65 458. 08 0 d a ou Oz C 2-7-1 1. 76 472. 1 ou 0 0II ow zu 2-8 hX HN N~CN$-1 95 470. 12 zea H 2-9 . N 2. 03 484. 1 °s t RI Retention No. R r- M+l time (min) 0 OII 2-10 cl HCNtN$-1 78 434. 06 ci o 2-11'CNC 1. 87 448. 03 ci 0 HNC N- N 2-12 Sr 1. 9 460. 02 vs oit HN 2-13-EÇ HN N<N $- vs HNCSCt4- 2-14 N 1. 96 482. 07 r F 2-15 F HN N<N-1. 9 468. 11 FTF F 2-16 d N-cN--1. 9 428. 14 0 0 2-17 <y-1. 65 460. 04 ou o han 2-18--Yl N 1. 79 474. 05 ' 0 2-19' NN 2. 08 456. 42 R'Retention p time (mm) RUZ 0 2-20 ÇJp HNN-2. 08 498. 02 off F F 2-21 r HN NN. z- 1. 97 484. 48 OF //O HN C,, ct4- 2-22'119 N 2. 16 520. 1 r, o 6 2 23 5 3 HN N<N$-2 08 506. 1 oxo , Pl HN L X N 2-24 On H2f N$-2 498. 08 0 \I o 2-25'T N-C-19 i 0 0 2-26 1. 91 491. 97 Br Bu O 2-27 Ty"'C'1. 83 479. 94 Ber d N- 2-28 2. 03 442. 11 -yy b 2-29. -1. 99 428. 13 R'Retention finie (min) Ru F H0 230 EJv HN$ 1. 83 462. 05 C, F 0 o 2-31'Y L'\-/'1. 76 448. 04 \L7 0 os 2-32 T-J 1. 76 439. 08 con 6 CN -LP 0 f ! l 2-33 T. - 1. 67 425. 09 ce 0 I Hr (--v ! r'. 7 N 'N 1. 85 481. 05 Q N-6 0 2-35 1 /'1. 79 467. 27 vs N HN- N 2, 36 1. 93 470. 05 0 0 2-37 T'1. 88 456. 06 xi 0 CN H N 2-38 1. 78 469. 05 O, Con 2-39 L/Lj'1. 7 455. 06 ou C R1 Retention No. R eS.. » 1 R2 firm (iiin) pT tm' ! e (mm) 0 0 2-40 MJ 3 HQNtNy-2. 95 414. 22 0 21 C-2. 84 400. 1 zu xi o HN=N_ 1. 6 430 oX C

Preparation of 3-aryloxy- (4'acylamino)-benzyl piperidine Scheme 3 ) tLR R'1. Na (OAc) 3BH, 1% AcOH H2N ° 1 ClCH2CH2Cl, rt, 18h tN + BocHN 2. 4 M HCI/Dioxane, 2h. 2HCI 9NH RC02H, EDCI, HOBt NMM, DMF (or THFor CH2CI2) H rt, 18h. N (N ( 0 OR ° A, Nsoo < 1 RCOCI, DIEA, CH2C12 rt, 18h.

3-Aryloxy benzaldehyde 1 (1.2 eq) is mixed with 4N-Boc-amino-piperidine (1 eq.) and sodium triacetoxy borohydride (1.5 eq. ) in dichloroethane containing acetic acid (1%) and the resulting mixture is stirred at room temperature overnight. The reaction mixture is diluted with CH2C12 and washed with saturated aqueous sodium bicarbonate solution and brine and dried over sodium sulfate. Column chromatography provides the corresponding N- Boc-benzyl amine. Removal of the Boc protecting group with 4M HC1/dioxane solution provides as the dihydrochloride salt.

The dihydrochloride salt (1 eq) was treated with the appropriate carboxylic acid (1.2 eq) in the presence of EDCI (1.2 eq), HOBt and N-methyl morpholine (4 eq) in DMF (or THF or CH2C12) for 16-18h at room temperature. The solvent was evaporated and the residue was taken up in CH2C12 (or ethyl acetate) and washed with saturated aqueous sodium bicarbonate solution and brine and dried over sodium sulfate. Column chromatography provides the corresponding amide 3. Alternatively, the dihydrochloride salt was treated with the appropriate acid chloride (1.2 eq) in the presence of DIEA (4 eq) in CH2C12 for 18h at room temperature. Workup as above and chromatography provides the desired amide 3.

3-1: N-[1-(3-Phenoxy-benzyl)-piperidin-4-yl]-propionamide 3-2: N- [1- (3-Phenoxy-benzyl)-piperidin-4-yl]-2-phenyl-acetamide 3-3: N-[1-(3-Phenoxy-benzyl)-piperidin-4-yl]-benzamide 3-4: N-[1-(3-Phenoxy-benzyl)-piperidin-4-yl]-3-phenyl-propionamid e 3-5: 2- (2-Bromo-phenyl)-N- [ 1- (3-phenoxy-benzyl)-piperidin-4-yl]-acetamide 3-6: 2- (3, 4-Dimethoxy-phenyl)-N- [l- (3-phenoxy-benzyl)-piperidin-4-yl]-acetamide 3-7: 2-(3-Dimethoxy-phenyl)-N-[1-(3-phenoxy-benzyl)-piperidin-4-y l]-acetamide 3-8: N- [1- (3-Phenoxy-benzyl)-piperidin-4-yl]-2-thiophen-2-yl-acetamide 3-9: 2-Phenoxy-N- [1- (3-phenoxy-benzyl)-piperidin-4-yl]-acetamide 3-10: 3-Cyclopentyl-N-[1-(3-phenoxy-benzyl)-piperidin-4-yl]-propio namide 3-11: 3,5, 5-Trimethyl-hexanoic acid [1- (3-phenoxy-benzyl)-piperidin-4-yl]-amide 3-12: 2-Cyclopentyl-N- [1- (3-phenoxy-benzyl)-piperidin-4-yl]-acetamide 3-13: N-[1-(3-Phenoxy-benzyl)-piperidin-4-yl]-2-(4-phenoxymethyl-p henyl)-acetamide 3-14: N- [1- (3-Phenoxy-benzyl)-piperidin-4-yl]-2, 2-diphenyl-acetamide 3-15: 2-(1H-Indol-3-yl)-2-oxo-N-[1-(3-phenoxy-benzyl)-piperidin-4- yl]-acetamide 3-16: 2- (4-Chloro-phenyl)-N- [l- (3-phenoxy-benzyl)-piperidin-4-yl]-acetamide 3-17: N- [l- (3-Phenoxy-benzyl)-piperidin-4-yl]-2- (3-trifluoromethyl-phenyl)-acetamide 3-18: 2- (3, 4-Dichloro-phenyl)-N- [1- (3-phenoxy-benzyl)-piperidin-4-yl]-acetamide 3-19: 2- (2-Methyl-lH-indol-3-yl)-N- [1- (3-phenoxy-benzyl)-piperidin-4-yl]-acetamide 3-20: N-[1-(3-Phenoxy-benzyl)-piperidin-4-yl]-2-o-tolyl-acetamide 3-21: 2- (2, 6-Dichloro-phenyl)-N- {l- [3- (2-methoxy-phenoxy)-benzyl]-piperidm-4-yl}- acetamide 3-22: 2-(4-Fluoro-phenyl)-N-{1-[3-(2-methoxy-phenoxy)-benzyl]-pipe ridin-4-yl}-acetamide 3-23: 4- {1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylcarbamoyl}-3, 4-dihydro-1 H- isoquinoline-2-carboxylic acid tert-butyl ester 3-24: 1- (4-Chloro-phenyl)-cyclopentanecarboxylic acid {l- [3- (2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-amide 3-25: N-{1-[3-(2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-(3-met hyl-isoxazol-5-yl)- acetamide 3-26: N- {l- [3- (2-Methoxy-phenoxy)-benzyl]-piperidm-4-yl}-2, 2-diphenyl-acetamide 3-27: N- {1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2- (2-methyl-lH-indol-3-yl)- acetamide 3-28: N- l- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-o-tolyl-acetam ide 3-29: 2-Phenyl-N- {1- [3- (2-trifluoromethoxy-phenoxy)-benzyl]-piperidin-4-yl}-acetami de 3-30: N-f 1- [3- (2-Chloro-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl-acetamid e 3-31 : N-{1-[3-(2-Benzyloxy-phenoxy)-benzyl]-piperidin-4-yl}-2-phen yl-acetamide 3-32: N- {l- [3- (4-Fluoro-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl-acetamid e 3-33: 2- (4-Chloro-phenyl)-N- {1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}- isobutyramide 3-34: 4-11- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylcarbamoy11-4-pheny l-piperidine- 1-carboxylic acid tert-butyl ester 3-35 : 1-Phenyl-cyclopentanecarboxylic acid {l- [3- (2-methoxy-phenoxy)-benzyl]-piperidin- 4-yl}-amide 3-36: 2-(2-Bromo-phenyl)-N-{1-[3-(2-methoxy-phenoxy)-benzyl]-piper idin-4-yl}-acetamide 3-37: N-{1-[3-(4-Cyano-2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}- 2-phenyl-acetamide 3-3 8 : N- 1- [3- (2-Cyclopentyloxy-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl- acetamide 3-39 : : N- {1-[3-(2-Bromo-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl-ace tamide 3-40: N- 1- [3- (2-Ethyl-phenoxy)-benzyl]-piperidin-4-yl}-2-pheenyl-acetamid e

3-41: N- {1- [3- (4-Fluoro-2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-pheny l-acetamide 3-42: N- {1- [3- (2-Cyano-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl-acetamide 3-43: N-{1-[3-(2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2R-pheny l-propionamide 3-44: N-{1-[3-(2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl -butyramide 3-45: 2- (4-Isobutyl-phenyl)-N- 1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}- propionamide 3-46: N- 1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl-propion amide 3-47: N- {l- [3- (2-Isoxazol-5-yl-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl-a cetamide 3-48: N- {1- [3- (2-Allyloxy-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl-acetam ide 3-49: N- {1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl-propion amide 3-50: 1- (4-Chloro-phenyl)-cyclohexanecarboxylic acid {l- [3- (2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-amide 3-51: 1-p-Tolyl-cyclopentanecarboxylic acid {l- [3- (2-methoxy-phenoxy)-benzyl]-piperidin- 4-yl}-amide 3-52: 1-(2-Fluoro-phenyl)-cyclopentanecarboxylic acid {l- [3- (2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-amide 3-53: 2- (4-Chloro-phenyl)-N- {1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}- propionamide 3-54: 1-(2, 4-Dichloro-phenyl) -cyclopropanecarboxylic acid {l- [3- (2-methoxy-phenoxy)- benzyl]-piperidin-4-yl}-amide 3-55: 3-Oxo-indan-1-carboxylic acid {l- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}- amide 3-56: N- {l- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2- (3-methyl-benzo [b] thiophen- 2-yl)-acetamide 3-57: 2-Benzo [b] thiophen-3-yl-N- {l- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}- acetamide 3-58: N- {l- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2- (5-methyl-2-phenyl-oxazol- 4-yl)-acetamide 3-59: 1- (4-Methoxy-phenyl)-cyclopentanecarboxylic acid {1-[3-(2-methoxy-phenoxy)- benzyl]-piperidin-4-yl}-amide 3-60: 1-(2-Chloro-6-fluoro-phenyl)-cyclopentanecarboxylic acid {1-[3-(2-methoxy- phenoxy)-benzyl]-piperidin-4-yl}-amide 3-61: 1- (4-Fluoro-phenyl)-cyclopentanecarboxylic acid {1-[3-(2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-amide 3-62: 1-Phenyl-cyclopropanecarboxylic acid {l- [3- (2-methoxy-phenoxy)-benzyl]-piperidin- 4-yl}-amide 3-63: N-{1-[3-(2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-thioph en-3-yl-acetamide 3-64: 1-Phenyl-cyclopentanecarboxylic acid {l- [3- (2-chloro-phenoxy)-benzyl]-piperidin-4- yl}-amide 3-65: 4-{1-[3-(2-Chloro-phenoxy)-benzyl]-piperidin-4-ylcarbamoyl}- 4-phenyl-piperidine-1- carboxylic acid tert-butyl ester 3-66: 1- (5-Methyl-2-phenyl-oxazol-4-yl)-cyclopentanecarboxylic acid {l- [3- (2-methoxy- phenoxy)-benzyl]-piperidin-4-yl}-amide 3-67: 1-Thiophen-2-yl-cyclopentanecarboxylic acid {l- [3- (2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-amide 3-68: N-f 1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2- (5-methyl-1-phenyl-1H- pyrazol-3-yl)-acetamide 3-69: 4-Phenyl-tetrahydro-pyran-4-carboxylic acid {1- [3- (2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-amide

3-70: N-{1-[3-(2-Methoxy-5-methyl-phenoxy)-benzyl]-piperidin-4-yl} -2-phenyl-acetamide 3-71: 3- 1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylcarbamoyl}-3-pheny l-pyrrolidine- 1-carboxylic acid tert-butyl ester 3-72: 1-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-cyclopentanecarboxylic acid f 1- [3- (2- methoxy-phenoxy)-benzyl]-piperidin-4-yl}-amide 3-73: 1-Benzo [b] thiophen-3-yl-cyclopentanecarboxylic acid {1-[3-(2-methoxy-phenoxy)- benzyl]-piperidin-4-yl}-amide 3-74: 2- [5- (4-Chloro-benzoyl)-thiophen-3-yl]-N- 1- [3- (2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-acetamide 3-75: N- 1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-pyridin-3-yl-a cetamide 3-76: 2,2, 2-Trifluoro-N- ( 1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-ylcarbamoyl}- phenyl-methyl)-acetamide 3-77: 2-Oxo-1, 2,3, 4-tetrahydro-quinoline-4-carboxylic acid {l- [3- (2-methoxy-phenoxy)- benzyl]-piperidin-4-yl}-amide 3-78: 1- (4-Chloro-phenyl)-cyclopropanecarboxylic acid {l- [3- (2-methoxy-phenoxy)-bcnzyl]- piperidin-4-yl}-amide 3-79: 1- (4-Methoxy-phenyl)-cyclopropanecarboxylic acid {1-[3-(2-methoxy-phenoxy)- benzyl]-piperidin-4-yl}-amide 3-80: N- {l- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-thiophen-3-yl- isobutyramide 3-81: N- 1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2- (2-metliyl-lH-indol-3-yl)- isobutyramide 3-82: 2- (lH-hidol-3-yl)-N-11- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-ylf- isobutyramide 3: 83: N- {1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl-acetami de Table 3 No. R Rl Retention M+1 time (min) l 3-1 2. 49 339 w 3-2 2. 68 401 3-3 zu 2. 64 387 3-4 zu 1. 6 415 ;' 3-5 ttC BX 1. 64 479 / 3-6 1. 66 461 0 3-7 1. 74 431 r "s 3-8 w I 1. 6 407 3-9 1. 74 417 3-10 z S 1. 83 407

Retention M+1 No. R Ri.,.. M+l time (min) 3-11 1. 97 423 3-12 1. 71 393 f'1 3-13 ? t°4 2. 05 551 zu 3-14-ZLc) 2. 03 477 315, < 1. 83 454 H 3-16 1. 87 435 3-17 1. 85 469 F-f-F EDCI 3-18 1. 9 469 3-19 1. 76 454 H 3-20 > 1. 73 415

No. Retention.., time (min) cri 3- 1 -21 3-22 1. 78 449 0, F i o I 3-22-t < 1. 99 572 0,--96 3-24-,, JP 2. 19 519 0, 1. 61 436 -25 ni I I i 3-26-zz 9 < 2. 1 507 i 3-27 1. 7 484 H \ 3-28 1. 69 445 0, 3-29 F F 2. 05 485 FI 3 30-t < 1. 92 435 Cl

No. R R Retention M+1 No. R Ri.,.. M+l time (min) 3-31-Y '0 2. 1 507 0--- 3-32 1. 76 419 s 3-33 1. 9 493 0, ci N 3 34- ; 2. 02 600 if ri 3-35--"-y 2. 02 485 0 Br 3-36--Ip-ii-, b 1. 75 510 0, 3-37 . I 1. 66 456 xi 3-38 M 1 2. 01 485 0-0 3-39-x 13 1. 86 479 sr 3-40 1. 93 429

No. R R, Retention M+1 No. R Ri.... M+l time (min) F 3-41 1. 76 449 o 3-42 1. 67 426 ZON 3-43 1. 73 445 0 3 44 x 3 1. 89 459 0 ' fT) JL 3-45'- 'L I 2. 09 501 3-46 x % 1. 72 445 o, - JJ), T-, . , 3-47 x 1. 83 468 N N 3-48 1. 88 457 0, 3-49 1. 83 445 3-50 43 cl 2. 24 534 cl

No. R Ru Retention time (min) 3-51 2. 11 499 o, i 3-52 9 % 1. 99 503 3-53't'c. 1-96 480 0, ci ci 3-54-'r'Y 2. 09 526 o rT) 3-55'hr"C 1. 55 471 s rj' /i s 3-57-x43 X 1 77 487 'W. 3-58''r'0'1. 72 512 3-59 1. 92 515 O O rT) c. 3-60-R-% 1. 99 538

- Retention-., No. R Ri.,,.. M+l time (mm) 3-61 1. 97 503 0 3-62 1. 78 457 3-63 1. 65 437 0, s 3-64-tt 9-< 1. 91 490 ci 0 ci 2. 27 605 a 3-66 2. 16 566 ou 3-67 1. 98 491 3-67 N 3-68-zt 9 SNç 1. 83 512 3-69-xt 9 < 1. 79 501 o,

T. T r< Retention.,, No. R Ri.... M+l time (min) 3-70 1. 64 445 a zizi 3-71-'. 2. 01 586 if 3-72-ttp WNw 1. 8 565 0 i 3-73-tt 9 < 1. 91 541 ou -IL 1. 99 561 3-74 3-75-tt 9 3t< 1. 1 432 0_' !'N F O 3-76 p 1. 82 542 3-77 1. 35 486 3-78'z o 1. 9 492 0, ci n V 3-79 1. 84 487 o o No. R R Retention M+1 time (min) time (mm) 3-80-tp'% ? 1. 75 465 0 3-81 1. 83 512 0 nu 3-82 xtp'< 1. 81 498 0_ N 3-83-x t<1 1. 65 431 O

Scheme 4 Boc H N H 4M N-0 neo (9-0-N, _, aop HCI/Dioxane-61-or Na 3-23 4 0 3-23 4 oll, Scheme 5 Boc H N N L n , ql n In i I FiCI/Dioxane /O N \ R rt, 2h. R 5 CH3CH2SO2CI, DIEAS/CH3CH2Br, DIEA CH2CI2, rt, 16h. CH2CI2, rt, 16h. '°/ O=S Non H N eNJaOJSR ¢ CN/OJ 3 /O N 6 R 7 4: 1, 2,3, 4-Tetrahydro-isoquinoline-4-carboxylic acid f 1- [3- (2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-amide

3-23 (0. 12 g, 0.17 mmol) was treated with 4M HCl/dioxane for 2h at room temperature. The solvent was evaporated and the residue was triturated with ether and filtered to give the dihydrochloride salt 4 (95 mg, 94%). 1H NMR is consistent with assigned structure. LC/MS : UV Retention time: 1.33 min, M+1 = 472.

5-1: 4-Phenyl-piperidine-4-carboxylic acid {1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4- yl}-amide 3-34 (0.4 g, 0.67 mmol) was treated with 4M HCl/dioxane for 2h at room temperature. The solvent was evaporated and the residue was triturated with ether and filtered to give the dihydrochloride salt 5-1 (300 mg, 90%). 1H NMR is consistent with assigned structure. LC/MS: UV Retention time: 1.36 min, M+1 = 500.

5-2 : 3-Phenyl-pyrrolidine-3-carboxylic acid {1-[3-(2-methoxy-phenoxy)-benzyl]-piperidin- 4-yl}-amide 3-72 was treated with 4M HCl/dioxane for 2h at room temperature. The solvent was evaporated and the residue was triturated with ether and filtered to give the dihydrochloride

salt 5-2. 1H NMR is consistent with assigned structure. LC/MS : UV Retention time: 1.19 min, M+1 = 486.

5-3: 4-Phenyl-piperidine-4-carboxylic acid {1- [3- (2-chloro-phenoxy)-benzyl]-piperidin-4- yl}-amide

3-65 was treated with 4M HCl/dioxane for 2h at room temperature. The solvent was evaporated and the residue was triturated with ether and filtered to give the dihydrochloride salt 5-3. 1H NMR is consistent with assigned structure. LC/MS: UV Retention time: 1.42 min, M+1 = 505.

5-4: 4-Phenyl-piperidine-4-carboxylic acid {l- [3- (2-methoxy-5-methyl-phenoxy)-benzyl]- piperidin-4-yl}-amide

The amine was treated with 4M HCI/dioxane for 2h at room temperature. The solvent was evaporated and the residue was triturated with ether and filtered to give the dihydrochloride salt 5-4. 1H NMR is consistent with assigned structure. LC/MS : UV Retention time: 1.18 min, M+1 = 514.

6-1: 1-Ethanesulfonyl-4-phenyl-piperidine-4-carboxylic acid f 1- [3- (2-methoxy-phenoxy)- benzyl]-piperidin-4-yl}-amide

Compound 5-1 (0.225, 0.4 mmol) was mixed with DIEA (0.31 g, 2.4 mmol) and ethyl sulfonyl chloride (0.062 g, 0. 48 mmol) in CH2C12 and the resulting solution was stirred at room temperature for 18h. The reaction mixture is diluted with CH2Cl2 and washed with saturated aqueous sodium bicarbonate solution and brine and dried over sodium sulfate.

Column chromatography (5-10% MeOH/CH2Cl2) provided the N-sulfonyl ethyl analog 6-1 (0.16 g, 68%). 1H NMR is consistent with assigned structure. LC/MS: UV Retention time: 1. 75 min, M+1 = 592.

6-2: 1-Ethanesulfonyl-3-phenyl-pyrrolidine-3-carboxylic acid {l- [3- (2-methoxy-phenoxy)- benzyl]-piperidin-4-yl}-amide Compound 5-2 was mixed with DIEA and ethyl sulfonyl chloride in CH2C12 and the resulting solution was stirred at room temperature for 18h. The reaction mixture was diluted with CH2C12 and washed with saturated aqueous sodium bicarbonate solution and brine and dried over sodium sulfate. Column chromatography provided the N-sulfonyl ethyl analog 6- 2. 1H NMR is consistent with assigned structure. LC/MS : UV Retention time: 1.80 min, M+1 = 578.

7-1: 1-Ethyl-4-phenyl-piperidine-4-carboxylic acid {l- [3- (2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-amide

Compound 5-1 was mixed with DIEA and ethyl bromide in CH2C12 and the resulting solution was stirred at room temperature for 18h. Standard work-up (as above) and column chromatography provided the corresponding N-ethyl analog 7-1. 1H NMR is consistent with assigned structure. LC/MS: W Retention time: 1.39 min, M+1 = 528.

7-2: 1-Ethyl-3-phenyl-pyrrolidine-3-carboxylic acid {l- [3- (2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-amide Compound 5-2 was mixed with DIEA and ethyl bromide in CH2C12 and the resulting solution was stirred at room temperature for 18h. Standard work-up (as above) and column chromatography provided the corresponding N-ethyl analog 7-2. 1H NMR is consistent with assigned structure. LC/MS: UV Retention time: 1.29 min, M+1 = 514.

Preparation of phenyl-piperidine-4-carboxylic acid {1- [3-phenoxy-benzyl]-piperidin-4-yl}- amide Scheme 6: Boc Boc + Cl--L-f cl NaH, 0 OC 10 N NAOH, Ethanol OH N then 60 OC 78 OC R- Boc Boc 2 HCI N +H2N_o EDCI, HOBT H OU N \ I \ I THF, NMO r I I R1 R1 RAZZ H 1 H N. 2 HCI 4M HCI/Dioxane H 8 R1 ruz 1. R3Br TEA, CH2c 2. 4N HCI/ Dioxan/ 0 o N 2 hui R2 eOH ° CN l3so) 43 4 2 H Cl 8 Ri 3 8 R R 8

Substituted 4-cyano-piperidine-l-carboxylic acid tert-butyl ester Substituted acetonitrile (1 mmol) was added along with bis- (2-chloro-ethyl)-carbamic acid tert-butyl ester (1.0 mmol) in DMF and cooled to 0 °C. Sodium hydride (3.0 mmol) was added to the mixture portionwise over-20 min. The reaction was allowed to warm to room temperature and then heated to 60 °C for 16h. The reaction was quenched by addition to ice water and the aqueous phase was extracted 3x EtOAc. The organics were collected together and washed 2 x water, lx brine and dried over MgS04, filtered and concentrated down. The product was purified by flash chromatography with 100% EtOAc to give the substituted 4- cyano-piperidine-l-carboxylic acid tert-butyl ester. 1H NMR data is consistent with the assigned structure.

Substituted 4-piperidine-1, 4-dicarboxylic acid mono-tert-butyl ester

Substituted 4-cyanopiperidine-1-carboxylic acid tert-butyl ester was dissolved in ethanol and a ION solution of NaOH was added. The reaction mixture was heated for 24h at 60 °C. The ethanol was removed in vacuo and the basic solution was washed with EtOAc and the aqueous layer was acidified with conc. HC1 and extracted 3x EtOAc. The organics were collected together and dried over MgS04, filtered and concentrated down. The product was purified by flash chromatography to give the substituted 4-piperidine-1, 4-dicarboxylic acid mono-tert-butyl ester. 1H NMR data is consistent with the assigned structure.

Substituted 4-piperidine-4-carboxylic acid {l- [3- (2-chloro-phenoxy)-benzyl]-piperidin-4-yl}- amide 1- [3- (2-Chloro-phenoxy)-benzyl]-piperdin-4-ylamine (1.0 equ) and the corresponding substituted 4-phenyl-piperidine-1, 4-dicarboxylic acid mono-tert-butyl ester acid (1.05 equ) were mixed with HOBt (1.5 equ. ), EDCI (1.3 equ. ) in THF with N-methyl morpholine (5.0 equ. ). The reaction was allowed to stir at room temperature for 10 h. The reaction was diluted with ethyl acetate and washed with IN HC1, IN NaOH and brine. The organics were dried over Mg2S04, filtered and concentrated down. The product was purified by flash chromatography with 100% EtOAc to give the corresponding N {1- [3- (2-chloro-phenoxy)- benzyl]-piperdin-4-yl} acetamide.

The amine was treated with 4N HCl/dioxane for 2h at room temperature. The solvent was evaporated and the residue was triturated with ether and filtered to give the dihydrochloride salt. 1H NMR is consistent with assigned structure.

8-1: 4-p-Tolyl-piperidine-4-carboxylic acid {l- [3- (2-chloro-phenoxy)-benzyl]-piperidin-4- yl}-amide 8-2: 1-Ethyl-4-p-tolyl-piperidine-4-carboxylic acid {1- [3- (2-chloro-phenoxy)-benzyl]- piperidin-4-yl}-amide 8-3: 2- (4-1- [3- (2-Chloro-phenoxy)-benzyl]-piperidin-4-ylcarbamoyl}-4-p-toly l-piperidin-1- yl) -2-methyl-propionic acid 8-4: 4-(4-Fluoro-phenyl)-piperidine-4-carboxylic acid {1-[3-(2-chloro-phenoxy)-benzyl]- piperidin-4-yl}-amide 8-5: 1-Ethyl-4- (4-fluoro-phenyl)-piperidine-4-carboxylic acid {1- [3- (2-chloro-phenoxy)- benzyl]-piperidin-4-yl}-amide 8-6: 2- [4- 1- [3- (2-Chloro-phenoxy)-benzyl]-piperidin-4-ylcarbamoyl}-4- (4-fluoro-phenyl)- piperidin-1-yl]-2-methyl-propionic acid 8-7: 4- (3-Fluoro-phenyl)-piperidine-4-carboxylic acid {1-[3-(2-chloro-phenoxy)-benzyl]- piperidin-4-yl}-amide 8-8: 1-Ethyl-4-(3-fluoro-phenyl)-piperidine-4-carboxylic acid {l- [3- (2-chloro-phenoxy)- benzyl]-piperidin-4-yl}-amide 8-9: 4-(2-Fluoro-phenyl)-piperidine-4-carboxylic acid {1-[3-(2-chloro-phenoxy)-benzyl]- piperidin-4-yl}-amide 8-10: 1-Ethyl-4-(2-fluoro-phenyl)-piperidine-4-carboxylic acid {l- [3- (2-chloro-phenoxy)- benzyl]-piperidin-4-yl}-amide 8-11: 4-Phenyl-piperidine-4-carboxylic acid {1- [3- (2-chloro-phenoxy)-benzyl]-piperidin-4- yl}-amide 8-12: 1-Ethyl-4-phenyl-piperidine-4-carboxylic acid {1-[3-(2-chloro-phenoxy)-benzyl]- piperidin-4-yl}-amide 8-13: 1-Methanesulfonyl-4-phenyl-piperidine-4-carboxylic acid fl- [3- (2-chloro-phenoxy)- benzyl]-piperidin-4-yl}-amide 8-14: 2- (4- {1- [3- (2-Chloro-phenoxy)-benzyl]-piperidin-4-ylcarbamoyl}-4-phenyl -piperidin- 1-yl)-2-methyl-propionic acid 8-15 : 2- (4- {1- [3- (2-Chloro-phenoxy)-benzyl]-piperidin-4-ylcarbamoyl}-4-phenyl -piperidin- 1-yl)-2-methyl-propionic acid ethyl ester 8-16 : 4- (4-Bromo-phenyl)-piperidine-4-carboxylic acid {1- [3- (2-chloro-phenoxy)-benzyl]- piperidin-4-yl}-amide 8-17 : 4-(4-Bromo-phenyl)-1-ethyl-piperidine-4-carboxylic acid {1-[3-(2-chloro-phenoxy)- benzyl]-piperidin-4-yl}-amide 8-18 : 1-Ethyl-4-thiophen-3-yl-piperidine-4-carboxylic acid {1- [3- (2-chloro-phenoxy)- benzyl]-piperidin-4-yl}-amide 8-19: 4-{1-[3-(2-Chloro-phenoxy)-benzyl]-piperidin-4-ylcarbamoyl}- 4-thiophen-3-yl- piperidine-1-carboxylic acid tert-butyl ester 8-20 : 4'- {1- [3- (2-Chloro-phenoxy)-benzyl]-piperidin-4-ylcarbamoyl}-3', 4', 5', 6'-tetrahydro- 2'H- [3, 4'] bipyridinyl-1'-carboxylic acid tert-butyl ester

8-21: 1-Isobutyl-4-phenyl-piperidine-4-carboxylic acid {l- [3- (2-chloro-phenoxy)-benzyl]- piperidin-4-yl}-amide 8-22: 1-Isopropyl-4-phenyl-piperidine-4-carboxylic acid {1-[3-(2-chloro-phenoxy)-benzyl]- piperidin-4-yl}-amide 8-23: 4-Phenyl-piperidine-1, 4-dicarboxylic acid 4- ({1-[3-(2-chloro-phenoxy)-benzyl]- piperidin-4-yl}-amide) 1-ethylamide 8-24: 4- 1- [3- (2-Chloro-phenoxy)-benzyl]-piperidin-4-ylcarbamoyl}-4-phenyl -piperidine-1- carboxylic acid ethyl ester 8-25: 1- (2-Cyclopentyl-acetyl)-4-phenyl-piperidine-4-carboxylic acid {1-[3-(2-methoxy- phenoxy)-benzyl]-piperidin-4-yl}-amide 8-26: 1- (2-Carbamoyl-ethyl)-4-phenyl-piperidine-4-carboxylic acid {l- [3- (2-methoxy- phenoxy)-benzyl]-piperidin-4-yl}-amide 8-27: 1-Isobutyl-4-phenyl-piperidine-4-carboxylic acid f 1- [3- (2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-amide 8-28: 1-Ethyl-4-phenyl-piperidine-4-carboxylic acid {1-[3-(2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-amide Table 4 No. R Ri R2 Retention time M+1 (min) 8-1 X-C1-H 1. 28 519 8-2-cri 1. 38 547 8-3 ¢ Fs'-C1 4OH 1. 55 605 0 8-4,-C1-H 1. 36 523 F 8-5-cri 1. 41 551 FEZ 8-6 N-ci OH 1. 60 609 8-7 gS-C1-H 1. 32 523 y 8-8-ci 1. 38 551 F 8-9 I '. ;-Cl-H 1. 34 523 F 8-10 N-ci 1. 35 551 F 8-11 gS,--C1-H 1. 31 505 r 8-12-ci 1. 33 533 i 8-13-ci 91 lp 1. 84 597 LJ 8-14-ci OH 1. 43 590 o 8-15 X-Cl o 1. 44 618 zozo BrX-C1-H 1. 48 583 Bu 8-17-ci 1. 38 612 Br No. R Rl R2 Retention time M+1 (min) 8-18-ci 1. 15 539 s 8-19 ¢$,-C1-H 1. 23 510 \1 8-20 ¢>'-C1-H 0. 91 505 N 8-21-ci 1. 44 561 i 8-22-ci 1. 39 547 8-23 ¢ FS--C1 1. 68 576 N 8-24-ci 0 1. 94 577 J 0- 8-25 ¢>a--OMe, C> 1. 98 610 i 8-26 -OMe 9 1. 28 571 1-NH2 8-27 rr' Y" 8-27-ome IN 1. 41 556 i 8-28 I y,. ;-QMe'. . 1. 2 528 r Preparation of 1- (3-phenoxy-benzyl) piperdin-4yl-1, 3-dihydrobenzimidazol-2-one Scheme 7:

NCO RSO2CI with TEA, CH2Cì2 RN1S0 N \ N i i or 14-RC (O) CI with TEA, CH2CI2 Naop p _ __ R or o RBr with CsCO3, DMF, 70°C R 2 9 2 (1.0 equ. ) was added to DMF followed by Cs2CO3 (1.5 equ. ) and the corresponding alkyl bromide (1.5 equ. ) in the case of the alkylation. The reaction was heated to 70 °C for 20h. The reaction mixture was filtered and concentrated down. The residue was partitioned between ether and H2O. The aqueous layer was extracted 3x with ether. The organics were collected together and washed 3x with water and dried over MgS04. The organics were filtered and concentrated down. The products were purified to give the desired products 9 9-1: 1-Ethanesulfonyl-3- [1- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro-benzoimidazol- 2-one 9-2: 1-Ethyl-3- [1- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro-benzoimidazol-2-one 9-3: 1-Ethyl-3-f 1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro- benzoimidazol-2-one 9-4: 1-Isobutyl-3- [1- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro-benzoimidazol-2-one 9-5: 3- {2-Oxo-3- [l- (3-phenoxy-benzyl)-piperidin-4-yl]-2, 3-dihydro-benzoimidazol-1-yl}- propionamide 9-6: 1- (2-Oxo-oxazolidin-5-ylmethyl)-3- [l- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro- benzoimidazol-2-one 9-7: 1- [1- (3-Phenoxy-benzyl)-piperidin-4-yl]-3- (2, 2, 2-trifluoro-ethyl)-1, 3-dihydro- benzoimidazol-2-one 9-8: 1-[2-(1-Methyl-pyrrolidin-2-yl)-ethyl]-3-[1-(3-phenoxy-benzy l)-piperidina4-yl]-1, 3- dihydro-benzoimidazol-2-one 9-9: 1-Phenethyl-3- [1- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro-benzoimidazol-2-one 9-10: 1-Benzyl-3- {1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro- benzoimidazol-2-one 9-11: 1-Pentanoyl-3- [l- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro-benzoimidazol-2-one 9-12: 1- [2- (4-Chloro-phenyl)-acetyl]-3- [l- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro- benzoimidazol-2-one 9-13: 1-(4-Chloro-phenylmethanesulfonyl)-3- [1-(3-phenoxy-benzyl)-piperidin-4-yl]-1, 3- dihydro-benzoimidazol-2-one

9-14: 1-(2-Cyclopentyl-acetyl)-3-[1-(3-phenoxy-benzyl)-piperidin-4 -yl]-1, 3-dihydro- benzoimidazol-2-one 9-15: 1- (2-Morpholin-4-yl-ethyl)-3- [ 1- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro- benzoimidazol-2-one 9-16: 1- (2-Diethylamino-ethyl)-3- [ 1- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro- benzoimidazol-2-one Table 5

No. R Rl Retention time M+1 (min) 9-1-H 0,, 0 1. 79 522. 01 s 9-2-H 1. 82 428 9-3-OMe M~ 1. 75 458 9-4-H 1. 97 486. 09 9-5-H o 1. 72 501. 09 ao NH2 9-6-H 1. 75 529. 07 ou 0 9-7-H 1-'CF, 1. 98 512. 09 9-8-H 1. 42 541. 13 N 9-9-H 2. 09 534. 31 9-10-OMe . 2. 11 430 '- 9-11-H ° 2. 21 514. 12 T 9-12-H o c 2. 26 582. 0 9-13-H 2. 06 617. 95 . 9-14-H j ? r') 2. 38 540. 59 9-15-H ro 1. 30 543. 09 5~NJ 9-16-H 1. 37 529. 13 zL~ N

Preparation of the 1- (3-phenoxy-benzyl) piperdin-4yl-1, 3-dihydrobenzimidazol-2-one Scheme 8 : NHBoc 2 HCI O R 1. Na (OAc) 3BH, CH2C12 + 0 ACOH H2N 2. 4 N Dioxane/HCI Ri 1 NO2 /NOZ NHzH 'H r cl N_o 4CI (q) N 9 HN-f° N-NN. J ! N-propanol n-Or o'p Ri 10 Ru 11 O O 0 HN 12 I N_o R 1 RI Rl 10: (2-nitrophenyl)- [phenoxy-benzyl)-piperdine-4yl]-amine 1- (3-phenoxy-benzyl)-piperdine-4-ylamine (1.0 equ) was added to DIPEA (5.5 equ. ) in DMF, to the above was added the appropriate chloronitrobenzene (1.1 equ). The reaction mixture was heated to 100 °C for 48 h and then concentrated down. The residue was partitioned between ether and water. The organics were collected together and washed with 1N HCI, 3x water and lx brine. The organics were dried over MgS04, filtered and concentrated down to give 10. The solid residues 10 were taken directly on to the following step.

11: (2-nitrophenyl)- [phenoxy-benzyl)-piperdine-4yl]-amine

The corresponding aryl nitro 10 (1.0 equ) were reduced using iron and ammonium chloride. The aryl nitro 10 (1.0 equ) was added to 2-propanol, followed by a 0.34M solution of NH4C1 (1.5 equ. ) and 3 equ. of iron. The reaction was heated to 60 °C for 5 h, the color darkened considerable during this time. The reaction was filtered through Celite and concentrated down. The aqueous solution was extracted with methylene chloride 3x. The organics were washed with brine and dried over MgS04. The corresponding amines 11 were purified with MeOH/CH2Cl2.

12: 1- (3-phenoxy-benzyl) piperdin-4yl-1, 3-dihydrobenzimidazol-2-one N- [1- (3-Phenoxy-benzyl)-piperidin-4-yl]-benzene-1, 2-diamine 11 were cyclized with carbonyl diimidazole (CDI). The corresponding N- [l- (3-phenoxy-benzyl)-piperidin-4-yl]- benzene-1, 2-diamine 11 compounds (1.0 equ. ) were dissolved in THF and carbonyl diimidazole (1.5 equ) was added. The reaction was heated to reflux for 4 h. The reaction was diluted with EtOAc and washed with water and brine. The organic layer was dried over MgS04, filtered and concentrated down to give each of the corresponding substituted benzimidazole 12. Each compound 12 was purified using acetonitrile/H2O with fonnic acid, to give the formate salts of 12. 12-1: 4-Chloro-1- 1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-1, 3-dihydro- benzoimidazol-2-one

12-2: 4-Chloro-1- [1- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro-benzoimidazol-2-one 12-3: 6-Chloro-1- [1- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro-benzoimidazol-2-one 12-4: 5-Acetyl-l- [l- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro-benzoimidazol-2-one 12-5: 5-Chloro-1- [I- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro-benzoimidazol-2-one 12-6: 1- [l- (3-Phenoxy-benzyl)-piperidin-4-yl]-5-trifluoromethyl-1, 3-dihydro-benzoimidazol- 2-one 12-7: 7-Chloro-1- [1- (3-phenoxy-benzyl)-piperidin-4-yl]-1, 3-dihydro-benzoimidazol-2-one Table 6 No. A B CD R Retention M+1 time (min) 12-1 Cl H H H OMe 1. 73 464 12-2 Cl H H H H 1.79 434.13 12-3 H H ci H H 2.01 434.03 12-4 H C (O) CH3 H H H 1.58 442.07 12-5 H ci H H H 1.75 434.00 12-6 H CF3 H H H 1.99 468.03 12-7 H H H ci H 1.99 434.02 Preparation of 1- (3-phenoxy-benzyl) piperdin-4yl]-lH-benzoimidazole Scheme 9:

13: 2-Methyl-l- [l- (3-phenoxy-benzyl)-piperdin-4-yl]-lH-benzoimidazole N- [1- (3-Phenoxy-benzyl)-piperidin-4-yl]-benzene-1, 2-diamine, 11 (1.0 equ. ) was mixed with 4N HC1 (aq) and 1.0 equ of AcOH. The reaction mixture was allowed to heat at reflux for 10h. The reaction mixture was neutralized with NaHCO3 and extracted with methylene chloride (3X). The organics were collected together and washed with brine and dried over MgS04, filtered and concentrated down. The product was purified by flash chromatography with a gradient 100% CH2C12 to 96% CH2Cl2 / 4% MeOH to give a 39% yield of 13. Retention time 1.23, LCMS 398. 05, 1H NMR data is consistent with the assigned structure.

14: 1- [1- (3-Phenoxy-benzyl)-piperdin-4-yl]-1H-benzoimidazol-2-ylamine N- [1- (3-Phenoxy-benzyl)-piperidin-4-yl]-benzene-1, 2-diamine, 11 was mixed with water and methanol and a solution of cyanogen bromide (1.0 equ, 5. 0M solution in acetonitrile). The reaction was allowed to stir overnight at room temperature. Activated carbon was added to decolorize the reaction and filtered. The filtrate was brought to pH > 9 with ammonium hydroxide and extracted with CH2C12. The aqueous layer was extracted 3x

and the organics were collected together and washed with brine, dried over MgS04, filtered and concentrated down. The product was purified by flash chromatography with a gradient 100% CH2C12 to 90% CH2C12/10% MeOH to give a 29% yield of 14. Retention time 1.51, LCMS 399. 07,'H NMR data is consistent with the assigned structure.

Scheme 10: HN- HN- HN-f' Lawesson Reagent o i w Toluene O'v 2-41 15 15: 1- [1- (3-Phenoxy-benzyl)-piperdin-4-yl]-1, 3-dihydro-benzoimidazole-2-thione 1- [1- (3-Phenoxy-benzyl)-piperdin-4-yl]-1, 3-dihydro-benzoimidazol-2-one (1.0 equ. ) was mixed with 1. 1 equ of Lawesson reagent in toluene and heated to reflux overnight. The reaction mixture was concentrated down and purified by flash chromatography with a gradient 100% CH2Cl2 to 92% CH2Cl2 / 8% MeOH to give a 12% yield of 15. 1H NMR data is consistent with the assigned structure.

Preparation of 3-phenoxybenzylamines Scheme 11: 3-phenoxybenzaldehyde was mixed with an approriate amine (1.2 eq. ) and sodium triacetoxy borohydride (1.2 eq. ) in dichloroethane containing acetic acid (1%) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2C12 and washed with saturated aqueous sodium bicarbonate solution and brine and dried over sodium sulfate. Column chromatography provided the corresponding 3- aryloxy-benzyl amine 16.

16-1: 4, 5-Phenyl-9- (3-phenoxy-benzyl)-l-oxa-3, 9-diaza-spiro [5.5] undec-4-en-2-one 16-2: 9- [3- (2-Methoxy-phenoxy)-benzyl]-4, 5-phenyl-l-oxa-3, 9-diaza-spiro [5.5] undec-4-en- 2-one 16-3: 2-Benzyl-8- (-3-phenoxy-benzyl)-2, 8-diaza-spiro [4.5] decan-3-one 16-4: 2-Benzyl-8- [3- (methoxy-phenoxy)-benzyl]-2, 8-diaza-spiro [4.5] decan-3-one 16-5: 3, 4-Thiophen-9- (3-phenoxy-benzyl)-1-oxa-9-aza-spiro [5.5] undecen-2-one 16-6: 3, 4-Thiophen--9- [3- (2-methoxy-phenoxy)-benzyl]-1-oxa-9-aza-spiro [5.5] undecen-2- one 16-7: 4, 5-Pyridine-9- (3-phenoxy-benzyl)-l-oxa-3, 9-diaza-spiro [5.5] undec-4-en-2-one 16-8: 1- (3-Phenoxy-benzyl)-4-phenyl-piperdin-4-ol 16-9: (4-Fluorophenyl)- [1- (3-phenoxy-benzyl)-piperdin-4-yl]-metlianone 16-10: 4-Fluoro-phenyl)- {1- [3- (2-metlioxy-phenoxy)-benzyl] piperdin-4-yl} methanone 16-11: 2- (4-Bromo-benzyl)-8- (3-phenoxy-benzyl)-2, 8-diaza-spiro [4.5] decan-l-one 16-12: 2-Benzyl-9- (3-phenoxy-benzyl)-2, 9-diaza-spiro [5.5] undecane 16-13: 4- (5-Furan-2yl-lH-pyrazol-3-yl)-l- (3-phenoxy-benzyl)-piperdine 16-14: 4- (5-Furan-2yl-lH-pyrazol-3-yl)-l- (3- (-2-methoxy-phenoxy)-benzyl]-piperdine 16-15: 2- [1- (3-Phenoxy-benzyl)-piperdin-4-yl]-ethanol 16-16: 2- [1- (3- (2-Methoxy-phenoxy)-benzyl]-piperdin-4-yl]-ethanol 16-17: 2-Benzyl-8- [3-phenoxy-benzyl]-1, 2, 8-triaza-spiro [4.5] decan-3-one 16-18: 2-Benzyl-8- [3- (2-methoxy-phenoxy)-benzyl]-1, 2, 8-triaza-spiro [4.5] decan-3-one 16-19: [1- (3-Phenoxy-benzyl)-piperdin-4-yl]-diphenyl-methanol 16-20: 1- (3-Phenoxy-benzyl)-4-phenyl-piperdine 16-21: [1- (3-Phenoxy-benzyl)-piperdin-4-yl]-phenyl-acetonitrile 16-22: 1- (3-Phenoxy-benzyl)-4-phenyl-piperdine-4-carbonitrile 16-23: 1- (3-Phenoxy-benzyl)-4-phenyl-piperdine-4-carboxylic acid 16-24: 2- (3-Phenoxy-benzyl)-decahydro-isoquinoline 16-25: (4-Chloro-phenyl)- [1- (3-phenoxy-benzyl)-piperdin-4-yl]-methanone 16-26: 1- [1- (3-Phenoxy-benzyl)-piperdin-4yl]-lH-benzotriazole 16-27: 2- (3-Phenoxy-benzyl)-1, 2,3, 4-tetrahydro-isoquinoline 16-28: 1- [1- (3-Phenoxy-benzyl)-4-phenyl-piperdin-4-yl-ethanone 16-29: 4-Benzyl-1- (3-phenoxy-benzyl)-piperdine 16-30: 3- (3-Phenoxy-benzyl)-1, 2,3, 4,5, 6-hexahydro-1, 5-methano-pyrido [1, 2-a] [1, 5] diazocin- 8-one 16-31: 2- (4-Chloro-phenyl)-5- (3-phenoxy-benzyl)-2, 5-diaza-bicylco [2.2. 1] heptane 16-32: [1- (3-Phenoxy-benzyl)-piperdin-4-yl]-phenyl-methanone 16-33: 1- (3-Phenoxy-benzyl)-azepane 16-34: 1, 3, 3-Trimethyl-6- (3-phenoxy-benzyl)-6-aza-bicyclo [3.2. 1] octane 16-35: 4- [5- (4-Methoxy-phenyl)-lH-pyrazol-3-yl]-1- (3-phenoxy-benzyl)-piperdine 16-36 : 2- [1- (3-Phenoxy-benzyl)-piperdin-4-yl]-benzothiazole

16-37: 1- (3-Phenoxy-benzyl)-pyrrolidine 16-38: 6-Fluoro-2- (3-phenoxy-benzyl)-2, 3,4, 9-tetrahydro-lH-p-carboline 16-39: 3- (3-Phenoxy-benzyl)-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine 16-40: 4-Methyl-1-(3-phenoxy-benzyl)-4-phenyl-piperdine 16-41: 9- [3- (2-Methoxy-phenoxy)-benzyl]-2, 3-phenyl-l-oxa-5, 9-diaza-spiro [5.5] undec-2-en- 4-one 16-42: 1- (3-Phenoxy-benzyl)-piperdine-3-carboxylic acid ethyl ester Table 7 No. R IR I Retention time M+1 (min) 16-1 1. 76 415. 15 0 0 N. O O 16-2 nu 1. 72 445 oye OMe HO, N. 16-3 0 1. 74 427. 22 i NN i 16-4 > ° 1. 73 457 oye 6 OMe 16-5 3. 13 406. 13 s p 16-6 1. 77 435 N' OMe 16-7 1. 64 416. 15 ' N 16-8 i/=\ 2. 71 360. 17 =' ; HO'\N- 16-9 1. 90 390. 16 fez 0 16-10 F 1. 72 420 y OMe OON 16-11 BrO- 3. 29 505. 14 nez No. R, R1 Retention time M+1 (min) 16-12 2. 97 413. 27 XN, 5) Oc. 16-13 1. 78 400. 64 N'S'. 'N N 16-14 ¢2 WC 1. 77 432 OM 16-15 w"o 2. 05 312. 20 N, 5 16-16 HO 1. 52 342. 2 OMe N2. OMe 16-17 m °yL 2. 73 428. 23 rr. N NtN S 0' 16-18 16-18 0 1. 81 458 I N. OMe i I H 16-19 16-19 1 3. 27 450. 26 Ha HO 16-20 3. 64 344. 21 N<5 ! 16-21 3. 45 383. 20 ,, c 1 . ci N \, Nt 16-22 1. 89 369. 13 I 16-23 H02C 1. 98 388. 26 (J- No. R xi Retention time M+l (min) 2 16-24 3. 71 322. 21 Nez H 16-25 ¢) cb 3. 67 406. 28 y 16-26 N eN, 1. 56 385. 11 NNcS' 16-27 3. 67 316. 17 16-28 3. 38 386. 21 m 0 H3C N2. 16-29 3. 51 358. 24 i o k N ? 16-30 -. N : 1 2. 83 373. 19 0 11 O 16-31 C tA 2. 06 391. 09 w N 16-32 OYON, 1. 92 372. 15 N 16-33 1. 61 282. 15 - 16-34 N., H 1. 89 336. 53 m No. R IR Retention time M+1 (min) 2 16-35 Me 1. 68 440. 16 vol N N ? 16-36 1. 95 401. 11 Ny 'H. 16-37 g CrNt 1. 49 254. 10 16-38 2. 34 373. 06 N N 16-39 C < 1. 81 330. 14 Nys N 16-40 \, 2. 20 358. 14 N 16-41 < 9 1. 45 431. 06 OMe 0 N, HN H Nfr 16-42 g X 1. 74 444 N N

Preparation of 4-Chloro-N-{1-[3-(2-methoxy-phenoxy)-benzyl]-piperidin-4-yl} -2-phenyl- , butyramide Scheme 12: H 0 0 i. 2-Br-Chloroethane Me2A]'N'Soc eoc , Boc ii. aq. HCL CH2CI2, rt-Boc EtO'OEt \- /O \ HO 17 1. MsCl, TEA, NaBH3CN, MeOH, CH, rt AcOH, o-CH3-aldehyde, 2h NH 3 Cl 18 (3 Cl 18 / CI 18 O han Nal, K2CO3, DMF, 50 C ° CI N N ° \ O O d \ O O ci N 17: 4- (4-Hydroxy-2-phenyl-butyrylamino)-piperidine-1-carboxylic acid tert-butyl ester

To an ice cooled solution of 4-amino-N-Boc-piperidone (1.04 g, 5.2 mmol) in dichloromethane (15 mL), was added Me3Al (2M in toluene, 2.6 mL, 5.2 mmol). The resultant solution was stirred at rt for 0.5 h followed by the addition of a-phenyl-y- butyrolactone (0.767 g, 4.7 mmol) as a solution in dichloromethane (5 mL). This solution was stirred overnight. The reaction mixture was quenched with saturated NH4C1 solution and extracted with methylene chloride. The organic extracts were dried over MgS04, filtered and concentrated to provide the crude product as a white solid. Silica chromatography using (9: 1 DCM: MeOH) provided the desired product 17 (0.82 g, 48%) as a white solid. 1H NMR is consistent with assigned structure. Anal. Calcd for C20H30N204 : C, 66.27, H, 8.34, N, 7.73. Found: C, 66.06 ; H, 8.41 ; N, 7.68.

18: 4- (4-Chloro-2-phenyl-butyrylamino)-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 17 (149 mg, 0.45 mmol) in dichloromethane (3 mL) was added methanesulfonyl chloride (35 uL, 0.45 mmol) and TEA (62 uL, 0.45 mmol). The resultant mixture was stirred at rt for 6 h. The reaction solution was quenched with 1 N HC1 solution and extracted with methylene chloride. The organic layer was dried over MgS04, filtered and concentrated to provide the crude product. Purification using silica gel chromatography (30% ethyl acetate in hexanes) provided the chloro product 18 (83 mg, 49%) as an oil. To a solution of the product in dichloromethane (5 mL), was added trifluoromethyl acetic acid (1 mL) and the reaction was stirred at rt for 1 h. The reaction solution was concentrated to provide the crude product that was used without further purification. 1H NMR is consistent with assigned structure. LC-MS (ES+): 280, ret. time = 1.10.

19: 4-Chloro-N- {1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl-butyram ide To a solution of 18 in dichloromethane (5 mL) was added trifluoromethyl acetic acid (1 mL). The resultant solution was stirred at rt for 1.5 h then concentrated in vacuo to provide the free amine as its TFA salt. This material was used directly in the next reaction without further purification. To a solution of the crude amine in methanol (5 mL) was added 3- (o-methoxyphenoxy) benzaldehyde 1-1 (350 mg, 2.2 mmol) and sodium cyanoborohydride (136 mg, 2.2 mmol). The reaction solution was adjusted to pH 6 by adding acetic acid then stirred at rt for 2 h. The reaction solution was quenched with saturated NaHCO3 solution and extracted with diethyl ether. The organic extract was dried over MgS04, filtered and concentrated to provide the crude product. Purification using silica gel chromatography (20% ethyl acetate in hexanes) provided the desired product 19 (53 mg, 50%). lH NMR is consistent with assigned structure. LC-MS (ES+): 493, ret. time = 1.70.

20: l- {l- [3- (2-Mcthoxy-phenoxy)-benzyl]-piperidin-4-yl}-3-phenyl-pyrroli dm-2-one

To a solution of 19 (53 mg, 0.10 mmol) in DMF (5 mL) was added a catalytic amount of potassium iodide and potassium carbonate (14 mg, 0.10 mmol). The resultant solution was stirred for 15 h at rt then heated for an additional 24 h. The reaction solution was cooled to rt and excess DMF was removed in. vacuo. Flash chromatography using (9: 1: 0.5%, ethyl acetate: methanol, triethylamine) provided 20 (20 mg, 43%). IH NMR is consistent with assigned structure. LC-MS (ES+): 457, ret. time = 1.07.

21-1,21-2 : 4-Hydroxy-N- {1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl- butyramide/4-Hydroxy-N- [1- (3-phenoxy-benzyl)-piperidin-4-yl]-2-phenyl-butyramide To a solution of 17 (544 mg, 1.43 mmol) in methylene chloride (10 mL) was added TFA (2 mL) and the resultant solution was stirred for 2 h at rt. Methylene chloride and TFA were removed in vacuo and crude amine was used without further purification. 21-1: To a solution of the crude amine in methanol was added 3- (o-methoxyphenoxy) benzaldehyde (1- 1) (814 mg, 3.6 mmol) and sodium cyanoborohydride (449 mg, 7.1 mmol). The reaction solution was adjusted to pH 6 by adding acetic acid then stirred at rt for 4 h. Additional portions of aldehyde 1-1 (1.6 g, 7.2 mmol) and NaBH3CN (449 mg, 7.2 mmol) were added to the reaction solution and the solution was stirred overnight at rt. The reaction mixture was

quenched with saturated NaHCO3 solution and extracted with diethyl ether. The organic extract was dried over MgS04, filtered and concentrated to provide the crude product. HPLC chromatography (Phenomenex C18 column, 10 micron/60x21. 2 mm) using 100: 0 solvent A: B to 100% B over 27 minutes (A = 99% H20/1% CH3CN/0. 1% formic acid, B = 95% CH3CN/5% H2O/0. 1% formic acid) provided the desired product 21-1 (678 mg, 62%). lH NMR is consistent with assigned structure. LC-MS (ES+): 445, ret. time = 1. 71.

21-2: To a solution of the crude amine (0.13 mmol) in methanol was added 3- phenoxybenzaldehyde (36uL, 0.20 mmol) and sodium cyanoborohydride (84 mg, 1.3 mmol).

The reaction solution was adjusted to pH 6 by adding acetic acid and stirred at overnight.

During the course of the reaction, an additional portion of phenoxybenaldehyde (1.6 g, 7.2 mmol) was added to the reaction solution after 6 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with diethyl ether. The organic extract was dried over MgS04, filtered and concentrated to provide the crude product. HPLC chromatography (Phenomenex C18 column, 10 micron/60x21. 2 mm) using 85: 15 solvent A: B to 100% B over 25 minutes (A = 99% H2O/1% CH3CN/0. 1% formic acid, B = 95% CH3CN/5% H20/0. 1 % formic acid) provided the desired product 21-2 (9 mg, 16%). 1H NMR is consistent with assigned structure. LC-MS (ES+): 475, ret. time = 1.70.

22-1,22-2 : N-11- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yll-2-phenyl-4-pyrro lidin-l- <BR> <BR> <BR> yl-butyramide/4-Diethylamino-N- {1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-<BR> <BR> <BR> <BR> <BR> <BR> phenyl-butyramide To a solution of 19 (154 mg, 0.32 mmol) in dichloromethane (2 mL) was added methanesulfonyl chloride (28 uL, 0.32 mmol), and triethylamine (58 uL, 0.42 mmol). The resultant solution was stirred at rt for 4 h. The reaction solution was quenched with 1 N HC1 solution and extracted with methylene chloride. The organic extracts were dried over

MgS04, filtered and concentrated to provide the crude chloride compound as a brown residue. This product was used in subsequent reactions without further purification.

22-1: To a solution of the crude chloride (-0. 16 mmol) in dioxane (1 mL) was added pyrrolidine (0.540 mL, 6.2 mmol). The resultant solution was heated for 12 h at 60°C. Upon cooling to rt, the reaction solution was concentrated and the crude product was further purified by flash chromatography (10% methanol in dichloromethane) (18 mg, 21%). 1H NMR is consistent with assigned structure. LC-MS (ES+): 528, ret. time = 1. 91.

22-2: To a solution of the crude chloride (-0. 16 mmol) in dioxane (1 mL) was added diethyl amine (0.66 mL, 6.2 mmol). The resultant solution was heated for 48 h at 60°C. After 12 h, an additional diethylamine was added (0.66 mL, 6.2 mmol). Upon cooling to rt, the reaction solution was concentrated and the crude product was further purified by flash chromatography (10% methanol in dichloromethane) to provide the desired product 22-2 (27 mg, 32%). IH NMR is consistent with assigned structure. LC-MS (ES+): 530, ret. time = 1.14.

23: Piperidine-1, 4-dicarboxylic acid 1-benzyl ester 4-ethyl ester To an iced cooled solution of ethyl isonipecoate (15.4 mL, 0.1 mol) and triethylamine (27.8 mL, 0.2 mol) in dichloromethane (300 mL) was added Cbz-Cl (15.7 mL, 0.11 mol) dropwise using a slow addition funnel. The reaction solution was stirred at rt for 2 days. To this solution was added 1 N HC1 and product was extracted with dichloromethane. The organic extracts were dried over MgS04, filtered and concentrated to provide the desired product 23 as a pink semi-solid (16 g, 55%). This product was used'without further purification. tHNMR is consistent with assigned structure. LC-MS (ES+): 292, ret time = 2.49.

24: 4-Hydroxymethyl-piperidine-l-carboxylic acid benzyl ester

To a solution of 23 (5. 82 g, 20 mmol) in toluene (60 mL) cooled to-60°C, was added diisobutylaluminium hydride (40 mL, 40 mmol). The resultant solution was warmed to rt overnight. The reaction solution was quenched with 1 N HC1 and extracted with ethyl ether.

The organic extracts were dried over MgS04, filtered and concentrated to provide the desired product as an oil. Flash chromatography (20% ethyl acetate in hexanes) provided the desired product 24 as an oil (2.0 g, 40%). IH NMR is consistent with assigned structure.

25: 4-Formyl-piperidine-l-carboxylic acid benzyl ester To a solution of DMSO (1.6 mL, 23 mmol) in methylene chloride (50 mL) cooled to- 60°C, was added oxalyl chloride (1.25 mL, 14.3 mmol) dropwise. The resultant solution was stirred at-60°C for 15 minutes followed by the addition of 24 (2.8 g, 9.5 mmol) as a solution in methylene chloride. The solution was stirred for an additional 15 minutes at-60°C. After that time, triethylamine (6.65 mL, 47.8 mmol) was added in one portion and the reaction solution was warmed to rt over 1.5 hour. The reaction solution was quenched with 1 N HC1, extracted with dichloromethane, dried over MgSO4, and concentrated to provide the crude product as an yellow oil. Flash chromatography (20-30% ethyl acetate in hexanes) provided the desired product 25 as a clear oil. 1H NMR is consistent with assigned structure.

26: 4- (2, 3-dihydro-lH-indol-3-yl)-piperidine-l-carboxylic acid benzyl ester

To a degassed solution of toluene and acetonitrile (49: 1 v/v, 15 mL total) was added phenyl hydrazine (0.45 mL, 4.5 mmol) and trifluoromethyl acetic acid (1.1 mL, 13.6 mmol).

The reaction solution was heated to 35 °C. To the reaction mixture was added dropwise aldehyde 25 (1.2 g, 4.1 mmol), as a solution in the toluene/acetonitriile solution (3 mL total).

The resultant solution was heated at 35 °C for 20 h. The solution was then cooled to-10°C and to it was added NaBH4 (233 mg, 62 mmol). The reaction mixture was quenched with 1 N HC1 and extracted with ethyl ether. The organic extracts were dried over MgS04, filtered and concentrated to provide the desired product. Flash chromatography (20-30% ethyl acetate in hexanes) provided 26 (585 mg, 44%). IH NMR is consistent with assigned structure. LC-MS (ES+): 323, ret. time = 1.89.

27: 4- (2, 3-dihydro-1-methanesulfonyl-indol-3-yl)-piperidine-1-carboxy lic acid benzyl ester To a solution of 26 (585 mg, 1.8 mmol) in dichloromethane (5 mL) and triethylamine (0.33 mL, 2.4 mmol) cooled to 0 °C was added was added methanesulfonylchloride (0.158 mL, 2.0 mmol). The reaction solution was warmed to rt over 5 h. The reaction mixture was quenched with 1 N HC1 and extracted with ethyl acetate. The organic extracts were dried over MgS04, filtered and concentrated to provide the crude product as an oil. Flash chromatography using 20-30% ethyl acetate in hexanes provided the desired product 27 (550 mg, 76%) as a white foam. in NMR is consistent with assigned structure. LC-MS (ES+): 401, ret time = 2. 71. 28-1,28-2 : N- [3- (2-methoxy-phenoxy)-benzyl]-4- (2, 3-dihydro-l- (methanesulfonyl)-indol-3- <BR> <BR> yl)-piperidine/N- [3- (2-chloro-phenoxy)-benzyl]-4- (2, 3-dihydro-l- (methanesulfonyl)-indol- 3-yl)-piperidine

Amine 27 (510 mg, 1.3 mmol), 10% Pd-C (107 mg) and ethanol (20 mL) were combined in a pressure vessel. The vessel was pressurized to 45 psi with hydrogen gas then heated at 65 °C for 24 h. The reaction vessel was cooled to rt and Pd-C removed by filtration through a plug of celite. The celite pad was washed with extra amounts of ethanol. The organic solution was concentrated to provide the desired product (258 mg, 68%). The product was used directly in the next reaction.

28-1: To the crude hydrogenation product (124 mg, 0.47 mmol) and o-methoxy-aldehyde 1-1 (138 mg, 0.61 mmol) in methanol, was added sodium cyanoborohydride (29 mg, 0.47 mmol).

The reaction solution was acidified to pH 6 with acetic acid and stirred at rt overnight. The reaction solution was quenched with IN HC1 solution and extracted with methylene chloride.

The organic extracts were dried over MgS04, filtered and concentrated to provide the crude product. Flash chromotography (20% ethyl acetate in hexanes) provided the desired 28-1 as a white foam. IH NMR is consistent with assigned structure. Anal. Calcd: C, 67.74 ; H, 6.32, N, 5.85. Found; C, 67.64, H, 6.34, N, 5.74. LC-MS (ES+): 479, ret time = 1.71.

28-2: To the crude hydrogenation product (124 mg, 0.47 mmol) and o-chloro-aldehyde 1-6 (142 mg, 0.61 mmol) in methanol, was added sodium cyanoborohydride (29 mg, 0.47 mmol).

The reaction solution was acidified to pH 6 with acetic acid and stirred at rt overnight. The reaction solution was quenched with IN HC1 solution and extracted with methylene chloride.

The organic extracts were dried over MgS04, filtered and concentrated to provide the crude product. Flash chromotography (20% ethyl acetate in hexanes) provided the desired product 28-2 as a white foam. lH NMR is consistent with assigned structure. Anal. calcd : C, 64.65 ; H, 5.63, N, 5.80. Found; C, 64.40, H, 5.74, N, 5.74. LC-MS (ES+): 482, ret time = 1. 80. Preparation of N- (3- f Ethyl- [3-phenoxy-benzyl]-amino}-propyl)-2-acetamide Scheme 13: /i 0 1'0 Fi Rt + NaBH4, MEOH BocHN n 0 BocHN. NH n = 1, 2 n 29 n = 1, 2 1. CH3CHO, NaBH3CN Rl MeOH BocHN''N o RCOCI, Et3N, CH2CI2 _ 2. 4M HCI/Dioxane n = 1, 2 30 ru RJ N. ( N \ I O \ R9 R N 0 n = 1, 2 n = 1, 2 n=1, 2 31

29: (3- {Ethyl- [3- (2-methoxy-phenoxy)-benzyl]-ammo}-propyl)-carbamic acidtert-butyl ester

A solution of N- (3-aminopropyl)-carbamic acid t-butyl ester (2.61 g, 15 mmol) and o-methoxy-aldehyde 1-1 (3.42 g, 15 mmol) in methanol (60 mL) was heated to reflux for 48 h. The resultant solution was cooled to rt and to it was added sodium borohydride (0.561 mg, 15 mmol). The reaction solution was stirred for 1 day at rt then quenched with 1N HC1 and extracted with methylene chloride. The organic extract was dried over magnesium sulfate, filtered and concentrated to provide the crude product as an oil. This material was used directly in the next reaction without further purification. 1H NMR is consistent with assigned structure. LC-MS (ES+): 387, ret time = 1.50.

30: N-1-Ethyl-Nl- [3- (2-methoxy-phenoxy)-benzyl]-propane-1, 3-diamine dihydrochloride

To the crude product (-15 mmol) 29 dissolved in methanol (40 mL) was added acetaldehyde (2.5 mL, 45 mmol) and NaBH3CN (1 g, 15 mmol). The resultant solution was stirred overnight at rt. The reaction solution was quenched with saturated ammonium chloride solution, extracted with methylene chloride. The organic extracts were dried over MgS04, filtered and concentrated to provide the desired product as an oil. This material was dissolved with 4N HC1 in dioxane (80 mL), stirred at rt for 3 h, and concentrated to provide 30 (5 g, 92%) as an off-white solid. This material was used directly in the next reaction without further purification. 1H NMR is consistent with assigned structure. LC-MS (ES+): 315, ret. time.

31: N- (3- {Ethyl- [3- (2-methoxy-phenoxy)-benzyl]-amino}-propyl)-2-phenyl-acetamid e

To a solution of diamine 30 (0.359 g, 1 mmol) in methylene chloride (5 mL) was added triethylamine (0.4 mL, 3 mmol) and phenylacetyl chloride (132 uL, 1.1 mmol). The resultant solution was agitated on the orbital shaker overnight. The crude reaction solution was concentrated in vacuo to provide the product as an oil. Flash chromatography on Si02 provided the desired product 31 as on oil, which was converted to its HC1 salt following conventional methods. 1H NMR is consistent with assigned structure. LC-MS (ES+): 463, ret. time = 0.79 min.

31-1: 2- (4-Benzyloxy-phenyl)-N- {2- [ethyl- (3-phenoxy-benzyl)-amino]-ethyl}-acetamide 31-2: N- {2- [Ethyl- (3-phenoxy-benzyl)-amino]-ethyl}-2- (3-methoxy-phenyl)-acetamide 31-3: N- {2- [Ethyl- (3-phenoxy-benzyl)-amino]-ethyl}-2-thiophen-2-yl-acetamide 31-4: N- 2- [Ethyl- (3-phenoxy-benzyl)-amino]-ethyl}-2- (4-fluoro-phenyl)-acetamide

31-5: N- {2- [Ethyl- (3-phenoxy-benzyl)-amino]-ethyl}-4-fluoro-benzamide 31-6: 2-(3,4-Dimethoxy-phenyl)-N-{2-[ethyl-(3-phenoxy-benzyl)-amin o]-ethyl}-acetamide 31-7: N-{2-[Ethyl-(3-phenoxy-benzyl)-amino]-ethyl}-2-phenoxy-aceta mide 31-8: 3-{2-[Ethyl-(3-phenoxy-benzyl)-amino]-ethyl}-1-methyl-1-phen yl-urea 31-9: N- {2- [Ethyl- (3-phenoxy-benzyl)-amino]-ethyl}-3-phenyl-propionamide 31-10: N-{3-[Ethyl-(3-phenoxy-benzyl)-amino]-propyl}-2,2-diphenyl-a cetamide 31-11: 2- (4-Benzyloxy-phenyl)-N- 3- [ethyl- (3-phenoxy-benzyl)-amino]-propyl}-acetamide 31-12: N-{3-[Ethyl-(3-phenoxy-benzyl)-amino]-propyl}-2-(3-methoxy-p henyl)-acetamide 31-13: 2- (2-Bromo-phenyl)-N- 3- [ethyl- (3-phenoxy-benzyl)-amino]-propyl}-acetamideO 31-14: N-{3-[Ethyl-(3-phenoxy-benzyl)-amino]-propyl}-2-(4-fluoro-ph enyl)-acetamide 31-15: N- 3- [Ethyl- (3-phenoxy-benzyl)-amino]-propyl}-4-fluoro-benzamide 31-16: N-{3-[Ethyl-(3-phenoxy-benzyl)-amino]-pyropyl}-2-phenoxy-ace tamide 31-17: N- {3- [Ethyl- (3-phenoxy-benzyl)-amino]-propyl}-3-phenyl-acrylamide 31-18 : 3-Cyclopentyl-N- {3- [ethyl- (3-phenoxy-benzyl)-amino]-propyl}-propionamide 31-19: N-{3-[Ethyl-(3-phenoxy-benzyl)-amino]-propyl}-3-phenyl-propi onamide 31-20: N-f 3- [Ethyl- (3-phenoxy-benzyl)-amino]-propyl}-2-thiophen-2-yl-acetamide 31-21: 3,5, 5-Trimethyl-hexanoic acid {3- [ethyl- (3-phenoxy-benzyl)-amino]-propyl}-amide 31-22: N- (3- {Ethyl- [3- (2-methoxy-phenoxy)-benzyl]-amino}-propyl)-2- (3-methoxy-phenyl)- acetamide 31-23: N-{3-{Ethyl-[3-(2-methoxy-phenoxy)-benzyl]-amino}-propyl)-2- thiophen-2-yl- acetamide 31-24: N-(3-{Ethyl-[3-(2-methoxy-phenoxy)-benzyl]-amino}-propyl)-4- fluoro-benzamide 31-25: N- (3-Ethyl- [3- (2-methoxy-phenoxy)-benzyl]-amino}-propyl)-2- (4-fluoro-phenyl)- acetamide 31-26: 2- (3, 4-Dimethoxy-phenyl)-N- (3- {ethyl- [3- (2-methoxy-phenoxy)-benzyl]-amino}- propyl)-acetamide 31-27: N- (3- {Ethyl- [3- (2-methoxy-phenoxy)-benzyl]-amino}-propyl)-C-phenyl- methanesulfonamide 31-28: 3- (3- {Ethyl- [3- (2-methoxy-phenoxy)-benzyl]-amino}-propyl)-1-methyl-1-phenyl -urea 31-29: (3-{Ethyl-[3-(2-methoxy-phenoxy)-benzyl]-amino}-propyl)-carb amic acid 4- methoxy-phenyl ester 31-30: 2-(2-Bromo-phenyl)-N-(3-{ethyl-[3-(2-methoxy-phenoxy)-benzyl ]-amino}-propyl)- acetamide 31-31: N- (3-Ethyl- [3- (2-methoxy-phenoxy)-benzyl]-amino}-propyl)-3-phenyl- propionamide 31-32: N- (3- {Ethyl- [3- (2-methoxy-phenoxy)-benzyl]-amino}-propyl)-2-phenyl-acetamid e Table 9 Retention No. R n Ri..,.. M+1 time (min) 31-1 0, 0 1 0 1 H 2 495 kJUk 31-2 1 0 1 H 1. 64 419 0-1 31-3 1 H 1. 64 395 31-4 1 H 1. 67 407 F 31-5 F-C_ I H 1. 68 393 o 31-6 sO, ¢ 1 H 1. 58 449 os 31-7 aoz ; 1 H 1. 7 405 0 0 31-8 ¢y 1 H 1. 67 404 zozo 31-9 ~) fS 1 H 1. 61 403 0 No. R Rl n Retention M+l No. R Ri n.,.. M+l time (min) I ° w 31-10 H 2 2 479 j 31-11 °"CU. H 2 2 509 31-12 W H 2 1. 68 433 01 !) ° 31-13 S"--H 2 1. 79 482 13r 31-14 H 2 1. 7 421 31-15 H 2 1. 69 407 0 31-16 H 2 1. 75 419 0 0 31-17 r H 2 1. 78 415 0 31-18 H 2 1. 85 409 J 31-19 H 2 1. 78 417 0 31-20'H 2 1. 62 409 po 31-21 o H 2 2. 01 425 L. No. R R n Retention M+1 i time (mm) time (mm) 31-22 ¢ OMe 2 1. 58 463 o 31-23 5m0 OMe 2 1. 61 439 31-24 oye 2 1. 58 437 0 31-25 OMe 2 1. 63 451 31-26 sOr OMe 2 1. 53 493 0-1 31-27 oye 2 1. 62 469 31-28 ¢y OMe 2 1. 64 448 0 31-29 XoJi OMe 2 1. 62 465 31-30 OMe 2 1. 72 512 sr 31-31 OMe 2 1. 62 447 0 31-32 cuz-OMe 2 1. 6 433 Preparation of 2-{1-[3-phenoxy-benzyl]-piperidin-4-ylamino}-3-phenyl-alkyl acid methyl ester Scheme 14: ,, 1. Na (OAc) 3BH, DUE 0-LN H,, a 2, conc. HCI CNa 32 R1 0 R, 0-Y 32 Scheme 15:

33: {1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylamino}-acetic acid methyl ester

To a solution of ketone 32-2 (500 mg, 1.6 mmol) and glycine methyl ester HC1 (301 mg, 2.4 mmol) in methanol (10 mL) was added sodium cyanoborohydride (100 mg, 1.6 mmol). The resultant solution was stirred at rt overnight. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl ether. The organic layer was dried over MgS04, filtered and concentrated to provide the desired product 33 which was clean enough to use without further purification. 1H NMR is consistent with assigned structure. LC-MS (ES+): 385, ret. time = 0.86 min.

34: [f 1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}- (2-phenyl-butyryl)-amino]-acetic acid methyl ester

To a solution of amine 33 (175 mg, 0.46 mmol) in dichloromethane (5 mL) were added 2-Phenyl-butyryl chloride (86 uL, 0.51 mmol) and triethylamine (0. 32 mL, 2.3 mmol).

The resultant solution was stirred at rt for 2h then quenched with saturated sodium bicarbonate solution. The organic layer was dried over MgS04, filtered and concentrated to provide the crude product 34. Flash chromatography using (95: 5 EtOAc: Hexanes w/0.5% TEA) provided the desired product 34. 1H NMR is consistent with assigned structure. LC- MS (ES+): 531, ret. time = 1. 72 min.

35: [ {1-[3-(2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-(2-phenyl- butyryl)-amino]-acetic acid To a solution of amine 34 (94 mg, 0.17 mmol) in THF/water (4: 1,10 mL) was added lithium hydroxide (8.2 mg, 0.19 mmol). The resultant solution was stirred at rt for 7h. The reaction solution was quenched with ammonium acetate solution and extracted with ethyl ether. The organic layer was dried over MgS04, filtered and concentrated to provide the crude product 35. HPLC chromatography (phenomenex C18 column, 10 micron/60x21. 2 mm) using 85: 15 solvent A: B to 100% B over 25 minutes (A = 99% H20/1 % CH3CN/0. 1 % formic acid, B = 95% CH3CN/5% H20/0. 1% formic acid) provided the desired product 35.

IH NMR is consistent with the assigned structure. LC-MS (ES+): 517, ret. time = 1. 67 min.

36: {l- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylamino}-acetic acid benzyl ester

To a solution of ketone 32-2 (500 mg, 1.6 mmol) and glycine benzyl ester HC1 (324 mg, 1.6 mmol) in methanol (10 mL) was added sodium cyanoborohydride (101 mg, 1.6 mmol). The resultant solution was stirred at rt overnight. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl ether. The organic layer was dried over MgS04, filtered and concentrated to provide the desired product 36. Flash chromatography using (95: 5 EtOAc: hexanes w/0.5% TEA) provided the desired product.

IH NMR is consistent with assigned structure. LC-MS (ES+): 461, ret. time = 1.22 min.

37: (S)-2- {l- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylamino}-3-phenyl-pr opionic acid methyl ester To a solution of ketone 32-2 (160 mg, 0.5 mmol) and (L) -phenylalanine methyl ester HC1 (301 mg, 0.5 mmol) in methanol (5 mL) was added sodium cyanoborohydride (64 mg, 1.0 mmol). The resultant solution was stirred at rt overnight. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl ether. The organic layer was dried over MgS04, filtered and concentrated to provide the desired product 37. Flash chromatography using (70% ethyl acetate in hexanes) provided the desired product 37 (243 mg, 100%). IH NMR is consistent with assigned structure. LC-MS (ES+): 475, ret. time = 1. 44 min.

38 : (S)-2- (Acetyl-fl- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yll-amino)-3-phenyl- propionic acid methyl ester

To a solution of amine 37 (175 mg, 0.46 mmol) in dichloromethane (5 mL) were added aetyl chloride (39 uL, 0.55 mmol) and triethylamine (0.146 mL, 2.3 mmol). The resultant solution was stirred at rt overnight then quenched with saturated sodium bicarbonate solution. The organic layer was dried over MgS04, filtered and concentrated to provide the crude product 38. Flash chromatography using (95: 5 EtOAc: hexanes w/0.5% TEA) provided the desired product 38. in NMR is consistent with assigned structure. LC-MS (ES+): 517, ret. time = 1.57 min.

39: (S)-2- (Acetyl- {1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-amino)-3-phenyl- propionic acid To a solution of amine 38 (74 mg, 0.14 mmol) in THF: water (4: 1,10 mL) was added lithium hydroxide (7.2 mg, 0.19 mmol). The resultant solution was stirred at rt for 7h. The reaction solution was quenched with ammonium acetate solution and extracted with ethyl ether. The organic layer was dried over MgS04, filtered and concentrated to provide the product 39 (57 mg, 81%). 1H NMR is consistent with the assigned structure. LC-MS (ES+): 503, ret. time = 1. 59 min.

40: 3- (4-Chloro-phenyl)-2- {l- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-ylamino}- propionic acid methyl ester

To a solution of ketone 32-2 (240 mg, 0.77 mmol) and p-chloro-phenylalanine methyl ester HC1 (202 mg, 0.81 mmol) in methanol (8 mL) was added sodium cyanoborohydride (97 mg, 1.5 mmol). The resultant solution was stirred at rt overnight. The reaction mixture was quenched with saturated NaHC03 solution and extracted with ethyl ether. The organic layer was dried over MgS04, filtered and concentrated to provide the desired product 40. Flash chromatography using (70% ethyl acetate in hexanes) provided the desired product 40 (193 mg, 49 %).'H NMR is consistent with assigned structure. LC-MS (ES+): 509, ret. time = 1. 65 min.

41: 2- (Acetyl- f 1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl-amin)-3- (4-chloro- phenyl) -propionic acid methyl ester To a solution of amine 40 (193 mg, 0.38 mmol) in dichloromethane (5 mL) were added acetyl chloride (28 uL, 0.39 mmol) and triethylamine (0.106 mL, 0.76 mmol). The resultant solution was stirred at rt overnight then quenched with saturated sodium bicarbonate solution. The organic layer was dried over MgS04, filtered and concentrated to provide the crude product 41. Flash chromatography using (95: 5 EtOAc: hexanes w/0.5% TEA) provided the desired product 41. 1H NMR is consistent with assigned structure. LC-MS (ES+): 551, ret. time = 1.65 min.

42: 2- (Acetyl- {l- [3- (2-methoxy-phenoxy)-benzyl]-pipcridin-4-yl}-amino)-3- (4-chloro- phenyl)-propionic acid

To a solution of amine 41 (77 mg, 0.14 mmol) in THF/water (4: 1,10 mL) was added lithium hydroxide (7.2 mg, 0.17 mmol). The resultant solution was stirred at rt for 7h. The reaction solution was quenched with ammonium acetate solution and extracted with ethyl ether. The organic layer was dried over MgS04, filtered and concentrated to provide the product 42 (38 mg, 46%). 1H NMR is consistent with the assigned structure. LC-MS (ES+): 537, ret. time = 1.71 min.

43: 2-Phenyl-pentanedioic acid 5-dimethylamide 1- ( {1- [3- (2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-amide) To a solution of amide 3-85 (302 mg, 0.7 mmol) in THF/DMF (1: 1,8 mL), was added sodium hydride (60% dispersion in mineral oil, 62 mg). The resultant solution was stirred at rt for 10 minutes followed by the addition of N, N dimethyl acrylamide (72 uL, 0.7 mmol).

The reaction solution was heated at 40 °C for 2d. The reaction solution was quenched with saturated NH4Cl solution and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated to provide the crude product 43. Flash chromatography (5-10% methanol in ethyl acetate) provided the desired product 43 as a white foam (121 mg, 33%). IH NMR is consistent with the assigned structure. LC-MS (ES+): 530, ret. time = 1. 51 min.

44: 5-Morpholin-4-yl-5-oxo-2-phenyl-pentanoic acid {l- [3- (2-methoxy-phenoxy)-benzyl]- piperidin-4-yl}-amide

To a solution of amide 3-85 (204 mg, 0.5 mmol) in THF/DMF (1 : 1,4 mL), was added sodium hydride (60% dispersion in mineral oil, 42 mg). The resultant solution was stirred at rt for 10 minutes followed by the addition of 1-Morpholin-4-yl-propenone (60 uL, 0.5 mmol). The reaction solution was heated at 40 °C for 2d. The reaction solution was quenched with saturated NH4C1 solution and extracted with dichloromethane. The organic layer was dried over MgS04, filtered and concentrated to provide the crude product 44. Flash chromatography (5-10% methanol in ethyl acetate) provided the desired product 44 as a white foam (56 mg, 20%). IH NMR is consistent with the assigned structure. LC-MS (ES+): 572, ret. time = 1.54 min.

45: 4-11- [3- (2-Methoxy-phenoxy)-belizyl]-piperidin-4-ylcarbamoyll-4-phen yl-butyric acid tert-butyl ester To a solution of amide 3-85 (272 mg, 0.63 mmol) in THF/DMF (1 : 1, 7 mL), was added sodium hydride (60% dispersion in mineral oil, 56 mg). The resultant solution was stirred at rt for 10 minutes followed by the addition of acrylic acid tert-butyl ester (93 uL, 0.63 mmol). The reaction solution was heated at 40 °C for 2d. The reaction solution was quenched with saturated NH4C1 solution and extracted with dichloromethane. The organic layer was dried over MgS04, filtered and concentrated to provide the crude product 45. HPLC chromatography (phenomenex C18 column, 10 micron/60x21. 2 mm) using 75: 25 solvent A: B to 100% solvent B over 23 minutes (A = 99% H20/1% CH3CN/0. 1% formic

acid, B = 95% CH3CN/5% H20/0.1% formic acid) provided the desired product 45. in NMR is consistent with the assigned structure. LC-MS (ES+): 559, ret. time = 2.16 min.

46: 2-Oxo-1, 2,3, 4-tetrahydro-quinoline-4-carboxylic acid {l- [3- (2-methoxy-phenoxy)- benzyl]-piperidin-4-yl}-amide

To a solution of 2-Oxo-1,2, 3,4-tetrahydro-quinoline-4-carboxylic acid (80 mg, 0.42 mmol) in DCM: THF (1: 1,5 mL) were added hydroxybenzotriazole (57 mg, 0.42 mmol) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDC1) (120 mg, 0.63 mmol). The reaction solution was stirred at rt for 10 minutes followed by the addition of amine 2 (176 mg, 0.5 mmol) and N-methyl morpholine (230 uL, 2.1 mmol). The reaction solution was stirred overnight at rt. The reaction solution was concentrated and the crude residue purified by flash chromatography (2-10% methanol in DCM). 1H NMR is consistent with the assigned structure. LC-MS (ES+): 486, ret. time = 1. 35 min.

47: Ethyl- {l- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-amine

To a solution of ketone 32-2 (200 mg, 0.64 mmol) and ethylamine (2M in THF; 2.5 mL, 2.56 mmol) in dichloroethane (7 mL), was added sodium triacetoxyborohydride (272 t mg, 1.28 mmol). The resultant solution was stirred at rt overnight then quenched with aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer way dried over MgS04, filtered and concentrated to provide the desire product that could be used without further purification. LC-MS (ES+): 341, ret. time = 0.83 min.

48: N-Ethyl-N- {1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-2-phenyl-acetami de

To a solution of amine 47 in dichloromethane was added triethylamine (0.41 mL, 2.9 mmol) and phenylacetyl chloride (86 uL, 0.65 mmol). The resultant solution was stirred overnight. The reaction mixture was quenched with saturated NH4C1 solution and extracted with dichloromethane. The organic layer was dried over MgS04, filtered and concentrated to provide the crude product that was purified by flash chromatography (95: 5 ethyl acetate: hexanes w/0.5% TEA). 1H NMR is consistent with the assigned structure. LC-MS (ES+): 459, ret. time = 1.62 min.

Preparation of [4- (3-Aryloxy-benzyl)- [1, 4] diazepan-1-yl]-alkanone Scheme 16: 1. Na (OAc) 3BH 0 2drops AcOH SO !/DCE HN , 2. 4M HCI/dioxane N O R NH R R R-CI, TEA N) r l I CH2CI2 N s sOH Y 50 R,

49: 1- (3-Phenoxy-benzyl)- [1, 4] diazepane

To a flamed 250 mL round bottomed flask charged with N2 was added dichloroethane (lOOmL), 3-phenoxy-benzaldehyde (1-1, 4.13 mL, 24 mmol, 0.96 eq), [1, 4] diazepane-1- carboxylic acid tert-butyl ester (5.03 g, 25 mmol, 1.0 eq), sodium triacetoxy-borohydride (15.9 g, 75 mmol, 3 eq), and two drops of acetic acid. The solution was allowed to stir at room temperature overnight. The reaction was quenched by slow addition of methyl alcohol (5mL) and water (50 mL), extracted with CH2C12, washed with 1N NaOH, brine, dried over MgS04, filtered and concentrated under reduced pressure at 40°C to provide a yellow oil.

The residue was dissolved in 4M HC1 in dioxane (35 mL), stirred for two hours and concentrated under reduced pressure at 40°C to provide a white solid. Trituration with diethylether afforded 8.0 g (90%) of 1- (3-phenoxy-benzyl)- [1, 4] diazepane 49 as the bis- hydrochloride salt. 1H NMR is consistent with the assigned structure. LC-MS (ES+): 283, ret. time: 0.94 min.

50 : [4- (3-Aryloxy-benzyl)- [1, 4] diazepan-1-yl]-alkanone To a scintillation vial was added 1- (3-phenoxy-benzyl)- [1, 4] diazepane, 49 (178 mg, 0.5 mmol), triethylamine (0.2 mL, 1.5 mmol), acid chloride (R-C1/structures are in the data sheets, 0.5 mmol) and CH2C12 (5 mL). The solution was placed on an orbital shaker overnight, washed with IN HC1 (3x5mL), NaHCO3 (3x5mL), brine, dried over MgS04, filtered and concentrated under reduced pressure at 40 °C to provide a yellow oil. Flash chromatography (Si02, Biotage 10 g column, eluent: 95: 5: 0.5 ethyl acetate/hexanes/triethyl amine) afforded a residue which was dissolved in 4M HC1 in dioxane (10 mL), stirred for 2 hours and concentrated under reduced pressure at 40°C to provide a white powder.

Trituration with diethylether afforded 50 as the hydrochloride salt.

50-1: 2-Phenoxy-1- [4- (3-phenoxy-benzyl)- [1, 4] diazepan-1-yl]-ethanone 50-2: (4-Chloro-phenyl)- [4- (3-phenoxy-benzyl)- [1, 4] diazepan-1-yl]-methanone 50-3: (4-Fluoro-phenyl)- [4- (3-phenoxy-benzyl)- [1, 4] diazepan-1-yl]-methanone 50-4: 3,5, 5-Trimethyl-1- [4- (3-phenoxy-benzyl)- [1, 4] diazepan-1-yl]-hexan-1-one 50-5: 2- (2-Bromo-phenyl)-l- [4- (3-phenoxy-benzyl)- [l, 4] diazepan-1-yl]-ethanone 50-6: 2- (3-Methoxy-phenyl)-l- [4- (3-phenoxy-benzyl)- [1, 4] diazepan-1-yl]-ethanone 50-7: 1- [4- (3-Phenoxy-benzyl)- [1, 4] diazepan-1-yl]-2-thiophen-2-yl-ethanone 50-8 : 2-(3,5-Dimethoxy-phenyl)-1-[4-(3-phenoxy-benzyl)-[1, 4] diazepan-1-yl]-ethanone 50-9: 2- (4-Fluoro-phenyl)-1- [4- (3-phenoxy-benzyl)- [ 1, 4] diazepan-1-yl]-ethanone 50-10: 1- [4- (3-Phenoxy-benzyl)- [1, 4] diazepan-1-yl]-2, 2-diphenyl-ethanone 50-11: 1- [4- (3-Phenoxy-benzyl)- [1, 4] diazepan-1-yl]-3-phenyl-propan-1-one 50-12 : 1- [4- (3-Phenoxy-benzyl)- [1, 4] diazepan-1-yl]-3-phenyl-propenone 50-13 : 2-(4-Benzyloxy-phenyl)-1-[4-(3-phenoxy-benzyl)-[1, 4] diazepan-1-yl]-ethanone 50-14: 2- (3, 4-Dimethoxy-phenyl)-l- {4- [3- (2-methoxy-phenoxy)-benzyl]- [l, 4] diazepan-1- yl}-ethanone 50-15: l- {4- [3- (2-Methoxy-phenoxy)-benzyl]- [l, 4] diazepan-1-yl}-2- (3-methoxyphenyl)- ethanone 50-16: 2- (2-Bromo-phenyl)-1- {4- [3- (2-methoxy-phenoxy)-benzyl]- [ 1, 4] diazepan-1-yl} ethanone 50-17: 1-{4-[3-(2-Methoxy-phenoxy)-benzyl]-[1, 4] diazepan-1-yl}-2-thiophen-2-yl-ethanone 50-18 : 2- (4-Fluoro-phenyl)-l-14- [3- (2-metlioxy-phenoxy)-benzyl]- [1, 4] diazepan-1-yl}- ethanone 50-19: (4-Chloro-phenyl)-{4-[3-(2-methoxy-phenoxy)-benzyl]-[1, 4] diazepan-1-yl}- methanone 50-20: l- {4- [3- (2-Methoxy-phenoxy)-benzyl]- [l, 4] diazepan-1-yl}-3-phenyl-propan-1-one 50-21: 1- [3- (2-Methoxy-phenoxy)-benzyl]-4-phenylmethanesulfonyl- [ 1, 4] diazepane 50-22: 4- [3- (2-Methoxy-phenoxy)-benzyl]- [1, 4] diazepane-1-carboxylic acid 4-methoxy- phenyl ester 50-23: 4- [3- (2-Methoxy-phenoxy)-benzyl]- [1, 4] diazepane-l-carboxylic acid methyl-phenyl- amide 50-24: 1-f4- [3- (2-Methoxy-phenoxy)-benzyl]- [1, 4] diazepan-1-yl}-2-phenyl-ethanone 50-25: (4-Fluoro-phenyl) - {4-[3-(2-methoxy-phenoxy)-benzyl]-[1, 4] diazepan-1-yl}- methanone Table 10: Retention No. R Ri Time M+1 (min) 0 50-1 C ASE H 1. 63 417 o 50-2 cox H 1. 68 421 o 0 50-3 EXr H 1. 57 405 f t 0 50-4 vs H 1. 81 423 ° 50-5 Ty'' 479, 481 Br 50-6 s H 1-53 431 0 50-7 H 1. 50 407 s o 50-8 X H 1. 54 461 , O 50-9 H 1. 54 419 o 50-10 H 1. 78 477 sl 0 50-11 0 H 1. 68 415 i 0 50-12 H 1. 76 413 FY 50-13 < H 2. 05 507 No. R R Retention Time (min) OMe 50-14 Me OMe 1. 48 491 po OMe 50-15 e OMe 1. 58 461 o fi 0 50-16 wus OMe 1. 62 511 Br 0 50-17 OMe 1. 46 437 50-18 0 OMe 1. 56 449 50-18 I , OMe 1. 56 449 0 50-19 Cl/@ OMe 1. 61 451 CI 0 50-20 S OMe 1. 58 445 cl OMe 1. 62 467 Me0 Y o 50-22 JL A, c OMe 1. 60 463 0 OMe 1. 52 446 I r _ O 50-24 OMe 1. 51 431 ruz 0 50-25, OMe 1. 47 435 F Preparation of 1-[3-(2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-ylamine derivatives Scheme 17: 1. Na (OAc) 3BH 0 2 drops AcOH I I p /DCE/ O O 2HCì O/\ N H p 2HCI 1-1 TEA 51 0 CH2CI2 09 CHaCl2

51: 1- [3- (2-Methoxy-phenoxy)-benzyl]-pynolidin-3-ylamine

Experimental procedure followed that of 1- (3-phenoxy-benzyl)- [1, 4] diazepane 49.

1H NMR is consistent with the assigned structure. LC-MS (ES+): 299, ret. time = 0. 85 min.

52: 1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-ylamine derivatives Experimental procedure followed that of 50.

52-1: 2- (3, 4-Dimethoxy-phenyl) -N- {1- [3- (2-methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}- acetamide 52-2: 2- (2-Bromo-phenyl)-N- {1- [3- (2-methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}- acetamide 52-3: N- {1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-2-thiophen-2-yl -acetamide

52-4: 2-(4-Chloro-phenyl)-N-{1-[3-(2-methoxy-phenoxy)-benzyl]-pyrr olidin-3-yl}- acetamide 52-5: N-fl- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-2- [4- (4-methyl-benzyloxy)- phenyl]-acetamide Table 11 No. R Retention Time No R,., M+1 (min) OCH3 52-1 OCH3 1 0 1. 61 477 1 ° 52-2 Y--Al 1. 59 497, 495 Br 0 52-3 Wu 1. 47 423 cul Yi o 52-4 ClX 1. 84 451 01-11 o 52-5 < 2. 09 523 Preparation of 1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3- (R)-ylamine derivatives Scheme 18: 1. Na (OAc) 3BH 2 drops AcOH -4 H DCE H H -7 (HN... Q, 2. 4NHC. d. cxaneH, N.. Q [J 2HCI 1-1 R-CI, TEA RN, HNO N-, N CH2CI2 54

53: 1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3- (R)-ylamine

Experimental procedure followed that of 1- (3-phenoxy-benzyl)- [1, 4] diazepane 49.

IH NMR is consistent with the assigned structure. LC-MS (ES+): 299, ret. time = 0.85 54: 1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3- (R)-ylamine derivatives

Experimental procedure followed that of 50.

54-1: (R) -2- (3,4-Dimethoxy-phenyl)-N- {1- [3- (2-methoxy-phenoxy)-benzyl]-pyrrolidin-3- yl}-acetamide 54-2: (R)-N- {1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-2- (3-methoxy-phenyl)- acetamide 54-3: (R)-2- (2-Bromo-phenyl)-N- {1- [3- (2-methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}- acetamide 54-4: (R)-N-{1-[3-(2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-2-t hiophen-2-yl- acetamide 54-5: (R)-2- (4-Fluoro-phenyl)-N- {1- [3- (2-methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}- acetamide <BR> <BR> 54-6: (R) -4-Fluoro-N- {l- [3- (2-methoxy-phenoxy)-benzyl]-pyrrolidin-3-yll-benzamide 54-7: (R)-4-Chloro-N- {1-[3-(2-methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-benzamide 54-8 : (R)-N- {1- [3- (2-Methoxy-phenoxy)-b enzyl]-pyrrolidin-3-yl}-2-phenoxy-acetamide 54-9: (R)-N-{1-[3-(2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-3-p henyl]acrylamide 54-10: (R)-N-l- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-3-phenyl-propio namide

54-11: (R)-N-1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-C-phenyl- metlianesulfonamide 54-12: (R)-N- 1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-C- (2-nitro-phenyl)- methanesulfonamide 54-13: (R)- l- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-carbamic acid phenyl ester 54-14: (R)-{1-[3-(2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-carba mic acid 4-chloro- phenyl ester 54-15: (R)- {1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-carbamic acid 4-fluoro- phenyl ester 54-16: (R)- 1- [3-(2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-carbamic acid 4-methoxy- phenyl ester 54-17: (R)-3-{1-[3-(2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-1-m ethyl-1-phenyl-urea 54-18: (R)-4-Chloro-N-(4-chloro-benzyl)-N-{1-[3-(2-methoxy-phenoxy) -benzyl]- pyrrolidin-3-yl}-benzamide Table 12 No. R Retention Time (min) (nun) OMe 54-1 Meol0, 1. 57 477 w OMe 54-2 ou 1. 70 447 w 54-3 Y--AZ 1. 90 496 Br 54-4 L 1-76 423 54-5 UJ''-72 435 0 54-6 fi 1. 72 421 pu k 54-7 1. 84 437 ce 0 C 1. 74 433 o 54-9 1. 61 429 o 54-10 1. 69 431 54-11 1. 68 453 O,,, O 54-12 1. 69 498 NO2 ) 0 54-13 cl 1. 70 419 u No. R Retention Time (min) (nun) S o 54-14 uOt, 1. 80 453 OU/ 54-15 uO) %"+ 1. 73 437 MeOs O O 54-16 uOt, r 1. 56 449 razz 54-17 K/1. 55 432 o 54-18 --k 2. 25 575 I Preparation of 1- [3- (2-Methoxy-phenoxy)-benzyl]-piperazine derivatives Scheme 19: 1. Na (OAc) 3BH 2drops AcOH 0 DUE HN H I i I +/ON 2. 4N HCI/dioxane O O O NH 2HCI O \ Ou 1-1 R-CI, TEA Method A N-1 r CH2CI2 Nj XNV W EDCI, HOBS NMM 56 oll, Method B CH2CI2

55: 1- [3- (2-Methoxy-phenoxy)-benzyl]-piperazine Experimental procedure followed that of 1- (3-phenoxy-benzyl)- [1, 4] diazepane 49.

1H NMR is consistent with the assigned structure. LC-MS (ES+): 299, ret. time = 1.01 min.

56: 1- [3- (2-Methoxy-phenoxy)-benzyl]-piperazine derivatives

Method A: Experimental procedure followed that of 50.

Method B: A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 135 mg, 1.0 mmol), and 1 mmol of the corresponding acid in methylene chloride was stirred for 20 minutes at room temperature. To the resulting solution, N-methylmorpholine (NMM, 0.55 mL, 5 mmol) and 1- [l- (2-methoxy-benzyl)-piperidin-4-ylmethyl]-piperidin-4-ylamine (55,401 mg, 1.2 mmol) were added and the solution was allowed to stir overnight. The resulting solution was washed with 1N NaOH (2x 5mL), water (lx 5mL), brine (lx 5mL), dried over magnesium sulfate filtered and concentrated under reduced pressure at 40°C. Flash chromatography (5% hexane in ethyl acetate, 0.5% TEA) provided an oil. The residue was dissolved in 4N HC1 in dioxane (10 mL), stirred for two hours and concentrated under reduced pressure at 40 °C to provide a solid. Trituration with diethylether afforded 56 as the hydrochloride salt.

56-1: 2- (3, 4-Dimethoxy-phenyl)-1- {4- [3- (2-methoxy-phenoxy)-benzyl]-piperazin-1-yl}- ethanone 56-2 : 1- {4-[3-(2-Methoxy-phenoxy)-benzyl]-piperazin-1-yl3-2-(3-metho xy-phenyl)- ethanone 56-3: 1-4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-l-yl}-2-thiophen-2-yl- ethanone 56-4: 2- (4-Fluoro-phenyl)-1- {4- [3- (2-methoxy-phenoxy)-benzyl]-piperazin-1-yl}-ethanone 56-5: (4-Fluoro-phenyl)-f 4- [3- (2-methoxy-phenoxy)-benzyl]-piperazin-1-yl}-methanone 56-6: 2- (4-Chloro-phenyl)-l- {4- [3- (2-methoxy-phenoxy)-benzyl]-piperazin-l-yl}-ethanone 56-7: 2-(4-Benzyloxy-phenyl)-1-{4-[3-(2-methoxy-phenoxy)-benzyl]-p iperazin-1-yl}- ethanone

56-8: 1- {4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-1-yl}-3-phenyl-propan- 1-one 56-9: 4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazine-l-carboxylic acidphenyl ester 56-10: 1- {4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-1-yl}-2-phenoxy-ethano ne 56-11: 1- [3- (2-Methoxy-phenoxy)-benzyl]-4- (2-nitro-phenyhnethanesulfonyl)-piperazine 56-12: 4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazine-1-carboxylic acid 4-fluoro-phenyl ester 56-13: l- {4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-l-yl}-2, 2-diphenyl-ethanone 56-14: 4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazine-l-carboxylic acid methyl-phenyl- amide 56-15: 4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazine-l-carboxylic acid 4-methoxy-phenyl ester 56-16: 4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazine-l-carboxylic acid 4-chloro-phenyl ester 56-17: [1- (2, 4-Dicliloro-phenyl)-cyclopropyl]- {4- [3- (2-methoxy-phenoxy)-benzyl]- piperazin-1-yl}-methanone 56-18: [1- (2-Fluoro-phenyl)-cyclopentyl]- {4- [3- (2-methoxy-phenoxy)-benzyl]-piperazin-1- yl}-methanone 56-19: {4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-1-yl}- (l-phenyl-cyclopentyl)- methanone 56-20: {4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-l-yl}- (l-p-tolyl-cyclopentyl)- methanone 56-21 : 1- {4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-1-yl}-2-phenyl-propan- 1-one 56-22: 1-14- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin- 1-yll-2-phenyl-propan-1-one 56-23: 2- (4-Chloro-phenyl)-1- {4- [3- (2-methoxy-phenoxy)-benzyl]-piperazin-1-yl}-2- methyl-propan-1-one 56-24: [l- (4-Chloro-phenyl)-cyclopentyl]- {4- [3- (2-methoxy-phenoxy)-benzyl]-piperazin-l- yl}-methanone 56-25: 2- (4-Chloro-phenyl)-1- {4- [3- (2-methoxy-phenoxy)-benzyl]-piperazin-1-yl}-propan- 1-one 56-26: 1- {4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-1-yl}-2-phenyl-ethanon e 56-27: 1-f 4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-1-yl}-2-phenyl-butan-1 -one 56-28: {4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-1-yl}- (1-phenyl-cyclopropyl)- methanone 56-29: [1- (4-Fluoro-phenyl)-cyclopentyl]- {4- [3- (2-methoxy-phenoxy)-benzyl]-piperazin-1- yl}-methanone 56-30: 1- {4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-1-yl}-2, 2-diphenyl-propan-1-one 56-31: {4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-l-yl}- (2-phenyl-cyclopropyl)- methanone 56-32: {4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-l-yl}- (l, 2,3, 4-tetrahydro-naphthalen- 2-yl)-methanone 56-33: Bicyclo [4.2. 0] octa-1 (6), 2, 4-trien-7-yl- {4- [3- (2-methoxy-phenoxy)-benzyl]-piperazin- l-yl}-methanone 56-34: l- {4- [3- (2-Methoxy-phenoxy)-benzyl]-piperazin-l-yl}-3, 3-diphenyl-propan-l-one 56-35: 3- (4-Fluoro-phenyl)-1- {4- [3- (2-methoxy-phenoxy)-benzyl]-piperazin-1-yl}- propenone 56-36: [1- (4-Chloro-phenyl)-cyclopropyl]- {4- [3- (2-methoxy-phenoxy)-benzyl]-piperazin-1- yl}-methanone Table 13 No. R Retention Time (min) OMe OMe 56-1 1. 43 477 56-1 OMe 56-2 1S, 1. 59 447 56-3 <, 1. 54 423 F 56-4"CU 1. 65 435 o 56-5 Fiz : 1. 57 421 C 1 0 56-6 -1. 70 451 56-7 TOLjy 1. 91 523 0 56-8 1. 62 431 r o 56-9 1. 66 419 0,-/ 56-10 f°" 1. 60 433 56-11, 8. 0 1. 83 498 Nos 56-12 Clo° ? 1. 72 437 56-13/1. 92 493 0 56-14 ONy 1. 58 432 56-15 Meoo, 0 1. 67 449 P 56-16 doua 1. 86 453 ci ci 56-17 1. 84 513, 511 No. R Retention Time (min) 56-18 56-18 1. 80 490 F 56-19 1. 84 472 56-20 , 1. 92 486 56-21 1. 64 432 56-22 1. 64 432 56-23 Cl X 1. 80 479 56-24 56-24 1. 95 505 56-25 1. 78 466 o 56-26 CLJL,. 1-55 418 56-27 1. 69 445 56-28 xi 1. 60 443 56-29 <y''' 56-29 </1. 88 490 56-30 1. 95 508 1. 95 508 56-31 < vJ4y 1. 64 443 56-32 1. 71 457 56-33 1. 57 429 I 56-34 1. 89 508 No. R Retention Time (min) 56-35 I ' 1. 68 448 F 56-36 y''-S1 478, 476

Preparation of α-{1-[3-(2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-methyla mine derivatives Scheme 20: 1. Na (OAc) 3BH 2 drops AcOH H N Dé HAN 2. 4N HCI/dioxane HNH 2HCI y 57 1-1 57 R-CI, TEA R, 3 CH2CI 58

57: a- {1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-methylamine

Experimental procedure followed that of 1- (3-phenoxy-benzyl)- [1, 4] diazepane 49.

1H NMR is consistent with the assigned structure. LC-MS (ES+): 327, ret. time = 0.95 min.

58 : a- l- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-methylamine derivatives Experimental procedure followed that of 50.

58-1 : 2- (3, 4-Dimethoxy-phenyl)-N- [2- (3, 4-dimethoxy-phenyl) -acetyl]-N- {1-[3-(2- methoxy-phenoxy)-benzyl]-piperidin-4-ylmethyl}-acetamide 58-2: N-{1-[3-(2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylmethyl}-2- (3-methoxy-phenyl)- acetamide 58-3 : 2-(2-Bromo-phenyl)-N- {1- [3-(2-methoxy-phenoxy)-benzyl]-piperidin-4-ylmethyl}- acetamide 58-4: N- {l- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylmethyl}-2-thiophen -2-yl- acetamide 58-5: 2- (4-Fluoro-phenyl)-N- {1- [3-(2-methoxy-phenoxy)-b enzyl]-pip eridin-4-ylmethyl}- acetamide 58-6: 2-(4-Chloro-phenyl)-N-{1-[3-(2-methoxy-phenoxy)-benzyl]-pipe ridin-4-ylmethyl}- acetamide 58-7: N- {1- [3-(2-Methoxy-phenoxy)-benzyl]-pip eridin-4-ylmethyl}-3-phenyl- propionamide 58-8 : N- 1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylmethyl}-a-phenyl- methanesulfonamide 58-9: {1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylmethyl}-carbamic acid 4- methoxy-phenyl ester 58-10: N-11- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylmetliyl)-2-phenyl- acetamide 58-11: 3-{1-[3-(2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylmethyl}-1- methyl-1-phenyl-urea 58-12: 4-Fluoro-N- {1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-ylmethyl}-benzamide Table 14 No. R Retention Time (min) OMe 58-1 MeO\ 1. 66 683 zu OMe 58-2 1. 52 476 frizz O 58-3 1. 60 523, 521 Br 68-4 y 1 0 1. 48 451 e lit, s ; l 58-5 0 1. 56 463 -- 58-6 LiJL 1-64 479 0 o 58-7 ¢<s 1. 64 459 , O O. 58-8 1. 71 481 Me0 58-9 WOJ4/1. 69 477 ) 0 58-10 1. 62 445 vs 58-11 C N Jk 1. 51 460 N 0 58-12 1. 51 449 F Preparation of 1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-ylamine derivatives Scheme 21 :

1. Na (OAc) 3BH 2drops AcOH H DCE H BocHN 2. 4N HCI/dioxane H N O z o Nj/BocHN 2HCI "our) t 0 0 "'o 1-1 60 R-CI, TEA Method Au CH2CI2 HN N,-, HN R-CO2H, EDCI, HOBt R 2HCI NMM 61 Method B CH2CI2 59: f 1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester

A solution of pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.30g, 6. 98 mmol), 3- phenoxy benzaldehyde (1-1, 1. 5g, 6.57 mmol), Na (OAc) 3BH (4.2g, 19.82 mmol) and acetic acid (0.5 mL) was stirred in methylene chloride (50 mL) at room temperature under nitrogen for 24 hrs. The resulting solution was washed with 1 N NaOH (3 x 100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide a crude oil, which was used without further purification. 1H NMR is consistent with the assigned structure. LC-MS (ES+): Fonnic Acid-Standard, M+1 = 399, ret. time = 1. 35 min.

60: 1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-ylamine

1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester was dissolved in 30 mL of 4N HC1 in dioxane, stirred at 0°C for 15 min and allowed to warm to room temperature over 1.5 hrs. The solution was concentrated under reduced pressure and triturated in diethylether to provide 2.34 g (96%) of 1- [3- (2-methoxy-phenoxy)-benzyl]- pyrrolidin-3-ylamine 60 as a white solid. 1H NMR is consistent with the assigned structure.

LC-MS (ES+): Formic Acid-Standard, M+1 = 299, ret. time = 0.76 min.

61: 1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-ylamine derivatives Method A: To a solution of 1- [3- (2-methoxy-phenoxy)-benzyl]-pyrrolidin-3-ylamine 60 (186 mg, 0.5 mmol) in dichloromethane (5 mL) was added triethylamine (0. 2mL, 1.5 mmol) and acid chloride (0.5 mmol). The solution was stirred overnight at room temperature and concentrated in vacuo to provide an oil. Flash chromatography on Si02 (5% hexane in ethyl acetate with 0.5% triethyl amine) provided 61 as an oil which was converted to its HCl salt by treatment with 4N HCl in dioxane. Trituration with diethyl ether afforded 61 as a white powder.

Method B: A solution of 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 288 mg, 1.5 mmol), 1-hydroxybenzotriazole hydrate (HOBt, 135 mg, 1.0 mmol), and 1 mmol

of the corresponding acid in methylene chloride was stirred for 20 minutes. To the resulting solution, N-methylmorpholine (NMM, 0.55 mL, 5 mmol) and 1- [3- (2-methoxy-phenoxy)- benzyl] -pyrrolidin-3-ylamine (60,401 mg, 1.2 mmol) were added and the solution was allowed to stir at room temperature overnight. The resulting solution was washed with 1N NaOH (2 x 5mL), water (1 x 5mL), brine (1 x 5mL), dried over magnesium sulfate filtered and concentrated under reduced pressure at 40 °C. Flash chromatography (5% hexane in ethyl acetate, 0.5% TEA) provided an oil. The residue was dissolved in 4N HC1 in dioxane (10 mL), stirred for two hours and concentrated under reduced pressure at 40°C to provide a solid. Trituration with diethyl ether afforded 61 as the hydrochloride salt.

61-1: (S)-2- (2-Bromo-phenyl)-N- {1- [3- (2-methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}- acetamide.

61-2: (S)-N- {1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-2- (3-methoxy-phenyl)- acetamide 61-3: (S)-N- 1- [3- (2-Methoxy-phenoxy)-benzyl] pyrrolidin-3-yl}-2-phenyl-acetamide 61-4: (S)-N-{1-[3-(2-Methoxy-phenoxy)benzyl]-pyrroldin-3-yl}-2-thi ophene-2-yl-acetimide 61-5: (S)-N f 1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-3-phenyl-propio namide 61-6: (S)-4-Flouro-N- 1- [3- (2-methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-benzamide 61-7: (S)-2- (4-Flouro-phenyl)-N- 1- [3- (2-methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}- acetamide 61-8: (S)-2- (3, 4-Dimethoxy-phenyl)-N-11- [3- (2-methoxy-phenoxy)-belizyl]-pyrrolidin-3-yl)- acetamide 61-9: (S)-N-11- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yll-benzenesulfonam ide 61-10: (S)-N f 1- [3- (2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-3-phenyl-acryla mide 61-11: (S)-1-(2, 4-Dichloro-phenyl) -cyclopropanecarboxylic acid fl- [3- (2-methoxy- phenoxy)-benzyl]-pyrrolidin-3-yl}-amide 61-12: (S)-1-(2-Fluoro-phenyl)-cyclopentecarboxylic acid {1-[3-(2-methoxy-phenoxy)- benzyl]-pyrrolidin-3-yl}-amide 61-13:(S)-1-Phenyl-cyclopentanecarboxlic acid {1- [3- (20mothoxy-phenoxy)-benzyl]- pyrrolidin-3-yl}-amide 61-14: (S)-1-p-Tolyl-cyclopentanecarboyxlic acid {1- [3- (2-methoxy-phenoxy)-benzyl]- pyrrolidin-3-yl}-amide 61-15: (S)-N- {-[3-(2-Methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}-2-p-tolyl- isobutyramide 61-16: (S)-1-(4-Chloro-phenyl)-cyclopentanecarboyxlic acid {1-[3-(2-methoxy-phenoxy)- benzyl]-pyrrolidin-3-yl}-amide 61-17: (S)-2-(4-Chloro-phenyl)-N- {1- [3-(2-methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}- propionamide

61-18: (S)-1- (4-Chloro-phenyl)-cyclohexanecarboxylic acid {1-[3-(2-methoxy-phenoxy)- benzyl]-pyrrolidin-3-yl}-amide 61-19: (S)-2- (2, 6-Dichloro-phenyl)-N f 1- [3- (2-methoxy-phenoxy)-benzyl]-pyrrolidin-3-yl}- acetamide Table 15 No. R Retention time (min) o 61-1 1. 62 495 Br O 61-2 ou 1. 61 447 0 o 61-3 1. 51 417 0 61-4 c, 1. 46 424 61-5 ¢< 1. 57 432 o F 61-6 I 1. 63 421 0 61-7 1. 54 435 o I o 0 61-7 L4<''' 61-8 b,-OV 1. 45 478 61-9 =0 1. 6 453 1t \, J ov 0 0 1. 72 429

No. R Retention time (min) M+1 ci 61-11 1. 99 511 ci I 61-12 X 1. 88 489 F I 61-1 3 ¢9 1. 92 471 I 61-14 \¢9 2 485 U I 61-15 1. 9 479 a 61-16 2 505 U ci o 61-17 A) ; 1. 84 465 c I 61-18 2. 12 519 ci 61-19 9 ¢S 1. 75 485 ci

Preparation of Ethyl- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-3-yl-amine derivatives Scheme 22: nr N H2 HUI CNJ H I I I\/I NaBH4, Pyridine Nv v o 1. CH3CH0, NaBH3CN No 0 + MeOH s/2. 4N HCI/Dioxane N o° N boa 62 63 ou o ou 1-1 i TEA, R-CI R I/ o HCI Ci HC ! 64

62: 3- [3- (2-Methoxy-phenoxy)-benzylamino]-piperidine-1-carboxylic acid tert-butyl ester

A solution of 3-amino-piperidine-l-carboxylic acid tert-buyl ester (2.35 g, 11.7 mmol), aldehyde 1-1 (2.94 g, 12.9 mmol), pyridine (0.5 ml) in methanol (30 mLs) was heated to reflux at 70°C for 24 hours. The solution was cooled to 0°C. While stirring over ice, NaBH4 (443mg, 11.7 mmol) was added. The reaction was stirred overnight (warming to room temperature) and was quenched with 1 N HCI. The reaction mixture was extracted with ethyl acetate (3 x 200 mL), washed with NaHC03 (2 x 100 mL), dried over magnesium sulfate and concentrated under reduced pressure to provide 3- [3- (2-methoxy-phenoxy)-benzylamino]- piperidine-l-carboxylic acid tert-butyl ester 62 as an oil, which was used without further purification. 1H NMR is consistent with the assigned structure.

63: Ethyl- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-3-yl-amine

A solution of 3- [3- (2-methoxy-phenoxy)-benzylamino]-piperidine-l-carboxylic acid tert-butyl ester (4.8 g, 11.7 mmol), aldehyde 1-1 (1.54g, 35 mmol), and NaBH3CN (735 mg, 11.7 mmol) in methanol (60 mL) was stirred at room temperature overnight. The resulting

reaction solution was then taken up in ethyl acetate (3 x 100 mL), washed with NaHCO3 (3x100 mL), dried over MgS04, filtered and concentrated under reduced pressure. Flash chromatography on Si02 (10% ethyl acetate in hexane) provided 3-f ethyl- [3- (2-methoxy- phenoxy)-benzyl]-amino}-piperidine-l-carboxylic acid tert-butyl ester as an oil, which was used without further purification. 1H NMR is consistent with the assigned structure. LC-MS (ES+): Formic Acid-Standard, M+1 = 441, ret. time = 1.74 min. To the crude product 3- {ethyl- [3- (2-methoxy-phenoxy)-benzyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester 30 mL of 4 M HC1 in dioxane was added, stirred for 15 minutes and allowed to warm to room temperature over 1.5 hrs.. The solution was concentrated under reduced pressure and triturated with diethyl ether to afford 0.73g (18%) ofethyl- [3- (2-methoxy-phenoxy)-benzyl]- piperidin-3-yl-amine 63 as a white solid. 1H NMR is consistent with the assigned structure.

LC-MS (ES+): Formic Acid-Standard, M+1 = 341, ret. time =1.39 min.

64: Ethyl- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-3-yl-amine derivatives To a solution of ethyl- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-3-yl-amine 63 (170 mg, 0.5 mmol) in dichloromethane (5 mL) was added triethylamine (0.2mL, 1.5 mmol) and acid chloride (0.5 mmol). The reaction was stirred overnight at room temperature and concentrated in vacuo to provide an oil. Flash chromatography on Si02 (40% hexanes in ethyl acetate with 0.5% TEA) provided 64, as an oil which was converted to its HC1 salt by treatment with 4.0 M HC1 in dioxane. The product was triturated in diethyl ether to afford a powder.

64-1: 1- (3- {Ethyl- [3- (2-methoxy-phenoxy)-benzyl]-amino}-piperidin-1-yl)-2-phenyl- ethanone 64-2: 2- (2-Bromo-phenyl)-1- (3- {ethyl- [3- (2-methoxy-phenoxy)-benzyl]-amino}-piperidin- 1-yl)-ethanone

Preparation of N-ethyl-2- {4-hydroxy-1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}- benzenesulfonamide Scheme 23: R 0 EtNHz + n-BuLi, THF boy i s THF dSO NHEt 0 °C R 2 N OH Boc SO2NHEt 65 66 R 0 1 R BF3*Et2O NH + HAI 0 STAB I N neat \ I i I r Cat. AcOH O S-N DCE OH RX SO2NHEt 67 68

65: Benzenesulfonamide To a solution of benzenesulfonyl chloride (1 eq) in anhydrous THF (1 mL per mmol benzenesulfonyl chloride), amine (2.2 eq) was added at 0 °C. The mixture was stirred at RT for 1. 5h. Then sat. NaHCO3 solution (20 mL) was added to quench the reaction. The phases were separated and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over MgS04 and concentrated to yield a desired product as a white solid or colorless oil. The crude material was pure enough to be used in the next step.

65-1: N-Ethyl-4-methyl-benzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a white solid in 100% yield. 1H NMR data is consistent with the assigned structure.

65-2: 4-Chloro-N-ethyl-benzenesulfonamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in 100% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 221 (M+1), ret. time, 2.29 (HPLC system A).

65-3: N-Ethyl-benzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a colorless oil (yield 100%). 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 186 (M+1), ret. time, 1.88 (HPLC system A).

65-4: N-Etliyl-a-phenyl-methanesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 100% yield. 1H NMR data is consistent with the assigned structure.

65-5: 4-tert-Butyl-N-ethyl-benzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a white solid (yield 100%). 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 242 (M+1), ret. time, 2.77 (HPLC system A).

65-6: Biphenyl-4-sulfonic acid ethylamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid (yield 100%). 1H NMR data is consistent with the assigned structure: MS (EST), M/Z, 262 (M+1), ret. time, 2.63 (HPLC system A).

65-7: Naphthalene-2-sulfonic acid ethylamide The title compound was prepared according to the general experimental procedure and was obtained as a white solid (yield 100%). 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 236 (M+1), ret. time, 2.39 (HPLC system A).

65-8: 4-N-Dimetliyl-benzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a white solid in 100% yield. 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 186 (M+1), ret. time, 1.91 (HPLC system A).

65-9: N-Isopropyl-4-methyl-benzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a colorless oil in 100% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 214 (M+1), ret. time, 2.35 (HPLC system A).

65-10: N, N-Diethyl-4-methyl-benzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 100% yield. 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 228 (M+1), ret. time, 2.72 (HPLC system A).

65-11: N-Ethyl-4-methoxy-benzenesulfonamide

The title compound was prepared according to the general experimental procedure and was obtained as a colorless oil in a 100% yield. 1H NMR data is consistent with the assigned structure: MS (EStl), M/Z, 216 (M+1), ret. time, 1.99 (HPLC system A).

66: Substituted 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester To a solution of benzenesulfonamide 91 (1 eq) in anhydrous THF (5 mL per mmol benzenesulfonamide) under Ar, n-BuLi (2.1 eq, 1.6 M in Hexane) was added dropwise at 0°C. The mixture was stirred at 0 °C for 40 min. Then tert-butyl 4-oxo- piperidinecarboxylate (1.1 eq) in THF (1 mL per mmol ter-butyl 4-oxo- piperidinecarboxylate) was added. The reaction mixture was stirred at RT overnight. H20 (10 mL) was added to quench the reaction. The phases were separated. The aqueous phase was extracted with EtOAc (3x10 mL). The combined organic phases were dried over MgS04. The crude product was purified using silica gel, eluting with EtOAc/hexane (1/4 to 1/2), to give the desired product 66 (yield 35-75%).

66-1: 4- (2-Ethylsulfamoyl-4-methyl-phenyl)-4-hydroxy-piperidine-1-ca rboxylic acid tert- butyl ester The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 88% yield. 1H NMR data is consistent with the assigned structure.

66-2: 4- (4-Chloro-2-ethylsulfamoyl-phenyl)-4-hydroxy-piperidine-l-ca rboxylic acid tert- butyl ester

The title compound was prepared according to the general experimental procedure and was obtained as a colorless oil (yield 76%). 1H NMR data is consistent with the assigned structure: MS (ESI-), M/Z, 417 (M-1), ret. time, 2.98 (HPLC system A).

66-3: 4- (2-Ethylsulfamoyl-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared according to the general experimental procedure and was obtained as a colorless oil in a 62% yield. 1H NMR data is consistent with the assigned structure: MS (ESI-), M/Z, 383 (M-1), ret. time, 2.78 (HPLC system A).

66-4: 4- (2-Ethylsulfamoylmethyl-phenyl)-4-hydroxy-piperidine-l-carbo xylic acid tert-butyl ester

The title compound was prepared according to the general experimental procedure and was obtained as white foam in 87% yield. 1H NMR data is consistent with the assigned structure.

67: Spiro [1, 2-benzoisothiazole-3 (2H), 4'-piperdines-ethyl-l, l-dioxide] A 50 mL round-bottom flask was charged with the starting material 4- hydroxypiperidine 66 (1 eq). BF3-Et2O (7.7 eq) was added. The resulting mixture was stirred at RT overnight. IN NaOH solution was added to basify the mixture. The aqueous

phase was extracted with CH2Cl2 (3X15 mL). The organic phases were dried over MgS04 and concentrated. The desired product 67 was recrystallized from MeOH (yield 60-90%).

67-1: Spiro [1, 2-benzoisothiazole-3 (2H), 4'-piperdines-ethyl-1, 1-dioxide-4-methyl] The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 64% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 281 (M+1), ret. time, 1.14 (HPLC system A).

67-2: Spiro [1,2-benzoisothiazole-3 (2H), 4'-piperdines-ethyl-1,1-dioxide-4-chloro] The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 76% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 301 (M+1), ret. time, 1.16 (HPLC system A).

67-3: Spiro [1, 2-benzoisothiazole-3 (2H), 4'-piperdines-ethyl-1, 1-dioxide] The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 68% yield'H NMR data is consistent with the assigned structure: MS (ES : v), M/Z, 267 (M+1), ret. time, 0.98 (HPLC system A).

67-4: N-Ethyl-a- [2- (4-hydroxy-piperidin-4-yl)-phenyl]-methanesulfonamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 100% yield. 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 300 (M+1), ret. time, 0. 78 (HPLC system A).

68: Substituted N-Ethyl-2- [4-hydroxy-1- (3-phenoxy-benzyl)-piperidin-4-yl]-5-methyl- benzenesulfonamide To a solution of piperidine 67 (1 eq) in anhydrous dichloroethane (10 mL per mmol piperidine 67), aromatic aldehyde 1 (1.1 eq) and sodium triacetoxyborohydride (1.6 eq) were added. Cat. AcOH was added (1 drop). The mixture was stirred at RT overnight. Then sat.

NaHC03 solution was added to quench the reaction. The phases were separated. The aqueous phase was extracted with EtOAc (3X10 mL). The combined organic phases were dried over MgS04. The crude product was purified, using chromatography on silica gel, to give the desired product 68. The fonnate salt or HC1 salt was prepared by treating a solution of free base in Et2O with 1M formic acid or 1M HC1 solution in Et20.

68-1: N-Ethyl-2- [4-hydroxy-1- (3-phenoxy-benzyl)-piperidin-4-yl]-5-metliyl- benzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a colorless oil in a 74% yield. 1H NMR data is consistent with the

assigned structure: MS (ES), M/Z, 481 (M+1), ret. time, 1.86 (HPLC system A); Anal Calcd for C27H32N204S : C, 67.47 ; H, 6.71 ; N, 5.83. Found: C, 67.08 ; H, 6.76 ; N, 5.75.

68-2: N-Ethyl-2- {4-hydroxy-l- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-5-methyl- benzenesulfonamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 59% yield. 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 511 (M+1), ret. time, 1.76 (HPLC system A); Anal Calcd for C2gH34N2O5S'CH202'H2O : C, 60.61 ; H, 6.66 ; N, 4.87. Found: C, 60.52 ; H, 6.52 ; N, 4.71.

68-3: 2- 1- [3- (2-Chloro-phenoxy)-benzyl]-4-hydroxy-piperidin-4-yl}-N-ethyl -5-methyl- benzenesulfonamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 65% yield NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 515 (M+1), ret. time, 1.83 (HPLC system A); Anal calcd for C27H3lClN204S'0. 75CH202 : C, 60.65 ; H, 5.96 ; N, 5.10. Found: C, 60.70 ; H, 5.96 ; N, 5.08. 68-4 : 5-Chloro-N-ethyl-2- [4-hydroxy-l- (3-phenoxy-benzyl)-piperidin-4-yl]- benzenesulfonamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 60% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 501 (M+1), ret. time, 1.79 (HPLC system A); Anal calcd for C26H29ClN204SCH202O0. 4H20 ; C, 58.51 ; H, 5.78 ; N, 5.05. Found: C, 58.50 ; H, 5.55 ; N, 4.97.

68-5: 5-Chloro-N-ethyl-2-f 4-hydroxy-1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}- b enzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 40% yield NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 532 (M+1), ret. time, 1. 81 (HPLC system A); Anal calcd for C27H31ClN2O5S#CH2O2#1. 3H20 ; C, 56.00 ; H, 5.98 ; N, 4.66. Found: C, 56.03 ; H, 5.83 ; N, 4.36.

68-6: N-Ethyl-2- [4-hydroxy-1- (3-phenoxy-benzyl)-piperidin-4-yl]-benzenesulfonamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 53% yield NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 467 (M+1), ret. time, 1.74 (HPLC system A); Anal calcd for C26H30N2O4S#CH2O2#0. 5H20 ; C, 61.43 ; H, 6.56 ; N, 5.21. Found: C, 61.65 ; H, 6.16 ; N, 4.83.

68-7: N-Ethyl-2- {4-hydroxy-l- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}- benzenesulfonamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid (yield 53%). 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 497 (M+1), ret. time, 1.63 (HPLC system A); Anal Calcd for C27H32N205S"CH202 ; C, 61.97 ; H, 6.32 ; N, 5.16. Found: C, 61.68 ; H, 6. 39 ; N, 5.03.

68-8: N-Ethyl-a- {2- [4-hydroxy-1- (3-phenoxy-benzyl)-piperidin-4-yl]-phenyl}- methanesulfonamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in 33% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 481 (M+1), ret. time, 1.61 (HPLC system A); Anal calcd for C27H32N204S'CH202'0. 75H20 ; C, 62.26 ; H, 6.62 ; N, 5.19. Found: C, 62.20 ; H, 6.64 ; N, 5.05. 68-9: N-Ethyl-C- (2- {4-hydroxy-1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-phenyl)- methanesulfonamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in 52% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 511 (M+1), ret. time, 1.67 (HPLC system A); Anal calcd for C2gH34N2O5S'CH202'2H2O ; C, 58.77 ; H, 6.80 ; N, 4.73. Found: C, 58.89 ; H, 6.50 ; N, 4.45.

Scheme 24:

69: 4-aryl-4-hydroxy-l- (3-phenoxy-benzyl)-piperidine To a solution of benzenesulfonamide 91 (1 eq) in anhydrous THF (5 mL per mmol sulfonamide) under Ar, 71-BuLi (2 eq, 2. 5M solution in hexane) was added dropwise at 0°C.

The mixture was stirred at 0°C for 15 min, then RT for 15 min. Piperidone 32 (1 eq) in anhydrous THF (1 mL per mmol piperidone) was added. The final reaction mixture was stirred at RT overnight. H20 (20 mL) was added to quench the reaction. The phases were separated. The aqueous phase was extracted with EtOAc (3X15 mL). The combined organic phases were dried over MgS04. The crude product was purified using chromatography over silica gel, to give the desired product 69. The formate salt was prepared by treating a solution of free base in Et2O with 1M formic acid solution in Et20.

69-1 : 3- [4-Hydroxy-l- (3-phenoxy-benzyl)-piperidin-4-yl]-biphenyl-4-sulfonic acid ethylamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 22% yield. 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 543 (M+1), ret. time, 2.04 (HPLC system A); Anal calcd for C32H34N204S-CH202-0. 5H20 ; C, 66.31 ; H, 6.24 ; N, 4.69. Found: C, 66.02 ; H, 6.21 ; N, 4.58.

69-2: 2- [4-Hydroxy-1- (3-phenoxy-benzyl)-piperidin-4-yl]-4, N-dimethyl-benzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 31% yield. 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 467 (M+1), ret. time, 1.74 (HPLC system A); Anal calcd for C26H3oN204S-0. 5CH202 ; C, 65.01 ; H, 6.38 ; N, 5.72. Found: C, 65.08 ; H, 6.43 ; N, 5.68.

69-3: 2- 4-Hydroxy-1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-4, N-dimethyl- benzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 15% yield. 1H NMR data is consistent with the

assigned structure: MS (ES), M/Z, 497 (M+1), ret. time, 1.74 (HPLC system A); Anal calcd for C27H32N2O5S#0. 8CH202 ; C, 60.37 ; H, 6.44 ; N, 5.03. Found: C, 60.35 ; H, 6.27 ; N, 4. 86.

69-4: 2- [4-Hydroxy-1- (3-phenoxy-benzyl)-piperidin-4-yl]-N-isopropyl-4-methyl- benzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 34% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 495 (M+1), ret. time, 1.90 (HPLC system A); Anal calcd for C28H34N204S-0. 25CH202; C, 67.04 ; H, 6.87 ; N, 5.53. Found: C, 67.06 ; H, 6.78 ; N, 5.40.

69-5: 2- {4-Hydroxy-1- [3- (2-methoxy-phenoxy)-henzyl]-piperidin-4-yl}-N-isopropyl-4- methyl-benzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 21% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 525 (M+1), ret. time, 1.97 (HPLC system A); Anal calcd for C29H36N205S-0. 5CH202 ; C, 64.69 ; H, 6.81 ; N, 5.11. Found: C, 64.90 ; H, 6.86 ; N, 5.04.

69-6: N, N-Diethyl-2-[4-hydroxy-1-(3-phenoxy-benzyl)-piperidin-4-yl]- 4-methyl- benzenesulfonamide

The title compound was prepared according to the general experimental procedure (using 1 eq n-BuLi) and was obtained as a white solid in a 34% yield. This compound was converted into acetic acid salt. 1H NMR data is consistent with the assigned structure : MS (ES), M/Z, 509 (M+1), ret. time, 2.01 (HPLC system A); Anal calcd for C2gH36N204StO. 2AcOH; C, 67.82 ; H, 7.12 ; N, 5.38. Found: C, 67.75 ; H, 7.19 ; N, 5.02.

69-7: N, N-Diethyl-2- {4-hydroxy-1- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-4- methyl-benzenesulfonamide

The title compound was prepared according to the general experimental procedure (using 1 eq n-BuLi) and was obtained as a white solid in a 23% yield. 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 539 (M+1), ret. time, 1.95 (HPLC system A); Anal calcd for C30H38N2O5S#CH2O2#0.57H2O; C, 62.24 ; H, 6.99 ; N, 4.68. Found: C, 62.16 ; H, 6.89 ; N, 4.47.

69-8 : 3- {4-Hydroxy-1- [3-(2-methoxy-phenoxy)-b enzyl]-piperidin-4-yl}-naphthalene-2- sulfonic acid ethylamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in 7% yield. 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 547 (M+1), ret. time, 2.05 (HPLC system A); Anal calcd for C31H34N2O5S#CH2O2 ; C, 64.85 ; H, 6.12 ; N, 4.73. Found: C, 65.08 ; H, 6.37 ; N, 4.35. 69-9: 3- [4-Hydroxy-1- (3-phenoxy-benzyl)-piperidin-4-yl]-naphthalene-2-sulfonic acid ethylamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 18% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 517 (M+1), ret. time, 2.02 (HPLC system A); Anal calcd for C3oH32N204S'CH202'0. 5H2O ; C, 65.13 ; H, 6.70 ; N, 4.90. Found: C, 65.17 ; H, 6.40 ; N, 4.60.

69-10: 4-tert-Butyl-N-ethyl-2- {4-hydroxy-l- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4- yl}-benzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 42% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 553 (M+1), ret. time, 2.15 (HPLC system A); Anal calcd for C3lH40N2OsSCH202-1H2O ; C, 62.32 ; H, 7.19 ; N, 4.54. Found: C, 62.52 ; H, 6.92 ; N, 4. 51.

69-11: N-Ethyl-2- {4-hydroxy-l- [3- (2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-4- methoxy-benzenesulfonamide

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 14% yield. 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 527 (M+1), ret. time, 1.90 (HPLC system A); Anal calcd for C28H34N206S'CH202'1H2O ; C, 58.97 ; H, 6.48 ; N, 4.74. Found: C, 58.70 ; H, 6.39 ; N, 4.50.

69-12: N-Ethyl-2- [4-hydroxy-1- (3-phenoxy-benzyl)-piperidin-4-yl]-4-methoxy- benzenesulfonamide The title compound was prepared according to the general experimental procedure and was obtained as a white solid in 50% yield. 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 497 (M+1), ret. time, 1.90 (HPLC system A); Anal calcd for C27H32N205SCH202e1. 25H2O ; C, 59.51 ; H, 6.51 ; N, 4.96. Found: C, 59.47 ; H, 6.45 ; N, 4.69.

69-13: 4- [2- (2, 2-Dimethyl-2, 5-dihydro-oxazol-4-yl)-phenyl]-1- (3-phenoxy-benzyl)- piperidin-4-ol

The title compound was prepared according to the general experimental procedure and was obtained as a white in a 36% yield. 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 457 (M+1), ret. time, 1.29 (HPLC system A); Anal calcd for C30H34N203S'CH202'0. 25H2O ; C, 71.45 ; H, 7.06 ; N, 5.38. Found: C, 71.50 ; H, 7.10 ; N, 5.24.

Scheme 25: Scheme 26: 70: Spiro [isobenzofuran-1 (3R), 4'-piperdin]-3-one, l'- [ [3- (2- methoxyphenoxy) phenyl] methyl] To a solution of N, N-diethylbenzamide (300.00 mg, 1.69 mmol) in anhydrous THF (5 mL) under Ar, TMEDA (0.25 mL, 1.69 mmol) was added. After cooling to-78°C. Sec-BuLi (1.30 mL, 1.69 mmol, 1.3M solution in cyclohexane) was added dropwise. The resulting mixture was stirred for 30 min at-78°C. Then piperidone 32-2 (525.00 mg, 1.69 mmol) in anhydrous THF (1 mL) was added. The final reaction mixture was stirred and allowed to warm from-78°C to RT overnight. H20 (10 mL) was added to quench the reaction. The phases were separated. The aqueous phase was extracted with EtOAc (3X15 mL). The combined organic phases were dried over MgS04. The crude product was purified using chromatography on silica gel, to give the desired product (258.00 mg, yield 37%). The HC1

salt was prepared by treating a solution of free base in Et2O with 1M HC1 solution in Et2O.

1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 415 (M+1), ret. time, 1.74 (HPLC system A); Anal calcd for C26H2sNO4HCllH2O ; C, 66.45 ; H, 6.01 ; N, 2.98.

Found: C, 66.72 ; H, 6.01 ; N, 2.97.

71: 2- {4-Hydroxy-1- [3-(2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-benzoic acid To a solution of 70 (190 mg, 0.45 mmol) in THF/H20 (10 mL, 10: 1), LiOH (109.00 mg, 4.50 mmol) was added. The mixture was heated to reflux overnight, then brought to pH 7 using aqueous 1M HCl. Sat. NH4Cl solution (10 mL) was added, and the phases were separated. The aqueous phase was extracted with EtOAc (3X5 mL). The combined organic phases were dried over MgS04 and concentrated. The desired product was obtained by recrystallization in MeOH (50 mg, yield 25%). 1H NMR data is consistent with the assigned structure: MS (ESI-), M/Z, 432 (M-1), ret. time, 1.73 (HPLC system A); Anal calcd for C26H27N05-1. 1H20 ; C, 68.89 ; H, 6.47 ; N, 3.09. Found: C, 68.70 ; H, 6.77 ; N, 3.47.

Scheme 27: N-N Sec-BuLi TMED I N/o w N'W II I H THF Li O Rl'-35OCto-300C Rl'C Li R2 32 N. N.. N /+ n N n t . t N''N ) LH ? 2 OH 72 72: 1- [3- (2-Methoxy-phenoxy)-benzyl]-4- [2- (lH-tetrazol-5-yl)-aryl]-piperidin-4-ol

To a solution of 5-phenyl-tetrazole (1 eq) in anhydrous THF (5 mL per mmol tetrazol) under Ar, tetramethyl-ethylenediamine (1 eq) was added. After cooling to-35 °C- 30 °C. Sec-BuLi (3 eq, 1.3M solution in cyclohexane) was added dropwise. The resulting mixture was stirred for 45 min at-35°C~-30°C. Then piperidone (1 eq) in anhydrous THF (1 mL) was added. The final reaction mixture was stirred at-35 °C-30 °C for 5h. Sat. NH4C1 solution (10 mL) was added to quench the reaction. The pH was adjusted to-7 with aqueous 1 M HCl. The phases were separated. The aqueous phase was extracted with THF (3 x 15 mL). The combined organic phases were dried over MgS04. The crude product was purified using silica gel, eluting with EtOAc/MeOH (9: 1), to give the desired product as a white solid.

The product was recrystallized from MeOH.

72-1: 1- [3- (2-Methoxy-phenoxy)-benzyl]-4- [2- (lH-tetrazol-5-yl)-phenyl]-piperidin-4-ol

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in 7% yield. 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 458 (M+1), ret ; time, 1.72 (HPLC system A); Anal calcd for C26H27N503-1. 6H20 ; C, 64. 21 ; H, 6.24 ; N, 14.40. Found: C, 64. 01 ; H, 6.10 ; N, 14.19.

72-2: 4- [5-Chloro-2- (lH-tetrazol-5-yl)-phenyl]-l- [3- (2-methoxy-phenoxy)-benzyl]-piperidin- 4-ol

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in 14% yield. tH NMR data is consistent with the assigned structure: MS (ES), M/Z, 492 (M+1), ret. time, 1.92 (HPLC system A); Anal calcd for C26H26CIN503-1. 6H20 ; C, 59.96 ; H, 5.69 ; N, 13.45. Found: C, 59.96 ; H, 5.45 ; N, 13.39.

Scheme 28: 9 0 SOoNHEt SOzNHEt n-BuL ! S02NHEt BOC + (BOC) p0 + I-N MEOH N S TUF OU Bn BOC OMe 0°C-RT MeO 74 73 4M HCI Dioxane 0 ow SO2NHEt - N NaBH3CN OHC O NHHCI "cor Cat. ACOH Mu0 Me0 OH MeOH 76 1-1 75

73: 3-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 1-benzyl-3-methyl-4-piperidone (6.50 g, 31.97 mmol) in MeOH (50 mL), di-tert-butyl dicarbonate (10.46 g, 47.96 mmol) and Pd (OH) 2 (0.70 g, 10wt%) were added. The reaction mixture was placed under H2 on a Parr shaker apparatus at 40 psi overnight at RT. The mixture was filtered through celite and concentrated. The resulting crude product was purified using silica gel, eluting with EtOAc/hexane (1/4), to give the desired product as a white solid (5.73 g, yield 84%). 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 158 (M-56), ret. time, 2.03 (HPLC system A).

74: 4- (2-Ethylsulfamoyl-5-methoxy-phenyl)-4-hydroxy-3-metliyl-pipe ridine-l-carboxylic acid tert-butyl ester

The title compound was prepared according to the general experimental procedure and was obtained as a white foam in a 38% yield. 1H NMR data is consistent with the assigned structure. This compound was used directly in the next step.

75: N-Ethyl-2-(4-hydroxy-3-methyl-piperidin-4-yl)-4-methoxy-benz enesulfonamide hydrochloride salt

4-(2-Ethylsulfamoyl-5-methoxy-phenyl)-4-hydroxy-3-methyl-pip eridine-1-carboxylic acid tert-butyl ester (0.38 g, 0.89 mmol) was dissolved in 4M HC1 solution in dioxane (2 mL, 8. 00 mmol). The mixture was stirred at RT for lh. Then the mixture was concentrated to give a white solid. The white solid was washed with Et20 (10 mL) to generate 0.32g of the desired product. 1H NMR data is consistent with the assigned structure. MS (ESt), M/Z, 329 (M+1), ret. time, 1.25 (HPLC system A).

76: N-Ethyl-2- {4-hydroxy-l- [3- (2-methoxy-phenoxy)-benzyl]-3-methyl-piperidin-4-yl}-4- methoxy-benzenesulfonamide

To a solution of N-ethyl-2- (4-hydroxy-3-methyl-piperidin-4-yl)-4-methoxy- benzenesulfonamide hydrochloride salt (1 eq) in anhydrous MeOH (10 mL per mmol piperidine), aromatic aldehyde 1-1 (1.1 eq) and sodium cyanoborohydride (1.6 eq) were added. Cat. AcOH was used to adjust pH to 6. The mixture was stirred at RT overnight.

Then sat. NaHCO3 solution was added to quench the reaction. The phases were separated.

The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over MgS04. The crude product was purified using chromatography on silica gel to give the desired product. The formate salt or HC1 salt was prepared by treating a solution of free base in Et20 with 1M formic acid or HC1 solution in EtzO. H NfvIR data is consistent with the assigned structure: MS (ES), M/Z, 541 (M+1), ret. time, 1.95 (HPLC system A);

Anal calcd for C29H36N206SCH202*0. 9H2O ; C, 59.76 ; H, 6.65 ; N, 4.65. Found: C, 60.06 ; H, 6.53 ; N, 4.27.

Scheme 29:

77: 1-Benzyl-4- (4-chloro-phenyl)-piperidin-4-ol

To a solution of N-benzylpiperidone (3.0 mL, 16.2 mmol) in anhydrous THF (100 mL), 4-chlorophenyl magnesium bromide (25 mL, 25 mmol, 1M solution in Et2O) was added at RT. The mixture was stirred at rt for 5h. Then sat. NaCl solution (20 mL) was added to quench the reaction. The phased were separated. The aqueous phase was extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over MgS04 and concentrated.

The crude product was purified on silica gel, eluting with CH2Cl2/MeOH (95: 5), to give the desired product as a yellow oil (4. 98 g, yield 100%). 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 302 (M+1), ret. time, 1.30 (HPLC system A) 78: N-[1-Benzyl-4-(4-chloro-phenyl)-piperidin-4-yl]-acetamide

To a solution of acetonitrile (9 mL) in acetic acid (6 mL) was treated with concentrated H2SO4 (3 mL), and N-benzyl- [4- (4-chlorophenyl)]-4-hydroxy piperidine 77 (2.78 g, 9.20 mmol) was added. The mixture was stirred at rt for 2h. Then the reaction mixture was cooled to 0°C and quenched with 1N NaOH solution. The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over MgS04 and concentrated to give a white solid. The solid was triturated with CH2C12 and Hexane to afford the desired product XH (2.11 g, yield 67%). 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 343 (M+1), ret. time, 1.25 (HPLC system A).

N- [4- (4-Chloro-phenyl)-piperidin-4-yl]-acetamide hydrochloride salt (79) To a solution of N- [l-Benzyl-4- (4-chloro-phenyl)-piperidin-4-yl]-acetamide 78 (2.63 g, 7.68 mmol) in anhydrous dichloroethane (30 mL), 1-chloroethyl chloroformate (1.07 mL, 10.00 mmol) was added. The mixture was heated to reflux for 4h. After cooling to RT, the solvent was removed. MeOH (10 mL) was added. The mixture was heated to reflux for 4h. After removing the solvent, the residue was triturated with EtOAc to give a white solid XI (1.64 g, yield 74%). 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 253 (M+1), ret. time, 2.31 (HPLC system A).

80-1 : N- [4- (4-Chloro-phenyl)-1- (3-phenoxy-benzyl)-piperidin-4-yl]-acetamide

The title compound was prepared according to the experimental procedure for 76 and was obtained as a white solid (free base, yield 53%). 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 435 (M+1), ret. time, 1.87 (HPLC system A); Anal calcd for C26H27C1N202 ; C, 71.80 ; H, 6.26 ; N, 6.44. Found: C, 71.49 ; H, 6.00 ; N, 6.41.

80-2: N-{4-(4-Chloro-phenyl)-1-[3-(2-methoxy-phenoxy)-benzyl]-pipe ridin-4-yl}-acetamide

The title compound was prepared according to the experimental procedure for 76 and was obtained as a white solid (free base, yield 46%). 1H NMR data is consistent with the assigned structure: MS (ESI)+, M/Z, 465 (M+1), ret. time, 1.84 (HPLC system A); Anal calcd for C27H29C1N203-0. 2H20 ; C, 69.21 ; H, 6.32 ; N, 5.98. Found: C, 69.24 ; H, 6.22 ; N, 5.84.

Scheme 30: 81: 1-Benzhydryl-azetidin-3-one

To a solution of 1-benzhydrylazetan-3-ol (1.08 g, 4.51 mmol) in anhydrous dichloromethane (10 mL), tetrapropylammonium perruthenate (0.070 g, 0.2 mmol), N- methymorpholine N-oxide (1.17 g, 10 mmol) and 4A molecular sieves were added. The mixture was stirred at RT for 2h. The mixture was filtered and concentrated. The crude product was chromatographed on silica gel, eluting with hexane/EtOAc (3/2), to give 1.06 g of the desired product as a white solid in 99% yield. 1H NMR data is consistent with the assigned structure.

82: 1-Benzhydryl-3- (4-chloro-phenyl)-azetidin-3-ol To a solution of 4-chlorophenyl magnesium bromide (4 mL, 4.00 mmol, 1M in THF) at 0°C, ketone 81 (0.59 g, 2.50 mmol) was added. The mixture was warmed to RT and stirred for 2. 5h. Then Sat. NaCI solution was added to quench the reaction. The phases were separated. The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over MgS04. The crude product was purified by chromatography on silica gel, to give the desired product 82 (0.75 g, yield 86%). 1H NMR data is consistent with the assigned structure.

83: 3- (4-Chloro-phenyl)-azetidin-3-ol hydrochloride salt

The title compound was prepared according to the experimental procedure for compound 79 and was obtained as a white solid (free base, yield 69%). 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 184 (M+1), ret. time, 0.51 (HPLC system A).

84-1: 3- (4-Chloro-phenyl)-1- (3-phenoxy-benzyl)-azetidin-3-ol

The title compound was prepared according to the general experimental procedure for 76 and was obtained as a white solid (free base, yield 94%). 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 367 (M+1), ret. time, 1.81 (HPLC system A); Anal Calcd for C22H2oClN02 ; C, 72.23 ; H, 5.51 ; N, 3.83. Found: C, 71.98 ; H, 5.65 ; N, 3.74.

84-2: 3- (4-Chloro-phenyl)-l- [3- (2-methoxy-phenoxy)-benzyl]-azetidin-3-ol

The title compound was prepared according to the general experimental procedure for 76 and was obtained as a white solid (free base, yield 65%). 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 396 (M+1), ret. time, 1.78 (HPLC system A); Anal calcd for C23H22C1N03 ; C, 68.23 ; H, 5.73 ; N, 3.46. Found: C, 68.27 ; H, 5.52 ; N, 3.43.

Scheme 31 : R2 p R2 R Op r-N R3 'r-N12+'ONa CICH2CH2H \ 32 R3 Cat. AcOH 85 0 or Cl Cl CDI/THF 1 N NaOH reflux Tol/H20 R2 ---'06 o /Y 0 86 \ 86

85-1 : (lR, 2S)-2- [1- (3-Phenoxy-benzyl)-piperidin-4-ylamino]-1-phenyl-propan-l-ol The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid (yield 80%). 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 417 (M+1), ret. time, 1.17 (HPLC system A); Anal Calcd for C27H32N2O2#2HCl0.9H2O ; C, 64.13 ; H, 7.14 ; N, 5.54. Found: C, 64.21 ; H, 7.03 ; N, 5.53.

85-2: (lR, 2S)-2-{1-[3-(2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylamino} -1-phenyl-propan- l-ol

The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid (yield 83%). 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 447 (M+1), ret. time, 1.19 (HPLC system A); Anal Calcd for C28H34N203-2HC11. 5H20 ; C, 61.53 ; H, 7.19 ; N, 5.13. Found: C, 61.66 ; H, 7.05 ; N, 5.13.

85-3: N- {1-[3-(2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-N'-phenyl- ethane-1, 2-diamine

The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid (yield 86%). 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 432 (M+1), ret. time, 1.26 (HPLC system A); Anal calcd for C27H33N3O2#3HCl1H2O ; C, 58.02 ; H, 6.85 ; N, 7.52. Found: C, 57.95 ; H, 6.70 ; N, 7.40.

85-4: (2S)-2- {l- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-ylamino}-3-phenyl-pr opan-l- ol (85-4)

The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 77% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 447 (M+1), ret. time, 1.30 (HPLC system A); Anal calcd for C2sH34N203'2HCl'1. 5H20 ; C, 61.53 ; H, 7.19 ; N, 5.13. Found: C, 61.49 ; H, 6.91 ; N, 5.09.

85-5: (2S)-2-[1-(3-Phenoxy-benzyl)-piperidin-4-ylamino]-3-phenyl-p ropan-1-ol

The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 84% yield. 1H NMR data is consistent with the assigned structure: MS. (ESI+), M/Z, 417 (M+1), ret. time, 1.33 (HPLC system A); Anal Calcd for C27H32N2022HC1-0. 6H20 ; C, 64.82 ; H, 7.09 ; N, 5.60. Found: C, 64.79 ; H, 7.07 ; N, 5.62.

86: 1- (3-phenoxy-benzyl)- 4-substituted piperidines Procedure A: To a solution of amino alcohol or diamine 85 in toluene (1 mL per 0.1 mmol amino alcohol), 1N NaOH solution (0.5 mL per 0.1 mmol amino alcohol) was added. The mixture was cooled to 0°C. Phosgene (1 mL per 0.2 mmol amino alcohol, 20 wt% in toluene) was added. The final mixture was stirred at 0°C for 1. 5h. Then sat. NaHCO3 solution (5 mL) was added to quench the reaction. The phases were separated. The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over MgS04 and concentrated. The crude product was purified on silica gel, eluting with EtOAc/hexane (1/4 to 1/2), to give the desired product 86 (yield 35-75%).

Procedure B: To a solution of amino alcohol 85 (1 eq) in anhydrous THF (10 mL per mmol HQ), 1, 1'-carbonyldimidazole (3 eq) was added. The reaction was stirred at RT or reflux for overnight. Then sat NaHCO3 solution (10 mL) was added to quench the reaction. The phases were separated. The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over MgS04 and concentrated. The crude product was purified by chromatography on silica gel to give the desired product 86. The HC1 salt was prepared by treating a solution of free base in Et2O with 1M HC1 solution in Et20.

86-1: (1R, 2S)-4-Methyl-3- [l- (3-phenoxy-benzyl)-piperidin-4-yl]-5-phenyl-oxazolidin-2-one

The title compound was prepared according to the general experimental procedure A and was obtained as a white solid in a 37% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 443 (M+1), ret. time, 1.90 (HPLC system A); Anal Calcd for C2sH30N203HC1 ; C, 70.21 ; H, 6.52 ; N, 5.85. Found: C, 70.01 ; H, 6.72 ; N, 5.90.

86-2: (1R, 2S)-3-{1-[3-(2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-4-me thyl-5-phenyl- oxazolidin-2-one

The title compound was prepared according to the general experimental procedure A and was obtained as a white solid in a 25% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 473 (M+1), ret. time, 1.92 (HPLC system A); Anal Calcd for C2gH32N204HCl0. 4H20 ; C, 67.47 ; H, 6.60 ; N, 5.43. Found: C, 67.63 ; H, 6.49 ; N, 5.32.

86-3: 1- {1- [3- (2-Metlioxy-phenoxy)-benzyl]-piperidin-4-yl}-3-phenyl-imidaz olidin-2-one

The title compound was prepared according to the general experimental procedure A and was obtained as a white solid in a 43% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 458 (M+1), ret. time, 1.90 (HPLC system A); Anal Calcd for C28H3iN303'HCl'1. 75H20 ; C, 66.26 ; H, 6.65 ; N, 8.28. Found: C, 66.44 ; H, 6.51 ; N, 8.13.

86-4 : (4S)-4-Benzyl-3- [l- (3-phenoxy-benzyl)-piperidin-4-yl]-oxazolidin-2-one

The title compound was prepared according to the general experimental procedure B and was obtained as a white solid in a 93% yield. 1H NMR data is consistent with the assigned structure: MS (ESt), MIZ, 443 (M+1), ret. time, 1.90 (HPLC system A); Anal Calcd for C28H3oN203-HCl-H20 ; C, 67.06 ; H, 6.73 ; N, 5.59. Found: C, 67.18 ; H, 6.41 ; N, 5.52.

86-5: (4S) -4-Benzyl-3- {1-[3-(2-methoxy-phenoxy)-benzyl]-piperidin-4-yl}-oxazolidin -2- one The title compound was prepared according to the general experimental procedure B and was obtained as a white solid in a 67% yield. 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 474 (M+1), ret. time, 1.87 (HPLC system A); Anal Calcd for C29H32N204-HC1-H20 ; C, 66.09 ; H, 6.69 ; N, 5.32. Found: C, 66.14 ; H, 6.72 ; N, 5.13.

Scheme 32: Rt R'I R2 R2 STAB H N CDI N RiNH + l or phosgene 1/ OH Z N Boc 80-90% Rz Boc EtaN/CHCIz O N Boc 87 88 1HCI/Dioxane i R'I R2 R'I R2 O\ff-N Op NaBH3CN oyal op yN MEOH, 0"ONM-HCI p Cat. AcOH 90 Rus 1 89 87-1 : 4-[(1R)-2-HYydroxy-1-phenyl-ethylamino)-piperidine-1-carboxy lic acid tert-butyl ester

The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 88% yield. 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 321 (M+1), ret. time, 1. 38 (HPLC system A); Anal Calcd for C18H28N2O3 ; C, 67.47 ; H, 8. 81 ; N, 8. 74. Found: C, 67.42 ; H, 8.82 ; N, 8.61.

87-2 : 4- [ (lS)-2-Hydroxy-l-phenyl-ethylamino]-piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 94% yield. 1H NMR data is consistent with the assigned structure: MS (ES1F), MIZ, 321 (M+1), ret. time, 1.40 (HPLC system A); Anal calcd for Ci8H2sN203'0. 1H20 ; C, 67.09 ; H, 8.82 ; N, 8.69. Found: C, 66.99 ; H, 8.82 ; N, 8.60.

87-3: 4-(2-Hydroxy-2-phenyl-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 80% yield. 1H NMR data is consistent with the assigned structure: MS (ES), MIZ, 321 (M+1), ret. time, 1.41 (HPLC system A); Anal Calcd for C18H28N203@0. 3H20 ; C, 66.35 ; H, 8. 85 ; N, 8.60. Found: C, 66.37 ; H, 8. 80; N, 8.51.

87-4: 4- (2-Hydroxy-l-methyl-ethylamino)-piperidine-l-carboxylic acid tert-butyl ester The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 88% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 259 (M+1), ret. time, 1.03 (HPLC system A); Anal calcd for C13H26N203 ; C, 60.44 ; H, 10.14 ; N, 10.84. Found: C, 60.36 ; H, 10.15 ; N, 10.72.

88: 2-Oxo-oxazolidin-3-yl-piperidine-1-carboxylic acid tert-butyl esters To a solution of amino alcohol 87 (1 eq) in anhydrous CH2C12 (2 mL per mmol 88), triethylamine (2 eq) and phosgene (2 eq 20 wt% in toluene) were added at 0 °C. The reaction mixture was stirred at 0°C for 2h. Then sat. NaHC03 solution (10 mL) was added to quench the reaction. The phases were separated. The aqueous phase was extracted with EtOAc (3 x10 mL). The combined organic phases were dried over MgS04. The crude product was purified by chromatography on silica gel, to give the desired product 88.

88-1: 4- [ (4R)-2-Oxo-4-phenyl-oxazolidin-3-yl]-piperidine-l-carboxylic acidtert-butyl ester

The title compound was prepared according to the general experimental procedure and was obtained as a colorless oil in a 65% yield. 1H NMR data is consistent with the assigned structure: MS (ESTF), M/Z, 347 (M+1), ret. time, 2.53 (HPLC system A); Anal Calcd for C19H26N204 ; C, 65. 88 ; H, 7.56 ; N, 8.09. Found: C, 65.90 ; H, 7.67 ; N, 8.02.

88-2: 4- [ (4S)-2-Oxo-4-phenyl-oxazolidin-3-yl]-piperidine-l-carboxylic acid tert-butyl ester

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 51% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 347 (M+1), ret. time, 2.55 (HPLC system A); Anal calcd for Cl9H26N204 ; C, 65. 88 ; H, 7.56 ; N, 8.09. Found: C, 65.97 ; H, 7. 68 ; N, 8.08.

88-3: 4-(2-Oxo-5-phenyl-oxazolidin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared according to the general experimental procedure and was obtained as a colorless oil in a 81% yield. 1H NMR data is consistent with the assigned structure: Anal calcd for C19H26N204 ; C, 65.88 ; H, 7.56 ; N, 8.09. Found: C, 65.90 ; H, 7.67 ; N, 8. 02.

88-4: 4- (4-Methyl-2-oxo-oxazolidin-3-yl)-piperidine-l-carboxylic acid tert-butyl ester

The title compound was prepared according to the general experimental procedure and was obtained as a colorless oil in a 81% yield. 1H NMR data is consistent with the assigned structure.

89: 3-piperidin-4-yl-oxazolidin-2-one To a solution of 4N HCl solution in dioxane (1 mL per mmol compound 88), the Boc- piperidone 88 was added. The mixture was stirred at RT for lh. After concentration, the white solid was washed with Et2O (3 x 5 mL) to afford the desired hydrochloride salt 89.

89-1 : (4R)-4-Phenyl-3-piperidin-4-yl-oxazolidin-2-one The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 100% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), MIZ, 247 (M+1), ret. time, 0.92 (HPLC system A); Anal Calcd for C14Hi8N202-HClH20 ; C, 55. 91 ; H, 7.04 ; N, 9. 31. Found: C, 56.04 ; H, 6.97 ; N, 9.15.

89-2: (4S) -4-Phenyl-3-piperidin-4-yl-oxazolidin-2-one

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 90% yield. 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 247 (M+1), ret. time, 0.87 (HPLC system A); Anal Calcd for Ci4HisN202'HCl'H20 ; C, 55.91 ; H, 7.04 ; N, 9.31. Found: C, 56.07 ; H, 6.84 ; N, 9.37.

89-3: 5-Phenyl-3-piperidin-4-yl-oxazolidin-2-one

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 95% yield. 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 247 (M+1), ret. time, 0.92 (HPLC system A); Anal calcd for C 4Hi8N202'HCI ; C, 59.47 ; H, 6.77 ; N, 9.91. Found: C, 59.75 ; H, 6.88 ; N, 9.92.

89-4: 4-Methyl-3-piperidin-4-yl-oxazolidin-2-one

The title compound was prepared according to the general experimental procedure and was obtained as a white solid in a 98% yield. 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 185 (M+1), ret. time, 0.21 (ion trace) (HPLC system A); Anal calcd for C9Hl6N202-HCI ; C, 48.98 ; H, 7.76 ; N, 12.69. Found: C, 48.72 ; H, 7.75 ; N, 12.44.

90-1 : (4R)-3- {1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-4-phenyl-oxazoli din-2-one

The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 33% yield. 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 459 (M+1), ret. time, 1.64 (HPLC system A); Anal calcd for C28H3oN204'HCl-CH2Cl2-0. 4H20; C, 61.02 ; H, 5.93 ; N, 4.95. Found: C, 61.02 ; H, 5.95 ; N, 4.93.

90-2: (4R)-3- [l- (3-Phenoxy-benzyl)-piperidin-4-yl]-4-phenyl-oxazolidin-2-one The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 47% yield. 1H NMR data is consistent with the assigned structure: MS (ES), MIZ, 429 (M+1), ret. time, 1.72 (HPLC system A); Anal Calcd for C27H28N203HCl-0. 15CH2Cl2'0. 75H20; C, 61.47 ; H, 5.95 ; N, 5.17. Found: C, 61.25 ; H, 5.92 ; N, 5.43.

90-3: (4R)-3- {1- [3- (2-Chloro-phenoxy)-benzyl]-piperidin-4-yl}-4-phenyl-oxazolid in-2-one

The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 44% yield. 1H NMR data is consistent with the assigned structure: MS (ESI+), M/Z, 463 (M+1), ret. time, 1.78 (HPLC system A); Anal calcd for C27H27ClN2O3#HCl#0. 75CH2Cl2H20 ; C, 57.35 ; H, 5.46 ; N, 4.82. Found: C, 57.07 ; H, 5.44 ; N, 4. 61.

90-4: (4S)-3- {1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-4-phenyl-oxazoli din-2-one The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 72% yield. 1H NMR data is consistent with the assigned structure: MS (ES), M/Z, 459 (M+1), ret. time, 1.79 (HPLC system A); Anal calcd for C28H30N2O4#HCl#1. 5H20 ; C, 64.42 ; H, 6.56 ; N, 5.37. Found: C, 64.29 ; H, 6.42 ; N, 5.22.

90-5: (4S)-3- 1- [3- (2-Chloro-phenoxy)-benzyl]-piperidin-4-yl}-4-phenyl-oxazolid in-2-one The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 46% yield. 1H NMR data is consistent with the assigned structure: MS (ESt), MIZ, 463 (M+1), ret. time, 1.84 (HPLC system A); Anal Calcd for C27H27ClN2O3#HCl#1.5H2O ; C, 61.60 ; H, 5.94 ; N, 5.32. Found: C, 61.84 ; H, 5.85 ; N, 5. 21.

90-6: 3- {1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-5-phenyl-oxazoli din-2-one

The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 50% yield. 1H NMR data is consistent with the assigned structure: MS (ESt), M/Z, 459 (M+1), ret. time, 1.74 (HPLC system A); Anal calcd for C28H3oN204HCl0. 25H20; C, 67.33 ; H, 6.36 ; N, 5.61. Found: C, 67.22 ; H, 6.43 ; N, 5.44.

90-7: 3- 1-[3-(2-Chloro-phenoxy)-benzyl]-piperidin-4-yl}-5-phenyl-oxa zolidin-2-one The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 37% yield. 1H NMR data is consistent with the assigned structure: MS (ESI), M/Z, 463 (M+1), ret. time, 1.90 (HPLC system A); Anal Calcd for C27H27ClN203HCl-H20 ; C, 62.67 ; H, 5.84 ; N, 5.41. Found: C, 62.95 ; H, 5. 80 ; N, 5.30.

90-8: 3- {1- [3- (2-Methoxy-phenoxy)-benzyl]-piperidin-4-yl}-4-methyl-oxazoli din-2-one The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid in a 59% yield. 1H NMR data is consistent with the

assigned structure: MS (ESI+), M/Z, 397 (M+1), ret. time, 1.48 (HPLC system A); Anal calcd for C23H28N2O4#HCl#1. 5H2O ; C, 60.06 ; H, 7.01 ; N, 6.09. Found: C, 59.78 ; H, 6.70 ; N, 6.46.

92: 4- (4-Chloro-phenyl)-l- (3-phenoxy-benzyl)-piperidin-4-ol The title compound was prepared according to the general experimental procedure for 68 and was obtained as a white solid (free base, yield 86%). 1H NMR data is consistent with the assigned structure: MS (ES), MIZ, 394 (M+1), ret. time, 1.94 (HPLC system A); Anal calcd for C24H24ClNO2#0. 2H20 ; C, 72.52 ; H, 6.19 ; N, 3.52. Found: C, 72.56 ; H, 6.37 ; N, 3.36.

Scheme 33: B (OH) 2 R_C ut N NaZC03, Pd (PPh3) 4 s 94 93 X SH Ethanol i Ethanoi Ethanol Cs2CO3, Pd2 (dba) 3, 95 BINAP NH , Toluene Oxone, EtOH, Ha0 R R_C CNs I/W I RN N", A Su O O 97 96 15 93: 1- (3-Iodo-benzyl)-piperdine-4-carboxylic acid ethyl ester

3-Iodobenzylbromide (1.3 equ) and ethylisonipecotate (1.0 equ. ) were added together in acetonitrile, followed by 3.0 equ. of diisoproylethylamine. The reaction was allowed to stir at room temperature for 3h. The reaction mixture was concentrated down and partitioned between 1N HC1 and CH2C12. The aqueous layer was extracted 3x and washed with brine and dried over MgS04. The organics were filtered and concentrated down. The product was purified by flash chromatography with 2% MeOH/98% CH2C12 to give a 94% yield of the corresponding iodide 93-1.

95: 1- (3-Phenylsulfanyl-benzyl)-piperdine-4-carboxylic acid ethyl ester The aryl iodide (1.0 equ) 93-1 was added to ethanol, followed by tetrakistriphenylphospine palladium (0) (0.1 equ), 1.0 equ of benzene thiol and 1.0 equ of sodium tert-butoxide. The reaction was allowed to heat to reflux for 16h and cooled to room temperature. The mixture was diluted with ether and water. The aqueous layer was extracted 3x with ether and washed with brine and dried over MgS04. The organics were filtered and concentrated down. The product was purified by flash chromatography with 4% MeOH/96% CH2C12 to give a 74% yield of 95-1. Retention time 3.46, LCMS 356. 27,'H NMR data is consistent with the assigned structure.

97: 1- (3-Phenylamino-benzyl)-piperdine-4-carboxylic acid ethyl ester

The aryl iodide (1.0 equ) 93-1 was added to aniline (1.2 equ), Pd2 (dba) 3 (0.05 equ), 0.03 equ of BINAP, 1.4 equ. of cesium carbonate in toluene. The reaction mixture was heated to 100 °C for 34 h and cooled to room temperature. The mixture was diluted with ether and filtered. The organics were concentrated down and chromatographed directly. The

product was purified by flash chromatography with 2% MeOH/98% CHUCK to give 97-1.

Retention time 2.32, LCMS 341. 23, 1H NMR data is consistent with the assigned structure.

94-, 1 : 1-Biphenyl-3-ylmethyl-piperdine-4-carboxylic acid ethyl ester

The aryl iodide (1.0 equ) 93-1 was dissolved in toluene (0.4M) and 0.05 equ of tetrakis triphenylphosphine palladium (0) was added and stirred for 10 min. To the above mixture was added 1.1 equ of phenyl boronic acid in ethanol (0.9 M) and a 2 M solution of sodium carbonate. The reaction mixture was refluxed for 14 h and cooled to room temperature. The reaction mixture was diluted with ethyl ether and water. The aqueous layer was seperated and extracted 2x with ether and washed with brine and dried over MgS04. The organics were filtered and concentrated down. The product was purified by flash chromatography with 2% MeOH/98% CH2C12 to give 96% of 94-1. Retention time 2.49, LCMS 324. 30, 1H NMR data is consistent with the assigned structure.

96-1 : 1- (3-Benzenesulfonyl-benzyl)-piperdine-4-carboxylic acid ethyl ester

95-1 (1.0 equ. ) was added to a solution of oxone in ethanol (2.0 mL) and 0.5 mL of water. This solution was stirred for 3 h at room temperature. The reaction was filtered and CH2C12 was added. The organic phase was collected and washed with water, brine and dried over MgS04, filtered and concentrated down. The product was purified by flash chromatography with 8% MeOH/92% CH2Cl2 to give 76% of 96-1. Retention time 2.70, LCMS 388. 23, IH NMR data is consistent with the assigned structure.

93-2: 1- (3-Iodo-benzyl)-4-methyl piperdine

3-Iodobenzylbromide (1.3 equ) and 4-methylpiperdine (1.0 equ. ) were added together in acetonitrile, followed by 3.0 equ. of diisoproylethylamine. The reaction was allowed to stir at room temperature for 3h. The reaction mixture was concentrated down and partitioned between 1N HC1 and CH2Ck. The aqueous layer was extracted 3x and washed with brine and dried over MgS04. The organics were filtered and concentrated down. The product was purified with 2% MeOH/98% CH2C12 to give a 76% yield of the corresponding iodide 93-2.

Retention time 2.77, LCMS 316. 16, 1H NMR data is consistent with the assigned structure.

95-2: 4-Methyl-l- (3-phenylsulfanyl-benzyl)-piperdine The aryl iodide (1.0 equ) 93-2 was added to ethanol, followed by tetraldstriphenylphospine palladium (0) (0.1 equ), 1.0 equ of benzene thiol and 1.0 equ of sodium tert-butoxide. The reaction was allowed to heat to reflux for 16 h and cooled to room temperature. The mixture was diluted with ether and water. The aqueous layer was extracted 3x with ether and washed with brine and dried over MgS04. The organics were filtered and concentrated down. The product was purified with 3% MeOH/97% CHUCK to give a 72% yield of 95-2. Retention time 3.19, LCMS 298. 23,'H NMR data is consistent with the assigned structure.

97-2: [3-(4-Methyl-piperidin-l-ylmethyl)-phenyl]-phenylamine

The aryl iodide (1.0 equ) 93-2 was added to aniline (1.2 equ), Pd2 (dba) 3 (0.05 equ), 0.03 equ of BINAP, 1.4 equ. of cesium carbonate in toluene. The reaction mixture was heated to 100 °C for 34 h and cooled to room temperature. The mixture was diluted with ether and filtered. The organics were concentrated down and chromatographed directly. The product was purified by flash chromatography with 2% MeOH/98% CH2C12 to give 97-2.

Retention time 2. 31, LCMS 281. 2, 1H NMR data is consistent with the assigned structure.

94-2: 1-Biphenyl-3-ylmethyl-4-methyl-piperdine

The aryl iodide (1.0 equ) 93-2 was added to 0.05 equ of tetrakis triphenylphosphine palladium (0) in toluene (0.4 M) and stirred for 10 min. To the above mixture was added 1. 1 equ of phenyl boronic acid in ethanol (0.9 M) and a 2 M solution of sodium carbonate (4.7 equ. ). The reaction mixture was refluxed for 14 h and cooled to room temperature. The reaction mixture was diluted with ethyl ether and water. The aqueous layer was seperated and extracted 2x with ether and washed with brine and dried over MgS04. The organics were filtered and concentrated down. The product was purified by flash chromatography with 2% MeOH/98% CH2C12 to give 85% yield of 94-2. Retention time 3.48, LCMS 266. 21, 1H NMR data is consistent with the assigned structure.

96-2: 1- (3-Benzenesulfonyl-benzyl)-4-methyl-piperdine

95-2 (1.0 equ. ) was added to a solution of oxone in ethanol (2.0 mL) and 0.5 mL of water. This solution was stirred for 3 h at room temperature. The reaction was filtered and CHUCK was added. The organic phase was collected and washed with water, brine and dried over MgS04, filtered and concentrated down. The product was purified by flash

chromatography with 5% MeOH/95% CH2C12 to give 40% of 96-2. Retention time 2.31, LCMS 281. 22, 1H NMR data is consistent with the assigned structure.

Scheme 34: NBS, Benzoyl Peroxide CC14 Br I/I/ O 0 98 R Rx DIPEA, CH3CN NH R= CO2CH2CH3, CH3 , R_o Ro R N I Et3SiH, TFA, CH2CI2 CNs X o 0 100 99 99-1: 1- (3-Benzoyl-benzyl)-piperdine-4-carboxylic acid ethyl ester To a solution of 3-methylbenzophenone (1.0 equ. ) in benzene was added 1.1 equ of NBS and 0.007 equ. of benzoyl peroxide. The reaction was heated to reflux for 5h, during which time the mixture went from colorless to orange. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated down to yield the benzylic bromide 98, which was used directly in the next reaction.

The bromide 98 was added to 4-isonipecotate piperdine (1.3 equ. ) in acetonitrile (0. 1M) along with 3.51 mL of DIPEA. The reaction mixture was allowed to stir at room temperature for 3 h and concentrated down. The product was purified by flash chromatography with 2% MeOH/98% CH2Cl2 to give 25 % (2 steps) of 99-1. Retention time 2.94, LCMS 352. 28, 1H NMR data is consistent with the assigned structure.

100-1 :- (3-Benzyl-benzyl)-piperdine-4-carboxylic acid ethyl ester

99-1 was added along with TFA at 0°C, 2.25 equ of triethylsilane was added dropwise, once the addition was complete the reaction was allowed to stir at room temperature for 18h. Water was added to quench the reaction and stirred for lh, additionally methylene chloride was added. The organics were removed and washed with brine and dried over MgS04, filtered and concentrated down. The product was purified by flash chromatography with 4% MeOH/96% CH2C12 to give 86 % of 100-1. Retention time 2.89, LCMS 338. 26, 1H NMR data is consistent with the assigned structure.

99-2: [3- (4-Methyl-piperdin-l-ylmethyl)-phenyl]-phenyl-methanone To a solution of 3-methylbenzophenone (1.0 equ. ) in benzene was added 1. 1 equ of NBS and 0.007 equ. of benzoyl peroxide. The reaction was heated to reflux for 5h, during which time the mixture went from colorless to orange. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated down to yield the benzylic bromide 98, which was used directly in the next reaction.

The bromide 98 was added with 4-methyl piperdine (1.3 equ. ) in acetonitrile (0. 1M) along with 3.51 mL of DIPEA. The reaction mixture was allowed to stir at room temperature for 3 h and concentrated down. The product was purified by flash chromatography with 2% MeOH/98% CH2Cl2 to give 50 % (2 steps) of 99-2. Retention time 2.37, LCMS 294. 21, 1H NMR data is consistent with the assigned structure.

100-2: 1- (3-Benzyl-benzyl)-4-methyl-piperdine

99-2 was added along with TFA (1.3M) at 0°C. To the above was added 2.25 equ of triethylsilane dropwise, once the addition was complete the reaction was allowed to stir at room temperature for 18h. Water was added to quench the reaction and stirred for lh, additionally methylene chloride was added. The organics were removed and washed with brine and dried over MgS ? 4, filtered and concentrated down. The product was purified by flash chromatography with 5% MeOH/95, % CH2Cl2 to give 68 % of 100-2. Retention time 2.46, LCMS 280. 23,'H NMR data is consistent with the assigned structure.

Scheme 35 : 101: 1- [3-Phenoxy-benzoyl)-piperdin-4-carboxylic acid ethyl ester 3-phenoxybenzoic acid (1.0 equ) and ethylisonipecotate (1.05 equ) were mixed with HOBt (1.5 equ. ), EDCI (1.3 equ. ) in THF with N-methyl morpholine (2.0 equ. ). The reaction was allowed to stir at room temperature for 10 h. The reaction was diluted with ethyl acetate and washed with IN HCI, IN NaOH and brine. The organics were dried over Mg2S04, filtered and concentrated down. The product was purified by flash chromatography with 1.5% MeOH/98.5 % CH2C12 to give in 98% yield of 101 1- [3-phenoxy-benzoyl)-piperdin-4- carboxylic acid ethyl ester. Retention time 2.87, LCMS354. 27,'H NMR data is consistent with the assigned structure.

Scheme 36:

102: N-{1-[3(2-Methoxy-phenoxy)-benzenesulfonyl]-piperdin-4-yl}-2 -phenyl-acetamide 4- (phenylacetamide) piperdine (1.0 equ. ), 3- (2-methoxyphenoxy) phenylsulfonyl chloride, and triethylamine (1.5 equ) were added together in CH2Cl2 and allowed to stir at room temperature for 3h. The reaction was concentrated down and purified by flash chromatography with 100% CHUCK to 4% MeOH/96% CH2Cl2 to give 45 % of 102.

Retention time 2.59, LCMS 480. 96, 1H NMR data is consistent with the assigned structure.

103: 1- {1- [3 (2-Methoxy-phenoxy)-benzenesulfonyl]-piperdin-4-yl}-1, 3-dihydro- benzoimidazol-2-one

4-(2-keto-1-benzimidazole) piperdine (l. Oequ.), 3- (2-methoxyphenoxy) phenyl sulfonyl chloride, and triethylamine (1.5 equ) were added together in CH2C12 and allowed to stir at room temperature for 3h. The reaction was concentrated down and purified by flash

chromatography with 100% CH2C12 to 4% MeOH/96% CH2Cl2 to give 31 % of 103.

Retention time 2. 51, LCMS 479. 94, 1H NMR data is consistent with the assigned structure.

104: 8-[3(2-Methoxy-phenoxy)-benzenesulfonyl]-1-phenyl-1, 3,8-triaza-spiro [4.5] decan-4- one

l-phenyl-1, 3,8-triazaspiro [4,5]-decan-4-one (1.0 equ. ), 3- (2- methoxyphenoxy) phenylsulfonyl chloride, and triethylamine (1.5 equ) were added together in CH2C12 and allowed to stir at room temperature for 3h. The reaction was concentrated down and purified by flash chromatography with 100% CH2C12 to 4% MeOH/96% CH2Cl2 to give 45 % of 104. Retention time 2.72, LCMS 493. 96, 1H NMR data is consistent with the assigned structure.

Scheme 37: 105 : 1- [1- (3-Iodo-benzyl)-piperdin-4-yl]-1, 3-dihydro-benzimidazol-2-one

3-Iodobenzylbromide (1.0 equ) and 4- (2-keto-l-benzimidazole) piperdine (1.3 equ. ) were added together in acetonitrile, followed by 3.0 equ. of diisoproylethylamine. The reaction was allowed to stir at room temperature for 3h. The reaction mixture was concentrated down and partitioned between IN HC1 and CH2Clz. The aqueous layer was extracted 3x and washed with brine and dried over MgS04. The organics were filtered and concentrated down. The product was purified by flash chromatography with 2% MeOH/ 98% CH2C12 to give the corresponding iodide 105.

106: 8- (3-Iodo-benzyl)-1-phenyl-1, 3,8-triaza-spiro [4.5]-decan-4-one 3-Iodobenzylbromide (1.0 equ) and 1-phenyl-1, 3,8-triazaspiro [4,5]-decan-4-one (1.3 equ. ) were added together in acetonitrile, followed by 3.0 equ. of diisoproylethylamine. The reaction was allowed to stir at room temperature for 3h. The reaction mixture was concentrated down and partitioned between 1N HC1 and CH2C12. The aqueous layer was extracted 3x and washed with brine and dried over MgS04. The organics were filtered and concentrated down. The product was purified by flash chromatography with 2% MeOH/ 98% CH2CI2 to give the corresponding iodide 106.

107: 1- [1- (2', 6'-Dichloro-biphenyl-3-ylmethyl)-piperdin-4-yl]-1, 3-dihydro-benzoimidazol-2- one

The aryl iodide (1.0 equ) 105 was added to 0.05 equ of tetrakis triphenylphosphine palladium (0) in toluene (0.4 M) and stirred for 10 min. To the above mixture was added 1.1 equ of 2,6-dichlorophenyl boronic acid in ethanol (0.9 M) and a 2 M solution of sodium carbonate (4.7 equ. ). The reaction mixture was refluxed for 14 h and cooled to room temperature. The reaction mixture was diluted with ethyl ether and water. The aqueous layer was seperated and extracted 2x with ether and washed with brine and dried over MgS04. The organics were filtered and concentrated down. The product was purified by flash chromatography with 100% EtOAc to give 23 % yield of 107. Retention time 1.68, LCMS 452. 01, 1H NMR data is consistent with the assigned structure.

108: 8-(2', 6'-Dichloro-biphenyl-3-ylmethyl)-1-phenyl-1, 3,8-triaza-spiro [4.5] decan-4-one The aryl iodide (1.0 equ) 106 was added to 0.05 equ oftetraldstriphenylphosphine palladium (0) in toluene (0.4 M) and stirred for 10 min. To the above mixture was added 1.1 equ of 2,6-dichlorophenyl boronic acid in ethanol (0.9 M) and a 2 M solution of sodium carbonate (4.7 equ. ). The reaction mixture was refluxed for 14 h and cooled to room temperature. The reaction mixture was diluted with ethyl ether and water. The aqueous layer was seperated and extracted 2x with ether and washed with brine and dried over MgS04. The organics were filtered and concentrated down. The product was purified by flash chromatography with 100% EtOAc to give 23 % yield of 108. Retention time 1.76, LCMS 465. 97,'H NMR data is consistent with the assigned structure.

Experimental II : CCR8 BINDING PROTOCOL

L1. 2-CCR8 cells are stable recombinant LI. 2 cells overexpressing the CCR8 receptor.

The cells were routinely cultured and passaged in RPMI based medium. The incubators were set at 37° C, 6% C02 and 90% relative humidity. The density of the cell suspension was maintained around 0.7 to 1.0 million cells per ml. Cells were removed from the culture after about 2 months and replaced with freshly thawed cells of lower passage number. On Day 1, the cells were split to be approximately 0.5 millions/ml for next day assay by dilution into fresh RPMI medium in the morning. N-butyric acid (500 mM) to a final concentration of 5 mM was added into the cell suspension (1: 100 dilution) in late afternoon. On Day 2, the cells were harvested by spinning down the cells for 5 minutes (1350 rpm) in a table top centrifuge, and the cells were washed with 35 ml of assay binding buffer once, and then re-suspend the cells into the binding buffer at 2 millions cells per ml of the buffer.

A 10-point dose-response curve (final concentrations are 100µM, 33.3 µM, 11.1 µM, 3. 70 I1M, 0.411 µM, 0.137 M, 0.0457 µM, 0.0152 µM, 0. 00508, uM) was prepared by diluting a 20 mM solution of the compounds 1: 2 (6 p. L into 6 µL DMSO) and then serially diluting the sample 1: 3 (4 µL into 8 I1L DMSO). To prepare a screen for the compounds (at 10 µM and 1 p. M), a 20 mM solution of the compounds was diluted 1: 20 (1, uL into 19 pL DMSO). The sample was then subsequently diluted 1: 10 dilution (2 u. L into 18 J. L of DMSO).

To prepare the compound plate, 1 jj. L from each of the above DMSO solutions was transferred into each well of a polypropylene 96-well plate for the following binding experiment. 1 gL of DMSO was stamped into each well of the blank control. 50 uL of the L1. 2-CCR8 cell suspension (2 million cells/mL) was added into each well of the compound plate (100,000 cells/well), and pipette up and down three times to mix. Then 1 I1L of the 10 FM cold I-309 solution was added into control wells, Al 1, B11, C11 and Dl 11 as non-specific

control. The cells were incubated with the compounds for 40 min. at room temperature.

Then 50 uL of 0.2 nui25 1-1-309 solution was added into each well of the above plate. The radioligand was added to the mixture of cells and compounds and incubated at room temperature for one hour. 100 1L of 0.33% PEI solution was added into each well of the filter plate (GF/B), and incubated for about half an hour at room temperature. The samples were harvested using Packard cell harvester, the plates were washed with 4 wells of cold assay wash buffer, the harvester was opened, and the plate was dried under vacuum for about 30 seconds. The filter plate was then air-dried overnight, the plates were bottom-sealed, 500 gL MicroScint-20 fluid was added to each well, and the top of the plate sealed using Topseal.

The plate was read on the Topcount.

All patents, literature citations and publications disclosed within the application are herein incorporated by reference.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.